US 5,210,079 AGranted

Treatment of chronic renal failure with imidazole angiotensin-II receptor antagonists

AssigneeE. I. Du Pont de Nemours and Company

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

Life of this patent

Estimating the term…

Abstract

Substituted imidazoles such as 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxy methyl)imidazole and 2-butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)-methyl]-5-(hydroxymethyl)imi dazole and pharmaceutically acceptable salts thereof are useful for treating chronic renal failure, mediated by angiotensin-II.

Claims31

Dependent claims

A method of treating chronic renal failure mediated by AII in a mammal comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition having the formula (I):

##STR37## wherein R.sup.1 is 4--CO.sub.2 H;
4--CO.sub.2 R.sup.9 ;
##STR38## 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 ;
CONHOR.sup.12 ;
SO.sub.2 NH.sub.2 ;
##STR39## aryl;
or furyl;
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 2 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;
##STR40## 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, and 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 -tetrazolyl;
##STR41## R.sup.9 is ##STR42## 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 ;
##STR43## 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 ##STR44## 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, or ##STR45## 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, ##STR46## 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--, --NH--, ##STR47## --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28)--, --NR.sup.23 SO.sub.2 --, --SO.sub.2 NR.sup.23 --, --C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR48## 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 salt of these compounds;
provided that:
(1) the R.sup.1 group is not in the ortho position;
(2) when R.sup.1 is ##STR49## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR50## 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 ##STR51## 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 ##STR52## 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 ##STR53## 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 ##STR54## R.sup.6 is not methoxybenzyl;
(9) the R.sup.6 group is not --CHFCH.sub.2 CH.sub.2 CH.sub.3 or CH.sub.2 OH;
(10) when r=O, R.sup.1 is ##STR55## X is --NH--CO--, 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 ##STR56## X is --NH--CO--, 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 = ##STR57## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 3-(tetrazol-5-yl);
(13) when r=1, R.sup.1 = ##STR58## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 4-(tetrazol-5-yl).

82 more elements

##STR69## wherein R.sup.1 is 4--CO.sub.2 H;
4--CO.sub.2 R.sup.9 ;
##STR70## 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 ;
CONHOR.sup.12 ;
SO.sub.2 NH.sub.2 ;
##STR71## aryl;
or furyl;
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;
##STR72## 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 -tetrazolyl;
##STR73## R.sup.9 is ##STR74## 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 ;
##STR75## --PO.sub.3 H.sub.2 ;
--C(CF.sub.3).sub.2 OH;
--NHSO.sub.2 CH.sub.3 ;
--NHSO.sub.2 CF.sub.3 ;
--NHCOCF.sub.3 ;
--CONHOR.sup.12 ;
--SO.sub.2 NH.sub.2 ;
##STR76## 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 ##STR77## 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, or ##STR78## 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, ##STR79## 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--, --NH--, ##STR80## --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28)--, --NR.sup.23 SO.sub.2 --, --SO.sub.2 NR.sup.23 --, --C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR81## 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;
or a pharmaceutically acceptable salt thereof;
provided that:
(1) the R.sup.1 group is not in the ortho position;
(2) when R.sup.1 is ##STR82## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR83## 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 ##STR84## 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 ##STR85## 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 ##STR86## 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 ##STR87## R.sup.6 is not methoxybenzyl;
(9) the R.sup.6 group is not --CHFCH.sub.2 CH.sub.2 CH.sub.3 or CH.sub.2 OH;
(10) when r=O, R.sup.1 is ##STR88## X is --NH--CO--, 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 ##STR89## X is NH--CO--, 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 = ##STR90## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 3-(tetrazol-5-yl);
(13) when r=1, R.sup.1 = ##STR91## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 4-(tetrazol-5-yl).

90 more elements

##STR98## wherein R.sup.1 is 4--CO.sub.2 H;
4--CO.sub.2 R.sup.9 ;
##STR99## -- NHSO.sub.2 CH.sub.3 ;
--4--NHSO.sub.2 CF.sub.3 ;
--CONHOR.sup.12 ;
##STR100## 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 ;
CONHOR.sup.12 ;
SO.sub.2 NH.sub.2 ;
##STR101## aryl;
or furyl;
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;
##STR102## 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 ##STR103## R.sup.9 is ##STR104## 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 ;
##STR105## --PO.sub.3 H.sub.2 ;
--C(CF.sub.3).sub.2 OH;
--NHSO.sub.2 CH.sub.3 ;
--NHSO.sub.2 CF.sub.3 ;
--NHCOCF.sub.3 ;
--CONHOR.sup.12 ;
--SO.sub.2 NH.sub.2 ;
##STR106## 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 ##STR107## 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, or ##STR108## 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, ##STR109## 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.r 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--, --NH--, ##STR110## --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28)--, --NR.sup.23 SO.sub.2 --, --SO.sub.2 NR.sup.23 --, --C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR111## 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;
or a pharmaceutically acceptable salt thereof;
provided that:
(1) the R.sup.1 group is not in the ortho position;
(2) when R.sup.1 is ##STR112## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR113## 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 ##STR114## 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 ##STR115## R.sup.6 is not methoxybenzyl;
(7) the R.sup.6 group is not ##STR116## or CH.sub.2 OH.

81 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/832,638Filed 7 Feb 1992 · continuation
Priority: 7 Jan 1988
Granted: 11 May 1993
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

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…
A61K 31/415
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2-Diazoles
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 233/56
Having two double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms or radicals containing only…

Family

Serial142,580Parent of this continuation-in-part · filed 7 Jan 1988
Serial279,194Parent of this continuation-in-part · filed 6 Dec 1988
Serial373,755Parent of this continuation-in-part · filed 30 Jun 1989
Serial542,351Parent of this continuation · filed 22 Jun 1990
US 5,138,069 AParent of this continuation-in-part
US 5,210,079 AThis patent

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

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Abstract

##STR37## wherein R.sup.1 is 4--CO.sub.2 H;
4--CO.sub.2 R.sup.9 ;
##STR38## 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 ;
CONHOR.sup.12 ;
SO.sub.2 NH.sub.2 ;
##STR39## aryl;
or furyl;
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 2 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;
##STR40## 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, and 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 -tetrazolyl;
##STR41## R.sup.9 is ##STR42## 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 ;
##STR43## 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 ##STR44## 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, or ##STR45## 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, ##STR46## 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--, --NH--, ##STR47## --OCH.sub.2 --, --CH.sub.2 O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHC(R.sup.27)(R.sup.28)--, --NR.sup.23 SO.sub.2 --, --SO.sub.2 NR.sup.23 --, --C(R.sup.27)(R.sup.28)NH--, --CH.dbd.CH--, --CF.dbd.CF--, --CH.dbd.CF--, --CF.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CF.sub.2 CF.sub.2 --, ##STR48## 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 salt of these compounds;
provided that:
(1) the R.sup.1 group is not in the ortho position;
(2) when R.sup.1 is ##STR49## X is a single bond, and R.sup.13 is CO.sub.2 H, or ##STR50## 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 ##STR51## 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 ##STR52## 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 ##STR53## 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 ##STR54## R.sup.6 is not methoxybenzyl;
(9) the R.sup.6 group is not --CHFCH.sub.2 CH.sub.2 CH.sub.3 or CH.sub.2 OH;
(10) when r=O, R.sup.1 is ##STR55## X is --NH--CO--, 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 ##STR56## X is --NH--CO--, 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 = ##STR57## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 3-(tetrazol-5-yl);
(13) when r=1, R.sup.1 = ##STR58## X is a single bond, R.sup.7 is Cl, and R.sup.8 is --CHO, then R.sup.13 is not 4-(tetrazol-5-yl).

82 more elements

Facts

Application

07/832,638Filed 7 Feb 1992 · continuation

Priority

7 Jan 1988

Granted

11 May 1993

Term ends

Not estimatedThe source records don’t support an estimate.

Classification25 codes

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…
A61K 31/415
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2-Diazoles
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 233/56
Having two double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms or radicals containing only…

Family

Serial142,580Parent of this continuation-in-part · filed 7 Jan 1988

Serial279,194Parent of this continuation-in-part · filed 6 Dec 1988

Serial373,755Parent of this continuation-in-part · filed 30 Jun 1989

Serial542,351Parent of this continuation · filed 22 Jun 1990

US 5,138,069 AParent of this continuation-in-part

US 5,210,079 AThis patent

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