# US 9,434,736 B2 · Compounds, compositions and methods of agelastatin alkaloids

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- Number: US 9,434,736 B2
- Document ID: US9434736B2
- Status: Granted
- Kind: B2
- Application number: 14/490,146
- Filed: 2014-09-18
- Published: 2015-03-19
- Granted: 2016-09-06
- Earliest claimed: 2013-09-19
- Assignees: Massachusetts Institute of Technology
- Applicants: Massachusetts Institute of Technology; The Board of Trustees of the University of Illinois
- Inventors: Mohammad Movassaghi; Paul J. Hergenrother
- Web page: https://patentgrep.com/patent/US9434736B2

## CPC

- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61P 35/02: specific for leukemia
- C07D 487/14: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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

### Claim 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:
R1 is —H or —CH3;
R2 is —OH or —OCH3;
R3 is —H or —OH; and
R4 is —H when R1 is H, or —Br when R1 is —CH3; 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.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is —CH3.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

The method of claim 1, wherein R4 is —Br when R1 is —CH3.

### Claim 6 (depends on 1)

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 μM, less than about 0.1 μM, or less than about 0.05 μM.

### Claim 7 (depends on 6)

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

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound is

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound is

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 1)

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.

### Claim 14 (depends on 1)

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.

### Claim 15 (depends on 1)

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.

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

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.

### Claim 19 (depends on 1)

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.

### Claim 20 (depends on 19)

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