Urolithin PDE2 inhibitor compounds and preparation method thereof

A technology of PDE2 and urolithin, which is applied in the field of urolithin PDE2 inhibitor compounds and their preparation, and can solve problems such as no PDE2 inhibitors on the market

Pending Publication Date: 2021-09-14
CHANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The problem to be solved by the present invention: In order to overcome the shortcomings of existing inhibitors, such as the lack of PDE2 inhibitors on the market, and devel

Method used

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  • Urolithin PDE2 inhibitor compounds and preparation method thereof
  • Urolithin PDE2 inhibitor compounds and preparation method thereof
  • Urolithin PDE2 inhibitor compounds and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] (1-1) 2-((6-oxo-6H-benzo[c]benzopyran-3-yl)oxy)acetic acid

[0048]

[0049] Add powdery white solid powder urolithin B (1mmol) and bromoacetic acid (5mmol), catalyst potassium carbonate (5mmol) and potassium iodide (1mmol) in a 500ml round bottom flask, add enough acetone solvent to make the compound dissolve. Condensate and reflux under the condition of 60°C in an oil bath, react for about 20 hours, and use TLC to detect whether the reaction is complete, wherein the developer is: methanol: dichloromethane = 1:5; The solution is clear and transparent, and the solution is light yellow. The pH value was adjusted to 3 with concentrated hydrochloric acid, and a light yellow solid was precipitated, filtered with suction, washed with a large amount of water, and dried to obtain the intermediate product 2-((6-oxo-6H-benzo[c]benzopyridine pyran-3-yl)oxy)acetic acid.

[0050] 2-((6-oxo-6H-benzo[c]benzopyran-3-yl)oxy)acetic acid (1-1): white solid, yield: 59.4%; M.p.>300°C; ...

Embodiment 2

[0055] (2-1) Synthesis of urolithin B amide derivatives (1a—1m)

[0056]

[0057] Dissolve the solid (1-1) obtained in the previous step in 20 mL of DMF at room temperature, add EDCl, HOBt, and DIEA in sequence and stir. After activating for 1 h, add dropwise R 2 NH 2 , stirred for a certain period of time, and followed the reaction with TLC. After the reaction, the reaction solution was added dropwise to saturated NaHCO 3 In the aqueous solution, a flocculent solid is formed, and after standing still, it is filtered, the solid is washed with a large amount of water, and dried to obtain the urolithin B amide derivative. Purify with methanol / dichloromethane at a volume ratio of 1:400.

[0058]

[0059]

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Abstract

The invention provides urolithin PDE2 inhibitor compounds and a preparation method thereof, and belongs to the field of medicinal chemistry. Two types of compounds are obtained through two-step simple reaction, and 22 brand-new PDE2 inhibitor compounds are obtained in total; the method for synthesizing the compounds is simple, convenient, energy-saving and environment-friendly; in a first step, the reaction is simple, column chromatography is not needed, the purity is high, the yield is high, and the total yield is 54% or above; and in the second step, the reaction is carried out at room temperature, no by-product is generated, the purity and yield of the target product are greatly improved, the HPLC purity of the obtained compounds is high and reaches 97% or above, and the total yield is high and reaches 30.0% or above.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a urolithin PDE2 inhibitor compound and a preparation method thereof. Background technique [0002] Hydroxy-substituted benzo[c]benzopyran-6-one derivatives, also known as urolithins, are intestinal metabolites of ellagic acid. So far, dozens of urolithin metabolites have been identified (Figure 1). Urolithin can protect the hippocampus of the brain by reducing the formation of advanced glycation end products and inducing autophagy cells. It can be used in the treatment of progressive neurodegenerative diseases, such as typical Alzheimer's disease (AD) and Parkinson's disease (PD), showing great therapeutic potential. [0003] [0004] Phosphodiesterase 2 (PDE2) is mainly distributed in brain and heart cells, through the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) catalyzed by PDE2, it maintains the levels of in...

Claims

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Application Information

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IPC IPC(8): C07D311/80C07D407/12C07D409/12C07D405/12
CPCC07D311/80C07D407/12C07D409/12C07D405/12
Inventor 宋国强夏颜谈颖狄万慧王贺成唐龙冯筱晴黄险峰
Owner CHANGZHOU UNIV
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