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Nitrogen-containing heterocyclic compound as well as preparation method and application thereof

A nitrogen-heterocyclic compound and composition technology, applied in the field of nitrogen-containing heterocyclic compounds, can solve problems such as unpredictable recovery time, lack of effective coping methods for patients, and delayed wake-up time

Active Publication Date: 2020-12-15
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The wake-up time of propofol will be delayed to 90 minutes after long-term continuous administration, and the delay in extubation will be extended to about 5 hours (Mesnil M. Intensive Care Med.2011; 37(6):933-41.) , and the recovery time after continuous use of propofol becomes unpredictable in the presence of other drugs (Tryba M and Kulka PJ.Drugs.1993;45(3):338-52)
Sevoflurane is an inhaled anesthetic. Because the rate of its elimination through the lungs can be adjusted by increasing the frequency of mechanical ventilation, its clearance time is controllable to a certain extent, but the delay in extubation after long-term use is still as long as 30 minutes.
[0004] In summary, there is no product or technology that can quickly and controllably reduce or even eliminate the accumulation of general anesthetic drugs. There is still a lack of effective countermeasures for the harm caused by the accumulation of general anesthetic drugs to patients, and the accumulation of general anesthetic drugs still needs to be solved.

Method used

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  • Nitrogen-containing heterocyclic compound as well as preparation method and application thereof
  • Nitrogen-containing heterocyclic compound as well as preparation method and application thereof
  • Nitrogen-containing heterocyclic compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046]

[0047] Dissolve 1 mmol of etomidate acid (CAS: 56649-48-0) in 20 mL of N,N-dimethylformamide (DMF), add 1 mmol of 4-bromo-crotonic acid methyl ester (CAS: 1117-71-1 ), add 2mmol anhydrous potassium carbonate powder. Stir at room temperature for 20 minutes and filter. The filtrate was washed into 120 mL of water, extracted with 50 mL of ethyl acetate, and the organic layer was washed once with water. Add an appropriate amount of anhydrous sodium sulfate to dry the organic layer for 8 hours, filter, evaporate the filtrate to dryness under reduced pressure, and purify the residue by silica gel column chromatography (cyclohexane v / ethyl acetate v=3:1) to obtain a colorless transparent oil 1.2 g, yield: 38.2%.

[0048] 1 HNMR (CDCl 3 ,400MHz)δ:1.85(3H,d,J=8Hz),3.82(3H,s),4.80~4.92(2H,m),5.99~6.04(1H,m),6.27~6.33(1H,m), 6.93~6.96(1H,m),7.16~7.32(m,5H),7.75(1H,s),7.86(1H,s).

Embodiment 2

[0050]

[0051] Dissolve 1mmol etomidate acid (CAS:56649-48-0) in 20mL N,N-dimethylformamide (DMF), add 1mmol ethyl 4-bromo-(E)crotonate (CAS:37746- 78-4), add 2 mmol of anhydrous potassium carbonate powder. Stir at room temperature for 20 minutes and filter. The filtrate was washed into 120 mL of water, extracted with 50 mL of ethyl acetate, and the organic layer was washed once with water. Add an appropriate amount of anhydrous sodium sulfate to dry the organic layer for 8 hours, filter, evaporate the filtrate to dryness under reduced pressure, and purify the residue by silica gel column chromatography (cyclohexane v / ethyl acetate v=3:1) to obtain a colorless transparent oil 1.61 g, yield: 49.1%.

[0052] 1 HNMR (CDCl 3 ,400MHz) δ: 1.30(3H,t,J=8Hz),1.87(3H,d,J=8Hz),4.21(2H,q,J=8Hz),4.81~4.93(2H,m),6.00~6.05 (1H,m),6.29~6.35(1H,m),6.95~6.99(1H,m),7.17~7.34(m,5H),7.77(1H,s),7.85(1H,s).

Embodiment 3

[0054]

[0055] Dissolve 1mmol etomidate acid (CAS:56649-48-0) in 20mL N,N-dimethylformamide (DMF), add 1mmol 4-bromo-isopropyl crotonate (CAS:29619-54- 3), add 2mmol anhydrous potassium carbonate powder. Stir at room temperature for 20 minutes and filter. The filtrate was washed into 120 mL of water, extracted with 50 mL of ethyl acetate, and the organic layer was washed once with water. Add an appropriate amount of anhydrous sodium sulfate to dry the organic layer for 8 hours, filter, evaporate the filtrate to dryness under reduced pressure, and purify the residue by silica gel column chromatography (cyclohexane v / ethyl acetate v=3:1) to obtain a colorless transparent oil 1.72 g, yield: 50.3%.

[0056] 1 HNMR (CDCl 3 ,400MHz) δ: 1.17(6H,d,J=8Hz), 1.85(3H,d,J=8Hz), 4.78~4.94(3H,m), 6.02~6.06(1H,m), 6.25~6.31(1H ,m), 6.92~6.96(1H,m), 7.18~7.36(m,5H), 7.71(1H,s), 7.83(1H,s).

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Abstract

The invention relates to a nitrogen-containing heterocyclic compound, or an optical isomer, a stereoisomer, a solvate, a pharmaceutically acceptable salt, a crystal or an isotope replacement form thereof. The structure of the nitrogen-containing heterocyclic compound is shown as a formula (I). The compound disclosed by the invention can generate a rapid and reversible anesthetic effect in an animal body. In addition, the compounds also have molecular reaction specificity, and the pharmacological action of the compounds can be reversed by specific molecules. The compound provided by the invention can thoroughly solve the accumulation problem of general anesthetics, reduce the anesthesia risk and medical burden of patients, and reduce the occupation of medical resources. Definitions of substituents in the general formula are consistent with those in the specification.

Description

technical field [0001] The invention relates to a nitrogen-containing heterocyclic compound with central inhibitory effect and its preparation method and application. Background technique [0002] Drug accumulation in general anesthesia is a major challenge in clinical anesthesia. The harm caused by the accumulation of anesthetic drugs is huge, and the most important harm is the delay in awakening. The main reason for the delay in awakening is also the accumulation of anesthetic drugs (MillerRD, editor. Miller's Anesthesia. 2010.pp.2722–3.). The period of full recovery of physiological functions after general anesthesia is called the recovery period of general anesthesia, which can be divided into four stages: ① The depth of anesthesia decreases, and the period of gradual recovery of sensory and motor functions. ② Spontaneous breathing occurs, and the ventilation volume can gradually meet the body's needs. ③Respiratory reflex recovery period. ④ Consciousness, orientation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/90A61K31/4164A61P25/04A61P29/00A61P25/20
CPCC07D233/90A61P25/04A61P29/00A61P25/20
Inventor 杨俊刘进柯博文唐磊
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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