8-substituted styryl xanthine derivative and application thereof

An alkyl and aryl technology, applied in the field of medicine, can solve problems such as the distribution limitation of adenosine A, and achieve the effects of good brain/plasma ratio, good metabolic stability, and good pharmacokinetic properties

Active Publication Date: 2020-04-17
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

[0266] Example 1 (E)-1,3-diethyl-7-methyl-8-(4-(piperazine-1-carbonyl)styryl)-1H-purine-2,6(3H,7H) - Synthesis of diketones

[0267]

[0268] Step 1) Synthesis of (E)-3-(4-(methoxycarbonyl)phenyl)acrylic acid

[0269]

[0270] Methyl 4-formylbenzoate (6.0 g, 36.5 mmol), malonic acid (5.7 g, 54.8 mmol), piperidine (2.2 mL, 24 mmol) and pyridine (10 mL) were added to a 100 mL single-necked round bottom flask, The oil bath was reacted at 100°C for 2 hours. Cool to room temperature after the reaction, spin dry under reduced pressure, add hydrochloric acid (12M) to adjust pH = 2, filter, and dry at 60°C to obtain a white solid (7.3g, 96.9%).

[0271] MS(ESI,pos.ion)m / z:207.1[M+H] + ;

[0272] 1 H NMR (400MHz, DMSO-d 6 )δ (ppm) 7.97 (d, J = 8.2Hz, 2H), 7.82 (d, J = 8.2Hz, 2H), 7.63 (d, J = 16.0Hz, 1H), 6.66 (d, J = 16.0Hz, 1H), 3.86(s, 3H).

[0273] Step 2) (E)-methyl 4-(3-((6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Synthesis of (yl)amino)-3-o...

Embodiment 2

[0298] Example 2 (E)-1,3-diethyl-7-methyl-8-(4-(4-methylpiperazine-1-carbonyl)styryl)-1H-purine-2,6( Synthesis of 3H,7H)-diketones

[0299]

[0300] (E)-1,3-diethyl-7-methyl-8-(4-(piperazine-1-carbonyl)styryl)-1H-purine-2,6(3H, 7H)-diketone (0.6g, 1.37mmol) and methanol (10mL) were added to a 100mL single-necked round bottom flask, and aqueous formaldehyde (1.02mL, 13.8mmol, 37mass%) and acetic acid (0.24mL, 4.13mmol) were added, stirred After reacting for 15 minutes, add sodium cyanoborohydride (0.27g, 4.13mmol), transfer to 25°C and continue stirring for 12 hours; stop the reaction, add water (30mL), dichloromethane extraction (50mL), liquid separation, organic The phase was spin-dried under reduced pressure, separated and purified by column chromatography (dichloromethane / methanol (v / v)=15 / 1) to obtain the title compound as a pale yellow solid (0.421 g, 68.1%).

[0301] MS(ESI,pos.ion)m / z:451.2[M+H] + ;

[0302] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.78 (d, J = 15.7Hz,...

Embodiment 3

[0303] Example 3 (E)-1,3-diethyl-7-methyl-8-(4-(4-ethylpiperazine-1-carbonyl)styryl)-1H-purine-2,6( Synthesis of 3H,7H)-diketones

[0304]

[0305] (E)-1,3-diethyl-7-methyl-8-(4-(piperazine-1-carbonyl)styryl)-1H-purine-2,6(3H, 7H)-diketone (1.0g, 2.29mmol) and acetonitrile (20mL) were added to a 100mL single-necked round-bottomed flask, N,N-diisopropylethylamine (1.13mL, 6.78mmol) was added dropwise, and ethyl iodide was added dropwise Alkane (0.38mL, 4.76mmol), continue to stir and react for 11 hours; stop the reaction, spin dry under reduced pressure, separate and purify by column chromatography (petroleum ether / ethyl acetate (v / v)=1 / 1) to obtain the title compound as yellow Solid (0.91 g, 85%).

[0306] MS(ESI,pos.ion)m / z:465.2[M+H] + ;

[0307] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.81 (d, J = 15.7Hz, 1H), 7.63 (d, J = 8.1Hz, 2H), 7.47 (d, J = 8.1Hz, 2H), 6.98 (d, J = 15.7Hz, 1H), 4.23(q, J=7.0Hz, 2H), 4.15–4.04(m, 5H), 3.83(brs, 2H), 3.50(brs, 2H), 2.63–2.41(m, 6H),...

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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 8-substituted styryl xanthine derivative. The 8-substituted styryl xanthine derivative can be used as a selective adenosine A2A receptor antagonist. The invention also relates to a method for preparing the 8-substituted styryl xanthine derivative and the pharmaceutical composition, and application of the 8-substituted styryl xanthine derivative and the pharmaceutical compositionin 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): C07D473/06A61K31/522A61K31/5377A61P25/16A61P25/24A61P25/28A61P9/10A61P11/06A61P19/10A61P21/00A61P25/14A61P29/00A61P35/00
CPCA61P9/10A61P11/06A61P19/10A61P21/00A61P25/14A61P25/16A61P25/24A61P25/28A61P29/00A61P35/00C07D473/06
Inventor 金传飞钟文和邓高伟
Owner SUNSHINE LAKE PHARM CO LTD
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