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Nitrogen-containing fused tricyclic derivatives 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, achieve good brain/plasma ratio, good clinical application prospects, and stable properties.

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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  • Nitrogen-containing fused tricyclic derivatives and application thereof
  • Nitrogen-containing fused tricyclic derivatives and application thereof
  • Nitrogen-containing fused tricyclic derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0258] Example 1 2-(furan-2-yl)-7-((6-((oxetan-3-yloxy)methyl)pyridin-2-yl)methyl)-7H-pyrazole[ Synthesis of 4,3-e][1,2,4]triazol[1,5-c]pyrimidin-5-amine

[0259]

[0260] Step 1) Synthesis of 2-(bromomethyl)-6-((oxetan-3-yloxy)methyl)pyridine

[0261]

[0262] Add oxetan-3-ol (0.6g, 8.1mmol) and tetrahydrofuran (25mL) into a 100mL single-necked round-bottomed flask, stir at 5°C for 10 minutes, add sodium hydride (486mg, 12.2mmol), continue After stirring for 30 minutes, 2,6-bis(bromomethyl)pyridine (3.2 g, 12.1 mmol) was added, and transferred to an oil bath at 72° C. to react for 18 hours. Stop the reaction, add water (60mL) after cooling to room temperature, then add dichloromethane (60mL) for extraction, separate layers, collect the organic phase, spin dry under reduced pressure, separate and purify by column chromatography (petroleum ether / ethyl acetate (v / v)=3 / 1) The title compound was obtained as a light brown liquid (0.94 g, 45%).

[0263] MS(ESI,pos.ion)m / ...

Embodiment 2

[0269] Example 2 (S)-2-(furan-2-yl)-7-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-7H- Synthesis of pyrazol[4,3-e][1,2,4]triazol[1,5-c]pyrimidin-5-amine

[0270]

[0271] Step 1) Synthesis of (S)-2-(bromomethyl)-6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridine

[0272]

[0273] Add (S)-tetrahydrofuran-3-ol (0.9g, 10.22mmol) and tetrahydrofuran (35mL) into a 100mL single-necked round bottom flask, stir at 5°C for 10 minutes, then add sodium hydride (613mg, 15.3mmol), After continuing to stir for 30 minutes, 2,6-bis(bromomethyl)pyridine (4.0 g, 15.1 mmol) was added, and transferred to an oil bath at 75° C. for 8 hours. Stop the reaction, add water (60mL) after cooling to room temperature, then add dichloromethane (60mL) for extraction, separate layers, collect the organic phase, spin dry under reduced pressure, separate and purify by column chromatography (petroleum ether / ethyl acetate (v / v)=3 / 1) The title compound was obtained as a light brown liquid (1.1...

Embodiment 3

[0280] Example 3 (R)-2-(furan-2-yl)-7-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-7H- Synthesis of pyrazol[4,3-e][1,2,4]triazol[1,5-c]pyrimidin-5-amine

[0281]

[0282] Step 1) Synthesis of (R)-2-(bromomethyl)-6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridine

[0283]

[0284] Add (R)-tetrahydrofuran-3-ol (0.7g, 7.9mmol) and tetrahydrofuran (30mL) into a 100mL single-necked round bottom flask, stir at 5°C for 10 minutes, then add sodium hydride (477mg, 11.9mmol), After continuing to stir for 30 minutes, 2,6-bis(bromomethyl)pyridine (3.16 g, 11.9 mmol) was added, and transferred to an oil bath at 72° C. for 18 hours. Stop the reaction, add water (60mL) after cooling to room temperature, then add dichloromethane (60mL) for extraction, separate layers, collect the organic phase, spin dry under reduced pressure, separate and purify by column chromatography (petroleum ether / ethyl acetate (v / v)=3 / 1) The title compound was obtained as a light brown liquid (1.0...

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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): C07D487/14A61K31/519A61P25/16
CPCA61P25/16C07D487/14
Inventor 金传飞钟文和邓康
Owner SUNSHINE LAKE PHARM CO LTD
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