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Novel sialic acid derivant, preparation method thereof, drug composite comprising the same and application thereof

A compound and solvate technology, applied in the field of medicinal chemistry, can solve the problem of low oral bioavailability

Inactive Publication Date: 2012-07-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although zanamivir has no related drug resistance and serious side effects reported so far, its oral bioavailability is low, so it can only be used as spray and inhalation

Method used

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  • Novel sialic acid derivant, preparation method thereof, drug composite comprising the same and application thereof
  • Novel sialic acid derivant, preparation method thereof, drug composite comprising the same and application thereof
  • Novel sialic acid derivant, preparation method thereof, drug composite comprising the same and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0227] (4S, 5R, 6R)-N-benzyl-4-guanidino-5-acetamido-6[(1R,2R)-1,2,3-trihydroxypropyl]-5,6-dihydro- Preparation of 4H-pyran-2-carboxamide (10a-1)

[0228] 1. Cesium 5α-acetylamino-2α, 4β-dihydroxy-6β-D-glyceryl-tetrahydro-2H-pyran-2-carboxylate (1a-1)

[0229]

[0230] Dissolve N-acetylneuraminic acid (NANA, 10g, 32.4mmol) in 10ml of water, add cesium carbonate (5g) to adjust the pH value to neutral (pH7-8), evaporate the solvent under reduced pressure, and pump dry to obtain glass fragments like solid 1a-1;

[0231] 2. Benzyl 5α-acetylamino-2α, 4β-dihydroxy-6β-D-glyceryl-tetrahydro-2H-pyran-2-carboxylate (2a)

[0232]

[0233] Add DMF (15ml) and benzyl bromide (6ml) to 1a-1, stir overnight at room temperature, the reaction solution slowly has a lot of white solids precipitate out, filter with suction, add dichloromethane (500ml) while the filtrate is stirred, white solids precipitate out, Suction filtration, washing with dichloromethane, and air-drying in a cool plac...

Embodiment 2

[0259] (4S, 5R, 6R)-N-[(4-methoxyphenyl)methyl]-4-guanidino-5-acetamido-6[(1R,2R)-1,2,3-trihydroxy Preparation of Propyl]-5,6-dihydro-4H-pyran-2-carboxamide (10a-2)

[0260]Benzylamine is replaced by 4-methoxybenzylamine, and the remaining raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product (4S, 5R, 6R)-N-[(4-methoxyphenyl)methyl base]-4-guanidino-5-acetylamino-6[(1R,2R)-1,2,3-trihydroxypropyl]-5,6-dihydro-4H-pyran-2-carboxamide. 1 H-NMR (CD 3 OD, 300MHz): δ2.01(s, 3H), 3.34(s, 2H), 3.65-3.78(m, 2H), 3.77(s, 3H), 4.16-4.22(m, 2H), 4.36-4.42( m, 3H), 5.72(s, 1H), 6.86(d, 8.4Hz, 2H), 7.22(d, 8.4Hz, 2H); LC-MS m / z 452[M+H] + ;

Embodiment 3

[0262] (4S, 5R, 6R)-N-[(3-methoxyphenyl)methyl]-4-guanidino-5-acetamido-6[(1R,2R)-1,2,3-trihydroxy Propyl]-5,6-dihydro-4H-pyran-2-carboxamide (10a-3)

[0263] Benzylamine is replaced by 3-methoxybenzylamine, and the remaining raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product (4S, 5R, 6R)-N-[(3-methoxyphenyl)methyl Base]-4-guanidino-5-acetylamino-6[(1R,2R)-1,2,3-trihydroxypropyl]-5,6-dihydro-4H-pyran-2-carboxamide; 1 H-NMR (CD3OD, 300MHz): δ2.01(s, 3H), 3.66-3.70(m, 2H), 3.77-3.82(m, 4H), 4.18-4.24(m, 2H), 4.41-4.49(m , 5H), 5.74(d, 2.4Hz, 1H), 6.81(d, 9.6Hz, 1H), 6.87(d, 7.5Hz, 1H), 7.22(t, 8.4Hz, 1H), 7.30(s, 1H) ;LC-MS m / z 452[M+H] + ;

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Abstract

The invention relates to a novel sialic acid derivant represented by the following general formula, a preparation method thereof, a drug composite comprising the same and an application of the novel sialic acid derivant in preparing neuraminidase inhibitor and drug capable of treating and preventing relevant diseases of influenza viruses. The compound and the neuraminidase have high binding activity, and cells can be effectively prevented from being infected by viruses in a biotic experiment test. Therefore, the compound is the strong neuraminidase inhibitor and is possible to develop into a new anti-influenza virus drug.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a neuraminidase inhibitor used for treating diseases related to influenza virus. More specifically, the present invention relates to a novel class of sialic acid derivatives (I) capable of inhibiting neuraminidase and a preparation method thereof; the present invention also relates to pharmaceutical compositions comprising such compounds, such compounds and their Application of the pharmaceutical composition in preparing medicines for preventing and treating diseases related to influenza virus. Background technique [0002] Neuraminidase (NA) is an important glycoprotein on the envelope of influenza virus. On the one hand, NA can catalyze the cleavage of the ketoglycoside linking bridge between the N-acetylneuraminic acid present at the end of sialic acid and the adjacent sugar group, thereby promoting the release of newly formed virus progeny particles from the host cell surf...

Claims

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Application Information

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IPC IPC(8): C07D309/28A61K31/351A61P31/16
CPCY02P20/55
Inventor 柳红左建平蒋华良冯恩光何佩岚朱维良王晋芳周宇郑明月李建唐炜陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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