The enantiomers of the teratogenic thalidomide analogue EM 12

Abstract

The plasma pharmacokinetics of the enantiomers of 2-(2,6-dioxopiperidine-3-yl)-phthalimidine (EM 12) and the racemic mixture of this substance were investigated in Callithrix jacchus, a thalidomide-sensitive primate. Single doses of 5 mg/kg body wt were administered orally or intraperitoneally. Maximum plasma concentrations were reached 1 h after administration of the enantiomers, and 3 h after application of the racemate. The mean plasma elimination half-life was in the range of 5 h for the enantiomers, as well as for the racemic mixture, although there was a tendency toward slower elimination and higher plasma AUC values of the S-enantiomer: thus, after administration of the (greater than 99%) pure enantiomers, the plasma AUC value of the administered S-enantiomer was found to be more than one-third higher than that of the administered R-enantiomer. Racemisation of the R- and the S-form of EM 12 occurred both in vitro (phosphate buffer, pH 7.4, 37 degrees C) and in vivo. The maximum plasma concentrations of the antipodes produced via chiral inversion were between 13% and 21%; the plasma AUC values of the resulting antipodes were between 24% and 30% of the corresponding values of total EM 12. The plasma pharmacokinetic data, including the extent of the chiral inversion obtained after p.o. and i.p. application of the substances, were in the same range. The results indicate that both enantiomers racemise with appreciable rates; this may be expected to complicate the interpretation of studies designed to evaluate stereoselective differences with respect to teratological activities of EM 12 and related substances such as thalidomide.

Highly enantioselective reduction of the C–C double bond of N-phenyl-2-methyl- and N-phenyl-2,3-dimethyl- maleimides by fungal strains

“…[3][4][5][6] Chiral products obtained through bioconversions offer the advantage of employing a renewable and natural source of reagents and avoiding the use of solvents while operating at room temperature. 1 Among the different catalysts, fungi are capable of catalyzing chemical reactions of diverse types and accepting a wide range of substrates.…”

Thalidomide Metabolites and Analogues. 3. Synthesis and Antiangiogenic Activity of the Teratogenic and TNFα-Modulatory Thalidomide Analogue 2-(2,6-Dioxopiperidine-3-yl)phthalimidine

“…The conversion of the PMB-protected phthalimide 7 to the phthalimidine (isoindolinone) moiety of 10 was based on the chemoselective aluminum-amalgam-mediated reduction of the phthalimide group to the corresponding hydroxylactam, followed by phenylthiation and desulfurization, as briefly described in a preliminary communication (Scheme 2). 7 While the direct phthalimide to phthalimidine conversion may sometimes be facilitated with zinc/acetic acid, 18 the overall procedure described herein is milder and also avoids the employment of the lessselective hydridic reducing agents. Exposure of the N-PMB glutarimide 7 to freshly prepared aluminum amalgam (Al/Hg) in tetrahydrofuran/water followed by removal of the solid byproducts and reaction solvent system provided the crude hydroxylactam-substituted N-PMB-imide 8 without any concomitant reduction of the glutarimide ring.…”

Role of racemization in optically active drugs development

“…2-Phthalimidinoglutarimide and 2-phthalimidoadipinimide (derivatives of thalidomide) showed a rapid racemization. 59,60 Nunes et al 61 described the epimerization reaction of pilocarpine (2S:3R) at C-2 chiral atom at pH 7.4 and 358C with half life of 36 days.…”