FARNESOID X RECEPTOR MODULATORS
The present invention provides a compound of formula (I): or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described herein. The present invention relates generally to selective FXR agonists and to methods of making and using them.
1 . A method for treating or preventing gastrointestinal disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt or amino acid conjugate thereof, wherein:
R 1 is beta-hydroxyl;
R 2 is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more R a ;
R 3 is hydrogen, hydroxyl, alkyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more R b ;
R 4 is alkyl, alkenyl, alkynyl, or halogen, wherein said alkyl is unsubstituted or substituted with one or more R c ;
R a , R b , and R c are each independently halogen or hydroxyl;
R 5 is hydroxyl, OSO3H, OSO3 − , O(CO)CH3, OPO3H2, OPO32 − , or hydrogen; and
R 6 is hydroxyl, OSO3H, OSO3 − , O(CO)CH3, OPO3H2, OPO32 − , or hydrogen;
or taken together R 5 and R 6 with the carbon atom to which they are attached form a carbonyl.
2 . The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt or amino acid conjugate thereof.
3 . The method of claim 1 , wherein one of R 2 or R 3 is hydroxyl or halogen and the remaining R 2 or R 3 is hydrogen or unsubstituted alkyl.
4 . The method of claim 3 , wherein one of R 2 or R 3 is hydroxyl and the remaining R 2 or R 3 is hydrogen.
5 . The method of claim 1 , wherein one of R 5 or R 6 is hydroxyl and the remaining R 5 or R 6 is hydrogen.
6 . The method of claim 1 , wherein R 2 is hydroxyl or halogen.
7 . The method of claim 1 , wherein R 3 is hydrogen or unsubstituted alkyl.
8 . The method of claim 7 , wherein R 3 is methyl.
9 . The method of claim 1 , wherein R 2 is hydroxyl and R 3 is hydrogen.
10 . The method of claim 1 , wherein R 5 is hydroxyl.
11 . The method of claim 1 , wherein R 6 is hydrogen.
12 . The method of claim 1 , wherein R 2 and R 5 are each hydroxyl and R 3 and R 6 are each hydrogen.
13 . The method of claim 1 , wherein R 4 is alkyl.
14 . The method of claim 13 , wherein R 4 is unsubstituted alkyl.
15 . The method of claim 14 , wherein R 4 is ethyl.
16 . The method of claim 1 , wherein the gastrointestinal disease is selected from inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis, and microscopic colitis.
17 . The method of claim 16 , wherein the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.
18 . A method for treating or preventing gastrointestinal disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the following formula:
or a pharmaceutically acceptable salt or amino acid conjugate thereof.
19 . The method of claim 18 , wherein the gastrointestinal disease is selected from inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis, and microscopic colitis.
20 . The method of claim 19 , wherein the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.