Benzimidazole compounds for modulating IgE and inhibiting cellular proliferation

• US 20040214821A1
• Filed: 03/05/2004
• Published: 10/28/2004
• Est. Priority Date: 03/12/2001
• Status: Active Grant

• Current Assignee: Jagadish C. Sircar, Mark L. Richards
• Original Assignee: Jagadish C. Sircar, Mark L. Richards
• Inventors: Sircar, Jagadish C., Richards, Mark L.
• Granted Patent: US 7,282,518 B2
• Time in Patent Office: Days
• US Class Current: 514/227.8
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention is directed to small molecule inhibitors of the IgE response to allergens, which are useful in the treatment of allergy and/or asthma or any diseases where IgE is pathogenic. This invention also relates to benzimidazole molecules that are cellular proliferation inhibitors and thus are useful as anticancer agents.

Claims

1. A pharmaceutical composition for treating an allergic reaction associated with increased IgE levels in a mammal comprising any one or more of the following compounds:

2. The compound of claim 1, wherein said polycyclic aliphatic group is selected from the group consisting of adamantyl, bicycloheptyl, camphoryl, bicyclo[2,2,2]octanyl and norbornyl.

3. The compound of claim 1, wherein said heteroaryl and said substituted hsteroaryl is selected from the group consisting of pyridines, thiazoles, isothiazoles, oxazoles, pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles, pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines, pyrazoles, imidazoles, indoles, quinolines, isoquinolines, benzothiophines, benzofurans, parathiazines, pyrans, chromenes, pyrrolidines, pyrazolidines, imidazolidines, morpholines, thiomorpholines, and the corresponding heterocyclics.

4. The pharmaceutical composition of claim 1, further comprising at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.

5. A method for treating an allergic reaction in a mammal wherein said reaction is caused by an increase in IgE levels comprising administering an IgE-suppressing amount of at least one compound of claim 1.

6. The method of claim 5 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.

7. The method of claim 6, wherein said at least one additional ingredient is selected from the group consisting of a short-acting β

₂-adrenergic agonist, a long-acting β

₂-adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.

8. The method of claim 6, wherein said at least one additional ingredient is combined with said at least one IgE-suppressing compound in a pharmaceutically acceptable diluent and co-administered to the mammal.

9. The method of claim 8, wherein said at least one IgE-suppressing compound is administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day.

10. The method of claim 9, wherein said dose is administered in divided doses at regular periodic intervals.

11. The method of claim 10, wherein said regular periodic intervals occur daily.

12. A method for treating asthma in a mammal comprising administering an IgE-suppressing amount of at least one compound of claim 1.

13. The method of claim 12 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said asthma.

14. The method of claim 13, wherein said additional ingredient is selected from the group consisting of a short-acting β

₂-adrenergic agonist, a long-acting β

₂-adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.

15. A method for inhibiting cellular proliferation in a mammal comprising administering an amount of at least one compound of claim 1.

16. The method of claim 15 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said cellular proliferation.

17. The method of claim 16, wherein said at least one additional ingredient is selected from the group consisting of antifungals, antivirals, antibiotics, anti-inflammatories, and anticancer agents.

18. The method of claim 16, wherein said at least one additional ingredient is selected from the group consisting of alkylating agent, antimetabolite, DNA cutter, topoisomerase I poison, topoisomerase II poison, DNA binder, and spindle poison.

19. The method of claim 16, wherein said at least one additional ingredient is combined with said at least one compound of claim 1 in a pharmaceutically acceptable diluent and co-administered to the mammal.

20. The method of claim 19, wherein said at least one compound of claim 1 is administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day.

21. The method of claim 20, wherein said dose is administered in divided doses at regular periodic intervals.

22. The method of claim 21, wherein said regular periodic intervals occur daily.

23. The method of claim 15 further comprising administering at least one other therapy which is effective in ameliorating at least one symptom associated with cellular proliferation.

24. The method of claim 23, wherein said therapy is an anti-cancer therapy.

25. The method of claim 23, wherein said therapy is selected from the group consisting of radiation, immunotherapy, gene therapy, and surgery.

26. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

27. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

28. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of:

48. The method of claim 45, wherein said at least one additional ingredient is combined with said at least one compound of claim 1 in a pharmaceutically acceptable diluent and co-administered to the mammal.

49. The method of claim 48, wherein said at least one compound of claim 1 is administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day.

50. The method of claim 49, wherein said dose is administered in divided doses at regular periodic intervals.

51. The method of claim 50, wherein said regular periodic intervals occur daily.

63. The method of claim 60, wherein said at least one additional ingredient is combined with said at least one compound of claim 1 in a pharmaceutically acceptable diluent and co-administered to the mammal.

64. The method of claim 59, wherein said at least one compound of claim 1 is administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day.

65. The method of claim 64, wherein said dose is administered in divided doses at regular periodic intervals.

66. The method of claim 65, wherein said regular periodic intervals occur daily.

29. A method of preparing a compound or salt thereof having the formula:

30. A pharmaceutical composition for treating an allergic reaction associated with increased IgE levels in a mammal comprising any one or more of the following compounds:

31. The compound of claim 30, wherein said polycyclic aliphatic group is selected from the group consisting of adamantyl, bicycloheptyl, camphoryl, bicyclo[2,2,2]octanyl and norbornyl.

32. The compound of claim 30, wherein said heteroaryl and said substituted hsteroaryl is selected from the group consisting of pyridines, thiazoles, isothiazoles, oxazoles, pyrimidines, pyrazines, furans, thiophenes, isoxazoles, pyrroles, pyridazines, 1,2,3-triazines, 1,2,4-triazines, 1,3,5-triazines, pyrazoles, imidazoles, indoles, quinolines, isoquinolines, benzothiophines, benzofurans, parathiazines, pyrans, chromenes, pyrrolidines, pyrazolidines, imidazolidines, morpholines, thiomorpholines, and the corresponding heterocyclics.

33. The pharmaceutical composition of claim 30, further comprising at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.

34. A method for treating an allergic reaction in a mammal wherein said reaction is caused by an increase in IgE levels comprising administering an IgE-suppressing amount of at least one compound of claim 30.

35. The method of claim 34 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.

36. The method of claim 35, wherein said at least one additional ingredient is selected from the group consisting of a short-acting β

₂-adrenergic agonist, a long-acting β

2-adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.

37. The method of claim 35, wherein said at least one additional ingredient is combined with said at least one IgE-suppressing compound in a pharmaceutically acceptable diluent and co-administered to the mammal.

38. The method of claim 37, wherein said at least one IgE-suppressing compound is administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day.

39. The method of claim 38, wherein said dose is administered in divided doses at regular periodic intervals.

40. The method of claim 39, wherein said regular periodic intervals occur daily.

41. A method for treating or preventing asthma in a mammal comprising administering an IgE-suppressing amount of at least one compound of claim 30.

42. The method of claim 41 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said asthma.

43. The method of claim 42, wherein said additional ingredient is selected from the group consisting of a short-acting β

₂-adrenergic agonist, a long-acting β

₂-adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.

44. A method for inhibiting cellular proliferation in a mammal comprising administering an amount of at least one compound of claim 30.

45. The method of claim 44 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said cellular proliferation.

46. The method of claim 45, wherein said at least one additional ingredient is selected from the group consisting of antifungals, antivirals, antibiotics, anti-inflammatories, and anticancer agents.

47. The method of claim 45, wherein said at least one additional ingredient is selected from the group consisting of alkylating agent, antimetabolite, DNA cutter, topoisomerase I poison, topoisomerase II poison, DNA binder, and spindle poison.

52. The method of claim 44 further comprising administering at least one other therapy which is effective in ameliorating at least one symptom associated with cellular proliferation.

53. The method of claim 52, wherein said therapy is an anti-cancer therapy.

54. The method of claim 52, wherein said therapy is selected from the group consisting of radiation, immunotherapy, gene therapy, and surgery.

55. The pharmaceutical composition of claim 30, wherein the compound is selected from the group consisting of:

56. The pharmaceutical composition of claim 30, wherein the compound is selected from the group consisting of:

57. A method of preparing a compound or salt thereof having the formula:

58. A method of preparing a compound or salt thereof having the formula:

59. A method for inhibiting cellular proliferation in a mammal comprising administering an amount of at least one compound of the following formula:

60. The method of claim 59 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said cellular proliferation.

61. The method of claim 60, wherein said at least one additional ingredient is selected from the group consisting of antifungals, antivirals, antibiotics, anti-inflammatories, and anticancer agents.

62. The method of claim 60, wherein said at least one additional ingredient is selected from the group consisting of alkylating agent, antimetabolite, DNA cutter, topoisomerase I poison, topoisomerase II poison, DNA binder, and spindle poison.

67. The method of claim 59 further comprising administering at least one other therapy which is effective in ameliorating at least one symptom associated with cellular proliferation.

68. The method of claim 67, wherein said therapy is an anti-cancer therapy.

69. The method of claim 67, wherein said therapy is selected from the group consisting of radiation, immunotherapy, gene therapy, and surgery.