6-cyclohexyl methyl substituted s-DABO compound, method for synthesizing same and uses thereof

A cyclohexyl, compound technology, applied in the field of 6-cyclohexyl substituted S-DABO compounds, can solve the problems of drug resistance, limitation of NNRTIs antiviral potential, mutation, etc., to achieve convenient synthesis, good resistance Receptivity, strong inhibitory effect

Inactive Publication Date: 2008-05-14
YUNNAN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, NNRTIs can easily mutate HIV-1RT and form drug resistance, which limits the antiviral potential of NNRTIs

Method used

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  • 6-cyclohexyl methyl substituted s-DABO compound, method for synthesizing same and uses thereof
  • 6-cyclohexyl methyl substituted s-DABO compound, method for synthesizing same and uses thereof
  • 6-cyclohexyl methyl substituted s-DABO compound, method for synthesizing same and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The preparation of embodiment one β-ketoester (3)

[0035] Method 1: Preparation with chloromethylcyclohexane as raw material

[0036] The preparation of cyclohexyl acetonitrile (5): add 30ml dry ethanol, 7.35g (0.15mol) NaCN in the round bottom flask, stir until NaCN dissolves completely, add 0.1mol chloromethylcyclohexane, reflux and stir for 4 hours, Evaporate the solvent under reduced pressure, add water to dissolve, extract with ethyl acetate, combine the organic layers, and successively wash with saturated NaHCO 3 , washed with salt water, anhydrous CaCl 2 After drying, cyclohexylacetonitrile was obtained as a yellow oil.

[0037] Preparation of β-ketoester (3): activate zinc powder with 3M HCl, distilled water, absolute ethanol, and absolute ether sequentially. Activated zinc powder (45 g, 0.68 mol) was suspended in refluxing THF (400 mL) under nitrogen protection, and a few drops of 6 were added thereto to initiate the reaction. After the green color appeared ...

Embodiment 2

[0042] The synthesis of embodiment two 5-alkyl-6-cyclohexylmethylthiouracil (2)

[0043] General operation of the reaction: Add 50ml of absolute ethanol and 0.6g of metallic sodium (26.2mmol) into a round bottom flask to prepare a sodium alkoxide solution. Add thiourea (1.39g, 18.2mmol) and compound 3 (13.1mmol), stir under reflux, cool down after TLC traces the disappearance of the raw material point, evaporate ethanol under reduced pressure, dissolve the residue with 20ml of water, precipitate out after acidification with HCl, and filter with suction , washed the precipitate with water and diethyl ether, dried in vacuo, and recrystallized with an appropriate solvent to obtain 5-alkyl-6-cyclohexylmethylthiouracil (2).

Embodiment 3

[0044] Example 3 Synthesis of 5-alkyl-6-cyclohexylmethyl-2-substituted uracil (1)

[0045] General operation of the reaction: 5-alkyl-6-cyclohexyl-2-thiouracil (2) (3mmol) and K 2 CO 3 (3.3mmol) was dissolved in 10ml of anhydrous DMF, stirred at room temperature for 30min, added bromide (3.3mmol), continued stirring reaction at 70-80°C, followed by TLC, until the raw material point disappeared (12-24h), stop the reaction , filtered, and the solvent was evaporated under reduced pressure, and the residue was dissolved in 30ml of dichloromethane, washed with saturated brine, anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure to obtain oily or solid crude products, which were purified by column chromatography to obtain pure compounds of various 5-alkyl-6-cyclohexylmethyl-2-substituted uracils (1).

[0046]

[0047] Operation as above, column chromatography separation (P:E=2:1) ​​to obtain white powder 1a, yield: 54%; melting point: 190-192°C,...

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Abstract

The invention discloses 6-cyclohexyl methyl substituted S-DABO type compound, the synthesis method and the application, belonging to the medical technical field. The invention relates to a 5-alkyl-6-cyclohexyl methyl-2-(alkyl, naphthenic base, naphthenic base methyl, substituted phenylethanone) thiouracil type compound, which has general formula as shown in (I): wherein, R1 is alkyl of C1-3; alkyl, naphthenic base and naphthenic base methyl of R2=C1-8 are as shown in (II); wherein, X=OCH3, H, OH, halogen. Chloromethyl cyclohexane or cyclohexyl acetic acid is respectively used as raw material to prepare Beta- keto ester which is made into a key intermediate 5-alkyl-6-cyclohexyl methyl thiouracil together with thiourea through close loop condensation under the catalyzing of sodium alkoxide; target molecule is prepared through S-alkylation guiding C2-side chain. The invention has the advantages of simple and easy synthesis method, obvious anti-HIV virus activity and anti-resistance for the drugs and ability to be used as an alternative for anti-HIV drug.

Description

technical field [0001] The invention belongs to the technical field of medicines, and specifically relates to 6-cyclohexylmethyl substituted S-DABO compounds, their synthesis method and application. Background technique [0002] In the research of anti-HIV drugs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have clear targets and mechanisms of action, have the characteristics of diverse structures, high efficiency and low toxicity, and synergistic effects with other types of anti-HIV drugs. It is of great significance in the research and development of viral drugs (E. De Clercq. Chemistry Biodiversity, 2004, 1, 44-64). However, NNRTIs can easily mutate HIV-1RT and form drug resistance, which limits the antiviral potential of NNRTIs. Therefore, constantly looking for NNRTIs with novel structure, high efficiency and low toxicity to overcome or improve the drug resistance of existing drugs has become the main direction of NNRTIs new drug research and development. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/56A61K31/505A61P31/18
Inventor 何严萍郑永唐李聪张虽栓龙晶欧灵澄
Owner YUNNAN UNIV
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