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Homopiperazine acethydrazide derivative with low neurotoxicity and preparation method and application thereof

A compound, prodrug technology, applied in the field of preparing said compound

Active Publication Date: 2012-05-16
DONGGUAN ZHENGXING BEITE MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, experiments in mice showed that GPQ-Cl had significant symptoms of neurotoxicity after high-dose administration (mainly manifested as jumping, tremor, and unsteady standing, etc.)

Method used

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  • Homopiperazine acethydrazide derivative with low neurotoxicity and preparation method and application thereof
  • Homopiperazine acethydrazide derivative with low neurotoxicity and preparation method and application thereof
  • Homopiperazine acethydrazide derivative with low neurotoxicity and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Example 1, 2-(4-p-sulfonamidobenzyl-[1,4]diazepan-1-yl)-acetyl(3-allyl-2-hydroxyl-methylenebenzene) Preparation of hydrazine fumaric acid

[0131] The reaction process is as follows:

[0132]

[0133] Step 1. At room temperature, under the condition of electromagnetic stirring, a mixed solution of 2.45g (20mmol) ethyl 2-chloroacetate and 20ml methanol was added dropwise in a reaction flask equipped with 10g (100mmol) homopiperazine and 20ml methanol. The dropwise addition was completed within half an hour, stirred at room temperature for 5 hours, after the reaction was completed, filtered, the filter cake was washed with a small amount of acetone, the filtrate was combined, concentrated to remove methanol, water was added to the raffinate, extracted twice with ethyl acetate, combined, anhydrous MgS0 4 After drying, concentration, and silica gel column separation of the residue, 1.86 g of the product ([1,4]diazepan-1-yl)ethyl acetate was obtained, with a yield of 50...

Embodiment 2

[0138] Example 2, 2-(4-p-nitrobenzyl-[1,4]diazepan-1-yl)-acetyl(3-allyl-2-hydroxyl-methylenephenyl)hydrazine preparation of

[0139] The reaction process is as follows:

[0140]

[0141] Step 1. At room temperature, under the condition of electromagnetic stirring, add ([1,4]diazepan-1-yl) ethyl acetate and 1.01g ( 10mmol) of triethylamine, stirred evenly, then added 2.16g (10mmol) of p-nitrobenzyl bromide in batches, reacted at room temperature for 6 hours, and stopped the reaction after the end of the detection reaction. Filter, wash the filter cake with a small amount of acetone, combine the filtrates, concentrate, and purify the residue on a silica gel column to obtain off-white solid product (4-p-nitrobenzyl-[1,4]diazepan-1-yl)acetic acid Ethyl ester 3g, yield 93.4%. Mass spectrum: 322 (M+1).

[0142] Step 2. At room temperature, under the condition of electromagnetic stirring, add 5ml of methanol and 1.61g (5mmol) of (4-p-nitrobenzyl-[1,4]diazepan-1-yl to the react...

Embodiment 3

[0144] Example 3, 2-(4-m-carboxybenzyl-[1,4]diazepan-1-yl)-acetyl (3-allyl-2-hydroxyl-methylenephenyl)hydrazine preparation

[0145] The reaction process is as follows:

[0146]

[0147]Step 1. At room temperature, under the condition of electromagnetic stirring, add 10ml acetone, 1.86g (10mmol) ([1,4]diazepan-1-yl) ethyl acetate and 2.02g ( 20mmol) of triethylamine, stirred evenly, then added 1.70g (10mmol) of m-chloromethylbenzoic acid in batches, reacted at room temperature for 6 hours, and stopped the reaction after the detection reaction was completed. Filtration, the filter cake was washed with a small amount of acetone, the combined filtrate was concentrated, and the residue was purified by a silica gel column to obtain an off-white solid product (4-m-carboxybenzyl-[1,4]diazepan-1-yl) ethyl acetate Esters 2.4g, yield 75%. Mass spectrum: 321 (M+1).

[0148] Step 2. At room temperature, under the condition of electromagnetic stirring, add 5ml of methanol and 1.61g ...

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PUM

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Abstract

The invention relates to a homopiperazine acethydrazide derivative compound or pharmaceutically acceptable salt, a solvate, a stereoisomer or a prodrug shown in the formula I, wherein all symbols are described in the description. The invention also relates to the preparation method of the compound, application of the compound in the preparation of drugs for curing and / or preventing tumors and / or cancers, a method for curing and / or preventing tumors and / or cancers by the compound, and a drug compound with the compound with effective quantity for cure and / or prevention. The compound prepared by the invention can selectively kill some cancer cells, and has strong anticancer activity, greatly-reduced neurotoxicity and wide clinic application prospect.

Description

technical field [0001] The present invention relates to a class of novel homopiperazine acetyl hydrazide compounds with low neurotoxicity, and the present invention also relates to a method for preparing the compound, which is used in the preparation of medicines for treating and / or preventing tumors and / or cancers purposes, and pharmaceutical compositions comprising said compounds. Background technique [0002] GPQ-Cl (as follows) has been proved to be a molecule with obvious anti-tumor activity, and has little toxic side effects on normal cells. For details, please refer to another Chinese patent application 200910127432.8 of the applicant. Therefore, the development of such compounds has very important practical value. [0003] [0004] GPQ-Cl structural formula [0005] However, experiments in mice showed that GPQ-Cl had significant symptoms of neurotoxicity (mainly manifested as jumping, tremor, and unsteady standing, etc.) after high-dose administration. It is ve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/08A61K31/551A61P35/00A61P35/02
Inventor 钟宪斌谭孟群程笠人
Owner DONGGUAN ZHENGXING BEITE MEDICINE TECH CO LTD
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