Author: SOMADA, Atsushi ; HARASAKI, Tamako ; UCHIDA, Takuya ; YASUDA, Hiroshi ; KONOSU, Toshiyuki ; FUKUOKA, Takashi ; MORI, Makoto ; NAKAMURA, Yoshie ; SEKI, Shinobu ; NAKAGAWA, Akihiko ; KAMAI, Yasuki ; OIDA, Sadao ; INOUE, Shin-ichi ; HARADA, Yoshiko ; SETA, Yasuo ; OHYA, Satoshi ; SHIBAYAMA, Takahiro

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.

01 Jan 2000·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Synthesis and Antifungal Activities of R-102557 and Related Dioxane-Triazole Derivatives.

Q4 · MEDICINE

Article

Author: Kamai, Yasuki ; Yasuda, Hiroshi ; Fukuoka, Takashi ; Oida, Sadao ; Konosu, Toshiyuki ; Habuki, Shinobu ; Tajima, Yawara ; Somada, Atsushi ; Harasaki, Tamako ; Tanaka, Teruo ; Ohya, Satoshi ; Nakamura, Yoshie

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Aspergillosis	Discovery	JP	Sankyo Co., Ltd. (Tokyo)	-
Candidiasis	Discovery	JP	Sankyo Co., Ltd. (Tokyo)	-
Cryptococcosis	Discovery	JP	Sankyo Co., Ltd. (Tokyo)	-

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