TREATMENTS OF B-CELL PROLIFERATIVE DISORDERS

• US 20090053168A1
• Filed: 07/17/2008
• Published: 02/26/2009
• Est. Priority Date: 07/17/2007
• Status: Abandoned Application

• Current Assignee: Zalicus Inc. (EPIRUS Biopharmaceuticals, Inc.)
• Original Assignee: Zalicus Inc. (EPIRUS Biopharmaceuticals, Inc.)
• Inventors: Lee, Margaret S., Rickles, Richard
• Application Number:
  US12/175,219
• Publication Number:
  US 20090053168A1
• Time in Patent Office: Days
• US Class Current: 424/85.200
• 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 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 38/204 IL-6
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The invention provides compositions and methods for the treatment of B-cell proliferative disorders that employ an A2A receptor agonist or one or more PDE inhibitors. The methods and compositions may further include an antiproliferative compound.

Claims

1. A method of treating a B-cell proliferative disorder, said method comprising administering to a patient an A2A receptor agonist in an amount effective to treat said B-cell proliferative disorder.

3. The method of claim 1 or 2, wherein said A2A receptor agonist is selected from the group consisting of the compounds listed in Tables 1 and 2.

19. The method of claim 1, 2, 7, 8, or 9, wherein said B-cell proliferative disorder is selected from the group consisting of autoimmune lymphoproliferative disease, B-cell CLL, B-cell prolymphocyte leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma, follicular lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT type), nodal marginal zone lymphoma, splenic marginal zone lymphoma, hairy cell leukemia, plasmacytoma, diffuse large B-cell lymphoma, Burkitt lymphoma, multiple myeloma, indolent myeloma, smoldering myeloma, monoclonal gammopathy of unknown significance (MGUS), B-cell non-Hodgkin'"'"'s lymphoma, small lymphocytic lymphoma, monoclonal immunoglobin deposition diseases, heavy chain diseases, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, precursor B-lymphoblastic leukemia/lymphoma, Hodgkin'"'"'s lymphoma, nodular lymphocyte predominant Hodgkin'"'"'s lymphoma, classical Hodgkin'"'"'s lymphoma, nodular sclerosis Hodgkin'"'"'s lymphoma, mixed cellularity Hodgkin'"'"'s lymphoma, lymphocyte-rich classical Hodgkin'"'"'s lymphoma, lymphocyte depleted Hodgkin'"'"'s lymphoma, post-transplant lymphoproliferative disorder, and Waldenstrom'"'"'s macroglobulinemia.

20. The method of claim 19, wherein said B-cell proliferative disorder is multiple myeloma.

21. The method of claim 1, 2, 7, 8, or 9, wherein said patient is not suffering from a comorbid immunoinflammatory disorder.

22. The method of claim 1, 2, 7, 8, or 9, wherein said antiproliferative compound is selected from the group consisting of alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF alpha agonists/antagonists, endothelin A receptor antagonist, retinoic acid receptor agonists, immuno-modulators, hormonal and antihormonal agents, photodynamic agents, tyrosine kinase inhibitors, antisense compounds, corticosteroids, HSP90 inhibitors, proteosome inhibitors, CD40 inhibitors, anti-CSI antibodies, FGFR3 inhibitors, VEGF inhibitors, MEK inhibitors, cyclin D1 inhibitors, NF-kB inhibitors, anthracyclines, histone deacetylases, kinesin inhibitors, phosphatase inhibitors, COX2 inhibitors, mTOR inhibitors, calcineurin antagonists, and IMiDs.

23. The method of claim 22, wherein said antiproliferative compound is selected from the compounds listed in Tables 3 and 4.

24. The method of claim 1, 2, 7, 8, or 9, wherein said antiproliferative compound is administered in a combination with at least a second antiproliferative compound.

25. The method of claim 24, wherein said combination is selected from the group consisting of CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone), VAD (vincristine, doxorubicin, and dexamethasone), MP (melphalan and prednisone), DT (dexamethasone and thalidomide), DM (dexamethasone and melphalan), DR (dexamethasone and Revlimid), DV (dexamethasone and Velcade), RV (Revlimid and Velcade), and cyclophosphamide and etoposide.

2. A method of treating a B-cell proliferative disorder, said method comprising administering to a patient a combination of an A2A receptor agonist and an antiproliferative compound in amounts that together are effective to treat said B-cell proliferative disorder.

4. The method of claim 2, wherein said A2A receptor agonist and antiproliferative compound are administered simultaneously.

5. The method of claim 2, wherein said A2A receptor agonist and antiproliferative compound are administered within 14 days of one another.

6. The method of claim 2, wherein said antiproliferative compound is IL-6.

7. A method of treating a B-cell proliferative disorder, said method comprising administering to a patient a combination of a PDE inhibitor and an antiproliferative compound other than a glucocorticoid in amounts that together are effective to treat said B-cell proliferative disorder.

10. The method of claim 7 or 9, wherein said PDE inhibitor is selected from the group consisting of the compounds listed in Tables 5 and 6.

12. The method of claim 7, wherein said PDE inhibitor is active against at least two of PDE 2, 3,4, and 7.

13. The method of claim 7, wherein said combination comprises two or more PDE inhibitors that when combined are active against at least two of PDE 2, 3, 4, and 7.

14. The method of claim 7 or 9, wherein said PDE inhibitor and antiproliferative compound are administered simultaneously.

15. The method of claim 7 or 9, wherein said PDE inhibitor and antiproliferative compound are administered within 14 days of one another.

18. The method of claim 7, wherein said PDE inhibitor is active against PDE 4.

8. A method of treating a B-cell proliferative disorder, said method comprising administering to a patient a combination of two or more PDE inhibitors having activity against at least two of PDE 2, 3, 4, and 7 and an antiproliferative compound in amounts that together are effective to treat said B-cell proliferative disorder.

11. The method of claim 8, wherein at least one of said PDE inhibitors is selected from the group consisting of the compounds listed in Tables 5 and 6.

16. The method of claim 8, wherein said PDE inhibitors and antiproliferative compound are administered simultaneously.

17. The method of claim 8, wherein said PDE inhibitors and antiproliferative compound are administered within 14 days of one another.

9. A method of treating a B-cell proliferative disorder, said method comprising administering to a patient a combination of a PDE inhibitor having activity against at least two of PDE 2, 3, 4, and 7 and an antiproliferative compound in amounts that together are effective to treat said B-cell proliferative disorder.

26. A kit comprising (i) an A2A receptor agonist and (ii) an antiproliferative compound in amounts that together are effective to treat a B-cell proliferative disorder.

30. The kit of claims 26-29, wherein said antiproliferative compound is selected from the group consisting of alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF alpha agonists/antagonists, endothelin A receptor antagonist, retinoic acid receptor agonists, immuno-modulators, hormonal and antihormonal agents, photodynamic agents, tyrosine kinase inhibitors, antisense compounds, corticosteroids, HSP90 inhibitors, proteosome inhibitors, CD40 inhibitors, anti-CSI antibodies, FGFR3 inhibitors, VEGF inhibitors, MEK inhibitors, cyclin D1 inhibitors, NF-kB inhibitors, anthracyclines, histone deacetylases, kinesin inhibitors, phosphatase inhibitors, COX2 inhibitors, mTOR inhibitors, calcineurin antagonists, and IMiDs.

31. The kit of claims 26-29, wherein said antiproliferative compound is selected from the compounds listed in Tables 3 and 4.

32. The kit of claims 26-29, further comprising at least a second antiproliferative compound in a combination with said antiproliferative compound.

33. The kit of claims 32, wherein said combination is selected from the group consisting of CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone), VAD (vincristine, doxorubicin, and dexamethasone), MP (melphalan and prednisone), DT (dexamethasone and thalidomide), DM (dexamethasone and melphalan), DR (dexamethasone and Revlimid), DV (dexamethasone and Velcade), RV (Revlimid and Velcade), and cyclophosphamide and etoposide.

34. The kit of claims 26-29, further comprising instructions for administering (i) and (ii) to a patient for the treatment of a B-cell proliferative disorder.

27. A kit comprising (i) a PDE inhibitor and (ii) an antiproliferative compound other than a glucocorticoid in amounts that together are effective to treat a B-cell proliferative disorder.

28. A kit comprising (i) a PDE inhibitor having activity against at least two of PDE 2, 3, 4, and 7 and (ii) an antiproliferative compound in amounts that together are effective to treat a B-cell proliferative disorder.

29. A kit comprising (i) two or more PDE inhibitors that when combined have activity against at least two of PDE 2, 3, 4, and 7 and (ii) an antiproliferative compound in amounts that together are effective to treat a B-cell proliferative disorder.

35. A pharmaceutical composition comprising (i) an A2A receptor agonist and (ii) an antiproliferative compound together in an amount effective to treat a B-cell proliferative disorder and (iii) a pharmaceutically acceptable carrier.

36. A pharmaceutical composition comprising (i) a PDE inhibitor and (ii) an antiproliferative compound other than a glucocorticoid together in an amount effective to treat a B-cell proliferative disorder and (iii) a pharmaceutically acceptable carrier.

37. A pharmaceutical composition comprising (i) two or more PDE inhibitors that when combined have activity against at least two of PDE 2, 3, 4, and 7 and (ii) an antiproliferative compound together in an amount effective to treat a B-cell proliferative disorder and (iii) a pharmaceutically acceptable carrier.

38. A pharmaceutical composition comprising (i) a PDE inhibitor having activity against at least two of PDE 2, 3, 4, and 7 and (ii) an antiproliferative compound in amounts that together are effective to treat a B-cell proliferative disorder and (iii) a pharmaceutically acceptable carrier.

39. A kit comprising:

(i) a composition comprising an A2A receptor agonist and an antiproliferative compound; and

(ii) instructions for administering said composition to a patient for the treatment of a B-cell proliferative disorder.

40. A kit comprising:

(i) an A2A receptor agonist; and

(ii) instructions for administering said A2A receptor agonist with an antiproliferative compound to a patient for the treatment of a B-cell proliferative disorder.

41. A kit comprising:

(i) a composition comprising a PDE inhibitor and an antiproliferative compound other than a glucocorticoid; and

(ii) instructions for administering said composition to a patient for the treatment of a B-cell proliferative disorder.

42. A kit comprising:

(i) a composition comprising a PDE inhibitor having activity against at least two of PDE 2, 3, 4, and 7 and an antiproliferative compound; and

(ii) instructions for administering said composition to a patient for the treatment of a B-cell proliferative disorder.

43. A kit comprising:

(i) a composition comprising two or more PDE inhibitors that when combined have activity against at least two of PDE 2, 3, 4, and 7 and an antiproliferative compound; and

(iii) instructions for administering said composition to a patient for the treatment of a B-cell proliferative disorder.

44. A kit comprising:

(i) a PDE inhibitor; and

(ii) instructions for administering said PDE inhibitor and an antiproliferative compound to a patient for the treatment of a B-cell proliferative disorder, wherein said antiproliferative compound is not a glucocorticoid or said PDE inhibitor has activity against at least two of PDE 2, 3, 4, and 7.

45. A kit comprising:

(i) two or more PDE inhibitors that when combined have activity against at least two of PDE2,3, 4, and 7; and

(ii) instructions for administering said two or more PDE inhibitors and an antiproliferative compound to a patient for the treatment of a B-cell proliferative disorder.