Syntheses and biological activities of 13-substituted avermectin aglycons.

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.

Novel analgesic-antiinflammatory salicylates.

5-(2,4-Difluorophenyl)salicylic acid, diflunisal (25), is the best compound, in terms of both efficacy and safety, from over 500 salicylates investigated in our laboratories. It is a chemically distinct, nonacetylating salicylic acid, more active than aspirin as an analgesic and antiinflammatory agent and superior in duration of action and therapeutic index. Some recent clinical and biochemical observations are briefly discussed.

4-amino-6-(trichloroethenyl)-1,3-benzenedisulfonamide, a new, potent fasciolicide.

The synthesis and fasciolicidal activity of 4-amino-6-(trichloroethenyl)-1,3-benzenedisulfonamide are reported. A single dose of 15 mg/kg was effective in removing over 90% of immature Fasciola hepatica from sheep (6 weeks after infection) and calves (8 weeks after infection). A 2.5 mg/kg dose removed over 90% of mature (16 weeks old) liver fluke from sheep. Single oral doses up to 400 mg/kg were tolerated by sheep without gross toxic symptoms.