Synthesis and anthelmintic activity of 13-alkoxymilbemycin derivatives.

The synthesis ofmilbemycin derivatives having alkyloxy groups at the C-1 3 position was studied and a series of these analogs of milbemycin A4 and A3 was prepared by the reaction of 13-iodomilbemycin with a variety of alcohols.13/?-Phenethyloxy derivatives were found to possess excellent anthelmintic activity.Especially, the activities of derivatives with TV-substituted 4-aminophenethyloxy groups were comparable to or superior to ivermectin against Nippostrongylus brasiliensis in rats.The milbemycins are a family of 16-membered ring macrocyclic lactones isolated from Streptomyces hydroscopicus1}, which are known to possess high anthelmintic, acaricidal, and insecticidal activity2).Both the native compound, which consists of a 3:7 mixture of milbemycin A3 (la) and A4 (lb), and its 5-oxime3) are nowin commercial use as agricultural chemicals and for the market of small animal health, respectively.The avermectins, which have closely related structures and biological activities to the milbemycins, are produced by a culture of Streptomyces avermitilis4).Ivermectin (Id), a mixture of 22,23-dihydroavermectin Bla and Blb, is widely used as a potent antiparasitic agent for controlling parasitic infections of livestock5*.The fundamental structural difference between the milbemycins and ivermectin is that the former lack the a-L-oleandosyl-a-L-oleandosyl group at the C-13 position.Merck chemists