Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10457703-B2
Application number	US-201615085800-A
Country	US
Kind code	B2
Filing date	Mar 30, 2016
Priority date	Mar 31, 2015
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

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

What is claimed is:

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

wherein:
R a is hydrogen or methyl;
R b is selected from the group consisting of:
1) C(O)NR 10 R 11 ;
2) C(O)NHSO 2 R 1 ;
3) —SO 2 R 1 ; and
4) —C(O)R 1 ;

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 hydrogen;
R c is hydrogen;
m is selected from 0, 1, 2 and 3;
R 3 is hydrogen or hydroxyl;
R 4 is hydrogen or hydroxyl;
R 5 and R 6 are independently selected from hydrogen and hydroxyl protecting group;
R 7 is selected from the group consisting of:
Hydrogen and substituted or unsubstituted —C 1 -C 8 alkyl;

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. The compound of claim 1 represented by Formula II, or a pharmaceutically acceptable salt 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. The compound of claim 1 represented by one of formulas (III-4), (III-5), (III-6), (III-10), (III-11), (III-12), (III-16), (III-17) and (III-18), or a pharmaceutically acceptable salt thereof:

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

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

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

5. A compound, 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 thereof:

TABLE 1

Compound
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

H

14
0

H

15
0
Methyl
Me

16
0
Ethyl
Me

17
0
Isopropyl
Me

18
0
t-Butyl
Me

19
0
Propyl
Me

20
0
Benzyl
Me

21
0
Vinyl
Me

22
0
Allyl
Me

23
0
CF 3
Me

24

Assignees

• Enanta Pharm Inc

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

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

• A61P37/02

  Immunomodulators · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title