Synthesis of Sch 51048, a novel orally active azole antifungal, is described. Based on its superior oral efficacy over other available agents against a variety of fungal pathogens in normal and immunocompromised animal infection models, Sch 51048 is a subject for possible clinical evaluation.
The management of life threatening invasive mycoses in severely immunocompromised patient populations remains a major challenge. In fact the response of systemic Candida, Aspergillus and meningeal Cryptococcus infections in the neutropenic patient to any form of antifungal therapy is anything but satisfactory. Use of parenteral amphotericin B (AMB), the only broad-spectrum drug for such infections is often limited by its high toxicity and lack of oral bioavailability. 1 Most recently introduction of itraconazole (ITZ) and fluconazole (FLZ) into clinical practice has provided some alternatives to available treatments for systemic infections. Both compounds offer certain advantages over AMB and ketoconazole in terms of oral efficacy and relative lack of toxicity; ITZ is the most effective of the azoles for the treatment of Aspergillosis. 2 As part of an extensive search for orally effective agents, we reported on a series of novel tetrahydrofuran based azole antifungals having broad-spectrum activity. Close attention to stereo and regiochemical requirements for optimal oral activity led to discovery of 2,2,4-cis-substituted tetrahydrofurans with specific placement of the ring oxygen. 3a This interesting finding could not have been predicted at the outset.