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Claims for Patent: 7,538,133

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Claims for Patent: 7,538,133

Title:Benzimidazole derivatives, their production and use
Abstract: Benzimidazole derivatives of the formula (I): ##STR00001## 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 II 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 (Higashinada-ku, JP), Nishikawa; Kohei (Nishikyo-ku, JP), Kato; Takeshi (Higashiosaka, JP)
Assignee: Takeda Pharmaceutical Company Limited (Osaka, JP)
Application Number:11/594,982
Patent Claims: 1. A compound of the formula: ##STR00046## 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; or a pharmaceutically acceptable salt thereof.

2. A compound of according to claim 1, which is a compound of the formula: ##STR00047## 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 or an amide thereof; 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; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, wherein R.sup.1 is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or aralkyl group.

4. A compound according to claim 1, wherein R.sup.1 is an alkyl, alkenyl, alkynyl, or cycloalkyl group, which may be substituted with hydroxyl, an optionally substituted amino group, halogen or a lower (C.sub.1-4) alkoxy group.

5. A compound according to claim 1, wherein R.sup.1 is a lower (C.sub.1-5) alkyl or lower (C.sub.2-5) alkenyl group optionally substituted with hydroxyl, an amino group, halogen or a lower (C.sub.1-4) alkoxy group.

6. A compound according to claim 4, wherein the alkyl is a lower alkyl group having 1 to about 8 carbon atoms, which may be straight or branched.

7. A compound according to claim 6, wherein the lower alkyl group is unsubstituted or substituted with hydroxyl, an optionally substituted amino group, halogen or a lower (C.sub.1-4) alkoxy group.

8. A compound according to claim 1, wherein R.sup.1 is a lower alkyl group having 1 to about 8 carbon atoms.

9. A compound according to claim 3, wherein the aryl group is phenyl which may be substituted with halogen, nitro, lower (C.sub.1-4) alkoxy, or lower (C.sub.1-4) alkyl.

10. A compound according to claim 3, wherein the aralkyl group is phenyl-lower (C.sub.1-4) alkyl which may be substituted with halogen, nitro, lower (C.sub.1-4) alkoxy, or lower (C.sub.1-4) alkyl.

11. A compound according to claim 1, wherein R.sup.2 is carboxyl, tetrazolyl, trifluoromethanesulfonic amide, phosphoric acid, sulfonic acid, cyano, or lower (C.sub.1-4) alkoxycarbonyl, which may be protected with an optionally substituted lower alkyl group or an acyl group.

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

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

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

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

16. A compound according to claim 15, wherein D' is hydroxyl, a lower (C.sub.1-6) alkoxy group optionally substituted with hydroxyl, optionally substituted amino, halogen, lower (C.sub.1-6) alkoxy, lower (C.sub.1-6) alkylthio or optionally 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 optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, lower (C.sub.2-3) alkenyl which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, optionally 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 optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, lower (C.sub.2-3) alkenyloxy which is substituted with optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, or optionally substituted aryloxy.

17. A compound according to claim 1, wherein R' is a group capable of forming an anion or convertible thereinto either chemically or under biological and/or physiological conditions.

18. A compound according to claim 1, wherein R' is a group capable of forming the residue: --COO-- or convertible thereinto.

19. A compound according to claim 15, wherein D' is hydroxyl, a lower (C.sub.1-6) alkoxy group optionally substituted with hydroxyl, lower (C.sub.1-6) alkoxy or optionally substituted dioxolenyl on the alkyl moiety, a lower (C.sub.2-3) alkenyloxy optionally substituted with optionally 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 optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, optionally 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 optionally substituted aryl or cycloalkyl having 5 to 7 carbon atoms, or optionally substituted aryloxy.

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

21. 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, optionally substituted phenyl, straight or branched lower alkoxy having 1 to 6 carbon atoms or cycloalkyloxy having 5 to 7 carbon atoms.

22. A compound according to claim 1, wherein R' is a tetrazolyl group optionally protected with optionally substituted lower alkyl or acyl, trifluoromethanesulfonic amide, phosphoric acid or sulfonic acid.

23. A compound according to claim 1, wherein the ring A is a benzene ring which may contain, in addition to the R' group, a substituent being selected from the group consisting of halogen nitro, cyano, optionally substituted amino, a group having the formula: --W--R.sup.13 wherein W is a chemical bond, --O--, --S--, or ##STR00048## and R.sup.13 is hydrogen or an optionally substituted lower alkyl group, a group having the formula: --(CH.sub.2).sub.p--CO-D wherein D is hydrogen, hydroxyl, optionally substituted amino, or optionally substituted alkoxy, and p is 0 or 1, tetrazolyl optionally protected with an optionally substituted lower alkyl group or an acyl group, trifluoromethanesulfonic amide, phosphoric acid, or sulfonic acid.

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

25. A compound according to claim 1, wherein X is a chemical bond, lower (C.sub.1-4) alkylene, ##STR00049##

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

27. A compound according to claim 1, wherein Y is --O--, --SO.sub.m-- wherein m is 0, 1, or 2, or --N(R.sup.4)-- wherein R.sup.4 is hydrogen or an optionally substituted lower (C.sub.1-4) alkyl group.

28. A compound according to claim 1, wherein Y--R.sup.1 is --N(R.sup.4)--R.sup.1 wherein R.sup.1 and R.sup.4 are taken together with the N atom attached thereto to form a heterocyclic ring.

29. A compound according to claim 1, which is ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

30. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylic acid or a pro-drug thereof.

31. A compound according to claim 30, which is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylic acid or a pharmaceutically acceptable salt thereof.

32. A compound according to claim 1, which is ethyl 2-propoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-c- arboxylate or a pharmaceutically acceptable salt thereof.

33. A compound according to claim 1, which is p-propoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-c- arboxylic acid or a pharmaceutically acceptable salt thereof.

34. A compound according to claim 1, which is ethyl 2-methylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-- 7-carboxylate or a pharmaceutically acceptable salt thereof.

35. A compound according to claim 1, which is ethyl 2-ethylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7- -carboxylate or a pharmaceutically acceptable salt thereof.

36. A compound according to claim 1, which is ethyl 2-propylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-- 7-carboxylate or a pharmaceutically acceptable salt thereof.

37. A compound according to claim 1, which is 2-methylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-- 7-carboxylic acid or a pharmaceutically acceptable salt thereof.

38. A compound according to claim 1, which is 2-ethylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7- -carboxylic acid or a pharmaceutically acceptable salt thereof.

39. A compound according to claim 1, which is 2-propylthio-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-- 7-carboxylic acid or a pharmaceutically acceptable salt thereof.

40. A compound according to claim 1, which is methyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

41. A compound according to claim 1, which is ethyl 2-ethylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-- carboxylate or a pharmaceutically acceptable salt thereof.

42. A compound according to claim 1, which is ethyl 2-propylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole- -7-carboxylate or a pharmaceutically acceptable salt thereof.

43. A compound according to claim 1, which is pivaloyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]benzimidazole-7-carboxyla- te or a pharmaceutically acceptable salt thereof.

44. A compound according to claim 1, which is methyl 2-methoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-c- arboxylate or a pharmaceutically acceptable salt thereof.

45. A compound according to claim 1, which is 2-methoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-c- arboxylic acid or a pharmaceutically acceptable salt thereof.

46. A compound according to claim 1, which is 2-ethylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-- 7-carboxylic acid or a pharmaceutically acceptable salt thereof.

47. A compound according to claim 1, which is 2-propylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole- -7-carboxylic acid or a pharmaceutically acceptable salt thereof.

48. A compound according to claim 1, which is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

49. A compound according to claim 1, which is acetoxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

50. A compound according to claim 1, which is propionyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

51. A compound according to claim 1, which is butyryloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

52. A compound according to claim 1, which is isobutyryloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

53. A compound according to claim 1, which is 1-(ethoxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

54. A compound according to claim 1, which is 1-acetoxyethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

55. A compound according to claim 1, which is 1-(isopropoxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

56. A compound according to claim 1, which is cyclohexylcarbonyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

57. A compound according to claim 1, which is benzoyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

58. A compound according to claim 1, which is (E)-cinnamoyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

59. A compound according to claim 1, which is cyclopentylcarbonyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.

60. A compound according to claim 1, which is pivaloyloxymethyl 2-ethylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-- 7-carboxylate or a pharmaceutically acceptable salt thereof.

61. A compound according to claim 1, which is 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethylamino-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-- 7-carboxylate or a pharmaceutically acceptable salt thereof.

62. A compound according to claim 1, which is 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-ca- rboxylate or a pharmaceutically acceptable salt thereof.
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