Crown ether ring-shaped quinazoline nitrogen mustard compound, and preparation method and application thereof in tumor treatment

A technology of quinazoline mustards and compounds, which is applied in the field of crown ether cyclic quinazoline mustards and their preparation and tumor treatment applications, can solve the problems of not fully tapping the potential and achieve good anti-tumor Activity and selectivity, fewer synthetic steps, and easy synthesis

Inactive Publication Date: 2014-02-26
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the current reports, there are few studies on the nitrogen mustard compounds with crown ether cyclic quinazol

Method used

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  • Crown ether ring-shaped quinazoline nitrogen mustard compound, and preparation method and application thereof in tumor treatment
  • Crown ether ring-shaped quinazoline nitrogen mustard compound, and preparation method and application thereof in tumor treatment
  • Crown ether ring-shaped quinazoline nitrogen mustard compound, and preparation method and application thereof in tumor treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] N 1 , N 1 -Bis(2-chloroethyl)-N 2 -(6,7-Benzo-9-crown-3-quinazolin-4-yl) o-phenylenediamine (A 1 )

[0026]

[0027] 1.1 Synthesis of N,N-bis(2-hydroxyethyl)-2-nitroaniline

[0028] Add 1.58g (10mmol) of o-nitrochlorobenzene and 2.12g (20mmol) of diethanolamine into a 25mL round-bottomed flask, and then heat it to 115-120°C to react. TCL detects the reaction process. After 7 hours, the reaction is basically complete, and the reaction is stopped. The entire reaction system was poured into 90°C hot water while it was hot and stirred vigorously. The product was precipitated in the form of oil, and then the oil was extracted with ethyl acetate, washed with water, dried, and purified by column chromatography (petroleum ether: ethyl acetate). Ester = 1:1) separation and purification to obtain a purple oily product with a yield of 39%. The obtained spectrum is consistent with that reported in the literature.

[0029]

[0030] 1.2 Synthesis of N,N-bis(2-methylsulfon...

Embodiment 2

[0061] N 1 , N 1 -Bis(2-chloroethyl)-N 3 -(6,7-benzo-12-crown-4-quinazolin-4-yl) m-phenylenediamine (B 2 )

[0062]

[0063] 2.1 Synthesis of N,N-bis(2-hydroxyethyl)-3-nitroaniline

[0064] Take 5.52 g (0.04 mol) of 3-nitroaniline, add it to 80 mL of 25% acetic acid aqueous solution, and add 10 mL of ethylene oxide dropwise under ice cooling. Warm up to room temperature, stir for 72 hours, filter with suction, wash the filter cake with water, and dry to obtain 8.02 g of a yellow-orange solid with a yield of 88%. The obtained spectrum is consistent with that reported in the literature.

[0065]

[0066] 2.2 Synthesis of N,N-bis(2-methylsulfonate ethyl)-3-nitroaniline

[0067] Take 2.26g (0.01mol) of N,N-bis(2-hydroxyethyl)-3-nitroaniline, add it to 30mL redistilled dichloromethane, add 3.32mL (0.025mol) triethylamine under ice-cooling, Then 1.93 mL (0.025 mol) of methanesulfonyl chloride was added. After 10 minutes, TLC tracked until the reaction was complete. The...

Embodiment 3

[0097] N 1 , N 1 -Bis(2-chloroethyl)-N 4 -(6,7-benzo-15-crown-5-quinazolin-4-yl)-p-phenylenediamine (C 3 )

[0098]

[0099] synthetic route:

[0100] 3.1 Synthesis of N,N-bis(2-hydroxyethyl)-4-nitroaniline

[0101] Add 1.58g (10mmol) of p-nitrochlorobenzene and 2.12g (20mmol) of diethanolamine to a 25mL round-bottomed flask, and then heat it to 115-120°C to react. TCL detects the reaction process. After 10 hours, the reaction is basically complete, and the reaction is stopped. The entire reaction system was poured into hot water at 90°C while it was hot and stirred vigorously. The product was precipitated in the form of a solid, which was filtered to obtain a bright yellow solid with a yield of 39%. The obtained spectrum is consistent with that reported in the literature.

[0102]

[0103] 3.2 Synthesis of N,N-bis(2-methylsulfonate ethyl)-4-nitroaniline

[0104] Dissolve 400mg of N,N-bis(2-hydroxyethyl)-4-nitroaniline in 13.25mL THF / CH 2 Cl 2 = 1:3 mixed solven...

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Abstract

A new crown ether ring-shaped quinazoline nitrogen mustard compound or a pharmaceutically-acceptable salt thereof is characterized in that: one end is provided with a nitrogen mustard alkylated group; the other end is provided with a 6,7-substituted crown ether ring-shaped quinazoline structure; a substituted group R is located at a site 4 of a quinazoline matrix and represents 2-nitrogen mustard group, 3-nitrogen mustard group or 4-nitrogen mustard group; a crown ether ring is located at sites 6 and 7 of the quinazoline matrix and represents 9-crown-3, 12-crown-4 or 15-crown-5; and the compound has a structure represented by a formula I. Experiments show that the compound has better antitumor activity and also has selectivity on different tumor cells. At the same time, the compound is easy to synthesize and simple in operation. Advantages of the compound show that the compound has great potential to become a drug for treatment of tumor.

Description

Technical field: [0001] The invention relates to a new class of crown ether cyclic quinazoline mustard compounds, a preparation method thereof and an application as a drug for treating tumors. Background technique: [0002] Tumor is a major killer threatening human health. However, its pathogenesis is complicated and difficult to treat. Scientists are trying to find better anti-tumor drugs to treat it through continuous efforts. [0003] Nitrogen mustard compounds are an early and important class of alkylated antineoplastic drugs. These drugs are easy to synthesize and low in cost. They are widely used clinically and play an important role in the treatment of tumors. However, due to the high toxicity, poor selectivity, and low therapeutic efficiency of this class of drugs, it has greatly attracted and encouraged countless researchers to devote themselves to the research and development of nitrogen mustards. The carrier part of the nitrogen mustard can be used to improve th...

Claims

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Application Information

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IPC IPC(8): C07D491/056A61K31/519A61P35/00
CPCC07D491/056
Inventor 齐传民宁红玉赵明霞常进任红玉李石磊贺勇
Owner BEIJING NORMAL UNIVERSITY
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