CN-122010859-A - Small molecular compound and preparation method and application thereof

Abstract

The invention discloses a small molecular compound and a preparation method and application thereof, in particular to application of the small molecular compound in preparing medicines for protecting and treating drug-induced liver diseases. The compound can remarkably inhibit infiltration of hepatocyte inflammatory cells, inhibit collagen fiber proliferation, effectively resist drug-induced liver injury, can be used for preparing drug-induced liver injury drugs, and provides better choice for patients.

Inventors

• HAO HAIPING
• XU XIAOWEI
• HU HUIJIAN
• WANG HONG
• SONG JIALU
• DENG XINRAN
• TANG BIN

Assignees

• 中国药科大学

Dates

Publication Date

20260512

Application Date

20251226

Claims (10)

1. 1. A small molecule compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in comp.25: 。
2. 2. a method of preparing the small molecule compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising the steps of: (1) Reacting the compound 1, the compound 2 and oxalyl chloride under alkaline conditions to obtain a compound 3; (2) Reacting the compound 3 with a compound 4 to obtain a compound 4; (3) Compound 4 and compound 5 were reacted under acidic conditions followed by ring closure under basic conditions to give small molecule compound comp.25.
3. 3. The preparation method according to claim 2, wherein in the step (1), the compound 2 is reacted with oxalyl chloride in an organic solvent, and then the compound 1 and an alkaline agent are added to react.
4. 4. The process according to claim 3, wherein in the step (1), the basic agent is triethylamine or N, N-diisopropylethylamine, and the organic solvent is methylene chloride.
5. 5. The process of claim 2, wherein in step (2), compound 3 is reacted with compound 4 in toluene or dioxane to compound 4.
6. 6. The preparation method of claim 2, wherein in the step (3), the compound 4, the compound 5, the hydrochloric acid solution and the acetic acid solution are reacted in a mixed solvent, the product is collected and added with an organic solvent, then the pH is adjusted to 8-9, the small molecular compound shown in the formula I is obtained by ring closure, and the mixed solvent comprises alcohols and water, and the organic solvent is ethanol.
7. 7. A pharmaceutical composition comprising the small molecule compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
8. 8. A pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is in the form of an oral formulation.
9. 9. Use of a small molecule compound according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of liver injury.
10. 10. The use according to claim 9, wherein the liver injury is a liver injury caused by NG25/tnfα.

Description

Small molecular compound and preparation method and application thereof Technical Field The invention relates to a small molecular compound, a preparation method and application thereof, in particular to the application in preparation of drugs for protecting and treating drug-induced liver injury. The invention belongs to the technical field of biological medicine. Background The liver is used as a chemical plant of human body and plays key physiological functions of detoxification, metabolism, synthesis and the like. Liver injury is the destruction and dysfunction of hepatocytes caused by a variety of factors (e.g., viruses, alcohol, metabolic abnormalities, drugs, etc.). Worldwide, liver damage is an important cause of liver fibrosis, cirrhosis and even liver failure. Among them, drug-induced liver injury is a preventable iatrogenic disease, and has recently been a focus of attention in the field of liver science due to the rising incidence and potential serious risk. Drug-induced liver injury (DILI) refers to liver injury caused by various prescriptions, non-prescriptions, herbs or dietary supplements. It is one of the important causes of acute liver failure (Acute hepatic failure, ALF) and the most common cause of withdrawal of drugs from the market. The global incidence rate is 10-15/10 ten thousand people each year, and the incidence rate in adverse events of hospitalization is as high as 10% -15%. In recent years, with rapid increase of clinical medication types and increase of probability of self-administration or random increase of drug dosage of patients, incidence of drug-induced liver injury is correspondingly increased, and up to now ‌ 1,240,240 ‌ drugs/herbal preparations (wherein prescription drugs/over-the-counter drugs ‌ >900 ‌) can definitely cause drug-induced liver injury. The drug-induced liver injury seriously threatens human health and life, and the protection of liver health is an unprecedented task in front of us. Acetaminophen (Acetaminophen, APAP), also known as paracetamol, is an important class of non-steroidal anti-inflammatory drugs that are widely used worldwide for their remarkable antipyretic analgesic effects. However, the concomitant excellent therapeutic effect is a serious hepatotoxicity problem caused by excessive use and abuse thereof. This phenomenon has been a major cause of drug-induced liver injury and acute liver failure worldwide, especially in developed countries in Europe and America, and has raised continuous high attention in clinical and basic research fields, and the core mechanism of hepatic injury caused by APAP is "toxic storm" caused by its unique metabolic pathway, APAP is metabolized in vivo by CYP2E1 enzyme, high-activity intermediate metabolite N-Acetyl-p-benzoquinone imine is generated, NAPQI, under therapeutic dose, NAPQI can be rapidly combined and detoxified by rich glutathione in liver, and then safely discharged out of body, and once taken excessively, NAPQI generated in vivo will far exceed the reserves and synthesis capacity of glutathione. These unbound NAPQIs accumulate in large amounts within hepatocytes, act as powerful electrophiles and free radicals, bind covalently to critical cellular proteins, and induce severe oxidative stress. This directly leads to mitochondrial dysfunction of hepatocytes, energy failure, and eventually initiates a cell death pathway such as programmed necrosis, manifesting as large-area hepatocyte necrosis. The only recognized specific drug for treating the hepatic injury caused by APAP is ‌ N-acetylcysteine (N-ACETYLCYSTEINE, NAC), but the treatment effect is not obvious, the main reason is that the hepatic injury mechanism caused by APAP is quite complex, the rigid constraint exists in the treatment time window, the drug is required to be administered within 8 hours of the hepatic injury, in addition, recent researches show that the reasons of multi-drug combination, drug substitution change, symptom hiding and the like caused by population aging obviously increase the complexity of APAP poisoning and the NAC treatment risk. There are a large number of drugs currently being developed, such as the mitochondrial targeting antioxidant Mito-TEMPO ‌, the bifunctional molecule conjugate NAC-pyrimidine, hepatocyte growth factor activator HEPAGENIN, epigenetic regulator GS-5801, etc., but the therapeutic effect is still poor, so the development of new therapeutic drugs is urgent. Disclosure of Invention The invention aims to provide a small molecular compound for protecting and treating liver injury, and provides a preparation method of the small molecular compound, and further aims to provide a pharmaceutical composition and application of the small molecular compound. The technical scheme is that the small molecule compound or the pharmaceutically acceptable salt thereof provided by the invention has a structure shown in Comp.25: the preparation method of the small molecule compound or the pharmaceutically acceptab