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An accurate and reproducible high-performance liquid chromatographic (HPLC) method has been developed and validated for the direct separation of individual enantiomers of lansoprazole, a potent proton pump inhibitor belonging to the family of the substituted benzimidazoles. The enantiomers were resolved on a Chiralpak IA by using a mobile phase consisting of methyl-tert-butyl ether (MtBE)-ethyl acetate (EA)-ethanol (EtOH)-diethylamine (DEA) in the ratio 60:40:5:0.1 (v/v/v/v). Baseline separation of the enantiomers of lansoprazole was obtained with a resolution factor of 8.14. The standard curves for the two enantiomers were linear (r(2)>0.999) in the concentration range of 10-80microg/ml with a working concentration of about 60microg/ml for each enantiomer. Apparent recovery was 100.8% with a relative standard deviation less than 2%. The limit of quantization for each enantiomer of lansoprazole was 0.22microg/ml. The intra-day precisions were in the range of 0.21-0.36 and 0.59-0.66 while the inter-day precisions were in the range of 0.55-1.24 and 0.66-1.19% in terms of retention times and area response RSD% for (R)-(+)- and (S)-(-)-lansoprazole, respectively. The method was also able to resolve impurities from the enantiomers of lansoprazole.

Substituted 4-heteroaryl-2-phenylquinolines were synthesized and tested on NK-2 and NK-3 receptors in order to get a better insight in the structure-activity relationship. On the whole, these molecules, which can be regarded as bioisosters of the NK-3 antagonist SB 218795, displayed a lower activity than the template. Ring electronic distribution and H-bond donor and acceptor positions played some role in selectivity, 2-imidazolyl substituted 2a showing affinity mainly towards NK-3 while 3-pyrazolyl substituted 4 displayed a preferential interaction with NK-2 receptor. Structural characterization of the synthesized compounds was achieved by NMR and mass techniques. Bidimensional 1H-NOESY experiments were a helpful tool for the assignment of the isomeric structures of compounds 9 and llb-c.

The direct HPLC enantioseparation of Mianserin and a series of aptazepine derivatives is accomplished on polysaccharide-based chiral stationary phases (CSPs). The resolutions are performed on the coated-type Chiralcel OD and Chiralpak AD CSPs and on the first commercially available immobilized-type Chiralpak IA CSP, in normal-phase and polar-organic modes. The complete separation of enantiomers of all racemates investigated was successfully achieved under at least one of CSP/eluent combinations employed. Pure alcohols such ethanol or 2-propanol, with a fixed percentage of DEA added, serve as valuable alternatives to the more common n-hexane-based normal-phase eluents in resolution of Mianserin on the AD CSP. In order to study the chiroptical properties of aptazepine derivatives, chromatographic resolutions are carried out at semipreparative scale using Chiralpak AD and Chiralpak IA as CSPs. Nonconventional dichloromethane-based eluents have permitted to expand the chiral resolving ability of the immobilized Chiralpak IA CSP and to perform mg-scale enantioseparations with an analytical-size column. Assignment of the absolute configuration of the separated enantiomers is empirically established by comparing their chiroptical data with those of structurally related Mianserin. Chirality, 2006. © 2006 Wiley-Liss, Inc.

A series of 4-amino-2-methylquinoline and 4-aminoquinazoline derivatives, including the reference NOP antagonist JTC-801, were synthesized by an alternative pathway and their in vitro pharmacological properties were investigated. 3-Substitution of the quinoline ring resulted very critical for affinity. So 3-methyl derivative 4j showed a similar potency compared with the reference 4h while bulky lipophilic or electron withdrawing groups in the same position strongly decreased affinity. Structural and conformational requirements for affinity were outlined by NOE NMR and computational methods and suggestions for a pharmacophore model design were provided.

The HPLC enantiomer separation of a novel series of C5-chiral 1-acetyl-3-(4-hydroxy- and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole derivatives, with inhibitory activity against monoamine oxidases (MAO) type A and B, was accomplished using polysaccharide-based chiral stationary phases (CSPs: Chiralpak AD, Chiralcel OD, and Chiralcel OJ). Pure alcohols, such as ethanol and 2-propanol, and typical normal-phase binary mixtures, such as n-hexane and alcohol modifier, were used as mobile phases. Single enantiomers of several analytes examinated were isolated on a semipreparative scale, and their chiroptical properties were measured. The assignment of the absolute configuration was established for one compound by single-crystal X-ray diffraction method and for the other three by CD spectroscopy. The inhibitory activity against MAO of racemic samples and single enantiomers were evaluated in vitro. Chirality 16:625–636, 2004. © 2004 Wiley-Liss, Inc.