Title of Invention	SUBSTITUTED CYCLOALKENE DERIVATIVE
Abstract	It is intended to provide a substituted cycloalkene derivative represented by the general formula (I) which has an action of suppressing intracellular signal transduction or cell activation caused by endotoxin and a cell response such as hyperproduction of an inflammatory mediator caused by them, a pharmacologically acceptable salt thereof, a method for producing the same, and a pharmaceutical containing the cycloalkene derivative as an active ingredient, which is excellent in prevention and/or treatment of a disease such as sepsis (septic shock, disseminated intravascular co-agulation, multiple organ failure or the like). General formula (I): {In the formula, X and Y represent a group which forms the ring A with the carbon atom of the ring B to which X and Y are bound or the like, I and m independently represent an integer of 0 to 3 and I +m is 1 to 3. R1 represents an aliphatic hydrocarbon group which may be substituted or the like, n represents an integer of 0 to 3. R3 represents a hydrogen atom, an alkyl group which may be substituted or the like, R3 represents a phenyl group which may be substituted or the like, and R5 represents a hydrogen atom, an alkyl group which may be substituted or the like.}

Title of Invention

SUBSTITUTED CYCLOALKENE DERIVATIVE

Abstract

It is intended to provide a substituted cycloalkene derivative represented by the general formula (I) which has an action of suppressing intracellular signal transduction or cell activation caused by endotoxin and a cell response such as hyperproduction of an inflammatory mediator caused by them, a pharmacologically acceptable salt thereof, a method for producing the same, and a pharmaceutical containing the cycloalkene derivative as an active ingredient, which is excellent in prevention and/or treatment of a disease such as sepsis (septic shock, disseminated intravascular co-agulation, multiple organ failure or the like). General formula (I): {In the formula, X and Y represent a group which forms the ring A with the carbon atom of the ring B to which X and Y are bound or the like, I and m independently represent an integer of 0 to 3 and I +m is 1 to 3. R1 represents an aliphatic hydrocarbon group which may be substituted or the like, n represents an integer of 0 to 3. R3 represents a hydrogen atom, an alkyl group which may be substituted or the like, R3 represents a phenyl group which may be substituted or the like, and R5 represents a hydrogen atom, an alkyl group which may be substituted or the like.}

Full Text	Specification Substituted Cycloalkene Derivative [TECHNICAL FIELD] The present invention relates to a novel compound which has an action to suppress intracellular signal transduction or cell activation in various cells such as monocytes, macrophages and vascular endothelial cells, the intracellular signal transduction or cell activation being induced by endotoxin, and to suppress the generation of inflammatory mediators such as TNF-a due to the intracellular signal transduction and cell activation, and which is useful as a prophylactic and/or therapeutic agent for various diseases such as sepsis (septic shock, disseminated intravascular coagulation, multiple organ failure and the like), a production method therefor and a use thereof. [BACKGROUND ART] Sepsis is a systemic inflammatory response syndrome (SIRS) which occurs due to an excess inflammatory response of a biological body against bacterial infection, and is a disease which may result in death when it is accompanied by shock or organ failure. Since there are only a few agents that are effective against sepsis until now, it is considered to be a disease that is difficult to prevent and treat. However, since its fatality is high and the number of patients is large, development of therapeutic agents for it is particularly important (for example, refer to Non-patent document 1). Endotoxin (lipopolysaccharide, LPS), which is a membrane component of bacteria, acts against cells such as monocytes, macrophages and vascular endothelial cells, induces an excess generation of various inflammatory mediators such as TNF-a and the like, causes sudden blood pressure reduction, blood coagulation disorders, cardiovascular disturbances and the like in addition to systemic inflammatory responses, and thus exhibits sepsis (for example, refer to Non-patent document 2). Lipid A, which corresponds to lipopolysaccharide and its partial structure, activates intracellular signal transduction via TLR4 (Toll-like receptor 4), which is a functional cell surface receptor, after binding with CD14 (for example, refer to Non- patent document 3). Accordingly, lipid A initiates various cell responses represented by the generation of inflammatory mediators. Therefore, it is considered that a substance which suppresses the intracellular signal transduction or cell activation induced by endotoxin, and various cell responses induced by intracellular signal transduction and cell activation, the various cell responses being represented by an excess generation of inflammatory mediators such as TNF-a, can be an effective prophylactic and therapeutic agent for sepsis (for example, refer to Non-patent document 3, Non-patent document 4, Patent document 1 and Patent document 2). Intracellular signal transduction or cell activation induced by endotoxin, and various cell responses induced by the intracellular signal transduction and cell activation, the various cell responses being represented by an excess generation of inflammatory mediators such as TNF-a, lead to development and progress of various diseases such as ischemic brain disorder, arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complication, joint inflammation, osteoporosis, osteopenia, autoimmune disease, tissue disorder and rejection after organ transplantation, bacterial infection, virus infection, gastritis, pancreatitis, nephritis, pneumonia, hepatitis and leukemia, in addition to the aforementioned sepsis (for example, Non-patent document 5 and Patent document 3). Therefore, a substance which suppresses intracellular signal transduction or cell activation induced by endotoxin, and various cell responses induced by the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-a, is considered to be effective as a prophylactic and/or therapeutic agent for these various diseases, and thus the development of an excellent therapeutic agent has been desired. [Non-patent Document 1] Iqbal et al., Expert Opin. Emerging Drugs, Vol. 7, page 111, 2002 [Non-patent Document 2] Hawkins et al., Current Topics in Medicinal Chemistry, Vol. 4, page 1147, 2004 [Non-patent Document 3] Beutler, Nature, Vol. 430, pages 257- 263, 2004 [Non-patent Document 4] Kakutani et al., Inflammation Research, Vol. 48, page 461, 1999 [Non-patent Document 5] Donald N. Cook et al., Nature Immunology, Vol. 5, pages 975-979, 2004 [Patent Document 1] Japanese Patent Appication (Kokai) No. 2000- 178246 [Patent Document 2] Japanese Patent Application (Kokai) No. 2004-2370 [Patent Document 3] International Publication WO 00/41698 Pamphlet [DISCLOSURE OF THE INVENTION] [Problems to be Solved by the Invention] As a result of conducting extensive studies on the pharmacological activity of various substituted cycloalkene derivatives for the purpose of developing a compound which has an activity to suppress intracellular signal transduction or cell activation in various cells such as monocytes, macrophages and vascular endothelial cells, the intracellular signal transduction or the cell activation being induced by endotoxin, and to suppress various cell responses induced by the intracellular signal transduction and cell activation, such as an excess generation of inflammatory mediators such as TNF-α, the inventors of the present invention found that a substituted cycloalkene derivative having a unique structure possesses an excellent suppressing effect against intracellular signal transduction or cell activation induced by endotoxin, and against cell responses induced by the intracellular signal transduction and cell activation, such as an excess generation of inflammatory mediators such as TNF-α, and found that it is useful as a prophylactic and/or therapeutic agent for various diseases such as sepsis which are associated with intracellular signal transduction or cell activation induced by endotoxin, and with cell responses induced by the intracellular signal transduction and the cell activation, thereby leading to completion of the present invention. The present invention provides a substituted cycloalkene derivative which possesses an activity to suppress intracellular signal transduction or cell activation induced by endotoxin, and cell responses due to the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α, pharmacologically acceptable salts thereof, a production method therefor, and a medicament containing the aforementioned substituted cycloalkene derivative as an active ingredient, which is excellent for prophylaxis and/or treatment of various diseases caused by intracellular signal transduction or cell activation induced by endotoxin, and caused by cell responses including an excess generation of inflammatory mediators such as TNF-α, the cell responses being induced by the intracellular signal transduction and cell activation. [Means for Solving the Problems] Accordingly, the present invention provides: (1) A compound represented by the general formula (I): {wherein X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, X and Y together represent a substituent of ring B, or X and Y each represents a hydrogen atom. 1) In the case where X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A: ring A represents a 3- to 7-membered heterocyclyl ring [in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkanoyl group which may be substituted with a group selected from Substituent group a), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO2, the heterocyclyl ring may include an unsaturated bond, may form a fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group a, a cyclopropyl a C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with 1 to 5 groups selected from Substituent group a, a C2-Cs alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group a, and a C2-C6 alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group a] or a 3- to 7-membered cycloalkyl ring (the cycloalkyl ring may include an unsaturated bond, may form a fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of Substituent group a, a cyclopropyl C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with 1 to 5 groups selected from Substituent group a, a C2-C6 alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group a, and a C2-C6 alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group a). 2) In the case where X and Y together represent a substituent of ring B: X and Y represent an oxo group or a thioxo group. 1 and m, independently from each other, represent an integer of 0 to 3, and 1 + m is 1 to 3. R1 represents an aliphatic hydrocarbon group which may be substituted with a group selected from Substituent group p and Substituent group y (the aliphatic hydrocarbon group represents a C1-C20 alkyl group, C3-C10 cycloalkyl group, C4-C12 cycloalkylalkyl group, C3-C6 alkenyl group or C3-C6 alkynyl group), a phenyl group which may be substituted with a group selected from Substituent group 8, a group having the formula OR4 (R4 represents a hydrogen atom or an aliphatic hydrocarbon group which may be substituted with a group selected from Substituent group β and Substituent group y, the aliphatic hydrocarbon group represents the same as aforementioned) or a halogen atom. n represents an integer of 0 to 3. R2 represents a hydrogen atom, a C1-C6 alkyl group which may be substituted with a group selected from Substituent group β, a C2-C6 alkenyl group which may be substituted with a group selected from Substituent group β, or a C2-C6 alkynyl group which may be substituted with a group selected from Substituent group β. R3 represents a phenyl group which may be substituted with a group selected from Substituent group e, or a 5- or 6-membered heteroaryl group which may be substituted with a group selected from Substituent group s (the heteroaryl group includes 1 to 3 hetero atoms selected from a nitrogen atom, oxygen atom and sulfur atom). R5 represents a hydrogen atom, a C1-C6 alkyl group which may be substituted with a group selected from Substituent group β, a C2-C6 alkenyl group which may be substituted with a group selected from Substituent group β, or a C2-C6 alkynyl group which may be substituted with a group selected from Substituent group β. Provided that in the case where R3 is a phenyl group which may be substituted with a group selected from Substituent group 8, X and Y represent the aforementioned (1) or (2). Substituent group a represents a hydroxy group, halogen atom, C1-Cs alkoxy group, halogeno C1-C6 alkoxy group, carboxy group, C1-C6 alkoxy-carbonyl group; carbamoyl group which may be substituted with a group selected from a C1-C6 alkyl group, C2-C5 alkenyl group, C2-C6 alkynyl group, C1-Cs alkanoyl group or C2-C6 alkenyl-carbonyl group; and a group having the formula NR6R7. R6 and R7, independently from each other, represent a hydrogen atom, C1-C6 alkyl group, C2-C6 alkenyl group, C2-Cs alkynyl group, C1-C6 alkanoyl group or C2-C6 alkenyl-carbonyl group, or together with the nitrogen atom to which they are bound form a heterocyclyl group. Substituent group β represents an oxo group, hydroxy group, cyclopropyl group, C1-C6 alkoxy group, C1-C6 alkylthio group, nitro group, halogen atom, cyano group, carboxy group, C1-C10 alkoxy-carbonyl group, C1-C6 alkanoyl group, C2-C4 alkenyl-carbonyl group, C2-Cs alkanoyloxy group, C2- C4 alkenyl-carbonyloxy group; carbamoyl group which may be substituted with a group selected from a C1-C4 alkyl group, phenyl group, C1-C7 acyl group and C1-C4 alkoxy-phenyl group; thiocarbamoyl group which may be substituted with a C1-C4 alkyl group or phenyl group; carbamoyloxy group which may be substituted with a C1-C4 alkyl group or phenyl group; C1-C6 alkanoylamino group, C1-C10 alkoxy-carboxamide group, C1-C10 alkoxy-carbonyloxy group, and ureido group which may be substituted with a C1-C4 alkyl group or phenyl group. Substituent group y represents a heterocyclic group, C3-C10 cycloalkyloxy group, C6-C10 aryloxy group, C7-C19 aralkyloxy group, heterocyclyloxy group, C3-C10 cycloalkylthio group, C6-C10 arylthio group, C7-C19 aralkylthio group, heterocyclylthio group, heterocyclylsulfinyl group, heterocyclylsulfonyl group, C3-C6 cycloalkyloxy-carbonyl group, C6-C10 aryloxy-carbonyl group, C7-C19 aralkyloxy-carbonyl group, heterocyclyloxycarbonyl group, C6-C10 aryl-carbonyl group, C6-C10 aryl-carbonyloxy group, C6-C10 aryl-carbonylamino group, C6-C10 aryloxy-carboxamide group, C7-C19 aralkyloxy-carboxamide group, Cs-C10 aryloxy-carbonyloxy group, C7-C19 aralkyloxy-carbonyloxy group, C3-C10 cycloalkyloxy-carbonyloxy group and C6-C10 aryl group which may be substituted with a group selected from Substituent group β. Substituent group δ represents a hydroxy group, nitro group, cyano group, halogen atom, C1-C6 alkyl group, halogeno C1-C6 alkyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, carboxy group, C1-C6 alkanoyl group, C1-C6 alkoxy-carbonyl group, C1-C6 alkanoylamino group, C1-C6 alkylthio group, carbamoyl group, C1-C6 alkyl-carbamoyl group, C1-C6 alkoxy-carbonyl C1-C6 alkyl-carbamoyl group, 1,3- diacylguanidino C1-C6 alkyl group, a group having the formula NR6R7 (R6 and R7 are the same as R6 and R7 of Substituent group a) , C3-C6 cycloalkyl group, C6-C10 aryl group and 5-membered heteroaryl group. Substituent group 8 represents a hydroxy group, nitro group, cyano group, halogen atom, C1-C14 alkyl group, cyclopropyl C1-C14 alkyl group, halogeno C1-C14 alkyl group, C1-C14 alkoxy group, halogeno C1-C14 alkoxy group, carboxy group, C1-C14 alkanoyl group, C1-C14 alkoxy-carbonyl group, C1-C14 alkanoylamino group, C1-C14 alkylthio group, carbamoyl group, C1- C14 alkyl-carbamoyl group, C1-C14 alkoxy-carbonyl C1-C14 alkyl- carbamoyl group, 1,3-diacylguanidino C1-C14 alkyl group, a group having the formula NR6R7 (R6 and R7 are the same as R6 and R7 of Substituent group a), C3-C6 cycloalkyl group, C6-C10 aryl group and 5-membered heteroaryl group} or a pharmacologically acceptable salt thereof, (2) The compound or pharmacologically acceptable salt thereof according to the aforementioned (1), wherein 1 is 0 and m is an integer of 1 to 3, (3) The compound or pharmacologically acceptable salt thereof according to the aforementioned (1), wherein 1 is 0 and m is 2, (4) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (3), wherein X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 7-membered heterocyclyl ring [in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkanoyl group which may be substituted with a group selected from Substituent group a), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO2, the heterocyclyl ring may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atoms) or 5- or 6-membered cycloalkyl ring, and ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group a, a cyclopropyl C1-C6 alkyl group and a C1-C6 alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α] or a 3- to 7-membered saturated cycloalkyl ring (the 3- to 7-membered saturated cycloalkyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxy group, hydroxymethyl group, 1,2- dihydroxyethyl group, 1,2,3-trihydroxypropyl group, 1,2,3,4- tetrahydroxybutyl group and acetylamino group), (5) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (3), wherein X and Y represent a group in which X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 7-membered heterocyclyl ring [in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO2, the heterocyclyl ring may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atoms) or 5- or 6-membered cycloalkyl ring, and ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group a and a C1-C6 alkyl group which may be substituted with 1 to 4 groups selected from Substituent group a] or a 3- to 5-membered saturated cycloalkyl ring (the 3- to 5-membered saturated cycloalkyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group), (6) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (3), wherein X and Y represent a group in which X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 7-membered heterocyclyl ring [the 3- to 7-membered heterocyclyl ring is oxirane, oxolane, tetrahydrofuran, tetrahydropyran, 1,3- dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3- dithiane, 1,1,3,3-tetraoxo-l,3-dithiolane, 1,3-oxathiolane, 1,3- oxathiane or 1,3-oxathiepane, these heterocyclyl rings may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the 5- or 6- membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine or 1,3-dioxane) or cyclohexyl ring, and ring A, including the fused ring or spiro ring, may be substituted with 1 or 2 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group a (Substituent group a represents a hydroxy group and a group having the formula NR6R7, and R6 and R7, independently from each other, represent a hydrogen atom or C1-C6 alkanoyl group), a methyl group, an ethyl group and a C1-C6 alkyl group which is substituted with 1 to 4 hydroxy groups], or a cyclopropyl or cyclopentyl ring (the cyclopropyl or cyclopentyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3- trihydroxypropyl group, and 1,2,3,4-tetrahydroxybutyl group), (7) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (3), wherein X and Y represent a group in which X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 6-membered heterocyclyl ring {the heterocyclyl ring is oxirane, tetrahydrofuran, 1,3-dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, 1,3-oxathiolane, or 1,3-oxathiane, these heterocyclyl rings may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the 5- or 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran or 1,3- dioxane) or cyclohexyl ring, and ring A, including the fused ring and spiro ring, may be substituted with 1 or 2 groups selected from the group consisting of Substituent group a [Substituent group a represents a hydroxy group and a group having the formula NR6R7 (R6 and R7, independently from each other, represent a hydrogen atom or acetyl group)], a methyl group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3- trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group}, (8) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (7), wherein n is 0 or 1, and R1 is a hydroxy group, halogen atom, C1-C6 alkyl group or C1-C6 alkoxy group, (9) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (7), wherein n is 0 or 1, and R1 is a fluorine atom or methyl group, (10) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (7), wherein n is 0, (11) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (10), wherein R2 is a C1-C6 alkyl group, (12) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (10), wherein R2 is a C1-C4 alkyl group, (13) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (10), wherein R2 is an ethyl group, (14) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (13), wherein R3 is a phenyl group which may be substituted with a group selected from Substituent group s, or a pyrrolyl group which may be substituted with a group selected from Substituent group s, and Substituent group a is a halogen atom, C1-C14 alkyl group and halogeno C1-C14 alkyl group, (15) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (13), wherein R3 is a phenyl group which may be substituted with a group aelected from Substituent group a, or a pyrrolyl group which may be substituted with a group aelected from Substituent group a, and Substituent group a is a fluorine atom, chlorine atom, bromine atom, C3-Ca alkyl group and halogeno C4-C8 alkyl group, (16) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (13), wherein R3 is a phenyl group which may be substituted with a group a elected from Substituent group a, and Substituent group ε is a fluorine atom, chlorine atom and C3-C8 alkyl group, (17) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (16), wherein R5 is a hydrogen atom or C1-C6 alkyl group, (18) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (16), wherein R5 is a hydrogen atom or methyl group, -(19) The compound or pharmacologically acceptable salt thereof according to any one of the aforementioned (1) to (16), wherein R5 is a hydrogen atom, (20) The compounds of the following group aelected from the aforementioned (1) or pharmacologically acceptable salt thereof: ethyl 8-[N-(2-chlorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chlorophenyl)sulfamoyl]-2,3-bis(1,2- dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis (1,2- dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2- hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2- dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2- (1,2,3- trihydroxypropyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2- (1,2,3,4-tetrahydroxybutyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 2,3-bis(acetylaminomethyl)-8-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-hydroxy- 1,5-dioxaspiro[5.5]undec-7 -ene-8 -carboxylate, ethyl 3-acetylamino-9-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-8- carboxylate, ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3- bis(hydroxymethyl)-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate, ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 8-[N-(2-hexylphenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1, 4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-hexylphenyl)sulfamoyl]-2,3-bis(1,2- dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2- hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate, ethyl 8-[N-(2-heptylphenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-heptylphenyl)sulfamoyl]-2,3-bis(1,2- dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2- heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 8-[N-(2-bromophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromophenyl)sulfamoyl]-2,3-bis(1,2- dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 2,3-bis(hydroxymethyl)-8-[N-(2- pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(2- pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2- pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2- octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, ethyl 8- [N-(4-fluoro-2-propylphenyl)sulfamoyl]-2,3- bis (hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2- propylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, and ethyl 8-[N-(2-chloro-4-fluorophenyl)-N-methylsulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate, (21) A medicament containing the compound or pharmacologically acceptable salt thereof selected from any one of the aforementioned (1) to (20) as an active ingredient, (22) The medicament according to the aforementioned (21) for use in suppressing intracellular signal transduction or cell activation induced by endotoxin, (23) The medicament according to the aforementioned (21) for use in suppressing the generation of inflammatory mediators due to intracellular signal transduction or cell activation induced by endotoxin, (24) The medicament according to the aforementioned (21) for use in suppressing the generation of inflammatory mediators due to intracellular signal transduction or cell activation induced by endotoxin, (25) The medicament according to the aforementioned (21) for use as a prophylactic and/or therapeutic agent for a disease mediated by an inflammatory mediator, of which generation is induced by endotoxin, (26) The medicament according to the aforementioned (21) for use as a prophylactic and/or therapeutic agent for a disease mediated by an inflammatory mediator, which is generated due to intracellular signal transduction or cell activation induced by endotoxin, (27) The medicament according to the aforementioned (21) for use as a prophylactic and/or therapeutic agent for sepsis, and (i) a method of suppressing intracellular signal transduction induced by endotoxin and suppressing excess generation of inflammatory mediators such as TNF-α which is induced by the intracellular signal transduction, and (ii) a method of preventing and/or treating a disease mediated by intracellular signal transduction and by an inflammatory mediator which is generated due to the intracellular signal transduction, comprising administering an effective amount of the compound according to any one of the aforementioned (1) to (20) or pharmacologically acceptable salt thereof to a warm-blood animal (preferably a human). [EFFECTS OF THE INVENTION] The substituted cycloalkene derivative according to the present invention having the general formula (I) has excellent activity to suppress intracellular signal transduction or cell activation induced by endotoxin and to suppress excess generation of inflammatory mediators such as TNF-α due to the intracellular signal transduction and cell activation, and is useful as a medicament, especially as a prophylactic and/or therapeutic agent for ischemic brain disorder, arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complication, joint inflammation, osteoporosis, osteopenia, sepsis, autoimmune disease, tissue disorder and rejection after organ transplantation, bacterial infection, virus infection, gastritis, pancreatitis, nephritis, pneumonia, hepatitis, leukemia and the like, which are induced by the intervention of the intracellular signal transduction or cell activation, and by inflammatory mediators due to the intracellular signal transduction and cell activation. [BEST MODE FOR CARRYING OUT THE INVENTION] "Halogen atom" in the definitions of R1, Substituent group α, Substituent group β, Substituent group δ and Substituent group ε includes, for example, a fluorine atom, chlorine atom, bromine atom or iodine atom. With respect to R1, it is preferably a fluorine atom or chlorine atom, more preferably a fluorine atom. With respect to Substituent group Ε, it is preferably a fluorine atom, chlorine atom or bromine atom, more preferably a fluorine atom or chlorine atom. "Alkyl group" in the definitions of the NR group which may be included in ring A, substituent of ring A, R1, R2, R5, R6, R7, Substituent group β, Substituent group δ and Substituent group e includes a linear or branched alkyl group. "C1-C6 alkyl group" of "C1-C6 alkyl group which may be substituted with a group aelected from Substituent group α" in the definition of the NR group which may be included in ring A; "C1-C6 alkyl group" of "cyclopropyl C1-C6 alkyl group" in the definition of a substituent of ring A; "C1-C6 alkyl group" of "C1-C6 alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α" in the definition of a substituent of ring A; "CX-C6 alkyl group" of "C1-C6 alkyl group which may be substituted with a group aelected from Substituent group P" in the definitions of R2 and R5; and "C1-C6 alkyl group" in the definitions of Substituent group δ, R6 and R7 are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3- methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3- dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl group or the like. Among the 'C1-C6 alkyl groups", the one with respect to the NR group which may be included in ring A is preferably methyl. With respect to a substituent of ring A, it is preferably a C1-C4 alkyl group. With respect to R2, it is preferably a C1-C4 alkyl group, more preferably ethyl. With respect to R5, it is preferably methyl. With respect to R6 and R7, it is preferably methyl. With respect to Substituent group 8, it is preferably a C1-C4 alkyl group. C1-C14 alkyl groups of "C1-C14 alkyl group" and "cyclopropyl C1-C14 alkyl group" in the definition of Substituent group a are, for example, the aforementioned "C1-C6 alkyl group", octyl, nonyl, decyl, dodecyl, tetradecyl or the like. With respect to "C1-C14 alkyl group" in the definition of Substituent group a, it is preferably C3-C8 alkyl group. "C1-C20 alkyl group" in the definition of R1 is, for example, the aforementioned "C1-C14 alkyl group", pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl or the like. Preferably, it is a C1-C6 alkyl group, and more preferably a methyl group. "Alkenyl group" in the definitions of the NR group which may be included in ring A, substituent of ring A, R1, R2, R5, R6, R7 and Substituent group a is a linear or branched alkenyl group. "C3-C6 alkenyl group" in the definition of R1 is, for example, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2- butenyl, l-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2- methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2- pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, l-methyl-4-pentenyl, 2-methyl- 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl, preferably a C3-C4 alkenyl group. "C2-C6 alkenyl group" of "C2-C6 alkenyl group which may be substituted with a group aelected from Substituent group a" in the definition of the NR group which may be included in ring A; "C2-C6 alkenyl group" of "C2-C6 alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group α" in the definition of substituent of ring A; "C2-C6 alkenyl group" of "C2-C6 alkenyl group which may be substituted with a group aelected from Substituent group β" in the definitions of R2 and R5; and "C2-C6 alkenyl group" in the definitions of R6 and R7 are, for example, vinyl or the aforementioned "C3-C6 alkenyl group", preferably a C3-C4 alkenyl group. "Alkynyl group" in the definitions of the NR group which may be included in ring A, substituent of ring A, R1, R2, R5, R6, R7 and Substituent group α is a linear or branched alkynyl group. "C3-C6 alkynyl group" in the definition of R1 is, for example, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2- butynyl, 1-ethyl-2-butynyl, 3-butynyl, l-methyl-3-butynyl, 2- methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2- pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl, preferably a C3-C4 alkyl group. "C2-C6 alkynyl group" of "C2-C6 alkynyl group which may be substituted with a group aelected from Substituent group α" in the definition of the NR group which may be included in ring A; "C2-C6 alkynyl group" of "C2-C6 alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group a" in the definition of substituent of ring A; "C2-C6 alkynyl group" of "C2-C6 alkynyl group which may be substituted with a group aelected from Substituent group β" in the definitions of R2 and R5; and "C2-C6 alkynyl group" in the definitions of R6 and R7 are, for example, ethynyl or the aforementioned "C3-C5 alkynyl group", preferably a C3-C4 alkynyl group. "C3-Cs cycloalkyl group" in the definitions of Substituent group δ and Substituent group e are, for example, cyclopropyl, cyclopentyl or cyclohexyl. "3- to 7-membered cycloalkyl ring" in the definition of ring A may include an unsaturated bond, and such ring is, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane or cycloheptadiene. The aforementioned "3- to 7-membered cycloalkyl ring" may form a fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and such cycloalkyl ring is, for example, 2-oxa-bicyclo[4,3,0]nonan-8- ylidene, 3-oxa-bicyclo[3,3,0]heptan-7-ylidene, 2,4-dioxa- spiro[6.6]undecan-8-ylidene, bicyclo[4,3,0]nonan-7-ylidene, spiro[6.6]undecan-8-ylidene or the like. In addition, the aforementioned "3- to 7-membered cycloalkyl ring" may not form a fused ring or spiro ring, and may be substituted with an oxo group or a thioxo group. With respect to the aforementioned "cycloalkyl ring", a cycloalkyl ring, fused ring which is fused to the cycloalkyl ring, or spiro ring which is spiro bound to the cycloalkyl ring may be substituted with the same or different 1 to 4 (preferably 1 or 2) groups selected from the group consisting of Substituent group a, cyclopropyl C1-C6 alkyl group, C1-Cs alkyl group which may be substituted with 1 to 5 groups selected from Substituent group a, C2-C6 alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group a and C2-Cs alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group a. Preferred examples of the ring are, 3- hydroxycyclopentane, 4-hydroxycyclohexane, 3- hydroxymethylcyclopentane, 3,4-dihydroxymethylcyclopentane, 4- hydroxymethylcyclohexane, 4,4-dihydroxymethylcyclohexane, 3- (1,2-dihydroxyethyl)cyclopentane, 4- (1,2- dihydroxyethyl)cyclohexane, 3,4-bis (1,2- dihydroxyethyl)cyclopentane, 4,4-bis(1,2- dihydroxyethyl)cyclohexane, 3 - (1,2,3 - trihydroxypropyl)cyclopentane, 4 - (1, 2 , 3 - trihydroxypropyl)cyclohexane, 3 - (1,2,3,4- tetrahydroxybutyl)cyclopentane, 4- (1,2,3,4- tetrahydroxybutyl)cyclohexane, 3-ethoxycarbonylcyclopentane, 4- ethoxycarbonylcyclohexane, 4,4-diethoxycarbonylcyclohexane, 3- carbamoylcyclopentane, 4-carbamoylcyclohexane, 3- acetylaminocyclopentane, 4-acetylaminocyclohexane, 3,4- diacetylaminomethylcyclopentane, 2,3,4,5- tetrahydroxybicyclo[4,3,0]nonane (the binding position with ring B is the 8-position), 3-oxa-bicyclo[3,3,0]octane (the binding position with ring B is the 7-position), 2,4-dihydroxymethyl-3- oxa-bicyclo[3,3,0]octane (the binding position with ring B is the 7-position), and 2,4-dioxaspiro[5.5]undecane (the binding position with ring B is the 9-position). "Cycloalkyl ring" in the definition of ring A is, among the aforementioned rings, preferably a 3- to 7-membered cycloalkyl ring which may be substituted with 1 or 2 groups selected from a hydroxymethyl group consisting of a hydroxy group, -trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group, 1,2-dihydroxyethyl group, groups 1, 2 and 3, more preferably a 3- to 5-membered saturated cycloalkyl ring which may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group,1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group, and particularly preferably a cyclopropyl or cyclopentyl ring which may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3- trihydroxypropyl group and 1,2,3,4-tetrahydroxybutyl group. "C3-C10 cycloalkyl group" in the definition of R1 is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclocyclheptyl or cyclooctyl. "C4-C12 cycloalkylalkyl group" in the definition of R1 is, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl or cycloheptylmethyl, preferably a C4-C8 cycloalkylalkyl group, more preferably a C4-C7 cycloalkylalkyl group. With respect to "3- to 7-membered heterocyclyl ring" in the definition of ring A, X and Y included in the ring, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 group or C1-C6 alkylcarbonyl group which may be substituted with a group aelected from Substituent group a), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO2, preferably any one selected from a carbon atom, an oxygen atom, a sulfur atom, a group having the formula SO, and a group having the formula SO2. The 3-to 7-membered heterocyclyl ring may include an unsaturated bond. Examples of such ring are, a heterocyclyl ring including a nitrogen atom such as aziridine, azetidine, pyrrolidine, pyrroline, piperidine and imidazolidine; a heterocyclyl ring including an oxygen atom such as oxirane, oxetane, tetrahydrofuran, oxolene, tetrahydropyran, dihydropyran, oxepane, 1,3-dioxolane, 1,3-dioxane and 1,3-dioxepane; a heterocyclyl ring including a sulfur atom, a group having the formula SO or a group having the formula SO2 such as thiirane, thietane, thiolane, thiolene, thiane, thiepane, 1,3-dithiolane, 1,3-dithiane, 1,3-dithiepane, 1,3-dioxo-1,3-dithiolane, 1,3- dioxo-1,3-dithiane, 1,1,3,3-tetraoxo-1,3-dithiolane and 1,1,3,3- tetraoxo-1,3-dithiane; a heterocyclyl ring including an oxygen atom and a sulfur atom such as 1,3-oxathiolane, 1,3-oxathiane and 1,3-oxathiepane; a heterocyclyl ring including a nitrogen atom and an oxygen atom such as 1,3-oxapyrrolidine and 1,3- oxapyrroline; and a heterocyclyl ring including a nitrogen atom and a sulfur atom such as 1,3-thiapyrrolidine and 1,3- thiapyrroline. Preferably, it is oxirane, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3- dithiolane, 1,3-dithiane, 1,1,3,3-tetraoxo-l,3-dithiolane, 1,3- oxathiolane, 1,3-oxathiane or 1,3-oxathiepane. More preferably, it is oxirane, tetrahydrofuran, 1,3- dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, 1,3- oxathiolane or 1,3-oxathiane. Even more preferably, it is oxirane, 1,3-dioxolane, 1,3- dioxane or 1,3-oxathiolane. The aforementioned "3- to 7-membered heterocyclyl ring" may form a fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring or 3- to 7-membered cycloalkyl ring, preferably may form a fused ring or spiro ring with a 5- or 6- membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atom) or 5- or 6- membered cycloalkyl ring, and more preferably may form a fused ring or spiro ring with tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, 1,3-dioxane or cyclohexyl ring. Examples of such heterocyclyl ring are 2,4-dioxa- bicyclo [3,3,0]octane (the binding position with ring B is the 3- position), 2,4,7-trioxa-bicyclo[3,3,0]octane (the binding position with ring B is the 3-position), 7,9-dioxa- bicyclo[4,3,0]nonane (the binding position with ring B is the 8- position), 7-aza-2,4-dioxa-bicyclo[3,3,0]octane (the binding position with ring B is the 3-position), 2,4,8,10- tetraoxaspiro[5,5]undecane (the binding position with ring B is the 3-position) and the like. The binding position of these rings with ring B is the same as the aforedescribed one. In addition, the aforementioned "3- to 7-membered heterocyclyl ring" may not form a fused ring or spiro ring, and may be substituted with an oxo group or a thioxo group. With respect to the aforementioned "heterocyclyl ring", heterocyclyl ring, fused ring which is fused to the heterocyclyl ring or spiro ring which is spiro bound to the heterocyclyl ring may be substituted with the same or different 1 to 4 (preferably 1 or 2) substituents. The substituent is a group aelected from the group consisting of an oxo group, a thioxo group, Substituent group a, a cyclopropyl C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with 1 to 5 groups selected from Substituent group a, a C2-C6 alkenyl group which may be substituted with 1 to 5 groups selected from Substituent group a and a C2-C6 alkynyl group which may be substituted with 1 to 5 groups selected from Substituent group a. The substituent is preferably a group aelected from the group consisting of an oxo group, a thioxo group, Substituent group a, a cyclopropyl C1-C6 alkyl group and a C1-C6 alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α. More preferably, it is a group aelected from the group consisting of an oxo group, a thioxo group, Substituent group a and a C1-C6 alkyl group which may be substituted with 1 to 4 groups selected from Substituent group a. Even more preferably, it is 1 or 2 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group a (Substituent group a is a hydroxy group and a group having the formula NR6R7, and R6 and R7, independently from each other, represent a hydrogen atom or C1-C6 alkylcarbonyl group), a methyl group, an ethyl group and a C1-C6 alkyl group aubstituted with 1 to 4 hydroxy groups. Further preferably, it is 1 or 2 groups selected from the group consisting of Substituent group a [Substituent group α represents a hydroxy group and a group having the formula NR6R7 (R5 and R7, independently from each other, represent a hydrogen atom or methylcarbonyl group)], a methyl group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3- trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group. As for such examples, oxirane, oxolane, tetrahydrofuran (traditional name, oxolane according IUPAC nomenclature), tetrahydropyran (traditional name, oxane according IUPAC nomenclature), 1,3-dioxolane, 1,3- dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3-dithiane, 1,3- oxathiolane, 1,3-oxathiane, 1,3-oxathiepane, tetrahydrooxazole, tetrahydro-1,3-oxadine, tetrahydrothiazol, tetrahydro-1,3- thiazine, 1,1,3,3-tetraoxo-1,3-dithiane, 2,4,7-trioxa- bicyclo[3,3,0]octane, 2,4-dithia-7-oxa-bicyclo[3,3,0]octane, 2- thia-4,7-dioxa-bicyclo[3,3,0]octane, 2,4,8,10- tetraoxaspiro[5.5]undecane, 2,4-dithia-8,10- dioxaspiro[5.5]undecane, 2-thia-4,8,10-trioxaspiro[5.5]undecane, 2-hydroxytetrahydrofuran, 4-hydroxy-1,3-dioxolane, 4,5- dihydroxy-1,3-dioxolane, 5-hydroxy-1,3-dioxane, 5,5-dihydroxy- 1,3-dioxane, 4-hydroxy-1,3-dithiolane, 4,5-dihydroxy-1,3- dithiolane, 5-hydroxy-1,3-dithiane, 5,5-dihydroxy-1,3-dithiane, 4-hydroxy-1,1,3,3-tetraoxo-1,3-dithiolane, 4, 5-dihydroxy- 1,1,3,3-tetraoxo-1,3-dithiolane, 4-hydroxy-1,3-oxathiolane, 5- hydroxy-1,3-oxathiane, 5,5-dihydroxy-1,3-oxathiane, 6,8- dihydroxy-2,4-dioxa-bicyclo[3,3,0]octane, 6,8-dihydroxy-2,4,7- trioxa-bicyclo[3,3,0]octane, 2,3,4,5-tetrahydroxy-7,9-dioxa- bicyclo[4,3,0]nonane, 6,8-dihydroxy-7-aza-2,4-dioxa- bicyclo[3,3,0]octane, 9-hydroxy-2,4,8,10- tetraoxaspiro[5.5]undecane, 2,3,4,5-tetrahydro-7,9-dithia- bicyclo[4,3,0]nonane, 2,3,4,5-tetrahydro-7-thia-9-oxa- bicyclo[4,3,0]nonane, 2-carboxytetrahydrofuran, 4-carboxy-1,3- dioxolane, 5-carboxy-1,3-dioxane, 4-carboxy-1,3-dithiolane, 5- carboxy-1,3-dithiane, 4-carboxy-l,1,3,3-tetraoxo-1,3-dithiolane, 4-carboxy-1,3-oxathiolane, 5-carboxy-1,3-oxathiane, 2-methoxycarbonyltetrahydrofuran, 4-methoxycarbonyl-1,3- dioxolane, 5-methoxycarbonyl-1,3-dioxane, 5,5-dimethoxycarbonyl- 1,3-dioxane, 4-methoxycarbonyl-1,3-dithiolane, 5- methoxycarbonyl-1,3-dithiane, 5,5-dimethoxycarbonyl-1,3- dithiane, 4-methoxycarbonyl-l,1,3,3-tetraoxo-1,3-dithiolane, 4- methoxycarbonyl-1,3-oxathiolane, 5-methoxycarbonyl-1,3- oxathiane, 5,5-dimethoxycarbonyl-1,3-oxathiane, 6,8- dimethoxycarbonyl-2,4-dioxa-bicyclo[3,3,0]octane, 6,8- dimethoxycarbonyl-2,4,7-trioxa-bicyclo[3,3,0]octane, 6,8- dimethoxycarbonyl-7-aza-2,4-dioxa-bicyclo[3,3,0]octane, 8- methoxycarbonyl-2,4,7,9-tetraoxaspiro[5.5]undecane, 2-ethoxycarbonyltetrahydrofuran, 4-ethoxycarbonyl-1,3-dioxolane, 5-ethoxycarbonyl-1,3-dioxane, 5,5-diethoxycarbonyl-1,3-dioxane, 4-ethoxycarbonyl-1,3-dithiolane, 5-ethoxycarbonyl-1,3-dithiane, 5,5-diethoxycarbonyl-1,3-dithiane, 4-ethoxycarbonyl-l,1,3,3- tetraoxo-1,3-dithiolane, 4-ethoxycarbonyl-1,3-oxathiolane, 5- ethoxycarbonyl-1,3-oxathiane, 5,5-diethoxycarbonyl-1,3- oxathiane, 6,8-diethoxycarbonyl-2,4-dioxa-bicyclo[3,3,0]octane, 6,8-diethoxycarbonyl-2,4,7-trioxa-bicyclo[3,3,0]octane, 6,8- diethoxycarbonyl-7-aza-2,4-dioxa-bicyclo[3,3,0]octane, 8- ethoxycarbonyl-2,4,7,9-tetraoxaspiro[5.5]undecane, 2-aminotetrahydrofuran, 4-amino-1,3-dioxolane, 4,5-diamino-1,3- dioxolane, 5-amino-1,3-dioxane, 4-amino-1,3-dithiolane, 4,5- diamino-1,3-dithiolane, 5-amino-1,3-dithiane, 4-amino-1,1,3,3- tetraoxo-1,3-dithiolane, 4-amino-1,3-oxathiolane, 5-amino-1,3- oxathiane, 2-acetylaminotetrahydrofuran, 4-acetylamino-1,3-dioxolane, 4,5- bis(acetylamino)-1,3-dioxolane, 5-acetylamino-1,3-dioxane, 4- acetylamino-1,3-dithiolane, 4,5-bis(acetylamino)-1,3-dithiolane, 5-acetylamino-1,3-dithiane, 4-acetylamino-1,1,3,3-tetraoxo-1,3- dithiolane, 4-acetylamino-1,3-oxathiolane, 5-acetylamino-1,3- oxathiane, 6,8-diacetylamino-2,4-dioxa-bicyclo[3,3,0]octane, 6,8-diacetylamino-2,4,7-trioxa-bicyclo[3,3,0]octane, 6,8- diacetylamino-7-aza-2,4-dioxa-bicyclo[3,3,0]octane, 8- acetylamino-2,4,7,9-tetraoxaspiro[5.5]undecane, 2-methyltetrahydrofuran, 4-methyl-1,3-dioxolane, 4,5-dimethyl- 1,3-dioxolane, 5-methyl-1,3-dioxane, 4-methyl-1,3-dithiolane, 4,5-dimethyl-1,3-dithiolane, 5-methyl-1,3-dithiane, 4-methyl- 1,1,3,3-tetraoxo-1,3-dithiolane, 4-methyl-1,3-oxathiolane, 5- methyl-1,3-oxathiane, 5,5-dimethyl-1,3-dioxane, 5,5-dimethyl-1,3-dithiane, 5,5- dimethyl-1,3-oxathiane, 2-ethyltetrahydrofuran, 4-ethyl-1,3-dioxolane, 4,5-diethyl-1,3- dioxolane, 5-ethy1-1,3-dioxane, 4-ethyl-1,3-dithiolane, 4,5- diethyl-1,3-dithiolane, 5-ethyl-1,3-dithiane, 4-ethyl-l,1,3,3- tetraoxo-1,3-dithiolane, 4-ethyl-1,3-oxathiolane, 5-ethyl-1,3- oxathiane, 2-hydroxymethyltetrahydrofuran, 4-hydroxymethyl-1,3-dioxolane, 5-hydroxymethyl-1,3-dioxane, 5,5-dihydroxymethyl-1,3-dioxane, 4- hydroxymethyl-1,3-dithiolane, 5-hydroxymethyl-1,3-dithiane, 5,5- dihydroxymethyl-1,3-dithiane, 4-hydroxymethyl-1,1,3,3-tetraoxo- 1, 3-dithiolane, 4-hydroxymethyl-1,3-oxathiolane, 5- hydroxymethyl-1,3-oxathiane, 5,5-dihydroxymethyl-1,3-oxathiane, 4,5-dihydroxymethyl-1,3-dioxolane, 4,5-dihydroxymethyl-1,3- dithiolane, 4,5-dihydroxymethyl-1,3-oxathiolane, 5,5- dihydroxymethyl-1,3-dioxane, 5,5-dihydroxymethyl-1,3-dithiane, 5,5-dihydroxymethyl-1,3-oxathiane, 6,8-dihydroxymethyl-2,4,7- trioxa-bicyclo[3,3,0]octane, 6,8-dihydroxymethyl-2,4-dithia-7- oxa-bicyclo[3,3,0]octane, 6,8-dihydroxymethyl-2-thia-4,7-dioxa- bicyclo [3,3,0]octane, 6-oxo-8-hydroxymethyl-2,4,7-trioxa- bicyclo[3,3,0]octane, 2-(1,2-dihydroxyethyl)tetrahydrofuran, 4-(1,2-dihydroxyethyl)- 1,3-dioxolane, 5-(1,2-dihydroxyethyl)-1,3-dioxane, 5,5-bis (1,2- dihydroxyethyl)-1,3-dioxane, 4-(1,2-dihydroxyethyl)-1,3- dithiolane, 5-(1,2-dihydroxyethyl)-1,3-dithiane, 5,5-bis (1,2- dihydroxyethyl)-1,3-dithiane, 4-(1,2-dihydroxyethyl)-1,1,3,3- tetraoxo-1,3-dithiolane, 4-(1,2-dihydroxyethyl)-1,3-oxathiolane, 5-(1,2-dihydroxyethyl)-1,3-oxathiane, 5,5-bis(1,2- dihydroxyethyl)-1,3-oxathiane, 4,5-bis(1,2-dihydroxyethyl)-1,3-dioxolane, 4,5-bis (1,2- dihydroxyethyl)-1,3-dithiolane, 4,5-bis(1,2-dihydroxyethyl)-1,3- oxathiolane, 4,5-bis(1-hydroxyethyl)-1,3-dioxolane, 4,5-bis(1-hydroxypropyl)- 1,3-dioxolane, 2-(1,2,3-trihydroxypropyl)tetrahydrofuran, 4- (1,2,3- trihydroxypropyl)-1,3-dioxolane, 5-(1,2,3-trihydroxypropyl)-1,3- dioxane, 5,5-bis(1,2,3-trihydroxypropyl)-1,3-dioxane, 4-(1,2,3- trihydroxypropyl)-1,3-dithiolane, 5-(1,2,3-trihydroxypropyl)- 1,3-dithiane, 5,5-bis(1,2,3-trihydroxypropyl)-1,3-dithiane, 4- (1,2,3-trihydroxypropyl)-1,1,3,3-tetraoxo-1,3-dithiolane, 4- (1,2,3-trihydroxypropyl)-1,3-oxathiolane, 5- (1,2- dihydroxyethyl)-1,3-oxathiane, 5,5-bis(1,2,3-trihydroxypropyl)- 1,3-oxathiane, 2-(1,2,3,4-tetrahydroxybutyl)tetrahydrofuran, 4-(1,2,3,4- tetrahydroxybutyl)-1,3-dioxolane, 5-(1,2,3,4-tetrahydroxybutyl)- 1,3-dioxane, 5,5-bis(1,2,3,4-tetrahydroxybutyl)-1,3-dioxane, 4- (1,2,3,4-tetrahydroxybutyl)-1,3-dithiolane, 5-(1,2,3,4- tetrahydroxybutyl)-1,3-dithiane, 5,5-bis(1,2,3,4- tetrahydroxybutyl)-1,3-dithiane, 4-(1,2,3,4-tetrahydroxybutyl)- 1,1,3,3-tetraoxo-1,3-dithiolane, 4-(1,2,3,4-tetrahydroxybutyl)- 1,3-oxathiolane, 5-(1,2,3,4-tetrahydroxybutyl)-1,3-oxathiane, 5,5-bis(l,2,3,4-tetrahydroxybutyl)-1,3-oxathiane, 2-acetylaminomethyltetrahydrofuran, 4-acetylaminomethyl-1,3- dioxolane, 4,5-diacetylaminomethyl-1,3-dioxolane, 5- acetylaminomethyl-1,3-dioxane, 4-acetylaminomethyl-1,3- dithiolane, 4,5-diacetylaminomethyl-1,3-dithiolane, 5- acetylaminomethyl-1,3-dithiane, 4-acetylaminomethyl-l,1,3,3- tetraoxo-1,3-dithiolane, 4-acetylaminomethyl-1,3-oxathiolane, 5- acetylaminomethyl-1,3-oxathiane, 4,5-diacetylaminomethyl-1,3-dioxolane, 4,5-diacetylaminomethyl- 1,3-dithiolane, 4,5-diacetylaminomethyl-1,3-oxathiolane, 2-vinyltetrahydrofuran, 4-vinyl-1,3-dioxolane, 4,5-divinyl-1,3- dioxolane, 5-vinyl-1,3-dioxane, 4-vinyl-1,3-dithiolane, 4,5- divinyl-1,3-dithiolane, 5-vinyl-1,3-dithiane, 4-vinyl-l,1,3,3- tetraoxo-1,3-dithiolane, 4-vinyl-1,3-oxathiolane, 5-vinyl-1,3- oxathiane, 2-propenyltetrahydrofuran, 4-propenyl-1,3-dioxolane, 4,5- dipropeny1-1,3-dioxolane, 5-propenyl-1,3-dioxane, 4-propenyl- 1,3-dithiolane, 4,5-dipropenyl-1,3-dithiolane, 5-propenyl-1,3 - dithiane, 4-propenyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4- propenyl-1,3-oxathiolane, 5-propenyl-1,3-oxathiane, 2-propynyltetrahydrofuran, 4-propynyl-1,3-dioxolane, 4,5- dipropyny1-1,3-dioxolane, 5-propynyl-1,3-dioxane, 4-propynyl- 1,3-dithiolane, 4,5-dipropynyl-1,3-dithiolane, 5-propynyl-1,3- dithiane, 4-propynyl-l,1,3,3-tetraoxo-1,3-dithiolane, 4- propynyl-1,3-oxathiolane and 5-propynyl-1,3-oxathiane can be mentioned. "C6-C10 aryl group" of "C6-C10 aryl group which may be substituted with a group aelected from Substituent group P" in the definition of Substituent group j; and "C6-C10 aryl group" in the definitions of Substituent group 5 and Substituent group e are, for example, phenyl or naphthyl. With respect to the "C6-C10 aryl group which may be substituted with a group aelected from Substituent group (3" , the "C6-C10 aryl group" is substituted with a substituent selected from Substituent group (3 at a substitutable position, the substituent is not limited to one, and may be the same or different plural (2 to 4) substituents. "5- or 6-membered heteroaryl group" in the definition of R3 includes 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. As for such heteroaryl, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, piridazinyl, pyrimidinyl and pyradinyl can be mentioned, and it is preferably furyl, thienyl, pyrrolyl, pyridyl or pyrimidinyl, more preferably pyrrolyl. "5-membered heteroaryl group" in the definitions of Substituent group 8 and Substituent group a is, for example, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thienyl or furyl. "Halogeno C1-C6 alkyl group" in the definition of Substituent group 8 is, for example, trifluoromethyl or trifluoroethyl. "Halogeno C1-C14 alkyl group" in the definition of Substituent group e is, for example, the aforementioned "halogeno C1-C6 alkyl group", 4,4,4-trifluorobutyl, 5,5,5- trifluoropentyl, 6,6,6-trifluorohexyl, 7,7,7-trifluoroheptyl or 8,8,8-trifluorooctyl, preferably a halogeno C4-C8 alkyl group. "C1-C6 alkoxy group" in the definitions of Substituent group a, Substituent group \|3 and Substituent group 8 represents a group in which an oxygen atom is bound to the aforementioned "C1-C6 alkyl group", for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy, isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy, neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2- methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1- sulfur atom is bound to the aforementioned wC1-C6 alkyl group", and the sulfur atom may be oxidized. Preferably, it is a C1-C4 alkylthio group, for example, methylthio, ethylthio, n- propylthio, n-butylthio, methylsulfinyl or methylsulfonyl. With respect to "C1-C14 alkylthio group" in the definition of Substituent group a, the sulfur atom to which the alkyl group is bound may be oxidized, and it is for example, the aforementioned "C1-C6 alkylthio group", n-heptylthio, 3- methylhexylthio, n-octylthio, 2,4-dimethylhexylthio, n- octylthio, or 2,3,6-trimethylheptylthio, preferably a C1-C10 alkylthio group, and more preferably a C4-C8 alkylthio group. With respect to "C3-C10 cycloalkylthio group" in the definition of Substituent group γ, the sulfur atom may be oxidized, and it is for example, cyclopropylthio, cyclohexylthio, cyclopentylsulfinyl or cyclohexylsulfonyl. With respect to "C6-C10 arylthio group" in the definition of Substituent group γ, the sulfur atom may be oxidized, and it is for example, phenylthio, naphthylthio, phenylsulfinyl or phenylsulfonyl. With respect to "C7-C19 aralkylthio group" in the definition of Substituent group γ, the sulfur atom may be oxidized, and it is for example, benzylthio, phenylethylthio, benzhydrylthio, benzylsulfinyl or benzylsulfonyl. "C1-C6 alkanoyl group" in the definitions of R6, R7, Substituent group β and Substituent group 8 represents a group in which a hydrogen atom or C1-C5 alkyl group is bound to a carbonyl group, and is for example, formyl, acetyl, propionyl, butyryl, valeryl or pyvaloyl. "C1-C14 alkanoyl group" in the definition of Substituent group a is, for example, the aforementioned "C1-C6 alkanoyl group", octanoyl, decanoyl, dodecanoyl or tetradecanoyl. "C2-C4 alkenyl-carbonyl group" in the definition of Substituent group p is, for example, acryloyl or crotonoyl. "C2-C6 alkenyl-carbonyl group" in the definitions of Rs and R7 is, for example, the aforementioned "C2-C4 alkenyl-carbonyl group", 1,3-butadienylcarbonyl or 3-methyl-2-butenylcarbonyl. "C6-C10 aryl-carbonyl group" in the definition of Substituent group y is, for example, benzoyl, naphthoyl or phenylacetyl. "C1-C6 alkoxy-carbonyl group" in the definitions of Substituent group α and Substituent group δ represents a group in which the aforementioned "C1-C6 alkoxy group" is bound to a carbonyl group, and is for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n- butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl or the like. "C1-C10 alkoxy-carbonyl group" in the definition of Substituent group β is, for example, the aforementioned "C1-C6 alkoxycarbonyl group", heptyloxy, octyloxy, nonyloxy or decyloxy. "C1-C14 alkoxy-carbonyl group" in the definition of Substituent group ε is, for example, the aforementioned "C1-C10 alkoxy-carbonyl group", dodecyloxycarbonyl or tetradecyloxycarbonyl, preferably a C1-C10 alkoxy-carbonyl group, and more preferably a C4-C8 alkoxy-carbonyl group. "C3-C6 cycloalkyloxycarbonyl group" in the definition of Substituent group γ is, for example, cyclopropyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl or norbornyloxycarbonyl. "C6-C10 aryloxy-carbonyl group" in the definition of Substituent group γ is, for example, phenoxycarbonyl or naphthyloxycarbonyl. "C7-C19 aralkyloxy-carbonyl group" in the definition of Substituent group γ is, for example, benzyloxycarbonyl, benzhydryloxycarbonyl or 2-phenethyloxycarbonyl. "C2-C6 alkanoyloxy group" in the definition of Substituent group β represents a group in which the C2-C6 alkanoyl group is bound to an oxygen atom, and is for example, acetoxy, propionyloxy, butyryloxy, valeryloxy or pivaloyloxy. "C1-C10 alkoxy-carbonyloxy group" in the definition of Substituent group β is, for example, methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy, n-butoxycarbonyloxy, tert-butoxycarbonyloxy, n- pentyloxycarbonyloxy or n-hexyloxycarbonyloxy. "C6-C10 aryl-carbonyloxy group" in the definition of Substituent group γ is, for example, benzoyloxy, naphthoyloxy or phenylacetoxy. "Carbamoyl group which may be substituted with a group aelected from a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkanoyl group or C2-C6 alkenyl-carbonyl group" in the definition of Substituent group a is a carbamoyl group or cyclic aminocarbonyl group which may be substituted with 1 or 2 substituents selected from C1-C6 alkyl groups such as methyl, ethyl, propyl and the like, C2-C6 alkenyl groups such as vinyl, allyl, isopropenyl and the like, C2-C6 alkynyl groups such as ethynyl and the like, C1-C6 alkanoyl groups such as acetyl and the like, and C2-C6 alkenyl-carbonyl groups such as acryloyl and the like, preferably, specifically for example, a carbamoyl group or cyclic aminocarbonyl group which may be substituted with 1 or 2 substituents selected from a C1-C6 alkyl group and a C1-C6 alkanoyl group, more preferably a carbamoyl group or cyclic aminocarbonyl group which is substituted with 1 or 2 C1-C2 alkanoyl groups. Specifically, it is carbamoyl, N- methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl or N-acetylcarbamoyl, preferably N-acetyl carbamoyl. "Carbamoyl group which may be substituted with a group aelected from a Cx-C4 alkyl group, phenyl group, C1-C7 acyl group and C1-C4 alkoxyphenyl group" in the definition of Substituent group β is a carbamoyl group or cyclic aminocarbonyl group which may be substituted with 1 or 2 substituents selected from C1-C4 alkyl groups such as methyl, ethyl and the like, phenyl group, C1-C7 acyl groups such as acetyl, propionyl, benzoyl and the like, and C1-C4 alkoxyphenyl groups such as methoxyphenyl and the like, specifically for example, carbamoyl, N-methylcarbamoyl, N- ethylcarbamoyl, N,N-dimethylcarbamoyl, N/N-diethylcarbamoyl, N- phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N-(p- methoxyphenyl)carbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperadinylcarbonyl or morpholinocarbonyl. "Thiocarbamoyl group which may be substituted with a C1-C4 alkyl group or phenyl group" in the definition of Substituent group β is a thiocarbamoyl group which may be substituted with 1 or 2 substituents selected from C1-C4 alkyl groups such as methyl, ethyl and the like, and a phenyl group, specifically for example, thiocarbamoyl, N-methylthiocarbamoyl or N- phenylthiocarbamoyl. "Carbamoyloxy group which may be substituted with a C1-C4 alkyl group or phenyl group" in the definition of Substituent group β is a carbamoyloxy group which may be substituted with 1 or 2 substituents selected from C1-C4 alkyl groups such as methyl, ethyl and the like, and a phenyl group, specifically for example, carbamoyloxy, N-methyl carbamoyloxy, N,N-dimethyl carbamoyloxy, N-ethylcarbamoyloxy or N-phenyl carbamoyloxy. With respect to "group having the formula NR6R7" in the definitions of Substituent group a, Substituent group 8 and Substituent group ε, R6 and R7, independently from each other, represent a hydrogen atom, C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C1-C6 alkanoyl group or C2-Cs alkenyl- carbonyl group, or, together with the nitrogen atom to which R6 and R7 are bound, form a heterocyclyl group. Preferably, it is a group in which R6 and R7 are a hydrogen atom, C1-C6 alkyl group or C1-C6 alkanoyl group, more preferably a group in which R6 and R7 are a hydrogen atom, C1-C4 alkyl group or C1-C4 alkanoyl group, even more preferably a group in which R6 and R7 are a hydrogen atom or C1-C2 alkanoyl group. Specifically it is amino, methylamino, ethylamino, dimethylamino, diethylamino or acetylamino, preferably acetylamino. "C1-C6 alkanoylamino group" in the definitions of Substituent group β and Substituent group δ is, for example, acetamide, propionamide, butyroamide, valeroamide or pivaloamide. "C1-C14 alkanoylamino group" in the definition of Substituent group e is, for example, the aforementioned "C1-C6 alkanoylamino group", octanoylamino, decanoylamino, dodecanoylamino or tetradecanoylamino. "C1-C10 alkoxy-carboxamide group" in the definition of Substituent group β is, for example, methoxycarboxamide, ethoxycarboxamide or tert-butoxycarboxamide. "Ureido group which may be substituted with a C1-C4 alkyl group or phenyl group" in the definition of Substituent group β is, for example, an ureido group which may be substituted with 1 to 3 (preferably 1 or 2) substituents selected from C1-C4 alkyl groups such as a methyl group, ethyl group and the like, and a phenyl group, and it is for example, ureido, 1-methylureido, 3- methylureido, 3,3-dimethylureido, 1,3-dimethylureido or 3- phenylureido. "C6-C10 aryl-carbonylamino group" in the definition of Substituent group γ is, for example, benzamide, naphthoamide or phthalimide. "C6-C10 aryloxy-carboxamide group" in the definition of Substituent group y is, for example, phenoxycarboxamide. "C7-C19 aralkyloxy-carboxamide group" in the definition of Substituent group y is, for example, benzyloxycarboxamide or benzhydryloxycarboxamide. "C3-C10 cycloalkyloxy-carbonyloxy group" in the definition of Substituent group γ is, for example, opropyloxycarbonyloxy or cyclohexyloxycarbonyloxy. "C6-C10 aryloxy-carbonyloxy group" in the definition of Substituent group γ is, for example, phenoxycarbonyloxy or naphthyloxycarbonyloxy. "C7-C19 aralkyloxy-carbonyloxy group" in the definition of Substituent group γ is, for example, benzyloxycarbonyloxy, 1- phenylethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy or benzhydryloxycarbonyloxy. "Heterocyclyl group" in the definition of Substituent group y; and "heterocyclyl group" of "heterocyclyloxy group", "heterocyclylthio group", "heterocyclylsulfinyl group", "heterocyclylsulfonyl group" and "heterocyclyloxycarbonyl group" represent a 5- to 8-membered ring (preferably 5- or 6-membered ring) group or a fused ring group thereof, which contains 1 to several (preferably 1 to 4) hetero atoms such as nitrogen atoms (may be oxidized), oxygen atoms and sulfur atoms. Examples of such "heterocyclyl group" are pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, pyranyl, thiopyranyl, dioxynyl, dioxolyl, quinolyl, pyrido[2,3-d]pyrimidyl, 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthylidyl group, thieno[2,3-d]pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl and dioxanyl. These heterocyclyl groups may be substituted at substitutable positions with 1 to 3 substituents selected from C1-C4 alkyl groups such as methyl, ethyl and the like, a hydroxy group, an oxo group and C1-C4 alkoxy groups such as methoxy, ethoxy and the like. "C1-C6 alkyl-carbamoyl group" in the definition of Substituent group δ is, for example, methylcarbamoyl, dimethylcarbamoyl or propylcarbamoyl. "C1-C14 alkyl-carbamoyl group" in the definition of Substituent group a is, for example, the aforementioned "C1-C6 alkyl-carbamoyl group", octylcarbamoyl, decylcarbamoyl, dodecylcarbamoyl or tetradecylcarbamoyl, preferably a C1-C10 alkyl-carbamoyl group, and more preferably a C4-C8 alkyl- carbamoyl group. "C1-C6 alkoxy-carbonyl C1-C6 alkyl-carbamoyl group" in the definition of Substituent group δ is, for example, butoxycarbonylmethylcarbamoyl or ethoxycarbonylmethylcarbamoyl. "C1-C14 alkoxy-carbonyl C1-C14 alkyl-carbamoyl group" in the definition of Substituent group Ε is, for example, the aforementioned "C1-C6 alkoxy-carbonyl C1-C6 alkyl-carbamoyl group" or octyloxycarbonylmethylcarbamoyl, preferably a C1-C10 alkoxy-carbonyl C1-C10 alkyl-carbamoyl group, and more preferably a C4-C8 alkoxy-carbonyl C4-C8 alkyl-carbamoyl group. "1,3-diacylguanidino C1-C6 alkyl group" in the definition of Substituent group δ is, for example, 1,3- diacetylguanidinomethyl or 1,3-bis-tert- butoxycarbonylguanidinomethyl. "1,3-diacylguanidino C1-C14 alkyl group" in the definition of Substituent group a is, for example, the aforementioned "1,3- diacylguanidino C1-C6 alkyl group", 1,3-diacetylguanidinooctyl or 1,3-bis-tert-butoxycarbonylguanidinooctyl, preferably a 1,3- diacylguanidino C1-C10 alkyl group, and more preferably a 1,3- diacylguanidino C4-C8 alkyl group. X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, respectively represent a hydrogen atom, or X and Y together represent a substituent of ring B (the substituent is an oxo group or a thioxo group), and preferably represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, or respectively represent a hydrogen atom. In a preferred example, in the case where X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, ring A is a 3- to 7-membered heterocyclyl ring or 3- to 7-membered saturated cycloalkyl ring. With respect to the heterocyclyl ring, X and Y included in the ring, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom, a C1-Cs alkyl group which may be substituted with a group aelected from Substituent group a, a C2-C6 alkenyl group which may be substituted with a group selected from Substituent group α, a C2-C6 alkynyl group which may be substituted with a group aelected from Substituent group a or a C1-C6 alkanoyl group which may be substituted with a group aelected from Substituent group α), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO2, may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atom) or 5- or 6-membered cycloalkyl ring, either ring of the heterocyclyl ring, or the fused ring which is fused to the heterocyclyl ring or the spiro ring which is spiro bound to the heterocyclyl ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group a, a cyclopropyl C1-C6 alkyl group and a C1-C6 alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α. The 3- to 7-membered saturated cycloalkyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxy group, a hydroxymethyl group, a 1,2- dihydroxyethyl group, a 1,2,3 -trihydroxypropyl group, a 1,2,3,4- tetrahydroxybutyl group and an acetylamino group. Ring A is, more preferably, a 3- to 7-membered heterocyclyl ring or 3- to 5-membered cycloalkyl ring. With respect to the heterocyclyl ring which is a more preferred example of ring A, X and Y included in the ring, independently from each other, represent any one selected from a carbon atom, an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO2, may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atom) or 5- or 6-membered cycloalkyl ring, and either ring of the heterocyclyl ring, or the fused ring which is fused to the heterocyclyl ring or the spiro ring which is spiro bound to the heterocyclyl ring, may be substituted with the same or different 1 to 4 groups selected from an oxo group, a thioxo group, Substituent group a and a C1-C6 alkyl group which may be substituted with 1 to 4 groups selected from Substituent group α. The 3- to 5-membered cycloalkyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3- trihydroxypropyl group, a 1,2,3,4-tetrahydroxybutyl group and an acetylamino group. Ring A is, more preferably, the heterocyclyl ring or the undermentioned cyclopropyl or cyclopentyl ring described below. Examples of such heterocyclyl ring are, oxirane, tetrahydrofuran, tetrahydropyrane, 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3-dithiane, 1,1,3,3-tetraoxo-1,3-dithiolane, 1,3-oxathiolane, 1,3-oxathiane or 1,3-oxathiepane, these heterocyclyl rings may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring is tetrahydrofuran, tetrahydropyrane, pyrrolidine, piperidine or 1,3-dioxane) or cyclohexyl ring, either ring of the heterocyclyl ring, or the fused ring which is fused to the heterocyclyl ring or the spiro ring which is spiro bound to the heterocyclyl ring, may be substituted with 1 or 2 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group a (Substituent group α represents a hydroxy group and a group having the formula NR6R7, and R6 and R7, independently from each other, represent a hydrogen atom or a C1-C6 alkanoyl group), a methyl group, an ethyl group and a C1-C6 alkyl group which is substituted with 1 to 4 hydroxy groups. In addition, the cyclopropyl or cyclopentyl ring is a cyclopropyl or cyclopentyl ring which may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3- trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group. Ring A is, further preferably for example, oxirane, tetrahydrofuran, 1,3-dioxolane, 1,3-dioxane, 1,3- dithiolane, 1,3-dithiane, 1,3-oxathiolane or 1,3-oxathiane, these heterocyclyl rings may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring is tetrahydrofuran, tetrahydropyrane or 1,3-dioxane) or cyclohexyl ring, and either ring of the heterocyclyl ring, or the fused ring which is fused to the heterocyclyl ring or the spiro ring which is spiro bound to the heterocyclyl ring, may be substituted with 1 or 2 groups selected from the group consisting of Substituent group a [Substituent group a represents a hydroxy group and a group having the formula NR6R7 (R6 and R7, independently from each other, represent a hydrogen atom or acetyl group)], a methyl group, an ethyl group, a hydroxymethyl group, a 1,2- dihydroxyethyl group, a 1,2,3-trihydroxypropyl group and a 1, 2, 3,4-tetrahydroxybutyl group. Ring A is, particularly preferably, oxirane, 1,3-dioxolane, 1,3-dioxane or 1,3-oxathiolane, these heterocyclyl rings may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring is tetrahydrofuran, tetrahydropyrane or 1, 3-dioxane) or cyclohexyl ring, and either ring of the heterocyclyl ring, or the fused ring which is fused to the heterocyclyl ring or the spiro ring which is spiro bound to the heterocyclyl ring may be substituted with 1 or 2 groups selected from the group consisting of Substituent group a [Substituent group a represents a hydroxy group and a group having the formula NR6R7 (R6 and R7, independently from each other, represent a hydrogen atom or acetyl group)], a methyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group. Preferred specific examples of ring A are, cyclopropyl, 1-hydroxymethylcyclopropyl, 1,2-dihydroxymethyl cyclopropyl, cyclopentyl, 2-hydroxymethylcyclopentyl, 2,3- dihydroxymethylcyclopentyl, 2,3-bis(1,2- dihydroxyethyl)cyclopentyl, 2-(1,2-dihydroxyethyl)cyclopentyl, 2 -(1,2,3 -trihydroxypropyl)cyclopentyl, 2- (1,2,3,4- tetrahydroxybutyl)cyclopentyl, oxirane, tetrahydrofuran, tetrahydropyrane, 1,3-dioxolane, 1,3- dioxane, 1,3-oxathiolane, 4-hydroxymethyl-1,3-dioxolane, 4,5- dihydroxymethyl-1,3-dioxolane, 4,5-bis(1,2-dihydroxyethyl)-1,3- dioxolane, 4-(1,2-dihydroxyethyl)-1,3-dioxolane, 4-(1,2,3- trihydroxypropyl)-1,3-dioxolane, 4-(1,2,3,4-tetrahydroxybutyl)- 1,3-dioxolane, 4,5-diacetylaminomethyl-1,3-dioxolane, 5-hydroxy -1,3-dioxane, 5,5-dihydroxymethyl-1,3-dioxane, 5-acetylamino- 1,3-dioxane, 5,5-diethoxycarbonyl-1,3-dioxane and 2,4,7,9- tetraoxaspiro[5.5]undecane, more preferred specific examples are, 4-hydroxymethyl-1,3- dioxolane, 4,5-dihydroxymethyl-1,3-dioxolane, 4,5-bis(1,2- dihydroxyethyl)-1,3-dioxolane, 4-(1,2-dihydroxyethyl)-1,3- dioxolane, 4-(1,2,3-trihydroxypropyl)-1,3-dioxolane, 4-(1,2,3,4- tetrahydroxybutyl)-1,3-dioxolane, 4,5-diacetylaminomethyl-1,3- dioxolane, 5-hydroxy-1,3-dioxane, 5-acetylamino-1,3-dioxane and 5,5-dihydroxymethyl-1,3-dioxane. Ring B is a 5- to 7-membered cycloalkene group. Here, 1 and m, which are parameters to determine the number of members of ring B, independently from each other, are an integer of 0 to 3, and 1+m is 1 to 3 . The 1+m being 1 to 3 represents that ring B is 5- to 7-membered. Preferably, 1 is 0, and m is an integer of 1 to 3. More preferably, it is a cyclohexynyl group in which 1 is 0, and m is 1. Among the groups defined as R1, preferred is a hydroxy group, halogen atom, C1-Cg alkyl group or C1-C6 alkoxy group, more preferred is a hydroxy group, fluorine atom, chlorine atom, methyl group, ethyl group, propyl group, methoxy group or ethoxy group, further preferred is a fluorine atom or methyl group. The number of substitutions n, which is the number of R1 that are substituted to ring B, is 0 to 3, preferably 0 or 1. More preferably, n is 0. Among the groups defined as R2, preferred is a C1-C6 alkyl group which may be substituted with a group aelected from Substituent group β, more preferred is a C1-C6 alkyl group, further preferred is a C1-C4 alkyl group, and particularly preferred is an ethyl group. Among the groups defined as R3, "5- or 6-membered heteroaryl group" of "5- or 6-membered heteroaryl group which may be substituted with a group aelected from Substituent group ε" is particularly preferably a pyrrolyl group. That is, preferably R3 is a phenyl or pyrrolyl group which may be substituted with a group aelected from Substituent group e. Preferably, it is a phenyl or pyrrolyl group which may be substituted with a group aelected from a halogen atom, C1-C14 alkyl group and halogeno C1-C14 alkyl group, more preferably a phenyl or pyrrolyl group which may be substituted with a group aelected from a fluorine atom, chlorine atom, C1-C10 alkyl group, halogeno C1-C10 alkyl group and cyclopropyl C1-Ci0 alkyl group, even more preferably a phenyl or pyrrolyl group which may be substituted with a group aelected from a fluorine atom, chlorine atom, bromine atom, C3-C8 alkyl group and halogeno C4-C8 alkyl group, and further preferably a phenyl group which may be substituted with a group aelected from a fluorine atom, chlorine atom and C3-C8 alkyl group. In addition, in the case where it is substituted by a substituent, the position of substitution is preferably the 2- position or 4-position. R3 is, for example, a phenyl group, halogenophenyl group, C1-C14 alkylphenyl group, cyclopropyl C1-C14 alkylphenyl group, C1-C14 alkoxyphenyl group, C3-C14 alkoxycarbonyphenyl group, carboxylphenyl group, nitrophenyl group, cyanophenyl group, halogeno C1-C14 alkylphenyl group, halogeno C1-C14 alkoxyphenyl group, C1-C14 alkanoylphenyl group, phenyl group which is substituted with a 5-mettibered heteroaryl group, C1-C14 alkoxy-carbonyl-C1-C14 alkyl- carbamoylphenyl group, 1,3-diacylguanidino-C1-C14 alkylphenyl group, phenyl group which is substituted with a halogen and C1- C14 alkyl, phenyl group which is substituted with a halogen and C1-C14 alkoxycarbonyl, phenyl group which is substituted with a halogen and cyano, phenyl group which is substituted with a halogen and a 5-membered heteroaryl group, phenyl group which is substituted with a halogen and C1-C14 alkoxy-carbonyl-C1-C14 alkyl-carbamoyl, pyrrolyl group, halogenopyrrolyl group, C1-C14 alkylpyrrolyl group, cyclopropyl C1-C14 alkylpyrrolyl group, C1-C14 alkoxypyrrolyl group, C1-C14 alkoxycarbonylpyrrolyl group, carboxylpyrrolyl group, nitropyrrolyl group, cyanopyrrolyl group, halogeno C1-C14 alkylpyrrolyl group, halogeno C1-C14 alkoxypyrrolyl group, C1-C14 alkanoylpyrrolyl group, pyrrolyl group which is substituted with a 5-membered heteroaryl group, C1-C14 alkoxy-carbonyl-C1-C14 alkyl-carbamoylpyrrolyl group, 1,3- diacylguanidino-C1-C14 alkylpyrrolyl group, pyrrolyl group which is substituted with a halogen and C1-C14 alkyl, pyrrolyl group which is substituted with a halogen and C1-C14 alkoxycarbonyl, pyrrolyl group which is substituted with a halogen and cyano, pyrrolyl group which is substituted with a halogen and a 5- membered heteroaryl group, pyrrolyl group which is substituted with a halogen and C1-C14 alkoxy-carbonyl-C1-C14 alkyl-carbamoyl, or the like. Among them, specific examples are preferably, phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- iodophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4- chlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4- difluorophenyl, 2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5- dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,4- difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl, 3,5- dichlorophenyl, 2,4-dibromophenyl, 2,6-dibromophenyl, 4-chloro- 2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl, 2-bromo-4-fluorophenyl, 3-chloro-4-fluorophenyl, 2-bromo-4- chlorophenyl, 5-chloro-2-fluorophenyl, 4-bromo-2-chlorophenyl, 2-chloro-6-fluorophenyl, 2,4-dimethoxyphenyl, 2,3,4- trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-4,6-difluorophenyl, 2,6-dichloro-4-fluorophenyl, 2- bromo-6-chloro-4-fluorophenyl, 2-methylphenyl, 2-ethylphenyl, 2- (n-propyl)phenyl, 2-(n-butyl)phenyl, 2-(n-pentyl)phenyl, 2-(n- hexyl)phenyl, 2-(n-heptyl)phenyl, 2-(n-octyl)phenyl, 2-(n- nonyl)phenyl, 2-(n-decyl)phenyl, 2-(n-undecyl)phenyl, 2-(n- dodecyl)phenyl, 2-(n-tridecyl)phenyl, 2-(n-tetradecyl)phenyl, 2- ethynylphenyl, 2-isopropylphenyl, 2-t-butylphenyl, 2-sec- butylphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-difluoromethoxyphenyl, 2- methylsulfanylphenyl, 2-acetylphenyl, 2-benzylphenyl, 2- (morpholin-4-yl)phenyl, 2-[2-(pyridine-4-yl)ethyl]phenyl, 2-[2- (t-butoxycarbonyamino)ethyl]phenyl, 2-aminophenyl, 2,6- diisopropylphenyl, 2-chloro-4-methylphenyl, 4-fluoro-3- trifluoromethylphenyl, 4-fluoro-3-methoxyphenyl, 4-chloro-2- methoxycarbonylphenyl, 2-fluoro-4-methoxyphenyl, 4-chloro-2- methylphenyl, 2-fluoro-4-methylphenyl, 2-fluoro-5-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-6-methylphenyl, 4-t-butyl-2- chlorophenyl, 2-bromo-4-isopropylphenyl, 4-chloro-2-methoxy-5- methylphenyl, 4-fluoro-2-methylphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(n-propyl)phenyl, 2-(n-butyl)-4-fluorophenyl, 4- fluoro-2-(n-pentyl)phenyl, 4-fluoro-2-(n-hexyl)phenyl, 4-fluoro- 2-(n-heptyl)phenyl, 4-fluoro-2-(n-octyl)phenyl, 4-fluoro-2-(n- nonyl)phenyl, 2-(n-decyl)-4-fluorophenyl, 4-fluoro-2-(n- undecyl)phenyl, 2-(n-dodecyl)-4-fluorophenyl, 4-fluoro-2-(n- tridecyl)phenyl, 4-fluoro-2-(n-tetradecyl)phenyl, 2- trifluoromethylphenyl, 2-(2,2,2-trifluoroethyl)phenyl, 2- (3,3,3- trifluoropropyl)phenyl, 2-(4,4,4-trifluorobutyl)phenyl, 2- (5,5,5-trifluoropentyl)phenyl, 2-(6,6,6-trifluorohexyl)phenyl, 2-(7,7,7-trifluoroheptyl)phenyl, 2-(8,8,8-trifluorooctyl)phenyl, 2-(9,9,9-trifluorononyl)phenyl, 2- (10,10,10- trifluorodecyl)phenyl, 2-cyclopropylethylphenyl, 2-[3- cyclopropyl-(n-propyl)]phenyl, 2-[4-cyclopropyl-(n- butyl)]phenyl, 2-[5-cyclopropyl-(n-pentyl)]phenyl, 2-[6- cyclopropyl-(n-hexyl)]phenyl, 2-[7-cyclopropyl-(n- heptyl)]phenyl, 2-[8-cyclopropyl-(n-octyl)]phenyl, pyrrolyl, 2- fluoropyrrolyl, 2-chloropyrrolyl, 2-bromopyrrolyl, 2,5- difluoropyrrolyl, 2,5-dichloropyrrolyl, 2,5-dibromopyrrolyl, 2- chloro-5-fluoropyrrolyl, 2-methylpyrrolyl, 2-ethylpyrrolyl, 2- (n-propyl)pyrrolyl, 2 -(n-butyl)pyrrolyl, 2 -(n-pentyl)pyrrolyl, 2-(n-hexyl)pyrrolyl, 2-(n-heptyl}pyrrolyl, 2-(n-octyl)pyrrolyl, 2-(n-nonyl)pyrrolyl and 2-(n-decyl)pyrrolyl, more preferably, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodo phenyl, 4- fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-chloro- 4-fluorophenyl, 2-bromo-4-fluorophenyl, 3 -chloro-4 -fluorophenyl, 2-bromo-4-chlorophenyl, 2,4-dimethoxyphenyl, 2-chloro-4,6-difluorophenyl, 2,6-dichloro-4-fluorophenyl, 2- bromo-6-chloro-4-fluorophenyl, 2-methylphenyl, 2-ethylphenyl, 2- (n-propyl)phenyl, 2-(n-butyl)phenyl, 2-(n-pentyl)phenyl, 2-(n- hexy1)phenyl, 2-(n-heptyl)phenyl, 2-(n-octyl)phenyl, 2-(n- nonyl)phenyl, 2-(n-decyl)phenyl, 2-ethynylphenyl, 2-sec-butylphenyl, 2-methoxyphenyl, 2- methylsulfanylphenyl, 2-benzylphenyl, 2-[2-(t- butoxycarbonylaraino)ethyl]phenyl, 4-chloro-2-methylphenyl, 2- fluoro-5-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-6- methylphenyl, 4-chloro-2-methoxy-5-methylphenyl, 4-fluoro-2- methylphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(n- propyl)phenyl, 2-(n-butyl)-4-fluorophenyl, 4-fluoro-2-(n- pentyl)phenyl, 4-fluoro-2-(n-hexyl)phenyl, 4-fluoro-2-(n- heptyl)phenyl, 4-fluoro-2-(n-octyl)phenyl, 4-fluoro-2-(n- nonyl)phenyl, 2-(n-decyl)-4-fluorophenyl, 2-(n-butyl)pyrrolyl, 2-(n-pentyl)pyrrolyl, 2-(n-hexyl)pyrrolyl, 2-(n-heptyl)pyrrolyl and 2-(n-octyl)pyrrolyl, and even more preferably, 2-chlorophenyl, 2-bromophenyl, 2,4-difluorophenyl, 2-chloro-4- fluorophenyl, 2-bromo-4-fluorophenyl, 2-(n-pentyl)phenyl, 2-(n- hexyl)phenyl, 2-(n-heptyl)phenyl, 2-chloro-6-methylphenyl, 4- fluoro-2-(n-propyl)phenyl, 2-(n-butyl)-4-fluorophenyl, 4-fluoro- 2-(n-pentyl)phenyl, 4-fluoro-2-(n-hexyl)phenyl, 4-fluoro-2-(n- heptyl)phenyl and 4-fluoro-2-(n-octyl)phenyl. With respect to the "pharmacologically acceptable salts thereof", since the compound having the general formula (I) of the present invention can be converted to a salt by reaction with an acid in the case where it has a basic group auch as an amino group, or by reaction with a base in the case where it has an acidic group auch as a carboxyl group, salts thereof are represented. Salts of a basic group are preferably inorganic acid salts such as hydrohalogenic acid salts including hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates, phosphates or the like; lower alkanesulfonic acid salts such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, arylsulfonic acid salts such as benzene, sulfonate and p- toluenesulfonate, organic acid salts such as acetate, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates, maleates or the like; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate, On the other hand, salts of an acidic group are preferably alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt; inorganic salts such as ammonium salt, amine salts including organic salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N- methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dieyelohexylamine salt, N,N'- dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt and tris(hydroxymethyl)aminomethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate. The compounds having the general formula (I) according to the present invention or pharmacologically acceptable salts thereof have an asymmetric carbon atom in their molecules, and thus stereoisomers of R configuration and S configuration exist. Each of them, or a compound with an arbitrary ratio of these, is also included in the present invention. With respect to such stereoisomers, the compound (I) can be synthesized by using an optically resolved starting compound, or a synthesized compound (I) can be optically resolved by ordinary optical resolution or separation methods if desired. There exist optical isomers with respect to the compound having the general formula (I) according to the present invention or pharmacologically acceptable salts thereof, and each of the optical isomers and mixtures of such isomers are also included in the present invention. When the compound having the general formula (I) and pharmacologically acceptable salts thereof are exposed to the atmosphere or are recrystallized, they may absorb moisture, resulting in cases such as the adhesion of adsorbed water and the generation of hydrates. Such hydrated compounds and salts are also included in the present invention. As representative compounds of the present invention, the compounds listed in the following Tables 1 to 3 can be mentioned for example, but the present invention is not limited to these compounds. Abbreviations and "ring 1" to "ring 18" in the tables are as follows. tz1 : tetrahydrothiazol-2-ylidene tzn :tetrahydro-1,3-thiazin-2-ylidene In the Tables, "di" indicates that there are two identical substituents, and "tri" indicates that there are three identical substituents. The binding position of rings 1 to 21 with ring B is the position indicated by a black dot, which is located at the right end of the aforementioned chemical structure. The substituents represented by the abbreviations as X can be mentioned, even more preferably, exemplified compound No. 1-206 : ethyl 8-[N-(2- chlorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-210: ethyl 8-[N-(2- chlorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-294: ethyl 8-[N-(2,4- difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro [4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-298: ethyl 8-[N-(2,4- difluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-378: ethyl 8-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-2-hydroxymethyl-l,4-dioxaspiro[4.5]dec- 6 -ene-7 -carboxy1ate, exemplified compound No. 1-382: ethyl 8-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-386: ethyl 8-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-3 90: ethyl 8-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-2-(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-394: ethyl 8-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-2-(1,2,3-trihydroxypropyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-398: ethyl 8-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-2-(1,2,3,4-tetrahydroxybutyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-410: ethyl 2,3- bis (acetylaminomethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]- 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-418: ethyl 9-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-3-hydroxy-1,5-dioxaspiro[5.5]undec-7- ene-8 -carboxylat e, exemplified compound No. 1-422: ethyl 3-acetylamino-9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7- ene- 8 -carboxylate, exemplified compound No. 1-430: ethyl 9-[N-(2-chloro-4- fluorophenyl)sulfamoyl]-3,3-bis(hydroxymethyl)-1,5- dioxaspiro[5.5]undec-7-ene-8-carboxylate, exemplified compound No. 1-646: ethyl 8-[N-(2-butyl-4- fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-650: ethyl 8-[N-(2-butyl-4- fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-734: ethyl 8-[N-(2- hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-738: ethyl 8-[N-(2-hexyl phenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-822: ethyl 8-[N-(4-fluoro-2- hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-826: ethyl 2,3-bis (1,2- dihydroxyethyl)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-910: ethyl 8-[N-(2- heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-914: ethyl 8-[N-(2- heptylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-998: ethyl 8-[N-(4-fluoro-2- heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1002: ethyl 2,3-bis (1,2- dihydroxyethyl)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1392: ethyl 8-[N-(2- bromophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1396: ethyl 8-[N-(2- bromophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1480: ethyl 8-[N-(2-chloro-6- methylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1484: ethyl 8-[N-(2-chloro-6- methylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1568: ethyl 8-[N-(2-bromo-4- fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1572: ethyl 8-[N-(2-bromo-4- fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1656: ethyl 2,3- bis (hydroxymethyl) -8-[N-(2-pentylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1660: ethyl 2,3-bis(1,2- dihydroxyethyl)-8-[N-(2-pentylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1744: ethyl 8-[N-(4-fluoro-2- pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1748: ethyl 2,3-bis(1,2- dihydroxyethyl)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1920: ethyl 8-[N-(4-fluoro-2- octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-1924: ethyl 2,3-bis(1,2- dihydroxyethyl)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-2095: ethyl 8-[N-(4-fluoro-2- propylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, exemplified compound No. 1-2099: ethyl 2,3-bis(1,2- dihydroxyethyl)-8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate and exemplified compound No. 2-15: ethyl 8-[N-(2-chloro-4- fluorophenyl)-N-methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro [4.5]dec-6-ene-7-carboxylate can be mentioned. The compound having the general formula (I) according to the present invention can easily be prepared in accordance with Method A to Method C shown hereafter. Method A is a method to prepare a compound having the general formula (I), by introducing a cyclic ketal in the initial stage of the preparation. Method B is a method to prepare a compound having the general formula (I), by introducing a cyclic ketal in the final stage of the preparation. Method C is a method to prepare a compound having the general formula (I) , by introducing R5 in the final stage of the preparation. In the aforementioned Method A to Method C, ring A, ring B, X, Y, R1, R2, R3, R5, m and n have the same meanings as defined above, L represents a leaving group and Z represents a protective group. In the reactions of Method A to Method C, in the case where the compound as the reactive substrate has a group auch as an amino group, hydroxy group and/or carboxyl group, which inhibits the intended reaction, these groups may be protected with a protective group as necessary. The protective group of a group which inhibits the intended reaction is not limited so long as it is a protective group which is ordinarily used to conduct the reaction, and may be, for example, a protective group described in "Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene & P. G. M. Wuts; John Wiley & Sons, Inc." A protective group of an amino group can be used without particular limitation so long as it is a group generally used as a protective group of an amino group, and preferably, formyl, the aforementioned Cx-Cg alkylcarbonyl group; the aforementioned arylcarbonyl group; the aforementioned C1-C6 alkoxycarbonyl group; the aforementioned C3-C6 alkanoyl group which is substituted with halogen; aralkyl groups such as benzyl, phenethyl, 3 -phenylpropyl, 4-phenylbuty 1, a-naphthylmethyl, β- naphthylmethyl, diphenylmethyl, triphenylmethyl, a- naphthyldiphenylmethyl or 9-anthrylmethyl; the aforementioned aralkyloxycarbonyl group and the like can be mentioned. A protective group of a hydroxy group can be used without particular limitation so long as it is a group generally used as a protective group of a hydroxy group, and preferably, formyl, C1-C6 alkylcarbonyl groups such as acetyl, arylcarbonyls such as benzoyl group; and alkoxylated alkoxymethyls such as 2- methoxyethoxymethyl can be mentioned. A protective group of a carboxyl group can be used without particular limitation so long as it is a group generally used as a protective group of a carboxyl group, and preferably, the aforementioned C1-C6 alkyl group; and aralkyl groups such as benzyl, phenethyl and phenylpropyl can be mentioned. Further, these protective groups of groups which inhibit the intended reaction may be cleaved as necessary. The cleavage reaction of these protective groups, which is the desired reaction, may be conducted in accordance with conventional procedures which are used in the field of synthetic organic chemistry (for example, the procedure described in the aforementioned Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene & P. G. M. Wuts; John Wiley & Sons, Inc). Step 1 of Method A is a step to react a ketone compound (1) with a compound (2) or a compound (3), which is compound (2) having its terminal substituted with a trimethylsilyl group (described as TMS in the aforementioned scheme), in an inert solvent in the presence of acid, to prepare a cyclic ketal compound (4). This step can adopt a cyclic ketalation reaction (protection) of a ketone, which is widely used in general organic synthesis, and can be conducted in accordance with the procedure described in T. W. Greene, P. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, Chapter 4, pp. 293-368, John Wiley & Sons, Inc. and the like, or in accordance with similar procedures. Here, the cyclic ketal compound (4) can also be prepared by the following procedure (Step 1' of Method A). Step 1' of Method A is a step to react a dimethylketal compound (5) with compound (2) or compound (3), in an inert solvent in the presence of acid, to prepare a cyclic ketal compound (4). This reaction can be conducted in accordance with the same procedure as or based on the procedure of Step 1. Step 2 of Method A is a step to allow the cyclic ketal compound (4) obtained by Step 1 or Step 1' to undergo a Dieckmann reaction, to prepare a ketoester compound (7). This step can adopt a Dieckmann reaction which is widely used generally in organic synthesis, and can be conducted in accordance with the procedure described in Chemical Pharmaceutical Bulletin (Chem. Pharm. Bull.) Vol. 29, pp. 3238- 3248 (1981) and the like, or based on that procedure. Here, the ketoester compound (7) can also be prepared by the following procedure (Step 2' of Method A). Step 2' of Method A is a step to react a ketone compound (6) with a dialkyl carbonate, in an inert solvent in the presence of base, to prepare a ketoester compound (7). This step can adopt an ester group introducing reaction which is widely used generally in organic synthesis, and can be conducted in accordance with the procedure described in Canadian Journal of Chemistry (Can. J. Chem.) Vol. 70, pp. 1406-1426 (1992) and the like, or based on that procedure. Step 3 of Method A is a step to enolate the ketoester compound (7) obtained in Step 2 or Step 2', in an inert solvent in the presence of base, to prepare a compound (8) having a leaving group L. This step can be conducted in accordance with the procedure described in Journal of American Chemical Society (J. Am. Chem. Soc), Vol. 120, pp. 3664-3670 (1998) and the like, or based on that procedure. "Leaving group" in the definition of L generally represents a group which leaves as a nucleophilic residue, and for example, halogen atoms such as a fluorine atom, chlorine atom, bromine atom and iodine atom; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; and arylsulfonyloxy groups such as benzenesulfonyloxy, p- toluenesulfonyloxy and p-nitrobenzenesulfonyloxy can be mentioned. Preferably, it is a halogeno lower alkanesulfonyloxy group, particularly preferably a trifluoromethanesulfonyloxy group. The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene,- ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; amides such as formamide, N, N- dimethylformamide, N,W-dimethylacetamide, N-methyl-2- pyrrolidinone and hexamethylphosphorotriamide; or a solvent mixture of these can be mentioned. Preferably, it is a halogenated hydrocarbon, more preferably dichloromethane. The base used includes inorganic bases such as alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal fluorides such as sodium fluoride and potassium fluoride; organic bases such as alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; N- methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, W-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N- dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), preferably alkali metal hydrides or organic bases, and more preferably sodium hydride or diisopropylethylamine. Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from -100°C to 100°C, preferably from -78°C to 50°C. Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally in the range from 1 minute to 48 hours, preferably from 5 minutes to 12 hours. Step 4 of Method A is a step to react the compound (8) having a leaving group L obtained in Step 3 with a thiol compound (9) in an inert solvent in the presence of a base, to prepare compound (10). "Protective group" of the sulfanyl group in the definition of Z is not particularly limited so long as it is a protective group of a sulfanyl group which is widely used generally in organic synthesis, and alkanoyl groups such as formyl, acetyl, propionyl and butyryl, and arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, pyridoyl, thienoyl and furoyl can be mentioned, for example. Preferably, it is a group which forms a pharmacologically acceptable ester, and is more preferably an acetyl group. The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; aprotic polar solvents such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; or a solvent mixture of these can be mentioned. Preferably, it is an aprotic polar solvent, more preferably N, N-dimethylformamide. The base used includes inorganic bases such as alkali metal carbonates, e.g. sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal fluorides such as sodium fluoride and potassium fluoride; organic bases such as alkali metal alkoxides, e.g. sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; N- methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, W-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-[N,N- dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) can be mentioned, and is preferably an alkali metal hydride, more preferably sodium hydride or potassium hydride. Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from -78°C to 100°C, preferably from -20°C to 50°C. Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally in the range from 1 minute to 120 hours, preferably from 10 minutes to 72 hours. Step 5 of Method A is a step to deprotect the protective group of the sulfanyl group of the compound (10) obtained in Step 4, in an inert solvent, to prepare compound (11). This step is a deprotection step of a protective group of a sulfanyl group which is widely used in general organic synthesis, and is conducted in accordance with the procedure described in the aforementioned "Protective Groups in Organic Synthesis, 3rd edition, T. W. Greene & P. G. M. Wuts; John wiley & Sons, Inc." and the like, or based on that procedure, and can be preferably conducted by a deprotection procedure in an inert solvent in the presence of base. The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t- butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and 2-methoxyethanol; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, W-methyl-2- pyrrolidinone and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; or a solvent mixture of these can be mentioned, and is preferably an alcohol, and more preferably methanol or ethanol. The base used includes alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate and lithium hydrogencarbonate; organic bases such as alkali metal alkoxides, e.g. sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N- methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (W,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), preferably alkali metal carbonates, and more preferably potassium carbonate. Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from -78°C to 100°C, preferably from -20°C to 50°C. Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally from 1 minute to 24 hours, preferably from 5 minutes to 5 hours. Step 6 of Method A is a step to chlorosulfonylate the thiol group of the compound (11) obtained in Step 5, in an inert solvent, to prepare compound (12). This step can be conducted in accordance with the procedure described in Journal of Organic Chemistry (J. Org. Chem.), Vol. 16, pp. 621-625 (1951) and the like, or based on that procedure. The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane' ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, ji-butanol, isobutanol, t- butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and 2-methoxyethanol; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; carboxylic acids such as formic acid, acetic acid, propionic acid and trifluoroacetic acid; water; or a solvent mixture of these can be mentioned. Preferably, it is a solvent mixture of carboxylic acids and water or a solvent mixture of nitriles and water, more preferably a solvent mixture of acetic acid and water, or a solvent mixture of acetonitrile and water. Reaction temperature varies according to the starting compound and reaction reagent, and the reaction is conducted from -78°C to 100°C, preferably from -20°C to 50°C. Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally from 1 minute to 12 hours, preferably from 5 minutes to 1 hour. Step 7 of Method A is a step to react the compound (12) obtained in Step 6 with an amine compound (13) in an inert solvent in the presence or absence of base, to prepare a compound of general formula (I). The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycoldimethyl ether; aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; or a solvent mixture of these can be FP0628s P96425/acf/translation of PCT spec 25/02/08 mentioned. Preferably, it is an ester, more preferably ethyl acetate. The base used includes alkali metal hydrates such as lithium hydrate, sodium hydrate and potassium hydrate; organic bases such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N- methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N, W-dimethylaniline, N, N-diethylaniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), preferably organic bases, and more preferably triethylamine. Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from -78°C to 100°C, preferably from -20°C to 50°C. Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally in the range from 1 minute to 120 hours, preferably from 10 minutes to 48 hours. Step 8 of Method B is a step to hydrolyze the cyclic ketal compound (14) obtained in Method A in an inert solvent in the presence of acid, to prepare a ketone compound (15). This step can adopt a deprotection reaction of a cyclic ketal compound which is widely used generally in organic synthesis, and can be conducted in accordance with the procedure described in the aforementioned T. W. Greene, O. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, Chapter 4, pp. 293-3 68, John Wiley & Sons, Inc. and the like, or based on that procedure. Step 9 of Method B is a step to prepare a dimethylketal compound (16) with the ketone compound (15) obtained in Step 8 in an inert solvent in the presence of acid. This step can adopt a dimethylketalation reaction (protection) of a ketone which is widely used generally in organic synthesis, and can be conducted in accordance with the procedure described in the aforementioned T. W. Greene, 0. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, Chapter 4, pp. 293-368, John Wiley & Sons, Inc. and the like, or based on that procedure. Step 10 of Method B is a step to react the ketone compound (15) obtained in Step 8 with the compound (2) or compound (3) in an inert solvent in the presence of acid, to prepare a compound having the general formula (I). Here, this reaction can be conducted in accordance with a similar procedure to Step 1. Step 10' of Method B is a step to react the dimethylketal compound (16) obtained in Step 9 with the compound (2) or compound (3) in an inert solvent in the presence of acid, to prepare a compound having the general formula (I). Here, this reaction can be conducted in accordance with a similar procedure to Step 1'. Step 11 of Method C is a step, in the case where Rs of the cyclic ketal compound (14) obtained in Method A or the compound having the general formula (I) obtained in Method B is a hydrogen atom, to react it with R5-L (17) in an inert solvent in the presence of base, to prepare a compound having the general formula (I) which is substituted with a desired R5. R5 and L represent the same meanings as described above, and "leaving group" in the definition of L represents a group which leaves as a nucleophilic residue, and for example, halogen atoms such as a fluorine atom, chlorine atom, bromine atom and iodine atom; lower-alkane sulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy and p- nitrobenzenesulfonyloxy; can be mentioned. Preferably, it is a halogen atom, particularly preferably an iodine atom. The inert solvent used is not particularly limited so long as it does not inhibit the reaction and dissolves the starting material to some degree, and includes, for example, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar solvents such as dimethylformamide, dimethylacetamide and dimethyl sulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as pentane, hexane and heptane, preferably, ethers, ketones or aprotic polar solvents, and more preferably, tetrahydrofuran, acetone or dimethylformamide. The base used includes alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; organic bases such as alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; W-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N- methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,AT-diethylaniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), preferably alkali metal carbonates, and more preferably potassium carbonate. Reaction temperature varies depending on the starting compound and reaction reagent, and the reaction is conducted from -78°C to 150°C, preferably from -20°C to 100°C. Reaction time varies depending on the reaction temperature, starting compound, reaction reagent or the type of solvent used, and it is generally in the range from 1 minute to 24 hours, preferably from 10 minutes to 5 hours. After each of the aforementioned reactions is completed, the desired compound is collected from the reaction mixture in accordance with general procedures. For example, the reaction mixture is neutralized as needed, and after filtration to remove insoluble matters in the case where insoluble matters exist, the reaction solution is extracted with an organic solvent such as ethyl acetate, which does not blend with water. Then after washing the reaction solution with water and the like, the organic layer containing the desired compound is separated and dried over anhydrous magnesium sulfate and the like, and then the solvent is evaporated to give the desired compound. The obtained desired compound may, if necessary, be separated and purified by ordinary procedures such as recrystallization and reprecipitation, or by a procedure generally used for separation and purification of organic compounds such as appropriately combining an adsorption column chromatography method which uses silica gel, alumina or florisil of magnesium-silica type as a support; a method using a synthetic adsorbent agent such as distribution column chromatography which uses Sephadex LH-2 0 (produced by Pharmacia), Amberlite XAD-11 (produced by Rohm and Haas) or Diaion HP-20 (produced by Mitsubishi Chemical Corporation) as a support, a method using ion exchange chromatography, or normal phase or reverse phase column chromatography by silica gel or alkylated silica gel (preferably high performance liquid chromatography) and eluting with an appropriate eluent. The starting compounds such as (1), (2), (3), (5), (6), (9), (13) and (17) as reactive substances of the present invention are publicly known or can easily be prepared in accordance with publicly known procedures. The compound having the general formula (I) according to the present invention or pharmacologically acceptable salts thereof possesses excellent activity to suppress intracellular signal transduction or cell activation in various cells such as monocytes, macrophages and vascular endothelial cells, the intracellular signal transduction and cell activation being induced by endotoxin, and to suppress various cell responses induced by the intracellular signal transduction and cell activation such as an excess generation of inflammatory mediators such as TNF-α. Therefore, it is useful as a medicament, especially as a prophylactic and/or therapeutic agent for various diseases which are associated with intracellular signal transduction or cell activation induced by endotoxin, and with various cell responses (for example, excess generation of inflammatory mediators such as TNF-α) which are induced by the intracellular signal transduction and cell activation. As for such medicament, a prophylactic and/or therapeutic agent for ischemic brain disorder, arteriosclerosis, poor prognosis after coronary angioplasty, heart failure, diabetes, diabetic complication, joint inflammation, osteoporosis, osteopenia, sepsis, autoimmune disease, tissue disorder and rejection after organ transplantation, bacterial infection, virus infection, gastritis, pancreatitis, nephritis, pneumonia, hepatitis or leukemia can be mentioned. In the case where the compound having the general formula (I) according to the present invention or the pharmacologically acceptable salts thereof is used as a prophylactic agent or a therapeutic agent for the aforementioned diseases, it can be mixed with excipients, diluents and the like that are themselves pharmacologically acceptable, and administered orally as a tablet, capsule, granules, powder or syrup, or administrated parenterally as an injection for subcutaneous injection, intramuscular injection or intravenous injection or as a suppository. These pharmaceutical preparations are prepared in accordance with known processes by using additives including excipients (for example, organic excipients such as sugar derivatives, e.g. lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives, e.g. corn starch, potato starch, a-starch or dextrin; cellulose derivatives, e.g. crystalline cellulose; gum arabic; dextrane; or pullulan, and inorganic excipients such as silicate derivatives, e.g. light silicic anhydride, synthetic aluminum silicate, calcium silicate, metamagnesium aluminate; phosphates, e.g. calcium hydrogenphosphate; carbonates, e.g. calcium carbonate; salts of sulfuric acid such as calcium sulfate, can be mentioned), lubricants (for example, stearic acid, stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloid silica; waxes such as bees wax or spermaceti, boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as silicic anhydride or silicate hydrate; and the aforementioned starch derivatives can be mentioned), binders (for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol and compounds similar to the aforementioned excipient can be mentioned), disintegrants (for example, cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or internally crosslinked sodium carboxymethyl cellulose; or chemically modified starches or celluloses such as carboxymethyl starch, sodium carboxymethyl starch or crosslinked polyvinylpyrrolidone can be mentioned), emulsifiers (for example, colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester), stabilizers (for example, paraoxybenzoic acid esters such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenyl ethyl alcohol, benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid can be mentioned) and corrigents (for example, commonly used sweeteners, acidifiers or fragrances can be mentioned) or diluents. The amount of dosage varies according to symptoms and age, and it is desirable that the compound of the present invention is administered orally or parenterally to an adult human within a lower limit of 0.01 mg/kg (preferably 0.10 mg/kg) and an upper limit of 1000 mg/kg (preferably 100 mg/kg) per day, once a day or several times in parts depending on the symptoms. [EXAMPLES] Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, however, the scope of the present invention is not limited to these. Example 1 Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-364 (la) Ethyl 8-acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-ene- 7-carboxylate 19.97 g (55.4 mmol) of ethyl 8- trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7- carboxylate [compound described as compound 6 in Tetrahedron Letter, Vol. 39, pp. 6139-6142 (1998)] was dissolved in 200 ml of dimethylformamide, and 9.50 g (83.1 mmol) of potassium thioacetate was added thereto with stirring under ice-cooling, followed by stirring at room temperature for 91 hours. To the reaction solution was added ice water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate =17:3) to give 7.15 g of the title compound as a pale brown oil (yield: 45%). 1H-NMR spectrum (400 MHz, CDCl3) δ ppm: 4.20 (2H, q, 7Hz), 4.04-3.96 (4H, m), 2.73-2.66 (4H, m), 2.34 (3H, s), 1.87 (2H, t, J=6Hz), 1.28 (3H, t, J=7Hz). (lb) Ethyl 8-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-7- carboxylate 7.14 g (24.9 mmol) of ethyl 8-acetylsulfanyl-1,4- dioxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (la) was dissolved in 145 ml of methanol, and 2.58 g (18.7 mmol) of potassium carbonate was added thereto with stirring under ice- cooling, followed by stirring at the same temperature for 1 hour and then at room temperature for 1 hour. The reaction solution was made acidic by addition of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =9:1) to give 5.63 g of the title compound as a pale yellow oil (yield: 92%). 1H-NMR spectrum (40 0 MHz, CDCl3) δ ppm: 4.32 (1H, s), 4.21 (2H, q, 7Hz), 4.04-3.95 (4H, m), 2.72-2.67 (2H, m), 2.59-2.57 (2H, m), 1.82 (2H, t, J=7Hz), 1.30 (3H, t, J=7Hz). (1c) Ethyl 8-chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene- 7-carboxylate To a saturated solution prepared by blowing chlorine gas into 80 ml of solution mixture of acetonitrile-water (1:1) for 2 0 minutes was added a solution of 5.00 g (20.5 mmol) of ethyl 8-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (lb) in 10 ml of acetonitrile with stirring under ice- cooling. Chlorine gas was further blown into the reaction solution for 10 minutes at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =2:1) to give 5.83 g of the title compound as a colorless oil (yield: 92%). 1H-NMR spectrum (40 0 MHz, CDCl3) δ ppm: 4.30 (2H, q, 7Hz), 4.05-3.98 (4H, m), 2.91-2.86 (2H, m), 2.71- 2.69 (2H, m), 1.93 (2H, t, J=7Hz), 1.34 (3H, t, J=7Hz). (1d) Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate To a solution of 197 mg (1.35 mmol) of 2-chloro-4- fluoroaniline and 0.20 ml (1.42 mmol) of triethylamine in 5 ml of ethyl acetate was added dropwise a solution of 400 mg (1.29 mmol) of ethyl 8-chlorosulfonyl-l,4-dioxaspiro[4.5]dec-7-ene-7- carboxylate obtained in (lc) in 3 ml of ethyl acetate with stirring under ice-cooling, followed by stirring at room temperature for 48 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 3:1), and the resulting solid was further washed with a mixed solution of hexane-isopropyl ether (1:1) to give 325 mg of the title compound as a white powder (yield: 60%). Melting point 117-119°C 1H-NMR spectrum (400 MHz, CDCl3) 8ppm: 7.67 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.05-6.98 (2H, m) , 6.83 (1H, s) , 4.43-4.41 (1H, m) , 4.26-4.01 (5H, m) , 3.95-3.88 (1H, m), 2.56-2.45 (2H, m), 2.24-2.11 (1H, m), 1.88- 1.80 (1H, m), 1.27 (3H, t, J=7Hz). Example 2 Ethyl 8-(N-phenylsulfamoyl)-1,4-dioxaspiro[4.5]dec-6-ene- 7-carboxylate (Exemplified compound No. 1-12) Following the process described in Example (1d), aniline was used in place of 2-chloro-4-fluoroaniline to give the title compound as an amorphous substance (yield: 81%). 1H-NMR spectrum (4 00 MHz, CDCl3) 5ppm: 7.37-7.31 (4H, m), 7.21-7.15 (1H, m), 6.95 (1H, s), 6.85-6.87 (1H, m), 4.30-4.20 (3H, m), 4.13-4.01 (3H, m), 3.94-3.88 (1H, m) , 2.48-2.41 (1H, m) , 2.31 (1H, , td, J=14Hz, 3Hz) , 2.10-2.00 (1H ,m), 1.86-1.80 (1H ,m), 1.31 (3H, t, J=7Hz). Example 3 Ethyl 8-[N- (2-butylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (exemplified compound No. 1-540) Following the process described in Example (1d), 2- butylaniline was used in place of 2-chloro-4-fluoroaniline to give the title compound as a colorless oil (56% yield). 1H-NMR spectrum (4 00 MHz, CDCl3) δppm: 7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85- 6.84 (1H, m), 6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H, m) , 3.95-3.89 (1H, m) , 2.71-2.62 (2H, m) , 2.54-2.38 (2H, m) , 2.19-2.09 (1H, m) , 1.86-1.81 (1H, m) , 1.62-1.53 (2H, m) , 1.45- 1.34 (2H, m), 1.26 (3H, t, J=7Hz), 0.95 (3H, t, J=7Hz). Example 4 Ethyl 8-[N- (2-hexylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-716) Following the process described in Example (1d), 2- hexylaniline was used in place of 2-chloro-4-fluoroaniline to give the title compound as a pale yellow oil (82% yield). 1H-NMR spectrum (400 MHz, CDCl3) δppm: 7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85- 6.84 (1H, m), 6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H, m) , 3.95-3.89 (1H, m) , 2.70-2.61 (2H, m) , 2.54-2.38 (2H, m) , 2.19-2.09 (1H, m) , 1.86-1.81 (1H, m) , 1.64-1.54 (2H, m) , 1.41- 1.24 (6H, m) , 1.26 (3H, t, J=7Hz) , 0.91-0.85 (3H, m) . Example 5 Ethyl 8-[N- (2-heptylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-892) Following the process described in Example (1d), 2- heptylaniline was used in place of 2-chloro-4-fluoroaniline to give the title compound as a pale yellow oil (87% yield). 1H-NMR spectrum (400 MHz, CDCl3) δppm: 7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85- 6.84 (1H, m), 6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H, m) , 3.95-3.89 (1H, m) , 2.69-2.61 (2H, m) , 2.54-2.38 (2H, m) , 2.19-2.09 (1H, m), 1.86-1.81 (1H, m), 1.64-1.54 (2H, m), 1.42- 1.23 (8H, m), 1.26 (3H, t, J=7Hz), 0.88 (3H, t, J=7Hz). Example 6 Ethyl 8-[N- (lH-pyrrol-1-yl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1062) Following the process described in Example (1d), 1H- pyrrol-1-ylamine was used in place of 2-chloro-4-fluoroaniline to give the title compound as a white powder (yield: 33%). Melting point: 115-117°C 1H-NMR spectrum (400 MHz, CDCl3) δppm: 8.05 (1H, s), 6.99 (2H, t, J=2Hz), 6.94 (1H, s), 6.17 (2H, t, J=2Hz), 4.55-4.51 (1H, m), 4.30 (2H, q, J=7Hz), 4.14-4.03 (3H, m) , 3.98-3.89 (1H, m) , 2.51-2.44 (1H, m) , 2.26-2.05 (2H, m) , 1.89-1.83 (1H, m), 1.35 (3H, t, J=7Hz). Example 7 Ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-353) To 2.55 g (6.07 mmol) of ethyl 8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 1 was added 100 ml of a mixed solution of 1N hydrochloric acid-tetrahydrofuran (1:1), and the reaction solution was stirred at room temperature for 64 hours. Tetrahydrofuran was distilled off under reduced pressure, the residue was extracted by addition of ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =4:1), to give 2.19 g of the title compound as a pale brown powder (yield: 96%) . Melting point: 128-130°C 1H-NMR spectrum (400 MHz, CDCl3) δ ppm: 7.69 (1H, dd, J=9Hz, 5Hz), 7.20 (1H, dd, J=8Hz, 3Hz), 7.09-7.03 (1H, m), 6.91 (2H, s), 4.68 (1H, dd, J=5Hz, 2Hz), 4.28-4.18 (2H, m) , 3.21-3.09 (1H, m) , 2.80-2.72 (1H, m) , 2.57-2.49 (1H, m) , 2.44-2.31 (1H, m), 1.28 (3H, t, J=7Hz). Example 8 Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,5- dioxaspiro[5.5]undec-7-ene-8-carboxylate (exemplified compound No. 1-365) 100 mg (0.27 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 2 ml of toluene, and 0.04 ml (0.54 mmol) of propane-1,3-diol and 68 mg (0.27 mmol) of pyridinium p-toluenesulfonate were added thereto, followed by heating under reflux for 1 hour. After the reaction solution was cooled to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 2:1), and the resulting solid was further washed with hexane to give 60 mg of the title compound as a white powder (yield: 51%). Melting point: 120-121°C 1H-NMR spectrum (400 MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz), 7.36 (1H, s), 7.14 (1H, dd, J=8Hz, 3Hz), 7.01 (1H, dd, J=7Hz, 2Hz), 6.98 (1H, s), 4.45-4.39 (1H, m) , 4.27-4.12 (2H, m) , 4.11-3.84 (4H, m) , 2.46-2.06 (4H, m) , 1.92-1.67 (2H, m), 1.28 (3H, t, J=7Hz). Example 9 Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3,3- dimethyl-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate (Exemplified compound No. 1-426) Following the process described in Example 8, 2,2- dimethylpropane-1,3-diol was used in place of propane-1,3-diol to give the title compound as a pale brown oil (yield: 64%). 1H-NMR spectrum (400 MHz, CDCl3) δ ppm: 7.64 (1H, dd, J=9Hz, 5Hz), 7.31 (1H, s), 7.13 (1H, dd, J=8Hz, 3Hz) , 7.04-6.94 (2H, m) , 4.45-4.39 (1H, m) , 4.27-4.12 (2H, m) , 3.69-3.46 (4H, m), 2.42-2.11 (4H, m), 1.28 (3H, t, J=7Hz), 1.03 (3H, s), 0.97 (3H, s). Example 10 Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl] -1,4- dithiaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-367) 100 mg (0.27 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 1 ml of dichloromethane and 0.034 ml (0.405 mmol) of ethane-1,2-dithiol and 0.025 ml (0.203 mmol) of boron trifluoride diethyl etherate were added thereto with stirring under ice-cooling,followed by stirring at room temperature for 1 hour. To the reaction solution was added a IN aqueous sodium hydroxide solution and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resulting solid was washed with diethyl ether and then with hexane to give 325 mg of the title compound as a white powder (76% yield). Melting point: 160-161°C 1H-NMR spectrum (400 MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.10 (1H, s) , 7.04-6.96 (2H, m) , 4.40 (1H, d, J=5Hz) , 4.25-4.10 (2H, m) , 3.52-3.26 (4H, m), 2.82-2.72 (1H, m), 2.58-2.50 (1H, m), 2.33- 2.24 (1H, m), 2.11-1.99 (1H, m), 1.27 (3H, t, J=7Hz). Example 11 Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,5- dithiaspiro[5.5]undec-7-ene-8-carboxylate (Exemplified compound No. 1-368) Following the process described in Example 10, propane- 1,3-dithiol was used in place of ethane-1,2-dithiol to give the title compound as an amorphous substance (72% yield). 1H-NMR spectrum (40 0 MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz), 7.40 (1H, s), 7.14 (1H, dd, J= 8Hz, 3Hz), 7.03-6.96 (1H, m), 6.94 (1H, s), 4.51 (1H, d, J=5Hz), 4.24-4.11 (2H, m), 3.17-3.07 (1H, m), 2.98-2.77 (3H, m), 2.61- 2.51 (1H, m), 2.47-2.38 (1H, m), 2.36-2.27 (1H, m), 2.25-2.13 (1H, m), 2.12-1.95 (2H, m), 1.27 (3H, t, J=7Hz). Example 12 Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1-oxa-4- thiaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-371) Following the process described in Example 10, 2- mercaptoethal was used in place of ethane-1,2-dithiol to give the title compound as a white powder (61% yield). Melting point: 133-134°C 1H-NMR spectrum (400 MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.06 (0.4H, s), 7.04-6.96 (2.6H, m), 4.46 (0.4H, dd, J=5Hz, 3Hz), 4.39-4.01 (4.6H, m), 3.23-3.06 (2H, m), 2.77-2.51 (1.6H, m), 2.45-2.36 (0.4H, m) , 2.20-2.00 (2H, m) , 1.27 (3H, t, J=7Hz) . Example 13 Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,1,4,4- tetraoxo-1λ6, 4λ6-dithiaspiro [4.5] dec-6-ene-7-carboxylate (Exemplified compound No. 1-3 69) 80 mg (0.18 mmol) of ethyl 8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dithiaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 10 was dissolved in 2 ml of dichloromethane, 91 mg (1.08 mmol) of sodium hydrogencarbonate was added thereto and subsequently 239 mg (0.90 mmol) of m- chloroperbenzoic acid (65%) was added with stirring under ice- cooling, followed by stirring at room temperature for 5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane : ethyl acetate =1:1) to give 42 mg of the title compound as a white powder (yield: 45%). Melting point: 88-90°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, dd, J=8Hz, 3Hz), 7.06-6.98 (2H, m) , 6.92 (1H, s) , 4.57 (1H, d, J=5Hz), 4.26-4.16 (2H, m) , 3.79-3.60 (4H, m), 3.14-2.98 (1H, m), 2.69-2.60 (1H, m), 2.45- 2.36 (1H, m), 2.29-2.16 (1H, m), 1.28 (3H, t, J=7Hz). Example 14 Ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl] -1- oxaspiro[2.5]oct-4-ene-5-carboxylate (Exemplified compound No. 1-360) 50 mg (0.133 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 0.01 ml (0.146 mmol) of dibromomethane were dissolved in 1 ml of tetrahydrofuran, and 0.18 ml (0.279 mmol) of n-butyllithium/hexane solution (1.58 M) was added dropwise thereto at -78°C, followed by stirring at room temperature for 4 hours. After the reaction solution was cooled with ice, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane : ethyl acetate =2:1) to give 7 mg of the title compound as a yellow oil (yield: 14%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.68 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, dd, J=8Hz, 3Hz), 7.07-6.91 (2H, m) , 6.60 (1H, s) , 4.50 (1H, d, J=4Hz) , 4.27-4.06 (2H, m) , 2.98-2.92 (1H; m) , 2.91-2.88 (1H, m) , 2.83-2.70 (1H, m) , 2.68- 2.59 (1H, m), 2.21-2.07 (2H, m) , 1.25 (3H, t, J=7Hz). Example 15 Ethyl (2S)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2- hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (exemplified compound No. 1-3 78) 100 mg (0.27 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3-oxo-1-eyelohexene-1-carboxylate obtained in Example 7 and 69 mg (0.35 mmol) of (i?)-2,3- dihydroxypropyl benzoate were dissolved in 2 ml of dichloromethane and 0.19 ml (1.05 mmol) of isopropoxytrimethylsilane and 2 µl (0.014 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added thereto with stirring under ice-cooling, followed by stirring at the same temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 1:1), to give 121 mg of ethyl (2R) -2-benzoyloxymethyl-8- [N- (2-chloro- 4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate as a pale yellow oil (yield: 81%). Subsequently, 121 mg (0.22 mmol) of this compound was dissolved in 2 ml of a mixture of methanol-tetrahydrofuran (1:1), and to the solution was added 0.5 ml (0.50 mmol) of 1N aqueous sodium hydroxide with stirring under ice-cooling, followed by stirring at the same temperature for 3 0 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 1:1) to give 41 mg of the title compound as an amorphous substance (yield: 41%) . 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.64 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.06-6.97 (2H, m), 6.89 (0.25H, s), 6.86 (0.25H, s), 6.80 (0.25H, s), 6.78 (0.25H, s), 4.43-4.31 (1.75H, m), 4.26-4.02 (3.25H, m), 3.95- 3.87 (0.75H, m), 3.85-3.77 (1H, m), 3.75-3.69 (0.25H, m), 3.68- 3.59 (1H, m), 2.65-2.38 (2H, m), 2.25-2.11 (1H, m), 2.11-2.05 (0.25H, m), 2.03-1.97 (0.25H, m), 1.94-1.81 (1.5H, m), 1.26 (3H, t, J=7Hz). Example 16 Ethyl (2i?) -8- [N- (2-chloro-4-f luorophenyl) sulfamoyl] -2- hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-378) (16a) Ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3,3- dimethoxy-1-cyclohexene-1-carboxylate 6.1 g (16.2 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 was dissolved in 12 0 ml of methanol and 4.1 g (16.2 mmol) of pyridinium p-toluenesulfonate and 8.86 ml (81.0 mmol) of trimethoxymethane were sequentially added thereto with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =2:1) to give 6.0 g of the title compound as a white powder (yield: 88%). Melting point: 97-98°C 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.07-6.97 (3H, m), 4.41 (1H, d, J=4Hz), 4.28-4.12 (2H, m), 3.29 (3H, s), 3.23 (3H, s), 2.47-2.38 (1H, m), 2.31-2.21 (1H, m), 2.18-2.06 (1H, m), 2.01-1.93 (1H, m), 1.28 (3H, t, J=7Hz). (16b) Ethyl (2R)-8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-2-hydroxymethyl-l,4-dioxaspiro[4.5]dec- 6-ene-7-carboxylate 342 mg (0.81 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexen-1-carboxylate obtained in (16a) and 206 mg (1.05 mmol) of (S)-2,3- dihydroxypropyl benzoate were dissolved in 7 ml of dichloromethane, and 0.56 ml (3.15 mmol) of isopropoxytrimethylsilane and 7 µl (0.041 mmol) of trimethylsilyl trifluoromethanesulfonate were added thereto sequentially with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 1:1), to give 410 mg of ethyl (2S)-2-benzoyloxymethyl-8-[N- (2-chloro- 4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate as a colorless oil (yield: 91%). Subsequently, 410 mg (0.74 mmol) of this compound was dissolved in 10 ml of a mixture of methanol-tetrahydrofuran (1:1) and 3 ml (3.0 mmol) of 1N aqueous sodium hydroxide was added thereto, followed by stirring for 15 minutes at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 1:1) to give 293 mg of the title compound as an amorphous substance (yield: 88%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.64 (1H, dd, J=9Hz, 5Hz) , 7.14 (1H, dd, J=8Hz, 3Hz), 7.04-6.95 (2H, m), 6.89 (0.42H, s), 6.86 (0.02H, s), 6.80 (0.02H, s), 6.78 (0.42H, s), 4.43-4.31 (1.5H, m), 4.26-4.02 (2.5H, m), 3.96-3.89 (1H, m) , 3.83-3.77 (0.5H, m) , 3.75-3.69 (0.5H, m) , 3.68-3.59 (1H, m), 2.65-2.41 (2H, m), 2.25-2.10 (1H, m), 1.93-1.82 (1H, m), 1.77-1.67 (0.5H, br. s), 1.58 (0.5H, br. s), 1.26 (3H, t, J=7Hz). Example 17 Ethyl {2R,2R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] - 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-382) Following the process described in Example (16b), 1,4-di- O-benzoyl-D-threitol was used in place of (S)-2,3- dihydroxypropyl benzoate to give the title compound as an amorphous substance (yield: 44%). (17a) Ethyl (2R,3R)-2,3-bis(benzoyloxymethyl)-8-[N- (2- chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate 1.46 g (3.08 mmol) of 1,4-di-O-benzoyl-2,3-di-O- trimethylsilyl-D-threitol obtained in Reference Example 18 was suspended in 2 ml of acetonitrile, and 0.04 ml (0.24 mmol) of trimethylsilyl trifluoromethanesulfonate and a solution of 1.00 g (2.37 mmol) of ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) in 5 ml of acetonitrile were sequentially added thereto with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 2:1) to give 1.50 g of the title compound as a pale yellow powder (yield: 92%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 8.10-8.04 (4H, m), 7.68-7.57 (3H, m), 7.49-7.44 (4H, m), 7.16 (1H, dt, J=8.0Hz, 2.6Hz), 7.05-7.00 (2H, m), 6.87 (1H, d, J=14.0Hz), 4.66-4.07 (9H, m), 2.63-2.44 (2H, m), 2.25-2.19 (1H, m), 1.94 (1H, t, J=15.2Hz), 1.19 (3H, t, J=7.0Hz). (17b) Ethyl {2R,3R)-8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate 1.50 g (2.18 mmol) of ethyl [2R,3R)-2,3- bis(benzoyloxymethyl)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in (17a) was dissolved in 10 ml of a mixture of methanol-tetrahydrofuran (4:1), and 10 ml (10.0 mmol) of 1N aqueous sodium hydroxide was added thereto with stirring under ice-cooling, followed by stirring for 15 minutes at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 1:1) to give 900 mg of the title compound as a white amorphous substance (yield: 86%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.69-7.64 (1H, m) , 7.16 (1H, dd, J=8Hz, 3Hz) , 7.05-6.99 (2H, m) , 6.91-6.90 (0.5H, m), 6.85-6.84 (0.5H, m) , 4.43-4.41 (1H, m) , 4.27-4.09 (3.5H, m), 4.05-4.01 (0.5H, m) , 3.93-3.81 (2H, m) , 3.75-3.69 (2H, m), 2.59-2.45 (2H, m), 2.23-1.50 (4H, m), 1.29- 1.24 (3H, m). Example 18 Ethyl (25,35)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-382) Following the process described in Example (16b), 1,4-di- O-benzoyl-1-threitol was used in place of (5)-2,3- dihydroxypropyl benzoate to give the title compound as an amorphous substance (34% yield). Following the process described in Example 17 (alternative procedure), 1, 4-di-Obenzoyl-2, 3-di-O- trimethylsilyl-1-threitol obtained in Reference Example 19 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D- threitol to give the title compound as an amorphous substance (yield: 73%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.69-7.64 (1H, m) , 7.16 (1H, dd, J=8Hz, 3Hz) , 7.05-6.99 (2H, m) , 6.91-6.90 (0.5H, m) , 6.85-6.84 (0.5H, m) , 4.43-4.41 (1H, m) , 4.27-4.09 (3.5H, m) , 4.05-4.01 (0.5H, m) , 3.93-3.81 (2H, m) , 3.75-3.69 (2H, m), 2.59-2.45 (2H, m), 2.23-1.50 (4H, m), 1.29- 1.24 (3H, m). Example 19 Ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-meso-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-382) 200 mg (0.47 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1- carboxylate obtained in Example (16a) and 290 mg (0.61 mmol) of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol obtained in Reference Example 1 were dissolved in 4 ml of dichloromethane and 4 µl (0.024 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =2:1) to give 171 mg of ethyl meso-2,3- bis[(benzoyloxy)methyl]-8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate as an amorphous substance (yield: 53%). Subsequently, 170 mg (0.25 mmol) of this compound was dissolved in 10 ml of a mixture of methanol-tetrahydrofuran (1:1), and 3 ml (3.0 mmol) of 1N aqueous sodium hydroxide was added thereto with stirring under ice-cooling, followed by stirring for 15 minutes at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 1:3) to give 105 mg of the title compound as an amorphous substance (yield: 8 9%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.64 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, dd, J=8Hz, 3Hz), 7.04-6.95 (2H, m), 6.93 (0.4H, s), 6.72 (0.6H, s), 4.49-4.33 (2.4H, m), 4.32-4.26 (0.6H, m), 4.25-4.07 (2H, m), 3.93-3.70 (4H, m), 2.69- 2.58 (0.4H, m) , 2.58-2.35 (3.6H, m) , 2.24-2.09 (1H, m) , 1.99- 1.91 (0.6H, m), 1.90-1.83 (0.4H, m), 1.27 (3H, t, J=7Hz). Example 2 0 Ethyl (2R) -8- [N- (2-chloro-4-f luorophenyl) sulfamoyl] -2- ((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-3 90) 300 mg (0.71 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1- carboxylate obtained in Example (16a) and 43 6 mg (1.42 mmol) of (4R,5R)-2,2-dimethyl-4,5- bis[(trimethylsilyl)oxy]methyl[1.3]dioxolane were dissolved in 12 ml of dichloromethane and 26 µl (0.142 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 90 hours at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 4:1) to give 90 mg of ethyl (21?)-8-[N- (2-chloro-4- fluorophenyl) sulfamoyl] -2- ( (4R) -2 , 2-dimethyl [1.3] dioxolan-4-yl) - 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as an amorphous substance (yield: 24%). Subsequently, to 85 mg (0.163 mmol) of this compound was added 4 ml of a mixture of acetic acid-water (1:1), followed by stirring overnight at room temperature. The reaction solution was neutralized with addition of saturated aqueous sodium hydrogencarbonate, and the mixture was then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 46 mg of the title compound as an amorphous substance (yield: 5 9%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.69-7.64 (1H, m), 7.19-7.15 (1H, m), 7.06-6.98 (2H, m), 6.89- 6.80 (1H, m), 4.43-4.41 (1H, m), 4.38-4.08 (4H, m), 4.03-3.95 (0.7H, m), 3.86 (0.3H, t, J=8Hz), 3.77-3.63 (3H, m), 2.67-2.37 (3H, m), 2.22-1.84 (3H, m), 1.30-1.25 (3H, m). Example 21 Ethyl (21?) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- ( (2R) -1,2, 3-trihydroxypropyl) -1, 4-dioxaspiro [4.5] dec-6-ene-7- carboxylate (Exemplified compound No. 1-3 94) 547 mg (1.07 mmol) of 1,3,4,5,7-penta-O-trimethylsilyl-D- arabitol obtained in Reference Example 2 was dissolved in 3 ml of nitromethane, to the resulting solution was added 13 µl (0.007 mmol) of trimethylsilyl trifluoromethanesulfonate and was then added 300 mg (0.71 mmol) of ethyl 6- [N- (2-chloro-4- fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1- carboxylate obtained in Example (16a) with stirring under ice- cooling, followed by stirring for 1 hour at the same temperature. A saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 151 mg of the title compound as an amorphous substance (yield: 42%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9Hz, 5Hz) , 7.19-7.15 (1H, m) , 7.10-6.99 (2H, m) , 6.86 (0.5H, s), 6.82-6.80 (0.5H, m), 4.42-4.39 (1H, m), 4.28- 3.65 (9H, m) , 3.20-1.40 (3H, br) , 2.57-2.43 (2H, m) , 2.23-2.09 (1H, m) , 1.92-1.82 (1H, m) , 1.29-1.25 (3H, m) . Example 22 Ethyl (2R) -8- [N- (2-chloro-4-f luorophenyl) sulfamoyl] -2- ((1S,2R,3R)-1,2,3,4-tetrahydroxybutyl)-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate (Exemplified compound No. 1-398) 200 mg (0.47 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1- carboxylate obtained in Example (16a) and 434 mg (0.71 mmol) of 1, 2 , 3,4,5,6-hexa-O-trimethylsilyl-D-mannitol were dissolved in 4 ml of dichloromethane, to the resulting solution were added sequentially 0.12 ml (0.47 mmol) of isopropoxytrimethylsilane and 4 µl (0.024 mmol) of trimethylsilyl trifluoromethanesulfonate with stirring under ice-cooling, followed by stirring overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; dichloromethane : methanol = 10:1) to give 13 0 mg of the title compound as an amorphous substance (yield: 51%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.62 (1H, dd, J=9Hz, 5Hz) , 7.22-7.12 (2H, m) , 7.04-6.96 (1H, m) , 6.88-6.84 (0.2H, m), 6.80-6.77 (0.4H, m), 6.76 (0.4H, s), 4.41- 4.31 (1H, m), 4.25-4.03 (4H, m), 3.98-3.63 (6H, m), 2.54-2.41 (2H, m), 2.22-2.08 (1H, m), 1.92-1.81 (1H, m), 1.26 (3H, t, J=7Hz). Example 23 Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2,3-bis((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-386) Following the process described in Example 19, l,6-di-O- benzoyl-2,3,4,5-tetra-O-trimethylsilyl-D-mannitol obtained in Reference Example 3 was used in place of 1,4-di-O-benzoyl-2,3 - di-O-trimethylsilyl-meso-erythritol to give the title compound as a white powder (yield: 11%). Melting point: 55-56°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz) , 7.20-7.13 (2H, m) , 7.06-7.00 (1H, m) , 6.80 (0.5H, s), 6.78 (0.5H, s), 4.38 (1H, d, J=5Hz), 4.26-4.00 (5H, m), 3.98-3.88 (1.5H, m), 3.87-3.65 (5.5H, m), 2.78-2.56 (2H, m), 2.55-2.40 (2H, m), 2.23-2.09 (1H, m), 1.92-1.80 (1H, m) , 1.26 (3H, t, J=7Hz) . Example 24 Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3-hydroxy- 1,5-dioxaspiro [5 . 5] undec — 7-ene-8-carboxylate (exemplified compound No. 1-418) Following the process described in Example 19, 2- trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamantan-1- carboxylate obtained in Reference Example 4 was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol to give the title compound as an amorphous substance (yield: 17%). 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 7.69-7.64 (1H, m), 7.52-7.51 (0.5H, m), 7.18-7.15 (1H, m), 7.08- 6.99 (2.5H, m), 4.45-4.42 (1H, m), 4.31-4.05 (4H, m), 3.88-3.74 (2H, m), 3.72-3.63 (1H, m), 2.78-2.52 (1H, br), 2.48-1.97 (4H, m) , 1.31-1.26 (3H, m) . Example 25 Ethyl 12-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2,4,8,5- tetraoxadispiro[5.2.5.2]hexadec-10-ene-ll-carboxylate (Exemplified compound No. 1-434) 100 mg (0.266 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 156 mg (0.53 2 mmol) of 5,5- bis[(trimethylsilyl)oxy]methyl[1.3]dioxane were dissolved in 2 ml of dichloromethane and 10 µl (0.053 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto at -78°C, followed by stirring for 3 0 minutes at the same temperature and then for 2 hours at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 2:1) and the resulting solid was further washed with isopropoyl ether to give 49 mg of the title compound as a white powder (yield: 52%). Melting point: 156-157°C 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.05-6.98 (2H, m), 4.83 (1H, d, J=6Hz), 4.78 (1H, d, J=6Hz), 4.44-4.42 (1H, m) , 4.29-4.14 (2H, m) , 3.87-3.70 (8H, m) , 2.44-2.38 (1H, m), 2.32-2.24 (1H, m), 2.18-2.08 (2H, m), 1.28 (3H, t, J=7Hz). Example 2 6 Ethyl 3-acetylamino-9-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-8- carboxylate (Exemplified compound No. 1-422) 500 mg (1.19 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1- carboxylate obtained in Example (16a) and 205 mg (1.54 mmol) of N-(2-hydroxy-1-hydroxymethylethyl)acetamide were dissolved in 20 ml of dichloromethane, and 0.84 ml (4.74 mmol) of isopropoxytrimethylsilane and 43 µl (0.24 mmol) of trimethylsilyl trifluoromethanesulfonate were added sequentially with stirring under ice-cooling, followed by stirring for 30 minutes at the same temperature, and further for 66 hours at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate : methanol = 39:1) to give 288 mg of the title compound as an amorphous substance (yield: 50%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9Hz, 5Hz), 7.62-7.60 (0.5H, m), 7.17 (1H, dd, J=8Hz, 3Hz), 7.05-6.99 (2H, m), 6.93-6.91 (0.5H, m), 6.35 (1H, br.d, J=8Hz), 4.46-4.42 (1H, m), 4.35-4.11 (4H, m), 4.03-3.95 (1H, m) , 3.82-3.70 (2H, m) , 2.60-2.55 (0.5H, m) , 2.48-2.01 (3H, m), 2.06 (3H, s), 1.95-1.90 (0.5H, m), 1.30 (3H, t, J=7Hz). Example 2 7 Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3,3- bis(hydroxymethyl)-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate (Exemplified compound No. 1-430) 500 mg (1.19 mmol) of ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1- carboxylate obtained in Example (16a) and 1.0 g (2.38 mmol) of 1,3-bis[(trimethylsilyl)oxy]-2,2- bis[(trimethylsilyl)oxy]methylpropane were dissolved in 10 ml dichloromethane and 10 ul (0.06 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 510 mg of the title compound as an amorphous substance (yield: 87%). ^-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9Hz, 5Hz), 7.28 (1H, s), 7.17 (1H, dd, J=8Hz, 3Hz), 7.11 (1H, s), 7.07-6.98 (1H, m), 4.42 (1H, d, J=4Hz), 4.30-4.10 (2H, m), 3.92-3.68 (8H, m), 2.54-2.36 (3H, m), 2.34- 2.23 (1H, m), 2.21-2.07 (2H, m), 1.28 (3H, t, J=7Hz). Example 28 Triethy1 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,5- dioxaspiro[5.5]undec-7-ene-3,3,8-tricarboxylate (Exemplified compound No. 1-438) Following the process described in Example 27, diethyl 2,2-bis[(trimethylsilyl)oxyjmethylmalonate obtained in Reference Example 5 was used in place of 1,3-bis[(trimethylsilyl)oxy]-2,2- bis [ (trimethylsilyl) oxy]methylpropane to give the title compound as an amorphous substance (yield: 42%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz), 7.23-7.21 (1H, m), 7.16 (1H, dd, J=8Hz, 3Hz) , 7.04-6.99 (1H, m) , 6.97 (1H, s) , 4.43-4.36 (3H, m) , 4.31-4.13 (8H, m), 2.44-2.37 (1H, m), 2.33-2.25 (1H, m), 2.19- 2.06 (2H, m), 1.283 (3H, t, J=7Hz), 1.280 (6H, t, J=7Hz). Example 2 9 Ethyl 6- [N- (2-chloro-4- fluorophenyl)sulfamoyl]spiro[2.5]oct-4-ene-5-carboxylate (Exemplified compound No. 1-355) (29a) Ethyl 3- [1- (2- ethoxycarbonylethyl)cyclopropyl]propionate 24.5 ml (24.5 mmol) of 1.0 M diethyl zinc/hexane solution was added to 3 0 ml of dichloromethane, and then a solution of 1.89 ml (24.5 mmol) of trifluoroacetic acid in 10 ml of dichloromethane was added with stirring under ice-cooling. The reaction solution was stirred for 20 minutes at the same temperature, then a solution of 1.97 ml (24.5 mmol) of diiodomethane in 10 ml of dichloromethane was added and stirred for 20 minutes, and 1.40 g (6.13 mmol) of a solution of diethyl 4-methyleneheptanedicarboxylate (compound described in J.A.C.S. 107, 13, 3981-3997 (1985)) in 10 ml of dichloromethane was further added. After the reaction solution was stirred for 6 hours at room temperature, ice water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =5:1) to give 1.48 g of the title compound as a brown oil (yield: 99%). 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 4.10 (2H, q, J=7Hz), 3.37-2.31 (4H, m), 1.60-1.53 (4H, m), 1.25 (6H, t, J=7Hz), 0.31 (4H, s). (29b) Ethyl 6-hydroxyspiro[2.5]oct-5-ene-5-carboxylate 1.46 g (6.03 mmol) of ethyl 3-[l-(2- ethoxycarbonylethyl)cyclopropyl]propionate obtained in (29a) was dissolved in 60 ml of tetrahydrofuran and 1.35 g (12.1 mmol) of potassium t-butoxide was added thereto, followed by stirring for 1 hour at room temperature. The reaction solution was cooled with ice and made acidic by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 1.05 g of the title compound as a yellow oil (yield: 89%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 12.23 (0.7H, s), 4.26-4.09 (2H, m), 3.50 (0.3H, dd, J=10Hz, 6Hz), 2.57-2.42 (0.7H, m), 2.36 (2H, t, J=6Hz), 2.03-1.94 (0.3H, m) , 1.66-1.52 (1H, m) , 1.48 (2H, t, J=6Hz) , 1.28 (3H, J=7Hz) , 0.60-0.30 (4H, m). (29c) Ethyl 6-trifluoromethanesulfonyloxyspiro[2.5]oct-5- ene-5-carboxylate 1.05 g (5.35 mmol) of ethyl ethyl 6-hydroxyspiro[2.5]oct- 5-ene-5-carboxylate obtained in (29b) was dissolved in 30 ml of dichloromethane, and 0.99 ml (5.89 mmol) of diisopropylethylamine and 1.40 ml (8.03 mmol) of trifluoromethanesulfonic anhydride were added sequentially with stirring at -78°C. After the reaction solution was stirred for 3 hours at the same temperature, it was warmed to room temperature. The reaction solution was poured into saturated aqueous sodium hydrogencarbonate and the mixure was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 1.56 g of the title compound as a brown oil (yield: 89%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.26 (2H, q, J=7Hz), 2.57-2.46 (2H, m), 2.35-2.29 (2H, m), 1.60- 1.53 (2H, m) , 1.32 (3H, t, J=7Hz) , 0.49-0.40 (4H, m) . (29d) Ethyl 6-mercaptospiro[2.5]oct-5-ene-5-carboxylate Following the process described in Example (la), ethyl 6- trifluoromethanesulfonyloxyspiro[2.5]oct-5-ene-5-carboxylate obtained in (29c) was used in place of ethyl 8- trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7- carboxylate to give ethyl 6-acetylsulfanylspiro[2.5]oct-5-ene-5- carboxylate as a pale yellow oil (yield: 58%). Subsequently, 700 mg (2.75 mmol) of this compound was dissolved in 14 ml of ethanol, and 2.75 ml (11 mmol) of 4N hydrogen chloride/dioxane solution was added thereto with stirring under ice-cooling, followed by stirring for 4 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 10:1), to give 3 00 mg of the title compound as a pale yellow oil (yield: 51%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.19 (2H, q, J=7Hz), 4.12 (1H, s), 2.57 (2H, t, J=6Hz), 2.22- 2.18 (2H, m), 1.46 (2H, t, J=6Hz), 1.29 (3H, t, J=7Hz), 0.40- 0.33 (4H, m). (29e) Ethyl 6-(chlorosulfonyl)spiro[2.5]oct-5-ene-5- carboxylate 7 ml of acetic acid was added to 651 mg (4.23 mmol) of sodium perborate tetrahydrate, the mixture was heated to 5 0°C, and a solution of 3 00 mg (1.41 mmol) of ethyl 6- mercaptospiro[2.5]oct-5-ene-5-carboxylate obtained in (29d) in 3 ml of acetic acid was added thereto, followed by stirring for 2 hours at the same temperature and further for 3 hours at 8 0°C. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 5 ml of thionyl chloride was added to the residue, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature again and concentrated under reduced pressure. Ice water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 5:1 to give 195 mg of the title compound as a colorless oil (yield: 50%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.28 (2H, q, J=7Hz), 2.77-2.69 (2H, m), 2.43-2.38 (2H, m), 1.62 (2H, t, J=6Hz) , 1.33 (3H, t, J=7Hz) , 0.52-0.46 (4H, m) . (29f) Ethyl 6-[N- (2-chloro-4- fluorophenyl)sulfamoyl]spiro[2.5]oct-4-ene-5-carboxylate Following the process described in Example (1d), ethyl 6- (chlorosulfonyl)spiro[2.5]oct-5-ene-5-carboxylate obtained in (29e) was used in place of ethyl 8-chlorosulfonyl-l,4- dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title compound as a white powder (yield: 17%). Melting point: 125-126°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.69 (1H, dd, J=9Hz, 5Hz), 7.13 (1H, dd, J=8Hz, 3Hz), 7.03-6.96 (2H, m) , 6.58 (1H, s) , 4.53 (1H, d, J=5Hz) , 4.20-4.04 (2H, m) , 2.62-2.50 (2H, m), 1.98-1.85 (1H, m), 1.23 (3H, t, J=7Hz), 1.22- 1.13 (1H, m) , 1.09-0.99 (2H, m) , 0.93-0.80 (2H, m) . Example 3 0 Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1- oxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity diastereomer), (high polarity diastereomer) (Exemplified compound No. 1-3 62) (3 0a) 7-(1,3-Dioxan-2-yl)-5-[2-(1,3-dioxan-2- yl)ethyl]heptane-1,5-diol 43 0 mg (5 mmol) of ^-butyrolactone was dissolved in 10 ml of tetrahydrofuran, and 22 ml (11 mmol) of 0.5 M (1,3-dioxan-2- ylethyl)magnesium bromide/tetrahydrofuran solution was added thereto with stirring under ice-cooling, followed by stirring for 3 hours at 50°C. After the reaction solution was cooled with ice, saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate : ethanol = 10:1) to give 880 mg of the title compound as a colorless oil (yield: 55%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 4.51 (2H, t, J=5Hz), 4.08 (4H, dd, J=10Hz, 4Hz), 3.79-3.70 (4H, m), 3.61 (2H, t, J=6Hz), 2.13-2.00 (2H, m), 1.68-1.56 (12H, m), 1.55-1.49 (2H, m) , 1.37-1.29 (2H, m) . (30b) 2-(2-{2-[2-(1,3-dioxan-2-yl)ethyl]tetrahydrofuran- 2-yl}ethyl)-1,3-dioxane 2.60 g (8.17 mmol) of 7-(1,3-dioxan-2-yl)-5-[2-(1,3- dioxan-2-yl)ethyl]heptane-1,5-diol obtained in (30a) was dissolved in 45 ml of pyridine, and a solution of 1.64 g (8.58 mmol) of p-toluenesulfonyl chloride in 15 ml of pyridine was added thereto with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature and further for 3 hours at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =1:1) to give 1.31 g of the title compound as a colorless oil (yield: 53 %). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.50 (2H, t, J=5Hz), 4.09 (2H, dd, J=llHz, 5Hz), 3.83-3.68 (6H, m), 2.15-1.99 (2H, m), 1.92-1.82 (2H, m), 1.73-1.48 (12H, m), 1.38-1.29 (2H, m). (30c) Ethyl 3-[2-(2-ethoxycarbonylethyl)tetrahydrofuran- 2-yl]propionate 1.31 g (43.6 mmol) of 2-(2-{2-[2-(1,3-dioxan-2- yl)ethyl]tetrahydrofuran-2-yl}ethyl)-1,3-dioxane obtained in (3 0b) was dissolved in 15 ml of acetone, and 16.3 ml (43.6 mmol) of Jones reagent was added thereto with stirring under ice- cooling, followed by stirring for 3 hours at room temperature. The reaction solution was cooled with ice, and then the reaction was terminated by addition of isopropyl alcohol. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was dissolved in 15 ml of ethanol, and 0.76 ml (10.5 mmol) of thionyl chloride was added, followed by stirring overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =1:1) to give 610 mg of the title compound as a yellow oil (yield: 51%). 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 4.13 (4H, q, J=7Hz), 3.78 (2H, t, J=7Hz), 2.37-2.31 (4H, m), 1.95-1.87 (2H, m), 1.86-1.79 (4H, m), 1.71 (2H, t, J=7Hz), 1.26 (6H, t, J=7Hz). (30d) Ethyl 8-oxo-1-oxaspiro[4.5]decane-7-carboxylate 610 mg (2.24 mmol) of ethyl 3-[2-(2- ethoxycarbonylethyl)tetrahydrofuran-2-yl]propionate obtained in (30c) was dissolved in 18 ml of tetrahydrofuran, and 503 mg (4.48 mmol) of potassium t-butoxide was added thereto, followed by heating under reflux for 1 hour. After the reaction solution was cooled with ice, the reaction solution was made acidic by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =2:1) to give 340 mg of the title compound as a colorless oil (yield: 67%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 12.24 (1H, s) , 4.26-4.12 (2H, m) , 3.96-3.79 (2H, m) , 2.63-2.47 (1H, m), 2.43-2.12 (3H, m), 2.05-1.86 (2H, m), 1.86-1.60 (4H, m), 1.30 (3H, t, J=7Hz). (30e) Ethyl 8-trifluoromethanesulfonyloxy-1- oxaspiro [4.5]dec-7-ene-7-carboxylate To a suspension of 72 mg of 55% sodium hydride (1.65 mmol)/3 ml of dichloromethane, was added a solution of 340 mg (1.50 mmol) of ethyl 8-oxo-1-oxaspiro[4.5]decane-7-carboxylate obtained in (2 9d) in 4 ml of dichloromethane with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. Subsequently, the reaction solution was cooled to -78°C, and 0.28 ml (1.65 mmol) of trifluoromethanesulfonic anhydride was added thereto. The mixture was stirred for 1 hour at the same temperature, and then warmed to room temperature. After ice water was added to the reaction solution to terminate the reaction, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 480 mg of the title compound as a pale yellow oil (yield: 89%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 4.26 (2H, q, J=7Hz), 3.92-3.81 (2H, m), 2.74-2.63 (1H, m), 2.62- 2.48 (2H, m), 2.45-2.34 (1H, m), 2.04-1.68 (6H, m), 1.32 (3H, t, J=7Hz). (30f) Ethyl 8-acetylthio-1-oxaspiro[4.5]dec-7-ene-7- carboxylate Following the process described in Example (la), ethyl 8- trifluoromethanesulfonyloxy-1-oxaspiro[4.5]dec-7-ene-7- carboxylate obtained in (3 0e) was used in place of ethyl 8- trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7- carboxylate to give the title compound as a yellow oil (yield: 32%) . 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.18 (2H, q, J=7Hz), 3.91-3.83 (2H, m), 2.65-2.60 (1H, m), 2.60- 2.51 (2H, m), 2.40-2.35 (1H, m), 2.32 (2.6H, s), 2.29 (0.4H, s), 2.00-1.93 (2H, m), 1.87-1.67 (4H, m), 1.28 (3H, t, J= 7Hz). (30g) Ethyl 8-mercapto-1-oxaspiro[4.5]dec-7-ene-7- carboxylate 120 mg (0.42 mmol) of ethyl 8-acetylthio-1- oxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (30f) was dissolved in 3 ml of ethanol, and 1 ml (4 mmol) of 4N hydrogen chloride/dioxane solution was added thereto, followed by stirring for 4 hours at room temperature. The reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 3:1) to give 100 mg of the title compound as a pale yellow oil (98% yield). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.24-4.16 (2H, m) , 4.12 (1H, s), 3.91-3.80 (2H, m) , 2.84-2.71 (1H, m) , 2.52-2.34 (3H, m) , 2.01-1.90 (2H, m) , 1.82-1.58 (4H, m), 1.23 (3H, t, J=7Hz). (30h) Ethyl 8-chlorosulfonyl-1-oxaspiro[4.5]dec-7-ene-7- carboxylate 100 mg (0.41 mmol) of ethyl 8-mercapto-1- oxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (30f) was dissolved in 4 ml of solution mixture of acetic acid and water (acetic acid : water = 1:1), and chlorine gas was blown into the reaction solution with stirring under ice-cooling for 15 minutes. Ice water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 3:1) to give 108 mg of the title compound as a colorless oil (yield: 85%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.28 (2H, q, J=7Hz), 3.88 (2H, t, J=7Hz) , 2.92-2.81 (1H, m) , 2.77-2.66 (1H, m), 1.58 (2H, m), 2.06-1.89 (3H, m), 1.80 (2H, t, 7Hz), 1.77-1.67 (1H, m) , 1.34 (3H, t, J=7Hz). (30i) Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1- oxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity diastereomer), (high polarity diastereomer) To a solution of 57 mg. (0.39 mmol) of 2-chloro-4- fluoroaniline and 0.05 ml (0.39 mmol) of triethylamine in 1 ml of ethyl acetate, was added dropwise a solution of 108 mg (0.35 mmol) of ethyl 8-chlorosulfonyl-1-oxaspiro[4.5]dec-7-ene-7- carboxylate obtained in (2 9h) in 2 ml of ethyl acetate with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane : ethyl acetate = 3:1) to give 12 mg of low polarity diastereomer of the title compound as a white powder and 20 mg of high polarity diastereomer of the title compound as an amorphous substance (yield: 8%, 14%). (Low polarity diastereomer) Melting point: 112-114°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.04-6.97 (1H, m), 6.95 (1H, s), 6.90 (1H, s), 4.45 (1H, dd, J=6Hz, 2Hz), 4.22-4.10 (2H, m), 3.96-3.88 (1H, m), 3.86-3.79 (1H, m), 2.41- 2.33 (1H, m), 2.29-2.18 (1H, m), 2.13-2.01 (4H, m), 1.94-1.79 (2H, m), 1.25 (3H, t, J=7Hz). (High polarity diastereomer) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9Hz, 5Hz), 7.13 (1H, dd, J=8Hz, 3Hz), 7.04-6.96 (2H, m) , 6.95 (1H, s) , 4.36 (1H, d, J=5Hz) , 4.22-4.10 (2H, m) , 4.03-3.96 (1H, m), 3.93-3.85 (1H, m), 2.56-2.48 (1H, m), 2.40- 2.29 (1H, m), 2.06-1.63 (6H, m), 1.26 (3H, t, J=7Hz). Example 31 Ethyl 6-[N- (1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1- carboxylate (Exemplified compound No. 1-1057) To a solution of 1.0 g (12.18 mmol) of lH-pyrrol-1- ylamine and 1.8 ml (13.40 mmol) of triethylamine in 60 ml of ethyl acetate was added dropwise a solution of 3.6 g (12.18 mmol) of ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate (compound disclosed in the specification of Japanese Patent Application (Kokai) No. 2000-178246) in 12 ml of ethyl acetate with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 3:1)and the resulting solid was further washed with isopropyl ether to give 1.9 g of the title compound as a white powder (yield: 52%). Melting point: 85-86°C 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 8.15 (1H, s), 7.44-7.42 (1H, m), 7.02 (2H, t, J=2Hz), 6.17 (2H, t, J=2Hz), 4.57-4.56 (1H, m), 4.29 (2H, q, J=7Hz), 2.52-2.46 (2H, m), 2.32-2.23 (1H, m), 1.93-1.66 (3H, m), 1.34 (3H, t, J=7Hz). Example 3 2 Ethyl 6-[N-(2-methyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1176) Following the process described in Example 31, 2-methyl- 1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 32%). Melting point: 100-101°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.95 (1H, s), 7.43-7.39 (1H, m), 7.03-6.99 (1H, m), 6.07 (1H, t, J=4Hz), 5.88-5.84 (1H, m), 4.60-4.55 (1H, m), 4.26 (2H, q, J=7Hz), 2.56-2.43 (2H, m), 2.34-2.20 (1H, m), 2.29 (3H, s), 1.95-1.66 (3H, m), 1.33 (3H, t, J=7Hz). (Example 33) Ethyl 6-[N- (2-ethyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1193) Following the process described in Example 31, 2-ethyl- 1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 51%). Melting point: 77-73°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.13 (1H, t, J=4Hz), 5.92-5.87 (1H, m), 4.62-4.57 (1H, m), 4.28 (2H, q, J=7Hz) , 2.79-2.64 (2H, m) , 2.58-2.42 (2H, m) , 2.35-2.21 (1H, m) , 1.95-1.65 (3H, m), 1.33 (3H, t, J=7Hz), 1.24 (3H, t, J=8Hz). Examp1e 34 Ethyl 6- [N- (2-propyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1210) Following the process described in Example 31, 2-propyl- 1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 31%). Melting point: 66-6B°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.12 (1H, t, J=3Hz), 5.92-5.87 (1H, m), 4.62-4.57 (1H, m), 4.27 (2H, q, J=7Hz), 2.73-2.62 (2H, m) , 2.57-2.43 (2H, m) , 2.34-2.21 (1H, m) , 1.95-1.63 (5H, m), 1.33 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz). Example 3 5 Ethyl 6-[N- (2-butyl-1H-pyrrol-1-yl)sulfamoyl] -1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1227) Following the process described in Example 31, 2-butyl- IH-pyrrol-1-ylamine was used in place of IH-pyrrol-1-ylamine to give the title compound as a white powder (yield: 26%). Melting point: 49-50°C 1H-NMR spectrum (40CMHz, CDCl3) δ ppm: 7.94 (1H, s) , 7.43-7.39 (1H, m) , 7.01-6.98 (1H, m) , 6.11-6.08 (1H, m), 5.89-5.85 (IK, m), 4.60-4.55 (1H, m), 4.26 (2H, q, J=7Hz) , 2.71-2.65 (2H, m) , 2.56-2.43 (2H, m) , 2.33-2.20 (1H, m) , 1.94-1.57 (5H, m), 1.45-1.35 (2H, m), 1.32 (3K, t, J=7Hz), 0.93 (3H, t, J=7Hz) . Example 36 Ethyl 6-[N- (2-pentyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1244) Following the process described in Example 31, 2-pentyl- 1H-pyrrol-1-ylamine obtained in Reference Example 6 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a white powder (yield: 33%) . Melting point: 60-61°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.9 6 (1H, s), 7.46-7.41 (1H, m), 7.04-7.00 (1H, m), 6.12 (1H, t, J=3Hz), 5.92-5.86 (1H, m) , 4.62-4.56 (1H, m) , 4.28 (2H, q, J=7Hz) , 2.72-2.65 (2H, m) , 2.57-2.44 (2H, m) , 2.34-2.21 (1H, m) , 1.95-1.59 (5H, m), 1.42-1.29 (4H,m), 1.34 (3H, t, J=7Hz), 0.89 (3H, t, J=7Hz). Example 3 7 Ethyl 6-[N- (2-hexyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1261) Following the process described in Example 31, 2-hexyl- 1H-pyrrol-1-ylamine obtained in Reference Example 7 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a yellow oil (yield: 46%) . 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.93 (1H, s), 7.43-7.39 (1H, m), 7.01-6.98 (1H, m), 6.12-6.08 (1H, m), 5.89-5.85 (1H, m), 4.60-4.55 (1H, m), 4.27 (2H, q, J='Hz), 2.71-2.64 (2H, m), 2.56-2.43 (2H, m), 2.33-2.21 (1H, m), 1.91-1.58 (5H,m), 1.42-1.27 (6H, m), 1.33 (3H, t, J=7Hz), 0.88 (3H, t, J=7Hz). Example 38 Ethyl 6- [N- (2-heptyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1278) Following the process described in Example 31, 2-heptyl- 1H-pyrrol-1-ylamine obtained in Reference Example 8 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a colorless oil (yield: 13%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.11 (1H, t, J=3Hz), 5.96-5.86 (1H, m), 4.62-4.56 (1H, m), 4.28 (2H, q, J=7Hz) , 2.72-2.62 (2H, m) , 2.58-2.43 (2H, m) , 2.35-2.21 (1H, m) , 1.94-1.59 (5H, m), 1.41-1.22 (8H, m), 1.33 (3H, t, J=7Hz), 0.88 (3H, t, J=7Hz). Example 3 9 Ethyl 6-[N- (2-octyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1295) Following the process described in Example 31, 2-octyl- 1H-pyrrol-1-ylamine obtained in Reference Example 8 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a pale yellow oil (yield: 18%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.96 (1H, s), 7.46-7.41 (1H, m), 7.04-7.00 (1H, m), 6.11 (1H, t, J=4Hz) , 5.91-5.86 (1H, m) , 4.61-4.57 (1H, m) , 4.28 (2H, q, J=7Hz) , 2.71-2.64 (2H, m) , 2.57-2.44 (2H, m) , 2.34-2.20 (1H, m) , 1.95-1.58 (5H, m), 1.42-1.19 (10H, m), 1.33 (3H, t, J=7Hz), 0.88 (3H, t, J=7Hz). Example 40 Ethyl 6-[N- (2-cyclopropyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1312) Following the process described in Example 31, 2- cyclopropyl-1H-pyrrol-1-ylamine obtained in Reference Example 10 was used in place of 1H-pyrrol-1-ylamine to give the title compound as a pale pink powder (yield: 42%). Melting point: 95-96°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm:. 7.87 (1H, s), 7.41-7.37 (1H, m), 6.98-6.95 (1H, m), 6.05-6.02 (1H, m), 5.69-5.66 (1H, m), 4.66-4.61 (1H, m), 4.25 (2H, q, J=7Hz) , 2.60-2.43 (2H, m) , 2.34-2.20 (1H, m) , 2.05-1.87 (2H, m) , 1.82-1.68 (2H, m), 1.31 (3H, t, J=7Hz), 0.94-0.82 (2H, m), 0.73- 0.65 (1H, m) , 0.59-0.51 (1H, m) . Example 41 Ethyl 6-[N- (2-phenyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1329) Following the process described in Example 31, 2-phenyl- 1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to give the title compound as a pale yellow powder (yield: 21%). Melting point: 160-I61°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.99 (1H, s), 7.57 (2H, d, J=8Hz), 7.39 (2H, t, J=8Hz), 7.33- 7.2 7 (2H, m), 7.14-7.11 (1H, m), 6.32-6.28 (1H, m), 6.25 (1H, t, J=4Hz), 4.22 (2H, q, J=7Hz), 4.18-4.14 (1H, m), 2.44-2.32 (1H, m) , 2.24-2.07 (2H, m) , 1.91-1.75 (1H, m) , 1.67-1.51 (1H, m) , 1.40-1.29 (1H, m), 1.28 (3H, t, J=7Hz). Example 42 Ethyl 6-[N- (2,5-dimethyl-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxyiate (Exemplified compound No. 1-1346) Following the process described in Example 31, 2,5- dimethyl-1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1- ylamine to give the title compound as a white powder (yield: 29%) . Melting point: 96-97°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.88 (1H, s) , 7.40-7.35 (1H, m) , 5.75 (2H, s), 4.58-4.52 (1H, m) , 4.24 (2H, q, 7Hz), 2.69-2.61 (1H, m) , 2.53-2.42 (1H, m) , 2.33-2.19 (1H, m), 2.26 (6H, s), 2.02-1.91 ilH, m), 1.86-1.73 (2H, m), 1.30 (3H, t, J=7Hz). Example 43 Ethyl 6-[N- (2-chloro-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1091) 150 mg (0.503 mmol) of ethyl 6-[N- (1H-pyrrol-1- yl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 31 was dissolved in 3 ml of tetrahydrofuran, and 70 mg (0.528 mmol) of iV-chlorosuccinimide was added thereto with stirring under ice-cooling, followed by stirring overnight at room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane : ethyl acetate = 2:1) and the resulting solid was further washed with isopropyl ether to give 50 mg of the title compound as a white powder (yield: 3 0%). Melting point: 60-61°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.91 (1H, s), 7.43-7.37 (1H, m), 7.04 (1H, dd, J=4Hz, 2Hz), 6.14 (1H, t, J=4Hz) , 6.10 (1H, dd, J=4Hz, 2Hz) , 4.65-4.61 (1H, m) , 4.26 (2H, q, J=7Hz), 2.61-2.44 (2H, m), 2.33-2.21 (1H, m), 2.05- 1.90 (1H, m), 1.83-1.71 (2H, m), 1.30 (3H, t, J=7Hz). Example 44 Ethyl 6-[N- (2-bromo-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (exemplified compound No. 1-1108) Following the process described in Example 43, N- bromosuccinimide was used in place of N-chlorosuccinimide to give the title compound as a white powder (yield: 50%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.85 (1H, s), 7.42-7.38 (1H, m), 7.15 (1H, dd, J=4Hz, 2Hz), 6.22-6.17 (2H, m), 4.67-4.62 (1H, m), 4.25 (2H, q, J=7Hz), 2.60- 2.44 (2H, m), 2.33-2.20 (1H, m), 2.05-1.92 (1H, m), 1.83-1.70 (2H, m), 1.30 (3H, t, J=7Hz). Example 45 Ethyl 6-[N- (2,5-dichloro-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1142) Following the process described in Example 42, 2.1 equivalent of N-chlorosuccinimide was used relative to ethyl 6- [N-(1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 31 to give the title compound as a pale yellow oil (yield: 25%). Melting point: 144-145°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 8.08 (1H,3), 7.39-7.33 (1H, m) , 6.07 (2H, s) , 4.89-4.83 (1H, m) , 4.24 (2H, q, J=7Hz), 2.67-2.58 (1H, m), 2.52-2.42 (1H, m), 2.31- 2.19 (1H, m), 2.03-1.88 (1H, m), 1.87-1.72 (2H, m), 1.29 (3H, t, J=7Hz). Example 46 Ethyl 6-[N- (2,5-dibromo-1H-pyrrol-1-yl)sulfamoyl]-1- cyclohexene-1-carboxylate (Exemplified compound No. 1-1159) Following the process described in Example 44, 2.1 equivalent of N-bromosuccinimide was used relative to ethyl 6- [N- (1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 31 to give the title compound as a white powder (yield: 3%). Melting point: 123-124°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 8.05 (1H, s), 7.40-7.35 (1H, m), 6.24 (2H, s), 5.02-4.95 (1H, m), 4.25 (2H, q, J=7Hz), 2.69-2.60 (1H, m), 2.53-2.42 (1H, m), 2.33-2.19 (1H, m), 2.02-1.90 (1H, m), 1.87-1.72 (2H, m), 1.29 (3H, t, J=7Hz). Example 47 t-Butyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-89) (47a) 8-[N- (2-Chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylic acid 1.8 g (4.29 mmol) of ethyl 8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 1 was dissolved in 60 ml of a water-tetrahydrofuran (1:1) solution, . and 900 mg (21.45 mmol) of lithium hydroxide was added thereto, followed by stirring for 7 hours at 50°C. The reaction solution was cooled with ice, it was then made acidic by addition of 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was washed with hexane to give 1.43 g of the title compound as a pale brown powder (yield: 85%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.68 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.04-6.93 (3H, m), 4.36 (1H, d, J=5Hz), 4.16-4.02 (3H, m), 3.97-3.88 (1H, m) , 2.57-2.45 (3H, m) , 2.25-2.13 (1H, m) , 1.90-1.82 (1H, m) . (47b) t-Butyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate 100 mg (0.26 mmol) of 8- [N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylic acid obtained in (47a) was dissolved in 2 ml of toluene, and 1 ml of N,N-dimethylformamide di-t-butyl acetal was added thereto, followed by stirring for 3 hours at 100°C. After the reaction solution was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; dichloromethane : methanol = 1:50) to give 52 mg of the title compound as a white amorphous substance (yield: 45%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.64 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, dd, J=8Hz, 3Hz), 7.05-6.98 (2H, m) , 6.71 (1H, s) , 4.42-4.38 (1H, m) , 4.13-4.01 (3H, m) , 3.95-3.88 (1H, m), 2.51-2.40 (2H, m), 2.21-2.10 (1H, m), 1.86- 1.79 (1H, m), 1.46 (9H, s). Following the process described in Example (47b), various corresponding acetals were used in place of N, N- dimethylformamide di-t-butyl acetal to synthesize the compounds of Examples 48 to 51. Example 4 8 Methyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-73) White powder (yield: 50%) 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.06-6.99 (1H, m) , 6.98 (1H, s) , 6.84 (1H, s) , 4.43-4.38 (1H, m) , 4.15- 3.99 (3H, m), 3.95-3.88 (1H, m), 3.73 (3H, s), 2.56-2.43 (2H, m) , 2.24-2.12 (1H, m) , 1.88-1.79 (1H, m) . Example 49 Propyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-77) White amorphous substance (yield: 18%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.05-6.97 (2H, m) , 6.81 (1H, s) , 4.42 (1H, d, J=5Hz) , 4.16-3.99 (5H, m) , 3.95-3.88 (1H, m), 2.55-2.44 (2H, m), 2.24-2.11 (1H, m), 1.88- 1.81 (1H, m), 1.71-1.60 (2H, m), 0.94 (3H, t, J=7Hz). Example 50 Butyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-81) White powder (yield: 26%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.05-6.96 (2H, m) , 6.80 (1H, s) , 4.42 (1H, d, J=5Hz) , 4.20-4.00 (5H, m) , 3.95-3.87 (1H, m), 2.55-2.44 (2H, m), 2.24-2.11 (1H, m), 1.88- 1.80 (1H, m), 1.66-1.57 (2H, m), 1.43-1.32 (2H, m), 0.93 (3H, t, J=7Hz). Example 51 Isopropyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-85) White powder (yield: 21%) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.06-6.98 (2H, m) , 6.78 (1H, s) , 5.11-4.99 (1H, m) , 4.42 (1H,, d, J=5Hz) , 4.15-3.99 (3H, m) , 3.95-3.88 (1H, m) , 2.55-2.43 (2H, m) , 2.24- 2.11 (1H, m), 1.99-1.79 (1H, m), 1.26 (3H, d, J=2Hz), 1.24 (3H, d, J=2Hz). (Example 52) Acetoxymethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]- 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 3-93) 1 g (2.55 mmol) of 8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylic acid obtained in Example 47a was dissolved in 2 0 ml of acetonitrile, and 0.50 ml (5.10 mmol) of bromomethyl acetate, 499 mg (1.53 mmol) of cesium carbonate and 471 mg (1.28 mmol) of tetrabutylammonium iodide were added thereto, followed by stirring for 1 hour at room temperature. 0.1 N hydrochloric acid was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; dichloromethane : methanol = 49:1) to give 833 mg of the title compound as an amorphous substance (yield: 70%) . 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9Hz, 5Hz), 7.18 (1H, dd, J=8Hz, 3Hz), 7.08-7.02 (1H, m) , 7.01 (1H, s) , 6.92 (1H, s) , 5.80 (2H, s) , 4.41 (1H, dd, J=6Hz, 2Hz), 4.15-4.01 (3H, m), 3.94-3.88 (1H, m), 2.48 (1H, td, J=14Hz, 4Hz), 2.44-2.37 (1H, m), 2.22-2.14 (1H, m), 2.12 (3H, s) , 1.85-1.79 (1H, m) . Following the process described in Example (1d), various corresponding anilines were used in place of 2-chloro-4- fluoroaniline to synthesize the compounds of Examples 53 to 121. Example 53 Ethyl 8-[N- (2-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2217) Oil (yield: 61%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.67-7.62 (1H, m), 7.17-7.09 (3H, m), 6.96 (1H, d, J=3Hz), 6.83 (1H, t, J=lHz), 4.43-4.40 (1H, m), 4.24-4.01 (5H, m), 3.95-3.89 (1H, m) , 2.55-2.41 (2H, m) , 2.21-2.10 (1H, m) , 1.89-1.81 (1H, m), 1.27 (3H, t, J=7Hz). Example 54 Ethyl 8-[N- (2-chlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-188) Pale brown powder (yield: 69%) Melting point: 157-160°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.70 (1H, dd, J=8Hz, 1Hz), 7.39 (1H, dd, J=8Hz, 2Hz), 7.31-7.26 (1H, m), 7.10-7.05 (2H, m), 6.83 (1H, t, J=lHz), 4.49-4.46 (1H, m) , 4.24-4.02 (5H, m) , 3.95-3.89 (1H, m) , 2.60-2.48 (2H, m) , 2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.24 (3H, t, J=7Hz). Example 55 Ethyl 8-[N- (2-bromophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1374) Oil (yield: 59%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.70 (1H, dd, J=8Hz, 1Hz), 7.55 (1H, dd, J=8Hz, 2Hz), 7.36-7.30 (1H, m), 7.04-6.98 (2H, m), 6.83 (1H, t, J=lHz), 4.50-4.47 (1H, m) , 4.23-4.01 (5H, m) , 3.95-3.88 (1H, m) , 2.62-2.49 (2H, m) , 2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.24 (3H, t, J=7Hz). Example 56 Ethyl 8-[N- (2-iodophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2224) Amorphous substance (yield: 53%) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.79 (1H, dd, J=8Hz, 1Hz), 7.67 (1H, dd, J=8Hz, 1Hz), 7.38-7.33 (1H, m), 6.88-6.82 (3H, m) , 4.49 (1H, d, J=5Hz), 4.24-4.01 (5H, m) , 3.95-3.88 (1H, m) , 2.63-2.49 (2H, m) , 2.24-2.13 (1H, m) , 1.88-1.81 (1H, m), 1.24 (3H, t, J=7Hz). Example 57 Ethyl 8-[N- (4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-100) White powder (yield: 87%) Melting point: 141-146°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.38-7.33 (2H, m), 7.07-7.01 (3H, m), 6.87 (1H, t, J=lHz), 4.30- 4.21 (3H, m), 4.14-4.01 (3H, m), 3.95-3.89 (1H, m), 2.45-2.38 (1H, m), 2.27 (1H, td, J=14Hz, 3Hz), 2.09-1.99 (1H, m), 1.87- 1.80 (1H, m), 1.33 (3H, t, J=7Hz). Example 58 Ethyl 8-[N- (4-chlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2231) White powder (yield: 81%) Melting point: 153-156°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.31 (4H, s), 7.03 (1H, s), 6.87 (1H, t, J=lHz), 4.29-4.19 (3H, m) , 4.14-4.02 (3H, m) , 3.95-3.89 (1H, m) , 2.47-2.40 (1H, m) , 2.27 (1H, td, J=14Hz, 3Hz), 2.10-2.00 (1H, m), 1.88-1.81 (1H, m) , 1.32 (3H, t, J=7Hz) . Example 59 Ethyl 8-[N- (2-methylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Eexemplified compound No. 1-2238) White powder (yield: 75%) Melting point: 101-104°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.56-7.53 (1H, m), 7.23-7.18 (2H, m), 7.11-7.06 (1H, m), 6.85 (1H, t, J=lHz), 6.62 (1H, s), 4.44 (1H, dd, J=6Hz, 2Hz), 4.25- 4.01 (5H, m) , 3.95-3.89 (1H, m) , 2.55-2.48 (1H, m) , 2.42 (1H, td, J=14Hz, 4Hz), 2.34 (3H, s), 2.19-2.09 (1H, m), 1.88-1.81 (1H, m), 1.26 (3H, t, J=7Hz). Example 6 0 Ethyl 8-[N- (2-ethylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2245) White powder (yield: 66%) Melting point: 83-87°C 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.54 (1H, dd, J=8Hz, 1Hz), 7.25-7.19 (2H, m), 7.14 (1H, td, J=7Hz, 1Hz), 6.85 (1H, s), 6.63 (1H, s), 4.47 (1H, dd, J=6Hz, 2Hz) , 4.25-4.02 (5H, m) , 2.75-2.66 (2H, m) , 2.54-2.48 (1H, m) , 2.43 (1H, td, J=14Hz, 4Hz), 2.19-2.11 (1H, m), 1.87-1.81 (1H, m) , 1.28-1.23 (6H, m) . Example 61 Ethyl 8-[N- (2-propylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1989) Oil (53% yield) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.55-7.52 (1H, m), 7.23-7.18 (2H, m), 7.14-7.09 (1H, m), 6.85 (1H, t, J=lHz), 6.64 (1H, s), 4.48-4.44 (1H, m), 4.24-4.02 (5H, m) , 3.95-3.89 (1H, m) , 2.67-2.62 (2H, m) , 2.54-2.39 (2H, m) , 2.20-2.10 (1H, m), 1.87-1.81 (1H, m), 1.69-1.58 (2H, m), 1.26 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz). Example 62 Ethyl 8-[N- (2-ethynylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2252) Oil (yield: 19%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=8Hz, 1Hz), 7.47 (1H, dd, J=8Hz, 2Hz), 7.37 (1H, td, J=8Hz, 2Hz), 7.21 (1H, s), 7.07 (1H, td, J=8Hz, 1Hz), 6.82 (1H, t, J=lHz), 4.52-4.49 (1H, m), 4.22-4.01 (5H, m), 3.95-3.88 (1H, m) , 3.49 (1H, s) , 2.65-2.50 (2H, m) , 2.24-2.13 (1H, m) , 1.88-1.81 (1H, m), 1.22 (3H, t, J=7Hz). Example 63 Ethyl 8-[N- (2-isopropylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2259) Pale brown powder (yield: 65%) Melting point: 115-118°C 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.53-7.49 (1H, m), 7.34-7.30 (1H, m), 7.23-7.17 (2H, m), 6.86 (1H, s), 6.69 (1H, s), 4.47 (1H, dd, J=6Hz, 2Hz), 4.27-4.02 (5H, m) , 3.95-3.89 (1H, m) , 3.33-3.24 (1H, m) , 2.53-2.47 (1H, m) , 2.42 (1H, td, J=14Hz, 3Hz), 2.18-2.10 (1H, m), 1.86-1.81 (1H, m) , 1.29-1.21 (9H, m) . Example 64 Ethyl 8-[N- (2-t-butylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2266) White powder (yield: 53%) Melting point: 117-120°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.45 (1H, dd, J=8Hz, 1Hz), 7.38 (1H, dd, J=8Hz, 2Hz), 7.23 (1H, td, J=8Hz, 2Hz), 7.12-7.07 (1H, m), 6.86 (1H, t, J=lHz), 6.64 (1H, s), 4.64-4.61 (1H, m), 4.24-4.03 (5H, m), 3.97-3.90 (1H, m), 2.65-2.53 (2H, m), 2.28-2.18 (1H, m), 1.90-1.83 (1H, m), 1.45 (9H, s), 1.23 (3H, t, J=7Hz). Example 65 Ethyl 8-[N- (2-sec-butylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2273) Oil (71% yield) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.54-7.49 (1H, m), 7.29-7.16 (3H, m), 6.86 (1H, dt, J=5Hz, 1Hz), 6.68 (1H, d, J=10Hz) , 4.47-4.44 (1H, m) , 4.27-4.02 (5H, m) , 3.95-3.89 (1H, m), 3.12-2.95 (1H, m), 2.53-2.35 (2H, m), 2.19- 2.07 (1H, m) , 1.86-1.80 (1H, m) , 1.70-1.55 (2H, m) , 1.31-1.19 (6H, m) , 0 .91-0.80 (3H, m) . Example 66 Ethyl 8-[N- (2-methoxyphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2280) White powder (yield: 70%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.57 (1H, dd, J=8Hz, 2Hz), 7.11-7.05 (2H, m), 6.96 (1H, td, J=8Hz, 1Hz), 6.89 (1H, dd, J=8Hz, 1Hz), 6.79 (1H, t, J=lHz), 4.44 (1H, d, J=4Hz), 4.21-4.00 (5H, m), 3.94-3.84 (4H, m), 2.58 (1H, td, J=14Hz, 4Hz) , 2.50-2.43 (1H, m) , 2.18-2.08 (1H, m) , 1.84-1.77 (1H, m), 1.23 (3H, t, J=7Hz). Example 67 Ethyl 8-[N- (2-ethoxyphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2287) White powder (yield: 60%) Melting point: 129-134°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.58 (1H, dd, J=8Hz, 2Hz), 7.12 (1H, s), 7.06 (1H, td, J=8Hz, 2Hz), 6.95 (1H, td, J=8Hz, 2Hz), 6.87 (1H, dd, J=8Hz, 1Hz), 6.79 (1H, t, J=lHz), 4.45-4.42 (1H, m), 4.20-4.00 (7H, m), 3.94-3.87 (1H, m) , 2.57 (1H, td, J=14Hz, 4Hz), 2.50-2.44 (1H, m), 2.18- 2.08 (1H, m), 1.85-1.78 (1H, m), 1.45 (3H, t, J=7Hz), 1.23 (3H, t, J=7Hz). Example 68 Ethyl 8-[N- (2-difluoromethoxyphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2294) White powder (yield: 48%) Melting point: 85-88°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.69 (1H, dd, J=8Hz, 2Hz), 7.25-7.08 (4H, m), 6.84 (1H, s), 6.57 (1H, dd, J=74Hz, 73Hz) , 4.44-4.41 (1H, m) , 4.21-4.02 (5H, m) , 3.95-3.89 (1H, m), 2.57-2.44 (2H, m), 2.21-2.10 (1H, m), 1.90- 1.82 (1H, m), 1.26 (3H, t, J=7Hz). Example 69 Ethyl 8-[N- (2-methylsulfanylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2301) White powder (yield: 56%) Melting point: 93-95°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.70 (1H, s), 7.63 (1H, dd, J=8Hz, 1Hz), 7.51 (1H, dd, J=8Hz, 2Hz), 7.33-7.28 (1H, m), 7.08 (1H, td, J=8Hz, 1Hz), 6.82 (1H, q, J=lHz), 4.50 (1H, d, J=4Hz), 4.21-4.01 (5H, m), 3.95-3.88 (1H, m), 2.65-2.50 (2H, m), 2.38 (3H, s), 2.23-2.12 (1H, m), 1.88- 1.81 (1H, m), 1.25-1.21 (3H, m). Example 70 Ethyl 8-[N- (2-acetylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2308) Oil (yield: 25%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 11.46 (1H, s), 7.91 (1H, dd, J=8Hz, 1Hz), 7.85 (1H, dd, J=8Hz, 1Hz), 7.59-7.54 (1H, m), 7.15-7.10 (1H, m), 6.80 (1H, t, J=lHz), 4.50-4.47 (1H, m), 4.16-4.00 (5H, m), 3.94-3.88 (1H, m), 2.68- 2.59 (4H, m), 2.56-2.49 (1H, m), 2.20-2.09 (1H, m), 1.87-1.80 (1H, m), 1.25 (3H, t, J=7Hz). Example 71 Ethyl 8-[N- (2-benzylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2315) White powder (yield: 73%) Melting point: 127-129°C 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.58 (1H, dd, J=8Hz, 1Hz), 7.32-7.13 (8H, m), 6.80 (1H, s), 6.50 (1H, s), 4.36 (1H, dd, J=6Hz, 2Hz), 4.23-4.00 (7H, m), 3.93-3.87 (1H, m), 2.36 (1H, td, J=14Hz, 4Hz), 2.19-2.13 (1H, m), 2.03- 1.94 (1H, m), 1.76-1.70 (1H, m), 1.26 (3H, t, J=7Hz). Example 72 Ethyl 8-{N- [2-(morpholin-4-yl)phenyl]sulfamoyl}-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2322) White powder (yield: 71%) Melting point: 118-121°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 8.10 (1H, s), 7.58 (1H, dd, J=8Hz, 2Hz), 7.23 (1H, dd, J=8Hz, 2Hz), 7.20-7.15 (1H, m), 7.07 (1H, td, J=8Hz, 2Hz), 6.82 (1H, t, 1Hz) , 4.47-4.44 (1H, m) , 4.15-4.00 (5H, m) , 3.95-3.85 (5H, m) , 2.92-2.83 (4H, m), 2.59-2.50 (2H, m), 2.24-2.12 (1H, m) , 1.90- 1.82 (1H, m), 1.23 (3H, t, J=7Hz). Example 73 Ethyl 8-[N- (9H-fluoren-1-yl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2329) Pale brown powder (yield: 60%) Melting point: 156-160°C 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.78 (1H, d, J=7Hz), 7.62 (1H, d, J=8Hz), 7.58 (1H, d, J=7Hz), 7.54 (1H, d, J=8Hz), 7.42-7.37 (2H, m), 7.34 (1H, td, J=7Hz, 1Hz), 6.92 (1H, s), 6.86 (1H, s), 4.45 (1H, dd, J=6Hz, 2Hz), 4.22-4.00 (5H, m), 3.96 (2H, s), 3.94-3.89 (1H, m), 2.56-2.50 (1H, m), 2.37 (1H, td, J=14Hz, 3Hz), 2.17-2.08 (1H, m), 1.88- 1.82 (1H, m), 1.26 (3H, t, J=7Hz). Example 74 Ethyl 8-(N-{2-[2-(pyridin-4-yl)ethyl]phenylJsulfamoyl)- 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2336) White powder (yield: 26%) Melting point: 77-80°C 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 8.50-8.47 (2H, m), 7.54-7.52 (1H, m), 7.26-7.22 (1H, m), 7.19- 7.13 (4H, m), 6.89 (1H, t, J=lHz), 6.80 (1H, s), 4.43 (1H, dd, J=6Hz, 3Hz), 4.25-4.18 (2H, m), 4.14-4.03 (3H, m), 3.96-3.90 (1H, m) , 3.15-3.00 (2H, m) , 2.99-2.89 (2H, m) , 2.54-2.48 (1H, m), 2.33 (1H, td, J=14Hz, 3Hz), 2.17-2.09 (1H, m), 1.88-1.82 (1H, m) , 1.29 (3H, t, J=7Hz) . Example 75 Ethyl 8- (N-{2-[2-(t- butoxycarbonylamino)ethyl]phenyl}sulfamoyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2343) Amorphous substance (yield: 65%) 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 8.00 (1H, s), 7.62 (1H, d, J=8Hz), 7.24 (1H, td, J=8Hz, 2Hz), 7.17 (1H, d, J=7Hz), 7.10 (1H, t, J=7Hz), 6.83 (1H, s), 4.90 (1H, brs), 4.46 (1H, d, J=5Hz), 4.23-4.01 (5H, m), 3.94-3.88 (1H, m), 3.27 (2H, q, J=7Hz), 2.96-2.83 (2H, m), 2.59-2.52 (2H, m) , 2.18-2.09 (1H, m) , 1.83-1.78 (1H, m) , 1.48-1.41 (9H, m) , 1.27 (3H, t, J=7Hz). Example 76 Ethyl 8-[N- (2-aminophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2350) Oil (yield: 13%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.39 (1H, dd, J=8Hz, 2Hz), 7.11-7.06 (1H, m), 6.89 (1H, t, J=lHz), 6.79-6.73 (2H, m), 4.46 (1H, dd, J=6Hz, 3Hz), 4.31-3.86 (3H, m), 4.28 (2H, q, J=7Hz), 4.11-4.02 (3H, m), 3.95-3.89 (1H, m), 2.48-2.41 (1H, m), 2.24 (1H, td, J=14Hz, 3Hz), 2.13-2.03 (1H, m) , 1.86-1.79 (1H, m) , 1.32 (3H, t, J=7Hz) . Example 77 Ethyl 8-[N- (2,4-difluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-276) White powder (yield: 74%) Melting point: 128-131°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.64-7.57 (1H, m), 6.97 (1H, brs), 6.93-6.86 (2H, m), 6.84 (1H, t, J=lHz), 4.36 (1H, dd, J=6Hz, 2Hz), 4.28-4.02 (5H, m), 3.95- 3.90 (1H, m), 2.53-2.46 (1H, m), 2.40 (1H, td, J=14Hz, 4Hz), 2.21-2.10 (1H, m), 1.88-1.81 (1H, m), 1.29 (3H, t, J=7Hz). Example 78 Ethyl 8-[N- (2-bromo-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1550) Pale yellow powder (yield: 48%) Melting point: 106-111°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.68 (1H, dd, J=9Hz, 5Hz), 7.32 (1H, dd, J=8Hz, 3Hz), 7.10-7.04 (1H, m) , 6.94 (1H, s) , 6.82 (1H, t, J=lHz) , 4.46-4.43 (1H, m) , 4.26-4.01 (5H, m), 3.95-3.89 (1H, m), 2.57-2.47 (2H, m), 2.24- 2.13 (1H, m), 1.87-1.81 (1H, m), 1.26 (3H, t, J=7Hz). Example 79 Ethyl 8-[N- (4-fluoro-2-methylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2357) White powder (yield: 79%) Melting point: 103-105°C 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.96-6.85 (3H, m), 6.64 (1H, brs), 4.39 (1H, dd, J=6Hz, 3Hz) , 4.27-4.18 (2H, m) , 4.14-4.02 (3H, m) , 3.96-3.89 (1H, m), 2.52-2.45 (1H, m), 2.40-2.31 (4H, m), 2.18- 2.08 (1H, m), 1.87-1.80 (1H, m), 1.29 (3H, t, J=7Hz). Example 80 Ethyl 8-[N- (3-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2364) Pale brown powder (yield: 81%) Melting point: 111-118°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.47 (1H, dd, J=6Hz, 3Hz) , 7.29-7.25 (1H, m) , 7.15-7.09 (2H, m) , 6.88 (1H, s), 4.28 (2H, q, J=7Hz), 4.21-4.18 (1H, m), 4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.49-2.41 (1H, m), 2.25 (1H, td, J=14Hz, 3Hz), 2.12-2.01 (1H, m), 1.89-1.82 (1H, m), 1.34 (3H, t, J=7Hz). Example 81 Ethyl 8- [N- (4-fluoro-3-trifluoromethylphenyl)sulfamoyl]- 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2371) White powder (yield: 78%) Melting point: 109-111°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.64-7.57 (2H, m), 7.27-7.17 (2H, m), 6.89 (1H, s), 4.28 (2H, q, J=7Hz) , 4.19-4.16 (1H, m) , 4.14-4.03 (3H, m) , 3.96-3.89 (1H, m) , 2.49-2.42 (1H, m), 2.26 (1H, td, J=14Hz, 3Hz), 2.13-2.03 (1H, m), 1.89-1.83 (1H, m), 1.34 (3H, t, J=7Hz). Example 82 Ethyl 8-[N- (4-fluoro-3-methoxy phenyl)sulfamoyl]-1,4- dioxaspiro[4.5dec-6-ene-7-carboxylate (Exemplified compound No. 1-2378) Oil (yield: 72%) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.09 (1H, dd, J=7Hz, 2Hz), 7.03 (1H, dd, J=llHz, 9Hz), 6.96 (1H, brs) , 6.88-6.83 (2H, m) , 4.30-4.23 (3H, m) , 4.14-4.02 (3H, m) , 3.95-3.89 (4H, m) , 2.46-2.38 (1H, m) , 2.27 (1H, td, J=14Hz, 3Hz), 2.10-2.00 (1H, m), 1.88-1.81 (1H, m), 1.33 (3H, t, J=7Hz). Example 83 Ethyl 8-[N- (3,4-difluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2385) Pale brown powder (yield: 94%) Melting point: 118-121°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.33-7.26 (1H, m), 7.18-7.06 (3H, m), 6.89 (1H, s), 4.28 (2H, q, J=7Hz), 4.19 (1H, dd, J=5Hz, 3Hz), 4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.48-2.41 (1H, m), 2.25 (1H, td, J=14Hz, 3Hz), 2.11- 2.01 (1H, m), 1.89-1.82 (1H, m), 1.34 (3H, t, J=7Hz). Example 84 Ethyl 8-[N- (2,4-dimethoxyphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2392) White powder (yield: 49%) Melting point: 118-121°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.47-7.45 (1H, m) , 6.78 (2H, d, J=9.8Hz), 6.50-6.47 (2H, m) , 4.38 (1H, d, J=4.7Hz), 4.21-3.80 (12H, m), 2.54 (1H, dt, J=14.2Hz, 7.2Hz), 2.45-2.38 (1H, m), 2.14-2.08 (1H, m), 1.81- 1.76 (1H, m), 1.25 (3H, t, J=7.0Hz). Example 85 Ethyl 8- [N- (2-butyl-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-628) Brown oil (yield: 82%) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.94 (1H, dd, J=10Hz, 3Hz), 6.92-6.86 (2H, m), 6.60 (1H, s), 4.41 (1H, dd, J=6Hz, 2Hz), 4.28-4.18 (2H, m) , 4.14-4.02 (3H, m) , 3.96-3.89 (1H, m) , 2.75-2.63 (2H, m) , 2.52-2.45 (1H, m), 2.37 (1H, dt, J=14Hz, 3Hz), 2.18-2.08 (1H, m), 1.87-1.80 (1H, m), 1.63-1.52 (2H, m), 1.44-1.35 (2H, m), 1.29 (3H, t, J=7Hz), 0.95 (3H, t, J=8Hz). Example 8 6 Ethyl 8- [N- (4-fluoro-2-pentylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1726) Brown oil (yield: 78%) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.49 (1H, dd;, J=9Hz, 5Hz), 6.94 (1H, dd, J=10Hz, 3Hz), 6.92- 6.85 (2H, m), 6.61 (1H, s), 4.40 (1H, dd, J=6Hz, 2Hz), 4.27-4.18 (2H, m), 4.14-4.02 (3H, m), 3.95-3.90 (1H, m), 2.76-2.61 (2H, m) , 2.52-2.45 (1H, m) , 2.37 (1H, dt, J=14Hz, 3Hz) , 2.18-2.09 (1H, m), 1.87-1.81 (1H, m), 1.65-1.52 (2H, m), 1.39-1.32 (4H, m) , 1.30 (3H, t, J=7Hz) , 0.90 (3H, t, J=7Hz) . Example 87 Ethyl 8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-804) Pale brown oil (yield: 58%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.96-6.85 (3H, m), 6.61 (1H, s), 4.40 (1H, dd, J=6Hz, 2Hz) , 4.28-4.18 (2H, m) , 4.14-4.02 (3H, m) , 3.95-3.89 (1H, m), 2.76-2.61 (2H, m), 2.52-2.45 (1H, m), 2.37 (1H, td, J=14Hz, 3Hz), 2.18-2.08 (1H, m), 1.87-1.81 (1H, m), 1.63-1.52 (2H, m) , 1.42-1.25 (9H, m) , 0.91-0.85 (3H, m) . Example 88 Ethyl 8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-980) Pale yellow oil (yield: 85%) 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.96-6.87 (3H, m), 6.63 (1H, s), 4.41 (1H, dd, J=6Hz, 2Hz) , 4.27-4.19 (2H, m) , 4.14-3.91 (4H, m) , 2.76-2.62 (2H, m), 2.52-2.46 (1H, m), 2.37 (1H, dt, J=14Hz, 3Hz), 2.18-2.09 (1H, m) , 1.84 (1H, dt, J=13Hz, 4Hz), 1.62-1.55 (2H, m), 1.40-1.24 (11H, m), 0.88 (3H, t, J=7Hz). Example 8 9 Ethyl 8- [N- (4-fluoro-2-octylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1902) Pale yellow oil (yield: 72%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.96-6.87 (3H, m), 6.62 (1H, s), 4.40 (1H, dd, J=6Hz, 2Hz) , 4.27-4.19 (2H, m) , 4.15-3.90 (4H, m) , 2.74-2.62 (2H, m), 2.52-2.46 (1H, m), 2.37 (1H, dt, J=14Hz, 3Hz), 2.18-2.10 (1H, m), 1.86-1.81 (1H, m), 1.63-1.53 (2H, m), 1.40-1.24 (13H, m), 0.88 (3H, t, J=7Hz). Example 90 Ethyl 8-[N- (4-fluoro-2-nonylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2602) Pale orange oil (yield: 82%) 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.94 (1H, dd, J=9Hz, 3Hz), 6.92-6.85 (2H, m), 6.62 (1H, s), 4.40 (1H, dd, J=6Hz, 2Hz), 4.28-4.17 (2H, m) , 4.15-4.03 (3H, m) , 3.95-3.90 (1H, m) , 2.75-2.62 (2H, m) , 2.52-2.45 (1H, m), 2.37 (1H, td, J=14Hz, 3Hz), 2.18-2.09 (1H, m) , 1.86-1.81 (1H, m) , 1.63-1.53 (2H, m) , 1.39-1.22 (15H, m) , 0.88 (3H, t, J=7Hz). Example 91 Ethyl 8-[N- (2-decyl-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2616) Pale yellow oil (yield: 83%) 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.94 (1H, dd, J=9Hz, 3Hz), 6.92-6.85 (2H, m), 6.62 (1H, s), 4.40 (1H, dd, J=5Hz, 3Hz), 4.28-4.17 (2H, m) , 4.15-4.03 (3H, m) , 3.95-3.90 (1H, m) , 2.75-2.62 (2H, m) , 2.51-2.45 (1H, m), 2.37 (1H, td, J=14Hz, 3Hz), 2.18-2.09 (1H, m) , 1.86-1.81 (1H, m) , 1.63-1.53 (2H, m) , 1.39-1.22 (17H, m) , 0.88 (3H, t, J=7Hz). Example 92 Ethyl 8-[N- (4-chloro-2-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2399) White powder (yield: 65%) Melting point: 130-133°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.62-7.56 (1H, m), 7.18-7.11 (2H, m), 7.02 (1H, s), 6.84 (1H, t, J=lHz) , 4.37 (1H, dd, J=6Hz, 2Hz) , 4.25-4.02 (5H, m) , 3.96-3.89 (1H, m), 2.55-2.48 (1H, m), 2.42 (1H, td, J=14Hz, 4Hz), 2.21- 2.11 (1H, m), 1.88-1.82 (1H, m), 1.29 (3H, t, J=7Hz). Example 93 Ethyl 8-[N- (2-bromo-4-chlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2406) Pale brown powder (yield: 51%) Melting point: 100-110°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.64 (1H, d, J=9Hz), 7.56 (1H, d, J=3Hz), 7.31 (1H, dd, J=9Hz, 3Hz) , 7.02 (1H, s) , 6.83 (1H, t, J=lHz) , 4.47-4.43 (1H, m) , 4.23-4.02 (5H, m), 3.95-3.89 (1H, m), 2.58-2.48 (2H, m), 2.24- 2.14 (1H, m), 1.89-1.82 (1H, m), 1.26 (3H, t, J=7Hz). Example 94 Ethyl 8-[N- (4-chloro-2-methylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2413) White powder (yield: 74%) Melting point: 123-126°C 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.49 (1H, d, J=9Hz), 4.21-4.15 (2H, m), 6.86 (1H, t, J=lHz), 6.65 (1H, s) , 4.38 (1H, dd, J=6Hz, 3Hz) , 4.24-4.15 (2H, m) , 4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.54-2.47 (1H, m), 2.41- 2.32 (4H, m), 2.19-2.09 (1H, m), 1.88-1.82 (1H, m), 1.29 (3H, t, J=7Hz). Example 95 Ethyl 8-[N- (4-chloro-2-methoxycarbonylphenyl)sulfamoyl]- 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2420) White powder (yield: 46%) Melting point: 131-134°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 10.48 (1H, s), 8.00 (1H, d, J=3Hz), 7.79 (1H, d, J=9Hz), 7.50 (1H, dd, J=9Hz, 3Hz), 6.80 (1H, t, J=lHz), 4.47 (1H, dd, J=6Hz, 2Hz) , 4.14-4.01 (5H, m) , 3.95-3.88 (4H, m) , 2.66-2.50 (2H, m) , 2.22-2.11 (1H, m), 1.88-1.81 (1H, m), 1.25 (3H, t, J=7Hz). Example 96 Ethyl 8-[N- (3,4-dichlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2427) White powder (yield: 66%) Melting point: 163-164°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.49 (1H, d, J=2Hz), 7.41 (1H, d, J=9Hz), 7.23 (1H, dd, J=9Hz, 3Hz), 7.16 (1H, s), 6.88 (1H, t, J=lHz), 4.27 (2H, q, J=7Hz), 4.21 (1H, q, J=3Hz), 4.14-4.02 (3H, m), 3.96-3.88 (1H, m), 2.50- 2.43 (1H, m) , 2.27 (1H, td, J=14Hz, 3Hz) , 2.13-2.03 (1H, m) , 1.89-1.82 (1H, m), 1.33 (3H, t, J=7Hz). Example 97 Ethyl 8-[N- (2,5-difluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2434) Pale brown powder (yield: 61%) Melting point: 125-128°C 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.45-7.41 (1H, m), 7.09-7.00 (2H, m), 6.86 (1H, s), 6.80-6.74 (1H, m), 4.41 (1H, dd, J=6Hz, 2Hz), 4.26-4.02 (5H, m), 3.95-3.90 (1H, m), 2.58-2.52 (1H, m), 2.44 (1H, td, J=14Hz, 3Hz), 2.23- 2.14 (1H, m), 1.89-1.84 (1H, m), 1.28 (3H, t, J=7Hz). Example 98 Ethyl 8-[N- (2,6-difluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2441) White powder (yield: 56%) Melting point: 129-131°C 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.25-7.18 (1H, m), 7.01-6.95 (2H, m), 6.89-6.87 (2H, m), 4.64 (1H, dd, J=5Hz, 2Hz) , 4.31-4.21 (2H, m) , 4.15-4.03 (3H, m) , 3.96-3.91 (1H, m), 2.63-2.57 (1H, m), 2.36 (1H, td, J=14Hz, 3Hz), 2.26-2.17 (1H, m), 1.87-1.82 (1H, m), 1.29 (3H, t, J=7Hz). Example 99 Ethyl 8-[N- (2-fluoro-4-methylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2448) White powder (yield: 69%) Melting point: 136-138°C 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.49 (1H, t, J=9Hz), 6.95-6.92 (2H, m), 6.86 (1H, d, J=2Hz), 6.83 (1H, s), 4.40-4.37 (1H, m), 4.26-4.15 (2H, m), 4.13-4.01 (3H, m), 3.94-3.89 (1H, m), 2.51-2.40 (2H, m), 2.32 (3H, s), 2.18-2.09 (1H, m), 1.86-1.81 (1H, m), 1.27 (3H, t, J=7Hz). Example 100 Ethyl 8-[N- (2-fluoro-5-methylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2455) Oil (yield: 63%) 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.43 (1H, dd, J=8Hz, 2Hz), 6.98 (1H, dd, J=10Hz, 8Hz), 6.91-6.87 (2H, m), 6.83 (1H, t, J=lHz), 4.42 (1H, dd, J=6Hz, 2Hz), 4.26- 4.02 (5H, m), 3.95-3.89 (1H, m), 2.54-2.42 (2H, m), 2.20-2.12 (1H, m) , 1.87-1.82 (1H, m) , 1.27 (3H, t, J=7Hz) . Example 101 Ethyl 8-[N- (2-fluoro-4-methoxyphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2462) Pale brown powder (yield: 57%) Melting point: 167-169°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.50 (1H, t, J=9Hz), 6.82 (1H, t, J=lHz), 6.79 (1H, brs), 6.71- 6.67 (2H, m), 4.38-4.35 (1H, m), 4.28-4.19 (2H, m), 4.14-4.01 (3H, m) , 3.95-3.88 (1H, m) , 3.79 (3H, s) , 2.49-2.36 (2H, m) , 2.18-2.08 (1H, m), 1.86-1.79 (1H, m), 1.29 (3H, t, J=7Hz). Example 102 Ethyl 8-[N- (5-chloro-2-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. . 1-2469) White powder (yield: 55%) Melting point: 88-90°C 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.68-7.65 (1H, m), 7.07-7.01 (3H, m), 6.86 (1H, s), 4.40 (1H, dd, J=6Hz, 2Hz), 4.27-4.15 (2H, m) , 4.14-4.03 (3H, m) , 3.96-3.90 (1H, m), 2.58-2.52 (1H, m), 2.43 (1H, td, J=14Hz, 3Hz), 2.23- 2.15 (1H, m), 1.89-1.84 (1H, m), 1.29 (3H, t, J=7Hz). Example 103 Ethyl 8-[N- (2,3,4-trifluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2476) White powder (yield: 71%) Melting point: 149-152°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.41-7.34 (1H, m), 7.14 (1H, brs), 7.02-6.93 (1H, m), 6.85 (1H, t, J=lHz), 4.36 (1H, dd, J=6Hz, 2Hz), 4.28-4.20 (2H, m), 4.14- 4.02 (3H, m) , 3.96-3.90 (1H, m) , 2.55-2.46 (1H, m) , 2.38 (1H, td, J=14Hz, 4Hz), 2.22-2.12 (1H, m), 1.89-1.82 (1H, m), 1.31 (3H, t, J=7Hz). Example 104 Ethyl 8-[N- (2,4,5-trifluorophenyl)sulfamoyl]-1,4- dioxaspiro [4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2483) White powder (yield: 72%) Melting point: 104-107°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.60-7.52 (1H, m), 7.05-6.97 (2H, m), 6.86 (1H, t, J=lHz), 4.35 (1H, dd, J=6Hz, 2Hz) , 4.28-4.19 (2H, m) , 4.15-4.02 (3H, m) , 3.96-3.90 (1H, m), 2.56-2.49 (1H, m), 2.38 (1H, td, J=14Hz, 4Hz), 2.23-2.12 (1H, m), 1.90-1.83 (1H, m), 1.30 (3H, t, J=7Hz). Example 105 Ethyl 8-[N- (2,4,6-trifluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2490) White powder (yield: 61%) Melting point: 131-133°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 6.91 (1H, s), 6.88 (1H, t, J=lHz), 6.80-6.72 (2H, m), 4.55 (1H, dd, J=6Hz, 3Hz), 4.31-4.23 (2H, m), 4.14-4.03 (3H, m), 3.96-3.90 (1H, m), 2.62-2.55 (1H, m), 2.32 (1H, td, J=14Hz, 3Hz), 2.25- 2.15 (1H, m), 1.88-1.81 (1H, m), 1.31 (3H, t, J=7Hz). Example 106 Ethyl 8-[N- (2,4-dichlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2497) Pale brown powder (yield: 67%) Melting point: 109-111°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.65 (1H, d, J=9Hz) , 7.41 (1H, d, J=2Hz) , 7.28-7.24 (1H, m) , 7.07 (1H, s), 6.83 (1H, s), 4.46-4.42 (1H, m), 4.24-4.02 (5H, m) , 3.98-3.89 (1H, m) , 2.56-2.46 (2H, m) , 2.24-2.13 (1H, m) , 1.89-1.82 (1H, m), 1.26 (3H, t, J=7Hz). Example 107 Ethyl 8-[N- (4-bromo-2-chlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2504) White powder (yield: 74%) Melting point: 102-107°C 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.59 (1H, d, J=9Hz) , 7.55 (1H, d, J=2Hz) , 7.40 (1H, dd, J=9Hz, 2Hz), 7.08 (1H, s), 6.83 (1H, s), 4.44 (1H, d, J=5Hz), 4.23-4.02 (5H, m), 3.95-3.89 (1H, m), 2.55-2.47 (2H, m), 2.23-2.14 (1H, m), 1.89-1.83 (1H, m), 1.26 (3H, t, J=7Hz). Ethyl 8-[N- (2-chloro-4-methylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-452) Pale brown powder (yield: 69%) Melting point: 130-135°C 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.57 (1H, d, J=9Hz), 7.20 (1H, d, J=2Hz), 7.10-7.06 (1H, m), 6.97 (1H, s), 6.81 (1H, d, J=lHz), 4.44 (1H, d, J=5Hz), 4.25- 4.00 (5H, m), 3.95-3.87 (1H, m), 2.59-2.45 (2H, m), 2.31 (3H, s), 2.22-2.10 (1H, m), 1.87-1.79 (1H, m), 1.25 (3H, t, J=7Hz). Example 109 Ethyl 8-[N- (4-t-butyl-2-chlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2511) Amorphous substance (yield: 49%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.61 (1H, d, J=9Hz), 7.38 (1H, d, J=2Hz), 7.29 (1H, dd, J=9Hz, 2Hz), 7.00 (1H, s), 6.82 (1H, s), 4.46 (1H, d, J=4Hz), 4.23-4.01 (5H, m), 3.95-3.88 (1H, m), 2.59-2.47 (2H, m), 2.23-2.12 (1H, m) , 1.87-1.80 (1H, m) , 1.29 (9H, s) , 1.25-1.21 (3H, m) . Example 110 Ethyl 8-[N- (2-chloro-6-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2518) Amorphous substance (yield: 62%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.27-7.24 (1H, m), 7.21-7.15 (1H, m), 7.12-7.06 (1H, m), 6.98 (1H, s), 6.86 (1H, s), 4.77-4.74 (1H, m), 4.30-4.21 (2H, m), 4.15-4.03 (3H, m), 3.96-3.90 (1H, m), 2.67-2.60 (1H, m), 2.38 (1H, td, J=14Hz, 3Hz) , 2.28-2.17 (1H, m) , 1.88-1.81 (1H, m) , 1.29 (3H, t, J=7Hz). Example 111 Ethyl 8-[N- (2,6-dichlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2525) Amorphous substance (yield: 24%) 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.39 (1H, s), 7.38 (1H, s), 7.27 (1H, s), 7.17 (1H, t, J=8Hz), 6.87 (1H, s), 4.88 (1H, dd, J=5Hz, 3Hz), 4.29 (2H, q, J=7Hz), 4.15-4.03 (3H, m), 3.96-3.91 (1H, m), 2.68-2.62 (1H, m), 2.31 (1H, td, J=14Hz, 3Hz) , 2.26-2.18 (1H, m) , 1.88-1.82 (1H, m) , 1.31 (3H, t, J=7Hz). Example 112 Ethyl 8-[N- (2-chloro-6-methylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1462) Amorphous substance (yield: 55%) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.29-7.23 (1H, m), 7.20-7.09 (3H, m), 6.84 (1H, t, J=lHz), 4.80- 4.77 (1H, m), 4.30-4.20 (2H, m), 4.13-4.00 (3H, m), 3.95-3.89 (1H, m), 2.58-2.46 (4H, m), 2.33 (1H, td, J=14Hz; 3Hz) , 2.25- 2.14 (1H, m), 1.85-1.78 (1H, m), 1.28 (3H, t, J=7Hz). Example 113 Ethyl 8-[N- (2,3-dichlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2532) Amorphous substance (yield: 70%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66-7.61 (1H, m), 7.26-7.19 (3H, m), 6.83 (1H, s), 4.46 (1H, d, J=5Hz), 4.22-4.01 (5H, m), 3.95-3.89 (1H, m), 2.57-2.48 (2H, m), 2.25-2.14 (1H, m), 1.89-1.82 (1H, m), 1.25 (3H, t, J=7Hz). Example 114 Ethyl 8-[N- (2,5-dichlorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2539) White powder (yield: 78%) Melting point: 120-124°C 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.72 (1H, d, J=2Hz), 7.31 (1H, d, J=9Hz), 7.11 (1H, s), 7.05 (1H, dd, J=9Hz, 2Hz), 6.86 (1H, s), 4.46 (1H, dd, J=6Hz, 2Hz), 4.25-4.03 (5H, m), 3.95-3.90 (1H, m), 2.58-2.48 (2H, m), 2.26- 2.17 (1H, m), 1.90-1.84 (1H, m), 1.26 (3H, t, J=7Hz). Example 115 Ethyl 8-[N- (2-chloro-4,6-difluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2546) Oil (yield: 29%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.07-7.03 (1H, m), 6.99 (1H, s), 6.91-6.83 (2H, m), 4.67 (1H, dd, J=5Hz, 3Hz), 4.31-4.23 (2H, m), 4.14-4.03 (3H, m), 3.97-3.90 (1H, m), 2.65-2.57 (1H, m), 2.34 (1H, td, J=14Hz, 3Hz), 2.27- 2.17 (1H, m), 1.88-1.81 (1H, m), 1.31 (3H, t, J=7Hz). Example 116 Ethyl 8-[N- (2,6-dichloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2553) Amorphous substance (yield: 3 9%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.22 (1H, s), 7.17 (2H, d, J=7Hz), 6.88 (1H, t, J=lHz), 4.84- 4.81 (1H, m), 4.29 (2H, q, J=7Hz), 4.14-4.03 (3H, m), 3.97-3.90 (1H, m), 2.67-2.60 (1H, m), 2.34-2.17 (2H, m), 1.88-1.81 (1H, m), 1.33 (3H, t, J=7Hz). Example 117 Ethyl 8-[N- (2-bromo-6-chloro-4-fluorophenyl)sulfamoyl]- 1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2560) Amorphous substance (yield: 46%) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.35 (1H, dd, J=7.5Hz, 2.8Hz), 7.24-7.21 (2H, m), 7.24 (1H, s), 4.90 (1H, d, J=5.1Hz), 4.30 (2H, q, J=7.2Hz), 4.14-3.92 (4H, m) , 2.67-2.62 (1H, m), 2.33-2.18 (2H, m), 1.88-1.84 (1H, m), 1.33 (3H, t, J=6.6Hz). Example 118 Ethyl 8-[N- (4-chloro-2-methoxy-5-methylphenyl)sulfamoyl]- 1, 4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2567) White powder (yield: 54%) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.43 (1H, s), 6.96 (1H, s), 6.87 (1H, s), 6.78 (1H, t, J=lHz), 4.41 (1H, dd, J=6Hz, 2Hz) , 4.20-4.00 (5H, m) , 3.94-3.88 (1H, m) , 3.85 (3H, s), 2.58-2.43 (2H, m), 2.31 (3H, s), 2.20-2.08 (1H, m), 1.85-1.78 (1H, m), 1.25 (3H, t, J=7Hz). Example 119 Ethyl 8-[N- (2,4-dibromophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2574) Oil (yield: 56%) 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.70 (1H, d, J=2Hz), 7.59 (1H, d, J=9Hz), 7.44 (1H, dd, J=9Hz, 2Hz), 7.02 (1H, s), 6.83 (1H, s), 4.47-4.44 (1H, m), 4.23-4.02 (5H, m), 3.95-3.90 (1H, m), 2.57-2.49 (2H, m), 2.23-2.15 (1H, m), 1.88-1.83 (1H, m), 1.26 (3H, t, J=7Hz). Example 12 0 Ethyl 8-[N- (2,6-dibromophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2581) Amorphous substance (yield: 41%) 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.61 (2H, d, J=8Hz), 7.26 (1H, brs), 7.02 (1H, t, J=8Hz), 6.88 (1H, s), 5.02-5.00 (1H, m), 4.29 (2H, q, J=7Hz), 4.15-3.91 (4H, m) , 2.70-2.64 (1H, m) , 2.33-2.19 (2H, m) , 1.87-1.83 (1H, m) , 1.32 (3H, t, J=7Hz). Example 121 Ethyl 8-[N- (2-bromo-4-isopropylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2588) White powder (yield: 51%) Melting point: 130-134°C 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.60 (1H, d, J=8Hz), 7.40 (1H, d, J=2Hz), 7.18 (1H, dd, J=8Hz, 2Hz), 6.94 (1H, s), 6.82 (1H, s), 4.48-4.46 (1H, m), 4.24-4.01 (5H, m), 3.94-3.88 (1H, m), 2.89-2.83 (1H, m), 2.60-2.47 (2H, m) , 2.22-2.13 (1H, m) , 1.86-1.81 (1H, m) , 1.25-1.21 (9H, m) . Example 122 Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-3 64) Ethyl 8-[N- (2-chloro-4-fluoropheny1)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 1 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 1:1 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 6.1 minutes high polarity compound (second peak): 10.5 minutes (low polarity compound, first peak) Melting point: 116-117°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.68 (1H, dd, J=9.2Hz, 5.3Hz), 7.17 (1H, dd, J=7.8Hz, 2.7Hz), 7.05-7.00 (2H, m), 6.83 (1H, s), 4.43 (1H, d, J=5.4Hz), 4.26- 3.90 (6H, m), 2.55-2.47 (2H, m), 4.15-2.47 (1H, m), 4.02-2.13 (1H, m), 1.27 (3H, t, J=7.0Hz). (high polarity compound, second peak) Melting point: 116-117°C 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.68 (1H, dd, J==9.0Hz, 5.5Hz), 7.17 (1H, dd, J=8.0Hz, 2.9Hz), 7.06-7.00 (2H, m), 6.84 (1H, s), 4.43 (1H, d, J=5.4Hz), 4.26- 3.90 (6H, m), 2.55-2.47 (2H, m), 1.13-2.23 (1H, m), 1.87-1.83 (1H, m), 1.27 (3H, t, J=6.6Hz). Example 123 Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-7-ene-8-carboxylate (123a) Ethyl 7-trifluoromethanesulfonyloxy-1,4- dioxaspiro[4.5]dec-7-ene-8-carboxylate Following the process described in Example (3 0e), ethyl 7-oxo-1,4-dioxaspiro[4.5]decane-8-carboxylate [compound disclosed as Compound 292c in US Patent application No. US2004/259914 A1] was used in place of ethyl 8-oxo-1- oxaspiro[4.5]decane-7-carboxylate to give the title compound as a white powder (yield: 96%) . 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.28 (2H, q, J=7Hz), 4.04-3.96 (4H, m), 2.65-2.61 (4H, m), 1.82- 1.78 (2H, m), 1.32 (3H, t, J=7Hz). (123b) Ethyl 7-acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7- ene- 8 -carboxylate Following the process described in Example (la), ethyl 7- trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-8- carboxylate obtained in (123a) was used in place of ethyl 8- trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7- carboxylate to obtain the title compound as a pale brown oil (yield: 83%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.21 (2H, q, 7Hz), 4.04-3.96 (4H, m), 2.72-2.65 (4H, m), 2.32 (3H, s), 1.85 (2H, t, J=7Hz), 1.29 (3H, t, J=7Hz). (123c) Ethyl 7-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-8- carboxylate Following the process described in Example (lb), ethyl 7- acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate obtained in (123b) was used in place of ethyl 8-acetylsulfanyl- 1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title compound as a pale brown powder (yield: 85%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 4.22 (2H, q, 7Hz), 4.20 (1H, s), 4.02-3.95 (4H, m), 2.69-2.66 (2H, m), 2.61-2.56 (2H, m), 1.82-1.78 (2H, m), 1.30 (3H, t, J=7Hz). (123d) Ethyl 7-chlorosulfonyl-l,4-dioxaspiro[4.5]dec-7- ene-8-carboxylate Following the process described in Example (lc), ethyl 7- mercapto-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate obtained in (123c) was used in place of ethyl 8-mercapto-1,4- dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title compound as a colorless oil (yield: 62%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 4.31 (2H, q, 7Hz), 4.09-4.00 (4H, m), 2.82-2.73 (4H, m), 1.86 (2H, t, J=7Hz), 1.35 (3H, t, J=7Hz). (123e) Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate Following the process described in Example (1d), ethyl 7- chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate obtained in (123d) was used in place of ethyl 8-chlorosulfonyl- 1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title compound as a white powder (yield: 61%). Melting point: 120-122°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.81 (1H, s) , 7.66 (1H, dd, J=9Hz, 5Hz) , 7.14-7.10 (2H, m) , 6.98-6.92 (1H, m), 4.71-4.67 (1H, m), 4.22-3.96 (6H, m), 2.75- 2.56 (3H, m), 2.08-2.02 (1H, m), 1.24 (3H, t, J=7Hz). Example 124 Ethyl 2-bromoethyl-8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate Following the process described in Example (17a), 1- bromo-2,3-bis[(trimethylsilyl)oxy]propane was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (yield: 100%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9.2 and 5.3Hz), 7.17 (1H, dd, J=7.8 and 2.8Hz), 7.05-6.99 (2H, m), 6.86-6.77 (1H, m), 4.53-3.84 (6H, m), 3.53- 3.31 (2H, m), 2.66-2.41 (2H, m), 2.24-2.12 (1H, m), 1.89-1.86 (1H, m) , 1.28-1.24 (3H, m) . Example 125 Ethyl (2S)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2- methoxycarbonylmethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate Following the process described in Example (17a), methyl (S)-3,4-bis[(trimethylsilyl)oxy]butyrate obtained in Reference Example 20 was used in place of 1,4-di-O-benzoyl-2,3-di-O- trimethylsilyl-D-threitol to give the title compound as a colorless oil (yield: 96%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9.0Hz, 5.4Hz), 7.16 (1H, dd, J=7.9Hz, 2.8Hz), 7.05-6.98 (2H, m), 6.88-6.76 (1H, m), 4.63-4.58 (1H, m), 4.47- 4.41 (1H, m) , 4.32-4.10 (3H, m) , 3.84-3.59 (4H, m) , 2.85-2.39 (4H, m), 2.21-2.16 (1H, m), 1.89-1.80 (1H, m), 1.29-1.24 (3H, m) . Example 126 Ethyl 3-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-7,12- dioxaspiro[5.6]dodec-1-ene-2-carboxylate (Exemplified compound No. 1-366) 34 mg (0.61 mmol) of 1,4-butanediol was dissolved in 5 ml of dichloromethane, 0.3 2 ml (1.83 mmol) of isopropoxytrimethylsilane, and 200 mg (0.47 mmol) of ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene- 1-carboxylate obtained in Example (16a) and 4 ul (0.024 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 3:1), and the resulting solid was further washed with hexane to give 6 mg of the title compound as a white powder (yield: 3%). Melting point: 142-144°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.68 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.04 (1H, s), 7.03-6.98 (2H, m), 4.44-4.40 (1H, m), 4.27-4.11 (2H, m), 3.91-3.62 (4H, m), 2.46-2.38 (1H, m), 2.31-2.21 (1H, m), 2.17- 1.94 (2H, m), 1.71-1.58 (4H, m), 1.27 (3H, t, J=7Hz). Example 127 Ethyl 4-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 3a' ,4',6',6a'-tetrahydrospiro[cyclohex-2-ene-l,2'-furo[3.4- d] [1.3]dioxol]-3-carboxylate (Exemplified compound No. 1-402) Following the process described in Example 21, 1,4- anhydro-2,3-di-O-trimethylsilyl-meso-erythritol obtained in Reference Example 21 was used in place of 1,3,4,5,7-penta-O- trimethylsilyl-D-arabitol to give the title compound as a white powder (yield: 56%). Melting point: 227-228°C 1H-NMR spectrum (400MHz, CDCl3+CD3OD) δ ppm: 7.61 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.07-6.97 (1H, m) , 6.91 (1H, s) , 4.93 (1H, dd, J=6Hz, 4Hz) , 4.81 (1H, dd, J=6Hz, 4Hz), 4.39 (1H, d, J=5Hz), 4.26-4.05 (3H, m), 4.01 (1H, d, J=llHz), 3.51-3.41 (2H, m), 2.54-2.34 (2H, m), 2.20-2.07 (1H, m), 1.90-1.79 (1H, m), 1.25 (3H, t, J=7Hz). Example 12 8 Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2,2,3,3- tetramethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate Following the process described in Example (17a), 2,3- dimethyl-2,3-bis[(trimethylsilyl)oxy]butane was used in place of 1, 4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a pale yellow oil (yield: 10%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=8.8Hz, 5.6Hz), 7.16 (1H, dd, J=7.8Hz, 2.7Hz), 7.04-7.03 (1H, m), 6.89 (1H, s), 4.37 (1H, d, J=4.0Hz), 4.25- 4.10 (2H, m), 2.51-2.43 (2H, m), 2.24-2.14 (1H, m), 1.94-1.89 (1H, m) , 1.31-1.23 (15H, m) . Example 12 9 Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2,2,3- triethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate Following the process described in Example (17a), 3- ethyl-3,4-bis[(trimethylsilyl)oxy]hexane obtained in Reference Example 22 was used in place of 1,4-di-O-benzoyl-2,3-di-O- trimethylsilyl-D-threitol to give the title compound as a white powder (yield: 88%) . Melting point: 124-126°C 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.69-7.66 (1H, m), 7.17-7.15 (1H, m), 7.04-7.00 (2H, m), 6.88- 6.69 (1H, m), 4.40-4.39 (1H, m), 4.28-4.10 (2H, m), 3.90-3.68 (1H, m), 2.54-2.31 (2H, m), 2.25-2.12 (1H, m), 1.85-1.37 (7H, m) , 1.29-1.24 (3H, m) , 1.08-0.84 (9H, m) . Example 13 0 Ethyl (3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2,2,3-triphenyl-l,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate Following the process described in Example (17a), (R)-l,2- bis[(trimethylsilyl)oxy]-1,1,2-triphenylethane obtained in Reference Example 23 was used in place of 1,4-di-O-benzoyl-2,3- di-O-trimethylsilyl-D-threitol to give the title compound as a colorless oil (yield: 30%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.22-6.91 (20H, m), 5.99-5.76 (1H, m), 4.54-4.32 (1H, m), 4.34- 4.08 (2H, m), 2.87-1.97 (4H, m), 1.36-1.14 (3H, m). Example 131 Ethyl (2R,3R) -8- [N- (2-chlorophenyl) sulfamoyl] -2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-206) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[W-(2- chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 54 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 31%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.71-7.67 (1H, m), 7.41-7.38 (1H, m), 7.32-7.26 (1H, m), 7.14- 7.06 (2H, m), 6.90 (0.5H, t, J=lHz), 6.84 (0.5H, t, J=lHz), 4.47 (1H, dd, J=6Hz, 2Hz), 4.26-4.07 (3.5H, m), 4.05-4.00 (0.5H, m), 3.94-3.80 (2H, m), 3.77-3.67 (2H, m), 2.64-2.47 (2H, m), 2.27- 1.87 (4H, m) , 1.27-1.22 (3H, m) . Example 13 2 Ethyl (2R,3R)-8-[N- (2-bromophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-1392) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8- [N- (2- bromophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate obtained in Example 55 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-G- ene- 7-carboxylate to give the title compound as an amorphous substance (yield: 28%) 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.71-7.67 (1H, m), 7.56 (1H, d, J=8Hz), 7.35-7.31 (1H, m), 7.07- 6.98 (2H, m), 6.90 (0.5H, s), 6.84 (0.5H, s), 4.48 (1H, d, J=5Hz), 4.25-4.08 (3.5H, m), 4.06-4.01 (0.5H, m), 3.94-3.80 (2H, m) , 3.76-3.68 (2H, m) , 2.65-2.48 (2H, m) , 2.23-1.87 (4H, m) , 1.27-1.22 (3H, m). Example 133 Ethyl (2R,3R) -2,3-bis (hydroxymethyl) -8- [N- (2- iodophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2226) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2-iodophenyl)sulfamoyl]- 1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate obtained in Example 56 was used in place of ethyl 8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate to give the title compound as an amorphous substance (yield: 26%). 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.80 (1H, d, J=8Hz), 7.68-7.63 (1H, m), 7.38-7.33 (1H, m), 6.90- 6.83 (3H, m), 4.50-4.46 (1H, m), 4.27-4.09 (3.5H, m), 4.06-4.02 (0.5H, m), 3.94-3.80 (2H, m), 3.77-3.68 (2H, m), 3.53 (1H, brs), 2.66-2.56 (1H, m), 2.55-2.49 (1H, m), 2.24-2.14 (1H, m), 2.00- 1.85 (2H, m), 1.27-1.23 (3H, m). Example 134 Ethyl (21R,3R) -8- [N- (2-hexylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-734) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2- hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 4 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as a colorless oil (yield: 28%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.54-7.50 (1H, m), 7.23-7.17 (2H, m), 7.15-7.09 (1H, m), 6.94- 6.91 (0.5H, m), 6.88-6.85 (0.5H, m), 6.70 (0.5H, s), 6.65 (0.5H, s) , 4.48-4.43 (1H, m) , 4.28-4.08 (3.5H, m) , 4.06-4.00 (0.5H, m) , 3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.70-2.61 (2H, m), 2.55- 2.41 (2H, m), 2.21-2.07 (1H, m), 1.96-1.75 (3H, m), 1.64-1.52 (2H, m) , 1.42-1.23 (9H, m) , 0.91-0.85 (3H, m) . Example 13 5 Ethyl (2R,3R)-8-[N- (2-heptylphenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-910) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8- [N- (2- heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 5 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as a colorless oil (yield: 33%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.54-7.50 (1H, m), 7.23-7.18 (2H, m), 7.14-7.09 (1H, m), 6.94- 6.91 (0.5H, m), 6.88-6.85 (0.5H, m), 6.70 (0.5H, s), 6.65 (0.5H, s), 4.47-4.43 (1H, m), 4.28-4.08 (3.5H, m), 4.06-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.70-2.61 (2H, m), 2.54- 2.41 (2H, m), 2.20-2.08 (1H, m), 1.96-1.74 (3H, m), 1.64-1.53 (2H, m), 1.41-1.22 (11H, m), 0.88 (3H, t, J=7Hz). Example 13 6 Ethyl (2R,3R)-8-[N- (2-chloro-4-methylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-470) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2-chloro-4- methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 10 8 was used in place of ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec- 6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 50%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.56 (1H, dd, J=8Hz, 2Hz) , 7.23-7.21 (1H, m) , 7.11-7.07 (1H, m) , 7.01 (1H, brs), 6.90 (0.5H, t, J=lHz), 6.84-6.82 (0.5H, m), 4.44 (1H, dd, J=6Hz, 2Hz), 4.27-4.08 (3.5H, m), 4.05-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.77-3.68 (2H, m), 2.63-2.44 (2H, m), 2.31 (3H, s) , 2.22-1.62 (4H, m) , 1.29-1.23 (3H, m) . Example 137 Ethyl (2R,3R)-8- [N- (2,4-dichlorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2499) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N-(2,4- dichlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 106 was used in place of ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec- 6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 22%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.64 (1H, dd, J=9Hz, 2Hz), 7.41 (1H, d, J=2Hz), 7.28-7.25 (1H, m), 7.07 (1H, brs), 6.91 (0.5H, t, J=lHz), 6.85 (0.5H, t, J=lHz), 4.43 (1H, dd, J=6Hz, 2Hz) , 4.26-4.09 (3.5H, m), 4.07- 4.02 (0.5H, m), 3.94-3.81 (2H, m), 3.77-3.68 (2H, m), 2.60-2.47 (2H, m) , 2.24-1.85 (4H, m) , 1.29-1.24 (3H, m) . Example 138 Ethyl (2R,3R)-8-[N- (2-bromo-4-chlorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-2408) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2-bromo-4- chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 93 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 10%). 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.64 (1H, dd, J=9Hz, 3Hz), 7.57 (1H, d, J=2Hz), 7.31 (1H, dd, J=9Hz, 2Hz), 7.01 (1H, brs), 6.91 (0.5H, s), 6.85 (0.5H, s), 4.45 (1H, d, J=4Hz), 4.26-4.10 (3.5H, m), 4.06-4.02 (0.5H, m), 3.94-3.82 (2H, m), 3.77-3.69 (2H, m), 2.61-2.48 (2H, m), 2.24- 2.15 (1H, m) , 2.02-1.85 (3H, m) , 1.29-1.24 (3H, m) . Example 139 Ethyl (2R,3R)-8-[N- (2-chloro-6-methylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-1480) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2-chloro-6- methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 112 was used in place of ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec- 6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 45%). 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.28 (1H, dd, J=8Hz, 1Hz), 7.23-7.07 (3H, m), 6.93-6.91 (0.5H, m) , 6.86-6.85 (0.5H, m) , 4.80-4.76 (1H, m) , 4.30-4.17 (3H, m) , 4.11-4.07 (0.5H, m) , 4.04-4.00 (0.5H, m) , 3.92-3.81 (2H, m) , 3.75-3.69 (2H, m), 2.59-2.48 (3H, m), 2.42-2.33 (1H, m), 2.26- 2.15 (1H, m) , 2.07 (1H, brs) , 1.94-1.85 (1H, m) , 1.63 (1H, brs) , 1.29-1.24 (3H, m). Example 140 Ethyl (2R,3R)-8-[N- (3-chloro-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-2366) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8- [N- (3-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 8 0 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 47%) . 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.47 (1H, dd, J=6Hz, 3Hz) , 7.29-7.25 (1H, m) , 7.17-7.06 (2H, m) , 6.97 (0.5H, t, J=lHz), 6.93-6.92 (0.5H, m) , 4.33-4.09 (4.5H, m) , 4.06-4.02 (0.5H, m) , 3.94-3.82 (2H, m) , 3.77-3.68 (2H, m) , 2.48- 2.40 (1H, m), 2.34-2.24 (1H, m), 2.12-2.01 (2H, m), 1.97-1.89 (2H, m), 1.35 (3H, t, J=7Hz). Example 141 Ethyl (2R,3R)-8-[N- (2-chloro-4,6- difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2548) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2-chloro-4,6- difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 115 was used in place of ethyl 8- [JV- (2-chloro-4-f luorophenyl) sulfamoyl] -1, 4-dioxaspiro [4.5] dec- 6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 35%). 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.07-6.85 (4H, m), 4.67 (1H, dd, J=10Hz, 6Hz), 4.32-4.19 (3H, m) , 4.14-4.02 (1H, m) , 3.93-3.82 (2H, m) , 3.76-3.70 (2H, m) , 2.66-2.55 (1H, m), 2.43-2.34 (1H, m), 2.28-2.17 (1H, m), 2.06- 1.88 (3H, m) , 1.33-1.29 (3H, m) . Example 142 Ethyl (212,31?)-8-[N- (2,6-dichloro-4- fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2555) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2,6-dichloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 116 was used in place of ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec- 6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 25%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.26-7.05 (3H, m), 6.97-6.95 (0.5H, m), 6.90-6.89 (0.5H, m), 4.85-4.80 (1H, m), 4.33-4.19 (3H, m), 4.13-4.08 (0.5H, m), 4.06- 4.02 (0.5H, m), 3.93-3.82 (2H, m), 3.76-3.70 (2H, m), 2.72-2.56 (1H, m), 2.39-2.20 (2H, m), 2.05-1.59 (3H, m), 1.35-1.30 (3H, m) . Example 143 Ethyl (21R, 3R) -8- [N- (2-bromo-6-chloro-4- fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2562) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2-bromo-6-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate obtained in Example 117 was used in place of ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec- 6-ene-7-carboxylate to give the title compound as an amorphous substance (yield: 29%). 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.36-7.31 (1H, m) , 7.23-7.19 (1H, m) , 7.16 (1H, brs) , 6.95 (0.5H, s), 6.90-6.88 (0.5H, m), 4.91-4.85 (1H, m), 4.33-4.17 (3H, m), 4.15-4.00 (1H, m), 3.94-3.80 (2H, m), 3.76-3.70 (2H, m) , 3.55 (1H, brs), 2.70-2.57 (1H, m) , 2.38-2.16 (2H, m) , 1.96- 1.87 (2H, m), 1.35-1.30 (3H, m). Example 144 Ethyl {2R,3R)-8-[N- (2,4-difluorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-294) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[iV-(2,4- difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 77 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 35%) . 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.63-7.56 (1H, m), 7.07 (1H, brs), 6.94-6.85 (3H, m), 4.38-4.34 (1H, m), 4.30-4.08 (3.5H, m), 4.06-4.00 (0.5H, m), 3.93-3.81 (2H, m), 3.78-3.68 (2H, m), 2.53-2.40 (2H, m), 2.38-1.87 (4H, m) , 1.31-1.27 (3H, m) . Example 145 Ethyl (2S,3S)-8-[N- (2,4-difluorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-294) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N-(2,4- difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 77 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 58%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.62-7.57 (1H, m), 6.93-6.86 (3H, m), 4.37-4.34 (1H, m), 4.29- 4.18 (3H, m), 4.13-4.09 (0.5H, m), 4.06-4.01 (0.5H, m), 3.94- 3.82 (2H, m), 3.76-3.69 (2H, m), 2.53-2.39 (2H, m), 2.21-1.50 (4H, m) , 1.32-1.27 (3H, m) . Example 146 Ethyl (2R,3R)-8-[N- (2-bromo-4-fluorophenyl)sulfamoyl] - 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-1568) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2-bromo-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 78 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 33%). 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.69-7.64 (1H, m) , 7.33 (1H, dd, J=7Hz, 3Hz) , 7.10-7.05 (1H, m) , 6.93 (1H, brs), 6.93 (0.5H, s), 6.84 (0.5H, s), 4.44 (1H, d, J=4Hz) , 4.27-4.09 (3.5H, m) , 4.06-4.01 (0.5H, m) , 3.94-3.80 (2H, m), 3.77-3.68 (2H, m), 3.54 (1H, brs), 2.61-2.46 (2H, m), 2.23- 2.14 (1H, m) , 2.02-1.85 (2H, m) , 1.29-1.24 (3H, m) . Example 147 Ethyl (2S,3S)-8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-1568) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N- (2-bromo-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate obtained in Example 78 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as a white amorphous substance (yield: 49%) . 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.69-7.65 (1H, m) , 7.33 (1H, dd, J=8Hz, 3Hz) , 7.10-7.06 (1H, m) , 6.99 (1H, brs), 6.91 (0.5H, s), 6.83 (0.5H, s), 4.44 (1H, d, J=4Hz) , 4.24-3.73 (8H, m) , 2.61-2.48 (2H, m) , 2.61-2.48 (1H, m) , 1.96-1.87 (1H, m), 1.26 (3H, t, J=6Hz). Example 148 Ethyl (2R,3R)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl] - 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-646) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2-butyl-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 85 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as a pale red amorphous substance (yield: 40%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.51-7.45 (1H, m), 6.97-6.85 (3H, m), 6.65 (0.5H, s), 6.59 (0.5H, s), 4.43-4.36 (1H, m), 4.29-4.16 (3H, m), 4.13-4.08 (0.5H, m), 4.07-4.01 (0.5H, m), 3.95-3.80 (2H, m), 3.77-3.68 (2H, m), 2.78-2.62 (2H, m), 2.53-2.35 (2H, m), 2.19-1.84 (4H, m), 1.65-1.49 (2H, m), 1.44-1.35 (2H, m), 1.33-1.27 (3H, m), 0.95 (3H, t, J=7Hz). Example 149 Ethyl (2S,3S)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-646) Following the process described in Examples 7, (16a) and 18 (alternative procedure) , ethyl 8-[N- (2-butyl-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 85 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as a pale red amorphous substance (yield: 14%) . 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.50-7.44 (1H, m), 6.98-6.86 (3H, m), 6.73 (0.4H, s), 6.68 (0.6H, s) , 4.43-4.37 (1H, m) , 4.26-4.16 (3H, m) , 4.11-4.07 (0.4H, m) , 4.05-3.99 (0.6H, m) , 3.90-3.80 (2H, m) , 3.78-3.68 (2H, m), 2.77-2.62 (2H, m), 2.53-2.23 (3H, m), 2.20-2.07 (2H, m) , 1.96-1.86 (1H, m) , 1.63-1.53 (2H, m) , 1.44-1.34 (2H, m) , 1.32-1.26 (3H, m), 0.95 (3H, t, J=7Hz). Example 15 0 Ethyl (2R,3R)-8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate (Exemplified compound No. 1-1744) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (4-fluoro-2- pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 86 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as a pale red amorphous substance (yield: 33%). 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.50-7.43 (1H, m), 6.97-6.85 (3H, m), 6.67 (0.5H, s), 6.61 (0.5H, s), 4.42-4.37 (1H, m), 4.30-4.17 (3H, m), 4.12-4.08 (0.5H, m) , 4.05-4.01 (0.5H, m) , 3.93-3.82 (2H, m) , 3.76-3.68 (2H, m), 2.77-2.61 (2H, m), 2.53-2.35 (2H, m), 2.19-1.80 (4H, m) , 1.66-1.50 (2H, m) , 1.40-1.22 (7H, m) , 0.95-0.87 (3H, m) . Example 151 Ethyl (2S,35)-8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-1744) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N- (4-fluoro-2- pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 86 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as a pale red amorphous substance (yield: 30%). 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.50-7.42 (1H, m), 6.97-6.84 (3H, m), 6.77 (0.5H, s), 6.72 (0.5H, s), 4.42-4.36 (1H, m), 4.30-4.14 (3H, m), 4.12-4.05 (0.5H, m), 4.04-3.98 (0.5H, m), 3.91-3.77 (2H, m), 3.76-3.67 (2H, m), 2.76-2.59 (2H, m), 2.53-2.20 (4H, m), 2.20-2.06 (1H, m) , 1.97-1.84 (1H, m) , 1.66-1.52 (2H, m) , 1.41-1.22 (7H, m) , 0.95-0.88 (3H, m). Example 152 Ethyl (2R,3R)-8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate (Exemplified compound No. 1-822) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (4-fluoro-2- hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 87 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 54%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.50-7.45 (1H, m), 6.96-6.86 (3H, m), 6.67 (0.5H, s), 6.61 (0.5H, s), 4.41-4.37 (1H, m), 4.30-4.16 (3H, m), 4.13-4.08 (0.5H, m), 4.06-4.01 (0.5H, m), 3.93-3.81 (2H, m), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.52-2.36 (2H, m), 2.20-1.50 (6H, m) , 1.41-1.26 (9H, m) , 0.91-0.86 (3H, m) . Example 153 Ethyl (2S,3S)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-822) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N- (4-fluoro-2- hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate obtained in Example 87 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-G- ene- 7 -carboxylate to give the title compound as an amorphous substance (yield: 54%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.50-7.44 (1H, m), 6.96-6.86 (3H, m), 6.70-6.67 (0.5H, m), 6.64- 6.61 (0.5H, m) , 4.41-4.37 (1H, m) , 4.29-4.15 (3H, m) , 4.12-4.07 (0.5H, m) , 4.05-4.00 (0.5H, m) , 3.93-3.80 (2H, m) , 3.76-3.68 (2H, m), 2.76-2.61 (2H, m), 2.52-2.35 (2H, m), 2.31-1.51 (6H, m) , 1.40-1.26 (9H, m) , 0.91-0.86 (3H, m) . Example 154 Ethyl (2R,3R)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-998) Following the process described in Example 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (4-fluoro-2- heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 88 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 41%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.49 (1H, m), 6.96-6.87 (3H, m), 6.68 (0.5H, s), 6.61 (0.5H, s), 4.41-4.40 (1H, m), 4.30-3.71 (8H, m), 2.72-2.65 (2H, m), 2.48- 2.39 (2H, m), 2.14-2.10 (2H, m), 1.95-1.87 (2H, m), 1.37-1.22 (11H, m), 0.88 (3H, t, J=7Hz). Example 155 Ethyl (2S,3S)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-998) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N- (4-fluoro-2- heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 88 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as a white amorphous substance (yield: 70%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.50, 7.48 (1H, m), 6.97-6.88 (3H, m), 6.70 (0.5H, s), 6.70 (0.5H, s), 4.41-4.39 (1H, m), 4.28-3.71 (8H, m), 2.75-2.63 (2H, m) , 2.51-2.37 (2H, m) , 2.19-2.10 (2H, m) , 1.95-1.88 (2H, m) , 1.35-1.23 (11H, m), 0.88 (3H, t, J=7Hz). Example 156 Ethyl (2R,3R)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-1920) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8- [N- (4-fluoro-2- octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 89 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene- 7 -carboxy late to give the title compound as an amorphous substance (yield: 47%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.51-7.47 (1H, m), 6.97-6.88 (3H, m), 6.71 (0.5H, s), 6.64 (0.5H, s) , 4.41-4.39 (1H, m) , 4.28-3.72 (8H, m) , 2.76-2.62 (2H, m) , 2.51-2.37 (2H, m) , 2.18-1.89 (4H, m) , 1.37-1.27 (13H, m) , 0.88 (3H, t, J=7Hz). Example 157 Ethyl {2S,3S)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-1920) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8- [N- (4-fluoro-2- octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 89 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 51%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.97-6.88 (3H, m), 6.69 (0.5H, s), 6.63 (0.5H, s), 4.41-4.39 (1H, m), 4.31-3.70 (8H, m), 2.72-2.66 (2H, m), 2.52-2.37 (2H, m), 2.19-1.88 (4H, m), 1.37-1.27 (13H, m) , 0.88 (3H, t, J=7Hz) . Example 158 Ethyl (2R,3R)-8-[N- (4-fluoro-2-nonylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-2604) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (4-fluoro-2- nonylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 90 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 48%) . This compound was separable into two optical isomers in accordance with the following HPLC conditions. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Fow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 4.43 minutes high polarity compound (second peak): 4.73 minutes 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.50-7.45 (1H, m), 6.97-6.86 (3H, m), 6.66 (0.5H, s), 6.60 (0.5H, s), 4.42-4.37 (1H, m), 4.28-4.18 (3H, m), 4.13-4.08 (0.5H, m) , 4.06-4.01 (0.5H, m) , 3.95-3.81 (2H, m) , 3.76-3.69 (2H, m), 2.77-2.61 (2H, m), 2.53-2.35 (2H, m), 2.19-1.99 (2H, m) , 1.96-1.86 (2H, m) , 1.64-1.52 (2H, m) , 1.40-1.18 (15H, m), 0.91-0.85 (3H, m). Example 15 9 Ethyl (2S,3S)-8-[N- (4-fluoro-2-nonylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate (Exemplified compound No. 1-2604) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N- (4-fluoro-2- nonylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 90 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 54%) . This compound was separable into two optical isomers in accordance with the following HPLC conditions. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 4:1 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 6.7 minutes high polarity compound (second peak): 10.1 minutes 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.50-7.45 (1H, m) , 6.97-6.86 (3H, m) , 6.71 (0.5H, s) , 6.65 (0.5H, s), 4.42-4.37 (1H, m), 4.30-4.16 (3H, m), 4.13-4.08 (0.5H, m), 4.05-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.77-3.69 (2H, m), 2.76-2.61 (2H, m), 2.52-2.01 (5H, m), 1.95-1.86 (1H, m), 1.64-1.52 (2H, m), 1.41-1.22 (15H, m), 0.88 (3H, t, J=7Hz). Example 160 Ethyl (2R,3R)-8-[N- (2-decyl-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate (Exemplified compound No. 1-2618) Following the process described in Examples 7, (16a) and 17 (alternative procedure), ethyl 8-[N- (2-decyl-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 91 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 35%) . This compound was separable into two optical isomers in accordance with the following HPLC conditions. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 4.3 0 minutes high polarity compound (second peak): 4.55 minutes 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.51-7.45 (1H, m), 6.97-6.86 (3H, m), 6.67 (0.5H, s), 6.61 (0.5H, s) , 4.42-4.36 (1H, m) , 4.30-4.17 (3H, m) , 4.13-4.08 (0.5H, m) , 4.06-4.01 (0.5H, m) , 3.94-3.80 (2H, m) , 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.53-2.35 (2H, m), 2.19-2.00 (2H, m), 1.99-1.86 (2H, m), 1.65-1.51 (2H, m), 1.40-1.18 (17H, m), 0.91-0.85 (3H, m). Example 161 Ethyl (2S,3S) -8-[N- (2-decyl-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-2618) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N- (2-decyl-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 91 was used in place of ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 56%). This compound was separable into two optical isomers in accordance with the following HPLC conditions. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol =4:1 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 6.4 minutes high polarity compound (second peak): 9.1 minutes 1H-NMR spectrum (5 00MHz, CDCl3) δ ppm: 7.50-7.45 (1H, m), 6.97-6.87 (3H, m), 6.70 (0.5H, s), 6.64 (0.5H, s), 4.42-4.38 (1H, m), 4.30-4.17 (3H, m), 4.12-4.08 (0.5H, m) , 4.05-4.01 (0.5H, m) , 3.93-3.81 (2H, m) , 3.78-3.69 (2H, m), 2.76-2.62 (2H, m), 2.52-2.37 (2H, m) , 2.33-2.09 (2H, m), 2.06-1.87 (2H, m), 1.63-1.52 (2H, m), 1.40-1.22 (17H, m), 0.88 (3H, t, J=7Hz). Example 162 Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2 , 3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-382) Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 17 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 2 5 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 4:1 Flow rate : 1.0 ml/min Temperature : 4 0°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 12.0 minutes high polarity compound (second peak): 16.5 minutes (Low polarity compound, first peak) Optical rotation [α]D+86.7 (c = 2.0, MeOH) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.07-6.98 (2H, m), 6.91 (1H, s), 4.42 (1H, dd, J=6Hz, 2Hz), 4.28-4.08 (4H, m), 3.91 (1H, dd, J=12Hz, 4Hz), 3.84 (1H, dd, J=12Hz, 4HZ), 3.77-3.68 (2H, m), 2.60-2.43 (2H, m), 2.26-2.11 (1H, m), 1.99- 1.87 (1H, m), 1.58 (2H, bs), 1.27 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.07-6.98 (2H, m), 6.84 (1H, s), 4.42 (1H, d, J=5Hz), 4.28-4.08 (3H, m), 4.07-4.01 (1H, m), 3.93-3.82 (2H, m), 3.77-3.68 (2H, m), 2.61- 2.46 (2H, m), 2.24-2.11 (1H, m), 1.95-1.87 (1H, m), 1.57 (2H, bs), 1.27 (3H, t, J=7Hz). Example 163 Ethyl (2S,3S) -8- [N- (2-chloro-4-fluorophenyl)sulfamoyl] - 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-382) Ethyl (2S,3S)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2, 3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 18 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 4:1 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 11.4 minutes high polarity compound (second peak): 2 7.4 minutes (Low polarity compound, first peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.06-7.00 (1H, m) , 6.98 (1H, s) , 6.84 (1H, s) , 4.42 (1H, d, J=5Hz) , 4.27- 4.09 (3H, m), 4.07-4.00 (1H, m), 3.93-3.83 (2H, m), 3.76-3.68 (2H, m), 2.60-2.47 (2H, m), 2.24-2.12 (1H, m), 1.95-1.60 (3H, m) , 1.27 (3H, t, J=7Hz).. (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.06-6.99 (2H, m), 6.90 (1H, s), 4.44-4.41 (1H, m), 4.27-4.09 (4H, m), 3.91 (1H, dd, J=12Hz, 4Hz), 3.84 (1H, dd, J=12Hz, 4HZ), 3.77- 3.67 (2H, m), 2.60-2.45 (2H, m), 2.24-2.12 (1H, m), 2.00-1.65 (3H, m), 1.27 (3H, t, J=7Hz). Example 164 Ethyl (2R,3R) -8- [N- (2,4-difluorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-294) Ethyl (2R,3R) -8- [N- (2 , 4-dif luorophenyl) sulfamoyl] -2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 144 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 4:1 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 13.7 minutes high polarity compound (second peak): 15.9 minutes (Low polarity compound, first peak) 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.62-7.57 (1H, m), 6.93-6.87 (3H, m), 4.36 (1H, q, J=3Hz), 4.28- 4.18 (3H, m), 4.15-4.09 (1H, m), 3.91 (1H, dd, J=12Hz, 4Hz), 3.84 (1H, dd, J=12Hz, 4Hz), 3.75-3.70 (2H, m), 2.51-2.40 (2H, m), 2.20-2.12 (1H, m), 1.96-1.90 (1H, m), 1.61 (2H, brs), 1.29 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.62-7.57 (1H, m), 6.97 (1H, brs), 6.93-6.86 (3H, m), 4.37-4.35 (1H, m), 4.29-4.17 (3H, m), 4.06-4.02 (1H, m), 3.91-3.84 (2H, m), 3.76-3.69 (2H, m), 2.53-2.41 (2H, m), 2.20-2.11 (1H, m), 2.05 (1H, brs), 1.94-1.88 (2H, m), 1.29 (3H, t, J=7Hz). Example 165 Ethyl (2S,3S)-8-[N- (2,4-difluorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-294) Ethyl (2S,3S)-8-[N- (2,4-difluorophenyl)sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 145 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 4 0°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 6.9 minutes high polarity compound (second peak): 10.7 minutes (Low polarity compound, first peak) 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.62-7.57 (1H, m), 6.93-6.86 (3H, m), 4.36 (1H, d, J=4Hz), 4.29- 4.18 (3H, m), 4.06-4.01 (1H, m), 3.91-3.84 (2H, m), 3.75-3.70 (2H, m), 2.52-2.42 (2H, m), 2.19-1.50 (4H, m), 1.29 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.62-7.57 (1H, m), 6.93-6.87 (3H, m), 4.36 (1H, dd, J=6Hz, 3Hz), 4.29-4.18 (3H, m), 4.13-4.09 (1H, m), 3.91 (1H, dd, J=12Hz, 4Hz), 3.84 (1H, dd, J=12Hz, 4Hz), 3.75-3.70 (2H, m), 2.51-2.40 (2H, m), 2.20-1.50 (4H, m), 1.29 (3H, t, J=7Hz). Example 166 Ethyl {2R,3R)-8-[N- (2-bromo-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1568) Ethyl [2R,3R)-8-[N- (2-bromo-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 146 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 4 0°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 6.8 minutes high polarity compound (second peak): 8.8 minutes (Low polarity compound, first peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.68 (1H, dd, J=9.2Hz, 5.2Hz), 7.34 (1H, dd, J=7.6Hz, 2.9Hz), 7.11-7.06 (1H, m), 6.91 (1H, s), 4.44 (1H, dd, J=5.8Hz, 2.0Hz), 4.28-4.10 (4H, m), 3.93-3.70 (4H, m), 2.60-2.47 (2H, m), 2.24- 2.14 (1H, m), 1.97-1.92 (1H, m), 1.27 (3H, t, J=7.0Hz). (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9.2Hz, 5.3Hz), 7.34 (1H, dd, J=7.6Hz, 2.9Hz), 7.11-7.06 (1H, m), 6.85 (1H, s), 4.44 (1H, d, J=5.0Hz), 4.27- 4.02 (4H, m), 3.92-3.84 (2H, m), 3.76-3.70 (2H, m), 2.61-2.48 (2H, m), 2.23-2.15 (1H, m), 1.92-1.88 (1H, m), 1.27 (3H, t, J=7.2Hz). Example 167 Ethyl (2S,3S) -8- [N- (2-bromo-4-fluorophenyl)sulfamoyl] - 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1568) Ethyl (2S,3S)-8-[N- (2-bromo-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 147 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 6.7 minutes high polarity compound (second peak): 13.2 minutes (Low polarity compound, first peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9Hz, 5Hz), 7.33 (1H, dd, J=8Hz, 3Hz), 7.10-7.06 (1H, m) , 6.84 (1H, s) , 4.44 (1H, d, J=5Hz) , 4.24-3.70 (8H, m) , 2.61-2.48 (2H, m), 2.24-1.87 (2H, m), 1.26 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9Hz, 5Hz), 7.33 (1H, dd, J=8Hz, 3Hz), 7.10-7.05 (1H, m) , 6.91 (1H, s) , 4.44 (1H, d, J=6Hz) , 4.27-3.69 (8H, m) , 2.59-2.48 (2H, m), 2.23-1.91 (2H, m), 1.26 (3H, t, J=7Hz). Example 168 Ethyl (2R,3R)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-646) Ethyl (2R,3R)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 148 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a pale red amorphous substance and a white powder. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol =7:3 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 5.02 minutes high polarity compound (second peak): 5.24 minutes (Low polarity compound, first peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.98-6.93 (2H, m), 6.90 (1H, dt, J=8Hz, 3Hz), 6.67 (1H, s), 4.40 (1H, dd, J=6Hz, 3Hz), 4.29-4.19 (3H, m), 4.13-4.08 (1H, m), 3.92 (1H, dd, J=12Hz, 4Hz), 3.85 (1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m), 2.78-2.62 (2H, m), 2.53- 2.35 (2H, m), 2.19-1.80 (4H, m), 1.65-1.49 (2H, m), 1.44-1.34 (2H, m), 1.31 (3H, t, J=7Hz), 0.95 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.95 (1H, dd, J=9Hz, 3Hz,), 6.93-6.86 (2H, m) , 6.62 (1H, s) , 4.41 (1H, d, J=4Hz) , 4.28-4.17 (3H, m) , 4.05-4.01 (1H, m) , 3.91-3.83 (2H, m) , 3.77-3.69 (2H, m), 2.77- 2.62 (2H, m), 2.53-2.35 (2H, m), 2.18-1.76 (4H, m), 1.65-1.50 (2H, m), 1.44-1.35 (2H, m), 1.30 (3H, t, J=7Hz), 0.95 (3H, t, J=7Hz). Example 169 Ethyl (2S,35)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-646) i Ethyl (2S,3S)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate obtained in Example 149 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder and a pale red amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 5.08 minutes high polarity compound (second peak): 5.58 minutes (Low polarity compound, first peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.47 (1H, dd, J=9Hz, 5Hz), 6.95 (1H, dd, J=9Hz, 3Hz,), 6.93-6.86 (2H, m) , 6.61 (1H, s) , 4.41 (1H, d, J=4Hz) , 4.26-4.16 (3H, m) , 4.05-3.99 (1H, m), 3.90-3.80 (2H, m), 3.78-3.68 (2H, m), 2.77- 2.62 (2H, m) , 2.53-2.39 (2H, m) , 2.33-2.05 (2H, m) , 1.96-1.86 (1H, m), 1.80-1.65 (1H, m), 1.63-1.52 (2H, m), 1.44-1.35 (2H, m), 1.29 (3H, t, J=7Hz), 0.95 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.99-6.86 (3H, m), 6.70 (1H, s), 4.40 (1H, dd, J=6Hz, 3Hz), 4.29-4.17 (3H, m), 4.13-4.07 (1H, m), 3.90 (1H, dd, J=12Hz, 4Hz), 3.84 (1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m), 2.77-2.62 (2H, m), 2.53-2.23 (3H, m), 2.20-2.00 (2H, m), 1.96-1.86 (1H, m), 1.63-1.52 (2H, m), 1.44-1.34 (2H, m), 1.30 (3H, t, J=7Hz), 0.95 (3H, t, J=7Hz). Example 170 Ethyl (2i?, 3R) -8- [N- (4-f luoro-2-pentylphenyl) sulfamoyl] - 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1744) Ethyl (2R,3R) -8- [N- (4-f luoro-2-pentylphenyl) sulfamoyl] - 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 150 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 2 5 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a pale red amorphous substance and a white powder. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 4.83 minutes high polarity compound (second peak): 5.01 minutes (Low polarity compound, first peak) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.97-6.92 (2H, m), 6.90 (1H, dt, J=8Hz, 3Hz), 6.66 (1H, s), 4.40 (1H, dd, J=6Hz, 3Hz), 4.28-4.18 (3H, m), 4.14-4.07 (1H, m), 3.92 (1H, dd, J=12Hz, 4Hz), 3.85 (1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.50- 2.35 (2H, m), 2.19-2.08 (1H, m), 1.97-1.87 (1H, m), 1.81-1.49 (4H, m), 1.40-1.32 (4H, m), 1.30 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.95 (1H, dd, J=9Hz, 3Hz), 6.93-6.86 (2H, m) , 6.60 (1H, s) , 4.41 (1H, d, J=5Hz) , 4.29-4.17 (3H, m) , 4.07-4.01 (1H, m), 3.93-3.84 (2H, m), 3.76-3.69 (2H, m), 2.76- 2.61 (2H, m), 2.54-2.36 (2H, m), 2.19-2.07 (1H, m), 2.06-1.70 (3H, m), 1.66-1.50 (2H, m), 1.40-1.32 (4H, m), 1.30 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). Example 171 Ethyl (2S,3S)-8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1744) Ethyl (2S,3S)-8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 151 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder and a pale red amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purity were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 4.90 minutes high polarity compound (second peak): 6.18 minutes (Low polarity compound, first peak) 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.97-6.85 (3H, m), 6.59 (1H, s), 4.40 (1H, d, J=5Hz), 4.29-4.17 (3H, m), 4.06-4.00 (1H, m), 3.91-3.83 (2H, m), 3.76-3.69 (2H, m), 2.76-2.59 (2H, m), 2.53-2.36 (2H, m) , 2.20-2.06 (1H, m) , 1.94-1.85 (1H, m) , 1.80-1.50 (4H, m) , 1.41-1.22 (7H, m), 0.91 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.47 (1H, dd, J=9Hz, 5Hz) , 6.97-6.92 (2H, m) , 6.89 (1H, dt, J=8Hz, 3Hz), 6.73 (1H, s), 4.40 (1H, dd, J=6Hz, 3Hz), 4.28-4.17 (3H, m), 4.12-4.05 (1H, m), 3.89 (1H, dd, J=12Hz, 4Hz), 3.82 (1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.51- 2.35 (2H, m), 2.26-2.01 (2H, m), 1.97-1.68 (2H, m), 1.66-1.54 (2H, m), 1.41-1.31 (4H, m), 1.29 (3H, t, J=7Hz), 0.90 (3H, t, J=7Hz). Example 172 Ethyl (2R, 3R) -8- [N- (4-fluoro-2-hexylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-822) Ethyl (2R,3R)-8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 152 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 9:1 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 25.2 minutes high polarity compound (second peak): 2 9.3 minutes (Low polarity compound, first peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.97-6.87 (3H, m), 6.66 (1H, s), 4.41-4.37 (1H, m), 4.29-4.19 (3H, m), 4.13-4.09 (1H, m), 3.95- 3.88 (1H, m), 3.87-3.81 (1H, m), 3.77-3.69 (2H, m), 2.77-2.62 (2H, m), 2.51-2.36 (2H, m), 2.19-2.09 (2H, m), 1.95-1.89 (2H, m) , 1.63-1.52 (2H, m) , 1.40-1.28 (9H, m) , 0.91-0.86 (3H, m) . (High polarity compound, second peak) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.47 (1H, dd, J=9Hz, 5Hz), 6.96-6.86 (3H, m), 6.63 (1H, s), 4.42-4.39 (1H, m), 4.30-4.16 (3H, m), 4.06-4.01 (1H, m), 3.91- 3.83 (2H, m), 3.77-3.69 (2H, m), 2.76-2.61 (2H, m), 2.53-2.37 (2H, m), 2.18-2.08 (2H, m), 2.03-1.98 (1H, m), 1.93-1.86 (1H, m) , 1.63-1.52 (2H, m) , 1.41-1.26 (9H, m) , 0.91-0.86 (3H, m) . Example 173 Ethyl (2S,3S)-8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-822) Ethyl {2S,3S)-8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate obtained in Example 153 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as an amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol =4:1 Flow rate : 1.0 ml/min Temperature : 4 0°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 7.6 minutes high polarity compound (second peak): 10.6 minutes (Low polarity compound, first peak) 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.95 (1H, dd, J=9Hz, 3Hz), 6.92-6.87 (2H, m) , 6.61 (1H, s) , 4.40 (1H, d, J=4Hz) , 4.29-4.17 (3H, m) , 4.06-4.02 (1H, m), 3.91-3.84 (2H, m), 3.76-3.70 (2H, m), 2.75- 2.62 (2H, m), 2.52-2.46 (1H, m), 2.42 (1H, td, J=14Hz, 3Hz), 2.17-2.09 (1H, m) , 2.05 (1H, dd, J=8Hz, 5Hz) , 1.96-1.87 (2H, m) , 1.64-1.53 (2H, m) , 1.40-1.27 (9H, m) , 0.91-0.87 (3H, m) . (High polarity compound, second peak) 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.96-6.93 (2H, m), 6.90 (1H, td, J=8Hz, 3Hz), 6.67 (1H, m), 4.39 (1H, dd, J=6Hz, 4Hz), 4.30-4.19 (3H, m), 4.13-4.09 (1H, m), 3.91 (1H, dt, J=12Hz, 4Hz), 3.84 (1H, dt, J=12Hz, 4Hz) , 3.76-3.69 (2H, m) , 2.76-2.63 (2H, m) , 2.50-2.44 (1H, m), 2.40 (1H, td, J=13Hz, 3Hz), 2.18-2.10 (2H, m) , 1.95-1.89 (2H, m) , 1.63-1.53 (2H, m) , 1.40-1.28 (9H, m) , 0.91-0.87 (3H, m). Example 174 Ethyl (2R,3R)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-998) Ethyl {2R,3R)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 154 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify the two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 9:1 Flow rate : 1.0 ml/min Temperature : 4 0°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 23.9 minutes high polarity compound (second peak): 27.4 minutes (Low polarity compound, first peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=8Hz, 5Hz), 6.96-6.88 (3H, m), 6.67 (1H, s), 4.40-4.38 (1H, m), 4.27-3.69 (8H, m), 2.72-2.62 (2H, m), 2.49- 1.89 (6H, m), 1.34-1.25 (11H, m), 0.88 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.47 (1H, dd, J=9Hz, 5Hz), 6.96-6.87 (3H, m), 6.64 (1H, brs), 4.40 (1H, d, J=4Hz), 4.29-3.71 (8H, m), 2.75-2.61 (2H, m), 2.51- 2.37 (2H, m), 2.17-1.86 (4H, m), 1.42-1.22 (11H, m), 0.88 (3H, t, J=7Hz). Example 175 Ethyl (2S,3S)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]- 2 , 3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-998) Ethyl (2S,3S)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 155 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder and a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 4 0°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 4.8 minutes high polarity compound (second peak): 6.3 minutes (Low polarity compound, first peak) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.97-6.88 (3H, m), 6.64 (1H, s), 4.41 (1H, d, J=4Hz), 4.27-3.72 (8H, m), 2.75-2.62 (2H, m), 2.51-2.38 (2H, m), 2.18-1.38 (4H, m), 1.38-1.28 (11H, m), 0.88 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) 6 ppm: 7.49 (1H, dd, J=9Hz, 5Hz), 6.97-6.88 (3H, m), 6.69 (1H, s), 4.41-4.39 (1H, m), 4.29-3.71 (8H, m), 2.77-2.62 (2H, m), 2.49- 1.90 (6H, m), 1.38-1.29 (11H, m), 0.89 (3H, t, J=7Hz). Example 176 Ethyl (2R,3R)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1920) Ethyl (21R, 31R) -8- [N- (4-f luoro-2-octylphenyl) sulfamoyl] - 2 , 3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 156 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 9:1 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 22.9 minutes high polarity compound (second peak): 25.8 minutes (Low polarity compound, first peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz), 6.96-6.88 (3H, m), 6.68 (1H, s), 6.68-4.40 (1H, m), 4.28-3.70 (8H, m), 4.28-3.70 (2H, m), 2.52- 1.89 (6H, m), 1.36-1.19 (13H, m), 0.88 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 7.46 (1H, dd, J=9Hz, 5Hz), 6.95-6.87 (3H, m), 4.40 (1H, d, J=5Hz) , 4.28-3.71 (8H, m) , 2.73-2.60 (2H, m) , 2.50-1.87 (6H, m) , 1.31-1.25 (13H, m), 0.89 (3H, t, J=7Hz). Example 177 Ethyl (2S,3S)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-1920) Ethyl (2S,35)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 157 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white powder and a colorless oil. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 4.7 minutes high polarity compound (second peak): 6.1 minutes (Low polarity compound, first peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.48 (1H, dd, J=9Hz, 5Hz) , 6.97-6.88 (3H, m), 6.63 (1H, s), 4.41 (1H, d, J=5Hz), 4.28-3.71 (8H, m), 2.75-2.62 (2H, m), 2.51-1.88 (6H, m), 1.38-1.27 (13H, m), 0.88 (3H, t, J=7Hz). (High polarity compound, second peak) 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=9Hz, 6Hz) , 6.97-6.88 (3H, m) , 6.97-6.88 (1H, m) , 4.41-4.38 (1H, m), 4.31-3.71 (8H, m), 2.77-2.63 (2H, m), 2.50- 1.90 (6H, m), 2.50-1.90 (13H, m), 0.88 (3H, t, J=7Hz). Example 178 Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate Following the process described in Example (17a), 1,4-di- O-methyl-2,3-di-O-trimethylsilyl-D-threitol was used in place of 1, 4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a colorless oil (yield: 89%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.68-7.64 (1H, m), 7.16 (1H, dd, J=8.1Hz, 3.0Hz), 7.17-7.16 (3H, m) , 4.39 (1H, d, J=3.5Hz), 4.24-3.98 (4H, m) , 3.43-3.42 (4H, m) , 3.43 (1.5H, s), 3.42 (1.5H, s), 3.39 (1.5H, s), 3.38 (1.5H, s), 2.57-2.45 (2H, m) , 2.57-2.45 (1H, m) , 1.96-1.86 (1H, m) , 1.27 (3H, dt, J=6.9Hz, 2.1Hz). Example 179 Ethyl (2S,3S)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate Following the process described in Example (17a), 1,4-di- O-methyl-2,3-di-O-trimethylsilyl-1-threitol was used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a colorless oil (91% yield). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.68-7.64 (1H, m), 7.16 (1H, dd, J=7.8 and 2.4Hz), 7.04-7.00 (2H, m), 6.89 (1H, s), 4.40-4.39 (1H, m), 4.23-3.97 (4H, m), 3.62-3.47 (4H, m), 3.43 (1.5H, s), 3.41 (1.5H, s), 3.39 (1.5H, s), 3.38 (1.5H, s), 2.58-2.45 (2H, m), 2.26-2.16 (1H, m), 1.96- 1.86 (1H, m), 1.26 (3H, dt, J=7.0 and 3.5Hz). Example 180 Ethyl (2S,3S)-2,3-bis(benzyloxymethyl)-8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate Following the process described in Example (17a), 1,4-di- O-benzyl-2,3-di-O-trimethylsilyl-1-threitol was used in place of l,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a colorless oil (yield: 94%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.69-7.64 (1H, m), 7.37-7.26 (10H, m), 7.16 (1H, dd, J=7.8Hz, 2.8Hz), 7.04-6.90 (3H, m), 4.64-4.51 (4H, m), 4.40 (1H, t, J=4.5Hz), 4.30-4.05 (4H, m), 3.68-3.57 (4H, m), 2.58-2.45 (2H, m) , 2.25-2.17 (1H, m), 1.96-1.86 (1H, m) , 1.21 (3H, dt, J=7.0Hz, 3.5Hz) . Example 181 Ethyl (2R,3R)-2,3-bis(acetoxymethyl)-8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate Following the process described in Example (17a), 1,4-di- O-acetyl-2,3-di-O-trimethylsilyl-D-threitol obtained in Reference Example 24 was used in place of l,4-di-O-benzoyl-2,3- di-O-trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (50% yield). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.67 (1H, dd, J=9.2Hz, 5.3Hz), 7.17 (1H, dd, J=7.9Hz, 2.8Hz), 7.05-7.00 (2H, m), 6.90-6.76 (1H, m), 4.41 (1H, d, J=4.7Hz), 4.37-4.37 (8H, m), 2.60-2.46 (2H, m), 2.23-2.04 (8H, m), 1.26 (3H, t, J=7.0Hz). Example 182 Ethyl (2S,3S)-2,3-bis(acetylaminomethyl)-8-[N- (2-chloro- 4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-410) 218 mg (1.07 mmol) of N- (4-acetylamino-2R, 3R- dihydroxybutyl)acetamide and 0.57 ml (3.20 mmol) of isopropoxytrimethylsilane were dissolved in 3 ml of nitromethane, and 13 µl (0.071 mmol) of trimethylsilyl trifluoromethanesulfonate and 300 mg (0.711 mmol) of ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene- 1-carboxylate obtained in Example (16a) were sequentially added thereto with stirring under ice-cooling, followed by stirring for 3 hours at the same temperature and then for 116 hours at room temperature. To the reaction solution was added saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate : methanol =9:1) to give 203 mg of the title compound as an amorphous substance (yield: 51%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.68-7.63 (1H, m), 7.20-7.15 (1H, m), 7.08-7.00 (2H, m), 6.78- 6.73 (1H, m), 6.46-6.38 (1H, m), 6.34-6.26 (1H, m), 4.42-4.39 (1H, m), 4.29-4.14 (2H, m), 3.96-3.85 (1.5H, m), 3.75-3.69 (0.5H, m), 3.61-3.42 (4H, m), 2.55-2.43 (2H, m), 2.21-2.01 (7H, m) , 1.90-1.78 (1H, m) , 1.31-1.25 (3H, m) . Example 183 Ethyl (2i?,3i?) -8- [N- (2-chloro-4-f luorophenyl) sulfamoyl] - 2,3-bis((R)-1-hydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-2163) Following the process described in Example 17 (alternative procedure) , (1R, 2R, 3R, 4R) -4-benzoyloxy-1-methyl-2,3 - bis[(trimethylsilyl)oxy]pentyl benzoate obtained in Reference Example 25 was used in place of 1,4-di-O-benzoyl-2,3-di-O- trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (yield: 3 3%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.66 (1H, dd, J=9.0 and 5.0Hz), 7.17 (1H, dd, J=7.8 and 2.7Hz), 7.09 (1H, d, J=9.0Hz), 7.05-7.00 (1H, m), 6.80 (0.5H, s), 6.76 (0.5H, s), 4.39 (1H, d, J=5.4Hz), 4.27-4.09 (2H, m), 3.88-3.56 (4H, m), 2.50-2.42 (2H, m), 2.19-2.11 (1H, m), 1.85-1.79 (1H, m), 1.33 (3H, t, J=5.3Hz), 1.27 (6H, t, J=7.0Hz). Example 184 Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2,3-bis((R)-1-hydroxypropyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-2164) Following the process described in Example 17 (alternative procedure) , (1R, 2R, 3R,4R) -4-benzoyloxy-1-ethyl-2 , 3- bis[(trimethylsilyl)oxy]hexyl benzoate obtained in Reference Example 26 was used in place of 1,4-di-O-benzoyl-2,3-di-O- trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (yield: 21%) . 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.68 (1H, dd, J=9.2Hz, 5.2Hz), 7.18 (1H, dd, J=7.4Hz, 2.4Hz), 7.06-7.01 (2H, m), 6.81 (0.5H, s), 6.78 (0.5H, s), 4.40 (1H, d, J=5.1Hz), 4.29-4.12 (2H, m), 3.88-3.55 (4H, m), 3.03 (1H, brs), 2.92 (1H, brs), 2.51-2.41 (2H, m), 2.21-2.13 (2H, m), 1.90-1.73 (1H, m), 1.55-1.43 (3H, m), 1.29 (3H, t, J=7.2Hz), 1.05-0.97 (6H, m) . Example 18 5 Ethyl (3a' R,6a'R,6'R) -4-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-6'-hydroxymethyl-4'-oxo-3a',4',6',6a'- tetrahydrospiro[cyclohex-2-ene-l,2'-furo[3.4-d][1.3]dioxol]-3- carboxylate (Exemplified compound No. 1-2165) Following the process described in Example (17a), (3R,4R,5R)-3,4-bis[(trimethylsilyl)oxy]-5- [(trimethylsilyl)oxy]methyldihydrofuran-2-one was used in place of 1, 4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the title compound as a white amorphous substance (yield: 25%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 7.69-7.64 (1H, m), 7.20-7.16 (1H, m), 7.06-6.96 (2H, m), 6.82- 6.68 (1H, m), 5.04-4.62 (3H, m), 4.44-4.40 (1H, m), 4.26-4.14 (2H, m), 4.05-3.98 (1H, m), 3.90-3.81 (1H, m), 2.74-2.46 (2H, m) , 2.24-2.12 (1H, m) , 1.97-1.83 (2H, m) , 1.30-1.26 (3H, m) . Example 186 Ethyl (2J?,3i?) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] - 2, 3-bis((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (low polarity compound, first peak), (high polarity compound, second peak) (Exemplified compound No. 1-386) Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]- 2,3-bis((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 23 was subjected to high performance liquid chromatography (column; CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol) to separate and purify two optical isomers, and low polarity compound (first peak) and high polarity compound (second peak) were respectively obtained as a white amorphous substance. According to the result of HPLC analysis of the two optical isomers obtained under the conditions below, their optical purities were respectively >99%ee. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 7:3 Flow rate : 1.0 ml/min Temperature : 4 0°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 7.3 minutes high polarity compound (second peak): 9.9 minutes (Low polarity compound, first peak) 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.65 (1H, dd, J=9Hz, 5Hz), 7.21 (1H, bs), 7.17 (1H, dd, J=8Hz, 3Hz), 7.06-6.99 (1H, m), 6.80 (1H, s), 4.38 (1H, d, J=5Hz), 4.27-4.12 (4H, m), 4.08 (2H, d, J=7Hz), 3.95-3.88 (1H, m), 3.87- 3.64 (5H, m), 2.98-2.68 (2H, m), 2.54-2.42 (2H, m), 2.22-2.08 (1H, m) , 1.91-1.82 (1H, m) , 1.25 (3H, t, J=7Hz) . (High polarity compound, second peak) 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.63 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, bs), 7.12 (1H, dd, J=8Hz, 3Hz), 7.05-6.97 (1H, m), 6.76 (1H, s), 4.37 (1H, d, J=6Hz), 4.27-4.01 (5H, m), 3.97-3.86 (2H, m), 3.85-3.45 (5H, m), 2.77- 2.57 (2H, m), 2.52-2.41 (2H, m), 2.21-2.08 (1H, m), 1.89-1.80 (1H, m), 1.26 (3H, t, J=7Hz). Example 18 7 Ethyl-(2R,3R)-8-[N- (2-chloro-4-fluorophenyl)-N- methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec- 6-ene-7-carboxylate (Exemplified compound No. 2-15) 235 mg (0.49 mmol) of ethyl (2R,3R)-8-[N- (2-chloro-4- fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro [4.5]dec-6-ene-7-carboxylate obtained in Example 17 was dissolved in 1.5 ml of acetone, and 84 mg (0.59 mmol) of methyl iodide and 13 8 mg (1.00 mmol) of potassium carbonate were added sequentially, followed by stirring for 3 hours at 50°C. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 1:3) to give 175 mg of the title compound as a white amorphous substance (yield: 73%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.57 (1H, brs) , 7.22 (1H, dd, J=8Hz, 3Hz) , 7.05-7.00 (1H, m) , 6.87 (0.5H, s), 6.79 (0.5H, s), 4.58 (1H, brs), 4.28-3.73 (8H, m), 3.25 (3H, s), 2.60-1.80 (6H, m), 1.26 (3H, t, J=7Hz). Example 188 Ethyl 8-[N- (4-fluoro-2-propylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No. 1-2077) Following the process described in Example (1d), 4- fluoro-2-propylphenylamine obtained in Reference Example 27 was used in place of 2-chloro-4-fluoroaniline to give the title compound as an oil (yield: 84%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 8.09-8.07 (4H, m) , 7.59-7.55 (2H, m) , 7.47-7.43 (4H, m) , 7.47- 7.43 (2H, m), 3.96 (2H, s), 2.00-1.79 (4H, m), 1.02 (6H, t, J=7Hz), 0.07 (18H, s). Example 18 9 Ethyl (2S,3S)-8-[N- (4-fluoro-2-propylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-2095) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8-[N- (4-fluoro-2- propylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 188 was used in place of ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec- 6-ene-7-carboxylate to give the title compound as a white amorphous substance (38% yield). This compound was separable into two optical isomers in accordance with the following HPLC conditions. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 4:1 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 9.6 minutes high polarity compound (second peak): 14.1 minutes 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.51-7.47 (1H, m), 6.97-6.88 (3H, m), 6.70 (0.5H, s), 6.64 (0.5H, s), 4.42-4.39 (1H, m), 4.28-3.72 (8H, m), 2.75-2.61 (2H, m) , 2.52-2.37 (2H, m) , 2.19-1.87 (4H, m) , 1.68-1.57 (2H, m) , 1.32-1.28 (3H, m), 0.99 (3H, t, J=8Hz). Example 190 Ethyl (2R,3R) -2,3-bis ( (1R) -1, 2-dihydroxyethyl) -8- [N- (4- fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-1748) Following the process described in Examples 7, (16a) and 23, ethyl 8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 86 was used in place of ethyl 8- [N- (2-chloro-4- fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7- carboxylate to give the title compound as a white powder (yield: 33%) . This compound was separable into two optical isomers in accordance with the following HPLC conditions. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol =7:3 Flow rate : 1.0 ml/min Temperature : 40°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 5.2 9 minutes high polarity compound (second peak): 5.82 minutes 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.49-7.44 (1H, m), 6.97-6.86 (2H, m), 6.84 (0.5H, m), 6.82 (0.5H, m) , 6.73 (0.5H, s), 6.69 (0.5H, s), 4.41-4.36 (1H, m) , 4.27-4.17 (2H, m), 4.12-4.01 (1.5H, m), 3.97-3.88 (1.5H, m), 3.88-3.67 (5H, m), 2.77-2.60 (2H, m), 2.50-2.30 (2H, m), 2.20- 1.40 (8H, m) , 1.39-1.25 (7H, m) , 0.93-0.86 (3H, m) . Example 191 Ethyl (2S,35)-8-[N- (4-fluoro-2-methylphenyl)sulfamoyl]- 2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate (Exemplified compound No. 1-2359) Following the process described in Examples 7, (16a) and 18 (alternative procedure), ethyl 8- [N- (4-fluoro-2- methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7- carboxylate obtained in Example 79 was used in place of ethyl 8- [N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6- ene-7-carboxylate to give the title compound as an amorphous substance (yield: 49%) . This compound was separable into two optical isomers in accordance with the following HPLC conditions. HPLC conditions Column : CHIRALPAK AD-H (produced by Daicel Chemical Industries, Ltd. inner diameter 0.46 cm, length 25 cm) Mobile phase : hexane : 2-propanol = 4:1 Flow rate : 1.0 ml/min Temperature : 4 0°C Detection : 254 nm (UV) Retention time : low polarity compound (first peak): 13.5 minutes high polarity compound (second peak): 19.6 minutes 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.49 (1H, dd, J=8.8Hz, 5.3Hz), 6.96-6.88 (3H, m), 6.70 (0.5H, brs) , 6.64 (0.5H, brs) , 4.40-4.37 (1H, m) , 4.28-3.70 (8H, m) , 2.51-2.32 (5H, m) , 2.21-1.87 (2H, m) , 1.31-1.27 (3H, m) . [Reference Examples] Reference Example 1 1,4-Di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol 300 mg (0.90 mmol) of 1,4-di-O-benzoyl-meso-erythritol (compound described in J. Am. Chem. Soc., 82, 2585 (I960)), 0.28 ml (1.98 mmol) of triethylamine and 11 mg (0.09 mmol) of 4- dimethylaminopyridine were dissolved in 6 ml of dichloromethane, and 0.24 ml (1.89 mmol) of trimethylsilyl chloride was added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. To the reaction solution was added saturated aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate alone) to give 418 mg of the title compound as a white powder (yield: 98%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 8.04 (4H, d, J=7Hz) , 7.55 (2H, t, J=7Hz) , 7.43 (4H, t, J=7Hz) , 4.53 (2H, dd, J=12Hz, J=3Hz), 4.36 (2H, dd, J=12Hz, 5Hz), 4.13- 4.08 (2H, m) 0.13 (18H, s). Reference Example 2 1,3,4,5,7-Penta-O-trimethylsilyl-D-arabitol Following the process described in Reference Example 1, D- arabitol was used in place of 1,4-di-O-benzoyl-meso-erythritol to give the title compound as a colorless oil (yield: 26%). 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 3.84-3.80 (1H, m) , 3.76-3.68 (3H, m) , 3.63-3.54 (2H, m) , 3.49 (1H, dd, J=10Hz, J=7Hz), 0.14-0.09 (45H, m). Reference Example 3 1,6-Di-O-benzoyl-2,3,4,5-tetra-O-trimethylsilyl-D- mannitol Following the process described in Reference Example 1, 1,6-di-O-benzoyl-D-mannitol was used in place of 1,4-di-O- benzoyl-meso-erythritol to give the title compound as a pale brown oil (yield: 98%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 8.05 (4H, d, J=7Hz), 7.55 (2H, t, J=7Hz), 7.43 (4H, t, J=7Hz), 4.59 (2H, dd, J=12Hz, 2Hz), 4.38-4.31 (2H, m), 4.24-4.20 (2H, m), 3.83 (2H, br.s), 0.17 (18H, s), 0.11 (18H, s). Reference Example 4 2-Trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamantane-1-carboxylate (4a) 2-Phenyl[1.3]dioxan-5-ol adamantane-1-carboxylate 1.00 g (5.55 mmol) of 2-phenyl[1.3]dioxan-5-ol, 1.16 ml (8.32 mmol) of triethylamine and 68 rag (0.56 mmol) of 4- dimethylaminopyridine were dissolved in 2 0 ml of dichloromethane, and 1.28 g (6.10 mmol) of 1-adamantanecarbonyl chloride was added thereto with stirring under ice-cooling, followed by stirring for 3 0 minutes at the same temperature, and then further for 15 hours at room temperature. Dichloromethane was distilled off under reduced pressure, and to the residue was added aqueous sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 9:1) to give 1.52 g of the title compound as a pale yellow powder (yield: 80%) . 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.52-7.48 (2H, m), 7.42-7.33 (3H, m), 5.54 (1H, s), 4.68-4.66 (1H, m), 4.26-4.22 (2H, m), 4.18-4.13 (2H, m), 2.07-2.01 (3H, m), 2.01-1.97 (6H, m), 1.77-1.69 (6H, m). (4b) 2-Hydroxy-1-hydroxymethylethyl adamantane-1- carboxylate 400 mg (1.17 mmol) of 2-phenyl[1.3]dioxan-5-yl adamantane-1-carboxylate obtained in (4a) was dissolved in 8 ml of ethyl acetate and 400 mg of 20% palladium hydroxide-carbon (water content: 50%) was added thereto, followed by stirring for 4 hours under hydrogen atmosphere at room temperature. After the catalyst was filtered, the filtrate was concentrated under reduced pressure to give 2 94 mg of the title compound as a white powder (yield: 99%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.90-4.85 (1H, m), 3.84-3.76 (4H, m), 2.16-2.00 (5H, m), 1.94- 1.87 (6H, m) , 1.78-1.67 (6H, m) . (4c) 2-Trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamant ane-1-c arboxylate Following the process described in Reference Example 1, 2-hydroxy-1-hydroxymethylethyl adamantane-1-carboxylate obtained in (4b) was used in place of 1,4-di-O-benzoyl-meso-erythritol to give the title compound as a colorless oil (yield: 70%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.85-4.79 (1H, m), 3.72-3.61 (4H, m), 2.04-1.97 (3H, m), 1.92- 1.83 (6H, m), 1.76-1.65 (6H, m), 0.11 (18H, s). Reference Example 5 Diethyl 2,2-bis[(trimethylsilyl)oxy]methylmalonate Following the process described in Reference Example 1, diethyl 2,2-bis(hydroxymethyl)malonate was used in place of 1,4- di-O-benzoyl-meso-erythritol to give the title compound as a colorless oil (yield: 75%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.17 (4H, q, J=7Hz), 4.04 (4H, s), 1.23 (6H, t, J=7Hz), 0.07 (18H, s) . Reference Example 6 2 -Pentyl-1H- pyrrol-1-ylamine (6a) (2£)-4-Oxo-2-nonenal 2.0 g (14.47 mmol) of 2-pentylfuran was dissolved in 60 ml of dichloromethane, and 3.84 g (14.47 mmol) of 65% m- chloroperbenzoic acid was added dropwise thereto with stirring under ice-cooling, followed by stirring for 1 hour at the same temperature. To the reaction solution was added saturated aqueous sodium carbonate and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure to give 1.62 g of the title compound as a yellow oil (yield: 73%). 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 10.23 (1H, d, J=7Hz), 6.95 (1H, d, J=12Hz), 6.18 (1H, dd, J=12Hz, 7Hz), 2.26 (2H, t, J=7Hz), 1.73-1.61 (2H, m), 1.40-1.26 (4H, m), 0.91 (3H, t, J=6Hz). (6b) 4 -Oxononanal 1.62 g (10.5 mmol) of (2E) -4-oxo-2-nonenal obtained in (6a) was dissolved in 30 ml of ethyl acetate, and 160 mg of 10% palladium-carbon (water content: 50%) was added thereto, followed by restirring for 2 hours under hydrogen atmosphere at room temperature. After the catalyst was filtered, the filtrate was concentrated under reduced pressure to give 1.50 g of the title compound as a pale yellow oil (91% yield). 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 9.81 (1H, s), 2.81-2.67 (4H, m), 2.47 (2H, t, J=7HZ), 1.67-1.53 (2H, m), 1.38-1.21 (4H, m), 0.89 (3H, t, J=7Hz). (6c) Benzyl 2-pentyl-1H-pyrrol-1-ylcarbamate 1.5 0 g (9.60 mmol) of 4-oxononanal obtained in (6b) was dissolved in 45 ml of ethanol-acetic acid (2:1) solution mixture, and 1.60 g (9.60 mmol) of benzyl hydrazinecarboxylate was added thereto, followed by stirring for 1 hour at 8 0°C. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =2:1) to give 2.12 g of the title compound as a yellow oil (77% yield). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 7.36 (5H, bs), 7.21 (1H, ds), 6.63-6.59 (1H, m), 6.07 (1H, t, J=4Hz) , 5.89-5.84 (1H, m) , 5.22 (2H, ds) , 2.46-2.36 (2H, m) , 1.63-1.49 (2H, m), 1.37-1.22 (4H, m), 0.88 (3H, t, J=7Hz). (6d) 2 -Pentyl-1H- pyrrole-1-amine 1.0 g (3.49 mmol) of benzyl 2-pentyl-1H-pyrrol-1- ylcarbamate obtained in (6c) was dissolved in 2 0 ml of ethanol, and 100 mg of 10% palladium-carbon (water content: 50%) was added thereto, followed by stirring for 2 hours under hydrogen atmosphere at room temperature. After the catalyst was filtered, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 2:1) to give 430 mg of the title compound as a yellow oil (yield: 81%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 6.68 (1H, m), 5.97 (1H, t, J=3Hz), 5.82-5.77 (1H, m), 4.52 (2H, s), 2.58 (2H, t, J=8Hz), 1.69-1.57 (2H, m), 1.44-1.31 (4H, m), 0.91 (3H, t, J=7Hz). Reference Example 7 2-Hexyl-1H- pyrrol-1-ylamine Following the procedure described in Reference Example 6, 2-hexylfuran was used as the starting material in place of 2- pentylfuran to give the title compound as a yellow oil (yield: 29%) . 1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm: 6.67-6.63 (1H, m), 5.99-5.94 (1H, m), 5.81-5.77 (1H, m), 4.52 (2H, br.s), 2.62-2.55 (2H, m), 1.67-1.56 (2H, m), 1.44-1.21 (6H, m), 0.89 (3H, t, J=7Hz). Reference Example 8 2-Heptyl-1H- pyrrol-1-ylamine Following the procedure described in Reference Example 6, 2-heptylfuran was used as the starting material in place of 2- pentylfuran to give the title compound as a pale yellow soild (yield: 59%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 6.67-6.63 (1H, m), 5.99-5.94 (1H, m), 5.81-5.77 (1H, m), 4.52 (2H, br.s), 2.62-2.55 (2H, m), 1.67-1.53 (2H, m), 1.44-1.21 (8H, m), 0.89 (3H, t, J=7Hz). Reference Example 9 2-Octyl-1H- pyrrol-1-ylamine Following the procedure described in Reference Example 6, 2-octylfuran was used as the starting material in place of 2- pentylfuran to give the title compound as a yellow oil (yield: 11%) . 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 6.65-6.61 (1H, m), 5.97-5.93 (1H, m), 5.78-5.75 (1H, m), 4.51 (2H, br.s), 2.60-2.55 (2H, m), 1.66-1.54 (2H, m), 1.42-1.21 (10H, m), 0.88 (3H, t, J=7Hz). Reference Example 10 2-Cyclopropyl-1H- pyrrol-1-ylamine (10a) 4-Cyclopropyl-4-oxobutanal 230 mg (1.79 mmol) of 1-cyclopropyl-4-hydroxy-1-butanone was dissolved in 7 ml of dichloromethane, and 580 mg (2.69 mmol) of pyridinium chlorochromate was added thereto,followed by stirring for 1 hour at room temperature. To the reaction solution was added diethyl ether, the mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; diethyl ether alone) to give 176 mg of the title compound as a pale yellow oil (yield: 78%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 9.78 (1H, s), 2.91 (2H, t, J=7Hz), 2.78-2.71 (2H, m), 2.01-1.93 (1H, m) , 1.08-1.01 (2H, m) , 0.96-0.88 (2H, m) . (10b) 2-Cyclopropyl-1H- pyrrol-1-ylamine Following the procedures described in Reference Examples (6c) and (6d), 4-cyclopropyl-4-oxobutanal obtained in (10a) was used in place of 4-oxononanal to give the title compound as a pale yellow oil (yield: 45%) . 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 6.70-6.64 (1H, m), 5.94-5.88 (1H, m), 5.71-5.64 (1H, m), 4.69 (2H, br.s), 1.83-1.72 (1H, m), 0.91-0.83 (2H, m), 0.64-0.57 (2H, m) . Reference Example 11 4 -Fluoro-2-heptylphenylamine (11a) 4-Fluoro-2-(hept-1-enyl)-1-nitrobenzene 3.0 g (7.0 mmol) of hexyltriphenylphosphonium bromide was suspended in 30 ml of tetrahydrofuran, and 4.5 ml (7.0mmol) of n-butyl lithium/hexane solution (1.56 M) was added dropwise thereto at -10°C. After the reaction solution was stirred for 10 minutes at the same temperature, 846 mg (5.0 mmol) of 4-fluoro- 2-nitrobenzaldehyde was added, and the reaction solution was further stirred for 1 hour. To the reaction solution was added IN aqueous potassium hydrogensulfate and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium hydrogencarbonate and water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 19:1) to give 917 mg of the title compound as a pale yellow oil (yield: 77%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 8.09 (1.7H, dd, J=9Hz, 5Hz), 7.97 (1H, dd, J=9Hz, 5Hz), 7.26- 6.99 (5.4H, m), 6.89 (1H, d, J=16Hz), 6.69 (1.7H, d, J=llHz), 6.26 (1H, dt, J=16Hz, 7Hz), 5.87 (1.7H, dt, J=12Hz, 8Hz), 2.28 (2H, q, J=7Hz), 2.10 (3.4H, q, J=7Hz), 1.52-1.23 (16.2H, m), 0.91 (3H, m), 0.86 (5.1H, m). (11b) 4-Fluoro-2-heptylphenylamine 910 mg (3.8 mmol) of 4-fluoro-2-(hept-1-enyl)-1- nitrobenzene obtained in (11a) was dissolved in 5 ml of ethanol, and 100 mg of 10% palladium-carbon (water content: 50%) was added thereto, followed by stirring for 2 hours under hydrogen atmosphere at room temperature. After the catalyst was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =9:1) to give 730 mg of the title compound as a pale yellow oil (yield: 91%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 6.80-6.71 (2H, m), 6.61 (1H, dd, J=9Hz, 5Hz), 3.47 (2H, brs), 2.45 (2H, t, J=7Hz), 1.64-1.58 (2H, m), 1.42-1.24 (8H, m), 0.89 (3H, t, J=6Hz). Reference Example 12 2-Butyl-4-fluorophenylamine Following the procedure described in Reference Example 11, propyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a brown oil (yield: 78%) . 1H-NMR spectrum (40 0MHz, CDCl3) 5 ppm: 6.80-6.69 (2H, m), 6.60 (1H, dd,, J=9Hz, 5Hz), 3.51 (2H, bs), 2.46 (2H, t, J=8Hz), 1.63-1.56 (2H, m), 1.45-1.37 (2H, m), 0.96 (3H, t, J=7Hz). Reference Example 13 4 -Fluoro-2-pentylphenylamine Following the procedure described in Reference Example 11, butyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a yellow oil (yield: 78%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 6.80-6.69 (2H, m), 6.60 (1H, dd,, J=9Hz, 5Hz), 3.50 (2H, bs), 2.45 (2H, t, J=8Hz), 1.64-1.58 (2H, m), 1.45-1.36 (4H, m), 0.91 (3H, t, J=7Hz). Reference Example 14 4 -Fluoro-2-hexylphenylamine Following the procedure described in Reference Example 11, pentyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a pale brown oil (yield: 63%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 6.81-6.71 (2H, m), 6.66 (1H, dd, J=9Hz, 5Hz), 4.19 (2H, brs), 2.48 (2H, t, J=8Hz), 1.65-1.57 (2H, m), 1.43-1.25 (6H, m), 0.92- 0.85 (3H, m). Reference Example 15 4 -Fluoro-2 -octylphenylamine Following the procedure described in Reference Example 11, heptyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a pale yellow oil (yield: 65%) 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 6.80-6.71 (2H, m), 6.61 (1H, dd, J=9Hz, 5Hz), 2.45 (2H, t, J=7Hz), 1.64-1.56 (2H, m), 1.38-1.22 (10H, m), 0.88 (3H, t, J=7Hz). Reference Example 16 4-Fluoro-2-nonylphenylamine Following the procedure described in Reference Example 11, octyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a pale brown oil (yield: 97%). 1H-NMR spectrum (50 0MHz, CDCl3) δ ppm: 6.77 (1H, dd, J=10Hz, 3Hz), 6.72 (1H, td, J=8Hz, 3Hz), 6.59 (1H, dd, J=9Hz, 5Hz), 3.46 (2H, brs), 2.45 (2H, t, J=8Hz), 1.64-1.56 (2H, m), 1.44-1.21 (12H, m), 0.88 (3H, t, J=7Hz). Reference Example 17 2-Decyl-4 -fluorophenylamine Following the procedure described in Reference Example 11, nonyltriphenylphosphonium bromide was used in place of hexyltriphenylphosphonium bromide to give the title compound as a pale brown oil (yield: 67%). 1H-NMR spectrum (500MHz, CDCl3) δ ppm: 6.77 (1H, dd, J=10Hz, 3Hz), 6.73 (1H, dd, J=8Hz, 3Hz), 6.60 (1H, dd, J=9Hz, 5Hz), 3.47 (2H, brs), 2.45 (2H, t, J=8Hz), 1.64-1.56 (2H, m), 1.43-1.21 (14H, m), 0.88 (3H, t, J=7Hz). Reference Example 18 l,4-Di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol 17.48 g (52.9 mmol) of 1,4-di-O-benzoyl-D-threitol and 10.8 g (159 mmol) of imidazol were dissolved in 250 ml of dichloromethane, and 12.6 g (116 mmol) of chlorotrimethylsilane was added thereto with stirring under ice-cooling, followed by stirring for 1 hour at room temperature. The reaction solution was directly subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 20:1-5:1) to give 24.5 9 g of the title compound as a white powder (yield: 98%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 8.04 (4H, dd, J=8Hz, J=lHz), 7.57-7.52 (2H, m), 7.46-7.40 (4H, m) , 4.50 (2H, dd, J=llHz, J=4Hz) , 4.48-4.33 (2H, m) , 4.13-4.08 (2H, m), 0.14 (18H, s). Reference Example 19 1,4-Di-O-benzoyl-2,3-di-O-trimethylsilyl-1-threitol Following the process described in Reference Example 18, 1,4-di-O-benzoyl-1-threitol was used in place of 1,4-di-O- benzoyl-D-threitol to give the title compound as a white powder (yield: 98%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 8.04 (4H, dd, J=8Hz, J=lHz), 7.57-7.52 (2H, m), 7.46-7.40 (4H, m) , 4.50 (2H, dd, J=llHz, J=4Hz) , 4.48-4.33 (2H, m) , 4.13-4.08 (2H, m), 0.14 (18H, s). Reference Example 2 0 Methyl (S)-3,4-bis[(trimethylsilyl)oxy]butyrate Following the process described in Reference Example 18, methyl (S)-3,4-dihydroxybutyrate was used in place of 1,4-di-O- benzoyl-D-threitol to give the title compound as an oil (yield: 62%) . 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 4.18-4.12 (1H, m), 3.67 (3H, s), 3.52 (1H, dd, J=10Hz, 6Hz), 3.40 (1H, dd, J=10Hz, 6Hz), 2.59 (1H, dd, J=15Hz, 5Hz), 2.37 (1H, dd, J=15Hz, 7Hz), 0.10 (18H, s). Reference Example 21 1,4-Anhydro-2, 3-di-O-trimethylsilyl-jneso-erythritol Following the process described in Reference Example 1, 1,4-anhydroerythritol was used in place of 1,4-di-O-benzoyl- meso-erythritol to give the title compound as a colorless oil (yield: 21%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.15-4.10 (2H, m), 3.92-3.85 (2H, m), 3.68-3.62 (2H, m), 0.14 (18H, s) . Reference Example 22 3-Ethyl-3,4-bis[(trimethylsilyl)oxy]hexane (22a) 3-Ethylhexane-3,4-diol 590 mg (5.0 mmol) of dimethyloxalate was dissolved in 20 ml of tetrahydrofuran, and 22 ml (22 mmol) of 1.0 M ethyl magnesium bromide/tetrahydrofuran solution was added thereto with stirring under ice-cooling, followed by stirring for 2 hours at the same temperature. The reaction solution was made acidic by addition of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =3:1) to give 276 mg of the title compound as an oil (yield: 38%). 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 3.45-3.41 (1H, m) , 1.87 (1H, d, J=6Hz) , 1.75 (1H, s) , 1.70-1.31 (6H, m), 1.04 (3H, t, J=7Hz), 0.89 (3H, t, J=8Hz), 0.89 (3H, t, J=8Hz). (22b) 3-Ethyl-3,4-bis[(trimethylsilyl)oxy]hexane 2 70 mg (1.85 mmol) of 3-ethylhexane-3,4-diol obtained in (22a) was dissolved in 5 ml of pyridine, and 597 mg (3.7 mmol) of 1,1,1,3,3,3-hexamethylsilazane and 1.20 g (11 mmol) of chlorotrimethylsilane were added sequentially, followed by stirring for 2 hours at the same temperature and further overnight at room temperature. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate =9:1) to give 469 mg of the title compound as an oil (yield: 88%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 3.38 (1H, dd, J=9.0Hz, 3.0Hz), 1.68-1.33 (6H, m), 0.90 (3H, t, J=6.0Hz), 0.92-0.90 (6H, m), 0.11-0.08 (18H, m). Reference Example 23 (R) -1, 2-Bis [ (trimethylsilyl) oxy] -1,1, 2-triphenylethane Following the process described in Reference Example 18, (R)-1,1,2-triphenyl-l,2-ethanediol was used in place of 1,4-di- O-benzoyl-D-threitol to give the title compound as a powder (yield: 99%). 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 7.28-7.18 (15H, m), 5.51 (1H, s), -0.05 (9H, s), -0.16 (9H, s). Reference Example 24 1,4-Di-O-acetyl-2,3-di-O-trimethylsilyl-D-threitol Following the process described in Reference Example 18, 1,4-di-O-acetyl-D-threitol was used in place of 1,4-di-O- benzoyl-D-threitol to give the title compound as an oil (yield: 96%) . 1H-NMR spectrum (400MHz, CDCl3) δ ppm: 4.20 (2H, dd, J=llHz, 4Hz), 4.01 (2H, dd, J=llHz, 7Hz), 3.88- 3.84 (2H, m), 2.06 (6H, s), 0.13 (18H, s). Reference Example 25 (1R,2R,3R,4R)-4-Benzoyloxy-1-methyl-2,3 - bis[(trimethylsilyl)oxy]pentyl benzoate Following the process described in Reference Example 18, (li?, 2S, 3S, 4R) -4-benzoyloxy-2 , 3-dihydroxy-1-methylpentyl benzoate was used in place of 1,4-di-O-benzoyl-D-threitol to give the title compound as an oil (yield: 86%). 1H-NMR spectrum (4 00MHz, CDCl3) δ ppm: 8.06-8.04 (4H, m), 7.57-7.54 (2H, m), 7.46-7.42 (4H, m), 5.31- 5.25 (2H, m), 3.98-3.97 (2H, m), 1.41 (6H, d, J=6Hz), 0.12 (18H, s) . Reference Example 26 (1R,2R,3R,4:R) -4-Benzoyloxy-1-ethyl-2,3 - bis[(trimethylsilyl)oxy]hexyl benzoate Following the process described in Reference Example 18, (1R,2S,3S,4R)-4-benzoyloxy-1-ethyl-2,3-dihydroxyhexyl benzoate was used in place of 1,4-di-O-benzoyl-D-threitol to give the title compound as an oil (yield: 82%). 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 8.09-8.07 (4H, m), 7.59-7.55 (2H, m), 7.47-7.43 (4H, m), 7.47- 7.43 (2H, m), 3.96 (2H, s), 2.00-1.79 (4H, m), 1.02 (6H, t, J=7Hz), 0.07 (18H, s). Reference Example 2 7 4-Fluoro-2-propylphenylamine Following the process described in Reference Example 11, ethyltriphenylphosphonium bromide was used, in place of hexyltriphenylphosphonium bromide to give the title compound as a pale yellow oil (yield: 17%) . 1H-NMR spectrum (40 0MHz, CDCl3) δ ppm: 6.80-6.59 (3H, m), 3.48 (2H, brs), 2.45 (2H, t, J=7Hz), 1.70- 1.58 (2H, m), 1.01 (3H, t, J=8Hz). (Test Example 1) Suppression effect against endotoxin stimulated TNF-α production in cells (in vitro) The suppression rate of the compound according to the present invention against TNF-α production when human monocyte cell line U93 7 was stimulated by endotoxin, was measured. Specifically, to RPMI1640 medium containing 10% (volume %) of heat-inactivated new born calf serum, was added 12-O- tetradecanoylphorbol 13-acetate so that its final concentration became 30 ng/ml. U937 cells were suspended with the medium and plated to a 96 well culture plate (Sumilon) so that number of cells/volume was 2 x 104/0.1 ml, and were then cultured for 3 days at 37°C in a carbon dioxide incubator with 5% C02 and 100% humidity. After completion of incubation, the culture supernatant was removed. The compound according to the present invention was added to each of the wells in various concentrations, and lypopolysaccharide (LPS) (E.coli 0111:B4, Sigma) was also added so that its final concentration was 3 0 ng/ml. After incubating the culture plate in the carbon dioxide incubator again for 4.5 hours, the culture supernatant was collected. By using a 384 half well black plate (Greiner) and HTRF quantitative kit of CIS Bio International, the concentration of TNF-α in the culture supernatant was measured as time-resolved fluorescence with Discovery (Packard). From the measured value in the absence of LPS (X), measured value in the absence of the compound according to the present invention (Y) and measured value in the presence of the compound according to the present invention (Z), the suppression rate of TNF-α production was obtained by the following calculation formula [I]. Suppression rate of TNF-α production (%)={l-(Z-X)/(Y- X)}xl00 [I] In the present test, the compound according to the present invention showed an excellent suppression effect against endotoxin stimulated TNF-α production in cells. (Test Example 2) Suppression effect against elevated TNF-α concentration in blood (in vivo) The suppression effect of the compound according to the present invention against elevated TNF-α concentration in blood was evaluated. The test for TNF-α concentration elevation in blood was conducted in accordance with the process of Parant et al, which is described in Journal of Leukocyte Biology, Vol. 47, p. 164 (1990). In the test, 3 to 4 male Sprague Dawley rats (8-9 weeks old) were used for each group. 4 hours before the administration of LPS, muramyl dipeptide dissolved in a physiological saline solution (1 mg/ml) was administered to the tail vein at a rate of 1 ml/kg. 0.5 hours before the administration of LPS, the rats were anaesthetized with pentobarbital (40 mg/kg), and the compound according to the present invention dissolved in 5% dimethyl acetamide/ 95% polyethylene glycol 400 solution was administered to the right femoral vein at a rate of 1 ml/kg. The control group was administered with 5% dimethyl acetamide/95% polyethylene glycol 400 solution at a rate of 1 ml/kg. LPS dissolved in a physiological saline solution (3 pg/ml) was administered to the left femoral vein at a rate of 1 ml/kg. 2 hours after the administration of LPS, blood was collected using 3.8%(w/v) sodium citrate solution as an anticoagulant, and blood plasma was separated by centrifuge (10,000 g, 5 minutes, 4°C) . TNF-α concentration in the blood plasma was measured using a TNF-α quantitative kit (Bio Source International, Inc.). From the TNF-α concentration in the blood of control group (X) and the TNF-α concentration in the blood of the group administered with the compound according to the present invention (Y), the TNF-α production suppression rate was calculated using the following calculation formula [II]. TNF-α production suppression rate (%)={l-Y/X}xl00 [II] In the present test, the compound according to the present invention showed excellent suppression effects against elevated TNF-α concentration in blood. WE CLAIM: 1. A compound represented by the general formula (I): {wherein X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A, or X and Y together represent a substituent of ring B, (1) in the case where X and Y represent a group in which X and Y together with the carbon atom of ring B to which they are bound form ring A: ring A represents a 3- to 7-membered heterocyclyl ring [ in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO2, the heterocyclyl ring may include an unsaturated bond, may form a fused ring or spiro ring with a 3- to 7-membered heterocyclyl ring, and ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α, a cyclopropyl C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with 1 to 5 groups selected from Substituent group α ; (2) in the case where X and Y together represent a substituent of ring B: X and Y represent an oxo group; I and m, independently from each other, represent an integer of 0 to 3, and I + m is -1 to 3; n represents an integer of 0; R2 represents a hydrogen atom, a C1-C6 alkyl group which may be substituted with group(s) selected from Substituent group β, R3 represents a phenyl group which may be substituted with group(s) selected from Substituent group ε, or a 5- or 6-membered heteroaryl group which may be substituted with group(s) selected from Substituent group ε (the heteroaryl group includes 1 to 3 hetero atoms selected from a nitrogen atom; R5 represents a hydrogen atom, provided that in the case where R3 is a phenyl group which may be substituted with group(s) selected from Substituent group ε, X and Y represent the aforementioned (1) or (2); Substituent group α represents a hydroxy group, halogen atom, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, carboxy group, C1-C6 alkoxy-carbonyl group; and a group having the formula NR6R7, and R6 and R7, independently from each other, represent a hydrogen atom, C1-C6 alkanoyl group, or together with the nitrogen atom to which they are bound form a heterocyclyl group; Substituent group β represents C1-C6 alkoxy group and C1-C6 alkoxy-carbonyl group; Substituent group ε represents a hydroxy group, halogen atom, C1-C14 alkyl group, cyclopropyl C1-C14 alkyl group, halogeno C1-C14 alkyl group, C1-C14 alkoxy group, halogeno C1-C14 alkoxy group, carboxy group, C1-C14 alkanoyl group, C1-C14 alkoxy-carbonyl group, C1-C14 alkylthio group, carbamoyl group, C1-C14 alkyl-carbamoyl group, group having the formula NR6R7 (R6 and R7 are the same as R6 and R7 of Substituent group α), C6-C10 aryl group and 5-membered heteroaryl group} or a pharmacologically acceptable salt thereof. 2. The compound or pharmacologically acceptable salt thereof as claimed in claim 1, wherein I is 0 and m is an integer of 1 to 3. 3. The compound or pharmacologically acceptable salt thereof as claimed in claim 1, wherein I is 0 and m is 2. 4. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 7-membered heterocyclyl ring [in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, a group having the formula NR (R represents a hydrogen atom or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkanoyl group which may be substituted with group(s) selected from Substituent group α), an oxygen atom, a sulfur atom, a group having the formula SO and a group having the formula SO2, the heterocyclyl ring may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atom) or 5- to 6-membered cycloalkyl ring, and ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, substituent group α, a cyclopropyl C1-C6 alkyl group and a C1-C6 alkyl group which may be substituted with 1 to 5 groups selected from substituent group α] 5. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein X and Y represent a group in which X and T together with the carbon atom of ring B form ring A, and ring A is a 3- to 7-membered heterocyclyl ring [ in the heterocyclyl ring, X and Y, independently from each other, represent any one selected from a carbon atom, an oxygen atom, sulfur atom, a group having the formula SO and a group having the formula SO2 the heterocyclyl ring may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms as hetero atoms) or 5- or 6-membered cycloalkyl ring, and ring A, including the fused ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α and a C1-C6 alkyl group which may be substituted with 1 to 4 groups selected from Substituent group α] or a 3- to 5-membered saturated cycloalkyl ring (the 3- to 5-membered saturated cycloalkyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group). 6. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein X and Y represent a group in which X and Y together with the carbon atom of ring B form ring A, and ring A is a 3-to 7-membered heterocyclyl ring [the 3- to 7-membered heterocyclyl ring is oxirane, oxolane, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3- dithiane, 1,1,3,3-tetraoxo-1,3-dithiolane, 1,3-oxathiolane, 1,3-oxathiane or 1,3- oxathiepane, these heterocyclyl rings may form a fused ring or spiro ring with a 5-or 6-membered heterocyclyl ring (the 5- or 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydrophyran, pyrrolidine, piperidine or 1,3-dioxane) or cyclohexyl ring, and ring A, including the fused ring and spiro ring, may be substituted with 1 or 2 groups selected from the group consisting of an oxo group, a thioxo group, Substituent group α (Substituent group α represents a hydroxy group and a group having the formula NR6R7, and R6 and R7, independently from each other, represent a hydrogen atom or C1-C6 alkanoyl group), a methyl group, an ethyl group and a C1-C6 alkyl group which is substituted with 1 to 4 hydroxy groups], or a cyclopropyl or cyclopentyl ring (the cyclopropyl or cyclopentyl ring may be substituted with 1 or 2 groups selected from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3- trihydroxypropyl group, and a 1,2,3,4-tetrahydroxybutyl group). 7. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein X and Y represent a group in which X and Y together with the carbon atom of ring B form ring A, and ring A is a 3- to 6-membered heterocyclyl ring {the heterocyclyl ring is oxirane, tetrahydrofuran, 1, 3-dioxolane, 1,3-dioxane, 1, 3-dithiolane, 1,3-dithiane, 1, 3-oxathiolane, or 1,3-oxathiane, these heterocyclyl rings may form a fused ring or spiro ring with a 5- or 6-membered heterocyclyl ring (the 5- or 6-membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran or 1,3- dioxane) or cyclohexyl ring, and ring A, including the fused ring or spiro ring, may be substituted with 1 or 2 groups selected from the group consisting of Substituent group α [ Substituent group α represents a hydroxyl group and a group having the formula NR6R7( R6 and R7. independently from each other, represent a hydrogen atom or acetyl group], a methyl group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3- trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group}. 8. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 7, wherein n is 0 or 1, and R1 is a hydroxyl group, halogen atom, C1-C6 alkyl group or C1-C6 alkoxy group. 9. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 7, wherein n is 0 or 1, and R1 is a fluorine atom or methyl group. 10. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 7, wherein n is 0. 11. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 10, wherein R2 is a C1-C6 alkyl group. 12. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 10, wherein R2 is a C1-C4 alkyl group. 13. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 10, wherein R2 is an ethyl group. 14. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 13, wherein R3 is a phenyl group which may be substituted with group(s) selected from Substituent group ε, or a pyrrolyl group which may be substituted with group(s) selected from Substituent group ε, and Substituent group ε is a halogen atom, C1-C14 alkyl group and halogeno C1-C14 alkyl group. 15. The compound or pharmacologically acceptable salt thereof as claimed any one of claims 1 to 13, wherein R3 is a phenyl group which may be substituted with group(s) selected from Substituent group ε, or a pyrrolyl group which may be substituted with group(s) selected from Substituent group ε, and Substituent group ε is a fluorine atom, chlorine atom, bromine atom, C3-C8 alkyl group and halogeno C4-C8 alkyl group. 16. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 13, wherein R3 is a phenyl group which may be substituted with group(s) selected from Substituent group ε, and Substituent group ε is a fluorine atom, chlorine atom and C3-C8 alkyl group. 17. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 16, wherein R5 is a hydrogen atom or C1-C6 alkyl group. 18. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 16, wherein R5 is a hydrogen atom or methyl group. 19. The compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 16, wherein R5 is a hydrogen atom. 20. The compounds of the following group aelected from claim 1 or pharmacologically acceptable salt thereof: ethyl 8-[N-(2-chlorophenyl) sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec- 6-ene-7-carboxylate, ethyl 8-[N-(2-chlorophenyl) sulfamoyl]-2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2,4-difluorophenyl) sulfamoyl]-2,3-bis (hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl) -1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl) sulfamoyl] -2- hydroxymethyl-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis(hydroxymethyl) -1,4 dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro - 4 - fluorophenyl) sulfamoyl] -2, 3-bis(1, 2-dihydroxyethyl) -1,4- dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2-dihydroxyethyl)-1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate, ethyl 8-[N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (1,2,3-trihydroxypropyl) -1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (1,2,3,4-tetrahydroxybutyl) -1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 2,3-bis (acetylaminomethyl) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4- dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 9-[N- (2-chloro-4-fluorophenyl) sulfamoyl] -3- hydroxy-1,5-dioxaspiro[5.5] undec- 7-ene-8-carboxylate, ethyl 3-acetylamino -9- [N-(2-chloro-4-fluorophenyl) sulfamoyl] -1,5- dioxaspiro [5.5] undec-7-ene-8-carboxylate, ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3- bis (hydroxymethyl) -1,5- dioxaspiro [5.5] undec -7-ene-8-carboxylate, ethyl8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl8-[N-(2-butyl-4-fluorophenyl) sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2-hexylphenyl) sulfamoyl] -2,3- bis (hydroxymethyl) -1,4- dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2-hexylphenyl) sulfamoyl] -2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-hexylphenyl) sulfamoyl] -2,3- bis (hydroxymethyl)-1,4- dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl) -8- [N-(4-fluoro-2-hexylphenyl) sulfamoyl] -1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate, ethyl 8-[N-(2-heptylphenyl) sulfamoyl] -2,3- bis (hydroxymethyl) -1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2-heptylphenyl) sulfamoyl] -2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 8- [N-(4-fluoro-2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4- dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl) -8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -1,4- dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromophenyl) sulfamoyl] -2,3- bis(hydroxymethyl)-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromophenyl) sulfamoyl] -2,3- bis (1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8- [N-(2-chloro-6-methylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4- d ioxaspi ro[4.5] dec-6-ene-7-carboxylate, ethyl8-[N-(2-chloro-6-methylphenyl) sulfamoyl] -2,3- bis (1,2-dihydroxyethyl) -1,4- dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 8- [N-(2-bromo-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4- dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(2-bromo-4-fluorophenyl) sulfamoyl] -2,3- bis (1,2-dihydroxyethyl) -1,4- dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 2,3-bis(hydroxymethyl)-8-[N-(2-pentylphenyl) sulfamoyl]-1,4-dioxaspiro[4.5] dec- 6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 2,3-bis(1,2-dihydroxyethyl) -8- [N-(4-fluoro-2-pentylphenyl) sulfamoyl ] -1,4- dioxaspiro [4.5] dec-6-ene-7-carboxylate ethyl 8-[N-(4-fluoro-2-octylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4- dioxaspiro [4.5] dec-6-ene-7-carboxylate, ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N-(4-fluoro-2-octylphenyl) sulfamoyl] -1,4- dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 8- [N- (4-fluoro-2-propylphenyl) sulfamoyl] -2,3- bis (hydroxymethyl) -1,4- dioxaspiro[4.5] dec-6-ene-7-carboxylate, ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N-(4-fluoro-2-propylphenyl) sulfamoyl] -1,4- dioxaspiro[4.5] dec-6-ene-7-carboxylate, and ethyl 8-[N-(2-chloro-4-fluorophenyl)-N-methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4- dioxaspiro[4.5]dec-6-ene-7-carboxylate. 21. A medicament containing the compound or pharmacologically acceptable salt thereof as claimed in any one of claims 1 to 20 as an active ingredient. 22. A potassium salt of ethyl (2R, 3R) -8- [N-(2-Chloro-4-fluorophenyl) sulfhmoyl]-2, 3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate. 23. Potassium (2-Chloro-4-fluorophenyl) { [(2R, 3R, 8R)7- (ethoxycarbonyl) -2, 3-bis (hydroxymethyl) -1, 4-dioxaspiro [4.5] dec-6-ene-8-yl ] sulfonyl} axanide. ABSTRACT Title: "SUBSTITUTED CYCLOALKENE DERIVATIVE" It is intended to provide a substituted cycloalkene derivative represented by the general formula (I) which has an action of suppressing intracellular signal transduction or cell activation caused by endotoxin and a cell response such as hyperproduction of an inflammatory mediator caused by them, a pharmacologically acceptable salt thereof, a method for producing the same, and a pharmaceutical containing the cycloalkene derivative as an active ingredient, which is excellent in prevention and/or treatment of a disease such as sepsis (septic shock, disseminated intravascular co-agulation, multiple organ failure or the like). General formula (I): {In the formula, X and Y represent a group which forms the ring A with the carbon atom of the ring B to which X and Y are bound or the like, I and m independently represent an integer of 0 to 3 and I +m is 1 to 3. R1 represents an aliphatic hydrocarbon group which may be substituted or the like, n represents an integer of 0 to 3. R3 represents a hydrogen atom, an alkyl group which may be substituted or the like, R3 represents a phenyl group which may be substituted or the like, and R5 represents a hydrogen atom, an alkyl group which may be substituted or the like.}

Full Text

Specification
Substituted Cycloalkene Derivative
[TECHNICAL FIELD]
The present invention relates to a novel compound which
has an action to suppress intracellular signal transduction or
cell activation in various cells such as monocytes, macrophages
and vascular endothelial cells, the intracellular signal
transduction or cell activation being induced by endotoxin, and
to suppress the generation of inflammatory mediators such as
TNF-a due to the intracellular signal transduction and cell
activation, and which is useful as a prophylactic and/or
therapeutic agent for various diseases such as sepsis (septic
shock, disseminated intravascular coagulation, multiple organ
failure and the like), a production method therefor and a use
thereof.
[BACKGROUND ART]
Sepsis is a systemic inflammatory response syndrome
(SIRS) which occurs due to an excess inflammatory response of a
biological body against bacterial infection, and is a disease
which may result in death when it is accompanied by shock or
organ failure. Since there are only a few agents that are
effective against sepsis until now, it is considered to be a
disease that is difficult to prevent and treat. However, since
its fatality is high and the number of patients is large,
development of therapeutic agents for it is particularly
important (for example, refer to Non-patent document 1).
Endotoxin (lipopolysaccharide, LPS), which is a membrane
component of bacteria, acts against cells such as monocytes,
macrophages and vascular endothelial cells, induces an excess
generation of various inflammatory mediators such as TNF-a and
the like, causes sudden blood pressure reduction, blood
coagulation disorders, cardiovascular disturbances and the like
in addition to systemic inflammatory responses, and thus
exhibits sepsis (for example, refer to Non-patent document 2).

Lipid A, which corresponds to lipopolysaccharide and its partial
structure, activates intracellular signal transduction via TLR4
(Toll-like receptor 4), which is a functional cell surface
receptor, after binding with CD14 (for example, refer to Non-
patent document 3). Accordingly, lipid A initiates various cell
responses represented by the generation of inflammatory
mediators. Therefore, it is considered that a substance which
suppresses the intracellular signal transduction or cell
activation induced by endotoxin, and various cell responses
induced by intracellular signal transduction and cell
activation, the various cell responses being represented by an
excess generation of inflammatory mediators such as TNF-a, can
be an effective prophylactic and therapeutic agent for sepsis
(for example, refer to Non-patent document 3, Non-patent
document 4, Patent document 1 and Patent document 2).
Intracellular signal transduction or cell activation
induced by endotoxin, and various cell responses induced by the
intracellular signal transduction and cell activation, the
various cell responses being represented by an excess generation
of inflammatory mediators such as TNF-a, lead to development and
progress of various diseases such as ischemic brain disorder,
arteriosclerosis, poor prognosis after coronary angioplasty,
heart failure, diabetes, diabetic complication, joint
inflammation, osteoporosis, osteopenia, autoimmune disease,
tissue disorder and rejection after organ transplantation,
bacterial infection, virus infection, gastritis, pancreatitis,
nephritis, pneumonia, hepatitis and leukemia, in addition to the
aforementioned sepsis (for example, Non-patent document 5 and
Patent document 3).
Therefore, a substance which suppresses intracellular
signal transduction or cell activation induced by endotoxin, and
various cell responses induced by the intracellular signal
transduction and cell activation such as an excess generation of
inflammatory mediators such as TNF-a, is considered to be
effective as a prophylactic and/or therapeutic agent for these

various diseases, and thus the development of an excellent
therapeutic agent has been desired.
[Non-patent Document 1] Iqbal et al., Expert Opin. Emerging
Drugs, Vol. 7, page 111, 2002
[Non-patent Document 2] Hawkins et al., Current Topics in
Medicinal Chemistry, Vol. 4, page 1147, 2004
[Non-patent Document 3] Beutler, Nature, Vol. 430, pages 257-
263, 2004
[Non-patent Document 4] Kakutani et al., Inflammation Research,
Vol. 48, page 461, 1999
[Non-patent Document 5] Donald N. Cook et al., Nature
Immunology, Vol. 5, pages 975-979, 2004
[Patent Document 1] Japanese Patent Appication (Kokai) No. 2000-
178246
[Patent Document 2] Japanese Patent Application (Kokai) No.
2004-2370
[Patent Document 3] International Publication WO 00/41698
Pamphlet
[DISCLOSURE OF THE INVENTION]
[Problems to be Solved by the Invention]
As a result of conducting extensive studies on the
pharmacological activity of various substituted cycloalkene
derivatives for the purpose of developing a compound which has
an activity to suppress intracellular signal transduction or
cell activation in various cells such as monocytes, macrophages
and vascular endothelial cells, the intracellular signal
transduction or the cell activation being induced by endotoxin,
and to suppress various cell responses induced by the
intracellular signal transduction and cell activation, such as
an excess generation of inflammatory mediators such as TNF-α,
the inventors of the present invention found that a substituted
cycloalkene derivative having a unique structure possesses an
excellent suppressing effect against intracellular signal
transduction or cell activation induced by endotoxin, and
against cell responses induced by the intracellular signal

transduction and cell activation, such as an excess generation
of inflammatory mediators such as TNF-α, and found that it is
useful as a prophylactic and/or therapeutic agent for various
diseases such as sepsis which are associated with intracellular
signal transduction or cell activation induced by endotoxin, and
with cell responses induced by the intracellular signal
transduction and the cell activation, thereby leading to
completion of the present invention.
The present invention provides a substituted cycloalkene
derivative which possesses an activity to suppress intracellular
signal transduction or cell activation induced by endotoxin, and
cell responses due to the intracellular signal transduction and
cell activation such as an excess generation of inflammatory
mediators such as TNF-α, pharmacologically acceptable salts
thereof, a production method therefor, and a medicament
containing the aforementioned substituted cycloalkene derivative
as an active ingredient, which is excellent for prophylaxis
and/or treatment of various diseases caused by intracellular
signal transduction or cell activation induced by endotoxin, and
caused by cell responses including an excess generation of
inflammatory mediators such as TNF-α, the cell responses being
induced by the intracellular signal transduction and cell
activation.
[Means for Solving the Problems]
Accordingly, the present invention provides:
(1) A compound represented by the general formula (I):

{wherein
X and Y represent a group in which X and Y together with
the carbon atom of ring B to which they are bound form ring A, X
and Y together represent a substituent of ring B, or X and Y
each represents a hydrogen atom.
1) In the case where X and Y represent a group in which X and Y
together with the carbon atom of ring B to which they are bound
form ring A:
ring A represents
a 3- to 7-membered heterocyclyl ring [in the heterocyclyl ring,
X and Y, independently from each other, represent any one
selected from a carbon atom, a group having the formula NR (R
represents a hydrogen atom or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6
alkynyl or C1-C6 alkanoyl group which may be substituted with a
group selected from Substituent group a), an oxygen atom, a
sulfur atom, a group having the formula SO and a group having
the formula SO2,
the heterocyclyl ring may include an unsaturated bond,
may form a fused ring or spiro ring with a 3- to 7-membered
heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and
ring A, including the fused ring or spiro ring, may be
substituted with the same or different 1 to 4 groups selected
from the group consisting of an oxo group, a thioxo group,
Substituent group a, a cyclopropyl a C1-C6 alkyl group,
a C1-C6 alkyl group which may be substituted with 1 to 5 groups
selected from Substituent group a,
a C2-Cs alkenyl group which may be substituted with 1 to 5 groups
selected from Substituent group a, and a C2-C6 alkynyl group
which may be substituted with 1 to 5 groups selected from
Substituent group a]
or
a 3- to 7-membered cycloalkyl ring (the cycloalkyl ring may
include an unsaturated bond,
may form a fused ring or spiro ring with a 3- to 7-membered

heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and
ring A, including the fused ring or spiro ring, may be
substituted with the same or different 1 to 4 groups selected
from the group consisting of Substituent group a, a cyclopropyl
C1-C6 alkyl group,
a C1-C6 alkyl group which may be substituted with 1 to 5 groups
selected from Substituent group a,
a C2-C6 alkenyl group which may be substituted with 1 to 5 groups
selected from Substituent group a, and
a C2-C6 alkynyl group which may be substituted with 1 to 5 groups
selected from Substituent group a).
2) In the case where X and Y together represent a substituent of
ring B:
X and Y represent an oxo group or a thioxo group.
1 and m, independently from each other, represent an integer of
0 to 3, and
1 + m is 1 to 3.
R1 represents
an aliphatic hydrocarbon group which may be substituted with a
group selected from Substituent group p and Substituent group y
(the aliphatic hydrocarbon group represents a C1-C20 alkyl group,
C3-C10 cycloalkyl group, C4-C12 cycloalkylalkyl group, C3-C6
alkenyl group or C3-C6 alkynyl group),
a phenyl group which may be substituted with a group selected
from Substituent group 8,
a group having the formula OR4 (R4 represents a hydrogen atom or
an aliphatic hydrocarbon group which may be substituted with a
group selected from Substituent group β and Substituent group y,
the aliphatic hydrocarbon group represents the same as
aforementioned) or
a halogen atom.

n represents an integer of 0 to 3.
R2 represents a hydrogen atom,
a C1-C6 alkyl group which may be substituted with a group
selected from Substituent group β,
a C2-C6 alkenyl group which may be substituted with a group
selected from Substituent group β, or
a C2-C6 alkynyl group which may be substituted with a group
selected from Substituent group β.
R3 represents
a phenyl group which may be substituted with a group selected
from Substituent group e, or
a 5- or 6-membered heteroaryl group which may be substituted
with a group selected from Substituent group s (the heteroaryl
group includes 1 to 3 hetero atoms selected from a nitrogen
atom, oxygen atom and sulfur atom).
R5 represents a hydrogen atom,
a C1-C6 alkyl group which may be substituted with a group
selected from Substituent group β,
a C2-C6 alkenyl group which may be substituted with a group
selected from Substituent group β, or
a C2-C6 alkynyl group which may be substituted with a group
selected from Substituent group β.
Provided that in the case where R3 is a phenyl group which may
be substituted with a group selected from Substituent group 8, X
and Y represent the aforementioned (1) or (2).
Substituent group a represents
a hydroxy group, halogen atom, C1-Cs alkoxy group, halogeno C1-C6
alkoxy group, carboxy group, C1-C6 alkoxy-carbonyl group;
carbamoyl group which may be substituted with a group selected

from a C1-C6 alkyl group, C2-C5 alkenyl group, C2-C6 alkynyl
group, C1-Cs alkanoyl group or C2-C6 alkenyl-carbonyl group;
and a group having the formula NR6R7.
R6 and R7, independently from each other, represent a hydrogen
atom, C1-C6 alkyl group, C2-C6 alkenyl group, C2-Cs alkynyl group,
C1-C6 alkanoyl group or C2-C6 alkenyl-carbonyl group, or together
with the nitrogen atom to which they are bound form a
heterocyclyl group.
Substituent group β represents
an oxo group, hydroxy group, cyclopropyl group, C1-C6 alkoxy
group, C1-C6 alkylthio group, nitro group, halogen atom, cyano
group, carboxy group, C1-C10 alkoxy-carbonyl group, C1-C6 alkanoyl
group, C2-C4 alkenyl-carbonyl group, C2-Cs alkanoyloxy group, C2-
C4 alkenyl-carbonyloxy group;
carbamoyl group which may be substituted with a group selected
from a C1-C4 alkyl group, phenyl group, C1-C7 acyl group and C1-C4
alkoxy-phenyl group;
thiocarbamoyl group which may be substituted with a C1-C4 alkyl
group or phenyl group;
carbamoyloxy group which may be substituted with a C1-C4 alkyl
group or phenyl group;
C1-C6 alkanoylamino group, C1-C10 alkoxy-carboxamide group, C1-C10
alkoxy-carbonyloxy group, and
ureido group which may be substituted with a C1-C4 alkyl group or
phenyl group.
Substituent group y represents
a heterocyclic group, C3-C10 cycloalkyloxy group, C6-C10 aryloxy
group, C7-C19 aralkyloxy group, heterocyclyloxy group, C3-C10
cycloalkylthio group, C6-C10 arylthio group, C7-C19 aralkylthio
group, heterocyclylthio group, heterocyclylsulfinyl group,
heterocyclylsulfonyl group, C3-C6 cycloalkyloxy-carbonyl group,
C6-C10 aryloxy-carbonyl group, C7-C19 aralkyloxy-carbonyl group,
heterocyclyloxycarbonyl group, C6-C10 aryl-carbonyl group, C6-C10
aryl-carbonyloxy group, C6-C10 aryl-carbonylamino group, C6-C10

aryloxy-carboxamide group, C7-C19 aralkyloxy-carboxamide group,
Cs-C10 aryloxy-carbonyloxy group, C7-C19 aralkyloxy-carbonyloxy
group, C3-C10 cycloalkyloxy-carbonyloxy group and C6-C10 aryl
group which may be substituted with a group selected from
Substituent group β.
Substituent group δ represents
a hydroxy group, nitro group, cyano group, halogen atom, C1-C6
alkyl group, halogeno C1-C6 alkyl group, C1-C6 alkoxy group,
halogeno C1-C6 alkoxy group, carboxy group, C1-C6 alkanoyl group,
C1-C6 alkoxy-carbonyl group, C1-C6 alkanoylamino group, C1-C6
alkylthio group, carbamoyl group, C1-C6 alkyl-carbamoyl group,
C1-C6 alkoxy-carbonyl C1-C6 alkyl-carbamoyl group, 1,3-
diacylguanidino C1-C6 alkyl group, a group having the formula
NR6R7 (R6 and R7 are the same as R6 and R7 of Substituent group
a) , C3-C6 cycloalkyl group, C6-C10 aryl group and 5-membered
heteroaryl group.
Substituent group 8 represents
a hydroxy group, nitro group, cyano group, halogen atom, C1-C14
alkyl group, cyclopropyl C1-C14 alkyl group, halogeno C1-C14 alkyl
group, C1-C14 alkoxy group, halogeno C1-C14 alkoxy group, carboxy
group, C1-C14 alkanoyl group, C1-C14 alkoxy-carbonyl group, C1-C14
alkanoylamino group, C1-C14 alkylthio group, carbamoyl group, C1-
C14 alkyl-carbamoyl group, C1-C14 alkoxy-carbonyl C1-C14 alkyl-
carbamoyl group, 1,3-diacylguanidino C1-C14 alkyl group, a group
having the formula NR6R7 (R6 and R7 are the same as R6 and R7 of
Substituent group a), C3-C6 cycloalkyl group, C6-C10 aryl group
and 5-membered heteroaryl group}
or a pharmacologically acceptable salt thereof,
(2) The compound or pharmacologically acceptable salt
thereof according to the aforementioned (1), wherein 1 is 0 and
m is an integer of 1 to 3,
(3) The compound or pharmacologically acceptable salt
thereof according to the aforementioned (1), wherein 1 is 0 and

m is 2,
(4) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (3),
wherein
X and Y together with the carbon atom of ring B form ring A, and
ring A is
a 3- to 7-membered heterocyclyl ring
[in the heterocyclyl ring, X and Y, independently from each
other, represent any one selected from a carbon atom, a group
having the formula NR (R represents a hydrogen atom or a C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkanoyl group which
may be substituted with a group selected from Substituent group
a), an oxygen atom, a sulfur atom, a group having the formula SO
and a group having the formula SO2,
the heterocyclyl ring may form a fused ring or spiro ring
with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring
includes 1 or 2 oxygen and/or nitrogen atoms as hetero atoms) or
5- or 6-membered cycloalkyl ring, and
ring A, including the fused ring or spiro ring, may be
substituted with the same or different 1 to 4 groups selected
from the group consisting of an oxo group, a thioxo group,
Substituent group a, a cyclopropyl C1-C6 alkyl group and a C1-C6
alkyl group which may be substituted with 1 to 5 groups selected
from Substituent group α]
or
a 3- to 7-membered saturated cycloalkyl ring
(the 3- to 7-membered saturated cycloalkyl ring may be
substituted with 1 or 2 groups selected from the group
consisting of a hydroxy group, hydroxymethyl group, 1,2-
dihydroxyethyl group, 1,2,3-trihydroxypropyl group, 1,2,3,4-
tetrahydroxybutyl group and acetylamino group),
(5) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (3),
wherein
X and Y represent a group in which X and Y together with the

carbon atom of ring B form ring A, and ring A is
a 3- to 7-membered heterocyclyl ring
[in the heterocyclyl ring, X and Y, independently from each
other, represent any one selected from a carbon atom, an oxygen
atom, a sulfur atom, a group having the formula SO and a group
having the formula SO2,
the heterocyclyl ring may form a fused ring or spiro ring with a
5- or 6-membered heterocyclyl ring (the heterocyclyl ring
includes 1 or 2 oxygen and/or nitrogen atoms as hetero atoms) or
5- or 6-membered cycloalkyl ring, and
ring A, including the fused ring or spiro ring, may be
substituted with the same or different 1 to 4 groups selected
from the group consisting of an oxo group, a thioxo group,
Substituent group a and a C1-C6 alkyl group which may be
substituted with 1 to 4 groups selected from Substituent group
a]
or
a 3- to 5-membered saturated cycloalkyl ring
(the 3- to 5-membered saturated cycloalkyl ring may be
substituted with 1 or 2 groups selected from the group
consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group,
1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group
and acetylamino group),
(6) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (3),
wherein
X and Y represent a group in which X and Y together with the
carbon atom of ring B form ring A, and ring A is
a 3- to 7-membered heterocyclyl ring
[the 3- to 7-membered heterocyclyl ring is
oxirane, oxolane, tetrahydrofuran, tetrahydropyran, 1,3-
dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3-
dithiane, 1,1,3,3-tetraoxo-l,3-dithiolane, 1,3-oxathiolane, 1,3-
oxathiane or 1,3-oxathiepane,
these heterocyclyl rings may form a fused ring or spiro
ring with a 5- or 6-membered heterocyclyl ring (the 5- or 6-

membered heterocyclyl ring is tetrahydrofuran, tetrahydropyran,
pyrrolidine, piperidine or 1,3-dioxane) or cyclohexyl ring, and
ring A, including the fused ring or spiro ring, may be
substituted with 1 or 2 groups selected from the group
consisting of an oxo group, a thioxo group, Substituent group a
(Substituent group a represents a hydroxy group and a group
having the formula NR6R7, and R6 and R7, independently from each
other, represent a hydrogen atom or C1-C6 alkanoyl group), a
methyl group, an ethyl group and a C1-C6 alkyl group which is
substituted with 1 to 4 hydroxy groups],
or
a cyclopropyl or cyclopentyl ring
(the cyclopropyl or cyclopentyl ring may be substituted with 1
or 2 groups selected from the group consisting of a
hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-
trihydroxypropyl group, and 1,2,3,4-tetrahydroxybutyl group),
(7) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (3),
wherein
X and Y represent a group in which X and Y together with the
carbon atom of ring B form ring A, and ring A is
a 3- to 6-membered heterocyclyl ring
{the heterocyclyl ring is
oxirane, tetrahydrofuran,
1,3-dioxolane, 1,3-dioxane,
1,3-dithiolane, 1,3-dithiane,
1,3-oxathiolane, or 1,3-oxathiane,
these heterocyclyl rings may form a fused ring or spiro ring
with a 5- or 6-membered heterocyclyl ring (the 5- or 6-membered
heterocyclyl ring is tetrahydrofuran, tetrahydropyran or 1,3-
dioxane) or cyclohexyl ring, and
ring A, including the fused ring and spiro ring, may be
substituted with 1 or 2 groups selected from the group
consisting of Substituent group a [Substituent group a
represents a hydroxy group and a group having the formula NR6R7

(R6 and R7, independently from each other, represent a hydrogen
atom or acetyl group)], a methyl group, an ethyl group, a
hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-
trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group},
(8) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (7),
wherein
n is 0 or 1, and
R1 is a hydroxy group, halogen atom, C1-C6 alkyl group or
C1-C6 alkoxy group,
(9) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (7),
wherein
n is 0 or 1, and
R1 is a fluorine atom or methyl group,
(10) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (7),
wherein n is 0,
(11) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (10),
wherein R2 is a C1-C6 alkyl group,
(12) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (10),
wherein R2 is a C1-C4 alkyl group,
(13) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (10),
wherein R2 is an ethyl group,
(14) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (13),
wherein
R3 is
a phenyl group which may be substituted with a group
selected from Substituent group s, or
a pyrrolyl group which may be substituted with a group
selected from Substituent group s, and

Substituent group a is a halogen atom, C1-C14 alkyl group
and halogeno C1-C14 alkyl group,
(15) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (13),
wherein
R3 is
a phenyl group which may be substituted with a group aelected from Substituent group a, or
a pyrrolyl group which may be substituted with a group aelected from Substituent group a, and
Substituent group a is a fluorine atom, chlorine atom,
bromine atom, C3-Ca alkyl group and halogeno C4-C8 alkyl group,
(16) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (13),
wherein
R3 is
a phenyl group which may be substituted with a group a
elected from Substituent group a, and
Substituent group ε is a fluorine atom, chlorine atom and
C3-C8 alkyl group,
(17) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (16),
wherein R5 is a hydrogen atom or C1-C6 alkyl group,
(18) The compound or pharmacologically acceptable salt
thereof according to any one of the aforementioned (1) to (16),
wherein R5 is a hydrogen atom or methyl group,
-(19) The compound or pharmacologically acceptable salt thereof
according to any one of the aforementioned (1) to (16), wherein
R5 is a hydrogen atom,
(20) The compounds of the following group aelected from
the aforementioned (1) or pharmacologically acceptable salt
thereof:
ethyl 8-[N-(2-chlorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chlorophenyl)sulfamoyl]-2,3-bis(1,2-

dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis (1,2-
dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-
hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2,3-
bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2-
dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2- (1,2,3-
trihydroxypropyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-
(1,2,3,4-tetrahydroxybutyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 2,3-bis(acetylaminomethyl)-8-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-hydroxy-
1,5-dioxaspiro[5.5]undec-7 -ene-8 -carboxylate,
ethyl 3-acetylamino-9-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-8-
carboxylate,
ethyl 9-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-
bis(hydroxymethyl)-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate,
ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-
bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 8-[N-(2-hexylphenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1, 4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,

ethyl 8-[N-(2-hexylphenyl)sulfamoyl]-2,3-bis(1,2-
dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-
hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate,
ethyl 8-[N-(2-heptylphenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-heptylphenyl)sulfamoyl]-2,3-bis(1,2-
dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-
heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 8-[N-(2-bromophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-bromophenyl)sulfamoyl]-2,3-bis(1,2-
dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro-6-methylphenyl)sulfamoyl]-2,3-
bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-2,3-
bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 2,3-bis(hydroxymethyl)-8-[N-(2-
pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(2-
pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,

ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-
pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-
octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
ethyl 8- [N-(4-fluoro-2-propylphenyl)sulfamoyl]-2,3-
bis (hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(4-fluoro-2-
propylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate, and
ethyl 8-[N-(2-chloro-4-fluorophenyl)-N-methylsulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate,
(21) A medicament containing the compound or
pharmacologically acceptable salt thereof selected from any one
of the aforementioned (1) to (20) as an active ingredient,
(22) The medicament according to the aforementioned (21)
for use in suppressing intracellular signal transduction or cell
activation induced by endotoxin,
(23) The medicament according to the aforementioned (21)
for use in suppressing the generation of inflammatory mediators
due to intracellular signal transduction or cell activation
induced by endotoxin,
(24) The medicament according to the aforementioned (21)
for use in suppressing the generation of inflammatory mediators
due to intracellular signal transduction or cell activation
induced by endotoxin,
(25) The medicament according to the aforementioned (21)
for use as a prophylactic and/or therapeutic agent for a disease
mediated by an inflammatory mediator, of which generation is
induced by endotoxin,

(26) The medicament according to the aforementioned (21)
for use as a prophylactic and/or therapeutic agent for a disease
mediated by an inflammatory mediator, which is generated due to
intracellular signal transduction or cell activation induced by
endotoxin,
(27) The medicament according to the aforementioned (21)
for use as a prophylactic and/or therapeutic agent for sepsis,
and
(i) a method of suppressing intracellular signal transduction
induced by endotoxin and suppressing excess generation of
inflammatory mediators such as TNF-α which is induced by the
intracellular signal transduction, and (ii) a method of
preventing and/or treating a disease mediated by intracellular
signal transduction and by an inflammatory mediator which is
generated due to the intracellular signal transduction,
comprising administering an effective amount of the compound
according to any one of the aforementioned (1) to (20) or
pharmacologically acceptable salt thereof to a warm-blood animal
(preferably a human).
[EFFECTS OF THE INVENTION]
The substituted cycloalkene derivative according to the
present invention having the general formula (I) has excellent
activity to suppress intracellular signal transduction or cell
activation induced by endotoxin and to suppress excess
generation of inflammatory mediators such as TNF-α due to the
intracellular signal transduction and cell activation, and is
useful as a medicament, especially as a prophylactic and/or
therapeutic agent for ischemic brain disorder, arteriosclerosis,
poor prognosis after coronary angioplasty, heart failure,
diabetes, diabetic complication, joint inflammation,
osteoporosis, osteopenia, sepsis, autoimmune disease, tissue
disorder and rejection after organ transplantation, bacterial
infection, virus infection, gastritis, pancreatitis, nephritis,
pneumonia, hepatitis, leukemia and the like, which are induced
by the intervention of the intracellular signal transduction or

cell activation, and by inflammatory mediators due to the
intracellular signal transduction and cell activation.
[BEST MODE FOR CARRYING OUT THE INVENTION]
"Halogen atom" in the definitions of R1, Substituent group
α, Substituent group β, Substituent group δ and Substituent
group ε includes, for example, a fluorine atom, chlorine atom,
bromine atom or iodine atom.
With respect to R1, it is preferably a fluorine atom or
chlorine atom, more preferably a fluorine atom.
With respect to Substituent group Ε, it is preferably a
fluorine atom, chlorine atom or bromine atom, more preferably a
fluorine atom or chlorine atom.
"Alkyl group" in the definitions of the NR group which
may be included in ring A, substituent of ring A, R1, R2, R5, R6,
R7, Substituent group β, Substituent group δ and Substituent
group e includes a linear or branched alkyl group.
"C1-C6 alkyl group" of "C1-C6 alkyl group which may be
substituted with a group aelected from Substituent group α" in
the definition of the NR group which may be included in ring A;
"C1-C6 alkyl group" of "cyclopropyl C1-C6 alkyl group" in the
definition of a substituent of ring A; "C1-C6 alkyl group" of
"C1-C6 alkyl group which may be substituted with 1 to 5 groups
selected from Substituent group α" in the definition of a
substituent of ring A; "CX-C6 alkyl group" of "C1-C6 alkyl group
which may be substituted with a group aelected from Substituent
group P" in the definitions of R2 and R5; and "C1-C6 alkyl group"
in the definitions of Substituent group δ, R6 and R7 are, for
example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl,
neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-
methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-
dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl group or the
like.

Among the 'C1-C6 alkyl groups", the one with respect to
the NR group which may be included in ring A is preferably
methyl.
With respect to a substituent of ring A, it is preferably
a C1-C4 alkyl group.
With respect to R2, it is preferably a C1-C4 alkyl group,
more preferably ethyl.
With respect to R5, it is preferably methyl.
With respect to R6 and R7, it is preferably methyl.
With respect to Substituent group 8, it is preferably a
C1-C4 alkyl group.
C1-C14 alkyl groups of "C1-C14 alkyl group" and "cyclopropyl
C1-C14 alkyl group" in the definition of Substituent group a are,
for example, the aforementioned "C1-C6 alkyl group", octyl,
nonyl, decyl, dodecyl, tetradecyl or the like.
With respect to "C1-C14 alkyl group" in the definition of
Substituent group a, it is preferably C3-C8 alkyl group.
"C1-C20 alkyl group" in the definition of R1 is, for
example, the aforementioned "C1-C14 alkyl group", pentadecyl,
hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl or the like.
Preferably, it is a C1-C6 alkyl group, and more preferably a
methyl group.
"Alkenyl group" in the definitions of the NR group which
may be included in ring A, substituent of ring A, R1, R2, R5, R6,
R7 and Substituent group a is a linear or branched alkenyl
group.
"C3-C6 alkenyl group" in the definition of R1 is, for
example, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,
2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-
butenyl, l-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-
methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-
pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl,
2-methyl-3-pentenyl, 4-pentenyl, l-methyl-4-pentenyl, 2-methyl-
4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl,
preferably a C3-C4 alkenyl group.

"C2-C6 alkenyl group" of "C2-C6 alkenyl group which may be
substituted with a group aelected from Substituent group a" in
the definition of the NR group which may be included in ring A;
"C2-C6 alkenyl group" of "C2-C6 alkenyl group which may be
substituted with 1 to 5 groups selected from Substituent group
α" in the definition of substituent of ring A; "C2-C6 alkenyl
group" of "C2-C6 alkenyl group which may be substituted with a
group aelected from Substituent group β" in the definitions of
R2 and R5; and "C2-C6 alkenyl group" in the definitions of R6 and
R7 are, for example, vinyl or the aforementioned "C3-C6 alkenyl
group", preferably a C3-C4 alkenyl group.
"Alkynyl group" in the definitions of the NR group which
may be included in ring A, substituent of ring A, R1, R2, R5, R6,
R7 and Substituent group α is a linear or branched alkynyl
group.
"C3-C6 alkynyl group" in the definition of R1 is, for
example, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-
butynyl, 1-ethyl-2-butynyl, 3-butynyl, l-methyl-3-butynyl, 2-
methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-
pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl,
4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl,
3-hexynyl, 4-hexynyl or 5-hexynyl, preferably a C3-C4 alkyl
group.
"C2-C6 alkynyl group" of "C2-C6 alkynyl group which may be
substituted with a group aelected from Substituent group α" in
the definition of the NR group which may be included in ring A;
"C2-C6 alkynyl group" of "C2-C6 alkynyl group which may be
substituted with 1 to 5 groups selected from Substituent group
a" in the definition of substituent of ring A; "C2-C6 alkynyl
group" of "C2-C6 alkynyl group which may be substituted with a
group aelected from Substituent group β" in the definitions of
R2 and R5; and "C2-C6 alkynyl group" in the definitions of R6 and
R7 are, for example, ethynyl or the aforementioned "C3-C5 alkynyl
group", preferably a C3-C4 alkynyl group.
"C3-Cs cycloalkyl group" in the definitions of Substituent

group δ and Substituent group e are, for example, cyclopropyl,
cyclopentyl or cyclohexyl.
"3- to 7-membered cycloalkyl ring" in the definition of
ring A may include an unsaturated bond, and such ring is, for
example, cyclopropane, cyclobutane, cyclopentane, cyclopentene,
cyclohexane, cyclohexene, cyclohexadiene, cycloheptane or
cycloheptadiene.
The aforementioned "3- to 7-membered cycloalkyl ring" may
form a fused ring or spiro ring with a 3- to 7-membered
heterocyclyl ring or 3- to 7-membered cycloalkyl ring, and such
cycloalkyl ring is, for example, 2-oxa-bicyclo[4,3,0]nonan-8-
ylidene, 3-oxa-bicyclo[3,3,0]heptan-7-ylidene, 2,4-dioxa-
spiro[6.6]undecan-8-ylidene, bicyclo[4,3,0]nonan-7-ylidene,
spiro[6.6]undecan-8-ylidene or the like.
In addition, the aforementioned "3- to 7-membered
cycloalkyl ring" may not form a fused ring or spiro ring, and
may be substituted with an oxo group or a thioxo group.
With respect to the aforementioned "cycloalkyl ring", a
cycloalkyl ring, fused ring which is fused to the cycloalkyl
ring, or spiro ring which is spiro bound to the cycloalkyl ring
may be substituted with the same or different 1 to 4 (preferably
1 or 2) groups selected from the group consisting of Substituent
group a, cyclopropyl C1-C6 alkyl group, C1-Cs alkyl group which
may be substituted with 1 to 5 groups selected from Substituent
group a, C2-C6 alkenyl group which may be substituted with 1 to 5
groups selected from Substituent group a and C2-Cs alkynyl group
which may be substituted with 1 to 5 groups selected from
Substituent group a.
Preferred examples of the ring are, 3-
hydroxycyclopentane, 4-hydroxycyclohexane, 3-
hydroxymethylcyclopentane, 3,4-dihydroxymethylcyclopentane, 4-
hydroxymethylcyclohexane, 4,4-dihydroxymethylcyclohexane, 3-
(1,2-dihydroxyethyl)cyclopentane, 4- (1,2-
dihydroxyethyl)cyclohexane, 3,4-bis (1,2-
dihydroxyethyl)cyclopentane, 4,4-bis(1,2-

dihydroxyethyl)cyclohexane, 3 - (1,2,3 -
trihydroxypropyl)cyclopentane, 4 - (1, 2 , 3 -
trihydroxypropyl)cyclohexane, 3 - (1,2,3,4-
tetrahydroxybutyl)cyclopentane, 4- (1,2,3,4-
tetrahydroxybutyl)cyclohexane, 3-ethoxycarbonylcyclopentane, 4-
ethoxycarbonylcyclohexane, 4,4-diethoxycarbonylcyclohexane, 3-
carbamoylcyclopentane, 4-carbamoylcyclohexane, 3-
acetylaminocyclopentane, 4-acetylaminocyclohexane, 3,4-
diacetylaminomethylcyclopentane, 2,3,4,5-
tetrahydroxybicyclo[4,3,0]nonane (the binding position with ring
B is the 8-position), 3-oxa-bicyclo[3,3,0]octane (the binding
position with ring B is the 7-position), 2,4-dihydroxymethyl-3-
oxa-bicyclo[3,3,0]octane (the binding position with ring B is
the 7-position), and 2,4-dioxaspiro[5.5]undecane (the binding
position with ring B is the 9-position).
"Cycloalkyl ring" in the definition of ring A is, among
the aforementioned rings, preferably a 3- to 7-membered
cycloalkyl ring which may be substituted with 1 or 2 groups
selected from a hydroxymethyl group consisting of a hydroxy
group, -trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl group
and acetylamino group, 1,2-dihydroxyethyl group, groups 1, 2 and
3, more preferably a 3- to 5-membered saturated cycloalkyl ring
which may be substituted with 1 or 2 groups selected from the
group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl
group,1,2,3-trihydroxypropyl group, 1,2,3,4-tetrahydroxybutyl
group and acetylamino group, and particularly preferably a
cyclopropyl or cyclopentyl ring which may be substituted with 1
or 2 groups selected from the group consisting of a
hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-
trihydroxypropyl group and 1,2,3,4-tetrahydroxybutyl group.
"C3-C10 cycloalkyl group" in the definition of R1 is, for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclocyclheptyl or cyclooctyl.
"C4-C12 cycloalkylalkyl group" in the definition of R1 is,
for example, cyclopropylmethyl, cyclopentylmethyl,
cyclohexylmethyl or cycloheptylmethyl, preferably a C4-C8

cycloalkylalkyl group, more preferably a C4-C7 cycloalkylalkyl
group.
With respect to "3- to 7-membered heterocyclyl ring" in
the definition of ring A, X and Y included in the ring,
independently from each other, represent any one selected from a
carbon atom, a group having the formula NR (R represents a
hydrogen atom or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 group or C1-C6
alkylcarbonyl group which may be substituted with a group
aelected from Substituent group a), an oxygen atom, a sulfur
atom, a group having the formula SO and a group having the
formula SO2, preferably any one selected from a carbon atom, an
oxygen atom, a sulfur atom, a group having the formula SO, and a
group having the formula SO2. The 3-to 7-membered heterocyclyl
ring may include an unsaturated bond.
Examples of such ring are, a heterocyclyl ring including
a nitrogen atom such as aziridine, azetidine, pyrrolidine,
pyrroline, piperidine and imidazolidine; a heterocyclyl ring
including an oxygen atom such as oxirane, oxetane,
tetrahydrofuran, oxolene, tetrahydropyran, dihydropyran,
oxepane, 1,3-dioxolane, 1,3-dioxane and 1,3-dioxepane; a
heterocyclyl ring including a sulfur atom, a group having the
formula SO or a group having the formula SO2 such as thiirane,
thietane, thiolane, thiolene, thiane, thiepane, 1,3-dithiolane,
1,3-dithiane, 1,3-dithiepane, 1,3-dioxo-1,3-dithiolane, 1,3-
dioxo-1,3-dithiane, 1,1,3,3-tetraoxo-1,3-dithiolane and 1,1,3,3-
tetraoxo-1,3-dithiane; a heterocyclyl ring including an oxygen
atom and a sulfur atom such as 1,3-oxathiolane, 1,3-oxathiane
and 1,3-oxathiepane; a heterocyclyl ring including a nitrogen
atom and an oxygen atom such as 1,3-oxapyrrolidine and 1,3-
oxapyrroline; and a heterocyclyl ring including a nitrogen atom
and a sulfur atom such as 1,3-thiapyrrolidine and 1,3-
thiapyrroline.
Preferably, it is oxirane, tetrahydrofuran,
tetrahydropyran, 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3-
dithiolane, 1,3-dithiane, 1,1,3,3-tetraoxo-l,3-dithiolane, 1,3-
oxathiolane, 1,3-oxathiane or 1,3-oxathiepane.

More preferably, it is oxirane, tetrahydrofuran, 1,3-
dioxolane, 1,3-dioxane, 1,3-dithiolane, 1,3-dithiane, 1,3-
oxathiolane or 1,3-oxathiane.
Even more preferably, it is oxirane, 1,3-dioxolane, 1,3-
dioxane or 1,3-oxathiolane.
The aforementioned "3- to 7-membered heterocyclyl ring"
may form a fused ring or spiro ring with a 3- to 7-membered
heterocyclyl ring or 3- to 7-membered cycloalkyl ring,
preferably may form a fused ring or spiro ring with a 5- or 6-
membered heterocyclyl ring (the heterocyclyl ring includes 1 or
2 oxygen and/or nitrogen atoms as hetero atom) or 5- or 6-
membered cycloalkyl ring, and more preferably may form a fused
ring or spiro ring with tetrahydrofuran, tetrahydropyran,
pyrrolidine, piperidine, 1,3-dioxane or cyclohexyl ring.
Examples of such heterocyclyl ring are 2,4-dioxa-
bicyclo [3,3,0]octane (the binding position with ring B is the 3-
position), 2,4,7-trioxa-bicyclo[3,3,0]octane (the binding
position with ring B is the 3-position), 7,9-dioxa-
bicyclo[4,3,0]nonane (the binding position with ring B is the 8-
position), 7-aza-2,4-dioxa-bicyclo[3,3,0]octane (the binding
position with ring B is the 3-position), 2,4,8,10-
tetraoxaspiro[5,5]undecane (the binding position with ring B is
the 3-position) and the like. The binding position of these
rings with ring B is the same as the aforedescribed one.
In addition, the aforementioned "3- to 7-membered
heterocyclyl ring" may not form a fused ring or spiro ring, and
may be substituted with an oxo group or a thioxo group.
With respect to the aforementioned "heterocyclyl ring",
heterocyclyl ring, fused ring which is fused to the heterocyclyl
ring or spiro ring which is spiro bound to the heterocyclyl ring
may be substituted with the same or different 1 to 4 (preferably
1 or 2) substituents.
The substituent is a group aelected from the group
consisting of an oxo group, a thioxo group, Substituent group a,
a cyclopropyl C1-C6 alkyl group, a C1-C6 alkyl group which may be
substituted with 1 to 5 groups selected from Substituent group

a, a C2-C6 alkenyl group which may be substituted with 1 to 5
groups selected from Substituent group a and a C2-C6 alkynyl
group which may be substituted with 1 to 5 groups selected from
Substituent group a.
The substituent is preferably a group aelected from the
group consisting of an oxo group, a thioxo group, Substituent
group a, a cyclopropyl C1-C6 alkyl group and a C1-C6 alkyl group
which may be substituted with 1 to 5 groups selected from
Substituent group α.
More preferably, it is a group aelected from the group
consisting of an oxo group, a thioxo group, Substituent group a
and a C1-C6 alkyl group which may be substituted with 1 to 4
groups selected from Substituent group a.
Even more preferably, it is 1 or 2 groups selected from
the group consisting of an oxo group, a thioxo group,
Substituent group a (Substituent group a is a hydroxy group and
a group having the formula NR6R7, and R6 and R7, independently
from each other, represent a hydrogen atom or C1-C6 alkylcarbonyl
group), a methyl group, an ethyl group and a C1-C6 alkyl group
aubstituted with 1 to 4 hydroxy groups.
Further preferably, it is 1 or 2 groups selected from the
group consisting of Substituent group a [Substituent group α
represents a hydroxy group and a group having the formula NR6R7
(R5 and R7, independently from each other, represent a hydrogen
atom or methylcarbonyl group)], a methyl group, an ethyl group,
a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-
trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group.
As for such examples,
oxirane, oxolane, tetrahydrofuran (traditional name, oxolane
according IUPAC nomenclature), tetrahydropyran (traditional
name, oxane according IUPAC nomenclature), 1,3-dioxolane, 1,3-
dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3-dithiane, 1,3-
oxathiolane, 1,3-oxathiane, 1,3-oxathiepane, tetrahydrooxazole,
tetrahydro-1,3-oxadine, tetrahydrothiazol, tetrahydro-1,3-
thiazine, 1,1,3,3-tetraoxo-1,3-dithiane, 2,4,7-trioxa-

bicyclo[3,3,0]octane, 2,4-dithia-7-oxa-bicyclo[3,3,0]octane, 2-
thia-4,7-dioxa-bicyclo[3,3,0]octane, 2,4,8,10-
tetraoxaspiro[5.5]undecane, 2,4-dithia-8,10-
dioxaspiro[5.5]undecane, 2-thia-4,8,10-trioxaspiro[5.5]undecane,
2-hydroxytetrahydrofuran, 4-hydroxy-1,3-dioxolane, 4,5-
dihydroxy-1,3-dioxolane, 5-hydroxy-1,3-dioxane, 5,5-dihydroxy-
1,3-dioxane, 4-hydroxy-1,3-dithiolane, 4,5-dihydroxy-1,3-
dithiolane, 5-hydroxy-1,3-dithiane, 5,5-dihydroxy-1,3-dithiane,
4-hydroxy-1,1,3,3-tetraoxo-1,3-dithiolane, 4, 5-dihydroxy-
1,1,3,3-tetraoxo-1,3-dithiolane, 4-hydroxy-1,3-oxathiolane, 5-
hydroxy-1,3-oxathiane, 5,5-dihydroxy-1,3-oxathiane, 6,8-
dihydroxy-2,4-dioxa-bicyclo[3,3,0]octane, 6,8-dihydroxy-2,4,7-
trioxa-bicyclo[3,3,0]octane, 2,3,4,5-tetrahydroxy-7,9-dioxa-
bicyclo[4,3,0]nonane, 6,8-dihydroxy-7-aza-2,4-dioxa-
bicyclo[3,3,0]octane, 9-hydroxy-2,4,8,10-
tetraoxaspiro[5.5]undecane, 2,3,4,5-tetrahydro-7,9-dithia-
bicyclo[4,3,0]nonane, 2,3,4,5-tetrahydro-7-thia-9-oxa-
bicyclo[4,3,0]nonane, 2-carboxytetrahydrofuran, 4-carboxy-1,3-
dioxolane, 5-carboxy-1,3-dioxane, 4-carboxy-1,3-dithiolane, 5-
carboxy-1,3-dithiane, 4-carboxy-l,1,3,3-tetraoxo-1,3-dithiolane,
4-carboxy-1,3-oxathiolane, 5-carboxy-1,3-oxathiane,
2-methoxycarbonyltetrahydrofuran, 4-methoxycarbonyl-1,3-
dioxolane, 5-methoxycarbonyl-1,3-dioxane, 5,5-dimethoxycarbonyl-
1,3-dioxane, 4-methoxycarbonyl-1,3-dithiolane, 5-
methoxycarbonyl-1,3-dithiane, 5,5-dimethoxycarbonyl-1,3-
dithiane, 4-methoxycarbonyl-l,1,3,3-tetraoxo-1,3-dithiolane, 4-
methoxycarbonyl-1,3-oxathiolane, 5-methoxycarbonyl-1,3-
oxathiane, 5,5-dimethoxycarbonyl-1,3-oxathiane, 6,8-
dimethoxycarbonyl-2,4-dioxa-bicyclo[3,3,0]octane, 6,8-
dimethoxycarbonyl-2,4,7-trioxa-bicyclo[3,3,0]octane, 6,8-
dimethoxycarbonyl-7-aza-2,4-dioxa-bicyclo[3,3,0]octane, 8-
methoxycarbonyl-2,4,7,9-tetraoxaspiro[5.5]undecane,
2-ethoxycarbonyltetrahydrofuran, 4-ethoxycarbonyl-1,3-dioxolane,
5-ethoxycarbonyl-1,3-dioxane, 5,5-diethoxycarbonyl-1,3-dioxane,
4-ethoxycarbonyl-1,3-dithiolane, 5-ethoxycarbonyl-1,3-dithiane,
5,5-diethoxycarbonyl-1,3-dithiane, 4-ethoxycarbonyl-l,1,3,3-

tetraoxo-1,3-dithiolane, 4-ethoxycarbonyl-1,3-oxathiolane, 5-
ethoxycarbonyl-1,3-oxathiane, 5,5-diethoxycarbonyl-1,3-
oxathiane, 6,8-diethoxycarbonyl-2,4-dioxa-bicyclo[3,3,0]octane,
6,8-diethoxycarbonyl-2,4,7-trioxa-bicyclo[3,3,0]octane, 6,8-
diethoxycarbonyl-7-aza-2,4-dioxa-bicyclo[3,3,0]octane, 8-
ethoxycarbonyl-2,4,7,9-tetraoxaspiro[5.5]undecane,
2-aminotetrahydrofuran, 4-amino-1,3-dioxolane, 4,5-diamino-1,3-
dioxolane, 5-amino-1,3-dioxane, 4-amino-1,3-dithiolane, 4,5-
diamino-1,3-dithiolane, 5-amino-1,3-dithiane, 4-amino-1,1,3,3-
tetraoxo-1,3-dithiolane, 4-amino-1,3-oxathiolane, 5-amino-1,3-
oxathiane,
2-acetylaminotetrahydrofuran, 4-acetylamino-1,3-dioxolane, 4,5-
bis(acetylamino)-1,3-dioxolane, 5-acetylamino-1,3-dioxane, 4-
acetylamino-1,3-dithiolane, 4,5-bis(acetylamino)-1,3-dithiolane,
5-acetylamino-1,3-dithiane, 4-acetylamino-1,1,3,3-tetraoxo-1,3-
dithiolane, 4-acetylamino-1,3-oxathiolane, 5-acetylamino-1,3-
oxathiane, 6,8-diacetylamino-2,4-dioxa-bicyclo[3,3,0]octane,
6,8-diacetylamino-2,4,7-trioxa-bicyclo[3,3,0]octane, 6,8-
diacetylamino-7-aza-2,4-dioxa-bicyclo[3,3,0]octane, 8-
acetylamino-2,4,7,9-tetraoxaspiro[5.5]undecane,
2-methyltetrahydrofuran, 4-methyl-1,3-dioxolane, 4,5-dimethyl-
1,3-dioxolane, 5-methyl-1,3-dioxane, 4-methyl-1,3-dithiolane,
4,5-dimethyl-1,3-dithiolane, 5-methyl-1,3-dithiane, 4-methyl-
1,1,3,3-tetraoxo-1,3-dithiolane, 4-methyl-1,3-oxathiolane, 5-
methyl-1,3-oxathiane,
5,5-dimethyl-1,3-dioxane, 5,5-dimethyl-1,3-dithiane, 5,5-
dimethyl-1,3-oxathiane,
2-ethyltetrahydrofuran, 4-ethyl-1,3-dioxolane, 4,5-diethyl-1,3-
dioxolane, 5-ethy1-1,3-dioxane, 4-ethyl-1,3-dithiolane, 4,5-
diethyl-1,3-dithiolane, 5-ethyl-1,3-dithiane, 4-ethyl-l,1,3,3-
tetraoxo-1,3-dithiolane, 4-ethyl-1,3-oxathiolane, 5-ethyl-1,3-
oxathiane,
2-hydroxymethyltetrahydrofuran, 4-hydroxymethyl-1,3-dioxolane,
5-hydroxymethyl-1,3-dioxane, 5,5-dihydroxymethyl-1,3-dioxane, 4-
hydroxymethyl-1,3-dithiolane, 5-hydroxymethyl-1,3-dithiane, 5,5-
dihydroxymethyl-1,3-dithiane, 4-hydroxymethyl-1,1,3,3-tetraoxo-

1, 3-dithiolane, 4-hydroxymethyl-1,3-oxathiolane, 5-
hydroxymethyl-1,3-oxathiane, 5,5-dihydroxymethyl-1,3-oxathiane,
4,5-dihydroxymethyl-1,3-dioxolane, 4,5-dihydroxymethyl-1,3-
dithiolane, 4,5-dihydroxymethyl-1,3-oxathiolane, 5,5-
dihydroxymethyl-1,3-dioxane, 5,5-dihydroxymethyl-1,3-dithiane,
5,5-dihydroxymethyl-1,3-oxathiane, 6,8-dihydroxymethyl-2,4,7-
trioxa-bicyclo[3,3,0]octane, 6,8-dihydroxymethyl-2,4-dithia-7-
oxa-bicyclo[3,3,0]octane, 6,8-dihydroxymethyl-2-thia-4,7-dioxa-
bicyclo [3,3,0]octane, 6-oxo-8-hydroxymethyl-2,4,7-trioxa-
bicyclo[3,3,0]octane,
2-(1,2-dihydroxyethyl)tetrahydrofuran, 4-(1,2-dihydroxyethyl)-
1,3-dioxolane, 5-(1,2-dihydroxyethyl)-1,3-dioxane, 5,5-bis (1,2-
dihydroxyethyl)-1,3-dioxane, 4-(1,2-dihydroxyethyl)-1,3-
dithiolane, 5-(1,2-dihydroxyethyl)-1,3-dithiane, 5,5-bis (1,2-
dihydroxyethyl)-1,3-dithiane, 4-(1,2-dihydroxyethyl)-1,1,3,3-
tetraoxo-1,3-dithiolane, 4-(1,2-dihydroxyethyl)-1,3-oxathiolane,
5-(1,2-dihydroxyethyl)-1,3-oxathiane, 5,5-bis(1,2-
dihydroxyethyl)-1,3-oxathiane,
4,5-bis(1,2-dihydroxyethyl)-1,3-dioxolane, 4,5-bis (1,2-
dihydroxyethyl)-1,3-dithiolane, 4,5-bis(1,2-dihydroxyethyl)-1,3-
oxathiolane,
4,5-bis(1-hydroxyethyl)-1,3-dioxolane, 4,5-bis(1-hydroxypropyl)-
1,3-dioxolane,
2-(1,2,3-trihydroxypropyl)tetrahydrofuran, 4- (1,2,3-
trihydroxypropyl)-1,3-dioxolane, 5-(1,2,3-trihydroxypropyl)-1,3-
dioxane, 5,5-bis(1,2,3-trihydroxypropyl)-1,3-dioxane, 4-(1,2,3-
trihydroxypropyl)-1,3-dithiolane, 5-(1,2,3-trihydroxypropyl)-
1,3-dithiane, 5,5-bis(1,2,3-trihydroxypropyl)-1,3-dithiane, 4-
(1,2,3-trihydroxypropyl)-1,1,3,3-tetraoxo-1,3-dithiolane, 4-
(1,2,3-trihydroxypropyl)-1,3-oxathiolane, 5- (1,2-
dihydroxyethyl)-1,3-oxathiane, 5,5-bis(1,2,3-trihydroxypropyl)-
1,3-oxathiane,
2-(1,2,3,4-tetrahydroxybutyl)tetrahydrofuran, 4-(1,2,3,4-
tetrahydroxybutyl)-1,3-dioxolane, 5-(1,2,3,4-tetrahydroxybutyl)-
1,3-dioxane, 5,5-bis(1,2,3,4-tetrahydroxybutyl)-1,3-dioxane, 4-
(1,2,3,4-tetrahydroxybutyl)-1,3-dithiolane, 5-(1,2,3,4-

tetrahydroxybutyl)-1,3-dithiane, 5,5-bis(1,2,3,4-
tetrahydroxybutyl)-1,3-dithiane, 4-(1,2,3,4-tetrahydroxybutyl)-
1,1,3,3-tetraoxo-1,3-dithiolane, 4-(1,2,3,4-tetrahydroxybutyl)-
1,3-oxathiolane, 5-(1,2,3,4-tetrahydroxybutyl)-1,3-oxathiane,
5,5-bis(l,2,3,4-tetrahydroxybutyl)-1,3-oxathiane,
2-acetylaminomethyltetrahydrofuran, 4-acetylaminomethyl-1,3-
dioxolane, 4,5-diacetylaminomethyl-1,3-dioxolane, 5-
acetylaminomethyl-1,3-dioxane, 4-acetylaminomethyl-1,3-
dithiolane, 4,5-diacetylaminomethyl-1,3-dithiolane, 5-
acetylaminomethyl-1,3-dithiane, 4-acetylaminomethyl-l,1,3,3-
tetraoxo-1,3-dithiolane, 4-acetylaminomethyl-1,3-oxathiolane, 5-
acetylaminomethyl-1,3-oxathiane,
4,5-diacetylaminomethyl-1,3-dioxolane, 4,5-diacetylaminomethyl-
1,3-dithiolane, 4,5-diacetylaminomethyl-1,3-oxathiolane,
2-vinyltetrahydrofuran, 4-vinyl-1,3-dioxolane, 4,5-divinyl-1,3-
dioxolane, 5-vinyl-1,3-dioxane, 4-vinyl-1,3-dithiolane, 4,5-
divinyl-1,3-dithiolane, 5-vinyl-1,3-dithiane, 4-vinyl-l,1,3,3-
tetraoxo-1,3-dithiolane, 4-vinyl-1,3-oxathiolane, 5-vinyl-1,3-
oxathiane,
2-propenyltetrahydrofuran, 4-propenyl-1,3-dioxolane, 4,5-
dipropeny1-1,3-dioxolane, 5-propenyl-1,3-dioxane, 4-propenyl-
1,3-dithiolane, 4,5-dipropenyl-1,3-dithiolane, 5-propenyl-1,3 -
dithiane, 4-propenyl-1,1,3,3-tetraoxo-1,3-dithiolane, 4-
propenyl-1,3-oxathiolane, 5-propenyl-1,3-oxathiane,
2-propynyltetrahydrofuran, 4-propynyl-1,3-dioxolane, 4,5-
dipropyny1-1,3-dioxolane, 5-propynyl-1,3-dioxane, 4-propynyl-
1,3-dithiolane, 4,5-dipropynyl-1,3-dithiolane, 5-propynyl-1,3-
dithiane, 4-propynyl-l,1,3,3-tetraoxo-1,3-dithiolane, 4-
propynyl-1,3-oxathiolane and 5-propynyl-1,3-oxathiane can be
mentioned.
"C6-C10 aryl group" of "C6-C10 aryl group which may be
substituted with a group aelected from Substituent group P" in
the definition of Substituent group j; and "C6-C10 aryl group" in
the definitions of Substituent group 5 and Substituent group e
are, for example, phenyl or naphthyl.

With respect to the "C6-C10 aryl group which may be
substituted with a group aelected from Substituent group (3" , the
"C6-C10 aryl group" is substituted with a substituent selected
from Substituent group (3 at a substitutable position, the
substituent is not limited to one, and may be the same or
different plural (2 to 4) substituents.
"5- or 6-membered heteroaryl group" in the definition of
R3 includes 1 to 3 hetero atoms selected from a nitrogen atom,
an oxygen atom and a sulfur atom. As for such heteroaryl, for
example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,
piridazinyl, pyrimidinyl and pyradinyl can be mentioned, and it
is preferably furyl, thienyl, pyrrolyl, pyridyl or pyrimidinyl,
more preferably pyrrolyl.
"5-membered heteroaryl group" in the definitions of
Substituent group 8 and Substituent group a is, for example,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thienyl or
furyl.
"Halogeno C1-C6 alkyl group" in the definition of
Substituent group 8 is, for example, trifluoromethyl or
trifluoroethyl.
"Halogeno C1-C14 alkyl group" in the definition of
Substituent group e is, for example, the aforementioned
"halogeno C1-C6 alkyl group", 4,4,4-trifluorobutyl, 5,5,5-
trifluoropentyl, 6,6,6-trifluorohexyl, 7,7,7-trifluoroheptyl or
8,8,8-trifluorooctyl, preferably a halogeno C4-C8 alkyl group.
"C1-C6 alkoxy group" in the definitions of Substituent
group a, Substituent group |3 and Substituent group 8 represents
a group in which an oxygen atom is bound to the aforementioned
"C1-C6 alkyl group", for example, methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy,
isopentoxy, 2-methylbutoxy, 1-ethylpropoxy, 2-ethylpropoxy,
neopentoxy, hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-
methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-

sulfur atom is bound to the aforementioned wC1-C6 alkyl group",
and the sulfur atom may be oxidized. Preferably, it is a C1-C4
alkylthio group, for example, methylthio, ethylthio, n-
propylthio, n-butylthio, methylsulfinyl or methylsulfonyl.
With respect to "C1-C14 alkylthio group" in the definition
of Substituent group a, the sulfur atom to which the alkyl group
is bound may be oxidized, and it is for example, the
aforementioned "C1-C6 alkylthio group", n-heptylthio, 3-
methylhexylthio, n-octylthio, 2,4-dimethylhexylthio, n-
octylthio, or 2,3,6-trimethylheptylthio, preferably a C1-C10
alkylthio group, and more preferably a C4-C8 alkylthio group.
With respect to "C3-C10 cycloalkylthio group" in the
definition of Substituent group γ, the sulfur atom may be
oxidized, and it is for example, cyclopropylthio,
cyclohexylthio, cyclopentylsulfinyl or cyclohexylsulfonyl.
With respect to "C6-C10 arylthio group" in the definition
of Substituent group γ, the sulfur atom may be oxidized, and it
is for example, phenylthio, naphthylthio, phenylsulfinyl or
phenylsulfonyl.
With respect to "C7-C19 aralkylthio group" in the
definition of Substituent group γ, the sulfur atom may be
oxidized, and it is for example, benzylthio, phenylethylthio,
benzhydrylthio, benzylsulfinyl or benzylsulfonyl.
"C1-C6 alkanoyl group" in the definitions of R6, R7,
Substituent group β and Substituent group 8 represents a group
in which a hydrogen atom or C1-C5 alkyl group is bound to a
carbonyl group, and is for example, formyl, acetyl, propionyl,
butyryl, valeryl or pyvaloyl.
"C1-C14 alkanoyl group" in the definition of Substituent
group a is, for example, the aforementioned "C1-C6 alkanoyl
group", octanoyl, decanoyl, dodecanoyl or tetradecanoyl.
"C2-C4 alkenyl-carbonyl group" in the definition of
Substituent group p is, for example, acryloyl or crotonoyl.
"C2-C6 alkenyl-carbonyl group" in the definitions of Rs and
R7 is, for example, the aforementioned "C2-C4 alkenyl-carbonyl

group", 1,3-butadienylcarbonyl or 3-methyl-2-butenylcarbonyl.
"C6-C10 aryl-carbonyl group" in the definition of
Substituent group y is, for example, benzoyl, naphthoyl or
phenylacetyl.
"C1-C6 alkoxy-carbonyl group" in the definitions of
Substituent group α and Substituent group δ represents a group
in which the aforementioned "C1-C6 alkoxy group" is bound to a
carbonyl group, and is for example, methoxycarbonyl,
ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-
butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl or the
like.
"C1-C10 alkoxy-carbonyl group" in the definition of
Substituent group β is, for example, the aforementioned "C1-C6
alkoxycarbonyl group", heptyloxy, octyloxy, nonyloxy or
decyloxy.
"C1-C14 alkoxy-carbonyl group" in the definition of
Substituent group ε is, for example, the aforementioned "C1-C10
alkoxy-carbonyl group", dodecyloxycarbonyl or
tetradecyloxycarbonyl, preferably a C1-C10 alkoxy-carbonyl group,
and more preferably a C4-C8 alkoxy-carbonyl group.
"C3-C6 cycloalkyloxycarbonyl group" in the definition of
Substituent group γ is, for example, cyclopropyloxycarbonyl,
cyclopentyloxycarbonyl, cyclohexyloxycarbonyl or
norbornyloxycarbonyl.
"C6-C10 aryloxy-carbonyl group" in the definition of
Substituent group γ is, for example, phenoxycarbonyl or
naphthyloxycarbonyl.
"C7-C19 aralkyloxy-carbonyl group" in the definition of
Substituent group γ is, for example, benzyloxycarbonyl,
benzhydryloxycarbonyl or 2-phenethyloxycarbonyl.
"C2-C6 alkanoyloxy group" in the definition of Substituent
group β represents a group in which the C2-C6 alkanoyl group is
bound to an oxygen atom, and is for example, acetoxy,
propionyloxy, butyryloxy, valeryloxy or pivaloyloxy.
"C1-C10 alkoxy-carbonyloxy group" in the definition of

Substituent group β is, for example, methoxycarbonyloxy,
ethoxycarbonyloxy, n-propoxycarbonyloxy, isopropoxycarbonyloxy,
n-butoxycarbonyloxy, tert-butoxycarbonyloxy, n-
pentyloxycarbonyloxy or n-hexyloxycarbonyloxy.
"C6-C10 aryl-carbonyloxy group" in the definition of
Substituent group γ is, for example, benzoyloxy, naphthoyloxy or
phenylacetoxy.
"Carbamoyl group which may be substituted with a group
aelected from a C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6
alkynyl group, C1-C6 alkanoyl group or C2-C6 alkenyl-carbonyl
group" in the definition of Substituent group a is a carbamoyl
group or cyclic aminocarbonyl group which may be substituted
with 1 or 2 substituents selected from C1-C6 alkyl groups such as
methyl, ethyl, propyl and the like, C2-C6 alkenyl groups such as
vinyl, allyl, isopropenyl and the like, C2-C6 alkynyl groups such
as ethynyl and the like, C1-C6 alkanoyl groups such as acetyl and
the like, and C2-C6 alkenyl-carbonyl groups such as acryloyl and
the like, preferably, specifically for example, a carbamoyl
group or cyclic aminocarbonyl group which may be substituted
with 1 or 2 substituents selected from a C1-C6 alkyl group and a
C1-C6 alkanoyl group, more preferably a carbamoyl group or cyclic
aminocarbonyl group which is substituted with 1 or 2 C1-C2
alkanoyl groups. Specifically, it is carbamoyl, N-
methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-
diethylcarbamoyl or N-acetylcarbamoyl, preferably N-acetyl
carbamoyl.
"Carbamoyl group which may be substituted with a group
aelected from a Cx-C4 alkyl group, phenyl group, C1-C7 acyl group
and C1-C4 alkoxyphenyl group" in the definition of Substituent
group β is a carbamoyl group or cyclic aminocarbonyl group which
may be substituted with 1 or 2 substituents selected from C1-C4
alkyl groups such as methyl, ethyl and the like, phenyl group,
C1-C7 acyl groups such as acetyl, propionyl, benzoyl and the
like, and C1-C4 alkoxyphenyl groups such as methoxyphenyl and the
like, specifically for example, carbamoyl, N-methylcarbamoyl, N-

ethylcarbamoyl, N,N-dimethylcarbamoyl, N/N-diethylcarbamoyl, N-
phenylcarbamoyl, N-acetylcarbamoyl, N-benzoylcarbamoyl, N-(p-
methoxyphenyl)carbamoyl, 1-pyrrolidinylcarbonyl,
piperidinocarbonyl, 1-piperadinylcarbonyl or morpholinocarbonyl.
"Thiocarbamoyl group which may be substituted with a C1-C4
alkyl group or phenyl group" in the definition of Substituent
group β is a thiocarbamoyl group which may be substituted with 1
or 2 substituents selected from C1-C4 alkyl groups such as
methyl, ethyl and the like, and a phenyl group, specifically for
example, thiocarbamoyl, N-methylthiocarbamoyl or N-
phenylthiocarbamoyl.
"Carbamoyloxy group which may be substituted with a C1-C4
alkyl group or phenyl group" in the definition of Substituent
group β is a carbamoyloxy group which may be substituted with 1
or 2 substituents selected from C1-C4 alkyl groups such as
methyl, ethyl and the like, and a phenyl group, specifically for
example, carbamoyloxy, N-methyl carbamoyloxy, N,N-dimethyl
carbamoyloxy, N-ethylcarbamoyloxy or N-phenyl carbamoyloxy.
With respect to "group having the formula NR6R7" in the
definitions of Substituent group a, Substituent group 8 and
Substituent group ε, R6 and R7, independently from each other,
represent a hydrogen atom, C1-C6 alkyl group, C2-C6 alkenyl
group, C2-C6 alkynyl group, C1-C6 alkanoyl group or C2-Cs alkenyl-
carbonyl group, or, together with the nitrogen atom to which R6
and R7 are bound, form a heterocyclyl group. Preferably, it is a
group in which R6 and R7 are a hydrogen atom, C1-C6 alkyl group
or C1-C6 alkanoyl group, more preferably a group in which R6 and
R7 are a hydrogen atom, C1-C4 alkyl group or C1-C4 alkanoyl group,
even more preferably a group in which R6 and R7 are a hydrogen
atom or C1-C2 alkanoyl group. Specifically it is amino,
methylamino, ethylamino, dimethylamino, diethylamino or
acetylamino, preferably acetylamino.
"C1-C6 alkanoylamino group" in the definitions of
Substituent group β and Substituent group δ is, for example,
acetamide, propionamide, butyroamide, valeroamide or

pivaloamide.
"C1-C14 alkanoylamino group" in the definition of
Substituent group e is, for example, the aforementioned "C1-C6
alkanoylamino group", octanoylamino, decanoylamino,
dodecanoylamino or tetradecanoylamino.
"C1-C10 alkoxy-carboxamide group" in the definition of
Substituent group β is, for example, methoxycarboxamide,
ethoxycarboxamide or tert-butoxycarboxamide.
"Ureido group which may be substituted with a C1-C4 alkyl
group or phenyl group" in the definition of Substituent group β
is, for example, an ureido group which may be substituted with 1
to 3 (preferably 1 or 2) substituents selected from C1-C4 alkyl
groups such as a methyl group, ethyl group and the like, and a
phenyl group, and it is for example, ureido, 1-methylureido, 3-
methylureido, 3,3-dimethylureido, 1,3-dimethylureido or 3-
phenylureido.
"C6-C10 aryl-carbonylamino group" in the definition of
Substituent group γ is, for example, benzamide, naphthoamide or
phthalimide.
"C6-C10 aryloxy-carboxamide group" in the definition of
Substituent group y is, for example, phenoxycarboxamide.
"C7-C19 aralkyloxy-carboxamide group" in the definition of
Substituent group y is, for example, benzyloxycarboxamide or
benzhydryloxycarboxamide.
"C3-C10 cycloalkyloxy-carbonyloxy group" in the definition
of Substituent group γ is, for example,
opropyloxycarbonyloxy or cyclohexyloxycarbonyloxy.
"C6-C10 aryloxy-carbonyloxy group" in the definition of
Substituent group γ is, for example, phenoxycarbonyloxy or
naphthyloxycarbonyloxy.
"C7-C19 aralkyloxy-carbonyloxy group" in the definition of
Substituent group γ is, for example, benzyloxycarbonyloxy, 1-
phenylethyloxycarbonyloxy, 2-phenylethyloxycarbonyloxy or
benzhydryloxycarbonyloxy.
"Heterocyclyl group" in the definition of Substituent

group y; and "heterocyclyl group" of "heterocyclyloxy group",
"heterocyclylthio group", "heterocyclylsulfinyl group",
"heterocyclylsulfonyl group" and "heterocyclyloxycarbonyl group"
represent a 5- to 8-membered ring (preferably 5- or 6-membered
ring) group or a fused ring group thereof, which contains 1 to
several (preferably 1 to 4) hetero atoms such as nitrogen atoms
(may be oxidized), oxygen atoms and sulfur atoms. Examples of
such "heterocyclyl group" are pyrrolyl, pyrazolyl, imidazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl,
oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,
1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, indolyl, pyranyl, thiopyranyl, dioxynyl, dioxolyl,
quinolyl, pyrido[2,3-d]pyrimidyl, 1,5-, 1,6-, 1,7-, 1,8-, 2,6-
or 2,7-naphthylidyl group, thieno[2,3-d]pyridyl, benzopyranyl,
tetrahydrofuryl, tetrahydropyranyl, dioxolanyl and dioxanyl.
These heterocyclyl groups may be substituted at
substitutable positions with 1 to 3 substituents selected from
C1-C4 alkyl groups such as methyl, ethyl and the like, a hydroxy
group, an oxo group and C1-C4 alkoxy groups such as methoxy,
ethoxy and the like.
"C1-C6 alkyl-carbamoyl group" in the definition of
Substituent group δ is, for example, methylcarbamoyl,
dimethylcarbamoyl or propylcarbamoyl.
"C1-C14 alkyl-carbamoyl group" in the definition of
Substituent group a is, for example, the aforementioned "C1-C6
alkyl-carbamoyl group", octylcarbamoyl, decylcarbamoyl,
dodecylcarbamoyl or tetradecylcarbamoyl, preferably a C1-C10
alkyl-carbamoyl group, and more preferably a C4-C8 alkyl-
carbamoyl group.
"C1-C6 alkoxy-carbonyl C1-C6 alkyl-carbamoyl group" in the
definition of Substituent group δ is, for example,
butoxycarbonylmethylcarbamoyl or ethoxycarbonylmethylcarbamoyl.
"C1-C14 alkoxy-carbonyl C1-C14 alkyl-carbamoyl group" in the

definition of Substituent group Ε is, for example, the
aforementioned "C1-C6 alkoxy-carbonyl C1-C6 alkyl-carbamoyl
group" or octyloxycarbonylmethylcarbamoyl,
preferably a C1-C10 alkoxy-carbonyl C1-C10 alkyl-carbamoyl group,
and more preferably a C4-C8 alkoxy-carbonyl C4-C8 alkyl-carbamoyl
group.
"1,3-diacylguanidino C1-C6 alkyl group" in the definition
of Substituent group δ is, for example, 1,3-
diacetylguanidinomethyl or 1,3-bis-tert-
butoxycarbonylguanidinomethyl.
"1,3-diacylguanidino C1-C14 alkyl group" in the definition
of Substituent group a is, for example, the aforementioned "1,3-
diacylguanidino C1-C6 alkyl group", 1,3-diacetylguanidinooctyl or
1,3-bis-tert-butoxycarbonylguanidinooctyl, preferably a 1,3-
diacylguanidino C1-C10 alkyl group, and more preferably a 1,3-
diacylguanidino C4-C8 alkyl group.
X and Y represent a group in which X and Y together with
the carbon atom of ring B to which they are bound form ring A,
respectively represent a hydrogen atom, or X and Y together
represent a substituent of ring B (the substituent is an oxo
group or a thioxo group), and preferably represent a group in
which X and Y together with the carbon atom of ring B to which
they are bound form ring A, or respectively represent a hydrogen
atom.
In a preferred example, in the case where X and Y
represent a group in which X and Y together with the carbon atom
of ring B to which they are bound form ring A, ring A is a 3- to
7-membered heterocyclyl ring or 3- to 7-membered saturated
cycloalkyl ring.
With respect to the heterocyclyl ring, X and Y included
in the ring, independently from each other, represent any one
selected from a carbon atom, a group having the formula NR (R
represents a hydrogen atom, a C1-Cs alkyl group which may be
substituted with a group aelected from Substituent group a, a
C2-C6 alkenyl group which may be substituted with a group

selected from Substituent group α, a C2-C6 alkynyl group which
may be substituted with a group aelected from Substituent group
a or a C1-C6 alkanoyl group which may be substituted with a
group aelected from Substituent group α), an oxygen atom, a sulfur
atom, a group having the formula SO and a group having the
formula SO2,
may form a fused ring or spiro ring with a 5- or 6-membered
heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen
and/or nitrogen atoms as hetero atom) or 5- or 6-membered
cycloalkyl ring,
either ring of the heterocyclyl ring, or the fused ring which is
fused to the heterocyclyl ring or the spiro ring which is spiro
bound to the heterocyclyl ring, may be substituted with the same
or different 1 to 4 groups selected from the group consisting of
an oxo group, a thioxo group, Substituent group a, a cyclopropyl
C1-C6 alkyl group and a C1-C6 alkyl group which may be
substituted with 1 to 5 groups selected from Substituent group
α.
The 3- to 7-membered saturated cycloalkyl ring may be
substituted with 1 or 2 groups selected from the group
consisting of a hydroxy group, a hydroxymethyl group, a 1,2-
dihydroxyethyl group, a 1,2,3 -trihydroxypropyl group, a 1,2,3,4-
tetrahydroxybutyl group and an acetylamino group.
Ring A is, more preferably, a 3- to 7-membered
heterocyclyl ring or 3- to 5-membered cycloalkyl ring.
With respect to the heterocyclyl ring which is a more
preferred example of ring A, X and Y included in the ring,
independently from each other, represent any one selected from a
carbon atom, an oxygen atom, a sulfur atom, a group having the
formula SO and a group having the formula SO2,
may form a fused ring or spiro ring with a 5- or 6-membered
heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen
and/or nitrogen atoms as hetero atom) or 5- or 6-membered
cycloalkyl ring, and
either ring of the heterocyclyl ring, or the fused ring which is

fused to the heterocyclyl ring or the spiro ring which is spiro
bound to the heterocyclyl ring, may be substituted with the same
or different 1 to 4 groups selected from an oxo group, a thioxo
group, Substituent group a and a C1-C6 alkyl group which may be
substituted with 1 to 4 groups selected from Substituent group
α.
The 3- to 5-membered cycloalkyl ring may be substituted
with 1 or 2 groups selected from the group consisting of a
hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-
trihydroxypropyl group, a 1,2,3,4-tetrahydroxybutyl group and an
acetylamino group.
Ring A is, more preferably, the heterocyclyl ring or the
undermentioned cyclopropyl or cyclopentyl ring described below.
Examples of such heterocyclyl ring are,
oxirane, tetrahydrofuran, tetrahydropyrane,
1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane,
1,3-dithiolane, 1,3-dithiane,
1,1,3,3-tetraoxo-1,3-dithiolane,
1,3-oxathiolane, 1,3-oxathiane or 1,3-oxathiepane,
these heterocyclyl rings may form a fused ring or spiro ring
with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring
is tetrahydrofuran, tetrahydropyrane, pyrrolidine, piperidine or
1,3-dioxane) or cyclohexyl ring,
either ring of the heterocyclyl ring, or the fused ring which is
fused to the heterocyclyl ring or the spiro ring which is spiro
bound to the heterocyclyl ring, may be substituted with 1 or 2
groups selected from the group consisting of an oxo group, a
thioxo group, Substituent group a (Substituent group α
represents a hydroxy group and a group having the formula NR6R7,
and R6 and R7, independently from each other, represent a
hydrogen atom or a C1-C6 alkanoyl group), a methyl group, an
ethyl group and a C1-C6 alkyl group which is substituted with 1
to 4 hydroxy groups.
In addition, the cyclopropyl or cyclopentyl ring is a
cyclopropyl or cyclopentyl ring which may be substituted with 1

or 2 groups selected from the group consisting of a
hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-
trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group.
Ring A is, further preferably for example,
oxirane, tetrahydrofuran, 1,3-dioxolane, 1,3-dioxane, 1,3-
dithiolane, 1,3-dithiane, 1,3-oxathiolane or 1,3-oxathiane,
these heterocyclyl rings may form a fused ring or spiro ring
with a 5- or 6-membered heterocyclyl ring (the heterocyclyl ring
is tetrahydrofuran, tetrahydropyrane or 1,3-dioxane) or
cyclohexyl ring, and
either ring of the heterocyclyl ring, or the fused ring which is
fused to the heterocyclyl ring or the spiro ring which is spiro
bound to the heterocyclyl ring, may be substituted with 1 or 2
groups selected from the group consisting of Substituent group a
[Substituent group a represents a hydroxy group and a group
having the formula NR6R7 (R6 and R7, independently from each
other, represent a hydrogen atom or acetyl group)], a methyl
group, an ethyl group, a hydroxymethyl group, a 1,2-
dihydroxyethyl group, a 1,2,3-trihydroxypropyl group and a
1, 2, 3,4-tetrahydroxybutyl group.
Ring A is, particularly preferably,
oxirane, 1,3-dioxolane, 1,3-dioxane or 1,3-oxathiolane, these
heterocyclyl rings may form a fused ring or spiro ring with a 5-
or 6-membered heterocyclyl ring (the heterocyclyl ring is
tetrahydrofuran, tetrahydropyrane or 1, 3-dioxane) or cyclohexyl
ring, and
either ring of the heterocyclyl ring, or the fused ring which is
fused to the heterocyclyl ring or the spiro ring which is spiro
bound to the heterocyclyl ring may be substituted with 1 or 2
groups selected from the group consisting of Substituent group a
[Substituent group a represents a hydroxy group and a group
having the formula NR6R7 (R6 and R7, independently from each
other, represent a hydrogen atom or acetyl group)], a methyl
group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a
1,2,3-trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl

group.
Preferred specific examples of ring A are,
cyclopropyl, 1-hydroxymethylcyclopropyl, 1,2-dihydroxymethyl
cyclopropyl, cyclopentyl, 2-hydroxymethylcyclopentyl, 2,3-
dihydroxymethylcyclopentyl, 2,3-bis(1,2-
dihydroxyethyl)cyclopentyl, 2-(1,2-dihydroxyethyl)cyclopentyl,
2 -(1,2,3 -trihydroxypropyl)cyclopentyl, 2- (1,2,3,4-
tetrahydroxybutyl)cyclopentyl,
oxirane, tetrahydrofuran, tetrahydropyrane, 1,3-dioxolane, 1,3-
dioxane, 1,3-oxathiolane, 4-hydroxymethyl-1,3-dioxolane, 4,5-
dihydroxymethyl-1,3-dioxolane, 4,5-bis(1,2-dihydroxyethyl)-1,3-
dioxolane, 4-(1,2-dihydroxyethyl)-1,3-dioxolane, 4-(1,2,3-
trihydroxypropyl)-1,3-dioxolane, 4-(1,2,3,4-tetrahydroxybutyl)-
1,3-dioxolane, 4,5-diacetylaminomethyl-1,3-dioxolane, 5-hydroxy
-1,3-dioxane, 5,5-dihydroxymethyl-1,3-dioxane, 5-acetylamino-
1,3-dioxane, 5,5-diethoxycarbonyl-1,3-dioxane and 2,4,7,9-
tetraoxaspiro[5.5]undecane,
more preferred specific examples are, 4-hydroxymethyl-1,3-
dioxolane, 4,5-dihydroxymethyl-1,3-dioxolane, 4,5-bis(1,2-
dihydroxyethyl)-1,3-dioxolane, 4-(1,2-dihydroxyethyl)-1,3-
dioxolane, 4-(1,2,3-trihydroxypropyl)-1,3-dioxolane, 4-(1,2,3,4-
tetrahydroxybutyl)-1,3-dioxolane, 4,5-diacetylaminomethyl-1,3-
dioxolane, 5-hydroxy-1,3-dioxane, 5-acetylamino-1,3-dioxane and
5,5-dihydroxymethyl-1,3-dioxane.
Ring B is a 5- to 7-membered cycloalkene group. Here, 1
and m, which are parameters to determine the number of members
of ring B, independently from each other, are an integer of 0 to
3, and 1+m is 1 to 3 . The 1+m being 1 to 3 represents that ring
B is 5- to 7-membered. Preferably, 1 is 0, and m is an integer
of 1 to 3. More preferably, it is a cyclohexynyl group in which
1 is 0, and m is 1.
Among the groups defined as R1, preferred is a hydroxy
group, halogen atom, C1-Cg alkyl group or C1-C6 alkoxy group,
more preferred is a hydroxy group, fluorine atom, chlorine atom,
methyl group, ethyl group, propyl group, methoxy group or ethoxy
group, further preferred is a fluorine atom or methyl group.

The number of substitutions n, which is the number of R1
that are substituted to ring B, is 0 to 3, preferably 0 or 1.
More preferably, n is 0.
Among the groups defined as R2, preferred is a C1-C6 alkyl
group which may be substituted with a group aelected from
Substituent group β, more preferred is a C1-C6 alkyl group,
further preferred is a C1-C4 alkyl group, and particularly
preferred is an ethyl group.
Among the groups defined as R3, "5- or 6-membered
heteroaryl group" of "5- or 6-membered heteroaryl group which
may be substituted with a group aelected from Substituent group
ε" is particularly preferably a pyrrolyl group. That is,
preferably R3 is a phenyl or pyrrolyl group which may be
substituted with a group aelected from Substituent group e.
Preferably, it is a phenyl or pyrrolyl group which may be
substituted with a group aelected from a halogen atom, C1-C14
alkyl group and halogeno C1-C14 alkyl group, more preferably a
phenyl or pyrrolyl group which may be substituted with a group
aelected from a fluorine atom, chlorine atom, C1-C10 alkyl group,
halogeno C1-C10 alkyl group and cyclopropyl C1-Ci0 alkyl group,
even more preferably a phenyl or pyrrolyl group which may be
substituted with a group aelected from a fluorine atom, chlorine
atom, bromine atom, C3-C8 alkyl group and halogeno C4-C8 alkyl
group, and further preferably a phenyl group which may be
substituted with a group aelected from a fluorine atom, chlorine
atom and C3-C8 alkyl group.
In addition, in the case where it is substituted by a
substituent, the position of substitution is preferably the 2-
position or 4-position.
R3 is, for example,
a phenyl group, halogenophenyl group, C1-C14 alkylphenyl group,
cyclopropyl C1-C14 alkylphenyl group, C1-C14 alkoxyphenyl group,
C3-C14 alkoxycarbonyphenyl group, carboxylphenyl group,
nitrophenyl group, cyanophenyl group, halogeno C1-C14 alkylphenyl
group, halogeno C1-C14 alkoxyphenyl group, C1-C14 alkanoylphenyl

group, phenyl group which is substituted with a 5-mettibered
heteroaryl group, C1-C14 alkoxy-carbonyl-C1-C14 alkyl-
carbamoylphenyl group, 1,3-diacylguanidino-C1-C14 alkylphenyl
group, phenyl group which is substituted with a halogen and C1-
C14 alkyl, phenyl group which is substituted with a halogen and
C1-C14 alkoxycarbonyl, phenyl group which is substituted with a
halogen and cyano, phenyl group which is substituted with a
halogen and a 5-membered heteroaryl group, phenyl group which is
substituted with a halogen and C1-C14 alkoxy-carbonyl-C1-C14
alkyl-carbamoyl,
pyrrolyl group, halogenopyrrolyl group, C1-C14 alkylpyrrolyl
group, cyclopropyl C1-C14 alkylpyrrolyl group, C1-C14
alkoxypyrrolyl group, C1-C14 alkoxycarbonylpyrrolyl group,
carboxylpyrrolyl group, nitropyrrolyl group, cyanopyrrolyl
group, halogeno C1-C14 alkylpyrrolyl group, halogeno C1-C14
alkoxypyrrolyl group, C1-C14 alkanoylpyrrolyl group, pyrrolyl
group which is substituted with a 5-membered heteroaryl group,
C1-C14 alkoxy-carbonyl-C1-C14 alkyl-carbamoylpyrrolyl group, 1,3-
diacylguanidino-C1-C14 alkylpyrrolyl group, pyrrolyl group which
is substituted with a halogen and C1-C14 alkyl, pyrrolyl group
which is substituted with a halogen and C1-C14 alkoxycarbonyl,
pyrrolyl group which is substituted with a halogen and cyano,
pyrrolyl group which is substituted with a halogen and a 5-
membered heteroaryl group, pyrrolyl group which is substituted
with a halogen and C1-C14 alkoxy-carbonyl-C1-C14 alkyl-carbamoyl,
or the like.
Among them, specific examples are preferably,
phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-
iodophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-
chlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-
difluorophenyl, 2,4-dichlorophenyl, 2,5-difluorophenyl, 2,5-
dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,4-
difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl, 3,5-
dichlorophenyl, 2,4-dibromophenyl, 2,6-dibromophenyl, 4-chloro-
2-fluorophenyl, 2-chloro-4-fluorophenyl, 4-bromo-2-fluorophenyl,
2-bromo-4-fluorophenyl, 3-chloro-4-fluorophenyl, 2-bromo-4-

chlorophenyl, 5-chloro-2-fluorophenyl, 4-bromo-2-chlorophenyl,
2-chloro-6-fluorophenyl, 2,4-dimethoxyphenyl, 2,3,4-
trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl,
2-chloro-4,6-difluorophenyl, 2,6-dichloro-4-fluorophenyl, 2-
bromo-6-chloro-4-fluorophenyl, 2-methylphenyl, 2-ethylphenyl, 2-
(n-propyl)phenyl, 2-(n-butyl)phenyl, 2-(n-pentyl)phenyl, 2-(n-
hexyl)phenyl, 2-(n-heptyl)phenyl, 2-(n-octyl)phenyl, 2-(n-
nonyl)phenyl, 2-(n-decyl)phenyl, 2-(n-undecyl)phenyl, 2-(n-
dodecyl)phenyl, 2-(n-tridecyl)phenyl, 2-(n-tetradecyl)phenyl, 2-
ethynylphenyl, 2-isopropylphenyl, 2-t-butylphenyl, 2-sec-
butylphenyl,
2-methoxyphenyl, 2-ethoxyphenyl, 2-difluoromethoxyphenyl, 2-
methylsulfanylphenyl, 2-acetylphenyl, 2-benzylphenyl, 2-
(morpholin-4-yl)phenyl, 2-[2-(pyridine-4-yl)ethyl]phenyl, 2-[2-
(t-butoxycarbonyamino)ethyl]phenyl, 2-aminophenyl, 2,6-
diisopropylphenyl, 2-chloro-4-methylphenyl, 4-fluoro-3-
trifluoromethylphenyl, 4-fluoro-3-methoxyphenyl, 4-chloro-2-
methoxycarbonylphenyl, 2-fluoro-4-methoxyphenyl, 4-chloro-2-
methylphenyl, 2-fluoro-4-methylphenyl, 2-fluoro-5-methylphenyl,
2-chloro-4-methylphenyl, 2-chloro-6-methylphenyl, 4-t-butyl-2-
chlorophenyl, 2-bromo-4-isopropylphenyl, 4-chloro-2-methoxy-5-
methylphenyl, 4-fluoro-2-methylphenyl, 2-ethyl-4-fluorophenyl,
4-fluoro-2-(n-propyl)phenyl, 2-(n-butyl)-4-fluorophenyl, 4-
fluoro-2-(n-pentyl)phenyl, 4-fluoro-2-(n-hexyl)phenyl, 4-fluoro-
2-(n-heptyl)phenyl, 4-fluoro-2-(n-octyl)phenyl, 4-fluoro-2-(n-
nonyl)phenyl, 2-(n-decyl)-4-fluorophenyl, 4-fluoro-2-(n-
undecyl)phenyl, 2-(n-dodecyl)-4-fluorophenyl, 4-fluoro-2-(n-
tridecyl)phenyl, 4-fluoro-2-(n-tetradecyl)phenyl, 2-
trifluoromethylphenyl, 2-(2,2,2-trifluoroethyl)phenyl, 2- (3,3,3-
trifluoropropyl)phenyl, 2-(4,4,4-trifluorobutyl)phenyl, 2-
(5,5,5-trifluoropentyl)phenyl, 2-(6,6,6-trifluorohexyl)phenyl,
2-(7,7,7-trifluoroheptyl)phenyl, 2-(8,8,8-trifluorooctyl)phenyl,
2-(9,9,9-trifluorononyl)phenyl, 2- (10,10,10-
trifluorodecyl)phenyl, 2-cyclopropylethylphenyl, 2-[3-
cyclopropyl-(n-propyl)]phenyl, 2-[4-cyclopropyl-(n-
butyl)]phenyl, 2-[5-cyclopropyl-(n-pentyl)]phenyl, 2-[6-

cyclopropyl-(n-hexyl)]phenyl, 2-[7-cyclopropyl-(n-
heptyl)]phenyl, 2-[8-cyclopropyl-(n-octyl)]phenyl, pyrrolyl, 2-
fluoropyrrolyl, 2-chloropyrrolyl, 2-bromopyrrolyl, 2,5-
difluoropyrrolyl, 2,5-dichloropyrrolyl, 2,5-dibromopyrrolyl, 2-
chloro-5-fluoropyrrolyl, 2-methylpyrrolyl, 2-ethylpyrrolyl, 2-
(n-propyl)pyrrolyl, 2 -(n-butyl)pyrrolyl, 2 -(n-pentyl)pyrrolyl,
2-(n-hexyl)pyrrolyl, 2-(n-heptyl}pyrrolyl, 2-(n-octyl)pyrrolyl,
2-(n-nonyl)pyrrolyl and 2-(n-decyl)pyrrolyl,
more preferably,
2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-iodo phenyl, 4-
fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-chloro-
4-fluorophenyl, 2-bromo-4-fluorophenyl, 3 -chloro-4 -fluorophenyl,
2-bromo-4-chlorophenyl, 2,4-dimethoxyphenyl,
2-chloro-4,6-difluorophenyl, 2,6-dichloro-4-fluorophenyl, 2-
bromo-6-chloro-4-fluorophenyl, 2-methylphenyl, 2-ethylphenyl, 2-
(n-propyl)phenyl, 2-(n-butyl)phenyl, 2-(n-pentyl)phenyl, 2-(n-
hexy1)phenyl, 2-(n-heptyl)phenyl, 2-(n-octyl)phenyl, 2-(n-
nonyl)phenyl, 2-(n-decyl)phenyl,
2-ethynylphenyl, 2-sec-butylphenyl, 2-methoxyphenyl, 2-
methylsulfanylphenyl, 2-benzylphenyl, 2-[2-(t-
butoxycarbonylaraino)ethyl]phenyl, 4-chloro-2-methylphenyl, 2-
fluoro-5-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-6-
methylphenyl, 4-chloro-2-methoxy-5-methylphenyl, 4-fluoro-2-
methylphenyl, 2-ethyl-4-fluorophenyl, 4-fluoro-2-(n-
propyl)phenyl, 2-(n-butyl)-4-fluorophenyl, 4-fluoro-2-(n-
pentyl)phenyl, 4-fluoro-2-(n-hexyl)phenyl, 4-fluoro-2-(n-
heptyl)phenyl, 4-fluoro-2-(n-octyl)phenyl, 4-fluoro-2-(n-
nonyl)phenyl, 2-(n-decyl)-4-fluorophenyl, 2-(n-butyl)pyrrolyl,
2-(n-pentyl)pyrrolyl, 2-(n-hexyl)pyrrolyl, 2-(n-heptyl)pyrrolyl
and 2-(n-octyl)pyrrolyl, and
even more preferably,
2-chlorophenyl, 2-bromophenyl, 2,4-difluorophenyl, 2-chloro-4-
fluorophenyl, 2-bromo-4-fluorophenyl, 2-(n-pentyl)phenyl, 2-(n-
hexyl)phenyl, 2-(n-heptyl)phenyl, 2-chloro-6-methylphenyl, 4-
fluoro-2-(n-propyl)phenyl, 2-(n-butyl)-4-fluorophenyl, 4-fluoro-
2-(n-pentyl)phenyl, 4-fluoro-2-(n-hexyl)phenyl, 4-fluoro-2-(n-

heptyl)phenyl and 4-fluoro-2-(n-octyl)phenyl.
With respect to the "pharmacologically acceptable salts
thereof", since the compound having the general formula (I) of
the present invention can be converted to a salt by reaction
with an acid in the case where it has a basic group auch as an
amino group, or by reaction with a base in the case where it has
an acidic group auch as a carboxyl group, salts thereof are
represented.
Salts of a basic group are preferably inorganic acid
salts such as hydrohalogenic acid salts including hydrochloride,
hydrobromide and hydroiodide, nitrates, perchlorates, sulfates,
phosphates or the like; lower alkanesulfonic acid salts such as
methanesulfonate, trifluoromethanesulfonate and ethanesulfonate,
arylsulfonic acid salts such as benzene, sulfonate and p-
toluenesulfonate, organic acid salts such as acetate, malates,
fumarates, succinates, citrates, ascorbates, tartrates,
oxalates, maleates or the like; and amino acid salts such as
glycine salt, lysine salt, arginine salt, ornithine salt,
glutamate and aspartate,
On the other hand, salts of an acidic group are
preferably alkali metal salts such as sodium salt, potassium
salt and lithium salt, alkaline earth metal salts such as
calcium salt and magnesium salt, metal salts such as aluminum
salt and iron salt; inorganic salts such as ammonium salt, amine
salts including organic salts such as t-octylamine salt,
dibenzylamine salt, morpholine salt, glucosamine salt,
phenylglycine alkyl ester salt, ethylenediamine salt, N-
methylglucamine salt, guanidine salt, diethylamine salt,
triethylamine salt, dieyelohexylamine salt, N,N'-
dibenzylethylenediamine salt, chloroprocaine salt, procaine
salt, diethanolamine salt, N-benzylphenethylamine salt,
piperazine salt, tetramethylammonium salt and
tris(hydroxymethyl)aminomethane salt; and amino acid salts such
as glycine salt, lysine salt, arginine salt, ornithine salt,
glutamate and aspartate.
The compounds having the general formula (I) according to

the present invention or pharmacologically acceptable salts
thereof have an asymmetric carbon atom in their molecules, and
thus stereoisomers of R configuration and S configuration exist.
Each of them, or a compound with an arbitrary ratio of these, is
also included in the present invention. With respect to such
stereoisomers, the compound (I) can be synthesized by using an
optically resolved starting compound, or a synthesized compound
(I) can be optically resolved by ordinary optical resolution or
separation methods if desired.
There exist optical isomers with respect to the compound
having the general formula (I) according to the present
invention or pharmacologically acceptable salts thereof, and
each of the optical isomers and mixtures of such isomers are
also included in the present invention.
When the compound having the general formula (I) and
pharmacologically acceptable salts thereof are exposed to the
atmosphere or are recrystallized, they may absorb moisture,
resulting in cases such as the adhesion of adsorbed water and
the generation of hydrates. Such hydrated compounds and salts
are also included in the present invention.
As representative compounds of the present invention, the
compounds listed in the following Tables 1 to 3 can be mentioned
for example, but the present invention is not limited to these
compounds.
Abbreviations and "ring 1" to "ring 18" in the tables are
as follows.

tz1 : tetrahydrothiazol-2-ylidene
tzn :tetrahydro-1,3-thiazin-2-ylidene
In the Tables, "di" indicates that there are two
identical substituents, and "tri" indicates that there are three
identical substituents.

The binding position of rings 1 to 21 with ring B is the
position indicated by a black dot, which is located at the right
end of the aforementioned chemical structure.
The substituents represented by the abbreviations as X

can be mentioned,
even more preferably,
exemplified compound No. 1-206 : ethyl 8-[N-(2-
chlorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-210: ethyl 8-[N-(2-
chlorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-294: ethyl 8-[N-(2,4-

difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro [4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-298: ethyl 8-[N-(2,4-
difluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-378: ethyl 8-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-2-hydroxymethyl-l,4-dioxaspiro[4.5]dec-
6 -ene-7 -carboxy1ate,
exemplified compound No. 1-382: ethyl 8-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-386: ethyl 8-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-3 90: ethyl 8-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-2-(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-394: ethyl 8-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-2-(1,2,3-trihydroxypropyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-398: ethyl 8-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-2-(1,2,3,4-tetrahydroxybutyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-410: ethyl 2,3-
bis (acetylaminomethyl)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-
1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-418: ethyl 9-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-3-hydroxy-1,5-dioxaspiro[5.5]undec-7-
ene-8 -carboxylat e,
exemplified compound No. 1-422: ethyl 3-acetylamino-9-[N-
(2-chloro-4-fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-
ene- 8 -carboxylate,
exemplified compound No. 1-430: ethyl 9-[N-(2-chloro-4-
fluorophenyl)sulfamoyl]-3,3-bis(hydroxymethyl)-1,5-
dioxaspiro[5.5]undec-7-ene-8-carboxylate,
exemplified compound No. 1-646: ethyl 8-[N-(2-butyl-4-

fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-650: ethyl 8-[N-(2-butyl-4-
fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-734: ethyl 8-[N-(2-
hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-738: ethyl 8-[N-(2-hexyl
phenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-822: ethyl 8-[N-(4-fluoro-2-
hexylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-826: ethyl 2,3-bis (1,2-
dihydroxyethyl)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-910: ethyl 8-[N-(2-
heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-914: ethyl 8-[N-(2-
heptylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-998: ethyl 8-[N-(4-fluoro-2-
heptylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1002: ethyl 2,3-bis (1,2-
dihydroxyethyl)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1392: ethyl 8-[N-(2-
bromophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1396: ethyl 8-[N-(2-
bromophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1480: ethyl 8-[N-(2-chloro-6-

methylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1484: ethyl 8-[N-(2-chloro-6-
methylphenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1568: ethyl 8-[N-(2-bromo-4-
fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1572: ethyl 8-[N-(2-bromo-4-
fluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1656: ethyl 2,3-
bis (hydroxymethyl) -8-[N-(2-pentylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1660: ethyl 2,3-bis(1,2-
dihydroxyethyl)-8-[N-(2-pentylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1744: ethyl 8-[N-(4-fluoro-2-
pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1748: ethyl 2,3-bis(1,2-
dihydroxyethyl)-8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1920: ethyl 8-[N-(4-fluoro-2-
octylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-1924: ethyl 2,3-bis(1,2-
dihydroxyethyl)-8-[N-(4-fluoro-2-octylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-2095: ethyl 8-[N-(4-fluoro-2-
propylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
exemplified compound No. 1-2099: ethyl 2,3-bis(1,2-
dihydroxyethyl)-8-[N-(4-fluoro-2-propylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate
and

exemplified compound No. 2-15: ethyl 8-[N-(2-chloro-4-
fluorophenyl)-N-methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro [4.5]dec-6-ene-7-carboxylate
can be mentioned.
The compound having the general formula (I) according to
the present invention can easily be prepared in accordance with
Method A to Method C shown hereafter.
Method A is a method to prepare a compound having the
general formula (I), by introducing a cyclic ketal in the
initial stage of the preparation.
Method B is a method to prepare a compound having the
general formula (I), by introducing a cyclic ketal in the final
stage of the preparation.
Method C is a method to prepare a compound having the
general formula (I) , by introducing R5 in the final stage of the
preparation.

In the aforementioned Method A to Method C, ring A, ring
B, X, Y, R1, R2, R3, R5, m and n have the same meanings as
defined above, L represents a leaving group and Z represents a
protective group.
In the reactions of Method A to Method C, in the case
where the compound as the reactive substrate has a group auch as
an amino group, hydroxy group and/or carboxyl group, which
inhibits the intended reaction, these groups may be protected

with a protective group as necessary. The protective group of a
group which inhibits the intended reaction is not limited so
long as it is a protective group which is ordinarily used to
conduct the reaction, and may be, for example, a protective
group described in "Protective Groups in Organic Synthesis, 3rd
edition, T. W. Greene & P. G. M. Wuts; John Wiley & Sons, Inc."
A protective group of an amino group can be used without
particular limitation so long as it is a group generally used as
a protective group of an amino group, and preferably, formyl,
the aforementioned Cx-Cg alkylcarbonyl group; the aforementioned
arylcarbonyl group; the aforementioned C1-C6 alkoxycarbonyl
group; the aforementioned C3-C6 alkanoyl group which is
substituted with halogen; aralkyl groups such as benzyl,
phenethyl, 3 -phenylpropyl, 4-phenylbuty 1, a-naphthylmethyl, β-
naphthylmethyl, diphenylmethyl, triphenylmethyl, a-
naphthyldiphenylmethyl or 9-anthrylmethyl; the aforementioned
aralkyloxycarbonyl group and the like can be mentioned.
A protective group of a hydroxy group can be used without
particular limitation so long as it is a group generally used as
a protective group of a hydroxy group, and preferably, formyl,
C1-C6 alkylcarbonyl groups such as acetyl, arylcarbonyls such as
benzoyl group; and alkoxylated alkoxymethyls such as 2-
methoxyethoxymethyl can be mentioned.
A protective group of a carboxyl group can be used
without particular limitation so long as it is a group generally
used as a protective group of a carboxyl group, and preferably,
the aforementioned C1-C6 alkyl group; and aralkyl groups such as
benzyl, phenethyl and phenylpropyl can be mentioned.
Further, these protective groups of groups which inhibit
the intended reaction may be cleaved as necessary. The cleavage
reaction of these protective groups, which is the desired
reaction, may be conducted in accordance with conventional
procedures which are used in the field of synthetic organic
chemistry (for example, the procedure described in the
aforementioned Protective Groups in Organic Synthesis, 3rd
edition, T. W. Greene & P. G. M. Wuts; John Wiley & Sons, Inc).

Step 1 of Method A is a step to react a ketone compound
(1) with a compound (2) or a compound (3), which is compound (2)
having its terminal substituted with a trimethylsilyl group
(described as TMS in the aforementioned scheme), in an inert
solvent in the presence of acid, to prepare a cyclic ketal
compound (4).
This step can adopt a cyclic ketalation reaction
(protection) of a ketone, which is widely used in general
organic synthesis, and can be conducted in accordance with the
procedure described in T. W. Greene, P. G. Wuts, Protective
Groups in Organic Synthesis. Third Edition, 1999, Chapter 4, pp.
293-368, John Wiley & Sons, Inc. and the like, or in accordance
with similar procedures.
Here, the cyclic ketal compound (4) can also be prepared
by the following procedure (Step 1' of Method A).
Step 1' of Method A is a step to react a dimethylketal
compound (5) with compound (2) or compound (3), in an inert
solvent in the presence of acid, to prepare a cyclic ketal
compound (4). This reaction can be conducted in accordance with
the same procedure as or based on the procedure of Step 1.
Step 2 of Method A is a step to allow the cyclic ketal
compound (4) obtained by Step 1 or Step 1' to undergo a
Dieckmann reaction, to prepare a ketoester compound (7).
This step can adopt a Dieckmann reaction which is widely
used generally in organic synthesis, and can be conducted in
accordance with the procedure described in Chemical
Pharmaceutical Bulletin (Chem. Pharm. Bull.) Vol. 29, pp. 3238-
3248 (1981) and the like, or based on that procedure.
Here, the ketoester compound (7) can also be prepared by
the following procedure (Step 2' of Method A).
Step 2' of Method A is a step to react a ketone compound
(6) with a dialkyl carbonate, in an inert solvent in the
presence of base, to prepare a ketoester compound (7).
This step can adopt an ester group introducing reaction
which is widely used generally in organic synthesis, and can be

conducted in accordance with the procedure described in Canadian
Journal of Chemistry (Can. J. Chem.) Vol. 70, pp. 1406-1426
(1992) and the like, or based on that procedure.
Step 3 of Method A is a step to enolate the ketoester
compound (7) obtained in Step 2 or Step 2', in an inert solvent
in the presence of base, to prepare a compound (8) having a
leaving group L.
This step can be conducted in accordance with the
procedure described in Journal of American Chemical Society (J.
Am. Chem. Soc), Vol. 120, pp. 3664-3670 (1998) and the like, or
based on that procedure.
"Leaving group" in the definition of L generally
represents a group which leaves as a nucleophilic residue, and
for example, halogen atoms such as a fluorine atom, chlorine
atom, bromine atom and iodine atom; lower alkanesulfonyloxy
groups such as methanesulfonyloxy and ethanesulfonyloxy;
halogeno lower alkanesulfonyloxy groups such as
trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy;
and arylsulfonyloxy groups such as benzenesulfonyloxy, p-
toluenesulfonyloxy and p-nitrobenzenesulfonyloxy can be
mentioned. Preferably, it is a halogeno lower alkanesulfonyloxy
group, particularly preferably a trifluoromethanesulfonyloxy
group.
The inert solvent used is not particularly limited so
long as it does not inhibit the reaction and dissolves the
starting material to some degree, and for example, aromatic
hydrocarbons such as benzene, toluene and xylene; halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene and
dichlorobenzene,- ethers such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethyleneglycoldimethyl ether; amides such as formamide, N, N-
dimethylformamide, N,W-dimethylacetamide, N-methyl-2-
pyrrolidinone and hexamethylphosphorotriamide; or a solvent
mixture of these can be mentioned. Preferably, it is a
halogenated hydrocarbon, more preferably dichloromethane.

The base used includes inorganic bases such as alkali
metal carbonates such as sodium carbonate, potassium carbonate
and lithium carbonate; alkali metal hydrogen carbonates such as
sodium hydrogen carbonate, potassium hydrogen carbonate and
lithium hydrogen carbonate; alkali metal hydrides such as
lithium hydride, sodium hydride and potassium hydride; alkali
metal fluorides such as sodium fluoride and potassium fluoride;
organic bases such as alkali metal alkoxides such as sodium
methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, potassium t-butoxide and lithium methoxide; N-
methylmorpholine, triethylamine, tripropylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine, W-methylpiperidine,
pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-
dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-
diazabicyclo[2.2.2]octane (DABCO) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), preferably alkali metal
hydrides or organic bases, and more preferably sodium hydride or
diisopropylethylamine.
Reaction temperature varies depending on the starting
compound and reaction reagent, and the reaction is conducted
from -100°C to 100°C, preferably from -78°C to 50°C.
Reaction time varies depending on the reaction
temperature, starting compound, reaction reagent or the type of
solvent used, and it is generally in the range from 1 minute to
48 hours, preferably from 5 minutes to 12 hours.
Step 4 of Method A is a step to react the compound (8)
having a leaving group L obtained in Step 3 with a thiol
compound (9) in an inert solvent in the presence of a base, to
prepare compound (10).
"Protective group" of the sulfanyl group in the
definition of Z is not particularly limited so long as it is a
protective group of a sulfanyl group which is widely used
generally in organic synthesis, and alkanoyl groups such as
formyl, acetyl, propionyl and butyryl, and arylcarbonyl groups

such as benzoyl, α-naphthoyl, β-naphthoyl, pyridoyl, thienoyl
and furoyl can be mentioned, for example. Preferably, it is a
group which forms a pharmacologically acceptable ester, and is
more preferably an acetyl group.
The inert solvent used is not particularly limited so
long as it does not inhibit the reaction and dissolves the
starting material to some degree, and for example, aromatic
hydrocarbons such as benzene, toluene and xylene; halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene and
dichlorobenzene; ethers such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethyleneglycoldimethyl ether; aprotic polar solvents such as
formamide, N, N-dimethylformamide, N, N-dimethylacetamide and
dimethyl sulfoxide; or a solvent mixture of these can be
mentioned. Preferably, it is an aprotic polar solvent, more
preferably N, N-dimethylformamide.
The base used includes inorganic bases such as alkali
metal carbonates, e.g. sodium carbonate, potassium carbonate and
lithium carbonate; alkali metal hydrogen carbonates such as
sodium hydrogen carbonate, potassium hydrogen carbonate and
lithium hydrogen carbonate; alkali metal hydrides such as
lithium hydride, sodium hydride and potassium hydride; alkali
metal fluorides such as sodium fluoride and potassium fluoride;
organic bases such as alkali metal alkoxides, e.g. sodium
methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, potassium t-butoxide and lithium methoxide; N-
methylmorpholine, triethylamine, tripropylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine, W-methylpiperidine,
pyridine, 4-pyrrolidinopyridine, picoline, 4-[N,N-
dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-
diazabicyclo[2.2.2]octane (DABCO) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) can be mentioned, and is
preferably an alkali metal hydride, more preferably sodium

hydride or potassium hydride.
Reaction temperature varies depending on the starting
compound and reaction reagent, and the reaction is conducted
from -78°C to 100°C, preferably from -20°C to 50°C.
Reaction time varies depending on the reaction
temperature, starting compound, reaction reagent or the type of
solvent used, and it is generally in the range from 1 minute to
120 hours, preferably from 10 minutes to 72 hours.
Step 5 of Method A is a step to deprotect the protective
group of the sulfanyl group of the compound (10) obtained in
Step 4, in an inert solvent, to prepare compound (11).
This step is a deprotection step of a protective group of
a sulfanyl group which is widely used in general organic
synthesis, and is conducted in accordance with the procedure
described in the aforementioned "Protective Groups in Organic
Synthesis, 3rd edition, T. W. Greene & P. G. M. Wuts; John wiley
& Sons, Inc." and the like, or based on that procedure, and can
be preferably conducted by a deprotection procedure in an inert
solvent in the presence of base.
The inert solvent used is not particularly limited so
long as it does not inhibit the reaction and dissolves the
starting material to some degree, and for example, aromatic
hydrocarbons such as benzene, toluene and xylene; halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride, dichloroethane, chlorobenzene and
dichlorobenzene; ethers such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethyleneglycoldimethyl ether; alcohols such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol,
cyclohexanol and 2-methoxyethanol; amides such as formamide,
N,N-dimethylformamide, N,N-dimethylacetamide, W-methyl-2-
pyrrolidinone and hexamethylphosphorotriamide; sulfoxides such
as dimethyl sulfoxide and sulfolane; or a solvent mixture of
these can be mentioned, and is preferably an alcohol, and more
preferably methanol or ethanol.

The base used includes alkali metal carbonates such as
sodium carbonate, potassium carbonate and lithium carbonate;
alkali metal hydrogen carbonates such as sodium
hydrogencarbonate, potassium hydrogencarbonate and lithium
hydrogencarbonate; organic bases such as alkali metal alkoxides,
e.g. sodium methoxide, sodium ethoxide, potassium methoxide,
potassium ethoxide, potassium t-butoxide and lithium methoxide;
N-methylmorpholine, triethylamine, tripropylamine,
tributylamine, diisopropylethylamine, dicyclohexylamine, N-
methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-
(W,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-
diazabicyclo[2.2.2]octane (DABCO) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), preferably alkali metal
carbonates, and more preferably potassium carbonate.
Reaction temperature varies depending on the starting
compound and reaction reagent, and the reaction is conducted
from -78°C to 100°C, preferably from -20°C to 50°C.
Reaction time varies depending on the reaction
temperature, starting compound, reaction reagent or the type of
solvent used, and it is generally from 1 minute to 24 hours,
preferably from 5 minutes to 5 hours.
Step 6 of Method A is a step to chlorosulfonylate the
thiol group of the compound (11) obtained in Step 5, in an inert
solvent, to prepare compound (12).
This step can be conducted in accordance with the
procedure described in Journal of Organic Chemistry (J. Org.
Chem.), Vol. 16, pp. 621-625 (1951) and the like, or based on
that procedure.
The inert solvent used is not particularly limited so
long as it does not inhibit the reaction and dissolves the
starting material to some degree, and for example, aromatic
hydrocarbons such as benzene, toluene and xylene; halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride and dichloroethane' ethers such as diethyl ether,

diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethyleneglycoldimethyl ether; alcohols such as methanol,
ethanol, n-propanol, isopropanol, ji-butanol, isobutanol, t-
butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol,
cyclohexanol and 2-methoxyethanol; aprotic polar solvents such
as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl
sulfoxide; nitriles such as acetonitrile; esters such as methyl
acetate and ethyl acetate; carboxylic acids such as formic acid,
acetic acid, propionic acid and trifluoroacetic acid; water; or
a solvent mixture of these can be mentioned. Preferably, it is
a solvent mixture of carboxylic acids and water or a solvent
mixture of nitriles and water, more preferably a solvent mixture
of acetic acid and water, or a solvent mixture of acetonitrile
and water.
Reaction temperature varies according to the starting
compound and reaction reagent, and the reaction is conducted
from -78°C to 100°C, preferably from -20°C to 50°C.
Reaction time varies depending on the reaction
temperature, starting compound, reaction reagent or the type of
solvent used, and it is generally from 1 minute to 12 hours,
preferably from 5 minutes to 1 hour.
Step 7 of Method A is a step to react the compound (12)
obtained in Step 6 with an amine compound (13) in an inert
solvent in the presence or absence of base, to prepare a
compound of general formula (I).
The inert solvent used is not particularly limited so
long as it does not inhibit the reaction and dissolves the
starting material to some degree, and for example, aromatic
hydrocarbons such as benzene, toluene and xylene; halogenated
hydrocarbons such as dichloromethane, chloroform, carbon
tetrachloride and dichloroethane; ethers such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethyleneglycoldimethyl ether; aprotic polar solvents such as
N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl
sulfoxide; nitriles such as acetonitrile; esters such as methyl
acetate and ethyl acetate; or a solvent mixture of these can be

FP0628s

P96425/acf/translation of PCT spec 25/02/08

mentioned. Preferably, it is an ester, more preferably ethyl
acetate.
The base used includes alkali metal hydrates such as
lithium hydrate, sodium hydrate and potassium hydrate; organic
bases such as N-methylmorpholine, triethylamine, tripropylamine,
tributylamine, diisopropylethylamine, dicyclohexylamine, N-
methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-
(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N, W-dimethylaniline, N, N-diethylaniline, 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-
diazabicyclo[2.2.2]octane (DABCO) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), preferably organic bases,
and more preferably triethylamine.
Reaction temperature varies depending on the starting
compound and reaction reagent, and the reaction is conducted
from -78°C to 100°C, preferably from -20°C to 50°C.
Reaction time varies depending on the reaction
temperature, starting compound, reaction reagent or the type of
solvent used, and it is generally in the range from 1 minute to
120 hours, preferably from 10 minutes to 48 hours.

Step 8 of Method B is a step to hydrolyze the cyclic
ketal compound (14) obtained in Method A in an inert solvent in
the presence of acid, to prepare a ketone compound (15).
This step can adopt a deprotection reaction of a cyclic
ketal compound which is widely used generally in organic
synthesis, and can be conducted in accordance with the procedure
described in the aforementioned T. W. Greene, O. G. Wuts,
Protective Groups in Organic Synthesis. Third Edition, 1999,
Chapter 4, pp. 293-3 68, John Wiley & Sons, Inc. and the like, or
based on that procedure.
Step 9 of Method B is a step to prepare a dimethylketal
compound (16) with the ketone compound (15) obtained in Step 8
in an inert solvent in the presence of acid.
This step can adopt a dimethylketalation reaction
(protection) of a ketone which is widely used generally in

organic synthesis, and can be conducted in accordance with the
procedure described in the aforementioned T. W. Greene, 0. G.
Wuts, Protective Groups in Organic Synthesis. Third Edition,
1999, Chapter 4, pp. 293-368, John Wiley & Sons, Inc. and the
like, or based on that procedure.
Step 10 of Method B is a step to react the ketone
compound (15) obtained in Step 8 with the compound (2) or
compound (3) in an inert solvent in the presence of acid, to
prepare a compound having the general formula (I).
Here, this reaction can be conducted in accordance with a
similar procedure to Step 1.
Step 10' of Method B is a step to react the dimethylketal
compound (16) obtained in Step 9 with the compound (2) or
compound (3) in an inert solvent in the presence of acid, to
prepare a compound having the general formula (I).
Here, this reaction can be conducted in accordance with a
similar procedure to Step 1'.

Step 11 of Method C is a step, in the case where Rs of the
cyclic ketal compound (14) obtained in Method A or the compound
having the general formula (I) obtained in Method B is a
hydrogen atom, to react it with R5-L (17) in an inert solvent in
the presence of base, to prepare a compound having the general
formula (I) which is substituted with a desired R5.
R5 and L represent the same meanings as described above,
and "leaving group" in the definition of L represents a group
which leaves as a nucleophilic residue, and for example, halogen
atoms such as a fluorine atom, chlorine atom, bromine atom and
iodine atom; lower-alkane sulfonyloxy groups such as
methanesulfonyloxy and ethanesulfonyloxy; halogeno lower
alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and
pentafluoroethanesulfonyloxy; arylsulfonyloxy groups such as
benzenesulfonyloxy, p-toluenesulfonyloxy and p-
nitrobenzenesulfonyloxy; can be mentioned. Preferably, it is a
halogen atom, particularly preferably an iodine atom.
The inert solvent used is not particularly limited so

long as it does not inhibit the reaction and dissolves the
starting material to some degree, and includes, for example,
ketones such as acetone, methyl ethyl ketone, methyl isobutyl
ketone, isophorone and cyclohexanone; ethers such as diethyl
ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic
polar solvents such as dimethylformamide, dimethylacetamide and
dimethyl sulfoxide; nitriles such as acetonitrile; esters such
as methyl acetate and ethyl acetate; aromatic hydrocarbons such
as benzene, toluene and xylene; aliphatic hydrocarbons such as
pentane, hexane and heptane, preferably, ethers, ketones or
aprotic polar solvents, and more preferably, tetrahydrofuran,
acetone or dimethylformamide.
The base used includes alkali metal carbonates such as
sodium carbonate, potassium carbonate and lithium carbonate;
alkali metal hydrogen carbonates such as sodium hydrogen
carbonate, potassium hydrogen carbonate and lithium hydrogen
carbonate; organic bases such as alkali metal alkoxides such as
sodium methoxide, sodium ethoxide, potassium methoxide,
potassium ethoxide, potassium t-butoxide and lithium methoxide;
W-methylmorpholine, triethylamine, tripropylamine,
tributylamine, diisopropylethylamine, dicyclohexylamine, N-
methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-
(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline, N,AT-diethylaniline, 1,5-
diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-
diazabicyclo[2.2.2]octane (DABCO) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), preferably alkali metal
carbonates, and more preferably potassium carbonate.
Reaction temperature varies depending on the starting
compound and reaction reagent, and the reaction is conducted
from -78°C to 150°C, preferably from -20°C to 100°C.
Reaction time varies depending on the reaction
temperature, starting compound, reaction reagent or the type of
solvent used, and it is generally in the range from 1 minute to
24 hours, preferably from 10 minutes to 5 hours.
After each of the aforementioned reactions is completed,

the desired compound is collected from the reaction mixture in
accordance with general procedures.
For example, the reaction mixture is neutralized as
needed, and after filtration to remove insoluble matters in the
case where insoluble matters exist, the reaction solution is
extracted with an organic solvent such as ethyl acetate, which
does not blend with water. Then after washing the reaction
solution with water and the like, the organic layer containing
the desired compound is separated and dried over anhydrous
magnesium sulfate and the like, and then the solvent is
evaporated to give the desired compound.
The obtained desired compound may, if necessary, be
separated and purified by ordinary procedures such as
recrystallization and reprecipitation, or by a procedure
generally used for separation and purification of organic
compounds such as appropriately combining an adsorption column
chromatography method which uses silica gel, alumina or florisil
of magnesium-silica type as a support; a method using a
synthetic adsorbent agent such as distribution column
chromatography which uses Sephadex LH-2 0 (produced by
Pharmacia), Amberlite XAD-11 (produced by Rohm and Haas) or
Diaion HP-20 (produced by Mitsubishi Chemical Corporation) as a
support, a method using ion exchange chromatography, or normal
phase or reverse phase column chromatography by silica gel or
alkylated silica gel (preferably high performance liquid
chromatography) and eluting with an appropriate eluent.
The starting compounds such as (1), (2), (3), (5), (6),
(9), (13) and (17) as reactive substances of the present
invention are publicly known or can easily be prepared in
accordance with publicly known procedures.
The compound having the general formula (I) according to
the present invention or pharmacologically acceptable salts
thereof possesses excellent activity to suppress intracellular
signal transduction or cell activation in various cells such as
monocytes, macrophages and vascular endothelial cells, the
intracellular signal transduction and cell activation being

induced by endotoxin, and to suppress various cell responses
induced by the intracellular signal transduction and cell
activation such as an excess generation of inflammatory
mediators such as TNF-α. Therefore, it is useful as a
medicament, especially as a prophylactic and/or therapeutic
agent for various diseases which are associated with
intracellular signal transduction or cell activation induced by
endotoxin, and with various cell responses (for example, excess
generation of inflammatory mediators such as TNF-α) which are
induced by the intracellular signal transduction and cell
activation. As for such medicament, a prophylactic and/or
therapeutic agent for ischemic brain disorder, arteriosclerosis,
poor prognosis after coronary angioplasty, heart failure,
diabetes, diabetic complication, joint inflammation,
osteoporosis, osteopenia, sepsis, autoimmune disease, tissue
disorder and rejection after organ transplantation, bacterial
infection, virus infection, gastritis, pancreatitis, nephritis,
pneumonia, hepatitis or leukemia can be mentioned.
In the case where the compound having the general formula
(I) according to the present invention or the pharmacologically
acceptable salts thereof is used as a prophylactic agent or a
therapeutic agent for the aforementioned diseases, it can be
mixed with excipients, diluents and the like that are themselves
pharmacologically acceptable, and administered orally as a
tablet, capsule, granules, powder or syrup, or administrated
parenterally as an injection for subcutaneous injection,
intramuscular injection or intravenous injection or as a
suppository.
These pharmaceutical preparations are prepared in
accordance with known processes by using additives including
excipients (for example, organic excipients such as sugar
derivatives, e.g. lactose, sucrose, glucose, mannitol or
sorbitol; starch derivatives, e.g. corn starch, potato starch,
a-starch or dextrin; cellulose derivatives, e.g. crystalline
cellulose; gum arabic; dextrane; or pullulan, and inorganic

excipients such as silicate derivatives, e.g. light silicic
anhydride, synthetic aluminum silicate, calcium silicate,
metamagnesium aluminate; phosphates, e.g. calcium
hydrogenphosphate; carbonates, e.g. calcium carbonate; salts of
sulfuric acid such as calcium sulfate, can be mentioned),
lubricants (for example, stearic acid, stearic acid metal salts
such as calcium stearate or magnesium stearate; talc; colloid
silica; waxes such as bees wax or spermaceti, boric acid; adipic
acid; sulfates such as sodium sulfate; glycol; fumaric acid;
sodium benzoate; DL leucine; lauryl sulfates such as sodium
lauryl sulfate or magnesium lauryl sulfate; silicic acids such
as silicic anhydride or silicate hydrate; and the aforementioned
starch derivatives can be mentioned), binders (for example,
hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
polyvinylpyrrolidone, macrogol and compounds similar to the
aforementioned excipient can be mentioned), disintegrants (for
example, cellulose derivatives such as low-substituted
hydroxypropyl cellulose, carboxymethyl cellulose, calcium
carboxymethyl cellulose or internally crosslinked sodium
carboxymethyl cellulose; or chemically modified starches or
celluloses such as carboxymethyl starch, sodium carboxymethyl
starch or crosslinked polyvinylpyrrolidone can be mentioned),
emulsifiers (for example, colloidal clays such as bentonite or
bee gum; metal hydroxides such as magnesium hydroxide or
aluminum hydroxide; anionic surfactants such as sodium lauryl
sulfate or calcium stearate; cationic surfactants such as
benzalkonium chloride; and nonionic surfactants such as
polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid
ester or sucrose fatty acid ester), stabilizers (for example,
paraoxybenzoic acid esters such as methyl paraben or propyl
paraben; alcohols such as chlorobutanol, benzyl alcohol or
phenyl ethyl alcohol, benzalkonium chloride; phenols such as
phenol or cresol; thimerosal; dehydroacetic acid; and sorbic
acid can be mentioned) and corrigents (for example, commonly
used sweeteners, acidifiers or fragrances can be mentioned) or
diluents.

The amount of dosage varies according to symptoms and
age, and it is desirable that the compound of the present
invention is administered orally or parenterally to an adult
human within a lower limit of 0.01 mg/kg (preferably 0.10 mg/kg)
and an upper limit of 1000 mg/kg (preferably 100 mg/kg) per day,
once a day or several times in parts depending on the symptoms.
[EXAMPLES]
Hereinafter, the present invention will be described in
detail with reference to Examples and Test Examples, however,
the scope of the present invention is not limited to these.
Example 1
Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-364

(la) Ethyl 8-acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-ene-
7-carboxylate
19.97 g (55.4 mmol) of ethyl 8-
trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-
carboxylate [compound described as compound 6 in Tetrahedron
Letter, Vol. 39, pp. 6139-6142 (1998)] was dissolved in 200 ml
of dimethylformamide, and 9.50 g (83.1 mmol) of potassium
thioacetate was added thereto with stirring under ice-cooling,
followed by stirring at room temperature for 91 hours. To the
reaction solution was added ice water and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane: ethyl

acetate =17:3) to give 7.15 g of the title compound as a pale
brown oil (yield: 45%).
1H-NMR spectrum (400 MHz, CDCl3) δ ppm:
4.20 (2H, q, 7Hz), 4.04-3.96 (4H, m), 2.73-2.66 (4H, m), 2.34
(3H, s), 1.87 (2H, t, J=6Hz), 1.28 (3H, t, J=7Hz).
(lb) Ethyl 8-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-7-
carboxylate
7.14 g (24.9 mmol) of ethyl 8-acetylsulfanyl-1,4-
dioxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (la) was
dissolved in 145 ml of methanol, and 2.58 g (18.7 mmol) of
potassium carbonate was added thereto with stirring under ice-
cooling, followed by stirring at the same temperature for 1 hour
and then at room temperature for 1 hour. The reaction solution
was made acidic by addition of 1N hydrochloric acid and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous magnesium sulfate,
followed by concentration under reduced pressure. The residue
was subjected to silica gel column chromatography (solvent;
hexane : ethyl acetate =9:1) to give 5.63 g of the title
compound as a pale yellow oil (yield: 92%).
1H-NMR spectrum (40 0 MHz, CDCl3) δ ppm:
4.32 (1H, s), 4.21 (2H, q, 7Hz), 4.04-3.95 (4H, m), 2.72-2.67
(2H, m), 2.59-2.57 (2H, m), 1.82 (2H, t, J=7Hz), 1.30 (3H, t,
J=7Hz).
(1c) Ethyl 8-chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene-
7-carboxylate
To a saturated solution prepared by blowing chlorine gas
into 80 ml of solution mixture of acetonitrile-water (1:1) for
2 0 minutes was added a solution of 5.00 g (20.5 mmol) of ethyl
8-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate obtained
in (lb) in 10 ml of acetonitrile with stirring under ice-
cooling. Chlorine gas was further blown into the reaction
solution for 10 minutes at the same temperature. Water was
added to the reaction solution and the mixture was extracted

with ethyl acetate. The organic layer was washed with water and
dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate =2:1) to give 5.83 g of the title compound as a
colorless oil (yield: 92%).
1H-NMR spectrum (40 0 MHz, CDCl3) δ ppm:
4.30 (2H, q, 7Hz), 4.05-3.98 (4H, m), 2.91-2.86 (2H, m), 2.71-
2.69 (2H, m), 1.93 (2H, t, J=7Hz), 1.34 (3H, t, J=7Hz).
(1d) Ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate
To a solution of 197 mg (1.35 mmol) of 2-chloro-4-
fluoroaniline and 0.20 ml (1.42 mmol) of triethylamine in 5 ml
of ethyl acetate was added dropwise a solution of 400 mg (1.29
mmol) of ethyl 8-chlorosulfonyl-l,4-dioxaspiro[4.5]dec-7-ene-7-
carboxylate obtained in (lc) in 3 ml of ethyl acetate with
stirring under ice-cooling, followed by stirring at room
temperature for 48 hours. Water was added to the reaction
solution and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and dried over anhydrous
magnesium sulfate, followed by concentration under reduced
pressure. The residue was subjected to silica gel column
chromatography (solvent; hexane : ethyl acetate = 3:1), and the
resulting solid was further washed with a mixed solution of
hexane-isopropyl ether (1:1) to give 325 mg of the title
compound as a white powder (yield: 60%).
Melting point 117-119°C
1H-NMR spectrum (400 MHz, CDCl3) 8ppm:
7.67 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.05-6.98
(2H, m) , 6.83 (1H, s) , 4.43-4.41 (1H, m) , 4.26-4.01 (5H, m) ,
3.95-3.88 (1H, m), 2.56-2.45 (2H, m), 2.24-2.11 (1H, m), 1.88-
1.80 (1H, m), 1.27 (3H, t, J=7Hz).
Example 2

Ethyl 8-(N-phenylsulfamoyl)-1,4-dioxaspiro[4.5]dec-6-ene-
7-carboxylate (Exemplified compound No. 1-12)

Following the process described in Example (1d), aniline
was used in place of 2-chloro-4-fluoroaniline to give the title
compound as an amorphous substance (yield: 81%).
1H-NMR spectrum (4 00 MHz, CDCl3) 5ppm:
7.37-7.31 (4H, m), 7.21-7.15 (1H, m), 6.95 (1H, s), 6.85-6.87
(1H, m), 4.30-4.20 (3H, m), 4.13-4.01 (3H, m), 3.94-3.88 (1H,
m) , 2.48-2.41 (1H, m) , 2.31 (1H, , td, J=14Hz, 3Hz) , 2.10-2.00
(1H ,m), 1.86-1.80 (1H ,m), 1.31 (3H, t, J=7Hz).
Example 3
Ethyl 8-[N- (2-butylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (exemplified compound No.
1-540)

Following the process described in Example (1d), 2-
butylaniline was used in place of 2-chloro-4-fluoroaniline to
give the title compound as a colorless oil (56% yield).
1H-NMR spectrum (4 00 MHz, CDCl3) δppm:
7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85-
6.84 (1H, m), 6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H,
m) , 3.95-3.89 (1H, m) , 2.71-2.62 (2H, m) , 2.54-2.38 (2H, m) ,
2.19-2.09 (1H, m) , 1.86-1.81 (1H, m) , 1.62-1.53 (2H, m) , 1.45-
1.34 (2H, m), 1.26 (3H, t, J=7Hz), 0.95 (3H, t, J=7Hz).

Example 4
Ethyl 8-[N- (2-hexylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-716)

Following the process described in Example (1d), 2-
hexylaniline was used in place of 2-chloro-4-fluoroaniline to
give the title compound as a pale yellow oil (82% yield).
1H-NMR spectrum (400 MHz, CDCl3) δppm:
7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85-
6.84 (1H, m), 6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H,
m) , 3.95-3.89 (1H, m) , 2.70-2.61 (2H, m) , 2.54-2.38 (2H, m) ,
2.19-2.09 (1H, m) , 1.86-1.81 (1H, m) , 1.64-1.54 (2H, m) , 1.41-
1.24 (6H, m) , 1.26 (3H, t, J=7Hz) , 0.91-0.85 (3H, m) .
Example 5
Ethyl 8-[N- (2-heptylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-892)

Following the process described in Example (1d), 2-
heptylaniline was used in place of 2-chloro-4-fluoroaniline to
give the title compound as a pale yellow oil (87% yield).
1H-NMR spectrum (400 MHz, CDCl3) δppm:
7.55-7.52 (1H, m), 7.22-7.17 (2H, m), 7.13-7.08 (1H, m), 6.85-
6.84 (1H, m), 6.63 (1H, s), 4.47-4.44 (1H, m), 4.25-4.02 (5H,
m) , 3.95-3.89 (1H, m) , 2.69-2.61 (2H, m) , 2.54-2.38 (2H, m) ,
2.19-2.09 (1H, m), 1.86-1.81 (1H, m), 1.64-1.54 (2H, m), 1.42-

1.23 (8H, m), 1.26 (3H, t, J=7Hz), 0.88 (3H, t, J=7Hz).
Example 6
Ethyl 8-[N- (lH-pyrrol-1-yl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-1062)

Following the process described in Example (1d), 1H-
pyrrol-1-ylamine was used in place of 2-chloro-4-fluoroaniline
to give the title compound as a white powder (yield: 33%).
Melting point: 115-117°C
1H-NMR spectrum (400 MHz, CDCl3) δppm:
8.05 (1H, s), 6.99 (2H, t, J=2Hz), 6.94 (1H, s), 6.17 (2H, t,
J=2Hz), 4.55-4.51 (1H, m), 4.30 (2H, q, J=7Hz), 4.14-4.03 (3H,
m) , 3.98-3.89 (1H, m) , 2.51-2.44 (1H, m) , 2.26-2.05 (2H, m) ,
1.89-1.83 (1H, m), 1.35 (3H, t, J=7Hz).
Example 7
Ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-353)

To 2.55 g (6.07 mmol) of ethyl 8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 1 was added 100 ml of a mixed
solution of 1N hydrochloric acid-tetrahydrofuran (1:1), and the
reaction solution was stirred at room temperature for 64 hours.
Tetrahydrofuran was distilled off under reduced pressure, the
residue was extracted by addition of ethyl acetate, and the

organic layer was washed with water and dried over anhydrous
magnesium sulfate, followed by concentration under reduced
pressure. The residue was subjected to silica gel column
chromatography (solvent; hexane : ethyl acetate =4:1), to give
2.19 g of the title compound as a pale brown powder (yield:
96%) .
Melting point: 128-130°C
1H-NMR spectrum (400 MHz, CDCl3) δ ppm:
7.69 (1H, dd, J=9Hz, 5Hz), 7.20 (1H, dd, J=8Hz, 3Hz), 7.09-7.03
(1H, m), 6.91 (2H, s), 4.68 (1H, dd, J=5Hz, 2Hz), 4.28-4.18 (2H,
m) , 3.21-3.09 (1H, m) , 2.80-2.72 (1H, m) , 2.57-2.49 (1H, m) ,
2.44-2.31 (1H, m), 1.28 (3H, t, J=7Hz).
Example 8
Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,5-
dioxaspiro[5.5]undec-7-ene-8-carboxylate (exemplified compound
No. 1-365)

100 mg (0.27 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate
obtained in Example 7 was dissolved in 2 ml of toluene, and 0.04
ml (0.54 mmol) of propane-1,3-diol and 68 mg (0.27 mmol) of
pyridinium p-toluenesulfonate were added thereto, followed by
heating under reflux for 1 hour. After the reaction solution
was cooled to room temperature, a saturated aqueous sodium
hydrogencarbonate solution was added and extracted with ethyl
acetate. The organic layer was washed with water and dried over
anhydrous magnesium sulfate, followed by concentration under
reduced pressure. The residue was subjected to silica gel
column chromatography (solvent; hexane : ethyl acetate = 2:1),
and the resulting solid was further washed with hexane to give

60 mg of the title compound as a white powder (yield: 51%).
Melting point: 120-121°C
1H-NMR spectrum (400 MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz), 7.36 (1H, s), 7.14 (1H, dd, J=8Hz,
3Hz), 7.01 (1H, dd, J=7Hz, 2Hz), 6.98 (1H, s), 4.45-4.39 (1H,
m) , 4.27-4.12 (2H, m) , 4.11-3.84 (4H, m) , 2.46-2.06 (4H, m) ,
1.92-1.67 (2H, m), 1.28 (3H, t, J=7Hz).
Example 9
Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3,3-
dimethyl-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate
(Exemplified compound No. 1-426)

Following the process described in Example 8, 2,2-
dimethylpropane-1,3-diol was used in place of propane-1,3-diol
to give the title compound as a pale brown oil (yield: 64%).
1H-NMR spectrum (400 MHz, CDCl3) δ ppm:
7.64 (1H, dd, J=9Hz, 5Hz), 7.31 (1H, s), 7.13 (1H, dd, J=8Hz,
3Hz) , 7.04-6.94 (2H, m) , 4.45-4.39 (1H, m) , 4.27-4.12 (2H, m) ,
3.69-3.46 (4H, m), 2.42-2.11 (4H, m), 1.28 (3H, t, J=7Hz), 1.03
(3H, s), 0.97 (3H, s).
Example 10
Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl] -1,4-
dithiaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound
No. 1-367)

100 mg (0.27 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate
obtained in Example 7 was dissolved in 1 ml of dichloromethane
and 0.034 ml (0.405 mmol) of ethane-1,2-dithiol and 0.025 ml
(0.203 mmol) of boron trifluoride diethyl etherate were added
thereto with stirring under ice-cooling,followed by stirring at
room temperature for 1 hour. To the reaction solution was added
a IN aqueous sodium hydroxide solution and the mixture was
extracted with diethyl ether. The organic layer was washed with
water and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The resulting solid was
washed with diethyl ether and then with hexane to give 325 mg of
the title compound as a white powder (76% yield).
Melting point: 160-161°C
1H-NMR spectrum (400 MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.10 (1H,
s) , 7.04-6.96 (2H, m) , 4.40 (1H, d, J=5Hz) , 4.25-4.10 (2H, m) ,
3.52-3.26 (4H, m), 2.82-2.72 (1H, m), 2.58-2.50 (1H, m), 2.33-
2.24 (1H, m), 2.11-1.99 (1H, m), 1.27 (3H, t, J=7Hz).
Example 11
Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,5-
dithiaspiro[5.5]undec-7-ene-8-carboxylate (Exemplified compound
No. 1-368)

Following the process described in Example 10, propane-
1,3-dithiol was used in place of ethane-1,2-dithiol to give the
title compound as an amorphous substance (72% yield).
1H-NMR spectrum (40 0 MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz), 7.40 (1H, s), 7.14 (1H, dd, J= 8Hz,
3Hz), 7.03-6.96 (1H, m), 6.94 (1H, s), 4.51 (1H, d, J=5Hz),

4.24-4.11 (2H, m), 3.17-3.07 (1H, m), 2.98-2.77 (3H, m), 2.61-
2.51 (1H, m), 2.47-2.38 (1H, m), 2.36-2.27 (1H, m), 2.25-2.13
(1H, m), 2.12-1.95 (2H, m), 1.27 (3H, t, J=7Hz).
Example 12
Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1-oxa-4-
thiaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-371)

Following the process described in Example 10, 2-
mercaptoethal was used in place of ethane-1,2-dithiol to give
the title compound as a white powder (61% yield).
Melting point: 133-134°C
1H-NMR spectrum (400 MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.06
(0.4H, s), 7.04-6.96 (2.6H, m), 4.46 (0.4H, dd, J=5Hz, 3Hz),
4.39-4.01 (4.6H, m), 3.23-3.06 (2H, m), 2.77-2.51 (1.6H, m),
2.45-2.36 (0.4H, m) , 2.20-2.00 (2H, m) , 1.27 (3H, t, J=7Hz) .
Example 13
Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,1,4,4-
tetraoxo-1λ6, 4λ6-dithiaspiro [4.5] dec-6-ene-7-carboxylate
(Exemplified compound No. 1-3 69)

80 mg (0.18 mmol) of ethyl 8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dithiaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 10 was dissolved in 2 ml of

dichloromethane, 91 mg (1.08 mmol) of sodium hydrogencarbonate
was added thereto and subsequently 239 mg (0.90 mmol) of m-
chloroperbenzoic acid (65%) was added with stirring under ice-
cooling, followed by stirring at room temperature for 5 hours.
Water was added to the reaction solution and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel thin layer chromatography (solvent; hexane : ethyl
acetate =1:1) to give 42 mg of the title compound as a white
powder (yield: 45%).
Melting point: 88-90°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, dd, J=8Hz, 3Hz), 7.06-6.98
(2H, m) , 6.92 (1H, s) , 4.57 (1H, d, J=5Hz), 4.26-4.16 (2H, m) ,
3.79-3.60 (4H, m), 3.14-2.98 (1H, m), 2.69-2.60 (1H, m), 2.45-
2.36 (1H, m), 2.29-2.16 (1H, m), 1.28 (3H, t, J=7Hz).
Example 14
Ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl] -1-
oxaspiro[2.5]oct-4-ene-5-carboxylate (Exemplified compound No.
1-360)

50 mg (0.133 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate
obtained in Example 7 and 0.01 ml (0.146 mmol) of dibromomethane
were dissolved in 1 ml of tetrahydrofuran, and 0.18 ml (0.279
mmol) of n-butyllithium/hexane solution (1.58 M) was added
dropwise thereto at -78°C, followed by stirring at room
temperature for 4 hours. After the reaction solution was cooled
with ice, a saturated aqueous ammonium chloride solution was
added and the mixture was extracted with ethyl acetate. The

organic layer was washed with water and dried over anhydrous
magnesium sulfate, followed by concentration under reduced
pressure. The residue was subjected to silica gel thin layer
chromatography (solvent; hexane : ethyl acetate =2:1) to give 7
mg of the title compound as a yellow oil (yield: 14%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.68 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, dd, J=8Hz, 3Hz), 7.07-6.91
(2H, m) , 6.60 (1H, s) , 4.50 (1H, d, J=4Hz) , 4.27-4.06 (2H, m) ,
2.98-2.92 (1H; m) , 2.91-2.88 (1H, m) , 2.83-2.70 (1H, m) , 2.68-
2.59 (1H, m), 2.21-2.07 (2H, m) , 1.25 (3H, t, J=7Hz).
Example 15
Ethyl (2S)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2-
hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(exemplified compound No. 1-3 78)

100 mg (0.27 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3-oxo-1-eyelohexene-1-carboxylate
obtained in Example 7 and 69 mg (0.35 mmol) of (i?)-2,3-
dihydroxypropyl benzoate were dissolved in 2 ml of
dichloromethane and 0.19 ml (1.05 mmol) of
isopropoxytrimethylsilane and 2 µl (0.014 mmol) of
trimethylsilyl trifluoromethanesulfonate were sequentially added
thereto with stirring under ice-cooling, followed by stirring at
the same temperature for 1 hour. Water was added to the
reaction solution and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and dried over
anhydrous magnesium sulfate, followed by concentration under
reduced pressure. The residue was subjected to silica gel
column chromatography (solvent; hexane : ethyl acetate = 1:1),

to give 121 mg of ethyl (2R) -2-benzoyloxymethyl-8- [N- (2-chloro-
4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate as a pale yellow oil (yield: 81%).
Subsequently, 121 mg (0.22 mmol) of this compound was
dissolved in 2 ml of a mixture of methanol-tetrahydrofuran
(1:1), and to the solution was added 0.5 ml (0.50 mmol) of 1N
aqueous sodium hydroxide with stirring under ice-cooling,
followed by stirring at the same temperature for 3 0 minutes.
Water was added to the reaction solution and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate = 1:1) to give 41 mg of the title compound as an
amorphous substance (yield: 41%) .
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.64 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.06-6.97
(2H, m), 6.89 (0.25H, s), 6.86 (0.25H, s), 6.80 (0.25H, s), 6.78
(0.25H, s), 4.43-4.31 (1.75H, m), 4.26-4.02 (3.25H, m), 3.95-
3.87 (0.75H, m), 3.85-3.77 (1H, m), 3.75-3.69 (0.25H, m), 3.68-
3.59 (1H, m), 2.65-2.38 (2H, m), 2.25-2.11 (1H, m), 2.11-2.05
(0.25H, m), 2.03-1.97 (0.25H, m), 1.94-1.81 (1.5H, m), 1.26 (3H,
t, J=7Hz).
Example 16
Ethyl (2i?) -8- [N- (2-chloro-4-f luorophenyl) sulfamoyl] -2-
hydroxymethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-378)

(16a) Ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3,3-
dimethoxy-1-cyclohexene-1-carboxylate

6.1 g (16.2 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate
obtained in Example 7 was dissolved in 12 0 ml of methanol and
4.1 g (16.2 mmol) of pyridinium p-toluenesulfonate and 8.86 ml
(81.0 mmol) of trimethoxymethane were sequentially added thereto
with stirring under ice-cooling, followed by stirring overnight
at room temperature. Water was added to the reaction solution
and the mixture was extracted with ethyl acetate. The organic
layer was washed with water and dried over anhydrous magnesium
sulfate, followed by concentration under reduced pressure. The
residue was subjected to silica gel column chromatography
(solvent; hexane : ethyl acetate =2:1) to give 6.0 g of the
title compound as a white powder (yield: 88%).
Melting point: 97-98°C
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.07-6.97
(3H, m), 4.41 (1H, d, J=4Hz), 4.28-4.12 (2H, m), 3.29 (3H, s),
3.23 (3H, s), 2.47-2.38 (1H, m), 2.31-2.21 (1H, m), 2.18-2.06
(1H, m), 2.01-1.93 (1H, m), 1.28 (3H, t, J=7Hz).
(16b) Ethyl (2R)-8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-2-hydroxymethyl-l,4-dioxaspiro[4.5]dec-
6-ene-7-carboxylate
342 mg (0.81 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexen-1-carboxylate
obtained in (16a) and 206 mg (1.05 mmol) of (S)-2,3-
dihydroxypropyl benzoate were dissolved in 7 ml of
dichloromethane, and 0.56 ml (3.15 mmol) of
isopropoxytrimethylsilane and 7 µl (0.041 mmol) of
trimethylsilyl trifluoromethanesulfonate were added thereto
sequentially with stirring under ice-cooling, followed by
stirring for 1 hour at the same temperature. Water was added to
the reaction solution and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and dried over
anhydrous magnesium sulfate, followed by concentration under
reduced pressure. The residue was subjected to silica gel

column chromatography (solvent; hexane : ethyl acetate = 1:1),
to give 410 mg of ethyl (2S)-2-benzoyloxymethyl-8-[N- (2-chloro-
4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate as a colorless oil (yield: 91%).
Subsequently, 410 mg (0.74 mmol) of this compound was
dissolved in 10 ml of a mixture of methanol-tetrahydrofuran
(1:1) and 3 ml (3.0 mmol) of 1N aqueous sodium hydroxide was
added thereto, followed by stirring for 15 minutes at room
temperature. Water was added to the reaction solution and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous magnesium sulfate,
followed by concentration under reduced pressure. The residue
was subjected to silica gel column chromatography (solvent;
hexane : ethyl acetate = 1:1) to give 293 mg of the title
compound as an amorphous substance (yield: 88%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.64 (1H, dd, J=9Hz, 5Hz) , 7.14 (1H, dd, J=8Hz, 3Hz), 7.04-6.95
(2H, m), 6.89 (0.42H, s), 6.86 (0.02H, s), 6.80 (0.02H, s), 6.78
(0.42H, s), 4.43-4.31 (1.5H, m), 4.26-4.02 (2.5H, m), 3.96-3.89
(1H, m) , 3.83-3.77 (0.5H, m) , 3.75-3.69 (0.5H, m) , 3.68-3.59
(1H, m), 2.65-2.41 (2H, m), 2.25-2.10 (1H, m), 1.93-1.82 (1H,
m), 1.77-1.67 (0.5H, br. s), 1.58 (0.5H, br. s), 1.26 (3H, t,
J=7Hz).
Example 17
Ethyl {2R,2R) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-382)

Following the process described in Example (16b), 1,4-di-
O-benzoyl-D-threitol was used in place of (S)-2,3-

dihydroxypropyl benzoate to give the title compound as an
amorphous substance (yield: 44%).

(17a) Ethyl (2R,3R)-2,3-bis(benzoyloxymethyl)-8-[N- (2-
chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate
1.46 g (3.08 mmol) of 1,4-di-O-benzoyl-2,3-di-O-
trimethylsilyl-D-threitol obtained in Reference Example 18 was
suspended in 2 ml of acetonitrile, and 0.04 ml (0.24 mmol) of
trimethylsilyl trifluoromethanesulfonate and a solution of 1.00
g (2.37 mmol) of ethyl 6-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example
(16a) in 5 ml of acetonitrile were sequentially added thereto
with stirring under ice-cooling, followed by stirring for 1 hour
at the same temperature. The reaction solution was concentrated
under reduced pressure, and the residue was subjected to silica
gel column chromatography (solvent; hexane : ethyl acetate =
2:1) to give 1.50 g of the title compound as a pale yellow
powder (yield: 92%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
8.10-8.04 (4H, m), 7.68-7.57 (3H, m), 7.49-7.44 (4H, m), 7.16
(1H, dt, J=8.0Hz, 2.6Hz), 7.05-7.00 (2H, m), 6.87 (1H, d,
J=14.0Hz), 4.66-4.07 (9H, m), 2.63-2.44 (2H, m), 2.25-2.19 (1H,
m), 1.94 (1H, t, J=15.2Hz), 1.19 (3H, t, J=7.0Hz).
(17b) Ethyl {2R,3R)-8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate
1.50 g (2.18 mmol) of ethyl [2R,3R)-2,3-
bis(benzoyloxymethyl)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in (17a) was
dissolved in 10 ml of a mixture of methanol-tetrahydrofuran
(4:1), and 10 ml (10.0 mmol) of 1N aqueous sodium hydroxide was
added thereto with stirring under ice-cooling, followed by
stirring for 15 minutes at the same temperature. Water was
added to the reaction solution and the mixture was extracted
with ethyl acetate. The organic layer was washed with water and

dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate = 1:1) to give 900 mg of the title compound as a white
amorphous substance (yield: 86%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.69-7.64 (1H, m) , 7.16 (1H, dd, J=8Hz, 3Hz) , 7.05-6.99 (2H, m) ,
6.91-6.90 (0.5H, m), 6.85-6.84 (0.5H, m) , 4.43-4.41 (1H, m) ,
4.27-4.09 (3.5H, m), 4.05-4.01 (0.5H, m) , 3.93-3.81 (2H, m) ,
3.75-3.69 (2H, m), 2.59-2.45 (2H, m), 2.23-1.50 (4H, m), 1.29-
1.24 (3H, m).
Example 18
Ethyl (25,35)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-382)

Following the process described in Example (16b), 1,4-di-
O-benzoyl-1-threitol was used in place of (5)-2,3-
dihydroxypropyl benzoate to give the title compound as an
amorphous substance (34% yield).

Following the process described in Example 17
(alternative procedure), 1, 4-di-Obenzoyl-2, 3-di-O-
trimethylsilyl-1-threitol obtained in Reference Example 19 was
used in place of 1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-
threitol to give the title compound as an amorphous substance
(yield: 73%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.69-7.64 (1H, m) , 7.16 (1H, dd, J=8Hz, 3Hz) , 7.05-6.99 (2H, m) ,

6.91-6.90 (0.5H, m) , 6.85-6.84 (0.5H, m) , 4.43-4.41 (1H, m) ,
4.27-4.09 (3.5H, m) , 4.05-4.01 (0.5H, m) , 3.93-3.81 (2H, m) ,
3.75-3.69 (2H, m), 2.59-2.45 (2H, m), 2.23-1.50 (4H, m), 1.29-
1.24 (3H, m).
Example 19
Ethyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-meso-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-382)

200 mg (0.47 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-
carboxylate obtained in Example (16a) and 290 mg (0.61 mmol) of
1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol
obtained in Reference Example 1 were dissolved in 4 ml of
dichloromethane and 4 µl (0.024 mmol) of trimethylsilyl
trifluoromethanesulfonate was added thereto with stirring under
ice-cooling, followed by stirring for 1 hour at the same
temperature. Water was added to the reaction solution and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous magnesium sulfate,
followed by concentration under reduced pressure. The residue
was subjected to silica gel column chromatography (solvent;
hexane : ethyl acetate =2:1) to give 171 mg of ethyl meso-2,3-
bis[(benzoyloxy)methyl]-8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate as an amorphous substance (yield: 53%).
Subsequently, 170 mg (0.25 mmol) of this compound was
dissolved in 10 ml of a mixture of methanol-tetrahydrofuran
(1:1), and 3 ml (3.0 mmol) of 1N aqueous sodium hydroxide was
added thereto with stirring under ice-cooling, followed by

stirring for 15 minutes at the same temperature. Water was
added to the reaction solution and the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate = 1:3) to give 105 mg of the title compound as an
amorphous substance (yield: 8 9%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.64 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, dd, J=8Hz, 3Hz), 7.04-6.95
(2H, m), 6.93 (0.4H, s), 6.72 (0.6H, s), 4.49-4.33 (2.4H, m),
4.32-4.26 (0.6H, m), 4.25-4.07 (2H, m), 3.93-3.70 (4H, m), 2.69-
2.58 (0.4H, m) , 2.58-2.35 (3.6H, m) , 2.24-2.09 (1H, m) , 1.99-
1.91 (0.6H, m), 1.90-1.83 (0.4H, m), 1.27 (3H, t, J=7Hz).
Example 2 0
Ethyl (2R) -8- [N- (2-chloro-4-f luorophenyl) sulfamoyl] -2-
((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-3 90)

300 mg (0.71 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-
carboxylate obtained in Example (16a) and 43 6 mg (1.42 mmol) of
(4R,5R)-2,2-dimethyl-4,5-
bis[(trimethylsilyl)oxy]methyl[1.3]dioxolane were dissolved in
12 ml of dichloromethane and 26 µl (0.142 mmol) of
trimethylsilyl trifluoromethanesulfonate was added thereto with
stirring under ice-cooling, followed by stirring for 90 hours at
room temperature. Saturated aqueous sodium hydrogencarbonate

was added to the reaction solution and the mixture was extracted
with dichloromethane. The organic layer was washed with water
and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate = 4:1) to give 90 mg of ethyl (21?)-8-[N- (2-chloro-4-
fluorophenyl) sulfamoyl] -2- ( (4R) -2 , 2-dimethyl [1.3] dioxolan-4-yl) -
1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as an amorphous
substance (yield: 24%).
Subsequently, to 85 mg (0.163 mmol) of this compound was
added 4 ml of a mixture of acetic acid-water (1:1), followed by
stirring overnight at room temperature. The reaction solution
was neutralized with addition of saturated aqueous sodium
hydrogencarbonate, and the mixture was then extracted with ethyl
acetate. The organic layer was washed with water and dried over
anhydrous magnesium sulfate, followed by concentration under
reduced pressure. The residue was subjected to silica gel
column chromatography (solvent; ethyl acetate alone) to give 46
mg of the title compound as an amorphous substance (yield: 5 9%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.69-7.64 (1H, m), 7.19-7.15 (1H, m), 7.06-6.98 (2H, m), 6.89-
6.80 (1H, m), 4.43-4.41 (1H, m), 4.38-4.08 (4H, m), 4.03-3.95
(0.7H, m), 3.86 (0.3H, t, J=8Hz), 3.77-3.63 (3H, m), 2.67-2.37
(3H, m), 2.22-1.84 (3H, m), 1.30-1.25 (3H, m).
Example 21
Ethyl (21?) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2-
( (2R) -1,2, 3-trihydroxypropyl) -1, 4-dioxaspiro [4.5] dec-6-ene-7-
carboxylate (Exemplified compound No. 1-3 94)

547 mg (1.07 mmol) of 1,3,4,5,7-penta-O-trimethylsilyl-D-
arabitol obtained in Reference Example 2 was dissolved in 3 ml
of nitromethane, to the resulting solution was added 13 µl
(0.007 mmol) of trimethylsilyl trifluoromethanesulfonate and was
then added 300 mg (0.71 mmol) of ethyl 6- [N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-
carboxylate obtained in Example (16a) with stirring under ice-
cooling, followed by stirring for 1 hour at the same
temperature. A saturated aqueous sodium hydrogencarbonate was
added to the reaction solution and the mixture was extracted
with dichloromethane. The organic layer was washed with water
and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; ethyl acetate
alone) to give 151 mg of the title compound as an amorphous
substance (yield: 42%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9Hz, 5Hz) , 7.19-7.15 (1H, m) , 7.10-6.99 (2H, m) ,
6.86 (0.5H, s), 6.82-6.80 (0.5H, m), 4.42-4.39 (1H, m), 4.28-
3.65 (9H, m) , 3.20-1.40 (3H, br) , 2.57-2.43 (2H, m) , 2.23-2.09
(1H, m) , 1.92-1.82 (1H, m) , 1.29-1.25 (3H, m) .
Example 22
Ethyl (2R) -8- [N- (2-chloro-4-f luorophenyl) sulfamoyl] -2-
((1S,2R,3R)-1,2,3,4-tetrahydroxybutyl)-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate (Exemplified compound No. 1-398)

200 mg (0.47 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-
carboxylate obtained in Example (16a) and 434 mg (0.71 mmol) of
1, 2 , 3,4,5,6-hexa-O-trimethylsilyl-D-mannitol were dissolved in 4
ml of dichloromethane, to the resulting solution were added
sequentially 0.12 ml (0.47 mmol) of isopropoxytrimethylsilane
and 4 µl (0.024 mmol) of trimethylsilyl
trifluoromethanesulfonate with stirring under ice-cooling,
followed by stirring overnight at room temperature. Saturated
aqueous sodium hydrogencarbonate was added to the reaction
solution and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and dried over anhydrous
magnesium sulfate, followed by concentration under reduced
pressure. The residue was subjected to silica gel column
chromatography (solvent; dichloromethane : methanol = 10:1) to
give 13 0 mg of the title compound as an amorphous substance
(yield: 51%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.62 (1H, dd, J=9Hz, 5Hz) , 7.22-7.12 (2H, m) , 7.04-6.96 (1H, m) ,
6.88-6.84 (0.2H, m), 6.80-6.77 (0.4H, m), 6.76 (0.4H, s), 4.41-
4.31 (1H, m), 4.25-4.03 (4H, m), 3.98-3.63 (6H, m), 2.54-2.41
(2H, m), 2.22-2.08 (1H, m), 1.92-1.81 (1H, m), 1.26 (3H, t,
J=7Hz).
Example 23
Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2,3-bis((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-386)

Following the process described in Example 19, l,6-di-O-
benzoyl-2,3,4,5-tetra-O-trimethylsilyl-D-mannitol obtained in
Reference Example 3 was used in place of 1,4-di-O-benzoyl-2,3 -
di-O-trimethylsilyl-meso-erythritol to give the title compound
as a white powder (yield: 11%).
Melting point: 55-56°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz) , 7.20-7.13 (2H, m) , 7.06-7.00 (1H, m) ,
6.80 (0.5H, s), 6.78 (0.5H, s), 4.38 (1H, d, J=5Hz), 4.26-4.00
(5H, m), 3.98-3.88 (1.5H, m), 3.87-3.65 (5.5H, m), 2.78-2.56
(2H, m), 2.55-2.40 (2H, m), 2.23-2.09 (1H, m), 1.92-1.80 (1H,
m) , 1.26 (3H, t, J=7Hz) .
Example 24
Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3-hydroxy-
1,5-dioxaspiro [5 . 5] undec — 7-ene-8-carboxylate (exemplified
compound No. 1-418)

Following the process described in Example 19, 2-
trimethylsilyloxy-1-trimethylsilyloxymethylethyl adamantan-1-
carboxylate obtained in Reference Example 4 was used in place of
1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol to give
the title compound as an amorphous substance (yield: 17%).
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:

7.69-7.64 (1H, m), 7.52-7.51 (0.5H, m), 7.18-7.15 (1H, m), 7.08-
6.99 (2.5H, m), 4.45-4.42 (1H, m), 4.31-4.05 (4H, m), 3.88-3.74
(2H, m), 3.72-3.63 (1H, m), 2.78-2.52 (1H, br), 2.48-1.97 (4H,
m) , 1.31-1.26 (3H, m) .
Example 25
Ethyl 12-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2,4,8,5-
tetraoxadispiro[5.2.5.2]hexadec-10-ene-ll-carboxylate
(Exemplified compound No. 1-434)

100 mg (0.266 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate
obtained in Example 7 and 156 mg (0.53 2 mmol) of 5,5-
bis[(trimethylsilyl)oxy]methyl[1.3]dioxane were dissolved in 2
ml of dichloromethane and 10 µl (0.053 mmol) of trimethylsilyl
trifluoromethanesulfonate was added thereto at -78°C, followed
by stirring for 3 0 minutes at the same temperature and then for
2 hours at room temperature. Saturated aqueous sodium
hydrogencarbonate was added to the reaction solution and the
mixture was extracted with dichloromethane. The organic layer
was washed with water and dried over anhydrous magnesium
sulfate, followed by concentration under reduced pressure. The
residue was subjected to silica gel column chromatography
(solvent; hexane : ethyl acetate = 2:1) and the resulting solid
was further washed with isopropoyl ether to give 49 mg of the
title compound as a white powder (yield: 52%).
Melting point: 156-157°C
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.05-6.98
(2H, m), 4.83 (1H, d, J=6Hz), 4.78 (1H, d, J=6Hz), 4.44-4.42

(1H, m) , 4.29-4.14 (2H, m) , 3.87-3.70 (8H, m) , 2.44-2.38 (1H,
m), 2.32-2.24 (1H, m), 2.18-2.08 (2H, m), 1.28 (3H, t, J=7Hz).
Example 2 6
Ethyl 3-acetylamino-9-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,5-dioxaspiro[5.5]undec-7-ene-8-
carboxylate (Exemplified compound No. 1-422)

500 mg (1.19 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-
carboxylate obtained in Example (16a) and 205 mg (1.54 mmol) of
N-(2-hydroxy-1-hydroxymethylethyl)acetamide were dissolved in 20
ml of dichloromethane, and 0.84 ml (4.74 mmol) of
isopropoxytrimethylsilane and 43 µl (0.24 mmol) of
trimethylsilyl trifluoromethanesulfonate were added sequentially
with stirring under ice-cooling, followed by stirring for 30
minutes at the same temperature, and further for 66 hours at
room temperature. Saturated aqueous sodium hydrogencarbonate
was added to the reaction solution and the mixture was extracted
with dichloromethane. The organic layer was washed with water
and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; ethyl acetate :
methanol = 39:1) to give 288 mg of the title compound as an
amorphous substance (yield: 50%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9Hz, 5Hz), 7.62-7.60 (0.5H, m), 7.17 (1H, dd,
J=8Hz, 3Hz), 7.05-6.99 (2H, m), 6.93-6.91 (0.5H, m), 6.35 (1H,
br.d, J=8Hz), 4.46-4.42 (1H, m), 4.35-4.11 (4H, m), 4.03-3.95
(1H, m) , 3.82-3.70 (2H, m) , 2.60-2.55 (0.5H, m) , 2.48-2.01 (3H,
m), 2.06 (3H, s), 1.95-1.90 (0.5H, m), 1.30 (3H, t, J=7Hz).

Example 2 7
Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-3,3-
bis(hydroxymethyl)-1,5-dioxaspiro[5.5]undec-7-ene-8-carboxylate
(Exemplified compound No. 1-430)

500 mg (1.19 mmol) of ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-
carboxylate obtained in Example (16a) and 1.0 g (2.38 mmol) of
1,3-bis[(trimethylsilyl)oxy]-2,2-
bis[(trimethylsilyl)oxy]methylpropane were dissolved in 10 ml
dichloromethane and 10 ul (0.06 mmol) of trimethylsilyl
trifluoromethanesulfonate was added thereto with stirring under
ice-cooling, followed by stirring for 2 hours at the same
temperature. Water was added to the reaction solution and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous magnesium sulfate,
followed by concentration under reduced pressure. The residue
was subjected to silica gel column chromatography (solvent;
ethyl acetate alone) to give 510 mg of the title compound as an
amorphous substance (yield: 87%).
^-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9Hz, 5Hz), 7.28 (1H, s), 7.17 (1H, dd, J=8Hz,
3Hz), 7.11 (1H, s), 7.07-6.98 (1H, m), 4.42 (1H, d, J=4Hz),
4.30-4.10 (2H, m), 3.92-3.68 (8H, m), 2.54-2.36 (3H, m), 2.34-
2.23 (1H, m), 2.21-2.07 (2H, m), 1.28 (3H, t, J=7Hz).
Example 28
Triethy1 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,5-
dioxaspiro[5.5]undec-7-ene-3,3,8-tricarboxylate (Exemplified

compound No. 1-438)

Following the process described in Example 27, diethyl
2,2-bis[(trimethylsilyl)oxyjmethylmalonate obtained in Reference
Example 5 was used in place of 1,3-bis[(trimethylsilyl)oxy]-2,2-
bis [ (trimethylsilyl) oxy]methylpropane to give the title compound
as an amorphous substance (yield: 42%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz), 7.23-7.21 (1H, m), 7.16 (1H, dd,
J=8Hz, 3Hz) , 7.04-6.99 (1H, m) , 6.97 (1H, s) , 4.43-4.36 (3H, m) ,
4.31-4.13 (8H, m), 2.44-2.37 (1H, m), 2.33-2.25 (1H, m), 2.19-
2.06 (2H, m), 1.283 (3H, t, J=7Hz), 1.280 (6H, t, J=7Hz).
Example 2 9
Ethyl 6- [N- (2-chloro-4-
fluorophenyl)sulfamoyl]spiro[2.5]oct-4-ene-5-carboxylate
(Exemplified compound No. 1-355)

(29a) Ethyl 3- [1- (2-
ethoxycarbonylethyl)cyclopropyl]propionate
24.5 ml (24.5 mmol) of 1.0 M diethyl zinc/hexane solution
was added to 3 0 ml of dichloromethane, and then a solution of
1.89 ml (24.5 mmol) of trifluoroacetic acid in 10 ml of
dichloromethane was added with stirring under ice-cooling. The
reaction solution was stirred for 20 minutes at the same
temperature, then a solution of 1.97 ml (24.5 mmol) of
diiodomethane in 10 ml of dichloromethane was added and stirred

for 20 minutes, and 1.40 g (6.13 mmol) of a solution of diethyl
4-methyleneheptanedicarboxylate (compound described in J.A.C.S.
107, 13, 3981-3997 (1985)) in 10 ml of dichloromethane was
further added. After the reaction solution was stirred for 6
hours at room temperature, ice water was added to the reaction
solution and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and dried over anhydrous
magnesium sulfate, followed by concentration under reduced
pressure. The residue was subjected to silica gel column
chromatography (solvent; hexane : ethyl acetate =5:1) to give
1.48 g of the title compound as a brown oil (yield: 99%).
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
4.10 (2H, q, J=7Hz), 3.37-2.31 (4H, m), 1.60-1.53 (4H, m), 1.25
(6H, t, J=7Hz), 0.31 (4H, s).
(29b) Ethyl 6-hydroxyspiro[2.5]oct-5-ene-5-carboxylate
1.46 g (6.03 mmol) of ethyl 3-[l-(2-
ethoxycarbonylethyl)cyclopropyl]propionate obtained in (29a) was
dissolved in 60 ml of tetrahydrofuran and 1.35 g (12.1 mmol) of
potassium t-butoxide was added thereto, followed by stirring for
1 hour at room temperature. The reaction solution was cooled
with ice and made acidic by addition of 1N hydrochloric acid,
and the mixture was extracted with ethyl acetate. The organic
layer was washed with water and dried over anhydrous magnesium
sulfate, followed by concentration under reduced pressure. The
residue was subjected to silica gel column chromatography
(solvent; ethyl acetate alone) to give 1.05 g of the title
compound as a yellow oil (yield: 89%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
12.23 (0.7H, s), 4.26-4.09 (2H, m), 3.50 (0.3H, dd, J=10Hz,
6Hz), 2.57-2.42 (0.7H, m), 2.36 (2H, t, J=6Hz), 2.03-1.94 (0.3H,
m) , 1.66-1.52 (1H, m) , 1.48 (2H, t, J=6Hz) , 1.28 (3H, J=7Hz) ,
0.60-0.30 (4H, m).
(29c) Ethyl 6-trifluoromethanesulfonyloxyspiro[2.5]oct-5-
ene-5-carboxylate
1.05 g (5.35 mmol) of ethyl ethyl 6-hydroxyspiro[2.5]oct-
5-ene-5-carboxylate obtained in (29b) was dissolved in 30 ml of

dichloromethane, and 0.99 ml (5.89 mmol) of
diisopropylethylamine and 1.40 ml (8.03 mmol) of
trifluoromethanesulfonic anhydride were added sequentially with
stirring at -78°C. After the reaction solution was stirred for 3
hours at the same temperature, it was warmed to room
temperature. The reaction solution was poured into saturated
aqueous sodium hydrogencarbonate and the mixure was extracted
with ethyl acetate. The organic layer was washed with water and
dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; ethyl acetate
alone) to give 1.56 g of the title compound as a brown oil
(yield: 89%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.26 (2H, q, J=7Hz), 2.57-2.46 (2H, m), 2.35-2.29 (2H, m), 1.60-
1.53 (2H, m) , 1.32 (3H, t, J=7Hz) , 0.49-0.40 (4H, m) .
(29d) Ethyl 6-mercaptospiro[2.5]oct-5-ene-5-carboxylate
Following the process described in Example (la), ethyl 6-
trifluoromethanesulfonyloxyspiro[2.5]oct-5-ene-5-carboxylate
obtained in (29c) was used in place of ethyl 8-
trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-
carboxylate to give ethyl 6-acetylsulfanylspiro[2.5]oct-5-ene-5-
carboxylate as a pale yellow oil (yield: 58%).
Subsequently, 700 mg (2.75 mmol) of this compound was
dissolved in 14 ml of ethanol, and 2.75 ml (11 mmol) of 4N
hydrogen chloride/dioxane solution was added thereto with
stirring under ice-cooling, followed by stirring for 4 hours at
room temperature. The reaction solution was concentrated under
reduced pressure, and the residue was subjected to silica gel
column chromatography (solvent; hexane : ethyl acetate = 10:1),
to give 3 00 mg of the title compound as a pale yellow oil
(yield: 51%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.19 (2H, q, J=7Hz), 4.12 (1H, s), 2.57 (2H, t, J=6Hz), 2.22-
2.18 (2H, m), 1.46 (2H, t, J=6Hz), 1.29 (3H, t, J=7Hz), 0.40-

0.33 (4H, m).
(29e) Ethyl 6-(chlorosulfonyl)spiro[2.5]oct-5-ene-5-
carboxylate
7 ml of acetic acid was added to 651 mg (4.23 mmol) of
sodium perborate tetrahydrate, the mixture was heated to 5 0°C,
and a solution of 3 00 mg (1.41 mmol) of ethyl 6-
mercaptospiro[2.5]oct-5-ene-5-carboxylate obtained in (29d) in 3
ml of acetic acid was added thereto, followed by stirring for 2
hours at the same temperature and further for 3 hours at 8 0°C.
The reaction solution was cooled to room temperature and
concentrated under reduced pressure. 5 ml of thionyl chloride
was added to the residue, and the mixture was heated under
reflux for 2 hours. The reaction solution was cooled to room
temperature again and concentrated under reduced pressure. Ice
water was added to the residue and the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate = 5:1 to give 195 mg of the title compound as a
colorless oil (yield: 50%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.28 (2H, q, J=7Hz), 2.77-2.69 (2H, m), 2.43-2.38 (2H, m), 1.62
(2H, t, J=6Hz) , 1.33 (3H, t, J=7Hz) , 0.52-0.46 (4H, m) .
(29f) Ethyl 6-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]spiro[2.5]oct-4-ene-5-carboxylate
Following the process described in Example (1d), ethyl 6-
(chlorosulfonyl)spiro[2.5]oct-5-ene-5-carboxylate obtained in
(29e) was used in place of ethyl 8-chlorosulfonyl-l,4-
dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title
compound as a white powder (yield: 17%).
Melting point: 125-126°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.69 (1H, dd, J=9Hz, 5Hz), 7.13 (1H, dd, J=8Hz, 3Hz), 7.03-6.96
(2H, m) , 6.58 (1H, s) , 4.53 (1H, d, J=5Hz) , 4.20-4.04 (2H, m) ,

2.62-2.50 (2H, m), 1.98-1.85 (1H, m), 1.23 (3H, t, J=7Hz), 1.22-
1.13 (1H, m) , 1.09-0.99 (2H, m) , 0.93-0.80 (2H, m) .
Example 3 0
Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1-
oxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity
diastereomer), (high polarity diastereomer) (Exemplified
compound No. 1-3 62)

(3 0a) 7-(1,3-Dioxan-2-yl)-5-[2-(1,3-dioxan-2-
yl)ethyl]heptane-1,5-diol
43 0 mg (5 mmol) of ^-butyrolactone was dissolved in 10 ml
of tetrahydrofuran, and 22 ml (11 mmol) of 0.5 M (1,3-dioxan-2-
ylethyl)magnesium bromide/tetrahydrofuran solution was added
thereto with stirring under ice-cooling, followed by stirring
for 3 hours at 50°C. After the reaction solution was cooled with
ice, saturated aqueous ammonium chloride was added and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous magnesium sulfate,
followed by concentration under reduced pressure. The residue
was subjected to silica gel column chromatography (solvent;
ethyl acetate : ethanol = 10:1) to give 880 mg of the title
compound as a colorless oil (yield: 55%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
4.51 (2H, t, J=5Hz), 4.08 (4H, dd, J=10Hz, 4Hz), 3.79-3.70 (4H,
m), 3.61 (2H, t, J=6Hz), 2.13-2.00 (2H, m), 1.68-1.56 (12H, m),
1.55-1.49 (2H, m) , 1.37-1.29 (2H, m) .
(30b) 2-(2-{2-[2-(1,3-dioxan-2-yl)ethyl]tetrahydrofuran-
2-yl}ethyl)-1,3-dioxane
2.60 g (8.17 mmol) of 7-(1,3-dioxan-2-yl)-5-[2-(1,3-
dioxan-2-yl)ethyl]heptane-1,5-diol obtained in (30a) was

dissolved in 45 ml of pyridine, and a solution of 1.64 g (8.58
mmol) of p-toluenesulfonyl chloride in 15 ml of pyridine was
added thereto with stirring under ice-cooling, followed by
stirring for 1 hour at the same temperature and further for 3
hours at room temperature. Water was added to the reaction
solution and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and dried over anhydrous
magnesium sulfate, followed by concentration under reduced
pressure. The residue was subjected to silica gel column
chromatography (solvent; hexane : ethyl acetate =1:1) to give
1.31 g of the title compound as a colorless oil (yield: 53 %).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.50 (2H, t, J=5Hz), 4.09 (2H, dd, J=llHz, 5Hz), 3.83-3.68 (6H,
m), 2.15-1.99 (2H, m), 1.92-1.82 (2H, m), 1.73-1.48 (12H, m),
1.38-1.29 (2H, m).
(30c) Ethyl 3-[2-(2-ethoxycarbonylethyl)tetrahydrofuran-
2-yl]propionate
1.31 g (43.6 mmol) of 2-(2-{2-[2-(1,3-dioxan-2-
yl)ethyl]tetrahydrofuran-2-yl}ethyl)-1,3-dioxane obtained in
(3 0b) was dissolved in 15 ml of acetone, and 16.3 ml (43.6 mmol)
of Jones reagent was added thereto with stirring under ice-
cooling, followed by stirring for 3 hours at room temperature.
The reaction solution was cooled with ice, and then the reaction
was terminated by addition of isopropyl alcohol. Water was
added to the reaction solution and the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was dissolved
in 15 ml of ethanol, and 0.76 ml (10.5 mmol) of thionyl chloride
was added, followed by stirring overnight at room temperature.
The reaction solution was concentrated under reduced pressure,
and the residue was subjected to silica gel column
chromatography (solvent; hexane : ethyl acetate =1:1) to give
610 mg of the title compound as a yellow oil (yield: 51%).
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
4.13 (4H, q, J=7Hz), 3.78 (2H, t, J=7Hz), 2.37-2.31 (4H, m),

1.95-1.87 (2H, m), 1.86-1.79 (4H, m), 1.71 (2H, t, J=7Hz), 1.26
(6H, t, J=7Hz).
(30d) Ethyl 8-oxo-1-oxaspiro[4.5]decane-7-carboxylate
610 mg (2.24 mmol) of ethyl 3-[2-(2-
ethoxycarbonylethyl)tetrahydrofuran-2-yl]propionate obtained in
(30c) was dissolved in 18 ml of tetrahydrofuran, and 503 mg
(4.48 mmol) of potassium t-butoxide was added thereto, followed
by heating under reflux for 1 hour. After the reaction solution
was cooled with ice, the reaction solution was made acidic by
addition of 1N hydrochloric acid, and the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate =2:1) to give 340 mg of the title compound as a
colorless oil (yield: 67%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
12.24 (1H, s) , 4.26-4.12 (2H, m) , 3.96-3.79 (2H, m) , 2.63-2.47
(1H, m), 2.43-2.12 (3H, m), 2.05-1.86 (2H, m), 1.86-1.60 (4H,
m), 1.30 (3H, t, J=7Hz).
(30e) Ethyl 8-trifluoromethanesulfonyloxy-1-
oxaspiro [4.5]dec-7-ene-7-carboxylate
To a suspension of 72 mg of 55% sodium hydride (1.65
mmol)/3 ml of dichloromethane, was added a solution of 340 mg
(1.50 mmol) of ethyl 8-oxo-1-oxaspiro[4.5]decane-7-carboxylate
obtained in (2 9d) in 4 ml of dichloromethane with stirring under
ice-cooling, followed by stirring for 1 hour at the same
temperature. Subsequently, the reaction solution was cooled to
-78°C, and 0.28 ml (1.65 mmol) of trifluoromethanesulfonic
anhydride was added thereto. The mixture was stirred for 1 hour
at the same temperature, and then warmed to room temperature.
After ice water was added to the reaction solution to terminate
the reaction, the mixture was extracted with ethyl acetate. The
organic layer was washed with water and dried over anhydrous
magnesium sulfate, followed by concentration under reduced
pressure. The residue was subjected to silica gel column

chromatography (solvent; ethyl acetate alone) to give 480 mg of
the title compound as a pale yellow oil (yield: 89%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
4.26 (2H, q, J=7Hz), 3.92-3.81 (2H, m), 2.74-2.63 (1H, m), 2.62-
2.48 (2H, m), 2.45-2.34 (1H, m), 2.04-1.68 (6H, m), 1.32 (3H, t,
J=7Hz).
(30f) Ethyl 8-acetylthio-1-oxaspiro[4.5]dec-7-ene-7-
carboxylate
Following the process described in Example (la), ethyl 8-
trifluoromethanesulfonyloxy-1-oxaspiro[4.5]dec-7-ene-7-
carboxylate obtained in (3 0e) was used in place of ethyl 8-
trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-
carboxylate to give the title compound as a yellow oil (yield:
32%) .
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.18 (2H, q, J=7Hz), 3.91-3.83 (2H, m), 2.65-2.60 (1H, m), 2.60-
2.51 (2H, m), 2.40-2.35 (1H, m), 2.32 (2.6H, s), 2.29 (0.4H, s),
2.00-1.93 (2H, m), 1.87-1.67 (4H, m), 1.28 (3H, t, J= 7Hz).
(30g) Ethyl 8-mercapto-1-oxaspiro[4.5]dec-7-ene-7-
carboxylate
120 mg (0.42 mmol) of ethyl 8-acetylthio-1-
oxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (30f) was
dissolved in 3 ml of ethanol, and 1 ml (4 mmol) of 4N hydrogen
chloride/dioxane solution was added thereto, followed by
stirring for 4 hours at room temperature. The reaction solution
was concentrated under reduced pressure and the residue was
subjected to silica gel column chromatography (solvent; hexane :
ethyl acetate = 3:1) to give 100 mg of the title compound as a
pale yellow oil (98% yield).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.24-4.16 (2H, m) , 4.12 (1H, s), 3.91-3.80 (2H, m) , 2.84-2.71
(1H, m) , 2.52-2.34 (3H, m) , 2.01-1.90 (2H, m) , 1.82-1.58 (4H,
m), 1.23 (3H, t, J=7Hz).
(30h) Ethyl 8-chlorosulfonyl-1-oxaspiro[4.5]dec-7-ene-7-
carboxylate

100 mg (0.41 mmol) of ethyl 8-mercapto-1-
oxaspiro[4.5]dec-7-ene-7-carboxylate obtained in (30f) was
dissolved in 4 ml of solution mixture of acetic acid and water
(acetic acid : water = 1:1), and chlorine gas was blown into the
reaction solution with stirring under ice-cooling for 15
minutes. Ice water was added to the reaction solution and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous sodium sulfate,
followed by concentration under reduced pressure. The residue
was subjected to silica gel column chromatography (solvent;
hexane : ethyl acetate = 3:1) to give 108 mg of the title
compound as a colorless oil (yield: 85%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.28 (2H, q, J=7Hz), 3.88 (2H, t, J=7Hz) , 2.92-2.81 (1H, m) ,
2.77-2.66 (1H, m), 1.58 (2H, m), 2.06-1.89 (3H, m), 1.80 (2H, t,
7Hz), 1.77-1.67 (1H, m) , 1.34 (3H, t, J=7Hz).
(30i) Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1-
oxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity
diastereomer), (high polarity diastereomer)
To a solution of 57 mg. (0.39 mmol) of 2-chloro-4-
fluoroaniline and 0.05 ml (0.39 mmol) of triethylamine in 1 ml
of ethyl acetate, was added dropwise a solution of 108 mg (0.35
mmol) of ethyl 8-chlorosulfonyl-1-oxaspiro[4.5]dec-7-ene-7-
carboxylate obtained in (2 9h) in 2 ml of ethyl acetate with
stirring under ice-cooling, followed by stirring overnight at
room temperature. Water was added to the reaction solution and
the mixture was extracted with ethyl acetate. The organic layer
was washed with water and dried over anhydrous magnesium
sulfate, followed by concentration under reduced pressure. The
residue was subjected to silica gel thin layer chromatography
(solvent; hexane : ethyl acetate = 3:1) to give 12 mg of low
polarity diastereomer of the title compound as a white powder
and 20 mg of high polarity diastereomer of the title compound as
an amorphous substance (yield: 8%, 14%).
(Low polarity diastereomer)
Melting point: 112-114°C

1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz), 7.14 (1H, dd, J=8Hz, 3Hz), 7.04-6.97
(1H, m), 6.95 (1H, s), 6.90 (1H, s), 4.45 (1H, dd, J=6Hz, 2Hz),
4.22-4.10 (2H, m), 3.96-3.88 (1H, m), 3.86-3.79 (1H, m), 2.41-
2.33 (1H, m), 2.29-2.18 (1H, m), 2.13-2.01 (4H, m), 1.94-1.79
(2H, m), 1.25 (3H, t, J=7Hz).
(High polarity diastereomer)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9Hz, 5Hz), 7.13 (1H, dd, J=8Hz, 3Hz), 7.04-6.96
(2H, m) , 6.95 (1H, s) , 4.36 (1H, d, J=5Hz) , 4.22-4.10 (2H, m) ,
4.03-3.96 (1H, m), 3.93-3.85 (1H, m), 2.56-2.48 (1H, m), 2.40-
2.29 (1H, m), 2.06-1.63 (6H, m), 1.26 (3H, t, J=7Hz).
Example 31
Ethyl 6-[N- (1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-
carboxylate (Exemplified compound No. 1-1057)

To a solution of 1.0 g (12.18 mmol) of lH-pyrrol-1-
ylamine and 1.8 ml (13.40 mmol) of triethylamine in 60 ml of
ethyl acetate was added dropwise a solution of 3.6 g (12.18
mmol) of ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate
(compound disclosed in the specification of Japanese Patent
Application (Kokai) No. 2000-178246) in 12 ml of ethyl acetate
with stirring under ice-cooling, followed by stirring overnight
at room temperature. Water was added to the reaction solution
and the mixture was extracted with ethyl acetate. The organic
layer was washed with water and dried over anhydrous magnesium
sulfate, followed by concentration under reduced pressure. The
residue was subjected to silica gel column chromatography
(solvent; hexane : ethyl acetate = 3:1)and the resulting solid
was further washed with isopropyl ether to give 1.9 g of the
title compound as a white powder (yield: 52%).

Melting point: 85-86°C
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
8.15 (1H, s), 7.44-7.42 (1H, m), 7.02 (2H, t, J=2Hz), 6.17 (2H,
t, J=2Hz), 4.57-4.56 (1H, m), 4.29 (2H, q, J=7Hz), 2.52-2.46
(2H, m), 2.32-2.23 (1H, m), 1.93-1.66 (3H, m), 1.34 (3H, t,
J=7Hz).
Example 3 2
Ethyl 6-[N-(2-methyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1176)

Following the process described in Example 31, 2-methyl-
1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to
give the title compound as a white powder (yield: 32%).
Melting point: 100-101°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.95 (1H, s), 7.43-7.39 (1H, m), 7.03-6.99 (1H, m), 6.07 (1H, t,
J=4Hz), 5.88-5.84 (1H, m), 4.60-4.55 (1H, m), 4.26 (2H, q,
J=7Hz), 2.56-2.43 (2H, m), 2.34-2.20 (1H, m), 2.29 (3H, s),
1.95-1.66 (3H, m), 1.33 (3H, t, J=7Hz).
(Example 33)
Ethyl 6-[N- (2-ethyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1193)

Following the process described in Example 31, 2-ethyl-
1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to
give the title compound as a white powder (yield: 51%).
Melting point: 77-73°C

1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.13 (1H, t,
J=4Hz), 5.92-5.87 (1H, m), 4.62-4.57 (1H, m), 4.28 (2H, q,
J=7Hz) , 2.79-2.64 (2H, m) , 2.58-2.42 (2H, m) , 2.35-2.21 (1H, m) ,
1.95-1.65 (3H, m), 1.33 (3H, t, J=7Hz), 1.24 (3H, t, J=8Hz).
Examp1e 34
Ethyl 6- [N- (2-propyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1210)

Following the process described in Example 31, 2-propyl-
1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to
give the title compound as a white powder (yield: 31%).
Melting point: 66-6B°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.12 (1H, t,
J=3Hz), 5.92-5.87 (1H, m), 4.62-4.57 (1H, m), 4.27 (2H, q,
J=7Hz), 2.73-2.62 (2H, m) , 2.57-2.43 (2H, m) , 2.34-2.21 (1H, m) ,
1.95-1.63 (5H, m), 1.33 (3H, t, J=7Hz), 0.99 (3H, t, J=7Hz).
Example 3 5
Ethyl 6-[N- (2-butyl-1H-pyrrol-1-yl)sulfamoyl] -1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1227)

Following the process described in Example 31, 2-butyl-
IH-pyrrol-1-ylamine was used in place of IH-pyrrol-1-ylamine to
give the title compound as a white powder (yield: 26%).
Melting point: 49-50°C
1H-NMR spectrum (40CMHz, CDCl3) δ ppm:

7.94 (1H, s) , 7.43-7.39 (1H, m) , 7.01-6.98 (1H, m) , 6.11-6.08
(1H, m), 5.89-5.85 (IK, m), 4.60-4.55 (1H, m), 4.26 (2H, q,
J=7Hz) , 2.71-2.65 (2H, m) , 2.56-2.43 (2H, m) , 2.33-2.20 (1H, m) ,
1.94-1.57 (5H, m), 1.45-1.35 (2H, m), 1.32 (3K, t, J=7Hz), 0.93
(3H, t, J=7Hz) .
Example 36
Ethyl 6-[N- (2-pentyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1244)

Following the process described in Example 31, 2-pentyl-
1H-pyrrol-1-ylamine obtained in Reference Example 6 was used in
place of 1H-pyrrol-1-ylamine to give the title compound as a
white powder (yield: 33%) .
Melting point: 60-61°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.9 6 (1H, s), 7.46-7.41 (1H, m), 7.04-7.00 (1H, m), 6.12 (1H, t,
J=3Hz), 5.92-5.86 (1H, m) , 4.62-4.56 (1H, m) , 4.28 (2H, q,
J=7Hz) , 2.72-2.65 (2H, m) , 2.57-2.44 (2H, m) , 2.34-2.21 (1H, m) ,
1.95-1.59 (5H, m), 1.42-1.29 (4H,m), 1.34 (3H, t, J=7Hz), 0.89
(3H, t, J=7Hz).
Example 3 7
Ethyl 6-[N- (2-hexyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1261)

Following the process described in Example 31, 2-hexyl-
1H-pyrrol-1-ylamine obtained in Reference Example 7 was used in
place of 1H-pyrrol-1-ylamine to give the title compound as a

yellow oil (yield: 46%) .
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.93 (1H, s), 7.43-7.39 (1H, m), 7.01-6.98 (1H, m), 6.12-6.08
(1H, m), 5.89-5.85 (1H, m), 4.60-4.55 (1H, m), 4.27 (2H, q,
J='Hz), 2.71-2.64 (2H, m), 2.56-2.43 (2H, m), 2.33-2.21 (1H, m),
1.91-1.58 (5H,m), 1.42-1.27 (6H, m), 1.33 (3H, t, J=7Hz), 0.88
(3H, t, J=7Hz).
Example 38
Ethyl 6- [N- (2-heptyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1278)

Following the process described in Example 31, 2-heptyl-
1H-pyrrol-1-ylamine obtained in Reference Example 8 was used in
place of 1H-pyrrol-1-ylamine to give the title compound as a
colorless oil (yield: 13%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.97 (1H, s), 7.46-7.41 (1H, m), 7.04-7.01 (1H, m), 6.11 (1H, t,
J=3Hz), 5.96-5.86 (1H, m), 4.62-4.56 (1H, m), 4.28 (2H, q,
J=7Hz) , 2.72-2.62 (2H, m) , 2.58-2.43 (2H, m) , 2.35-2.21 (1H, m) ,
1.94-1.59 (5H, m), 1.41-1.22 (8H, m), 1.33 (3H, t, J=7Hz), 0.88
(3H, t, J=7Hz).
Example 3 9
Ethyl 6-[N- (2-octyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1295)

Following the process described in Example 31, 2-octyl-
1H-pyrrol-1-ylamine obtained in Reference Example 8 was used in

place of 1H-pyrrol-1-ylamine to give the title compound as a
pale yellow oil (yield: 18%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.96 (1H, s), 7.46-7.41 (1H, m), 7.04-7.00 (1H, m), 6.11 (1H, t,
J=4Hz) , 5.91-5.86 (1H, m) , 4.61-4.57 (1H, m) , 4.28 (2H, q,
J=7Hz) , 2.71-2.64 (2H, m) , 2.57-2.44 (2H, m) , 2.34-2.20 (1H, m) ,
1.95-1.58 (5H, m), 1.42-1.19 (10H, m), 1.33 (3H, t, J=7Hz), 0.88
(3H, t, J=7Hz).
Example 40
Ethyl 6-[N- (2-cyclopropyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1312)

Following the process described in Example 31, 2-
cyclopropyl-1H-pyrrol-1-ylamine obtained in Reference Example 10
was used in place of 1H-pyrrol-1-ylamine to give the title
compound as a pale pink powder (yield: 42%).
Melting point: 95-96°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:.
7.87 (1H, s), 7.41-7.37 (1H, m), 6.98-6.95 (1H, m), 6.05-6.02
(1H, m), 5.69-5.66 (1H, m), 4.66-4.61 (1H, m), 4.25 (2H, q,
J=7Hz) , 2.60-2.43 (2H, m) , 2.34-2.20 (1H, m) , 2.05-1.87 (2H, m) ,
1.82-1.68 (2H, m), 1.31 (3H, t, J=7Hz), 0.94-0.82 (2H, m), 0.73-
0.65 (1H, m) , 0.59-0.51 (1H, m) .
Example 41
Ethyl 6-[N- (2-phenyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1329)

Following the process described in Example 31, 2-phenyl-
1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-ylamine to
give the title compound as a pale yellow powder (yield: 21%).
Melting point: 160-I61°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.99 (1H, s), 7.57 (2H, d, J=8Hz), 7.39 (2H, t, J=8Hz), 7.33-
7.2 7 (2H, m), 7.14-7.11 (1H, m), 6.32-6.28 (1H, m), 6.25 (1H, t,
J=4Hz), 4.22 (2H, q, J=7Hz), 4.18-4.14 (1H, m), 2.44-2.32 (1H,
m) , 2.24-2.07 (2H, m) , 1.91-1.75 (1H, m) , 1.67-1.51 (1H, m) ,
1.40-1.29 (1H, m), 1.28 (3H, t, J=7Hz).
Example 42
Ethyl 6-[N- (2,5-dimethyl-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxyiate (Exemplified compound No. 1-1346)

Following the process described in Example 31, 2,5-
dimethyl-1H-pyrrol-1-ylamine was used in place of 1H-pyrrol-1-
ylamine to give the title compound as a white powder (yield:
29%) .
Melting point: 96-97°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.88 (1H, s) , 7.40-7.35 (1H, m) , 5.75 (2H, s), 4.58-4.52 (1H,
m) , 4.24 (2H, q, 7Hz), 2.69-2.61 (1H, m) , 2.53-2.42 (1H, m) ,
2.33-2.19 (1H, m), 2.26 (6H, s), 2.02-1.91 ilH, m), 1.86-1.73
(2H, m), 1.30 (3H, t, J=7Hz).
Example 43
Ethyl 6-[N- (2-chloro-1H-pyrrol-1-yl)sulfamoyl]-1-

cyclohexene-1-carboxylate (Exemplified compound No. 1-1091)

150 mg (0.503 mmol) of ethyl 6-[N- (1H-pyrrol-1-
yl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 31
was dissolved in 3 ml of tetrahydrofuran, and 70 mg (0.528 mmol)
of iV-chlorosuccinimide was added thereto with stirring under
ice-cooling, followed by stirring overnight at room temperature.
Water was added to the reaction solution and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel thin layer chromatography (solvent; hexane : ethyl
acetate = 2:1) and the resulting solid was further washed with
isopropyl ether to give 50 mg of the title compound as a white
powder (yield: 3 0%).
Melting point: 60-61°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.91 (1H, s), 7.43-7.37 (1H, m), 7.04 (1H, dd, J=4Hz, 2Hz), 6.14
(1H, t, J=4Hz) , 6.10 (1H, dd, J=4Hz, 2Hz) , 4.65-4.61 (1H, m) ,
4.26 (2H, q, J=7Hz), 2.61-2.44 (2H, m), 2.33-2.21 (1H, m), 2.05-
1.90 (1H, m), 1.83-1.71 (2H, m), 1.30 (3H, t, J=7Hz).
Example 44
Ethyl 6-[N- (2-bromo-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (exemplified compound No. 1-1108)

Following the process described in Example 43, N-
bromosuccinimide was used in place of N-chlorosuccinimide to
give the title compound as a white powder (yield: 50%).

1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.85 (1H, s), 7.42-7.38 (1H, m), 7.15 (1H, dd, J=4Hz, 2Hz),
6.22-6.17 (2H, m), 4.67-4.62 (1H, m), 4.25 (2H, q, J=7Hz), 2.60-
2.44 (2H, m), 2.33-2.20 (1H, m), 2.05-1.92 (1H, m), 1.83-1.70
(2H, m), 1.30 (3H, t, J=7Hz).
Example 45
Ethyl 6-[N- (2,5-dichloro-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1142)

Following the process described in Example 42, 2.1
equivalent of N-chlorosuccinimide was used relative to ethyl 6-
[N-(1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate
obtained in Example 31 to give the title compound as a pale
yellow oil (yield: 25%).
Melting point: 144-145°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
8.08 (1H,3), 7.39-7.33 (1H, m) , 6.07 (2H, s) , 4.89-4.83 (1H, m) ,
4.24 (2H, q, J=7Hz), 2.67-2.58 (1H, m), 2.52-2.42 (1H, m), 2.31-
2.19 (1H, m), 2.03-1.88 (1H, m), 1.87-1.72 (2H, m), 1.29 (3H, t,
J=7Hz).
Example 46
Ethyl 6-[N- (2,5-dibromo-1H-pyrrol-1-yl)sulfamoyl]-1-
cyclohexene-1-carboxylate (Exemplified compound No. 1-1159)

Following the process described in Example 44, 2.1
equivalent of N-bromosuccinimide was used relative to ethyl 6-

[N- (1H-pyrrol-1-yl)sulfamoyl]-1-cyclohexene-1-carboxylate
obtained in Example 31 to give the title compound as a white
powder (yield: 3%).
Melting point: 123-124°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
8.05 (1H, s), 7.40-7.35 (1H, m), 6.24 (2H, s), 5.02-4.95 (1H,
m), 4.25 (2H, q, J=7Hz), 2.69-2.60 (1H, m), 2.53-2.42 (1H, m),
2.33-2.19 (1H, m), 2.02-1.90 (1H, m), 1.87-1.72 (2H, m), 1.29
(3H, t, J=7Hz).
Example 47
t-Butyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
3-89)

(47a) 8-[N- (2-Chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylic acid
1.8 g (4.29 mmol) of ethyl 8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 1 was dissolved in 60 ml of a
water-tetrahydrofuran (1:1) solution, . and 900 mg (21.45 mmol) of
lithium hydroxide was added thereto, followed by stirring for 7
hours at 50°C. The reaction solution was cooled with ice, it was
then made acidic by addition of 1N hydrochloric acid, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous magnesium sulfate,
followed by concentration under reduced pressure. The residue
was washed with hexane to give 1.43 g of the title compound as a
pale brown powder (yield: 85%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.68 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.04-6.93

(3H, m), 4.36 (1H, d, J=5Hz), 4.16-4.02 (3H, m), 3.97-3.88 (1H,
m) , 2.57-2.45 (3H, m) , 2.25-2.13 (1H, m) , 1.90-1.82 (1H, m) .
(47b) t-Butyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
100 mg (0.26 mmol) of 8- [N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylic acid obtained in (47a) was dissolved in 2 ml of
toluene, and 1 ml of N,N-dimethylformamide di-t-butyl acetal was
added thereto, followed by stirring for 3 hours at 100°C. After
the reaction solution was cooled to room temperature, water was
added and the mixture was extracted with ethyl acetate. The
organic layer was washed with water and dried over anhydrous
magnesium sulfate, followed by concentration under reduced
pressure. The residue was subjected to silica gel thin layer
chromatography (solvent; dichloromethane : methanol = 1:50) to
give 52 mg of the title compound as a white amorphous substance
(yield: 45%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.64 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, dd, J=8Hz, 3Hz), 7.05-6.98
(2H, m) , 6.71 (1H, s) , 4.42-4.38 (1H, m) , 4.13-4.01 (3H, m) ,
3.95-3.88 (1H, m), 2.51-2.40 (2H, m), 2.21-2.10 (1H, m), 1.86-
1.79 (1H, m), 1.46 (9H, s).
Following the process described in Example (47b), various
corresponding acetals were used in place of N, N-
dimethylformamide di-t-butyl acetal to synthesize the compounds
of Examples 48 to 51.
Example 4 8
Methyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
3-73)

White powder (yield: 50%)
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.06-6.99
(1H, m) , 6.98 (1H, s) , 6.84 (1H, s) , 4.43-4.38 (1H, m) , 4.15-
3.99 (3H, m), 3.95-3.88 (1H, m), 3.73 (3H, s), 2.56-2.43 (2H,
m) , 2.24-2.12 (1H, m) , 1.88-1.79 (1H, m) .
Example 49
Propyl 8- [N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
3-77)

White amorphous substance (yield: 18%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.05-6.97
(2H, m) , 6.81 (1H, s) , 4.42 (1H, d, J=5Hz) , 4.16-3.99 (5H, m) ,
3.95-3.88 (1H, m), 2.55-2.44 (2H, m), 2.24-2.11 (1H, m), 1.88-
1.81 (1H, m), 1.71-1.60 (2H, m), 0.94 (3H, t, J=7Hz).
Example 50
Butyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
3-81)

White powder (yield: 26%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.05-6.96
(2H, m) , 6.80 (1H, s) , 4.42 (1H, d, J=5Hz) , 4.20-4.00 (5H, m) ,
3.95-3.87 (1H, m), 2.55-2.44 (2H, m), 2.24-2.11 (1H, m), 1.88-
1.80 (1H, m), 1.66-1.57 (2H, m), 1.43-1.32 (2H, m), 0.93 (3H, t,
J=7Hz).
Example 51
Isopropyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
3-85)

White powder (yield: 21%)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.06-6.98
(2H, m) , 6.78 (1H, s) , 5.11-4.99 (1H, m) , 4.42 (1H,, d, J=5Hz) ,
4.15-3.99 (3H, m) , 3.95-3.88 (1H, m) , 2.55-2.43 (2H, m) , 2.24-
2.11 (1H, m), 1.99-1.79 (1H, m), 1.26 (3H, d, J=2Hz), 1.24 (3H,
d, J=2Hz).
(Example 52)
Acetoxymethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-
1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound
No. 3-93)

1 g (2.55 mmol) of 8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylic acid obtained in Example 47a was dissolved in 2 0 ml
of acetonitrile, and 0.50 ml (5.10 mmol) of bromomethyl acetate,
499 mg (1.53 mmol) of cesium carbonate and 471 mg (1.28 mmol) of
tetrabutylammonium iodide were added thereto, followed by
stirring for 1 hour at room temperature. 0.1 N hydrochloric
acid was added to the reaction solution and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; dichloromethane :
methanol = 49:1) to give 833 mg of the title compound as an
amorphous substance (yield: 70%) .
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9Hz, 5Hz), 7.18 (1H, dd, J=8Hz, 3Hz), 7.08-7.02
(1H, m) , 7.01 (1H, s) , 6.92 (1H, s) , 5.80 (2H, s) , 4.41 (1H, dd,
J=6Hz, 2Hz), 4.15-4.01 (3H, m), 3.94-3.88 (1H, m), 2.48 (1H, td,
J=14Hz, 4Hz), 2.44-2.37 (1H, m), 2.22-2.14 (1H, m), 2.12 (3H,
s) , 1.85-1.79 (1H, m) .
Following the process described in Example (1d), various
corresponding anilines were used in place of 2-chloro-4-
fluoroaniline to synthesize the compounds of Examples 53 to 121.
Example 53
Ethyl 8-[N- (2-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2217)

Oil (yield: 61%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.67-7.62 (1H, m), 7.17-7.09 (3H, m), 6.96 (1H, d, J=3Hz), 6.83
(1H, t, J=lHz), 4.43-4.40 (1H, m), 4.24-4.01 (5H, m), 3.95-3.89
(1H, m) , 2.55-2.41 (2H, m) , 2.21-2.10 (1H, m) , 1.89-1.81 (1H,
m), 1.27 (3H, t, J=7Hz).
Example 54
Ethyl 8-[N- (2-chlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-188)

Pale brown powder (yield: 69%)
Melting point: 157-160°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.70 (1H, dd, J=8Hz, 1Hz), 7.39 (1H, dd, J=8Hz, 2Hz), 7.31-7.26
(1H, m), 7.10-7.05 (2H, m), 6.83 (1H, t, J=lHz), 4.49-4.46 (1H,
m) , 4.24-4.02 (5H, m) , 3.95-3.89 (1H, m) , 2.60-2.48 (2H, m) ,
2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.24 (3H, t, J=7Hz).
Example 55
Ethyl 8-[N- (2-bromophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-1374)

Oil (yield: 59%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.70 (1H, dd, J=8Hz, 1Hz), 7.55 (1H, dd, J=8Hz, 2Hz), 7.36-7.30
(1H, m), 7.04-6.98 (2H, m), 6.83 (1H, t, J=lHz), 4.50-4.47 (1H,
m) , 4.23-4.01 (5H, m) , 3.95-3.88 (1H, m) , 2.62-2.49 (2H, m) ,
2.24-2.13 (1H, m), 1.88-1.81 (1H, m), 1.24 (3H, t, J=7Hz).
Example 56
Ethyl 8-[N- (2-iodophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2224)

Amorphous substance (yield: 53%)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.79 (1H, dd, J=8Hz, 1Hz), 7.67 (1H, dd, J=8Hz, 1Hz), 7.38-7.33
(1H, m), 6.88-6.82 (3H, m) , 4.49 (1H, d, J=5Hz), 4.24-4.01 (5H,
m) , 3.95-3.88 (1H, m) , 2.63-2.49 (2H, m) , 2.24-2.13 (1H, m) ,
1.88-1.81 (1H, m), 1.24 (3H, t, J=7Hz).
Example 57
Ethyl 8-[N- (4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-100)

White powder (yield: 87%)
Melting point: 141-146°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.38-7.33 (2H, m), 7.07-7.01 (3H, m), 6.87 (1H, t, J=lHz), 4.30-
4.21 (3H, m), 4.14-4.01 (3H, m), 3.95-3.89 (1H, m), 2.45-2.38
(1H, m), 2.27 (1H, td, J=14Hz, 3Hz), 2.09-1.99 (1H, m), 1.87-
1.80 (1H, m), 1.33 (3H, t, J=7Hz).
Example 58
Ethyl 8-[N- (4-chlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2231)

White powder (yield: 81%)
Melting point: 153-156°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.31 (4H, s), 7.03 (1H, s), 6.87 (1H, t, J=lHz), 4.29-4.19 (3H,
m) , 4.14-4.02 (3H, m) , 3.95-3.89 (1H, m) , 2.47-2.40 (1H, m) ,
2.27 (1H, td, J=14Hz, 3Hz), 2.10-2.00 (1H, m), 1.88-1.81 (1H,
m) , 1.32 (3H, t, J=7Hz) .
Example 59
Ethyl 8-[N- (2-methylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Eexemplified compound
No. 1-2238)

White powder (yield: 75%)

Melting point: 101-104°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.56-7.53 (1H, m), 7.23-7.18 (2H, m), 7.11-7.06 (1H, m), 6.85
(1H, t, J=lHz), 6.62 (1H, s), 4.44 (1H, dd, J=6Hz, 2Hz), 4.25-
4.01 (5H, m) , 3.95-3.89 (1H, m) , 2.55-2.48 (1H, m) , 2.42 (1H,
td, J=14Hz, 4Hz), 2.34 (3H, s), 2.19-2.09 (1H, m), 1.88-1.81
(1H, m), 1.26 (3H, t, J=7Hz).
Example 6 0
Ethyl 8-[N- (2-ethylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2245)

White powder (yield: 66%)
Melting point: 83-87°C
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.54 (1H, dd, J=8Hz, 1Hz), 7.25-7.19 (2H, m), 7.14 (1H, td,
J=7Hz, 1Hz), 6.85 (1H, s), 6.63 (1H, s), 4.47 (1H, dd, J=6Hz,
2Hz) , 4.25-4.02 (5H, m) , 2.75-2.66 (2H, m) , 2.54-2.48 (1H, m) ,
2.43 (1H, td, J=14Hz, 4Hz), 2.19-2.11 (1H, m), 1.87-1.81 (1H,
m) , 1.28-1.23 (6H, m) .
Example 61
Ethyl 8-[N- (2-propylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-1989)

Oil (53% yield)

1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.55-7.52 (1H, m), 7.23-7.18 (2H, m), 7.14-7.09 (1H, m), 6.85
(1H, t, J=lHz), 6.64 (1H, s), 4.48-4.44 (1H, m), 4.24-4.02 (5H,
m) , 3.95-3.89 (1H, m) , 2.67-2.62 (2H, m) , 2.54-2.39 (2H, m) ,
2.20-2.10 (1H, m), 1.87-1.81 (1H, m), 1.69-1.58 (2H, m), 1.26
(3H, t, J=7Hz), 0.99 (3H, t, J=7Hz).
Example 62
Ethyl 8-[N- (2-ethynylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2252)

Oil (yield: 19%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=8Hz, 1Hz), 7.47 (1H, dd, J=8Hz, 2Hz), 7.37 (1H,
td, J=8Hz, 2Hz), 7.21 (1H, s), 7.07 (1H, td, J=8Hz, 1Hz), 6.82
(1H, t, J=lHz), 4.52-4.49 (1H, m), 4.22-4.01 (5H, m), 3.95-3.88
(1H, m) , 3.49 (1H, s) , 2.65-2.50 (2H, m) , 2.24-2.13 (1H, m) ,
1.88-1.81 (1H, m), 1.22 (3H, t, J=7Hz).
Example 63
Ethyl 8-[N- (2-isopropylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2259)

Pale brown powder (yield: 65%)
Melting point: 115-118°C
1H-NMR spectrum (500MHz, CDCl3) δ ppm:

7.53-7.49 (1H, m), 7.34-7.30 (1H, m), 7.23-7.17 (2H, m), 6.86
(1H, s), 6.69 (1H, s), 4.47 (1H, dd, J=6Hz, 2Hz), 4.27-4.02 (5H,
m) , 3.95-3.89 (1H, m) , 3.33-3.24 (1H, m) , 2.53-2.47 (1H, m) ,
2.42 (1H, td, J=14Hz, 3Hz), 2.18-2.10 (1H, m), 1.86-1.81 (1H,
m) , 1.29-1.21 (9H, m) .
Example 64
Ethyl 8-[N- (2-t-butylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2266)

White powder (yield: 53%)
Melting point: 117-120°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.45 (1H, dd, J=8Hz, 1Hz), 7.38 (1H, dd, J=8Hz, 2Hz), 7.23 (1H,
td, J=8Hz, 2Hz), 7.12-7.07 (1H, m), 6.86 (1H, t, J=lHz), 6.64
(1H, s), 4.64-4.61 (1H, m), 4.24-4.03 (5H, m), 3.97-3.90 (1H,
m), 2.65-2.53 (2H, m), 2.28-2.18 (1H, m), 1.90-1.83 (1H, m),
1.45 (9H, s), 1.23 (3H, t, J=7Hz).
Example 65
Ethyl 8-[N- (2-sec-butylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2273)

Oil (71% yield)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.54-7.49 (1H, m), 7.29-7.16 (3H, m), 6.86 (1H, dt, J=5Hz, 1Hz),

6.68 (1H, d, J=10Hz) , 4.47-4.44 (1H, m) , 4.27-4.02 (5H, m) ,
3.95-3.89 (1H, m), 3.12-2.95 (1H, m), 2.53-2.35 (2H, m), 2.19-
2.07 (1H, m) , 1.86-1.80 (1H, m) , 1.70-1.55 (2H, m) , 1.31-1.19
(6H, m) , 0 .91-0.80 (3H, m) .
Example 66
Ethyl 8-[N- (2-methoxyphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2280)

White powder (yield: 70%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.57 (1H, dd, J=8Hz, 2Hz), 7.11-7.05 (2H, m), 6.96 (1H, td,
J=8Hz, 1Hz), 6.89 (1H, dd, J=8Hz, 1Hz), 6.79 (1H, t, J=lHz),
4.44 (1H, d, J=4Hz), 4.21-4.00 (5H, m), 3.94-3.84 (4H, m), 2.58
(1H, td, J=14Hz, 4Hz) , 2.50-2.43 (1H, m) , 2.18-2.08 (1H, m) ,
1.84-1.77 (1H, m), 1.23 (3H, t, J=7Hz).
Example 67
Ethyl 8-[N- (2-ethoxyphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2287)

White powder (yield: 60%)
Melting point: 129-134°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.58 (1H, dd, J=8Hz, 2Hz), 7.12 (1H, s), 7.06 (1H, td, J=8Hz,
2Hz), 6.95 (1H, td, J=8Hz, 2Hz), 6.87 (1H, dd, J=8Hz, 1Hz), 6.79

(1H, t, J=lHz), 4.45-4.42 (1H, m), 4.20-4.00 (7H, m), 3.94-3.87
(1H, m) , 2.57 (1H, td, J=14Hz, 4Hz), 2.50-2.44 (1H, m), 2.18-
2.08 (1H, m), 1.85-1.78 (1H, m), 1.45 (3H, t, J=7Hz), 1.23 (3H,
t, J=7Hz).
Example 68
Ethyl 8-[N- (2-difluoromethoxyphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2294)

White powder (yield: 48%)
Melting point: 85-88°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.69 (1H, dd, J=8Hz, 2Hz), 7.25-7.08 (4H, m), 6.84 (1H, s), 6.57
(1H, dd, J=74Hz, 73Hz) , 4.44-4.41 (1H, m) , 4.21-4.02 (5H, m) ,
3.95-3.89 (1H, m), 2.57-2.44 (2H, m), 2.21-2.10 (1H, m), 1.90-
1.82 (1H, m), 1.26 (3H, t, J=7Hz).
Example 69
Ethyl 8-[N- (2-methylsulfanylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2301)

White powder (yield: 56%)
Melting point: 93-95°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.70 (1H, s), 7.63 (1H, dd, J=8Hz, 1Hz), 7.51 (1H, dd, J=8Hz,
2Hz), 7.33-7.28 (1H, m), 7.08 (1H, td, J=8Hz, 1Hz), 6.82 (1H, q,

J=lHz), 4.50 (1H, d, J=4Hz), 4.21-4.01 (5H, m), 3.95-3.88 (1H,
m), 2.65-2.50 (2H, m), 2.38 (3H, s), 2.23-2.12 (1H, m), 1.88-
1.81 (1H, m), 1.25-1.21 (3H, m).
Example 70
Ethyl 8-[N- (2-acetylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2308)

Oil (yield: 25%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
11.46 (1H, s), 7.91 (1H, dd, J=8Hz, 1Hz), 7.85 (1H, dd, J=8Hz,
1Hz), 7.59-7.54 (1H, m), 7.15-7.10 (1H, m), 6.80 (1H, t, J=lHz),
4.50-4.47 (1H, m), 4.16-4.00 (5H, m), 3.94-3.88 (1H, m), 2.68-
2.59 (4H, m), 2.56-2.49 (1H, m), 2.20-2.09 (1H, m), 1.87-1.80
(1H, m), 1.25 (3H, t, J=7Hz).
Example 71
Ethyl 8-[N- (2-benzylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2315)

White powder (yield: 73%)
Melting point: 127-129°C
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.58 (1H, dd, J=8Hz, 1Hz), 7.32-7.13 (8H, m), 6.80 (1H, s), 6.50
(1H, s), 4.36 (1H, dd, J=6Hz, 2Hz), 4.23-4.00 (7H, m), 3.93-3.87
(1H, m), 2.36 (1H, td, J=14Hz, 4Hz), 2.19-2.13 (1H, m), 2.03-

1.94 (1H, m), 1.76-1.70 (1H, m), 1.26 (3H, t, J=7Hz).
Example 72
Ethyl 8-{N- [2-(morpholin-4-yl)phenyl]sulfamoyl}-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2322)

White powder (yield: 71%)
Melting point: 118-121°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
8.10 (1H, s), 7.58 (1H, dd, J=8Hz, 2Hz), 7.23 (1H, dd, J=8Hz,
2Hz), 7.20-7.15 (1H, m), 7.07 (1H, td, J=8Hz, 2Hz), 6.82 (1H, t,
1Hz) , 4.47-4.44 (1H, m) , 4.15-4.00 (5H, m) , 3.95-3.85 (5H, m) ,
2.92-2.83 (4H, m), 2.59-2.50 (2H, m), 2.24-2.12 (1H, m) , 1.90-
1.82 (1H, m), 1.23 (3H, t, J=7Hz).
Example 73
Ethyl 8-[N- (9H-fluoren-1-yl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2329)

Pale brown powder (yield: 60%)
Melting point: 156-160°C
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.78 (1H, d, J=7Hz), 7.62 (1H, d, J=8Hz), 7.58 (1H, d, J=7Hz),
7.54 (1H, d, J=8Hz), 7.42-7.37 (2H, m), 7.34 (1H, td, J=7Hz,
1Hz), 6.92 (1H, s), 6.86 (1H, s), 4.45 (1H, dd, J=6Hz, 2Hz),

4.22-4.00 (5H, m), 3.96 (2H, s), 3.94-3.89 (1H, m), 2.56-2.50
(1H, m), 2.37 (1H, td, J=14Hz, 3Hz), 2.17-2.08 (1H, m), 1.88-
1.82 (1H, m), 1.26 (3H, t, J=7Hz).
Example 74
Ethyl 8-(N-{2-[2-(pyridin-4-yl)ethyl]phenylJsulfamoyl)-
1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound
No. 1-2336)

White powder (yield: 26%)
Melting point: 77-80°C
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
8.50-8.47 (2H, m), 7.54-7.52 (1H, m), 7.26-7.22 (1H, m), 7.19-
7.13 (4H, m), 6.89 (1H, t, J=lHz), 6.80 (1H, s), 4.43 (1H, dd,
J=6Hz, 3Hz), 4.25-4.18 (2H, m), 4.14-4.03 (3H, m), 3.96-3.90
(1H, m) , 3.15-3.00 (2H, m) , 2.99-2.89 (2H, m) , 2.54-2.48 (1H,
m), 2.33 (1H, td, J=14Hz, 3Hz), 2.17-2.09 (1H, m), 1.88-1.82
(1H, m) , 1.29 (3H, t, J=7Hz) .
Example 75
Ethyl 8- (N-{2-[2-(t-
butoxycarbonylamino)ethyl]phenyl}sulfamoyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2343)

Amorphous substance (yield: 65%)
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
8.00 (1H, s), 7.62 (1H, d, J=8Hz), 7.24 (1H, td, J=8Hz, 2Hz),

7.17 (1H, d, J=7Hz), 7.10 (1H, t, J=7Hz), 6.83 (1H, s), 4.90
(1H, brs), 4.46 (1H, d, J=5Hz), 4.23-4.01 (5H, m), 3.94-3.88
(1H, m), 3.27 (2H, q, J=7Hz), 2.96-2.83 (2H, m), 2.59-2.52 (2H,
m) , 2.18-2.09 (1H, m) , 1.83-1.78 (1H, m) , 1.48-1.41 (9H, m) ,
1.27 (3H, t, J=7Hz).
Example 76
Ethyl 8-[N- (2-aminophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2350)

Oil (yield: 13%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.39 (1H, dd, J=8Hz, 2Hz), 7.11-7.06 (1H, m), 6.89 (1H, t,
J=lHz), 6.79-6.73 (2H, m), 4.46 (1H, dd, J=6Hz, 3Hz), 4.31-3.86
(3H, m), 4.28 (2H, q, J=7Hz), 4.11-4.02 (3H, m), 3.95-3.89 (1H,
m), 2.48-2.41 (1H, m), 2.24 (1H, td, J=14Hz, 3Hz), 2.13-2.03
(1H, m) , 1.86-1.79 (1H, m) , 1.32 (3H, t, J=7Hz) .
Example 77
Ethyl 8-[N- (2,4-difluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-276)

White powder (yield: 74%)
Melting point: 128-131°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:

7.64-7.57 (1H, m), 6.97 (1H, brs), 6.93-6.86 (2H, m), 6.84 (1H,
t, J=lHz), 4.36 (1H, dd, J=6Hz, 2Hz), 4.28-4.02 (5H, m), 3.95-
3.90 (1H, m), 2.53-2.46 (1H, m), 2.40 (1H, td, J=14Hz, 4Hz),
2.21-2.10 (1H, m), 1.88-1.81 (1H, m), 1.29 (3H, t, J=7Hz).
Example 78
Ethyl 8-[N- (2-bromo-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-1550)

Pale yellow powder (yield: 48%)
Melting point: 106-111°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.68 (1H, dd, J=9Hz, 5Hz), 7.32 (1H, dd, J=8Hz, 3Hz), 7.10-7.04
(1H, m) , 6.94 (1H, s) , 6.82 (1H, t, J=lHz) , 4.46-4.43 (1H, m) ,
4.26-4.01 (5H, m), 3.95-3.89 (1H, m), 2.57-2.47 (2H, m), 2.24-
2.13 (1H, m), 1.87-1.81 (1H, m), 1.26 (3H, t, J=7Hz).
Example 79
Ethyl 8-[N- (4-fluoro-2-methylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2357)

White powder (yield: 79%)
Melting point: 103-105°C
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.96-6.85 (3H, m), 6.64 (1H, brs),

4.39 (1H, dd, J=6Hz, 3Hz) , 4.27-4.18 (2H, m) , 4.14-4.02 (3H, m) ,
3.96-3.89 (1H, m), 2.52-2.45 (1H, m), 2.40-2.31 (4H, m), 2.18-
2.08 (1H, m), 1.87-1.80 (1H, m), 1.29 (3H, t, J=7Hz).
Example 80
Ethyl 8-[N- (3-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2364)

Pale brown powder (yield: 81%)
Melting point: 111-118°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.47 (1H, dd, J=6Hz, 3Hz) , 7.29-7.25 (1H, m) , 7.15-7.09 (2H, m) ,
6.88 (1H, s), 4.28 (2H, q, J=7Hz), 4.21-4.18 (1H, m), 4.14-4.02
(3H, m), 3.96-3.89 (1H, m), 2.49-2.41 (1H, m), 2.25 (1H, td,
J=14Hz, 3Hz), 2.12-2.01 (1H, m), 1.89-1.82 (1H, m), 1.34 (3H, t,
J=7Hz).
Example 81
Ethyl 8- [N- (4-fluoro-3-trifluoromethylphenyl)sulfamoyl]-
1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound
No. 1-2371)

White powder (yield: 78%)
Melting point: 109-111°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.64-7.57 (2H, m), 7.27-7.17 (2H, m), 6.89 (1H, s), 4.28 (2H, q,
J=7Hz) , 4.19-4.16 (1H, m) , 4.14-4.03 (3H, m) , 3.96-3.89 (1H, m) ,

2.49-2.42 (1H, m), 2.26 (1H, td, J=14Hz, 3Hz), 2.13-2.03 (1H,
m), 1.89-1.83 (1H, m), 1.34 (3H, t, J=7Hz).
Example 82
Ethyl 8-[N- (4-fluoro-3-methoxy phenyl)sulfamoyl]-1,4-
dioxaspiro[4.5dec-6-ene-7-carboxylate (Exemplified compound No.
1-2378)

Oil (yield: 72%)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.09 (1H, dd, J=7Hz, 2Hz), 7.03 (1H, dd, J=llHz, 9Hz), 6.96 (1H,
brs) , 6.88-6.83 (2H, m) , 4.30-4.23 (3H, m) , 4.14-4.02 (3H, m) ,
3.95-3.89 (4H, m) , 2.46-2.38 (1H, m) , 2.27 (1H, td, J=14Hz,
3Hz), 2.10-2.00 (1H, m), 1.88-1.81 (1H, m), 1.33 (3H, t, J=7Hz).
Example 83
Ethyl 8-[N- (3,4-difluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2385)

Pale brown powder (yield: 94%)
Melting point: 118-121°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.33-7.26 (1H, m), 7.18-7.06 (3H, m), 6.89 (1H, s), 4.28 (2H, q,
J=7Hz), 4.19 (1H, dd, J=5Hz, 3Hz), 4.14-4.02 (3H, m), 3.96-3.89
(1H, m), 2.48-2.41 (1H, m), 2.25 (1H, td, J=14Hz, 3Hz), 2.11-
2.01 (1H, m), 1.89-1.82 (1H, m), 1.34 (3H, t, J=7Hz).

Example 84
Ethyl 8-[N- (2,4-dimethoxyphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2392)

White powder (yield: 49%)
Melting point: 118-121°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.47-7.45 (1H, m) , 6.78 (2H, d, J=9.8Hz), 6.50-6.47 (2H, m) ,
4.38 (1H, d, J=4.7Hz), 4.21-3.80 (12H, m), 2.54 (1H, dt,
J=14.2Hz, 7.2Hz), 2.45-2.38 (1H, m), 2.14-2.08 (1H, m), 1.81-
1.76 (1H, m), 1.25 (3H, t, J=7.0Hz).
Example 85
Ethyl 8- [N- (2-butyl-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-628)

Brown oil (yield: 82%)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.94 (1H, dd, J=10Hz, 3Hz), 6.92-6.86
(2H, m), 6.60 (1H, s), 4.41 (1H, dd, J=6Hz, 2Hz), 4.28-4.18 (2H,
m) , 4.14-4.02 (3H, m) , 3.96-3.89 (1H, m) , 2.75-2.63 (2H, m) ,
2.52-2.45 (1H, m), 2.37 (1H, dt, J=14Hz, 3Hz), 2.18-2.08 (1H,
m), 1.87-1.80 (1H, m), 1.63-1.52 (2H, m), 1.44-1.35 (2H, m),
1.29 (3H, t, J=7Hz), 0.95 (3H, t, J=8Hz).

Example 8 6
Ethyl 8- [N- (4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-1726)

Brown oil (yield: 78%)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.49 (1H, dd;, J=9Hz, 5Hz), 6.94 (1H, dd, J=10Hz, 3Hz), 6.92-
6.85 (2H, m), 6.61 (1H, s), 4.40 (1H, dd, J=6Hz, 2Hz), 4.27-4.18
(2H, m), 4.14-4.02 (3H, m), 3.95-3.90 (1H, m), 2.76-2.61 (2H,
m) , 2.52-2.45 (1H, m) , 2.37 (1H, dt, J=14Hz, 3Hz) , 2.18-2.09
(1H, m), 1.87-1.81 (1H, m), 1.65-1.52 (2H, m), 1.39-1.32 (4H,
m) , 1.30 (3H, t, J=7Hz) , 0.90 (3H, t, J=7Hz) .
Example 87
Ethyl 8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-804)

Pale brown oil (yield: 58%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.96-6.85 (3H, m), 6.61 (1H, s), 4.40
(1H, dd, J=6Hz, 2Hz) , 4.28-4.18 (2H, m) , 4.14-4.02 (3H, m) ,
3.95-3.89 (1H, m), 2.76-2.61 (2H, m), 2.52-2.45 (1H, m), 2.37
(1H, td, J=14Hz, 3Hz), 2.18-2.08 (1H, m), 1.87-1.81 (1H, m),
1.63-1.52 (2H, m) , 1.42-1.25 (9H, m) , 0.91-0.85 (3H, m) .

Example 88
Ethyl 8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-980)

Pale yellow oil (yield: 85%)
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.96-6.87 (3H, m), 6.63 (1H, s), 4.41
(1H, dd, J=6Hz, 2Hz) , 4.27-4.19 (2H, m) , 4.14-3.91 (4H, m) ,
2.76-2.62 (2H, m), 2.52-2.46 (1H, m), 2.37 (1H, dt, J=14Hz,
3Hz), 2.18-2.09 (1H, m) , 1.84 (1H, dt, J=13Hz, 4Hz), 1.62-1.55
(2H, m), 1.40-1.24 (11H, m), 0.88 (3H, t, J=7Hz).
Example 8 9
Ethyl 8- [N- (4-fluoro-2-octylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-1902)

Pale yellow oil (yield: 72%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.96-6.87 (3H, m), 6.62 (1H, s), 4.40
(1H, dd, J=6Hz, 2Hz) , 4.27-4.19 (2H, m) , 4.15-3.90 (4H, m) ,
2.74-2.62 (2H, m), 2.52-2.46 (1H, m), 2.37 (1H, dt, J=14Hz,
3Hz), 2.18-2.10 (1H, m), 1.86-1.81 (1H, m), 1.63-1.53 (2H, m),
1.40-1.24 (13H, m), 0.88 (3H, t, J=7Hz).

Example 90
Ethyl 8-[N- (4-fluoro-2-nonylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2602)

Pale orange oil (yield: 82%)
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.94 (1H, dd, J=9Hz, 3Hz), 6.92-6.85
(2H, m), 6.62 (1H, s), 4.40 (1H, dd, J=6Hz, 2Hz), 4.28-4.17 (2H,
m) , 4.15-4.03 (3H, m) , 3.95-3.90 (1H, m) , 2.75-2.62 (2H, m) ,
2.52-2.45 (1H, m), 2.37 (1H, td, J=14Hz, 3Hz), 2.18-2.09 (1H,
m) , 1.86-1.81 (1H, m) , 1.63-1.53 (2H, m) , 1.39-1.22 (15H, m) ,
0.88 (3H, t, J=7Hz).
Example 91
Ethyl 8-[N- (2-decyl-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2616)

Pale yellow oil (yield: 83%)
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.94 (1H, dd, J=9Hz, 3Hz), 6.92-6.85
(2H, m), 6.62 (1H, s), 4.40 (1H, dd, J=5Hz, 3Hz), 4.28-4.17 (2H,
m) , 4.15-4.03 (3H, m) , 3.95-3.90 (1H, m) , 2.75-2.62 (2H, m) ,
2.51-2.45 (1H, m), 2.37 (1H, td, J=14Hz, 3Hz), 2.18-2.09 (1H,
m) , 1.86-1.81 (1H, m) , 1.63-1.53 (2H, m) , 1.39-1.22 (17H, m) ,
0.88 (3H, t, J=7Hz).

Example 92
Ethyl 8-[N- (4-chloro-2-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2399)

White powder (yield: 65%)
Melting point: 130-133°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.62-7.56 (1H, m), 7.18-7.11 (2H, m), 7.02 (1H, s), 6.84 (1H, t,
J=lHz) , 4.37 (1H, dd, J=6Hz, 2Hz) , 4.25-4.02 (5H, m) , 3.96-3.89
(1H, m), 2.55-2.48 (1H, m), 2.42 (1H, td, J=14Hz, 4Hz), 2.21-
2.11 (1H, m), 1.88-1.82 (1H, m), 1.29 (3H, t, J=7Hz).
Example 93
Ethyl 8-[N- (2-bromo-4-chlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2406)

Pale brown powder (yield: 51%)
Melting point: 100-110°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.64 (1H, d, J=9Hz), 7.56 (1H, d, J=3Hz), 7.31 (1H, dd, J=9Hz,
3Hz) , 7.02 (1H, s) , 6.83 (1H, t, J=lHz) , 4.47-4.43 (1H, m) ,
4.23-4.02 (5H, m), 3.95-3.89 (1H, m), 2.58-2.48 (2H, m), 2.24-
2.14 (1H, m), 1.89-1.82 (1H, m), 1.26 (3H, t, J=7Hz).

Example 94
Ethyl 8-[N- (4-chloro-2-methylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2413)

White powder (yield: 74%)
Melting point: 123-126°C
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.49 (1H, d, J=9Hz), 4.21-4.15 (2H, m), 6.86 (1H, t, J=lHz),
6.65 (1H, s) , 4.38 (1H, dd, J=6Hz, 3Hz) , 4.24-4.15 (2H, m) ,
4.14-4.02 (3H, m), 3.96-3.89 (1H, m), 2.54-2.47 (1H, m), 2.41-
2.32 (4H, m), 2.19-2.09 (1H, m), 1.88-1.82 (1H, m), 1.29 (3H, t,
J=7Hz).
Example 95
Ethyl 8-[N- (4-chloro-2-methoxycarbonylphenyl)sulfamoyl]-
1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound
No. 1-2420)

White powder (yield: 46%)
Melting point: 131-134°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
10.48 (1H, s), 8.00 (1H, d, J=3Hz), 7.79 (1H, d, J=9Hz), 7.50
(1H, dd, J=9Hz, 3Hz), 6.80 (1H, t, J=lHz), 4.47 (1H, dd, J=6Hz,
2Hz) , 4.14-4.01 (5H, m) , 3.95-3.88 (4H, m) , 2.66-2.50 (2H, m) ,
2.22-2.11 (1H, m), 1.88-1.81 (1H, m), 1.25 (3H, t, J=7Hz).

Example 96
Ethyl 8-[N- (3,4-dichlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2427)

White powder (yield: 66%)
Melting point: 163-164°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.49 (1H, d, J=2Hz), 7.41 (1H, d, J=9Hz), 7.23 (1H, dd, J=9Hz,
3Hz), 7.16 (1H, s), 6.88 (1H, t, J=lHz), 4.27 (2H, q, J=7Hz),
4.21 (1H, q, J=3Hz), 4.14-4.02 (3H, m), 3.96-3.88 (1H, m), 2.50-
2.43 (1H, m) , 2.27 (1H, td, J=14Hz, 3Hz) , 2.13-2.03 (1H, m) ,
1.89-1.82 (1H, m), 1.33 (3H, t, J=7Hz).
Example 97
Ethyl 8-[N- (2,5-difluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2434)

Pale brown powder (yield: 61%)
Melting point: 125-128°C
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.45-7.41 (1H, m), 7.09-7.00 (2H, m), 6.86 (1H, s), 6.80-6.74
(1H, m), 4.41 (1H, dd, J=6Hz, 2Hz), 4.26-4.02 (5H, m), 3.95-3.90
(1H, m), 2.58-2.52 (1H, m), 2.44 (1H, td, J=14Hz, 3Hz), 2.23-
2.14 (1H, m), 1.89-1.84 (1H, m), 1.28 (3H, t, J=7Hz).

Example 98
Ethyl 8-[N- (2,6-difluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2441)

White powder (yield: 56%)
Melting point: 129-131°C
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.25-7.18 (1H, m), 7.01-6.95 (2H, m), 6.89-6.87 (2H, m), 4.64
(1H, dd, J=5Hz, 2Hz) , 4.31-4.21 (2H, m) , 4.15-4.03 (3H, m) ,
3.96-3.91 (1H, m), 2.63-2.57 (1H, m), 2.36 (1H, td, J=14Hz,
3Hz), 2.26-2.17 (1H, m), 1.87-1.82 (1H, m), 1.29 (3H, t, J=7Hz).
Example 99
Ethyl 8-[N- (2-fluoro-4-methylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2448)

White powder (yield: 69%)
Melting point: 136-138°C
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.49 (1H, t, J=9Hz), 6.95-6.92 (2H, m), 6.86 (1H, d, J=2Hz),
6.83 (1H, s), 4.40-4.37 (1H, m), 4.26-4.15 (2H, m), 4.13-4.01
(3H, m), 3.94-3.89 (1H, m), 2.51-2.40 (2H, m), 2.32 (3H, s),
2.18-2.09 (1H, m), 1.86-1.81 (1H, m), 1.27 (3H, t, J=7Hz).

Example 100
Ethyl 8-[N- (2-fluoro-5-methylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2455)

Oil (yield: 63%)
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.43 (1H, dd, J=8Hz, 2Hz), 6.98 (1H, dd, J=10Hz, 8Hz), 6.91-6.87
(2H, m), 6.83 (1H, t, J=lHz), 4.42 (1H, dd, J=6Hz, 2Hz), 4.26-
4.02 (5H, m), 3.95-3.89 (1H, m), 2.54-2.42 (2H, m), 2.20-2.12
(1H, m) , 1.87-1.82 (1H, m) , 1.27 (3H, t, J=7Hz) .
Example 101
Ethyl 8-[N- (2-fluoro-4-methoxyphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2462)

Pale brown powder (yield: 57%)
Melting point: 167-169°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.50 (1H, t, J=9Hz), 6.82 (1H, t, J=lHz), 6.79 (1H, brs), 6.71-
6.67 (2H, m), 4.38-4.35 (1H, m), 4.28-4.19 (2H, m), 4.14-4.01
(3H, m) , 3.95-3.88 (1H, m) , 3.79 (3H, s) , 2.49-2.36 (2H, m) ,
2.18-2.08 (1H, m), 1.86-1.79 (1H, m), 1.29 (3H, t, J=7Hz).
Example 102

Ethyl 8-[N- (5-chloro-2-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
. 1-2469)

White powder (yield: 55%)
Melting point: 88-90°C
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.68-7.65 (1H, m), 7.07-7.01 (3H, m), 6.86 (1H, s), 4.40 (1H,
dd, J=6Hz, 2Hz), 4.27-4.15 (2H, m) , 4.14-4.03 (3H, m) , 3.96-3.90
(1H, m), 2.58-2.52 (1H, m), 2.43 (1H, td, J=14Hz, 3Hz), 2.23-
2.15 (1H, m), 1.89-1.84 (1H, m), 1.29 (3H, t, J=7Hz).
Example 103
Ethyl 8-[N- (2,3,4-trifluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2476)

White powder (yield: 71%)
Melting point: 149-152°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.41-7.34 (1H, m), 7.14 (1H, brs), 7.02-6.93 (1H, m), 6.85 (1H,
t, J=lHz), 4.36 (1H, dd, J=6Hz, 2Hz), 4.28-4.20 (2H, m), 4.14-
4.02 (3H, m) , 3.96-3.90 (1H, m) , 2.55-2.46 (1H, m) , 2.38 (1H,
td, J=14Hz, 4Hz), 2.22-2.12 (1H, m), 1.89-1.82 (1H, m), 1.31
(3H, t, J=7Hz).

Example 104
Ethyl 8-[N- (2,4,5-trifluorophenyl)sulfamoyl]-1,4-
dioxaspiro [4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2483)

White powder (yield: 72%)
Melting point: 104-107°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.60-7.52 (1H, m), 7.05-6.97 (2H, m), 6.86 (1H, t, J=lHz), 4.35
(1H, dd, J=6Hz, 2Hz) , 4.28-4.19 (2H, m) , 4.15-4.02 (3H, m) ,
3.96-3.90 (1H, m), 2.56-2.49 (1H, m), 2.38 (1H, td, J=14Hz,
4Hz), 2.23-2.12 (1H, m), 1.90-1.83 (1H, m), 1.30 (3H, t, J=7Hz).
Example 105
Ethyl 8-[N- (2,4,6-trifluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2490)

White powder (yield: 61%)
Melting point: 131-133°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
6.91 (1H, s), 6.88 (1H, t, J=lHz), 6.80-6.72 (2H, m), 4.55 (1H,
dd, J=6Hz, 3Hz), 4.31-4.23 (2H, m), 4.14-4.03 (3H, m), 3.96-3.90
(1H, m), 2.62-2.55 (1H, m), 2.32 (1H, td, J=14Hz, 3Hz), 2.25-
2.15 (1H, m), 1.88-1.81 (1H, m), 1.31 (3H, t, J=7Hz).

Example 106
Ethyl 8-[N- (2,4-dichlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2497)

Pale brown powder (yield: 67%)
Melting point: 109-111°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.65 (1H, d, J=9Hz) , 7.41 (1H, d, J=2Hz) , 7.28-7.24 (1H, m) ,
7.07 (1H, s), 6.83 (1H, s), 4.46-4.42 (1H, m), 4.24-4.02 (5H,
m) , 3.98-3.89 (1H, m) , 2.56-2.46 (2H, m) , 2.24-2.13 (1H, m) ,
1.89-1.82 (1H, m), 1.26 (3H, t, J=7Hz).
Example 107
Ethyl 8-[N- (4-bromo-2-chlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2504)

White powder (yield: 74%)
Melting point: 102-107°C
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.59 (1H, d, J=9Hz) , 7.55 (1H, d, J=2Hz) , 7.40 (1H, dd, J=9Hz,
2Hz), 7.08 (1H, s), 6.83 (1H, s), 4.44 (1H, d, J=5Hz), 4.23-4.02
(5H, m), 3.95-3.89 (1H, m), 2.55-2.47 (2H, m), 2.23-2.14 (1H,
m), 1.89-1.83 (1H, m), 1.26 (3H, t, J=7Hz).

Ethyl 8-[N- (2-chloro-4-methylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-452)

Pale brown powder (yield: 69%)
Melting point: 130-135°C
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.57 (1H, d, J=9Hz), 7.20 (1H, d, J=2Hz), 7.10-7.06 (1H, m),
6.97 (1H, s), 6.81 (1H, d, J=lHz), 4.44 (1H, d, J=5Hz), 4.25-
4.00 (5H, m), 3.95-3.87 (1H, m), 2.59-2.45 (2H, m), 2.31 (3H,
s), 2.22-2.10 (1H, m), 1.87-1.79 (1H, m), 1.25 (3H, t, J=7Hz).
Example 109
Ethyl 8-[N- (4-t-butyl-2-chlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2511)

Amorphous substance (yield: 49%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.61 (1H, d, J=9Hz), 7.38 (1H, d, J=2Hz), 7.29 (1H, dd, J=9Hz,
2Hz), 7.00 (1H, s), 6.82 (1H, s), 4.46 (1H, d, J=4Hz), 4.23-4.01
(5H, m), 3.95-3.88 (1H, m), 2.59-2.47 (2H, m), 2.23-2.12 (1H,
m) , 1.87-1.80 (1H, m) , 1.29 (9H, s) , 1.25-1.21 (3H, m) .
Example 110
Ethyl 8-[N- (2-chloro-6-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.

1-2518)

Amorphous substance (yield: 62%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.27-7.24 (1H, m), 7.21-7.15 (1H, m), 7.12-7.06 (1H, m), 6.98
(1H, s), 6.86 (1H, s), 4.77-4.74 (1H, m), 4.30-4.21 (2H, m),
4.15-4.03 (3H, m), 3.96-3.90 (1H, m), 2.67-2.60 (1H, m), 2.38
(1H, td, J=14Hz, 3Hz) , 2.28-2.17 (1H, m) , 1.88-1.81 (1H, m) ,
1.29 (3H, t, J=7Hz).
Example 111
Ethyl 8-[N- (2,6-dichlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2525)

Amorphous substance (yield: 24%)
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.39 (1H, s), 7.38 (1H, s), 7.27 (1H, s), 7.17 (1H, t, J=8Hz),
6.87 (1H, s), 4.88 (1H, dd, J=5Hz, 3Hz), 4.29 (2H, q, J=7Hz),
4.15-4.03 (3H, m), 3.96-3.91 (1H, m), 2.68-2.62 (1H, m), 2.31
(1H, td, J=14Hz, 3Hz) , 2.26-2.18 (1H, m) , 1.88-1.82 (1H, m) ,
1.31 (3H, t, J=7Hz).
Example 112
Ethyl 8-[N- (2-chloro-6-methylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-1462)

Amorphous substance (yield: 55%)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.29-7.23 (1H, m), 7.20-7.09 (3H, m), 6.84 (1H, t, J=lHz), 4.80-
4.77 (1H, m), 4.30-4.20 (2H, m), 4.13-4.00 (3H, m), 3.95-3.89
(1H, m), 2.58-2.46 (4H, m), 2.33 (1H, td, J=14Hz; 3Hz) , 2.25-
2.14 (1H, m), 1.85-1.78 (1H, m), 1.28 (3H, t, J=7Hz).
Example 113
Ethyl 8-[N- (2,3-dichlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2532)

Amorphous substance (yield: 70%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66-7.61 (1H, m), 7.26-7.19 (3H, m), 6.83 (1H, s), 4.46 (1H, d,
J=5Hz), 4.22-4.01 (5H, m), 3.95-3.89 (1H, m), 2.57-2.48 (2H, m),
2.25-2.14 (1H, m), 1.89-1.82 (1H, m), 1.25 (3H, t, J=7Hz).
Example 114
Ethyl 8-[N- (2,5-dichlorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2539)

White powder (yield: 78%)
Melting point: 120-124°C
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.72 (1H, d, J=2Hz), 7.31 (1H, d, J=9Hz), 7.11 (1H, s), 7.05
(1H, dd, J=9Hz, 2Hz), 6.86 (1H, s), 4.46 (1H, dd, J=6Hz, 2Hz),
4.25-4.03 (5H, m), 3.95-3.90 (1H, m), 2.58-2.48 (2H, m), 2.26-
2.17 (1H, m), 1.90-1.84 (1H, m), 1.26 (3H, t, J=7Hz).
Example 115
Ethyl 8-[N- (2-chloro-4,6-difluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2546)

Oil (yield: 29%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.07-7.03 (1H, m), 6.99 (1H, s), 6.91-6.83 (2H, m), 4.67 (1H,
dd, J=5Hz, 3Hz), 4.31-4.23 (2H, m), 4.14-4.03 (3H, m), 3.97-3.90
(1H, m), 2.65-2.57 (1H, m), 2.34 (1H, td, J=14Hz, 3Hz), 2.27-
2.17 (1H, m), 1.88-1.81 (1H, m), 1.31 (3H, t, J=7Hz).
Example 116
Ethyl 8-[N- (2,6-dichloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2553)

Amorphous substance (yield: 3 9%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.22 (1H, s), 7.17 (2H, d, J=7Hz), 6.88 (1H, t, J=lHz), 4.84-
4.81 (1H, m), 4.29 (2H, q, J=7Hz), 4.14-4.03 (3H, m), 3.97-3.90
(1H, m), 2.67-2.60 (1H, m), 2.34-2.17 (2H, m), 1.88-1.81 (1H,
m), 1.33 (3H, t, J=7Hz).
Example 117
Ethyl 8-[N- (2-bromo-6-chloro-4-fluorophenyl)sulfamoyl]-
1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound
No. 1-2560)

Amorphous substance (yield: 46%)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.35 (1H, dd, J=7.5Hz, 2.8Hz), 7.24-7.21 (2H, m), 7.24 (1H, s),
4.90 (1H, d, J=5.1Hz), 4.30 (2H, q, J=7.2Hz), 4.14-3.92 (4H, m) ,
2.67-2.62 (1H, m), 2.33-2.18 (2H, m), 1.88-1.84 (1H, m), 1.33
(3H, t, J=6.6Hz).
Example 118
Ethyl 8-[N- (4-chloro-2-methoxy-5-methylphenyl)sulfamoyl]-
1, 4-dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound
No. 1-2567)

White powder (yield: 54%)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.43 (1H, s), 6.96 (1H, s), 6.87 (1H, s), 6.78 (1H, t, J=lHz),
4.41 (1H, dd, J=6Hz, 2Hz) , 4.20-4.00 (5H, m) , 3.94-3.88 (1H, m) ,
3.85 (3H, s), 2.58-2.43 (2H, m), 2.31 (3H, s), 2.20-2.08 (1H,
m), 1.85-1.78 (1H, m), 1.25 (3H, t, J=7Hz).
Example 119
Ethyl 8-[N- (2,4-dibromophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2574)

Oil (yield: 56%)
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.70 (1H, d, J=2Hz), 7.59 (1H, d, J=9Hz), 7.44 (1H, dd, J=9Hz,
2Hz), 7.02 (1H, s), 6.83 (1H, s), 4.47-4.44 (1H, m), 4.23-4.02
(5H, m), 3.95-3.90 (1H, m), 2.57-2.49 (2H, m), 2.23-2.15 (1H,
m), 1.88-1.83 (1H, m), 1.26 (3H, t, J=7Hz).
Example 12 0
Ethyl 8-[N- (2,6-dibromophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2581)

Amorphous substance (yield: 41%)
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.61 (2H, d, J=8Hz), 7.26 (1H, brs), 7.02 (1H, t, J=8Hz), 6.88
(1H, s), 5.02-5.00 (1H, m), 4.29 (2H, q, J=7Hz), 4.15-3.91 (4H,
m) , 2.70-2.64 (1H, m) , 2.33-2.19 (2H, m) , 1.87-1.83 (1H, m) ,
1.32 (3H, t, J=7Hz).
Example 121
Ethyl 8-[N- (2-bromo-4-isopropylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2588)

White powder (yield: 51%)
Melting point: 130-134°C
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.60 (1H, d, J=8Hz), 7.40 (1H, d, J=2Hz), 7.18 (1H, dd, J=8Hz,
2Hz), 6.94 (1H, s), 6.82 (1H, s), 4.48-4.46 (1H, m), 4.24-4.01
(5H, m), 3.94-3.88 (1H, m), 2.89-2.83 (1H, m), 2.60-2.47 (2H,
m) , 2.22-2.13 (1H, m) , 1.86-1.81 (1H, m) , 1.25-1.21 (9H, m) .
Example 122
Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (low polarity compound,
first peak), (high polarity compound, second peak) (Exemplified
compound No. 1-3 64)

Ethyl 8-[N- (2-chloro-4-fluoropheny1)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 1 was
subjected to high performance liquid chromatography (column;
CHIRALPAK AD-H, size; inner diameter 2 cm, length 25 cm,
solvent; hexane : 2-propanol) to separate and purify two optical
isomers, and low polarity compound (first peak) and high
polarity compound (second peak) were respectively obtained as a
white powder. According to the result of HPLC analysis of the
two optical isomers obtained under the conditions below, their
optical purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 1:1
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 6.1
minutes
high polarity compound (second peak):
10.5 minutes
(low polarity compound, first peak)
Melting point: 116-117°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.68 (1H, dd, J=9.2Hz, 5.3Hz), 7.17 (1H, dd, J=7.8Hz, 2.7Hz),
7.05-7.00 (2H, m), 6.83 (1H, s), 4.43 (1H, d, J=5.4Hz), 4.26-
3.90 (6H, m), 2.55-2.47 (2H, m), 4.15-2.47 (1H, m), 4.02-2.13
(1H, m), 1.27 (3H, t, J=7.0Hz).
(high polarity compound, second peak)
Melting point: 116-117°C

1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.68 (1H, dd, J==9.0Hz, 5.5Hz), 7.17 (1H, dd, J=8.0Hz, 2.9Hz),
7.06-7.00 (2H, m), 6.84 (1H, s), 4.43 (1H, d, J=5.4Hz), 4.26-
3.90 (6H, m), 2.55-2.47 (2H, m), 1.13-2.23 (1H, m), 1.87-1.83
(1H, m), 1.27 (3H, t, J=6.6Hz).
Example 123
Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-7-ene-8-carboxylate

(123a) Ethyl 7-trifluoromethanesulfonyloxy-1,4-
dioxaspiro[4.5]dec-7-ene-8-carboxylate
Following the process described in Example (3 0e), ethyl
7-oxo-1,4-dioxaspiro[4.5]decane-8-carboxylate [compound
disclosed as Compound 292c in US Patent application No.
US2004/259914 A1] was used in place of ethyl 8-oxo-1-
oxaspiro[4.5]decane-7-carboxylate to give the title compound as
a white powder (yield: 96%) .
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.28 (2H, q, J=7Hz), 4.04-3.96 (4H, m), 2.65-2.61 (4H, m), 1.82-
1.78 (2H, m), 1.32 (3H, t, J=7Hz).
(123b) Ethyl 7-acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-
ene- 8 -carboxylate
Following the process described in Example (la), ethyl 7-
trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-8-
carboxylate obtained in (123a) was used in place of ethyl 8-
trifluoromethanesulfonyloxy-1,4-dioxaspiro[4.5]dec-7-ene-7-
carboxylate to obtain the title compound as a pale brown oil
(yield: 83%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.21 (2H, q, 7Hz), 4.04-3.96 (4H, m), 2.72-2.65 (4H, m), 2.32
(3H, s), 1.85 (2H, t, J=7Hz), 1.29 (3H, t, J=7Hz).

(123c) Ethyl 7-mercapto-1,4-dioxaspiro[4.5]dec-7-ene-8-
carboxylate
Following the process described in Example (lb), ethyl 7-
acetylsulfanyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate
obtained in (123b) was used in place of ethyl 8-acetylsulfanyl-
1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title
compound as a pale brown powder (yield: 85%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
4.22 (2H, q, 7Hz), 4.20 (1H, s), 4.02-3.95 (4H, m), 2.69-2.66
(2H, m), 2.61-2.56 (2H, m), 1.82-1.78 (2H, m), 1.30 (3H, t,
J=7Hz).
(123d) Ethyl 7-chlorosulfonyl-l,4-dioxaspiro[4.5]dec-7-
ene-8-carboxylate
Following the process described in Example (lc), ethyl 7-
mercapto-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate obtained in
(123c) was used in place of ethyl 8-mercapto-1,4-
dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title
compound as a colorless oil (yield: 62%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
4.31 (2H, q, 7Hz), 4.09-4.00 (4H, m), 2.82-2.73 (4H, m), 1.86
(2H, t, J=7Hz), 1.35 (3H, t, J=7Hz).
(123e) Ethyl 9-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate
Following the process described in Example (1d), ethyl 7-
chlorosulfonyl-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate
obtained in (123d) was used in place of ethyl 8-chlorosulfonyl-
1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate to give the title
compound as a white powder (yield: 61%).
Melting point: 120-122°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.81 (1H, s) , 7.66 (1H, dd, J=9Hz, 5Hz) , 7.14-7.10 (2H, m) ,
6.98-6.92 (1H, m), 4.71-4.67 (1H, m), 4.22-3.96 (6H, m), 2.75-
2.56 (3H, m), 2.08-2.02 (1H, m), 1.24 (3H, t, J=7Hz).

Example 124
Ethyl 2-bromoethyl-8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate

Following the process described in Example (17a), 1-
bromo-2,3-bis[(trimethylsilyl)oxy]propane was used in place of
1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the
title compound as a white amorphous substance (yield: 100%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9.2 and 5.3Hz), 7.17 (1H, dd, J=7.8 and 2.8Hz),
7.05-6.99 (2H, m), 6.86-6.77 (1H, m), 4.53-3.84 (6H, m), 3.53-
3.31 (2H, m), 2.66-2.41 (2H, m), 2.24-2.12 (1H, m), 1.89-1.86
(1H, m) , 1.28-1.24 (3H, m) .
Example 125
Ethyl (2S)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2-
methoxycarbonylmethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), methyl
(S)-3,4-bis[(trimethylsilyl)oxy]butyrate obtained in Reference
Example 20 was used in place of 1,4-di-O-benzoyl-2,3-di-O-
trimethylsilyl-D-threitol to give the title compound as a
colorless oil (yield: 96%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:

7.67 (1H, dd, J=9.0Hz, 5.4Hz), 7.16 (1H, dd, J=7.9Hz, 2.8Hz),
7.05-6.98 (2H, m), 6.88-6.76 (1H, m), 4.63-4.58 (1H, m), 4.47-
4.41 (1H, m) , 4.32-4.10 (3H, m) , 3.84-3.59 (4H, m) , 2.85-2.39
(4H, m), 2.21-2.16 (1H, m), 1.89-1.80 (1H, m), 1.29-1.24 (3H,
m) .
Example 126
Ethyl 3-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-7,12-
dioxaspiro[5.6]dodec-1-ene-2-carboxylate (Exemplified compound
No. 1-366)

34 mg (0.61 mmol) of 1,4-butanediol was dissolved in 5 ml
of dichloromethane, 0.3 2 ml (1.83 mmol) of
isopropoxytrimethylsilane, and 200 mg (0.47 mmol) of ethyl 6-[N-
(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-
1-carboxylate obtained in Example (16a) and 4 ul (0.024 mmol) of
trimethylsilyl trifluoromethanesulfonate were sequentially added
thereto with stirring under ice-cooling, followed by stirring
for 2 hours at the same temperature. Saturated aqueous sodium
hydrogencarbonate was added to the reaction solution and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous magnesium sulfate,
followed by concentration under reduced pressure. The residue
was subjected to silica gel column chromatography (solvent;
hexane : ethyl acetate = 3:1), and the resulting solid was
further washed with hexane to give 6 mg of the title compound as
a white powder (yield: 3%).
Melting point: 142-144°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.68 (1H, dd, J=9Hz, 5Hz), 7.16 (1H, dd, J=8Hz, 3Hz), 7.04 (1H,
s), 7.03-6.98 (2H, m), 4.44-4.40 (1H, m), 4.27-4.11 (2H, m),

3.91-3.62 (4H, m), 2.46-2.38 (1H, m), 2.31-2.21 (1H, m), 2.17-
1.94 (2H, m), 1.71-1.58 (4H, m), 1.27 (3H, t, J=7Hz).
Example 127
Ethyl 4-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
3a' ,4',6',6a'-tetrahydrospiro[cyclohex-2-ene-l,2'-furo[3.4-
d] [1.3]dioxol]-3-carboxylate (Exemplified compound No. 1-402)

Following the process described in Example 21, 1,4-
anhydro-2,3-di-O-trimethylsilyl-meso-erythritol obtained in
Reference Example 21 was used in place of 1,3,4,5,7-penta-O-
trimethylsilyl-D-arabitol to give the title compound as a white
powder (yield: 56%).
Melting point: 227-228°C
1H-NMR spectrum (400MHz, CDCl3+CD3OD) δ ppm:
7.61 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.07-6.97
(1H, m) , 6.91 (1H, s) , 4.93 (1H, dd, J=6Hz, 4Hz) , 4.81 (1H, dd,
J=6Hz, 4Hz), 4.39 (1H, d, J=5Hz), 4.26-4.05 (3H, m), 4.01 (1H,
d, J=llHz), 3.51-3.41 (2H, m), 2.54-2.34 (2H, m), 2.20-2.07 (1H,
m), 1.90-1.79 (1H, m), 1.25 (3H, t, J=7Hz).
Example 12 8
Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2,2,3,3-
tetramethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), 2,3-

dimethyl-2,3-bis[(trimethylsilyl)oxy]butane was used in place of
1, 4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the
title compound as a pale yellow oil (yield: 10%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=8.8Hz, 5.6Hz), 7.16 (1H, dd, J=7.8Hz, 2.7Hz),
7.04-7.03 (1H, m), 6.89 (1H, s), 4.37 (1H, d, J=4.0Hz), 4.25-
4.10 (2H, m), 2.51-2.43 (2H, m), 2.24-2.14 (1H, m), 1.94-1.89
(1H, m) , 1.31-1.23 (15H, m) .
Example 12 9
Ethyl 8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-2,2,3-
triethyl-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), 3-
ethyl-3,4-bis[(trimethylsilyl)oxy]hexane obtained in Reference
Example 22 was used in place of 1,4-di-O-benzoyl-2,3-di-O-
trimethylsilyl-D-threitol to give the title compound as a white
powder (yield: 88%) .
Melting point: 124-126°C
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.69-7.66 (1H, m), 7.17-7.15 (1H, m), 7.04-7.00 (2H, m), 6.88-
6.69 (1H, m), 4.40-4.39 (1H, m), 4.28-4.10 (2H, m), 3.90-3.68
(1H, m), 2.54-2.31 (2H, m), 2.25-2.12 (1H, m), 1.85-1.37 (7H,
m) , 1.29-1.24 (3H, m) , 1.08-0.84 (9H, m) .
Example 13 0
Ethyl (3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2,2,3-triphenyl-l,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate

Following the process described in Example (17a), (R)-l,2-
bis[(trimethylsilyl)oxy]-1,1,2-triphenylethane obtained in
Reference Example 23 was used in place of 1,4-di-O-benzoyl-2,3-
di-O-trimethylsilyl-D-threitol to give the title compound as a
colorless oil (yield: 30%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.22-6.91 (20H, m), 5.99-5.76 (1H, m), 4.54-4.32 (1H, m), 4.34-
4.08 (2H, m), 2.87-1.97 (4H, m), 1.36-1.14 (3H, m).
Example 131
Ethyl (2R,3R) -8- [N- (2-chlorophenyl) sulfamoyl] -2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-206)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[W-(2-
chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 54 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 31%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.71-7.67 (1H, m), 7.41-7.38 (1H, m), 7.32-7.26 (1H, m), 7.14-
7.06 (2H, m), 6.90 (0.5H, t, J=lHz), 6.84 (0.5H, t, J=lHz), 4.47
(1H, dd, J=6Hz, 2Hz), 4.26-4.07 (3.5H, m), 4.05-4.00 (0.5H, m),
3.94-3.80 (2H, m), 3.77-3.67 (2H, m), 2.64-2.47 (2H, m), 2.27-

1.87 (4H, m) , 1.27-1.22 (3H, m) .
Example 13 2
Ethyl (2R,3R)-8-[N- (2-bromophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-1392)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8- [N- (2-
bromophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate obtained in Example 55 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-G-
ene- 7-carboxylate to give the title compound as an amorphous
substance (yield: 28%)
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.71-7.67 (1H, m), 7.56 (1H, d, J=8Hz), 7.35-7.31 (1H, m), 7.07-
6.98 (2H, m), 6.90 (0.5H, s), 6.84 (0.5H, s), 4.48 (1H, d,
J=5Hz), 4.25-4.08 (3.5H, m), 4.06-4.01 (0.5H, m), 3.94-3.80 (2H,
m) , 3.76-3.68 (2H, m) , 2.65-2.48 (2H, m) , 2.23-1.87 (4H, m) ,
1.27-1.22 (3H, m).
Example 133
Ethyl (2R,3R) -2,3-bis (hydroxymethyl) -8- [N- (2-
iodophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-2226)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2-iodophenyl)sulfamoyl]-
1,4-dioxaspiro [4.5]dec-6-ene-7-carboxylate obtained in Example
56 was used in place of ethyl 8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate to give the title compound as an amorphous substance
(yield: 26%).
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.80 (1H, d, J=8Hz), 7.68-7.63 (1H, m), 7.38-7.33 (1H, m), 6.90-
6.83 (3H, m), 4.50-4.46 (1H, m), 4.27-4.09 (3.5H, m), 4.06-4.02
(0.5H, m), 3.94-3.80 (2H, m), 3.77-3.68 (2H, m), 3.53 (1H, brs),
2.66-2.56 (1H, m), 2.55-2.49 (1H, m), 2.24-2.14 (1H, m), 2.00-
1.85 (2H, m), 1.27-1.23 (3H, m).
Example 134
Ethyl (21R,3R) -8- [N- (2-hexylphenyl) sulfamoyl] -2,3-bis
(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-734)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N-(2-
hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 4 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as a colorless oil
(yield: 28%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.54-7.50 (1H, m), 7.23-7.17 (2H, m), 7.15-7.09 (1H, m), 6.94-
6.91 (0.5H, m), 6.88-6.85 (0.5H, m), 6.70 (0.5H, s), 6.65 (0.5H,
s) , 4.48-4.43 (1H, m) , 4.28-4.08 (3.5H, m) , 4.06-4.00 (0.5H, m) ,
3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.70-2.61 (2H, m), 2.55-

2.41 (2H, m), 2.21-2.07 (1H, m), 1.96-1.75 (3H, m), 1.64-1.52
(2H, m) , 1.42-1.23 (9H, m) , 0.91-0.85 (3H, m) .
Example 13 5
Ethyl (2R,3R)-8-[N- (2-heptylphenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-910)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8- [N- (2-
heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 5 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as a colorless oil
(yield: 33%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.54-7.50 (1H, m), 7.23-7.18 (2H, m), 7.14-7.09 (1H, m), 6.94-
6.91 (0.5H, m), 6.88-6.85 (0.5H, m), 6.70 (0.5H, s), 6.65 (0.5H,
s), 4.47-4.43 (1H, m), 4.28-4.08 (3.5H, m), 4.06-4.00 (0.5H, m),
3.93-3.80 (2H, m), 3.76-3.68 (2H, m), 2.70-2.61 (2H, m), 2.54-
2.41 (2H, m), 2.20-2.08 (1H, m), 1.96-1.74 (3H, m), 1.64-1.53
(2H, m), 1.41-1.22 (11H, m), 0.88 (3H, t, J=7Hz).
Example 13 6
Ethyl (2R,3R)-8-[N- (2-chloro-4-methylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-470)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2-chloro-4-
methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 10 8 was used in place of ethyl
8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-
6-ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 50%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.56 (1H, dd, J=8Hz, 2Hz) , 7.23-7.21 (1H, m) , 7.11-7.07 (1H, m) ,
7.01 (1H, brs), 6.90 (0.5H, t, J=lHz), 6.84-6.82 (0.5H, m), 4.44
(1H, dd, J=6Hz, 2Hz), 4.27-4.08 (3.5H, m), 4.05-4.00 (0.5H, m),
3.93-3.80 (2H, m), 3.77-3.68 (2H, m), 2.63-2.44 (2H, m), 2.31
(3H, s) , 2.22-1.62 (4H, m) , 1.29-1.23 (3H, m) .
Example 137
Ethyl (2R,3R)-8- [N- (2,4-dichlorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-2499)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N-(2,4-
dichlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 106 was used in place of ethyl
8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-
6-ene-7-carboxylate to give the title compound as an amorphous

substance (yield: 22%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.64 (1H, dd, J=9Hz, 2Hz), 7.41 (1H, d, J=2Hz), 7.28-7.25 (1H,
m), 7.07 (1H, brs), 6.91 (0.5H, t, J=lHz), 6.85 (0.5H, t,
J=lHz), 4.43 (1H, dd, J=6Hz, 2Hz) , 4.26-4.09 (3.5H, m), 4.07-
4.02 (0.5H, m), 3.94-3.81 (2H, m), 3.77-3.68 (2H, m), 2.60-2.47
(2H, m) , 2.24-1.85 (4H, m) , 1.29-1.24 (3H, m) .
Example 138
Ethyl (2R,3R)-8-[N- (2-bromo-4-chlorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2408)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2-bromo-4-
chlorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 93 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 10%).
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.64 (1H, dd, J=9Hz, 3Hz), 7.57 (1H, d, J=2Hz), 7.31 (1H, dd,
J=9Hz, 2Hz), 7.01 (1H, brs), 6.91 (0.5H, s), 6.85 (0.5H, s),
4.45 (1H, d, J=4Hz), 4.26-4.10 (3.5H, m), 4.06-4.02 (0.5H, m),
3.94-3.82 (2H, m), 3.77-3.69 (2H, m), 2.61-2.48 (2H, m), 2.24-
2.15 (1H, m) , 2.02-1.85 (3H, m) , 1.29-1.24 (3H, m) .
Example 139
Ethyl (2R,3R)-8-[N- (2-chloro-6-methylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-

carboxylate (Exemplified compound No. 1-1480)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2-chloro-6-
methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 112 was used in place of ethyl
8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-
6-ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 45%).
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.28 (1H, dd, J=8Hz, 1Hz), 7.23-7.07 (3H, m), 6.93-6.91 (0.5H,
m) , 6.86-6.85 (0.5H, m) , 4.80-4.76 (1H, m) , 4.30-4.17 (3H, m) ,
4.11-4.07 (0.5H, m) , 4.04-4.00 (0.5H, m) , 3.92-3.81 (2H, m) ,
3.75-3.69 (2H, m), 2.59-2.48 (3H, m), 2.42-2.33 (1H, m), 2.26-
2.15 (1H, m) , 2.07 (1H, brs) , 1.94-1.85 (1H, m) , 1.63 (1H, brs) ,
1.29-1.24 (3H, m).
Example 140
Ethyl (2R,3R)-8-[N- (3-chloro-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2366)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8- [N- (3-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-

carboxylate obtained in Example 8 0 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 47%) .
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.47 (1H, dd, J=6Hz, 3Hz) , 7.29-7.25 (1H, m) , 7.17-7.06 (2H, m) ,
6.97 (0.5H, t, J=lHz), 6.93-6.92 (0.5H, m) , 4.33-4.09 (4.5H, m) ,
4.06-4.02 (0.5H, m) , 3.94-3.82 (2H, m) , 3.77-3.68 (2H, m) , 2.48-
2.40 (1H, m), 2.34-2.24 (1H, m), 2.12-2.01 (2H, m), 1.97-1.89
(2H, m), 1.35 (3H, t, J=7Hz).
Example 141
Ethyl (2R,3R)-8-[N- (2-chloro-4,6-
difluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2548)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2-chloro-4,6-
difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 115 was used in place of ethyl
8- [JV- (2-chloro-4-f luorophenyl) sulfamoyl] -1, 4-dioxaspiro [4.5] dec-
6-ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 35%).
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.07-6.85 (4H, m), 4.67 (1H, dd, J=10Hz, 6Hz), 4.32-4.19 (3H,
m) , 4.14-4.02 (1H, m) , 3.93-3.82 (2H, m) , 3.76-3.70 (2H, m) ,
2.66-2.55 (1H, m), 2.43-2.34 (1H, m), 2.28-2.17 (1H, m), 2.06-
1.88 (3H, m) , 1.33-1.29 (3H, m) .

Example 142
Ethyl (212,31?)-8-[N- (2,6-dichloro-4-
fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2555)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2,6-dichloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 116 was used in place of ethyl
8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-
6-ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 25%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.26-7.05 (3H, m), 6.97-6.95 (0.5H, m), 6.90-6.89 (0.5H, m),
4.85-4.80 (1H, m), 4.33-4.19 (3H, m), 4.13-4.08 (0.5H, m), 4.06-
4.02 (0.5H, m), 3.93-3.82 (2H, m), 3.76-3.70 (2H, m), 2.72-2.56
(1H, m), 2.39-2.20 (2H, m), 2.05-1.59 (3H, m), 1.35-1.30 (3H,
m) .
Example 143
Ethyl (21R, 3R) -8- [N- (2-bromo-6-chloro-4-
fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2562)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2-bromo-6-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate obtained in Example 117 was used in place of ethyl
8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-
6-ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 29%).
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.36-7.31 (1H, m) , 7.23-7.19 (1H, m) , 7.16 (1H, brs) , 6.95
(0.5H, s), 6.90-6.88 (0.5H, m), 4.91-4.85 (1H, m), 4.33-4.17
(3H, m), 4.15-4.00 (1H, m), 3.94-3.80 (2H, m), 3.76-3.70 (2H,
m) , 3.55 (1H, brs), 2.70-2.57 (1H, m) , 2.38-2.16 (2H, m) , 1.96-
1.87 (2H, m), 1.35-1.30 (3H, m).
Example 144
Ethyl {2R,3R)-8-[N- (2,4-difluorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-294)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[iV-(2,4-
difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 77 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-
ene-7-carboxylate to give the title compound as an amorphous

substance (yield: 35%) .
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.63-7.56 (1H, m), 7.07 (1H, brs), 6.94-6.85 (3H, m), 4.38-4.34
(1H, m), 4.30-4.08 (3.5H, m), 4.06-4.00 (0.5H, m), 3.93-3.81
(2H, m), 3.78-3.68 (2H, m), 2.53-2.40 (2H, m), 2.38-1.87 (4H,
m) , 1.31-1.27 (3H, m) .
Example 145
Ethyl (2S,3S)-8-[N- (2,4-difluorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(Exemplified compound No. 1-294)

Following the process described in Examples 7, (16a) and
18 (alternative procedure), ethyl 8-[N-(2,4-
difluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 77 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 58%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.62-7.57 (1H, m), 6.93-6.86 (3H, m), 4.37-4.34 (1H, m), 4.29-
4.18 (3H, m), 4.13-4.09 (0.5H, m), 4.06-4.01 (0.5H, m), 3.94-
3.82 (2H, m), 3.76-3.69 (2H, m), 2.53-2.39 (2H, m), 2.21-1.50
(4H, m) , 1.32-1.27 (3H, m) .
Example 146
Ethyl (2R,3R)-8-[N- (2-bromo-4-fluorophenyl)sulfamoyl] -
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-1568)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2-bromo-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 78 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 33%).
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.69-7.64 (1H, m) , 7.33 (1H, dd, J=7Hz, 3Hz) , 7.10-7.05 (1H, m) ,
6.93 (1H, brs), 6.93 (0.5H, s), 6.84 (0.5H, s), 4.44 (1H, d,
J=4Hz) , 4.27-4.09 (3.5H, m) , 4.06-4.01 (0.5H, m) , 3.94-3.80 (2H,
m), 3.77-3.68 (2H, m), 3.54 (1H, brs), 2.61-2.46 (2H, m), 2.23-
2.14 (1H, m) , 2.02-1.85 (2H, m) , 1.29-1.24 (3H, m) .
Example 147
Ethyl (2S,3S)-8-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-1568)

Following the process described in Examples 7, (16a) and
18 (alternative procedure), ethyl 8-[N- (2-bromo-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate obtained in Example 78 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as a white

amorphous substance (yield: 49%) .
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.69-7.65 (1H, m) , 7.33 (1H, dd, J=8Hz, 3Hz) , 7.10-7.06 (1H, m) ,
6.99 (1H, brs), 6.91 (0.5H, s), 6.83 (0.5H, s), 4.44 (1H, d,
J=4Hz) , 4.24-3.73 (8H, m) , 2.61-2.48 (2H, m) , 2.61-2.48 (1H, m) ,
1.96-1.87 (1H, m), 1.26 (3H, t, J=6Hz).
Example 148
Ethyl (2R,3R)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl] -
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-646)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2-butyl-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 85 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as a pale red
amorphous substance (yield: 40%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.51-7.45 (1H, m), 6.97-6.85 (3H, m), 6.65 (0.5H, s), 6.59
(0.5H, s), 4.43-4.36 (1H, m), 4.29-4.16 (3H, m), 4.13-4.08
(0.5H, m), 4.07-4.01 (0.5H, m), 3.95-3.80 (2H, m), 3.77-3.68
(2H, m), 2.78-2.62 (2H, m), 2.53-2.35 (2H, m), 2.19-1.84 (4H,
m), 1.65-1.49 (2H, m), 1.44-1.35 (2H, m), 1.33-1.27 (3H, m),
0.95 (3H, t, J=7Hz).
Example 149
Ethyl (2S,3S)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-

carboxylate (Exemplified compound No. 1-646)

Following the process described in Examples 7, (16a) and
18 (alternative procedure) , ethyl 8-[N- (2-butyl-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 85 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as a pale red
amorphous substance (yield: 14%) .
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.50-7.44 (1H, m), 6.98-6.86 (3H, m), 6.73 (0.4H, s), 6.68
(0.6H, s) , 4.43-4.37 (1H, m) , 4.26-4.16 (3H, m) , 4.11-4.07
(0.4H, m) , 4.05-3.99 (0.6H, m) , 3.90-3.80 (2H, m) , 3.78-3.68
(2H, m), 2.77-2.62 (2H, m), 2.53-2.23 (3H, m), 2.20-2.07 (2H,
m) , 1.96-1.86 (1H, m) , 1.63-1.53 (2H, m) , 1.44-1.34 (2H, m) ,
1.32-1.26 (3H, m), 0.95 (3H, t, J=7Hz).
Example 15 0
Ethyl (2R,3R)-8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate (Exemplified compound No. 1-1744)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (4-fluoro-2-
pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-

carboxylate obtained in Example 86 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as a pale red
amorphous substance (yield: 33%).
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.50-7.43 (1H, m), 6.97-6.85 (3H, m), 6.67 (0.5H, s), 6.61
(0.5H, s), 4.42-4.37 (1H, m), 4.30-4.17 (3H, m), 4.12-4.08
(0.5H, m) , 4.05-4.01 (0.5H, m) , 3.93-3.82 (2H, m) , 3.76-3.68
(2H, m), 2.77-2.61 (2H, m), 2.53-2.35 (2H, m), 2.19-1.80 (4H,
m) , 1.66-1.50 (2H, m) , 1.40-1.22 (7H, m) , 0.95-0.87 (3H, m) .
Example 151
Ethyl (2S,35)-8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-1744)

Following the process described in Examples 7, (16a) and
18 (alternative procedure), ethyl 8-[N- (4-fluoro-2-
pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 86 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as a pale red
amorphous substance (yield: 30%).
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.50-7.42 (1H, m), 6.97-6.84 (3H, m), 6.77 (0.5H, s), 6.72
(0.5H, s), 4.42-4.36 (1H, m), 4.30-4.14 (3H, m), 4.12-4.05
(0.5H, m), 4.04-3.98 (0.5H, m), 3.91-3.77 (2H, m), 3.76-3.67
(2H, m), 2.76-2.59 (2H, m), 2.53-2.20 (4H, m), 2.20-2.06 (1H,
m) , 1.97-1.84 (1H, m) , 1.66-1.52 (2H, m) , 1.41-1.22 (7H, m) ,
0.95-0.88 (3H, m).

Example 152
Ethyl (2R,3R)-8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate (Exemplified compound No. 1-822)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (4-fluoro-2-
hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 87 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 54%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.50-7.45 (1H, m), 6.96-6.86 (3H, m), 6.67 (0.5H, s), 6.61
(0.5H, s), 4.41-4.37 (1H, m), 4.30-4.16 (3H, m), 4.13-4.08
(0.5H, m), 4.06-4.01 (0.5H, m), 3.93-3.81 (2H, m), 3.76-3.69
(2H, m), 2.76-2.61 (2H, m), 2.52-2.36 (2H, m), 2.20-1.50 (6H,
m) , 1.41-1.26 (9H, m) , 0.91-0.86 (3H, m) .
Example 153
Ethyl (2S,3S)-8-[N-(4-fluoro-2-hexylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-822)

Following the process described in Examples 7, (16a) and
18 (alternative procedure), ethyl 8-[N- (4-fluoro-2-
hexylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate obtained in Example 87 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-G-
ene- 7 -carboxylate to give the title compound as an amorphous
substance (yield: 54%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.50-7.44 (1H, m), 6.96-6.86 (3H, m), 6.70-6.67 (0.5H, m), 6.64-
6.61 (0.5H, m) , 4.41-4.37 (1H, m) , 4.29-4.15 (3H, m) , 4.12-4.07
(0.5H, m) , 4.05-4.00 (0.5H, m) , 3.93-3.80 (2H, m) , 3.76-3.68
(2H, m), 2.76-2.61 (2H, m), 2.52-2.35 (2H, m), 2.31-1.51 (6H,
m) , 1.40-1.26 (9H, m) , 0.91-0.86 (3H, m) .
Example 154
Ethyl (2R,3R)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-998)

Following the process described in Example 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (4-fluoro-2-
heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 88 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 41%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.49 (1H, m), 6.96-6.87 (3H, m), 6.68 (0.5H, s), 6.61 (0.5H, s),
4.41-4.40 (1H, m), 4.30-3.71 (8H, m), 2.72-2.65 (2H, m), 2.48-
2.39 (2H, m), 2.14-2.10 (2H, m), 1.95-1.87 (2H, m), 1.37-1.22

(11H, m), 0.88 (3H, t, J=7Hz).
Example 155
Ethyl (2S,3S)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-998)

Following the process described in Examples 7, (16a) and
18 (alternative procedure), ethyl 8-[N- (4-fluoro-2-
heptylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 88 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as a white
amorphous substance (yield: 70%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.50, 7.48 (1H, m), 6.97-6.88 (3H, m), 6.70 (0.5H, s), 6.70
(0.5H, s), 4.41-4.39 (1H, m), 4.28-3.71 (8H, m), 2.75-2.63 (2H,
m) , 2.51-2.37 (2H, m) , 2.19-2.10 (2H, m) , 1.95-1.88 (2H, m) ,
1.35-1.23 (11H, m), 0.88 (3H, t, J=7Hz).
Example 156
Ethyl (2R,3R)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-1920)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8- [N- (4-fluoro-2-
octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 89 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene- 7 -carboxy late to give the title compound as an amorphous
substance (yield: 47%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.51-7.47 (1H, m), 6.97-6.88 (3H, m), 6.71 (0.5H, s), 6.64
(0.5H, s) , 4.41-4.39 (1H, m) , 4.28-3.72 (8H, m) , 2.76-2.62 (2H,
m) , 2.51-2.37 (2H, m) , 2.18-1.89 (4H, m) , 1.37-1.27 (13H, m) ,
0.88 (3H, t, J=7Hz).
Example 157
Ethyl {2S,3S)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-1920)

Following the process described in Examples 7, (16a) and
18 (alternative procedure), ethyl 8- [N- (4-fluoro-2-
octylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 89 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 51%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.97-6.88 (3H, m), 6.69 (0.5H, s),
6.63 (0.5H, s), 4.41-4.39 (1H, m), 4.31-3.70 (8H, m), 2.72-2.66
(2H, m), 2.52-2.37 (2H, m), 2.19-1.88 (4H, m), 1.37-1.27 (13H,
m) , 0.88 (3H, t, J=7Hz) .

Example 158
Ethyl (2R,3R)-8-[N- (4-fluoro-2-nonylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2604)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (4-fluoro-2-
nonylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 90 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 48%) . This compound was separable into two
optical isomers in accordance with the following HPLC
conditions.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Fow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 4.43
minutes
high polarity compound (second peak):
4.73 minutes
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.50-7.45 (1H, m), 6.97-6.86 (3H, m), 6.66 (0.5H, s), 6.60
(0.5H, s), 4.42-4.37 (1H, m), 4.28-4.18 (3H, m), 4.13-4.08

(0.5H, m) , 4.06-4.01 (0.5H, m) , 3.95-3.81 (2H, m) , 3.76-3.69
(2H, m), 2.77-2.61 (2H, m), 2.53-2.35 (2H, m), 2.19-1.99 (2H,
m) , 1.96-1.86 (2H, m) , 1.64-1.52 (2H, m) , 1.40-1.18 (15H, m),
0.91-0.85 (3H, m).
Example 15 9
Ethyl (2S,3S)-8-[N- (4-fluoro-2-nonylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2604)

Following the process described in Examples 7, (16a) and
18 (alternative procedure), ethyl 8-[N- (4-fluoro-2-
nonylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 90 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 54%) . This compound was separable into two
optical isomers in accordance with the following HPLC
conditions.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 4:1
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 6.7
minutes
high polarity compound (second peak):
10.1 minutes

1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.50-7.45 (1H, m) , 6.97-6.86 (3H, m) , 6.71 (0.5H, s) , 6.65
(0.5H, s), 4.42-4.37 (1H, m), 4.30-4.16 (3H, m), 4.13-4.08
(0.5H, m), 4.05-4.00 (0.5H, m), 3.93-3.80 (2H, m), 3.77-3.69
(2H, m), 2.76-2.61 (2H, m), 2.52-2.01 (5H, m), 1.95-1.86 (1H,
m), 1.64-1.52 (2H, m), 1.41-1.22 (15H, m), 0.88 (3H, t, J=7Hz).
Example 160
Ethyl (2R,3R)-8-[N- (2-decyl-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2618)

Following the process described in Examples 7, (16a) and
17 (alternative procedure), ethyl 8-[N- (2-decyl-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 91 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 35%) . This compound was separable into two
optical isomers in accordance with the following HPLC
conditions.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 4.3 0

minutes
high polarity compound (second peak):
4.55 minutes
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.51-7.45 (1H, m), 6.97-6.86 (3H, m), 6.67 (0.5H, s), 6.61
(0.5H, s) , 4.42-4.36 (1H, m) , 4.30-4.17 (3H, m) , 4.13-4.08
(0.5H, m) , 4.06-4.01 (0.5H, m) , 3.94-3.80 (2H, m) , 3.76-3.69
(2H, m), 2.76-2.61 (2H, m), 2.53-2.35 (2H, m), 2.19-2.00 (2H,
m), 1.99-1.86 (2H, m), 1.65-1.51 (2H, m), 1.40-1.18 (17H, m),
0.91-0.85 (3H, m).
Example 161
Ethyl (2S,3S) -8-[N- (2-decyl-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2618)

Following the process described in Examples 7, (16a) and
18 (alternative procedure), ethyl 8-[N- (2-decyl-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 91 was used in place of ethyl 8-
[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 56%). This compound was separable into two
optical isomers in accordance with the following HPLC
conditions.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol =4:1
Flow rate : 1.0 ml/min

Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 6.4
minutes
high polarity compound (second peak): 9.1
minutes
1H-NMR spectrum (5 00MHz, CDCl3) δ ppm:
7.50-7.45 (1H, m), 6.97-6.87 (3H, m), 6.70 (0.5H, s), 6.64
(0.5H, s), 4.42-4.38 (1H, m), 4.30-4.17 (3H, m), 4.12-4.08
(0.5H, m) , 4.05-4.01 (0.5H, m) , 3.93-3.81 (2H, m) , 3.78-3.69
(2H, m), 2.76-2.62 (2H, m), 2.52-2.37 (2H, m) , 2.33-2.09 (2H,
m), 2.06-1.87 (2H, m), 1.63-1.52 (2H, m), 1.40-1.22 (17H, m),
0.88 (3H, t, J=7Hz).
Example 162
Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2 , 3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-382)

Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 17 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 2 5 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a white amorphous substance.
According to the result of HPLC analysis of the two optical
isomers obtained under the conditions below, their optical

purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 4:1
Flow rate : 1.0 ml/min
Temperature : 4 0°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 12.0
minutes
high polarity compound (second peak):
16.5 minutes
(Low polarity compound, first peak)
Optical rotation [α]D+86.7 (c = 2.0, MeOH)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.07-6.98
(2H, m), 6.91 (1H, s), 4.42 (1H, dd, J=6Hz, 2Hz), 4.28-4.08 (4H,
m), 3.91 (1H, dd, J=12Hz, 4Hz), 3.84 (1H, dd, J=12Hz, 4HZ),
3.77-3.68 (2H, m), 2.60-2.43 (2H, m), 2.26-2.11 (1H, m), 1.99-
1.87 (1H, m), 1.58 (2H, bs), 1.27 (3H, t, J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.07-6.98
(2H, m), 6.84 (1H, s), 4.42 (1H, d, J=5Hz), 4.28-4.08 (3H, m),
4.07-4.01 (1H, m), 3.93-3.82 (2H, m), 3.77-3.68 (2H, m), 2.61-
2.46 (2H, m), 2.24-2.11 (1H, m), 1.95-1.87 (1H, m), 1.57 (2H,
bs), 1.27 (3H, t, J=7Hz).
Example 163
Ethyl (2S,3S) -8- [N- (2-chloro-4-fluorophenyl)sulfamoyl] -
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-382)

Ethyl (2S,3S)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2, 3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 18 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a white amorphous substance.
According to the result of HPLC analysis of the two optical
isomers obtained under the conditions below, their optical
purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 4:1
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 11.4
minutes
high polarity compound (second peak):
2 7.4 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.06-7.00
(1H, m) , 6.98 (1H, s) , 6.84 (1H, s) , 4.42 (1H, d, J=5Hz) , 4.27-
4.09 (3H, m), 4.07-4.00 (1H, m), 3.93-3.83 (2H, m), 3.76-3.68
(2H, m), 2.60-2.47 (2H, m), 2.24-2.12 (1H, m), 1.95-1.60 (3H,
m) , 1.27 (3H, t, J=7Hz)..

(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9Hz, 5Hz), 7.17 (1H, dd, J=8Hz, 3Hz), 7.06-6.99
(2H, m), 6.90 (1H, s), 4.44-4.41 (1H, m), 4.27-4.09 (4H, m),
3.91 (1H, dd, J=12Hz, 4Hz), 3.84 (1H, dd, J=12Hz, 4HZ), 3.77-
3.67 (2H, m), 2.60-2.45 (2H, m), 2.24-2.12 (1H, m), 2.00-1.65
(3H, m), 1.27 (3H, t, J=7Hz).
Example 164
Ethyl (2R,3R) -8- [N- (2,4-difluorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(low polarity compound, first peak), (high polarity compound,
second peak) (Exemplified compound No. 1-294)

Ethyl (2R,3R) -8- [N- (2 , 4-dif luorophenyl) sulfamoyl] -2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
obtained in Example 144 was subjected to high performance liquid
chromatography (column; CHIRALPAK AD-H, size; inner diameter 2
cm, length 25 cm, solvent; hexane : 2-propanol) to separate and
purify two optical isomers, and low polarity compound (first
peak) and high polarity compound (second peak) were respectively
obtained as an amorphous substance. According to the result of
HPLC analysis of the two optical isomers obtained under the
conditions below, their optical purities were respectively
>99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 4:1
Flow rate : 1.0 ml/min

Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 13.7
minutes
high polarity compound (second peak):
15.9 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.62-7.57 (1H, m), 6.93-6.87 (3H, m), 4.36 (1H, q, J=3Hz), 4.28-
4.18 (3H, m), 4.15-4.09 (1H, m), 3.91 (1H, dd, J=12Hz, 4Hz),
3.84 (1H, dd, J=12Hz, 4Hz), 3.75-3.70 (2H, m), 2.51-2.40 (2H,
m), 2.20-2.12 (1H, m), 1.96-1.90 (1H, m), 1.61 (2H, brs), 1.29
(3H, t, J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.62-7.57 (1H, m), 6.97 (1H, brs), 6.93-6.86 (3H, m), 4.37-4.35
(1H, m), 4.29-4.17 (3H, m), 4.06-4.02 (1H, m), 3.91-3.84 (2H,
m), 3.76-3.69 (2H, m), 2.53-2.41 (2H, m), 2.20-2.11 (1H, m),
2.05 (1H, brs), 1.94-1.88 (2H, m), 1.29 (3H, t, J=7Hz).
Example 165
Ethyl (2S,3S)-8-[N- (2,4-difluorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
(low polarity compound, first peak), (high polarity compound,
second peak) (Exemplified compound No. 1-294)

Ethyl (2S,3S)-8-[N- (2,4-difluorophenyl)sulfamoyl]-2,3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate
obtained in Example 145 was subjected to high performance liquid
chromatography (column; CHIRALPAK AD-H, size; inner diameter 2

cm, length 25 cm, solvent; hexane : 2-propanol) to separate and
purify two optical isomers, and low polarity compound (first
peak) and high polarity compound (second peak) were respectively
obtained as an amorphous substance. According to the result of
HPLC analysis of the two optical isomers obtained under the
conditions below, their optical purities were respectively
>99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min
Temperature : 4 0°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 6.9
minutes
high polarity compound (second peak):
10.7 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.62-7.57 (1H, m), 6.93-6.86 (3H, m), 4.36 (1H, d, J=4Hz), 4.29-
4.18 (3H, m), 4.06-4.01 (1H, m), 3.91-3.84 (2H, m), 3.75-3.70
(2H, m), 2.52-2.42 (2H, m), 2.19-1.50 (4H, m), 1.29 (3H, t,
J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.62-7.57 (1H, m), 6.93-6.87 (3H, m), 4.36 (1H, dd, J=6Hz, 3Hz),
4.29-4.18 (3H, m), 4.13-4.09 (1H, m), 3.91 (1H, dd, J=12Hz,
4Hz), 3.84 (1H, dd, J=12Hz, 4Hz), 3.75-3.70 (2H, m), 2.51-2.40
(2H, m), 2.20-1.50 (4H, m), 1.29 (3H, t, J=7Hz).
Example 166
Ethyl {2R,3R)-8-[N- (2-bromo-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-

carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-1568)

Ethyl [2R,3R)-8-[N- (2-bromo-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 146 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as an amorphous substance. According
to the result of HPLC analysis of the two optical isomers
obtained under the conditions below, their optical purities were
respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min
Temperature : 4 0°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 6.8
minutes
high polarity compound (second peak): 8.8
minutes
(Low polarity compound, first peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.68 (1H, dd, J=9.2Hz, 5.2Hz), 7.34 (1H, dd, J=7.6Hz, 2.9Hz),
7.11-7.06 (1H, m), 6.91 (1H, s), 4.44 (1H, dd, J=5.8Hz, 2.0Hz),

4.28-4.10 (4H, m), 3.93-3.70 (4H, m), 2.60-2.47 (2H, m), 2.24-
2.14 (1H, m), 1.97-1.92 (1H, m), 1.27 (3H, t, J=7.0Hz).
(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9.2Hz, 5.3Hz), 7.34 (1H, dd, J=7.6Hz, 2.9Hz),
7.11-7.06 (1H, m), 6.85 (1H, s), 4.44 (1H, d, J=5.0Hz), 4.27-
4.02 (4H, m), 3.92-3.84 (2H, m), 3.76-3.70 (2H, m), 2.61-2.48
(2H, m), 2.23-2.15 (1H, m), 1.92-1.88 (1H, m), 1.27 (3H, t,
J=7.2Hz).
Example 167
Ethyl (2S,3S) -8- [N- (2-bromo-4-fluorophenyl)sulfamoyl] -
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-1568)

Ethyl (2S,3S)-8-[N- (2-bromo-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 147 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as an amorphous substance. According
to the result of HPLC analysis of the two optical isomers
obtained under the conditions below, their optical purities were
respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)

Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 6.7
minutes
high polarity compound (second peak):
13.2 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9Hz, 5Hz), 7.33 (1H, dd, J=8Hz, 3Hz), 7.10-7.06
(1H, m) , 6.84 (1H, s) , 4.44 (1H, d, J=5Hz) , 4.24-3.70 (8H, m) ,
2.61-2.48 (2H, m), 2.24-1.87 (2H, m), 1.26 (3H, t, J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9Hz, 5Hz), 7.33 (1H, dd, J=8Hz, 3Hz), 7.10-7.05
(1H, m) , 6.91 (1H, s) , 4.44 (1H, d, J=6Hz) , 4.27-3.69 (8H, m) ,
2.59-2.48 (2H, m), 2.23-1.91 (2H, m), 1.26 (3H, t, J=7Hz).
Example 168
Ethyl (2R,3R)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-646)

Ethyl (2R,3R)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 148 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;

inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a pale red amorphous substance and
a white powder. According to the result of HPLC analysis of the
two optical isomers obtained under the conditions below, their
optical purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol =7:3
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 5.02
minutes
high polarity compound (second peak):
5.24 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.98-6.93 (2H, m), 6.90 (1H, dt,
J=8Hz, 3Hz), 6.67 (1H, s), 4.40 (1H, dd, J=6Hz, 3Hz), 4.29-4.19
(3H, m), 4.13-4.08 (1H, m), 3.92 (1H, dd, J=12Hz, 4Hz), 3.85
(1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m), 2.78-2.62 (2H, m), 2.53-
2.35 (2H, m), 2.19-1.80 (4H, m), 1.65-1.49 (2H, m), 1.44-1.34
(2H, m), 1.31 (3H, t, J=7Hz), 0.95 (3H, t, J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.95 (1H, dd, J=9Hz, 3Hz,), 6.93-6.86
(2H, m) , 6.62 (1H, s) , 4.41 (1H, d, J=4Hz) , 4.28-4.17 (3H, m) ,
4.05-4.01 (1H, m) , 3.91-3.83 (2H, m) , 3.77-3.69 (2H, m), 2.77-
2.62 (2H, m), 2.53-2.35 (2H, m), 2.18-1.76 (4H, m), 1.65-1.50
(2H, m), 1.44-1.35 (2H, m), 1.30 (3H, t, J=7Hz), 0.95 (3H, t,
J=7Hz).

Example 169
Ethyl (2S,35)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-646)

i
Ethyl (2S,3S)-8-[N- (2-butyl-4-fluorophenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate obtained in Example 149 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a white powder and a pale red
amorphous substance. According to the result of HPLC analysis
of the two optical isomers obtained under the conditions below,
their optical purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 5.08
minutes
high polarity compound (second peak):
5.58 minutes
(Low polarity compound, first peak)

1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.47 (1H, dd, J=9Hz, 5Hz), 6.95 (1H, dd, J=9Hz, 3Hz,), 6.93-6.86
(2H, m) , 6.61 (1H, s) , 4.41 (1H, d, J=4Hz) , 4.26-4.16 (3H, m) ,
4.05-3.99 (1H, m), 3.90-3.80 (2H, m), 3.78-3.68 (2H, m), 2.77-
2.62 (2H, m) , 2.53-2.39 (2H, m) , 2.33-2.05 (2H, m) , 1.96-1.86
(1H, m), 1.80-1.65 (1H, m), 1.63-1.52 (2H, m), 1.44-1.35 (2H,
m), 1.29 (3H, t, J=7Hz), 0.95 (3H, t, J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.99-6.86 (3H, m), 6.70 (1H, s), 4.40
(1H, dd, J=6Hz, 3Hz), 4.29-4.17 (3H, m), 4.13-4.07 (1H, m), 3.90
(1H, dd, J=12Hz, 4Hz), 3.84 (1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H,
m), 2.77-2.62 (2H, m), 2.53-2.23 (3H, m), 2.20-2.00 (2H, m),
1.96-1.86 (1H, m), 1.63-1.52 (2H, m), 1.44-1.34 (2H, m), 1.30
(3H, t, J=7Hz), 0.95 (3H, t, J=7Hz).
Example 170
Ethyl (2i?, 3R) -8- [N- (4-f luoro-2-pentylphenyl) sulfamoyl] -
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-1744)

Ethyl (2R,3R) -8- [N- (4-f luoro-2-pentylphenyl) sulfamoyl] -
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 150 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 2 5 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a pale red amorphous substance and

a white powder. According to the result of HPLC analysis of the
two optical isomers obtained under the conditions below, their
optical purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 4.83
minutes
high polarity compound (second peak):
5.01 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.97-6.92 (2H, m), 6.90 (1H, dt,
J=8Hz, 3Hz), 6.66 (1H, s), 4.40 (1H, dd, J=6Hz, 3Hz), 4.28-4.18
(3H, m), 4.14-4.07 (1H, m), 3.92 (1H, dd, J=12Hz, 4Hz), 3.85
(1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.50-
2.35 (2H, m), 2.19-2.08 (1H, m), 1.97-1.87 (1H, m), 1.81-1.49
(4H, m), 1.40-1.32 (4H, m), 1.30 (3H, t, J=7Hz), 0.90 (3H, t,
J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.95 (1H, dd, J=9Hz, 3Hz), 6.93-6.86
(2H, m) , 6.60 (1H, s) , 4.41 (1H, d, J=5Hz) , 4.29-4.17 (3H, m) ,
4.07-4.01 (1H, m), 3.93-3.84 (2H, m), 3.76-3.69 (2H, m), 2.76-
2.61 (2H, m), 2.54-2.36 (2H, m), 2.19-2.07 (1H, m), 2.06-1.70
(3H, m), 1.66-1.50 (2H, m), 1.40-1.32 (4H, m), 1.30 (3H, t,
J=7Hz), 0.90 (3H, t, J=7Hz).
Example 171
Ethyl (2S,3S)-8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]-

2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-1744)

Ethyl (2S,3S)-8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 151 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a white powder and a pale red
amorphous substance. According to the result of HPLC analysis
of the two optical isomers obtained under the conditions below,
their optical purity were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 4.90
minutes
high polarity compound (second peak):
6.18 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.97-6.85 (3H, m), 6.59 (1H, s), 4.40

(1H, d, J=5Hz), 4.29-4.17 (3H, m), 4.06-4.00 (1H, m), 3.91-3.83
(2H, m), 3.76-3.69 (2H, m), 2.76-2.59 (2H, m), 2.53-2.36 (2H,
m) , 2.20-2.06 (1H, m) , 1.94-1.85 (1H, m) , 1.80-1.50 (4H, m) ,
1.41-1.22 (7H, m), 0.91 (3H, t, J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.47 (1H, dd, J=9Hz, 5Hz) , 6.97-6.92 (2H, m) , 6.89 (1H, dt,
J=8Hz, 3Hz), 6.73 (1H, s), 4.40 (1H, dd, J=6Hz, 3Hz), 4.28-4.17
(3H, m), 4.12-4.05 (1H, m), 3.89 (1H, dd, J=12Hz, 4Hz), 3.82
(1H, dd, 12Hz, 4Hz), 3.76-3.69 (2H, m), 2.76-2.61 (2H, m), 2.51-
2.35 (2H, m), 2.26-2.01 (2H, m), 1.97-1.68 (2H, m), 1.66-1.54
(2H, m), 1.41-1.31 (4H, m), 1.29 (3H, t, J=7Hz), 0.90 (3H, t,
J=7Hz).
Example 172
Ethyl (2R, 3R) -8- [N- (4-fluoro-2-hexylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-822)

Ethyl (2R,3R)-8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 152 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as an amorphous substance. According
to the result of HPLC analysis of the two optical isomers
obtained under the conditions below, their optical purities were
respectively >99%ee.

HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 9:1
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 25.2
minutes
high polarity compound (second peak):
2 9.3 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.97-6.87 (3H, m), 6.66 (1H, s),
4.41-4.37 (1H, m), 4.29-4.19 (3H, m), 4.13-4.09 (1H, m), 3.95-
3.88 (1H, m), 3.87-3.81 (1H, m), 3.77-3.69 (2H, m), 2.77-2.62
(2H, m), 2.51-2.36 (2H, m), 2.19-2.09 (2H, m), 1.95-1.89 (2H,
m) , 1.63-1.52 (2H, m) , 1.40-1.28 (9H, m) , 0.91-0.86 (3H, m) .
(High polarity compound, second peak)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.47 (1H, dd, J=9Hz, 5Hz), 6.96-6.86 (3H, m), 6.63 (1H, s),
4.42-4.39 (1H, m), 4.30-4.16 (3H, m), 4.06-4.01 (1H, m), 3.91-
3.83 (2H, m), 3.77-3.69 (2H, m), 2.76-2.61 (2H, m), 2.53-2.37
(2H, m), 2.18-2.08 (2H, m), 2.03-1.98 (1H, m), 1.93-1.86 (1H,
m) , 1.63-1.52 (2H, m) , 1.41-1.26 (9H, m) , 0.91-0.86 (3H, m) .
Example 173
Ethyl (2S,3S)-8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-822)

Ethyl {2S,3S)-8-[N- (4-fluoro-2-hexylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate obtained in Example 153 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as an amorphous substance. According
to the result of HPLC analysis of the two optical isomers
obtained under the conditions below, their optical purities were
respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol =4:1
Flow rate : 1.0 ml/min
Temperature : 4 0°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 7.6
minutes
high polarity compound (second peak):
10.6 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.95 (1H, dd, J=9Hz, 3Hz), 6.92-6.87
(2H, m) , 6.61 (1H, s) , 4.40 (1H, d, J=4Hz) , 4.29-4.17 (3H, m) ,
4.06-4.02 (1H, m), 3.91-3.84 (2H, m), 3.76-3.70 (2H, m), 2.75-
2.62 (2H, m), 2.52-2.46 (1H, m), 2.42 (1H, td, J=14Hz, 3Hz),
2.17-2.09 (1H, m) , 2.05 (1H, dd, J=8Hz, 5Hz) , 1.96-1.87 (2H, m) ,

1.64-1.53 (2H, m) , 1.40-1.27 (9H, m) , 0.91-0.87 (3H, m) .
(High polarity compound, second peak)
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.96-6.93 (2H, m), 6.90 (1H, td,
J=8Hz, 3Hz), 6.67 (1H, m), 4.39 (1H, dd, J=6Hz, 4Hz), 4.30-4.19
(3H, m), 4.13-4.09 (1H, m), 3.91 (1H, dt, J=12Hz, 4Hz), 3.84
(1H, dt, J=12Hz, 4Hz) , 3.76-3.69 (2H, m) , 2.76-2.63 (2H, m) ,
2.50-2.44 (1H, m), 2.40 (1H, td, J=13Hz, 3Hz), 2.18-2.10 (2H,
m) , 1.95-1.89 (2H, m) , 1.63-1.53 (2H, m) , 1.40-1.28 (9H, m) ,
0.91-0.87 (3H, m).
Example 174
Ethyl (2R,3R)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-998)

Ethyl {2R,3R)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 154 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify the two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a white amorphous substance.
According to the result of HPLC analysis of the two optical
isomers obtained under the conditions below, their optical
purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.

inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 9:1
Flow rate : 1.0 ml/min
Temperature : 4 0°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 23.9
minutes
high polarity compound (second peak):
27.4 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=8Hz, 5Hz), 6.96-6.88 (3H, m), 6.67 (1H, s),
4.40-4.38 (1H, m), 4.27-3.69 (8H, m), 2.72-2.62 (2H, m), 2.49-
1.89 (6H, m), 1.34-1.25 (11H, m), 0.88 (3H, t, J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.47 (1H, dd, J=9Hz, 5Hz), 6.96-6.87 (3H, m), 6.64 (1H, brs),
4.40 (1H, d, J=4Hz), 4.29-3.71 (8H, m), 2.75-2.61 (2H, m), 2.51-
2.37 (2H, m), 2.17-1.86 (4H, m), 1.42-1.22 (11H, m), 0.88 (3H,
t, J=7Hz).
Example 175
Ethyl (2S,3S)-8-[N- (4-fluoro-2-heptylphenyl)sulfamoyl]-
2 , 3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-998)

Ethyl (2S,3S)-8-[N-(4-fluoro-2-heptylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 155 was subjected to high

performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a white powder and a white
amorphous substance. According to the result of HPLC analysis
of the two optical isomers obtained under the conditions below,
their optical purities were respectively >99%ee.
HPLC conditions
column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min
Temperature : 4 0°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 4.8
minutes
high polarity compound (second peak): 6.3
minutes
(Low polarity compound, first peak)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.97-6.88 (3H, m), 6.64 (1H, s), 4.41
(1H, d, J=4Hz), 4.27-3.72 (8H, m), 2.75-2.62 (2H, m), 2.51-2.38
(2H, m), 2.18-1.38 (4H, m), 1.38-1.28 (11H, m), 0.88 (3H, t,
J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) 6 ppm:
7.49 (1H, dd, J=9Hz, 5Hz), 6.97-6.88 (3H, m), 6.69 (1H, s),
4.41-4.39 (1H, m), 4.29-3.71 (8H, m), 2.77-2.62 (2H, m), 2.49-
1.90 (6H, m), 1.38-1.29 (11H, m), 0.89 (3H, t, J=7Hz).
Example 176
Ethyl (2R,3R)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-

carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-1920)

Ethyl (21R, 31R) -8- [N- (4-f luoro-2-octylphenyl) sulfamoyl] -
2 , 3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 156 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a white amorphous substance.
According to the result of HPLC analysis of the two optical
isomers obtained under the conditions below, their optical
purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 9:1
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 22.9
minutes
high polarity compound (second peak):
25.8 minutes
(Low polarity compound, first peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz), 6.96-6.88 (3H, m), 6.68 (1H, s),
6.68-4.40 (1H, m), 4.28-3.70 (8H, m), 4.28-3.70 (2H, m), 2.52-

1.89 (6H, m), 1.36-1.19 (13H, m), 0.88 (3H, t, J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
7.46 (1H, dd, J=9Hz, 5Hz), 6.95-6.87 (3H, m), 4.40 (1H, d,
J=5Hz) , 4.28-3.71 (8H, m) , 2.73-2.60 (2H, m) , 2.50-1.87 (6H, m) ,
1.31-1.25 (13H, m), 0.89 (3H, t, J=7Hz).
Example 177
Ethyl (2S,3S)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-1920)

Ethyl (2S,35)-8-[N- (4-fluoro-2-octylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 157 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a white powder and a colorless
oil. According to the result of HPLC analysis of the two
optical isomers obtained under the conditions below, their
optical purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min

Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 4.7
minutes
high polarity compound (second peak): 6.1
minutes
(Low polarity compound, first peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.48 (1H, dd, J=9Hz, 5Hz) , 6.97-6.88 (3H, m), 6.63 (1H, s), 4.41
(1H, d, J=5Hz), 4.28-3.71 (8H, m), 2.75-2.62 (2H, m), 2.51-1.88
(6H, m), 1.38-1.27 (13H, m), 0.88 (3H, t, J=7Hz).
(High polarity compound, second peak)
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=9Hz, 6Hz) , 6.97-6.88 (3H, m) , 6.97-6.88 (1H, m) ,
4.41-4.38 (1H, m), 4.31-3.71 (8H, m), 2.77-2.63 (2H, m), 2.50-
1.90 (6H, m), 2.50-1.90 (13H, m), 0.88 (3H, t, J=7Hz).
Example 178
Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate

Following the process described in Example (17a), 1,4-di-
O-methyl-2,3-di-O-trimethylsilyl-D-threitol was used in place of
1, 4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the
title compound as a colorless oil (yield: 89%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.68-7.64 (1H, m), 7.16 (1H, dd, J=8.1Hz, 3.0Hz), 7.17-7.16 (3H,
m) , 4.39 (1H, d, J=3.5Hz), 4.24-3.98 (4H, m) , 3.43-3.42 (4H, m) ,
3.43 (1.5H, s), 3.42 (1.5H, s), 3.39 (1.5H, s), 3.38 (1.5H, s),

2.57-2.45 (2H, m) , 2.57-2.45 (1H, m) , 1.96-1.86 (1H, m) , 1.27
(3H, dt, J=6.9Hz, 2.1Hz).
Example 179
Ethyl (2S,3S)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2,3-bis(methoxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate

Following the process described in Example (17a), 1,4-di-
O-methyl-2,3-di-O-trimethylsilyl-1-threitol was used in place of
1,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the
title compound as a colorless oil (91% yield).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.68-7.64 (1H, m), 7.16 (1H, dd, J=7.8 and 2.4Hz), 7.04-7.00
(2H, m), 6.89 (1H, s), 4.40-4.39 (1H, m), 4.23-3.97 (4H, m),
3.62-3.47 (4H, m), 3.43 (1.5H, s), 3.41 (1.5H, s), 3.39 (1.5H,
s), 3.38 (1.5H, s), 2.58-2.45 (2H, m), 2.26-2.16 (1H, m), 1.96-
1.86 (1H, m), 1.26 (3H, dt, J=7.0 and 3.5Hz).
Example 180
Ethyl (2S,3S)-2,3-bis(benzyloxymethyl)-8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate

Following the process described in Example (17a), 1,4-di-

O-benzyl-2,3-di-O-trimethylsilyl-1-threitol was used in place of
l,4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give the
title compound as a colorless oil (yield: 94%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.69-7.64 (1H, m), 7.37-7.26 (10H, m), 7.16 (1H, dd, J=7.8Hz,
2.8Hz), 7.04-6.90 (3H, m), 4.64-4.51 (4H, m), 4.40 (1H, t,
J=4.5Hz), 4.30-4.05 (4H, m), 3.68-3.57 (4H, m), 2.58-2.45 (2H,
m) , 2.25-2.17 (1H, m), 1.96-1.86 (1H, m) , 1.21 (3H, dt, J=7.0Hz,
3.5Hz) .
Example 181
Ethyl (2R,3R)-2,3-bis(acetoxymethyl)-8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate

Following the process described in Example (17a), 1,4-di-
O-acetyl-2,3-di-O-trimethylsilyl-D-threitol obtained in
Reference Example 24 was used in place of l,4-di-O-benzoyl-2,3-
di-O-trimethylsilyl-D-threitol to give the title compound as a
white amorphous substance (50% yield).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.67 (1H, dd, J=9.2Hz, 5.3Hz), 7.17 (1H, dd, J=7.9Hz, 2.8Hz),
7.05-7.00 (2H, m), 6.90-6.76 (1H, m), 4.41 (1H, d, J=4.7Hz),
4.37-4.37 (8H, m), 2.60-2.46 (2H, m), 2.23-2.04 (8H, m), 1.26
(3H, t, J=7.0Hz).
Example 182
Ethyl (2S,3S)-2,3-bis(acetylaminomethyl)-8-[N- (2-chloro-
4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-410)

218 mg (1.07 mmol) of N- (4-acetylamino-2R, 3R-
dihydroxybutyl)acetamide and 0.57 ml (3.20 mmol) of
isopropoxytrimethylsilane were dissolved in 3 ml of
nitromethane, and 13 µl (0.071 mmol) of trimethylsilyl
trifluoromethanesulfonate and 300 mg (0.711 mmol) of ethyl 6-[N-
(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-
1-carboxylate obtained in Example (16a) were sequentially added
thereto with stirring under ice-cooling, followed by stirring
for 3 hours at the same temperature and then for 116 hours at
room temperature. To the reaction solution was added saturated
aqueous sodium hydrogencarbonate and the mixture was extracted
with ethyl acetate. The organic layer was washed with water and
dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; ethyl acetate :
methanol =9:1) to give 203 mg of the title compound as an
amorphous substance (yield: 51%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.68-7.63 (1H, m), 7.20-7.15 (1H, m), 7.08-7.00 (2H, m), 6.78-
6.73 (1H, m), 6.46-6.38 (1H, m), 6.34-6.26 (1H, m), 4.42-4.39
(1H, m), 4.29-4.14 (2H, m), 3.96-3.85 (1.5H, m), 3.75-3.69
(0.5H, m), 3.61-3.42 (4H, m), 2.55-2.43 (2H, m), 2.21-2.01 (7H,
m) , 1.90-1.78 (1H, m) , 1.31-1.25 (3H, m) .
Example 183
Ethyl (2i?,3i?) -8- [N- (2-chloro-4-f luorophenyl) sulfamoyl] -
2,3-bis((R)-1-hydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2163)

Following the process described in Example 17 (alternative
procedure) , (1R, 2R, 3R, 4R) -4-benzoyloxy-1-methyl-2,3 -
bis[(trimethylsilyl)oxy]pentyl benzoate obtained in Reference
Example 25 was used in place of 1,4-di-O-benzoyl-2,3-di-O-
trimethylsilyl-D-threitol to give the title compound as a white
amorphous substance (yield: 3 3%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.66 (1H, dd, J=9.0 and 5.0Hz), 7.17 (1H, dd, J=7.8 and 2.7Hz),
7.09 (1H, d, J=9.0Hz), 7.05-7.00 (1H, m), 6.80 (0.5H, s), 6.76
(0.5H, s), 4.39 (1H, d, J=5.4Hz), 4.27-4.09 (2H, m), 3.88-3.56
(4H, m), 2.50-2.42 (2H, m), 2.19-2.11 (1H, m), 1.85-1.79 (1H,
m), 1.33 (3H, t, J=5.3Hz), 1.27 (6H, t, J=7.0Hz).
Example 184
Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2,3-bis((R)-1-hydroxypropyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2164)

Following the process described in Example 17
(alternative procedure) , (1R, 2R, 3R,4R) -4-benzoyloxy-1-ethyl-2 , 3-
bis[(trimethylsilyl)oxy]hexyl benzoate obtained in Reference
Example 26 was used in place of 1,4-di-O-benzoyl-2,3-di-O-
trimethylsilyl-D-threitol to give the title compound as a white
amorphous substance (yield: 21%) .

1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.68 (1H, dd, J=9.2Hz, 5.2Hz), 7.18 (1H, dd, J=7.4Hz, 2.4Hz),
7.06-7.01 (2H, m), 6.81 (0.5H, s), 6.78 (0.5H, s), 4.40 (1H, d,
J=5.1Hz), 4.29-4.12 (2H, m), 3.88-3.55 (4H, m), 3.03 (1H, brs),
2.92 (1H, brs), 2.51-2.41 (2H, m), 2.21-2.13 (2H, m), 1.90-1.73
(1H, m), 1.55-1.43 (3H, m), 1.29 (3H, t, J=7.2Hz), 1.05-0.97
(6H, m) .
Example 18 5
Ethyl (3a' R,6a'R,6'R) -4-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-6'-hydroxymethyl-4'-oxo-3a',4',6',6a'-
tetrahydrospiro[cyclohex-2-ene-l,2'-furo[3.4-d][1.3]dioxol]-3-
carboxylate (Exemplified compound No. 1-2165)

Following the process described in Example (17a),
(3R,4R,5R)-3,4-bis[(trimethylsilyl)oxy]-5-
[(trimethylsilyl)oxy]methyldihydrofuran-2-one was used in place
of 1, 4-di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol to give
the title compound as a white amorphous substance (yield: 25%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
7.69-7.64 (1H, m), 7.20-7.16 (1H, m), 7.06-6.96 (2H, m), 6.82-
6.68 (1H, m), 5.04-4.62 (3H, m), 4.44-4.40 (1H, m), 4.26-4.14
(2H, m), 4.05-3.98 (1H, m), 3.90-3.81 (1H, m), 2.74-2.46 (2H,
m) , 2.24-2.12 (1H, m) , 1.97-1.83 (2H, m) , 1.30-1.26 (3H, m) .
Example 186
Ethyl (2J?,3i?) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -
2, 3-bis((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (low polarity compound, first peak), (high polarity
compound, second peak) (Exemplified compound No. 1-386)

Ethyl (2R,3R)-8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-
2,3-bis((1R)-1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 23 was subjected to high
performance liquid chromatography (column; CHIRALPAK AD-H, size;
inner diameter 2 cm, length 25 cm, solvent; hexane : 2-propanol)
to separate and purify two optical isomers, and low polarity
compound (first peak) and high polarity compound (second peak)
were respectively obtained as a white amorphous substance.
According to the result of HPLC analysis of the two optical
isomers obtained under the conditions below, their optical
purities were respectively >99%ee.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 7:3
Flow rate : 1.0 ml/min
Temperature : 4 0°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 7.3
minutes
high polarity compound (second peak): 9.9
minutes
(Low polarity compound, first peak)
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.65 (1H, dd, J=9Hz, 5Hz), 7.21 (1H, bs), 7.17 (1H, dd, J=8Hz,
3Hz), 7.06-6.99 (1H, m), 6.80 (1H, s), 4.38 (1H, d, J=5Hz),
4.27-4.12 (4H, m), 4.08 (2H, d, J=7Hz), 3.95-3.88 (1H, m), 3.87-

3.64 (5H, m), 2.98-2.68 (2H, m), 2.54-2.42 (2H, m), 2.22-2.08
(1H, m) , 1.91-1.82 (1H, m) , 1.25 (3H, t, J=7Hz) .
(High polarity compound, second peak)
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.63 (1H, dd, J=9Hz, 5Hz), 7.15 (1H, bs), 7.12 (1H, dd, J=8Hz,
3Hz), 7.05-6.97 (1H, m), 6.76 (1H, s), 4.37 (1H, d, J=6Hz),
4.27-4.01 (5H, m), 3.97-3.86 (2H, m), 3.85-3.45 (5H, m), 2.77-
2.57 (2H, m), 2.52-2.41 (2H, m), 2.21-2.08 (1H, m), 1.89-1.80
(1H, m), 1.26 (3H, t, J=7Hz).
Example 18 7
Ethyl-(2R,3R)-8-[N- (2-chloro-4-fluorophenyl)-N-
methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-
6-ene-7-carboxylate (Exemplified compound No. 2-15)

235 mg (0.49 mmol) of ethyl (2R,3R)-8-[N- (2-chloro-4-
fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro [4.5]dec-6-ene-7-carboxylate obtained in Example 17
was dissolved in 1.5 ml of acetone, and 84 mg (0.59 mmol) of
methyl iodide and 13 8 mg (1.00 mmol) of potassium carbonate were
added sequentially, followed by stirring for 3 hours at 50°C.
After the reaction solution was filtered, the filtrate was
concentrated under reduced pressure, and the residue was
subjected to silica gel column chromatography (solvent; hexane :
ethyl acetate = 1:3) to give 175 mg of the title compound as a
white amorphous substance (yield: 73%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.57 (1H, brs) , 7.22 (1H, dd, J=8Hz, 3Hz) , 7.05-7.00 (1H, m) ,
6.87 (0.5H, s), 6.79 (0.5H, s), 4.58 (1H, brs), 4.28-3.73 (8H,
m), 3.25 (3H, s), 2.60-1.80 (6H, m), 1.26 (3H, t, J=7Hz).

Example 188
Ethyl 8-[N- (4-fluoro-2-propylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate (Exemplified compound No.
1-2077)

Following the process described in Example (1d), 4-
fluoro-2-propylphenylamine obtained in Reference Example 27 was
used in place of 2-chloro-4-fluoroaniline to give the title
compound as an oil (yield: 84%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
8.09-8.07 (4H, m) , 7.59-7.55 (2H, m) , 7.47-7.43 (4H, m) , 7.47-
7.43 (2H, m), 3.96 (2H, s), 2.00-1.79 (4H, m), 1.02 (6H, t,
J=7Hz), 0.07 (18H, s).
Example 18 9
Ethyl (2S,3S)-8-[N- (4-fluoro-2-propylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2095)

Following the process described in Examples 7, (16a) and
18 (alternative procedure), ethyl 8-[N- (4-fluoro-2-
propylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 188 was used in place of ethyl
8-[N- (2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-
6-ene-7-carboxylate to give the title compound as a white

amorphous substance (38% yield). This compound was separable
into two optical isomers in accordance with the following HPLC
conditions.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 4:1
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 9.6
minutes
high polarity compound (second peak):
14.1 minutes
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.51-7.47 (1H, m), 6.97-6.88 (3H, m), 6.70 (0.5H, s), 6.64
(0.5H, s), 4.42-4.39 (1H, m), 4.28-3.72 (8H, m), 2.75-2.61 (2H,
m) , 2.52-2.37 (2H, m) , 2.19-1.87 (4H, m) , 1.68-1.57 (2H, m) ,
1.32-1.28 (3H, m), 0.99 (3H, t, J=8Hz).
Example 190
Ethyl (2R,3R) -2,3-bis ( (1R) -1, 2-dihydroxyethyl) -8- [N- (4-
fluoro-2-pentylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-1748)

Following the process described in Examples 7, (16a) and
23, ethyl 8-[N- (4-fluoro-2-pentylphenyl)sulfamoyl]-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate obtained in Example 86

was used in place of ethyl 8- [N- (2-chloro-4-
fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5] dec-6-ene-7-
carboxylate to give the title compound as a white powder (yield:
33%) . This compound was separable into two optical isomers in
accordance with the following HPLC conditions.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol =7:3
Flow rate : 1.0 ml/min
Temperature : 40°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 5.2 9
minutes
high polarity compound (second peak):
5.82 minutes
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.49-7.44 (1H, m), 6.97-6.86 (2H, m), 6.84 (0.5H, m), 6.82
(0.5H, m) , 6.73 (0.5H, s), 6.69 (0.5H, s), 4.41-4.36 (1H, m) ,
4.27-4.17 (2H, m), 4.12-4.01 (1.5H, m), 3.97-3.88 (1.5H, m),
3.88-3.67 (5H, m), 2.77-2.60 (2H, m), 2.50-2.30 (2H, m), 2.20-
1.40 (8H, m) , 1.39-1.25 (7H, m) , 0.93-0.86 (3H, m) .
Example 191
Ethyl (2S,35)-8-[N- (4-fluoro-2-methylphenyl)sulfamoyl]-
2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate (Exemplified compound No. 1-2359)

Following the process described in Examples 7, (16a) and

18 (alternative procedure), ethyl 8- [N- (4-fluoro-2-
methylphenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-
carboxylate obtained in Example 79 was used in place of ethyl 8-
[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-
ene-7-carboxylate to give the title compound as an amorphous
substance (yield: 49%) . This compound was separable into two
optical isomers in accordance with the following HPLC
conditions.
HPLC conditions
Column : CHIRALPAK AD-H (produced by Daicel
Chemical Industries, Ltd.
inner diameter 0.46 cm, length 25 cm)
Mobile phase : hexane : 2-propanol = 4:1
Flow rate : 1.0 ml/min
Temperature : 4 0°C
Detection : 254 nm (UV)
Retention time : low polarity compound (first peak): 13.5
minutes
high polarity compound (second peak):
19.6 minutes
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.49 (1H, dd, J=8.8Hz, 5.3Hz), 6.96-6.88 (3H, m), 6.70 (0.5H,
brs) , 6.64 (0.5H, brs) , 4.40-4.37 (1H, m) , 4.28-3.70 (8H, m) ,
2.51-2.32 (5H, m) , 2.21-1.87 (2H, m) , 1.31-1.27 (3H, m) .
[Reference Examples]
Reference Example 1
1,4-Di-O-benzoyl-2,3-di-O-trimethylsilyl-meso-erythritol
300 mg (0.90 mmol) of 1,4-di-O-benzoyl-meso-erythritol
(compound described in J. Am. Chem. Soc., 82, 2585 (I960)), 0.28
ml (1.98 mmol) of triethylamine and 11 mg (0.09 mmol) of 4-
dimethylaminopyridine were dissolved in 6 ml of dichloromethane,
and 0.24 ml (1.89 mmol) of trimethylsilyl chloride was added
thereto with stirring under ice-cooling, followed by stirring
for 2 hours at the same temperature. To the reaction solution
was added saturated aqueous sodium hydrogencarbonate and the

mixture was extracted with ethyl acetate. The organic layer was
washed with water and dried over anhydrous sodium sulfate,
followed by concentration under reduced pressure. The residue
was subjected to silica gel column chromatography (solvent;
ethyl acetate alone) to give 418 mg of the title compound as a
white powder (yield: 98%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
8.04 (4H, d, J=7Hz) , 7.55 (2H, t, J=7Hz) , 7.43 (4H, t, J=7Hz) ,
4.53 (2H, dd, J=12Hz, J=3Hz), 4.36 (2H, dd, J=12Hz, 5Hz), 4.13-
4.08 (2H, m) 0.13 (18H, s).
Reference Example 2
1,3,4,5,7-Penta-O-trimethylsilyl-D-arabitol
Following the process described in Reference Example 1, D-
arabitol was used in place of 1,4-di-O-benzoyl-meso-erythritol
to give the title compound as a colorless oil (yield: 26%).
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
3.84-3.80 (1H, m) , 3.76-3.68 (3H, m) , 3.63-3.54 (2H, m) , 3.49
(1H, dd, J=10Hz, J=7Hz), 0.14-0.09 (45H, m).
Reference Example 3
1,6-Di-O-benzoyl-2,3,4,5-tetra-O-trimethylsilyl-D-
mannitol
Following the process described in Reference Example 1,
1,6-di-O-benzoyl-D-mannitol was used in place of 1,4-di-O-
benzoyl-meso-erythritol to give the title compound as a pale
brown oil (yield: 98%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
8.05 (4H, d, J=7Hz), 7.55 (2H, t, J=7Hz), 7.43 (4H, t, J=7Hz),
4.59 (2H, dd, J=12Hz, 2Hz), 4.38-4.31 (2H, m), 4.24-4.20 (2H,
m), 3.83 (2H, br.s), 0.17 (18H, s), 0.11 (18H, s).
Reference Example 4
2-Trimethylsilyloxy-1-trimethylsilyloxymethylethyl
adamantane-1-carboxylate

(4a) 2-Phenyl[1.3]dioxan-5-ol adamantane-1-carboxylate
1.00 g (5.55 mmol) of 2-phenyl[1.3]dioxan-5-ol, 1.16 ml
(8.32 mmol) of triethylamine and 68 rag (0.56 mmol) of 4-
dimethylaminopyridine were dissolved in 2 0 ml of
dichloromethane, and 1.28 g (6.10 mmol) of 1-adamantanecarbonyl
chloride was added thereto with stirring under ice-cooling,
followed by stirring for 3 0 minutes at the same temperature, and
then further for 15 hours at room temperature. Dichloromethane
was distilled off under reduced pressure, and to the residue was
added aqueous sodium hydrogencarbonate and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate = 9:1) to give 1.52 g of the title compound as a pale
yellow powder (yield: 80%) .
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.52-7.48 (2H, m), 7.42-7.33 (3H, m), 5.54 (1H, s), 4.68-4.66
(1H, m), 4.26-4.22 (2H, m), 4.18-4.13 (2H, m), 2.07-2.01 (3H,
m), 2.01-1.97 (6H, m), 1.77-1.69 (6H, m).
(4b) 2-Hydroxy-1-hydroxymethylethyl adamantane-1-
carboxylate
400 mg (1.17 mmol) of 2-phenyl[1.3]dioxan-5-yl
adamantane-1-carboxylate obtained in (4a) was dissolved in 8 ml
of ethyl acetate and 400 mg of 20% palladium hydroxide-carbon
(water content: 50%) was added thereto, followed by stirring for
4 hours under hydrogen atmosphere at room temperature. After
the catalyst was filtered, the filtrate was concentrated under
reduced pressure to give 2 94 mg of the title compound as a white
powder (yield: 99%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.90-4.85 (1H, m), 3.84-3.76 (4H, m), 2.16-2.00 (5H, m), 1.94-
1.87 (6H, m) , 1.78-1.67 (6H, m) .
(4c) 2-Trimethylsilyloxy-1-trimethylsilyloxymethylethyl
adamant ane-1-c arboxylate
Following the process described in Reference Example 1,

2-hydroxy-1-hydroxymethylethyl adamantane-1-carboxylate obtained
in (4b) was used in place of 1,4-di-O-benzoyl-meso-erythritol to
give the title compound as a colorless oil (yield: 70%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.85-4.79 (1H, m), 3.72-3.61 (4H, m), 2.04-1.97 (3H, m), 1.92-
1.83 (6H, m), 1.76-1.65 (6H, m), 0.11 (18H, s).
Reference Example 5
Diethyl 2,2-bis[(trimethylsilyl)oxy]methylmalonate
Following the process described in Reference Example 1,
diethyl 2,2-bis(hydroxymethyl)malonate was used in place of 1,4-
di-O-benzoyl-meso-erythritol to give the title compound as a
colorless oil (yield: 75%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.17 (4H, q, J=7Hz), 4.04 (4H, s), 1.23 (6H, t, J=7Hz), 0.07
(18H, s) .
Reference Example 6
2 -Pentyl-1H- pyrrol-1-ylamine
(6a) (2£)-4-Oxo-2-nonenal
2.0 g (14.47 mmol) of 2-pentylfuran was dissolved in 60
ml of dichloromethane, and 3.84 g (14.47 mmol) of 65% m-
chloroperbenzoic acid was added dropwise thereto with stirring
under ice-cooling, followed by stirring for 1 hour at the same
temperature. To the reaction solution was added saturated
aqueous sodium carbonate and the mixture was extracted with
dichloromethane. The organic layer was washed with water, dried
over anhydrous magnesium sulfate, and was then concentrated
under reduced pressure to give 1.62 g of the title compound as a
yellow oil (yield: 73%).
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
10.23 (1H, d, J=7Hz), 6.95 (1H, d, J=12Hz), 6.18 (1H, dd,
J=12Hz, 7Hz), 2.26 (2H, t, J=7Hz), 1.73-1.61 (2H, m), 1.40-1.26
(4H, m), 0.91 (3H, t, J=6Hz).
(6b) 4 -Oxononanal

1.62 g (10.5 mmol) of (2E) -4-oxo-2-nonenal obtained in
(6a) was dissolved in 30 ml of ethyl acetate, and 160 mg of 10%
palladium-carbon (water content: 50%) was added thereto,
followed by restirring for 2 hours under hydrogen atmosphere at
room temperature. After the catalyst was filtered, the filtrate
was concentrated under reduced pressure to give 1.50 g of the
title compound as a pale yellow oil (91% yield).
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
9.81 (1H, s), 2.81-2.67 (4H, m), 2.47 (2H, t, J=7HZ), 1.67-1.53
(2H, m), 1.38-1.21 (4H, m), 0.89 (3H, t, J=7Hz).
(6c) Benzyl 2-pentyl-1H-pyrrol-1-ylcarbamate
1.5 0 g (9.60 mmol) of 4-oxononanal obtained in (6b) was
dissolved in 45 ml of ethanol-acetic acid (2:1) solution
mixture, and 1.60 g (9.60 mmol) of benzyl hydrazinecarboxylate
was added thereto, followed by stirring for 1 hour at 8 0°C. The
reaction solution was concentrated under reduced pressure, and
the residue was subjected to silica gel column chromatography
(solvent; hexane : ethyl acetate =2:1) to give 2.12 g of the
title compound as a yellow oil (77% yield).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
7.36 (5H, bs), 7.21 (1H, ds), 6.63-6.59 (1H, m), 6.07 (1H, t,
J=4Hz) , 5.89-5.84 (1H, m) , 5.22 (2H, ds) , 2.46-2.36 (2H, m) ,
1.63-1.49 (2H, m), 1.37-1.22 (4H, m), 0.88 (3H, t, J=7Hz).
(6d) 2 -Pentyl-1H- pyrrole-1-amine
1.0 g (3.49 mmol) of benzyl 2-pentyl-1H-pyrrol-1-
ylcarbamate obtained in (6c) was dissolved in 2 0 ml of ethanol,
and 100 mg of 10% palladium-carbon (water content: 50%) was
added thereto, followed by stirring for 2 hours under hydrogen
atmosphere at room temperature. After the catalyst was
filtered, the filtrate was concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography
(solvent; hexane : ethyl acetate = 2:1) to give 430 mg of the
title compound as a yellow oil (yield: 81%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
6.68 (1H, m), 5.97 (1H, t, J=3Hz), 5.82-5.77 (1H, m), 4.52 (2H,

s), 2.58 (2H, t, J=8Hz), 1.69-1.57 (2H, m), 1.44-1.31 (4H, m),
0.91 (3H, t, J=7Hz).
Reference Example 7
2-Hexyl-1H- pyrrol-1-ylamine
Following the procedure described in Reference Example 6,
2-hexylfuran was used as the starting material in place of 2-
pentylfuran to give the title compound as a yellow oil (yield:
29%) .
1H-NMR spectrum (4 0 0MHz, CDCl3) δ ppm:
6.67-6.63 (1H, m), 5.99-5.94 (1H, m), 5.81-5.77 (1H, m), 4.52
(2H, br.s), 2.62-2.55 (2H, m), 1.67-1.56 (2H, m), 1.44-1.21 (6H,
m), 0.89 (3H, t, J=7Hz).
Reference Example 8
2-Heptyl-1H- pyrrol-1-ylamine
Following the procedure described in Reference Example 6,
2-heptylfuran was used as the starting material in place of 2-
pentylfuran to give the title compound as a pale yellow soild
(yield: 59%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
6.67-6.63 (1H, m), 5.99-5.94 (1H, m), 5.81-5.77 (1H, m), 4.52
(2H, br.s), 2.62-2.55 (2H, m), 1.67-1.53 (2H, m), 1.44-1.21 (8H,
m), 0.89 (3H, t, J=7Hz).
Reference Example 9
2-Octyl-1H- pyrrol-1-ylamine
Following the procedure described in Reference Example 6,
2-octylfuran was used as the starting material in place of 2-
pentylfuran to give the title compound as a yellow oil (yield:
11%) .
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
6.65-6.61 (1H, m), 5.97-5.93 (1H, m), 5.78-5.75 (1H, m), 4.51
(2H, br.s), 2.60-2.55 (2H, m), 1.66-1.54 (2H, m), 1.42-1.21
(10H, m), 0.88 (3H, t, J=7Hz).

Reference Example 10
2-Cyclopropyl-1H- pyrrol-1-ylamine
(10a) 4-Cyclopropyl-4-oxobutanal
230 mg (1.79 mmol) of 1-cyclopropyl-4-hydroxy-1-butanone
was dissolved in 7 ml of dichloromethane, and 580 mg (2.69 mmol)
of pyridinium chlorochromate was added thereto,followed by
stirring for 1 hour at room temperature. To the reaction
solution was added diethyl ether, the mixture was filtered using
Celite, and the filtrate was concentrated under reduced
pressure. The residue was subjected to silica gel column
chromatography (solvent; diethyl ether alone) to give 176 mg of
the title compound as a pale yellow oil (yield: 78%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
9.78 (1H, s), 2.91 (2H, t, J=7Hz), 2.78-2.71 (2H, m), 2.01-1.93
(1H, m) , 1.08-1.01 (2H, m) , 0.96-0.88 (2H, m) .
(10b) 2-Cyclopropyl-1H- pyrrol-1-ylamine
Following the procedures described in Reference Examples
(6c) and (6d), 4-cyclopropyl-4-oxobutanal obtained in (10a) was
used in place of 4-oxononanal to give the title compound as a
pale yellow oil (yield: 45%) .
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
6.70-6.64 (1H, m), 5.94-5.88 (1H, m), 5.71-5.64 (1H, m), 4.69
(2H, br.s), 1.83-1.72 (1H, m), 0.91-0.83 (2H, m), 0.64-0.57 (2H,
m) .
Reference Example 11
4 -Fluoro-2-heptylphenylamine
(11a) 4-Fluoro-2-(hept-1-enyl)-1-nitrobenzene
3.0 g (7.0 mmol) of hexyltriphenylphosphonium bromide was
suspended in 30 ml of tetrahydrofuran, and 4.5 ml (7.0mmol) of
n-butyl lithium/hexane solution (1.56 M) was added dropwise
thereto at -10°C. After the reaction solution was stirred for 10
minutes at the same temperature, 846 mg (5.0 mmol) of 4-fluoro-
2-nitrobenzaldehyde was added, and the reaction solution was

further stirred for 1 hour. To the reaction solution was added
IN aqueous potassium hydrogensulfate and the mixture was
extracted with ethyl acetate. The organic layer was washed
sequentially with saturated aqueous sodium hydrogencarbonate and
water and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate = 19:1) to give 917 mg of the title compound as a pale
yellow oil (yield: 77%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
8.09 (1.7H, dd, J=9Hz, 5Hz), 7.97 (1H, dd, J=9Hz, 5Hz), 7.26-
6.99 (5.4H, m), 6.89 (1H, d, J=16Hz), 6.69 (1.7H, d, J=llHz),
6.26 (1H, dt, J=16Hz, 7Hz), 5.87 (1.7H, dt, J=12Hz, 8Hz), 2.28
(2H, q, J=7Hz), 2.10 (3.4H, q, J=7Hz), 1.52-1.23 (16.2H, m),
0.91 (3H, m), 0.86 (5.1H, m).
(11b) 4-Fluoro-2-heptylphenylamine
910 mg (3.8 mmol) of 4-fluoro-2-(hept-1-enyl)-1-
nitrobenzene obtained in (11a) was dissolved in 5 ml of ethanol,
and 100 mg of 10% palladium-carbon (water content: 50%) was
added thereto, followed by stirring for 2 hours under hydrogen
atmosphere at room temperature. After the catalyst was
filtered, the filtrate was concentrated under reduced pressure,
and the residue was subjected to silica gel column
chromatography (solvent; hexane : ethyl acetate =9:1) to give
730 mg of the title compound as a pale yellow oil (yield: 91%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
6.80-6.71 (2H, m), 6.61 (1H, dd, J=9Hz, 5Hz), 3.47 (2H, brs),
2.45 (2H, t, J=7Hz), 1.64-1.58 (2H, m), 1.42-1.24 (8H, m), 0.89
(3H, t, J=6Hz).
Reference Example 12
2-Butyl-4-fluorophenylamine
Following the procedure described in Reference Example
11, propyltriphenylphosphonium bromide was used in place of
hexyltriphenylphosphonium bromide to give the title compound as
a brown oil (yield: 78%) .

1H-NMR spectrum (40 0MHz, CDCl3) 5 ppm:
6.80-6.69 (2H, m), 6.60 (1H, dd,, J=9Hz, 5Hz), 3.51 (2H, bs),
2.46 (2H, t, J=8Hz), 1.63-1.56 (2H, m), 1.45-1.37 (2H, m), 0.96
(3H, t, J=7Hz).
Reference Example 13
4 -Fluoro-2-pentylphenylamine
Following the procedure described in Reference Example
11, butyltriphenylphosphonium bromide was used in place of
hexyltriphenylphosphonium bromide to give the title compound as
a yellow oil (yield: 78%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
6.80-6.69 (2H, m), 6.60 (1H, dd,, J=9Hz, 5Hz), 3.50 (2H, bs),
2.45 (2H, t, J=8Hz), 1.64-1.58 (2H, m), 1.45-1.36 (4H, m), 0.91
(3H, t, J=7Hz).
Reference Example 14
4 -Fluoro-2-hexylphenylamine
Following the procedure described in Reference Example
11, pentyltriphenylphosphonium bromide was used in place of
hexyltriphenylphosphonium bromide to give the title compound as
a pale brown oil (yield: 63%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
6.81-6.71 (2H, m), 6.66 (1H, dd, J=9Hz, 5Hz), 4.19 (2H, brs),
2.48 (2H, t, J=8Hz), 1.65-1.57 (2H, m), 1.43-1.25 (6H, m), 0.92-
0.85 (3H, m).
Reference Example 15
4 -Fluoro-2 -octylphenylamine
Following the procedure described in Reference Example
11, heptyltriphenylphosphonium bromide was used in place of
hexyltriphenylphosphonium bromide to give the title compound as
a pale yellow oil (yield: 65%)
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
6.80-6.71 (2H, m), 6.61 (1H, dd, J=9Hz, 5Hz), 2.45 (2H, t,

J=7Hz), 1.64-1.56 (2H, m), 1.38-1.22 (10H, m), 0.88 (3H, t,
J=7Hz).
Reference Example 16
4-Fluoro-2-nonylphenylamine
Following the procedure described in Reference Example
11, octyltriphenylphosphonium bromide was used in place of
hexyltriphenylphosphonium bromide to give the title compound as
a pale brown oil (yield: 97%).
1H-NMR spectrum (50 0MHz, CDCl3) δ ppm:
6.77 (1H, dd, J=10Hz, 3Hz), 6.72 (1H, td, J=8Hz, 3Hz), 6.59 (1H,
dd, J=9Hz, 5Hz), 3.46 (2H, brs), 2.45 (2H, t, J=8Hz), 1.64-1.56
(2H, m), 1.44-1.21 (12H, m), 0.88 (3H, t, J=7Hz).
Reference Example 17
2-Decyl-4 -fluorophenylamine
Following the procedure described in Reference Example
11, nonyltriphenylphosphonium bromide was used in place of
hexyltriphenylphosphonium bromide to give the title compound as
a pale brown oil (yield: 67%).
1H-NMR spectrum (500MHz, CDCl3) δ ppm:
6.77 (1H, dd, J=10Hz, 3Hz), 6.73 (1H, dd, J=8Hz, 3Hz), 6.60 (1H,
dd, J=9Hz, 5Hz), 3.47 (2H, brs), 2.45 (2H, t, J=8Hz), 1.64-1.56
(2H, m), 1.43-1.21 (14H, m), 0.88 (3H, t, J=7Hz).
Reference Example 18
l,4-Di-O-benzoyl-2,3-di-O-trimethylsilyl-D-threitol
17.48 g (52.9 mmol) of 1,4-di-O-benzoyl-D-threitol and
10.8 g (159 mmol) of imidazol were dissolved in 250 ml of
dichloromethane, and 12.6 g (116 mmol) of chlorotrimethylsilane
was added thereto with stirring under ice-cooling, followed by
stirring for 1 hour at room temperature. The reaction solution
was directly subjected to silica gel column chromatography
(solvent; hexane : ethyl acetate = 20:1-5:1) to give 24.5 9 g of
the title compound as a white powder (yield: 98%).

1H-NMR spectrum (400MHz, CDCl3) δ ppm:
8.04 (4H, dd, J=8Hz, J=lHz), 7.57-7.52 (2H, m), 7.46-7.40 (4H,
m) , 4.50 (2H, dd, J=llHz, J=4Hz) , 4.48-4.33 (2H, m) , 4.13-4.08
(2H, m), 0.14 (18H, s).
Reference Example 19
1,4-Di-O-benzoyl-2,3-di-O-trimethylsilyl-1-threitol
Following the process described in Reference Example 18,
1,4-di-O-benzoyl-1-threitol was used in place of 1,4-di-O-
benzoyl-D-threitol to give the title compound as a white powder
(yield: 98%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
8.04 (4H, dd, J=8Hz, J=lHz), 7.57-7.52 (2H, m), 7.46-7.40 (4H,
m) , 4.50 (2H, dd, J=llHz, J=4Hz) , 4.48-4.33 (2H, m) , 4.13-4.08
(2H, m), 0.14 (18H, s).
Reference Example 2 0
Methyl (S)-3,4-bis[(trimethylsilyl)oxy]butyrate
Following the process described in Reference Example 18,
methyl (S)-3,4-dihydroxybutyrate was used in place of 1,4-di-O-
benzoyl-D-threitol to give the title compound as an oil (yield:
62%) .
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
4.18-4.12 (1H, m), 3.67 (3H, s), 3.52 (1H, dd, J=10Hz, 6Hz),
3.40 (1H, dd, J=10Hz, 6Hz), 2.59 (1H, dd, J=15Hz, 5Hz), 2.37
(1H, dd, J=15Hz, 7Hz), 0.10 (18H, s).
Reference Example 21
1,4-Anhydro-2, 3-di-O-trimethylsilyl-jneso-erythritol
Following the process described in Reference Example 1,
1,4-anhydroerythritol was used in place of 1,4-di-O-benzoyl-
meso-erythritol to give the title compound as a colorless oil
(yield: 21%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.15-4.10 (2H, m), 3.92-3.85 (2H, m), 3.68-3.62 (2H, m), 0.14

(18H, s) .
Reference Example 22
3-Ethyl-3,4-bis[(trimethylsilyl)oxy]hexane
(22a) 3-Ethylhexane-3,4-diol
590 mg (5.0 mmol) of dimethyloxalate was dissolved in 20
ml of tetrahydrofuran, and 22 ml (22 mmol) of 1.0 M ethyl
magnesium bromide/tetrahydrofuran solution was added thereto
with stirring under ice-cooling, followed by stirring for 2
hours at the same temperature. The reaction solution was made
acidic by addition of 1N hydrochloric acid and the mixture was
extracted with ethyl acetate. The organic layer was washed with
water and dried over anhydrous magnesium sulfate, followed by
concentration under reduced pressure. The residue was subjected
to silica gel column chromatography (solvent; hexane : ethyl
acetate =3:1) to give 276 mg of the title compound as an oil
(yield: 38%).
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
3.45-3.41 (1H, m) , 1.87 (1H, d, J=6Hz) , 1.75 (1H, s) , 1.70-1.31
(6H, m), 1.04 (3H, t, J=7Hz), 0.89 (3H, t, J=8Hz), 0.89 (3H, t,
J=8Hz).
(22b) 3-Ethyl-3,4-bis[(trimethylsilyl)oxy]hexane
2 70 mg (1.85 mmol) of 3-ethylhexane-3,4-diol obtained in
(22a) was dissolved in 5 ml of pyridine, and 597 mg (3.7 mmol)
of 1,1,1,3,3,3-hexamethylsilazane and 1.20 g (11 mmol) of
chlorotrimethylsilane were added sequentially, followed by
stirring for 2 hours at the same temperature and further
overnight at room temperature. To the reaction solution was
added water and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and dried over anhydrous
sodium sulfate, followed by concentration under reduced
pressure. The residue was subjected to silica gel column
chromatography (solvent; hexane : ethyl acetate =9:1) to give
469 mg of the title compound as an oil (yield: 88%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
3.38 (1H, dd, J=9.0Hz, 3.0Hz), 1.68-1.33 (6H, m), 0.90 (3H, t,

J=6.0Hz), 0.92-0.90 (6H, m), 0.11-0.08 (18H, m).
Reference Example 23
(R) -1, 2-Bis [ (trimethylsilyl) oxy] -1,1, 2-triphenylethane
Following the process described in Reference Example 18,
(R)-1,1,2-triphenyl-l,2-ethanediol was used in place of 1,4-di-
O-benzoyl-D-threitol to give the title compound as a powder
(yield: 99%).
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
7.28-7.18 (15H, m), 5.51 (1H, s), -0.05 (9H, s), -0.16 (9H, s).
Reference Example 24
1,4-Di-O-acetyl-2,3-di-O-trimethylsilyl-D-threitol
Following the process described in Reference Example 18,
1,4-di-O-acetyl-D-threitol was used in place of 1,4-di-O-
benzoyl-D-threitol to give the title compound as an oil (yield:
96%) .
1H-NMR spectrum (400MHz, CDCl3) δ ppm:
4.20 (2H, dd, J=llHz, 4Hz), 4.01 (2H, dd, J=llHz, 7Hz), 3.88-
3.84 (2H, m), 2.06 (6H, s), 0.13 (18H, s).
Reference Example 25
(1R,2R,3R,4R)-4-Benzoyloxy-1-methyl-2,3 -
bis[(trimethylsilyl)oxy]pentyl benzoate
Following the process described in Reference Example 18,
(li?, 2S, 3S, 4R) -4-benzoyloxy-2 , 3-dihydroxy-1-methylpentyl benzoate
was used in place of 1,4-di-O-benzoyl-D-threitol to give the
title compound as an oil (yield: 86%).
1H-NMR spectrum (4 00MHz, CDCl3) δ ppm:
8.06-8.04 (4H, m), 7.57-7.54 (2H, m), 7.46-7.42 (4H, m), 5.31-
5.25 (2H, m), 3.98-3.97 (2H, m), 1.41 (6H, d, J=6Hz), 0.12 (18H,
s) .
Reference Example 26
(1R,2R,3R,4:R) -4-Benzoyloxy-1-ethyl-2,3 -

bis[(trimethylsilyl)oxy]hexyl benzoate
Following the process described in Reference Example 18,
(1R,2S,3S,4R)-4-benzoyloxy-1-ethyl-2,3-dihydroxyhexyl benzoate
was used in place of 1,4-di-O-benzoyl-D-threitol to give the
title compound as an oil (yield: 82%).
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
8.09-8.07 (4H, m), 7.59-7.55 (2H, m), 7.47-7.43 (4H, m), 7.47-
7.43 (2H, m), 3.96 (2H, s), 2.00-1.79 (4H, m), 1.02 (6H, t,
J=7Hz), 0.07 (18H, s).
Reference Example 2 7
4-Fluoro-2-propylphenylamine
Following the process described in Reference Example 11,
ethyltriphenylphosphonium bromide was used, in place of
hexyltriphenylphosphonium bromide to give the title compound as
a pale yellow oil (yield: 17%) .
1H-NMR spectrum (40 0MHz, CDCl3) δ ppm:
6.80-6.59 (3H, m), 3.48 (2H, brs), 2.45 (2H, t, J=7Hz), 1.70-
1.58 (2H, m), 1.01 (3H, t, J=8Hz).

(Test Example 1) Suppression effect against endotoxin stimulated
TNF-α production in cells (in vitro)
The suppression rate of the compound according to the
present invention against TNF-α production when human monocyte
cell line U93 7 was stimulated by endotoxin, was measured.
Specifically, to RPMI1640 medium containing 10% (volume %) of
heat-inactivated new born calf serum, was added 12-O-
tetradecanoylphorbol 13-acetate so that its final concentration
became 30 ng/ml. U937 cells were suspended with the medium and
plated to a 96 well culture plate (Sumilon) so that number of
cells/volume was 2 x 104/0.1 ml, and were then cultured for 3
days at 37°C in a carbon dioxide incubator with 5% C02 and 100%
humidity. After completion of incubation, the culture
supernatant was removed. The compound according to the present

invention was added to each of the wells in various
concentrations, and lypopolysaccharide (LPS) (E.coli 0111:B4,
Sigma) was also added so that its final concentration was 3 0
ng/ml. After incubating the culture plate in the carbon dioxide
incubator again for 4.5 hours, the culture supernatant was
collected. By using a 384 half well black plate (Greiner) and
HTRF quantitative kit of CIS Bio International, the
concentration of TNF-α in the culture supernatant was measured
as time-resolved fluorescence with Discovery (Packard). From
the measured value in the absence of LPS (X), measured value in
the absence of the compound according to the present invention
(Y) and measured value in the presence of the compound according
to the present invention (Z), the suppression rate of TNF-α
production was obtained by the following calculation formula
[I].
Suppression rate of TNF-α production (%)={l-(Z-X)/(Y-
X)}xl00 [I]
In the present test, the compound according to the
present invention showed an excellent suppression effect against
endotoxin stimulated TNF-α production in cells.
(Test Example 2) Suppression effect against elevated TNF-α
concentration in blood (in vivo)
The suppression effect of the compound according to the
present invention against elevated TNF-α concentration in blood
was evaluated. The test for TNF-α concentration elevation in
blood was conducted in accordance with the process of Parant et
al, which is described in Journal of Leukocyte Biology, Vol. 47,
p. 164 (1990).
In the test, 3 to 4 male Sprague Dawley rats (8-9 weeks
old) were used for each group.
4 hours before the administration of LPS, muramyl
dipeptide dissolved in a physiological saline solution (1 mg/ml)

was administered to the tail vein at a rate of 1 ml/kg. 0.5
hours before the administration of LPS, the rats were
anaesthetized with pentobarbital (40 mg/kg), and the compound
according to the present invention dissolved in 5% dimethyl
acetamide/ 95% polyethylene glycol 400 solution was administered
to the right femoral vein at a rate of 1 ml/kg. The control
group was administered with 5% dimethyl acetamide/95%
polyethylene glycol 400 solution at a rate of 1 ml/kg. LPS
dissolved in a physiological saline solution (3 pg/ml) was
administered to the left femoral vein at a rate of 1 ml/kg. 2
hours after the administration of LPS, blood was collected using
3.8%(w/v) sodium citrate solution as an anticoagulant, and blood
plasma was separated by centrifuge (10,000 g, 5 minutes, 4°C) .
TNF-α concentration in the blood plasma was measured using a
TNF-α quantitative kit (Bio Source International, Inc.). From
the TNF-α concentration in the blood of control group (X) and
the TNF-α concentration in the blood of the group administered
with the compound according to the present invention (Y), the
TNF-α production suppression rate was calculated using the
following calculation formula [II].
TNF-α production suppression rate (%)={l-Y/X}xl00 [II]
In the present test, the compound according to the
present invention showed excellent suppression effects against
elevated TNF-α concentration in blood.

WE CLAIM:
1. A compound represented by the general formula (I):

{wherein
X and Y represent a group in which X and Y together with the carbon atom of ring B to
which they are bound form ring A, or X and Y together represent a substituent of ring B,
(1) in the case where X and Y represent a group in which X and Y together with the
carbon atom of ring B to which they are bound form ring A:
ring A represents
a 3- to 7-membered heterocyclyl ring [ in the heterocyclyl ring, X and Y, independently
from each other, represent any one selected from a carbon atom, an oxygen atom, a
sulfur atom, a group having the formula SO and a group having the formula SO2,
the heterocyclyl ring may include an unsaturated bond, may form a fused ring or spiro
ring with a 3- to 7-membered heterocyclyl ring, and ring A, including the fused ring or
spiro ring, may be substituted with the same or different 1 to 4 groups selected from
the group consisting of an oxo group, a thioxo group, Substituent group α, a
cyclopropyl C1-C6 alkyl group, a C1-C6 alkyl group which may be substituted with 1 to
5 groups selected from Substituent group α ;
(2) in the case where X and Y together represent a substituent of ring B:
X and Y represent an oxo group;
I and m, independently from each other, represent an integer of 0 to 3, and
I + m is -1 to 3;

n represents an integer of 0;
R2 represents a hydrogen atom,
a C1-C6 alkyl group which may be substituted with group(s) selected from Substituent
group β,
R3 represents
a phenyl group which may be substituted with group(s) selected from Substituent
group ε, or
a 5- or 6-membered heteroaryl group which may be substituted with group(s) selected
from Substituent group ε (the heteroaryl group includes 1 to 3 hetero atoms selected
from a nitrogen atom;
R5 represents a hydrogen atom, provided that in the case where R3 is a phenyl group
which may be substituted with group(s) selected from Substituent group ε, X and Y
represent the aforementioned (1) or (2);
Substituent group α represents
a hydroxy group, halogen atom, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group,
carboxy group, C1-C6 alkoxy-carbonyl group;
and a group having the formula NR6R7, and
R6 and R7, independently from each other, represent a hydrogen atom, C1-C6 alkanoyl
group, or together with the nitrogen atom to which they are bound form a heterocyclyl
group;
Substituent group β represents
C1-C6 alkoxy group and C1-C6 alkoxy-carbonyl group;

Substituent group ε represents
a hydroxy group, halogen atom, C1-C14 alkyl group, cyclopropyl C1-C14 alkyl group,
halogeno C1-C14 alkyl group, C1-C14 alkoxy group, halogeno C1-C14 alkoxy group,
carboxy group, C1-C14 alkanoyl group, C1-C14 alkoxy-carbonyl group, C1-C14 alkylthio
group, carbamoyl group, C1-C14 alkyl-carbamoyl group, group having the formula
NR6R7 (R6 and R7 are the same as R6 and R7 of Substituent group α), C6-C10 aryl
group and 5-membered heteroaryl group}
or a pharmacologically acceptable salt thereof.
2. The compound or pharmacologically acceptable salt thereof as claimed in claim 1,
wherein I is 0 and m is an integer of 1 to 3.
3. The compound or pharmacologically acceptable salt thereof as claimed in claim 1,
wherein I is 0 and m is 2.
4. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 3, wherein X and Y together with the carbon atom of ring B form ring A,
and ring A is
a 3- to 7-membered heterocyclyl ring
[in the heterocyclyl ring, X and Y, independently from each other, represent any one
selected from a carbon atom, a group having the formula NR (R represents a
hydrogen atom or a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 alkanoyl group
which may be substituted with group(s) selected from Substituent group α), an oxygen
atom, a sulfur atom, a group having the formula SO and a group having the formula
SO2,

the heterocyclyl ring may form a fused ring or spiro ring with a 5- or 6-membered
heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms
as hetero atom) or 5- to 6-membered cycloalkyl ring, and
ring A, including the fused ring or spiro ring, may be substituted with the same or
different 1 to 4 groups selected from the group consisting of an oxo group, a thioxo
group, substituent group α, a cyclopropyl C1-C6 alkyl group and a C1-C6 alkyl group
which may be substituted with 1 to 5 groups selected from substituent group α]
5. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 3, wherein X and Y represent a group in which X and T together with the
carbon atom of ring B form ring A, and ring A is a 3- to 7-membered heterocyclyl ring
[ in the heterocyclyl ring, X and Y, independently from each other, represent any one
selected from a carbon atom, an oxygen atom, sulfur atom, a group having the
formula SO and a group having the formula SO2
the heterocyclyl ring may form a fused ring or spiro ring with a 5- or 6-membered
heterocyclyl ring (the heterocyclyl ring includes 1 or 2 oxygen and/or nitrogen atoms
as hetero atoms) or 5- or 6-membered cycloalkyl ring, and ring A, including the fused
ring or spiro ring, may be substituted with the same or different 1 to 4 groups selected
from the group consisting of an oxo group, a thioxo group, Substituent group α and a
C1-C6 alkyl group which may be substituted with 1 to 4 groups selected from
Substituent group α]
or
a 3- to 5-membered saturated cycloalkyl ring (the 3- to 5-membered saturated
cycloalkyl ring may be substituted with 1 or 2 groups selected from the group
consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-trihydroxypropyl
group, 1,2,3,4-tetrahydroxybutyl group and acetylamino group).

6. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 3, wherein X and Y represent a group in which X and Y together with the
carbon atom of ring B form ring A, and ring A is a 3-to 7-membered heterocyclyl ring
[the 3- to 7-membered heterocyclyl ring is oxirane, oxolane, tetrahydrofuran,
tetrahydropyran, 1,3-dioxolane, 1,3-dioxane, 1,3-dioxepane, 1,3-dithiolane, 1,3-
dithiane, 1,1,3,3-tetraoxo-1,3-dithiolane, 1,3-oxathiolane, 1,3-oxathiane or 1,3-
oxathiepane,
these heterocyclyl rings may form a fused ring or spiro ring with a 5-or 6-membered
heterocyclyl ring (the 5- or 6-membered heterocyclyl ring is tetrahydrofuran,
tetrahydrophyran, pyrrolidine, piperidine or 1,3-dioxane) or cyclohexyl ring, and ring A,
including the fused ring and spiro ring, may be substituted with 1 or 2 groups selected
from the group consisting of an oxo group, a thioxo group, Substituent group α
(Substituent group α represents a hydroxy group and a group having the formula
NR6R7, and R6 and R7, independently from each other, represent a hydrogen atom or
C1-C6 alkanoyl group), a methyl group, an ethyl group and a C1-C6 alkyl group which is
substituted with 1 to 4 hydroxy groups],
or
a cyclopropyl or cyclopentyl ring
(the cyclopropyl or cyclopentyl ring may be substituted with 1 or 2 groups selected
from the group consisting of a hydroxymethyl group, 1,2-dihydroxyethyl group, 1,2,3-
trihydroxypropyl group, and a 1,2,3,4-tetrahydroxybutyl group).
7. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 3, wherein X and Y represent a group in which X and Y together with the
carbon atom of ring B form ring A, and ring A is a 3- to 6-membered heterocyclyl ring
{the heterocyclyl ring is oxirane, tetrahydrofuran, 1, 3-dioxolane, 1,3-dioxane,
1, 3-dithiolane, 1,3-dithiane,
1, 3-oxathiolane, or 1,3-oxathiane,

these heterocyclyl rings may form a fused ring or spiro ring with a 5- or 6-membered
heterocyclyl ring (the 5- or 6-membered heterocyclyl ring is tetrahydrofuran,
tetrahydropyran or 1,3- dioxane) or cyclohexyl ring, and
ring A, including the fused ring or spiro ring, may be substituted with 1 or 2 groups
selected from the group consisting of Substituent group α [ Substituent group α
represents a hydroxyl group and a group having the formula NR6R7( R6 and R7.
independently from each other, represent a hydrogen atom or acetyl group], a methyl
group, an ethyl group, a hydroxymethyl group, a 1,2-dihydroxyethyl group, a 1,2,3-
trihydroxypropyl group and a 1,2,3,4-tetrahydroxybutyl group}.
8. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 7, wherein
n is 0 or 1, and
R1 is a hydroxyl group, halogen atom, C1-C6 alkyl group or C1-C6 alkoxy group.
9. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 7, wherein
n is 0 or 1, and
R1 is a fluorine atom or methyl group.
10. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 7, wherein n is 0.
11. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 10, wherein R2 is a C1-C6 alkyl group.

12. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 10, wherein R2 is a C1-C4 alkyl group.
13. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 10, wherein R2 is an ethyl group.
14. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 13, wherein
R3 is
a phenyl group which may be substituted with group(s) selected from Substituent
group ε, or
a pyrrolyl group which may be substituted with group(s) selected from Substituent
group ε, and
Substituent group ε is a halogen atom, C1-C14 alkyl group and halogeno C1-C14 alkyl
group.
15. The compound or pharmacologically acceptable salt thereof as claimed any one of
claims 1 to 13, wherein
R3 is
a phenyl group which may be substituted with group(s) selected from Substituent
group ε, or
a pyrrolyl group which may be substituted with group(s) selected from Substituent
group ε, and
Substituent group ε is a fluorine atom, chlorine atom, bromine atom, C3-C8 alkyl group
and halogeno C4-C8 alkyl group.

16. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 13, wherein
R3 is
a phenyl group which may be substituted with group(s) selected from Substituent
group ε, and
Substituent group ε is a fluorine atom, chlorine atom and C3-C8 alkyl group.
17. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 16, wherein R5 is a hydrogen atom or C1-C6 alkyl group.
18. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 16, wherein R5 is a hydrogen atom or methyl group.
19. The compound or pharmacologically acceptable salt thereof as claimed in any one of
claims 1 to 16, wherein R5 is a hydrogen atom.
20. The compounds of the following group aelected from claim 1 or pharmacologically
acceptable salt thereof:
ethyl 8-[N-(2-chlorophenyl) sulfamoyl]-2,3- bis(hydroxymethyl)-1,4-dioxaspiro[4.5] dec-
6-ene-7-carboxylate,
ethyl 8-[N-(2-chlorophenyl) sulfamoyl]-2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro
[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2,4-difluorophenyl) sulfamoyl]-2,3-bis (hydroxymethyl)-1,4-dioxaspiro[4.5]
dec-6-ene-7-carboxylate,
ethyl 8-[N-(2,4-difluorophenyl)sulfamoyl]-2,3-bis(1,2-dihydroxyethyl) -1,4-dioxaspiro
[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro-4-fluorophenyl) sulfamoyl] -2- hydroxymethyl-1,4-dioxaspiro[4.5]
dec-6-ene-7-carboxylate,

ethyl 8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -2,3-bis(hydroxymethyl) -1,4
dioxaspiro [4.5] dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro - 4 - fluorophenyl) sulfamoyl] -2, 3-bis(1, 2-dihydroxyethyl) -1,4-
dioxaspiro[4.5] dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-(1,2-dihydroxyethyl)-1,4-dioxaspiro
[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (1,2,3-trihydroxypropyl) -1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 8-[N- (2-chloro-4-fluorophenyl) sulfamoyl] -2- (1,2,3,4-tetrahydroxybutyl) -1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,
ethyl 2,3-bis (acetylaminomethyl) -8- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1,4-
dioxaspiro [4.5] dec-6-ene-7-carboxylate,
ethyl 9-[N- (2-chloro-4-fluorophenyl) sulfamoyl] -3- hydroxy-1,5-dioxaspiro[5.5] undec-
7-ene-8-carboxylate,
ethyl 3-acetylamino -9- [N-(2-chloro-4-fluorophenyl) sulfamoyl] -1,5- dioxaspiro [5.5]
undec-7-ene-8-carboxylate,
ethyl 9- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3- bis (hydroxymethyl) -1,5-
dioxaspiro [5.5] undec -7-ene-8-carboxylate,
ethyl8-[N-(2-butyl-4-fluorophenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]
dec-6-ene-7-carboxylate,
ethyl8-[N-(2-butyl-4-fluorophenyl) sulfamoyl]-2,3-bis(1,2-dihydroxyethyl)-1,4-dioxaspiro
[4.5] dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-hexylphenyl) sulfamoyl] -2,3- bis (hydroxymethyl) -1,4- dioxaspiro [4.5]
dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-hexylphenyl) sulfamoyl] -2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]
dec-6-ene-7-carboxylate,
ethyl 8-[N-(4-fluoro-2-hexylphenyl) sulfamoyl] -2,3- bis (hydroxymethyl)-1,4-
dioxaspiro[4.5] dec-6-ene-7-carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl) -8- [N-(4-fluoro-2-hexylphenyl) sulfamoyl] -1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate,

ethyl 8-[N-(2-heptylphenyl) sulfamoyl] -2,3- bis (hydroxymethyl) -1,4-dioxaspiro[4.5]
dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-heptylphenyl) sulfamoyl] -2,3- bis(1,2-dihydroxyethyl)-1,4-dioxaspiro [4.5]
dec-6-ene-7-carboxylate,
ethyl 8- [N-(4-fluoro-2-heptylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-
dioxaspiro[4.5] dec-6-ene-7-carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl) -8- [N- (4-fluoro-2-heptylphenyl) sulfamoyl] -1,4-
dioxaspiro[4.5] dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-bromophenyl) sulfamoyl] -2,3- bis(hydroxymethyl)-1,4-dioxaspiro [4.5]
dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-bromophenyl) sulfamoyl] -2,3- bis (1,2-dihydroxyethyl)-1,4-dioxaspiro[4.5]
dec-6-ene-7-carboxylate,
ethyl 8- [N-(2-chloro-6-methylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-
d ioxaspi ro[4.5] dec-6-ene-7-carboxylate,
ethyl8-[N-(2-chloro-6-methylphenyl) sulfamoyl] -2,3- bis (1,2-dihydroxyethyl) -1,4-
dioxaspiro [4.5] dec-6-ene-7-carboxylate,
ethyl 8- [N-(2-bromo-4-fluorophenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4-
dioxaspiro [4.5] dec-6-ene-7-carboxylate,
ethyl 8-[N-(2-bromo-4-fluorophenyl) sulfamoyl] -2,3- bis (1,2-dihydroxyethyl) -1,4-
dioxaspiro [4.5] dec-6-ene-7-carboxylate,
ethyl 2,3-bis(hydroxymethyl)-8-[N-(2-pentylphenyl) sulfamoyl]-1,4-dioxaspiro[4.5] dec-
6-ene-7-carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl)-8-[N-(2-pentylphenyl) sulfamoyl] -1,4-dioxaspiro[4.5]
dec-6-ene-7-carboxylate,
ethyl 8-[N-(4-fluoro-2-pentylphenyl)sulfamoyl]-2,3-bis(hydroxymethyl)-1,4-dioxaspiro
[4.5] dec-6-ene-7-carboxylate,
ethyl 2,3-bis(1,2-dihydroxyethyl) -8- [N-(4-fluoro-2-pentylphenyl) sulfamoyl ] -1,4-
dioxaspiro [4.5] dec-6-ene-7-carboxylate
ethyl 8-[N-(4-fluoro-2-octylphenyl) sulfamoyl] -2,3-bis (hydroxymethyl) -1,4- dioxaspiro
[4.5] dec-6-ene-7-carboxylate,

ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N-(4-fluoro-2-octylphenyl) sulfamoyl] -1,4-
dioxaspiro[4.5] dec-6-ene-7-carboxylate,
ethyl 8- [N- (4-fluoro-2-propylphenyl) sulfamoyl] -2,3- bis (hydroxymethyl) -1,4-
dioxaspiro[4.5] dec-6-ene-7-carboxylate,
ethyl 2,3-bis (1,2-dihydroxyethyl) -8- [N-(4-fluoro-2-propylphenyl) sulfamoyl] -1,4-
dioxaspiro[4.5] dec-6-ene-7-carboxylate, and
ethyl 8-[N-(2-chloro-4-fluorophenyl)-N-methylsulfamoyl]-2,3-bis(hydroxymethyl)-1,4-
dioxaspiro[4.5]dec-6-ene-7-carboxylate.
21. A medicament containing the compound or pharmacologically acceptable salt thereof
as claimed in any one of claims 1 to 20 as an active ingredient.
22. A potassium salt of ethyl (2R, 3R) -8- [N-(2-Chloro-4-fluorophenyl) sulfhmoyl]-2, 3-
bis(hydroxymethyl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate.
23. Potassium (2-Chloro-4-fluorophenyl) { [(2R, 3R, 8R)7- (ethoxycarbonyl) -2, 3-bis
(hydroxymethyl) -1, 4-dioxaspiro [4.5] dec-6-ene-8-yl ] sulfonyl} axanide.

ABSTRACT

Title: "SUBSTITUTED CYCLOALKENE DERIVATIVE"

It is intended to provide a substituted cycloalkene derivative represented by the general
formula (I) which has an action of suppressing intracellular signal transduction or cell
activation caused by endotoxin and a cell response such as hyperproduction of an
inflammatory mediator caused by them, a pharmacologically acceptable salt thereof, a
method for producing the same, and a pharmaceutical containing the cycloalkene
derivative as an active ingredient, which is excellent in prevention and/or treatment of a
disease such as sepsis (septic shock, disseminated intravascular co-agulation, multiple
organ failure or the like). General formula (I): {In the formula, X and Y represent a group
which forms the ring A with the carbon atom of the ring B to which X and Y are bound or
the like, I and m independently represent an integer of 0 to 3 and I +m is 1 to 3. R1
represents an aliphatic hydrocarbon group which may be substituted or the like, n
represents an integer of 0 to 3. R3 represents a hydrogen atom, an alkyl group which may
be substituted or the like, R3 represents a phenyl group which may be substituted or the
like, and R5 represents a hydrogen atom, an alkyl group which may be substituted or the
like.}

Documents:

01054-kolnp-2008-abstract.pdf

01054-kolnp-2008-claims.pdf

01054-kolnp-2008-correspondence others.pdf

01054-kolnp-2008-form 1.pdf

01054-kolnp-2008-form 2.pdf

01054-kolnp-2008-form 3.pdf

01054-kolnp-2008-form 5.pdf

01054-kolnp-2008-international search report.pdf

01054-kolnp-2008-pct request form.pdf

1054-KOLNP-2008-(01-03-2012)-CORRESPONDENCE.pdf

1054-KOLNP-2008-(22-09-2011)-AMANDED CLAIMS.pdf

1054-KOLNP-2008-(22-09-2011)-DESCRIPTION (COMPLETE).pdf

1054-KOLNP-2008-(22-09-2011)-EXAMINATION REPORT REPLY RECIEVED.pdf

1054-KOLNP-2008-(22-09-2011)-FORM 1.pdf

1054-KOLNP-2008-(22-09-2011)-FORM 2.pdf

1054-KOLNP-2008-(22-09-2011)-FORM 3.pdf

1054-KOLNP-2008-(22-09-2011)-OTHERS.pdf

1054-KOLNP-2008-(22-09-2011)-PA.pdf

1054-KOLNP-2008-(22-09-2011)-PETITION UNDER RULE 137.pdf

1054-KOLNP-2008-CORRESPONDENCE OTHERS 1.1.pdf

1054-KOLNP-2008-CORRESPONDENCE OTHERS 1.2.pdf

1054-KOLNP-2008-CORRESPONDENCE OTHERS-1.1.pdf

1054-KOLNP-2008-CORRESPONDENCE.pdf

1054-KOLNP-2008-EXAMINATION REPORT.pdf

1054-KOLNP-2008-FORM 18 1.1.pdf

1054-kolnp-2008-form 18.pdf

1054-KOLNP-2008-GPA.pdf

1054-KOLNP-2008-GRANTED-ABSTRACT.pdf

1054-KOLNP-2008-GRANTED-CLAIMS.pdf

1054-KOLNP-2008-GRANTED-DESCRIPTION (COMPLETE).pdf

1054-KOLNP-2008-GRANTED-FORM 1.pdf

1054-KOLNP-2008-GRANTED-FORM 2.pdf

1054-KOLNP-2008-GRANTED-SPECIFICATION.pdf

1054-KOLNP-2008-INTERNATIONAL EXM REPORT.pdf

1054-KOLNP-2008-INTERNATIONAL PRELIMINARY EXAMINATION REPORT.pdf

1054-KOLNP-2008-INTERNATIONAL PUBLICATION.pdf

1054-KOLNP-2008-INTERNATIONAL SEARCH REPORT 1.1.pdf

1054-KOLNP-2008-OTHERS 1.1.pdf

1054-KOLNP-2008-OTHERS PCT FORM.pdf

1054-KOLNP-2008-OTHERS.pdf

1054-KOLNP-2008-PCT REQUEST FORM.pdf

1054-KOLNP-2008-PRIORITY DOCUMENT.pdf

1054-KOLNP-2008-REPLY TO EXAMINATION REPORT.pdf

1054-KOLNP-2008-TRANSLATED COPY OF PRIORITY DOCUMENT.pdf

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Patent Number

259093

Indian Patent Application Number

1054/KOLNP/2008

PG Journal Number

09/2014

Publication Date

28-Feb-2014

Grant Date

25-Feb-2014

Date of Filing

11-Mar-2008

Name of Patentee

DAIICHI SANKYO COMPANY, LIMITED

Applicant Address

3-5-1, NIHONBASHI-HONCHO, CHUO-KU, TOKYO

Inventors:

#	Inventor's Name	Inventor's Address
1	KIMURA, TOMIO	C/O. DAIICHI SANKYO COMPANY, LIMITED, 1-2-58, HIROMACHI, SHINAGAWA-KU, TOKYO 140-8710
2	NAGASAKI, TAKAYOSHI	C/O. DAIICHI SANKYO COMPANY, LIMITED, 1-2-58, HIROMACHI, SHINAGAWA-KU, TOKYO 140-8710
3	SUGIDACHI, ATSUHIRO	C/O. DAIICHI SANKYO COMPANY, LIMITED, 1-2-58, HIROMACHI, SHINAGAWA-KU, TOKYO 140-8710
4	ANDO, OSAMU	C/O. DAIICHI SANKYO COMPANY, LIMITED, 1-2-58, HIROMACHI, SHINAGAWA-KU, TOKYO 140-8710
5	OHKAWA, NOBUYUKI	C/O. DAIICHI SANKYO COMPANY, LIMITED, 1-2-58, HIROMACHI, SHINAGAWA-KU, TOKYO 140-8710

PCT International Classification Number

C07C 311/14

PCT International Application Number

PCT/JP2006/318103

PCT International Filing date

2006-09-13

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2005-267504	2005-09-14	Japan