Salt of omecamtiv mecarbil and process for preparing salt

Patent metadata

Field	Value
Publication number	US-2016016906-A1
Application number	US-201414773436-A
Country	US
Kind code	A1
Filing date	Mar 14, 2014
Priority date	Mar 14, 2013
Publication date	Jan 21, 2016
Grant date	—

Abstract

Provided are omecamtiv mecarbil dihydrochloride salt forms, compositions and pharmaceutical formulations thereof, and methods for their preparation and use. Omecamtiv mecarbil (AMG 423, CK-1827452), having the structure:

First claim

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.

Assignees

• Amgen Inc
• Cytokinetics Inc

Inventors

• Cui Sheng
• Morrison Henry
• Nagapudi Karthik
• Walker Shawn
• Bernard Charles
• Hansen Karl Bennett
• Langille Neil Fred
• Allgeier Alan Martin
• Mennen Steven
• Woo Jacqueline
• Morgan Bradley Paul
• Muci Alex

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61K9/2013

  Organic compounds, e.g. phospholipids, fats · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• C07D213/75 Primary

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title