An alkynyl sulfone derivative, a preparation method thereof and applications thereof

Abstract

The present invention discloses an alkynyl sulfone derivative, and its structural general formula is shown as formula (I), #imgabs0# (I), wherein when R1 is methoxy, R2 is selected from 4-trifluoromethyl, 4-trifluoromethoxy, 4-tert-butyl, 4-bromo, 4-chloro, 4-cyano, 2-methyl; when R1 is hydrogen, R2 is selected from 4-methyl, 4-phenyl; when R2 is methyl, R1 is selected from thiophene, 4-chloro, 4-isopropyl, 4-bromo, 4-ester group. The present invention synthesizes an alkynyl sulfone compound by using benzenesulfonyl hydrazide and alkynyl bromide under visible light promotion. The method of the present invention has mild reaction conditions, no harmful substances are generated during the synthesis process, is green and environmentally friendly, has a high yield, low cost, is easy to operate, can be used for small-dose reactions, and is also suitable for industrial production. The alkynyl sulfone compounds 1-14 of the present invention have a stronger activation ability for the Nrf2 / ARE signaling pathway, indicating that the alkynyl sulfone compounds 1-14 have good antioxidant ability.

Description

Technical Field

[0001] The present invention belongs to the technical field, and particularly relates to an alkynyl sulfone derivative, a preparation method thereof and an application thereof. Background Art

[0002] Redox reaction is the most basic chemical reaction in the body. Under normal circumstances, the body maintains a relatively constant redox state between oxidation and antioxidation, keeping the body's oxidation system and antioxidant system in a dynamic balance state and maintaining the stability of the body's internal environment. When various harmful factors inside and outside the body act on the body, it will cause abnormal functions of cell mitochondria and endoplasmic reticulum, generating excessive reactive oxygen species (ROS) or reactive nitrogen species (RNS). If the body's antioxidant capacity is relatively or absolutely insufficient, the body's ability to scavenge excess harmful free radicals will decline, leading to a disorder in the balance between reactive oxygen species and antioxidants in the body. The excess ROS or RNS participate in the oxidation of biological macromolecules, causing cell or tissue damage, that is, oxidative stress occurs. Long-term oxidative stress will lead to a pathological process of cell or tissue dysfunction, thereby promoting the occurrence and development of a series of chronic diseases. For example, cancers, diabetes, cardiovascular diseases, and neurodegenerative diseases are all closely related to the body's oxidative stress.

[0003] The nuclear factor erythroid 2-related factor 2 (Nrf2) / antioxidant response element (ARE) signaling pathway (i.e., the Nrf2 / ARE signaling pathway) is an important endogenous antioxidant pathway in cells and the main regulator of the body's antioxidant response, which can resist oxidative stress responses caused by various reasons. Under normal circumstances, the transcription factor Nrf2 is coupled with the Keap1 protein and bound to cytoplasmic actin and anchored in the cytoplasm, and its expression level is maintained at a relatively low level. When stimulated by external stimuli or ROS, the coupling of Nrf2 and Keap1 will be untied, and the free Nrf2 translocates into the nucleus, recognizes and binds to ARE, thereby initiating the expression of downstream phase II detoxification genes and antioxidant genes such as NAD(P)H: quinone oxidoreductase 1 (NQO1), glutathione peroxidase (GPX), heme oxygenase 1 (HO-1), and superoxide dismutase (SOD), etc., thereby enhancing the cell's antioxidant capacity and protecting the cell from oxidative damage. Since the Nrf2 / ARE signaling pathway participates in resisting external oxidative stress responses and is also a key signaling pathway for enhancing the body's antioxidant capacity, it has become a target for antioxidant drugs. Activators of the Nrf2 / ARE signaling pathway have shown good preventive and therapeutic effects in various diseases induced by oxidative stress. For example, plant polyphenol antioxidants such as resveratrol, curcumin, procyanidins, quercetin, and tea polyphenols can all activate the Nrf2 / ARE signaling pathway, improve the antioxidant capacity of cells, and thus exert their medicinal value.

[0004] Alkynyl sulfone derivatives are a class of compounds containing unsaturated C-C triple bonds, which have high chemical reactivity. They are important intermediates that can be converted into other heterocyclic compounds, possess various biological activities, and have extensive applications in the fields of life science, organic synthesis, and drug synthesis. In the existing reports, alkenyl sulfone compounds containing unsaturated C-C double bonds have been reported to be able to activate Nrf2 and thus exert pharmacological effects in the treatment of Parkinson's disease, while there is no corresponding report on the similar physiological activities of alkynyl sulfone compounds. Summary of the Invention

[0005] The first object of the present invention is to provide an alkynyl sulfone derivative, and the second object of the present invention is to provide a preparation method and application of the alkynyl sulfone derivative.

[0006] The first object of the present invention is achieved as follows. An alkynyl sulfone derivative has a general structural formula as shown in (Ⅰ) ( Figure 1 ):

[0007]

[0008] Wherein, when R 1 is methoxy, R 2 is selected from 4-trifluoromethyl, 4-trifluoromethoxy, 4-tert-butyl, 4-bromo, 4-chloro, 4-cyano, 2-methyl;

[0009] When R 1 is hydrogen, R 2 is selected from 4-methyl, 4-phenyl;

[0010] When R 2 is methyl, R 1 is selected from thiophene, 4-chloro, 4-isopropyl, 4-bromo, 4-ester group.

[0011] The second object of the present invention is achieved as follows. The preparation method of the alkynyl sulfone derivative is realized according to the following steps: Under an argon atmosphere, using R 1 -substituted bromophenylacetylene and R 2 -substituted benzenesulfonyl hydrazide as substrate raw materials, adding a base, TBHP and potassium iodide into a reaction tube, dissolving with acetonitrile, irradiating with a blue light lamp with a power of 20W - 30W and a wavelength of 460nm - 470nm at room temperature and stirring the reaction until the substrate reaction is complete. After the reaction is completed, the reaction solution is concentrated and then separated and purified by silica gel column chromatography, using petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent, collecting the elution part with petroleum ether / ethyl acetate = 20:1, and concentrating the eluate to obtain the purified target compound.

[0012] Use of the alkynyl sulfone derivative or a pharmaceutically acceptable salt thereof in the preparation of an antioxidant drug for in vitro or in vivo use and in the activation of the Nrf2 / ARE signaling pathway.

[0013] The beneficial effects of the present invention are as follows:

[0014] 1. The present invention synthesizes alkynyl sulfone compounds by using benzenesulfonyl hydrazide and alkynyl bromide under visible light promotion. The method of the present invention has mild reaction conditions, no harmful substances are generated during the synthesis process, is green and environmentally friendly, has a high yield, low cost, and is convenient to operate. It can be used for small-dose reactions and is also suitable for industrial production.

[0015] 2. The present invention provides 14 alkynyl sulfone compounds. Compounds 1-14 have excellent in vitro antioxidant activities. Compared with the alkenyl sulfone compounds (Ref01) with antioxidant activities reported in the previous literature (J. Med. Chem. 2014, 57, 1473-1487) ( Figure 1 ), compounds 1-14 have a stronger activation ability for the Nrf2 / ARE signaling pathway, indicating that alkynyl sulfone compounds 1-14 have good antioxidant abilities and have good development and application prospects in diseases caused by oxidative stress. Description of the Drawings

[0016] Figure 1 It is the general structural formula of the alkynyl sulfone derivative of the present invention;

[0017] Figure 2 It is the chemical structural formula of the alkenyl sulfone compound Ref01;

[0018] Figure 3 It is the 1H NMR spectrum of compound 1 of the present invention;

[0019] Figure 4 It is the 13C NMR spectrum of compound 1 of the present invention;

[0020] Figure 5 It is the 1H NMR spectrum of compound 2 of the present invention;

[0021] Figure 6 It is the 13C NMR spectrum of compound 2 of the present invention;

[0022] Figure 7 It is the 1H NMR spectrum of compound 3 of the present invention;

[0023] Figure 8 It is the 13C NMR spectrum of compound 3 of the present invention;

[0024] Figure 9 It is the 1H NMR spectrum of compound 4 of the present invention;

[0025] Figure 1013C NMR spectrum of Compound 4 of the present invention;

[0026] Figure 11 Activation effect diagrams of Compounds 1-14 of the present invention and the reference vinyl sulfone compound Ref01 on the Nrf2 / ARE signaling pathway. Detailed implementation manners

[0027] The present invention is further described below, but it is not limited to the present invention in any way. Any transformation based on the present invention falls within the protection scope of the present invention.

[0028] The present invention provides an alkynyl sulfone derivative, and its general structural formula is shown as (Ⅰ):

[0029]

[0030] Among them, when R 1 is methoxy, R 2 is selected from 4-trifluoromethyl, 4-trifluoromethoxy, 4-tert-butyl, 4-bromo, 4-chloro, 4-cyano, 2-methyl;

[0031] When R 1 is hydrogen, R 2 is selected from 4-methyl, 4-phenyl;

[0032] When R 2 is methyl, R 1 is selected from thiophene, 4-chloro, 4-isopropyl, 4-bromo, 4-ester group.

[0033] The alkynyl sulfone compound is preferably:

[0034] methyl-4-((phenylethynyl)sulfonyl)benzene (Compound 1);

[0035] 1-methoxy-4-(((4-(trifluoromethyl)phenyl)sulfonyl)ethynyl)benzene (Compound 2);

[0036] 1-methoxy-4-(((4-(trifluoromethoxy)phenyl)sulfonyl)ethynyl)benzene (Compound 3);

[0037] 3-(tosylethynyl)thiophene (Compound 4);

[0038] 1-chloro-4-(tosylethynyl)benzene (Compound 5);

[0039] 1-(tert-butyl)-4-(((4-methoxyphenyl)ethynyl)sulfonyl)benzene (Compound 6);

[0040] 4-((phenylethynyl)sulfonyl)-1,1'-biphenyl (Compound 7);

[0041] 1-(((4-methoxyphenyl)ethynyl)sulfonyl)-2-methylbenzene (Compound 8);

[0042] 1-isopropyl-4-(tosylethynyl)benzene (Compound 9);

[0043] 1-chloro-4-(((4-methoxyphenyl)ethynyl)sulfonyl)benzene (Compound 10);

[0044] 1-bromo-4-(((4-methoxyphenyl)ethynyl)sulfonyl)benzene (Compound 11);

[0045] 1-bromo-4-(tosylethynyl)benzene (Compound 12);

[0046] methyl 4-(tosylethynyl)benzoate (Compound 13);

[0047] 4-(((4-methoxyphenyl)ethynyl)sulfonyl)benzonitrile (Compound 14);

[0048] The structural formulas of Compounds 1 - 14 are respectively shown as 1 - 14 in Formula (II).

[0049]

[0050] The present invention also provides a preparation method of the alkynyl sulfone derivative, which is realized according to the following steps: Under an argon atmosphere, using R 1 substituted bromophenylacetylene and R 2Using a substituted benzenesulfonyl hydrazide as the substrate raw material, add a base, TBHP, and potassium iodide to a reaction tube, dissolve with acetonitrile, irradiate with a blue light lamp with a power of 20 W - 30 W and a wavelength of 460 nm - 470 nm at room temperature, and stir the reaction until the substrate reaction is complete. After the reaction is completed, concentrate the reaction solution and then separate and purify it by silica gel column chromatography. Using petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent, collect the elution part with petroleum ether / ethyl acetate = 20:1, and after concentrating the eluate, the purified target compound is obtained.

[0051] The said R 1 The substituted bromophenylacetylene compound is any one of bromophenylacetylene, 4-methoxybromophenylacetylene, 3-(bromoethynyl)thiophene, 4-chlorobromophenylacetylene, 4-isopropylbromophenylacetylene, 4-bromobromophenylacetylene, 4-esterbromophenylacetylene;

[0052] The said R 2 The substituted benzenesulfonyl hydrazide compound is any one of 4-methylbenzenesulfonyl hydrazide, 4-trifluoromethylbenzenesulfonyl hydrazide, 4-trifluoromethoxybenzenesulfonyl hydrazide, 4-tert-butylbenzenesulfonyl hydrazide, 4-bromobenzenesulfonyl hydrazide, 4-chlorobenzenesulfonyl hydrazide, 4-cyanobenzenesulfonyl hydrazide, 2-methylbenzenesulfonyl hydrazide, 4-phenylbenzenesulfonyl hydrazide.

[0053] The said base is potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, potassium acetate or sodium acetate.

[0054] The said photocatalyst is Ru(bpy) 3 Cl 2 、Acr-Mes + -Me、fac-Ir(ppy) 3 or Eosin Y.

[0055] The said R 1 The substituted bromophenylacetylene compound, R 2 The substituted benzenesulfonyl hydrazide compound, base, potassium iodide, TBHP and photocatalyst have a molar ratio range of (1 - 1.5):(1 - 2.5):1:1:1:0.02.

[0056] The present invention also provides the use of the alkynyl sulfone derivative or a pharmaceutically acceptable salt thereof in the preparation of an antioxidant drug for in vitro or in vivo use.

[0057] The present invention further provides the use of the alkynyl sulfone derivative or a pharmaceutically acceptable salt thereof in activating the Nrf2 / ARE signaling pathway.

[0058] Example 1

[0059] Compound 1: 1-methyl-4-((phenylethynyl)sulfonyl)benzene; white solid,

[0060] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), p-toluenesulfonyl hydrazide (18.7 mg, 0.1 mmol), phenylethynyl bromide (45.3 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as the solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred at a rate of 1000 r / min until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent. The fraction with petroleum ether / ethyl acetate = 20:1 was collected, concentrated, and Compound 1 was obtained with a yield of 85%.

[0061] 1 H NMR (400 MHz, Chloroform-d) δ 7.99–7.94 (m, 2H), 7.54–7.50 (m, 2H), 7.50–7.44 (m, 1H), 7.38 (dt, J = 8.6, 7.2 Hz, 4H), 2.47 (s, 3H). (See Figure 3 )

[0062] 13 C NMR (101 MHz, Chloroform-d) δ 145.39, 138.98, 132.72, 131.47, 130.01, 128.67, 127.51, 118.03, 92.99, 85.62, 21.74. (See Figure 4 ).

[0063] The reaction formula is as follows:

[0064]

[0065] Example 2

[0066] Compound 2: 1-methoxy-4-(((4-(trifluoromethyl)phenyl)sulfonyl)ethynyl)benzene; yellow solid.

[0067] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-trifluoromethylbenzenesulfonyl hydrazide (25.4 mg, 0.1 mmol), 4-methoxyphenyl ethynyl bromide (52.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent. The fraction with petroleum ether / ethyl acetate = 20:1 was collected, concentrated, and compound 2 was obtained with a yield of 80%.

[0068] 1 H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 8.1 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.53–7.46 (m, 2H), 6.92–6.86 (m, 2H), 3.84 (s, 3H). (See Figure 5 )

[0069] 13 C NMR (101 MHz, Chloroform-d) δ 162.52, 134.92, 127.90 (2C), 126.53 (q, 1 J F-C = 4.0 Hz), 114.56, 114.39, 108.99, 96.29, 83.99, 55.51. (See Figure 6 ).

[0070] The reaction formula is as follows:

[0071]

[0072] Example 3

[0073] Compound 3: 1-((phenylethynyl)sulfonyl)-4-(trifluoromethoxy)benzene; white solid.

[0074] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-trifluoromethoxybenzenesulfonyl hydrazide (25.6 mg, 0.1 mmol), 4-methoxyphenyl ethynyl bromide (52.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent. The fraction with petroleum ether / ethyl acetate = 20:1 was collected, concentrated, and compound 3 was obtained with a yield of 90%.

[0075] 1 H NMR (400 MHz, Chloroform-d) δ 8.16–8.10 (m, 2H), 7.53–7.46 (m, 2H), 7.41 (d, J = 9.0 Hz, 2H), 6.93–6.85 (m, 2H), 3.84 (s, 3H). (See Figure 7 )

[0076] 13 C NMR (101 MHz, Chloroform-d) δ 162.40, 153.13 (q, 2 J F-C = 4 Hz), 140.30, 134.83 (2C), 129.66, 121.27 (q, 1 J F-C = 46.5 Hz), 118.92, 114.52 (2C), 109.20, 95.46, 84.28, 55.49. (See Figure 8 ).

[0077] The reaction scheme is as follows:

[0078]

[0079] Example 4

[0080] Compound 4: 3-(tosylethynyl)thiophene; white solid.

[0081] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-methylbenzenesulfonyl hydrazide (18.7 mg, 0.1 mmol), 3-(bromoethynyl)thiophene (46.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent. The fraction with petroleum ether / ethyl acetate = 20:1 was collected and concentrated to obtain compound 4 with a yield of 75%.

[0082] 1 H NMR (400 MHz, Chloroform-d) δ 7.97–7.93 (m, 2H), 7.74 (dd, J = 3.0, 1.2 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 5.1, 3.0 Hz, 1H), 7.17 (dd, J = 5.1, 1.2 Hz, 1H), 2.47 (s, 3H). (See Figure 9 )

[0083] 13 C NMR (101 MHz, Chloroform-d) δ 144.34, 137.94, 133.51 (2C), 128.97, 128.74, 126.48, 125.48 (2C), 116.22, 87.58, 84.51, 20.72. (See Figure 10 )

[0084] The reaction formula is as follows:

[0085]

[0086] Example 5

[0087] Compound 5: 1-chloro-4-(tosylethynyl)benzene, a white solid.

[0088] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-methylbenzenesulfonyl hydrazide (18.7 mg, 0.1 mmol), 4-chlorophenylethynyl bromide (53.9 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain compound 5 with a yield of 88%.

[0089] 1 H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.38 (dd, J = 18.7, 8.3 Hz, 4H), 2.48 (s, 3H).

[0090] 13 C NMR (101 MHz, Chloroform-d) δ 145.58, 138.73, 138.01, 133.91, 130.07, 129.20, 127.59, 116.51, 91.53, 86.48, 21.76.

[0091] The reaction formula is as follows:

[0092]

[0093] Example 6

[0094] Compound 6: 1-(tert-butyl)-4-(((4-methoxyphenyl)ethynyl)sulfonyl)benzene, yellow solid.

[0095] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-tert-butylbenzenesulfonyl hydrazide (22.8 mg, 0.1 mmol), 4-methoxyphenyl ethynyl bromide (52.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain compound 6 with a yield of 98%.

[0096] 1 H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 8.7 Hz, 2H), 7.62–7.57 (m, 2H), 7.50–7.45 (m, 2H), 6.90–6.84 (m, 2H), 3.82 (s, 3H), 1.36 (s, 9H).

[0097] 13 C NMR (101 MHz, Chloroform-d) δ 162.12, 158.04, 139.09, 134.69 (2C), 127.20 (2C), 126.36 (2C), 114.42 (2C), 109.69, 94.11, 84.85, 55.47, 35.35, 31.06 (3C).

[0098] The reaction formula is as follows:

[0099]

[0100] Example 7

[0101] Compound 7: 4-((phenylethynyl)sulfonyl)-1,1'-biphenyl; white solid.

[0102] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-phenylbenzenesulfonylhydrazide (24.8 mg, 0.1 mmol), 4-methoxyphenyl ethynyl bromide (52.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain compound 7 with a yield of 98%.

[0103] 1 H NMR (400 MHz, Chloroform-d) δ 8.17–8.12 (m, 2H), 7.84–7.77 (m, 2H), 7.62 (dt, J = 8.4, 2.0 Hz, 2H), 7.58–7.34 (m, 8H).

[0104] 13 C NMR (101 MHz, Chloroform-d) δ 147.21, 140.30, 139.07, 132.79 (2C), 131.57, 129.13 (2C), 128.80 (2C), 128.70, 128.01, 127.44 (2C), 117.94, 93.45, 85.50.

[0105] The reaction formula is as follows:

[0106]

[0107] Example 8

[0108] Compound 8: 1-(((4-methoxyphenyl)ethynyl)sulfonyl)-2-methylbenzene, white solid.

[0109] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 2-phenylbenzenesulfonylhydrazide (18.7 mg, 0.1 mmol), 4-methoxybromoethynylbenzene (52.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain compound 8 with a yield of 89%.

[0110] 1 H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 9.4 Hz, 1H), 7.58–7.34 (m, 5H), 6.88 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H), 2.82 (s, 3H).

[0111] 13 C NMR (101 MHz, Chloroform-d) δ 162.19, 139.98, 138.33, 134.75, 133.94 (2C), 132.72, 128.56, 126.47, 114.50 (2C), 109.54, 93.10, 84.37, 55.49, 20.09.

[0112] The reaction formula is as follows:

[0113]

[0114] Example 9

[0115] Compound 9: 1-isopropyl-4-(tosylethynyl)benzene, a white solid.

[0116] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 2-phenylbenzenesulfonylhydrazide (18.7 mg, 0.1 mmol), 4-isopropylbromoethynylbenzene (59.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain compound 9 with a yield of 80%.

[0117] 1 H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 8.4 Hz, 2H), 7.43 (s, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 2.91 (p, J = 6.9 Hz, 1H), 2.46 (s, 3H), 1.22 (d, J = 6.9 Hz, 6H).

[0118] 13 C NMR (101 MHz, Chloroform-d) δ 153.08, 145.22, 139.18, 132.86 (2C), 129.95 (2C), 127.43 (2C), 126.88 (2C), 115.19, 93.76, 85.14, 34.31, 23.56 (2C), 21.72.

[0119] The reaction formula is as follows:

[0120]

[0121] Example 10

[0122] Compound 10: 1-chloro-4-(((4-methoxyphenyl)ethynyl)sulfonyl)benzene, a white solid.

[0123] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-chlorobenzenesulfonyl hydrazide (20.7 mg, 0.1 mmol), 4-methoxyphenyl ethynyl bromide (52.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain compound 10 with a yield of 96%.

[0124] 1 H NMR (400 MHz, Chloroform-d) δ 8.02–7.99 (m, 2H), 7.59–7.54 (m, 2H), 7.50–7.45 (m, 2H), 6.91–6.85 (m, 2H), 3.83 (s, 3H).

[0125] 13 C NMR (101 MHz, Chloroform-d) δ 162.35, 140.74, 140.59, 134.79, 129.68, 128.82, 114.52, 109.24, 95.29, 84.37, 55.50.

[0126] The reaction formula is as follows:

[0127]

[0128] Example 11

[0129] Compound 11: 1-bromo-4-(((4-methoxyphenyl)ethynyl)sulfonyl)benzene, white solid.

[0130] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-bromobenzenesulfonyl hydrazide (25.1 mg, 0.1 mmol), 4-methoxyphenylethynyl bromide (52.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain compound 11 with a yield of 85%.

[0131] 1 H NMR (400 MHz, Chloroform-d) δ 7.97–7.90 (m, 2H), 7.76–7.70 (m, 2H), 7.51–7.45 (m, 2H), 6.92–6.85 (m, 2H), 3.83 (s, 3H).

[0132] 13 C NMR (101 MHz, Chloroform-d) δ 162.36, 141.10, 134.81, 132.68, 132.49, 129.36 (2C), 129.03, 128.87, 114.52 (2C), 109.21, 95.37, 84.32, 55.51.

[0133] The reaction formula is as follows:

[0134]

[0135] Example 12

[0136] Compound 12: 1-butyl-4-(tosylethynyl)benzene, a white solid.

[0137] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-methylbenzenesulfonyl hydrazide (18.7 mg, 0.1 mmol), 4-bromophenylethynyl bromide (65 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain compound 12 with a yield of 90%.

[0138] 1 H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.43–7.35 (m, 4H), 2.48 (s, 3H).

[0139] The reaction formula is as follows:

[0140]

[0141] Example 13

[0142] Compound 13: methyl 4-(tosylethynyl)benzoate, a white solid.

[0143] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-methylbenzenesulfonyl hydrazide (18.7 mg, 0.1 mmol), 4-(ester group)bromophenylethynyl bromide (60 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain compound 13 with a yield of 30%.

[0144] 1 H NMR (400 MHz, Chloroform-d) δ 8.06–7.94 (m, 4H), 7.61–7.57 (m, 2H), 7.44–7.38 (m, 2H), 3.93 (s, 3H), 2.48 (s, 3H).

[0145] 13 C NMR (101 MHz, Chloroform-d) δ 165.84, 145.72, 138.56, 132.66, 132.44, 130.11, 129.66, 127.68, 122.42, 91.19, 87.61, 52.54, 21.78.

[0146] The reaction formula is as follows:

[0147]

[0148] Example 14

[0149] Compound 14: 4-(((4-methoxyphenyl)ethynyl)sulfonyl)benzonitrile, a white solid.

[0150] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), 4-cyanobenzenesulfonyl hydrazide (19.7 mg, 0.1 mmol), 4-methoxyphenyl ethynyl bromide (52.8 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography [petroleum ether / ethyl acetate] to obtain Compound 14 with a yield of 60%.

[0151] 1 H NMR (400 MHz, Chloroform-d) δ 8.23–8.17 (m, 2H), 7.92–7.87 (m, 2H), 7.52–7.47 (m, 2H), 6.93–6.87 (m, 2H), 3.84 (s, 3H).

[0152] 13 C NMR (101 MHz, Chloroform-d) δ 162.67, 146.02, 134.99 (2C), 133.15 (2C), 127.96 (2C), 117.63, 117.11, 114.63 (2C), 108.79, 96.97, 83.76, 55.54.

[0153] The reaction formula is as follows:

[0154]

[0155] Example 15

[0156] In a glove box, under an argon atmosphere, in a reaction tube, Ru(bpy) 3 Cl 2 (1.50 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium carbonate (13.8 mg, 0.1 mmol), p-toluenesulfonyl hydrazide (18.7 mg, 0.1 mmol), phenylethynyl bromide (45.3 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol), and finally 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 20 W and a wavelength of 470 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent. The fraction with petroleum ether / ethyl acetate = 20:1 was collected and concentrated to obtain Compound 1.

[0157] Example 16

[0158] In a glove box, under an argon atmosphere, in a reaction tube, Acr-Mes + -Me (1.0 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), sodium bicarbonate (8.4 mg, 0.1 mmol), p-toluenesulfonyl hydrazide (18.7 mg, 0.1 mmol), phenylethynyl bromide (45.3 mg, 0.25 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol), and finally 1 mL of acetonitrile was added as a solvent. Then the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 470 nm and stirred until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent. The fraction with petroleum ether / ethyl acetate = 20:1 was collected and concentrated to obtain Compound 1.

[0159] Example 17

[0160] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), p-toluenesulfonyl hydrazide (28.05 mg, 0.15 mmol), bromophenylacetylene (18.12 mg, 0.1 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then, the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred at a rate of 1000 r / min until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was subjected to silica gel column chromatography with petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent. The fraction with petroleum ether / ethyl acetate = 20:1 was collected, concentrated, and compound 1 was obtained with a yield of 60%.

[0161] Example 18

[0162] In a glove box, under an argon atmosphere, in a reaction tube, Eosin Y (1.4 mg, 0.002 mmol), potassium iodide (16.6 mg, 0.1 mmol), potassium bicarbonate (10.0 mg, 0.1 mmol), p-toluenesulfonyl hydrazide (18.7 mg, 0.1 mmol), bromophenylacetylene (18.12 mg, 0.1 mmol), tert-butyl hydroperoxide (10 μL, 0.1 mmol) were added. Finally, 1 mL of acetonitrile was added as a solvent. Then, the reaction tube was placed under a blue light with a power of 30 W and a wavelength of 460 nm and stirred at a rate of 1000 r / min until the substrate reaction was complete (monitored by TLC). The reaction solution was concentrated, and the crude product was subjected to silica gel column chromatography with petroleum ether / ethyl acetate (30:1 - 20:1) as the eluent. The fraction with petroleum ether / ethyl acetate = 20:1 was collected, concentrated, and compound 1 was obtained with a yield of 48%.

[0163] Test Example 1 Activation effect of alkynyl sulfone compounds 1 - 14 of the present invention on the Nrf2 / ARE signaling pathway

[0164] Test principle: Nuclear transcription-related factor 2 (NRF2) is the main regulator of the adaptive antioxidant response. The antioxidant response element (ARE) is a specific DNA-promoter binding sequence, which can initiate the expression of phase II detoxifying enzymes and antioxidant enzyme genes, thus ensuring the normal operation of cell tissue functions. Transfect the ARE-Luc luciferase reporter gene plasmid into cells. When ARE binds to the Nrf2 transcription factor, it can regulate the genes involved in protecting cells from oxidative damage. The regulatory effect of compounds on the Nrf2 / ARE signaling pathway can be investigated using the reporter gene detection method.

[0165] Test method: HEK293T cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C in a cell culture incubator containing 5% CO 2 . HEK293T cells in the logarithmic growth phase were seeded in a 24-well cell culture plate and cultured for 24 h. pARE-Luc (500 ng / well) and pRL-TK (20 ng / well) plasmids were transfected with Lipofectamine 2000. After continued culture for 18 h, distilled water (negative control group) with 1 / 10 volume of the reaction system, compounds 1-14 with different concentrations (50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.13 μM, 1.56 μM) and the reference vinyl sulfone compound Ref01 were added respectively, and the incubation was continued for 6 h. The supernatant was discarded, the cells were lysed by shaking at room temperature for 15 min, the supernatant was collected by centrifugation, and the fluorescence value was detected with a dual-luciferase reporter assay kit. Under the same experimental conditions, the cytotoxicity of the compounds to HEK293 cells was detected by the sulforhodamine B (SRB) method. After treating the cells with the compounds according to the above experimental conditions, pre-cooled 50% trichloroacetic acid solution was added to fix the cells, and then the surviving cells were stained with SRB solution. Finally, Tris solution was added to dissolve SRB, and the absorbance was detected at a wavelength of 520 nm.

[0166] Experimental results: As Figure 11 shown in the results, compared with the reference vinyl sulfone compound Ref01, compounds 1-14 of the present invention can significantly promote the activation of the Nrf2 / ARE signaling pathway, and their activation effects on the Nrf2 / ARE signaling pathway show an obvious dose-dependence. Compounds 1, 4, 12 and 13 had the strongest activation effects on the Nrf2 / ARE pathway at a concentration of 12.5 μM, and their activation multiples for this pathway were 6.89, 4.31, 5.77 and 4.33 times respectively; compounds 2, 3, 5, 6, 8, 10 and 11 had the strongest activation effects on the Nrf2 / ARE pathway at a concentration of 6.25 μM, and their activation multiples for this pathway were 4.77, 5.27, 3.47, 8.12, 6.24 and 4.28 times respectively; compounds 7 and 9 had the strongest activation effects on the Nrf2 / ARE pathway at a concentration of 3.13 μM, and their activation multiples for this pathway were 2.02 and 3.55 times respectively; compound 14 had the strongest activation effect on the Nrf2 / ARE pathway at a concentration of 25 μM, and its activation multiple for this pathway was 5.48 times.

[0167] The cytotoxicity results of compounds 1-14 to HEK293T cells under the same experimental conditions are shown in Table 1. From Figure 11As can be seen from Table 1, Compounds 1-14 can significantly inhibit the proliferation of HEK293T cells at high concentrations. Due to cytotoxic effects, their effects on the Nrf2 / ARE pathway at high concentrations are shown to be inhibitory. However, at concentrations without obvious cytotoxic effects, Compounds 1-14 can significantly activate the Nrf2 / ARE pathway.

[0168] Table 1 Results of the cytotoxic effects of Compounds 1-14 and Ref01 on HEK293T cells.

[0169]

[0170]

Claims

1. A preparation method of an Nrf2 / ARE signaling pathway activator, wherein the Nrf2 / ARE signaling pathway activator is an alkynyl sulfone derivative represented by structural general formula (I): （Ⅰ） Wherein, When R 1 is methoxy, R 2 is selected from 4-trifluoromethyl, 4-trifluoromethoxy, 4-tert-butyl, 4-bromo, 4-chloro, 2-methyl; When R 1 is hydrogen, R 2 is selected from 4-methyl, 4-phenyl; When R 2 is methyl, R 1 is selected from thiophene, 4-chloro, 4-isopropyl, 4-bromo; It is characterized in that the preparation method is realized according to the following steps: Under an argon atmosphere, using R 1 -substituted bromophenylacetylene and R 2 -substituted benzenesulfonylhydrazide as the substrate raw materials, adding a photocatalyst, a base, TBHP and potassium iodide into a reaction tube, dissolving with acetonitrile, irradiating with a blue light lamp with a power of 30 W and a wavelength of 460 nm and stirring the reaction at room temperature until the substrate reaction is complete. After the reaction is completed, concentrating the reaction solution and then separating and purifying it by silica gel column chromatography, eluting with a petroleum ether / ethyl acetate gradient of 30:1 to 20:1, collecting the elution part with petroleum ether / ethyl acetate = 20:1, and concentrating the eluate to obtain the purified target compound; The base is potassium bicarbonate, and the photocatalyst is Eosin Y; the R 1 substituted bromophenylacetylene compound, R 2 The molar ratio of the substituted benzenesulfonylhydrazide compound, base, potassium iodide, TBHP and photocatalyst is 2.5:1:1:1:1:0.02.

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