US 5,138,069 AGranted

Angiotensin II receptor blocking imidazoles

AssigneeE. I. Du Pont de Nemours and Company

InventorsDavid J. Carini, John J. V. Duncia, Pancras C. B. Wong

Life of this patent

Estimating the term…

Abstract

Substituted imidazoles such as ##STR1## are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure.

Claims39

Dependent claims

An antihypertensive compound of the formula:

##STR487## wherein R.sup.1 is ##STR488## R.sup.2 is H;
Cl;
Br;
I;
F;
NO.sub.2 ;
CN;
alkyl of 1 to 4 carbon atoms;
acyloxy of 1 to 4 carbon atoms;
alkoxy of 1 to 4 carbon atoms;
CO.sub.2 H;
CO.sub.2 R.sup.9 ;
NHSO.sub.2 CH.sub.3 ;
NHSO.sub.2 CF.sub.3 ;
##STR489## R.sup.3 is H;
Cl, Br, I or F;
alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
R.sup.4 is CN, NO.sub.2 or CO.sub.2 R.sup.11 ;
R.sup.5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms alkenyl or alkynyl of 2 to 4 carbon atoms;
R.sup.6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO.sub.2 R.sup.14 ;
cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms;
cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms;
(CH.sub.2).sub.s Z(CH.sub.2).sub.m R.sup.5 optionally substituted with F or CO.sub.2 R.sup.14 ;
benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;
R.sup.7 is H, F, Cl, Br, I, NO.sub.2, C.sub.v F.sub.2v+1, where v=1-6, C.sub.6 F.sub.5 ;
CN;
##STR490## straight or branched alkyl of 1 to 6 carbon atoms;
phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms;
or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH.sub.3, CF.sub.3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl;
R.sup.8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F;
phenylalkenyl wherein the alkenyl portion is 2 to 6 carbon atoms;
--(CH.sub.2).sub.m -imidazol-1-yl;
--(CH.sub.2).sub.m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO.sub.2 CH.sub.3 or alkyl of 1 to 4 carbon atoms;
--(CH.sub.2).sub.s -tetrasolyl;
##STR491## R.sup.9 is ##STR492## R.sup.10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH.sub.2).sub.p C.sub.6 H.sub.5 ;
R.sup.11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R.sup.12 is H, methyl or benzyl;
R.sup.13 is --CO.sub.2 H;
--CO.sub.2 R.sup.9 ;
--CH.sub.2 CO.sub.2 H, --CH.sub.2 CO.sub.2 R.sup.9 ;
##STR493## R.sup.14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R.sup.15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl;
R.sup.16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.p C.sub.6 H.sub.5, OR.sup.17, or NR.sup.18 R.sup.19 ;
R.sup.17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R.sup.18 and R.sup.19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, .alpha.-methylbenzyl, or taken together with the nitrogen form a ring of the formula ##STR494## Q is NR.sup.20, O or CH.sub.2 ;
R.sup.20 is H, alkyl of 1-4 carbon atoms, or phenyl;
R.sup.21 is alkyl of 1 to 6 carbon atoms, --NR.sup.22 R.sup.23, ##STR495## R.sup.22 and R.sup.23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH.sub.2).sub.u where u is 3-6;
R.sup.24 is H, CH.sub.3 or --C.sub.6 H.sub.5 ;
R.sup.25 is NR.sup.27 R.sup.28, OR.sup.28, NHCONH.sub.2, NHCSNH.sub.2, ##STR496## R.sup.26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;
R.sup.27 and R.sup.28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
R.sup.29 and R.sup.30 are independently alkyl of 1-4 carbon atoms or taken together are --(CH.sub.2).sub.q --;
R.sup.31 is H, alkyl of 1 to 4 carbon atoms, --CH.sub.2 CH.dbd.CH.sub.2 or --CH.sub.2 C.sub.6 H.sub.4 R.sup.32 ;
R.sup.32 is H, NO.sub.2, NH.sub.2, OH or OCH.sub.3 ;
X is a carbon--carbon single bond, --CO--, --CH.sub.2 --, --O--, --S--, ##STR497## Y is O or S;
Z is O, NR.sup.11, or S;
m is 1 to 5;
n is 1 to 10;
p is 0 to 3;
q is 2 to 3;
r is 0 to 2;
s is 0 to 5;
t is 0 or 1;
and pharmaceutically acceptable salts of these compounds;
provided that:
(1) the R.sup.1 group is not in the ortho position;
(2) when R.sup.1 is ##STR498## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR499## then R.sup.13 must be in the ortho or meta position;
or when R.sup.1 and X are as above and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, R.sup.13 must be ortho;
(3) when R.sup.1 is ##STR500## and X is other than a single bond, then R.sup.13 must be ortho except when X=NR.sup.23 CO and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, then R.sup.13 must be ortho or meta;
(4) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, R.sup.6 cannot be S-alkyl;
(5) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH.sub.2 OH, CH.sub.2 OCOCH.sub.3, or CH.sub.2 CO.sub.2 H;
(6) when R.sup.1 is ##STR501## X is --OCH.sub.2 --, and R.sup.13 is 2--CO.sub.2 H, and R.sup.7 is H then R.sup.6 is not C.sub.2 H.sub.5 S;
(7) when R.sup.1 is ##STR502## and R.sup.6 is n-hexyl then R.sup.7 and R.sup.8 are not both hydrogen;
(8) when R.sup.1 is ##STR503## R.sup.6 is not methoxybenzyl;
(9) the R.sup.6 group is not ##STR504## (10) when r=0, R.sup.1 is ##STR505## X is ##STR506## R.sup.13 is 2-NHSO.sub.2 CF.sub.3, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ;
(11) when r=0, R.sup.1 is ##STR507## X is ##STR508## R.sup.13 is 2--COOH, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ;
(12) when r=1, R.sup.1 = ##STR509## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 3-(tetrasol-5-yl);
(13) when r=1, R.sup.1 = ##STR510## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 4-(tetrasol-5-yl);
(14) when r=0, then R.sup.1 is not 4-NHSO.sub.2 CH.sub.3 or 4-NHSO.sub.2 CF.sub.3.

75 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/279,194Filed 6 Dec 1988 · continuation in part
Priority: 11 Jul 1986
Granted: 11 Aug 1992
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 233/56
Having two double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms or radicals containing only…
C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
C07D 233/64
Having two double bonds between ring members or between ring members and non-ring members: with substituted hydrocarbon radicals attached to ring…
C07D 233/68
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…

Family

Serial884,920Parent of this continuation-in-part · filed 11 Jul 1986
Serial50,341Parent of this continuation-in-part · filed 22 May 1987
Serial142,580Parent of this continuation-in-part · filed 7 Jan 1988
US 5,138,069 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Substituted imidazoles such as ##STR1## are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure.

An antihypertensive compound of the formula:

##STR487## wherein R.sup.1 is ##STR488## R.sup.2 is H;
Cl;
Br;
I;
F;
NO.sub.2 ;
CN;
alkyl of 1 to 4 carbon atoms;
acyloxy of 1 to 4 carbon atoms;
alkoxy of 1 to 4 carbon atoms;
CO.sub.2 H;
CO.sub.2 R.sup.9 ;
NHSO.sub.2 CH.sub.3 ;
NHSO.sub.2 CF.sub.3 ;
##STR489## R.sup.3 is H;
Cl, Br, I or F;
alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
R.sup.4 is CN, NO.sub.2 or CO.sub.2 R.sup.11 ;
R.sup.5 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms alkenyl or alkynyl of 2 to 4 carbon atoms;
R.sup.6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms or the same groups substituted with F or CO.sub.2 R.sup.14 ;
cycloalkyl of 3 to 8 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms;
cycloalkylalkenyl or cycloalkylalkynyl of 5 to 10 carbon atoms;
(CH.sub.2).sub.s Z(CH.sub.2).sub.m R.sup.5 optionally substituted with F or CO.sub.2 R.sup.14 ;
benzyl or benzyl substituted on the phenyl ring with 1 or 2 halogens, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or nitro;
R.sup.7 is H, F, Cl, Br, I, NO.sub.2, C.sub.v F.sub.2v+1, where v=1-6, C.sub.6 F.sub.5 ;
CN;
##STR490## straight or branched alkyl of 1 to 6 carbon atoms;
phenyl or phenylalkyl, where alkyl is 1 to 3 carbon atoms;
or substituted phenyl or substituted phenylalkyl, where alkyl is 1 to 3 carbon atoms, substituted with one or two substituents selected from alkyl of 1 to 4 carbon atoms, F, Cl, Br, OH, OCH.sub.3, CF.sub.3, and COOR, where R is H, alkyl of 1 to 4 carbon atoms, or phenyl;
R.sup.8 is H, CN, alkyl of 1 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, or the same groups substituted with F;
phenylalkenyl wherein the alkenyl portion is 2 to 6 carbon atoms;
--(CH.sub.2).sub.m -imidazol-1-yl;
--(CH.sub.2).sub.m -1,2,3-triazolyl optionally substituted with one or two groups selected from CO.sub.2 CH.sub.3 or alkyl of 1 to 4 carbon atoms;
--(CH.sub.2).sub.s -tetrasolyl;
##STR491## R.sup.9 is ##STR492## R.sup.10 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, 1-adamantyl, 1-naphthyl, 1-(1-naphthyl)ethyl, or (CH.sub.2).sub.p C.sub.6 H.sub.5 ;
R.sup.11 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R.sup.12 is H, methyl or benzyl;
R.sup.13 is --CO.sub.2 H;
--CO.sub.2 R.sup.9 ;
--CH.sub.2 CO.sub.2 H, --CH.sub.2 CO.sub.2 R.sup.9 ;
##STR493## R.sup.14 is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R.sup.15 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl;
R.sup.16 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.p C.sub.6 H.sub.5, OR.sup.17, or NR.sup.18 R.sup.19 ;
R.sup.17 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;
R.sup.18 and R.sup.19 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, .alpha.-methylbenzyl, or taken together with the nitrogen form a ring of the formula ##STR494## Q is NR.sup.20, O or CH.sub.2 ;
R.sup.20 is H, alkyl of 1-4 carbon atoms, or phenyl;
R.sup.21 is alkyl of 1 to 6 carbon atoms, --NR.sup.22 R.sup.23, ##STR495## R.sup.22 and R.sup.23 independently are H, alkyl of 1 to 6 carbon atoms, benzyl, or are taken together as (CH.sub.2).sub.u where u is 3-6;
R.sup.24 is H, CH.sub.3 or --C.sub.6 H.sub.5 ;
R.sup.25 is NR.sup.27 R.sup.28, OR.sup.28, NHCONH.sub.2, NHCSNH.sub.2, ##STR496## R.sup.26 is hydrogen, alkyl with from 1 to 6 carbon atoms, benzyl, or allyl;
R.sup.27 and R.sup.28 are independently hydrogen, alkyl with from 1 to 5 carbon atoms, or phenyl;
R.sup.29 and R.sup.30 are independently alkyl of 1-4 carbon atoms or taken together are --(CH.sub.2).sub.q --;
R.sup.31 is H, alkyl of 1 to 4 carbon atoms, --CH.sub.2 CH.dbd.CH.sub.2 or --CH.sub.2 C.sub.6 H.sub.4 R.sup.32 ;
R.sup.32 is H, NO.sub.2, NH.sub.2, OH or OCH.sub.3 ;
X is a carbon--carbon single bond, --CO--, --CH.sub.2 --, --O--, --S--, ##STR497## Y is O or S;
Z is O, NR.sup.11, or S;
m is 1 to 5;
n is 1 to 10;
p is 0 to 3;
q is 2 to 3;
r is 0 to 2;
s is 0 to 5;
t is 0 or 1;
and pharmaceutically acceptable salts of these compounds;
provided that:
(1) the R.sup.1 group is not in the ortho position;
(2) when R.sup.1 is ##STR498## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR499## then R.sup.13 must be in the ortho or meta position;
or when R.sup.1 and X are as above and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, R.sup.13 must be ortho;
(3) when R.sup.1 is ##STR500## and X is other than a single bond, then R.sup.13 must be ortho except when X=NR.sup.23 CO and R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, then R.sup.13 must be ortho or meta;
(4) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, R.sup.6 cannot be S-alkyl;
(5) when R.sup.1 is 4--CO.sub.2 H or a salt thereof, the substituent on the 4-position of the imidazole cannot be CH.sub.2 OH, CH.sub.2 OCOCH.sub.3, or CH.sub.2 CO.sub.2 H;
(6) when R.sup.1 is ##STR501## X is --OCH.sub.2 --, and R.sup.13 is 2--CO.sub.2 H, and R.sup.7 is H then R.sup.6 is not C.sub.2 H.sub.5 S;
(7) when R.sup.1 is ##STR502## and R.sup.6 is n-hexyl then R.sup.7 and R.sup.8 are not both hydrogen;
(8) when R.sup.1 is ##STR503## R.sup.6 is not methoxybenzyl;
(9) the R.sup.6 group is not ##STR504## (10) when r=0, R.sup.1 is ##STR505## X is ##STR506## R.sup.13 is 2-NHSO.sub.2 CF.sub.3, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ;
(11) when r=0, R.sup.1 is ##STR507## X is ##STR508## R.sup.13 is 2--COOH, and R.sup.6 is n-propyl, then R.sup.7 and R.sup.8 are not --CO.sub.2 CH.sub.3 ;
(12) when r=1, R.sup.1 = ##STR509## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 3-(tetrasol-5-yl);
(13) when r=1, R.sup.1 = ##STR510## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 4-(tetrasol-5-yl);
(14) when r=0, then R.sup.1 is not 4-NHSO.sub.2 CH.sub.3 or 4-NHSO.sub.2 CF.sub.3.

75 more elements

Facts

Application

07/279,194Filed 6 Dec 1988 · continuation in part

Priority

11 Jul 1986

Granted

11 Aug 1992

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 233/56
Having two double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms or radicals containing only…
C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
C07D 233/64
Having two double bonds between ring members or between ring members and non-ring members: with substituted hydrocarbon radicals attached to ring…
C07D 233/68
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…