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3-Substituted oxy-2-pyrazine carboxamide compounds and their use

A technology of pyrazinecarboxamide and compound, which is applied in the field of preparing antiviral drugs, can solve the problems of large dosage, short half-life, poor pharmacokinetic properties and the like, and achieves the effect of high bioavailability

Active Publication Date: 2015-09-16
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although T1105 and T705 have good antiviral effects in in vitro models, both compounds have some unfavorable pharmacokinetic properties, which are not conducive to their drug efficacy
For example, the oral absorption of T1105 is very poor, and the elimination in the body is also very fast. It shows good anti-foot-and-mouth disease activity in vitro, with an IC50 of 1.6ug / mL, but oral administration to pigs, twice a day, should reach 200mg / Kg The dose can achieve the ideal anti-foot-and-mouth disease effect
The oral absorption of T705 is very good, but the elimination is fast, and there is a problem of short half-life, which leads to a large dosage of T705. The daily oral dosage is 800mg-2400mg

Method used

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  • 3-Substituted oxy-2-pyrazine carboxamide compounds and their use
  • 3-Substituted oxy-2-pyrazine carboxamide compounds and their use
  • 3-Substituted oxy-2-pyrazine carboxamide compounds and their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1 Preparation of 3-(n-Propyloxy)-2-pyrazinecarboxamide (Compound 1) (Method 1).

[0065]

[0066] In a dry three-neck flask equipped with a thermometer, a condenser and a drying tube, add 30 mL of anhydrous propanol, add 146 mg (6.34 mmol) of sodium, stir at room temperature or slightly heat until the sodium particles completely disappear, add the purified 3- Chloro-2-pyrazinecarboxamide 500mg (3.17mmol), heat up to 80°C, react for 20min, after cooling to room temperature, add 1mL of glacial acetic acid, concentrate to dryness under reduced pressure, after mixing the sample with silica gel, flash chromatography column separation (dichloro methane / methanol) to obtain the target compound, 1 HNMR (CDCl 3 )δ1.50(3H,t,J=7.2Hz),4.58(2H,q,J=7.2Hz),6.07(1H,brs),7.62(1H,brs),8.26(1H,s),8.28( 1H,s); EIMS(m / e,100),167(M + ,25),150(60),123(35),96(40),80(40),68(100).

Embodiment 2

[0067] Example 2 Preparation of 3-(n-propyloxy)-2-pyrazinecarboxamide (Compound 1) (Method 2).

[0068] step 1 Preparation of 3-(n-propyloxy)-2-pyrazinecarbonitrile

[0069]

[0070] In a dry three-neck flask with a thermometer, a condenser and a drying tube, add 10 mL of anhydrous DMF, add 3-chloro-pyrazine-2-carbonitrile (978 mg, 7.00 mmol), stir to dissolve, add anhydrous Propanol (841mg, 14mmol) and anhydrous triethylamine (1.5ml, about 11.85mmol), heated to 80-120-C for 2 hours, cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with water, chlorinated Washed with sodium solution, concentrated to dryness under reduced pressure, the crude product obtained was directly used in the next reaction without separation after drying.

[0071] step 2 Preparation of 3-(n-propyloxy)-2-pyrazinecarboxamide (Compound 1)

[0072]

[0073] In a three-necked flask with a thermometer, add 3-(n-propyloxy)-2-pyrazinecarbonitrile (980mg, about...

Embodiment 3

[0074] Example 3 Preparation of 3-(isopropyloxy)-2-pyrazinecarboxamide (compound 2)

[0075] The method is the same as in Example 1, except that n-propanol is replaced with isopropanol to obtain the title compound, 1 HNMR (CDCl 3 )δ1.45(6H,d,J=6.0Hz),5.50(2H,t,J=7.2Hz),6.14(1H,brs),7.69(1H,brs),8.27(1H,d,J=2.4 Hz), 8.29(1H,d,J=2.4Hz); ESIMS(m / e)182(MH + ).

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Abstract

Disclosed are a 3-alkoxy-substituted-2-pyrazinyl formamide compound having a structure represented by formula I and use thereof in preparing anti-viral medications. The compound disclosed exerts anti-viral effects in vivo by means of metabolism into T1105 or T705 through esterate or P450 enzyme.

Description

technical field [0001] The present invention relates to pyrazine carboxamide compound, its preparation method and its application for preparing antiviral medicine. Background technique [0002] 3-oxo-3,4-dihydro-2-pyrazine carboxamide (T1105) and 6-fluoro 3-oxo-3,4-dihydro-2-pyrazine carboxamide (T705) (see the picture below ) are RNA polymerase inhibitors of a class of viruses and have good antiviral effects. [0003] [0004] According to reports, T705 alone or in combination with neuraminidase inhibitors, such as oseltamivir phosphate, has a good anti-influenza virus effect (Antimicrobial Agents and Chemotherapy, 2007, Vol.51, No.3, 845-851 ; Antimicrobial Agents and Chemotherapy, 2010, p.126–133, PCT Patent: WO2000010569). T1105 has shown a very good effect against foot-and-mouth disease virus in vivo and in vitro models (PCT patent: WO20071139081). In addition, T705 also has a good curative effect on diseases caused by other RNA viruses. For example, T705 has a t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/24
CPCC07D241/24A61P31/14
Inventor 李松李行舟钟武王莉莉郑志兵肖军海周辛波陈伟赵国明王晓奎
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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