RESUMO
1-Phenyl-1H-tetrazole-5-thiol 1 (PT-thiol) is employed in a unique Markovnikov-selective formal hydroamination of styrenyl compounds in the presence of catalytic amounts of Ga(OTf)3. This gives rise to the formation of tetrazolothione moieties in an atom-economical manner. Mechanistically, we have determined that this transformation may occur by kinetically favored hydrothiolation, followed by rearrangement to the observed hydroamination products.
RESUMO
BT-sulfones react with aromatic aldehydes to furnish trisubstituted alkenes with excellent Z stereoselectivity. These sulfones are synthesized by hydrothiolation of styrene and styrenyl derivatives (followed by oxidation). This method provides a conceptually novel way to prepare these important sulfur compounds.
RESUMO
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Assuntos
Compostos de Anilina/química , Benzamidas/química , Receptor CB2 de Canabinoide/agonistas , Sulfonamidas/química , Compostos de Anilina/síntese química , Compostos de Anilina/farmacocinética , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinéticaRESUMO
Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.