Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-9682052-B2
Application number	US-201514838842-A
Country	US
Kind code	B2
Filing date	Aug 28, 2015
Priority date	Nov 2, 2011
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

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 I:

where:
R 1 is selected from H, —C 1-8 alkyl,—C 1-6 alkylene-OC(O)R 10 , and

where R 10 is —C 1-6 alkyl, —O—C 1-6 alkyl, or —CH(R 15 )—NHC(O)O—C 1-6 alkyl, R 14 is —C 1-6 alkyl; R 15 is —CH(CH 3 ) 2 ;
R 2 is —OR 21 or —CH 2 OR 21 ; and R 3 is H or —CH 3 ; where R 21 is H, —C(O)—C 1-6 alkyl, —C(O)—CH(R 22 )—NH 2 , —C(O)—CH(R 22 )—NHC(O)O—C 1-6 alkyl, or —P(O)(OR 23 ) 2 ; R 22 is H, —CH 3 , —CH(CH 3 ) 2 , phenyl, or benzyl; R 23 is H, —C 1-6 alkyl, or phenyl;
Z is selected from —CH— and —N—;
R 4 is selected from H, —C 1-8 alkyl, —C 1-3 alkylene-O—C 1-8 alkyl, —C 1-3 alkylene-O—C 6-10 aryl, -[(CH 2 ) 2 O] 1-3 CH 3 , and

where R 44 is —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; each R 6 is independently selected from halo, —OH, —CH 3 , —OCH 3 , —CN, and —CF 3 ;
where each alkyl group in R 1 and R 4 is optionally substituted with 1 to 8 fluoro atoms; and
where the methylene linker on the biphenyl is optionally substituted with one or two —C 1-6 alkyl groups or cyclopropyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , where R 1 is H.

3. The compound of claim 1 , where R 1 is selected from H, —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , —(CH 2 ) 6 CH 3 , —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)CH 2 CH 3 , —CH 2 OC(O)(CH 2 ) 2 CH 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)—CH[CH(CH 3 ) 2 ]—NHC(O)O—CH 3 , and

where R 14 is —CH 3 .

4. The compound of claim 1 , where R 2 is —OR 21 , R 3 is H, and R 21 is H.

5. The compound of claim 1 , where R 2 is —OR 21 , R 3 is —CH 3 , and R 21 is H.

6. The compound of claim 1 , where R 2 is —CH 2 OR 21 , R 3 is H, and R 21 is H.

7. The compound of claim 1 , where R 2 is —CH 2 OR 21 , R 3 is —CH 3 , and R 21 is H.

8. The compound of claim 1 , where R 4 is H.

9. The compound of claim 1 , where R 4 is selected from H, —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , —C(CH 3 ) 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —(CH 2 ) 3 —O—CH 2 CH 3 , —(CH 2 ) 2 —O-phenyl, —(CH 2 ) 2 OCH 3 , and

where R 44 is —CH 3 .

10. The compound of claim 1 , where a is 0, or a is 1 and R 5 is halo.

11. The compound of claim 1 , where b is 0, or b is 1 and R 6 is halo, or b is 2 and each R 6 is independently selected from halo and —CH 3 .

12. The compound of claim 1 , where:
a is 0 and b is 0; or
a is 0, b is 1, and R 6 is 2′-fluoro, 3′-fluoro, 3′-chloro, or 4′-flouro; or
a is 0, b is 2, and R 6 is 2′-fluoro, 5′-chloro or 2′-methyl, 5′-chloro or 2′,5′-dichloro; or
a is 1, R 5 is 3-chloro, and b is 0; or
a is 1, R 5 is 3-chloro, b is 1, and R 6 is 3′-chloro; or
a is 1, R 5 is 3-chloro, b is 2, and R 6 is 2′-fluoro, 5′-chloro.

13. The compound of claim 1 , where R 1 is selected from H, —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , —(CH 2 ) 6 CH 3 , —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —CH 2 OC(O)CH 3 , —CH 2 OC(O)CH 2 CH 3 , —CH 2 OC(O)(CH 2 ) 2 CH 3 , —CH 2 OC(O)OCH 2 CH 3 , —CH 2 OC(O)—CH[CH(CH 3 ) 2 ]—NHC(O)O—CH 3 , and

where R 14 is —CH 3 ;
R 4 is selected from

H, —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , —C(CH 3 ) 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —(CH 2 ) 3 —O—CH 2 CH 3 , —(CH 2 ) 2 —O-phenyl, —(CH 2 ) 2 OCH 3 , and

where R 44 is —CH 3 ; and
a is 0 and b is 0; or a is 0, b is 1, and R 6 is 2′-fluoro, 3′-fluoro, 3′-chloro, or 4′-flouro; or a is 0, b is 2, and R 6 is 2′-fluoro, 5′-chloro or 2′-methyl, 5′-chloro or 2′,5′-dichloro; or a is 1, R 5 is 3-chloro, and b is 0; or a is 1, R 5 is 3-chloro, b is 1, and R 6 is 3′-chloro; or a is 1, R 5 is 3-chloro, b is 2, and R 6 is 2′-fluoro, 5′-chloro.

14. The compound of claim 5 , where R 1 is H or —C 1-8 alkyl; Z is —N—; R 4 is H or —C 1-8 alkyl; and a and b are 0.

15. The compound of claim 14 , where R 1 and R 4 are H.

16. The compound of claim 6 , where R 1 is H or —C 1-8 alkyl; Z is —CH—; R 4 is H or —C 1-8 alkyl; a is 0 or a is 1 and R 5 is halo; b is 0 or b is 1 or 2 and R 6 is halo; and where the methylene linker on the biphenyl is optionally substituted with two —CH 3 groups.

17. The compound of claim 16 , where R 1 is H, —CH 2 CH 3 , or —(CH 2 ) 3 CH 3 ; R 4 is H; a is 0 or a is 1 and R 5 is 3-chloro; b is 0 or b is 1 and R 6 is 2′-fluoro, 3′-fluoro, 3′-chloro, or 4′-flouro.

18. The compound of claim 7 , where R 1 is H or —C 1-8 alkyl; Z is —CH—; R 4 is H or —C 1-8 alkyl; a is 0; and b is 0, or b is 1 and R 6 is halo.

19. The compound of claim 18 , where R 1 is H or —CH 2 CH 3 ; R 4 is H or —CH 2 CH(CH 3 ) 2 ; and b is 0, or b is 1 and R 6 is 2′-fluoro, 3′-fluoro, 3′-chloro, or 4′-flouro.

20. The compound of claim 1 , where R 2 is —OR 21 or —CH 2 OR 21 ; and R 3 is H or —CH 3 ; where R 21 is H.

21. The compound of claim 1 , where the compound has the formula:

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21 , where R 1 is H.

23. The compound of claim 21 , where R 4 is C 1-8 alkyl.

24. The compound of claim 21 , where R 4 is CH 2 CH 3 .

25. The compound of claim 21 , where R 21 is H.

26. The compound of claim 21 , where Z is —CH—.

27. The compound of claim 21 , where a is 0.

28. The compound of claim 21 , where b is 2.

29. The compound of claim 21 , where a is 0; b is 2; and R 6 is 2′-fluoro, 5′-chloro.

30. A pharmaceutical composition comprising the compound of claim 1 or claim 21 and a pharmaceutically acceptable carrier.

31. The pharmaceutical composition of claim 30 , further comprising a therapeutic agent selected from adenosine receptor antagonists, α-adrenergic receptor antagonists, β 1 -adrenergic receptor antagonists, β 2 -adrenergic receptor agonists, dual-acting β-adrenergic receptor antagonist/α 1 -receptor antagonists, advanced glycation end product breakers, aldosterone antagonists, aldosterone synthase inhibitors, aminopeptidase N inhibitors, androgens, angiotensin-converting enzyme inhibitors and dual-acting angiotensin-converting enzyme/neprilysin inhibitors, angiotensin-converting enzyme 2 activators and stimulators, angiotensin-II vaccines, anticoagulants, anti-diabetic agents, antidiarrheal agents, anti-glaucoma agents, anti-lipid agents, antinociceptive agents, anti-thrombotic agents, AT 1 recept

Assignees

• Hughes Adam D
• Fenster Erik
• Fleury Melissa
• Gendron Roland
• Moran Edmund J
• Theravance Biopharma R&D Ip Llc

Inventors

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

Classifications

• 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

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title