The V1a receptor is a major contributor in mediating the social and emotional effects of arginine-vasopressin (AVP); therefore it represents a promising target in the treatment of several neuropsychiatric conditions. The aim of this research was to design and synthesize novel and selective V1a antagonists with improved in vitro and in vivo profiles. Through optimization and detailed SAR studies, we developed low nanomolar antagonists, and further characterizations led to the discovery of the clinical candidate compound 43 (RGH-122). The CNS activity of the compound was determined in a 3-chamber social preference test of autism in which RGH-122 successfully enhanced social preference with the lowest effective dose of 1.5 mg/kg.

A new class of selective vasopressin receptor 1A (V1A) antagonists was identified, where "methyl-scan" was performed around the benzene ring of the 5-hydroxy-triazolobenzazepine core. This led to the synthesis of two 10-methyl derivatives, each possessing a chiral axis and a stereogenic center. The four atropisomeric stereoisomers (involving two enantiomer pairs and atropisomeric diastereomers) could be successfully isolated and spectroscopically characterized. According to the in vitro pharmacological profiles of the compounds, the human V1A receptor has a strong preference toward the isomers having an aR axial chirality, the most active isomer being the aR,5S isomer. Furthermore, the structure-activity relationships obtained for the isomers and for the newly synthesized analogues could be tentatively explained by an in silico study.

Hydroxycinnamic acids represent a versatile group of dietary plant antioxidants. Oxidation of methyl-p-coumarate (pcm) and methyl caffeate (cm) was previously found to yield potent antitumor metabolites. Here, we report the formation of potentially bioactive products of pcm and cm oxidized with peroxynitrite (ONOO¯), a biologically relevant reactive nitrogen species (RNS), or with α,α′-azodiisobutyramidine dihydrochloride (AAPH) as a chemical model for reactive oxygen species (ROS). A continuous flow system was developed to achieve reproducible in situ ONOO¯ formation. Reaction mixtures were tested for their cytotoxic effect on HeLa, SiHa, MCF-7 and MDA-MB-231 cells. The reaction of pcm with ONOO¯ produced two fragments, an o-nitrophenol derivative, and a new chlorinated compound. Bioactivity-guided isolation from the reaction mixture of cm with AAPH produced two dimerization products, including a dihydrobenzofuran lignan that exerted strong antitumor activity in vitro, and has potent in vivo antimetastatic activity which was previously reported. This compound was also detected from the reaction between cm and ONOO¯. Our results demonstrate the ROS/RNS dependent formation of chemically stable metabolites, including a potent antitumor agent (5), from hydroxycinnamic acids. This suggests that diversity-oriented synthesis using ROS/RNS to obtain oxidized antioxidant metabolite mixtures may serve as a valid natural product-based drug discovery strategy.

We hereby report the biomimetic synthesis of three flavonoid alkaloids, namely 8-(2″-pyrrolidinon-5″-yl)quercetin, 6-(2″-pyrrolidinon-5″-yl)-(–)-epicatechin and 8-(2″-pyrrolidinon-5″-yl)-(–)-epicatechin. These known natural products were prepared via an acid-catalysed regioselective phenolic Mannich reaction involving the electrophilic attack of an N-acyliminium ion on the corresponding flavonoidal precursors. The products were purified by preparative HPLC. The reactions showed high C8-regioselectivity. The major isomers of the synthesized flavonoid alkaloids were further characterized in terms of their medicinal-chemical properties.

New enantiopure dimethyl-substituted acridino-18-crown-6 and acridino-21-crown-7 ethers containing a carboxyl group at position 9 of the acridine ring [(S, S)-8, (S, S)9, (R,R)-10] were synthesized. The pK(a) values of the new crown ethers [(S, S)-8, (S, S)-9, (R, R)-10] and of an earlier reported macrocycle [(R, R)-2] were determined by UV-pH titrations. Crown ether (S, S)-8 was attached to silica gel by covalent bonds and the enantiomeric separation ability of the newly prepared chiral stationary phase [(S, S)-CSP-12] was studied by high-performance liquid chromatography (HPLC). Homochiral preference was observed and the best separation was achieved for the enantiomers of 1-NEA. Ligands (S, S)-9 and (R, R)-10 are precursors of enantioselective sensor and selector molecules for the enantiomers of protonated primary amines, amino acids, and their derivatives.

In medicinal chemistry, the development of synthetic procedures for the access of new heterocyclic systems as potential scaffolds is elementary. Herein, we report our results on the formation of small drug-like heterocycles, utilizing flow chemistry. This approach enables the extension of the reaction parameter window, including high-pressure/high-temperature or hazardous chemistry. In our work, various novel condensed tricyclic benzothiazoles fused with furo- and thieno-rings were synthesized applying a multistep continuous-flow protocol. The process includes two ring closure steps and a nitro group reduction step. Batch and telescoped continuous-flow syntheses were also designed and performed.

This paper reports a novel method for the preparation of chiral stationary phases (CSPs) using an acridino-18-crown-6 ether selector as a model compound. Chiral stationary phase (R,R)-CSP- 2A: was obtained by in situ continuously recirculating the solution of carboxyl-substituted acridino-18-crown-6 ether (R,R)- 4: , dicyclohexylcarbodiimide and 3-(triethoxysilyl)propylamine through a high-performance liquid chromatography (HPLC) column containing blank silica gel in elevated pressure and temperature. The enantiomer separating ability of chiral stationary phase (R,R)-CSP- 2A: was investigated by HPLC using mixtures of enantiomers of 1-(1-naphthyl)ethylamine hydrogen perchlorate, 1-(2-naphthyl)ethylamine, 1-(4-bromophenyl)ethylamine and 1-(4-nitrophenyl)ethylamine hydrogen chloride. The best results were found for the separation of the mixtures of enantiomers of Br-PEA.

This paper reports the enantioseparation ability of a pyridino-18-crown-6 ether-based chiral stationary phase [(S,S)-CSP-1]. The enantiomeric discrimination of chiral stationary phase (S,S)-CSP-1 was evaluated by HPLC using the mixtures of enantiomers of various protonated primary aralkylamines [1-phenylethylamine hydrogen perchlorate (PEA), 2,3-dihydro-1H-inden-1-amine (1-aminoindan), 2,2'-(1,2-diaminoethane-1,2-diyl) diphenol (HPEN)] and perchlorate salts of α-amino acid esters [alanine benzyl ester (Ala-OBn), phenylalanine benzyl ester (Phe-OBn), phenylalanine methyl ester (Phe-OMe), phenylglycine methyl ester (PhGly-OMe), glutamic acid dibenzyl ester (Glu-diOBn), and valine benzyl ester (Val-OBn)]. The best enantioseparation was achieved in the case of PEA. The high enantioselectivity was rationalized by the strong π-π interaction of the extended π system of the aryl-substituted pyridine unit.

ABSTRACT The enantiomeric separation ability of the newly prepared chiral stationary phases containing acridino‐18‐crown‐6 ether selectors was studied by high‐performance liquid chromatography (HPLC). The chiral stationary phases separated the enantiomers of selected protonated primary aralkylamines efficiently. The best results were found for the separation of the mixtures of enantiomers of NO 2 ‐PEA. Chirality 26:651–654, 2014. © 2014 Wiley Periodicals, Inc.

This paper reports the preparation and testing of three new pyridino-18-crown-6 ether-based chiral stationary phases (S,S)-CSP-12, (S,S)-CSP-17 and (S,S)-CSP-20. Secondary amine (S,S)-7 was first transformed to triethoxysilyl derivative (S,S)-11, which contains a urea unit by treating the former with 3-(triethoxysilyl)propyl isocyanate. Next, (S,S)-11 was heated with spherical HPLC quality silica gel in toluene to obtain (S,S)-CSP-12. In order to acetylate the 3-aminopropylsilyl groups bonded to the silica gel during immobilization of the triethoxysilyl derivative (S,S)-11, we pumped acetic anhydride and triethylamine in DMF through the column to give the modified chiral stationary phase (S,S)-CSP-20.Triflate (S,S)-13 was first transformed to a pyridino-18-crown-6 ether derivative (S,S)-15, which contains a 4-(methoxycarbonyl)phenyl substituent at the 4-position of the pyridine ring by a Suzuki carbon-carbon coupling reaction. The hydrolysis of ester (S,S)-15 gave carboxylic acid (S,S)-21. Carboxylic acid (S,S)-21 was reacted with an excess of thionyl chloride to form the appropriate acyl chloride, which was treated with 3-(triethoxysilyl)propylamine in the presence of triethylamine in THF to furnish triethoxysilyl derivative (S,S)-16 containing an amide unit. Triethoxysilyl derivative (S,S)-16 was heated with spherical HPLC quality silica gel in toluene to give the chiral stationary phase (S,S)-CSP-17.The enantiomer separating ability of chiral stationary phases (S,S)-CSP-12, (S,S)-CSP-17 and (S,S)-CSP-20 were tested by using mixtures of enantiomers of 1-(1-naphthyl)ethylamine hydrogen perchlorate (1-NEA), 1-(2-naphthyl)ethylamine (2-NEA), 1-(4-bromophenyl)ethylamine (Br-PEA) and 1-(4-nitrophenyl)ethylamine hydrogen chloride (NO2-PEA). Chiral stationary phase (S,S)-CSP-17 showed the best enantiomer separating ability for the mixtures of enantiomers of amine compounds amongst the pyridino-crown ether-based CSPs ever synthesized. The high enantioselectivity is probably due to the strong pi-pi interaction of the extended pi system of the aryl-substituted pyridine unit. (C) 2012 Elsevier Ltd. All rights reserved.

(cis-1S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, or sertraline hydrochloride, is a very effective antidepressant. This report presents a novel industrial synthesis of sertraline hydrochloride that is in many respects more advantageous than processes reported thus far. N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-methanamine N-oxide is used as intermediate in our process, which is a stable compound in normal conditions. It can be obtained in a simple reaction from the corresponding tetralone in good yield, using acceptable reagents with regard to environmental and safety respects. Its reduction to the desired cis-racemic amine is stereoselective, and thus it provides sertraline hydrochloride with a purity required for pharmaceutical ingredients.