- Visible-Light-Induced Intramolecular C(sp2)-H Amination and Aziridination of Azidoformates via a Triplet Nitrene Pathway
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Catalytic intramolecular C-H amination and aziridination reactions of o-allylphenyl azidoformates have been achieved under visible-light irradiation, providing a mild, clean, and efficient method for the synthesis of useful benzoxazolones and [5.1.0] bicyclic aziridines. Mechanistic studies suggest that a triplet nitrene acts as the reactive intermediate. The chemoselectivity of the reaction, with alkyl olefin aziridination ? electron deficient olefin aziridination ≈ C(sp2)-H amination ? C(sp3)-H amination was observed, which may be instructive in the development of an understanding of visible-light-induced triplet nitrene transformation reactions.
- Zhang, Yipin,Dong, Xunqing,Wu, Yanan,Li, Guigen,Lu, Hongjian
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supporting information
p. 4838 - 4842
(2018/08/24)
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- Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates
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Fentanyl is a powerful opiate analgesic typically used for the treatment of severe and chronic pain, but its prescription is strongly limited by the well-documented side-effects. Different approaches have been applied to develop strong analgesic drugs with reduced pharmacologic side-effects. One of the most promising is the design of multitarget drugs. In this paper we report the synthesis, characterization and biological evaluation of twelve new 4-anilidopiperidine (fentanyl analogues). In vivo hot-Plate test, shows a moderate antinociceptive activity for compounds OMDM585 and OMDM586, despite the weak binding affinity on both μ and δ-opioid receptors. A strong inverse agonist activity in the GTP-binding assay was revealed suggesting the involvement of alternative systems in the brain. Fatty acid amide hydrolase inhibition was evaluated, together with binding assays of cannabinoid receptors. We can conclude that compounds OMDM585 and 586 are capable to elicit antinociception due to their multitarget activity on different systems involved in pain modulation.
- Monti, Ludovica,Stefanucci, Azzurra,Pieretti, Stefano,Marzoli, Francesca,Fidanza, Lorenzo,Mollica, Adriano,Mirzaie, Sako,Carradori, Simone,De Petrocellis, Luciano,Schiano Moriello, Aniello,Benyhe, Sándor,Zádor, Ferenc,Sz?cs, Edina,?tv?s, Ferenc,Erdei, Anna I.,Samavati, Reza,Dvorácskó, Szabolcs,T?mb?ly, Csaba,Novellino, Ettore
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p. 1638 - 1647
(2016/10/09)
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- Synthesis and biological evaluation of piperazinyl carbamates and ureas as fatty acid amide hydrolase (FAAH) and transient receptor potential (TRP) channel dual ligands
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The evaluation of a series of piperazinyl carbamates and ureas, designed on the basis of previously reported TRPV1 antagonists and FAAH inhibitors, led to the identification of some 'dual-action' compounds targeting both FAAH and TRPV1 or TRPA1 receptors.
- Morera, Enrico,De Petrocellis, Luciano,Morera, Ludovica,Moriello, Aniello Schiano,Ligresti, Alessia,Nalli, Marianna,Woodward, David F.,Di Marzo, Vincenzo,Ortar, Giorgio
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scheme or table
p. 6806 - 6809
(2010/06/12)
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- New N-arachidonoylserotonin analogues with potential "dual" mechanism of action against pain
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N-Arachidonoylserotonin (AA-5-HT, 1a) is an inhibitor of fatty acid amide hydrolase (FAAH) that acts also as an antagonist of transient receptor potential vanilloid-type 1 (TRPV1) channels and is analgesic in rodents. We modified the chemical structure of 1a with the aim of developing "hybrid" FAAH/TRPV1 blockers more potent than the parent compound or obtaining analogues with single activity at either of the two targets to study the mechanism of the analgesic action of 1a. Thirty-eight AA-5-HT analogues, containing a serotonin "head" bound to a variety of lipophilic moieties via amide, urea, or carbamate functionalities, were synthesized. Unlike 1a, most of the new compounds possessed activity at only one of the two considered targets. The amides 1b and 1c of α- and γ-linolenic acid, however, showed "hybrid" activity similar to 1a. The carbamate 3f (OMDM106), although unable to antagonize TRPV1 receptors, was the most potent FAAH inhibitor in this study (IC50 = 0.5 μM). Compounds 3f and 1m (OMDM129), which exhibited activity at only FAAH or TRPV1, respectively, were 10-fold less potent than 1a at preventing formalin-induced hyperalgesia in mice.
- Ortar, Giorgio,Cascio, Maria Grazia,De Petrocellis, Luciano,Morera, Enrico,Rossi, Francesca,Schiano-Moriello, Aniello,Nalli, Marianna,De Novellis, Vito,Woodward, David F.,Maione, Sabatino,Di Marzo, Vincenzo
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p. 6554 - 6569
(2008/09/17)
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- Heat-sensitive recording materials and phenol compounds
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Heat-sensitive recording materials contain an electron-donating chromogenic compound and an electron-attracting compound. The recording materials also contain at least one compound represented by the following formula: STR1 wherein R1 and R3 mean a hydrogen atom or an alkyl, aralkyl or aryl group, R2 and R4 denote an alkyl, alkenyl, aralkyl or aryl group, X1, X2, Y1 and Y2 stand for an oxygen or a sulfur atom, and --Z1 -- and --Z2 -- are a specific aromatic group. Also provided are phenol compounds represented by the following formula: STR2 wherein R1, R2, X1 and Y1 have the same meanings as defined above; R5 and R6 are a hydrogen or halogen atom or an alkyl, alkoxy, aralkyl, aryl or hydroxyl group; p and q stand for an integer of 1-4; R5 and R6 may be either the same or different when p and q represent an integer of 2 or greater; and --Z3 -- means a specific divalent group.
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- Cyclization-Activated Prodrugs: N-(Substituted 2-hydroxyphenyl and 2-hydroxypropyl)carbamates Based on Ring-Opened Derivatives of Active Benzoxazolones and Oxazolidinones as Mutual Prodrugs of Acetaminophen
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N-(Substituted 2-hydroxyphenyl)- and N-(substituted 2-hydroxypropyl)carbamates based on masked active benzoxazolones (model A) and oxazolidinones (model B), respectively, were synthesized and evaluated as potential drug delivery systems.A series of alkyl and aryl N-(5-chloro-2-hydroxyphenyl)carbamates 1 related to model A was prepared.These are open drugs of the skeletal muscle relaxant chlorzoxazone.The corresponding 4-acetamidophenyl ester named chloracetamol is a mutual prodrug of chloroxazone and acetaminophen.Chlorzacetamol and two other mutual prodrugs of active bezoxazolones and acetaminophen were obtained in a two-step process via condensation of 4-acetamidophenyl 1,2,2,2-tetrachloroethyl carbonate with the appropiate anilines.Based on model B, two mutual prodrugs of acetaminophen and active oxazolidinones (metaxalone and mephenoxalone) were similarly obtained using the appropiate amines.All the carbamate prodrugs prepared were found to release the parent drugs in aqueous (pH 6-11) and plasma (pH 7.4) media.The detailed mechanistic study of prodrugs 1 carried out in aqueous medium at 37 deg C shows a change in the Broensted-type relationship log t1/2 vs pKa of the leaving groups ROH: log t1/2 = 0.46pKa - 3.55 for aryl and trihalogenoethyl esters and log t1/2 = 1.46pKa - 16.03 for alkyl esters.This change is consistent with a cyclization mechanism involving a change in the rate-limiting step from formation of a cyclic tetrahedral intermediate (step k1) to departure of the leaving group ROH (step k2) when the leaving group ability decreases.This mechanism occurs for all the prodrugs related to model A.Regeneration of the parent drugs from mutual prodrugs related to model B takes place by means of a rate-limiting elimination-addition reaction (E1cB mechanism).This affords acetaminophen and the corresponding 2-hydroxypropyl isocyanate intermediates which cyclize at any pH to the corresponding oxazolidinone drugs.As opposed to model A, the rates of hydrolysis of mutual prodrugs of model B clearly exhibit a catalytic role of the plasma.It is concluded from the plasma studies that the carbamate substrates can be enzymatically transformed into potent electrophiles, i.e., isocyanates.In the case of the present study, the prodrugs are 2-hydroxycarbamates for which the propinquity of the hydroxyl residue and the isocyanate group enforces a cyclization reaction.This mechanistic particularity precludes their potential toxicity in terms of potent electrophiles capable of modifying critical macromolecules.
- Vigroux, Alain,Bergon, Michel,Zedde, Chantal
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p. 3983 - 3994
(2007/10/03)
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- Nouvelles syntheses de phenyl-4 allophanates
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The synthesis of eighteen alkyl or phenyl 4-phenylallophanates is described.The classical methods used for the preparation of allophanates - namely, condensation between an isocyanate and a carbamate, reaction between a urea and a carbonate, desulphurization of 3-thioallophanic acid esters - proved to be unsuitable for the synthesis of 4-phenylallophanic acid phenyl esters.Variously substituted 4-phenylallophanates can be obtained by reacting a chloroformate with a phenylurea in the presence of pyridine, which promotes the transfer of the carboxylate group.The occurence of electrondonating substituents, such as CH3, at the nitrogen atom receiving the carboxylate group promotes the reaction.The low yields observed for aliphatic esters can be accounted for by the instability of the alkyl chloroformate-pyridine complex.The structures of the derivatives synthesized was corroborated by the analysis of their n.m.r. and u.v. spectra. Non-commercial phenyl chloroformates were prepared by reacting phosgene with a sodium phenolate in the presence of anhydrous benzene.
- Al Sabbagh, Mohamed Mowafak,Calmon, Michelle,Calmon, Jean-Pierre
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