Biphenyl diarylpyrimidine derivative containing chiral hydroxymethylene structure as well as preparation method and application thereof

A technology of biphenyl diarylpyrimidine and hydroxymethylene, which is applied in the field of medicine and can solve problems such as poor water solubility

Active Publication Date: 2020-06-19
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the rapid emergence of virus mutants and the poor water solubility of these compounds (ETR, <<1μg / mL; RPV, 20ng / mL) and the side effects caused by long-term administration limit their clinical use. Therefore, the further development of new high-efficiency non-nucleoside reverse transcriptase inhibitors with broad-spectrum antiviral activity and excellent pharmacokinetic properties has become one of the hot spots of medicinal chemists.

Method used

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  • Biphenyl diarylpyrimidine derivative containing chiral hydroxymethylene structure as well as preparation method and application thereof
  • Biphenyl diarylpyrimidine derivative containing chiral hydroxymethylene structure as well as preparation method and application thereof
  • Biphenyl diarylpyrimidine derivative containing chiral hydroxymethylene structure as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: the preparation of final product I

[0028] Compound II obtains racemate product Ras-1 under the effect of reducing agent, on this basis, utilizes appropriate resolution method to carry out chiral resolution to above-mentioned obtained racemate compound and obtain corresponding R enantiomer (R- 1) and the R enantiomer (S-1). The reduction conditions are: one or more of borane reagent reduction, aluminum alkoxide reagent reduction, sodium borohydride or potassium borohydride reduction, lithium aluminum hydride reduction, and hydrogenation reduction under metal catalysis such as Pt, Pd, Ni, etc. . Solvents are methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, ethyl acetate One or more of esters, etc.; the reaction temperature is 0-200°C, and the reaction time is 1-4h. The resolution method is one or more of crystallization...

Embodiment 2

[0052] Example 2: X-ray Single Crystal Diffraction of a Single Enantiomer

[0053] The absolute configuration of the single enantiomer was confirmed by X-ray single crystal diffraction.

[0054] Preparation of single crystal: Dissolve the single enantiomer completely in the solvent at room temperature or under heating conditions, then keep the solution relatively sealed and let it stand at room temperature to slowly evaporate the solvent until a single crystal grows. The selected solvents here are methanol, ethanol, n-propanol, isopropanol, n-butanol, dichloromethane, dichloroethane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, cyclic One or more of hexane and petroleum ether. The crystal growth time is 5-20 days. The preparation method of the crystal and the X-ray single crystal diffraction results are described in detail below by taking the methyl-substituted compound on biphenyl as an example.

[0055] Dissolve the monomethyl-substitu...

Embodiment 3

[0059] Embodiment 3: anti-HIV biological activity test

[0060] The anti-HIV virus activity at the cell level in vitro was determined by the Rega Institute of Pharmacy at Katholleke University in Belgium, mainly including: inhibitory activity and cytotoxicity to HIV-infected MT-4 cells. The method is as follows: make the compound in HIV-infected MT-4 cells, at different time of HIV infection, use the MTT method to measure the protective effect of the drug on the cytopathy induced by HIV mutagenesis, and calculate that 50% of the cells are free from HIV-induced cytopathy half effective concentration EC 50 , the toxicity assay is carried out in parallel with the anti-HIV activity experiment, also in MT-4 cell culture, the concentration (CC 50 ), and calculate the selectivity index SI=CC 50 / EC 50 .

[0061] Materials and Methods:

[0062] The anti-HIV activity of each compound is monitored by the inhibitory effect of the drug on the cytopathic effect caused by HIV in cells....

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diarylpyrimidine derivative containing a chiral hydroxymethylene structure as well as preparation andapplication thereof. The biphenyl diarylpyrimidine derivative with the compound structure containing a chiral hydroxymethylene structure comprises medicinal salt, stereochemical isomers, hydrates andsolvates of the biphenyl diarylpyrimidine derivative, X-ray diffraction single crystals of polycrystals or eutectic crystals and single enantiomers of the biphenyl diarylpyrimidine derivative, and precursors and derivatives of the biphenyl diarylpyrimidine derivative with the same biological function. The invention also comprises a preparation method of the compound and an application of a composition containing one or more compounds in related medicines for treating AIDS and the like. In-vitro cell level anti-HIV-1 activity experiment results show that the small molecules have relatively strong anti-HIV-1 biological activity, can significantly inhibit virus replication in MT-4 cells infected by HIV-1 viruses, have relatively low cytotoxicity, and are expected to become anti-HIV candidatedrugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a biphenyl diarylpyrimidine derivative containing a chiral hydroxymethylene structure, a preparation method thereof, and an application in treating AIDS and other related drugs. Background technique [0002] AIDS, Acquired Immunodeficiency Syndrome (AIDS), is caused by human immunodeficiency virus (Human Immunodeficiency virus, HIV-1) infection leading to immunodeficiency, which leads to a series of major epidemics of pathogenic infections and tumors STDs. Since the first case was confirmed by the US Centers for Disease Control (CDC) in 1981, AIDS has spread rapidly around the world and has become a major global public health problem, killing more than 32 million people so far. [0003] Reverse transcriptase (Reverse transcriptase, RT) plays a key role in the life cycle of HIV virus replication, responsible for the reverse transcription of viral RNA into DNA-RNA hybr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42A61K31/505A61P31/18
CPCC07D239/42A61P31/18C07B2200/07C07B2200/13
Inventor 陈芬儿庄春林陈晓梅定力王佳琦
Owner FUDAN UNIV
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