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Xanthine derivative as well as preparation method and application thereof

A derivative, xanthine technology, applied in the field of medicine, can solve the problems of fast conversion, poor photosensitivity, and no reports.

Inactive Publication Date: 2020-07-10
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although istradefylline has a good therapeutic effect, it also has certain defects: on the one hand, although its conjugated double bond structure exists stably in the trans configuration in the solid state, it has poor photosensitivity in solution, Easy to convert to the cis configuration, usually the more dilute the concentration, the faster the conversion
[0006] The xanthine derivatives involved in this patent are used as A 2A Research on receptor antagonists has not been reported yet

Method used

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  • Xanthine derivative as well as preparation method and application thereof
  • Xanthine derivative as well as preparation method and application thereof
  • Xanthine derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Preparation of 8-(benzo[b]thiophen-2-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (Compound 1):

[0048] 1mmol of intermediate A (5,6-diamino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione) and 1mmol of EDC (1-ethyl-(3-dimethyl Aminopropyl) carbodiimide hydrochloride) was sequentially added to the reaction flask, 5mL of dioxane and 5mL of water were added, and 1mmol of benzo[b]thiophene-2-carboxylic acid was added under stirring at room temperature, to the reaction solution 1M HCl aqueous solution was added dropwise to adjust the pH=5~6, and the amide compound was reacted under stirring at room temperature; the reaction was detected by TLC (developing agent was chloroform:methanol=20:1). Heat up to reflux reaction; TLC detection reaction (developing agent is chloroform:methanol=20:1), after the reaction is completed, use 1M hydrochloric acid aqueous solution to adjust PH=5~6, precipitate a large number of solids, filter and wash with water, ethanol recrystallization to obtain c...

Embodiment 2

[0050] Preparation of 1,3-dimethyl-8-(1-methyl-1H-indol-2-yl)-1H-purine-2,6(3H,7H)-dione (compound 2):

[0051]1mmol of intermediate A (5,6-diamino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione) and 1.3mmol of EDC (1-ethyl-(3-di Methylaminopropyl) carbodiimide hydrochloride) was added to the reaction flask in turn, 5 mL of dioxane and 5 mL of water were added, and 1.2 mmol of 1-methyl-1H-indole-2-carboxylic acid was added under stirring at room temperature , in the reaction solution, dropwise add 1M HCl aqueous solution to adjust PH=5~6, react under stirring at room temperature to generate amide compound; and 1mL water, warming up to reflux reaction; TLC detection reaction (developing agent is chloroform:methanol=20:1), after the completion of the reaction, use 1M hydrochloric acid aqueous solution to adjust the pH=5~6, a large amount of solids are precipitated, filtered and washed with water, and recrystallized from ethanol to obtain Compound 2; 1H-NMR (400MHz, DMSO-d6): δ3.28(s, ...

Embodiment 3

[0053] Preparation of 1,3-diethyl-8-(1-methyl-1H-indol-2-yl)-1H-purine-2,6(3H,7H)-dione (compound 3):

[0054] 1mmol of intermediate A (5,6-diamino-1,3-diethylpyrimidine-2,4(1H,3H)-dione) and 1mmol of EDC (1-ethyl-(3-dimethyl Aminopropyl) carbodiimide hydrochloride) was sequentially added to the reaction flask, 5 mL of dioxane and 5 mL of water were added, and 1 mmol of 1-methyl-1H-indole-2-carboxylic acid was added under stirring at room temperature. In the reaction solution, 1M HCl aqueous solution was added dropwise to adjust the pH=5~6, and the amide compound was reacted under stirring at room temperature; the reaction was detected by TLC (developing agent was chloroform:methanol=20:1), after the reaction was completed, 1.5mmol of NaOH solid and Heat 1mL of water to 110°C for reflux reaction; TLC detection reaction (developing solvent: chloroform:methanol=20:1), after the completion of the reaction, use 1M hydrochloric acid aqueous solution to adjust the pH to 5-6, a large...

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Abstract

The invention provides a xanthine derivative as well as a preparation method and application thereof, and particularly relates to application of the xanthine derivative serving as A2A receptor antagonists in preparation of medicines for treating adenosine receptor A2A related diseases. The xanthine derivative provided by the invention has better water solubility than istradefylline, and the bioavailability is greatly improved; the purpose of the present invention is to design and synthesize a novel xanthine derivative having good A2A receptor inhibitory activity. The prepared compound shows agood result in an A2A receptor activity test.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a xanthine derivative and its application. Specifically, it relates to the application of the compound as an A2A receptor antagonist in the preparation of medicines for treating diseases related to adenosine receptor A2A. Background technique [0002] Adenosine is an important neurotransmitter and regulator with physiological activity in the human body. The adenosine receptor is located on the cell membrane and is a transmembrane G-protein coupled receptor. Typically, adenosine receptors are divided into the following four subtypes: A1, A2A, A2B, and A3 receptors. Adenosine A2A receptor antagonists have the effect of treating various chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and Huntington's disease, etc., which is a hot research field in recent years. [0003] Itradefylline is a selective adenosine A 2A Receptor antagonists, developed ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/06C07D473/08A61K31/522A61P25/00A61P25/16A61P25/14A61P25/28
CPCA61P25/00A61P25/14A61P25/16A61P25/28C07D473/06C07D473/08
Inventor 徐启乐徐豪杰牛笑怡高学霞沈红毕娜娜
Owner SHANDONG XINHUA PHARMA CO LTD
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