[1,2,3] triazolyl substituted quinolines and coumarins as inhibitors of leukotriene biosynthesis

A compound, selected technology, applied in the direction of drug combination, medical preparation containing active ingredient, anti-inflammatory agent, etc.

Inactive Publication Date: 2010-02-24
MERCK CANADA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Despite significant therapeutic advances in the treatment and prevention of conditions affected by 5-LO inhibition, other treatment options are still needed

Method used

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  • [1,2,3] triazolyl substituted quinolines and coumarins as inhibitors of leukotriene biosynthesis
  • [1,2,3] triazolyl substituted quinolines and coumarins as inhibitors of leukotriene biosynthesis
  • [1,2,3] triazolyl substituted quinolines and coumarins as inhibitors of leukotriene biosynthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0172] (S)-4-(3-fluorophenyl)-7-({4-[1-hydroxyl-1-(trifluoromethyl)propyl]-1H-1,2,3-triazole-1- Base} A Base) -2H-benzopyran-2-one

[0173]

[0174] Step 1: 3-(Trifluoromethyl)-1-(trimethylsilyl)pent-1-yn-3-ol

[0175]

[0176] To a solution of trimethylsilylacetylene (6.0 g, 61.1 mmol) in THF (80 mL) cooled at -78 °C was added dropwise 1.6 M n-butyllithium in hexane (38 mL, 61.1 mmol). The solution was then stirred for 1 hour before a solution of trifluoromethyl ethyl ketone (10 g, 79.4 mmol) in THF (25 ml) was added slowly. The reaction was stirred at -78°C for 4 hours. The reaction was then poured into saturated ammonium chloride solution and the aqueous layer was extracted (4x) with diethyl ether. The combined organic layers were washed with brine, washed with MgSO 4 Dry, filter and concentrate under reduced pressure. The obtained crude residue was used directly in the next step. 1 H NMR (400MHz, acetone-d 6 ): 5.83 (s, 1H), 1.80 (q, 2H), 1.14 (t, 3H), 0....

Embodiment 1A

[0203] Preparation of (S)-4-(3-fluorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazole-1 -base} A Alternatives to -2H-benzopyran-2-one

[0204] step 1 A 100 mL flask equipped with a mechanical stirrer, thermocouple, nitrogen inlet and cooling bath was charged with trimethylsilylacetylene (3.5 g, 1.50 eq) and MTBE (12.0 mL). The mixture was cooled to -67°C and 2.26M n-BuLi (11.2 mL, 1.05 eq) was added to the solution over 1 h keeping the reaction mixture below -50°C. The reaction mixture was aged for 45 minutes, then 1,1,1-trifluoro-2-butanone (3.3 mL, 1.00 eq) was added over a period of 1 hour (internal temperature maintained below -50°C). The mixture was aged for 20 minutes, then p-nitrobenzoyl chloride (4.7 g, 1.05 eq) in THF (7.0 mL) was added over 1 hour, keeping the reaction mixture below -30 °C. The reaction mixture was allowed to warm to 5°C over 3 hours.

[0205] The reaction was quenched by carefully adding water (9.0 mL). Solka Floc (0.2...

Embodiment 2

[0224] (S)-4-(4-fluorophenyl)-7-[4-(1-hydroxy-1-trifluoromethyl-propyl)-[1,2,3]triazol-1-ylmethyl ]-Benzo Pyran-2-one

[0225]

[0226] 1 H NMR (400MHz, acetone-d 6 ): 8.21(s, 1H), 7.7-7.6(m, 1H), 7.53(d, 1H), 7.42-7.35(m, 3H), 7.31(d, 1H), 6.4(s, 1H), 5.85( s, 2H), 5.47 (s, 1H), 2.41-2.3 (m, 1H), 2.15-2.05 (m, 1H), 0.86 (t, 3H).

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Abstract

The instant invention provides compounds of Formula (I) which are leukotriene biosynthesis inhibitors. Compounds of Formula (I) are useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.

Description

field of invention [0001] The present invention relates to novel compounds useful as inhibitors of leukotriene biosynthesis. Background of the invention [0002] Inhibition of leukotriene biosynthesis has been an active area of ​​pharmaceutical research for many years. Leukotrienes constitute a group of locally acting hormones produced from arachidonic acid in living systems. Leukotrienes are potent contraction and inflammation regulators derived from the oxidation of arachidonic acid catalyzed by 5-lipoxygenase. One class of leukotriene biosynthesis inhibitors are those known to act by inhibiting 5-lipoxygenase (5-LO). [0003] The main leukotriene is leukotriene B4 (abbreviated as LTB 4 ), LTC 4 、LTD 4 and LTE 4 . The biosynthesis of these leukotrienes results from the action of the enzyme 5-lipoxygenase on arachidonic acid called leukotriene A 4 (LTA 4 ), which are converted to other leukotrienes by subsequent enzymatic steps. The biosynthesis and metabolism of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06A61K31/4192A61K31/422A61K31/427A61K31/4709A61K31/496A61K31/5377A61P11/06A61P29/00A61P37/08A61P9/10C07D401/06C07D401/14C07D405/14C07D409/14C07D413/14C07D417/14
CPCC07D401/14C07D405/06C07D417/14C07D413/14C07D405/14C07D401/06C07D409/14A61P9/10A61P11/00A61P11/02A61P11/06A61P29/00A61P37/08A61P43/00
Inventor Y·迪沙姆R·弗雷内特R·弗里森M·加农Y·加罗E·L·格林H·朱托S·拉利伯特B·麦凯
Owner MERCK CANADA
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