Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processed for its manufacture and its use

Abstract

The invention relates to a new crystalline form of the methanesulfonic acid addition salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide of formula 1, which may be used for example for tumour therapy.

1 . A form of the monomethanesulfonic acid addition salt of a compound of formula I,  
       
         
           
           
               
               
           
         
         comprising at least 90% by weight crystals of the β-modification, said crystals of the β-modification being non-hygroscopic and remaining essentially dry in a glass climatic chamber at 25° C. and relative humidities up to and including 93%.  
       
     
     
         2 . A crystalline form according to  claim 1  of the methanesulfonic acid addition salt of a compound of formula I, which comprises at least 95% by weight crystals of the β-modification and remains dry at 93% relative humidity and 25° C.  
     
     
         3 . A crystalline form according to  claim 1  of the methanesulfonic acid addition salt of a compound of formula I, which comprises at least 99% by weight crystals of the β-modification and remains dry at 93% relative humidity and 25° C.  
     
     
         4 . The β-crystal form according to  claim 1  of the methanesulfonic acid addition salt of a compound of formula I, which comprises at least 99% by weight crystals of the β-modification and has a melting point below 225° C.  
     
     
         5 . The β-crystal form according to  claim 1  of the methanesulfonic acid addition salt of a compound of formula I, which comprises at least 99% by weight crystals of the β-modification and has a melting point of less than 217° C., defined as the start of melting in the differential scanning calorimetry thermogram.  
     
     
         6 . The β-crystal form according to  claim 1  of the methanesulfonic acid addition salt of a compound of formula I, which shows on X-ray diffraction a peak at an angle of refraction 2theta of 20°, said peak having a relative line intensity of 65 as compared to the most intense line in the diagram.  
     
     
         7 . The β-crystal form according to  claim 3  of the methanesulfonic acid addition salt of a compound of formula I, which shows in an X-ray diffraction diagram lines having a relative line intensity, as compared to the most intense line in the diagram, of 20 or more at the following angles of refraction 2theta (relative line intensities given in parentheses): 9.7° (40), 13.9° (26), 14.7° (23), 17.5° (57), 18.2° (90), 20.0° (65), 20.6° (76), 21.1° (100), 22.1° (89), 22.7° (38), 23.8° (44), 29.8° (23) and 30.8° (20).  
     
     
         8 . The β-crystal form according to  claim 5  of the methanesulfonic acid addition salt of a compound of formula I, which has a melting point of 217° C., defined as the start of melting in the differential scanning calorimetry diagram, and which shows essentially the x-ray diffraction diagram shown in  FIG. 2 .  
     
     
         9 . The β-crystal form according to  claim 1  of the methanesulfonic acid addition salt of a compound of formula I for use in a process for diagnostic or therapeutic treatment of the human or animal body.  
     
     
         10 . A pharmaceutical composition, comprising the β-crystal form according to  claim 1  of the methanesulfonic acid addition salt of a compound of formula I and a pharmaceutically acceptable carrier.  
     
     
         11 . Use of the β-crystal form according to  claim 1  of the methanesulfonic acid addition salt of a compound of formula I for the preparation of a pharmacological agent for the treatment of a tumour disease.  
     
     
         12 . Processes for the preparation of the β-crystal form according to  claim 1  of the methanesulfonic acid addition salt of a compound of formula I characterised by 
 a) digesting another crystal form or an amorphous starting material of the methanesulfonic acid addition salt of a compound of formula I with a suitable polar solvent in suspension at a temperature between 20 and 50° C., or    b) dissolving another crystal form or an amorphous starting material of the methanesulfonic acid addition salt of a compound of formula I, in a polar solvent at a suitable temperature of 25° C. up to the reflux temperature of the reaction mixture, and then initiating crystallisation by adding a small amount of the β-crystal form as seed crystal at a temperature between 20 and 70° C.