The molecular structure of itraconazole, C35H38C12-N804, has been determined from single-crystal X-ray diffraction data. The two molecules in the asymmetric unit differ mainly in the conformation of the methoxyt Internal code of the Janssen Research Foundation: R51211.Acta Crystallographica Section C ISSN 0108-2701ISSN 0108- © 1996 2226 C35H38CI2NsO4 phenylpiperazine moiety. Apart from a 180 ° rotation of the triazole ring, the geometry of the dichlorophenylethoxytriazole moiety is almost the same as the dichlorophenylethoxyimidazole geometry found in miconazole, econazole and ketoconazole.
CommentItraconazole, (I), is an oral antifungal triazole registered in most countries of the world. In comparison with miconazole and ketoconazole, itraconazole is essentially a more potent antifungal agent with a wider spectrum, a slower clearance and reduced toxicity. All antifungal azoles probably act by an identical mechanism of inhibition of the fungal cytochrome P-450 enzymes. The potency seems to be determined by the affinity and geometric orientation of the nitrogen heterocycle to the heme iron ion, by protonation of the N3 or N4 atom in the imidazole or triazole ring, and by the affinity of the non-ligand portion for the apoprotein of cytochrome P-450 (Vanden Bossche, Marichal, Gorrens, Geerts & Janssen, 1988). The crystal structure of itraconazole has been determined for comparison with the structures of ketoconazole (Peeters, Blaton & De Ranter, 1979a), miconazole (Peeters, Blaton & De Ranter, 1979b) and econazole (Freer, Pearson & Salole, 1986). The asymmetric unit contains two molecules (A and B) partly related by a pseudo-inversion centre at ca 0.25,0.49,0.25 (Fig. 1). The sec-butyl side chain is statistically disordered in both molecules implying that both the R and S configurations are present. The main difference between the two molecules is the orientation of the methoxyphenylpiperazine moiety. In molecule A, the methoxy group is almost perpendicular to the phenyl ring, whereas in molecule B, it is almost coplanar with the phenyl ring. As a consequence, the C70--O71--C72 and O71--C72---C77 angles are enlarged by ca 4 °.Each molecule contains seven rings of which the triazole and benzene rings are essentially planar with a maximum deviation of 0.014 (5) t Partial occupancies (see below). .353 (7) N51--N52 .326 (7) N51---C55 .458 (7) N51--C56 .320 (9) N52---C53 .333 (8) C53--N54 .33 (1) N54----C55 .531 (7) C56--C57 .411 (5) C57--O58 .392 (6) C57--O61 .543 (8) C57--C62 1.444 (7) O58--C59 1.518 (7) C59--C60 1.507 (9) C59---C70 1.423 (6) C60--O61 1.390 (7) C62--C63 1.387 (6) C62--C67 1.395 (8) C63---C64 1.722 (5) C63--C168 1.366 (7) C64--C65 1.377 (8) C65--C66 1.729 (6) C65---C169 1.378 (8) C66--C67 1.426 (6) C70--O71 1.404 (8)2228 C35H38C12N804 N92 -0.9180 (6) 0.2246 (3) 0.1045 (2) N93 -0.9247 (7) 0.2081 (3) 0.1730 (2O71---C72 1.384 (9) C72--C73 1.358 (8) C72---C77 1.382 (9) C73---C74 1.386 (8) C74--C75 1.384 (9) C75--C76 1.427 (8) C75--N78 1.38 ( 1 ) C76--C77 1.452 (7) N78--C79 1.434 (8) N78---C8...