CN118388421A - Curcumin derivative, preparation method and application - Google Patents

Abstract

The invention discloses a curcumin derivative, which is a compound shown as a formula (1)Wherein R is halogen, 4-ethyl, 4-nitro or 3, 4-dimethoxy, a preparation method thereof, and a pharmaceutical composition taking the compound as an active ingredient, and application thereof in preparing anti-septicemia medicaments. The preparation method of the compound has the advantages of mild reaction conditions, simple and easily obtained reagents and the like. Experiments prove that the compound disclosed by the invention can effectively inhibit the septicemia induced by LPS, can be used for preparing anti-septicemia medicaments, does not have serious drug resistance, and can be better used for treating clinical septicemia.

Description

Curcumin derivative, preparation method and application

Technical Field

The invention particularly relates to a curcumin derivative, a preparation method thereof, a pharmaceutical composition taking the curcumin derivative as an active ingredient and application of the curcumin derivative in preparation of anti-septicemia medicines.

Background

Sepsis (Sepsis) is a clinical syndrome in which the host's response to infection is deregulated resulting in life threatening organ dysfunction, and in severe cases, multiple organ failure, septic shock and even death. Sepsis is often the leading cause of death in clinically critical patients.

Sepsis patients often manifest clinically with recurrent aversion to cold and even chills, accelerated heartbeat, shortness of breath, severe complications of Disseminated Intravascular Coagulation (DIC), respiratory distress syndrome (ARDS) and Multiple Organ Dysfunction Syndrome (MODS). Children and critically ill patients are often the primary subjects of sepsis. In recent years, although the medical technology level is continuously improved, the problem of high mortality rate of septicemia and complications still needs to be solved, and in recent years, related researches find that therapeutic drugs related to septicemia mainly comprise antibiotics, but long-term use of antibiotics can cause liver and kidney injury, and are extremely easy to generate drug resistance, so that the conventional antibiotics have poor therapeutic effect. In order to improve the therapeutic effect, new compounds having new structural features and mechanisms of action need to be studied.

Disclosure of Invention

The invention aims to solve the problems, and provides a series of novel curcumin derivatives, a preparation method thereof and a pharmaceutical composition taking the compounds as active ingredients, and experiments prove that the compounds have good anti-septicemia effect and can be applied to preparation of anti-septicemia medicines.

The present invention provides a compound represented by the general formula (1):

wherein R is preferably halogen, 4-ethyl, 4-nitro or 3, 4-dimethoxy, R can also be other substituents with good activity.

A process for the preparation of a compound as described above comprising the steps of:

S1, taking substituted aniline as a reaction raw material, taking absolute ethyl alcohol as a reaction solvent, adding triethyl orthoformate and methyl hydrazinoformate, continuously heating, tracking the reaction by TLC, and extracting a reactant by ethyl acetate after the reaction is completed to obtain an intermediate product 1a;

s2, mixing and heating the intermediate product 1a, formaldehyde and acetic acid, taking anhydrous acetonitrile as a reaction solvent, tracking the reaction through TLC, evaporating and concentrating reactants after the reaction is completed, and recrystallizing to obtain an intermediate product 1b;

s3, taking DCM as a solvent, continuously stirring the 1b and pyridinium dichromate at room temperature, reacting for 12 hours, adding water, fully mixing, and carrying out suction filtration to obtain a compound 1c;

S4, mixing the compound 1c with curcumin with equal molar weight, adding piperidine and acetic acid, continuously heating in a methanol environment, and purifying by a column chromatography after the reaction is completed to obtain the target compound 1d.

The invention also provides a pharmaceutical composition for treating septicemia, which takes the compound of the invention as an active ingredient and contains the compound with effective treatment dose and one or more pharmaceutically acceptable medicinal carriers or auxiliary materials. The pharmaceutically acceptable medicinal carrier or auxiliary material can be selected from excipients, auxiliary materials or solvents commonly used in pharmaceutical preparations. Such as sucrose, gelatin, talc, magnesium stearate, hypromellose, dextrin, acacia, starch, syrup, glyceryl monostearate, fatty acid, glucose solution, water, ethanol, physiological saline, etc.

The invention provides application of the compound in preparing a medicament for treating septicemia.

A process for preparing the compounds of the formula (1) according to the invention, which comprises starting from the compounds of the formula (2):

。

The synthesis method is simple and easy to obtain, mild in reaction condition and low in production cost.

The compound represented by the general formula 1 and the pharmaceutical composition thereof can be used for preparing anti-sepsis drugs.

The compounds of the present invention have anti-sepsis activity, making them useful as anti-sepsis agents. Pharmacological test results of the preferred compound (1E, 6E) -4- [4- (4-fluorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) methylene ] -1, 7-bis (4-hydroxy-3-methoxyphenyl) hepta-1, 6-diene-3, 5-dione (compound 1 d) in the present invention are shown in FIG. 1. After the target compound 1d is purified, the inflammatory response of the mice, which is presented by infection of septicemia, is obviously relieved, and compared with a low-dose group, the high-dose group has more obvious effect. The results of the drug safety experiments are shown in tables 1 and 2, and the weight of the mice is obviously increased within five days after oral administration, and no abnormal reaction occurs. At present, antibiotics are mainly adopted for treating septicemia clinically, and most of the antibiotics cannot play a good role in treatment due to the existence of drug-resistant strains. The compound has the greatest advantages of providing a series of compounds with novel structural characteristics and action mechanisms, and compared with antibiotics, the compound has no serious drug resistance and can be better used for treating clinical septicemia.

Drawings

FIG. 1 shows the results of pharmacological experiments (mg/kg, oral administration) of the target compound 1d against sepsis.

FIG. 2 is a view of the HE stained sections of the liver from each experimental group (A: blank group; B: model group; C: low dose group; D: high dose group).

Detailed Description

The above-described contents of the present invention will be further described in detail by way of preferred embodiments of the synthesis examples and pharmacological experimental examples of the objective compound 1d, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to only the examples described below.

Preparation example 1:

The synthesis of the target compound 1 will be described by taking the synthesis of (1E, 6E) -4- [4- (4-fluorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) methylene ] -1, 7-bis (4-hydroxy-3-methoxyphenyl) hepta-1, 6-diene-3, 5-dione (compound 1 d) as an example.

Using compound 2 (i.e. the general formula 2) as a reaction raw material, using absolute ethyl alcohol as a reaction solvent, adding triethyl orthoformate and methyl hydrazinoformate, and continuously heating. The reaction was followed by TLC, after completion of the reaction was extracted with ethyl acetate to give intermediate 1a.

The intermediate 1a, formaldehyde and acetic acid are mixed and heated, anhydrous acetonitrile is used as a reaction solvent, the reaction is tracked by TLC, and after the reaction is completed, the reactant is evaporated and concentrated, and the important intermediate 1b is obtained through recrystallization.

And (3) continuously stirring the 1b and pyridinium dichromate at room temperature by taking DCM as a solvent, reacting for about 12 hours, adding water, fully mixing and carrying out suction filtration to obtain the compound 1c.

Mixing the compound 1c with curcumin with equal molar quantity, adding a proper amount of piperidine and acetic acid, continuously heating in a methanol environment, and obtaining the target compound 1d through column chromatography after the reaction is completed. Yield: 56.3%;

The reaction formula of the preparation process is as follows:

。

example a: safety evaluation and anti-septicemia pharmacological experiments

Four doses of 100, 200, 300, 400 mg/kg of compound were prepared for use; 30 mice are divided into 3 groups, 5 female mice and 5 male mice in each group are fed after normal feeding for one week, water is not interrupted before feeding for 8h, four doses of compound 1 ml are respectively irrigated to male mice and female mice, and a blank control group is irrigated with 5% of hydroxymethyl cellulose sodium with the same amount. The administration was continued for 3 days and observed for 5 days. The average body weight of the mice increased significantly, and no abnormality occurred.

Table 1: compound 1d results of drug safety evaluation (Male mice, mg/kg, oral administration)

。

Table 2: compound 1d results of drug safety evaluation (Male mice, mg/kg, oral administration)

。

An anti-sepsis effect study of (1 e,6 e) -4- [4- (4-fluorophenyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) methylene ] -1, 7-bis (4-hydroxy-3-methoxyphenyl) hepta-1, 6-diene-3, 5-dione (compound 1 d), comprising the steps of:

(1) Male ICR mice weighing 23-28g were divided into 4 groups (blank, model, high and low dose) of five animals each; alternating the brightness for 12 hours to cut off grains and water;

(2) LPS (25 mug/kg) and D-GaIN (600 mg/kg) are prepared into a mixed solution for standby;

(3) Compound 1d was formulated for use at both 300mg/kg and 100mg/kg doses;

(4) Compound 1d at 300mg/kg and 100mg/kg was intragastrically administered to high and low dose groups of mice, respectively; the other groups are irrigated with the same amount of physiological saline;

(5) After 30min, the other groups except for the blank group are injected with LPS/D-GaIN mixed solution in the abdominal cavity, and the blank group is injected with equivalent physiological saline;

(6) Blood is taken from the orbital venous plexus of the mice after 6 hours to detect serum aspartate Aminotransferase (AST) and alanine Aminotransferase (ALT); detecting liver indexes MDA and SOD, and performing statistical analysis;

(7) The livers of each group of mice are taken for embedding wax blocks, and tissue sections are prepared for HE staining observation.

The mice are subjected to gastric lavage administration by adopting high and low doses, liver injury degree of a comparison model group of the high and low doses is improved, AST (AST reduction), ALT (ALT) reduction, MDA (MDA) reduction and SOD (superoxide dismutase) increase are shown, improvement effect of the high dose group is better, all experimental data are expressed by x+/-s, single factor variance analysis is carried out by using graphPad prism5.0 statistical software, and P <0.05 shows that difference has statistical significance.

The pharmacological test results (mg/kg, oral administration) of compound 1d against sepsis are shown in figure 1.

The observation patterns of the HE stained sections of the livers of each experimental group (A: blank group; B: model group; C: low dose group; D: high dose group) are shown in FIG. 2.

Conclusion: the experimental study shows that the compound 1d has an anti-septicemia effect, has no toxic or side effect, can be used for the preparation of subsequent anti-septicemia medicaments and other researches, and is a medicinal composition for treating septicemia, wherein the medicinal composition comprises a therapeutically effective amount of the compound and one or more pharmaceutically acceptable medicinal carriers or auxiliary materials. Use of compound 1d in the manufacture of a medicament for the treatment of sepsis.

The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above examples. Modifications, variations, or substitutions by one of ordinary skill in the art are intended to be included within the scope of the present invention.

Claims (4)

1. A compound represented by the following general formula (1):

，

wherein R is halogen, 4-ethyl, 4-nitro or 3, 4-dimethoxy.

2. A process for the preparation of a compound according to claim 1, comprising the steps of:

S1, taking substituted aniline as a reaction raw material, taking absolute ethyl alcohol as a reaction solvent, adding triethyl orthoformate and methyl hydrazinoformate, continuously heating, tracking the reaction by TLC, and extracting a reactant by ethyl acetate after the reaction is completed to obtain an intermediate product 1a;

s2, mixing and heating the intermediate product 1a, formaldehyde and acetic acid, taking anhydrous acetonitrile as a reaction solvent, tracking the reaction through TLC, evaporating and concentrating reactants after the reaction is completed, and recrystallizing to obtain an intermediate product 1b;

s3, taking DCM as a solvent, continuously stirring the 1b and pyridinium dichromate at room temperature, reacting for 12 hours, adding water, fully mixing, and carrying out suction filtration to obtain a compound 1c;

S4, mixing the compound 1c with curcumin with equal molar weight, adding piperidine and acetic acid, continuously heating in a methanol environment, and purifying by a column chromatography after the reaction is completed to obtain the target compound.

3. A pharmaceutical composition for the treatment of sepsis comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable pharmaceutical carrier or adjuvant.

4. Use of a compound according to claim 1 for the preparation of a medicament for the treatment of sepsis.