EP0212903A2
Expired / Lapsed
EP
⏱️ 0.0 years remaining
Polypeptide derivatives containing 5-amino-2,5-disubstituted-4-hydroxypentanoic acid residues
Assignee: Pfizer Inc
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Filing: 1986-08-04
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Granted: —
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Expires: 2006-08-04
Abstract
Abstract Polypeptide derivatives containing 5-amino-2,5-disubstituted-4-hydroxypentanoic acid residues are of the formula:wherein, for example in a preferred embodiment R is t-butyloxycarbonyl, m and n are each 0 or 1, their sum being at least 1; R is cyclohexylmethyl; R<sup>2</sup> is 2-methylpropyl, 2-methyl-2--propenyl, benzyl, 4-chlorobenzyl, 3-chlorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 2-chlorobenzyl or cyclohexylmethyl; R<sup>3</sup> is hydrogen; R<sup>4</sup> is hydrogen, methyl, 4-aminobutyl, 2-carboxyethyl, 3-(ethoxycarbonyl)propyl or 3-(benzyloxycarbonyl)propyl; W is phenylalanyl, W<sup>1</sup> is histidyl and W<sup>2</sup> is lysyl.These compounds are useful for inhibiting the angiotensinogen cleaving action of the enzyme renin having particular utility in the treatment of hypertension.
Inventors
- 👤 Jasjit Singh Bindra
- 👤 Robert Louis Rosati
- 👤 Edward Fox Kleinman
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-11-09 10:12
CPC Classifications
C; C07; C07K; C07K7/00; C07K7/04; C07K7/14; C07D; C07D307/00; C07D307/02; C07D307/26; C07D307/30; C07D307/32; C07D307/33; A; A61; A61P; A61P43/00; A61P9/00; A61P9/12; C07C; C07C271/00; C07C271/06; C07C271/08; C07C271/10; C07C271/22; C07D207/00; C07D207/02; C07D207/04; C07D207/10; C07D207/16; C07D217/00; C07D217/02; C07D217/06; C07D405/00; C07D405/02; C07D405/12; C07K5/00; C07K5/02; C07K5/0227; Y; Y10; Y10S; Y10S530/00; Y10S530/86
Claims Analysis
Total Claims: 21
Claim 1
Independent Claim
379 words
A polypeptide derivative of the formula or a pharmaceutically acceptable salt thereof, wherein n and m are each 1 or 0, the sum of n and m being at least 1; W is where R is phenyl, 1-naphthyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-imidazolyl, propyl or isopropyl; W 1 is W 2 is where R 6 is -NH 2 , or -CH 2 NH 2 ; when n is 1, R is hydrogen, an amino-protecting acyl moiety having a molecular weight of less than 500, prolyl, pyroglutamyl, or prolyl or pyroglutamyl protected on nitrogen with said amino-protecting acyl moiety; and when n is O, R is phenoxyacetyl or 2-benzyl-3-phenylpropionyl; R 1 and R 2 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 7 -C 9 )phenylalkyl, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )(cycloalkyl)-alkyl, (C 5 -C 10 )(cycloalkenyl) alkyl, or one of said groups mono- or disubstituted on an aromatic ring by the same or different substituents which are (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro; and (a) R 3 and R 4 are taken separately, and are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 7 -Cg) p hen y l alkyl, (C 11 -C 13 )-naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl or adamantyl; or R 3 is hydrogen and R 4 is p and q are each independently zero or an integer from 1 to 6; r is zero or 1; Q is -CH 2 -, -CH=CH-, -O-, -NH-, -CHOH- or -CO-; Y is methyl, phenyl, -COOR , -CONR 9 R 10 , -CONHCOOCH 2 C 6 H 5 , NH 2 , -NHCOCH 2 C 6 H 5 , and R 7 , R 8 , R 9 and R 10 are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, (C 4 -C 7 )cycloalkyl, (C 7 -C 9 )-phenylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or adamantyl; or ( b ) R 3 and R 4 are taken together with the nitrogen to which they are attached to form a pyrrole, indoline, isoindoline, piperidine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, perhydro- azepine, or morpholine ring system.
Claim 2
Dependent Claim
379 words
A polypeptide derivative of the formula or a pharmaceutically acceptable salt thereof, wherein n and m are each 1 or 0, the sum of n and m being at least 1; W is where R is phenyl, 1-naphthyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-imidazolyl, propyl or isopropyl; W 1 is W 2 is where R 6 is -NH 2 , or -CH 2 NH 2 ; when n is 1, R is hydrogen, an amino-protecting acyl moiety having a molecular weight of less than 500, prolyl, pyroglutamyl, or prolyl or pyroglutamyl protected on nitrogen with said amino-protecting acyl moiety; and when n is O, R is phenoxyacetyl or 2-benzyl-3-phenylpropionyl; R 1 and R 2 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 7 -C 9 )phenylalkyl, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )(cycloalkyl)-alkyl, (C 5 -C 10 )(cycloalkenyl) alkyl, or one of said groups mono- or disubstituted on an aromatic ring by the same or different substituents which are (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro; and (a) R 3 and R 4 are taken separately, and are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 7 -Cg) p hen y l alkyl, (C 11 -C 13 )-naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl or adamantyl; or R 3 is hydrogen and R 4 is p and q are each independently zero or an integer from 1 to 6; r is zero or 1; Q is -CH 2 -, -CH=CH-, -O-, -NH-, -CHOH- or -CO-; Y is methyl, phenyl, -COOR , -CONR 9 R 10 , -CONHCOOCH 2 C 6 H 5 , NH 2 , -NHCOCH 2 C 6 H 5 , and R 7 , R 8 , R 9 and R 10 are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, (C 4 -C 7 )cycloalkyl, (C 7 -C 9 )-phenylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or adamantyl; or ( b ) R 3 and R 4 are taken together with the nitrogen to which they are attached to form a pyrrole, indoline, isoindoline, piperidine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, perhydro- azepine, or morpholine ring system.
Claim 3
Dependent Claim
13 words
A compound of claim 1 wherein n is 1 and R is t-butoxycarbonyl.
Claim 4
Dependent Claim
24 words
A compound of claim 2 wherein R is cyclohexylmethyl and R 2 is 2-methylpropyl, 2-methyl-2-propenyl, benzyl, 4-chlorobenzyl, 3-chlorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 2-chlorobenzyl, or cyclohexylmethyl.
Claim 5
Dependent Claim
17 words
A compound of claim 3 wherein m is 0, W is phenylalanyl, and W 1 is histidyl.
Claim 6
Dependent Claim
27 words
A compound of claim 4 wherein R 2 is 2-methylpropyl or 2-methyl-2-propenyl, R 3 is hydrogen, and R 4 is hydrogen, methyl, 4-aminobutyl, 2-carboxyethyl, 3-(ethoxycarbonyl)propyl or 3-(benzyloxycarbonyl)-propyl.
Claim 7
Dependent Claim
26 words
A compound of claim 4 wherein R 2 is benzyl, 4-chlorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 3-chlorobenzyl or 2-chlorobenzyl, R 3 is hydrogen and R 4 is methyl.
Claim 8
Dependent Claim
18 words
The compound of claim 4 wherein R 2 is cyclohexylmethyl, R 3 is hydrogen and R is methyl.
Claim 9
Dependent Claim
29 words
A compound of claim 2 wherein m is 1, W is phenylalanyl, W 1 is histidyl, W 2 is lysyl, R 1 is cyclohexylmethyl and R 2 is 2-methylpropyl.
Claim 10
Dependent Claim
28 words
A compound of claim 1 wherein n is 0, m is 1, W is histidyl, W 2 is lysyl, R 1 is cyclohexylmethyl and R 2 is 2-methylpropyl.
Claim 11
Dependent Claim
328 words
A compound of the formula wherein R1 and R 2 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 7 -C 9 )-phenylalkyl, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )-(cycloalkyl)alkyl, (C 5 -C 10 )(cycloalkenyl)alkyl, or one of said groups mono- or disubstituted on an aromatic ring by the same or different substituents which are (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro; W 3 is where R 14 is -NHCO 2 CH 2 C 6 H 5 , -NHCNHCO 2 CH 2 C 6 H 5 or -CH 2 NHCO 2 CH 2 C 6 H 5 ; NH R 11 is hydrogen or t-butoxycarbonyl, and (a) R 12 and R 13 are taken separately and are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, naphthyl, ( C4 - C7 )cycloalkyl, (C 7 -C 9 )phenylalkyl, (C 11 -C 13 )-naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl or adamantyl, or R 12 is hydrogen and R 13 is p and q are each independently zero or an integer from 1 to 6; r is zero or 1; Q is -CH 2 -, -CH=CH-, -O-, -NH-, -CHOH- or -CO-; Y 1 is methyl, phenyl, -COOR 18 , -CONR 9 R 10 , -CONHCOOCH 2 C 6 H 5 , -NHCOCH 2 C 6 H 5 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, (C 4 -C 7 )cycloalkyl, (C 7 -C 9 )phenylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or adamantyl; and R 18 is independently a value of R 7 other than hydrogen; or ( b ) R 12 and R 13 are taken together with the nitrogen to which they are attached to form a pyrrole, indoline, isoindoline, piperidine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, perhydro- azepin, or morpholine ring system.
Claim 12
Dependent Claim
328 words
A compound of the formula wherein R1 and R 2 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 7 -C 9 )-phenylalkyl, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )-(cycloalkyl)alkyl, (C 5 -C 10 )(cycloalkenyl)alkyl, or one of said groups mono- or disubstituted on an aromatic ring by the same or different substituents which are (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro; W 3 is where R 14 is -NHCO 2 CH 2 C 6 H 5 , -NHCNHCO 2 CH 2 C 6 H 5 or -CH 2 NHCO 2 CH 2 C 6 H 5 ; NH R 11 is hydrogen or t-butoxycarbonyl, and (a) R 12 and R 13 are taken separately and are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, naphthyl, ( C4 - C7 )cycloalkyl, (C 7 -C 9 )phenylalkyl, (C 11 -C 13 )-naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl or adamantyl, or R 12 is hydrogen and R 13 is p and q are each independently zero or an integer from 1 to 6; r is zero or 1; Q is -CH 2 -, -CH=CH-, -O-, -NH-, -CHOH- or -CO-; Y 1 is methyl, phenyl, -COOR 18 , -CONR 9 R 10 , -CONHCOOCH 2 C 6 H 5 , -NHCOCH 2 C 6 H 5 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, (C 1 -C 6 )alkyl, phenyl, (C 4 -C 7 )cycloalkyl, (C 7 -C 9 )phenylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or adamantyl; and R 18 is independently a value of R 7 other than hydrogen; or ( b ) R 12 and R 13 are taken together with the nitrogen to which they are attached to form a pyrrole, indoline, isoindoline, piperidine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, perhydro- azepin, or morpholine ring system.
Claim 13
Dependent Claim
5 words
A compound of the formula
Claim 14
Dependent Claim
5 words
A compound of the formula
Claim 15
Dependent Claim
116 words
A stereoselective process which comprises reacting an aldehyde of the formula wherein R 16 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 7 -C 9 )phenylalkyl, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or one of said groups mono-or disubstituted on the aromatic ring with the same or different groups selected from (C I -C 3 )alk y l, (C 1 -C 3 )alkoxy, fluoro or chloro, with LiC=CCOOR 15 , wherein R 15 is (C 1 -C 3 )alkyl, in a reaction inert solvent at -50° to -80°C. to predominantly form a compound of the formula
Claim 16
Dependent Claim
116 words
A stereoselective process which comprises reacting an aldehyde of the formula wherein R 16 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 7 -C 9 )phenylalkyl, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or one of said groups mono-or disubstituted on the aromatic ring with the same or different groups selected from (C I -C 3 )alk y l, (C 1 -C 3 )alkoxy, fluoro or chloro, with LiC=CCOOR 15 , wherein R 15 is (C 1 -C 3 )alkyl, in a reaction inert solvent at -50° to -80°C. to predominantly form a compound of the formula
Claim 17
Dependent Claim
44 words
A process of claim 12 which further comprises the steps of: (a) hydrogenation of the compound of the formula (C) to form a compound of the formula and (b) cyclization of the compound of the formula (D) to form a compound of the formula
Claim 18
Dependent Claim
93 words
A compound of the formula or wherein R 15 is (C 1 -C 3 )alkyl; and R 16 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 7 -Cg) p hen y lalk y l, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or one of said groups mono or disubstituted on the aromatic ring with the same or different groups selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro.
Claim 19
Dependent Claim
93 words
A compound of the formula or wherein R 15 is (C 1 -C 3 )alkyl; and R 16 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C 4 -C 7 )cycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 7 -Cg) p hen y lalk y l, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or one of said groups mono or disubstituted on the aromatic ring with the same or different groups selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro.
Claim 20
Dependent Claim
170 words
A stereoselective process for the preparation of a compound of the formula wherein R 16 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C4-C7)cycloalkyl, (C4-C7)cycloalkenyl, (C 7 -C 9 ) p hen y lalk y l, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or one or said groups mono or disubstituted on an aromatic ring with the same or different substituents which are (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro; and R 17 is (C 1 -C 6 )(2-alkenyl), (C4-C7)(cyclo-2-alkenyl), benzyl; or naphthylmethyl or one of said groups mono- or disubstituted on an aromatic with the same or different substituents which are (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro; which comprises reacting a lactone of the formula with substantially one molar equivalent of an organic halide of the formula wherein X is chloro, bromo or iodo; in the presence of a substantial excess of a strong base of low nucleophilicity.
Claim 21
Dependent Claim
170 words
A stereoselective process for the preparation of a compound of the formula wherein R 16 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkenyl, phenyl, naphthyl, (C4-C7)cycloalkyl, (C4-C7)cycloalkenyl, (C 7 -C 9 ) p hen y lalk y l, (C 11 -C 13 )naphthylalkyl, (C 5 -C 10 )(cycloalkyl)alkyl, or one or said groups mono or disubstituted on an aromatic ring with the same or different substituents which are (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro; and R 17 is (C 1 -C 6 )(2-alkenyl), (C4-C7)(cyclo-2-alkenyl), benzyl; or naphthylmethyl or one of said groups mono- or disubstituted on an aromatic with the same or different substituents which are (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, fluoro or chloro; which comprises reacting a lactone of the formula with substantially one molar equivalent of an organic halide of the formula wherein X is chloro, bromo or iodo; in the presence of a substantial excess of a strong base of low nucleophilicity.
References Cited (Backward Citations)
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