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Archiv Der Pharmazie Jun 2022To improve the metabolic stability and receptor selectivity of ifenprodil (1), the benzoxazolone moiety of besonprodil (2) and the 3-benzazepone moiety of WMS-1410 (3)...
To improve the metabolic stability and receptor selectivity of ifenprodil (1), the benzoxazolone moiety of besonprodil (2) and the 3-benzazepone moiety of WMS-1410 (3) were merged to obtain oxazolobenzazepines of type 4. The 5-(hydroxyethyl)benzoxazolone 7 representing the first key intermediate was prepared in four steps starting with the 4-(2-hydroxyethyl)phenol (8). Mitsunobu reaction of primary alcohol 7 with N-sulfonylated glycine esters established the necessary side chain. The intramolecular Friedel-Crafts acylation of acid 12a containing the N-tosyl protective group led upon decarbonylation exclusively to the tricyclic tetrahydroisoquinoline 14. Protection of the amino moiety by the stronger electron-withdrawing triflyl group resulted in the desired 3-benzazepine 15 without the formation of analogous isoquinoline. The triflyl protective group was cleaved off by K CO -induced elimination of trifluoromethanesulfinate. In a one-pot three-step procedure, various oxazolobenzazepinediones 15 were obtained, which were reduced to afford the desired secondary alcohols 18.
Topics: Benzazepines; Phenols; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship
PubMed: 35224754
DOI: 10.1002/ardp.202200020 -
Drugs Mar 2010Tolvaptan is an orally administered, nonpeptide, selective arginine vasopressin V(2) receptor antagonist that increases free water clearance, thereby correcting low... (Review)
Review
Tolvaptan is an orally administered, nonpeptide, selective arginine vasopressin V(2) receptor antagonist that increases free water clearance, thereby correcting low serum sodium levels. SALT-1 and -2, two identical, randomized, double-blind, placebo-controlled, multicentre trials, included patients with hypervolaemic or euvolaemic hyponatraemia (serum sodium <135 mmol/L) associated with heart failure, cirrhosis or the syndrome of inappropriate antidiuretic hormone secretion. In both trials, patients receiving (in addition to standard medical treatment) tolvaptan 15-60 mg once daily (titrated according to response) for up to 30 days (n = 95 and 118) experienced significantly greater improvements than those receiving placebo (n = 89 and 114) for the co-primary endpoints of the change in average daily area under the curve for the serum sodium level from baseline to day 4 and from baseline to day 30. This beneficial effect of tolvaptan on serum sodium levels in SALT-1 and -2 was observed in patients with mild (serum sodium <135 mmol/L) and in those with marked (serum sodium <130 mmol/L) hyponatraemia at baseline. Tolvaptan was also superior to placebo in increasing serum sodium levels from baseline to day 7 in a subgroup of 323 patients with hyponatraemia (serum sodium <134 mmol/L) in the randomized, double-blind, multicentre EVEREST trials, which included patients who were hospitalized for worsening heart failure. Tolvaptan was generally well tolerated in clinical trials. The most frequently reported adverse events were thirst and dry mouth, which result from the pharmacodynamic effects of the drug.
Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Humans; Hyponatremia; Tolvaptan
PubMed: 20205486
DOI: 10.2165/11204630-000000000-00000 -
Journal of Medicinal Chemistry Feb 19751,5-Ethano-2,3,4,5-tetrahydro-1H-3-benzazepine, from the LiA1H4 reduction of 2-benzyloxy-1,5-ethano-4-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine, was converted to N-alkyl,...
1,5-Ethano-2,3,4,5-tetrahydro-1H-3-benzazepine, from the LiA1H4 reduction of 2-benzyloxy-1,5-ethano-4-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine, was converted to N-alkyl, aralkyl, cycloalkyl, and alkenyl derivatives which were inactive as morphine type analgetics in mice. The LiA1H4 reduction of 2-benzyloxy-1,5-etheno-4-oxo-2,3,4,5-tetrahydro-1H-3-benzazepine gave unstable products from which only the skeletally rearranged dihydro- and tetrahydrobenzo[e]isoindolines, were isolated.
Topics: Administration, Oral; Analgesics; Animals; Benzazepines; Bridged-Ring Compounds; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Mice; Pain; Reaction Time; Structure-Activity Relationship
PubMed: 1120989
DOI: 10.1021/jm00236a022 -
The Journal of Organic Chemistry Jul 2015A novel procedure for the Heck-Suzuki tandem reaction suitable for the construction of nitrogen-containing medium rings was developed to provide access toward the...
A novel procedure for the Heck-Suzuki tandem reaction suitable for the construction of nitrogen-containing medium rings was developed to provide access toward the 3-benzazepine framework.
Topics: Benzazepines; Catalysis; Molecular Structure; Nitrogen
PubMed: 25996648
DOI: 10.1021/acs.joc.5b00670 -
Molecular Neurobiology Nov 2017Excitotoxicty, a key pathogenic event is characteristic of the onset and development of neurodegeneration. The glutamatergic neurotransmission mediated through different...
Excitotoxicty, a key pathogenic event is characteristic of the onset and development of neurodegeneration. The glutamatergic neurotransmission mediated through different glutamate receptor subtypes plays a pivotal role in the onset of excitotoxicity. The role of NMDA receptor (NMDAR), a glutamate receptor subtype, has been well established in the excitotoxicity pathogenesis. NMDAR overactivation triggers excessive calcium influx resulting in excitotoxic neuronal cell death. In the present study, a series of benzazepine derivatives, with the core structure of 3-methyltetrahydro-3H-benzazepin-2-one, were synthesised in our laboratory and their NMDAR antagonist activity was determined against NMDA-induced excitotoxicity using SH-SY5Y cells. In order to assess the multi-target-directed potential of the synthesised compounds, Aβ aggregation inhibitory activity of the most potent benzazepines was evaluated using thioflavin T (ThT) and Congo red (CR) binding assays as Aβ also imparts toxicity, at least in part, through NMDAR overactivation. Furthermore, neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic activities of the two potential test compounds (7 and 14) were evaluated using primary rat hippocampal neuronal culture against Aβ-induced toxicity. Finally, in vivo neuroprotective potential of 7 and 14 was assessed using intracerebroventricular (ICV) rat model of Aβ-induced toxicity. All of the synthesised benzazepines have shown significant neuroprotection against NMDA-induced excitotoxicity. The most potent compound (14) showed relatively higher affinity for the glycine binding site as compared with the glutamate binding site of NMDAR in the molecular docking studies. 7 and 14 have been shown experimentally to abrogate Aβ aggregation efficiently. Additionally, 7 and 14 showed significant neuroprotective, free radical scavenging, anti-oxidant and anti-apoptotic properties in different in vitro and in vivo experimental models. Finally, 7 and 14 attenuated Aβ-induced tau phosphorylation by abrogating activation of tau kinases, i.e. MAPK and GSK-3β. Thus, the results revealed multi-target-directed potential of some of the synthesised novel benzazepines against excitotoxicity.
Topics: Animals; Benzazepines; Cell Line, Tumor; Cells, Cultured; Drug Delivery Systems; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Glycogen Synthase Kinase 3 beta; Humans; Rats; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate
PubMed: 27744571
DOI: 10.1007/s12035-016-0184-9 -
Journal of Medicinal Chemistry Nov 1983The 2-benzazepine 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (1) has been selected for development as an anxiolytic agent. In support of this program,...
The 2-benzazepine 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (1) has been selected for development as an anxiolytic agent. In support of this program, we have confirmed by chemical synthesis the structures of three in vitro (rat liver homogenate) metabolites of 1 and confirmed the structure of the major in vivo (dog and man) metabolite of 1, compound 2. Two of the metabolites, arising from hydroxylation of the pyrimidobenzazepine ring at the 5-position (2) and N-oxide formation at the 3-position of the pyrimidobenzazepine ring (3), were found to be as active as 1 in a series of pharmacological tests. The third metabolite, formed by hydroxylation of the 7-phenyl group in the 4-position (4), was found to be inactive in the same pharmacological screens.
Topics: Animals; Anti-Anxiety Agents; Benzazepines; Biological Assay; Diazepam; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Conformation; Motor Activity; Receptors, Cell Surface; Receptors, GABA-A; Spectrophotometry, Infrared; Structure-Activity Relationship
PubMed: 6138437
DOI: 10.1021/jm00365a009 -
Drugs in R&D 2004Conivaptan [YM 087], a benzazepine derivative, belongs to a series of highly potent, orally active arginine vasopressin V1 and V2 receptor antagonists that are being... (Review)
Review
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.
Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Clinical Trials as Topic; Diuretics; Dose-Response Relationship, Drug; Heart Failure; Humans; Metabolic Diseases; Randomized Controlled Trials as Topic; Rats
PubMed: 15293869
DOI: 10.2165/00126839-200405020-00005 -
Journal of Medicinal Chemistry Nov 1983A series of 5H-pyrimido[5,4-d][2]benzazepines has been synthesized, starting from the corresponding 2-benzazepin-5-ones, and evaluated as potential anxiolytic agents.... (Comparative Study)
Comparative Study
A series of 5H-pyrimido[5,4-d][2]benzazepines has been synthesized, starting from the corresponding 2-benzazepin-5-ones, and evaluated as potential anxiolytic agents. Selected compounds from this series show a pharmacological profile of action different than that of diazepam. They are more potent than diazepam in the anti-pentylenetetrazole test and in the [3H]diazepam binding assay, yet show less activity in the inclined screen test. A pharmacological data profile is given for 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (7c). The structure-activity relationships of these potential anxiolytic agents are discussed.
Topics: Animals; Anti-Anxiety Agents; Benzazepines; Biological Assay; Diazepam; Drug Evaluation, Preclinical; Drug Interactions; Ethanol; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Mice; Motor Activity; Pyrimidines; Receptors, Cell Surface; Receptors, GABA-A; Reflex; Spectrophotometry, Infrared; Structure-Activity Relationship
PubMed: 6138436
DOI: 10.1021/jm00365a008 -
Drug and Therapeutics Bulletin Mar 1973
Clinical Trial
Topics: Benzazepines; Clinical Trials as Topic; Costs and Cost Analysis; Humans; Hypnotics and Sedatives; Ketones
PubMed: 4580878
DOI: No ID Found -
Acta Crystallographica. Section C,... May 2016Tetrahydro-1-benzazepines have been described as potential antiparasitic drugs for the treatment of chagas disease and leishmaniasis, two of the most important so-called...
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.
Topics: Antiparasitic Agents; Benzazepines; Chagas Disease; Crystallography, X-Ray; Humans; Hydrogen Bonding; Leishmania infantum; Leishmaniasis, Visceral; Models, Molecular; Naphthalenes; Phase Transition; Trypanosoma cruzi
PubMed: 27146563
DOI: 10.1107/S2053229616004885