Alpha-hydroxy,-amino and -fluoro derivatives of beta-sulphonyl hydroxamic acids as matrix metalloproteinases inhibitors

Abstract

The present invention provides a compound of formula (1), or pharmaceutical acceptable salts thereof wherein R1 is C4-12 alkyl, C4-12 alkenyl, C4-12 alkynyl, —(CH2)h-C3-8 cycloalkyl, substituted and unsubstituted —(CH2)h-aryl, substituted and unsubstituted-(CH2)h-het, R2 is substituted and unsubstituted C1-12 alkyl, substituted and unsubstituted C2-12 alkenyl, substituted and unsubstituted C2-12 alkynyl, substituted and unsubstituted-(CH2)h-C3-8 cycloakyl, substituted and unsubstituted —(CH2)h-C3-8 unsubstituted-(CH2)h-C3-8 cycloakyl, substituted and unsubstituted —(CH2)h-C3-8 cycloalkenyl, substituted and unsubstituted-(CH2)h-aryl, substituted and unsubstituted-(CH2)h-heterocyclic ring, substituted and unsubstituted —(CH2)i-X—R4 (X is —O—, —S(═O)j-, —NR7-, —S(═O)2NR8-, or —C(═O)—), and —(CH2)iCHR5R6. The compounds are inhibitors of matrix metalloproteinases involved in tissue degradation

We claim:  
     
         1 . A compound of formula I  
       
         
           
           
               
               
           
         
       
       or pharmaceutical acceptable salts thereof wherein: 
 R 1  is 
 a) C 4-12  alkyl,  
 b) C 4-12  alkenyl,  
 c) C 4-12  alkynyl,  
 d) —(CH 2 ) h —C 3-8  cycloalkyl,  
 e) —(CH 2 ) h -aryl,  
 f) —(CH 2 ) h -het,  
 
 R 2  is 
 a) C 1-12  alkyl,  
 b) C 2-12  alkenyl,  
 c) C 2-12  alkynyl,  
 d) —(CH 2 ) h —C 3-8  cycloalkyl,  
 e) —(CH 2 ) h —C 3-8  cycloalkenyl,  
 f) —(CH 2 ) h -aryl  
 g) —(CH 2 ) h -het,  
 h) —(CH 2 ) h -Q,  
 i) —(CH 2 ) i -Q or —(CH 2 ) l —X—R 4 , optionally the —(CH 2 ) l — chain can be substituted with one or two C 1-4  alkyl or phenyl, which in turn can be substituted with one to three halo or C 1-4  alkyl, or  
 l) —(CH 2 ) h CHR 5 R 6 ;  
 
 R 3  is 
 a) H,  
 b) C 3-6  cycloalkyl,  
 c) C 1-4  alkyl, or  
 d) —(CH 2 ) h -phenyl;  
 
 X is 
 a) —O—,  
 b) —S(═O)j-,  
 c) —NR 7 —,  
 d) —S(═O) 2 NR 8 —, or  
 e) —C(═O)—;  
 
 R 4  is 
 a) H,  
 b) C 1-8  alkyl,  
 c) —(CH 2 ) h -phenyl, or  
 d) —(CH 2 ) h -het;  
 
 R 5  is 
 a) C 1-4  alkyl, or  
 b) —C(═O)R 3 ;  
 
 R 6  is 
 a) —C(═O)R 3 , or  
 b) —(CH 2 ) h C(═O)R 3 ;  
 
 R 7  is 
 a) H,  
 b) C 1-4  alkyl,  
 c) —(CH 2 ) h -phenyl,  
 d) —C(═O)—R 3 ,  
 e) —S(═O) 2 R 3 , or  
 f) —C(═O)OR 3 ;  
 
 R 8  is 
 a) C 1-4  alkyl, or  
 b) —(CH 2 ) h -phenyl;  
 
 Y is 
 a) —OH,  
 b) —NR 9 R 10 , or  
 c) fluoro;  
 
 R 9  and R 10  are the same and different and are 
 a) H,  
 b) —C(═O)—R 3 ,  
 c) —C(═O)—OR 3 , or  
 d) —C(═O)—NHR 3 ;  
 
 aryl is monocarbocyclic, or bicarbocyclic aromatic moiety;  
 het is 5- to 10-membered unsaturated monomonocyclic or bicyclic heterocyclic moiety having one to three atoms selected from the group consisting of oxygen, nitrogen, and sulfur;  
 Q is 5- to 10-membered saturated monocyclic or bicyclic heterocyclic moiety having one to two atoms selected from the group consisting of oxygen, nitrogen, and sulfur;  
 aryl, het, C 1-12  alkyl, C 1-4  alkyl C 2-12  alkenyl, C 2-12  alkynyl, —C 3-8  cycloalkyl, —C 3-8  cycloalkenyl, Q and phenyl being optionally substituted;  
 h is 0, 1, 2, 3, 4, 5, or 6; i is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; j is 0, 1, or 2; and with the following provisos: 
 a) where R 2  is C 1-6  alkyl, Y is other than —NR 9 R 10 ,  
 b) where h is 0, het is attached to the α-position via carbon atom of heterocyclic moiety, and  
 c) where h is 0, Q is attached to the α-position via carbon atom of heterocyclic moiety.  
 
 
     
     
         2 . A compound of formula I according to  claim 1  wherein 
 R 1  is 
 a) C 4-10  alkyl,  
 b) —(CH 2 ) h -aryl, or  
 c) —(CH 2 ) h -aryl substituted with C 1-4  alkyl, C 1-4  alkoxy, phenyl, 4-chlorophenyl, O-phenyl, het, O-het, halo, —NO 2 , —CF 3 , —CN, or —N(C 1-4  alkyl) 2 ;  
 
 R 2  is 
 a) —(CH 2 ) h -Q, or C(CH 3 ) 2 -Q or  
 b) —(CH 2 ) i —X—R 4 , C(CH 3 ) 2 —X—R 4 ;  
 
 X is 
 a) —S(═O) j —,  
 b) —NR 7 —;  
 
 R 4  is 
 a) H,  
 b) C 1-8  alkyl,  
 c) —(CH 2 ) h -phenyl,  
 d) —(CH 2 ) h -phenyl substituted with one to three C 1-4  alkyl, C 1-4  alkoxy, phenyl, C 1-4  phenoxy, het, halo, —NO 2 , or —CN, or  
 e) —(CH 2 ) h -het;  
 
 R 7  is 
 a) —C(═O)—R 3 ;  
 
 Y is 
 a) —OH;  
 
 R 3 , aryl, het, Q, h, i, j are as defined above, and with the proviso that where h is 0, Q is attached to the α-position via carbon atom of heterocyclic moiety.  
 
     
     
         3 . A compound of formula I according to  claim 1  wherein 
 R 1  is 
 a) —(CH 2 ) h -phenyl, or  
 b) —(CH 2 ) h -phenyl substituted with C 1-4  alkoxy, phenyl, 4-chlorophenyl, O-phenyl, O-(pyrid-4-yl) or halo;  
 
 R 2  is 
 a) —(CH 2 ) i —S(═O) 2 —R 4 , or  
 b) —(CH 2 ) i —NHR 7 ;  
 
 R 4  is 
 a) C 1-8  alkyl,  
 b) —(CH 2 ) h -phenyl, or  
 c) —(CH 2 ) h -phenyl substituted with one to three C 1-4  alkyl, C 1-4  alkoxy, phenyl, C 1-4  phenoxy, or halo;  
 
 R 7  is 
 a) —C(═O)C 1-4  alkyl,  
 b) —C(═O)C 3-6  cycloalkyl,  
 c) —C(═O)(CH 2 ) h -phenyl, or  
 d) —C(═O)—(CH 2 ) h -phenyl substituted with one to three C 1-4  alkyl, C 1-4  alkoxy, or halo;  
 
 Y is 
 a) —OH;  
 
 and h and i are as defined above.  
 
     
     
         4 . A compound of formula 8  
       
         
           
           
               
               
           
         
       
       or pharmaceutical acceptable salts thereof wherein R 1 , R 2  and Y are as defined in  claim 1 .  
     
     
         5 . A compound of  claim 1  which is 
 N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-phenylbenzenesulfonyl)-propionamide,  
 N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-fluorobenzenesulfonyl)-propionamide,  
 N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-n-butylbenzenesulfonyl)-propionamide,  
 N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(4-methoxybenzenesulfonyl)-propionamide,  
 N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(N-benzenecarbonylamino)-propionamide,  
 N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-[N-(cyclopentylcarbonyl)amino]-propionamide,  
 N-Hydroxy-2-hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(N-(4-methoxybenzenecarbonyl)amino)-propionamide,  
 N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-methoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-methoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1 -butylhydantoin-3-yl)methyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(methylthio)methyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(phenylthio)methyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(benzylthio)methyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(pyrid-2-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(2-aminothiazol-5-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-methyltetrazol-5-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(pyrid-2-yl)methylthiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)methylthiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-benzyl-1H-imidazol-2-yl)methylthiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(5-methylisoxazol-3-yl)methylthiomethyl-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(2-benzylthio-2-methylethyl)-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-[2-(pyrid-2-yl)thio-2-methylethyl]-3-(4-butoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-chlorobiphenylsulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-chlorobiphenylsulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-chlorobiphenylsulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(phenylthio)methyl-3-(4-chlorobiphenylsulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(benzylthio)methyl-3-(4-chlorobiphenylsulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(pyrid-2-yl)methylthiomethyl-3-(4-chlorobiphenylsulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(5-methylisoxazol-3-yl)methylthiomethyl-3-(4-chlorobiphenylsulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-[2-(1-methylhydantoin-3-yl)-2-methylethyl]-3-(4-chlorobiphenylsulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-[2-(pyrid-2-yl)thio-2-methylethyl]-3-(4-chlorobiphenylsulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-benzylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(phenylthio)methyl-3-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(benzylthio)methyl-3-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(pyrid-2-yl)methylthiomethyl-3-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)methylthiomethyl-3-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-[2-(1-methylhydantoin-3-yl)-2-methylethyl]-3-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-[2-(1-methyl-1H-imidazol-2-yl)thio-2-methylethyl]-(4-phenoxybenzenesulfonyl)propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-[4-(pyrid-4-yl)-benzenesulfonyl]propionamide;  
 N-Hydroxy-2-hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-[4-(pyrid-4-yl)-benzenesulfonyl]propionamide;  
 N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-[4-(pyrid-4-yl)benzenesulfonyl]propionamide;  
 N-Hydroxy-2-hydroxy-2-(phenylthio)methyl-3-[4-(pyrid-4-yl)benzenesulfonyl]propionamide;  
 N-Hydroxy-2-hydroxy-2-(benzylthio)methyl-3-[4-(pyrid-4-yl)benzenesulfonyl]propionamide;  
 N-Hydroxy-2-hydroxy-2-(2-benzylthio-2-methylethyl)-3-[4-(pyrid-4-yl)-benzenesulfonyl]-propionamide;  
 N-Hydroxy-2-hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-[4-(pyrid-4-yl)oxybenzenesulfonyl]propionamide or  
 N-Hydroxy-2-hydroxy-2-(benzylthio)methyl-3-[4-(pyrid-4-yl)oxybenzenesulfonyl]propionamide.  
 
     
     
         6 . A compound of  claim 4  which is: 
 2-Hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-butoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-butoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-(phenylthio)methyl-3-(4-butoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-(benzylthio)methyl-3-(4-butoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-(2-benzylthio-2-methylethyl)-3-(4-butoxybenzenesulfonyl)-propionic acid;  
 2-Hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-chlorobiphenylsulfonyl)propionic acid;  
 2-Hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-chlorobiphenylsulfonyl)-propionic acid;  
 2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-chlorobiphenylsulfonyl)propionic acid;  
 2-Hydroxy-2-(phenylthio)methyl-3-(4-chlorobiphenylsulfonyl)propionic acid;  
 2-Hydroxy-2-(benzylthio)methyl-3-(4-chlorobiphenylsulfonyl)propionic acid;  
 2-Hydroxy-2-(pyrid-2-yl)thiomethyl-3-(4-chlorobiphenylsulfonyl)propionic acid;  
 2-Hydroxy-2-(5-methylisoxazol-3-yl)methylthiomethyl-3-(4-chlorobiphenylsulfonyl)propionic acid;  
 2-Hydroxy-2-[2-(1-methylhydantoin-3-yl)-2-methylethyl]-3-(4-chlorobiphenylsulfonyl)propionic acid;  
 2-Hydroxy-2-(2-benzylthio-2-methylethyl)-3-(4-chlorobiphenylsulfonyl)-propionic acid;  
 2-Hydroxy-2-(1-methylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-(1-butylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-(4-phenoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-(phenylthio)methyl-3-(4-phenoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-(benzylthio)methyl-3-(4-phenoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-[2-(1-methylhydantoin-3-yl)-2-methylethyl]-3-(4-phenoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-[2-(1-methyl-1H-imidazol-2-yl)thio-2-methylethyl]-(4-phenoxybenzenesulfonyl)propionic acid;  
 2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-[4-(pyrid-4-yl)benzene-sulfonyl]propionic acid;  
 2-Hydroxy-2-(phenylthio)methyl-3-[4-(pyrid-4-yl)benzenesulfonyl]propionic acid or  
 2-Hydroxy-2-(1,5,5-trimethylhydantoin-3-yl)methyl-3-[4-(pyrid-4-yl)oxybenzenesulfonyl]propionic acid.  
 
     
     
         7 . A method of inhibiting excess matrix metalloproteinase which comprises administering to a patient in need thereof an effective amount of a compound of  claim 1 .  
     
     
         8 . A method of  claim 7  wherein matrix metalloproteinases comprises stromelysin, collagenase, and gelatinase.  
     
     
         9 . A method of treating a human suffering from or susceptible to diseases involving connective tissue degradation which comprises administering to a patient in need thereof an effective amount of a compound of  claim 1 .  
     
     
         10 . A method of  claim 9  wherein the diseases related to connective tissue degradation are osteoarthrits, rheumatoid arthritis, septic arthritis, and osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, inflammation, or asthma.  
     
     
         11 . The method of  claim 7  wherein the effective amount of the compound of  claim 1  is administered orally, parenterally, or topically in a pharmaceutical composition.  
     
     
         12 . The method of  claim 9  wherein the effective amount of the compound of  claim 1  is administered orally, parenterally, or topically in a pharmaceutical composition.  
     
     
         13 . The method of  claim 7  wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.  
     
     
         14 . The method of  claim 9  wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.  
     
     
         15 . A pharmaceutical composition which comprises an amount of the compound of  claim 1  effective to inhibit excess matrix metalloproteinase and a pharmaceutically acceptable carrier.  
     
     
         16 . A compound of  claim 1  for for use as a medicament.  
     
     
         17 . Use of a compound of  claim 1  for the manufacture of a medicament for inhibiting excess matrix metalloproteinase in a human suffering from or susceptible to a diseases involving connective tissue degradation.  
     
     
         18 . The use of  claim 17  wherein matrix metalloproteinases comprises collagenases, stromelysins, or gelatinases.  
     
     
         19 . The use of  claim 17  wherein the disease related to connective tissue degradation is osteoarthrits, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, or gastric ulceration.