ISOTOPICALLY LABELED BILE ACID DERIVATIVES
The present application relates to isotopically labeled compounds of Formula I and methods of preparation and use thereof
1 . A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein
R 1 is OH, O-glucuronide, OSO 3 H, SO 3 H, CO 2 R 5 , 14 CO 2 R 5 , C(O)R 6 , 14 C(O)R 6 ;
R 2 is H, D, or OH;
R 3 is OH or O-glucuronide;
R 4 is OH or O-glucuronide;
R 5 is H or substituted or unsubstituted alkyl;
R 6 is NH(CH 2 ) 2 SO 3 H, NHCH 2 CO 2 H, or N(CH 3 )CH 2 CO 2 H or glucuronic acid moieties,
wherein hydrogens in can be replaced with deuterium;
R 11 is Z 11b , hydroxy, halogen, alkoxy, or oxo when Z 11a is not present;
R 16 is Z 16a , hydroxy, halogen, alkoxy, or oxo when Z 16b is not present;
R 23 is Z 23a or alkyl; and
Z 1a , Z 1b , Z 2a , Z 2b , Z 3 , Z 4a , Z 4b , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 11a , Z 11b , Z 12 , Z 14 , Z 15a , Z 15b , Z 16a , Z 16b , Z 17 , Z 18 , Z 19 , Z 20 , Z 21 , Z 22a , Z 22b , Z 23a , Z 23b , Z 24a , Z 24b , or Z 25 is independently selected from H (hydrogen) or D (deuterium), and at least one of Z 1a , Z 1b , Z 2a , Z 2b , Z 3 , Z 4a , Z 4b , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Z 11a , Z 11b , Z 12 , Z 14 , Z 15a , Z 15b , Z 16a , Z 16b , Z 17 , Z 18 , Z 19 , Z 20 , Z 21 , Z 22a , Z 22b , Z 23a , Z 23b , Z 24a , Z 24b , or Z 25 is D; and
any carbon atom is 12 C, 13 C, or 14 C.
2 . The compound of claim 1 wherein R 2 is H.
3 . The compound of claim 1 wherein R 2 is OH.
4 . The compound of claim 3 wherein R 2 is alpha-OH.
5 . The compound of claim 1 , wherein R 6 is taurine (—NH(CH 2 ) 2 SO 3 H), glycine (—NHCH 2 CO 2 H), or sarcosine (—N(CH 3 )CH 2 CO 2 H).
6 . The compound of claim 1 , wherein compound of Formula I is a compound of Formula II
7 . The compound of claim 1 , wherein compound of Formula I is a compound of Formula III
8 . The compound of claim 1 , wherein compound of Formula I is a compound of Formula IV
9 . The compound of claim 1 , wherein compound of Formula I is a compound of Formula V
10 . The compound of claim 1 , wherein compound of Formula I is a compound of Formula VI
11 . The compound of claim 1 , wherein compound of Formula I is a compound of Formula VII
12 . The compound of claim 1 , wherein compound of Formula I is a compound of Formula VIII
wherein R 1 is 14 CO 2 R 5 or 14 C(O)R 6 .