Synthesis and pharmacological activity of 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide (TKS159) and its optical isomers

Of 4-amino-5-chloro-2-methoxy-N-(1-ethyl-2-hydroxymethyl-4-pyrrolidinyl)ben zamide, four optical isomers, (2S,4S)-1 (TKS159), (2S,4R)-25, (2R,4S)-26 an d (2R,JR)-27, were prepared from optically active 4-amino-1-ethyl-2-hydroxy methylpyrrolidine di-p-toluenesulfonate [(2S,4S)-14, (2S,4R)-17, (2R,4S)-20 and (2R, IR)-23, respectively]. The requisites, (2S,4S)-14, (2S,4R)-17, (2 R,4S)-20 and (2R,4R)-23, were prepared from a commercially available trans- 4-hydroxy-L-proline. The absolute configurations of (2S,4S)-1 (TKS159), (2S ,4R)-25, (2R,4S)-26 and (2R,4R)-27 were spectroscopically determined. Of th e benzamide derivatives, four optical isomers, (2S,4S)-1, (2S,4R)-25, (2R,4 S)-26 and (2R,4R)-27, showed a relatively potent affinity for 5-hydroxytryp tamine 4 (5-HT4) receptors in a radioligand binding assay ([H-3]GR113808), The activities of 25-27 were less effective than that of 1 for the gastric emptying of a phenol red semisolid meal in rats. All this suggests that the most potent of the isomers was 4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-eth yl-2-hydroxymethyl-4-pyrrolidinyl]benzamide (1).