Compound of multiple substituted uracil class, preparation method and usage

A uracil and compound technology, applied in the field of S-DABO analogue 2--5-alkyl-6-naphthylmethyl-uracil, can solve the problem of increasing drug resistance and screening novel structures, limiting antiviral potential etc. to achieve the effects of novel structure, high selectivity index, and small cytotoxicity

Inactive Publication Date: 2006-03-15
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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] Example 1: Synthesis of 2-[(substituted phenylcarbonylmethylsulfide)-6-(1-naphthylmethyl)-5-isopropyluracil

[0031] The general operation of the reaction:

[0032] Combine 5-alkyl-6-(1-naphthylmethyl)-2-thiouracil (3mmol) and K 2 CO 3 Put it in the flask, add 10ml dry DMF, stir at room temperature for half an hour, add α-bromoketone R 1 COCH 2 Br (3.3mmol), continue to stir the reaction at 55°C, TLC tracked the disappearance of the raw material for about 22 hours, stop the reaction, pour the reaction solution into 30mL ice water, stir to precipitate the precipitate, filter, wash the precipitate with water, and dry with suction to obtain the crude , Further column chromatography purification can get various white powders. Recrystallization with an appropriate solvent can give white crystals of 5-alkyl-6-(1-naphthylmethyl)-2-(substituted arylcarbonylmethylthio)uracil.

[0033] Different 5-alkyl-6-(1-naphthylmethyl)-2-thiouracils and different α-bromoketones were used to obta...

Embodiment 2

[0046] Example 2: Synthesis of 2-[(Alkoxycarbonylmethylsulfide)-6-(1-naphthylmethyl)5-isopropyluracil

[0047] The general operation of the reaction:

[0048] Combine 5-alkyl-6-(1-naphthylmethyl)-2-thiouracil (3mmol) and K 2 CO 3 Put it in the flask, add 10ml dry DMF, stir at room temperature for half an hour, add BrCH 2 COO R 1 Of α-bromoacetate (3.9mmol), continue to stir and react at 25°C for about 10 hours, TLC traces to the disappearance of the raw material point, the reaction is stopped, the solvent is removed by rotary evaporation under reduced pressure, and 30ml of CH is added. 2 Cl 2 The residue was dissolved, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent under reduced pressure to obtain a crude product, and further purified by column chromatography to obtain various white powders. Recrystallization with a suitable solvent can give white crystals of 5-alkyl-6-(1-naphthylmethyl)-2-(alkoxycarbonylmethylthio)uracil.

[004...

Embodiment 3

[0056] Example 3 Anti-HIV biological activity test

[0057] The anti-HIV-1 virus activity at the cellular level in vitro was determined by the Rega Institute of Pharmaceutical Sciences, Katholleke University, Belgium, including: the inhibitory activity on HIV-1 infected MT-4 cells and the 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 determine the protective effect of the drug on HIV-induced cytopathic changes, and calculate that 50% of the cells are protected from The concentration required for HIV-induced cytopathy is the half effective concentration IC 50 , Toxicity test and anti-HIV activity test are operated in parallel. Also in MT-4 cell culture, the MTT method is used to determine the concentration of the compound that makes 50% of uninfected cells cytopathic (CC 50 ), and calculate the selectivity index SI=CC 50 / IC 50 .

[0058] Materials and Methods:

[0059] T...

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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 an anti-HIV virus reagent, and further is the method and application of S-DABO analogue 2-(substituted aryl or alkoxycarbonyl methyl sulfide)-5-alkyl-6-naphthylmethyl-uracil . This series of compounds not only have significant anti-HIV-1 virus activity, but also have an inhibitory effect on HIV-2 SOD virus strains. It also shows HIV-1 (IIIB) mutant virus SO561945 (Y181C and K103A double mutant strains). To a certain degree of tolerance, this series of compounds may also act on other targets besides HIV-1RT. Background technique [0002] AIDS (Acquired immune deficiency syndrome) is caused by human immunodeficiency virus (HIV). [0003] Reverse transcriptase (RT) plays a leading role in the reverse transcription of HIV from mRNA to DNA, and has become an important target for the design of anti-HIV drugs. [0004] Among HIV RT target drugs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as Nevirapine (Nevirapine...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/56A61K31/513A61P31/18
Inventor 陈芬儿何严萍
Owner FUDAN UNIV
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