A general synthetic method suitable for the introduction of deuterium or tritium in buspirone type anxiolytic agents

Abstract

SUMMARYIn recent years, a number of putative non-benzodiazepine anxiolytic agents incorporating the 4-aminobutylimide or sulfonamide-imide linkage have been reported and at least two of these, buspirone and gepirone, have been shown to have anxiolytic activity in man. In order to study the metabolism, body distribution and binding affinities of this class of compound, it was of interest to devise a precursor which could be specifically labelled with tritium to high specific activity. We have devised a synthetic route to the corresponding but-2-ynyl and but-2-enyl analogs of gepirone and have converted the latter to dideuterogepirone as an example of the methodology. Thus the method chosen has been found to be practical and is believed to be of sufficient generality to enable the synthesis of a variety of derivatives of this type containing either two or four atoms of label. Furthermore, by appropriate choice of reagents, incorporation of 14C into these compounds may be achieved.Key words: 4-Aminobutylimides, Anxiolylics, 3H or D. Gepirone INTRODUCT IONIn recent years, a number of new pharmacological agents in which a 4-pyrirnidinylpiperazine group is linked to an imide-(1 -3) or sulfonamide-hide (4) moiety by a saturated, four-carbon linker have been found to possess pharmacological properties indicative of anxiolytic activity in man distinct from the activities of classical benzodiazepine anxiolytics. These properties, including freedom from benzodiazepine-related side effects, such as abuse potential and interactions with alcohol, have engendered much research into the mechanism of action of such agents and to the clinical investigation of a number of related derivatives@, 6). To this end, syntheses of specifically labelled 4C-and 5N-buspirone (7) , tetradeuterated buspirone (8) and Vitiated ipsapirone (9) have been reported. In the process of similar studies in our laboratories, it became of interest to study the receptor binding properties of compounds of this type and thus to synthesize agents specifically labelled with tritium at a known site for this purpose. It was also of interest to devise a synthetic methodology of general utility which could be utilized for the synthesis of analogous compounds. Finally, we hoped to incorporate more than one atom of label into such molecules so that high specific activity could be achieved. Reduction of an olefin (or an acetylene) with tritium provides a convenient, high yield method for accomplishing these objectives and can often be 0362 -4803/89/060701-06$05 .OO 0