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PubMedDate not supplied

Centrally mediated cardiovascular effects of B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine dihydrochloride), a hypotensive agent of the "clonidine type".

Intravenous injection of 30 micrograms/kg of B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine dihydrochloride) into cats lead initially to an increase in blood pressure and then to a long-lasting decrease in blood pressure and heart rate. The central site of the hypotensive and bradycardiac action was demonstrated by the significantly greater effect after intracisternal (i.ci.) than after intravenous injection of B-HT 920, 3 micrograms/kg. The drug decreased the rate of spontaneous discharges in preganglionic splanchnic nerve fibers of normal and noradrenaline-depleted cats (3 micrograms/kg, i.ci.). Vagally mediated reflex bradycardia elicited by angiotensin injection in beta-adrenoceptor-blocked dogs was facilitated by intracisternal injection of 10 micrograms/kg B-HT 920. Both sympathoinhibition and vagal reflex facilitation were antagonized by the alpha-adrenoceptor-blocking agent piperoxan (50 micrograms/kg, i.ci). Therefore, B-HT 920 can be classified as an agent of the clonidine type, despite its different chemical structure. Quantitative differences between B-HT 920 and clonidine are discussed with respect to the greater alpha 2/alpha 1 adrenoceptor activity ratio of the former drug, as reported previously.

Animals↗
PubMed2004

Studies of Abeta pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575).

A previous study by us suggests the utility of cerebrospinal fluid (CSF) and plasma Abeta as biomarkers of beta- or gamma-secretase inhibition. The present study characterized further Abeta pharmacodynamics in these tissues from Tg2576 mice and examined their correlation with brain Abeta after acute treatment with a potent gamma-secretase inhibitor, N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY-411575). A single dose of LY-411575 dose-dependently (0.1-10 mg/kg p.o.) reduced Abeta(1-40) and Abeta(1-42) in the CSF and the brain. In contrast, plasma Abeta levels were increased by 0.1 mg/kg LY-411575 and were followed by a dose-dependent reduction at higher doses. The time courses of Abeta reduction and recovery were distinct for the three tissues: maximal declines in Abeta levels were evident by 3 h in the CSF and plasma but not until 9 h in the brain. A recovery in Abeta levels was underway in the CSF by 9 h and nearly completed by 24 h in all tissues. The differential time courses in the three compartments do not seem to be due to pharmacokinetic factors. Five days of twice-daily treatment with LY-411575 not only sustained the Abeta reductions in all tissues but also significantly augmented the efficacy in the brain and plasma. The increased efficacy occurred in the absence of compound accumulation and was consistent with the recovery rates in each compartment. Overall, Abeta in the CSF and not plasma seems to be a better biomarker of brain Abeta reduction; however, the time course of Abeta changes needs to be established in clinical studies.

Alanine↗
PubMed2005

Quantitative measurement of changes in amyloid-beta(40) in the rat brain and cerebrospinal fluid following treatment with the gamma-secretase inhibitor LY-411575 [N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide].

The efficacy of gamma-secretase inhibitors in vivo has, to date, been generally assessed in transgenic mouse models expressing increased levels of amyloid-beta (Abeta) peptide thereby allowing the detection of changes in Abeta production. However, it is not clear whether the in vivo potency of gamma-secretase inhibitors is independent of the level of amyloid precursor protein expression. In other words, does a gamma-secretase inhibitor have the same effect in nontransgenic physiological animals versus transgenic overexpressing animals? In the present study, an immunoassay has been developed which can detect Abeta(40) in the rat brain, where concentrations are much lower than those seen in transgenic mice such as Tg2576 (c. 0.7 and 25 nM, respectively) and in cerebrospinal fluid (CSF, c. 0.3 nM). Using this immunoassay, the effects of the gamma-secretase inhibitor LY-411575 [N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide] were assessed and robust dose-dependent reductions in rat brain and CSF Abeta(40) levels were observed with ID(50) values of 1.3 mg/kg for both brain and CSF. These values were comparable with those calculated for LY-411575 in transgenic mice. Time course experiments using LY-411575 demonstrated comparable temporal reductions in rat brain and CSF Abeta(40), further suggesting these two pools of Abeta are related. Accordingly, when all the data for the dose-response curve and time course were correlated, a strong association was observed between the brain and CSF Abeta(40) levels. These data demonstrate the utility of the rat as a novel approach for assessing the effects of gamma-secretase inhibitors on central nervous system Abeta(40) levels in vivo.

Alanine↗
PubMed2006

Studies to investigate the in vivo therapeutic window of the gamma-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY411,575) in the CRND8 mouse.

Accumulation of amyloid beta-peptide (Abeta) is considered a key step in the etiology of Alzheimer's disease. Abeta is produced by sequential cleavage of the amyloid precursor protein by beta- and gamma-secretase enzymes. Consequently, inhibition of gamma-secretase provides a promising therapeutic approach to treat Alzheimer's disease. Preclinically, several gamma-secretase inhibitors have been shown to reduce plasma and brain Abeta, although they also produce mechanism-based side effects, including thymus atrophy and intestinal goblet cell hyperplasia. The present studies sought to establish an efficient screen for determining the therapeutic window of gamma-secretase inhibitors and to test various means of maximizing this window. Six-day oral administration of the gamma-secretase inhibitor N(2)-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N(1)-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-l-alaninamide (LY411,575) reduced cortical Abeta(40) in young (preplaque) transgenic CRND8 mice (ED(50) approximately 0.6 mg/kg) and produced significant thymus atrophy and intestinal goblet cell hyperplasia at higher doses (>3 mg/kg). The therapeutic window was similar after oral and subcutaneous administration and in young and aged CRND8 mice. Both the thymus and intestinal side effects were reversible after a 2-week washout period. Three-week treatment with 1 mg/kg LY411,575 reduced cortical Abeta(40) by 69% without inducing intestinal effects, although a previously unreported change in coat color was observed. These studies demonstrate that the 3- to 5-fold therapeutic window for LY411,575 can be exploited to obtain reduction in Abeta levels without induction of intestinal side effects, that intermittent treatment could be used to mitigate side effects, and that a 6-day dosing paradigm can be used to rapidly determine the therapeutic window of novel gamma-secretase inhibitors.

Administration, Oral↗
PubMedDate not supplied

Syntheses of new 5,6,7,8-tetrahydropyrrolo [2,3-d]azepine ring system.

A first synthesis of pyrrolo[2,3-d]azepine ring system starting from pyrrole and perhydroazepine derivatives was reported. In addition, Lansbury's reaction is developed through the use of para-toluene sulphonic acid (p-TsOH) as a new catalyst for this reaction.

Alkylation↗
PubMed2002

Synthesis and structure-activity relationship of 2-(aminoalkyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives: a novel series of 5-HT(2A/2C) receptor antagonists. Part 2.

Following the programme started at Janssen Research Foundation searching for 5-HT(2A/2C) antagonists, we now report on the synthesis of a series of substituted 2-(Dimethylaminomethyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives. The 5-HT(2A), 5-HT(2C) and H(1) receptor affinities as well as the mCPP antagonistic activity of the compounds synthesised is described.

Azepines↗
PubMed2001

[Synthesis and antibacterial activity of the new 9-aminoacridine, 10,11-dihydro-5H-dibenzo[b,f]azepine, polyfluoro 5,6-dihydro-1,3,5-oxadiazine derivatives].

Screening among 9-aminoacridine, 10,11-dihydro-5H-dibenz[b, f]azepine and polyfluoro 5,6-dihydro-1,3,5-oxadiazine derivatives allowed to isolate compounds with potential antibacterial activity. Schemes of the active compounds synthesis are given. The most important is the estimation of the oxydiazines activity against gram-positive microorganisms including methicillin-resistant staphylococci. Special attention is paid to the activity of iminodibenzyl derivatives against multiresistant gram-negative microorganisms.

Aminacrine↗
PubMed1987

Pharmacodynamics of the new H1-antagonist 3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine hydrochloride in volunteers.

The inhibitory effects of 3-amino-9,13b-dihydro-1H-dibenz[1,5-a]azepine hydrochloride (WAL 801 CL), a new H1-receptor antagonist, on histamine-induced skin wheals were studied in 9 volunteers. The study was a double-blind, randomized (Latin square) change-over, intraindividual comparison of the effects of single doses of 2,6 and 18 mg WAL 801 CL and of placebo and 2 mg ketotifen on skin wheals induced by intradermal injections of 5 micrograms hystamine 1, 2, 4, 6 and 8 h after administration of the drugs. The injection of 5 micrograms was also made prior to each drug administration. The effects on psychological performance and the subjective state were also evaluated. The following tests were employed: simple visual reaction time (RT), critical flicker fusion frequency (C3F) and von Zerssen's self-rating scale Bf-S, assessing state of mood. There was a washout period of at least 72 h between each course of treatment. A decrease in the size of the histamine wheal was observed 1 h after WAL 801 CL and was maintained for at least 8 h. The reduction in the size of the histamine wheal was between 44% (2.0 mg) and 71% (18.0 mg). After ketotifen a marked decrease in the wheal area was observed between 4 and 8 h after administration of the drug, with maximum histamine antagonism of 59% after 6 h. The inhibitory effects of 6 and 18 mg WAL 801 CL and 2 mg ketotifen were statistically significant compared with placebo. 8 of 9 subjects felt tired (subjective report) after ketotifen, corresponding changes could be detected by Zerssen's state of mood scale Bf-S, but not by other psychological performance measures (RT, C3F).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Pharmacological properties of the novel antimuscarinic agent 4-[2-(1,2-benzisoxazol-3-yl)-2-(hexahydro-1H-azepin-1-yl)a cetoxy]-1-et hyl-1- methylpiperidinium iodide.

Pharmacological properties of 4-[2-(1, 2-benzisoxazol-3-yl)-2-(hexahydro-1H-azepin-1-yl)acetoxy]-1- ethyl-1- methylpiperidinium iodide (SX-810) were investigated and the following results were obtained. 1. In isolated guinea-pig ileum, SX-810 showed a competitive antagonistic effect against acetylcholine with a pA2 value of 7.93. 2. SX-810 (10-50 mg/kg p.o. or 10-50 micrograms/kg i.v.) inhibited the gastroduodenal contractions induced by bethanechol and carbachol in anaesthetized rats. 3. SX-810 (10-100 mg/kg p.o.) inhibited spontaneous gastric motility in conscious rats and rabbits. 4. SX-810 (10-100 mg/kg p.o.) inhibited gastric secretion in pylorus-ligated rats. 5. SX-810 (20-200 mg/kg p.o. or 1-10 mg/kg s.c.) inhibited the ulceration induced by pylorus ligation or by exposure to restrained and water-immersed stress in rats. 6. When administered orally to rats, SX-810 had no mydriatic effect even at 3000 mg/kg, but subcutaneously administered SX-810 (0.5-10 mg/kg) exhibited such action. 7. When administered orally to rats, SX-810 (100-500 mg/kg) caused no significant inhibition of the salivation induced by pilocarpine, but subcutaneously administered SX-810 (0.5-10 mg/kg) exhibited an inhibition of the salivation. In rabbits, SX-810 (200-500 mg/kg p.o.) also caused no significant inhibition of the salivation except at an extremely high dose of 1000 mg/kg p.o. 8. SX-810 (100-500 mg/kg p.o.) caused no significant effect on urine and electrolyte excretion in rats. These results indicate that oral use of SX-810 exhibits marked spasmolytic and antiulcerative activities without exerting systemic antimuscarinic side effects.

Animals↗
PubMed1994

New classes of antimuscarinic agents endowed with selective antispasmodic properties. 1-Arylsulfonyl pyrrolidin-2-ones and 2-thiones, 1-arylsulfonyl piperidin-2-ones and 2-thiones and 1-arylsulfonyl hexahydro-2H-azepin-2-one.

A series of 1-arylsulfonylpyrrolidin-2-ones (and 2-thiones), 1-aryl sulfonylpiperidin-2-ones (and 2-thiones) and 1-arylsulfonyl hexahydro-2H-azepin-2-one were synthesized and submitted to a battery of binding assays. The compounds showed little or no affinity for the receptors tested other than muscarinic receptors labelled either with [3H]pirenzepine or with [3H]quinuclidinyl benzilate. When tested in the isolated guinea pig ileum, they antagonized the contractions induced by acetylcholine and behaved as competitive muscarinic antagonists. After parenteral administration in mice, most compounds inhibited carbachol-induced diarrhoea but were less effective in counteracting salivation and lacrimation and showed little or no mydriatic action, thus displaying selectivity at the intestinal level. The reference drugs tested, atropine, butyl scopolamine and cimetropium bromide were far less selective. maximal in vivo activity was obtained by introducing diethylamino or 1-piperidino or 1-hexahydroazepinyl groups in the 4-position of the phenyl ring while the enlargement of a 5- to a 6-membered lactam ring or its conversion into a thiolactam had a less marked effect. The most interesting compounds were further evaluated for their ability to antagonize carbachol-induced colonic hypermotility in the rat and arecoline-induced analgesia in mice. The effect on gastric acid secretion in the rat was also investigated. The overall in vivo data showed that compounds 14, 15, 26 and 27, i.e. those bearing a 1-hexahydroazepinyl group in the 4-position of the phenyl ring, were the most potent and selective compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Substituent-dependent reactivity in the photodimerization of N-substituted dibenz[b,f]azepines.

The photoprocesses of a series of N-substituted dibenz[b,f]azepines (iminostilbenes) were studied by absorption and emission spectroscopy, by laser flash photolysis, and by preparative irradiation with NMR analysis. In solutions, 2pi+2pi photodimers of N-cyano and N-acyl dibenzazepines are formed via the triplet state upon acetone- or benzophenone-sensitized energy transfer. T-T absorption spectra were measured and absorption coefficients were determined. The triplet energy transfer is equally efficient for N-alkyl dibenzazepines, which do not dimerize. Excited states of npi* character in the latter cases are discussed to rationalize the different reactivities. In spite of negligible intersystem crossing of 21 dibenzazepine derivatives, photodimers of N-acyl and N-cyano dibenzazepines are formed upon direct excitation in concentrated solutions (0.01-0.1 mol dm(-3)) as well as in the solid state. A selective anti-configuration of the photodimers was found throughout.

Journal Article↗
PubMed2007

Mechanistic study on rearrangement cascades starting from annulated 2-aza-hepta-2,4-dienyl-6-ynyl anions: formation of aniline and azepine derivatives.

Deprotonation of benzothiophene-derived alkynyl imine 11 with lithium diisopropylamide (LDA) and subsequent transmetalation with ZnCl2 etherate furnished azepine 12 upon aqueous workup. Similarly, alkynyl benzaldimine 1a gave a mixture of benzazepine 13 and naphthylamine 14. Allylic benzonitriles 15 a,b reacted to produce naphthylamine 16 upon deprotonation with LDA at room temperature. In an analogous manner, imino benzonitrile 17 may be converted into 4-amino isoquinoline 18 by means of an intramolecular nucleophilic attack on the nitrile function upon treatment with LDA. The allylic benzonitriles 19 a,b were prepared by LDA treatment of alkynyl imine 11. They were further converted to amino dibenzothiophene 20 by LDA deprotonation and aqueous workup. These various transformations represent the key steps of a multistep reaction cascade, which was previously postulated on the basis of quantum chemical calculations. Thus, all features of this complex rearrangement mechanism could now be confirmed experimentally. DFT calculations support the lower reactivity of zinc species in the ring-opening step compared to the lithium intermediates. All new compounds were completely characterized by spectroscopic data, including X-ray diffraction studies for the key compounds 12, 19 a, and 20.

Journal Article↗
PubMed1976

Synthesis and antimalarial activity of dibenz[c, e]azepine derivatives.

A series of 6-alkyl-2,10-bis(trifluoromethyl)-5H-dibenz-[c,e]azepines were synthesized via a condensation reaction between 5,5'-bis(trifluoromethyl)-2,2'-diformylbiphenyl and the appropriate amine. These compounds were screened for antimalarial activity and were found to be inactive.

Animals↗
PubMed1985

Oxidation in H2O and D2O of 6-ethyl-5H-dibenz(c,e)azepine and 1-methylnicotinamide by aldehyde oxidase from rabbit liver.

We report the solvent hydrogen isotope effects associated with the oxidation of 6-ethyl-5H-dibenz(c,e)azepine (6-ED) and 1-methylnicotinamide (1-MN) catalyzed by aldehyde oxidase from rabbit liver using two assay methods. The first uses 2,6-dichlorophenolindophenol (DCI) as electron acceptor in an indirect assay in which the bleaching of DCI is measured as the substrate is oxidized. The second uses molecular oxygen as electron acceptor in a direct assay in which the oxidation of 1-MN to its pyridones is accompanied by an increase in absorbance at 300 nm and the oxidation of 6-ED to its lactam product is accompanied by a decrease in absorbance at 335 nm. We have found a solvent hydrogen isotope effect close to unity in the turnover number for each substrate and for each assay method. The solvent hydrogen isotope effects on kcat/Km ranged from 0.4 to 1.1. We conclude that changes in bonding of hydrogen in solvent water, including hydrolysis of or general base attack on an enzyme-intermediate complex, do not play a rate-contributing role in the maximal velocity of oxidation of 1-MN and 6-ED catalyzed by aldehyde oxidase from rabbit liver.

Aldehyde Oxidase↗
PubMed2006

Matrix compare analysis discriminates subtle structural differences in a family of novel antiproliferative agents, diaryl-3-hydroxy-2,3,3a,10a-tetrahydrobenzo[b]cycylopenta[e]azepine-4,10(1H,5H)-diones.

A diastereoselective synthesis of diaryl-3-hydroxy-2,3,3a,10a-tetrahydrobenzo[b]cycylopenta[e]azepine-4,10(1H,5H)-diones is described employing a tandem Michael-aldol addition as key step. The novel compounds exhibit antiproliferative activity in a panel of in vitro cultivated cancer cell lines. The bioinformatic tool COMPARE was able to discriminate between two closely related subgroups of the title compounds, namely 1,3- and 2,3-disubstituted derivatives.

Animals↗
PubMed2003

Design and synthesis of orally bioavailable inhibitors of inducible nitric oxide synthase. synthesis and biological evaluation of dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines.

The process of discovery and biological evaluation of alpha,beta-unsaturated cyclic amidines, as selective inhibitors of inducible nitric oxide synthase (iNOS), is reported. Dihydropyridin-2(1H)-imines and 1,5,6,7-tetrahydro-2H-azepin-2-imines were synthesized and biologically evaluated both in vitro and in vivo using a nitric oxide synthase inhibition assay. Compounds 1, 5, 6, 8-12 and 16 exhibited potent inhibition of iNOS. Among these, compounds 6, 7, 10, 11 and 16 showed 5- to 19-fold isoform selectivity. Compounds 1, 6, 10, 11 and 16 also showed potent inhibitory activity in the NOx accumulation assay in mice. Compounds 1 and 6 showed excellent bioavailability (BA) in rats when administered orally. Full details are presented here, including the structure-activity relationship (SAR) studies, the chemistry of these compounds, and the pharmacokinetic data and the computer-aided docking study of 10 with hiNOS.

Animals↗