Salt form of a human histone methyltransferase EZH2 inhibitor

• US 10,245,269 B2
• Filed: 12/11/2017
• Issued: 04/02/2019
• Est. Priority Date: 04/13/2012
• Status: Active Grant

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated), Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated), Epizyme, Inc. (Ipsen Sa)
• Inventors: Kuntz, Kevin Wayne, Huang, Kuan-Chun, Choi, Hyeong Wook, Sanders, Kristen, Mathieu, Steven, Chanda, Arani, Fang, Francis
• Primary Examiner(s): Anderson, Rebecca L
• Assistant Examiner(s): Cheng, Karen
• Application Number:
  US15/837,390
• Publication Number:
  US 20180243316A1
• Time in Patent Office: 477 Days
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

1. A method of inhibiting the histone methyltransferase activity of EZH2 in a subject in need thereof comprising administering to the subject an effective amount of a solid crystalline form 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 solid crystalline form 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.

3. The method of claim 1, wherein said solid crystalline form exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta selected from peaks 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.

4. The method of claim 1, wherein said solid crystalline form 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.

5. The method of claim 1, wherein said solid crystalline form exhibits an X-ray powder diffraction pattern having at least 6 characteristic peaks expressed in degrees 2-theta selected from peaks 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.

6. The method of claim 1, wherein said solid crystalline form exhibits an X-ray powder diffraction pattern substantially in accordance with FIG. 1.

7. The method of claim 1, wherein said solid crystalline form exhibits a differential scanning calorimetry thermogram having a characteristic peak expressed in units of °

C. at a temperature of 255+/−

5°

C.

8. The method of claim 1, wherein said solid crystalline form exhibits a differential scanning calorimetry thermogram substantially in accordance with FIG. 3.

9. The method of claim 1, wherein said solid crystalline form is substantially free of impurities.

10. The method of claim 1, wherein said solid crystalline form is 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.

2. A method of inhibiting the histone methyltransferase activity of EZH2 in vitro comprising administering a solid crystalline form 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 solid crystalline form 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.

11. The method of claim 2, wherein said solid crystalline form exhibits an X-ray powder diffraction pattern having one or more characteristic peaks expressed in degrees 2-theta selected from peaks 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.

12. The method of claim 2, wherein said solid crystalline form 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.

13. The method of claim 2, wherein said solid crystalline form exhibits an X-ray powder diffraction pattern having at least 6 characteristic peaks expressed in degrees 2-theta selected from peaks 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.

14. The method of claim 2, wherein said solid crystalline form exhibits an X-ray powder diffraction pattern substantially in accordance with FIG. 1.

15. The method of claim 2, wherein said solid crystalline form exhibits a differential scanning calorimetry thermogram having a characteristic peak expressed in units of °

C. at a temperature of 255+/−

5°

C.

16. The method of claim 2, wherein said solid crystalline form exhibits a differential scanning calorimetry thermogram substantially in accordance with FIG. 3.

17. The method of claim 2, wherein said solid crystalline form is substantially free of impurities.

18. The method of claim 2, wherein said solid crystalline form is 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.