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A kind of chloroethyl nitrosourea with anticancer activity and its synthesis method

An anticancer activity, sodium nitrite technology, applied in the direction of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc. The effect of improving targeting and improving drug resistance

Active Publication Date: 2016-03-09
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The present invention aims at the easy generation of drug resistance of chloroethylnitrosourea in the prior art, which leads to the reduction of anticancer activity and the combination of chloroethylnitrosourea and O 6 -Benzylguanine combined drug has a relatively large deficiency of normal cytotoxicity, providing a kind of compound N-(2-chloroethyl)-N'-2-(O with higher anticancer activity 6 -Benzyl-9-guanine base) alkyl-N-nitrosourea (I) and its synthetic method

Method used

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  • A kind of chloroethyl nitrosourea with anticancer activity and its synthesis method
  • A kind of chloroethyl nitrosourea with anticancer activity and its synthesis method
  • A kind of chloroethyl nitrosourea with anticancer activity and its synthesis method

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Embodiment 1

[0071] Embodiment 1: N-(2-chloroethyl)-N'-3-(O 6 Synthesis of -Benzyl-9-guanyl)ethyl-N-nitrosourea (compound 1)

[0072] 1) N9-Bromoethyl-O 6 -Synthesis of benzylguanine

[0073] Weigh O 6 -Benzylguanine (0.96g, 4mmol), anhydrous potassium carbonate (1.66g, 12mmol) were added to a three-necked flask, 100mL of acetone was added, the temperature was slowly raised to 50°C, and 1,2-dibromoethane (3.10 g, 16mmol), continue to react for 48h after dropping, monitor the progress of the reaction by thin-layer chromatography, filter to the point where there is no raw material, collect the filtrate, distill the solvent under reduced pressure at 40°C, and dissolve the obtained yellow oil in 2mL Methanol was separated and purified by silica gel column chromatography. The eluents were petroleum ether and ethyl acetate. Gradient elution was adopted, and the volume ratio of petroleum ether / ethyl acetate was gradually increased from 2:1 to 5:1. Vacuum at 60°C Drying gave white solid N9-bro...

Embodiment 2

[0096] Embodiment 2: N-(2-chloroethyl)-N'-3-(O 6 Synthesis of -Benzyl-9-guanyl)propyl-N-nitrosourea (compound 2)

[0097] 1) N9-bromopropyl-O 6 -Synthesis of benzylguanine

[0098] Weigh O 6 -Benzylguanine (0.48g, 2mmol), anhydrous potassium carbonate (0.55g, 4mmol) were added to a three-necked flask, 50mL of acetone was added, the temperature was slowly raised to 40°C, and 1,3-dibromopropane (1.62g ,8mmol), continue to react for 72h after dropping. Thin-layer chromatography was used to monitor the degree of progress of the reaction, and to the point where there was no raw material, it was filtered. Collect the filtrate, spin the solvent under reduced pressure at 35°C, dissolve the obtained yellow oil in 1 mL of methanol, and separate and purify it by silica gel column chromatography. The eluents are petroleum ether and ethyl acetate, and gradient elution is used. The volume ratio of ethyl acetate / ethyl acetate gradually increased from 2:1 to 5:1. Vacuum drying at 60°C ga...

Embodiment 3

[0121] Embodiment 3: N-(2-chloroethyl)-N'-3-(O 6 Synthesis of -Benzyl-9-guanyl)ethyl-N-nitrosourea (Compound 3)

[0122] 1) N9-bromobutyl-O 6 -Synthesis of benzylguanine

[0123] Weigh O 6 -Benzylguanine (1.93g, 8mmol), anhydrous potassium carbonate (2.21g, 16mmol) were added to a three-necked flask, 150mL of acetone was added, the temperature was slowly raised to 60°C, and 1,4-dibromobutane (6.91 g, 32mmol), continue to react for 40h after dropping, and monitor the progress of the reaction by thin-layer chromatography, and filter after no raw material point. The filtrate was collected, and the solvent was spin-dried under reduced pressure at 40°C. The obtained yellow oil was dissolved in 4 mL of methanol, and separated and purified by silica gel column chromatography. The volume ratio of ethyl ester was gradually increased from 2:1 to 5:1, and dried under vacuum at 60°C to obtain white solid N9-bromobutyl-O 6 - Benzylguanine (1.35 g, 5.0 mmol), yield 63%.

[0124] UV la...

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Abstract

The invention relates to novel chloroethyl nitrosourea with anticancer activity and a synthesizing method thereof. The chloroethyl nitrosourea is a compound with a structure of the general formula (I), wherein n is an integer of 2 to 6. The chloroethyl nitrosourea can be used for treating gliomatosis cerebri, colon cancer and leukemia; compared with the existing nitrosourea-type anticancer medicine, the drug resistance is lower, the chemical therapy effect is better, the preparation method is simple in operation, the reaction yield is high, the toxicity is small, the cost is low, the method is suitable for the industrialized production, the development prospect is wide, and the application value is good.

Description

technical field [0001] The present invention relates to novel chloroethyl nitrosourea and its synthesis method, in particular to N-(2-chloroethyl)-N'-2-(O 6 -Benzyl-9-guaninyl)alkyl-N-nitrosoureas and methods for their synthesis. Background technique [0002] The main treatments for solid tumors include radiotherapy, surgery, chemotherapy, and biological therapy, and anticancer drugs have become a rapidly developing frontier in recent years. Nitrosoureas have shown good anticancer activity in both animal experiments and clinical applications, so they are widely used in the treatment of brain tumors, malignant lymphomas, leukemias, gliomas, and melanomas. Studies have shown that the main target of the interaction between nitrosourea and biological macromolecules is the DNA base, which can modify the N and O positions on the DNA base, thereby causing damage such as single / double strand breaks, or inducing sister chromosomal single body exchange and chromosomal aberrations. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/18A61K31/655A61P35/00A61P35/02
CPCC07D473/18
Inventor 赵丽娇李莉莉王雅朦钟儒刚
Owner BEIJING UNIV OF TECH
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