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Application of piperaquine nitrogen oxide in preparation of medicines for resisting malaria

A nitrogen oxide and anti-malarial technology, applied in drug combinations, anti-infectives, and resistance to vector-borne diseases, etc., can solve the problem of slow action of piperaquine, less research on the chemical properties, biological activities and uses of compounds, and hinder the technical field Research and development and other issues to achieve good antimalarial activity and scientific and rigorous experimental design

Inactive Publication Date: 2016-10-05
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] However, the effect of piperaquine is slow, and it will undergo metabolic processes such as nitrogen oxidation and carboxylation in the human body and animals to form a variety of metabolites. However, the current research on these two metabolites mainly focuses on the structural identification and preparation methods of the compounds, while there are few studies on the chemical properties, biological activities and uses of the compounds. Molecular structure is also difficult to deduce its biological activity and use
As for whether piperaquine nitrogen oxide has antimalarial activity, some studies have mentioned that it does not have antimalarial activity, which leads people to not consider it in follow-up studies or it is difficult to think that piperaquine nitrogen oxide has antimalarial activity. The possibility of application in malaria (due to the existence of contrary technical teachings, it is easy for technicians to form a mindset), hinders people's research and development in this technical field, thus forming a certain technical prejudice, which further restricts piperaquine nitrogen. Application of oxides in the preparation of antimalarial drugs

Method used

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  • Application of piperaquine nitrogen oxide in preparation of medicines for resisting malaria
  • Application of piperaquine nitrogen oxide in preparation of medicines for resisting malaria
  • Application of piperaquine nitrogen oxide in preparation of medicines for resisting malaria

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: the synthesis of piperaquine mono-nitrogen oxide and piperaquine di-nitrogen oxide

[0028] (1) piperazine (4.3g, 5.05mol) and Na 2 CO 3 (4g) was miscible in 20mL ethanol, then added 4-7 dichloroquinoline (5g, 2.525mol) in ethanol (15mL) solution, reacted at 80°C for 3h, and refluxed the reaction solution at room temperature for 3h, after the reaction was completed, the reaction The liquid solvent was evaporated to dryness, water (30mL) was added, then extracted with ethyl acetate (3×15mL), the combined organic layers were washed with Na 2 SO 4 After drying, the organic solvent was evaporated to dryness, and the sample was purified by silica gel column (eluent: methanol, dichloromethane) to obtain compound 3 as a light yellow solid. The synthetic route is as follows:

[0029]

[0030] (2) piperazine (0.04g, 0.2336mmol) and NaHCO 3 (4.0g) was miscible in 30mL ethanol, compound 5 (0.05g, 0.2336mmol) was added, the reaction solution was stirred and re...

Embodiment 2

[0039] Embodiment 2: in vitro activity test

[0040] 1. Test material:

[0041] Plasmodium: International Standard Strain 3D7 of Plasmodium falciparum, cited from ATCC Biological Resource Conservation Center of the United States; infection before experiment

[0042] Rate dilution is 0.5%, 2% blood pressure volume.

[0043] Piperaquine phosphate: purchased from Wuhan Xinjialing Biotechnology Co., Ltd. (batch number: 140305; purity 99.4%).

[0044] Chloroquine phosphate: purchased from China National Institutes for Food and Drug Control (batch number: 100421-200401; purity 98.9%).

[0045] Piperaquine mono-nitrogen oxide and piperaquine bis-nitrogen oxide: compounds M1 and M2 prepared in Example 1, the structure and purity of which were verified by MS, NMR and HPLC methods (purity>99.0%).

[0046] 2. Test method and grouping:

[0047] (1) Piperaquine phosphate treatment group (PQP group): piperaquine phosphate was prepared with dimethyl sulfoxide (DMSO) as 5 The mol / L stoc...

Embodiment 3

[0058] Embodiment 3: animal experiments

[0059] 1. Experimental materials:

[0060] Experimental animals: ICR mice, weighing 22±2g, purchased from the Experimental Animal Center of Shanxi Medical University.

[0061] Plasmodium falciparum: Plasmodium yoelii strain BY265, cited from ATCC Biological Resource Conservation Center, USA.

[0062] Piperaquine phosphate (PQP): purchased from Wuhan Xinjialing Biotechnology Co., Ltd. (batch number: 140305; purity 99.4%).

[0063] Piperaquine mono-nitrogen oxide M1 and piperaquine bis-nitrogen oxide M2: prepared in Example 1, the structure and purity were verified by MS, NMR and HPLC methods (purity>99.0%).

[0064] 2. Plasmodium falciparum inhibition experiment

[0065] Three dose groups (1, 2, 4 mg / kg) were set up for piperaquine mono-nitrogen oxide M1 and piperaquine bis-nitrogen oxide M2, with 6 mice in each group; the positive control drug was piperaquine phosphate group, and the dose was 4 mg / kg . Mice were injected intraperi...

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Abstract

The invention discloses application of piperaquine mono-nitrogen oxide and / or piperaquine dinitrogen oxide or pharmaceutically acceptable salt in preparation of medicines for resisting malaria. According to the unexpected discovery, piperaquine mono-nitrogen oxide and piperaquine dinitrogen oxide have a remarkable inhibition effect on growth of plasmodium and development of agamont. In-vitro tests prove that the piperaquine mono-nitrogen oxide and piperaquine dinitrogen oxide show the activity of inhibiting development of plasmodium agamont at a relatively low concentration (7.8nM); and in-vivo tests prove that oral piperaquine mono-nitrogen oxide and piperaquine dinitrogen oxide have a remarkable effect on inhibiting plasmodium falciparum.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the application of a class of piperaquine nitrogen oxides in the preparation of antimalarial drugs. Background technique [0002] Malaria is a vector-borne infectious disease caused by infection with Plasmodium parasites through the bite of Anopheles mosquitoes or the transfusion of the blood of a person with Plasmodium. The treatment of falciparum malaria currently mainly adopts "artemisinin-based combination therapy" (ACT) recommended by the World Health Organization (WHO), that is, artemisinin-based drugs combined with another long-acting antimalarial drug. Among them, piperaquine (Piperaquine; 1,3-bis[4-(7-chloro-quinolin-4-yl)piperazin-1-yl]propane) is one of the long-acting antimalarials recommended by WHO, and it is often used as Exists in the form of phosphate salt, the molecular formula is C 29 h 32 N 6 Cl 2 4H 3 PO 4 4H 2 O. [0003] However, the effect of pi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/496A61K31/357A61P33/06
CPCA61K31/357A61K31/496A61K2300/00Y02A50/30
Inventor 邢杰孟凡英周洪昌蔡天宇刘慧香杨爱娟
Owner SHANDONG UNIV
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