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EP0229667A2 Expired / Lapsed EP ⏱️ 0.0 years remaining

Peptidylaminodiols

Assignee: Abbott Laboratories
•
Filing: 1987-01-15
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Granted: —
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Expires: 2007-01-15
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Abstract

Abstract A renin inhibiting compound of the formula: wherein A is a substituent; W is C=O or CHOH; U is CH₂ or NR₂, provided that when W is CHOH then U is CH₂; R₁ is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, α, α -dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; R₂ is hydrogen or loweralkyl; R₃ is loweralkyl, [(alkoxy)alkoxy]alkyl, (thioalkoxy)alkyl, lowerakenyl, benzyl or heterocyclic ring substituted methyl; R₄ is loweralkyl, cycloalkylmethyl or benzyl; R₅ is vinyl, formyl, hydroxymethyl or hydrogen; R₇ is hydrogen or loweralkyl; R₈ and R₉ are independently selected from OH and NH₂; and R₆ is hydrogen, loweralkyl, vinyl or arylalkyl; provided that when R₅ and R₇ are both hydrogen and R₈ and R₉ are OH, the carbon bearing R₅ is of the "R" configuration and the carbon bearing R₆ is of the "S" configuration; or pharmaceutically acceptable salts or esters thereof. Also disclosed are renin inhibiting compositions, a method of treating hypertension, methods of making the renin inhibiting compounds and intermediates useful in making the renin inhibiting compounds.

Inventors

  • 👤 Jay Richard Luly
  • 👤 Dale John Kempf
  • 👤 Jacob John Plattner

Bibliographic Details

Application Number —
Jurisdiction EP
Data Source google_patents
Last Synchronized 2026-11-08 13:44
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/04; C07K7/14; C07D; C07D233/00; C07D233/54; C07D233/64; A; A61; A61P; A61P43/00; A61P9/00; A61P9/12; C07K5/00; C07K5/02; C07K5/0202; C07K5/0227; C07K5/04; C07K5/06; C07K5/06008; C07K5/06017; C07K5/06026; C07K5/06034; C07K5/06043; C07K5/0606; C07K5/06078; C07K5/08; C07K5/0802; C07K5/0804; C07K5/0806; C07K5/0808; C07K5/0821; C07K5/0823; A61K; A61K38/00; Y; Y02; Y02P; Y02P20/00; Y02P20/50; Y02P20/55

Claims Analysis

Total Claims: 31
Claim 1
Independent Claim 251 words
A renin inhibiting compound of the formula: wherein A is hydrogen; loweralkyl; arylalkyl; OR₁₀ or SR₁₀ wherein R₁₀ is hydrogen, loweralkyl or aminoalkyl; NR₁₁R₁₂ wherein R₁₁ and R₁₂ are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; wherein B is NH, alkylamino, S, O, CH₂ or CHOH and R₁₃ is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, or an unsubstituted heterocyclic or a monosubstituted heterocyclic wherein the substituent is hydroxy, oxo, amino, alkylamino, dialkylamino or loweralkyl, provided that when the heterocyclic is unsaturated the substituent cannot be oxo; W is C=O or CHOH; U is CH₂ or NR₂, provided that when W is CHOH, U is CH₂; R₁ is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, α, α-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided if R₁ is phenoxy, thiophenoxy or anilino, B is CH₂ or CHOH or A is hydrogen; R₂ is hydrogen or loweralkyl; R₃ is loweralkyl, loweralkenyl, [(alkoxy)alkoxy]alkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; R₄ is loweralkyl, cycloalkylmethyl or benzyl; R₅ is vinyl, formyl, hydroxymethyl or hydrogen; R₇ is hydrogen or loweralkyl; R₈ and R₉ are independently selected from OH and NH₂; and R₆ is hydrogen, loweralkyl, vinyl or arylalkyl; provided that when R₅ and R₇ are both hydrogen and R₈ and R₉ are OH, the carbon bearing R₅ is of the "R" configuration and the carbon bearing R₆ is of the "S" configuration; or pharmaceutically acceptable salts or esters thereof.
Claim 2
Dependent Claim 251 words
A renin inhibiting compound of the formula: wherein A is hydrogen; loweralkyl; arylalkyl; OR₁₀ or SR₁₀ wherein R₁₀ is hydrogen, loweralkyl or aminoalkyl; NR₁₁R₁₂ wherein R₁₁ and R₁₂ are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; wherein B is NH, alkylamino, S, O, CH₂ or CHOH and R₁₃ is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, or an unsubstituted heterocyclic or a monosubstituted heterocyclic wherein the substituent is hydroxy, oxo, amino, alkylamino, dialkylamino or loweralkyl, provided that when the heterocyclic is unsaturated the substituent cannot be oxo; W is C=O or CHOH; U is CH₂ or NR₂, provided that when W is CHOH, U is CH₂; R₁ is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (4-imidazoyl)methyl, α, α-dimethylbenzyl, 1-benzyloxyethyl, phenethyl, phenoxy, thiophenoxy or anilino; provided if R₁ is phenoxy, thiophenoxy or anilino, B is CH₂ or CHOH or A is hydrogen; R₂ is hydrogen or loweralkyl; R₃ is loweralkyl, loweralkenyl, [(alkoxy)alkoxy]alkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl; R₄ is loweralkyl, cycloalkylmethyl or benzyl; R₅ is vinyl, formyl, hydroxymethyl or hydrogen; R₇ is hydrogen or loweralkyl; R₈ and R₉ are independently selected from OH and NH₂; and R₆ is hydrogen, loweralkyl, vinyl or arylalkyl; provided that when R₅ and R₇ are both hydrogen and R₈ and R₉ are OH, the carbon bearing R₅ is of the "R" configuration and the carbon bearing R₆ is of the "S" configuration; or pharmaceutically acceptable salts or esters thereof.
Claim 3
Dependent Claim 85 words
The renin inhibiting compounds of Claim 1 wherein the heterocyclic is: wherein n is 1 or 2 and X is N, NH, O or S, provided that X is the point of connection only when X is N, wherein Y is NH, N-loweralkyl, O, S or SO₂, or wherein Z₁ is N, O, or S and not the point of connection and Z₂ is N when it is the point of connection and NH, O or S when it is not the point of connection.
Claim 4
Dependent Claim 20 words
The renin inhibiting compounds of Claim 1 wherein R₁ is benzyl or 4-methoxybenzyl, R₃ is (4-imidazoyl)methyl and R₄ is cyclohexylmethyl.
Claim 5
Dependent Claim 18 words
The renin inhibiting compound of Claim 1 wherein R₂, R₅ and R₇ are hydrogen; and R₆ is isobutyl.
Claim 6
Dependent Claim 205 words
A renin inhibiting compound of the formula: wherein A is hydrogen; loweralkyl; arylalkyl; OR₁₀ or SR₁₀ wherein R₁₀ is hydrogen, loweralkyl or aminoalkyl; NR₁₁R₁₂ wherein R₁₁ and R₁₂ are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; wherein B is NH, alkylamino, S, O, CH₂ or CHOH and R₁₃ is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, wherein n is 1 or 2 and X is N, NH, O or S, provided that X is the point of connection only when X is N, wherein Y is NH, N-loweralkyl, O, S or SO₂, or wherein Z₁ is N, O, or S and not the point of connection and Z₂ is N when it is the point of connection and NH, O or S when it is not the point of connection; R₁ is benzyl or 4-methoxybenzyl, R₂ is hydrogen or methyl, R₃ is (4-imidazoyl)methyl, R₄ is cyclohexylmethyl, R₅ is hydrogen, R₆ is isobutyl, R₇ is hydrogen, R₈ is OH and R₉ is OH and the carbon bearing R₅ is of the "R" configuration and the carbon bearing R₆ is of the "S" configuration; or pharmaceutically acceptable salt or esters thereof.
Claim 7
Dependent Claim 205 words
A renin inhibiting compound of the formula: wherein A is hydrogen; loweralkyl; arylalkyl; OR₁₀ or SR₁₀ wherein R₁₀ is hydrogen, loweralkyl or aminoalkyl; NR₁₁R₁₂ wherein R₁₁ and R₁₂ are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl and hydroxyalkyl; wherein B is NH, alkylamino, S, O, CH₂ or CHOH and R₁₃ is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl, wherein n is 1 or 2 and X is N, NH, O or S, provided that X is the point of connection only when X is N, wherein Y is NH, N-loweralkyl, O, S or SO₂, or wherein Z₁ is N, O, or S and not the point of connection and Z₂ is N when it is the point of connection and NH, O or S when it is not the point of connection; R₁ is benzyl or 4-methoxybenzyl, R₂ is hydrogen or methyl, R₃ is (4-imidazoyl)methyl, R₄ is cyclohexylmethyl, R₅ is hydrogen, R₆ is isobutyl, R₇ is hydrogen, R₈ is OH and R₉ is OH and the carbon bearing R₅ is of the "R" configuration and the carbon bearing R₆ is of the "S" configuration; or pharmaceutically acceptable salt or esters thereof.
Claim 8
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is (β,β-dimethyl)-β-alanylamino, R₁ is 4-methoxybenzyl and R₂ is hydrogen.
Claim 9
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is ethoxycarbonylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 10
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is (N,N-dimethyl)glycylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 11
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is β-alanylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 12
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is methylaminoacetamido, R₁ is benzyl and R₂ is hydrogen.
Claim 13
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is 4-aminobutyrylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 14
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is isonipecotylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 15
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is D-alanylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 16
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is (β,β-dimethyl)-β-alanylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 17
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is prolylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 18
Dependent Claim 20 words
The renin inhibiting compound of Claim 5 wherein A is (α, α- dimethyl)-β-alanylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 19
Dependent Claim 19 words
The renin inhibiting compound of Claim 5 wherein A is (α, α-dimethyl)-glycylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 20
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is imidazol-4-yl-acetylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 21
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is (4-morpholinyl)carbonyloxy, R₁ is benzyl and R₂ is hydrogen.
Claim 22
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A i (1-piperazinyl)carbonyloxy, R₁ is benzyl and R₂ is hydrogen.
Claim 23
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is (4-morpholinyl)carbonylamino, R₁ is benzyl and R₂ is hydrogen.
Claim 24
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is (4-morpholinyl)carbonylmethyl, R₁ is benzyl and R₂ is hydrogen.
Claim 25
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is n-butylamino, R₁ is 4-methoxybenzyl and R₂ is hydrogen.
Claim 26
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is (4-morpholinyl)carbonylamino, R₁ is 4-methoxybenzyl and R₂ is hydrogen.
Claim 27
Dependent Claim 18 words
The renin inhibiting compound of Claim 5 wherein A is isonipecotylamino, R₁ is 4-methoxybenzyl and R₂ is hydrogen.
Claim 28
Dependent Claim 24 words
A pharmaceutical composition for treating renin-associated hypertension, comprising a pharmaceutical carrier and a therapeutically effective amount of the compound of Claim 1 or 5.
Claim 29
Dependent Claim 36 words
A compound of the formula: wherein R is loweralkyl, cycloalkylmethyl or benzyl; R′ is hydrogen, loweralkyl, vinyl or arylalkyl; P₂ and P₃ are independently selected from hydrogen and an O-protecting group; or acid addition salts thereof.
Claim 30
Dependent Claim 36 words
A compound of the formula: wherein R is loweralkyl, cycloalkylmethyl or benzyl; R′ is hydrogen, loweralkyl, vinyl or arylalkyl; P₂ and P₃ are independently selected from hydrogen and an O-protecting group; or acid addition salts thereof.
Claim 31
Dependent Claim 55 words
A process of making a compound of Claim 1 comprising the step of coupling an N-protected amino acid with a compound of the formula: wherein R is loweralkyl, cycloalkylmethyl or benzyl; R′ is hydrogen, loweralkyl, vinyl or arylalkyl; P₂ and P₃ are independently selected from hydrogen and an O-protecting group: or acid addition salts thereof.

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