No abstract

Tioconazole (UK-20,349), a new antifungal imidazole derivative, was compared with miconazole for activity in vitro against Candida spp., Torulopsis glabrata, Cryptococcus neoformans, Aspergillus spp., and dermatophyte fungi ( Trichophyton spp. and Microsporum spp.). Tioconazole was more active than miconazole against all the fungal species examined except Aspergillus , against which both agents showed similar activity. Both tioconazole and miconazole inhibited the growth of all fungi examined at concentrations well below their quoted minimum inhibitory concentrations. Their activity against fungi in vivo was investigated in mice infected systemically with Candida albicans . Both agents significantly reduced the numbers of viable Candida cells recoverable from the kidneys of infected animals, with tioconazole producing a generally more marked reduction. After administration of a single oral dose (25 mg/kg) to beagle dogs or white mice, higher and more sustained circulating levels of bioactive drug were detectable of tioconazole than of miconazole. These observations suggest that tioconazole may have potential in the treatment of both superficial and systemic mycoses in humans.

Nitrogen has been extruded from several 1,2,3-triazoles by flash vacuum pyrolysis and the fate of the resulting iminocarbenes has been determined. 1 -Alkyl-4,5-diphenyl-1,2,3-triazoles (1 ) gave nitriles (Scheme I ) and isoquinolines and hydroxyisoquinolines (Scheme 2). the former by Wolff rearrangement and the latter by 1.4hydrogen transfer in the iminocarbene. 1,4-Dimethyl-5-phenyl-1,2,3-triazole (3) and 1.5-dimethyl-4-phenyl-1.2.3-triazole (4) both gave 3-methylisoquinoline ; a mechanism involving a common. 1 H-azirine intermediate is proposed (Scheme 4). From both 4-and 5-phenyl-l-(1 -phenylvinyl)-I ,2,3-triazole [(5a) and (6a)l mixtures of 2.4-and 2.5-diphenylpyrrole were isolated ; similarly the corresponding 1 -phenyltriazoles gave mixtures of 2-and 3-phenylindole (Scheme 5). 4.5-Diphenyl-v-triazole also gave 2-phenylindole. The formation of these products is rationalised in terms of 1 H-azirine intermediates in the pyrolyses.

2H-Azirines ( 2 ) are isolated in low to moderate yields after oxidation of N-aminophthalimide by lead tetra-acetate in the presence of the alkynes propyne, but-2-yne, pent-I -yne, and hex-3-yne. A mechanism for the reaction is proposed which involves the transient formation and rearrangement of 1 H-azirines (1 ). Some unsuccessful attempts to generate I H-azirines by alternative routes are described. Reports that the products of the reactions of 1,2,3-triazole-4,5-dicarboxylic acid with acetic anhydride and of p-benzoquinone with p-nitrophenyl azide are 1 H-azirines are shown to be incorrect.No 1H-azirines ( 1) have yet been isolated, although many ZH-azirines (2) are known.3 The instability of 1Hazirines can be attributed to the antiaromatic character of the planar system. Molecular orbital calculations have confirmed that there is a destabilising interaction between the electrons of the x-bond and the lone pair on nitrogen : the calculations predict a non-planar structure 1

Szcmmary l-Phthalimido-l,2,3-triazoles (1) thermally fragment in the vapour phase; the products isolated are 2Hazirines (2) and compounds derived from these azirines by further fragmentation or rearrangement.