Isoquinuclidine-based expectorants. Synthesis and biological activities of N-alkoxybenzylisoquinuclidines

Article abstract of DOI:10.1016/S0223-5234(97)81675-3

N-Di-, trialkoxybenzylisoquinuclidines and related compounds were synthesized and evaluated for expectorant activities. Structure-activity relationship investigations in this series showed that both the trialkoxyphenyl ring and the basic nitrogen atom at the benzylic position were necessary for activity. N-Trialkoxybenzylisoquinuclidines 7a, 7c, 7d, 7f and 7g significantly increased bronchial secretion, and ethoxy derivative 7c showed the highest activity in these compounds. The n-propyloxy derivatives 7d and 7f also accelerated bronchoalveolar surfactant secretion with about two to four times more activity than ambroxol (7d and 7f; ED₅₀ = 27.5 and 15.5 mg/kg po, respectively); however, compounds 7a, 7c and 7g were less active than ambroxol. Compounds 7d and 7f were selected for further examination. These compounds displayed antioxidant activity in vitro (7d and 7f; IC₅₀ = 48.0 and 66.0 μM, respectively). Compound 7d also showed inhibition on bradykinin- or antigen-induced airway inflammation in guinea pigs. These findings suggest that compounds 7d and 7f are potent expectorants with antiinflammatory activity.