Bile acid derivatives and methods for synthesis and use

Abstract

Provided herein, inter alia, are methods for the preparation of modulators of farnesoid X receptor (FXR), and compositions and uses of the modulators of FXR.

1 . A method of synthesizing a compound having the following structure, 
       
         
           
           
               
               
           
         
         the method comprising,
 (i) contacting a compound of formula (II) 
 
       
       
         
           
           
               
               
           
         
       
       wherein R 11  is R 11A  or R 11B , with an oxidizing reagent to provide a compound of formula (III-A) or (III-B), 
       
         
           
           
               
               
           
         
         
           (ii) when the product of step (i) has a structure according to formula (III-A), contacting the compound of formula (III-A) with an alcohol protecting agent to provide a compound of formula (III-B); 
           (iii) contacting a compound of formula (III-B) with an alkylating agent in the presence of a sterically hindered base to provide a compound of formula (IV), 
         
       
       
         
           
           
               
               
           
         
         
           (iv) optionally contacting the compound of formula (IV) with an alcohol deprotecting agent to provide a compound of formula (IV-A), 
         
       
       
         
           
           
               
               
           
         
         
           (v) treatment of the compound of formula (IV) or (IV-A) with a reducing agent to provide a compound of formula (I) or (I-A), 
         
       
       
         
           
           
               
               
           
         
       
       and
   (vi) when the product of step (v) has a structure according to formula (I-A), contacting the compound of formula with an alcohol deprotecting agent to provide a compound of formula (I-A);   wherein,
 L 1  is —C(O)—, —C(O)O—, —C(O)NH—, or —CH 2 —; 
 R 1  is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, —OR 1A , —NHR 1A , —COOH, —COH 2 , —NO 2 , —SH, —SO 2 Cl, —SO  3 H, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a carboxylate protecting group; 
 R 2  is hydrogen or unsubstituted alkyl; 
 R 3  is hydrogen, unsubstituted alkyl, or —OR 3A ; 
 R 4  is hydrogen, unsubstituted alkyl, or —OR 4A ; 
 R 5  is hydrogen, unsubstituted alkyl, or —OR 5A ; 
 R 6  is hydrogen, unsubstituted alkyl, or —OR 6A ; 
 R 7  is hydrogen, unsubstituted alkyl, or —OR 7A ; 
 R 8  is hydrogen, unsubstituted alkyl, or —OR 8A ; 
 R 9  is hydrogen, unsubstituted alkyl, or —OR 9A ; 
 R 10  is hydrogen, unsubstituted alkyl, or —OR 10A ; 
 R 11A  is hydrogen; 
 R 11B  is an alcohol protecting group; 
 R 12  is hydrogen, unsubstituted alkyl, or —OR 12A ; 
 R 13  is unsubstituted alkyl; 
 R 1A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 12A  and R 13A  are independently hydrogen, unsubstituted alkyl, or an alcohol protecting group. 
   
 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein R 11B  is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or —SiR 11C R 11D R 11E , wherein R 11C , R 11D , and R 11E  are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the compound of formula (I) has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         7 .- 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the compound of formula (I) is 6-α-ethyl-ursodeoxycholic acid (6-EUDCA) having the following structure, 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 1 , wherein the oxidizing reagent of step (a) is a chromium oxidant, a ruthenium oxidant, a manganese oxidant, an activated dimethylsulfoxide oxidant, or a hypervalent iodine oxidant. 
     
     
         12 .- 13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein said sterically hindered base of step (iii) is lithium diisopropylamide (LDA), (M +1 )HMDS, (M +1 )tBuO, (M +1 )TMP, (M +1 )PhO, (M +1 )MeO, (M +1 )EtO, DBU, Dabco, N,N-dichlorohexylmethylamine, N,N-diisopropyl-2-ethylbutylamine, 2,6-di-tert-butyl-4-methylpyridine, pentamethylpiperidine, MTBD, PMDBD, TBD, or tri-tert-butylpyridine, wherein (M +1 ) is Na, K, or Li. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein step (iii) comprises a second base. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein said alkylation agent of step (iii) is an alkyl halide. 
     
     
         19 .- 21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein the reducing agent of step (v) comprises an aluminum alkoxide and an alcohol. 
     
     
         23 .- 24 . (canceled) 
     
     
         25 . An insulin peptide hormone covalently bonded to a compound of Formula (I), Formula (I-C), Formula (I-D), Formula (I-E), or Formula (I-F). 
     
     
         26 . The insulin peptide hormone of  claim 25 , wherein the insulin peptide hormone is human insulin. 
     
     
         27 . The insulin peptide hormone of  claim 25 , wherein lysine B29 of the insulin peptide hormone is covalently bonded to a compound of Formula (I), Formula (I-C), Formula (I-D), Formula (I-E), or Formula (I-F). 
     
     
         28 . A pharmaceutical composition comprising the insulin peptide hormone of  claim 25  and a pharmaceutically acceptable excipient. 
     
     
         29 .- 30 . (canceled) 
     
     
         31 . A compound having the following structure, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 L 1  is —C(O)—, —C(O)O—, —C(O)NH—, or —CH 2 —; 
 R L  is L 2 -R L2 ; 
 R 2  is hydrogen or unsubstituted alkyl; 
 R 3  is hydrogen, unsubstituted alkyl, or —OR 3A ; 
 R 4  is hydrogen, unsubstituted alkyl, or —OR 4A ; 
 R 5  is hydrogen, unsubstituted alkyl, or —OR 5A ; 
 R 6  is hydrogen, unsubstituted alkyl, or —OR 6A ; 
 R 7  is hydrogen, unsubstituted alkyl, or —OR 7A ; 
 R 8  is hydrogen, unsubstituted alkyl, or —OR 8A ; 
 R 9  is hydrogen, unsubstituted alkyl, or —OR 9A ; 
 R 10  is hydrogen, unsubstituted alkyl, or —OR 10A ; 
 R 11A  is hydrogen; 
 R 11B  is an alcohol protecting group; 
 R 12  is hydrogen, unsubstituted alkyl, or —OR 12A ; 
 R 13  is unsubstituted alkyl; 
 R 1A , R 3A , R 4A , R 5A , R 6A , R 7A , R 8A , R 9A , R 10A , R 12A  and R 13A  are independently hydrogen, unsubstituted alkyl, or an alcohol protecting group; 
 L 2  is a bond, —NR L1 —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
 R L1  is hydrogen or unsubstituted alkyl; and 
 R L2  is an amino acid of an insulin peptide hormone. 
 
       
     
     
         32 . The compound of  claim 31 , wherein the compound has the structure, 
       
         
           
           
               
               
           
         
       
     
     
         33 . (canceled) 
     
     
         34 . The compound of  claim 31 , where R L2  is lysine B29 of the insulin peptide hormone. 
     
     
         35 . A pharmaceutical composition comprising the insulin peptide hormone of  claim 31  and a pharmaceutically acceptable excipient. 
     
     
         36 .- 37 . (canceled) 
     
     
         38 . A pharmaceutical composition comprising 6-α-ethyl-ursodeoxycholic acid (6-EUDCA) having the following structure, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         39 . A method of modulating farnesoid X receptor (FXR) activity, said method comprising contacting the farnesoid X receptor (FXR) with 6-α-ethyl-ursodeoxycholic acid (6-EUDCA) having the following structure, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         40 . A method of treating a disorder or condition mediated by farnesoid X receptor (FXR) activity, said method comprising administering to a subject in need thereof an effective amount of 6-α-ethyl-ursodeoxycholic acid (6-EUDCA) having the following structure, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The method of  claim 40 , wherein said disorder or condition is cholestasis, diabetes, cholesterol gallstone disease (CGD) or liver disease. 
     
     
         42 . The method of  claim 41 , wherein the liver disease is nonalcoholic steatohepatitis (NASH). 
     
     
         43 . (canceled)