Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-10829438-B2
Application number	US-201916392920-A
Country	US
Kind code	B2
Filing date	Apr 24, 2019
Priority date	Jun 8, 2012
Publication date	Nov 10, 2020
Grant date	Nov 10, 2020

Abstract

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

where R a , R b , R 2 , R 7 , and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. The compounds described herein are prodrugs of compounds having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising these compounds; methods of using these compounds; and processes and intermediates for preparing these compounds.

First claim

What is claimed is:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
R a is selected from H and F;
R b is Cl;
R 2 is selected from H, —C(O)—C 1-6 alkyl, —C(O)CHR d —NH 2 , —C(O)CHR d —NHC(O)O—C 1-6 alkyl, —C(O)CH[CH(CH 3 ) 2 ]NH 2 and —P(O)(OR e ) 2 ;

R 7 is selected from H, —CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 CF 3 , —(CH 2 ) 2 CF 3 , —CH 2 CF 2 CH 3 , —CH 2 CF 2 CF 3 , —C(CH 3 )(CF 3 ) 2 , —CH(CH 2 CH 3 )CF 3 , —CH(CH 3 )CF 2 CF 3 , —(CH 2 ) 2-3 OH, —CH 2 CH(NH 2 )COOCH 3 , —(CH 2 ) 20 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —C 2-4 alkylene-N(CH 3 ) 2 , —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d -NHC(O)O—C 1-6 alkyl, benzyl and

P is selected from H and an amino-protecting group;
each R c is independently selected from H and —C 1-3 alkyl;
each R d is independently selected from H, —CH 3 , —CH(CH 3 ) 2 , phenyl and benzyl; and
each R e is independently selected from H, —C 1-6 alkyl and phenyl.

2. The compound of claim 1 , wherein R 2 is H.

3. The compound of claim 1 , wherein R 7 is selected from H, —CH 2 CH 3 and —CH 2 CH(CH 3 ) 2 .

4. The compound of claim 3 , wherein R 7 is —CH 2 CH 3 .

5. The compound of claim 2 , wherein R 7 is —CH 2 CH 3 .

6. The compound of claim 1 , wherein P is selected from H, t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl and t-butyldimethylsilyl.

7. The compound of claim 6 , wherein P is H.

8. The compound of claim 5 , wherein P is H.

9. The compound of claim 1 , wherein R a is H.

10. The compound of claim 1 , wherein R a is F.

11. The compound of claim 8 , wherein IV is F.

12. The compound of claim 1 , wherein the compound is (2R,4R)-4-amino-5-(5′-chloro-2′-fluoro-biphenyl-4-yl)-2-hydroxypentanoic acid or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , wherein the compound is (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound is (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid 2,2,3,3,3-pentafluoropropyl ester or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid butyryloxymethyl ester or a pharmaceutically acceptable salt thereof.

17. A method of performing a coupling reaction, comprising contacting the compound of claim 1 with a carboxylic acid.

18. The method of claim 17 , wherein the reaction is conducted in the presence of a coupling reagent.

19. The method of claim 18 , wherein the coupling reagent is selected from BOP, PyBOP, HATU, DCC, EDC, CDI and HOBt.

20. The method of claim 17 , wherein the reaction is conducted in the presence of a base.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Fleury Melissa
• Hughes Adam D

Classifications

• A61K31/4192 Primary

  1,2,3-Triazoles · CPC title

• C07F9/6503

  Five-membered rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title