8-substituted aromatic ring vinyl xanthine derivative and application thereof

An aryl and heteroaryl technology, applied in the field of medicine, can solve problems such as the distribution limitation of adenosine A, and achieve the effects of good bioavailability, good clinical application prospects, and stable properties

Active Publication Date: 2020-06-26
DONGGUAN HEC NEW DRUG R&D CO LTD +1
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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 aromatic ring vinyl xanthine derivative and application thereof
  • 8-substituted aromatic ring vinyl xanthine derivative and application thereof
  • 8-substituted aromatic ring vinyl xanthine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0276] Example 1 (E)-8-(4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy)styryl)-1,3-diethyl Synthesis of -7-methyl-1H-purine-2,6(3H,7H)-dione

[0277]

[0278] Step 1) Synthesis of 1,1-dioxotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate

[0279] At 25°C, p-toluenesulfonyl chloride (4.0g, 20.98mmol) and triethylamine (8.82mL, 63.0mmol) were added to a 100mL single-necked flask, dichloromethane (30mL) was added, and tetrahydro-2H- Thiopyran-4-ol 1,1-dioxide (4.1 g, 27.27 mmol), reacted for 24 hours. Add water (40mL), then add dichloromethane (20mL), separate the layers, collect the organic phase, spin dry under reduced pressure, separate and purify by column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1~5 / 1) The title compound was obtained as a pale yellow solid (4.2 g, 66%).

[0280] MS(ESI,pos.ion)m / z:305.1[M+H] + ;

[0281] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.81 (d, J = 8.2Hz, 2H), 7.39 (d, J = 8.1Hz, 2H), 5.38–5.28 (m, 1H), 4.76–4.66 (m, 4H), 2.49...

Embodiment 2

[0300] Example 2 (E)-8-(4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluorostyryl)-1,3 Synthesis of -diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione

[0301]

[0302] Step 1) Synthesis of 4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluorobenzaldehyde

[0303] The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, 1,1-dioxotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (2.0g, 6.57mmol) and 3-fluoro-4-hydroxybenzaldehyde (1.38g, 9.86mmol) were prepared by reacting in N,N-dimethylformamide (10mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether / Ethyl acetate (v / v) = 10 / 1) gave the title compound as a light yellow solid (1.25 g, 70%).

[0304] MS(ESI,pos.ion)m / z:273.2[M+H] + ;

[0305] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 9.90 (d, J = 1.9Hz, 1H), 7.67 (d, J = 8.8Hz, 2H), 7.15 (t, J = 7.8Hz, 1H), 4.81 (brs, 1H), 3.53– 3.34(m,2H),3.02–2.96(m,2H),2.60–2...

Embodiment 3

[0319] Example 3 (E)-8-(4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy)-3-chlorostyryl)-1,3 Synthesis of -diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione

[0320]

[0321] Step 1) Synthesis of 4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy)-3-chlorobenzaldehyde

[0322] The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, 1,1-dioxotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (0.5g, 3.28mmol) and 3-chloro-4-hydroxybenzaldehyde (468mg, 3.0mmol) were prepared by reacting in N,N-dimethylformamide (10mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether / acetic acid Ethyl ester (v / v)=10 / 1) afforded the title compound as a yellow solid (0.605 g, 70%).

[0323] MS(ESI,pos.ion)m / z:289.2[M+H] + .

[0324] Step 2) (E)-3-(4-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy)-3-chlorophenyl)propene acid synthesis

[0325] The title compound of this step was prepared ...

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Abstract

The invention discloses a 8-substituted aromatic ring vinyl xanthine derivative and application thereof, and particularly relates to a novel 8-substituted aromatic ring vinyl xanthine derivative and apharmaceutical 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, and application 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 aromatic ring vinyl xanthine derivatives and pharmaceutical compositions containing these compounds, as well as their application methods and applications. In particular, the novel 8-substituted aromatic ring vinylxanthine 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/06A61K31/522A61P25/16A61P29/00A61P25/24A61P9/10A61P11/06A61P25/32A61P25/14A61P19/10
CPCC07D473/06A61P25/16A61P29/00A61P25/24A61P9/10A61P11/06A61P25/32A61P25/14A61P19/10A61K31/198A61K31/522A61K45/06
Inventor 金传飞钟文和许腾飞
Owner DONGGUAN HEC NEW DRUG R&D CO LTD
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