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 selected from:
(a) (2S,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;
(b) (2S,4R)-5-(3′-chlorobiphenyl-4-yl)-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methoxymethyl-2-methylpentanoic acid;
(c) (2S,4R)-5-(3′-chlorobiphenyl-4-yl)-2-ethoxymethyl-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;
(d) (2S,4R)-5-biphenyl-4-yl-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-hydroxymethyl-2-methylpentanoic acid;
(e) (2S,4R)-5-biphenyl-4-yl-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methoxymethyl-2-methylpentanoic acid;
(f) (2S,4R)-5-biphenyl-4-yl-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methoxymethyl-2-methylpentanoic acid;
(g) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3-methoxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;
(h) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-[(3-ethylisoxazole-5-carbonyl)amino]-2-hydroxymethyl-2-methylpentanoic acid;
(i) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-4-[(3-isobutylisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;
(j) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-4-[(3-propylisoxazole-5-carbonyl)amino]pentanoic acid;
(k) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methoxymethyl-2-methylpentanoic acid;
(l) (2S,4R)-5-(3′-chlorobiphenyl-4-yl)-2-(2-hydroxyethoxymethyl)-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;
(m) (2S,4R)-5-(3′-chlorobiphenyl-4-yl)-2-ethoxymethyl-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;
(n) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-ethoxymethyl-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;
(o) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-ethoxymethyl-4-[(3-ethylisoxazole-5-carbonyl)amino]-2-methylpentanoic acid;
(p) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-[(3-hydroxyisoxazole-5-carbonyl)amino]-2-hydroxymethyl-2-methylpentanoic acid; and
(q) (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-[(3-ethylisoxazole-5-carbonyl)amino]-2-methoxymethyl-2-methylpentanoic acid.
2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .
3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound of claim 1 , and an AT 1 receptor antagonist.
4. The pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound of claim 1 , and a phosphodiesterase (PDE) inhibitor.
5. The pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound of claim 1 , and a renin inhibitor.
6. The pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound of claim 1 , and a diuretic.
7. A method for treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of the compound of claim 1 .