Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-9688616-B2
Application number	US-201615219478-A
Country	US
Kind code	B2
Filing date	Jul 26, 2016
Priority date	Mar 5, 2013
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

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

where R 1 -R 5 and X 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:

where:
R 14 is —O-benzyl; pyridine optionally substituted with halo, —OH, C 1-6 alkyl, or —O—C 1-6 alkyl; furan; or phenyl substituted with halo, —OH, —O—C 1-6 alkyl, or —NO 2 ;
or a pharmaceutically acceptable salt thereof.

2. A compound selected from:
(a) (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-{2-[N′-(2-hydroxybenzoyl)hydrazino]-2-oxo-acetylamino}pentanoic acid;
(b) (2R,4R)-4-[2-(N′-benzyloxycarbonyl-hydrazino)-2-oxo-acetylamino]-5-(3′-chloro-biphenyl-4-yl)-2-hydroxypentanoic acid;
(c) (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-4-{2-[N′-(6-chloro-pyridine-3-carbonyl)-hydrazino]-2-oxo-acetylamino}-2-hydroxypentanoic acid;
(d) (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-{2-oxo-2-[N′-(pyridine-3-carbonyl)-hydrazino]acetylamino}pentanoic acid;
(e) (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-{2-oxo-2-[N′-(pyridine-4-carbonyl)-hydrazino]acetylamino}pentanoic acid;
(f) (2R,4R)-5-(3 ‘-chlorobiphenyl-4-yl)-4-{2-[N’-(furan-2-carbonyl)-hydrazino]-2-oxo-acetylamino}-2-hydroxypentanoic acid;
(g) (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-{2-[N′-(2-nitro-benzoyl)-hydrazino]-2-oxo-acetylamino}pentanoic acid; or
a pharmaceutically acceptable salt thereof.

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

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

5. 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 2 .

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Fenster Erik
• Fleury Melissa
• Hughes Adam D

Classifications

• A61P9/04

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

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61K31/4406

  only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455) · CPC title