A kind of hydroxamic acid derivative and its preparation method and application

A derivative, hydroxamic acid technology, applied in the field of hydroxamic acid derivatives and its preparation, to achieve good bactericidal activity and low toxicity

Active Publication Date: 2021-02-02
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the past 20 years, scientists have designed and synthesized various types of LpxC inhibitors. Although many reported compounds have good preclinical data, there is still a need for new LpxC inhibitors that are not only effective against Gram-negative bacteria. Bactericidally active with acceptable toxicity or tolerability

Method used

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  • A kind of hydroxamic acid derivative and its preparation method and application
  • A kind of hydroxamic acid derivative and its preparation method and application
  • A kind of hydroxamic acid derivative and its preparation method and application

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preparation example Construction

[0047] The present invention also provides a method for preparing the hydroxamic acid derivatives described in the above technical scheme, comprising the following steps:

[0048] Mixing the compound with the structure shown in formula II, Dess-Martin oxidant and methylene chloride, and performing an oxidation reaction to obtain the compound with the structure shown in formula III;

[0049] Mixing the compound having the structure shown in formula III, triphenylphosphine, carbon tetrabromide and dichloromethane, performing Corey-Fuchs reaction to obtain the compound having the structure shown in formula IV;

[0050] The compound having the structure shown in formula IV, Pd 2 (dba) 3 1. Mixing a compound having a structure shown in formula a, triethylamine and N,N-dimethylformamide, performing a Sonogashira coupling reaction to obtain a compound having a structure shown in formula V;

[0051] Mixing the compound having the structure shown in formula V, tetrahydrofuran and sod...

Embodiment 1

[0120] N-((S)-3-amino-1-(hydroxylamino)-3-methyl-1-oxobut-2-yl)-4-(((1R,2S)-2-methoxycyclo Preparation of pentyl)but-1,3-diyn-1-yl)benzamide: (the preparation process is shown in formula 4)

[0121]

[0122] Preparation of (1S, 2S)-2-methoxycyclopentane-1-carbaldehyde (Ⅲ-1):

[0123] At -10°C, in a solution of II-1 (8.85g, 68mmol) in dichloromethane (250mL), add Dess Martin oxidant (DMP) (30.96g, 73mmol) in batches, and control the addition rate so that the reaction system The temperature of the mixture was kept between -7°C and -10°C, after the addition was complete, it was stirred at room temperature for 4h. After the reaction was over, move to an ice bath, add saturated aqueous sodium thiosulfate (100mL) and saturated aqueous sodium bicarbonate (250mL) successively to quench the reaction, remove the solid by filtration, leave the layers to stand, and wash the aqueous layer with dichloromethane Extract three times (100mL×3), combine the organic phases, dry over anhydrous ...

Embodiment 2

[0137] (S)-N-(3-amino-1-(hydroxyamino)-3-methyl-1-oxobut-2-yl)-4-((4-nitrophenyl)butan-1,3 -diyn-1-yl) preparation of piperazine-1-carboxamide (I-2): (preparation process is shown in formula 5)

[0138]

[0139] 4-Nitrobenzaldehyde (Ⅲ-2)

[0140] At -10°C, in a solution of II-2 (11.50g, 75mmol) in dichloromethane (250mL), add Dess Martin oxidant (DMP) (34.10g, 80mmol) in batches, and control the rate of addition so that the reaction system The temperature of the mixture was kept between -7°C and -10°C, after the addition was complete, it was stirred at room temperature for 4h. After the reaction was completed, it was moved to an ice bath, and a saturated aqueous solution of sodium thiosulfate (120 mL) and a saturated aqueous solution of sodium bicarbonate (250 mL) were sequentially added to quench the reaction. The solid was removed by filtration, the layers were left to stand, the aqueous layer was extracted three times with dichloromethane (120mL×3), the organic phases ...

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Abstract

The invention relates to the technical field of enzyme inhibitors, in particular to a hydroxamic acid derivative and its preparation method and application. The hydroxamic acid group in the hydroxamic acid derivatives provided by the present invention is chelated with the active zinc ion in the active region of the LpxC enzyme, and contains a hydrophobic side chain combined with the hydrophobic channel in the LpxC enzyme, the above two The content of the aspect ensures that the hydroxamic acid derivatives have better bactericidal activity and lower toxicity to LpxC; the present invention also provides a preparation method of the hydroxamic acid derivatives, and the preparation method has a short reaction time , high yield.

Description

technical field [0001] The invention relates to the technical field of enzyme inhibitors, in particular to a hydroxamic acid derivative and its preparation method and application. Background technique [0002] Super bacteria and human beings are constantly fighting each other. From the 1930s when Fleming discovered penicillin, the first antibiotics were born, but bacteria also began to evolve and fight. Today, bacterial drug resistance is becoming more and more serious, while the development of new antibiotics is relatively lagging behind. About 700,000 people die from drug-resistant bacterial infections every year in the world, and 230,000 newborns die because of this. If new antibiotics cannot be developed to control the spread of superbugs, it is estimated that in 2050, the global death toll due to bacterial infections will reach about 1,000 Around 10,000 will be the highest point of all diseases. [0003] UDP-3-O(R-hydroxytetradecanoyl)-N-acetamidoglucose deacetylase ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C259/06C07D295/195C07D295/155A61P31/04C07C45/29C07C47/37C07C41/30C07C43/192C07C67/343C07C69/78C07C51/09C07C65/28C07C269/06C07C271/22C07C231/12C07C235/42
CPCC07C259/06C07D295/195C07D295/155A61P31/04C07C45/29C07C41/30C07C67/343C07C51/09C07C269/06C07C231/12C07C2601/08C07C47/37C07C43/192C07C69/78C07C65/28C07C271/22C07C235/42C07D295/215C07B2200/07
Inventor 王玉成游雪甫王菊仙杜潇楠王明华朱梅张国宁
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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