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One category of oxadiazole sulfoxide compounds comprising alcoxyl p-substituted benzene, and preparation method and application thereof

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

Active Publication Date: 2015-04-22
肇庆市科至自动化设备有限公司
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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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  • One category of oxadiazole sulfoxide compounds comprising alcoxyl p-substituted benzene, and preparation method and application thereof
  • One category of oxadiazole sulfoxide compounds comprising alcoxyl p-substituted benzene, and preparation method and application thereof
  • One category of oxadiazole sulfoxide compounds comprising alcoxyl p-substituted benzene, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] A. Synthesis of IV-1

[0027] 2.08 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=520 ([M+Na] + ).

[0028] B. Synthesis of I-1

[0029] 2.49g (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 2-5

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

[0032]

[0033] Among them, Example 5 is a comparative compound (still a brand new structure discovered by the applicant), to fully illustrate the pharmacological effect.

Embodiment 6

[0034] Example 6 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 drugs associated with thrombotic diseases, in particular to a category of PAR-1 antagonists of an oxadiazole sulfoxide structure comprising alkoxy p-substituted benzene, a preparation method of the PAR-1 antagonists, and application of drug combinations comprising the alkoxy p-substituted benzene and the alkoxy p-substituted benzene in preparation of the drugs for treating the thrombotic diseases. Please see the formula in the specification, wherein R1 and R2 are defined according to the description 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 containing oxadiazole sulfoxide structures with structures such as alkoxy para-substituted phenyls and a preparation method thereof, which have a therapeutic effect on thrombotic diseases, and their preparation methods. pharmaceutical composition. 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 platel...

Claims

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Application Information

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IPC IPC(8): C07D271/113A61K31/5377A61P7/02A61P9/10
CPCC07D271/113
Inventor 蔡子洋
Owner 肇庆市科至自动化设备有限公司
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