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Purine derivative as well as preparation method and medical application thereof

A technology of derivatives and prodrugs, applied in the field of novel purine derivatives

Pending Publication Date: 2020-07-07
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] There are currently 4 compounds in clinical research: Servier's S-81694 (clinical phase I / II), Bayer's BAY-1217389 (clinical phase I), University Health Network CFI-402257 (clinical phase I / II) and Boston Pharmaceuticals' BOS-172722 (clinical phase I), many companies have published patents (for example: WO2009156315 / WO2014131739 / WO2015070349 / WO2014037750), but there is no TTK selective inhibitor on the market

Method used

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  • Purine derivative as well as preparation method and medical application thereof
  • Purine derivative as well as preparation method and medical application thereof
  • Purine derivative as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] N-cyclopropyl-4-(2-(4-methoxyphenoxy)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-9H-purine-9 -yl)-2-methylbenzamide (compound 1)

[0166]

[0167] Step 1: 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (compound 1-2)

[0168] Add 2,6-dichloro-9H-purine (1.89g, 10mmol) into 100mL ethyl acetate, add TsOH (172mg, 1mmol), dihydropyran (100mg, 1.2mmol), and keep warm at 50°C for reaction 2 Hour. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrated residue was separated and purified by column chromatography to obtain 1.63 g of the title compound.

[0169] ESI-MS(m / z):273.2[M+H] +

[0170] Step 2: 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-9H-purin-6-amine (Compounds 1-3)

[0171] Compound 1-2 (272 mg, 1 mmol), 4-aminomethyltetrahydropyran (138 mg, 1.2 mmol), and triethylamine (202 mg, 2 mmol) were dissolved in te...

Embodiment 2

[0183] N-cyclopropyl-4-(2-(2,3-difluoro-4-methoxyphenoxy)-6-(((tetrahydro-2H-pyran-4-yl)methyl)amino )-9H-purin-9-yl)-2-methylbenzamide (compound 19)

[0184]

[0185] Step 1: 2-(2,3-difluoro-4-methoxyphenoxy)-9-(tetrahydro-2H-pyran-2-yl)-N-((tetrahydro-2H-pyran -4-yl)methyl)-9H-purin-6-amine (compound 19-1)

[0186] Compound 1-3 (70.2mg, 0.2mmol), 2,3-difluoro-4-methoxyphenol (40mg, 0.24mmol), Pd 2 (dba) 3 (18.3mg, 0.02mmol), di-tBuxphos (17mg, 0.04mmol), Cs 2 CO 3 (130.3mg, 0.4mmol) was added to toluene (5mL), under nitrogen protection, and reacted at 120°C for 12 hours. Cool to room temperature, add water, extract with ethyl acetate, combine the organic phases, and dry over anhydrous sodium sulfate. The concentrated residue is purified by column chromatography to obtain 78 mg of the title compound. ESI-MS(m / z):477.2[M+H] +

[0187] Step 2: 2-(2,3-difluoro-4-methoxyphenoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)-9H-purin-6-amine (Compound 19-2)

[0188] Compound 1...

Embodiment 3

[0194] N-cyclopropyl-4-(2-(4-methoxyphenoxy)-6-((3,3,3-trifluoropropyl)amino)-9H-purin-9-yl)-2 -Toluamide (compound 14)

[0195]

[0196] Step 1: 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-N-(3,3,3-trifluoropropyl)-9H-purin-6-amine (compound 14-1 )

[0197] Add compound 1-2 (272mg, 1mmol), 3,3,3-trifluoropropylamine (136mg, 1.2mmol), triethylamine (202mg, 2mmol) into tetrahydrofuran (5mL), and react at room temperature for 2.0 hours. Water and ethyl acetate were added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography to obtain 312 mg of the title compound.

[0198] ESI-MS(m / z):350.2[M+H] +

[0199] Step 2: 2-(4-methoxyphenoxy)-9-(tetrahydro-2H-pyran-2-yl)-N-(3,3,3-trifluoropropyl)-9H-purine -6-amine (compound 14-2)

[0200] Compound 14-1 (69mg, 0.2mmol), 4-methoxyphenol (29.8mg, 0.24mmol), Pd 2 (dba) 3 (18.3mg, 0.02mmol), di-tBuxphos (17mg, 0.04mmol), Cs 2 CO 3 (130....

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Abstract

The invention provides a novel purine derivative, a preparation method thereof, a pharmaceutical composition containing the same, and application of the same in medicine. Particularly, the invention relates to a compound shown as a formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound to prevention or treatment of diseases related to TTK activity.

Description

technical field [0001] The present invention relates to a class of novel purine derivatives, a preparation method thereof, a pharmaceutical composition containing the compound and its application in medicine. Background technique [0002] Spindle Assembly Checkpoint (Spindle Assembly Checkpoint, SAC) is one of the main checkpoints in the cell cycle. SAC monitors the arrangement of chromosomes on the equatorial plate and the separation to the poles of the spindle, ensuring kinetochore-microtubule adhesion and mitosis Integrity, so that all chromosomes are placed on the equatorial plate and enter anaphase after bipolar orientation, ensuring that chromosomes are accurately distributed to daughter cells during mitosis (Nature Reviews Molecular Cell Biology, vol.8, no.5, pp. 379-393, 2007; Cell Proliferation, vol.44, no.5, pp.391-400, 2011.). When spindle microtubules are misconnected to chromosomes or spindle assembly goes wrong, the spindle checkpoint is activated and inhibits...

Claims

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Application Information

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IPC IPC(8): C07D473/18C07D473/16A61K31/52A61P35/00A61P35/02
CPCC07D473/18C07D473/16A61P35/00A61P35/02Y02P20/55
Inventor 吴勇勇朱加望王超磊李桂英蔡家强王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD