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

• US 9,090,652 B2
• Filed: 08/28/2013
• Issued: 07/28/2015
• Est. Priority Date: 06/27/2006
• Status: Active Grant

• Current Assignee: Intercept Pharmaceuticals Inc.
• Original Assignee: Intercept Pharmaceuticals Inc.
• Inventors: Pellicciari, Roberto, Fiorucci, Stefano, Pruzanski, Mark
• Primary Examiner(s): Badio, Barbara P
• Application Number:
  US14/012,401
• Publication Number:
  US 20140057886A1
• Time in Patent Office: 699 Days
• Field of Search: 552/553, 514/182
• US Class Current: 1/1
• 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 compound selected from

2. A method for treating an FXR-mediated disease or condition in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1, wherein the FXR-mediated disease or condition is selected from:

cholestasis;

colitis;

a chronic liver disease selected from primary biliary cirrhosis, primary sclerosing cholangitis, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis,

a gastrointestinal disease selected from inflammatory bowel disease, irritable bowel syndrome, bacterial overgrowth, and malabsorption;

a renal disease selected from diabetic nephropathy, focal segmental glomerulosclerosis, and chronic glomerulonephritis;

a cardiovascular disease selected from atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia; and

a metabolic disease selected from insulin resistance, Type I and Type II diabetes, and obesity.

3. The method of claim 2, wherein the FXR-mediated disease or condition is cholestasis.

4. The method of claim 2, wherein the FXR-mediated disease or condition is a chronic liver disease.

5. The method of claim 2, wherein the FXR-mediated disease or condition is a gastrointestinal disease.

6. The method of claim 2, wherein the FXR-mediated disease or condition is a renal disease.

7. The method of claim 2, wherein the FXR-mediated disease or condition is a cardiovascular disease.

8. The method of claim 2, wherein the FXR-mediated disease or condition is a metabolic disease.

9. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.