Long-chain amine-substituted dimethylanilinium compounds, preparation, self-assembly structure and use

A dimethylanilinium and compound technology, which is applied in the field of long-chain amine-substituted dimethylanilinium compounds, can solve problems such as inability to meet, increase the duration of local anesthesia, and limited liquid capacity of local muscle tissue.

Active Publication Date: 2022-03-04
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, all local anesthetic drugs in clinical practice are molecules without charge, which can only achieve local anesthesia and analgesia for no more than 8 hours, and cannot meet the requirements of postoperative wound recovery, long-term pain and advanced cancer pain, reaching 120 hours The need for long-acting local anesthesia
The duration of local anesthesia cannot be increased by increasing the volume of local injection fluid due to the limited fluid capacity of local muscle tissue

Method used

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  • Long-chain amine-substituted dimethylanilinium compounds, preparation, self-assembly structure and use
  • Long-chain amine-substituted dimethylanilinium compounds, preparation, self-assembly structure and use
  • Long-chain amine-substituted dimethylanilinium compounds, preparation, self-assembly structure and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051]

[0052] Add 6.0 g of compound (V), 1.2 g of pyridine, and 100 mL of dichloromethane into a 200 mL round bottom bottle, and stir well at room temperature. At room temperature, 20 mL of dichloromethane dissolved with 1.1 g of n-butylamine was added dropwise for 15 minutes. Stir at reflux at 40°C for 16h.

[0053] Cool to room temperature, wash with 20 mL x 2 of saturated aqueous sodium bromide, separate the organic phase, and concentrate to dryness. Silica gel column chromatography using dichloromethane:methanol=20:1 as the eluent gave a light yellow colloidal solid with a yield of 32%. 1 H NMR (300MHz, CDCl 3 )δ: 7.02~7.08(m, 3H), 4.80(br, 2H), 4.54(t, J=4.8Hz, 2H), 4.07(t, J=4.8Hz, 2H), 3.70~3.79(m, 4H ), 2.20(s, 6H), 1.33~1.40(m, 4H), 1.30(t, J=4.8Hz, 6H), 0.90(t, J=7.2Hz, 3H). HRMS: [C 20 h 36 N 3 O] +, 334.2853, found 334.2858. As detected by ion chromatography, the bromide ion content is 99.8%.

Embodiment 2

[0055]

[0056] Dissolve 2.0 g of the product of Example 1 in 100 mL of dichloromethane, wash with 20 mL of saturated aqueous sodium chloride solution x 7, separate the organic phase, and concentrate to dryness. Silica gel column chromatography using dichloromethane:methanol=5:1 as the eluent gave a light yellow colloidal solid with a yield of 45%. As detected by ion chromatography, the chloride ion content is 99.6%.

Embodiment 3

[0058]

[0059] Add 3.0 g of the product of Example 1, 0.6 g of pyridine, and 100 mL of dichloromethane into a 200 mL round bottom bottle, and stir evenly at room temperature. At room temperature, 20 mL of a dichloromethane solution in which the amount of iodomethane dissolved in the amount of the example product and the like was added dropwise, and the drop was completed in 15 minutes. Stir at reflux at 40°C for 16h.

[0060] Cool to room temperature, wash with 10 mL x 5 saturated sodium bromide aqueous solution, separate the organic phase, and concentrate to dryness. Silica gel column chromatography using dichloromethane:methanol=20:1 as the eluent gave a light yellow colloidal solid in a yield of 27%. 1 H NMR (300MHz, CDCl 3 )δ: 7.02~7.08(m, 3H), 4.80(br, 2H), 4.54(t, J=4.8Hz, 2H), 4.07(t, J=4.8Hz, 2H), 3.70~3.79(m, 4H ), 2.28(s, 3H), 2.18(s, 6H), 1.33~1.40(m, 4H), 1.30(t, J=4.8Hz, 6H), 0.90(t, J=7.2Hz, 3H). HRMS: [C 21 h 38 N 3 O] + , 348.3009, found 348.3012. ...

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Abstract

Long-chain amine-substituted dimethylanilinium compounds, preparation, self-assembly structure and use. This type of compound can have super long-acting anesthetic effect and low neuropathological damage. It is a kind of long-chain amine-substituted N-diethylaminoacetyl-2,6-dimethylanilinium compound, and its structure is shown in formula (I) , and salts of such compounds, the structure of which is shown in formula (II). The compound can self-assemble in aqueous solvents to form microscopic particles including spherical micelles, Janus micelles and vesicles, and can exert long-term local anesthesia in vivo, and the local anesthesia and / or analgesic time can exceed 120 hours, neuropathological damage is low, and the safety is much higher than that of the published long-acting local anesthetic compounds.

Description

technical field [0001] The invention relates to a long-chain amine-substituted dimethylanilinium compound with ultra-long-acting anesthetic effect and low nerve damage, as well as its preparation method, self-assembly structure and application. 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 mechanism of action of local anesthetic drugs is currently recognized as blocking the voltage-gated Na+ channel on the nerve cell membrane to block conduction and produce local anesthesia. [0003] The effects of local anesthetics are generally localized at the site of administration and disappear rapidly as the drug diffuses from the site of administration. If a long-acting local anesthetic effect is desired, in addition to improvi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/04C07C231/12C07C51/41C07C53/10C07C59/255C07C303/32C07C309/04C07C309/30C07C309/06A61K31/167A61P23/02A61P25/04A61P17/04
CPCC07C237/04C07C53/10C07C59/255C07C309/04C07C309/30C07C309/06A61P23/02A61P25/04A61P17/04
Inventor 刘进唐磊张文胜杨俊柯博文
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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