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Bernhard Wunsch - One of the best experts on this subject based on the ideXlab platform.
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synthesis σ receptor affinity and pharmacological evaluation of 5 phenylsulfanyl and 5 benzyl substituted tetrahydro 2 Benzazepines
ChemMedChem, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Bernhard WunschAbstract:: 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.
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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, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Roland Fröhlich, Kirstin Lehmkuhl, Bernhard WunschAbstract: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.
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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, 2013Co-Authors: Peer Hasebein, Dirk Schepmann, Katharina Aulinger, Bernhard WunschAbstract: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.
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Unexpected Formation of Thiophene-annulated Tetrahydro-3- Benzazepines by Alkylation of Thiolactams with Ethyl Bromoacetate
Zeitschrift für Naturforschung B, 2013Co-Authors: Soumya Sarkar, Roland Fröhlich, Bernhard WunschAbstract:In order to synthesize enantiomerically pure tetrahydro-3-Benzazepines with diverse substitution patterns, the lactams 3 were converted into thiolactams 4 upon treatment with Lawesson’s reagent. Instead of an Eschenmoser sulfide contraction a thiophene annulation reaction occurred, when the thiolactams 4 were reacted with ethyl bromoacetate. Altogether, enantiomerically pure thiopheneannulated 3-Benzazepines 7 were prepared in a very short reaction sequence (five reaction steps) starting from commercially available o-phenylenediacetic acid
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microwave assisted synthesis of 3 benzazepin 2 ones as building blocks for 2 3 disubstituted tetrahydro 3 Benzazepines
Tetrahedron, 2012Co-Authors: Soumya Sarkar, Roland Fröhlich, Dirk Schepmann, Syed Masood Husain, Bernhard WunschAbstract:Abstract Microwave assisted condensation of primary amines with keto acids 1a–c provided directly 3,4-disubstituted 1,3-dihydro-3-benzazepin-2-ones 2. Whereas small amine size, such as NH3 afforded high yields of secondary lactams 2a, 2d, and 2g, primary amines with larger substituents in α-position led to lower yields of 2 or even to regioisomeric indanone derivatives 4. However, subsequent alkylation of 2a, 2d, and 2g with various alkyl halides provided the corresponding N-substituted 3-benzazepin-2-ones 2 in good yields. Hydrogenation of 2 followed by BH3 reduction led to 3-Benzazepines 9. 3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (9c) reveals high σ1 affinity and selectivity over σ2 and NMDA receptors.
Dirk Schepmann - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold.
European Journal of Medicinal Chemistry, 2017Co-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 KitamuraAbstract: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.
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synthesis σ receptor affinity and pharmacological evaluation of 5 phenylsulfanyl and 5 benzyl substituted tetrahydro 2 Benzazepines
ChemMedChem, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Bernhard WunschAbstract:: 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.
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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, 2014Co-Authors: Peer Hasebein, Bastian Frehland, Dirk Schepmann, Roland Fröhlich, Kirstin Lehmkuhl, Bernhard WunschAbstract: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.
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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, 2013Co-Authors: Peer Hasebein, Dirk Schepmann, Katharina Aulinger, Bernhard WunschAbstract: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.
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microwave assisted synthesis of 3 benzazepin 2 ones as building blocks for 2 3 disubstituted tetrahydro 3 Benzazepines
Tetrahedron, 2012Co-Authors: Soumya Sarkar, Roland Fröhlich, Dirk Schepmann, Syed Masood Husain, Bernhard WunschAbstract:Abstract Microwave assisted condensation of primary amines with keto acids 1a–c provided directly 3,4-disubstituted 1,3-dihydro-3-benzazepin-2-ones 2. Whereas small amine size, such as NH3 afforded high yields of secondary lactams 2a, 2d, and 2g, primary amines with larger substituents in α-position led to lower yields of 2 or even to regioisomeric indanone derivatives 4. However, subsequent alkylation of 2a, 2d, and 2g with various alkyl halides provided the corresponding N-substituted 3-benzazepin-2-ones 2 in good yields. Hydrogenation of 2 followed by BH3 reduction led to 3-Benzazepines 9. 3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (9c) reveals high σ1 affinity and selectivity over σ2 and NMDA receptors.
Keith Ramig - One of the best experts on this subject based on the ideXlab platform.
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Oxidative ring-contraction of 3H-1-Benzazepines to quinoline derivatives
Tetrahedron Letters, 2015Co-Authors: Sasan Karimi, Keith Ramig, Edyta M. Greer, David J. Szalda, Shuai Ma, Gopal SubramaniamAbstract: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.
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regioselective alkylation reactions of 2 4 diphenyl 3h 1 benzazepine give either 3 alkyl 3h 1 Benzazepines or 1 alkyl 1h 1 Benzazepines
ChemInform, 2015Co-Authors: Allen Ko, Sasan Karimi, Edyta M. Greer, David J. Szalda, Gopal Subramaniam, Jeffrey Li, Keith RamigAbstract: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.
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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, 2014Co-Authors: Allen Ko, Sasan Karimi, Edyta M. Greer, David J. Szalda, Gopal Subramaniam, Jeffrey Li, Keith RamigAbstract: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.
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nmr spectroscopic and computational study of conformational isomerism in substituted 2 aryl 3h 1 Benzazepines toward isolable atropisomeric benzazepine enantiomers
Journal of Organic Chemistry, 2013Co-Authors: Keith Ramig, Sasan Karimi, Edyta M. Greer, David J. Szalda, Allen Ko, Laura Boulos, Jiansan Gu, Nathan Dvorkin, Hema Bhramdat, Gopal SubramaniamAbstract:Certain 2-aryl-3H-1-Benzazepines are conformationally mobile on the NMR time scale. Variable-temperature NMR experiments bolstered by calculations indicate that alkylation of the azepine ring will slow the interconversion of conformational enantiomers markedly. DFT studies show that, while the substitution patterns of the aryl groups at C2 and C4 do not exert large effects on the rate of enantiomerization, alkylation at C5 slows it appreciably. Alkylation at C3 slows enantiomerization even more, possibly to the extent that isolation of atropisomers might be attempted.
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Tandem ring-contraction/decarbonylation of 2,4-diphenyl-3H-1-benzazepine to 2,4-diphenylquinoline
Tetrahedron, 2013Co-Authors: Sasan Karimi, Keith Ramig, Edyta M. Greer, David J. Szalda, William F. Berkowitz, Prakash Prasad, Gopal SubramaniamAbstract:Attempted free-radical bromination of 2,4-diphenyl-3H-1-benzazepine (3) with NBS led to an unusual ring-contraction reaction, giving rise to 2,4-diphenylquinoline (5) in high yield. This is a convenient path for the synthesis of a quinoline in one step from the easily accessible 1-benzazepine. We have elucidated the mechanism of ring-contraction reaction using 13C-labeled and deuterated Benzazepines, and DFT calculations. There is strong experimental evidence that the departing carbon atom is initially part of a reactive intermediate dibromomethyl cation, which leads to methyl formate upon reaction with methanol. In the absence of methanol, water can complete the ring-contraction. In this case, the departing carbon atom is in the form of carbon monoxide.
Gopal Subramaniam - One of the best experts on this subject based on the ideXlab platform.
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Oxidative ring-contraction of 3H-1-Benzazepines to quinoline derivatives
Tetrahedron Letters, 2015Co-Authors: Sasan Karimi, Keith Ramig, Edyta M. Greer, David J. Szalda, Shuai Ma, Gopal SubramaniamAbstract: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.
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regioselective alkylation reactions of 2 4 diphenyl 3h 1 benzazepine give either 3 alkyl 3h 1 Benzazepines or 1 alkyl 1h 1 Benzazepines
ChemInform, 2015Co-Authors: Allen Ko, Sasan Karimi, Edyta M. Greer, David J. Szalda, Gopal Subramaniam, Jeffrey Li, Keith RamigAbstract: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.
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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, 2014Co-Authors: Allen Ko, Sasan Karimi, Edyta M. Greer, David J. Szalda, Gopal Subramaniam, Jeffrey Li, Keith RamigAbstract: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.
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nmr spectroscopic and computational study of conformational isomerism in substituted 2 aryl 3h 1 Benzazepines toward isolable atropisomeric benzazepine enantiomers
Journal of Organic Chemistry, 2013Co-Authors: Keith Ramig, Sasan Karimi, Edyta M. Greer, David J. Szalda, Allen Ko, Laura Boulos, Jiansan Gu, Nathan Dvorkin, Hema Bhramdat, Gopal SubramaniamAbstract:Certain 2-aryl-3H-1-Benzazepines are conformationally mobile on the NMR time scale. Variable-temperature NMR experiments bolstered by calculations indicate that alkylation of the azepine ring will slow the interconversion of conformational enantiomers markedly. DFT studies show that, while the substitution patterns of the aryl groups at C2 and C4 do not exert large effects on the rate of enantiomerization, alkylation at C5 slows it appreciably. Alkylation at C3 slows enantiomerization even more, possibly to the extent that isolation of atropisomers might be attempted.
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Tandem ring-contraction/decarbonylation of 2,4-diphenyl-3H-1-benzazepine to 2,4-diphenylquinoline
Tetrahedron, 2013Co-Authors: Sasan Karimi, Keith Ramig, Edyta M. Greer, David J. Szalda, William F. Berkowitz, Prakash Prasad, Gopal SubramaniamAbstract:Attempted free-radical bromination of 2,4-diphenyl-3H-1-benzazepine (3) with NBS led to an unusual ring-contraction reaction, giving rise to 2,4-diphenylquinoline (5) in high yield. This is a convenient path for the synthesis of a quinoline in one step from the easily accessible 1-benzazepine. We have elucidated the mechanism of ring-contraction reaction using 13C-labeled and deuterated Benzazepines, and DFT calculations. There is strong experimental evidence that the departing carbon atom is initially part of a reactive intermediate dibromomethyl cation, which leads to methyl formate upon reaction with methanol. In the absence of methanol, water can complete the ring-contraction. In this case, the departing carbon atom is in the form of carbon monoxide.
Hidenori Ogawa - One of the best experts on this subject based on the ideXlab platform.
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7 chloro 5 hydroxy 1 2 methyl 4 2 methylbenzoyl amino benzoyl 2 3 4 5 tetrahydro 1h 1 benzazepine opc 41061 a potent orally active nonpeptide arginine vasopressin v2 receptor antagonist
Bioorganic & Medicinal Chemistry, 1999Co-Authors: K Kondo, Hidenori Ogawa, Hiroshi Yamashita, Yoshitaka Yamamura, Hisashi Miyamoto, Kazuyoshi Kitano, Michinori Tanaka, Kenji Nakaya, Shigeki Nakamura, Toshiyuki OnogawaAbstract:We previously reported a series of benzazepine derivatives as orally active nonpeptide arginine vasopressin (AVP) V2 receptor antagonists. After the lead structure OPC-31260 was structurally evaluated and optimized, the introduction of the 7-Cl moiety on the benzazepine and 2-CH3 on the aminobenzoyl moiety enhanced its oral activity. The new AVP-V2 selective antagonist OPC-41061 was determined to be a potent and orally active agent.
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orally active nonpeptide vasopressin v2 receptor antagonists a novel series of 1 4 benzoylamino benzoyl 2 3 4 5 tetrahydro 1h Benzazepines and related compounds
Journal of Medicinal Chemistry, 1996Co-Authors: Hidenori Ogawa, Hiroshi Yamashita, K Kondo, Yoshitaka Yamamura, Hisashi Miyamoto, Kazuyoshi Kitano, Michinori Tanaka, Kenji Nakaya, Shigeki Nakamura, Toyoki MoriAbstract:This paper describes a novel series of nonpeptide vasopressin V2 receptor antagonists. It has been demonstrated that the 1-[4-(benzoylamino)benzoyl]-2,3,4,5-1H-Benzazepines and 1-[4-(benzoylamino)benzoyl]-2,3,4,5-1H-1,5-benzodiazepines show a high affinity for V2 (and V1a) receptors. Among the 1-[4-(benzoylamino)benzoyl]-2,3,4,5-1H-benzazepine series, compounds with an alkylamino group on the benzazepine ring have been shown to have oral activity. A lipophilic group at the ortho position on the terminal benzoyl ring is important for both high V2 receptor affinity and oral activity. On the basis of these favorable properties, clinical testing of 31b has begun for use as an oral and iv aquaretic agent.
