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Triazolium salts as PAR1 inhibitors, production thereof, and use as medicaments

A R21, C-R1 technology, applied in the direction of drug combination, antipyretics, anti-inflammatory agents, etc.

Inactive Publication Date: 2013-08-28
SANOFI AVENTIS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This dual activity of thrombin against coagulation factor VIII results in a self-limiting protease complex formation and thus localized blood coagulation

Method used

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  • Triazolium salts as PAR1 inhibitors, production thereof, and use as medicaments
  • Triazolium salts as PAR1 inhibitors, production thereof, and use as medicaments
  • Triazolium salts as PAR1 inhibitors, production thereof, and use as medicaments

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1001]1-{2-[3-Acetylamino-5-(pentafluorothio)phenyl]-2-oxoethyl}-3-amino-6-ethoxy-[1,2,4]tri Azolo[4,3-b]pyridazine-1- Trifluoroacetate

[1002]

[1003] a) 3-nitro-5-pentafluorothiobenzoic acid

[1004]

[1005] 3-Pentafluorothiobenzoic acid (5.0 g) was dissolved in fuming nitric acid (20 ml) and stirred at room temperature with the removal of moisture. Concentrated sulfuric acid (3ml) was then added, and the mixture was stirred at 75°C. After stirring at 75°C for 5 hours, sulfuric acid (1.5 ml) was added, and after stirring at 75°C for 2 hours, the mixture was allowed to stand overnight. The mixture was then added to ice-water and stirred for 2 hours. The precipitate formed was filtered off with suction and dried under high vacuum. 4.2 g of 3-pentafluorothio-5-nitrobenzoic acid are obtained. The mother liquor is extracted 3 times with dichloromethane, the combined dichloromethane phases are dried over magnesium sulfate and the solvent is concentrated, thus obtai...

Embodiment 4

[1034] 3-Amino-1-[2-(3-tert-butyl-4-methoxy-5-(morpholin-4-yl)phenyl)-2-oxoethyl]-6-trifluoromethyl -[1,2,4]triazolo[4,3-a]pyridine-1- Trifluoroacetate

[1035]

[1036] Dissolve 6-trifluoromethyl-[1,2,4]triazolo[4,3-a]pyridin-3-ylamine hydrobromide (W1.301; 309mg) in a small amount of water, The potassium solution was basified and extracted 3 times with EA. The combined EA phases were dried over magnesium sulfate, filtered and concentrated. This gave 212 mg of the free base, which was dissolved in DMF (5 ml) at room temperature with stirring. 2-Bromo-1-(3-tert-butyl-4-methoxy-5-(morpholin-4-yl)phenyl)ethanone (01.003; 427 mg in 1 ml DMF was slowly added over 15 minutes solution). The mixture was stirred at room temperature for 7 hours, then allowed to stand overnight. It was then stirred at 40°C for 2 hours and at 60°C for 3 hours. The solvent was then removed and the residue was purified by preparative HPLC. Fractions containing the desired product were combined,...

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Abstract

The invention relates to novel compounds of formula I where X, A−, Q1, Q2, Q3, R2, R3, R4, R5, R6, R7, R8 and R9 are each as defined below. The compounds of formula I have antithrombotic activity and inhibit especially protease-activated receptor 1 (PAR1). The invention further relates to a process for preparing the compound of formula I and to the use thereof as a medicament.

Description

technical field [0001] The present invention relates to novel compounds of formula I: [0002] [0003] where X, A - , Q1, Q2, Q3, R2, R3, R4, R5, R6, R7, R8 and R9 are each defined below. The compound of formula I has antithrombotic activity and in particular inhibits protease-activated receptor 1 (PAR1). The invention also relates to processes for the preparation of compounds of formula I and their use as medicaments. Background technique [0004] Protease-activated receptor 1 (PAR1 ) is a thrombin receptor belonging to the class of G protein-coupled receptors (GPCRs). The gene for PAR1 is located on chromosome 5q13, consists of two exons and covers a region of about 27 kb. [0005] PAR1 is especially expressed in endothelial cells, smooth muscle cells, fibroblasts, neurons and human platelets. In the case of platelets, PAR1 is an important receptor for signaling and is involved in the initiation of platelet aggregation. [0006] Activation of PAR occurs by proteo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/5025A61P7/02
CPCC07D471/04C07D487/04A61P11/00A61P17/00A61P17/02A61P19/02A61P25/00A61P27/02A61P29/00A61P3/00A61P3/14A61P31/00A61P35/00A61P35/04A61P37/00A61P37/08A61P7/00A61P7/02A61P7/04A61P9/00A61P9/06A61P9/10A61P3/10
Inventor 尤维·海内尔特沃尔克马·韦纳马赛厄斯·赫尔曼卡尔·舍纳芬格亨宁·斯坦哈根
Owner SANOFI AVENTIS SA