Phenyl-indole compounds for modulating IgE and inhibiting cellular proliferation

• US 20040180946A1
• Filed: 09/12/2003
• Published: 09/16/2004
• Est. Priority Date: 09/12/2002
• Status: Active Grant

• Current Assignee: Avanir Pharmaceuticals (Otsuka Holdings Company Limited)
• Original Assignee: Avanir Pharmaceuticals (Otsuka Holdings Company Limited)
• Inventors: Ramnauth, Jailall, Sircar, Jagadish C., Richards, Mark L.
• Granted Patent: US 7,375,118 B2
• Time in Patent Office: Days
• US Class Current: 514/419
• 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 31/404 Indoles, e.g. pindolol
• 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 209/10 with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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 phenyl-indole molecules that are cellular proliferation inhibitors and thus are useful as anticancer agents. This invention further relates to small molecules which suppress cytokines and leukocytes.

Claims

1. A pharmaceutical composition for treating or preventing an allergic reaction associated with increased IgE levels, inhibiting cellular proliferation, and/or inhibiting cytokines or leukocytes 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 heteroaryl 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, iso-quinolines, 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, cell proliferation and/or inhibition of cytokines or leukocytes.

5. The pharmaceutical composition of claim 1, wherein R₁ and R₂ are independently selected from the following:

6. The pharmaceutical composition of claim 1 comprising a compound selected from the group consisting of compounds S1-S123, T1-T102, U1-U18, and V1-V28.

7. A pharmaceutical composition for treating or preventing an allergic reaction associated with increased IgE levels, inhibiting cellular proliferation, and/or inhibiting cytokines or leukocytes in a mammal comprising any one or more of the following compounds:

8. The pharmaceutical composition of claim 7 comprising a compound selected from the group consisting of compounds S-6, S-96, and S-97.

9. A pharmaceutical composition for treating or preventing an allergic reaction associated with increased IgE levels, inhibiting cellular proliferation, and/or inhibiting cytokines or leukocytes in a mammal comprising any one or more of the following compounds:

10. The pharmaceutical composition of claim 9 comprising a compound selected from the group consisting of compounds T-3, T-83, and T-102.

11. A pharmaceutical composition for treating or preventing an allergic reaction associated with increased IgE levels, inhibiting cellular proliferation, and/or inhibiting cytokines or leukocytes in a mammal comprising any one or more of the following compounds:

12. The pharmaceutical composition of claim 11 comprising a compound selected from the group consisting of compounds T-88, T-89, T-90, T-91, T-94, and T-96.

13. A method for treating or preventing an allergic reaction and/or for inhibiting cytokines or leukocytes in a mammal comprising administering an effective amount of at least one of the following compounds:

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

15. The method of claim 14, 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.

16. The method of claim 14, wherein said at least one additional ingredient is combined with said compound in a pharmaceutically acceptable diluent and co-administered to the mammal.

17. The method of claim 13, wherein said compound is administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day.

18. The method of claim 17, wherein said dose is administered in divided doses at regular periodic intervals.

19. The method of claim 18, wherein said regular periodic intervals occur daily.

20. A method for treating or preventing asthma in a mammal comprising administering an IgE-suppressing amount of at least one of the following compounds:

21. The method of claim 20 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said asthma.

22. The method of claim 21, 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.

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

24. The method of claim 23 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said cellular proliferation.

25. The method of claim 24, wherein said at least one additional ingredient is selected from the group consisting of antifungals, antivirals, antibiotics, anti-inflammatories, and anticancer agents.

26. The method of claim 24, 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.

27. The method of claim 24, wherein said at least one additional ingredient is combined with said compound in a pharmaceutically acceptable diluent and co-administered to the mammal.

28. The method of claim 23, wherein said compound is administered at a dose of about 0.01 mg to about 100 mg per kg body weight per day.

29. The method of claim 28, wherein said dose is administered in divided doses at regular periodic intervals.

30. The method of claim 29, wherein said regular periodic intervals occur daily.

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

32. The method of claim 31, wherein said therapy is an anti-cancer therapy.

33. The method of claim 31, wherein said therapy is selected from the group consisting of radiation, immunotherapy, gene therapy, and surgery.

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

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

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

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

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

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

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

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