Compounds, compositions and methods of agelastatin alkaloids

• US 9,434,736 B2
• Filed: 09/18/2014
• Issued: 09/06/2016
• Est. Priority Date: 09/19/2013
• Status: Active Grant

• Current Assignee: Board of Trustees of The University of Illinois, Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Movassaghi, Mohammad, Hergenrother, Paul J.
• Primary Examiner(s): West, Theodore R
• Application Number:
  US14/490,146
• Publication Number:
  US 20150080405A1
• Time in Patent Office: 719 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 487/14 Ortho-condensed systems

Abstract

The present invention, among other things, provides compounds, compositions and methods for treatment of cancer. In some embodiments, the present invention provides methods for treating blood cancer using agelastatin alkaloids.

Claims

1. A method comprising:

administering to a subject in need thereof a therapeutically effective amount of a compound of formula I;

2. The method of claim 1, wherein R¹ is —

CH₃.

3. The method of claim 1, wherein R² is —

OH.

4. The method of claim 1, wherein R³ is —

H.

5. The method of claim 1, wherein R⁴ is —

Br when R¹ is —

CH₃.

6. The method of claim 1, wherein the compound of formula I has a 48-hour IC₅₀ for a blood cancer cell line of less than about 0.2 μ

M, less than about 0.1 μ

M, or less than about 0.05 μ

M.

7. The method of claim 6, wherein the blood cancer cell line is U-937, CEM, Jurkat, Daudi, HL-60, or CA46.

8. The method of claim 1, wherein the compound of formula I has lower IC₅₀ for each of U-937, CEM, Jurkat, Daudi, HL-60 and CA46 cell lines than for each of Hela, A549 and BT549 cell lines.

9. The method of claim 1, wherein the compound is selected from:

10. The method of claim 1, wherein the compound is

11. The method of claim 1, wherein the compound is

12. The method of claim 1, wherein the compound of formula I has no or low hemolytic activity at about 300 μ

M.

13. The method of claim 1, wherein the compound of formula I has no or low hemolytic activity at a concentration about 500 fold of its IC₅₀ for a blood cancer cell line, at a concentration about 1,000 fold of its IC₅₀ for a blood cancer cell line, at a concentration about 5,000 fold of its IC₅₀ for a blood cancer cell line, or at a concentration about 10,000 fold of its IC₅₀ for a blood cancer cell line.

14. The method of claim 1, wherein the compound of formula I causes less than about 10% hemolysis two hours after administration at about 300 μ

M.

15. The method of claim 1, wherein the compound of formula I causes less than about 10% hemolysis two hours after administration at a concentration about 500 fold of its IC₅₀ for a blood cancer cell line, at a concentration about 1,000 fold of its IC₅₀ for a blood cancer cell line, at a concentration about 5,000 fold of its IC₅₀ for a blood cancer cell line, or at a concentration about 10,000 fold of its IC₅₀ for a blood cancer cell line.

16. The method of claim 1, wherein the compound of formula I does not affect tubulin dynamics within cells.

17. The method of claim 1, wherein the blood cancer is leukemia, lymphoma, or myeloma.

18. The method of claim 1, wherein the blood cancer is selected from acute lymphoblastic leukemia (ALL), acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia “

AML”

, acute promyelocytic leukemia (APL), acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia CML, chronic lymphocytic leukemia CLL, hairy cell leukemia, multiple myeloma, acute and chronic leukemias, lymphobastic, myelogenous, lymphocytic, myelocytic leukemias, Hodgkin'"'"'s disease, non-Hodgkin'"'"'s Lymphoma, Multiple myeloma, Waldenströ

m'"'"'s macroglobulinemia, Heavy chain disease and Polycythemia vera.

19. The method of claim 1, wherein the compound of formula I is administered in a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.