Quinolines derivative and preparation method thereof and application of quinolines derivative to preparation of anti-tumor medicine

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: 2017-01-04
SUN YAT SEN UNIV
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  • 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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  • Quinolines derivative and preparation method thereof and application of quinolines derivative to preparation of anti-tumor medicine
  • Quinolines derivative and preparation method thereof and application of quinolines derivative to preparation of anti-tumor medicine
  • Quinolines derivative and preparation method thereof and application of quinolines derivative to preparation of anti-tumor medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Synthesis of compound S4

[0055] Dissolve 0.1 mol of phenoxyacetic acid in 150 mL of chloroform, add 17.5 mL of thionyl chloride to reflux at 60°C for 3 hours, and then rotate under reduced pressure to remove the solvent to obtain a brown liquid. Then add acetonitrile as a solvent and mix with 0.1 mol of o-aminobenzene The formic acid undergoes a condensation reaction to obtain S1. The PPA is then preheated to 130° C. and added to S1 for cyclization reaction to obtain S2. S2 is reacted with thionyl chloride at 80°C under DMF catalysis to obtain compound S3. Then, 2.2 g of p-toluenesulfonic acid monohydrate was heated to 120° C. in a pressure tube, 5 mmol S3 was added, stirred for 10 minutes, and cooled to room temperature. Add 10mmol propargylamine and react at 120°C for 6 hours. After the reaction is completed, cool, dissolve the solid with 30mL chloroform: methanol=2:1, adjust the pH to 12 with 1N NaOH solution, then extract twice with 50mL chloroform, wash...

Embodiment 2

[0058] Example 2: Synthesis of compound CK1

[0059] Take compound S4 (0.25g, 1mmol) in a 50mL single-necked flask, add 10mL of tetrahydrofuran, add 2mL of pre-prepared solution containing (25mg, 0.1mmol) copper sulfate pentahydrate, 2mL of the ready-to-use containing (50mg, 0.2 mmol) 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 is completed, the solvent is spin-dried and purified by column chromatography to obtain a pale yellow solid CK1 (mobile phase: dichloromethane: methanol = 200-50:1; ammonia 0.5%).

[0060] The yield was 88%. m.p.121.5-122.6℃; 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 )δ158.1,147.1,146.9,145.5,133.7,130.0,129.5,128.0,12...

Embodiment 3

[0062] Example 3: 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 CK2 as a light yellow solid.

[0064] The yield was 83%. m.p.133.1-134.3℃; 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 = 6.9 Hz, 4H), 0.79 (t, J = 6.9 Hz, 6H). 13 C NMR(101MHz, CDCl 3 )δ158.1,146.9,146.7,145.3,133.8,133.7,130.1,129.4,128.1,124.1,123.3,123.2,122.8,122.2,120.4,118.1,111.8,52.7,49.0,47.1,40.9,11.7. HPLC purity: 99.2% .HRMS(ESI)m / z:calcd forC 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 antineoplastic drugs. Background technique [0002] Cancer is one of the main diseases threatening human health and life safety. According to statistics, there are about 6 million new cancer patients worldwide each year. The research and development of anti-cancer drugs has always been a hot spot for chemists and pharmacologists. Finding anti-cancer drugs with high efficiency, high selectivity and low side effects is one of the important directions of drug research and development. [0003] Designing and synthesizing anti-cancer drugs with DNA as the target, especially designing and synthesizing small molecule inhibitors for the special nucleic acid high-level structure in the promoter region of the oncogene c-myc, which has important physiological significance, is an impor...

Claims

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Application Information

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Patent Type & Authority Applications(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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