Bile acid derivatives as FXR agonists and methods of use thereof
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.
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 .