Tetravalent zanamivir and its preparation method and application

A zanamivir and reaction technology, applied in the field of medicine, can solve the problems of complicated administration routes, restricted promotion, etc., and achieve the effects of high-efficiency anti-influenza virus activity and high-efficiency inhibitory effect

Active Publication Date: 2015-10-28
INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the complexity of the route of administration, its clinical application is greatly limited.

Method used

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  • Tetravalent zanamivir and its preparation method and application
  • Tetravalent zanamivir and its preparation method and application
  • Tetravalent zanamivir and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1, preparation tetravalent zanamivir

[0052] (1) Dissolve 2.8 g of triethylene glycol (m=3) in tetrahydrofuran, add 1.4 mL of triethylamine and stir for 30 min, then add 1.9 g of solid p-toluenesulfonyl chloride, react at room temperature for 16 h, filter and spin dry. Using 100-200 mesh silica gel column chromatography and gradient elution, 2.52 g of mono-p-tosylated polyethylene glycol was obtained with a yield of 58%.

[0053] The reaction equation of this step is as follows:

[0054]

[0055] (2) Dissolve 2.52 g of the mono-p-toluenesulfonated polyethylene glycol prepared in the previous step in acetonitrile, add 0.57 g of solid sodium azide, react at 80°C for 3 hours, filter and spin dry, then add a small amount of ethyl acetate ester, filtered and spin-dried to obtain 1.53 g of monoazidated polyethylene glycol, a colorless transparent liquid, with a yield of 86.5%.

[0056] The reaction equation of this step is as follows:

[0057]

[0058] (3...

Embodiment 2

[0083] Embodiment 2, the enzyme activity inhibition test of tetravalent zanamivir to NA neuraminidase

[0084] Tetra-PEG3-zanamivir, tetra-PEG6-zanamivir, tetra-PEG12-zanamivir and zanamivir (zanamivir) were prepared into 50μM, 5μM, 500μM, 50nM, 5nM, 0.5nM, 0.1nM PBS solutions. Add 10 μL of the inhibitor solution configured above and 10 μL of NA neuraminidase Tris PH=8.0 buffer to a 96well standard opaque plate and incubate for 30 min in a 37°C incubator, then add 30 μL of 167 μM 4-MUNANA fluorescent substrate Immediately put the 96-well plate into a microplate reader to measure the fluorescence value of 355-460nM for 30min. The obtained data were processed with GraphPad Prism software, and IC50 was calculated, as shown in the data in Table 1.

[0085] Table 1 Quadrivalent zanamivir molecule and zanamivir inhibitory effect on NA neuraminidase

[0086]

[0087] As can be seen from the above table, the three tetravalent zanamivir molecules tetra-PEG3-zanamivir, tetra-PEG6-z...

Embodiment 3

[0088] Example 3, Inhibition Test of Tetravalent Zanamivir on Influenza Virus Infected MDCK Cells

[0089] Tetra-PEG3-zanamivir, tetra-PEG6-zanamivir, tetra-PEG12-zanamivir and zanamivir were prepared in 500nM, 250nM, 125nM, 62.5nM, 31.25nM, 2nM, 1nM, 0.5nM, 0.125nM and 0.0625nM PBS solutions. MDCK cells (Beijing Jiaxin Risheng Technology Co., Ltd.) were cultured according to conventional cell culture methods. Digest MDCK cells with trypsin, divide evenly into 96-well plates, 100 μL / well, and ensure that the number of cells is (2-8)×10 5 / hole; CO 2 The cells were cultured in an incubator for 24 hours. Inactivate DMEM solutions of different concentrations in a water bath at 56°C for 30 minutes, dilute them 2-fold, mix them with an equal amount of influenza virus (diluted in serum-free DMEM medium) containing 100 TCID50, and incubate at 37°C for 1 hour. Discard the cell culture medium in the 96-well plate, add 100 μL / well of serum-virus mixture, and place in CO 2 In the ce...

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Abstract

The invention discloses tetravalent zanamivir, its preparation method and its application. A structural formula of tetravalent zanamivir is shown as a formula I, wherein m in the formula is a number between 3 and 12. The invention also provides the application of tetravalent zanamivir in the formula I in preparation of medicines for resisting influenza, and the application concretely appears as 1) or 2): 1) the anti-influenza medicines can inhibit enzymatic activity of neuraminidase; and 2)the anti-influenza medicines can inhibit the growth of the cells infected by influenza. The provided tetravalent zanamivir can used for treating various viral influenza. Compared with the current zanamivir, tetravalent zanamivir has anti-influenza virus activity with higher efficiency, and has inhibition effect with high efficiency to the drug-resistant strains of influenza virus; and the provided tetravalent zanamivir can be prepared to oral medicines.

Description

technical field [0001] The invention relates to a tetravalent zanamivir and a preparation method and application thereof, belonging to the field of medicine. Background technique [0002] Zanamivir, whose trade name is Relenza, is a marketed anti-influenza drug developed by Australia's Biota Company, and its structural formula is as follows. It mainly prevents the budding process of newly assembled influenza virus from the host cell content into the cytosol by inhibiting the activity of neuraminidase on the surface of influenza virus. [0003] [0004] Because zanamivir is so water soluble, it is quickly metabolized after entering the human body and excreted in the form of urine, so it is made into a nasal spray. Due to the complexity of the route of administration, its clinical application is greatly limited. [0005] In the literature Nature.403, 2000, 669-672, the pentavalent inhibitor designed according to the spatial layout of the five groups of drug-binding sites ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48C07D405/14A61K31/4192A61K31/77A61P31/16
Inventor 李学兵傅立峰高福严景华毕玉海吴燕
Owner INST OF MICROBIOLOGY - CHINESE ACAD OF SCI
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