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Novel PAR-1 inhibitor, preparation method and application thereof in prevention and/or treatment of thrombotic diseases

A technology for PAR-1 and thrombotic diseases, applied in the field of novel PAR-1 inhibitors and their preparation, can solve the problems of low activity of the compound and the value only reaches the micromolar level, etc., and achieves high activity, good economy, and easy industrialization. The effect of mass production

Active Publication Date: 2019-12-31
SHANDONG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, from the biological activity data of the compounds published in the invention patent, there are the following problems: the activity of the compound is low, and its IC 50 Values ​​only reach the micromolar level

Method used

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  • Novel PAR-1 inhibitor, preparation method and application thereof in prevention and/or treatment of thrombotic diseases
  • Novel PAR-1 inhibitor, preparation method and application thereof in prevention and/or treatment of thrombotic diseases
  • Novel PAR-1 inhibitor, preparation method and application thereof in prevention and/or treatment of thrombotic diseases

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Experimental program
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Effect test

Embodiment 1

[0039] The preparation method of described novel PAR-1 inhibitor (compound I), concrete steps are as follows:

[0040] (1) Preparation of Compound IV

[0041]Weigh 4.20g of sclareolide and place it in a round bottom flask, add 75mL of tetrahydrofuran to dissolve it. Next, 25 mL of a 1M tetrahydrofuran solution of potassium hexamethyldisilazane and 2.8 mL of trimethoxyphosphine were slowly added to the round bottom flask in sequence. Finally, oxygen was introduced and reacted at -78°C. After the reaction was completed, the system was cooled down to room temperature, and the solvent was distilled off under reduced pressure to obtain compound II as a white solid. The prepared compound II was dissolved in 100 mL of anhydrous tetrahydrofuran, and placed in an ice-water bath to cool down to 2.5±2.5°C. Then weigh 1.60 g of lithium aluminum hydride and slowly add it into the round bottom flask. After the addition, the system was raised to room temperature and the reaction was comple...

Embodiment 2

[0045] The preparation method of described novel PAR-1 inhibitor (compound I), concrete steps are as follows:

[0046] (1) Preparation of Compound IV

[0047] Weigh 100.0 g of sclareolide and place it in a round bottom flask, add 1.7 L of tetrahydrofuran to dissolve it. Then, 595 mL of a 1M tetrahydrofuran solution of potassium hexamethyldisilazane and 67 mL of trimethoxyphosphine were slowly added to the round bottom flask in sequence. Finally, oxygen was introduced and reacted at -78°C. After the reaction was completed, the system was lowered to room temperature, and the solvent was evaporated under reduced pressure to obtain compound II as a white solid; after dissolving the prepared compound II in 24L anhydrous tetrahydrofuran, place Cool down to 2±1°C in an ice-water bath. Then weigh 38.1g of lithium aluminum hydride and slowly add it into the round bottom flask. After the addition, the system was raised to room temperature and the reaction was complete at room temperat...

Embodiment 3

[0051] Determination of biological activity (PAR-1 inhibitory activity) of compounds

[0052] 1. Cell culture

[0053] 1.1 Cell recovery

[0054] The HEK293-Gα15-PAR1 cell line (HD Biosciences stable cell line) was quickly taken out of the liquid nitrogen tank, and kept shaking in a 37°C water bath until it completely melted. Quickly add the cell suspension to the preheated medium (90% DMEM + 10% FBS + 1X Pen / Strep), put it into a centrifuge, and centrifuge at 1000 rpm for 10 minutes. Take out the centrifuge tube, discard the supernatant, add fresh preheated medium to the centrifuge tube, resuspend the cells, add the cell suspension to the culture dish, 37°C, 5% CO 2 nourish.

[0055] 1.2 Subculture

[0056] When the cells grow to 80-90% of the culture dish, gently wash the cells with 0.05% trypsin-EDTA, remove part of the digestion solution and incubate for 2-3 minutes, stop the digestion with a new medium, blow the cells gently with the tip of the pipette and Cells are ...

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Abstract

Belonging to the technical field of blood coagulation resistance, the invention particularly relates to a novel PAR-1 inhibitor, a preparation method and application thereof in prevention and / or treatment of thrombotic diseases. The novel PAR-1 inhibitor has a structural formula shown as the specification. A commercially available natural product sclareolide is adopted as the raw material, and thenovel PAR-1 inhibitor is prepared through four-step reaction. According to the PAR-1 inhibitor, the parent nucleus is highly similar to vorapaxar, the action target is clear, the structure is novel,and the activity is high, the IC50 value can reach the nanomole level, the safety is high, the preparation cost is low, and industrial batch production is easy to realize, therefore the PAR-1 inhibitor has good application prospects in serving as a candidate drug for treating thrombotic diseases.

Description

technical field [0001] The invention belongs to the technical field of blood anticoagulation, and specifically relates to a novel PAR-1 inhibitor, a preparation method thereof, and an application in preventing and / or treating thrombotic diseases. Background technique [0002] According to the "China Cardiovascular Disease Report 2017" recently released by the National Center for Cardiovascular Diseases, there are about 290 million patients with cardiovascular and cerebrovascular diseases (including coronary heart disease, stroke, heart failure, hypertension, etc.) growth trend. Among the total causes of death among urban and rural residents, cardiovascular and cerebrovascular diseases rank first, higher than tumors and other diseases. It is worth noting that the incidence of thrombotic diseases caused by vascular embolism in cardiovascular and cerebrovascular diseases (such as cerebral thrombosis, cerebral infarction, myocardial infarction, heart failure, cardiogenic shock,...

Claims

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Application Information

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IPC IPC(8): C07D213/30A61K31/4418A61P7/02A61P9/10A61P9/12A61P9/04A61P13/12A61P9/00
CPCA61P7/02A61P9/00A61P9/04A61P9/10A61P9/12A61P13/12C07D213/30
Inventor 董旭于康娄红祥孙斌
Owner SHANDONG UNIV
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