RESUMEN
A stability-indicating high-performance liquid chromatography method to quantify 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoroisoindoline-1,3-dione (NSC-726796) and its three main degradation products was developed. This method was used to investigate its degradation kinetics and mechanism. The reaction follows first-order kinetics and appears to be base catalyzed with the maximum stability at pH 1. The products were identified as 2-(2,4-difluorophenylcarbamoyl)-3,4,5,6-tetrafluorobenzoic acid (NSC-749820), 2,4-difluoroaniline, and tetrafluorophthalic acid. The parent drug, NSC-726796, was also found to react with methanol and ethanol. NSC-726796 demonstrates antiangiogenic activity, however, when its degradant NSC749820 does not show antiangiogenic activity.
Asunto(s)
Inhibidores de la Angiogénesis/química , Ftalimidas/química , Inhibidores de la Angiogénesis/farmacología , Compuestos de Anilina/química , Animales , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Etanol/química , Concentración de Iones de Hidrógeno , Hidrólisis , Cinética , Metanol/química , Neovascularización Fisiológica/efectos de los fármacos , Ácidos Ftálicos/química , Ftalimidas/farmacología , Ratas , Reproducibilidad de los Resultados , Solventes/química , Tecnología Farmacéutica/métodos , Temperatura , Técnicas de Cultivo de TejidosRESUMEN
In vivo, the DNA methyltransferase inhibitor, 5-fluoro-2'-deoxycytidine (FdCyd, NSC-48006), is rapidly converted to its unwanted metabolites. Tetrahydrouridine (THU, NSC-112907), a cytidine deaminase inhibitor can block the first metabolic step in FdCyd catabolism. Clinical studies have shown that co-administration with THU can inhibit the metabolism of FdCyd. The National Cancer Institute is particularly interested in a 1:5 FdCyd/THU formulation. The purpose of this study was to investigate the in vitro pH stability of FdCyd and THU individually and in combination. A stability-indicating high-performance liquid chromatography method for the quantification of both compounds and their degradants was developed using a ZIC(R)-HILIC column. The effect of THU and FdCyd on the in vitro degradation of each other was studied as a function of pH from 1.0 to 7.4 in aqueous solutions at 37 degrees C. The degradation of FdCyd appears to be first-order and acid-catalyzed. THU equilibrates with at least one of its degradants. The combination of FdCyd and THU in solution does not affect the stability of either compound. The stability and compatibility of FdCyd and THU in the solid state at increased relative humidity and at various temperatures are also evaluated.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Tetrahidrouridina , Animales , Cromatografía Líquida de Alta Presión , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Cinética , Ratones , Temperatura , Tetrahidrouridina/química , Tetrahidrouridina/metabolismo , Tetrahidrouridina/farmacología , AguaRESUMEN
The title compound, C(14)H(5)F(6)NO(3), was synthesized by condensation of tetra-fluoro-phthalic anhydride and 2,4-difluoro-aniline. It was then recrystallized from hexane to give a nonmerohedral twin with two crystallographically unique mol-ecules in the asymmetric unit. The refined twin fraction is 0.460â (3). Torsional differences between the aryl rings and the central amide group account for the presence of two unique mol-ecules. The compound packs as double tapes formed by O-Hâ¯O and N-Hâ¯O hydrogen-bonding inter-actions between each unique mol-ecule and its symmetry equivalents.