NEW POTENT AZOMETHINE PRODRUGS OF THE HISTAMINE H-3 RECEPTOR AGONIST (R)-ALPHA-METHYLHISTAMINE CONTAINING A HETEROARYLPHENYL PARTIAL STRUCTURE

The therapeutic value of histamine H-3-receptor ligands is under curre nt investigation. On the basis of recently described diaryl imine prod rugs of the histamine H-3-receptor agonist (R)-alpha-methyl-histamine (1) a series of new azomethine prodrugs containing five- and six-membe red heterocycles were synthesized and tested for their in vitro hydrol ysis rates in vivo activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fas t. On the contrary, prodrugs containing five-membered heterocycles app eared to be highly effective for the CNS delivery structure and pharma cokinetic profile was observed. Particularly -4-yl)-2-proyl]imino](1H- pyrrol-2-yl)methyl]phenol (8c), the 2-furanyl analogue 8d, and its 3-f uranyl isomer 8e proved to be equipotent to the most potent of recentl y described halogenated diaryl imine prodrug, 8c exhibited an incompar ably long lasting delivery of 1 in the CNS and can thus be regarded as a 'retard' prodrug. Assuming that a therapeutic indication of histami ne H-3-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrug, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use .