N-3-sulfonyl ethylamine substituted-5-cyclopropane spiro-hydantoin derivative as well as preparation method and application thereof

A technology of spirohydantoin and sulfonylethylamide, which can be used in drug combinations, pharmaceutical formulations, and medical preparations containing active ingredients, etc., and can solve problems such as cognitive dysfunction, severe allergic reactions, and adverse reactions. , to achieve the effect of high yield and simple preparation method

Active Publication Date: 2014-08-13
广东智普生命科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the new antiepileptic drugs have partially improved the shortcomings of some antiepileptic drugs, most of the new drugs can still be accompanied by some special adverse reactions, such as cognitive dysfunction, acute eye symptoms, severe allergic reactions, etc.

Method used

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  • N-3-sulfonyl ethylamine substituted-5-cyclopropane spiro-hydantoin derivative as well as preparation method and application thereof
  • N-3-sulfonyl ethylamine substituted-5-cyclopropane spiro-hydantoin derivative as well as preparation method and application thereof
  • N-3-sulfonyl ethylamine substituted-5-cyclopropane spiro-hydantoin derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1: Synthesis of ethyl 1-isocyanate-2,2-dimethylcyclopropanecarboxylate (compound 2)

[0020] Dissolve ethyl 1-carboxy-2,2-dimethylcyclopropanecarboxylate (10 mmol) in anhydrous tetrahydrofuran (30 mL), cool to about -15°C in an ice-salt bath, and then add ethyl chloroformate sequentially (10mmol) and N-methylpyrrolidone (NMM), immediately produced a white precipitate. After the mixture was stirred at this temperature for 20 minutes, NaN3 (10 mmol) was added to the reaction solution, and stirring was continued for 2 hours. After the reaction is complete, add a small amount of water to dissolve the insoluble matter, extract with ethyl acetate, wash with saturated brine (2×10 mL), and dry overnight with anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure to obtain a pale yellow liquid. Dissolve it in toluene (30 mL), install a spherical condenser, oil seal, and heat under stirring until no gas is generated. The solvent is evaporated...

Embodiment 2

[0021] Example 2: Synthesis of 6-(2-aminoethyl)-1,1-dimethyl-4,6-diazaspiro[2.4]heptane-5,7-dione (compound 3)

[0022] At 5°C, the colorless thick liquid compound obtained in Example 1 was dissolved in anhydrous tetrahydrofuran, and the resulting solution was added dropwise to 100mml of ethylenediamine in 50ml of THF until the reaction was complete (the end of the reaction was monitored by TLC). Remove the solvent by pressure distillation, use dichloromethane / methanol as the eluent, and immediately column chromatography to obtain compound 3, namely 6-(2-aminoethyl)-1,1-dimethyl-4,6-diazepine Spiro[2.4]heptane-5,7-dione.

Embodiment 3

[0023] Example 3: N-(2-(1,1-Dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]hept-6-yl)ethyl)methanesulfonamide ( Synthesis of compound 4a)

[0024] Dissolve 6-(2-aminoethyl)-1,1-dimethyl-4,6-diazaspiro[2.4]heptane-5,7-dione (10 mmol) in dry dichloromethane (30 mL), cool to about -5°C in an ice-salt bath, then add triethylamine (30mmol), at this temperature, add dropwise methylene chloride solution dissolved in methanesulfonyl chloride. Continue to stir until the reaction is complete (TLC detection). After the reaction is complete, add a small amount of water to dissolve the insoluble matter, extract with ethyl acetate, wash with saturated brine (2×10 mL), and dry overnight with anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure to obtain a pale yellow liquid. Transfer the crude product to a silica gel column, use petroleum ether / ethyl acetate as eluent, collect the components at Rf = 0.3, and evaporate the solvent under reduced pressure to obtain a whi...

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Abstract

The invention relates to a sulfonyl ethylamine substituted-containing cyclopropane spiro-hydantoin derivative which has a structural formula shown in the specification, wherein R1 is phenyl, substituted phenyl and heterocyclic aryl. A preparation method of the derivative comprises the following steps: reacting ethyl 1-carboxyl-2,2-dimethyl cyclohexane carboxylate with ethyl chloroformate and generating ethyl 1-acyl azide-2,2-dimethyl cyclohexane carboxylate in the presence of NaN3; performing Curtius rearrangement on ethyl 1-acyl azide-2,2-dimethyl cyclohexane carboxylate to generate corresponding isocyanate, reacting isocyanate with ethidene diamine to obtain N-3-(2-amino)-ethyl-5-cyclopropane spiro-hydantoin, and reacting N-3-(2-amino)-ethyl-5-cyclopropane spiro-hydantoin with corresponding sulfonyl chloride under basic conditions to generate a target product, namely the cyclopropane spiro-hydantoin derivative. The cyclopropane spiro-hydantoin derivative is very good in anti-convulsion activity, simple to prepare and relatively high in yield.

Description

technical field [0001] The invention relates to a hydantoin derivative, a preparation method and application thereof. Background technique [0002] Hydantoin, also known as hydantoin, has attracted widespread attention since its discovery in 1861. Some hydantoin derivatives have unique pharmacological activities and are widely used in medicine. Among them, a representative one is phenytoin, whose chemical name is 5-ethyl-5-phenylhydantoin, which is a common drug for the treatment of epilepsy. However, it has been clinically found that long-term use of phenytoin sodium can cause gingival hyperplasia, with large side effects. [0003] Since the 1980s, with the in-depth study of the pathogenesis of epilepsy, the mechanism of action of antiepileptic drugs has been clarified, and some new antiepileptic drugs have been designed on this basis. At present, the new antiepileptic drugs that have been approved for clinical application abroad are: zonisamide, oxcarbazepine, lamotrigi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/02C07D409/12C07D405/12C07D401/12A61K31/4184A61K31/4439A61P25/08
CPCC07D235/02C07D401/12C07D405/12C07D409/12
Inventor 胡先明李金平刘鹏肖玉玲
Owner 广东智普生命科技有限公司
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