3-(imidazolyl)-pyrazolo[3,4-b]pyridines

Abstract

Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are 3-imidazoyl-pyrazolo[3,4-b]pyridine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated disease, and as controls in assays for the identification of competitive CCR1 antagonists.

What is claimed is: 
     
         1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         2 . A compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. 
       
     
     
         3 . A compound of  claim 2 , in a hydrate form. 
     
     
         4 . A compound of  claim 2 , in a pharmaceutically acceptable salt form. 
     
     
         5 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient or carrier. 
     
     
         6 . A pharmaceutical composition comprising the compound of  claim 2  and a pharmaceutically acceptable excipient or carrier. 
     
     
         7 . A method of preparing the compound of  claim 1 , said method comprising:
 (a) contacting a compound having the formula:   
       
         
           
           
               
               
           
         
       
       with an imidazole-forming reagent under conditions sufficient to form said compound of  claim 1 . 
     
     
         8 . A method in accordance with  claim 7 , wherein said imidazole-forming reagent is selected from the group consisting of glyoxal or a glyoxal equivalent. 
     
     
         9 . A method in accordance with  claim 7 , wherein said imidazole-forming reagent is glyoxal and said contacting is in the presence of ammonium acetate. 
     
     
         10 . A method of preparing the compound of  claim 1 , said method comprising:
 (a) contacting a compound having the formula:   
       
         
           
           
               
               
           
         
         with ethylenediamine to form an imidazoline product; and 
         (b) oxidizing said imidazoline product to form said compound of  claim 1 . 
       
     
     
         11 . A method in accordance with  claim 10 , wherein said oxidizing is carried out with a reagent selected from the group consisting of KMnO 4 , MnO 2 , PhI(OAc) 2 , Swern reagents and Dess-Martin periodane. 
     
     
         12 . A method of treating CCR1-mediated diseases or conditions comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 2 . 
     
     
         13 . A method in accordance with  claim 12 , wherein said CCR1-mediated disease or condition is an inflammatory condition. 
     
     
         14 . A method in accordance with  claim 12 , wherein said CCR1-mediated disease or condition is an immunoregulatory disorder. 
     
     
         15 . A method in accordance with  claim 12 , wherein said CCR1-mediated disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, transplant rejection, restenosis, dermatitis, eczema, urticaria, vasculitis, inflammatory bowel disease, food allergy, asthma, Alzheimer's disease, Parkinson's disease, psoriasis, lupus erythematosus, osteoarthritis, stroke, restenosis and encephalomyelitis. 
     
     
         16 . A method in accordance with  claim 12 , wherein said administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical. 
     
     
         17 . A method in accordance with  claim 12 , wherein said compound is administered in combination with an anti-inflammatory agent, analgesic agent, an anti-proliferative agent, a metabolic inhibitor, a leukocyte migration inhibitor or an immuno modulator. 
     
     
         18 . A method in accordance with  claim 12 , wherein said compound is