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Nucleoside analogue as well as preparation method and application thereof

A nucleoside analog and reaction technology, which can be used in the preparation of sugar derivatives, chemical instruments and methods, drug combinations, etc., and can solve the problems of poor oral bioavailability and low intestinal permeability.

Active Publication Date: 2021-05-11
DALIAN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since nucleoside molecules themselves are mostly polar molecules that hinder their passage across cell boundaries via the paracellular pathway, they are less intestinally permeable and therefore less oral bioavailable

Method used

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  • Nucleoside analogue as well as preparation method and application thereof
  • Nucleoside analogue as well as preparation method and application thereof
  • Nucleoside analogue as well as preparation method and application thereof

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preparation example Construction

[0032] The present invention also provides a method for preparing nucleoside analogs described in the above technical scheme, comprising the following steps:

[0033] The L-alanine benzyl ester hydrochloride (formula a) after dissolving is mixed with triethylamine, carries out neutralization reaction, obtains free L-alanine benzyl ester, and free L-alanine benzyl ester Mix with phenyl phosphate dichloride (b) to carry out the first substitution reaction to obtain an intermediate product A, and mix the intermediate product A with p-nitrophenol (c) and triethylamine to perform a second substitution reaction to obtain the formula Compound shown in 1,

[0034]

[0035] Dissolving N6-methyl deoxyadenosine (formula 2) in a mixed solution of anhydrous tetrahydrofuran and N-methylpyrrolidone, adding tert-butylmagnesium chloride for activation reaction, to obtain activated N6-methyl deoxyadenosine, and The activated N6-methyl deoxyadenosine is mixed with the compound shown in formu...

Embodiment 1

[0055] Carry out the synthesis of nucleoside analogs of the present invention according to the following reaction formula:

[0056]

[0057] 1) The first step is to synthesize compound 1 (i.e. the compound shown in formula 1):

[0058]

[0059] Under argon protection, 21.568g of L-alanine benzyl ester hydrochloride (0.1mol, 1eq) was dissolved in 200ml of dichloromethane, 21.25g of triethylamine (0.21mol, 2.1eq) was added, and the temperature was lowered to -78 °C, 23.2 g of phenyl phosphate dichloride (0.11 mol, 1.1 eq) was added dropwise, and after the addition was completed, it was kept at -78 °C for 30 min. Raised to room temperature for 3h. Then it was lowered to 0° C., and 13.91 g of p-nitrophenol (0.1 mol, 1 eq) and 10.12 g of triethylamine (0.1 mol, 1 eq) were added. After the addition, keep warm for 30 minutes, then rise to room temperature and react for 5 hours, and spot the plate (petroleum ether: ethyl acetate). After the reaction was completed, the solutio...

Embodiment 2

[0069] Examples of enhanced bioavailability

[0070] Add 0.1mM N6-methyldeoxyadenosine (dm6A) and the nucleoside analog QKY-613 of the present invention to Hela cells respectively, add DMSO to the control group (Ctrl), add PBS buffer to wash three times after 12 hours, and wash three times every 1 *10^7 cells were added with 100 microliters of cell metabolite extraction reagent (volume ratio of methanol, acetonitrile and water: 40:40:20), after repeated freezing and thawing with liquid nitrogen and 37°C, at 4°C, 1,3000rpm / min centrifuged for 15min, and the supernatant was taken to obtain cell metabolites. Quantitative detection of N6-Methyl-dATP in the extracted metabolites by liquid chromatography tandem mass spectrometry. The result shows that the drug QKY-613 cell availability of the new synthesis of the present invention is obviously higher than dm6A, as table 1 and Figure 5 shown in Table 1 and Figure 5 is the free intracellular N6-methyldeoxyadenosine triphosphate ...

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Abstract

The invention relates to a nucleoside analogue as well as a preparation method and application thereof, and belongs to the technical field of antiviral drugs. The nucleoside analogue disclosed by the invention is benzyl(((((2R,3S)-3-hydroxy-5-(6-(methylamino)-9H-purine-9-yl) tetrahydrofuran-2-yl) methoxy)(phenoxy) phosphoryl)-L-alaninate, and the structural formula of the nucleoside analogue is shown as a formula I in the specification. The nucleoside analogue disclosed by the invention is high in bioavailability, has anti-cancer and anti-virus effects, and can also improve the inherent immunity.

Description

technical field [0001] The invention relates to the technical field of antiviral drugs, in particular to a nucleoside analog and its preparation method and application. Background technique [0002] Viral infectious diseases are raging all over the world, so as a global public health problem, it is particularly important to develop new antiviral drugs. Among the currently marketed and clinically applied antiviral drugs, nucleoside compounds account for more than half, and play a very important role in antiviral therapy, such as cancer and herpes simplex virus (HSV), adenovirus (AdV), Human cytomegalovirus (HCMV), human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) and other viral infections. Many nucleoside analogs are enzyme inhibitors during viral replication, which can inhibit the activity of viral DNA polymerase and reverse transcriptase and participate in the competitive incorporation of nucleotides into the viral DNA chain, thereby...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/207C07H1/00A61K39/00A61P37/04A61P35/00A61P31/22A61P31/20
CPCC07H19/207C07H1/00A61K39/00A61P37/04A61P35/00A61P31/22A61P31/20A61K2039/53Y02A50/30
Inventor 杨庆凯王丽娜王凯孙震宋成丽
Owner DALIAN MEDICAL UNIVERSITY
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