Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-11547687-B2
Application number	US-202016923396-A
Country	US
Kind code	B2
Filing date	Jul 8, 2020
Priority date	Nov 2, 2011
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

In one aspect, the invention relates to compounds having the formula:

where R 1 -R 6 , a, b, and Z are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.

First claim

What is claimed is:

1. A compound of formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from H and —C 1-8 alkyl;
R 2 is —OH or —CH 2 OH;
R 3 is H or —CH 3 ;
R 4 is selected from H and —C 1-6 alkyl;
a is 0 or 1;
R 5 is selected from halo, —CH 3 , —CF 3 , and —CN;
b is 0 or an integer from 1 to 3; and
each R 6 is independently selected from halo, —OH, —CH 3 , —OCH 3 , —CN, and —CF 3 ;
wherein each alkyl group in R 1 and R 4 is optionally substituted with 1 to 8 fluoro atoms.

2. The compound or salt of claim 1 , wherein R 1 is H.

3. The compound or salt of claim 2 , wherein R 2 is —CH 2 OH and R 3 is —CH 3 .

4. The compound or salt of claim 3 , wherein R 4 is selected from H, —CH 2 CH 3 , and —CH 2 CH(CH 3 ) 2 .

5. The compound or salt of claim 4 , wherein a is 0; b is 1 or 2; and each R 6 is independently selected from halo.

6. The compound or salt of claim 1 , wherein the compound is a compound of formula (Ia-1):

7. The compound or salt of claim 6 , wherein R 1 is H.

8. The compound or salt of claim 7 , wherein R 2 is —CH 2 OH and R 3 is —CH 3 .

9. The compound or salt of claim 8 , wherein R 4 is selected from H, —CH 2 CH 3 , and —CH 2 CH(CH 3 ) 2 .

10. The compound or salt of claim 9 , wherein a is 0; b is 1 or 2; and each R 6 is independently selected from halo.

11. The compound or salt of claim 1 , wherein the compound is a compound of the formula:

12. The compound or salt of claim 11 , wherein b is 1 or 2 and each R 6 is independently selected from halo.

13. A compound of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

14. A pharmaceutical composition comprising the compound or salt of claim 10 and a pharmaceutically acceptable carrier.

15. A method of treating a disease mediated at least in part by neprilysin in a subject in need thereof, comprising administering to the subject an effective amount of the compound or salt of claim 10 .

16. The method of claim 15 , wherein the disease is selected from hypertension, heart failure, and renal disease.

17. The method of claim 15 , further comprising administering an AT 1 receptor antagonist.

18. A method of treating a disease mediated at least in part by neprilysin in a subject in need thereof, comprising administering to the subject an effective amount of the compound, salt, or prodrug of claim 13 .

19. The method of claim 18 , wherein the disease is selected from hypertension, heart failure, and renal disease.

20. A method of treating hypertension, heart failure, or renal disease in a subject in need thereof, comprising administering to the subject an AT 1 receptor antagonist and an effective amount of the compound or salt of claim 10 .

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Hughes Adam D
• Fenster Erik
• Fleury Melissa
• Gendron Roland
• Moran Edmund J

Classifications

• A61K31/16

  Amides, e.g. hydroxamic acids · CPC title

• C07C243/26

  with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07D319/06

  not condensed with other rings · CPC title

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07D207/263

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms · CPC title