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Quaternary ammonium salt compound as well as preparation method and application thereof

A compound and solvate technology, applied in the field of chemical medicine, can solve the problems of muscle and nerve injury, poor local anesthesia selectivity, and no selective local anesthetic effect, etc.

Active Publication Date: 2020-05-15
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this type of compound can obtain a long-term local anesthetic effect to a certain extent, because this type of compound has a structure similar to a surfactant, although it can obtain a long-acting effect to a certain extent, it will also cause severe muscle and muscle pain at the local injection site. Nerve damage, poor safety
At the same time, similar compounds that have been reported so far do not have selective local anesthetic effect and cannot meet the clinical needs.
Therefore, whether QX314 is used alone, QX314 is used in combination with other active drugs, or the QX314 long-chain compound with surfactant structure features has the defects of poor safety and poor local anesthesia selectivity

Method used

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  • Quaternary ammonium salt compound as well as preparation method and application thereof
  • Quaternary ammonium salt compound as well as preparation method and application thereof
  • Quaternary ammonium salt compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Embodiment 1, the preparation of compound of the present invention

[0100]

[0101] Compound 1a (5.0g, 45.39mmol) was dissolved in 15mL of 1,3-dibromopropane, heated to 75°C for 40h, monitored by TLC (DCM:MeOH=10:1, R f = 0.3). Add an appropriate amount of ethyl acetate to form a viscous syrupy substance, pour off the supernatant, and the remaining 6g of crude product is dissolved in 30mL of methanol and then mixed with silica gel. After dry loading, the sample is purified by silica gel column chromatography. The eluent is CH 2 Cl 2 : MeOH=10:1, the eluate was collected and concentrated to obtain 3 g of crude product. Ethyl acetate and dichloromethane were recrystallized to obtain 2.5 g of off-white solid powder (1b), yield: 31.6%, which was used for the next reaction.

[0102] Intermediate 1b (2.00g, 3.66mmol) and N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (0.934g, 4.03mmol, CAS: 15883-20-2 ) was dissolved in 20mL of ethanol, DIPEA (0.94g, 1.21mL, 7.32mmol...

Embodiment 2

[0103] Embodiment 2, the preparation of compound of the present invention

[0104]

[0105] Compound 2a (2.0g, 40.32mmol) was dissolved in 5mL of bis(2-bromoethyl)ether, heated to 75°C for 24h, monitored by TLC (DCM:MeOH=10:1, R f = 0.3). An appropriate amount of ethyl acetate was added, and the reaction solution solidified to produce a white solid. 3 g of the crude product was filtered out and purified by silica gel column chromatography. The eluent is CH 2 Cl 2 :MeOH=20:1, the eluate was collected and concentrated to obtain 5.9g of white solid (2b), yield: 31.5%, which was used for the next reaction.

[0106]Intermediate 2b (1.0g, 2.16mmol) and N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (0.55g, 2.37mmol, CAS: 15883-20-2) prepared above Dissolve in 15mL of ethanol, add DIPEA (0.53g, 0.68ml, 4.12mol), react at 30°C for 10 days, evaporate the solvent, and purify the crude product by silica gel column chromatography, the eluent is CH 2 Cl 2 : MeOH=10:1, the eluate w...

Embodiment 3

[0107] Embodiment 3, the preparation of compound of the present invention

[0108]

[0109] Compound 3a (500mg, 1.2mmol), 1,14-dibromotetradecane (2g, 6.0mmol) was dissolved in 5mL of acetonitrile, heated to 70°C for 24h, monitored by TLC (DCM:MeOH=20:1, R f = 0.3). An appropriate amount of ethyl acetate was added, and the reaction solution solidified to produce a white solid. The crude product, 0.9 g of the white solid, was filtered out and purified by silica gel column chromatography. The eluent is CH 2 Cl 2 : MeOH=20:1, the eluate was collected and concentrated to obtain 500 mg of white powdery solid (3b), yield: 54.1%, which was used for the next reaction.

[0110] Intermediates 3b (500mg, 0.65mmol) and 3c (0.18g, 0.71mmol) prepared above were dissolved in 30ml of ethanol and 5ml of methanol mixed solvent, DIPEA (0.17g, 0.21mL, 1.3mmol) was added, and reacted at 30°C for 10 sky. After the reaction was complete, it was purified by silica gel column chromatography. ...

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Abstract

The invention discloses a quaternary ammonium salt compound as well as a preparation method and application thereof, and belongs to the field of chemical medicines. The present invention provides a compound represented by a formula I, or a pharmaceutically acceptable salt, a stereoisomer, a solvate, a prodrug, or a metabolite thereof. The compound takes effect fast, a long-time local anesthesia effect is achieved after single administration, the sensory nerve blocking time is longer than the motor nerve blocking time, the long-acting local anesthetic effect and the selective local anesthetic effect are achieved, and meanwhile, the side effect of the quaternary ammonium salt compound with the structural characteristics of a surfactant is obviously reduced. The compound has high safety, namely, the compound shown in the formula I and the pharmaceutically acceptable salt thereof can be used for preparing safe medicines with long-time local anesthesia and selective local anesthesia effects. The compound has the advantages of long local anesthesia action time, good local anesthesia selectivity and high safety.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to a quaternary ammonium salt compound and its preparation method and application. Background technique [0002] Local anesthetics are a class of drugs that can reversibly block the generation and transmission of sensory nerve impulses locally, referred to as "local anesthetics". When animals or humans are conscious, these drugs can locally reversibly block the generation and signal transmission of sensory nerve impulses, causing temporary loss of sensation in the parts innervated by the relevant nerves, thereby reversibly causing pain loss in local tissues. Generally, the effect of local anesthetics is localized at the site of administration and disappears rapidly as the drug diffuses from the site of administration. Local anesthetics directly inhibit the relevant ion channels on nerve cells and fiber membranes, block the generation of action potentials and the co...

Claims

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Application Information

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IPC IPC(8): C07D211/60C07D413/06C07D413/12C07D207/16C07D205/04C07D223/06A61P23/02A61K31/445A61K31/55A61K31/397A61K31/401A61K31/5377
CPCC07D211/60C07D413/06C07D413/12C07D207/16C07D205/04C07D223/06A61P23/02
Inventor 柯博文刘进张文胜杨俊唐磊
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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