Benzothieno-dinitrogen compound, preparation method and application of benzothieno-dinitrogen compound
By reacting benzothiophene azadiene with β-sulfonamide substituted enone or alkenes under inorganic base catalysis, the problem of lack of effective catalytic synthesis in the prior art is solved, and the efficient synthesis of benzothiophene diazole compounds is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202411592671.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-08
- Publication Date
- 2025-03-11
AI Technical Summary
A catalytic method for developing a simple synthesis strategy to construct a benzothienodianitrogen skeleton is lacking in the prior art.
Benzothiophene azadiene and beta-sulfonamide substituted enone or alkenyl ester are constructed by reacting the benzothiophene azadiene under the catalysis of the inorganic base.
The efficient and convenient synthesis of benzothienodiazole compounds is achieved, and the use of transition metals, strong acids or strong bases is avoided. The reaction conditions are mild and suitable for industrial production.
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Figure CN119591615A_ABST
Abstract
Description
Technical Field
[0001] The present invention mainly relates to an efficient and convenient synthesis method of benzothiophene diazepine compounds and application of the same in pharmaceutical preparation. Background Art
[0002] The benzothiophene diazepine skeleton has a special structure, and its core skeleton is widely present in natural products and drugs. For example, mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a Ser / Thr protein kinase in the calcium / calmodulin-dependent protein kinase family. MK2 is a direct substrate of p38 kinase and plays an important role in the production of cytokines. Compound 1 is an effective MK2 inhibitor. AP521 is a potential new anxiolytic drug that works by enhancing 5-HT transmission in the mPFC and possibly antagonist-like activity on presynaptic 5-HT1A receptors. AP521 can also be used as a postsynaptic 5-HT1A receptor agonist for the treatment of anxiety disorders. Y-931 is a potential new atypical antipsychotic drug with a low risk of extrapyramidal syndrome (EPS) and the characteristics of improving NMDA receptor hypofunction, which can be used to improve the treatment of schizophrenia with a low risk of EPS. Molecules containing the diazepine mother core are also a class of structures with multiple pharmacological activities, such as compound 4, which has antibacterial activity. In addition, a variety of natural compounds containing the benzothiophene diazepine skeleton have been found to have significant biological activities.
[0003]
[0004] Natural products and active molecules containing benzothienodiazepine skeleton The development of a simple synthesis strategy for the skeleton has always been a topic of great concern in the organic community, but there are few reports on catalytic synthesis methods for synthesizing the skeleton. The goal of the present invention is to design a simple and practical catalytic method to construct the skeleton. Organic base catalysis is a very good catalyst in cyclization reactions and is often used as an efficient catalyst for cyclization reactions. Therefore, the present invention splits the parent core structure into benzothiophene azadiene and β-sulfonamide-substituted enone or enester, and efficiently constructs the parent core structure through base catalysis. Summary of the invention
[0005] In view of the above technical problems, the present invention provides a benzothiophene diazepine compound, a preparation method thereof and an application thereof in pharmaceutical preparation. The inventors have found through research that benzothiophene azadiene is a unique class of compounds containing a benzothiophene skeleton, which has the characteristics of stability and easy preparation. In view of this, the present invention designs a reaction method for preparing benzothiophene diazepine compounds by reacting benzothiophene azadiene with a β-sulfonamide-substituted enone or enester.
[0006] The present invention provides a method for synthesizing a benzothiophene diazepine compound. Under the condition of inorganic base catalysis, benzothiophene azadiene and β-sulfonamide substituted enone or enester are used as reaction materials, and react in a reaction solvent to effectively achieve the corresponding conversion to prepare a benzothiophene diazepine compound as shown in formula (III). The reaction process is shown in the following reaction formula (a):
[0007] In the above reaction formula, R 1 is a benzene ring, a substituted benzene ring, an alkyl group or an alkane containing an aromatic group; R 2 is a benzene ring, a substituted benzene ring, or an aromatic heterocycle; preferably, R 1 is methyl, cyclopropyl, tert-butoxy, benzyloxy, benzhydryloxy, phenyl, or substituted phenyl; R 2 is phenyl, 2-fluorophenyl, 2-methylphenyl, 2-bromophenyl, 2-methoxyphenyl, 2-naphthyl, 2-thiophene, 3-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-methylphenyl, 4-nitrophenyl; As shown in the above reaction formula (a), the present invention utilizes the benzothiophene azadiene shown in formula (I) and a β-sulfonamide-substituted enone or enester as reaction raw materials, and reacts in a reaction solvent under the action of an inorganic base to obtain a benzothiophene diazepine compound shown in formula (III).
[0008] In the present invention, the catalyst is Et3N, DMAP, DABCO, DBU, NaOH, NaHCO3, t BuONa, Cs2CO3, K2CO3, Na2CO3.
[0009] In the present invention, the solvent is any one or any combination of CHCl3, DCM, DCE, Toluene, THF, MeCN, Acetone, EtOH. Preferably, the solvent is dichloroethane.
[0010] In the present invention, the ratio of the starting material benzothiophene azadiene as shown in formula (I) to the starting material β-sulfonamide substituted enone or enester as shown in formula (II) is 1:1-1:2. Preferably, the ratio of the two is 1.0:1.2.
[0011] In the present invention, the reaction temperature is 10-80°C, preferably 20-30°C.
[0012] The synthesis reaction of the present invention comprises the following steps: The reaction described in reaction formula (a) comprises the following steps: adding benzothiophene azadiene, β-sulfonamide substituted enone or enester, and dichloroethane into a reaction container, and stirring the reaction at room temperature to obtain a benzothiophene diazepine compound represented by formula (III).
[0013] In a specific example, as shown in reaction formula (a), the synthesis reaction of the present invention is to add benzothiophene azadiene (X mmol), β-sulfonamide substituted enone or enester (Y mmol), and solvent (V mL) into a reaction bottle A, and stir the reaction system at room temperature for 12 hours. After the reaction is completed, the reaction system is cooled to room temperature, concentrated, and separated by column chromatography to obtain the target product.
[0014] The present invention also provides a benzothiophene diazepine compound as shown in formula (III) prepared according to the above-mentioned synthesis method of the present invention, Formula (III); Among them, R 1 is a benzene ring, a substituted benzene ring, an alkyl group or an aryl-containing alkane; R 2 It is a benzene ring, a substituted benzene ring, or an aromatic heterocycle.
[0015] The present invention also provides a method for using the benzothienodiazepine compound represented by the above formula (III) in the synthesis of potential drugs containing a benzothienodiazepine skeleton.
[0016] The present invention has the following advantages: (1) no transition metal is required as a catalyst; (2) no strong acid or strong base is required; (3) no oxidizing or reducing agent is required; (4) the inorganic base is cheap and readily available and stable in the air; (5) the reaction substrate is easy to prepare; (6) the reaction is easy to operate, environmentally friendly, and has practical value.
[0017] The invention uses an easily prepared benzothiophene azadiene compound and a β-sulfonamide substituted enone or enester compound as reaction raw materials, and reacts under the action of an inorganic base to obtain a benzothiophene diazepine compound. The reaction operation is simple, the reaction conditions are relatively mild, and the benzothiophene diazepine compound is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 is the hydrogen spectrum of compound 1.
[0019] Figure 2 is the carbon spectrum of compound 1.
[0020] Figure 3 is the hydrogen spectrum of compound 10.
[0021] Figure 4 is the carbon spectrum of compound 10. DETAILED DESCRIPTION
[0022] The present invention is further described in detail in conjunction with the following specific examples, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no special restrictions. The data given in the following examples include specific operations and reaction conditions and products. The purity of the product is identified by nuclear magnetic resonance.
[0023] The synthesis reaction of the benzothiophene diazepine compound of the present invention comprises the following steps: using benzothiophene azadiene and β-sulfonamide substituted enone or enester as reaction raw materials, reacting in a reaction solvent under the catalytic action of an inorganic base to obtain the benzothiophene diazepine compound; and screening the catalyst and solvent conditions, which are specifically as follows:
[0024]
[0025] Given the above-mentioned screening conditions, the following examples use Cs2CO3 as a catalyst and DCE as a solvent, react at room temperature for 12 h, and then concentrate and separate by column chromatography to obtain the desired product, such as the benzothiophene diazepine compounds shown in Table 1, which are all products synthesized by the method of the present invention. There is no public document disclosing these compounds.
[0026] Table 1 New benzothiophene diazepine compounds of the present invention
[0027] Example 1
[0028] After adding benzothiophene azadiene (39.1 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into a reaction tube, β-sulfonamide substituted enone (37.8 mg, 0.12 mmol, 1.2 equiv.) was added, and then an inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %) was added, and stirred at room temperature for 12 hours. The reaction solution was then decompressed to remove the solvent, and the product 1 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 90%, 20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d8.09 (d, J = 8.0 Hz, 1H), 8.01 –7.98 (m, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.68 – 7.26 (m, 10H), 7.24 – 6.79 (m,7H), 5.43 (s, 1H), 5.25 – 5.17 (m, 1H), 4.04 – 3.99 (m, 1H), 3.90 – 3.85 (m,1H), 3.03 – 2.92 (m, 2H), 2.51 (s, 3H), 2.27 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 197.3, 144.2, 142.7, 141.2, 139.5, 139.1, 136.9, 136.8, 136.4, 136.0, 133.6,130.2, 128.9, 128.8, 128.4, 128.3, 128.0, 127.0, 125.9, 125.2, 125.1, 123.5,121.8, 61.2, 57.6, 47.6, 44.3, 21.7, 21.3.HRMS (ESI)m / z: calcd. forC 39 H 35 N2O5S3 + (M + H) + 707.1703, found 707.1704. Example 2
[0029] After adding benzothiophene azadiene (39.1 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into the reaction tube, β-sulfonamide substituted ene ester (41.4 mg, 0.12 mmol, 1.2 equiv.) was added, and then the inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %) was added and stirred at room temperature for 12 hours. The reaction solution was then decompressed to remove the solvent, and the product 2 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 87%, 20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d 8.09 (d, J= 7.6 Hz,1H), 7.78 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.49 – 7.29 (m, 11H),7.25 – 6.76 (m, 7H), 5.37 (s, 1H), 5.15 – 5.09 (m, 3H), 3.89 – 3.84 (m, 1H),3.13 – 3.07 (m, 1H), 2.89 – 2.84 (m, 1H), 2.60 – 2.49 (m, 4H), 2.30 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 169.9, 144.1, 142.7, 141.1, 139.3, 139.0, 136.8,136.7, 136.0, 135.4, 130.1, 128.9, 128.8, 128.59, 128.58, 128.4, 128.0,126.9, 125.7, 125.2, 125.0, 123.8, 121.6, 67.0, 61.2, 57.7, 47.7, 39.6, 21.7,21.3.HRMS (ESI)m / z: calcd. for C 40 H 37 N2O6S3 + (M + H) + 737.1808, found 737.1813. Example 3
[0030] After adding benzothiophene azadiene (39.1 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into the reaction tube, β-sulfonamide substituted enone (30.4 mg, 0.12 mmol, 1.2 equiv.) was added, and then the inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %) was added and stirred at room temperature for 12 hours. The reaction solution was then decompressed to remove the solvent, and the product 3 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 71%, 20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d 8.05 (d,J = 8.0 Hz,1H), 7.76 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.48 – 7.31 (m, 6H),7.22 – 6.67 (m, 7H), 5.39 (s, 1H), 5.08 – 5.01 (m, 1H), 4.00 – 3.95 (m, 1H),3.23 – 3.17 (m, 1H), 2.88 – 2.82 (m, 1H), 2.50 (s, 3H), 2.49 – 2.42 (m, 1H), 2.27 (s, 3H), 2.24 (s, 3H). 13 C NMR (100 MHz, CDCl3) d .7, 125.2, 125.1, 123.5, 121.7, 61.1, 57.0, 48.8, 47.6, 30.3, 21.7, 21.3. Example 4
[0031] After adding benzothiophene azadiene (39.1 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into a reaction tube, β-sulfonamide substituted enone (33.5 mg, 0.12 mmol, 1.2 equiv.) was added, and then an inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %) was added, and stirred at room temperature for 12 hours. The reaction solution was then decompressed to remove the solvent, and the product 4 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 85% 20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d 8.06 (d, J = 8.0 Hz,1H), 7.77 (d, J = 8.4 Hz, 2H), 7.57 (d, J= 8.0 Hz, 1H), 7.48 – 7.30 (m, 7H),7.20 – 6.83 (m, 7H), 5.37 (s, 1H), 5.12 – 5.05 (m, 1H), 3.96 – 3.91 (m, 1H),3.42 – 3.37 (m, 1H), 2.94 – 2.88 (m, 1H), 2.63 – 2.56 (m, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.08 – 2.02 (m, 1H), 1.10 – 0.88 (m, 4H). 13 C NMR (100 MHz,CDCl3) d 207.8, 144.1, 142.7, 141.2, 139.4, 139.0, 136.83, 136.80, 136.0,130.2, 128.9, 128.8, 128.4, 127.9, 127.0, 125.9, 125.2, 125.0, 123.6, 121.7,61.2, 57.2, 48.9, 47.6, 21.7, 21.3, 20.8, 11.8, 11.2. Example 5
[0032] After adding benzothiophene azadiene (39.1 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into the reaction tube, β-sulfonamide substituted enone (41.4 mg, 0.12 mmol, 1.2 equiv.) was added, and then the inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %) was added, and stirred at room temperature for 12 hours. The reaction solution was then decompressed to remove the solvent, and the product 5 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 73%, 20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d 8.07 (d, J = 8.0 Hz,1H), 7.94 (d, J = 8.4 Hz, 2H), 7.78 (d, J= 8.0 Hz, 2H), 7.70 – 7.20 (m, 10H),7.19 – 6.57 (m, 7H), 5.41 (s, 1H), 5.21 – 5.14 (m, 1H), 4.02 – 3.97 (m, 1H),3.84 – 3.79 (m, 1H), 3.04 – 2.89 (m, 2H), 2.51 (s, 3H), 2.27 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 196.1, 144.3, 142.8, 141.2, 140.1, 139.4, 139.0, 136.9,136.7, 135.9, 134.7, 130.2, 129.7, 129.1, 128.9, 128.8, 128.4, 127.9, 127.0,125.8, 125.2, 125.1, 123.4, 121.8, 61.2, 57.6, 47.6, 44.2, 21.7, 21.3.HRMS(ESI)m / z: calcd. for C 39 H 34 ClN2O5S3 + (M + H) + 741.1313, found 741.1333. Example 6
[0033] After adding benzothiophene azadiene (39.7 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into the reaction tube, add β-sulfonamide substituted enone (37.8 mg, 0.12 mmol, 1.2 equiv.), then add inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %), and stir at room temperature for 12 hours. Then the reaction solution was decompressed to remove the solvent, and the product 6 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 63%, 20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d 8.06 (d, J = 8.0 Hz,1H), 7.97 (d, J = 7.2 Hz, 2H), 7.75 (d, J= 8.4 Hz, 2H), 7.64– 7.58 (m, 2H), 7.51– 7.44 (m, 3H), 7.39– 7.34 (m, 3H), 7.13 (d, J = 5.1 Hz, 1H), 7.03– 6.90(m, 6H), 6.06 (s, 1H), 5.22– 5.15 (m, 1H), 4.00– 3.95 (m, 1H), 3.87– 3.82 (m,1H), 3.01– 2.83 (m, 2H), 2.48 (s, 3H), 2.28 (s, 3H). 13 C NMR (100 MHz, CDCl3) d .7, 121.8, 57.8, 57.7, 46.7, 44.0, 21.7, 21.4. Example 7
[0034] After adding benzothiophene azadiene (40.5 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into the reaction tube, β-sulfonamide substituted enone (37.8 mg, 0.12 mmol, 1.2 equiv.) was added, and then the inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %) was added, and stirred at room temperature for 12 hours. The reaction solution was then decompressed to remove the solvent, and the product 7 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 63%, 20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d 8.08 (d, J = 8.0 Hz,1H), 8.00 (d, J = 7.2 Hz, 2H), 7.79 (d, J= 8.4 Hz, 2H), 7.62– 7.33 (m, 8H), 7.12– 7.10 (m, 2H), 6.91– 6.84 (m, 6H), 5.39 (s, 1H), 5.22– 5.14 (m, 1H), 4.06– 4.01 (m, 1H), 3.91– 3.86 (m, 1H), 3.04– 2.92 (m, 2H), 2.50 (s, 3H), 2.27 (s, 3H), 1.62 (s, 3H). 13 C NMR (100 MHz, CDCl3) d 9.8, 124.7, 125.14, 125.09, 123.4, 121.8, 61.2, 57.7,47.8, 44.3, 21.7, 21.3, 21.2. Example 8
[0035] After adding benzothiophene azadiene (46.9 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into the reaction tube, β-sulfonamide substituted enone (37.8 mg, 0.12 mmol, 1.2 equiv.) was added, and then the inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %) was added, and stirred at room temperature for 12 hours. The reaction solution was then decompressed to remove the solvent, and the product 8 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 61%, 20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d 8.07 (d, J = 8.0 Hz,1H), 7.99 (d, J = 7.6 Hz, 2H), 7.79 (d, J= 8.0 Hz, 2H), 7.62– 7.34 (m, 10H), 6.98– 6.92 (m, 6H), 5.37 (s, 1H), 5.22– 5.16 (m, 1H), 4.14– 4.09 (m, 1H), 3.89– 3.84 (m, 1H), 3.00– 2.93 (m, 2H), 2.51 (s, 3H), 2.31 (s, 3H). 13 C NMR (100 MHz, CDCl3) d .5, 121.9, 60.5, 57.7, 47.8, 44.2, 21.7, 21.4. Example 9
[0036] After adding 2-fluorobenzothiophene azadiene (40.5 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into a reaction tube, β-sulfonamide substituted enone (37.8 mg, 0.12 mmol, 1.2 equiv.) was added, and then an inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %) was added, and stirred at room temperature for 12 hours. The reaction solution was then decompressed to remove the solvent, and the product 10 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 71%, >20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d 8.08 (d, J = 8.0 Hz,1H), 8.00 (d, J = 7.2 Hz, 2H), 7.79 (d, J= 8.4 Hz, 2H), 7.63 – 7.33 (m, 8H),7.12 – 6.88 (s, 8H), 5.39 (s, 1H), 5.23 – 5.15 (m, 1H), 4.03 – 3.98 (m, 1H),3.89 – 3.84 (m, 1H), 3.02 – 2.91 (m, 2H), 2.50 (s, 3H), 2.36 (s, 3H), 2.28(s, 3H). 13 C NMR (100 MHz, CDCl3) d 9.8, 197.3, 144.2, 142.6, 141.5, 139.2, 138.8,136.87, 136.85, 136.6, 136.4, 136.0, 133.6, 130.2, 128.9, 128.8, 128.3,127.9, 127.1, 125.8, 125.12, 123.5, 121.8, 60.9, 57.7, 47.6, 44.3,21.7, 21.3, 21.2. Example 10
[0037] After adding 4-fluorobenzothiophene azadiene (40.5 mg, 0.10 mmol, 1.0 equiv.) and the reaction solvent dichloroethane (1 mL) into the reaction tube, β-sulfonamide substituted enone (37.8 mg, 0.12 mmol, 1.2 equiv.) was added, and then the inorganic base Cs2CO3 (3.3 mg, 0.01 mmol, 10 mol %) was added and stirred at room temperature for 12 hours. The reaction solution was then decompressed to remove the solvent, and the product 11 was obtained after column chromatography separation (eluent polarity: petroleum ether / ethyl acetate / dichloromethane 5:1:1). Yield: 77%, >20:1 d.r. ; 1 H NMR (400 MHz, CDCl3) d 8.06 (d, J = 8.0 Hz,1H), 7.99 (d, J = 7.6 Hz, 2H), 7.78 (d, J= 8.0 Hz, 2H), 7.63– 7.60 (m, 2H),7.53– 7.34 (m, 7H), 6.97– 6.90 (m, 4H), 5.39 (s, 1H), 5.22– 5.14 (m, 1H),4.10– 4.04 (m, 1H), 3.88– 3.83 (m, 1H), 3.01– 2.93 (m, 2H), 2.50 (s, 3H), 2.31 (s, 3H). 13 C NMR (100 MHz, CDCl3) d .9, 135.9, 133.6, 131.4, 130.2, 129.0, 128.8, 128.2,127.9, 126.8, 126.3, 125.3, 125.2, 123.5, 122.9, 121.8, 60.5, 57.6, 47.7,44.2, 21.7, 21.4. Embodiment 11 In vitro inhibitory activity of benzothienodiazepines on α-glucosidase The present invention uses the in vitro inhibitory activity of the enzyme α-glucosidase to detect the inhibitory activity of multiple compounds on α-glucosidase, and acarbose is a positive drug. The reaction solution is prepared, and the sample and the positive drug are dissolved in DMSO, and the compound concentrations are 90, 30, and 10 μM respectively.
[0038] The experiment was divided into enzyme activity group (50 μL α-glucosidase solution and 20 μL PBS solution), enzyme blank group (70 μL PBS solution), positive group (50 μL α-glucosidase solution and 20 μL positive drug solution), positive blank group (50 μL PBS solution and 20 μL positive drug solution), sample group (50 μL α-glucosidase solution and 20 μL sample solution) and sample blank group (50 μL PBS solution and 20 μL sample solution).
[0039] Add the above dosage to a 96-well plate, three in each group, shake and mix for 2 minutes, react at 37 ºC for 10 minutes, add 25μL substrate (PNPG) solution, shake and mix for 2 minutes, react at 37℃ for 30 minutes, add 100μL Na2CO3 to stop the reaction, shake and mix for 5 minutes. After the addition of the substrate (PNPG), the α-glucosidase is catalyzed to decompose into p-nitrophenol (PNP) and glucose. PNP is a colored substance that develops color under alkaline conditions and has specific absorption at 405nm. The inhibitory activity of the sample is obtained by measuring the absorbance OD. By making a regression equation for different concentrations of inhibitors and the corresponding inhibition rate, the half inhibition concentration (IC 50 ). Cell viability was determined using the following formula: (1-Δ-like / Δ-enzyme) × 100%.
[0040] Table 1: Test results of compounds .
Claims
1. A method for synthesizing a benzothienodiazepine compound, characterized in that: A benzothiophene azadiene and a β-sulfonamide substituted enone or enester are used as reaction raw materials, and react in a reaction solvent under the catalysis of an inorganic base to obtain a benzothiophene diazepine compound as shown in formula (III); wherein R 1 is a benzene ring, a substituted benzene ring, an alkyl group or an aryl-containing alkane; R 2 is a benzene ring, a substituted benzene ring, or an aromatic heterocycle. The reaction process is shown in reaction formula (a); 2. The synthesis method according to claim 1, characterized in that The catalyst is selected from Et3N, DMAP, DABCO, DBU, NaOH, NaHCO3, t BuONa, Cs2CO3, K2CO3, Na2CO3.
3. The synthesis method according to claim 1, characterized in that The reaction solvent is selected from any one or more combinations of CHCl3, DCM, DCE, Toluene, THF, MeCN, Acetone, and EtOH.
4. The synthesis method according to claim 1, characterized in that In the reaction, the molar ratio of the raw material benzothiophene azadiene to the β-sulfonamide substituted enone or enester is 1:1-2:
1.
5. The synthesis method according to claim 1, characterized in that The reaction temperature is 10-80°C.
6. A benzothienodiazepine compound prepared by the synthesis method according to any one of claim 1, characterized in that: Its structure is shown in formula (III): Formula (III); Among them, R 1 is a benzene ring, a substituted benzene ring, an alkyl group or an aryl-containing alkane; R 2 It is a benzene ring, a substituted benzene ring, or an aromatic heterocycle.
7. The benzothienodiazepine compound according to claim 6, characterized in that: Its structure is shown in formula (III): Formula (III); Among them, R 1 Any one selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-hexyl, cyclopropyl, benzyl, benzyloxy, tert-butoxy, benzhydryloxy, phenyl, 4-chlorophenyl, and 3-methoxyphenyl; R 2 Any one selected from phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methoxyphenyl, 2-methylphenyl, 2-naphthyl, 2-thienyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3-methoxyphenyl, 3-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-nitrophenyl and 4-methoxyphenyl.
8. Use of the benzothienodiazepine compound according to claim 6 or 7 in the preparation of a drug for treating diabetes, wherein the anti-sugar activity comprises an inhibitory activity against α-glucosidase.