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Platelet aggregation inhibitor, and preparation method and application thereof

A solvate and compound technology, applied in the field of medicine, can solve the problem of unsatisfactory anti-platelet aggregation treatment effect and achieve good anti-platelet aggregation effect

Active Publication Date: 2016-04-13
BEIJING PRELUDE PHARM SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the overall therapeutic effect of the compound against platelet aggregation is still unsatisfactory, including the oral dose and the frequency of daily administration

Method used

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  • Platelet aggregation inhibitor, and preparation method and application thereof
  • Platelet aggregation inhibitor, and preparation method and application thereof
  • Platelet aggregation inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: the preparation of compound A of the present invention

[0051]

[0052] The concrete preparation method of compound A of the present invention is as follows:

[0053] step 1:

[0054]

[0055]Under a nitrogen inert atmosphere, place (1S,2S,3R,5S)-3-(7-[[(2S)-2-(3,4-difluorophenyl )cyclopropyl]amino]-5-(propylmercapto)-3H-[1,2,3]triazol[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy ) cyclopentane-1,2-diol (2 g, 3.79 mmol, 1.00 equiv, 99%) and 4-methylbenzenesulfonic acid (20 mg, 0.12 mmol, 0.03 equiv, 99%) in acetone (50 mL), Then 2,2-dimethoxypropane (800 mg, 7.68 mmol, 2.03 equiv) was added dropwise with stirring at room temperature. The resulting solution was stirred at 30°C for 12 hours. The pH of the solution was adjusted to 7 with sodium bicarbonate. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography and eluted with ethyl acetate:petroleum ether (1:50~1:3) to o...

Embodiment 2

[0067] Embodiment 2: the preparation of compound B of the present invention

[0068]

[0069] The concrete preparation method of compound B of the present invention is as follows:

[0070] step 1:

[0071]

[0072] Under a nitrogen inert atmosphere, place tert-butyl N-[3-[(3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2, 2-Dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-5-(propylmercapto)-3H-[1,2,3]triazole [4,5-d]pyrimidin-7-yl]-N-[(2S)-2-(3,4-difluorophenyl)cyclopropyl]carbamate (110mg, 0.16mmol, 1.00eq, 99%) and triethylamine (Et 3 N) (35 mg, 0.34 mmol, 2.08 equiv, 99%) in dichloromethane (DCM) (20 mL), then 2-methylbutyryl chloride (28 mg, 0.26 mmol, 1.58 equiv) was added dropwise with stirring. The resulting solution was stirred at 0 °C for 1.5 h, quenched by adding 50 mL of water / ice, and extracted 3 times with 50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a s...

Embodiment 3

[0078] Embodiment 3: the preparation of compound C of the present invention

[0079]

[0080] The specific preparation method of compound C of the present invention is as follows:

[0081] step 1:

[0082]

[0083] Under a nitrogen inert atmosphere, put tert-butyl N-[3-[(3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)- 2,2-Dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-5-(propylmercapto)-3H-[1,2,3] Triazol[4,5-d]pyrimidin-7-yl]-N-[(2S)-2-(3,4-difluorophenyl)cyclopropyl]carbamate (300mg, 0.45mmol, 1.00 Equiv, 99%) in trimethyl phosphate (3 mL), then phosphorus oxychloride (105 mg, 0.68 mmol, 1.51 eq, 99%) was added dropwise. The resulting solution was stirred at 10-15°C for 16 hours, added 50 mL of water / ice to terminate the reaction, and extracted three times with 50 mL of ethyl acetate. The combined organic layers were concentrated in vacuo to afford 200 mg (48%) of (2-[[(3aR,4S,6R,6aS)-6-(7-[[(tert-butoxy)carbonyl][(2S) -2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylme...

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Abstract

The invention provides a compound represented by a formula (I), or pharmaceutically acceptable salts, solvates, polymorphs, enantiomers or racemic mixtures thereof. In the formula (I), R1 is substituted or unsubstituted lower alkyl; R2 is phenyl or phenyl substituted by one or more halogen atoms; R3 is O(CH2)nR4, wherein n is an integer selected from 1-6, and R4 is OC(O)R5 or OP(O)(OH)2, wherein R5 is substituted or unsubstituted lower alkyl or R6NH2, wherein R6 is substituted or unsubstituted lower alkyl.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a platelet aggregation inhibitor and its preparation method and application. Background technique [0002] Antiplatelet therapy plays an important role in the prevention of atherosclerotic complications in patients with acute coronary syndrome (ACS) and / or undergoing percutaneous coronary intervention (PCI). [0003] Ticagrelor is a novel, selective and reversible P2Y12 adenosine diphosphate receptor (ADP) antagonist developed by AstraZeneca. The drug does not require metabolic activation, has obvious inhibitory effect on platelet aggregation induced by adenosine diphosphate (ADP), and takes effect quickly after oral administration, and can effectively improve the symptoms of patients with acute coronary syndrome. Unlike thienopyridines, ticagrelor is a reversible inhibitor of P2Y12 receptors, so it is especially suitable for patients who need anticoagulant therapy ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P7/02A61P9/10
CPCY02P20/55
Inventor 王志岩史高德王斗
Owner BEIJING PRELUDE PHARM SCI & TECH
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