Electrochemically promoted synthesis methods and applications of indole-benzo[selenium]azine ketones

Abstract

This invention relates to the field of electrochemical organic synthesis technology, specifically providing an electrochemically promoted method and application for the synthesis of indole-benzo[selenium]azine ketones. A C3-selenoindole derivative, an organoselenium catalyst, an electrolyte, and an acid are added to an organic solvent to form a reaction system. A graphite felt is used as the anode, and a platinum sheet as the cathode, and a constant current reaction is carried out at room temperature in an air atmosphere. After the reaction is complete, the reactants are post-treated to obtain indole-benzo[selenium]azine ketones. The obtained compounds exhibit significant anti-inflammatory and anti-ulcer dual activities, achieving dual anti-inflammatory and anti-ulcer effects. This solves the problem that traditional NSAIDs only have anti-inflammatory properties but easily cause gastrointestinal damage, and has value for further research and application.

Description

Technical Field

[0001] This invention relates to the field of electrochemical organic synthesis technology, specifically providing an electrochemically promoted method and application for the synthesis of indole-benzo[selenium]azine ketones. Background Technology

[0002] Indole-benzoxazines are an important class of nitrogen-containing heterocyclic compounds. As core derivatives of indole heterocycles, they exhibit excellent biological activity in the pharmaceutical field and are key structural units for antibacterial, anticancer, antihypertensive, anti-inflammatory, and central nervous system active drugs, possessing high application value in drug development and pharmaceutical intermediate synthesis. Since the introduction of selenium atoms can regulate the electron distribution, lipophilicity, and metabolic stability of molecules, introducing selenium atoms into the benzoxazine skeleton to construct indole-benzoxazines is expected to yield novel heterocyclic molecular libraries with novel three-dimensional configurations and unique electron distributions. Such skeletons may not only inherit the dual biological activities of indole and selenium heterocycles but may also generate new pharmacological activities through skeleton synergy effects, possessing potential drug discovery value. However, to date, no indole-benzoxazines have been reported in the literature or patents, and research on their synthetic methodologies remains lacking.

[0003] As a cutting-edge innovation in the field of organic synthesis, electrochemical synthesis is reshaping the development landscape of modern organic chemistry with its unique synthetic logic and green advantages. This system uses electrons as clean, residue-free redox reagents, eliminating the need for stoichiometric oxidants and reductants at the source, significantly reducing byproduct generation and environmental impact. It also possesses core characteristics such as mild reaction conditions, high atom economy, and broad substrate applicability, perfectly meeting the development needs of sustainable synthetic chemistry under carbon neutrality. It has become an ideal strategy for constructing complex organic molecules and developing novel chemical bond transformation modes, demonstrating extremely strong scientific research value and application potential.

[0004] On the other hand, compared with traditional organometallic complex catalysts, organoselenium catalysts have unique advantages such as good environmental friendliness, low preparation cost, stability in air, and easy control of reaction conditions. Based on these advantages, the application of organoselenium catalysts in electrochemical organic synthesis has gradually attracted widespread attention from researchers in recent years.

[0005] However, in actual reaction processes, many organoselenium catalytic systems still rely on superstoichiometric oxidants (such as persulfates, high-valent iodine reagents, and hydrogen peroxide) to achieve the recycling and regeneration of active selenium species. This not only violates the principles of green chemistry but also increases the difficulty of product separation and purification. Furthermore, traditional chemical oxidants often have poor selectivity, easily leading to over-oxidation of substrates (especially electron-rich heterocycles such as indoles) or the generation of side reactions; at the same time, the use of strong oxidants also limits the functional group tolerance of the substrates, making it difficult to be compatible with substrates containing sensitive groups. Summary of the Invention

[0006] The purpose of this invention is to provide an electrochemically promoted method for the synthesis and application of indole-benzo[selenium]azine ketone compounds, in order to solve the technical problems mentioned in the background art.

[0007] To achieve the above objectives, the technical solution of this invention is as follows: An electrochemically promoted synthesis method for indole-benzo[selenium]azine ketones is as follows: A C3-selenoindole derivative having the structure shown in formula (I), an organoselenium catalyst, an electrolyte, and an acid are added to an organic solvent to form a reaction system. A constant current reaction is carried out under room temperature and electrostatic conditions. After the reaction is complete, the solvent is removed from the reaction solution under reduced pressure to obtain a crude product. The crude product is purified by column chromatography to obtain an indole-benzo[selenium]azine ketone compound with the structure shown in formula (II). The reaction equation is shown below:

[0008]

[0009] Wherein, the compound of formula (I) is a C3-selenoindole derivative, R1 is a C1-C4 alkyl group; R2 is hydrogen, halogen, C1-C4 alkyl group, or C1-C3 alkoxy group; R3 is a C1-C4 alkyl group, benzyl group, phenyl group, or a phenyl group substituted with one or more substituents, wherein the substituents are C1-C4 alkoxy groups, C1-C4 alkyl groups, trifluoromethyl groups, cyano groups, or halogen groups.

[0010] The molar ratio of C3-selenoindole with the structure shown in formula (I) to the organoselenium catalyst and the acid is 1:0.1:0.1-1:0.1:0.5, preferably 1:0.1:0.2.

[0011] The organoselenium catalyst is any one of dibenzyl diselenide, dimethyl diselenide, or diethyl diselenide, with dibenzyl diselenide being preferred.

[0012] The acid is any one of p-toluenesulfonic acid, formic acid, acetic acid, or trifluoroacetic acid, with acetic acid being preferred.

[0013] The anode material of the constant current reaction electrode is one of graphite felt, platinum sheet, zinc sheet, aluminum sheet, and carbon rod, with graphite felt being preferred; the cathode material is one of platinum sheet, nickel sheet, tin sheet, lead sheet, and copper sheet, with platinum sheet being preferred.

[0014] The constant current for the reaction is 6-12 mA, preferably 8 mA, using a diaphragmless single-chamber electrolytic cell, with a reaction time of 18-24 h, preferably 20 h, and a reaction temperature of room temperature.

[0015] The electrolyte is any one of tetrabutylammonium tetrafluoroborate, sodium tetrafluoroborate, lithium perchlorate, and sodium perchlorate, preferably tetrabutylammonium tetrafluoroborate; the molar concentration of the electrolyte relative to the organic solvent in the reaction system (electrolyte / organic solvent) is 0.03 mol / L-0.05 mol / L, preferably 0.05 mol / L.

[0016] The organic solvent is any one of chloroform, nitromethane, dichloromethane, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, or acetonitrile, preferably dichloroethane.

[0017] After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated by column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate was (5-1):1. The eluent was collected, and the solvent was rotary evaporated to obtain the indo-benzoxenone compound shown in formula (II).

[0018] The indobenzobenzoxazine ketone compound prepared by this invention has excellent dual anti-inflammatory and anti-ulcer effects, and can be well applied to the preparation of drugs with dual anti-inflammatory and anti-ulcer effects.

[0019] Furthermore, the present invention relates to a pharmaceutical composition comprising an effective amount of the indobenzobenzoxazine compound of the present invention, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carriers or excipients include solid excipients or liquid excipients. Solid excipients include, but are not limited to, inert fillers (such as lactose, sucrose, starch, microcrystalline cellulose, etc.), binders, disintegrants, or lubricants. Liquid excipients include, but are not limited to, sterile aqueous solutions (such as water for injection, physiological saline, buffer solutions) or pharmaceutical organic solvents (such as ethanol, propylene glycol, polyethylene glycol, vegetable oils, etc.) for the preparation of injections, oral solutions, or topical formulations.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] (1) This invention provides a method for the electrochemical construction of indole-benzo[selenium]azine ketone compounds, which is green and environmentally friendly.

[0022] (2) The reaction of the present invention can be carried out at room temperature, and the target product can be obtained in just one step. It has high yield, good functional group compatibility, simple post-processing, and good application potential.

[0023] (3) Experiments have shown that the indole-benzo[seleno]azonone compounds provided by this invention have excellent dual anti-inflammatory and anti-ulcer activities. Therefore, the compounds of this invention have important prospects for pharmaceutical use. Detailed Implementation

[0024] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] This invention provides the following technical solution: An electrochemically promoted synthesis method for indole-benzo[selenium]azine ketones is as follows: A C3-selenoindole derivative having the structure shown in formula (I), an organoselenium catalyst, an electrolyte, and an acid are added to an organic solvent. A constant current reaction is carried out at room temperature and under electrostatic conditions. After the reaction, the solvent is removed from the reaction solution under reduced pressure to obtain a crude product. The crude product is purified by column chromatography to obtain an indole-benzo[selenium]azine ketone compound with the structure shown in formula (II). The reaction equation is shown below:

[0026]

[0027] Wherein, the compound of formula (I) is a C3-selenoindole derivative, R1 is a C1-C4 alkyl group; R2 is hydrogen, halogen, C1-C4 alkyl group, or C1-C3 alkoxy group; R3 is a C1-C4 alkyl group, benzyl group, phenyl group, or a phenyl group substituted with one or more substituents, wherein the substituents are C1-C4 alkoxy groups, C1-C4 alkyl groups, trifluoromethyl groups, cyano groups, or halogen groups.

[0028] Example 1

[0029] The reaction equation is shown below:

[0030]

[0031] Under air atmosphere, N-methyl-2-((1-methyl-1H-indol-3-yl)selenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), acetic acid (0.1 mmol), and 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution (5 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After addition, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 105 mg of the target compound, with a yield of 61%.

[0032] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 7.69 – 7.65 (m, 1H), 7.62 – 7.60 (m, 1H), 7.42 – 7.36 (m, 1H), 7.34 – 7.31 (m, 1H), 7.30 – 7.26(m, 2H), 7.24 – 7.21 (m, 2H), 4.24 – 4.15 (m, 1H), 4.01 – 3.96 (m, 3H), 3.62 (s, 3H); 13 C NMR (100 MHz, CDCl3): δ 170.8, 145.8, 139.2, 136.5, 134.2, 133.1,130.8, 130.6, 128.7, 126.8, 122.6, 121.7, 119.2, 110.0, 105.1, 39.1, 35.0.

[0033] Example 2

[0034] Under air atmosphere, N-methyl-2-((1-methyl-1H-indol-3-yl)selenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), p-toluenesulfonic acid (0.1 mmol), and 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution (5 mL) were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After addition, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 84 mg of the target compound, with a yield of 49%.

[0035] Example 3

[0036] Under air atmosphere, N-methyl-2-((1-methyl-1H-indol-3-yl)selenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), formic acid (0.1 mmol), and 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution (5 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After addition, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 94 mg of the target compound, with a yield of 55%.

[0037] Example 4

[0038] Under air atmosphere, N-methyl-2-((1-methyl-1H-indol-3-yl)selenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), acetic acid (0.1 mmol), and 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution (5 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After addition, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 10 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 101 mg of the target compound, with a yield of 59%.

[0039] Example 5

[0040] Under air atmosphere, N-methyl-2-((1-methyl-1H-indol-3-yl)selenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), acetic acid (0.1 mmol), and 0.05 mol / L sodium tetrafluoroborate / dichloroethane solution (5 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After addition, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 85 mg of the target compound, with a yield of 50%.

[0041] Example 6

[0042] Under air atmosphere, N-methyl-2-((1-methyl-1H-indol-3-yl)selenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), acetic acid (0.1 mmol), and 0.05 mol / L lithium perchlorate / dichloroethane solution (5 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 87 mg of the target compound, with a yield of 52%.

[0043] Example 7

[0044] The reaction equation is shown below:

[0045]

[0046] Under air atmosphere, 0.5 mmol of 2-(1-ethyl-1H-indol-3-ylselenoyl)-N-methylbenzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After addition, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 104 mg of the target compound, with a yield of 58%.

[0047] The NMR data of the obtained product are as follows: 1H NMR (400 MHz, CDCl3): δ 7.71 – 7.69 (m, 1H), 7.67 – 7.65 (m, 1H), 7.45 – 7.39 (m, 1H), 7.33 – 7.30 (m, 1H), 7.28 – 7.24(m, 2H), 7.24 – 7.21 (m, 2H), 4.28 – 4.13 (m, 1H), 4.15 – 4.11 (m, 1H), 3.66(s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 171.2, 145.2,139.2, 138.1, 134.8, 132.9, 130.6, 130.3, 128.3, 126.9, 122.5, 121.1, 119.3,110.0, 105.2, 39.4, 37.8, 14.8.

[0048] Example 8

[0049] The reaction equation is shown below:

[0050]

[0051] Under air atmosphere, 0.5 mmol of 2-(1-ethyl-1H-indol-3-ylselenoyl)-N-p-tolylbenzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After addition, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 4 / 1) to obtain 182 mg of the target compound, with a yield of 84%.

[0052] The NMR data of the obtained product are as follows: 1H NMR (400 MHz, CDCl3): δ 7.68 – 7.66 (m, 1H), 7.64 (dd, J = 7.5, 1.7 Hz, 1H), 7.37 (dd, J = 7.7, 1.3 Hz, 1H), 7.33 – 7.26(m, 2H), 7.21 (dd, J = 7.5, 1.4 Hz, 1H), 7.18 – 7.15 (m, 3H), 7.14 – 7.08 (m,3H), 3.82 (dq, J = 14.5, 7.3 Hz, 1H), 3.61 (dq, J = 14.3, 7.1 Hz, 1H), 2.31(s, 3H), 0.68 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 169.9, 143.3,139.5, 138.3, 137.6, 137.3, 133.6, 131.9, 130.7, 130.1, 129.7, 128.3, 127.1,126.6, 122.7, 120.4, 119.2, 109.7, 106.2, 38.1, 21.3, 14.0.

[0053] Example 9

[0054] The reaction equation is shown below:

[0055]

[0056] In an air atmosphere, 0.5 mmol of 2-((1-ethyl-7-methyl-1H-indol-3-yl)selenoyl)-N-p-tolylbenzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was carried out continuously for 20 hours in an air atmosphere at room temperature. After the reaction was complete, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 4 / 1) to obtain 179 mg of the target compound, with a yield of 80%.

[0057] The NMR data of the obtained product are as follows: 1H NMR (400 MHz, CDCl3): δ 7.65 (dd, J = 7.6, 1.7Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 7.6, 1.4 Hz, 1H), 7.34 –7.27 (m, 2H), 7.23 – 7.11 (m, 4H), 7.05 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.2Hz, 1H), 4.12 – 3.98 (m, 1H), 3.92 – 3.76 (m, 1H), 2.51 (s, 3H), 2.33 (s,3H), 0.76 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 169.5, 143.6,139.2, 138.1, 137.8, 137.3, 132.4, 131.2, 130.8, 130.2, 129.0, 128.1, 128.0,126.5, 126.1, 121.6, 120.4, 117.0, 108.9, 40.1, 21.3, 19.6, 16.1.

[0058] Example 10

[0059] The reaction equation is shown below:

[0060]

[0061] In an air atmosphere, 0.5 mmol of 2-((1-ethyl-5-methoxy-1H-indol-3-yl)selenoyl)-N-p-tolylbenzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was carried out continuously for 20 hours in an air atmosphere at room temperature. After the reaction was complete, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 1 / 1) to obtain 158 mg of the target compound, with a yield of 68%.

[0062] The NMR data of the obtained product are as follows: 1H NMR (400 MHz, CDCl3): δ 7.65 (dd, J = 7.5, 1.7Hz, 1H), 7.38 (dd, J = 7.6, 1.5 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.22 –7.12 (m, 4H), 7.10 (d, J = 2.5 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 6.75 (dd, J= 8.8, 2.5 Hz, 1H), 3.91 – 3.82 (s, 3H), 3.81 – 3.78 (m, 1H), 3.65 – 3.52 (m,1H), 2.31 (s, 3H), 0.69 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ169.8, 155.2, 143.4, 139.1, 138.3, 137.8, 137.2, 131.7, 130.5, 130.1, 129.2,128.3, 128.2, 127.2, 127.0, 113.2, 110.8, 106.5, 100.3, 56.2, 39.1, 21.0,13.7.

[0063] Example 11

[0064] The reaction equation is shown below:

[0065]

[0066] In an air atmosphere, 0.5 mmol of 2-((1-ethyl-5-fluoro-1H-indol-3-yl)selenoyl)-N-p-tolylbenzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was carried out continuously for 20 hours in an air atmosphere at room temperature. After the reaction was complete, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 4 / 1) to obtain 171 mg of the target compound, with a yield of 76%.

[0067] The NMR data of the obtained product are as follows: 1H NMR (400 MHz, CDCl3): δ 7.78 (dd, J = 7.5, 1.7Hz, 1H), 7.66 (dd, J = 8.7, 5.3 Hz, 1H), 7.47 (dd, J = 7.6, 1.4 Hz, 1H), 7.34(d, J = 8.4 Hz, 2H), 7.31 (td, J = 7.5, 1.4 Hz, 1H), 7.29 – 7.25 (m, 3H), 6.97 (td, J = 9.6, 2.2 Hz, 1H), 6.87 (dd, J = 9.7, 2.2 Hz, 1H), 3.94 – 3.81(m, 1H), 3.73 – 3.60 (m, 1H), 2.51 (s, 3H), 0.75 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 169.6, 160.3 (d, J = 239.5 Hz), 143.2, 139.0, 138.1,138.2, 137.9 (d, J = 3.7 Hz), 133.5 (d, J = 12.1 Hz), 132.8, 130.9, 130.0,129.1, 128.8, 127.2, 123.1, 119.9 (d, J = 9.9 Hz), 109.6 (d, J = 24.5 Hz),107.4, 96.0 (d, J = 26.8 Hz), 39.6, 21.2, 13.2.

[0068] Example 12

[0069] The reaction equation is shown below:

[0070]

[0071] In an air atmosphere, 0.5 mmol of 2-((5-chloro-1-ethyl-1H-indol-3-yl)selenoyl)-N-p-tolylbenzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was carried out continuously for 20 hours in an air atmosphere at room temperature. After the reaction was complete, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 4 / 1) to obtain 189 mg of the target compound, with a yield of 81%.

[0072] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.6 Hz,1H), 7.65 (dd, J = 8.8, 1.6 Hz, 1H), 7.47 (dd, J = 7.5, 1.6 Hz, 1H), 7.38 –7.35 (m, 2H), 7.34 – 7.29 (m, 3H), 7.27 (d, J = 1.6 Hz, 1H), 7.22 – 7.17 (m,2H), 3.98 – 3.85 (m, 1H), 3.70 – 3.63 (m, 1H), 2.42 (s, 3H), 0.75 (t, J = 7.2Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 169.3, 142.9, 139.5, 138.2, 137.6, 137.3,134.4, 132.3, 130.7, 130.5, 129.8, 128.5, 128.2, 127.3, 125.3, 121.8, 119.7,109.8, 107.4, 39.5, 21.3, 13.6.

[0073] Example 13

[0074] The reaction equation is shown below:

[0075]

[0076] In an air atmosphere, 0.5 mmol of 2-((5-bromo-1-ethyl-1H-indol-3-yl)selenoyl)-N-p-tolylbenzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was carried out continuously for 20 hours in an air atmosphere at room temperature. After the reaction was complete, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 4 / 1) to obtain 200 mg of the target compound, with a yield of 78%.

[0077] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 2.0 Hz,1H), 7.74 (dd, J = 7.5, 1.8 Hz, 1H), 7.45 (dd, J = 7.4, 1.5 Hz, 1H), 7.38 (d,J = 8.4 Hz, 2H), 7.34 – 7.22 (m, 5H), 7.16 (d, J = 8.7 Hz, 1H), 3.97 – 3.84(m, 1H), 3.72 – 3.65 (m, 1H), 2.42 (s, 3H), 0.78 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 169.3, 142.6, 139.0, 138.5, 137.9, 137.6, 132.4, 132.5,130.8, 130.1, 129.7, 128.2, 128.2, 127.2, 125.7, 121.1, 114.4, 111.2, 106.6,39.2, 21.3, 13.8.

[0078] Example 14

[0079] The reaction equation is shown below:

[0080]

[0081] Under air atmosphere, N-ethyl-2-(1-ethyl-1H-indol-3-ylselenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), acetic acid (0.1 mmol), and 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution (5 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After addition, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain 113 mg of the target compound, with a yield of 61%.

[0082] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 8.29 – 8.25 (m, 1H), 7.56 (dd, J = 7.5, 1.3 Hz, 1H), 7.48 (td, J = 7.8, 1.3 Hz, 1H), 7.37 (td, J =7.5, 1.6 Hz, 1H), 7.32 (td, J = 7.6, 1.4 Hz, 1H), 7.21 (td, J = 7.6, 1.0 Hz,1H), 7.16 – 7.11 (m, 1H), 6.97 (d, J = 7.9 Hz, 1H), 3.81 (m, 2H), 3.69 (m,1H), 3.34 (m,1H), 1.26 (t, J = 7.2 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 173.2, 164.7, 141.8, 132.2, 131.2, 130.9, 130.2, 129.6,126.8, 126.3, 126.1, 124.8, 123.6, 109.2, 40.3, 35.0, 13.2, 12.1.

[0083] Example 15

[0084] The reaction equation is shown below:

[0085]

[0086] Under air atmosphere, N-benzyl-2-(1-ethyl-1H-indol-3-ylselenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), acetic acid (0.1 mmol), and 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution (5 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After addition, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were fitted into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours under air atmosphere and room temperature. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether / ethyl acetate = 4 / 1) to obtain 152 mg of the target compound, with a yield of 70%.

[0087] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 8.43 – 8.28 (m, 1H),7.57 (dd, J = 7.6, 1.0 Hz, 1H), 7.43 – 7.32 (m, 3H), 7.22 – 7.14 (m, 2H),7.14 – 7.05 (m, 3H), 6.81 – 6.72 (m, 2H), 6.68 (d, J = 7.9 Hz, 1H), 5.61 (d,J = 14.9 Hz, 1H), 4.26 (d, J = 14.9 Hz, 1H), 3.32 – 3.15 (m, 2H), 0.82 (t, J= 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 173.2, 166.5, 143.4, 134.8, 132.4,131.1, 130.8, 129.2, 128.7 (2C), 128.0 (2C), 127.2, 126.5, 126.5, 126.3,123.5, 122.2, 109.2, 48.5, 35.1, 12.8.

[0088] Example 16

[0089] The reaction equation is shown below:

[0090]

[0091] In an air atmosphere, 0.5 mmol of 2-((1-ethyl-1H-indol-3-yl)selenoyl)-N-(3-methoxyphenyl)benzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was carried out continuously for 20 hours in an air atmosphere at room temperature. After the reaction was complete, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 1 / 1) to obtain 171 mg of the target compound, with a yield of 76%.

[0092] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 7.83 – 7.76 (m, 1H), 7.78 – 7.72 (m, 1H), 7.51 – 7.43 (m, 1H), 7.36 (t, J = 8.2 Hz, 1H), 7.32 (dd,J = 7.5, 1.4 Hz, 1H), 7.27 – 7.21 (m, 4H), 7.13 – 7.09 (m, 2H), 6.92 (ddd, J= 8.3, 2.5, 1.0 Hz, 1H), 4.13 – 3.93 (m, 1H), 3.88 (s, 3H), 3.72 (m, 1H),0.85 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 169.3, 161.2, 143.4,141.1, 139.6, 137.8, 133.5, 131.4, 130.8, 130.1, 129.9, 128.2, 126.6, 122.2,120.1, 119.7, 119.4, 113.6, 112.9, 109.6, 107.2, 55.6, 39.2, 13.7.

[0093] Example 17

[0094] The reaction equation is shown below:

[0095]

[0096] In an air atmosphere, N-(4-cyanophenyl)-2-((1-ethyl-1H-indol-3-yl)selenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), acetic acid (0.1 mmol), and 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution (5 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was carried out continuously for 20 hours in an air atmosphere at room temperature. After the reaction was complete, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 4 / 1) to obtain 107 mg of the target compound, with a yield of 48%.

[0097] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 7.82 – 7.77 (m, 2H), 7.77 – 7.74 (m, 2H), 7.68 – 7.61 (m, 2H), 7.54 – 7.46 (m, 1H), 7.35 (td, J =7.5, 1.6 Hz, 1H), 7.32 – 7.28 (m, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.27 (d, J =2.2 Hz, 1H), 7.25 – 7.22 (m, 1H), 3.97 – 3.85 (m, 1H), 3.74 – 3.59 (m, 1H),0.82 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 169.6, 144.5, 143.1,138.4, 136.2, 133.9, 133.2, 132.2, 131.0, 130.2, 128.6, 127.2, 126.7, 123.7,121.8, 119.0, 118.1, 110.7, 109.9, 108.6, 38.9, 14.2.

[0098] Example 18

[0099] The reaction equation is shown below:

[0100]

[0101] In an air atmosphere, 0.5 mmol of 2-((1-ethyl-1H-indol-3-yl)selenoyl)-N-(4-trifluoromethylphenyl)benzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragm-free single-chamber electrolytic cell (diaphragm-free three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was continued for 20 hours in an air atmosphere at room temperature. After the reaction was complete, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 4 / 1) to obtain 168 mg of the target compound, with a yield of 69%.

[0102] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 7.83 – 7.78 (m, 1H), 7.76 – 7.72 (m, 3H), 7.67 – 7.62 (m, 2H), 7.51 – 7.46 (m, 1H), 7.32 (td, J =7.5, 1.5 Hz, 1H), 7.31 – 7.25 (m, 3H), 7.25 – 7.22 (m, 1H), 3.99 – 3.86 (m,1H), 3.75 – 3.67 (m, 1H), 0.81 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 168.9, 143.3, 143.1, 138.3, 136.0, 133.9, 132.2, 131.1, 130.0, 129.2 (q, J= 32.6 Hz), 128.7, 127.2 (2C), 126.8, 126.4 (q, J = 3.4 Hz), 123.3, 121.0,119.1, 109.7, 108.1, 39.0, 13.6.

[0103] Example 19

[0104]

[0105] In an air atmosphere, 0.5 mmol of 2-((1-ethyl-1H-indol-3-yl)selenoyl)-N-(4-fluorophenyl)benzamide, 0.05 mmol of Bn2Se2, 0.1 mmol of acetic acid, and 5 mL of 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was carried out continuously for 20 hours in an air atmosphere at room temperature. After the reaction was complete, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 4 / 1) to obtain 162 mg of the target compound, with a yield of 74%.

[0106] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 7.83 – 7.78 (m, 1H), 7.76 (dd, J = 7.5, 1.7 Hz, 1H), 7.54 – 7.42 (m, 3H), 7.31 (td, J = 7.5, 1.5Hz, 1H), 7.30 – 7.23 (m, 4H), 7.19 – 7.15 (m, 2H), 4.12 – 3.86 (m, 1H), 3.80– 3.66 (m, 1H), 0.81 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3): δ 169.3,161.2 (d, J = 248.1 Hz), 143.1, 138.0, 137.2, 136.6 (d, J = 3.3 Hz), 133.7,132.1, 131.2, 130.4, 129.0 (d, J = 8.5 Hz), 128.2, 126.8, 123.1, 121.1,119.0, 116.2 (d, J = 22.9 Hz), 109.7, 107.2, 39.1, 13.6.

[0107] Example 20

[0108]

[0109] In an air atmosphere, N-(2-bromophenyl)-2-((1-ethyl-1H-indol-3-yl)selenobenzamide (0.5 mmol), Bn2Se2 (0.05 mmol), acetic acid (0.1 mmol), and 0.05 mol / L tetrabutylammonium tetrafluoroborate / dichloroethane solution (5 mL) were added to a diaphragmless single-chamber electrolytic cell (diaphragmless three-necked flask) equipped with a magnetic stirrer. After the addition was complete, a graphite felt anode (1.5 cm × 1.5 cm) and a platinum cathode (1.5 cm × 1.5 cm) were assembled into the three-necked flask, respectively. The electrolysis current was set to 8 mA, and the electrolysis reaction was carried out continuously for 20 hours under air atmosphere and room temperature conditions. After the reaction was completed, the organic phase was removed from the solvent by a rotary evaporator, and the residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent petroleum ether / ethyl acetate = 4 / 1) to obtain 120 mg of the target compound, with a yield of 48%.

[0110] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3): δ 7.77 – 7.65 (m, 2H), 7.57 (dd, J = 7.5, 1.6 Hz, 1H), 7.39 (dd, J = 7.6, 1.3 Hz, 1H), 7.31 – 7.23(m, 1H), 7.22 (dd, J = 7.5, 1.4 Hz, 1H), 7.18 – 7.15 (m, 4H), 7.15 – 7.11 (m,2H), 4.13 – 3.98 (m, 1H), 3.82 – 3.67 (m, 1H), 0.62 (t, J = 7.2 Hz, 3H); 13 CNMR (100 MHz, CDCl3): δ 168.7, 142.4, 140.2, 139.9, 138.2, 134.4, 133.0,130.9, 130.7, 130.8, 129.9, 129.5, 129.1, 128.0, 126.4, 123.8, 122.9, 120.5,119.2, 109.1, 106.5, 39.1, 13.9.

[0111] Example 21 Study on dual anti-inflammatory and anti-ulcer activity

[0112] The indole-benzo[seleno]azonone compounds provided by this invention have significant anti-inflammatory and anti-ulcer effects, and are effective against sPLA2 and H. + / K + All ATPases showed good inhibitory effects.

[0113] VRV-PL-8a (sPLA2) and H + / K + IC50 data for ATPase inhibitory activity were determined in four replicate experiments. LY-311727 was used as a positive control for sPLA2 inhibition, and omeprazole was used as a positive control for H+ / K+ ATPase inhibition. Homogeneous VRV-PL-8a was purified from Russell's viper venom using CM-Sephadex C-25 column chromatography combined with Sephadex G-50 gel filtration as the prototype for sPLA2. H+ / K+ ATPase from porcine gastric mucosa was used as another detection target. The protein content of VRV-PL-8a was first quantified using the Lowry method. Then, indole-benzo[a]selenoxone derivative 1a-1o, the positive control LY-311727, and omeprazole were incubated with the two enzymes in vitro. The sPLA2 inhibitory activity was detected using egg yolk-derived phosphatidylcholine as a substrate in a solution containing 40 mM Ca2+. 2+ In a 0.05 M Tris-HCl buffer (pH 7.5) system, incubation at 37 °C allowed the enzyme to catalyze the hydrolysis of the substrate to produce free fatty acids. After lipid extraction using a modified Dole extraction method, the lipids were complexed with cobalt reagent and reacted with α-nitroso-β-naphthol for color development. The absorbance was measured at 500 nm, and the amount of free fatty acids produced was quantified using linoleic acid as a standard to reflect enzyme activity. Simultaneously, using egg yolk and hematocrit as substrates, the inhibitory effect of the compound on VRV-PL-8a-mediated indirect hemolysis was determined using classical methods. + / K + ATPase inhibitory activity was determined by initiating the enzymatic reaction with ATP, incubating at 37°C for 15 minutes, and then terminating the reaction with 1.0 mL of ice-cold 20% trichloroacetic acid. The content of inorganic phosphate produced by ATP hydrolysis was then detected using the Fiske Subbarow method to reflect enzyme activity. Subsequently, the IC50 values ​​of the two enzyme activities under different concentrations of compounds were calculated by fitting sigmoid four-parameter logistic curves. The final results are presented as mean ± standard error (SEM).

[0114] Detailed test results are shown in the table below:

[0115] sample sPLA2 IC50(μM) ±SEM H+ / K+ ATPase IC50 (μM) ± SEM LY-311727 2.501 ± 0.013 nd Omeprazole nd 1.031 ± 0.107 1a 15.127 ± 0.133 10.451 ± 0.048 1b 13.014 ± 0.110 9.012 ± 0.076 1c 13.192 ± 0.195 7.014 ± 0.057 1d 15.746 ± 0.512 10.045 ± 0.015 1e 23.128 ± 0.221 5.143 ± 0.050 1f 8.192 ± 0.205 3.499 ± 0.051 1g 19.287 ± 0.162 5.277 ± 0.051 1h 6.946 ± 0.107 2.725 ± 0.048 1i 17.054 ± 0.280 11.014 ± 0.023 1j 12.992 ± 0.501 8.248 ± 0.019 1k 5.012 ± 0.151 1.028 ± 0.032 1l 26.882 ± 0.507 3.732 ± 0.037 1m 23.397 ± 0.205 5.099 ± 0.051 1n 26.235 ± 0.327 7.032 ± 0.064 1o 22.142 ± 0.190 2.112 ± 0.021

[0116] Test results show that most of the compounds of this invention have significant dual anti-inflammatory and anti-ulcer activities, and their inhibitory activities are superior to or close to those of the controls LY-311727 and omeprazole. In particular, compounds 1f, 1h, and 1k have significant dual anti-inflammatory and anti-ulcer effects, and their inhibitory activities against sPLA2 and H are also significant. + / K +All ATPases showed good inhibitory effects. These compounds exert their anti-inflammatory effects by targeting the inflammation-initiating enzyme sPLA2, while also inhibiting gastric wall H... + / K + ATPase prevents gastric ulcers, achieving dual anti-inflammatory and anti-ulcer effects, thus solving the problem that traditional NSAIDs, which only have anti-inflammatory properties, are prone to causing gastrointestinal damage.

[0117] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for the electrochemically promoted synthesis of indole-benzo[seleno]azonone compounds, characterized in that, The synthesis method is as follows: a C3-selenoindole derivative having the structure shown in formula (I), an organoselenium catalyst, an electrolyte, and an acid are added to an organic solvent, and a constant current reaction is carried out under room temperature and electrostatic conditions. After the reaction is completed, the organic solvent is removed from the reaction solution under reduced pressure to obtain a crude product. The crude product is purified by column chromatography, the eluent is collected, and the solvent is rotary evaporated to obtain an indole-benzoxeneazine compound with the structure shown in formula (II). The reaction equation is shown below: ， Wherein, the compound of formula (I) is a C3-selenoindole derivative, R1 is a C1-C4 alkyl group; R2 is hydrogen, halogen, C1-C4 alkyl group, or C1-C3 alkoxy group; R3 is a C1-C4 alkyl group, benzyl group, phenyl group, or phenyl group substituted with one or more substituents, wherein the substituents are C1-C4 alkoxy groups, C1-C4 alkyl groups, trifluoromethyl groups, cyano groups, or halogen groups.

2. The method for electrochemically promoted synthesis of indole-benzo[seleno]azonone compounds according to claim 1, characterized in that, The molar ratio of C3-selenoindole with the structure shown in formula (I) to the organoselenium catalyst and the acid is 1:0.1:0.1-1:0.1:0.

5.

3. The method for electrochemically promoted synthesis of indole-benzo[selenium]azine ketones according to claim 1, characterized in that, The organoselenium catalyst is any one of dibenzyl diselenide, dimethyl diselenide, or diethyl diselenide; the acid is any one of p-toluenesulfonic acid, formic acid, acetic acid, or trifluoroacetic acid.

4. The method for electrochemically promoted synthesis of indole-benzo[seleno]azonone compounds according to claim 1, characterized in that, The electrolyte is any one of tetrabutylammonium tetrafluoroborate, sodium tetrafluoroborate, lithium perchlorate, or sodium perchlorate; the organic solvent is any one of chloroform, nitromethane, dichloromethane, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, or acetonitrile; the molar concentration of the electrolyte relative to the organic solvent in the reaction system is 0.03 mol / L to 0.05 mol / L.

5. The method for electrochemically promoted synthesis of indolobenzoxenone compounds according to claim 1, characterized in that, The constant current for the reaction was 6-12 mA, the reaction time was 18-24 h, and the reaction temperature was room temperature.

6. The method for electrochemically promoted synthesis of indole-benzo[seleno]azonone compounds according to claim 1, characterized in that, When performing a constant current reaction, a diaphragmless single-chamber electrolytic cell is used; the anode material is one of graphite felt, platinum sheet, zinc sheet, aluminum sheet, and carbon rod, and the cathode material is one of platinum sheet, nickel sheet, tin sheet, lead sheet, and copper sheet.

7. The method for electrochemically promoted synthesis of indo-benzo[selenium]azine ketones according to claim 1, characterized in that, Column chromatography purification was performed using a mixture of petroleum ether and ethyl acetate as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate was 5 to 1:

1.

8. An indobenzobenzoxazine compound synthesized by the method according to any one of claims 1-7.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises an indobenzobenzazepine compound synthesized by any one of claims 1-7, a medically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

10. An application of the pharmaceutical composition according to claim 9, characterized in that, The pharmaceutical composition is used to prepare a medicine for treating and / or preventing inflammation-related diseases, while relieving gastric mucosal damage caused by conventional anti-inflammatory drugs.

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