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Claims for Patent: 6,280,959

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Claims for Patent: 6,280,959

Title: Metal complexes
Abstract:The invention describes zinc chelated dimeric cell-surface receptor ligands, pharmaceutical compositions containing these compounds, methods of using these compounds as agonist of dimeric cell-surface receptors. Novel processes used in preparing the compounds are also described. Further, the invention describes novel receptor binding moieties of the zinc chelated cell-surface receptor ligands.
Inventor(s): Gleason; John G. (Downingtown, PA), Luengo; Juan I. (Audubon, PA)
Assignee: SmithKline Beecham Corporation (Philadelphia, PA)
Application Number:09/530,307
Patent Claims: 1. A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a zinc chelated dimeric cell-surface receptor ligand.

2. A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an organic molecule having a molecular weight from about 100 to about 850, containing of from 1 to 4 zinc binding motifs and provided that each zinc binding motif forms at least two coordinate bonds to a zinc ion.

3. A method for identifying agonists of dimeric cell-surface receptors which comprises contacting the receptor with dimeric cell-surface receptor ligand candidates in the presence of a zinc ion source, and selecting ligand candidates which bind to the receptor.

4. A process for the preparation of a zinc chelated dimeric cell-surface receptor ligand which comprises reacting one or more receptor binding moieties and a zinc ion source followed by optional isolation of the zinc chelated dimeric cell-surface receptor ligand.

5. A zinc chelated cell-surface receptor ligand prepared by the process of claim 4.

6. A zinc chelated cell-surface receptor ligand.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 5.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 6.

9. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of claim 5 which process comprises bringing the compound into association with the pharmaceutically acceptable carrier or diluent.

10. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of claim 6 which process comprises bringing the compound into association with the pharmaceutically acceptable carrier or diluent.

11. An isolated dimeric cell-surface receptor binding moiety of a zinc chelated cell-surface receptor ligand.

12. A dimeric cell-surface receptor binding moiety.

13. The method of claim 1 wherein the cell-surface receptor is the EPO receptor.

14. The method of claim 2 wherein the cell-surface receptor is the EPO receptor.

15. A method for agonizing the EPO receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

16. A method for agonizing the EPO receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 11.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 12.

19. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of claim 11 which process comprises bringing the compound into association with the pharmaceutically acceptable carrier or diluent.

20. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of a compound of claim 12 which process comprises bringing the compound into association with the pharmaceutically acceptable carrier or diluent.

21. A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

22. A method for agonizing dimeric cell-surface receptors in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

23. A compound of claim 11 for use as an active therapeutic substance.

24. A compound of claim 12 for use as an active therapeutic substance.

25. The method of claim 1 wherein the dimeric cell-surface receptor is the M-CSF receptor.

26. The method of claim 2 wherein the dimeric cell-surface receptor is the M-CSF receptor.

27. A method for agonizing the M-CSF receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

28. A method for agonizing the M-CSF receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

29. The method of claim 1 wherein the dimeric cell-surface receptor is the GRH receptor.

30. The method of claim 2 wherein the dimeric cell-surface receptor is the GRH receptor.

31. A method for agonizing the GRH receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

32. A method for agonizing the GRH receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

33. The method of claim 1 wherein the dimeric cell-surface receptor is the TPO receptor.

34. The method of claim 2 wherein the dimeric cell-surface receptor is the TPO receptor.

35. A method for agonizing the TPO receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

36. A method for agonizing the TPO receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

37. The method of claim 1 wherein the dimeric cell-surface receptor is the leptin receptor.

38. The method of claim 2 wherein the dimeric cell-surface receptor is the leptin receptor.

39. A method for agonizing the leptin receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

40. A method for agonizing the leptin receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

41. The method of claim 1 wherein the dimeric cell-surface receptor is the IFN receptor.

42. The method of claim 2 wherein the dimeric cell-surface receptor is the IFN receptor.

43. A method for agonizing the IFN receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

44. A method for agonizing the IFN receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

45. The method of claim 1 wherein the dimeric cell-surface receptor is the insulin receptor.

46. The method of claim 2 wherein the dimeric cell-surface receptor is the insulin receptor.

47. A method for agonizing the insulin receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

48. A method for agonizing the insulin receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

49. The method of claim 1 wherein the dimeric cell-surface receptor is selected from the TRK receptors.

50. The method of claim 2 wherein the dimeric cell-surface receptor is selected from the TRK receptors.

51. A method for agonizing a selected TRK receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 11.

52. A method for agonizing a selected TRK receptor in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of claim 12.

53. The method of claim 1 wherein said metal chelated dimeric cell-surface receptor ligand comprises a symmetrical multimer of a receptor binding moiety.
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