Synthesis and Anxiolytic Activity of N-Substituted Cyclic Imides(1R*,2S*,3R*,4S*)-N-(4-(4-(2-Pyrimidinyl)-1-piperazinyl)butyl)-2,3-bicyclo(2.2.1)heptanedicarboximide(Tandospirone) and Related Compounds.

Abstract

A series of cyclic imides bearing a omega-(4-aryl and 4-heteroaryl-1-piperazinyl)alkyl moieties was synthesized and tested in vivo for anxiolytic activity. The in vitro binding affinities of these compounds were also examined for 5-HT1A receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, (1R*,2S*,-3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3- bicyclo[2.2.1]heptanedicarboximide (1: tandospirone), was found to be equipotent with buspirone in its anxiolytic activity and more anxio-selective than buspirone and diazepam. Tandospirone (1) is currently undergoing clinical evaluation as a selective anxiolytic agent.

Derivatives as 5HT1A Receptor Ligands-Past and Present

“…The launch of Buspirone led to the synthesis of several N4-(2-pyrimidinyl)piperazines containing an N1-imidobutyl substituent, as a potential third generation of anxiolytic agents [18,[76][77][78][79], such as Gepirone [18,80,81], Tandospirone [18,82,83] and Zalospirone [84,85]. In the Buspirone analogs, the 1-(2-pyrimidinyl) piperazine moiety is coupled via an alkyl chain to an amide function.…”

TRPV1 modulators: Synthesis and in vitro evaluation of 1-heteroaryl piperidinecarboxamide and piperazinylurea derivatives

“…Coupling of 1-heteroarylpiperazine 33 [20] and 34 [21] with a variety of phenyl N-aryl-carbamates 35a-f in DMSO solution provided piperazinylureas 36e44 in 64e93% yields. With some modification of reported procedures [22], phenyl N-aryl-carbamates 35a-f were synthesized upon reacting commercially available substituted anilines with phenyl chloroformate in THF solution in presence of diisopropyl ethylamine (DIPEA) as a base (Scheme 4).…”

Lewis acid free high speed synthesis of nimesulide-based novel N-substituted cyclic imides

“…[1][2][3][4][5][6][7][8][9][10][11] On the other hand N-(4-nitro-2-phenoxy phenyl) methanesulfonamide or nimesulide B (see Figure 1), a preferential cyclooxygenase-2 (COX-2) inhibitor is one of the well known non-steroidal anti-inflammatory drugs (NSAIDs) that has been utilized to treat pain and other inflammatory diseases. Because of their common antiinflammatory properties and our interest in nimesulide derivatives 12 as potential anti-inflammatory agents we decided to prepare compound C having structural features of both A and B.…”