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MN-18), a Phenethylamine Derivative N–OH-EDMA, and a Cathinone Derivative Dimethoxy-A-PHP, Newly Identified in Illegal Products

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MN-18), a Phenethylamine Derivative N–OH-EDMA, and a Cathinone Derivative Dimethoxy-A-PHP, Newly Identified in Illegal Products Forensic Toxicol (2015) 33:244–259 DOI 10.1007/s11419-015-0268-7 ORIGINAL ARTICLE A synthetic cannabinoid FDU-NNEI, two 2H-indazole isomers of synthetic cannabinoids AB-CHMINACA and NNEI indazole analog (MN-18), a phenethylamine derivative N–OH-EDMA, and a cathinone derivative dimethoxy-a-PHP, newly identified in illegal products Nahoko Uchiyama • Yoshihiko Shimokawa • Ruri Kikura-Hanajiri • Yosuke Demizu • Yukihiro Goda • Takashi Hakamatsuka Received: 26 December 2014 / Accepted: 20 January 2015 / Published online: 11 February 2015 Ó Japanese Association of Forensic Toxicology and Springer Japan 2015 Abstract Six new psychoactive substances were identified Introduction together with two other substances (compounds 1–8)in illegal products by our ongoing survey in Japan between The consumption of new psychoactive substances (NPSs) January and July 2014. A new synthetic cannabinoid, FDU- including synthetic cannabinoids and cathinone derivatives NNEI [1-(4-fluorobenzyl)-N-(naphthalen-1-yl)-1H-indole- has become widespread despite regulatory control mea- 3-carboxamide, 2], was detected with the newly distributed sures [1–7]. The EMCDDA (European Monitoring Centre synthetic cannabinoid FDU-PB-22 (1). Two 2H-indazole for Drugs and Drug Addiction) reported that 81 NPSs were isomers of synthetic cannabinoids, AB-CHMINACA 2H- identified by the EU early warning system in 2013, with 37 indazole analog (3) and NNEI 2H-indazole analog (4), were NPSs reported from January to May 2014 [2]. Ninety-seven newly identified with 1H-indazoles [AB-CHMINACA and NPSs were reported to the UNODC (United Nations Office NNEI indazole analog (MN-18)]. In addition, 2-methyl- on Drugs and Crime) in 2013 alone [3]. propyl N-(naphthalen-1-yl) carbamate (5) and isobutyl We previously reported the appearance of 45 newly 1-pentyl-1H-indazole-3-carboxylate (6) were detected in il- distributed substances in Japan between January 2013 and legal products. Compound 6 is considered to be a by-product May 2014, by our ongoing survey of NPSs in the illegal of the preparation of NNEI indazole analog from compound 5 drug market in Japan [8–10]. The detected compounds and 1-pentyl-1H-indazole. A phenethylamine derivative, N– were 18 synthetic cannabinoids, 13 cathinone derivatives, OH-EDMA [N-hydroxy-3,4-ethylenedioxy-N-methylam- five phenethylamines, and nine other substances, including phetamine, 7], and a cathinone derivative, dimethoxy-a-PHP the N-methyl-D-aspartate (NMDA) channel blocker (dimethoxy-a-pyrrolidinohexanophenone, 8), were newly diphenidine [8–10]. In the present study, we describe the identified in illegal products. Among them, compounds 1 and identification of eight newly distributed compounds: four 8 have been controlled as designated substances (Shitei- synthetic cannabinoids (1–4), two other substances (5 and Yakubutsu) under the Pharmaceutical Affairs Law in Japan 6), a phenethylamine derivative (7), and a cathinone since August and November 2014, respectively. derivative (8) in illegal products purchased from January to July 2014 (Fig. 1a). Keywords 2H-indazole isomer Á Synthetic cannabinoid Á FDU-NNEI Á N–OH-EDMA Á Dimethoxy-a-PHP Á Cathinone derivative Materials and methods N. Uchiyama (&) Á Y. Shimokawa Á R. Kikura-Hanajiri Á Samples for analyses Y. Demizu Á Y. Goda Á T. Hakamatsuka Division of Pharmacognosy, Phytochemistry and Narcotics, The analyzed samples were purchased via the Internet National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan between January and July 2014 as 241 chemical-type or e-mail: [email protected] herbal-type products being sold in Japan. Among them, we 123 Forensic Toxicol (2015) 33:244–259 245 Fig. 1 Structures of the newly (a) detected compounds (1–8, a), detected, but known compounds (b), and related compounds (c) (b) (c) show the analysis data of five products (A–E) for approximately 3 g of mixed dried plants. The single describing the identification of compounds 1–8 in this pa- powder-type product called ‘‘fragrance powder’’ consisted per. Each of the herbal-type products (A–D) contained of 400 mg of a brown powder (E). 123 246 Forensic Toxicol (2015) 33:244–259 UV (290 nm) TIC (a) 1 (e) Diphenidine Diphenidine (min) 1 (b) TIC Diphenidine 1 (min) 252 (f) Compound 1 (55.80 min) (min) O (c) Compound 1 (11.4 min) O N [M+H]+ 109 F [M+] (d) Authentic FDU-PB-22 (11.3 min) (g) Authentic FDU-PB-22 (55.76 min) [M+H]+ [M+] Fig. 2 Liquid chromatography–mass spectrometry (LC–MS) and gas electrospray ionization (ESI) mass and ultraviolet (UV) spectra of chromatography–mass spectrometry (GC–MS) analyses of product A. peaks 1 (c) and the authentic FDU-PB-22 (d) are shown. TIC (e), The liquid chromatography–ultraviolet-photodiode array (LC–UV- electron ionization (EI) mass spectra of peaks 1 (f) and the authentic PDA) chromatogram (a), total ion chromatogram (TIC) (b), and FDU-PB-22 (g) obtained by GC–MS are also shown Chemicals and reagents ISOTEC division of Sigma-Aldrich (St. Louis, MO, USA). FDU-PB-22 (1), FUB-PB-22, AB-CHMINACA, 5-fluoro-AMB, AM-2201 indazole analog (THJ-2201), Preparation of sample solutions NNEI indazole analog (MN-18), 4-methylbuphedrone, DL-4662, and 3,4-EDMA were purchased from Cayman For the qualitative analyses, 10 mg of each herbal-type Chemical (Ann Arbor, MI, USA); 2-methylpropyl product was crushed into powder and extracted with 1 ml N-(naphthalen-1-yl) carbamate (5) and diphenidine from of methanol under ultrasonication for 10 min. A 2-mg Otava Ltd. (Toronto, Canada) and Tocris Bioscience portion of each powder-type product was extracted with (Bristol, UK), respectively. All other common chemicals 1 ml of methanol under ultrasonication for 10 min. After and solvents were of analytical reagent grade or high- centrifugation (3,000 rpm, 5 min) of each extract, the performance liquid chromatography (HPLC) grade. As supernatant solution was passed through a centrifugal filter solvents for nuclear magnetic resonance (NMR) analysis, (Ultrafree-MC, 0.45-lm filter unit; Millipore, Bedford, chloroform-d3 (99.96 %), methanol-d4 (99.96 %), MA, USA) to serve as the sample solution for the analyses. methanol-d3 (99 %), pyridine-d5 (99.96 %), and dimethyl If necessary, the solution was diluted with methanol to a sulfoxide (DMSO)-d6 (99.96 %) were purchased from the suitable concentration before instrumental analyses. 123 Forensic Toxicol (2015) 33:244–259 247 (a) UV (296 nm) FUB-PB-22 (f) TIC 4-Methylbuphedrone 8-Quinolinol 2 4-Methylbuphedrone FUB-PB-22 (min) (b) TIC FUB-PB-22 4-Methylbuphedrone 2 2 (min) (min) (c) m/z 395 (g) Compound 2 (59.35 min) 252 O 2 N H N 285 109 (min) F m/z 397 (d) FUB-PB-22 [M+] (min) (e) Compound 2 (29.4 min) [M+H]+ Fig. 3 LC-MS and GC–MS analyses of product B. LC–UV-PDA shown. TIC (f) and EI mass spectrum of peak 2 (g) obtained by GC– chromatogram (a), TIC (b), extracted-ion chromatograms at m/z 395 MS are also presented (c) and 397 (d), and ESI mass and UV spectra of peak 2 (e) are Analytical conditions min. The elution program (2) used for the analysis of cathinone derivatives and other compounds was as follows: Each sample solution was analyzed by ultra-performance 5 % B to 20 % B (0–20 min), and up to 80 % B liquid chromatography-electrospray ionization–mass spec- (20–30 min, 10-min hold). In this study, products A, B, and trometry (UPLC-ESI–MS) and by gas chromatography– D were analyzed using program (1), and products C and E mass spectrometry (GC–MS) in the electron ionization (EI) analyzed using program (2). GC–EI–MS was performed on mode according to our previous report [11]. Two elution an Agilent 6890N GC with a 5975 mass selective detector programs were used in the LC–MS analysis. Each analysis (Agilent Technologies, Santa Clara, CA, USA) using a was carried out with a binary mobile phase consisting of capillary column (HP-1MS capillary, 30 m 9 0.25 mm solvent A (0.1 % formic acid in water) and solvent B i.d., 0.25-lm film thickness; Agilent Technologies) with (0.1 % formic acid in acetonitrile). The elution program (1) helium gas as a carrier at 0.7 ml/min. The conditions were: used for analysis of cannabinoids was as follows: 35 % B electron energy, 70 eV; injector temperature, 220 °C; (4-min hold), 65 % B to 75 % B (4–16 min), and up to injection, splitless mode for 1.0 min; oven temperature 90 % B (16–17 min, 6-min hold) at a flow rate of 0.3 ml/ program, 80 °C (1-min hold) and increase at a rate of 123 248 Forensic Toxicol (2015) 33:244–259 Fig. 4 Results of HH (b) correlation spectroscopy (HH (a) COSY), heteronuclear multiple- bond correlation (HMBC), selected nuclear Overhauser effect (NOE) correlations (a), 1H-15N HMBC correlations (b) and deuterium-induced isotope shift of NH protons for the 13C nuclear magnetic resonance (NMR) signals of compound 2 (FDU-NNEI) in CD3OD (c) (c) 5 °C/min to 190 °C (15-min hold) followed by increase at The nuclear magnetic resonance (NMR) spectra were 10 °C/min up to 310 °C (15-min hold); transfer line tem- obtained on ECA-800 and 600 spectrometers (JEOL, perature, 280 °C; scan range, m/z 40–550. Tokyo, Japan). Assignments were made via 1HNMR,13C The obtained GC mass spectra were compared to those NMR, heteronuclear multiple quantum coherence of an EI-MS library (Mass Spectra of Designer Drugs (HMQC), heteronuclear multiple-bond correlation 2013; WILEY–VCH, Weinheim, Germany). We also used (HMBC), 15N HMBC, HH correlation spectroscopy (HH our in-house EI-MS library of designer drugs obtained by COSY), nuclear Overhauser effect (NOE), and incredible our ongoing survey of illegal products and commercially natural abundance double-quantum transfer experiment available reagents for the structural elucidation.
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