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Details for Patent: 5,354,867

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Details for Patent: 5,354,867

Title: Angiotensin II receptor blocking imidazoles
Abstract:Substituted imidazoles such as ##STR1## are useful as angiotensin II blockers. These compounds have activity in treating hypertension and congestive heart failure.
Inventor(s): Carini; David J. (Wilmington, DE), Duncia; John Jonas V. (Newark, DE), Wong; Pancras C. (Wilmington, DE)
Assignee: E. I. Du Pont de Nemours and Company (Wilmington, DE)
Filing Date:Apr 15, 1993
Application Number:08/047,883
Claims:1. An antihypertensive compound of the formula ##STR290## wherein R.sup.1 is ##STR291## 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 ; ##STR292## 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.6 is alkyl of 2 to 10 carbon atoms, alkenyl or alkynyl of 3 to 10 carbon atoms

R.sup.7 is vinyl; cycloalkylidenyl; alkynyl of 2-10 carbon atoms; phenylalkynyl where the alkynyl portion is 2-6 carbon atoms; heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl, 2-, 4- or 5-imidazolyl; o-, m- or p-biphenylyl; o-, m- or p-phenoxyphenyl; substituted phenylalkynyl where the alkynyl portion is 2-6 carbon atoms, heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl, 2-, 4- or 5-imidazolyl, o-, m- or p-biphenylyl or o-, m- or p-phenoxyphenyl substituted with 1or 2 substituents selected from halogen, hydroxy, mercapto, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, --NO.sub.2 --, --CN, --CF.sub.3, --COR.sup.16, --CH.sub.2 OR.sup.17, --NHCOR.sup.17, --CONR.sup.18 R.sup.19, S(O).sub.r R.sup.17, and SO.sub.2 NR.sup.18 R.sup.19 ; 2-, 4- or 5-imidazolyl substituted on ring nitrogen with alkyl of 1-5 carbon atoms, phenyl or benzyl; or substituted alkyl, alkenyl, or alkynyl of 1 to 10 carbon atoms substituted with an unsubstituted heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl, 2-, 4- or 5-imidazolyl, o-, m- or p-biphenylyl or o-, m- or p-phenoxyphenyl or a heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl, 2-, 4- or 5-imidazolyl, o-, m- or p-biphenylyl or o-, m- or p-phenoxylphenyl substituted with 1 or 2substituents selected from halogen, hydroxy, mercapto, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, --NO.sub.2, --CN, --CF.sub.3, --COR.sup.16, --CH.sub.2 OR.sup.17, --NHCOR.sup. 17, --CONR.sup.18 R.sup.19, S(O).sub.r R.sup.17, and SO.sub.2 NR.sup.18 R.sup.19 ; --S--(O).sub.r -heteroaryl, --S--(O).sub.r -biphenylyl, --S(O).sub.r -phenoxyphenyl, --S(O).sub.r R.sup.17, --NR.sup.18 R.sup.19, N-imidazolyl, where heteroaryl is a heterocycle defined in the scope of R.sup.7 and where the phenyl group in R.sup.17 of --S--(O).sub.r R.sup.17, the N-imidazolyl, is unsubstituted or substituted with one or two substituents selected from halogen, hydroxy, mercapto, alkoxy of 1-5 carbon atoms, alkyl of 1-5 carbon atoms, --NO.sub.2, --CN, --CF.sub.3, --COR.sup.16, --CH.sub.2 OR.sup.17, --NHCOR.sup.17, --CONR.sup.18 R.sup.19, S(O).sub.r R.sup.17, and SO.sub.2 NR.sup.18 R.sup.19 ;

R.sup.8 is ##STR293## R.sup.9 is ##STR294## 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; --NHSO.sub.2 CH.sub.3 ; --NHSO.sub.2 CF.sub.3 ; ##STR295## 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, a-methylbenzyl, or taken together with the nitrogen form a ring of the formula ##STR296## Q is NR.sup.20, 0 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 ##STR297## 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.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;

Y is 0 or S;

m is 1 to 5;

n is 1 to 10;

p is 0 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.13 is CO.sub.2 H, or ##STR298## then R.sup.13 must be in the ortho or meta position; or when R.sup.13 is NHSO.sub.2 CF.sub.3 or NHSO.sub.2 CH.sub.3, R.sup.13 must be ortho.

2. A compound of claim 1 having the formula: ##STR299## wherein R.sup.1 is ##STR300## R.sup.8 is --(CH.sub.2).sub.m -tetrazolyl, --(CH.sub.2).sub.n OR.sup.11 ; ##STR301## R.sup.16 is H, alkyl of 1 to 5 carbon atoms, OR.sup.17, or NR.sup.18 R.sup.19.

3. A compound of claim 2 wherein:

R.sup.2 is H, alkyl of 1 to 4 carbon atoms, halogen, or alkoxy of 1 to 4 carbon atoms;

R.sup.6 is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;

R.sup.7 is heteroaryl selected from 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl, or p-biphenylyl; ##STR302## R.sup.8 is --(CH.sub.2).sub.m OR.sup.11 ; ##STR303## --(CH.sub.2).sub.m NHSO.sub.2 R.sup.10 ; or --COR.sup.16 ; R.sup.10 is CF.sub.3, alkyl of 1 to 6 carbon atoms or phenyl;

R.sup.11 is H, or alkyl of 1 to 4 carbon atoms;

R.sup.13 is CO.sub.2 H; NHSO.sub.2 CF.sub.3 or ##STR304## R.sup.14 is H, or alkyl of 1 to 4 carbon atoms; R.sup.15 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;

R.sup.16 is H, alkyl of 1 to 5 carbon atoms; OR.sup.17 ; or ##STR305## m is 1 to 5; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 wherein R.sup.1 is ##STR306## and X is a single bond, or a pharmaceutically suitable salt thereof.

5. A pharmaceutical composition comprising a pharmaceutically suitable carrier and a compound of any one of claims 4 and 1-3.
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