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

A compound and solvate technology, applied in the field of medicinal chemistry, can solve the problems of increasing medical costs and the incidence of infection, the inability to recover motor function after surgery, and limiting the wide application of local anesthetics, etc., to achieve long-term local anesthesia , Long-acting selective local anesthesia, long-term effect

Pending Publication Date: 2022-02-22
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the short duration of the effect of traditional local anesthetics, an analgesic pump has to be used to maintain the nerve block, and catheters are placed in the spinal canal, nerve root, subcutaneous and other parts, which greatly increases the medical cost and the incidence of infection
[0004] On the other hand, traditional local anesthetics do not have specific selectivity for nerve block, and block various nerve fibers extensively during use, affecting various nerve functions such as sensation, pain, movem

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0283] Example 1, Preparation of Compounds of the Invention

[0284]

[0285] Compound 1a (10.0 g, 40.59 mmol) was dissolved in 15 mL of 1,3-dibromoles, heated to 70 ° C for 48 h, TLC monitoring (DCM: MeOH = 10: 1, V / V, R) f = 0.3). The appropriate amount of petroleum ether was added, and the viscous syrup-like substance was formed, poured out of the upper tank, and 13.5 g of the remaining crude product was dissolved with 25 ml of methanol, and the silica gel was simatted after drying. Eluent: DCM: MeOH = 10: 1, V / V, collect eluting eluting eluting eluting eluting eluting eluting elut elut elut Ethyl acetate and dichloromethane were recrystallized to prepare a 8.8 g of a white solid powder (intermediate 1b) with a yield of 58.9% for the next reaction.

[0286] The above-mentioned intermediate 1b (1.00 g, 2.17 mmol), Sn- (2,6-dimethylphenyl) -2-piperidine (0.505 g, 2.17 mmol) was dissolved in 10 ml of ethanol, DIPEA (0.99 g, 0.78 mL, 4.74 mmol) was added, warmed to 80 ° C, he...

Example Embodiment

[0287] Example 2, Preparation of Compounds of the Invention

[0288]

[0289] Compound 2a (10.0 g, 40.59 mmol) was dissolved in 15 mL of 1,5-dibromoprice, heated to 75 ° C for 36 h, TLC monitoring (DCM: MeOH = 10: 1, V / V, R) f = 0.3). The appropriate amount of petroleum ether was added, and the viscous syrup-like substance was formed, poured out of the upper tank, and the remaining crude product was dissolved, and after dissolving with silica gel, the silica gel column chromatography was purified. Eluent: DCM: MeOH = 10: 1, V / V, collect eluting eluting eluting eluting eluting eluting eluting eluting eluting elut Ethyl acetate and dichloromethane were recrystallized to prepare 10.1 g of a white solid powder (intermediate 2b), the yield was 62.8% for the next reaction.

[0290] The above-mentioned intermediate 2b (1.00 g, 2.52 mmol), Sn- (2,6-dimethylphenyl) -2-piperidine (0.585 g, 2.28 mmol) was dissolved in 10 ml of ethanol, DIPEA (0.99 g, 0.78 mL, 4.74 mmol) was added, warm...

Example Embodiment

[0291] Example 3, Preparation of Compounds of the Invention

[0292]

[0293]Compound 3A (10.0 g, 34.67 mmol) was dissolved in 15 mL of 1,5-dibromoprice, heated to 75 ° C for 48 h, TLC monitoring (DCM: MeOH = 10: 1, V / V, R) f = 0.3). The appropriate amount of petroleum ether was added, and the viscous syrup-like substance was added, poured out of the upper layer, 14 g of the remaining crude product, mixed with silica gel after dissolving using 25 ml of methanol, and the silica gel column chromatography was purified. Eluent: DCM: MeOH = 10: 1, V / V, collect eluting eluting eluting eluting eluting eluting eluting elut elut elut Ethyl acetate and dichloromethane were recrystallized to prepare 8.6 g of a white solid powder (intermediate 3b), yield 56.7% for the next reaction.

[0294] The above-mentioned intermediate 3b (1.00 g, 2.28 mmol), Sn- (2,6-dimethylphenyl) -2-piperidine (0.530 g, 2.28 mmol) was dissolved in 10 ml of ethanol, DIPEA (0.99 g, 0.78 mL, 4.74 mmol) was added, ...

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Abstract

The invention provides a quaternary ammonium salt compound for anesthesia as well as a preparation method and application thereof, and belongs to the field of medical chemistry. The quaternary ammonium salt compound is a compound represented by a formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof. The quaternary ammonium salt compound disclosed by the invention takes effect quickly when being used for local anesthesia, the anesthesia time is long after single administration, the sensory nerve block time is longer than the motor nerve block time, the quaternary ammonium salt compound has a long-acting local anesthesia effect and a selective local anesthesia effect, the side effects of local anesthesia medicines in the prior art are remarkably reduced, and the quaternary ammonium salt compound has better safety. The quaternary ammonium salt compound disclosed by the invention can be used for preparing safe medicines with long-time local anesthesia and selective local anesthesia effects, and has the advantages of long local anesthesia action time, good local anesthesia selectivity, smaller nerve injury and high safety.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a quaternary ammonium salt compound used for anesthesia, a preparation method and application 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 co...

Claims

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Application Information

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IPC IPC(8): C07D409/12C07D211/60C07D225/02C07D295/15C07D401/06C07D205/04C07D207/16C07D223/06C07D207/09C07D223/04C07D265/30C07D265/06A61P23/02A61K31/4535A61K31/452A61K31/4545A61K31/4523A61K31/454A61K31/55A61K31/397A61K31/395A61K31/40A61K31/496A61K31/495A61K31/5377A61K31/5375A61K31/5355A61K31/535
CPCC07D409/12C07D211/60C07D225/02C07D295/15C07D401/06C07D205/04C07D207/16C07D223/06C07D207/09C07D223/04C07D265/30C07D265/06A61P23/02A61K31/395A61K31/397A61K31/40A61K31/452A61K31/4523A61K31/4535A61K31/454A61K31/4545A61K31/495A61K31/496A61K31/535A61K31/5355A61K31/5375A61K31/5377A61K31/55Y02P20/55
Inventor 柯博文刘进
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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