CN113999148A - 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, belonging to the field of medicines. The structural formula of the compound is shown in a general formula (I), the compound has targeted Keap1 blocking Keap1-Nrf2 dimerization activity, and the compound activates Nrf2 by inhibiting Keap1-Nrf2 interaction, so that the oxidative stress induced organism injury is relieved, and no obvious toxic effect exists.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medical application of N- (4- (substituted sulfonylamino) phenyl) sulfonamide compounds, in particular to an application of the compounds in preventing and treating myocardial cell injury induced by abnormal oxidative stress.
Background
Reactive Oxygen Species (ROS) are a series of metabolites produced by aerobic cells during their metabolism, and are involved in the conduction of various signal 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 to tissue cells. Oxidative damage to proteins by reactive oxygen species is associated with the development of aging, tumors, diabetes, and many neurodegenerative diseases. Therefore, finding effective anti-ROS drugs is of great importance for maintaining the redox balance in vivo.
Kelch-like epichlorohydrin related protein-1 (Keap1) -activated nuclear factor E2 related factor (Nrf2) -Antioxidant Response Element (ARE) is an important signal pathway for maintaining redox balance in vivo. The transcription regulation factor Nrf2 is a key factor for regulating the oxidative stress response of cells in vivo, belongs to the nuclear transcription factor of a CNC-bZiP transcription factor family, and improves the survival capability of the cells by regulating a series of antioxidant proteins and detoxification protection genes in vivo. The combination of Nrf2 and ARE can regulate the transcription of about 250 genes, and has important roles in regulating cell defense systems and relieving oxidative stress. Research shows that Nrf2 has close relation with the occurrence and development of various human diseases such as diabetes, tumor, liver disease, kidney disease, respiratory system disease, nervous system disease, skin disease, metabolic disease, heavy metal poisoning and the like by regulating and controlling oxidative stress reaction.
Currently, strategies to upregulate Nrf2 include primarily Nrf2 agonists and Keap1-Nrf2 protein-protein interaction (PPI) inhibitors. Nrf2 agonists, such as dimethyl fumarate, are currently marketed for the treatment of relapsing multiple sclerosis, but most Nrf2 agonists lack target specificity, which limits their use in clinical practice. In contrast, protein-protein interaction inhibitors that directly interfere with Keap1-Nrf2 binding are considered to be more promising approaches.
Xiu E Feng and the like synthesize a class of fluorine-containing phenolic compounds containing nitrogen heterocycles, and the nitrified heterocycles and fluorine atoms are introduced into 2, 5 '-dibromo-4, 5, 2' -trihydroxy benzophenone to prepare the compound. Molecular docking suggests that the compound binds stably to the receptor protein by hydrogen bond formation, the conjugated six-membered ring is close to the key residue Arg-415 of Nrf2 attached to Keap1-Kelch, affecting its properties, and this change results in Nrf2 dissociation entering the nucleus from the junction with Keap1-Kelch, exerting its antioxidant protection (fluor bound induced heterocyclic moieties, a class of novel Keap1-Nrf2 protein-protein interaction inhibitors: synthesis, antioxidant Chemistry and molecular binding. medicinal research. volume 28, pages 1319-.
The negative regulatory protein of Nrf2 is Keap 1. Under quiescent conditions, Nrf2 was anchored in the cytoplasm by binding to Keap1, while Keap1 in turn promoted ubiquitination and subsequent proteolysis of Ndf 2. This sequestration and further degradation of Nrf2 in the cytoplasm is the mechanism of inhibition of Nrf2 by Keap 1. Because 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, thereby promoting Nrf2 to enter the nucleus to regulate the transcription of multiple antioxidant genes and protect the organism from oxidative damage. Therefore, the design of the Keap1 inhibitor with a novel structure has 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 Nrf2 to enter the nucleus to exert the function of regulating the transcription of multiple antioxidant genes, and protect the organism from oxidative damage.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides an N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound or a pharmaceutically acceptable salt thereof, wherein the structural formula of the compound is shown as a general formula (I),
wherein R is1、R2Selected from phenyl, phenyl containing an electron-donating substituent or an electron-withdrawing substituent on a benzene ring, heteroaryl containing an electron-withdrawing substituent on a heteroaryl ring, 1' -biphenyl-4-yl and phenylmethyl; or R2Selected from the group consisting of naphthalen-1-yl, naphthalen-2-yl;
R3、R4selected from hydrogen and alkanes containing electron-withdrawing substituents in the chain.
Preferably, R1Is phenyl or phenyl with an electron-donating substituent on a benzene ring, wherein the electron-donating substituent on the benzene ring is methyl or methoxyl;
or, the benzene ring contains phenyl of an electron-withdrawing substituent, and the electron-withdrawing substituent on the benzene ring is cyano;
or, heteroaryl containing electron-withdrawing substituent on the heteroaryl ring, wherein the heteroaryl is thiophene-2-yl or pyridine-3-yl, and the electron-withdrawing substituent on the heteroaryl ring is chlorine atom;
or, 1,1' -biphenyl-4-yl, phenylmethyl;
r2 is phenyl, phenyl containing electron-donating substituent on benzene ring, wherein the electron-donating substituent on the benzene ring is methyl or methoxyl;
or, the benzene ring contains phenyl of electron-withdrawing substituent, the electron-withdrawing substituent on the benzene ring is trifluoromethyl, cyano;
or, heteroaryl containing electron-withdrawing substituent on the heteroaryl ring, wherein the heteroaryl is thiophene-2-yl, pyridine-3-yl or 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, R1Is any one of the following substituents:
R2is any one of the following substituents:
R3、R4is any one of the following substituents:
more preferably, the compound has the 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 ways:
mode 2, includes the following steps:
(1) dissolving p-phenylenediamine in organic solvent, adding organic base catalyst, then dripping R2Sulfonyl chloride of substituent group, the molar ratio of the sulfonyl chloride to the p-phenylenediamine is 0.5:1-1.5:1, stirring and reacting at the temperature of 0-40 ℃, and separating and purifying after the reaction is finished to obtain an intermediate product II-1;
(2) dissolving intermediate product II-1 in organic solvent, adding organic base catalyst, and dripping1The molar ratio of sulfonyl chloride of substituent group to intermediate product II-1 is 0.5:1-1.5:1, stirring and reacting at 0-40 deg.C, and then separating and purifying to obtain R in the general formula (I)1And R2Is not the same and R3And R4A target compound II-2 which is H;
mode 3, includes the following steps:
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, wherein the molar ratio of the potassium carbonate to the compound I-2 or II-2 is 1:1-5:1, dropwise adding ethyl bromoacetate, wherein the molar ratio of the ethyl bromoacetate to the compound I-2 or II-2 is 2:1-3:1, continuously reacting at the temperature of 0-40 ℃, and then separating to obtain an intermediate III-1;
2) dissolving the intermediate III-1 in methanol, tetrahydrofuran or water, adding 10-20% sodium hydroxide aqueous solution by mass percent, stirring for reaction at 0-100 ℃, adjusting the pH of the system to 2-3 by hydrochloric acid, and separating to obtain R in the general structural formula (I)3And R4The 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 the modes 1 and 2, when the sulfonyl chloride is added dropwise, the reaction system is placed in an ice-water bath, and after the addition is completed, the reaction system is transferred to room temperature to perform a stirring reaction.
Preferably, in the step 1) of the mode 3, ethyl bromoacetate is dropwise added at room temperature, and after the dropwise addition is completed, stirring reaction is continued at room temperature; in step 2), the temperature of the stirring reaction was 85 ℃.
In the reaction process, a thin-layer plate (TLC) is used for tracking the reaction, and separation and purification are carried out after the reaction is finished. Preferably, the reaction time is 6 to 18 hours with stirring in the mode 1; in the mode 2, the reaction in the step (1) is 6 to 16 hours, and the reaction time in the step (2) is 5 to 10 hours; the reaction of step 1) in the 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 mode 1 and the mode 2 includes: removing the organic solvent by reduced pressure distillation, extracting with ethyl acetate, collecting the organic phase, washing, drying by distillation under reduced pressure, redissolving, and performing chromatographic purification to obtain a target compound;
the separation in the mode 3 includes: and after the reaction is finished, pouring the reaction system into ice water, stirring, carrying out suction filtration, collecting the precipitate, washing and drying to obtain the target compound.
Under the condition of the mode 1, the yield of the product 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 the pharmaceutically acceptable salt thereof in preparing a medicament for treating diseases caused by oxidative stress injury.
The research shows that the compound has the activity of targeting Keap1 to block the binding of the compound and an Nrf2 peptide fragment, and is expected to be used as a Keap1-Nrf2 PPI inhibitor for treating oxidative stress (ROS) injury.
Specifically, the compound or the pharmaceutically acceptable salt thereof can reduce oxidative stress injury by inhibiting Keap1-Nrf2 interaction.
Further, the disease is myocardial cell damage caused by abnormal oxidative stress.
The research of the invention shows that the N- (4- (substituted sulfonylamino) phenyl) sulfonamide compound can protect the myocardial cells from being damaged by oxidative stress by blocking Keap1-Nrf2 dimerization and activating Nrf2, and has no obvious toxic effect on the myocardial cells.
The invention has the following beneficial effects:
the invention provides an N- (4- (substituted sulfonylamino) phenyl) sulfonamide compound with targeted Keap1 blocking Keap1-Nrf2 dimerization activity, which can relieve oxidative stress induced organism injury by inhibiting Keap1-Nrf2 interaction and has better safety, so the compound provided by the invention has good development prospect in preparation of a medicine for treating oxidative stress injury.
Drawings
FIG. 1 is a graph showing the effect of compound III-2 c on the expression of Nrf2 protein in H9c2 cells.
FIG. 2 is a graph of the effect of compound III-2 c on LPS-induced H9c2 cell damage.
FIG. 3 is a graph of the effect of compound III-2 c on LPS-induced ROS levels in H9c 2.
Detailed Description
The present invention is further illustrated by the following specific examples. The following examples are merely illustrative of the present invention and are not intended to limit the scope of the invention. It is intended that all modifications or alterations to the methods, procedures or conditions of the present invention be made without departing from the spirit or essential characteristics thereof.
The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1
The synthesis of the N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound has the following synthetic route:
route 1:
step 1-1:
p-phenylenediamine (1g,9.2mmol,1equiv.) is dissolved in anhydrous dichloromethane (10mL), pyridine (1mL) is added, the reaction system is placed in an ice-water bath condition, and R is slowly added dropwise1(R2) Substituted sulfonyl chloride (2.5equiv.) after the completion of the addition of sulfonyl chloride, the reaction was transferred to room temperature and stirring was continued for 6-18 hours. TLC tracing reaction, after the reaction is finished, evaporating the organic solvent under reduced pressure (40 ℃), adding 20mL of water and 30mL of ethyl acetate for extraction, discarding the water layer, washing the ethyl acetate layer with 4mL of water for 5 times (4 mL. times.5), then washing with 4mL of saturated saline solution for 2 times (4 mL. times.2), evaporating under reduced pressure (45 ℃), and separating and purifying by column chromatography (petroleum ether: ethyl acetate gradient elution) to obtain the target compound I-2.
1. When R is1(R2) The substituted sulfonyl chloride is benzenesulfonyl chloride to give the product:
n, N' - (1, 4-phenylene) diphenylsulfonamide (I-2 a)
White powder, yield:80%, melting point: 242.6-243.5 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.11(2H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C18H16N2O4S2[M+Na]+411.0444,found 411.0446.
2. When R is1(R2) The substituted sulfonyl chloride is 2,4, 6-trimethylbenzenesulfonyl chloride to give 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 deg.C.1H NMR(400MHz,DMSO-d6)δ(ppm):9.89(2H,s,-NHSO2-),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-CH3,6-CH3),2.21(6H,s,4-CH3).13CNMR(100MHz,DMSO-d6)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 C24H28N2O4S2[M+Na]+495.1383,found 495.1388.
3. When R is1(R2) The substituted sulfonyl chloride is 4-methoxybenzenesulfonyl chloride to give the product:
n, N' - (1, 4-phenylene) bis (4-methoxybenzenesulfonamide) (I-2 c)
White powder, yield: 82%, melting point: 226.8-227.7 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.95(2H,s,-NHSO2-),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,-OCH3).13C NMR(100MHz,DMSO-d6)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 C20H20N2O6S2[M+Na]+471.0655,found 471.0646.
4、When R is1(R2) The substituted sulfonyl chloride is 4-cyanobenzene sulfonyl chloride to give the product:
n, N' - (1, 4-phenylene) bis (4-cyanobenzenesulfonamide) (I-2 d)
White powder, yield: 73%, melting point: 218.6-219.5 ℃.1H NMR(400MHz,DMSO-d6)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,-NHSO2-).13C NMR(100MHz,DMSO-d6)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 C20H14N4O4S2[M+Na]+461.0349,found 461.0342.
5. When R is1(R2) The substituted sulfonyl chloride being [1,1' -biphenyl]-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 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.17(2H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C30H24N2O4S2[M+Na]+563.1070,found 563.1061.
6. When R is1(R2) The substituted sulfonyl chloride was 1-phenylmethanesulfonyl chloride to give the product:
n, N' - (1, 4-phenylene) bis (1-phenylmethanesulfonamide) (I-2 f)
White powder, yield: 51%, melting point: 263.8-264.7 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.74(2H,s,-NHSO2-),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,-SO2CH 2-).13C NMR(100MHz,DMSO-d6)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 C20H20N2O4S2[M+Na]+439.0757,found 439.0753.
7. When R is1(R2) The substituted sulfonyl chloride is pyridine-3-sulfonyl chloride to give the product:
n, N' - (1, 4-phenylene) bis (pyridine-3-sulfonamide) (I-2 g)
Pale yellow powder, yield: 66%, melting point: 179.9-180.8 ℃.1H NMR(400MHz,DMSO-d6)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,J1＝8.4Hz,J2＝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).13C NMR(100MHz,DMSO-d6)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 C16H14N4O4S2[M+H]+391.0529,found 391.0523.
8. When R is1(R2) The substituted sulfonyl chloride is thiophene-2-sulfonyl chloride 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 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.25(2H,s,-NHSO2-),7.89(2H,dd,J1＝4.8Hz,J2＝1.2Hz,H-3),7.42(2H,dd,J1＝4.0Hz,J2＝1.2Hz,H-5),7.11-7.09(2H,m,H-4),7.00(4H,s,H-b,H-c,H-e,H-f).13C NMR(100MHz,DMSO-d6)δ(ppm):134.0×2,133.2×2,132.2×4,127.5×2,121.9×4.HRMS(ESI,m/z)calcd.for C14H12N2O4S4[M-H]-398.9607,found 398.9606.
9. When R is1(R2) The substituted sulfonyl chloride is 5-chlorothiophene-2-sulfonyl chloride which is used 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 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.46(2H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C14H10Cl2N2O4S4[M+Na]+490.8793,found 490.8789.
Example 2
The synthesis of the N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound has the following synthetic route:
route 2:
step 2-1:
p-phenylenediamine (2g,18.5mmol,1equiv.) is dissolved in anhydrous dichloromethane (20mL), triethylamine (1mL) is added, the reaction system is placed in an ice-water bath condition, and R is slowly added dropwise2Substituted sulfonyl chloride (1.2equiv.) after the completion of the addition of sulfonyl chloride, the reaction was transferred to room temperature and stirring was continued for 6-16 hours. TLC tracking reaction, after the reaction is finished, evaporating the organic solvent under reduced pressure (40 ℃), adding 40mL of water and 60mL of ethyl acetate for extraction, removing the water layer, washing the ethyl acetate layer with 8mL of water for 5 times (8mL multiplied by 5), then washing with 8mL of saturated saline for 2 times (8mL multiplied by 2), evaporating under reduced pressure (45 ℃), separating and purifying by column chromatography (petroleum ether: ethyl acetate gradient elution) to obtain an intermediate II-1, and directly using the intermediate II-1 in the next reaction.
Step 2-2:
dissolving the intermediate II-1 (1g,1equiv.) in anhydrous tetrahydrofuran (10mL), adding triethylamine (1mL), placing the reaction system in an ice-water bath condition, slowly dropwise adding 4-methoxybenzenesulfonyl chloride (1.2equiv.) until the dropwise adding of the 4-methoxybenzenesulfonyl chloride is finished, transferring the reaction system to room temperature, and continuously stirring for 5-10 hours. TLC tracing reaction, after the reaction is finished, evaporating the organic solvent under reduced pressure (40 ℃), adding 20mL of water and 30mL of ethyl acetate for extraction, discarding the water layer, washing the ethyl acetate layer with 4mL of water for 5 times (4 mL. times.5), then washing with 4mL of saturated saline solution for 2 times (4 mL. times.2), evaporating under reduced pressure (45 ℃), and separating and purifying by column chromatography (petroleum ether: ethyl acetate gradient elution) to obtain the target compound II-2.
1. When R in step 2-12The substituted sulfonyl chloride is benzenesulfonyl chloride to give the product:
4-methoxy-N- (4- (phenylsulfonamido) phenyl) benzenesulfonamide (II-2 a)
Pale yellow powder, yield: 71%, melting point: 201.6-202.5 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.09(1H,s,-NHSO2-),9.96(1H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C19H18N2O5S2[M+Na]+441.0549,found 441.0546.
2. When R in step 2-12The substituted sulfonyl chloride is p-toluenesulfonyl chloride to give the product:
4-methoxy-N- (4- ((4-methylphenyl) sulfonylamino) phenyl) benzenesulfonamide (II-2 b)
Pale yellow powder, yield: 72%, melting point: 190.8-191.7 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.00(1H,s,-NHSO2-),9.95(1H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C20H20N2O5S2[M-H]-431.0741,found 431.0737.
3. When R in step 2-12The substituted sulfonyl chloride is 2,4, 6-trimethylbenzenesulfonyl chloride to give the product:
n- (4- ((4-methoxyphenyl) sulfonylamino) phenyl) -2,4, 6-trimethylbenzenesulfonamide (II-2 c)
White powder, yield: 74%, melting point: 213.9-214.8 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.95(1H,s,-NHSO2-),9.90(1H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C22H24N2O5S2[M-H]-459.1054,found 459.1053.
4. When R in step 2-12The substituted sulfonyl chloride is 4- (trifluoromethyl) benzenesulfonyl chloride to give the product:
4-methoxy-N- (4- ((4- (trifluoromethyl) phenyl) sulfonamido) phenyl) benzenesulfonamide (II-2 d)
Pale yellow powder, yield: 77%, melting point: 211.4-212.3 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.32(1H,s,-NHSO2-),10.02(1H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C20H17F3N2O5S2[M-H]-485.0458,found 485.0461.
5. When R in step 2-12The substituted sulfonyl chloride being [1,1' -biphenyl]-4-sulfonyl chloride to give the product:
n- (4- ((4-methoxyphenyl) sulfonamido) phenyl) - [1,1' -biphenyl ] -4-sulfonamide (II-2 e)
White powder, yield: 60%, melting point: 193.0-193.9 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.15(1H,s,-NHSO2-),9.96(1H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C25H22N2O5S2[M-H]-493.0897,found 493.0897.
6. When R in step 2-12The substituted sulfonyl chloride was 1-phenylmethanesulfonyl chloride to give the product:
4-methoxy-N- (4- ((phenylmethyl) sulfonamido) phenyl) benzenesulfonamide (II-2 f)
White powder, yield: 70%, melting point: 185.7-186.6 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.99(1H,s,-NHSO2-),9.70(1H,s,-NHSO2-),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,-SO2CH 2-),3.77(3H,s,-OCH 3).13C NMR(100MHz,DMSO-d6)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 C20H20N2O5S2(M-H)-431.0741,found 431.0752.
7. When R in step 2-12The substituted sulfonyl chloride is naphthalene-2-sulfonyl chloride to give the product:
n- (4- ((4-methoxyphenyl) sulfonamido) phenyl) naphthalene-2-sulfonamide (II-2 g)
White powder, yield: 65%, melting point: 183.9-184.8 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.11(1H,s,-NHSO2-),10.10(1H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C23H20N2O5S2[M-H]-467.0741,found 467.0741.
8. When R in step 2-12The substituted sulfonyl chloride is naphthalene-1-sulfonyl chloride to give the product:
n- (4- ((4-methoxyphenyl) sulfonamido) phenyl) naphthalene-1-sulfonamide (II-2 h)
Pale yellow powder, yield: 60%, melting point: 193.5-194.4 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.49(1H,s,-NHSO2-),9.89(1H,s,-NHSO2-),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).13C NMR(100MHz,DMSO-d6)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 C23H20N2O5S2[M-H]-467.0741,found 467.0741.
9. When R in step 2-12The substituted sulfonyl chloride is quinoline-8-sulfonyl chloride to give the product:
n- (4- ((4-methoxyphenyl) sulfonamido) phenyl) quinoline-8-sulfonamide (II-2 i)
White powder, yield: 85%, melting point: 228.2-229.1 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):9.90(1H,s,-NHSO2-),9.84(1H,s,-NHSO2-),9.07(1H,dd,J1＝4.4Hz,J2＝2.0Hz,H-2),8.49(1H,dd,J1＝8.4Hz,J2＝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).13C NMR(100MHz,DMSO-d6)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 C22H19N3O5S2[M-H]-468.0693,found 468.0690.
10. When R in step 2-12The substituted sulfonyl chloride is pyridine-3-sulfonyl chloride to give the product:
n- (4- ((4-methoxyphenyl) sulfonamido) phenyl) pyridine-3-sulfonamide (II-2 j)
Pale yellow powder, yield: 61%, melting point: 141.8-142.7 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):10.23(1H,s,-NHSO2-),10.06(1H,s,-NHSO2-),8.76(1H,dd,J1＝8.8Hz,J2＝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).13C NMR(100MHz,DMSO-d6)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 C18H17N3O5S2[M-H]-418.0537,found 418.0536.
Example 3
The synthesis of the N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound has the following synthetic route:
route 3:
step 3-1:
the compound I-2 (II-2) (2g,1equiv.) synthesized in example 1 (example 2) was dissolved in N, N-dimethylformamide (20mL), potassium carbonate (3equiv.) was added, ethyl bromoacetate (2.2equiv.) was added dropwise at room temperature, stirring was continued at room temperature for 12-16 hours, the reaction was followed by TLC, after completion of the reaction, the system was poured into 40mL of ice water, stirred for half an hour, filtered, the filter cake was washed 3 times (4 mL. times.3) with 4mL of ice water, and dried (40 ℃ C.) to obtain intermediate III-1, which was used directly in the next reaction.
Step 3-2:
dissolving the synthesized compound III-1 (1g,1equiv.) in methanol (10mL), adding 10% sodium hydroxide aqueous solution (5mL), stirring at 85 ℃ for 5-7 hours, tracking the reaction by TLC, distilling the system under reduced pressure (45 ℃) after the reaction is finished, evaporating part of methanol, pouring the residue into 20mL of ice water, adding 2M hydrochloric acid to adjust the pH of the system to 2-3, filtering, adding 2mL of ice water into a filter cake, washing for 3 times (2mL multiplied by 3), and drying (40 ℃) to obtain the target compound III-2.
1. In step 3-1, starting from the I-2 a synthesized in example 1, the product is obtained:
2,2' - (1, 4-Phenylenebis ((phenylsulfonyl) azadialkyl)) diacetic acid (III-2 a)
White powder, yield: 69%, melting point: 259.5-260.4 ℃.1H NMR(400MHz,DMSO-d6)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 2COOH).13C NMR(100MHz,DMSO-d6)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 C22H20N2O8S2[M-H]-503.0588,found 503.0602.
2. In step 3-1, starting from the I-2 c synthesized in example 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 ℃.1H NMR(400MHz,DMSO-d6)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 2COOH),3.83(6H,s,-OCH3).13C NMR(100MHz,DMSO-d6)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 C24H24N2O10S2[M-H]-563.0800,found 563.0814.
3. In step 3-1, II-2 j synthesized in example 2 was used as a starting material to obtain a product:
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 ℃.1H NMR(400MHz,DMSO-d6)δ(ppm):12.94(2H,s,-COOH),8.86(1H,dd,J1＝4.8Hz,J2＝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,J1＝8.0Hz,J2＝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 2COOH),4.37(2H,s,-CH 2COOH),3.84(3H,s,-OCH 3).13C NMR(100MHz,DMSO-d6)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 C22H21N3O9S2[M-H]-534.0646, found 534.0645 biological test example 1
Fluorescence Polarization (FP) assay: labeling of 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)2400nM Keap1 protein, and 10uL of the compound synthesized in examples 1-3 at different concentrations, after incubation for 30 minutes, FP values were measured using a Synergy H4 full-function microplate reader, with excitation and emission wavelengths of 485nM and 535nM, respectively, and the half-Inhibitory Concentrations (IC) were calculated from the inhibitory rates at each concentration (IC)50)。
As shown in table 1, the compounds target Keap1 to block IC binding to Nrf2 peptide fragment50Are all less than 100. mu.M, wherein the activity of the compound III-2 c is optimal and reaches 0.89 +/-0.11. mu.M.
TABLE 1 Fluorescence Polarization (FP) assay test for inhibitory Activity of target Compounds against Keap1-Nrf2 PPI
Biological test example 2
Detecting the effect of compound III-2 c on the expression of Nrf2 protein in H9c2 cells:
h9c2 cultured in DMEM medium containing 10% fetal bovine serum was plated in six-well plates at 5X 10 per well5Cells, 2 days after treatment with the compound, were lysed and protein was extracted. Thereafter, protein samples were separated by SDS-PAGE and transferred to PVDF membranes, which were then blocked in 5% skim milk for 1 hour at room temperature and incubated overnight with the corresponding Nrf2 primary antibody at 4 ℃. The membrane was then washed 3 times with 1 × TBST solution and incubated with secondary antibody 1 at room temperatureAnd (4) hours. Finally, the membrane was washed and detected and analyzed by a ChemiDoc XRS + system.
As shown in figure 1, Nrf2 exhibited a dose-dependent increase in protein level upon addition of compound iii-2 c, indicating that the compound was able to upregulate Nrf2 protein expression.
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 at a density of 5000 cells/well in 96-well plates, LPS (1. mu.g/ml) was added, and compounds III-2 c were added at different concentration gradients, and a blank set was set. After 24 hours of incubation at 37 ℃, 10% MTS solution was added to each well, followed by incubation at 37 ℃ for another 30 minutes. Finally, absorbance at 490nm was measured using a Synergy H4 microplate reader.
As shown in fig. 2, cells containing compound iii-2 c were able to significantly reduce LPS-induced H9c2 cell damage compared to cells without compound iii-2 c.
Biological test example 4
Flow cytometry determination of intracellular ROS levels:
2, 7-dichlorodihydrofluorescein diacetate (DCFH-DA) is a common ROS sensitive dye used to detect ROS levels in cells. H9c2 cells at 3X 105The density of individual cells/well was seeded in 6-well plates and cells were cultured overnight. Then, the cells were pretreated with DMSO or 10. mu.M test compound for 12 hours, and then incubated with 1. mu.g/ml LPS for 12 hours. Thereafter, the cells were collected and stained with 10. mu.MDFH-DA in DMEM medium (37 ℃ C., dark environment) without fetal bovine serum for 30 minutes, and finally washed 3 times with PBS, and then the fluorescence signal was detected using a FACSCalibur flow cytometer.
As shown in FIG. 3, the addition of compound III-2 c reduced ROS in the cells of group III-2 c compared to LPS group, indicating that compound III-2 c was able to reduce LPS-induced oxidative damage in the cells.
Claims (10)
1. An N- (4- (substituted sulfonyl amino) phenyl) sulfonamide compound or a pharmaceutically acceptable salt thereof, which is characterized in that the structural formula of the compound is shown as a general formula (I),
wherein R is1、R2Selected from phenyl, phenyl containing an electron-donating substituent or an electron-withdrawing substituent on a benzene ring, heteroaryl containing an electron-withdrawing substituent on a heteroaryl ring, 1' -biphenyl-4-yl and phenylmethyl; or R2Selected from the group consisting of naphthalen-1-yl, naphthalen-2-yl;
R3、R4selected from hydrogen and alkanes containing electron-withdrawing substituents in the chain.
2. A N- (4- (substituted sulfonylamino) phenyl) sulfonamide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is1The electron-donating substituent on the benzene ring is methyl or methoxy, and the electron-withdrawing substituent is cyano; r1The electron-withdrawing substituent on the heteroaromatic ring is chlorine atom, and the heteroaromatic group is thiophene-2-group or pyridine-3-group;
R2the electron-donating substituent on the benzene ring is methyl or methoxy, and the electron-withdrawing substituent is trifluoromethyl or cyano; r2The electron-withdrawing substituent on the heteroaromatic ring is a chlorine atom, and the heteroaromatic group is a thiophene-2-yl group, a pyridine-3-yl group or a quinoline-8-yl group.
3. A N- (4- (substituted sulfonylamino) phenyl) sulfonamide compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is1Is any one of the following substituents:
R2is any one of the following substituents:
R3、R4is any one of the following substituents:
4. a N- (4- (substituted sulfonylamino) phenyl) sulfonamide compound of claim 1, wherein the compound has the structural formula:
5. the process for producing N- (4- (substituted sulfonylamino) phenyl) sulfonamides or their pharmaceutically acceptable salts according to any one of claims 1 to 4, wherein the compound is produced by any one of the following means,
mode 1, including the steps of: dissolving p-phenylenediamine in organic solvent, adding organic base catalyst, then dripping R1Or R2The molar ratio of sulfonyl chloride to p-phenylenediamine of the sulfonyl chloride of the substituent group is 2:1-3:1, the mixture is stirred and reacted at the temperature of 0-40 ℃, and R in the structural general formula (I) is obtained by separation and purification after the reaction is finished1And R2Are identical and R3And R4A target compound I-2 which is H;
mode 2, includes the following steps:
(1) dissolving p-phenylenediamine in organic solvent, adding organic base to catalyzeAdding the agent dropwise with the compound containing R2Sulfonyl chloride of substituent group, the molar ratio of the sulfonyl chloride to the p-phenylenediamine is 0.5:1-1.5:1, stirring and reacting at the temperature of 0-40 ℃, and separating and purifying after the reaction is finished to obtain an intermediate product II-1;
(2) dissolving intermediate product II-1 in organic solvent, adding organic base catalyst, and dripping1The molar ratio of sulfonyl chloride of substituent group to intermediate product II-1 is 0.5:1-1.5:1, stirring and reacting at 0-40 deg.C, and then separating and purifying to obtain R in the general formula (I)1And R2Is not the same and R3And R4A target compound II-2 which is H;
mode 3, includes the following steps:
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, wherein the molar ratio of the potassium carbonate to the compound I-2 or II-2 is 1:1-5:1, dropwise adding ethyl bromoacetate, wherein the molar ratio of the ethyl bromoacetate to the compound I-2 or II-2 is 2:1-3:1, continuously reacting at the temperature of 0-40 ℃, and then separating to obtain an intermediate III-1;
2) dissolving the intermediate III-1 in methanol, tetrahydrofuran or water, adding 10-20% sodium hydroxide aqueous solution by mass percent, stirring for reaction at 0-100 ℃, adjusting the pH of the system to 2-3 by hydrochloric acid, and separating to obtain R in the general structural formula (I)3And R4The target compound III-2 is carboxymethyl.
6. The method of claim 5, wherein the organic solvent is anhydrous dichloromethane, anhydrous tetrahydrofuran, or anhydrous DMF; the organic base catalyst is pyridine or triethylamine.
7. The method of claim 5, wherein the separation and purification in the mode 1 and the mode 2 comprises: removing the organic solvent by reduced pressure distillation, extracting with ethyl acetate, collecting the organic phase, washing, drying by distillation under reduced pressure, redissolving, and performing chromatographic purification to obtain a target compound;
the separation in the mode 3 includes: and after the reaction is finished, pouring the reaction system into ice water, stirring, carrying out suction filtration, collecting the precipitate, washing and drying to obtain the target compound.
8. Use of a compound of the N- (4- (substituted sulfonylamino) phenyl) sulfonamide group according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease caused by oxidative stress injury.
9. The use according to claim 8, wherein the disease is myocardial cell damage resulting from abnormal oxidative stress.
10. The use of claim 8, wherein the compound or pharmaceutically acceptable salt thereof reduces oxidative stress injury by inhibiting Keap1-Nrf2 interactions.
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| WO2016007993A1 (en) * | 2014-07-16 | 2016-01-21 | University Of South Australia | Benzene sulfonamide-based inhibitors of sphingosine kinase |
| CN108752245A (en) * | 2018-07-16 | 2018-11-06 | 宁夏医科大学 | Naphthalene sulfonylamide acetamides and its application and pharmaceutical composition |
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| WO2016007993A1 (en) * | 2014-07-16 | 2016-01-21 | University Of South Australia | Benzene sulfonamide-based inhibitors of sphingosine kinase |
| CN108752245A (en) * | 2018-07-16 | 2018-11-06 | 宁夏医科大学 | Naphthalene sulfonylamide acetamides and its application and pharmaceutical composition |
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| CN115925606A (en) * | 2023-01-05 | 2023-04-07 | 宁夏医科大学 | 5- (3- (sulfonamido) phenyl) -1H-pyrrole-2-carboxylic acid derivative and preparation method and application thereof |
| CN115925606B (en) * | 2023-01-05 | 2023-10-13 | 宁夏医科大学 | 5- (3- (sulfonamide) phenyl) -1H-pyrrole-2-carboxylic acid derivative and preparation method and application thereof |
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