Avermectins milbemycin derivatives

JD Bu Lock, AC Goudie, KS Holdom, SP Gibson. New antiparasitic avermectin and milbemycin derivatives. Eur Pat Appl 214 731A, 1986. 

Althouj h the concern of this publication is agricultural pest mana ent, this article will review some of the animal and human he th data, since the major impact of the avermectins lies in that area, and crop protection is of secondary importance. Currently two avermectin derivatives, ivermectin and avermectin Bl, are commercially available for animal health applications. A third one, doramectin, is under development by Pfizer (FIGURE 1). Avermectin Bl, with the generic name abamectin, is the major and most important product of the fermentation of Streptomyces avermitilis. It also serves as the starting material for the chemical conversion to ivermectin via selective hydrogenation of the 22,23 double bond. Milbemycin derivatives have only recently become commercially available. Milbemycin A /A has just been introduced in Japan for crop protection,... 

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different stmctural features and biological properties, moxidectin and milbemycin oxime, were more recentiy introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

Included in the class of macrocyclic lactones are avermectins and milbemycins, which are fermentation products possessing a 16-member cyclic lactone, a spiroketal moiety, and a disaccharide unit. Abamycin, ivermectin, doramectin, and eprinomycin are the avermectins most often available for anthelminthic treatment of livestock, whereas moxidectin is a milbemycin with worldwide acclaim as a cattle anthelminthic. Other anthelminthics currently used in food-producing animals are clorsulon, which is a benzenesulphonamide derivative praziquantel, which is a racemate derivative of pyrazino-isoquinoline and hygromycin B, which is an aminoglycoside antibiotic that exhibits anthelminthic properties. 

Little is known about the nervous systems of cestodes and trematodes except that they probably differ from those of nematodes, since milbemycins and avermectins have no effect on them. However, a highly effective anti schistosomal and antitapeworm agent, praziquantel (see Chapter 54 Clinical Pharmacology of the Anthelmintic Drugs), is known to enhance Ca2+ influx and induce muscular contraction in those parasites, though it exerts no action on nematodes or insects. Some benzodiazepine derivatives have activities similar to those of praziquantel these activities are unrelated to the anxiolytic activities in the mammalian central nervous system. The nerves and muscles in schistosomes and tapeworms are thus interesting subjects for future chemotherapeutic studies. 

In the syntheses of fragments of the antiparasitic compounds avermectins or milbemycins selenocycloetherification was used for the construction of a highly substituted hexahydroben-zofuran derivative (Table 8, entry 8)29. The intramolecular cyclization of a cyclohexadienyl hydroxymethyl ketone with phenylselenenyl chloride proceeded stereoselectively in a 1,4-fash-ion resulting in an anti orientation of oxygen and selenium. This was followed by oxidation and rearrangement. 

Like avermectins, the milbemycins have also undergone extensive molecular modifications. A number of synthetic milbemycins have been found to possess a wide-spectrum of parasiticidal and insecticidal activities [67-83]. The structure-achv-ity analysis would indicate that the milbemycins having different functional groups at positions 13,14 and 5 generally retain biological activity. The important milbemy-cin derivatives thus prepared include 13-substituted milbemycins of the type 31 [64,73-75] and 32 [76-78], 14-substituted milbemycins (33) [79], 5-keto/oximinomilbe-mycins (34) [81,82], 35 [80] and 36 [83]. 

The avermectins, which possess potent anthelmintic and insecticidal activities, have structural features similar to the milbemycins. The C-15 to C-28 spiroketal-containing unit (690) of avermectin Bia aglycone (691) is s)mthesized in optically pure form by coupling L-malic acid-derived lactone 687 with D-glucose-derived acetylene 688. Partial reduction of the... 

First structure-activity relationships relating to crop protection targets were reported by Fisher in 1984 [47]. This study showed that avermectin Bia was somewhat more active then mUbemydn D against Tetranychus urticae, Hdiothis virescens, and Mdoidogyne incognita. As milbemycin D can be viewed as the 22,23-dihydro-13-desoxy derivative of avermectin Bib, this comparison reflects the influence of the disaccharide portion of avermectins on their activity as pesticides. 

The dioxaspiro [5,5j undecane (45), a building block for the anti-parasitic agents milbemycin and avermectin, has been constructed in enantiomerically pure form from the dideoxy-sugar anhydride (46), which yields the phosphonium salt (47) on treatment with triphenyl-phosphonium tetrafluoroborate the ylide derived from (47) was... 

Avermectins and milbemycins have been reviewed. A total synthesis of avermectin 31 has been carried out from non-carbohydrate precursors, using a 2-hydroxypropanal derivative to synthesize the oleandrose unit. Avermectin analogues having spacer units between the glycone and aglycone are mentioned in Chapter 3. 

---