Disclosure of Invention
The invention provides an N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound and a preparation method and application thereof, wherein the N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound has better antitumor activity.
The technical scheme of the invention is as follows:
an N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound has a structure shown in a formula (I):
in the formula (I), R is H, C1~C5Alkyl radical, C1~C5One or more of alkoxy, halogen and cyano.
Preferably, the compound is one of compounds VI01 to VI 10;
the structures of compounds VI 01-VI 10 are as follows:
the definition of R is shown in the following table:
compound (I)
|
R
|
VI01
|
H
|
VI02
|
2' -methyl group
|
VI03
|
3' -methyl group
|
VI04
|
4' -methyl group
|
VI05
|
4' -methoxy radical
|
VI06
|
3 ', 4 ', 5 ' -trimethoxy
|
VI07
|
4’-F
|
VI08
|
4’-Cl
|
VI09
|
4’-CN
|
VI10
|
3’-F-4’-CN |
Preferably, compound VI01 has the following structural formula:
preferably, compound VI10 has the following structural formula:
the invention also provides a preparation method of the N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound, which comprises the following steps:
(1) under the action of alkali, carrying out amidation reaction on p-methoxybenzenesulfonyl chloride and 4-bromo-1-naphthylamine to obtain N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide;
(2) under the action of a palladium catalyst and alkali, N- (4-bromo-1-naphthyl) -4-methoxybenzenesulphonamide and substituted phenylboronic acid are subjected to coupling reaction to obtain the N- (1-substituted naphthyl) -4-methoxybenzenesulphonamide compound.
Preferably, compound VI10 is prepared as follows:
(1) adding p-methoxybenzenesulfonyl chloride, 4-bromo-1-naphthylamine and pyridine into dichloromethane, stirring at normal temperature overnight, extracting with an HCl aqueous solution after reaction is finished, drying an organic layer with anhydrous sodium sulfate, carrying out vacuum filtration, and drying filter residues to obtain an intermediate N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide;
(2) dissolving N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide, 3-fluoro-4-cyanobenzene sulfonamide, tetrakis (triphenylphosphine) palladium and potassium carbonate in a mixed solvent of tetrahydrofuran and ultrapure water, heating and refluxing at 70 ℃ in a nitrogen-filled environment, detecting the reaction process by TLC (thin layer chromatography), after the reaction is finished, respectively adding saturated sodium bicarbonate and saturated sodium chloride solutions for extraction, drying an organic layer by anhydrous sodium sulfate, carrying out spin drying to prepare sand, and carrying out separation and purification by column chromatography to obtain the N- (1-substituted naphthyl) -4-methoxybenzenesulfonamide compound.
The invention also provides application of the N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide compound in preparing antitumor drugs.
Preferably, the antitumor drug is used for inhibiting breast cancer, colon cancer or lung cancer.
The N- (1-substituted naphthyl) -4-methoxy benzene sulfonamide derivative shows certain antitumor activity. According to the result of the anti-tumor activity test, the compounds VI01 and VI10 show the biological activity equivalent to or even better than that of the positive control drug C188-9; among them, the compound VI10 with the best activity shows excellent activity (IC50 is 4.13-6.55 mu M) on A549, MDA-MB-231 and HCT-116 highly expressed by STAT3, and is superior to the positive control C188-9.
Synthesis of the Compound of example 1
1.1A specific synthetic route for the compounds is shown below:
the specific reaction conditions are as follows: a, pyridine, DCM and rt are stirred overnight; b is N2,pd(pph3)4,K2CO3, THF,H2O,70℃;
1.2 synthetic procedure
Synthesis of VI series compounds
a. The starting materials p-methoxybenzenesulfonyl chloride (207mg,1mmol), 4-bromo-1-naphthylamine (444 mg,2mmol), and pyridine (200 μ L) were weighed into dichloromethane (5mL), stirred overnight at room temperature, and the progress of the reaction was monitored by TLC. After the reaction, the mixture was extracted with 1M HCl (10X 3mL), and the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the residue was dried and weighed to give intermediate N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide.
b. The intermediates N- (4-bromo-1-naphthyl) -4-methoxybenzenesulfonamide (200mg, 0.6mmol), the corresponding substituted phenylboronic acid (0.72mmol), tetrakis (triphenylphosphine) palladium [ pd (pph3)4, 46mg, 0.04 mmol ], and potassium carbonate (207mg, 1.5mmol) were weighed out and dissolved in tetrahydrofuran: ultrapure water 2: 1 (THF: H2O ═ 10:5mL), under a nitrogen-filled atmosphere, the mixture was heated under reflux at 70 ℃ and the progress of the reaction was checked by TLC. After completion of the reaction, saturated sodium bicarbonate (15X 3mL) and a saturated sodium chloride solution (15X 3mL) were added and extracted, respectively. And drying the organic layer by using anhydrous sodium sulfate, carrying out spin-drying to prepare sand, and separating and purifying by using column chromatography to obtain the target compound (VI 01-12). The melting point was measured, the yield was calculated, and the results were confirmed by UPLC-MS, 1H-NMR, 13C-NMR.
1.3 results of the experiment
The synthesized target compound is a compound VI 01-10, and the structure is as follows:
the definition and yield of R are shown in the following table:
compound (I)
|
R
|
Yield%
|
VI 01
|
H
|
42.44
|
VI 02
|
2’-methyl
|
46.28
|
VI 03
|
3’-methyl
|
50.14
|
VI 04
|
4’-methyl
|
42.50
|
VI 05
|
4’-methoxy
|
40.16
|
VI 06
|
3’,4’,5’-trimethoxy
|
27.30
|
VI 07
|
4’-fluoro
|
43.54
|
VI 08
|
4’-chloro
|
36.33
|
VI 09
|
4’-cyanide
|
15.26
|
VI 10
|
3’-fluoro-4’-cyanide
|
30.52 |
UPLC-MS of a portion of the target compound synthesized including the active compound,1H-NMR and13the physicochemical data such as C-NMR are as follows:
4-methoxy-N-(4-phenylnaphthalen-1-yl)benzenesulfonamide(VI 01)
Chemical Formula:C23H19NO3S;MP:156.6~157.1℃;ESI-MS:390.07 [M+H]+;1H-NMR(500MHz,DMSO-d6)δ(ppm):10.188(s,1H,-SO2NH-), 8.166(d,1H,J=8.0Hz,Ar-H),7.755(d,1H,J=7.5Hz,Ar-H),7.699(d, 1H,J=19.0Hz,Ar-H),7.544(m,7H,Ar-H),7.327(d,1H,J=7.5Hz,Ar-H),7.208 (d,1H,J=8.0Hz,Ar-H),7.058(d,2H,J=9.0Hz,Ar-H),3.796(s,3H,-OCH3); 13C-NMR(125MHz,DMSO-d6):162.335,139.567,138.018,132.210,131.941,131.588,129.727,129,676,128.902,128.432,127.452,126.463, 126.390,125.847,125.490,123.677,122.353,114.296,55.597;
4-methoxy-N-(4-(o-tolyl)naphthalen-1-yl)benzenesulfonamide(VI02)
Chemical Formula:C24H21NO3S;MP:148.4~149.8℃;ESI-MS:404.22 [M+H]+;1H-NMR(400MHz,DMSO-d6)δ(ppm):10.189(s,1H,-SO2NH-), 8.180(d,1H,J=8.0Hz,Ar-H),7.705(m,2H,Ar-H),7.468(m,2H,Ar-H),7.387 (m,2H,Ar-H),7.309(m,2H,Ar-H),7.244(d,2H,J=4.5Hz,Ar-H),7.198(m, 1H,Ar-H),7.070(m,2H,Ar-H),3.817(s,3H,-OCH3),1,919(s,3H,-CH3); 13C-NMR(125MHz,DMSO-d6):162.324,139.177,137.535,135.936,132.106,131.999,131.891,129.933,129.384,128.868,127.757,126.419, 126.070,125.781,125.746,125.477,123.632,122.278,114.240,55.594, 19.556;
4-methoxy-N-(4-(4-methoxyphenyl)naphthalen-1-yl)benzenesulfonam ide(VI05)
Chemical Formula:C24H21NO4S;MP:155.1~157.0℃;ESI-MS:420.32 [M+H]+;1H-NMR(500MHz,DMSO-d6)δ(ppm):10.171(s,1H,-SO2NH-), 8.178(m,1H,Ar-H),7.813(m,1H,Ar-H),7.719(m,2H,Ar-H),7.500(m, 2H,Ar-H),7.380(m,2H,Ar-H),7.319(d,1H,J=8.0Hz,Ar-H),7.210(d, 1H,J=9.5Hz,Ar-H),7.091(m,4H,Ar-H),3.856(s,3H,-OCH3),3.822(s,3H, -OCH3);13C-NMR(125MHz,DMSO-d6):162.316,158.702,137.819, 131.969,131.826,131.784,131.731,130.863,129.790,128.896,126.296, 125.766,125.587,123.662,122.513,114.281,113.919,55.590,55.155;
N-(4-(4-fluorophenyl)naphthalen-1-yl)-4-methoxybenzenesulfonamid e(VI07)
Chemical Formula:C23H18FNO3S;MP:151.9~152.2℃;ESI-MS: 408.28[M+H]+;1H-NMR(500MHz,DMSO-d6)δ(ppm):10.202(s, 1H,-SO2NH-),8.167(d,1H,J=8.0Hz Ar-H),7.704(t,3H,J=9.0HzAr-H), 7.482(m,4H,Ar-H),7.336(m,3H,Ar-H),7.202(d,1H,J=8.0Hz,Ar-H), 7.055(d,2H,J=8.5Hz,Ar-H),3.793(s,3H,-OCH3);13C-NMR(125MHz,DMSO-d6):162.339,160.680,136.847,135.847,132.396,131.935,131.726, 131.662,131.633,129.635,128.896,128.576,126.548,125.891,125.350, 123.705,122.239,115.380,115.209,114.293,55.595;
N-(4-(4-cyanophenyl)naphthalen-1-yl)-4-methoxybenzenesulfonamide (VI09)
Chemical Formula:C24H18N2O3S;MP:153.9~155.1℃;ESI-MS: 415.23[M+H]+;1H-NMR(400MHz,DMSO-d6)δ(ppm):10.294(s, 1H,-SO2NH-),8.215(dt,1H,J=4.4Hz Ar-H),8.000(d,2H,J=8.4Hz,Ar-H), 7.719(m,3H,Ar-H),7.666(d,2H,J=8.0Hz Ar-H),7.538(m,2H,Ar-H), 7.403(d,1H,J=7.6Hz,Ar-H),7.277(d,1H,J=7.6Hz,Ar-H),7.080(d, 2H,J=8.8Hz,Ar-H),3.816(s,3H,-OCH3);13C-NMR(125MHz,DMSO-d6): 162.383,144.481,136.026,133.166,132.372,131.840,131.086,130.816, 129.400,128.901,126.951,126.757,126.121,125.039,123.772,121.901, 118.754,114.328,110.311;
the properties and solubility of the target compound synthesized by the present invention are as follows:
most of target compounds have ideal yield, and are mostly white, light yellow and brown; all compounds were soluble in DMSO, DCM, EA, MeOH and EtOH.
The target compound synthesized by the method has a mass spectrum result, and a [ M + H ] + molecular ion peak can be seen; 1H-NMR spectrum results show that all compound hydrogen numbers, corresponding chemical shifts, coupling constants and the like can be consistent with theoretical values of corresponding compounds; the results of 13C-NMR spectra show that the carbon peak shifts and the number of all compounds are consistent with theoretical data;