Crystalline forms of hydrochloride salts of thienopyrimidine compound

Patent metadata

Field	Value
Publication number	US-11008333-B2
Application number	US-201616066388-A
Country	US
Kind code	B2
Filing date	Dec 30, 2016
Priority date	Dec 31, 2015
Publication date	May 18, 2021
Grant date	May 18, 2021

Abstract

A crystalline form of an alkyl benzene sulfonyl urea compound that is useful as an oral antidiabetics is disclosed. Specifically, the compound is a hydrochloride salt of N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide of the following formula I. A pharmaceutical composition containing the compound is also disclosed:

First claim

The invention claimed is:

1. A crystalline form of a dihydrochloride monohydrate (2HCl.1H 2 O) of the compound of Formula 1, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angle 2θ values of 5.6°±0.2°, 11.1°±0.2°, 14.0°±0.2°, 20.8°±0.2, and 27.3°±0.2° when irradiated with a Cu—Kα light source:

2. The crystalline form of the dihydrochloride monohydrate of claim 1 , wherein the crystalline form further comprises peaks at diffraction angle 2θ value of 21.1°±0.2° when irradiated with a Cu—Kα light source.

3. The crystalline form of the dihydrochloride monohydrate of claim 1 , wherein the crystalline form has a 3 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 44.6±0.2 ppm and 56.6±0.2 ppm.

4. The crystalline form of the dihydrochloride monohydrate of claim 1 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 149.6±0.2 ppm, 152.6±0.2 ppm and 164.3±0.2 ppm.

5. The crystalline form of the dihydrochloride monohydrate of claim 2 , wherein the crystalline form has
a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 44.6±0.2 ppm and 56.6±0.2 ppm.

6. The crystalline form of the dihydrochloride monohydrate of claim 2 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 149.6±0.2 ppm, 152.6±0.2 ppm and 164.3±0.2 ppm.

7. A crystalline form of a dihydrochloride monohydrate (2HCl.1H 2 O) of the compound of Formula 1 having an X-ray powder diffraction pattern comprising peaks at diffraction angle 2θ values of 6.4°±0.2°, 8.1°±0.2°, 9.7°±0.2°, 12.8°±0.2°, 16.0°±0.2°, 20.8°±0.2°±22.0°±0.2°, 24.1°±0.2°, 26.3°±0.2°, and 27.1°±0.2 when irradiated with a Cu—Kα light source:

8. The crystalline form of the dihydrochloride monohydrate of claim 7 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 43.4±0.2 ppm and 45.2±0.2 ppm.

9. The crystalline form of the dihydrochloride monohydrate of claim 7 , wherein the crystalline form has a 3 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 117.0±0.2 ppm, 149.8±0.2 ppm and 165.2±0.2 ppm.

10. A crystalline form of a dihydrochloride trihydrate (2HCl.3H 2 O) of the compound of Formula 1 having an X-ray powder diffraction pattern comprising peaks at diffraction angle 2θ values of 4.6°±0.2°, 8.6°±0.2°, 15.8°±0.2°, 17.2°±0.2°, 19.7°±0.2°, 25.1°±0.2°, and 26.3°±0.2° when irradiated with a Cu—Kα light source:

11. The crystalline form of the dihydrochloride trihydrate of claim 10 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 45.0±0.2 ppm and 53.8±0.2 ppm.

12. The crystalline form of the dihydrochloride trihydrate of claim 10 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 117.6±0.2 ppm and 150.2±0.2 ppm.

13. A crystalline form of a dihydrochloride trihydrate (2HCl.3H 2 O) of the compound of Formula 1 having an X-ray powder diffraction pattern comprising peaks at diffraction angle 2θ values of 6.4°±0.2°, 7.0°±0.2°, 12.8°±0.2°, 15.5°±0.2°, 18.2°±0.2°, 21.0°±0.2°, and 27.9°±0.2 when irradiated with a Cu—Kα light source:

14. The crystalline form of the dihydrochloride trihydrate of claim 13 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 43.8±0.2 ppm and 53.8±0.2 ppm.

15. The crystalline form of the dihydrochloride trihydrate of claim 13 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 117.7±0.2 ppm, 153.1±0.2 ppm and 165.6±0.2 ppm.

16. A crystalline form of a monohydrochloride monohydrate (1HCl.1H 2 O) of the compound of Formula 1 having an X-ray powder diffraction pattern comprising peaks at diffraction angle 2θ values of 7.8°±0.2°, 10.7°±0.2°, 13.0°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 22.0°±0.2°, 22.5°±0.2°, 24.6°±0.2° and 25.3°±0.2, and 25.7°±0.2° when irradiated with a Cu—Kα light source:

17. The crystalline form of the monohydrochloride monohydrate of claim 16 , wherein the crystalline form has having a 3 C solid state NMR spectrum comprising peaks at the following 3 C chemical shifts: 42.5±0.2 ppm and 54.4±0.2 ppm.

18. The crystalline form of the monohydrochloride monohydrate of claim 16 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 124.1±0.2 ppm, 131.8±0.2 ppm and 164.7±0.2 ppm.

19. A crystalline form of a monohydrochloride dihydrate (1HCl.2H 2 O), of the compound of Formula 1 having an X-ray powder diffraction pattern comprising peaks at diffraction angle 2θ values of 7.5°±0.2°, 15.1°±0.2°, 20.0°±0.2°, 21.2°±0.2° and 25.1°±0.2° when irradiated with a Cu—Kα light source:

20. The crystalline form of the monohydrochloride dihydrate of claim 19 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 43.1±0.2 ppm and 53.2±0.2 ppm.

21. The crystalline form of the monohydrochloride dihydrate of claim 19 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 117.6±0.2 ppm, 133.4±0.2 ppm and 164.3±0.2 ppm.

22. A crystalline form of a monohydrochloride dihydrate (1HCl.2H 2 O), of the compound of Formula 1 having an X-ray powder diffraction pattern comprising peaks at diffraction angle 2θ values of 8.7°±0.2°, 11.6°±0.2°, 17.5°±0.2°, 19.4°±0.2°, 23.1°±0.2°, and 26.1°±0.2° when irradiated with a Cu—Kα light source:

23. The crystalline form of the monohydrochloride dihydrate of claim 22 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 41.3±0.2 ppm, 48.8±0.2 ppm and 55.9±0.2 ppm.

24. The crystalline form of the monohydrochloride dihydrate of claim 22 , wherein the crystalline form has a 13 C solid state NMR spectrum comprising peaks at the following 13 C chemical shifts: 119.0±0.2 ppm, 152.7±0.2 ppm and 165.0±0.2 ppm.

25. The crystalline form of the dihydrochloride monohydrate of claim 1 , wherein the crystalline form is substantially pure.

26. A pharmaceutical composition comprising the dihydrochloride monohydrate of claim 1 and at least one pharmaceutically acceptable carrier or diluent.

Assignees

• Hanmi Pharm Ind Co Ltd

Inventors

• Baek Jong Ouk
• Jeon Ji Young
• Oh Hee Sook
• Kim Hee Cheol
• Jang Sun Young
• Ha Tae Hee

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title