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PubMedDate not supplied

6-[N,S-dimethyl-N'-cyanothioureidomethyl]-6,11-dihydro-5H- dibenz[b,e]azepine hydrochloride (Fran 12): a histamine and 5-hydroxytryptamine antagonist with pressor properties.

We have synthesized and examined some of the pharmacological properties of 6-[N,S-dimethyl-N'-cyanoisothioureidomethyl]-6,11-dihydro-5H- dibenz(b,e)azepine hydrochloride (Fran 12), a derivative of 6-methylaminomethyl-6,11-dihydro-5H- dibenz[b,e,]azepine. In the guinea-pig isolated ileum, Fran 12 (10(-7)-10(-5) M) caused parallel rightward shifts of the concentration-response curves to histamine. A Schild plot gave a pA2 of 7.48, with a slope not significantly different from -1.0. In the rat stomach fundus strip and in endothelium-denuded aortic rings, Fran 12 inhibited contractile responses to 5-hydroxytryptamine in a non-competitive manner. In both chloralose-anaesthetized and pithed rats, it inhibited pressor responses to 5-hydroxytryptamine. It had no effect on depressor responses to 5-hydroxytryptamine in anaesthetized rats. In pithed rats, Fran 12 (0.25-2 mg/kg, i.v.) produced dose-dependent increases in blood pressure. These were not inhibited by i.v. phentolamine, prazosin, yohimbine, propranolol, methysergide, pentolinium or atropine but were inhibited by verapamil. These results indicate that Fran 12 is a histamine and 5-hydroxytryptamine antagonist which also exerts pressor effects via a peripheral action. The pressor action does not appear to be mediated via effects on alpha 1- or alpha 2-adrenoceptors, muscarinic or nicotinic cholinoceptors or 5-hydroxytryptamine receptors, although calcium channel activation may play a role.

Adrenergic alpha-Agonists↗
PubMed1978

[Tetrahydropyridoazepine and tetrahydropyridoazepinone derivatives. I. Derivatives of 2,3,4,5-tetrahydro-1H-pyrido[3,2b]azepine and of the corresponding lactam].

Preparation of N-derivatives of 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepine and, in one case, of 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepine-2-one was achieved by introducing the substituents COCl, CONH2, CO2(CH2)3N(CH3)2, COCH2Br and (CH2)3N(CH3)2. The pharmacological results indicate some effect on the ANS.

Adrenergic alpha-Antagonists↗
PubMed2003

Insecticidal pyrido[1,2-a]azepine alkaloids and related derivatives from Stemona species.

Eight new alkaloids, the pyrido[1,2-a]azepines stemokerrin, methoxystemokerrin-N-oxide, oxystemokerrin, oxystemokerrin-N-oxide, and pyridostemin, along with the pyrrolo[1,2-a]azepines dehydroprotostemonine, oxyprotostemonine, and stemocochinin were isolated from four Stemona species together with the known compounds protostemonine, stemofoline, 2'-hydroxystemofoline, and parvistemonine. Their structures were elucidated by 1H and 13C NMR including 2D methods and two key compounds additionally by X-ray diffraction. Besides the formation of a six membered piperidine ring, additional oxygen bridges and N-oxides contributed to structural diversity. The co-occurrence of pyrrolo- and pyridoazepines suggested biosynthetic connections starting from more widespread protostemonine type precursors. Bioassays with lipophilic crude extracts against Spodoptera littoralis displayed very strong insecticidal activity for the roots of S. curtisii and S. cochinchinensis, moderate activity for S. kerrii, but only weak effects for the unidentified species HG 915. The insect toxicity was mainly caused by the accumulation of stemofoline, oxystemokerrin, and dehydroprotostemonine displaying two different modes of action. Based on the various insecticidal activities of 13 derivatives structure-activity relationships became apparent.

Alkaloids↗
PubMed2002

Quantitative model studies on the efficiency of precursors in the formation of cooling-active 1-pyrrolidinyl-2-cyclopenten-1-ones and bitter-tasting cyclopenta-[b]azepin-8(1H)-ones.

The yields of the cooling-active compounds 3-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (1) and 5-methyl-2-(1-pyrrolidinyl)-2-cyclopenten-1-one (2) as well as the bitter tastants 7-methyl-2,3,6,7-tetrahydrocyclopenta-[b]azepin-8(1H)-one (3) and 7-methyl-2,3,4,5,6,7-hexahydrocyclopenta-[b]azepin-8(1H)-one (4) obtained by heating mixtures of possible Maillard-type precursors in model systems varying in temperature, pH value, or water content were determined quantitatively. The results showed that hexose-derived cyclotene is the common precursor for all four tastants and that the formation of each individual tastant is strongly determined by the structure of the nitrogen-containing precursor, e.g., reaction of cyclotene with pyrrolidine formed by thermal decarboxylation of L-proline produced the cooling compounds 1 and 2 only, whereas in the presence of 1-pyrroline formed upon Strecker reactions of L-proline, the bitter tasting azepinone 3 was produced exclusively. In contrast, the structure of the secondary amino acid L-proline enabled the formation of compound 4, whereas the pyrrolidine and 1-pyrroline, respectively, do not generate this tastant. In addition, a nonvolatile, tasteless intermediate, (S)-3-methyl-2-[(2'-carboxy)-1-pyrrolidinyl]-2-cyclopenten-1-one (5), was isolated from the cyclotene/L-proline reaction mixture and could be confirmed as an efficient precursor for the cooling compound 1. The data, obtained by these studies, are the scientific basis to tailor the desired overall flavor of foods by means of a more controlled Maillard-type technology.

Amino Acids↗
PubMed2006

Novel parallel reaction between a [1,5] sigmatropic alkylthio shift and a [1,5] sigmatropic hydrogen shift observed in a 2H-azepine ring.

Although heating 2-methoxy-2H-azepine results in a [1,5] sigmatropic hydrogen shift, heating 2-propylthio-2H-azepine results in not only a [1,5] sigmatropic hydrogen shift but also a [1,5] sigmatropic propylthio shift. Kinetic measurements reveal that migratory aptitudes increase in the order of MeO < H, PrS. These [1,5] sigmatropic shifts are discussed on the basis of ab initio DFT calculations. [reaction: see text].

Journal Article↗
PubMed2004

Homoheteroaromaticity: the case study of azepine and dibenzazepine.

Geometrical and energetic DFT calculations as well as GIAO and NICS chemical shifts have been calculated for 1H-azepine and 5H-dibenz[b,f]azepine and their cations. The last compound has been studied experimentally by 1H and 13C NMR in neutral and acidic conditions establishing that the cation corresponds to an N-protonated structure. The conclusion is that the neutral molecules are antiaromatic while the cations are aromatic (homoheteroaromaticity).

Journal Article↗
PubMed1977

[Derivatographic analysis of 6-beta-[(hexahydro-1H-azepin-1-yl) methylenamino]penicillanic acid].

Derivatographic analysis of 5 samples of 6-beta-(hexahydro-IH-azepin-I-yl)methylenamino penicillanic acid was performed. In addition to the antibiotic the samples had water and acetone in their composition. No effects associated with changes in the physical and chemical state of the substance were observed on the derivatogramme of the samples containing 0.2 and 0.8 per cent of water up 140 degrees C. With a further increase in the temperature an exothermic effect was observed with maximum at 152--153 degrees C connected with melting and chemical degradation of the substance. The derivatogrammes of the samples containing 89--96.4 per cent of the antibiotic were characterized by an endothermic effect with minimum at 65 degrees C caused by evaporation of acetone and partially water from them and by an exothermic effect with maximum at 120 degrees C practically not accompanied by any change in the weight resulting from chemical interaction of the antibiotic with water. The study showed sensitivity of 6-beta-(hexahydro-IH-azepin-I-yl)methylenaminopenicillanic acid to the presence of even insignificant amounts of water in it, maximum elimination of which from the antibiotic is an important factor of increasing its stability.

Crystallization↗
PubMed1988

Influence of 1-dodecylhexahydro-2H-azepin-2-one (Azone) on the in vitro permeation of verapamil hydrochloride across rat, hairless mouse, and human cadaver skin.

The effect of 1-dodecylhexahydro-2H-azepine-2-one (Azone; laurocapran; 1) on the permeation of verapamil hydrochloride (2) through rat skin was studied. Compound 1 was used in various concentrations in the donor phase. The permeation of the drug increased significantly in the presence of 1 and the enhancement in permeation was dependent on the concentration of 1. A comparison of the enhancing effect of 3% 1 on permeation of 2 through rat, hairless mouse, and human cadaver skin was made. Compound 1 altered the permeability of hairless mouse skin significantly, whereas the effect on rat and human skin was comparable and not very drastic.

Animals↗
PubMed1991

Inhibition by talipexole, a thiazolo-azepine derivative, of dopaminergic neurons in the ventral tegmental area.

A microiontophoretic study using rats anesthetized with chloral hydrate and immobilized with gallamine triethiodide was carried out to compare the effect of talipexole (B-HT 920 CL2:2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo [4,5-d]-azepine-dihydrochloride), a dopamine autoreceptor agonist, on dopaminergic neurons in the ventral tegmental area (VTA) to non-dopaminergic neurons in the VTA. VTA neurons were classified into two types according to the responses to antidromic stimulation of the nucleus accumbens (Acc): type I neurons with a long spike latency (8.69 +/- 0.24 msec) upon Acc stimulation and low spontaneous firing rate (6.80 +/- 1.34/sec), and type II neurons with a short latency (2.76 +/- 0.20 msec) and high spontaneous firing rate (26.77 +/- 7.05/sec), probably corresponding to dopaminergic and non-dopaminergic neurons, respectively. In type I neurons, microiontophoretic application of talipexole and dopamine inhibited antidromic spike generation elicited by Acc stimulation, and talipexole-induced inhibition was antagonized by domperidone (dopamine D-2 antagonist). In type II neurons, however, the antidromic spikes were not affected by either talipexole or dopamine. Furthermore, spontaneous firing was also inhibited by iontophoretically applied talipexole and dopamine in most type I neurons, but rarely affected by either drug. Inhibitory effects of talipexole were antagonized by domperidone. These results suggest that talipexole acts on dopamine D-2 receptors, thereby inhibiting the dopaminergic neurons in the VTA.

Animals↗
PubMed2001

Evaluation of derivatives of 3-(2-oxo-1-pyrrolidine)hexahydro-1H-azepine-2-one as dermal penetration enhancers: side chain length variation and molecular modeling.

The present study examined the enhancement effect of two series of compounds derived from 3-(2-oxo-1-pyrrolidine)hexahydro-1H-azepine-2-one. One series possessed alkyl side chains (series I) and the other alkyl ester side chains (series II). An in vitro diffusion study was performed to investigate the effect of variation in alkyl/alkyl ester side chain length of two series of compounds on the permeation of hydrocortisone (HC) across hairless mouse skin. The permeability coefficient (P), 24 h receptor concentration (Q(24)) and skin content (SC), as well as the enhancement ratios (ER) for each parameter were recorded. A parabolic relationship was observed between the ER(P), and the alkyl side chain length of the enhancers. The relationship between the length of ester side chains and ER(P) appeared to be relatively linear with R(2) of 0.9676. The relationship between the calculated lipophilicity (CL) and enhancement activity of the enhancers showed that for CL 5-9, series I showed higher P values compared with Azone, but this was not observed with series II. For CL values 4.57-7.75, a significant correlation existed between P of HC and CL of series II compounds (R(2)=0.9967). 1-Tetradecyl-3-(2-oxo-1-pyrrolidine)-epsilon-caprolactam showed the highest P and Q(24), with 40.5- and 18.6-fold increases over the control. In conclusion, the alkyl side chain series of compounds showed more enhancing activity than the alkyl ester side chain series.

Animals↗
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 1.

The synthesis of a series of novel 2-(aminoalkyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives as well as their 5-HT(2A/2C) and H(1) receptor binding affinities are described. The in vivo activity as potential anxiolytics of the synthesised compounds was measured in a mCPP challenge test. One of the compounds, 2a, proved to be a potent 5-HT(2A/2C) receptor antagonist showing as well oral activity and therefore could be considered as a potential anxiolytic/antidepressant agent.

Animals↗
PubMed2003

Parallel liquid synthesis of N,N'-Disubstituted 3-amino azepin-2-ones as potent and specific farnesyl transferase inhibitors.

A rapid structure-activity study was performed by parallel liquid synthesis on N,N'-disubstitution of 3-amino azepin-2-one to afford potent and specific farnesyl transferase inhibitors with low nM enzymatic and cellular activities. The activities of the selected compounds were validated in vivo, and compounds 41a and 44a presented significant antitumour activity.

Alkyl and Aryl Transferases↗
PubMed2004

Synthesis of 2,4-diamino-6-[2'-O-(omega-carboxyalkyl)oxydibenz[b,f]azepin-5-yl]methylpteridines as potent and selective inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase.

Six previously undescribed N-(2,4-diaminopteridin-6-yl)methyldibenz[b,f]azepines with water-solubilizing O-carboxyalkyloxy or O-carboxybenzyloxy side chains at the 2'-position were synthesized and compared with trimethoprim (TMP) and piritrexim (PTX) as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three of the opportunistic organisms known to cause significant morbidity and mortality in patients with AIDS and other disorders of the immune system. The ability of the new analogues to inhibit reduction of dihydrofolate to tetrahydrofolate by Pc, Tg, Ma, and rat DHFR was determined, and the selectivity index (SI) was calculated from the ratio IC(50)(rat DHFR)/IC(50)(Pc, Tg, or Ma DHFR). The IC(50) values of the 2'-O-carboxypropyl analogue (10), with SI values in parentheses, were 1.1 nM (1300) against Pc DHFR, 9.9 nM (120) against Tg DHFR, and 2.0 nM (600) against Ma DHFR. The corresponding values for the 2'-O-(4-carboxybenzyloxy) analogue (12) were 1.0 nM (560), 22 nM (21), and 0.75 nM (630). By comparison, the IC(50) and SI values for TMP were Pc, 13 000 nM (14); Tg, 2800 nM (65); and Ma, 300 nM (610). For the prototypical potent but nonselective inhibitors PTX and TMX, respectively, these values were Pc, 13 nM (0.26) and 47 nM (0.17); Tg, 4.3 nM (0.76) and 16 nM (0.50); Ma, 0.61 nM (5.4) and 1.5 nM (5.3). Thus 10 and 12 met the criterion for DHFR inhibitors that combine the high selectivity of TMP with the high potency of PTX and TMX.

Animals↗
PubMed2006

Isoelectronic homologues and isomers: tropolone, 5-azatropolone, 1-H-azepine-4,5-dione, saddle points, and ions.

Computational studies of 12 64-electron homologues and isomers of tropolone in the S(0) electronic ground state are reported. Three minimum-energy structures, tropolone (Tp), 5-azatropolone (5Azt), and 5-H-5-azatropolonium (5AztH(+)), have an internal H-bond and planar C(s)) geometry, and three, tropolonate (TpO(-)), 5-azatropolonate (5AzO(-)), and 1-H-azepine-4,5-dione (45Di), lack the H-bond and have twisted C(2) geometry. All 6 substances have an equal double-minimum potential energy surface and a saddle point with planar C(2)(v) geometry. The energy for the gas-phase isomerization reaction 45Di --> 5Azt is near +4 kJ mol(-1) at the MP4(SDQ)/6-311++G(df,pd)//MP2/6-311++G(df,pd) (energy//geometry) theoretical level and around -20 kJ mol(-1) at lower theoretical levels. The dipole moments computed for 45Di and 5Azt are 9.6 and 2.1 D, respectively, and this large difference contributes to MO-computed free energies of solvation that strongly favor--as experimentally observed--45Di over 5Azt in chloroform solvent. The MO-computed energy for the gas-phase protonation reaction 45Di + H(+) --> 5AztH(+) is -956.4 kJ mol(-1), leading to 926.8 kJ mol(-1) as the estimated proton affinity for 45Di at 298 K and 1 atm. The intramolecular dynamical properties predicted for 5Azt and 5AztH(+) parallel those observed for tropolone. They are therefore expected to exhibit spectral tunneling doublets. Once they are synthesized, they should contribute importantly to the understanding of multidimensional intramolecular H transfer and dynamical coupling processes.

Aza Compounds↗
PubMed2004

Tin-free radical cyclizations for the synthesis of 7-azaoxindoles, 7-azaindolines, tetrahydro[1,8]naphthyridines, and tetrahydro-5H-pyrido[2,3-b]azepin-8-ones.

[reaction: see text] Compounds containing a pyridine nucleus fused to a saturated nitrogen-containing ring, including 7-azaoxindoles, 7-azaindolines, tetrahydro[1,8]naphthyridines, and tetrahydro-5H-pyrido[2,3-b]azepin-8-ones, were prepared in good yield starting from various 2,6-dichloropyridines. The method hinges on a free-radical xanthate-mediated cyclization or intermolecular addition/cyclization sequence for the construction of the new fused rings.

Azepines↗
PubMed2002

Identification of a S-hexahydro-1H-azepine-1-carbonyl adduct produced by molinate on rat hemoglobin beta(2) and beta(3) chains in vivo.

Molinate is a thiocarbamate herbicide used in the rice industry for over 25 years, and regulatory reports have shown that administration of molinate results in reproductive toxicity in male rats. Previous in vitro studies indicate that molinate undergoes oxidative metabolism, forming reactive electrophilic intermediates capable of undergoing nucleophilic addition by protein nucleophiles. On the basis of in vitro studies, carbamylation of an active site serine residue in Hydrolase A has been proposed to be the mechanism responsible for the observed testicular toxicity. The experiments presented here utilize hemoglobin to characterize covalent protein modifications produced in vivo by molinate. Rats were dosed intraperitoneally with molinate as a function of exposure duration. Examination of globin from molinate-treated rats by HPLC demonstrated a new peak in the isolated samples and, when collected and analyzed using MALDI-TOF MS, revealed a 126 Da increase in mass relative to the native beta(3) chain. Digestion of the globin using Glu-C and analysis by MALDI-TOF MS revealed two modified peptide fragments at m/z 2743 and 4985 consistent with a 126 Da increase to peptide fragments [122-146] and [102-146] in the unmodified beta(2) and beta(3) chains of globin. Using selected reaction monitoring LC/MS/MS, S-hexahydro-1H-azepine-1-carbonyl cysteine (HHAC-Cys) was identified in the globin hydrolysates isolated from the molinate-treated rats, but not in the control samples, and the quantity of adduct exhibited a cumulative dose response. These experiments demonstrate the ability of molinate to covalently modify proteins in vivo in a dose dependent manner. For hemoglobin this modification was a carbamylation at Cys-125 similar to the modification produced by disulfiram and N,N-diethyldithiocarbamate. The ability of molinate to covalently modify cysteine residues provides a potential mechanism to account for enzyme inhibition following molinate exposure and suggests that enzymes with cysteine residues in their active site may be inhibited by molinate.

Animals↗