Salt of omecamtiv mecarbil and process for preparing salt

Abstract

Provided are omecamtiv mecarbil dihydrochloride salt forms, compositions and pharmaceutical formulations thereof, and methods for their preparation and use.

What is claimed: 
     
         1 . A method of preparing omecamtiv mecarbil dihydrochloride monohydrate salt comprising:
 a) admixing methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate and phenyl chloroformate to form 4-(2-fluoro-3-((phenoxycarbonyl)amino)benzyl)piperazine-1-carboxylate,   b) admixing 4-(2-fluoro-3-((phenoxycarbonyl)amino)benzyl)piperazine-1-carboxylate with 6-methylpyridin-3-amine to form omecamtiv mecarbil as a free base, and   c) crystallizing the omecamtiv mecarbil free base in the presence of aqueous hydrochloric acid and an alcohol solvent to form omecamtiv mecarbil dihydrochloride monohydrate salt.   
     
     
         2 . The method of  claim 1 , wherein step a) comprises admixing in the presence of 1-methyl-2-pyrrolidinone. 
     
     
         3 . The method  claim 1 , wherein step b) comprises admixing in the presence of diisopropylethylamine. 
     
     
         4 . The method of  claim 1 , wherein the alcohol solvent comprises isopropyl alcohol. 
     
     
         5 . The method of  claim 1 , further comprising preparing methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate by hydrogenating methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-caboxylate in the presence of palladium on carbon. 
     
     
         6 . The method of  claim 1 , further comprising formulating omecamtiv mecarbil dihydrochloride monohydrate salt to form a pharmaceutical composition. 
     
     
         7 . A pharmaceutical composition comprising omecamtiv mecarbil dihydrochloride hydrate salt and a pharmaceutically acceptable excipient. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the omecamtiv mecarbil dihydrochloride hydrate salt is characterized by an X-ray powder diffraction pattern comprising peaks at about 6.6, 14.9, 20.1, 21.4, and 26.8±0.2° 2θ using CuKα radiation. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the X-ray powder diffraction pattern further comprises peaks at 8.4, 24.2, 26.0, and 33.3±0.2° 2θ using CuKα radiation. 
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein the X-ray powder diffraction patter further comprises peaks at about 6.2, 9.7, 13.2, 14.3, 15.4, 16.3, 16.9, 18.9, 19.5, 20.7, 21.8, 22.8, 23.6, 25.1, 27.3, 27.7, 28.4, 29.4, 30.2, 31.2, 31.5, 31.9, 33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5, and 39.7±0.2° θ using Cu Kα radiation. 
     
     
         11 . The pharmaceutical composition of  claim 8 , having an X-ray powder diffraction pattern substantially as shown in  FIG.  2   . 
     
     
         12 . The pharmaceutical composition of  claim 8 , having an endothermic transition at about 230° C. to about 240° C., as measured by differential scanning calorimetry. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the endothermic transition is at about 235° C.