Avermectin acyl derivatives with anthelmintic activity

Abstract

Avermectins A2a, B1a and B2a (1, 2 and 3) were acetylated to give 4''''- and 23-acetates 4 and 5 and 4'''',23-diacetate 6 from 1, the 4''''- and 5-acetates 7 and 8 and 4'''',5-diacetate 9 from 2 and triacetate 10 from 3. Structure proof by 300-MHz 1H NMR and mass spectral fragmentation is discussed for 10. Forcing acetylation conditions generated from 1 and 3 the identical aromatic diacetate 11. Good antihelminthic activities in gerbils and sheep for 4"-acetylated derivatives 4 and 7 prompted the preparation of additional 4''''-acylated derivatives of 2 with pivaloyl, n-octanoyl, succinoyl, carbamoyl, dimethylcarbamoyl and N-acetylglycyl substituents, prepared from the 5-O-tert-butyldimethylsilyl-protected intermediate 12. Other key intermediates were the trichloroethoxysuccinoyl derivative 18 and 4-nitrophenyl carbonate 21. Antihelminthic activities against Trichostrongylus colubriformis in gerbils comparable in potency to the natural product 2 are shown by the more polar substituted derivatives 20, 23 and 27. Substitution of the 5-hydroxy group or its loss due to aromatization results in drastically reduced antihelminthic potency.