Solid forms of an antiviral compound

• US 8,969,588 B2
• Filed: 03/13/2013
• Issued: 03/03/2015
• 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, Wang, Fang, Shi, Bing, Mogalian, Erik
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US13/800,374
• Publication Number:
  US 20130324496A1
• Time in Patent Office: 720 Days
• Field of Search: 548/300.7
• US Class Current: 548/300.7
• 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 diacetone solvate (Compound I Form I) characterized by an X-ray powder diffractogram comprising the following peaks:

6.8, 12.5, and 19.8 °

2θ

±

0.2 °

2θ

, as determined on a diffractometer using Cu—

Kα

radiation at a wavelength of 1.54178 Å

.

2. Compound I Form I according to claim 1, wherein the diffractogram further comprises peaks at 10.2, 11.1, and 23.8 °

2θ

±

0.2 °

2θ

.

3. Compound I Form I according to claim 1, wherein the diffractogram is substantially as shown in FIG. 2.

4. Compound I Form I according to claim 1, characterized by a differential scanning calorimetry (DSC) curve that comprises a minor endothenn at about 124°

C. and a major endotherm at about 162°

C.

5. Compound I Form 1 according to claim 4, wherein the DSC curve is substantially as shown in FIG. 3.

11. A pharmaceutical composition comprising a compound of Compound I Form I according to claim 1, or Compound I Form II according to claim 6, and a pharmaceutically acceptable excipient.

12. A method for treating a subject suffering from hepatitis C virus (HCV), comprising administering to the subject a therapeutically effective amount of Compound I Form I according to claim 1, or Compound I Form II according to claim 6.

13. The method according to claim 12, comprising further administering to the subject at least one anti-HCV agent.

14. The method according to claim 13, wherein the anti-HCV agent is a compound selected from the group consisting of ribavirin,

6. 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 monoacetone solvate (Compound I Form II) characterized by an X-ray powder diffractogram comprising the following peaks:

12.2, 12.7, and 20.5 °

2θ

±

0.2 °

2θ

, as determined on a diffractometer using Cu—

Kα

radiation at a wavelength of 1.54178 Å

.

7. Compound I Form II according to claim 6, wherein the diffractogram further comprises peaks at 7.5, 11.4, and 20.0 °

2θ

±

0.2 °

2θ

.

8. Compound I Form II according to claim 6, wherein the diffractogram is substantially as shown in FIG. 4.

9. Compound I Form II according to claim 6, characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 130°

C.

10. Compound I Form H according to claim 9, wherein the DSC curve is substantially as shown in FIG. 5.

15. A process for making 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 diacetone solvate (Compound I Form I) characterized by an X-ray powder diffractogram comprising the following peaks:

6.8, 12.5, and 19.8 °

2θ

±

0.2 °

2θ

, as determined on a diffractometer using Cu-Kα

radiation at a wavelength of 1.54178 Å

, comprising the step of

(1) contacting amorphous (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 with acetone,

whereby Compound I Form I is formed.

16. The process according to claim 15, further comprising the step of

(2) isolating Compound I Form I.

17. A process for making 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 monoacetone solvate (Compound I Form II) characterized by an X-ray powder diffractogram comprising the following peaks:

12.2, 12.7, and 20.5°

2θ

±

0.2 °

2θ

, as determined on a diffractometer using Cu—

Kα

radiation at a wavelength of 1.54178 Å

, comprising the step of;

(1) partially desolvating 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 diacetone solvate (Compound I Form I) characterized by an X-ray powder diffractogram comprising the following peaks;

6.8, 12.5, and 19.8 °

2θ

±

0.2 °

2θ

, as determined on a diffractometer using Cu—

Kα

radiation at a wavelength of 1.54178 Å

,

whereby Compound I Form II is formed.