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5-Aryl-1,3,4-thiodiazole/1,3,4-oxadiazole-2-amine compound and preparation method and application thereof

A technology of amine compounds and thiadiazoles, applied in the field of medicine, can solve the problems such as no literature reports, and achieve the effects of good inhibitory activity, high yield and novel structure

Active Publication Date: 2020-11-24
HUANGHUAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is currently no literature report on the anti-influenza virus activity of 1,3,4-thiadiazole / 1,3,4-oxadiazole

Method used

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  • 5-Aryl-1,3,4-thiodiazole/1,3,4-oxadiazole-2-amine compound and preparation method and application thereof
  • 5-Aryl-1,3,4-thiodiazole/1,3,4-oxadiazole-2-amine compound and preparation method and application thereof
  • 5-Aryl-1,3,4-thiodiazole/1,3,4-oxadiazole-2-amine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] 2-(5-(cyclohexaneimin-1-yl)pyrazin-2-yl)-5-tert-butyl-1,3,4-oxadiazole (Ⅰ-1) and 2-(5-( Synthesis of cyclohexylimin-1-yl)pyrazin-2-yl)-5-tert-butyl-1,3,4-thiadiazole (Ⅱ-1)

[0037]

[0038] 1) Using methyl 5-chloropyrazine-2-carboxylate as a raw material, obtain 5-(cyclohexylimino-1-yl)pyrazine-2-hydrazide through hydrazinolysis reaction: take a 100mL round-bottomed flask, place in At 0°C, methyl 5-chloropyrazine-2-carboxylate (5.18g, 30mmol), CH 3CN (18mL), cyclohexylimine (3.27g, 33mmol, 3.7mL) were stirred evenly, and then DIPEA (10mL) was added dropwise. After the addition was complete, the reaction was stirred at 85°C and refluxed for 10h. Concentrate by rotary evaporation under reduced pressure, dissolve with dichloromethane (200mL), wash with saturated sodium bicarbonate solution and saturated brine successively, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound (4.5g). Proceed to the next ...

Embodiment 2

[0046] 2-(5-(cyclohexaneimin-1-yl)pyrazin-2-yl)-5-tert-butyl-1,3,4-oxadiazole (Ⅰ-2) and 2-(5-( Synthesis of Cyclohexylimin-1-yl)pyrazin-2-yl)-5-tert-butyl-1,3,4-thiadiazole (Ⅱ-2)

[0047]

[0048] 1) Using methyl 5-chloropyrazine-2-carboxylate as a raw material, obtain 5-(cyclohexylimino-1-yl)pyrazine-2-hydrazide through hydrazinolysis reaction: same as step 1 in Example 1 ).

[0049] 2) 5-(cyclohexylimino-1-yl)pyrazine-2-hydrazide reacts with cyclohexyl isothiocyanate to generate amidothiourea compound: take a 25mL round bottom flask and add the compound obtained in the previous step ( 300mg, 1.28mmol), cyclohexyl isothiocyanate (198.1mg, 1.4mmol) and absolute ethanol 5mL. After the addition was complete, the reaction was heated to 80° C., and the reaction was completed in 4 hours. Slowly cooled to room temperature, and then placed in the refrigerator for 4 hours, the solid precipitated, filtered, washed with cold ethanol, and dried to obtain 378 mg of cyclohexyl amidot...

Embodiment 3

[0057] 5-(5-(Cyclohexylimin-1-yl)pyrazin-2-yl)-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1. 1] Hept-3-yl)-1,3,4-oxadiazol-2-amine (Ⅰ-3) and 5-(5-(cyclohexylimin-1-yl)pyrazin-2-yl) -N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)-1,3,4-thiadiazol-2-amine Synthesis of (Ⅱ-3)

[0058]

[0059] In embodiment 1, step 2) tert-butyl isothiocyanate is replaced with pinanyl-3-isothiocyanate, and other operations are the same as in embodiment 1. 5-(5-(Cyclohexylimin-1-yl)pyrazin-2-yl)-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1 .1] Hept-3-yl)-1,3,4-oxadiazol-2-amine (I-3) and 5-(5-(cyclohexylimin-1-yl)pyrazin-2-yl )-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)-1,3,4-thiadiazole-2- Amine (II-3) was purified by column chromatography to obtain compounds I-3 and II-3 (10 mg, yield 83.3%) and (140 mg, yield 85.3%), respectively.

[0060] Wherein the synthesis process of pinanyl-3-isothiocyanate is as follows: take a 250mL round bottom flask, add pinaneamine (4.5g,...

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Abstract

The invention discloses a 5-aryl-1,3,4-thiodiazole / 1,3,4-oxadiazole-2 amine compound. The general molecular formula is shown as I or II, the structure is novel, and the compound has good inhibitory activity against influenza virus. The invention further discloses a preparation method of the 5-aryl-1,3,4-thiodiazole / 1,3,4-oxadiazole-2 amine compound, the preparation process is simple and the yieldis high, two active compounds can be obtained at the same time, and the preparation method conforms to the atom economy. The invention further discloses application of the 5-aryl-1,3,4-thiodiazole / 1,3,4-oxadiazole-2 amine compound and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof to the preparation of anti-influenza-virus drugs, the inhibitory activity against influenza virus is high, the toxic and side effects are small, and the development potential is good, and the anti-influenza-virus drugs can be used as a potential anti-influenza lead compound for furtherdevelopment. The invention further provides a pharmaceutical composition comprising the 5-aryl-1,3,4-thiodiazole / 1,3,4-oxadiazole-2 amine compound, and the pharmaceutical composition can be made intovarious dosage forms according to needs, and has important practical significance and economic benefits for the prevention and treatment of influenza that endangers health of people.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a 5-aryl-1,3,4-thiadiazole / 1,3,4-oxadiazol-2-amine compound and a preparation method and application thereof. Background technique [0002] Influenza virus is a pathogen that causes acute upper and lower respiratory diseases, which are manifested as fever, cough, myalgia, sore throat, nasal congestion and other symptoms. Influenza virus is also the chief culprit of annual seasonal epidemics (such as H3N2) and occasional influenza (such as H1N1), which seriously endangers human health and causes huge losses to society and economy. Prevention and control of influenza has also become a serious public health problem. The emergence of highly pathogenic avian influenza from time to time, such as 1997H5N1, 2009H1N1 and 2013H7N9, always warns the potential of a new round of influenza outbreaks in humans. Vaccination is the best way to prevent influenza. However, the subtypes and ratios o...

Claims

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Application Information

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IPC IPC(8): C07D413/04C07D417/04A61K31/497A61P31/16
CPCC07D413/04C07D417/04A61P31/16Y02A50/30
Inventor 董江红裴青蓝王盼盼张向飞
Owner HUANGHUAI UNIV
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