Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016289262-A1
Application number	US-201615085800-A
Country	US
Kind code	A1
Filing date	Mar 30, 2016
Priority date	Mar 31, 2015
Publication date	Oct 6, 2016
Grant date	—

Abstract

The present invention provides compounds represented by Formula I, or pharmaceutically acceptable salts, stereoisomers, solvates, hydrates or combination thereof,

The invention also provides pharmaceutical compositions comprising these compounds and methods of using this compounds for treating FXR-mediated or TGR5-mediated diseases or conditions.

First claim

1 . A compound represented by Formula I or a pharmaceutically acceptable salt or prodrug thereof:

wherein:
R a is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 6 alkoxy;
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 arylalkyl;
7) Substituted or unsubstituted aryl;

R b is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted arylalkyl;
6) Substituted or unsubstituted aryl;
7) —C(O)NR 10 R 11 ;
8) —C(O)NHSO 2 R 1 ; 9) —SO 2 R 1 ; and
10) —C(O)R 1 ;

or R a and R b are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring;
R 1 is selected from the group consisting of:
1) Halogen;
2) Hydroxyl;
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 aryl;
8) Substituted or unsubstituted arylalkyl;
9) Substituted or unsubstituted heterocycloalkyl;
10) Substituted or unsubstituted heteroaryl;
11) Substituted or unsubstituted heteroarylalkyl; and
12) —NR 10 R 11 ;

R 2 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted arylalkyl; and
6) Substituted or unsubstituted aryl;

R c is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted arylalkyl; and
6) Substituted or unsubstituted aryl;

or R 2 and R c are taken together with the carbon atom to which they are attached to form a cyclic ring;
m is selected from 0, 1, 2 and 3;
R 3 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 or —OPO 3 2− ;
R 4 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 2 or —NHR 2 ;
or R 3 and R 4 are taken together with the carbons they attached form —CH═CH— or cycloalkyl ring or heterocycloalkyl ring;
R 5 and R 6 are independently selected from hydrogen or hydroxyl protecting group such as, but not limited to acetyl, trimethyl silyl, or benzyl;
R 7 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; and
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl; and

R 10 and R 11 are each independently selected from hydrogen, substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl, or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.

2 . A compound of claim 1 , represented by Formula II or a pharmaceutically acceptable salt or prodrug thereof:

wherein R a , R b , R c , R 2 , R 3 , R 4 , R 7 and m are as defined in claim 1 .

3 . A compound of claim 1 , represented by one of formulas (III-1˜III-18), or a pharmaceutically acceptable salt or prodrug thereof:

wherein, R a , R b , R c , R 1 , R 2 , R 7 and m are as defined in claim 1 .

4 . A compound of claim 1 , represented by Formula IV or a pharmaceutically acceptable salt or prodrug thereof:

wherein, R a , R b , and m are as defined in claim 1 .

5 . The compound of claim 4 , selected from compounds of Formula IV wherein, R a , R b , and m are delineated for each compound in Table 1, or a pharmaceutically acceptable salt or prodrug thereof:

TABLE 1

Example
m
R a
R b

 1
0
Methyl
H

 2
0
Ethyl
H

 3
0
Isopropyl
H

 4
0
Butyl
H

 5
0
t-Butyl
H

 6
0
Propyl
H

 7
0
Benzyl
H

 8
0
Vinyl
H

 9
0
Allyl
H

10
0
CF 3
H

11
0

H

12
0

H

13
0

Assignees

• Enanta Pharm Inc

Inventors

• Wang Guoqiang
• Or Yat Sun
• Shen Ruichao
• Xing Xuechao
• Long Jiang
• Dai Peng
• Granger Brett
• He Jing

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title