Polymorph of N-(3-{[(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2-methylalaninamide

Patent metadata

Field	Value
Publication number	US-9388143-B2
Application number	US-201514645937-A
Country	US
Kind code	B2
Filing date	Mar 12, 2015
Priority date	Sep 13, 2012
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

Provided herein are various polymorph forms of N-(3-{[(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2-methylalaninamide.

First claim

What is claimed is:

1. Polymorph E of N-(3-{[(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2-methylalaninamide.

2. The polymorph of claim 1 , wherein the polymorph exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at angles of 18.3°±0.3° and 24.4°±0.3°.

3. The polymorph of claim 1 , wherein the polymorph exhibits characteristic peaks at angles of 18.8°±0.3° and 23.7°±0.3°.

4. The polymorph of claim 1 , wherein the polymorph exhibits characteristic peaks at angles of 10.1°±0.3° and 28.3°±0.3°.

5. The polymorph of claim 1 , wherein the polymorph exhibits characteristic peaks at angles of 9.8°±0.3° and 23.2°±0.3°.

6. The polymorph of claim 1 , wherein the polymorph exhibits characteristic peaks at angles of 9.8°±0.3°, 10.1°±0.3°, 18.3°±0.3°, 18.8°±0.3°, 23.2°±0.3°, 23.7°±0.3°, 28.3°±0.3° and 24.4°±0.3°.

7. The polymorph of claim 1 , wherein the polymorph exhibits an X-ray powder diffraction pattern in accordance with FIG. 1 .

8. The polymorph of claim 1 , wherein the polymorph exhibits a Fourier transform infrared spectrum having characteristic peaks expressed in units of cm −1 at values of 1682, about 1296 and about 1136.

9. The polymorph of claim 1 , wherein the polymorph exhibits a Fourier transform infrared spectrum in accordance with FIG. 2 .

10. The polymorph of claim 1 , wherein the polymorph exhibits a differential scanning calorimetry thermogram having a characteristic peak at a temperature of 232.6±2° C.

11. The polymorph of claim 1 , wherein the polymorph exhibits a differential scanning calorimetry thermogram in accordance with FIG. 3 .

12. The polymorph of claim 1 , wherein the polymorph exhibits a melting point of 230-235° C.

13. The polymorph of claim 12 , wherein the polymorph has an enthalpy of fusion of 114 J/g.

14. The polymorph of claim 1 , wherein the polymorph exhibits a thermogravimetry curve in accordance with FIG. 5 .

15. The polymorph of claim 1 , containing less than 1% by weight total impurities.

16. The polymorph of claim 1 , containing less than 0.1% by weight total impurities.

17. A pharmaceutical composition comprising the polymorph of claim 1 , and a pharmaceutically acceptable carrier or diluent.

18. The pharmaceutical composition of claim 17 , wherein the composition comprises at least 50.0% by weight of polymorph E based on the total weight of N-(3-{[(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2-methylalaninamide in the composition.

19. The pharmaceutical composition of claim 17 , wherein the composition comprises at least 99.0% by weight of polymorph E based on the total weight of N-(3-{[(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2-methylalaninamide in the composition.

20. The pharmaceutical composition of claim 17 , wherein the composition is formulated for oral administration in the form of a pill, capsule, lozenge or tablet.

21. The pharmaceutical composition of claim 17 , wherein the composition is in the form of a suspension.

22. A process for the preparation of the polymorph according to claim 1 , which comprises the following steps: (a) dissolving N-(3-{[(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2-methylalaninamide in a first solvent, (b) optionally adding a second solvent, and (e) optionally seeding the mixture.

23. The process of claim 22 , which comprises the following steps: (a) dissolving N-(3-{[(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2-methylalaninamide in tetrahydrofuran, (b) concentrating the mixture, (c) reducing the temperature of the mixture, (d) adding ethanol to the mixture, (e) seeding the mixture, and (f) lowering the temperature of the mixture.

24. The process of claim 22 , which comprises the following steps: (a) dissolving N-(3-{[(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2-methylalaninamide in dimethylacetamide, (b) adding toluene, (c) lowering the temperature of the mixture, (d) filtering solids from the mixture and washing the solids, (e) suspending the filtered solids in ethanol, and (f) seeding the mixture.

25. The process of claim 22 , which comprises the following steps: (a) dissolving N-(3-{[(2Z)-3-[(2-chloro-5-methoxyphenyl)amino]quinoxalin-2(1H)-ylidene]sulfamoyl}phenyl)-2-methylalaninamide in dimethylsulfoxide, (b) adding ethanol to the mixture, (c) filtering solids from the mixture, (d) suspending the solids in ethanol, and (e) seeding the mixture.

Assignees

• Sanofi Sa

Inventors

• Baulier Virginie
• Fugier Matthieu
• Kozlovic Stephane
• Perrin Marc-Antoine
• Baillon Bruno
• Comte Myriam

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D241/44 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title