Synthesis and structure activity studies of novel H3-receptor histamine antagonists

This thesis describes various novel approaches to the design and synthesis of potential H3-receptor histamine antagonists. The goal is to provide the basis for the design of a nontoxic, brain penetrating compound which could be used as a prototype drug for investigative clinical studies in humans. The novel compounds were submitted for in vitro testing on rat cerebral cortex as potential antagonists. The results were used as a guide to making further modifications of structures. Thioperamide (N-cyclohexyl-4-(4-imidazolyl)-1-piperidine carbothioamide), the published first selective H3 antagonist, was taken as a lead compound. Early in the work, the synthesis of 4-(4-piperidyl)imidazole, the key intermediate to thioperamide, was investigated and a modified and reliable route was established. This is a useful intermediate for the preparation of other analogues of thioperamide. One such novel analogue was prepared, where the cyclohexyl thiourea was replaced by a substituted aminopyridyl moiety leading to a highly potent antagonist displaying higher in vivo activity than thioperamide. Ring-opened analogues of thioperamide in which the piperidyl imidazole was replaced by histamine or a thiomethyl homologue showed a reduction in activity. Histamine was used as the chemical starting material to prepare novel derivatives, in which the primary amine was coupled with different heterocycles, via aromatic nucleophilic substitution. Various substituents in different positions of the heterocyclic ring were investigated by introduction of groups such as NO2, N-oxide, NH2, CO2CH3, CF3, CH3 and Cl. The possibility that they affected activity through an electronic effect was studied by seeking Quantitative Structure Activity Relationships. Novel substituted heterocyclic derivatives of N'-methylhistamine and 2-pyridyl ethylamine were synthesised. The heterocyclic ring moiety was also replaced by a substituted phenyl group. Other compounds with the methylthioethylamine side chain replacing that of histamine have been prepared. The side chain amino NH of some of the histamine pyridyl derivatives was replaced with sulphur. One of these compounds was as active as thioperamide. A shorter chain analogue was also prepared. In vitro testing results showed that all these compounds are antagonists at the histamine H3-receptor. The most potent antagonists were tested in vivo