Compounds, compositions and methods of agelastatin alkaloids

Patent metadata

Field	Value
Publication number	US-9434736-B2
Application number	US-201414490146-A
Country	US
Kind code	B2
Filing date	Sep 18, 2014
Priority date	Sep 19, 2013
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

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.

First claim

The invention claimed is:

1. A method comprising:
administering to a subject in need thereof a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is —H or —CH 3 ;
R 2 is —OH or —OCH 3 ;
R 3 is —H or —OH; and
R 4 is —H when R 1 is H, or —Br when R 1 is —CH 3 ; and

wherein said method treats blood cancer, inhibits growth of blood cancer cells, inhibits proliferation of blood cancer cells, promotes apoptosis of blood cancer cells, arrests cell cycle in blood cancer cells, or induces arrest in G2/M phase in blood cancer cells, or any combination thereof.

2. The method of claim 1 , wherein R 1 is —CH 3 .

3. The method of claim 1 , wherein R 2 is —OH.

4. The method of claim 1 , wherein R 3 is —H.

5. The method of claim 1 , wherein R 4 is —Br when R 1 is —CH 3 .

6. The method of claim 1 , wherein the compound of formula I has a 48-hour IC 50 for a blood cancer cell line of less than about 0.2 μM, less than about 0.1 μM, or less than about 0.05 μM.

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 IC 50 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 μM.

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 IC 50 for a blood cancer cell line, at a concentration about 1,000 fold of its IC 50 for a blood cancer cell line, at a concentration about 5,000 fold of its IC 50 for a blood cancer cell line, or at a concentration about 10,000 fold of its IC 50 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 μM.

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 IC 50 for a blood cancer cell line, at a concentration about 1,000 fold of its IC 50 for a blood cancer cell line, at a concentration about 5,000 fold of its IC 50 for a blood cancer cell line, or at a concentration about 10,000 fold of its IC 50 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, Waldenström'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.

Assignees

• Massachusetts Inst Technology
• Univ Illinois

Inventors

• Movassaghi Mohammad
• Hergenrother Paul J

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07D487/14 Primary

  Ortho-condensed systems · CPC title

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title