Crystalline forms of (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-0-tolyl-thiazolidin-4-one

Patent metadata

Field	Value
Publication number	US-9062014-B2
Application number	US-200913125102-A
Country	US
Kind code	B2
Filing date	Oct 19, 2009
Priority date	Oct 20, 2008
Publication date	Jun 23, 2015
Grant date	Jun 23, 2015

Abstract

The invention relates to crystalline forms of (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one, processes for the preparation thereof, pharmaceutical compositions containing said crystalline forms, and their use as compounds improving vascular function and as immunomodulating agents, either alone or in combination with other active compounds or therapies.

First claim

The invention claimed is:

1. A crystalline form of the compound (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one containing from 0 to 0.5 equivalents of H 2 O per equivalent of (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one, characterised by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 7.0°, 11.2°, and 12.6°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ=1.5406 Å), and wherein the accuracy of the 2θ values is in the range of +/− 0.2°.

2. The crystalline form according to claim 1 , characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 7.0°, 11.2°, 12.6°, 16.6°, 18.8°, 21.3°, 23.6°, and 26.0°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ=1.5406 Å).

3. The crystalline form according to claim 1 , which has a melting point of about 113° C. as determined by differential scanning calorimetry.

4. The crystalline form according to claim 1 containing 0.5 equivalents of H 2 O per equivalent of (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one.

5. The crystalline form according to claim 2 containing 0.5 equivalents of H 2 O per equivalent of (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one.

6. The crystalline form according to claim 2 , which has a melting point of about 113° C. as determined by differential scanning calorimetry.

7. The crystalline form according to claim 4 , which has a melting point of about 113° C. as determined by differential scanning calorimetry.

8. The crystalline form according to claim 5 , which has a melting point of about 113° C. as determined by differential scanning calorimetry.

9. A pharmaceutical composition comprising the crystalline form according to claim 1 and a pharmaceutically acceptable carrier.

10. A method of treatment or prophylaxis of rejection of transplanted organs selected from kidney, liver, heart and lung; or graft-versus-host diseases brought about by stem cell transplantation; or a method of treatment of any of the following disorders: autoimmune syndromes selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease, and Hashimoto's thyroiditis; and atopic dermatitis, wherein said method comprises administering to a subject in need thereof an effective amount of the crystalline form according to claim 1 .

11. A crystalline form of the compound (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one containing from 0 to 0.5 equivalents of H 2 O per equivalent of (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one, characterised by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 10.5°, 22.2°, and 23.4°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ=1.5406 A), and wherein the accuracy of the 28 values is in the range of +/− 0.2°.

12. The crystalline form according to claim 11 , characterised by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 10.5°, 11.1°, 11.4°, 13.6°, 13.9°, 16.3°, 20.8°, 22.2°, 23.4°, 24.1°, 25.7°, 27.7°, 27.9°, 28.7°, and 29.3°, wherein the X-ray powder diffraction diagram is obtained by using Cu Kα1 radiation (λ=1.5406 Å).

13. The crystalline form according to claim 11 , which has a melting point of about 133° C. as determined by differential scanning calorimetry.

14. The crystalline form according to claim 11 , wherein the compound (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one is in anhydrous form.

15. The crystalline form according to claim 12 , wherein the compound (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one is in anhydrous form.

16. The crystalline form according to claim 12 , which has a melting point of about 133° C. as determined by differential scanning calorimetry.

17. The crystalline form according to claim 14 , which has a melting point of about 133° C. as determined by differential scanning calorimetry.

18. The crystalline form according to claim 15 , which has a melting point of about 133° C. as determined by differential scanning calorimetry.

19. A pharmaceutical composition comprising the crystalline form according to claim 11 and a pharmaceutically acceptable carrier.

20. A method of treatment or prophylaxis of rejection of transplanted organs selected from kidney, liver, heart and lung; or graft-versus-host diseases brought about by stem cell transplantation; or a method of treatment of any of the following disorders: autoimmune syndromes selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease; and Hashimoto's thyroiditis; and atopic dermatitis, wherein said method comprises administering to a subject in need thereof an effective amount of the crystalline form according to claim 11 .

Assignees

• Bonham Nicholas
• Buchmann Stephan
• Eberlin Alex
• Imboden Christoph
• Von Raumer Markus
• Actelion Pharmaceuticals Ltd

Inventors

• Bonham Nicholas
• Buchmann Stephan
• Eberlin Alex
• Imboden Christoph
• Von Raumer Markus

Classifications

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title