Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11040998-B2
Application number	US-201916593262-A
Country	US
Kind code	B2
Filing date	Oct 4, 2019
Priority date	Mar 31, 2015
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

Abstract

The present invention provides compounds represented by Formula I, or pharmaceutically acceptable salts, stereoisomers, solvates, hydrates or combination thereof,The invention also provides pharmaceutical compositions comprising these compounds and methods of using this compounds for treating FXR-mediated or TGR5-mediated diseases or conditions.

First claim

What is claimed is:

1. A compound represented by Formula (III-10) or a pharmaceutically acceptable salt thereof:

wherein:
R 1 is selected from the group consisting of:
1) Halogen;
2) Hydroxyl;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl;
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
7) Substituted or unsubstituted aryl;
8) Substituted or unsubstituted arylalkyl;
9) Substituted or unsubstituted heterocycloalkyl;
10) Substituted or unsubstituted heteroaryl;
11) Substituted or unsubstituted heteroarylalkyl; and
12)—NR 10 R 11 ;

R 2 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted arylalkyl; and
6) Substituted or unsubstituted aryl;

R c is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted arylalkyl; and
6) Substituted or unsubstituted aryl;

m is selected from 0, 1, 2 and 3;
R 7 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl; and
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl; and

R 10 and R 11 are each independently selected from hydrogen, substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted-C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl, or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.

2. A method for treating a disease or condition selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, Type II diabetes, and hepatocellular carcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

3. The method according to claim 2 , wherein the disease or condition is selected from the group consisting of primary biliary cirrhosis, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.

4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

5. The compound of claim 1 , wherein R 2 and R c are both hydrogen, R 7 is ethyl, and m is 0 or 1.

6. The compound of claim 1 , selected from the compounds set forth in the table below:

Compound
Structure

 4

 6

10

14

15

30

44-b

79

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , having the structure

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 6 , having the structure

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 6 , having the structure

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 6 , having the structure

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 6 , having the structure

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 6 , having the structure

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 6 , having the structure

or a pharmaceutically acceptable salt thereof.

14. The

Assignees

• Enanta Pharm Inc

Inventors

• Wang Guoqiang
• Or Yat Sun
• Shen Ruichao
• Xing Xuechao
• Long Jiang
• Dai Peng
• Granger Brett
• He Jing

Classifications

• A61K31/57 Primary

  substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone · CPC title

• C07J9/00

  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 · CPC title

• C07J41/0088

  containing unsubstituted amino radicals · CPC title

• C07J41/005 Primary

  the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title