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Substituted piperazine N-ethyl sulfonamide derivative and preparation and application thereof

A technology of sulfonamide and derivatives, applied in the field of preparing antitumor drugs, can solve the problem of low selectivity of PKB

Inactive Publication Date: 2012-07-04
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since these compounds have effects on a variety of targets, the selectivity for PKB is not high

Method used

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  • Substituted piperazine N-ethyl sulfonamide derivative and preparation and application thereof
  • Substituted piperazine N-ethyl sulfonamide derivative and preparation and application thereof
  • Substituted piperazine N-ethyl sulfonamide derivative and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 : Preparation of N-[(1R)-2-hydroxyl-1-methylethyl]isoquinoline-5-sulfonamide (IV)

[0041]

[0042] This example relates to a general synthetic method of a class of substituted piperazine ethyl sulfonamide derivatives intermediate (IV). It specifically relates to the synthesis of N-[(1R)-2-hydroxyl-1-methylethyl]isoquinoline-5-sulfonamide. The compound is formed by condensation of L-propanol and isoquinoline-5-sulfonyl chloride.

[0043]Slowly add L-alanine (4.85g, 55.0mmol) to the tetrahydrofuran reaction solution (150mL) of lithium aluminum hydride (3.0g, 78.9mmol) under ice-cooling, add water and 15% NaOH solution after reacting for 20 hours The reaction was terminated, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain a light yellow solid. The crude product was subjected to silica gel column chromatography to obtain 3.41 g of L-propanol as a colorless oil, with a yield of 82.5%. 1 H-NMR (CDCl 3 ): δ3.4...

Embodiment 2

[0045] Example 2 : Preparation of (2R)-2-[(isoquinolin-5-ylsulfonyl)amino]propyl methanesulfonate (III)

[0046]

[0047] This example relates to a general synthetic method of a class of substituted piperazine ethylsulfonamide derivative intermediate (III). It specifically relates to the synthesis of (2R)-2-[(isoquinolin-5-ylsulfonyl)amino]propyl methanesulfonate. N-[(1R)-2-Hydroxy-1-methylethyl]isoquinoline-5-sulfonamide (3g, 13.0mmol) and triethylamine (2.01g, 19.9mmol) were dissolved in dry dichloromethane (120mL), after cooling in an ice bath, methanesulfonyl chloride (1.67g, 15.0mmol) was slowly added dropwise, washed with saturated sodium carbonate after half an hour, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure to obtain the crude product, the crude product Through silica gel column chromatography, 3.39 g of (2R)-2-[(isoquinolin-5-ylsulfonyl)amino]propyl methanesulfonate was obtained as a white solid, with a yield of 75...

Embodiment 3

[0048] Example 3 : Preparation of 1-(4-chlorobenzyl)piperazine (II)

[0049]

[0050] This example relates to a general synthetic method of a class of substituted piperazine ethyl sulfonamide derivatives intermediate (II). In particular it relates to the synthesis of 1-(4-chlorobenzyl)piperazine. Tert-butylpiperazine-1-carbonate (2.34g, 12.6mmol), 4-chlorobenzyl chloride (1.69g, 10.5mmol), triethylamine (2.1g, 20.5mmol) in acetonitrile (40mL) solution in After stirring at 60°C for 12 hours, the solvent was evaporated under reduced pressure, and the residue was partitioned and extracted with chloroform-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product. The resulting crude tert-butyl-4-(4-chlorobenzyl)piperazine-1-carbonate (2.1 g, 0.01 mol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (5.80 g, 0.08 mol), the reaction was contin...

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Abstract

The invention provides a substituted piperazine N-ethyl sulfonamide derivative and medicinal salt thereof. The acyl chloride derivative thereof is obtained by chlorination of substituted sulfoacid by thionyl chloride; substituted L-type amino acid is reduced by lithium aluminium hydride reduction to obtain L-type alkamines compound; the L-type alkamines compound and the substituted sulfoacid derivative are carried out with coupling reaction and protected by mesyl chloride to obtain methanesulfonate derivative; mono-Boc protection piperazine is performed with substitution reaction and trifluoroacetic acid deprotection to obtain monosubstitution piperazine; and the monosubstitution piperazine is carried out with substitution reaction under the catalysis of organic amine to obtain the substituted piperazine N-Ethyl sulfonamide derivative. The virus activity test to five tumour cells in vitro by the compound provided by the invention shows that the in vitro virus activity test of the derivative shows the activity of parts of compound is higher than or comparative to positive control antitumor drug. The invention can be applied in preparing drug for preventing and curing tumour. The general formula of the compound of the invention is shown in the specification.

Description

field of invention [0001] The invention belongs to the field of medicinal chemistry and pharmacology, and relates to substituted piperazine ethyl sulfonamide derivatives and their preparation, as well as the application of the compounds in the preparation of antitumor drugs. Background of the invention [0002] Apoptosis is an important life phenomenon, and the abnormality of apoptosis is an important link in the occurrence and development of tumors. As an important molecule that mediates cell survival signals, protein kinase PKB plays an important role in the regulation of cell apoptosis. The activation process of PKB is the central part of the cell survival signal transduction pathway, and inhibiting the activity of PKB in various ways can promote the process of cell apoptosis. Protein kinase PKB will be a new and good antitumor drug target. In the current research on protein kinase inhibitors, Novartis's Gleevec and Astrazenca's Iressa have entered clinical application ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/02C07D417/12C07D401/12C07D295/13C07D277/32C07D213/61A61K31/496A61K31/495A61P35/00
Inventor 邹宏斌贾平祝华健章国林俞永平
Owner ZHEJIANG UNIV
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