N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl, or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors

Abstract

Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. TNF-α converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. The present invention provides low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-α converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection having the formula wherein R 2 and R 3 form a heterocyclic ring and A is S, S(O), or S(O)2, and R 1 and R 4 are defined herein.

What is claimed is:  
     
         1 . A compound according to formula I  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ;  
 or heteroaryl-(CH 2 ) 0-6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R 5 ;  
 
 A is —S—, —SO— or SO 2 —;  
 R 2  and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R 7  optionally having one or two double bonds;  
 R 4  is hydrogen, 
 alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ;  
 C 3  to C 8  cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ;  
 
 R 5  is H, C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1  to C 12  alkyl, C 2  to C 12  alkenyl, C 2 -C 12  alkynyl, F, Cl, Br, I, CN, CHO, C 1 -C 6  alkoxy, aryloxy, heteroaryloxy, C 3 -C 6  alkenyloxy, C 3 -C 6  alkynyloxy, C 1 -C 6  alkoxyaryl, C 1 -C 6  alkoxyheteroaryl, C 1 -C 6  alkylamino-C 1 -C 6  alkoxy, C 1 -C 2  alkylene dioxy, aryloxy-C 1 -C 6  alkyl amine, C 1 -C 12  perfluoro alkyl, S(O) n -C 1 -C 6  alkyl, S(O) n -aryl where n is 0, 1 or 2; OCOO C 1 -C 6  alkyl, OCOOaryl, OCONR 6 , COOH, COO C 1 -C 6  alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, —NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl,SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3  to C 8  cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , wherein C 1 -C 6  alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 R 6  is H, C 1  to C 18  alkyl optionally substituted with OH; C 3  to C 6  alkenyl, C 3  to C 6  alkynyl, C 1  to C 6  perfluoro alkyl, S(O) n -C 1 -C 6  alkyl S(O) n  aryl where n is 0, 1 or 2; or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 and R 7  is C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1 -C 12  perfluoro alkyl, S(O) n -C 1 -C 6 -alkyl, S(O) n -aryl where n is 0, 1 or 2; COO—C 1 -C 6 -alkyl, COaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 , SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO—C 1 -C 6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C 1 -C 6  alkyl; 
 alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ;  
 biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C 1 -C 6  alkyl, optionally substituted with one or two groups selected independently from R 5 ; or  
 R 8 R 9 N—C 1 -C 6 -alkoxyaryl-C 1 -C 6 -alkyl where R 8  and R 9  are independently selected from C 1 -C 6  alkyl or R 8  and R 9  together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;  
 
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein: 
 R 1  is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 aryl of 6 to 10 carbon atoms, optionally substituted with one to two groups selected independently from R 5 ;  
 cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one to two groups selected independently from R 5 ;  
 saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10 members containing one heteroatom selected from O, S or NR 7 , optionally substituted with one to two groups selected independently from R 5 ;  
 or heteroaryl-(CH 2 ) 0-6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R 5 ;  
 
 A is —S—, —SO— or SO 2 —;  
 R 2  and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R 7  optionally having one or two double bonds;  
 R 4  is hydrogen, 
 alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ;  
 C 3  to C 8  cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ;  
 
 R 5  is H, F, Cl, Br, I, CN, CHO, C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1  to C 12  alkyl, C 2  to C 12  alkenyl, C 2 -C 12  alkynyl, C 1 -C 6  alkoxy, aryloxy, heteroaryloxy, C 3 -C 6  alkenyloxy, C 3 -C 6  alkynyloxy, C 1 -C 6  alkoxyaryl, C 1 -C 6  alkoxyheteroaryl, C 1 -C 6 -alkylamino-C 1 -C 6  alkoxy, C 1 -C 2 -alkylene dioxy, aryloxy-C 1 -C 6  alkyl amine, C 1 -C 12 perfluoro alkyl, S(O) n -C 1 -C 6  alkyl, S(O) n -aryl where n is 0, 1 or 2; OCOO—C 1 -C 6  alkyl, OCOOaryl, OCONR 6 , COOH, COO—C 1 -C 6  alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3  to C 8  cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 ; 
 wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 
 R 6  is H, C 1  to C 18  alkyl optionally substituted with OH; C 3  to C 6  alkenyl, C 3  to C 6  alkynyl, C 1  to C 6  perfluoro alkyl, S(O) n  alkyl or aryl where n is 0, 1, or 2; or COheteroaryl; 
 wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 
 and R 7  is C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1 -C 12  perfluoro alkyl, S(O) n -alkyl, S(O) n -aryl where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 ,SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 alkyl, CONHSO 2 aryl, aryl, heteroaryl; wherein C 1 -C 6  alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy; 
 alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ;  
 biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C 1 -C 6  alkyl, optionally substituted with one or two groups selected independently from R 5 ;  
 R 8 R 9 N—C 1 -C 6 -alkoxyaryl-C 1 -C 6 -alkyl where R 8  and R 9  are independently selected from C 1 -C 6  alkyl or R 8  and R 9  together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;  
 
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . A compound according to  claim 2  wherein 
 R 1  is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, thienyl, imidazolyl or furanyl, optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, heteroaryloxy, C 3 -C 6  alkenyloxy, C 3 -C 6  alkynyloxy, halogen; or S(O) n —C 1 -C 6 alkyl C 1 -C 6  alkoxyaryl or C 1 -C 6  alkoxyheteroaryl;  
 A is —S—, —SO— or —SO 2 —;  
 R 2  and R 3  , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R 7  optionally having one or two double bonds;  
 R 4  is hydrogen, 
 alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ;  
 C 3  to C 8  cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ;  
 
 R 5  is H, C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1  to C 12  alkyl, C 2  to C 12  alkenyl, C 2 -C 12  alkynyl, F, Cl, Br, I, CN, CHO, C 1 -C 6  alkoxy, aryloxy, heteroaryloxy, C 3 -C 6  alkenyloxy, C 3 -C 6  alkynyloxy, C 1 -C 6  alkylamino-C 1 -C 6  alkoxy, C 1 -C 2  alkylene dioxy, aryloxy-C 1 -C 6  alkyl amine, C 1 -C 12  perfluoro alkyl, S(O) n -C 1 -C 6  alkyl, S(O) n -aryl where n is 0, 1 or 2; OCOO C 1 -C 6  alkyl, OCOOaryl, OCONR 6 , COOH, COO C 1 -C 6  alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, —NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3  to C 8  cycloalkyl; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , wherein C 1 -C 6  alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 R 6  is H, C 1  to C 18  alkyl optionally substituted with OH; C 3  to C 6  alkenyl, C 3  to C 6  alkynyl, C 1  to C 6  perfluoro alkyl, S(O) n  alkyl or aryl where n is 0, 1 or 2; or COheteroaryl; wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 and R 7  is C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1 -C 12  perfluoro alkyl, S(O) n -alkyl, S(O) n -aryl where n is 0, 1 or 2; COOalkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 ,SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 alkyl, CONHSO 2 aryl, aryl, or heteroaryl; where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C 1 -C 6  alkyl; 
 alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkyl of 7 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ;  
 biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR—C 1 -C 6  alkyl, optionally substituted with one or two groups selected independently from R 5 ;  
 R 8 R 9 N—C 1 -C 6 -alkoxyaryl-C 1 -C 6 -alkyl where R 8  and R 9  are independently selected from C 1 -C 6  alkyl or R 8  and R 9  together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;  
 
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         4 . A compound according to  claim 1  which is 1-benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof.  
     
     
         5 . A compound according to  claim 1  which is 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof.  
     
     
         6 . A compound according to  claim 1  which is 1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.  
     
     
         7 . A compound according to  claim 1  which is 4-(4-methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.  
     
     
         8 . A compound according to  claim 1  which is 4-(4-methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.  
     
     
         9 . A compound according to  claim 1  which is 1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.  
     
     
         10 . A compound according to  claim 1  which is 4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxamide or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A compound according to  claim 1  which is 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutically acceptable salt thereof.  
     
     
         12 . A compound according to  claim 1  which is 4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy amide or a pharmaceutically accepted salt thereof.  
     
     
         13 . A compound according to  claim 1  which is 1-benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         14 . A compound according to  claim 1  which is 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         15 . A compound according to  claim 1  which is 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         16 . A compound according to  claim 1  which is 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         17 . A compound according to  claim 1  which is 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         18 . A compound according to  claim 1  which is 1-n-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         19 . A compound according to  claim 1  which is 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-methyl-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         20 . A compound according to  claim 1  which is 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-ethyl-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         21 . A compound according to  claim 1  which is 1-butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         22 . A compound according to  claim 1  which is 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         23 . A compound according to  claim 1  which is 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         24 . A compound according to  claim 1  which is 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         25 . A compound according to  claim 1  which is 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         26 . A compound according to  claim 1  which is 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         27 . A compound according to  claim 1  which is 4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         28 . A compound according to  claim 1  which is 4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         29 . A compound according to  claim 1  which is 1-(3,4-dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide or a pharmaceutical salt thereof.  
     
     
         30 . A compound according to  claim 1  which is [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.  
     
     
         31 . A compound according to  claim 1  which is 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.  
     
     
         32 . A compound according to  claim 1  which is [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.  
     
     
         33 . A compound according to  claim 1  which is 4-(4-butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.  
     
     
         34 . A compound according to  claim 1  which is 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.  
     
     
         35 . A compound according to  claim 1  which is 4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid hydroxamide or a pharmaceutical salt thereof.  
     
     
         36 . A compound according to  claim 1  or a pharmaceutically acceptable salt thereof which is selected from the group of compounds consisting of: 
 4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide,  
 1-tert-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,  
 1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,  
 1-cyclooctyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,  
 1-ethyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,  
 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,  
 1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,  
 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,  
 1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,  
 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,  
 4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,  
 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid hydroxyamide,  
 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide,  
 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,  
 4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide,  
 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide,  
 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide,  
 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide, and  
 4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxy amide.  
 
     
     
         37 . A method of inhibiting pathological changes mediated by matrix metalloproteinases in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a matrix metalloproteinase inhibiting compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ;  
 or heteroaryl-(CH 2 ) 0-6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R 5 ;  
 
 A is —S—, —SO— or SO 2 —;  
 R 2  and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R 7  optionally having one or two double bonds;  
 R 4  is hydrogen, 
 alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ;  
 C 3  to C 8  cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ;  
 
 R 5  is H, C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1  to C 12  alkyl, C 2  to C 12  alkenyl, C 2 -C 12  alkynyl, F, Cl, Br, I, CN, CHO, C 1 -C 6  alkoxy, aryloxy, heteroaryloxy, C 3 -C 6  alkenyloxy, C 3 -C 6  alkynyloxy, C 1 -C 6  alkoxyaryl, C 1 -C 6  alkoxyheteroaryl, C 1 -C 6  alkylamino-C 1 -C 6  alkoxy, C 1 -C 2  alkylene dioxy, aryloxy-C 1 -C 6  alkyl amine, C 1 -C 12  perfluoro alkyl, S(O) n -C 1 -C 6  alkyl, S(O) n -aryl where n is 0, 1 or 2; OCOO C 1 -C 6  alkyl, OCOOaryl, OCONR 6 , COOH, COO C 1 -C 6  alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, —NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3  to C 8  cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , wherein C 1 -C 6  alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 R 6  is H, C 1  to C 18  alkyl optionally substituted with OH; C 3  to C 6  alkenyl, C 3  to C 6  alkynyl, C 1  to C 6  perfluoro alkyl, S(O) n -C 1 -C 6  alkyl S(O) n  aryl where n is 0, 1 or 2; or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 and R 7  is C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1 -C 12  perfluoro alkyl, S(O) n -C 1 -C 6 -alkyl, S(O) n -aryl where n is 0, 1 or 2; COO—C 1 -C 6 -alkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 , SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO—C 1 -C 6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C 1 -C 6  alkyl; 
 alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ;  
 biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C 1 -C 6  alkyl, optionally substituted with one or two groups selected independently from R 5 ; or  
 R 8 R 9 N—C 1 -C 6 -alkoxyaryl-C 1 -C 6 -alkyl where R 8  and R 9  are independently selected from C 1 -C 6  alkyl or R 8  and R 9  together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;  
 
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         38 . A method according to  claim 37  wherein the condition treated is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, or periodontal disease.  
     
     
         39 . A method according to  claim 37  wherein the condition treated is age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection.  
     
     
         40 . A method of inhibiting pathological changes mediated by TNF-α converting enzyme (TACE) in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a TACE inhibiting compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ;  
 or heteroaryl-(CH 2 ) 0-6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R 5 ;  
 
 A is —S—, —SO— or SO 2 —;  
 R 2  and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R 7  optionally having one or two double bonds;  
 R 4  is hydrogen, 
 alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ;  
 C 3  to C 8  cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ;  
 
 R 5  is H, C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1  to C 12  alkyl, C 2  to C 12  alkenyl, C 2 -C 12  alkynyl, F, Cl, Br, I, CN, CHO, C 1 -C 6  alkoxy, aryloxy, heteroaryloxy, C 3 -C 6  alkenyloxy, C 3 -C 6  alkynyloxy, C 1 -C 6  alkoxyaryl, C 1 -C 6  alkoxyheteroaryl, C 1 -C 6  alkylamino-C 1 -C 6  alkoxy, C 1 -C 2  alkylene dioxy, aryloxy-C 1 -C 6  alkyl amine, C 1 -C 12  perfluoro alkyl, S(O) n -C 1 -C 6  alkyl, S(O) n -aryl where n is 0, 1 or 2; OCOO C 1 -C 6  alkyl, OCOOaryl, OCONR 6 , COOH, COO C 1 -C 6  alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, —NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3  to C 8  cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , wherein C 1 -C 6  alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 R 6  is H, C 1  to C 18  alkyl optionally substituted with OH; C 3  to C 6  alkenyl, C 3  to C 6  alkynyl, C 1  to C 6  perfluoro alkyl, S(O) n -C 1 -C 6  alkyl S(O) n  aryl where n is 0, 1 or 2; or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 and R 7  is C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1 -C 12  perfluoro alkyl, S(O) n -C 1 -C 6 -alkyl, S(O) n -aryl where n is 0, 1 or 2; COO—C 1 -C 6 -alkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 , SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO—C 1 -C 6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C 1 -C 6  alkyl; 
 alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ;  
 biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C 1 -C 6  alkyl, optionally substituted with one or two groups selected independently from R 5 ; or  
 R 8 R 9 N—C 1 -C 6 -alkoxyaryl-C 1 -C 6 -alkyl where R 8  and R 9  are independently selected from C 1 -C 6  alkyl or R 8  and R 9  together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;  
 
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         41 . The method according to claim  40  wherein the condition treated is rheumatoid arthritis, graft rejection, cachexia, anorexia, inflamnation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, or HIV infection.  
     
     
         42 . A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a matrix metalloproteinase or TACE inhibiting compound according to the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ; 
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ;  
 or heteroaryl-(CH 2 ) 0-6 - wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R 5 ;  
 
 A is —S—, —SO— or SO 2 —;  
 R 2  and R 3 , taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R 7  optionally having one or two double bonds;  
 R 4  is hydrogen, 
 alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 phenyl or naphthyl optionally substituted with one or two groups selected independently from R 5 ;  
 C 3  to C 8  cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , optionally substituted with one or two groups selected independently from R 5 ;  
 
 R 5  is H, C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1  to C 12  alkyl, C 2  to C 12  alkenyl, C 2 -C 12  alkynyl, F, Cl, Br, I, CN, CHO, C 1 -C 6  alkoxy, aryloxy, heteroaryloxy, C 3 -C 6  aLkenyloxy, C 3 -C 6  alkynyloxy, C 1 -C 6  alkoxyaryl, C 1 -C 6  alkoxyheteroaryl, C 1 -C 6  alkylamino-C 1 -C 6  alkoxy, C 1 -C 2  alkylene dioxy, aryloxy-C 1 -C 6  alkyl amine, C 1 -C 12  perfluoro alkyl, S(O) n -C 1 -C 6  alkyl, S(O) n -aryl where n is 0, 1 or 2; OCOO C 1 -C 6  alkyl, OCOOaryl, OCONR 6 , COOH, COO C 1 -C 6  alkyl, COOaryl, CONR 6 R 6 , CONHOH, NR 6 R 6 , SO 2 NR 6 R 6 , NR 6 SO 2 aryl, —NR 6 CONR 6 R 6 , NHSO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, SO 2 NHCOaryl, CONHSO 2 —C 1 -C 6  alkyl, CONHSO 2 aryl, NH 2 , OH, aryl, heteroaryl, C 3  to C 8  cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR 7 , wherein C 1 -C 6  alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 R 6  is H, C 1  to C 18  alkyl optionally substituted with OH; C 3  to C 6  alkenyl, C 3  to C 6  alkynyl, C 1  to C 6  perfluoro alkyl, S(O) n -C 1 -C 6  alkyl S(O) n  aryl where n is 0, 1 or 2; or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR 7  and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy;  
 and R 7  is C 7 -C 11  aroyl, C 2 -C 6  alkanoyl, C 1 -C 12  perfluoro alkyl, S(O) n -C 1 -C 6 -alkyl, S(O) n -aryl where n is 0, 1 or 2; COO—C 1 -C 6 -alkyl, COOaryl, CONHR 6 , CONR 6 R 6 , CONHOH, SO 2 NR 6 R 6 , SO 2 CF 3 , SO 2 NHheteroaryl, SO 2 NHCOaryl, CONHSO—C 1 -C 6 -alkyl, CONHSO 2 aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C 1 -C 6  alkyl; 
 alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R 5 ;  
 alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R 5 ;  
 biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R 5 ;  
 arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R 5 ;  
 cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, wherein the cycloalkyl or bicycloalkyl group is optionally substituted with one or two groups selected independently from R 5 ;  
 saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N—C 1 -C 6  alkyl, optionally substituted with one or two groups selected independently from R 5 ; or  
 R 8 R 9 N—C 1 -C 6 -alkoxyaryl-C 1 -C 6 -alkyl where R 8  and R 9  are independently selected from C 1 -C 6  alkyl or R 8  and R 9  together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;  
 
 or a pharmaceutically acceptable salt thereof.