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Details for Patent: 5,128,355

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Details for Patent: 5,128,355

Title: Treatment of congestive heart failure with angiotensin 11 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 J. V. (Newark, DE)
Assignee: E. I. Du Pont de Nemours and Company (Wilmington, DE)
Filing Date:Nov 13, 1989
Application Number:07/435,869
Claims:1. A method of treating congestive heart failure in a warm-blooded animal comprising administering to the animal, in an amount effective to correct the hemodynamic burden on the heart and relieve the congestion, an imidazole compound of the formula: ##STR495## wherein: R.sup.1 is ##STR496## 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, aryl, furyl or ##STR497## R.sup.3 is H, Cl, Br, I, 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 60 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.5 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 to 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, ##STR498## 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; ##STR499## R.sup.9 is ##STR500## 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 ##STR501## 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, or 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 H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl, .alpha.-methylbenzyl, or taken together with the nitrogen form a ring of the formula: ##STR502## Q is NR.sup.20, O or CH.sub.2 ; R.sup.20 is H, alkyl of 1 to 4 carbon atoms or phenyl;

R.sup.21 is alkyl or 1 to 6 carbon atoms, --NR.sup.22 R.sup.23, or ##STR503## 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, ##STR504## R.sup.26 is H, alkyl with from 1 to 6 carbon atoms, benzyl or allyl; R.sup.27 and R.sup.28 are independently H, alkyl with from 1 to 5 carbon atoms or phenyl;

R.sup.29 and R.sup.30 are independently alkyl of 1 to 4 carbon atoms, or taken together are --(CH.sub.2).sub.q --;

R.sup.- 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--, ##STR505## 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 to 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 ##STR506## X is a single bond, and R.sup.13 is CO.sub.2 H or ##STR507## 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 ##STR508## 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 ##STR509## 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 ##STR510## 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 ##STR511## R.sup.6 is not methoxybenzyl; (9) the R.sup.6 group is not ##STR512## or CH.sub.2 OH; (10) when r=0, R.sup.1 is ##STR513## X is ##STR514## 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 ##STR515## X is ##STR516## 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 is ##STR517## 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 is ##STR518## 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);

(14) when r=0, then R.sup.1 is not 4-NHSO.sub.2 CH.sub.3 or 4-NHSO.sub.4 CF.sub.3.

2. Method of claim 1 wherein the imidazole compound is a compound having the formula: ##STR519## wherein R.sup.1 is --CO.sub.2 H; --NHSO.sub.2 CF.sub.3 ; ##STR520## R.sup.6 is alkyl of 3 to 10 carbon atoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; benzyl or benzyl substituted on the phenyl ring with 1 or 2 groups selected from alkoxy of 1 to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, and nitro;

R.sup.8 is phenylalkenyl wherein the aliphatic portion is 2 to 4 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.m -tetrazolyl; ##STR521## R.sup.13 is --CO.sub.2 H, --CO.sub.2 R.sup.9, NHSO.sub.2 CF.sub.3, SO.sub.3 H or ##STR522## R.sup.16 is H, alkyl of 1 to 5 carbon atoms, OR.sup.17 or NR.sup.18 R.sup.19 ;

X is a carbon-carbon single bond, --CO--, --CONR.sup.23 --, --CH.sub.2 CH.sub.2 --, --NR.sup.23 CO--, --OCH.sub.2 --, --CH.sub.2 O, --O--, --SCH.sub.2 --, --CH.sub.2 S--, --NHCH.sub.2 --, --CH.sub.2 NH-- or or a pharmaceutically suitable salt thereof.

3. Method of claim 2 wherein the imidazole compound is a compound 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 H, Cl, Br, I; C.sub.v F.sub.2v+1, where v=1-3; or --COR.sup.16 ;

R.sup.8 is ##STR523## 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, CO.sub.2 CH.sub.2 OCOC(CH.sub.3).sub.3 ; NHSO.sub.2 CF.sub.3 ; or ##STR524## R.sup.14 is H, 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 ##STR525## m is 1 to 5; X is a single bond, --O--, --CO--, --NHCO-- or --OCH2--;

or a pharmaceutically suitable salt thereof.

4. Method of claim 3 wherein the imidazole compound is a compound wherein

R.sup.1 is ##STR526## and X is a single bond; or a pharmaceutically suitable salt thereof.

5. Method of claim 4 wherein the imidazole compound is 2-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxy methyl)imidazole, or a pharmaceutically acceptable salt thereof.

6. Method of claim 4 wherein the imidazole compound is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymethyl)-imi dazole, or a pharmaceutically acceptable salt thereof.

7. Method of claim 4 wherein the imidazole compound is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-[(methoxycarbonyl)- aminomethyl]imidazole, or a pharmaceutically acceptable salt thereof.

8. Method of claim 4 wherein the imidazole compound is 2-Butyl-4-chloro-1[(2'-carboxybiphenyl-4-yl)methyl]-5-[(propoxycarbonyl)-a minomethyl]imidazole, or a pharmaceutically acceptable salt thereof.

9. Method of claim 4 wherein the imidazole compound is 2-Butyl-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxalde hyde, or a pharmaceutically acceptable salt thereof.

10. Method of claim 4 wherein the in imidazole compound is 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.

11. Method of claim 4 wherein the imidazole compound is 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-(hydroxymeth yl)imidazole, or a pharmaceutically acceptable salt thereof.

12. Method of claim 4 wherein the imidazole compound is 2-(1E-Butenyl)-4-chloro-1-[(2'-carboxybiphenyl-4-yl)methyl]imidazole-5-car boxaldehyde, or a pharmaceutically acceptable salt thereof.

13. Method of claim 4 wherein the imidazole compound is 2-propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydrox ymethyl)imidazole, or a pharmaceutically acceptable salt thereof.

14. Method of claim 4 wherein the imidazole compound is 2-propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole- 5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.

15. Method of claim 4 wherein the imidazole compound is 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)imidazole-5 -carboxaldehyde, or pharmaceutically acceptable salt thereof.

16. Method of claim 4 wherein the imidazole compound is 2-(1E-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]5-hydro xymethyl)imidazole, or a pharmaceutically acceptable salt thereof.

17. Method of claim 4 wherein the imidazole compound is 2(1E-butenyl)4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imida zole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.

18. Method of claim 4 wherein the imidazole compound is 2-butyl-4-chloro-1-[(2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5 -carboxylic acid, or a pharmaceutically acceptable salt thereof.

19. Method of claim 4 wherein the imidazole compound is 2-propyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole -5-carboxylic acid, or a pharmaceutically acceptable salt thereof.

20. Method of claim 4 wherein the imidazole compound is 2-propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)-methyl] imidazole-5-carboxylic acid, or a pharmaceutically acceptable salt thereof.

21. Method of claim 4 wherein the imidazole compound is 2-propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)-methyl- 5-(hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof.

22. Method of claim 4 wherein the imidazole compound is 2-butyl-4-trifluoromethyl-1[(2'-1H-tetrazol-5-yl)biphenyl-4-yl)-methyl]imi dazole-5-carboxylic acid, or a pharmaceutically acceptable salt thereof.

23. Method of claim 4 wherein the imidazole compound is 2-propyl-4-trifluoromethyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-imidazole-5 -carboxaldehyde, or a pharmaceutically acceptable salt thereof.

24. Method of claim 4 wherein the imidazole compound is 2-propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] -5-(hydroxymethyl)imidazole, or a pharmaceutically acceptable salt thereof.

25. Method of claim 4 wherein the imidazole compound is 2-Propyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-4,5-dicar boxylic acid, or a pharmaceutically acceptable salt thereof.

26. Method of claim 4 wherein the imidazole compound is 2-Propyl-4 -pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole- 5-carboxylic acid, or a pharmaceutically acceptable salt thereof.

27. Method of claim 4 wherein the imidazole compound is 2-Propyl-4-pentafluoroethyl-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]im idazole-5-carboxaldehyde, or a pharmaceutically acceptable salt thereof.
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