CN117024298A

CN117024298A - Tertiary amide compound containing naphthyl and its preparation method and application

Info

Publication number: CN117024298A
Application number: CN202310995011.7A
Authority: CN
Inventors: 付冬君
Original assignee: Beijing University of Chinese Medicine
Current assignee: Beijing University of Chinese Medicine
Priority date: 2023-08-08
Filing date: 2023-08-08
Publication date: 2023-11-10

Abstract

The application discloses a tertiary amide compound containing naphthyl and a preparation method and application thereof, belonging to the technical field of medicines. In-vitro antitumor activity tests show that the tertiary amide compound containing naphthyl has obvious inhibition activity on the growth of various tumor cells (human esophageal cancer cells EC9706, human gastric cancer cells SGC7901, human colorectal adenocarcinoma cells HT-29, human gastric cancer cells MGC-803, human breast cancer cells MCF7 and human prostate cancer cells PC-3), has obviously better activity than that of an antitumor drug 5-fluorouracil, and can be used as a lead compound or a candidate compound for the development of broad-spectrum antitumor drugs.

Description

Tertiary amide compound containing naphthyl and its preparation method and application

Technical Field

The application relates to the technical field of medicines, in particular to a tertiary amide compound containing naphthyl and a preparation method and application thereof.

Background

Malignant tumors are one of the major health problems facing the world, and their morbidity and mortality have remained high. The national cause of death monitoring report in 2019 shows that malignant tumor is the first cause of death and accounts for 24.09% of all resident causes of death. The relative survival rate of malignant tumors in China is about 40.5% in 5 years, and the medical cost caused by malignant tumors per year is more than 2200 hundred million. Therefore, the prevention and control of malignant tumor and the treatment situation in China are very serious, and a novel powerful antitumor drug is needed in clinic.

Naphthalene (naphthalene) is the simplest polycyclic aromatic hydrocarbon, and has the chemical formula C ₁₀ H ₈ Is formed by fusing 2 benzene rings with 2 adjacent carbon atoms. Naphthalene compounds are widely used as raw materials for preparing dyes, resins, solvents, etc., and as insect repellents. However, the broad-spectrum antitumor activity of tertiary amide compounds containing naphthyl groups and their use as broad-spectrum antitumor drugs have been rarely reported. The tertiary amide compound containing naphthyl with broad-spectrum anti-tumor activity is found to have important scientific and clinical significance.

Disclosure of Invention

The application aims to provide a tertiary amide compound containing naphthyl, a preparation method and application thereof, so as to solve the problems in the prior art.

In order to achieve the above object, the present application provides the following solutions:

the application provides a tertiary amide compound containing naphthyl, which is represented by a general formula (I),

wherein,comprises->

Preferably, the method comprises the steps of:

the application also provides a preparation method of the tertiary amide compound containing naphthyl, which comprises the following steps:

(1) Dissolving 2- (chloromethyl) naphthalene and 3,4, 5-trimethoxyaniline in an organic solvent, carrying out reflux reaction under alkaline conditions, extracting, drying and concentrating to obtain an intermediate II;

(2) Dissolving an aromatic compound containing an acetyl chloride group and an intermediate II in an organic solvent, reacting under an alkaline condition, carrying out suction filtration, extracting and drying to obtain the tertiary amide compound containing the naphthyl.

Preferably, the following reactions are included:

preferably, the extraction is performed three times with water and saturated saline, respectively.

Preferably, the drying is performed by using a drying agent.

Preferably, the desiccant comprises anhydrous magnesium sulfate.

Preferably, the organic solvent comprises at least one of dichloromethane, toluene, dimethyl sulfoxide, chloroform, ethyl acetate, N-dimethylformamide, methanol, dioxane, ethanol, acetone, propanol, tetrahydrofuran, isopropanol, N-butanol, and acetonitrile.

Preferably, the reflux reaction time is 6 to 10 hours.

Preferably, the aromatic compound containing an acetyl chloride group includes 4-methylphenylacetyl chloride, 2- (2-naphthyl) acetyl chloride, 2, 6-dichlorobenzoyl chloride, 2-methylphenylacetyl chloride, cyclopentylacetyl chloride, phenylacetyl chloride, 3-bromophenylacetyl chloride, 3, 4-dimethoxyphenylacetyl chloride, 4-bromophenylacetyl chloride, 2, 5-dimethoxyphenylacetyl chloride, 4-fluorobenzeneacetyl chloride.

Preferably, the alkaline conditions have a pH of 7 to 14.

Preferably, the pH is adjusted by at least one of sodium carbonate, potassium hydroxide, sodium bicarbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate, sodium phosphate dodecahydrate, sodium methoxide, sodium phosphate, potassium phosphate, pyridine, triethylamine, diethylamine, ammonia monohydrate, calcium hydroxide, and potassium t-butoxide.

Preferably, the reaction temperature under alkaline conditions is 25-100 ℃ and the reaction time is 2-12h.

The application also provides application of the tertiary amide compound containing naphthyl in preparing antitumor drugs.

Preferably, the medicine comprises the tertiary amide compound containing naphthyl and a pharmaceutically acceptable carrier.

Preferably, the tumor includes esophageal cancer, gastric cancer, colorectal adenocarcinoma, gastric cancer, breast cancer and prostate cancer.

The application discloses the following technical effects:

the application simply and efficiently synthesizes the tertiary amide compound containing the naphthyl group with novel structure, and an in vitro anti-tumor activity test of the compound shows that the tertiary amide compound containing the naphthyl group has obvious inhibition effect on the growth of various tumor cells, including human esophageal cancer cells EC9706, human gastric cancer cells SGC7901, human colorectal adenocarcinoma cells HT-29, human gastric cancer cells MGC-803, human breast cancer cells MCF7 and human prostate cancer cells PC-3. The activity is obviously superior to that of the antitumor drug 5-fluorouracil, and the antitumor drug can be used as a lead compound or a candidate compound for developing broad-spectrum antitumor drugs.

Drawings

In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.

FIG. 1 shows a compound (D8) ¹ H-NMR chart;

FIG. 2 shows the compound (D8) ¹³ C-NMR spectrum.

Detailed Description

Various exemplary embodiments of the application will now be described in detail, which should not be considered as limiting the application, but rather as more detailed descriptions of certain aspects, features and embodiments of the application.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. In addition, for numerical ranges in this disclosure, it is understood that each intermediate value between the upper and lower limits of the ranges is also specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the application. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.

It will be apparent to those skilled in the art that various modifications and variations can be made in the specific embodiments of the application described herein without departing from the scope or spirit of the application. Other embodiments will be apparent to those skilled in the art from consideration of the specification of the present application. The specification and examples of the present application are exemplary only.

As used herein, the terms "comprising," "including," "having," "containing," and the like are intended to be inclusive and mean an inclusion, but not limited to.

The technical scheme of the application is conventional in the field, and the reagents or raw materials are purchased from commercial sources or are disclosed.

Example 1

1. Preparation of Compound (D1)

Partolylacetyl chloride (5 mmol) and intermediate C (6 mmol) were dissolved in dichloromethane (40 ml), potassium bicarbonate (6 mmol) was added and the reaction was heated at 40 ℃. TLC monitored the progress of the reaction, after completion of the reaction, 3 times with water (20 mL each), 3 times with saturated brine (20 mL each), the dichloromethane organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and the petroleum ether/ethyl acetate=10:1 is eluted to obtain the compound (D1), and the yield reaches 85.7%.

2. Preparation of Compound (D2)

2- (2-naphthyl) acetyl chloride (3 mmol) and intermediate C (4 mmol) were dissolved in acetone (25 ml), sodium bicarbonate (4 mmol) was added and the reaction was heated at 60 ℃. TLC monitors the reaction progress, after the reaction is finished, suction filtration and decompression concentration are carried out. The concentrate was dissolved in 30mL of ethyl acetate, extracted 3 times with 15mL each time, and extracted 3 times with 15mL each time of saturated brine, and the ethyl acetate organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=12:1 is eluted to obtain compound (D2), and the yield reaches 87.2%.

3. Preparation of Compound (D3)

(2, 6-dichlorophenyl) acetyl chloride (2 mmol) and intermediate C (3 mmol) were dissolved in methanol (15 ml), sodium carbonate (1.5 mmol) was added and the reaction was heated at 50 ℃. TLC monitors the reaction progress, after the reaction is finished, suction filtration and decompression concentration are carried out. The concentrate was dissolved in 20mL of ethyl acetate, extracted 3 times with water (10 mL each time), extracted 3 times with saturated brine (10 mL each time), and the ethyl acetate organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=10:1 is eluted to obtain compound (D3), and the yield reaches 90.1%.

4. Preparation of Compound (D4)

O-tolylacetyl chloride (6 mmol) and intermediate C (7.2 mmol) were dissolved in dichloromethane (30 ml), potassium bicarbonate (7.2 mmol) was added and the reaction was heated at 40 ℃. TLC monitored the progress of the reaction, after completion of the reaction, 3 times with water (15 mL each), 3 times with saturated brine (15 mL each), and the dichloromethane organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=9:1 is eluted to obtain compound (D4), and the yield reaches 94.2%.

5. Preparation of Compound (D5)

Cyclopentylacetylchloride (4 mmol) and intermediate C (5 mmol) were dissolved in ethanol (20 ml), triethylamine (5 mmol) was added and reacted by heating at 80 ℃. TLC monitors the reaction progress, after the reaction is finished, suction filtration and decompression concentration are carried out. The concentrate was dissolved in 20mL of ethyl acetate, extracted 3 times with water (10 mL each time), extracted 3 times with saturated brine (10 mL each time), and the ethyl acetate organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=12:1 is eluted to obtain compound (D5), and the yield reaches 88.6%.

6. Preparation of Compound (D6)

Phenylacetyl chloride (2 mmol) and intermediate C (3 mmol) were dissolved in acetonitrile (10 ml), sodium bicarbonate (3 mmol) was added and the reaction was heated at 85 ℃. TLC monitors the reaction progress, after the reaction is finished, suction filtration and decompression concentration are carried out. The concentrate was dissolved in 10mL of ethyl acetate, extracted 3 times with water (10 mL each time), extracted 3 times with saturated brine (10 mL each time), and the ethyl acetate organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=12:1 is eluted to obtain compound (D6), and the yield reaches 95.4%.

7. Preparation of Compound (D7)

3-Bromophenylacetyl chloride (5 mmol) and intermediate C (6 mmol) were dissolved in ethanol (10 ml), potassium tert-butoxide (6 mmol) was added and the reaction was heated at 85 ℃. TLC monitors the reaction progress, after the reaction is finished, suction filtration and decompression concentration are carried out. The concentrate was dissolved in 15mL of ethyl acetate, extracted 3 times with water (15 mL each time), and extracted 3 times with saturated brine (15 mL each time), and the ethyl acetate organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=9:1 is eluted to obtain compound (D7), and the yield reaches 86.2%.

8. Preparation of Compound (D8)

2-thiopheneacetyl chloride (3 mmol) and intermediate C (4 mmol) were dissolved in acetonitrile (15 ml), diethylamine (6 mmol) was added, and the mixture was heated at 85 ℃. TLC monitors the reaction progress, after the reaction is finished, suction filtration and decompression concentration are carried out. The concentrate was dissolved in 20mL of ethyl acetate, extracted 3 times with 15mL each time, and extracted 3 times with 15mL each time of saturated brine, and the ethyl acetate organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=10:1 is eluted to obtain compound (D8), and the yield reaches 91.7%.

9. Preparation of Compound (D9)

(3, 4-Dimethoxyphenyl) acetyl chloride (5 mmol) and intermediate C (6 mmol) were dissolved in tetrahydrofuran (25 ml), pyridine (6 mmol) was added thereto, and the reaction was heated at 66 ℃. TLC monitors the reaction progress, after the reaction is finished, suction filtration and decompression concentration are carried out. The concentrate was dissolved in 30mL of ethyl acetate, extracted 3 times with water (20 mL each time), then extracted 3 times with saturated brine (20 mL each time), the ethyl acetate organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and the petroleum ether/ethyl acetate=11:1 is eluted to obtain the compound (D9), and the yield reaches 94.5%.

10. Preparation of Compound (D10)

2- (4-bromophenyl) acetyl chloride (7 mmol) and intermediate C (8 mmol) were dissolved in 1, 4-dioxane (30 ml), and ammonia monohydrate (10 mmol) was added thereto to heat the reaction at 100 ℃. TLC monitors the reaction progress, after the reaction is finished, suction filtration and decompression concentration are carried out. The concentrate was dissolved in 30mL of ethyl acetate, extracted 3 times with water (20 mL each time), then extracted 3 times with saturated brine (20 mL each time), the ethyl acetate organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=9:1 is eluted to obtain compound (D10), and the yield reaches 85.9%.

11. Preparation of Compound (D11)

(2, 5-Dimethoxyphenyl) acetyl chloride (3 mmol) and intermediate C (5 mmol) were dissolved in chloroform (15 ml), pyridine (5 mmol) was added thereto, and the mixture was heated at 60 ℃. TLC monitors the reaction progress, after the reaction is finished, suction filtration and decompression concentration are carried out. The concentrate was dissolved in 15mL of ethyl acetate, extracted 3 times with water (10 mL each time), and extracted 3 times with saturated brine (10 mL each time), and the ethyl acetate organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=12:1 is eluted to obtain compound (D11), and the yield reaches 93.6%.

12. Preparation of Compound (D12)

4-Fluorophenylacetyl chloride (1 mmol) and intermediate C (1.5 mmol) were dissolved in methylene chloride (10 ml), and sodium hydrogen carbonate (1.5 mmol) was added thereto to heat the mixture at 40℃to react. TLC monitored the progress of the reaction, after completion of the reaction, 3 times with water (10 mL each), 3 times with saturated brine (10 mL each), and the dichloromethane organic phase was dried over anhydrous magnesium sulfate, the residue was filtered off, and the filtrate was distilled under reduced pressure. The crude product is separated and purified by silica gel column chromatography, and petroleum ether/ethyl acetate=9:1 is eluted to obtain compound (D12), and the yield reaches 89.6%.

Example 2

Determination of antitumor Activity of Compounds:

the compounds used in the screening are synthesized and purified by the application. Sample stock solution: 1-2mg of the sample was weighed and placed in a 1mL EP tube, then prepared into a 10mM solution with DMSO, and stored at 4 ℃. Human esophageal cancer cells EC9706, human gastric cancer cells SGC7901, human colorectal adenocarcinoma cells HT-29, human gastric cancer cells MGC-803, human breast cancer cells MCF7 and human prostatic cancer cells PC-3 in the logarithmic growth phase are inoculated into a 96-well plate, after 24 hours of culture, the culture medium is discarded, and a compound with the concentration of 1 mu M is added. After 48h of drug action, 20 mu L of MTT is added into each hole, after continuous culture for 4h, liquid is sucked, 100 mu L of DMSO is added, the vibration is uniform, absorbance value is detected at 490nm of an enzyme-labeled instrument, and the cell survival rate is calculated. The antitumor drug 5-fluorouracil (5-Fu) is used as a reference substance, and the experimental results are shown in Table 1.

TABLE 1 survival of 1. Mu.M Compounds interfering with tumor cells

As can be seen from Table 1, the compounds D1-D12 have broad-spectrum antitumor activity, and the tertiary amide compounds containing naphthyl can be used as candidates or lead compounds for further development and applied to preparation of antitumor drugs. And the antitumor activity of the compound D8 is obviously better than that of 5-fluorouracil.

Compound D8 was formulated into various concentrations of the drug solution. Taking human esophageal cancer cells EC9706, human gastric cancer cells SGC7901, human colorectal adenocarcinoma cells HT-29, human gastric cancer cells MGC-803, human breast cancer cells MCF7 and human prostatic cancer cells PC-3 in the logarithmic growth phase, inoculating into a 96-well plate, culturing for 24 hours, discarding the culture medium, and adding the compound D8. After 48h of drug action, 20 mu L of MTT is added into each hole, after continuous culture for 4h, liquid is sucked, 100 mu L of DMSO is added, vibration is uniform, absorbance value is detected at 490nm of an enzyme-labeled instrument, and IC of the compound D8 is calculated ₅₀ Values. The experimental results are shown in Table 2.

TABLE 2 IC of Compound D8 ₅₀ Value of

As can be seen from table 2, compound D8 has remarkable antitumor activity against human esophageal cancer cells EC9706, human gastric cancer cells SGC7901, human colorectal adenocarcinoma cells HT-29, human gastric cancer cells MGC-803, human breast cancer cells MCF7 and human prostate cancer cells PC-3. The compound D8 can be used as a candidate or lead compound for further development and applied to preparing broad-spectrum strong-effect antitumor drugs.

The above embodiments are only illustrative of the preferred embodiments of the present application and are not intended to limit the scope of the present application, and various modifications and improvements made by those skilled in the art to the technical solutions of the present application should fall within the protection scope defined by the claims of the present application without departing from the design spirit of the present application.

Claims

1. A tertiary amide compound containing naphthyl is characterized in that the tertiary amide compound is represented by a general formula (I),

wherein,comprises->

2. The tertiary amide compound including naphthyl group according to claim 1, comprising:

3. process for the preparation of tertiary amides containing naphthyl groups according to any one of claims 1-2, characterized in that it comprises the following steps:

4. A method of preparation according to claim 3, wherein the reflux reaction time is from 6 to 10 hours.

5. The method according to claim 3 or 4, wherein the aromatic compound containing an acetyl chloride group comprises 4-methylbenzoyl chloride, 2- (2-naphthyl) acetyl chloride, 2, 6-dichlorobenzoyl chloride, 2-methylbenzoyl chloride, cyclopentylacetyl chloride, phenylacetyl chloride, 3-bromophenylacetyl chloride, 3, 4-dimethoxyphenylacetyl chloride, 4-bromophenylacetyl chloride, 2, 5-dimethoxyphenylacetyl chloride, 4-fluorobenzeneacetyl chloride.

6. The method according to any one of claims 3 to 5, wherein the alkaline condition has a pH of 7 to 14.

7. The process according to claim 6, wherein the reaction temperature is 25 to 100℃and the reaction time is 2 to 12 hours under alkaline conditions.

8. Use of a tertiary amide compound containing a naphthyl group according to any one of claims 1-2 in the preparation of an antitumor drug.

9. The use according to claim 8, wherein the medicament comprises a tertiary amide containing a naphthyl group according to any one of claims 1-2 and a pharmaceutically acceptable carrier.