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Novel compounds of reverse-turn mimetics, method for manufacturing the same and use thereof

A technology of compound and chemical formula, applied in the field of new compound of back-folding simulant, to achieve the effect of easy preparation and high solubility

Active Publication Date: 2012-05-16
JW PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although a large number of back-turn mimics have been prepared, only a few compounds have been found to be highly biologically active

Method used

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  • Novel compounds of reverse-turn mimetics, method for manufacturing the same and use thereof
  • Novel compounds of reverse-turn mimetics, method for manufacturing the same and use thereof
  • Novel compounds of reverse-turn mimetics, method for manufacturing the same and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0101] A better understanding of the invention may be obtained by the following examples, which are intended to illustrate the invention and should not be construed as limiting it.

[0102] As demonstrated herein, compounds of formula I exhibit anticancer activity.

[0103] The production method of the present invention is described in detail as follows.

[0104]

[0105]

[0106] In Reaction Scheme 1, side chain S3 can be prepared as follows.

[0107]

Embodiment 1

[0110] Synthesis of S3

[0111] 2-(1-allyl-4-benzylureaamino)acetic acid

[0112] 67 g of ethyl hydrazinoacetate was dissolved in 673 ml of THF (tetrahydrofuran), and mixed with 121 ml of TEA (triethylamine). 41 ml of allyl bromide were added dropwise to the reaction mixture during 20 min. The solution was stirred for 5 hours and filtered. To the resulting filtrate was added dropwise 53 ml of benzyl isocyanate during 15 min, followed by stirring at room temperature for 30 min. Afterwards, a solution of 48 g of KOH (sodium hydroxide) dissolved in 673 ml of distilled water was added dropwise, followed by stirring for 30 min. Separate layers were produced by adding 403 ml of MC (dichloromethane) and 269 ml of hexane and stirring. The aqueous solution was washed once with 201 ml of MC (dichloromethane). The aqueous solution was adjusted to pH 2-3 using 100 ml of concentrated HCl. After stirring for 30 min, the pH-adjusted solution was extracted with 1009 ml of MC (dichlorome...

Embodiment 2

[0115] Synthesis of P9

[0116] 3-Acetyl-1H-indole-7-carbaldehyde

[0117] 23.5ml of AcCl (acetyl chloride) was added dropwise with stirring to 55g of AlCl dissolved in 400ml of MC (dichloromethane) 3 in the solution. To this solution was added dropwise a solution of 40 g of the starting material (indole-7-carbaldehyde) dissolved in 400 ml of MC (dichloromethane). The temperature of the solution must be maintained at 0-5[deg.] C. immediately after the addition and subsequently warmed to room temperature. Reaction progress was monitored using thin layer chromatography (TLC) and high performance liquid chromatography. After the reaction was completed, the solution was subjected to layer separation with water. The thus formed organic layer was subjected to MgSO 4 (Magnesium sulfate), filtered and then concentrated at 40° C. to give 41 g of the concentrated residue P9 (yield 80%).

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PUM

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Abstract

Disclosed are novel reverse turn mimetics based on the framework of pyrazino-triazinone, and the use thereof in the treatment of cancers, particularly, acute myeloid leukemia. A method is also provided for manufacturing the reverse turn mimetics on a mass scale.

Description

technical field [0001] The present invention relates to novel compounds that are snapback mimetics, methods for their preparation, and their use in the treatment of diseases such as acute myeloid leukemia. Background technique [0002] Random screening of molecules for possible activity as therapeutic agents has been performed for many years and resulted in a large number of important drug discoveries. More recently, non-peptidic compounds have been developed that more closely mimic the secondary structure of the turn-back found in biologically active proteins or peptides. For example, US Patent 5,440,013 and PCT Application Publications WO94 / 03494, WO01 / 00210A1, and WO01 / 16135A2 - all to Kahn - each disclose conformationally constrained non-peptidic compounds that mimic the secondary structure of a turn . In addition, US Patents 5,929,237 and 6,013,458, both to Kahn, describe conformationally restricted compounds that mimic the secondary structure of the turn-back region ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D403/02
CPCC07F9/6561C07D487/04A61P35/00A61P35/02A61K31/5025C07F9/65611
Inventor 郑敬允郑宰旭郑珉旭郑熙暻罗炫柱马相镐李庸实
Owner JW PHARMA CORP