Avermectins derivatives

Table III. Activity of Avermectin Derivatives against Adult Gastrointestinal Helminths of Experimentally Infected Sheep on Oral Administration.

A mild procedure for the appendage of MOM groups to acid-sensitive substrates is illustrated by the protection of the allylic alcohol in Avermectin derivative 259.1 using [(methoxymethyl)thio]-2-pyridine (259 2) sitver(I) Inflate and sodium acetate in THF at room temperature [Scheme 4.259],479 Primary secondary and tertiary alcohols and phenols are methoxymethylated in good yield though phenols are slower to react. Reagent 259.2 (bp 66 °C/0.088 kPa) is easily prepared in 75% yield by the reaction of pyridine-2-thiol with dimethoxy-methane activated by trifluoroborane etherate. 

Davies et al. [378b] studied the bioconcentration of ivermectin (22,23-dihy-droavermectin Bj) in mussels Mytilus edulis). Ivermectin has been proposed as a chemotherapeutant for the treatment of farmed salmon infected with sea lice. The commercial ivermectin contains two avermectin derivatives at least 80% of 22,23-dihydroavermectin Bj (C48H74O14 molecular mass 874.5 g mol 0 and not more than 20% of 22,23-dihydroavermectin Bjb (C47H72O14, molecular mass 860.5 g mol 0- Both compounds possess nearly the same molecular dimensions with the same cross-section of ca. 25 A as avermectin Bj. The water solubility of ivermectin is low, between 6 and 9 pg 1. For comparison, the solubility of hexachlorobenzene (HCB) in water is 5 pg h. ... 

Transesterification can be used to cleave the acyl group from an ester to release the alcohol. The mildness of the reaction conditions enables chemoselective transformation. A siloxy group /S to a ketone group was not eliminated (Eq. 225) [524], and formation of an epoxide from the unprotected bromohydrin did not occur (Eq. 226) [525]. Similarly, in the synthesis of an avermectin derivative, delactonization was carried out by the titanium-based method as shown in Eq. (227) [526]. 

Meinke, P.T., O Connor, S.P., Mrozik, H., and Fisher, M.H., Synthesis of ring-contracted, 25-nor-6,5-spiroketal-modified avermectin derivatives. Tetrahedron Lett., 33, 1203, 1992. 

The Avermectin derivative was protected under the illustrated mild and nearly neutral conditions. The reagent is easily prepared from the thiol and CH2(OMe)2 with BF3-Et20 activation. 

A systematic approach by scientists at Pfizer using a mutant of S. avermitilis devoid of branched chain 2-oxo acid dehydrogenase, which blocks the fermentation of 2 -methylbutyrate, with the addition of a wide variety of carboxylic acids leads to avermectin derivatives with a modified C-25 side chain (Scheme 18)... 

A Pfizer group evaluated a wide range of avermectin derivatives for flea activity in an in vitro feeding screen using the cat flea Ctenocephalides felis, which... 

Omura, S., Sunazuka, T., Turberg, A., VonSamson-Himmelstjerma, G., Hansen, O., and Harder, A. (2000). Preparation of avermectin derivatives as antiparasitic agents. PCT/JPOO/0069, The Kitasato Institute. 

Table 29.6.4 shows the acaricidal and insecticidal activity of milbemectin, as described by Aold et al. [50]. Except for effects against some insects (Thrips and some Lepidoptera), milbemectin is mainly an acaricide. This is consistent with the structure-activity relationships observed with avermectin derivatives [28]. In general, compounds with Upophilic substituents on Cl 3 (or unsubstituted ones) are highly active, while polar substituents diminish the activity (cf Schemes 29.6.3 and 29.6.4). 

Scheme 29.6.5. Activity of 4"-amino-avermectin derivatives against Tetranychus urticae (T.u.) and Spodoptera eridania (S.e.), LC90 in ppm R = C2H5 (>80%) and CH3 (<20%).

Chemical derivatization and stability aspects of selected avermectin derivatives known for their action against a broad range of nematode and anthropod animal parasites 12CPB931. 

Ozonolysis of a silylated avermectin derivative gave improved access to oleandrosyloleandrose (49), and the compound... 

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,... 

Meinke, P. T. O Connor, S. P. Mrozik, H. Fisher M. H. Synthesis of Ring-Contracted 25-nor-6,5-Spiroketal-Modified Avermectin Derivatives. Tetrahedron Lett. 1992 33 1203-1206. 

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