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Benzo‐fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1‐arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring‐expanded ureas with acid triggers a two‐atom ring contraction—an 'azatropic shift' in which one urea nitrogen displaces the other—with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1‐aryl‐tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps. [ABSTRACT FROM AUTHOR]

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1‐substituted 1‐ethynyl‐2‐vinyldi‐ and tetrahydroisoquinolines undergo [3,3]‐sigmatropic rearrangement providing pyrrolo[2,1‐b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b‐dihydro‐6H‐pyrido[2,1‐a]isoquinolines. [ABSTRACT FROM AUTHOR]

Bridged benzazepine scaffolds, possessing unique structural and physicochemical activities, are widespread in various natural products and drugs. The construction of these skeletons often requires elaborate synthetic effort with low efficiency. Herein, we develop a simple and divergent approach for constructing various bridged benzazepines by a photocatalytic intermolecular dearomatization of naphthalene derivatives with readily available α‐amino acids. The bridged motif is created via a cascade sequence involving photocatalytic 1,4‐hydroaminoalkylation, alkene isomerization and cyclization. Interestingly, the diastereoselectivity can be regulated through different reaction modes in the cyclization step. Moreover, aminohydroxylation and its further bromination have also been demonstrated to access highly functionalized bridged benzazepines. Preliminary mechanistic studies have been performed to get insights into the mechanism. This method provides a divergent synthetic approach for construction of highly functionalized bridged benzazepines, which have been otherwise difficult to access. [ABSTRACT FROM AUTHOR]

A new preparatively convenient approach to the synthesis of biopromising 1‐fluoroalkyl‐substituted 2,4,5,6‐tetrahydro‐1H‐imidazo[1,2‐a][1]benzazepines has been developed, based on the chemoselective photoreduction‐catalyzed fluoroalkylation cyclization of N‐allyl‐4,5‐dihydro‐3H‐1‐benzazepin‐2‐amines in the presence of fluorescein as an organocatalyst. The use of comparatively inexpensive perfluoroalkyl iodides (RfI), mild reaction conditions and a wide range of substituents introduced make this method very attractive for the preparation of imidazobenzazepines with a variety of fluorinated moieties. [ABSTRACT FROM AUTHOR]

Aims: Dopamine transporter (DAT) can regulate DA homeostasis and has been implicated in many nervous system diseases. Whether DAT is involved in the protection against ischemic stroke is unclear., Methods: In vivo microdialysis measurements of DA were recorded in the ischemic penumbral area of mice with middle cerebral artery occlusion (MCAO). DAT coding gene, Slc6a3 mutation, and DAT overexpression animals were performed MCAO. Madopar (compound formulation of levodopa) and nomifensine (DA reuptake inhibitor) were administered in MCAO animals. Brain slices were prepared in Slc6a3 mutation or wild-type (WT) animals with MCAO to record miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). The effects of DA and its dopamine-1 receptor (D 1 R) antagonists (SCH-23390) on mEPSCs, mIPSCs, and neurons protection were recorded., Results: MCAO caused a prominent increase in DA. Slc6a3 mutation significantly attenuated the ischemic injury, whereas DAT overexpression aggravated this injury. Both nomifensine and madopar protected against brain injury. Slc6a3 mutation and DA restored the disturbance of mEPSCs and mIPSC, and protected against neuron death, which was abolished by SCH-23390., Conclusion: DAT inhibition might be explored as a strategy for ischemic stroke prevention. DA and D 1 R involve in the restoration of synaptic dysfunction and neuron protection., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

A two‐step protocol involving cyclization and deprotection towards the synthesis of C‐1 arylated benzazepines has been developed under transition‐metal oxidant free conditions. The coupling reaction of α ‐lithiated carbanion, generated from Boc‐protected amine, with in situ generated aryne proceeds well intramolecularly. A variety of substrates were explored with corresponding products in moderate yield. [ABSTRACT FROM AUTHOR]

We describe the divergent construction of two nitrogen‐containing polycyclic systems by gold‐catalyzed cycloisomerizations. The gold‐catalyzed cascade hydroamination and 7‐endo‐dig‐selective cycloisomerization of nitrogen‐tethered 1,8‐diynes yielded indolo[1,7‐ab]benzazepines in one pot. In contrast, when Johnphos‐coordinated gold catalyst was used, the same 1,8‐diynes were transformed into indolo[1,2‐a]quinolines by 6‐endo‐dig‐selective cycloisomerization along with rearrangement of the substituent on one of the alkynes. The reaction of a naphthalene‐tethered substrate provided a helically chiral aza[6]helicene. [ABSTRACT FROM AUTHOR]

A remote cascade asymmetric inverse‐electron‐demand oxa‐Diels‐Alder reaction of allyl ketones with isatin‐derived β,γ‐unsaturated α‐keto esters has been developed in the presence of a chiral bifunctional squaramide catalyst. Taking advantage of the secondary amide activating group, a series of enantioenriched 3,4'‐pyranyl spirooxindole derivatives bearing three contiguous chiral centers were attained in high yields (84 to >99%) with excellent enantioselectivities (96–99% ee). Moreover, the gram‐scale synthesis and the construction of 1‐benzazepine scaffold by the product were also demonstrated. [ABSTRACT FROM AUTHOR]

In this research, we investigated preparation of pyridazino benzazepine derivatives in high yields via the domino and one‐pot reaction of isatoic anhydride, N‐methylimidazole, alkyl bromides, activated acetylenic compounds, and hydrazine in ionic liquid as green media at 80°C. Also, antioxidation property of some prepared pyridazino benzazepines due to having pyridazin and benzazepine core is investigated by employing of trapping diphenyl‐picrylhydrazine radical and ability of ferric reduction experiment. Our procedure has a few benefits relative to reported method such as good rate of reaction, product with high efficiency, and simple separation of product from mixture of reaction. [ABSTRACT FROM AUTHOR]

Benzazepines and benzodiazepines, benzofused seven‐membered N‐heterocycles, compose an important family of natural products and pharmaceuticals. Although certainly important and effectives, classical synthetic methods of these cyclic compounds involve methodologies that often require multistep procedures, with generation of waste materials and lack of sustainability. By contrast, cycloadditions based on transition metal catalyzed C−H bond activations (oxidative annulations) have emerged as appealing strategies for more sustainable synthetic processes. In this review, we focus our attention to describe the state‐of‐the‐art transition‐metal‐catalyzed annulations via C−H activations to benzazepines and benzodiazepines. [ABSTRACT FROM AUTHOR]

We report the cycloaddition between vinyl aziridines and arynes. Depending on the reaction conditions and the choice of the aryne precursor, the aziridinium intermediate can be trapped through two distinct mechanistic pathways. The first one proceeds through a formal [5+2] cycloaddition to furnish valuable multi‐substituted benzazepines. In the second pathway, the aziridinium is intercepted by a fluoride ion to afford allylic fluorides in good yields. Both reactions proceed stereospecifically and furnish enantiopure benzazepines and allylic fluorides. [ABSTRACT FROM AUTHOR]

A novel and efficient heterogeneous gold(I)‐catalyzed highly regio‐ and chemoselective oxidative ring expansion of 2‐alkynyl‐1,2‐dihydropyridines or ‐quinolines has been developed that proceeds smoothly through exclusive 1,2‐migration of a vinyl or phenyl group with pyridine N‐oxide as oxidant under mild conditions. The reaction provides a general and practical method for the synthesis of a wide variety of azepine derivatives with high atom‐economy, high to excellent yield, broad functional group tolerance, and recyclability of the gold(I) catalyst. The present method is an attractive alternative to construct functionalized azepines or benzazepines. [ABSTRACT FROM AUTHOR]

A concise, efficient and versatile route from simple starting materials to tricyclic tetrahydro‐1‐benzazepines carrying [a]‐fused heterocyclic units is reported. Thus, the easily accessible methyl 2‐[(2‐allyl‐4‐chlorophenyl)amino]acetate, (I), was converted, via (2RS,4SR)‐7‐chloro‐2,3,4,5‐tetrahydro‐1,4‐epoxy‐1‐benzo[b]azepine‐2‐carboxylate, (II), to the key intermediate methyl (2RS,4SR)‐7‐chloro‐4‐hydroxy‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepine‐2‐carboxylate, (III). Chloroacetylation of (III) provided the two regioisomers methyl (2RS,4SR)‐7‐chloro‐1‐(2‐chloroacetyl)‐4‐hydroxy‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepine‐2‐carboxylate, (IVa), and methyl (2RS,4SR)‐7‐chloro‐4‐(2‐chloroacetoxy)‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepine‐2‐carboxylate, C14H15Cl2NO4, (IVb), as the major and minor products, respectively, and further reaction of (IVa) with aminoethanol gave the tricyclic target compound (4aRS,6SR)‐9‐chloro‐6‐hydroxy‐3‐(2‐hydroxyethyl)‐2,3,4a,5,6,7‐hexahydrobenzo[f]pyrazino[1,2‐a]azepine‐1,4‐dione, C15H17ClN2O4, (V). Reaction of ester (III) with hydrazine hydrate gave the corresponding carbohydrazide (VI), which, with trimethoxymethane, gave a second tricyclic target product, (4aRS,6SR)‐9‐chloro‐6‐hydroxy‐4a,5,6,7‐tetrahydrobenzo[f][1,2,4]triazino[4,5‐a]azepin‐4(3H)‐one, C12H12ClN3O2, (VII). Full spectroscopic characterization (IR, 1H and 13C NMR, and mass spectrometry) is reported for each of compounds (I)–(III), (IVa), (IVb) and (V)–(VII), along with the molecular and supramolecular structures of (IVb), (V) and (VII). In each of (IVb), (V) and (VII), the azepine ring adopts a chair conformation and the six‐membered heterocyclic rings in (V) and (VII) adopt approximate boat forms. The molecules in (IVb), (V) and (VII) are linked, in each case, into complex hydrogen‐bonded sheets, but these sheets all contain a different range of hydrogen‐bond types: N—H...O, C—H...O, C—H...N and C—H...π(arene) in (IVb), multiple C—H...O hydrogen bonds in (V), and N—H...N, O—H...O, C—H...N, C—H...O and C—H...π(arene) in (VII). Two new tricyclic tetrahydro‐1‐benzazepines containing [a]‐fused heterocyclic units have been prepared from simple precursors and characterized spectroscopically. The crystal structures of one intermediate and two products have been determined; in all three, multiple hydrogen bonds generate complex sheet structures. [ABSTRACT FROM AUTHOR]

Bioactive 2‐benzazepines were accessed in an atom‐ and step‐economical manner through a versatile palladium‐catalyzed C−H activation strategy. The C−H arylation required low catalyst loading and a mild base, which was reflected by a broad scope and high functional‐group tolerance. The benzotriazolodiazepinones were identified as new heat shock protein 90 (Hsp90) inhibiting lead compounds, with considerable potential for anti‐cancer applications. Building with Pd: A new palladium‐catalyzed C−H activation strategy to access 2‐benzazepines in an atom‐ and step‐economical manner is reported. The C−H arylation featured low catalyst loading and a mild base, as reflected by a broad scope and high functional‐group tolerance. One of our benzotriazolodiazepinones was identified as a new heat shock protein 90 (Hsp90) nanomolar inhibitor, with potential for anti‐cancer applications. [ABSTRACT FROM AUTHOR]

The tetrahydro‐1‐benzazepine or benzo[b]azepine ring system is found in a number of drug molecules although methods to access 2,2‐disubstituted derivatives are rare. Here we report the preparation of N‐tert‐butoxycarbonyl‐2‐phenyltetrahydro‐1‐benzazepine followed by lithiation and trapping with electrophiles. The metallation reaction was optimized by using React‐IR spectroscopy, and VT‐NMR spectroscopy allowed the determination of the rate of rotation of the Boc group (approximate ΔG‡ 63 kJ/mol at –50 °C). The resulting organolithium was quenched to give either 2,2‐disubstituted products or, with certain electrophiles, the ortho‐substituted products, presumably through an η3‐coordinated benzyllithium intermediate. The chemistry was shown to be amenable to extension to the 7‐methoxy analog. Removal of the Boc group from the nitrogen atom led to amine products. React‐IR and VT‐NMR spectroscopy (ΔG‡ 63 kJ/mol at –50 °C for Boc rotation) were used to optimise the lithiation of N‐Boc‐2‐phenyltetrahydro‐1‐benzazepine. The intermediate organolithium was treated with electrophiles to provide a selection of substituted products, with functionalisation either at C‐2 or at the ortho position of the phenyl ring. [ABSTRACT FROM AUTHOR]

Abstract: A total synthesis of a benzazepine natural product was achieved via an alternative strategy using a Strecker‐type synthesis/Heck coupling process to construct the core ring. A comparison of spectral data of the target molecule with the previously reported one suggested the need for structure revision. The compound described herein also showed cytotoxic properties. [ABSTRACT FROM AUTHOR]

Abstract: Tetrahydroisoquinolines and tetrahydrobenzazepines were prepared by acid‐promoted ring contraction of cyclic ureas, which were themselves formed by ring expansion of indolines and tetrahydroquinolines. The consequent overall one‐carbon insertion reaction gives these 6‐ and 7‐membered heterocyclic scaffolds in three steps from readily available precursors. Other ring sizes may be formed by an alternative elimination reaction of bicyclic structures. Scalability of the method was demonstrated by operating it in a flow system. [ABSTRACT FROM AUTHOR]

In this paper, we disclose a novel strategy for the phosphine-catalyzed cycloaddition/SN2 substitution domino reaction, giving functionalized O-bridged benzoazepine and benzoxazepine derivatives in moderate to good yields. Changing the N-H protecting group of ortho-aminotrifluoroacetophenone derivatives gave different bridged-ring products in one step. [ABSTRACT FROM AUTHOR]

Aim To assess the correlation between response to tolvaptan and treatment-related factors in liver cirrhosis patients. Methods This single-center retrospective study was carried out at Shonan Kamakura General Hospital in Kanagawa, Japan, between October 2013 and September 2015. Forty-three liver cirrhosis patients (mean age, 65.7 years) with insufficient responses to conventional diuretics for at least 7 days were enrolled. All patients received oral tolvaptan (7.5 mg/day for 7 days) and guideline-directed medical therapy including sodium intake restrictions. A responder to tolvaptan was defined as a patient having a ≥2-kg decrease in body weight 1 week after commencing drug treatment, and a non-responder was defined as a patient not losing ≥2 kg in body weight 1 week after commencing treatment. We investigated the correlation of change in body weight for 1 week after drug administration compared to baseline clinical characteristics. Results The mean body weight change from the baseline on the final dosing day was −2.47 ± 3.34 kg ( P < 0.0001). There were 20 (46.5%) responders to tolvaptan. Urinary sodium and volume excretion was higher in responders than in non-responders (108.2 ± 70.5 vs 42.6 ± 36.7, P = 0.0003; 1462.8 ± 625.7 vs 960.9 ± 600.6, P = 0.0073). Logistic regression analyses for responders to tolvaptan were carried out, and independent correlation of the responders was urinary sodium excretion ( P = 0.0114; hazard ratio, 0.9418; 95% confidence interval, 0.8768−0.9896) in the multivariate analyses. Conclusion In decompensated liver cirrhosis patients, urinary excretion sodium showed good correlation with tolvaptan response. [ABSTRACT FROM AUTHOR]

A metal-free synthesis of biologically important benzazepines is achieved through a single synthetic operation involving an oxidative C-H bond functionalization and ring expansion with diazomethanes as key reagent. This represents a new, strong methodology for the straightforward construction of the seven-ring N-heterocyclic structures under mild conditions using a 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) oxoammonium salt as oxidant. Moderate to good yields are achieved from simple, readily available tetrahydroisoquinolines, and this methodology has been further successfully applied for the synthesis of the 3-benzazepine drug Lorcaserin. A possible mechanistic pathway for the ring expansion step, comprising the extrusion of nitrogen in a concerted asynchronic process, is proposed based on both mechanistic proof and density function theory (DFT) calculations. [ABSTRACT FROM AUTHOR]

A new π-conjugated system of nitrogen-containing polycyclic compounds was constructed by cationic AuI-catalyzed cycloisomerization. Intramolecular reaction of 9-(2-alkynylphenyl)-9 H-carbazole derivatives gave a variety of penta- and hexacyclic compounds possessing a dibenzazepine skeleton. The rigid carbazole structure was responsible for efficient 7- endo- dig cycloisomerization. [ABSTRACT FROM AUTHOR]

(−)-Stepholidine is an active ingredient of the Chinese herb Stephania and naturally occurring tetrahydroprotoberberine alkaloid with mixed dopamine receptor D1 agonistic and dopamine receptor D2 antagonistic activities. In this work, a series of novel hexahydrobenzo[4,5]azepino [2,1-a]isoquinolines were designed and synthesized as ring-expanded analogues of (−)-Stepholidine. Initial pharmacological assays demonstrated that a benzazepine replacement was associated with significant increase in selectivity and functional reversal at dopamine receptor D1. Compound-(−)- 15e ( Ki = 5.32 ± 0.01 n m) is more potent than (−)-Stepholidine ( Ki = 13 n m) and was identified as a selective dopamine receptor D1 antagonist ( IC50 = 0.14 μ m). Moreover, molecular modeling suggested that (−)- 15e might exert its dopamine receptor D1 antagonistic activities through interacting with the transmembrane helix 7 of dopamine receptor D1. [ABSTRACT FROM AUTHOR]

A strategy for the NHC-catalyzed asymmetric synthesis of spirobenzazepinones, spiro-1,2-diazepinones, and spiro-1,2-oxazepinones has been developed via [3+4]-cycloaddition reactions of isatin-derived enals (3C component) with in-situ-generated aza- o-quinone methides, azoalkenes, and nitrosoalkenes (4atom components). The [3+4] annulation strategy leads to the seven-membered target spiro heterocycles bearing an oxindole moiety in high yields and excellent enantioselectivities with a wide variety of substrates. Notably, the benzazepinone synthesis is atroposelective and an all-carbon spiro stereocenter is generated. [ABSTRACT FROM AUTHOR]

Two strategies were pursued for the synthesis of 2-benzazepin-1-ones 16 and 17 with an N/O-acetal or enamide in 3-position. Establishment of the propionaldehyde substructure first and subsequently the amide moiety via a four step sequence failed to provide amides 11. However the Pd-catalyzed of 2-iodobenzamides 13 with allyl alcohol and subsequent reaction of the products 14/ 15 with acid led to 2-benzazepin-1-ones in a two-step sequence. Depending on the size of the N-substituent the 3-methoxy derivative 16a or the dihydro-2-benzazepine 17b was formed. [ABSTRACT FROM AUTHOR]

This paper provides the full 13C NMR assignments for the trifluoroacetamides of five potentially appetite‐reducing 5‐HT2C benzazepine receptor agonists and two open‐ring synthetic precursors. These compounds exist in solution as mixtures of two rotamers for each of which the 13C NMR signals have now been assigned with the assistance of 2D NMR experiments and the carbonyl‐induced shifts of the neighboring 13CH2 resonances and long‐range 13C/19F couplings. [ABSTRACT FROM AUTHOR]

Tetrahydro-1-benzazepines have been described as potential antiparasitic drugs for the treatment of chagas disease and leishmaniasis, two of the most important so-called `forgotten tropical diseases' affecting South and Central America, caused by Trypanosoma cruzi and Leishmania chagasi parasites, respectively. Continuing our extensive work describing the structural characteristics of some related compounds with interesting biological properties, the crystallographic features of three epoxy-1-benzazepines, namely (2 SR,4 RS)-6,8-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1 H-1,4-epoxy-1-benzazepine, (1), (2 SR,4 RS)-6,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1 H-1,4-epoxy-1-benzazepine, (2), and (2 SR,4 RS)-8,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1 H-1,4-epoxy-1-benzazepine, (3), all C22H21NO, and two 1-benzazepin-4-ols, namely 7-fluoro- cis-2-[( E)-styryl]-2,3,4,5-tetrahydro-1 H-1-benzazepin-4-ol, C18H18FNO, (4), and 7-fluoro- cis-2-[( E)-pent-1-enyl]-2,3,4,5-tetrahydro-1 H-1-benzazepin-4-ol, C15H20FNO, (5), are described. Some peculiarities in the crystallization behaviour were found, involving significant variations in the crystalline structures as a result of modest changes in the peripheral substituents in (1)-(3) and the occurrence of discrete disorder due to the molecular overlay of enantiomers with more than one conformation in (5). In particular, an interesting phase change on cooling was observed for compound (5), accompanied by an approximate fourfold increase of the unit-cell volume and a change of the Z′ value from 1 to 4. This transition is a consequence of the partial ordering of the pentenyl chains in half of the molecules breaking half of the symmetry axes observed in the room-temperature structure of (5). The structural assembly in all the title compounds is characterized by not only (N,O)-H...(O,N) hydrogen bonds, but also by unconventional C-H...O contacts, resulting in a wide diversity of packing. [ABSTRACT FROM AUTHOR]

The secondary metabolite, turkiyenine, is a probable bioactive component of the medicinal plant, Hypecoum procumbens L. Structurally, it is an isoquinoline-derived alkaloid composed of dihydrobenzofuran and 3-benzazepine-1-one moieties arranged in a unique spirocyclic structure. Yet despite the intriguing structure and medicinal relevance of benzofuran and benzazepine motifs, neither a synthetic study nor a biological evaluation of turkiyenine have been reported to date. Herein we communicate the first total synthesis of the proposed structure of turkiyenine, and on the basis of X-ray crystallography show that the proposed structure is incorrect. The key steps of our synthesis include an aza-spiro annulation onto a benzofuran using a rhodium-nitrenoid to construct a 3-alkyl-3-amino- 2,3-dihydrobenzofuran, an acyl-alkylation of an aryne onto a β- ketolactam to form a 3-benzazepine-1-one, and chemoselective reduction of an amide in the presence of a ketone. [ABSTRACT FROM AUTHOR]

A simple and effective two-step approach to tricyclic pyrimidine-fused benzazepines has been adapted to give the tetracyclic analogues. In ( RS)-8-chloro-6-methyl-1,2,6,7-tetrahydropyrimido[5′,4′:6,7]azepino[3,2,1- hi]indole, C15H14ClN3, (I), the five-membered ring adopts an envelope conformation, as does the reduced pyridine ring in ( RS)-9-chloro-7-methyl-2,3,7,8-tetrahydro-1 H-pyrimido[5′,4′:6,7]azepino[3,2,1- ij]quinoline, C16H16ClN3, (II). However, the seven-membered rings in (I) and (II) adopt very different conformations, with the result that the methyl substituent occupies a quasi-axial site in (I) but a quasi-equatorial site in (II). The molecules of (I) are linked by C-H...N hydrogen bonds to form C(5) chains and inversion-related pairs of chains are linked by a π-π stacking interaction. A combination of a C-H...π hydrogen bond and two C-Cl...π interactions links the molecules of (II) into complex sheets. Comparisons are made with some similar fused heterocyclic compounds. [ABSTRACT FROM AUTHOR]

A short and highly stereoselective chiral pool synthesis of tetrahydro-3-benzazepines as potential drug molecules is described, using simple enantiopure amino acids as the chiral building blocks. Intramolecular Friedel-Crafts alkylation towards seven-membered rings was achieved with high diastereoselectivity for the first time and accomplished by a biocompatible calcium catalyst. The simple and cost efficient approach allows for the variation of all substituents in the 3-benzazepine by a change of the substitution pattern in one or more of the reagents, while leaving the general synthetic route unchanged. Furthermore, assignment of the absolute configuration of the 3-benzazepine derivative is straightforward, based on the amino acid building block employed. [ABSTRACT FROM AUTHOR]

A novel osmium-catalyzed cyclization of o-alkynyl phenethylamines to give 3-benzazepines is reported. The procedure allows the straightforward preparation of a broad range of dopaminergic 3-benzazepine derivatives. Mechanistic investigations revealed that the process takes place via osmacyclopropene intermediates, which were isolated and characterized by X-ray crystallography. [ABSTRACT FROM AUTHOR]

A Brønsted acid catalyzed redox-annulated cascade reaction between 2-arylpyrroles and 2-(pyrrolidin-1-yl)-, 2-(piperidin-1-yl), or 2-morpholinobenzaldehydes has been developed. This dehydration/1,5-hydride shift/cyclization sequence results in the construction of two new C(sp2)-C(sp3) bonds, providing structurally diverse 1,2-pyrrole-annulated benzazepines in yields of 25-65 %. [ABSTRACT FROM AUTHOR]

An efficient method for the construction of cyclopropane-fused dihydroquinolines was established by a novel Povarov-type three-component reaction of aromatic aldehydes, anilines and cyclopropenes in the presence of trifluoromethanesulfonic acid. The reaction proceeded in a regioselective and diastereoselective manner. Furthermore, the dihydroquinolines were smoothly converted to benzazepine derivatives via a ring opening/isomerization sequence, further expanding the synthetic scope. [ABSTRACT FROM AUTHOR]

A detailed examination of the synthesis of functionalized 6,11-dihydro-5 H-benzo[ b]pyrimido[5,4- f]azepines 4 is described. Base-promoted aromatic nucleophilic substitution of 5-allyl-4,6-dichloropyrimidines 1a- c with different N-substituted anilines and indoline gave the corresponding aminolysis products 3a- p, which on acid-promoted intramolecular Friedel-Crafts cyclization produced the target polysubstituted 6,11-dihydro-5 H-benzo[ b]pyrimido[5,4- f]azepines 4a- p in moderate to very high yields. [ABSTRACT FROM AUTHOR]

We have synthesized a large number of tricyclic 2-substituted 4-alkylamino-5,6-dihydro[1]benzazepino[5,4- d]pyrimidines as part of our research to develop new effective antiplatelet drugs. A variety of alkyl and aryl groups were used as substituents at the 2-position. Evaluation of the effects of the newly synthesized compounds on collagen-induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin. [ABSTRACT FROM AUTHOR]

Libraries of tricyclic 2-substituted 4-alkylamino-9-chloro-5,6-dihydropyrimido[5,4- d]benzazepines and tetracyclic 12-substituted 8-chloro-1,2,5,6-tetrahydro-4 H-imidazo[1′,2′:1,6]pyrimido[5,4- d]benzazepines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2-position. Evaluation of the effects of the newly synthesized compounds on collagen-induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin. [ABSTRACT FROM AUTHOR]

A gold-catalyzed highly regio- and chemoselective oxidative ring expansion of 2-alkynyl-1,2-dihydropyridines and its analogues using pyridine-N-oxide as the oxidant has been developed. Ring expansion proceeds through exclusive 1,2-migration of a vinyl or phenyl group, whereas no 1,2-H and 1,2-N migration take place. The reaction provides an efficient and attractive route to various types of medium-sized azepine derivatives in generally high to excellent yields with a broad functional group tolerance. DFT studies indicate that the reaction proceeds through the formation of a cyclopropyl gold intermediate, and no gold carbene species is involved. [ABSTRACT FROM AUTHOR]

The morbidity and mortality of a severe calcium channel blocker intoxication is high due to serious toxic cardiac effects. Its treatment is supported by low-quality evidence from the heterogeneous literature. We describe a case of a severe diltiazem intoxication and critically appraise the efficacy and role of high-dose calcium and glucagon infusions. A 53-year-old woman was admitted to the emergency department with a cardiogenic shock with complete AV block, not responding to atropine, isoprenaline and an external pacemaker. Later on, it became clear that she had a severe diltiazem intoxication which was successfully treated with isotone fluids, inotropes, vasopressors and continuous infusion of high-dose calcium and glucagon. The patient developed, however, an acute, necrotizing pancreatitis, probably related to iatrogenic high calcium levels. This case demonstrates lack of consensus regarding target levels of serum calcium for treatment of a severe diltiazem intoxication. Goal-directed tapering of calcium should prevent side effects of iatrogenic hypercalcaemia. The contribution of glucagon infusions is doubtful due to the instability of solubilized glucagon. This might explain why the effect of glucagon is variable in the literature. [ABSTRACT FROM AUTHOR]

A solvent-controlled cascade process has been identified for the dual purpose of the preparation of either dihydrocarbazoles or dihydropyridoindoles from identical N-aryl-α,β-unsaturated nitrones and electron-deficient allene starting materials. These reactions proceed smoothly under mild metal-free conditions affording a range of two types of skeletally distinct indole-based heterocycles in high yield and diastereoselectivity. These transformations demonstrate the use of a bifurcated cascade process that hinges on the ring-opening event of a benzazepine intermediate for the synthesis of skeletally diverse heterocyclic products and rapid access to biologically-significant, indole-based structures. [ABSTRACT FROM AUTHOR]

The efficacy and safety of retreatment with varenicline in smokers attempting to quit were evaluated in this randomized, double-blind, placebo-controlled, multicenter trial (Australia, Belgium, Canada, the Czech Republic, France, Germany, the United Kingdom, and the United States). Participants were generally healthy adult smokers (≥10 cigarettes/day) with ≥1 prior quit attempt (≥2 weeks) using varenicline and no quit attempts in ≤3 months; they were randomly assigned (1:1) to 12 weeks' varenicline (n = 251) or placebo (n = 247) treatment, with individual counseling, plus 40 weeks' nontreatment follow-up. The primary efficacy end point was the carbon monoxide-confirmed (≤10 ppm) continuous abstinence rate for weeks 9-12, which was 45.0% (varenicline; n = 249) vs. 11.8% (placebo; n = 245; odds ratio: 7.08; 95% confidence interval: 4.34, 11.55; P < 0.0001). Common varenicline group adverse events were nausea, abnormal dreams, and headache, with no reported suicidal behavior. Varenicline is efficacious and well tolerated in smokers who have previously taken it. Abstinence rates are comparable with rates reported for varenicline-naive smokers. [ABSTRACT FROM AUTHOR]

Aims Risk stratification in patients admitted with worsening heart failure (HF) is essential for tailoring therapy and counselling. Risk models are available but rarely used, in part because many require laboratory and imaging results that are not routinely available. Body temperature is associated with prognosis in other illnesses, and we hypothesized that low body temperature would be associated with worse outcomes in patients admitted with worsening HF. Methods and results The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial was an event-driven, randomized, double-blind, placebo-controlled study of tolvaptan in 4133 patients hospitalized for worsening HF with an EF <40%. Co-primary endpoints were all-cause mortality and cardiovascular (CV) death or HF rehospitalization. Body temperature was measured orally at randomization and entered in analyses both as a continuous variable and categorized into three groups (<36°C, 36–36.5°C, and >36.5°C) using Cox regression models. The composite of CV death or HF rehospitalization occurred in 1544 patients within 1 year. For every 1°C decrease in body temperature, the risk of adverse outcomes increased by 16% [hazard raio (HR) 1.16, 95% confidence interval (CI) 1.04–1.28], after adjustment for age, gender, race, systolic blood pressure, EF, blood urea nitrogen, and serum sodium. In fully adjusted analysis, the risk of adverse outcomes in the lowest body temperature group (<36°C) was 51% higher than that of the index group (>36.5°C) (HR 1.35, 95% CI 1.15–1.58). Conclusions Low body temperature is an independent marker of poor cardiovascular outcomes in patients admitted with worsening HF and reduced EF. [ABSTRACT FROM PUBLISHER]

Background and Aims: In Australia, patterns of use of smoking cessation medications and factors associated with their dispensing are currently not known. This study aimed to measure the demographic and clinical factors associated with varenicline dispensing compared with nicotine replacement therapy (NRT) and bupropion among first-time users of Pharmaceutical Benefits Scheme (PBS) subsidised smoking cessation medicines in Australia and to characterise those who discontinued varenicline treatment prematurely., Design: Retrospective, population-based study. Logistic regression was used to identify factors associated with varenicline dispensing compared with NRT and bupropion. Sensitivity analyses estimated the proportion of individuals who completed the recommended 12 weeks of varenicline treatment., Setting and Participants: First-time users of PBS subsidised smoking cessation medicines in Australia. Individuals first dispensed a smoking cessation medicine between 2011 and 2019 were identified from a 10% random sample of the national dispensing claims data., Measurements: The outcome for the regression analysis was the dispensing of varenicline compared with NRT and bupropion. The dispensing of a smoking cessation medicine was identified using the World Health Organization Anatomical Therapeutic Chemical Classification System and PBS item codes. Independent variables included demographic and clinical characteristics such as sex, age, concessional status, year of treatment initiation and comorbidities identified using the Rx-Risk index. The proportion of people who discontinued varenicline treatment after the initiation pack was determined using prescription refill data., Findings: A total of 94 532 people had their first PBS subsidised smoking cessation medicine. Of these, 62 367 (66.0%) were dispensed varenicline, 29 949 (31.7%) NRT and 2216 (2.3%) bupropion. The odds of varenicline dispensing were higher in males (OR, 1.18; 95% CI, 1.14-1.21), but lower in older adults (0.86 [0.82-0.90] in above 30 years to 0.49 [0.47-0.52] in 61 years and above), among concession beneficiaries (0.44; 0.43-0.46), and those with congestive heart failure (0.60; 0.53-0.68), depression (0.61; 0.54-0.69), anxiety (0.70; 0.66-0.73), psychotic illness (0.39; 0.37-0.42), and chronic obstructive pulmonary disease (0.87; 0.82-0.92). The majority (37 670; 60.4%) of those dispensed varenicline discontinued treatment after the initiation pack. Anxiety and psychotic illnesses were significantly more prevalent in those who discontinued treatment. Only 2804 (4.5%) of those dispensed varenicline completed 12 weeks of treatment., Conclusion: Individuals dispensed varenicline in Australia appear to be healthier compared with those who are dispensed nicotine replacement therapy or bupropion., (© 2022 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

The structures are reported of nine closely related tetrahydro-1,4-epoxy-1-benzazepines carrying pendant heterocyclic substituents, namely: 2- exo-(5-nitrofuran-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1 H-1-benzazepine, C14H12N2O4, (I), 7-fluoro-2- exo-(1-methyl-1 H-pyrrol-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1 H-1-benzazepine, C15H15FN2O, (II), 7-fluoro-2- exo-(5-methylfuran-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1 H-1-benzazepine, C15H14FNO2, (III), 7-fluoro-2- exo-(3-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1 H-1-benzazepine, C15H14FNOS, (IV), 7-fluoro-2- exo-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1 H-1-benzazepine, C15H14FNOS, (V), 7-chloro-2- exo-(5-methylfuran-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1 H-1-benzazepine, C15H14ClNO2, (VI), 2- exo-(5-methylfuran-2-yl)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1,4-epoxy-1 H-1-benzazepine, C16H14F3NO3, (VII), 2- exo-(3-methylthiophen-2-yl)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1,4-epoxy-1 H-1-benzazepine, C16H14F3NO2S, (VIII), and 2- exo-(5-nitrofuran-2-yl)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1,4-epoxy-1 H-1-benzazepine, C15H11F3N2O5, (IX). All nine compounds crystallize in centrosymmetric space groups as racemic mixtures with configuration (2 RS,4 SR). There are no direction-specific interactions between the molecules in (V). The molecules in (III), (IV), (VI) and (VII) are linked into simple chains, by means of a single C-H...O hydrogen bond in each of (III), (VI) and (VII), and by means of a single C-H...π(arene) hydrogen bond in (IV), while the molecules in (VIII) are linked into a chain of rings. In each of (I) and (II), a combination of one C-H...O hydrogen bond and one C-H...π(arene) hydrogen bond links the molecules into sheets, albeit of completely different construction in the two compounds. In (IX), the sheet structure is built from a combination of four independent C-H...O hydrogen bonds and one C-H...π(arene) hydrogen bond. Comparisons are made with some related compounds. [ABSTRACT FROM AUTHOR]

A novel construction of 2-benzazepine derivatives based on TiCl4-mediated tandem Mannich reaction of electron-rich benzyl iminium ions with alkenyl ethers and Friedel- Crafts-type alkylation is described. The protocol is amenable to provide the tricyclic furo[3,2- d][2]benzazepine and pyrano[3,2- d][2]benzazepine derivatives, respectively, with 2,3-dihydrofuran or 3,4-dihydro-2 H-pyran as the substrates. [ABSTRACT FROM AUTHOR]

Background & Aims: Tolvaptan, vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites., Methods: From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; >1.5 kg decrease of BW) were included in the GWAS and replication study., Results: Genome-wide association study showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 × 10 -8 ). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 0.92, P = .003; OR = 1.02, P = .02 and OR = 3.98, P = .000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234 + BUN*0.077 + Na*-0.179) (1 + exp (score)) was determined for the detection of non-responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774., Conclusion: SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (>38.6%) can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: Analysed using classical frequentist hypothesis testing with alpha set to 0.05, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) did not find enough evidence to reject the hypothesis of no difference in neuropsychiatric adverse events (NPSAEs) attributable to varenicline, bupropion, or nicotine patch compared with placebo. This might be because the null hypothesis was true or because the data were insensitive. The present study aimed to test the hypothesis more directly using Bayes factors., Design: EAGLES was a randomised, double-blind, triple-dummy, controlled trial., Setting: Global (16 countries across five continents), between November 2011 and January 2015., Participants: Participants were smokers with (n = 4116) and without (n = 4028) psychiatric disorders., Interventions: Varenicline (1 mg twice daily), bupropion (150 mg twice daily), nicotine patch (21 mg once daily with taper) and matched placebos., Measurements: The outcomes included: (i) a composite measure of moderate/severe NPSAEs; and (ii) a composite measure of severe NPSAEs. The relative evidence for there being no difference in NPSAEs versus data insensitivity for the medications was calculated in the full and sub-samples using Bayes factors and corresponding robustness regions., Findings: For all but two comparisons, Bayes factors were <1/3, indicating moderate to strong evidence for no difference in risk of NPSAEs between active medications and placebo (Bayes factor = 0.02-0.23). In the psychiatric cohort versus placebo, the data were suggestive, but not conclusive of no increase in NPSAEs with varenicline (Bayes factor = 0.52) and bupropion (Bayes factor = 0.71). Here, the robustness regions ruled out a ≥7% and ≥8% risk increase with varenicline and bupropion, respectively., Conclusions: Secondary analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study trial using Bayes factors provides moderate to strong evidence that use of varenicline, bupropion or nicotine patches for smoking cessation does not increase the risk of neuropsychiatric adverse events relative to use of placebo in smokers without a history of psychiatric disorder. For smokers with a history of psychiatric disorder the evidence also points to no increased risk but with less confidence., (© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Aims: To use a database of national essential medicine lists to determine how many include the three tobacco dependence medicines: nicotine replacement therapy, varenicline and bupropion., Methods: Retrospective observational study using national essential medicine lists for 137 countries., Results: Of the 137 countries, 34 listed at least one of the three tobacco dependence medicines included in this analysis. Bupropion was listed by 23 countries, nicotine replacement therapy by 17 countries and varenicline by eight countries., Conclusions: Tobacco dependence medicines do not appear on the essential medicines lists of most countries., (©2020 Society for the Study of Addiction.)

Repeated cocaine exposure causes long-lasting neuroadaptations that involve alterations in cellular signaling and gene expression mediated by dopamine in different brain regions, such as the striatum. Previous studies have pointed out to the dopamine D1 receptor as one major player in psychostimulants-induced behavioral, cellular, and molecular changes. However, the role of other dopamine receptors has not been fully characterized. Here we used dopamine D2 receptor knockout (D2 -/- ) mice to explore the role of D2 receptor (D2R) in behavioral sensitization and its associated gene expression after acute and chronic cocaine and amphetamine administration. We also studied the impact of D2R elimination in D1R-mediated responses. We found that cocaine- and amphetamine-induced behavioral sensitization is deficient in D2 -/- mice. The expression of dynorphin, primarily regulated by D1R and a marker of direct-pathway striatal neurons, is attenuated in naïve- and in cocaine- or amphetamine-treated D2 -/- mice. Moreover, c-Fos expression observed in D2 -/- mice was reduced in acutely but not in chronically treated animals. Interestingly, inactivation of D2R increased c-Fos expression in neurons of the striatopallidal pathway. Finally, elimination of D2R blunted the locomotor and striatal c-Fos response to the full D1 agonist SKF81297. In conclusion, D2R is critical for the development of behavioral sensitization and the associated gene expression, after cocaine administration, and it is required for the locomotor responses promoted by D1R activation., (© 2019 Society for the Study of Addiction.)

A one-pot three-component cyclization of diazo compounds as nucleophiles with primary aromatic amines and alkynylbenzaldehydes gives 3-benzazepines via a cascade imine--yne cyclization/nucleophilic addition/1,2-aryl migrations. Diazo dihydroisoquinolines are obtained under slightly modified conditions. [ABSTRACT FROM AUTHOR]

Using 2-iodobenzoic acid as common starting material, two 2-benzazepin-1-one derivatives (VIII) and (XII) are prepared. [ABSTRACT FROM AUTHOR]