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(Compound1) for use in S1P 1 receptor-associated disorders

Arena Pharmaceuticals, Inc.

2024

Online Patent

Zugriff:

View record in USPTO Patent Grants (Volltext)

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).

Titel:	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(Compound1) for use in S1P 1 receptor-associated disorders
Autor/in / Beteiligte Person:	Arena Pharmaceuticals, Inc.
Link:	View record in USPTO Patent Grants (Volltext)
Veröffentlichung:	2024
Medientyp:	Patent
Sonstiges:	Nachgewiesen in: USPTO Patent Grants Sprachen: English Patent Number: 11884,626 Publication Date: January 30, 2024 Appl. No: 17/375063 Application Filed: July 14, 2021 Assignees: Arena Pharmaceuticals, Inc. (New York, NY, US) Claim: 1. A method for treating an S1P 1 receptor-associated disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid in the form of a crystalline free-plate habit substantially free of radial clusters or spherulites, wherein the S1P1 receptor-associated disorder is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, inflammatory bowel disease, Crohn's disease, and ulcerative colitis. Claim: 2. The method according to claim 1 , wherein the crystalline free-plate habit has a BET specific surface area of about 0.1 m 2 /g to about 5.0 m 2 /g. Claim: 3. The method according to claim 1 , wherein the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, and 20.5°±0.2°. Claim: 4. The method according to claim 1 , wherein the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, and 24.6°±0.2°. Claim: 5. The method according to claim 1 , wherein the crystalline free-plate habit has a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°, 28.8°±0.2°, and 37.3°±0.2°. Claim: 6. The method according to claim 1 , wherein the crystalline free-plate habit has a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5° C. to 208.1° C. at a scan rate of 10° C./minute. Claim: 7. The method according to claim 1 , wherein the crystalline free-plate habit has a differential scanning calorimetry trace conducted at a scan rate of 10° C./minute comprising an endotherm substantially as depicted in any one of FIGS. 6 to 10 and FIGS. 22 to 25 . Claim: 8. The method according to claim 1 , wherein the crystalline free-plate habit has: 1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, and 24.6°±0.2°; 2) a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5° C. to t 208.5° C. at a scan rate of 10° C./minute; 3) a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.3% weight or less at 90% RH; and/or 4) a BET specific surface area of about 0.6 m 2 /g to about 4.0 m 2 /g. Claim: 9. The method according to claim 1 , wherein the crystalline free-plate habit has: 1) a powder X-ray diffraction pattern comprising peaks, in terms of 2θ, at 8.2°±0.2°, 16.4°±0.2°, 20.5°±0.2°, 24.6°±0.2°, 28.8°±0.2°, and 37.3°±0.2°; 2) a differential scanning calorimetry trace comprising an endotherm with an extrapolated onset temperature of 205.5° C. to 208.1° C. at a scan rate of 10° C./minute; 3) a dynamic moisture sorption (DMS) profile with an adsorption phase from 30% RH to 90% RH wherein said crystalline free-plate habit gains about 0.2% weight or less at 90% RH; and/or 4) a BET specific surface area of about 0.6 m 2 /g to about 4.0 m 2 /g. Claim: 10. A method for treating an S1P1 receptor-associated disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid in the form of a crystalline free-plate habit; wherein said crystalline free-plate habit is formed by a process comprising the steps of: a) heating 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 water to a first heating temperature to form a second mixture; b) cooling the second mixture to a first cooling temperature followed by adding a first additional amount of the water-miscible anti-solvent to the second mixture while maintaining the first cooling temperature and thereafter heating to a second heating temperature to form a suspension; c) cycling Step b) optionally once or twice; and d) cooling the suspension to a second cooling temperature to form the 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 the S1P1 receptor-associated disorder is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, inflammatory bowel disease, Crohn's disease, and ulcerative colitis. Claim: 11. A method of claim 1 wherein the therapeutically effective amount of L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethypenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid in the form of a crystalline free-plate habit substantially free of radial clusters or spherulites administered is in a pharmaceutical composition. Claim: 12. The method of claim 11 , wherein the pharmaceutical composition is in the form of a tablet. Claim: 13. The method according to claim 1 , wherein the S1P1 receptor-associated disorder is selected from the group consisting of atopic dermatitis, Crohn's disease, inflammatory bowel disease, and ulcerative colitis. Claim: 14. The method according to claim 1 , wherein the S1P1 receptor-associated disorder is ulcerative colitis. Claim: 15. The method according to claim 1 , wherein the S1P1 receptor-associated disorder is Crohn's disease. Claim: 16. The method according to claim 1 , wherein the S1P1 receptor-associated disorder is atopic dermatitis. 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WO 2011/094008 August 2011 ; WO 2011/109471 September 2011 ; WO 2011/127051 October 2011 ; WO 2012/015758 February 2012 ; WO 2012/040279 March 2012 ; WO 2012/109108 August 2012 ; WO 2012/135570 October 2012 ; WO 2012/145361 October 2012 ; WO 2012/145603 October 2012 ; WO 2012/145604 October 2012 ; WO 2012/170702 December 2012 ; WO 2013/055910 April 2013 ; WO 2014/136282 September 2014 ; WO 2016/112075 July 2016 ; WO 2016/209809 December 2016 ; WO 2018/151834 August 2018 ; WO 2018/151873 August 2018 ; WO 2020/146529 July 2020 Other References: Primary Examiner: Coleman, Brenda L Attorney, Agent or Firm: Shao, Feng

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