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Ligustrazine-butyphthalide combination compound, preparation method of ligustrazine-butyphthalide combination compound, and application of ligustrazine-butyphthalide combination compound to pharmaceuticals

A technology of ligustrazine and butylphthalide, applied in the field of Ligustrazine-butylphthalide combination compound and its preparation, can solve the problems of short half-life, poor fat solubility, poor water solubility, etc., to prolong half-life, improve bioavailability, The effect of improving fat solubility

Active Publication Date: 2017-07-07
GUIZHOU MEDICAL UNIV
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Problems solved by technology

[0005] The technical problem solved by the present invention is: Ligustrazine has poor fat solubility as a drug, fast metabolism and short half-life, and butylphthalide has poor water solubility as a drug. The technical means adopted are: optimize the structure of Ligustrazine and butylphthalide, design, synthesize Ligustrazine-butylphthalide combination compound, the invention provides a ligustrazine-butylphthalide combination compound, a preparation method thereof, and an application in medicine. The synthesized ligustrazine-butylphthalide combination compound can increase the ligustrazine The fat-solubility of butylphthalide and the water-solubility of butylphthalide make it enter the human body and undergo the action of esterase enzymes. The efficacy of the two can achieve a synergistic effect, prolong the half-life of the drug, and improve its bioavailability

Method used

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  • Ligustrazine-butyphthalide combination compound, preparation method of ligustrazine-butyphthalide combination compound, and application of ligustrazine-butyphthalide combination compound to pharmaceuticals
  • Ligustrazine-butyphthalide combination compound, preparation method of ligustrazine-butyphthalide combination compound, and application of ligustrazine-butyphthalide combination compound to pharmaceuticals
  • Ligustrazine-butyphthalide combination compound, preparation method of ligustrazine-butyphthalide combination compound, and application of ligustrazine-butyphthalide combination compound to pharmaceuticals

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preparation example Construction

[0027] The preparation method of ligustrazine-butylphthalide complex compounds of the present invention comprises the following steps: using phthalic anhydride and ligustrazine as starting materials, through NBS free radical bromination, n-butyllithium nucleophilic addition , P-toluenesulfonic acid catalytic dehydration, ester hydrolysis under alkaline conditions, Pd / C plus H 2 Reduction, esterification reaction, Ligustrazine - butylphthalide splicing compounds were obtained. The specific reaction of synthetic target compound 1, 2, 3 is as follows:

[0028]

[0029] Synthetic routes of target compounds 1, 2, 3

Embodiment 1

[0031] The preparation of (3,5,6-trimethylpyrazin-2-yl) methyl-2-pentanoyl benzoate (1) comprises the following steps:

[0032] (1) Synthesis of 2-bromomethyl-3,5,6-trimethylpyrazine (4): Add 20.0g (348mmol) TMP, 18.2g (103mmol) N-bromosuccinate in a 250mL round bottom flask imide (NBS), with 80mL CCl 4 After dissolving the raw material, irradiate with a 60W incandescent lamp and reflux for 12 hours. After TLC detects that the reaction is complete, filter it with suction and evaporate the filtrate to obtain the crude product, which is purified by silica gel column chromatography with V (petroleum ether): V (ethyl acetate) = 12:1 to obtain 15.4 g of white solid, 70% yield, m.p.41-42°C. 1 HNMR (CDCl 3 ,400MHz), δ:4.55(s,2H),2.58(s,3H),2.51(s,3H),2.50(s,3H);HRMS:Calcd.for C 8 h 12 BrN 2 (M+H):215.0175. Found: 215.0176.

[0033](2) Synthesis of 3Z-n-butenylphthalide (6): Add 20.0g (135mmol) phthalic anhydride 5 in a 500mL three-necked bottle, nitrogen protection, add 200mL a...

Embodiment 2

[0037] 2-{[1-(3,5,6-Trimethylpyrazin-2-yl)methoxy]pentyl}benzoic acid (2) and (3,5,6-trimethylpyrazin-2 - Base) the preparation of methyl-2-{1-[(3,5,6-trimethylpyrazin-2-yl) methoxy] pentyl} benzoate (3), comprises the following steps:

[0038] (1) Synthesis of 3-n-butylphthalide (NBP): In a 150mL round bottom flask, weigh 2.00g (10.6mmol) of intermediate 6, dilute and dissolve with 60mL of absolute ethanol, add 100mg of 10% Pd / C , replacing the hydrogen, and stirring overnight. After the completion of the reaction as detected by TLC, it was filtered through diatomaceous earth and concentrated to obtain 1.99 g of a colorless oily liquid with a yield of 99%. 1 HNMR (CDCl 3 , 400MHz), δ: 7.91(d, 1H, J=7.6Hz), 7.67(td, 1H, J=7.6, 1.0Hz), 7.54(t, 1H, J=7.6Hz), 7.45(d, 1H, J=7.6Hz), 5.49(dd, 1H, J=8.0, 4.8Hz), 2.08-2.00(m, 1H), 1.80-1.74(m, 1H), 1.50-1.34(m, 4H), 0.92(t ,3H,J=6.8Hz); HRMS: Calcd.for C 12 h 14 o 2 Na(M+Na):213.0886. Found: 213.0884.

[0039] (2) Synthesis of...

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Abstract

The invention discloses a ligustrazine-butyphthalide combination compound, a preparation method of the ligustrazine-butyphthalide combination compound and an application of the ligustrazine-butyphthalide combination compound to pharmaceuticals. The ligustrazine-butyphthalide combination compound has the following structural formula I as in the description. The phthalic anhydride and the ligustrazine are taken as starting materials, bromization, nucleophilic addition, catalytic dehydration, ester hydrolysis, reduction and esterification reactions are conduced to prepare the ligustrazine-butyphthalide combination compound; a pharmaceutical composition takes the ligustrazine-butyphthalide combination compound as an active pharmaceutical ingredient and is a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, intermedium or a composition. The prepared ligustrazine-butyphthalide combination compound has an excellent effect of inhibiting in-vitro platelet aggregation (ADP) induced platelet aggregation, has a better in-vivo pharmacokinetics properties, and can be used for preventing and treating cardiovascular and cerebrovascular diseases, vascular senile dementia and the complications.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to ligustrazine-butylphthalide combination compound, a preparation method thereof, and an application in medicine. Background technique [0002] With the continuous improvement of people's living standards, the improvement of dietary nutrition and structure, the reduction of labor intensity and the emergence of social aging, cardiovascular and cerebrovascular diseases have become one of the most important causes of human morbidity and death. According to the report of the World Health Organization, people who die from cardiovascular and cerebrovascular diseases account for 1 / 3 of the total death toll in the world every year. The 2008 Statistical Bulletin on the Development of China's Health Services shows that the number of deaths from cardiovascular and cerebrovascular diseases has accounted for 40.3% of the total death toll in the country, and the most rapi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/12A61K31/4965A61K31/497A61P7/02A61P9/00A61P1/00A61P11/00A61P25/28
CPCC07D241/12
Inventor 汤磊樊玲玲刘健陈文章朱桃
Owner GUIZHOU MEDICAL UNIV
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