Mercaptopropionamide compounds, preparation method and medicinal use thereof

A technology of mercaptopropionamide and compound, applied in antibacterial drugs, organic chemistry, pharmaceutical formulations and other directions, can solve problems such as unreported anti-gram-negative bacteria activity

Active Publication Date: 2021-05-04
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on the research status of the prior art, the inventors of the present application intend to provide a small molecule inhibitor of NDM-1 and its medicinal use, the target compound involved and its corresponding NDM-1 enzyme inhibitory activity and its combination with meropenem No reports of activity against Gram-negative bacteria

Method used

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  • Mercaptopropionamide compounds, preparation method and medicinal use thereof
  • Mercaptopropionamide compounds, preparation method and medicinal use thereof
  • Mercaptopropionamide compounds, preparation method and medicinal use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]Example 1: 2 - (((1,1'-biphenyl) -4-yl) methyl) acrylate

[0055]

[0056]It is weighted 4-boron acid 500 mg (2.5 mmol), 2-bromoethacrylate 400 mg (2.1 mmol), 7.0 mg (0.02 mmol) of palladfluoroacetate and 177 mg (3.1 mmol) of potassium hydroxide (3.1 mmol) dissolved in 20 ml water After stirring at 90 ° C for 3 hours, it was extracted 3 times with dichloromethane, and the organic phase was mixed with anhydrous sodium sulfate, and the organic solvent was evaporated under reduced pressure, and the column chromatography was separated to obtain a colorless transparent oil liquid 527mg. 94.1% yield;

[0057]1H NMR (400MHz, CDCL3Δ: 7.60 (D, J = 7.2 Hz, 2H), 7.55 (D, J = 8.0 Hz, 2H), 7.41 (T, J = 7.4 Hz, 2H), 7.34 (S, 1H), 7.30 (D, J = 8.0Hz, 2H), 6.30 (S, 1H), 5.50 (S, 1H), 4.20 (DD, J = 7.2, 7.2 Hz, 2H), 3.71 (S, 2H), 1.26 (T, J = 7.2 Hz, 3H) .si-ms (m / z): 267.1 (m + h)+.

Embodiment 2

[0058]Example 2: 2 - ((1,1'-biphenyl) -4-yl) methyl) acrylic acid

[0059]

[0060]It is proud of the intermediate 2 - ((1,1,1, 1'-biphenyl) -4-yl) methacrylate 527 mg to 50 ml of tomato bottle, dissolved in 5 ml of tetrahydrofuran, and then add 3M aqueous sodium hydroxide aqueous solution 30ml, The reaction was stirred at 90 ° C for 4 h, and pH was adjusted to 2-3, and the mixture was extracted 3 times with 2M sulfuric acid, and the organic layer, sodium alhydrate sodium sulfate was combined, and the column chromatography was purified to give a white solid 429 mg, yield 90.9%;

[0061]1HNMR (400MHz, DMSO-D6Δ: 12.57 (S, 1H), 7.62 (DD, J = 7.6, 8.0 Hz, 4H), 7.45 (T, J = 7.4 Hz, 2H), 7.34 (T, J = 7.4 Hz, 1H), 7.29 ( D, J = 8.0Hz, 2H), 6.13 (S, 1H), 5.63 (S, 1H), 3.60 (S, 2H) .si-MS (M / Z): 239.1 (M + H)+.

Embodiment 3

[0062]Example 3: 3 - ((1,1'-biphenyl) -4-yl) -2 - ((acetyl) methyl) propionic acid

[0063]

[0064]3 ((1,1, 1'-biphenyl) -4-yl) methacrylic acid 429 mg, placed in a 50 ml of tomato bottle, add 20 ml of dichloromethane, ultrasound to dissolve the sample, then add catalytic amount Triethylamine, then dripped 1.8 ml (411 mg) of 10 ml of dichloromethane, which was diluted with 10 ml of dichloromethane, continued at room temperature and stirring at room temperature, and evaporated. Purification of acetic acid, column chromatography, gave 392 mg of white solid, yield 69.3%;

[0065]1H NMR (400MHz, CDCL3Δ: 11.15 (S, 1H), 7.48-7.35 (m, 6H), 7.26-7.21 (m, 3H), 3.09 (m, 1H), 3.00 (D, J = 7.2 Hz, 2H), 2.94 (D , J = 7.6Hz, 2H), 2.26 (s, 3h) .si-ms (m / z): 315.1 (M + H)+.

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PUM

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Abstract

The present invention belongs to the field of biomedicine, and specifically relates to mercaptopropionamide compounds represented by formula (I) and their medicinal salts, their preparation methods and their medicinal uses, especially in the preparation of drugs against Gram-resistant negative bacteria. application. Some compounds of the present invention have been tested for NDM-1 enzyme activity, and combined with meropenem to test their antibacterial activity in vitro. The experimental results show that some compounds of the present invention have better NDM-1 enzyme inhibitory activity, And can significantly reduce the minimum inhibitory concentration (MIC value) of meropenem; the compound of the present invention and its salts can be used to prepare NDM-1 enzyme inhibition, and can be combined with meropenem to make a compound preparation for anti-Gram Negative resistant bacteria.

Description

Technical field[0001]The present invention belongs to the biopharmaceutical field, a mercaptoamide compound and a pharmaceutical salt thereof, specifically, a mercaptoamide compound and a pharmaceutically acceptable salt thereof, and a pharmaceutical use thereof, particularly in the preparation of revolutionary Application in the bacterial drug.Background technique[0002]Since Fleming in the 1930s, penicillin found penicillin and used for clinically, β-lactam antibiotics made a huge contribution to human health. However, due to the abuse of antibiotics in recent years, the problem of drug resistance in bacteria is increasingly serious, and bacterial infections have once again become an important reason for harm human health.[0003]Studies have shown that bacteria have a variety of mechanisms that produce drug resistance, mainly including changes in the target target, decrease in bacterial membrane permeability, and the effect of the outer draft pump, the formation of the biological fi...

Claims

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Application Information

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IPC IPC(8): C07C323/52C07C323/56C07D333/76C07C327/22A61K31/165A61K31/195A61K31/381A61K31/265A61P31/04
CPCC07C323/52C07C323/56C07C327/22C07D333/76
Inventor 孙逊孟志胡付品俞立挺韩吉来
Owner FUDAN UNIV
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