Farnesoid X receptor modulators

Patent metadata

Field	Value
Publication number	US-9611289-B2
Application number	US-201414120366-A
Country	US
Kind code	B2
Filing date	May 14, 2014
Priority date	May 14, 2013
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

The present invention provides a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described herein. The present invention relates generally to selective FXR agonists and to methods of making and using them.

First claim

The invention claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein:
R 1 is beta-hydroxyl;
R 2 is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more R a ;
R 3 is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more R b ;
R 4 is alkyl, alkenyl, alkynyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more R c ;
R a , R b , and R c are each independently halogen or hydroxyl;
R 5 is hydroxyl, OSO 3 H, OSO 3 − , O(CO)CH 3 , OPO 3 H 2 , OPO 3 2− , or hydrogen; and
R 6 is hydroxyl, OSO 3 H, OSO 3 − , O(CO)CH 3 , OPO 3 H 2 , OPO 3 2− , or hydrogen;
or taken together R 5 and R 6 with the carbon atom to which they are attached form a carbonyl.

2. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt or amino acid conjugate thereof.

3. The compound of claim 1 , wherein one of R 2 or R 3 is hydroxyl or halogen and the remaining R 2 or R 3 is hydrogen or unsubstituted alkyl.

4. The compound of claim 3 , wherein one of R 2 or R 3 is hydroxyl and the remaining R 2 or R 3 is hydrogen.

5. The compound of claim 1 , wherein one of R 5 or R 6 is hydroxyl and the remaining R 5 or R 6 is hydrogen.

6. The compound of claim 1 , wherein R 2 is hydroxyl or halogen.

7. The compound of claim 1 , wherein R 3 is hydrogen or unsubstituted alkyl.

8. The compound of claim 7 , wherein R 3 is methyl.

9. The compound of claim 1 , wherein R 2 is hydroxyl and R 3 is hydrogen.

10. The compound of claim 1 , wherein R 5 is hydroxyl.

11. The compound of claim 1 , wherein R 6 is hydrogen.

12. The compound of claim 1 , wherein R 2 and R 5 are each hydroxyl and R 3 and R 6 are each hydrogen.

13. The compound of claim 1 , wherein R 4 is alkyl.

14. The compound of claim 13 , wherein R 4 is unsubstituted alkyl.

15. The compound of claim 14 , wherein R 4 is ethyl.

16. A compound of the following formula:

or a pharmaceutically acceptable salt or amino acid conjugate thereof.

17. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, and a pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising a compound of claim 16 or a pharmaceutically acceptable salt or amino acid conjugate thereof, and a pharmaceutically acceptable excipient.

19. A method of treating a chronic liver disease or condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein the chronic liver disease or condition 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.

20. A method of treating a chronic liver disease or condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of claim 16 or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein the chronic liver disease or condition 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.

Assignees

• Intercept Pharmaceuticals Inc

Inventors

• Pellicciari Roberto

Classifications

• C07J41/0061

  one of the carbon atoms being part of an amide group · CPC title

• C07J71/001

  Oxiranes · CPC title

• C07J31/006

  not covered by C07J31/003 · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61K31/575 Primary

  substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol · CPC title