Synthesis of 3-Aryl-2,4-dioxo-1,2,3,4-tetrahydroquinazolines and 2-Arylamino-4-oxo-4<i>H</i>-3,1-benzoxazines from Methyl<i>N</i>-Aryldithiocarbamates

Garin, Jorge L.; Meléndez, Enrique; Merchán, F. L.; Tejero, Tomás; Villarroya, E.

doi:10.1055/s-1983-30357

Cited by 20 publications

(13 citation statements)

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“…12 Surprisingly, it did not prove to be effective as an MGL inhibitor. Because physicochemical analyses confirmed the correct structure of the synthesized compound, 13 we concluded that the activity previously attributed to URB754 was due to an impurity in the commercial sample. In the present communication we report on the analysis of the commercial sample (henceforth referred to as "SPECS") used in our tests and on the identification of its bioactive component.…”

Section: Introductionmentioning

confidence: 70%

“…13 This procedure repeatedly gave in our hands compounds 1, 2 and 4 in addition to the desired compound URB754. Compounds 1 and 2 were obtained in variable amounts depending on the reaction conditions (temperature, duration, work up procedure) and could be completely eliminated by column chromatography and recrystallization of URB754.…”

Section: Analysis Of Specs Product Lot Id N° Ao-095/41416985mentioning

confidence: 86%

“…13 To a hot suspension of 6-methyl-2-p-tolylaminobenzo[d]oxazin-4-one (0.35 g, 1.3 mmol) in EtOH (15 mL), 2N NaOH (10 mL) was added. The solution was refluxed for 10 min, cooled at room temperature, acidified with HCl 20%, and the precipitate filtered.…”

Section: -Methyl-2-p-tolylaminobenzo[d][13]oxazin-4-one (Urb754 Symentioning

confidence: 99%

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Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

et al. 2007

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The compound URB754 was recently identified as a potent inhibitor of the endocannabinoid‐deactivating enzyme monoacylglycerol lipase (MGL) by screening of a commercial chemical library. Based on HPLC/MS, NMR and EI/MS analyses, the present paper shows that the MGL‐inhibitory activity attributed to URB754 is in fact due to a chemical impurity present in the commercial sample, identified as bis(methylthio)mercurane. Although this organomercurial compound is highly potent at inhibiting MGL (IC50 = 11.9±1.1 nM), its biological use is prohibited by its toxicity and target promiscuity.

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Section: Introductionmentioning

confidence: 70%

Section: Analysis Of Specs Product Lot Id N° Ao-095/41416985mentioning

confidence: 86%

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Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

et al. 2007

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“…4a-j did not give coloration with FeCl 3 , neither did they display IR absorptions at about 3700 cm -1 or 2700 cm -1 indicative of a free OH group or a chelated enolic structure. Furthermore the 1 H-NMR spectra of 4a-j did not display absorbtions which may be atrributed to the chelated (δ 16.5 ppm) or free (δ 10−11 ppm) enolic proton [11,12].…”

Section: Chemistrymentioning

confidence: 99%

Synthesis, Characterization and Analgesic Activity of New 4-Arylhydrazono-3-methoxymethyl-2-pyrazolin-5-ones

Ergenç

Çapan

Demirdamar

2011

Arzneimittelforschung

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New 4-arylhydrazono-3-methoxymethyl-2-pyrazolin-5-ones (5a-j) and 4-arylhydrazono-3-methoxymethyl-1-phenyl-2pyrazolin-5-ones (6a-j) were synthesized by the reaction of ten novel methyl 2-arylhydrazono-4-methoxy-3-oxobutanoates (4a-j) with hydrazine hydrate and phenylhydrazine, respectively. Treatment of 5a with acetic anhydride yielded 1-acetyl-4arylhydrazono-3-methoxymethyl-2pyrazolin-5-one (7). The structures of the tautomerically dynamic compounds were established by spectral data (IR, 1 H-NMR, (Turkey) b 13 C-NMR, EIMS and CIMS) and elemental analysis. The analgesic activity of the title compounds was determined by the modified Koster's test. The most active compound was 4-[(4-chlorophenyl)hydrazono]-3-methoxymethyl-1-phenyl-2pyrazolin-5-one (6c) demonstrating twice the activity (60 %) exerted by the reference drug acetylsalicylic acid (ASA, 27 %). The majority of the tested compounds were found to be more effective than ASA.(7). Die Strukturaufklärung dieser tautomerisch dynamischen Verbindungen erfolgte mit Hilfe von Spektraldaten (IR,

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“…This compound was isolated from a library of serine hydrolase inhibitors, and inhibits recombinant rat MAGL with an IC 50 value of 200 nM and more weakly FAAH with an IC 50 of 32 M [120]. Synthesis of URB754 was reported in the eighties by Garin et al by cyclisation of potassium 5-methylanthranilate and methyl-N-(4-methylphenyl)dithiocarbamate in presence of HgO below room temperature [121]. However, very recently, URB754 was reported to lack inhibitory activity upon the 2-AG hydrolysis by rat cerebellar membranes, suggesting either a difference between the previously characterized MAGLcy and the membrane-bound MAGL or a difference in purity between the two sources of URB754 used by the authors of the studies [122].…”

Section: Iiib Magl Inhibitors That Do Not Share Similarities With Thmentioning

confidence: 99%

Overview of the Chemical Families of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Inhibitors

Vandevoorde

2008

CTMC

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The family of the endogenous agonists of the cannabinoid receptors--i.e., the endocannabinoids--includes several polyunsaturated fatty acid amides and esters. Arachidonoylethanolamide (anandamide, AEA) and 2-arachidon-oylglycerol (2-AG) are, respectively, the leads of these chemical families. So far, two enzymes responsible for the metabolism of AEA and 2-AG have been described: fatty acid amide hydrolase (FAAH) which hydrolyzes AEA and in some cells 2-AG, and Monoacylglycerol Lipase (MAGL) which hydrolyzes 2-AG. In spite of the early characterisation of MAGL and the nearly simultaneous clonings of the two enzymes, most of the efforts were dedicated to the study of FAAH and consequentially, the range of FAAH inhibitors available nowadays exceeds the number of compounds active upon MAGL. FAAH inhibitors can be divided in two major groups, the first one includes the inhibitors inspired by the chemical structures of FAAH substrates, which carry an arachidonoyl-, oleoyl- or palmitoyl-carbon chain that mimic the fatty acid chains of anandamide, oleamide and palmitoylethanolamide. The second group involves compounds that do not share similarities with the endocannabinoids, such as the carbamates, oxazolopyridins, 2-thioxoimidazolidin-4-ones, imidazolidine-2,4-diones and the non-steroidal anti-inflammatory drugs. However, the family of MAGL inhibitors contains few members and most of them exhibit a lack of selectivity. The purpose of this review is to give an overview of the families of synthetic inhibitors of FAAH and MAGL. The synthetic pathways, the chemical features, potencies, selectivities and modes of inhibition are listed and discussed in order to facilitate their comparison.

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Synthesis of 3-Aryl-2,4-dioxo-1,2,3,4-tetrahydroquinazolines and 2-Arylamino-4-oxo-4H-3,1-benzoxazines from MethylN-Aryldithiocarbamates

Cited by 20 publications

References 0 publications

Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

Identification of a Bioactive Impurity in a Commercial Sample of 6‐Methyl‐2‐p‐Tolylaminobenzo[d][1,3]Oxazin‐4‐One (URB754)

Synthesis, Characterization and Analgesic Activity of New 4-Arylhydrazono-3-methoxymethyl-2-pyrazolin-5-ones

Overview of the Chemical Families of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Inhibitors

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