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Artesunate succinylated derivative and preparation method and application thereof in medicines

A technology of artesunate and succinate, which is applied in the direction of organic chemical methods, drug combinations, and medical preparations containing active ingredients, etc., can solve the inconvenience of rescue medication for critically ill patients, the short half-life of artesunate, and the existence of liver and kidney toxicity To achieve the effect of improving the pathological changes of the pancreas, improving the state of the pancreas, and reducing serum inflammatory factors

Active Publication Date: 2020-07-03
ARMY MEDICAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, due to the short half-life of artesunate (t 1 / 2 21.6-45.6 minutes), in the treatment of sepsis or acute pancreatitis, continuous intravenous administration or repeated extravascular administration is required, which is not convenient for rescue medication of critically ill patients, and there is a risk of liver and kidney toxicity

Method used

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  • Artesunate succinylated derivative and preparation method and application thereof in medicines
  • Artesunate succinylated derivative and preparation method and application thereof in medicines
  • Artesunate succinylated derivative and preparation method and application thereof in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The preparation of embodiment 1 artesunate

[0041] The reaction formula is as follows:

[0042]

[0043]1, the preparation of artesunate ethylene glycol ester (formula II compound)

[0044] Taking artesunate as raw material, add artesunate (1g, 2.6mmol), dicyclohexylcarbodiimide (DCC, 0.59g, 2.86mmol), 4-dimethylaminopyridine (DMAP , 0.1g, 0.78mmol), 5ml of dichloromethane, stirred and reacted at 0°C for 1h, added ethylene glycol (0.18g, 2.86mmol), reacted at room temperature for 10 hours, after the reaction was detected by TLC, filtered, and the filtrate was concentrated , and the residue was separated by column chromatography to obtain the target product, artesunate glycol ester (1 g, yield 90%, colorless oil).

[0045] Product H NMR spectrum: 1 H NMR (400MHz, CDCl 3 ):δ=6.79(d,J=8.01H),5.44(s,1H),4.30-4.18(m,2H),3.81(m,2H),2.78-2.68(m,4H),2.60-2.55( m, 1H), 2.42-2.34 (m, 1H), 2.06-1.24 (m, 16H), 0.96 (d, J=4.03H), 0.86 (d, J=4.03H) ppm.

[0046] 2, the prep...

Embodiment 2

[0049] Example 2 Artesunate Treatment of Sepsis Action Test

[0050] First, establish a sepsis mouse model of mice challenged with sublethal doses of heat-inactivated Escherichia coli, and observe the therapeutic effects of artesunate (AS) and artesunate (DA) alone on the model, whether Improve the inflammatory response and reduce the levels of inflammatory factors in sepsis model animals.

[0051] LD50 50 For (618.24mg / kg); The cytotoxicity test result of DA sees ( figure 1 ): mouse monocyte-macrophage (RAW264.7 cell), 10% inhibition rate of DA (IC 10 ) was 2.03 μM, while IC in rat pancreatic acinar cells (AR42J cells) 10 2.84μM, with IC 10 The converted safe dosage for mice is about 4.2 mg / kg. The clinical dosage of artesunate AS is 60mg / d, and the equivalent dosage used in mice is about 7.5mg / kg converted according to the human-mouse body surface area dosage formula.

[0052] A mouse model of sepsis was established by tail vein injection of sublethal doses of heat-kil...

Embodiment 3

[0056] Example 3 Effect test of artesunate in treating acute pancreatitis

[0057] A mouse model of acute pancreatitis induced by cerulein combined with lipopolysaccharide, to observe the therapeutic effects of artesunate (AS) and artesunate (DA) alone on the model, whether it can improve the pancreas inflammatory response of acute pancreatitis model animals , reducing enzyme activity.

[0058] A mouse model of acute pancreatitis was established using cerulein combined with LPS (lipopolysaccharide). The experimental mice were fasted for 12 h before model making, and were not allowed to drink water. 80 mice, half male and half male, were randomly divided into 8 groups with 10 mice in each group. Acute pancreatitis mouse model was prepared by injecting LPS (10 mg / kg) for the last time with 100 μg / kg cerulein for 6 consecutive times with an interval of 1 hour. The groups were divided into: three doses of artesunate treatment group (DA4.0 mg / kg, DA2.0 mg / kg group, DA1.0 mg / kg g...

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Abstract

The invention discloses an artesunate succinylated derivative and a preparation method thereof. The artesunate succinylated derivative is dihydroartemisinin-1, 2-alpha-succinic acid-ethylene glycol-succinic acid diester, and the artesunate succinylated derivative has stronger pharmacological activity and safety than artesunate, and can be used for preparing medicines for preventing and treating sepsis and pancreatitis.

Description

technical field [0001] The invention belongs to the field of medicine and pharmaceutical preparations, and specifically relates to a succinate derivative of artesunate and a preparation method thereof, and the use of the succinate derivative of artesunate in the preparation and treatment of sepsis and sepsis-related Use in medicine for diseases such as pancreatitis. Background technique [0002] Sepsis is a systemic inflammatory response syndrome (SIRS) caused by infection, and it is also one of the serious complications of major surgery, various infections, trauma, burns, and hypoxia-reperfusion injury. Uncontrolled, continuously amplified SIRS is the leading cause of death in patients with sepsis. The treatment of clinical sepsis is very difficult. Non-specific treatments such as glucocorticoids and symptomatic treatments such as the prevention and treatment of organ failure and shock are mainly used. The mortality rate is still high, and about 200,000 people die of sepsi...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61K31/357A61P1/18A61P29/00
CPCC07D493/20A61P1/18A61P29/00C07B2200/07
Inventor 岑彦艳潘夕春蒋坤魏晔
Owner ARMY MEDICAL UNIV
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