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Benzotriazine compound with PAR4 antagonistic activity and application thereof

A compound and solvate technology, applied in the field of chemical drugs, can solve problems such as marketed and oral small-molecule PAR4 antagonists.

Active Publication Date: 2020-07-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far no oral small molecule PAR4 antagonists have been marketed

Method used

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  • Benzotriazine compound with PAR4 antagonistic activity and application thereof
  • Benzotriazine compound with PAR4 antagonistic activity and application thereof
  • Benzotriazine compound with PAR4 antagonistic activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] 4-Chloro-6-methoxy-2-(3-(methoxymethyl)-6-methylbenzo[e][1,2,4]triazin-8-yl)benzo[d ]thiazole (Compound 1)

[0061]

[0062] Compound 1-1 (1.00 g, 5.70 mmol) was dissolved in THF (10 mL), and 40% sodium methoxide in methanol (2 mL) was slowly added dropwise at room temperature, and stirred at room temperature for 2.5 h. The reaction was monitored by TLC. After the raw materials were reacted, saturated ammonium chloride (20 mL) was added to quench the reaction, and ethyl acetate (20 mL×3) was added for extraction. The organic phase was washed with saturated sodium bicarbonate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography, eluting with PE / EA=20 / 1-10 / 1, gave compound 1-2 (1.04 g) as light yellow solid, yield 94%, Rf=0.5 (PE / EA=3 / 1).

[0063]Compound 1-2 (1.00g, 5.33mmol) was dissolved in methanol (25mL), zinc powder (3.5g, 53.3mmol) and ammonium chloride (5.72g, 106.6mmol) were added, an...

Embodiment 2

[0076] 8-(4-chloro-6-methoxybenzo[d]thiazol-2-yl)-N,6-dimethylbenzo[e][1,2,4]triazin-3-amine ( Compound 2)

[0077]

[0078] At room temperature, compound 1-10 (1.0 g, 3.39 mmol) was dissolved in THF (20 mL), and aqueous sodium hydroxide solution (1 M, 7 mL) was slowly added dropwise, stirred for 1 h, and the reaction was monitored by TLC. After the reaction of the raw materials, dilute hydrochloric acid (1.0M, 10mL) was slowly added dropwise, extracted with EA (20mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, silica gel column chromatography, DCM / MeOH Rinse with / AcOH=10 / 1 / 1 to obtain the crude compound 2-1 as a brown-black oil. Rf=0.2-0.4 (DCM / MeOH / AcOH=5 / 1 / 1, severe tailing).

[0079] Under nitrogen protection, compound 2-1 (900mg, 3.36mmol) was dissolved in anhydrous tert-butanol (5mL), added activated 4A molecular sieves and stirred at room temperature for 2h, and diphenylphosphoryl azide (1.02...

Embodiment 3

[0085] 8-(4-Chloro-6-methoxybenzo[d]thiazol-2-yl)-6-methylbenzo[e][1,2,4]triazine-3-carboxylic acid ethyl ester ( Compound 4)

[0086]

[0087] Compound 1-10 (500mg, 1.69mmol), pinacol diboronate (860mg, 3.38mmol) and anhydrous potassium acetate (340mg, 3.38mmol) were added to anhydrous 1,4-dioxane (10mL), Under strict nitrogen protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (75mg, 0.1mmol) was added, and the temperature was raised to 120°C for 2h under reflux. The reaction was monitored by TLC. After the raw materials have been reacted, the reaction is cooled to room temperature, and EA / H 2 O was separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Wet sample loading, flash silica gel column chromatography, eluting with DCM / MeOH=50 / 1, the crude product containing compound 4-1 was obtained as a dark oily substance. It was used in the next reaction without further purification.

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PUM

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Abstract

The invention discloses a benzotriazine compound with PAR4 antagonistic activity and application thereof. The present invention relates to a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, solvate or prodrug thereof, and the compound of the present invention has significant antagonistic activity on PAR4, thereby effectively inhibiting platelet aggregation, and thus can be used for the preparation of a medicament for preventing or treating a variety of thromboembolic diseases.

Description

technical field [0001] The invention belongs to the technical field of chemical medicine, and particularly provides a compound as a PAR4 antagonist for anti-platelet aggregation. Background technique [0002] Thromboembolic disease is currently one of the leading causes of death in the world, and existing antiplatelet drugs have shortcomings that limit their clinical safety and / or practicability. Thrombin protease receptor-4 (PAR4), one of three platelet G protein-coupled receptors (GPCRs) that bind thrombin (the other two being PAR1 and PAR3), mediates a relatively slow but highly robust Sustained calcium mobilization by rods is critical during the late diffusion phase of platelet activation (Wong, Seiffert et al. 2017). Targeted antagonism of PAR4 may be safer and more effective, and blocking persistent calcium signaling from PAR4 may prevent the growth of deleterious stable thrombi, while preserving PAR1 transient signaling to preserve initial thrombus formation (Angioli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D417/04C07D471/04A61K31/53A61K31/695A61K31/427C07F7/08A61P9/10A61P7/02
CPCC07D401/04C07D417/04C07D471/04C07F7/0834A61P9/10A61P7/02
Inventor 朱雄刘尚德孔毅张玮琪袁铎张韬郑毅政张纵硕
Owner CHINA PHARM UNIV
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