Inhibitors of the renal outer medullary potassium channel

摘要

This invention relates to compounds of Formula I having the following general structure:
Z1—Y1—(CH2)n1—R—(CH2)n2—Y2—Z2
wherein R represents a fused bicyclic or spirocyclic aliphatic diamine and pharmaceutically acceptable salts thereof which are inhibitors of the Renal Outer Medullary Potassium (ROMK) channel (Kir1.1). The compounds are useful as diuretics and natriuretics and therefore are useful for the therapy and prophylaxis of disorders resulting from excessive salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure.

主权项

1. A compound having structural Formula I:
Z1—Y1—(CH2)n1—R—(CH2)n2—Y2—Z2  I or a pharmaceutically acceptable salt thereof wherein: n1 and n2 can be individually either 0 or 1; R represents a fused bicyclic or spirocyclic aliphatic diamine having one of the following structures: wherein R-I represents a 9-11-membered saturated bicyclic heterocyclic ring system sharing 1 carbon atom, and R-II represents a 8-10-membered saturated bicyclic heterocyclic ring system sharing 2 carbon atoms, wherein each ring of R-I and each ring of R-II has 1 Nitrogen atom; R5 is —H, —F with the proviso that —F is not attached to a carbon that is also attached to nitrogen, —CH3, —CF3, —CHF2, —CH2F, or —CH2OH, or R5 represents di-substitution on a single carbon with two of —F with the proviso that —F is not attached to a carbon that is also attached to nitrogen or two of —CH3; Z1 is:Z2 is: one of W1 and W2 is N and the other is CH; R1 and R2 are each independently —H, —F, —Cl, —Br, cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3alkyl optionally substituted with 1-3 of —F; one of R3a and R3b is —CN, tetrazolyl, or —S(O)2C(1-3)alkyl and the other is —H, —F, —Cl, —Br, —S—CH3, —NH—CH3, —O-cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3 alkyl optionally substituted with 1-3 of —F; one of R4a and R4b is CN, tetrazolyl, or —S(O)2C(1-3)alkyl and the other is —H, —F, —Cl, —Br, —S—CH3, —NH—CH3, —O-cyclopropyl, —C1-3alkyl optionally substituted with 1-3 of —F, or —OC1-3 alkyl optionally substituted with 1-3 of —F; Ra, Raa, Rb and Rbb are each independently —H, —F, —Cl, —C1-3alkyl optionally substituted with 1 to 3 of —F, or —OC1-3alkyl optionally substituted with 1 to 3 of —F; Rc and Rd are each independently —H, —F, —Cl, —C1-3alkyl optionally substituted with 1 to 3 of F, or —OC1-3alkyl optionally substituted with 1 to 3 of —F; and one of Y1 or Y2 is —CH(OH)—; and the other is —CH(OH)—; —C(O)—; or —S(O)2—; provided that where Y1 or Y2 is —C(O)— or —S(O)2—, then the adjacent n1 or n2, respectively, is 0; and provided further that where n1 or n2 is 0, the adjacent Y1 or Y2 is —C(O)— or —S(O)2—.