Neprilysin inhibitors
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.
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.