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Quinolinone-containing pyrimido-five-membered heterocyclic compounds and a preparation method and application thereof

A technology for five-membered heterocycles and compounds, which is applied in the field of novel pyrimido five-membered heterocycles containing quinolinones, which can solve the problems of reduced drug efficacy and achieve the effect of simple and feasible synthetic methods and good application prospects

Active Publication Date: 2018-06-01
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, with the long-term application of first- and second-generation EGFR inhibitors, tumor biology studies have found that most patients have drug-resistant mutations, mainly EGFR-T790M mutations, which reduce the efficacy of first- and second-generation drugs; The new generation of EGFR inhibitors will cause side effects such as nausea and skin rash due to the inhibition of EGFR-wt while playing a therapeutic role (Liao BC, Lin CC, Lee JH, YangJC. Update on recent preclinical and clinical studies of T790M mutant-specific irreversible Epidermal growth factor receptor tyrosine kinase inhibitors[J].Journal of biomedical science,2016,23(1):86)

Method used

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  • Quinolinone-containing pyrimido-five-membered heterocyclic compounds and a preparation method and application thereof
  • Quinolinone-containing pyrimido-five-membered heterocyclic compounds and a preparation method and application thereof
  • Quinolinone-containing pyrimido-five-membered heterocyclic compounds and a preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: the preparation of compound 3

[0031]

[0032] To a mixed solution of acetone (8mL) and water (16mL), add m-methoxyaniline (1g, 8.12mmoL), potassium carbonate (1.68g, 12.18mmoL), cinnamoyl chloride (1.62g, 9.74mmoL) successively, ice The bath was stirred for 30 min, and the reaction was monitored by TLC. After the reaction, the reaction system was poured into ice water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 3 with a yield of 98%. White solid,Mp 114-115℃. 1 H NMR (400MHz, DMSO-d 6 )δ10.19(s,1H),7.61(dd,J=13.0,12.1Hz,3H),7.49–7.38(m,4H),7.22(dd,J=8.8,3.9Hz,2H),6.83(d ,J=15.7Hz,1H),6.69–6.62(m,1H),3.75(s,3H). 13 C NMR (100MHz, DMSO-d 6 )δ163.53, 159.52, 140.39, 140.20, 134.68, 129.76, 129.55, 128.99, 127.69, 122.23, 111.55, 108.76, 105.08, 54.95.

Embodiment 2

[0033] Embodiment 2: the preparation of compound 4

[0034]

[0035] Under ice bath, aluminum trichloride (3.16g, 23.69mmoL) was added in batches to the suspension of compound 3 (1g, 3.95mmoL) in chlorobenzene (30mL), and the reaction system was gradually heated to 120°C and refluxed for 3-5h , TLC monitors the reaction system. After the reaction, the reaction system was evaporated to dryness under reduced pressure, separated and purified by silica gel column chromatography to obtain compound 4 with a yield of 54%. Brownsolid,Mp>300℃. 1 H NMR (400MHz, DMSO-d 6 )δ11.50(s,1H),10.11(s,1H),7.73(d,J=9.4Hz,1H),7.44(d,J=8.5Hz,1H),6.72–6.56(m,2H), 6.21(d,J=9.4Hz,1H). 13 C NMR (100MHz, DMSO-d 6 )δ162.29, 160.06, 141.05, 140.45, 129.42, 116.07, 112.94, 112.46, 100.09.

Embodiment 3

[0036]Embodiment 3: the preparation of compound 5

[0037]

[0038] Compound 4 (0.7g, 4.34mmoL) and 2,4-dichlorothieno[3,2-d]pyrimidine (1.07g, 5.21mmoL) were added to the reaction flask, and then potassium carbonate (1.8g, 13.03mmoL ), water (10mL), acetonitrile (50mL), reflux at 70°C for 2-5h, and monitor the reaction system by TLC. After the reaction, a white solid was precipitated, cooled, suction filtered, the filter cake was washed several times with dichloromethane and water, and dried in a vacuum oven to obtain compound 5 with a yield of 78%. White solid,Mp>300℃. 1 H NMR (400MHz, DMSO-d 6 )δ8.57(d, J=5.4Hz, 1H), 7.90(d, J=9.5Hz, 1H), 7.75(d, J=8.6Hz, 1H), 7.65(d, J=5.4Hz, 1H) ,7.24(d,J=2.2Hz,1H),7.14(dd,J=8.5,2.3Hz,1H),6.50(d,J=9.5Hz,1H). 13 C NMR (100MHz, DMSO-d 6 )δ164.43, 163.92, 163.05, 154.81, 152.33, 141.50, 139.72, 139.15, 129.33, 123.51, 121.73, 117.73, 116.29, 115.28, 108.54.

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Abstract

The invention discloses quinolinone-containing pyrimido-five-membered heterocyclic compounds and a preparation method and application thereof and belongs to the field of medicinal chemistry. The compounds are shown in the general formula I. The compounds have significant inhibitory and killing effects on a variety of tumor cells such as H1975, A549, PC9, PC3 and HGC and have good inhibitory activity to a human epidermal growth factor receptor EGFR-L858R / T790M mutant in the in-vitro kinase level. The compounds can be used as candidate or lead compounds in preparation of antitumor drugs.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of novel quinolinone-containing pyrimido five-membered heterocyclic compounds, their preparation method, activity evaluation and their application as a class of new antitumor drug lead compounds. Background technique [0002] Tumor is a disease that seriously endangers human health and is difficult to overcome. There are many broad-spectrum anti-tumor drugs that have been marketed, but there are some common problems, such as high toxicity, weak targeting, and easy drug resistance. In contrast, targeted drugs are committed to continuously improving the therapeutic effect and reducing adverse reactions, and their research and development has received more and more attention. Abnormally expressed protein targets in tumor cells are the breakthroughs in current research and development. [0003] Epidermal growth factor receptor (hereinafter referred to as EGFR) is a glycopr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04A61K31/519A61K31/5377A61K31/541A61P35/00
CPCC07D495/04
Inventor 赵文余斌陈阳
Owner ZHENGZHOU UNIV
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