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3-oxide-2-methylamide derivatives as well as preparation method and use thereof

A technology of oxypyrazine and formamide, which is applied in the field of pyrazine-2-carboxamide derivatives, can solve the problems of low water solubility, achieve the effects of improved solubility, improved antiviral activity, and high yield of finished products

Active Publication Date: 2008-07-30
李湘益
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In order to overcome the deficiency of low water solubility of 3-oxopyrazine-2-carboxamide compounds, the present invention provides a 3-oxopyrazine-2-carboxamide derivative to improve its water solubility and enhance its drug activity

Method used

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  • 3-oxide-2-methylamide derivatives as well as preparation method and use thereof
  • 3-oxide-2-methylamide derivatives as well as preparation method and use thereof
  • 3-oxide-2-methylamide derivatives as well as preparation method and use thereof

Examples

Experimental program
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Effect test

Synthetic example 1

[0030] Synthesis of compound 9:

[0031] Compound 7 (1.72 g, 0.01 mol) was dissolved in 30 ml of DMF, and K 2 CO 3 (3g), 2-chloromethoxyethyl acetate 8 (1.53g, 0.01mol). A small amount of KI was added to the mixture, and stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in 100 ml of chloroform, Washed once with water, washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (using 10% methanol-dichloromethane) to obtain compound 9 (1.95 g, yield 68%). The melting point is 188-190°C. HRMS (ESI) Calcd.for C 11 h 13 FN 2 o 6 : 288.2292; Found 288.2290.

Synthetic example 2

[0033] Synthesis of compound 2:

[0034] Compound 9 (1 g, 0.0035 mol) and 7N methanol solution of ammonia were mixed and sealed at room temperature for three days. The solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography (using 10% methanol-dichloromethane) to obtain Compound 2 (0.75 g, 93%). Melting point 212-215°C. HRMS (ESI) Calcd.for C 8 h 10 FN 3 o 4 : 231.1812; Found 231.1810.

Synthetic example 3

[0036] Synthesis of Compound 10:

[0037] Compound 2 (2.31 g, 0.01 mol) was dissolved in 70 mL of anhydrous dichloromethane, tetra-tert-butoxy (0.4 mL, 0.01 mol), triethylamine (2.12 mL, 0.015 mol) and diethyl chlorophosphate were added (1.42 mL, 0.01 mol). The mixture was stirred at room temperature for 24 hours, 80 ml of water was added, the organic layer was separated, and the aqueous phase was extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was subjected to silica gel column chromatography Compound 10 was isolated (5% methanol-dichloromethane) (3.2 g, 87% yield). HRMS (ESI) Calcd.for C 12 h 19 FN 3 o 7 P: 368.2674; Found 368.2675.

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Abstract

The invention relates to a substituted 3-oxygen pyrazine-2-formamide derivative, as well as the preparation method and the medical application thereof. The derivative adopts the chemical structural general formula (I), wherein, R represents any one component of hydrogen atoms, alkyl, naphthene base, heterocyclic alkyl, aryl, and heteroaryl; R<1> represents any one component of hydrogen, halogen, alkoxy, alkyl, alkyl halide base, acyl, carboxyl, aldehyde group, ester group, amide group, hydroxyl, methoxyl, nitro, amino, substituted amino, nitroso, cyan, sulfur cyan, allyl, and alkynyl; Y represents oxygen, sulfur or nitrogen atoms; R2 represents any one component of various substituted and unsubstituted alkoxyl alkyl with hydroxyl at the end, and substituted alkoxyl alkyl with thymidine monophophosphate ester group, diphosphate ester group, and triphosphate at the end; and substituted alkoxyl alkyl with phosphoryl at the end. The invention has the advantages that through a coupling non-cyclic nucleoside analog into substituted 3-oxygen pyrazine-2-formamide and the phosphorylation thereof, the dissolvability is greatly improved, and the antivirus activity can also be improved greatly.

Description

technical field [0001] The invention relates to a pyrazine-2-carboxamide derivative, in particular to a substituted 3-oxopyrazine-2-carboxamide derivative, its preparation method and its application in medicine. technical background [0002] World Patent WO 2000010569 A1 discloses a series of pyrazine-2-carboxamide compounds; recent studies have shown that representative compound 1 (6-fluoro-3-hydroxyl-pyrazine-2-carboxamide) has a strong Antimicrobial Agents and Chemotherapy (Antimicrobial Agents and Chemotherapy, 2007, Vol.51, No.3, 845-851), especially has a superior anti-avian influenza virus effect. However, the low water solubility of these compounds leads to relatively low bioavailability. [0003] [0004] According to literature reports (Antimicrobial Agents And Chemotherapy, Mar.2005, 981-986), compound 1 is a prodrug, which works by being metabolized into nucleoside triphosphate and reacting competitively with GTP. And nucleoside triphosphate is ring structur...

Claims

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Application Information

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IPC IPC(8): C07D241/28C07F9/6509A61K31/4965A61K31/675A61P31/12A61P35/00
Inventor 靳广毅
Owner 李湘益
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