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6-hydrazone-8-azapurine compound and its preparation method and application

A technology of heteropurines and compounds, applied in the field of 6-hydrazone-8-azapurine compounds and their preparation, can solve problems such as dyspnea and limit the wide-scale use of ticagrelor

Active Publication Date: 2019-04-19
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ticagrelor is the first marketed anti-platelet aggregation drug containing 8-azapurine structure, oral activity, and direct action. However, clinical studies have found that some patients taking ticagrelor have dyspnea, transient Adverse reactions such as ventricular pause and hemorrhagic risk, especially hemorrhagic events are common adverse reactions of antithrombotic drugs, which limit the wider use of ticagrelor

Method used

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  • 6-hydrazone-8-azapurine compound and its preparation method and application
  • 6-hydrazone-8-azapurine compound and its preparation method and application
  • 6-hydrazone-8-azapurine compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] (1)(1S,2R,3S,4R)-6-[[5-amino-6-chloro-2-(propylthiouracil)-4-yl]-amino]-2,2-dimethyl Preparation of tetrahydro-4H-cyclopentyl[d][1,3]dioxan-4-ol

[0023] Add 4,6-dichloro-5-amino-2-propylthiopyrimidine (16.10g, 0.068mol) to 300ml 1,4-dioxane, add 2-[[(3R,4S ,6R,6S)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-alcohol mandelate (22.03g, 0.075mol) and N,N-diisopropylethylamine (43.94g, 0.34mol), heated to 100°C for reaction, the color of the reaction system gradually changed from yellow to brown, and the reaction progress was monitored by thin-layer chromatography. After 26 hours, After the basic reaction of the system is completed, cool down to room temperature, then add 500ml of water, extract, separate the liquids, extract the water phase twice with ethyl acetate, combine the organic phases, wash once with saturated saline, and dry the organic phases with anhydrous magnesium sulfate. Then the organic solvent was distilled off under reduced pressu...

Embodiment 2

[0035] 9-[(1'R,2'S,3'R,4'S)-2',3',4'-trihydroxycyclopent-1'-yl]-9H-2-propylthio-6-(3, 4-difluorobenzaldehyde hydrazone)-8-azapurine (Ib)

[0036]

[0037] The preparation method is similar to the step (3) of Example 1. White solid, melting point 153.6-155.0°C. 1 H NMR (400MHz, DMSO-d 6 ):δ(ppm)1.02(3H,t,-CH 3 ,J=7.2Hz),1.73(2H,m,CH 2 ),1.98(1H,m,5'-CH 2 ),2.63(1H,m,5'-CH 2 ),3.15(2H,CH 2 ),3.82(1H,s,CH),3.97(1H,s,CH),4.72(1H,m,CH),4.93(1H,OH),5.03(1H,m,CH),5.11(1H,OH ), 5.14 (1H, OH), 7.57 (1H, m, Ph-H), 7.71 (1H, s, Ph-H), 7.94 (1H, s, Ph-H), 8.23, 8.49 (1H, =CH ),11.06,11.49(1H,NH).HRMS(ESI)for[M+H] + :calcd 466.14674,found466.14656.

Embodiment 3

[0039] 9-[(1'R,2'S,3'R,4'S)-2',3',4'-trihydroxycyclopent-1'-yl]-9H-2-propylthio-6-(2- Hydroxybenzaldehyde (hydrazone)-8-azapurine (Ic)

[0040]

[0041] The preparation method is similar to the step (3) of Example 1. Yellow solid, melting point 231.9-232.8°C. 1 H NMR (400MHz, DMSO-d 6 ): δ (ppm) 1.01 (3H, t, J = 7.3Hz), 1.72 (2H, m), 1.98 (1H, ddd, J = 13.5, 9.0, 4.4Hz), 2.64 (1H, ddd, J = 13.5 ,9.0,4.4Hz),3.15(2H,m),3.81(1H,dd,J=4.7,4.0Hz),3.96(1H,ddd,J=7.0,7.0,4.4Hz),4.73(1H,ddd, J=9.0,4.7,4.0Hz), 4.99(1H,d,J=4.0Hz),5.04(1H,q,J=9.0Hz),5.11(1H,d,J=7.0Hz),5.14(1H, d, J = 4.0Hz), 6.94 (2H, m), 7.32 (1H, t, J = 7.7Hz), 7.46 (1H, d, J = 7.6Hz), 8.42, 8.69 (1H, = CH), 11.06 ,11.49(1H,NH),12.67(1H,OH). 13 C NMR (100MHz, DMSO-d 6 ): δ (ppm) 13.76, 22.83, 32.74, 36.38, 61.68, 73.65, 74.97, 77.27, 117.41, 118.60, 119.83, 122.87, 131.41, 131.87, 148.74, 151.44, 152.81, 169.37 M+H] + :calcd446.16050,found446.16021.

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Abstract

The invention relates to a 6-hydrazone radical-8-aza-purine compound and a preparing method and an application thereof and belongs to the fields of preparation of novel compounds and medicine application. The general molecular formula of the compound is shown in the description, wherein R1 is hydroxide radical, methylol group and hydroxyethoxy, R2 is hydrogen, hydroxide radical, and fluorine, R3 is methyl, ethyl, propyl and 3,3-trifluoropropyl group, and R4 is aryl group, substitutional aryl group, ceteroary, and substitutional ceteroary. A midbody is used as reaction substrate, wherein the formula of the midbody is shown in the description, the midbody and a hydrazine and aldehydes compound are subjected to a condensation reaction, and the 6-hydrazone radical-8-aza-purine compound is obtained. According to the novel 6-hydrazone radical-8-aza-purine compound, the antiplatelet aggregation activity is high, the bleeding side effect is low, and the compound can be used for preparing the antiplatelet aggregation medicine and preventing and treating the related thrombotic disease.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to the technical field of anti-platelet aggregation drugs, in particular to a class of 6-hydrazone-8-azapurine compounds and a preparation method thereof, and to the application of such compounds in anti-platelet aggregation drugs . Background technique [0002] Cardiovascular and cerebrovascular diseases have become one of the main causes of death in the world today, and the formation of thrombus is considered to be the direct cause of death from stroke, acute coronary syndrome and other related diseases. Antiplatelet aggregation drugs are mainstream drugs for the prevention and treatment of thrombotic cardiovascular and cerebrovascular diseases. Ticagrelor is the first marketed anti-platelet aggregation drug containing 8-azapurine structure, oral activity, and direct action. However, clinical studies have found that some patients taking ticagrelor have dyspnea, transient Advers...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P7/02
CPCC07D487/04
Inventor 闫红王业明胡盛全孙武积赵志昌宋秀庆
Owner BEIJING UNIV OF TECH
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