Benzoic acid derivatives of bile acid as FXR/TGR5 agonists and methods of use thereof
The present invention provides compounds of Formula I: pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated by FXR and/or TGR5.
1. A compound represented by Formula I
or a pharmaceutically acceptable salt or ester thereof, wherein:
—Ar—R 1 is selected from the groups set forth below, each of which is optionally substituted when possible:
R 1 is —C(O)R 11 ; —C(O)NR 12 R 13 , —C(O)NHSO 2 R 11 , —P(O)(R 11 ) 2 , —CN, or tetrazolyl;
L is selected from the group consisting of:
1) Substituted or unsubstituted —C 1 -C 8 -alkylene;
2) Substituted or unsubstituted —C 2 -C 8 -alkenylene;
3) Substituted or unsubstituted —C 2 -C 8 -alkynylene;
4) Substituted or unsubstituted —C 3 -C 8 -cycloalkylene;
5) Substituted or unsubstituted —C 1 -C 7 alkoxylene;
6) Substituted or unsubstituted —C 1 -C 7 aminoalkylene;
7) Substituted or unsubstituted —C 3 -C 7 heterocycloalkylene;
8) Substituted or unsubstituted —C 1 -C 8 -alkylene-C 3 -C 8 -cycloalkylene;
9) Substituted or unsubstituted —C 1 -C 8 -alkylene-C 3 -C 7 -heterocycloalkylene;
10) Substituted or unsubstituted alkylaryl; and
11) Substituted or unsubstituted alkylheteroaryl;
R 2 is hydrogen, hydroxyl, halogen, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ;
R 3 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 12 or —NHR 12 ;
alternatively, R 2 and R 3 are taken together with the carbon atoms to which they are attached to form —CH═CH—, cycloalkyl or heterocycloalkyl;
R 4 and R 5 are each independently hydrogen or a hydroxyl protecting group;
R 6 is ethyl;
R 11 at each occurrence is independently selected from the group consisting of:
1) Hydrogen,
2) Halogen;
3) Hydroxyl;
4) Substituted or unsubstituted —C 1 -C 8 alkoxy;
5) Substituted or unsubstituted —C 1 -C 8 arylalkyl;
6) Substituted or unsubstituted —C 2 -C 8 alkenyl;
7) Substituted or unsubstituted —C 2 -C 8 heteroarylalkynyl;
8) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
9) Substituted or unsubstituted —C 3 -C 8 cycloalkenyl;
10) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
11) Substituted or unsubstituted aryl;
12) Substituted or unsubstituted arylalkyl;
13) Substituted or unsubstituted heteroaryl; and
14) Substituted or unsubstituted heteroarylalkyl; and
R 12 and R 13 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 2 -C 8 -alkenyl, optionally substituted —C 2 -C 8 -alkynyl; optionally substituted —C 3 -C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;
alternatively, R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring.
2. The compound of claim 1 , represented by Formula II,
or a pharmaceutically acceptable salt or ester thereof, wherein R 1 , Ar, L, R 2 , R 3 , and R 6 are as defined in claim 1 .
3. The compound of claim 1 , represented by Formula III,
or a pharmaceutically acceptable salt or ester thereof, wherein R 1 , Ar, L, R 2 , and R 6 are as defined in claim 1 .
4. The compound of claim 1 , represented by Formula IV,
or a pharmaceutically acceptable salt or ester thereof, wherein R 1 , Ar and L are as defined in claim 1 .
5. The compound of claim 1 , wherein L is selected from the groups set forth below, each of which is optionally substituted:
wherein m is 1, 2, 3, 4, 5, 6, or 7 and n is 1, 2, or 3.
6. A compound selected from compounds 1 to 42 below
or a pharmaceutically acceptable salt or ester thereof.
7. A compound, selected from the compounds set forth below or a pharmaceutically acceptable salt or ester thereof:
Compound
Structure
1
2
3
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
8. A pharmaceutical composition comprising a compound represented by Formula I,
or a pharmaceutically acceptable salt or ester thereof, wherein:
—Ar—R 1 is selected from the groups set forth below, each of which is optionally substituted when possible:
R 1 is —C(O)R 11 ; —C(O)NR 12 R 13 , —C(O)NHSO 2 R 11 , —P(O)(R 11 ) 2 , —CN, or tetrazolyl;
L is selected from the group consisting of:
1) Substituted or unsubstituted —C 1 -C 8 -alkylene;
2) Substituted or unsubstituted —C 2 -C 8 -alkenylene;
3) Substituted or unsubstituted —C 2 -C 8 -alkynylene;
4) Substituted or unsubstituted —C 3 -C 8 -cycloalkylene;
5) Substituted or unsubstituted —C 1 -C 7 alkoxylene;
6) Substituted or unsubstituted —C 1 -C 7 aminoalkylene;
7) Substituted or unsubstituted —C 3 -C 7 heterocycloalkylene;
8) Substituted or unsubstituted —C 1 -C 8 -alkylene-C 3 -C 8 -cycloalkylene;
9) Substituted or unsubstituted —C 1 -C 8 -alkylene-C 3 -C 7 -heterocycloalkylene;
10) Substituted or unsubstituted alkylaryl; and
11) Substituted or unsubstituted alkylheteroaryl;
R 2 is hydrogen, hydroxyl, halogen, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ;
R 3 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 —, —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 12 or —NHR 12 ;
alternatively, R 2 and R 3 are taken together with the carbon atoms to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
R 4 and R 5 are each independently hydrogen or a hydroxyl protecting group;
R 6 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl;
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
7) Substituted or unsubstituted —C 1 -C 7 alkoxyl;
8) Substituted or unsubstituted —C 1 -C 7 aminoalkyl; and
9) Substituted or unsubstituted —C 3 -C 7 heterocycloalkyl;
R at each occurrence is independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Hydroxyl;
4) Substituted or unsubstituted —C 1 -C 8 alkoxy;
5) Substituted or unsubstituted —C 1 -C 8 alkyl;
6) Substituted or unsubstituted —C 2 -C 8 alkenyl;
7) Substituted or unsubstituted —C 2 -C 8 alkynyl;
8) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
9) Substituted or unsubstituted —C 3 -C 8 cycloalkenyl;
10) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
11) Substituted or unsubstituted aryl;
12) Substituted or unsubstituted arylalkyl;
13) Substituted or unsubstituted heteroaryl; and
14) Substituted or unsubstituted heteroarylalkyl; and
R 12 and R 13 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 2 -C 8 -alkenyl, optionally substituted —C 2 -C 8 -alkynyl;
optionally substituted —C 3 -C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; alternatively, R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring; and
a pharmaceutically acceptable carrier.
9. A method for ameliorating a disease or condition selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, Type II diabetes, and hepatocellular carcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 8 .
10. The method of claim 9 , wherein the disease or condition is primary biliary cirrhosis.
11. The method of claim 9 , wherein the disease or condition is nonalcoholic steatohepatitis.
12. The method of claim 9 , wherein the disease or condition is nonalcoholic fatty liver disease.