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1,4-disubstituted-2-piperazinone compounds and pharmaceutical use thereof

A disubstituted, piperazinone technology, applied in 1,4-disubstituted-2-piperazinone compounds and its application in medicine, can solve problems such as toxic and side effects

Active Publication Date: 2019-11-01
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have found that the level of GSK 3β that causes biological dysfunction in the body is only 2-3 times the normal level, and excessive inhibition of its activity is likely to cause serious toxic side effects

Method used

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  • 1,4-disubstituted-2-piperazinone compounds and pharmaceutical use thereof
  • 1,4-disubstituted-2-piperazinone compounds and pharmaceutical use thereof
  • 1,4-disubstituted-2-piperazinone compounds and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1: Preparation of 1-(2-nitrobenzyl)-4-(3-phenylpropionyl)piperazin-2-one (3), its structural formula is as follows:

[0023]

[0024] The first step: preparation of tert-butyl-4-(2-nitrobenzyl)-3-oxo-piperazine-1-carboxylate (1)

[0025]

[0026] Add 4-Boc-piperazinone (2.0g, 0.01mol), 2-nitrobenzyl bromide (2.4g, 0.01mol), potassium carbonate (2.7g, 0.02mol), acetone (100mL) to the reaction flask, and reflux React overnight. Dilute with ethyl acetate, wash with 1 mol / L aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain a crude product, which is subjected to silica gel column chromatography (PE:EA=40:60) to obtain 1.5 g of a light yellow solid with a yield of 45%. 1 H NMR (400MHz, CDCl 3 )δppm 8.04(d,J=8.1Hz,1H),7.62(t,J=7.6Hz,1H),7.46(t,J=7.8Hz,1H),7.37(d,J=7.9Hz,1H), 5.00(s, 2H), 4.21(s, 2H), 3.69(t, J=5.5Hz, 2H), 3.36(t, J=5.4Hz,...

Embodiment 2

[0033] Embodiment 2: Preparation of 4-(3-(4-methoxyphenyl)propionyl)-1-(2-nitrobenzyl)piperazin-2-one (4), its structural formula is as follows:

[0034]

[0035] The preparation method is the same as that of the above-mentioned compound 3, and 4-methoxyphenylpropionic acid is used instead of phenylpropionic acid. A light yellow oil was obtained with a yield of 90%. ESI-MS m / z:398.2[M+H] + , 1 H NMR (400MHz, CDCl 3 )δppm 8.03(dd, J=12.1,8.1Hz,1H),7.62(dd,J=8.3,7.0Hz,1H),7.46(t,J=8.0Hz,1H),7.33(dd, J=26.1, 7.8Hz, 1H), 7.12(t, J=8.8Hz, 2H), 6.82(t, J=9.1Hz, 2H), 4.94(s, 2H), 4.35(s, 1H), 4.12(s, 1H) ,3.84(t,J=5.5Hz,1H),3.81-3.75(m,3H),3.58(t,J=5.4Hz,1H),3.30(t,J=5.5Hz,1H),3.22(t, J=5.4Hz, 1H), 2.94(t, J=7.5Hz, 2H), 2.65-2.58(m, 2H).

Embodiment 3

[0036] Example 3: Preparation of 1-acryloyl-4-benzoylpiperazin-2-one (6), whose structural formula is as follows:

[0037]

[0038] The first step: preparation of 4-benzoylpiperazin-2-one (5)

[0039]

[0040] Add 2-piperazinone (300mg, 3mmol), benzoic acid (402mg, 3.3mmol), HBTU (1.7g, 4.5mmol), DIPEA (1.6mL, 9mmol), dichloromethane (20mL) into the reaction flask, room temperature Reaction 8h. Diluted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain a crude product, which is subjected to silica gel column chromatography (DCM:MeOH=95:5) to obtain 550 mg of a light yellow oil, with a yield of 90%, ESI-MS m / z: 259.1 [M+H] + .

[0041] The second step: preparation of 1-acryloyl-4-benzoylpiperazin-2-one (6)

[0042]

[0043] Add 5 (408mg, 2mmol), DIPEA (1.0mL, 6mmol), dichloromethane (20mL) into the reaction flask, add acryloyl chloride (600μL, 6mmol) under ice bath, remove the ice...

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Abstract

The invention belongs to the technical field of medicine and relates to a 1,4-disubstituted-2-piperazinone compound having a general structure formula of the formula I, and pharmaceutical use thereof.The compound can selectively inhibit activity of glycogen syntheses kinase 3beta (GSK 3beta), and can be used for preparing medicines preventing and / or treating diseases with GSK 3beta abnormal pathological features, the diseases including cancer, neurological disease, metabolic syndrome and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to 1,4-disubstituted-2-piperazinone compounds of general formula I and their application in medicine. The 1,4-disubstituted-2-piperazinone compounds can selectively inhibit the activity of glycogen synthesis kinase-3β (GSK 3β), and can be used for the prevention and / or treatment of diseases with abnormal pathological characteristics of GSK 3β Drugs for diseases including cancer, neurological diseases, metabolic syndrome, etc. Background technique [0002] State Office of the Prior Art Separated Glycogen synthase kinase-3β (Glycogen synthase kinase-3β, GSK 3β) is a multifunctional serine / threonine protein kinase that can phosphorylate and inactivate glycogen synthase. Studies have shown that GSK 3β can phosphorylate a variety of substrate proteins and participate in multiple important signal transduction pathways in vivo, including insulin signaling pathway, Wnt signaling pathway and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/08A61K31/495A61P35/00A61P35/02A61P25/28A61P25/16A61P25/00A61P21/00A61P3/10A61P29/00
CPCC07D241/08A61P35/00A61P35/02A61P25/28A61P25/16A61P25/00A61P21/00A61P3/10A61P29/00
Inventor 楚勇高扬叶德泳
Owner FUDAN UNIV
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