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Trans-cyclohexane amide compound and preparation method and medicinal application thereof

A compound, cyclohexane-based technology, applied in the field of drugs related to thrombosis diseases, which 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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  • Trans-cyclohexane amide compound and preparation method and medicinal application thereof
  • Trans-cyclohexane amide compound and preparation method and medicinal application thereof
  • Trans-cyclohexane amide compound and preparation method and medicinal application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Preparation of Compound I-1

[0024]

[0025] In a 100 mL round bottom flask, 1.84 g (10 mmol) of compound II, 1.68 g (10 mmol) of compound III-1 and 20 mL of dry THF were added. The resulting mixture was stirred under cooling in an ice-water bath. After adding 2.48 g (12 mmol) of DCC, Continue to stir overnight at room temperature. TLC showed that the reaction was complete.

[0026] The reaction mixture was poured into ice water, stirred, and extracted with 50 mL×3 dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated on a rotary evaporator to obtain a residue column. Purified by chromatography to obtain product I-1 as a white solid. ESI-MS, m / z=335([M+H] + ).

Embodiment 2

[0027] Example 2 Preparation of Compound I-2

[0028]

[0029] In a 100 mL round bottom flask, 1.84 g (10 mmol) of compound II, 1.26 g (10 mmol) of compound III-2 and 20 mL of dry THF were added. The resulting mixture was stirred under cooling in an ice-water bath. After adding 2.48 g (12 mmol) of DCC, Continue to stir overnight at room temperature. TLC showed that the reaction was complete.

[0030] The reaction mixture was poured into ice water, stirred, and extracted with 50 mL×3 dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated on a rotary evaporator to obtain a residue column. Purified by chromatography to obtain product I-2 as a white solid. ESI-MS, m / z=293([M+H] + ).

Embodiment 3

[0031] Example 3 In vitro platelet aggregation inhibition test

[0032] In a 96-well plate, the pharmacological test of the substance is performed in platelet aggregation induced by TRAP (thrombin receptor activating peptide). 3.13% sodium citrate solution was added to the syringe in advance, and then 20mL of healthy volunteers’ blood was drawn, centrifuged at 1500g for 20 minutes, the platelet-rich plasma (PRP) was separated and used 1μLPGE1 solution (500μg / mL ethanol Solution) / mL PRP. After incubating for 5 minutes at room temperature, it was centrifuged at 1200 g for 20 minutes to remove leukocytes. The white blood cell-free PRP was transferred to 15 mL PP tubes in batches of 5 mL / portion, and centrifuged at 3600 g to precipitate platelets. Then, the upper plasma was decanted, and the platelet pellet obtained from 5mL PRP was resuspended in 1mL Tyrode (120mM NaCl, 2.6mM KCl, 12mM NaHCO 3 , 0.39mM NaH 2 PO 4 , 10mMHEPES, 0.35% BSA, 5.5mM glucose, pH=7.4), and use Tyrode to ad...

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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 structure containing 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 C3-C8 cycloalkyl.

Description

Technical field [0001] The invention relates to the field of medicines related to thrombotic diseases. Specifically, the present invention relates to a class of PAR-1 antagonists containing a trans-cyclohexaneamide structure, which have a therapeutic effect on thrombotic diseases, and a preparation method thereof, pharmaceutical compositions containing them, and medical uses. Background technique [0002] Protease Activated Acceptor-1 (PAR-1) is a new target of antiplatelet antithrombotic drugs discovered recently. Protease activated receptor 1 is also called thrombin receptor. Thrombin is activated by the coagulation chain and acts on platelets through PAR-1 receptor to activate platelets, causing platelet aggregation to cause thrombus and coagulation. Thrombus caused by PAR-1 is rich in platelet components, which is the main cause of arterial thrombosis. PAR-1 antagonists can block thrombin from activating platelets, thereby blocking arterial thrombosis, and can be used to tr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/185A61P7/02
CPCC07D295/185
Inventor 郭章华
Owner ZHEJIANG PHARMA COLLEGE
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