Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity

Abstract

Hydroxamic and carboxylic acid derivatives having MMP and TNF inhibitory activity.

We claim:  
     
         1 . A compound of formula (Ic)  
       B—SO 2 —CH 2 —CHR 1 —CO—NHOH   (Ic)  
       wherein 
 R 1  is C 1-6  alkyl substituted with R 9 ;  
 B is aryl or heteroaryl, either of which is optionally substituted by a substituent selected from R 5 , C 1-6  alkyl-R 5 , C 2-6  alkenyl-R 5 , aryl (optionally substituted with R 5 ), aryl-C 1-6  alkyl-R 5 , C 1-6  alkyl-aryl (optionally substituted with R 5 ), C 1-6  alkyl-heteroaryl (optionally substituted with R 5 ), aryl-C 2-6  alkenyl-R 7 , heteroaryl (optionally substituted with R 5 ), heteroaryl-C 1-6  alkyl-R 5 , cycloalkyl (optionally substituted with R 5 ), benzofused cycloalkyl (optionally substituted with R 5 ), heterocycloalkyl (optionally substituted with R 5 ), benzofused heterocycloalkyl (optionally substituted with R 5 ), and the groups:  
                     
 R 2  is H or C 1-6  alkyl;  
 R 5  is C 1-6  alkyl, C 2-6  alkenyl-R 7 , halogen, CN, NO 2 , N(R 6 ) 2 , OR 6 , COR 6 , CO 2 R 2 , CON(R 6 ) 2 , NR 6 R 7 , S(O) 0-2 R 8  or SO 2 N(R 6 ) 2 ;  
 R 6  is H or a group selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl and C 1-6  alkyl-heterocycloalkyl, wherein said group is optionally substituted with R 8 , COR 8 , SO 0-2 R 8 , CO 2 R 8 , OR 8 , CONR 2 R 8 , NR 2 R 8 , halogen, CN, SO 2 NR 2 R 8  or NO 2 , and for each case of N(R 6 ) 2  the R 6  groups are the same or different or N(R 6 ) 2  is heterocycloalkyl optionally substituted with R 8 , COR 8 , SO 0-2 R 8 , CO 2 R 8 , OR 8 , CONR 2 R 8 , NR 2 R 8 , halogen, CN, SO 2 NR 2 R 8  or NO 2 ;  
 R 7  is COR 6 , CON(R 6 ) 2 , CO 2 R 8  or SO 2 R 8 ;  
 R 8  is C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl; and  
 R 9  is phthalimido, succinimido or the group:  
                     
 or an N-oxide, salt, solvate, hydrate, protected amino or protected carboxy derivative thereof.  
 
     
     
         2 . The compound according to  claim 1 , wherein R 1  is ethyl or propyl.  
     
     
         3 . The compound according to  claim 1 , wherein R 2  is methyl.  
     
     
         4 . The compound according to  claim 1 , wherein B is optionally substituted phenyl, furanyl, thiophenyl, pyridyl or pyridyl-N-oxide.  
     
     
         5 . The compound according to  claim 1 , wherein R 5  is OR 6  or COR 6 .  
     
     
         6 . The compound according to  claim 5 , wherein R 6  is optionally substituted C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl.  
     
     
         7 . The compound according to  claim 6 , wherein R 6  is optionally substituted methyl, phenyl, furanyl, thiophenyl, pyridyl, pyridyl-N-oxide, methyl-pyridyl, ethyl-pyridyl, methyl-furanyl, ethyl-furanyl, methyl-thiophenyl or ethyl-thiophenyl.  
     
     
         8 . The compound according to  claim 1 , wherein R 6  is substituted with R 8 , OR 8 , F, Cl, Br, I or CN.  
     
     
         9 . The compound according to  claim 8 , wherein R 6  is substituted with phenyl, OCH 3  or Cl.  
     
     
         10 . The compound according to  claim 1 , selected from the group consisting of: 
 2-(4-Methoxyphenylsulfonylmethyl)-5-phthalimido-pentanoic Acid N-Hydroxy Amide;    2-(4-Methoxyphenylsulfonylmethyl)-4-phthalimido-butanoic Acid N-Hydroxy Amide;    2-(4-Methoxyphenylsulfonylmethyl)-5-succinimido-pentanoic Acid N-Hydroxy Amide;    2-(4-Benzoylphenyl)sulfonylmethyl-5-succinimido-pentanoic Acid N-Hydroxy Amide;    2-(4-Methoxyphenylsulfonylmethyl)-5-(3,3,4-trimethylhydantoin-1-yl)pentanoic Acid N-Hydroxy Amide;    2-(4-Methoxyphenylsulfonylmethyl)-4-(3,3,4-trimethylhydantoin-1-yl)butanoic Acid N-Hydroxy Amide;    2-((4-Trifluoromethoxyphenylsulfonyl)methyl)-5-(1,5,5-trimethylhydantoin-3-yl)pentanoic Acid N-Hydroxy Amide;    2-(4-benzoylphenyl)sulfonylmethyl-4-(3,3,4-trimethylhydantoin-1-yl)butanoic Acid N-Hydroxy Amide;    2-((4-Benzoylphenyl)sulfonylmethyl)-5-(3,3,4-trimethylhydantoin-1-yl)pentanoic Acid N-Hydroxy Amide;    2-((4-(4-Pyridinoyl)phenyl)sulfonylmethyl)-5-(3,3,4-trimethylhydantoin-1-yl)pentanoic Acid N-Hydroxy Amide;    2-((4-(2-Thienoyl)phenyl)sulfonylmethyl)-5-(3,3,4-trimethylhydantoin-1-yl)pentanoic Acid N-Hydroxy Amide; and    2-(1-Oxy-pyridine-4-sulfonylmethyl)-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)pentanoic acid hydroxyamide.    
     
     
         11 . A method for the treatment or prevention of a condition associated with matrix metalloproteinases or that is mediated by TNF α or enzymes involved in the shedding of L-selectin, the TNF receptors or IL-6 receptors, which comprises administration of a compound of  claim 1  to a patient in need thereof.  
     
     
         12 . The method according to  claim 11 , wherein the condition is selected from the group consisting of cancer, inflammation and inflammatory diseases, tissue degeneration, periodontal disease, ophthalmological disease, dermatological disorders, fever, cardiovascular effects, haemorrhage, coagulation and acute phase response, cachexia, anorexia, acute infection, HIV infection, shock states, graft versus host reactions, autoimmune disease, reperfusion injury, meningitis, migraine, and aspirin-independent anti-thrombosis.  
     
     
         13 . The method according to  claim 11 , wherein the condition is selected from the group consisting of tumour growth, angiogenesis, tumour invasion and spread, metastases, malignant ascites, and malignant pleural effusion.  
     
     
         14 . The method according to  claim 11 , wherein the condition is selected from the group consisting of cerebral ischaemia, ischaemic heart disease, rheumatoid arthritis, osteoarthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration, Alzheimer's, atherosclerosis, stroke, vasculitis, Crohn's disease, and ulcerative colitis.  
     
     
         15 . The method according to  claim 11 , wherein the condition is selected from the group consisting of corneal ulceration, retinopathy, and surgical wound healing.  
     
     
         16 . The method according to  claim 11 , wherein the condition is selected from the group consisting of psoriasis, atopic dermatitis, chronic ulcers, and epidermolysis bullosa.  
     
     
         17 . The method according to  claim 11 , wherein the condition is selected from the group consisting of periodontitis, and gingivitis.  
     
     
         18 . The method according to  claim 11 , wherein the condition is selected from the group consisting of rhinitis, allergic conjunctivitis, eczema, and anaphylaxis.  
     
     
         19 . The method according to  claim 11 , wherein the condition is selected from the group consisting of restenosis, congestive heart failure, endometriosis, atherosclerosis, and endosclerosis.