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Pyrazine compound containing diethylene substituent and composition and application thereof

A kind of compound and composition technology, applied in the field of pyrazine compounds

Active Publication Date: 2015-03-11
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to literature reports, other anti-influenza virus drugs have good inhibitory effects on viruses and antiviral application prospects, but further demonstration is often needed

Method used

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  • Pyrazine compound containing diethylene substituent and composition and application thereof
  • Pyrazine compound containing diethylene substituent and composition and application thereof
  • Pyrazine compound containing diethylene substituent and composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0212] Example 1: 3-(((3-(hydroxymethyl)cyclobutyl)methyl)amino)pyrazine-2-carbonitrile

[0213]

[0214] Step 1: Synthesis of 3-chloropyrazine-2-carbonitrile

[0215] At 0°C, add phosphorus oxychloride (2 mL, 40 mmol) and diisopropylethylamine (3.5 mL) dropwise to a solution of 3-hydroxypyrazine-2-carboxamide (5 g, 37 mmol) in chlorobenzene (20 mL) ,80mmol). The reaction solution was stirred overnight at 90°C. After completion of the reaction, the reaction solution was concentrated under reduced pressure, the resulting residue was diluted with 20 mL of water, the resulting mixture was extracted with EtOAc (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and removed under reduced pressure, and the residue was filtered through a silica gel column. Purification by chromatography (eluent: PE / EtOAc (V / V) = 10 / 1) afforded the title compound (4.5 g, 79%) as a white solid.

[0216] 1 H NMR (400MHz, CD 3 OD):δ8.67(d,1H),8.63(d,1H).

[...

Embodiment 2

[0223] Example 2: 3-(((3-(hydroxymethyl)cyclobutyl)methyl)amino)pyrazine-2-carboxamidine

[0224]

[0225] Step 1: Synthesis of 3-((3-carbamimidinopyrazin-2-ylamino)methyl)cyclobutyl)methylbenzoate

[0226] Dissolve (3-((3-cyanopyrazin-2-ylamino)methyl)cyclobutyl)methylbenzoate (0.2 g, 3 mmol) in 10 mL of methanol, then add NaOMe (0.04 g, 6 mmol). The reaction solution was stirred at room temperature for 1 h, and NH 4Cl (0.03g, 5mmol), the resulting reaction solution was stirred overnight at room temperature. After the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: DCM / MeOH=10 / 1) to obtain the title compound (0.12 g, 79%) as a white solid.

[0227] MS:(ESI,pos.ion)m / z:268.3[M+1] + .

[0228] Step 2: Synthesis of 3-((3-(hydroxymethyl)cyclobutyl)methylamino)pyrazine-2-carboxamidine

[0229] 3-((3-Carboxamidinopyrazin-2-ylamino)methyl)cyclobutyl)methylbenzoate (0.25 g, 4 mmol) was d...

Embodiment 3

[0231] Example 3: 3-(((3-(Hydroxymethyl)cyclobutyl)methyl)amino)pyrazine-2-carboxamide

[0232]

[0233] Step 1: Synthesis of (3-((3-carboxamidopyrazin-2-ylamino)methyl)cyclobutyl)methylbenzoate

[0234] Potassium carbonate (3.8mg, 0.02mmol, 0.1eq) was added to (3-((3-cyanopyrazin-2-ylamino)methyl)cyclobutyl)methylbenzoic acid (0.12g, 2mmol, 1eq ) in DMSO solution (10 mL), the mixture was stirred for 30 min, then 10 mL of hydrogen peroxide was added, the resulting mixture continued to react at room temperature for 2 h, and then 5 mL of water was added to quench the reaction, the solid product was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a residue, which was directly used in the next reaction .

[0235] MS:(ESI,pos.ion)m / z:268.3[M+1] + .

[0236] Step 2: Synthesis of 3-(((3-(hydroxymethyl)cyclobutyl)methyl)amino)pyrazine-2-carboxamide

[0237] Dissolve (3-((3-carboxamidopyrazin-2-ylamino)methyl)cyclobutyl)methylbenzoate (0...

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Abstract

The invention relates to a pyrazine compound containing a diethylene substituent and application thereof as a medicine, particularly application thereof to preparation of medicines for preventing and treating various influenza viruses. Particularly, the invention relates a compound of which the general formula I is shown in the specification, or a stereoisomer, a geometrical isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and all variables are defined in the specification. The invention also relates to application of the compound of which the general formula I is shown in the specification, or the stereoisomer, the geometrical isomer, the tautomer, the nitrogen oxide, the hydrate, the solvate, the metabolite, the pharmaceutically acceptable salt or the prodrug thereof as medicines, particularly application of the compound as a medicine for preventing and treating influenza viruses.

Description

technical field [0001] The invention relates to a pyrazine compound containing a cyclobutane substituent and its use as medicine. The compound of the invention is suitable for the preparation of antiviral medicine. The present invention also relates to pharmaceutical compositions containing these compounds, and to the use of said compounds, alone or in combination with other agents, for the prevention and treatment of various viruses, especially for the prevention and treatment of influenza viruses. Background technique [0002] Influenza (influenza, referred to as influenza) is an acute respiratory infection caused by influenza virus, and it is also a highly contagious and fast-spreading disease. It is mainly spread through droplets in the air, person-to-person contact or contact with contaminated items. Typical clinical symptoms are: sudden onset of high fever, general pain, significant fatigue and mild respiratory symptoms. Generally, autumn and winter are the high-inci...

Claims

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Application Information

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IPC IPC(8): C07D241/26C07D241/28A61K31/4965A61P31/16
CPCC07D241/26C07D241/28
Inventor 任青云刘辛昌唐昌华张健存张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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