Substituted bisphenyl butanoic ester derivatives as NEP inhibitors

Patent metadata

Field	Value
Publication number	US-11426375-B2
Application number	US-202016854355-A
Country	US
Kind code	B2
Filing date	Apr 21, 2020
Priority date	Feb 7, 2018
Publication date	Aug 30, 2022
Grant date	Aug 30, 2022

Abstract

The present disclosure provides a compound of Formula (I);or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are defined herein. The disclosure also relates to a method for manufacturing the compounds of the disclosure, and its therapeutic uses. The present disclosure further provides pharmaceutical composition of the compounds of the disclosure and a combination of pharmacologically active agents and a compound of the disclosure.

First claim

What is claimed is:

1. A method of inhibiting neutral endopeptidase activity in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound of the Formula (I):

wherein:
R 1 is H or (C 1 -C 4 )alkyl;
R 2 is H, (C 1 -C 4 )alkyl, (C 6 -C 10 ) aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the alkyl is optionally substituted with one or more R 3 , and wherein the aryl and heteroaryl are optionally substituted with one or more R 4 ;
each R 3 is independently at each occurrence —NH 2 , (C 1 -C 4 )alkylamino, (C 1 -C 4 )dialkylamino, —OH, —SH, —S(C 1 -C 4 )alkyl, —CO 2 H, —CONH 2 , —NHC(NH)NH 2 , (C 6 -C 10 ) aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R 5 ;
each R 4 is independently at each occurrence (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halogen, —NH 2 , —OH, or CN; and
each R 5 is independently at each occurrence (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halogen, —NH 2 , —OH, or CN;

or a pharmaceutically acceptable salt thereof;
wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered together, concomitantly or sequentially with an Angiotensin Receptor Blocker selected from candesartan, losartan, irbesartan, telmisartan, olmesartan, eprosartan, fimasartan, and azilsartan, or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 , wherein R 1 is H, ethyl, or t-butyl.

4. The method according to claim 1 , wherein R 2 is H or (C 1 -C 4 )alkyl optionally substituted with one to two R 3 .

5. The method according to claim 1 , wherein R 2 is H or (C 1 -C 4 )alkyl optionally substituted with —NH 2 .

6. The method according to claim 1 , wherein R 1 is H, ethyl, or t-butyl, and R 2 is H or (C 4 )alkyl optionally substituted with —NH 2 .

7. The method according to claim 1 , wherein the compound is selected from:
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-leucine;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-lysine; and
tert-butyl (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-lysinate;
ethyl (2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-(4-(((S)-1-ethoxy-4-methyl-1-oxopentan-2-yl)amino)-4-oxobutanamido)-2-methylpentanoate;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-arginine;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-histidine;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)glycine;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-alanine;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-valine;
(4-(((2S, 4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-phenylalanine;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-tryptophan; and
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-isoleucine;
or a pharmaceutically acceptable salt thereof.

8. The method according to claim 1 , wherein the compound is (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-leucine or a pharmaceutically acceptable salt thereof.

9. The method according to claim 1 , wherein the compound is (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-histidine or a pharmaceutically acceptable salt thereof.

10. A method of treating a disorder or a disease associated with neutral endopeptidase activity in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound of the Formula (I):

wherein:
R 1 is H or (C 1 -C 4 )alkyl;
R 2 is H, (C 1 -C 4 )alkyl, (C 6 -C 10 ) aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the alkyl is optionally substituted with one or more R 3 , and wherein the aryl and heteroaryl are optionally substituted with one or more R 4 ;
each R 3 is independently at each occurrence —NH 2 , (C 1 -C 4 )alkylamino, (C 1 -C 4 )dialkylamino, —OH, —SH, —S(C 1 -C 4 )alkyl, —CO 2 H, —CONH 2 , —NHC(NH)NH 2 , (C 6 -C 10 ) aryl, or 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R 5 ;
each R 4 is independently at each occurrence (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halogen, —NH 2 , —OH, or CN; and
each R 5 is independently at each occurrence (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )haloalkoxy, halogen, —NH 2 , —OH, or CN;

or a pharmaceutically acceptable salt thereof;
wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered together, concomitantly or sequentially with an Angiotensin Receptor Blocker selected from candesartan, losartan, irbesartan, telmisartan, olmesartan, eprosartan, fimasartan, and azilsartan, or a pharmaceutically acceptable salt thereof.

11. The method according to claim 10 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof.

12. The method according to claim 10 , wherein R 1 is H, ethyl, or t-butyl.

13. The method according to claim 10 , wherein R 2 is H or (C 1 -C 4 )alkyl optionally substituted with one to two R 3 .

14. The method according to claim 10 , wherein R 2 is H or (C 1 -C 4 )alkyl optionally substituted with —NH 2 .

15. The method according to claim 10 , wherein R 1 is H, ethyl, or t-butyl, and R 2 is H or (C 4 )alkyl optionally substituted with —NH 2 .

16. The method according to claim 10 , wherein the compound is selected from:
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-leucine;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-lysine; and
tert-butyl (4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-lysinate;
ethyl (2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-(4-(((S)-1-ethoxy-4-methyl-1-oxopentan-2-yl)amino)-4-oxobutanamido)-2-methylpentanoate;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-arginine;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoyl)-L-histidine;
(4-(((2S,4R)-1-([1,1′-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4

Assignees

• Novartis Ag

Inventors

• Chai Yongshuai
• Godtfredsen Sven Erik
• Kagan Mark
• Liu Yugang
• Prashad Mahavir
• Wang Zhaoyin
• Zhu Saijie

Classifications

• C07C279/14 Primary

  being further substituted by carboxyl groups · CPC title

• A61P43/00

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

• A61P25/24

  Antidepressants · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title