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A class of oxadiazole sulfoxide compounds containing cyanobenzene, its preparation method and use

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

Active Publication Date: 2016-03-09
珠海横琴长满欧国际贸易有限公司
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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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  • A class of oxadiazole sulfoxide compounds containing cyanobenzene, its preparation method and use
  • A class of oxadiazole sulfoxide compounds containing cyanobenzene, its preparation method and use
  • A class of oxadiazole sulfoxide compounds containing cyanobenzene, its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024]

[0025] A. Synthesis of IV-1

[0026] 2.03 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=515 ([M+Na] + ).

[0027] B. Synthesis of I-1

[0028] 2.46g (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

[0030] According to the method of Example 1, the following compounds with general formula I were synthesized.

[0031]

[0032] 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

[0033] Example 5 In vitro platelet aggregation inhibition test

[0034] Pharmacological tests of substances were performed in TRAP (thrombin receptor activating peptide)-induced platelet aggregation in 96-well plates. Add 3.13% sodium citrate solution to the syringe in advance, then draw 20mL of blood from healthy volunteers, centrifuge at 1500g for 20 minutes, separate the platelet-rich plasma (PRP) and wash it with 1μL PGE1 solution (500μg / mL ethanol solution) / mLPRP 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 layer of plasma, 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 adjust to Platelet count of 3×105 / μL....

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PUM

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Abstract

The invention relates to the field of drugs associated with thrombotic diseases, in particular to a category of PAR-1 antagonists of an oxadiazole sulfoxide structure comprising nitrile substituted benzene, a preparation method of the PAR-1 antagonists, and application of drug combinations comprising the nitrile substituted benzene and the nitrile substituted benzene in preparation of the drugs for treating the thrombotic diseases. Please see the formula in the specification, wherein R is selected from -CN.

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 nitrile-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, ther...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D271/113A61K31/5377A61P7/02A61P9/10
CPCC07D271/113
Inventor 蔡子洋
Owner 珠海横琴长满欧国际贸易有限公司
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