Azoles development

Figure 4. N-trityl- and N-dipheny1-methyl-azoles developed for practical use.

B. Azole antifungals include systemic agents such as keto-conazole, fluconazole, itraconazole, and voriconazole. Topical agents used for the treatment of vaginal candidiasis and thrush include miconazole and clotrimazole. The pharmacologic properties of the systemic azoles differ considerably. Ketoconazole, the first oral azole developed, has poor bioavailability and requires an acidic environment for enhanced absorption. Thus, initial studies required ketoconazole to be administered with a cola to increase bioavailability. Fluconazole, unlike itraconazole and ketoconazole, is hydrophillic and has increased penetration across the blood-brain barrier. Fluconazole is also the only azole that is renally eliminated. 

In the coming years, one can expect a great development in nitrogen NMR spectroscopy for the study of azoles (for recent work see (82JOC5132, 83HCA1537)). At this moment most... 

While significant amounts of experimental data are available on the side-chain tautomerism of the functionalized azoles, most are of qualitative character and not fully systematic. No accurate structural correlations which would allow rehable predictions of the energy preferences of a specific tautomer or the state of a tautomeric equilibrium at given conditions have been developed. Nevertheless, trends can be discerned, some of which have previously been formulated [76AHC(S1), pp. 386-391, 443-446]. More recent studies discussed in this section have confirmed the validity of the following ... 

Selenazole is a 5-membered heterocycle of the azole series, containing two heteroatoms. Other members of this group include thiazole and oxazole, whose chemistry is more developed because of their easier access and lower toxicity. The numbering of the heterocyclic system is as follows ... 

Aqueous Diels-Alder reaction has also been applied at the industrial level. 2,2,5-Trisubstituted tetrahydrofurans 21 are a class of active azole antifungals. Workers at Schering-Plough [21] developed a synthetic approach based on a Diels-Alder reaction between 2-arylfurans 22 and ethyl acetylenedicarboxylate (Scheme 6.9). Under thermal conditions the reaction gave a low yield of... 

Hlasta and Deng have developed a two-step solid-phase method for the decoration of azoles at C-2 [188]. First, imidazole was loaded onto a polystyrene-bound carbamyl chloride via a benzaldehyde bridge (Fig. 40). The 2-substi-tuted imidazole was efficiently cleaved in good yields in the presence of various nucleophiles (i.e., water, alcohols, and amines), trifluoroacetic acid, and boron trifluoride under microwave irradiation in a closed vessel at 120 °C for 5 min. 

Keto con azole Inhibits several 200 mg twice reactions develops with continued use. Hematologic disturbances and hypothyroidism also seen. Generally well High potential for drug interactions due to potent induction of hepatic enzymes. Effective in a majority of causes ... 

Several routes have been reported for the synthesis of aromatic poly(azole)s such as poly(benzimidazole), poly(benzoaxazole), and poly(benzthiazole) melt polycondensation of dicarboxylic acid diphenyl esters with tetramines21 and high-temperature solution polycondensation of dicarboxylic acids or their derivatives with tetramine hydrochlorides in PPA.22 PPA acts as condensing agent and solvent. Ueda etal.23 developed a modified method for the synthesis ofpolyazoles with the use of PPM A. 

The ditetrazolium salts (309) have been patented for use in electrochromic electrodes which are used in display devices <89JAP01230026) and tetrazolium salts have also been developed for cell bioassays for neurotoxins active on voltage-sensitive sodium channels <93MI 417-03). Tests for inhibition of corrosion of zinc and brass carried out on 5-aminotetrazole showed it to be ineffective relative to other azoles <86MI 417-01). A number of tetrazoles including the 5-amino, 5-methyl, and 5-phenyl derivatives have been separately incorporated into surfactants used for corrosion inhibition with copper in water <9lMl4l7-07). Photopolymerizable resin compositions which are highly resistant... 

One of the oldest methods to get insight into molecular structure, the study of acid-base properties, is today in rapid development. This is particularly true for the azoles due to the following reasons. 

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

The development of the single enantiomer azole within the family of compounds used for gastrointestinal treatments is exemplified by Astra-Zeneca s Esomeprazole (a potent gastric acid secretion inhibitor) (Eigure 1.54). This development gave the impetus for the search for industrial chiral sulfoxidation catalysts. 

The biological activity of azoles and their derivatives (indoles, purines, etc.) and their abundance as structural motif in natural products made them a prime target and test ground in the development of catalytic transformations. This chapter is mainly dedicated to the reactions of monocyclic five membered heterocycles and indole. The chemistry of other condensed systems of importance, such as purines, is discussed in Chapter 8. 

The selective arylation of azoles, including imidazole, was achieved by Sames. Under the developed conditions, including the use of magnesium oxide as base, imidazole was arylated in the 4-position selectively, while the addition of a stoichiometric amount of copper(I) iodide led to the reversal of the regiochemistry, resulting in the selective formation of 2-phenylimidazole (6.89.),120... 

P Csl/rnoIfK f 3)- W s obt ic d by H nry(Rff 2) on heating 1-formamido-3-nitroguanidine with anhyd NaaCOa in a small amt of water for 25 min according to the procedure developed by J.Thiele K.Heidenreich,Ber 26, 2599(1893) for the prepn of aiuinoinethyicrx-azole. The reaction may be represented as follows ... 

---