US 5,476,847 A · Derivatives of phosphinic acid useful as endothelin converting enzyme inhibitors

Abstract

Phosphinic acid derivatives of the structural formula ##STR1## or a pharmaceutically acceptable salt thereof, wherein R is H, alkyl or alkanoyloxymethylene; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are H, alkyl, alkenyl, alkenylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, carboxyalkyl, thioalkyl, alkoxythioalkyl, aminoalkyl, alkylaminoalkyl, cycloalkyl-substituted alkyl or heterocycloalkyl; or R.sub.1 and R.sub.2 form a cycloalkyl ring of 3-8 members and R.sub.3 and R.sub.4 are as defined; or R.sub.3 and R.sub.4 form a cycloalkyl ring of 3-7 members and R.sub.1 and R.sub.2 are as defined; or R.sub.1 and R.sub.2 together, and R.sub.3 and R.sub.4 together, each form a cycloalkyl ring; R.sub.5 is --OR.sub.9 or --NHR.sub.9, wherein R.sub.9 is hydrogen or alkyl; n is 0 or 1; A.sub.1 is p-aminobenzoyl or p-aminobenzenesulfonyl, or A.sub.1 and R.sub.5 together form a radical of an .alpha.-aminoacyl derivative; and R.sub.6 is phenylmethoxycarbonyl, arylcarbonyl, heteroarylcarbonyl or --A.sub.2 --R.sub.7, wherein A.sub.2 is a divalent .alpha.-aminoacyl radical, and R.sub.7 is a substituent on the .alpha.-amino atom selected from H, R.sub.8 OCO--, R.sub.8 SO.sub.2 -- and R.sub.8 NHCO--, wherein R.sub.8 is aryl, arylmethyl or (C.sub.1 -C.sub.8)alkyl; are disclosed for use as endothelin converting enzyme inhibitors; also disclosed are a genus of novel compounds wherein R.sup.3 and R.sup.4 form a cycloalkyl ring, and pharmaceutical compositions comprising said novel compounds.

Claims29

Dependent claims

A compound represented by the structural formula ##STR74## or a pharmaceutically acceptable salt thereof, wherein R is H, (C.sub.1 -C.sub.8)alkyl or (C.sub.1 -C.sub.8)alkanoyloxymethylene;

R.sub.1 and R.sub.2, are independently selected from the group consisting of H, (C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.8)alkenyl, (C.sub.1 -C.sub.8)alkenyl(C.sub.1 -C.sub.8)alkyl, aryl, aryl(C.sub.1 -C.sub.8)alkyl, hydroxy-(C.sub.1 -C.sub.8)alkyl, carboxy(C.sub.1 -C.sub.8)alkyl, thio(C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.6)alkoxythio(C.sub.1 -C.sub.8)alkyl, amino(C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.8)alkylamino(C.sub.1 -C.sub.8)alkyl and cycloalkyl-substituted(C.sub.1 -C.sub.8)alkyl;
or R.sub.1 and R.sub.2, together with the carbon to which they are attached, form a cycloalkyl ring of 3 to 8 members;
R.sub.5 is --OR.sub.9 or --NHR.sub.9, wherein R.sub.9 is hydrogen or (C.sub.1 -C.sub.8)alkyl;
n is 0 or 1;
q is 2 to 6;
A.sub.1 and R.sub.5 together are ##STR75## or A.sub.1 and R.sub.5 together form a radical of an .alpha.-aminoacyl derivative, wherein A.sub.1 is a divalent .alpha.-aminoacyl radical attached to the molecule at the .alpha.-amino group, and wherein R.sub.5 is attached to the acyl terminus of A.sub.1 ;
R.sub.6 is phenylmethoxycarbonyl, arylcarbonyl, or --A.sub.2 --R.sub.7, wherein A.sub.2 is a divalent .alpha.-aminoacyl radical attached to the molecule at the acyl terminus, and wherein R.sub.7 is a substituent on the .alpha.-amino atom selected from the group consisting of H, R.sub.8 OCO--, R.sub.8 SO.sub.2 -- and R.sub.8 NHCO--, wherein R.sub.8 is aryl, arylmethyl or (C.sub.1 -C.sub.8)alkyl.

4 more elements

A method of inhibiting endothelin converting enzyme comprising administering to a mammal in need of such treatment a compound represented by the structural formula ##STR76## or a pharmaceutically acceptable salt thereof, wherein R is H, (C.sub.1 -C.sub.8)alkyl or (C.sub.1 -C.sub.8)alkanoyloxymethylene;

R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently selected from the group consisting of H, (C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.8)alkenyl, (C.sub.1 -C.sub.8)alkenyl(C.sub.1 -C.sub.8)alkyl, aryl, aryl(C.sub.1 -C.sub.8)alkyl, hydroxy-(C.sub.1 -C.sub.8)alkyl, carboxy(C.sub.1 -C.sub.8)alkyl, thio(C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.6)alkoxythio(C.sub.1 -C.sub.8)alkyl, amino(C.sub.1 -C.sub.8)alkyl, (C.sub.1 -C.sub.8)alkylamino(C.sub.1 -C.sub.8)alkyl, and cycloalkyl-substituted(C.sub.1 -C.sub.8)alkyl;
or R.sub.1 and R.sub.2, together with the carbon to which they are attached, form a cycloalkyl ring of 3 to 8 members and R.sub.3 and R.sub.4 are as defined above;
or R.sub.3 and R.sub.4, together with the carbon to which they are attached, form a cycloalkyl ring of 3 to 7 members and R.sub.1 and R.sub.2 are as defined above;
or R.sub.1 and R.sub.2 together, and R.sub.3 and R.sub.4 together, each form a cycloalkyl ring as defined above;
R.sub.5 is --OR.sub.9 or --NHR.sub.9, wherein R.sub.9 is hydrogen or (C.sub.1 -C.sub.8)alkyl;
n is 0 or 1;
A.sub.1 and R.sub.5 together are ##STR77## or A.sub.1 and R.sub.5 together form a radical of an .alpha.-aminoacyl derivative, wherein A.sub.1 is a divalent .alpha.-aminoacyl radical attached to the molecule at the .alpha.-amino group, and wherein R.sub.5 is attached to the acyl terminus of A.sub.1 ;
R.sub.6 is phenylmethoxycarbonyl, arylcarbonyl, or --A.sub.2 --R.sub.7, wherein A.sub.2 is a divalent .alpha.-aminoacyl radical attached to the molecule at the acyl terminus, and wherein R.sub.7 is a substituent on the .alpha.-amino atom selected from the group consisting of H, R.sub.8 OCO--, R.sub.8 SO.sub.2 -- and R.sub.8 NHCO--, wherein R.sub.8 is aryl, arylmethyl or (C.sub.1 -C.sub.8)alkyl.

5 more elements

Dependencies are inferred from the claim text.

Derivatives of phosphinic acid useful as endothelin converting enzyme inhibitors

Life of this patent

Derivatives of phosphinic acid useful as endothelin converting enzyme inhibitors

Life of this patent

Abstract

Claims29