Solid Salt Forms Of A Pyrrole Substituted 2-Indolinone

Abstract

The present invention relates to solid salt forms of the 3-pyrrole substituted 2-indolinone compound 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide. It also relates to polymorphs of the phosphate salt of the amide. The invention further relates to the use of the salts and polymorphs in the treatment of protein kinase related disorders.

1 . Salt forms of a base, wherein the base is 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide, and wherein the salt form is selected from the group consisting of the citrate and phosphate salts, and solvates and polymorphs thereof. 
     
     
         2 . A salt form of  claim 1 , wherein the salt is the phosphate salt with the structure: 
       
         
           
           
               
               
           
         
       
       and solvates and polymorphs thereof. 
     
     
         3 . The salt form of  claim 2 , with a molecular formula of C 22 H 25 FN 4 O 2 .H 3 PO 4  and a melting point from about 285 to about 290° C. 
     
     
         4 . A polymorph (Form 1) of the phosphate salt of  claim 2 , wherein said polymorph has a powder X-ray diffraction spectrum comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 20.8, 24.5, 25.9, and 27.0 obtained using CuKα 1  emission (wavelength=1.5406 Angstroms). 
     
     
         5 . A salt form of  claim 1 , wherein the salt is the citrate salt with the structure: 
       
         
           
           
               
               
           
         
       
       and solvates and polymorphs thereof. 
     
     
         6 . The salt form of  claim 5 , with a molecular formula of C 22 H 25 FN 4 O 2 .C 6 H 8 O 7  and a melting point from about 178 to about 183° C. 
     
     
         7 . The salt form of  claim 5 , having a powder X-ray diffraction pattern comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 9.1, 9.4, 14.2, 25.4, and 26.8 obtained using CuKα 1  emission (wavelength=1.5406 Angstroms). 
     
     
         8 . A pharmaceutical composition comprising the phosphate salt of  claim 2 , the citrate salt of  claim 5 , or a solvate or polymorph thereof, and a pharmaceutically acceptable carrier or excipient. 
     
     
         9 . A method for the modulation of the catalytic activity of protein kinases comprising contacting said protein kinase with the phosphate salt of  claim 2 , the citrate salt of  claim 5 , or a solvate or polymorph thereof. 
     
     
         10 . A protein kinase of  claim 9 , wherein the protein kinase is selected from the group consisting of receptor tyrosine kinases, non-receptor protein tyrosine kinases, and serine/threonine protein kinases. 
     
     
         11 . A method of preventing or treating a protein kinase related disorder in an organism comprising administering to said organism a therapeutically effective amount of a pharmaceutical composition of  claim 8 . 
     
     
         12 . The method of  claim 11 , wherein the protein kinase related disorder is mast cell tumor or mastocytosis. 
     
     
         13 . A method of preparing phosphate salt crystals of the base of  claim 1 , which comprises:
 (a) introducing a stoichiometric amount of phosphoric acid to the base in a solution comprising a solvent or a mixture of solvents;   (b) crystallizing the phosphate salt from solution; and   (c) separating the phosphate salt crystals from the solvent solution.   
     
     
         14 . A method of preparing polymorphs of the phosphate salt of  claim 2 , which comprises:
 (a) introducing the phosphate salt to a solution comprising a solvent or a mixture of solvents;   (b) optionally, adding a bridging solvent to the solution; and   (c) separating the polymorph crystals from the solvent solution.   
     
     
         15 . The method of  claim 14 , wherein the solvent of step (a) comprises methanol. 
     
     
         16 . A method of preparing citrate salt crystals of the base of  claim 1 , which comprises:
 (a) introducing a stoichiometric amount of citric acid to the base in a solution comprising a solvent or a mixture of solvents;   (b) crystallizing the citrate salt crystals from solution; and   (c) separating the citrate salt crystals from the solvent solution.   
     
     
         17 . A use of the phosphate salt of  claim 2 , the citrate salt of  claim 5 , or a solvate or polymorph thereof, in the preparation of a medicament which is useful in the treatment of a disease mediated by abnormal PK activity.