Benzazepine Derivatives Research Articles

A Novel Construction of 2‐Benzazepine Scaffold Based on TiCl4‐Mediated Tandem Mannich Reaction–Aromatic Electrophilic Substitution

AbstractA 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‐2H‐pyran as the substrates.

Morita–Baylis–Hillman route to 4 H-pyrrolo[1,2- a][1]benzazepine derivatives

A simple method for synthesizing substituted 4 H-pyrrolo[1,2- a][1]benzazepines using acid-assisted cyclization of the Morita–Baylis–Hillman adducts of 2-(1 H-pyrrol-1-yl)benzaldehydes with methyl acrylate or methyl vinyl ketone as a key step has been developed.

Novel 2,4-Methanoadamantane-Benzazepine by Domino Photochemistry of N-(1-adamantyl)phthalimide

The photochemical reaction of N-(1-adamantyl)phthalimide (1) gives cleanly one product, the novel hexacyclic benzazepine derivative of 2,4-methanoadamantane 2. Its structure was characterized by spectroscopic methods and X-ray analysis and represent the first example of the 2-azahexacyclo[8.7.1.1 (1,4).0 (4,9).0 (11,16).0 (12,18)]nonadeca-4,6,8-triene skeleton. The product is formed by a domino process of two consecutive excited-state intramolecular gamma-hydrogen-transfer reactions. Base hydrolysis of the benzazepine 2 gives in high yield the keto derivative of the 1,2-substituted adamantane epsilon-amino acid 3.

First synthesis of selenadiazolo[3,4‐i] Benzazepine derivatives

Abstractmagnified image5‐Methyl‐4‐nitro‐2,1,3‐benzoselenadiazole (1) was converted into (E)‐5‐(2‐dimethylamino)vinylbenzo‐[c](1,2,5)selenadiazole‐4‐amine (4) by initial treatment with dimethylformamide dimethyl acetal (DMFDMA) (2) followed by selective reduction using ammonium bromide in methanol. Compound 4 afforded the selenadiazolo[3,4‐i][1]benzazepine derivatives (7, 10, 13, 15) upon treatment with malononitrile (5), ethyl cyanoacetate (8) and cyanoacetamide (11) respectively.

Molecular Modeling of Benzothiazepine Binding in the L-type Calcium Channel

Benz(othi)azepine (BTZ) derivatives constitute one of three major classes of L-type Ca(2+) channel ligands. Despite intensive experimental studies, no three-dimensional model of BTZ binding is available. Here we have built KvAP- and KcsA-based models of the Ca(v)1.2 pore domain in the open and closed states and used multiple Monte Carlo minimizations to dock representative ligands. In our open channel model, key functional groups of BTZs interact with BTZ-sensing residues, which were identified in previous mutational experiments. The bulky tricyclic moiety occupies interface between domains III and IV, while the ammonium group protrudes into the inner pore, where it is stabilized by nucleophilic C-ends of the pore helices. In the closed channel model, contacts with several ligand-sensing residues in the inner helices are lost, which weakens ligand-channel interactions. An important feature of the ligand-binding mode in both open and closed channels is an interaction between the BTZ carbonyl group and a Ca(2+) ion chelated by the selectivity filter glutamates in domains III and IV. In the absence of Ca(2+), the tricyclic BTZ moiety remains in the domain interface, while the ammonium group directly interacts with a glutamate residue in the selectivity filter. Our model suggests that the Ca(2+) potentiation involves a direct electrostatic interaction between aCa(2+) ion and the ligand rather than an allosteric mechanism. Energy profiles indicate that BTZs can reach the binding site from the domain interface, whereas access through the open activation gate is unlikely, because reorientation of the bulky molecule in the pore is hindered.

Synthesis and structure–activity relationships of a series of benzazepine derivatives as 5-HT 2C receptor agonists

To identify potent and selective 5-HT 2C receptor agonists, a series of novel benzazepine derivatives were synthesized, and their structure–activity relationships examined. The compounds were evaluated for their 5-HT 2C, 5-HT 2A, and 5-HT 2B receptor binding affinity and intrinsic activity for the 5-HT 2C and 5-HT 2A receptors. Among these compounds, 6,7-dichloro-2,3,4,5-tetrahydro-1 H-3-benzazepine ( 6) was effective in a rat penile erection model when administered po, which is a symptom of the serotonin syndrome reflecting 5-HT 2C receptor activation. Moreover, compound 6 was characterized as a partial agonist of 5-HT 2A receptors; therefore, it had little effect on the cardiovascular system.

Solid-Phase Preparation of a Pilot Library Derived from the 2,3,4,5-Tetrahydro-1H-benzo[b]azepin-5-amine Scaffold

A convenient and reliable solid-phase strategy for the synthesis of di- and trisubstituted benzazepine derivatives was developed. 5-Amino-1-tert-butoxycarbonyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine and 5-amino-1-tert-butoxycarbonyl-7-bromo-2,3,4,5-tetrahydro-1H-benzo[b]azepine G-protein coupled receptor-targeted (GPCR-targeted) scaffolds were efficiently synthesized in a six-step solution-phase process, immobilized on the acid-labile FMPB-AM resin, and further functionalized through acylation, sulfonation, reductive amination, alkylation, and Suzuki or Buchwald-Hartwig cross-coupling reactions. The efficacy of this strategy was exemplified by the preparation of an original pilot library of di- and trisubstituted benzazepines obtained in high purity as assessed by both 1H NMR and liquid chromatography/mass spectrometry (LC/MS) analysis.

Substituent activity relationship studies on new azolo benzoxazepinyl oxazolidinones

In an effort to discover potent antibacterials based on the entropically favored ‘bioactive conformation’ approach, a series of novel tricyclic molecules mimicking the conformationally constrained structure of Linezolid is reported. Based on the initial tricyclic molecule 1, the benzazepine derivative 2 was designed where the tricyclic structure had more flexibility around C–N bond compared to 1. While, the molecule 2 was less active, the molecule 3 showed promising antibacterial activity presumably after having obtained rigidity due to pyrrole ring. The syntheses, SAR studies, and evaluation of 3 as a lead compound are reported.

A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan

A practical preparation of benzazepine derivatives using a series of radical and ionic reactions is reported. This approach was applied to the synthesis of tolvaptan, a very promising vasopressin V 2 receptor antagonist currently in clinical trials.

Efficient Synthesis of Functionalized Benzazepine Derivatives Utilizing Intramolecular Mitsunobu Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Efficient Synthesis of Functionalized Benzazepine Derivatives Utilizing Intramolecular Mitsunobu Reaction

The 5-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine derivative (2), which is a typical metabolite of mozavaptan (1) having the 2,3,4,5-tetrahydro-1H-benzazepine skeleton, was synthesized by utilizing the intramolecular Mitsunobu reaction of the corresponding 2-(4-hydroxybutyl)aniline derivative. In the intramolecular Mitsunobu reaction, effect of the substituent group on nitrogen atom, influence of the functional group applying to synthesis of the other metabolites (3, 4 and 5) and utilization of synthesis of 2-substituent benzazepine derivatives were investigated.

An efficient approach to isoindolo[2,1- b][2]benzazepines via intramolecular [4+2] cycloaddition of maleic anhydride to 4-α-furyl-4- N-benzylaminobut-1-enes

Acylation of 4-α-furyl-4- N-benzylaminobut-1-enes with maleic anhydride gave 4-oxo-3-aza-10-oxatricyclo[5.2.1.0 1,5]dec-8-ene-6-carboxylic acid via amide formation followed by intramolecular Diels–Alder reaction of furan (IMDAF). The cycloaddition proceeded under mild reaction conditions (25 °C) and provided only the exo-adduct in quantitative yield. Treatment of this compound with PPA gave isoindolo[2,1- b][2]benzazepine derivatives via ring opening, aromatization and intramolecular electrophilic alkylation. In order to extend the scope of the reaction sequence, 7-oxo-5,11b,12,13-tetrahydro-7 H-isoindolo[2,1- b][2]benzazepine-8-carboxylic acids were further transformed into useful synthetic intermediates.

Conivaptan: YM 087.

Conivaptan [YM 087], a benzazepine derivative, belongs to a series of highly potent, orally active arginine vasopressin V1 and V2 receptor antagonists that are being developed by Yamanouchi. Yamanouchi licensed conivaptan to Warner-Lambert for co-development and marketing in the Americas, Europe and Africa. In return, Yamanouchi has rights to market atorvastatin in Japan. In June 2000, Warner-Lambert merged with Pfizer. The resulting company retained the Pfizer name. However, Yamanouchi and Pfizer discontinued the co-development and marketing agreement for conivaptan. Yamanouchi is continuing the independent development of conivaptan in the US and Europe. Yamanouchi is developing an oral drug delivery formulation of conivaptan for administration in patients with chronic heart failure. The company has initiated the ADVANCE (A Dose evaluation of a Vasopressin ANtagonist in CHF patients undergoing Exercise) trial, a double-blind, multicentre trial in which 345 patients with heart failure will receive placebo or one of three doses of conivaptan for 12 weeks and their functional capacity will be assessed. Conivaptan demonstrated a potent diuretic effect in animal studies.

Aromatic Allylation via Diazotization: Variation of the Allylic Moiety and a Short Route to a Benzazepine Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Structure-activity study of novel tricyclic benzazepine arginine vasopressin antagonists.

Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists. Several tricyclic compounds showed potent antagonistic activity in rat AVP receptors V(1a) and V(2). Derivatives containing pyrrolo-tricyclic amines, 13i-k, 30, and 31 also showed selectivity for the V(2) receptor.

Studies on (1S)-N-(1-Phenylethyl)- phthalimide: Synthesis of Both Chiral Spiro Indane and Benzazepine Derivatives

Chiral spiro indane and benzazepine compounds in isoindolinone series were prepared easily by n-cationic cyclization of the N-acyliminium ions (5-9) or the acylium ion (17) precursors with trifluoroacetic acid or aluminumtrichloride, respectively. The stereochemistry and the ratio of diastereomeric mixtures observed during these process were also discussed.

Synthesis of a Benzo[5,6]cyclohepta[1,2-b]thiophene and Thieno[3,2-c]benzazepine Derivatives

A new series of 2-methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[5,6]cyclohepta[1,2-b]thiophene (5) and 2-methyl-4-(4-methylpiperazin-1-yl)thieno[3,2-c][1]benzazepine derivatives 6b-f have been synthesized from 2-methylthiophene and phthalic anhydride. Preparation of the key intermediate 2-methyl-4,5-dihydro-10H-benzo[5,6]cyclohepta[1,2-b]thiophene-4-one (12) and 2-methylthieno[3,2-c][1]benzazepine-4(5H),10-dione (16) were carried out by intramolecular dehydration of the phenylacetic acid 11 and Lewis acid associated cyclization of the isocyanate 14, respectively.

Studies on the syntheses and reaction of nitrogen-containing heterocyclic compounds centered the naphthyridines

1, X-Naphthyridines (X = 5, 6, and 8) (1-3) were synthesized in a high yield by the Skraup reactions of 4-, 3-, and 2-aminopyridines with glycerol, in the presence of ferrous sulfate and boric acid. The improved syntheses were applied to the syntheses of 1,5-, 1,6-, and 1,8-naphthyridines (4-28), pyridonaphthyridines (31, 32), benzonaphthyridines (38-42), naphthonaphthyridines (44, 48, 49, 59). New synthetic methods of naphtho[1,2-b or 2,1-b][1,8]naphthyridine (62, 63), benzo[b][1,8]naphthyridine (41) and benzo[g]quinoline (67) were developed and their compounds obtained conveniently. Reissert reaction of 1,6-naphthyridine (2) using triethylbenzylammonium chloride (TEBA) produced Reissert compounds and ring-opened compounds. Reissert reaction of 1,7-naphthyridine (29), 4,7- (87), 4,6-phenanthroline (38) gave the Reissert compounds, and the compounds (2, 38) gave their pseudo bases (79, 90). Reissert-type reactions of benzo[f]quinoline (68), and 1,7-phenanthroline (105) with acyl chloride and phosphite, gave alpha- and gamma-phosphonate, and 87 produced alpha,alpha'-(108a-c) and alpha,gamma'-diphosphonates (109a-c). The structure of 108c-1 was determined to be trans-type by an X-ray analysis. Compounds 1-3, 29, and benzo[f or h]quinoline were treated with dimetyl sulfoxide in the presence of sodium hydride to give mainly methylated compounds at the position para to the ring-nitrogen. When benzo[f or h]quinoline N-oxide was treated with methylsulfinylmethyl carbanion in the usual procedure, a new reaction took place to produce phenanthrene in an excellent yield. The same reaction of 1,10-, 1,7-, or 4,7-phenanthroline N-oxides (143-145) resulted in the liberation of the N-oxide group to form benzo[f or h]quinoline, but isoquinoline N-oxide afforded to benzazepine derivatives (161). Reaction of quinaldine with methylsulfinylmethyl carbanion gave novel tricyclic compound (121a). The oxidation of 41, 62, and 63 with peroxy acids afforded novel products such as seven-membered 1,4-oxazepine derivatives.

7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist

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.

4,10-dihydro-5 H-thieno[3,2- c][1]benzazepine derivatives and 9,10-dihydro-4 H-thieno[2,3- c][1]benzazepine derivatives as orally active arginine vasopressin receptor antagonists

Synthesis and structure-activity relationships (SAR) of arginine vasopressin receptor (AVP) antagonists are described. Potent and orally active compounds are prepared when tricyclic 10,11-dihydro-5 H-pyrrolo[2,1- c][1,4]benzodiazepine moiety in VPA-985 1 is replaced with a compound 7 or 12.