CN103183623A - A group of benzene sulfonamido benzamide derivatives, and preparation and application thereof - Google Patents
A group of benzene sulfonamido benzamide derivatives, and preparation and application thereof Download PDFInfo
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- CN103183623A CN103183623A CN2013100773109A CN201310077310A CN103183623A CN 103183623 A CN103183623 A CN 103183623A CN 2013100773109 A CN2013100773109 A CN 2013100773109A CN 201310077310 A CN201310077310 A CN 201310077310A CN 103183623 A CN103183623 A CN 103183623A
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Abstract
The invention relates to a group of benzene sulfonamido benzamide derivatives, and a preparation method and an application thereof. The research results indicate that the compounds obviously inhibit the apical sodium-dependent bile acid transporter (ASBT) at the cellular level, thereby being expected to be researched and developed to become a clinically effective medicament for treating hyperlipemia and cholestatic diseases.
Description
Technical field:
The invention belongs to pharmacy field, specifically, relate to one group of benzene sulfonamido benzamide derivatives and preparation and the application in lipidemia and cholestasis.
Background technology:
Cardiovascular disorder is listed in first of the three big diseases (cardiovascular disorder, tumour, communicable disease) of current threat human health.Atherosclerosis is the pathologic basis of cardiovascular disorder, and the generation development of it and numerous disease has relation.Atherosclerotic generation and serum cholesterol and low-density lipoprotein are not normal closely related.Liver and gastrointestinal system are the major organs of cholesterol and lipoprotein metabolism, and the enterohepatic circulation of bile acide has important role for absorption and the metabolism of cholesterol and lipid.
At present, the fat-reducing medicament of clinical application mainly contains nicotinic acid, the special class of shellfish, cholic acid chelating agent and statins.The mechanism of action of nicotinic acid is the effect that strengthens lipoprotein lipase, reduce free fatty acid levels, but its untoward reaction is more, so seldom use.Its mechanism of action of the special class fat regulation medicine of shellfish is to activate peroxisome activated form propagation acceptor (PPAR), strengthens the effect of lipoprotein lipase, and the non-cardiovascular disease of such medicine causes death dangerous than higher, has therefore limited the application of this type of medicine.Cholic acid chelating agent class medicine by conjugated bile acid, increase it and drain, thereby accelerate cholesterol to the conversion of bile acide, cholic acid chelating agent class medicine exists that taking dose is big, gastrointestinal reaction obviously, shortcoming such as patient tolerability difference.Statins is a line medicine for the treatment of hyperlipidaemic conditions, its mechanism of action is to suppress hydroxyl first glutaryl CoA reductase activity in the body, but takes serious adverse reactions such as can causing gastrointestinal dysfunction syndromes, fash, spirit depressing, rhabdomyolysis and hepar damnification for a long time.Therefore, people have and have made extensive work aspect other mechanism of action fat-reducing medicaments seeking research and development, and the ASBT inhibitor is exactly one of research focus wherein.
Apical sodium dependency cholic acid transporter ASBT mainly is expressed in side, intestinal cell film chamber brush border, can with enteric cavity in medicine directly contact, therefore the ASBT Depressant just can suppress transporter under the situation that does not enter the body circulation, the performance pharmacological action, and enter the toxic side effect that body circulation medication amount major general is conducive to reduce medicine.Therefore, ASBT can be used as the novel targets for the treatment of hyperlipidemia and cholestasis.
In the research aspect the inhibition ASBT activity, up to now, Shang Weijian has the pertinent literature report about the benzene sulfonamido benzamide derivatives, and this research will have good clinical application prospect.
One of purpose of the present invention is that one group of new benzene sulfonamido benzamide compound is provided.
Two of purpose of the present invention is that the preparation method of described benzene sulfonamido benzamide compound is provided.
Three of purpose of the present invention is that the new purposes of described benzene sulfonamido benzamide compound in treatment hyperlipidemia and cholestasis is provided.
Summary of the invention:
The invention provides a class benzene sulfonamido benzamide derivatives, its structure is shown in logical formula I:
In the formula:
R
1-Independent representative-OCH
3,-F ,-CONHCH
3,-OCF
3Or-NO
2
R
2-Independently represent single replacement, two replacement, trisubstituted-OCH
3,-F ,-Cl ,-CF
3,-OCF
3,-OCF
2H ,-CH
3,-OH;
Two substituent positions can be ortho position, a position, contraposition in the B ring.
The application of benzene sulfonamido benzamide derivatives of the present invention in treatment cardiovascular and cerebrovascular diseases especially hyperlipidaemia and cholestasis, its target compound is brought into play pharmacological action by suppressing apical sodium dependency cholic acid transporter (ASBT).
The synthetic method of the logical formula I compound of the present invention, be that benzene sulfonyl chloride with various replacements is starting raw material, methyl benzoate condensation with the amino replacement, prepare corresponding benzsulfamide, again with sodium hydroxide with hydrolysis of ester group, and with the aniline condensation that replaces, prepare a series of new benzene sulfonamido benzamide derivatives.
The synthetic route of the logical formula I compound that the present invention relates to is as follows:
The present invention also provides a class pharmaceutical composition, and said composition is to be effective constituent with described benzene sulfonamido benzamide derivatives, forms with pharmaceutically acceptable one or more carriers.
Pharmacological experiment studies show that institute's test compounds has significant inhibitory effect at cell levels to ASBT, presents blood fat reducing and the activity that stops cholestasis preferably.
Embodiment:
Following examples are only understood the present invention better for help those skilled in the art, but do not limit the present invention in any way.
＜embodiment 1 〉
(a) preparation of methyl benzoate 2-(3-nitrobenzene sulfonamide base)
With methyl o-aminobenzoate (10g, 42.8mmol) and pyridine (3.4mL 42.8mmol) is added in the tetrahydrofuran (THF) (120mL), 25 ℃ of stirring reactions are after 0.5 hour, (5.4mL, 42.8mmol), reaction solution reacted 9 hours for 25 ℃ to be added dropwise to the 3-nitrobenzene sulfonyl chloride.Remove reaction solution under reduced pressure tetrahydrofuran (THF), the residual solution impouring to 100mL water, is separated out a large amount of red solid, the hydrochloric acid of Dropwise 5 % to the pH value of solution is 5, stirs suction filtration after 0.5 hour, washes filter cake to filtrate with water and is neutrality, the vacuum-drying filter cake gets red powder solid 10.6g, yield 74%.
1H-NMR(400MHz,DMSO):3.75(3H,s),7.25(1H,t,J=6.0Hz),7.39(1H,d,J=6.0Hz),7.57(1H,t,J=6.0Hz),7.79(1H,dd,J
1=6.0Hz,J
2=1.2Hz),7.85(1H,t,J=6.4Hz),8.15(1H,d,J=6.4Hz),8.44-8.47(2H,m),10.49(1H,s).MS?m/z:359.07[M+Na]
+.
(b) benzoic preparation 2-(3-nitrobenzene sulfonamide base)
(5.7g 17.0mmol) is added in the ethanol (20mL), adds 10% aqueous sodium hydroxide solution (12mL) again, and reaction solution was warming up to 80 ℃ of back flow reaction 8 hours with the product of embodiment 1 step (a).Concentration of reaction solution, the back adds water (12mL) in concentrated solution, be 2 with the hydrochloric acid adjust pH of 6N, stirs suction filtration after 0.5 hour, and washing filter cake with water is neutrality to filtrate, and the vacuum-drying filter cake gets white powder solid 4.7g, yield 86.2%.
1H-NMR(400MHz,DMSO):7.17(1H,t,J=7.6Hz),7.47(1H,d,J=8.0Hz),7.56(1H,t,J=8.4Hz),7.82-7.88(2H,m),8.19(1H,d,J=7.6Hz),8.45-8.47(2H,m),11.28(1H,s).MS?m/z:321.08[M-H]
-.
(c) N-(3,5-difluorophenyl)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
(0.32g 1mmol) is dissolved in (10mL) among the DMF, is added dropwise to HOBt(0.2g in reaction flask with the product of embodiment 1 step (b), 1.5mmol), EDCHCl(0.29g, 1.5mmol), DIPEA(0.27g, 2mmol) and 3,5 ?difluoroaniline (0.13g, DMF solution 1mmol), room temperature reaction 14 hours will produce a large amount of solids in the reaction solution impouring water, suction filtration, water washing, vacuum-drying obtain off-white powder shape solid 0.34g, yield 78%.
1H-NMR(400MHz,DMSO):7.01(1H,d,J=6.0Hz),7.23(1H,t,J=6.0Hz),7.35-7.41(3H,m),7.44-7.46(1H,m),7.48-7.52(2H,m),8.03(1H,t,J=6.4Hz),8.45(1H,d,J=6.4Hz),8.67(1H,dd,J1=6.8Hz,J2=1.2Hz),8.73(1H,s),10.24(1H,s).MS?m/z:432.12[M-H]
-.
＜embodiment 2 〉
(a) N-(3-hydroxyl-4-p-methoxy-phenyl)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), product and 3-hydroxyl-4-anisidine with embodiment 1 step (b), prepare N-(3-hydroxyl-4-p-methoxy-phenyl)-2-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 65.1%.
1H-NMR(400MHz,DMSO):3.30(3H,s),7.01(1H,d,J=6.0Hz),7.23(1H,t,J=6.0Hz),7.35-7.40(3H,m),7.44-7.47(1H,m),7.49-7.52(2H,m),8.03(1H,t,J=6.4Hz),8.45(1H,d,J=6.4Hz),8.67(1H,d?J=6.4Hz),8.73(1H,s),10.24(1H,s).MS?m/z:442.08[M-H]
-.
＜embodiment 3 〉
(a) N-(3,5-dichlorophenyl)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and 3, the 5-dichlorphenamide bulk powder of embodiment 1 step (b), prepare N-(3, the 5-dichlorophenyl)-and 2-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 72.3%.
1H-NMR(400MHz,DMSO):7.30-7.36(3H,m),7.51(1H,t,J=8.0Hz),7.60(1H,d,J=7.2Hz),7.64(2H,d,J=2.0Hz),7.73(1H,t,J=8.0Hz),8.06(1H,d,J=8.4Hz),8.31-8.33(1H,m),8.40-8.41(1H,m),10.31(1H,s),10.45(1H,s).MS?m/z:464.07[M-H]
-.
＜embodiment 4 〉
(a) N-(3,4,5-trichlorophenyl)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), product and 3-hydroxyl-4-anisidine with embodiment 1 step (b) prepare N-(3,4, the 5-trichlorophenyl)-and 2-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 63%.
1H-NMR(400MHz,DMSO):7.30(1H,d,J=7.6Hz),7.35(1H,s),7.51(1H,t,J=7.6Hz),7.59(1H,d,J=8.0Hz),7.74(1H,t,J=8.0Hz),7.84(2H,s),8.05(1H,d,J=8.0Hz),8.30(1H,dd,J
1=8.0Hz,J
2=2.0Hz),8.40(1H,t,J=2.0Hz),10.29(1H,s),10.50(1H,s).MS?m/z:499.04[M-H]
-.
＜embodiment 5 〉
(a) N-(2,4 – dichlorophenyls)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and 2, the 4 – dichlorphenamide bulk powders of embodiment 1 step (b), prepare N-(2,4 – dichlorophenyls)-and 2-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 49.6%.
1H-NMR(DMSO-d
6)δ:7.37-7.33(m,2H),7.53-7.48(m,2H),7.66(s,1H),7.73(s,1H),7.84(t,J=8.0Hz,2H),8.15(d,J=7.6Hz,1H),8.40(s,1H),8.46(d,J=8.4Hz,1H),10.25(s,1H),10.89(s,1H).MS?m/z:464.07[M-H]
-.
＜embodiment 6 〉
(a) N-(3-chloro-phenyl-)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), product and 3-chloroaniline with embodiment 1 step (b) prepare the N-(3-chloro-phenyl-)-2-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 70.2%.
1H-NMR(400MHz,DMSO):7.15(1H,d,J=8.0Hz),7.31-7.35(3H,m),7.46(1H,d,J=8.4Hz),7.50(1H,t,J=8.0Hz),7.63(1H,d,J=7.6Hz),7.72(1H,t,J=8.0Hz),7.77(1H,s),8.07(1H,d,J=8.0Hz),8.32(1H,dd,J
1=8.0Hz,J
2=1.6Hz),8.39(1H,t,J=2.4Hz),10.33(1H,s),10.40(1H,s).MS?m/z:430.09[M-H]
-.
＜embodiment 7 〉
(a) N-(3-chloro-4-fluorophenyl)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), product and 3-chloro-4-fluoroaniline with embodiment 1 step (b), prepare N-(3-chloro-4-fluorophenyl)-2-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 80.6%.
1H-NMR(400MHz,DMSO):7.33-7.40(3H,m),7.45-7.53(2H,m),7.61(1H,d,J=7.2Hz),7.72(1H,t,J=8.0Hz),7.87(1H,dd,J
1=6.8Hz,J
2=2.4Hz),8.06(1H,d,J=8.4Hz),8.32(1H,dd,J
1=8.4Hz,J
2=1.6Hz),8.38(1H,t,J=4.0Hz),10.35(1H,s),10.38(1H,s).MS?m/z:448.07[M-H]
-.
＜embodiment 8 〉
(a) N-(3-trifluoromethyl-4-aminomethyl phenyl)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), with the product of embodiment 1 step (b) and 3 ?San Fu Jia Ji ?4 ?monomethylaniline, prepare N-(3-trifluoromethyl-4-aminomethyl phenyl)-2-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 40.3%.
1H-NMR(400MHz,DMSO):2.40(3H,s),7.31-7.38(3H,m),7.51(1H,t,J=7.6Hz),7.64(1H,d,J=7.6Hz),7.70(2H,t,J=8.0Hz),7.97(1H,d,J=1.2Hz),8.06(1H,d,J=8.0Hz),8.27-8.30(1H,m),8.37(1H,t,J=2.0Hz),10.36(1H,s),10.42(1H,s).MS?m/z:478.10[M-H]
-.
＜embodiment 9 〉
(a) N-(3-difluoro-methoxy phenyl)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), with the product of embodiment 1 step (b) and 3 ?difluoro-methoxy-aniline, prepare N-(3-difluoro-methoxy phenyl)-2-(3-nitrobenzene sulfonamide base) benzamide compounds, be the yellow powder shape, yield 43.3%.
1H-NMR(400MHz,DMSO):6.91(1H,d,J=8.0Hz),7.19(1H,s),7.31-7.42(4H,m),7.49-7.53(2H,m),7.63(1H,d,J=7.6Hz),7.71(1H,t,J=8.0Hz),8.08(1H,d,J=8.0Hz),8.31(1H,dd,J
1=8.0Hz,J
2=1.2Hz),8.38(1H,t,J=2.0Hz),10.33(1H,s),10.41(1H,s).MS?m/z:462.15[M-H]
-.
＜embodiment 10 〉
(a) N-(3-Trifluoromethoxyphen-l)-and 2-(3-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), product and 3-trifluoro-methoxyaniline with embodiment 1 step (b), prepare the N-(3-Trifluoromethoxyphen-l)-2-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 47.6%.
1H-NMR(400MHz,DMSO):7.08(1H,d,J=8.0Hz),7.33(2H,t,J=8.0Hz),7.44(1H,t,J=8.0Hz),7.49-7.54(2H,m),7.63(1H,d,J=7.6Hz),7.70(2H,t,J=8.0Hz),8.07(1H,d,J=7.6Hz),8.31(1H,dd,J
1=8.4Hz,J
2=1.6Hz),8.39(1H,t,J=2.0Hz),10.37(1H,s),10.42(1H,s).MS?m/z:504.12[M+Na]
+.
＜embodiment 11 〉
(a) preparation of methyl benzoate 2-(4-nitrobenzene sulfonamide base)
According to the method preparation of embodiment 1 step (a), be raw material with 4-nitrobenzene sulfonyl chloride, methyl o-aminobenzoate, prepare 2-(4-nitrobenzene sulfonamide base) the methyl benzoate compound, be the pale yellow powder shape, yield 67.7%.
1H-NMR(400MHz,DMSO):3.76(3H,s),7.25(1H,t,J=6.0Hz),7.40(1H,d,J=6.8Hz),7.58(1H,t,J=6.0Hz),7.80(1H,dd,J
1=6.4Hz,J
2=0.8Hz),8.01(2H,d,J=7.2Hz),8.35(2H,d,J=7.2Hz),10.55(1H,s).MS?m/z:335.08[M-H]
-.
(b) benzoic preparation 2-(4-nitrobenzene sulfonamide base)
According to the method preparation of embodiment 1 step (b), the product preparation with embodiment 11 steps (a) obtains subtitle compounds, is the off-white powder shape, yield 82.5%.
1H-NMR(400MHz,DMSO):7.16(1H,t,J=6.0Hz),7.47(1H,d,J=6.4Hz),7.55(1H,t,J=6.8Hz),7.89(1H,dd,J
1=6.0Hz,J
2=1.2Hz),8.05(2H,d,J=7.2Hz),8.34(2H,d,J=7.2Hz),10.39(1H,s).MS?m/z:321.00[M-H]
-.
(c) N-(3,5-difluorophenyl)-and 2-(4-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), product and 3,5-difluoroaniline with embodiment 11 steps (b) prepare N-(3, the 5-difluorophenyl)-2-(4-nitrobenzene sulfonamide base) benzamide compounds, be the yellow powder shape, yield 71.2%.
1H-NMR(400MHz,DMSO):6.92-6.98(1H,m),7.15(1H,t,J=7.2Hz),7.28-7.36(2H,m),7.46-7.61(3H,m),7.88(1H,d,J=8.4Hz),8.05(1H,d,J=8.4Hz),8.20(1H,d,J=8.8Hz),8.33(1H,d,J=8.8Hz),10.27(1H,s),10.44(1H,s).MS?m/z:432.16[M-H]
-.
＜embodiment 12 〉
(a) N-(3,5-dichlorophenyl)-and 2-(4-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and 3, the 5-dichlorphenamide bulk powder of embodiment 11 steps (b), prepare N-(3, the 5-dichlorophenyl)-and 2-(4-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 67.9%.
1H-NMR(400MHz,DMSO):7.31-7.36(3H,m),7.52(1H,t,J=7.6Hz),7.61(1H,d,J=7.2Hz),7.64(2H,d,J=1.2Hz),7.90(2H,d,J=8.8Hz),8.22(2H,d,J=8.8Hz),10.30(1H,s),10.42(1H,s).MS?m/z:464.08[M-H]
-.
＜embodiment 13 〉
(a) N-(2,4 – dichlorophenyls)-and 2-(4-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and the 2,4 dichloro aniline of embodiment 11 steps (b), prepare N-(2,4 – dichlorophenyls)-and 2-(4-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 78%.
1H-NMR(400MHz,DMSO):7.31-7.37(2H,m),7.46-7.57(3H,m),7.72(1H,d,J=2.0Hz),7.97(2H,d,J=8.8Hz),8.33(3H,m),10.25(1H,s),10.96(1H,s).MSm/z:464.08[M-H]
-.
＜embodiment 14 〉
(a) N-(3-chloro-phenyl-)-and 2-(4-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), product and 3-chloroaniline with embodiment 11 steps (b) prepare the N-(3-chloro-phenyl-)-2-(4-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 72%.
1H-NMR(400MHz,DMSO):7.15(1H,dd,J
1=8.0Hz,J
2=1.2Hz),7.33(1H,t,J=8.0Hz),7.46-7.54(2H,m),7.64(1H,d,J=7.2Hz),7.74(1H,t,J=2.0Hz),7.90(2H,d,J=8.4Hz),8.06(1H,d,J=7.2Hz),8.21(2H,d,J=8.4Hz),8.34(1H,d,J=8.4Hz),10.32(1H,s),10.41(1H,s).MS?m/z:430.11[M-H]
-.
＜embodiment 15 〉
(a) N-(3-chloro-4-fluorophenyl)-and 2-(4-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), product and 3-chloro-4-fluoroaniline with embodiment 11 steps (b), prepare N-(3-chloro-4-fluorophenyl)-2-(4-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 66%.
1H-NMR(400MHz,DMSO):7.35-7.40(3H,m),7.48-7.54(2H,m),7.64(1H,d,J=7.2Hz),7.85(1H,dd,J
1=7.2Hz,J
2=2.4Hz),7.91(2H,d,J=8.8Hz),8.21(2H,d,J=8.8Hz),10.33(1H,s),10.39(1H,s).MS?m/z:448.07[M-H]
-.
＜embodiment 16 〉
(a) N-(3-difluoro-methoxy phenyl)-and 2-(4-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), product and 3-difluoro-methoxy-aniline with embodiment 11 steps (b), prepare N-(3-difluoro-methoxy phenyl)-2-(4-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 62.6%.
1H-NMR(400MHz,DMSO):6.91(1H,d,J=8.8Hz),7.19(1H,s),7.33-7.41(3H,m),7.49-7.54(2H,m),7.65(1H,d,J=7.2Hz),7.92(2H,d,J=8.8Hz),8.21(2H,d,J=8.8Hz),10.33(1H,s),10.44(1H,s).MS?m/z:462.15[M-H]
-.
＜embodiment 17 〉
(a) N-(3-Trifluoromethoxyphen-l)-and 2-(4-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), product and 3-trifluoro-methoxyaniline with embodiment 11 steps (b), prepare the N-(3-Trifluoromethoxyphen-l)-2-(4-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 69%.
1H-NMR(400MHz,DMSO):7.08(1H,d,J=7.6Hz),7.33(2H,d,J=8.0Hz),7.44(1H,t,J=8.0Hz),7.53(2H,d,J=8.0Hz),7.65(1H,d,J=7.2Hz),7.73(1H,s),7.91(2H,d,J=8.8Hz),8.20(2H,d,J=8.8Hz),10.38(1H,s),10.40(1H,s).MSm/z:480.21[M-H]
-.
＜embodiment 18 〉
(a) N-(3,4 – dichlorophenyls)-and 2-(4-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and 3, the 4 – dichlorphenamide bulk powders of embodiment 11 steps (b), prepare N-(3,4 – dichlorophenyls)-and 2-(4-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 71%.
1H-NMR(400MHz,DMSO):7.32-7.34(2H,m),7.52(1H,dd,J
1=8.4Hz,J
2=2.4Hz),7.56(2H,t,J=8.8Hz),7.62(1H,d,J=7.2Hz),7.90(2H,d,J=8.8Hz),7.92(1H,s),8.21(2H,d,J=8.8Hz),10.35(1H,s),10.39(1H,s).MS?m/z:464.08[M-H]
-.
＜embodiment 19 〉
(a) N-(3,5-Dimethoxyphenyl)-and 2-(4-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and 3, the 5-dimethoxyaniline of embodiment 11 steps (b), prepare N-(3, the 5-Dimethoxyphenyl)-and 2-(4-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 72%.
1H-NMR(400MHz,DMSO):3.72(6H,s),6.25(1H,t,J=2.0Hz),6.83(1H,d,J=2.0Hz),7.32(1H,t,J=7.2Hz),7.37(1H,d,J=7.6Hz),7.52(1H,t,J=7.6Hz),7.61(1H,d,J=8.0Hz),7.90(2H,d,J=8.8Hz),8.18(2H,d,J=8.8Hz),10.06(1H,s),10.41(1H,s).MS?m/z:456.18[M-H]
-.
＜embodiment 20 〉
(a) preparation of methyl benzoate 3-(3-nitrobenzene sulfonamide base)
According to the method preparation of embodiment 1 step (a), be the former 3-(3-nitrobenzene sulfonamide base for preparing with 3-nitrobenzene sulfonyl chloride, gavaculine methyl esters) the methyl benzoate compound, be the off-white powder shape, yield 83%.
1H-NMR(DMSO-d
6)δ:3.82(s,3H),7.37-7.45(m,2H),7.66(d,J=7.6Hz,1H),7.72(s,1H),7.86(t,J=8.0Hz,1H),8.13(d,J=7.6Hz,1H),8.45(dd,J
1=8.0Hz,J
2=2.0Hz,1H),8.49(t,J=2.0Hz,1H),10.80(s,1H).MS?m/z:335.16[M-H]
-.
(b) benzoic preparation 3-(3-nitrobenzene sulfonamide base)
According to the preparation of the method for embodiment 1 step (b), with the product preparation of embodiment 20 steps (a), obtain 3 ?(3 ?nitrobenzene sulfonamide base) benzoic acid compounds, be the off-white powder shape, yield 72%.
1H-NMR(DMSO-d
6)δ:7.34-7.41(m,2H),7.63(d,J=7.2Hz,1H),7.69(s,1H),7.86(t,J=8.0Hz,1H),8.12(d,J=8.0Hz,1H),8.45(dd,J
1=8.0Hz,J
2=2.0Hz,1H),8.49(t,J=2.0Hz,1H),10.80(s,1H),13.10(s,1H).MS?m/z:321.08[M-H]
-.
(c) N-(3-chloro-4-fluorophenyl)-and 3-(3-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), product and 3-chloro-4-fluoroaniline with embodiment 20 steps (b), prepare N-(3-chloro-4-fluorophenyl)-3-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 67%.
1H-NMR(DMSO-d
6)δ:7.31-7.33(m,1H),7.37-7.45(m,2H),7.63-7.67(m,3H),7.86(t,J=8.0Hz,1H),8.01(dd,J
1=7.2Hz,J
2=2.8Hz,1H),8.13-8.15(m,1H),8.43-8.46(m,1H),8.51(t,J=2.0Hz,1H),10.41(s,1H),10.80(s,1H).MS?m/z:448.07[M-H]
-.
＜embodiment 21 〉
(a) N-(3-difluoro-methoxy phenyl)-and 3-(3-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), product and 3-difluoro-methoxy-aniline with embodiment 20 steps (b), prepare N-(3-difluoro-methoxy phenyl)-3-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 69%.
1H-NMR(DMSO-d
6)δ:6.90(d,J=8.0Hz,1H),7.19(s,1H),7.31-7.44(m,3H),7.59(d,J=8.0Hz,1H),7.66(d,J=8.0Hz,3H),7.85(t,J=8.0Hz,1H),8.15(d,J=8.0Hz,1H),8.45(d,J=8.0Hz,1H),8.51(s,1H),10.39(s,1H),10.80(s,1H).MSm/z:462.15[M-H]
-.
＜embodiment 22 〉
(a) N-(3,4 – dichlorophenyls)-and 3-(3-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and 3, the 4 – dichlorphenamide bulk powders of embodiment 20 steps (b), prepare N-(3,4 – dichlorophenyls)-and 3-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 61%.
1H-NMR(DMSO-d
6)δ:7.32(d,J=8.0Hz,1H),7.43(t,J=8.0Hz,1H),7.59-7.70(m,4H),7.85(t,J=8.0Hz,1H),8.09(d,J=2.4Hz,1H),8.15(d,J=8.0Hz,1H),8.45(d,J=8.0Hz,1H),8.51(s,1H),10.48(s,1H),10.80(s,1H).MS?m/z:464.08[M-H]
-.
＜embodiment 23 〉
(a) preparation of methyl benzoate 4-(3-nitrobenzene sulfonamide base)
According to the method preparation of embodiment 1 step (a), be raw material with 3-nitrobenzene sulfonyl chloride, methyl p-aminobenzoate, prepare 4-(3-nitrobenzene sulfonamide base) the methyl benzoate compound, be the off-white powder shape, yield 89%.
1H-NMR(DMSO-d
6)δ:3.78(s,3H),7.25(d,J=8.8Hz,2H),7.84-7.89(m,3H),8.20(d,J=8.0Hz,1H),8.45(dd,J
1=8.0Hz,J
2=2.0Hz,1H),8.54(t,J=2.0Hz,1H),11.10(s,1H).MS?m/z:335.16[M-H]
-.
(b) benzoic preparation 4-(3-nitrobenzene sulfonamide base)
According to the preparation of the method for embodiment 1 step (b), with the product of embodiment 23 steps (a), prepare 4 ?(3 ?nitrobenzene sulfonamide base) benzoic acid compounds, be the off-white powder shape, yield 70%.
1H-NMR(DMSO-d
6)δ:7.22(d,J=8.8Hz,2H),7.81-7.89(m,3H),8.20(d,J=8.0Hz,1H),8.45(dd,J
1=8.0Hz,J
2=2.0Hz,1H),8.54(t,J=2.0Hz,1H),11.06(s,1H),12.80(s,1H).MS?m/z:321.08[M-H]
-.
(c) N-(3-Trifluoromethoxyphen-l)-and 4-(3-nitrobenzene sulfonamide base) preparation of benzamide
Method preparation according to embodiment 1 step (c), product and 3-trifluoro-methoxyaniline with embodiment 23 steps (b), prepare the N-(3-Trifluoromethoxyphen-l)-4-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 63%.
1H-NMR(DMSO-d
6)δ:7.09(d,J=8.8Hz,1H),7.26(d,J=8.0Hz,2H),7.46(t,J=8.0Hz,1H),7.71(d,J=8.0Hz,1H),7.85-7.91(m,4H),8.23(d,J=8.0Hz,1H),8.47(dd,J
1=8.0Hz,J
2=2.0Hz,1H),8.57(s,1H),10.37(s,1H),11.04(s,1H).MS?m/z:480.21[M-H]
-.
＜embodiment 24 〉
(a) N-(3,4 – dichlorophenyls)-and 4-(3-nitrobenzene sulfonamide base) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and 3, the 4 – dichlorphenamide bulk powders of embodiment 23 steps (b), prepare N-(3,4 – dichlorophenyls)-and 4-(3-nitrobenzene sulfonamide base) benzamide compounds, be the off-white powder shape, yield 53%.
1H-NMR(DMSO-d
6)δ:7.25(d,J=8.0Hz,2H),7.59(d,J=8.8Hz,1H),7.69(dd,J
1=8.8Hz,J
2=2.4Hz,1H),7.83-7.90(m,3H),8.09(d,J=2.0Hz,1H),8.22(d,J=8.0Hz,1H),8.47(dd,J
1=8.0Hz,J
2=2.0Hz,1H),8.56(s,1H),10.34(s,1H),11.04(s,1H).MS?m/z:464.08[M-H]
-.
＜embodiment 25 〉
(a) preparation of methyl benzoate 2-(3-fluorobenzene sulfoamido)
According to the method preparation of embodiment 1 step (a), be raw material with 3-fluorobenzene SULPHURYL CHLORIDE, methyl o-aminobenzoate, prepare 2-(3-fluorobenzene sulfoamido) the methyl benzoate compound, be the off-white powder shape, yield 79%.
1H-NMR(DMSO-d
6)δ:3.80(s,3H),7.22(t,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),7.51-7.63(m,5H),7.83(dd,J
1=8.0Hz,J
2=1.6Hz,1H),10.42(s,1H).MS?m/z:310.95[M+H]
+.
(b) benzoic preparation 2-(3-fluorobenzene sulfoamido)
According to the method preparation of embodiment 1 step (b), the product preparation with embodiment 25 steps (a) obtains subtitle compounds, is the off-white powder shape, yield 70%.
1H-NMR(DMSO-d
6)δ:7.16(t,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),7.51-7.66(m,5H),7.90(dd,J
1=8.0Hz,J
2=1.6Hz,1H),11.22(s,1H).MS?m/z:294.09[M-H]
-.
(c) N-(3-Trifluoromethoxyphen-l)-and 2-(3-fluorobenzene sulfoamido) preparation of benzamide
The method preparation of embodiment 1 step (c), product and 3-trifluoro-methoxyaniline with embodiment 25 steps (b), prepare the N-(3-Trifluoromethoxyphen-l)-2-(3-fluorobenzene sulfoamido) benzamide compounds, be the off-white powder shape, yield 63%.
1H-NMR(DMSO-d
6)δ:7.11(d,J=8.4Hz,1H),7.26-7.34(m,2H),7.39-7.57(m,6H),7.62(d,J=8.4Hz,1H),7.70(d,J=7.2Hz,1H),7.79(s,1H),10.37(s,1H),10.52(s,1H).MS?m/z:453.11[M-H]
-.
＜embodiment 26 〉
(a) N-(3-chloro-4 fluorophenyls)-and 2-(3-fluorobenzene sulfoamido) preparation of benzamide
According to the method preparation of embodiment 1 step (c), product and 3-chloro-4 fluoroanilines with embodiment 25 steps (b) prepare N-(3-chloro-4 fluorophenyls)-2-(3-fluorobenzene sulfoamido) benzamide compounds, be the off-white powder shape, yield 55%.
1H-NMR(DMSO-d
6)δ:7.29(t,J=7.6Hz,1H),7.35(d,J=8.0Hz,1H),7.41-7.59(m,7H),7.70(d,J=7.6Hz,1H),7.95(dd,J
1=6.8Hz,J
2=2.4Hz,1H),10.41(s,1H),10.47(s,1H).MS?m/z:421.81[M-H]
-.
＜embodiment 27 〉
(a) N-(2,4-dichlorophenyl)-and 2-(3-fluorobenzene sulfoamido) preparation of benzamide
According to the method preparation of embodiment 1 step (c), product and 2,4 dichloro aniline with embodiment 25 steps (b) prepare N-(2, the 4-dichlorophenyl)-2-(3-fluorobenzene sulfoamido) benzamide compounds, be the off-white powder shape, yield 65%.
1H-NMR(DMSO-d
6)δ:7.29(t,J=7.2Hz,1H),7.40(d,J=8.0Hz,1H),7.50-7.64(m,7H),7.75(d,J=2.0Hz,1H),7.88(d,J=8.0Hz,1H),10.34(s,1H),10.90(s,1H).MS?m/z:438.21[M-H]
-.
＜embodiment 28 〉
(a) preparation of methyl benzoate 2-(3-methoxybenzenesulphoismide base)
According to the method preparation of embodiment 1 step (a), be raw material with 3-methoxyl group SULPHURYL CHLORIDE, methyl o-aminobenzoate, prepare subtitle compounds, be the off-white powder shape, yield 72%.
1H-NMR(DMSO-d
6)δ:3.76(s,3H),3.81(s,3H),7.17-7.24(m,3H),7.34(d,J=7.6Hz,1H),7.47(t,J=8.0Hz,2H),7.58(t,J=8.0Hz,1H),7.84(dd,J
1=8.0Hz,J
2=1.6Hz,1H),10.37(s,1H).MS?m/z:322.35[M+H]
+.
(b) benzoic preparation 2-(3-methoxyl group sulfoamido)
According to the preparation of the method for embodiment 1 step (b), with the product of embodiment 28 steps (a), prepare 2 ?(3 ?methoxyl group sulfoamido) benzoic acid compounds, be the off-white powder shape, yield 70%.
1H-NMR(DMSO-d
6)δ:3.76(s,3H),7.12(t,J=8.0Hz,1H),7.20(dd,J
1=8.0Hz,J
2=2.4Hz,1H),7.26(t,J=2.0Hz,1H),7.35(d,J=8.0Hz,1H),7.47(t,J=8.0Hz,1H),7.52-7.58(m,2H),7.89(dd,J
1=8.0Hz,J
2=1.6Hz,1H),11.08(s,1H),13.97(s,1H).MS?m/z:306.32[M-H]
-.
(c) N-(2,4-dichlorophenyl)-and 2-(3-methoxy benzene sulfonamido) preparation of benzamide
According to the method preparation of embodiment 1 step (c), product and 2,4 dichloro aniline with embodiment 28 steps (b) prepare N-(2, the 4-dichlorophenyl)-2-(3-methoxy benzene sulfonamido) benzamide compounds, be the off-white powder shape, yield 56%.
1H-NMR(DMSO-d
6)δ:3.73(s,3H),7.19-7.30(m,4H),7.43-7.54(m,4H),7.61(d,J=8.4Hz,1H),7.75(d,J=1.6Hz,1H),7.88(d,J=8.0Hz,1H),10.35(s,1H),10.85(s,1H).MS?m/z:450.31[M-H]
-.
＜embodiment 29 〉
(a) N-(3-chloro-4-fluorophenyl)-and 2-(3-methoxy benzene sulfonamido) preparation of benzamide
Method preparation according to embodiment 1 step (c), with product and the 2,4 dichloro aniline of embodiment 28 steps (b), prepare N-(3-chloro-4-fluorophenyl)-2-(3-methoxy benzene sulfonamido) benzamide compounds, be the off-white powder shape, yield 65%.
1H-NMR(DMSO-d
6)δ:3.67(s,3H),7.12(dd,J
1=8.0Hz,J
2=2.4Hz,1H),7.25-7.29(m,2H),7.36-7.45(m,3H),7.51(t,J=7.6Hz,1H),7.56-7.60(m,1H),7.71(d,J=7.6Hz,1H),7.94(dd,J
1=6.8Hz,J
2=2.4Hz,1H),10.36(s,1H),10.46(s,1H).MS?m/z:433.81[M-H]
-.
＜embodiment 30 〉
(a) benzoic preparation 2-(3-trifluoromethoxy sulfoamido)
Method preparation according to embodiment 1 step (a), be raw material with 3-trifluoromethoxy SULPHURYL CHLORIDE, methyl o-aminobenzoate, prepare 2-(3-trifluoromethoxy sulfoamido) methyl benzoate, again with the method for embodiment 1 step (b), prepare 2-(3-trifluoromethoxy sulfoamido) benzoic acid compounds, be the off-white powder shape, yield 45%.
1H-NMR(DMSO-d
6)δ:11.17(s,1H),7.89(dd,J
1=7.6Hz,J
2=1.2Hz,1H),7.84(d,J=7.6Hz,1H),7.74-7.67(m,3H),7.57(t,J=8.0Hz,1H),7.50(d,J=8.0Hz,1H),7.17(t,J=8.0Hz,1H).MS?m/z:460.11[M-H]
-.
(b) N-(2,4-dichlorophenyl)-and 2-(3-trifluoromethoxy benzaldehyde sulfoamido) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and the 2,4 dichloro aniline of embodiment 30 steps (a), prepare N-(2, the 4-dichlorophenyl)-and 2-(3-trifluoromethoxy benzaldehyde sulfoamido) benzamide compounds, be the off-white powder shape, yield 57%.
1H-NMR(DMSO-d
6)δ:
1H-NMR(DMSO-d
6)δ:7.30(t,J=7.6Hz,1H),7.35(d,J=8.0Hz,1H),7.49-7.51(m,2H),7.62-7.78(m,6H),7.88(d,J=7.6Hz,1H),10.31(s,1H),10.94(s,1H).MS?m/z:504.31[M-H]
-.
＜embodiment 31 〉
(a) N-(3,4-dichlorophenyl)-and 2-(3-trifluoromethoxy benzaldehyde sulfoamido) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and 3, the 4-dichlorphenamide bulk powder of embodiment 30 steps (a), prepare N-(3, the 4-dichlorophenyl)-and 2-(3-trifluoromethoxy benzaldehyde sulfoamido) benzamide compounds, be the off-white powder shape, yield 67%.
1H-NMR(DMSO-d
6)δ:7.32(t,J=8.0Hz,2H),7.51(t,J=8.0Hz,1H),7.58-7.74(m,7H),8.05(d,J=2.0Hz,1H),10.40(s,1H),10.53(s,1H).MS?m/z:504.31[M-H]
-.
＜embodiment 32 〉
(a) preparation of methyl benzoate 2-(4-acetamido sulfoamido)
According to the method preparation of embodiment 1 step (a), be raw material with 4-acetamido SULPHURYL CHLORIDE, methyl o-aminobenzoate, prepare 2-(4-acetamido sulfoamido) the methyl benzoate compound, be the off-white powder shape, yield 82%.
1H-NMR(DMSO-d
6)δ:2.04(s,3H),3.82(s,3H),7.15(t,J=7.5Hz,1H),7.45(d,J=8Hz,1H),7.55(t,J=8Hz,1H),7.71(dd,J
1=14.0Hz,J
2=9.0Hz,4H),7.83(d,J=8Hz,1H),10.31(s,1H),10.36(s,1H).MS?m/z:347.14[M-H]
-.
(b) preparation of methyl benzoate 2-(4-acetamido sulfoamido)
According to the method preparation of embodiment 1 step (b), with the product of embodiment 32 steps (a), preparation
Obtain 2-(4-acetamido sulfoamido) the methyl benzoate compound, be the off-white powder shape, yield 67%.
1H-NMR(DMSO-d
6)δ:2.04(s,3H),7.08-7.12(m,1H),7.47-7.48(m,1H),7.52-7.55(m,1H),7.69-7.70(m,2H),7.73-7.75(m,2H),7.87(dd,J
1=8.0Hz,J
2=1.5Hz,1H),10.31(s,1H),10.36(s,1H),13.93(s,1H).MS?m/z:333.01[M-H]
-.
(c) N-(3,5-dichlorophenyl)-2-(4 ?the acetamido benzene sulfonamido) preparation of benzamide
According to the method preparation of embodiment 1 step (c), with product and 3, the 5-dichlorphenamide bulk powder of embodiment 32 steps (b), prepare N-(3, the 5-dichlorophenyl)-and 2-(4-acetamido benzene sulfonamido) benzamide compounds, be the off-white powder shape, yield 57%.
1H-NMR(DMSO-d
6)δ:
1H-NMR(DMSO-d
6)δ:2.04(s,3H),7.26(t,J=7.2Hz,1H),7.35-7.36(m,2H),7.48-7.52(m,1H),7.62(m,4H),7.68(dd,J
1=7.6Hz,J
2=1.2Hz,1H),7.73(d,J=2Hz,2H),10.01(s,1H),10.22(s,1H),10.51(s,1H).MS?m/z:477.31[M-H]
-.
＜embodiment 33〉The compounds of this invention suppresses the test of ABST activity
The compounds of this invention is carried out suppressing on the pharmacology experiment of ASBT activity; adopt people HEK293T cell; in the DMEM of 10%FBS nutrient solution, cultivate; screened preceding 24 hours; be taped against in 12 orifice plates with 300,000/hole; pcDNA3.1/hASBT plasmid or pcDNA3.1 empty carrier with the 0.5ug/ hole carries out transfection (lipofactamine2000, reverse transfection method) simultaneously.Cell cultures after the transfection 24 hours is revised a little with reference to ordinary method, carries out the taurocholate transport activity analysis of Na ionic dependent.Primary process is as follows: the cell of 12 orifice plates base soln (116mM NaCl (Choline Cl), 5.3mM KCl, the 1.1mMKH of preheating
2PO
4, 0.8mM MgSO
4, 1.8mM CaCl
211mM D-Dextrose/D-Glucose; and10mMHEPES; pH7.4) leniently clean twice; the base soln that then 0.5mL is contained the testing compound (being dissolved in DMSO in advance) of the taurocholate ([3H] taurocholic acid) of 1 μ Ci/mL3H mark and prescribed concentration joins in 12 orifice plates; 37 ℃ leave standstill 10min after; give a baby a bath on the third day after its birth time with the precooling base soln; add 0.3mL/ hole lysate (0.5%triton x-100); with rifle pressure-vaccum lysing cell or vibration repeatedly; avoid bubble as far as possible; about 20min; lysate is transferred in special-purpose 24 orifice plates of liquid scintillation instrument, adds the scintillation solution (as 0.7mL) of appropriate volume, measure with the PE MicroBeta2 of company liquid scintillation instrument after sealing lid.IC50 cuts the compound concentration that suppresses the taurocholate transport activity of ASBT albumen 50% behind the background value, uses the SigmaPlot10.0 computed in software.
Table 1 representation compound of the present invention is to the IC50 of people HEK293T cell ASBT
Experimental result shows that all test compounds all have significant inhibitory effect at cell levels to ASBT in the table 1.
Claims (5)
1. one group of benzene sulfonamido benzamide derivatives, its structure is shown in general formula (1):
In the formula:
R
1-Independent representative-OCH
3,-F ,-CONHCH
3,-CF
3,-OCF
3Or-NO
2
R
2-Independently represent single replacement, two replacement, trisubstituted-OCH
3,-F ,-Cl ,-CF
3,-OCF
3,-OCF
2H ,-CH
3,-OH;
Two substituent positions can be ortho position, a position, contraposition in the B ring.
2. the method for preparing the described derivative of claim 1, be that benzene sulfonyl chloride with various replacements is starting raw material, methyl benzoate condensation with the amino replacement, prepare corresponding benzsulfamide, again with sodium hydroxide with hydrolysis of ester group, and with the aniline condensation that replaces, thereby obtain a series of new benzene sulfonamido benzamide derivatives.
3. the application of the described derivative of claim 1 in preparation treatment cardiovascular and cerebrovascular diseases medicament.
4. be effective constituent with the described derivative of claim 1, with the composition of pharmaceutically acceptable carrier composition.
5. the application of the described composition of claim 4 in preparation treatment cardiovascular and cerebrovascular diseases medicament.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105395532A (en) * | 2015-11-25 | 2016-03-16 | 中国医学科学院医药生物技术研究所 | Application of 2-benzenesulfonamido benzamide compound in liver injury protection and hepatic fibrosis control |
| CN105837501A (en) * | 2016-03-31 | 2016-08-10 | 常州大学 | Synthetic method of 4-(bromoamino)-N-(pyrid-2-yl)benzene sulfonic acid |
| CN108938615A (en) * | 2017-05-22 | 2018-12-07 | 中国医学科学院医药生物技术研究所 | Benzene sulfonamido benzamide compound is used to treat the purposes of non-alcohol fatty liver |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105395532A (en) * | 2015-11-25 | 2016-03-16 | 中国医学科学院医药生物技术研究所 | Application of 2-benzenesulfonamido benzamide compound in liver injury protection and hepatic fibrosis control |
| US20180333376A1 (en) * | 2015-11-25 | 2018-11-22 | Hebei Medfaith Pharmaceutical Technology Co., Ltd. | Use of (benzenesulfonamido) benzamide compounds for inhibiting liver fibrosis |
| US10933038B2 (en) * | 2015-11-25 | 2021-03-02 | Hebei Medfaith Pharmaceutical Technology Co., Ltd. | Use of (benzenesulfonamido) benzamide compounds for inhibiting liver fibrosis |
| CN105837501A (en) * | 2016-03-31 | 2016-08-10 | 常州大学 | Synthetic method of 4-(bromoamino)-N-(pyrid-2-yl)benzene sulfonic acid |
| CN108938615A (en) * | 2017-05-22 | 2018-12-07 | 中国医学科学院医药生物技术研究所 | Benzene sulfonamido benzamide compound is used to treat the purposes of non-alcohol fatty liver |
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