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Halogenated pyridyl containing trans-cyclohexane amide compound and application thereof

A technology of compounds and substituents, applied in the field of PAR-1 antagonists with a trans-cyclohexane amide structure and its preparation, can solve the problems of high bleeding risk and other problems

Inactive Publication Date: 2015-02-18
ZHEJIANG PHARMA COLLEGE
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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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  • Halogenated pyridyl containing trans-cyclohexane amide compound and application thereof
  • Halogenated pyridyl containing trans-cyclohexane amide compound and application thereof
  • Halogenated pyridyl containing trans-cyclohexane amide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Preparation of Compound I-1

[0026]

[0027] Raw materials: commercially available or homemade.

[0028] In a 100mL round bottom flask, add 1.84g (10mmol) compound II, 1.98g (10mmol) compound III-1 and 20mL dry THF, the resulting mixture was stirred under ice-water bath cooling, after adding 2.48g (12mmol) DCC, Stirring was continued overnight at room temperature. TLC showed the reaction was complete.

[0029] The reaction mixture was poured into ice water, stirred, extracted with 50mL×3 dichloromethane, combined and extracted organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated on a rotary evaporator, and the obtained residue column Chromatographic purification afforded product I-1 as a white solid, ESI-MS, m / z=365 ([M+H] + ).

Embodiment 2-8

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

[0032]

[0033]

Embodiment 9

[0034] Example 9 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 NaHCO 3 , 0.39mM NaH 2 PO 4 , 10 mM HEPES, 0.35% BSA, 5.5 mM glucose, pH=7.4), and adj...

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Abstract

The invention relates to the field of thrombotic disease related medicines. Specifically, the invention relates to a trans-cyclohexane amide structured PAR-1 antagonist containing structures, such as halogenated pyridyl and the like, a preparation method of the antagonist and application of the antagonist in preparation of medicines for treating thrombotic diseases, wherein R is selected from C1-C3 alkyl and F, Cl, Br and I substituent.

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 a trans-cyclohexyl amide structure containing halogenated pyridyl and other structures that have a therapeutic effect on thrombotic diseases and their preparation methods, pharmaceutical compositions containing them and Use in medicine. 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, t...

Claims

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Application Information

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IPC IPC(8): C07D213/74A61P7/02
CPCC07D213/74
Inventor 郭章华
Owner ZHEJIANG PHARMA COLLEGE
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