Methods of treating cell proliferative disorders
View Patent ↗The present disclosure provides methods for the treatment of cell proliferative disorders by administration of a Syk kinase or Syk/Flt-3 kinase inhibitor. Cell proliferative disorders treatable by the methods include, hematopoietic neoplasms and virally associated tumors. The compounds are also directed to therapeutic or prophylactic inhibition of tumor metastasis.
1. A method of treating a cell proliferative disorder, comprising:
administering to a subject in need thereof an amount of a prodrug, or a salt thereof, of a Syk kinase inhibitory compound effective to treat the cell proliferative disorder, the prodrug having the structure
wherein
each R 30 , R 31 and R 32 is independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, (C6-C14) aryl, phenyl, 5-14 membered heteroaryl, (C7-C20) arylalkyl, benzyl, 7-20 membered heteroarylalkyl, —OR, chloro, fluoro, bromo, cyano, nitro, —C(O)R, —C(O)OR, —NRR, —S(O) 2 NRR, —C(O)NRR, —N(R)S(O) 2 R and —NC(O)OR, where each R is independently selected from hydrogen and lower alkyl; and
R P is selected from —CH 2 —O—P(O)(OH) 2 , —CH 2 CH 2 —O—P(O)(OH) 2 , —CH 2 OH.
2. The method of claim 1 in which the cell proliferative disorder is a hematopoietic neoplasm.
3. The method of claim 2 in which the hematopoietic neoplasm is a lymphoid neoplasm.
4. The method of claim 3 in which the lymphoid neoplasm is a T cell neoplasm.
5. The method of claim 4 in which the T cell neoplasm is T lymphoblastic leukemia.
6. The method of claim 3 in which the lymphoid neoplasm is a B cell neoplasm.
7. The method of claim 6 in which the B cell neoplasm is B-lymphoblastic leukemia.
8. The method of claim 6 in which the B cell neoplasm is Burkitt's lymphoma.
9. The method of claim 1 in which the cell proliferative disorder is a myeloid neoplasm.
10. The method of claim 9 in which the myeloid neoplasm is a myeloproliferative disease.
11. The method of claim 10 in which the myeloproliferative disease is chronic myelogenous leukemia (CML).
12. The method of claim 9 in which the myeloid neoplasm is myelodysplastic disease.
13. The method of claim 12 in which the myelodysplastic disease is chronic myelomonocytic leukemia.
14. The method of claim 9 in which the myeloid neoplasm is myelodysplastic syndrome.
15. The method of claim 9 in which the myeloid neoplasm is acute myeloid leukemia.
16. The method of claim 15 in which the acute myeloid leukemia is associated with activity of a TEL/Syk fusion protein.
17. The method of claim 2 in which the hematopoietic neoplasm is selected from acute myelogenous leukemia, B-precursor cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, myelodysplastic syndrome, and chronic myelogenous leukemia.
18. The method of claim 1 in which the proliferative disorder is a virally-mediated tumor arising from modulation of Syk kinase activity.
19. The method of claim 18 in which the virally mediated tumor arising from modulation of Syk kinase activity.
20. The method of claim 18 in which the virally mediated tumor is associated with Karposi's sarcoma associated herpes virus.
21. The method of claim 20 in which the virally mediated tumor is associated with the activity of K1 protein of Karoposi's sarcoma associated herpes virus.
22. The method of claim 18 in which the virally mediated tumor is associated with Epstein Barr Virus.
23. The method of claim 22 in which the virally mediated tumor is associated with the activity of LMP2A protein of the Epstein Barr Virus.
24. The method of claim 18 in which the virally mediated tumor is associated with HTLV-1 virus.
25. The method of claim 1 in which the prodrug is of the formula:
26. The method of claim 1 , in which the prodrug is administered in combination with another Syk inhibitory compound.
27. The method of claim 1 in which the prodrug is administered adjunctively with an Abl kinase inhibitor.
28. The method of claim 27 in which the Abl kinase inhibitor is 2-phenylaminopyrimidine.
29. The method of claim 27 in which the prodrug and the Abl kinase inhibitor are administered sequentially.
30. The method of claim 27 in which the prodrug and the Abl kinase inhibitor are administered simultaneously.
31. The method of claim 1 , wherein the prodrug has the structure
32. The method of claim 31 , wherein a salt of the prodrug is administered.
33. The method of claim 32 , wherein the salt is a sodium salt, a potassium salt, a lithium salt, an alkylamino salt, a magnesium salt, a calcium salt, or an ammonium salt.
34. The method of claim 1 , wherein the prodrug is administered orally.
35. The method of claim 6 , wherein the B cell neoplasm is B-cell chronic lymphocytic leukemia.
36. The method of claim 6 , wherein the B cell neoplasm is diffuse large B-cell lymphoma.
37. The method of claim 1 , wherein the prodrug is administered as a disodium salt.
38. The method of claim 31 , wherein the prodrug is administered as a disodium salt.
39. The method of claim 38 , wherein the cell proliferative disorder is a B cell neoplasm.
40. The method of claim 39 , wherein the B cell neoplasm is diffuse large B-cell lymphoma.