No abstract

Evaluation of a series of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acids linked to the 2-hydroxyacetophenone pharmacophore present in the standard peptidoleukotriene antogonist FPL 55712 (1) has led to the discovery of Ro 23-3544 (7), an antagonist possessing greater potency and duration of action vs LTD4 than the standard (aerosol route of administration, guinea pig bronchoconstriction model). Interestingly, this compound also potently inhibited bronchoconstriction induced by LTB4 whereas 1 did not. Attempts to establish structure--activity relationships in this series involved modifications in the 2-hydroxyacetophenone moiety, the linking chain, and the chroman system. All variations produced analogues which were either inactive or possessed reduced potency relative to acid 7. Optical resolution of 7 was achieved by two methods. Absolute configurations of the enantiomers were determined via X-ray crystallographic analyses of an intermediate as well as a salt of the S enantiomer. Although the enantiomers exhibited similar potencies in in vitro assays and in vivo when administered intravenously, significant differences were observed in the guinea pig bronchoconstriction model vs LTC4 and LTD4 when administered by the aerosol route (S antipode 15-fold more potent). The properties of 7 have been compared with several recently reported leukotriene antagonists.

Thirty-six substituted phenyl 2-propynyl ethers and thioethers were tested for synergistic activity toward carbaryl in the housefly. The most active compounds, namely the 2,3,6-trichloro, 2,4-dibromo, 2-nitro, 3-nitro, and 2-nitro-4-chlorophenyl 2propynyl ethers lowered the LD50 for carbaryl to less than 0.1 ag per fly. Substitution with more than one nitro group or more than three halogens decreased activity, as did the introduction of an alkyl, alkoxy, or aryl group or the formation of a thioether.

Zusammenfassung. I n der Annahme, dass gewisse Aminosauren im Gewebe von Saugetieren Vorlaufer fur salkaloidische >) Tetrahydro-isochinoline sein konnten, wurden L-Dopa und dessen zwei Monomethylather mit Formaldehyd und Acetaldehyd kondensiert. Die absolute Stereochemie der erhaltenen 1-Methyl-substituierten Tetrahydro-isochinoline wurde durch Rontgen-Analyse einer Schlusselverbindung sichergestellt.

No abstract