Patent EA-002882-B1 (EA)
Title: Hydroxamic acid derivatives as matrix metalloprotease (mmp) inhibitors
Inventor: DACK KEVIN NEIL
IPC: A61K31/453
Filed: 1998-10-09
Abstract: 1. A compound of formula (I):   or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, wherein the broken line represents an optional bond; A is C or CH; B is CH2, O or absent; R<1> and R<2> are each independently selected from hydrogen, C1-C6 alkyl optionally substituted with C1-C4 alkoxy or phenyl, and C1-C6 alkenyl; or, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl group which optionally incorporates a heteroatom linkage selected from O, SO, SO2 and NR<6> or which is optionally benzo-fused; R<3> is hydrogen, halo, R<7> or OR<7> ; R<4> is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl or halo; R<6> is hydrogen or C1-C4 alkyl; R<7> is a monocyclic or bicyclic ring system selected from phenyl, thienyl, furyl, pyridinyl, pyrimidinyl, naphthyl, indanyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzodioxolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl and benzodioxanyl, any of which ring systems is optionally substituted with one or two substituents selected from C1-C4 alkyl optionally substituted with C1-C4 alkoxy or hydroxy, C1-C4 alkoxy optionally substituted with C1-C4 alkoxy or hydroxy, C1-C4 alkylthio, trifluoromethyl, trifluoromethoxy, halo and cyano; m is 1 or 2; and n is 0, 1 or 2; with the proviso that B is not O when A is C. 2. A compound according to Claim 1 wherein B is absent; R<1> is hydrogen, C1-C4 alkyl optionally substituted with methoxy or phenyl, or C1-C5 alkenyl; R<2> is hydrogen or C1-C4 alkyl; or R<1> and R<2>, together with the carbon atom to which they are attached, form a C4-C5 cycloalkyl group which optionally incorporates a heteroatom linkage selected from O and NR<6> or which is optionally benzo-fused; R<3> is selected from 4-phenyl, 4-pyridinyl, 4-(indan-5-yl), 4-(2,3-dihydrobenzofuran-5-yl), 4-(quinolin-3-yl), 4-(benzodioxol-5-yl) and 4-(benzimidazol-5-yl), any of which is optionally substituted with one or two substituents selected from C1-C3 alkyl optionally substituted with methoxy or hydroxy, C1-C3 alkoxy optionally substituted with methoxy or hydroxy, methylthio, trifluoromethyl, trifluoromethoxy, fluoro, chloro and cyano; R<4> is hydrogen, methyl, ethyl, methoxy, trifluoromethyl, fluoro or chloro; R<6> is methyl; m is 2; and n is 1. 3. A compound according to Claim 2 wherein R<1> is hydrogen, methyl, ethyl, 2-methylprop-1-yl, but-1-yl, 2-methoxyethyl, benzyl, 3-phenylprop-1-yl, allyl, 2-methylallyl, 3,3-dimethylallyl; or R<2> is hydrogen, methyl or ethyl; or R<1> and R<2>, together with the carbon atom to which they are attached, form a cyclobutyl, cyclopentyl, tetrahydropyran-4,4-diyl, 1-methylpiperidin-4,4-diyl or indan-2,2-diyl group; R<3> is 4-phenyl, 4-(2-methylphenyl), 4-(3-methylphenyl), 4-(3-ethylphenyl), 4-[3-(prop-2-yl)phenyl], 4-(3,5-dimethylphenyl), 4-(3-methoxymethylphenyl), 4-(3-hydroxymethylphenyl), 4-(2-methoxyphenyl), 4-(3-methoxyphenyl), 4-(3-ethoxyphenyl), 4-(4-ethoxyphenyl), 4-[3-(prop-1-oxy)phenyl], 4-[3-(prop-2-oxy)phenyl], 4-[4-(prop-2-oxy)phenyl], 4-(3,4-dimethoxyphenyl), 4-[3-(2-methoxyethoxy)phenyl], 4-[3-(2-hydroxyethoxy)phenyl], 4-(3-methylthiophenyl), 4-(3-trifluoromethylphenyl), 4-(3-trifluoromethoxyphenyl), 4-(2-fluorophenyl), 4-(3-chloro-4-fluorophenyl), 4-(3-cyanophenyl), 4-(pyridin-2-yl), 4-(pyridin-3-yl), 4-(pyridin-4-yl), 4-(6-ethoxypyridin-2-yl), 4-(5-ethoxypyridin-3-yl), 4-(indan-5-yl), 4-(2,3-dihydrobenzofuran-5-yl), 4-(quinolin-3-yl), 4-(benzodioxol-5-yl), 4-(2,2-dimethylbenzodioxol-5-yl) and 4-(1,2-dimethylbenzimidazol-5-yl); or R<4> is hydrogen, 2-methyl, 3-methyl, 3-ethyl, 3-methoxy, 3-trifluoromethyl, 3-fluoro or 3-chloro. 4. A compound according to Claim 3 wherein R<1> and R<2> are both hydrogen or methyl or, together with the carbon atom to which they are attached, form a cyclobutyl, cyclopentyl, tetrahydropyran-4,4-diyl or 1-methylpiperidin-4,4-diyl group; R<3> is 4-phenyl, 4-(3-methoxyphenyl), 4-(3-ethoxyphenyl), 4-[3-(2-methoxyethoxy)phenyl], 4-[3-(2-hydroxyethoxy)phenyl] or 4-(6-ethoxypyridin-2-yl); and R<4> is 3-methyl or 3-methoxy. 5. A compound according to Claim 4 wherein the compound of formula (I) is selected from N-hydroxy-2-{4-[4-(3-ethoxyphenyl)-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-ylsulphonyl}acetamide; N-hydroxy-2-{4-[4-(3-ethoxyphenyl)-3-methylphenyl]-1,2,3,6-tetrahydropyridin-1-ylsulphonyl}-2-methylpropanamide; N-hydroxy-2-{4-[4-(3-ethoxyphenyl)-3-methylphenyl]piperidin-1-ylsulphonyl}-2-methylpropanamide; N-hydroxy-1-{4-[4-(3-methoxyphenyl)-3-methylphenyl]piperidin-1-ylsulphonyl} cyclopentanecarboxamide; N-hydroxy-1-{4-[4-(3-methoxyphenyl)-3-methylphenyl]piperidin-1-ylsulphonyl} cyclobutanecarboxamide; N-hydroxy-2-{4-[4-(3-ethoxyphenyl)-3-methoxyphenyl]piperidin-1-ylsulphonyl} -2-methylpropanamide; N-hydroxy-2-{4-[4-(6-ethoxypyridin-2-yl)-3-methylphenyl]piperidin-1-ylsulphonyl}-2-methylpropanamide; N-hydroxy-2-{4-[4-(3-[2-methoxyethoxy]phenyl)-3-methylphenyl]piperidin-1-ylsulphonyl}-2-methylpropanamide; and N-hydroxy-2-{4-[4-(3-[2-hydroxyethoxy]phenyl)-3-methylphenyl]piperidine-1-ylsulphonyl}-2-methylpropanamide. 6. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, according to any of Claims 1-5, together with a pharmaceutically acceptable diluent or carrier. 7. A veterinary formulation comprising a compound of formula (I), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, according to any of Claims 1-5, together with a veterinarily acceptable diluent or carrier. 8. A use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, according to any of Claims 1-5 as a medicine for human. 9. A use of the pharmaceutical composition according to Claim 6 as a medicine for human. 10. A use of the compound of formula (I) or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, according to any of Claims 1-5 as a medicine for animal. 11. A use of the veterinary composition according to Claim 7 as a medicine for animal. 12. A use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, according to any of Claims 1-5 for producing a medicine for human for treating or prophylaxis of pathological condition which requires inhibitor of MMP. 13. A use of the compound of formula (I) or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, according to any of Claims 1-5 for producing a medicine for animal for treating or prophylaxis of pathological condition which requires inhibitor of MMP. 14. A method according to Claim 12 or 13 wherein the inhibitor is a MMP-3 inhibitor. 15. A use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, according to any of Claims 1-5 for producing a medicine for human for treating or prophylaxis of atherosclerotic plaque rupture, myocardial infarction, heart failure, restenosis, stroke, periodontal disease, tissue ulceration, wound repair, skin diseases, cancer metastasis, tumor angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells. 16. A use of the compound of formula (I) or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, according to any of Claims 1-5 for producing a medicine for animal for treating or prophylaxis of atherosclerotic plaque rupture, myocardial infarction, heart failure, restenosis, stroke, periodontal disease, tissue ulceration, wound repair, skin diseases, cancer metastasis, tumor angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells. 17. A compound of formula (II):   wherein R<5> is hydrogen or C1-C3 alkyl, and the broken line, A,B, R<1>, R<2>, R<3>, R<4>, m and n are as previously defined for formula (I) in Claim 1. 18. A compound of Claim 17, wherein R<5> is C1-C3 alkyl, R<3> is bromo or iodo, R<4> is hydrogen, C1-C4 alkyl, C1-C4 alkoxy or trifluoromethyl. 19. A compound of Claim 17, wherein R<5> is C1-C3 alkyl, R<3> is R<7>, and R<4> is hydrogen, C1-C4 alkyl, C1-C4 alkoxy or trifluoromethyl, where the reaction of the compound of Claim 18 is carried out with compound of formula R<7>B(OH)2 or R<7>Sn(alkyl)3, wherein R<7> is such as defined above in Claim 1 and possible substituents on R<7 >are optionally protected by appropriate protecting group. 20. A process of Claim 19, wherein the reaction with a compound of formula R<7>B(OH)2 is carried out. 21. A method for treating or prophylaxis of pathological condition which requires inhibitor of MMP, in a mammal (including human), at that a therapeutically effective amount of the compound of formula (I) is administered to said mammal, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, according to any of Claims 1-5, or a pharmaceutical composition or veterinary compound, which comprise any of above mentioned according to Claim 6 or 7, correspondingly. 22. A method according to Claim 21 wherein the inhibitor is a MMP-3 inhibitor. 23. A method for treating or prophylaxis of of atherosclerotic plaque rupture, myocardial infarction, heart failure, restenosis, stroke, periodontal disease, tissue ulceration, wound repair, skin diseases, cancer metastasis, tumor angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflam