Maleate salts of a quinazoline derivative useful as an antiangiogenic agent

Abstract

The present invention relates to AZD2171 maleate salt, to particular crystalline forms of AZD2171 maleate salt, to processes for their preparation, to pharmaceutical compositions containing them as active ingredient, to their use in the manufacture of medicaments for use in the production of antiangiogenic and/or vascular permeability reducing effects in warm-blooded animals such as humans, and to their use in methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability.

1 . A maleate salt of AZD2171.  
   
   
       2 . A maleate salt of AZD2171, according to  claim 1 , in the crystalline form, Form A.  
   
   
       3 . A maleate salt of AZD2171, according to  claim 1 , in the crystalline form, Form B.  
   
   
       4 . A maleate salt of AZD2171, according to  claim 2 , in the crystalline form, Form A, wherein said salt has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta=21.5°.  
   
   
       5 . A maleate salt of AZD2171, according to  claim 2 , in the crystalline form, Form A, wherein said salt has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta=16.4°.  
   
   
       6 . A maleate salt of AZD2171, according to  claim 2 , in the crystalline form, Form A, wherein said salt has an X-ray powder diffraction pattern with at least two specific peaks at about 2-theta=21.5 and 16.4°.  
   
   
       7 . A maleate salt of AZD2171, according to  claim 2 , in the crystalline form, Form A, wherein said salt has an X-ray powder diffraction pattern with specific peaks at about 2-theta=21.5, 16.4, 24.4, 20.7, 25.0, 16.9, 12.1, 22.2, 17.4 and 17.6°.  
   
   
       8 . A maleate salt of AZD2171, according to  claim 2 , in the crystalline form, Form A, wherein said salt has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in  FIG. 5 .  
   
   
       9 . A maleate salt of AZD2171, according to  claim 3 , in the crystalline form, Form B, wherein said salt has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta=24.2°.  
   
   
       10 . A maleate salt of AZD2171, according to  claim 3 , in the crystalline form, Form B, wherein said salt has an X-ray powder diffraction pattern with at least one specific peak at about 2-theta=22.7°.  
   
   
       11 . A maleate salt of AZD2171, according to  claim 3 , in the crystalline form, Form B, wherein said salt has an X-ray powder diffraction pattern with at least two specific peaks at about 2-theta=24.2 and 22.7°.  
   
   
       12 . A maleate salt of AZD2171, according to  claim 3 , in the crystalline form, Form B, wherein said salt has an X-ray powder diffraction pattern with specific peaks at about 2-theta=24.2, 22.7, 15.7, 12.0, 27.1, 25.0, 17.7, 15.0, 23.1 and 12.6°.  
   
   
       13 . A maleate salt of AZD2171, according to  claim 3 , in the crystalline form, Form B, wherein said salt has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in  FIG. 8 .  
   
   
       14 . A pharmaceutical composition which comprises a maleate salt of AZD2171 according to  claim 1  in association with a pharmaceutically acceptable excipient or carrier.  
   
   
       15 . A pharmaceutical composition according to  claim 14  wherein the AZD2171 maleate salt is in the crystalline form, Form A.  
   
   
       16 . A pharmaceutical composition according to  claim 14  wherein the AZD2171 maleate salt is in the crystalline form, Form B.  
   
   
       17 . A process for the preparation of a maleate salt of AZD2171 in the crystalline form Form A, as claimed in  claim 2 , which comprises: 
 (i) dissolving AZD2171 free base in an organic solvent to form a solution;    (ii) adding an aqueous solution of maleic acid or adding a solution of maleic acid in an organic solvent;    (iii) allowing spontaneous nucleation to occur;    (iv) slurrying the mixture in a solvent until all the AZD2171 maleate is Form A; and    (v) isolating the crystalline solid so formed.    
   
   
       18 . A process for the preparation of a maleate salt of AZD2171 in the crystalline form Form A, as claimed in  claim 2 , which comprises: 
 (i) dissolving AZD2171 free base in an organic solvent to form a solution;    (ii) adding an aqueous solution of maleic acid or adding a solution of maleic acid in an organic solvent;    (iii) obtaining a solution and adding a seed of AZD2171 maleate Form A to initiate crystallisation of AZD2171 maleate Form A; and    (iv) isolating the crystalline solid so formed.    
   
   
       19 . A process for the preparation of a maleate salt of AZD2171 in the crystalline form Form B, as claimed in  claim 3 , which comprises: 
 (i) dissolving AZD2171 maleate in an organic solvent to form a solution;    (ii) adding the solution to a solvent in which AZD2171 maleate has a lower solubility than it does in NMP;    (iii) crystallisation of AZD2171 maleate Form B then occurs; and    (iv) isolating the crystalline solid so formed.    
   
   
       20 . Use of a maleate salt of AZD2171 as claimed in  claim 1  in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human being.  
   
   
       21 . A method for producing an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of an AZD2171 maleate salt as claimed in  claim 1.