Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-12016835-B2
Application number	US-202217990329-A
Country	US
Kind code	B2
Filing date	Nov 18, 2022
Priority date	Nov 2, 2011
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

Abstract

In one aspect, the invention relates to compounds having the formula:where R1-R6, 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 method of treating a disease mediated at least in part by neprilysin in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of compound of formula (Ma):

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 method of claim 1 , wherein the disease is a cardiovascular disease, diarrhea, renal disease, glaucoma, or pain.

3. The method of claim 2 , wherein the cardiovascular disease is hypertension or heart failure.

4. The method of claim 1 , wherein the disease is a renal disease.

5. The method of claim 1 , further comprising administering a therapeutic agent selected from an adenosine receptor antagonist, an α-adrenergic receptor antagonist, a β 1 -adrenergic receptor antagonist, a β 2 -adrenergic receptor agonist, a dual-acting β-adrenergic receptor antagonist/al-receptor antagonist, an advanced glycation end product breaker, an aldosterone antagonist, an aldosterone synthase inhibitor, an aminopeptidase N inhibitor, an androgen, an angiotensin-converting enzyme inhibitor, a dual-acting angiotensin-converting enzyme/neprilysin inhibitor, an angiotensin-converting enzyme 2 activator, an angiotensin-converting enzyme 2 stimulator, an angiotensin-II vaccine, an anticoagulant, an anti-diabetic agent, an antidiarrheal agent, an anti-glaucoma agent, an anti-lipid agent, an antinociceptive agent, an anti-thrombotic agents, an AT 1 receptor antagonist, a dual-acting AT 1 receptor antagonist/neprilysin inhibitor, a multifunctional angiotensin receptor blocker, a bradykinin receptor antagonist, a calcium channel blocker, a chymase inhibitor, digoxin, a diuretic, a dopamine agonist, an endothelin converting enzyme inhibitor, an endothelin receptor antagonist, HMG-CoA reductase inhibitor, an estrogen, an estrogen receptor agonist, an estrogen receptor antagonist, a monoamine reuptake inhibitor, a muscle relaxant, a natriuretic peptide, a natriuretic peptide analog, a natriuretic peptide clearance receptor antagonist, a neprilysin inhibitor, a nitric oxide donor, a non-steroidal anti-inflammatory agent, an N-methyl d-aspartate receptor antagonist, an opioid receptor agonist, a phosphodiesterase inhibitor, a prostaglandin analog, a prostaglandin receptor agonist, a renin inhibitor, a selective serotonin reuptake inhibitor, a sodium channel blocker, a soluble guanylate cyclase stimulator, a soluble guanylate cyclase activator, a tricyclic antidepressant, and a vasopressin receptor antagonist, or a combination thereof.

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

7. The method of claim 6 , wherein the AT 1 receptor antagonist is selected from abitesartan, azilsartan, azilsartan medoxomil, benzyllosartan, candesartan, candesartan cilexetil, elisartan, embusartan, enoltasosartan, eprosartan, EXP3174, fonsartan, forasartan, glycyllosartan, irbesartan, isoteoline, losartan, medoximil, milfasartan, olmesartan, olmesartan medoxomil, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, TAK-591, tasosartan, telmisartan, valsartan, and zolasartan.

8. The method of claim 1 , wherein R 1 is H.

9. The method of claim 1 , wherein R 2 is —CH 2 OH and R 3 is —CH 3 .

10. The method of claim 1 , wherein R 4 is selected from H, —CH 2 CH 3 , and —CH 2 CH(CH 3 ) 2 .

11. The method of claim 1 , wherein a is 0; b is 1 or 2; and each R 6 is independently selected from halo.

12. The method of claim 1 , wherein the compound is a compound of formula:

13. The method of claim 12 , wherein R 1 is H.

14. The method of claim 12 , wherein R 2 is —CH 2 OH and R 3 is —CH 3 .

15. The method of claim 12 , wherein R 4 is selected from H, —CH 2 CH 3 , and —CH 2 CH(CH 3 ) 2 .

16. The method of claim 12 , wherein a is 0; b is 1 or 2; and each R 6 is independently selected from halo.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

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

Classifications

• C07C243/28

  to hydrogen atoms or to carbon atoms of a saturated carbon skeleton · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/365

  Lactones · CPC title

• A61K31/27

  of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine · CPC title

• A61K31/24

  having an amino or nitro group · CPC title