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Preparation method and application of multi-target inhibitor acting on QC and GSK-3beta

An inhibitor, multi-targeting technology, applied in the field of preparation of multi-targeting inhibitors, can solve the problems of limited molecular activity, low drugability of lead compounds, insufficient molecular structure diversity, etc., and achieve the effect of expanding structural diversity

Active Publication Date: 2020-04-03
SHENZHEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In view of the above-mentioned deficiencies in the prior art, the purpose of the present invention is to provide a preparation method and application of a multi-targeted inhibitor acting on QC and GSK-3β, aiming to solve the problem of compound effect in the existing anti-AD drug research. Single target, insufficient molecular structure diversity, limited molecular activity, and low druggability of lead compounds

Method used

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  • Preparation method and application of multi-target inhibitor acting on QC and GSK-3beta
  • Preparation method and application of multi-target inhibitor acting on QC and GSK-3beta
  • Preparation method and application of multi-target inhibitor acting on QC and GSK-3beta

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] figure 1 It is a schematic diagram of the synthetic route of the multi-target inhibitor in this example.

[0048] (1) Synthesis of intermediate product III:

[0049] a, with anhydrous CH 2 Cl 2 As a solvent, add 1 mole of raw material I, and add no less than 8 moles of anhydrous AlCl 3 , after stirring for 0.5h, dropwise add no less than 3 moles of methoxy oxalyl chloride solution II, stir at room temperature for 6-10h, add excess saturated NaHCO 3 solution, extracted 3 times with ethyl acetate, combined the organic phases, and used anhydrous Na 2 SO 4 Drying, concentration, and column chromatography to prepare product III, calculate the yield, and identify the structure;

[0050] (2) Synthesis of intermediate product VI:

[0051] b. With anhydrous CH 2 Cl 2 As a solvent, cool in an ice bath, add 1 mole of raw material IV, stir to dissolve, dropwise add not less than 4 moles of oxalyl chloride solution, dropwise add 2 drops of DMF, stir to room temperature, rea...

Embodiment 2

[0059] 3-(5-((1H-Benzo[d]imidazole-5-yl)methyl)-5H-pyrrolo[3,2-d]pyrimidine-7-yl)-4-phenyl-1H-pyrrole Preparation of -2,5-dione:

[0060] a. 20ml anhydrous CH 2 Cl 2 Add 0.105Mol 5H-pyrrolo[3,2-d]pyrimidine, add 1.107Mol anhydrous AlCl 3 , after stirring for 0.5h, add dropwise 0.439Mol methoxy oxalyl chloride solution, stir at room temperature for 6.5h, add 30ml saturated NaHCO 3 solution, extracted with ethyl acetate 20ml × 3 times, combined organic phase, anhydrous Na 2 SO 4 Drying, concentration, and column chromatography prepared methyl 2-oxo-2(5H-pyrrolo[3,2-d]pyrimidin-7-yl)acetate in a yield of 72%;

[0061] b. 20ml of anhydrous CH cooled in an ice bath 2 Cl 2 Add 0.114Mol phenylacetic acid, stir to dissolve, dropwise add 0.524Mol oxalyl chloride solution, dropwise add 2 drops of DMF, stir to room temperature, react for 3h, evaporate the solvent, add 15ml of anhydrous THF, cool in an ice bath, dropwise add 60ml of concentrated ammonia water , reacted for 0.5h, a...

Embodiment 3

[0068] 3-(1-((1H-Benzo[d]imidazole-5-yl)methyl)-5-nitro-1H-indole-3-yl)-4-(4-methoxyphenyl) - Preparation of 1H-pyrrole-2,5-dione:

[0069] a. 20ml anhydrous CH 2 Cl 2 Add 0.112Mol 5-nitro-1H-indole, add 1.326Mol anhydrous AlCl 3 , after stirring for 0.5h, dropwise add 0.513Mol methoxy oxalyl chloride solution, stir at room temperature for 8h, add 30ml saturated NaHCO 3 solution, extracted with ethyl acetate 20ml × 3 times, combined organic phase, anhydrous Na 2 SO 4 Drying, concentration, and column chromatography prepared 2-(5-nitro-1H-indol-3-yl)-2-oxoacetic acid methyl ester with a yield of 53%;

[0070] b. 20ml of anhydrous CH cooled in an ice bath 2 Cl 2 Add 0.108Mol p-methoxyphenylacetic acid, stir to dissolve, add dropwise 0.493Mol oxalyl chloride solution, add dropwise 2 drops of DMF, stir to room temperature, react for 2.5h, evaporate the solvent, add 15ml of anhydrous THF, and cool in an ice bath. Add 60ml concentrated ammonia water dropwise, react for 1h, a...

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Abstract

The invention discloses a preparation method and application of a multi-target inhibitor acting on QC and GSK-3 beta. The structural general formula of the multi-target inhibitor prepared by the method is shown in the specification. According to the invention, according to active center crystal structures of target QC and GSK-3 beta zymoprotein, multiple high-activity pharmacophores are integrated, the multi-target inhibitor capable of acting on QC and GSK-3 beta at the same time is prepared through framework transition and recombination design, the multi-target inhibitor is molecules with multiple target points and high activity, the molecular structure diversity of a lead drug is remarkably expanded, and the research and development of innovative anti-AD drugs and AD diagnostic kits areactively promoted, and the preparation method of the multi-target inhibitor provided by the invention is simple and easy to operate.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method and application of a multi-target inhibitor acting on QC and GSK-3β. Background technique [0002] Alzheimer's disease (Alzheimer's disease, AD) is a common neurodegenerative disease, the main form of senile dementia, AD patients account for more than 65% of the total number of senile dementia patients. The clinical symptoms of AD include progressive memory and cognitive dysfunction, etc. It is characterized by irreversibility, high morbidity, and high mortality. It has become the third largest worldwide health, economic, and social problem. However, the exact pathological mechanism of AD is still unclear, and there is no specific drug for clinical treatment. The research of innovative anti-AD drugs is imminent. Contents of the invention [0003] In view of the above-mentioned deficiencies in the prior art, the purpose of the present invention is to prov...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D403/14C07D401/14A61K31/519A61K31/4184A61K31/4439A61P25/28
CPCC07D487/04C07D403/14C07D401/14A61K31/519A61K31/4184A61K31/4439A61P25/28
Inventor 吴海强贺震旦刘志刚谢亚洲余熙欧阳娜尚琦邹浩曼刘立忠吴序栎
Owner SHENZHEN UNIV
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