Piempel u. a.: F.xperinientelle Befunde ii ber ciii neues, oral wirksames Antimykotikum Deutsche Medizinische Wochenschrift Experimentelle Befunde über ein neues, oral wirksames Antimykotikum mit breitem Wirkungsspektrum Nach den Blut-und Gewebespiegein, die mit verschiedenen Dosen von Bis-phenyl-(2-chlorphenyl)-1-imidazolyl-methan (BAY b 5097) bei Versuchstieren und Patienten erreicht werden, kann die Empfindlichkeitsgrenze pathogener Pilze in vivo mit 4-6 (-8) '/ml angenommen werden. In diesem Konzentrationsbereich in vivo sicher erreichbar sind 1. alle geprüften Candida-Arten, vor allem C. albicans und C. tropicalis, 2. die Dermatophyten der Gattungen Trichophyton und Microsporon, 3. die Sproßpilze der Gattungen Coccidioides immitis, Paracoccidioides brasiliensis, Histoplasma capsulatum und Cryptococcus neoformans, 4. die Aspergillen, 5. die Chromomyceten der Gattungen Phialophora und Hormodendrum, 6. Cladosporium carrioni. In vivo möglicherweise noch erreichbar sind die Allescherien, das biphasische Sporotrichon Schenckii sowie Schimmelpilze der Gattungen Mucor und Blakeslea, die nur ausnahmsweise pathogen sind. Nicht mehr im In-vivo-Wirkungsspektrum liegen Madurella-Arten und die aufgrund ihrer Zellwandstruktur zu den Bakterien zählenden, aerob wachsenden Strahlenpilze Nocardia asteroides und N. brasiliensis. Nach unseren tierexperimentellen Daten wirkt BAY b 5097 bei oraler Applikation bei System-und Dermatomykosen in der erforderlichen Dosierung zuverlässig. Die optimale Therapiedauer im Tierexperiment beträgt bei System-Mykosen 8-12 Tage, bei Dermatomykosen 12-16 Tage, eine kürzere Therapiedauer führt zu Rezidiven.

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Die zum Teil nach literaturbekannten Verfahren hergestellten Triphenylmethylchloride (III) reagieren mit Imidazol (VII) in polaren organischen Lö= sungsmitteln (Dimethylformamid, Dimethylsulfoxid, Acetonitril) in Gegenwart von tert. Aminen ( ;z.B. Triäthylamin) bei 207‐ 80°C in guten Ausbeuten zu den 1‐Triphenylmethylimidazolen (VIII).

A new triazole, Bay R 3783, was compared with ketoconazole, itraconazole, and fluconazole, which were given via the alimentary tract at three dosages, and amphotericin B, which was given at 1 mg/kg intraperitoneally, in murine models of the systemic mycoses coccidioidomycosis, histoplasmosis, and blastomycosis. In a pulmonary coccidioidomycosis model, Bay R 3783, fluconazole, and itraconazole were essentially equally efficacious and more active than ketoconazole in protecting mice against death; but they were inferior to amphotericin B. In a short-term organ load experiment, Bay R 3783 and amphotericin B were equally effective and were more effective than the other drugs in reducing the amount of Coccidioides immitis in the lungs. Against meningocerebral coccidioidomycosis, Bay R 3783, itraconazole, and fluconazole at 25 mg/kg and amphotericin B prevented death only during therapy, with mortalities ensuing shortly thereafter. In mice with systemic histoplasmosis, Bay R 3783 and itraconazole at 25 mg/kg and amphotericin B prevented death in all mice through a 44-day observation period. Clearance of Histoplasma capsulatum from organs was similar in mice treated with Bay R 3783 and itraconazole; this clearance was greater than that in mice treated with ketoconazole and fluconazole but less than that in mice treated with amphotericin B. In mice with systemic blastomycosis, Bay R 3783 at 25 mg/kg yielded 90% survivors at 60 days, which was greater than that achieved with amphotericin B (60%) or itraconazole (30%). Clearance of Blastomyces dermatitidis from the lungs was greatest with Bay R 3783, followed by that with amphotericin B, itraconazole, fluconazole, and ketoconazole, in that order. Therefore, Bay R 3783 showed effectiveness comparable to or exceeding those of itraconazole and fluconazole and exceeding that of ketoconazole against these systemic mycoses in mice.The chemotherapy of systemic infections caused by dimorphic fungi has relied on amphotericin B for three decades, and in recent years this polyene has been supplemented or supplanted by flucytosine and by the antifungal azoles. Whereas miconazole has found some utility by the parenteral, particularly intrathecal and intraventricular, routes (15), other azoles (ketoconazole, itraconazole, and fluconazole) have the advantage of being effective even when given by the oral route. The newer triazoles itraconazole and fluconazole additionally appear to have the advantages of less toxicity and apparently greater potency than ketoconazole against some systemic pathogens and greater activity than ketoconazole against meningocerebral infections (1-5, 12, 13, 16, 17).Previous in vitro studies with Bay R 3783 and several other azoles against Coccidioides immitis (7) and fluconazole and ketoconazole against Histoplasma capsulatum (14) demonstrated the activity of this class of drug against the dimorphic fungal pathogens. This lead to the present study, in which Bay R 3783 (Fig. 1)

Summary According to data on the imidazole antimycotics at present on the market, none of these products satisfactorily fills the gaps which exist in the treatment for mycoses of internal organs, although they have brought considerable progress in the topical treatment of mycoses. On the basis of their very broad spectrum and high intensity of activity under suitable test conditions, and the comparatively tolerable amount of side effects in man, the present imidazole antimycotics are considered to be an encouraging start for future development of derivatives which will lead to products with considerably better pharmacokinetic, and therefore better therapeutic, properties.