Synthesis and antifungal activities of (2R,3R)-2-aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives as topical antifungal agents.
2-Aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives I were prepared by ring-opening reaction of epoxides II with excess amine, and their antifungal activities were evaluated as topical agents. Azolyl-cyclic amine derivatives with a methylene group showed extremely strong activity with a broad spectrum in vitro. In general, anti-Trichophyton mentagrophytes activities of most of the topical antifungal agents are substantially reduced by addition of keratin (a major constituent of the keratinized tissue). However, the triazole derivative (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidino)-1-(1H-1,2 ,4- triazol-1-yl)-2-butanol ((-)-40, KP-103) showed very little deactivation by addition of keratin. This biological characteristic of triazole derivative (-)-40 resulted in excellent therapeutic efficacy on dermatophytosis superior to that of the corresponding imidazole derivative ((-)-41).
Ogura
H
H
Development Research Laboratories, Kaken Pharmaceutical Co., Ltd., Kyoto, Japan.
Kobayashi
H
H
Nagai
K
K
Nishida
T
T
Naito
T
T
Tatsumi
Y
Y
Yokoo
M
M
Arika
T
T
D000818:Animals; D000891:Anti-Infective Agents, Local / Q000138:chemical synthesis* / Q000627:therapeutic use; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D000440:Butanols / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D020650:Combinatorial Chemistry Techniques; D006168:Guinea Pigs; D006197:Hair; D008297:Male; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D014005:Tinea / Q000188:drug therapy; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use
D000891:Anti-Infective Agents, Local; D000935:Antifungal Agents; D000440:Butanols; D014230:Triazoles