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Nifurazide derivatives and their preparation methods and uses

A technology of drugs and compounds, applied in the field of chemical medicine, can solve the problem that pulmonary fibrosis needs to be further improved, and achieve the effects of inhibiting epithelial cell-mesenchymal transition, reducing the proliferation of collagen fibers in lung tissue, and having less toxic and side effects

Active Publication Date: 2022-05-27
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the prevention and treatment effect of nifurazide on pulmonary fibrosis needs to be further improved.

Method used

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  • Nifurazide derivatives and their preparation methods and uses
  • Nifurazide derivatives and their preparation methods and uses
  • Nifurazide derivatives and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Example 1 Preparation of compound SN2-5

[0093]

[0094] Take raw material 1 (10 mmol), cesium carbonate (15 mmol), dissolve in DMF (15 mL), add compound 2 (50 mmol) and react at 60 ° C for 1 h. After TLC detects the reaction is complete, use ethyl acetate / water / saturated common salt successively After extraction with water, the organic phase was concentrated to obtain a crude product, which was purified by column chromatography (eluent: PE / EA=20 / 1-8 / 1) to obtain Intermediate 1. White solid, 90% yield.

[0095] Wherein, PE is petroleum ether, and EA is ethyl acetate.

[0096]

[0097] The intermediate 1 (1 mmol) and potassium carbonate (2 mmol) were dissolved in acetonitrile (10 mL), piperidine (2 mmol) was added, and the reaction was refluxed at 85° C. for 3 h. After the completion of the reaction was detected by TLC, the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate / water / saturated brine, and the organic phase was...

Embodiment 2

[0104] Example 2 Preparation of compound SN1-7

[0105]

[0106] Take nifurazide (1 mmol, 276 mg), KI (potassium iodide, 0.1 mmol, 20 mg) and dissolve in DMF (10 mL), then add 1,3-dibromopropane (1.4 mmol, 143 μL) and DIEA (N , N-diisopropylethylamine, 1.5 mmol, 0.5 mL) was reacted at 80 ° C for 5 hours, TLC detection, after the reaction was complete, the reaction system was added to 100 mL of water, extracted with ethyl acetate 3 times, and then with saturated salt After extraction with water once, the combined organic phases were concentrated to obtain the crude product, which was purified by thin layer chromatography (eluent: DCM / MeOH=50 / 1) to obtain the final product SN1-7. Yellow solid, 50% yield.

[0107] Referring to the method of Example 2, the raw materials were replaced with corresponding raw materials to prepare compounds SN1-1 to SN1-6 and SN1-8 to SN1-29 of the present invention.

[0108] Table 1 Hydrogen spectrum and mass spectrum data of the compounds of th...

experiment example 1

[0119] Solubility test of compound of experimental example 1

[0120] 1. Experimental method

[0121] The water solubility of the compounds was determined by high performance liquid chromatography. Taking compound SN1-25 as an example, the water solubility test method is as follows: compound SN1-25 is prepared with methanol as solvent at 2, 1, 0.5, 0.25, 0.1, 0 mg / mL, and the standard curve is obtained by HPLC determination. Then compound SN1-25 (2 mg) was added to 1.5 mL EP tubes, and 1 mL of pure water was added. The EP tubes were sonicated for 30 seconds, and allowed to stand for 1 h to obtain a saturated solution. High performance liquid chromatography was used to test the compound SN1- in the saturated solution. 25, that is, the water solubility of compounds SN1-25. The test methods for the water solubility of the remaining compounds were carried out with reference to the SN1-25 compound. Nifurazide was used as a control.

[0122] 2. Experimental results

[0123] Tab...

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Abstract

The invention provides a nifurazide derivative and its preparation method and application, belonging to the field of chemical medicine. The structure of the nifurazide derivatives is shown in formula I. The nifurazide derivatives can effectively inhibit the proliferation of fibroblasts and the proliferation of human hepatic stellate cells, and most of the compounds have better inhibitory effects than nifurazide. The derivative can also reduce the proliferation of collagen fibers in the lung tissue of mice with pulmonary fibrosis, improve the interstitial fibrosis of mice, maintain the normal lung structure of mice, and even reverse the changes in lung structure of mice with pulmonary fibrosis. Humanized mice have good therapeutic effects and can be used to prepare candidate drugs for preventing and / or treating fibrosis. At the same time, the derivative has an excellent inhibitory effect on the proliferation of various tumor cells including breast cancer, colorectal adenocarcinoma, colon cancer and liver cancer, and can be used to prepare drug candidates for the prevention and / or treatment of various tumors. bright future.

Description

technical field [0001] The invention relates to nifurazide derivatives, a preparation method and application thereof, and belongs to the field of chemical medicine. Background technique [0002] Pulmonary fibrosis (PF) is a fatal lung disease characterized by damage and abnormal proliferation of alveolar epithelial cells, deposition of extracellular matrix (ECM) and proliferation and proliferation of fibroblasts. activation, leading to structural destruction of the lungs and loss of respiratory function. Pulmonary fibrosis is a chronic disease with high mortality, but its specific pathogenesis is still unclear. Pulmonary fibrosis may be caused by many factors, such as lung injury, smoking, environmental factors, drugs, etc. These factors lead to damage to alveolar epithelial cells, resulting in oxidative stress, inflammation, apoptosis and other reactions. This stage will release a large amount of pulmonary fibrosis. Cytokines and other active substances stimulate the prol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/70C07D333/42A61K31/496A61K31/443A61K31/4436A61K31/345A61K31/381A61K31/5377A61P35/00
CPCC07D307/70C07D333/42A61P35/00
Inventor 叶庭洪魏于全苏兴萍谭醉于艳
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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