Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-9422245-B2
Application number	US-201514624729-A
Country	US
Kind code	B2
Filing date	Feb 18, 2015
Priority date	May 31, 2011
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

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

where R 1 , R 2 , R 3 , R 4 , and R 5 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

What is claimed is:

1. A compound of formula II:

where:
R 1 is —OR 10 ;
R 2 is H or —OR 20 ;
R 3 is selected from H, Cl, F, —CH 3 , and —CF 3 ;
R 4 is selected from H; —C 1-6 alkyl; —C 2-3 alkylene-OH; —[(CH 2 ) 2 O] 1-3 CH 3 ; —C 1-3 alkylene-C(O)OR 40 ; —CH 2 —C(O)NR 41 R 42 ; —C 0-2 alkylene-pyridine optionally substituted with halo; —CH 2 — isoxazole optionally substituted with methyl; —CH 2 -pyrimidine optionally substituted with —O—C 1-6 alkyl; —C 2 alkylene-phenyl;

R 5 is selected from H; halo; —C 0-5 alkylene-OH; —NH 2 ; —C 1-6 alkyl; —CF 3 ; —C 3-7 cycloalkyl; —C 0-2 alkylene-O—C 1-6 alkyl; —C(O)R 50 ; —C 0-1 alkylene-C(O)OR 51 ; —C(O)NR 52 R 53 ; —NHC(O)R 54 ; —NO 2 ; furan; pyrazine; naphthalene; pyridine; pyrazole optionally substituted with methyl; thiophene optionally substituted with methyl; and phenyl optionally substituted with one or two groups independently selected from halo, —OH, —CF 3 , —OCH 3 , —NHC(O)CH 3 , and phenyl;
R 10 , R 40 , and R 51 are independently selected from H, —C 1-6 alkyl, —C 1-3 alkylene-C 6-10 aryl, —C 1-3 alkylene-C 1-9 heteroaryl, —C 3-7 cycloalkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —C 1-6 alkylene-OC(O)R 13 , —C 1-6 alkylene-NR 14 R 15 , —C 1-6 alkylene-C(O)R 17 , —C 0-6 alkylenemorpholine, —C 1-6 alkylene-SO 2 —C 1-6 alkyl,

R 13 is selected from —C 1-6 alkyl, —O—C 1-6 alkyl, —C 3-7 cycloalkyl, —O—C 3-7 cycloalkyl, phenyl, —O— phenyl, —NR 14 R 15 , and —CH(NH 2 )CH 2 COOCH 3 ; R— 14 and R 15 are independently selected from H, —C 1-6 alkyl, and benzyl, or R 14 and R 15 are taken together as —(CH 2 ) 3-6 —, —C(O)—(CH 2 ) 3 —, or —(CH 2 ) 2 O(CH 2 ) 2 —; R 16 is —C 1-6 alkyl or —O 0-6 alkylene-C 6-10 aryl; R 17 is selected from —O—C 1-6 alkyl, —O-benzyl, and —NR 14 R 15 ;
R 20 is H or is taken together with R 10 to form —CR 21 R 22 —; R 21 and R 22 are independently selected from H, —C 1-6 alkyl, and —O—C 3-7 cycloalkyl, or R 21 and R 22 are taken together to form ═O;
R 41 , R 42 , R 52 , and R 53 are independently selected from H, —C 1-6 alkyl, —CH 2 COOH, —(CH 2 ) 2 OH, —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 SO 2 NH 2 , —(CH 2 ) 2 N(CH 3 ) 2 , —C 3-7 cycloalkyl, and —(CH 2 ) 2 -imidazole; or R 41 and R 42 or R 52 and R 53 are taken together to form a saturated or partially unsaturated —C 3-5 heterocycle optionally substituted with —OH, —COOR 40 , or —CONH 2 , and optionally containing an oxygen atom in the ring;
R 43 , R 44 , R 45 , R 46 , and R 47 are independently selected from H, halo, —C 1-6 alkyl, —O—C 1-6 alkyl, and —S—C 1-6 alkyl, where each —C 1-6 alkyl is optionally substituted with 1-5 fluoro atoms;
R 50 is H or —C 1-6 alkyl; and
R 54 is selected from —C 1-6 alkyl; —C 0-1 alkylene-O—C 1-6 alkyl; phenyl optionally substituted with halo or —OCH 3 ; and —C 1-9 heteroaryl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , where R 10 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —C 1-6 alkylene-SO 2 —C 1-6 alkyl, and

R 16 is —C 1-6 alkyl; R 2 is H or —OR 20 ; R 20 is H; R 3 is selected from H, Cl, —CH 3 , and —CF 3 ; R 4 is selected from H, —C 1-6 alkyl, —C 2-3 alkylene-OH, —[(CH 2 ) 2 O] 1-3 CH 3 , —C 1-3 alkylene-C(O)OR 40 , —C 0-2 alkylene-pyridine, —CH 2 -isoxazole substituted with methyl, —CH 2 -pyrimidine substituted with —O—C 1-6 alkyl, —C 2 alkylene-phenyl,

R 40 is H; R 43 is selected from H, halo, —C 1-6 alkyl, and —CF 3 ; R 44 is selected from H, halo, —CF 3 , —O—C 1-6 alkyl, —OCF 3 , and —SF 3 ; R 45 is selected from H, halo, —C 1-6 alkyl, —CF 3 , —O—C 1-6 alkyl, —OCHF 2 , —OCF 3 , and —S—C 1-6 alkyl; R 46 is H or halo; R 47 is selected from H, halo, and —C 1-6 alkyl; and R 5 is selected from H, —C 0-5 alkylene-OH, —C 1-6 alkyl, —C 3-7 cycloalkyl, —C(O)R 50 , —C 0-1 alkylene-C(O)OR 51 , —C(O)NR 52 R 53 , —NHC(O)R 54 , —NO 2 , furan, pyrazine, naphthalene, and phenyl optionally substituted with one or two groups independently selected from halo, —OH, —NHC(O)CH 3 , and phenyl; R 50 is —C 1-6 alkyl; R 51 is H; R 52 and R 53 are independently selected from —C 1-6 alkyl, —C 3-7 cycloalkyl, and —(CH 2 ) 2 -imidazole; or R 52 and R 53 are taken together to form a saturated —C 3-5 heterocycle optionally substituted with —OH or —COOR 40 , and optionally containing an oxygen atom in the ring; R 40 is H; and R 54 is phenyl substituted with halo.

3. The compound of claim 1 , which is 5-[(1R,2R)-2-carboxy-1-(2-chloro-benzyl)-2-hydroxy-ethylcarbamoyl]-2-(3-methoxy-benzyl)-2H-pyrazole-3-carboxylic acid.

4. The compound of claim 1 , which is 5-[(1R,2R)-2-carboxy-1-(2-chloro-benzyl)-2-hydroxy-ethylcarbamoyl]-2-(2,6-difluoro-benzyl)-2H-pyrazole-3-carboxylic acid.

5. The compound of claim 1 , which is 5-[(1R,2R)-2-carboxy-1-(2-chloro-benzyl)-2-hydroxy-ethylcarbamoyl]-2-(2-ethoxy-pyrimidin-5-ylmethyl)-2H-pyrazole-3-carboxylic acid.

6. The compound of claim 1 , which is 5-[(1R,2R)-2-carboxy-2-hydroxy-1-(2-trifluoromethyl-benzyl)-ethylcarbamoyl]-2H-pyrazole-3-carboxylic acid.

7. The compound of claim 1 , which is 5-((1R,2R)-1-benzyl-2-carboxy-2-hydroxy-ethylcarbamoyl)-2-(4-chloro-2,6-difluoro-benzyl)-2H-pyrazole-3-carboxylic acid.

8. The compound of claim 1 , which is 5-((1R,2R)-1-benzyl-2-carboxy-2-hydroxy-ethylcarbamoyl)-2-(3-fluoro-benzyl)-2H-pyrazole-3-carboxylic acid.

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

10. The pharmaceutical composition of claim 9 , further comprising an AT 1 receptor antagonist.

11. 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 .

Assignees

• Gendron Roland
• Hughes Adam D
• Theravance Biopharma R&D Ip Llc

Inventors

• Gendron Roland
• Hughes Adam D

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/04

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