Polysubstituted quinazoline compound and application thereof

A compound, deuterated methyl technology, applied in the field of multi-substituted quinazoline compounds, can solve the problems of inability to reach tumor cells and poor curative effect, and achieve good pharmacodynamic performance, high inhibitory activity, and excellent brain barrier penetration performance Effect

Inactive Publication Date: 2020-10-30
JIANGNAN UNIV +1
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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
[0014] At the same time, some of the current quinazoline ring drugs have poor efficacy, and it is still necessary to further improve the permeability of the brain barrier, enhance metabolic stability, improve pharmacokinetic properties and drug potential

Method used

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  • Polysubstituted quinazoline compound and application thereof
  • Polysubstituted quinazoline compound and application thereof
  • Polysubstituted quinazoline compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] Example 1: 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (R)-2-methyl-4-(cyclopropylmethyl ) piperazine-1-carboxylate

[0146]

[0147] Cyclopropylformaldehyde (47.24 mg, 0.67 mmol) was added to a solution of intermediate 6 (200 mg, 0.45 mmol) in dichloromethane (15 mL), and the reaction was stirred under nitrogen atmosphere at room temperature for 0.5 h. A mixture of sodium cyanoborohydride (113 mg, 1.8 mmol), acetic acid (2 mL) and methanol (10 mL) was added to the reaction system, stirred at room temperature for 2 h, and the reaction was detected by TLC. Add water to the reaction system, adjust the pH value to 8.0-9.0 with saturated aqueous sodium bicarbonate solution, separate the layers, extract with dichloromethane, combine the organic layers, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and perform silica gel column chromatography ( Dichloromethane-methanol, volume ratio 20:1) was separated and purified to obt...

Embodiment 2

[0148] Example 2: 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (R)-2-methyl-4-(2-ethylbutyl base)-piperazine-1-carboxylate

[0149]

[0150] The synthetic method refers to Example 1, wherein 2-ethylbutanal replaces cyclopropylformaldehyde.

[0151] MS-ESI(m / z):530.30[M+H] + ; 1 H-NMR (400MHz, DMSO-d 6 )δ:9.73(s,1H),8.47(s,1H),8.22(s,1H),7.56~7.45(m,2H),7.33(s,1H),7.28(t,J=7.7Hz,1H ),4.41~4.20(m,1H),3.95(s,3H),3.86~3.64(m,1H),3.31~2.27(m,1H),2.85(d,J=11.2Hz,1H),2.73( d, J=11.4Hz, 1H), 2.17(dd, J=12.3, 7.6Hz, 1H), 2.10(dd, J=12.1, 6.6Hz, 2H), 2.00~1.92(m, 1H), 1.48~1.43 (m,1H),1.40~1.28(m,7H),0.86(t,J=7.4Hz,6H).

Embodiment 3

[0152] Example 3: 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (R)-2-methyl-4-(2-methylpentane base) piperazine-1-carboxylate

[0153]

[0154] The synthetic method refers to Example 1, wherein 2-methylpentanal replaces cyclopropylformaldehyde.

[0155] MS-ESI(m / z):530.30[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ:9.73(s,1H),8.47(s,1H),8.22(s,1H),7.54~7.46(m,2H),7.33(s,1H),7.28(t,J=7.7Hz,1H ),4.42~4.25(m,1H),3.95(s,3H),3.86~3.72(m,1H),3.28~3.15(m,1H),2.83(t,J=12.0Hz,1H),2.73( t, J=10.6Hz, 1H), 2.18~1.92(m, 4H), 1.67(s, 1H), 1.45~1.28(m, 6H), 1.13~1.01(m, 1H), 0.90~0.86(m, 6H).

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PUM

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Abstract

The invention discloses a polysubstituted quinazoline compound and an application thereof, and belongs to the field of chemical medicines. The substituted quinazoline compound represented by the general formula (I) and the pharmaceutically acceptable salt thereof have excellent brain barrier permeability, enhanced metabolic stability and longer metabolic half-life period, show higher inhibitory activity on an activated or drug-resistant mutant form EGFR than a wild type EGFR, and can effectively reduce side effects.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to a multi-substituted quinazoline compound and its application. 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 tumor cells, and is closely related to human cancers such as lung cancer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61P35/00A61P35/04A61P11/00A61K31/517
CPCC07D403/12A61P35/00A61P35/04A61P11/00
Inventor 唐春雷张月范为正范文华张立勋张晴张永杰韩忝甫
Owner JIANGNAN UNIV
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