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Applications of 2,3-dihydro[1,5] benzothiazepine compounds or salts thereof in preparation of GSK-3beta inhibitor

A technology of benzothiazepine and hetero compounds, which is applied in the field of medicinal chemistry of the present invention and can solve problems such as inactivation

Inactive Publication Date: 2012-11-14
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Amino acid residues after GSK-3 autophosphorylation can occupy this special region and lead to the inactivation of GSK-3

Method used

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  • Applications of 2,3-dihydro[1,5] benzothiazepine compounds or salts thereof in preparation of GSK-3beta inhibitor
  • Applications of 2,3-dihydro[1,5] benzothiazepine compounds or salts thereof in preparation of GSK-3beta inhibitor
  • Applications of 2,3-dihydro[1,5] benzothiazepine compounds or salts thereof in preparation of GSK-3beta inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: Preparation of 5-benzyl-2,3-dihydro-2-(2-furan)[1,5]benzothiazepine -4-keto (CYbc)

[0041] (a). Preparation of 2-furan acrylic acid

[0042]

[0043] Malonic acid (20.8g, 0.2mol), furfural (16.6ml, 0.2mol), pyridine (10ml, 0.12mol) and 0.5mL piperidine were uniformly mixed, stirred and refluxed for 2 hours. Ammonia water was adjusted to make alkaline, hydrochloric acid was added to the water phase to make it acidic, the solid was collected, washed with water until neutral, and recrystallized with 50% ethanol / water solution to obtain 18.95 g of colorless crystals, with a yield of 69%. through 1 HNMR and MS confirmed the structure. 1 HNMR (400MHz, CDCl 3 ): δppm: 6.32 (d, 1H, J = 16.04Hz, = C H-COOH); 6.49-6.50 (dd, 1H, J = 1.96Hz, J = 3.52Hz, furan-4H); 6.68 (d, 1H, J = 3.13Hz, furan-3H); 7.52 (d, 1H, J =15.56Hz, furan-5H); δ7.52 (d, 1H, J=1.96Hz, -CH=CH-COOH). MS (-ESI): 137.1 (M-H) - , 275.0(2M-H) - .

[0044] (b).2,3-dihydro-2-(2-furyl)[1,5]be...

Embodiment 2

[0051] Example 2: Preparation of 5-(4-chlorobenzyl)-2,3-dihydro-2-(2-furyl)[1,5]benzothiazepine -4-keto (HZaa)

[0052] White needle crystals, yield 94%. 1 HNMR (400MHz, CDCl 3 ): δppm: 7.47 (d, 1H, J = 7.6Hz); 7.40 (td, 1H, J = 7.0, 1.3Hz); 7.29 (d, 1H, J = 4.4Hz); 7.24 (s, 2H); 7.23 (s, 2H); 7.20 (d, 1H, J = 3.6Hz); 7.18 (t, 1H, J = 7.5Hz); 5.99 (d, 1H, J = 3.0); 5.25 (d, 1H, J = 15.2 Hz); 4.86 (d, 1H, J=15.2Hz); 4.90-4.85 (m, 1H); 2.91-2.79 (m, 2H,). MS (API-ES); m / z 370.0 (M + +H), 392.1 (M+Na).

Embodiment 3

[0053] Example 3: Preparation of 5-(3-chlorobenzyl)-2,3-dihydro-2-(2-furyl)[1,5]benzothiazepine -4-keto (HZah)

[0054] Pale yellow solid, yield 85%. 1 HNMR (400MHz, CDCl 3 ): δppm: 2.81-2.93 (m, 2H, -CH 2 -); 4.87-4.91(m, 1H); 4.93(d, 1H, J=15.21Hz, AB); 5.19(d, 1H, J=15.30Hz, AB); 6.00(d, 1H, J=2.96Hz ); 6.26 (s, 1H); 7.16-7.49 (m, 9H, PhH). MS (+ESI): 370.0 (M+H) + .

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PUM

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and discloses 2,3-dihydro[1,5] benzothiazepine compounds of non-adenosine triphosphate (ATP) competitive inhibition glycogen synthase kinase-3beta (GSK-3beta) with a structure shown in formula I. The compounds can inhibit the activity of the GSK-3beta in a non ATP competitive mode, and can be used as micromolecule inhibitors of the GSK-3beta for preparing medicines for preventing or treating GSK-3beta related diseases. The invention further provides applications of the compounds, pharmaceutical acceptable salts thereof, or medicine compositions thereof to preventing or treating the GSK-3beta related diseases. The GSK-3beta related diseases can be diabetes and an Alzheimer's disease.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to 2,3-dihydro[1,5]benzothiazepine Compounds and pharmaceutical uses thereof, in particular to 2,3-dihydro[1,5]benzothiazepines Compounds or salts thereof and their use in the preparation of drugs for inhibiting the activity of glycogen synthase kinase-3β (GSK-3β), in particular to a class of compounds capable of inhibiting glycogen synthase kinase-3β (GSK-3β) in a non-ATP competition mode ) 2,3-dihydro[1,5]benzothiazepine compounds, which can be used as non-ATP competitive small molecule inhibitors of GSK-3β for the preparation of prevention or treatment related to GSK-3β Medicines for diseases. Background technique: [0002] According to the forecast of the International Diabetes Federation, due to poor eating habits and lack of exercise, there will be as many as 300 million people with diabetes worldwide in 2025. Most of them are type 2 diabetic patients. In China, diabetes ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04C07D281/02A61K31/554A61P3/10A61P25/28
Inventor 楚勇黄朝辉胡海荣叶德泳
Owner FUDAN UNIV
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