Effect of Linking Bridge Modifications on the Antipsychotic Profile of Some Phthalimide and Isoindolinone Derivatives

Abstract

A series of phthalimide and isoindolinone derivatives bridged to 4-(1,2-benzisothiazol-3-yl)-1-piperazinyl was prepared. The compounds were evaluated in vitro at dopamine D2 and serotonin 5-HT1a and 5-HT2 receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. The effects of bridge length and conformation on the biological activity of these potential antipsychotic agents are discussed. A four-carbon spacer provided optimal activity within the two homologous series. Conformational investigations of the lead compound, isoindolinone 2, were conducted in an attempt to account for the superior activity observed for the butyl derivatives. On the basis of NMR and molecular modeling studies, two types of folded structures were proposed and several conformationally restrained analogues were synthesized. In general, restrictions incorporated within the linking bridge were detrimental to activity.

Observations on the direct amidocyclopropanation of alkenes using organozinc carbenoids

“…All of the carbenoid precursors could be employed in the amidocyclopropanation reaction with the exception of diethoxymethylphthalimide 14. Since the phthalimide functional group is known to be reduced under dissolving metal conditions, 14 this observation is perhaps unsurprising. As anticipated, the amidocyclopropanation of electron-rich alkenes (Entries 8 and 10) proceeded in higher yield than the amidocyclopropanation of electron deficient alkenes (Entry 9) and in the cyclopropanation of diene 38 (Entry 23), chemoselective cyclopropanation of the more electron-rich alkene was observed.…”

Synthesis and biological evaluation of phthalimide dithiocarbamate and dithioate derivatives as anti-proliferative and anti-angiogenic agents-I

“…Phthalimide (1) with its (NH) acidic hydrogen underwent reaction with formaldehyde affording the intermediate hydroxymethyl derivative 2 that was subjected to chlorination using thionyl chloride to furnish the chloromethylene derivative 3 with perfect yields according to the reported procedure [26]. Similarly, N-chloroethylene phthalimide derivative could be prepared by condensation of phthalic anhydride (4) with ethanolamine to construct the hydroxyethyl derivative 5 that is to be subsequently halogennated to afford chloroethyl derivative 6 [27][28][29]. Alternatively, N-bromoethylene phthalimide derivative could be prepared by the reaction of phthalimide 1 with potassium hydroxide to afford potassium phthalimide which reacted with ethylene dibromide to give bromoethyl derivative 7 [30].…”

Catalyst-free one-pot synthesis of isoindolin-1-imine derivatives via three-component reaction

“…[1][2][3][4][5] Among them, the class of isoindolin-1-imines has also received much effort due to their biological activities, such as NR2B-selective NMDA receptor antagonists, 6 thrombin receptor (PAR-1)…”