BILE ACID DERIVATIVES AND METHODS FOR SYNTHESIS AND USE
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)