Caffeoylquinic acid derivative and preparation method and application thereof
阅读说明：本技术 一种咖啡酰奎宁酸类衍生物及其制备方法和用途 (Caffeoylquinic acid derivative and preparation method and application thereof ) 是由 田瑜 许旭东 郭鹏 吴崇明 尚海 于 2019-01-10 设计创作，主要内容包括：本发明公开了一种咖啡酰奎宁酸类衍生物及其制备方法和用途,具有通式(Ⅰ)所示的结构。本发明以3-O-咖啡酰奎宁酸为原料,保留3-O-咖啡酰奎宁酸的结构骨架,在1位羧基上引入不同胺基取代基,4,5位羟基被缩酮取代或裸露,合成了新型的具有降脂活性的的咖啡酰奎宁酸类衍生物,合成方法简便,产物纯度高。与3-O-咖啡酰奎宁酸比较而言,本发明提供的咖啡酰奎宁酸类衍生物具有更好的降脂活性。<Image he="531" wi="648" file="DDA0001941435280000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a caffeoylquinic acid derivative, a preparation method and application thereof, and the caffeoylquinic acid derivative has a structure shown in a general formula (I). The invention takes 3-O-caffeoylquinic acid as a raw material, reserves the structural skeleton of the 3-O-caffeoylquinic acid and is positioned at 1 positionDifferent amino substituent groups are introduced into carboxyl, 4, 5-position hydroxyl groups are substituted or exposed by ketal, and the novel caffeoylquinic acid derivative with lipid-lowering activity is synthesized, the synthesis method is simple and convenient, and the product purity is high. Compared with 3-O-caffeoylquinic acid, the caffeoylquinic acid derivative provided by the invention has better lipid-lowering activity.)
1. A caffeoylquinic acid derivative, which is characterized by having a structure shown in a general formula (I):
in the formula: r6Is an H atom;
R4and R5Is an H atom;
R2and R3Is H atom or propylidene;
R1selected from 1-18 carbonsAlkyl amines, aryl amines having 6 to 10 carbons or saturated or unsaturated cyclic amines having 3 to 7 carbon atoms.
2. The caffeoylquinic acid derivative of claim 1, wherein R is1Selected from alkylamines containing 3-8 carbons, arylamines containing 7-8 carbons or saturated cyclic amines containing 5-6 carbons.
3. The caffeoylquinic acid derivative of claim 2, wherein R is1Selected from n-butylamino, isobutylamino, n-octylamino, propargylamino, benzylamino, piperidinyl or cyclohexylamino.
4. A process for the preparation of caffeoylquinic acid derivatives, as claimed in any one of claims 1-3, comprising the steps of:
(1) reacting 3-O-caffeoylquinic acid with 2, 2-dimethoxypropane to generate an intermediate;
(2) and carrying out condensation reaction on the intermediate and amine to generate a target compound caffeoylquinic acid derivative.
5. The process for producing a caffeoylquinic acid derivative according to claim 4, which further comprises, after the step (2):
(3): carrying out deprotection reaction on the target compound caffeoylquinic acid derivative.
6. The process for producing a caffeoylquinic acid derivative according to claim 4, which comprises the steps of:
(1) reacting 3-O-caffeoylquinic acid and 2, 2-dimethoxypropane in anhydrous acetone by taking p-toluenesulfonic acid as a catalyst to generate an intermediate shown in a formula (II);
(2) the intermediate shown in the formula (II) is subjected to condensation reaction with amine in a mixed solvent of anhydrous acetonitrile and tetrahydrofuran under the condensation condition of BOP and DIEA to generate the target compound caffeoylquinic acid derivative.
7. The process for producing a caffeoylquinic acid derivative according to claim 6, which further comprises, after the step (2):
(3): removing acetonylidene protection from a target compound caffeoylquinic acid derivative in a mixed solution of trifluoroacetic acid, dichloromethane and water.
8. A pharmaceutical composition comprising the caffeoylquinic acid derivative according to any one of claims 1-3 and a pharmaceutically acceptable carrier.
9. Use of the caffeoylquinic acid derivatives of any one of claims 1-3 in the preparation of a medicament for the prevention and/or treatment of hyperlipidemia.
10. Use of a caffeoylquinic acid derivative as defined in any of claims 1-3 in the preparation of a medicament for the prevention and/or treatment of atherosclerosis.
Technical Field
The invention relates to the field of pharmaceutical chemistry and therapeutics, in particular to a caffeoylquinic acid derivative, a preparation method and application thereof.
Background
The hyperlipidemia (hyperlipidemia, H L P) can induce clinical common cardiovascular and cerebrovascular diseases, and is one of the potential factors threatening human health, at present, the dyslipidemia patients in China reach 2.0 hundred million, the morbidity of normal people reaches 35-40%, and the middle-aged and elderly people reach more than 60%.
Currently, the common lipid-lowering drugs in clinic mainly include statin lipid-regulating drugs (atorvastatin and lovastatin), fibrate drugs (gemfibrozil and fenofibrate), nicotinic acid drugs (acipimox) and the like. However, these drugs acting on a single target point have various unsatisfactory side effects in clinical application, such as severe myopathy and rhabdomyolysis, and hepatotoxicity in the current first ten drugs of the world sold atorvastatin (also known as lipitor) as an HMG-CoA reductase inhibitor; even the new drug lomitapide, which has just been approved by the FDA to be marketed in 12 months 2012 for the treatment of familial hypercholesterolemia, is indicated to be at risk for gastrointestinal reactions and hepatotoxicity. Therefore, the search for lipid-lowering drugs with significant efficacy, safety and reliability is a subject worthy of long-term research by medical workers.
However, from the actual situation of our country, we completely imitate the western countries to find the lead compound from the artificially synthesized product, and create a new lipid-lowering drug with high efficiency and low toxicity, which is difficult to get a major breakthrough in a short period, but the natural product rich in the traditional clinically effective drug has the specific structural diversity and multi-target action mechanism, and is more and more favored by researchers at home and abroad, such as berberine which is the main lipid-lowering active ingredient in the Chinese medicine coptis root.
The action mechanism of traditional Chinese medicine lipid regulation is complex compared with western medicines, adverse reactions are less, and lipid reduction is achieved mainly by reducing absorption of exogenous lipid in intestinal tracts, inhibiting synthesis of endogenous lipid and regulating lipid metabolism. For example, a single Chinese medicine (kudzu root, ginseng, salvia miltiorrhiza, ginkgo leaf and the like) with the function of regulating blood fat; the lipid-lowering natural product can be polysaccharides (fructus Lycii polysaccharide, fructus Cucurbitae Moschatae polysaccharide), flavonoids (dihydrotanshinone, folium Ginkgo flavone) and polyphenols (catechin). In recent years, many folk traditional medicines are found to have good lipid regulating effect and are gradually developed into medicines, for example, a Xuezhikang capsule (main component red yeast) developed by limited northern Weixin biotechnology has completed phase II clinical research in the United states at present, and Jianjiandong subject group of institute of biotechnology of Chinese academy of medicine sciences finds that berberine also has good lipid lowering activity, is completely different from the action mechanism of statin lipid lowering medicines, and theoretically provides a new molecular target for searching for novel lipid lowering medicines. Different from the single-target western medicines which are clinically and frequently adopted at the present stage and easily cause adverse reactions, the multi-target characteristics of the natural medicines are probably the reasons for less toxic and side effects, so the method has epoch significance for the deep exploration and research of the natural medicines.
Disclosure of Invention
In view of the above, the present invention aims to provide a caffeoylquinic acid derivative, and a preparation method and a use thereof, wherein the caffeoylquinic acid derivative has a good lipid-lowering effect.
In view of the above object, the present invention provides a caffeoylquinic acid derivative having a structure represented by general formula (i):
in the formula: r6Is an H atom;
R4and R5Is an H atom;
R2and R3Is H atom or propylidene;
R1selected from alkylamines containing 1-18 carbons, arylamines containing 6-10 carbons or saturated or unsaturated cyclic amines containing 3-7 carbons.
In some embodiments of the invention, R1Selected from alkylamines containing 3-8 carbons, arylamines containing 7-8 carbons or saturated cyclic amines containing 5-6 carbons.
In some embodiments of the invention, R1Selected from n-butylamino, isobutylamino, n-octylamino, propargylamino, benzylamino, piperidinyl or cyclohexylamino.
The invention also provides a preparation method of the caffeoylquinic acid derivative, which comprises the following steps:
(1) reacting 3-O-caffeoylquinic acid with 2, 2-dimethoxypropane to generate an intermediate;
(2) and carrying out condensation reaction on the intermediate and amine to generate a target compound caffeoylquinic acid derivative.
In some embodiments of the present invention, after step (2), further comprising:
(3): carrying out deprotection reaction on the target compound caffeoylquinic acid derivative.
In some embodiments of the present invention, the method for preparing caffeoylquinic acid derivatives comprises the following steps:
(1) reacting 3-O-caffeoylquinic acid and 2, 2-dimethoxypropane in anhydrous acetone by taking p-toluenesulfonic acid as a catalyst to generate an intermediate shown in a formula (II);
(2) the intermediate shown in the formula (II) is subjected to condensation reaction with amine in a mixed solvent of anhydrous acetonitrile and tetrahydrofuran under the condensation condition of BOP and DIEA to generate the target compound caffeoylquinic acid derivative.
In some embodiments of the present invention, after step (2), further comprising:
(3): removing acetonylidene protection from a target compound caffeoylquinic acid derivative in a mixed solution of trifluoroacetic acid, dichloromethane and water.
The invention also provides a pharmaceutical composition, which comprises the caffeoylquinic acid derivative and a medicinal carrier.
The invention also provides application of the caffeoylquinic acid derivatives in preparing a medicament for preventing and/or treating hyperlipidemia.
The invention also provides application of the caffeoylquinic acid derivatives in preparing medicaments for preventing and/or treating atherosclerosis.
From the above, the invention can be seen in that 3-O-caffeoylquinic acid is used as a raw material, the structural skeleton of the 3-O-caffeoylquinic acid is kept, different amino substituent groups are introduced to the carboxyl group at the 1 position, and the hydroxyl groups at the 4 and 5 positions are substituted or exposed by ketal, so that the novel caffeoylquinic acid derivative with lipid-lowering activity is synthesized, the synthesis method is simple and convenient, and the product purity is high. Compared with 3-O-caffeoylquinic acid, the caffeoylquinic acid derivative provided by the invention has better lipid-lowering activity. The invention fully utilizes medicinal plant resources found from natural products, deeply researches and develops to find compounds with unique chemical structures, and finds the lipid-lowering medicament for clinical application.
Drawings
FIG. 1 is a graph of the modulating effect of chlorogenic acid and its derivatives on oleic acid-induced lipid accumulation in HepG2 hepatocytes; wherein, A picture shows the regulation effect of caffeoylquinic acid derivatives 3a, 3b, 3c, 3d, 3e and 3f on lipid accumulation caused by oleic acid in HepG2 liver cells; the B picture shows that the caffeoylquinic acid derivatives 4a, 4B, 4c, 4d, 4e and 4f have the regulating effect on lipid accumulation initiated by oleic acid in HepG2 liver cells, CA is chlorogenic acid, S is simvastatin, M is oleic acid, K is a control, and # p <0.001 is very obvious compared with the cells (K) treated by the control group; p <0.05 was significantly different relative to cells treated with oleic acid (M); p <0.01 was significant relative to oleic acid (M) -treated cells; the cells differed significantly with p <0.001 versus oleic acid (M) treated cells.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments below.
The invention provides a caffeoylquinic acid derivative, which has a structure shown in a general formula (I):
in the formula: r6Is an H atom;
R4and R5Is an H atom;
R2and R3Is H atom or propylidene;
R1selected from alkylamines containing 1-18 carbons, arylamines containing 6-10 carbons or saturated or unsaturated cyclic amines containing 3-7 carbons.
As an embodiment of the present invention, R1Selected from alkylamines containing 3-8 carbons, arylamines containing 7-8 carbons or saturated cyclic amines containing 5-6 carbons.
As an embodiment of the present invention, R1Selected from n-butylamino, isobutylamino, n-octylamino, propargylamino, benzylamino, piperidinyl or cyclohexylamino.
As an embodiment of the present invention, when R6Is an H atom; r4And R5Is an H atom; r2And R3Is propylidene; the structure shown in the formula (I) is as follows:
when R is1Is n-butylamino, and is a tertiary amino,the caffeoylquinic acid derivative is now designated 3 a.
When R is1Is an isobutylamino group, and the like,the caffeoylquinic acid derivative is named 3 b.
When R is1Is a n-octylamino group, and the amino acid is,the caffeoylquinic acid derivative is named 3 c.
When R is1Is a propargylamine group, and is a propargylamine group,the caffeoylquinic acid derivative is named 3 d.
When R is1Is a benzylamino group, and is a benzyl amine group,the caffeoylquinic acid derivative is named 3 e.
When R is1Is a piperidine group, and is a cyclic or cyclic piperidine group,the caffeoylquinic acid derivative is named 3 f.
When R is1Is a cyclohexylamino group, and is a cyclohexylamino group,the caffeoylquinic acid derivative was named 3g at this time.
As an embodiment of the present invention, when R6Is an H atom; r4And R5Is an H atom; r2And R3Is an H atom; the structure shown in the formula (I) is as follows:
when R is1Is n-butylamino, and is a tertiary amino,the caffeoylquinic acid derivative is now designated 4 a.
When R is1Is an isobutylamino group, and the like,the caffeoylquinic acid derivative is named 4 b.
When R is1Is a n-octylamino group, and the amino acid is,the caffeoylquinic acid derivative is named 4 c.
When R is1Is a propargylamine group, and is a propargylamine group,the caffeoylquinic acid derivative is named 4 d.
When R is1Is a benzylamino group, and is a benzyl amine group,the caffeoylquinic acid derivative is named 4 e.
When R is1Is a piperidine group, and is a cyclic or cyclic piperidine group,the caffeoylquinic acid derivative is named 4 f.
When R is1Is a cyclohexylamino group, and is a cyclohexylamino group,the caffeoylquinic acid derivative was named 4g at this time.
The invention also provides a preparation method of the caffeoylquinic acid derivative, which comprises the following steps:
(1) reacting 3-O-caffeoylquinic acid with 2, 2-dimethoxypropane to generate an intermediate;
(2) and carrying out condensation reaction on the intermediate and amine to generate a target compound caffeoylquinic acid derivative.
Specifically, the synthetic route of the caffeoylquinic acid derivative is as follows:
(1) synthesis reaction of intermediate 2
Taking a compound 1 (3-O-caffeoylquinic acid) as an initial raw material, and reacting 4, 5-hydroxy of the 3-O-caffeoylquinic acid with 2, 2-Dimethyloxypropane (DMP) in anhydrous acetone under the catalysis of p-toluenesulfonic acid (TsOH) to obtain an intermediate 2;
wherein, the structural formula of the 2, 2-dimethoxypropane is as follows:
(2) synthesis reaction of target Compound
Intermediate 2 was condensed with BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) and DIEA (N, N-diisopropylethylamine) in anhydrous acetonitrile (CH)3CN) and Tetrahydrofuran (THF) to generate a target compound caffeoylquinic acid derivative through a condensation reaction with amine, wherein the target compound caffeoylquinic acid derivative comprises 3a, 3b, 3c, 3d, 3e, 3f and 3 g.
In one embodiment of the present invention, the target compound caffeoylquinic acid derivative of step (2) is subjected to deprotection reaction to obtain the target compounds caffeoylquinic acid derivatives 4a, 4b, 4c, 4d, 4e, 4f and 4 g.
Specifically, the synthetic route is as follows:
the caffeoylquinic acid derivatives of the target compounds comprise 3a, 3b, 3c, 3d, 3e, 3f and 3g, and the acetonylidene protection is removed from a mixed solution of trifluoroacetic acid (TFA), Dichloromethane (DCM) and water, so that caffeoylquinic acid derivatives of the target compounds, 4a, 4b, 4c, 4d, 4e, 4f and 4g, are respectively obtained.
The general synthetic route of the target compound caffeoylquinic acid derivative is as follows:
wherein, (A) DMP, TsOH, acetone; (B) BOP, DIEA, amines; (C) TFA, DCM, H2O(9:1:1).
Therefore, according to the structural characteristics of the 3-O-caffeoylquinic acid, the hydroxyl at the 4, 5-position of the 3-O-caffeoylquinic acid is reacted with 2, 2-Dimethoxypropane (DMP), so that the hydroxyl at the 4, 5-position of the 3-O-caffeoylquinic acid is substituted by ketal to obtain an intermediate 2; then reacting the intermediate 2 with various amines, and introducing different amino substituent groups on the 1-position carboxyl group to obtain the caffeoylquinic acid derivatives; or the acetonylidene protection is further removed from the obtained caffeoylquinic acid derivative, so that the hydroxyl groups at the 4 and 5 positions are exposed. The preparation method of the caffeoylquinic acid derivative provided by the invention has the advantages of simple and convenient synthesis method and high product purity.
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