Recently the incidence of serious fungal infection has become very prominent in patients undergoing chemotherapy for cancer, organ transplants and patients with AIDS. Most of these infections are caused by opportunistic pathogens like Candida spp., Aspergillus spp., Pneumocystis camii and Cryptococcus neoformans. The antifungal agents available in the market suffer with draw backs such as, toxicity, narrow spectrum of activity, fungistatic profile rather fungicidal. Some of them also exhibit drug-drug interactions and, as a result, therapy becomes very complex. In view of the high incidence of fungal infections in immunocompromised patients and the recent trend for the steady increase of the populations of these patients, demands for new antifungal agents with broad spectrum of activity and good pharmacokinetic properties have increased.
Within the available drugs to treat fungal infections, the azole class appears to be more promising. This class of compounds inhibit the biosynthesis of ergosterol in fungi, which is the main constituent of fungal cell membrane. Fluconazole and itraconazole are routinely used for maintenance of fungal infections. Although fluconazole is highly bioavailable, it is not active against filamentous fungi and emergence of fungal resistance has been reported recently (Antimicrob. Agents Chemother. 1995, 39, 1-8). Itraconazole is active against filamentous fungi, but it shows inconsistent results, maybe due to its high protein binding properties and less bioavailability. During the last few years, several research groups have been actively searching for new azoles with optimum pharmacokinetic properties. As a result, a number of candidate azoles have emerged, and some of them are undergoing preclinical and clinical evaluation. Some of the candidate azoles are disclosed in the following publications:
Sch 51048 (Drugs of the Future, 1995, 20, 241-247). PA0 Sch 56592; Antimicrob. Agents Chemother. (1996, 40, 1910-1913; 36th Interscience Conference Antimicrob. Agents Chemother. September 1996, New Orleans, Abst. F87-F102). PA0 UK-109, 496 (Drugs of the Future, 1996, 21, 266-271; EP 440372). PA0 TAK-187; 36th Interscience Conference Antimicrob. Agents Chemother. September 1996, New Orleans, Abst. F74; EP 567982). PA0 KP-103 (36th Interscience Conference Antimicrob. Agents Chemother. September 1996, New Orleans, Abst. F78, WO 94126734). PA0 ER-30346 (Drugs of the Future, 1996, 21, 20-24)
In the present invention, we report new triazoles with broad spectrum anti-fungal activity. The triazoles are particularly effective against systemic and lung invasive fungal infections.