- The Trifluoromethyl Group as a Bioisosteric Replacement of the Aliphatic Nitro Group in CB1 Receptor Positive Allosteric Modulators
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The first generation of CB1 positive allosteric modulators (e.g., ZCZ011) featured a 3-nitroalkyl-2-phenyl-indole structure. Although a small number of drugs include the nitro group, it is generally not regarded as being "drug-like", and this is particularly true for aliphatic nitro groups. There are very few case studies where an appropriate bioisostere replaced a nitro group that had a direct role in binding. This may be indicative of the difficulty of replicating its binding interactions. Herein, we report the design and synthesis of ligands targeting the allosteric binding site on the CB1 cannabinoid receptor, in which a CF3 group successfully replaced the aliphatic NO2. In general, the CF3-bearing compounds were more potent than their NO2 equivalents and also showed improved in vitro metabolic stability. The CF3 analogue (1) with the best balance of properties was selected for further pharmacological evaluation. Pilot in vivo studies showed that (±)-1 has similar activity to (±)-ZCZ011, with both showing promising efficacy in a mouse model of neuropathic pain.
- Tseng, Chih-Chung,Baillie, Gemma,Donvito, Giulia,Mustafa, Mohammed A.,Juola, Sophie E.,Zanato, Chiara,Massarenti, Chiara,Dall'Angelo, Sergio,Harrison, William T. A.,Lichtman, Aron H.,Ross, Ruth A.,Zanda, Matteo,Greig, Iain R.
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supporting information
p. 5049 - 5062
(2019/05/28)
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- C-C Bond-Forming Strategy by Manganese-Catalyzed Oxidative Ring-Opening Cyanation and Ethynylation of Cyclobutanol Derivatives
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A novel C-C bond-forming strategy employing manganese-catalyzed ring-opening of cyclobutanol substrates, followed by cyanation or ethynylation, is described. A cyano C1 unit and ethynyl C2 unit are regiospecifically introduced to the γ-position of ketones at room temperature, providing a mild yet powerful method for production of elusive aliphatic nitriles and alkynes. All transformations described are based on a common sequence: 1) oxidative ring-opening of cyclobutanol substrates by C-C bond cleavage; 2) radical addition to triple bonds bearing an arylsulfonyl group; and 3) radical-mediated C-S bond cleavage.
- Ren, Rongguo,Wu, Zhen,Xu, Yan,Zhu, Chen
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supporting information
p. 2866 - 2869
(2016/02/27)
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- CANNABINOID TYPE 1 RECEPTOR MODULATORS
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The present disclosure relates to indole derivatives of the formula (I) which are cannabinoid type 1 receptor modulators and which are useful in the treatment of diseases in which modulation of the receptor is beneficial; to processes for their preparatio
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Paragraph 00193-00195
(2016/03/22)
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- Metal or ammonium alginates as Lewis base catalysts for the 1,2-addition of silyl nucleophiles to carbonyl compounds
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Several metal (Na+, Ca2+) or ammonium (n-Bu 4N+) derivatives of alginic acid, an abundant bio-polymer obtained from the cell walls of brown algae, were synthesized. Their potential to act as organocatalysts to catalyze the 1,2-addition of various silyl derivatives to carbonyl compounds was evaluated for the first time. Ammonium alginate 1h is able to promote the reaction in modest to good isolated yields (up to 98%) affording access to a large range of substrates (β-cyano alcohols or ester, β-substituted methylacrylate or acrylonitrile, and cyanohydrin) by using only 5 mol % of catalyst.
- Verrier, Cécile,Oudeyer, Sylvain,Dez, Isabelle,Levacher, Vincent
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supporting information; experimental part
p. 1958 - 1960
(2012/05/19)
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- Michael Addition of Acetonitrile to Chalcones under Ultrasound Irradiation
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When chalcones were treated with potassium superoxide (KO2) in acetonitrile under ultrasound irradiation, chalcone-acetonitrile adducts were obtained in moderate yields.
- Shibata, Katsuyoshi,Urano, Katsuyoshi,Matsui, Masaki
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p. 519 - 520
(2007/10/02)
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- ACTIVATION OF SILICON-HYDROGEN, SILICON-OXYGEN, SILICON-NITROGEN BONDS IN HETEROGENEOUS PHASE SOME NEW METHODS IN ORGANIC SYNTHESIS
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Anionic activation of Si-H, Si-O and Si-N bonds by fluoride ions under heterogeneous conditions is reported: Si-H activated by KF or CsF is a powerful and selective reducing reagent; the carbonyl group of aldehydes, ketones or esters can be reduced without reduction of other functional groups (C=C, NO2, Br, amido).Furthermore, selective reductions of aldehydes in the presence of ketones and ketones in the presence of carboxylic esters are also possible.CsF in the presence of Si(OR)4 is found to be very efficient in promoting Michael additions of monoketones andarylacetonitriles on different kinds of Michael acceptors such as α, β unsaturated ketones, esters, nitriles and even amides.This constitutes an extension of Michael reaction since the addition occurs even with crowded ketones.N,N bis(silyl)enamines activated by fluoride ions react with carbonyl compounds and provide an interesting route to 2-aza-1,3 dienes.
- Corriu, R. J. P.,Perz, R.,Reye, C.
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p. 999 - 1010
(2007/10/02)
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- EXTENSION DE LA REACTION DE MICHAEL EN PRESENCE CsF/Si(OR)4
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An extension of the Michael reaction is described.CsF in the presence of Si(OR)4 is found to be very efficient for carrying out Michael additions of monoketones and arylacetonitriles on different kinds of Michael acceptors: α,β unsaturated ketones, esters
- Boyer, J.,Corriu, R. J. P.,Perz, R.,Reye, C.
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p. 117 - 122
(2007/10/02)
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