Pyrimido-[4, 5-d] [1, 3] oxazine-2-ketone derivative serving as EGFR (epidermal growth factor receptor) inhibitor and application of derivative

A C1-C3, drug technology, applied in the field of medicinal chemistry, can solve the problems of low maximum tolerated dose, poor EGFR selectivity, and ineffective clinical trials

Active Publication Date: 2017-09-05
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, due to the poor selectivity of these drugs to wild-type and mutant EGFR, their maximum tolerated dose (MTD) is low, and the effect of clinical trials is not obvious

Method used

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  • Pyrimido-[4, 5-d] [1, 3] oxazine-2-ketone derivative serving as EGFR (epidermal growth factor receptor) inhibitor and application of derivative
  • Pyrimido-[4, 5-d] [1, 3] oxazine-2-ketone derivative serving as EGFR (epidermal growth factor receptor) inhibitor and application of derivative
  • Pyrimido-[4, 5-d] [1, 3] oxazine-2-ketone derivative serving as EGFR (epidermal growth factor receptor) inhibitor and application of derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0103] The concrete synthetic method of above-mentioned steps a-h is as follows:

[0104] 1. Synthesis of ethyl 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5-carboxylate

[0105]

[0106] Weigh ethyl 2,4-dichloro-5-pyrimidinecarboxylate (22.100g, 100mmol) and DIPEA (12.900g, 100mmol) in a 500mL single-necked flask, and add 100mL of acetonitrile to dissolve. Another tert-butyl (3-aminophenyl)carbamate (20.800g, 100mmol) was dissolved in 100mL of acetonitrile, added dropwise to the above reaction solution, and refluxed for 6h after the dropwise addition. TLC traced to the conversion of raw materials, cooled to room temperature, suction filtered, washed with acetonitrile, and dried the filter cake to obtain 4-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-2-chloropyrimidine-5 - Ethyl formate 33.710 g. 1 H NMR (400MHz, DMSO-d 6 )δ10.23(s,1H),9.50(s,1H),8.80(s,1H),7.70(s,1H),7.35(d,J=8.0Hz,1H),7.29(t,J=8.0 Hz,1H),7.23(d,J=8.0Hz,1H),4.38(q,J=7.2Hz,2H),1....

Embodiment 2

[0170] Example 2. Biological activity test

[0171] The compound provided by the invention is carried out as follows to the in vitro inhibitory effect experiment of EGFR kinase activity:

[0172] In vitro enzyme activity analysis: wild-type and mutant (L858 / T790M) EGFR were purchased from Invitrogen. A set from 5.1×10 for all compounds to be tested -11 mol / L to 1.0×10 -6 10 concentration gradients of mol / L.

[0173] The concentrations of different kinases were determined by optimization experiments, and the corresponding concentrations were: EGFR (PV3872, Invitrogen) 0.287 μg / μL, EGFR-L858R / T790M (PV4879, Invitrogen) 0.055 μg / μL. Compounds from 5.1x10 in DMSO -9 M to 1x10 -4 M was diluted three-fold. 4 μL of compound was dissolved in 96 μL of water to obtain a 4x compound solution. 40 μM ATP is dissolved in 1.33x Kinase Buffer, the Kinase / Peptide Mix contains 2x Kinase, 4 μM Tyrosine 4 Peptide is ready for use. A 10 μL kinase reaction consists of 2.5 μL compound soluti...

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Abstract

The invention relates to a pyrimido-[4, 5-d] [1, 3] oxazine-2-ketone derivative serving as an EGFR (epidermal growth factor receptor) inhibitor and an application of the derivative, in particular to a compound as shown in a formula I, a medicine composition comprising the compound as shown in the formula I and an application of the compound to preparation of a medicine for treating EGFR related diseases or inhibiting EGFR.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry; in particular, the present invention relates to novel 1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives, which are synthesized The method and its application as an EGFR inhibitor in the preparation of medicines for tumor-related diseases. Background technique [0002] Cancer, also known as malignant tumor, is a large class of diseases characterized by abnormal cell proliferation and metastasis. It has the characteristics of high morbidity and mortality. It is one of the malignant diseases that threaten human health and cause death. According to research data, there were 12.7 million cancer patients in the world in 2008, of which more than 7 million died. In the world, 20% of new tumor patients are in China, and 24% of tumor death patients are in China. If effective prevention measures are not taken, or a better treatment plan is proposed, it is estimated that by 2030, there ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04A61K31/5365A61P35/00
Inventor 李洪林徐玉芳谢华郝永佳陈卓孙德恒吕剑昆徐玉琼童依陈海洋赵振江丁健
Owner EAST CHINA UNIV OF SCI & TECH
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