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

Active Publication Date: 2021-08-27
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

[0147] Example 1: 4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl(R)-2-methyl-4-(cyclopropylmethyl ) piperazine-1-carboxylate

[0148]

[0149] Cyclopropylcarbaldehyde (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 at room temperature for 0.5 h under nitrogen atmosphere. 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 completed by TLC detection. Water was added to the reaction system, the pH value was adjusted to 8.0-9.0 with saturated aqueous sodium bicarbonate solution, the layers were separated, extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the mixture was subjected to silica gel column chromatography ( Dichloromethan...

Embodiment 2

[0150] Example 2: 4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl(R)-2-methyl-4-(2-ethylbutane) yl)-piperazine-1-carboxylate

[0151]

[0152] The synthetic method refers to Example 1, wherein 2-ethylbutanal replaces cyclopropylcarbaldehyde.

[0153] 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

[0154] Example 3: 4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl(R)-2-methyl-4-(2-methylpentan yl)piperazine-1-carboxylate

[0155]

[0156] The synthetic method refers to Example 1, wherein 2-methylpentanal replaces cyclopropylcarbaldehyde.

[0157] 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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Abstract

The invention discloses a polysubstituted quinazoline compound and application thereof, and belongs to the field of chemical medicines. The substituted quinazoline compound shown in 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 activated or drug-resistant mutant form EGFR than wild type EGFR, and can effectively reduce side effects.

Description

technical field [0001] The invention belongs to the field of chemical medicine, in particular to a polysubstituted quinazoline compound and application thereof. Background technique [0002] Epidermal growth factor receptor (EGFR) is a member of the erbB receptor family of transmembrane protein tyrosine kinases that, when bound to growth factor ligands such as epidermal growth factor (EGF), can bind to additional Homodimerization of EGFR molecules, or heterodimerization with another family member such as erbB2 (HER2), erbB3 (HER3), or erbB4 (HER4), homodimerization and / or heterodimerization of erbB receptors Dimerization results in the phosphorylation of key tyrosine residues in the cell and in the stimulation of many intracellular signaling pathways involved in cell proliferation and survival. Dysregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and is closely related in human cancers such as lung, head...

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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