Preparation method and purpose of 3-alkoxy-substituent-2-pyrazinyl formamide compounds

A technology for pyrazinecarboxamide and compounds is applied in the field of preparing antiviral drugs, and can solve the problems of short half-life, poor pharmacokinetic properties, adverse drug effects and the like

Active Publication Date: 2013-01-02
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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  • Preparation method and purpose of 3-alkoxy-substituent-2-pyrazinyl formamide compounds
  • Preparation method and purpose of 3-alkoxy-substituent-2-pyrazinyl formamide compounds
  • Preparation method and purpose of 3-alkoxy-substituent-2-pyrazinyl formamide compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 13

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

[0065]

[0066] In a dry three-necked flask with a thermometer, condenser and drying tube, add 30mL of anhydrous propanol, add 146mg (6.34mmol) of sodium, stir at room temperature or slightly heat until the sodium particles disappear completely, add the purified 3- Chloro-2-pyrazinecarboxamide 500mg (3.17mmol), heated to 80°C, reacted for 20min, cooled to room temperature, added 1mL of glacial acetic acid, concentrated under reduced pressure to dryness, mixed with silica gel and separated by Flash chromatography column (two Methyl chloride / methanol elution) to obtain the target compound, 1 HNMR (CDCl 3 )Δ1.50(3H,t,J=7.2Hz),

[0067] 4.58(2H,q,J=7.2Hz), 6.07(1H,brs), 7.62(1H,brs), 8.26(1H,s), 8.28(1H,s);

[0068] EIMS(m / e,100),167(M + ,25),150(60),123(35),96(40),80(40),68(100).

Embodiment 23

[0069] Example 2 Preparation of 3-(n-propyloxy)-2-pyrazinecarboxamide (Compound 1) (Method 2).

[0070] step 1 Preparation of 3-(n-propyloxy)-2-pyrazinecarbonitrile

[0071]

[0072] In a dry three-necked flask with thermometer, condenser and drying tube, add 10 mL of anhydrous DMF, add 3-chloro-pyrazine-2-carbonitrile (978 mg, 7.00 mmol), stir to dissolve, add anhydrous n-propyl Alcohol (841mg, 14mmol) and anhydrous triethylamine (1.5ml, about 11.85mmol), warm up to 80-120C and react for 2 hours, after cooling to room temperature, dilute with water, extract with ethyl acetate, wash with water, and wash with sodium chloride solution , Concentrate to dryness under reduced pressure to obtain the crude product without separation, and use it directly in the next reaction after drying.

[0073] Step 2 Preparation of 3-(n-propyloxy)-2-pyrazinecarboxamide (Compound 1)

[0074]

[0075] In a three-necked flask with a thermometer, add 3-(n-propyloxy)-2-pyrazinecarbonitrile (980mg, about 6m...

Embodiment 3

[0077] Example 3 Preparation of 3-(isopropyloxy)-2-pyrazinecarboxamide (compound 2)

[0078] The method is the same as in Example 1, except that isopropanol is used instead of n-propanol 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

The invention related to 3-alkoxy-substituent-2-pyrazinyl formamide compounds with a structure represented by the general formula I, and an application thereof in preparing antiviral medicines. The compounds provided by the invention perform antiviral effects in vivo through a process of being metabolized into T1105 or T705 by esterase or P450 enzyme. Compared with prototype medicines T1105 or T705, the compounds with the general formula I have substantial advantages of high bioavailability and long in-vivo action time.

Description

Technical field [0001] The invention relates to a pyrazinecarboxamide compound, a preparation method thereof and its use for preparing antiviral drugs. Background technique [0002] 3-oxo-3,4-dihydro-2-pyrazinecarboxamide (T1105) and 6-fluoro3-oxo-3,4-dihydro-2-pyrazinecarboxamide (T705) (see The following formula) is a class of virus RNA polymerase inhibitors with good antiviral effects. [0003] [0004] According to reports, T705 used alone or in combination with neuraminidase inhibitors, such as oseltamivir phosphate, has a good effect against influenza virus (Antimicrobial Agents and Chemotherapy, 2007, Vol. 51, No. 3,845-851 ; Antimicrobial Agents and Chemotherapy, 2010, p.126133, PCT Patent: WO2000010569). T1105 has shown very good effects against foot-and-mouth disease virus in in vivo and in vitro models (PCT Patent: WO20071139081). In addition, T705 also has a good effect on diseases caused by other RNA viruses. For example, T705 has a therapeutic effect on western eq...

Claims

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Application Information

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Patent Type & Authority Applications(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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