Use of c-src inhibitors alone or in combination with st1571 for the treatment of leukaemia

Abstract

The invention relates to a combination which comprises (a) at least one compound decreasing the c-Src activity and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamdio]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine or the monomethanesulfonate salt thereof; to pharmaceutical compositions comprising said combinations; and to a method of treating a warm-blooded animal having leukaemia, especially chronic myelogenous leukaemia, comprising administering to the animal at least one compound inhibiting the activity of a member of the Src kinase family, the Tee kinase family or a Raf kinase inhibitor, in particular inhibiting the c-Src protein tyrosine kinase activity or inhibiting simultaneously the c-Src protein tyrosine kinase activity and the Bcr-Abl tyrosine kinase activity, alone or in combination with a Bcr-Abl inhibitor, in particular N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}4-(3-pyridyl)-2-pyrimidine-amine.

1 . Combination which comprises (a) at least one compound decreasing the c-Src activity protein tyrosine kinase and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.  
     
     
         2 . Combination according to  claim 1  wherein compound inhibiting the c-Src protein tyrosine kinase activity is selected from a compound of formula I  
       
         
           
           
               
               
           
         
       
       and a compound of formula V  
       
         
           
           
               
               
           
         
       
     
     
         3 . Combination according to  claim 1  wherein compound (b) is used in the form of its monomethanesulfonate salt.  
     
     
         4 . A combination according to  claims 1  to  3  for use in the therapeutic or diagnostic treatment of the animal or human body.  
     
     
         5 . Use of a combination according to claims  1  to for the manufacture of a medicament for the treatment of leukaemia.  
     
     
         6 . Method of treating a warm-blooded animal having leukaemia comprising administering to the animal at least one compound inhibiting the activity of a member of the Src kinase family, the Btk kinase family, the Tec kinase family or a Raf kinase inhibitor, in a quantity which is therapeutically effective against leukaemia, alone or in combination with a Bcr-Abl inhibitor.  
     
     
         7 . Method of treating a warm-blooded animal having leukaemia comprising administering to the animal at least one compound inhibiting the c-Src protein tyrosine kinase activity in a quantity which is therapeutically effective against leukaemia, in which method said compounds can also be present in the form of their pharmaceutically acceptable salts.  
     
     
         8 . Method according to  claim 7 , wherein the compound inhibiting the c-Src protein tyrosine kinase activity is selected from a compound of formula I  
       
         
           
           
               
               
           
         
       
       and a compound of formula V  
       
         
           
           
               
               
           
         
       
     
     
         9 . Method of treating a warm-blooded animal having leukaemia comprising administering to the animal (a) at least one compound decreasing the c-Src activity and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine in a quantity which is jointly therapeutically effective against leukaemia.  
     
     
         10 . Method according to  claim 9 , wherein the compound inhibiting the c-Src protein tyrosine kinase activity is selected from a compound of formula I  
       
         
           
           
               
               
           
         
       
       and a compound of formula V  
       
         
           
           
               
               
           
         
       
     
     
         11 . Method of treating a warm-blooded animal having leukaemia comprising administering to the animal at least one compound inhibiting the c-Src protein tyrosine kinase activity and the Bcr-Abl tyrosine kinase activity, in a quantity which is therapeutically effective against leukaemia in which method said compounds can also be present in the form of their pharmaceutically acceptable salts.  
     
     
         12 . Method according to  claim 11 , wherein the compound inhibiting the c-Src protein tyrosine kinase activity and the Bcr-Abl tyrosine kinase activity is a compound of formula V  
       
         
           
           
               
               
           
         
       
     
     
         13 . Method according to  claim 6  wherein said leukaemia is resistent to mono-therapy employing N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine as sole active agent.  
     
     
         14 . Method according to  claim 6  wherein said leukaemia is chronic myelogenous leukaemia.  
     
     
         15 . Use of a compound inhibiting the c-Src protein tyrosine kinase activity for the manufacture of a medicament for the treatment of leukaemia.  
     
     
         16 . Use of a compound inhibiting the c-Src protein tyrosine kinase activity and the Bcr-Abl tyrosine kinase activity for the manufacture of a medicament for the treatment of leukaemia.  
     
     
         17 . A pharmaceutical composition comprising a quantity which is jointly therapeutically effective against leukaemia of a combination according to claims  1  and at least one pharmaceutically acceptable carrier.  
     
     
         18 . A commercial package comprising at least one c-Src protein tyrosine kinase activity inhibitor together with instructions for use thereof in the treatment of leukaemia.  
     
     
         19 . A commercial package comprising (a) at least one compound decreasing the c-Src protein tyrosine kinase activity and (b) N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine in free form or in the form of a pharmaceutically acceptable salt, together with instructions for simultaneous, separate or sequential use thereof in the treatment of leukaemia.