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PAR (Protease Activated Receptor)-1 antagonist as well as preparation method and application of PAR-1 antagonist

One aspect, the technology of oral preparations, applied in the field of pharmaceutical compositions containing it, can solve problems such as high bleeding risk

Inactive Publication Date: 2014-10-08
王佳
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of these drugs is the greater risk of bleeding

Method used

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  • PAR (Protease Activated Receptor)-1 antagonist as well as preparation method and application of PAR-1 antagonist
  • PAR (Protease Activated Receptor)-1 antagonist as well as preparation method and application of PAR-1 antagonist
  • PAR (Protease Activated Receptor)-1 antagonist as well as preparation method and application of PAR-1 antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] Reaction raw materials: self-made, conventional method.

[0027] 1.46 g (10 mmol) compound II , 3.70 g (10 mmol) compound III and 4.15 g (30 mmol) of solid potassium carbonate were stirred overnight in 20 mL of acetonitrile, and then heated to reflux for 3 hours.

[0028] The reaction mixture was cooled slightly and poured into 200 mL ice water, stirred, adjusted to pH = 4 with concentrated hydrochloric acid, extracted with 50 mL × 3 dichloromethane, combined organic phases, washed with brine, dried over anhydrous sodium sulfate, and dried on a rotary evaporator The solvent was evaporated, and the obtained residue was purified by column chromatography to obtain pure I , white solid, MS, m / z = 458 ([M+Na] + ).

Embodiment 2

[0029] Example 2 In vitro platelet aggregation inhibition test

[0030] Pharmacological tests of substances were performed in TRAP (thrombin receptor activating peptide)-induced platelet aggregation in 96-well plates. 3.13% sodium citrate solution was pre-added in the syringe, and then 20 mL of blood from healthy volunteers was drawn in, at 1500 g Platelet-rich plasma (PRP) was separated by centrifugation for 20 minutes and treated with 1 μL PGE1 solution (500 μg / mL in ethanol) / mL PRP. After incubation at room temperature for 5 minutes, they were centrifuged at 1200 g for 20 minutes to remove leukocytes. Transfer the leukocyte-free PRP to 15 mL PP tubes in batches at 5 mL / portion, and centrifuge at 3600 g to pellet the platelets. Then, decant the upper plasma layer and resuspend the platelet pellet from 5 mL of PRP in 1 mL of Tyrode (120 mM NaCl, 2.6 mM KCl, 12 mM NaHCO3, 0.39 mM NaH2PO4, 10 mM HEPES, 0.35% BSA, 5.5 mM Glucose, pH = 7.4) and adjusted to a platelet count o...

Embodiment 3

[0034] Dosage / tablet

[0035] Compound I 5mg

[0036] Microcrystalline Cellulose 80 mg

[0037] Pregelatinized starch 70 mg

[0038] Polyvinylpyrrolidone 6 mg

[0039] Carboxymethyl starch sodium salt 5 mg

[0040] Magnesium stearate 2 mg

[0041]Talc 2 mg.

[0042] Sieve the active ingredient, pregelatinized starch and microcrystalline cellulose, mix well, add polyvinylpyrrolidone solution, mix, make soft material, sieve, make wet granules, dry at 50-60°C, carboxymethyl Sodium starch salt, magnesium stearate and talc powder are pre-screened and then added to the above granules for tableting.

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Abstract

The invention relates to the field of thrombotic disease related drugs and particularly relates to a PAR (Protease Activated Receptor)-1 antagonist with a brand new structure as the specification, a preparation method of the PAR-1 antagonist, a pharmaceutical composition containing the PAR-1 antagonist and an application of the PAR-1 antagonist to preparation of drugs for treating thrombotic diseases.

Description

technical field [0001] The invention relates to the field of drugs related to thrombosis diseases. Specifically, the present invention relates to a PAR-1 antagonist with a new structure and a preparation method thereof, as well as a pharmaceutical composition containing it, which has a therapeutic effect on thrombotic diseases. Background technique [0002] Protease Activated Acceptor-1 (PAR-1) is a new target of anti-platelet antithrombotic drugs discovered recently. Protease-activated receptor 1 is also called thrombin receptor. After thrombin is activated by the coagulation chain, it acts on platelets through PAR-1 receptors to activate platelets, causing platelet aggregation and causing thrombus and coagulation. The thrombus induced by PAR-1 is rich in platelet components, which is the main cause of arterial thrombus. PAR-1 antagonists can block thrombin from activating platelets, thereby blocking arterial thrombus formation, and can be used to treat acute coronary syn...

Claims

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Application Information

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IPC IPC(8): C07D257/04A61K31/5377A61P7/02
CPCC07D257/04
Inventor 张远强
Owner 王佳
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