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Beta-elemene diamine derivatives, synthesis method and use thereof

A technology of elemene diamine and synthesis method, which is applied in the direction of amine active ingredients, drug combination, chemical instrument and method, etc., can solve the problems of poor water solubility and limited clinical application, and achieve good water solubility and good antitumor drug high efficacy and high bioavailability

Inactive Publication Date: 2008-08-13
SHANGHAI INST OF APPLIED PHYSICS - CHINESE ACAD OF SCI
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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 diamine derivatives, synthesis method and use thereof
  • Beta-elemene diamine derivatives, synthesis method and use thereof
  • Beta-elemene diamine derivatives, synthesis method and use thereof

Examples

Experimental program
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Effect test

Embodiment 1～9

[0038] Embodiment 1~9β-elemene diamine derivative

[0039] Table 1 shows Examples 1-9 of β-elemene diamine derivatives with the structural formula shown in Formula I.

[0040] Formula I

[0041] Table 1 Examples 1-9 of β-elemene diamine derivatives

[0042]

[0043] The synthesis of reference example β-elemene chloride

[0044] 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:

[0045]Dissolve 0.01mol β-elemene in 10mL of dichloromethane, add 2mL of formic acid, control the temperature at 0-5°C, slowly add 15mL of 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 ...

Embodiment 2

[0052] Method Example 2 β-elemene monosubstituted hexamethylenediamine derivative (compound of formula I, wherein n=0, m=3)

[0053]

[0054] The β-elemene chlorinated mixture was mixed with NH 2 (CH 2 CH 2 ) 3 NHBoc was dissolved in acetonitrile and Na 2 CO 3 . β-elemene chloride and NH 2 (CH 2 CH 2 ) 3 The molar ratio of NHBoc is 1:2; 2 CO 3 The molar ratio is 1:10. It can be reacted for 3 hours at 120°C. The identification results are as follows:

[0055] 1 H-NMR (CDCl 3 , TMS, 400MHz), δ: 0.99(s, 3H), 1.25-1.80(m, 15H), 1.44(s, 9H), 1.71(s, 3H), 2.01-2.11(m, 1H), 2.97(t , J=7.65, 2H), 3.08(q, J=6.34, 2H), 3.64(s, 2H), 4.58(s, 1H), 4.82(s, 1H), 4.88(s, 1H), 4.92(d , J=3.74, 1H), 5.18(s, 1H), 5.23(s, 1H), 5.80(dd, J=17.76, 10.54, 1H).

Embodiment 3

[0056] Method Example 3 Compound of Formula I (n=2, m=1)

[0057]

[0058] The β-elemene chlorinated mixture was mixed with NH 2 (CH 2 CH 2 O) 2 CH 2 CH 2 NHBoc was dissolved in acetonitrile, KOH and XI were added. β-elemene chloride and NH 2 (CH 2 CH 2 O) 2 (CH 2 CH 2 ) 1 The molar ratio of NHBoc is 1:3; the molar ratio to KOH is 1:5; the molar amount of KI is 5% of the molar amount of β-elemene chloride. React at 70°C for 15 hours, and the identification results are as follows:

[0059] 1 H-NMR (CDCl 3 , TMS, 500MHz), δ: 1.00(s, 3H), 1.30-1.53(m, 10H), 1.44(s, 9H), 1.53-1.65(m, 2H), 1.71(s, 3H), 1.85-1.92 (m, 2H), 2.08-2.23(m, 2H), 2.88(t, J=7.5, 2H), 3.08(d, J=4.61, 2H), 3.54-3.63(m, 2H), 4.58(s, 1H), 4.83(s, 1H), 4.89(s, 1H), 4.91(d, J=6.66, 1H), 5.26(s, 1H), 5.35(s, 1H), 5.82(dd, J=17.29, 11.11, 1H).

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Abstract

The invention beta-elemene diamine derivatives represented by formula I, and pharmaceutically acceptable salts thereof, wherein, R1 and R2 are H or -NH(CH2CH2O)n(CH2CH2)mNH-Boc independently, but are not H at the same time; Boc is t-butoxycarbonyl; m is an integer of 1-3; n is an integer of 0-112. The also discloses a synthesis method of beta-elemene diamine derivatives, comprising: dissolving beta-elemene chlorine substitutes and NH2(Ch2CH2O)n(CH2CH2)mNHBoc in solvent, and adding alkali catalysts to perform reaction. The invention further dicloses application of beta-elemene diamine derivatives in preparing anticancer drugs, and as reaction intermediates in preparing other beta-elemene derivatives. The beta-elemene monosubstituted amine derivatives of the invention have good water-solubility and higher anticancer activity than that of beta-elemene.

Description

technical field [0001] The present invention relates to a novel β-elemene diamine derivative and its pharmaceutically acceptable salt, its synthesis method and its application in the fields of medicine and synthesis of β-elemene derivatives. 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 as follows: [0003] [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. In the prior art, the main work is to improve water solubility by synthesizing β-elemene derivatives. [0005] Jia Weimin once conducted a...

Claims

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Application Information

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IPC IPC(8): C07C217/08C07C213/08A61K31/13A61P35/00
Inventor 沈玉梅任云峰成康民孙艳红王谋华
Owner SHANGHAI INST OF APPLIED PHYSICS - CHINESE ACAD OF SCI
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