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A kind of quinoline derivatives and its preparation method and application in the preparation of antitumor drugs

A derivative and quinoline technology, applied in the field of medicinal chemistry, can solve the problems of limited resources, the need to improve the selection ability, and the limitation of anti-cancer applications, and achieve the effect of strong interaction

Active Publication Date: 2019-02-12
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Although the anticancer effect of indoquinoline compounds has been confirmed, but due to the fact that a variety of indoquinoline compounds currently available against lymphoma-specific targets (G-quadruplex DNA in the c-myc promoter ) selection ability still needs to be improved, and due to the limited resources of indoquinoline compounds in nature, at present, the application of indoquinoline compounds in anticancer aspects still has great limitations

Method used

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  • A kind of quinoline derivatives and its preparation method and application in the preparation of antitumor drugs
  • A kind of quinoline derivatives and its preparation method and application in the preparation of antitumor drugs
  • A kind of quinoline derivatives and its preparation method and application in the preparation of antitumor drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1: the synthesis of compound S4

[0055] Dissolve 0.1mol of phenoxyacetic acid in 150mL of chloroform, add 17.5mL of thionyl chloride to reflux at 60°C for 3 hours, then remove the solvent by rotary evaporation under reduced pressure to obtain a brown liquid, then add acetonitrile as a solvent and mix with 0.1mol of anthranilic acid Formic acid undergoes condensation reaction to obtain S1. Then preheat PPA to 130°C and add S1 for ring closure reaction to obtain S2. Compound S3 was obtained by reacting S2 with thionyl chloride at 80°C under the catalysis of DMF. Then, 2.2 g of p-toluenesulfonic acid monohydrate was heated to 120° C. in a pressure-resistant tube, and then 5 mmol of S3 was added, stirred for 10 minutes, and cooled to room temperature. Add 10 mmol propargylamine, and react at 120° C. for 6 hours. Cool after the reaction is complete, dissolve the solid with 30mL chloroform:methanol=2:1, adjust the pH to 12 with 1N NaOH solution, extract twice wi...

Embodiment 2

[0058] Embodiment 2: the synthesis of compound CK1

[0059] Take compound S4 (0.25g, 1mmol) and place it in a 50mL single-necked bottle, add 10mL of tetrahydrofuran, add 2mL of pre-prepared solution containing (25mg, 0.1mmol) copper sulfate pentahydrate, 2mL of the existing solution containing (50mg, 0.2 mmol) of sodium ascorbate solution, and finally add 1.2 equivalents of: N,N-dimethyl-2-azidoethylamine. The reaction was stirred at 35°C and monitored by TLC. After the reaction was completed, the solvent was spin-dried and purified by column chromatography to obtain light yellow solid CK1 (mobile phase: dichloromethane:methanol=200-50:1; ammonia water 0.5%).

[0060] Yield 88%. m.p.121.5-122.6°C; 1 H NMR (400MHz, CDCl 3 )δ8.41(d, J=7.7Hz,1H),8.18(dd,J=8.5,0.7Hz,1H),7.94(d,J=8.5Hz,1H),7.71(s,1H),7.66– 7.58(m,3H),7.43(ddd,J=15.3,7.1,1.2Hz,2H),5.94(s,1H),5.36(d,J=5.8Hz,2H),4.38(t,J=6.2Hz ,2H),2.69(t,J=6.2Hz,2H),2.19–2.14(s,6H). 13 C NMR (101MHz, CDCl 3 )δ158.1, 147.1, 14...

Embodiment 3

[0062] Embodiment 3: the synthesis of compound CK2

[0063] The method is the same as in Example 2, except that N,N-diethyl-2-azidoethylamine is used instead of N,N-dimethyl-2-azidoethylamine to obtain light yellow solid CK2.

[0064] Yield 83%. m.p.133.1-134.3°C; 1 H NMR (400MHz, CDCl 3 )δ8.39(d, J=6.9Hz, 1H), 8.19(d, J=8.4Hz, 1H), 7.93(d, J=8.5Hz, 1H), 7.63(dt, J=19.1, 7.5Hz, 4H), 7.45(t, J=7.3Hz, 2H), 5.81(s, 1H), 5.36(d, J=5.8Hz, 2H), 4.33(s, 2H), 2.78(s, 2H), 2.40( d,J=6.9Hz,4H),0.79(t,J=6.9Hz,6H). 13 C NMR (101MHz, CDCl 3 )δ 158.1, 146.9, 146.7, 145.3, 133.8, 133.7, 130.1, 129.4, 128.1, 124.1, 123.3, 123.2, 122.8, 122.2, 120.4, 118.1, 111.8, 52.7, 49.0, 47.1, 40.9H, 12 pPLC. .HRMS(ESI)m / z:calcd for C 24 h 26 N 6 O,[M+H] + ,415.2241found 415.2246.

[0065]

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Abstract

The invention discloses a quinolines derivative. The structural formula of the quinolines derivative is shown as the formula (I) or the formula (II) in the description, wherein R represents hydroxyl, phenyl, substituted phenyl, naphthenic base, amino, substituted amino, pentabasic or hexabasic heterocyclic group, C1 to C8 alkyl or substituted C1 to C8 alkyl, halogeno or glycosyl; X is N, O or S; Y is C1 to C3 alkyl or hydrogen and n is an integer from 0 to 6. The invention further discloses a preparation method and application of the quinolines derivative. The quinolines derivative provided by the invention has a very strong inhibition effect on transcription expression of a cancer gene c-myc and has a remarkable inhibition effect on a plurality of cancer cell plants and particularly has a relatively strong inhibition effect on lymphoma cells; the quinolines derivative has small toxicity on normal cells and has a wide application space in the preparation of an anti-tumor medicine.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a quinoline derivative, a preparation method thereof and an application in the preparation of antitumor drugs. Background technique [0002] Cancer is one of the major diseases that threaten human health and life safety. According to statistics, there are about 6 million new cancer patients in the world every year. The research and development of anticancer drugs has always been the focus of chemists and pharmacologists. Finding anticancer drugs with high efficiency, high selectivity and low toxicity is one of the important directions of drug research and development. [0003] Designing and synthesizing anticancer drugs with DNA as the target, especially designing and synthesizing small molecule inhibitors targeting the special nucleic acid advanced structure in the promoter region of the oncogene c-myc, which has important physiological significance, is an imp...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/048C07D471/04A61K31/4355A61K31/437A61K31/5377A61K31/4545A61K31/496A61P35/00
CPCC07D471/04C07D491/048
Inventor 欧田苗曾德颖黄志纾古练权王世珂邝国滔
Owner SUN YAT SEN UNIV
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