Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines — an update comprising adinazolam,cloniprazepam, fonazepam, 3‐hydroxyphenazepam,metizolam and nitrazolam

Designer benzodiazepines represent an emerging class of new psychoactive substances. While other classes of new psychoactive substances such as cannabinoid receptor agonists and designer stimulants are mainly consumed for hedonistic reasons, designer benzodiazepines may also be consumed as ‘self‐medication’ by persons suffering from anxiety or other psychiatric disorders or as stand‐by ‘antidote’ by users of stimulant and hallucinogenic drugs. In the present study, five benzodiazepines (adinazolam, cloniprazepam, fonazepam, 3‐hydroxyphenazepam and nitrazolam) and one thienodiazepine (metizolam) offered as ‘research chemicals’ on the Internet were characterized and their main in vitro phase I metabolites tentatively identified after incubation with pooled human liver microsomes. For all compounds, the structural formula declared by the vendor was confirmed by nuclear magnetic resonance spectroscopy, gas chromatography–mass spectrometry (MS), liquid chromatography MS/MS and liquid chromatography quadrupole time‐of‐flight MS analysis. The detected in vitro phase I metabolites of adinazolam were N‐desmethyladinazolam and N‐didesmethyladinazolam. Metizolam showed a similar metabolism to other thienodiazepines comprising monohydroxylations and dihydroxylation. Cloniprazepam was metabolized to numerous metabolites with the main metabolic steps being N‐dealkylation, hydroxylation and reduction of the nitro function. It has to be noted that clonazepam is a metabolite of cloniprazepam, which may lead to difficulties when interpreting analytical findings. Nitrazolam and fonazepam both underwent monohydroxylation and reduction of the nitro function. In the case of 3‐OH‐phenazepam, no in vitro phase I metabolites were detected. Formation of licensed benzodiazepines (clonazepam after uptake of cloniprazepam) and the sale of metabolites of prescribed benzodiazepines (fonazepam, identical to norflunitrazepam, and 3‐hydroxyphenazepam) present the risk of incorrect interpretation of analytical findings. Copyright © 2016 John Wiley & Sons, Ltd.     

1‐[(4‐Chloro­benzoyl)­methyl]‐4‐(N,N‐di­methyl­amino)­pyridinium bromide sesquihydrate and 1‐[(4‐bromo­benzoyl)­methyl]‐4‐(N,N‐di­methyl­amino)­pyridinium bromide sesquihydrate

The title compounds, C₁₅H₁₆ClN₂O⁺·Br⁻·1.5H₂O and C₁₅H₁₆BrN₂O⁺·Br⁻·1.5H₂O, are isomorphous. The benzene ring is oriented nearly normal to the pyridine ring in both compounds. The molecular packing is mainly influenced by intermolecular O—H⋯O and O—H⋯Br interactions, as well as weak intramolecular C—H⋯O interactions. The H₂OBr⁻ units form an extended water–bromide chain, with a bridging water mol­ecule on a twofold axis.     

Radical polymerization and copolymerization of methyl α-(2-carbomethoxyethyl)acrylate,a dimer of methyl acrylate,as a polymerizable α-substituted acrylate

Polymerization and copolymerization of methyl α-(2-carbomethoxyethyl)acrylate (MMEA), which is known as a dimer of methyl acrylate, were studied in relation to steric hindrance-assisted polymerization. The propagating polymer radical from MMEA was detected as a five-line spectrum and quantified by ESR spectroscopy during the bulk polymerization at 40–80°C. The absolute rate constants of propagation and termination (κ_p and κ_t) for MMEA at 60°C (κ_p = 19 L/mol s and κ_t = 5.1 × 10⁵ L/mol s) were evaluated using the concentration of the propagating radical at the steady state. The balance of the propagation and termination rates allows polymer formation from MMEA. The polymerization rate of MMEA at 60°C was less than that of MMA by a factor of about 4 at a constant monomer concentration. Although no influence of ceiling temperature was observed at a temperature ranging from 40 to 70°C, addition-fragmentation in competition with propagation reduced the molecular weight of the polymer. The content of the unsaturated end group was estimated to be 0.1% at 60°C to the total amount of the monomer units consisting of the main chain. MMEA exhibited reactivities almost similar to those of MMA toward polymer radicals. It is concluded that MMEA is one of the polymerizable acrylates bearing a substituted alkyl group as an α-substituent. Characterization of poly(MMEA) was also carried out. © 1996 John Wiley & Sons, Inc.     

The behaviour of stereoisomeric ions in the gas phase: 2—Negative and positive chemical ionization of cyclohexanehexacarboxylic methyl esters

The positive ion chemical ionization (CI (isobutane)), negative ion chemical ionization (NICI) electron attachment (CH₄, He) and NICI (OH^?) spectra of the title compounds have been studied in detail with the aid of deuterium-labelled derivatives. The obtained results show that under CI conditions the stereospecificity is retained. Interesting correlations with the condensed phase epimerization yields are emphasized.     

Theoretical Design of High‐spin Organic Molecules with —·N—N— as a Spin‐containing Fragment and Heterocycles as an End Group

Novel stable high spin molecules possessing three different arranged fashions are designed with –·N–N< as a spin‐containing (SC) fragment, various aromatic, such as benzene ( 1 ), pyridine ( 2 ), pyridazine ( 3 ), pyrimidine ( 4 ), pyrazine ( 5 ), triazine ( 6 ) as end groups (EG) and phenyl as a ferromagnetic coupling (FC) unit. The effects of a different end groups on the spin multiplicities of the ground states and their stabilities were investigated by means of AM1‐CI approach. It has been found that the spin densities on the two atoms of the SC fragment are different from delocalization resulting in the specific stability of –·N–N<. In these molecules, the stabilities of the triplet states decrease when the distance between the atoms of central SC (–N–) increases. The orders of the stability of triplet states for 1an , 1bn , 1cn [They are isomers in which SC is connected with FC in different way ( 1an , N₁NNN₁; 1bn , N₁N N₁N; 1cn , NN₁N₁N) and six heterocycles are EG] show that the stability of triplet states with heterocycles as end groups is higher than that with phenyl as end groups, and in the order:triazine (EG)>pyrimidine, pyrazine>pyridine, pyridazine.     

Effects of alcohols on micellization and on the reaction methyl 4‐nitrobenzenesulfonate + Br− in cetyltrimethylammonium bromide aqueous micellar solutions

The effects of n‐hexanol, n‐pentanol, and n‐butanol on the critical micelle concentration (cmc), on the micellar ionization degree (α), and on the rate of the reaction methyl 4‐nitrobenzenesulfonate + Br^? have been investigated in cetyltrimethylammonium bromide (CTAB) aqueous solutions. An increase in the alcohol concentration present in the solution produces a decrease in the cmc and an increase in the micellar ionization degree. Kinetic data show that the observed rate constant decreases as alcohol concentration increases. This result was rationalized by considering variations in the equilibrium binding constant of the methyl 4‐nitrobenzenesulfonate molecules to the micelles, variations in the interfacial bromide ion concentration, and variations in the characteristics of the water–alcohol bulk phase provoked by the presence of alcohols. When these operative factors are considered, kinetic data in this and other works show that the second‐order rate constants in the micellar pseudophases of water–alcohol micellar solutions are quite similar to those estimated in the absence of alcohols. © 2004 Wiley Periodicals, Inc. Int J Chem Kinet 36: 634–641, 2004     

Raman spectroscopic investigation of the phase behavior and phase transitions in a poly(methyl methacrylate)‐carbon dioxide system

Laser Raman spectroscopy, in conjunction with an optical high‐pressure cell, was used to investigate the poly(methyl methacrylate)‐carbon dioxide system. The Raman shifts associated with carbon dioxide molecules in the gas phase and those dissolved in the polymer were used to derive sorption kinetics of carbon dioxide and the carbon dioxide‐induced phase changes in the polymer. Measurements were made in the temperature and pressure ranges in which this system is known to exhibit retrograde vitrification behavior. The Raman results on the sorption kinetics and on the onset of plasticization were in agreement with those obtained by gravimetric and calorimetric techniques, respectively. This technique provides a versatile and rapid way of characterizing polymer‐gas systems and information that so far has been obtainable only through painstaking and time‐consuming techniques. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 2214–2217, 2003     

Kinetics and mechanisms of gas phase elimination of ethyl 1‐piperidine carboxylate,ethyl pipecolinate,and (revisited) ethyl 1‐methyl pipecolinate

The kinetics of the gas‐phase elimination of the title compounds has been determined in a static reaction system over the temperature range of 340–420°C and pressure range of 45–96 Torr. The reactions proved to be homogeneous, unimolecular, and obey a first‐order rate law. The estimated rate coefficients are represented by the following Arrhenius expressions: Ethyl 1‐piperidine carboxylate Ethyl pipecolinate Ethyl 1‐methyl pipecolinate The first step of decomposition of these esters is the formation of the corresponding carboxylic acids and ethylene. The acid intermediate undergoes a very fast decarboxylation process. The mechanism of this elimination reactions is suggested on the basis of the kinetic and thermodynamic parameters. © 2005 Wiley Periodicals, Inc. Int J Chem Kinet 37: 383–389, 2005     

First Experimental and Theoretical Kinetic Study of the Reaction of 4‐Hydroxy‐4‐methyl 2‐pentanone as a Function of Temperature

In this work, experimental and theoretical rate coefficients were determined for the first time for the gas‐phase reaction of 4‐hydroxy‐4‐methyl‐2‐pentanone (4H4M2P) with OH radicals as a function of temperature. Experimental studies were carried out over the pressure range of 5–80 Torr and the temperature range of 280–365 K, by using a cryogenically cooled cell coupled to the pulsed laser photolysis‐laser induced fluorescence (PLP–LIF) technique. A detailed oxidation mechanism of 4H4M2P with OH radicals was discussed theoretically under three hydrogen abstraction pathways by using density functional theory calculations and wave function based MP2 method. Single‐point energy calculations were performed at CCSD(T) level of theory with 6–311++G(d,p) basis set. The H‐atom abstraction from the ‐CH₂ group was found to be the dominant channel. The reaction force analysis predicts that the abstraction process is mainly dominated by structural rearrangement. Linear kinetic behavior for all the pathways was found in the range of 278–365 K. An atmospheric lifetime less than 3 days was evaluated for 4H4M2P with respect to its reaction with OH, indicating that the reaction with OH of 4H4M2P may be competitive with losses via photolysis.     

Ion–molecule reaction in the gas phase 4—Stereospecific nucleophilic substitution under ammonia chemical ionization conditions from diastereomeric methyl and benzyl ethers of 3-hydroxy steroids

The ammonia chemical ionization (CI/[NH₄⁺]) mass spectra of a series of diastereomeric methyl and benzyl ethers derived from 3-hydroxy steroids (unsaturated in position 5 and saturated) have been studied. The adduct ions [M+NH₄]⁺ and [MH]⁺ and the substitution product ions [M+NH₄? ROH]⁺ (thereafter called [M_sH]⁺) are characterized by an inversion in their relative stabilites in relation to their initial configuration. [M+NH₄]_α⁺ and [MH]_α⁺ formed from the α-Δ⁵-steroid isomers are stabilized by the presence of a hydrogen bond which is not possible for the β-isomers. This stereochemical effect has also been observed in the mass analysed ion kinetic energy (MIKE) spectra of [M+NH₄]⁺ and [MH]⁺. The MIKE spectra of [M_sH]⁺ indicate that those issued from the β-isomers are more stable than the one originating from the α-isomers. This behavior is also observed in the first field free region (HV scan spectra) for [MH]⁺, [M_sH]⁺ and [M+NH₄]⁺ which are precursors of the ethylenic carbocations (base peak in the conventional CI/[NH₄]⁺ spectra). Mechanisms, such as S_N1 and S_Ni, have been ruled out for the formation of [M_sH]⁺, but instead the data support an S_N2 mechanism during the ion-molecule reaction between [M+NH₄]⁺ and NH₃.     

Bis{μ‐2‐[(2‐carbamoylhydrazin‐1‐ylidene)methyl]phenolato}bis[chloridozinc(II)] methanol disolvate,with non‐aromatic–aromatic π–π stacking and N—H...Cl—Zn hydrogen bonding

Centrosymmetric dimers of Zn^II with singly deprotonated 2‐[(2‐carbamoylhydrazin‐1‐ylidene)methyl]phenolate, [Zn₂(C₈H₈N₃O₂)Cl₂]·2CH₃OH, form an infinite one‐dimensional hydrogen‐bonded chain which is further aggregated by non‐aromatic–aromatic π–π stacking and nonclassical N—H...Cl hydrogen bonding.     

Transformations of methyl L-(—)-thiazolidine-4-carboxylate, 2-amino-2-thiazoline and 2-aminothiazole into thiazoloazines and azolothiazoles

In the search for potential immunomodulators methyl L-(—)-thiazolidine-4-carboxylate (2), 2-amino-2-thiazoline (12), and 2-aminothiazole (19) were transformed into derivatives of various bicyclic systems. Thus, from compound 2 derivatives of perhydrothiazolo[3,4-a]pyrazine 4 and 5, perhydrothiazolo[4,3-c]-[1,4]oxazine 7, and perhydroimidazo[1,5-c]thiazole 9a,b, from compound 12 derivatives of 2,3-dihydro-thiazolo[2,3-b]pyrimidine 13a,b , and from compound 19 derivatives of imidazo[2,1-b]thiazole 21, 22, 24, and 25 were prepared. 6-(p-Sulfamoylphenyl)-7-oxoperhydroimidazo[1,5-c]thiazole-5-thione (9a) was found to exhibit immunorestoration activity.     

N,N′‐Bis­[tris­(hydroxy­methyl)­methyl]­ethanedi­amide: six O—H⃛O hydrogen bonds generate only a two‐­dimensional structure

Molecules of the title compound, C₁₀H₂₀N₂O₈, adopt a conformation which is almost centrosymmetric. The mol­ecules are disordered over two sets of sites with an occupancy ratio of 0.94:0.06. In the major form, there are two intramolecular O—H?O hydrogen bonds [O?O 2.756 (4) and 2.765 (4) Å; O—H?O 144 and 146°], in which the two amidic O atoms act as acceptors. In addition, there are four intermolecular O—H?O hydrogen bonds [O?O 2.650 (3)–2.666 (3) Å; O—H?O 158–171°]; these link each mol­ecule to six others in a continuous sheet structure which contains five distinct ring motifs, two of the S(7) type, two of the R(10) type and one of the R(22) type.     

Determination of 3,5,6‐trichloro‐2‐pyridinol,phoxim and chlorpyrifos‐methyl in water samples using a new pretreatment method coupled with high‐performance liquid chromatography

A novel low‐density solvent‐based vortex‐assisted surfactant‐enhanced‐emulsification liquid–liquid microextraction with the solidification of floating organic droplet method coupled with high‐performance liquid chromatography was developed for the determination of 3,5,6‐trichloro‐2‐pyridinol, phoxim and chlorpyrifos‐methyl in water samples. In this method, the addition of a surfactant could enhance the speed of the mass transfer from the sample solution into the extraction solvent. The extraction solvent could be dispersed into the aqueous by the vortex process. The main parameters affecting the extraction efficiency were investigated and the optimum conditions were established as follows: 80 μL 1‐undecanol as extraction solvent, 0.2 mmol/L of Triton X‐114 selected as the surfactant, the vortex time was fixed at 60 s with the vortex agitator set at 3000 rpm, the concentration of acetic acid in sample solution was 0.4% v/v and 1.0 g addition of NaCl. Under the optimum conditions, the enrichment factors were from 172 to 186 for the three analytes. The linear ranges were from 0.5 to 500 μg/L with a coefficient of determination (r²) of between 0.9991 and 0.9995. Limits of detections were varied between 0.05 and 0.12 μg/L. The relative standard deviations (n = 6) ranged from 0.26 to 2.62%.     

Naphthalene‐1,6‐diol: a three‐dimensional framework built from O—H...O,O—H...π and C—H...O hydrogen bonds

The asymmetric unit of the title compound, C₁₀H₈O₂, contains two practically planar symmetry‐independent molecules linked by one O—H...O hydrogen bond. Molecules are further linked into a three‐dimensional network, which is built from R₆⁶(36), R₆⁶(18), R₆⁶(30) and R₄⁴(26) rings formed by the combined effect of three O—H...O and one C—H...O hydrogen bond. This network is additionally stabilized by an O—H...π interaction.     

Kinetics of methyl methacrylate and n‐butyl acrylate copolymerization mediated by 2‐cyanoprop‐2‐yl dithiobenzoate as a RAFT agent

The RAFT (co)polymerization kinetics of methyl methacrylate (MMA) and n‐butyl acrylate (BA) mediated by 2‐cyanoprop‐2‐yl dithiobenzoate was studied with various RAFT concentrations and monomer compositions. The homopolymerization of MMA gave the highest rate. Increasing the BA fraction f_BA dramatically decreased the copolymerization rate. The rate reached the lowest point at f_MMA ～ 0.2. This observation is in sharp contrast to the conventional RAFT‐free copolymerization, where BA homopolymerization gave the highest rate and the copolymerization rate decreased monotonously with increasing f_MMA. This peculiar phenomenon can be explained by the RAFT retardation effect. The RAFT copolymerization rate can be described by 〈R_p〉/〈R_p〉₀ = (1 + 2(〈k_c〉/〈k_t〉)〈K〉)[RAFT]₀)^?0.5, where 〈R_p〉₀ is the RAFT‐free copolymerization rate and 〈K〉 is the apparent addition–fragmentation equilibrium coefficient. A theoretical expression of 〈K〉 based on a terminal model of addition and fragmentation reactions was derived and successfully applied to predict the RAFT copolymerization kinetics with the rate parameters obtained from the homopolymerization systems. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 3098–3111, 2007     

Convenient Synthesis of 14‐Aryl‐14‐H‐dibenzo[a,j]xanthenes Catalyzed by Acyclic Brønsted Acidic Ionic Liquid [H—NMP]+[HSO4]− under Microwave Irradiation

Efficient method for direct preparation of 14‐aryl‐14‐H‐dibenzo[a,j]xanthenes through condensation of β‐naphthol with various aromatic aldehydes in the presence of the catalytic amount of [H—NMP]⁺[HSO₄]^? under microwave irradiation was described. This method has the advantages such as; very easy reaction workup, absolute separation of catalyst from the reaction mixture and smooth recyclability of catalyst. In this reaction 14‐aryl‐14‐H‐dibenzo[a,j]xanthenes were obtained as desired products in excellent yields and short reaction times via green and one‐pot procedure.     

Synthesis of a New Class of Sulfonamido Bis Heterocycles—Pyrrolyl/Pyrazolyl‐1,3,4‐oxadiazoles, 1,3,4‐Thiadiazoles,and 1,2,4‐Triazoles

A new class of sulfonamido bis heterocycles—pyrrolyl/pyrazolyl‐oxadiazoles, thiadiazoles, and triazoles—were prepared from arylaminosulfonylacetic acid hydrazide and E‐aroylethenesulfonylacetic acid adopting simple and versatile synthetic methodologies.