1,2,3-triazole compounds with antitumor effect, and preparation method and application thereof

Abstract

The application discloses 1,2,3-triazole compounds with antitumor effects and a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The application simply and efficiently synthesizes novel 1,2,3-triazole compounds, and does not involve heavy metal catalysts or microwave reactions. In vitro antitumor activity tests of the compounds show that the 1,2,3-triazole compounds have certain inhibitory effects on the growth of digestive tract tumor cells (human gastric cancer SGC7901 cells, human colon cancer HT-29 cells and human esophageal cancer EC9706 cells). The 1,2,3-triazole compounds can be used as candidate or lead compounds for further development, and are applied to the preparation of antitumor drugs, especially anti-digestive tract tumor drugs.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, in particular to a 1,2,3-triazole compound with anti-tumor effect and a preparation method and application thereof. BACKGROUND

[0002] Gastrointestinal tumor refers to the occurrence of tumor in the corresponding organs or tissues of the digestive system of the patient, and common ones are esophageal cancer, colon cancer, gastric cancer, liver cancer, and pancreatic cancer. About 300,000 people die of esophageal cancer worldwide every year, and about 150,000 people die of esophageal cancer in China every year on average. The incidence of colorectal cancer in China ranks fourth among all malignant tumors, with 383,000 new cases and 187,000 deaths every year. Gastric cancer is one of the most common malignant tumors in China, and about 170,000 people die of gastric cancer every year. Therefore, it is of great scientific and clinical significance to develop a potent anti-gastrointestinal tumor drug. In recent years, more and more studies have shown that 1,2,3-triazole is an effective pharmacologically active fragment, 1,2,3-triazole compounds have anti-oxidation, anti-fungal, anti-viral and anti-tumor activities, and 1,2,3-triazole is used to design and synthesize anti-gastrointestinal tumor drugs. However, it is one of the difficulties in the field of 1,2,3-triazole drugs to synthesize 1,2,3-triazole compounds with novel structure and anti-gastrointestinal tumor activity by a simple and efficient preparation method. SUMMARY

[0003] The purpose of the present application is to provide a 1,2,3-triazole compound with anti-tumor effect and a preparation method and application thereof, so as to solve the problems existing in the prior art.

[0004] To achieve the above-mentioned purpose, the present application provides the following solutions.

[0005] The present application provides a 1,2,3-triazole compound with anti-tumor effect, which is represented by general formula (I),

[0006]

[0007] Among them, represents

[0008]

[0009] Preferably, the 1,2,3-triazole compound comprises:

[0010]

[0011] The present application also provides a preparation method of the 1,2,3-triazole compound, characterized in that it comprises the following reaction:

[0012] Preferably, the method comprises the following steps:

[0013] (1) heating 4-methoxyphenol and bromopropargyl to obtain an alkyne intermediate B;

[0014] (2) heating the methylene chloride-containing aromatic ring compound II and 3,4,5-trimethoxyaniline to obtain a secondary amine intermediate III; reacting III with chloroacetyl chloride at room temperature to prepare a tertiary amide IV; adding sodium azide and reacting at room temperature to prepare an azide intermediate V;

[0015] (3) adding the alkyne intermediate B, the azide intermediate V, a copper salt and a ligand in a mixed solvent of acetone and water, and reacting at room temperature to prepare the 1,2,3-triazole compound I;

[0016] The step (1) and the step (2) are not in sequence.

[0017] Preferably, in the step (1), the heating reaction is carried out under weak alkaline conditions in dichloromethane as a solvent, the heating temperature is 40°C, and the heating time is 4h.

[0018] Preferably, in the step (2), the methylene chloride-containing aromatic ring compound II is any one of 1-(chloromethyl)naphthalene, 1,3-dichloro-5-chloromethylbenzene, 2,3,4,5,6-pentafluorobenzyl chloride, 2,3-difluorobenzyl chloride, 2,3-dichlorobenzyl chloride, 2,3-dimethylbenzyl chloride, 2,4,5-trifluorobenzyl chloride, 4-methoxybenzyl chloride, 2,4,6-trimethylbenzyl chloride, 2,4-difluorobenzyl chloride, 2,4-dichlorobenzyl chloride, 1-[4-(chloromethyl)phenyl]-1H-pyrazole, 2-chloromethyl-4-methylquinazoline, 1-(chloromethyl)-1H-benzotriazole and 4-chloromethyl-3,5-dimethylisoxazole;

[0019] The heating reaction is carried out in dichloromethane as a solvent, the heating temperature is 40°C, and the heating time is 4h.

[0020] Preferably, in the step (3), the volume ratio of the acetone to the water is 1:5-1:0.5.

[0021] Preferably, in the step (3), the copper salt is any one of cuprous chloride, copper sulfate pentahydrate, cuprous iodide, copper acetate and cuprous bromide;

[0022] The ligand is any one of diisopropylamine, benzylamine, triethylamine, diphenylamine, dimethylpyridine and sodium ascorbate.

[0023] The application further provides use of the 1,2,3-triazole compound in preparation of an antitumor drug.

[0024] The present application also provides an antitumor drug, comprising the 1,2,3-triazole compound and a pharmaceutically acceptable carrier.

[0025] Based on the above technical solutions, the present application has the following technical effects:

[0026] The present application simply and efficiently synthesizes the novel 1,2,3-triazole compound, and does not involve heavy metal catalysts or microwave reactions. The in vitro antitumor activity test of the compound shows that the 1,2,3-triazole compound has a certain inhibitory effect on the growth of digestive tract tumor cells (human gastric cancer SGC7901 cells, human colon cancer HT-29 cells and human esophageal cancer EC9706 cells). The 1,2,3-triazole compound of the present application can be used as a candidate or a lead compound for further development, and is applied to the preparation of an antitumor drug, especially an anti-digestive tract tumor drug. BRIEF DESCRIPTION OF DRAWINGS

[0027] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed in the embodiments will be briefly introduced below. Obviously, the drawings in the following description only constitute some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0028] Figure 1 The H-NMR chart of compound (G8) is as follows: 1 H-NMR chart;

[0029] Figure 2 The C-NMR chart of compound (G8) is as follows: 13 C-NMR chart. DETAILED DESCRIPTION

[0030] Various exemplary embodiments of the present application will now be described in detail, which should not be considered as limiting the present application, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present application.

[0031] It should be understood that the terms described in the present application are only for describing the specific embodiments, and are not used to limit the present application. In addition, for the numerical range in the present application, it should be understood that each intermediate value between the upper limit and the lower limit of the range is also specifically disclosed. Each smaller range between any stated value or intermediate value in the stated range and any other stated value or intermediate value in the stated range is also included in the present application. The upper limit and the lower limit of these smaller ranges can be independently included or excluded from the range.

[0032] Unless otherwise indicated, all technical and scientific terms have the same meaning as those one of ordinary skill in the art of the disclosure would attribute to such terms. Although preferred methods and materials are described, any method and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure. All documents mentioned herein are incorporated by reference to disclose and describe in further detail the methods and / or materials associated with the documents. In the case of conflict between the content of the specification and that of any document incorporated herein by reference, the content of the specification controls.

[0033] Many modifications and variations of the present disclosure described in the specification are possible without departing from the scope or spirit of the present disclosure. Other implementations of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the present disclosure. The specification and examples are illustrative only.

[0034] As used herein, "comprise", "comprising", "have", "having", "include", "including", "contain", "containing", "provide", "providing", "carry", "carrying" and the like can have the meaning ascribed to them by the US Patent and Trademark Office's interpretation rule 101, 37 C.F.R. § 1.56(b).

[0035] The technical solutions described in the present disclosure are conventional solutions in the art, and the reagents or raw materials used are commercially available or have been disclosed, unless otherwise specified.

[0036] Example 1

[0037] 1. Preparation of compound (G4)

[0038] 2,3-difluorobenzyl chloride (5 mmol) and 3,4,5-trimethoxyaniline (4 mmol) were dissolved in dichloromethane (15 mL) and heated at 40 °C. The reaction was monitored by TLC until completion. The secondary amine intermediate D4 was obtained by concentration and drying. Chloroacetyl chloride (6 mmol) was dissolved in dichloromethane (10 mL) and the reaction was carried out at room temperature until completion, monitored by TLC. The tertiary amide E4 was obtained by concentration and drying. Sodium azide (6 mmol) was added and the reaction was carried out at room temperature until completion, monitored by TLC. The azide intermediate F4 was obtained by recrystallization from ethanol. Alkynyl intermediate B (6 mmol) and azide intermediate F4 were added to a mixture of acetone (5 mL) and water (5 mL). Copper sulfate pentahydrate (0.5 mmol) and sodium ascorbate (0.25 mmol) were added and the reaction was carried out at room temperature until completion, monitored by TLC. The 1,2,3-triazole compound (G4) was obtained as a crude product. Filtration was performed and ethyl acetate (30 mL) was added for extraction and saturated brine (30 mL) was added for extraction. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was separated and purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate = 9:1. Compound (G4) was obtained. The yield of compound G4 was 76.5%.

[0039] 2. Preparation of compound (G8)

[0040] 4-methoxybenzyl chloride (10 mmol) and 3,4,5-trimethoxyaniline (12 mmol) were dissolved in dichloromethane (30 mL) and heated at 40 °C. The reaction was monitored by TLC until completion. The secondary amine intermediate D8 was obtained by concentration and drying. Chloroacetyl chloride (12 mmol) was dissolved in dichloromethane (20 mL) and the reaction was carried out at room temperature until completion, monitored by TLC. The tertiary amide E8 was obtained by concentration and drying. Sodium azide (12 mmol) was added and the reaction was carried out at room temperature until completion, monitored by TLC. The azide intermediate F8 was obtained by recrystallization from ethanol. Alkynyl intermediate B (12 mmol) and azide intermediate F8 were added to a mixture of acetone (10 mL) and water (10 mL). Copper iodide (1 mmol) and dimethylpyridine (1 mmol) were added and the reaction was carried out at room temperature until completion, monitored by TLC. The crude 1,2,3-triazole compound (G8) was obtained. Filtration was performed and ethyl acetate (40 mL) was added to extract and saturated brine (40 mL) was added to extract. The organic layer was dried over anhydrous magnesium sulfate. The compound (G8) was obtained by column chromatography using silica gel column to purify the organic layer, eluted with petroleum ether / ethyl acetate = 9:1. The yield of compound G8 was 83.6%.

[0041] 3. Preparation of compound (G12)

[0042] 1-[4-(chloromethyl)phenyl]-1H-pyrazole (7 mmol) and 3,4,5-trimethoxyaniline (8.4 mmol) were dissolved in dichloromethane (15 mL) and heated at 40 °C. The reaction was monitored by TLC until completion. The secondary amine intermediate D12 was obtained by concentration and drying. Chloroacetyl chloride (8.4 mmol) was dissolved in dichloromethane (15 mL) and the reaction was carried out at room temperature until completion, monitored by TLC. The tertiary amide E12 was obtained by concentration and drying. Sodium azide (8.4 mmol) was added and the reaction was carried out at room temperature until completion, monitored by TLC. The azide intermediate F12 was obtained by recrystallization from ethanol. Alkynyl intermediate B (12 mmol) and azide intermediate F12 were added to a mixture of acetone (7 mL) and water (7 mL). Copper acetate (0.7 mmol) and dimethylpyridine (0.7 mmol) were added and the reaction was carried out at room temperature until completion, monitored by TLC. The crude 1,2,3-triazole compound (G12) was obtained. Filtration was performed and ethyl acetate (40 mL) was added to extract and saturated brine (40 mL) was added to extract. The organic layer was dried over anhydrous magnesium sulfate. The compound (G12) was obtained by column chromatography using silica gel column to purify the organic layer, eluted with petroleum ether / ethyl acetate = 10:1. The yield of compound G12 was 80.2%.

[0043] 4. Preparation of compound (G15)

[0044] 4-chloromethyl-3,5-dimethylisoxazole (8 mmol) and 3,4,5-trimethoxyaniline (10 mmol) were dissolved in dichloromethane (20 mL) and heated at 40 °C. The reaction was monitored by TLC until completion. The secondary amine intermediate D15 was obtained by concentration and drying. Chloroacetyl chloride (10 mmol) was dissolved in dichloromethane (15 mL) and the reaction was carried out at room temperature until completion, monitored by TLC. The tertiary amide E15 was obtained by concentration and drying. Sodium azide (10 mmol) was added and the reaction was carried out at room temperature until completion, monitored by TLC. The azide intermediate F15 was obtained by recrystallization from ethanol. Alkynyl intermediate B (10 mmol) and azide intermediate F15 were added to a mixture of acetone (8 mL) and water (8 mL). Copper sulfate pentahydrate (0.8 mmol) and sodium ascorbate (0.4 mmol) were added and the reaction was carried out at room temperature until completion, monitored by TLC. The 1,2,3-triazole compound (G15) was obtained as a crude product. Filtration was performed and ethyl acetate (35 mL) was added for extraction. Saturated brine (35 mL) was added for extraction and the mixture was dried over anhydrous magnesium sulfate. The organic layer was separated and purified by silica gel column chromatography using petroleum ether / ethyl acetate = 12:1 as the eluent. Compound (G15) was obtained in a yield of 61.7%.

[0045] 5. The yields of compounds G1, G2, G3, G5, G6, G7, G9, G10, G11, G13, and G14 are shown in Table 1.

[0046] Table 1 Yields of compounds G1, G2, G3, G5, G6, G7, G9, G10, G11, G13, and G14

[0047] Compound G1 G2 G3 G5 G6 G7 G9 G10 G11 A13 G14 Yield (%) Figure 1 Figure 2 Compound Yield (%) 73.5 59.8 82.3 79.1 82.5 70.6 65.4 90.1 69.4 75.2 81.7

[0048] Example 2

[0049] Determination of the antitumor activity of the compounds:

[0050] 1-2 mg of the above 1,2,3-triazole compound was weighed into a 1 mL EP tube and dissolved in DMSO to prepare a 10 mM solution, which was stored at 4 °C. Human gastric cancer SGC7901 cells, human colon cancer HT-29 cells, and human esophageal cancer EC9706 cells in the logarithmic growth phase were inoculated into 96-well plates and cultured for 24 h. The culture medium was discarded and different concentrations of the compound were added. After 48 h of drug treatment, 20 μL of MTT was added to each well, and the cells were further cultured for 4 h. The liquid was then removed, 100 μL of DMSO was added, and the mixture was shaken uniformly. The absorbance value was detected at 490 nm using a microplate reader, and the tumor cell survival rate was calculated. The antitumor drug 5-fluorouracil (5-Fu) was used as a control. The experimental results are shown in Table 1.

[0051] Table 1 Tumor cell survival rates under the intervention of different concentrations of the compound

[0052]

[0053] As can be seen from Table 1, the novel compounds (G4, G8, G12, G15) in Example 1 have significantly better anti-tumor activities on human gastric cancer SGC7901 cells, human colon cancer HT-29 cells and human esophageal cancer EC9706 cells than the control drug 5-fluorouracil (5-Fu). The 1,2,3-triazole compounds can be used as candidate or lead compounds for further development to prepare anti-tumor drugs.

[0054] The other compounds (G1, G2, G3, G5, G6, G7, G9, G10, G11, G13, G14) have anti-tumor activities on human esophageal cancer cells EC9706 and human prostate cancer cells 22RV1 equivalent to G8.

[0055] The above-described examples are only used to describe the preferred modes of the present application, and are not intended to limit the scope of the present application. Without departing from the design spirit of the present application, various modifications and improvements to the technical solutions of the present application made by those skilled in the art shall fall within the protection scope of the present application as defined by the claims.

Claims

1. Use of 1,2,3-triazole compounds having an antitumor effect in the manufacture of an antitumor drug, characterized in that, The 1,2,3-triazole compound is represented by general formula (I), wherein represent The tumor is colon cancer or esophageal cancer.

2. Use according to claim 1, characterized in that, The 1,2,3-triazole compound comprises:

3. Use according to claim 1 or 2, characterized in that, The preparation method of the 1,2,3-triazole compound comprises the following reaction:

4. Use according to claim 3, characterized in that, Comprise the following steps: (1) 4-methoxyphenol is reacted with bromine propargyl by heating to obtain the acetylenic intermediate B; (2) the aryl ring compound II containing methylene chloride is reacted with 3,4,5-trimethoxyaniline by heating to obtain the secondary amine intermediate III; III is reacted with chloroacetyl chloride at room temperature to prepare the tertiary amide IV; sodium azide is added and reacted at room temperature to prepare the azide intermediate V; (3) in a mixed solvent of acetone and water, acetylenic intermediate B, azide intermediate V, copper salt and ligand are added and reacted at room temperature to prepare the 1,2,3-triazole compound I; Steps (1) and (2) are not in sequence.

5. Use according to claim 4, characterized in that, In step (1), the heating reaction is carried out under weak alkaline conditions with dichloromethane as the solvent, the heating temperature is 40°C, and the heating time is 4h.

6. Use according to claim 4, characterized in that, In step (2), the aryl ring compound II containing methylene chloride is any one of 1-(chloromethyl)naphthalene, 1,3-dichloro-5-chloromethylbenzene, 2,3,4,5,6-pentafluorobenzyl chloride, 2,3-difluorobenzyl chloride, 2,3-dichlorobenzyl chloride, 2,3-dimethylbenzyl chloride, 2,4,5-trifluorobenzyl chloride, 4-methoxybenzyl chloride, 2,4,6-trimethylbenzyl chloride, 2,4-difluorobenzyl chloride, 2,4-dichlorobenzyl chloride, 1-[4-(chloromethyl)phenyl]-1H-pyrazole, 2-chloromethyl-4-methylquinazoline, 1-(chloromethyl)-1H-benzotriazole and 4-chloromethyl-3,5-dimethylisoxazole; The heating reaction is carried out with dichloromethane as the solvent, the heating temperature is 40°C, and the heating time is 4h.

7. Use according to claim 4, characterized in that, In step (3), the volume ratio of acetone to water is 1:5-1:0.

5.

8. Use according to claim 4, characterized in that, In step (3), the copper salt is any one of cuprous chloride, copper sulfate pentahydrate, cuprous iodide, copper acetate, cuprous bromide; The ligand is any one of diisopropylamine, benzylamine, triethylamine, diphenylamine, dimethylpyridine and sodium ascorbate.

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