N-(HYDROXYETHYL)BUTANEDIAMIDE DERIVATIVES,THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

摘要

Disclosed herein are compounds of the formula: A-N(R<1>)C(O)CH2CHR<2>C(O)-B wherein A is an oxygen-bearing radical selected from the group consisting of: (a) HO-CH(R<3>)CH2 wherein R<3> is, for example, hydrogen, lower alkyl, lower cycloalkyl, phenyl or an unsubstituted five- or six-membered heterocyclic ring containing one or two heteroatoms selected from the group of N, O or S; (b) HO-CH2CH(R<4>) wherein R<4> is, for example, lower alkyl or phenyl(lower)alkyl; and (c) HO-CR<5>(R<6>)CH2 wherein each of R<5> and R<6> is lower alkyl; or R<5> and R<6> 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))CH2 wherein each of R<5A> and R<6A> is lower alkyl; or R<5A> and R<6A> together with the carbon atom to which they are attached form a 1,1-(lower cycloalkanediyl); and (e) (lower alkyl)C(O)CH2; R<1> is, for example, benzyl, alkyl, a substituted alkyl such as cyclohexylmethyl, or R<7>R<8>NC(O)CH2 wherein R<7> and R<8> are alkyl such as methyl or ethyl; R<2> 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.