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Alkoxy phenyl substituted trans-cyclohexane amide compound and application 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: 2015-02-18
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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  • Alkoxy phenyl substituted trans-cyclohexane amide compound and application thereof
  • Alkoxy phenyl substituted trans-cyclohexane amide compound and application thereof
  • Alkoxy phenyl substituted trans-cyclohexane amide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The preparation of embodiment 1 compound I-1

[0026]

[0027] Raw materials: commercially available or homemade.

[0028] In a 100mL round bottom flask, add 1.84g (10mmol) compound II and 10mL redistilled SOCl 2 , and then heated to reflux for 3 hours with stirring.

[0029] The reaction mixture was evaporated under reduced pressure to remove excess SOCl 2 , the residue II-C was dissolved in 20 mL of dry dichloromethane, the resulting mixture was stirred under cooling in an ice-water bath, and slowly added dropwise from 1.92 g (10 mmol) III-1 and 3.04 g (30 mmol) of triethylamine dissolved in 5 mL of dry solution in dichloromethane and continued to stir overnight at room temperature. TLC showed the reaction was complete.

[0030] 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 ...

Embodiment 2-12

[0032] Referring to the method of Examples 1 and 2, the following compounds with general formula I were synthesized.

[0033]

Embodiment 7

[0034] Example 7 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 pre-added in the syringe, and then 20 mL of blood from healthy volunteers was drawn in, centrifuged at 1500 g for 20 minutes, and the platelet-rich plasma (PRP) was separated and mixed with 1 μL PGEl 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 adjus...

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PUM

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Abstract

The invention relates to the field of thrombotic disease related medicines. Specifically, the invention relates to a terminal alkoxy phenyl substituted trans-cyclohexane amide structured PAR-1 antagonist, a preparation method thereof and application of the antagonist in preparation of medicines for treating thrombotic diseases, wherein R is selected from C1-C3 alkyl and C3-C5 cycloalkyl.

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 substituted with terminal alkoxyphenyl groups 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, thereby...

Claims

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Application Information

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IPC IPC(8): C07D295/185A61P7/02
CPCC07D295/185
Inventor 郭章华
Owner ZHEJIANG PHARMA COLLEGE
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