Processes for the preparation of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof

Patent metadata

Field	Value
Publication number	US-2016016904-A1
Application number	US-201514870752-A
Country	US
Kind code	A1
Filing date	Sep 30, 2015
Priority date	Jan 27, 2010
Publication date	Jan 21, 2016
Grant date	—

Abstract

The present invention relates to processes and intermediates useful in the preparation of (R)-2-(7-(4-cyclopentyl-3-(trifluromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid of Formula (I) and salts thereof, an S1P1 receptor modulator that is useful 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 vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development and atherosclerosis).

First claim

1 . A process for preparing a pharmaceutical composition, comprising:
a) hydrolyzing a compound of Formula (IIk):

wherein R 3 is C 1 -C 6 alkyl;

in the presence of 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 of Formula (Ia):

and
b) admixing (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (Formula (Ia)), or a salt thereof, with a pharmaceutically acceptable carrier.

2 . The process according to claim 1 , wherein R 3 is ethyl.

3 . The process according to claim 1 , wherein said lipase is immobilized Candida antarctica lipase B.

4 . The process according to claim 1 , wherein said hydrolyzing-step solvent comprises dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), or acetonitrile.

5 . The process according to claim 1 , wherein said hydrolyzing-step solvent comprises acetonitrile.

6 . The process according to claim 1 , wherein:
said compound of Formula (IIk) is:

said lipase is immobilized Candida antarctica lipase B; and
said hydrolyzing-step solvent comprises acetonitrile.

7 . The process according to claim 1 , wherein said hydrolyzing in step a), is conducted in the presence of a phosphate buffer at a pH of about 7.6 to about 8.0.

8 . The process according to claim 7 , wherein said phosphate buffer is a potassium phosphate buffer.

9 . The process according to claim 1 , wherein said hydrolyzing in step a), is conducted at a temperature of about 30° C. to about 55° C.

10 . The process according to claim 1 , wherein said hydrolyzing in step a), further comprises the step of isolating said (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, wherein after said isolating, said (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid has an enantiomeric excess of about 95% or greater.

11 - 61 . (canceled)

62 . The process according to claim 6 , wherein said hydrolyzing in step a), is conducted in the presence of a phosphate buffer at a pH of about 7.6 to about 8.0.

63 . The process according to claim 62 , wherein said phosphate buffer is a potassium phosphate buffer.

64 . The process according to claim 63 , wherein said hydrolyzing in step a), is conducted at a temperature of about 30° C. to about 55° C.

65 . The process according to claim 1 , wherein the composition is suitable for oral, rectal, nasal, topical, buccal, sub-lingual, vaginal, parenteral, intramuscular, sub-cutaneous, or intravenous administration; or suitable for administration by inhalation, insufflation or by a transdermal patch.

66 . The process according to claim 1 , wherein the composition is suitable for oral administration.

67 . The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises a diluent.

68 . The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises mannitol.

69 . The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises a lubricant.

70 . The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises magnesium stearate.

71 . The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises a tablet disintegrating agent.

72 . The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises a diluent, a lubricant, and a tablet disintegrating agent.

73 . The process according to claim 1 , wherein the pharmaceutically acceptable carrier comprises mannitol and magnesium stearate.

74 . A pharmaceutical composition produced by the process of claim 1 .

75 . A method of treating an S1P1 receptor-associated disorder in an individual, comprising administering to said individual in need thereof a pharmaceutical composition of claim 74 .

Assignees

• Arena Pharm Inc

Inventors

• Montalban Antonio Garrido
• Buzard Daniel J
• Demattei John A
• Gharbaoui Tawfik
• Johannsen Stephen R
• Krishnan Ashwin M
• Kuhlman Young Mi
• Ma You-An
• Martinelli Michael John
• Sato Suzanne Michiko
• Sengupta Dipanjan

Classifications

• A61P37/06

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

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title