Quaternary ammonium salt compound and preparation method and application thereof

A compound and solvate technology, applied in the field of quaternary ammonium salt compounds and their preparation and application, can solve the problems of muscle and nerve injury, poor safety, poor selectivity of local anesthesia, etc.

Active Publication Date: 2019-08-23
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 and preparation method and application thereof
  • Quaternary ammonium salt compound and preparation method and application thereof
  • Quaternary ammonium salt compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Embodiment 1, the preparation of compound of the present invention

[0093]

[0094] Compound 1a (10.0g, 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 15g of the remaining 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. Eluent: CH 2 Cl 2 : MeOH=10:1, the eluate was collected and concentrated to obtain 7.0 g of crude product. Ethyl acetate and dichloromethane were recrystallized to obtain 6.6 g of off-white solid powder (intermediate 1b), yield: 34.4%, which was used for the next reaction.

[0095] Intermediate 1b (1.00g, 2.37mmol), N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (0.604g, 2.61mmol, CAS: 15883-20-2 ) was dissolved in 10mL of ethanol, DIPEA (0.99g, 0.78mL, ...

Embodiment 2

[0096] Embodiment 2, the preparation of compound of the present invention

[0097]

[0098] Compound 2a (10.0g, 40.32mmol) was dissolved in 20mL of 1,3-dibromobutane, 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. The crude product, 16.0 g of the white solid, was filtered out and purified by silica gel column chromatography. Eluent: CH 2 Cl 2 : MeOH=20:1, the eluate was collected and concentrated to obtain 5.9 g of white solid (intermediate 2b), yield: 31.5%, which was used for the next reaction.

[0099] Intermediate 2b (1.0g, 2.16mmol), 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 to dryness, and purify the crude product by silica gel column chromatography, eluent: CH 2 C...

Embodiment 3

[0100] Embodiment 3, the preparation of compound of the present invention

[0101]

[0102] Compound 3a (2.0g, 8.06mmol) was dissolved in 4mL of 1,5-dibromopentane, 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 1.6 g of the white solid was filtered out and purified by silica gel column chromatography. Eluent: CH 2 Cl 2 : MeOH=20:1, the eluate was collected and concentrated to obtain 1.8 g of white powdery solid (intermediate 3b), yield: 46.7%, which was used for the next reaction.

[0103] Intermediate 3b (1.8g, 3.77mmol), N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (0.96g, 4.14mmol, CAS: 15883-20-2) prepared above Dissolve in 30ml of ethanol and 5ml of methanol mixed solvent, add DIPEA (0.97g, 1.24ml, 7.54mmol), and react at 30°C for 18 days. After the reaction was complete, it was purified by silica gel column ch...

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Abstract

The invention discloses a quaternary ammonium salt compound and a preparation method and application thereof. The invention provides a compound shown in a formula I with a novel structure, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof. The compound has the advantages of rapid onset of action, long-termlocal anesthesia effect after single administration, sensory nerve block time greater than motor nerve block time, and both long-term local anesthesia effect and selective local anesthesia effect, remarkably reduces side effects of QX314 and QX314 compositions and quaternary ammonium salt compounds with surfactant structural characteristics, and has better safety. Namely, the compound of formula Iand the pharmaceutically acceptable salt thereof can be used for preparing safe drugs with long-term local anesthesia and selective local anesthesia effects, and have the advantages of long-term local anesthesia, good local anesthesia selectivity, less nerve damage and high safety.

Description

technical field [0001] The invention relates to a quaternary ammonium salt compound and a preparation method and use thereof. Background technique [0002] Local anesthetics (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". A class of drugs that reversibly blocks the generation and signal conduction of sensory nerve impulses locally, causing temporary sensory loss in the innervated parts of animals or humans, thereby reversibly causing pain loss in local tissues. Typically, 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 conduction of nerve impulses, thereby producing local anesthesia. The currently recognize...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60C07D207/16C07D205/04C07D223/06C07C237/04C07C327/22C07C323/25C07C319/20C07C231/12C07C227/18C07C229/16A61P23/02A61K31/167A61K31/223A61K31/265A61K31/55A61K31/445A61K31/397
CPCC07D211/60C07D207/16C07D205/04C07D223/06C07C237/04A61P23/02C07D225/02C07C231/12C07C229/16C07C323/25C07C327/22C07C237/06
Inventor 刘进柯博文张文胜杨俊唐磊
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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