Methods of modulating c-kit tyrosine protein kinase function with indolinone compounds

Abstract

The present invention concerns compounds and their use to inhibit the activity of a receptor tyrosine kinase. The invention is preferably used to treat cell proliferative disorders such as cancers characterized by over-activity or inappropriate activity c-kit kinase.

1 . A method for treating or preventing an abnormal condition in an organism, wherein said abnormal condition is associated with an aberration in a signal transduction pathway mediated by a c-kit kinase, wherein said method comprises the step of administering to said organism a therapeutically effective amount of an indolinone compound that modulates, in vitro, the catalytic activity of c-kit kinase.  
     
     
         2 . The method of  claim 1  wherein said aberration in said signal transduction pathway is mediated by an interaction between said c-kit kinase and a natural binding partner, and said indolinone compound modulates, in vitro, the interaction between said c-kit kinase and said natural binding partner.  
     
     
         3 . The method of  claim 1  wherein said abnormal condition is a disease related to inappropriate c-kit kinase signal transduction.  
     
     
         4 . The method of  claim 1 , wherein said abnormal condition is selected from the group consisting of mastocytosis, the presence of one or more mast cell tumors, asthma, and allergy associated chronic rhinitis.  
     
     
         5 . The method of  claim 1 , wherein said abnormal condition is selected from the group consisting of small cell lung cancer, non-small cell lung cancer, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, a colorectal carcinoma, a gastric carcinoma, a gastrointestinal stromal tumor, a testicular cancer, a glioblastoma, and an astrocytoma.  
     
     
         6 . The method of  claim 1  wherein said organism is a mammal.  
     
     
         7 . The method of  claim 1  wherein said organism is a human.  
     
     
         8 . The method of any one of claims  1 ,  2  and  3  wherein said indolinone compound is a compound of the structure set forth in Formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 (a) Y is selected from the group consisting of oxygen, sulfur and nitrogen substituted with a hydrogen;  
 (b) R 1 , R 2 , R 3 , and R 4  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′;  
 (c) R 5  is 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, CONRR′, a six-membered heteroaryl ring system containing 1 or 2 N, O, or S atoms; and a six-membered aryl ring system; and  
 (d) 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′,  
                     
 
     
     
         9 . The method of any one of claims  1 ,  2  and  3  wherein said indolinone compound is a compound of the structure set forth in Formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 (a) Y is selected from the group consisting of sulfur and nitrogen substituted with a hydrogen;  
 (b) R 1  is independently selected from the group consisting of hydrogen and methyl;  
 (c) R 2  is independently selected from the group consisting of hydrogen, chlorine, bromine, —C(O)CH 3 , —SO 2 NH 2 , and SO 2 N(CH 3 ) 2 ;  
 (d) R 3  is independently selected from the group consisting of hydrogen, methyl, and —CH 2 CH 2 COOH; and  
 (e) R 4  and R 5  are independently selected from the group consisting of hydrogen, methyl, —CH 2 CH 2 COOH, and substituents that when taken together form a six-membered aliphatic or aromatic ring.  
 
     
     
         10 . The method of any one of claims  1 ,  2  and  3  wherein said indolinone compound is selected from the group consisting of compounds