Bis(morpholinoalkoxy)quinazoline derivatives and their use in antitumor

A technology of morpholinyl alkane and quinazoline, which is applied in the field of bisquinazoline derivatives or their pharmaceutically acceptable salts, and can solve problems such as difficult tumor treatment

Inactive Publication Date: 2022-03-01
SHAANXI NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, long-term use of these drugs will produce obvious drug resistance, which will bring difficulties to the later treatment of tumors.

Method used

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  • Bis(morpholinoalkoxy)quinazoline derivatives and their use in antitumor
  • Bis(morpholinoalkoxy)quinazoline derivatives and their use in antitumor
  • Bis(morpholinoalkoxy)quinazoline derivatives and their use in antitumor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1: 4-[4-(E)-(propen-1-yl)anilino]-6,7-bis[3-(4-morpholinyl)propoxyl]quinazoline (A) synthesis

[0069] (1) Preparation of 3,4-bis(3-chloropropoxy)benzonitrile

[0070]

[0071] Sequentially add anhydrous K 2 CO 3 (0.03mol), 0.6mL of PEG-400 and 30mL of acetonitrile, 1,3-bromochloropropane (0.06mol), heated to 60 ° C, and added 3,4-dihydroxybenzonitrile (0.01mol) in six times, Continue the reaction, TLC tracking [developer: ethyl acetate: petroleum ether (1:4, V / V)] to the completion of the reaction, the reaction time is about 3h. Stop the reaction and filter while hot to remove K 2 CO 3 , the filter cake was washed three times with hot acetonitrile, and the filtrate was distilled to recover acetonitrile and 1,3-bromochloropropane to obtain a brown oily residue, which was separated by silica gel column chromatography [ethyl acetate:petroleum ether (1:6, V / V)] to obtain white solid 3,4-bis(3-chloropropoxy)benzonitrile (yield 86.4%).

[0072] (2) Prepara...

Embodiment 2

[0091] Example 2: 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6,7-bis[3-(4-morpholinyl)propoxy]quinazoline (B) Synthesis

[0092] Step (1)~(4) is the same as embodiment 1,

[0093] (5) Preparation of 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6,7-bis(3-chloropropoxy)quinazoline

[0094]

[0095] According to the method of step 5 of example 1, 4-(E)-aminophenylpropene in step 5 of example 1 was replaced with 3-chloro-4-(3-fluorobenzyloxy)aniline (1.10mmol) to prepare a white Solid 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6,7-bis(3-chloropropoxy)quinazoline (yield 93.8%).

[0096] (6) 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6,7-bis[3-(4-morpholinyl)propoxy]quinazoline (B) preparation

[0097]

[0098] According to the method of step 6 of Example 1, with 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6,7-bis(3-chloropropoxy)quinazoline (0.50mmol ) instead of 4-[4-(E)-(propene-1-yl)anilino]-6,7-bis(3-chloropropoxy)quinazoline in Step 6 of Example 1, to prepare a light yellow s...

Embodiment 3

[0103] Example 3: Synthesis of 4-(3-ethynylanilino)-6,7-bis[3-(4-morpholinyl)propoxy]quinazoline (C)

[0104] Steps (1)-(4) are the same as in Example 1.

[0105] (5) Preparation of 4-(3-ethynylanilino)-6,7-bis(3-chloropropoxy)quinazoline

[0106]

[0107] According to the method of step 5 of example 1, 4-(E)-aminophenylpropene in step 5 of example 1 was replaced with 3-ethynylaniline (1.10mmol) to prepare a white solid 4-(3-ethynylaniline) -6,7-bis(3-chloropropoxy)quinazoline (yield 90.6%).

[0108] (6) Preparation of 4-(3-ethynylanilino)-6,7-bis[3-(4-morpholinyl)propoxy]quinazoline (C)

[0109]

[0110] According to the method of step 6 of embodiment 1, replace 4- [4-(E)-(propen-1-yl)anilino]-6,7-bis(3-chloropropoxy)quinazoline was prepared as light yellow solid C (yield 71.5%).

[0111] m.p.:91.5–92.7℃; HRMS(C 30 h 37 N 5 o 4 )m / z[M+H] + :532.2920 (calculated value: 532.2924).

[0112] 1 H-NMR (600MHz, DMSO-d 6 )δ (ppm): 9.51 (s, 1H), 8.49 (s, 1H), 8.02–8....

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Abstract

The invention belongs to the field of medicine and discloses bis(morpholinoalkoxy)quinazoline derivatives and their application in antitumor, in particular to compounds represented by formula (I) or pharmaceutically acceptable salts thereof, Preparation method, pharmaceutical composition containing the compound and its use in antitumor. This kind of compound has great effect on the proliferation of human skin squamous cell carcinoma cell line A431, human non-small cell lung cancer cell line A549, human colon cancer cell line SW480 and human lung cancer cell line NCI‑H1975 containing EGFR T790M / L858R double mutation. Good inhibitory effect.

Description

technical field [0001] The present invention relates to a novel bis(morpholinoalkoxy)quinazoline derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and its use in antitumor . Background technique [0002] Most of the traditional anticancer drugs are cytotoxic drugs. While killing cancer cells, these drugs have great toxic and side effects on normal human tissue cells. In order to improve the selectivity of drugs on cancer cells, we use Research on targeted drug therapy methods targeting key genes, regulatory molecules and specific cell receptors has become a hotspot. [0003] Epidermal growth factor receptor (EGFR) tyrosine kinase is one of the important targets for cancer therapy. When EGFR is overexpressed and abnormally activated in the human body, the growth regulation of the cells is out of control, the death is blocked, and the cells are always in a state of abnormal proliferati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94A61K31/5377A61P35/00A61P35/02
CPCC07D239/94
Inventor 李宝林陈丽张娅玲刘娟张喜全顾红梅徐宏江杨玲
Owner SHAANXI NORMAL UNIV
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