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

A stereoisomer, selected technology, applied in the field of medicine, can solve the problems of no medicine available, poor metabolic stability, etc.

Active Publication Date: 2019-12-17
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 ice bath, add 4-hydroxy-1-piperidinecarboxylic acid benzyl ester (17.80g, 76.0mmol) and DMF (100ml) successively to the three-necked flask, and then add 60% sodium hydride (3.79g, 95.0mmol) in batches to the system ), after reacting at 0°C for 0.5h, 4-bromo-5-fluoro-2-nitrobenzoic acid (10.00g, 37.9mmol) was added to the above system in batches, and after reacting at 0°C for 1h, it was detected that the reaction was complete. The pH was adjusted to 3-4 with 2N HCl aqueous solution under an ice bath, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and the crude product was directly carried out to the next step.

[0137] Step 2: Synthesis...

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: Synthetic 4-((7-bromo-4-((3,4-dichloro-2-fluorophenyl)amine)-quinazolin-6-yl)oxy)piperidine- 1-Benzyl carboxylate.

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

[0169]

[0170]At room temperature, sequentially add 4-((7-bromo-4-((3,4-dichloro-2-fluorophenyl)amine)-quinazolin-6-yl)oxy)piperidine -1-benzyl formate (0.90g, 1.45mmol), 1-methyl-1H-imidazole-4-boronic acid pinacol ester (0.362g, 1.74mmol), Pd(dppf)Cl 2 (0.106g, 0.145mmol), 2N K 2 CO 3 (4.0mL), DMF (12mL), heated to 70°C and reacted overnight, cooled to room temperature after the reaction, added 50mL ethyl acetate, washed with aqueous solution (20mL x2), and the aqueous phase was back-extracted once with EA (20mL), combined The ...

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: Synthetic 4-((7-bromo-4-((3-chloro-4-fluorophenyl)amine)-quinazolin-6-yl)oxy)piperidine-1-formyl benzyl with reference to Example 1 ester.

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

[0182]

[0183] At room temperature, sequentially add 4-((7-bromo-4-((3-chloro-4-fluorophenyl)amine)-quinazolin-6-yl)oxy)piperidine-1-carboxylic acid Benzyl ester (0.50g, 0.85mmol), 1-methyl-1H-pyrazole-4-boronic acid (0.129g, 1.03mmol), 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 ethyl acetate, washed with water (50mL x3), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, column Chromatogr...

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Abstract

The invention relates to a quinoline or quinazoline derivative with a structure as shown in a formula (I), a pharmaceutical composition containing the compound as shown in the formula (I) and application of the compound in preparation of drugs for preventing or treating human epidermal growth factor receptor Her / erbB family related diseases, and particularly relates to application of the compoundsfor preventing or treating tumors associated with protein tyrosine kinase, wherein each substituent in the formula (I) is the same as the definition 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 application 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. They have an extracellular binding region that binds growth factors, a transmembrane domain, and an intracellular part. The function of the intracellular part is to convert specific tyrosine in proteins as a kinase Phosphorylation of residues and affect cell proliferation. [0004] Human epidermal growth factor receptors (human epidermal growth factor receptors, Her / erbB) family, including 4 members, namely EGFR (erbB-1 / HER1), erbB-2 (HER2 / neu), erbB-3 ...

Claims

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Application Information

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Patent Type & Authority Applications(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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