Piperidino-Hydrocarbon compounds as novel non-Imidazole histamine H3-Receptor antagonists Original Research Article

In search for novel non-imidazole histamine H3-receptor antagonists, piperidino-hydrocarbon compounds were synthesized using the known non-imidazole histamine H3-receptor antagonist FUB 637 (3-phenylpropyl 3-piperidinopropyl ether) as lead structure. Piperidino-alkyl derivatives containing highly flexible side chains (2, 4–7) were prepared via N-alkylation. Compounds containing unsaturated alkyl groups were synthesized in order to investigate the impact of rigidifying the side chain (8–16). Terminal alkynes were prepared by alkylation of lithium acetylide-ethylenediamine complex, disubstituted alkynes were synthesized by alkylation of the appropriate acetylene in the presence of n-butyllithium-N,N,N′,N′-tetramethylene-ethylene-diamine complex. The novel compounds were investigated in an in vitro functional assay on the guinea-pig ileum, in which N-(7-phenylhept-3-ynyl)piperidine (14) proved to be of good potency in this class (pA2=7.21). In an in vivo assay the compounds were additionally screened for their abilities to influence central H3-histaminergic neuron activity in mice with regard to their oral availabilities and distribution properties. In this screening, N-pent-4-ynylpiperidine (9) and N-hex-5-ynylpiperidine (10) proved to be highly potent and orally available histamine H3-receptor antagonists. The ED50 values for 9 and 10 were 1.3 and 1.4 mg/kg po, respectively, which is in the potency range of the reference antagonist thioperamide.