Claims for Patent: 6,022,873

Summary for Patent: 6,022,873

Title:	Metalloproteinase inhibitors
Abstract:	Compounds of formula (I) ##STR1## wherein n, V, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined in the specification are matrix metalloproteinase inhibitors.
Inventor(s):	Beckett; Raymond Paul (Oxford, GB), Martin; Fionna Mitchell (Oxford, GB), Miller; Andrew (Oxford, GB), Todd; Richard Simon (Oxford, GB), Whittaker; Mark (Oxford, GB)
Assignee:	British Biotech Pharmaceuticals Limited (GB)
Application Number:	09/121,033
Patent Claims:	1. A compound of formula (I) ##STR73## wherein V is HO-- or HONH-- n is 1, 2, 3 or 4; R.sub.1 is a C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, perfluoroalkyl, phenyl(C.sub.1 -C.sub.6 alkyl)-, heteroaryl(C.sub.1 -C.sub.6 alkyl)-, non-aryl heterocyclyl(C.sub.1 -C.sub.6 alkyl)-, cycloalkyl(C.sub.1 -C.sub.6 alkyl)-, cycloalkenyl(C.sub.1 -C.sub.6 alkyl)-, phenoxy(C.sub.1 -C.sub.6 alkyl)-, heteroaryloxy(C.sub.1 -C.sub.6 alkyl)-, phenyl(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)-, heteroaryl(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)-, phenyl(C.sub.1 -C.sub.6 alkyl)S(C.sub.1 -C.sub.6 alkyl)- or heteroaryl(C.sub.1 -C.sub.6 alkyl)S(C.sub.1 -C.sub.6 alkyl)- group, any one of which may be optionally substituted by C.sub.1 -C.sub.6 alkyl, trifluoromethyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, halo, cyano (--CN), phenyl, substituted phenyl or heteroaryl; R.sub.2 is a saturated 5- to 8-membered monocyclic N-heterocyclic ring which is attached via the N atom and which, (i) optionally contains as a ring member O, S, SO, SO.sub.2, or NR.sub.5 wherein R.sub.5 is hydrogen, hydroxy, C.sub.1 -C.sub.6 alkyl, (C.sub.1 -C.sub.6 alkoxy)C.sub.1 -C.sub.6 alkyl, benzyl, acyl, an amino protecting group, or a group --SO.sub.2 R.sub.6 wherein R.sub.6 is C.sub.1 -C.sub.6 alkyl or a substituted or unsubstituted phenyl or heteroaryl group, and/or (ii) is optionally substituted on one or more C atoms by hydroxy, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, cyano, oxo, ketalised oxo, amino, mono(C.sub.1 -C.sub.6 alkyl)amino, di(C.sub.1 -C.sub.6 alkyl)amino, carboxy, C.sub.1 -C.sub.6 alkoxycarbonyl, hydroxymethyl, C.sub.1 -C.sub.6 alkoxymethyl, carbamoyl, mono(C.sub.1 -C.sub.6 alkyl)carbamoyl, di(C.sub.1 -C.sub.6 alkyl)carbamoyl, or hydroxyimino; R.sub.3 is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.8 cycloalkyl, or acetyl; and R.sub.4 is optionally substituted C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, cycloalkyl, cycloalkyl(C.sub.1 -C.sub.6 alkyl)-, cycloalkenyl, cycloalkenyl(C.sub.1 -C.sub.6 alkyl)-, di-(C.sub.1 -C.sub.6 alkyl)amino, phenyl, phenyl(C.sub.1 -C.sub.6 alkyl)-, biphenyl, phenyl-heteroaryl, naphthyl, non-aryl heterocyclyl, non-aryl heterocyclyl(C.sub.1 -C.sub.6 alkyl)-, heteroaryl or heteroaryl(C.sub.1 -C.sub.6 alkyl)-; heteroaryl-phenyl; heteroaryl-heteroaryl; aryloxyaryl; or a pharmaceutically acceptable salt hydrate or solvate thereof. 2. A compound as claimed in claim 1 wherein the C atom carrying the R.sub.1 group has the R stereoconfiguration, and the C atom carrying the --(C.dbd.O)V group has the S stereoconfiguration. 3. A compound as claimed in claim 1 or claim 2 wherein n is 1. 4. A compound as claimed in claim 1 wherein V is HONH--. 5. A compound as claimed in claim 1 wherein R.sub.1 is optionally substituted C.sub.1 -C.sub.12 alkyl or C.sub.3 -C.sub.6 alkenyl; cycloalkyl(C.sub.1 -C.sub.6 alkyl); phenyl(C.sub.1 -C.sub.6 alkyl)- or phenoxy(C.sub.1 -C.sub.6 alkyl), either of which may be optionally substituted in the phenyl ring by halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or phenyl. 6. A compound as claimed in claim 5 wherein R.sub.1 is n-propyl, isopropyl, n-butyl, iso-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclobutylethyl, 1,1,1-trifluoropropyl, phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, 4-phenylphenylpropyl, 4-(4-chlorophenyl)phenylpropyl or phenoxybutyl. 7. A compound as claimed in claim 1 wherein R.sub.2 is substituted or unsubstituted 1-pyrrolidinyl, piperidino, 1-piperazinyl, hexahydro-1-pyridazinyl, morpholino, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl 1-oxide, tetrahydro-1,4-thiazin-4-yl 1,1-dioxide, thiazolidin-3-yl, hexahydroazipino, or octahydroazocino. 8. A compound as claimed in claim 1 wherein R.sub.2 is piperidin-1-yl. 9. A compound as claimed in claim 1 wherein R.sub.3 is hydrogen, methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, n-pentyl, n-hexyl, or acetyl. 10. A compound as claimed in claim 1 wherein R.sub.3 is hydrogen, acetyl or methyl. 11. A compound as claimed in claim 1 wherein R.sub.4 is substituted or unsubstituted methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, phenyl, biphenyl, naphth-1-yl, naphth-2-yl, benzyl, thien-2-yl, furan-2-yl, pyrrolyl, imidazol-2-yl, benzimidazolyl, thiazol-2-yl, benzothiazol-2-yl, pyrazolyl, isoxazol-5-yl, isothiazolyl, triazolyl, thiadiazol-5-yl, oxadiazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxides of pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, quinolinyl, 1,2-pyridazin-3-yl, 1,3-pyrimidin-5-yl, pyrazin-2-yl, triazinyl, piperazin-1-yl, indol-2-yl, benzimidazol-2-yl, benzotriazol-2-yl, 1,3-dithian-2-yl, and benzothien-2-yl, or quinolin-3-yl. 12. A compound as claimed in claim 11 wherein R.sub.4 is 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-(n-butoxy)phenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-5-trifluoromethyphenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethyl, 2,5-dimethyl-4-chlorophenyl, 2-methoxy-5-chlorophenyl, 2-t-butylphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 4-t-butyl-2,6-dimethylphenyl, 4-(1,1-dimethylpropyl)phenyl, 4-phenylphenyl, 4-(4-chlorophenyl)phenyl, 4-(pyridin-4-yl)phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-N,N-dimethylaminophenyl, 3-N,N-dimethylaminophenyl, 4-N,N-dimethylaminophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 6-dimethylaminonaphth-1-yl; N.sup.1 -methyl-3-methyl-5-chloroimidazol-4-yl, 4-ethoxycarbonylmethyl-thiazol-2-yl, 4-phenylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 5-bromothiazol-2-yl, 4-tert-butylthiazol-2-yl, 1,2,4-oxadiazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, or 5-methyl-1,3,4-thiadiazol-2-yl. 13. A compound as claimed in claim 11 wherein R.sub.4 is methyl, ethyl, n-butyl, n-octyl, dimethylamino, trifluoromethyl, phenyl, 4-methoxyphenyl, 4-butoxyphenyl, 2,5-dimethoxyphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-chloro-5-methoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 5-chloro-1,3-dimethyl-phenyl-, 5-chloro- 1,3-dimethyl-1H-pyrazol-4-yl, naphth-1-yl, naphth-2-yl, 5-dimethylaminonaphth-1-yl, thien-2-yl, 4-methylphenylmethyl, 4-(1,1-dimethylpropyl)phenyl, 4-biphenyl, or quinolin-8-yl. 14. A compound as claimed in claim 1 or claim 2 wherein n is 1, V is HONH--, R.sub.1 is C.sub.1 -C.sub.6 alkyl, fluoro-substituted C.sub.1 -C.sub.12 alkyl, or cycloalkyl(C.sub.1 -C.sub.6 alkyl), R.sub.2 is piperidin-1-yl, and R.sub.3 is hydrogen, acetyl or methyl. 15. A compound as claimed in claim 14 wherein R.sub.4 is methyl, ethyl, n-butyl, n-octyl, dimethylamino, trifluoromethyl, phenyl, 4-methoxyphenyl, 4-butoxyphenyl, 2,5-dimethoxyphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-chloro-5-methoxyphenyl, 2-chloro-5-trifluoromethylphenyl, 5-chloro-1,3-dimethyl-phenyl-, 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, naphth-1-yl, naphth-2-yl, 5-dimethylaminonaphth-1-yl, thien-2-yl, 4-methylphenylmethyl, 4-(1,1-dimethylpropyl)phenyl, 4-biphenyl, or quinolin-8-yl. 16. A compound as claimed in claim 1 wherein R.sub.1 is a C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl, phenyl(C.sub.1 -C.sub.6 alkyl)-, heteroaryl(C.sub.1 -C.sub.6 alkyl)-, non-aryl heterocyclyl(C.sub.1 -C.sub.6 alkyl)-, cycloalkyl(C.sub.1 -C.sub.6 alkyl)-, cycloalkenyl(C.sub.1 -C.sub.6 alkyl)-, phenoxy(C.sub.1 -C.sub.6 alkyl)-, heteroaryloxy(C.sub.1 -C.sub.6 alkyl)-, phenyl(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)-, heteroaryl(C.sub.1 -C.sub.6 alkyl)O(C.sub.1 -C.sub.6 alkyl)-, phenyl(C.sub.1 -C.sub.6 alkyl)S(C.sub.1 -C.sub.6 alkyl)-or heteroaryl(C.sub.1 -C.sub.6 alkyl)S(C.sub.1 -C.sub.6 alkyl)- group, any one of which may be optionally substituted by C.sub.1 -C.sub.6 alkyl, trifluoromethyl, C.sub.1 -C.sub.6 alkoxy, halo, cyano (--CN), phenyl, substituted phenyl or heteroaryl; and R.sub.4 is optionally substituted C.sub.1 -C.sub.6 alkyl, cycloalkyl, cycloalkenyl, di-(C.sub.1 -C.sub.6 alkyl)amino, heterocyclyl, phenyl, naphthyl, or heteroaryl; or a pharmaceutically acceptable salt hydrate or solvate thereof. 17. A compound as claimed in claim 1 which is selected from the group consisting of 2S-{[(4-Methoxybenzenesulfonyl)-methyl-amino]-methyl}-5-methyl-3R-(piperidi ne-1-carbonyl)-hexanoic acid hydroxyamide, 5-Methyl-2S-{[methyl-(toluene-4-sulfonyl)-amino]-methyl]-3R-(piperidine-1-c arbonyl)-hexanoic acid hydroxyamide, 2S-{[(5-Dimethylamino-naphthalene-1-sulfonyl)-methyl-amino]-methyl}-5-methy l-3R-(piperidine-1-carbonyl)-hexanoic acid hydroxyamide, 5-Methyl-2S-{[methyl-(naphthalene-2-sulfonyl)-amino]-methyl-3R-(piperidine- 1-carbonyl)-hexanoic acid hydroxyamide, 5-Methyl-2S-[(methyl-phenylmethanesulfonyl-amino)-methyl]-3R-(piperidine-1- carbonyl)-hexanoic acid hydroxyamide, 2S-{[(4-Butoxybenzenesulfonyl)-methyl-amino]-methyl}-5-methyl-3R-(piperidin e-1-carbonyl)-hexanoic acid hydroxyamide, 2S-{[(Biphenyl-4-sulfonyl)-methyl-amino}-methyl}-5-methyl-3R-(piperidine-1- carbonyl)-hexanoic acid hydroxyamide, and pharmaceutically acceptable salts, hydrates and solvates thereof. 18. A compound which is a member of the group consisting of: 2S-{[(5-Dimethylaminonaphthalene-1-sulfonyl)-methyl-amino]-methyl}-5-methyl -3R-(morpholine-4-carbonyl)-hexanoic acid hydroxyamide 3R-Cyclopentylmethyl-N-hydroxy-2S-[(methanesulfonyl-methyl-amino)-methyl)]- 4-oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-[(methanesulfonyl-methyl-amino)-methyl)]- 4-morpholin-4-yl-4-oxo-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-{[(4-benzenesulfonyl)-methyl-amino]-methy l}-4-oxo-4-piperidine-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-{[(4-benzenesulfonyl)-methyl-amino]-methy l}-4-morpholin-4-yl-4-oxo-butyramide 2S-[(Methanesulfonyl-methyl-amino)-methyl]-5-methyl-3R-(morpholine-4-carbon yl)-hexanoic acid hydroxyamide 2S-{[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-methyl}-5-methyl-3R-(morpholi ne-4-carbonyl)-hexanoic acid hydroxyamide 2S-{[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-methyl}-5-methyl-3R-(piperidi ne-1-carbonyl)-hexanoic acid hydroxyamide 3R-Cyclopentylmethyl-2S-{[ethyl-(4-methoxy-benzenesulfonyl)-amino]-methyl}- N-hydroxy-4-oxo-4-morpholine-1-yl-butyramide 3R-Cyclopentylmethyl-2S-{[ethyl-(4-methoxy-benzenesulfonyl)-amino]-methyl}- N-hydroxy-4-morpholine-4-yl-4-oxo-butyramide 3R-Cyclopentylmethyl-2S-{[(5-dimethyamino-naphthalene-1-sulfonyl)-methyl-am ino]-methyl}-N-hydroxy-4-oxo-4-piperidine-1-yl-butyramide 3R-Cyclopentylmethyl-2S-{[(5-dimethyamino-naphthalene-1-sulfonyl)-methyl-am ino]-methyl}-N-hydroxy-4-morpholine-4-yl-4-oxo-butyramide 2S-{[(5-Dimethylaminonaphthalene-1-sulfonyl)-ethyl-amino]-methyl}-5-methyl- 3R-(morpholine-4-carbonyl)-hexanoic acid hydroxyamide 2S-{[(5-Dimethylaminonaphthalene-1-sulfonyl)-methyl-amino]-methyl}-5-methyl -3R-(piperidine-1-carbonyl)-hexanoic acid hydroxyamide 3R-Cyclopentylmethyl-2S-[(ethanesulfonyl-methyl-amino)-methyl]-N-hydroxy-4- oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-{[methyl-(propane-2-sulfonyl]-amino]-meth yl}-4-oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-{[methyl-(octane-1-sulfonyl)-amino]-methy l}-4-oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-[(methyl-trifluoromethanesulfonyl-amino)- methyl]-4-oxo-4-piperidin-1-yl-butyramide 2S-{[(4-Chloro-benzenesulfonyl)-methyl-amino]methyl}-3R-cyclopentylmethyl-N -hydroxy-4-oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-{[methyl-(quinoline-8-sulfonyl)-amino]-me thyl}-4-oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-{[methyl-(naphthalene-1-sulfonyl)-amino]- methyl}-4-oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-{[(isoquinoline-5-sulfonyl)-methyl- amino]-methyl}4-oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-2S-{[(6-dimethylamino-naphthalene-1-sulfonyl)-methyl-a mino]-methyl}-N-hydroxy-4-oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-2S-{[dimethylsulfamoyl-methyl-amino]-methyl}-N-hydroxy -4-oxo-4-piperidin-1-yl-butyramide 2S-[(Butyl-methanesulfonyl-amino)-methyl]-3R-cyclopentylmethyl-N-hydroxy-4- oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-[(isopropyl-methanesulfonyl)-amino)-methy l]-4-oxo-4-piperidin-1-yl-butyramide 2S-[(tert-Butyl-methanesulfonyl)-amino)-methyl]-3R-cyclopentylmethyl-N-hydr oxy-4-oxo-4-piperidin-1-yl-butyramide 3R-Cyclopentylmethyl-N-hydroxy-2S-[(cyclopropyl-methanesulfonyl)-amino)-met hyl]-4-oxo-4-piperidin-1-yl-butyramide 2S-[(Cyclopentyl-methanesulfonyl)-amino)-methyl]-3R-cyclopentylmethyl-N-hyd roxy-4-oxo-4-piperidin-1-yl-butyramide and pharmaceutically acceptable salts hydrates and solvates thereof. 19. A pharmaceutical or veterinary composition comprising a compound as claimed in claim 1 or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof, together with a pharmaceutically or veterinarily acceptable excipient or carrier. 20. A method of treating a disease or condition mediated by collagenase, which method comprises administering to the mammal in need thereof an inhibiting amount of collagenase inhibiting amount of a compound as claimed in claim 1. 21. A method as claimed in claim 20, wherein the mammal suffers from a disease or condition selected from a group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, tumor invasion by secondary metastasis and a neuroinflammatory disorder. 22. A compound as claimed in claim 7 wherein R.sub.2 is selected from the group consisting of piperidin-1-yl, 2-(methylcarbamoyl)-1-pyrrolidinyl, 2-(hydroxymethyl)-1-pyrrolidinyl, 4-hydroxypiperidino, 2-(methylcarbamoyl)piperidino, 4-hydroxyiminopiperidino, 4-methoxypiperidino, 4-methyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 1,4-dioxa-8-azaspirodecan-8-yl, hexahydro-3-(methylcarbamoyl)-2-pyridazinyl, hexahydro-1-(benzyloxycarbonyl)-2-pyridazinyl, 5,5-dimethyl-4-methylcarbamoyl-thiazolidin-3-yl, or 5,5-dimethyl-4-propylcarbamoyl-thiazolidin-3-yl.

Details for Patent 6,022,873

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2016-10-19