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Benzyl isoquinoline compounds, preparation method and application thereof

A technology of benzylisoquinolines and compounds, which is applied in the fields of sulfonate preparation, organic chemistry, drug combination, etc., can solve problems such as severe allergies, and achieve the effect of avoiding side effects

Pending Publication Date: 2020-09-15
SICHUAN DAOZHEN TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] It can be seen that the current reversal technology of muscle relaxant drugs requires external administration of a large number of molecules that have nothing to do with the therapeutic effect to release the muscle relaxant effect. Some of these relatively large doses of rescue agents have been reported to have certain side effects on the body, such as severe allergies (LMenéndez- Ozcoidi, Anaesthesia, 2011, 66(3):217-9)

Method used

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  • Benzyl isoquinoline compounds, preparation method and application thereof
  • Benzyl isoquinoline compounds, preparation method and application thereof
  • Benzyl isoquinoline compounds, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035]

[0036] Put 715 mg of labdansu (CAS: 1699-51-0) and 334 mg of methyl 3-bromopropionate in 30 mL of acetonitrile, stir at 55°C for 24 hours, evaporate the acetonitrile to dryness under reduced pressure, and perform column chromatography (dichloromethane / methanol) =10 / 1) to obtain 590mg of N-methyl-N-propionic acid methyl ester labdansin quaternary ammonium salt, add 2N aqueous sodium hydroxide solution 20mL, hydrolyze at room temperature for 2 hours, adjust the Ph value to 9 with hydrobromic acid aqueous solution, reduce The solvent was evaporated to dryness under pressure, and the crude product was subjected to column chromatography (dichloromethane / methanol=10 / 1) to obtain 280 mg of N-methyl-N-propionyllaudansin quaternary ammonium bromide sodium salt, namely Fragment a.

[0037] 3-(Methylamino)-1-propanol (CAS: 42055-15-2) 178 mg and 4-nitrobenzyl bromide (CAS: 100-11-8) 648 mg were dissolved in 30 mL of acetonitrile, stirred at 55°C for 24 hours, Acetonitrile was...

Embodiment 2

[0041]

[0042] Fragment a was prepared according to the method described in Example 1.

[0043] 178mg of 3-(methylamino)-1-propanol (CAS: 42055-15-2) and 410mg of 4-chlorobenzyl bromide were dissolved in 30mL of acetonitrile, stirred at 50°C for 3 hours, then 450mg of 4-nitrobenzyl bromide was added, Stir at 55°C for 24 hours, evaporate acetonitrile to dryness under reduced pressure, and obtain brominated N-methyl-N-hydroxypropyl-N-p-chlorobenzyl-N- 435 mg of p-nitrobenzyl quaternary ammonium salt, add 20 mL of dichloromethane, 200 mg of chloromethyl chloroformate and 350 mg of pyridine, stir at room temperature for 5 hours, and obtain brominated N-methyl-N-chloromethyl carbonate propyl group by column chromatography -415 mg of N-p-chlorobenzyl-N-p-nitrobenzyl quaternary ammonium salt, namely fragment b.

[0044] Dissolve 261 mg of Fragment b and 266 mg of Fragment a in 20 mL of DMF, stir and react at room temperature for 36 hours, evaporate the DMF to dryness under reduc...

Embodiment 3

[0047]

[0048] Put 715 mg of labdansu (CAS: 1699-51-0) and 304 mg of methyl 2-bromoacetate in 30 mL of acetonitrile, stir at 55°C for 24 hours, evaporate the acetonitrile to dryness under reduced pressure, and perform column chromatography (dichloromethane / methanol = 10 / 1) to obtain 510mg of N-methyl-N-methyl acetate labdansin quaternary ammonium salt, add 2N aqueous sodium hydroxide solution 20mL, hydrolyze at room temperature for 2 hours, adjust the pH value to 9 with hydrobromic acid aqueous solution, evaporate under reduced pressure The solvent was dried, and the crude product was subjected to column chromatography (dichloromethane / methanol=10 / 1) to obtain 280 mg of N-methyl-N-acetoxylaudansin quaternary ammonium bromide sodium salt, namely Fragment a.

[0049] Add 150 mg of 2-(methylamino)-ethanol (CAS: 109-83-1) and 410 mg of 4-chlorobenzyl bromide in 30 mL of acetonitrile, stir at 50°C for 3 hours, then add 378 mg of 4-fluorobenzyl bromide, and stir at 55°C for 24 H...

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Abstract

The invention relates to a class of benzyl isoquinoline compounds, a preparation method and application thereof, wherein the structure of the compound is represented by a formula I. The stereoisomer with the structure represented by the formula (I) or the stereoisomer mixture or the pharmaceutically acceptable salt, the solvate of the stereoisomer or the stereoisomer mixture, and the pharmaceutical composition formed by the stereoisomer or the stereoisomer mixture and the pharmaceutically acceptable carrier can generate a neuromuscular junction retardation effect and are applied to the field of preparation of muscle relaxation drugs. Each substituent is consistent with that in the specification.

Description

technical field [0001] The invention relates to a class of benzylisoquinoline compounds, a preparation method and use. Background technique [0002] Neuromuscular junction blockers, also known as muscle relaxants, are essential drugs during surgery. This type of drug relaxes the skeletal muscle of the patient during the operation, which is convenient for tracheal intubation, myometriotomy and other surgical operations. It is difficult to carry out the above operation under the condition of poor muscle relaxation. The use of neuromuscular junction blockers has a long history. Starting from the first clinical use of tubocura, various compounds with different structures have been used and eliminated clinically. At present, according to the structure type of drugs, there are three main types of muscle relaxants in clinical use: succinylcholine, aminosteroids and benzylisoquinolines. According to the mechanism of action, succinylcholine belongs to depolarizing muscle relaxants...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/20C07D217/18C07C303/32C07C309/30A61P21/02A61K31/472
CPCC07D217/20C07D217/18A61P21/02
Inventor 刘力铭
Owner SICHUAN DAOZHEN TECH CO LTD
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