Claims for Patent: 9,394,283

Summary for Patent: 9,394,283

Title:	Salt form of a human histone methyltransferase EZH2 inhibitor
Abstract:	Provided herein is N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydr- o-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-ca- rboxamide hydrobromide. Also provided herein is a particular polymorph form of this compound.
Inventor(s):	Kuntz; Kevin Wayne (Woburn, MA), Huang; Kuan-Chun (Andover, MA), Choi; Hyeong Wook (Andover, MA), Sanders; Kristen (Gilmanton, NH), Mathieu; Steven (Andover, MA), Chanda; Arani (Malden, MA), Fang; Frances (Andover, MA)
Assignee:	Epizyme, Inc. (Cambridge, MA) Eisai R&D Management Co., LTD. (Tokyo, JP)
Application Number:	14/394,431
Patent Claims:	1. A polymorph of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydr- o-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-ca- rboxamide 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(tetrahydr- o-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-ca- rboxamide 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(tetrahydr- o-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-ca- rboxamide hydrobromide, wherein the polymorph exhibits a differential scanning calorimetry thermogram having a characteristic peak expressed in units of .degree. C. at a temperature of 255+/-5.degree. 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(tetrahydr- o-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-ca- rboxamide hydrobromide, comprising the following steps: (a) dissolving a polymorph of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydr- o-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-ca- rboxamide 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 .degree. C. at a temperature of 255+1-5.degree. 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 .degree. C. at a temperature of 255+1-5.degree. 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(tetrahydr- o-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-ca- rboxamide 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(tetrahydr- o-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-ca- rboxamide hydrobromide.