Flavone derivative containing sulfonamide structure as well as preparation method and application of flavone derivative

Abstract

The invention discloses a flavone derivative containing a sulfonamide structure and a preparation method and application of the flavone derivative, and the flavone derivative has the following general formula structure: # imgabs0. The flavone derivative containing the sulfonamide structure is based on a combination mode of the flavone derivative containing the sulfonamide structure and Keap1 protein, and is combined with computer-aided drug design to introduce a sulfonyl group on a flavone skeleton, so that the flavone derivative containing the sulfonamide structure is obtained. The hydrogen bond interaction between the compound and amino acid residues Arg415 and Ser508 in the binding pocket is enhanced; meanwhile, the aromatic structure can be deeply combined with a pocket to enhance the hydrophobic binding force with amino acid residues such as Tyr525 and Tyr334, the water solubility is improved, and the biological activity of the target compound for interfering the Keap1-Nrf2 protein interaction is further improved.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to flavonoid derivatives, and specifically relates to a class of flavonoid derivatives containing a sulfonamide structure, a pharmaceutical salt, a pharmaceutical composition, a preparation method thereof and an application thereof in the treatment of liver damage. Background Art

[0002] When an organism is exposed to external stimuli, it will cause an increase in free radicals (reactive oxygen species, ROS; reactive nitrogen species, RNS), resulting in an unbalanced defense between reactive oxidants and antioxidants, leading to oxidative stress in the body. It has been reported that the pathogenic mechanisms of more than 200 chronic diseases are related to oxidative stress, including cancer, inflammatory diseases, neurodegenerative diseases, autoimmune diseases, and cardiovascular diseases. Therefore, maintaining redox homeostasis plays an important role in preventing the occurrence and development of a variety of chronic diseases characterized by oxidative stress. The body has evolved a complex defense system to cope with the continuous damage of oxidative stress, such as limiting the production of free radicals and inducing the production of protective proteins to alleviate tissue damage. Nrf2 (nuclear factor erythroid 2-related factor 2) is the most important transcription factor for cellular defense against oxidative stress. It can bind to the antioxidant response element (ARE) to initiate the transcription of cytoprotective genes, such as heme oxygenase-1 (HMOX1), NAD(P)H / quinone oxidoreductase 1 (NQO1), glutamate-cysteine ​​ligase (GCLC / GCLM), inflammatory regulators, transporters, etc. These cytoprotective proteins are involved in regulating the homeostasis of the internal environment, allowing cells to respond adaptively and survive under stress conditions. Given the key role of Nrf2 in maintaining cellular redox homeostasis, activation of Nrf2 is considered a potential way to treat a variety of chronic diseases driven by oxidative stress.

[0003] There are two ways for Keap1-dependent Nrf2 activation: (a) covalent modification of active cysteines in the Kelch domain (Cys151, Cys257, Cys273, Cys288, Cys297, Cys434, Cys613, etc.) interferes with the precise assembly of the Keap1-Nrf2 complex and activates Nrf2; (b) non-covalent binding to the Keap1 binding cavity disrupts the function of its E3 ubiquitin ligase substrate and positively regulates Nrf2 by inhibiting the ubiquitination and proteasomal degradation of Nrf2. Studies have shown that covalent Nrf2 activators are also highly reactive to thiols in other biomacromolecules. Therefore, non-covalent Nrf2 agonists that can specifically recognize Keap1 proteins and reduce off-target side effects have become the main research objects in this field.

[0004] At present, there are more than 50 small molecule inhibitors of non-covalent Keap1-Nrf2 protein interaction with micromolar and below levels. According to the chemical structure, they can be divided into six categories: naphthalenesulfonamides, isoquinolines, triazoles, pyrazole carboxylic acids, natural products and others. While these inhibitors have improved target affinity, their drugability has always faced many problems. For example, the carboxyl group is the key pharmacophore for Keap1 inhibitors to exert biological activity, but its strong polarity and hydrophobicity make the molecular pharmacokinetic properties poor. So far, only a few compounds have reported oral bioavailability, but it is not ideal. Therefore, the key scientific issue that needs to be paid attention to for this type of compound is to effectively combine target affinity and drugability by using medicinal chemistry methods, such as fragment addition, drug-like group fusion, bioisostere replacement, etc.

[0005] Flavonoid compounds are abundant in nature, not only cheap and easy to obtain, but also have multiple medicinal values ​​such as anti-cancer, anti-oxidation, hypolipidemic, antibacterial, etc. Flavonoid compounds have also been widely reported as Keap1 inhibitors. Therefore, the present invention takes the natural flavonoid skeleton as a guide, under the guidance of the three key pharmacophore requirements (aromatic system, benzene sulfonamide and acidic group) of non-covalent Keap1 inhibitors, and uses the medicinal chemistry strategy of fragment addition to design and synthesize sulfonamide-flavonoid series derivatives, in order to screen out candidate compounds with higher activity and better oral bioavailability. Summary of the invention

[0006] The purpose of the present invention is to provide a sulfonamide-containing flavonoid compound with strong biological activity, high selectivity and good oral bioavailability and a preparation method thereof, so as to achieve the treatment of inflammatory diseases including liver damage.

[0007] In a first aspect of the present invention, a flavonoid derivative containing a sulfonamide structure is provided, which has the following general structure:

[0008]

[0009] Among them, R 1 One selected from the group consisting of benzene ring and substituted benzene ring, thiophene and its oxides, thiazole and its oxides, pyrrole and its oxides, pyrazole (pyran) and its oxides, imidazole and its oxides, (iso)oxazole and its oxides, pyrazolone, furan, pyridine, oxazine and its oxides, cyclopentadiene, tetrahydrothiophene and other episulfides (sulfoxides and sulfones), tetrahydrofuran and other epoxy compounds and optionally substituted cycloalkanes;

[0010] R 2 -H, -CH 2 -,-O-,-S-,-C(O),-S(O)- and -S(O) 2 -A linking group;

[0011] R 3 are independently selected from hydrogen, cyano, nitro, hydroxyl, halogen, amino, C 3～6 Cycloalkoxy, C 3～6 Cycloalkylamino, optionally substituted C 1～6 Alkyl, optionally substituted C 2～6 Alkenyl, optionally substituted C 2～6 Alkynyl or C 1～6 One of the group consisting of alkoxy group, carboxyl group, ester group and amide group.

[0012] The present invention is based on the binding mode of flavonoid derivatives containing sulfonamide structure and Keap1 protein, combined with computer-aided drug design, and introduces sulfonyl groups on the flavonoid skeleton to enhance the hydrogen bond interaction between the compound and the amino acid residues Arg415 and Ser508 in the binding pocket; at the same time, the aromatic structure can penetrate into the binding pocket to strengthen the hydrophobic binding force with amino acid residues such as Tyr525 and Tyr334, thereby improving water solubility and further enhancing the biological activity of the target compound in interfering with the Keap1-Nrf2 protein interaction.

[0013] Preferably, the flavonoid derivative containing a sulfonamide structure provided by the present invention has a structural formula selected from any one of the following:

[0014]

[0015]

[0016] The second aspect of the present invention provides a method for preparing the above-mentioned flavonoid derivative containing a sulfonamide structure, and the preparation route is as follows:

[0017] The preparation method comprises the following steps: using substituted sulfonyl chloride II and flavonoid derivative III as raw materials to react under the action of a base, and washing, drying, filtering, concentrating and recrystallizing the reaction solution to obtain a key intermediate (IV).

[0018] The preferred conditions for the above reaction are as follows:

[0019] The reaction solvent is selected from one or more of the group consisting of acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, isopropanol, n-butanol and isobutanol.

[0020] The base is selected from one or more inorganic bases in the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and sodium hydrogen; or one or more organic bases in the group consisting of pyridine, N,N-dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine and potassium tert-butoxide.

[0021] The molar ratio of the substituted sulfonyl chloride compound II, the flavonoid derivative III and the base is 1:1:1.5-1:2:3.

[0022] The reaction temperature is 20-35°C and the reaction time is 4-10h.

[0023] The inventors have confirmed through a large number of experimental studies and practical explorations that in the method for preparing the flavonoid derivatives containing a sulfonamide structure, when the above-mentioned components, molar ratios and reaction conditions are used, the conversion rate and selectivity of the prepared target product are relatively high, and the yield after separation and purification is higher.

[0024] In an embodiment of the present invention, the separation and purification of the flavonoid derivatives containing a sulfonamide structure described herein can be carried out by any suitable separation or purification method, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low pressure or high pressure liquid chromatography or a combination of these methods. Specific examples of suitable separation and purification methods can be found in the specific examples below. Of course, other equivalent separation or purification methods can also be used.

[0025] In a third aspect, the present invention provides pharmaceutically acceptable salts of the above-mentioned flavonoid derivatives containing a sulfonamide structure, including hydrochloride, hydrobromide, sulfate, phosphate, acetate, methanesulfonate, p-toluenesulfonate, tartrate, citrate, fumarate or malate, as well as pharmaceutically acceptable prodrugs and derivatives.

[0026] The pharmaceutically acceptable salts described in the third aspect of the present invention can be prepared by conventional methods. For example, they can be prepared by the following method: dissolving the compound of formula (I) in an excess of an acidic aqueous solution (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid, citric acid, fumaric acid or malic acid), and adding an organic solvent miscible with water (e.g., methanol, ethanol, acetone or acetonitrile), and the formed salt spontaneously precipitates from the solution.

[0027] In a fourth aspect, the present invention provides use of the above-mentioned flavonoid derivative containing a sulfonamide structure or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating oxidative stress.

[0028] In the specific implementation of the present invention, AML12 or PHM is counted and then calculated as 1x10 5 / well were planted in a 12-well plate, and different concentrations of the flavonoid derivatives or their pharmaceutical salts containing sulfonamide structure to be tested were given after adherence. After 16 hours, the cells were lysed, and on the one hand, the total cell protein was extracted for Western blot experiments. On the other hand, total mRNA was extracted for RT-qPCR experiments, and the main detection objects were Nrf2, GCLM, Akr1c1 and HO-1. The results showed that the flavonoid derivatives or their pharmaceutical salts with sulfonamide structure of the present invention showed a significant increase in GCLM mRNA expression, and the target molecule could interfere with Keap1-Nrf2 protein-protein interaction, promote Nrf2 to enter the nucleus and regulate the expression of downstream genes. Subsequently, taking acute liver injury in mice as an example, the dominant compound (Ip) was further verified, and the results showed that it could significantly reduce liver damage and inflammatory response.

[0029] In a fifth aspect, the present invention provides a pharmaceutical composition for treating oxidative stress injury, which is used for preventing and treating oxidative stress injury, and comprises an active ingredient and a pharmaceutical carrier, wherein the active ingredient is the flavonoid derivative containing a sulfonamide structure described in the first aspect of the present invention or the pharmaceutical salt described in the third aspect of the present invention.

[0030] The pharmaceutical carrier is selected from conventional pharmaceutical carriers in the pharmaceutical field, including diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, dissolving agents, dissolution aids, colorants, deodorants, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives, antioxidants, etc. When preparing the medicament of the present invention, the optional fillers include but are not limited to: starch, powdered sugar, calcium phosphate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, etc.; the optional binders include but are not limited to: sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, gelatinized starch, etc.; the optional disintegrants include but are not limited to: dry starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, etc.; the optional lubricants include but are not limited to: magnesium stearate, talc, sodium lauryl sulfate, micro-powder silica gel, etc.

[0031] The pharmaceutical composition can be prepared into various dosage forms such as dispersants, suspensions, tablets, pills, powders, suppositories, powders, fine granules, granules, syrups, granules, capsules, sprays, sustained-release agents, injections, lozenges, inhalants, ointments, eye drops, nose drops, ear drops and patches according to conventional production methods in the pharmaceutical field. It can also be mixed with one or more pharmaceutical carriers or drugs as an active ingredient to prepare a desired dosage form.

[0032] The sixth aspect of the present invention provides a method for preventing and treating oxidative stress damage, which is achieved by administering an effective dose of the pharmaceutical composition of the fifth aspect of the present invention to the subject. The results of the in vitro cell level and in vivo activity experiments of the present invention show that the series of compounds (I) have significant Keap1-Nrf2 protein interaction inhibitory activity and have good water solubility.

[0033] The subjects of administration of the drug of the present invention (prevention and / or treatment subjects) include animals, preferably mammals, and more preferably any treatment for diseases or conditions in humans, including: (i) preventing the occurrence of the disease or condition in the subject; (ii) inhibiting the disease or condition; (iii) alleviating the disease or condition; or (iv) alleviating the condition / symptoms caused by the disease.

[0034] In terms of administration routes, the drug is administered to a subject (e.g., a mammal including a human) in need of prevention and / or treatment by oral administration (e.g., powder, tablet, coated tablet, capsule, microcapsule, solution, suspension or emulsion), rectal administration (e.g., suppository), parenteral administration (e.g., intravenous, intramuscular, subcutaneous or intraperitoneal injection or infusion of the composition), respiratory administration (e.g., by inhalation or insufflation of liquid or powder), transdermal administration (e.g., patch) or topical administration (e.g., cream, ointment or patch).

[0035] Among them, the acceptable liquid dosage form for parenteral administration is a sterile isotonic solution, which may contain other adjuvants in addition to the solvent to control the pH and preserve the composition. In the case of the soft pharmaceutical composition as a suppository, the active ingredient (a flavonoid derivative containing a sulfonamide structure as described in the first aspect) is uniformly dispersed in a carrier (for example, in polyethylene glycol or cocoa butter).

[0036] During the treatment process, the effective dose of the pharmaceutical composition refers to the amount as defined above that is sufficient for effective treatment when applied to a subject in need of prevention and / or treatment. The effective dose of the pharmaceutical composition of the present invention can vary within a wide range. However, in each specific case, it should certainly vary according to the subject and the disease state to be treated, the severity of the pain and the mode of administration. In the case of oral administration, the daily dose for adults can be 25mg-100mg of the active ingredient (a flavonoid derivative containing a sulfonamide structure described in the first aspect) or a corresponding amount of its pharmaceutically acceptable salt. The daily dose can be administered in a single dose or in divided doses.

[0037] Preferably, the pharmaceutical composition of the present invention can be used together with one or more other active agents in a combined therapy. For example, the pharmaceutical preparation of the active compound can be used together with one or more other antiviral agents, antibiotics, and anti-inflammatory drugs (e.g., respectively, simultaneously or sequentially).

[0038] Finally, it should be noted that the hydrates, solvates, polymorphs, codrugs, cocrystals of the flavonoid derivatives containing a sulfonamide structure of the present invention, as well as their prodrugs, tautomers, racemates, enantiomers or diastereomers, derivatives or mixtures thereof with the same biological functions also fall within the scope of the active ingredients of the pharmaceutical composition of the present invention.

[0039] Compared with the prior art, the flavonoid derivatives with sulfonamide structure provided by the present invention achieve the following beneficial effects: based on the binding mode of flavonoid derivatives containing sulfonamide structure and Keap1 protein, the present invention combines computer-aided drug design to introduce sulfonyl groups on the flavonoid skeleton, and enhances the hydrogen bond interaction between the compound and the amino acid residues Arg415 and Ser508 in the binding pocket; at the same time, the aromatic structure can penetrate into the binding pocket to strengthen the hydrophobic binding force with amino acid residues such as Tyr525 and Tyr334, and further enhance the biological activity of the target compound interfering with the Keap1-Nrf2 protein interaction. In addition, the in vitro cell level and animal level activity experiments of the present invention show that the series of compounds have a more significant Keap1-Nrf2 protein interaction inhibitory activity and have good water solubility. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The serum ALT and AST levels of mice in each group are shown: (A) serum ALT level detection; (B) serum AST level detection;

[0041] Figure 2 The results of H&E, MPO and F4 / 80 staining of the liver of mice in each group are shown. DETAILED DESCRIPTION

[0042] The objects, advantages and features of the present invention are illustrated and explained by the following non-limiting description of the preferred embodiments. The examples given in conjunction with the accompanying drawings are only used to explain the present invention and are not used to limit the scope of implementation of the present invention. The technical features involved in each embodiment of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0043] For technicians in chemistry, biochemistry or related fields, many modifications and changes can be made without departing from the spirit of the present invention and the scope of protection of the claims, all of which fall within the scope of protection of the present invention.

[0044] Statement: The raw materials used in the present invention are all commercially available.

[0045] The present invention adopts the following synthetic route to prepare the flavonoid derivative containing sulfonamide structure:

[0046]

[0047] The preparation method comprises the following steps: adding compound III and a base to a solvent, stirring for 30 minutes, then adding compound II, and stirring at 20-35°C for 4-10 hours. TLC monitors the reaction until the raw material is completely consumed. The reaction solution is poured into ethyl acetate, washed with water and saturated brine in sequence, and the organic phase is dried over anhydrous sodium sulfate overnight. Filtering, concentrating, and recrystallizing from ethyl acetate and petroleum ether to obtain the target product.

[0048] The preparation and characterization of specific compounds refer to Examples 1 to 18:

[0049] Example 1: Preparation of flavonoid derivatives containing sulfonamide structure (Ia)

[0050]

[0051] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.88mmol) were added to dichloromethane (3mL), stirred for 30min, and then 4-methylbenzenesulfonylchloride (4-toluenesulfonyl chloride) (0.35mmol) was added and stirred at 25°C for 4h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ia).

[0052] Characterization results of the target product (Ia): Yield 63%, white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ11.30(s,1H),8.20–8.12(m,2H),8.04(d,J=8.7Hz,1H),7.96(d,J=8.2Hz,2H),7.60–7.50(m ,3H),7.35(dd,J=8.7,2.1Hz,1H),7.25–7.19(m,2H),6.99(s,1H),3.99(s,3H),2.47(s,3H).MS calcd for C 23 H 19 NO 5 S[M+H] + 422.1, found 422.2. HPLC analysis: retention time=9.054min; peak area, 98.50% (λ=254nm).

[0053] Example 2: Preparation of flavonoid derivatives containing sulfonamide structure (Ib)

[0054]

[0055] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.91mmol) were added to dichloromethane (3mL), stirred for 30min, and then 2,4-dimethylbenzenesulfonylchloride (0.30mmol) was added and stirred at 25℃ for 6h. The reaction was monitored by TLC until the raw material was completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ib).

[0056] Characterization results of the target product (Ib): Yield 53%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.33(s,1H),8.12-7.86(m,5H),7.32-7.13(m,6H),3.89(d,J=6.8Hz,3H),2.62(s,3H),2.31(s,3H).MS calcd for C 24 H 21 NO 5 S[M+H] + 436.1, found 436.2. HPLC analysis: retention time=9.361min; peak area, 98.51% (λ=254nm).

[0057] Example 3: Preparation of flavonoid derivatives containing sulfonamide structure (Ic)

[0058]

[0059] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.90mmol) were added to dichloromethane (3mL), stirred for 30min, and then 2,3,5,6-tetramethylbenzenesulfonyl chloride (0.32mmol) was added and stirred at 25℃ for 5h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in sequence, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ic).

[0060] Characterization results of the target product (Ic): Yield 44%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.16(s,1H),7.94(d,J=8.6Hz,2H),7.85(d,J=8.7Hz,1H),7.23(s,1H) ,7.14–7.01(m,4H),6.79(s,1H),3.83(s,3H),2.57(s,6H),2.20(s,6H).MS calcd for C 26 H 25 NO 5 S[M+H] + 464.1, found 464.2. HPLC analysis: retention time=9.994min; peak area, 95.30% (λ=254nm).

[0061] Example 4: Preparation of flavonoid derivatives containing sulfonamide structure (Id)

[0062]

[0063] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.94mmol) were added to dichloromethane (3mL), stirred for 30min, and then 4-ethylbenzenesulfonylchloride (0.32mmol) was added and stirred at 25°C for 6h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Id).

[0064] Characterization results of the target product (Id): Yield 49%, white solid. 1 HNMR (400 MHz, DMSO-d 6)δ11.13(s,1H),7.99(dd,J=8.8,1.7Hz,2H),7.88(dd,J=8.7,1.2Hz,1H),7.86–7.79(m,2H),7.46–7.38(m,3H),7.19(d,J= 8.7Hz,1H),7.10–7.03(m,2H),6.83(t,J=1.0Hz,1H),3.83(t,J=1.0Hz,3H),2.61(q,J=7.6Hz,2H),1.12(t,J=7.6Hz,3H).MS calcd forC 24 H 21 NO 5 S[M+H] + 436.1, found 436.3. HPLC analysis: retention time=8.978min; peak area, 99% (λ=254nm).

[0065] Example 5: Preparation of flavonoid derivatives containing sulfonamide structure (Ie)

[0066]

[0067] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.70mmol) were added to dichloromethane (3mL), stirred for 30min, and then 4-isopropylbenzenesulfonylchloride (0.30mmol) was added and stirred at 35°C for 4h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ie).

[0068] Characterization results of the target product (Ie): Yield 68%, white solid. 1 HNMR (400 MHz, DMSO-d 6)δ11.17(s,1H),7.99(d,J=2.2Hz,1H),7.98(d,J=2.1Hz,1H),7.89(d,J=8 .7Hz,1H),7.87–7.83(m,2H),7.47(s,1H),7.45(s,1H),7.44(d,J=2.0Hz, 1H),7.21(dd,J=8.7,2.1Hz,1H),7.07(d,J=2.2Hz,1H),7.05(d,J=2.0Hz, 1H),6.83(s,1H),3.83(s,3H),2.95–2.86(m,1H),1.14(d,J=6.9Hz,6H).MS calcd for C 25 H 23 NO 5 S[M+H] + 450.1, found 450.2. HPLC analysis: retention time=9.478min; peak area, 99% (λ=254nm).

[0069] Example 6: Preparation of flavonoid derivatives containing sulfonamide structure (If)

[0070]

[0071] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.80mmol) were added to dichloromethane (3mL), stirred for 30min, and then 2-methoxybenzenesulfonylchloride (0.31mmol) was added and stirred at 25°C for 5h. The reaction was monitored by TLC until the raw material was completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (If).

[0072] Characterization results of the target product (If): Yield 46%, white solid. 1 HNMR (400 MHz, DMSO-d 6)δ10.97(s,1H),8.00–7.90(m,3H),7.86(dd,J=8.8,3.3Hz,1H),7.60(s,1H),7.35(s,1H),7.21(d,J=9.5Hz,2H) ,7.12(d,J=8.9Hz,1H),7.07–7.01(m,2H),6.79(d,J=3.4Hz,1H),3.89(d,J=3.5Hz,3H),3.83(d,J=3.6Hz,3H).MS calcd for C 23 H 19 NO 6 S[M+H] + 438.1, found 438.2. HPLC analysis: retention time=8.983min; peak area, 93.35% (λ=254nm).

[0073] Example 7: Preparation of flavonoid derivatives containing sulfonamide structure (Ig)

[0074]

[0075] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.90mmol) were added to dichloromethane (3mL), stirred for 30min, and then 3-methoxybenzenesulfonylchloride (0.30mmol) was added and stirred at 25℃ for 7h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ig).

[0076] Characterization results of the target product (Ig): Yield 55%, white solid. 1 HNMR (400 MHz, DMSO-d 6)δ11.17(s,1H),8.01(s,1H),7.99(s,1H),7.90(d,J=8.6Hz,1H),7.51(d,J=7.6Hz,2H),7.43(dd,J=7.9, 2.0Hz,2H),7.22(dd,J=9.3,3.7Hz,2H),7.06(d,J=8.4Hz,2H),6.83(s,1H),3.84(s,3H),3.80(s,3H).MS calcd for C 23 H 19 NO 6 S[M+H] + 438.1, found 438.1. HPLC analysis: retention time=8.974min; peak area, 95.09% (λ=254nm).

[0077] Example 8: Preparation of flavonoid derivatives containing sulfonamide structure (Ih)

[0078]

[0079] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.75mmol) were added to dichloromethane (3mL), stirred for 30min, and then 4-methoxybenzenesulfonylchloride (0.30mmol) was added and stirred at 30℃ for 5h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ih).

[0080] Characterization results of the target product (Ih): Yield 51%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.09(s,1H),8.05(d,J=8.3Hz,2H),7.89(d,J=10.0Hz,3H),7.45(s,1H), 7.22(d,J=8.8Hz,1H),7.13(s,4H),6.88(s,1H),3.88(s,3H),3.82(s,3H).MS calcd for C 23 H 19 NO 6 S[M+H]+ 438.1, found 438.1.HPLC analysis: retention time=8.870min; peak area, 98.40% (λ=254nm).

[0081] Example 9: Preparation of flavonoid derivatives containing sulfonamide structure (Ii)

[0082]

[0083] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.92mmol) were added to dichloromethane (3mL), stirred for 30min, and then 2,4-dimethoxybenzenesulfonyl chloride (0.36mmol) was added and stirred at 25℃ for 8h. The reaction was monitored by TLC until the raw material was completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in sequence, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ii).

[0084] Characterization results of the target product (Ii): Yield 67%, white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ10.95–10.79(m,1H),8.01–7.80(m,4H),7.38–7.29(m,1H),7.20(d,J=7.7Hz,1H),7.15-7.00(m,2H),6.81(dd,J=6 .6,3.5Hz,1H),6.66(dd,J=6.7,3.4Hz,2H),3.88(t,J=4.9Hz,3H),3.85–3.81(m,3H),3.78(dd,J=6.5,3.4Hz,3H).MS calcd for C 24 H 21 NO 7 S[M+H] + 468.1, found 468.2. HPLC analysis: retention time=8.805min; peak area, 97.14% (λ=254nm).

[0085] Example 10: Preparation of flavonoid derivatives (Ij) containing sulfonamide structure

[0086]

[0087] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.80mmol) were added to dichloromethane (3mL), stirred for 30min, and then 4-butoxybenzenesulfonylchloride (0.30mmol) was added and stirred at 25°C for 6h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ij).

[0088] Characterization results of the target product (Ij): Yield 46%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.05(s,1H),8.03–7.98(m,2H),7.88(d,J=8.6Hz,1H),7.85–7.80(m,2H),7.40(d,J=2.0Hz,1H),7.19(dd,J=8.7,2.0Hz,1H),7.1 1–7.04(m,4H),6.83(s,1H),3.97(t,J=6.5Hz,2H),3.84(s,3H),1.68–1.58(m,2H),1.41–1.29(m,2H),0.86(t,J=7.4Hz,3H).MScalcd for C 26 H 25 NO 6 S[M+H] + 480.1, found 480.2. HPLC analysis: retention time=9.694min; peak area, 98.98% (λ=254nm).

[0089] Example 11: Preparation of flavonoid derivatives containing sulfonamide structure (Ik)

[0090]

[0091] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.90mmol) were added to dichloromethane (3mL), stirred for 30min, and then 2-trifluoromethoxybenzenesulfonyl chloride (0.35mmol) was added and stirred at 25℃ for 4h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in sequence, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ik).

[0092] Characterization results of the target product (Ik): Yield 47%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.49(s,1H),8.16(dt,J=8.0,1.3Hz,1H),8.03–7.97(m,2H),7.91(dd,J=8.6,1.0Hz,1H),7.80(td,J=7.9,1.5Hz,1H),7.63–7.56 (m,2H),7.39(d,J=2.1Hz,1H),7.21(dt,J=8.8,1.5Hz,1H),7.11–7.06(m,2H),6.85(d,J=1.1Hz,1H),3.84(d,J=1.0Hz,3H).MScalcd for C 23 H 16 F 3 NO 6 S[M+H] + 492.1, found 492.2. HPLC analysis: retention time=9.005min; peak area, 95.95% (λ=254nm).

[0093] Example 12: Preparation of flavonoid derivatives containing sulfonamide structure (I1)

[0094]

[0095] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.75mmol) were added to dichloromethane (3mL), stirred for 30min, and then 3-trifluoromethoxybenzenesulfonyl chloride (0.30mmol) was added and stirred at 35℃ for 4h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Il).

[0096] Characterization results of the target product (Il): Yield 52%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.31(s,1H),8.02(d,J=8.6Hz,2H),7.92(dd,J=11.1,8.6Hz,2H),7.84(s,1H),7.75(t,J=8.0Hz,1H),7.6 9(d,J=8.3Hz,1H),7.46–7.42(m,1H),7.23–7.18(m,1H),7.08(d,J=8.6Hz,2H),6.86(s,1H),3.84(s,3H).MS calcd for C 23 H 16 F 3 NO 6 S[M+H] + 492.1, found492.3. HPLC analysis: retention time=9.234min; peak area, 99.23% (λ=254nm).

[0097] Example 13: Preparation of flavonoid derivatives containing sulfonamide structure (Im)

[0098]

[0099] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.96mmol) were added to dichloromethane (3mL), stirred for 30min, then 4-trifluoromethoxybenzenesulfonyl chloride (0.36mmol) was added and stirred at 25℃ for 5h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in sequence, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Im).

[0100] Characterization results of the target product (Im): Yield 48%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.33(s,1H),8.07(d,J=2.7Hz,1H),8.04(t,J=3.0Hz,2H),8.02(d,J=1.9Hz,1H),7.92(d,J=8.7Hz,1H),7.60(d,J=8.5Hz ,2H),7.46(d,J=2.2Hz,1H),7.22(dd,J=8.7,2.2Hz,1H),7.13–7.06(m,2H),6.86(d,J=2.4Hz,1H),3.85(d,J=2.5Hz,3H).MS calcd forC 23 H 16 F 3 NO 6 S[M+H] + 492.1, found 492.0. HPLC analysis: retention time=9.277min; peak area, 97.88% (λ=254nm).

[0101] Example 14: Preparation of flavonoid derivatives containing sulfonamide structure (In)

[0102]

[0103] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.85mmol) were added to dichloromethane (3mL), stirred for 30min, and then 2-fluorobenzenesulfonylchloride (0.30mmol) was added and stirred at 30℃ for 4h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (In).

[0104] Characterization results of the target product (In): Yield 56%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.54(s,1H),8.08–7.97(m,3H),7.91(dd,J=8.6,1.2Hz,1H),7.77–7.70(m,1H),7.50–7.37(m,3 H),7.22(dt,J=8.7,1.6Hz,1H),7.11–7.06(m,2H),6.84(d,J=1.1Hz,1H),3.85(d,J=1.2Hz,3H).MS calcd for C 22 H 16 FNO 5 S[M+H] + 426.1, found 426.2. HPLC analysis: retention time=8.798min; peak area, 97.43% (λ=254nm).

[0105] Example 15: Preparation of flavonoid derivatives containing sulfonamide structure (Io)

[0106]

[0107] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.95mmol) were added to dichloromethane (3mL), stirred for 30min, and then 3-fluorobenzenesulfonylchloride (0.34mmol) was added and stirred at 25℃ for 5h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Io).

[0108] Characterization results of the target product (Io): Yield 54%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.29(s,1H),8.02(t,J=1.3Hz,1H),8.00(t,J=1.4Hz,1H),7.91(dd,J=8 .6,1.0Hz,1H),7.75(t,J=8.7Hz,2H),7.70–7.63(m,1H),7.53(t,J=8.3Hz, 1H), 7.44 (dd, J=2.1, 0.9Hz, 1H), 7.21 (dd, J=8.7, 2.1Hz, 1H), 7.08 (t, J=1. 3Hz,1H),7.07–7.04(m,1H),6.84(d,J=1.0Hz,1H),3.83(d,J=1.0Hz,3H).MS calcd for C 22 H 16 FNO 5 S[M+H] + 426.1, found426.1. HPLC analysis: retention time=8.963min; peak area, 99% (λ=254nm).

[0109] Example 16: Preparation of flavonoid derivatives containing sulfonamide structure (Ip)

[0110]

[0111] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.98mmol) were added to dichloromethane (3mL), stirred for 30min, and then 4-fluorobenzenesulfonylchloride (0.32mmol) was added and stirred at 30℃ for 6h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ip).

[0112] Characterization results of the target product (Ip): Yield 63%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.19(s,1H),8.03(s,1H),8.01–7.95(m,3H),7.90(d,J=8.6Hz,1H),7.48–7.40(m, 3H),7.22–7.16(m,1H),7.12–7.05(m,2H),6.84(d,J=0.6Hz,1H),3.87–3.80(m,3H).MS calcdfor C 22 H 16 FNO 5 S[M+H] + 426.1, found 426.1.HPLC analysis: retention time=9.270min; peak area, 99% (λ=254nm).

[0113] Example 17: Preparation of flavonoid derivatives containing sulfonamide structure (Iq)

[0114]

[0115] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.78mmol) were added to dichloromethane (3mL), stirred for 30min, then 2-chloro-4-fluorobenzenesulfonyl chloride (0.30mmol) was added, and stirred at 25℃ for 5h. The reaction was monitored by TLC until the raw material was completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Iq).

[0116] Characterization results of the target product (Iq): Yield 62%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.58(s,1H),8.31(d,J=8.9Hz,1H),7.99(dd,J=8.8,1.3Hz,2H),7.90(dd,J=8.7,1.2Hz,1H),7.72(d,J=8.6,1H),7.50–7. 43(m,1H),7.36–7.33(m,1H),7.21(dt,J=8.8,1.5Hz,1H),7.10–7.04(m,2H),6.83(d,J=1.3Hz,1H),3.84(d,J=1.3Hz,3H).MS calcdfor C 22 H 15 ClFNO 5 S[M+H] + 460.0, found 460.1. HPLC analysis: retention time=9.119min; peak area, 97.49% (λ=254nm).

[0117] Example 18: Preparation of flavonoid derivatives (Ir) containing sulfonamide structure

[0118]

[0119] At room temperature, 7-amino-2-(4-methoxyphenyl)-4H-chromen-4-one (0.38mmol) and pyridine (0.90mmol) were added to dichloromethane (3mL), stirred for 30min, then 3-chloro-4-fluorobenzenesulfonyl chloride (0.35mmol) was added, and stirred at 25℃ for 4h. The reaction was monitored by TLC until the raw materials were completely consumed. The reaction solution was poured into ethyl acetate (15mL), washed with water (6mL×3) and saturated brine (6mL×2) in turn, and the organic phase was dried over anhydrous sodium sulfate overnight. Then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product (Ir).

[0120] Characterization results of the target product (Ir): Yield 72%, white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ11.31(s,1H),8.12(dd,J=6.7,2.3Hz,1H),8.06–7.99(m,2H),7.93(dd,J=10.1,4.9Hz,2H),7.65(t,J=8. 9Hz,1H),7.46(d,J=2.0Hz,1H),7.22(dd,J=8.6,2.1Hz,1H),7.13–7.05(m,2H),6.85(s,1H),3.84(s,3H).MS calcd for C 22 H 15 ClFNO 5 S[M+H] + 460.0, found 460.2. HPLC analysis: retention time=9.450min; peak area, 99.20% (λ=254nm).

[0121] Experimental Example 19: Detection of Keap1-Nrf2 signaling pathway at the cellular level under the action of compounds

[0122] Count AML12 or PHM and convert it into 1x10 5 The cells were planted at a density of 1 / well in a 12-well plate. After the cells adhered to the wall, different concentrations of the test compounds were added and control wells were set. After 16 hours, the cells were lysed and the total cell protein was extracted for Western blot experiments. On the other hand, the total mRNA was extracted for RT-qPCR experiments. The main detection targets were Nrf2, GCLM, Akr1c1 and HO-1.

[0123] Real-time PCR was used to detect the expression of GCLM mRNA, a downstream gene of Nrf2, in cells. The results are shown in Table 1. Compared with the positive control SFN group, compound 1p showed a significant increase in GCLM mRNA expression. This result indicates that the target molecule can interfere with the Keap1-Nrf2 protein-protein interaction, promote Nrf2 entry into the nucleus and regulate the expression of downstream genes.

[0124] Table 1 Summary of the results of Keap1-Nrf2 signaling pathway detection at the cellular level under the action of compounds Ia~Ir

[0125]

[0126] a All data represent mean values ​​of at least three separate experiments. b SFN: sulforaphen, positive control.

[0127] Experimental Example 20: Compound Ip effectively alleviates APAP-induced acute liver injury in mice

[0128] The mice were injected with APAP (400 mg / kg) to induce acute liver injury, and two different doses of compound Ip (Low dose: 12.5 mg / kg and High dose: 25 mg / kg) were given for treatment. The serum liver function indicators ALT and AST of the mice were tested first. The results showed that compared with the normal group of mice, the blood ALT and AST of the mice injected with APAP 12 hours later were significantly increased ( Figure 1 ), and obvious centrilobular hepatocyte necrosis was found in the liver sections ( Figure 2 ), indicating that the mouse liver had been significantly damaged; and the number of F4 / 80-positive macrophages and MPO neutrophils infiltrating in the liver of mice in the APAP group was significantly increased compared with the control group. Treatment with compound Ip can significantly reduce 12h after APAP injection. The levels of ALT and AST in the blood of mice, and the infiltration of F4 / 80-positive macrophages and MPO neutrophils were also significantly reduced compared with the APAP group. This shows that compound Ip can significantly reduce liver damage and inflammatory response within 12h after APAP injection.

[0129] It should be noted that although the above embodiments have been described in this article, the patent protection scope of the present invention is not limited thereby. When the technical parameters and raw material components that are not described in detail are changed within the parameter range listed in the present invention, the same or similar technical effects as those of the above embodiments can still be obtained, and they still belong to the protection scope of the present invention. Therefore, based on the innovative concept of the present invention, the changes and modifications made to the embodiments described herein, or the equivalent structure or equivalent process transformation made by the contents of the specification and drawings of the present invention, directly or indirectly applying the above technical solutions to other related technical fields are all included in the patent protection scope of the present invention.

Claims

1. A flavonoid derivative containing a sulfonamide structure, characterized in that: It has the following general structure: Among them, R 1 One selected from the group consisting of benzene ring and substituted benzene ring, thiophene and its oxides, thiazole and its oxides, pyrrole and its oxides, pyrazole (pyran) and its oxides, imidazole and its oxides, (iso)oxazole and its oxides, pyrazolone, furan, pyridine, oxazine and its oxides, cyclopentadiene, tetrahydrothiophene and other episulfides (sulfoxides and sulfones), tetrahydrofuran and other epoxy compounds and optionally substituted cycloalkanes; R 2 is a linker selected from -H, -CH2-, -O-, -S-, -C(O), -S(O)- and -S(O)2-; R 3 are independently selected from hydrogen, cyano, nitro, hydroxyl, halogen, amino, C 3～6 Cycloalkoxy, C 3～6 Cycloalkylamino, optionally substituted C 1～6 Alkyl, optionally substituted C 2～6 Alkenyl, optionally substituted C 2～6 Alkynyl or C 1～6 One of the group consisting of alkoxy group, carboxyl group, ester group and amide group.

2. The flavonoid derivative containing a sulfonamide structure according to claim 1, characterized in that: The structural formula of the flavonoid derivative containing a sulfonamide structure is selected from any one of the following:

3. The method for preparing a flavonoid derivative containing a sulfonamide structure according to claim 1 or 2, characterized in that: The reaction route is as follows: The method comprises the following steps: using substituted sulfonyl chloride II and flavonoid derivative III as raw materials to react under the action of a base, and washing, drying, filtering, concentrating and recrystallizing the reaction solution to obtain a key intermediate (IV).

4. The preparation method according to claim 3, characterized in that: The reaction solvent is selected from one or more of the group consisting of acetone, acetonitrile, toluene, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, isopropanol, n-butanol and isobutanol; The base is selected from one or more inorganic bases in the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and sodium hydrogen; or one or more organic bases in the group consisting of pyridine, N,N-dimethylaminopyridine, triethylamine, diisopropylethylamine, tributylamine and potassium tert-butoxide.

5. The preparation method according to claim 3, characterized in that: The molar ratio of the substituted sulfonyl chloride compound II, the flavonoid derivative III and the base is 1:1:1.5-1:2:3; The reaction temperature is 20-35°C and the reaction time is 4-10h; During the reaction, the reaction was monitored by TLC until the raw material was completely consumed; the reaction solution was poured into ethyl acetate, washed with water and saturated brine in sequence, and the organic phase was dried over anhydrous sodium sulfate overnight; then, it was filtered, concentrated, and recrystallized from ethyl acetate and petroleum ether to obtain the target product.

6. A pharmaceutically acceptable salt of a flavonoid derivative containing a sulfonamide structure, characterized in that: These include hydrochloride, hydrobromide, sulfate, phosphate, acetate, methanesulfonate, p-toluenesulfonate, tartrate, citrate, fumarate or malate, as well as pharmaceutically acceptable prodrugs and derivatives.

7. Use of a flavonoid derivative containing a sulfonamide structure or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating oxidative stress damage.

8. The use according to claim 7, characterized in that: The drug for preventing or treating oxidative stress damage is a drug that can interfere with Keap1-Nrf2 protein-protein interaction and promote Nrf2 to enter the nucleus.

9. A pharmaceutical composition for treating oxidative stress damage, characterized in that: The invention comprises an active component and a pharmaceutical carrier, wherein the active component is the flavonoid derivative containing a sulfonamide structure according to claim 1 or 2 or the pharmaceutical salt according to claim 6.

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