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- Nachgewiesen in: USPTO Patent Applications
- Sprachen: English
- Document Number: 20240140911
- Publication Date: May 2, 2024
- Appl. No: 18/542913
- Application Filed: December 18, 2023
- Assignees: Arena Pharmaceuticals, Inc. (New York, NY, US)
- Claim: 1. 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 that is substantially free of radial clusters or spherulites, said method comprising the steps of: 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.
- Claim: 2. A method according to claim 1, 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 that is substantially free of radial clusters or spherulites, said method comprising the steps of: a) hydrolyzing a compound of Formula (IIa): [chemical expression included] wherein R3 is C1-C6 alkyl; in the presence of a hydrolyzing mixture comprising a lipase and a hydrolyzing-step solvent to form (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid; b) 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; c) 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.; d) 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; e) cooling said 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.; f) cycling Step e) optionally one or more times, wherein said first cooling temperature at each cycle may be the same or different and said second heating temperature at each cycle may be the same or different; and g) 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.
- Claim: 3. The method according to claim 2, wherein said hydrolyzing-step solvent comprises acetonitrile.
- Claim: 4. The method according to claim 2, wherein: said compound of Formula (IIa) is: [chemical expression included] said lipase is immobilized Candida Antarctica lipase B; and said hydrolyzing-step solvent comprises acetonitrile.
- Claim: 5. The method of claim 2, 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.
- Claim: 6. The method of claim 2, wherein said hydrolyzing is conducted at a temperature of about 35° C. to about 45° C.
- Claim: 7. The method of claim 2, 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.
- Claim: 8. The method of claim 2, 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.
- Claim: 9. The method of claim 2, wherein said water-miscible anti-solvent comprises a solvent selected from the group consisting of: acetonitrile, acetone, tetrahydrofuran, and C2-C4 alkanol.
- Claim: 10. The method of claim 2, wherein said water-miscible anti-solvent comprises 2-propanol.
- Claim: 11. The method of claim 10, 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.
- Claim: 12. The method of claim 8, 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.
- Claim: 13. The method of claim 8, wherein the weight ratio of L-arginine and H2O is about 1.0:1.2 to about 1.0:1.5.
- Claim: 14. The method of claim 8, wherein said salt-forming mixture prior to said adding L-arginine is at a temperature of about 18° C. to about 30° C.
- Claim: 15. The method of claim 10, 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.
- Claim: 16. The method of claim 8, wherein said salt-forming mixture during said adding L-arginine is at a temperature of about 18° C. to about 30° C.
- Claim: 17. The method of claim 8, 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.
- Claim: 18. The method of claim 2, wherein said first additional amount of said water-miscible anti-solvent is added during a first time point and a second time point.
- Claim: 19. The method of claim 18, wherein about 8% to about 12% of said first additional amount of said water-miscible anti-solvent is added at said first time point.
- Claim: 20. The method of claim 18, wherein said first additional amount of said water-miscible anti-solvent is added at said first time point to form a cloudy mixture.
- Claim: 21. The method of claim 18, 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.
- Claim: 22. The method of claim 18, 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.
- Claim: 23. The method of claim 2, 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.
- Claim: 24. The method of claim 2, wherein said cycling in Step f) comprises said cycling Step e) two times.
- Claim: 25. The method of claim 24, 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.
- Claim: 26. The method of claim 25, 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.
- Claim: 27. The method of claim 2, wherein said cycling in Step f) comprises said cycling Step e) three times.
- Claim: 28. The method of claim 27, 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.
- Claim: 29. The method of claim 28, 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.
- Claim: 30. The method of claim 1, wherein said first additional amount of said water-miscible anti-solvent is added during a first time point and a second time point.
- Claim: 31. The method of claim 30, wherein about 8% to about 12% of said first additional amount of said water-miscible anti-solvent is added at said first time point.
- Claim: 32. The method of claim 30, wherein said first additional amount of said water-miscible anti-solvent is added at said first time point to form a cloudy mixture.
- Claim: 33. The method of claim 30, 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.
- Claim: 34. The method of claim 30, 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.
- Claim: 35. The method of claim 1, wherein cooling said suspension to said first cooling temperature in Step d) is conducted at a rate of about 9° C./hour to about 11° C./hour.
- Claim: 36. The method of claim 1, wherein said cycling in Step e) comprises said cycling Step d) two times.
- Claim: 37. The method of claim 36, wherein said cycling Step d) 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.
- Claim: 38. The method of claim 37, 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.
- Claim: 39. The method of claim 1, wherein said cycling in Step e) comprises said cycling Step d) three times.
- Claim: 40. The method of claim 39, wherein said cycling Step d) 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.
- Current International Class: 07; 07
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