Author/Authors :
Yasutsugu Ueda، نويسنده , , John D. Matiskella، نويسنده , , Jerzy Golik، نويسنده , , Timothy P. Connolly، نويسنده , , Thomas W. Hudyma، نويسنده , , Srini Venkatesh، نويسنده , , Mandar Dali، نويسنده , , Shin-Hong Kang، نويسنده , , Nancy Barbour، نويسنده , , Ravi Tejwani، نويسنده , , Sailesh Varia، نويسنده , , Jay Knipe، نويسنده , , Ming Zheng، نويسنده , , Marina Mathew، نويسنده , , Kathy Mosure، نويسنده , , Junius Clark، نويسنده , , Lucinda Lamb، نويسنده , , Ivette Medin، نويسنده , , Qi Gao، نويسنده , , Stella Huang، نويسنده , , et al.، نويسنده ,
Abstract :
Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and bis-tert-butyl chloromethylphosphate, but under two different conditions. Both derivatives were highly soluble in water and converted to the parent in alkaline phosphatase, and also in vivo (rat). However, BMS-315801 was found to be less stable than BMS-379224 in water at neutral pH. BMS-379224 (2) has proved to be one of the most promising prodrugs of ravuconazole that we tested, and it is currently in clinical evaluation as an intravenous formulation of the broad spectrum antifungal azole, ravuconazole.
