阅读说明：本技术 迷迭香酸衍生物及其制备方法和应用 (rosmarinic acid derivatives, and preparation method and application thereof ) 是由 蒋伟哲 蒋敏捷 李清 于 2018-12-26 设计创作，主要内容包括：本发明涉及迷迭香酸衍生物及其制备方法,本发明公开的迷迭香酸类似物或含有其药物在临床上可接受的盐,在治疗肝癌、肺癌、直肠癌等肿瘤疾病拥有良好的应用前景。(The invention relates to a rosmarinic acid derivative and a preparation method thereof, and the rosmarinic acid analogue or the clinically acceptable salt containing the rosmarinic acid analogue has good application prospect in treating tumor diseases such as liver cancer, lung cancer, rectal cancer and the like.)

1. A rosmarinic acid derivative characterized by the following general formula (I):

wherein:

R₁Selected from hydrogen, methyl or ethyl;

R₂selected from the group consisting of (3, 4-dihydroxyphenyl) propenyl, (3-hydroxy-4-methoxyphenyl) propenyl, (3, 4-methylenedioxyphenyl) propenyl, (3, 4-dimethoxyphenyl) propenyl, (4-hydroxy-3, 5-dimethoxyphenyl) propenyl, (3,4, 5-trimethoxyphenyl) propenyl, (3-chlorophenyl) propenyl, (3, 4-difluorophenyl) propenyl, (4-methoxyphenyl) propenyl, (3, 4-dimethoxyphenyl) propyl, 2-acetamido-3- (4-hydroxyphenyl) propyl, (3-bromo-4-hydroxy-5-methoxyphenyl) propenyl, and mixtures thereof, (4- (benzyloxy) -3-methoxyphenyl) propenyl, (3-methoxy-4-acetoxyphenyl) propenyl, (2,3, 4-trimethoxyphenyl) propenyl, (4, 5-dihydroxy-2-nitrophenyl) propenyl, or (2-bromo-4, 5-methylenedioxybenzene)yl) propenyl group.

2. The rosmarinic acid derivative of claim 1, wherein the compound has the structure:

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-dihydroxyphenyl) acrylamido) propanoate (I-1);

(S,E) -3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-dihydroxyphenyl) acrylamido) propionic acid (I-2);

(S,E) -ethyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-dihydroxyphenyl) acrylamido) propionate (I-3);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3-hydroxy-4-methoxyphenyl) acrylamido) propanoate (I-4);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-methylenedioxyphenyl) acrylamido) propanoate (I-5);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-dimethoxyphenyl) acrylamido) propanoate (I-6);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (4-hydroxy-3, 5-dimethoxyphenyl) acrylamido) propanoate (I-7);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3,4, 5-trimethoxyphenyl) acrylamido) propanoate (I-8);

(S,E) -methyl 2- (3- (3-chlorophenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-9);

(S) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-dimethoxyphenyl) propaneamido) propanoate (I-10);

(S,E) -methyl 2- (3- (3, 4-difluorophenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-11);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (4-methoxyphenyl) acrylamido) propanoate (I-12);

(S,E) -methyl 2- (3- (2-bromo-4, 5-dimethoxyphenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-13);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (4-hydroxyphenyl) acrylamido) propanoate (I-14);

(S)-2-((S) -methyl 2-acetylamino-3- (4-hydroxyphenyl) propaneamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-15);

(S,E) -methyl 2- (3- (3-bromo-4-hydroxy-5-methoxyphenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-16);

(S,E) -methyl 2- (3- (4- (benzyloxy) -3-methoxyphenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-17);

(S,E) -methyl 2- (3- (3-methoxy-4-acetoxyphenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-18);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (2,3, 4-trimethoxyphenyl) acrylamido) propanoate (I-19);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (4, 5-dihydroxy-2-nitrophenyl) acrylamido) propanoate (I-20);

(S,E) -methyl 2- (3- (2-bromo-4, 5-methylenedioxyphenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-21);

It corresponds to the structural formula:

。

3. the rosmarinic acid derivative of claim 1, which is prepared by the method comprising:

the compounds of the general formula (II) and the general formula (III) are subjected to condensation reaction under alkaline condition, and then hydrolyzed to obtain the compound of the general formula (I).

4. Use of a rosmarinic acid derivative according to claim 1 in the preparation of a medicament for the treatment of liver, lung or colon cancer.

Technical Field

The present invention relates to a novel rosmarinic acid derivative or a pharmaceutical composition containing the same, and a preparation method thereof. The invention further relates to application of the rosmarinic acid derivative or a pharmaceutical composition containing the rosmarinic acid derivative in preparing a therapeutic agent, in particular to application of the rosmarinic acid derivative or the pharmaceutical composition containing the rosmarinic acid derivative in preparing a medicament for treating tumor diseases such as liver cancer, lung cancer and the like.

Background

With the increasing pollution of human living environment, especially the severe pollution of air and water source, the incidence and mortality of malignant tumor is on the rising trend year by year. The research on safe and effective antitumor drugs is a new idea for the research and development of current antitumor drugs and is also a problem to be urgently solved by current researchers. Therefore, the development of safe and effective antitumor drugs has important research value and application prospect.

rosmarinic acid is a natural product extracted from plants. The research on the in vivo and in vitro anti-liver cancer effect of the rosmarinic acid shows that the rosmarinic acid has obvious anti-liver cancer effect in vivo and in vitro. However, new compounds with better stability and stronger activity are still needed to be developed for research on antitumor activity and antitumor drugs with clinical application value. The invention designs the compound with the structure shown in the general formula (I) and finds that the structure shows excellent effect.

disclosure of Invention

The object of the present invention is to provide a compound represented by the general formula (I).

wherein:

R₁Selected from hydrogen, methyl, ethyl. R₂Selected from the group consisting of (3, 4-dihydroxyphenyl) propenyl, (3-hydroxy-4-methoxyphenyl) propenyl, (3, 4-methylenedioxyphenyl) propenyl, (3, 4-dimethoxyphenyl) propenyl, (4-hydroxy-3, 5-dimethoxyphenyl) propenyl, (3,4, 5-trimethoxyphenyl) propenyl, (3-chlorophenyl) propenyl, (3, 4-difluorophenyl) propenyl, (4-methoxyphenyl) propenyl, (3, 4-dimethoxyphenyl) propyl, 2-acetamido-3- (4-hydroxyphenyl) propyl, (3-bromo-4-hydroxy-5-methoxyphenyl) propenyl, and mixtures thereof, (4- (benzyloxy) -3-methoxyphenyl) propenyl group, (3-methoxy-4-acetoxyphenyl) propenyl group, (2,3, 4-trimethoxyphenyl) propenyl group, (4, 5-dihydroxy-2-nitrophenyl) propenyl group, (2-bromo-4, 5-methylenedioxyphenyl) propenyl group.

Preferred compounds thereof are:

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-dihydroxyphenyl) acrylamido) propanoate (I-1);

(S,E) -3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-dihydroxyphenyl) acrylamido) propionic acid (I-2);

(S,E) -3- (3, 4-dihydroxyphenyl)) -ethyl 2- (3- (3, 4-dihydroxyphenyl) acrylamido) propionate (I-3);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3-hydroxy-4-methoxyphenyl) acrylamido) propanoate (I-4);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-methylenedioxyphenyl) acrylamido) propanoate (I-5);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-dimethoxyphenyl) acrylamido) propanoate (I-6);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (4-hydroxy-3, 5-dimethoxyphenyl) acrylamido) propanoate (I-7);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3,4, 5-trimethoxyphenyl) acrylamido) propanoate (I-8);

(S,E) -methyl 2- (3- (3-chlorophenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-9);

(S) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (3, 4-dimethoxyphenyl) propaneamido) propanoate (I-10);

(S,E) -methyl 2- (3- (3, 4-difluorophenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-11);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (4-methoxyphenyl) acrylamido) propanoate (I-12);

(S,E) -methyl 2- (3- (2-bromo-4, 5-dimethoxyphenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-13);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (4-hydroxyphenyl) acrylamido) propanoate (I-14);

(S)-2-((S) -methyl 2-acetylamino-3- (4-hydroxyphenyl) propaneamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-15);

(S,E) -methyl 2- (3- (3-bromo-4-hydroxy-5-methoxyphenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-16);

(S,E) -2- (3- (4- (benzyloxy) -3-methoxyphenyl)acrylamido) -methyl 3- (3, 4-dihydroxyphenyl) propionate (I-17);

(S,E) -methyl 2- (3- (3-methoxy-4-acetoxyphenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-18);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (2,3, 4-trimethoxyphenyl) acrylamido) propanoate (I-19);

(S,E) -methyl 3- (3, 4-dihydroxyphenyl) -2- (3- (4, 5-dihydroxy-2-nitrophenyl) acrylamido) propanoate (I-20);

(S,E) -methyl 2- (3- (2-bromo-4, 5-methylenedioxyphenyl) acrylamido) -3- (3, 4-dihydroxyphenyl) propanoate (I-21);

It corresponds to the structural formula:

The invention further relates to a method for preparing the compound shown in the general formula (1).

The compounds of the general formula (II) and the general formula (III) are subjected to condensation reaction under alkaline condition, and then hydrolyzed to obtain the compound of the general formula (I), R₁，R₂Is as defined in claim 1.

the invention also aims to provide the application of the compound shown in the general formula (I) in preparing the medicines for treating tumor diseases such as liver cancer, lung cancer and the like.

Synthesis of the Compounds of the invention

in order to achieve the purpose of the invention, the invention adopts the following technical scheme:

The preparation method of the compound shown in the general formula (I) comprises the following steps:

Taking levodopa 1) as a raw material, and obtaining II through esterification reaction; the compounds II and III are condensed and (or) hydrolyzed to obtain the compound with the general formula (I).

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.