CN101362719B - Chinolines derivates and composition containing thereof - Google Patents

Chinolines derivates and composition containing thereof Download PDF

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CN101362719B
CN101362719B CN2007101199826A CN200710119982A CN101362719B CN 101362719 B CN101362719 B CN 101362719B CN 2007101199826 A CN2007101199826 A CN 2007101199826A CN 200710119982 A CN200710119982 A CN 200710119982A CN 101362719 B CN101362719 B CN 101362719B
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quinoline
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quinoline derivatives
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CN101362719A (en
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何兰
常河西
周强
潘宣
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Beijing Normal University
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Beijing Normal University
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Abstract

The invention relates to a series of quinoline derivatives and compounds containing the quinoline derivatives. Activity test result shows that the quinoline derivatives show relatively high anti-tumor activity to intestinal cancer cells (HCT-8), liver cancer cells (Bel-7402), gastric cancer cells (BGC-823), lung cancer cells (A549) and ovarian cancer cells (A2780). The quinoline derivatives and the compounds can be used for preparing medicines for countering (curing) colon, liver, stomach, lung and ovarian cancers.

Description

Quinoline derivatives and the compsn that comprises it
Technical field
The present invention relates to a series of quinoline derivatives, and the compsn that has comprised these quinoline derivatives.
Background technology
Antitumor drug commonly used clinically at present mainly contains cytotoxic drug and target therapeutic agent.Compare with traditional cell toxicity medicament, target therapeutic agent does not only have dose-dependently, and selectivity is strong, is difficult for producing resistance, and can obviously improves patient's quality of life.EGF-R ELISA (epidermal growth factor receptor EGFR) suppressor factor is as one of antineoplastic target medicine; Through selective exclusion EGFR signal-transduction system, realized in different entities knurl (nonsmall-cell lung cancer, mammary cancer etc.) patient inhibition to the EGFR over-expresses.In recent years; Designed the EGFR tyrosine kinase inhibitor of a large amount of safe, efficient, highly selectivies; Alternative blocking EGFR signal-transduction system; Clinical test results shows that its bioavailability is high, selectivity is strong, better tolerance, untoward reaction are slight, has notable antitumor activity, for EGFR dependent tumors or partial dependency property tumor treatment provide hope.
Based on EGFR being had the structure that suppresses active compound, can the EGFR suppressor factor roughly be divided into three types of 3-cyano quinolines series derivates, quinazoline series derivates and quinoline series derivates to what be used for that clinical EGFR inhibitor medicaments and document report.Above-mentioned three compounds compare, and the quinoline series derivates has characteristics such as structure is simple relatively, raw material is easy to get, cost is low, experiment condition is gentle, convenient post-treatment, high, the suitable industriallization of productive rate.Quinoline derivatives has tangible CDCC, and structure and anti-tumor activity have directly related.
Summary of the invention
The objective of the invention is to obtain better anticancer effect,, therefrom filter out the compound that effectively has anti-tumor activity through changing the substituting group on aniline analogue and 6,7.
To achieve these goals, the present invention on basis to the relationship analysis of the structure of EGFR suppressor factor in the past and anti-tumor activity, design and complete synthesis a series of quinoline derivatives.
The invention discloses this serial quinoline derivatives and preparation method thereof, and the compsn that adopts this quinoline derivatives, above-mentioned quinoline derivatives and compsn can be used for preparation antagonism (treatment) colorectal carcinoma, liver cancer, cancer of the stomach, the medicine of lung cancer and ovarian cancer.
Quinoline derivatives provided by the invention, and the compsn that has comprised these quinoline derivatives comprise the compound of formula I:
Figure S071B9982620070831D000021
Formula I
Perhaps salt comprises pharmaceutically acceptable or non-pharmacy acceptable salt, prodrug.
Wherein, R1 is Cl, methyl or ethynyl;
R2 is H or F;
R3 is H, CH 3, CH 2CH 2OCH 3, or the morpholino propyl group
Figure S071B9982620070831D000022
Preferably, R3 is H, and R2 is H, and R1 is chlorine (4d), methyl (4c), or ethynyl (4b).
Preferably, R3 is H, and R2 is a fluorine, and R1 is chlorine (4a).
Preferably, R3 is CH 3, R2 is H, R1 is chlorine (2d), methyl (2c), or ethynyl (2b).
Preferably, R3 is CH 3, R2 is a fluorine, R1 is chlorine (2a).
Preferably, R3 is CH 2CH 2OCH 3, R2 is H, R1 is chlorine (6d), methyl (6c), or ethynyl (6b).
Preferably, R3 is CH 2CH 2OCH 3, R2 is a fluorine, R1 is chlorine (6a).
Preferably, R3 is the morpholino propyl group, and R2 is H, and R1 is chlorine (8c), methyl (8b), or ethynyl.
Preferably, R3 is the morpholino propyl group, and R2 is a fluorine, and R1 is chlorine (8a).
Quinoline derivatives provided by the invention, and the compsn that has comprised these quinoline derivatives comprise the compound of formula II:
Figure S071B9982620070831D000023
Formula II
Perhaps salt comprises pharmaceutically acceptable or non-pharmacy acceptable salt, prodrug.
Wherein, R4 is H or F; R5 is Cl;
R6 is H, CH 3, CH 2CH 2OCH 3, or the morpholino propyl group
Figure S071B9982620070831D000024
Preferably, R6 is H, and R5 is a chlorine, and R4 is H (5a) or F.
Preferably, R6 is CH 3, R5 is a chlorine, R4 is H (3b) or F (3a).
Preferably, R6 is CH 2CH 2OCH 3, R5 is a chlorine, R4 is H or F (7a).
Preferably, R6 is the morpholino propyl group, and R5 is a chlorine, and R4 is H or F (9a).
The invention also discloses the midbody compound 1h and the 1i of the above-mentioned quinoline derivatives of preparation, its chemical formula is following:
Determination of activity is the result show; Quinoline derivatives provided by the invention is to colon cancer cell (HCT-8); Liver cancer cell (Bel-7402), gastric carcinoma cells (BGC-823), lung carcinoma cell (A549) and Proliferation of Human Ovarian Cell (A2780) all show higher anti-tumor activity.So this serial quinoline derivatives and the compsn that adopts this quinoline derivatives can be used for preparation antagonism (treatment) colorectal carcinoma, liver cancer, cancer of the stomach, the medicine of lung cancer and ovarian cancer.
Description of drawings
Fig. 1 is the synoptic diagram of synthetic route one of the present invention;
Fig. 2 is the synoptic diagram of synthetic route two of the present invention;
Fig. 3 is the synoptic diagram of synthetic route three of the present invention;
Fig. 4 is the synoptic diagram of synthetic route four of the present invention;
Fig. 5 is the synoptic diagram of synthetic route five of the present invention;
Fig. 6 is the nmr spectrum of compound 1h;
Fig. 7 is the nmr spectrum of compound 1i;
Fig. 8 is the infrared spectrum of compound 2a;
Fig. 9 is the nmr spectrum of compound 2a;
Figure 10 is the carbon-13 nmr spectra of compound 2a;
Figure 11 is the mass spectrogram of compound 2a.
Embodiment
1, reagent and instrument
Silica gel: column chromatography is with 200-300 order silica gel, thin layer plate silica gel for chromatography GF 254, all available from Chinese Haiyang Chemical Plant, Qingdao.
Solvent: analyze pure, available from the Beijing Chemical Plant, dry according to a conventional method or heavily steam the back and use.
Developer: iodine developer.
2, instrument
Ir spectra: AVATAR-360FT-IR IR
Nucleus magnetic resonance: Avance Brucker-500MHz ( 1H NMR) or Avance Brucker-125MHz ( 13C NMR) resonance appearance (TMS marks in doing, and chemical shift is represented with ppm)
Fusing point: the X-4 of Beijing Ketai Co. Ltd. micro melting point apparatus, temperature is not proofreaied and correct
Mass spectrum: Agilent HPLC MSD
Ultimate analysis: Perkin-Elmer240-c elemental analyser
Embodiment 1,1,2-dimethoxy benzene (compound 1a) synthetic
As shown in Figure 1, be lower than 30 ℃, under the vigorous stirring 30% sodium hydroxide solution 126.8g slowly is added drop-wise in the reaction flask that contains pyrocatechol 20g (181.8mmol), after dropwising, the water-bath controlled temperature is slowly dripping (CH below 30 ℃ 3) 2SO 439.6mL (272.7mmol), reflux.The reaction back that finishes adds suitable quantity of water, extracts with ETHYLE ACETATE-aqueous systems, gets organic layer, uses anhydrous magnesium sulfate drying, and (sherwood oil: ETHYLE ACETATE=50:1) obtains colourless liquid compound 1a (C to purification by silica gel column chromatography after the filtering and concentrating 8H 10O 2, FW138.07) 24.05g, productive rate 95.9%.
Embodiment 2,3,4-dimethoxy-acetophenone (compound 1b) synthetic
Figure S071B9982620070831D000042
As shown in Figure 1, with ZnCl 26.24g (45.9mmol) join in the solution of compound 1a4.22g (30.6mmol) and diacetyl oxide 8.7mL (91.8mmol), stirring at room 2h adds suitable quantity of water, K after reaction finishes 2CO 3Neutralization, ETHYLE ACETATE-aqueous systems extraction is used the anhydrous magnesium sulfate drying organic layer, filtering and concentrating, purification by silica gel column chromatography (sherwood oil: ETHYLE ACETATE=8:1), obtain little yellow solid compound 1b (C 10H 12O 3, FW180.08) 5.0g, m.p.49-50 ℃, productive rate 90.2%.
Embodiment 3,2-nitro-4,5-dimethoxy-acetophenone (compound 1c) synthetic
Figure S071B9982620070831D000043
As shown in Figure 1, with compound 1b1.5g (8.3mmol), join within the 1h in the reaction flask that contains the 9mL concentrated nitric acid, keep internal reaction temperature between 18-22 ℃ under stirring.After dropwising, restir 1h pours in the 120mL water.Collected product after the cooling and obtained compound 1c (C with ethyl alcohol recrystallization 10H 11NO 5, FW225.06) 0.93g, m.p.135-136 ℃, productive rate 50%.
Embodiment 4,2-are amino-4,5-dimethoxy-acetophenone (compound 1d) synthetic
Figure S071B9982620070831D000051
As shown in Figure 1, in two-mouth bottle, add compound 1c1.263g (5.6mmol), Fe powder 1.88g (33.5mmol), AcOH24mL, EtOH24mL, H 2O12.2mL, concentrated hydrochloric acid 1mL, reflux, underpressure distillation concentrated after reaction finished, and used K 2CO 3The solution neutralization, ethyl acetate extraction, anhydrous magnesium sulfate drying organic layer, rapid column chromatography (sherwood oil: ETHYLE ACETATE=3:1), finally obtain yellow solid compound 1d (C 10H 13NO 3, FW195.09) 0.904g, m.p.108-109 ℃, productive rate 82.2%.
IR(KBr)υ3445，3338，1634，1589，1541，1510，1464，1247，1210，1166，1059cm -1
1H?NMR(CDCl 3，500MHz)δ7.13(s，1H)，6.14(s，1H)，3.90(s，3H)，3.87(s，3H)，2.55(s，3H)
Embodiment 5,6,7-dimethoxy-quinoline ketone (compound 1e) synthetic
Figure S071B9982620070831D000052
As shown in Figure 1, compound 1d2.874g (14.5mmol) is dissolved in the reaction flask that contains glycol dimethyl ether 71.2mL, add NaOMe9.36g (173.4mmol); Stirring at room 70min; Slowly drip ethyl formate 23.4mL (289mmol), stirring at room 2h adds 5mL H 2O fully stirs, and filtering-depositing is used H respectively 2O, 1,4-dioxane, ETHYLE ACETATE washing precipitation, the final white solid compound 1e (C that gets 11H 11NO 3, FW205.07) 5.191g, m.p.124-125 ℃, productive rate 79%.
1H?NMR(DMSO-d 6，500MHz)δ7.81(d，J＝7.3Hz，1H)，7.45(s，1H)，6.98(s，1H)，6.0(d，J＝7.3Hz，1H)，3.86(s，3H)，3.82(s，3H)
Embodiment 6,4-chloro-6,7-dimethoxy-quinoline (compound 1f) synthetic
As shown in Figure 1, add compound 1e2.348g (11.5mmol), POCl in the single port bottle 313.6mL the frozen water cooling added 20mL H down after heating reflux reaction finished 2O, NaHCO 3The pale precipitation that obtains is filtered in the saturated solution neutralization, and washing finally obtains solid chemical compound 1fC 11H 10ClNO 2, FW223.04) 2.49g, m.p.139-140 ℃, productive rate 96.9%.
1H?NMR(CDCl 3，500MHz)δ8.62(brs，1H)，7.48(s，1H)，7.45(s，1H)，7.40(d，J＝3.5Hz，1H)，4.09(s，3H)，4.08(s，3H)
Synthesizing of embodiment 7,4-chloro-6-hydroxyl-7-methoxy quinoline (compound 1g)
Figure S071B9982620070831D000061
As shown in Figure 3, with compound 1f1.863g (8.3mmol), DL-dl-methionine 1.8g (18.7mmol), methanesulfonic 25mL places the 100mL two-mouth bottle, and oil bath is heated to 120 ℃ and keeps 3h.After finishing, reaction adds 50mL water, Na 2CO 3Neutralization, the ethyl acetate extraction separatory is got organic layer and is used anhydrous Na 2SO 4Drying, after the filtering and concentrating, quick silica gel column chromatography (sherwood oil: acetone=2:1), obtain white solid compound 1g (C 10H 8ClNO 2, FW209.02) 0.409g, m.p.119-120 ℃, productive rate 57.1%.
1H?NMR(DMSO-d 6，500MHz)δ8.56(brs，1H)，7.51(brs，1H)，7.44(s，1H)，7.40(s，1H)，3.97(s，3H)
Synthesizing of embodiment 8,4-chloro-6-(2-methoxy ethoxy)-7-methoxy quinoline (compound 1h)
Figure S071B9982620070831D000062
As shown in Figure 4, with compound 1g0.5g (2.38mmol), bromo-ethyl-methyl ether 1.66g (11.9mmol) is dissolved in the reaction flask that contains DMF31mL, adds K 2CO 32.3g (16.7mmol), oil bath is heated to 90 ℃ and keeps 4.5h.After finishing, reaction adds NH 4The neutralization of Cl saturated solution, the ethyl acetate extraction separatory is got the organic layer anhydrous Na 2SO 4Drying, after the filtering and concentrating, quick silica gel column chromatography (sherwood oil: acetone=4:1), obtain white solid compound 1h (C 13H 14ClNO 3FW267.07) 0.467g, m.p.89-91 ℃, productive rate 73.2%.
It is as shown in Figure 6, 1H NMR (CDCl 3, 500MHz) δ 8.61 (d, J=4.8Hz, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.38 (d, J=4.8Hz, 1H), 4.38 (t, J=4.6Hz, 2H), 4.05 (s, 3H), 3.93 (t, J=4.7Hz, 2H), 3.52 (s, 3H)
Synthesizing of embodiment 9,4-chloro-6-(3-morpholino propoxy-)-7-methoxy quinoline (compound 1i)
Figure S071B9982620070831D000063
As shown in Figure 5, compound 1g0.45g (2.14mmol) input is contained in the reaction flask of 28mL DMF, and the turbid solution heating that forms is melted to clarification, stir adding K down 2CO 32.07g (15mmol), be warming up to 60 ℃, reaction 4.5h with 1-chloro-3-morpholino propane 1.71g (10.7mmol).Back adding 50mL H finishes 2O uses NH 4The Cl regulator solution is to neutral, and ETHYLE ACETATE-aqueous systems extraction separatory is used the anhydrous sodium sulfate drying organic layer, filtering and concentrating, silica gel column chromatography (sherwood oil: acetone=2:1), finally obtain white crystal compound 1i (C 17H 21ClN 2O 3, FW336.12) 0.409g, m.p.119-120 ℃, productive rate 57.1%.
It is as shown in Figure 7, 1H NMR (CDCl 3, 500MHz) δ 8.60 (d, J=4.8Hz, 1H), 7.44 (s, 2H), 7.37 (d, J=4.8Hz, 1H), 4.30 (t, J=6.5Hz, 2H), 4.05 (s, 3H), 3.78 (m, 4H), 2.64 (m, 2H), 2.55 (m, 4H), 2.18 (t, J=6.6Hz, 2H)
Embodiment 10,4-(3-chloro-4-fluoroanilino)-6,7-dimethoxy-quinoline (compound 2a) synthetic
Figure S071B9982620070831D000071
As shown in Figure 2; Compound 1f0.1g (0.45mmol) is dissolved in the reaction flask that contains i-PrOH15mL, in the i-PrOH (15mL) of 3-chloro-4-fluoroaniline solution, drips 2 concentrated hydrochloric acids, and it is added in the quinoline solution; Reflux; Add 3-chloro-4-fluoroaniline 0.222g, the postcooling that reacts completely adds saturated NaHCO 3Solution generates a large amount of white precipitates, filters, and washing precipitation obtains white solid compound 2a (C 17H 14ClFN 2O 2FW332.07) 0.142g, m.p.191-192 ℃, productive rate 95.3%.
Shown in Fig. 8-11, the spectrum analysis result of compound 2a is following:
IR(KBr)υ3439，3282，1630，1587，1506，1256，1220cm -1
1H?NMR(CDCl 3，500MHz)δ8.46(s，1H)，7.42(s，1H)，7.36(s，1H)，7.20(m，2H)，7.1(s，1H)，6.84(d，J＝4.8Hz，1H)，6.37(s，1H)，4.05(s，6H)
13C?NMR(CDCl 3，125MHz)δ154.7，152.2，148.8，148.6，146.3，146.2，138.7，123.9，122.6，120.3，117.9，114.4，108.5，101.7，101.2，56.3，56.0
EIMS(m/z)332.0(M +，63％)，334.1(M ++2，33％)
EA(％)：found?C，61.56；H，4.20；N，8.27；Calcd?C，61.36；H，4.24；N，8.42
Embodiment 11,4-(3-acetylenylbenzene amido)-6,7-dimethoxy-quinoline (compound 2b) synthetic
Figure S071B9982620070831D000072
As shown in Figure 2, compound 1f0.212g (0.95mmol) is dissolved in contains in the i-PrOH30mL reaction flask, in the i-PrOH of m-aminophenyl acetylene 0.166g (1.42mmol) (30mL) solution, drip 2 concentrated hydrochloric acids; Two kinds of solution Hybrid Heating are refluxed; The postcooling that reacts completely adds saturated NaHCO3 solution, generates a large amount of white precipitates; The filtration washing deposition is with white precipitate column chromatography purification (CHCl 3: CH 3OH=30:1) obtain little yellow solid compound 2b (C 19H 16N 2O 2, FW304.12) 0.245g, m.p.221-223 ℃, productive rate 89.7%.
IR(KBr)υ3249，1659，1582，1508，1438，1274，1255cm -1
1H?NMR(DMSO-d 6，500MHz)δ8.33(d，J＝5.3Hz，1H)，7.63(s，1H)，7.41(m，3H)，7.27(s，1H)，7.22(d，J＝6.7Hz，1H)，6.90(d，J＝5.4Hz，1H)，4.21(s，1H)，3.93(s，3H)，3.91(s，3H)
13C?NMR(DMSO-d 6，125MHz)152.5，148.9，148.0，146.7，145.4，141.5，130.3，127.0，125.0，123.2，122.7，114.5，107.8，101.9，101.4，83.7，81.3，56.4，56.0
EIMS(m/z)304.1(M +，60％)
EA(％)：found?C，74.51；H，5.16；N，9.29；Calcd?C，74.98；H，5.30；N，9.20
Embodiment 12,4-(3-toluidine)-6,7-dimethoxy-quinoline (compound 2c) synthetic
Figure S071B9982620070831D000081
As shown in Figure 2; Compound 1f0.5g (2.23mmol) is dissolved in contains in the i-PrOH10mL reaction flask, in the i-PrOH (10mL) of a monomethylaniline 0.478g (4.46mmol) solution, drip 2 concentrated hydrochloric acids, with two kinds of solution mixings post-heating backflows; The postcooling that reacts completely adds saturated NaHCO 3Solution obtains white solid compound 2c (C with the sedimentation and filtration washing 18H 18N 2O 2, FW294.14) 0.337g, m.p.225-226 ℃, productive rate 51.2%.
IR(KBr)υ3266，1631，1592，1515，1489，1275，1255cm -1
1H?NMR(CDCl 3，500MHz)δ8.44(d，J＝5.3Hz，1H)，7.39(s，1H)，7.30(m，1H)，7.17(s，1H)，7.11(m，2H)，6.97(m，2H)，6.66(s，1H)，4.0(s，3H)，3.99(s，3H)，2.39(s，3H)
13C?NMR(CDCl 3，125MHz)152.3，149.1，148.5，146.6，146.0，140.5，139.6，129.4，124.9，122.7，119.1，114.6，108.8，102.8，98.9，56.1，55.9，21.4
EIMS(m/z)294.2(M +，75％)
EA(％)：found?C，72.99；H，5.67；N，9.30；Calcd?C，73.45；H，6.16；N，9.52
Embodiment 13,4-(3-chloroanilino)-6,7-dimethoxy-quinoline (compound 2d) synthetic
Figure S071B9982620070831D000091
As shown in Figure 2; Compound 1f0.5g (2.23mmol) is dissolved in the reaction flask that contains i-PrOH10mL, in the i-PrOH of m-chloro aniline 0.569g (4.46mmol) (10mL) solution, drips 2 concentrated hydrochloric acids, and two kinds of solution mixing post-heating are refluxed; The postcooling that reacts completely adds saturated NaHCO 3Solution generates a large amount of white precipitates, and the filtration washing deposition obtains white solid compound 2d (C 17H 15ClN 2O 2, FW314.08) 0.643g, m.p.209-210 ℃, productive rate 91.5%.
IR(KBr)3601，1625，1576，1510，1258，1213cm -1
1H?NMR(DMSO-d 6，500MHz)δ8.34(d，J＝4.8Hz，1H)，7.6(s，1H)，7.41(t，J＝7.9Hz，1H)，7.33(m，2H)，7.28(s，1H)，7.13(d，J＝7.8Hz，1H)，6.97(d，J＝4.9Hz，1H)，3.93(s，3H)，3.91(s，3H)
13C?NMR(DMSO-d 6，125MHz)152.3，148.9，148.6，146.2，145.8，143.2，134.1，131.4，122.9，121.0，119.8，114.9，108.5，102.6，101.3，56.3，56.0
EIMS(m/z)314.2(M +，10％)，316.2(M ++2，5％)
EA(％)：found?C，65.22；H，4.51；N，8.62；Calcd?C，64.87；H，4.80；N，8.90
Embodiment 14,2,3-dimethoxy-8-fluoro-9-chloro-11H-indoles [3,2-c] quinoline (compound 3a) synthetic
As shown in Figure 2, with compound 2a0.1g (0.3mmol) and Pd (CH 3COO) 20.135g (0.6mmol) be dissolved in and contain acetate 15mL and MeSO 3In the H1mL reaction flask, N 2Protection refluxed 3h, strong aqua neutralization, CHCl 3: CH 3OH=50:1 extracts separatory, anhydrous sodium sulfate drying organic layer, filtering and concentrating, column chromatography purification (CHCl 3: CH 3CH 2OH=10:1), finally obtain pale solid compound 3a (C 17H 12ClFN 2O 2, FW330.06) 0.030g, m.p.287-289 ℃, productive rate 30.3%.
IR(KBr)υ3418，1628，1514，1467，1287，1062cm -1
1H?NMR(DMSO-d 6，500MHz)δ9.46(s，1H)，8.34(d，J＝9.6Hz，1H)，7.93(s，1H)，7.88(d，J＝6.1Hz，1H)，7.54(s，1H)，4.0(s，3H)，3.97(s，3H)
13C?NMR(DMSO-d 6，125MHz)δ154.0，152.2，152.1，149.7，142.3，140.9，139.6，135.7，121.7，118.0，113.4，111.0，107.8，107.1，101.7，56.4，56.2
EIMS(m/z)330.0(M +，65％)，332.0(M ++2，25％)
EA(％)：found?C，61.88；H，3.73；N，8.37；Calcd?C，61.73；H，3.66；N，8.47
Embodiment 15,2,3-dimethoxy-9-chloro-11H-indoles [3,2-c] quinoline (compound 3b) synthetic
Figure S071B9982620070831D000101
As shown in Figure 2, with compound 2d0.315g (1mmol) and Pd (CH 3COO) 20.449g (2mmol) be dissolved in and contain CH 3COOH66mL and MeSO 3In the H4mL reaction flask, N 2The protection refluxed, after reaction finishes, NaHCO 3The saturated solution neutralization, CHCl 3: CH 3OH=50:1 extracts separatory, anhydrous sodium sulfate drying organic layer, filtering and concentrating, column chromatography purification (CHCl 3: CH 3CH 2OH=20:1), finally obtain pale solid compound 3b (C 17H 13ClN 2O 2, FW312.07) 0.119g, m.p.260-261 ℃, productive rate 38%.
IR(KBr)υ1571，1512，1286，1230，1065cm -1
1H?NMR(DMSO-d 6，500MHz)δ9.38(s，1H)，8.25(d，J＝8.3Hz，1H)，7.87(s，1H)，7.70(s，1H)，7.51(s，1H)，7.33(d，J＝8.3Hz，1H)，3.99(s，3H)，3.94(s，3H)
13C?NMR(DMSO-d 6，125MHz)δ151.5，149.4，142.2，141.9，140.8，139.7，130.2，121.8，121.4，121.1，113.5，111.8，111.3，109.0，101.6，56.3，56.1
EIMS(m/z)312.2(M +，50％)，314.4(M ++2，18％)
EA(％)：found?C，64.95；H，4.13；N，8.99；Calcd?C，65.29；H，4.19；N，8.96
Synthesizing of embodiment 16,4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxy quinoline (compound 4a)
As shown in Figure 3, compound 1g0.5g (2.38mmol) is dissolved in the reaction flask that contains i-PrOH10mL, in the i-PrOH10mL solution of 3-chlorine 4-fluoroaniline 0.693g (4.76mL), drip 2 concentrated hydrochloric acids, two kinds of solution mixing post-heating are refluxed.After finishing, reaction adds saturated NaHCO 3The solution neutralization, ethyl acetate extraction, anhydrous sodium sulfate drying organic layer, filtering and concentrating, rapid column chromatography (CHCl 3: CH 3CH 2OH=10:1), finally obtain yellow-green colour solid chemical compound 4a (C 16H 12ClFN 2O 2, FW318.06) 0.27g, productive rate m.p.241-242 ℃, 35.5%.
IR(KBr)υ3041，1728，1587，1503，1279，1223，1071cm -1
1H?NMR(DMSO-d 6，500MHz)δ8.34(d，J＝6.7Hz，1H)，7.81(s，1H)，7.69(m，1H)，7.57(t，J＝8.9Hz，1H)，7.46(m，1H)，7.35(s，1H)，6.75(d，J＝6.7Hz，1H)，3.9(s，3H)
13C?NMR(DMSO-d 6，125MHz)δ155.2，152.8，148.1，146.9，145.7，142.4，138.1，124.4，123.2，120.4，118.0，114.7，106.0，105.0，101.4，56.3
EIMS(m/z)319.1(M ++1，54％)
EA(％)：found?C，60.61；H，4.14；N，8.62；Calcd?C，60.29；H，3.79；N，8.79
Synthesizing of embodiment 17,4-(3-acetylenylbenzene amido)-6-hydroxyl-7-methoxy quinoline (compound 4b)
Figure S071B9982620070831D000111
As shown in Figure 3; Compound 1g0.2g (0.95mmol) is dissolved in the reaction flask that contains i-PrOH10mL; In the i-PrOH of m-aminophenyl acetylene 0.223g (1.9mmol) (10mL) solution, drip 2 concentrated hydrochloric acids; And with two kinds of solution mixing post-heating backflows, the postcooling that reacts completely adds saturated NaHCO 3Solution, ethyl acetate extraction, anhydrous sodium sulfate drying organic layer, filtering and concentrating, rapid column chromatography (CHCl 3: CH 3OH=10:1), finally obtain yellow-green colour solid chemical compound 4b (C 18H 14N 2O 2, FW290.11) 0.235g, m.p251-252 ℃, productive rate 85%.
IR(KBr)υ3282，3212，1594，1576，1522，1482cm -1
1H?NMR(DMSO-d 6，500MHz)δ8.33(d，J＝6.2Hz，1H)，7.75(s，1H)，7.46(m，3H)，7.34(m，2H)，6.83(d，J＝6.2Hz，1H)，4.24(s，1H)，3.99(s，3H)
13C?NMR(DMSO-d 6，125MHz)153.7，149.9，147.4，143.5，140.0，130.5，128.6，126.4，124.2，123.4，114.1，104.9，103.9，100.9，83.4，81.8，56.5
EIMSm/z290.5(M +，25％)
EA(％)：found?C，74.39；H，4.86；N，9.61；Calcd?C，74.47；H，4.86；N，9.65
Synthesizing of embodiment 18,4-(3-toluidine)-6-hydroxyl-7-methoxy quinoline (compound 4c)
Figure S071B9982620070831D000112
As shown in Figure 3; Compound 1g0.5g (2.38mmol) is dissolved in the reaction flask that contains i-PrOH10mL, in the i-PrOH (10mL) of a monomethylaniline 0.5g (4.76mmol) solution, drips 2 concentrated hydrochloric acids, and two kinds of solution mixing post-heating are refluxed; The postcooling that reacts completely adds saturated NaHCO 3Solution, ethyl acetate extraction, anhydrous sodium sulfate drying organic layer, filtering and concentrating, rapid column chromatography (CHCl 3: CH 3OH=10:1), finally obtain yellow-green colour solid chemical compound 4c (C 17H 16N 2O 2, FW280.12) 0.273g, m.p.228-229 ℃, productive rate 30.7%.
IR(KBr)υ3227，1604，1589，1525，1506，1286，1261，1219cm -1
1H?NMR(DMSO-d 6，500MHz)δ8.25(d，J＝5.4Hz，1H)，7.61(s，1H)，7.26(m，2H)，7.12(m，2H)，6.92(d，J＝7.5Hz，1H)，6.82(d，J＝5.5Hz，1H)，3.94(s，3H)，2.31(s，3H)
13C?NMR(DMSO-d 6，125MHz)δ152.0，147.2，147.1，146.4，144.5，141.2，139.1，129.6，124.5，122.7，119.3，115.2，107.5，105.0，101.5，56.1，21.5
EIMS(m/z)282.3(M ++2，100％)
EA(％)：found?C，72.37；H，6.11；N，9.54；Calcd?C，72.84；H，5.75；N，9.99
Synthesizing of embodiment 19,4-(3-chloroanilino)-6-hydroxyl-7-methoxy quinoline (compound 4d)
Figure S071B9982620070831D000121
As shown in Figure 3; Compound 1g0.5g (2.38mmol) is dissolved in the reaction flask that contains i-PrOH10mL, in the i-PrOH of m-chloro aniline 0.607g (4.76mmol) (10mL) solution, drips 2 concentrated hydrochloric acids, and two kinds of solution mixing post-heating are refluxed; The postcooling that reacts completely adds saturated NaHCO 3Solution, ethyl acetate extraction, anhydrous sodium sulfate drying organic layer, filtering and concentrating, rapid column chromatography (CHCl 3: CH 3OH=10:1), finally obtain yellow-green colour solid chemical compound 4d (C 16H 13ClN 2O 2, FW300.07) 0.47g, m.p.255-256 ℃, productive rate 65.6%.
IR(KBr)υ3054，1587，1523，1479，1294，1241cm －1
1H?NMR(DMSO-d 6，500MHz)δ8.34(d，J＝5.6Hz，1H)，7.6(s，1H)，7.41(t，J＝8.0Hz，1H)，7.36(s，1H)，7.30(m，2H)，7.14(d，J＝7.9Hz，1H)，6.93(d，J＝5.6Hz，1H)，3.96(s，3H)
13C?NMR(DMSO-d 6，125MHz)δ152.7，147.1，146.9，146.1，143.2，142.9，134.1，131.4，123.3，121.2，120.1，115.3，106.5，105.0，102.5，56.3
EIMSm/z301.2(M ++1，8％)
EA(％)：found?C，64.23；H，4.69；N，8.95；Calcd?C，63.90；H，4.36；N，9.31
Synthesizing of embodiment 20,2-hydroxyl-3-methoxyl group-9-chloro-11H-indoles [3.2-c] quinoline (compound 5a)
As shown in Figure 3, with compound 4d0.2g (0.66mmol) and Pd (CH 3COO) 20.298g (1.3mmol) be dissolved in and contain acetate 44mL and MeSO 3In the reaction flask of H1mL, N 2The protection refluxed, after reaction finished, underpressure distillation concentrated, saturated NaHCO 3Neutralization, CHCl 3: CH 3OH=50:1 extracts separatory, anhydrous sodium sulfate drying organic layer, filtering and concentrating, column chromatography purification (CHCl 3: CH 3OH=10:1), finally obtain pale solid compound 5a (C 16H 11ClN 2O 2, FW298.05) 0.130g, m.p.280-281 ℃, productive rate 65.3%.
IR(KBr)υ3082，2926，2849，1701，1608，1529，1458，1296，1067，853，808cm -1
1H?NMR(DMSO-d 6，500MHz)δ9.39(s，1H)，8.27(d，J＝8.4Hz，1H)，7.72(s，1H)，7.67(d，J＝1.6Hz，1H)，7.53(s，1H)，7.33(dd，J＝8.4，1.7Hz，1H)，3.98(s，1H)
13C?NMR(DMSO-d 6，125MHz)δ151.4，147.3，141.2，140.7，139.9，130.2，121.8，121.4，121.2，113.2，111.8，108.6，104.7，56.2
EIMS?m/z298.9(M +，100％)
EA(％)：found?C，64.32；H，3.49；N，9.55；Calcd?C，64.33；H，3.71；N，9.38
Synthesizing of embodiment 21,4-(3-chloro-4-fluoroanilino)-6-(2-methoxy ethoxy)-7-methoxy quinoline (compound 6a)
Figure S071B9982620070831D000131
As shown in Figure 4, compound 1h0.2g (0.75mmol) is dissolved in the reaction flask that contains i-PrOH10mL, in the i-PrOH (10mL) of 3-chloro-4-fluoroaniline solution, drip 2 concentrated hydrochloric acids; And with in its adding reaction flask; Reflux, the postcooling that reacts completely adds saturated NaHCO 3Solution generates a large amount of white precipitates, and the filtration washing deposition obtains white solid compound 6a (C 19H 18ClFN 2O 3, FW376.10) 0.224g, m.p.90-91 ℃, productive rate 79.7%.
IR(KBr)υ1633，1594，1515，1503，1471，1250，1229，1133cm -1
1H?NMR(CDCl 3，500MHz)δ8.46(d，J＝5.3Hz，1H)，7.38(s，1H)，7.34(m，1H)，7.21(s，1H)，7.19(s，1H)，7.16(m，1H)，6.83(d，J＝5.3Hz，1H)，6.59(s，1H)，4.27(t，J＝4.7Hz，2H)，4.0(s，3H)，3.86(d，J＝4.7Hz，2H)，3.48(s，3H)
13C?NMR(CDCl 3，125MHz)δ155.8，153.9，152.7，148.8，148.4，146.4，146.2，137.4，124.3，122.0，117.4，114.3，109.0，102.5，100.8，70.9，68.6，59.3，56.0
EIMS(m/z)376.2(M +，45％)
EA(％)：found?C，60.78；H，4.75；N，7.21；Calcd?C，60.56；H，4.81；N，7.43
Synthesizing of embodiment 22,4-(3-acetylenylbenzene amido)-7-methoxyl group-6-(2-methoxy ethoxy) quinoline (compound 6b)
Figure S071B9982620070831D000141
As shown in Figure 4; Compound 1h0.2g (0.75mmol) is dissolved in the reaction flask that contains i-PrOH10mL; In the i-PrOH of m-aminophenyl acetylene 0.175g (1.5mmol) (10mL) solution, drip 2 concentrated hydrochloric acids, and it is added in the reaction flask reflux; The postcooling that reacts completely adds saturated NaHCO 3Solution generates a large amount of white precipitates, and the filtration washing deposition obtains pale solid compound 6b (C 21H 20N 2O 3, FW348.15) 0.128g, m.p.88-89 ℃, productive rate 49.2%.
IR(KBr)υ3479，3246，1626，1574，1506，1451，1357，1254，1216，1132cm -1
1H?NMR(CDCl 3，500MHz)δ8.38(d，J＝5.4Hz，1H)，7.44(s，1H)，7.35(m，2H)，7.32～7.27(m，3H)，6.94(d，J＝5.3Hz，1H)，4.29(t，J＝4.6Hz，2H)，3.97(s，3H)，3.85(t，J＝3.8Hz，2H)，3.47(s，3H)，3.13(s，1H)
13C?NMR(CDCl 3，125MHz)δ152.9，148.5，148.0，146.3，145.6，140.6，129.7，127.6，124.9，123.5，122.1，114.5，108.3，102.9，101.0，83.0，77.8，70.9，68.7，59.3，56.0
EIMS(m/z)348.3(M +，30％)
EA(％)：found?C，72.83；H，5.77；N，8.16；Calcd?C，72.40；H，5.79；N，8.04
Synthesizing of embodiment 23,4-(3-toluidine)-6-(2-methoxy ethoxy)-7-methoxy quinoline (compound 6c)
Figure S071B9982620070831D000142
As shown in Figure 4; Compound 1h0.323g (1.2mmol) is dissolved in the reaction flask that contains i-PrOH10mL; In the i-PrOH (10mL) of a monomethylaniline 0.258g (2.4mmol) solution, drip 2 concentrated hydrochloric acids; And with two kinds of solution mixing post-heating backflows, the postcooling that reacts completely adds saturated NaHCO 3Solution, the filtration washing deposition obtains white solid compound 6c (C 20H 22N 2O 3, FW338.16) 0.212g, m.p.200-201 ℃, productive rate 52%.
IR(KBr)υ3419，1633，1589，1509，1471，1276，1228cm -1
1H?NMR(CDCl 3，500MHz)δ8.42(d，J＝5.3Hz，1H)，7.39(s，1H)，7.31(m，1H)，7.26(s，1H)，7.13(m，2H)，6.9(d，J＝7.4Hz，1H)，6.95(d，J＝5.4Hz，1H)，4.32(t，J＝4.6Hz，2H)，4.0(s，3H)，3.88(t，J＝4.8Hz，2H)，3.50(s，3H)，2.4(s，3H)
13C?NMR(CDCl 3，125MHz)δ152.8，148.3，148.0，146.9，140.2，139.6，129.4，125.0，122.7，119.1，114.2，108.4，102.3，101.2，70.9，68.8，59.3，56.0，21.5
EIMS(m/z)338.4(M +，15％)
EA(％)：found?C，71.35；H，6.21；N，8.47；Calcd?C，70.99；H，6.55；N，8.28
Synthesizing of embodiment 24,4-(3-chloroanilino)-6-(2-methoxy ethoxy)-7-methoxy quinoline (compound 6d)
Figure S071B9982620070831D000151
As shown in Figure 4, compound 1h0.5g (1.87mmol) is dissolved in the reaction flask that contains i-PrOH10mL, in the i-PrOH of m-chloro aniline 0.476g (3.73mmol) (10mL) solution, drip 2 concentrated hydrochloric acids; And with two kinds of solution mixing post-heating backflows; The postcooling that reacts completely adds saturated NaHCO3 solution, generates a large amount of white precipitates; The filtration washing deposition obtains white solid compound 6d (C 19H 19ClN 2O 3, FW358.11) 0.293g, m.p.81-82 ℃, productive rate 43.7%.
IR(KBr)υ3288，1625，1579，1505，1479，1256，1208，1095cm -1
1H?NMR(CDCl 3，500MHz)δ8.47(d，J＝5.3Hz，1H)，7.39(s，1H)，7.33(t，J＝8.0Hz，1H)，7.29(m，1H)7.24(s，1H)，7.18(dd，J＝6.7，1.3Hz，1H)，7.12(dd，J＝6.9，1.0Hz，1H)，7.0(d，J＝5.3Hz，1H)，4.29(t，J＝4.6Hz，2H)，3.99(s，3H)，3.86(t，J＝4.8Hz，2H)，3.49(s，3H)
13C?NMR(CDCl 3，125MHz)δ152.8，148.7，148.6，146.4，145.4，142.2，135.2，130.6，123.6，121.0，119.1，114.8，108.9，103.6，101.0，70.9，68.7，59.3，56.0
EIMS(m/z)358.3(M +，5％)
EA(％)：found?C，63.44；H，5.19；N，7.99；Calcd?C，63.60；H，5.34；N，7.81
Synthesizing of embodiment 25,2-(2-methoxy ethoxy)-3-methoxyl group-8-fluoro-9-chloro-11H-indoles [3,2-c] quinoline (compound 7a)
As shown in Figure 4, with compound 6a0.3g (0.8mmol) and Pd (CH 3COO) 20.357g (1.6mmol) be dissolved in and contain acetate 55mL and MeSO 3In the reaction flask of H3.3mL, N 2The protection refluxed, the reaction finish after with underpressure distillation, saturated NaHCO 3The solution neutralization, CHCl 3: CH 3OH=50:1 extracts separatory, anhydrous sodium sulfate drying organic layer, filtering and concentrating, column chromatography purification (CHCl 3: CH 3OH=10:1), finally obtain pale solid compound 7a (C 19H 16ClFN 2O 3, FW374.08) 0.167g, m.p.107-108 ℃, productive rate 56%.
IR(KBr)υ3401.3067，1631，1556，1511，1466，1288，1129cm -1
1H?NMR(DMSO-d 6，500MHz)δ9.36(s，1H)，8.29(d，J＝9.6Hz，1H)，7.85(s，1H)，7.81(d，J＝6.1Hz，1H)，7.50(s，1H)，4.28(t，J＝4.4Hz，2H)，3.95(s，3H)，3.81(t，J＝4.4Hz，2H)，3.38(s，3H)
13C?NMR(DMSO-d 6，125MHz)δ153.8，151.9，151.8，148.5，142.5，141.7，135.5，132.0，129.1，113.5，113.1，111.2，109.1，107.5，102.6，70.6，68.3，58.8，56.1.
EIMS(m/z)374.2(M +，47％)，376.4(M ++2，15％)
EA(％)：found?C，60.46；H，4.11；N，7.91；Calcd?C，60.89；H，4.30；N，7.47
Synthesizing of embodiment 26,4-(3-chloro-4-fluoroanilino)-6-(3-morpholino propoxy-)-7-methoxy quinoline (compound 8a)
Figure S071B9982620070831D000161
As shown in Figure 5, compound 1i0.2g (0.6mmol) is dissolved in the reaction flask that contains i-PrOH10mL, in the i-PrOH (10mL) of 3-chloro-4-fluoroaniline solution, drip 2 concentrated hydrochloric acids; And with in its adding reaction flask; Reflux, the postcooling that reacts completely adds saturated NaHCO 3Solution, ethyl acetate extraction, dry organic layer, filtering and concentrating, rapid column chromatography (CHCl 3: CH 3OH=10:1), finally obtain white solid compound 8a (C 23H 25ClFN 3O 3, FW445.16) 0.225g, m.p.183-184 ℃, productive rate 85%.
IR(KBr)υ3340，1625，1582，1531，1500，1247，1114cm -1
1H?NMR(CDCl 3，500MHz)δ8.41(d，J＝5.3Hz，1H)，7.39(s，1H)，7.37(s，1H)，7.20(m，3H)，6.82(d，J＝5.3Hz，1H)，4.22(t，J＝6.6Hz，2H)，4.01(s，3H)，3.74(t，J＝4.3Hz，4H)，2.59(t，J＝7.0Hz，2H)，2.51(m，4H)，2.13(m，2H)
13C?NMR(CDCl 3，125MHz)δ156.0，153.0，148.7，147.1，147.0，137.0，130.9，128.8，124.6，122.3，117.4，114.2，107.7，102.2，100.6，67.5，66.9，56.1，55.4，53.7，26.1
EIMS(m/z)445.2(M +，64％)，447.4(M ++2，20％)
EA(％)：found?C，61.89；H，5.72；N，9.67；Calcd?C，61.95；H，5.65；N，9.42
Synthesizing of embodiment 27,4-(3-toluidine)-6-(3-morpholine third generation oxygen base)-7-methoxy quinoline (compound 8b)
Figure S071B9982620070831D000162
As shown in Figure 5; Compound 1i0.47g (1.4mmol) is dissolved in the reaction flask that contains i-PrOH10mL; In the i-PrOH (10mL) of a monomethylaniline 0.302g (2.8mmol) solution, drip 2 concentrated hydrochloric acids, and it is added in the reaction flask reflux; The postcooling that reacts completely adds saturated NaHCO 3Solution, ethyl acetate extraction, dry organic layer, filtering and concentrating, rapid column chromatography (CHCl 3: CH 3OH=20:1), obtain solid chemical compound 8b (C 24H 29N 3O 3, FW407.22) 0.2g, m.p.198-199 ℃, productive rate 35.1%.
IR(KBr)υ1623，1578，1507，1487，1274，1210，1116cm -1
1H?NMR(CDCl 3，500MHz)δ8.30(d，J＝5.0Hz，1H)，7.32～7.28(m，3H)，7.16(m，2H)，7.01(d，J＝7.5Hz，1H)，6.9(d，J＝5.3Hz，1H)，4.22(t，J＝6.6Hz，2H)，3.97(s，3H)，3.74(t，J＝4.3Hz，4H)，2.57(t，J＝7.1Hz，2H)，2.49(m，4H)，2.40(s，3H)，2.12(t，J＝6.9Hz，2H)
13C?NMR(CDCl 3，125MHz)δ152.9，148.5，147.4，146.8，140.0，139.7，129.5，125.3，122.8，119.2，114.1，107.4，102.1，100.7，67.5，67.0，56.0，55.4，53.7，26.2，21.5
EIMS(m/z)407.3(M +，55％)
EA(％)：found?C，71.03；H，7.25；N，10.57；Calcd?C，70.74；H，7.17；N，10.31
Synthesizing of embodiment 28,4-(3-chloroanilino)-6-(3-morpholino propoxy-)-7-methoxy quinoline (compound 8c)
As shown in Figure 5; Compound 1h0.71g (2.1mmol) is dissolved in the reaction flask that contains i-PrOH10mL, in the i-PrOH of m-chloro aniline 0.542g (4.3mmol) (10mL) solution, drips 2 concentrated hydrochloric acids, and two kinds of solution mixing post-heating are refluxed; The postcooling that reacts completely adds saturated NaHCO 3Solution and ethyl acetate solution generate a large amount of white precipitates, and the filtration washing deposition obtains white solid compound 8c (C 23H 26ClN 3O 3, FW427.17) 0.746g, m.p.173-174 ℃, productive rate 82.6%.
IR(KBr)υ3391，3035，1607，1590，1511，1465，1275cm -1
1H?NMR(CDCl 3，500MHz)δ8.44(m，1H)，7.35(s，1H)，7.29(m，3H)，7.20(d，J＝7.9Hz，1H)，7.11(d，J＝7.9Hz，1H)，7.0(d，J＝5.3Hz，1H)，4.1(m，2H)，3.94(s，3H)，3.7(t，J＝4.1Hz，4H)，2.5(t，J＝7.0Hz，2H)，2.4(m，4H)，2.05(m，2H)
13C?NMR(DMSO-d 6，125MHz)δ155.3，153.2，148.9，140.6，139.4，135.7，134.4，131.9，127.3，125.4，124.2，112.2，104.2，100.4，100.0，67.2，63.8，56.8，54.1，51.6，23.3
EIMS(m/s)427.1(M +，30％)，429.4(M ++2，12％)
EA(％)：found?C，64.43；H，6.27；N，9.71；Calcd?C，64.55；H，6.12；N，9.82
Synthesizing of embodiment 29,2-(3-morpholino propoxy-)-3-methoxyl group-8-fluoro-9-chloro-11H-indoles [3.2-c] quinoline (compound 9a)
Figure S071B9982620070831D000181
As shown in Figure 5, with compound 8a0.2g (0.45mmol) and Pd (CH 3COO) 20.203g (0.9mmol) be dissolved in and contain acetate 30mL and MeSO 3In the reaction flask of H2mL, N 2The protection refluxed, the reaction finish after with underpressure distillation, saturated NaHCO 3The solution neutralization, CHCl 3: CH 3OH=50:1 extracts separatory, anhydrous sodium sulfate drying organic layer, filtering and concentrating, column chromatography purification (CHCl 3: CH 3OH=5:1), finally obtain pale solid compound 9a (C 23H 23ClFN 3O 3, FW443.14) 0.045g, m.p.189-190 ℃, productive rate 22.6%.
IR(KBr)υ3394，1510，1464，1286，1258，1114，1060cm -1
1H?NMR(DMSO-d 6，500MHz)δ9.38(s，1H)，8.33(d，J＝9.6Hz，1H)，7.90(s，1H)，7.84(d，J＝6.1Hz，1H)，7.53(s，1H)，4.22(t，J＝6.1Hz，2H)，3.9(s，3H)，3.61(m，4H)，2.56(m，2H)，2.47(m，4H)，2.06(m，2H)
13C?NMR(DMSO-d 6，125MHz)δ153.8，151.6，148.6，142.8，142.4，141.5，135.4，121.9，117.3，113.5，113.0，111.3，109.6，107.6，102.5，67.2，66.5，56.1，55.3，53.7，26.1
EIMS(m/s)444.4(M ++1，45％)
EA(％)：found?C，62.57；H，5.19；N，9.82；Calcd?C，62.23；H，5.22；N，9.47
Embodiment 30, antitumour activity screening experiment
Cancer cells is used in experiment
Colon cancer cell (HCT-8), liver cancer cell (Bel-7402), gastric carcinoma cells (BGC-823), lung carcinoma cell (A549) and Proliferation of Human Ovarian Cell (A2780), the institute of materia medica provides by Beijing.
Experimental technique
The present invention adopts mtt assay that the synthetic compound 2a-2d of institute, 3a, 3b, 4a-4d, 5a, 6a-6d, 7a, 8a-8c and 9a have been done the antitumour activity experiment.
The cell in vegetative period of taking the logarithm is with 1.2～1.5 * 10 4Concentration be inoculated in 96 well culture plates cultivate 24h after, the experimental group medicine is added to respectively in 96 plate holes, make final quality concentration be respectively 0.5,5.0,50 μ g/mL; Taxol continues to cultivate 72h, abandoning supernatant as positive control at 37 ℃; Every hole adds the MTT solution 100 μ L of 0.5mg/mL, and vibration shakes up, after continuing to cultivate 4h; Abandoning supernatant adds the DMSO of 100 μ L, slight jolting dissolving Formazan.Measure every hole absorbance with ELIASA, the detection wavelength is 570nm, and reference wavelength 650nm calculates the cell half-inhibition concentration.
Experimental result
This serial quinolines is to colon cancer cell (HCT-8), liver cancer cell (Bel-7402), and gastric carcinoma cells (BGC-823), the restraining effect of lung carcinoma cell (A549) and Proliferation of Human Ovarian Cell (A2780) is listed in table 1.
1, can find out that from table 1 majority of compounds all shows good antineoplastic activity.
2, when the 6-position is the methoxyl group replacement (2a-2d); 4-(3-chloro-4-fluoroanilino)-6,7-dimethoxy-quinoline activity is higher, 4-(3-acetylenylbenzene amido)-6; 7-dimethoxy-quinoline and 4-(3-toluidine)-6; The 7-dimethoxy-quinoline takes second place, 4-(3-chloroanilino)-6,7-dimethoxy-quinoline a little less than.
3, when the 6-bit substituent is changed to the hydroxyl replacement by methoxyl group (4a-4d); 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxy quinoline has active the inhibition to BGC-823 and A2780, and 4-(3-acetylenylbenzene amido)-6-hydroxyl-7-methoxy quinoline, 4-(3-toluidine)-6-hydroxyl-7-methoxy quinoline and 4-(3-chloroanilino)-6-hydroxyl-7-methoxy quinoline all do not have activity.
4, when the 6-bit substituent is changed to the replacement of 2-methoxy ethoxy by methoxyl group (6a-6d); 4-(3-chloro-4-fluoroanilino)-6-(2-methoxy ethoxy)-7-methoxy quinoline, 4-(3-acetylenylbenzene amido)-7-methoxyl group-6-(2-methoxy ethoxy) quinoline and 4-(3-chloroanilino)-6-(2-methoxy ethoxy)-7-methoxy quinoline all show certain activity, and 4-(3-toluidine)-6-(2-methoxy ethoxy)-7-methoxy quinoline unrestraint is active.
5, (8a～8c) when the 6-bit substituent is changed to 3-morpholine third generation oxygen base by methoxyl group; Inhibition activity with 4-(3-chloro-4-fluoroanilino)-6-(3-morpholino propoxy-)-7-methoxy quinoline is the highest, and 4-(3-toluidine)-6-(3-morpholine third generation oxygen base)-7-methoxy quinoline and 4-(3-chloroanilino)-6-(3-morpholino propoxy-)-7-methoxy quinoline also show active preferably.
6, the compound 2 that contains the quino-indole structure; 3-dimethoxy-8-fluoro-9-chloro-11H-indoles [3.2-c] quinoline (3a); 2; 3-dimethoxy-9-chloro-11H-indoles [3.2-c] quinoline (3b); 2-hydroxyl-3-methoxyl group-9-chloro-11H-indoles [3.2-c] quinoline (5a), 2-(2-methoxy ethoxy)-3-methoxyl group-8-fluoro-9-chloro-11H-indoles [3.2-c] (7a) and 2-(3-morpholino propoxy-)-3-methoxyl group-8-fluoro-9-chloro-11H-indoles [3.2-c] (9a), it is active all to show higher inhibition.
Table 1, antitumor activity of compound MTT The selection result
Figure S071B9982620070831D000201
Experiment conclusion
1, visible when 6 bit substituents are replaced by methoxyl group; No matter on 4 be which kind of substituting group; Compound provided by the invention all shows greater activity, explains that methoxyl group is an activation group, and hydroxyl comparatively speaking suppresses not have tangible activation effect to activity; (6a～6d), it is active that 6c shows unexpected unrestraint, although other compound also shows certain activity, compares apparent slightly inferior generally with 2 series when the 2-methoxy ethoxy replaced when the 6-bit substituent is changed to by methoxyl group.It is thus clear that substituent different meetings produce bigger influence to compound activity.See that to a certain extent the 2-methoxy ethoxy also is an activation group; When the 6-bit substituent is changed to 3-morpholine third generation oxygen base by methoxyl group (8a～8c), suppressing equally matched on the activity with substituted 2 series compounds of methoxyl group, and higher than the substituted compound activity of 2-methoxy ethoxy.It is thus clear that 3-morpholine third generation oxygen base is a potential activation group.
2, the compound 3a that contains the quino-indole structure, 3b, 5a, 7a and 9a all show higher inhibition activity, wherein with compound 3a (2,3-dimethoxy-8-fluoro-9-chloro-11H-indoles [3.2-c] quinoline) IC are particularly given prominence in the inhibition of A2780 50<0.1 * 10 -6M.Thus it is clear that, have indole structure quinoline compound ten minutes potentialization in the activity performance, for the structural research of quinoline antineoplastic compound provides a new thinking.
3, when different compounds acts on identical cancer cells; To the colon cancer cell effect the strongest be 3a and 8a; To the liver cancer cell effect the strongest be 2a, 3a and 8a, to the gastric carcinoma cells effect the strongest be 2a; To the lung carcinoma cell effect the strongest be 3a, to the Proliferation of Human Ovarian Cell effect the strongest be 3a.Can find out that it is best that 3a acts on the antitumour activity that shows in 5 kinds of knurl strains.Only account for the total ratio of compound from activated compound quantity and see that this series compound will be a little more than other four kinds of cancer cells to Proliferation of Human Ovarian Cell A2780 antitumour activity, Proliferation of Human Ovarian Cell is responsive to its inhibited reaction to this compounds.
4, see IC on the whole 50<1 * 10 -6The compound of M all contains 3-chloro-4-fluoroanilino part, has explained that 3-chloro-4-fluoroanilino is a crucial active substituent.And when 4 bit substituents are the 3-chloroanilino (2d, 4d and 6d), the activity change of compound is little, and visible 3-chloroanilino is not an activation group, keeps this group, and 6 replacements of conversion are little to the activity influence of compound.
The height that the quinoline series derivates shows at anti-tumor aspect suppresses active provides new approaches for antitumor research.Consideration can through change 4-bit substituent and 6-position side chain (as; Introduce methoxyl group, 3-morpholine third generation oxygen base etc.); Or thereby the synthetic quinoline series derivates that contains indole structure is realized the change and the lifting of compound activity, the antineoplastic compound that discovery has lateral reactivity.
Compare with existing compound, quinoline series compound provided by the invention, not only synthetic route is short; Raw material is simple and easy to; The experiment aftertreatment is simple and easy to operate, and has higher anti-tumor activity on the whole, for the structure activity relationship of further furtheing investigate this compounds is from now on laid a good foundation.

Claims (8)

1. quinoline derivatives, it is the compound of formula I:
Figure FDA0000102380240000011
Formula I
Perhaps pharmacy acceptable salt;
Wherein, R1 is C1, methyl or ethynyl;
R2 is H or F;
R3 is H, CH 3, CH 2CH 2OCH 3, or the morpholino propyl group.
2. quinoline derivatives as claimed in claim 1 is characterized in that: R1 is a chlorine, and R2 is H or F, and R3 is H, CH 3, CH 2CH 2OCH 3, or the morpholino propyl group.
3. quinoline derivatives as claimed in claim 1 is characterized in that: R1 is a methyl, and R2 is H, and R3 is H, CH 3, CH 2CH 2OCH 3, or the morpholino propyl group.
4. quinoline derivatives as claimed in claim 1 is characterized in that: R1 is an ethynyl, and R2 is H, and R3 is H, CH 3, or CH 2CH 2OCH 3
5. quinoline derivatives, it is the compound of formula II:
Figure FDA0000102380240000012
Formula II
Perhaps pharmacy acceptable salt;
Wherein, R4 is H or F;
R5 is a chlorine;
R6 is H, CH 3, CH 2CH 2OCH 3, or the morpholino propyl group.
6. quinoline derivatives as claimed in claim 5 is characterized in that: R4 is F, and R6 is CH 3, CH 2CH 2OCH 3, or the morpholino propyl group.
7. quinoline derivatives as claimed in claim 5 is characterized in that: R4 is H, and R6 is H, or CH 3
8. the described quinoline derivatives of one of claim 1 to 7 is in preparation antagonism colorectal carcinoma, liver cancer, the application in the medicine of cancer of the stomach and ovarian cancer.
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