SYNTHESIS AND ANTIFUNGAL ACTIVITY OF NEW AZOLE DERIVATIVES CONTAININGAN N-ACYLMORPHOLINE RING

A series of azole derivatives carrying an N-acylmorpholine ring are de scribed. The compounds were chemically designed to simulate the lanost erol D ring, taking advantage of the conformational preferences of 2-a lkyl-1-acylmorpholines. Three structural variables, the nature of the N-benzoyl group, the phenyl substituents, and the degree of oxidation at carbon 2 of the morpholine, were optimized for maximum activity. On ly the (5R,6R) isomers showed antifungal activity. Cyclic hemiacetal(- )-39a (UR-9746) and cyclic ether (-)-41 (UR-9751) were selected for fu rther development. In vitro, (-)-41 was clearly more active than (-)-3 9a and somewhat less active than the acyclic counterpart (-)-7. lit vi vo activity was assessed by a systemic (mouse) and a vaginal (rat) can didosis model. In the former, (-)-39a, (-)-41, and (-)-7 at 1 mg/kg gi ven 1, 4, and 24 h postinfection displayed 90-100% protection from mor tality on day 9. Compound (-)-39a was slightly more potent than (-)-41 and similar in potency to (-)-7. The three compounds were superior in potency to fluconazole and similar in potency to SCH-42427 in this te st. In the vaginal model, (-)-39a and (-)-41 given daily during 3 days after infection at 0.5 mg/kg showed high levels of protection on days 10 and 15. At 0.25 mg/kg, (-)-39a was slightly more potent than SCH-4 2427 and (-)-7 and superior in potency to (-)-41 and fluconazole in th is model. Preliminary 28-day toxicity tests at 100 mg/kg/day po in rat s indicated no or very mild adverse effects for the two UR compounds.