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A kind of quinazolinone and α, β-unsaturated ketone conjugate derivative and its preparation method and application

A quinazolinone and unsaturated technology, applied in the field of medicinal chemistry, can solve the problems of high toxicity and side effects, drug resistance, etc., and achieve the effects of inhibiting proliferation, broadly anti-tumor, and inhibiting transcription and expression

Active Publication Date: 2020-03-20
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

High toxicity and side effects, drug resistance and other issues are still the main obstacles to clinical tumor drug treatment

Method used

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  • A kind of quinazolinone and α, β-unsaturated ketone conjugate derivative and its preparation method and application
  • A kind of quinazolinone and α, β-unsaturated ketone conjugate derivative and its preparation method and application
  • A kind of quinazolinone and α, β-unsaturated ketone conjugate derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: the synthesis of compound 2

[0046]

[0047] Put 2-amino-4,5-difluorobenzoic acid (5g, 29mmol) and 2-pyrrolidone (5mL) in a 100mL single-necked flask, and add 20mL of phosphorus oxychloride (POCl 3), let it drip for 30min, heat and reflux at 103°C for 24h, add the reaction system dropwise into 200mL ice water, adjust the pH to weak alkalinity with concentrated NaOH solution, and filter with suction to obtain the crude product, which is purified by silica gel column chromatography (elution Reagent: V (petroleum ether): V (ethyl acetate) = 1:1) to obtain compound m1, 5.4 g, yield 85%.

[0048] 1 H NMR (400MHz, CDCl 3 )δ8.20–7.85(m,1H),7.60–7.34(m,1H),4.42–4.06(m,2H),3.19(td,J=7.9,2.7Hz,2H),2.43–2.16(m, 2H).LC-MS m / z:223[M+H] +.

Embodiment 2

[0049] Embodiment 2: the synthesis of compound 3

[0050]

[0051] Take compound 2 (2.22g, 10mmol), diethylaminopropylamine (3ml, 24mmol), put it in a thick-walled pressure bottle, heat and stir at 100°C overnight to obtain an orange-yellow solution, and after the reaction system cools down to room temperature, there are a large amount of light A yellow precipitate was precipitated, filtered with suction, and the filter cake was obtained as a milky white solid, which was vacuum-dried to obtain 2.3 g of a milky white solid, with a yield of 69%.

[0052] 1 H NMR (400MHz, CDCl 3 )δ7.72(d,J=11.7Hz,1H),6.72(s,1H),6.67(d,J=7.7Hz,1H),4.19–4.12(m,2H),3.31(dd,J=10.6 ,5.8Hz,2H),3.11(t,J=7.9Hz,2H),2.63–2.59(m,2H),2.55(q,J=7.1Hz,4H),2.30–2.19(m,2H),1.89 –1.81(m,2H),1.06(t,J=7.1Hz,6H).

Embodiment 3

[0053] Embodiment 3: the synthesis of compound 4

[0054]

[0055] According to the synthetic method of 3, 1.8 g milky white solid was obtained, and the yield was 52%. 1 H NMR (400MHz, CDCl 3 )δ7.67(d,J=11.7Hz,1H),6.62(d,J=7.7Hz,1H),4.13–4.05(m,2H),3.72–3.67(m,2H),3.66–3.61(m ,2H),3.25(dd,J=11.1,5.8Hz,2H),3.04(t,J=7.9Hz,4H),2.51–2.46(m,3H),2.24–2.12(m,4H),1.86– 1.75(m,2H).

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Abstract

The invention discloses a quinazolinone and alpha, beta-unsaturated ketone conjugated derivative. The quinazolinone and alpha, beta-unsaturated ketone conjugated derivative has a structural formula shown as a formula (I) or a formula (II) in the description, wherein R1 is hydrogen, amino groups, substituted amino groups, or five-membered or six-membered heterocyclic groups; R2 is hydrogen, phenyl, substituted phenyl, or benzo-heterocycle compound; the substituted group is selected from C1-5 alkyl, C1-8 alkoxy, halogeno group, phenyl, amino groups, or five-membered or six-membered heterocyclic groups. The quinazolinone and alpha, beta-unsaturated ketone conjugated derivative provided by the invention can effectively inhibit the growth of various tumor cells; the transcription and the expression of protooncogene c-MYC can be obviously inhibited; wide application space is realized in the anti-tumor medicine preparation. The formulas (I) and (II) are shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and more specifically relates to a conjugated derivative of quinazolinone and α, β-unsaturated ketone and its preparation method and application. Background technique [0002] Malignant tumors are a large class of diseases that endanger human health. According to the World Health Organization (WHO), 8 million people die of cancer every year in the world, and nearly 2 million people die of cancer every year in China. In recent years, major breakthroughs have been made in the research and development of anticancer drugs, and many new drugs have entered clinical research, but there are still many challenges. High toxicity and side effects, drug resistance and other issues are still the main obstacles to clinical tumor drug treatment. [0003] As an important proto-oncogene, c-MYC regulates cell proliferation, differentiation, metabolism, apoptosis and other life processes. Studies have...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61K31/5377A61P35/00
CPCC07D487/04
Inventor 黄志纾谭嘉恒王玉青王晨曦
Owner SUN YAT SEN UNIV
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