N-substituted imidazole carboxylate compound, preparation method and use thereof

一种酯类化合物、咪唑羧酸的技术，应用在有机化学、药物组合、麻醉剂等方向，能够解决弱中枢抑制活性等问题，达到降低副作用、肌肉震颤的几率低、皮质功能恢复快的效果

Active Publication Date: 2018-02-02
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The metabolite of CPMM is CPMM-ECA, which has very weak central inhibitory activity (Ervin Pejo et al. 2016), but whether it has corticosteroid inhibitory activity has not been directly studied

Method used

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  • N-substituted imidazole carboxylate compound, preparation method and use thereof
  • N-substituted imidazole carboxylate compound, preparation method and use thereof
  • N-substituted imidazole carboxylate compound, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add 1.29 g of chloromethyl chloroformate (CAS: 22128-62-7) into 30 mL of anhydrous dichloromethane, add 0.36 g of anhydrous methanol, drop in 1.6 g of pyridine under cold water cooling, and stir for 2 hours. Add 50 mL of dichloromethane, and wash the organic layer twice with 2N hydrochloric acid, then once with water, separate the organic layer, and dry over anhydrous sodium sulfate overnight. After filtration, the filtrate was evaporated to dryness to obtain 1.15 g of crude methyl chloromethyl carbonate, which was directly used in the next reaction.

[0036] Dissolve 216 mg of etomidate acid (CAS: 56649-48-0) in 20 mL of DMF, add 136 mg of methyl chloromethyl carbonate, add 275 mg of potassium carbonate, and stir at room temperature for 3 hours. After the reaction solution was filtered, it was poured into 150 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried overnight with anhydrous sodium sulfate, the filtrate was filtered t...

Embodiment 2

[0042] Add 1.29 g of chloromethyl chloroformate (CAS: 22128-62-7) into 30 mL of anhydrous dichloromethane, add 0.48 g of absolute ethanol, drop in 1.6 g of pyridine under cold water cooling, and stir for 2 hours. Add 50 mL of dichloromethane, and wash the organic layer twice with 2N hydrochloric acid, then once with water, separate the organic layer, and dry over anhydrous sodium sulfate overnight. After filtration, the filtrate was evaporated to dryness to obtain 1.19 g of crude ethyl chloromethyl carbonate, which was directly used in the next reaction.

[0043] Dissolve 216 mg of etomidate acid (CAS: 56649-48-0) in 20 mL of DMF, add 165 mg of ethyl chloromethyl carbonate, add 275 mg of potassium carbonate, and stir at room temperature for 3 hours. After the reaction solution was filtered, it was poured into 150 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried overnight with anhydrous sodium sulfate, the filtrate was filtered the n...

Embodiment 3

[0049] Add 1.29 g of chloromethyl chloroformate (CAS: 22128-62-7) into 30 mL of anhydrous dichloromethane, add 0.66 g of isopropanol, drop in 1.6 g of pyridine under cold water cooling, and stir for 2 hours. Add 50 mL of dichloromethane, and wash the organic layer twice with 2N hydrochloric acid, then once with water, separate the organic layer, and dry over anhydrous sodium sulfate overnight. After filtration, the filtrate was evaporated to dryness to obtain 1.28 g of crude isopropyl chloromethyl carbonate, which was directly used in the next reaction.

[0050] Dissolve 216mg of etomidate acid in 20mL of DMF, add 155mg of isopropyl chloromethyl carbonate, add 275mg of potassium carbonate, stir at room temperature for 3 hours, and spot the plate. The basic reaction of raw materials is complete. After the reaction solution was filtered, it was poured into 150 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried overnight with anhydrous ...

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Abstract

A N-substituted imidazole carboxylate compound shown as a formula (I), a preparation method and use thereof are disclosed. In the formula (I), C * is a R type chiral carbon atom, R 1 and R 2 are independently selected from the group consisting of H, methyl, ethyl, cyclopropyl, cyclobutyl or isopropyl or a C2-5 ene-group formed by R1 and R2; and R3 is substituted or unsubstituted C1-18 saturated orunsaturated aliphatic hydrocarbon or aromatic hydrocarbon, wherein the aliphatic hydrocarbon includes a linear, branched or cyclic aliphatic hydrocarbon group. The N-substituted imidazole carboxylatecompound or pharmaceutically acceptable salts thereof can be used to prepare central inhibitory drugs that exert sedative, hypnotic and / or anesthetic effects on humans or animals, can produce rapid and reversible anesthetic effects, and rapidly metabolises into inactive etomidate acid, and after drug withdrawal, recovery quality is good; body's corticosteroid function can be quickly recovered after single administration or continuous administration, the incidence of muscle tremor is low after the administration, and after the drug withdrawal, the recovery is quick.

Description

technical field [0001] The invention relates to an N-substituted imidazole carboxylate compound with short-acting anesthetic effect and rapid recovery after drug withdrawal, a preparation method and application. Background technique [0002] Etomidate is a long-established intravenous general anesthetic drug. Because of its rapid onset and short maintenance time, it is an ideal intravenous general anesthesia drug. At the same time, due to its unique pharmacological characteristics of good cardiovascular stability, the inhibition of the body's circulation during anesthesia is the smallest among the general anesthetics currently used clinically, so it is especially suitable for patients with heart failure and elderly surgical patients (Bovill JG. 2006 ; Passot S et al. 2005). The anesthetic mechanism of etomidate has been clarified, mainly through the central inhibitory receptor GABA A The receptor binds, making that receptor more sensitive to the inhibitory neurotransmitte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/90A61P25/20A61P23/00
CPCC07D233/90A61P23/00
Inventor 刘进杨俊张文胜柯博文唐磊王斌
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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