| Title of Invention | "BENZOPYRAN COMPOUNDS SUBSTITUTED WITH THIOXOBENZOXAZOLES" |
|---|---|
| Abstract | The present invention relates to benzopyran derivatives substituted with a thioxobenzoxazoie derivative, or pharmaceutically acceptable salts thereof, processes for preparing the same and a pharmarceutical composition containing the above as an effective ingredient. Benzopyran derivatives substituted with thioxobenzoxazoie derivatives, represented in <Formula 1>, have the function of protecting heart from ischemia-reperfusion both in vivo and in vitro, so that a pharmaceutical composition containing benzopyran derivatives substituted with thioxobenzoxoazole derivatives or pharmaceutically acceptable salts thereof of the present invention as an effective ingredient can be effectively used for the protection of tissues influenced by ischemia-reperfusion, for example, for the protection of heart, nervous cells, brain, retinal cells, storage organs, etc, and for the treatment of diseases caused by ischemia-reperfusion. |
| Full Text | BENZOPYRAN DERIVATIVES SUBSTITUTED WITH A THIOXOBENZOXAZOLE DERIVATIVE, PHARMACEUTICALS ACCEPTABLE SALTS THEREOF, THEIR PREPARATIONS PHARMACEUTICAL COMPOSITIONS CONTAINING THEM DETAILED DISCRIPTION OF THE INVENTION [ PURPOSE OF THE INVENTION FIELD OF THE INVENTION AND BACKGROUND ] The present invention relates to benzcpyran derivatives substituted with a thioxobenzoxazole derivative, represented in pharmaceutically acceptable salts thereof, processes for preparing the same and pharmaceutical composirions containing them as an effective ingredient. i (Wherein, R1, R2, R3, R4, R5 and * are as in the description.) defined Ischemic heart disease results from myocardial ischemia developed by a serious deficiency of oxygen supply caused by interruption of blood flow to heart by a reason like arteriosclerosis (G. J. Grover, Cab. J. Physiol. 75, 309, 1997; G. D. Lopaschuk et al. So .ence & Medicine 42, 1997). Myocardial ischemia induces pathological changes in cells progressively, leading to irreversible myocardial damage and even necroses of cells and tissues, at last. In early stage when dkmage is reversible, irreversible damage might be prevented by reperfusion through surgical operations such as (percutaneous transluminal coronary angioplasty) PTCA and CABG (coronary artery bypass graft) or iasing thrombolytics, but the restoration of flov-i by reperfusion therapy is accompanied by a further injurious phenomenon called reperfusion injury O. J. Hearse, Medicographia 18, 22, 1996) . It is difficult to clearly separate ischemic injury from that mediated by reperfusion. Reperfusion injury is caused by sudden restoration of blood flow by reperfusion therapy, mainly due to reactive oxygen free radicals and caJLcium overload. Reperfusion injury includes a rangb of events, such as arrhythmia, vascular damage, myocajrdial dysfunction and serious neurocognitive dysfunction, j In order to delay damage by ischemia and minimize reperfusion injury, studies have actively been undergoing on pharmacotherapy using immune modulators, agents to suppress apoptosis, ion channel modulators, etc, artificial blood products to enhance the oxygen carrying potential of blood, and development of devices and operation procedures, but neither of them has been in commercial use, so far. As an ion channel modulators, an inhibitor of Na-H exchanger (NHE),: an adenosine Ai/A2 antagonist and a KATP opener (ATPsensitive potassium channel opener) draw our attention. According to earlier reports, diazoxide, a KATP opener, can reduce damage due to oxidative stress by suppressing the generation of oxygen free radicals; in mitochondria by inducing oxidation of flavoprotein I (A. A. Starkov, Biosci, Rep. 11, 273, 1997; V. P. Skulachev, Q. Rev. Biophus. 29, 169, 1996), and the opening of KATP relates to the generation of antioxidant enzymes :(S. Okubo et al., Mol. and cell Biochem, 196, 3, 1999) jand the decrease of release of excitatory amino acids (J-L Moreau, G. Huber, Brain Res., 31, 65, 1999). KATP/ found first in myocardium, is widely distributed! in many organs and tissues, for example, beta-cells! of pancreas, smooth muscle, kidney and central nervous system, so that it has been a major target for the Jdevelopment of a novel medicine. Atwal et al have reported that benzopyranyl cyanoguanidines (BMS-1801448) having a structure represented in the below opens KATP selectively, meaning that it might have cardioprotective function, which provides a chance to develop a novel therapeutic agent for ischemic heart diseases. Thus, the inventors of present invention synthesized benzopyran derivatives substituted with a thioxobenzoxazole derivative, in which the guanidjinyl group substituted in the 4-position of benzopyran; was cyclized to a benzene ring, aniline nitrogen was changed into oxygen to form a benzoxazole ring and Ncyano group was changed into thioxo group. And the present inventors completed this invention by confirming that the compound of the invention had an excellent cardioprotective effect against damage by ischemia-reperfusion, so that it could be effectively used as a protective agent or therapeutic agent for ischemia-reperfusion related diseases. Precisely, the compound can be used for the treatment of ischemic heart diseases such as myocardial infarction, unstable angina pectoris, the protection of heart upon thrombolytic therapy or reperfusion therapy such as PTCA (percutaneous transluminal coronary angioplasty) and CABG (coronary artery bypass graft), and the protection of ischemia-reperfusion related tissues such as nerve cells, brain, retinal cells, storage organs, etc. TECHNICAL SOLUTION OF THE INVENTION It is an object of this invention to provide benzopyran derivatives substituted with a thioxobenzoxazole derivative, or pharmaceutically acceptable salts thereof, processes for preparing the same and a pharmarceutical composition containing the above as an effective ingredient. SUMMARY OF THE INVENTION In order to achieve the above object, the present invention provides benzopyran derivatives substituted with a thioxobenzoxazole derivative, represented in acceptable salts thereof. The present invention also provides preparation processes for benzopyran derivatives substituted with a thioxobenzoxazole derivative, represented in The present invention futher provides a pharmaceutical composition containing benzopyran derivatives substituted with a thioxobenzoxazole derivative, represented in pharmaceutically acceptable salts of the same as an effective ingredient. Hereinafter, the present invention is described in detail. The present invention provides benzopyran derivatives substituted with a thioxobenzoxazole derivative, represented in pharmaceutically acceptable salts thereof. (Wherein, R1 is N02, NH2, H, CN, NHCOCH3, NHCOPh, NHCOCF3 or NHS02CH3;' R2 is OR , ° , CH2ORa, C02Ra or Ra Wherein, Ra is GI ~C4 straight or branched alkyl; Z is C2 ~C6 straight or branched alkyl; R3 is OH or OCOCH3; R4 and R5 are independently H, Ci~C4 straight or branched alkyl, Cl, Br, F, N02, OMe, C02Me or CF3; represents a chiral carbon.) The present invention also provides, in addition to benzopyran derivatives represented in and pharmaceutically acceptable salts, solvates, and hydrates thereof. Benzopyran derivatives of the present invention represented in mixture but also any diastereoisomer in which at least one carbon in the 2, 3, or 4-positon is chiral. In the above position are chiral, 3,4-dihydro benzopyran compounds of the present invention are in the form of diastereoisomers as seen in (Ii) , (12) / (Is)/ and (1$) in the below (Wherein, R1, R2, R3, R4, and R5 are as defined in Preferably, 1) (2R, 3R, dimethoxymethyl-2 2H-l-benzopyran; 2)(2R, 3S, dimethoxymethyl-2 2H-l-benzopyran; 3) (2S, 3R, dimethoxymethyl-2 2H-l-benzopyran; 4)(2S, 3S, dimethoxymethyl-2 2H-l-benzopyran; the compounds of 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- -methyl-4-(2-thioxobenzoxazol-3-yl)- 4R)-6-nitro-3,4-dihydro-3-hydroxy-2- -methyl-4-(2-thioxobenzoxazol-3-yl)- 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- -methyl-4-(2-thioxobenzoxazol-3-yl)- 4R) -6-nitro-3,4-dihydro-3-hydroxy-2- -methyl-4-(2-thioxobenzoxazol-3-yl)- 5) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(6-methyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 6) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(4-methyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 7) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-chloro-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 8) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-methyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 9) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(6-nitro-2-thioxobenzoxazole -3-yl)-2H-l-benzopyran; 10) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxyraethyl-2-methyl-4- (5-methoxy-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 11) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-bromo-2-thioxobenzoxazol- 3-yl)-2H-l-benzopyran; 12) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-t-butoxy-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 13) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(6-fluoro-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 14) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(4-methoxycarbonyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 15) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-methoxycarbonyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 16) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydrcxy-2- dimethoxymethyl-2-methyl-4-(5-trifluoromethyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 17) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl•- 2H-l-benzopyran; 18) (2S, 3S, 4R)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)- 2H-l-benzopyran; 19) (2S, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)- 2H-l-benzopyran; 20) (2R, 3S, 4R)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yI)- 2H-l-benzopyran; 21) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(6-methyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 22) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-methyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 23) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(4-methyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 24) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-chloro-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 25) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-methoxy-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 26) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-t-butoxy-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 27) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(6-fluoro-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 28) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-methoxycarbonyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 29) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(4-methoxycarbonyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 30) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4-(5-trifluoromethyl-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 31)(2R, 3R, 4S)-6-nitro-3,4-dihydro-3-acetoxy-2- dimethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)- 2H-l-benzopyran; 32) (2R, 3R, 4S)-6-amino-3,4-dihydro-3-acetoxy-2- dimethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)- 2H-l-benzopyran; 33) (2R, 3R, 4S)-6-acetylamino-3,4-dihydro-3- hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 34) (2R, 3R, 4S)-6-acetylamino-3,4-dihydro-3- acetoxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 35) (2R, 3R, 4S)-6-benzoylamino-3,4-dihydro-3- hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 36) (2R, 3R, 4S)-6-trifluoroacetylamino-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 37) (2R, 3R, 4S)-6-methanesulfonylamino-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 38) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- methoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl) -2H- 1-benzopyran; 39) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- methoxymethyl-2-methyl-4-(5-chloro-2- thioxobenzoxazol3- yl)-2H-l-benzopyran; 40) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- methoxycarbonyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)- 2H-l-benzopyran; 41) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- methoxycarbonyl-2-methyl-4-(5-chloro-2- thioxobenzoxazol-3-yl)-2H-l-benzopyran; 42) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- ([1,3]dioxolan-2-yl)-2-methyl-4-(2-thioxobenzoxazol-3- yl)-2H-l-benzopyran; 43) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- ([1,3]dioxan-2-yl)-2-methyl-4-(2-thioxobenzoxazol-3- yl)-2H-l-benzopyran; 44) (2R, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- diethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)-2H- 1-benzopyran; 45) (2R, 3S, 4R)-6-nitro-3,4-dihydro-3-hydroxy-2- diethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)-2H- 1-benzopyran; 46) (2S, 3R, 4S)-6-nitro-3,4-dihydro-3-hydroxy-2- diethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)-2H- 1-benzopyran; 47) (2S, 3S, 4R)-6-nitro-3,4-dihydro-3-hydroxy-2- diethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)-2H- 1-benzopyran; and 48) (2S, 3R, 4S) -6-amino-3, 4-dihydro-3-hydroxy-2- diethoxymethyl-2-methyl-4-(2-thioxobenzoxazol-3-yl)-2H- 1-benzopyran. The compounds of the above present invention are available in the form of pharmaceutically acceptable salts, and acid addition salts prepared by pharmaceutically acceptable free acids or metal salts are useful. The acid salts of the compounds according to the present invention can be prepared in the customary manner, for example by dissolving the compound of precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It is also possible to prepare the acid salt by heating equivalent amounts of the compound of glycol monomethyl ether, and then evaporating the mixture to dryness or filtering off the precipitated salt with suction. Whether it is inorganic or organic, a free acid can be used if it is pharmaceutically acceptable. Examples of the inorganic free acid include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Available organic free acids are exemplified by citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4- toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid and aspartic acid. Also, the compounds of form of pharmaceutically acceptable alkali metal or alkaline earth metal salts. The alkali metal or alkaline earth metal salts of the compounds of compound of alkaline earth metal hydroxide solution, filtering off the undissolved materials and evaporating the filtrate to dryness. Sodium, potassium or calcium salts are pharmaceutically suitable. The present invention also provides processes for preparing benzopyran derivatives substituted with a thioxobenzoxazole derivative, represented in Particularly, the present invention provides a process for preparing a compound of Formula (I) . As shown in (HI) with a 2-aminophenol compound (IV) in the presence of a proper metal salt gives a compound of Formula (V). Then, cyclization of compound (V) using an appropriate thiocarbonyl transfer reagent, affords a 2- thioxobenzoxazole compound (I'). Finally, benzopyran compound of Formula (I) can be prepared by changing substituents R1, R2, R3, R4 and R5. This is defined as ^preparation process 1' hereafter. (Figure Removed) (Wherein, R1, R2, R3, R4, R5 and * are as defined in The present invention also provides another process to prepare a compound of Formula (I). As shown in (IV) using thiocarbonyl transfer reagent gives 2- thioxobenzoxazole of formula (VI) . Then, epoxide ring opening of compound (HI) is accomplished by reaction with a compound (VI) in the presence of a proper base, giving a compound of Formula (I' ) . Finally, a benzopyran derivative (I) can be prepared by changing substituents. This is defined as 'preparation process 2' hereafter. (Figure Removed) (Wherein, R , R , R , R% Rb and * are as defined In the present invention, a compound of diastereomer from the corresponding diastereomer of starting material. Each diastereomer can also be obtained by separating the diastereomeric mixture of compound (I) prepared from a diastereomeric mixture of starting material. The separation of diastereomers can be performed by generally known column chromatography or recrystallization. The preparation processes for benzopyran derivatives substituted with a thioxobenzoxazole derivative represented in invention are illustrated in more detail hereinafter. I. Preparation of starting material (1) Preparation of epoxide compound (ffl) Epoxide compound (HI) used as a starting material in the above explained in Korean Patent No. 2000-60647 and U.S. Patent 6,323,238. As shown in the below diastereomer (HZi), (m2) , (Eh) and (ffi4) of a compound (HI) can be possibly prepared from olefin compounds (W i) and (VH2) by employing an Mn (III) Salen epoxidation catalyst described in the above patents. (Wherein, R1 and R2 are as defined in The preparation process for the compounds of comprises the following steps: 1) preparing compound (V) by reaction of epoxide compound (M) and 2-aminophenol compound (IV) in the presence of a proper metal salt in proper solvent; 2) preparing 2-thioxobenzoxazole compound (I') by cyclization of the compound (V) using thiocarbonyl transfer reagent; and 3) preparing compound (I) by changing substituents of the compound (I'). The step 1) is a reaction of epoxide compound (III) with 2-aminophenol compound (IV) in proper solvent in the presence of a proper metal salt. As a metal salt, Mg(ClO4)2, CoCl2, LiC104, NaC104, CaCl2, ZnCl;, LiBF4 or Zn(Tf)2 can be used, and as a solvent, acetonitrile, tetrahydrofuran or dimethylformamide is available and acetonitrile is preferable among them. Reaction temperature ranges from room temperature to the boiling point of a solvent. In case that an individual stereoisomer of epoxide compound (HI) is used as a starting material, an individual stereroisomer with a stereochemistry corresponding to the compound used as a starting material will be obtained. As shown in the below be prepared from each epoxide compound (ffli) , (DD^) / (d 3) and (EU) . (Figure Removed) In cyclization of the above step 2), thiocarbonyl transfer reagent can be selected from a group consisting of carbon disulfide, and thiophosgens such as thiourea, 1,1' -thiocarbonyldiimidazole, l/l1- thiocarbonyldi-1,2,4-triazole, di-2-pyridyl thiocarbonate, 1,1'-thiocarbonyl-2,2'-pyridone, etc. In the above step 3), a compound (I) is prepared by changing substituents R1, R2, R3, R4 and R5 by alkylation, acylation, reduction, or substitution, etc. For example, as shown in compound (I) is amino group, the compound of the present invention can be prepared by reducing nitro group, for which hydrogenation is performed using a metal catalyst such as platinum, palladium on carbon (Pd/C) or Raney-nickel in proper solvent. An alternative way is reduction of nitro group using a reducing agent like NaBH4 in the presence of CuSO,}, Cu(OAc)2, CoCl2, SnCl2 or NiCl2. In this reaction, preferable solvent is a mixture of water and methanol and reaction temperature rangs from room temperature to the boiling point of a solvent. Reduction S (Wherein, R2, R4, R5 and * are as defined in III. Preparation process 2 Another process to prepare a compound (I) of compound (VI) is prepared by cyclization of 2- aminophenol compound (IV) such thiocarbonyl transfer reagents as in step 2) of the preparation process 1. In step 2), a compound (I') is prepared by epoxide ring opening, in which a compound (VI) is reacted with epoxide compound (ffl) in the presence of base. Both inorganic base such as sodium hydride, potassium t-butoxide, sodium methoxide, etc and organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc, are available. In step 3), a compound (I) is prepared by changing substituents by the same process as used in the preparation process 1. The present invention further provides a pharmaceutical composition for carioprotection containing benzopyran derivatives substituted with a thioxobenzoxazole derivative, represented in effective ingredient. When tested in ischemic heart models of Langendorff using isolated rat hearts, compounds of the present invention significantly prolong the time to contracture (TTC) , an index of heart protection, and improve recovery of the cardiac function (left ventricular developed pressure x heart rate, LVDP x HR) after reperfusion, but reduce release of lacrate dehydrogenase (LDH), an index for cell damage, which are similar or superior to cardioprotecting activity of BMS-180448, a control. In ischemic myocardium models using anesthetized rat, compounds of the present invention also show similar antiischemic activity to BMS-180448. In conclusion, the compounds of the present invention show excellent cardioprotecting activity in vitro and in vivo as well, so that they can be effectively applied as a cardioprotective medicine and a preventing or therapeutic agent for both ischemic heart diseases such as myocardial infarction, unstable angina pectoris, etc, and other troubles, caused by thrombolytics or reperfusion therapy like ?TCA (percutaneous transluminal coronary angioplasty) and CABG (coronary artery bypass graft), such as decrease of myocardial contractility, damage of myocardial cells, change of energy metabolism, decline of cognitive capability, etc. EXAMPLES Practical and presently preferred embodiments of the present invention are illustrative as shown in the following Examples. However, it will be appreciated that those skilled in the art, on consideration of this disclosure, may make modifications and improvements within the spirit and scope of the present invention. In the present invention, infrared spectroscopy, nuclear magnetic resonance spectroscopy, mass spectroscopy, liquid chromatography, x-ray crystallography, polarimetry were used along with the comparison of estimated results of elemental analysis of the representative compounds with analyzed results of them in order to confirm their molecular structures. Example 1: Preparation of (2R, 3R, 4S)-6-nitro-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-[(2- hydroxyphenyl)amino]-2H-l-benzopyran 400 nig (1.42 mmol) of epoxide compound (2R, 3R, 4R)-6-nitro-3,4-dihydro-3,4-epoxy-2-dimethoxymethyl-2- methyl-2H-l-benzopyran and 155 rag (1.42 mmol) of 2- aminophenol were dissolved in 1 m£ of acetonicrile (CH3CN), then 318 mg (1.42 mmol) of magnesium perchlorate [Mg(0104)2] was added thereto. The reaction was stirred at room temperature for 1 hour, 10 mi of saturated NaHCOs solution was added, and aqueous layer was extracted with 30 m£ of ethyl acetate. Organic layer was dried over anhydrous MgSO-i, concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate = 2:1), to give 518 nig (yield: 93%) of the target compound. ^H NMR (200 MHz, CDC13) 6l.39(s, 3H) , 3.61(s, 3H) , 3.62(s, 3H), 3.85(s, 1H) , 4.13(d, 1H) , 4.23(d, 1H) , 4.44(s, 1H) , 6.75(br-s, 1H), 6.78-6.93(m, 5H), 8.06(dd, 1H), 8.45(d, 1H) dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl) -2H-l-benzopyran 800 mg (2.05 mmol) of the compound obtained in the above step 1 was dissolved in 8 m£ of CH2C12, then 470 mg (2.05 mmol) of di-2-pyridyl thionocarbonate and 25 mg (0.2 mmol) of 4-dimethylaminopyridine were added thereto. The reaction was stirred at room temperature for 2 hours, 20m£ of saturated NaHC03 solution was added, and aqueous layer was extracted with 30 ml? of dichloromethane . Organic layer was washed with brine and dried over anhydrous MgS04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane : ethyl acetate = 1:1), to give 220 mg (yield: 97%) of the target compound. XH NMR (200 MHz, CDC13) 6l.53(s, 3H) , 3.62(s, 3H) , 3.66(sf 3H), 4.50(s, 1H) , 4.83(dd, 1H) , 6.42(d, 6.51(d, 1H), 7.02-7.23(m, 2H) , 7.38(d, 1H) , 7.78(d, 8.15(dd, Example 2: Preparation of (2R, 3S, 4R) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2 -methyl- 4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (2- hydroxyphenyl) amino] -2H-l-benzopyran 500 nig (1.78 mmol) of epoxide compound (2R, 3S, 4S) -6-nitro-3, 4-dihydro-3, 4-epoxy-2-dimethoxymethyl-2- methyl-2H-l-benzopyran and 194 rag (1.78 mmol) of 2- aminophenol were reacted according to the procedure described in the above step 1 of the example 1, to give 615 nig (yield: 89%) of the target compound. *H XMR (200 MHz, CDC13) 8l.50(s, 3H) , 3.52(s, 6H) , 4.05-4.23 (m, 3H) , 4.47(s, 1H) , 4.60(br-s, 1H) , 6.71- 6.96(m, 5H), 8.08(dd, 1H) , 8.38(d, dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 280 mg (0.72 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 2"0 ing (yield: 86%) of the target compound. 1R NMR (200 MHz, CDC13) 8l.67(s, 3H) , 3.53(s, 3H) , 3.57(s, 3H), 4.27(dd, 1H), 4.60(s, 1H) , 6.32(d, 6.78(d, 1H), 7.00-7.28(m, 3H) , 7.43(d, 1H) , 7.76(d, 8.16(dd, 1H) Example 3: Preparation of (2S, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (2- hydroxyphenyl) amino] -2H-l-benzopyran 300 nig (1.07 mmol) of epoxide compound (2S, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4-epoxy-2-dimethoxymethyl-2- raethyl-2H-l-benzopyran and 117 mg(1.07 mmol) of 2- aminophenol were reacted according to the procedure described in the above step 1 of the example 1, to give 329 rag (yield: 79%) of the target compound. XH NMR (200 MHz, CDC13) 6l.50(s, 3H) , 3.52(s, 6H) , 4.05-4.23(m, 3H) , 4.47(s, 1H) , 4.60(br-s, 1H) , 6.71- 6.96(m, 5H), 8.08(dd, 1H) , 8.38(d, dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 250 nig (0.64 mmol} of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 242 mg (yield: 88%) of the target compound. XH NMR (200 MHz, CDC13) 6l.67(s, 3H) , 3.54(s, 3H) , 3.57(s, 3H), 4.27(dd, 1H) , 4.60(s, 1H) , 6.33(d, 6.78(d, 1H), 7.00-7.22(m, 3H) , 7.43(d,l H) , 7.76(d, 8.16(dd, Example 4: Preparation of (2S, 3S, 4R) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (2- hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 1 g (3.56 mmol) of epoxide compound (2S, 3S, 4S) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 389 nig (3.56 mmol) of 2-aminophenol according to the procedure described in the step 1 of the example 1, to give 1.24 g (yield: 89%) of the target compound. XH NMR (200 MHz, CDC13) 6l.39(s, 3H) , 3.61(s, 3H) , 3.62(s, 3H), 3.85(s, 1H) , 4.13(d, 1H) , 4.23(d, 1H) , 4.44(s, 1H), 6.75(br-s, 1H) , 6.78-6.93(m, 5H) , 8.06(dd, 1H), 8.45(d, 1H) dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 350 rag (0.90 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 338 mg (yield: 87%) of the target compound. 1H NMR (200 MHz, CDC13) 8l.53(s, 3H) , 3.62(s, 3H) , 3.66(s, 3H) , 4.50(s, 1H) , 4.83(dd, 1H) , 6.42(d, 6.51(d, 1H), 7.02-7.23(m, 2H) , 7.38(d, 1H) , 7.78(d, 8.15(dd, Example 5: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 6- methyl-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (4- methyl-2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 300 mg(1.07 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 131 rag (1.07 mmol) of 5-methyl-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 281 rag (yield: 65%) of the target compound. XH NMR (200 MHz, CDC13) 61.36(3, 3H) , 2.26(s, 3H) , 3.61(3, 3H), 3.62(s, 3H) , 3.91(s, 1H) , 4.18(d, 1H) , 4.26(brms, 1H) , 4.41(s, 1H) , 6. 63-6.71 (m, 3H) , 6.86(dd, 2H) , 806(dd, 1H) , 8.54(d, 1H) Mass : 405(M+), 340, 272, 190, 144, 123, 75 dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 6- methyl-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 300 rag (0.74 mitiol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 264 mg (yield: 80%) of the target compound. XH NMR (200 MHz, CDC13) 8l.52(s, 3H) , 2.37(s, 3H) , 3.53(d, 3H), 4.46(s, 1H) , 4.80(dd, 1H) , 6.27(d, 6.47(d, 1H), 6.85(d, 1H) , 7.07(d, 1H) . 7.22(s, 7.75(d, 1H), 8.13(dd, Example 6: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (4- methyl-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ ( 6- methyl-2-hydroxyphenol) amino] -2H-l-benzopyran Reaction was performed with 1 g (3.56 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 0.44 g (3.56 mmol) of 3-methyl-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 1.15 g (yield: 80%) of the target compound. XH NMR (200 MHz, CDC13) 6l.32(s, 3H) , 2.33(s, 3H) , 3.23(s, 1H), 3.63(s, 3H) , 3.65(s, 3H) , 4.23(d, 1H) , 4.26(d, 1H), 4.42(s, 1H) , 4.48(d, 1H), 6.78-6.86(m, 3H), 6.89(d, 1H), 7.51(s, 1H), 8.01-8.07(dd, 1H) , 8.37(d, 1H) dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(4- methyl-2-thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 300 mg (0.74 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 137 nig (yield: 42%) of the target compound. *H NMR (200 MHz, CDC13) 6l.41(s, 3H) , 2.73(s, 3H), 3.60(3, 3H), 3.68(s, 3H) , 4.52{s, 1H) , 5.58(d, 1H) , 5.59(d, 1H), 7.02(d, 1H), 7.11-7.27(m, 3H), 7.76(d, 1H), 8.10(dd, 1H) Example 7; Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 5- chloro-2-thioxobenzoxazol-3-yl ) -2H-l-benzopyran . dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (5- chloro-2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 700 mg (2.48 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 356 nig (2.48 mmol) of 4-chloro-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 791 rag (yield: 89%) of the target compound. XH NMR (200 MHz, CDC13) 8l.41(s, 3H) , 3.61(s, 3H) , 3.62(sf 3H), 3.77{s, 1H) , 4.22(d, 1H) , 4.43(m, 2H) , 6.67(d, 2H), 6.80(d, 1H) , 6.91(d, 1H) , 8.07(dd, 8.35(d, dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (5- chloro-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 350 mg (0.82 mmol) of the compound prepared in the above step I according to the procedure described in the step 2 of the example 1, to give 348 mg (yield: 91%) of the target compound. XH NMR (200 MHz, CDC13) 6l.52(s, 3H) , 3.52(d, 1H) , 3.64(s, 3H) , 3.67(s, 3H) , 4.52(s, 1H) , 4.78(dd, 6.41(d, 1H), 6.47(d, 1H) , 7.11(d, 1H) , 7.20(dd, 7.34(d, 1H), 7.77{d, 1H) , 8.18(dd, Example 8: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (5- methyl-2-thioxobenzoxazol-3-yl ) -2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (5- methyl-2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 1 g (3 . 56 . mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 0.44 g (3.56 mmol) of 5-methyl-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 1.32 g (yield: 92%) of the target compound. H NMR (200 MHz, CDC13) 6l.39(s, 3H) , 2.24(s, 3H) , 3.31(s, 3H), 3.61(s, 3H) , 3.77(d, 1H) , 4.21(d, 4.43(s, 1H), 6.20(s, 1H) , 6.59(d, 1H) , 6.70(d, 6.92(d, 1H), 8.03(dd, 1H) , 8.44(d, dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 5- methyl-2-thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 300 rag (0.74 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 291 mg (yield: 88%) of the target compound. XH NMR (200 MHz, CDC13) 6l.66(s, 3H) , 2.25(s, 3H) , 3.36(3, 3H), 3.67(3, 3H) , 4.53(s, 1H) , 4.86(d, 1H) , 6.21(s, 1H), 6.53(d, 1H), 7.09(d, 1H) , 7.13(d, 7.27(d, 1H) , 7.76(s, 1H) , 8.13(dd, Example 9: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 6- nitro-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (4- nitro-2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 1 g (3.56 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 548 rag (3.56 mmol) of 5-nitro-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 927 rag (yield: 60%) of the target compound. XH NMR (200 MHz, CDC13) 6l.50(s, 3H) , 3.66(s, 6H) , 4.40(d, 1H), 4.49(s., 1H), 4.75(t, 1H) , 5.22(d, 6.61(d, 1H), 6.95(d, 1H) , 7.46(d, 1H) , 7.69(dd, 8.09(dd, 1H) , 8.18(d, dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 6- nitro-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 250 mg (0.57 itunol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 140 mg (yield: 51%) of the target compound. XH NMR (200 MHz, CDC13) 6l.54(s, 3H) , 3.54(s, 1H) , 3.63(s, 3H), 3.68(3, 3H) , 4.51(s, 1H) , 4.80(d, 1H) , 6.47(d, 1H) , 6.52(d, 1H) , 7.12(d, 1H) , 7.76(dd, 8.06(dd, 1H), 8.17(dd, 1H) , 8.25(d, Example 10: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (5- methoxy-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (5- methoxy-2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 200 mg (0.71 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 99 mg (0.71 mmol) of 4-methoxy-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 225 rag (yield: 89%) of the target compound. XH NMR (200 MHz, CDC13) 6l.38(s, 3H) , 3.60(s, 3H) , 3.61(s, 3H) , 3.60-3.80(br-s, 4H), 4.20(br-s, 2H) , 4.43(s, 1H), 6.20-6.80(br-s, 3H) , 6.90(d, 1H), 8.05(dd, 1H), 8.41(d, 1H) dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(5- methoxy-2-thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 320 rag (0.76 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 336 mg (yield: 96%) of the target compound. 1R NMR (200 MHz, CDC13) 6l.52(s, 3H) , 3.46(s, 1H) , 3.61-3.66(m, 6H) , 4.49(s, 1H) , 4.82(dd, 1H) , 5.96(d, 1H), 6.48(d, 1H) , 6.73(dd, 1H) , 7.07(d, 1H) , 7.30(d, 1H), 7.78(d, 1H), 8.14(dd, 1H) Example 11; Preparation of (2R, 3R, 4S)-6-nitro-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(5- bromo-2-thioxobenzoxazol-3-yl)-2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (5- bromo-2-hydroxyphenyl ) amino] -2H-l-benzopyran Reaction was performed with 500 mg (1.78 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 334 mg (1.78 mmol) of 4-bromo-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 535 mg (yield: 64%) of the target compound. XH NMR (200 MHz, CDC13) 6l.41(s, 3H) , 3.62(s, 3H) , 3.76(s, 1H), 4.24(d, 1H) , 4.43(m, 2H) , 6.67(d, 6.79(dd, 1H) , 6.89(d, 1H) , 6.93(d, 1H) , 8.05(dd, 8.35(d, dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (5- bromo-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 300 mg (0.64 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 316 mg (yield: 97%) of the target compound. XH NMR (200 MHz, CDC13) 6l.52(s, 3H) , 3.64(s, 3H) , 3.67(s, 3H), 4.52(s, 1H) , 4.82(d, 1H) , 6.44(d, 6.55(d, 1H), 7.13(d, 1H) , 7.30(d, 1H) , 7.34(dd, 7.77(d, 1H), 8.19(dd, Example 12; Preparation of (2R, 3R, 4S1-6-nitro-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(5-tbutoxy- 2-thioxobenzoxazol-3-vl)-2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(5-tbutoxy- 2-hydroxyphenyl)amino]-2H-l-benzopyran Reaction was performed with 500 mg (1.78 mmol) of epoxide compound (2R, 3R, 4R)-6-nitro-3,4-dihydro-3,4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 294 nig (1.78 mmol) of 4-t-butoxy-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 600 mg (yield: 76%) of the target compound. XH NMR (200 MHz, CDC13) 6l.27(s, 9H), 1.35(s, 3H) , 3.62(s, 3H), 3.63(3, 3H), 3.82(br-s, 1H), 3.94(s, 1H) , 4.29(d, 1H), 4.42(s, 1H) , 6.77-6.95(m, 5H) , 8.06(dd, 1H) , 8.58(d, 1H) dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(5- tbutoxy- 2-thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 350 mg (0.78 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 349 rag (yield: 92%) of the target compound. XH NMR (200 MHz, CDC13) 8l.ll(s, 9H) , 1.52(s, 3H) , 3.37(d, 1H), 3.58(s, 3H) , 3.67(s, 3H) , 4.50(s, 4.92(dd, 1H), 6.36(d, 1H) , 6.45(d, 1H) , 7.11(d, 7.24-7.32(m, 2H), 7.81(d, 1H), 8.14(dd, 1H) Example 13: Preparation of (2R, 3R, 4S)-6-nitro-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(6- fluoro-2-thioxobenzoxazol-3-yl)-2H-l-benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-[(5- fluoro-2-hydroxyphenyl)amino]-2H-l-benzopyran Reaction was performed with 500 mg (1.78 ramol) of epoxide compound (2R, 3R, 4R)-6-nitro-3,4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 226 mg (1.78 mmol) of 5-fluoro-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 365 mg (yield: 50%) of the target compound. 1H NMR (200 MHz, CDC13) 6l.35(s, 3H), 3.54(s, 1H), 3.63(3, 3H), 3.64(s, 3H) , 4.19(m, 3H) , 4.42(s, 1H) , 6.57(ddd, 1H), 6.65(dd, 1H), 6.90(d, 1H), 6.93(dd, 7.72(br-s, 1H), 8.07(dd, 1H), 8.56(d, dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 6- fluoro-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 309 mg (0.76 iranol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 290 mg (yield: 85%) of the target compound. XH NMR (200 MHz, CDC13) 5l.56(s, 3H) , 3.62(s, 3H) , 3.66(s, 3H) , 4.50(3, 1H) , 4.82(d, 1H) , 6.35(dd, 1H) , 6.49(d, 1H), 6.83(ddd, IE) , 7.11{d, 1H) , 7.20(dd, 1H) , 7.78(d, 1H), 8.17(dd, Example 14: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxvmethyl-2-methyl-4- (4- methoxycarbonyl-2-thioxobenzoxazol-3-yl) -2H-1- benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 6- methoxycarbonyl-2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 163 rag (0.58 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 97 nig (0.58 mmol) of 2-amino-hydroxybenzoic acid methyl ester according to the procedure described in the step 1 of the example 1, to give 214 mg (yield: 83%) of the target compound. XH NMR (200 MHz, CDC13) 8l.35(s, 3H) , 3.64(s, 3H), 3.65(3, 3H), 3.86(3, 3H) , 4.30(d, 1H) , 4.43(s, 1H) , 4 . 6 7 ( t , 1H), 6.87(t, 1H) , 7.08(d, 1H) , 7.17(d, 7.61(dd, 1H), 8.05(dd, 1H), 8.08(d, 1H), 8.21(d, dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(4- methoxycarbonyl-2-thioxobenzoxazol-3-yl)-2H-1- benzopyran Reaction was performed with 204 mg (0.46 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 152 nig (yield: 68%) of the target compound. NMR (200 MHz, CDC13) 6l.36(s, 3H) , 3.57(s, 3H), 3.67{s, 3H) , 3.94(s, 3H) , 4.46(s, 1H) , 5.41(d, 6 . 7 0 ( d , 1H), 7.01(d, 1H), 7.34(ddd, 1H) , 7.54(dd, 7.81(dd, 1H), 8.01(d, 1H), 8.13(dd, Example 15: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 5- methoxycarbonyl-2-thioxobenzoxazol-3-yl) -2H-1- benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (5- methoxycarbonyl-2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 1.173 g (4.17 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro- 3, 4-epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 697 mg (4.17 mmol) of 3-amino-4-hydroxybenzoic acid methyl ester according to the procedure described in the step 1 of the example 1, to give 305 mg (yield: 16%) of the target Compound. 1H NMR (200 MHz, CDC13) 8l.42(s, 3H) , 3.62(s, 6H) , 3.85(3, 3H), 4.27(d, 1H) , 4.44(m, 2H) , 6.80(d, 1H) , 6.93(d, 1H), 7.42(dd, 1H) , 7.53(d, 1H) , 8.04(dd, 8.34(d, dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (5- methoxycarbonyl-2-thioxobenzoxazol-3-yl) -2H-1- benzopyran Reaction was performed with 290 mg (0.65 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 152 mg (yield: 68%) of the target compound. XH NMR (200 MHz, CDC13) 6l.54(s, 3H) , 3.64(s, 3H) , 3.68(s, 3H), 3.86(s, 3H) , 4.53(s, 1H) , 4.89(d, 6.52(d, 1H), 7.14(m, 2H) , 7.47(d, 1H) , 7.78(m, 7.95(dd, 1H) , 8.15(m, Example 16: Preparation of (2R, 3R, 4S) -6-nitro-3 , 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (5- trif luoromethyl-2-thioxobenzoxazol-3-yl) -2H-1- benzopyran dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- [ (5- trif luoromethyl-2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 500 mg (1.78 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-dimethoxymethyl-2-methyl-2H-l-benzopyran and 315 nig (1.78 mmol) of 4-trif luoromethyl-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 259 nig (yield: 32%) of the target compound. XH NMR (200 MHz, CDC13) 8l.42(s, 3H), 3.62(s, 3H) , 3.62(s, 3H), 3.96(3, 1H) , 4.28(d, 1H) , 4.44(s, 1H) , 4.45(d, 1H) , 6.74(d, 1H) , 6.89-7.00(m, 3H) , 8.07(dd, 1H), 8.34(d, 1H) dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(5- trifluoromethyl-2-thioxobenzoxazol-3-yl)-2H-1- benzopyran Reaction was performed with 235 mg (0.51 iranol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 195 rag (yield: 76%) of the target compound. XH NMR (200 MHz, CDC13) 6l.45(s, 0.6H), 1.53(s, 2.4H), 3.55(s, 1H) , 3.61(s, 0.6H), 3.62(s, 2.4H), 3.67(3, 2.4H), 3.68(s, 0.6H), 4.51(s, 1H), 4.85(d, 1H) , 6.48(d, 1H), 6.63(s, 1H), 7.03(d, 0.2H), 7.12(d, 0.8H), 7.52-7.59(mf 2H), 7.73(d, 0.2H), 7.80(d, 0.8H), 8.18(dd, 1H) Example 17: Preparation of (2R, 3R, 4S)-6-amino-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran 200 nig (0.46 mmol} of the compound obtained in Example I was dissolved in 10 mi of methanol, to which 100 nig of Raney-Ni was added. Reaction was continued for 14 hours at room temperature with 3 atmospheric pressure of hydrogen gas. The reaction solution was filtered to eliminate Ni, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1), to give 177 nig (yield: 96%) of the target compound. XH NMR (200 MHz, CDC13) 6l.43(s, 3H) , 3.34(br-s, 2H), 3.47(br-s, 1H), 3.60(s, 3H), 3.62(s, 3H), 4.42(s, 1H), 4.75(d, 1H), 6.20(d, 1H), 6.31(d, 1H), 6.55-6.63(m, 2H), 6.78(d, 1H), 7.02-7.22(m, 2H), 7.35(dd, 1H) Example 18: Preparation of (2S, 3S, 4R)-6-amino-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 214 mg (0.49 mmol) of the compound prepared in Example 4 according to the procedure described in the example 17, to give 174 nig (yield: 88%) of the target compound. XH NMR (200 MHz, CDC13) 8l.43(s, 3H) , 3.34(br-s, 2H), 3.47(br-s, 1H), 3.60(s, 3H), 3.62(s, 3H), 4.42(s, , 4.75(d, 1H), 6.21(d, 1H) , 6.31(d, 1H), 6.57-6.63(m, 2H), 6.78(d, 1H), 7.06-7.26(m, 2H), 7.37(dd, 1H) Example 19: Preparation of (2S, 3R, 4S)-6-amino-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 242 mg (0.56 mmol) of the compound prepared in Example 3 according to the procedure described in the example 17, to give 177 rag (yield: 79%) of the target compound. XH NMR (200 MHz, CDC13) 5l.56(s, 3H) , 3.37(br-s, 2H), 3.43(br-s, 1H), 3.54{s, 3H), 3.60(s, 3H), 4.25(dd, 1H), 4.65(s, 1H), 6.19(d, 1H), 6.44(d, 1H), 6.54{d, 1H), 6.61(dd, 1H) , 6.80(d, 1H) , 7.09-7.23(m, 2H) , 7.38(d, 1H) Example 20: Preparation of (2R, 3S, 4R)-6-amino-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 187 mg (0.43 mmol) of the compound prepared in Example 2 according to the procedure described in the example 17, to give 142 mg (yield: 82%) of the target compound. XH NMR (200 MHz, CDC13) 6l.56(s, 3H) , 3.36(br-s, 2H), 3.42(br-s, 1H), 3.54(s, 3H), 3.59(s, 3H) , 4.24(dd, 1H) , 4.65(s, 1H) , 6.18(d, 1H) , 6.44(d,, 1H) , 6.52(d, 1H) , 6.61(dd, 1H) , 6.79(d, 1H) , 7.05-7.26(m, 2H) , 7.36{d, 1H) Example 21: Preparation of (2R, 3R, 4S)-6-amino-3,4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4-(6- methyl-2-thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 170 nig (0.38 mmol) of the compound prepared in Example 5 according to the procedure described in the example 17, to give 148 rag (yield: 93%) of the target compound. 1H NMR (200 MHz, CDC13) 61.42(3, 3H) , 2.37(s, 3H) , 3.32(s, 2H, NH2), 3.44(s, 1H, OH), 3.60(s, 3H), 3.61(s, 3H), 4.41(s, 1H), 4.73(d, 1H), 6.20(d, 1H), 6.28(d, 1H), 6.47(d, 1H), 6.58(dd, 1H) , 6.78(d, 1H) , 6.87(d, 1H) , 7.18(s, Example 22: Preparation of (2R, 3R, 4S) -6-amino-3f 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (5- methyl-2-thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 224 mg (0.50 mmol) of the compound prepared in Example 8 according to the procedure described in the example 11, to give 152 nig (yield: 73%) of the target compound. XH NMR (200 MHz, CDC13) 6l.42(s, 3H) , 2.25(s, 3H) , 3.61(s, 3H), 3.62(s, 3H) , 4.44(s, 1H) , 4.78(d, 1H) , 6.20(s, 1H), 6.27(d, 1H), 6.39(3, 1H) , 6.62(dd, 1H) , 6.77(d, 1H) , 6.95(d, 1H) , 7.19(d, Example 23: Preparation of (2R, 3R, 4S) -6-amino-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (4- methyl-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 107 mg (0.24 mmol) of the compound prepared in Example 6 according to the procedure described in the example 17, to give 82 mg 82%) of the target compound. NMR (200 MHz, CDC13) 61.47(8, 3H) , 1.91(s, 3H) , 3H) , 3.36(s, 3H) , 4.40(s, 1H) , 4.79(d, 1H) , 1H), 6.59(dd, 1H), 6.71(s, 1H) , 6.76(s, 1H) , 6.95(d, 1H), 7.12(t, 1H) , 7.23(d,lH) Example 24: Preparation of (2R, 3R, 4S) -6-amino-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 5- chloro-2-thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 218 mg (0.47 mmoi) of the compound prepared in Example 7 according to the procedure described in the example 17, to give 167 mg (yield: 81%) of the target compound. XH NMR (200 MHz, CDC13) 8l.41(s, 3H) , 3.37(br-s, 2H), 3.53(s, 1H) , 3.62(s, 3H) , 3.64(s, 3H) , 4.43(s, 1H) , 4.70(d, 1H), 6.19(d, 1H) , 6.27(d, 1H) , 6.58(d, 6.62(d, 1H) , 6.79(d, 1H) , 7.15(dd, 1H) , 7.27(d, Example 25: Preparation of (2R, 3R, 4S) -6-amino-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 5- methoxy-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 207 mg (0.45 mmol) of the compound prepared in Example 10 according to the procedure described in the example 17, to give 160 mg (yield: 82%) of the target compound. XH NMR (200 MHz, CDC13) 81.41(3, 3H) , 3.36(s, 1H) , 3.47(br-s, 2H) , 3.60{s, 3H) , 3.62(s, 3H) , 3.65(s, 3H) , 4.41(s, 1H), 4.75(d, 1H) , 6.14(d, 1H) , 6.22(d, 6.28(d, 1H), 6.57(dd, 1H) , 6.70(dd, 1H) , 6.77(d, 7.24(d, Example 26: Preparation of (2R, ' 3R, 4S) -6-amino-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 5- tbutoxy- 2-thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 220 mg (0.45 mmol) of the compound prepared in Example 12 according to the procedure described in the example 17, to give 167 nig (yield: 81%) of the target compound. 1H NMR (200 MHz, CDC13) 6l.l6(s, 3H) , 1.42(s, 3H) , 3.35(br-s, 3H) , 3.56(s, 3H) , 3.65(s, 3H) , 4.40(s, 1H) , 4.92(d, 1H), 6.24(s, 1H) , 6.26(d, 1H) , 6.59(m, 2H) , 6.79(d, 1H), 7.20-7.23(m, 2H) Example 27: Preparation of (2R, 3R, 4S) -6-amino-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- ( 6- f luoro-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 231 mg (0.51 mmol) of the compound prepared in Example 13 according to the procedure described in the example 17, to give 43 mg (yield: 20%) of the target compound. 1H NMR (200 MHz, CDC13) 6l.42(s, 3H) , 3.60(s, 3H) , 3.62(3, 3H) , 4.41(s, 1H) , 4.73(d, 1H) , 6.20(d, 1H) , 6.28(d, 1H) , 6.52(dd, 1H) , 6.60(ddd, 1H) , 6.76(d, 6.81(dd, 1H) , 7.13(dd, Example 28: Preparation of (2R, 3R, 4S) -6-amino-3 , 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (5- methoxycarbonyl-2-thioxobenzoxazol-3-yl) -2H-1- benzopyran Reaction was performed with 155 mg (0.32 mmol) of the compound prepared in Example 15 according to the procedure described in the example 17, to give 51 nig (yield: 35%) of the target compound. 1H NMR (200 MHz, CDC13) 8l.42(s, 3H) , 3.60(s, 3H) , 3.65(s, 3H) , 4.43(s, 1H) , 4.83(d, 1H) , 6.19(m, 6.26(d, 1H) , 6.60(dd, 1H) , 6.78(d, 1H) , 7.30(s, 7.40(d, 1H) , 7.92(dd, Example 29: Preparation of (2R, 3R, 4S) -6-amino-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (4- methoxycarbonyl-2-thioxobenzoxazol-3-yl) -2H-1- benzopyran Reaction was performed with 117 mg (0.24 imnol) of the compound prepared in Example 14 according to the procedure described in the example 17, to give 83 rag (yield: 75%) of the target compound. XH NMR (200 MHz, CDC13) 8l.29(s, 3H) , 3.54(s, 3H) , 3.66(s, 3H), 3.93(s, 3H) , 4.41(s, 1H) , 5.29(d, 1H) , 6.39(d, 1H), 6.58(t, 1H) , 6.71(m, 1H) , 7.26(m, 2H) , 7.47(d, 1H), 7.69(dd, Example 30; Preparation of (2R, 3R, 4S) -6-amino-3, 4- dihydro-3-hydroxy-2-dimethoxymethyl-2 -methyl- 4- (5- trifluoromethyl-2-thioxobenzoxazol-3-yl) -2H-1- benzopyran Reaction was performed with 100 mg (0.2 mmol) of the compound prepared in Example 16 according to the procedure described in the example 17, to give 78 mg (yield: 85%) of the target compound. XH NMR (200 MHz, CDC13) 8l.41(s, 3H) , 3.51(s, 1H) , 3.59(s, 3H), 3.64(s, 3H) , 4.42(s, 1H) , 4.77(d, 1H) , 6.22(d, 1H), 6.27(d, 1H) , 6.60(dd, 1H) , 6.81(m, 2H) , 7.46(m, 2H) Example 31: Preparation of (2R, 3R, 4S)-6-nitro-3,4- dihydro-3-acetoxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran 200 uig (0.46 mmol) of the compound obtained in Example 1 was dissolved in 2 m£ of dichloromethane, to which 87 ,uH (0.93 mmol) of acetic anhydride, 0.13 ml (0.93 mmol) of triethylamine and 17 rag (0.14 mmol) of 4-dimethylaminopyridine were added in that order. The reaction was stirred for 2 hours at room temperature, 10 m£ of saturated NaHCOs solution was added and extraction was performed with 30 m(J of dichloromethane. The extract was washed with brine and dried over anhydrous MgS04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate =2:1), to give 211 ing (yield: 97%) of the target compound. XH NMR (200 MHz, CDC13) 8l.56(s, 3H) , 2.02(s, 3H) , 3.54(3, 3H), 3.60(s, 3H) , 4.34(s, 1H) , 5.96(d, 1H) , 6.39(d, 1H), 6.59(d, 1H) , 7.06(m, 1H) , 7.16-7.25(m, 2H), 7.38(d, 1H), 7.79(d, 1H), 8.17(dd, Example 32: Preparation of (2R, 3R, 4S) -6-amino-3, 4- dihydro-3-acetoxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 106 mg (0.22 nunol) of the compound prepared in Example 31 according to the procedure described in the example 17, to give 85 mg (yield: 87%) of the target compound. XH NMR (200 MHz, CDC13) 6l.46(s, 3H) , 2.01(s, 3H) , 3.52(s, 3H), 3.56(s, 3H) , 4.28(s, 1H) , 5.89(d, 6.21(d, 1H), 6.38(d, 1H) , 6.61(m, ,2H) , 6.88(d, 7.07(m, 1H), 7.18(m, 1H) , 7.33(dd, Example 33: Preparation of (2R, 3R, 4S) -6-acetylamino- 3, 4-dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran 100 mg (0.25 mmol) of the compound obtained in Example 17 was dissolved in 2 m£ of dichloromethane, to which 23 id (0.25 mmol) of acetic anhydride, 52 fd (0.37 mmol) of triethylamine and 9.1 mg (0.07 mmol) of 4- dimethylaminopyridine were added in that order. The reaction was stirred for 3 hours at room temperature, 10 m£ of saturated NaHC03 solution was added and extraction was performed with 40 mi of dichloromethane. The extract was washed with brine and dried over anhydrous MgS04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1), to give 96 nig (yield: 86%) of the target compound. XH NMR (200 MHz, CDC13) 8l.45(s, 3H), 2.02(s, 3H) , 3.51{s, 1H), 3.61(s, 3H) , 3.64(s, 3H) , 4.45(s, 1H) , 4.79(d, 1H), 6.35(d, 1H) , 6.55(d, 1H) , 6.63(d, 1H) , 6.94(d, 1H), 7.02-7.22(m, 2H) , 7.32(d, 1H) , 7.76(dd, 1H) Example 34: Preparation of (2R, 3R, 4S)-6-acetylamino- 3,4-dihydro-3-acetoxy-2-dimethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 100 mg (0.25 mmol) of the compound prepared in the example 17, 76 //£ (0.75 mmol) of acetic anhydride, 104 [d (0.75 mmol) of triethylamine and 9 mg (0.07 mmol) of 4- dimethylaminopyridine according to the procedure described in Example 33, to give 113 mg (yield: 93%) of the target compound. 1H NMR (200 MHz, CDC13) 8l.48(s, 3H), 2.00(s, 3H), 2.02(s, 3H), 3.52(s, 3H) , 3.57(s, 3H) , 4.30(s, 5.92(d, 1H) , 6.44(d, 1H) , 6.53(d, 1H) , 6.68(d, 7.00-7.22(m, 3H) , 7.29(m, 1H) , 7.73 Example 35: Preparation of (2R, 3R, 4S) -6-benzoylamino- 3, 4-dihydro-3-hydroxy-2-dimethoxymethyl-2-methyl-4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran 80 nig (0.20 mmol) of the compound obtained in Example 17 was dissolved in 1 m£ of tetrahydropurane, to which 23 uA (0.20 mmol) of benzoil chloride and 42 fd (0.30 mmol) of triethylamine were added. They were reacted at room temperature for 1 hour. Then, 10 m£ of saturated NaHCOa solution was added and extraction was performed with 30 m£ of ethyl acetate. Organic layer was washed with brine and dried over anhydrous MgS04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1), to give 93 nig (yield: 92%) of the target compound. XH NMR (200 MHz, CDC13) 6l.47(s, 3H) , 3.51(br-s, 1H), 3.62(s, 3H) , 3.65(3, 3H) , 4.46(s, 1H) , 4.82(d, 1H) , 6.40(d, 1H) , 6.58(d, 1H), 6.77(s, 1H) , 7.01(d, 1H) , 7.07(t, 1H), 7.18(t, 1H), 7.32-7.49(m, 3H) , 7.70-7.76(m, 2H), 7.95(d, 1H) Example 36: Preparation of (2R, 3R, 4S)-6- trifluoroacetylamino-3, 4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4- (2-thioxobenzoxazol-3-yl) - 2H-l-benzopyran Reaction was performed with 80 mg (0.20 iranol) of the compound prepared in the example 17 and 28 fd (0.20 iranol) of trifluoroacetic anhydride according to the procedure described in Example 33, to give 94 nig (yield: 94%) of the target compound. XH NMR (300 MHz, CDC13) 6l.47(s, 3H) , 3.50(br-s, 1H), 3.61(s, 3H) , 3.65(s, 3H) , 4.46(s, 1H) , 4.83(d, 1H) , 6.40(d, 1H), 6.54(d, 1H) , 6.79(d, 1H) , 7.02(d, 7.09(dd, 1H), 7.21(dd, 1H) , 7.38(d, 1H) , 7.77(dd, Example 37; Preparation of (2R, 3R, 4S)-6- methanesulfonylamino-3, 4-dihydro-3-hydroxy-2- dimethoxymethyl-2-methyl-4- (2-thioxobenzoxazol-3-yl) - 2H-l-benzopyran 90 nig (0.22 mmol) of the compound prepared in Example 17 was dissolved in 1 in£ of dichloromethane, to which 58 fd (0.34 mmol) of methanesulfonyl chloride and 17 (d (0.22 mmol) of diaisopropylethylamine were added. The reaction was stirred for 10 hours at room temperature, 67 rag (yield: 64%) of the target compound was obtained through reaction accomplished by the same procedure as used in Example 33. !R NMR (300 MHz, CDC13) 6l.49(s, 3H), 2.68(s, 3H), 3.50(s, 1H), 3.60(s, 3H), 3.64(s, 3H) , 4.46(s, 4.78(d, 1H), 6.07(s, 1H) , 6.40(d, 1H) , 6.47(d, 6.60(d, 1H), 6.99(d, 1H), 7.08(dd, 1H), 7.20(dd, 7.29-7.39(m, 2H) Example 38; Preparation of (2R, 3R, 4S)-6-nitro-3,4- dihydro-3-hydroxy-2-methoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran dihydro-3-hydroxy-2-methoxymethyl-2-methyl-4-[(2- hydroxyphenyl)amino]-2H-l-benzopyran Reaction was performed with 200 mg (0.79 mmol) of epoxide compound (2R, 3R, 4R)-6-nitro-3,4-dihydro-3,4- epoxy-2-methoxymethyl-2-methyl-2H-l-benzopyran and 213 mg (0.95 mmol) of 2-aminophenol according to the procedure described in the step 1 of the example 1, to give 190 nig (yield: 67%) of the target compound. XH NMR (300 MHz, CDC13) 8l.31(s, 3H), 3.48(s, 3H), 3.62(d, 1H), 3.73(d, 1H), 4.12(d, 1H), 4.16(br-t, 4.50(br-t, 1H), 6.72-6.92(m, 5H) , 8.03(dd, 1H), 8.34(d, 1H) dihydro-3-hydroxy-2-methoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 120 fflg (0.30 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 110 mg (yield: 87%) of the target compound. XH NMR (300 MHz, CDC13) 6l.44(s, 3H), 2.95(d, 1H), 3.46(s, 3H) , 3.68(d, 1H) , 3.74(d, 1H) , 4.76(dd, 1H) , 6.36(d, 1H), 6.57(d, 1H), 7.05-7.41(m, 4H), 7.77(d, 1H), 8.14(dd, 1H) Example 39: Preparation of (2R, 3R, 4S)-6-nitro-3,4- dihydro-3-hydroxy-2-methoxymethyl-2-methyl-4-(5-chloro- 2-thioxobenzoxazol-3-yl)-2H-l-benzopyran dihydro-3-hydroxy-2-methoxymethyl-2-methyl-4-[(5- chloro-2-hydroxyphenyl)amino]-2H-l-benzopyran Reaction was performed with 400 rag (1.59 mmol) of epoxide compound (2R, 3R, 4R)-6-nitro-3, 4-dihydro-3,4- epoxy-2-methoxymethyl-2-methyl-2H-l-benzopyran and 390 mg (1.74 mmol) of 4-chloro-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 300 mg (yield: 48%) of the target compound. XH NMR (300 MHz, CDC13) 6l.34(s, 3H), 3.49(s, 3H) , 3.62(d, 1H), 3.74(d, 1H) , 4.15(d, 1H) , 4.50(d, 1H) , 6.61-6.69(m, 2H) , 6.81(s, 1H) , 6.91(d, 1H) , 8.02(dd, 1H), 8.23(d, 1H) dihydro-3-hydroxy-2-methoxymethyl-2-methyl-4-(5-chloro- 2-thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 120 mg (0.30 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 90 mg (yield: 67%) of the target compound. XH NMR (300 MHz, CDC13) 6l.44(s, 3H) , 2.95(br-s, 1H), 3.47(s, 3H), 3.68(d,lH), 3.72(dd, 2H), 4.69(d, 6.34(d, 1H), 6.53(d, 1H), 7.11-7.35(m, 3H), 7.76(d, 8.17(dd, Example 40: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-methoxycarbonyl-2-methyl-4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-methoxycarbonyl-2-methyl-4- [ (2- hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 200 mg (0.75 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-methoxycarbonyl-2-methyl-2H-l-benzopyran and 81 mg (0.74 mmol) of 2-aminophenol according to the procedure described in the step 1 of the example 1, to give 275 nig (yield: 95%) of the target compound. XH NMR (300 MHz, CDC13) 6l.72(s, 3H) , 2.36(br-s, 1H), 3.55(s, 3H), 4.35(d, 1H) , 4.43(d, 1H) , 5.60(br-s, 1H), 6.38(d, 1H) , 6.55(t, 1H) , 6.66(d, 1H) , 6.76(m, 1H) , 7.01(d, 1H) , 7.80(dd, 1H) , 8.34(d, dihydro-3-hydroxy-2-methoxycarbonyl-2-methyl-4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 120 mg (0.32 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 95 mg (yield: 71%) of the target compound. XH NMR (300 MHz, CDC13) 6l.76(s, 3H) , 3.32(br-s, 3.84(s, 3H) , 4.88(d, 1H) , 6.31(d, 1H) , 6.53(d, 1H), 7.05-7.27 (m, 3H) , 7.43(d, 1H) , 7.83(d, 1H) , 8.20(dd, Example 41: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-methoxycarbonyl-2-methyl-4- ( 5- chloro-2-thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-methoxycarbonyl-2-methyl-4- ( 5- chloro-2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 100 mg (0.40 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-methoxycarbonyl-2-methyl-2H-l-benzopyran and 99 nig (0.44 mmol) of 4-chloro-2-aminophenol according to the procedure described in the step 1 of the example 1, to give 150 mg (yield: 95%) of the target compound. 1H NMR (300 MHz, CDC13) 6l.73(s, 3H) , 2.70(br-s, 1H), 3.52(3, 3H), 4.36(d, 1H) , 4.38(d, 1H) , 5.87(br-s, 1H), 6.26(d, 1H) , 6.49(d, 1H) , 6.50(s, 1H) , 6.99(d, 1H) , 7.81(dd, 1H) , 8.34(d, dihydro-3-hydroxy-2-methoxycarbonyl-2-methyl-4- (5- chloro-2— thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 60 mg (0.14 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example I, to give 65 mg (yield: 98%) of the target compound. lti NMR (200 MHz, CDC13) 6l.73(s, 3H) , 3.40(d, 1H) , 3.88(s, 3H), 4.80(dd, 1H) , 6.29(s, 1H) , 6.50(d, 7.15-7.36(m, 3H) , 7.80(d, 1H) , 8.20(dd, Example 42: Preparation of (2R, 3R, 4S) -6-nitro-3, 4- dihydro-3-hydroxy-2-( [1, 3] dioxolan-2-yl) -2-methyl-4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2- ( [1, 3] dioxolan-2-yl) -2-methyl-4- [ (2-hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 900 mg (3.22 mmol) of epoxide compound (2R, 3R, 4R) -6-nitro-3, 4-dihydro-3, 4- ( [1, 3] dioxolan-2-yl) -2-methyl-2H-l-benzopyran and 352 nig (3.22 mmol) of 2-aminophenol according to the procedure described in the step 1 of the example 1, to give 965 mg (yield: 77%) of the target compound. XH NMR (300 MHz, CDC13) 8l.41(s, 3H) , 3.57(br-s, 1H), 4.03(m, 6H) , 4.51(d, 1H) , 5.41(s, 1H) , 6.76(m, 4H) , 6.95(d, 1H) , 8.04(dd, 1H) , 8.38(d, Mass : 388, 258, 190, 129, 109, 73 dihydro-3-hydroxy-2-([1,3]dioxolan-2-yl)-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 300 mg (0.77 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 193 nig (yield: 58%) of the target compound. XH NMR (300 MHz, CDC13) 6l.55(s, 3H) , 3.20(d, 1H), 4.10(m, 4H) , 4.77(dd, 1H) , 5.16(s, 1H) , 6.40(d, 1H) , 6.55(d, 1H), 7.06(t, 1H) , 7.09(d, 1H) , 7.13(t, 1H) , 7.42(d, 1H), 7.79(d, 1H), 8.02(dd, 1H) Mass : 430, 412, 339, 190, 73 Example 43: Preparation of (2R, 3R, 4S)-6-nitro-3,4- dihydro-3-hydroxy-2-([1,3]dioxan-2-yl)-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran dihydro-3-hydroxy-2-([1,3]dioxan-2-yl)-2-methyl-4-[(2- hydroxyphenyl)amino]-2H-l-benzopyran Reaction was performed with 600 mg (2.05 mmol) of epoxide compound (2R, 3R, 4R)-6-nitro-3,4-dihydro-3,4- ([1,3]dioxolan-2-yl)-2-methyl-2H-l-benzopyran and 668 mg (2.05 mmol) of 2-aminophenol according to the procedure described in the step 1 of the example 1, to give 668 nig (yield: 81%) of the target compound. XH NMR (300 MHz, CDC13) 6l.38(s, 3H), 1.49(d, 1H), 2.15(m, 1H), 3.95(m, 3H) , 4.08(d, 1H) , 4.33(m, 3H) , 4.40(t, 1H), 4.79(sf 1H), 6.84(m, 4H) , 6.97(d, 1H) , 8.06(dd, 1H), 8.60(d, 1H) Mass : 402, 258, 190, 143, 109, 87 dihydro-3-hydroxy-2-([1,3]dioxan-2-yl)-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 150 rag (0.37 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 138 mg (yield: 84%) of the target compound. XH NMR (300 MHz, CDC13) 8l.50(d, 1H) , 2.04(s, 3H) , 2.20(m, 1H), 3.92(m, 2H), 4.20(dd, 1H), 4.30(dd, 4.87(s, 1H), 5.32(d, 1H) , 6.45(d, 1H) , 6.52(d, 7.08(t, 1H), 7.23(m, 2H) , 7.42(d, 1H) , 7.72(d, 8.14(dd, 1H) Mass : 444, 426, 206, 160, 87 Example 44: Preparation of (2R, 3R, 4S)-6-nitro-3,4- dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4-[(2- hydroxyphenyl)amino]-2H-l-benzopyran Reaction was performed with 818 mg (2.64 mmol) of epoxide compound (2R, 3R, 4R)-6-nitro-3,4-dihydro-3,4- epoxy-2-diethoxymethyl-2-methyl-2H-l-benzopyran and 289 mg (2.64 mmol) of 2-aminophenol according to the procedure described in the step 1 of the example 1, to give 833 nig (yield: 75%) of the target compound. *H NMR (300 MHz, CDC13) 6l.26(m, 6H), 1.38(s, 3H) , 3.72(m, 2H), 3.89(m, 2H) , 3.92(d, 1H) , 4.08(3, 1H) , 4.26(d, 1H), 4.40(dd, 1H) , 4.57(s, 1H) , 6.43(s, 1H) , 6.82-6.92(m, 5H), 8.06(dd, 1H), 8.50(d, 1H) dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 200 rag (0.48 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 199 mg (yield: 90%) of the target compound. 1H NMR (300 MHz, CDC13) 6l.27(t, 6H) , 1.55(s, 3H) , 3.73(m, 3H), 3.92(m, 2H) , 4.65(s, 1H) , 4.88(d, 6.41(d, 1H) , 6.51(d, 1H), 7.05(m, 2H) , 7.22(dd, 7.42(d, 1H) , 7.79(d, 1H) , 8.14(dd, Example 45: Preparation of (2R, 3S, 4R) -6-nitro-3, 4- dihydro-3-hydroxy-2-diethoxymethyl-2 -methyl- 4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4- [ (2- hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 1.1 g (3.54 mmol) of epoxide compound (2R, 3S, 4S) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-diethoxymethyl-2-methyl-2H-l-benzopyran and 387 nig (3.54 mmol) of 2-aminophenol according to the procedure described in the step 1 of the example 1, to give 1.15 g (yield: 78%) of the target compound. 1H NMR (300 MHz, CDC13) 6l.07(t, 3H) , 1.24(t, 3H) , 1.54(s, 3H) , 3.58(m, 2H) , 3.80(m, 2H) , 4.03(dd, 1H) , 4.16(d, 1H) , 4.31(d, 1H) , 4 . 60 (m, 2H) , 5.78(br-s, 1H) , 6.72-6.87(m, 4H) , 6.91(d, 1H) , 8.08(dd, 1H) , 8.42(d, 1H) dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4-{2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 200 mg (0.48 iranol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example I, to give 169 mg (yield: 77%) of the target compound. XH NMR (300 MHz, CDC13) 80.84(t, 3H), 1.14(tf 3H), 1.68(s, 3H) , 3.61(m, 3H) , 3.78(m, 1H) , 3.87(m, 4.28(dd, 1H), 4.75(sf 1H) , 6.33(d, 1H) , 6.79(d, 7.03(dd, 1H), 7.06(d, 1H) , 7.21(dd, 1H), 7.42(d, 7.76(d, 1H), 8.16(dd, 1H) Mass : 460(M+) Example 46; Preparation of (2S, 3R, 4S)-6-nitro-3,4- dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4-[(2- hydroxyphenyl)amino]-2H-l-benzopyran Reaction was performed with 450 rag (1.45 mmol) of epoxide compound (2S, 3R, 4R)-6-nitro-3, 4-dihydro-3,4- epoxy-2-diethoxymethyl-2-methyl-2H-l-benzopyran and 159 mg (1.45 mmol) of 2-aminophenol according to the procedure described in the step 1 of the example 1, to give 555 nig (yield: 91%) of the target compound. XH NMR (300 MHz, CDC13) 6l.07(t, 3H) , 1.24(t, 3H) , 1.54(s, 3H) , 3.58(m, 2H) , 3.80(m, 2H) , 4.03(dd, 1H) , 4.16(dr 1H) , 4.31(d, 1H), 4.60(m, 2H), 5.78(br-s, 1H), 6.72-6.87(m, 4H) , 6.91(d, 1H) , 8.08(dd, 1H) , 8.42(d, 1H) dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4-(2- thioxobenzcxazol-3-yl)-2H-l-benzopyran Reaction was performed with 180 mg (0.43 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 159 mg (yield: 80%) of the target compound. XH NMR (300 MHz, CDC13) 60.84(t, 3H) , 1.14(t, 3H) , 1.68(s, 3H) , 3.61(m, 3H) , 3.78(m, 1H) , 3.87(m, 4.28(dd, 1H), 4.75(s, 1H) , 6.33(d, 1H) , 6.79(d, 7.03(dd, 1H), 7.06(d, 1H) , 7.21(dd, 1H) , 7.42(d, 7.76(d, 1H), 8.16(dd, Mass : 460(M+) Example 47: Preparation of (2S, 3S, 4R) -6-nitro-3, 4- dihydro-3-hydroxy-2-diethoxymethyl-2 -methyl- 4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4- [ (2- hydroxyphenyl) amino] -2H-l-benzopyran Reaction was performed with 346 mg (1.12 mmol) of epoxide compound (2S, 3S, 4S) -6-nitro-3, 4-dihydro-3, 4- epoxy-2-diethoxymethyl-2-methyl-2H-l-benzopyran and 122 mg (1.12 mmol) of 2-aminophenol according to the procedure described in the step 1 of the example 1, to give 416 nig (yield: 89%) of the target compound. XH NMR (300 MHz, CDC13) 8l.26(m, 6H) , 1.38(s, 3H) ,- 3.72(m, 2H), 3.89(m, 2H) , 3.92(d, 1H) , 4.08(s, 4.26(d, 1H), 4.40(dd, 1H) , 4.57(s, 1H) , 6.43(s, 6.82-6.92(m, 5H) , 8.06(dd, 1H) , 8.50(d, dihydro-3-hydroxy-2-diethoxymethyl-2 -methyl- 4- (2- thioxobenzoxazol-3-yl) -2H-l-benzopyran Reaction was performed with 130 mg (0.31 mmol) of the compound prepared in the above step 1 according to the procedure described in the step 2 of the example 1, to give 125 mg (yield: 87%) of the target compound. *H NMR (300 MHz, CDC13) 8l.27(t, 6H) , 1.55(s, 3H) , 3.73(m, 3H), 3.92(m, 2H) , 4.65(s, 1H) , 4.88(d, 1H) , 6.41(d, 1H) , 6.51(d, 1H) , 7.05(m, 2H) , 7.22(dd, 1H) , 7.42(d, 1H), 7.79(d, 1H), 8.14(dd, 1H) Mass : 460(M+) Example 48: Preparation of (2S, 3R, 4S)-6-amino-3,4- dihydro-3-hydroxy-2-diethoxymethyl-2-methyl-4-(2- thioxobenzoxazol-3-yl)-2H-l-benzopyran Reaction was performed with 200 mg (0.43 mmol) of the compound prepared in Example 46 according to the procedure described in the example 17, to give 177 mg (yield: 95%) of the target compound. :H NMR (300 MHz, CDC13) 60.84(t, 3H) , 1.14(t, 3H), 1.68(s, 3H), 3.61(m, 3H) , 3.78(m, 1H) , 3.87(m, 1H) , 4.28(dd, 1H), 4.75(s, 1H) , 6.33(d, 1H) , 6.79(d, 1H) , 7.03(dd, 1H), 7.06(d, 1H), 6.78(d,lH), 7.02-7.22(m,2H), 7.35(dd,lH) Mass : 430(M+) The following experiments were performed to investigate pharmacological activities of compounds of the present invention represented in Experimental Example I: Cardioprotective effect on isolated ischemia heart models of white rats The experiment confirming whether the compounds of effect) on ischemic heart was accomplished in the below. 100 mg/kg of sodium pentobarbital was injected in abdominal cavity of white male rats (300 ~ 450 g, obtained form the experimental animal team of the Korea Research Institute of Chemical Technology) to anesthetize them. Then, an intravenous injection of 1000 U/kg of heparin was performed before taking out heart. Particularly, cannula(PE 240) was inserted in the trachea, and artificial respiration was tried upon the rat by using a rodent ventilator. Under that condition, aortic cannula was inserted in the aorta and heart was taken out under retrograde perfusion. The extracted heart was hung on Langendorff apparatus quickly and unnecessary tissues on heart were removed. Perfusion was induced under static pressure (85 mmHg) with 37 °C modified Krebs-Henseleit bicarbonate buffer (composition KH2P04, 24.9 NaHC03, 2.52 CaCl2, 8.32 Glucose, 2.0 Pyruvate) saturated with 95% 02/5% C02. A metal cannula, to which a latex balloon filled with an ethanoldistilled water mixture (1:1 vol/vol) was linked, was inserted in left ventricle through pulmonary vein. Then, left ventricular pressure transmitted through the balloon was transduced by using pressure transducer, and amplified by using Plugsys bridge amplifier isovolumetrically. Then, the pressure was recorded in a recorder (Linearcorder mark 8 WR 3500) . Thereafter, heart was stabilized for 15 minutes. Then, left ventricular end diastolic pressure (LVEDP) was given by 5 mmHg and such volume of the balloon was kept all through the experiments. Baseline cardiac contractile function, heart rate (HR) , and coronary flow (CF) were measured. Cardiac contractile function was calculated by subtracting LVSP (left ventricular peak systolic pressure) from LVEDP (left ventricular end diastolic pressure), yielding LVDP (left ventricular developed pressure). Double product RPP (rate-pressure product)(DP), another important parameter for indirectly assessing cardiac performance in Langendorff heart, whose cardiac output could not be measured ordinarily, was calculated by multiplying HR by LVDP. Throughout the experiment, total coronary blood flow was measured by the use of coronary flow probe (diameter: 1.0 mm) installed in aortic cannula with electromagnetic flowmeter. Temperature of heart was steadily maintained by immersing the heart at 37 °C in physiological saline solution to which 95% 02/5% COz was constantly supplied. After stabilization for 15 min, the hearts were pretreated for 10 min with vehicle (0.04% DMSO) only or a compound of the present invention or the control material in the vehicle. Thereafter, cardiac contractile function, HR and CF were repeatedly measured. Global ischemia was induced by completely shutting off the perfusate for 30 min. Severity of ischemia was determined as the time to contracture (TTC, min) during global ischemia in which the first 5 mmHg increase in EDP was observed. Then, the hearts were reperfused and, 30 min later, contractile functions (LVDP, HR and CF) were repeatedly measured. After reperfusion was accomplished for 30 min, LDH (lactate dehydrogenase) was measured with a kit as a sensitive index for loss of cell viability. The results were shown in Table 1. Best View in Resolution of 1024x768 or later. Enable Javascript for Better Performance. |
|---|
5408-DELNP-2005-Abstract-(12-11-2008).pdf
5408-DELNP-2005-Abstract-(19-08-2008).pdf
5408-delnp-2005-assignment.pdf
5408-DELNP-2005-Claims-(12-11-2008).pdf
5408-DELNP-2005-Claims-(19-08-2008).pdf
5408-DELNP-2005-Correspondence-Others-(12-11-2008).pdf
5408-DELNP-2005-Correspondence-Others-(19-08-2008).pdf
5408-delnp-2005-correspondence-others.pdf
5408-delnp-2005-description (complete)-19-08-2008.pdf
5408-delnp-2005-description (complete).pdf
5408-DELNP-2005-Form-1-(12-11-2008).pdf
5408-DELNP-2005-Form-1-(19-08-2008).pdf
5408-DELNP-2005-Form-2-(12-11-2008).pdf
5408-DELNP-2005-Form-2-(19-08-2008).pdf
5408-DELNP-2005-Form-3-(19-08-2008).pdf
5408-DELNP-2005-GPA-(12-11-2008).pdf
5408-DELNP-2005-Petition-137-(12-11-2008).pdf
| Patent Number | 227257 | |||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Indian Patent Application Number | 5408/DELNP/2005 | |||||||||||||||||||||||||||||||||||||||
| PG Journal Number | 04/2009 | |||||||||||||||||||||||||||||||||||||||
| Publication Date | 23-Jan-2009 | |||||||||||||||||||||||||||||||||||||||
| Grant Date | 05-Jan-2009 | |||||||||||||||||||||||||||||||||||||||
| Date of Filing | 24-Nov-2005 | |||||||||||||||||||||||||||||||||||||||
| Name of Patentee | DONGBU HANNONG CHEMICAL CO. LTD., | |||||||||||||||||||||||||||||||||||||||
| Applicant Address | 19-20F, DONGBU FINANCIAL CENTER, 891-10 DAECHI-DONG, KANGNAM-KU, SEOUL 135-523 KOREA. | |||||||||||||||||||||||||||||||||||||||
Inventors:
|
||||||||||||||||||||||||||||||||||||||||
| PCT International Classification Number | C07D 413/04 | |||||||||||||||||||||||||||||||||||||||
| PCT International Application Number | PCT/KR2004/001271 | |||||||||||||||||||||||||||||||||||||||
| PCT International Filing date | 2004-05-28 | |||||||||||||||||||||||||||||||||||||||
PCT Conventions:
|
||||||||||||||||||||||||||||||||||||||||