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Nifuroxazide derivative as well as preparation method and application thereof

A compound and unsaturated technology, applied in the field of chemical medicine, can solve the problem of pulmonary fibrosis that needs to be further improved, and achieve the effect of inhibiting epithelial cell-mesenchymal transition, inhibiting proliferation, and reducing the proliferation of collagen fibers in lung tissue

Active Publication Date: 2021-09-03
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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  • Nifuroxazide derivative as well as preparation method and application thereof
  • Nifuroxazide derivative as well as preparation method and application thereof
  • Nifuroxazide derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Embodiment 1 prepares compound SN2-5

[0093]

[0094] Take raw material 1 (10mmol), cesium carbonate (15mmol), dissolve in DMF (15mL), then add compound 2 (50mmol) and react at 60°C for 1h. Extract with water and concentrate the organic phase to obtain a crude product, which is purified by column chromatography (eluent: PE / EA=20 / 1-8 / 1) to obtain Intermediate 1. White solid, yield 90%.

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

[0096]

[0097] Intermediate 1 (1 mmol) and potassium carbonate (2 mmol) were dissolved in acetonitrile (10 mL), then piperidine (2 mmol) was added and refluxed at 85° C. for 3 h. After the completion of the reaction as detected by TLC, the solvent was distilled off under reduced pressure, extracted with ethyl acetate / water / saturated brine in sequence, and the organic phase was concentrated to obtain a crude product. Purified by thin layer chromatography (eluent: DCM / MeOH=10:1) to obtain Intermediate 2. White...

Embodiment 2

[0104] Embodiment 2 prepares compound SN1-7

[0105]

[0106] Get nifurazide (1mmol, 276mg), KI (potassium iodide, 0.1mmol, 20mg) is dissolved in DMF (10mL), then add 1,3-dibromopropane (1.4mmol, 143 μ L) and DIEA (N , N-diisopropylethylamine, 1.5mmol, 0.5mL) was reacted at 80°C for 5 hours, and detected by TLC. After the reaction was complete, the reaction system was added to 100mL water, extracted 3 times with ethyl acetate, and then saturated with salt Water was extracted once, and the organic phases were combined and concentrated to obtain a 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, replacing the raw materials with corresponding raw materials, the compounds SN1-1~SN1-6, SN1-8~SN1-29 of the present invention were prepared.

[0108] Proton spectrum and mass spectrum data of the compound of the present invention in table ...

experiment example 1

[0119] The solubility test of experimental example 1 compound

[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, its water solubility test method is as follows: compound SN1-25 is prepared in methanol as solvent at 2, 1, 0.5, 0.25, 0.1, 0 mg / mL, and the standard curve is obtained by HPLC measurement. Then compound SN1-25 (2mg) was added to 1.5mL EP tube respectively, and 1mL pure water was added, the EP tube was ultrasonicated for 30 seconds, and the saturated solution was obtained by standing for 1h, and the compound SN1-25 in the saturated solution was tested by high performance liquid chromatography. The concentration of 25 is the water solubility of compound SN1-25. The test method of the water solubility of the remaining compounds is carried out with reference to the SN1-25 compound. Nifurazide was used as a control.

[0122] 2. Experimental resu...

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Abstract

The invention provides a nifuroxazide derivative as well as a preparation method and application thereof, and belongs to the field of chemical medicines. The structure of the nifuroxazide derivative is as shown in formula I in the specification. The nifuroxazide derivative can effectively inhibit the proliferation of fibroblasts and inhibit the proliferation of human hepatic stellate cells, and the inhibition effects of most compounds are superior to those of nifuroxazide. In addition, the derivative can also relieve lung tissue collagenous fiber proliferation of mice with pulmonary fibrosis, improve mouse pulmonary interstitial fibrosis, maintain normal lung structures of the mice and even reverse changes of the lung structures of the mice with pulmonary fibrosis, has a good treatment effect on the mice with pulmonary fibrosis, and can be used for preparing candidate drugs for preventing and / or treating fibrosis. Meanwhile, the derivative has an excellent inhibition effect on proliferation of various tumor cells including breast cancer, colorectal adenocarcinoma, colon cancer and liver cancer, can be used for preparing candidate drugs for preventing and / or treating various tumors, and has a wide application prospect.

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 pathological damage and abnormal proliferation of alveolar epithelial cells, deposition of extracellular matrix (ECM) and proliferation of fibroblasts and Activation, leading to structural damage to the lungs and loss of respiratory function. Pulmonary fibrosis is a chronic disease with a high mortality rate, 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 of alveolar epithelial cells, oxidative stress, inflammatory response, apoptosis and other reactions, which will release a large amount of Cytokines and other active substances stimulate the proliferation and activation of m...

Claims

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Application Information

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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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