SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF DUAL HISTAMINE H-2 AND GASTRIN RECEPTOR ANTAGONISTS WITH DECREASED HYDROPHOBICITY

In order to study structure-activity relationships of the previously r eported dual histamine H-2 and gastrin receptor antagonists and also t o improve their low oral absorbability, we tried two chemical modifica tions. One tried to decrease the high hydrophobicity of the parent hyb rid compounds to an appropriate level by incorporating a hydrophilic g roup into the molecule and the other by replacing the more hydrophobic groups with less hydrophobic ones. The former compounds (type I) invo lved hybrid compounds with a hydroxyl group at a position of a spacer, a piperidine moiety of H(2)A, or a phenyl ring at the C-5 of the benz odiazepine skeleton as well as those with a free carboxyl group in the piperidine moiety of H(2)A. The latter (type II) involved hybrid comp ounds with the C-5-phenyl group replaced with either a methyl group or hydrogen atom. Among them, only a type I compound, oxy)propylcarbamoy l]ethylcarbamoyl}methyl)carbamic acid ,3-dihydro-1H-1,4-benzodiazepin- 3-yl]ureido}benzyl ester (18), showed potent dual histamine H-2 and ga strin receptor antagonistic activity, whereas others resulted in a sig nificant decrease of histamine H-2 receptor antagonistic activity. The in vivo gastric acid antisecretory activity of 18 evaluated by Schild 's rat method, however, did not suggest any notable improvement in ora l absorbability. (C) 1997 Elsevier Science Ltd.