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Oxadiazole sulfoxide compound containing amino substituted benzene and preparation method and purposes thereof

A compound and alkyl technology, applied in the field of drugs related to thrombosis diseases, can solve problems such as high bleeding risk

Inactive Publication Date: 2015-04-08
FOSHAN SAIWEISI MEDICINE SCI & TECH
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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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  • Oxadiazole sulfoxide compound containing amino substituted benzene and preparation method and purposes thereof
  • Oxadiazole sulfoxide compound containing amino substituted benzene and preparation method and purposes thereof
  • Oxadiazole sulfoxide compound containing amino substituted benzene and preparation method and purposes thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] A. Synthesis of IV-1

[0027] 2.21 g (10 mmol) of compound II-1, 3.70 g (10 mmol) of compound III and 4.15 g (30 mmol) of solid potassium carbonate were stirred overnight in 20 mL of ethanol. The reaction mixture was poured into 200 mL of 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 evaporated the solvent on a rotary evaporator. The obtained residue was purified by column chromatography to obtain pure product IV-1, white solid, MS, m / z=533 ([M+Na] + ).

[0028] B. Synthesis of I-1

[0029] 2.55g (5mmol) of compound IV-1 was dissolved in 25mL of dichloromethane, stirred at -10°C, and 3.13g (20mmol) of m-chloroperoxybenzoic acid (mCPBA) was slowly added. After the reaction mixture was stirred at this temperature for 1 hour, stirring was continued overnight at room temperature. The reaction mixture was pou...

Embodiment 2-3

[0031] According to the method of Example 1, the following compounds with general formula I were synthesized.

[0032]

[0033] Among them, Example 4 is a comparative compound (still a brand new structure discovered by the applicant), to fully illustrate the pharmacological effect.

Embodiment 5

[0034] Example 5 In vitro platelet aggregation inhibition test

[0035] 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 added to the syringe in advance, and then 20 mL of blood from healthy volunteers was drawn in, centrifuged at 1500 g for 20 minutes, platelet-rich plasma (PRP) was separated and mixed with 1 μL of PGE1 solution (500 μg / mL ethanol solution) / mL PRP for treatment. 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 ...

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PUM

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Abstract

The invention relates to the field of medicines related with thrombotic diseases, in particular to PAR-1 antagonists which contain the amino substituted benzene and are of an oxadiazole sulfoxide structure, a preparation method thereof, medicine combinations containing the PAR-1 antagonists and applications of the PAR-1 antagonists in preparing medicines for treating thrombotic diseases. The formula is as follows, wherein the definition of R is as described in the specification.

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 with oxadiazole sulfoxide structures containing amine-substituted benzene and other structures that have a therapeutic effect on thrombotic diseases, and their preparation methods, as well as 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 antagonists can block thrombin from activating platelets, there...

Claims

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Application Information

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IPC IPC(8): C07D271/113A61P7/02
CPCC07D271/113
Inventor 蔡子洋
Owner FOSHAN SAIWEISI MEDICINE SCI & TECH
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