Compounds, compositions and methods

Patent metadata

Field	Value
Publication number	US-10035770-B2
Application number	US-201715480618-A
Country	US
Kind code	B2
Filing date	Apr 6, 2017
Priority date	Jun 17, 2004
Publication date	Jul 31, 2018
Grant date	Jul 31, 2018

Abstract

Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.

First claim

What is claimed is:

1. A compound of Formula 3B:

or a pharmaceutically acceptable salt thereof.

2. A compound of Formula 3C:

or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of O and NH.

3. A compound of Formula 3D:

or a pharmaceutically acceptable salt thereof.

4. A method of preparing a compound of Formula 3D:

or a pharmaceutically acceptable salt thereof, comprising
contacting a compound of Formula 3C:

wherein R is selected from the group consisting of O and NH, with methyl piperazine-1-carboxylate and a reducing agent to yield the compound of Formula 3D.

5. The method of claim 4 , wherein the compound of Formula 3C is prepared by reducing a compound of Formula 3B:

in the presence of a reducing agent to yield the compound of Formula 3C.

6. The method of claim 5 , wherein the compound of Formula 3B is prepared by contacting a compound of Formula 3A:

with sodium cyanide and nickel (II) bromide in an organic solvent to yield the compound of Formula 3B.

7. The method of claim 6 , wherein the sodium cyanide is present in an amount of at least 2 equivalents relative to the amount of the compound of Formula 3A.

8. The method of claim 6 , wherein the nickel (II) bromide is present in an amount of at least 1 equivalent relative to the amount of the compound of Formula 3A.

9. The method of claim 6 , wherein the organic solvent is 1-methyl-2-pyrrolidinone (NMP).

10. The method of claim 6 , wherein the reaction mixture is heated to between 195° C. and 205° C.

11. The method of claim 5 , wherein the reducing agent is present in an amount of at least 2 equivalents relative to the amount of the compound of Formula 3B.

12. The method of claim 5 , wherein the internal reaction temperature is maintained at ≤0° C. during the addition of the reducing agent.

13. The method of claim 5 , wherein the reducing agent used to form the compound of Formula 3C comprises diisobutyllithiumaluminum hydride (DIBAlH).

14. The method of claim 5 , wherein the DIBAlH is present in an amount of at least 2 equivalents relative to the amount of the compound of Formula 3B.

15. The method of claim 5 , wherein the compound of Formula 3C comprises a mixture of compounds 3C-A and 3C-B:

16. The method of claim 4 , wherein the methyl piperazine-1-carboxylate is present in an amount of at least 1 equivalent relative to the amount of the compound of Formula 3C.

17. The method of claim 4 , wherein the reducing agent used to form the compound of Formula 3D comprises sodium triacetoxyborohydride.

18. The method of claim 4 , wherein the internal reaction temperature is maintained below about 45° C. during the addition of the reducing agent.

19. The method of claim 4 , wherein the sodium triacetoxyborohydride is present in an amount of at least 1.5 equivalents relative to the amount of the compound of Formula 3C.

Assignees

• Cytokinetics Inc

Inventors

• Morgan Bradley Paul
• Muci Alex
• Lu Pu-Ping
• Kraynack Erica Anne
• Tochimoto Todd
• Morgans Jr David J

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/04

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title