title: Syntheses and biological activities of 13-substituted avermectin aglycons.
abstract: The reactions of sulfonate esters of the allylic/homoallylic 13-alcohol of 5-O-(tert-butyldimethylsilyl)-22,23-dihydroavermectin B1a aglycon (1a) were investigated. Nucleophilic substitution gave 13 beta-chloro and 13 beta-iodo derivatives, while solvolytic reaction conditions yielded 13 alpha-methoxy, 13 alpha-fluoro, and 13 alpha-chloro products. A mixture of 13 alpha- and 13 beta-fluorides was obtained upon reaction with DAST. The 13 beta-iodide gave, upon elimination with lutidine, the 8(9),10(11),12(13),14(15)-tetraene. The 13 beta-alcohol and the rearranged 15-ol 13(14)-ene and 15-amino 13(14)-ene derivatives were obtained by substitution via the allylic carbonium ion. MEM ethers 11 and 12 of the two epimeric 13-ols were prepared by alkylation with MEM chloride. In contrast, methylation of 1a with MeI and Ag2O in CH2Cl2 occurred exclusively at the tertiary 7-hydroxy group and not at the secondary 13 alpha-ol. Oxidation of the allylic alcohol 1a proceeded under Swern conditions but not with MnO2 to the 13-oxo aglycon, which was reduced by NaBH4 exclusively to the natural 13 alpha-ol, while reductive amination with NaCNBH3-NH4OAc gave the 13 alpha-amine. The methoxime derivative was obtained in the form of the two geometric isomers. Anthelmintic activities against the sheep nematode Trichostrongylus colubriformis, miticidal activities against the two-spotted spider mite (Tetranychus urticae), and insecticidal activities against the southern armyworm (Spodoptera eridania) as well as the binding constants to a free living nematode (Caenorhabditis elegans) derived receptor assay were obtained and compared to avermectin B1a, 22,23-dihydroavermectin B1a, and the 13-deoxy-22,23-dihydroavermectin B1 aglycon related to the milbemycins. None of the newly prepared derivatives exceeded the potency of the three reference compounds. Lipophilic 13-substituents such as halogen, alkoxy, and methoxime retained high biological activities in all assays, while the more polar substituents hydroxy and amino had weaker activities. Rearranged 15-substituted 13(14)-ene derivatives were completely inactive. The 13-oxo and the 12,13-dehydro analogues were only weakly active in vivo despite having good binding affinity to the receptor, possibly due to instability or poor absorption.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, Division of Merck & Co., Inc., Rahway, New Jersey 07065.
authors.forename: H
authors.initials: H
authors.lastname: Mrozik
authors.forename: B O
authors.initials: BO
authors.lastname: Linn
authors.forename: P
authors.initials: P
authors.lastname: Eskola
authors.forename: A
authors.initials: A
authors.lastname: Lusi
authors.forename: A
authors.initials: A
authors.lastname: Matzuk
authors.forename: F A
authors.initials: FA
authors.lastname: Preiser
authors.forename: D A
authors.initials: DA
authors.lastname: Ostlind
authors.forename: J M
authors.initials: JM
authors.lastname: Schaeffer
authors.forename: M H
authors.initials: MH
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000138:chemical synthesis* / Q000494:pharmacology; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000871:Anthelmintics; D007559:Ivermectin; C019264:avermectin