Pyrimidylaminobenzamide derivatives for the treatment of neurofibromatosis

Abstract

The present invention relates to the use of pyrimidylaminobenzamide derivatives for the preparation of a drug for the treatment of non-cancerous, benign brain tumors, especially for the curative and/or prophylactic treatment of NF, and to a method of treating non-cancerous, benign brain tumors, especially for the curative and/or prophylactic treatment of NF.

1 . A method of treating or preventing non-cancerous, benign brain tumors, comprising administering a pyrimidylaminobenzamide derivatives 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 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; and 
 R 3  represents hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-di-substituted carbamoyl, amino, mono- or di-substituted amino, cycloalkyl, heterocyclyl, an aryl group, or a mono- or bi-cyclic heteroaryl group comprising 0-, 1-, 2- or 3-ring nitrogen atoms and 0 or 1 oxygen atom and 0 or 1 sulfur atom, which groups in each case are unsubstituted or mono- or poly-substituted; or 
 R 1  and R 2 , together, represent alkylene with 4, 5 or 6 carbon atoms optionally mono- or di-substituted by lower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- or di-substituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene with 4 or 5 carbon atoms; oxaalkylene with 1 oxygen and 3 or 4 carbon atoms; or azaalkylene with 1 nitrogen and 3 or 4 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-di-substituted carbamoyl-lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl; 
 R 4  represents hydrogen, lower alkyl or halogen; and 
 
     an N-oxide or a pharmaceutically acceptable salt of such a compound. 
   
   
       2 . A method according to  claim 1 , where the non-cancerous, benign brain tumors are selected from neurofibromatosis type 1 or type 2. 
   
   
       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 pharmaceutically acceptable salts thereof. 
   
   
       4 . A method for treating mammals, including humans, suffering from non-cancerous, benign brain tumors comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (II): 
     
       
         
         
             
             
         
       
     
     or an N-oxide or pharmaceutically acceptable salts thereof. 
   
   
       5 . A pharmaceutical preparation for the treatment of non-cancerous, benign brain tumors, comprising a compound of formula (II): 
     
       
         
         
             
             
         
       
     
     or an N-oxide or pharmaceutically acceptable salts thereof.