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Beta-elemene monosubstituted amine derivatives, synthetic method and use thereof

A technology for elemene mono- and synthesis method, which is applied in the field of novel β-elemene mono-substituted amine derivatives and their synthesis, can solve the problems of poor water solubility, limited clinical application and the like, and achieves improved water solubility and anticancer activity. High, high bioavailability effect

Inactive Publication Date: 2008-08-13
SHANGHAI INST OF APPLIED PHYSICS - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] β-Elemene has been used clinically as a traditional Chinese medicine, but its clinical application is limited due to its extremely poor water solubility. Therefore, how to improve its water solubility has been attracting much attention

Method used

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  • Beta-elemene monosubstituted amine derivatives, synthetic method and use thereof
  • Beta-elemene monosubstituted amine derivatives, synthetic method and use thereof
  • Beta-elemene monosubstituted amine derivatives, synthetic method and use thereof

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Experimental program
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Effect test

Embodiment 1～24

[0030] Embodiment 1~24β-elemene monosubstituted amine derivative

[0031] Table 1 and Table 2 give examples 1 to 24 of β-elemene monosubstituted amine derivatives whose specific structures are A or B in formula I.

[0032]

[0033] Formula I

Embodiment 1～18

[0036] Table 2 Examples 19-24 of β-elemene monosubstituted amine derivatives

[0037]

[0038] The synthesis of reference example β-elemene chloride

[0039] According to the method of literature (Jia Weimin, synthesis, structure and structure-activity research of new anticancer drug β-elemene and its derivatives, doctoral thesis of Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 1991), the method for synthesizing β-elemene chloride, specifically Proceed as follows:

[0040] Dissolve 0.01mol β-elemene in 10mL dichloromethane, add 2mL formic acid, control the temperature at 0-5°C, slowly add 15mL sodium hypochlorite solution dropwise within 2 hours, and continue the reaction for 3-5 hours. After the reaction is complete, add saturated aqueous sodium bicarbonate solution to adjust the pH to 7-8, separate the reaction mixture and separate the organic phase. Sodium drying, filtration, removal of solvent dichloromethane, to obtain a light yellow oil, ...

Embodiment 1

[0043] Synthesis of method embodiment 1 β-elemene monosubstituted cyclohexylamine

[0044]

[0045] Mix 4.5mmol cyclohexylamine, 9mmol β-elemene chloride mixture (containing β-elemene chloride 4.5mmol), 9mmol NaOH and 5mL acetonitrile, and react at 90°C for 2 hours under stirring. After the reaction is completed, cool down, add 20mL saturated brine, then extract 3 times with 10mL dichloromethane, combine the organic phases, and wash the organic matter with anhydrous Na 2 SO 4 Dry, filter, and remove the solvent dichloromethane to obtain a crude product, which can be obtained by silica gel column chromatography and gradient elution with dichloromethane and methanol (volume ratio 20:1). 1 H-NMR identification results are as follows:

[0046] 1 H-NMR (CDCl 3 , TMS, 500MHz), δ0.99(s, 3H), 1.17-1.30(m, 4H), 1.35-1.59(m, 10H), 1.71(s, 3H), 1.78-1.90(m, 2H), 2.05 -2.26(m, 2H), 2.91-3.02(m, 1H), 3.50-3.66(m, 2H), 4.57(s, 1H), 4.82(s, 1H), 4.88(s, 1H), 4.90-4.92 (m, 1H), 5.23 (s...

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Abstract

The invention discloses beta-elemene monosubstituted amine derivatives represented by formula I, and pharmaceutically acceptable salts thereof, wherein, R1 is H, R2 is n-butyl, tert-butyl, cyclohexyl, cyclopentyl, cyclooctyl, isopropyl, p-carboxylphenyl, p-carboxy phenoxyphenylmethyl or phenylmethyl; or both R1 and R2 are ethyl or -CH2COOH; or R1NR2 is imidazole. The invention also discloses a synthesis method of beta-elemene monosubstituted amine derivatives, comprising: dissolving beta-elemene chlorine substitutes and amine in solvent, and adding alkali catalysts to perform reaction. The invention further dicloses application of beta-elemene monosubstituted amine derivatives as reaction intermediates in synthesizing other beta-elemene derivatives, and in preparing anticancer drugs. Compared with beta-elemene, the beta-elemene monosubstituted amine derivatives of the invention have better water-solubility and higher anticancer activity.

Description

technical field [0001] The present invention relates to a novel β-elemene monosubstituted amine derivative and its synthesis method and application. Background technique [0002] Cancer is a common disease that seriously endangers people's life and health at present. β-Elemene is the first anti-cancer active ingredient extracted from the rhizome of Zingiberaceae Wen Curcuma (Wen Curcuma) in my country in recent years. Its molecular formula is C 15 h 24 , the structural formula is shown in formula III. [0003] Formula III [0004] β-Elemene has been used clinically as a traditional Chinese medicine, but its clinical application is limited due to its extremely poor water solubility. Therefore, how to improve its water solubility has been attracting much attention. [0005] Jia Weimin conducted a systematic study on the structure-activity relationship of β-elemene, and the results showed that the anticancer activity of β-elemene is closely related to the three isolated do...

Claims

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Application Information

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IPC IPC(8): C07C211/25C07C211/27C07C229/54C07C229/38A61K31/13A61K31/195A61P35/00
Inventor 沈玉梅刘贵峰成康民孙艳红任云峰冯翠兰
Owner SHANGHAI INST OF APPLIED PHYSICS - CHINESE ACAD OF SCI
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