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Nitrogen-containing fused tricyclic derivative and application thereof

A compound, hydrate technology, applied in Parkinson's disease. , The field of nitrogen-containing fused tricyclic derivatives and pharmaceutical compositions containing these compounds can solve problems such as adenosine A distribution limitation, and achieve the effects of good brain/plasma ratio, good bioavailability, and good safety.

Inactive 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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  • Nitrogen-containing fused tricyclic derivative and application thereof
  • Nitrogen-containing fused tricyclic derivative and application thereof
  • Nitrogen-containing fused tricyclic derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0289] Example 1 2-(furan-2-yl)-7-(2-(4-(4-(oxetan-3-yloxy)phenyl)piperazin-1-yl)ethyl)- Synthesis of 7H-pyrazol[4,3-e][1,2,4]triazol[1,5-c]pyrimidin-5-amine

[0290]

[0291] Step 1) Synthesis of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde

[0292]

[0293] Phosphorus oxychloride (58.7mL, 630mmol) was added to a 500mL single-necked round bottom flask, and N,N-dimethylformamide (12.1mL, 157mmol) was added dropwise in a low temperature bath at 5°C, and then transferred to 25°C , added 2-amino-4,6-dihydroxypyrimidine (10 g, 78.7 mmol) in batches, and raised the temperature to 100° C. to react for 5 hours. Stop the reaction, remove most of the phosphorus oxychloride by rotary evaporation under reduced pressure, add water (900mL), stir at 25°C for 32 hours, filter, add the obtained solid into ethyl acetate (50mL), stir for 30 minutes, Filtration and drying of the filter cake afforded the title compound as a yellow solid (12.2 g, 80.8%).

[0294] MS(ESI,pos.ion)m / z:192...

Embodiment 2

[0315] Example 2 (R)-2-(furan-2-yl)-7-(2-(4-(4-((tetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl Synthesis of -7H-pyrazol[4,3-e][1,2,4]triazol[1,5-c]pyrimidin-5-amine

[0316]

[0317]The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 2-(5-amino-2-(furan-2-yl)-7H-pyrazol[4,3-e][1,2 ,4] Triazol[1,5-c]pyrimidin-7-yl)ethyl 4-methylbenzenesulfonate (0.708g, 1.61mmol), (R)-1-(4-((tetrahydrofuran-3 -yl)oxy)phenyl)piperazine (0.68g, 2.74mmol) and N,N-diisopropylethylamine (0.8mL, 4.85mmol) in N,N-dimethylformamide (20mL) The reaction was prepared, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v)=20 / 1) to obtain the title compound as a white solid (378 mg, 45.5%).

[0318] MS(ESI,pos.ion)m / z:516.3[M+H] + ;

[0319] 1 H NMR (400MHz, DMSO-d 6 )δ(ppm)8.16(s,1H),8.05(s,2H),7.93(s,1H),7.23(d,J=3.1Hz,1H),6.84(d,J=9.1Hz,2H), 6.77(d, J=9.1Hz, 2H), ...

Embodiment 3

[0320] Example 3 (S)-2-(furan-2-yl)-7-(2-(4-(4-((tetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl Synthesis of -7H-pyrazol[4,3-e][1,2,4]triazol[1,5-c]pyrimidin-5-amine

[0321]

[0322] The title compound of this step was prepared by referring to the method described in step 6 of Example 1, that is, 2-(5-amino-2-(furan-2-yl)-7H-pyrazol[4,3-e][1,2 ,4] Triazol[1,5-c]pyrimidin-7-yl)ethyl 4-methylbenzenesulfonate (0.5g, 1.14mmol), (S)-1-(4-((tetrahydrofuran-3 -yl)oxy)phenyl)piperazine (0.424g, 1.71mmol) and N,N-diisopropylethylamine (0.38mL, 2.3mmol) in N,N-dimethylformamide (15mL) The reaction was prepared, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v)=20 / 1) to obtain the title compound as a white solid (154 mg, 26.2%).

[0323] MS(ESI,pos.ion)m / z:516.3[M+H] + ;

[0324] 1 H NMR (400MHz, DMSO-d 6 )δ(ppm)8.17(s,1H),8.07(s,2H),7.94(s,1H),7.23(d,J=3.3Hz,1H),6.84(d,J=9.1Hz,2H), 6.78(d, J=9.0Hz, 2H), ...

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Abstract

The invention discloses a nitrogen-containing fused tricyclic derivative and application thereof, and particularly relates to a novel nitrogen-containing fused tricyclic derivative and a pharmaceutical composition containing the nitrogen-containing fused tricyclic derivative, and the nitrogen-containing fused tricyclic derivative 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 nitrogen-containing fused tricyclic derivatives, pharmaceutical compositions containing these compounds, and methods and uses thereof. In particular, the novel nitrogen-containing fused tricyclic 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 and slow progress...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/14A61K31/519A61P25/16A61P35/00A61P25/24A61P25/28A61P9/10A61P11/06A61P25/32A61P25/14A61P19/10
CPCA61P9/10A61P11/06A61P19/10A61P25/14A61P25/16A61P25/24A61P25/28A61P25/32A61P35/00C07D487/14
Inventor 金传飞钟文和邓康
Owner SUNSHINE LAKE PHARM CO LTD
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