Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands

Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a–i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1H and 13C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a–i and 7a–i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d

Synthesis of a New Scaffold: the 7H,8H-Pyrimido[1,6-b]pyridazin-6,8-dione Nucleus

This paper describes a modified method of preparation of a number of α-aryl-α-(pyridazin-3-yl)-acetonitriles via the C-arylation reaction of the corresponding carbanionsof phenylacetonitriles using 3-chloropyridazine derivatives. KOH and DMSO were used inthe deprotonation process, which made the reaction very simple and safe to perform.Nitriles were obtained in the hydrolysis reaction to the corresponding α-aryl-α-(pyridazin-3-yl)-acetamide derivatives, which were next subjected to cyclization to afford the finalproducts. A number of new derivatives of 7H,8H-pyrimido[1,6-b]pyridazin-6,8-dione weresynthesized in the cyclocondensation reaction of respective α-aryl-α-(pyridazin-3-yl)-acetamides with diethyl carbonate in the presence of EtONa. The structure andcomposition of the new compounds were confirmed by IR, 1H- and 13C- NMR analysesand by elemental C, H and N analysis

Synthesis of a New Scaffold: the 7H,8H-Pyrimido[1,6-b]pyridazin-6,8-dione Nucleus

Abstract: This paper describes a modified method of preparation of a number of α-aryl-α-(pyridazin-3-yl)-acetonitriles via the C-arylation reaction of the corresponding carbanions of phenylacetonitriles using 3-chloropyridazine derivatives. KOH and DMSO were used in the deprotonation process, which made the reaction very simple and safe to perform. Nitriles were obtained in the hydrolysis reaction to the corresponding α-aryl-α-(pyridazin-3-yl)-acetamide derivatives, which were next subjected to cyclization to afford the final products. A number of new derivatives of 7H,8H-pyrimido[1,6-b]pyridazin-6,8-dione were synthesized in the cyclocondensation reaction of respective α-aryl-α-(pyridazin-3-yl)acetamides with diethyl carbonate in the presence of EtONa. The structure and composition of the new compounds were confirmed by IR, 1 H- and 13 C- NMR analyses and by elemental C, H and N analysis

In Vitro approach for identification of a leading cytochrome P450 isoenzyme responsible for biotransformation of novel arylpiperazine drug candidates and their inhibition potency towards CYP3A4.

Presented article is a follow-up study of previous work, published in PLoS ONE in 2015 regarding metabolic stability of arylpiperazine derivatives, a very promising group of novel antidepressants. The aim of this study was to identify cytochrome P450 (CYP) isoforms that participate in the metabolism of some novel arylpiperazine derivatives developed by authors as well as their potency to inhibit reactions catalysed by identified lead metabolizing enzyme. Such studies allow to predict possible drug-drug interactions that might occur during co-administration of studied compounds with other drugs that are metabolized by identified enzyme. The compounds were incubated in vitro together with the isolated CYP isoforms. After the incubation, samples were analyzed by liquid chromatography coupled with mass spectrometry. The results showed main contribution of CYP3A4 isoform in biotransformation of the investigated derivatives. With CYP3A4 being the main CYP isoform responsible for the metabolism of arylpiperazine derivatives and at the same time being the main metabolizing enzyme for almost 50% of all drugs, a high chance of in vivo drug-drug interactions emerged. Therefore, IC50 values were also determined using testosterone hydroxylation as a probe reaction, specific for CYP3A4. The resulting values ranged from 6.13 to 15.85 µM, which places studied derivatives as moderate or weak inhibitors of CYP3A4. Those results, combined with conclusion that all of the arylpiperazine derivatives are also metabolized to some extent by other CYP isoforms (providing alternative metabolic pathways), result in conclusion that studied arylpiperazines might be safe for co-administration with other CYP3A4 substrates

The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives

This article describes the synthesis of new chiral 3-(piperidin-3-yl)-1H-indole derivatives (R)-10a-c and (S)-11a-c from the corresponding diastereomers: (3R, 2R) and (3S, 2R)-2-[3-(1H-indol-3-yl)-1-piperidyl]-2-phenyl-acetamides (3R, 2R)-4a, (3R, 2R)-6b, (3R, 2R)-8c and (3S, 2R)-5a, (3S, 2R)-7b, (3S, 2R)-9c. Diastereomers were obtained by N-alkylation of derivatives of racemic 3-(piperidin-3-yl)-1H-indoles 1a-c using (S)-2-(4-toluenesulfonyloxy)-phenylacetic amide (S)–II. The same method was applied to obtain (3R, 2S)-methyl-2-[3-(1H-indole-3-yl)-1-piperidyl]-2-phenylacetate (3R, 2S)-2a and (3S, 2S)-methyl-2-[3-(1H-indole-3-yl)-1-piperidyl]-2-phenylacetate (3S, 2S)-3a diastereomers by treating amine 1a with (R)-2-(4-toluenesulfonyloxy)-phenylacetic acid methylester (R)-I. Systematic studies via single crystal X-ray crystallography were used to determine the molecular structure of the racemates 1a-c and the absolute configuration of the enantiomers. The solid racemates 1b and 1c were “true racemates” crystallizing in a centrosymmetric space group, while 1a formed a racemic conglomerate of homoenantiomeric crystals. The absolute configuration was determined for the enantiomeric pairs (R)-10a/(S)-11a, (R)-10b/(S)-11b, and (R)-12c/(S)-13c, as well as for (3S,2S)-3a. Spectra of 1H, 13CNMR, HPLC, and HRMS for diastereomers and enantiomers were consistent with the determined structures