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Human epidermal growth factor receptor inhibitor and preparation method and application thereof

A technology of selecting compounds, applied in the field of medicine, can solve the problems of poor metabolic stability and no drugs available

Active Publication Date: 2022-07-05
JIANGSU VCARE PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, exon 20 insertion mutations in EGFR mutations are still clinically unavailable for treatment, and patients with such mutations are not sensitive to existing marketed EGFR inhibitors, and basically no drugs are available (SciTransl Med.2013 ,5,216ra177; Mol Cancer Ther.2013,12,220; Lancet Oncol.2012,13,23)
EGFR exon 20 insertion mutation new drug Poziotinib has entered clinical research, but the drug has poor metabolic stability

Method used

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  • Human epidermal growth factor receptor inhibitor and preparation method and application thereof
  • Human epidermal growth factor receptor inhibitor and preparation method and application thereof
  • Human epidermal growth factor receptor inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0132] 1-(4-((4-((3-Chloro-4-fluorophenyl)amine)-7-(1-methyl-1H-imidazol-4-yl)quinazolin-6-yl)oxy) piperidin-1-yl)prop-2-en-1-one

[0133]

[0134] Step 1: Synthesis of 5-((1-((benzyloxy)carbonyl)piperidin-4-yl)oxy)-4-bromo-2-nitrobenzoic acid

[0135]

[0136] Under the ice bath, benzyl 4-hydroxy-1-piperidinecarboxylate (17.80g, 76.0mmol) and DMF (100ml) were added successively to the there-necked flask, and 60% sodium hydride (3.79g, 95.0mmol) was added to the system in batches. ), after reacting at 0 °C for 0.5 h, 4-bromo-5-fluoro-2-nitrobenzoic acid (10.00 g, 37.9 mmol) was added to the above system in batches, and the reaction was complete after 1 h at 0 °C. The pH was adjusted to 3-4 with 2N HCl aqueous solution under ice bath, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and the crude product was directly used in the next step.

[0137] Step 2: Synthesis of (4-(2-bromo-5-(methoxycarbonyl)-...

Embodiment 2

[0165] 1-(4-((4-((3,4-Dichloro-2-fluorophenyl)amine)-7-(1-methyl-1H-imidazol-4-yl)quinazolin-6-yl )oxy)piperidin-1-yl)prop-2-en-1-one

[0166]

[0167] Step 1: Synthesis of 4-((7-bromo-4-((3,4-dichloro-2-fluorophenyl)amine)-quinazolin-6-yl)oxy)piperidine- Benzyl 1-carboxylate.

[0168] Step 2: 4-((4-((3,4-Dichloro-2-fluorophenyl)amine)-7-(1-methyl-1H-imidazol-4-yl)quinazolin-6-yl Synthesis of benzyl )oxy)piperidine-1-carboxylate

[0169]

[0170]At room temperature, add 4-((7-bromo-4-((3,4-dichloro-2-fluorophenyl)amine)-quinazolin-6-yl)oxy)piperidine successively to the single-necked flask - Benzyl 1-carboxylate (0.90 g, 1.45 mmol), 1-methyl-1H-imidazole-4-boronic acid pinacol ester (0.362 g, 1.74 mmol), Pd(dppf)Cl 2 (0.106g, 0.145mmol), 2N K 2 CO 3 (4.0mL), DMF (12mL), heated to 70°C to react overnight, cooled to room temperature after the reaction, 50mL of ethyl acetate was added, washed with aqueous solution (20mL x 2), the aqueous phase was back-extracted once ...

Embodiment 3

[0178] 1-(4-((4-((3-Chloro-4-fluorophenyl)amine)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-6-yl)oxy )piperidin-1-yl)prop-2-en-1-one

[0179]

[0180] Step 1: Synthesis of benzyl 4-((7-bromo-4-((3-chloro-4-fluoroaniline)amine)-quinazolin-6-yl)oxy)piperidine-1-carboxylate with reference to Example 1 ester.

[0181] Step 2: 4-((4-((3-Chloro-4-fluoroaniline)amine)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-6-yl)oxy ) benzyl piperidine-1-carboxylate

[0182]

[0183] At room temperature, add 4-((7-bromo-4-((3-chloro-4-fluoroaniline)amine)-quinazolin-6-yl)oxy)piperidine-1-carboxylic acid successively to the single-necked flask Benzyl ester (0.50 g, 0.85 mmol), 1-methyl-1H-pyrazole-4-boronic acid (0.129 g, 1.03 mmol), Pd(dppf)Cl 2 (0.063g, 0.085mmol), K 2 CO 3 (2N, 3.5mL), DMF (10mL), heated to 70°C to react overnight, cooled to room temperature after the reaction, added 100mL of ethyl acetate, washed with water (50mL x 3), dried over anhydrous sodium sulfate, evaporated to dryn...

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Abstract

The present invention relates to a quinoline or a quinazoline derivative having the structure of formula (I), a pharmaceutical composition containing the compound of formula (I), and the preparation of the compound for preventing or treating human epidermal growth factor receptor Her / erbB family related diseases Use of a medicament, particularly for the prevention or treatment of tumors associated with protein tyrosine kinases. wherein each substituent in the formula (I) is the same as defined in the specification.

Description

technical field [0001] The application belongs to the technical field of medicine, and specifically relates to quinoline or quinazoline derivatives and their use for preparing antitumor drugs. [0002] This application claims the priority of Chinese patent CN201810597222.4 (application date June 8, 2018, invention name human epidermal growth factor receptor inhibitor and its preparation method and application). Background technique [0003] Receptor tyrosine kinases are a class of enzymes that span the cell membrane, with an extracellular binding domain that binds growth factors, a transmembrane domain, and an intracellular portion that functions as a kinase to convert specific tyrosines in proteins. The residues are phosphorylated and affect cell proliferation. [0004] Human epidermal growth factor receptors (Her / erbB) family, including 4 members namely EGFR (erbB-1 / HER1), erbB-2 (HER2 / neu), erbB-3 (HER3) and erbB -4 (HER4), both belong to type I-receptor tyrosine kinase...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14A61K31/517A61P35/00A61P35/02
CPCC07D401/14A61K31/517A61P35/00A61P35/02
Inventor 吴勇周文斌龚彦春吴小东刘永强
Owner JIANGSU VCARE PHARMATECH
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