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 dihydrochloride salt of omecamtiv mecarbil. 
     
     
         2 . The form of  claim 1 , wherein the dihydrochloride salt is a monohydrate. 
     
     
         3 . The salt of  claim 1  or  2 , wherein the salt is crystalline. 
     
     
         4 . The salt of any one of  claims 1  to  3 , wherein the 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 Cu Kα radiation. 
     
     
         5 . The salt of  claim 4 , further comprising peaks at about 8.4, 24.2, 26.0, and 33.3±0.2° 2θ using Cu Kα radiation. 
     
     
         6 . The salt of  claim 4  or  5 , further comprising 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. 
     
     
         7 . The salt of any one of  claims 1  to  6 , having an X-ray powder diffraction pattern substantially as shown in  FIG. 8 . 
     
     
         8 . The salt of any one of  claims 1  to  7 , having a endothermic transition at about 230° C. to about 240° C., as measured by differential scanning calorimetry. 
     
     
         9 . The salt of  claim 8 , wherein the transition is at about 235° C. 
     
     
         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 any one of  claims 10  to  13 , wherein the trialkylamine base is triethylamine, diisopropylethylamine, or a combination thereof. 
     
     
         15 . The method of any one of  claims 10  to  14 , wherein the trialkylamine base comprises diisopropylethylamine. 
     
     
         16 . The method of any one of  claims 10  to  15 , wherein the alcohol solvent comprises isopropyl alcohol. 
     
     
         17 . The method of any one of  claims 10  to  16 , 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  or  18 , 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  or  21 , 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  or  23 , 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. 
     
     
         25 . The method of  claim 24 , wherein the XRPD pattern further comprises peaks at about 8.4, 24.2, 26.0, and 33.3±0.2° 2θ using Cu Kα radiation. 
     
     
         26 . The method of  claim 24  or  25 , 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.