Bile acid derivatives as FXR agonists and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10472386-B2
Application number	US-201815896400-A
Country	US
Kind code	B2
Filing date	Feb 14, 2018
Priority date	Feb 14, 2017
Publication date	Nov 12, 2019
Grant date	Nov 12, 2019

Abstract

The present invention provides compounds represented by Formula I, or pharmaceutically acceptable salts, prodrugs and esters 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 I or a pharmaceutically acceptable salt, ester or prodrug thereof:

is

R a and R b are independently selected from the group consisting of:
1) Hydrogen,
2) Optionally substituted —C 1 -C 8 alkyl,
3) Optionally substituted —C 2 -C 8 alkenyl,
4) Optionally substituted —C 2 -C 8 alkynyl,
5) Optionally substituted —C 3 -C 8 cycloalkyl,
6) Optionally substituted aryl,
7) Optionally substituted arylalkyl,
8) Optionally substituted 3- to 8- membered heterocycloalkyl,
9) Optionally substituted heteroaryl, and
10) Optionally substituted heteroarylalkyl;

m is selected from 1, 2 or 3;
R 1 is optionally substituted C 1 -C 6 alkyl, hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ;
R 2 is optionally substituted C 1 -C 6 alkyl, hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR a or —NHR a , wherein R a is previously defined; alternatively, R 1 and R 2 are taken together with the carbon atoms to which they attached to form —CH═CH— or cycloalkyl ring or heterocycloalkyl ring;
R 3a and R 3b are independently selected from hydrogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, or optionally substituted —O—C 1 -C 6 alkyl; alternatively, R 3a and R 3b are taken together with the carbon atom to which they attached to form —C(O); and
R 4 is selected from the group consisting of:
1) Hydrogen,
2) Halogen,
3) Optionally substituted —C 1 -C 8 alkyl,
4) Optionally substituted —C 2 -C 8 alkenyl,
5) Optionally substituted —C 2 -C 8 alkynyl, and
6) Optionally substituted —C 3 -C 8 cycloalkyl.

2. The compound of claim 1 , represented by Formula (Ia) or Formula (Ib), or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein R 1 , R 2 , R 4 , and

 are as defined in claim 1 .

3. The compound of claim 1 , represented by Formula (IIIa) or Formula (IIIb), or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein R 4 , R a , R b , and m are as defined in claim 1 .

4. The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt, ester or prodrug thereof:

5. The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt, ester or prodrug thereof:

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

7. A method for ameliorating 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 according to claim 1 .

8. A method of ameliorating primary biliary cirrhosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

9. A method of ameliorating nonalcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

10. A method of ameliorating nonalcoholic fatty liver disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

Assignees

• Enanta Pharm Inc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07J41/0055

  the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives · CPC title

• C07J51/00

  Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00 · CPC title

• C07J9/005

  containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton · CPC title

• C07J43/003 Primary

  not condensed · CPC title