Neprilysin inhibitors

Patent metadata

Field	Value
Publication number	US-11124502-B2
Application number	US-202016739525-A
Country	US
Kind code	B2
Filing date	Jan 10, 2020
Priority date	Aug 8, 2012
Publication date	Sep 21, 2021
Grant date	Sep 21, 2021

Abstract

In one aspect, the invention relates to compounds having the formula:where X, Ra, Rb, R2, and R7 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds 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 formula V:

or a salt or stereoisomer thereof, wherein:
R a is selected from Cl and F and R b is H; or R a is H and R b is selected from Cl and F; or R a is F and R b is Cl;
R 2 is selected from H, —C 1-6 alkyl, —(CH 2 ) 2-3 OR e , and —(CH 2 ) 2-3 NR e R e ;
R 3 is selected from —OH, —OCH 3 , —OCH 2 CH 3 , and —C 1-4 alkyl;
R 7 is selected from H, —C 1-6 alkyl, —[(CH 2 ) 2 O] 1-3 CH 3 , —CHR c OC(O)—C 1-4 alkyl, —CH 2 OC(O)CHR d —NH 2 , —CH 2 OC(O)CHR d —NHC(O)O—C 1-6 alkyl, —CHR c OC(O)O—C 2-4 alkyl, —CHR c OC(O)O-cyclohexyl, —CH 2 CH(NH 2 )C(O)OCH 3 , —C 2-4 alkylene-N(CH 3 ) 2 , —C 0-6 alkylenemorpholinyl, and

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

2. The compound, salt or stereoisomer of claim 1 , wherein R 2 is —C 1-6 alkyl.

3. The compound, salt or stereoisomer of claim 1 , wherein R 2 is selected from —CH 3 and —CH 2 CH 3 .

4. The compound, salt or stereoisomer of claim 1 , wherein R 2 is —CH 2 CH 3 .

5. The compound, salt or stereoisomer of claim 1 , wherein R 3 is —OH.

6. The compound, salt or stereoisomer of claim 4 , wherein R 3 is —OH.

7. The compound, salt or stereoisomer of claim 1 , wherein R 7 is H or —C 1-6 alkyl.

8. The compound, salt or stereoisomer of claim 1 , wherein R 7 is H.

9. The compound, salt or stereoisomer of claim 4 , wherein R 7 is H.

10. The compound, salt or stereoisomer of claim 6 , wherein R 7 is H.

11. The compound, salt or stereoisomer of claim 4 , wherein R a is F and R b is Cl.

12. The compound, salt or stereoisomer of claim 6 , wherein R a is F and R b is Cl.

13. The compound, salt or stereoisomer of claim 9 , wherein R a is F and R b is Cl.

14. A pharmaceutical composition comprising the compound, salt or stereoisomer of claim 1 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising the compound, salt or stereoisomer of claim 10 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising the compound, salt or stereoisomer of claim 13 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 15 , wherein the pharmaceutically acceptable carrier is magnesium stearate.

18. The pharmaceutical composition of claim 16 , wherein the pharmaceutically acceptable carrier is magnesium stearate.

19. An oral dosage form comprising the compound, salt or stereoisomer of claim 10 .

20. An oral dosage form comprising the compound, salt or stereoisomer of claim 13 .

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Fleury Melissa
• Hughes Adam D

Classifications

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D263/38

  attached in position 2 · CPC title

• C07D261/18

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• C07D249/04 Primary

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title

• C07D231/20

  One oxygen atom attached in position 3 or 5 · CPC title