Benzazepine Derivatives Research Articles

DABCO-catalyzed [3 + 4] annulations of Schiff bases with α-substituted allenes: Construction of functionalized benzazepine derivatives

DABCO-catalyzed [3 + 4] annulations of Schiff bases with α-substituted allenes: Construction of functionalized benzazepine derivatives

Visible-Light-Induced Regioselective Cascade Radical Cyclization of α-Bromocarbonyls: Access to Benzazepine Derivatives.

Visible-light-induced regioselective cascade radical cyclization of α-bromocarbonyls for the synthesis of benzazepine derivatives is described. In the presence of fac-Ir(ppy)3 (2.0 mol %) as a photocatalyst, 2,6-lutidine as a base, and dichloromethane as a solvent, the reactions proceed smoothly to afford seven-membered rings in good yields. This protocol features a broad substrate scope, excellent functional group tolerance, and mild reaction conditions. Preliminary mechanistic studies reveal that the generation of the α-carbon radical is more prone to react with the 1,1-diphenylethylene tethered acrylamide to generate the stable seven-membered heterocycle.

Phosphine-controlled divergent reactions of MBH-carbonates with azaheptafulvenes: access to o-anilinyl diene and benzazepine derivatives

A phosphine controlled divergent cascade reaction of MBH-carbonates with azaheptafulvenes was disclosed. PPh3 provided o-aminophenyl diene while PCy3 offered benzazepine derivative through formal [8 + 3] annulation/ring contraction cascade.

NHC-Catalyzed Regioselective Intramolecular Radical Cyclization Reaction for the Synthesis of Benzazepine Derivatives.

A novel and efficient strategy for the synthesis of a series of structurally interesting benzazepine derivatives via an N-heterocyclic carbene-catalyzed regioselective intramolecular radical cyclization has been developed. This protocol features good regioselectivity, good functional-group compatibility, and wide substrate scope, providing a transition-metal- and oxidant-free pathway to access the seven-membered rings under mild reaction conditions. Additionally, further transformation of benzazepines and a large-scale experiment were also conducted.

SPION nanoparticles for delivery of dopaminergic isoquinoline and benzazepine derivatives

Superparamagnetic iron nanoparticles (SPIONs) have become one of the most useful colloidal systems in nanomedicine. We report here the preparation of new hybrid core@shell systems based on SPION nanoparticles coated with a SiO2 shell (SPION@SiO2) and functionalized with carboxyl groups (SPION@SiO2-COOH). A series of new N-alkylamino- and N-alkylamido-terminated 1-phenyl- tetrahydroisoquinolines (THIQs) and 3-tetrahydrobenzazepines (THBs) derivatives presenting -SMe and -Cl groups, respectively, with potential dopaminergic activity, are synthesized and incorporated to the hybrid system. We include the synthetic details for THIQs and THBs derivatives preparation and investigate the influence of the terminal-functional group as well as the number of carbon atoms linked to THIQ and THB molecules during the coupling to the SPION@SiO2-COOH. Nuclear magnetic resonance (NMR) and electron ionization mass spectrometry (EI-MS) are used to characterize the synthesized THIQs and THBs. High-angle annular dark-field transmission electron microscopy (HAADF-TEM), energy dispersive X-ray transmission electron microscopy (EDX-TEM), and proton high-resolution magic angle spinning NMR spectroscopy1H HRMAS-NMR) are used to confirm the presence of THB and THIQ molecules onto the surface of the nanoparticles. The hybrid SPION@SiO2-THIQ and THB systems show significant activity toward the D2 receptor, reaching Ki values of about 20 nM, thus having potential application in the treatment of central nervous system (CNS) diseases.

Organophotoredox-Catalyzed Synthesis of Benzazepine Derivatives under Benign Conditions

Key words organophotoredox catalysis - benzazepines - ring opening - cyclization - halogen-atom transfer

Visible-light-mediated intramolecular radical cyclization of α-brominated amide-tethered alkylidenecyclopropanes.

A ring-opening/cyclization cascade reaction of α-brominated amide-tethered alkylidenecyclopropanes in the presence of photocatalyst 4CzIPN under visible-light irradiation was developed to afford polycyclic benzazepine derivatives in good yields with broad substrate scope and good functional tolerance. A plausible mechanism involving a halogen atom transfer (XAT) process and a radical chain process is proposed for this reaction. This study provides a concise and practical strategy for the synthesis of benzazepine derivatives.

Recent Progress on the Synthesis of Benzazepine Derivatives via Radical Cascade Cyclization Reactions

Recent Progress on the Synthesis of Benzazepine Derivatives via Radical Cascade Cyclization Reactions

A NOVEL METHOD FOR THE SYNTHESIS OF PYRIDO[1,2- b ][2]BENZAZEPINES ON THE BASIS OF 2-(BROMOMETHYL)BENZOPHENONES AND 2-(BROMOMETHYL)BENZALDEHYDE

A novel method for the synthesis of pyrido[1,2- b ][2]benzazepine derivatives is based on the reaction of 2-(bromomethyl)benzophenones and 2-(bromomethyl)benzaldehyde with 2-methylpyridines. The route of synthesis of 6 H -pyrido[1,2- b ][2]benzazepinium salts includes several steps with the possibility of isolating intermediate 1-benzyl-2-methylpyridinium and 11-aryl-11-hydroxy-11,12-dihydro-6 H- pyrido[1,2- b ][2]benzazepinium bromides. The efficiency of dehydration of intermediate carbinols increases with the use of protic solvents, an increase in heating time, and in the presence of electron-withdrawing substituents in the benzazepine moiety. The structure of the reaction products was proved by mass spectrometry, IR and one- and two-dimensional correlation NMR spectroscopy.

A novel method for the synthesis of pyrido[1,2-b][2]benzazepines on the basis of 2-(bromomethyl)benzophenones and 2-(bromomethyl)benzaldehyde

A novel method for the synthesis of pyrido[1,2-b][2]benzazepine derivatives is based on the reaction of 2-(bromomethyl)benzophenones and 2-(bromomethyl)benzaldehyde with 2-methylpyridines. The route of synthesis of 6H-pyrido[1,2-b][2]benzazepinium salts includes several steps with the possibility of isolating intermediate 1-benzyl-2-methylpyridinium and 11-aryl-11-hydroxy-11,12-dihydro-6Hpyrido[1,2-b][2]benzazepinium bromides. The efficiency of dehydration of intermediate carbinols increases with the use of protic solvents, an increase in heating time, and in the presence of electron-withdrawing substituents in the benzazepine moiety. The structure of the reaction products was proved by mass spectrometry, IR and one- and two-dimensional correlation NMR spectroscopy.

Primary screening for the toxicity of marine cyanobacteria Lyngbya bouillonii (Cyanophyceae: Oscillatoriales) recorded for the first time from Indian Ocean

Climate change has triggered an increased incidence of cyanobacterial blooms in the marine ecosystem. While most bloom-forming species cause widespread algal blooms, Lyngbya bouillonii, a benthic marine cyanobacteria forms localized blooms. This cyanobacteria, reported only from the tropical Pacific Ocean, has gained immense biomedical interest owing to an array of bioactive secondary metabolites it produces. While studying the occurrence and distribution of marine cyanobacteria across Andaman Nicobar Islands we encountered this species forming tenacious mats, attached to corals and quite often forming extensive localized blooms. Accordingly, L. bouillonii is being reported for the first time from the Indian Ocean. The symbiotic, snapping shrimp Alpheus frontalis was found to coexist within these cyanobacterial mats. Our initial toxicity studies showed L. bouillonii to possess toxins, causing mortality of brine shrimps with a LC50 of 0.8 mg/ml and causing DNA damage in human lymphocytes in vitro at concentrations as low as 1 ng/ml of crude cyanobacterial extract. Preliminary investigation revealed the presence of chlorinated fatty acid amides, fatty acid esters and benzazepine derivatives in the extract. Furthermore, how this cyanobacteria initially reached Indian waters and whether this is a bio-invasion is still being ascertained.

A COMPARATIVE ASSESSMENT OF VESICULAR FORMULATIONS: TRANSFERSOMES AND CONVENTIONAL LIPOSOMES LOADED IVABRADINE HYDROCHLORIDE

Objective: Ivabradine hydrochloride (IH), a benzazepine derivative used to treat cardiovascular disease angina pectoris. In this study IH-loaded novel carrier systems transfersomes (TFs) and conventional liposomes (CLs) were developed and compared for their efficacy to enhance the stability of drugs from degradation.
 Methods: TFs formulations (TF-1, TF-2 and TF-3) were prepared by using different biocompatible surfactants; tween-80 (TW), span-80(S) and sodium deoxycholate (SC) in the concentration ratio of 15 parts with 85 parts of soy phosphatidylcholine as phospholipid by thin-film hydration method. These vesicles were compared with CLs formulation (L-1) prepared in 7:3 molar ratio of soy phosphatidylcholine: cholesterol by following the same method. These vesicles were compared for physical appearance, vesicle shape, and size, percentage drug entrapment efficiency (%DEE), deformability index (DI), in vitro percentage cumulative drug release study, and physical stability studies. The chosen optimized novel carriers were observed under scanning electron microscopy.
 Results: The compared data demonstrated that the physical appearance for all vesicles was turbid and had a spherical shape. The size distribution was in the range of 129.0 nm to 273.5 nm in vesicles. The %DEE (79.0±0.94) and DI (35.0±1.9) was found maximum in TF-1 formulation that was 2.3 times higher than L-1 formulation. The in vitro percentage cumulative drug release study followed second-order polynomial kinetics that was 2.0 times higher than L-1and 2.9 times higher than the plain drug in 30 min (90.4±0.06%) from TF-1. The vesicles were found to be stable at refrigeration conditions.
 Conclusion: Thus, amongst of all vesicles TW loaded TFs (TF-1) was chosen as an excellent novel vesicular carrier for hydrophilic drugs due to its higher deformability behavior than CLs that protects the certain drugs from biodegradation and provides stability.

Ionic liquid promoted green synthesis of new pyridazino benzazepine derivatives: Evaluation of antioxidant activity

AbstractIn 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.

Visible-Light-Mediated Decarboxylative Tandem Carbocyclization of Acrylamide-Attached Alkylidenecyclopropanes: Access to Polycyclic Benzazepine Derivatives

A visible-light-mediated decarboxylative tandem carbocyclization of acrylamide-tethered alkylidenecyclopropanes with phenyliodine(III) diacetate and various aliphatic acids has been reported in this paper. An alkyl radical in situ generated from phenyliodine(III) dicarboxylates upon visible-light irradiation catalyzed by fac-Ir(ppy)3 adds to the less hindered central carbon of alkylidenecyclopropane to initiate the tandem annulation, generating tetracyclic benzazepine derivatives in moderate to good yields with broad substrate scope under mild conditions.

Production of benzazepine derivatives via four-component reaction of isatins: study of antioxidant activity.

In current research, benzazepine derivative is synthesized via a new process of four-component reaction of isatin or its derivatives, α-haloketones, activated acetylenic compounds, isoquinoline and potassium fluoride/clinoptilolite nanoparticles (KF/CP NPs) in acidic solution of H2O2 in water at room temperature. Also, antioxidation property of some prepared benzazepines is investigated by employing trapping diphenyl-picrylhydrazine (DPPH) radical and ability of ferric reduction experiment. Among investigated compounds, compounds 5c have good results relative to BHT and TBHQ as standard antioxidant. Also, the Gram-positive and Gram-negative bacteria disk diffusion research is used for the confirmation of antimicrobial power of some prepared benzazepines. The achieved outcomes of disk diffusion experiment showed that these compounds avoided the growth of bacteria. Our procedure has a few benefits relative to reported method such as good rate of reaction, product with high efficiency, simple removal of catalyst from mixture of reaction. In the yield of the product, KF/clinoptilolite nanoparticles show a satisfactory recyclable activity.

Comprehensive QSAR studies reveal structural insights into the NR2B subtype selective benzazepine derivatives as N-Methyl-d-Aspartate receptor antagonists

NMDA receptors are considered as high profile therapeutic target in the treatment of pain and neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's disease. NR2 subunit of NMDA receptor divided into four subunits i.e. NR2A, NR2B, NR2C and NR2D. Restricted distribution of NR2B subunit in the brain makes it potential target. In the present study, new structural insights into benzazepine derivatives as NR2B selective NMDA receptor antagonists have been reported using QSAR modelling. Total five QSAR models were developed using various statistical methods. 2D-QSAR models showed that chi3 and SsssNE-index descriptors are crucial for NMDA receptor antagonistic activity. Chi3 descriptor relates with non-hydrogen heteroatom connected with two or three bonds and SsssNE-index descriptor deals with Electrotopological state indices for number of nitrogen atom connected with three single bonds. Both the descriptors were negatively correlated with all the developed 2D-QSAR models. Significance of these descriptors is extensively studied in present work. In 3D-QSAR studies, steric and electrostatic fields were found to be important for antagonistic effect on NMDA receptors. 3D-QSAR studies clarify the substitution pattern of R group on nitrogen atom of benzazepine core. The substitutions with high electropositive with less or medium steric character are favourable for the activity. All developed models were critically validated to establish their reliability and accuracy for prediction of binding affinity of benzazepine derivatives towards NR2B subunit of NMDA receptor. The present study offered not only highly predictive and reliable QSAR models for benzazepine derivatives but also revealed some of the vital structural observations required for their higher binding affinity towards NR2B subunit of NMDA receptors.

Dopamine-induced functional activation of Gαq mediated by dopamine D1-like receptor in rat cerebral cortical membranes

Although multiple roles of dopamine through D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors are initiated primarily through stimulation or inhibition of adenylyl cyclase via Gs/olf or Gi/o, respectively, there have been many reports indicating diverse signaling mechanisms that involve alternative G protein coupling. In this study, dopamine-induced Gαq activation in rat brain membranes was investigated. Agonist-induced Gαq activation was assessed by increase in guanosine-5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding to Gαq determined by [35S]GTPγS binding/immunoprecipitation assay in rat brain membranes. Dopamine-stimulated Gαq functionality was highest in cortex as compared to hippocampus or striatum. In cerebral cortical membranes, this effect was mimicked by benzazepine derivatives with agonist properties at dopamine D1-like receptors, that is, SKF83959, SKF83822, R(+)-SKF81297, R(+)-SKF38393, and SKF82958, but not by the compounds with dopamine D2-like receptor agonist properties except for aripiprazole. Against expectation, stimulatory effects were also induced by SKF83566, R(+)-SCH23390, and pergolide. The pharmacological profiling by using a series of antagonists indicated that dopamine-induced response was mediated through dopamine D1-like receptor, which was distinct from the receptor involved in 5-HT-induced response (5-HT2A receptor). Conversely, the responses induced by SKF83566, R(+)-SCH23390, and pergolide were most likely mediated by 5-HT2A receptor, but not by dopamine D1-like receptor. Caution should be paid when interpreting the experimental data, especially in behavioral pharmacological research, in which SKF83566 or R(+)-SCH23390 is used as a standard selective dopamine D1-like receptor antagonist. Also, possible clinical implications of the agonistic effects of pergolide on 5-HT2A receptor has been mentioned.

Identification and Preclinical Evaluation of a Radiofluorinated Benzazepine Derivative for Imaging the GluN2B Subunit of the Ionotropic NMDA Receptor.

The previously reported carbon-11 labeled GluN2B PET radioligand 11C-Me-NB1 served as a starting point for derivatization and led to the successful development of a radiofluorinated analogue designated (R)-18F-OF-Me-NB1. Given the short physical half-life of 20.3 min for carbon-11, (R)-18F-OF-Me-NB1 with a physical half-life of 109.8 min would allow satellite distribution to nuclear medicine facilities without an on-site cyclotron. Methods: Two fluorinated Me-NB1 derivatives, OF-Me-NB1 and PF-Me-NB1, were synthesized. Upon chiral resolution, the respective enantiomers were radiolabeled with carbon-11 and assessed in a proof-of-concept study by applying in vitro autoradiography on rodent brain sections. Based on the autoradiograms, (R)-OF-Me-NB1 was selected for radiofluorination and preclinical evaluation by ex vivo autoradiography, PET imaging, biodistribution and metabolite studies in Wistar rats. To rule out off-target binding to the σ1 receptor, the brain uptake of (R)-18F-OF-Me-NB1 in wild-type mice was compared with σ1 receptor knock-out mice. Results: Autoradiographic assessment revealed that both enantiomers of 11C-PF-Me-NB1 distributed homogenously across all brain regions on rodent brain sections. In contrast, the two enantiomers of 11C-OF-Me-NB1 exhibited an entirely different behaviour. While (S)-11C-OF-Me-NB1 bound virtually to all brain regions with considerable σ1 receptor binding, (R)-11C-OF-Me-NB1 exhibited high selectivity and specificity for the GluN2B-rich rat forebrain. These findings were confirmed for the radiofluorinated analogue (R)-11C-OF-Me-NB1, which was obtained via copper-mediated radiofluorination in radiochemical yields of 13-25% and molar activities ranging from 61-168 GBq/µmol. PET imaging and biodistribution studies in Wistar rats indicated appropriate pharmacokinetic profile and high in vivo specific binding of (R)-18F-OF-Me-NB1 as revealed by blocking studies with GluN2B-antagonist CP101,606. Off-target binding to the σ1 receptor was excluded by PET imaging with σ1 receptor knock-out mice. Receptor occupancy experiments with CP101,606 revealed a D50-value of 8.3 µmol/kg (intravenous). Conclusion: (R)-18F-OF-Me-NB1 is a promising radiofluorinated probe that exhibits specificity and selectivity for the GluN2B-containing N-methyl-D-aspartate (NMDA) complex and enables in vivo target occupancy studies in rodents.

Identification and Preclinical Evaluation of a Radiofluorinated Benzazepine Derivative for Imaging the GluN2B Subunit of the Ionotropic NMDA Receptor: Supplemental Information

Identification and Preclinical Evaluation of a Radiofluorinated Benzazepine Derivative for Imaging the GluN2B Subunit of the Ionotropic NMDA Receptor: Supplemental Information

Electrophilic carbocyclization reactions of 2-(2-alkynylphenyl)amino-1,4-naphthoquinones.

An efficient Ag(i)-catalyzed method for the synthesis of 5H-benzo[b]naphtho[2,3-f]azepine-6,11-diones from 2-(2-ethynylphenyl)amino substituted 1,4-naphthoquinones has been developed. In this transformation new C-C bond formation occurred regioselectively via a 7-endo-dig cyclization. The related 13-iodine substituted benzazepine derivatives could also be produced exclusively by the I2-induced carbocyclization reaction of 2-(2-alkynylphenyl)amino substituted 1,4-naphthoquinones. This process has advantages such as mild reaction conditions and tolerance of a broad range of functional groups.