Salt form of a human histone methyltransferase EZH2 inhibitor

Patent metadata

Field	Value
Publication number	US-9872862-B2
Application number	US-201615199522-A
Country	US
Kind code	B2
Filing date	Jun 30, 2016
Priority date	Apr 13, 2012
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

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 method of treating a cell proliferative disorder of the lung, comprising administering to a subject in need thereof a therapeutically effective amount of 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 selected from peaks at about 3.9+/−0.3 degrees, about 17.5+/−0.3 degrees, and about 22.0+/−0.3 degrees 2-theta.

2. The method of claim 1 , wherein said polymorph is substantially free of impurities.

3. The method of claim 1 , wherein said polymorph 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.

4. The method of claim 1 , wherein said polymorph 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.

5. The method of claim 1 , wherein said 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.

6. The method of claim 1 , wherein said polymorph 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.

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

8. The method of claim 1 , wherein said polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at 3.9 degrees, 10.1 degrees, 14.3 degrees, 17.5 degrees, 18.7 degrees, 20.6 degrees, 20.9 degrees, 21.8 degrees, 22.0 degrees, 23.3 degrees and 23.6 degrees 2-theta.

9. The method of claim 1 , wherein said polymorph exhibits a differential scanning calorimetry thermogram having a characteristic peak expressed in units of ° C. at a temperature of 255+/−5° C.

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

11. The method of claim 1 , wherein said cell proliferative disorder of the lung is selected from lung cancer, a precancer or precancerous condition of the lung, benign growths or lesions of the lung, malignant growths or lesions of the lung, hyperplasia of the lung, metaplasia of the lung, and dysplasia of the lung.

12. The method of claim 11 , wherein said lung cancer is selected from malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, atypical carcinoid tumors, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, mesothelioma, scar carcinoma, bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, large cell neuroendocrine carcinoma, and lung neoplasms having histologic and ultrastructural heterogeneity.

13. The method of claim 12 , wherein said lung cancer is non-small cell lung cancer (NSCLC).

14. The method of claim 11 , wherein said metaplasia of the lung is selected from replacement of columnar epithelium with stratified squamous epithelium, squamous metaplasia, and benign reactive mesothelial metaplasia.

15. The method of claim 11 , wherein said dysplasia of the lung is mucosal dysplasia.

16. The method of claim 11 , wherein said hyperplasia of the lung is asbestos-induced hyperplasia.

17. The method of claim 1 , wherein said subject in need thereof is a subject with a prior lung disease selected from chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin's disease.

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