Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-10123984-B2
Application number	US-201715593833-A
Country	US
Kind code	B2
Filing date	May 12, 2017
Priority date	Nov 2, 2011
Publication date	Nov 13, 2018
Grant date	Nov 13, 2018

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:
(a) (2R,4R)-5-(5′-chloro-2′-methylbiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)-pentanoic acid;
(b) (2R,4R)-5-(5′-chloro-2′-methylbiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)-pentanoic acid isopropyl ester;
(c) (2R,4R)-5-(5′-chloro-2′-methylbiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid ethyl ester;
(d) (2R,4R)-5-(5′-chloro-2′-methylbiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid isobutyl ester;
(e) (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid;
(f) (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid ethyl ester;
(g) (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid isobutyl ester;
(h) (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid isopropyl ester;
(i) (2R,4R)-5-(3,3′-dichlorobiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid;
(j) (2R,4R)-5-(3,3′-dichlorobiphenyl-4-yl)-2-hydroxy-4-(isobutoxyoxalylamino)-pentanoic acid;
(k) (2R,4R)-5-(3,3′-dichlorobiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid isobutyl ester;
(l) (2R,4R)-5-(3,3′-dichlorobiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid isopropyl ester;
(m) (R)-3-[N-(3,5′-dichloro-2′-fluorobiphenyl-4-ylmethyl)-N′-oxalyl-hydrazino]-2-hydroxypropionic acid; or
a pharmaceutically-acceptable salt thereof.

2. A compound of:
(a) (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-(ethoxyoxalylamino)-2-hydroxy-pentanoic acid;
(b) (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-(isopropoxyoxalyl-amino)-pentanoic acid;
(c) (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-(isobutoxyoxalylamino)-pentanoic acid;
(d) (2R,4R)-5-(3,3′-dichlorobiphenyl-4-yl)-2-hydroxy-4-(oxalylamino)pentanoic acid ethyl ester; or
a pharmaceutically-acceptable salt thereof.

3. A pharmaceutical composition comprising the compound of claim 1 or claim 2 and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition of claim 3 , 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 receptor antagonists and dual-acting AT 1 receptor antagonist/neprilysin inhibitors and multifunctional angiotensin receptor blockers, bradykinin receptor antagonists, calcium channel blockers, chymase inhibitors, digoxin, diuretics, dopamine agonists, endothelin converting enzyme inhibitors, endothelin receptor antagonists, HMG-CoA reductase inhibitors, estrogens, estrogen receptor agonists and/or antagonists, monoamine reuptake inhibitors, muscle relaxants, natriuretic peptides and their analogs, natriuretic peptide clearance receptor antagonists, neprilysin inhibitors, nitric oxide donors, non-steroidal anti-inflammatory agents, N-methyl d-aspartate receptor antagonists, opioid receptor agonists, phosphodiesterase inhibitors, prostaglandin analogs, prostaglandin receptor agonists, renin inhibitors, selective serotonin reuptake inhibitors, sodium channel blocker, soluble guanylate cyclase stimulators and activators, tricyclic antidepressants, vasopressin receptor antagonists, and combinations thereof.

5. The pharmaceutical composition of claim 3 further comprising an AT 1 receptor antagonist.

6. The pharmaceutical composition of claim 5 , wherein the composition further comprises an AT 1 receptor antagonist 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; or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 3 , further comprising a phosphodiesterase (PDE) inhibitor.

8. The pharmaceutical composition of claim 3 , further comprising a renin inhibitor.

9. The pharmaceutical composition of claim 3 , further comprising a diuretic.

10. A method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of the compound of claim 1 or claim 2 .

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

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

Classifications

• A61P9/12

  Antihypertensives · 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

• A61P43/00

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

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title