Compounds with terminally-substituted phenyl triazole Schiff base structures and applications of compounds

A technology of compounds and substituents, applied in medical preparations containing active ingredients, organic chemistry, drug combinations, etc., can solve problems such as high bleeding risk

Active Publication Date: 2014-10-08
蚌埠格识知识产权运营有限公司
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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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  • Compounds with terminally-substituted phenyl triazole Schiff base structures and applications of compounds
  • Compounds with terminally-substituted phenyl triazole Schiff base structures and applications of compounds
  • Compounds with terminally-substituted phenyl triazole Schiff base structures and applications of compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035]

[0036] Reaction raw materials: self-made, conventional method.

[0037] 1.20 g (10 mmol) compound II-1 and 2.26g (10 mmol) of compound III-1 Dissolve in 20 mL of glacial acetic acid and heat to reflux overnight. After the reaction mixture was slightly cooled, it was poured into 200 mL of ice water, stirred, and the solid was collected by suction filtration, recrystallized from absolute ethanol, and vacuum-dried at room temperature to obtain the product IV-1 , white crystals. MS, m / z = 329 ([M+H] + ).

[0038] 1.65 g (5 mmol) compound IV-1 , 1.85 g (5 mmol) compound V and 2.07 g (15 mmol) of solid potassium carbonate were stirred overnight in 15 mL of acetonitrile, and then heated to reflux for 3 hours. 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 anhyd...

Embodiment 2-12

[0040] Referring to the method of Example 1, it is possible to synthesize I of the following compounds:

[0041]

[0042]

Embodiment 13

[0043] Example 13 In vitro platelet aggregation inhibition test

[0044] 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 gPlatelet-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 Tyrode adjusted to a platelet...

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PUM

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Abstract

The invention relates to the field of thrombotic disease related drugs, belongs to triazole Schiff base compounds with brand new structures and derivatives of the triazole Schiff base compounds and particularly relates to PAR (Protease Activated Receptor)-1 antagonists with terminally-substituted phenyl triazole Schiff base structures, preparation methods of the PAR-1 antagonists, pharmaceutical compositions containing the PAR-1 antagonists and applications of the PAR-1 antagonists to preparation of drugs for treating thrombotic diseases. The substituent groups R1 and R2 are defined as the specification.

Description

technical field [0001] The invention relates to the field of drugs related to thrombosis diseases. The present invention belongs to a class of triazole Schiff base compounds and their derivatives with a new skeleton, in particular, relates to a class of terminally substituted phenyl triazole Schiff base structure PAR-1 that has a therapeutic effect on thrombotic diseases Antagonists, methods for their preparation, and pharmaceutical compositions containing them. 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 antagonis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/12A61K31/5377A61P7/02
CPCC07D249/12
Inventor 张远强
Owner 蚌埠格识知识产权运营有限公司
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