Heterocyclic metalloprotease inhibitors

Abstract

The invention provides compounds of formula as described in the claims, or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof are useful as inhibitors of metalloproteases. Also disclosed are pharmaceutical compositions and methods of treating diseases, disorders and conditions characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

What is claimed is:  
     
         1 . A compound having a structure according to Formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is H;  
 R 2  is hydrogen, alkyl or acyl;  
 Ar is COR 3  or SO 2 R 4 ; and  
 R 3  is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino;  
 R 4  is alkyl, heteroalkyl, aryl, or heteroaryl, substituted or unsubstituted;  
 X is CH 2 , O, S, SO, SO 2 , or NR 5 , wherein R 5  is independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO 2 R 6 , COR 7 , CSR 8 , PO(R 9 ) 2  or may optionally form a ring with W; and  
 R 6  is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino;  
 R 7  is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino and alkylarylamino;  
 R 8  is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino;  
 R 9  is alkyl, aryl, heteroaryl, heteroalkyl;  
 W is hydrogen or one or more lower alkyl moieties, or is an alkylene, arylene, or heteroarylene bridge between two adjacent or nonadjacent carbons (thus forming a fused ring);  
 Y is independently one or more of hydrogen, hydroxy, SR 10 , SOR 4 , SO 2 R 4 , alkoxy, amino, wherein amino is of formula NR 11 ,R 12 , wherein R 11  and R 12  are independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO 2 R 6 , COR 7 , CSR 8 , PO(R 9 ) 2 ; and  
 R 10  is hydrogen, alkyl, aryl, heteroaryl;  
 Z is nil, a spiro moiety or an oxo group substituted on the heterocyclic ring;  
 n is 1-3.  
 This structure also includes an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.  
 
     
     
         2 . The compound of  claim 1 , wherein X is O, S, SO, SO 2 , or NR 5 , wherein R 5  is independently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO 2 R 7 , COR 8 , CSR 9 .  
     
     
         3 . The compound of  claim 1 , wherein Ar is SO 2 R 4  and R 4  is alkyl, heteroalkyl, aryl, or heteroaryl, substituted or unsubstituted.  
     
     
         4 . The compound of  claim 1 , wherein Ar is phenyl or substituted phenyl.  
     
     
         5 . The compound of  claim 4 , wherein Ar is substituted phenyl and the substitution is with hydroxy, alkoxy, nitro or halo.  
     
     
         6 . The compound of  claim 5 , wherein Ar is substituted with methoxy, bromo, nitro and butoxy.  
     
     
         7 . The compound of  claim 6 , wherein Ar is substituted at the ortho or para position relative to the sulfonyl.  
     
     
         8 . The compound of  claim 1 , wherein W is one or more of hydrogen or C 1  to C 4  alkyl.  
     
     
         9 . The compound of  claim 1 , wherein W is geminal C 1  to C 4  alkyl.  
     
     
         10 . The compound of  claim 1  wherein Z is an oxo moiety substituted on the heterocyclic ring.  
     
     
         11 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 1;  and    (b) a pharmaceutically-acceptable carrier.    
     
     
         12 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 4;  and    (b) a pharmaceutically-acceptable carrier.    
     
     
         13 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 5;  and    (b) a pharmaceutically-acceptable carrier.    
     
     
         14 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 9;  and    (b) a pharmaceutically-acceptable carrier.    
     
     
         15 . A pharmaceutical composition comprising: 
 (a) a safe and effective amount of a compound of  claim 10;  and    (b) a pharmaceutically-acceptable carrier.    
     
     
         16 . A method for preventing or treating a disease associated with unwanted metalloprotease activity in a mammalian subject, the method comprising administering to said subject a safe and effective amount of a compound of  claim 1 .  
     
     
         17 . A method for preventing or treating a disease associated with unwanted metalloprotease activity in a mammalian subject, the method comprising administering to said subject a safe and effective amount of a compound of  claim 4 .  
     
     
         18 . A method for preventing or treating a disease associated with unwanted metalloprotease activity in a human or other animal subject, the method comprising administering to said subject a safe and effective amount of a compound of  claim 5 .  
     
     
         19 . A method for preventing or treating a disease associated with unwanted metalloprotease activity in a mammalian subject, the method comprising administering to said subject a safe and effective amount of a compound of  claim 9 .  
     
     
         20 . A method for preventing or treating a disorder modulated by metalloproteases, wherein the disorder is chosen from the group comprising, arthritis, cancer, cardiovascular disorders, skin disorders, ocular disorders, inflammation and gum disease by administering to a mammal in need of such treatment, a safe and effective amount of a metalloprotease inhibitor according to  claim 1 .  
     
     
         21 . A method for preventing or treating a disorder according to  claim 20 , wherein the disorder is arthritis, and is chosen from the group comprising, osteoarthritis and rheumatoid arthritis.  
     
     
         22 . A method for preventing or treating a disorder according to  claim 20 , wherein the disorder is cancer, and the treatment prevents or arrests tumor growth and metastasis.  
     
     
         23 . A method for the preventing or treating a disorder according to  claim 20 , wherein the disorder is a cardiovascular disorder chosen from the group compromising dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis and aortic aneurysm.  
     
     
         24 . A method for the preventing or treating a disorder according to  claim 20 , wherein the disorder is an ocular disorder, and is chosen from the group comprising, corneal ulceration, lack of corneal healing, macular degeneration, and pterygium.  
     
     
         25 . A method for preventing or treating a disorder according to  claim 20 , wherein the disorder is gum disease, and is chosen from the group comprising, periodontal disease, and gingivitis.  
     
     
         26 . A method for preventing or treating a condition, according to  claim 20 , wherein the condition is skin condition chosen from the group comprising wrinkle repair and prevention, U. V. skin damage, epidermolysis bullosa, psoriasis, sclerodema, atopic dermatitis and scarring.  
     
     
         27 . A method for preventing the loosening of prosthetic devices chosen from the group comprising joint replacements and dental prosthesis by administering to a mammal in need of such treatment, a safe and effective amount of a metalloprotease inhibitor according to  claim 1 .  
     
     
         28 . A method for treating inflammatory conditions according to  claim 20 , chosen from the group comprising inflammatory bowel disease, Crohn's Disease, ulcerative colitis, pancreatitis, diverticulitis, acne inflammation, osteomylitis, bronchitis, arthritis, asthma.  
     
     
         29 . A method of treating multiple sclerosis, comprising administering to a mammal in need of such treatment, a safe and effective amount of a metalloprotease inhibitor according to  claim 1 .  
     
     
         30 . A method for treating musculoskeletal disease or cachexia comprising administering to a mammal in need of such treatment, a safe and effective amount of a metalloprotease inhibitor according to  claim 1.