CN102249997A - Group of 4-substituted phenylaminoquinoline compounds having antitumor activity - Google Patents

Group of 4-substituted phenylaminoquinoline compounds having antitumor activity Download PDF

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CN102249997A
CN102249997A CN201110136161XA CN201110136161A CN102249997A CN 102249997 A CN102249997 A CN 102249997A CN 201110136161X A CN201110136161X A CN 201110136161XA CN 201110136161 A CN201110136161 A CN 201110136161A CN 102249997 A CN102249997 A CN 102249997A
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compounds
group
substituted
phenylaminoquinoline
antitumor activity
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刘丹
孔建
张瑛
姜梦
宁志高
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Shenyang University of Chemical Technology
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Abstract

The invention provides a group of 4-substituted phenylaminoquinoline compounds having antitumor activity, relates to the field of pharmaceutical chemistry and particularly relates to a group of tyrosine kinase inhibitors (4-substituted phenylaminoquinoline compounds) having antitumor activity. The compounds have a chemical structure shown in general formula (I). The compounds have an inhibiting effect on EGFR (epidermal growth factor receptor) high-expression tumors and an especially strong inhibiting effect on stomach cancer cells. In the general formula (I), R1 is F or H, R2 is H or OCH3, and R3 represents one or more of halogen, CH3, OCH3, CH(CH3)2, NO2, OH and CN.

Description

One group of 4-substituted benzene aminoquinoline compounds with anti-tumor activity
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to one group of 4-substituted benzene aminoquinoline compounds with anti-tumor activity.
Background technology
Tyrosylprotein kinase (PTKs) is the key protein matter of intracellular signal transduction pathway, is that a class can catalytic tyrosine residue phosphorylation, the kinases that has vital role in cell growth, propagation, differentiation.The unconventionality expression of Tyrosylprotein kinase will cause cell proliferation to be regulated getting muddled, and will be also closely related with the chemotherapy resistance of the invasion and attack of tumour and transfer, tumor neovasculature generation, tumour.
Research is EGF-R ELISA (EGFR) the most widely in the protein tyrosine kinase, over surplus in the of nearly ten year, people design and filter out and can attack with EGFR is the organic micromolecule compound of target spot, and wherein successfully listings such as Buddhist nun are replaced for Buddhist nun and Ka Nai in imatinib, Gefitinib, dust Lip river.In these organic micromolecule compounds, quinazoline compounds is one of the most successful antineoplastic chemotherapy medicine classification, and Gefitinib, dust Lip river all belong to the quinazoline ditosylate salt tyrosine kinase inhibitor for Buddhist nun and Ka Nai for Buddhist nun etc.Based on this, the Pharmaceutical Chemist pair quinoline compound close with the quinazoline chemical structure carried out extensive studies, as the exploitation HKI-272 of Wyeth, SKI-606 is a 3-cyano quinolines class tyrosine kinase inhibitor, CN100540551C, CN100540552C discloses the anti-tumor activity of 3-cyano quinoline compound, CN1830964A discloses the restraining effect of 4-substituted benzene amino-3-nitroquinoline compound to A-431 human skin squamous cell carcinoma and MDA-MB-468 human breast cancer cell, and CN101258129A discloses the anti-tumor activity of 8-methoxyl group-2-phenoxyquinolines compound.
Summary of the invention
The object of the present invention is to provide a kind of is raw material with 2-anisidine (or 3-fluoroaniline) with ethoxy methylene diethyl malonate (EMME), through getting 4-chloroquinoline compound through condensation, the cyclization of Gould-Jacobs high temperature, hydrolysis, decarboxylation, chlorination reaction, further prepare 4-substituted benzene aminoquinoline compounds again with substituted aniline generation nucleophilic substitution reaction, this compound is inhibited to the tumour of EGF-R ELISA (EGFR) high expression level, especially has stronger restraining effect for stomach cancer cell.
The objective of the invention is to be achieved through the following technical solutions:
Primary aspect of the present invention has provided formula ICompound:
Figure 414486DEST_PATH_IMAGE001
Wherein, R 1=F or H,
R 2=H or OCH 3,
The one or more halogens of R3=, CH3, OCH3, CH (CH3) 2, NO2, OH, CN
Preferred compound of the present invention is specifically represented with following formula:
Compound of the present invention is adopted in the following method and is made:
Figure 518577DEST_PATH_IMAGE002
The present invention also provides the application of compound at the preparation antitumor drug.
Compound of the present invention is estimated with the pharmacology inspection procedure of standard, selecting tumour cell human cervical carcinoma Hela cell and people's cancer of the stomach BGC-823 cell of EGF-R ELISA (EGFR) high expression level is target cell, detect of the inhibition of this compounds with mtt assay, by power to the growth-inhibiting comparative compound antitumor action of tumour cell to growth of tumour cell.
Below be the pharmacological experiment and the data of The compounds of this invention:
The human cervical carcinoma Hela cell who takes the logarithm vegetative period and people's cancer of the stomach BGC-823 cell cultures are in 96 well culture plates, and every hole 100 μ L(approximately contain 4000 cells), put 37 ℃, cultivate in the 5% CO2 incubator.The administration group adds the tester that contains different concns after cultivating 24h, and each concentration is established three parallel holes at least.Negative control group adds and the isopyknic solvent of administration group, and establishes the blank group that only adds substratum, puts 37 ℃, cultivates in the 5% CO2 incubator.Abandon nutrient solution after 48 hours, every hole adds 50 μ L 1mg/mL MTT solution (PBS preparation).Hatched 4 hours for 37 ℃, abandon supernatant, every hole adds DMSO 150 μ L Rong Xie Jia Za particles, the gentle agitation dissolving.Under microplate reader wavelength 490nm condition, measure optical density value (OD), calculate the inhibiting rate of medicine pair cell with following formula:
Inhibiting rate=(negative control group OD value-dosing group OD value)/(negative control group OD value-blank group OD value) * 100%.
The pharmacological results sees Table 1 and table 2
Table 1 compound of the present invention is to the inhibiting rate (%) of cervical cancer HeLa cell growth
Figure 201110136161X100002DEST_PATH_IMAGE003
Table 2 compound of the present invention is to the inhibiting rate (%) of cancer of the stomach BGC-823 cell growth
Figure 918554DEST_PATH_IMAGE004
Gefitinib is the 4-anilinoquinazoline class EGFR tyrosine kinase inhibitor of AstraZeneca (AstraZeneca) company development, obtains the FDA approval in U.S.'s listing in 2003, is the active good antitumor medicine of open report, with it as positive control drug.Have certain anti-tumor activity by table 1 and the visible compound of the present invention of table 2, part of compounds is better than the positive control drug Gefitinib to HeLa Cells and people's cancer of the stomach BGC-823 cytoactive.
Advantage of the present invention and effect are:
The The compounds of this invention structure is simple relatively, is easy to preparation.Anti tumor activity in vitro studies show that this compound is inhibited to the tumour of EGF-R ELISA (EGFR) high expression level, especially has stronger restraining effect for stomach cancer cell.
Embodiment
Embodiment 1:
2-[(2-methoxyl group-phenylamino)-methylene radical]-diethyl malonate (a) synthetic
5.41 g (25.00 mmol) ethoxy methylene diethyl malonate and 6.5 mL toluene are put in the three-necked bottle, heated and stirred, slowly drip 3.08 g (25.00 mmol) 2-anisidine, in 83 ℃ of reaction 1.5 h, after reaction finishes the toluene steaming is removed, residuum adds normal hexane, stirring at room, filter, after the drying 5.85 g (79.72%) white solid a, m.p.48～50 ℃.
Embodiment 2:
Synthesizing of 4-hydroxyl-8-methoxyl group-quinoline-3-carboxylic acid ethyl ester (b)
With 8 mL Dowtherm-A(biphenyl-biphenyl ethers) reagent adds and to be equipped with in the 100 mL three-necked bottles of water distilling apparatus, heat under the magnetic agitation, 2.40 g (8.18 mmol) compound a drops in the reaction flask after dissolving with 4 mL Dowtherm-A, 250 ℃ are reacted 1h down.Be cooled to room temperature, add 12 mL sherwood oils, separate out solid.Filter, the filter cake petroleum ether, dry must 1.50 g (74.15%) white solid b, m.p.234～236 ℃, ESI-MS m/z:248.0 (M+H)+.
Embodiment 3:
Synthesizing of 4-hydroxyl-8-methoxyl group-quinoline-3-carboxylic acid (c)
Add 2.29 g (9.26 mmol) b and 2 mol/L sodium hydroxide solutions (20 mL) in the 100 mL three-necked bottles, stir back flow reaction 1.5 h down.Be cooled to room temperature, transfer pH to 4, separate out white solid with 4 mol/L hydrochloric acid, suction filtration, filter cake with water wash to neutral, after the drying 1.85 g (91.13%) white solid c, m.p.278～280 ℃.
Embodiment 4:
Synthesizing of 4-hydroxyl-8-methoxy quinoline (d)
Add 1.83 g (8.35mmol) c and 15 mL Dowtherm-A reagent in the three-necked bottle, back flow reaction 1 h is cooled to room temperature, adds 15 mL sherwood oils, separates out solid.Suction filtration, the filter cake petroleum ether, gray solid, silica gel chromatography, eluent is chloroform/methanol (V/V=20/1), 1.23 g (84.10%) white solid d, m.p.168～169 ℃, ESI-MS m/z:176.2 (M+H)+.
Embodiment 5:
Synthesizing of 4-chloro-8-methoxy quinoline (e)
1.20 g (6.85 mmol) d is dissolved in 30 mL 1, in the 2-ethylene dichloride, drip 1.26 g (8.22 mmol) phosphorus oxychloride, 1 h refluxes, be cooled to room temperature, under ice bath, transfer pH to neutral with ammoniacal liquor, get organic phase, organic phase is washed with saturated aqueous common salt (2 * 10 mL), and anhydrous magnesium sulfate drying removes solvent under reduced pressure and gets yellow solid, silica gel chromatography, eluent is petrol ether/ethyl acetate (V/V=1/1), 0.99 g (74.64%) faint yellow solid e, m.p.80～81 ℃.1H?NMR(300?MHz，CDCl3)：4.11（3H，s，OCH3），7.11?(1H，d，J=7.2?Hz，Ar-H-7)，7.53~7.60?(2H，m，Ar-H-3，6)，7.81（1H，dd，J=8.7?Hz，J=1.2?Hz，Ar-H-5），8.80?(1H，d，J=4.8?Hz，Ar-H-2)；ESI-MS(m/s):?194.4[M+H]+。
Embodiment 6:
Synthesizing of 4-(4 '-isopropyl benzene amino)-8-methoxy quinoline (9)
With 50mg (0.25mmol) e, 42mg (0.31mmol) 4-isopropyl aniline, 36mg (0.31mmol) pyridine hydrochloride is in the 6mL Virahol, backflow 1h, cooling adds the 4mL ether, the 10mL saturated sodium bicarbonate, stirring at room 0.5h, suction filtration, ether washing leaching cake, drying, 60mg (79.47%) white solid 9, m.p.236～238 ℃.1H?NMR(300?MHz，CDCl3)：?1.29?(6H，d，J=6.9?Hz，CH3)，2.90~2.99?(1H，m，CH)，4.08（3H，s，OCH3），6.96~6.99?(1H，m，Ar-H-3)，7.05?(1H，dd，J=6.9?Hz，J=2.1?Hz，Ar-H-7)，7.21~7.30?(4H，m，Ar-H-2,3’,4’,6’)，7.40~7.48?(2H，m，Ar-H-5,6)，?8.53?(1H，d，J=5.1?Hz，Ar-H-2)；ESI-MS?m/z:?293.6(M+H)+。
Embodiment 7:
Synthesizing of 4-(3 '-chlorobenzene amino)-7-fluorine quinoline (15).
Method according to embodiment 1 to 6 changes raw material into m-fluoroaniline and ethoxy methylene diethyl malonate reaction, and other preparation is identical, promptly.m.p.196-197℃。1H?NMR(600MHz,?CDCl3)?δ:?8.62-8.61(d,?1H,?2-H),?7.96-7.93(q,?1H,?5-H),?7.71-7.69(q,?1H,?8-H),?7.37-7.27(m,?3H,?6’-H,?5’-H,?6-H),?7.19-7.17(m,?2H,?2’-H,4’-H),?7.02-7.01(d,?1H,?3-H);?ESI-MS?m/z:?273.4(M+H)+。

Claims (3)

1. one group of 4-substituted benzene aminoquinoline compounds with anti-tumor activity is characterized in that, its chemical structure suc as formula ( I)Shown in:
Figure 118877DEST_PATH_IMAGE002
Wherein, R 1=F or H,
R 2=H or OCH 3,
R 3=one or more halogens, CH 3, OCH 3, CH (CH 3) 2, NO 2, OH, CN.
2. one group of 4-substituted benzene aminoquinoline compounds with anti-tumor activity according to claim 1 is characterized in that described compound is meant following compound:
Figure 276713DEST_PATH_IMAGE004
3. claim 1,2 described one group of 4-substituted benzene aminoquinoline compounds with anti-tumor activity is characterized in that 4-substituted benzene aminoquinoline compounds uses in the preparation antitumor drug.
CN201110136161XA 2011-05-25 2011-05-25 Group of 4-substituted phenylaminoquinoline compounds having antitumor activity Pending CN102249997A (en)

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CN104119350A (en) * 2013-04-28 2014-10-29 广东东阳光药业有限公司 Amino quinazoline derivatives as well as salts and application method thereof
WO2017198196A1 (en) * 2016-05-18 2017-11-23 王子厚 Quinoline derivative having anti-tumor activity
WO2018007648A1 (en) * 2016-07-08 2018-01-11 INSERM (Institut National de la Santé et de la Recherche Médicale) 4-anilino-quinoline compounds as anti-cancer agents
WO2019134975A1 (en) * 2018-01-05 2019-07-11 Institut National De La Sante Et De La Recherche Medicale (Inserm) Substituted halo-quinoline derivatives, method of preparation and applications thereof
CN115057816A (en) * 2022-02-23 2022-09-16 郑州大学 4-aminoquinoline compound, preparation method thereof and application thereof in antitumor drugs
CN116693452A (en) * 2023-05-24 2023-09-05 中山大学 Quinoline derivative and preparation method and application thereof

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104119350A (en) * 2013-04-28 2014-10-29 广东东阳光药业有限公司 Amino quinazoline derivatives as well as salts and application method thereof
US9556191B2 (en) 2013-04-28 2017-01-31 Sunshine Lake Pharma Co., Ltd. Aminoquinazoline derivatives and their salts and methods of use thereof
CN104119350B (en) * 2013-04-28 2017-04-12 广东东阳光药业有限公司 Amino quinazoline derivatives as well as salts and application method thereof
WO2017198196A1 (en) * 2016-05-18 2017-11-23 王子厚 Quinoline derivative having anti-tumor activity
WO2018007648A1 (en) * 2016-07-08 2018-01-11 INSERM (Institut National de la Santé et de la Recherche Médicale) 4-anilino-quinoline compounds as anti-cancer agents
JP7039579B2 (en) 2016-07-08 2022-03-22 アンセルム（アンスティチュート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル） 4-Anilino-quinoline compound as an anticancer agent
JP2019521193A (en) * 2016-07-08 2019-07-25 アンセルム（アンスティチュート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシェルシュ・メディカル） 4-Anilino-quinoline compounds as anticancer agents
AU2017294572B2 (en) * 2016-07-08 2021-11-04 Chu De Nice 4-anilino-quinoline compounds as anti-cancer agents
JP2021510176A (en) * 2018-01-05 2021-04-15 アンスティトゥート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシャルシュ・メディカル・（インセルム） Substituted haloquinolin derivative, its preparation method and application
CN112055706A (en) * 2018-01-05 2020-12-08 健康和医学国家研究院 Substituted halo-quinoline derivatives, process for their preparation and their use
WO2019134975A1 (en) * 2018-01-05 2019-07-11 Institut National De La Sante Et De La Recherche Medicale (Inserm) Substituted halo-quinoline derivatives, method of preparation and applications thereof
AU2019205595B2 (en) * 2018-01-05 2023-01-05 Centre Hospitalier Universitaire De Nice Substituted halo-quinoline derivatives, method of preparation and applications thereof
JP7268053B2 (en) 2018-01-05 2023-05-02 アンスティトゥート・ナシオナル・ドゥ・ラ・サンテ・エ・ドゥ・ラ・ルシャルシュ・メディカル・（インセルム） Substituted haloquinoline derivatives, methods for their preparation and applications
CN112055706B (en) * 2018-01-05 2023-11-10 健康和医学国家研究院 Substituted halo-quinoline derivatives, preparation method and application thereof
CN115057816A (en) * 2022-02-23 2022-09-16 郑州大学 4-aminoquinoline compound, preparation method thereof and application thereof in antitumor drugs
CN115057816B (en) * 2022-02-23 2023-05-23 郑州大学 4-aminoquinoline compound, preparation method thereof and application thereof in anti-tumor drugs
CN116693452A (en) * 2023-05-24 2023-09-05 中山大学 Quinoline derivative and preparation method and application thereof

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