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Gsk-3β inhibitor or salt thereof and pharmaceutical use thereof

A -3-oxo-4-, pharmaceutical technology, used in the prevention or treatment of GSK-3β-related diseases, the field of compounds that inhibit glycogen synthase kinase-3β (GSK-3β), and can solve multiple side effects And other issues

Active Publication Date: 2016-08-10
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the ATP binding region is ubiquitous and highly conserved in other protein kinases, such inhibitors may cause more side effects, and improving their selectivity for kinase action is the key to research and development

Method used

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  • Gsk-3β inhibitor or salt thereof and pharmaceutical use thereof
  • Gsk-3β inhibitor or salt thereof and pharmaceutical use thereof
  • Gsk-3β inhibitor or salt thereof and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Preparation of N'-lauroyl-3-oxo-4-benzyl-3,4-dihydro-2H-benzo[1,4]thiazine-2-carbohydrazide (A-11)

[0033]

[0034] (a) Preparation of (2H)1,4-benzothiazin-3(4H)-one (SQa)

[0035] Dissolve 3.0g of o-aminothiophenol (24mmol) in 40ml of anhydrous dichloromethane (DCM), slowly dropwise add chloroacetyl chloride, immediately produce a white precipitate, TLC detection, after 4h o-aminothiophenol disappears, stop the reaction , the solvent was distilled off under reduced pressure, the residue was dissolved in water, extracted with ethyl acetate (100ml×3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, petroleum ether / ethyl acetate (5:1) silica gel Separation by column chromatography yielded 1.06 g of light yellow crystals with a yield of 30%; m.p.182.6~183.8°C. 1 H-NMR (400MHz, DMSO-d 6 )δ10.57(s,1H),7.32(dd,J=8.0,1.4Hz,1H),7.23-7.13(m,1H),6.97(dtd,J=7.8,3.7,1.3Hz,2H),3.46 (s,2H);ESI-MS(m / z)166.0[M+H] + ...

Embodiment 2

[0044] Example 2: Preparation of N'-myristoyl-3-oxo-4-ethyl-3,4-dihydro-2H-benzo[1,4]thiazine-2-carbohydrazide (A-9)

[0045]

[0046] (a) Preparation of 4-ethyl-(2H)1,4-benzothiazin-3(4H)-one (SQb-2)

[0047] The preparation method is the same as that of SQb-1, and the product is a light yellow oil at room temperature, with a yield of 68%. 1 H-NMR (400MHz, CDCl 3 -d 3)δ7.36(dd, J=7.7,1.5Hz,1H),7.26-7.22(m,1H),7.14(dd,J=8.3,1.2Hz,1H),7.02(td,J=7.5,1.2Hz ,1H),4.05(q,J=7.1Hz,2H),3.38(s,2H),1.29(t,J=7.1Hz,3H);ESI-MS(m / z)194.1[M+H] + .

[0048] (b) Preparation of 2-methoxyformyl-4-ethyl-(2H)1,4-benzothiazin-3(4H)-one (SQc-2)

[0049] The preparation method is the same as that of SQc-1, and the product is a colorless oil at room temperature with a yield of 55%. 1 H-NMR (400MHz, CDCl 3 -d 3 )δ7.37(dd, J=7.7,1.5Hz,1H),7.31-7.27(m,1H),7.16(dd,J=8.3,1.2Hz,1H),7.04(td,J=7.6,1.2Hz ,1H),4.26(s,1H),4.22-3.94(m,2H),3.68(s,3H),1.32(t,J=7.1Hz,3H);ESI-MS(m / z)252.1[M +H] + .

[0...

Embodiment 3

[0054] Example 3: Preparation of N'-n-nonanoyl-3-oxo-4-ethyl-3,4-dihydro-2H-benzo[1,4]thiazine-2-carbohydrazide (A-6)

[0055]

[0056] The preparation method is the same as A-9, except that n-nonanoic acid is used instead of n-tetradecanoic acid; petroleum ether / ethyl acetate (2:1) silica gel column chromatography to obtain a white solid powder with a yield of 71.2%. m.p.176.1~178.1℃. 1 H-NMR (400MHz, DMSO-d 6 )δ10.18(d,J=2.1Hz,1H),9.95(d,J=2.1Hz,1H),7.42-7.36(m,1H),7.35-7.27(m,2H),7.06(ddd,J =8.2,5.3,3.2Hz,1H),4.35(s,1H),4.02(dp,J=43.7,7.1Hz,2H),2.06(t,J=7.3Hz,2H),1.46(q,J= 6.8,6.4Hz,2H),1.23(s,10H),1.16(t,J=7.0Hz,3H),0.85(t,J=6.7Hz,3H);ESI-MS(m / z)392.2[M +H] + .

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PUM

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Abstract

The invention belongs to the pharmaceutical chemistry field, and discloses a compound for inhibiting glycogen synthase kinase-3beta (GSK-3beta) in a formula I, its pharmaceutically acceptable salt, or an application of its pharmaceutical composition for preventing and treating the GSK-3beta-related diseases. The compound is a GSK-3beta small-molecule inhibitor, its action mode is non-ATP-competitive competition, and can be used for preparing the medicines for preventing and treating the GSK-3beta-related diseases, and the GSK-3beta-related diseases can be diabetes, Alzheimer's disease, stomach cancer, colorectal cancer, pancreas cancer, liver cancer or mixed acute leukemia. According to the compound, R1, R2, R3, X, Y are consistent with detailed description in the invention.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry. The invention relates to a GSK-3β inhibitor or a salt thereof, in particular to a compound capable of inhibiting glycogen synthase kinase-3β (GSK-3β) and its use in pharmacy. This type of compound is a small molecule inhibitor of GSK-3β, which can inhibit the activity of GSK-3β at micromolar concentration, and its action is characterized by non-ATP competitive inhibition. The present invention further includes the use of such compounds, their pharmaceutically acceptable salts, or their pharmaceutical compositions in the prevention or treatment of diseases related to GSK-3β. The disease related to GSK-3β can be diabetes, Alzheimer's disease, gastric cancer, colon cancer, pancreatic cancer, liver cancer, mixed leukemia, but is not limited thereto. Background technique [0002] The prior art discloses that Glycogen Synthase Kinase-3β (Glycogen Synthase Kinase-3, GSK-3) is a multifunctional serin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D279/16C07D241/44C07D239/96A61K31/5415A61K31/498A61K31/517A61P3/10A61P25/28A61P35/00A61P35/02
CPCC07D239/96C07D241/44C07D279/16
Inventor 楚勇鹿文博张鹏叶德泳
Owner FUDAN UNIV
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