LFA-1 INHIBITOR AND METHODS OF PREPARATION AND POLYMORPH THEREOF

• US 20140031387A1
• Filed: 07/25/2013
• Published: 01/30/2014
• 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., Hall, Michael, Iyer, Subashree
• Granted Patent: US 9,085,553 B2
• Time in Patent Office: Days
• US Class Current: 514/307
• 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 Fomula 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.

41. An isolated compound of Formula I:

42. An isolated compound according to claim 41, wherein said compound has an optical purity >

98%.

44. The polymorph of claim 42, wherein the polymorph is characterized as having an X-ray powder diffraction pattern with peaks at a reflection angle 20 of about 10.8, 16.4, and 21.8 degrees.

45. The polymorph of claim 42, wherein the polymorph undergoes a small endotherm at about 38°

C.

46. The polymorph of claim 42, wherein the polymorph undergoes a melting transition at about 156°

C.

47. The polymorph of claim 42, wherein the polymorph is produced from a crystallization of Form I in acetone and n-heptane.

49. The composition of claim 47, wherein said composition is at least about 50% by weight polymorph Form II.

50. The composition of claim 47, wherein said composition is less than about 5% by weight polymorph Form II.

51. The composition of claim 47, further comprising one or more solid forms selected from the group consisting of amorphous, Form I, Form III, Form IV, Form V, and Form VI.

52. The composition of claim 50, wherein said composition is at least about 50% by weight polymorph Form II.

53. The composition of claim 47, wherein said composition is less than about 5% by weight polymorph Form II.

16. A reaction mixture comprising a compound of Formula I:

17. The reaction mixture of claim 16, further comprising one or more solvents.

18. The reaction mixture of claim 17, wherein said one or more solvents are selected from the group consisting of water, acetone, methyl ethyl ketone, dioxane, and mixtures thereof.

19. The reaction mixture of claim 16, further comprising water and acetone.

20. The reaction mixture of claim 16, wherein said reaction mixture is biphasic.

21. The reaction mixture of claim 16, further comprising a base.

22. The reaction mixture of claim 21, wherein said base is sodium hydroxide.

23. The reaction mixture of claim 16, further comprising a phase transfer catalyst.

24. The reaction mixture of claim 23, wherein said phase transfer catalyst is a quaternary ammonium salt.

25. The reaction mixture of claim 23, wherein said phase transfer catalyst is tetrabutylammonium hydroxide.

26. The reaction mixture of claim 16, 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.

27. The reaction mixture of claim 16, wherein Fomula AA is:

28. The reaction mixture of claim 27, further comprising water, acetone, sodium hydroxide, and tetrabutylammonium hydroxide, or salts thereof.

29. A method of purifying a compound of Formula I:

30. The method of claim 29, wherein said aqueous acetone is used in an amount of about 7 volumes.

31. The method of claim 29, wherein said aqueous acetone is about 30% aqueous acetone.

32. The method of claim 29, further comprising addition of a pH modifier to produce a pH of less than about 5.

33. The method of claim 32, wherein said method produces a pH between about 1 and about 5.

34. The method of claim 32, wherein said pH modifier is selected from an organic or mineral acid.

35. The method of claim 32, wherein said pH modifier is hydrochloric acid.

36. The method of claim 29, wherein said removal of aqueous acetone is by filtration.

37. The method of claim 29, wherein said method is performed for a period of time ranging from about 1 hour to about 48 hours.

54. An isolated compound of Formula I:

38. A composition comprising a compound of Formula I:

39. The composition of claim 38, further comprising a pH modifier, wherein said composition has a pH of between about 1 and about 5.

40. The composition of claim 38, wherein said composition is heated above room temperature.

43. A compound of Formula I:

48. A solid composition comprising a pharmaceutically acceptable carrier and further comprising the compound of Formula I: