Hypolipidemic activity of phthalimide derivatives IV: Further chemical modification and investigation of the hypolipidemic activity of N-substituted imides.

A further investigation of N-substituted derivatives of phthalimide for hypolipidemic activity has revealed that the chain length, as well as the type of substitution on the N-alkyl chain of phthalimide is critical for biological activity. In these studies the hypolipidemic activity was not improved by extending the chain length beyond five carbon atoms in the alkyl and alkanoic acid series. Imido nitrogen substituents, other than alkanoic acids, methyl ketones, and alkyl groups, caused a reduction in hypolipidemic activity, e.g., hydroxy, amino, hydroxymethyl, or carbethoxy. Reduction of the keto group in the side chain to an alcohol, as well as forming derivatives of the keto group, did not improve the hypolipidemic activity with the exception of 1-N-phthalimidobutan-3-one semicarbazone. This compound demonstrated improved hypocholesterolemic activity over phthalimide and 1-N-phthalimidobutan-3-one. Substitution of the 3-position of the aromatic moiety of phthalimide with an amino or nitro group, as well as substituting a pyridine or cyclohexyl ring for the phenyl ring, led to the loss of hypolipidemic activity.