Preparation and uses of obeticholic acid

Patent metadata

Field	Value
Publication number	US-9982008-B2
Application number	US-201514979005-A
Country	US
Kind code	B2
Filing date	Dec 22, 2015
Priority date	Jun 19, 2012
Publication date	May 29, 2018
Grant date	May 29, 2018

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 crystalline form of obeticholic acid characterized by an X-ray powder diffraction pattern comprising characteristic peaks at 5.0±0.2 degrees 2-theta, 5.3±0.2 degrees 2-theta, and 16.8±0.2 degrees 2-theta, wherein the crystalline form of obeticholic acid is obtainable by a process comprising crystallizing crude obeticholic acid in n-butyl acetate.

2. The crystalline form of obeticholic acid of claim 1 , characterized by an X-ray powder diffraction pattern further comprising a peak at 6.3±0.2 degrees 2-theta.

3. The crystalline form of claim 1 characterized by an X-ray powder diffraction pattern further comprising a peak at 10.0±0.2 degrees 2-theta.

4. The crystalline form of claim 1 characterized by an X-ray powder diffraction pattern further comprising a peak at 11.0±0.2 degrees 2-theta.

5. The crystalline form of claim 1 characterized by an X-ray powder diffraction pattern further comprising a peak at 12.4±0.2 degrees 2-theta.

6. The crystalline form of claim 1 having a purity of greater than about 96%.

7. The crystalline form of claim 6 having a purity of greater than about 98%.

8. The crystalline form of claim 1 having a total of less than about 4% of one or more impurities selected from the group consisting of 6-ethylursodeoxycholic acid, 3 α-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, and 3α(3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oyloxy)-7α-hydroxy-6α-ethyl-5β-cholan-24-oic acid.

9. The crystalline form of claim 8 , wherein the total percentage of impurities is less than about 3.8%.

10. The crystalline form of claim 8 , wherein the total percentage of impurities is less than about 3.6%.

11. A crystalline form of obeticholic acid characterized by an X-ray powder diffraction pattern comprising a peak at 5.0±0.2 degrees 2-theta, 6.3±0.2 degrees 2-theta, 10.0±0.2 degrees 2-theta, 11.0±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, 16.0±0.2 degrees 2-theta, 16.5±0.2 degrees 2-theta, and 16.8±0.2 degrees 2-theta.

12. The crystalline form of claim 1 characterized by an X-ray powder diffraction pattern further comprising a peak at 7.7±0.2 degrees 2-theta.

13. The crystalline form of claim 1 characterized by an X-ray powder diffraction pattern further comprising a peak at 14.9±0.2 degrees 2-theta.

14. A crystalline form of obeticholic acid characterized by an X-ray powder diffraction pattern comprising a peak at 5.0±0.2 degrees 2-theta, 5.3±0.2 degrees 2-theta, 7.7±0.2 degrees 2-theta, 10.0±0.2 degrees 2-theta, 11.0±0.2 degrees 2-theta, 12.4±0.2 degrees 2-theta, and 14.9±0.2 degrees 2-theta.

Assignees

• Intercept Pharmaceuticals Inc

Inventors

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

Classifications

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61K31/575

  substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07J51/00

  Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00 · CPC title

• C07J9/005 Primary

  containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton · CPC title