[(10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde semicarbazones (sulfur) series substances as well as preparation method and application thereof

A technology of dihydroartemisinin and thiosemicarbazone, applied in the field of medicine, can solve the problems of drug resistance, short half-life, and increased recurrence rate

Inactive Publication Date: 2011-04-13
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Artemisinin is a sesquiterpene lactone containing peroxy groups extracted from the stems and leaves of Artemisia annua, Artemisia annua and its derivatives such as dihydroartemisinin, artemisinin The efficacy and characteristics of the antimalarial effects of ether, artether, artesunate, etc. have been affirmed, but the half-life of these drugs is generally short, which leads to increased frequency of medication, increased relapse rate, and reports of drug resistance

Method used

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  • [(10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde semicarbazones (sulfur) series substances as well as preparation method and application thereof
  • [(10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde semicarbazones (sulfur) series substances as well as preparation method and application thereof
  • [(10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde semicarbazones (sulfur) series substances as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0036] Experimental Example 1: Preparation of (10S)-9,10-dihydroartemisinin-10-oxybenzaldehyde

[0037] In a 250mL reaction flask, add 11.36g (40mmol) of dihydroartemisinin, 11.08mL (40mmol) of dry triethylamine and 50mL of dry methylene chloride in sequence, cool to -5°C, and add 11.12mL dropwise under stirring (40mmol) a mixture of trifluoroacetic anhydride and 30mL of dry dichloromethane, after dropping, continue to react at -5-0°C for 8 hours, and monitor the end point of the reaction by TLC to obtain 10(R)-trifluoroacetoxy-9 , 10-dihydroartemisinin (A-2) in dichloromethane. At -5-0°C, 9.76g (40mmol) 4-hydroxybenzaldehyde was added to the reaction liquid, and the reaction was continued for 6h at -5-0°C, and saturated NaHCO 3 solution to quench the reaction, respectively, with saturated NaHCO 3 solution (50mL×5) and water (50mL×5) to wash the reaction solution to neutrality, separate the organic layer, and wash with anhydrous Na 2 SO 4 Dry, filter off the desiccant, and...

experiment example 2

[0038] Experimental example 2: Preparation of 4-phenyl-1-{4-[(10S)-9,10-dihydroartemisinin-10-oxyl]benzaldehyde} semicarbazone

[0039] Add 0.77g (2mmol) (10S)-9,10-dihydroartemisinin-10-oxybenzaldehyde, 0.3g (2mmol) 4-phenylsemicarbazide, 20mL ethanol and 0.1ml Glacial acetic acid was stirred and reacted at room temperature for 3 hours, and the end point of the reaction was monitored by TLC. Solids were gradually precipitated in the reaction, filtered by suction, rinsed with a small amount of ethanol, and the product was 0.47 g of white needle crystals, with a yield of 45.3%. LC-MS (m / z): 522.2[M+H] + , 1 H-NMR (CDCl 3 )δ: 0.97 (3H, d, J = 5.7Hz), 1.04 (3H, d, J = 7.5Hz), 1.45 (3H, s), 2.34-2.45 (1H, m), 2.82-2.87 (1H, m ), 5.48(1H, s), 5.56(1H, d, J=3.3Hz), 7.16(2H, d, J=8.7Hz), 7, 60(2H, d, J=8.7Hz), 7.74(1H , s), 8.13(1H, s), 8.71(1H, s).

experiment example 3

[0040] Experimental Example 3: Preparation of 4-phenyl-1-{4-[(10S)-9,10-dihydroartemisinin-10-oxyl]benzaldehyde}thiosemicarbazone

[0041] 0.77g (2mmol) (10S)-9,10-dihydroartemisinin-10-oxybenzaldehyde, 0.33g (2mmol) 4-phenylthiosemicarbazide, 20mL ethanol and 0.1 ml of glacial acetic acid, stirred at room temperature for 5 hours, TLC monitored the reaction end point, the solid gradually precipitated out in the reaction, filtered with suction, rinsed with a small amount of ethanol, and the product was 0.42 g of light yellow needle crystals, with a yield of 39.1%, LC-MS ( m / z): 538.2 [M+H] + , 1 H-NMR (CDCl 3 )δ: 0.97 (3H, d, J = 6.0Hz), 1.03 (3H, d, J = 7.2Hz,), 1.44 (3H, s), 2.34-2.45 (1H, m), 2.82-2.87 (1H, m), 5.46(1H, s), 5.57(1H, d, J=3.3Hz), 7.17(2H, d, J=8.7Hz), 7.62(2H, d, J=9.0Hz), 7.79(1H, s), 9.17(1H, s), 9.22(1H, s).

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Abstract

The invention relates to [(10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde semicarbazones (sulfur) series substances and provides a structure, a preparation method and application of a novel artemisinine 10-locus derivative. The structural formula of the [(10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde semicarbazones (sulfur) series substance is shown in a formula I. The invention also relates to pharmaceutically-acceptable slats, a solvate, an optical isomer or a polymorphic substance of the [(10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde semicarbazones (sulfur) series substances and a medicinal composition by taking the compounds as active components. As novel antimalarial agents, anti-tumor agents and antifungal agents, the compounds can be used for treating or preventing malaria, mycotic infection, malignant tumor and the like. The compounds can be prepared by reacting dihydroartemisinine as an initial raw material with trifluoroacetic anhydride/triethylamine to obtain 10(R)-trifluoro-acetoxyl-9,10-dihydroartemisinine, directly reacting the 10(R)-trifluoro-acetoxyl-9,10-dihydroartemisinine with hydroxy benzaldehyde without separation to obtain (10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde, and reacting the (10S)-9,10-dihydroartemisinine-10-oxyl]benzaldehyde with the substituted amino (sulfur) urea compounds in acid catalysts and alcohol solvents to obtain target compounds.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a new artemisinin derivative and its preparation method and application, in particular to [(10S)-9,10-dihydroartemisinin-10-oxyl]benzaldehyde amido (Thio)urea series and its preparation method and application. Background technique [0002] Artemisinin is a sesquiterpene lactone containing peroxy groups extracted from the stems and leaves of Artemisia annua, Artemisia annua and its derivatives such as dihydroartemisinin, artemisinin The curative effect and characteristics of the antimalarial effects of ether, artether, artesunate, etc. have been affirmed, but the half-life of these drugs is generally short, which leads to an increase in the number of medications, an increase in the recurrence rate, and there have been reports of drug resistance. At present, scholars at home and abroad have carried out a lot of structural modification work on artemisinin, and found a number of arte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/20A61K31/357A61P33/06A61P35/00A61P31/10
CPCY02A50/30
Inventor 郭春刘杨骆伟孙历苏昕梁振高宁于士龙
Owner SHENYANG PHARMA UNIVERSITY
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