RESUMEN
4-(1,3-Thiazol-2-yl)morpholine derivatives have been identified as potent and selective inhibitors of phosphoinositide 3-kinase. The SAR data of selected examples are presented and the in vivo profiling of compound 18 is shown to demonstrate the utility of this class of compounds in xenograft models of tumor growth.
Asunto(s)
1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , Morfolinas/farmacología , Tiazoles/farmacología , Animales , Técnicas Químicas Combinatorias , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isoenzimas , Ratones , Estructura Molecular , Morfolinas/síntesis química , Morfolinas/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed.
Asunto(s)
Benzoxazinas/química , Química Farmacéutica/métodos , Oxazinas/síntesis química , Oxazinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Área Bajo la Curva , Benzoxazinas/farmacología , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Inflamación , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Isoformas de Proteínas , Relación Estructura-ActividadRESUMEN
The copper-catalyzed enantioselective conjugate addition of diethylzinc to 2-cyclohexen-1-one was investigated using (R,R)-bis-(t-butylmethylphosphino)methane (1c) as a chiral ligand. The reaction was carried out at 0 degrees C in THF-toluene as the solvent system and in the presence of 1.2 mol% of CuOTf afforded (S)-3-ethylcyclohexan-1-one with 85% ee.
RESUMEN
A heavily functionalized atropisomeric biphenyl derivative (4), which is designed to possess a large lateral dipole moment, has been synthesized with use of a Suzuki coupling as the key step and resolved by chiral HPLC. The final coupling reaction is complicated by rapid hydrolytic deboronation of the sterically hindered, electron poor boronate 22. Rigorously anhydrous conditions are therefore necessary to achieve the coupling.