8-substituted styryl xanthine derivative and application thereof

An alkyl and aryl technology, applied in drug combinations, active ingredients of heterocyclic compounds, blood diseases, etc., can solve problems such as adenosine A distribution limitation, achieve good brain/plasma ratio, good pharmacokinetic properties, good safety effect

Active Publication Date: 2021-02-02
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it was found that adenosine A 1 Receptors are distributed in high density in the brain, adenosine A 2A The distribution of receptors is more restricted

Method used

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  • 8-substituted styryl xanthine derivative and application thereof
  • 8-substituted styryl xanthine derivative and application thereof
  • 8-substituted styryl xanthine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0269] Example 1 (E)-1,3-diethyl-7-methyl-8-(4-(piperidin-4-yloxy)styryl)-1H-purine-2,6(3H, Synthesis of 7H)-diketones

[0270]

[0271] Step 1) Synthesis of tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate

[0272]

[0273] At 25°C, p-toluenesulfonyl chloride (7.1g, 37.0mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (5.0g, 24.8mmol) were added to a 100mL single-necked flask, and dichloromethane ( 40mL), then triethylamine (10.4mL, 74.2mmol) was added dropwise, and the reaction was continued for 18 hours; saturated sodium bicarbonate solution (30mL) was added, the liquid was separated, the organic phase was collected, spin-dried under reduced pressure, and separated and purified by column chromatography (Petroleum ether / ethyl acetate (v / v)=10 / 1~5 / 1) the title compound was obtained as a white solid (5.6 g, 63%).

[0274] MS(ESI,pos.ion)m / z:300.0[M+H-56] + ;

[0275] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.82 (d, J = 8.2Hz, 2H), 7.36 (d, J = 8.1Hz, 2H...

Embodiment 2

[0305] Example 2 (E)-1,3-diethyl-7-methyl-8-(4-((1-methylpiperidin-4-yl)oxy)styryl)-1H-purine- Synthesis of 2,6(3H,7H)-diketones

[0306]

[0307] (E)-1,3-diethyl-7-methyl-8-(4-(piperidin-4-yloxy)styryl)-1H-purine-2,6( 3H,7H)-diketone (0.5g, 1.18mmol) and methanol (10mL) were added to a 100mL single-necked round-bottomed flask, and aqueous formaldehyde (0.88mL, 12mmol, 37mass%) and acetic acid (142mg, 2.36mmol) were added, stirred After reacting for 15 minutes, add sodium cyanoborohydride (227mg, 3.54mmol), transfer to 25°C and continue stirring for 12 hours; stop the reaction, add water (30mL), dichloromethane extraction (50mL), liquid separation, organic phase After spin-drying under reduced pressure, separation and purification by column chromatography (dichloromethane / methanol (v / v)=15 / 1) gave the title compound as an off-white solid (0.49 g, 94.8%). MS(ESI,pos.ion)m / z:438.1[M+H] + ;

[0308] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.75 (d, J = 15.7Hz, 1H), 7.54 (d, J = ...

Embodiment 3

[0309] Example 3 (E)-1,3-diethyl-7-methyl-8-(4-((1-ethylpiperidin-4-yl)oxy)styryl)-1H-purine- Synthesis of 2,6(3H,7H)-diketones

[0310]

[0311] (E)-1,3-diethyl-7-methyl-8-(4-(piperidin-4-yloxy)styryl)-1H-purine-2,6( 3H,7H)-diketone (500mg, 1.18mmol) and acetonitrile (5mL) were added to a 50mL single-necked round bottom flask, N,N-diisopropylethylamine (0.56mL, 3.39mmol) was added, and then iodine was added dropwise Ethane (0.191mL, 2.38mmol), continue stirring for 3 hours; stop the reaction, spin dry under reduced pressure, separate and purify by column chromatography (dichloromethane / methanol (v / v)=30 / 1) to obtain the title compound as light Yellow solid (0.455 g, 85.3%).

[0312] MS(ESI,pos.ion)m / z:452.2[M+H] + ;

[0313] 1 H NMR (400MHz, CDCl 3 )δ7.75(d, J=15.7Hz, 1H), 7.57(d, J=8.6Hz, 2H), 6.95(d, J=8.6Hz, 2H), 6.81(d, J=15.7Hz, 1H) ,4.81(brs,1H),4.22(q,J=6.9Hz,2H),4.15–4.03(m,5H),3.47(brs,2H),3.30–3.08(m,4H),2.77(brs,2H ),2.34–2.18(m,2H),1.57(t,J=7.3Hz,3H),1....

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Abstract

The invention discloses an 8-substituted styryl xanthine derivative and application thereof, and particularly relates to a novel 8-substituted styryl xanthine derivative and a pharmaceutical composition containing the compound which can be used as a selective adenosine A2A receptor antagonist. The invention also relates to a method for preparing the compound and the pharmaceutical composition, andapplication of the compound and the pharmaceutical composition in preparation of drugs for treating adenosine A2A receptor related diseases, especially Parkinson's disease.

Description

technical field [0001] The invention belongs to the technical field of medicines, and specifically relates to novel 8-substituted styryl xanthine derivatives and pharmaceutical compositions containing these compounds, as well as their application methods and applications. In particular, the novel 8-substituted styrylxanthine derivatives described in the present invention can be used as selective adenosine A 2A Receptor antagonist, for preventing, treating or alleviating the relationship with adenosine A 2A Receptor-related diseases, especially Parkinson's disease. Background technique [0002] Parkinson's disease (Parkinson's disease, PD) is a common chronic degenerative disease of the nervous system, also known as Parkinson's paralysis. rare. The prevalence of PD in people over 65 years old in my country is about 1.7%. Most Parkinson's disease patients are sporadic cases, and less than 10% of patients have a family history. Parkinson's disease has an insidious onset an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/06A61K31/522A61P25/16A61P25/14A61P35/00A61P29/00A61P25/24A61P25/28A61P11/06A61P19/10A61P25/00A61P25/32A61P7/06
CPCC07D473/06A61P25/16A61P25/14A61P35/00A61P29/00A61P25/24A61P25/28A61P11/06A61P19/10A61P25/00A61P25/32A61P7/06A61P9/10A61K31/198A61K31/522
Inventor 金传飞钟文和许腾飞
Owner SUNSHINE LAKE PHARM CO LTD
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