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)benzamide, four optical isomers, (2S, 4S)-1 (TKS159), (2S, 4R)-25, (2R, 4S)-26 and (2R, 4R)-27, were prepared from optically active 4-amino-1-ethyl-2-hydroxymethylpyrrolidine di-p-toluenesulfonate [(2S, 4S)-14, (2S, 4R)-17, (2R, 4S)-20 and (2R, 4R)-23, respectively]. The requisites, (2S, 4S)-14, (2S, 4R)-17, (2R, 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 the benzamide derivatives, four optical isomers, (2S, 4S)-1, (2S, 4R)-25, (2R, 4S)-26 and (2R, 4R)-27, showed a relatively potent affinity for 5-hydroxytryptamine 4 (5-HT4) receptors in a radioligand binding assay ([3H]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-ethyl-2-hydroxymethyl-4-pyrrolidinyl]benzamide (1).