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Aromatic heterocyclic amine derivative as well as preparation method and application thereof

A technology of derivatives and heteroamines, applied in the field of compound synthesis, can solve the problems of poor druggability, poor water solubility, and low anti-HBV activity, and achieve good water solubility, large application prospects, and good druggability

Pending Publication Date: 2021-11-30
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Chinese patent CN108610301A discloses a class of chiral aromatic heteroamine derivatives, which are nucleocapsid inhibitors targeting HBV capsid assembly, but aromatic heteroamines with a p-methoxybenzamide structure at their ends Derivative compounds have poor water solubility and poor druggability, and most of the compounds have low or no anti-hepatitis B virus activity.

Method used

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  • Aromatic heterocyclic amine derivative as well as preparation method and application thereof
  • Aromatic heterocyclic amine derivative as well as preparation method and application thereof
  • Aromatic heterocyclic amine derivative as well as preparation method and application thereof

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Experimental program
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preparation example Construction

[0032] The preparation method of a new class of aromatic heteroamine derivatives, the basic synthetic route is as follows:

[0033]

[0034] a: Add 2-aminothiazole (compound 1) (2g, 20mmol, 1.0eq) and di-tert-butyl dicarbonate (6.548g, 30mmol, 1.5eq) to a 100mL round-bottomed flask in turn, then add anhydrous tetrahydrofuran to dissolve , react overnight at room temperature. The tetrahydrofuran was spin-dried under reduced pressure and separated by column chromatography to obtain compound 2 (3902 mg, 97.55%).

[0035] b: Add compound 2 (3mmol, 1.0eq) into a 100mL round-bottomed flask, put it on a vacuum pump for 30 minutes, then protect it with argon, add an appropriate amount of anhydrous tetrahydrofuran to dissolve, and put it in a low-temperature reaction bath at -78°C middle. After cooling to -78°C, n-butyllithium (12mmol, 4.0eq) was added slowly over 30 minutes. Then, the corresponding substituted benzaldehyde (4.5mmol, 1.5eq) dissolved in anhydrous THF was slowly a...

Embodiment 1

[0043] The chemical structural formula is as the synthesis of aromatic heteroamine derivatives shown in formula (II)

[0044]

[0045] Take the corresponding compound 5 (X is Y is ) (230mg, 0.5mmol), p-methoxybenzoyl chloride (102mg, 0.6mmol), dissolved in anhydrous dichloromethane, then added pyridine (158mg, 2mmol), and reacted overnight at room temperature. The dichloromethane was spin-dried under reduced pressure, and the pH was adjusted to about 4 with 1 mol / L hydrochloric acid, then extracted with ethyl acetate, washed with saturated sodium chloride solution, the organic layer was spin-dried under reduced pressure, and separated by column chromatography to obtain the compound.

[0046] data analysis: 1 H NMR (Bruker 500or 400MHz, the solvent is deuterated methanol, deuterated chloroform or deuterated DMSO), mass spectrometry (ESI, Thermofisher LCQ or QE), the data are as follows:

[0047] 1 H NMR(500MHz,DMSO)δ12.29(s,1H),10.16(s,1H),8.14(s,1H),8.03(d,J=8.9Hz,2H),7...

Embodiment 2

[0050] Synthesis of aromatic heteroamine derivatives with chemical structural formula as shown in formula (III)

[0051]

[0052] Take the corresponding compound 5 (X is Y is ) (376mg, 0.85mmol), p-methoxybenzoyl chloride (145mg, 0.85mmol), dissolved in anhydrous dichloromethane, then added pyridine (135mg, 1.7mmol), and reacted overnight at room temperature. The dichloromethane was spin-dried under reduced pressure, and the pH was adjusted to about 4 with 1 mol / L hydrochloric acid, then extracted with ethyl acetate, washed with saturated sodium chloride solution, the organic layer was spin-dried under reduced pressure, and separated by column chromatography to obtain the compound.

[0053] data analysis: 1 H NMR (Bruker 500or 400MHz, the solvent is deuterated methanol, deuterated chloroform or deuterated DMSO), mass spectrometry (ESI, Thermofisher LCQ or QE), the data are as follows:

[0054] 1 H NMR (500MHz, DMSO) δ12.29(s,1H),10.21(s,1H),8.06(d,J=2.1Hz,1H),8.02(d,J...

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Abstract

The invention discloses an aromatic heterocyclic amine derivative as well as a preparation method and application thereof. The structural formula of the aromatic heterocyclic amine derivative is shown as a formula (I), wherein R1 is selected from chlorine, methoxyl, nitryl, hydroxyl or amino; and R2 is selected from 3, 5-dimethyl isoxazolyl or bromine. An aromatic heterocyclic amine derivative compound provided by the invention is high in water solubility and high in druggability. Similarly, the compound also has an amide structure, and the compound found by the invention has good anti-hepatitis B virus activity; the structure of the compound provided by the invention has hydroxyl and amino, so that a novel inhibitor based on a proteolysis targeting chimera mechanism can be designed and synthesized, and the derivative has a relatively great application prospect.

Description

technical field [0001] The present invention relates to the technical field of compound synthesis, more specifically, to a class of aromatic heteroamine derivatives and their preparation methods and applications. Background technique [0002] Hepatitis B virus (HBV) is a common double-stranded hepatotropic DNA virus. Infection with this virus can cause acute and chronic liver damage. Long-term infection may cause hepatitis, liver cirrhosis and even liver cancer. At present, the drugs for treating hepatitis B mainly include interferon and nucleoside analogues (lavumidine, entecavir, telbivudine, etc.). Among them, interferon plays an anti-HBV role through immune regulation, and requires long-term injection of drugs. The disadvantage is that it is not convenient enough and the cost is high. Nucleoside analogs play a role by inhibiting the reverse transcriptase of hepatitis B virus, but the disadvantage is that it is easy to produce drug resistance. In addition, HBV can also ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/46C07D417/12A61P31/20
CPCC07D277/46C07D417/12A61P31/20
Inventor 柏川高银谊李凯丽
Owner SUN YAT SEN UNIV
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