Synthesis and Evaluation of Novel 2-Oxo-1,2-dihydro-3- quinolinecarboxamide Derivatives as Serotonin 5-HT 4 Receptor Agonists

distributed in humans and has a remarkable variety of physiological effects. Seven subtypes of 5-HT receptors have been reported. 5-HT4 receptors 3) modulate cholinergic nervemediated contraction in the guinea pig ileum and in the proximal colon, potentiate electrical field stimulation in the guinea pig ileum, and induce of chloride secretion in rat distal colon. These findings suggest that the 5-HT4 receptors in the gut play roles in the induction and maintenance of gastrointestinal motility, and that 5-HT4 receptor agonists activate gastrointestinal motor function and improve gastrointestinal dysfunction or conditions accompanied by motility failure. In fact, cisapride and renzapride, which stimulate 5-HT4 receptors, are reported to increase gastrointestinal motor function and to improve gastrointestinal conditions such as heartburn, anorexia, bowel pain, and abdominal distension accompanied by chronic gastritis, diabetes mellitus or postoperative gastroparesis. Three classes of compounds stimulating 5-HT4 receptors are known, 1) the indolealkylamines (5-HT, 5-methoxytryptamine), 2) the benzamides (metoclopramide, cisapride, renzapride, zacopride), and 3) the benzimidazolones (BIMU-8) (Fig. 1). Generally, these agents act on other monoamine receptors as well. For example, cisapride and metoclopramide are used clinically as 5-HT4 agonists, but both are apt to induce extrapyramidal syndrome as a result of D2 receptor antagonism. 15,16) Mosapride is modified at a tertiary amine in order to reduce extrapyramidal syndrome. There are many reports on the modification of tertiary amine moieties such as alkylamine, cyclic amine and azabicyclo structures. Among these amino moieties, azabicyclo structures exhibit potent and selective serotonin 5-HT4 receptor-stimulating activity. There are few reports, however, concerning modifications in the aromatic ring moiety of compounds stimulating 5-HT4 receptors. In the present study, we report the synthesis and 5-HT4 receptor-stimulating activity of 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives having azabicycloamine structures with the aim of finding a new class of heterocyclic compounds that stimulate 5-HT4 receptors. Chemistry Compounds 5a—e were prepared by the following synthetic pathway depicted in Chart 1. 2-Nitrobenzaldehyde 1 was condensed with diethyl malonate followed by a reduction of the nitro group to give 2-oxo-1,2-dihydro3-quinolinecarboxylate 3. Alkylation of 3 with appropriate December 2000 Notes Chem. Pharm. Bull. 48(12) 2003—2008 (2000) 2003