FXR small molecule agonist and preparation method therefor and use thereof

Patent metadata

Field	Value
Publication number	US-12240841-B2
Application number	US-202017603823-A
Country	US
Kind code	B2
Filing date	Apr 20, 2020
Priority date	Apr 19, 2019
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

Abstract

An FXR small molecule agonist and a preparation method therefor and a use thereof, having a structure as shown in formula (I). The compound represented by formula (I) has FXR agonistic activity and is capable of preparing drugs for treatment of FXR-related diseases.

First claim

The invention claimed is:

1. A compound represented by general formula I, or enantiomer, diastereomer, tautomer, racemate, solvate, prodrug or pharmaceutically acceptable salt thereof,

wherein, R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, halogen, halogenated C 1-6 alkyl, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1-6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, cyano or nitro;
R 2 is C 6 -C 12 aryl, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
Q is

wherein N is attached to A;
A is the following substituted or unsubstituted group: phenyl, pyridyl, thienyl, furyl, indazolyl, indolyl, benzothienyl, benzofuranyl, and the “substituted” means that there is one, two or three substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, halogenated C 1-6 alkyl, halogenated C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkoxy;
X is O or S.

2. The compound of claim 1 , wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.

3. The compound of claim 1 , wherein R 2 is phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl.

4. The compound of claim 1 , wherein Q is

wherein N is attached to A.

5. The compound of claim 1 , wherein A is the following substituted or unsubstituted group: phenyl, pyridyl, thienyl, furyl, indazolyl, indolyl, benzothienyl, benzofuranyl; and the “substituted” means that there is one or two substituents selected from the group consisting of fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, and C 3 -C 6 cycloalkoxy.

6. The compound of claim 1 , wherein the compound is:

7. A method for preparing the compound according to claim 1 , wherein the method comprises the following steps:

(a′) reacting a compound represented by general formula VII with hydroxylamine hydrochloride to produce a compound represented by general formula VIII;
(b′) reacting the compound represented by the general formula VIII under the action of phosgene, triphosgene, carbonyldiimidazole or thiocarbonyldiimidazole to produce the compound represented by the general formula I,
wherein, X, R 2 , Q, A, R 11 , R 12 , R 13 , R 14 and R 15 are defined as in claim 1 .

8. The method of claim 7 , wherein the compound represented by the general formula VII is prepared by the following steps:

a) reacting substituted benzaldehyde compound represented by general formula II as starting materials with hydroxylamine hydrochloride to obtain an intermediate and then chlorinating the intermediate with N-chlorosuccinimide (NCS) to produce a compound represented by general formula III;
b) reacting the compound represented by the general formula III with 3-oxopropionate to obtain a compound represented by the general formula IV;
c) reducing the ester in the compound represented by formula IV to produce alcohol, and then brominating to produce a compound represented by V;
d) reacting the compound represented by general formula V with Q-OH to produce a compound represented by general formula VI;
e) coupling the compound represented by general formula VI with Br-A-CN under the catalysis of copper or palladium to obtain the compound represented by general formula VII,
or prepared by the following steps:

f) reacting Q-OH with F-A-CN to generate a compound represented by general formula IX;
g) reacting a compound represented by the general formula V with the compound represented by the general formula IX to produce the compound represented by the general formula VII,
in each formula, R 2 , Q, A, R 11 , R 12 , R 13 , R 14 and R 15 are defined as in claim 1 .

9. A pharmaceutical composition comprising the compound of claim 1 , or the enantiomer, diastereomer, tautomer, racemate, solvate, prodrug, or pharmaceutically acceptable salt thereof; and
a pharmaceutically acceptable carrier.

10. An Farnesoid X receptor (FXR) agonist comprising the compound of claim 1 or the enantiomer, diastereomer, tautomer, racemate, solvate, prodrug, or pharmaceutically acceptable salt thereof.

11. A medicament for the treatment of a Farnesoid X receptor (FXR)-related disease comprising a compound of claim 1 or the enantiomer, diastereomer, tautomer, racemate, solvate, prodrug, or pharmaceutically acceptable salt thereof, wherein the FXR-related disease is a metabolic syndrome.

12. A method for reducing the levels of ALP, ALT, AST and TBA in serum in a subject in need thereof, the method comprising administering a compound of claim 1 or the enantiomer, diastereomer, tautomer, racemate, solvate, prodrug, or pharmaceutically acceptable salt thereof.

13. A method for reducing the amount of hydroxyproline in liver tissue in a subject in need thereof, the method comprising administering a compound of claim 1 or the enantiomer, diastereomer, tautomer, racemate, solvate, prodrug, or pharmaceutically acceptable salt thereof.

14. A method for down-regulating the expression of α-SMA and Collα1 mRNA in liver tissue in a subject in need thereof, the method comprising administering a compound of claim 1 or the enantiomer, diastereomer, tautomer, racemate, solvate, prodrug, or pharmaceutically acceptable salt thereof.

15. A method for reducing the content of collagen in the liver in a subject in need thereof, the method comprising administering a compound of claim 1 or the enantiomer, diastereomer, tautomer, racemate, solvate, prodrug, or pharmaceutically acceptable salt thereof.

Assignees

• Shanghai Inst Materia Medica Cas
• Van Andel Res Institute

Inventors

• Xu Huaqiang
• Li Jia
• Shi Jingjing
• Zang Yi
• Sun Dandan
• Liu Mingliang
• Xie Rongrong
• You Erli
• Gao Lixin
• Tan Qian

Classifications

• C07D451/06

  Oxygen atoms · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• C07D487/08

  Bridged systems · CPC title