N-(HYDROXYETHYL)BUTANEDIAMIDE DERIVATIVES AS RENIN INHIBITORS

摘要

Disclosed herein are compounds of the formula: A-N(R1)C(O)CH¿2CHR?2C(O)-B, wherein A is an oxygen-bearing radical selected from the group consisting of: (a) HO-CH(R3)CH2 wherein R3 is, for example, hydrogen, lower alkyl, lower cycloalkyl, phenyl or an unsubstituted five- or six-membered heterocyclic ring containing one or two hereroatoms selected from the group of N, O or S; (b) HO-CH¿2CH(R?4) wherein R4 is, for example, lower alkyl or phenyl(lower)alkyl; and (c) HO-CR5(R6)CH2 wherein each of R?5 and R6¿ is lower alkyl; or R?5 and R6¿ together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl), 1,1-(4-hydroxycyclohexanediyl) or 1,1-(4-oxocyclohexanediyl); (d) (lower alkoxy)CR?5A(R6A)CH¿2 wherein each of R?5A and R6A¿ is lower alkyl; or R?5A and R6A¿ together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl); and (e) (lower alkyl)C(O)CH¿2; R?1 is, for example, benzyl, alkyl, a substituted alkyl such as cyclohexylmethyl, or R7R8NC(O)CH¿2? wherein R?7 and R8¿ are alkyl such as methyl or ethyl; R2 is, for example, alkyl, cycloalkylmethyl, 1H-imidazol-4-ylmethyl, 4-thiazolylmethyl or (2-amino-4-thiazolyl)methyl; and B is a renin substrate transition state mimic, for example, [1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino. The compounds inhibit renin activity and are indicated for the treatment of hypertension and congestive heart failure.