Benzothiazole compounds containing an acetamide bond, and methods of making and using the same

Abstract

The application discloses a benzothiazole compound containing an acetamide bond, named N-(4-methylbenzothiazole-2-yl)-2-(pyrrolidine-1-yl)acetamide. A preparation method comprises the following steps: first, preparing an N-(4-methylbenzo[d]thiazole-2-yl)-3-chloroacetamide compound; dissolving the N-(4-methylbenzo[d]thiazole-2-yl)-3-chloroacetamide compound and anhydrous potassium carbonate in dichloromethane to obtain a reaction solution; under the condition of an ice water bath and stirring, adding tetrahydropyrrole dropwise into the reaction solution; reacting at room temperature; monitoring the reaction progress by using TLC; after the reaction is completed, quenching the reaction solution by using water; adjusting the pH to neutral; obtaining a solid crude product; and purifying the solid crude product by recrystallization with ethanol to obtain the benzothiazole compound containing the acetamide bond. The compound can effectively inhibit monoamine oxidase and has low cytotoxicity.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a benzothiazole compound containing an acetamide bond and a preparation method and application thereof. BACKGROUND

[0002] Depression is a common mental disorder. The clinical manifestations are low mood, inattention, severe delay in thinking and action, catatonic state, and even suicidal tendency. According to WHO statistics, depression has become a common disease worldwide, with more than 350 million people suffering from depression worldwide, and the patient growth rate has been about 18% in the past decade. It is estimated that 5% of adults worldwide suffer from depression every year, and depression has become a serious economic burden for families and society.

[0003] Therefore, it is urgent to solve the problems of depression pathogenesis and to find and develop anti-depression candidate compounds or drugs. SUMMARY

[0004] The present application aims to provide a benzothiazole compound containing an acetamide bond and a preparation method and application thereof to solve the above problems.

[0005] The technical scheme of the present application is:

[0006] A benzothiazole compound containing an acetamide bond, the name is N-(4-methylbenzothiazol-2-yl)-2-(pyrrolidin-1-yl)acetamide, and the structural formula is:

[0007]

[0008] Another technical scheme of the present application is:

[0009] A preparation method of a benzothiazole compound containing an acetamide bond, the method comprising the following steps:

[0010] (1) Preparation of N-(4-methylbenzo[d]thiazol-2-yl)-3-chloroacetamide compound: under ice water bath conditions, slowly drop the tetrahydrofuran solution containing chloroacetyl chloride into the tetrahydrofuran suspension reaction liquid containing 4-methyl-2-amino benzothiazole and anhydrous potassium carbonate, after the drop is completed, continue the ice water bath reaction for 10 minutes, then warm up to room temperature, and react at room temperature for 4 hours, the reaction progress is monitored by TLC, after the reaction is completed, pour the reaction liquid into an ice water mixture to quench, adjust the pH to neutral, and the solid is precipitated to obtain a crude product, and the crude product is separated by column to obtain white solid N-(4-methylbenzo[d]thiazol-2-yl)-3-chloroacetamide;

[0011] (2) the N-(4-methylbenzo[d]thiazol-2-yl)-3-chloroacetamide compound and anhydrous potassium carbonate are dissolved in dichloromethane to obtain a reaction solution, tetrahydropyrrole is added dropwise to the reaction solution under the condition of ice water bath and stirring, reaction is carried out at room temperature, the reaction process is monitored by TLC, after the reaction is completed, the reaction solution is quenched with water, the pH is adjusted to neutral to obtain a solid crude product, the solid crude product is purified by recrystallization with ethanol to obtain a benzothiazole compound containing an acetamide bond.

[0012] Further, in step (1), the molar ratio of the chloroacetyl chloride, 6-methyl-2-aminobenzothiazole and anhydrous potassium carbonate is 3:2:4.

[0013] Further, in step (1), the volume ratio of the tetrahydrofuran solution containing chloroacetyl chloride to the tetrahydrofuran suspension reaction solution containing 4-methyl-2-aminobenzothiazole and anhydrous potassium carbonate is 1:1.

[0014] Further, in step (1), the volume ratio of ethyl acetate to petroleum ether used for column separation is 1:15.

[0015] Further, in step (1), the pH is adjusted to neutral with 1M NaOH aqueous solution.

[0016] Further, in step (2), the molar ratio of the N-(4-methylbenzo[d]thiazol-2-yl)-3-chloroacetamide compound, anhydrous potassium carbonate and tetrahydropyrrole is 2:3:3.

[0017] Further, in step (2), the time for monitoring the reaction process by TLC is 5 hours.

[0018] Further, in step (2), the pH is adjusted to neutral with 3M NaOH aqueous solution.

[0019] The third technical solution of the present application is:

[0020] The application of a benzothiazole compound containing an acetamide bond in the preparation of an antidepressant and anti-Parkinson's disease drug.

[0021] The present application provides a benzothiazole compound containing an acetamide bond and a preparation method and application thereof, which can effectively inhibit monoamine oxidase and has low cytotoxicity. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 The structural formula of the benzothiazole compound containing an acetamide bond according to the present application;

[0023] Figure 2A preparation route chart of a benzothiazole compound (MBTPA-2023) containing an acetamide bond according to the present application. DETAILED DESCRIPTION

[0024] It is well known that monoamine oxidase (MAO) is a class of FAD-dependent enzymes, which widely exist in the mitochondrial membrane outside of nerve cells, neuroglia cells and other mammalian cells, and catalyze the oxidative deamination of exogenous and endogenous monoamine substances to produce corresponding hydrogen peroxide, aldehyde and substituted amine or ammonia. This enzyme is essential for the normal function of synaptic neurotransmission. MAO is composed of two different subtypes, namely MAO-A and MAO-B. Selective MAO-A inhibitors can be used for the treatment of depression, while selective and irreversible MAO-B inhibitors can be used for the treatment of Parkinson's disease.

[0025] Heterocyclic compounds are important compounds in the field of drug research and development, and the amount of heterocyclic compounds in the Comprehensive Medicinal Chemistry (CMC) database has exceeded 67%. Benzothiazole as a special drug scaffold structure is increasingly concerned by workers in the field of medicinal chemistry. It is used as an important pharmacophore for the treatment of various diseases in many marketed drugs. It is reported in the literature that benzothiazole derivatives have the activity of inhibiting monoamine oxidase.

[0026] The amide group as an advantage group plays a basic pharmacophore role in many drugs, because the amide group can better interact with the action site in the biological macromolecules in the human body. Pyrrolidine is also a heterocycle with multiple activities, and has been used in many drugs and drug researches. It is reported in the literature that compounds containing pyrrolidine have the activities of anti-depression and anti-Parkinson's disease.

[0027] Reference is made to Figure 1 , Figure 1 A structural formula of a benzothiazole compound containing an acetamide bond according to the present application. As shown in Figure 1 the object of the present application is to provide a benzothiazole compound containing an acetamide bond, i.e. N-(4-methylbenzothiazol-2-yl)-2-(pyrrolidin-1-yl)acetamide (MBTPA-2023), which is a monoamine oxidase inhibitor with strong activity and low toxicity.

[0028] In order to make the above object, features and advantages of the present application more apparent and easy to understand, the technical solutions of the present application will be further described below in combination with examples. However, the present application is not limited to the listed examples, and any known changes within the scope of the claimed rights of the present application are also included.

[0029] As used herein, the term "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the implementation can be included in at least one implementation of the disclosure. The appearances of the phrase "in one embodiment" or "in an embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are they necessarily all referring to a single, special implementation.

[0030] Example 1

[0031] This example demonstrates a method for preparing a benzothiazole compound containing an amide bond according to the following steps:

[0032] 1. Preparation of N-(4-methylbenzo[d]thiazol-2-yl)-3-chloroacetamide compound

[0033] A solution of 0.90 g of chloroacetyl chloride (0.015 mol) in tetrahydrofuran (10 mL) was slowly added dropwise to a suspension of 2.0 g of 4-methyl-2- aminobenzothiazole (0.010 mol) and 2.24 g of anhydrous potassium carbonate (0.020 mol) in tetrahydrofuran (10 mL) under an ice water bath (0 °C). After the addition was completed, the ice water bath (0 °C) was continued for 10 min, and then the temperature was raised to room temperature (25 °C) for about 4 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into an ice water mixture to quench, and then the pH was adjusted to neutral with a 1 M aqueous NaOH solution. The crude product was obtained as a solid. The crude product was separated by column (V 乙酸乙酯 :V 石油醚 = 1:15) to give N-(4-methylbenzo[d]thiazol-2-yl)-3-chloroacetamide as a white solid.

[0034] 2. Preparation of N-(4-methylbenzothiazol-2-yl)-2-(pyrrolidin-1-yl)acetamide (MBTPP-2022)

[0035] A solution of 2.0 g of N-(4-methylbenzo[d]thiazol-2-yl)-3-chloroacetamide (0.010 mol) and 1.30 g of anhydrous K2CO3 (0.015 mol) was dissolved in dichloromethane (10 mL). 2.54 g of tetrahydro-pyrrole (0.015 mol) was added dropwise under stirring in an ice water bath (0 °C). The reaction was carried out at room temperature (25 °C), and the progress of the reaction was monitored by TLC (5 h). After the reaction was completed, the reaction solution was quenched with water. The pH was adjusted to neutral with a 3 M NaOH solution. The crude product was obtained as a solid, which was then recrystallized from ethanol to give MBTPP-2022 as a white solid.

[0036] The preparation route of the target compound MBTPA-2023 is shown in Figure 2 , Figure 2A preparation route chart of a benzothiazole compound (MBTPA-2023) containing an acetamide bond described in the present application, physical data and spectral data are as follows:

[0037] HPLC / Purity:97.8949%(t R =7.866),Yield:72.86%,mp:156.3-156.9℃. 1 H

[0038] NMR(CDCl3,300MHz):δH=1.85-1.88(m,4H,NCH2CH2 of pyrrolidine ring),2.47(s,3H,-CH3),2.72(s,4H,NCH2CH2 of pyrrolidine ring),3.42(s,2H,COCH2),7.24(d,J=9.0Hz,1H,ph-H),7.61(s,1H,ph-H),7.66(d,J=9.0Hz,1H,ph-H); 13 C NMR(CDCl3,75MHz)δC=21.47,24.13,54.76,58.65,120.54,121.23,127.70,132.40,133.97,146.47,156.53,169.88.MS(ESI)calcd for[M+H] + =276.1,found 276.1.

[0039] Example 2

[0040] This embodiment case demonstrates the monoamine oxidase pharmacological activity as follows:

[0041] In the 96-well plate, add 25 μL of enzyme diluent (3 times dilution of stock solution) and 25 μL of 10% DMSO, after placing in a 37℃ constant temperature incubator for 1 h, add 120 μL of substrate and 80 μL of chromogenic solution in turn, and incubate at 37℃ for 30 min. The absorbance value Ablank of the blank control group, the absorbance value Asample of MBTPA-2023 and the positive control drug are detected by the enzyme marker.

[0042] MAO inhibitory activity (%) = [(Ablank-Aprotein)-(Asample or Apositive-Aprotein)] / (Ablank-Aprotein) x 100%

[0043] According to the results of the experimental samples on MAO inhibitory activity, in order to further determine the half inhibitory concentration (IC 50 ) value, the inhibitory rate of different concentrations obtained is substituted into the IC 50 software Prism8, and the IC50 Values.

[0044]

[0045] Table 1

[0046] Referring to Table 1, Table 1 is a table of inhibitory activity of the target compound MBTPA-2023 on MAO. As shown in Table 1, the compound MBTPA-2023 has certain inhibitory activity on MAO-A and MAO-B, but has stronger inhibitory activity on MAO-B (its IC 50 is 6.21±0.47 μM), showing certain antidepressant and anti-Parkinson's disease activity.

[0047] It should be noted that the above examples are only used to illustrate the technical solutions of the present application and not to limit it. Although the present application has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solutions of the present application can be modified or replaced equivalently without departing from the spirit and scope of the technical solutions of the present application, which should be covered in the scope of the claims of the present application.

Claims

1. The use of a benzothiazole compound containing an acetamide bond in the preparation of a medicament for antidepressant and anti-Parkinson's disease effects by inhibiting MAO-A and MAO-B, characterized in that: The structural formula of the benzothiazole compound containing the acetamide bond is: 。

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