BENZOXAZINES .2. 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 w as synthesized and evaluated for serotonin-3 (5-HT3) receptor antagoni stic activities by means of assays of 5-HT3 receptor binding and the a bility to antagonize the von Bezold-Jarisch reflex in rats, Replacemen t of the 1,4-benzoxazine ring with a 1,4-benzthiazine ring or seven-me mbered ring (i.e., 1,5-benzoxepine or 1,5-benzthiepine) resulted in de creased affinity for 5-HT3 receptor. Introduction of substituents at t he 2 position of the 1,4-benzoxazine ring increased the antagonistic a ctivities (dimethyl > methyl > dihydro > phenyl). The compounds bearin g 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 equipoten t 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 )-2,2, 4-trimethyl-2H-1,4-benzoxazine-8-carboxamide showed the highest affini ty for 5-HT3 receptors (K-i = 0.019 nM), and a long-lasting 5-HT3 rece ptor antagonistic activity as evidenced by antagonism to the von Bezol d-Jarisch reflex in rats. Such a long-lasting 5-HT3 receptor antagonis m 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]non3-yl moiety, which adopts the boat-chair conformation.