CN113999148B - N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound and application thereof - Google Patents
N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound and application thereof Download PDFInfo
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Abstract
The invention discloses an N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound and application thereof, and belongs to the field of medicines. The structural formula of the compound is shown as a general formula (I), the compound has the activity of blocking Keap1-Nrf2 dimerization by targeting Keap1, and can activate Nrf2 by inhibiting Keap1-Nrf2 interaction so as to relieve oxidative stress induced organism injury without obvious toxic effect, so that the compound provided by the invention has good development prospect in preparing medicaments for treating oxidative stress injury.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medical application of an N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound, in particular to an application in preventing and treating abnormal oxidative stress induced myocardial cell injury.
Background
Reactive Oxygen Species (ROS) are a series of metabolites produced by aerobic cells during metabolism, involved in the transduction of various signaling pathways within the cell. Sustained high levels of ROS can lead to intracellular energy disturbances, excessive lipid oxidation, further DNA damage and protein denaturation, leading to oxidative damage of tissue cells. Oxidative damage to proteins caused by reactive oxygen species is associated with the occurrence of aging, tumors, diabetes and many neurodegenerative diseases. Thus, the discovery of potent anti-ROS agents is of great importance for maintaining redox balance in vivo.
Kelch-like epichlorohydrin associated protein-1 (Keap 1) -activating nuclear factor E2 associated factor (Nrf 2) -Antioxidant Response Element (ARE) is an important signaling pathway to maintain redox balance in vivo. The transcription regulating factor Nrf2 is a key factor for regulating in vivo cell oxidative stress, belongs to the nuclear transcription factor of CNC-bZiP transcription factor family, and improves the survival ability of cells by regulating a series of antioxidant proteins and detoxification protection genes in vivo. Binding of Nrf2 to ARE can regulate transcription of about 250 genes, and has important roles in regulating cellular defense systems and alleviating oxidative stress. Research shows that Nrf2 has close relation with the occurrence and development of various human diseases such as diabetes, tumor, liver diseases, kidney diseases, respiratory diseases, nervous system diseases, skin diseases, metabolic diseases, heavy metal poisoning and the like by regulating and controlling oxidative stress.
Currently, strategies for upregulation of Nrf2 mainly include Nrf2 agonists and Keap1-Nrf2 protein-protein interaction (PPI) inhibitors. Nrf2 agonists, such as dimethyl fumarate, have been marketed for the treatment of relapsing multiple sclerosis, but most Nrf2 agonists lack target specificity, which limits their use in clinical practice. In contrast, inhibitors of protein-protein interactions that directly interfere with Keap1-Nrf2 binding are considered more promising approaches.
Xiu E Feng, and the like, synthesizes a class of fluorine-containing phenol compounds containing nitrogen heterocycles, and introduces nitrified heterocycles and fluorine atoms into 2,5 '-dibromo-4,5,2' -trihydroxybenzophenone. Molecular docking indicates that the compound stably binds to the receptor protein by forming hydrogen bonds, conjugated six-membered rings close to the critical residue Arg-415 of Nrf2 attached to Keap1-Kelch, affecting its properties, and this change results in dissociation of Nrf2 from the junction with Keap1-Kelch into the nucleus, exerting its antioxidant protective effect (Fluorophenols bearing nitrogenated heterocycle moieties, a class of novel Keap-Nrf 2 protein-protein interaction inhibitors: synthis, antioxidant stress screening and molecular dockerin. Medicinal Chemistry research 28, pages 1319-1337 (2019)).
The Nrf2 negative regulatory protein is Keap1. Under resting conditions Nrf2 is anchored in the cytoplasm by binding to Keap1, which in turn promotes ubiquitination and subsequent proteolysis of Ndf 2. This segregation and further degradation of Nrf2 in the cytoplasm is the mechanism by which Keap1 inhibits Nrf 2. Since Nrf2 activation results in a coordinated antioxidant and anti-inflammatory response, and Keap1 inhibits Nrf2 activation, keap1 has become a very attractive drug target.
The small molecule inhibitor blocks the combination with Nrf2 by targeting Keap1, so as to promote the nuclear penetration of the Nrf2 and regulate and control the transcription of various antioxidant genes, and protect the organism from oxidative damage. Therefore, keap1 inhibitors with novel structures are designed, and the Keap1 inhibitors have important scientific significance and clinical value.
Disclosure of Invention
The invention aims to provide a Keap1 inhibitor with a novel structure, which can block the combination with Nrf2 by targeting Keap1, further promote the nuclear penetration of the Nrf2 to play a role in regulating and controlling the transcription of various antioxidant genes and protect an organism from oxidative damage.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides an N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound or pharmaceutically acceptable salt thereof, the structural formula of the compound is shown as a general formula (I),
wherein R is 1 、R 2 Selected from phenyl, phenyl containing electron donating substituent on benzene ring or electron withdrawing substituent, heteroaryl containing electron withdrawing substituent on heteroaryl ring, 1' -biphenyl-4-yl, phenylmethyl; or R is 2 Selected from naphthalen-1-yl, naphthalen-2-yl;
R 3 、R 4 selected from hydrogen, alkanes containing electron withdrawing substituents in the chain.
Preferably, R 1 The phenyl is phenyl containing electron donating substituent on phenyl ring, and the electron donating substituent on the phenyl ring is methyl or methoxy;
or phenyl containing electron-withdrawing substituent on the benzene ring, wherein the electron-withdrawing substituent on the benzene ring is cyano;
or heteroaryl containing electron-withdrawing substituent on heteroaryl and heteroaryl ring, wherein the heteroaryl is thiophene-2-yl and pyridine-3-yl, and the electron-withdrawing substituent on the heteroaryl ring is chlorine atom;
or, 1' -biphenyl-4-yl, phenylmethyl;
r2 is phenyl, phenyl containing electron donating substituent on benzene ring, wherein the electron donating substituent on benzene ring is methyl or methoxy;
or phenyl containing electron-withdrawing substituent on the benzene ring, wherein the electron-withdrawing substituent on the benzene ring is trifluoromethyl or cyano;
or heteroaryl containing electron-withdrawing substituent on heteroaryl and heteroaryl ring, wherein the heteroaryl is thiophene-2-yl, pyridine-3-yl and quinoline-8-yl, and the electron-withdrawing substituent on the heteroaryl ring is chlorine atom;
or, naphthalen-1-yl, naphthalen-2-yl, 1' -biphenyl-4-yl, phenylmethyl.
Further preferably, R 1 Is any one of the following substituents:
R 2 is any one of the following substituents:
R 3 、R 4 is any one of the following substituents:
more preferably, the compound has the structural formula:
the invention also provides a method for preparing the N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound, which is prepared by any one of the following three modes:
mode 2, comprising the steps of:
(1) Dissolving p-phenylenediamine in organic solvent, adding organic base catalyst, and dropping R-containing solution 2 The molar ratio of the sulfonyl chloride to the p-phenylenediamine is 0.5:1-1.5:1, stirring is carried out at the temperature of 0-40 ℃ for reaction, and the intermediate product II-1 is obtained after separation and purification after the reaction is finished;
(2) Dissolving intermediate II-1 in organic solvent, adding organic base catalyst, and dripping R-containing solution 1 Sulfonyl chloride of substituent, wherein the molar ratio of the sulfonyl chloride to the intermediate product II-1 is 0.5:1-1.5:1, and the mixture is stirred and reacted at the temperature of 0-40 ℃, and then R in the structural general formula (I) is obtained through separation and purification 1 And R is 2 Is different and R 3 And R is 4 A target compound II-2 which is H;
mode 3, comprising the steps of:
1) Dissolving the compound I-2 prepared in the mode 1 or the compound II-2 prepared in the mode 2 in N, N-dimethylformamide, acetonitrile or acetone, adding potassium carbonate, dropwise adding ethyl bromoacetate, continuously reacting at the temperature of 0-40 ℃ under the condition that the molar ratio of the potassium carbonate to the compound I-2 or the compound II-2 is 1:1-5:1, and separating to obtain an intermediate III-1;
2) Dissolving an intermediate III-1 in methanol, tetrahydrofuran or water, adding 10-20% sodium hydroxide aqueous solution by mass percent, stirring at 0-100 ℃ for reaction, regulating the pH of the system to 2-3 by hydrochloric acid, and separating to obtain R in the structural formula (I) 3 And R is 4 The target compound III-2 is carboxymethyl.
Preferably, the organic solvent is anhydrous dichloromethane, anhydrous tetrahydrofuran or anhydrous DMF.
Preferably, the organic base catalyst is pyridine or triethylamine.
Preferably, in modes 1 and 2, when sulfonyl chloride is added dropwise, the reaction system is placed in an ice-water bath, and after the completion of the addition, the reaction system is transferred to room temperature to perform a stirring reaction.
Preferably, in step 1) of mode 3, ethyl bromoacetate is dropwise added at room temperature, and stirring reaction is continued at room temperature after the completion of the dropwise addition; in step 2), the temperature of the stirring reaction was 85 ℃.
In the reaction process, a thin layer plate (TLC) is utilized to track the reaction, and separation and purification are carried out after the reaction is finished. Preferably, the reaction time is from 6 to 18 hours with stirring in mode 1; the reaction of the step (1) in the mode 2 is 6-16 hours, and the reaction time of the step (2) is 5-10 hours; the reaction of step 1) in mode 3 is 12 to 16 hours and the reaction of step 2) is 5 to 7 hours.
Preferably, the separation and purification in the modes 1 and 2 include: removing the organic solvent by reduced pressure distillation, extracting with ethyl acetate, collecting the organic phase, washing, evaporating to dryness under reduced pressure, redissolving, and purifying by chromatography to obtain the target compound;
the separation in mode 3 includes: after the reaction is finished, pouring the reaction system into ice water, stirring, suction filtering, collecting precipitate, washing and drying to obtain the target compound.
Under the condition of the mode 1, the product yield is 51% -82%; under the condition of the mode 2, the product yield is 60% -85%; under the condition of the mode 3, the product yield is 60% -69%.
The invention also provides application of the N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound or pharmaceutically acceptable salt thereof in preparing a medicament for treating diseases caused by oxidative stress injury.
The research of the invention shows that the compound has the activity of targeting Keap1 to block the binding of the Keap1 and Nrf2 peptide fragment, and is expected to be used as a Keap1-Nrf2 PPI inhibitor for treating oxidative stress (ROS) injury.
Specifically, the compounds or pharmaceutically acceptable salts thereof reduce oxidative stress damage by inhibiting Keap1-Nrf2 interactions.
Further, the disease is myocardial cell injury caused by abnormal oxidative stress.
The research of the invention shows that the N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound can activate Nrf2 by blocking Keap1-Nrf2 dimerization, thereby protecting myocardial cells from oxidative stress injury, and has no obvious toxic effect on myocardial cells.
The invention has the beneficial effects that:
the invention provides an N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound with targeted Keap1 for blocking Keap1-Nrf2 dimerization activity, which can relieve oxidative stress induced organism injury by inhibiting Keap1-Nrf2 interaction and has better safety, so that the compound provided by the invention has good development prospect in preparing medicaments for treating oxidative stress injury.
Drawings
FIG. 1 shows the effect of compound III-2 c on the expression of Nrf2 protein in H9c2 cells.
FIG. 2 is the effect of compound III-2 c on lipopolysaccharide induced H9c2 cell damage.
FIG. 3 is the effect of compound III-2 c on lipopolysaccharide-induced ROS levels in H9c 2.
Detailed Description
The invention will be further illustrated with reference to specific examples. The following examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. Modifications and substitutions to methods, procedures, or conditions of the present invention without departing from the spirit and nature of the invention are intended to be within the scope of the present invention.
The test methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
Example 1
The synthesis of N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compounds is carried out by the following synthetic route:
route 1:
step 1-1:
p-phenylenediamine (1 g,9.2mmol,1 equiv.) was dissolved in anhydrous dichloromethane (10 mL), pyridine (1 mL) was added, the reaction system was placed in an ice water bath, and R was slowly added dropwise 1 (R 2 ) Substituted sulfonyl chloride (2.5 equiv.) after the sulfonyl chloride addition was completed, the reaction was transferred to room temperature and stirring was continued for 6-18 hours. TLC was used to follow up the reaction, after the completion of the reaction, the organic solvent was distilled off under reduced pressure (40 ℃ C.), then 20mL of water was added to extract with 30mL of ethyl acetate, the aqueous layer was discarded, the ethyl acetate layer was washed 5 times with 4mL of water (4 mL. Times.5), then with 2 times with 4mL of saturated brine (4 mL. Times.2), evaporated to dryness under reduced pressure (45 ℃ C.), and the target compound I-2 was obtained by column chromatography (petroleum ether: ethyl acetate gradient elution) separation and purification.
1. When R is 1 (R 2 ) The substituted sulfonyl chloride is benzenesulfonyl chloride, and the product is obtained:
n, N' - (1, 4-phenylene) diphenylsulfonamide (I-2 a)
White powder, yield: 80%, melting point: 242.6-243.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.11(2H,s,-NHSO 2 -),7.65(4H,d,J＝7.2Hz,H-2,H-6),7.59(2H,t,J＝7.2Hz,H-4),7.50(4H,t,J＝7.6Hz,H-3,H-5),6.92(4H,s,H-b,H-c,H-e,H-f). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):139.2×2,133.9×2,132.8×2,129.0×4,126.5×4,121.6×4.HRMS(ESI,m/z)calcd.for C 18 H 16 N 2 O 4 S 2 [M+Na] + 411.0444,found 411.0446.
2. When R is 1 (R 2 ) The substituted sulfonyl chloride is 2,4, 6-trimethylbenzenesulfonyl chloride to obtain the product:
n, N' - (1, 4-phenylene) bis (2, 4, 6-trimethylbenzenesulfonamide) (I-2 b)
Pale yellow powder, yield: 56%, melting point: 291.7-292.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.89(2H,s,-NHSO 2 -),6.94(4H,s,H-3,H-5),6.80(4H,s,H-b,H-c,H-e,H-f),2.41(12H,s,2-CH 3 ,6-CH 3 ),2.21(6H,s,4-CH 3 ). 13 CNMR(100MHz,DMSO-d 6 )δ(ppm):141.8×2,138.5×4,133.5×2,131.6×6,121.5×4,22.3×4,20.3×2.HRMS(ESI,m/z)calcd.for C 24 H 28 N 2 O 4 S 2 [M+Na] + 495.1383,found 495.1388.
3. When R is 1 (R 2 ) The substituted sulfonyl chloride is 4-methoxy benzene sulfonyl chloride, and the product is obtained:
n, N' - (1, 4-phenylene) bis (4-methoxybenzenesulfonamide) (I-2 c)
White powder, yield: 82%, melting point: 226.8-227.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.95(2H,s,-NHSO 2 -),7.58(4H,d,J＝8.8Hz,H-2,H-6),7.00(4H,d,J＝9.2Hz,H-3,H-5),6.90(4H,s,H-b,H-c,H-e,H-f),3.78(6H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.3×2,134.0×2,130.9×2,128.8×4,121.3×4,114.2×4,55.5×2.HRMS(ESI,m/z)calcd.for C 20 H 20 N 2 O 6 S 2 [M+Na] + 471.0655,found 471.0646.
4. When R is 1 (R 2 ) The substituted sulfonyl chloride is 4-cyano benzene sulfonyl chloride to obtain the product:
n, N' - (1, 4-phenylene) bis (4-cyanobenzenesulfonamide) (I-2 d)
White powder, yield: 73%, melting point: 218.6-219.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):8.18(4H,d,J＝8.4Hz,H-2,H-6),7.97(4H,d,J＝8.4Hz,H-3,H-5),6.64(2H,d,J＝8.4Hz,H-b,H-f),6.49(2H,d,J＝8.8Hz,H-c,H-e),5.72(2H,s,-NHSO 2 -). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):142.3×2,133.6×4,131.9×2,128.6×4,118.7×2,117.3×2,116.8×2,113.7×2.HRMS(ESI,m/z)calcd.for C 20 H 14 N 4 O 4 S 2 [M+Na] + 461.0349,found 461.0342.
5. When R is 1 (R 2 ) Substituted sulfonyl chlorides are [1,1' -biphenyls]-4-sulfonyl chloride to give the product:
n, N '- (1, 4-phenylene) bis ([ 1,1' -biphenyl ] -4-sulfonamide) (I-2 e)
White powder, yield: 59%, melting point: 233.5-234.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.17(2H,s,-NHSO 2 -),7.76-7.69(8H,m,H-2,H-3,H-5,H-6),7.62(4H,d,J＝8.4Hz,H-2′,H-6′),7.49-7.41(6H,m,H-3′,H-4′,H-5′),6.97(4H,s,H-b,H-c,H-e,H-f). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):144.1×2,136.2×2,133.5×2,129.0×4,128.5×4,128.4×2,127.3×4,127.2×4,127.0×2,121.6×2,121.4×2.HRMS(ESI,m/z)calcd.for C 30 H 24 N 2 O 4 S 2 [M+Na] + 563.1070,found 563.1061.
6. When R is 1 (R 2 ) The substituted sulfonyl chloride is 1-phenylmethanesulfonyl chloride, which gives the product:
n, N' - (1, 4-phenylene) bis (1-phenylmethanesulfonamide) (I-2 f)
White powder, yield: 51%, melting point: 263.8-264.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.74(2H,s,-NHSO 2 -),7.39-7.33(6H,m,H-3,H-4,H-5),7.29-7.26(4H,m,H-2,H-6),7.13(4H,s,H-b,H-c,H-e,H-f),4.42(4H,s,-SO 2 CH 2 -). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):134.0×2,130.9×4,129.5×2,128.3×4,128.1×2,120.6×4,56.7×2.HRMS(ESI,m/z)calcd.for C 20 H 20 N 2 O 4 S 2 [M+Na] + 439.0757,found 439.0753.
7. When R is 1 (R 2 ) The substituted sulfonyl chloride is pyridine-3-sulfonyl chloride, and the product is obtained:
n, N' - (1, 4-phenylene) bis (pyridine-3-sulfonamide) (I-2 g)
Pale yellow powder, yield: 66%, melting point: 179.9-180.8 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):8.99-8.89(4H,m,H-2,H-4),8.19(2H,d,J＝8.4Hz,H-6),7.74(2H,dd,J 1 ＝8.4Hz,J 2 ＝4.8Hz,H-5),7.18(2H,d,J＝8.8Hz,H-b,H-f),7.04(2H,d,J＝8.8Hz,H-c,H-e). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):155.1×2,148.1×2,136.1×2,134.8×2,132.4×2,124.6×2,124.4×2,120.1×2.HRMS(ESI,m/z)calcd.for C 16 H 14 N 4 O 4 S 2 [M+H] + 391.0529,found 391.0523.
8. When R is 1 (R 2 ) The substituted sulfonyl chloride is thiophene-2-sulfonyl chloride which is taken as a raw material to obtain a product:
n- (4- (thiophene-2-sulfonylamino) phenyl) thiophene-2-sulfonamide (I-2 h)
Yellow powder, yield: 54%, melting point: 196.9-197.8 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.25(2H,s,-NHSO 2 -),7.89(2H,dd,J 1 ＝4.8Hz,J 2 ＝1.2Hz,H-3),7.42(2H,dd,J 1 ＝4.0Hz,J 2 ＝1.2Hz,H-5),7.11-7.09(2H,m,H-4),7.00(4H,s,H-b,H-c,H-e,H-f). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):134.0×2,133.2×2,132.2×4,127.5×2,121.9×4.HRMS(ESI,m/z)calcd.for C 14 H 12 N 2 O 4 S 4 [M-H] - 398.9607,found 398.9606.
9. When R is 1 (R 2 ) The substituted sulfonyl chloride is 5-chlorothiophene-2-sulfonyl chloride which is taken as a raw material to obtain a product:
5-chloro-N- (4- ((5-chlorothiophene) -2-sulfonylamino) phenyl) thiophene-2-sulfonamide (I-2 i)
Yellow powder, yield: 55%, melting point: 164.1-165.0 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.46(2H,s,-NHSO 2 -),7.35(2H,d,J＝4.0Hz,H-3),7.18(2H,d,J＝4.4Hz,H-4),7.06(4H,s,H-b,H-c,H-e,H-f). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):135.8×2,132.2×2,131.5×2,128.3×2,127.8×2,122.4×2,113.8×2.HRMS(ESI,m/z)calcd.for C 14 H 10 Cl 2 N 2 O 4 S 4 [M+Na] + 490.8793,found 490.8789.
Example 2
The synthesis of N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compounds is carried out by the following synthetic route:
route 2:
step 2-1:
p-phenylenediamine (2 g,18.5mmol,1 equiv.) was dissolved in anhydrous dichloromethane (20 mL), triethylamine (1 mL) was added, the reaction system was placed in an ice-water bath, and R was slowly added dropwise 2 Substituted sulfonyl chloride (1.2 equiv.) after the sulfonyl chloride addition was completed, the reaction was transferred to room temperature and stirring was continued for 6-16 hours. TLC was used to follow up the reaction, after the reaction was completed, the organic solvent was distilled off under reduced pressure (40 ℃ C.), 40mL of water was added to extract with 60mL of ethyl acetate, the aqueous layer was discarded, the ethyl acetate layer was washed 5 times with 8mL of water (8 mL. Times.5), then with 8mL of saturated brine (8 mL. Times.2), dried under reduced pressure (45 ℃ C.), and the intermediate II-1 was isolated and purified by column chromatography (petroleum ether: ethyl acetate gradient elution) and used directly for the next reaction.
Step 2-2:
intermediate II-1 (1 g,1 equiv.) is dissolved in anhydrous tetrahydrofuran (10 mL), triethylamine (1 mL) is added, the reaction system is placed in ice-water bath conditions, 4-methoxybenzenesulfonyl chloride (1.2 equiv.) is slowly added dropwise, after the addition of 4-methoxybenzenesulfonyl chloride is completed, the reaction system is transferred to room temperature, and stirring is continued for 5-10 hours. TLC was used to follow up the reaction, after the completion of the reaction, the organic solvent was distilled off under reduced pressure (40 ℃ C.), then 20mL of water was added to extract with 30mL of ethyl acetate, the aqueous layer was discarded, the ethyl acetate layer was washed 5 times with 4mL of water (4 mL. Times.5), then with 2 times with 4mL of saturated brine (4 mL. Times.2), evaporated to dryness under reduced pressure (45 ℃ C.), and the target compound II-2 was isolated and purified by column chromatography (petroleum ether: ethyl acetate gradient elution).
1. When R is in step 2-1 2 The substituted sulfonyl chloride is benzenesulfonyl chloride, and the product is obtained:
4-methoxy-N- (4- (phenylsulfonamide) phenyl) benzenesulfonamide (II-2 a)
Pale yellow powder, yield: 71%, melting point: 201.6-202.5 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.09(1H,s,-NHSO 2 -),9.96(1H,s,-NHSO 2 -),7.64(2H,d,J＝8.0Hz,H-2,H-6),7.59-7.56(3H,m,H-4,H-2′,H-6′),7.49(2H,t,J＝7.2Hz,H-3,H-5),7.00(2H,d,J＝8.8Hz,H-3′,H-5′),6.90(4H,s,H-b,H-c,H-e,H-f),3.79(3H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.3,139.2,134.2,133.7,132.7,130.8,129.0×2,128.7×2,126.5×2,121.6×2,121.3×2,114.2×2,55.5.HRMS(ESI,m/z)calcd.for C 19 H 18 N 2 O 5 S 2 [M+Na] + 441.0549,found 441.0546.
2. When R is in step 2-1 2 The substituted sulfonyl chloride is p-toluenesulfonyl chloride, and the product is obtained:
4-methoxy-N- (4- ((4-methylphenyl) sulfonylamino) phenyl) benzenesulfonamide (II-2 b)
Pale yellow powder, yield: 72%, melting point: 190.8-191.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.00(1H,s,-NHSO 2 -),9.95(1H,s,-NHSO 2 -),7.58(2H,d,J＝8.8Hz,H-2,H-6),7.52(2H,d,J＝8.0Hz,H-2′,H-6′),7.28(2H,d,J＝8.0Hz,H-3,H-5),7.01(2H,d,J＝8.0Hz,H-3′,H-5′),6.90(4H,s,H-b,H-c,H-e,H-f),3.79(3H,s,-OCH 3 ),2.32(3H,s,4-CH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.3,136.4,134.1,130.9,129.5×2,129.3,128.8×2,126.7,126.6×2,121.4×2,121.3×2,114.2×2,55.5,20.9.HRMS(ESI,m/z)calcd.for C 20 H 20 N 2 O 5 S 2 [M-H] - 431.0741,found 431.0737.
3. When R is in step 2-1 2 The substituted sulfonyl chloride is 2,4, 6-trimethylbenzenesulfonyl chloride to obtain the product:
n- (4- ((4-methoxyphenyl) sulfonamido) phenyl) -2,4, 6-trimethylbenzenesulfonamide (II-2 c)
White powder, yield: 74%, melting point: 213.9-214.8 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.95(1H,s,-NHSO 2 -),9.90(1H,s,-NHSO 2 -),7.57(2H,d,J＝8.8Hz,H-2′,H-6′),7.00(2H,d,J＝8.8Hz,H-3′,H-5′),6.94(2H,s,H-3,H-5),6.89(2H,d,J＝8.8Hz,H-b,H-f),6.80(2H,d,J＝8.8Hz,H-c,H-e),3.79(3H,s,-OCH 3 ),2.42(6H,s,2-CH 3 ,6-CH 3 ),2.20(3H,s,4-CH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.3,141.8,138.5×2,134.0,133.6,133.4,131.6×2,130.8,128.7×2,121.5×2,121.3×2,114.2×2,55.5,22.3×2,20.3.HRMS(ESI,m/z)calcd.for C 22 H 24 N 2 O 5 S 2 [M-H] - 459.1054,found 459.1053.
4. When R is in step 2-1 2 The substituted sulfonyl chloride is 4- (trifluoromethyl) benzenesulfonyl chloride to give the product:
4-methoxy-N- (4- ((4- (trifluoromethyl) phenyl) sulphonylamino) phenyl) benzenesulfonamide (II-2 d)
Pale yellow powder, yield: 77%, melting point: 211.4-212.3 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.32(1H,s,-NHSO 2 -),10.02(1H,s,-NHSO 2 -),7.90(2H,d,J＝8.8Hz,H-3,H-5),7.85(2H,d,J＝8.0Hz,H-2,H-6),7.60(2H,d,J＝8.8Hz,H-2′,H-6′),7.00(2H,d,J＝8.8Hz,H-3′,H-5′),6.93(4H,d,J＝2.4Hz,H-b,H-c,H-e,H-f),3.78(3H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.3,143.1,134.7,132.9,130.8,128.8×2,127.7,127.5×2,126.4,126.3,124.9,122.1×2,121.2×2,114.2×2,55.5.HRMS(ESI,m/z)calcd.for C 20 H 17 F 3 N 2 O 5 S 2 [M-H] - 485.0458,found 485.0461.
5. When R is in step 2-1 2 Substituted sulfonyl chlorides are [1,1' -biphenyls ]]-4-sulfonyl chloride to give the product:
n- (4- ((4-methoxyphenyl) sulfamido) phenyl) - [1,1' -biphenyl ] -4-sulfamide (II-2 e)
White powder, yield: 60%, melting point: 193.0-193.9 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.15(1H,s,-NHSO 2 -),9.96(1H,s,-NHSO 2 -),7.80(2H,d,J＝8.4Hz,H-8,H-12),7.73-7.68(4H,m,H-2,H-3,H-5,H-6),7.57(2H,d,J＝9.2Hz,H-2′,H-6′),7.51-7.42(3H,m,H-9,H-10,H-11),6.99-6.91(6H,m,H-b,H-c,H-e,H-f,H-3′,H-5′),3.72(3H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.2,144.1,138.1,134.2,133.7,130.9,129.1,129.0×2,128.7×2,128.5,127.2×4,127.0×2,121.5×2,121.4×2,114.1×2,55.5.HRMS(ESI,m/z)calcd.for C 25 H 22 N 2 O 5 S 2 [M-H] - 493.0897,found 493.0897.
6. When R is in step 2-1 2 The substituted sulfonyl chloride is 1-phenylmethanesulfonyl chloride, which gives the product:
4-methoxy-N- (4- ((phenylmethyl) sulfonamido) phenyl) benzenesulfonamide (II-2 f)
White powder, yield: 70%, melting point: 185.7-186.6 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.99(1H,s,-NHSO 2 -),9.70(1H,s,-NHSO 2 -),7.66(2H,d,J＝9.2Hz,H-2′,H-6′),7.32-7.30(3H,m,H-2,H-4,H-6),7.21-7.18(2H,m,H-3,H-5),7.05(2H,d,J＝8.8Hz,H-3′,H-5′),7.01(4H,s,H-b,H-c,H-e,H-f),4.37(2H,s,-SO 2 CH 2 -),3.77(3H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.3,134.6,133.4,131.0,130.8×2,129.4,128.8×2,128.3×2,128.1,121.6×2,120.2×2,114.2×2,56.7,55.5.HRMS(ESI,m/z)calcd.for C 20 H 20 N 2 O 5 S 2 (M-H) - 431.0741,found 431.0752.
7. When R is in step 2-1 2 The substituted sulfonyl chloride is naphthalene-2-sulfonyl chloride, and the product is obtained:
n- (4- ((4-methoxyphenyl) sulfamido) phenyl) naphthalene-2-sulfamide (II-2 g)
White powder, yield: 65%, melting point: 183.9-184.8 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.11(1H,s,-NHSO 2 -),10.10(1H,s,-NHSO 2 -),8.33(1H,s,H-1),8.08(1H,d,J＝8.4Hz,H-4),8.04(1H,d,J＝8.8Hz,H-3),7.99(1H,d,J＝8.0Hz,H-8),7.71-7.62(3H,m,H-5,H-6,H-7),7.53(2H,d,J＝8.8Hz,H-2′,H-6′),6.95-6.87(6H,m,H-3′,H-5′,H-b,H-c,H-e,H-f),3.75(3H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.2,136.3,134.2,134.1,133.7,131.4,130.8,129.2,129.1,128.9,128.7×2,127.8,127.7,127.6,121.9,121.6×2,121.4×2,114.1×2,55.5.HRMS(ESI,m/z)calcd.for C 23 H 20 N 2 O 5 S 2 [M-H] - 467.0741,found 467.0741.
8. When R is in step 2-1 2 The substituted sulfonyl chloride is naphthalene-1-sulfonyl chloride, and the product is obtained:
n- (4- ((4-methoxyphenyl) sulfamido) phenyl) naphthalene-1-sulfonamide (II-2 h)
Pale yellow powder, yield: 60%, melting point: 193.5-194.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.49(1H,s,-NHSO 2 -),9.89(1H,s,-NHSO 2 -),8.64(1H,d,J＝8.0Hz,H-8),8.19(1H,d,J＝8.4Hz,H-4),8.11(1H,d,J＝6.8Hz,H-2),8.05(1H,d,J＝7.6Hz,H-5),7.65(2H,m,H-3,H-6),7.57(1H,d,J＝7.6Hz,H-7),7.53(2H,d,J＝8.4Hz,H-2′,H-6′),6.97(2H,d,J＝8.8Hz,H-3′,H-5′),6.83(4H,s,H-b,H-c,H-e,H-f),3.78(3H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.2,134.2,133.7,133.6,130.8,129.7,129.0×2,128.7×2,128.0,127.3,126.8×2,124.3,124.2,121.3×2,120.5×2,114.2×2,55.5.HRMS(ESI,m/z)calcd.for C 23 H 20 N 2 O 5 S 2 [M-H] - 467.0741,found 467.0741.
9. When R is in step 2-1 2 The substituted sulfonyl chloride is quinoline-8-sulfonyl chloride to obtain the product:
n- (4- ((4-methoxyphenyl) sulfamido) phenyl) quinoline-8-sulfamide (II-2 i)
White powder, yield: 85%, melting point: 228.2-229.1 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):9.90(1H,s,-NHSO 2 -),9.84(1H,s,-NHSO 2 -),9.07(1H,dd,J 1 ＝4.4Hz,J 2 ＝2.0Hz,H-2),8.49(1H,dd,J 1 ＝8.4Hz,J 2 ＝2.0Hz,H-4),8.28-8.22(2H,m,H-5,H-7),7.71-7.64(2H,m,H-3,H-6),7.50(2H,d,J＝8.8Hz,H-2′,H-6′),6.94(2H,d,J＝8.8Hz,H-3′,H-5′),6.85(2H,d,J＝8.8Hz,H-b,H-f),6.75(2H,d,J＝8.8Hz,H-c,H-e),3.77(3H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.2,151.3,142.6,136.9,135.0,134.1,133.9,133.7,132.0,130.8,128.6×2,128.2,125.5,122.5,121.1×4,114.1×2,55.5.HRMS(ESI,m/z)calcd.for C 22 H 19 N 3 O 5 S 2 [M-H] - 468.0693,found 468.0690.
10. When R is in step 2-1 2 The substituted sulfonyl chloride is pyridine-3-sulfonyl chloride, and the product is obtained:
n- (4- ((4-methoxyphenyl) sulfamido) phenyl) pyridine-3-sulfamide (II-2 j)
Pale yellow powder, yield: 61%, melting point: 141.8-142.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):10.23(1H,s,-NHSO 2 -),10.06(1H,s,-NHSO 2 -),8.76(1H,dd,J 1 ＝8.8Hz,J 2 ＝1.6Hz,H-4),8.74(1H,d,J＝1.6Hz,H-2),8.02-7.99(1H,m,H-6),7.58-7.54(3H,m,H-5,H-2′,H-6′),7.01(2H,d,J＝9.2Hz,H-3′,H-5′),6.93(4H,s,H-b,H-c,H-e,H-f),3.79(3H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):162.3,153.4,147.0,135.5,134.7,134.6,133.0,130.8,128.7×2,124.2,122.2×2,121.4×2,114.2×2,55.5.HRMS(ESI,m/z)calcd.for C 18 H 17 N 3 O 5 S 2 [M-H] - 418.0537,found 418.0536.
Example 3
The synthesis of N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compounds is carried out by the following synthetic route:
route 3:
step 3-1:
the compound i-2 (ii-2) (2 g,1 equiv.) synthesized in example 1 (example 2) was dissolved in N, N-dimethylformamide (20 mL), followed by dropwise addition of potassium carbonate (3 equiv.) followed by dropwise addition of ethyl bromoacetate (2.2 equiv.) at room temperature, stirring at room temperature for 12-16 hours, TLC followed by reaction, after completion of the reaction, the system was poured into 40mL ice water, stirring for half an hour, suction filtration, washing the cake with 4mL ice water 3 times (4 ml×3), and drying (40 ℃) to obtain intermediate iii-1, which was directly used for the next reaction.
Step 3-2:
dissolving the synthesized compound III-1 (1 g,1 equiv.) in methanol (10 mL), adding 10% aqueous sodium hydroxide solution (5 mL), stirring at 85deg.C for 5-7 hr, performing TLC tracking reaction, vacuum distilling the system (45deg.C) after the reaction is completed, evaporating part of methanol, pouring the residue into 20mL ice water, adding 2M hydrochloric acid to adjust pH of the system to 2-3, suction filtering, washing the filter cake with 2mL ice water for 3 times (2 mL×3), and oven drying (40deg.C) to obtain the target compound III-2.
1. Starting from I-2 a synthesized in example 1 in step 3-1, the product is obtained:
2,2' - (1, 4-phenylenedi ((phenylsulfonyl) azadialkyl)) diacetic acid (III-2 a)
White powder, yield: 69%, melting point: 259.5-260.4 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.87(2H,s,-COOH),7.71-7.67(2H,m,H-4),7.60-7.54(8H,m,H-2,H-3,H-5,H-6),7.09(4H,s,H-b,H-c,H-e,H-f),4.40(4H,s,-CH 2 COOH). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):169.7×2,138.4×2,138.1×2,133.2×2,129.1×4,127.8×4,127.1×4,51.8×2.HRMS(ESI,m/z)calcd.for C 22 H 20 N 2 O 8 S 2 [M-H] - 503.0588,found 503.0602.
2. Starting from I-2 c synthesized in example 1 in step 3-1, the product is obtained:
2,2' - (1, 4-phenylenedi (((4-methoxyphenyl) sulfonyl) azadialkyl)) diacetic acid (III-2 b)
White powder, yield: 65%, melting point: 240.9-241.8 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.89(2H,s,-COOH),7.53(4H,d,J＝8.8Hz,H-2,H-6),7.09(4H,s,H-b,H-c,H-e,H-f),7.06(4H,d,J＝8.8Hz,H-3,H-5),4.36(4H,s,-CH 2 COOH),3.83(6H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):169.8×2,162.6×2,138.5×2,129.6×2,129.4×4,127.6×4,114.2×4,55.6×2,51.6×2.HRMS(ESI,m/z)calcd.for C 24 H 24 N 2 O 10 S 2 [M-H] - 563.0800,found 563.0814.
3. Starting from II-2 j synthesized in example 2 in step 3-1, the product is obtained:
n- (4- ((N- (carboxymethyl) -4-methoxyphenyl) sulfonylamino) phenyl) -N- (pyridin-3-ylsulfonyl) glycine (III-2 c)
Pale yellow powder, yield: 60%, melting point: 238.8-239.7 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.94(2H,s,-COOH),8.86(1H,dd,J 1 ＝4.8Hz,J 2 ＝1.2Hz,H-4),8.68(1H,d,J＝2.0Hz,H-2),8.05-8.02(1H,m,H-6),7.62(1H,dd,J 1 ＝8.0Hz,J 2 ＝4.8Hz,H-5),7.52(2H,d,J＝8.8Hz,H-2′,H-6′),7.17-7.11(4H,m,H-b,H-c,H-e,H-f),7.07(2H,d,J＝8.8Hz,H-3′,H-5′),4.47(2H,s,-CH 2 COOH),4.37(2H,s,-CH 2 COOH),3.84(3H,s,-OCH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ(ppm):169.8×2,162.7,153.6,147.4,139.1,137.7,135.2,134.7,129.5,129.4×2,128.2×2,127.8×2,124.2,114.3×2,55.6,52.0,51.5.HRMS(ESI,m/z)calcd.for C 22 H 21 N 3 O 9 S 2 [M-H] - 534.0646,found 534.0645 biological test example 1
Fluorescence Polarization (FP) experiment: labelling of the polypeptide (FITC-LDEETGEFL-NH) with Fluorescein Isothiocyanate (FITC) 2 ) The effect of the small molecules synthesized in examples 1-3 on the keap1 protein FP was examined.
20nM FITC-LDEETGEFL-NH was added to HEPES buffer (pH 7.4,50mM EDTA, 150mM NaCl and 0.005% Tween-20) 2 After incubation for 30 min with 400nM Keap1 protein and 10uL of the compound synthesized in examples 1-3 at different concentrations, FP values were measured using a Synergy H4 full-function microplate reader, with excitation and emission wavelengths of 485nm and 535nm, respectively, and half-Inhibition Concentrations (IC) were calculated from the inhibition ratios at each concentration 50 )。
As shown in Table 1, compounds target Keap1 to block binding to the Nrf2 peptide fragment to IC 50 And the activity of the compound III-2 c is optimal and reaches 0.89+/-0.11 mu M.
TABLE 1 Fluorescence Polarization (FP) experiments to test the inhibitory Activity of target Compounds against Keap1-Nrf2 PPI
Biological test example 2
Detecting the effect of the compound III-2 c on the expression of the Nrf2 protein of the H9c2 cell:
h9c2 cultured in DMEM medium containing 10% fetal bovine serum was plated on six well plates, 5X 10 per well 5 Cells, after 2 days of treatment with the compound, were lysed and proteins were extracted. After that, protein samples were separated by SDS-PAGE and transferred to PVDF membranes, which were blocked in 5% skim milk for 1 hour at room temperature, and then incubated overnight at 4 ℃ with the corresponding Nrf2 primary antibody. The membrane was then washed 3 times with 1 XTBST solution and then incubated with secondary antibody for 1 hour at room temperature. Finally, the membranes were washed and detected and analyzed by the ChemiDoc xrs+ system.
As shown in FIG. 1, after the addition of compound III-2 c, nrf2 showed a dose-dependent increase in protein level, indicating that the compound was able to up-regulate the expression of the Nrf2 protein.
Biological test example 3
The protective effect of compound III-2 c on Lipopolysaccharide (LPS) -induced H9c2 cell damage was examined:
h9c2 cells were cultured in 96-well plates at a density of 5000 cells/well, LPS (1. Mu.g/ml) and compound III-2 c at different concentration gradients were added, and a blank set was set. After 24 hours incubation at 37 ℃, 10% mts solution was added to each well followed by an additional 30 minutes incubation at 37 ℃. Finally, the absorbance at 490nm was measured using a Synergy H4 microplate reader.
As shown in FIG. 2, cells containing the compound III-2 c were able to significantly reduce LPS-induced H9c2 cell damage compared to cells without the compound III-2 c.
Biological test example 4
Flow cytometry determines intracellular ROS levels:
2, 7-dichlorofluorescein diacetate (DCFH-DA) is a common ROS-sensitive dye used to detect ROS levels in cells. H9c2 cells were grown at 3X 10 5 The density of individual cells/well was seeded in 6-well plates and the cells were cultured overnight. Cells were then pretreated with DMSO or 10. Mu.M of the compound for 12 hours and incubated with 1. Mu.g/ml LPS for 12 hours. After that, cells were collected and stained with 10. Mu. MDFH-DA for 30 minutes in DMEM medium (37 ℃ C., dark environment) without fetal bovine serum, and finally washed 3 times with PBS, and fluorescence signals were detected using a FACSCalibur flow cytometer.
As shown in FIG. 3, the reduction of ROS in cells added to group III-2 c compared to the LPS group indicates that compound III-2 c is able to reduce the oxidative damage of cells induced by LPS.
Claims (7)
1. An N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound or pharmaceutically acceptable salt thereof, which is characterized in that the structural formula of the compound is shown as a formula (I),
wherein R is 1 Is that
R 2 Is->
R 3 、R 4 And is the same, selected from carboxymethyl.
2. A process for the preparation of an N- (4- (substituted sulfonylamino) phenyl) sulfonamide compound according to claim 1, comprising the steps of:
(1) Dissolving p-phenylenediamine in organic solvent, adding organic base catalyst, and dropping R-containing solution 2 Sulfonyl chloride of substituent, molar ratio of sulfonyl chloride to p-phenylenediamineStirring to react at 0.5:1-1.5:1 and 0-40 ℃ to obtain an intermediate product II-1 after the reaction is completed and separation and purification are carried out;
(2) Dissolving intermediate II-1 in organic solvent, adding organic base catalyst, and dripping R-containing solution 1 Sulfonyl chloride of substituent, wherein the molar ratio of the sulfonyl chloride to the intermediate product II-1 is 0.5:1-1.5:1, and the mixture is stirred and reacted at the temperature of 0-40 ℃, and then R in the structural general formula (I) is obtained through separation and purification 1 And R is 2 Is different and R 3 And R is 4 A target compound II-2 which is H;
(3) Dissolving a compound II-2 in N, N-dimethylformamide, acetonitrile or acetone, adding potassium carbonate, dropwise adding ethyl bromoacetate, continuously reacting at 0-40 ℃ under the condition that the molar ratio of the potassium carbonate to the compound II-2 is 1:1-5:1, and the molar ratio of the ethyl bromoacetate to the compound II-2 is 2:1-3:1, and separating to obtain an intermediate III-1;
(4) Dissolving an intermediate III-1 in methanol, tetrahydrofuran or water, adding 10-20% sodium hydroxide aqueous solution by mass percent, stirring at 0-100 ℃ for reaction, regulating the pH of the system to 2-3 by hydrochloric acid, and separating to obtain R in the structural formula (I) 3 And R is 4 The target compound III-2 is carboxymethyl.
3. The preparation method according to claim 2, wherein the organic solvent is anhydrous dichloromethane, anhydrous tetrahydrofuran or anhydrous DMF; the organic base catalyst is pyridine or triethylamine.
4. The method according to claim 2, wherein in the steps (1) and (2), the separation and purification comprises: removing the organic solvent by reduced pressure distillation, extracting with ethyl acetate, collecting the organic phase, washing, evaporating to dryness under reduced pressure, redissolving, and purifying by chromatography to obtain the target compound;
the separation in steps (3) and (4) comprises: after the reaction is finished, pouring the reaction system into ice water, stirring, suction filtering, collecting precipitate, washing and drying to obtain the target compound.
5. The use of an N- (4- (substituted sulfonylamino) phenyl) sulfonamide compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease caused by oxidative stress injury.
6. The use according to claim 5, wherein the disease is myocardial cell injury caused by abnormal oxidative stress.
7. The use of claim 5, wherein the compound or pharmaceutically acceptable salt thereof reduces oxidative stress damage by inhibiting Keap1-Nrf2 interactions.
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