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.

1 .- 9 . (canceled) 
     
     
         10 . A method of preparing omecamtiv mecarbil dihydrochloride hydrate comprising:
 (a) hydrogenating methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate in the presence of a hydrogenation catalyst to form methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate;   (b) admixing methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate and phenyl (6-methylpyridin-3-yl)carbamate in the presence of a trialkylamine base 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 hydrate salt.   
     
     
         11 . The method of  claim 10 , further comprising formulating omecamtiv mecarbil dihydrochloride hydrate salt. 
     
     
         12 . The method of  claim 10 , wherein the hydrogenation catalyst comprises palladium. 
     
     
         13 . The method of  claim 12 , wherein the hydrogenation catalyst is palladium on carbon. 
     
     
         14 . The method of  claim 10 , wherein the trialkylamine base is triethylamine, diisopropylethylamine, or a combination thereof. 
     
     
         15 . The method of  claim 10 , wherein the trialkylamine base comprises diisopropylethylamine. 
     
     
         16 . The method of  claim 10 , wherein the alcohol solvent comprises isopropyl alcohol. 
     
     
         17 . The method of  claim 10 , wherein the omecamtiv mecarbil dihydrochloride hydrate salt has an x-ray powder diffraction pattern (XRPD) comprising peaks at about 6.6, 14.9, 20.1, 21.4, and 26.8±0.2° 2θ using Cu Kα radiation. 
     
     
         18 . The method of  claim 17 , wherein the XRPD pattern further comprises peaks at about 8.4, 24.2, 26.0, and 33.3±0.2° 2θ using Cu Kα radiation. 
     
     
         19 . The method of  claim 17 , wherein the XRPD pattern 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° 2θ using Cu Kα radiation. 
     
     
         20 . A method of preparing omecamtiv mecarbil comprising
 admixing methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-caboxylate and phenyl (6-methylpyridin-3-yl)carbamate in the presence of a trialkylamine base to form omecamtiv mecarbil.   
     
     
         21 . The method of  claim 20 , wherein the trialkylamine base comprises diisopropylethylamine. 
     
     
         22 . The method of  claim 20 , further comprising crystallizing the omecamtiv mecarbil in the presence of aqueous hydrochloric acid and an alcohol solvent to form an omecamtiv mecarbil dihydrochloride hydrate salt. 
     
     
         23 . The method of  claim 22 , wherein the alcohol solvent comprises isopropyl alcohol. 
     
     
         24 . The method of  claim 22 , wherein the omecamtiv mecarbil dihydrochloride hydrate salt has an x-ray powder diffraction pattern (XRPD) comprising peaks at about 6.6, 14.9, 20.1, 21.4, and 26.8±0.2o 2θ using Cu Kα radiation. 
     
     
         25 . The method of  claim 24 , wherein the XRPD pattern further comprises peaks at about 8.4, 24.2, 26.0, and 33.3±0.2o 2θ using Cu Kα radiation. 
     
     
         26 . The method of  claim 24 , wherein the XRPD pattern 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±0.2o 2θ using Cu Kα radiation. 
     
     
         27 . A method of treating heart failure in a subject comprising administering to the subject a pharmaceutical formulation comprising omecamtiv mecarbil dihydrochloride hydrate salt and at least one pharmaceutically acceptable excipient. 
     
     
         28 . The method of  claim 27 , wherein the omecamtiv mecarbil dihydrochloride hydrate salt has an x-ray powder diffraction pattern (XRPD) comprising peaks at about 6.6, 14.9, 20.1, 21.4, and 26.8±0.2o 2θ using Cu Kα radiation. 
     
     
         29 . The method of  claim 28 , wherein the XRPD pattern further comprises peaks at about 8.4, 24.2, 26.0, and 33.3±0.2o 2θ using Cu Kα radiation. 
     
     
         30 . The method of  claim 28 , wherein the XRPD pattern 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±0.2o 2θ using Cu Kα radiation.