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N-substituted imidazole carboxylic ester compound with ultrashort-acting anesthetic effect, preparation method and use thereof

A technology of ester compounds and imidazole carboxylic acid, which is applied in the field of N-substituted imidazole carboxylic acid ester compounds, can solve the problems of imidazole derivatives with weak 11-β hydroxylase binding ability, strengthen drug molecules and enzyme molecules, etc.

Active Publication Date: 2014-02-19
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This side effect of etomidate is related to the imidazole structure in the drug molecule. An N atom in the imidazole ring can form a complex with the topological iron atom in 11-β hydroxylase, thereby strengthening the combination of the drug molecule and the enzyme molecule , so as to achieve the effect of inhibiting 11-β hydroxylase, and its binding ability with 11-β hydroxylase is better than that with GABA A The receptor binding ability is 100 times stronger, which poses a challenge to design imidazole derivatives with no or weaker 11-β hydroxylase binding ability

Method used

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  • N-substituted imidazole carboxylic ester compound with ultrashort-acting anesthetic effect, preparation method and use thereof
  • N-substituted imidazole carboxylic ester compound with ultrashort-acting anesthetic effect, preparation method and use thereof
  • N-substituted imidazole carboxylic ester compound with ultrashort-acting anesthetic effect, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034]N-substituted imidazole carboxylic acid compound (II) (2g, 9.26mmol) and ethylene glycol monoacetate (III) (0.96g, 9.26mmol) were dissolved in 50ml of dichloromethane, and a catalytic amount of DMAP (4- Dimethylaminopyridine), add dropwise 30ml of dichloromethane solution containing DCC (N,N-dicyclohexylcarbodiimide, 1.92g, 9.30mmol), stir at room temperature for 2 hours after dropping, and use thin layer chromatography Spot plate observation, N-substituted imidazole carboxylic acid compound (II) reacted completely. Filtrate, concentrate the filtrate under reduced pressure, add a small amount of ethyl acetate to dissolve the residue, put it in a refrigerator at minus 20°C overnight, filter out a small amount of precipitated solid the next day, and concentrate the filtrate to obtain a light yellow oil, which is subjected to silica gel column chromatography (developed Reagent: cyclohexane / ethyl acetate=7 / 1) to obtain 1.82 g of colorless and transparent oily product (I) (n=...

Embodiment 2

[0042] Dissolve N-substituted imidazole carboxylic acid compound (II) (2g, 9.26mmol) and ethylene glycol monoacetate (III) (0.96g, 9.26mmol) in 50ml DMF, add a catalytic amount of DMAP, dropwise add DCC ( 1.92g, 9.30mmol) in 30ml of DMF solution, stirred at room temperature for 2 hours after dropping, spot plate observation, N-substituted imidazole carboxylic acid compound (II) reacted completely. Pour the reaction solution into 300ml of water, add 200ml of ethyl acetate for extraction, separate the organic layer, wash once with water, add anhydrous sodium sulfate to the organic layer and dry overnight, filter the desiccant out the next day, concentrate the filtrate by evaporation under reduced pressure, add a small amount of acetic acid Dissolve the residue in ethyl ester, put it in minus 20°C refrigerator overnight, filter out a small amount of precipitated solid the next day, and concentrate the filtrate to obtain a light yellow oily product (I) (n=2, R' is acetyl group), wh...

Embodiment 3

[0044] Dissolve N-substituted imidazole carboxylic acid compound (II) (2g, 9.26mmol) and bromoethanol (IV) (1.16g, 9.26mmol) in 50ml DMF, add powdered sodium hydroxide (0.37g, 9.26mmol), in Stir at 60°C for 1 hour, spot plate observation, the reaction of N-substituted imidazole carboxylic acid compound (II) is complete. Pour the reaction solution into 250ml of water, add 150ml of ethyl acetate for extraction, separate the organic layer, wash once with water, add anhydrous sodium sulfate to the organic layer and dry overnight, filter the desiccant the next day, and evaporate the filtrate under reduced pressure to concentrate, and the crude product obtained is directly for the next reaction.

[0045] Dissolve the product obtained in the previous step in 50ml of DMF, add acetic acid (Ⅴ) (0.56g, 9.26mmol), add a catalytic amount of DMAP, then add 30ml of DMF solution containing DCC (1.92g, 9.30mmol) dropwise, and stir at room temperature after dropping 2 hours. Pour the reaction...

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Abstract

The invention discloses an N-substituted imidazole carboxylic ester compound with an ultrashort-acting anesthetic effect. The structure is shown in formula (I), wherein R is shown in the specification, or -(CH2)nOR'; n is an integer from 1 to 3; R' is selected from C1-4 alkyl and acyl; R' is not methyl when n is 2. The compound can generate a quick and reversible general anesthesia effect. An animal experiment shows that the compound and a pharmaceutically acceptable salt compound thereof have the characteristics that the effects are shorter than the etomidate anesthetic effect, can be prompted to carry put quick metabolism inside a body, can be used as ultrashort-acting general anesthesia drugs, and have significant advantages and good application prospects; shortening of the inhibition time on cortical hormone is also facilitated; the compound can be obtained from an N-substituted imidazole carboxylic acid compound, and corresponding alcohol and haloalcohol or ester, halide and the like thereof by condensation or substitution reaction.

Description

technical field [0001] The invention relates to an N-substituted imidazole carboxylate compound with an ultra-short-acting anesthetic effect, a preparation method and an application. Background technique [0002] Etomidate (R in the structure of formula (I) is an ethyl group) is an intravenous general anesthesia drug that has been on the market for a long time. The drug has a fast onset time and short maintenance time, and is an ideal intravenous general anesthesia drug. At the same time, it also has the unique pharmacological characteristics of excellent cardiovascular stability, and the inhibition of the body's circulation during anesthesia is the least among the general anesthetics currently used clinically, so it is especially suitable for surgical patients with cardiac insufficiency. 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 ...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D233/90A61K31/4178A61K31/4174A61P25/20A61P23/00
CPCC07D233/90C07D405/12
Inventor 杨俊张文胜刘进
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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