Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions

• US 8,546,365 B2
• Filed: 04/07/2011
• Issued: 10/01/2013
• Est. Priority Date: 06/27/2006
• Status: Active Grant

• Current Assignee: Intercept Pharmaceuticals Inc. (Alfasigma S.p.A.), Stefano Fiorucci
• Original Assignee: Intercept Pharmaceuticals Inc. (Alfasigma S.p.A.)
• Inventors: Pellicciari, Roberto, Fiorucci, Stefano, Pruzanski, Mark
• Primary Examiner(s): Badio, Barbara P
• Application Number:
  US13/082,261
• Publication Number:
  US 20120283234A1
• Time in Patent Office: 908 Days
• Field of Search: 514/182, 552/553
• 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: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07J 31/006 : not covered by C07J31/003
• CPC Class Codes: C07J 9/00 : Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Abstract

The present invention relates to compounds of formula (I):

• • wherein R is hydrogen or alpha-hydroxy,
  • the hydroxyl group in position 7 is in the alpha or beta position;
  • and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof.

Claims

1. A method for the treatment of a chronic liver disease selected from primary biliary cirrhosis, primary sclerosing cholangitis, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis (NASH) in a mammal comprising administering to the mammal suffering from the chronic liver disease a therapeutically effective amount of a compound of formula (I):

2. The method of claim 1, wherein the pharmaceutically acceptable salt is

3. The method of claim 1, wherein the pharmaceutically acceptable salt is

4. A method for the treatment of a gastrointestinal disease selected from inflammatory bowel disease, irritable bowel syndrome, bacterial overgrowth, and malabsorption comprising administering to the mammal suffering from the gasterointestinal disease a therapeutically effective amount of a compound of formula (I):

5. The method of claim 4, wherein the inflammatory bowel disease is selected from Crohn'"'"'s disease and ulcerative colitis.

6. The method of claim 4, wherein the pharmaceutically acceptable salt is

7. The method of claim 4, wherein the pharmaceutically acceptable salt is

8. A method for the treatment of a renal disease selected from diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), and chronic glomerulonephritis comprising administering to the mammal suffering from the renal disease a therapeutically effective amount of a compound of formula (I):

9. The method of claim 8, wherein the renal disease is diabetic nephropathy.

10. The method of claim 8, wherein the pharmaceutically acceptable salt is

11. The method of claim 8, wherein the pharmaceutically acceptable salt is

12. A method for the treatment of a cardiovascular disease selected from atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia comprising administering to the mammal suffering from the cardiovascular disease a therapeutically effective amount of a compound of formula (I):

13. The method of claim 12, wherein the cardiovascular disease is selected from hypertriglyceridemia, hypercholesterolemia, and atherosclerosis.

14. The method of claim 12, wherein the pharmaceutically acceptable salt is

15. The method of claim 12, wherein the pharmaceutically acceptable salt is

16. A method for the treatment of metabolic disease selected from insulin resistance, Type I and Type II diabetes, and obesity comprising administering to the mammal suffering from the metabolic disease a therapeutically effective amount of a compound of formula (I):

17. The method of claim 16, wherein the pharmaceutically acceptable salt is

18. The method of claim 16, wherein the pharmaceutically acceptable salt is