CN116987021A

CN116987021A - Novel isoindoline derivative with anti-tumor effect as well as preparation method and application thereof

Info

Publication number: CN116987021A
Application number: CN202310968496.0A
Authority: CN
Inventors: 付冬君
Original assignee: Beijing University of Chinese Medicine
Current assignee: Beijing University of Chinese Medicine
Priority date: 2023-08-03
Filing date: 2023-08-03
Publication date: 2023-11-03

Abstract

The application discloses a novel isoindoline derivative with an anti-tumor effect, and a preparation method and application thereof, and belongs to the technical field of medicines. The isoindoline compound with novel structure is synthesized by a simple and efficient one-step reaction, the total yield is more than 80%, and a heavy metal catalyst or a microwave reaction instrument is not involved. The in vitro anti-tumor activity test of the compounds shows that: it has certain inhibiting effect on the growth of various tumor cells. The novel isoindoline derivative can be used as a candidate or lead compound for further development and applied to preparation of antitumor drugs.

Description

Novel isoindoline derivative with anti-tumor effect as well as preparation method and application thereof

Technical Field

The application relates to the technical field of medicines, in particular to a novel isoindoline derivative with an anti-tumor effect, and a preparation method and application thereof.

Background

In recent years, more and more researches show that the isoindoline is an effective pharmacological activity fragment, and the isoindoline compound has antifungal, antioxidant, antiviral and antitumor activities and is used for designing and synthesizing antitumor drugs. The synthesis method of the isoindoline compound comprises an amination method of dihalide, a Diels-Alder reaction method, an intramolecular cyclization reaction method, an asymmetric synthesis method and a [2+2+2] cycloaddition reaction method, and the development of the isoindoline drug is limited by using a heavy metal catalyst or a microwave reaction instrument and the like. In a word, the synthesis of the novel isoindoline derivative with the anti-tumor activity by adopting a simple and efficient preparation method has important scientific and clinical significance.

Disclosure of Invention

The application aims to provide a novel isoindoline derivative with an anti-tumor effect, and 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 novel isoindoline derivative with an anti-tumor effect, which is represented by a general formula (I),

wherein ,comprises->

Preferably, the novel isoindoline derivatives comprise:

the application also provides a preparation method of the novel isoindoline derivative, which comprises the following reactions:

in an organic solvent, heating and reacting a compound shown in a formula II with pentafluorobenzenesulfonyl chloride under alkaline conditions to obtain the compound I.

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

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

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

Preferably, the temperature of the heating reaction is 25-120 ℃ and the reaction time is 4-15h.

The application also provides application of the novel isoindoline derivative in preparing antitumor drugs.

The application also provides an antitumor drug comprising the novel isoindoline derivative and a pharmaceutically acceptable carrier.

The application discloses the following technical effects:

the isoindoline compound with novel structure is synthesized by a simple and efficient one-step reaction, the total yield is more than 80%, and a heavy metal catalyst or a microwave reaction instrument is not involved. The in vitro anti-tumor activity test of the compounds shows that: it has certain inhibiting effect on the growth of various tumor cells. The novel isoindoline derivative can be used as a candidate or lead compound for further development and applied to preparation of 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 the compound (A5) ¹ H-NMR chart;

FIG. 2 shows the compound (A5) 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 (A1)

Into a 50ml three-necked flask were charged methanol (15 ml), 1-dimethyl-2, 3-dihydro-1H-isoindole (6 mmol), pentafluorobenzenesulfonyl chloride (8 mmol) and potassium hydrogencarbonate (8 mmol), and the mixture was reacted by heating at 65 ℃. TLC monitored the progress of the reaction, after the reaction was completed, distilled water was added to the system, the reaction was quenched, then extracted 3 times with ethyl acetate (20 mL each time), then 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 (A1), and the yield reaches 94.0%.

2. Preparation of Compound (A3)

To a 50ml three-necked flask were added acetonitrile (10 ml), 4-fluoroisoindoline (4 mmol), pentafluorobenzenesulfonyl chloride (6 mmol) and potassium carbonate (3 mmol), and the mixture was reacted by heating at 85 ℃. TLC monitored the progress of the reaction, after the reaction was completed, distilled water was added to the system, the reaction was quenched, then extracted 3 times with ethyl acetate (10 mL each time), then 3 times with saturated brine (10 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 (A3), and the yield reaches 91.8%.

3. Preparation of Compound (A5)

Into a 50ml three-necked flask were charged methanol (15 ml), isoindoline (5 mmol), pentafluorobenzenesulfonyl chloride (6 mmol) and sodium hydrogencarbonate (6 mmol), and the mixture was reacted by heating at 65 ℃. TLC monitors the progress of the reaction, after the reaction was completed, distilled water was added to the system, the reaction was quenched, then extracted 3 times with ethyl acetate (15 mL each time), then extracted 3 times with saturated brine (15 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=8:1 is eluted to obtain compound (A5), and the yield reaches 89.5%. Compound (A5) ¹ H-NMR chart ¹³ C-NMR spectrumShown in fig. 1-2.

4. Preparation of Compound (A8)

To a 50ml three-necked flask were added acetonitrile (10 ml), 5, 6-dimethoxyisoindoline (3 mmol), 2,3,4,5, 6-pentafluorobenzoyl chloride (4.5 mmol) and potassium hydrogencarbonate (4.5 mmol), and the mixture was reacted under heating at 82 ℃. TLC monitored the progress of the reaction, after the reaction was completed, distilled water was added to the system, the reaction was quenched, then extracted 3 times with ethyl acetate (20 mL each time), then 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 (A8), and the yield reaches 89.2%.

5. Preparation of Compound (A10)

In a 50ml three-necked flask were placed acetone (25 ml), 4-methylisoindoline (10 mmol), 2,3,4,5, 6-pentafluorobenzoyl chloride (11 mmol) and potassium hydrogencarbonate (11 mmol), followed by heating at 60 ℃. TLC monitored the progress of the reaction, after the reaction was completed, distilled water was added to the system, the reaction was quenched, then extracted 3 times with ethyl acetate (50 mL each time), then 3 times with saturated brine (50 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=7:1 is eluted to obtain compound (A10), and the yield reaches 91.4%.

6. Preparation of Compound (A12)

Into a 50ml three-necked flask were charged methanol (10 ml), 4-vinylisoindoline (5 mmol), 2,3,4,5, 6-pentafluorobenzoyl chloride (6 mmol) and potassium hydrogencarbonate (6 mmol), and the mixture was reacted under heating at 65 ℃. TLC monitored the progress of the reaction, after the reaction was completed, distilled water was added to the system, the reaction was quenched, then extracted 3 times with ethyl acetate (10 mL each time), then 3 times with saturated brine (10 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=10:1 is eluted to obtain compound (A12), and the yield reaches 87.3%.

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 a10 mM solution with DMSO, and stored at 4 ℃. Human esophageal cancer cells EC9706 and human prostatic cancer cells 22RV1 in logarithmic growth phase are inoculated into a 96-well plate, after 24h of culture, the culture medium is discarded, and compounds with different concentrations are 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 is used as a reference substance. The antitumor effect was confirmed by the compounds (A5, A8, A10) in examples 1 to 3, and the experimental results are shown in Table 1.

TABLE 1 survival of tumor cells under intervention of different concentrations of compound

As can be seen from table 1, the antitumor activity of the novel structural compounds (A5, A8, a 10) in example 1 on human esophageal cancer cells EC9706 and human prostate cancer cells 22RV1 was significantly better than that of the control drug 5-fluorouracil. The novel isoindoline derivative can be used as a candidate or lead compound for further development and applied to preparation of antitumor drugs.

The antitumor activity of the other compounds (A1, A2, A3, A4, A6, A7, A9, a11, a 12) against human esophageal cancer cells EC9706 and human prostate cancer cells 22RV1 was comparable to A5.

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 novel isoindoline derivative having an antitumor effect, characterized by being represented by the general formula (I),

wherein ,comprises->

2. The novel isoindoline derivative according to claim 1, characterized in that it comprises:

3. the process for the preparation of novel isoindoline derivatives according to any one of claims 1-2, characterized in that it comprises the following reactions:

4. The method according to claim 3, wherein the organic solvent comprises at least one of dichloromethane, dimethyl sulfoxide, N-dimethylformamide, ethyl acetate, methanol, ethanol, propanol, dioxane, acetone, tetrahydrofuran, isopropanol, toluene, and acetonitrile.

5. The method according to claim 3 or 4, wherein the alkaline condition has a pH of 7 to 14.

6. The method according to claim 5, wherein the pH is adjusted by at least one of potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, sodium phosphate dodecahydrate, sodium phosphate, triethylamine, potassium phosphate, pyridine, diethylamine, sodium methoxide, ammonia monohydrate and potassium t-butoxide.

7. The method according to any one of claims 3 to 6, wherein the heating reaction is carried out at a temperature of 25 to 120 ℃ for a reaction time of 4 to 15 hours.

8. Use of the novel isoindoline derivative according to any one of claims 1-2 for the preparation of an antitumor drug.

9. An antitumor agent comprising the novel isoindoline derivative of any one of claims 1-2 and a pharmaceutically acceptable carrier.