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A kind of artesunate polyethylene glycol derivative and its preparation method and application

A technology of polyethylene glycol and artesunate, applied in the field of medicine, can solve the problems of short clinical action time of oral tablets, high administration frequency, easy precipitation and the like

Active Publication Date: 2022-04-15
INST OF CHINESE MATERIA MEDICA CHINA ACAD OF CHINESE MEDICAL SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Artesunate (ART) is almost insoluble in water, and the clinical action time of oral tablets is short, and the frequency of administration is high. The powder injection needs 5% sodium bicarbonate to dissolve, and the stability is poor, and precipitation is easy to occur

Method used

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  • A kind of artesunate polyethylene glycol derivative and its preparation method and application
  • A kind of artesunate polyethylene glycol derivative and its preparation method and application
  • A kind of artesunate polyethylene glycol derivative and its preparation method and application

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preparation example Construction

[0052] The present invention also provides a method for preparing artesunate polyethylene glycol derivatives described in the above technical scheme, the preparation method of artesunate polyethylene glycol derivatives shown in formula (I) comprises the following steps:

[0053] (1) mixing artesunate with a modifier containing a disulfide bond, and coupling in the presence of a coupling agent and an organic base to obtain disulfide bond-modified artesunate;

[0054] (2) Mixing dihydroxypolyethylene glycol with an activator, and performing the first coupling in the presence of a coupling agent to obtain a polyethylene glycol-acid anhydride conjugate; the activator is selected from acid anhydride or diamine ;

[0055] (3) Mix the artesunate modified by the disulfide bond with the polyethylene glycol-acid anhydride conjugate, and carry out the second coupling in the presence of the coupling agent to obtain the polyethylene glycol derivative of artesunate thing;

[0056] There i...

Embodiment 1A

[0085] Embodiment 1ART-SS-PEG 5k - Preparation of SS-ART (artesunate polyethylene glycol derivative shown in formula (I))

[0086] Weigh 5.0g (1.0mmol) of dry dihydroxy mPEG 5k (5k means the molecular weight of mPEG is 5kDa) In a round bottomed flask, add mPEG 5k2 times the mass of succinic anhydride (SA) and 2 times the mass of catalysts DCC / NHS and DMAP were dissolved in an appropriate amount of dichloromethane and reacted at room temperature for 24 hours. After the reaction, the reaction system was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was purified by dialysis and lyophilized to give the product HOOC-PEG 5k -COOH.

[0087] Weigh ART (0.39g, 1.0mmol) into a round-bottomed branched flask, add HEDS twice the mass of ART and catalysts DCC / NHS and DMAP twice the mass, dissolve an appropriate amount of dichloromethane, and react at room temperature for 24 hours. After the reaction, filt...

Embodiment 2

[0093] Example 2mPEG 2k -Synthesis of SS-ART (artesunate polyethylene glycol derivative represented by formula (Ⅱ))

[0094] 1. Synthesis of carboxylated mPEG-SA-COOH

[0095] Weigh a certain amount of dry monohydroxy mPEG 2k (2k means the molecular weight of mPEG is 2kDa) In a round bottomed flask, add mPEG 2k 1 times the mass of succinic anhydride (SA), 1 times the mass of the catalyst DCC / NHS and 1 times the mass of DMAP were dissolved in 1 times the mass of dichloromethane, and reacted at room temperature for 24 hours. The mixture obtained after the reaction was filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was purified by dialysis for 48 hours and lyophilized to give the product mPEG 2k -SA-COOH.

[0096] 2. Esterification reaction between artesunate and bis(2-hydroxyethyl) disulfide (HEDS)

[0097] Weigh ART (0.55g, 1.43mmol) into a round-bottomed branched flask, add 1 times the amoun...

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Abstract

The present invention provides an artesunate polyethylene glycol derivative and its preparation method and application, a medicine for preventing and treating pneumonia, and relates to the field of pharmaceutical technology. The sulfur bond couples artesunate to polyethylene glycol, and the structural formula is shown in formula (I) or formula (II). The present invention adopts the disulfide bond to construct the conjugate of artesunate and polyethylene glycol, and the obtained artesunate polyethylene glycol derivative has good water solubility, stability, and rapid drug release under reducing conditions characteristics. Compared with artesunate, polyethylene glycol derivatives of artesunate provided by the present invention have a more significant effect on alleviating inflammation, and the therapeutic effect on mice with lung injury is also significantly better than artesunate, which is An effective drug against pneumonia.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to an artesunate polyethylene glycol derivative, a preparation method and application thereof, and a medicine for preventing and treating pneumonia. Background technique [0002] Artemisinin (Artemisinin, whose structural formula is shown in formula (A)) is a kind of colorless needle-like crystal of sesquiterpene lactones with peroxy groups extracted from the stems and leaves of the compound inflorescence plant Artemisia annua, and its molecular formula is C 15 h 22 o 5 , discovered by Chinese pharmacist Tu Youyou in 1972. Artemisinin is the most effective anti-malarial drug after pyrimethamine, chloroquine, and primaquine, especially for cerebral malaria and anti-chloroquine malaria. The only effective malaria treatment in the world". [0003] [0004] In 2005, the medical journal "The Lancet" published an article, pointing out that the study found that the sensitivity of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/60A61K31/357A61P11/00A61P35/00A61P29/00C08G65/332C08G65/334
CPCA61K47/60A61K31/357A61P11/00A61P35/00A61P29/00C08G65/3328C08G65/334
Inventor 赵庆贺陈燕军王亚杰
Owner INST OF CHINESE MATERIA MEDICA CHINA ACAD OF CHINESE MEDICAL SCI
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