New Alkoxypyridine‐sulfonamides: Synthesis, Biological Evaluation, and Physicochemical Properties

Abstract

AbstractAs a further phanmacomodulation of benzamide derivatives, two structural modifications were introduced by synthesizing pyridinesulfonamides 5 and 6 (Scheme). The pharmacological profile of substituted benzamides such as metoclopramide (2) is not retained in the pyridine‐sulfonarm'des 6: the latter have very low toxicity but do not exhibit any affinity for D2 and 5‐HT2 receptors, and gastrointestinal prokinetic activity is weak (Table 3), Lipophilicity does not seem to be a determining factor for this lack of activity. A conformational analysis shows that the sulfonamide group in 6 is rather unfavorable for an intramolecular H‐bond formation when compared to the carboxamide group of, e.g., 2. Nevertheless, the interaction remains possible and leads to a stable conformation (Fig. 1, Table 5.) Moreover, the sp3 character of the sulfonamide N‐atom of 6 modifies the relative spatial orientation of one substituent in relation to each of the others. This feature seems to be more important for the observed very low activity than the H‐bond formation itself.