TGR5 modulators and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11807659-B2
Application number	US-202217720938-A
Country	US
Kind code	B2
Filing date	Apr 14, 2022
Priority date	Jun 19, 2015
Publication date	Nov 7, 2023
Grant date	Nov 7, 2023

Abstract

The application relates to compounds of formula A:

or a salt, solvate, ester, tautomer, amino acide conjugate, or metabolite thereof. The compounds of formula A are TGR5 modulators useful for the treatment of various diseases, including metabolic disease, inflammatory disease, autoimmune disease, cardiac disease, kidney disease, cancer, and gastrointestinal disease.

First claim

The invention claimed is:

1. A method of treating a metabolic disease or disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula A:

or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
A is

 oxadiazolonyl, or isoxazolonyl, wherein the carbon atom marked with “*” is bonded to the carbon atom to which A is bonded;
n is 0, 1, or 2;
R 1 is H or OH;
R 2 is H or OH;
R 3 is CR 11 R 12 C(O)OH, C(O)NHR 31 , tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 —(C 1 -C 3 ) alkyl;
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that Ru and R 12 are not both H;
R 31 OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and

p is 1 or 2,
wherein the metabolic disease or disorder is selected from obesity, diabetes, diabesity, metabolic syndrome, insulin resistance, including pre-diabetic insulin resistance, hypertension, and dyslipidemia.

2. The method of claim 1 , wherein A is

3. The method of claim 1 , wherein R 1 and R 2 are each H.

4. The method of claim 1 , wherein R 1 is H, and R 2 is OH.

5. The method of claim 1 , wherein R 2 is H, and R 1 is OH.

6. The method of claim 1 , wherein R 1 and R 2 are each OH.

7. The method of claim 1 , wherein n is 1.

8. The method of claim 1 , wherein R 3 is tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 -(C 1 -C 3 ) alkyl.

9. The method of claim 1 , wherein the compound is of formula I:

or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that Ru and R 12 are not both H; and
R 13 is H or OH.

10. The method of claim 1 , wherein the compound is of formula II:

or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
q is 0, 1, or 2;
R 21 and R 22 are each independently H or OH; and
R 23 is tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 -(C 1 -C 3 ) alkyl.

11. The method of claim 10 , wherein the compound of formula II is

12. The method of claim 11 , wherein the compound of formula II is

13. The method of claim 1 , wherein the compound is of formula III:

or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
R 31 is OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and
p is 1 or 2.

14. A method of treating type II diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula A:

or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
A is

 oxadiazolonyl, or isoxazolonyl, wherein the carbon atom marked with “*” is bonded to the carbon atom to which A is bonded;
n is 0, 1, or 2;
R 1 is H or OH;
R 2 is H or OH;
R 3 is CR 11 R 12 C(O)OH, C(O)NHR 31 , tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 -(C 1 -C 3 ) alkyl;
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that Ru and R 12 are not both H;
R 31 is OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and

p is 1 or 2.

15. A method of treating a TGR5-mediated disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula A:

or a pharmaceutically acceptable salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof, wherein:
A is

 oxadiazolonyl, or isoxazolonyl, wherein the carbon atom marked with “*” is bonded to the carbon atom to which A is bonded;
n is 0, 1, or 2;
R 1 is H or OH;
R 2 is H or OH;
R 3 is CR 11 R 12 C(O)OH, C(O)NHR 31 , tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 -(C 1 -C 3 ) alkyl;
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that Ru and Rig are not both H;
R 31 is OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and

p is 1 or 2.

Assignees

• Intercept Pharmaceuticals Inc

Inventors

• Pellicciari Roberto
• Gioiello Antimo
• Macchiarulo Antonio
• Perron-Sierra Francoise
• Seedorf Klaus

Classifications

• C07J9/005 Primary

  containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton · CPC title

• A61P1/16 Primary

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• C07J41/00

  Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring · CPC title

• C07J41/0061

  one of the carbon atoms being part of an amide group · CPC title