Forms and salts of a dihydropyrrolo[1,2c]imidazolyl aldosterone synthase or aromatase inhibitor

Abstract

The invention relates to a phosphate salt or a nitrate salt of 4-(R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl-3-fluoro-benzonitrile, especially in crystalline form, and specific forms of these salts, as well as related invention embodiments. The salts and salt forms allow for the prophylactic and/or therapeutic treatment of aldosterone synthase and/or aromatase mediated diseases or disorders.

1 . A phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile in a crystalline modification called form A with an XRPD showing at least one of the following peaks, given as an angle of refraction 2-theta (2θ) values, where each peak may vary by ±0.5 degrees: 12.9, 16.3, and 20.4 degrees. 
     
     
         2 . The phosphate salt of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile in a crystalline modification called form A according to  claim 1 , with a molar ratio of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile to phosphate of about 1:1. 
     
     
         3 . The phosphate salt in a crystalline modification called form A according to  claim 1  having a melting point at least 50° C. higher than that of the free base. 
     
     
         4 . The phosphate salt according to  claim 1  having a melting point, using thermogravimetry/differential thermal analysis (TG/DTA), between 209 and 212° C. 
     
     
         5 . Crystalline Form A of the phosphate salt according to  claim 4  having a melting temperature of 210±0.5° C. determined by TG/DTA. 
     
     
         6 . The phosphate salt in the crystalline modification called Form A according to  claim 1  with an XRPD showing at least 4, 5, 6, 7, 8, 9 or all of the following peaks, given as angle of refraction 2-theta (θ) values, where each peak ±0.2 degrees: 6.0, 12.9, 15.5, 16.0, 16.3, 19.7, 20.4, 22.1, 24.3 and 29.2 degrees. 
     
     
         7 . The phosphate salt in the crystalline modification called Form A according to  claim 1  with an XRPD showing at least 7, 9, 11, 13, 15, 17 or all of the following peaks, where each peak may vary by ±0.2 degrees: 6.0, 10.0, 12.1, 12.9, 14.0, 14.5, 15.5, 16.0, 16.3, 17.5, 18.2, 18.4, 19.7, 20.4, 22.1, 24.3, 29.2. 
     
     
         8 . The phosphate salt in the crystalline modification called Form A according to  claim 1 , wherein the two largest peaks in the XRPD diagram have a relative intensity of 1 to 0.5 to 0.7, especially of 1 to 0.55 to 0.65, more especially of 0.57 to 0.61, e.g. of 1 to 0.59 (obtainable by integration of each of the peaks in the XRPD diagrams), the larger peak being at a 2-theta (θ) value of 6.0±0.2 degrees and the smaller peak at a 2-theta (θ) value of 19.7±0.2 degrees, respectively. 
     
     
         9 . The phosphate salt in the crystalline modification called Form A according to  claim 1  showing an XRPD as shown in  FIG. 1 -A. 
     
     
         10 . A process for making a phosphate salt, in crystalline form A, as defined in  claim 1 , of 4-(R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl-3-fluoro-benzonitrile, the process comprising:
 (a) providing a solution of 4-(R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl-3-fluoro-benzonitrile in either a protic or an aprotic polar solvent;   (b) adding nitric acid or especially phosphoric acid; and   (c) isolating the formed crystalline form of a nitrate salt or especially a phosphate salt of 4-(R)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl-3-fluoro-benzonitrile.   
     
     
         11 . A pharmaceutical composition comprising the phosphate in crystalline Form A according to  claim 1  for the treatment of Cushing's disease. 
     
     
         12 . A method of treatment comprising administering said phosphate salt in crystalline Form A according to  claim 1  to a mammal in need thereof in a therapeutically effective amount for treating Cushing's disease. 
     
     
         13 . A pharmaceutical composition comprising a phosphate salt in crystalline form A of 4-(R)-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile and one or more pharmaceutically acceptable excipients.