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Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitor

A heteroaryl and triazine-based technology, applied in the field of novel monoacylglycerol lipase inhibitors, can solve the problem that it is difficult to separate beneficial effects from harmful side effects

Inactive Publication Date: 2012-07-04
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Although the analgesic and anti-inflammatory effects of enhanced cannabinoid signaling have been conclusively demonstrated using synthetic cannabinoid agonists, it has been difficult to disentangle the beneficial effects of these compounds from the deleterious side effects

Method used

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  • Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitor
  • Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitor
  • Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0456] Example 1: Compound #12

[0457] Biphenyl-4-yl-[3-(4-pyrimidin-2-yl-piperazin-1-yl)-azetidin-1-yl]-methanone

[0458]

[0459] Step A: 2-[4-(1-Benzhydryl-azetidin-3-yl)-piperazin-1-yl]-pyrimidine

[0460] 2-Piperazin-1-yl-pyrimidine (2.48g, 15.10mmol, Alfa) and 1-benzhydryl-azetidin-3-yl methanesulfonate (4g, 12.6mmol, Oakwood) CH 3 To the solution of CN (40 mL) was added DIPEA (2.63 mL, 15.10 mmol). The resulting mixture was then refluxed for 2 h. The solvent was removed by evaporation and the residue was dissolved in CH 2 Cl 2 and NaHCO 3 Partition between aqueous solutions. with NaHCO 3 The organic layer was washed with aqueous solution (2x), then extracted with 1N HCl (2x). The aqueous layer was cooled, then the pH was adjusted with 1N NaOH. The resulting mixture was treated with CH 2 Cl 2 (2x) extraction. The organic layer was washed with MgSO 4 Dry and concentrate. The resulting residue was purified by MPLC to afford 2-[4-(1-benzhydryl-azet...

example 2

[0480] Example 2: Compound #139

[0481] (6-Trifluoromethyl-benzo[b]thiophen-2-yl)-[3-(4-pyrimidin-2-yl-piperazin-1-yl)-aza Cyclobutan-1-yl]-methanone

[0482]

[0483] Step A: tert-butyl 4-(2,2,2-trifluoro-acetyl)-piperazine-1-carboxylate

[0484] CH 2 Cl 2 (100mL) solution was added dropwise (CF 3 CO) 2 O (10.5 mL, 75.54 mmol). The resulting mixture was stirred at 0 °C for 2 h. Then 2N HCl (60 mL) was added. The organic layer was washed with MgSO 4 Dry, filter and concentrate. The resulting residue (title compound) was used in the next reaction without further purification. MS m / z (MH + -Boc)183.1, (MH + -C 4 h 9 )227.1; 1 H NMR (300MHz, CDCl 3 ): δ3.45-3.7 (m, 8H), 1.5 (s, 9H).

[0485] Step B: 2,2,2-Trifluoro-1-piperazin-1-yl-ethanone

[0486] CH 2 Cl 2 (60 mL) was added trifluoroacetic acid (18 mL). The resulting mixture was stirred at room temperature for 18 h. Solvent was removed by evaporation. Diethyl ether (100 mL) was added to the ...

example 3

[0500] Example 3 (in vitro analysis): MGL enzyme activity assay

[0501] All rate-based assays were performed in black 384-well polypropylene PCR microplates (Abgene) in a total volume of 30 μL. The substrate butyrate-4-methylumbelliferone (4MU-B; Sigma) and purified mutant MGL enzyme (mut-MGLL 11-313 L179S L186S) or purified wild-type MGL (wt-MGLL 6H-11- 313) were respectively diluted into 20 mM PIPES buffer (pH=7.0) containing 150 mM NaCl and 0.001% Tween 20. Compounds of formula (I) were pre-dispensed (50 nL) into assay plates using a Cartesian Hummingbird (Genomic Solutions, Ann Arbor, MI), followed by the addition of 4MU-B (25 μL of a 1.2X solution to a final concentration of 10 μM), followed by enzyme ( 5 μL of 6X solution to a final concentration of 5 nM) to initiate the reaction. Final compound concentrations ranged from 17 to 0.0003 [mu]M. Excitation and emission wavelengths of 335nm and 440nm at 37°C, respectively, and a bandwidth of 10nm (Safire 2 , Tecan) to ...

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Abstract

Disclosed are compounds, compositions and methods for treating diseases, syndromes, conditions and disorders that are affected by the inhibition of MGL, including pain. Such compounds are represented by Formula (I), wherein Y, r, R2 and Z are defined herein.

Description

[0001] Cross references to related patent applications [0002] This patent application claims the benefit of US Provisional Application No. 61 / 171,660, filed April 22, 2009, which is hereby incorporated by reference in its entirety. [0003] The title of this patent application and submitted on April 22, 2009 is "Heteroaromatic and Aromatic Piperazinyl Azetidinyl Amides as Monoacylglycerol Lipase Inhibitors" (as monoacylglycerol lipase inhibitors heteroaromatic and aromatic piperazinyl azetidinyl Amides) related to US Provisional Application No. 61 / 171,661. [0004] Statement Regarding Federally Funded Research and Development Programs [0005] The invention research and development project described below received no federal funding. technical field [0006] The present invention relates to novel monoacylglycerol lipase (MGL) inhibitors, pharmaceutical compositions comprising them and their use for treating, alleviating and / or preventing MGL disorders in subjects, includin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D403/12C07D403/14C07D405/14C07D409/12C07D409/14C07D413/12C07D417/12A61K31/496A61P29/00A61P25/00
CPCC07D401/14C07D401/12C07D413/14C07D405/14C07D409/12C07D417/12C07D403/14C07D409/14C07D413/12C07D403/12A61P1/00A61P25/00A61P25/04A61P25/22A61P25/24A61P29/00A61P43/00A61K31/496
Inventor K·M·谢瓦利耶S·L·达克斯C·M·弗罗尔斯L·刘M·J·马切拉格M·E·麦唐奈M·I·内伦S·普罗蒂M·托德S-P·张B·朱E·L·努尔顿J·克莱门特
Owner JANSSEN PHARMA NV
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