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1-Benzazepine

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Bernhard Wunsch – One of the best experts on this subject based on the ideXlab platform.

  • Fluorinated GluN2B Receptor Antagonists with a 3-Benzazepine Scaffold Designed for PET Studies.
    ChemMedChem, 2018
    Co-Authors: Marina Szermerski, Dirk Schepmann, Frederik Börgel, Ahmed Haider, Thomas Betzel, Simon M. Ametamey, Bernhard Wunsch
    Abstract:

    To analyze the N-methyl-d-aspartate (NMDA) receptor distribution in the central nervous system, fluorinated ligands that selectively address the ifenprodil binding site of GluN2B-subunit-containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 (3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1,7-diol) were pursued, including replacement of the benzylic OH moiety with a fluorine atom (13) and introduction of fluoroethoxy moieties at various positions (14 (7-position), 17 (9-position), 18a-c (1-position)). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a are the most promising ligands. Radiosynthesis of fluoroethoxy derivative [18 F]14 was performed by nucleophilic substitution of the phenol 2 with 2-[18 F]fluoroethyl tosylate. On rat brain slices the fluorinated PET tracer [18 F]14 accumulated in regions with high density of NMDA receptors containing GluN2B subunits. The bound radioactivity could not be replaced by (S)-glutamate. However, the GluN2B ligands eliprodil, Ro 25-6981, and the non-labeled 3-benzazepine 14 were able to abolish the specific binding of [18 F]14.

  • synthesis σ receptor affinity and pharmacological evaluation of 5 phenylsulfanyl and 5 benzyl substituted tetrahydro 2 benzazepines
    ChemMedChem, 2014
    Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Bernhard Wunsch
    Abstract:

    : In accordance with a novel strategy for generating the 2-benzazepine scaffold by connecting C6-C1 and C3-N building blocks, a set of 5-phenylsulfanyl- and 5-benzyl-substituted tetrahydro-2-benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ1 affinity was achieved for 2-benzazepines with linear or branched alk(en)yl residues containing at least an n-butyl substructure. The butyl- and 4-fluorobenzyl-substituted derivatives, (±)-5-benzyl-2-butyl-2,3,4,5-tetrahydro-1H-2-benzazepine (19 b) and (±)-5-benzyl-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (19 m), show high selectivity over more than 50 other relevant targets, including the σ2 subtype and various binding sites of the N-methyl-D-aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition-enhancing activity. Compound 19 m did not have any antidepressant-like effects in mice.

  • synthesis and pharmacological evaluation of like and unlike configured tetrahydro 2 benzazepines with the α substituted benzyl moiety in the 5 position
    Organic and Biomolecular Chemistry, 2014
    Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Roland Fröhlich, Kirstin Lehmkuhl, Bernhard Wunsch
    Abstract:

    A large set of tetrahydro-2-benzazepines with an α-hydroxy or α-(aryl)alkoxy substituted benzyl moiety in the 5-position was prepared according to the recently reported C6C1 + C3N synthetic strategy. The Heck reaction of 2-iodobenzaldehyde acetal 4 and the subsequent Stetter reaction led to the ketone 7, which was reduced diastereoselectively to form the like-configured alcohol 8. The diastereomeric unlike-configured alcohol 9 was obtained by a Mitsunobu inversion of 8. Alkylation and reductive cyclization of the diastereomeric alcohols 8 and 9 provided like- and unlike-configured 2-benzazepines 13 and 23, which allowed the introduction of various substituents at the N-atom. Analysis of the relationship between the structure and the σ1 affinity revealed that large substituents such as the butyl, benzyl or 4-phenylbutyl moiety at the benzazepine N-atom resulted in high affinity ligands. A p-methoxybenzyl ether is less tolerated by the σ1 receptor than a methyl ether or an alcohol. The unlike-configured alcohols 25d and 27d show slightly higher σ1 affinity than their like-configured diastereomers 15d and 17d. With respect to the σ1 affinity, σ1/σ2 selectivity and lipophilic ligand efficiency, like- and unlike-configured alcohols 15d and 25d represent the most promising σ1 ligands of this series. Interactions of the novel 2-benzazepines with various binding sites of the NMDA receptor were not observed.

Alirio Palma – One of the best experts on this subject based on the ideXlab platform.

  • Easy Access to Novel Tetrahydro-1-Benzazepine-2-carboxylic Acids and Tetrahydro-1-Benzazepines Carrying [a]-Fused Heterocyclic Units from 2-(Allylaryl)glycinates
    Synthesis, 2020
    Co-Authors: Sergio A. Guerrero, Lina M Acosta, Carlos M Sanabria, Justo Cobo, Manuel Nogueras, Juan Carlos Escobar Ramírez, Alirio Palma
    Abstract:

    A concise, efficient, and versatile approach to access novel tetrahydro-1H-benzo[b]azepine-2-carboxylic acids and tricyclic tetra­hydro-1-Benzazepines carrying [a]-fused heterocyclic units is reported. The easily accessible 2-(allylaryl)glycinates were used as starting material to synthesize, via the corresponding 1,4-epoxycycloadducts, the required key intermediate benzo[b]azepine-2-carboxylates. Hydrolysis of the latter afforded the targeted benzo[b]azepine-2-carboxylic acids. The key intermediate was also converted into N-2-chloroacetyl derivatives which, in turn, were transformed into the corresponding tricyclic target hexahydrobenzo[f]pyrazino[1,2-a]azepine-1,4-diones by reaction with benzylamine or aminoethanol. The reaction of the common intermediate with hydrazine gave the corresponding intermediate carbohydrazides, which, by reaction with trimethoxymethane, were transformed into another tricyclic target tetrahydrobenzo[f][1,2,4]tri­azino[4,5-a]azepin-4(3H)-ones. Full spectroscopic characterization (IR, HRMS, and 1H and 13C NMR) is also reported for each compound.

  • Crystal structures of five new substituted tetrahydro-1-Benzazepines with potential antiparasitic activity.
    Acta crystallographica. Section C Structural chemistry, 2016
    Co-Authors: Mario A Macías, Alirio Palma, Lina M Acosta, Carlos M Sanabria, Pascal Roussel, Gilles H Gauthier, Leopoldo Suescun
    Abstract:

    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 (2SR,4RS)-6,8-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-Benzazepine, (1), (2SR,4RS)-6,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-Benzazepine, (2), and (2SR,4RS)-8,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-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-1H-1-benzazepin-4-ol, C18H18FNO, (4), and 7-fluoro-cis-2-[(E)-pent-1-enyl]-2,3,4,5-tetrahydro-1H-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 -3 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.

  • stereoselective synthesis of novel 2 alkenyl 2 3 4 5 tetrahydro 1 4 epoxy 1 benzazepines and 2 alkenyl 2 3 4 5 tetrahydro 1h 1 benzazepin 4 ols
    Synthesis, 2012
    Co-Authors: Lina Acosta M Quintero, Alirio Palma, Manuel Nogueras, Justo Cobo
    Abstract:

    New series of polyfunctionalized 2,3,4,5-tetrahydro-1,4-epoxy-1-Benzazepines and 2,3,4,5-tetrahydro-1 H -1-benzazepin-4-ols substituted at C2 with 2-methylprop-1-enyl, ( E )-styryl, and ( E )-pent-1-enyl were synthesized starting from the corresponding N -alkenyl-substituted [prenyl, trans -cinnamyl, ( E )-hex-2-enyl] 2-allylanilines by a three-step sequence consisting of selective oxidoxidation of aromatic secondary amines, intramolecular nitrone–olefin 1,3-dipolar cycloaddition, and reductive cleavage. The intramolecular 1,3-dipolar cycloaddition is stereoselective favoring the exo -cycloadducts (ratio exo / endo 2–3:1). The stereochemistry was determined by exhaustive NMR analysis and X-ray diffraction.

Justo Cobo – One of the best experts on this subject based on the ideXlab platform.

  • Easy Access to Novel Tetrahydro-1-Benzazepine-2-carboxylic Acids and Tetrahydro-1-Benzazepines Carrying [a]-Fused Heterocyclic Units from 2-(Allylaryl)glycinates
    Synthesis, 2020
    Co-Authors: Sergio A. Guerrero, Lina M Acosta, Carlos M Sanabria, Justo Cobo, Manuel Nogueras, Juan Carlos Escobar Ramírez, Alirio Palma
    Abstract:

    A concise, efficient, and versatile approach to access novel tetrahydro-1H-benzo[b]azepine-2-carboxylic acids and tricyclic tetra­hydro-1-Benzazepines carrying [a]-fused heterocyclic units is reported. The easily accessible 2-(allylaryl)glycinates were used as starting material to synthesize, via the corresponding 1,4-epoxycycloadducts, the required key intermediate benzo[b]azepine-2-carboxylates. Hydrolysis of the latter afforded the targeted benzo[b]azepine-2-carboxylic acids. The key intermediate was also converted into N-2-chloroacetyl derivatives which, in turn, were transformed into the corresponding tricyclic target hexahydrobenzo[f]pyrazino[1,2-a]azepine-1,4-diones by reaction with benzylamine or aminoethanol. The reaction of the common intermediate with hydrazine gave the corresponding intermediate carbohydrazides, which, by reaction with trimethoxymethane, were transformed into another tricyclic target tetrahydrobenzo[f][1,2,4]tri­azino[4,5-a]azepin-4(3H)-ones. Full spectroscopic characterization (IR, HRMS, and 1H and 13C NMR) is also reported for each compound.

  • stereoselective synthesis of novel 2 alkenyl 2 3 4 5 tetrahydro 1 4 epoxy 1 benzazepines and 2 alkenyl 2 3 4 5 tetrahydro 1h 1 benzazepin 4 ols
    Synthesis, 2012
    Co-Authors: Lina Acosta M Quintero, Alirio Palma, Manuel Nogueras, Justo Cobo
    Abstract:

    New series of polyfunctionalized 2,3,4,5-tetrahydro-1,4-epoxy-1-Benzazepines and 2,3,4,5-tetrahydro-1 H -1-benzazepin-4-ols substituted at C2 with 2-methylprop-1-enyl, ( E )-styryl, and ( E )-pent-1-enyl were synthesized starting from the corresponding N -alkenyl-substituted [prenyl, trans -cinnamyl, ( E )-hex-2-enyl] 2-allylanilines by a three-step sequence consisting of selective oxidation of aromatic secondary amines, intramolecular nitrone–olefin 1,3-dipolar cycloaddition, and reductive cleavage. The intramolecular 1,3-dipolar cycloaddition is stereoselective favoring the exo -cycloadducts (ratio exo / endo 2–3:1). The stereochemistry was determined by exhaustive NMR analysis and X-ray diffraction.

  • Stereoselective Synthesis of Novel 2-Alkenyl-2,3,4,5-tetrahydro-1,4-epoxy-1-Benzazepines and 2-Alkenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols
    Synthesis, 2012
    Co-Authors: Lina M. Acosta Quintero, Alirio Palma, Manuel Nogueras, Justo Cobo
    Abstract:

    New series of polyfunctionalized 2,3,4,5-tetrahydro-1,4-epoxy-1-Benzazepines and 2,3,4,5-tetrahydro-1 H -1-benzazepin-4-ols substituted at C2 with 2-methylprop-1-enyl, ( E )-styryl, and ( E )-pent-1-enyl were synthesized starting from the corresponding N -alkenyl-substituted [prenyl, trans -cinnamyl, ( E )-hex-2-enyl] 2-allylanilines by a three-step sequence consisting of selective oxidoxidation of aromatic secondary amines, intramolecular nitrone–olefin 1,3-dipolar cycloaddition, and reductive cleavage. The intramolecular 1,3-dipolar cycloaddition is stereoselective favoring the exo -cycloadducts (ratio exo / endo 2–3:1). The stereochemistry was determined by exhaustive NMR analysis and X-ray diffraction.

Keith Ramig – One of the best experts on this subject based on the ideXlab platform.

Gopal Subramaniam – One of the best experts on this subject based on the ideXlab platform.

  • Oxidative ring-contraction of 3H-1-Benzazepines to quinoline derivatives
    Tetrahedron Letters, 2015
    Co-Authors: Sasan Karimi, Keith Ramig, Edyta M Greer, David J. Szalda, Shuai Ma, Gopal Subramaniam
    Abstract:

    Abstract When treated with SeO2, 2,4-diphenyl-3H-1-Benzazepine (1) is oxidized equally at C3 and C5, giving either products of rearrangement or fragmentation; in both cases quinoline derivatives are the primary products. When C3 is oxidized, electrocyclization followed by ring-opening with phenyl migration gives the major product phenyl(3-phenylquinolin-2-yl)methanone (6), whereas C5 oxidation produces 2,4-diphenylquinoline (2) and 1,2-bis(2,4-diphenylquinolin-3-yl)diselane (8). Oxidation of C5 in 1 also results in formation of 2-(3,5-diphenylfuran-2-yl)aniline (7). On the other hand, 3-methyl-2,4-diphenyl-3H-1-Benzazepine (9) upon treatment with SeO2 gives primarily a product of oxidation of C3, 2,3-diphenylquinoline (5). Oxidation of C5 in (9) is a minor pathway, and gives both 3-methyl-2,4-diphenylquinoline (10) and (3-methyl-2-phenylquinolin-4-yl)(phenyl)methanone (11). CO was detected as a byproduct in both reactions. Although the ring-contraction reaction using SeO2 has been previously noted, no mechanistic proofs have been firmly established. In this Letter, we provide evidence for the ring-contraction of benzazepines to quinolines through a fragmentation path (loss of CO and acetic acid) or through rearrangement.

  • regioselective alkylation reactions of 2 4 diphenyl 3h 1 benzazepine give either 3 alkyl 3h 1 benzazepines or 1 alkyl 1h 1 benzazepines
    ChemInform, 2015
    Co-Authors: Allen Ko, Sasan Karimi, Gopal Subramaniam, Edyta M Greer, David J. Szalda, Jeffrey Li, Keith Ramig
    Abstract:

    Deprotonation of benzazepine (I) followed by reaction with alkyl halides or tosylates give either products of alkylation at C3 or at the nitrogen as well as mixtures of both types of products.

  • regioselective alkylation reactions of 2 4 diphenyl 3h 1 benzazepine give either 3 alkyl 3h 1 benzazepines or 1 alkyl 1h 1 benzazepines
    Tetrahedron Letters, 2014
    Co-Authors: Allen Ko, Sasan Karimi, Gopal Subramaniam, Edyta M Greer, David J. Szalda, Jeffrey Li, Keith Ramig
    Abstract:

    2,4-Diphenyl-3H-1-Benzazepine is deprotonated with either LDA or KHMDS. The resulting anion is alkylated with alkyl halides or MeOTs, giving either products of alkylation at C3, or at N, or a mixture of both. The regioselectivity depends on the base, presence of the complexing agent HMPA, and the leaving group of the alkylating agent. Using MeI as alkylating agent gives exclusively the C3-methylated product, while using MeOTs gives exclusively the N-methylated product. The N-alkylated products show evidence of stereodynamic behavior in their NMR spectra.