Salt form of a human histone methyltransferase EZH2 inhibitor

Patent metadata

Field	Value
Publication number	US-9394283-B2
Application number	US-201314394431-A
Country	US
Kind code	B2
Filing date	Apr 11, 2013
Priority date	Apr 13, 2012
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

Abstract

Provided herein is N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide. Also provided herein is a particular polymorph form of this compound.

First claim

The invention claimed is:

1. A polymorph of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide, wherein the polymorph exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta at about 3.9+/−0.3 degrees, about 17.5+/−0.3 degrees, and about 22.0+/−0.3 degrees 2-theta.

2. A polymorph of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide, wherein the polymorph exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta at about 3.9+/−0.3 degrees, about 14.3+/−0.3 degrees, about 18.7+/−0.3 degrees, about 23.3+/−0.3 degrees, and about 23.6+/−0.3 degrees 2-theta.

3. The polymorph according to claim 1 , wherein the polymorph exhibits an X-ray powder diffraction pattern having at least 5 characteristic peaks expressed in degrees 2-theta at about 3.9+/−0.3 degrees, 10.1+/−0.3 degrees, 14.3+/−0.3 degrees, 17.5+/−0.3 degrees, 18.7+/−0.3 degrees, 20.6+/−0.3 degrees, 20.9+/−0.3 degrees, 21.8+/−0.3 degrees, 22.0+/−0.3 degrees, 23.3+/−0.3 degrees and 23.6+/−0.3 degrees 2-theta.

4. The polymorph according to claim 1 , wherein the polymorph exhibits an X-ray powder diffraction pattern having at least 6 characteristic peaks expressed in degrees 2-theta at about 3.9+/−0.3 degrees, 10.1+/−0.3 degrees, 14.3+/−0.3 degrees, 17.5+/−0.3 degrees, 18.7+/−0.3 degrees, 20.6+/−0.3 degrees, 20.9+/−0.3 degrees, 21.8+/−0.3 degrees, 22.0+/−0.3 degrees, 23.3+/−0.3 degrees and 23.6+/−0.3 degrees 2-theta.

5. The polymorph of claim 1 , wherein the polymorph exhibits an X-ray powder diffraction pattern substantially in accordance with FIG. 1 .

6. The polymorph of claim 1 , wherein the polymorph exhibits an X-ray powder diffraction pattern substantially in accordance with Table 1.

7. A polymorph of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide, wherein the polymorph exhibits a differential scanning calorimetry thermogram having a characteristic peak expressed in units of ° C. at a temperature of 255+/−5° C.

8. The polymorph of claim 7 , wherein the polymorph exhibits a differential scanning calorimetry thermogram substantially in accordance with FIG. 3 .

9. A method of recrystallizing a polymorph of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide, comprising the following steps: (a) dissolving a polymorph of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide in a first solvent, and (b) adding a second solvent, such that said polymorph is recrystallized.

10. The method of claim 9 , wherein the first solvent is ethanol, and the second solvent is MTBE.

11. A pharmaceutical composition comprising the polymorph of claim 1 , and a pharmaceutically acceptable carrier or diluent.

12. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of polymorph of claim 1 , wherein the cancer is lymphoma, leukemia, melanoma, prostate cancer or breast cancer.

13. The polymorph of claim 1 , wherein the polymorph exhibits a differential scanning calorimetry thermogram having a characteristic peak expressed in units of ° C. at a temperature of 255+1-5° C.

14. The polymorph of claim 1 , wherein the polymorph exhibits a differential scanning calorimetry thermogram substantially in accordance with FIG. 3 .

15. The polymorph of claim 2 , wherein the polymorph exhibits an X-ray powder diffraction pattern substantially in accordance with Table 1.

16. The polymorph of claim 2 , wherein the polymorph exhibits a differential scanning calorimetry thermogram having a characteristic peak expressed in units of ° C. at a temperature of 255+1-5° C.

17. The polymorph of claim 2 , wherein the polymorph exhibits a differential scanning calorimetry thermogram substantially in accordance with FIG. 3 .

18. A pharmaceutical composition comprising the polymorph of claim 2 , and a pharmaceutically acceptable carrier or diluent.

19. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the polymorph of claim 2 , wherein the cancer is lymphoma, leukemia, melanoma, prostate cancer or breast cancer.

20. A pharmaceutical composition comprising the polymorph of claim 13 , and a pharmaceutically acceptable carrier or diluent.

21. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the polymorph of claim 13 , wherein the cancer is lymphoma, leukemia, melanoma, prostate cancer or breast cancer.

22. The polymorph of claim 1 , wherein the N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide is a monohydrobromide.

23. The polymorph of claim 1 , wherein the polymorph is substantially free of impurities.

24. The polymorph of claim 23 , wherein the polymorph contains less than 10%, less than 5%, or less than 1% by weight total impurities.

25. The polymorph of claim 1 , wherein said polymorph is a crystalline solid substantially free of amorphous N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide hydrobromide.

Assignees

• Epizyme Inc
• Eisai R&D Man Co Ltd

Inventors

• Kuntz Kevin Wayne
• Huang Kuan-Chun
• Choi Hyeong Wook
• Sanders Kristen
• Mathieu Steven
• Chanda Arani
• Fang Frances

Classifications

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title