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PAR-1 (protease-activated receptor-1) antagonists for treating thrombotic diseases, as well as preparation and application thereof

A technology of reagents and alkaline conditions, applied in the field of PAR-1 antagonists containing an exocyclic imine structure and the preparation thereof, can solve the problems of high bleeding risk and the like, and achieve the effect of small bleeding risk

Active Publication Date: 2012-05-09
TIANJIN INSTITUTE OF PHARMA RESEARCH
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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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  • PAR-1 (protease-activated receptor-1) antagonists for treating thrombotic diseases, as well as preparation and application thereof
  • PAR-1 (protease-activated receptor-1) antagonists for treating thrombotic diseases, as well as preparation and application thereof
  • PAR-1 (protease-activated receptor-1) antagonists for treating thrombotic diseases, as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 1-[3-tert-Butyl-4-methoxy-5-(morpholin-4-yl)phenyl]-2-(5,6-diethoxy-2,3-dihydro-4- Preparation of fluoro-3-iminobenzo[d]isoxazol-2-yl)ethanone hydrobromide

[0050]

[0051] A. Preparation of 5,6-diethoxy-2,3-dihydro-4-fluoro-3-iminobenzo[d]isoxazole

[0052]

[0053] Add 2.25g (10mmol) of 2-fluoro-3,4-diethoxy-6-hydroxybenzonitrile and 20mL of anhydrous methanol to a 100mL round bottom flask, and the resulting mixture was stirred at room temperature to obtain a colorless and clear Solution. Add 1.20 g (30 mmol) of solid NaOH to the solution, continue to stir for 5 minutes, and then add 1.13 g (10 mmol) of hydroxylamine-O-sulfonic acid and a small amount of catalyst. The resulting mixture was stirred at room temperature for half an hour and then heated to reflux overnight. TLC showed that the reaction was complete. The reaction mixture was cooled and poured into 200 mL of ice water. The resulting mixture was extracted with 50 mL×3 of dichloromethane. The orga...

Embodiment 2

[0058] Example 2 1-[3-tert-Butyl-4-methoxy-5-(morpholin-4-yl)phenyl]-2-(5,6-diethoxy-2,3-dihydro-3- Preparation of iminobenzo[d]isoxazol-2-yl)ethanone hydrobromide

[0059]

[0060] A. Preparation of 5,6-diethoxy-2,3-dihydro-3-iminobenzo[d]isoxazole

[0061]

[0062] A 100 mL round bottom flask was charged with 2.22 g (10 mmol) 4,5-diethoxy-2-hydroxybenzonitrile and 20 mL of anhydrous methanol, and the resulting mixture was stirred at room temperature to obtain a colorless clear solution. Add 1.20 g (30 mmol) of solid NaOH to the solution, continue to stir for 5 minutes, and then add 1.13 g (10 mmol) of hydroxylamine-O-sulfonic acid and a small amount of catalyst. The resulting mixture was stirred at room temperature for half an hour and then heated to reflux overnight. TLC showed that the reaction was complete. The reaction mixture was cooled and poured into 200 mL of ice water. The resulting mixture was extracted with 50 mL×3 of dichloromethane. The organic phases were comb...

Embodiment 3

[0067] Example 3 1-[3-tert-butyl-4-methoxy-5-(morpholin-4-yl)phenyl]-2-(5,6-diethoxy-1,3-dihydro-1, Preparation of 1-dimethyl-4-fluoro-3-imino-2H-isoindol-2-yl)ethanone hydrobromide

[0068]

[0069] A. Preparation of 3,4-diethoxy-2-fluoro-6-(1-hydroxy-1-methyl)ethyl benzonitrile

[0070]

[0071] Add 5.35g (20mmol) 2-cyano-4,5-diethoxy-3-fluorobenzoic acid methyl ester to a 100mL round bottom flask, dissolve it with 20mL dry THF, add a magnet to Seal with a rubber stopper after purging with nitrogen. The flask was placed in an ice water bath to cool, and electromagnetically stirred. Using a syringe, 13.3 mL (40 mmol) of MeMgCl solution (3.0M THF solution) was added dropwise to the flask. After the addition was completed, the reaction mixture was stirred at this temperature for half an hour. The reaction mixture was slowly poured into 200 mL of ice water, stirred, and extracted with 50 mL×3 of dichloromethane, and the extracted organic phases were combined, washed with satur...

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PUM

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Abstract

The invention relates to PAR-1 (protease-activated receptor-1) antagonists for treating thrombotic diseases, as well as a preparation and application thereof. The antagonists are compounds shown in formula (I) or pharmaceutically acceptable salts thereof, wherein R<1> is C1-C3 alkyl, R<2> is H, F or Cl, R<3> is C1-C3 alkyl, and X is O, S, C(CH3)2, CH2CH2, CH=CH or NCH3. The invention also provides a preparation method of the compounds, a medicinal composition containing the compounds, and application of the compounds. The compounds provided by the invention can prevent and / or treat thrombotic diseases.

Description

Technical field [0001] The present invention belongs to the technical field of medicine. Specifically, the present invention relates to a PAR-1 antagonist containing an exocyclic imine structure for treating thrombotic diseases, and a preparation method and application thereof. 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. After thrombin is activated by coagulation chain, it acts on platelets through PAR-1 receptor to activate platelets, causing platelet aggregation to cause thrombus and coagulation. Thrombosis 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 treat Acute Coronary Syndrome. There have been several PAR-1 inhibitors in clinical studies (Chack...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/20C07D209/44C07D231/56C07D217/22C07D275/04A61K31/5377A61P7/02
Inventor 赵桂龙徐为人苗华明邵华刘巍王玉丽谭初兵张士俊汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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