Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
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.
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):
(I) or a pharmaceutically acceptable salt or amino acid conjugate thereof,
wherein R is hydrogen or alpha-hydroxy, and
the hydroxy group in the 7 position is in the alpha or beta position.
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):
(I) or a pharmaceutically acceptable salt or amino acid conjugate thereof,
wherein R is hydrogen or alpha-hydroxy, and
the hydroxy group in the 7 position is in the alpha or beta position.
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):
(I) or a pharmaceutically acceptable salt or amino acid conjugate thereof,
wherein R is hydrogen or alpha-hydroxy, and
the hydroxy group in the 7 position is in the alpha or beta position.
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):
(I) or a pharmaceutically acceptable salt or amino acid conjugate thereof,
wherein R is hydrogen or alpha-hydroxy, and
the hydroxy group in the 7 position is in the alpha or beta position.
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):
(I) or a pharmaceutically acceptable salt or amino acid conjugate thereof,
wherein R is hydrogen or alpha-hydroxy, and
the hydroxy group in the 7 position is in the alpha or beta position.
17. The method of claim 16 , wherein the pharmaceutically acceptable salt is
18. The method of claim 16 , wherein the pharmaceutically acceptable salt is