Synthesis and evaluation of sulfur-containing glutethimide derivatives for aromatase and desmolase inhibitory activity.

Novel sulfur-containing glutethimide derivatives, substituted with either thiol or methylsulfide groups in the ortho/para positions of the aromatic ring, were synthesized and tested for both human placental aromatase and bovine adrenocortical desmolase inhibitory activities. The synthesis was achieved by the chlorosulfonation of gluthethimide, which yielded a 3:1 mixture of the para to ortho sulfonyl chlorides 2a/b. The sulfonyl chlorides of gluthethimide were reduced with Zn/H2SO4 to give the thioglutethimides 3a/b, which in turn were methylated with MeI/EtOH to give the corresponding methylsulfides 4a/b. In comparison to aminoglutethimide (AG), 3a/b and 4a/b were weak inhibitors of aromatase, with 3a/b being more potent than 4a/b. Aromatase inhibition by the thiol compound was pH-dependent; 3a/b was most potent at higher pH (7.4) than at lower (6.6). This suggested that the thiolate form of 4 coordinates with the ferric heme of aromatase. Likewise, both 3a/b were less potent at inhibiting bovine adrenal desmolase than AG. Possible reasons for the surprisingly poor aromatase inhibitor activity of these compounds are discussed.

Evaluation of commercial and newly-synthesized amine accelerators for dental composites.

The characteristics of newly synthesized tertiary aromatic amines as accelerators for restorative resins have been evaluated. Comparison of the composites prepared with these and presently used accelerators indicate that resins formulated with 4-N,N-dimethylaminophenylacetic acid, its methyl ester or N,N-dimethylaminoglutethimide have properties generally better than comparable resins prepared with commercially used amines.

Identification and synthesis of a methylated catechol metabolite of glutethimide isolated from biological fluids of overdose victims.

Urine samples from victims severely intoxicated by glutethimide were hydrolyzed enzymatically. TLC, GLC, and mass spectral analyses revealed a methylated catechol metabolite of the parent drug. Two synthetic pathways are described for the preparation of 2-ethyl-2-(3-methoxy-4-hydroxyphenyl)glutarimide and 2-ethyl-2-(3-hydroxy-4-methoxyphenyl)glutarimde. Comparisons of GLC and mass spectral data to a compound isolated from the body fluids of glutethimide overdose victims conclusively identified a new 3-methoxy-4-hydroxyphenyl metabolite of glutethimide in humans.

Definitive characterization of the para-hydroxyphenyl metabolite of glutethimide in human urine.

The compound, 2-ethyl-2-(4-hydroxyphenyl)-glutarimide was prepared synthetically. Spectral data is presented which identifies this compound to be a metabolite of glutethimide isolated from enzymatically hydrolyzed human urine, following an overdose of the parent drug. New data supporting the structure of a minor metabolite, 2-ethyl-2-(3-methoxy-4-hydroxy)-glutarimide, is considered. Finally, gas chromatographic techniques have been perfected and are presented which yield complete purification of new metabolites of glutethimide.

Synthesis of an active hydroxylated glutethimide metabolite and some related analogs with sedative-hypnotic and anticonvulsant properties.

Two synthetic pathways are described for the preparation of 4-hydroxy-2-ethyl-2-phenylglutarimide (2), an active hydroxylated metabolite of glutethimide (1). Fourteen other glutethimide analogs were also synthesized and tested for biological activity. Most of the analogs exhibited sedative-hypnotic properties and compound 2 possessed the greatest activity compared to the parent drug. 4-Amino-2-ethyl-2-phenylglutarimide and 4-hydroxy-2-ethyl-2-phenylglutaconimide (13) exhibited the greatest potential as anticonvulsant agents. The structure-activity relationships of the series are discussed.