Neprilysin inhibitors
In one aspect, the invention relates to compounds having the formula: where X, R a , R b , R 2 , and R 7 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.
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 .