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Trans-cyclohexane amide compound of 4-pyridyl and use thereof

A compound, the technology of dicyclohexylcarbodiimide, is applied in the field of drugs related to thrombosis diseases, and can solve the problems of high bleeding risk and the like

Inactive Publication Date: 2015-02-04
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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  • Trans-cyclohexane amide compound of 4-pyridyl and use thereof
  • Trans-cyclohexane amide compound of 4-pyridyl and use thereof
  • Trans-cyclohexane amide compound of 4-pyridyl and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] The preparation of embodiment 1 compound I of the present invention

[0019]

[0020] In a 100mL round-bottomed flask, add 1.84g (10mmol) compound II, 1.62g (10mmol) compound III and 20mL dry THF, the resulting mixture is stirred under ice-water bath cooling, after adding 2.48g (12mmol) DCC, continue to Stir overnight at room temperature. TLC showed the reaction was complete.

[0021] 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 Purified by chromatography to obtain product I, a yellow-white solid, ESI-MS, m / z=330 ([M+H] + ).

Embodiment 2

[0022] The preparation of embodiment 2 comparative compound 1-2

[0023] In order to further compare the drug efficacy of this compound, the present invention records the following formula comparative compound I-2 (new compound, not yet disclosed) and its preparation method and pharmacological data:

[0024]

[0025] Its preparation method is as follows:

[0026]

[0027] In a 100mL round bottom flask, add 1.84g (10mmol) compound II, 1.26g (10mmol) compound III-2 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.

[0028] 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 Purifi...

Embodiment 3

[0029] Example 3 In vitro Platelet Aggregation Inhibition Test

[0030] 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 drugs associated with thrombotic diseases and particularly relates to a PAR-1 antagonist comprising a trans-cyclohexane amide structure of 4-pyridyl show in a formula (1) and application thereof in preparation of medicines for treating thrombotic diseases. The formula (1) is as shown 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 PAR-1 antagonist containing a 4-pyridyl trans-cyclohexaneamide structure that has a therapeutic effect on thrombotic diseases, and its application in the preparation of drugs for treating thrombotic diseases. 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 blocking arterial thrombus formation, and can be used ...

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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