RESUMO
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.
Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Morfolinas/farmacologia , Tiazóis/farmacologia , Animais , Técnicas de Química Combinatória , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoenzimas , Camundongos , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Benzoxazinas/química , Química Farmacêutica/métodos , Oxazinas/síntese química , Oxazinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Área Sob a Curva , Benzoxazinas/farmacologia , Cristalografia por Raios X/métodos , Desenho de Fármacos , Humanos , Inflamação , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Isoformas de Proteínas , Relação Estrutura-AtividadeRESUMO
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.
RESUMO
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.