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

A technology of diethylaminoacetyl and dimethylaniline, applied in the field of N-diethylaminoacetyl-2,6-dimethylaniline derivatives, preparation and application, can solve the problem that QX314 cannot be used clinically, sensory nerve cells Blocking and other problems, to achieve ideal clinical application prospects and value, and good animal tolerance

Active Publication Date: 2014-02-26
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

The invention provides N-diethylaminoacetyl-2,6-dimethylaniline derivatives, a preparation method and applications thereof. The structure of the derivatives is represented by the formula (I). The preparation method comprises the following steps: carrying out reactions between N-diethylaminoacetyl-2,6-dimethylaniline and halogenated compounds to obtain a corresponding quaternary ammonium salt intermediate, and then subjecting the quaternary ammonium salt intermediate to react with corresponding 2-methoxyl-4-subsituted phenol derivative raw material so as to obtain the N-diethylaminoacetyl-2,6-dimethylaniline derivatives. The derivatives can be used as a long-acting local anesthetic drug or a pain relieving drug capable of separating the motion and the feeling, can exert a reversible and lasting local anesthetic effect in organism bodies, do not affect motor function in a certain dosage range, and have an ideal retardant effect on separation of motion and feeling.

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 o...

Claims

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Application Information

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Patent Type & Authority Applications(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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