Benzoxazines. II. Synthesis, Conformational Analysis, and Structure-Activity Relationships of 3, 4-Dihydro-2H-1, 4-benzoxazine-8-carboxamide Derivatives as Potent and Long-Acting Serotonin-3 (5-HT3) Receptor Antagonists

A series of 3, 4-dihydro-2H-1, 4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activities by means of assays of 5-HT3 receptor binding and the ability to antagonize the von Bezold-Jarisch reflex in rats. Replacement of the 1, 4-benzoxazine ring with a 1, 4-benzthiazine ring or seven-membered ring (i.e., 1, 5-benzoxepine or 1, 5-benzthiepine) resulted in decreased affinity for 5-HT3 receptor. Introduction of substituents at the 2 position of the 1, 4-benzoxazine ring increased the antagonistic activities (dimethyl>methyl>dihydro>phenyl). The compounds bearing a 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety as the basic part of 3, 4-dihydro-2H-1, 4-benzoxazine-8-carboxamide derivatives were equipotent to those bearing 1-azabicyclo[2.2.2]oct-3-yl moiety. The 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety was confirmed to adopt a boat-chair conformation on the basis of both NMR studies and X-ray analysis. In this series, endo-6-chloro-3, 4-dihydro-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2, 2, 4-trimethyl-2H-1, 4-benzoxazine-8-carboxamide showed the highest affinity for 5-HT3 receptors (Ki=0.019 nM), and a long-lasting 5-HT3 receptor antagonistic activity as evidenced by antagonism to the von Bezold-Jarisch reflex in rats. Such a long-lasting 5-HT3 receptor antagonism would be attributed to the introduction of both two methyl groups at the 2 position of the benzoxazine ring and the 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety, which adopts the boat-chair conformation.