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Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors

A technology of isobutyl and phenylmethyl is applied in preparations for in vivo tests, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., which can solve the problem of separating beneficial effects from harmful side effects Kailai and other questions

Inactive Publication Date: 2012-05-16
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 inhibitors
  • Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors
  • Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 2

[0226] Example 2: (in vitro detection and analysis): MGL enzyme activity assay

[0227] All rat-based assays were performed in black 384-well polypropylene PCR microplates (Abgene) in a total volume of 30 μL. The substrate 4-methylumbelliferyl butyrate (4MU-B, Sigma) and the purified mutant MGL enzyme (mut-MGLL 11-313 L179S L186S) were diluted to 150 mM NaCl and 0.001% Tween 20, respectively. 20mM PIPES buffer (pH 7). The compound of formula (I) was pre-dispersed (50 nL) into the assay plate with a Cartisian Hummingbird pipette (Genomic Solutions (Ann Arbor, MI)), and then 4MU-B (25 μL of a 1.2X solution at a final concentration of 10 μM) was added, Enzyme (5 μL of a 6X solution at a final concentration of 5 nM) was then added 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 monitor the change in fluorescence d...

example 4

[0233] Example 4: 2-AG Accumulation Assay

[0234] HeLa cells were homogenized with a Polytron in 10 ml (about 400 million cells) of HEPES buffer (HEPES 20 mM, pH 7.4, NaCl 125 mM, EDTA 1 mM, KCl 5 mM, glucose 20 mM). Homogenates from 0.2 billion cells (0.5 ml) were incubated with MGL inhibitors for 15 minutes to block MGL activity, followed by incubation of HEPES buffer with calcium (10 mM) for 20 minutes. The total reaction volume was 5ml. The reaction was terminated by 6 mL of organic solvent extraction (2:1 chloroform / methanol). Methylarachidonyl fluorophosphonate (MAFP) was used as a positive control. In the absence of MAFP, 2-AG levels were about 3.4 pmol / sample. In the presence of 100 nM MAFP, 2-AG levels increased to 174 pmol / sample. The accumulated 2-AG in the organic phase was measured by HPLC / MS according to the following formula: %MAFP=(compound 2-AG / MAFP 2-AG)×100.

[0235] Representative compounds of formula (I) were tested according to the procedures desc...

example 5

[0238] Example 5: Oral Formulations - Hypothetical Example

[0239] As a specific example of the oral composition, 100 mg of Compound #1 prepared in Example 1 was formulated with well-pulverized lactose to provide a total amount of 580-590 mg to fill O-size hard capsules.

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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) as follows: wherein R1, W and (Ia): are defined herein.

Description

[0001] Cross references to related patent applications [0002] This patent application claims the benefit of US Provisional Application No. 61 / 171,661, filed April 22, 2009, which is hereby incorporated by reference in its entirety. [0003] This patent application and submitted on April 22, 2009, named Heteroaromatic and Aromatic Piperazinyl Azetidinyl Amides as Monoacylglycerol Lipase Inhibitors (heteroaromatic and aromatic piperazinyl azetidinyl as monoacylglycerol lipase inhibitor Amides) are related to US Provisional Patent Application Serial No. 61 / 171,660. [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 the use of a compound of formula (I) as defined herein for the treatment, alleviation and / or prevention of MGL disorders in a subject, including a lactating patient with a disease...

Claims

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Application Information

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IPC IPC(8): A61K31/496A61P29/00A61P25/02A61P1/06
CPCA61K31/496A61P1/04A61P1/06A61P25/00A61P25/02A61P25/04A61P29/00A61P43/00A61K9/0053A61K31/497A61K47/30A61K2121/00
Inventor C·M·弗罗尔斯M·I·内伦E·L·努尔顿S·普罗蒂M·托德S-P·张
Owner JANSSEN PHARMA NV
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