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Para-position substituted tetrazole acetophenone compound, preparation method and application

A technology of compounds and general formulas, which can be used in medical preparations containing active ingredients, organic chemistry, drug combinations, etc., and can solve problems such as high bleeding risk.

Active Publication Date: 2014-10-01
SUZHOU XINENG ENVIRONMENTAL SCI & TECH CO LTD
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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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  • Para-position substituted tetrazole acetophenone compound, preparation method and application
  • Para-position substituted tetrazole acetophenone compound, preparation method and application
  • Para-position substituted tetrazole acetophenone compound, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] .

[0034] Reaction raw materials: self-made, conventional method.

[0035] 1.76 g (10 mmol) compound II-1 , 3.70 g (10 mmol) compound III-1 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.

[0036] 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-1 , white solid, MS, m / z = 488 ([M+Na] + ).

Embodiment 2-5

[0038] According to the method of Example 1, synthesized with general formula I of the following compounds:

[0039] .

Embodiment 6

[0040] Example 6 In vitro platelet aggregation inhibition test

[0041] Pharmacological testing of substances 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 of 3 × 105 / μL ...

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PUM

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Abstract

The invention relates to the field of medicines related to thrombotic diseases, particularly to a para-position substituted PAR-1 (Protease Activated Acceptor-1) agonist containing a tetrazole acetophenone structure, a preparation method, a medicine composition containing the PAR-1 agonist, and application for preparing medicines for treating the thrombotic diseases. The definition of an R group is shown in the description.

Description

technical field [0001] The invention relates to the field of drugs related to thrombosis diseases. Specifically, the present invention relates to a class of PAR-1 antagonists containing a tetrazole acetophenone structure, a preparation method thereof, and a pharmaceutical composition containing them, which have 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...

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 SUZHOU XINENG ENVIRONMENTAL SCI & TECH CO LTD
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