Triazole derivative with anti-depression effect as well as preparation method and application thereof

Abstract

The invention relates to a preparation method and application of a triazole derivative with an antidepressant effect, and belongs to the technical field of synthesis of drugs. Based on a 2-[3-nitrile group-4-(2-isobutoxy)-phenyl]-4-methylthiazole-5-formic acid structure, terminal alkyne is introduced into the structure, and the triazole derivative with the antidepressant effect is prepared. According to the present invention, the novel compounds are obtained through the reaction of the compounds and the azide compounds through the click reaction, and the test results prove that the obtained compounds have good anti-inflammatory activity on LPS-induced BV2 cells, are expected to be used for the treatment of depression, and have strong guiding effects on the research and development of anti-depression drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of drugs, and particularly relates to a preparation method and application of a triazole derivative with antidepressant effects. Background Art

[0002] Neuroinflammation is an important pathological hallmark of depression. In the brains of patients with depression, the Aβ protein misfolds and aggregates, interacts with pattern recognition receptors on the surface of microglia, activates microglia, releases a large number of inflammatory factors, and causes neuroinflammation. Neuroinflammation will exacerbate neuronal damage, leading to chronic neuroinflammation. Some external or internal environmental factors can also trigger persistent neuroinflammation and increase the risk of the occurrence and development of depression. For example, infections, obesity, and traumatic brain injuries can all over-release and accumulate inflammatory factors, causing chronic neuroinflammation and thus increasing the likelihood of developing depression. The occurrence of specific inflammatory reactions in the brain tissue is a key step in the onset of depression. In addition to phagocytosis, activated microglia also release a variety of inflammatory factors, such as IL-1, IL-6, TNF-α, TGF-β, glutamate, iNOS, ROS, etc. Among them, IL-1β can activate astrocytes and release α1-activated protease, leading to Aβ fibrosis. At the same time, IL-1β can activate the NK-κB pathway, promote microglia to secrete pro-inflammatory factors, and form a vicious cycle. In addition, IL-1β can up-regulate the expression of APP and promote the production of complement protein C3 and carrier protein E. After iNOS is activated, it will release a large amount of NO, causing damage to neurons. The production of ROS will exacerbate the toxicity of Aβ and activate the NK-κB pathway, accelerating apoptosis. During the occurrence and development of depression, the continuous activation of microglia and the continuous interaction of the inflammatory factors and neurotoxic substances released by them ultimately lead to the continuous development of neurodegenerative diseases.

[0003] 2-[3-cyano-4-(2-isobutoxy)-phenyl]-4-methylthiazole-5-carboxylic acid is a new type of oral anti-hyperuricemic drug. Its therapeutic effect is achieved by promoting uric acid excretion and thus reducing serum uric acid. Compared with other drugs in the treatment of gout, it has advantages such as high potency, high selectivity, fewer side effects, and higher safety, and has gradually replaced allopurinol and benzbromarone and become the preferred drug for the current clinical treatment of gout and hyperuricemia.

[0004] N-substituted-1,2,3-triazoles are an important class of nitrogen-containing heterocyclic compounds, which play an important role in the fields of medicine, synthetic chemistry and materials. Among them, some 1,2,3-triazole derivatives have anti-inflammatory activity and can be used as potential drugs for the treatment of inflammation-related diseases. Novel 1,2,3-triazole derivatives can inhibit the secretion or activity of some inflammatory factors, thereby exerting an anti-inflammatory effect. Research has shown that some N-aryl-substituted-1,2,3-triazoles can inhibit the secretion of the IL-6 inflammatory factor. However, when microglia are stimulated by inflammation, they will release a large number of inflammatory factors, such as IL-6, IL-1β, TNF-α, etc., leading to neuronal damage and apoptosis. Our team cooperates with Jinan Aisi Pharmaceutical Technology Co., Ltd. Jinan Aisi Pharmaceutical Technology Co., Ltd. is responsible for the synthesis of compounds, and our team is responsible for activity testing, hoping that the synthesized novel 1,2,3-triazole derivatives may have potential anti-microglial inflammatory effects. Summary of the Invention

[0005] In view of the above problems, the purpose of the present invention is to provide a preparation method and application of triazole derivatives with antidepressant effects. The triazole derivatives prepared by the present invention have a novel structure, good anti-inflammatory activity, and play an important role in the research and development of antidepressant drugs.

[0006] To achieve the above purpose, the specific scheme adopted by the present invention is as follows:

[0007] In the first aspect, the present invention provides a triazole derivative with antidepressant activity, and its structure is: Wherein, R 1 , R 2 , R 3 , R 4 and R 5 are one or several of H, halogen, trifluoromethyl, ethyl, phenyl, hydroxyl, cyano, nitro, aromatic ring, etc.

[0008] Second aspect, the present invention provides a method for preparing the triazole derivative: Take 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-N-(2-methylbut-3-yn-2-yl)thiazole-5-carboxamide, an azide compound, sodium L-ascorbate and anhydrous CuSO4 and add them to a round-bottom flask equipped with a magnetic stirrer. Subsequently, add a mixed solvent 5 of water, tert-butanol and THF with a volume ratio of 1:1:1 to the flask, and stir at room temperature until all are dissolved; Keep at room temperature and stir overnight for 2 h; After detecting the completion of the reaction by TLC, extract with DCM, and collect the lower organic phase; Then back-extract with saturated brine, collect the lower organic phase, add anhydrous sodium sulfate thereto, stir well and let stand for 30 min, and then filter to remove anhydrous sodium sulfate; Distill under reduced pressure at 35 °C to obtain the crude product, and then separate and purify the obtained crude product by column chromatography to obtain a white solid, which is the triazole derivative; The azide compound is any one of 2-cyanobenzyl azide, 4-bromobenzyl azide, 2-chloro-5-fluorobenzyl azide, 3-fluorobenzyl azide, 2-bromobenzyl azide, zidovudine, 2-chlorophenyl azide, 2-fluorophenyl azide, 3-chlorophenyl azide, 4-chlorophenyl azide, 4-fluorophenyl azide, 2-trifluoromethylbenzyl azide, 2-trifluoromethoxyphenyl azide, 3-trifluoromethylbenzyl azide, 2-chloro-6-fluorobenzyl azide, 4-trifluoromethylbenzyl azide and 4-fluorobenzyl azide.

[0009] As a further optimization of the above technical solution, the present invention also provides a method for preparing individual raw materials used in the above preparation process.

[0010] Third aspect, the present invention provides the application of the above triazole derivative in the preparation of antidepressant drugs.

[0011] Beneficial effects: Based on the structure of 2-[3-cyano-4-(2-isobutoxy)-phenyl]-4-methylthiazole-5-carboxylic acid, an end alkyne is introduced into its structure, and then more than a dozen novel-structured compounds are obtained by click reaction with an azide compound. Experiments prove that the obtained compounds have good anti-inflammatory activity, are expected to be used for the treatment of depression, and have a strong guiding role in the research and development of antidepressant drugs. Description of the Drawings

[0012] Figure 1 is the 1H NMR spectrum of compound 8.16.

[0013] Figure 2 is the molecular docking schematic diagram of compound 8.16. Detailed Embodiments

[0014] The above content of the present invention will be further described in detail through the following examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0015] In the following examples, unless otherwise specified, the reagents used are all conventional commercially available reagents, and the operation methods adopted are all conventional technical means.

[0016] Example 1

[0017]

[0018] Add 263 kg of polyphosphoric acid to a 1000 L reaction kettle. Slowly drop 27 kg of drinking water while stirring. After adding, continue to stir for 10 min. Then open the cooling water valve to cool the mixture to 40 °C. Add 40 kg of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate. Open the circulating water valve, control the temperature of the reaction solution, and slowly add 235.5 kg of hexamine. Keep the temperature at 40 - 50 °C during the addition. After adding, open the steam valve and slowly heat the reaction solution to raise the temperature of the reaction solution to 90 - 95 °C. Keep the reaction at this temperature for about 1.0 hour. Take samples for detection and control by HPLC. When the content of ethyl 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylate is less than 0.5%, the reaction is completed. If the reaction is not complete, take samples every 0.5 h. After the reaction is completed, close the circulating water and cool the jacket with drinking water. After the internal temperature drops below 40 °C, slowly drop drinking water. After adding, stir for 2 hours and then cool to 5 ± 5 °C. Stir for crystallization for 2 hours and then centrifuge. Wash the filter cake with drinking water (3 - 4 times the amount each time) for 2 times and rinse once (1 time the amount) until the pH of the filtrate is close to neutral (the number of washing times is determined according to the actual centrifugation effect). Spin dry (try to extend the time to make the moisture content of the product less than 50%). After centrifugation, take samples for detection. If the related substances of the wet product meet the quality standards, directly conduct drying. Crush the filter cake and transfer it to a blast drying oven. Dry it at 55 - 65 °C for more than 6 h. Then transfer the filter cake to another clean reaction kettle containing ethanol (the mass of the filter cake * (1 - moisture content%) * 3), and add water to make the ethanol content 75%. Then heat to completely dissolve, then cool to 5 ± 5 °C, stir for crystallization for 1 h, centrifuge. Wash the filter cake once with cold ethanol (75%, 5 - 10 °C) and spin dry. Crush the filter cake and transfer it to a blast drying oven. Dry it at 55 - 65 °C for more than 6 h to obtain 202.1 g of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate

[0019] Example 2

[0020]

[0021] In a reactor equipped with a temperature control device, 29 g of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, 20 g of bromoisobutane, and 20 g of anhydrous potassium carbonate were added to 500 g of N,N-dimethylformamide. After stirring evenly, the mixture was heated to 90 °C and kept at this temperature for reaction for 5 h. Samples were taken for detection and monitored by HPLC. When the content of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate was less than 0.5%, the reaction was completed. If the reaction was not complete, samples were taken every 1 h. After the reaction was completed, the temperature was slowly lowered to 20 - 30 °C, and then 150 g of drinking water was slowly added. During the stirring process, the temperature of the reaction solution dropped to 5 - 10 °C, and crystallization was carried out by stirring for 1 h. After centrifugation, the filter cake was dried and transferred to another clean reactor containing 130 g of isopropanol. Pulping was carried out at room temperature for 1 h, then the temperature was lowered to 5 - 10 °C, and crystallization was carried out by stirring for 1 h. After centrifugation, the filter cake was rinsed with isopropanol (0.5 times the amount), filtered by suction, and dried to obtain 31.4 g of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate; 1 H NMR(400MHZ,DMSO-d6):10.42(s,1H),8.25(s,2H),7.38(d,J=8.0Hz,1H),4.33-4.28(m,2H),4.01(d,J=4.0Hz,2H),2.69(s,3H),2.18-2.06(m,1H),1.31(t,J=8.0Hz,3H),1.05-1.03(m,6H).

[0022] Example 3

[0023]

[0024] In a reactor equipped with a temperature control device, 300 g of anhydrous formic acid was added, and then 35 g of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate, 7.7 g of hydroxylamine hydrochloride, and 12.5 g of sodium formate dihydrate were added successively. The mixture was heated under reflux for 2 h, sampled for detection, and monitored by HPLC. The reaction was completed when the content of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate was less than 0.5% (during the reaction process, the color of the reaction solution changed from light yellow to yellow). If the reaction was not complete, samples were taken every 0.5 h. During the heating process, the reaction solution would quickly solidify, and the stirring speed needed to be increased to make it evenly stirred. After the reaction ended, the reaction solution was cooled to 20 - 30 °C, and the reaction solution would solidify. The stirring speed needed to be increased to make it evenly stirred, and then drinking water was slowly added. After adding, the temperature of the reaction solution was lowered to 10 - 20 °C, and crystallization was carried out by stirring for 1 h. After centrifugation, the filter cake was soaked and washed once with drinking water (2 times the amount), rinsed once with drinking water (1 time the amount), and rinsed once with ethanol-water (1:1, v:v, 1 time the amount). Finally, the pH of the washing solution was close to neutral. After drying, 140 kg of ethanol was added, and the mixture was heated under reflux and slurried for 1 h, then cooled to 5 - 10 °C, and crystallization was carried out by stirring for 1 h. After centrifugation, the filter cake was rinsed with ethanol (0.5 times the amount) and spin-dried to obtain 32.2 g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate.

[0025] Example 4

[0026]

[0027] In a reactor equipped with a temperature control device, 300 g of ethanol was added, and then 35 g of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate was added. The mixture was heated to 50 °C, and 20 g of 20% sodium hydroxide (during the addition of sodium hydroxide, the solid gradually dissolved) was slowly added dropwise. During the addition process, the temperature was maintained at 50 °C. After the addition was completed, stirring and reaction were continued for 1 h (during the reaction process, the reaction solution gradually became clear). Samples were taken for detection and monitored by HPLC. The reaction was completed when the content of ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate was less than 0.1%. If the reaction was not complete, samples were taken every 0.5 h. After the reaction ended, the reaction solution was cooled to below 20 °C, and 2 mol / L dilute hydrochloric acid was slowly added dropwise to adjust the pH to 2 - 3. During the acidification process, the temperature of the reaction solution was controlled to be less than 30 °C, and a large amount of milky white solid precipitated continuously during this period. After acidification, the mixture was kept at 10 - 20 °C and stirred for crystallization for 1 h. After centrifugation, the filter cake was soaked and washed once with drinking water (2 times the amount), rinsed once, and finally the pH of the washing solution was close to neutral. It was rinsed with ethanol (90%, 0.5 times the amount) and spin-dried to obtain 30.4 g of 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid.

[0028] Example 5

[0029]

[0030] To a 500 mL clean round-bottom flask equipped with a magnetic stir bar, 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid (0.02 mol), 2-methyl-2-aminobutyne (0.03 mol), HATU (0.03 mol) and DIPEA (0.06 mol) were added successively. Then, 300 mL of N,N-dimethylformamide was added to the system, and the mixture was stirred at room temperature for 1 h. 200 mL of water was added to the reaction system, and a large amount of solid precipitated during stirring. The solid was filtered and dried to obtain 7.3 g of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-N-(2-methylbut-3-yn-2-yl)thiazole-5-carboxamide.

[0031] Example 6

[0032] 2-(3-Cyano-4-isobutoxyphenyl)-4-methyl-N-(2-methylbut-3-yn-2-yl)thiazole-5-carboxamide (1 mmol), 2-cyanobenzyl azide (1.2 mmol), sodium L-ascorbate (2 mmol) and anhydrous CuSO4 (1 mmol) were added to a 100 mL round-bottom flask equipped with a magnetic stir bar. Subsequently, 50 mL of a mixed solvent of water:tert-butanol:THF = 1:1:1 (v / v / v) was added to the flask, and the mixture was stirred at room temperature for 10 min to completely dissolve it. Keeping at room temperature, the reaction was stirred overnight. After the reaction was completed as detected by TLC, it was extracted 3 times with DCM, and the lower organic phase was collected. It was back-extracted 3 times with saturated brine, and the lower organic phase was collected. Anhydrous sodium sulfate was added thereto, and after sufficient stirring, it was allowed to stand for 30 min, and then the anhydrous sodium sulfate was removed by filtration. The organic solvents such as DCM were removed by distillation under reduced pressure at 35 °C to obtain a crude product, and then the obtained crude product was separated and purified by column chromatography to obtain 8.1 of a solid; 1 HNMR(400MHz,DMSO-d6):8.36(s,1H),8.25(d,J=4.0Hz,1H),8.17(dd,J1=4.0Hz,J2=4.0Hz,1H),8.10(s,1H),7.93(d,J=4.0Hz,1H),7.73(t,J=8.0Hz,1H),7.57(t,J=8.0Hz,1H),7.38(d,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H),5.80(s,2H),4.01(d,J=8.0Hz,2H),2.56(s,3H),1.70(s,6H),1.03(s,3H),1.02(s,3H).

[0033] Example 7

[0034]

[0035] The synthesis method of compound 8.2 is similar to that of compound 8.1. 4-Bromobenzyl azide is used to replace 2-cyanobenzyl azide. The crude product is separated and purified by column chromatography to obtain solid 8.2; 1 H NMR(400MHz,DMSO-d6):8.32(s,1H),8.25(d,J=4.0Hz,1H),8.17(dd,J1=4.0Hz,J2=4.0Hz,1H),8.04(s,1H),7.59(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,1H),7.28(d,J=8.0Hz,2H),5.56(s,2H),4.01(d,J=8.0Hz,2H),2.56(s,3H),1.69(s,6H),1.03(s,3H),1.02(s,3H).

[0036] Example 8

[0037]

[0038] The synthesis method of compound 8.3 is similar to that of compound 8.1. 2-Chloro-5-fluorobenzyl azide is used to replace 2-cyanobenzyl azide. The crude product is separated and purified by column chromatography to obtain solid 8.3; 1 H NMR(400MHz,DMSO-d6):8.37(s,1H),8.25(d,J=4.0Hz,1H),8.18(dd,J1=4.0Hz,J2=4.0Hz,1H),8.08(s,1H),7.59(dd,J1=4.0Hz,J2=4.0Hz,1H),7.38(d,J=8.0Hz,1H),7.31-7.26(m,1H),6.94(dd,J1=4.0Hz,J2=4.0Hz,1H),5.68(s,2H),4.01(d,J=8.0Hz,2H),2.55(s,3H),1.71(s,6H),1.03(s,3H),1.02(s,3H).

[0039] Example 9

[0040]

[0041] The synthesis method of compound 8.4 is similar to that of compound 8.1. 3-Fluorobenzyl azide is used to replace 2-cyanobenzyl azide. The crude product is separated and purified by column chromatography to obtain solid 8.4; 11H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.25 (d, J = 4.0 Hz, 1H), 8.18 (dd, J1 = 4.0 Hz, J2 = 4.0 Hz, 1H), 8.08 (s, 1H), 7.46 - 7.37 (m, 2H), 7.20 - 7.12 (m, 3H), 5.61 (s, 2H), 4.01 (d, J = 8.0 Hz, 2H), 2.56 (s, 3H), 1.70 (s, 6H), 1.03 (s, 3H), 1.02 (s, 3H).

[0042] Example 10

[0043]

[0044] The synthesis method of Compound 8.5 is similar to that of Compound 8.1. Using 2-bromobenzyl azide to replace 2-cyanobenzyl azide, the crude product was separated and purified by column chromatography to obtain solid 8.5; 1 1H NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 8.25 (d, J = 4.0 Hz, 1H), 8.18 (dd, J1 = 4.0 Hz, J2 = 4.0 Hz, 1H), 8.03 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.42 - 7.29 (m, 3H), 7.06 (d, J = 8.0 Hz, 1H), 5.66 (s, 2H), 4.01 (d, J = 4.0 Hz, 2H), 2.56 (s, 3H), 2.15 - 2.05 (m, 1H), 1.70 (s, 6H), 1.03 (s, 3H), 1.02 (s, 3H).

[0045] Example 11

[0046] The synthesis method of Compound 8.6 is similar to that of Compound 8.1. Using zidovudine to replace 2-cyanobenzyl azide, the crude product was separated and purified by column chromatography to obtain solid 8.6; 1 1H NMR (400 MHz, DMSO-d6): δ 11.34 (s, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.21 (d, J = 12.0 Hz, 2H), 7.84 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.45 (t, J = 8.0 Hz, 1H), 5.30 - 5.20 (m, 2H), 4.23 (d, J = 8.0 Hz, 1H), 4.02 (d, J = 4.0 Hz, 2H), 3.74 - 3.64 (m, 3H), 2.61 (s, 3H), 2.41 - 2.15 (m, 2H), 1.84 - 1.81 (m, 5H), 1.74 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H).

[0047] Example 12

[0048]

[0049] The synthesis method of compound 8.7 is similar to that of compound 8.1. 2-chlorophenyl azide is used to replace 2-cyanobenzyl azide, and the crude product is separated and purified by column chromatography to obtain solid 8.7.

[0050] Example 13

[0051]

[0052] The synthesis method of compound 8.8 is similar to that of compound 8.1. 2-fluorophenyl azide is used to replace 2-cyanobenzyl azide, and the crude product is separated and purified by column chromatography to obtain solid 8.8.

[0053] Example 14

[0054]

[0055] The synthesis method of compound 8.9 is similar to that of compound 8.1. 3-chlorophenyl azide is used to replace 2-cyanobenzyl azide, and the crude product is separated and purified by column chromatography to obtain solid 8.9.

[0056] Example 15

[0057]

[0058] The synthesis method of compound 8.10 is similar to that of compound 8.1. 4-chlorophenyl azide is used to replace 2-cyanobenzyl azide, and the crude product is separated and purified by column chromatography to obtain solid 8.10; 1 H NMR(400MHz,DMSO-d6):8.75(s,1H),8.41(s,1H),8.25(s,1H),8.20(d,J=8.0Hz,1H),8.00(d,J=8.0Hz,2H),7.69(d,J=8.0Hz,2H),7.40(d,J=12.0Hz,1H),4.03(d,J=4.0Hz,2H),2.61(s,3H),1.79(m,6H),1.05(s,3H),1.04(s,3H).

[0059] Example 16

[0060]

[0061] The synthesis method of compound 8.11 is similar to that of compound 8.1. 4-fluorophenyl azide is used to replace 2-cyanobenzyl azide, and the crude product is separated and purified by column chromatography to obtain solid 8.11; 11H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 1H), 8.39 (s, 1H), 8.25 - 8.18 (m, 2H), 8.01 - 7.97 (m, 2H), 7.47 (t, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 4.03 (d, J = 4.0 Hz, 2H), 2.61 (s, 3H), 1.79 (m, 6H), 1.05 (s, 3H), 1.03 (s, 3H).

[0062] Example 17

[0063]

[0064] The synthesis method of compound 8.12 is similar to that of compound 8.1. 2-(Trifluoromethyl)benzyl azide was used to replace 2-cyanobenzyl azide. The crude product was separated and purified by column chromatography to obtain solid 8.12; 1 1H NMR (400 MHz, DMSO-d6): δ 8.32 (s, 1H), 8.25 (d, J = 4.0 Hz, 1H), 8.20 - 8.17 (m, 1H), 8.05 (s, 1H), 8.82 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.59 (t, J = 4.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.79 (s, 2H), 4.02 (d, J = 8.0 Hz, 2H), 2.57 (s, 3H), 1.79 (m, 6H), 1.05 (s, 3H), 1.03 (s, 3H).

[0065] Example 18

[0066]

[0067] The synthesis method of compound 8.13 is similar to that of compound 8.1. 2-(Trifluoromethoxy)phenyl azide was used to replace 2-cyanobenzyl azide. The crude product was separated and purified by column chromatography to obtain solid 8.13.

[0068] Example 19

[0069]

[0070] The synthesis method of compound 8.14 is similar to that of compound 8.1. 3-(Trifluoromethyl)benzyl azide was used to replace 2-cyanobenzyl azide. The crude product was separated and purified by column chromatography to obtain solid 8.14.

[0071] Example 20

[0072]

[0073] The synthesis method of Compound 8.15 is similar to that of Compound 8.1. 2-Chloro-6-fluorobenzyl azide was used to replace 2-cyanobenzyl azide, and the crude product was separated and purified by column chromatography to obtain solid 8.15.

[0074] Example 21

[0075]

[0076] The synthesis method of Compound 8.16 is similar to that of Compound 8.1. 4-Fluorobenzyl azide was used to replace 2-cyanobenzyl azide, and the crude product was separated and purified by column chromatography to obtain solid 8.16; 1 H NMR(400MHz,DMSO-d6):8.34(s,1H),8.25(d,J=4.0Hz,2H),8.19(dd,J1=4.0Hz,J2=4.0Hz,1H),8.04(s,1H),7.41-7.37(m,3H),7.24-7.20(m,2H),5.56(s,2H),4.01(d,J=4.0Hz,2H),2.56(s,3H),2.13-2.06(m,1H),1.69(m,6H),1.03(s,3H),1.02(s,3H).

[0077] 1H NMR is as Figure 1 shown, and molecular docking is as Figure 2 shown.

[0078] Example 22

[0079]

[0080] The synthesis method of Compound 8.17 is similar to that of Compound 8.1. 4-Trifluoromethylbenzyl azide was used to replace 2-cyanobenzyl azide, and the crude product was separated and purified by column chromatography to obtain white solid 8.17; 1 H NMR(400MHz,DMSO-d6):8.36(s,1H),8.25(d,J=4.0Hz,2H),8.19(dd,J1=4.0Hz,J2=4.0Hz,1H),8.09(s,1H),7.76(d,J=8.0Hz,2H),7.50(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,1H),5.70(s,2H),4.01(d,J=4.0Hz,2H),2.55(s,3H),2.13-2.06(m,1H),1.70(m,6H),1.03(s,3H),1.02(s,3H).

[0081] Example 23

[0082] Lipopolysaccharide (LPS)-induced BV2 cell inflammation model: BV2 cells were seeded at a density of 2×10 4 cells / well in a 96-well culture plate and incubated in a 37°C incubator with 5% CO2. After 24 hours of incubation, the corresponding concentration of the test compound was added to the treatment group and incubated for 2 hours. Subsequently, LPS with a final concentration of 100 ng / ml was added to both the treatment group and the LPS model group. After incubation in the incubator for 24 hours, the supernatant of each group was reacted with an equal volume of Griess buffer, and the OD value of each group was measured at a wavelength of 540 nm using a microplate reader (BioTek). We can very significantly find that most compounds inhibit the activity of LPS-induced BV2 cells better than resveratrol. At the same time, the inhibitory activity of compounds with better inhibitory activity against the NO production rate on IDO1 was studied using the IDO1 enzyme activity assay based on Hela cells. At a concentration of 10 μM, it was found that some compounds could inhibit the activity of IDO1, reaching 51.9%. We randomly selected a molecule from the group with better performance than the control and observed through molecular docking with the IDO1 target that the triazole in the compound structure could interact with the heme in the key active site of IDO1.

[0083] Table 1. Results of the improvement of compounds on LPS-induced BV2 cell inflammation In the detection of NO production rate, the NO production rate of the LPS model group was set as 100% (n = 3). The data in the table are expressed as mean ± S.E.M. * P<0.05, ** P<0.01 compared with the LPS group. Example 34

[0084] Cell viability detection: BV2 cells were seeded at a density of 2×10 4 cells / well in a 96-well culture plate and incubated in a 37°C incubator with 5% CO2. After 24 hours of incubation, the corresponding concentration of the test compound was added to the treatment group and incubated for 2 hours. Subsequently, LPS with a final concentration of 100 ng / mL was added to both the treatment group and the LPS model group. After further incubation for 24 hours, MTT with a final concentration of 0.5 mg / mL was added to each well for live cell staining. After incubation in the incubator for 1 hour, the culture medium was discarded, 100 μL of DMSO was added to each well, and the plate was shaken on a shaker to dissolve it completely. The OD value of each group was measured at a wavelength of 490 nm using a microplate reader (Biotek).

[0085] Table 2. Toxic effects of compounds on BV2 cells

[0086] In the cell viability assay, the cell viability of the LPS model group was set as 100% (n = 3). The data in the table are expressed as mean ± S.E.M. * P < 0.05, *** P < 0.001 compared to the LPS group.

[0087] The above embodiments have described the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A triazole derivative having an antidepressant effect, characterized in that: The structure of the triazole derivative is: Among them, R 1 , R 2 , R 3 , R 4 and R 5 It is one or more of H, halogen, trifluoromethyl, ethyl, phenyl, hydroxyl, cyano, nitro, aromatic ring, etc.

2. The method for preparing a triazole derivative according to claim 1, characterized in that: Take 2-(3-nitrile-4-isobutoxyphenyl)-4-methyl-N-(2-methylbut-3-yn-2-yl)thiazole-5-carboxamide, azide compounds, sodium L-ascorbate and anhydrous CuSO4 and add them to a round-bottom flask equipped with a stirrer, then add a mixed solvent of water, tert-butyl alcohol and THF to the flask, stir at room temperature to dissolve them all; keep room temperature and stir overnight to react; after the reaction is completed, extract with DCM, collect the lower organic phase; then back-extract with saturated brine, collect the lower organic phase, add anhydrous sodium sulfate thereto, stir well and let stand for a period of time, then filter to remove the anhydrous sodium sulfate; distill under reduced pressure at 35°C to obtain a crude product, and then separate and purify the obtained crude product by column chromatography to obtain a white solid, which is a triazole derivative; The azide compound is any one of 2-nitrile benzyl azide, 4-bromobenzyl azide, 2-chloro-5-fluorobenzyl azide, 3-fluorobenzyl azide, 2-bromobenzyl azide, zidovudine, 2-chlorophenyl azide, 2-fluorophenyl azide, 3-chlorophenyl azide, 4-chlorophenyl azide, 4-fluorophenyl azide, 2-trifluoromethylbenzyl azide, 2-trifluoromethoxyphenyl azide, 3-trifluoromethylbenzyl azide, 2-chloro-6-fluorobenzyl azide, 4-trifluoromethylbenzyl azide and 4-fluorobenzyl azide.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the 2-(3-nitrile-4-isobutoxyphenyl)-4-methyl-N-(2-methylbut-3-yn-2-yl)thiazole-5-carboxamide, the azide compound, sodium L-ascorbate and anhydrous CuSO4 is 1:1.2:2:

1.

4. The preparation method according to claim 2, characterized in that: The 2-(3-nitrile-4-isobutoxyphenyl)-4-methyl-N-(2-methylbut-3-yn-2-yl)thiazole-5-carboxamide in the raw materials was prepared by the following steps: Step 1, add polyphosphoric acid to the reaction tank, slowly add water dropwise while stirring, continue stirring after adding, cool the mixture to 40°C, add 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, control the temperature, slowly add urotropine, raise the temperature of the reaction solution to 90-95°C after adding, and keep warm for reaction; after the reaction is completed, cool to below 40°C, slowly add water dropwise, continue stirring after adding, and cool to 5±5°C, stir and crystallize for 2 hours, and centrifuge; the filter cake is soaked, washed, rinsed, crushed and dried to obtain 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester; the reaction formula is as follows: Step 2: In a reaction kettle, add 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, isobutane bromide and anhydrous potassium carbonate to N,N-dimethylformamide, stir evenly and heat to 90°C, keep warm and react for 5 hours. After the reaction is completed, slowly cool to 20-30°C, slowly add drinking water, cool the reaction solution and stir to crystallize, centrifuge, dry the filter cake and transfer to another clean reaction kettle filled with isopropanol, beat at room temperature, then cool and stir to crystallize, centrifuge, rinse the filter cake with isopropanol, filter and dry to obtain 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester; the reaction formula is as follows: Step 3, add anhydrous formic acid to the reactor, then add 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, hydroxylamine hydrochloride and sodium formate dihydrate in sequence, heat and reflux to react for 2h, cool to 20-30°C after the reaction, stir evenly, then slowly add drinking water, cool the reaction solution after adding, stir and crystallize, centrifuge, soak, wash, rinse and dry the filter cake, add ethanol, heat and reflux to pulp, then cool and stir and crystallize, centrifuge, rinse the filter cake with ethanol after centrifugation, and dry to obtain 2-(3-nitrile-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester; the reaction formula is as follows: Step 4, add ethanol to the reaction kettle, then add 2-(3-nitrile-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester, heat to 50°C, slowly add sodium hydroxide dropwise, continue stirring and reacting for 1h after the addition is completed, cool to below 20°C, slowly add dilute hydrochloric acid dropwise, adjust the pH to 2-3, control the temperature of the reaction solution to be less than 30°C during the acidification process, keep warm at 10-20°C after acidification, stir and crystallize, centrifuge, and soak, wash, rinse, and dry the filter cake to obtain 2-(3-nitrile-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid; the reaction formula is as follows: Step 5: Add 2-[3-nitrile-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid, 2-methyl-2-amino-butyne, HATU and DIPEA to a flask in sequence, then add N,N-dimethylformamide, stir at room temperature for 1 hour, add water, solid precipitates during stirring, filter and dry to obtain 2-(3-nitrile-4-isobutoxyphenyl)-4-methyl-N-(2-methylbut-3-yn-2-yl)thiazole-5-carboxamide; the reaction formula is as follows:

5. The preparation method according to claim 4, characterized in that: In step 5, the molar ratio of the feeding amounts of 2-[3-nitrile-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid, 2-methyl-2-amino-butyne, HATU and DIPEA is 1:1-1.5:1-1.5:2-3.

6. Use of the triazole derivative according to claim 1 in the preparation of antidepressant drugs.

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