Combination of a nitrogen mustard analogue and imatinib for the treatment of chronic lymphocytic leukemia

Abstract

The invention relates to a combination which comprises (a) a nitrogen mustard analogue selected from chlorambucil, chlornaphazine, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, navembichin, phenestrine, prednimustine, trofosfamide or uracil mustard and (b) 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide of formula or a pharmaceutically acceptable salt thereof, the invention pertains to the use of said combination for the treatment chronic lymphocytic leukemia.

1 . A combination for simultaneous, separate or sequential use which comprises (a) a nitrogen mustard analogue selected from chlorambucil, chlornaphazine, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, navembichin, phenestrine, prednimustine, trofosfamide and uracil mustard and (b) 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide having the following formula  
     
       
         
         
             
             
         
       
     
     in which the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt.  
   
   
       2 . The combination according to  claim 1  which is a fixed combined pharmaceutical composition.  
   
   
       3 . The combination according to  claim 1  wherein (a) and (b) are present in synergistically effective amounts.  
   
   
       4 . The combination according to  claim 1  wherein the nitrogen mustard analogue is chlorambucil.  
   
   
       5 . The combination according to  claim 1  used for the treatment of chronic lymphocytic leukemia.  
   
   
       6 . The combination according to  claim 1  used in a preparation of a medicament for the treatment of chronic lymphocytic leukemia.  
   
   
       7 . The combination according to  claim 5  wherein leukemia is a chlorambucil-resistant chronic lymphocytic leukemia.  
   
   
       8 . A method of treating a warm-blooded animal having chronic lymphocytic leukemia comprising administering to said animal a combination according to  claim 1  in a quantity which is jointly therapeutically effective against said disease and in which the compounds can also be present in the form of their pharmaceutically acceptable salts.  
   
   
       9 . The method according to  claim 8  wherein (a) chlorambucil is administered at a dose of 0.2 to 0.8 mg/kg of body weight/day and (b) 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide is administered at a dose of 50 mg to 800 mg per day.  
   
   
       10 . A pharmaceutical composition comprising a quantity, which is jointly therapeutically effective against chronic lymphocytic leukemia of the combination according to  claim 1  or and at least one pharmaceutically acceptable carrier.  
   
   
       11 . A commercial package comprising a pharmaceutical composition according to  claim 10  together with instructions for simultaneous, separate or sequential use thereof in the treatment of chronic lymphocytic leukemia.  
   
   
       12 . A method of treating a warm-blooded animal having chronic lymphocytic leukemia comprising 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide in free form or in the form of a pharmaceutically acceptable salt for the manufacture of a medicament in combination with a nitrogen mustard analog selected from chlorambucil, chlornaphazine, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, navembichin, phenestrine, prednimustine, trofosfamide and uracil mustard.  
   
   
       13 . The method according to  claim 12  wherein the nitrogen mustard analogue is chlorambucil.