Facile, alternative route to lubeluzole, its enantiomer, and the racemate

Lubeluzole [(S)-9] has been synthesized by a convergent synthesis, alkylation of N-methyl-N-piperidin-4-yl-1,3-benzothiazol-2-amine (4) with (+)-(R)-1-chloro-3-(3,4-difluorophenoxy)propan-2-ol [(+)-(R)-8] being the key step. Alcohol (+)-(R)-8 was obtained from commercially available (R)-epichlorohydrin [(R)-6], while the thiazole derivative 4 was easily obtained starting from N-protected piperidin-4-one (1) in a three-step procedure. The same method was used in order to obtain both the (R)-stereoisomer of lubeluzole [(R)-9] and its racemate [(RS)-9]. Overall yields ranged from 20% to 35%. The enantiomeric excess values for (S)-9 and (R)-9 were 97% and 94% respectively, as analyzed by chiral HPLC.     

Study on the stereoselective excretion of tetrahydropalmatine enantiomers in rats and identification of in vivo metabolites by liquid chromatography‐tandem mass spectrometry

The objective of this work was to study the stereoselectivity in excretion of tetrahydropalmatine (THP) enantiomers by rats and identify the metabolites of racemic THP (rac‐THP) in rat urine. Urine and bile samples were collected at various time intervals after a single oral dose of rac‐THP. The concentrations of THP enantiomers in rat urine and bile were determined using a modification of an achiral–chiral high‐performance liquid chromatographic (HPLC) method that had been previously published. The cumulative urinary excretion over 96 h of (?)‐THP and (+)‐THP was found to be 55.49 ± 36.9 μg and 18.33 ± 9.7 μg, respectively. The cumulative biliary excretion over 24 h of (?)‐THP and (+)‐THP was 19.19 ± 14.6 μg and 12.53 ± 10.4 μg, respectively. The enantiomeric (?/+) concentration ratios of THP changed from 2.80 to 5.15 in urine, and from 1.36 to 1.80 in bile. The mean cumulative amount of (?)‐THP was significantly higher than that of (+)‐THP both in urine and bile samples. However, the enantiomeric (?/+) concentration ratios in rat urine and bile were significantly lower than those ratios in rat plasma. These findings suggested the excretion of THP enantiomers was stereoselective rather than a reflection of chiral pharmacokinetic aspects in plasma and (?)‐THP was preferentially excreted in rat urine and bile. Three O‐demethylation metabolites and the parent drug rac‐THP were detected by liquid chromatography‐tandem mass spectrometry in rat urine. One metabolite was obtained by preparative HPLC and identified as 10‐O‐demethyl‐THP. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Stereoselective pharmacokinetics of clausenamide enantiomers and their major metabolites after single intravenous and oral administration to rats

The pharmacokinetics of clausenamide (CLA) enantiomers and their metabolites were investigated in Wistar rat. After intravenous and oral administration at a dose of 80 and 160 mg/kg each enantiomer, plasma concentrations of (-)- or (+)-CLA and its major metabolites were simultaneously determined by reverse-phase HPLC with UV detection. Notably, stereoselective differences in pharmacokinetics were found. The mean plasma levels of (+)-CLA were higher at almost all time points than those of (-)-CLA. (+)-CLA also exhibited greater t(max), C(max), t(1/2beta), AUC(0-12h), and AUC(0--> infinity) and smaller CL (or CL/F) and V(d) (or V(d)/F), than its antipode. The (+)/(-) isomer ratios for t(1/2beta), t(max), AUC(0-12 h), and AUC(0--> infinity), which ranged from 1.26 to 2.08. The ratio for CL (or CL/F) was about 0.5, and there were significant differences in these values between CLA enantiomers (P < 0.05), implying that the absorption, distribution, and elimination of (-)-CLA were more rapid than those of (+)-CLA. Similar findings for (-)-7-OH-CLA, the major metabolite of (-)-CLA, and (+)-4-OH-CLA, the major metabolite of (+)-CLA, can be also seen in rat plasma. The contributing factors for the differences in stereoselective pharmacokinetics of CLA enantiomers appeared to be involved in their different plasma protein binding, first-pass metabolism and interaction with CYP enzymes, especially with their metabolizing enzyme CYP 3A isoforms.     

Rac-Flurbiprofen is more ulcerogenic than its (S)-enantiomer

The most common, and sometimes life-threatening, side-effects associated with the human use of the analgesic, nonsteroidal antiinflammatory drugs (NSAIDs) are gastrointestinal. These include gastritis, ulceration, and severe bleeding. The aryl propionic acid class of NSAIDs are among the most widely used of these drugs in the world, including rac-ibuprofen, rac-flurbiprofen, and rac-ketoprofen. Marketed as racemates, it was assumed that the “inactive” (R)-enantiomers, having no cyclooxygenase inhibiting effect, also had no toxic effect. In a 30-day dose response study of (S)-, (R)-, and rac-flurbiprofen given daily over a range of doses the (R)-isomer alone proved to be without apparent gastrointestinal (GI) toxicity. On the other hand the racemate proved to be 2 to 4 times as ulcerogenic in enantiomerically equivalent doses as the (S)-enantiomer. These results have significant clinical implications. © 1993 Wiley-Liss, Inc.     

An in vitro study of the stereoselective dissolution of (rac)-verapamil from two sustained release formulations

The stereoselectivity of the in vitro dissolution of two commercially available sustained release formulations of rac-verapamil (rac-VER) has been investigated. The studies were carried out using a single-tablet continuous-flow apparatus and the concentrations of R- and S-VER released from the formulations were measured using enantioselective chromatography on a high performance liquid chromatography (HPLC) chiral stationary phase containing immobilized α₁-acid glycoprotein (Chiral AGP-column). The data from this study demonstrates that the two formulations have different dissolution profiles and that the amount of drug dissolved was highly dependent on pH. In addition, between pH 3 and 8, the total cumulative amount of R-VER released was greater than the amount of S-VER and a statistically significant difference (P < 0.01) was detected at pH 6. The results of this study indicate that bioavailability and bioequivalency studies should consider the possibility of enantioselective dissolution when racemic compounds are present in the formulations. © 1993 Wiley-Liss, Inc.     

Disposition and absorption of hydroxychloroquine enantiomers following a single dose of the racemate

The disposition of hydroxychloroquine enantiomers has been investigated in nine patients with rheumatoid arthritis following administration of a single dose of the racemate. Blood concentrations of (?)-(R)-hydroxychloroquine exceed those of (+)-(S)-hydroxychloroquine following both an oral and intravenous dose of the racemate. Maximum blood concentrations of (?)-(R)-hydroxychloroquine were higher than (+)-(S) -hydroxychloroquine after oral dosing (121 ± 56 and 99 ± 42 ng/ml, respectively, P = 0.009). The time to maximum concentration and the absorption half-life, calculated using deconvolution techniques, were similar for both enantiomers. The fractions of the dose of each enantiomer absorbed were similar, 0.74 and 0.77 for (?)-(R)- and (+)-(S)-hydroxychloroquine, respectively (P = 0.77). The data suggest that absorption of hydroxychloroquine is not enantioselective. The stereoselective disposition of hydroxychloroquine appears to be due to enantioselective metabolism and renal clearance, rather than stereoselectivity in absorption and distribution. © 1994 Wiley-Liss, Inc.     

Short and simple synthesis of (R)- and (S)-4-hydroxypentylaminoacetamide: both enantiomers of the (ω-1)-hydroxylated metabolite of milacemide

Both (R)- and (S)-4-hydroxypentylaminoacetamide have been synthesized by reductive amination of glycinamide on the γ-valerolactols corresponding to (R)- and (S)-γ-valerolactone, respectively. These enantiomeric lactones were readily obtained in high enantiomeric excess (ee) by enzymic porcine pancreatic lipase (PPL) kinetic resolution of rac-methyl γ-hydroxyvalerate. © 1992 Wiley-Liss, Inc.     

Chiral Assay of Atenolol Present in Microdialysis and Plasma Samples of Rats Using Chiral CBH as Stationary Phase

Two different enantioselective chiral chromatographic methods were developed and validated to investigate the disposition of the β₁-receptor antagonist atenolol in blood and in brain extracellular fluid of rats (tissue dialysates). System A for the plasma samples was a one-column chromatographic system with a Chiral CBH column with an aqueous buffer as mobile phase into which cellobiose was added for selective regulation of the retention of the internal standard, (S)-metoprolol. The plasma samples were analysed after a simple extraction procedure. The limit of quantitation was 0.2 μg/ml for the atenolol enantiomers. The repeatability of the medium concentration quality control plasma sample (6.0 μg rac-atenolol/ml) was 11–18% for the enantiomers. The dynamic linear range of the plasma samples was 0.5–20 μg/ml. For system B, since atenolol is an extremely hydrophilic drug, the tissue dialysate sample required a much more sensitive system as compared to the plasma samples. A coupled column system was used for peak compression of the enantiomers in the eluate after the separation on the Chiral CBH column, hence increasing the detection sensitivity. The limit of quantification was 0.045 μg/ml for the atenolol enantiomers in artificial CSF. The repeatability of the medium concentration quality control samples (0.1 and 4.0 μg rac-atenolol/ml in artificial CSF and Hepes Ringer, respectively) was 2.8–9.3% for the two enantiomers. The dynamic linear range of the brain samples was 0.05–1.0 and 0.5–20 μg/ml in artificial CSF and Hepes Ringer, respectively. Chirality 9:329–334, 1997. © 1997 Wiley-Liss, Inc.     

O-methylation of (+)-(R)- and (−)-(S)-6,7-dihydroxy-1-methyl-1,2,3,4-tetra-hydroisoquinoline (salsolinol) in the presence of pig brain catechol-o-methyltransferase

(+)-(R)- and (−)-(S)-salsolinol, dopamine-derived tetrahydroisoquinolines, were tested as substrates of pig brain soluble and membrane-bound catechol-O-methyltransferase (COMT) and as inhibitors of O-methylation of dopamine by soluble COMT in vitro. Methylation products were separated by high-performance liquid chromatography with electrochemical detection. Quantification of the products showed that O-methylation of (+)-(R)-salsolinol by soluble COMT afforded the 7-O-methylated product salsoline preferentially, whereas (−)-(S)-salsolinol yielded almost equivalent amounts of the 6- and 7-methyl ethers. Unlike O-methylation by soluble COMT, 7-O/6-O-methylation ratio produced by membrane-bound COMT varied with (+)-(R)-salsolinol concentration. As to the O-methylation of dopamine by soluble COMT, comparable competitive inhibition was observed with both (+)-(R)- and (−)-(S)-salsolinol. Chirality 9:367–372, 1997. © 1997 Wiley-Liss, Inc.     

Direct enantioselective separation of some propranolol analogs by HPLC on normal and reversed cellulose chiral stationary phases

The enantiomeric separation of several racemic aryloxyaminopropan-2-ol derivatives related to propranolol on normal and reversed phase of cellulose tris (3,5-dimethylphenylcarbamate) chiral stationary phases known as Chiralcel OD and Chiralcel OD-R were studied. It was observed that the chiral separation depends on the substitution pattern of the aryl group, i.e., 1-naphthyl, 2-naphthyl, and phenyl group and polarity on the basic nitrogen in the side chain. In both normal and reversed phase modes the (+)-R-enantiomer eluted first in all of the analogs resolved. It can be concluded that: (1) substituents on the side chain did affect the interaction of the enantiomers with the polar carbamate moiety in the CSP; and (2) the dipole-dipole stacking between the π-donor 3,5-dimethylphenyl carbamate group pending from the glucose rings of the CSP and π-acceptor aryl group of the analyte is crucial for the efficient chiral discrimination. The chiral recognition mechanism(s) between these analogs and the chiral stationary phases are proposed. © 1996 Wiley-Liss, Inc.