8-substituted styryl xanthine derivative and application thereof

An alkyl and compound technology, used in drug combinations, active ingredients of heterocyclic compounds, cardiovascular system diseases, etc., can solve problems such as adenosine A distribution limitation, achieve good brain/plasma ratio, stable properties, and good bioavailability degree of effect

Active Publication Date: 2020-04-28
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

[0291] Example 1 (E)-8-(3-(1H-pyrazol-1-yl)styryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H, Synthesis of 7H)-diketones

[0292]

[0293] Step 1) (E)-N-(6-amino-1,3-diethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3- Synthesis of (3-bromophenyl)acrylamide

[0294]

[0295] Add (E)-3-(3-bromophenyl)acrylic acid (3.3g, 14.5mmol) and dichloromethane (50mL) into a 100mL single-necked round bottom flask at 0°C, add N,N-diisopropyl Ethylamine (7.2mL, 43.6mmol) and HATU (6.6g, 16.8mmol), continue stirring for half an hour; then add 5,6-diamino-1,3-diethylpyrimidine-2,4(1H,3H )-diketone hydrochloride (3.0 g, 12.8 mmol), transferred to 25 ° C for 2 hours. Add water (30mL) and dichloromethane (30mL), separate the layers, collect the organic phase, spin dry under reduced pressure, separate and purify by column chromatography (dichloromethane / methanol (v / v)=20 / 1) to obtain the title compound as White solid (4.3 g, 82.6%).

[0296] MS(ESI,pos.ion)m / z:407.2[M+H] + ;

[0297]...

Embodiment 2

[0312] Example 2 (E)-8-(3-(1H-imidazol-1-yl)styryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H )-Diketone Synthesis

[0313]

[0314]The title compound of this step was prepared by referring to the method described in step 4 of Example 1, namely (E)-8-(3-bromostyryl)-1,3-diethyl-7-methyl-1H-purine- 2,6(3H,7H)-diketone (300mg, 0.74mmol), imidazole (100mg, 1.47mmol), cesium carbonate (0.4g, 1.23mmol), cuprous iodide (145mg, 0.76mmol), (1R, 2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (60mg, 0.42mmol) was prepared by reacting in N,N-dimethylformamide (15mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v)=50 / 1), the title compound was obtained as a yellow solid (178 mg, 61.3%).

[0315] MS(ESI,pos.ion)m / z:391.1[M+H] + ;

[0316] 1 H NMR (600MHz, CDCl 3 )δ (ppm) 7.85 (d, J = 15.7Hz, 2H), 7.62 (d, J = 7.5Hz, 2H), 7.56 (t, J = 7.8Hz, 1H), 7.46–7.41 (m, 2H), 7.02–6.98(m,2H),4.24(q,J=7.1Hz,2H),4.14–4.09(m...

Embodiment 3

[0317] Example 3 (E)-8-(3-(2H-1,2,3-triazol-2-yl)styryl)-1,3-diethyl-7-methyl-1H-purine Synthesis of -2,6(3H,7H)-dione

[0318]

[0319] The title compound of this step was prepared by referring to the method described in step 4 of Example 1, namely (E)-8-(3-bromostyryl)-1,3-diethyl-7-methyl-1H-purine- 2,6(3H,7H)-diketone (0.6g, 1.49mmol), triazole (200mg, 2.9mmol), cesium carbonate (0.73g, 2.24mmol), cuprous iodide (170mg, 0.89mmol), (1R,2R)-N 1 ,N 2 -Dimethylcyclohexane-1,2-diamine (130mg, 0.91mmol) was prepared by reacting in N,N-dimethylformamide (15mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether / Ethyl acetate (v / v)=10 / 1), the title compound was obtained as a yellow solid (225 mg, 38.6%).

[0320] MS(ESI,pos.ion)m / z:392.1[M+H] + ;

[0321] 1 H NMR (600MHz, CDCl 3 )δ (ppm) 8.36 (s, 1H), 8.11 (d, J = 4.4Hz, 1H), 7.89–7.86 (m, 3H), 7.56 (s, 2H), 7.06 (d, J = 15.6Hz, 1H ), 4.24(q, J=5.9Hz, 2H), 4.11(brs, 5...

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Abstract

The invention discloses an 8-substituted styryl xanthine derivative and application thereof, particularly relates to a novel 8-substituted styryl xanthine derivative and a pharmaceutical composition containing the compound, and 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 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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IPC IPC(8): C07D473/06A61P25/00A61P25/16A61P35/00A61P29/00A61P25/24A61P25/28A61P9/10A61P11/06A61P25/14A61P19/10A61P25/32A61P25/04A61K31/522
CPCA61P9/10A61P11/06A61P19/10A61P25/00A61P25/04A61P25/14A61P25/16A61P25/24A61P25/28A61P25/32A61P29/00A61P35/00C07D473/06
Inventor 金传飞钟文和张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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