Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
The present invention provides compounds of Formula I, pharmaceutical compositions comprising these compounds and methods of using these compounds to prevent or treat FXR-mediated or TGR5-mediated diseases or conditions.
1. A compound represented by Formula V-A or Formula V-B, 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 ;
m is selected from 0, 1, 2 and 3; 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. The compound of claim 1 , wherein R 1 is C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, phenyl-C 1 -C 4 -alkyl, substituted or unsubstituted C 3 -C 6 -cycloalkyl, C 1 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, 5- or 6-membered heterocycloalkyl, amino, substituted or unsubstituted phenyl or halogen.
3. The compound of claim 1 , wherein R 1 is selected from the groups set forth in the table below:
4. The compound of claim 1 , wherein R 1 is ethyl, butyl, t-butyl,
propyl, benzyl, vinyl, allyl, CF 3 , or fluoro.
5. The compound of claim 1 , wherein R 1 is dimethylamino or p-tert-butylphenyl.
6. The compound of claim 1 , selected from the compounds set forth in the table below, or a pharmaceutically acceptable salt thereof:
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
8. 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 .
9. The method according to claim 8 , wherein the disease or condition is primary biliary cirrhosis, nonalcoholic fatty liver disease, or nonalcoholic steatohepatitis.
10. A method for ameliorating nonalcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 6 .
11. A method for 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 6 .
12. A method for ameliorating primary biliary cirrhosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 6 .