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PubMed1983

2-Benzazepines. 4. [1,2,3]Triazolo[4,5-d][2]benzazepines and dibenzo[c,f][1,2,3]triazolo[3,4-a]azepines: synthesis and evaluation as central nervous system agents.

The facile synthesis of [1,2,3]triazolo((4,5-d][2]benzazepines and dibenzo[c,f][1,2,3]triazolo[3,4-a]azepines by the addition of sodium azide to acetylenic benzophenones is described. Examination of the pharmacological data indicates that selected triazolobenzazepines are as potent as diazepam in the anti-pentylenetetrazole test and are weaker in the inclined screen and rotarod tests, suggesting that these compounds have antianxiety properties similar to diazepam with fewer deficits in motor coordination. In addition, a possible diazepam antagonist was found in the triazolo-benzazepine series. The dibenzotriazoloazepines were found to be inactive in four standard CNS screening procedures.

Animals↗
PubMed2002

Synthesis and pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin and its enantiomers in comparison with the two antidepressants mianserin and mirtazapine.

The synthesis and resolution of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin (6-methoxymianserin, 6) are described. Furthermore, the in vitro and in vivo effects of 6 and its enantiomers are presented. 6 displayed high affinity for the 5-HT2A/2C receptors, only moderate affinity for the adrenoceptors, and no affinity for the NA reuptake site. Surprisingly, 6 also showed moderate to high affinity for the dopamine D2 receptor, an effect that resides in the (R)-(-)-enantiomer.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Synthesis and anticonvulsant activities of 3,3-dialkyl- and 3-alkyl-3-benzyl-2-piperidinones (delta-valerolactams) and hexahydro-2H-azepin-2-ones (epsilon-caprolactams).

A series of 3-substituted 2-piperidinone (delta-valerolactam) and hexahydro-2H-azepin-2-one (epsilon-caprolactam) derivatives were prepared and evaluated as anticonvulsants in mice. In the 2-piperidinone series, 3,3-diethyl compound 7b is the most effective anticonvulsant against pentylenetetrazole-induced seizures (ED50, 37 mg/kg; PI (TD50/ED50), 4.46), and 3-benzyl compound 4c (ED50, 41 mg/kg; PI, 7.05) is the most effective anticonvulsant against seizures induced by maximal electroshock. By contrast, none of the epsilon-caprolactams tested had anticonvulsant effects below doses causing rotorod toxicity. log P values were correlated with neurotoxicity and [35S]TBPS displacement, but not with anticonvulsant activity. Electrophysiological evaluations of selected compounds from each series indicated that both the delta-valero-lactams and epsilon-caprolactams potentiated GABA-mediated chloride currents in rat hippocampal neurons.

Animals↗
PubMed2006

Coupling-isomerization-N,S-ketene acetal-addition sequences--a three-component approach to highly fluorescent pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and pyrido[2,3-b]azepines.

Annelated 2-amino pyridines such as pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and pyrido[2,3-b]azepines can be synthesized in moderate to good yields in a consecutive one-pot three-component process by a coupling-isomerization-enamine-addition-cyclocondensation sequence of an electron-poor (hetero)aryl halide, a terminal propargyl N-tosylamine, and an N,S-ketene acetal. After the coupling-isomerization sequence, a Diels-Alder reaction with inverse electron demand of the intermediate enimine and the N,S-ketene acetal and subsequent aromatization furnish annelated 2-amino pyridines 4 that were unambiguously characterized by numerous X-ray structure analyses. These heterocycles are highly fluorescent and partially pH sensitive, and their electronic structure was studied with spectroscopic and computational methods.

Journal Article↗
PubMed2004

Rapid access to azepine-fused oxetanols from alkoxy-substituted maleimides.

[reaction: see text] UV irradiation of alkoxy-substituted N-alkenylmaleimides induces a sequence involving a [5 + 2] cycloaddition followed by a Norrish-Yang cyclization. The resulting highly strained alkylidene oxetanol-fused azepines are formed in good yield and with high diastereoselectivities

Journal Article↗
PubMed2006

Divergent cycloaddition and ring-closing metathesis approaches to indolizidine and pyrrolo[1,2-a]azepine skeletons from a chiral precursor: an expeditious route to (-)-8-epi-swainsonine triacetate.

[reaction: see text] A divergent strategy for the synthesis of diverse azabicyclic ring systems has been developed in which a chiral N-allylpyrrolidine derivative, obtained from a carbohydrate precursor was converted to (-)-8-epi-swainsonine triacetate by RCM and to a pyrrolo[1,2-a]azepine derivative and a 3-hydroxymethyl-substituted indolizidine by N-allylcarbohydrate nitrone and nitrile oxide cycloadditions.

Alkaloids↗
PubMed1993

The cytotoxicity of N-substituted diphenimides and 6,7-dihydro-5H-dibenz[c,e]azepines.

N-substituted diphenimides and 6,7-dihydro-5H-dibenz[c,e]azepines demonstrated significant cytotoxic activity against the growth of murine and human cells. These derivatives were active against leukemias, carcinomas and sarcomas. Different derivatives with N-substitutions showed specific activity against the growth of several tumor types. These agents inhibited L1210 leukemia IMP dehydrogenase and PRPP amido transferase activities; this was reflected in the inhibition of purine and DNA synthesis. Other sites inhibited to a minor degree by these agents included DNA polymerase alpha, r- and tRNA polymerases, ribonucleoside reductase, dihydrofolate reductase, pyrimidine synthesis, and nucleoside kinase. d(NTP) pool levels were reduced after 24 h incubation with these derivatives. L1210 DNA strand scission was evident after drug treatment.

Animals↗
PubMed2005

A pilot study on brain-to-plasma partition of 10,11-dyhydro-10-hydroxy-5H-dibenzo(b,f)azepine-5-carboxamide and MDR1 brain expression in epilepsy patients not responding to oxcarbazepine.

PURPOSE: We measured the brain-to-plasma partition of 10,11-dihydro-10-hydroxy-5H-dibenzo(b,f)azepine-5-carboxamide (10-OHCBZ) in epilepsy patients undergoing surgery to alleviate drug-resistant seizures and administered with different oral doses of oxcarbazepine (OXC). We addressed the possible contribution of the multidrug transporter P-glycoprotein (P-gp or MDR1) in determining 10-OHCBZ brain levels by measuring whether this active metabolite is a substrate of P-gp and the relation between the level of expression of MDR1 and the drug concentration in the same brain tissue specimens. METHODS: Steady-state plasma and brain concentrations (C(ss)) of 10-OHCBZ were determined intraoperatively in 11 patients by high-performance liquid chromatography (HPLC) with UV detection. The level of expression of MDR1 mRNA was measured in surgically resected brain tissue by reverse transcriptase polymerase chain reaction (RT-PCR). The ability of 10-OHCBZ to act as substate of P-gp was evaluated by measuring its uptake in cell lines expressing different levels of P-gp, in the presence or absence of a selective P-gp inhibitor. RESULTS: OXC was converted to 10-OHCBZ and to Di-OHCBZ, the two main metabolites measured in plasma. The brain concentrations of the active metabolite 10-OHCBZ did not reflect plasma C(ss). A significant inverse linear correlation was found between 10-OHCBZ brain-to-plasma concentration ratio and the level of brain expression of MDR1 mRNA. In vitro uptake studies demonstrated lower intracellular 10-OHCBZ levels in cells with higher P-gp expression. Intracellular drug concentration was increased by XR9576, a specific P-gp blocker. CONCLUSIONS: Pharmacologic failure of OXC in pharmacoresistant epilepsy is unlikely to be due to alterations in drug metabolism. 10-OHCBZ does not appear to cross the blood-brain barrier by simple diffusion, and it acts as a substrate of P-gp. The level of expression of MDR1 is inversely correlated with 10-OHCBZ concentration in the epileptic tissue. P-gp may play a role in the pharmacoresistance to OXC by determining the attainment of insufficient concentrations of its active metabolite at neuronal targets.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Syntheses and biological activities of optical isomers of 3-chloro-5-[3-(2-oxo-1,2,3,5,6,7,8,8a-octahydroimidazo[1,2-a]pyridine- 3-spiro-4'-piperidino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine (mosapramine) dihydrochloride.

Mosapramine (1) is a new neuroleptic drug with an asymmetric carbon atom (8a) in its imidazopyridine ring. The enantiomers of this agent were synthesized to compare their biological activities, such as antiapomorphine activity, affinity for dopamine D2 receptor and acute toxicity. The key intermediates, (R)-(-)- and (S)-(+)-2-oxo-1,2,3,5,6,7,8,8a-octahydroimidazo[1,2-a]pyridine- 3-spiro-4'-piperidines, were prepared by optical resolution of the corresponding (+/-)-compound and were treated with 3-chloro-5-(3-methanesulfonyloxypropyl)-10,11-dihydro-5H-dibenz[b, f]azepine to afford (R)-(-)-1 and (S)-(+)-1, respectively. There were few differences in the examined biological activities of the two enantiomers as their dihydrochlorides.

Animals↗
PubMed1992

[Studies on zwitter-ionization of drugs. I. Synthesis and pharmacological activities of N-alkylcarboxylic acid derivatives of 4-(2-chlorodibenz-[b,f][1,4]oxazepin-11-yl)piperazine, 4-(2-chlorodibenzo[b, f]-[1,4]thiazepin-11-yl)piperazine, and 4-(11H-dibenz-[b,e]azepin-6-yl)piperazine].

The piperazine N-alkylcarboxylic acids of 2-chlorodibenz[b,f][1,4] oxazepine (3a), 2-chlorodibenzo[b,f] [1,4] thiazepine (3b), and dipenz[b,e] azepine (3c) from the corresponding piperazines (1a-c, R1 = H) were synthesized via the piperazine N-alkylcarboxylates (2a-c). The pharmacological activities of the piperazine N-alkylcarboxylic acids (3a-c) were evaluated. Compared with the parent compounds (1a-c), 3a-c (n = 1-5) showed weak inhibitory activities on the uptake of noradrenaline and 5-hydroxytryptamine (5-HT) into hypothalamus vesicles and moderate antagonistic actions to 5-HT2 and H1 in several tissues.

Amoxapine↗
PubMed1976

[Stability of 6-beta-[(hexahydro-1H-azepin-l-yl)methyleneamino]-penicillanic acid in aqueous solutions].

Stability of acqueous solutions of 6-beta-[(hexahydro-IH-azepin-I-yl)methylenamino] penicillanic acid at various values of pH and temperature was studied. It was found that inactivation of the antibiotic in both the acid and the alkaline medium proceeded according to the equation of the 1st order. At pH 1.3 and a temperature of 35 degrees the half life of the antibiotic was 7 hours. The activation energy calculated according to the Arrenius equation was 13.5 kcal/mol at pH 1.3 and 22.2 kcal/mol at pH 10.5. The antibiotic was inactivated in glycol and phosphate buffers. Its qualitative analysis was performed according to an improved iodometric method.

Amidines↗
PubMed1989

Synthesis and biological activity of dibenz[c,e]azepines.

Synthesis and pharmacological screening of 68 dibenz[c,e]azepines are described. All were inactive as antidepressant agents, but two compounds showed good anticonvulsant activity. The structure-activity relationships of this class of compounds are discussed.

Animals↗
PubMed1985

[Summarized presentation of studies on the toxicology of 3-carbethoxyamino-5-dimethylamino-acetyl-10,11- dihydrobenz[b,f]azepine hydrochloride (Bonnecor, GS 015, AWD 19-166)].

To ensure toxicologically the potential antiarrhythmic agent 3-carbethoxyamino-5-dimethylamino-acetyl-10,11-dihydro-dibenz[b,f] azepine hydrochloride (Bonnecor, GS 015, AWD 19-166), the following preclinical studies have been made up to the present: Determination of the acute toxicity on mice and rats, toxicity test on the rat by repeated applications, study as to the action of GS 015 on the prenatal development of the rat, diverse toxicologic studies on reproduction, mutagenity tests by using the DNA repair test and the Ames test. The results of these studies are represented in a summarized form. A good tolerance of GS 015 can be derived from the results of the preclinical studies gained up to now.

Animals↗