Glutarimides, 2,6-dioxopiperidines are compounds that rarely occur in natural
sources, but so far isolated ones exert widespread pharmacological
activities, which makes them valuable as potential pharmacotherapeutics.
Glutarimides act as androgen receptor antagonists, anti-inflammatory,
anxiolytics, antibacterials, and tumor suppressing agents. Some synthetic
glutarimide derivatives are already in use as immunosuppressive and sedative
(e.g., thalidomide) or anxiolytics (buspirone) drugs. The wide applicability
of this class of compounds, justify the interest of scientists to explore new
pathways for its syntheses. General methods for synthesis of six-membered
imide ring, are presented in this paper. These methods include: a) reaction
of dicarboxylic acids with ammonia or primary amine, b) reactions of
cyclization: amido-acids, diamides, dinitriles, nitrilo-acids,
amido-nitriles, amido-esters, amidoacyl-chlorides or diacyl-chlorides, c)
adition of carbon-monoxide on a,b-unsaturated amides, d) oxidation reactions,
e) Michael adition of active methylen compounds on methacrylamide or
conjugated amides. Some of the described methods are used for closing
glutarimide ring in syntheses of farmacological active compounds sesbanimide
and aldose reductase inhibitors (ARI). Analyses of the geometry, as well as,
the spectroscopic analyses (NMR and FT-IR) of some glutarimides are presented
because of their broad spectrum of pharmacological activity. To elucidate
structures of glutarimides, geometrical parameters of newly synthesized
tert-pentyl-1-benzyl-4-methyl-glutarimide-3-carboxylate (PBMG) are analyzed
and compared with the experimental data from X-ray analysis for glutarimide.
Moreover, molecular electrostatic potential (MEP) surface which is plotted
over the optimized geometry to elucidate the reactivity of PBMG molecule is
analyzed. The electronic properties of glutarimide derivatives are explained
on the example of thalidomide. The Frontier Molecular Orbital (FMO) and their
energies are presented, as well as the energy gap between them.
Glutarimides: Biological activity, general synthetic methods and physicochemical properties
