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Conjugates of dihydroartemisinin and quinolones compounds as well as preparation method and application thereof

A technology of dihydroartemisinin and quinolones, which is applied in the chemical field, can solve the problems of low bioavailability and fast excretion in the body, and achieve the effect of simple preparation method

Active Publication Date: 2015-03-18
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Artemisinin was originally used in clinical treatment as a new class of antimalarial drugs with a new structure, showing unique therapeutic effects, but it is accompanied by the disadvantages of low bioavailability and rapid excretion in the body

Method used

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  • Conjugates of dihydroartemisinin and quinolones compounds as well as preparation method and application thereof
  • Conjugates of dihydroartemisinin and quinolones compounds as well as preparation method and application thereof
  • Conjugates of dihydroartemisinin and quinolones compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment 1, the synthesis of intermediate IM1

[0024]

[0025] In a 250mL round bottom flask, add SM, Et 2 O and 2-bromoethanol, add BF under ice bath cooling 3 ·Et 2 O, continue cooling and stirring the reaction in an ice bath, and monitor the progress of the reaction by TLC (thin layer chromatography). After the reaction is complete, add saturated NaHCO 3 The reaction was terminated, the layers were left to stand, the aqueous layer was extracted with ethyl acetate (EtOAc), the organic phases were combined, washed with saturated brine, anhydrous MgSO 4 Drying, suction filtration, the filtrate was rotary evaporated under reduced pressure to remove the solvent to obtain a crude product, which was recrystallized with petroleum ether-EtOAc mixed solvent to obtain a pure product, namely intermediate IM1. The specific synthesis conditions and results are shown in Table 1.

[0026] IM1 12β-(2-bromoethoxy)dihydroartemisinin: white solid; m.p.:162.0-162.8℃; (c=1mg / ...

Embodiment 2

[0029] Embodiment 2, the synthesis of target compound TM1

[0030]

[0031] Add quinolones (clenfloxacin, norfloxacin, ciprofloxacin or sarafloxacin), anhydrous K 2 CO 3 and N,N-dimethylformamide (DMF), stirred in a water bath at 60°C for 30 minutes (quinolones are slightly soluble), added intermediate IM1 (IM1 quickly and completely dissolved, and the reaction system gradually became a paste), and continued at 60°C The reaction was stirred in a water bath, and the progress of the reaction was monitored by TLC. After the reaction was completed, add water and stir, a large amount of solids were precipitated, extracted twice with 20mL EtOAc, the organic phases were combined, washed with 0.5N HCl and water successively, anhydrous Na 2 SO 4 Drying, suction filtration, the filtrate was rotary evaporated to remove the solvent to obtain a yellow viscous, which was purified by column chromatography, using dichloromethane-methanol (DCM-MeOH, volume ratio 90:1) as the eluent, coll...

Embodiment 3

[0038] Embodiment 3, the synthesis of intermediate IM2

[0039]

[0040] In a 250mL round bottom flask, add SM, Et 2 O and 3-bromo-1-propanol, add BF under ice bath cooling 3 ·Et 2 0, continue cooling and stirring the reaction in an ice bath, and monitor the progress of the reaction by TLC. After the reaction is complete, add saturated NaHCO 3 The reaction was terminated, the layers were left to stand, the aqueous layer was extracted with EtOAc, the organic phases were combined, washed with saturated brine, anhydrous MgSO 4 Dry, filter with suction, remove the solvent by rotary evaporation of the filtrate under reduced pressure to obtain a yellow oily mucus, purify by column chromatography, freeze the petroleum ether refrigerator to precipitate white crystals, filter with suction, freeze the mother liquor again to precipitate crystals, filter with suction, dry in vacuum, combine the crystals, and obtain Intermediate IM2. The specific synthesis conditions and results ar...

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Abstract

The invention discloses conjugates of dihydroartemisinin and quinolones compounds shown in formulae I to IV and officinal salt thereof, wherein X is -CH2CH2-, -CH2CH2CH2- or -COCH2CH2CO-. The conjugates have a certain antibacterial effect on a mycobacterium tuberculosis standard sensitive strain, a clinical separating sensitive strain and a clinical separating drug resistance strain, and especially the inhibitory effects of conjugates of dihydroartemisinin and clinafloxacin on the mycobacterium tuberculosis standard sensitive strain, the clinical separating sensitive strain and part of the clinical separating drug resistance strain are stronger than those of independent dihydroartemisinin and clinafloxacin. The conjugates can be used for preparing antituberculosis drugs and have a potential application prospect in tuberculosis prevention and cure field. The formulae I to IV are as shown in the specification.

Description

technical field [0001] The invention belongs to the field of chemistry, relates to a conjugate prepared by coupling two drugs, and also relates to a preparation method of the conjugate and its application in the field of pharmacy. Background technique [0002] Artemisinin was discovered by Tu Youyou from the plant Artemisia annua according to the description of ancient Chinese medical scientists. Artemisinin was initially used in clinical treatment as a class of antimalarial drugs with a new structure, which showed unique therapeutic effects, but it was accompanied by the disadvantages of low bioavailability and rapid excretion in the body. To overcome this problem, scientists derivatized its structure and synthesized the first generation of artemisinin derivatives. Representative molecules include dihydroartemisinin (DHA), artemether, artether and artesunate . This type of molecule shows more excellent pharmaceutical properties. Among them, dihydroartemisinin, artemether ...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61K31/4709A61K31/496A61P31/06
CPCC07D493/20
Inventor 杨大成周福委雷皇书范莉刘建何志琴邹艳冶赵雪晶
Owner SOUTHWEST UNIVERSITY
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