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n-[4-(Alkoxy)-phenylsulfonyl]-5-aryl-oxazole-2-thione neuraminidase inhibitors

A neuraminidase and benzenesulfonyl technology, applied in organic chemistry, drug combination and other directions, can solve the problem of low neuraminidase inhibitory activity and achieve the effects of good neuraminidase inhibitory activity and novel structure

Active Publication Date: 2019-10-01
SHANGHAI SCIENPHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Radix isatidis contains a variety of chemical components. Among them, some studies have shown that the epicalyptus (formula-1) in the extract of Radix isatidis has antiviral activity, but its inhibitory activity on neuraminidase is not high, IC 50 The value is millimolar level

Method used

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  • n-[4-(Alkoxy)-phenylsulfonyl]-5-aryl-oxazole-2-thione neuraminidase inhibitors
  • n-[4-(Alkoxy)-phenylsulfonyl]-5-aryl-oxazole-2-thione neuraminidase inhibitors
  • n-[4-(Alkoxy)-phenylsulfonyl]-5-aryl-oxazole-2-thione neuraminidase inhibitors

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Effect test

preparation example Construction

[0033] The preparation method of N-[4-(alkoxy)-benzenesulfonyl]-5-aryl-oxazole-2-thione neuraminidase inhibitor of the present invention, concrete steps are as follows:

[0034] (1) Add ArCHO (1.0mmol), TMSCN (2.0mmol) and LiClO in sequence to a 100mL eggplant-shaped bottle 4 ·3H 2 O (1.0mmol), react at room temperature for 0.5-1h. It was determined by TLC that the reaction of the raw materials was complete, extracted with ethyl acetate (3×10 mL), combined the organic phases and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by distillation and separated by silica gel column chromatography to obtain the aldehyde group addition product II;

[0035] ⑵Weigh NaBH 4 (3.0mmol) was dissolved in THF (5.0mL), and CF was slowly added dropwise at 0°C 3 COOH (1.0 mmol). Compound II was dissolved in THF (2 mL), added to the reaction system, and reacted at room temperature for 12 h. It was determined by TLC that the reaction of the ra...

Embodiment 1

[0041] Example 1: 3-(4-butoxy)benzenesulfonyl-5-4-(chlorostyryl)oxazole-2-thione

[0042]

[0043] IC 50 Value: 64 μM.

[0044] 1 H NMR (500MHz, CDCl 3)δ8.01(d, J=9.0Hz, 2H), 7.35–7.30(m, 4H), 6.99(d, J=9.0Hz, 2H), 6.62(d, J=15.5Hz, 1H), 6.20( dd,J=15.5,8.5Hz,1H),4.86–4.81(m,1H),4.56(m,2H),4.05(t,J=6.5Hz,2H),1.85–1.80(m,2H),1.56 –1.49(m,2H),1.02(t,J=7.5Hz,3H)

Embodiment 2

[0045] Example 2: 3-(4-Benzyloxy)phenylsulfonyl-5-(4-chlorostyryl)oxazole-2-thione

[0046]

[0047] IC 50 Value: 45 μM.

[0048] 1 H NMR (500MHz, CDCl 3 )δ8.03(d, J=9.0Hz, 2H), 7.45-7.41(m, 4H), 7.40-7.39(m, 1H), 7.3-7.30(m, 4H), 7.08(d, J=9.0Hz ,2H),6.62(d,J=15.5Hz,1H),6.20(dd,J=15.5,8.0Hz,1H),5.16(s,2H),4.86-4.82(m,1H),4.61–4.52( m,2H).

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Abstract

The invention discloses an N-[4-(alkoxyl)-benzenesulfonyl]-5-aryl-oxazole-2-thioketone neuraminidase inhibitor. A preparation method specifically comprises the following steps: (1) performing a reaction on aromatic aldehyde ArCHO, lithium perchlorate and trimethylsilyl cyanide to obtain a cyan analogue; (2) reducing the cyan analogue II to obtain a hydroxyl-substituted primary ammonia compound; (3) performing a reaction on the hydroxyl-substituted primary ammonia compound and carbon disulfide to obtain a 1,3-oxazole-2-thioketone intermediate; (4) performing a reaction on sodium 4-hydroxybenzenesulfonate and an alkylation reagent to obtain an ether compound; (5) performing a reaction on the ether compound and a chlorination reagent to obtain a sulfonyl chloride compound; and (6) substituting active hydrogen of imino groups in the 1,3-oxazole-2-thioketone intermediate to obtain a target compound. The compound synthesized by the preparation method is novel in structure and has relatively good neuraminidase inhibiting activity.

Description

technical field [0001] The invention relates to an N-[4-(alkoxy)-benzenesulfonyl]-5-aryl-oxazole-2-thione neuraminidase inhibitor and a preparation method thereof, belonging to the technical field of medicinal chemistry . Background technique [0002] Banlangen is cold in nature, bitter in taste, has the functions of cooling blood and relieving throat, clearing heat and detoxifying. It was first recorded in "Shen Nong's Materia Medica", and it is a commonly used traditional Chinese medicine in clinical practice. Radix isatidis contains a variety of chemical components. Among them, some studies have shown that the epicalyptus (formula-1) in the extract of Radix isatidis has antiviral activity, but its inhibitory activity on neuraminidase is not high, IC 50 Values ​​are millimolar levels. [0003] Contents of the invention [0004] In order to overcome the deficiencies of the prior art, the present invention takes Yichun as a modern compound and modifies its structure. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/16C07D413/04A61P43/00
Inventor 殷燕陆成张华孟凡丽潘金鹏孙玉星段永斌孙越赵连花王媛李柱
Owner SHANGHAI SCIENPHARM CO LTD