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Azetidine derivatives

A single ring, compound technology, applied in the field of azetidine derivatives, can solve the problem of increasing the concentration of prostamide

Active Publication Date: 2011-04-13
VERNALIS (R&D) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Concentrations of some prostamides may be increased in the presence of FAAH inhibitors

Method used

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  • Azetidine derivatives
  • Azetidine derivatives
  • Azetidine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1: 3-(Biphenyl-4-yloxy)-azetidine-1-carboxylic acid phenylamide

[0098]

[0099] step 1

[0100] 1-Benzhydryl-3-(biphenyl-4-yloxy)azetidine

[0101]

[0102] At room temperature, 4-phenylphenol (8.51 g, 50 mmol), 1-benzhydrylazetidin-3-ol (11.97 g, 50 mmol) and triphenylphosphine (13.11 g, 50 mmol) in acetonitrile (250 mL) was stirred for 20 minutes until all reactants were completely dissolved. Diisopropyl azodicarboxylate (9.84 mL, 10.11 g, 50 mmol) was added dropwise. A white precipitate formed and the initial reaction was mildly exothermic. The yellow color fades instantly. After 5 minutes, the reaction was heated to reflux temperature and stirred at this temperature for 3.25 hours when the precipitate dissolved. The mixture was cooled to room temperature and scraped with a spatula to induce crystallization. The mixture was cooled on ice and the solid was collected by filtration. The solid was further washed with cold acetonitrile and dried w...

Embodiment 2

[0109] Example 2: 3-(Biphenyl-4-yloxy)-azetidine-1-carboxylic acid (3-fluoro-phenyl)-amide

[0110]

[0111] The title compound was prepared as in Example 1, but using 3-fluorophenyl isocyanate instead of phenyl isocyanate. The obtained product is a white powder; LCMS retention time 2.61 minutes, m / z363.1[M+H] + ; 1 H nmr (400MHz; DMSO-d 6 )δ8.76 (s, 1H), 7.64-7.61 (m, 4H), 7.51-7.41 (m, 3H), 7.34-7.23 (m, 3H), 6.96 (d, 2H, J=8.4Hz), 6.77 -6.72 (m, 1H), 5.12-5.07 (m, 1H), 4.46 (dd, 2H, J = 9.2 and 6.4 Hz) and 3.94 (dd, 2H, J = 9.2 and 4.0 Hz).

Embodiment 3

[0112] Example 3: 3-(Biphenyl-4-yloxy)-azetidine-1-carboxylic acid (2-fluoro-phenyl)-amide

[0113]

[0114] The title compound was prepared following the procedure of Example 1, but using 2-fluorophenyl isocyanate instead of phenyl isocyanate. The product was purified by trituration with diethyl ether to afford the title compound as an off-white solid; LCMS retention time 2.60 min, m / z 363.1 [M+H] + ; 1 H nmr (400MHz; DMSO-d 6 )8.33(s, 1H), 7.64-7.58(m, 5H), 7.44(t, 2H, J=7.6Hz), 7.32(t, 1H, J=7.4Hz), 7.23-7.17(m, 1H), 7.14-7.08(m, 2H), 6.96(d, 2H, J=8.8Hz), 5.13-5.07(m, 1H), 4.45(dd, 2H, J=9.2 and 6.8Hz) and 3.94(dd, 2H, J = 9.2 and 3.6 Hz).

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PUM

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Abstract

Compounds of formula (I) are inhibitors of fatty acid amide hydrolase, (FAAH), and which are useful in the treatment of diseases or medical conditions which benefit from inhibition of FAAH activity, such as anxiety, depression pain, inflammation, and eating, sleep, neurodegenerative and movement disorders: Formula (I) Wherein Ar1 is optionally substituted phenyl or optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms; Ar2 is optionally substituted phenyl, optionally substituted monocyclic heteroaryl having 5 or 6 ring atoms or optionally substituted fused bicyclic heteroaryl having 5 or 6 ring atoms in each fused ring; and Ar3 is a divalent radical selected from the group consisting of optionally substituted phenylene and optionally substituted monocyclic heteroarylene radicals having 5 or 6 ring atoms.

Description

[0001] The present invention relates to a class of azetidine derivatives which are inhibitors of fatty acid amide hydrolase (FAAH) and can be used in the treatment of diseases or medicines which can be benefited by inhibiting the activity of FAAH Conditions such as treatment of anxiety, depression, pain, inflammation, as well as eating disorders, sleep disorders, neurodegenerative disorders and movement disorders. Background of the invention [0002] Endogenous agonists of the cannabinoid receptors CB1 and CB2 include the fatty acid amide anandamide (AEA). AEA is hydrolyzed to form arachidonic acid by membrane-bound protein fatty acid amide hydrolase (FAAH). FAAH was characterized in 1996 by Cravatt and co-workers (Cravatt, Nature 1996, 384, 83). The results demonstrate that FAAH additionally has an effect on the catabolism of a number of important lipid signaling fatty acid amides including: another major endocannabinoid, 2-arachidonoyl Glycerol (arachidonoylglycerol) (2-AG...

Claims

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Application Information

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IPC IPC(8): C07D205/04C07D401/12C07D401/14C07D413/14
CPCC07D401/14C07D401/12C07D413/14C07D205/04A61K31/4427A61K31/397A61K31/495A61K31/4439A61K31/497A61K31/501A61K31/506A61P1/00A61P1/08A61P11/00A61P13/02A61P13/12A61P17/04A61P19/02A61P19/10A61P21/00A61P25/00A61P25/02A61P25/04A61P25/08A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P27/02A61P27/06A61P29/00A61P3/04A61P31/04A61P31/12A61P33/00A61P35/00A61P37/00A61P37/02A61P37/08A61P43/00A61P9/00A61P9/10A61P9/12
Inventor S·拉夫雷S·沃尔斯T·哈特R·帕森斯P·布拉夫C·格雷厄姆A·马西亚斯
Owner VERNALIS (R&D) LTD
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