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Quinazoline derivative and preparation method thereof and application of quinazoline derivative for preparing anticancer drugs

A technology for anticancer drugs and derivatives, which is applied to quinazoline derivatives and their preparation, and is used in the field of anticancer drugs, which can solve problems such as application limitations and limited resources, and achieve tumor suppression, increase groove binding force, The effect of increasing selectivity

Inactive Publication Date: 2013-05-29
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the anticancer effect of indoquinoline compounds has been confirmed, the selection ability of the existing indoquinoline compounds to G-quadruplex DNA still needs to be improved, and at the same time due to the indoquinoline compounds in nature The resources of morphine compounds are limited. At present, the application of indoquinoline compounds in anticancer is still relatively limited.

Method used

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  • Quinazoline derivative and preparation method thereof and application of quinazoline derivative for preparing anticancer drugs
  • Quinazoline derivative and preparation method thereof and application of quinazoline derivative for preparing anticancer drugs
  • Quinazoline derivative and preparation method thereof and application of quinazoline derivative for preparing anticancer drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment one: the synthesis of compound QMC-2

[0038] Dissolve 549mmol of dry 4-chloro-2-nitrobenzoic acid in 50ml of thionyl chloride, and evaporate the thionyl chloride after reflux for 1.5h. The obtained brown liquid is slowly and dropwise added to the dissolved 766mmol of anthranilamide and 1532mmol of triethylamine in chloroform (200ml), stirred at room temperature for 5h, filtered, washed with ethanol, and recrystallized with ethanol to obtain white solid QMC-2.

[0039] Yield: 86%; 1 H NMR (400MHz, DMSO-d 6 ) 12.56(s, 1H), 8.44(d, J=8.2Hz, 1H), 8.39(s, 1H), 8.26(d, J=1.6Hz, 1H), 8.04-7.96(m, 1H), 7.93-7.85 (m, 2H), 7.81(s, 1H), 7.59(t, J=7.8Hz, 1H), 7.24(t, J=7.6Hz, 1H).ESI-MS m / z: 320[M+H] + .

[0040]

[0041] Compound QMC-2

Embodiment 2

[0042] Embodiment two: the synthesis of compound Q-2

[0043]

[0044] Compound Q-2

[0045] The method is the same as in Example 1, except that 2-nitrobenzoic acid is used instead of 4-chloro-2-nitrobenzoic acid to obtain white solid Q-2.

[0046] Yield: 88%; 1 H NMR (400MHz, DMSO) 12.57(s, 1H), 8.53(d, J=8.2Hz, 1H), 8.43(s, 1H), 8.13(d, J=8.3Hz, 1H), 7.95-7.78(m, 5H), 7.62(dd , J=11.4, 4.0Hz, 1H), 7.29-7.22(m, 1H).ESI-MS m / z: 286[M+H] + .

Embodiment 3

[0047] Embodiment three: the synthesis of compound QMC-3

[0048] Mix 376mmol dry QMC-2 with 100ml 10% potassium hydroxide aqueous solution and 100ml ethanol, and then react at 95°C for 4-5 hours. After the reaction, ethanol was distilled off, and the pH value of the solution was adjusted to between 1 and 3 with hydrochloric acid, and a large amount of white solids were precipitated, filtered and dried, and passed through petroleum ether / ethyl acetate (volume ratio 3 / 1) as eluent Purification by silica gel chromatography afforded QMC-3 as a white solid.

[0049] Yield: 92%; 1 H NMR (400MHz, DMSO) 12.87(s, 1H), 8.19(d, J=2.0Hz, 1H), 8.05(d, J=8.0Hz, 1H), 7.89(dd, J=8.4, 2.0Hz, 1H), 7.78(d, J =8.4Hz, 1H), 7.71(t, J=7.8Hz, 1H), 7.51(d, J=8.2Hz, 1H), 7.44(t, J=7.7Hz, 1H).ESI-MSm / z: 302 [M+H] + .

[0050]

[0051] Compound QMC-3

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Abstract

The invention belongs to the fields of drugs and chemical industry, and discloses a quinazoline derivative and a preparation method thereof and an application of the quinazoline derivative used as an anticancer drug. The structural formula of the quinazoline derivative is shown in the specifications, wherein R1 is NH(CH2)mNR5 or NH(CH2)m-Ar; R2 is NHCO(CH2)n NR5, NHCO(CH2)n-Ar, NHCO(CH2)nNH(CH2)nNR5 or NHCO(CH2)nNH(CH2)n-Ar; R3 is F, Cl, Br, I, H, CH3, SO2CH3 or OCH3; R4 is H, NHCO(CH2)nNR5, NHCO(CH2)n-Ar, NHCO(CH2)nNH(CH2)nNR5 or NHCO(CH2)nNH(CH2)n-Ar; -Ar represents various aromatic rings comprising various aromatic heterocyclic rings; m is equal to 2, 3 or 4; n is equal to 1, 2, 3, 4 or 5; and R5 represents alkyl of C1-6, cycloalkyl of C3-6, piperidyl, morpholinyl, piperazinyl or quinoxalinyl. The invention simultaneously discloses the preparation method of the quinazoline derivative and the application of the quinazoline derivative used as the anticancer drug. The experiment proves that the quinazoline derivative of the invention has strong inhibiting effect on telomere DNA expression, has obvious inhibiting effect on various kinds of cancer cell strains, has low toxicity to normal cells, and has wide application prospects in preparation of anticancer drugs.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a quinazoline derivative, a preparation method thereof, and an application thereof in the preparation of anticancer drugs. Background technique [0002] Cancer is one of the major diseases that threaten human health and life safety. According to statistics, there are about 4 million new cancer patients in the world every year. The research and development of anticancer drugs has always been a hot spot for chemists and pharmacologists. Finding anticancer drugs with high efficiency, high selectivity and less toxic side effects 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 advanced structure of telomeric DNA and proto-oncogene DNA, which have important physiological significance, is an i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94A61K31/517A61K31/5377A61P35/00
Inventor 黄志纾古练权李增卢宇靖
Owner SUN YAT SEN UNIV
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