LFA-1 inhibitor and methods of preparation and polymorph thereof

• US 9,085,553 B2
• Filed: 07/25/2013
• Issued: 07/21/2015
• Est. Priority Date: 07/25/2012
• Status: Active Grant

• Current Assignee: Bausch + Lomb Ireland Ltd. (Bausch Health Cos., Inc.)
• Original Assignee: Sarcode Bioscience Inc. (Shire plc)
• Inventors: Zeller, James Robert, Venkatraman, Sripathy, Brot, Elisabeth C. A., Iyer, Subashree, Hall, Michael
• Primary Examiner(s): NORTHINGTON DAVI, ZINNA
• Application Number:
  US13/950,807
• Publication Number:
  US 20140031387A1
• Time in Patent Office: 726 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 407/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Methods of preparation and purification of a compound of Formula I, intermediates thereof, a polymorph thereof, and related compounds are disclosed. Formulations and uses thereof in the treatment of LFA-1 mediated diseases are also disclosed.

Claims

1. A method of synthesizing a compound of Formula I:

2. The method of claim 1, wherein the biphasic conditions include aqueous acetone.

3. The method of claim 2, wherein the aqueous acetone is about 30% aqueous acetone.

4. The method of claim 2, wherein the aqueous acetone is present in an amount ranging from about 1:

1 to about 5;

1 by weight with respect to Formula AA.

5. The method of claim 1, wherein the base is sodium hydroxide.

6. The method of claim 5, wherein the sodium hydroxide is added in an amount ranging from about 1.0 to about 1.5 equivalents.

7. The method of claim 6, wherein the sodium hydroxide is added in an amount of about 1.2 equivalents.

8. The method of claim 1, further comprising a phase transfer catalyst.

9. The method of claim 8, wherein said phase transfer catalyst is a quaternary ammonium salt.

10. The method of claim 9, wherein said quaternary ammonium salt is tetrabutylammonium hydroxide.

11. The method of claim 8, wherein said phase transfer catalyst is present in an amount ranging from about 0.01 equivalents to about 0.5 equivalents.

12. The method of claim 1, wherein R is a substituted or unsubstituted group selected from lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, aryl, aralkyl, heterocyclyl, and heteroaryl groups.

13. The method of claim 1, wherein Formula AA is:

14. The method of claim 1, further comprising purifying said compound of Formula I by recrystallization.

15. The method of claim 14, wherein said recrystallization is performed with aqueous acetone.

16. A composition comprising a compound of Formula I: