Title of Invention

BENZAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY CYTOKINES

Abstract

A process for the preparation of an amide derivative of the Formula I, wherein: R1 and R2 , which may be the same or different, are selected from hydroxy, C1-6alkoxy, mercapto, C1-6alkylthio, amino, C1-6alkylamino, di-(C1-6alkyl)amino, carboxy, C1-6alkoxycarbonyl, carbamoyl, C1-6alkylcarbamoyl, di-C1-6alkylcarbamoyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, arylsulphinyl, arylsulphonyl, C1-6alkylaminosulphonyl, di-(C1-6alkyl)aminosulphonyl, nitro, cyano, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkanoylamino, C1-6alkoxycarbonylamino, C1-6alkanoyl, C1-6alkanoyloxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halo, trifluoromethyl, aryl, arylC1-6alkyl, arylC1-6alkoxy, heteroaryl, heteroarylC1-6alkyl, heterocyclyl and heterocyclylC1-6alkyl; m and p are independently 0-3, and when m and/or p is 2 or 3 each R' or R2 group may be the same or different; R3 is halo, cyano or C1-6alkoxy; q is 0-4; and R4 is aryl or cycloalkyl wherein R4 is optionally substituted with up to 3 substituents having any value defined for each R' group; or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, which comprises:- (a) the reaction of a compound of the Formula U with an acid of the Formula III or an activated derivative thereof, under standard amide bond forming conditions, wherein variable groups are as defined in claim 1 and wherein any functional group is protected if necessary, and: (i) removing any protecting groups; Formula V or an activated derivative thereof, with an aniline of the Formula VII (ii) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable ester; (b) the reaction of an acid of the Formula V under standard amide bond forming conditions, wherein variable groups are as defined in claim 1 and wherein any functional group is protected, if necessary, and: (i) removing any protecting groups; (ii) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable ester; or (c) for the preparation of a compound of the Formula I according to claim 1 wherein R or a substituent on R4 is an amino group, the reduction of a compound of the Formula I wherein R' or a substituent on R4 is a nitro group.

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] PROVISIONAL/ COMPLETE SPECIFICATION [See Section 10] "BENZAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY CYTOKINES" AstraZeneca AB, S-151 85 Sodertalje, Sweden The following specification particularly describes the nature of the invention and the manner in which it is to be performed :- BENZAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES MEDIATED BY CYTOKINES This invention concerns certain amide derivatives which are useful as inhibitors of cytokine mediated disease. The invention also concerns processes for the manufacture of the amide derivatives of the invention, pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of inhibition of cytokine mediated disease. The amide derivatives disclosed in the present invention are inhibitors of the production of cytokines such as Tumour Necrosis Factor (hereinafter TNF), for example TNFa, and various members of the interleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8. Accordingly the compounds of the invention will be useful in the treatment of diseases or medical conditions in which excessive production of cytokines occurs, for example excessive production of TNFa or IL-1. It is known that cytokines are produced by a wide variety of cells such as monocytes and macrophages and that they give rise to a variety of physiological effects which are believed to be important in disease or medical conditions such as inflammation and immunoregulation. For example, TNFa and IL-1 have been implicated in the cell signalling cascade which is believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. It is also known that, in certain cellular systems, TNFa production precedes and mediates the production of other cytokines such as IL-1. Abnormal levels of cytokines have also been implicated in, for example, the production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes, the stimulation of the release of proteolytic enzymes such as collagenase, the activation of the immune system, for example by stimulation of T-helper cells, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferation and to angiogenesis. Cytokines are also believed to be implicated in the production and development of disease states such as inflammatory and allergic diseases, for example inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, Crohn's disease and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis, allergic rhinitis and adult respiratory distress syndrome), and in the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart failure, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteoperosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. Excessive cytokine production has also been implicated in mediating certain complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in mediating certain complications of CNS surgery or injury such as neurotrauma and ischaemic stroke. Excessive cytokine production has also been implicated in mediating or exacerbating the development of diseases involving cartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis and multiple sclerosis. Evidence of the central role played by TNFa in the cell signalling cascade which gives rise to rheumatoid arthritis is provided by the efficacy in clinical studies of antibodies of TNFa (The Lancet. 1994, 344, 1125 and British Journal of Rheumatology. 1995, 34, 334). Thus cytokines such as TNFa and IL-1 are believed to be important mediators of a considerable range of diseases and medical conditions. Accordingly it is expected that inhibition of the production of and/or effects of these cytokines will be of benefit in the prophylaxis, control or treatment of such diseases and medical conditions. Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds inhibit the effects of cytokines by virtue of inhibition of the enzyme p38 kinase. p38 kinase, otherwise known as cytokine suppressive binding protein (hereinafter CSBP) and reactivating kinase (hereinafter RK), is a member of the mitogen-activated protein (hereinafter MAP) kinase family of enzymes which is known to be activated by physiological stress such as that induced by ionising radiation, cytotoxic agents, and toxins, for example endotoxins such as bacterial lipopolysaccharide, and by a variety of agents such as the cytokines, for example TNFa and IL-1. It is known that p38 kinase phosphorylates certain intracellular proteins which are involved in the cascade of enzymatic steps which leads to the biosynthesis and excretion of cytokines such as TNFa and IL-1. Known inhibitors of p38 kinase have been reviewed by G. J. Hanson in Expert Opinions on Therapeutic Patents, 1997, 7, 729-733. p38 kinase is known to exist in isoforms identified as p38a and p38β The compounds disclosed in the present invention are inhibitors of the production of cytokines such as TNF, in particular of TNFa, and various interleukins, in particular IL-1. It is known from J. Med. Chem.. 1996,39, 3343-3356, that certain benzamide derivatives can upregulate the expression of the low density lipoprotein (LDL) receptor in human hepatocyte cells. The disclosed compounds included certain N-(2-methoxyphenyl)-and N-(2-halogenophenyl)-benzamide derivatives. The compound N-(5-benzamido-2-chlorophenyl)benzamide is disclosed in J. Chem. Res. Synop., 1998, 182-183. 886-896 (Chemical Abstracts volume 129, abstract 67538). According to one aspect of the present invention there is provided a compound of the Formula I wherein: R1 and R2, which may be the same or different, are selected from hydroxy, C1-6alkoxy, mercapto, C1-6alkylthio, amino, C1-6alkylamino, di-(C1-6alkyl)amino, carboxy, C1-6alkoxycarbonyl, carbamoyl, C1-6alkylcarbamoyl, di-C1-6alkylcarbamoyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, arylsulphinyl, arylsulphonyl, C1-6alkylaminosulphonyl, di-(C1-6alkyl)aminosulphonyl, nitro, cyano, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkanoylamino, C1-6alkoxycarbonylamino, C1-6alkanoyl, C1-6alkanoyloxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halo, trifluoromethyl, aryl, arylC1-6alkyl, arylC1-6alkoxy, heteroaryl, heteroarylC1-6alkyl, heterocyclyl and heterocyclylC1-6alkyl; m and p are independently 0-3, and when m and/or p is 2 or 3 each R1 or R2 group may be the same or different; R3 is halo, cyano or C1-6alkoxy; q is 0-4; and R4 is aryl or cycloalkyl wherein R4 is optionally substituted with up to 3 substituents having any value defined for each R1 group; or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof; with the proviso that: N-[5-(3-cyclohexylpropionylamino)-2-methoxyphenyl]-4-acetoxybenzamide, N-[2-bromo-5-(3-cyclohexyIpropionylamino)phenyl]-4-hydroxybenzamide, N-[2-chloro-5-(3-cyclohexylpropionylamino)phenyl]-4-acetoxybenzamide, N-[2-chloro-5-(3-cyclohexylpropionylamino)phenyl]-4-hydroxybenzamide, N-[2-fluoro-5-(3-cyclohexylpropionylamino)phenyl]-4-hydroxybenzamideand N-(5-benzamido-2-chlorophenyl)benzamide are excluded. "Aryl" in terms such as "aryl", "arylC1-6alkyl", "arylthio", "arylsulphinyl", "arylsulphonyl" and "arylC1-6alkoxy" typically means phenyl or naphthyl, preferably phenyl. "Heteroaryl" in the terms "heteroaryl" and "heteroarylC1-6alkyl" means an aromatic mono- or bicyclic 5-10 membered ring with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur. Examples of 'heteroaryl' include thienyl, pyrrolyl, furyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl and cinnolinyl. "Heterocyclyl" in the terms "heterocyclyl" and "heterocyclylC1-6alkyl" means a non-aromatic mono- or bicyclic 5-10 membered ring with up to five ring hetero atoms selected from nitrogen, oxygen and sulphur. Examples of 'heterocyclyl' include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl and dihydropyrimidinyl. "Cycloalkyl" means a non-aromatic mono- or bicyclic 5-10 membered carbon ring. Examples of "cycloalkyl" include cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl and bicyclo[4.4.0]decyl. Typical values for other generic groups include: for C1-6alkoxy, for example, methoxy and ethoxy, for C1-6alkylthio, for example, methylthio and ethylthio, for C1-6alkylamino, for example, methylamino and ethylamino, for di-(C1-6alkyI)ainino, for example, dimethylamino, for C1-6alkoxycarbonyl, for example, methoxycarbonyl and ethoxycarbonyl, for C1-6alkylcarbamoyl, for example, methylcarbamoyl, for di-C1-6alkylcarbamoyl, for example, dimethylcarbamoyl, for C1-6alkylsulphinyl, for example, methylsulphinyl, for C1-6aIkylsulphonyl, for example, methylsulphonyl, for C1-6alkylaminosulphonyl, for example, methylaminosulphonyl, for di-(C1-6alkyl)aminosulphonyl, for example, dimethylaminosulphonyl, for cyanoC1-6alkyl, for example, cyanomethyl, for hydroxyC1-6alkyl, for example, hydroxymethyl, for aminoC1-6alkyl, for example, aminomethyl. for C1-6alkanoylamino, for example, formamido and acetamido, for C1-6alkoxycarbonylamino, for example, methoxycarbonylamino, for C1-6alkanoyl, for example, formyl and acetyl, for C1-6alkanoyloxy, for example, acetoxy, for C1-6alkyl, for example, methyl, ethyl, isopropyl and ten-butyl, for C2-6aIkenyl, for example, vinyl and allyl, for C2-6alkynyl, for example, ethynyl and 2-propynyl, for halo, for example, fluoro, chloro and bromo, for arylC1-6alkyl, for example, benzyl, and for arylC1-6aIkoxy, for example, benzyloxy. Any ring in R1 or R2 or any ring in a substituent on R4 may be optionally substituted, for example by up to 3 substituents. Suitable substituents include: hydroxy, C1-6alkoxy, mercapto, C1-6alkylthio, amino, C1-6alkylamino, di-(C1-6alkyl)amino, carboxy, carbamoyl, C1-6alkylcarbamoyl, di-C1-6alkylcarbamoyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl. arylsulphinyl, arylsulphonyl, C1-6alkylaminosulphonyl, di-(C1-6alkyl)aminosulphonyl, nitro, cyano, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkanoylamino, C1-6alkoxycarbonylamino, C1-6alkanoyl, C1-6alkanoyloxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halo and trifluoromethyl. In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms. It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting cytokines, in particular TNF. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, inhibitory properties against TNF may be evaluated using the standard laboratory techniques referred to hereinafter. Preferably R' is hydroxy, C1-6alkoxy, amino, C1-6alkylamino, di-(C1-6alkyl)amino, carboxy, C1-6alkoxycarbonyl, carbamoyl, C1-6alkylcarbamoyl, cyano, C1-6alkanoylamino, C1-6alkanoyl, C1-6alkanoyloxy, C1-6alkyl, halo, trifluoromethyl or heterocyclyl. Further preferably R' is aminoC1-6alkyl. More preferably R' is hydroxy, C1-6alkoxy, cyano. halo, morpholino or 4-methylpiperazin-1 -yl. Preferably m is 1 or 2. Conveniently p is 1 and R2 is C1-6alkoxy, carboxy, C1-6alkoxycarbonyl, C1-6alkyl or halo. Preferably p is 0. Preferably R3 is halo. Preferably q is 0, 1 or 2. More preferably q is 0. Preferably R4 is phenyl, cyclohexyl or cyclopentyl. More preferably R4 is phenyl. Preferred substituents on R4 are hydroxy, C1-6alkoxy, amino, C1-6alkylamino, di-(C1-6aIkyl)amino, carboxy, C1-6alkoxycarbonyl, nitro, cyano, C1-6alkanoylamino, C1-6alkanoyl, C1-6alkanoyloxy, C1-6alkyl, halo, trifluoromethyl, phenyl, phenylC1-6alkoxy and heterocyclyl. More preferably substituents on R4 are selected from hydroxy, cyano, dimethylamino, methoxy, ethoxy, fluoro, chloro and morpholino. Particular novel compounds of the invention include, for example, amide derivatives of the Formula I, or pharmaceutically-acceptable salts thereof, subject to the exclusions defined hereinbefore, wherein: - (a) R' is hydroxy, C1-6alkoxy, amino, C1-6alkylamino, di-(C1-6alkyl)amino. carboxy. C1-6alkoxycarbonyl, nitro, cyano, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkanoylamino, C1-6alkoxycarbonylamino, C1-6alkanoyl, C1-6alkanoyloxy, C1-6alkyl, halo or trifluoromethyl, and m is 1 or 2; and R2, R3 R4 p and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (b) R' is a non-aromatic saturated 5- or 6-membered heterocyclic ring with one or two heteroatoms selected from nitrogen, oxygen and sulphur, and m is I or 2; and R2, R3 R4 p and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (c) R' is a saturated heterocyclic ring selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and 4-(C1-6alky)piperazinyl, and m is 1 or 2; and R2, R3, R4, p and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (d) R2 is hydroxy, C1-6alkoxy, amino, C1-6alkylamino, di-(C1-6alkyl)amino, carboxy, C1-6alkoxycarbonyl, nitro, cyano, C1-6alkyl, halo or trifluoromethyl, and p is 1; and R', R3 R4 m and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (e) p is 0; and R', R3, R4, m and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (f) R3 is halo; and R', R2, R4, m, p and q have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (g) q is 1, 2, 3 or 4, and R4 is cycloalkyl; and R', R2, R3, m and p have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (h) q is 0, and R4 is phenyl which is optionally substituted with up to 3 substituents selected from hydroxy, C1-6alkoxy, amino, C1-6alkylamino, di-(C1-6alkyl)amino, carboxy, C1-6alkoxycarbonyl, nitro, cyano, C1-6alkoxycarbonylamino, C1-6alkanoyl, C1-6alkanoyloxy, C1-6alkyl, halo, trifluoromethyl, phenyl, benzyl and benzyloxy; and R', R2, R3, m and p have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (i) q is 0, and R4 is phenyl which is substituted with 1 or 2 substituents selected from heteroaryl, heteroarylC1-6alkyl, heterocyclyl and heterocyclylC1-6alkyl; and R', R2, R3, m and p have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; (j) q is 0, and R4 is phenyl which is substituted with 1 or 2 heterocyclyl groups comprising a non-aromatic saturated 5- or 6-membered heterocyclic ring with one or two heteroatoms selected from nitrogen, oxygen and sulphur; and R,, R2, R3, m and p have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention; and (k) q is 0, and R4 is phenyl which is substituted with 1 or 2 heterocyclic groups selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and 4-(C].6alkyl)piperazinyl; and R'. R2, R3, m and p have any of the meanings defined hereinbefore or in this section relating to particular novel compounds of the invention. A preferred compound of the invention is an amide derivative of the Formula I wherein R' is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, amino, methylamino. ethylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, cyano, acetamido, acetyl, acetoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, trifluoromethyl, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl or 4-methylpiperazin-l-yl; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; q is 1,2 or 3; and R4 is cyclohexyl or cyclopentyl; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention is an amide derivative of the Formula I wherein R' is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, cyano, acetamido, acetyl, acetoxy, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, fluoro, chloro, trifluoromethyl, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl or 4-methylpiperazin-l-yl; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; q is 0; and R4 is phenyl which is optionally substituted with 1 or 2 substituents selected from hydroxy, methoxy. ethoxy, propoxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, nitro, cyano, acetamido, acetyl, acetoxy, methyl, ethyl, fluoro, chloro, bromo, trifluoromethyl, phenyl, benzyloxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl and 4-methylpiperazin-l-yl; or a pharmaceutically-acceptable salt thereof A further preferred compound of the invention is an amide derivative of the Formula I wherein R' is hydroxy, methoxy, ethoxy, cyano, fluoro. chloro, morpholino or 4-methylpiperazin-l-yl; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; q is 0; and R4 is phenyl which is substituted with 1 or 2 substituents selected from hydroxy, methoxy, dimethylamino, methoxycarbonyl, cyano, fluoro, chloro and morpholino; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention is an amide derivative of the Formula I wherein R' is hydroxy, methoxy, ethoxy, amino, cyano, acetoxy, fluoro, chloro, morpholino or 4-methylpiperazin-l-yl; m is 1 or 2; p is 0; R3 is fluoro, chloro or bromo; q is 0; and R4 is phenyl which is unsubstituted or substituted with 1 or 2 substituents selected from hydroxy, methoxy, amino, dimethylamino, methoxycarbonyl, nitro, cyano, fluoro, chloro and morpholino; or a pharmaceutically-acceptable salt thereof. Particular preferred compounds of the invention include, for example:-N-[2-chloro-5-(3-cyanobenzamido)phenyl]-3,4-dimethoxybenzamide, N-[2-chloro-5-(3-dimethylaminobenzamido)phenyl]-3,4-dimethoxybenzamide, N-[2-chloro-5-(4-cyanobenzamido)phenyl]-3,4-dimethoxybenzamide and N-[2-chloro-5-(4-cyanobenzamido)phenyl]-3-(4-methylpiperazin-l-yl)benzamide; or the pharmaceutically-acceptable salts thereof. Further particular preferred compounds of the invention include, for example:-N-(5-benzamido-2-chlorophenyl)-3,4-dimethoxybenzamide, N-[2-chloro-5-(3-morpholinobenzamido)phenyl]-3,4-dimethoxybenzamide, N-[5-(4-aceioxybenzamido)-2-chlorophenyl)-4-cyanobenzamide, N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide and N-[2-chloro-5-(3-morpholinobenzamido)phenyl]-4-cyanobenzamide; or the pharmaceutically-acceptable salts thereof. A suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191(1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,285 (1988); and e) N. Kakeya, et al, Chem Pharm Bull, 32,692 (1984). Examples of such pro-drugs may be used to form in-vivo-cleavable esters of a compound of the Formula I. An in-vivo-cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically-acceptable esters for carboxy include C1-6alkoxymethyl esters, for example methoxymethyl; C1-6alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl esters; C1-6CycloalkoxycarbonyloxyC1-6alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolan-2-ylmethyl esters, for example 5-methy1-1-3-dioxolan-2-ylmethyl; and C1-6alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl; and may be formed at any carboxy group in the compounds of this invention. In order to use a compound of the Formula I or a pharmaceutically acceptable salt or in-vivo-cleavable ester thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. According to this aspect of the invention there is provided a pharmaceutical composition which comprises an amide derivative of the Formula 1, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as com starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; WE CLAIM: 1. A process for the preparation of an amide derivative of the Formula I, wherein: R1 and R2 , which may be the same or different, are selected from hydroxy, C1-6alkoxy, mercapto, C1-6alkylthio, amino, C1-6alkylamino, di-(C1-6alkyl)amino, carboxy, C1-6alkoxycarbonyl, carbamoyl, C1-6alkylcarbamoyl, di-C1-6alkylcarbamoyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, arylsulphinyl, arylsulphonyl, C1-6alkylaminosulphonyl, di-(C1-6alkyl)aminosulphonyl, nitro, cyano, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, C1-6alkanoylamino, C1-6alkoxycarbonylamino, C1-6alkanoyl, C1-6alkanoyloxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halo, trifluoromethyl, aryl, arylC1-6alkyl, arylC1-6alkoxy, heteroaryl, heteroarylC1-6alkyl, heterocyclyl and heterocyclylC1-6alkyl; m and p are independently 0-3, and when m and/or p is 2 or 3 each R' or R2 group may be the same or different; R3 is halo, cyano or C1-6alkoxy; q is 0-4; and R4 is aryl or cycloalkyl wherein R4 is optionally substituted with up to 3 substituents having any value defined for each R' group; or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, which comprises:- (a) the reaction of a compound of the Formula U with an acid of the Formula III or an activated derivative thereof, under standard amide bond forming conditions, wherein variable groups are as defined in claim 1 and wherein any functional group is protected if necessary, and: (i) removing any protecting groups; Formula V or an activated derivative thereof, with an aniline of the Formula VII (ii) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable ester; (b) the reaction of an acid of the Formula V under standard amide bond forming conditions, wherein variable groups are as defined in claim 1 and wherein any functional group is protected, if necessary, and: (i) removing any protecting groups; (ii) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable ester; or (c) for the preparation of a compound of the Formula I according to claim 1 wherein R or a substituent on R4 is an amino group, the reduction of a compound of the Formula I wherein R' or a substituent on R4 is a nitro group. Dated this 9th day of October, 2000. [SANJAY KUMAR] Of REMFRY & SAGAR ATTORNEY FOR THE APPLICANT[S]

Documents:

in-pct-2000-00476-mum-cancelled pages(14-06-2004).pdf

in-pct-2000-00476-mum-claims(granted)-(14-06-2004).doc

in-pct-2000-00476-mum-claims(granted)-(14-06-2004).pdf

in-pct-2000-00476-mum-correspondence(147-06-2004).pdf

in-pct-2000-00476-mum-correspondence(ipo)-(16-12-2002).pdf

in-pct-2000-00476-mum-form 1(09-10-2000).pdf

in-pct-2000-00476-mum-form 1a(14-06-2004).pdf

in-pct-2000-00476-mum-form 2(granted)-(14-06-2004).doc

in-pct-2000-00476-mum-form 2(granted)-(14-06-2004).pdf

in-pct-2000-00476-mum-form 3(09-10-2000).pdf

in-pct-2000-00476-mum-form 4(20-02-2004).pdf

in-pct-2000-00476-mum-form 5(09-10-2000).pdf

in-pct-2000-00476-mum-form-form-pct-isa-210(09-10-2000).pdf

in-pct-2000-00476-mum-form-pct-ipea-409(09-10-2000).pdf

in-pct-2000-00476-mum-power of authority(14-06-2004).pdf

in-pct-2000-00476-mum-power of authority(16-10-2000).pdf