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Beta-elemene derivatives containing nitrogen and their preparation method and use

A derivative, the technology of elemene, which is applied in the field of application of nitrogen-containing derivatives of β-elemene, can solve the problems of weak anticancer effect, insignificant curative effect, poor stability, etc.

Inactive Publication Date: 2006-10-11
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, elemene milk is used as a second-line anticancer drug in clinical practice. Its anticancer effect is weaker than that of 5-fluorouracil and cisplatin, and its effect on some solid tumors is not obvious.
Moreover, elemene has poor water solubility, and the clinically used dosage form is only emulsion, which has poor stability. Intravenous administration has obvious vascular irritation, and it is difficult to reach the site of action, which limits its clinical application.

Method used

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  • Beta-elemene derivatives containing nitrogen and their preparation method and use
  • Beta-elemene derivatives containing nitrogen and their preparation method and use
  • Beta-elemene derivatives containing nitrogen and their preparation method and use

Examples

Experimental program
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Effect test

Embodiment 1 2

[0027] The preparation of embodiment 1 dichloro-beta-elemene intermediate (II)

[0028] Add 26.0 g (0.127 mol) of β-elemene and 38 mL (0.67 mol) of glacial acetic acid into a three-necked bottle equipped with a mechanical stirrer, cool it to about 5°C with an ice-water bath, and add 198 mL of sodium hypochlorite solution dropwise under stirring ( 1.41mol / L, 0.275mol), the dropwise addition was completed in about 4 hours, and the reaction was continued for 1 hour. The reaction solution was transferred to a 1L separatory funnel, extracted twice with 50mL petroleum ether (60-90°C), the organic phases were combined, washed with water until neutral, and dried over anhydrous sodium sulfate. Petroleum ether was distilled off to obtain 30.5 g of a brown oily substance. GC showed that the product contained 15.0% monochloro-elemene and 54.6% dichloro-elemene. It was separated by silica gel column chromatography and eluted with petroleum ether.

Embodiment 2

[0029] General method for the preparation of embodiment 2 double-substituted β-elemene nitrogen-containing derivatives

[0030] Dissolve 16mmol of amine, 4mmol of dichloro-β-elemene and 16mmo of triethylamine in 10mL of N,N-dimethylformamide and reflux for 8-20h. The formed triethylamine hydrochloride needle crystals were filtered out, and 10 mL of water was added to the filtrate, extracted 4 times with petroleum ether-diethyl ether, the extract was dried and concentrated, and separated by silica gel column chromatography to obtain the product.

Embodiment 3

[0031] Example 3 Synthesis

[0032] Using 3,5-dimethylpiperazine as a raw material, it was prepared according to the general method for preparing nitrogen-containing derivatives of disubstituted β-elemene in Example 2. Add maleic acid acetone solution dropwise to form maleate to obtain white crystals, mp192.0-194.5°C. MS (m / z): 429 (M+1); 1 H-NMR (CDCl 3 )δ (ppm): 1.00 (15H, m), 1.40-1.65 (8H, m), 2.09 (4H, m), 2.60-2.98 (12H, m, ), 4.78-5.03 (6H, m), 5.76- 5.82 (1H,dd)

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Abstract

The invention discloses an A-elemene nitrogenous derivant, it providing the preparation and usage of A-elemene nitrogenous derivant, the structural formula is as picture shows, wherein R represent aliphatic amido of C1-C20, aromatic amido; amido of C1-C20 containing heterocycle; wherein cyclohexane skeleton has three chirality center. This derivant may has some physiologically active like alkaloid; meanwhile, it can increase polarity and making the synthesized derivant has certain alkalinity and it can reach the purpose of improving water-solubility salt-forming with inorganic acid or organic acid.

Description

Technical field: [0001] The present invention relates to new β-elemene nitrogen-containing derivatives and a preparation method thereof, to an intermediate for synthesizing said β-elemene nitrogen-containing derivatives and a preparation method thereof, and to said β-elemene nitrogen-containing derivatives Application of nitrogen derivatives. Background technique: [0002] The β-elemene (I) isolated from the volatile oil of Curcuma wenyujin Y.H.Chen et C.Ling (Curcuma wenyujin Y.H.Chen et C.Ling), also known as Wenzezhu, is a broad-spectrum anti-tumor drug elemene milk developed by my country. (Guo Yongming, Wu Xiuying, Chen Yuren. Isolation and identification of elemene in the volatile oil of Ezhu [J]. Chinese Medicine Bulletin, 1983, 8(30): 31-33.) β-elemene has a relatively strong effect on tumor cells High selectivity, no bone marrow suppression, no obvious liver and kidney toxicity, has dual effects of selectively inhibiting tumor cell proliferation and improving immune ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/04C07D211/06C07D265/30C07D207/04C07D233/00C07D333/06C07D405/12C07C211/40A61K31/381A61K31/40A61K31/435A61K31/495A61K31/496A61K31/13A61P35/00
Inventor 黄金华徐莉英景永奎王敏伟
Owner SHENYANG PHARMA UNIVERSITY
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