Resveratrol A ring N (CH)3)2Base derivatives, preparation method and application thereof
阅读说明：本技术 一种白藜芦醇a环n(ch3)2基衍生物及其制备方法和应用 (Resveratrol A ring N (CH)3)2Base derivatives, preparation method and application thereof ) 是由 刘展 刘索思 张渝 揭敏 吴维智 王向阳 蔡华 于 2020-08-20 设计创作，主要内容包括：本发明提供了一种白藜芦醇A环N(CH<Sub>3</Sub>)<Sub>2</Sub>基衍生物及其制备方法和应用,属于医药技术领域。本发明提供了一种具有式I所示的结构白藜芦醇A环N(CH<Sub>3</Sub>)<Sub>2</Sub>基衍生物,作为钠氢交换蛋白-1(NHE1)受体拮抗剂靶向性作用于NHE1受体,并且同时抑制磷脂酰肌醇3-激酶/蛋白质丝氨酸苏氨酸激酶(PI3K/AKT)信号通路和Janus激酶/信号转导与转录激活子(JAK/STAT)这2条信号传导通路,起到治疗酒精性脂肪肝的作用。<Image he="292" wi="700" file="DDA0002641580810000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides resveratrol A-ring N (CH) 3 ) 2 A derivative, a preparation method and application thereof, belonging to the technical field of medicine. The invention provides resveratrol A ring N (CH) with a structure shown in a formula I 3 ) 2 The derivative, as a sodium hydrogen exchanger-1 (NHE1) receptor antagonist, acts on an NHE1 receptor in a targeting way, and simultaneously inhibits 2 signal conduction paths of a phosphatidylinositol 3-kinase/protein serine threonine kinase (PI3K/AKT) signal path and a Janus kinase/signal transduction and transcription activator (JAK/STAT), thereby playing a role in treating alcoholic fatty liver.)
1. Resveratrol A ring N (CH)3)2A group derivative having the structure shown in formula I:
2. resveratrol A ring N (CH) as in claim 13)2The preparation method of the derivative is characterized by comprising the following steps:
mixing diethyl phosphite, an organic solvent, NaH and 4-methoxybenzyl bromide to carry out debromination reaction to obtain a compound with a structure shown in a formula 1;
mixing 4-dimethylamino salicylaldehyde, an organic solvent, chloromethyl methyl ether and diisopropylethylamine for a substitution reaction to obtain a compound with a structure shown in a formula 2;
mixing a compound with a structure shown in a formula 1, a compound with a structure shown in a formula 2, an organic solvent and NaH for a condensation reaction to obtain a compound with a structure shown in a formula 3;
mixing the compound with the structure shown in the formula 3, tert-butyl alcohol and pyridinium p-toluenesulfonate, and refluxing to obtain resveratrol A ring N (CH) with the structure shown in the formula I3)2A derivative of phenyl;
3. the preparation method according to claim 2, wherein the debromination reaction time is 1-3 hours.
4. The method according to claim 2, wherein the time for the substitution reaction is 10 to 30 min.
5. The method according to claim 2, wherein the condensation reaction is carried out at a temperature of 0 to 100 ℃ for 1 to 3 hours.
6. The preparation method according to claim 2, wherein the reflux temperature is 90-100 ℃ and the reflux time is 1-3 h.
7. The preparation method according to claim 2, wherein the molar ratio of the compound having the structure represented by formula 3 to the pyridinium p-toluenesulfonate is 1:2 to 2.1.
8. Resveratrol A ring N (CH) as in claim 13)2The derivative or resveratrol A ring N (CH) prepared by the preparation method of any one of claims 2-73)2The application of the derivative in preparing medicines for treating alcoholic fatty liver is provided.
9. The use of claim 8, wherein the medicament for treating alcoholic fatty liver disease comprises an effective amount of resveratrol A ring N (CH) having a structure shown in formula I3)2The derivative, the stereoisomer and the pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers, auxiliary materials, excipients and diluents.
10. The use of claim 8, wherein the dosage form of the drug for treating alcoholic fatty liver disease comprises a pharmaceutically acceptable dosage form of tablet, injection, capsule, granule, pill, powder, oral liquid, sustained release preparation, controlled release preparation or nano preparation.
Technical Field
The invention relates to the technical field of medicines, in particular to resveratrol A-ring N (CH)3)2A derivative, a preparation method and application thereof.
Background
Alcoholic fatty liver is a liver disease caused by long-term drinking, and is one of the types of alcoholic liver diseases. Alcoholic fatty liver is a common pathological change of the liver, not an independent disease. When liver cells are damaged, alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) overflow causes the ALT and AST contents in serum to be increased, so the degree of damage of the liver cells of the alcoholic fatty liver patients and the repair condition of the liver cells can be reflected by measuring the ALT and AST activities in the serum.
At present, the clinical treatment of alcoholic fatty liver does not have a unified standard, and commonly used auxiliary intervention means comprise insulin sensitizers, lipid regulating drugs, antioxidants and the like. Common drugs for treating alcoholic fatty liver include: western medicines such as choline methionine, lecithin, silymarin, inosine, coenzyme A, carnitine orotate and the like mainly have the functions of protecting liver cells and increasing fat transportation; ② antioxidants such as resveratrol, reduced glutathione, taurine, vitamin E, mainly for inhibiting cholesterol, triglyceride oxidation and lipid accumulation; ③ the Chinese herbs such as curcuma longa, prepared fleece-flower root and hawthorn fruit, etc., mainly have the functions of reducing blood fat and preventing cholesterol from depositing in the liver.
Disclosure of Invention
In view of the above, the present invention aims to provide a resveratrol A ring N (CH)3)2A derivative, a preparation method and application thereof. The invention providesResveratrol A Ring N (CH) supply3)2The derivative has therapeutic effect on alcoholic fatty liver.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides resveratrol A-ring N (CH)3)2A group derivative having the structure shown in formula I:
the invention also provides resveratrol A ring N (CH) in the technical scheme3)2A process for the preparation of a derivative comprising the steps of:
mixing diethyl phosphite, an organic solvent, NaH and 4-methoxybenzyl bromide to carry out debromination reaction to obtain a compound with a structure shown in a
mixing 4-dimethylamino salicylaldehyde, an organic solvent, chloromethyl methyl ether and diisopropylethylamine for a substitution reaction to obtain a compound with a structure shown in a
mixing a compound with a structure shown in a
mixing the compound with the structure shown in the
preferably, the time of the debromination reaction is 1-3 h.
Preferably, the time of the substitution reaction is 10-30 min.
Preferably, the condensation reaction is carried out at the temperature of 0-100 ℃ for 1-3 h.
Preferably, the reflux temperature is 90-100 ℃, and the reflux time is 1-3 h.
Preferably, the molar ratio of the compound with the structure shown in the
The invention also provides resveratrol A ring N (CH) in the technical scheme3)2The resveratrol A ring N (CH) prepared by the preparation method of the base derivative or the technical scheme3)2The application of the derivative in preparing medicines for treating alcoholic fatty liver is provided.
Preferably, the drug for treating alcoholic fatty liver disease comprises an effective dose of resveratrol A ring N (CH) with a structure shown in formula I3)2The derivative, the stereoisomer and the pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers, auxiliary materials, excipients and diluents.
Preferably, the dosage form of the drug for treating alcoholic fatty liver disease comprises pharmaceutically acceptable dosage forms of tablets, injections, capsules, granules, pills, powders, oral liquids, sustained release preparations, controlled release preparations or nano preparations.
The invention provides resveratrol A ring N (CH) with a structure shown in a formula I3)2The derivative, as a sodium hydrogen exchanger-1 (NHE1) receptor antagonist, acts on an NHE1 receptor in a targeting way, and simultaneously inhibits 2 signal conduction paths of a phosphatidylinositol 3-kinase/protein serine threonine kinase (PI3K/AKT) signal path and a Janus kinase/signal transduction and transcription activator (JAK/STAT), thereby playing a role in treating alcoholic fatty liver.
The invention also provides resveratrol A ring N (CH) in the technical scheme3)2The preparation method of the derivative has the advantages of mild conditions, low raw material cost, easy operation and high yield.
Drawings
FIG. 1 shows resveratrol A ring N (CH) prepared by the present invention3)2The signal path diagram of the mechanism of treating alcoholic fatty liver by the derivative is shown;
FIG. 2 shows that resveratrol A ring N (CH) prepared by the present invention3)2Reaction scheme of the derivatives;
FIG. 3 shows the effect of different experimental groups on the initial body mass;
FIG. 4 is a graph of the effect of different experimental groups on end body mass;
FIG. 5 is the effect of different experimental groups on hepatic index;
FIG. 6 is a graph of the effect of different experimental groups on serum TG content;
FIG. 7 is a graph of the effect of different experimental groups on serum TC levels;
FIG. 8 is a graph of the effect of different experimental groups on serum HDL-C levels;
FIG. 9 is a graph of the effect of different experimental groups on serum ALT levels;
FIG. 10 is a graph of the effect of different experimental groups on serum AST levels;
FIG. 11 shows the effect of different experimental groups on serum SOD levels;
FIG. 12 is a graph of the effect of different experimental groups on serum MDA content;
FIG. 13 shows the effect of different experimental groups on the subregional structure of the liver (400X);
FIG. 14 is a graph of the effect of different experimental groups on immunohistochemistry for hepatic NHE-1 expression (400X);
FIG. 15 is a graph of the effect of different experimental groups on hepatic NHE-1 expression of WesternBlot (400X);
FIG. 16 is a statistical plot of the effect of different experimental groups on hepatic NHE-1 expression of WesternBlot;
FIG. 17 shows the effect of different experimental groups on hepatic PI3K and STAT immunofluorescence (400 ×).
Detailed Description
The invention provides resveratrol A-ring N (CH)3)2A group derivative having the structure shown in formula I:
in the invention, the resveratrol A ring N (CH) with the structure shown in formula I3)2Chemical name of the derivative is 2-dihydroxy-4' -methoxy-4-dimethylamino-1, 2-diphenylethylene ((E) -5- (dimethyllami)no) -2- (4-methoxystyryl) phenol) with molecular formula C17H19NO2The molecular weight is 269.
FIG. 1 shows resveratrol A ring N (CH)3)2Resveratrol A-Ring N (CH) as a signaling pathway map for the treatment of fatty liver3)2The derivative, as a sodium hydrogen exchanger-1 (NHE1) receptor antagonist, acts on an NHE1 receptor in a targeting way, and simultaneously inhibits 2 signal conduction paths of a phosphatidylinositol 3-kinase/protein serine threonine kinase (PI3K/AKT) signal path and a Janus kinase/signal transduction and transcription activator (JAK/STAT), thereby playing a role in treating alcoholic fatty liver.
The invention also provides resveratrol A ring N (CH) in the technical scheme3)2A process for the preparation of a derivative comprising the steps of:
mixing diethyl phosphite, an organic solvent, NaH and 4-methoxybenzyl bromide to carry out debromination reaction to obtain a compound with a structure shown in a
mixing 4-dimethylamino salicylaldehyde, an organic solvent, chloromethyl methyl ether and diisopropylethylamine for a substitution reaction to obtain a compound with a structure shown in a
mixing a compound with a structure shown in a
mixing the compound with the structure shown in the
in the present invention, the raw materials used in the present invention are all commercially available products unless otherwise specified.
In the present invention, the reaction principle of the preparation method is shown in fig. 2.
The invention mixes diethyl phosphite, organic solvent, NaH and 4-methoxybenzyl bromide to carry out debromination reaction, and obtains a compound with a structure shown in a
In the present invention, the amount ratio of diethyl phosphite, organic solvent, NaH and 4-methoxybenzyl bromide is preferably 10 mmol: 8mL of: 15 mmol: 15 mmol.
In the invention, the time of the debromination reaction is preferably 1-3 h, and the temperature of the debromination reaction is preferably room temperature, so that additional heating or cooling is not required.
According to the invention, preferably, after diethyl phosphite is dissolved in DMF, NaH is added under the condition of ice-water bath, and 4-methoxybenzyl bromide is added after half an hour.
After the debromination reaction is finished, a saturated ammonium chloride solution is preferably added to quench the reaction, then dichloromethane is used for extraction, and column chromatography purification is carried out after reduced pressure distillation to obtain the compound with the structure shown in
The method comprises the step of mixing 4-dimethylamino salicylaldehyde, an organic solvent, chloromethyl methyl ether and diisopropylethylamine for substitution reaction to obtain a compound with a structure shown in a
In the invention, the dosage ratio of the 4-dimethylamino salicylaldehyde, the organic solvent, the chloromethyl methyl ether and the diisopropylethylamine is preferably 10 mmol: 40mL of: 15 mmol: 15 mmol.
In the present invention, the time of the substitution reaction is preferably 10 to 30 min.
In the invention, 4-dimethylamino salicylaldehyde is preferably dissolved in dichloromethane, and chloromethyl methyl ether and diisopropylethylamine are added under the condition of ice-water bath.
After the substitution reaction is finished, preferably, saturated ammonium chloride solution is added to quench the reaction, then dichloromethane is used for extraction, and column chromatography purification is carried out after reduced pressure distillation to obtain the compound with the structure shown in the
After obtaining the compounds with the structures shown in the
In the present invention, the compound having the structure represented by
In the invention, the condensation reaction is preferably carried out at the temperature of 0-100 ℃ for 1-3 h. In the present invention, the condensation reaction is preferably carried out in an oil bath.
According to the invention, the compound with the structure shown in the
After the condensation reaction is finished, the condensation product is preferably naturally cooled to room temperature, then a saturated ammonium chloride solution is added for quenching reaction, then dichloromethane is used for extraction, and column chromatography purification is carried out after reduced pressure distillation, so as to obtain the compound with the structure shown in the
After obtaining the compound with the structure shown in the
In the invention, the reflux temperature is preferably 90-100 ℃, more preferably 95 ℃, and the time is preferably 1-3 h. In the present invention, the reflux is preferably carried out in an oil bath pan.
In the invention, the molar ratio of the compound having the structure shown in the
In the present invention, the amount ratio of the compound having the structure represented by
According to the invention, the compound with the structure shown in the
After the reflux is finished, the reflux product is preferably naturally cooled to room temperature, water is added for quenching reaction, then dichloromethane is used for extraction, and after reduced pressure distillation and column chromatography purification, the compound with the structure shown in the
The invention also provides resveratrol A ring N (CH) in the technical scheme3)2The resveratrol A ring N (CH) prepared by the preparation method of the base derivative or the technical scheme3)2The application of the derivative in preparing medicines for treating alcoholic fatty liver is provided.
In the invention, the drug for treating alcoholic fatty liver disease preferably comprises resveratrol A ring N (CH) with the structure shown in formula I, wherein the effective dose is more than or equal to 10mg/kg3)2The derivative, the stereoisomer and the pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers, auxiliary materials, excipients and diluents. In the present invention, the effective dose is preferably not less than 10 mg/kg.
In the invention, the dosage form of the drug for treating alcoholic fatty liver preferably comprises a pharmaceutically acceptable dosage form of tablets, injections, capsules, granules, pills, powder, oral liquid, sustained release preparations, controlled release preparations or nano preparations.
To further illustrate the present invention, the following examples are given to provide resveratrol A ring N (CH)3)2The derivatives, the preparation and use thereof, and the microbial fuel cell on the sea bottom will be described in detail, but they should not be construed as limiting the scope of the present invention.
- 上一篇：一种医用注射器针头装配设备
- 下一篇：一种制备正壬酸香草酰胺的方法