N-substituted imidazolecarboxylic acid ester chiral compound containing ether side chain, preparation method and application thereof

A technology of imidazole carboxylate and chiral compounds, applied in the field of N-substituted imidazole carboxylate chiral compounds, can solve the weak 11-β hydroxylase binding ability of imidazole derivatives, strengthen the combination of drug molecules and enzyme molecules And other issues

Active Publication Date: 2014-04-23
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

Since the self-synthesis of corticosteroids is an important factor in the body's anti-inflammation, this shortcoming is unfavorable to the recovery of postoperative patients, and this adverse effect has been gradually confirmed by

Method used

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  • N-substituted imidazolecarboxylic acid ester chiral compound containing ether side chain, preparation method and application thereof
  • N-substituted imidazolecarboxylic acid ester chiral compound containing ether side chain, preparation method and application thereof
  • N-substituted imidazolecarboxylic acid ester chiral compound containing ether side chain, preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0023] Preparation of the compound of formula (I) of the present invention: compound of formula (II) (CAS: 56649-48-0) (216 mg, 1 mmol), compound of formula (III) (CAS: 6482-24-2) (278 mg , 2 mmol) and anhydrous potassium carbonate (564 mg, 3 mmol) were mixed in 15 mL N,N-dimethylformamide, and the mixture was stirred at 50°C overnight. The next day, the reaction solution was poured into 100 mL of cold water to obtain a clear solution, extracted 3 times with ethyl acetate (50 mL each time), the organic layers were combined, dried with anhydrous sodium sulfate overnight, filtered to obtain the filtrate, and the solvent was evaporated to dryness under reduced pressure The oily crude product was obtained, which was purified by a silica gel column (developing solvent: cyclohexane / ethyl acetate=3 / 2) to obtain 150 mg of a colorless oily product with a yield of 54%.

[0024] 1) NMR: Instrument: BRUKER, TMS as internal standard.

[0025] 1 H-NMR (400MHz CDCl 3 ) δ : 1.862 (3H, d,...

Embodiment 2

[0032]Preparation of the compound of formula (I) of the present invention: compound of formula (II) (CAS: 56649-48-0) (216 mg, 1 mmol), compound of formula (III) (CAS: 627-42-9) (188 mg , 2 mmol) and anhydrous potassium carbonate (564 mg, 3 mmol) were mixed in 15 mL N,N-dimethylformamide, and the mixture was stirred at 50°C overnight. The next day, the reaction solution was poured into 100 mL of cold water to obtain a clear solution, extracted 3 times with ethyl acetate (50 mL each time), the organic layers were combined, dried with anhydrous sodium sulfate overnight, filtered to obtain the filtrate, and the solvent was evaporated to dryness under reduced pressure The oily crude product was obtained, which was purified by a silica gel column (developing solvent: cyclohexane / ethyl acetate=3 / 2) to obtain 120 mg of a colorless oily product with a yield of 43%.

Embodiment 3

[0034] Preparation of S-type optical counterpart compound (Ⅳ):

[0035] S-(-)-1-(1-phenylethyl)-1-hydro-imidazole-5-carboxylic acid (CAS: 56649-49-1) 216 mg, 1 mmol), formula (Ⅲ) compound (CAS: 627-42-9) (188 mg, 2 mmol) and anhydrous potassium carbonate (564 mg, 3 mmol) were mixed in 15 mL N,N-dimethylformamide, and the mixture was stirred at 50°C overnight. The next day, the reaction solution was poured into 100 mL of cold water to obtain a clear solution, which was extracted three times with ethyl acetate (50 mL each time), the organic layers were combined, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and the solvent was evaporated to dryness under reduced pressure The oily crude product was obtained, which was purified by a silica gel column (developing solvent: cyclohexane / ethyl acetate=3 / 2) to obtain 170 mg of a colorless oily product, with a yield of 61.2%.

[0036] 1) NMR: Instrument: BRUKER, TMS as internal standard.

[0037] 1 H-NMR (400MH...

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Abstract

The invention relates to an N-substituted imidazolecarboxylic acid ester chiral compound containing an ether side chain, a preparation method and an application thereof. The structure of the compound is shown in the formula (I). The compound can produce rapid and reversible general anesthesia effect. Animal experiments show rapid and short-acting pharmacological characteristics of the compound, so that the compound can be used as a rapid and short-acting general anesthesia medicine, meanwhile, compared with etomidate, the compound can reduce the inhibition effect on synthesis of adrenal cortical hormone, recovery is rapid and thorough, and the compound has obvious advantages and good application prospect. The only chiral carbon in the structure of the compound must be of R type. An imidazole ring in the structure of the compound has acidifiable N atoms, so that the compound and medicinal salt molecules thereof can be applied to the preparation of central inhibitory medicines which can produce sedative and hypnotic and/or anesthetic effects on animals or persons through veins or paths outside veins.

Description

technical field [0001] The invention relates to an N-substituted imidazole carboxylate chiral compound containing an ether side chain, a preparation method and application. Background technique [0002] Etomidate 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 smallest among the general anesthetics currently used clinically, so it is especially suitable for surgical patients with cardiac insufficiency (J.F.Cotton, Anesthesiology 2009; 111: 240). The anesthetic mechanism of etomidate has been clarified, mainly through the central inhibitory receptor GABA A Binding makes the receptor more sensitive to the inhibitory neurotransmitter GABA, resultin...

Claims

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Application Information

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IPC IPC(8): C07D233/90A61P25/20A61P23/00
CPCC07D233/90A61P23/00A61P25/20Y02P20/55A61K9/0019A61K31/4164A61K31/4174C07B2200/07
Inventor 张文胜杨俊刘进唐磊柯博文
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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