Inhibitors of transcription factor NF-kappaB

Abstract

The present invention provides pharmaceutical compositions of salicylanilide inhibitors of transcription factor NF-κB, and methods for treating diseases in which activation of NF-κB is implicated. More specifically, the present invention provides methods of treatment of a variety of diseases associated with NF-κB activation including inflammatory disorders; particularly rheumatoid arthritis, inflammatory bowel disease, and asthma; dermatosis, including psoriasis and atopic dermatitis; autoimmune diseases; tissue and organ rejection; Alzheimer's disease; stroke; atherosclerosis; restenosis; cancer, including Hodgkin's disease; certain viral infections, including AIDS; osteoarthritis; osteoporosis; and Ataxia Telangiestasia by administering to a patient in need thereof a compound of the present invention.

We claim:  
     
         1 . A pharmaceutical composition comprising a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R A  substitutes ring A 0-3 times and is independently selected from the group consisting of: NO 2 , halogen, C 1-6 alkyl, trifluoromethyl, O-C 1-6 alkyl and S-C 1-6 alkyl; and  
 R B  substitutes ring B 0-3 times and is independently selected from the group consisting of: halogen, C(O)C 1-6 alkyl, C 1-6 alkyl, O-C 1-6 alkyl, S-C 1-6 alkyl, CH 2 -aryl, and aryl;  
 and pharmaceutically acceptable salts, hydrates and solvates thereof.  
 
     
     
         2 . A pharmaceutical composition according to  claim 1  wherein: 
 R A  occurs once and is R 1 ; and  
 R B  occurs twice and is independently R 2  and R 3 .  
 
     
     
         3 . A pharmaceutical composition according to  claim 1  comprising a compound of Formula II:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from the group consisting of: H, NO 2 , CF 3 , F, Cl, Br, and I;  
 R 2  is selected from the group consisting of: H and F; and  
 R 3  is selected from the group consisting of: F, Cl, Br, I, phenyl and C(O)C 1-6 alkyl;  
 and a pharmaceutically acceptable carrier, diluent or excipient.  
 
     
     
         4 . A pharmaceutical composition according to  claim 3  wherein C(O)C 1-6 alkyl is C(O)CH 3 .  
     
     
         5 . A pharmaceutical composition according to  claim 3  wherein said compound is selected from the group consisting of: 
 N-(4-phenyl-phenyl)-2-hydroxy-5-trifluoromethylcarboxamide;  
 N-(2,4-Difluorophenyl)-2-hydroxy-5-nitrocarboxamide;  
 N-(2,4-Difluorophenyl)-2-hydroxy-5-iodocarboxamide; and  
 N-(4-acetylphenyl)-2-hydroxy-5-iodocarboxamide.  
 
     
     
         6 . A method of inhibiting NF-κB comprising administering to a patient in need thereof an effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R A  substitutes ring A 0-3 times and is independently selected from the group consisting of: NO 2 , halogen, C 1-6 alkyl, trifluoromethyl, O-C 1-6 alkyl and S-C 1-6 alkyl; and  
 R B  substitutes ring B 0-3 times and is independently selected from the group consisting of: halogen, C(O)C 1-6 alkyl, C 1-6 alkyl, O-C 1-6 alkyl, S-C 1-6 alkyl, CH 2 -aryl, and aryl;  
 and pharmaceutically acceptable salts, hydrates and solvates thereof.  
 
     
     
         7 . A method according to  claim 6  wherein: 
 R A  occurs once and is R 1 ; and  
 R B  occurs twice and is independently R 2  and R 3 .  
 
     
     
         8 . A method according to  claim 7  comprising administering to a patient in need thereof an effective amount of a compound of Formula II:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from the group consisting of: H, NO 2 , CF 3 , F, Cl, Br, and I;  
 R 2  is selected from the group consisting of: H and F; and  
 R 3  is selected from the group consisting of: F, Cl, Br, I, phenyl and C(O)C 1-6 alkyl.  
 
     
     
         9 . A method according to  claim 8  wherein said compound is selected from the group consisting of: 
 N-(4-phenyl-phenyl)-2-hydroxy-5-trifluoromethylcarboxamide;  
 N-(2,4-Difluorophenyl)-2-hydroxy-5-nitrocarboxamide;  
 N-(2,4-Difluorophenyl)-2-hydroxy-5-iodocarboxamide; and  
 N-(4-acetylphenyl)-2-hydroxy-5-iodocarboxamide.  
 
     
     
         10 . A method of treating a disease characterized by excessive NF-κB activation comprising inhibiting said excessive activation by administering to a patient in need thereof an effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R A  substitutes ring A 0-3 times and is independently selected from the group consisting of: NO 2 , halogen,C 1-6 alkyl, trifluoromethyl, O-C 1-6 alkyl and S-C 1-6 alkyl; and  
 R B  substitutes ring B 0-3 times and is independently selected from the group consisting of: halogen,C(O)C 1-6 alkyl, C 1-6 alkyl, O-C 1-6 alkyl, S-C 1-6 alkyl, CH 2 -aryl, and aryl;  
 and pharmaceutically acceptable salts, hydrates and solvates thereof.  
 
     
     
         11 . A method according to  claim 10  wherein: 
 R A  occurs once and is R 1 ; and  
 R B  occurs twice and is independently R 2  and R 3 .  
 
     
     
         12 . A method according to  claim 11  comprising administering to a patient in need thereof an effective amount of a compound of Formula II:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from the group consisting of: H, NO 2 , CF 3 , F, Cl, Br, and I;  
 R 2  is selected from the group consisting of: H and F; and  
 R 3  is selected from the group consisting of: F, Cl, Br, I, phenyl and C(O)C 1-6 alkyl.  
 
     
     
         13 . A method according to  claim 12  wherein said compound is selected from the group consisting of: 
 N-(4-phenyl-phenyl)-2-hydroxy-5-trifluoromethylcarboxamide;  
 N-(2,4-Difluorophenyl)-2-hydroxy-5-nitrocarboxamide;  
 N-(2,4-Difluorophenyl)-2-hydroxy-5-iodocarboxamide; and  
 N-(4-acetylphenyl)-2-hydroxy-5-iodocarboxamide.  
 
     
     
         14 . A method according to  claims 10  to  13  wherein said disease is an inflammatory disorder.  
     
     
         15 . A method according to  claim 14  wherein said disease is selected from the group consisting of: rheumatoid arthritis, inflammatory bowel disease, and asthma.  
     
     
         16 . A method according to  claim 10  to  13  wherein said disease is dermatosis.  
     
     
         17 . A method according to  claim 16  wherein said disease is selected from the group consisting of: psoriasis and atopic dermatitis.  
     
     
         18 . A method according to  claim 10  to  13  wherein said disease is selected from the group consisting of: autoimmune diseases; tissue and organ rejection; Alzheimer's disease; stroke; atherosclerosis; restenosis; osteoarthritis; osteoporosis; and Ataxia Telangiestasia.  
     
     
         19 . A method according to  claim 10  to  13  wherein said disease is cancer.  
     
     
         20 . A method according to  claim 19  wherein said cancer is Hodgkins disease.  
     
     
         21 . A method according to  claim 10  to  13  wherein said disease is AIDS.