Steroids as agonists for FXR
The invention relates to compounds of formula (I): wherein R is ethyl, propyl or allyl, and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof. The compounds of formula (I) are useful as FXR agonists.
1. A process for preparing a compound of formula I:
or a pharmaceutically acceptable salt or amino acid conjugate thereof, comprising:
a) reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid with 3,4-dihydropyrane to prepare 3α-tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid;
b) reacting 3α-tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid with an alkyl bromide of the formula R—Br, wherein R is ethyl, to prepare a compound of formula II:
c) reacting the compound of formula II with sodium borohydride to prepare a compound of formula III:
d) reacting the compound of formula II with sodium hydroxide to prepare the compound of formula I.
2. A method of increasing flow of bile acids from the liver to the intestine in a subject suffering from a cholestatic liver disease, comprising administering to the subject a therapeutically effective amount of a compound of formula I:
or a pharmaceutically acceptable salt or amino acid conjugate thereof.
3. The method of claim 2 , wherein the compound is a glycine conjugate of the compound of formula I.
4. The method of claim 2 , wherein the compound is a taurine conjugate of the compound of formula I.
5. The method of claim 2 , wherein the compound is a pharmaceutically acceptable salt of the compound of formula I.
6. The method of claim 2 , wherein the subject is a mammal.
7. The method of claim 6 , wherein the mammal is a human.