Solid forms of an antiviral compound

• US 9,682,987 B2
• Filed: 08/13/2015
• Issued: 06/20/2017
• Est. Priority Date: 06/05/2012
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Scott, Robert William, Shi, Bing, Mogalian, Erik, Wang, Fang
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US14/825,386
• Publication Number:
  US 20150344488A1
• Time in Patent Office: 677 Days
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 487/08 Bridged systems

Abstract

Amorphous and crystalline solid forms of the anti-HCV compound (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Compound I) were prepared and characterized in the solid state:

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

Claims

1. Crystalline (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester ethyl acetate solvate (Compound I Form IV), characterized by an X-ray powder diffractogram comprising the following peaks:

15.1, 17.2, and 21.5°

2θ

+0.2 °

2θ

, as determined on a diffractometer using Cu-Kα

radiation at a wavelength of 1.54178 Å

.

2. Crystalline (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester ethyl acetate solvate (Compound I Form V), characterized by an X-ray powder diffractogram comprising the following peaks:

14.4, 15.3, and 17.4 °

20±

0.2°

20, as determined on a diffractometer using Cu-Kα

radiation at a wavelength of 1.54178 Å

.

3. Crystalline (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester isopropyl acetate solvate (Compound I Form VI), characterized by an X-ray powder diffractogram comprising the following peaks:

5.6, 13.3, and 21.1 °

2θ

±

0.2 °

2θ

, as determined on a diffractometer using Cu-Kα

radiation at a wavelength of 1.54178 Å

.