3H-[1, 2, 3] triazolo [4, 5-d] pyrimidine-5-amine derivative and application thereof

A -NO2, -NH2 technology, applied in Parkinson's disease. It can solve problems such as the distribution limitation of adenosine A, and achieve the effects of good bioavailability, good pharmacodynamics and pharmacokinetic properties, and good metabolic stability.

Active Publication Date: 2020-03-27
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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  • 3H-[1, 2, 3] triazolo [4, 5-d] pyrimidine-5-amine derivative and application thereof
  • 3H-[1, 2, 3] triazolo [4, 5-d] pyrimidine-5-amine derivative and application thereof
  • 3H-[1, 2, 3] triazolo [4, 5-d] pyrimidine-5-amine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0221] Example 1 3-(2-(4-(4-(2-methoxyethoxy)phenyl)piperazin-1-yl)ethyl)-7-(5-methylfuran-2-yl Synthesis of )-3H-[1,2,3]triazol[4,5-d]pyrimidin-5-amine

[0222]

[0223] Step 1) Synthesis of tert-butyl (2-hydroxyethyl) carbamate

[0224]

[0225] Add ethanolamine (4.48g, 73.3mmol) into a 100mL single-necked round bottom flask at 25°C, add dichloromethane (30mL) and Boc anhydride (4g, 18.3mmol), and continue the reaction for 12 hours. Stop the reaction, add water (20 mL), separate the layers, collect the organic phase, spin dry under reduced pressure, separate and purify by column chromatography (petroleum ether / ethyl acetate (v / v)=2 / 1) to obtain the title compound as a colorless liquid (2.3g, 78%).

[0226] 1 H NMR (400MHz, CDCl 3 )δ (ppm) 3.65 (dd, J = 9.8, 4.8Hz, 2H), 3.38 (s, 1H), 3.25 (d, J = 4.7Hz, 2H), 1.42 (s, 9H).

[0227] Step 2) Synthesis of 2-((tert-butoxycarbonyl)amino)ethyl 4-methylbenzenesulfonate

[0228]

[0229] At 25°C, p-toluenesulfonyl c...

Embodiment 2

[0253] Example 2 3-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)-7-(5-methylfuran-2-yl)-3H-[1 ,2,3]Synthesis of triazol[4,5-d]pyrimidin-5-amine

[0254]

[0255] Step 1) Synthesis of tert-butyl (2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)carbamate

[0256]

[0257] The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, 1-(2,4-difluorophenyl)piperazine (0.37g, 1.87mmol), 2-((tert-butoxycarbonyl)amino ) ethyl 4-methylbenzenesulfonate (0.5g, 1.58mmol) and potassium carbonate (0.44g, 3.18mmol) were prepared by reacting in acetonitrile (5mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v)=100 / 1) gave the title compound as a white solid (340 mg, 68.8%).

[0258] MS(ESI,pos.ion)m / z:342.1[M+H] + ;

[0259] 1 H NMR (400MHz, CDCl 3 )δ(ppm)6.96–6.88(m,1H),6.86–6.78(m,2H),3.29(t,J=4.5Hz,2H),3.06(brs,4H),2.65(brs,4H),2.55 (t,J=5.9Hz,2H),1.48...

Embodiment 3

[0277] Example 3 7-(5-methylfuran-2-yl)-3-(2-(4-(4-(oxetan-3-yloxy)phenyl)piperazin-1-yl) Synthesis of ethyl)-3H-[1,2,3]triazol[4,5-d]pyrimidin-5-amine

[0278]

[0279] Step 1) tert-Butyl(2-(4-(4-(oxetan-3-yloxy)phenyl)piperazin-1-yl)ethyl)carbamate Synthesis of esters

[0280]

[0281] The title compound of this step was prepared by referring to the method described in step 3 of Example 1, that is, 1-(4-(oxetan-3-yloxy)phenyl)piperazine (1.7g, 7.2mmol), 2- ((tert-butoxycarbonyl)amino)ethyl 4-methylbenzenesulfonate (3.4g, 10.8mmol) and potassium carbonate (1.3g, 9.4mmol) were prepared by reacting in acetonitrile (50mL), and the crude product was passed through a silica gel column Purification by chromatography (dichloromethane / methanol (v / v)=100 / 1) gave the title compound as a white solid (1.3 g, 47%).

[0282] MS(ESI,pos.ion)m / z:378.2[M+H] + ;

[0283] Step 2) Synthesis of 2-(4-(4-(oxetan-3-yloxy)phenyl)piperazin-1-yl)ethylamine

[0284]

[0285] The titl...

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Abstract

The invention discloses a 3H-[1, 2, 3] triazolo [4, 5-d] pyrimidine-5-amine derivative and application thereof and particularly relates to the novel 3H-[1, 2, 3] triazolo [4, 5-d] pyrimidine-5-amine derivative and a pharmaceutical composition containing the compound, and the 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 the 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 present invention belongs to the technical field of medicines, and in particular relates to novel 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine derivatives, pharmaceutical compositions containing these compounds, and methods of use thereof and uses. In particular, the novel 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine 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 in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P25/16A61P35/00A61P29/00A61P25/24A61P25/00A61P9/10A61P11/06A61P25/32A61P25/14A61P25/28A61P19/10
CPCA61P9/10A61P11/06A61P19/10A61P25/00A61P25/14A61P25/16A61P25/24A61P25/28A61P25/32A61P29/00A61P35/00C07D487/04
Inventor 金传飞钟文和张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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