bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved synthesis and pharmacologic activity of the enantiomers of a new benzofurane type antiarrhythmic compound
Authors: Ecker Gerhard , Fleischhacker Wilhelm , Helml Thomas , Noe Christian R. , Scasny Sonja , Lemmens‐Gruber Rosa , Studenik Christian , Marei Hesham , Heistracher Peter 
Published: January 2005

AbstractAn improved synthesis of the enantiomers of the new benzofurane‐type antiarrhythmic compound 1 is described, which makes use of the enantiomerically pure mbe‐lactol. Thus, acylation of the benzofurane 4 with acetic anhydride and subsequent bromination gave the bromoacetyl‐derivative 6, which, after reduction with LiAlH4, was protected with mbe‐lactol to give a mixture of the diastereomers 8A and 8b. After separation via column chromatography assignment of absolute configuration was carried out using a well‐established NMR‐ method. Reaction with propylamine and cleavage of the protective group gave (R)‐1 and (S)‐1, respectively. Enantiomeric purity was confirmed using a direct HPLC method with rsp‐cyclodextrine as stationary phase. Pharmacological investigations on isolated guinea pig heart muscle preparations showed that GE 68 and its two enantiomers did not significantly differ from each other with regard to their negative inotropic, negative chronotropic, and lack of β‐adrenoceptor blocking action. In contrast, the reference drug propafenone was equally potent in its negative inotropic and chronotropic activity as GE 68, but additionally showed a weak β‐adrenoceptor blocking activity. © 1994 Wiley‐Liss, Inc.
Stereoselective distribution of hydroxychloroquine in the rabbit following single and multiple oral doses of the racemate and the separate enantiomers
Authors: Ducharme Julie , Wainer Irving W. , Parenteau Heli I. , Rodman John H. 
Published: January 2005

AbstractHydroxychloroquine (HCQ) stereoselective distribution was investigated in rabbits after 20 mg/kg po of racemic‐HCQ (rac‐HCQ) and 20 mg/kg po of each enantiomer, 97% pure (−)‐(R)‐HCQ and 99% pure (+)‐(S)‐HCQ. Concentrations were 4 to 6 times higher in whole blood than in plasma. Melanin did not affect plasma and whole blood levels since concentrations did not differ between pigmented and nonpigmented animals. After single and multiple doses of the separate enantiomers, only 5–10% of the antipode could be measured, in blood or plasma. Therefore, there was no significant interconversion from one enantiomer into the other. Following rac‐HCQ, plasma (+)‐(S)‐levels always surpassed (−)‐(R)‐ones while in whole blood, (−)‐(R)‐HCQ concentrations were always the highest. When the enantiomers were administered separately, blood concentrations achieved after (−)‐(R)‐HCQ were higher, especially after multiple doses. These observations suggest that (−)‐(R)‐HCQ is preferentially concentrated by cellular components of blood. This enantioselective distribution of HCQ could be secondary to a stereoselective protein binding to plasma proteins, although a more specific binding of (−)‐(R)‐HCQ to blood cells cannot be ruled out. Since in whole blood (−)‐(R)‐HCQ is retained in cellular components, metabolism would favour the more available (+)‐(S)‐enantiomer. © 1994 Wiley‐Liss, Inc.
Stereoisomeric flavour compounds LXVII. 2‐, 3‐, and 4‐Alkyl‐branched acids, part 1: General approach to the synthesis of the enantiopure acids
Authors: Karl Volker , Kaunzinger Astrid , Gutser Jutta , Steuer Petra , Angles‐Angel Jorge , Mosandl Armin 
Published: January 2005

AbstractA general approach to the synthesis of 2‐, 3‐, and 4‐alkyl‐branched acids of high enantiomeric purity is described. The enantiopure 2‐alkyl‐branched acids are prepared via liquid chromatographic resolution of diastereomeric phenylglycinol amides and their absolute configuration is deduced from the 1H‐NMR data of the separated diastereomers. Chain elongation methods, by Arndt–Eistert synthesis, via 2‐alkylated alkyl carbonitrile or by malonic ester synthesis, are used to prepare 3‐ and 4‐alkyl‐branched acids of high configurational purity and known absolute configuration starting from the enantiomeric 2‐alkyl‐branched acids. © 1994 Wiley‐Liss, Inc.
Bidirectional chiral inversion of the enantiomers of the nonsteroidal antiinflammatory drug oxindanac in dogs
Authors: King Jonathan N. , Mauron Catherine , LeGoff Carmen , Hauffe Suzanne 
Published: January 2005

AbstractThe nonsteroidal antiinflammatory drug oxindanac exists as two enantiomers, with most of its pharmacological activity residing in the (S)‐isomer. The behavior of its enantiomers was investigated in dogs. Bidirectional inversion occurred in heparinised plasma and blood, with a ratio of enantiomers [S:R] of 7.3:1 being achieved at equilibrium after incubation for 24 h at 37°C. There was no detectable inversion of either isomer in plasma incubated at 4°C for up to 8 h or in aqueous solution at 37°C for up to 36 h. Bidirectional inversion also occurred in vivo, with a ratio of plasma AUC (0 ∞)s [S:R] of 8.1:1. The ratio of enantiomers reached equilibrium within 2 hr following (S)‐ or rac‐oxindanac, and within 8 h following (R)‐oxindanac. Elimination t½s of the isomers were the same (R, 12.1 h, S, 13.3 h). There were no differences in the ratio of enantiomers following oral or intravenous application, suggesting that a systemic site for inversion was predominant. Although concentrations of the respective isomers were similar at equilibrium following administration of either (R)‐, (S)‐, or rac‐oxindanac, AUC (0 ∞)s differed due to the delay in reaching equilibrium. The extent of inversion to the (S)‐isomer was 100, 73.2, and 60.7% after administration of (S)‐, rac‐, and (R)‐oxindanac, respectively. Although pharmacological activity might be equivalent at equilibrium following administration of either (R)‐, (S)‐, or rac‐oxindanac; efficacy at early time points should be superior in the order (S) > racemate > (R). In conclusion both enantiomers of oxindanac undergo conversion to their respective antipodes in dogs, although the inversion of R to S is more efficient than that of S to R. This bidirectional inversion occurred in vivo, and in vitro in plasma and blood. © 1994 Wiley‐Liss, Inc.
Implications of chirality on pharmacodynamic modeling
Authors: Wright Matthew R. 
Published: January 2005

AbstractAlthough the implications of stereochemistry for pharmacokinetics are relatively well appreciated only recently has its influence on pharmacodynamics begun to be examined. The implications of different pharmacological interactions between enantiomers with similar and different kinetic properties are examined through the use of simulation of the pharmacological effect vs. time profile. The influences of assuming that the pharmacological effect is solely the result of the more active enantiomer are also discussed. The simulations demonstrate that the less pharmacologically active enantiomer may have a significant influence on the observed effect vs. time profile and that the assumption that all of the observed pharmacological activity arises from the more active enantiomer may lead to highly inaccurate prediction of the pharmacodynamic parameters. Finally, these observations suggest that the pharmacodynamic profiles of a drug administered as a racemate or as a “pure” formulation of the more active enantiomer may be significantly different. © 1994 Wiley‐Liss, Inc.
HPLC and NMR methods for the quantitation of the (R)‐enantiomer in (−)‐(S)‐timolol maleate drug raw materials
Authors: Lacroix Pauline M. , Dawson Brian A. , Sears Roger W. , Black D. Bruce 
Published: January 2005

AbstractHPLC and 1H‐NMR methods for the quantitation of the (R)‐enantiomer in (−)‐(S)‐timolol maleate were developed and validated. The HPLC method requires a 25 cm × 4.6 mm 5 μm Chiracel OD‐H (cellulose tris‐3,5‐dimethylphenylcarbamate) column, a mobile phase of 0.2% (v/v) diethylamine and 4% (v/v) isopropanol in hexane at a flow rate of 1 ml/min and UV detection at 297 nm. A system suitability test was devised to verify the separation of the (R)‐ and (S)‐enantiomers of timolol from other drug‐related impurities. The NMR method requires the use of a high‐field NMR spectrometer (>360 MHz) and a chiral solvating agent, (−)‐(R)‐2,2,2‐trifluoro‐1‐(9‐anthrylethanol) (R‐TFAE). The limits of quantitation were 0.05% and 0.2% (m/m) for HPLC and NMR, respectively. The methods were applied to the determination of the (R)‐enantiomer in eight lots of raw material. The results for the two methods were in very good agreement, with results ranging from 0.1 to 4.1% (m/m) by HPLC and none detected to 4.3% (m/m) by NMR. The USP method for specific rotation was found to be unsuitable for detecting the presence of low levels of the (R)‐enantiomer in (−)‐(S)‐timolol maleate. © 1994 Wiley‐Liss, Inc.
Kinetics and stereochemistry of the microsomal epoxide hydrolase‐catalyzed hydrolysis of cis‐stilbene oxides
Authors: Bellucci Giuseppe , Chiappe Cinzia , Ingrosso Giovanni 
Published: January 2005

AbstractThe microsomal epoxide hydrolase (mEH)‐catalyzed hydrolysis of cis‐4,4′–dimethylstilbene oxide (1a), cis‐4,4′‐diethylstilbene oxide (1b), cis‐4,4′‐diisopropylstilbene oxide (1c), and cis‐4,4′‐dichlorostilbene oxide (1d) have been investigated using rabbit liver microsomal preparations. The kinetic parameters, Km and Vmax, and the absolute stereochemistry of the reactions have been determined and compared with those of cis‐stilbene oxide (1e). All epoxides 1a–d are hydrolyzed by mEH with high product enantioselectivity to give (R,R)‐(+)‐diols with ee ≥ 90%. The presence of the substituents on the phenyl rings markedly reduces the rates of mEH catalyzed hydrolysis with respect to cis‐stilbene oxide, by increasing Km and reducing Vmax in the cases of 1a, 1b, and 1d, or reducing only the Vmax in the case of 1c. The very low Vmax, together with a persistent ability to fit into the mEH active site, make all these epoxides, and particularly 1c, inhibitors of cis‐stilbene oxide hydrolysis. The kinetic and stereochemical results are interpreted on the basis of the proposed topology of the mEH active site. © 1994 Wiley‐Liss, Inc.
GABAB antagonists: Resolution, absolute stereochemistry, and pharmacology of (R)‐ and (S)‐phaclofen
Authors: Frydenvang Karla , Hansen Jan J. , Krogsgaard‐Larsen Povl , Mitrovic Ann , Tran Hue , Drew Colleen A. , Johnston Graham A. R. 
Published: January 2005

AbstractPhaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)‐3‐(4‐chlorophenyl)‐4‐aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral chromatographic techniques. The absolute stereochemistry of (−)‐(R)‐phaclofen was established by X‐ray crystallographic analysis. (−)‐(R)‐Phaclofen was shown to inhibit the binding of [3H]‐(R)‐baclofen to GABAB receptor sites on rat cerebellar membranes (IC50 = 76 ± 13 μM), whereas (+)‐(S)‐phaclofen was inactive in this binding assay (IC50 > 1000 μM). (−)‐(R)‐Phaclofen (200 μM) was equipotent with (RS)‐phaclofen (400 μM) in antagonizing the action of baclofen in rat cerebral cortical slices, while (+)‐(S)‐phaclofen (200 μM) was inactive. The structural similarity of the agonist (R)‐baclofen and the antagonist (−)‐(R)‐phaclofen suggests that these ligands interact with the GABAB receptor sites in a similar manner. Thus, it may be concluded that the different pharmacological effects of these compounds essentially result from the different spatial and proteolytic properties of their acid groups. © 1994 Wiley‐Liss, Inc.
Stereospecific synthesis and absolute configuration of mexiletine
Authors: Franchini Carlo , Cellucci Carla , Corbo Filomena , Lentini Giovanni , Scilimati Antonio , Tortorella Vincenzo , Stasi Francesca 
Published: January 2005

AbstractData on the absolute configuration of mexiletine (MEX) do not appear to have been published, although in several published reports the configuration is referred to as (−)‐(R) and (+)‐(S), based on information from manufactures providing the drug stereoisomers. We demonstrate that (−)‐MEX has the (R)‐configuration by mean of a new stereospecific synthesis. X‐Ray analysis of an optical active sample of (+)‐MEX as its hydrobromide salt, obtained from chemical resolution of the racemic mixture, was carried out in order to obtain precise information on bond lengths and angles, useful for studies on structure–activity relationships. We also report the NMR analysis in presence of Eu(hfc)3 as shift reagent, which represents a simple method for the determination of enantiomeric excess (ee) in addition to the well‐known chiral HPLC methods. © 1994 Wiley‐Liss, Inc.
Enantiomeric separation of tetrahydroisoquinoline alkaloids by high‐performance liquid chromatography with β‐cyclodextrin as chiral selector
Authors: Stammel Waltraud , Woesle Berthold , Thomas Helmut 
Published: January 2005

AbstractTetrahydroisoquinoline alkaloids, which are known to be present not only in plants but also in animals, including mammals, can be considered as condensation products of 2‐phenylethylamines (e.g., catecholamines) with aldehydes (e.g., acetaldehyde) or 2‐oxo acids (e.g., pyruvic acid). In this study the possibility of separating the optical isomers of several tetrahydroisoquinolines by high‐performance liquid chromatography was investigated. For isosalsoline, tetrahydropapaveroline and laudanosoline a good enantiomeric separation could be achieved by applying β‐cyclodextrin‐bonded silica as stationary phase in connection with various mobile phases. With respect to laudanosoline, the addition of β‐cyclodextrin as chiral selector to the mobile phase using a C18 reversed‐phase column as stationary phase revealed an even higher resolution when compared with the chiral columns. All tested tetrahydroisoquinolines which could be well separated into enantiomers bear a hydroxyl group at carbon atom 7 as a common structural feature. Those alkaloids substituted with a methoxy group on position 7 instead of a hydroxyl group (e.g., salsolidine) failed to be resolved into their optical isomers. Therefore, the presence of a hydroxyl group on C7 of the aromatic ring seems to be conducive to steric discrimination. However, the separation results for 1‐carboxysalsolinol were unsatisfactory although this molecule possesses a 7‐hydroxyl group. In this case the existence of a carboxyl group on C1 reduced the chiral recognition and thus the enantiomeric resolution. © 1995 Wiley‐Liss, Inc.
Enantiomeric separation and recognition mechanism of 2‐arylpropionic acid derivatives by high‐performance liquid chromatography using a chiral column
Authors: Asami Masato , Nakamura Kan‐ichi 
Published: January 2005

AbstractAn optical resolution of the amide derivatives of ibuprofen and the carbamate‐alkylester derivatives of the trans‐alcohol metabolite of loxoprofen and an analogous compound, CS‐670, was studied by chiral high‐performance liquid chromatography (HPLC). The chiral columns SUMIPAX OA‐4000 and OA‐4100 were used to investigate the enantiomeric separation behavior of these derivatives using both reversed and normal mobile phases. A better separation factor (α) of the amide and the carbamate ester derivatives was obtained in the normal mobile phase than in the reversed mobile phase HPLC. In addition, the recognition mechanisms of both amide and carbamate ester enantiomers were investigated by 1H‐nuclear magnetic resonance (NMR). It is suggested that the important driving forces for the enantiomeric separation are the formation of hydrogen bonding and the charge transfer complex between these derivatives and an active site of the chiral stationary phase. © 1995 Wiley‐Liss, Inc.
Studies in chiral symmetry breaking crystallization I: The effects of stirring and evaporation rates
Authors: Kondepudi Dilip K. , Digits Jennifer , Bullock Kimiley 
Published: January 2005

AbstractChiral symmetry breaking can be realized in stirred crystallization of Na‐ClO3. We present experimental and theoretical studies of the random distribution of crystal enantiomeric excess (cee) for various stirring and solvent evaporation rates. For a fixed solvent evaporation rate, as the stirring RPM is increased, the probability distribution of cee initially broadens and subsequently develops a sharp peak close to cee = 1. On further increase of stirring rate, the probability distribution once again broadens. This broad probability distribution becomes narrow, with a sharp peak near cee = 1, if the solvent evaporation rate is decreased. Thus we show some ways in which the probability distribution of cee can be controlled in stirred crystallization. In particular, our study shows that the stirring rate and the solvent evaporation rate can be adjusted to maximize crystal enantiomeric excess. © 1995 Wiley‐Liss, Inc.
Solubility phase diagram of praziquantel enantiomeric system
Authors: Lim Bee‐gim , Tan Reginald B. H. , Ng Siu‐choon , Ching Chi‐bun 
Published: January 2005

AbstractThe solubility behaviour of praziquantel enantiomeric system at −15°C, 4°C, and 15°C is presented. This system exhibits both a pseudoracemate behaviour and one which leads to the formation of enantiomerically pure crystals. For solutions with lower enantiomeric purity, the pseudoracemate behaviour is more prominent. Solid solutions are formed when the mixtures of the enantiomers are crystallised. The phase diagram shows a complete absence of a eutetic. For mixtures with higher enantiomeric purity, pure crystals of the excess enantiomer are obtained when the solution is crystallised. Temperature dependency of this polymorphism is not significant. With these phase diagrams, a method is suggested to obtain enantiomerically pure isomers of praziquantel from a partially resolved mixture. © 1995 Wiley‐Liss, Inc.
Circular dichroism spectroscopy of 2‐aminotetralins
Authors: Jansen Johanna M. , Johansson Anette M. , Karlén Anders , Hacksell Uli 
Published: January 2005

AbstractThe circular dichroism (CD) spectra of a series of oxygenated 2‐(dipropylamino)tetralin derivatives are reported. On the basis of known absolute configurations and conformational preferences of the compounds, the validity of published correlations between the sign of the 1Lb Cotton effect and the three‐dimensional structure was examined. Contrary to predictions, substitution in position 6 or 7 of the tetralin moiety did not change the sign of the 1Lb Cotton effect. An unexpected sign inversion was, however, observed in some of the compounds containing methyl substituents in the nonaromatic ring. The occurrence of this inversion was not correlated with a change in conformational behaviour and varied depending on the position and nature of the aromatic substituent. No correlations were obvious between the sign of the 1Lb Cotton effect and the absolute configuration and conformational preferences of the compounds. Therefore, at present, CD spectroscopy does not appear to be useful in assignments of the absolute configurations of 2‐(dipropylamino)tetralin derivatives. © 1995 Wiley‐Liss, Inc.
Synthesis of stereoisomers of antithrombotic nipecotamides
Authors: Zheng Xiaozhang , Day Cynthia , Gollamudi Ram 
Published: January 2005

AbstractThe stereoisomers of α,α′‐bis[3‐(N,N‐diethylcarbamoyl)‐piperidino]‐p‐xylene (1) were synthesized. Rac ethyl nipecotate was resolved by diastereomeric (‐)‐D‐ and (+)‐L‐tartrate salt formation. The enantiomeric esters were hydrolyzed to the corresponding nipecotic acids, which were then converted into t‐BOC derivatives. Treatment of the latter with diethylamine/isobutyl chloroformate and removal of the t‐BOC protecting group afforded (R)‐ and (S)‐N,N‐diethylnipecotamides. Condensation of the latter with α,α′‐dibromo‐p‐xylene gave (R,R)‐ and (S,S)‐1. The meso‐diastereomer was obtained by stereospecific synthesis in addition to our earlier procedure involving fractional crystallization of the diastereomeric mixture obtained by synthesis. The latter was resolved earlier into 1A,1B, and 1C using chiral high‐performance liquid chromatography (HPLC). Based on the stereospecific synthesis now achieved, 1A and 1B are assigned the configurations, (R,R) and (S,S) respectively, and 1C is assigned the meso configuration. The (R,S) structure of the latter is also confirmed by X‐ray crystallography. © 1995 Wiley‐Liss, Inc.
Chiral synthesis via organoboranes. 41. The utility of B‐chlorodiisopinocampheylborane for a general synthesis of enantiomerically pure drugs
Authors: Ramachandran P. Veeraraghavan , Gong Baoqing , Brown Herbert C. 
Published: January 2005

AbstractA general approach to the synthesis of enantiomerically pure α‐phenyl amino alcohols via the asymmetric reduction of α‐phenyl haloalkyl ketones or α‐phenyl aminoalkyl ketones with B‐chlorodiisopinocampheylborane is described. Using this approach, an improved synthesis of a potential antipsychotic, α‐(4‐fluorophenyl)‐4‐(2‐pyrimidinyl)‐1‐piperazinebutanol in ⩾98% ee, and the broncholdilator 1‐(2‐methoxy‐2‐phenethyl)‐4‐(3‐hydroxy‐3‐phenylpropyl)piperazine (eprozinol) in ⩾99% ee is achieved. © 1995 Wiley‐Liss, Inc.
A comparison of LC and SFC for cellulose‐ and amylose‐derived chiral stationary phases
Authors: Bargmann‐Leyder Nathalie , Tambuté André , Caude Marcel 
Published: January 2005

AbstractThis paper presents a systematic comparison of liquid chromatography (LC) and supercritical fluid chromatography (SFC) for Chiralcel OD and Chiralpak AD chiral stationary phases (CSPs), performed using various chiral compounds having a known or potential pharmaceutical activity. The chiral recognition mechanisms involved in LC and SFC for the enantiomeric separation of β‐blockers have been studied more particularly. As a general rule, it appears that the presence of polar functions, like primary or secondary hydroxyl or amine functions, may result in marked discrepancies in selectivity between LC and SFC. This result is peculiar to cellulose‐ and amylose‐derived CSPs, for which the interactions involved in chiral recognition mechanism are not always well balanced, contrary to what happens for independent CSPs. In the case of chiral resolution of polar solutes or polymer‐type CSPs, the analyst should try both the LC and SFC techniques to be able to choose the more stereoselective one. © 1995 Wiley‐Liss, Inc.
NMR investigations of the enantiomeric excess effects in solutions with weak intermolecular association
Authors: Fedin Erlen I. , Davankov Vadim A. 
Published: January 2005

AbstractThe main features of statistically controlled associate diasteromerism (SCAD) in solution as measured by nuclear magnetic resonance (NMR) are discussed. In an achiral solvent, (R)‐ and (S)‐enantiomers can demonstrate distinct NMR signals, with the intensity ratio equal to the concentration ratio. The previous theory of SCADA (anisochronism of nuclear magnetic moments caused by SCAD) is supplemented by treatment of enantiomeric excess phenomena in relation with the hypothesis that a sample consists totally of short‐living diastereomeric dimers which are involved in fast (on the NMR time scale) exchange by enantiomers. Thermodynamic parameters of SCAD as well as limits for enantioselectivity phenomena are estimated. © 1995 Wiley‐Liss, Inc.
Chiral separation of unmodified α‐hydroxy acids by ligand exchange HPLC using chiral copper(II) complexes of (S)‐phenylalaninamide as additives to the eluent
Authors: Galaverna Gianni , Pantò Francesco , Dossena Arnaldo , Marchelli Rosangela , Bigi Franca 
Published: January 2005

AbstractCopper(II) complexes of (S)‐phenylalaninamide have been successfully used for the direct enantiomeric separation of unmodified (R,S)‐α‐hydroxy acids in reversed phase high‐performance liquid chromatography (RP‐HPLC). The effect of various parameters (pH, eluent polarity, selector concentration) on enantioselectivity is discussed. Evidence is provided that a mechanism of ligand exchange is actually occurring during the chromatographic separation. The method is very convenient and easy to use, and the chiral selector is commercially available and can be recovered at the end of the analysis. A conventional achiral RP‐ODS‐2 column is used and no pretreatment of the samples is required. This method allows the accurate determination of the enantiomeric excess of α‐hydroxy acids in synthetic and biological samples. © 1995 Wiley‐Liss, Inc.