4-aminoquinazoline compound and preparation method and application thereof

A technology of aminoquinazolines and compounds, which is applied in the field of drug synthesis, and can solve the problems that anti-tumor drugs cannot meet the treatment requirements.

Inactive Publication Date: 2012-11-28
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The anticancer drugs currently used in clinical practice are far from meeting the requirements of treatment

Method used

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  • 4-aminoquinazoline compound and preparation method and application thereof
  • 4-aminoquinazoline compound and preparation method and application thereof
  • 4-aminoquinazoline compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1: Synthesis of Compounds 1 , (3-ethynyl-phenyl)-{7-methoxy-6-[3-(2-oxa-6-aza-spiro[3.3]heptane-6-yl)-ethoxy] - Quinazolin-4-yl}-amine

[0039] 1) Synthesis of 6,7-dimethoxy-3H-quinazolin-4-one

[0040] Methyl 2-amino-4,5-dimethoxybenzoate (31.5g, 149.1mmol) and amine formate (9.45 g, 149.0 mmol) in formamide (105ml) were reacted by heating at 200 °C for 2 hours. Then cool to room temperature, filter the reaction solution, wash the filter cake with water, and dry to obtain the product (26.3 g, 85.6%).

[0041] 2) Synthesis of 6-hydroxy-7-methoxy-3H-quinazolin-4-one.

[0042] Add 6,7-dimethoxy-3H-quinazolin-4-one (26.3 g, 127.5 mmol) and L-methionine (22.8 g, 153.0 mmol) to a solution of methanesulfonic acid (175.0 mL) In the reaction bottle, then heated and stirred at 100 ° C for 22 hours to the end of the reaction. After cooling the reaction solution to room temperature, the reaction solution was poured into a container filled with 1L ice, and continued to...

Embodiment 2

[0058] Embodiment 2: synthetic compound 2 , (3-ethynyl-phenyl)-{7-methoxy-6-[2-(2-oxa-6-aza-spiro[3.3]heptane-6-yl)-propoxy] - Quinazolin-4-yl}-amine

[0059] Add [6-(3-bromo-propoxy)-7-methoxy-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine (50 mg), acetonitrile (10ml), Na 2 CO 3 (250 mg) and 2-oxa-6-aza-spiro[3.3]heptane oxalate (50 mg). The reaction was heated at 70°C for 1 hour and the product (34 mg) was obtained by preparative HPLC. LC-MS (m / z): 431(M+). 1 H NMR (d6-DMSO, 400 MHz): 1.81(t, J=6.4Hz, 2H), 2.49(m,2H), 3.28(s,4H), 3.94(s,3H), 4.15(t, J= 6.4Hz, 2H), 4.21(s,1H), 4.60(s,4H), 7.21(m,2H), 7.41(t, J=8Hz, 1H), 7.82-7.99(m,3H) , 8.50(s ,1H), 9.53(s,1H). 13 C NMR (CD 3 OD, 400 MHz): 26.71, 38.859, 55.126, 55.401, 62.938, 66.690, 77.360, 80.853, 82.992, 101.897, 105.757, 109.099, 122.774, 125.539, 127.237, 128.471, 139.282, 146.202, 148.962, 152.420, 155.321, 156.928 。

[0060]

Embodiment 3

[0061] Embodiment 3: synthetic compound 3 , {6-[3-(2-sulfone hetero-6-aza-spiro[3.3]heptane-6-yl)-propoxy]-7-methoxy-quinazolin-4-yl}- (3-Ethynyl-phenyl)-amine

[0062] Add [6-(3-bromo-propoxy)-7-methoxy-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine (50 mg), acetonitrile (10ml), Na 2 CO 3 (250 mg) and 2-sulfone-6-aza-spiro[3.3]heptane oxalate (50 mg). The reaction was heated at 70°C for 1 hour and the product (6 mg) was obtained by preparative HPLC. LC-MS (m / z): 479(M+). 1 H NMR (CD 3 OD, 400 MHz): 1.98(m, 2H), 2.75-2.79(m,2H), 3.52(m,4H), 4.01(s,3H), 4.23(m,2H), 4.30(m,4H), 7.19(s,1H), 7.21-7.29(m,1H), 7.40(t, J=8Hz, 1H), 7.74-7.80(m,2H), 7.93(m,1H), 8.45(s,1H). 13 C NMR (CD 3 OD, 400 MHz): 24.818, 26.760, 55.169, 64.065, 66.722, 72.952, 77.304, 102.015, 105.799, 109.179, 122.859, 125.684, 127.355, 128.513, 139.243, 146.322, 149.098, 152.490, 155.480, 157.116。

[0063]

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Abstract

The invention belongs to the field of synthesis of medicaments, and relates to a 4-aminoquinazoline compound of a general formula (I), in particular to a 4-(3-acetenyl phenyl amino)-7-methoxy-quinazoline compound of which the 6th site is substituted by a quaternary heterocyclic ring, a preparation method for the compound and application in medicine. In vitro anti-tumor activity test results show that the compound has high anti-tumor activity and can be used for preparing new anti-tumor medicaments.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a novel 4-aminoquinazoline compound, a preparation method and an application. In particular, it relates to a 4-(3-ethynylphenylamino)-7-methoxy-quinazoline compound substituted with a four-membered heterocycle at the 6-position, a preparation method thereof, and a medical application thereof. Background technique [0002] Malignant tumor has become a common disease that seriously endangers people's life and health. According to incomplete statistics, there are about 20 million new cases in the world every year; in my country, there are about 1.6-2 million new cases and 1.3 million deaths each year. Statistics show that due to the ability of tumors to metastasize in the early stage, about 50% of patients with clinically diagnosed primary tumors have developed distant metastases, and the tumor cells grow rapidly and easily mutate, resulting in multidrug resistance and failure of chemot...

Claims

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Application Information

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IPC IPC(8): C07D491/107C07D495/10C07D405/12A61K31/517A61P35/00
Inventor 赵伟利董肖椿张卫星王锋李剑赵逸超赵风王雯
Owner FUDAN UNIV
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