Etomidate derivative and preparation method thereof

A compound, methyl technology, applied in the field of anesthetic drugs, can solve the problems of increased infection, unfavorable recovery of patients, and reduced usage rate of etomidate, etc., and achieves low toxicity and side effects, good prospects, and short maintenance time

Inactive Publication Date: 2019-05-14
BEIJING LANDAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, etomidate has an inhibitory effect on the synthesis of corticosteroids in the body, especially the inhibition of corticosteroids by long-term continuous infusion
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 clinical research, resulting in the usage rate of etomidate increasing with this understanding. Gradually decreased as the medical staff did not want patients receiving etomidate to face the risk of increased infection during postoperative recovery

Method used

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  • Etomidate derivative and preparation method thereof
  • Etomidate derivative and preparation method thereof
  • Etomidate derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] 1.1 Synthesis of Compound M

[0039] Etomidate (10.1g, 0.04mol) was dissolved in 100ml of methanol, and an aqueous solution of LiOH (2.0g, 0.08mol, 2eq, dissolved in 20ml of water) was added, then the reaction solution was stirred at room temperature for 5 hours, and then spun under reduced pressure. Dry methanol, adjust the pH of the aqueous phase to 2-3 with 1N HCl, and extract twice with ethyl acetate, combine the organic phases, and dry over anhydrous magnesium sulfate. Spin-dry under reduced pressure to obtain 7.1 g of white solid, yield 79%

[0040] LCMS:218[M+H] +

[0041] 1 H-NMR (DMSO, 300MHz)δ11.60(bs,1H),δ7.96(s,1H),δ7.84(s,1H),δ6.93-6.77(m,5H),δ5.15( bs, 1H), δ1.92 (d, 3H).

[0042] 1.2 Synthesis of compound 1

[0043] Dissolve M (1g, 4.6mmol, 1eq) in 15ml of acetonitrile, add K 2 CO 3 (1.3g, 9.2mmol, 2eq), the reaction solution was cooled to 0°C, and ethyl 1-bromoacetate (1.2g, 7.1mmol, 1.5eq) was added, and the reaction solution was slo...

Embodiment 2

[0047] Compound 2 can be prepared by the following reaction scheme

[0048]

[0049] Compound M (1.1g, 5mmol) was dissolved in dichloromethane solution (10ml), potassium carbonate (1.4g, 10mmol) was added to react at room temperature for 2 hours, cooled to 0-5°C, and 1-bromoethyl propionate was added (1.8g, 10mmol) Adjust the temperature to 10-15°C and stir the reaction for 30 hours, filter, remove the solvent in a rotary evaporator, and purify by column chromatography (ethyl acetate:n-hexane=1:4) to obtain light yellow 0.5 g of solid, yield 31%.

[0050] LCMS:317([M+H]+).

[0051] 1 H-NMR (CDCl 3 ,300MHz)δ7.88(s,1H),δ7.86(s,1H),δ7.25-7.05(m,5H),δ6.62(m,2H),δ5.17(m,1H), δ2.31(m,2H), δ1.89(d,3H), δ1.75(m,3H), δ1.15(m,3H)

Embodiment 3

[0053] Compound 3 can be prepared by the following reaction scheme

[0054]

[0055] Compound M (1.2g, 5.5mmol) was dissolved in N,N-dimethylformamide (10ml), sodium carbonate (0.6g, 6.6mmol) was added, and reacted at room temperature for 1 hour. Cool down to 0-5°C, add 1-bromoethyl tert-butyl carboxylate (1.3g, 6.0mmol), adjust the temperature to 10-15°C, stir for 36 hours, filter, add 100ml of purified water, add 30ml of ethyl acetate for extraction Three times, the solvent was removed in a rotary evaporator, and purified by column chromatography (ethyl acetate:n-hexane=1:5) to obtain 0.4 g of a light yellow solid with a yield of 21%.

[0056] MS (ESI) m / z 345 ([M+H] + )

[0057] 1 H-NMR (CDCl 3 ,300MHz)δ7.89(s,1H),δ7.86(s,1H),δ7.25-7.05(m,5H),δ6.59(m,1H),δ5.16(m,1H), δ1.89(s, 3H), δ1.72(d, 3H), δ1.24(s, 9H).

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Abstract

The invention discloses an etomidate analogue shown in a formula (I). The analogue which needs to be developed in the field keeps beneficial performances (such as quick action, almost no influences onblood pressure and high therapeutic index) of etomidate but does not cause a potential dangerous adrenal cortex function inhibition effect. The analogue enables safety in anesthetic action on critical patients. In the formula (I) as shown in the specification, R1 refers to polyhalogenated or non-substituted C1-C6 alkyl; R2 refers to hydrogen, methyl or ethyl; R3 refers to hydrogen, halogen, trifluoromethyl, trifluoroethyl or nitryl; when R2 refers to hydrogen, R3 is not hydrogen.

Description

technical field [0001] The invention relates to the field of anesthesia drugs, in particular to an anesthetic with a slight ultra-short-acting anesthetic effect on corticosteroid inhibition after long-term continuous infusion. Background technique [0002] Etomidate is an intravenous general anesthetic drug that has been on the market for a long time. The drug has a fast onset time and a short maintenance time. Compared with other general anesthetics, etomidate has an unusually high therapeutic index; in animals, The therapeutic index for etomidate was 26.4, compared with 4.6 and 3.1 for thiopental and propofol, respectively. Etomidate provided a relatively large margin of safety, which may reflect its lesser impact on cardiovascular and respiratory function. In contrast, propofol and thiopental reduce sympathetic afferents, blunt autonomic reflexes and directly impair myocardial contractility. Because etomidate has less effect on cardiovascular and respiratory functions, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/90A61K31/4174A61P23/00A61P25/20
Inventor 林静文其他发明人请求不公开姓名
Owner BEIJING LANDAN PHARMA TECH
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