Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compund1) for use in SIPI receptor-associated disorders
First Claim
1. A crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;
- wherein said crystalline free-plate habit has a BET specific surface area of about 0.1 m2/g to about 5.0 m2/g.
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Abstract
The present invention relates to, inter alia, a novel crystalline free-plate habit or morphology, processes for preparing the crystalline free-plate habit, and uses of the crystalline free-plate habit of the L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid (Compound 1) in the treatment of S1P1 receptor-associated disorders, for example, diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions characterized by an underlying defect in the vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development, and atherosclerosis).
79 Citations
50 Claims
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1. A crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid;
- wherein said crystalline free-plate habit has a BET specific surface area of about 0.1 m2/g to about 5.0 m2/g.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 47, 48, 49, 50)
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15. A method for preparing a crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, said method comprising the steps of:
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a) forming a first mixture comprising L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, a water-miscible anti-solvent, and H2O; b) heating the first mixture to a first heating temperature to form a second mixture;
wherein said first heating temperature is about 79°
C. to about 85°
C.;c) adding a first additional amount of said water-miscible anti-solvent to said second mixture while maintaining said first heating temperature to form a suspension; d) cooling the suspension to a first cooling temperature and thereafter heating to a second heating temperature;
wherein said first cooling temperature is about 18°
C. to about 22°
C., and said second heating temperature is about 69°
C. to about 73°
C.;e) cycling Step d) optionally one or more times, wherein the first cooling temperature at each cycle may be the same or different and the second heating temperature at each cycle may be the same or different; and f) cooling said suspension to a final cooling temperature to form said crystalline free-plate habit of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; wherein said final cooling temperature is about 18°
C. to about 22°
C.- View Dependent Claims (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46)
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17. The method according to claim 16, wherein said hydrolyzing-step solvent comprises acetonitrile.
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18. The method according to claim 16, wherein:
said compound of Formula (IIa) is;
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19. The method according to any one of claims 16 to 18, wherein said hydrolyzing is conducted in the presence of a phosphate buffer at a pH of about 6.9 to about 8.1, wherein said phosphate buffer is a potassium phosphate buffer.
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20. The method according to claim 16, wherein said hydrolyzing is conducted at a temperature of about 35°
- C. to about 45°
C.
- C. to about 45°
-
21. The method according to claim 16, wherein after said hydrolyzing, said (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is not isolated.
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22. The method according to claim 21, wherein after said hydrolyzing, said (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is present in an amount of at least 40% as determined by HPLC.
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23. The method according to claim 16, wherein forming said first mixture in Step b) comprises the step of adding L-arginine and H2O, either together or separately in any order, to a salt-forming mixture comprising (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and said water-miscible anti-solvent to form said first mixture.
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24. The method according to claim 23, wherein said adding L-arginine and H2O is conducted under an inert atmosphere comprising nitrogen.
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25. The method according to claim 16, wherein said water-miscible anti-solvent comprises a solvent selected from the group consisting of:
- acetonitrile, acetone, tetrahydrofuran, and C2-C4 alkanol.
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26. The method according to claim 16, wherein said water-miscible anti-solvent comprises 2-propanol.
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27. The method according to claim 23, wherein prior to adding said L-arginine and H2O, said salt-forming mixture comprises (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid and 2-propanol in a weight ratio of about 1.0:
- 6.0 to about 1.0;
8.0.
- 6.0 to about 1.0;
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28. The method according to claim 23, wherein the molar ratio between (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and L-arginine is about 1.0:
- 0.93 to about 1.0;
1.01.
- 0.93 to about 1.0;
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29. The method according to claim 23, wherein the weight ratio of L-arginine and H2O is about 1.0:
- 1.2 to about 1.0;
1.5.
- 1.2 to about 1.0;
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30. The method according to claim 23, wherein said salt-forming mixture prior to said adding L-arginine is at a temperature of about 18°
- C. to about 30°
C.
- C. to about 30°
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31. The method according to claim 23, wherein said salt-forming mixture comprises (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, 2-propanol, and water in a weight ratio of about 1.0:
- 6.0;
0.25 to about 1.0;
8.0;
0.7.
- 6.0;
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32. The method according to claim 23, wherein said salt-forming mixture during said adding L-arginine is at a temperature of about 18°
- C. to about 30°
C.
- C. to about 30°
-
33. The method according to claim 16, wherein said second mixture is substantially a homogeneous solution.
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34. The method according to claim 16, wherein the weight ratio of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid to said first additional amount of 2-propanol is about 1.00:
- 5.95 to about 1.00;
6.25.
- 5.95 to about 1.00;
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35. The method according to claim 16, wherein said first additional amount of said water-miscible anti-solvent is added during a first time point and a second time point.
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36. The method according to claim 35, wherein about 8% to about 12% of said first additional amount of said water-miscible anti-solvent is added at said first time point.
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37. The method according to claim 35, wherein said first additional amount of said water-miscible anti-solvent is added at said first time point to form a cloudy mixture.
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38. The method according to claim 35, wherein prior to said second time point, a seed crystal of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid is optionally added.
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39. The method according to claim 35, wherein said first additional amount of said water-miscible anti-solvent is added at said second time point at a rate to complete the addition in about 1.00 hour or greater.
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40. The method according to claim 16, wherein cooling said suspension to said first cooling temperature in Step e) is conducted at a rate of about 9°
- C./hour to about 11°
C./hour.
- C./hour to about 11°
-
41. The method according to claim 16, wherein said cycling in Step f) comprises said cycling Step e) two times.
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42. The method according to claim 41, wherein said cycling Step e) two times comprises cooling the suspension to a first cycling cooling temperature, heating the suspension to a first cycling heating temperature, cooling the suspension to a second cycling cooling temperature, and heating the suspension to a second cycling heating temperature.
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43. The method according to claim 42, wherein said first cycling cooling temperature is about 16°
- C. to about 26°
C., said first heating cycling temperature is about 55°
C. to about 65°
C., said second cycling cooling temperature is about 26°
C. to about 36°
C., and said second cycling heating temperature is about 45°
C. to about 55°
C.
- C. to about 26°
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44. The method according to claim 16, wherein said cycling in Step f) comprises said cycling Step e) three times.
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45. The method according to claim 44, wherein said cycling Step e) three times comprises:
- cooling the suspension to a first cycling cooling temperature, heating the suspension to a first cycling heating temperature, cooling the suspension to a second cycling cooling temperature, heating the suspension to a second cycling heating temperature, cooling the suspension to a third cycling cooling temperature, and heating the suspension to a third cycling heating temperature.
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46. The method according to claim 45, wherein said first cycling cooling temperature is about 16°
- C. to about 26°
C., said first heating cycling temperature is about 66°
C. to about 76°
C., said second cycling cooling temperature is about 16°
C. to about 26°
C., said second cycling heating temperature is about 55°
C. to about 65°
C., said third cycling cooling temperature is about 26°
C. to about 36°
C., and said third cycling heating temperature is about 45°
C. to about 55°
C.
- C. to about 26°
Specification