Isotopically labeled bile acid derivatives

Abstract

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 .