Patent EA-001460-B1 (EA)
Title: beta-SULPHONYL HYDROXAMIC ACIDS AS MATRIX METALLOPROTEINASES INHIBITORS
Inventor: WARPEHOSKI MARTHA A
IPC: C07C317/44
Filed: 1997-09-19
Abstract: 1. A compound of formula I   or pharmaceutical acceptable salts thereof wherein: R1 is a) C4-12 alkyl, b) C4-12 alkenyl, c) C4-12 alkynyl, d) -(CH2)h-C3-8 cycloalkyl, e) -(CH2)h-aryl, f) -(CH2)h-aryl substituted with C1-4 alkyl, C1-4 alkoxy, halo, -NO2, -CF3, -CN, -N(C1-4 alkyl)2, g) -(CH2)h-het, or h) -(CH2)h-het substituted with C1-4 alkyl, or halo; R2 is a) C1-12 alkyl, b) C1-12 alkyl substituted with one to three halo, -CN, -NO2, -CF3, -N(R3)2, -SR3, or OH, c) C2-12 alkenyl, d) C2-12 alkenyl substituted with one to three halo, -CN, -NO2, or -CF3, e) C2-12 alkynyl, f) C2-12 alkynyl substituted with one to three halo, -CN, -NO2, or -CF3, g) -(CH2)h-C3-8 cycloalkyl, h) -(CH2)h-C3-8 cycloalkyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo, i) -(CH2)h-C3-8 cycloalkenyl, j) -(CH2)h-C3-8 cycloalkenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo, k) -(CH2)h-aryl, l) -(CH2)h-aryl substituted with one to three C1-4 alkyl, C1-4 alkoxy, -CF3 -OH, -NO2, -CN, -N(R3)2, -SR3, -SO2(C1-4 alkoxy), -C(=O)R3, or NC(=O)R3, m) -(CH2)h-aryl substituted with one to five halo, n) -(CH2)h-het, o) -(CH2)h-het substituted with one to two C1-4 alkyl, or halo, p) -(CH2)h-Q, q) -(CH2)h-Q substituted with one to three C1-4 alkyl, C1-4 alkoxy, halo, or phenyl, r) -(CH2)i-X-R4, optionally the -(CH2)i- chain can be substituted with C1-4 alkyl or phenyl, which in turn can be substituted with one to three halo or C1-4 alkyl, or s) -(CH2)iCHR5R6; R3 is a) H, b) C1-4 alkyl, c) -(CH2)h-phenyl, or d) -(CH2)h-phenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo; X is a) -O-, b) -S(=O)j-, c) -NR7-, d) -S(=O)2NR8-, or e) -C(=O)-; R4 is a) H, b) C1-4 alkyl, c) -(CH2)h-phenyl, d) -(CH2)h-phenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, halo, -NO2, or -CN, or e) -(CH2)h-het; R5 is a) C1-4 alkyl, or b) -C(=O)R3; R6 is a) -C(=O)R3, or b) -(CH2)hC(=O)R3; R7 is a) H, b) C1-4 alkyl, c) -(CH2)h-phenyl, d) -(CH2)h-phenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo, e) -C(=O)R3, f) -S(=O)2R3, or g) -C(=O)OR3; R8 is a) C1-4 alkyl, b) -(CH2)h-phenyl, or c) -(CH2)h-phenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo; aryl is monocarbocyclic, or bicarbocyclic aromatic moiety; het is 5- to 10-membered unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of oxygen, nitrogen, and sulfur; Q is 5- to 10-membered saturated heterocyclic moiety having one to two atoms selected from the group consisting of oxygen, nitrogen, and sulfur; h is 0, 1, 2, 3, 4, 5, or 6; i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and j is 0, 1, or 2. 2. A compound of formula I according to claim 1 wherein R2 is a) C1-12 alkyl substituted with one to three halo, -CN, -NO2, -CF3-, -N(R3)2, -SR3, or OH, b) C2-12 alkenyl, c) C2-12 alkenyl substituted with one to three halo, -CN, -NO2, or -CF3, d) C2-12 alkynyl, e) C2-12 alkynyl substituted with one to three halo, -CN, -NO2, or -CF3, f) -(CH2)h-C3-8 cycloalkyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo, g) -(CH2)h-C3-8 cycloalkenyl, h) -(CH2)h-C3-8 cycloalkenyl substituted with one to three C1-4 alkyl, C1-4 alkoxy, or halo, i) aryl, j) aryl substituted with one to three C1-4 alkyl, C1-4 alkoxy, -CF3 -OH, -NO2, -CN, -N(R3)2, -SR3, -SO2(C1-4 alkoxy), -C(=O)R3, or -NC(=O)R3, k) -(CH2)h-het, l) -(CH2)h-het substituted with one to two C1-4 alkyl, or halo, m) -(CH2)i-Q, n) -(CH2)i-Q substituted with one to three C1-4 alkyl, C1-4 alkoxy, halo, or phenyl, o) -(CH2)iX-R4, optionally the -(CH2)i- chain can be substituted with C1-4 alkyl or phenyl, which in turn can be substituted with one to three halo or C1-4 alkyl, or p) -(CH2)hCHR5R6; wherein R3, X, R4, R5, R6, R7, R8, aryl, het and Q are as defined as in claim 1; wherein h is 0, 1, 2, 3, 4, 5, or 6; and i is 1, 2, 3, 4, 5 or 6. 3. A compound of formula I according to claim 1 wherein R2 is a) -(CH2)h-het, b) -(CH2)h-het substituted with one to two C1-4 alkyl, or halo, c) -(CH2)i-Q, d) -(CH2)i-Q substituted with one to three C1-4 alkyl, C1-4 alkoxy, halo, or phenyl, or e) -(CH2)i-X-R4, optionally the -(CH2)i- chain can be substituted with C1-4 alkyl or phenyl, which in turn can be substituted with one to three halo or C1-4 alkyl; wherein X, R4, R7, R8, aryl, het and Q are as defined as in claim 1; h is 0, 1, 2, 3, 4, 5, or 6; and i is 1, 2, 3, 4, 5 or 6. 4. A compound of formula I according to claim 1 wherein R1 is a) C4-8 alkyl, b) -(CH2)h-phenyl, or c) -(CH2)h-phenyl substituted with, C1-4 alkyl, C1-4 alkoxy, fluoro, chloro, or bromo; R2 is a) -(CH2)h-pyridyl, quinolinyl, pyrrolyl, thienyl, or thiazolyl, or indolyl, which can optionally be substituted with one to three C1-4 alkyl, C1-4 alkoxy, phenyl, fluoro, chloro, or bromo; b) -(CH2)h-piperidinyl, piperazinyl, morpholino, 4-thiomorpholinyl, butyrolactamyl, 2-oxo-oxazolidinyl, or 2,4-dioxo-imidazolidinyl, which can optionally be substituted with one to three C1-4 alkyl, phenyl, fluoro, chloro, or bromo; c) -(CH2)h-X-R4; X is a) -S(=O)j-, R4 is a) C1-8 alkyl, b) phenyl, or c) phenyl substituted with C1-4 alkyl, C1-4 alkoxy, or halo; h is 0, 1, 2, 3, 4, 5 or 6; i is 1, 2, 3, 4, 5 or 6; and j is 0, 1 or 2. 5. A compound of claim 1 wherein R1 is selected from the group consisting of n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, phenyl, 4-methylphenyl, 4-ethylphenyl, 4-tert-butylphenyl, 4-isopropylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-n-butyloxyphenyl, benzyl, 4-phenylbenzyl, 2-, 3-, or 4-fluorobenzyl, 2-, 3-, 4-chlorobenzyl, 2-, 3-, 4-bromobenzyl, and 4-ethoxybenzyl. 6. A compound of claim 1 wherein R2 is selected from the group consisting of methyl, 1-cyano-1-phenylmethyl, 2-cyanoethyl, 2-phenylethyl, 2-bromo-2-phenylethyl, 2-bromoethyl, propyl, isopropyl, 3-chloropropyl, 3-bromopropyl, n-butyl, isobutyl, 3-methylbutyl, 1-methylpropyl, tert-butyl, n-pentyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, n-hexadecyl, n-octadecyl, 2-propenyl, 2-propynyl, 3-butenyl, 4-pentenyl, 3-butenynyl, 4-pentenynyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 4-cyclohexylbutyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, phenylaminomethyl, phenylaminoethyl, phenyl, 4-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-ethoxyphenyl, benzyl, 4-methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, and 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-ethoxybenzyl, 4-nitrobenzyl, methylcarbonyl, 1-methylcarbonylmethyl, 2-phenylcarbonylethyl, isopropylcarbonyl, methoxycarbonyl, ethoxycarbonyl, 1,1-ethoxycarbonylmethyl, 2,2-ethoxycarbonylethyl, 1,2-ethoxycarbonylethyl, 2-methoxycarbonylpropyl, 3-methoxycarbonylpropyl, 1-ethoxycarbonylmethyl, 1-ethoxycarbonylethyl, phenylcarbonyl, phenylcarbonylmethyl, pyridylcarbonylmethyl, pyridylmethyl, pyridylethyl, quinolinylmethyl, pyrrolylmethyl, indolylmethyl, thienyl, thiazolyl, thienylmethyl, thienylethyl, piperidinyl, piperidinylmethyl piperazinylmethyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, thiomorpholinomethyl, thiomorpholinopropyl, 4-methoxybenzenesulfonylmethyl, 3-(4-methoxybenzenesulfonyl)aminopropyl, 3-(4-methoxybenzenesulfonyl)propyl, 3-hydroxy, amino, 3-phenoxypropyl, 2-phenylethyloxy, (4-butoxybenzenesulfonyl)methyl, methyl-3-(1,5,5-trimethylhydantoin), methyl-3-(1-butyl-5,5-dimethylhydantoin), (4-methoxybenzenesulfonyl)methyl, (4-chlorobenzenesulfonyl)methyl, (4-bromobenzenesulfonyl)methyl, (n-butylsulfonyl)methyl, (n-octylsulfonyl)methyl, 3-(4-methoxybenzenesulfonyl)propyl, (4-methylbenzenesulfonyl)methyl, (benzenesulfonyl)methyl, methyl-3-(1-methylhydantoin), methyl-3-(1-butylhydantoin) and methyl-3-(5,5-dimethylhydantoin). 8. A compound of claim 1 wherein R2 is selected from the group consisting of (4-methoxybenzenesulfonyl)methyl, (4-chlorobenzenesulfonyl)methyl, (4-bromobenzenesulfonyl)methyl, (n-butylsulfonyl)methyl, (n-octylsulfonyl)methyl, 3-(4-methoxybenzenesulfonyl)propyl, (4-methylbenzenesulfonyl)methyl, (benzenesulfonyl)methyl, methyl-3-(1-methylhydantoin), methyl-3-(1-butylhydantoin) and methyl-3-(5,5-dimethylhydantoin). 9. A compound of claim 1 which is (1) N-hydroxy 2-[(4-methoxybenzenesulfonyl)methyl]-3-phenyl-propionamide, (2) N-hydroxy 2-[(benzenesulfonyl)methyl]-3-phenyl-propionamide, (3) N-hydroxy 2-[(benzenesulfonyl)methyl]-propionamide, (4) N-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-methoxybenzenesulfonyl)-propionamide, (5) N-hydroxy-2-[(4-chlorobenzenesulfonyl)methyl]-3-(4-chlorobenzenesulfonyl)-propionamide, (6) N-hydroxy-2-[(4-bromobenzenesulfonyl)methyl]-3-(4-bromobenzenesulfonyl)-propionamide, (7) N-hydroxy-2-[(n-butylsulfonyl)methyl]-3-(n-butylsulfonyl)-propionamide, (8) N-hydroxy-2-[(n-octylsulfonyl)methyl]-3-(n-octylsulfonyl)-propionamide, (9) N-hydroxy-2-[(4-methylbenzenesulfonyl)methyl]-3-(4-methylbenzenesulfonyl)-propionamide, (10) N-hydroxy-2-[(benzenesulfonyl)methyl]-3-(benzenesulfonyl)-propionamide, (11) N-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-5-(4-methoxybenzenesulfonyl)-pentanamide, (12) N-hydroxy-2-[(n-octylsulfonyl)methyl]-3-(4-methoxybenzenesulfonyl)-propionamide, (13) N-hydroxy-2-[methyl-3-(1-methylhydantoin)]-3-(4-methoxybenzenesulfonyl)-propionamide, (14) N-hydroxy-2-[methyl-3-(1-butylhydantoin)]-3-4-(butoxybenzenesulfonyl)-propionamide, (15) N-hydroxy-2-[methyl-3-(1-butylhydantoin)]-3-(4-methoxybenzenesulfonyl)-propionamide, (16) N-hydroxy-2-[methyl-3-(5,5-dimethylhydantoin)]-3-(4-methoxybenzenesulfonyl)-propionamide, (17) (+)-N-hydroxy-2-[(n-octylsulfonyl)methyl]-3-(4-methoxybenzenesulfonyl)-propionamide, (18) (-)-N-hydroxy-2-[(n-octylsulfonyl)methyl]-3-(4-methoxybenzenesulfonyl)-propionamide, (19) (+)-N-hydroxy-2-[methyl-3-(1-methylhydantoin)]-3-(4-m