Motilides, Macrolides with Gastrointestinal Motor Stimulating Activity. : I. O-Substituted and Tertiary N-Substituted Derivatives of 8, 9-Anhydroerythromycin A 6, 9-Hemiacetal

Abstract

Chemical modifications of 8, 9-anhydroerythromycin A 6, 9-hemiacetal (1), which showed gastrointestinal motor stimulating (GMS) activity 10 times more potent than that of erythromycin A (EM-A), were undertaken to search for derivatives having stronger GMS activity and no antimicrobial activity; details are described in this and a subsequent paper. Displacement of a methyl group of the dimethylamino group of 1 with an ethyl group and an isopropyl group provided de(N-methyl)-N-ethyl-8, 9-anhydroerythromycin A 6, 9-hemiacetal (55) and de(N-methyl)-N-isopropyl-8, 9-anhydroerythromycin A 6, 9-hemiacetal (58), respectively. They showed significant GMS activity and no antibacterial activity. In particular, the GMS activity of 58 was increased to 248 times that of EM-A. EM-A and the derivatives obtained in this study mimic exogenous motilin in the dog. The name "motilide", meaning a motilin-like macrolide, is proposed for this new family of macrolide compounds.