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Triazolopyrimidine derivative, preparation method thereof, and application thereof in medicines

A technology of compounds and general formulas, which can be used in pharmaceutical formulations, antipyretics, drug combinations, etc., and can solve the problems of low activity, low selectivity, and low bioavailability.

Active Publication Date: 2019-03-29
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still problems such as low solubility, photosensitivity, low activity, low selectivity and low bioavailability

Method used

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  • Triazolopyrimidine derivative, preparation method thereof, and application thereof in medicines
  • Triazolopyrimidine derivative, preparation method thereof, and application thereof in medicines
  • Triazolopyrimidine derivative, preparation method thereof, and application thereof in medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0236] 8-(2-Methyl-6-(trifluoromethyl)pyridin-4-yl)-7-phenyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine 1

[0237]

[0238]

[0239] first step

[0240] 2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine 1b

[0241] Under a nitrogen atmosphere, (1,5-cyclooctadiene)methoxyiridium(I) dimer (1.0 g, 1.55 mmol), 4,4,4',4',5,5,5 ',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (15.7 g, 62.1 mmol) and 4,4'-di-tert-butyl-2, 2'-Dipyridine (0.83g, 3.1mmol) was dissolved in 100mL of n-hexane, heated to 50°C, stirred for 10 minutes, and 2-methyl-6-(trifluoromethyl)pyridine 1a (5g, 31mmol, Prepared by the known method "Chemical and Pharmaceutical Bulletin, 1990, 38(9), 2446-2458"), and continued stirring for 4 hours. The reaction was stopped, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography with developer system B to obtain the title compound 1b (6 g, y...

Embodiment 2

[0267] 8-(2,6-Dimethylpyridin-4-yl)-7-phenyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine 2

[0268]

[0269] first step

[0270] 5-Bromo-4-chloro-6-phenylpyrimidin-2-amine 2a

[0271] Compound 1e (13g, 7.34mmol) was dissolved in 300mL N,N-dimethylformamide, N-bromosuccinimide (12.38g, 69.54mmol) was added, and the reaction was stirred for 1 hour. The reaction was stopped, the reaction solution was poured into 1L of water, stirred for 20 minutes, filtered, and the filter cake was dried to obtain the crude title compound 2a (18 g), which was directly used in the next reaction without purification.

[0272] MS m / z(ESI):285.9[M+1]

[0273] second step

[0274] 5-Bromo-4-hydrazino-6-phenylpyrimidin-2-amine 2b

[0275] Crude compound 2a (17.99 g, 63.21 mmol) was dissolved in 120 mL of ethanol, 50 mL of 85% hydrazine hydrate was added, and the reaction was stirred for 17 hours. Stop the reaction, filter the reaction solution, wash the filter cake with ethanol (30mL×2) and n-hexan...

Embodiment 3

[0291] 2-Ethyl-8-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)-7-phenyl-[1,2,4]triazolo[1,5-c] Pyrimidin-5-amine 3

[0292]

[0293]

[0294] first step

[0295] 8-Bromo-3-ethyl-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 3a

[0296] Compound 2b (500 mg, 1.78 mmol) and (tri)ethyl orthopropionate (378 mg, 2.14 mmol) were dissolved in 20 mL of ethanol, and stirred for 2 hours under reflux. The reaction was stopped, cooled to room temperature, and the reaction liquid was concentrated under reduced pressure. The resulting residue was slurried with 5 mL of anhydrous ether for 0.5 hours, filtered, and the filter cake was dried to obtain the title compound 3a (495 mg, yield: 87.16%).

[0297] MS m / z(ESI):318.3[M+1]

[0298] second step

[0299] 2-Ethyl-8-(2-methyl-6-(trifluoromethyl)pyridin-4-yl)-7-phenyl-[1,2,4]triazolo[1,5-c] Pyrimidin-5-amine 3

[0300] Under a nitrogen atmosphere, compound 3a (150 mg, 0.471 mmol), compound 1b (189 mg, 0.66 mmol), [1,1'-bis(diphenylp...

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Abstract

The invention relates to a triazolopyrimidine derivative, a preparation method thereof, and an application thereof in medicines. In particular, the invention relates to the triazolopyrimidine derivative represented as the general formula (I), a preparation method thereof, a medicine composition containing the derivative, and an application of the derivative as a treatment agent, especially an application as an A2a receptor antagonist, and an application in preparation of a medicine for relieving symptoms and diseases by inhibiting the A2a receptor; wherein the substituent groups in the generalformula (I) are defined as the specification.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a triazolopyrimidine derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as A 2a Use of Receptor Antagonists and in the Preparation for Treatment by A 2a Use of a medicament for a condition or disorder ameliorated by inhibition of a receptor. Background technique [0002] Adenosine is a naturally occurring purine nucleoside that is an endogenous regulator of many physiological functions. It plays an important role in the regulation of cardiovascular system, central nervous system, respiratory system, kidney, fat and platelet function. [0003] The action of adenosine is mediated by the G protein-coupled receptor family. Currently, there are at least four subtypes of adenosine receptors, classified as A 1 、A 2a 、A 2b and A 3 . where A 1 and A 3 The receptor inhibi...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P25/24A61P25/28A61P25/00A61P25/14A61P1/16A61P17/00A61P9/10A61P25/30A61P29/00A61P35/02
CPCA61P1/16A61P9/10A61P17/00A61P25/00A61P25/14A61P25/24A61P25/28A61P25/30A61P29/00A61P35/00A61P35/02C07D487/04
Inventor 陆标王胜蓝沈晓冬贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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