Preparation and uses of obeticholic acid

Patent metadata

Field	Value
Publication number	US-10174073-B2
Application number	US-201715496398-A
Country	US
Kind code	B2
Filing date	Apr 25, 2017
Priority date	Jun 19, 2012
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

The present invention relates to obeticholic acid:

or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof. Obeticholic acid is useful for the treatment or prevention of a FXR mediated disease or condition, cardiovascular disease or cholestatic liver disease, and for reducing HDL cholesterol, for lowering triglycerides in a mammal, or for inhibition of fibrosis. The present invention also relates to processes for the synthesis of obeticholic acid.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising non-crystalline obeticholic acid (OCA) comprising less than 1% by weight of chenodeoxycholic acid (CDCA), wherein the non-crystalline OCA is prepared by a process comprising at least one step of crystallizing crude OCA using at least one organic solvent.

2. The pharmaceutical composition of claim 1 , wherein the at least one organic solvent is selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate.

3. The pharmaceutical composition of claim 1 , wherein the at least one organic solvent comprises n-butyl acetate.

4. The pharmaceutical composition of claim 1 , wherein the process further comprises the step of converting a crystalline form of OCA to the non-crystalline OCA by dissolving the crystalline form in an aqueous NaOH solution and adding HCl.

5. The pharmaceutical composition of claim 1 , wherein the process further comprises the step of reacting 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with NaBH 4 to form the crude OCA.

6. The pharmaceutical composition of claim 1 , wherein the non-crystalline OCA comprises a total of not more than 0.15% by weight of 6-ethylursodeoxycholic acid and 3α,7α-dihydroxy-6-ethyliden-5β-cholan-24-oic acid.

7. The pharmaceutical composition of claim 6 , wherein the non-crystalline OCA comprises a total of less than about 0.07% by weight of 6-ethylursodeoxycholic acid and 3α,7α-dihydroxy-6-ethyliden-5β-cholan-24-oic acid.

8. The pharmaceutical composition of claim 7 , wherein the non-crystalline OCA comprises a total of less than about 0.06% by weight of 6-ethylursodeoxycholic acid and 3α,7α-dihydroxy-6-ethyliden-5β-cholan-24-oic acid.

9. The pharmaceutical composition of claim 8 , wherein the non-crystalline OCA comprises a total of less than about 0.05% by weight of 6-ethylursodeoxycholic acid and 3α,7α-dihydroxy-6-ethyliden-5β-cholan-24-oic acid.

10. The pharmaceutical composition of claim 1 , wherein the non-crystalline OCA comprises not more than 0.15% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.

11. The pharmaceutical composition of claim 10 , wherein the non-crystalline OCA comprises less than 0.07% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.

12. The pharmaceutical composition of claim 11 , wherein the non-crystalline OCA comprises less than 0.06% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.

13. The pharmaceutical composition of claim 12 , wherein the non-crystalline OCA comprises less than 0.05% by weight of 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid.

14. The pharmaceutical composition of claim 1 , wherein the non-crystalline OCA comprises not more than 0.15% by weight of 6β-ethylchenodeoxycholic acid.

15. The pharmaceutical composition of claim 14 , wherein the non-crystalline OCA comprises less than about 0.07% by weight of 6β-ethylchenodeoxycholic acid.

16. The pharmaceutical composition of claim 15 , wherein the non-crystalline OCA comprises less than about 0.06% by weight of 6β-ethylchenodeoxycholic acid.

17. The pharmaceutical composition of claim 16 , wherein the non-crystalline OCA comprises less than about 0.05% by weight of 6β-ethylchenodeoxycholic acid.

18. The pharmaceutical composition of claim 1 , wherein the non-crystalline OCA comprises less than about 0.5% by weight of CDCA.

19. The pharmaceutical composition of claim 18 , wherein the non-crystalline OCA comprises less than about 0.3% by weight of CDCA.

20. The pharmaceutical composition of claim 19 , wherein the non-crystalline OCA comprises less than about 0.2% by weight of CDCA.

21. The pharmaceutical composition of claim 1 , wherein the non-crystalline OCA comprises from 0.01% by weight to less than 1% by weight of CDCA.

22. The pharmaceutical composition of claim 21 , wherein the non-crystalline OCA further comprises not more than 0.15% by weight of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.

23. The pharmaceutical composition of claim 22 , wherein the non-crystalline OCA comprises less than about 0.07% by weight of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.

24. The pharmaceutical composition of claim 23 , wherein the non-crystalline OCA comprises less than about 0.06% by weight of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.

25. The pharmaceutical composition of claim 24 , wherein the non-crystalline OCA comprises less than about 0.05% by weight of 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.

26. The pharmaceutical composition of claim 1 , wherein the non-crystalline OCA further comprises less than about 3% by weight of water.

27. A pharmaceutical composition comprising non-crystalline obeticholic acid (OCA) and not more than 1% by weight of chenodeoxycholic acid (CDCA), wherein the OCA is prepared by a process comprising at least one step of crystallizing crude OCA using an organic solvent selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate.

28. The pharmaceutical composition of claim 27 , wherein the solvent comprises n-butyl acetate.

29. The pharmaceutical composition of claim 27 , wherein the non-crystalline OCA comprises from 0.01% by weight to not more than 1% by weight of CDCA.

30. A crystalline form of obeticholic acid (OCA) produced by a process of crystallizing crude OCA using at least one organic solvent.

31. The crystalline form of OCA of claim 30 , wherein the at least one organic solvent is selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate.

32. The crystalline form of OCA of claim 31 , wherein the at least one organic solvent comprises n-butyl acetate.

33. A composition comprising a crystalline form of obeticholic acid (OCA), wherein the crystalline form of OCA is produced by a process comprising at least one step of crystallizing crude OCA using at least one organic solvent.

34. The composition of claim 33 , wherein the at least one organic solvent is selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate.

35. The composition of claim 34 , wherein the at least one organic solvent comprises n-butyl acetate.

36. A pharmaceutical composition comprising non-crystalline obeticholic acid (OCA), wherein the OCA is prepared by a process comprising at least one step of crystallizing crude OCA using at least one organic solvent, and wherein the OCA comprises a total of less than 2% by weight of one or more impurities selected from 6-ethylursodeoxycholic acid, 3α-hydroxy-6α-ethyl-7-cheto-5β-cholan-24-oic acid, 6β-ethylchenodeoxycholic acid, 3α,7α-dihydroxy-6-ethyliden-5β-cholan-24-oic acid, chenodeoxycholic acid (CDCA), and 3a (3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.

37. The pharmaceutical composition of claim 36 , wherein the at least one organic solvent is selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate.

38. The pharmaceutical composition of claim 37 , wherein the at least on

Assignees

• Intercept Pharmaceuticals Inc

Inventors

• Steiner André
• Waenerlund Poulsen Heidi
• Jolibois Emilie
• Rewolinski Melissa
• Gross Ralf
• Sharp Emma
• Dubas-Fisher Fiona
• Eberlin Alex

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title