Substituted benzamides with conformationally restricted side chains. 5. Azabicyclo[x.y.z] derivatives as 5-HT4 receptor agonists and gastric motility stimulants

Abstract

The syntheses of benzamides containing azabicyclo[x.y.z] side chains and their 5-HT4 receptor agonist and 5-HT3 receptor antagonist properties are described. These compounds were designed to mimic higher energy conformations of quinolizidine and indolizidine. High potency was achieved for both activities although an exactly paralleling SAR was not apparent. Introduction of O and S resulted in only marginal differences in potency which was more apparent for 5-HT3 antagonism. The introduction of a methyl group alpha to the basic nitrogen resulted in a reduction in 5-HT4 receptor agonist potency. Renzapride (5f) was identified for further evaluation for which both enantiomers had an identical pharmacological profile, as did an azatricyclic 9b, which contained a combination of the steric bulk of the two separate enantiomers.

5‐HT4 Receptor Ligands: Applications and New Prospects

“…18 In contrast with the reference compounds in the field such as MDL 72222 19 and ICS 205-930 20 the amidic derivatives were more potent than the corresponding esters. On the other hand, like benzamides such as zacopride 21 or renzapride 22 the hydrogen bond between the NH amidic and the carbonyl group of benzimidazolone ring stabilised the coplanar conformation. In contrast with ondansetron, these compounds were capable of enhancing the electric-field stimulated contraction of the intestine and possessed gastrokinetic properties.…”

Design and Synthesis of Naphthalenic Derivatives as Potential Inhibitors of Hydroxyindole-<I>O</I>-methyltransferase

“…To obtain unsubstituted butyric acid 9c (Figure 3; Table 1), we used the same method as for the synthesis of methoxylated intermediates (Leclerc et al 1998); the acid precursor was esteri®ed with methanol and thionyl chloride (Brenner & Huber 1953) (Figure 3). Ester 5a was reduced with lithium aluminium hydride to alcohol 6a that reacted with methane sulphonyl chloride to give mesylate 7a (King et al 1993). Nucleophilic displacement of Figure 2.…”

“…mesylate 7a with potassium cyanide in DMSO provided nitrile 8a (King et al 1993). Alkaline hydrolysis of 8a gave propanoic acid derivative 9a (Compagnon & Miocque 1970) which was transformed by the same route to butyryl homologue 9c.…”

Pyrrolizidine Esters and Amides as 5-HT4 Receptor Agonists and Antagonists

“…The Beecham group then also employed a pyrrolizidine scaffold. 28,29 More recently, the 5-HT 4 receptor agonist meso-pyrrolizidine 5 (SK-951) has been described which is a potent gastrointestinal prokinetic agent in rats and dogs. 30,31 Our own successful approach employing the pyrrolizidine moiety led to the potent 5-HT 4 receptor partial agonist 12a 32 by attaching the pyrrolizidine to the traditional aromatic moiety of prokinetic benzamides 1 and 2.…”