Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-9499487-B2
Application number	US-201213475076-A
Country	US
Kind code	B2
Filing date	May 18, 2012
Priority date	May 31, 2011
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

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

where R 1 , R 2 , R 3 , X, R 4 , R 5 , and R 6 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 process and intermediates for preparing such compounds.

First claim

The invention claimed is:

1. A compound of formula I:

where:
R 2 is OH; R 3 is —CF 3 ; R 1 is —OR 10 ; R 10 is H or —C 1-6 alkyl; X is pyridyltriazole; R 4 is H; R 5 is H; and R 6 is H.

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

3. The pharmaceutical composition of claim 2 , 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.

4. The pharmaceutical composition of claim 3 , wherein the therapeutic agent is an AT 1 receptor antagonist.

5. A process for preparing the compound of claim 1 , comprising the step of:
(a) coupling compound 1 with compound 2:

to produce a compound of formula I or a pharmaceutically acceptable salt thereof.

6. An intermediate useful in the synthesis of the compound of claim 1 , having formula II:

where P is selected from —O—P 1 ; P 1 is a carboxy-protecting group selected from methyl, ethyl, t-butyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t-butyldimethylsilyl, and diphenylmethyl; or a salt thereof.

7. 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 .

8. (2R,3R)-4-(2-chloro-phenyl)-2-hydroxy-3-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-butyric acid.

9. (2S,3R)-3-[(7-chloro-3H-benzotriazole-5-carbonyl)-amino]-4-(2-chloro-phenyl)-2-hydroxy-butyric acid.

10. (R)-4-(2-chloro-phenyl)-3-[(2-hydroxy-pyrimidine-5-carbonyl)-amino]-butyric acid.

Assignees

• Fleury Melissa
• Gendron Roland
• Hughes Adam D
• Schmidt Jane
• Theravance Biopharma R&D Ip Llc

Inventors

• Fleury Melissa
• Gendron Roland
• Hughes Adam D
• Schmidt Jane

Classifications

• A61P43/00

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

• A61P9/04

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

• A61P9/12

  Antihypertensives · CPC title

• C07D249/12

  Oxygen or sulfur atoms · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title