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Spiropyridone Derivatives and Applications

A technology of spiropyridone and derivatives, applied in organic chemistry, antiviral agents, etc., can solve problems such as unpredictability, and achieve the effect of anti-influenza A and inhibiting activity

Active Publication Date: 2021-11-12
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Emergence of drug-resistant influenza strains is common and unpredictable due to the high mutation rate of influenza viruses
Therefore, the drug resistance and timeliness of influenza virus to existing inhibitors are still the main challenges at present

Method used

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  • Spiropyridone Derivatives and Applications
  • Spiropyridone Derivatives and Applications
  • Spiropyridone Derivatives and Applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1 1'-Benzhydryl-5'-hydroxyl-3'-(2-methoxyethyl)-1'H, 3'H-spiro[cyclohexane-1,2'-pyridine[ 2,1-f][1,2,4]triazine]-4',6'-dione

[0052] step:

[0053] Raw material 1: 2-methyl-3-hydroxy-4H-pyran-4-one was prepared according to the method of document CN108947950 (A).

[0054] Starting material 2: Preparation of 2-methyl-3-(benzyloxy)-4H-pyran-4-one:

[0055]

[0056] Dissolve 2-methyl-3-hydroxyl-4H-pyran-4-one (1g, 8.0mmol) in 8ml of 95% ethanol, weigh sodium hydroxide (352mg, 8.8mmol) and dissolve it in 5ml of distilled water After the system was added, benzyl chloride (831ul, 7.2mmol) was added to the mixed system after the system was dissolved and reacted at 60°C for about 6 hours. ×), the organic layers were combined, washed with water (3×), washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain compound 2 (1.52 g, yield 88%). 1 H NMR (500MHz, CHCl 3 )δ7.59(d, J=5.5Hz, 1H), 7.40–7.31(m, 5H), 6.36(d, J=5.5Hz, 1H), 5.15...

Embodiment 2

[0081] Example 2 1'-Benzhydryl-5'-hydroxy-3'-(2-methoxyethyl)-1'H,3'H-spiro[cyclobutane-1,2'-pyridyl [2,1-f][1,2,4]triazine]-4',6'-dione hydrochloride

[0082] With reference to the method of Example 1, only cyclohexanone is replaced by cyclobutanone, and the yield is 88%. m.p.:144.3-144.8℃; 1 H NMR (500MHz, CDCl 3 )δ8.04(s,1H),7.95(s,1H),7.57(d,J=7.5Hz,2H),7.46(t,J=7.5Hz,2H),7.38(t,J=7.5Hz, 1H), 7.20(t, J=7.5Hz, 1H), 7.14(t, J=7.5Hz, 2H), 6.80(d, J=7.5Hz, 2H), 5.88(s, 1H), 4.19–4.15( m,1H),3.87–3.67(m,3H),3.49(s,3H),2.93–2.86(m,1H),2.32–2.15(m,4H),1.95–1.91(m,1H).HRMS( ESI): m / z calcd for (C 26 h 27 N 3 o 4 +H) + :446.2074; found: 446.2075.

Embodiment 3

[0083] Example 3 1'-Benzhydryl-5'-hydroxy-3'-(2-methoxyethyl)-2,3,5,6-tetrahydro-1'H, 3'H-spiro[ Pyran-4,2'-pyridine[2,1-f][1,2,4]triazine]-4',6'-dione hydrochloride

[0084] Referring to the method of Example 1, except that cyclohexanone was replaced by tetrahydropyrone, the yield was 83%. m.p.:>250℃; 1 H NMR (500MHz, DMSO) δ8.58(d, J=7.0Hz, 1H), 7.77(d, J=7.5Hz, 2H), 7.44(t, J=7.5Hz, 2H), 7.32(t, J =7.5Hz,1H),7.12(s,3H),6.98(s,2H),6.49(d,J=7.0Hz,1H),6.04(s,1H),3.97–3.89(m,2H),3.81 –3.74(m,2H),3.64–3.59(m,2H),3.42(s,3H),3.36(dd,J=11.5,4.5Hz,1H),3.21(t,J=11.5Hz,1H), 2.45–2.39(m,1H),2.10(d,J=14.0Hz,1H),1.99–1.93(m,1H),1.57(d,J=14.0Hz,1H).HRMS(ESI):m / z calcd for (C 27 h 29 N 3 o 5 +H) + :476.2180; found: 476.2183.

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Abstract

The invention discloses spirocyclic pyridone derivatives, which have the structure shown in general formula I. Studies have shown that the spirocyclic pyridone derivatives have a strong inhibitory effect on the activity of influenza A virus RNA polymerase, and can be used in the preparation of anti-influenza A drugs for inhibiting the activity of influenza A virus RNA polymerase. General formula I is as follows:

Description

technical field [0001] The invention belongs to the field of pharmacy, in particular to spirocyclic pyridone derivatives with 5′ cap-like structure (CAP)-dependent endonuclease inhibitory activity, and using the compound to prepare anti-influenza virus RNA polymerase activity inhibitors Application of Influenza A Molecular Drugs. [0002] technical background [0003] Influenza (influenza, referred to as influenza) is an acute respiratory infectious disease caused by influenza virus. Influenza causes 3 to 5 million severe cases and 250,000 to 500,000 deaths each year. Influenza viruses have the characteristics of high prevalence, widespread prevalence, and rapid transmission. The U.S. Food and Drug Administration (FDA) has approved three types of small molecules for the treatment of influenza, two M2 ion channel blockers, amantadine and rimantadine; three neuraminidase inhibitors, o celamivir, zanamivir, and peramivir; and baloxavir, a PA cap-dependent endonuclease inhibit...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/10C07D491/20A61P31/14
CPCA61P31/14C07D471/10C07D491/20
Inventor 陈文腾俞永平刘双容王思函刘祖东袁鑫
Owner ZHEJIANG UNIV