Crystalline forms of dihydropyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-9403814-B2
Application number	US-201314420666-A
Country	US
Kind code	B2
Filing date	Sep 27, 2013
Priority date	Sep 27, 2012
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The present invention relates to crystalline forms of dihydropyrimidine derivatives, and pharmaceutical compositions comprising the crystalline forms disclosed herein, which may be used for preventing, managing, treating or lessening the severity of a viral disease in a patient, especially hepatitis B infection or a disease caused by hepatitis B infection.

First claim

The invention claimed is:

1. A crystalline form of the compound of formula (I):

or a tautomer or a combination thereof, wherein the crystalline form is form A, form B, form C, form G, form H, form I or a combination thereof.

2. The crystalline form of claim 1 , wherein the crystalline form is form A having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 6.57°±0.2°, 13.13°±0.2°, 13.38°±0.2°, 19.73°±0.2°, 20.18°±0.2°, 20.90°±0.2°, 24.90°±0.2°, 26.63°±0.2° and 29.01°±0.2°.

3. The crystalline form of claim 1 , wherein the crystalline form is form A having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 6.57°±0.2°, 13.13°±0.2°, 13.38°±0.2°, 19.73°±0.2°, 20.18°±0.2°, 20.90°±0.2°, 22.43°±0.2°, 24.38°±0.2°, 24.90°±0.2°, 26.63°±0.2°, 27.93°±0.2° and 29.01°±0.2°.

4. The crystalline form of claim 1 , wherein the crystalline form is form A having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 6.57°±0.2°, 9.73°±0.2°, 11.14°±0.2°, 13.13°±0.2°, 13.38°±0.2°, 19.73°±0.2°, 20.18°±0.2°, 20.90°±0.2°, 22.43°±0.2°, 23.20°±0.2°, 24.38°±0.2°, 24.90°±0.2°, 26.63°±0.2°, 27.93°±0.2°, 29.01°±0.2°, 29.84°±0.2°, 30.78°±0.2° and 31.68°±0.2°.

5. The crystalline form of claim 1 , wherein the crystalline form is form A having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 162.3° C.±3° C.

6. The crystalline form of claim 1 , wherein the crystalline form is form B having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 6.68°±0.2°, 13.39°±0.2°, 19.65°±0.2°, 20.26°±0.2°, 22.45°±0.2°, 24.80°±0.2°, 25.01°±0.2°, 26.19°±0.2°, 26.61°±0.2° and 28.79°±0.2°.

7. The crystalline form of claim 1 , wherein the crystalline form is form B having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 6.68°±0.2°, 9.77°±0.2°, 9.98°±0.2°, 11.88°±0.2°, 13.39°±0.2°, 16.65°±0.2°, 17.66°±0.2°, 19.08°±0.2°, 19.65°±0.2°, 20.26°±0.2°, 20.81°±0.2°, 20.97°±0.2°, 22.45°±0.2°, 24.80°±0.2°, 25.01°±0.2°, 26.19°±0.2°, 26.61°±0.2°, 28.79°±0.2°, 29.78°±0.2°, 30.13°±0.2°, 31.61° 0.2°, 31.92°±0.2° and 32.45°±0.2°.

8. The crystalline form of claim 1 , wherein the crystalline form is form B having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 6.68°±0.2°, 9.77°±0.2°, 9.98°±0.2°, 11.88°±0.2°, 13.39°±0.2°, 14.62°±0.2°, 16.65°±0.2°, 17.66°±0.2°, 19.08°±0.2°, 19.65°±0.2°, 20.26°±0.2°, 20.81°±0.2°, 20.97°±0.2°, 22.07°±0.2°, 22.45°±0.2°, 24.80°±0.2°, 25.01°±0.2°, 25.45°±0.2°, 26.19°±0.2°, 26.61°±0.2°, 27.85°±0.2°, 28.15°±0.2°, 28.79°±0.2°, 29.35°±0.2°, 29.78°±0.2°, 30.13°±0.2°, 30.51°±0.2°, 31.29°±0.2°, 31.61°±0.2°, 31.92°±0.2°, 32.45°±0.2° and 35.41°±0.2°.

9. The crystalline form of claim 1 , wherein the crystalline form is form B having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 165.8° C.±3° C.

10. The crystalline form of claim 1 , wherein the crystalline form is form C having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 5.39°±0.2°, 13.25°±0.2°, 16.00°±0.2°, 17.27°±0.2°, 21.33°±0.2°, 21.92°±0.2°, 22.53°±0.2°, 23.47°±0.2°, 26.56°±0.2°, 26.87°±0.2°, 29.41°±0.2° and 32.22°±0.2°.

11. The crystalline form of claim 1 , wherein the crystalline form is form C having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 5.39°±0.2°, 13.25°±0.2°, 16.00°±0.2°, 17.27°±0.2°, 20.31°±0.2°, 21.33°±0.2°, 21.92°±0.2°, 22.53°±0.2°, 23.47°±0.2°, 23.58°±0.2°, 26.56°±0.2°, 26.87°±0.2°, 29.41°±0.2°, 30.52°±0.2°, 31.35°±0.2°, 32.05°±0.2° and 32.22°±0.2°.

12. The crystalline form of claim 1 , wherein the crystalline form is form C having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 5.39°±0.2°, 10.42°±0.2°, 10.69°±0.2°, 12.04°±0.2°, 13.25°±0.2°, 13.56°±0.2°, 16.00°±0.2°, 17.27°±0.2°, 19.61°±0.2°, 19.86°±0.2°, 20.02°±0.2°, 20.31°±0.2°, 21.33°±0.2°, 21.92°±0.2°, 22.17°±0.2°, 22.29°±0.2°, 22.53°±0.2°, 23.47°±0.2°, 23.58°±0.2°, 24.35°±0.2°, 24.96°±0.2°, 25.10°±0.2°, 26.39°±0.2°, 26.56°±0.2°, 26.87°±0.2°, 27.25°±0.2°, 27.64°±0.2°, 29.41°±0.2°, 29.90°±0.2°, 30.31°±0.2°, 30.52°±0.2°, 31.35°±0.2°, 32.05°±0.2°, 32.22°±0.2°, 32.96°±0.2°, 33.71°±0.2°, 34.11°±0.2°, 34.88°±0.2°, 36.23°±0.2° and 36.46°±0.2°.

13. The crystalline form of claim 1 , wherein the crystalline form is form C having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 172.6° C.±3° C.

14. The crystalline form of claim 1 , wherein the crystalline form is form G having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 16.47°±0.2°, 19.40°±0.2°, 20.61°±0.2°, 22.37°±0.2°, 22.82°±0.2°, 23.21°±0.2°, 25.66°±0.2°, 25.94°±0.2°, 26.87°±0.2°, 27.02°±0.2°, 28.11°±0.2° and 30.27°±0.2°.

15. The crystalline form of claim 1 , wherein the crystalline form is form G having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 9.99°±0.2°, 10.30°±0.2°, 16.47°±0.2°, 17.30°±0.2°, 19.40°±0.2°, 20.61°±0.2°, 21.26°±0.2°, 22.37°±0.2°, 22.82°±0.2°, 23.21°±0.2°, 23.58°±0.2°, 25.66°±0.2°, 25.94°±0.2°, 26.87°±0.2°, 27.02°±0.2°, 27.18°±0.2°, 28.11°±0.2°, 28.40°±0.2°, 29.98°±0.2°, 30.27°±0.2°, 31.14°±0.2°, 32.42°±0.2°, 33.11°±0.2° and 33.34°±0.2°.

16. The crystalline form of claim 1 , wherein the crystalline form is form G having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 7.07°±0.2°, 7.80°±0.2°, 9.99°±0.2°, 10.30°±0.2°, 11.14°±0.2°, 14.20°±0.2°, 15.36°±0.2°, 16.47°±0.2°, 17.30°±0.2°, 19.40°±0.2°, 19.73°±0.2°, 19.85°±0.2°, 20.40°±0.2°, 20.61°±0.2°, 21.26°±0.2°, 22.37°±0.2°, 22.82°±0.2°, 23.21°±0.2°, 23.58°±0.2°, 23.83°±0.2°, 24.58°±0.2°, 25.66°±0.2°, 25.94°±0.2°, 26.87°±0.2°, 27.02°±0.2°, 27.18°±0.2°, 27.79°±0.2°, 28.11°±0.2°, 28.40°±0.2°, 29.98°±0.2°, 30.27°±0.2°, 30.66°±0.2°, 31.14°±0.2°, 32.11°±0.2°, 32.42°±0.2°, 32.76°±0.2°, 33.11°±0.2° and 33.34°±0.2°.

17. The crystalline form of claim 1 , wherein the crystalline form is form G having a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 134.3° C.±3° C.

18. The crystalline form of claim 1 , wherein the crystalline form is form H having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 7.58°±0.2°, 10.29°±0.2°, 12.00°±0.2°, 19.07°±0.2°, 19.93°±0.2°, 20.78°±0.2°, 21.33°±0.2°, 21.48°±0.2°, 24.76°±0.2°, 25.59°±0.2°, 25.82°±0.2°, 26.01°±0.2° and 26.58°±0.2°.

19. The crystalline form of claim 1 , wherein the crystalline form is form H having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 7.58°±0.2°, 10.29°±0.2°, 12.00°±0.2°, 14.78°±0.2°, 17.69°±0.2°, 18.32°±0.2°, 19.07°±0.2°, 19.93°±0.2°, 20.13°±0.2°, 20.78°±0.2°, 21.33°±0.2°, 21.48°±0.2°, 22.60°±0.2°, 24.40°±0.2°, 24.58°±0.2°, 24.76°±0.2°, 25.59°±0.2°, 25.82°±0.2°, 26.01°±0.2°, 26.58°±0.2°, 27.15°±0.2°, 27.31°±0.2°, 27.49°±0.2°, 27.78°±0.2°, 31.69°±0.2° and 31.98°±0.2°.

20. The crystalline form of claim 1 , wherein the crystalline form is form H having an X-ray powder diffraction (XRPD) pattern comprising peaks expressed in degrees 2θ at 7.58°±0.2°, 10.29°±0.2°, 12.00°±0.2°, 14.78°±0.2°, 15.83°±0.2°, 16.49°±0.2°, 17.69°±0.2°, 18.32°±0.2°, 19.07°±0.2°, 19.24°±0.2°, 19.93°±0.2°, 20.13°±0.2°, 20.78°±0.2°, 21.33°±0.2°

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• Zhang Yingjun
• Ren Qingyun
• Liu Xinchang
• Wang Chaolei
• Wang Tianming
• Goldmann Siegfried

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61P1/16

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

• C07D417/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title