RESUMEN
(2'R)-Ethynyl uridine 3, and its (2'S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5'-O-triphosphates. Subsequently, this lead to the discovery of the 2'-ß-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleósidos/farmacología , Uridina/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Relación Estructura-Actividad , Uridina/análogos & derivados , Uridina/químicaRESUMEN
The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-ß (Aß) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Morfolinas/química , Morfolinas/farmacología , Sulfonamidas/química , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Inhibidores Enzimáticos/uso terapéutico , Femenino , Masculino , Ratones , Morfolinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
Studies directed at the synthesis of (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones from (Z)-3-aryl-3-haloenoic acids are described. The successful strategy relies on the preparation of (Z)-3-aryl-3-haloenoic acids from acetophenones through the corresponding (Z)-3-aryl-3-haloenals and the conversion of the (Z)-3-aryl-3-haloenoic acids to (Z)-5-benzylidene-4-aryl-5H-furan-2-ones. The furanones were subsequently treated with primary amines and dehydrated to the corresponding (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones.
RESUMEN
Betamethasone dipropionate is an active pharmaceutical ingredient (API) that is used in various dosage forms of finished products for the treatment of inflammatory disorders. An unknown degradant was observed during a solution stability study of betamethasone dipropionate. An approach that combines LC-MS(n), mechanism-based stress studies, semi-preparative HPLC purification and structure elucidation by NMR spectroscopy was used to identify the unknown species. The key step of this approach is the design of relevant stress studies based on the plausible degradation mechanism that is revealed by the informative LC-MS(n) analysis. The appropriately designed mechanism-based stress studies not only verify the degradation mechanism but also produce enough quantities of the unknown species for further structure elucidation/confirmation by NMR spectroscopy. With this strategy, the unknown degradant was rapidly identified as lumibetametasone dipropionate, a photodegradation product of betamethasone dipropionate.
Asunto(s)
Antiinflamatorios/análisis , Betametasona/análogos & derivados , Antiinflamatorios/química , Betametasona/análisis , Betametasona/química , Química Farmacéutica/métodos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Estabilidad de Medicamentos , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodosRESUMEN
A comprehensive study of nitration reaction of azatricyclic systems has been carried out. Whereas classical nitrations using KNO(3)-H(2)SO(4) at low temperatures gave nitrated products mainly at the 9-position, use of tetrabutylammonium nitrate-trifluoroacetic anhydride (TBAN-TFAA) resulted in exclusive nitration of the 3-position in the case carbamates 1, and 4-6 and the tricyclic ketone 7. These 3-nitro tricyclic derivatives have been valuable intermediates for the preparation of the very potent farnesyl protein transferase inhibitors such as the tricyclic pyridyl acetamide 32 and other new analogues.