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

• US 20080182832A1
• Filed: 06/27/2007
• Published: 07/31/2008
• 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: Fiorucci, Stefano, Pellicciari, Roberto, Pruzanski, Mark
• Granted Patent: US 7,932,244 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: 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 of formula (I):

7. A method for the prevention or treatment of an FXR-mediated disease or condition in a mammal comprising administering to the mammal suffering from an FXR-mediated disease or condition a therapeutically effective amount of a compound of formula (I) according to any one of claims 1-4.

14. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-4 and a pharmaceutically acceptable carrier or diluent.

15. Use of a compound of formula (I) as defined in claims 1-4 for the preparation of pharmaceutical compositions for the prevention or treatment of FXR-mediated diseases or conditions.

16. Use of a compound of formula (I) as defined in claims 1-4 for the preparation of pharmaceutical compositions for the prevention or treatment of a FXR-mediated disease or condition selected from the group consisting of chronic liver disease, gastrointestinal disease, renal disease, cardiovascular disease, and metabolic disease, cardiovascular disease, atherosclerosis, arteriosclerosis, hypercholesteremia, and hyperlipidemia.

17. Use of a compound of formula (I) as defined in claims 1-4 for the preparation of pharmaceutical compositions for the prevention or treatment of cholestatic liver diseases a chronic liver disease selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren'"'"'s syndrome, Sarcoidosis, Wilson'"'"'s disease, Gaucher'"'"'s disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

18. Use of a compound of formula (I) as defined in claims 1-4 for the preparation of pharmaceutical compositions for the prevention or treatment of a gastrointestinal disease selected from the group consisting of inflammatory bowel disease (IBD), Crohn'"'"'s disease, ulcerative colitis, irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis, and microscopic colitis.

19. Use of a compound of formula (I) as defined in claims 1-4 for the preparation of pharmaceutical compositions for the prevention or treatment of a renal disease selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease.

20. Use of a compound of formula (I) as defined in claims 1-4 for the preparation of pharmaceutical compositions for the prevention or treatment of a cardiovascular disease selected from the group consisting of atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia.atherosclerosis, arteriosclerosis, hypercholestremia, and hyperlipidemia.

21. Use of a compound of formula (I) as defined in claims 1-4 for the preparation of pharmaceutical compositions for the prevention or treatment of a metabolic disease selected from the group consisting of insulin resistance, Type I and Type II diabetes, and obesity.

22. Pharmaceutical compositions containing a compound of formula (I) as defined in claims 1-4 in admixture with pharmaceutically acceptable carriers and/or diluents.

2. A compound of formula (I) wherein the hydroxy group in 7 is in the alpha position and R is hydrogen.

3. A compound of formula (I) wherein the hydroxy group in 7 is in the beta position and R is hydrogen.

4. A compound of formula (I) wherein the hydroxy group in 7 is in the alpha position and R is alpha-hydroxy.

5. A compound of formula (I) wherein the pharmaceutically acceptable salt is:

8. A method according to claim 5 wherein the FXR-mediated disease or condition is selected from the group consisting of chronic liver disease, gastrointestinal disease, renal disease, cardiovascular disease, and metabolic disease.

6. A compound of formula (I) wherein the pharmaceutically acceptable salt is:

9. A method according to claim 6 wherein the chronic liver disease is selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren'"'"'s syndrome, Sarcoidosis, Wilson'"'"'s disease, Gaucher'"'"'s disease, hemochromatosis, and alpha 1-antitrypsin deficiency.

10. A method according to claim 6 wherein the gastrointestinal disease is selected from the group consisting of inflammatory bowel disease (IBD), Crohn'"'"'s disease, ulcerative colitis, irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis, and microscopic colitis.

11. A method according to claim 6 wherein the renal disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease.

12. A method according to claim 6 wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia.

13. A method according to claim 6 wherein the metabolic disease is selected from the group consisting of insulin resistance, Type I and Type II diabetes, and obesity.