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Azacyclo diketone compound and preparation method thereof

A compound, nitrogen heterocyclic technology, applied in the field of nitrogen heterocyclic diketone compound and its preparation

Inactive Publication Date: 2020-06-02
维清生物科技(上海)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, influenza virus drug resistance will inevitably appear, and small molecules with different chemical structures targeting the same target may have different drug resistance, so it is still necessary to develop new influenza virus nuclease endonuclease inhibitors

Method used

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  • Azacyclo diketone compound and preparation method thereof
  • Azacyclo diketone compound and preparation method thereof
  • Azacyclo diketone compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077]

[0078] 1-(6,11-Dihydrodibenzo[b,e]thieheptin-11-yl)-5-hydroxy-2,3-dihydro-1H-pyrido[1,2-b]pyridazine The specific reaction equation of -4,6-diketone is as follows:

[0079]

[0080] Step A: Methyl 3-(3-(benzyloxy)-4-oxo-4H-pyran-2-yl)-3-hydroxypropanoate (Compound 1.1)

[0081] Methyl acetate (1.92 g, 26 mmol) was dissolved in 20 mL of tetrahydrofuran solution, and LDA (0.5 M, 13 mL) was added dropwise at minus 65°C under nitrogen protection, and stirred for 1 hour. Add 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (2 g, 8.66 mmol), and keep stirring at -65°C for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride, extracted three times with 90 mL ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. Spin-dried and purified to obtain product 1.1 (1.54 g, yield: 59%). LCMS ESI(+) m / z: 305.1(M+1).

[0082] Step B: 3-(Benzyloxy)-2-(1,3-dihydroxypropyl)-4H-pyran-4-one (compound 1.2)

[0083] Compou...

Embodiment 2

[0108]

[0109] 1-(10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-yl)-5-hydroxy-2,3-dihydro-1H-pyrido[1,2 -b]pyridazine-4-,6-dione

[0110] The specific reaction equation is as follows:

[0111]

[0112] Step A: Use 10,11-dihydro-5H-dibenzo[a,d][7]annulen-5-ol to replace 6,11-dihydrodibenzo[b in Step K of Example 1 , e] thiaheptin-11-ol, compound 2.1 was synthesized. LCMS ESI(+) m / z: 465.2(M+1).

[0113] Step B: Using Step L in Example 1, Compound 2.2 was synthesized. LCMS ESI(+) m / z: 463.2(M+1).

[0114] Step C: Step M in Example 1 was used to synthesize Compound Example 2. LCMS ESI(+) m / z: 373.2(M+1).

Embodiment 3

[0116]

[0117] 1-(10-fluoro-6,11-dihydrodibenzo[b,e]thieheptin-11-yl)-5-hydroxy-3,3-dimethyl-2,3-dihydro-1H -pyrido[1,2-b]pyridazine-4,6-dione

[0118] The specific reaction equation is as follows:

[0119]

[0120] Step A: 3-(3-(Benzyloxy)-4-oxo-4H-pyran-2-yl)-3-hydroxy-2,2-dimethylpropanal (compound 3.1)

[0121] Dissolve 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde (10g, 43mmol) in 100mL tetrahydrofuran, add pyrrolidine (0.35mL, 17.5mmol) at room temperature, glacial acetic acid (3.73mL, 97mmol) and isobutyraldehyde (4.3g, 60mmol), stirred for 2 hours. The reaction solution was directly spin-dried, and purified by column chromatography to obtain product 3.1 (9 g, yield: 68.5%). LCMSESI(+)m / z:303.1(M+1).

[0122] Step B: 5-(Benzyloxy)-4-hydroxy-3,3-dimethyl-3H-pyrido[1,2-b]pyridazin-6(4H)-one (compound 3.2)

[0123] Compound 3.1 (13g, 43mmol) was dissolved in 200mL of N,N-dimethylformamide, hydrazine hydrochloride (30g, 430mmol) was added, and stirred at 80°C for 2 ...

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Abstract

The invention provides an azacyclo diketone compound, which is a compound represented by the following structure defined in the specification, or a pharmaceutically acceptable salt thereof. The invention provides a compound having an inhibitory activity on influenza (flu) virus proliferation, particularly on influenza-related cap-dependent endonuclease to inhibit influenza virus proliferation so as to treat or prevent influenza. The present invention relates to a substituted azacyclo diketone compound having inhibitory activity on cap-dependent endonuclease, and a pharmaceutical composition containing the substituted azacyclo diketone compound.

Description

technical field [0001] The invention relates to a compound with inhibitory activity on the proliferation of influenza (flu) virus, in particular, inhibiting influenza-related cap-dependent endonuclease to inhibit the proliferation of influenza virus, thereby treating or preventing influenza. In particular, substituted polycyclic pyridopyridazinedione derivatives having inhibitory activity against cap-dependent endonucleases, and pharmaceutical compositions containing them. Background technique [0002] Influenza viruses belong to the Orthomyxoviridae family of viruses and are negative-sense single-stranded RNA viruses. There are three known influenza viruses: Influenza A, Influenza B, and Influenza C. Influenza virus infection can cause acute respiratory infection, and can also cause other respiratory viral infections, including upper respiratory and lower respiratory viral infections. Viral infections of the upper respiratory tract involve the nose, sinuses, pharynx, and / ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D471/10C07D491/20C07D471/20C07D519/00C07D495/20A61K31/5025A61K31/503A61P31/16
CPCA61P31/16C07D471/04C07D471/10C07D471/20C07D491/20C07D495/20C07D519/00
Inventor 沈旺党奎峰刘劲强蔡雨婷陈春明韩巧靡佳晨沈家磊孙亚波王鑫张超章志高马随军徐华萍李博侯丹丹赖新忠
Owner 维清生物科技(上海)有限公司
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