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.

1 - 9 . (canceled)  
   
   
       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  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  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  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  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  wherein said disease is AIDS.