Neprilysin inhibitors
In one aspect, the invention relates to compounds having the formula: where R 1 -R 6 , a, b, and Z 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.
1. A compound of formula (IIIa):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from H and —C 1-8 alkyl;
R 2 is —OH or —CH 2 OH;
R 3 is H or —CH 3 ;
R 4 is selected from H and —C 1-6 alkyl;
a is 0 or 1;
R 5 is selected from halo, —CH 3 , —CF 3 , and —CN;
b is 0 or an integer from 1 to 3; and
each R 6 is independently selected from halo, —OH, —CH 3 , —OCH 3 , —CN, and —CF 3 ;
wherein each alkyl group in R 1 and R 4 is optionally substituted with 1 to 8 fluoro atoms.
2. The compound or salt of claim 1 , wherein R 1 is H.
3. The compound or salt of claim 2 , wherein R 2 is —CH 2 OH and R 3 is —CH 3 .
4. The compound or salt of claim 3 , wherein R 4 is selected from H, —CH 2 CH 3 , and —CH 2 CH(CH 3 ) 2 .
5. The compound or salt of claim 4 , wherein a is 0; b is 1 or 2; and each R 6 is independently selected from halo.
6. The compound or salt of claim 1 , wherein the compound is a compound of formula (Ia-1):
7. The compound or salt of claim 6 , wherein R 1 is H.
8. The compound or salt of claim 7 , wherein R 2 is —CH 2 OH and R 3 is —CH 3 .
9. The compound or salt of claim 8 , wherein R 4 is selected from H, —CH 2 CH 3 , and —CH 2 CH(CH 3 ) 2 .
10. The compound or salt of claim 9 , wherein a is 0; b is 1 or 2; and each R 6 is independently selected from halo.
11. The compound or salt of claim 1 , wherein the compound is a compound of the formula:
12. The compound or salt of claim 11 , wherein b is 1 or 2 and each R 6 is independently selected from halo.
13. A compound of the formula:
or a pharmaceutically acceptable salt or prodrug thereof.
14. A pharmaceutical composition comprising the compound or salt of claim 10 and a pharmaceutically acceptable carrier.
15. A method of treating a disease mediated at least in part by neprilysin in a subject in need thereof, comprising administering to the subject an effective amount of the compound or salt of claim 10 .
16. The method of claim 15 , wherein the disease is selected from hypertension, heart failure, and renal disease.
17. The method of claim 15 , further comprising administering an AT 1 receptor antagonist.
18. A method of treating a disease mediated at least in part by neprilysin in a subject in need thereof, comprising administering to the subject an effective amount of the compound, salt, or prodrug of claim 13 .
19. The method of claim 18 , wherein the disease is selected from hypertension, heart failure, and renal disease.
20. A method of treating hypertension, heart failure, or renal disease in a subject in need thereof, comprising administering to the subject an AT 1 receptor antagonist and an effective amount of the compound or salt of claim 10 .