Mesylic acid salt of acylthiourea compound, crystal of the same, and process for producing these

Patent metadata

Field	Value
Publication number	US-10143688-B2
Application number	US-201615570021-A
Country	US
Kind code	B2
Filing date	Apr 28, 2016
Priority date	Apr 30, 2015
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

An object of the present invention is to provide a salt compound of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide, which is useful as an antitumor agent, and crystal of the salt. The salt and the crystal are excellent in terms of solubility, stability, and peroral absorbability and can be mass-produced. The present invention relates to: a mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide; and the mesylic acid salt including a crystal which gives an X-ray powder diffraction spectrum having characteristic peaks at specific diffraction angles.

First claim

The invention claimed is:

1. A crystalline mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide having an X-ray powder diffraction spectrum with characteristic peaks at at least three diffraction angles (2θ±0.2°) selected from the group consisting of 6.7°, 7.9°, 9.6°, 12.5°, 13.8°, 19.8°, 21.2°, and 26.1°.

2. The crystalline mesylic acid salt according to claim 1 , having an X-ray powder diffraction spectrum with characteristic peaks at at least five diffraction angles (2θ±0.2°) selected from the group consisting of 6.7°, 7.9°, 9.6°, 12.5°, 13.8°, 19.8°, 21.2°, and 26.1°.

3. The crystalline mesylic acid salt according to claim 1 , having an X-ray powder diffraction spectrum with characteristic peaks at diffraction angles (2θ±0.2°) of 6.7°, 7.9°, 9.6°, 12.5°, 13.8°, 19.8°, 21.2°, and 26.1°.

4. The crystalline mesylic acid salt according to claim 1 , which shows an endothermic peak at 217±5° C. in differential thermal analysis.

5. A medicinal composition which comprises an effective amount of the crystalline mesylic acid salt according to claim 1 , and a pharmaceutically acceptable carrier.

6. A medicinal composition which comprises an effective amount of the crystalline mesylic acid salt according to claim 1 , and a pharmaceutically acceptable carrier, wherein the medicinal composition is suitable for oral administration.

7. A process for producing a crystalline mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide, the process comprising:
adding 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide and mesylic acid to a solvent, to obtain a mixture; and
stirring the mixture to precipitate a crystalline mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide,
wherein the crystalline mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide has an X-ray powder diffraction spectrum with characteristic peaks at at least three diffraction angles (2θ±0.2°) selected from the group consisting of 6.7°, 7.9°, 9.6°, 12.5°, 13.8°, 19.8°, 21.2°, and 26.1°.

8. The process according to claim 7 , wherein the crystalline mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide has an X-ray powder diffraction spectrum with characteristic peaks at at least five diffraction angles (2θ+0.2°) selected from the group consisting of 6.7°, 7.9°, 9.6°, 12.5°, 13.8°, 19.8°, 21.2°, and 26.1°.

9. The process according to claim 7 , wherein the crystalline mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide has an X-ray powder diffraction spectrum with characteristic peaks at diffraction angles (2θ+0.2°) of 6.7°, 7.9°, 9.6°, 12.5°, 13.8°, 19.8°, 21.2°, and 26.1°.

10. The process according to claim 7 , wherein the crystalline mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide shows an endothermic peak at 217±5° C. in differential thermal analysis.

11. The process according to claim 7 , wherein the solvent is at least one solvent selected from the group consisting of water, an alcohol, an aliphatic carboxylic acid ester, a ketone, an ether, a hydrocarbon, and an aprotic polar solvent.

12. The process according to claim 7 , wherein the solvent is at least one solvent selected from the group consisting of water, an alcohol, an aliphatic carboxylic acid ester, and a ketone.

13. The process according to claim 7 , wherein the solvent is ethanol, isopropanol, ethyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, or an acetone/water mixed solvent.

14. A crystalline mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide, wherein the crystalline mesylic acid salt is produced by a process comprising:
adding 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide and mesylic acid to a solvent, to obtain a mixture; and
stirring the mixture to precipitate a crystalline mesylic acid salt of 4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-7-methoxy-N-methylquinoline-6-carboxamide,
wherein the crystalline mesylic acid salt has an X-ray powder diffraction spectrum with characteristic peaks at at least three diffraction angles (2θ±0.2°) selected from the group consisting of 6.7°, 7.9°, 9.6°, 12.5°, 13.8°, 19.8°, 21.2°, and 26.1°.

15. The crystalline mesylic acid salt according to claim 14 , having an X-ray powder diffraction spectrum with characteristic peaks at at least five diffraction angles (2θ+0.2°) selected from the group consisting of 6.7°, 7.9°, 9.6°, 12.5°, 13.8°, 19.8°, 21.2°, and 26.1°.

16. The crystalline mesylic acid salt according to claim 14 , having an X-ray powder diffraction spectrum with characteristic peaks at diffraction angles (2θ±0.2°) of 6.7°, 7.9°, 9.6°, 12.5°, 13.8°, 19.8°, 21.2°, and 26.1°.

17. The crystalline mesylic acid salt according to claim 14 , which shows an endothermic peak at 217±5° C. in differential thermal analysis.

18. The crystalline mesylic acid salt according to claim 14 , wherein the solvent is at least one solvent selected from the group consisting of water, an alcohol, an aliphatic carboxylic acid ester, a ketone, an ether, a hydrocarbon, and an aprotic polar solvent.

19. The crystalline mesylic acid salt according to claim 14 , wherein the solvent is at least one solvent selected from the group consisting of water, an alcohol, an aliphatic carboxylic acid ester, and a ketone.

20. The crystalline mesylic acid salt according to claim 14 , wherein the solvent is ethanol, isopropanol, ethyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, or an acetone/water mixed solvent.

Assignees

• Taiho Pharmaceutical Co Ltd

Inventors

• Sato Ayako

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/17

  having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• C07D215/48

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title