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Details for Patent: 5,312,828

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Details for Patent: 5,312,828

Title: Substituted imidazoles having angiotensin II receptor blocking activity
Abstract:Angiotensin II receptor antagonists having the formula: ##STR1## which are useful in regulating hypertension and in the treatment of congestive heart failure, renal failure, and glaucoma, pharmaceutical compositions including these antagonists, and methods of using these compounds to produce angiotensin II receptor antagonism in mammals.
Inventor(s): Finkelstein; Joseph A. (N/A), N/A (King of Prussia, PA), Keenan; Richard M. (N/A), Weinstock; Joseph
Assignee:
Filing Date:Aug 14, 1991
Application Number:07/746,024
Claims:1. A compound of the formula. ##STR22## in which: R.sup.1 is adamantyl, phenyl, biphenyl, or naphthyl, with each aryl group being unsubstituted or substituted by one to three substituents selected, from Cl, Br, F, I, C.sub.1 -C.sub.6 alkyl, nitro, CO.sub.2 R.sup.7, tetrazol-5-yl, C.sub.1 -C.sub.6 alkoxy, hydroxy, SC.sub.1 -C.sub.6 alkyl, SO.sub.2 NHR.sup.7, NHSO.sub.2 R.sup.7, SO.sub.3 H, CONR.sup.7 R.sup.7, CN, SO.sub.2 C.sub.1 -C.sub.6 alkyl, NHSO.sub.2 R.sup.7, PO(OR.sup.7l ).sub.2, NR.sup.7 R.sup.7, NR.sup.7 COH, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, NR.sup.7 CON(R.sup.7).sub.2,

m is 0-4;

R.sup.2 is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 alkenyl, C.sub.3 -C.sub.10 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, or (CH.sub.2).sub.0-8 phenyl unsubstituted or substituted by one to three substituents selected from C.sub.1 -C.sub.6 alkyl, nitro, Cl, Br, F, I, hydroxy, C.sub.1 -C.sub.6 alkoxy, NR.sup.7 R.sup.7, CO.sub.2 R.sup.7, CN, CONR.sup.7 R.sup.7, tetrazol-5-yl, NR.sup.7 COC.sub.1 -C.sub.6 alkyl, SC.sub.1 -C.sub.6 alkyl, or SO.sub.2 C.sub.1 -C.sub.6 alkyl;

X is a single bond,

R.sup.3 is hydrogen, Cl, Br, F, I, CHO, hydroxymethyl, COOR.sup.7, CONR.sup.7 R.sup.7, NO.sub.2, CN, NR.sup.7 R.sup.7, or phenyl;

R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl-Y-, naphthyl-Y-, or biphenyl-Y-, wherein the aryl groups are unsubstituted or substituted by one to three substituents selected from Cl, Br, F, I, C.sub.1 -C.sub.6 alkoxy, hydroxy, CO.sub.2 R.sup.7, CN, NO.sub.2, tetrazol-5-yl, SO.sub.3 H, CF.sub.3, CONR.sup.7 R.sup.7, SO.sub.2 NHR.sup.7, C.sub.1 -C.sub.6 alkyl, or NR.sup.7 R.sup.7, or by methylenedioxy, phenoxy or phenyl, except that R.sup.4 and R.sup.5 are not both selected from hydrogen;

Y is a single bond, O, S, or C.sub.1 -C.sub.6 alkyl which is straight or branched or optionally substituted by phenyl or benzyl, wherein each of the aryl groups is unsubstituted or substituted by halo, NO.sub.2, CF.sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, CN, or CO.sub.2 R.sup.7 ;

R.sup.6 is --Z--COOR.sup.8 or --Z--CONR.sup.7 R.sup.7 ;

Z is a single bond, vinyl, --CH.sub.2 --O--CH.sub.2 --, methylene optionally substituted by C.sub.1 -C.sub.4 alkyl, one or two benzyl groups,

thienylmethyl, or furylmethyl, or --C(O)NHCHR.sup.9 --, wherein R.sup.9 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl, thienyl-methyl, or furylmethyl;

each R.sup.7 independently is hydrogen, C.sub.1 -C.sub.4 alkyl, or (CH.sub.2).sub.m phenyl, wherein m is 0-4; and

R.sup.8 is hydrogen, C.sub.1 --C.sub.6 alkyl, or 2-di(C.sub.1 -C.sub.4 alkyl)amino-2-oxoethyl; or

R.sup.5 and R.sup.6 are both hydrogen, R.sup.4 is --Z--COOR.sup.8 wherein R.sup.8 is as defined above and Z is other than a single bond; or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 in which one of R.sup.4 and R.sup.5 is hydrogen or C.sub.1 -C.sub.4 alkyl.

3. A compound of claim 2 in which R.sup.1 is phenyl unsubstituted or substituted by one to three substitutents selected from chloro, fluoro, trifluoromethyl, nitro, methyl, methoxy, hydroxy, sulfamyl, cyano, carboxy, carboC.sub.1 -C.sub.4 alkoxy, carbamoyl, or tetrazol-5-yl.

4. A compound of claim 3 in which R.sup.2 is C.sub.2 -C.sub.8 alkyl;

5. A compound of claim 4 in which R.sup.3 is hydrogen, chloro, fluoro, or trifluoromethyl and R.sup.4 is hydrogen or C.sub.1 -C.sub.4 alkyl.

6. A compound of claim 5 in which R.sup.6 is COOH and each R.sup.7 independently is H or CH.sub.3.

7. A compound of claim 6 in which R.sup.5 is C.sub.3 -C.sub.6 alkyl or benzyl unsubstituted or substituted by one to three substituents selected from Cl, Br, F, NO.sub.2, OCH.sub.3, OH, CF.sub.3, NR.sup.7 R.sup.7, CH.sub.3, or CO.sub.2 R.sup.7, or methylenedioxy.

8. A compound of claim 7 which is the E isomer, wherein the R.sup.6 group and the imidazole are trans to each other.

9. A compound of claim 8 which is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2- propenoic acid or a pharmaceutically acceptable salt thereof.

10. A compound of claim 8 which is (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3,4-dimet hoxyphenyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof.

11. A compound of claim 8 which is (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3,4-methy lenedioxyphenyl)methyl-2-propenoic acid or a pharmaceutically acceptable salt thereof.

12. A compound of claim 8 which is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-n-butyl-2 -propenoic acid or a pharmaceutically acceptable salt thereof.

13. A compound of claim 8 which is:

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-methoxyp henyl)methyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-pr openoic acid;

(E)-3-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl-2-ben zyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-4-chloro-1H-imidazol-5-yl]-2-be nzyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3,4-dihydr oxyphenyl)methyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-nitrophe nyl)methyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-N,N-dime thylaminophenyl)methyl-2-propenoic acid; or

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-aminophe nyl)methyl-2-propenoic acid; or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a pharmaceutical carrier and a compound of claim 1.

15. A pharmaceutical composition of claim 14 in which the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2- propenoic acid.

16. A pharmaceutical composition of claim 14 in which the compound is (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2-n-butyl-2 -propenoic acid.

17. A pharmaceutical composition of claim 14 in which the compound is (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3,4-dimet hoxyphenyl)methyl-2-propenoic acid.

18. A pharmaceutical composition of claim 14 in which the compound is (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3,4-methy lenedioxyphenyl)methyl-2-propenoic acid.

19. A pharmaceutical composition of claim 14 in which the compound is:

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-methoxyp henyl)methyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-pr openoic acid;

(E)-3-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl-2-ben zyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-4-chloro-1H-imidazol-5-yl]-2-be nzyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(3,4-dihydr oxyphenyl)methyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(2-nitrophe nyl)methyl-2-propenoic acid;

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-N,N-dime thylaminophenyl)methyl-2-propenoic acid; or

(E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-(4-aminophe nyl)methyl-2-propenoic acid.

20. A method of antagonizing angiotensin II which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

21. A method of treating hypertension which comprises administering to a subject in need thereof an effective amount of a compound of claim 1.

22. A method of treating congestive heart failure by administering to a subject in need thereof an effective amount of a compound of claim 1.

23. A method of treating renal failure by administering to a subject in need thereof an effective amount of a compound of claim 1.

24. A method of treating glaucoma by administering to a subject in need thereof an effective amount of a compound of claim 1.
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