Structure elucidation of the designer drug N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-3-(4-fluorophenyl)-pyrazole-5-carboxamide and the relevance of predicted (13) C NMR shifts - a case study.

The detailed structure elucidation process of the new cannabimimetic designer drug, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-3-(4-fluorophenyl)-pyrazole-5-carboxamide, with a highly substituted pyrazole skeleton, using nuclear magnetic resonance (NMR) spectroscopic and mass spectrometric (MS) techniques is described. After a first analysis of the NMR spectra and comparison with 48 possible pyrazole and imidazole structures, a subset of six positional isomeric pyrazoles and six imidazoles remained conceivable. Four substituents of the heterocyclic skeleton were identified: a proton bound to a pyrazole ring carbon atom; a 5-fluoropentyl group; a 4-fluorophenyl substituent; and a carbamoyl group, which is N-substituted with a methyl residue carrying a tert.-butyl and a carbamoyl substituent. The 5-fluoropentyl residue is situated at the nitrogen ring atom. Additional NMR experiments like the (1) H,(13) C HMBC were performed, but due to the small number of signals based on long-range couplings, the comparison of predicted and observed (13) C chemical shifts became necessary. The open access Internet shift prediction programs NMRDB, NMRSHIFTDB2, and CSEARCH were employed for the prediction of (13) C shift values which allowed an efficient and unambiguous structure determination. For the identified N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(5-fluoropentyl)-3-(4-fluorophenyl)-pyrazole-5-carboxamide, the best agreement between predicted (13) C shifts and the observed chemical shifts and long-range couplings for the pyrazole ring carbon atoms, with a standard error of about 2 ppm, was found with each of the predictions. For the comparison of measured and predicted chemical shifts model compounds with simple substituents proved helpful. The identified compound is a homologue of AZ-037 which is offered by Internet suppliers. Copyright © 2015 John Wiley & Sons, Ltd.

Tear film thickness after treatment with artificial tears in patients with moderate dry eye disease.

PURPOSE: This study was designed to investigate the effect of a single-drop instillation of different lacrimal substitutes on tear film thickness (TFT) assessed with optical coherence tomography in patients with mild to moderate dry eye disease. METHODS: The study was performed in a randomized, double-masked, controlled parallel group design. Patients received a single dose of either unpreserved trehalose 30 mg/mL and sodium hyaluronate 1.5 mg/mL (TH-SH, Thealoz Duo), unpreserved sodium hyaluronate, 0.15% (HA, Hyabak) or sodium chloride, 0.9% (NaCl, Hydrabak) eye drops. Sixty patients finished the study according to the protocol. TFT was measured with a custom-built ultrahigh-resolution Fourier domain optical coherence tomography system providing a resolution of 1.2 µm. RESULTS: The mean TFT before treatment was 2.5 ± 0.4 µm. Ten minutes after instillation, TFT significantly increased in the TH-SH group from 2.4 ± 0.4 to 3.1 ± 0.9 µm (P < 0.01) and in the HA group from 2.4 ± 0.3 to 2.9 ± 0.5 µm (P < 0.01), whereas no significant change was observed in the NaCl group (from 2.6 ± 0.4 to 2.7 ± 0.4 µm, P = 0.76). The increase in TFT remained statistically significant up to 240 minutes after administration of TH-SH. In contrast, the increase in TFT after administration of HA was only statistically significant at 10, 20, and 40 minutes after drop instillation. CONCLUSIONS: The findings of this study indicate that single instillation of TH-SH and HA eye drops increases TFT in patients with dry eye disease. The data also indicate longer corneal residence of the TH-containing eye drops. The effect of multiple instillation and long-term use of artificial tears on TFT warrants further investigation.

Mass and NMR spectroscopic characterization of 3,4-methylenedioxypyrovalerone: a designer drug with alpha-pyrrolidinophenone structure.

This study presents and discusses the nuclear magnetic resonance (NMR) spectroscopic and mass spectroscopic data of the designer drug 3,4-methylenedioxypyrovalerone (MDPV), a drug variant of pyrovalerone. MDPV was first seized in Germany in the year 2007. The structure elucidation of the aliphatic part of MDPV was carried out by product ion spectroscopy of the immonium ion with m/z 126 formed after electron ionization, and by 1D (1)H and (13)C NMR spectroscopy. Additional two-dimensional NMR spectroscopy was used to verify the structure of the alkyl side chain, and to determine the methylenedioxy position in the aromatic ring.

Mass spectral and NMR spectral data of two new designer drugs with an alpha-aminophenone structure: 4'-methyl-alpha-pyrrolidinohexanophenone and 4'-methyl-alpha-pyrrolidinobutyrophenone.

This study presents and discusses the nuclear magnetic resonance (NMR) spectroscopic and mass spectroscopic data of the new designer drug 4'-methyl-alpha-pyrrolidinobutyrophenone (MPBP) and its homolog 4'-methyl-alpha-pyrrolidinohexanophenone (MPHP) which were seized in 2004 and 2000 in Germany for the first time. The structure elucidation of the aliphatic part of MPBP was carried out by product ion spectroscopy of the immonium ion formed after electron ionization as well as with 1H and 13C NMR. Product ion spectroscopy of immonium ions again proved to be a powerful tool to determine the structure of designer drugs and to distinguish between isobaric structures of the alkyl-amino moiety.

Isomeric fluoro-methoxy-phenylalkylamines: a new series of controlled-substance analogues (designer drugs).

An impressively large number of clandestinely produced controlled-substance analogues (designer drugs) of amphetamine with high structural variety have been encountered in forensic samples in recent years. The continuous designer drug exploration and their widespread consumption results in an increasing number of reports regarding abuse and intoxication. This study presents the analytical properties of a series of new fluoro-methoxy-substituted controlled-substance analogues of amphetamine. Three ring positional isomeric fluoroamphetamines, two isomeric fluoromethoxyamphetamines, two N-alkyl 4-fluoroamphetamines, and one 4-fluorophenylbutan-2-amine were identified and differentiated by gas chromatography-mass spectrometry (GC-MS), 1H- and 13C-nuclear magnetic resonance (NMR), and gas chromatography-infrared spectroscopy (GC-IR). The regioisomeric 2-, 3-, and 4-fluoroamphetamines and the regioisomeric fluoro-methoxyamphetamines show virtually identical mass spectra so that this method is insufficient to discriminate between these closely related compounds. The mass spectra of the acetylated compounds allowed a differentiation of the 4-fluoroamphetamine from its regioisomeric 2- and 3-fluoroamphetamines. The gas chromatographic properties of the three regioisomeric fluoroamphetamines and their acetylated and trifluoroacetylated derivatives are also so similar that a complete separation of these compounds could not be achieved under GC-MS conditions. The two isomeric compounds 5-fluoro-2-methoxyamphetamine and 3-fluoro-4-methoxyamphetamine on the other hand showed significant different gas chromatographic retention times so that a separation was uncomplicated. The trifluoroacetylation of these compounds proved to be an effective method for their mass spectral differentiation. Gas chromatography-infrared spectroscopy and 1H- and 13C-nuclear magnetic resonance allowed an unequivocal differentiation of all studied regioisomeric fluoroamphetamines and fluoro-methoxyamphetamines.