Novel triazole compounds with a dioxane ring were synthesized. Condensation of the diol precursor 10 with various aromatic aldehydes 11-13 under acidic conditions afforded a series of dioxane-triazole compounds 14-16. The antifungal activities of the compounds 14-16 were evaluated in vivo in mice infection models against Candida and Aspergillus species. High activities were seen for the derivatives with one or two double bond(s) and an aromatic ring substituted with an electron-withdrawing group in the side chain. Among the derivatives, R-102557 (16R: Ar=4-(2,2,3,3-tetrafluoropropoxy)phenyl) showed excellent in vivo activities against Candida, Aspergillus and Cryptococcus species. It also showed high tolerance in a preliminary toxicity study in rats.

Recently we synthesized a series of dioxane-triazole antifungal agents, which are effective against systemic mycoses.1) From such compounds, R-102557 (3d) was chosen as a candidate compound for development on the basis of its in vivo activities in mice. Since it was found that R-102557's high in vivo activities were caused by its excessively long elimination half-life in plasma, 2) we determined to search for a similar compound but with a shorter half-life. In this paper, we will describe the synthesis and in vitro antifungal activities of our new compound CS-758 (3j; former name, R-120758), 3) which is currently under development as an antifungal agent against systemic mycoses.Starting our search, our attention was focused on minimun inhibitory concentrations (MICs) because as the elimination half-life in plasma gets shorter, the requirements for MICs become severer. We reasoned that, even if a compound with good MICs were to exhibit only fair in vivo activities in mice, the compound might still be able to remain sufficiently long in humans to exhibit reasonable therapeutic effects. On this assumption, some of the previous compounds, such as 3b-g, 1) were re-evaluated on the basis of MICs. Their precursor 1a was also submitted for MIC determination. Some additional compounds, such as 2a, 3a, 3h-j, were prepared.Preparation of the compounds 2a, 3a, 3h-j were done in acetalization reactions of 4 with aldehydes 5a, 6a, 6h-j, respectively (Chart 2). Previously, molecular sieves were then used to remove water, 1) but this time we conducted the reaction by concentrating a tetrahydrofuran (THF) solution containing 4, the aldehydes, and p-toluenesulfonic acid in a rotary evaporator. Aldehyde 6j, a precursor of CS-758, was Shinagawa-ku, Tokyo 140-8710, Japan. Received July 9, 2001; accepted September 17, 2001 Synthesis and in vitro antifungal activities of a novel triazole antifungal agent CS-758 (former name, R-120758) are described. The minimum inhibitory concentrations (MICs) of a series of dioxane-triazole compounds related to R-102557 were examined. Variation of the length of the chain between the dioxane ring and the phenyl ring revealed that the linkage with two double bonds is the most preferable. When a cyano group was introduced to the C4 position on the benzene ring, MICs improved further. A fluorine atom was introduced to obtain CS-758. The MICs of CS-758 surpassed those of fluconazole and itraconazole against Candida, Aspergillus and Cryptococcus species. The precursor (E,E)-aldehyde was synthesized stereoselectively from 3-fluoro-4-methylbenzonitrile using the Horner-Wadsworth-Emmons reaction.