- Synthesis and antifungal activity of new azole derivatives containing an N-acylmorpholine ring
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A series of azole derivatives carrying an N-acylmorpholine ring are described. The compounds were chemically designed to simulate the lanosterol D ring, taking advantage of the conformational preferences of 2-alkyl-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. Only the (5R,6R) isomers showed antifungal activity. Cyclic hemiacetal (-)-39a (UR-9746) and cyclic ether (-)-41 (UR-9751) were selected for further development. In vitro, (-)- 41 was clearly more active than (-)-39a and somewhat less active than the acyclic counterpart (-)-7. In vivo activity was assessed by a systemic (mouse) and a vaginal (rat) candidosis model. In the former, (-)-39a, (-)- 41, and (-)-7 at 1 mg/kg given 1, 4, and 24 h postinfection displayed 90- 100% protection from mortality 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 test. 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-42427 and (-)-7 and superior in potency to (-)-41 and fluconazole in this model. Preliminary 28-day toxicity tests at 100 mg/kg/day po in rats indicated no or very mild adverse effects for the two UR compounds.
- Bartroli,Turmo,Alguero,Boncompte,Vericat,Garcia-Rafanell,Forn
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p. 3918 - 3932
(2007/10/03)
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- Orally active azole derivatives
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The present invention relates to new orally active azole derivatives with antifungal activity of formula I STR1 wherein: X is CH or N; Ar represents phenyl substituted with halogen and/or trifluoromethyl; Z is --C(=O)-- or --SO2 --; R1 is CN, CO2 H, CO2 R7, CONR8 R9 or CH2 Y and then R3 is hydrogen, or R1 together with R3 forms a ring of formula I' STR2 wherein B is O, hydroxy or hydrogen; R4 is C1-4 alkyl; R5, R6, R8 and R9 are hydrogen or C1-4 alkyl; Y is --OH, --OR7, --OC(=O)R7, --NR8 R9, --NHC(=O)OR7 ; R7 is C1 -C4 -alkyl, phenyl-C1 -C4 -alkyl or optionally substituted phenyl; when Z is --C(=O)--, R2 is optionally susbtituted phenyl, or naphtyl; when Z is --SO2 --, R2 is C1-4 alkyl, phenyl-C1-4 -alkyl or optionally susbtituted phenyl.
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- Novel orally active antifungal agents
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The present invention relates to novel orally active antifungal agents of general formula Iwherein R1 represents hydrogen and R2 represents hydrogen or C1 4 alkyl, or R1 and R2 together represent a group -(CH2)-; p is 0 or 1, and the salts and solvates thereof.
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