Solid forms of an antiviral compound

• US 9,409,891 B2
• Filed: 06/24/2014
• Issued: 08/09/2016
• Est. Priority Date: 08/17/2012
• Status: Active Grant

• Current Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Hashash, Ahmad, Wolckenhauer, Scott, Shi, Bing
• Primary Examiner(s): Carter, Kendra D
• Application Number:
  US14/313,877
• Publication Number:
  US 20140309187A1
• Time in Patent Office: 777 Days
• US Class Current: 1/1
• 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: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 407/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/08 Bridged systems

Abstract

Crystalline solid forms and the amorphous form of the anti-HCV compound 5-(3,3-dimethylbutyn-1-yl)-3-[(cis-4-hydroxy-4-{[(3S)-tetrahydrofuran-3-yloxy]methyl}cyclohexyl){[(1R)-4-methylcyclohex-3-en-1-yl]carbonyl}amino]thiophene-2-carboxylic acid (Compound I) were prepared and characterized in the solid state:

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

Claims

1. Crystalline 5-(3,3-dimethylbutyn-1-yl)-3-[(cis-4-hydroxy-4-{[(3S)-tetrahydrofuran-3-yloxy]methyl}cyclohexyl){[(1R)-4-methylcyclohex-3-en-1-yl]carbonyl}-amino]thiophene-2-carboxylic acid monohydrate (Compound I Form VIII), characterized by an X-ray powder diffractogram comprising at least three of the following peaks:

3.8, 7.7, 7.9, 18.0, or 21.7 °

2θ

±

0.2 °

2θ

, as determined on a diffractometer using Cu-Kα

radiation.

2. Compound I Form VIII of claim 1, wherein the diffractogram comprises peaks at 3.8, 7.7, 7.9, 18.0, and 21.7 °

2θ

±

0.2 °

2θ

.

3. Compound I Form VIII of claim 1, wherein the diffractogram is substantially as shown in FIG. 18.

4. Compound I Form VIII of claim 1, characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 144°

C.

5. Compound I Form VIII of claim 4, wherein the DSC curve is substantially as shown in FIG. 19.

6. Compound I Form VIII of claim 1, characterized by a weight loss, as measured by thermogravimetric analysis (TGA), of about 3.2% at about 100°

C.

7. Compound I Form VIII of claim 6, wherein the TGA is substantially as shown in FIG. 19.

8. A pharmaceutical composition comprising Compound I Form VIII of claim 1 and a pharmaceutically acceptable excipient.

9. 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 VIII of claim 1.

10. The method of claim 9, comprising further administering to the subject at least one anti-HCV agent.

11. The method of claim 10, wherein the anti-HCV agent is a compound selected from the group consisting of ribavirin,

12. A process for making Compound I Form VIII of claim 1, comprising contacting 5-(3,3-dimethylbutyn-1-yl)-3-[(cis-4-hydroxy-4-{[(3S)-tetrahydrofuran-3-yloxy]methyl}cyclohexyl){[(1R)-4-methylcyclohex-3-en-1-yl]carbonyl}amino]thiophene-2-carboxylic acid with ethanol and water, whereby Compound I Form VIII is formed.

13. The process of claim 12, further comprising isolating Compound I Form VIII.

14. Crystalline 5-(3,3-dimethylbutyn-1-yl)-3-[(cis-4-hydroxy-4-{[(3S)-tetrahydrofuran-3-yloxy]methyl}cyclohexyl){[(1R)-4-methylcyclohex-3-en-1-yl]carbonyl}-amino]thiophene-2-carboxylic acid (Compound I Form XI), characterized by an X-ray powder diffractogram comprising at least three of the following peaks:

5.4, 5.7, 7.0, 7.9, or 8.6 °

2θ

±

0.2 °

2θ

, as determined on a diffractometer using Cu-Kα

.

15. Compound I Form XI of claim 14, wherein the diffractogram comprises peaks at 5.4, 5.7, 7.0, 7.9, and 8.6 °

2θ

±

0.2 °

2θ

.

16. Compound I Form XI of claim 14, wherein the diffractogram is substantially as shown in FIG. 24.

17. Compound I Form XI of claim 14, characterized by a weight loss, as measured by thermogravimetric analysis (TGA), of about 3% at about 160°

C.

18. Compound I Form XI of claim 17, wherein the TGA is substantially as shown in FIG. 25.

19. A pharmaceutical composition comprising Compound I Form XI of claim 14 and a pharmaceutically acceptable excipient.

20. 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 XI of claim 14.

21. The method of claim 20, comprising further administering to the subject at least one anti-HCV agent.

22. The method of claim 21, wherein the anti-HCV agent is a compound selected from the group consisting of ribavirin,

23. A process for making Compound I Form XI of claim 14, comprising desolvating Compound I Form X, whereby Compound I Form XI is formed.

24. The process of claim 23, further comprising isolating Compound I Form XI.