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Benzazepines

The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform

Bernhard Wunsch – 1st expert on this subject based on the ideXlab platform

  • 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.

  • heck reaction of ortho substituted iodobenzenes with α β unsaturated nitriles as a key step in the synthesis of tetrahydro 2 Benzazepines and hexahydro 3 benzazocines
    Tetrahedron, 2013
    Co-Authors: Peer Hasebein, Dirk Schepmann, Katharina Aulinger, Bernhard Wunsch

    Abstract:

    Abstract A novel strategy is reported for the synthesis of tetrahydro-2-Benzazepines 2 and hexahydro-3-benzazocines 3 comprising a Heck reaction of ortho -substituted iodobenzenes 6 and 14 with α,β-unsaturated nitriles. Hydrogenation of the resulting α,β-unsaturated nitriles 7 , 11 , 15 , and 16 was followed by reductive cyclization. It was shown that the formation of 2-Benzazepines was faster than the formation of 3-benzazocines, which was explained by the higher stability of the aliphatic dimethyl acetals in 17 and 18 . The tetrahydro-2-benzazepine 2d with an N -butyl residue reveals very high σ 1 affinity with a K i -value of 2.0 nM.

Dirk Schepmann – 2nd expert on this subject based on the ideXlab platform

  • Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold.
    European Journal of Medicinal Chemistry, 2017
    Co-Authors: Simone Thum, Dirk Schepmann, Artur K. Kokornaczyk, Tomoaki Seki, Monica De Maria, Natalia V. Ortiz Zacarías, Henk De Vries, Christina Weiss, Michael Koch, Masato Kitamura

    Abstract:

    Targeting CCR2 and CCR5 receptors is considered as promising concept for the development of novel antiinflammatory drugs. Herein, we present the development of the first probe-dependent positive allosteric modulator (PAM) of CCR5 receptors with a 2-benzazepine scaffold. Compound 14 (2-isobutyl-N-({[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-1-oxo-2,3-dihydro-1H-2-benzazepine-4-carboxamide) activates the CCR5 receptor in a CCL4-dependent manner, but does not compete with [3H]TAK-779 binding at the CCR5. Furthermore, introduction of a p-tolyl moiety at 7-position of the 2-benzazepine scaffold turns the CCR5 PAM 14 into the selective CCR2 receptor antagonist 26b. The structure affinity and activity relationships presented here offer new insights into ligand recognition by CCR2 and CCR5 receptors.

  • 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.

Keith Ramig – 3rd expert 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.