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Details for Patent: 6,355,808

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Details for Patent: 6,355,808

Title: Benzimidazole compounds, their production and use
Abstract:Benzimidazole derivatives of the formula (I): ##STR1## wherein the ring A is a benzene ring which may optionally contain substitution in addition to the R' group; R.sup.1 is hydrogen or an optionally substituted hydrocarbon residue; R.sup.2 is a group capable of forming an anion or a group convertible thereinto; X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; R' is carboxyl, an ester thereof, an amide thereof or a group capable of forming an anion or convertible to an anion; Y is --O--, --S(O).sub.m -- or --N(R.sup.4)-- wherein m is an integer of 0, 1 or 2 and R.sup.4 is hydrogen or an optionally substituted alkyl group; and n is an integer of 1 or 2; and the pharmaceutically acceptable salts thereof, have potent angiotensin .PI. antagonistic activity and antihypertensive activity, thus being useful as therapeutic agents for treating circulatory system diseases such as hypertensive diseases, heart diseases (e.g. hypercardia, heart failure, cardiac infarction, etc.), strokes, cerebral apoplexy, nephritis, etc.
Inventor(s): Naka; Takehiko (Kobe, JP), Nishikawa; Kohei (Kyoto, JP), Kato; Takeshi (Higashiosaka, JP)
Assignee: Takeda Chemical Industries, Ltd. (Osaka, JP)
Filing Date:Mar 27, 2001
Application Number:09/817,231
Claims:1. A compound selected from the group consisting of: ##STR46##

wherein the ring A is a benzene ring which, in addition the R' group, is substituted or unsubstituted; R.sup.2 is

1) carboxyl;

2) tetrazolyl;

3) trifluoromethanesulfonic amide;

4) phosphono (PO(OH).sub.2);

5) sulfo (SO.sub.3 H);

6) cyano; or

7) C.sub.1-4 alkoxycarbonyl; each of which is unprotected or protected with a substituted or unsubstituted lower alkyl group or an acyl group;

X is a direct bond or a spacer having an atomic length of two or less between the phenylene group and the phenyl group; R' is carboxyl, an ester thereof, or an amide thereof; R.sup.3 is a C.sub.1-4 alkyl group;

n is an integer of 1 or 2; or a salt thereof.

2. A compound according to claim 1, wherein R.sup.2 is cyano group.

3. A compound according to claim 1, wherein R.sup.2 is a tetrazolyl group unprotected or protected with unsubstituted or substituted lower alkyl or acyl, a carboxyl group unprotected or protected with unsubstituted or substituted lower alkyl, or trifluoromethanesulfonic amide.

4. A compound according to claim 1, wherein R.sup.2 is a tetrazolyl group.

5. A compound according to claim 1, wherein R' is a group having the formula: --CO--D' wherein D' is hydroxyl or unsubstituted or substituted alkoxy.

6. A compound according to claim 5, wherein D' is hydroxyl, a lower (C.sub.1-6) alkoxy group unsubstituted or substituted with hydroxyl, unsubstituted or substituted amino, halogen, lower (C.sub.1-6) alkoxy, lower (C.sub.1-6) alkylthio or unsubstituted or substituted dioxolenyl on the alkyl moiety, or a group having the formula: --OCH(R.sup.7)OCOR.sup.8 wherein R.sup.7 is hydrogen, straight or branched lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 5 to 7 carbon atoms and R.sup.8 is straight or branched lower alkyl having 1 to 6 carbon atoms, straight or branched lower alkenyl having 2 to about 8 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, lower (C.sub.1-3) alkyl which is substituted with unsubstituted or substituted aryl or cycloalkyl having 5 to 7 carbon atoms, lower (C.sub.2-3) alkenyl which is substituted with unsubstituted or substituted aryl or cycloalkyl having 5 to 7 carbon atoms, unsubstituted or substituted aryl, straight or branched lower alkoxy having 1 to 6 carbon atoms, straight or branched lower alkenyloxy having 2 to about 8 carbon atoms, cycloalkyloxy having 5 to 7 carbon atoms, lower (C.sub.1-3) alkoxy which is substituted with unsubstituted or substituted aryl or cycloalkyl having 5 to 7 carbon atoms, lower (C.sub.2-3) alkenyloxy which is substituted with unsubstituted or substituted aryl or cycloalkyl having 5 to 7 carbon atoms, or unsubstituted or substituted aryloxy.

7. A compound according to claim 5, wherein D' is hydroxyl, a lower (C.sub.1-6) alkoxy group unsubstituted or substituted with hydroxyl, lower (C.sub.1-6) alkoxy or unsubstituted or substituted dioxolenyl on the alkyl moiety, a lower (C.sub.2-3) alkenyloxy unsubstituted or substituted with unsubstituted or substituted aryl on the alkenyl moiety, or a group having the formula: --OCH(R.sup.7)OCOR.sup.8 wherein R.sup.7 is hydrogen, or straight or branched lower alkyl having 1 to 6 carbon atoms and R.sup.8 is straight or branched lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, lower (C.sub.1-3) alkyl which is substituted with unsubstituted or substituted aryl or cycloalkyl having 5 to 7 carbon atoms, unsubstituted or substituted aryl, straight or branched lower alkoxy having 1 to 6 carbon atoms, cycloalkyloxy having 5 to 7 carbon atoms, lower (C.sub.1-3) alkoxy which is substituted with unsubstituted or substituted aryl or cycloalkyl having 5 to 7 carbon atoms, or unsubstituted or substituted aryloxy.

8. A compound according to claim 1, wherein R' is carboxyl or a salt or anion thereof.

9. A compound according to claim 1, wherein R' is a group having the formula: --CO--OCH(R.sup.7)OCOR.sup.8 wherein R.sup.7 is hydrogen or straight or branched lower alkyl having 1 to 6 carbon atoms and R.sup.8 is straight or branched lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, unsubstituted or substituted phenyl, straight or branched lower alkoxy having 1 to 6 carbon atoms or cycloalkyloxy having 5 to 7 carbon atoms.

10. A compound according to claim 1, wherein R' is a tetrazolyl group unprotected or protected with substituted or unsubstituted lower alkyl or acyl, trifluoromethanesulfonic amide, phosphono (PO(OH).sub.2) or sulfo (SO.sub.3 H).

11. A compound according to claim 1, wherein the ring A is a benzene ring which contains, in addition to the R' group, a substituent being selected from the group consisting of halogen nitro, cyano, unsubstituted or substituted amino, a group having the formula: --W--R.sup.13

wherein W is a chemical bond, --O--, --S--, or

and R.sup.13 is hydrogen or an unsubstituted or substituted lower alkyl group, a group having the formula: --(CH.sub.2).sub.p --CO--D wherein D is hydrogen, hydroxyl, unsubstituted or substituted amino, or unsubstituted or substituted alkoxy, and p is 0 or 1, tetrazolyl unprotected or protected with an unsubstituted or substituted lower alkyl group or an acyl group, trifluoromethanesulfonic amide, phosphono (PO(OH).sub.2), or sulfo (SO.sub.3 H).

12. A compound according to claim 1, wherein the ring A is a benzene ring which contains no substitution in addition to the R' group.

13. A compound according to claim 1, wherein X is a chemical bond, lower (C.sub.1-4) alkylene, ##STR47##

14. A compound according to claim 1, wherein X is a chemical bond between the phenylene group and the phenyl group.

15. A compound according to claim 1, wherein n is an integer of 1.

16. A compound according to claim 1, which is methyl 2-[[N-tert-butoxycarbonyl-N-(2'-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobe nzoate or a salt thereof.

17. A compound according to claim 1, which is methyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate or a salt thereof.

18. A compound according to claim 1, which is methyl 3-amino-2-[[(2'cyanobiphenyl-4-yl)methyl]amino]benzoate or a salt thereof.

19. A method for producing a compound of the formula: ##STR48##

wherein each symbol is as defined in claim 1 or a salt thereof, which comprises reacting a compound of the formula: ##STR49##

wherein each symbol is as defined in claim 1 or a salt thereof with a compound of the formula: ##STR50##

wherein Z is halogen and the other symbols are as defined in claim 1 or a salt thereof.

20. A method for producing a compound of the formula: ##STR51##

wherein each symbol is as defined in claim 1 or a salt thereof, which comprises heating a compound of the formula: ##STR52##

wherein each symbol is as defined in claim 1 or a salt thereof in the presence of a mineral acid or an organic acid.

21. A method for producing a compound of the formula: ##STR53##

wherein each symbol is as defined in claim 1 or a salt thereof, which comprises reducing a compound of the formula: ##STR54##

wherein each symbol is as defined in claim 8 or a salt thereof.
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