CN103601719A - 2, 2'-bipyridine-6, 6'-diformyl-quinolyl-2-amine derivative, and preparation method and applications thereof - Google Patents

2, 2'-bipyridine-6, 6'-diformyl-quinolyl-2-amine derivative, and preparation method and applications thereof Download PDF

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CN103601719A
CN103601719A CN201310525135.5A CN201310525135A CN103601719A CN 103601719 A CN103601719 A CN 103601719A CN 201310525135 A CN201310525135 A CN 201310525135A CN 103601719 A CN103601719 A CN 103601719A
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CN103601719B (en
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唐亚林
王立霞
向俊锋
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Abstract

The invention discloses a 2, 2'-bipyridine-6, 6'-diformyl-quinolyl-2-amine derivative, and a preparation method and applications thereof. The 2, 2'-bipyridine-6, 6'-diformyl-quinolyl-2-amine derivative is represented by formula I. The 2, 2'-bipyridine-6, 6'-diformyl-quinolyl-2-amine derivative can be prepared by a multi-step organic synthetic reaction including Mitsunobu Reaction, acid amine condensation, and the like. The 2, 2'-bipyridine-6, 6'-diformyl-quinolyl-2-amine derivative possesses pervasive high-efficient inhibition effect on a plurality of cell strains, and is of significant importance in preparation of antitumor drugs.

Description

2,2 '-dipyridyl-6,6 '-diformyl-quinoline-2-sulfonamide derivatives and preparation method thereof and application
Technical field
The present invention relates to a kind of 2,2 '-dipyridyl-6,6 '-diformyl-quinoline-2-sulfonamide derivatives and preparation method thereof and application.
Background technology
As the synthetic skeleton of pharmaceutical active compounds and pharmaceutical chemistry, pyridine-2,6-diformyl-quinoline-3(or-6) being in the news has antitumour activity for the methyl salt (quinoline nitrogen-atoms forms quaternary ammonium salt) of-amine analogue.
In patent WO2004/072027A2 (US2007/0232572A1); methylated pyridine-2 have been recorded; 6-diformyl-quinoline-3(or-6) salt of-amine (quinoline nitrogen-atoms forms quaternary ammonium salt) has stronger stabilization for telomere G-tetra-serobilas, and has antitumour activity.
Summary of the invention
The object of this invention is to provide a kind of 2,2 '-dipyridyl-6,6 '-diformyl-quinoline-2-sulfonamide derivatives and preparation method thereof and application.
Provided by the invention 2,2 '-dipyridyl-6,6 '-diformyl-quinoline-2-sulfonamide derivatives, its general structure is suc as formula shown in I,
Figure BDA0000404938500000011
Formula I
In described formula I, R is-O (CH 2) mCH 3,-O (CH 2) nN (CH 3) 2,-O (CH 2) 2n (CH 2) 4,-O (CH 2) 2n (CH 2cH 3) 2or-O (CH 2) 2nH[(COO (CH 3) 3)];
M is the integer of 1-4; Concrete, m is 1,2,3,4, the integer of 1-3 or 2-4;
N is 2 or 3.
Concrete, compound shown in described formula I is any one in following compound
Figure BDA0000404938500000012
Figure BDA0000404938500000021
Figure BDA0000404938500000031
In addition, compound shown in above-mentioned formula I is acceptable salt pharmaceutically, also belongs to protection scope of the present invention.
Wherein, described salt is inorganic acid salt or organic acid salt;
Mineral acid in described inorganic acid salt is hydrochloric acid, sulfuric acid or phosphoric acid;
Organic acid in described organic acid salt is acetic acid, trifluoroacetic acid, propanedioic acid, citric acid or tosic acid.
Shown in the described formula I of preparation provided by the invention, the method for compound, comprises the steps:
By compound 2 shown in formula II, 2 '-dipyridyl-6, the chloro-N of 6 '-dioctyl phthalate and 1-, N, 2-trimethylammonium-1-allylamine reacts after 1-3 hours in-15-5 ℃ in organic solvent;
Add again organic bases to react after 0.5-1.5 hours in-15-5 ℃;
Add again the organic solution of the 4-of compound shown in formula III replacement-quinoline-2-ammonia to carry out acid amide condensation reaction 12-24 hours in room temperature, obtain compound shown in described formula I;
Formula II
Figure BDA0000404938500000033
Formula III
In described formula III, R is-O (CH 2) mCH 3,-O (CH 2) nN (CH 3) 2,-O (CH 2) 2n (CH 2) 4,-O (CH 2) 2n (CH 2cH 3) 2or-O (CH 2) 2nH[(COO (CH 3) 3)];
M is the integer of 1-4;
N is 2 or 3.
In aforesaid method, described organic bases is selected from least one in triethylamine, pyridine and piperidines;
Described organic solvent is selected from least one in methylene dichloride, trichloromethane and 1,2-ethylene dichloride;
In the organic solution of the replacement-quinoline-2-of compound 4-shown in described formula III ammonia, solvent is selected from least one in methylene dichloride, trichloromethane and 1,2-ethylene dichloride.
Compound shown in compound shown in formula II, formula III, the chloro-N of 1-, N, the molar ratio of 2-trimethylammonium-1-allylamine and organic bases is 0.5-1:1.0-2:1.0-2.5:1.0-2.5, is specially 0.7:1.4:1.5:1.8;
Described method specifically can be following steps:
By compound 2 shown in formula II, 2 '-dipyridyl-6, the chloro-N of 6 '-dioctyl phthalate and 1-, N, 2-trimethylammonium-1-allylamine reacts after 2 hours in 0 ℃ in organic solvent;
Add again organic bases to react after 1 hour in 0 ℃;
Add again the organic solution of the 4-of compound shown in formula III replacement-quinoline-2-ammonia to carry out acid amide condensation reaction 12 hours in room temperature, obtain compound shown in described formula I;
Compound shown in the formula I that the invention described above provides or described salt suppress the application in tumour product in preparation, also belong to protection scope of the present invention.Wherein, described tumour is mammary cancer, cancer of the stomach, cervical cancer, leukemia, liver cancer, lung cancer, colorectal carcinoma or liver cancer.
Concrete, described breast cancer cell is MCF-7 Human Breast Cancer Cells; Described stomach cancer cell behaviour BGC-823 Cells; Described cervical cancer cell is human cervical carcinoma Hela cell; Described leukemia cell is human leukemia HL-60 cell; Described liver cancer cell behaviour HepG-2 cell line; Described lung carcinoma cell behaviour lung cancer A549 cell; Described colon cancer cell is human colon carcinoma HCT-8 cell; Described liver cancer cell is human hepatocellular carcinoma BEL-7402 cell.
Shown in formula I provided by the invention 2,2 '-dipyridyl-6,6 '-diformyl-quinoline-2-sulfonamide derivatives, can experience two step organic synthesis preparations, comprises Mitsunobu Reaction, acid amide condensation etc.This 2,2 '-dipyridyl-6, to various kinds of cell, strain has pervasive efficient inhibiting rate to 6 '-diformyl-quinoline-2-sulfonamide derivatives, to preparing antitumor drug, has great importance.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated, but the present invention is not limited to following examples.Described method is ordinary method if no special instructions.Described starting material all can obtain from open commercial sources if no special instructions.
Formula III compound 4-replacement-quinoline-2-ammonia is all by 2-quinolylamine ketone and corresponding alcohol, to carry out Mitsunobu react to prepare and obtain:
Figure BDA0000404938500000041
Step specific as follows:
Correspondent alcohol or hydramine (5mmol), 2-amino-quinolinone (500mg, 3.1mmol), triphenylphosphine (1.65g, 6.3mmol) are dissolved in the tetrahydrofuran solution of new system (10ml), system is dropped to 0 ℃.Diisopropyl azodiformate (0.9ml, 4.7mmol) is slowly added drop-wise in above-mentioned system under argon shield.Permission system rises to room temperature.Stirring at room is carried out Mitsunobu reaction for 3 days, reacts substantially complete, stopped reaction aftertreatment.Through column chromatography, obtain corresponding product, productive rate is 61-73%.
4-methoxy quinoline-2-ammonia: (productive rate is 67% for white solid, 583mg), 1H NMR (400MHz; DMSO) δ 8.01 (d, J=8.0Hz, 1H), 7.57 (d; J=8.0Hz, 1H), 7.54 (t, J=7.2Hz; 1H), 7.24 (t, J=7.2Hz, 1H); 6.03 (s, 1H), 4.79 (s, br; 2H), 3.87 (s, 3H); 13C NMR (100MHz, CDCl3) δ 162.8,158.6,149.0,130.7,125.9,122.3,122.0,118.0,90.3,57.1; HRMS (ES) calculated for C10H11N2O ([M+H]+) m/z:175.08723, found175.08726.
4-ethoxyquinoline-2-ammonia: (productive rate is 71% for white solid, 667mg), 1H NMR (400MHz, DMSO) δ 8.02 (d; J=8.0Hz, 1H), 7.59 (d, J=8.0Hz, 1H); 7.55 (t, J=7.2Hz, 1H), 7.26 (t, J=7.2Hz; 1H), 6.07 (s, 1H), 4.76 (s; br, 2H), 3.84 (q, J=7.2Hz; 2H), 1.69 (t, J=7.2Hz, 3H); 13C NMR (100MHz, CDCl3) δ 162.8,158.1,148.6,129.8,124.9,121.7,121.0,117.9,89.9,58.0,15.8; HRMS (ES) calculated for C11H13N2O ([M+H]+) m/z:189.10264, found189.10266.
4-propoxy-quinoline-2-ammonia: (productive rate is 73% for white solid, 737mg), 1H NMR (400MHz, DMSO) δ 8.02 (d; J=8.0Hz, 1H), 7.58 (d, J=8.0Hz, 1H); 7.54 (t, J=7.2Hz, 1H), 7.25 (t, J=7.2Hz; 1H), 6.05 (s, 1H), 4.81 (s, br; 2H), 3.90 (t, J=8.0Hz, 2H), 1.58-1.54 (m; 2H), 0.89 (t, J=8.0Hz, 3H); 13C NMR (100MHz, CDCl3) δ 162.7,158.4,148.9,130.2,125.5,122.3,121.9,117.8,90.0,56.8,22.1,10.3; HRMS (ES) calculated for C12H15N2O ([M+H]+) m/z:203.11823, found203.11821.
4-butoxy quinoline-2-ammonia: (productive rate is 61% for white solid, 659mg), 1H NMR (400MHz, DMSO) δ 8.03 (d, J=8.0Hz; 1H), 7.59 (d, J=8.0Hz, 1H), 7.56 (t; J=7.2Hz, 1H), 7.26 (t, J=7.2Hz, 1H); 6.06 (s, 1H), 4.77 (s, br, 2H); 3.88 (t, J=8.0Hz, 2H), 2.03-1.99 (m, 2H); 1.44-1.41 (m, 2H), 0.72 (t, J=8.0Hz, 3H); 13C NMR (100MHz, CDCl3) δ 163.0,158.5,148.7,130.5,125.8,122.2,122.3,117.9,91.3,58.1,26.1,15.6,9.9; HRMS (ES) calculated for C13H17N2O ([M+H]+) m/z:217.13409, found217.13406.
4-(2-N, N dimethylamine base-oxyethyl group) quinoline-2-ammonia: (productive rate is 66% for white solid, 610mg), 1H NMR (400MHz; DMSO) δ 7.98 (d, J=8.0Hz, 1H), 7.58 (d, J=8.0Hz; 1H), 7.53 (t, J=7.2Hz, 1H), 7.21 (t; J=7.2Hz, 1H), 6.02 (s, 1H), 4.82 (s; br, 2H), 4.19 (t, J=5.6Hz, 2H); 2.87 (t, J=5.6Hz, 2H), 2.38 (s, 6H); 13C NMR (100MHz, DMSO) δ 162.7,158.2,148.4,130.2,125.5,122.0,121.9,117.8,90.0,67.0,57.9,46.2; HRMS (ES) calculated for C13H18N3O ([M+H]+) m/z:232.1450, found232.1461.
4-(3-N, N dimethylamine base-oxyethyl group) quinoline-2-ammonia: (productive rate is 71% for white solid, 870mg); 1H NMR (400MHz, DMSO) δ 7.99 (d, J=8.0Hz, 1H); (7.59 d, J=8.0Hz, 1H); (7.54 t, J=7.2Hz, 1H); (7.22 t, J=7.2Hz, 1H); 6.03 (s, 1H), 4.78 (s; br, 2H), 4.21 (t; J=6.8Hz, 2H), 2.93 (t; J=6.8Hz, 2H), 2.40 (s; 6H), 1.80-1.77 (m, 2H); 13C NMR (100MHz, DMSO) δ 162.9,158.5,148.7,130.3,125.7,122.1,121.6,118.8,89.7,67.4,58.2,45.9,21.3; HRMS (ES) calculated for C14H20N3O ([M+H]+) m/z:246.16062, found246.16058.
4-(2-Boc-oxyethyl group) quinoline-2-ammonia: (productive rate is 62% for white solid, 939mg), 1H NMR (400MHz, CDCl3) δ H7.97 (d, J=8.0Hz; 1H), 7.59 (d, J=8.0Hz, 1H), 7.54 (t; J=7.2Hz, 1H), 7.23 (t, J=7.2Hz, 1H); 6.02 (s, 1H), 5.00 (s, br, 1H); 4.69 (s, br, 2H), 4.16 (t, J=5.0Hz; 2H), 3.67 (m, 2H), 1.45 (s, 9H); 13C NMR (100MHz, CDCl3) δ 162.3,158.0,155.9,148.5,130.3,125.7,122.0,121.6,117.5,90.1,79.8,67.5,39.8,28.4; HRMS (ES) calculated for C16H22N3O3 ([M+H]+) m/z:304.1650, found304.1668.
4-(2-N, N dimethylamine base-oxyethyl group) quinoline-2-ammonia: (productive rate is 64% for white solid, 829mg); 1H NMR (400MHz, DMSO) δ 7.98 (d, J=8.0HZ, 1H); 7.59 (d, J=8.0Hz, 1H), 7.55 (t; J=7.2Hz, 1H), 7.22 (t, J=7.2Hz; 1H), 6.04 (s, 1H); (4.86 s, br, 2H); (4.24 t, J=6.8Hz, 2H); (2.91 t, J=6.8Hz, 2H); (2.43 q, J=7.2Hz, 4H); (1.01 t, J=7.2Hz, 6H); 13C NMR (100MHz, DMSO) δ 163.0,158.6,148.8,130.4,125.7,122.4,122.2,117.9,90.4,66.8,58.2,46.4,19.6; HRMS (ES) calculated for C15H22N3O ([M+H]+) m/z:260.17628, found260.17625.
4-(2-pyrroles-oxyethyl group)-quinoline-2-ammonia: (white solid, 874mg, 68%), 1H NMR (400MHz, CD3OD) δ H8.00 (d; J=8.0Hz, 1H), 7.53 (d, J=8.0Hz, 1H); 7.48 (t, J=8.0Hz, 1H), 7.20 (t, J=8.0Hz; 1H), 6.28 (s, 1H), 4.33 (t, J=6.8Hz; 2H), 3.10 (t, J=6.8Hz, 2H); 2.81-2.73 (m, 4H), 1.94-1.82 (m, 4H); 13C NMR (100MHz, CD3OD) δ C163.0,160.3,148.0,130.2,124.1,121.9,121.6,110.8,90.4,67.6,54.8,54.6,23.3; HRMS (ES) calculated for C15H20N3O ([M+H]+) m/z:258.1606, found258.1611.
Embodiment 1
Figure BDA0000404938500000061
By compound 2 shown in formula II, 2'-dipyridyl-6,6'-dioctyl phthalate (171mg, 0.7mmol) and the chloro-N of 1-, N, 2-trimethylammonium-1-allylamine (200ul, 1.50mmol) is dissolved in methylene dichloride, and system is placed in to ice-water bath temperature, stirs and reacts after 2 hours;
Add again triethylamine (250ul, 1.8mmol) to above-mentioned system, continue to stir and react after 1 hour at ice-water bath temperature;
The dichloromethane solution of the 4-methoxy quinoline-2-ammonia of compound shown in formula III (244mg, 1.4mmol) (5ml) is slowly added drop-wise in system, the reaction of reaction system stirring at room is spent the night again.After reacting completely, stop.Revolve desolventizing, acetonitrile recrystallization obtains white powder (228mg, 0.41mmol), productive rate 59%.
The structural confirmation result of this product is as follows:
1H?NMR(400MHz,DMSO)δ12.13(s,br,2H),8.94(d,J=8.4Hz,2H),8.32(s,2H),8.15(s,2H),7.95(s,4H),7.78(d,J=8.4Hz,2H),7.81(t,J=7.6Hz,2H),7.57(t,J=7.6Hz,2H),4.38(s,6H);
13C?NMR(100MHz,CDCl3)δ168.2,167.2,163.7,151.0,149.7,139.5,134.4,132.7,127.6,125.8,123.5,121.3,118.8,113.9,98.4,58.3;
HRMS(ES)calculated?for?C32H25N6O4([M+H]+)m/z:557.13973,found557.13970.
As from the foregoing, this product structure is correct, is the target compound of ownership formula I, and wherein, R is methoxyl group.
Embodiment 2
Figure BDA0000404938500000071
By compound 2,2'-dipyridyl-3,3'-dioctyl phthalate (171mg, 0.7mmol) and the chloro-N of 1-, N, 2-trimethylammonium-1-allylamine (200ul, 1.50mmol) is dissolved in methylene dichloride, and system is placed in to ice-water bath temperature, stirs and reacts after 2 hours;
Add again organic bases triethylamine (250ul, 1.8mmol) slowly to drop in above-mentioned system, continue to stir and react after 1 hour at ice-water bath temperature;
The dichloromethane solution of 4-ethoxyquinoline-2-ammonia (263mg, 1.4mmol) (5ml) is slowly added drop-wise in system, the reaction of reaction system stirring at room is spent the night again.After reacting completely, stop.Revolve desolventizing, acetonitrile recrystallization obtains white powder (253mg, 0.43mmol), productive rate 62%.
The structural confirmation result of this product is as follows:
1H?NMR(400MHz,DMSO)δ11.89(s,2H),8.86(d,J=8.4Hz,2H),8.33(s,2H),8.19(s,2H),7.98(s,4H),7.82(d,J=8.4Hz,2H),7.79(t,J=7.6Hz,2H),7.58(t,J=7.6Hz,2H),4.52(q,J=7.2Hz,4H),2.23(t,J=7.2Hz,6H);
13C?NMR(100MHz,CDCl3)δ168.6,167.4,163.1,151.9,149.2,139.0,134.1,132.3,127.2,125.4,123.1,121.34,118.2,113.3,98.7,67.3,29.3;
HRMS(ES)calculated?for?C34H29N6O4([M+H]+)m/z:585.22511,found585.22509.
As from the foregoing, this product structure is correct, is the target compound of ownership formula I, and wherein, R is oxyethyl group.
Embodiment 3
Figure BDA0000404938500000081
By compound 2,2'-dipyridyl-3,3'-dioctyl phthalate (171mg, 0.7mmol) and the chloro-N of 1-, N, 2-trimethylammonium-1-allylamine (200ul, 1.50mmol) is dissolved in methylene dichloride, and system is placed in to ice-water bath temperature, stirs and reacts after 2 hours;
Again triethylamine (250ul, 1.8mmol) is slowly dropped in above-mentioned system, continue to stir and react after 1 hour at ice-water bath temperature;
The dichloromethane solution of 4-propoxy-quinoline-2-ammonia (284mg, 1.4mmol) (5ml) is slowly added drop-wise in system, the reaction of reaction system stirring at room is spent the night again.After reacting completely, stop.Revolve desolventizing, acetonitrile recrystallization obtains white powder (227mg, 0.37mmol), productive rate 53%.
The structural confirmation result of this product is as follows:
1H?NMR(400MHz,DMSO)δ12.01(s,br,2H),8.87(d,J=8.4Hz,2H),8.35(s,2H),8.13(s,2H),7.92(s,4H),7.75(d,J=8.4Hz,2H),7.68(t,J=7.6Hz,2H),7.54(t,J=7.6Hz,2H),4.56(t,J=7.2Hz,4H),2.26-2.21(m,4H),0.98(t,J=6.4Hz,6H);
13C?NMR(100MHz,CDCl3)δ168.8,167.5,163.3,151.6,149.9,139.7,134.2,133.1,128.0,126.0,123.9,121.7,119.2,114.1,98.8,67.7,33.2,19.5;
HRMS(ES)calculated?for?C36H33N6O4([M+H]+)m/z:613.25633,found613.25634.
As from the foregoing, this product structure is correct, is the target compound of ownership formula I, and wherein, R is propoxy-.
Embodiment 4
Figure BDA0000404938500000091
By compound 2,2'-dipyridyl-3,3'-dioctyl phthalate (171mg, 0.7mmol) and the chloro-N of 1-, N, 2-trimethylammonium-1-allylamine (200ul, 1.50mmol) is dissolved in methylene dichloride, and system is placed in to ice-water bath temperature, stirs and reacts after 2 hours;
Again triethylamine (250ul, 1.8mmol) is slowly dropped in above-mentioned system, continue to stir and react after 1 hour at ice-water bath temperature;
The dichloromethane solution of 4-butoxy quinoline-2-ammonia (302mg, 1.4mmol) (5ml) is slowly added drop-wise in system, the reaction of reaction system stirring at room is spent the night again.After reacting completely, stop.Revolve desolventizing, acetonitrile recrystallization obtains white powder (318mg, 0.50mmol), productive rate 71%.
The structural confirmation result of this product is as follows:
1H?NMR(400MHz,DMSO)δ12.04(s,br,2H),8.89(d,J=8.4Hz,2H),8.31(s,2H),8.18(s,2H),7.98(s,4H),7.82(d,J=8.4Hz,2H),7.84(t,J=7.6Hz,2H),7.61(t,J=7.6Hz,2H),4.56(t,J=6.0Hz,4H),2.36-2.33(m,4H),1.53-1.50(m,4H),0.84(t,J=6.4Hz,6H);
13C?NMR(100MHz,CDCl3)δ169.0,167.9,164.5,151.7,150.4,140.2,135.1,133.2,128.3,126.4,124.2,122.0,119.5,114.6,99.1,68.0,36.4,21.3,13.6;
HRMS(ES)calculated?for?C38H37N6O4([M+H]+)m/z:641.28763,found641.28766.
As from the foregoing, this product structure is correct, is the target compound of ownership formula I, and wherein, R is butoxy.
Embodiment 5
By compound 2,2'-dipyridyl-3,3'-dioctyl phthalate (171mg, 0.7mmol) and the chloro-N of 1-, N, 2-trimethylammonium-1-allylamine (200ul, 1.50mmol) is dissolved in methylene dichloride, and system is placed in to ice-water bath temperature, stirs and reacts after 2 hours;
Again triethylamine (250ul, 1.8mmol) is slowly dropped in above-mentioned system, continue to stir and react after 1 hour at ice-water bath temperature;
The dichloromethane solution (5ml) of 4-(2-N, N dimethylamine base-oxyethyl group) quinoline-2-ammonia (323mg, 1.4mmol) is slowly added drop-wise in system, the reaction of reaction system stirring at room is spent the night again.After reacting completely, stop.Revolve desolventizing, acetonitrile recrystallization obtains white powder (277mg, 0.41mmol), productive rate 59%.
The structural confirmation result of this product is as follows:
1H?NMR(400MHz,DMSO)δ12.09(s,2H),8.91(d,J=8.4Hz,2H),8.35(s,2H),8.14(s,2H),7.95(s,4H),7.80(d,J=8.4Hz,2H),7.81(t,J=7.6Hz,2H),7.62(t,J=7.6Hz,2H),4.57(t,J=5.6Hz,4H),3.39(t,J=5.6Hz,4H),2.98(s,12H);
13C?NMR(100MHz,CDCl3)δ169.7,168.7,165.2,152.5,150.5,141.1,135.9,134.5,129.1,127.3,124.9,122.8,120.1,115.2,99.4,68.8,47.9,40.0;
HRMS(ES)calculated?for?C38H39N8O4([M+H]+)m/z:671.3094,found671.3103.
As from the foregoing, this product structure is correct, is the target compound of ownership formula I, and wherein, R is-O (CH 2) 2n (CH 3) 2.
Embodiment 6
Figure BDA0000404938500000101
By compound 2,2'-dipyridyl-3,3'-dioctyl phthalate (171mg, 0.7mmol) and the chloro-N of 1-, N, 2-trimethylammonium-1-allylamine (200ul, 1.50mmol) is dissolved in methylene dichloride, and system is placed in to ice-water bath temperature, stirs and reacts after 2 hours;
Again triethylamine (250ul, 1.8mmol) is slowly dropped in above-mentioned system, continue to stir and react after 1 hour at ice-water bath temperature;
The dichloromethane solution (5ml) of 4-(3-N, N dimethylamine base-oxyethyl group) quinoline-2-ammonia (343mg, 1.4mmol) is slowly added drop-wise in system, the reaction of reaction system stirring at room is spent the night again.After reacting completely, stop.Revolve desolventizing, acetonitrile recrystallization obtains white powder (313mg, 0.45mmol), productive rate 64%.
The structural confirmation result of this product is as follows:
1H?NMR(400MHz,DMSO)δ12.18(s,2H),8.90(d,J=8.4Hz,2H),8.29(s,2H),8.12(s,2H),7.92(s,4H),7.81(d,J=8.4Hz,2H),7.83(t,J=7.6Hz,2H),7.59(t,J=7.6Hz,2H),4.55(t,J=6.8Hz,4H),3.58(t,J=6.8Hz,4H),3.01(s,12H),2.01-1.99(m,4H);
13C?NMR(100MHz,CDCl3)δ170.1,169.2,165.7,153.0,151.7,141.5,136.4,134.7,129.6,126.8,124.5,122.3,119.8,114.9,99.4,69.7,59.1,44.4,19.3;
HRMS(ES)calculated?for?C40H43N8O4([M+H]+)m/z:699.34073,found699.34081.
As from the foregoing, this product structure is correct, is the target compound of ownership formula I, and wherein, R is-O (CH 2) 3n (CH 3) 2.
Embodiment 7
Figure BDA0000404938500000111
By compound 2,2'-dipyridyl-3,3'-dioctyl phthalate (171mg, 0.7mmol) and the chloro-N of 1-, N, 2-trimethylammonium-1-allylamine (200ul, 1.50mmol) is dissolved in methylene dichloride, and system is placed in to ice-water bath temperature, stirs and reacts after 2 hours;
Again triethylamine (250ul, 1.8mmol) is slowly dropped in above-mentioned system, continue to stir and react after 1 hour at ice-water bath temperature;
The dichloromethane solution of 4-(2-pyrroles-oxyethyl group) quinoline-2-ammonia (360mg, 1.4mmol) (5ml) is slowly added drop-wise in system, the reaction of reaction system stirring at room is spent the night again.After reacting completely, stop.Revolve desolventizing, acetonitrile recrystallization obtains white powder (334mg, 0.46mmol), productive rate 66%.
The structural confirmation result of this product is as follows:
1H?NMR(400MHz,DMSO)δ12.17(s,2H),8.93(d,J=8.4Hz,2H),8.41(s,2H),8.19(s,2H),8.05(s,4H),7.88(d,J=8.4Hz,2H),7.91(t,J=7.6Hz,2H),7.67(t,J=7.6Hz,2H),4.62(t,J=6.8Hz,4H),3.46(t,J=6.8Hz,4H),3.08-2.95(m,8H),1.99-1.96(m,8H);13C?NMR(100MHz,CDCl3)δ170.1,169.1,165.6,152.9,151.6,141.4,136.3,134.6,129.5,127.7,125.4,123.2,120.7,115.8,100.0,69.1,58.4,57.9,21.8;HRMS(ES)calculated?for?C42H43N8O4([M+H]+)m/z:723.34073,found723.34076.
As from the foregoing, this product structure is correct, is the target compound of ownership formula I, and wherein, R is-O (CH 2) 2n (CH 2) 4.
Embodiment 8
By compound 2,2'-dipyridyl-3,3'-dioctyl phthalate (171mg, 0.7mmol) and the chloro-N of 1-, N, 2-trimethylammonium-1-allylamine (200ul, 1.50mmol) is dissolved in methylene dichloride, and system is placed in to ice-water bath temperature, stirs and reacts after 2 hours;
Again triethylamine (250ul, 1.8mmol) is slowly dropped in above-mentioned system, continue to stir and react after 1 hour at ice-water bath temperature;
The dichloromethane solution (5ml) of 4-(2-N, N dimethylamine base-oxyethyl group) quinoline-2-ammonia (363mg, 1.4mmol) is slowly added drop-wise in system, the reaction of reaction system stirring at room is spent the night again.After reacting completely, stop.Revolve desolventizing, acetonitrile recrystallization obtains white powder (305mg, 0.42mmol), productive rate 60%.
The structural confirmation result of this product is as follows:
1H?NMR(400MHz,DMSO)δ12.17(s,2H),8.98(d,J=8.4Hz,2H),8.38(s,2H),8.21(s,2H),8.03(s,4H),7.96(d,J=8.4Hz,2H),7.88(t,J=7.6Hz,2H),7.65(t,J=7.6Hz,2H),4.56(t,J=7.2Hz,4H),3.22(t,J=7.2Hz,4H),2.58(q,J=7.6Hz,8H),1.12(t,J=7.6Hz,12H);13C?NMR(100MHz,CDCl3)δ171.1,170.0,165.5,152.8,151.5,141.3,136.2,132.7,134.5,129.3,127.6,125.3,123.1,120.6,113.9,100.2,69.1,61.4,47.9,20.1;HRMS(ES)calculated?for?C42H47N8O4([M+H]+)m/z:727.37203,found727.37201.
As from the foregoing, this product structure is correct, is the target compound of ownership formula I, and wherein, R is-O (CH 2) 2n (CH 2cH 3) 2.
Embodiment 9
By compound 2,2'-dipyridyl-3,3'-dioctyl phthalate (171mg, 0.7mmol) and the chloro-N of 1-, N, 2-trimethylammonium-1-allylamine (200ul, 1.50mmol) is dissolved in methylene dichloride, and system is placed in to ice-water bath temperature, stirs and reacts after 2 hours;
Again triethylamine (250ul, 1.8mmol) is slowly dropped in above-mentioned system, continue at ice-water bath temperature stirring reaction after 1 hour;
The dichloromethane solution (5ml) of 4-(2-Boc-oxyethyl group) quinoline-2-ammonia (424mg, 1.4mmol) is slowly added drop-wise in system, the reaction of reaction system stirring at room is spent the night again.After reacting completely, stop.Revolve desolventizing, acetonitrile recrystallization obtains white powder (359mg, 0.44mmol), productive rate 63%.
The structural confirmation result of this product is as follows:
1H?NMR(400MHz,DMSO)δ12.16(s,2H),8.87(d,J=8.4Hz,2H),8.43(s,2H),8.22(s,2H),8.05(s,4H),7.99(t,J=7.6Hz,2H),7.84(t,J=7.6Hz,2H),7.75(t,J=7.6Hz,2H),5.13(s,br,2H),4.42(t,J=6.4Hz,4H),3.74-3.70(m,4H),1.56(s,18H);13C?NMR(100MHz,CDCl3)δ171.2,169.9,166.7,154.0,152.7,142.5,137.4,135.7,130.6,128.8,126.5,124.3,121.8,116.9,101.4,68.7,47.2,43.4,19.3;HRMS(ES)calculated?for?C44H47N8O8([M+H]+)m/z:815.35169,found815.35168.
As from the foregoing, this product structure is correct, is the target compound of ownership formula I, and wherein, R is-O (CH 2) 2nH[(COO (CH 3) 3)].
Embodiment 10
Figure BDA0000404938500000131
Compound (100mg, 0.15mmol) shown in the formula I that embodiment 5 is obtained is dissolved in 2ml methylene dichloride/1ml trifluoroacetic acid, stirring at room 1 hour.Stopped reaction, revolves desolventizing, obtains the salt (135mg, 0.15mmol, 100%) of trifluoroacetic acid.
The structural confirmation data of this product are as follows:
Anal.Calcd?for?C 42H 40F 6N 8O 8：C,56.12;H,4.49;N,12.47.Found:C,56.23;H.4.43;N,12.73.
As from the foregoing, this product structure is correct.
2,2 '-dipyridyl-6, the extracorporeal anti-tumor medicament screening experiment of 6 '-diformyl--quinoline-2-sulfonamide derivatives is to take tumour cell as research object, by MTT colorimetric determination sample anti tumor activity in vitro.MTT colorimetry can detect the survival and growth of tumour cell, its detection principle is that the succinodehydrogenase in viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet Jie Jing formazan (Formazan), and be deposited in cell, and dead cell is without this function.Dimethyl sulfoxide (DMSO) (DMSO) can dissolved cell in formazan, with enzyme-linked immunosorbent assay instrument, at 570nm wavelength place, measure its light absorption value, the survival and growth situation of the reacting condition tumour cell by light absorption value.
Specific experiment step:
Tumour cell is in 37 ℃, 5%CO 2and under saturated humidity environment, be incubated at containing in 10% foetal calf serum 1640 substratum, when being logarithmic growth, cell goes down to posterity, adjust cell concn to 1 * 104/ml, inoculate 200 μ l in 96 well culture plates.Treat cell attachment growth 24h, add and detect sample and positive control drug 5-Fu10 μ l, final concentration is 5ug/ml, and control group adds equal-volume physiological saline simultaneously, jointly hatches 72h with cell.Hatch after end, careful suction abandoned cell conditioned medium, and adding final concentration is 0.5mg/ml MTT solution, continues to cultivate 4h.Supernatant is abandoned in suction, and every hole adds 150 μ l DMSO, puts low-speed oscillation 10min on shaking table, and crystallisate is fully dissolved, and measures light absorption value in microplate reader 570nm place.
Select primary dcreening operation inhibiting rate to be greater than 50% compound and carry out multiple sieve, the final concentration that compound to be sieved, positive drug and cell are hatched is jointly set as 25,5,1,0.2ug/ml, and additive method is the same, after measurement light absorption value, calculates IC50.
Method of calculation:
Sample inhibiting rate=[(contrast-blank)-(sample-blank)]/(contrast-blank) * 100%
The pharmacological results of table 1, embodiment 1:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 50.98 13.62
BEL-7402 60.42 14.20
A549 65.63 9.98
MCF-7 53.24 10.36
BGC-823 70.09 9.16
Hela 61.05 11.32
HL-60 58.07 16.51
HepG-2 60.72 8.65
Note: a, positive control medicine is 5 FU 5 fluorouracil.
The pharmacological results of table 2, embodiment 2:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 66.04 10.36
BEL-7402 54.02 11.69
A549 67.0 13.01
MCF-7 59.75 9.65
BGC-823 64.17 8.23
Hela 72.36 12.89
HL-60 60.43 13.11
HepG-2 52.05 14.42
Note: a, positive control medicine is 5 FU 5 fluorouracil
The pharmacological results of table 3, embodiment 3:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 60.19 14.16
BEL-7402 54.61 15.02
A549 19.52 ---
MCF-7 62.58 11.27
BGC-823 67.82 13.24
Hela 71.54 14.03
HL-60 60.11 9.69
HepG-2 63.14 8.83
Note: a, positive control medicine is 5 FU 5 fluorouracil.
The pharmacological results of table 4, embodiment 4:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 32.01 ---
BEL-7402 10.56 ---
A549 68.51 10.17
MCF-7 53.26 9.78
BGC-823 29.86 ---
Hela 76.32 8.59
HL-60 64.15 10.53
HepG-2 70.20 13.45
The pharmacological results of table 5, embodiment 5:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 75.33 11.18
BEL-7402 18.63 ---
A549 79.58 7.61
MCF-7 59.98 6.43
BGC-823 86.35 7.57
Hela 83.14 9.56
HL-60 91.23 6.52
HepG-2 85.66 9.82
The pharmacological results of table 6, embodiment 6:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 41.02 ---
BEL-7402 56.24 10.33
A549 90.02 6.54
MCF-7 70.16 5.46
BGC-823 30.83 ---
Hela 88.59 8.65
HL-60 91.21 5.31
HepG-2 79.08 8.74
The pharmacological results of table 7, embodiment 7:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 80.19 11.48
BEL-7402 14.61 ---
A549 89.52 6.39
MCF-7 63.05 5.32
BGC-823 87.82 8.31
Hela 81.54 8.96
HL-60 90.11 6.46
HepG-2 83.14 10.12
Note: a, positive control medicine is 5 FU 5 fluorouracil
The pharmacological results of table 8, embodiment 8:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 93.26 10.43
BEL-7402 84.32 8.16
A549 90.56 4.64
MCF-7 92.85 5.69
BGC-823 91.95 7.15
Hela 77.26 6.19
HL-60 79.03 8.38
HepG-2 84.71 9.31
Note: a, positive control medicine is 5 FU 5 fluorouracil
The pharmacological results of table 9, embodiment 9:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 82.21 8.03
BEL-7402 77.26 7.69
A549 69.36 7.24
MCF-7 81.20 10.01
BGC-823 79.56 7.88
Hela 74.35 8.27
HL-60 78.61 9.16
HepG-2 68.49 9.87
The pharmacological results of table 10, embodiment 10:
Cell strain Cell inhibitory rate (%) IC50(ug/ml) a
HCT-8 96.26 6.32
BEL-7402 95.36 5.45
A549 96.61 5.59
MCF-7 92.81 6.16
BGC-823 94.54 7.11
Hela 95.23 5.75
HL-60 88.17 6.43
HepG-2 89.95 5.83
Positive control drug 5 FU 5 fluorouracil:
Cell strain Cell inhibitory rate (%) IC50（ug/ml）
HCT-8 55.04 11.36
BEL-7402 69.67 10.84
A549 65.60 9.10
MCF-7 66.88 12.34
BGC-823 66.12 9.37
Hela 55.14 9.60
HL-60 81.63 11.51
HepG-2 55.31 10.48
The pharmacological results is summed up:
Take 5 FU 5 fluorouracil as contrast, evaluated the anti-tumor activity of embodiment 1-10.Screened cell strain human breast carcinoma (MCF-7), people's cancer of the stomach (BGC-823), human cervical carcinoma (Hela), human leukemia (HL-60), people's liver cancer (HepG-2), people's lung cancer (A549), human colon carcinoma (HCT-8), people's liver cancer (BEL-7402), result is respectively in Table 1-10.The anti-tumor activity that embodiment 1-10 all can do very well, and to various kinds of cell, strain has strong universality.

Claims (9)

1. compound shown in formula I,
Figure FDA0000404938490000011
Formula I
In described formula I, R is-O (CH 2) mCH 3,-O (CH 2) nN (CH 3) 2,-O (CH 2) 2n (CH 2) 4,-O (CH 2) 2n (CH 2cH 3) 2or-O (CH 2) 2nH[(COO (CH 3) 3)];
M is the integer of 1-4;
N is 2 or 3.
2. compound according to claim 1, is characterized in that: compound shown in described formula I is any one in following compound
Figure FDA0000404938490000012
Figure FDA0000404938490000021
3. the acceptable salt pharmaceutically of compound shown in formula I described in claim 1 or 2.
4. salt according to claim 3, is characterized in that: described salt is inorganic acid salt or organic acid salt;
Mineral acid in described inorganic acid salt is hydrochloric acid, sulfuric acid or phosphoric acid;
Organic acid in described organic acid salt is acetic acid, trifluoroacetic acid, propanedioic acid, citric acid or tosic acid.
5. prepare a method for compound shown in formula I described in claim 1 or 2, comprise the steps:
By compound 2 shown in formula II, 2 '-dipyridyl-6, the chloro-N of 6 '-dioctyl phthalate and 1-, N, 2-trimethylammonium-1-allylamine reacts after 1-3 hours in-15-5 ℃ in organic solvent;
Add again organic bases to react after 0.5-1.5 hours in-15-5 ℃;
Add again the organic solution of the 4-of compound shown in formula III replacement-quinoline-2-ammonia to carry out acid amide condensation reaction 12-24 hours in room temperature, obtain compound shown in described formula I;
Figure FDA0000404938490000031
Formula II
Figure FDA0000404938490000032
Formula III
In described formula III, R is-O (CH 2) mCH 3,-O (CH 2) nN (CH 3) 2,-O (CH 2) 2n (CH 2) 4,-O (CH 2) 2n (CH 2cH 3) 2or-O (CH 2) 2nH[(COO (CH 3) 3)];
M is the integer of 1-4;
N is 2 or 3.
6. method according to claim 5, is characterized in that: described organic bases is selected from least one in triethylamine, pyridine and piperidines;
Described organic solvent is selected from least one in methylene dichloride, trichloromethane and 1,2-ethylene dichloride;
In the organic solution of the replacement-quinoline-2-of compound 4-shown in described formula III ammonia, solvent is selected from least one in methylene dichloride, trichloromethane and 1,2-ethylene dichloride.
7. according to the method described in claim 5 or 6, it is characterized in that: in described method, compound shown in compound shown in formula II, formula III, the chloro-N of 1-, N, the molar ratio of 2-trimethylammonium-1-allylamine and organic bases is 0.5-1:1.0-2:1.0-2.5:1.0-2.5, is specially 0.7:1.4:1.5:1.8.
8. described in claim 1 or 2, described in compound shown in formula I or claim 3 or 4, salt suppresses the application in tumour product in preparation.
9. application according to claim 8, is characterized in that: described tumour is mammary cancer, cancer of the stomach, cervical cancer, leukemia, liver cancer, lung cancer, colorectal carcinoma or liver cancer.
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