Pyrimidylaminobenzamide Derivatives For Sytemic Mastocytosis

Abstract

The present invention relates to the use of pyrimidylaminobenzamide derivatives for the preparation of a drug for the treatment of systemic mastocytosis.

1 . A method for the treatment or prevention of systemic mastocytosis comprising administration of a pyrimidylaminobenzamide derivative of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, or phenyl-lower alkyl; 
         R 2  represents hydrogen, lower alkyl, optionally substituted by one or more identical or different radicals R 3 , cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; 
         and R 3  represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl group comprising zero, one, two or three ring nitrogen atoms and zero or one oxygen atom and zero or one sulfur atom, which groups in each case are unsubstituted or mono- or polysubstituted; 
         or wherein R 1  and R 2  together represent alkylene with four, five or six carbon atoms optionally mono- or disubstituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; 
         benzalkylene with four or five carbon atoms; oxaalkylene with one oxygen and three or four carbon atoms; or azaalkylene with one nitrogen and three or four carbon atoms wherein nitrogen is unsubstituted or substituted by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl, or pyrazinyl; 
         R 4  represents hydrogen, lower alkyl, or halogen; 
         and a N-oxide or a pharmaceutically acceptable salt of such a compound. 
       
     
     
         2 . A method according to  claim 1  where the systemic mastocytosis has resistance to imatinib. 
     
     
         3 . A method according to  claim 1  where the compound of formula (I) is 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide of formula (II): 
       
         
           
           
               
               
           
         
         and N-oxides or pharmacutially acceptable salts thereof. 
       
     
     
         4 . A method according to  claim 1  wherein the systemic mastocytosis is associated with FIP1L1-PDGFRα. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . A method according to  claim 1  for the treatment of systemic matocytosis associated with FIP1L1-PDGFRα-gene fusion. 
     
     
         8 . A method for treating mammals suffering from systemic mastocytosis comprising administering to a mammal in need of such treatment a FIP1L1-PDGFRα-induced inhibiting amount of a compound of formula (II): 
       
         
           
           
               
               
           
         
         or an N-oxide or pharmaceutically acceptable salts thereof. 
       
     
     
         9 . A pharmaceutical preparation for the treatment of FIP1L1-PDGFRα-induced systemic mastocytosis comprising a compound of formula (II): 
       
         
           
           
               
               
           
         
         or an N-oxide or pharmaceutically acceptable salts thereof. 
       
     
     
         10 . A method for treating mammals, including man, suffering from systemic mastocytosis comprising administering to a mammal in need of such treatment a compound of formula (II):