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

Aboul‐Enein, Hassan Y.; Schauberger, Charles W.; Hansen, Alfred R.; Fischer, Lawrence J.

doi:10.1021/jm00241a019

Cited by 26 publications

(3 citation statements)

References 7 publications

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“…N-AcetylAG and nitroG were obtained by published methods (Aboul-Enein et al, 1975); the preparation of N-formylAG is described below. ComponerAts were quantified by peak area with reference to the responses to known quantities of the authentic compounds.…”

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confidence: 99%

Polymorphically acetylated aminoglutethimide in humans

Coombes¹,

Foster²,

Harland³

et al. 1982

Br J Cancer

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Summary.-The urinary excretion during 24 h of aminoglutethimide (AG) its major metabolite (N-acetylAG) and two minor metabolites (N-formylAG and nitroG) were measured in 10 volunteers given AG who had been typed for acetylator phenotype using sulphadimidine. The slow acetylators of sulphadimidine excreted more AG (mean 28% of the administered dose) than did the fast acetylators (12%), but the latter excreted more of the dose as N-acetylAG (8.8%) than did the former (3.9O%).NitroG and N-formylAG were minor urinary metabolites of AG in humans. The former was more abundant in the urine of slow acetylators (0-10% of the dose) than in that of fast acetylators (0.047%o), whereas the respective proportions of doses excreted as the N-formyl derivative (0-475 and 0-465%o) were not significantly different for the two acetylator phenotypes. These results show that AG is among those drugs that are polymorphically acetylated in humans.

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confidence: 99%

Polymorphically acetylated aminoglutethimide in humans

Coombes¹,

Foster²,

Harland³

et al. 1982

Br J Cancer

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“…The known procedures [20,21] to prepare 6 were improved by treatment of 5 with bromine in refluxing acetic acid. Further reaction of 6 with sodium azide in hot aqueous DMSO according to ref.…”

Section: Chemistrymentioning

confidence: 99%

“…To elucidate the correct relative configuration of the substance, further analyses using chromatographic methods are in preparation. Some reports in the literature showed the nitrogen of the amino group of 7 to be sufficiently nucleophilic to react with several electrophilic substances [21,23] . For instance 7 was treated by Casini et al [23] with phthalic anhydride at high temperatures without solvent to give 9.…”

Section: Chemistrymentioning

confidence: 99%

5′-Substituted Thalidomide Analogs as Modulators of TNF-α

Teubert

Zwingenberger²,

Wnendt

et al. 1998

Arch. Pharm. Pharm. Med. Chem.

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The synthesis of 5′‐substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide (5) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8. In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9, 10, and 11. All final compounds were tested in vitro for their inhibitory activity on the release of TNF‐α, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5’ of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL‐2 in vitro.

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Addition and Substitution Reactions of Nitrile‐Stabilized Carbanions

1984

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The utilization of carbanions stabilized by various electron‐withdrawing groups to effect carboncarbon bond formation occupies a central position in organic synthesis. This chapter focuses on the reactions of nitrile‐stabilized carbanions with an array of carbon electrophiles and updates another chapter along these lines in this series. Subsequent review articles have dealt with various aspects of the chemistry of nitrile‐stabilized carbanions. In this review, the reactions of nitrile‐stabilized anions are grouped according to the nature of the substituents attached to the carbanion center bearing the nitrile group. These substituents include alkyl, alkenyl, alkynyl, and aryl groups as well as various α‐oriented halogen‐, oxygen‐, nitrogen‐, sulfur‐, and selenium‐containing groups. Notably absent from this survey are the carbanions derived from active methylene compounds bearing two electron‐withdrawing groups such as cyanoacetate esters, malononitriles, α‐sulfonylnitriles, and α‐phosphorylnitriles. Also absent are those carbanions such as Reissert compounds, which are the subject of comprehensive reviews. The chapter is arbitrarily subdivided into six sections: (1) reactions of alkyl‐, aryl‐, and heteroaryl‐substituted nitriles; (2) reactions of α,β‐ and β,γ‐unsaturated nitriles as well as tolunitriles; (3) reactions of cyanohydrins and their hydroxyl‐protected derivatives; (4) reactions of nitriles bearing α‐sulfur and α‐selenium substituents; (5) reactions of α‐(dialkylamino)nitriles; and (6) reactions of α‐halonitriles. Within each of these sections, the reactions are further subdivided according to the nature of the electrophile: (1) alkylation reactions employing alkyl halides, alkyl sulfonates, dialkyl sulfates, and epoxides; (2) arylation reactions involving the substitution of hydrogen, halogen, nitro, or alkoxy groups on aryl or heteroaryl substrates; (3) acylation reactions employing carboxylic esters, anhydrides, acid chlorides, dialkyl carbonates, and nitriles; (4) addition reactions involving aldehydes, ketones, imines, alkenes, and alkynes; and (5) Michael‐type addition reactions to unsaturated aldehydes, ketones, imines, sulfoxides, sulfones, and nitro compounds. Finally, a section involving cyclization reactions is included for each of the six groups of nitrile‐stabilized anions.

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

Cited by 26 publications

References 7 publications

Polymorphically acetylated aminoglutethimide in humans

Polymorphically acetylated aminoglutethimide in humans

5′-Substituted Thalidomide Analogs as Modulators of TNF-α

Addition and Substitution Reactions of Nitrile‐Stabilized Carbanions

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