N-diethylaminoacetyl-2,6-dimethylaniline derivatives, preparation method and applications thereof

A technology of diethylaminoacetyl and dimethylaniline, which is applied in the fields of N-diethylaminoacetyl-2,6-dimethylaniline derivatives, preparation and use, can solve the blockade of sensory nerve cells and the inability of QX314 to Clinical use and other issues, to achieve the effect of good animal tolerance, ideal clinical use prospects and value

Active Publication Date: 2014-08-06
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although capsaicin is used locally, and QX314 is used after the TRPV1 channel is opened, so that it can enter the sensory nerve cells through this channel to play a blocking effect, but due to the strong stimulation of capsaicin, animals or humans usually cannot tolerate it, resulting in QX314 has been unable to be used clinically and can only be used as a tool drug for the study of sodium ion channels

Method used

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  • N-diethylaminoacetyl-2,6-dimethylaniline derivatives, preparation method and applications thereof
  • N-diethylaminoacetyl-2,6-dimethylaniline derivatives, preparation method and applications thereof
  • N-diethylaminoacetyl-2,6-dimethylaniline derivatives, preparation method and applications thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of intermediate compound (Ⅳ)

[0036]

[0037] Dissolve 5g of N-diethylaminoacetyl-2,6-dimethylaniline in 50ml of 2-bromoethanol, react in a closed container at 90°C for 24h, then slowly add the reaction solution dropwise into 200ml of anhydrous ether and After continuous stirring, a white solid was precipitated, filtered and dried to obtain 2.37 g of product (Ⅳ), with a yield of 31%.

[0038] 1 H NMR (400MHz, CD 3 OD) TM : 7.11~7.16 (m, 3H), 4.50~4.51 (m, 2H), 4.05~4.07 (m, 2H),3.75~3.87(m, 6H), 2.26 (s, 6H), 1.43(t, J = 7.2Hz, 6H).

[0039] 13 C NMR (400MHz, CD 3 OD) TM : 8.28, 18.65, 56.81, 56.93, 58.48, 61.63, 128.92, 129.31, 134.19,

[0040] 136.80, 164.15.

[0041] Detection instrument: Agilent 1200 series 6130 mass spectrometer

[0042] ESI: C 16 h 27 N 2 o 2 + , [M] + : 279.2075.

Embodiment 2

[0044] Preparation of intermediate compound (Ⅳ)

[0045] Dissolve 5g of N-diethylaminoacetyl-2,6-dimethylaniline in 50ml of 2-bromoethanol, react in a closed container at 50°C for 72h, then slowly add the reaction solution dropwise to 200ml of anhydrous ether and keep After stirring, a white solid was precipitated, filtered, and dried to obtain 2.06 g of product (IV), with a yield of 27%.

Embodiment 3

[0047]

[0048] Compound (IV) (250 mg, 0.70 mmol) was dissolved in 20ml of acetone, cooled to 0°C, and triphosgene (208 mg, 0.70 mmol) and pyridine (166 mg, 2.10 mmol) were added under nitrogen protection. After the addition, the cold bath was removed, the reaction solution was reacted overnight at room temperature, filtered, and the crude product of the acid chloride intermediate obtained after the filtrate was concentrated was directly fed.

[0049] Add 20ml of acetone to the acid chloride intermediate, add artificial capsaicin (Ⅴ) (308 mg, 1.05 mmol), pyridine (111 mg, 1.40 mmol), stir the liquid at room temperature under nitrogen protection, filter, concentrate, and obtain by preparative chromatography Yellow softened solid product (I) 45 mg, two-step yield 9.5%. Test results:

[0050] 1 H NMR (400MHz, CD 3 OD) TM : 7.10~7.15 (m, 3H), 7.04 (s, 1H), 6.94 (d, J = 8.0Hz, 1H), 6.83 (d, J = 8.0Hz, 1H), 4.76 (m, 2H), 4.48 ( s, 2H), 4.36 (s, 2H), 4.20 (m, 2H), 3.76~3.83(...

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Abstract

N-diethylaminoacetyl-2,6-dimethylaniline derivative, preparation method and use. The structure of said derivative is shown in formula (I). During preparation, the corresponding quaternary ammonium salt intermediate compound can be prepared from N-diethylaminoacetyl-2,6-dimethylaniline and halogenated compounds first, and then the corresponding 2-methoxy-4-substituted phenol derivative It is obtained after the reaction of similar raw materials. The derivative can be used as a local anesthetic or analgesic drug with long-acting and motor-sensory separation, can exert a reversible and long-lasting local anesthetic effect in the living body, and has no effect on motor function within a certain dose range, and has ideal movement and sensation Detached blocking effect.

Description

technical field [0001] The invention relates to a novel derivative of N-diethylaminoacetyl-2,6-dimethylaniline, its preparation method and application. The derivative can be used as a local anesthetic or analgesic, and does not produce motor block when exerting sensory block. Background technique [0002] Local anesthetics (local anesthetics, local anesthetics) are a class of drugs that can reversibly block the generation and transmission of sensory nerve impulses in the local area of ​​the drug while keeping the patient or animal awake, causing pain loss in local tissues. The effect of local anesthetics is related to the diameter of nerve cells or nerve fibers and the anatomical characteristics of nerve tissue. The general rule is that nerve fiber endings, ganglia and synaptic sites of the central nervous system are most sensitive to local anesthetics, and thin nerve fibers are more likely to be blocked than thick nerve fibers. It can be effective at low concentrations on...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/04C07C231/12A61P23/02A61P29/00
Inventor 张文胜杨俊刘进
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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