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Compound of multiple substituted uracil class, preparation method and usage

A uracil, compound technology, applied in the field of S-DABO analog 2--5-alkyl-6-naphthylmethyl-uracil, can solve the limitation of antiviral potential, increase drug resistance and screen novel structures and other problems, to achieve the effect of novel structure, high selectivity index and high anti-HIV virus activity

Inactive Publication Date: 2005-01-12
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These NNRTIs drugs have significantly improved the clinical efficacy of anti-HIV infection and AIDS, and have significant advantages, but they will make HIV-1 resistant in a short time after they are used for treatment, which greatly limits their anti-HIV resistance. Unleashing the potential of the virus, therefore increasing the anti-drug resistance of existing drugs and screening candidates with novel structures is the focus of anti-AIDS drug research

Method used

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  • Compound of multiple substituted uracil class, preparation method and usage
  • Compound of multiple substituted uracil class, preparation method and usage
  • Compound of multiple substituted uracil class, preparation method and usage

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: The general operation of the synthetic reaction of 2-[(substituted phenylcarbonylmethylthio)-6-(1-naphthylmethyl)-5-isopropyluracil:

[0031] 5-Alkyl-6-(1-naphthylmethyl)-2-thiouracil (3mmol) and K 2 CO 3 Place in a flask, add 10ml of dry DMF, stir at room temperature for half an hour, add α-bromoketone R 1 COCH 2 Br (3.3mmol), continue stirring reaction at 55°C, TLC tracking about 22 hours raw material point disappears, stop the reaction, pour the reaction solution into 30mL ice water, stir to precipitate precipitate, filter, wash the precipitate with water, suction filter and dry to obtain the crude product , and further purified by column chromatography to obtain various white powders. Recrystallization with an appropriate solvent can give white crystals of 5-alkyl-6-(1-naphthylmethyl)-2-(substituted arylcarbonylmethylthio)uracil.

[0032] Using different 5-alkyl-6-(1-naphthylmethyl)-2-thiouracil and different α-bromoketones to obtain the target pro...

Embodiment 2

[0047] Embodiment 2: The general operation of the synthetic reaction of 2-[(alkoxycarbonylmethylthio)-6-(1-naphthylmethyl) 5-isopropyluracil:

[0048] 5-Alkyl-6-(1-naphthylmethyl)-2-thiouracil (3mmol) and K 2 CO 3 Place in a flask, add 10ml of dry DMF, stir at room temperature for half an hour, add BrCH 2 COOR 1 α-Bromoacetate (3.9mmol), continue to react with stirring at 25°C for about 10 hours, TLC traces that the raw material point disappears, stop the reaction, remove the solvent by rotary evaporation under reduced pressure, add 30mlCH 2 Cl 2 The residue was dissolved, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude products, which were further purified by column chromatography to obtain various white powders. Recrystallization with an appropriate solvent can give white crystals of 5-alkyl-6-(1-naphthylmethyl)-2-(alkoxycarbonylmethylthio)uracil.

[0049] Using different 5-alkyl-6-(...

Embodiment 3

[0057] Embodiment 3 anti-HIV biological activity test

[0058] The anti-HIV-1 viral activity at the cell level in vitro was determined by the Rega Institute of Pharmacy, Katholleke University, Belgium, mainly including: inhibitory activity on HIV-1 infected MT-4 cells, and cytotoxicity. The method is described as follows: make the compound in HIV-1 infected MT-4 cells, at different times of HIV-1 infection, use the MTT method to measure the protective effect of the drug on the cytopathic changes induced by HIV, and calculate that 50% of the cells are free from half effective concentration IC for HIV-induced cytopathy 50 , Toxicity determination and anti-HIV activity experiment are operated in parallel, also in MT-4 cell culture, the concentration (CC 50 ), and calculate the selectivity index SI=CC 50 / IC 50 .

[0059] Materials and Methods:

[0060] The anti-HIV activity of each compound is monitored by the inhibitory effect of the drug on the cytopathic effect caused by ...

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Abstract

This invention relates to S-DABO type reverse transcriptiveenzyme inhibitor-2-(substituted aryl alkyl or alkoxy carbonyl methyl sulfur)-5-alkyl-6-(1-naphthyl methyl) uracil compound, and its prepn. method, its application of anti-HIV virus, with its formula, where: R1=H, C1-5 alkyl; R2=C1-6 alkyl; C1-6 alkoxy, arylcyclo-R3, aryl heterocycle-R3, C3-6 cycloalkyl-R3, arylcyclo, aryl heterocycle, C3-6 cycloalkyl substituting group R3 being H, 1-3 same or different; C1-3 alkyl, halogen, group R3 being H, 1-3 same or different: C1-3 alkyl, halogen, C1-3 ether group, OH. In this invention, 5-alkyl-6-(1-naphthylmethyl) thiourea uracil is used as reactor reacting with alpha-halogenated ketone or alpha-halogenated acetate, in the presence of catalyst of K2CO3. Said invention products can eliminate HIV-1 virus, HIV-2 SOD virus and HIV-1 (III B) SO561945.

Description

technical field [0001] The present invention relates to a kind of anti-HIV virus agent, further say S-DABO analogue 2-(substituted aryl or alkoxycarbonylmethylthio)-5-alkyl-6-naphthylmethyl-uracil method and application . This series of compounds not only has significant anti-HIV-1 virus activity, but also can produce inhibitory effect on HIV-2 SOD virus strain, and is effective against HIV-1(III B ) mutant virus SO561945 (Y181C and K103A double mutant strain) also showed certain tolerance, and this series of compounds may also act on other targets besides HIV-1RT. Background technique [0002] AIDS (AIDS) is acquired immunodeficiency syndrome (Acquired immune deficiency syndrome) is caused by human immunodeficiency virus (Human immunodeficiency virus, HIV). [0003] Reverse transcriptase (Reverse transcriptase, RT) has become an important target for the design of anti-HIV drugs because it plays a leading role in the process of HIV reverse transcription from mRNA to DNA. ...

Claims

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Application Information

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IPC IPC(8): A61K31/513A61P31/18C07D239/56
Inventor 陈芬儿何严萍
Owner FUDAN UNIV
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