3-(4'-Bromobenzylindenyl)-2-indolinone and analogues thereof for the treatment of disease

Abstract

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

What is claimed is:  
     
         1 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein: 
 R 1  is H or alkyl;  
 R 2  is O or S;  
 R 3  is hydrogen;  
 R 4 , R 5 , R 6 , and R 7  are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO 2 NRR′, SO 3 R, SR, NO 2 , NRR′, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH 2 ) n CO 2 R, and CONRR′;  
 R 2 ′, R 3 ′, R 5 ′, and R 6 ′ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO 2 NRR′, SO 3 R, SR, NO 2 , NRR′, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH 2 ) n CO 2 R, and CONRR′;  
 n is 0-3;  
 Z is Br, Cl, F, I, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl;  
 R is H, alkyl or aryl; and  
 R′ is H, alkyl or aryl.  
 
     
     
         2 . The compound of  claim 1  wherein: 
 R 3 ′ is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, halogen, aryl and OR, where R is H, alkyl or aryl; and  
 R 5 ′ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, halogen, aryl and OR, where R is H, alkyl or aryl.  
 
     
     
         3 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound according to  claim 1 .  
     
     
         4 . A method for treating diseases related to unregulated tyrosine kinase signal transduction, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         5 . The method of  claim 4  wherein said disease is selected from the group consisting of cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases.  
     
     
         6 . The method of  claim 4  wherein the blood vessel proliferative disorder is selected from the group consisting of arthritis and restenosis.  
     
     
         7 . The method of  claim 4  wherein the fibrotic disorder is selected from the group consisting of hepatic cirrhosis and atherosclerosis.  
     
     
         8 . The method of  claim 4  wherein the mesangial cell proliferative disorder is selected from the group consisting of glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and glomerulopathies.  
     
     
         9 . The method of  claim 4  wherein the metabolic disorder is selected from the group consisting of psoriasis, diabetes mellitus, wound healing, inflammation and neurodegenerative diseases.  
     
     
         10 . A method for regulating tyrosine kinase signal transduction comprising administering to a subject a therapeutically effective amount of a compound according to  claim 1.