CN-117736081-B - Preparation method of polysubstituted phenyl Nur77 receptor modulator and application of polysubstituted phenyl Nur77 receptor modulator in anti-fibrosis aspect

Abstract

A preparation method of a polysubstituted phenyl Nur77 receptor modulator and application thereof in anti-fibrosis relates to trisubstituted phenyl derivatives and provides a polysubstituted phenyl derivative with a novel structure. Provides a preparation method of polysubstituted phenyl derivatives represented by structural formulas I, II and III. The application of the polysubstituted phenyl derivatives with new structures as Nur77 receptor modulators is provided, and the polysubstituted phenyl derivatives can improve liver injury, reduce collagen deposition, reduce serum glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels and improve fibrosis by regulating the activity of Nur77 related signal paths.

Inventors

• LIN TIANWEI
• HONG WENBIN
• Xiao Tianyi Chen

Assignees

• 厦门大学

Dates

Publication Date

20260505

Application Date

20231220

Claims (1)

1. 1. The application of the polysubstituted phenyl Nur77 receptor modulator is characterized in that the polysubstituted phenyl Nur77 receptor modulator comprises a compound A8 with the following structural formula: , The polysubstituted phenyl Nur77 receptor modulator is used for preparing medicines for treating anti-fibrosis diseases.

Description

Preparation method of polysubstituted phenyl Nur77 receptor modulator and application of polysubstituted phenyl Nur77 receptor modulator in anti-fibrosis aspect Technical Field The invention relates to the field of polysubstituted phenyl derivatives, in particular to a preparation method of a polysubstituted phenyl Nur77 receptor modulator and application thereof in anti-fibrosis. Background Liver fibrosis is mainly caused by viral or metabolic chronic liver diseases and is an important health problem. Many chronic factors can lead to the progression of liver fibrosis, including persistent viral infections (e.g., hepatitis b and c viruses), toxic lesions, long-term excessive alcohol consumption, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), autoimmune liver disease, and various metabolic and genetic diseases. Fibrosis is associated with liver disease progression and is a key factor in the risk of cirrhosis and hepatocellular carcinoma (HCC). Activation of Hepatic Stellate Cells (HSCs) is considered a critical event in the development of liver fibrosis. Following liver injury, dormant HSCs are activated and transformed into myofibroblasts, which are responsible for the excessive secretion of extracellular matrix (ECM) components. This process ultimately leads to excessive deposition of ECM in the liver. Excessive accumulation of ECM can trigger an abnormal wound healing response. Recent scientific advances have thoroughly changed our understanding of the mechanisms of liver fibrosis and demonstrated that liver fibrosis can be reversed by eliminating or eradicating pathogens (e.g., by controlling or curing viral infections). However, the reversal process tends to spread too slowly or rarely to prevent life threatening complications, especially in the late stages of fibrosis. Despite many efforts, currently available anti-fibrotic drug candidates have limited efficacy in clinical trials, and there is no approved liver fibrosis treatment to date. There is an urgent need to develop new anti-fibrotic compounds with new drug targets. Nuclear receptor 77 (Nur 77, also known as TR3 or NR4 A1) belongs to the steroid/thyroid hormone receptor superfamily and plays a different role in various physiological activities. Nur77 plays a key role in a variety of fibrotic and tissue remodeling diseases, including skin, lung, liver and kidney fibrosis. It is a potential drug target for anti-fibrosis treatment. In CCl 4-induced liver fibrosis liver tissue, nur77 cell levels were significantly reduced. Nur77 deficiency can lead to the progression of liver fibrosis in mice. TGF-. Beta.1 (transforming growth factor-. Beta.1) is known to be involved in liver fibrosis via Smad3 signaling pathway. Recent studies have shown that aberrant activation of the AKT signaling pathway in TGF- β1 driven liver fibrosis is a SMAD independent pathway. Activation of AKT signaling pathway in TGF- β1 treated LX2 cells (human hepatic stellate cells) promotes degradation of Nur77, resulting in activation of Hepatic Stellate Cells (HSCs). Therefore, stabilizing Nur77 or increasing its expression is a strategy for preventing liver fibrosis, and the development of Nur77 targeted anti-fibrosis drugs also has great potential for solving multiple organ fibrosis. Disclosure of Invention The invention aims to solve the problems in the prior art and provide a preparation method of a polysubstituted phenyl Nur77 receptor modulator and application of the polysubstituted phenyl Nur77 receptor modulator in anti-fibrosis aspect. In order to achieve the above purpose, the invention adopts the following technical scheme: the first object of the invention is to provide a polysubstituted phenyl Nur77 receptor modulator with a novel structure, which comprises at least one compound with the following structural formula: wherein R1 represents H, F, cl, br, OH, OMe, R2 represents linear alkyl with the length of 6-13, preferably n-octyl and n-nonyl, and R3 represents H, me and Et. The polysubstituted phenyl Nur77 receptor modulator is as follows: 1- (3, 4, 5-trihydroxyphenyl) -1-decanone (A1), 1- (3, 4, 5-trihydroxyphenyl) -1-decanone oxime (A2), 1- (3, 4, 5-Trihydroxyphenyl) decan-1-one O-methyloxime (A3), 1- (3, 5-dibromo-4-hydroxyphenyl) -1-decanone (A4), 1- (3, 5-Dihydroxy-4-methylphenyl) -1-decanone (A5), 1- (3, 5-dihydroxy-4-bromophenyl) decan-1-one O-ethyloxime (A6), 3,4, 5-Trihydroxy-N-octylbenzamide (A7), 3,4, 5-trihydroxy-N-methyl-N-octylbenzamide (A8), 3,4, 5-Trihydroxy-N-ethyl-N-octylbenzamide (A9), 4-fluoro-3-hydroxy-N-methyl-N-octylbenzamide (A10), 4-Fluoro-3-hydroxy-N-nonylbenzamide (A11), 4-fluoro-3-hydroxy-N-decylbenzamide (A12), 3-Fluoro-4-hydroxy-N-methyl-N-octylbenzamide (A13), 3-fluoro-4-hydroxy-N-nonylbenzamide (A14), 1- (3, 5-Dihydroxy-4-bromophenyl) -1-decanone (A15). The second object of the present invention is to provide a method for preparing a polysubstituted phenyl Nur77 receptor modulator. Route 1 1) Under ice