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Azo aryl nitrogen mustard-chloroethylnitrosourea coupled compound, and preparation method and application thereof

A compound and composition technology, applied in the preparation of antitumor drugs, in the field of the synthesis of aromatic nitrogen mustard-chloroethyl nitrosourea coupling molecules, can solve the problem of enhanced toxicity and side effects of CENUs and no tumor targeting And other issues

Active Publication Date: 2018-04-13
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing AGT inhibitors do not have tumor targeting, which makes them inhibit the AGT activity of normal cells while inhibiting the AGT activity of tumor cells, causing the toxic side effects of CENUs to be significantly enhanced.

Method used

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  • Azo aryl nitrogen mustard-chloroethylnitrosourea coupled compound, and preparation method and application thereof
  • Azo aryl nitrogen mustard-chloroethylnitrosourea coupled compound, and preparation method and application thereof
  • Azo aryl nitrogen mustard-chloroethylnitrosourea coupled compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1: (E)-3-(2-(6-(benzyloxy)-2-((4-(bis(2-chloroethyl)amino)phenyl)diazenyl)-9H- Synthesis of purin-9-yl)ethyl)-1-(2-chloroethyl)-1-nitrosourea (compound 1) 1) N9-bromoethyl-O 6 - Synthesis of Benzylguanine

[0060] Weigh O 6 -Benzylguanine (2.05g, 8.5mmol), anhydrous potassium carbonate (3.35g, 24.3mmol) were added to a 100mL round bottom flask, 50mL of acetone was added, the temperature was slowly raised to 52°C, and 1,2-dibromo was added dropwise Ethane (2.89 mL, 33 mmol), continued to react for 72 h after dripping, the reaction solution was filtered, the filtrate was collected, the solvent was evaporated under reduced pressure at 40°C, and then the solvent was separated and purified by silica gel column chromatography. The eluents were petroleum ether and acetic acid. Ethyl ester, gradient elution was adopted, the volume ratio of petroleum ether / ethyl acetate was gradually increased from 1:2 to 1:4, and the white solid N9-bromoethyl-O was obtained by vacuum ...

Embodiment 2

[0101] Example 2: (E)-3-(2-(6-(benzyloxy)-2-((4-(bis(2-chloroethyl)amino)phenyl)diazenyl)-9H- Synthesis of Purin-9-yl)ethyl)-1-(2-chloroethyl)-1-nitrosourea (Compound 1) 1) N9-Bromoethyl-O 6 -Synthesis of benzylguanine

[0102] Weigh O 6 - Benzylguanine (2.12g, 8.8mmol), anhydrous potassium carbonate (3.36g, 24.32mmol) were added to a 100mL round bottom flask, 50mL of acetone was added, the temperature was slowly raised to 52°C, and 1,2-dibromo Ethane (3.02mL, 34.5mmol), continue to react for 75h after dropping, filter the reaction solution, collect the filtrate, distill the solvent under reduced pressure at 40°C, and then separate and purify by silica gel column chromatography. The eluent is petroleum ether and Ethyl acetate, using gradient elution, the volume ratio of petroleum ether / ethyl acetate gradually increased from 1:2 to 1:4, and dried under vacuum at 40°C to obtain white solid N9-bromoethyl-O 6 - Benzylguanine (2.16 g, 6.22 mmol), yield 71%.

[0103] UVλ:248,283...

Embodiment 3

[0143] Example 3: (E)-3-(3-(6-(benzyloxy)-2-((4-bis(2-chloroethyl)amino)phenyl)diazenyl)-9H-purine Synthesis of -9-yl)propyl)-1-(2-chloroethyl)-1-nitrosourea (Compound 2)

[0144] 1) N9-bromopropyl-O 6 -Synthesis of benzylguanine

[0145] Weigh O 6 - Benzylguanine (1.45g, 6mmol), anhydrous potassium carbonate (2.76g, 20mmol) were added to a 50mL round bottom flask, 50mL of acetone was added, the temperature was slowly raised to 55°C, and 1,3 dibromopropane (3.03 mL, 30mmol), continue to react for 65h after dropping, filter the reaction solution, collect the filtrate, and distill off the solvent under reduced pressure at 45°C, then use silica gel column chromatography to separate and purify, the eluent is petroleum ether and ethyl acetate, using a gradient Elution, the volume ratio of petroleum ether / ethyl acetate gradually increased from 1:2 to 1:4, and vacuum drying at 40 °C gave white solid N9-bromopropyl-O 6 - Benzylguanine (1.41 g, 3.9 mmol), yield 65%.

[0146] UVλ:2...

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PUM

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Abstract

The invention relates to a compound has a structure represented by formula (I), or a pharmaceutically acceptable salt thereof. In the compound, the azo group is a low oxygen-activated pharmacophore, anitrogen-nitrogen double bond in the azo group cleaves and releases aromatic nitrogen mustard and an O6-BG analogue under tumor hypoxic conditions, and the aromatic nitrogen mustard and an O6-BG analogue act as an alkylating agent and an AGT inhibitor in a hypoxic area in a targeting manner to make tumor cells sensitive to the alkylating agent; and the CENUs pharmacophores in the compound can bedecompose to generate chloroethyl carbocations in order to cause cross-linking between DNA strands, so the growth of tumor cells is inhibited.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a method for synthesizing an aromatic nitrogen mustard-chloroethylnitrosourea coupling molecule targeting tumor hypoxia and its application in the preparation of antitumor drugs. Background technique [0002] Nitrogen mustards and nitrosoureas are two types of anticancer alkylating agents commonly used in clinical practice. The bis-β-chloroethylamino group in nitrogen mustard drugs is a functional group that plays an anti-tumor effect. This group is connected with different carrier structures to form aliphatic nitrogen mustards, aromatic nitrogen mustards, amino acid nitrogen mustards, and steroid nitrogen mustards. And heterocyclic nitrogen mustards, etc. The carrier part of the aromatic nitrogen mustard molecule is an aromatic group, and its anticancer mechanism is to first lose chloride ions to generate carbocation intermediates, and then react with the nucleophilic center on DNA to f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18A61K31/52A61P35/00A61P35/02
CPCC07D473/18
Inventor 赵丽娇余然葛瑶任婷宋秀庆钟儒刚
Owner BEIJING UNIV OF TECH
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