Solid forms of an antiviral compound

• US 9,884,873 B2
• Filed: 03/15/2017
• Issued: 02/06/2018
• Est. Priority Date: 06/11/2014
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Lapina, Olga Viktorovna, Shi, Bing, Wang, Fang, Wolckenhauer, Scott Alan
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US15/459,785
• Publication Number:
  US 20170247386A1
• Time in Patent Office: 328 Days
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 491/052 the oxygen-containing ring being six-membered

Abstract

Crystalline solid forms of methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (Compound I) were prepared and characterized in the solid state:

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

Claims

1. Crystalline methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′

,3′

;

6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate phosphate (Compound I Phosphate Form VIII) characterized by an X-ray powder diffractogram comprising the following peaks;

4.2, 8.3, and 16.0°

2θ

±

0.2°

2θ

, as determined on a diffractometer using Cu-Kα

radiation at a wavelength of 1.5406 Å

.

2. Compound I Phosphate Form VIII according to claim 1, wherein the diffractogram further comprises peaks at 10.1, 11.5, and 13.1°

2θ

±

0.2°

2θ

.

3. Compound I Phosphate Form VIII according to claim 1, wherein the diffractogram is substantially as shown in FIG. 21.

4. Compound I Phosphate Form VIII according to claim 1, characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 181°

C.

5. Compound I Phosphate Form VIII according to claim 4, wherein the DSC curve is substantially as shown in FIG. 22.

6. Crystalline methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′

,3′

;

6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate phosphate (Compound I Phosphate Form IX) characterized by an X-ray powder diffractogram comprising the following peaks;

8.4, 16.1, and 16.3°

2θ

±

0.2°

2θ

, as determined on a diffractometer using Cu-Kα

radiation at a wavelength of 1.5406 Å

.

7. Compound I Phosphate Form IX according to claim 6, wherein the diffractogram further comprises peaks at 10.2, 20.5, and 21.7°

2θ

±

0.2°

2θ

.

8. Compound I Phosphate Form IX according to claim 6, wherein the diffractogram is substantially as shown in FIG. 24.

9. Compound I Phosphate Form IX according to claim 6, characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 177°

C. and an endotherm at about 204°

C.

10. Compound I Phosphate Form IX according to claim 9, wherein the DSC curve is substantially as shown in FIG. 25.

11. Crystalline methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′

,3′

;

6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate phosphate (Compound I Phosphate Form XI) characterized by an X-ray powder diffractogram comprising the following peaks;

8.9, 13.1, and 18.1°

2θ

±

0.2°

2θ

, as determined on a diffractometer using Cu-Kα

radiation at a wavelength of 1.5406 Å

.

12. Compound I Phosphate Form XI according to claim 11, wherein the diffractogram further comprises peaks at 4.0 and 17.5°

2θ

±

0.2°

2θ

.

13. Compound I Phosphate Form XI according to claim 11, wherein the diffractogram is substantially as shown in FIG. 28.

14. Compound I Phosphate Form XI according to claim 11, characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 172°

C. and an endotherm at about 198°

C.

15. Compound I Phosphate Form XI according to claim 14, wherein the DSC curve is substantially as shown in FIG. 29.

16. Crystalline methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′

,3′

;

6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate phosphate (Compound I Phosphate Form XII) characterized by an X-ray powder diffractogram comprising the following peaks;

3.8, 7.5, and 16.9°

2θ

±

0.2°

2θ

, as determined on a diffractometer using Cu-Kα

radiation at a wavelength of 1.5406 Å

.

17. Compound I Phosphate Form XII according to claim 16, wherein the diffractogram further comprises peaks at 8.5, 10.0, and 12.4°

2θ

±

0.2°

2θ

.

18. Compound I Phosphate Form XII according to claim 16, wherein the diffractogram is substantially as shown in FIG. 31.

19. Compound I Phosphate Form XII according to claim 16, characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 205°

C. and an endotherm at about 229°

C.

20. Compound I Phosphate Form XII according to claim 16, wherein the DSC curve is substantially as shown in FIG. 32.