US2003022893A1PendingUtilityA1
Hydroxamic and carboxylic acid derivatives

Priority: Mar 22, 1999Filed: Aug 29, 2002Published: Jan 30, 2003
Est. expiryMar 22, 2019(expired)· nominal 20-yr term from priority
Inventors:Andrew Douglas Baxter David Alan Owen Duncan Batty Robert J. Watson
A61P 7/02A61P 43/00A61P 9/00A61P 7/00A61P 9/12A61P 9/04A61P 9/10A61P 9/02A61P 37/02A61P 37/00A61P 35/04A61P 25/00A61P 29/00A61P 27/14A61P 27/02A61P 25/06A61P 31/00A61P 35/00A61P 31/18A61P 15/00A61P 19/10A61P 11/06C07D 213/74A61P 17/06C07D 307/81C07C 311/13A61P 17/00A61P 19/00C07D 211/96C07D 295/26C07C 311/21A61P 1/14A61P 19/02A61P 1/02A61P 1/04C07D 215/58A61P 11/00A61P 11/02
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References
Claims
Abstract

The subject invention concerns methods and compounds that have utility in the treatment of a condition associated with matrix metalloproteinase, ADAM or ADAM-TS enzymes, a condition that is mediated by TNF α or a condition involving a membrane-shedding event that is mediated by a metalloproteinase. Compounds of the invention are of formula I (B) 2 N—X—(CH 2 ) m -W-(CR 1 R 2 ) n —COY (I) wherein n=0 or 1; m=0 or 1; X is S(O) 1-2 ; Y is OH or NHOH; W is aryl or heteroaryl; and the other groups are as defined herein.
Claims

exact text as granted — not AI-modified
1 . A compound of formula (I)  
       (B) 2 N—X—(CH 2 ) m -W-(CR 1 R 2 ) n —COY  (I)  
       wherein 
 n=0 or 1;  
 m=0 or 1;  
 X is S(O) 1-2 ;  
 Y is OH or NHOH;  
 W is aryl or heteroaryl;  
 R 1  is H, OR 7  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl or C 1-6  alkyl-heterocycloalkyl; and  
 R 2  is H or C 1-6  alkyl;  
 or CR 1 R 2  is cycloalkyl or heterocycloalkyl optionally substituted with R 3  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;  
 R 3  is OR 7 , COR 7 , CO 2 R 8 , CON(R 7 ) 2 , N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , S(O) 0-2 R 8 , SO 2 N(R 7 ) 2  or cycloimidyl (optionally substituted with R 4 );  
 R 4  is C 1-6  alkyl;  
 B is H or a group (optionally substituted with R 5  or R 6 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; and each instance of B may be the same or different;  
 or B-N-B is heterocycloalkyl optionally substituted with R 5 , R 6 , ═O or ═NOR 5 ;  
 R 5  is a group (optionally substituted with R 6 ) 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 or C 1-6  alkyl-heterocycloalkyl;  
 R 6  is a group selected from N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , OR 7 , COR 7 , CO 2 R 4 , CON(R 7 ) 2 , S(O) 0-2 R 8  or SO 2 N(R 7 ) 2 ;  
 R 7  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 or 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 4 R 8 , NR 4 R 8  or SO 2 NR 4 R 8  and for each case of N(R 7 ) 2  the R 7  groups are the same or different or N(R 7 ) 2  is heterocycloalkyl optionally substituted with R 8 , COR 8 , S(O) 0-2 R 8 , CO 2 R 8 , OR 8 , CONR 4 R 8 , NR 4 R 8  or SO 2  NR 4 R 8 ; and  
 R 8  is C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;  
 or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.  
 
     
     
         2 . The compound according to  claim 1 , wherein X is SO 2 .  
     
     
         3 . The compound according to  claim 1 , wherein B-N-B is optionally substituted heterocycloalkyl.  
     
     
         4 . The compound according to  claim 2 , wherein B-N-B is optionally substituted heterocycloalkyl.  
     
     
         5 . The compound according to  claim 1 , wherein Y is OH, m and n are both zero, and B-N-B is optionally substituted heterocycloalkyl.  
     
     
         6 . The compound according to  claim 1 , wherein Y is OH, with the proviso that m and n are not both zero.  
     
     
         7 . The compound according to  claim 1 , wherein Y is NHOH.  
     
     
         8 . The compound according to  claim 6 , wherein m=1.  
     
     
         9 . The compound according to  claim 7 , wherein m=1.  
     
     
         10 . The compound according to  claim 6 , wherein n=1.  
     
     
         11 . The compound according to  claim 7 , wherein n=1.  
     
     
         12 . The compound according to  claim 8 , wherein n=1.  
     
     
         13 . The compound according to  claim 6 , wherein m=1 and n=1.  
     
     
         14 . The compound according to  claim 7 , wherein m=1 and n=1.  
     
     
         15 . The compound according to  claim 6 , wherein at least one B is substituted C 1-6  alkyl-aryl.  
     
     
         16 . The compound according to  claim 1 , wherein B is H or a group (optionally substituted with R 5  or R 6 ) selected from C 1-6  alkyl, C 2   6  alkenyl, C 2-6  alkynyl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkenyl or heterocycloalkenyl; and each instance of B may be the same or different.  
     
     
         17 . The compound according to  claim 16 , wherein B is H or a group (optionally substituted with R 5  or R 6 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, heterocycloalkyl, C 1-6  alkylcycloalkyl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkenyl or heterocycloalkenyl; and each instance of B may be the same or different.  
     
     
         18 . The compound according to  claim 1 , wherein neither B is H.  
     
     
         19 . The compound according to  claim 18 , wherein B-N-B is heterocycloalkyl substituted with a substituted C 1-6  alkyl-aryl group.  
     
     
         20 . The compound according to  claim 18 , wherein B-N-B is heterocycloalkyl substituted with NOR 5 , R 6  or a group (optionally substituted with R 6 ) selected from C 1-6  alkyl, aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl or C 1-6  alkyl-heterocycloalkyl.  
     
     
         21 . The compound according to  claim 18 , wherein B-N-B is heterocycloalkyl substituted with NOR 5 , R 6  or a group (optionally substituted with R 6 ) selected from C 1-6  alkyl, aryl, heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl or C 1-6  alkyl-heterocycloalkyl.  
     
     
         22 . The compound according to  claim 18 , wherein B-N-B is heterocycloalkyl substituted with NOR 5 , R 6  or a group (optionally substituted with R 6 ) selected from C 1-6  alkyl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl or C 1-6  alkyl-heterocycloalkyl.  
     
     
         23 . The compound according to  claim 1 , selected from the group consisting of 
 2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]benzoic acid,    2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]benzoic acid,    2-[4-(4-difluoromethoxyphenyl)piperazine-1-sulfonyl]benzoic acid,    2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]benzoic acid,    2-[4-(4-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]benzoic acid,    2-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]benzoic acid,    2-(4-benzylpiperidine-1-sulfonyl)benzoic acid,    2-[4-(4-chlorophenyl)piperazine-1-sulfonylmethyl]benzoic acid,    {2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}acetic acid,    {2-[(4-methoxyphenyl)methyl-sulfamoyl]phenyl}acetic acid,    [2-(benzofuran-2-yl-methyl-methyl-sulfamoyl)phenyl]acetic acid,    [2-(4-pyridin-2-yl-piperazine-1-sulfonyl)phenyl]acetic acid,    {2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]phenyl}acetic acid,    {2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]phenyl}acetic acid,    [2-(4-chlorobenzoylpiperidine-1-sulfonyl)phenyl]acetic acid, and    [2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)phenyl]acetic acid.    
     
     
         24 . The compound according to  claim 1 , selected from the group consisting of 
 2-[(4-methoxyphenyl)methylsulfamoyl]benzoic acid,    2-[(4-(pyridin-2-yl)piperazine-1-sulfonyl]benzoic acid,    2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)benzoic acid,    2-[4-(4-chlorophenoxy)piperidine-1-sulfonylmethyl]benzoic acid,    2-[4-(4-chlorobenzoyl)piperidine-1-sulfonylmethyl]benzoic acid,    2-(3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)benzoic acid,    2-[(benzofuran-2-ylmethyl-methyl-sulfamoyl)methyl]benzoic acid,    2-[4-(pyridin-2-yl)piperazine-1-sulfonylmethyl]benzoic acid,    2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonylmethyl]benzoic acid,    2-[4-[4-(1,1-difluoromethoxy)phenyl]piperazine-1-sulfonylmethyl]benzoic acid,    2-([(4-methoxyphenyl)methyl-sulfamoyl]methyl)benzoic acid,    {2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetic acid,    {4,5-dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetic acid, and    2-{2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}-3-methylbutyric acid.    
     
     
         25 . A pharmaceutical composition for use in therapy, comprising a compound of  claim 1 , and a pharmaceutically-acceptable diluent or carrier.  
     
     
         26 . A method for the treatment or prevention of a condition associated with matrix metalloproteinase, ADAM or ADAM-TS enzymes, a condition that is mediated by TNF or a condition involving a membrane-shedding event that is mediated by a metalloproteinase, wherein said method comprises administering to a human or animal an effective amount of the compound of formula (I)  
       (B) 2 N—X—(CH 2 ) m -W-(CR 1 R 2 ) n —COY  (I)  
       wherein 
 n=0 or 1;  
 m=0 or 1;  
 X is S(O) 1-2 ;  
 Y is OH or NHOH;  
 W is aryl or heteroaryl;  
 R 1  is H, OR 7  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl or C 1-6  alkyl-heterocycloalkyl; and  
 R 2  is H or C 1-6  alkyl;  
 or CR 1 R 2  is cycloalkyl or heterocycloalkyl optionally substituted with R 3  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;  
 R 3  is OR 7 , COR 7 , CO 2 R 8 , CON(R 7 ) 2 , N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , S(O) 0-2 R 8 , SO 2 N(R 7 ) 2  or cycloimidyl (optionally substituted with R 4 );  
 R 4  is C 1-6  alkyl;  
 B is H or a group (optionally substituted with R 5  or R 6 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; and each instance of B may be the same or different;  
 or B-N-B is heterocycloalkyl optionally substituted with R 5 , R 6 , ═O or ═NOR 5 ;  
 R 5  is a group (optionally substituted with R 6 ) 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 or C 1-6  alkyl-heterocycloalkyl;  
 R 6  is a group selected from N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , OR 7 , COR 7 , CO 2 R 4 , CON(R 7 ) 2 , S(O) 0-2 R 8  or SO 2 N(R 7 ) 2 ;  
 R 7  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 or 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 4 R 8 , NR 4 R 8  or S 0   2 NR 4 R 8  and for each case of N(R 7 ) 2  the R 7  groups are the same or different or N(R 7 ) 2  is heterocycloalkyl optionally substituted with R 8 , COR 8 , S(O) 0-2 R 8 , CO 2 R 8 , OR 8 , CONR 4 R 8 , NR 4 R 8  or SO 2 NR 4 R 8 ; and  
 R 8  is C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;  
 or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.  
 
     
     
         27 . The method according to  claim 26 , wherein X is SO 2 .  
     
     
         28 . The method according to  claim 26 , wherein B-N-B is optionally substituted heterocycloalkyl.  
     
     
         29 . The method according to  claim 27 , wherein B-N-B is optionally substituted heterocycloalkyl.  
     
     
         30 . The method according to  claim 26 , 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.  
     
     
         31 . The method according to  claim 26 , wherein the condition is selected from the group consisting of tumour growth, angiogenesis, tumour invasion and spread, metastasis, malignant ascites and malignant pleural effusion.  
     
     
         32 . The method according to  claim 26 , wherein the condition is selected from the group consisting of cerebral ischaemia, ischaemic heart disease, rheumatoid arthritis, osteoarthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration, Alzheimer&#39;s, atherosclerosis, stroke and vasculitis.  
     
     
         33 . The method according to  claim 26 , wherein the condition is selected from the group consisting of Crohn&#39;s disease, ulcerative colitis, corneal ulceration, retinopathy, surgical wound healing, psoriasis, atopic dermatitis, chronic ulcers, epidermolysis bullosa, periodontitis, gingivitis, rhinitis, allergic conjunctivitis, eczema, anaphylaxis, restenosis, congestive heart failure, endometriosis, atherosclerosis, endosclerosis, pelvic inflammatory disease (PID), cancer-induced bone resorption, age-related macular degeneration, lung disease, cystic fibrosis adult respiratory distress syndrome (ARDS), emphysema, bronchitis obliterans-organising pneumonia (BOOP), idiopathic pulmonary fibrosis (PIF), diffuse alveolar damage, pulmonary Langerhan&#39;s cell granulamatosis, pulmonary lymphangioleiomyomatosis (LAM) and chronic obstructive pulmonary disease (COPD).  
     
     
         34 . The method according to  claim 26 , wherein the compound of formula (I) is selected from the group consisting of 
 2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]benzoic acid,    2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]benzoic acid,    2-[4-(4-difluoromethoxyphenyl)piperazine-1-sulfonyl]benzoic acid,    2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]benzoic acid,    2-[4-(4-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]benzoic acid,    2-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]benzoic acid,    2-(4-benzylpiperidine-1-sulfonyl)benzoic acid,    N-hydroxy-2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]benzamide,    N-hydroxy-2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]benzamide,    N-hydroxy-2-[4-(4-difluoromethoxyphenyl)piperazine-1-sulfonyl]benzamide,    N-hydroxy-2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]benzamide,    N-hydroxy-2-[4-(4-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]benzamide,    N-hydroxy-2-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]benzamide,    N-hydroxy-2-(4-benzylpiperidine-1-sulfonyl)benzamide,    2-[4-(4-chlorophenyl)piperazine-1-sulfonylmethyl]benzoic acid,    {2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}acetic acid,    {2-[(4-methoxyphenyl)methyl-sulfamoyl]phenyl}acetic acid,    [2-(benzofuran-2-yl-methyl-methyl-sulfamoyl)phenyl]acetic acid,    [2-(4-pyridin-2-yl-piperazine-1-sulfonyl)phenyl]acetic acid,    {2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]phenyl}acetic acid,    {2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]phenyl}acetic acid,    [2-(4-chlorobenzoylpiperidine-1-sulfonyl)phenyl]acetic acid,    [2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)phenyl]acetic acid,    2-[4-(4-chlorophenyl)piperazine-1-sulfonylmethyl]-N-hydroxybenzamide,    {2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide,    [2-(benzofuran-2-yl-methyl-methyl-sulfamoyl)phenyl]-N-hydroxyacetamide,    [2-(4-pyridin-2-yl-piperazine-1-sulfonyl)phenyl]-N-hydroxyacetamide,    2-{2-[4-(3,5-dichlorophenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide,    {2-[4-(4-chlorophenoxy)piperidine-1-sulfonyl]phenyl}-N-hydroxyacetamide,    [2-(4-benzoylpiperidine-1-sulfonyl)phenyl]-N-hydroxyacetamide,    [2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)phenyl]-N-hydroxyacetamide, and    {2-[(4-methoxyphenyl)methyl-sulfamoyl]phenyl}-N-hydroxyacetamide.    
     
     
         35 . The method according to  claim 26 , wherein the compound of formula (I) is selected from the group consisting of: 
 2-[(4-methoxyphenyl)methylsulfamoyl]benzoic acid,    2-[(4-(pyridin-2-yl)piperazine-1-sulfonyl]benzoic acid,    2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)benzoic acid,    N-hydroxy-2-[(4-methoxyphenyl)methylsulfamoyl]benzamide,    N-hydroxy-2-[4-(pyridin-2-yl)piperazine-1-sulfonyl]benzamide,    2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-N-hydroxybenzamide,    2-[4-(4-chlorophenoxy)piperidine-1-sulfonylmethyl]benzoic acid,    2-[4-(4-chlorobenzoyl)piperidine-1-sulfonylmethyl]benzoic acid,    2-(3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)benzoic acid,    2-[(benzofuran-2-ylmethyl-methyl-sulfamoyl)methyl]benzoic acid,    2-[4-(pyridin-2-yl)piperazine-1-sulfonylmethyl]benzoic acid,    2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonylmethyl]benzoic acid,    2-[4-[4-(1,1-difluoromethoxy)phenyl]piperazine-1-sulfonylmethyl]benzoic acid,    2-([(4-methoxyphenyl)methyl-sulfamoyl]methyl)benzoic acid,    2-[4-(4-chlorophenoxy)piperidine-1-sulphonylmethyl]-N-hydroxybenzamide,    2-[4-(4-chlorobenzoyl)piperidine-1-sulfonylmethyl]-N-hydroxybenzamide,    2-(3,4-dihydro-1H-isoquinoline-2-sulfonylmethyl)-N-hydroxybenzamide,    2-[(benzofuran-2-ylmethyl-methyl-sulfamoyl)methyl]-N-hydroxybenzamide,    N-Hydroxy-2-[4-(5-trifluromethylpyridin-2-yl)piperazine-1-sulfonylmethyl]benzamide,    2-{4-[4-(1,1-difluoromethoxy)phenyl]piperazine-1-sulphonylmethyl}-N-hydroxybenzamide,    N-hydroxy-2-{[(4-methoxyphenyl)methyl-sulfamoyl]methyl}benzamide,    {2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetic acid,    {4,5-dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetic acid,    2-{2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}-3-methylbutyric acid,    2-{2-[4-(4-difluoromethoxyphenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide,    N-hydroxy-2-{2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]phenyl}acetamide,    2-{4,5-dimethoxy-2-[4-(5-trifluoromethylpyridin-2-yl)-piperazine-1-sulfonyl]phenyl}-N-hydroxyacetamide,    2-{2-[4-(4-chlorophenyl)piperazine-1-sulfonyl]phenyl}-N-hydroxy-3-methylbutyramide,    2-(2-{4-[(4-chlorophenyl)hydroxyiminomethyl]piperidine-1-sulfonyl}phenyl)-N-hydroxyacetamide,    3-[4-(4-chlorophenyl)piperazine-1-sulfonyl]benzoic acid, and    3-[4-(4-chlorophenyl)piperazine-1-sulfonyl]-N-hydroxybenzamide.    
     
     
         36 . A method for the treatment or prevention of a condition associated with matrix metalloproteinase, ADAM or ADAM-TS enzymes, a condition that is mediated by TNF or a condition involving a membrane-shedding event that is mediated by a metalloproteinase, wherein said method comprises administering to a human or animal an effective amount of a compound selected from the group consisting of: 
 (a) a compound of formula (I)    (B) 2 N—X—(CH 2 ) m -W-(CR 1 R 2 ) n —COY  (I)    wherein    n=0;    m=0;    X is S(O) 1-2 ;    Y is OH;    W is aryl or heteroaryl;    R 1  is H, OR 7  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl or C 1-6  alkyl-heterocycloalkyl; and    R 2  is H or C 1-6  alkyl;    or CR 1 R 2  is cycloalkyl or heterocycloalkyl optionally substituted with R 3  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;    R 3  is OR 7 , COR 7 , CO 2 R 8 , CON(R 7 ) 2 , N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , S(O) 0-2 R 8 , SO 2 N(R 7 ) 2  or cycloimidyl (optionally substituted with R 4 );    R 4  is C 1-6  alkyl;    B-N-B is heterocycloalkyl optionally substituted with R 5 , R 6 , ═O or ═NOR 5 ;    R 5  is a group (optionally substituted with R 6 ) 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 or C 1-6  alkyl-heterocycloalkyl;    R 6  is a group selected from N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , OR 7 , COR 7 , CO 2 R 4 , CON(R 7 ) 2 , S(O) 0-2 R 8  or SO 2 N(R 7 ) 2 ;    R 7  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 or 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 4 R 8 , NR 4 R 8  or SO 2 NR 4 R 8  and for each case of N(R 7 ) 2  the R 7  groups are the same or different or N(R 7 ) 2  is heterocycloalkyl optionally substituted with R 8 , COR 8 , S(O) 0-2 R 8 , CO 2 R 8 , OR 8 , CONR 4 R 8 , NR 4 R 8  or SO 2 NR 4 R 8 ; and    R 8  is C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;    or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof;    (b) a compound of formula (I)    (B) 2 N—X—(CH 2 ) m -W-(CR 1 R 2 ) n —COY  (I)    wherein    n=0or 1;    m=0 or 1;    with the proviso that m and n are not both zero;    X is S(O) 1-2 ;    Y is OH;    W is aryl or heteroaryl;    R 1  is H, OR 7  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl or C 1-6  alkyl-heterocycloalkyl; and    R 2  is H or C 1-6  alkyl;    or CR 1 R 2  is cycloalkyl or heterocycloalkyl optionally substituted with R 3  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;    R 3  is OR 7 , COR 7 , CO 2 R 8 , CON(R 7 ) 2 , N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , S(O) 0-2 R 8 , SO 2 N(R 7 ) 2  or cycloimidyl (optionally substituted with R 4 );    R 4  is C 1-6  alkyl;    B is H or a group (optionally substituted with R 5  or R 6 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; and each instance of B may be the same or different;    or B-N-B is heterocycloalkyl optionally substituted with R 5 , R 6 , ═O or ═NOR 5 ;    R 5  is a group (optionally substituted with R 6 ) 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 or C 1-6  alkyl-heterocycloalkyl;    R 6  is a group selected from N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , OR 7 , COR 7 , CO 2 R 4 , CON(R 7 ) 2 , S(O) 0-2 R 8  or SO 2 N(R 7 ) 2 ;    R 7  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 or 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 4 R 8 , NR 4 R 8  or SO 2 NR 4 R 8  and for each case of N(R 7 ) 2  the R 7  groups are the same or different or N(R 7 ) 2  is heterocycloalkyl optionally substituted with R 8 , COR 8 , S(O) 0-2 R 8 , CO 2 R 8 , OR 8 , CONR 4 R 8 , NR 4 R 8  or SO 2 NR 4 R 8 ; and    R 8  is C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;    or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof; and    (c) a compound of formula (I)    (B) 2 N—X—(CH 2 ) m -W-(CR 1 R 2 ) n —COY  (I)    wherein    n=0 or 1;    m=0 or 1;    X is S(O) 1-2 ;    Y is NHOH;    W is aryl or heteroaryl;    R 1  is H, OR 7  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl or C 1-6  alkyl-heterocycloalkyl; and    R 2  is H or C 1-6  alkyl;    or CR 1 R 2  is cycloalkyl or heterocycloalkyl optionally substituted with R 3  or a group (optionally substituted with R 3 ) selected from C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;    R 3  is OR 7 , COR 7 , CO 2 R 8 , CON(R 7 ) 2 , N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , S(O) 0-2 R 8 , SO 2 N(R 7 ) 2  or cycloimidyl (optionally substituted with R 4 );    R 4  is C 1-6  alkyl;    B is H or a group (optionally substituted with R 5  or R 6 ) selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, C 1-6  alkyl-aryl, heteroaryl, C 1-6  alkyl-heteroaryl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; and each instance of B may be the same or different; cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl; and each instance of B may be the same or different;    or B-N-B is heterocycloalkyl optionally substituted with R 5 , R 6 , ═O or ═NOR 5 ;    R 5  is a group (optionally substituted with R 6 ) 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 or C 1-6  alkyl-heterocycloalkyl;    R 6  is a group selected from N(R 7 ) 2 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , NR 7 CO 2 R 8 , NR 7 SO 2 R 8 , OR 7 , COR 7 , CO 2 R 4 , CON(R 7 ) 2 , S(O) 0-2 R 8  or SO 2 N(R 7 ) 2 ;    R 7  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 or 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 4 R 8 , NR 4 R 8  or SO 2 NR 4 R 8  and for each case of N(R 7 ) 2  the R 7  groups are the same or different or N(R 7 ) 2  is heterocycloalkyl optionally substituted with R 8 , COR 8 , S(O) 0-2 R 8 , CO 2 R 8 , OR 8 , CONR 4 R 8 , NR 4 R 8  or SO 2 NR 4 R 8 ; and    R 8  is C 1-6  alkyl, aryl, C 1-6  alkyl-aryl, heteroaryl or C 1-6  alkyl-heteroaryl;    or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.    
     
     
         37 . The method according to  claim 36 , 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.  
     
     
         38 . The method according to  claim 36 , wherein the condition is selected from the group consisting of tumour growth, angiogenesis, tumour invasion and spread, metastasis, malignant ascites and malignant pleural effusion.  
     
     
         39 . The method according to  claim 36 , wherein the condition is selected from the group consisting of cerebral ischaemia, ischaemic heart disease, rheumatoid arthritis, osteoarthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration, Alzheimer&#39;s, atherosclerosis, stroke and vasculitis.  
     
     
         40 . The method according to  claim 36 , wherein the condition is selected from the group consisting of Crohn&#39;s disease, ulcerative colitis, corneal ulceration, retinopathy, surgical wound healing, psoriasis, atopic dermatitis, chronic ulcers, epidermolysis bullosa, periodontitis, gingivitis, rhinitis, allergic conjunctivitis, eczema, anaphylaxis, restenosis, congestive heart failure, endometriosis, atherosclerosis, endosclerosis, pelvic inflammatory disease (PID), cancer-induced bone resorption, age-related macular degeneration, lung disease, cystic fibrosis adult respiratory distress syndrome (ARDS), emphysema, bronchitis obliterans-organising pneumonia (BOOP), idiopathic pulmonary fibrosis (PIF), diffuse alveolar damage, pulmonary Langerhan&#39;s cell granulamatosis, pulmonary lymphangioleiomyomatosis, (LAM) and chronic obstructive pulmonary disease (COPD).
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