RESUMO
Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.
Assuntos
Prolina/química , Inibidores de Proteínas Quinases/química , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Triazinas/química , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Triazinas/farmacologiaRESUMO
Methodology to prepare 8-amido-2-amino-1,2,3,4-tetrahydro-2-dibenzofurans, analogues with a fluorine substituent incorporated in the 6-, 7-, and 9-positions, and a difluorinated analogue with fluorines in the 6- and 9-positions is described. The tetrahydrodibenzofuran ring systems are prepared by acid-catalyzed [3,3]-sigmatropic rearrangement of O-aryloximes. Regioselective reactions to prepare the requisite O-aryloxime intermediates from commercially available fluorobenzene derivatives are discussed.
Assuntos
Técnicas de Química Combinatória , Furanos/síntese química , Hidrocarbonetos Fluorados/síntese química , Oximas/química , Carbazóis/química , Catálise , Cromatografia Líquida de Alta Pressão , Fluorbenzenos/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Serotonina/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
When hydroboration of 1-octene is carried out in the presence of catalytic amounts of rhodium trichloride followed by the usual oxidation (hydrogen peroxide in aqueous alkali), only minor proportions of 1-octanol (2.4%) are formed accompanied by very significant amounts of 2- (17.4%), 3- (36.9%), and 4-octanol (43.3%). These product compositions are obtained in good overall yield when the borane-THF complex is slowly added to a stirred solution of 1-octene in THF solvent containing the rhodium trichloride. Isomerization of 1-octene to 2-, 3-, and 4-octene in the presence of rhodium trichloride alone is far too slow to account for the foregoing results. The mechanism likely involves multiple and reversible addition/elimination of a Rh-activated B-H species across the double bonds.