RESUMEN
The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Receptor TIE-2/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Estructura Molecular , Neoplasias/enzimología , Neoplasias/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Ratas , Ratas Sprague-Dawley , Receptor TIE-2/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report the diastereoselective and chromatography-free syntheses of four 2-phenyl-6-alkyl-3-aminopiperidines. Ring construction was accomplished through a nitro-Mannich reaction linking a nitroketone and phenylmethanimine, followed by a ring-closure condensation. Relative stereocontrol was achieved between C-2 and C-3 by kinetic protonation of a nitronate or by equilibration of the nitro group under thermodynamic control. Stereocontrol at C-6 was accomplished by utilizing a variety of imine reduction methods. The C-2/C-6-cis stereochemistry was established via triacetoxyborohydride iminium ion reduction, whereas the trans relationship was set either by triethylsilane/TFA acyliminium ion reduction or by Lewis acid catalyzed imine reduction with lithium aluminum hydride.