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Substituted quinazoline compound, pharmaceutical composition containing substituted quinazoline compound, and applications of substituted quinazoline compound

A compound and application technology, applied in the field of substituted quinazoline compounds, can solve the problem of not being able to reach tumor cells, etc., and achieve the effects of good pharmacodynamic performance, high inhibitory activity, and excellent brain barrier penetration performance

Active Publication Date: 2020-03-24
苏州润诺生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The incidence of leptomeningeal metastases is increasing, in part because cancer patients are living longer and because many chemotherapies and molecularly targeted therapies do not reach concentrations in the cerebrospinal fluid sufficient to kill tumor cells

Method used

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  • Substituted quinazoline compound, pharmaceutical composition containing substituted quinazoline compound, and applications of substituted quinazoline compound
  • Substituted quinazoline compound, pharmaceutical composition containing substituted quinazoline compound, and applications of substituted quinazoline compound
  • Substituted quinazoline compound, pharmaceutical composition containing substituted quinazoline compound, and applications of substituted quinazoline compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] 4-[(3-Chloro-2-fluorophenyl)amino]-7-deuteromethoxyquinazolin-6-yl-(2R)-2,4-dimethylpiperazine-1-carboxylic acid ester

[0118]

[0119] Intermediate H (8.1 g, 16 mmol, 87% purity), paraformaldehyde (1 g, 32 mmol) triethylamine (1.61 g, 16 mol) were dissolved in methanol (100 mL), and sodium cyanoborohydride (2 g , 32mmol), the reaction solution was stirred at room temperature for 10 hours, after the reaction was completed, the solvent was evaporated, the residue was added with water, extracted with ethyl acetate (3×100mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate) to obtain the target product Example 1 (5.5 g). 1 H-NMR (400MHz, CDCl 3 )δ: 8.78(s,1H), 8.54-8.49(m,1H), 7.64(s,1H), 7.42(br,1H), 7.34(s,1H), 7.20-7.16(m,2H), 4.51 -4.49(m,1H),4.22-4.03(m,1H),3.52-3...

Embodiment 1A

[0121] 4-[(3-Chloro-2-fluorophenyl)amino]-7-deuteromethoxyquinazolin-6-yl-(2R)-2,4-dimethylpiperazine-1-carboxylic acid Ester hydrochloride

[0122]

[0123] Example 1 (3.6g) was dissolved in acetonitrile (10mL), and 1N HCl (10mL) was slowly added under stirring. After stirring for a while, the solvent was removed by lyophilization to obtain Example 1A (3.85g) as a yellow solid. 1 H-NMR (400MHz,D 2 O)δ: 8.56(s,1H),8.32-8.14(m,1H),7.51(m,1H),7.40(m,1H),7.31(s,1H),7.25-7.16(m,3H), 4.75-4.53(m,1H),4.50-4.13(m,1H),4.09-3.96(m,3H),3.75-3.49(m,1H),3.25-3.13(m,1H),2.32(s,3H ),1.50(br,3H); MS m / z463.2(M+1) + .

Embodiment 2

[0125] 4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl-(2R)-2-methyl-4-deuteromethylpiperazine-1- Carboxylate

[0126]

[0127] Intermediate G (8.2g, 16mmol) and sodium hydride (24mmol) were dissolved in tetrahydrofuran (150mL), cooled to 0°C and stirred, and a solution of deuteromethyl iodide (3.5g, 24mmol) in tetrahydrofuran (20mL) was slowly added dropwise, During the dropwise addition process, the temperature of the reaction system was controlled between 0-5°C. After the reaction, add aqueous ammonium chloride solution (300mL) and stir, extract with ethyl acetate (3×200mL), dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. Silica gel Purified by column chromatography (petroleum ether: ethyl acetate) to obtain the target product Example 2 (5.2 g). 1 H-NMR (400MHz, CD 3 OD)δ: 8.77(s,1H),8.55-8.50(m,1H),7.66(s,1H),7.43(br,1H),7.35(s,1H),7.19-7.16(m,2H), 4.52-4.51(m,1H),4.19-4.04(m,1H),3.77(s,3H),3.50-3.30(m,1H),2.88(d,1H),2.72(d...

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Abstract

The invention relates to a substituted quinazoline compound, a pharmaceutical composition containing the compound, and applications of the compound, wherein the substituted quinazoline compound with ageneral formula (I) and the pharmaceutically acceptable salt thereof have excellent brain barrier permeability, enhanced metabolic stability and long metabolic half-life period, show high inhibitoryactivity on activated or drug-resistant mutant form EGFR compared with wild type EGFR, and can effectively reduce side effects.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and the invention relates to a class of substituted quinazoline compounds, a pharmaceutical composition containing the compound and the application of the compound. Background technique [0002] Epidermal growth factor receptor (EGFR), a transmembrane protein tyrosine kinase of the erbB receptor family, binds to growth factor ligands such as epidermal growth factor (EGF), and the receptor binds to additional Homodimerization of EGFR molecules or heterodimerization with another family member (eg, erbB2 (HER2), erbB3 (HER3), or erbB4 (HER4)), homodimerization and / or heterodimerization of erbB receptors Dimerization leads to phosphorylation of key intracellular tyrosine residues and to stimulation of many intracellular signaling pathways involved in cell proliferation and survival. Dysregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and survival of tum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/517A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D403/12
Inventor 范晶晶唐春雷范为正
Owner 苏州润诺生物科技有限公司
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