Oxindole derivatives

Abstract

The present invention is related to oxindole derivatives, compositions containing the same, and methods of use and manufacture of the same. Such compounds generally are useful pharmacologically as agents in those disease states alleviated by the alteration of mitogen activated signaling pathways in general, and in particular in the inhibition or antagonism of protein kinases, which pathologically involve aberrant cellular proliferation. Such disease states include tumor growth, restenosis, atherosclerosis, pain and thrombosis. In particular, the present invention relates to a series of substituted oxindole compounds, which exhibit Trk family protein tyrosine kinase inhibition, and which are useful in cancer therapy and chronic pain indications.

1 . A method of inhibiting TrkA kinase in a mammal, comprising administering to said mammal an effective amount of a compound of the formula II:  
     
       
         
         
             
             
         
       
     
     or salts, solvates, or physiological functional derivatives thereof  
     wherein: 
 R 1  is hydrogen;  
 R 2  is hydrogen; or  
 R 1  and R 2  are optionally joined to form a fused ring Het, wherein Het is a triazine ring;  
 R 3  is hydrogen;  
 R 4  is selected from the group consisting of  
 hydrogen,  
                     
 R 5  is hydrogen or  
                     
 R 4  and R 5  are optionally joined to form a fused cyclic urea ring; and  
 R 6 , R 7 , and R 8  are hydrogen.  
 
   
   
       2 . A method as claimed in  claim 1 , wherein R 1 , R 2 , R 3 , R 6 , R 7 , and R 8  are hydrogen and R 4  and R 5  are joined to form the fused cyclic urea ring —N(H)C(O)N(H)—.  
   
   
       3 . A method as claimed in  claim 1 , wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8  are hydrogen and R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       4 . A method as claimed in  claim 1 , wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8  are hydrogen and R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       5 . A method as claimed in  claim 1 , wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8  are hydrogen and R 4  is —CH 2 —C(O)NH 2 .  
   
   
       6 . A method as claimed in  claim 1 , wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , and R 8  are hydrogen and R 4  is  
     
       
         
         
             
             
         
       
     
   
   
       7 . A method as claimed in  claim 1 , wherein R 1  and R 2  are joined to form a fused triazine ring; R 3 , R 4 , R 6 , R 7 , and R 8  are hydrogen; and R 5  is  
     
       
         
         
             
             
         
       
     
   
   
       8 . A method as claimed in  claim 1 , where the compound of formula (II) is selected from the group: 
 5-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}-1,3-dihydro-2H-benzimidazol-2-one;    (3Z)-3-{[4-(1H-1,2,4-triazol-1-yl)anilino]-methylene}-1,3-dihydro-2H-indol-2-one;    3-ethyl-3-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]amino}phenyl)-2,6-piperidinedione;    (8Z)-8-{[3-(5-amino-1,3,4-oxadiazol-2-yl)anilino]methylene}-6,8-dihydro[1,2,3]triazolo[4,5-e]indol-7(3H)-one;    2-(4-{[(Z)-(2-oxo-1,2-dihydro-3H-indol-3-ylidene) methyl]amino}phenyl)acetamide; and    (3Z)-3-{[4-(1H-1,2,4-triazol-3-yl)anilino]methylene}-1,3-dihydro-2H-indol-2-one;    or salts, solvates or physiologically functional derivatives thereof.