Preparation and Uses of Obeticholic Acid

• US 20130345188A1
• Filed: 06/17/2013
• Published: 12/26/2013
• Est. Priority Date: 06/19/2012
• Status: Active Grant

• Current Assignee: Intercept Pharmaceuticals Inc.
• Original Assignee: Intercept Pharmaceuticals Inc.
• Inventors: Sharp, Emma, Eberlin, Alex, Steiner, Andr, Waenerlund Poulsen, Heidi, Jolibois, Emilie, Rewolinski, Melissa, Gross, Ralf, Dubas-Fisher, Fiona
• Granted Patent: US 9,238,673 B2
• Time in Patent Office: Days
• US Class Current: 514/182
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/04 for urolithiasis
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
• CPC Class Codes: C07J 9/005 containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

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.

Claims

1. A crystalline obeticholic acid Form C characterized by an X-ray diffraction pattern including characteristic peaks at about 4.2, 6.4, 9.5, 12.5, and 16.7 degrees 2-Theta.

2. The crystalline obeticholic acid Form C according to claim 1 characterized by an X-ray diffraction pattern substantially similar to that set forth in FIG. 5.

3. The crystalline obeticholic acid Form C according to claim 1, further characterized by a Differential Scanning calorimetry (DSC) thermogram having an endotherm value at about 98±

2°

C.

4. A process for preparing obeticholic acid Form 1, comprising the step of

converting crystalline obeticholic acid to obeticholic acid Form 1.

5. The process according to claim 4, comprising the steps of

reacting 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid with NaBH₄ to form crystalline obeticholic acid, and

converting crystalline obeticholic acid to obeticholic acid Form 1.

6. The process according to claim 5, comprising the steps of

reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid,

reacting 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid with NaBH₄ to form crystalline obeticholic acid, and

converting crystalline obeticholic acid to obeticholic acid Form 1.

7. The process according to claim 6, comprising the steps of

reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid,

reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid,

reacting 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid with NaBH₄ to form crystalline obeticholic acid, and

converting crystalline obeticholic acid to obeticholic acid Form 1.

8. The process according to claim 7, comprising the steps of

reacting 3α

,7-ditrimethylsilyloxy-5β

-chol-6-en-24-oic acid methyl ester with CH₃CHO to form E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid methyl ester,

reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid,

reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid,

reacting 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid with NaBH₄ to form crystalline obeticholic acid, and

converting crystalline obeticholic acid to obeticholic acid Form 1.

9. The process according to claim 8, comprising the steps of

reacting 3α

-hydroxy-7-keto-5β

-cholan-24-oic acid methyl ester with Li[N(CH(CH₃)₂)₂] and Si(CH₃)₃Cl to form 3α

,7-ditrimethylsilyloxy-5β

-chol-6-en-24-oic acid methyl ester,

reacting 3α

,7-ditrimethylsilyloxy-5β

-chol-6-en-24-oic acid methyl ester with CH₃CHO to form E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid methyl ester,

reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid,

reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid,

reacting 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid with NaBH₄ to form crystalline obeticholic acid, and

converting crystalline obeticholic acid to obeticholic acid Form 1.

10. The process according to claim 9, comprising the steps of

reacting 3α

-hydroxy-7-keto-5β

-cholan-24-oic acid with CH₃OH and H₂SO₄ to form 3α

-hydroxy-7-keto-5β

-cholan-24-oic acid methyl ester,

reacting 3α

-hydroxy-7-keto-5β

-cholan-24-oic acid methyl ester with Li[N(CH(CH₃)₂)₂] and Si(CH₃)₃Cl to form 3α

,7-ditrimethylsilyloxy-5β

-chol-6-en-24-oic acid methyl ester,

reacting 3α

,7-ditrimethylsilyloxy-5β

-chol-6-en-24-oic acid methyl ester with CH₃CHO to form E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid methyl ester,

reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid,

reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid,

reacting 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid with NaBH₄ to form crystalline obeticholic acid, and

converting crystalline obeticholic acid to obeticholic acid Form 1.

11. The process according to claim 10, wherein converting crystalline obeticholic acid Form C to obeticholic acid Form 1 comprises the step of dissolving crystalline obeticholic acid Form C in aqueous NaOH solution and adding HCl.

12. The process according to claim 10, wherein reacting 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid with NaBH₄ to form crystalline obeticholic acid is carried out at a temperature at about 85°

C. to about 110°

C. in a basic aqueous solution.

13. The process according to claim 10, wherein reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α

-hydroxy-6α

-ethyl-7-keto-5β

-cholan-24-oic acid is carried out at a temperature at about 90°

C. to about 110°

C. and at a pressure at about 4 to about 5 bars.

14. The process according to claim 10, wherein reacting E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid is carried out at a temperature at about 45°

C. to about 60°

C.

15. The process according to claim 10, wherein reacting 3α

,7-ditrimethylsilyloxy-5β

-chol-6-en-24-oic acid methyl ester with CH₃CHO to form E- or E/Z-3α

-hydroxy-6-ethylidene-7-keto-5β

-cholan-24-oic acid methyl ester is carried out in a polar aprotic solvent at a temperature at about −

50°

C. to about −

70°

C. in the presence of BF₃.

16. The process according to claim 10, wherein reacting 3α

-hydroxy-7-keto-5β

-cholan-24-oic acid methyl ester with Li[N(CH(CH₃)₂)₂] and Si(CH₃)₃Cl to form 3α

,7-ditrimethylsilyloxy-5β

-chol-6-en-24-oic acid methyl ester is carried out in a polar aprotic solvent at a temperature at about −

10°

C. to about −

30°

C.

17. The process according to claim 10, wherein reacting 3α

-hydroxy-7-keto-5β

-cholan-24-oic acid with CH₃OH and H₂SO₄ to form 3α

-hydroxy-7-keto-5β

-cholan-24-oic acid methyl ester is heated for about 3 hours and the pH of the reaction mixture is adjusted with an aqueous basic solution to a pH-value of about 6.5 to about 8.0.

19. A pharmaceutical composition comprising obeticholic acid Form 1 produced by the process of claim 4 and a pharmaceutically acceptable carrier.

20. A method of treating or preventing an FXR mediated disease or condition in a subject comprise of administering an effective amount of obeticholic acid Form 1 produced by the process of claim 4, wherein the disease or condition is selected from biliary atresia, cholestatic liver disease, biliary atresia, chronic liver disease, nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, primary biliary cirrhosis (PBC), liver damage due to progressive fibrosis, liver fibrosis, and cardiovascular diseases including atherosclerosis, arteriosclerosis, hypercholesteremia, and hyperlipidemia.

18. An obeticholic acid, or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof, having a potency of greater than about 98%, greater than about 98.5%, greater than about 99.0%, or greater than about 99.5%.