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Ligustrazine stilbenoids derivatives, preparation method thereof, medicament composition and use

A technology of stilbene and derivatives of ligustrazine, which is applied in the field of derivative drugs and can solve the problems of short half-life, accumulated poisoning, and fast metabolism

Active Publication Date: 2010-02-03
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Due to fast metabolism and short half-life of ligustrazine in the body, in order to maintain an effective therapeutic concentration of the drug, frequent administration is required clinically, so it is easy to cause accumulation poisoning, and its application is limited, see Xu Rui, Li Yuan, Huang Xi, Ligustrazine Research progress of pharmacokinetics, Journal of Anhui University of Traditional Chinese Medicine, 2002, 21(1): 58-61

Method used

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  • Ligustrazine stilbenoids derivatives, preparation method thereof, medicament composition and use
  • Ligustrazine stilbenoids derivatives, preparation method thereof, medicament composition and use
  • Ligustrazine stilbenoids derivatives, preparation method thereof, medicament composition and use

Examples

Experimental program
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Effect test

Embodiment 1

[0052] Example 1: Preparation of 2-styryl-3,5,6-trimethylpyrazine (A1)

[0053] Take 2-chloromethyl-3,5,6-trimethylpyrazine 5 (1.65g, 9.7mmol) in a two-necked flask, add newly distilled triethyl phosphite (1.92ml, 9.7mmol), mix The liquid was heated to slight boiling, and the reaction was monitored by TLC to complete, then cooled to room temperature. Under ice-salt bath conditions (below -5°C), add anhydrous tetrahydrofuran (10ml) and 60% NaH (mass ratio, 0.78g, 19.4mmol), stir well for 40min, then slowly drop into benzaldehyde (1.03g, 9.7mmol ) and anhydrous tetrahydrofuran (25ml) mixed solution, stirred at room temperature for 12h, TLC monitored that the reaction was complete, extracted with ethyl acetate, anhydrous Na 2 SO 4 After drying, the solvent was evaporated, and the residue was separated by flash column chromatography, the eluent was ethyl acetate:cyclohexane (1:10 volume ratio), recrystallized from methanol, and 2-styryl-3,5 was obtained as yellow crystals. , 6-...

Embodiment 2

[0055] Example 2: 2-(3-hydroxystyryl)-3,5,6-trimethylpyrazine (A2)

[0056] The method described in Example 1, except that the mixture of 3-hydroxybenzaldehyde (1.78g, 9.7mmol) and anhydrous tetrahydrofuran (25ml) was slowly added dropwise, and the eluent was ethyl acetate:cyclohexane (1:5 volume ratio) to obtain 0.9 g of white crystals, yield 40%, mp: 202-204 ° C.

[0057] Spectral analysis data: IR(KBr, cm -1 ): 3055 (v ＝CH ), 1631 (v CH＝CH ), 1607, 1578, 1489, 1468 (v CH＝CH , Ar), 1407 (v C＝N ), 872, 778, 687 (γ ＝CH outside); 1 H-NMR (DMSO, δppm): 9.49 (1H, s, -OH), 7.59 (1H, d, =CH-, J = 15.6Hz), 7.32 (1H, d, =CH-, J = 15.6Hz) , 7.20 (1H, t, Ar-H, J=7.8Hz), 7.13 (1H, d, Ar-H, J=7.7Hz), 7.10 (1H, s, Ar-H), 6.72 (1H, d, Ar-H, J=7.3Hz), 2.56 (3H, s, -CH 3 ), 2.50 (3H, s, -CH 3 ), 2.44 (3H, s, -CH 3 ); 13 C-NMR (DMSO, δppm): 149.41, 178.67, 146.25, 137.63 (pyrazine-C), 157.54, 137.63, 133.02, 129.62, 122.77, 118.26, 115.51, 113.41 (-CH=CH-Ar-C), 21.31 ( -CH 3 ), ...

Embodiment 3

[0058] Example 3: Preparation of 2-(3-chlorostyryl)-3,5,6-trimethylpyrazine (A3)

[0059] The method described in Example 1, except that the mixture of 3-chlorobenzaldehyde (1.46g, 9.7mmol) and anhydrous tetrahydrofuran (25ml) was slowly added dropwise, and the eluent was ethyl acetate:cyclohexane (1:5 volume ratio) to obtain 0.7 g of yellow crystals, yield 27%, mp: 92-94°C.

[0060] Spectral analysis data: IR(KBr, cm -1 ): 3054 (v ＝CH ), 1631 (v CH＝CH ), 1589, 1559, 1473 (v CH＝CH , Ar), 1424, 1405 (v C＝N ), 872, 799, 685 (γ ＝CH out of plane); 1H-NMR (CDCl 3, δppm): 7.73 (1H, d, = CH-, J = 15.6Hz), 7.29 (1H, d, = CH-, J = 15.7Hz), 7.60 (1H, s, Ar-H), 7.47 (1H , d, Ar-H, J=7.6Hz), 7.32 (1H, t, Ar-H, J=7.9Hz), 7.29 (1H, d, Ar-H, J=7.4Hz), 2.64 (3H, s ,-CH 3 ), 2.56 (3H, s, -CH 3 ), 2.54 (3H, s, -CH 3 ); 13 C-NMR (CDCl 3 , δppm): 150.62, 149.27, 147.29, 144.85 (pyrazine-C), 138.91, 134.72, 132.52, 129.93, 128.19, 126.84, 1125.50, 124.39 (-CH=CH-Ar-C); 21.78, 20.96 (3...

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Abstract

The invention relates to a kind of ligustrazine derivant, preparation method and medicinal compound and its application, belonging to chuanxiong rhizome derivant medicine technique. The structure general formula is as that: Ar is hydroxybenzene, fluorophenyl, chlorphenyl, methylbenzene, methoxybenzene, nitrobenzene, cyanobenzene, furan group, ligustrazine or thiofuran. Said preparation method comprises following steps: mixing intermediate 2- chloromethyl- 3, 5, 6- trimethyl pyrazine and halogenated benzyl, triethyl phosphite; heating and refluxing, adding waterless tetrahydrofuran and NaH at tetrahydrofuran bath condition, dropping mixing solution of aromatic aldchyde and waterless tetrahydrofuran, stirring, extracting, drying, filtering, steaming to remove disslovant, separating residueswith fast column chromatography, recrystallizing with methanol, and getting ligustrazine derivant. Said product and medical findings can be used to produce medicinal compound, and medicine for preventing angiocardiopathy and cerebrovascular diseases such as ischemic disease, atherosclerosis and coronary disease.

Description

(1) Technical field [0001] The invention relates to a derivative and a preparation method thereof, in particular to a tetramethylpyrazine stilbene derivative and a preparation method thereof, and to a pharmaceutical composition composed of the derivative and an auxiliary agent, belonging to the technical field of derivative drugs. (2) Background technology [0002] Cardiovascular and cerebrovascular diseases are clinical common and frequently-occurring diseases with the highest mortality and disability rates, and are identified by the World Health Organization (WHO) as the "number one killer" that endangers human health. According to the data released by the World Health Organization in 2006, about 15 million people die of cardiovascular and cerebrovascular diseases in the world every year, accounting for about 30% of the total death population. At present, there are many drugs for clinical treatment of cardiovascular and cerebrovascular diseases, but they generally have dis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D241/12C07D409/06C07D407/06A61K31/4965A61K31/497A61P9/10
Inventor 刘新泳邓利娟
Owner SHANDONG UNIV
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