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Application of piperlongumine compound in preparation of medicine for treating schistosomiasis japonicas and medicine composition

A technology of longamine base and schistosomiasis, which is applied in the field of drug treatment, can solve the problems of the advent of clinical drugs and the lag in the research and development of new drugs for schistosomiasis japonica.

Active Publication Date: 2022-07-05
GANNAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At the same time, compared with the rapid development of new drugs for other diseases, the research and development of new drugs for the treatment of schistosomiasis is relatively lagging behind, and no new clinical drugs have come out yet

Method used

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  • Application of piperlongumine compound in preparation of medicine for treating schistosomiasis japonicas and medicine composition
  • Application of piperlongumine compound in preparation of medicine for treating schistosomiasis japonicas and medicine composition
  • Application of piperlongumine compound in preparation of medicine for treating schistosomiasis japonicas and medicine composition

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preparation example Construction

[0038] In the present invention, the preparation method of the piperamine base compound preferably comprises the following steps:

[0039] When X is H, the substituted phenylacrylic acid, oxalyl chloride and the first solvent are mixed, and an acyl chloride reaction is carried out to obtain a phenylacryloyl chloride compound;

[0040] Mixing the phenylacryloyl chloride compound with the lactam lithium salt solution, and carrying out a first nucleophilic substitution reaction to obtain the longamine base compound;

[0041] When X is not H, mix substituted phenylacrylic acid, pivaloyl chloride, triethylamine and the second solvent, and carry out acidolysis reaction to obtain an acid anhydride compound;

[0042] Mixing the acid anhydride compound with the lactam lithium salt solution, and carrying out a second nucleophilic substitution reaction to obtain a longamine base compound;

[0043] The substituted phenylacrylic acid has the structure shown in formula 1; the lactam in the...

Embodiment 1

[0112] Synthesis of Longinaminine (Compound 1):

[0113] In a 50mL round-bottomed flask, add 20mL of anhydrous dichloromethane and 0.95g (4mmol) of 3,4,5-trimethoxyphenylacrylic acid (the second substituted phenylacrylic acid), dropwise add 5mL (59mmol) of oxalyl chloride, 30 After 5 hours of reaction at ℃, vacuum distillation was performed to obtain 3,4,5-trimethoxybenzene acryloyl chloride;

[0114] Under nitrogen protection, 0.19g (2mmol) of 5,6-dihydropyridin-2(1H)-one (the first lactam) was dissolved in 10mL of anhydrous tetrahydrofuran, cooled to -78°C; then 1.3mL was slowly added (2.2mmol) lithium diisopropylamide, react at -78°C for 45min to obtain a lithium lactam salt solution; add 4mmol of 3,4,5-trimethoxyphenylacryloyl chloride, continue to react at -78°C for 1h, then warm to room temperature The reaction was carried out for 12 h; after the reaction, 10 mL of saturated ammonium chloride solution was added to quench the reaction, extracted with dichloromethane, dri...

Embodiment 2

[0117] Synthesis of Compound 2

[0118] 10 mL of anhydrous dichloromethane and 0.95 g (4 mmol) of 3,4,5-trimethoxyphenylacrylic acid (the second substituted phenylacrylic acid) were added to a 25 mL round-bottomed flask, and 2.5 mL (29.5 mmol) was added dropwise with stirring. Oxalyl chloride, refluxed at 40°C for 4 hours, and then distilled under reduced pressure to obtain 3,4,5-trimethoxyphenylacryloyl chloride;

[0119] Under nitrogen protection, 0.26g (2mmol) of 3-chloro-5,6-dihydro-2(1H)-one (the first lactam) was dissolved in 5mL of anhydrous tetrahydrofuran, cooled to -78°C; then slowly Add 2.6 mL (4.4 mmol) of lithium diisopropylamide and react for 45 min to obtain a lithium lactam salt solution, add 4 mmol of 3,4,5-trimethoxybenzene acryloyl chloride, continue to react at -78°C for 2 hours, then warm to room temperature and react for 16 hours After the reaction, 10 mL of saturated ammonium chloride solution was added to quench the reaction, extracted with dichlorom...

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Abstract

The invention provides application of piperlongumine compounds in preparation of drugs for treating schistosomiasis japonicas and a pharmaceutical composition, and belongs to the technical field of drug treatment. Different substituent groups are introduced to the alpha position of Michael double bonds of piperlongumine, the obtained piperlongumine compound has efficient treatment activity on schistosoma japonicum, and the IC50 value of 72-hour in-vitro anti-schistosoma japonicum activity of the piperlongumine compound is 1-5 times that of piperlongumine. Wherein the IC50 value of the 72-hour in-vitro anti-schistosoma japonicum katsurada activity of the compound 9 is equivalent to that of clinical medicine positive control praziquantel.

Description

technical field [0001] The invention relates to the technical field of drug treatment, in particular to the application and pharmaceutical composition of a longamine alkaloid compound in the preparation of a drug for treating schistosomiasis japonica. Background technique [0002] Schistosomiasis japonicum is widely prevalent in southern China, and is the schistosomiasis with the most serious harm to human health and the most difficult control in the world. Due to the lack of vaccines, chemical drug therapy is currently the main means of prevention and treatment of schistosomiasis japonica. Praziquantel is the only designated drug recommended by the World Health Organization for the treatment of schistosomiasis japonica, and long-term large-scale repeated application will induce resistance of schistosomiasis. At the same time, compared with the rapid development of new drugs for other diseases, the research and development of new drugs for the treatment of schistosomiasis j...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/86C07D223/10A61K31/44A61K31/55A61P33/12
CPCC07D211/86C07D223/10A61P33/12Y02A50/30
Inventor 钱益平申昌德黄丽娜仲鑫路东亮邓修龙李勋范小林
Owner GANNAN NORMAL UNIV
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