Crystalline forms of an antiviral compound

Patent metadata

Field	Value
Publication number	US-9562058-B2
Application number	US-201414575966-A
Country	US
Kind code	B2
Filing date	Dec 18, 2014
Priority date	Dec 23, 2013
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

Crystalline forms of the anti-HCV compound (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide (Compound I) were prepared and characterized in the solid state:

Also provided are processes of manufacture and methods of using the crystalline forms.

First claim

What is claimed is:

1. A crystalline form of compound I:

wherein, the crystalline form is
an ethanol solvate (Compound I Form I), characterized by an X-ray powder diffractogram comprising peaks (±0.2°) at 8.6, 11.1, and 15.5 °2θ as determined on a diffractometer using Cu-Kα radiation.

2. Compound I Form I according to claim 1 , wherein the diffractogram further comprises
a peak at 12.9 °2θ±0.2°.

3. A pharmaceutical composition comprising a Compound I Form I according to claim 1 , and a pharmaceutically acceptable excipient.

4. A method for treating a subject suffering from hepatitis C virus (HCV), comprising administering to the subject a therapeutically effective amount of a Compound I Form I according to claim 1 and a pharmaceutically acceptable excipient.

5. The method according to claim 4 , comprising further administering to the subject at least one anti-HCV agent.

6. Compound I Form I according to claim 1 , wherein the diffractogram is substantially as shown in FIG. 1 .

7. Compound I Form I according to claim 1 , characterized by a differential scanning calorimetry (DSC) curve substantially as shown in FIG. 2 .

8. Compound I Form I according to claim 1 , characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 149° C., an exotherm at about 212° C., and an endotherm at about 275° C.

9. Compound I Form I according to claim 1 , characterized by a thermogravimetric analysis (TGA) comprising a thermogram substantially as shown in FIG. 3 .

10. Compound I Form I according to claim 1 , characterized by a thermogravimetric analysis (TGA) with a weight loss of about 8.4% in a temperature range of about 30° C. to about 350° C.

11. Compound I Form I according to claim 1 , characterized by a dynamic vapor sorption (DVS) curve substantially as shown in FIG. 4 .

12. New Compound I Form I according to claim 1 , characterized by a nuclear magnetic resonance spectrum ( 1 H NMR) substantially as shown in FIG. 5 .

13. Compound I Form I according to claim 1 , further comprising about 1.7 mole equivalents of ethanol.

Assignees

• Gilead Sciences Inc

Inventors

• Bringley Dustin
• Chan Johann
• Fung Peter
• Keaton Katie
• Lapina Olga
• Morrison Henry
• Pcion Dominika

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07K5/0808

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title