2, 4-disubstituted quinazoline compound for inhibiting EGFR (epidermal growth factor receptor) as well as preparation method and application of 2, 4-disubstituted quinazoline compound

A technology of quinazolines and compounds, which is applied in the field of antitumor pharmacy, can solve the problems of inability to activate downstream substrates, and achieve good antiproliferative activity

Active Publication Date: 2022-07-29
ZIGONG NO 4 PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the two classes of inhibitors work in different ways, Pin1 inhibitors work by making Pin1 unable to bind to substrates or disrupt its function of isomerizing pSer / Thr-Pro substrates, while EGFR inhibitors work by inhibiting EGFR Phosphorylated to make it inactive, so that it cannot activate downstream substrates

Method used

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  • 2, 4-disubstituted quinazoline compound for inhibiting EGFR (epidermal growth factor receptor) as well as preparation method and application of 2, 4-disubstituted quinazoline compound
  • 2, 4-disubstituted quinazoline compound for inhibiting EGFR (epidermal growth factor receptor) as well as preparation method and application of 2, 4-disubstituted quinazoline compound
  • 2, 4-disubstituted quinazoline compound for inhibiting EGFR (epidermal growth factor receptor) as well as preparation method and application of 2, 4-disubstituted quinazoline compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] A 2,4-disubstituted quinazoline compound for inhibiting EGFR, characterized in that: the general formula of the compound structure shown below or a pharmaceutically acceptable salt thereof is provided:

[0033]

[0034] Wherein, F represents a fluorine atom, the substituent on the 4th position is a fluorophenylacetamide group, the substituent on the 2nd position is a phenyl group, and the substituents on the phenyl group are acrylamide and piperazine.

Embodiment 2

[0036] A preparation method of 2,4-disubstituted quinazoline compounds for inhibiting EGFR, the steps are as follows:

[0037] (1) Intermediate 1 is synthesized:

[0038] Dissolve 2,4-dichloroquinazoline in isopropanol and stir, add p-phenylenediamine and DIPEA in turn, stir evenly, heat the reaction solution to 75°C for 5h, and filter under reduced pressure to obtain a yellow solid. After separation by column chromatography, intermediate 1 is obtained; wherein, the mass dosage is 2,4-dichloroquinazoline: isopropanol: p-phenylenediamine: DIPEA=260:8:80:0.6;

[0039] (2) the intermediate 1 was dissolved in tetrahydrofuran and stirred in an ice bath, p-fluorophenylacetyl chloride was added, triethylamine was added dropwise, then the temperature was raised to 20° C. for 3 hours, and concentrated under reduced pressure. After the crude product was separated by column chromatography Intermediate 2 was obtained; wherein, intermediate 1: tetrahydrofuran: p-fluorophenylacetyl chlorid...

Embodiment 3

[0048] A preparation method of 2,4-disubstituted quinazoline compounds for inhibiting EGFR, the steps are as follows:

[0049] (1) Intermediate 1 is synthesized:

[0050] Dissolve 2,4-dichloroquinazoline in isopropanol and stir, add p-phenylenediamine and DIPEA in turn, stir evenly, heat the reaction solution to 85°C for 3 hours, and filter under reduced pressure to obtain a yellow solid. After separation by column chromatography, intermediate 1 is obtained; wherein, the mass dosage is 2,4-dichloroquinazoline: isopropanol: p-phenylenediamine: DIPEA=280:10:90:0.7;

[0051] (2) the intermediate 1 was dissolved in tetrahydrofuran and stirred in an ice bath, p-fluorophenylacetyl chloride was added, triethylamine was added dropwise, then the temperature was raised to 30° C. to react for 1 hour, and concentrated under reduced pressure. After the crude product was separated by column chromatography Intermediate 2 was obtained; wherein, intermediate 1: tetrahydrofuran: p-fluorophenyl...

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PUM

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Abstract

The invention belongs to the technical field of anti-tumor pharmacy, and particularly relates to a 2, 4-disubstituted quinazoline compound for inhibiting EGFR (epidermal growth factor receptor) as well as a preparation method and application of the 2, 4-disubstituted quinazoline compound serving as a targeted EGFR L858R / T790M, and the 2, 4-disubstituted quinazoline compound comprises a compound shown in the specification or a pharmaceutically acceptable salt of the compound. The compound or the pharmaceutically acceptable salt thereof disclosed by the invention has the activity of inhibiting EGFR L858R / T790M, can be used as an EGFR L858R / T790M inhibitor, has anti-tumor activity, and can effectively inhibit the growth of tumor cells.

Description

technical field [0001] The invention belongs to the technical field of antitumor pharmacy, in particular to a 2,4-disubstituted quinazoline compound for inhibiting EGFR, a preparation method and application thereof. Background technique [0002] Epidermal growth factor receptor (EGFR) is a member of the HER family. EGFR is the expression product of the proto-oncogene c-erbB-1 and is a transmembrane tyrosine kinase receptor. EGFR plays an important role in physiological processes such as cell growth, proliferation and differentiation by affecting downstream signaling pathways such as PI3K / AKT. The loss of function or abnormal activity of EGFR can cause tumor, diabetes, immune deficiency and cardiovascular disease. In particular, EGFR has also been identified as a key target in non-small cell lung cancer. [0003] Existing EGFR tyrosine kinase inhibitors have been developed to third-generation inhibitors with the advantage of combining EGFR sensitive mutations and T790M mut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/95A61K31/517A61P35/00
CPCC07D239/95A61P35/00Y02P20/55
Inventor 黄霞殷国平吕禄楷徐平王贯王傲雪
Owner ZIGONG NO 4 PEOPLES HOSPITAL
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