Chemical compounds

Abstract

The present invention is related to aza-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 in a mammal, comprising administering to said mammal a compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 X is N and Z is CH; or  
 X is CH and Z is N;  
 R is hydrogen or halogen; and  
 A is selected from  
                     wherein R 1  is halogen, 
 R 2  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 1 -C 6  alkylsulfanyl, and;  
 R 3  is hydrogen or C 1 -C 6  alkyl; or  
   a salt or solvate thereof.    
 
   
   
       2 . A method as claimed in  claim 1 , wherein X is N and Z is CH.  
   
   
       3 . A method as claimed in  claim 1 , wherein X is CH and Z is N.  
   
   
       4 . A method as claimed in  claim 1 , wherein R is hydrogen, bromo or chloro.  
   
   
       5 . A method as claimed in  claim 1 , wherein A is,  
     
       
         
         
             
             
         
       
     
     and R 1  is halogen and R 2  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 1 -C 6  alkylsulfanyl.  
   
   
       6 . A method as claimed in  claim 1 , wherein A is,  
     
       
         
         
             
             
         
       
     
     and R 3  is hydrogen or C 1 -C 6  alkyl.  
   
   
       7 . A method as claimed in  claim 1 , wherein the compound of formula (I) is selected from:  
     
       
         
         
             
             
         
       
     
   
   
       8 . A method as claimed in  claim 1 , wherein the compound of formula (I) is 3-(3-Bromo-4-hydroxy-5-(2′methoxyphenyl)-benzylidene)-5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridine-2-one or a salt or solvate thereof.  
   
   
       9 . A method as claimed in  claim 1 , wherein the compound of formula (I) is (3Z)-3-[(1-methyl-1H-indol-3-yl)methylene]-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one or a salt or solvate thereof.  
   
   
       10 . A method as claimed in  claim 1 , wherein the compound of formula (I) is (3Z)-3-[(1H-indol-3-yl)methylene]-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one or a salt or solvate thereof.  
   
   
       11 . A method as claimed in  claim 1 , wherein the compound of formula (I) is 3-[(1-methyl-1H-indol-3-yl)methylene]-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one or a salt or solvate thereof.  
   
   
       12 . A method as claimed in  claim 1 , wherein the compound of formula (I) is 3-[(1H-indol-3-yl)methylene]-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one or a salt or solvate thereof.  
   
   
       13 . A method of inhibiting TrkA in a mammal, comprising administering to said mammal a pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in  claim 1  or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.  
   
   
       14 . A method of inhibiting TrkA in a mammal, comprising administering to said mammal a pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in  claim 7  or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.