Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 1 13The four stereoisomers of Ketoconazole 4a were evaluated for theireffectiveness as inhibitors of the cytochrome P450 involved in:(a) cholesterol biosynthesis and degradation (lanosterol 14-α−demethylase and cholesterol 7-α−hydroxylase); (b) steroid hormonebiosynthesis (cholesterol side chain cleavage, progesterone 17α,20-lyase,deoxycorticosterone 11-β hydroxylase and aromatase) and (c) xenobiotictransformation (lauric acid hydroxylation and progesterone2α −, 6 β −, 15 α −, 16 α −, 21 hydroxylation) 36 .It was shown that the cis-isomers are more potent inhibitors ofmammalian lanosterol 14-α−demethylase than the diastereomeric transisomers.The cis-(2S,4R) isomer is three times more active than itsantipode 36 .The most important analogues of Ketoconazole 4a are Terconazole4b, cis- 1,4,2- (2,4-dichlorophenyl) -2- (1-ylmethyl) -1,3 -dioxolan - 4-ylmetoxyphenyl -4- (methylethyl) piperazine, a triazole ketal synthesized byJanssen Pharmaceuticals. 39In this case the heterocyclic moiety is a 1,2,4 triazole instead of theimidazole, and contains a t-butyl group instead of an acetate group inposition 4 of the piperazine.In 1995, Menarini reported the first stereoselective synthesis of (+)-or(-)-Terconazole 4b.The synthesis of both enantiomers of Terconazole employed asstarting material (2R,4R)-(+)-and (2S,4S)-(-)-bromobenzoate 4d (Fig. 1.9)which have been also used as advanced chiral intermediates for thesynthesis of both enantiomers of ketoconazole 40 . Another synthesis of theanalogues of Ketoconazole 4c has been reported in 1994 41 .Terconazole 4b has also been shown to be highly effective in vivo forthe topical treatment of various experimental models of dermatomycosisand candidiasis. It also shows some oral activity against experimentallyinduced superficial mycoses 42 .1.2.2.2 Miconazole and its analogues 5a-d.Miconazole 5a and its analogues 5b-d are shown in Fig 1.11.Miconazole 1 - [2,4 - dichloro -β- (2,4-dichloro-benzyloxy) phenyl]imidazole nitrate 5a is a phenylethyl imidazole derivative synthesized byJanssen Pharmaceuticals in 1969 43 .