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PubMed2005

Practical asymmetric synthesis of a non-peptidic alphavbeta3 antagonist.

The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.

Azepines↗
PubMed2004

Type 2 intramolecular N-acylnitroso Diels-Alder reaction: scope and application to the synthesis of medium ring lactams.

Heteroatom variants of the type 2 intramolecular Diels-Alder reaction provide an efficient method for the preparation of bridged bicyclic heterocycles. The type 2 variant of the intramolecular N-acylnitroso Diels-Alder reaction is an effective method for the synthesis of bridged bicyclic oxazinolactams. Structural studies of the cycloadducts have allowed for quantification of the deformations of the bridgehead functionalities and provided a strategy for the stereoselective synthesis of substituted seven- and eight-membered ring lactams. Diastereoselective cycloadditions followed by cleavage of the oxazine ring afford azepin-2-ones or azocin-2-ones.

Acylation↗
PubMed1988

Percutaneous and systemic disposition of hexamethylene lauramide and its penetration enhancement effect on hydrocortisone in a rat sandwich skin-flap model.

The percutaneous absorption and distribution profile of hexamethylene lauramide (hexahydro-1-lauroyl-1H-azepine) were examined using a rat skin-flap model. After a topical dose to the skin flap, the drug concentrations in the vasculature at the site of drug application and in the systemic blood were monitored simultaneously. Hexamethylene lauramide penetrated the skin and reached a steady state in stratum corneum, viable epidermis, dermis, and cutaneous blood in 3 hr. Its concentration in the skin was much higher than that in the blood. Its apparent concentration in the epidermis was 19 times that in the dermis and about 3000 times that in the cutaneous blood. The percutaneous absorption of 14C-hexamethylene lauramide resulted in ascending systemic blood concentrations throughout the experimental period, whereas the cutaneous blood levels remained steady. The topically absorbed hexamethylene lauramide was quantitatively recovered in urine (85%) and feces (13%). The half-lives of urinary and fecal excretion of 14C-hexamethylene lauramide were 17 and 30 hr, respectively. Hexamethylene lauramide, when topically coadministered in an experimental formulation, enhanced the skin penetration of hydrocortisone with increased drug contents in the stratum corneum (2-fold) and with increased hydrocortisone concentrations in the cutaneous blood (3.4-fold) and the systemic blood (3.5-fold). The results indicated that the high concentration and retention of hexamethylene lauramide in stratum corneum and viable epidermis may contribute to its penetration enhancement effect in the skin. A steady state in percutaneous tissues was observed before the drug reached distribution equilibrium systemically. The systemic blood concentration of a topically applied agent therefore may not reflect its percutaneous kinetic processes before a systemic distribution equilibrium is reached.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1997

Alpha-adrenoceptors in equine digital veins: evidence for the presence of both alpha1 and alpha2-receptors mediating vasoconstriction.

Rings of equine digital vein examined under conditions of isometric tension recording constricted to alpha-adrenoceptor agonists with an order of potency of 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline bitartrate (UK 14304) = noradrenaline > 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d) azepine (BHT-920) > phenylephrine > dopamine > methoxamine. The maximum force generated was greatest for the non-selective agonist noradrenaline and lowest for the alpha2-selective agonist BHT-920 with the other agonists between these two extremes. Selective inactivation of alpha1-adrenoceptors (achieved by treating yohimbine-protected tissues with phenoxybenzamine) reduced the maximum responses of all agonists, the EC50 values of UK 14304, BHT-920 and noradrenaline and increased the EC50 values of phenylephrine and methoxamine. Prazosin (30 nM) had no inhibitory effect on responses to low concentrations of BHT-920 and UK 14304 and caused competitive inhibition of responses to phenylephrine and noradrenaline giving pKb values of 8.49 +/- 0.18 and 8.23 +/- 0.14, respectively. Yohimbine (0.1 microM) caused significant competitive inhibition of responses to BHT-920 and noradrenaline with calculated pKb values of 8.43 +/- 0.11 for BHT-920 and 7.43 +/- 0.31 for noradrenaline and non-competitive inhibition of responses to UK 14304. 2-[2-methoxy-1,4-benzodioxan-2-yl]-2-imidazoline (RX 821002; 10 nM) caused competitive inhibition of responses to BHT-920 (pKb 9.04 +/- 0.27) and dopamine (pKb 8.2 +/- 0.2). These data indicate that equine digital veins possess both post-synaptic alpha1 and alpha2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1990

B-HT 920--a novel dopamine autoreceptor agonist in the treatment of patients with schizophrenia.

In an open clinical trial the azepine derivative B-HT 920 was administered to patients with schizophrenia, paranoid type (according to ICD-9 and DSM-III criteria), in order to examine whether dopamine autoreceptor stimulation exerts antipsychotic effects. Twelve patients participated in the study and received the test drug orally for up to 28 days in a dose range from 0.3 to 1.2 mg/day. The following results emerged: in four patients a significant amelioration (reduction of initial BPRS scores by more than 50%) of psychotic symptomatology was observed; eight patients remained without improvement of psychopathology. Psychomotor activation was observed in seven patients, and prompted termination of the trial in two cases. No other marked adverse effects of B-HT 920 were noted, including EEG, ECG, and clinical chemistry parameters. As it was to be expected from the pharmacology of B-HT 920, plasma prolactin concentrations were significantly reduced two hours after oral application of a single dose of the drug. It remains to be clarified whether chronic treatment with B-HT 920 induces antipsychotic efficacy within as yet unidentified subsamples of schizophrenic patients. The observed activating effects of B-HT 920 may focus future investigative efforts toward study samples where negative symptoms predominate.

Adult↗
PubMed1980

Effect of cetiedil on erythrocyte sickling: new type of antisickling agent that may affect erythrocyte membranes.

The antisickling effect of cetiedil, alpha-cyclohexyl-3-thiopheneacetic acid 2-(hexahydro-1H-azepin-1-yl)-ethyl ester, has been investigated. The concentration of cetiedil required for 50% inhibition of erythrocyte sickling was about 140 micro M. An antisickling effect was achieved regardless of whether cetiedil was added before or after deoxygenation. The minimal gelling concentration of deoxy Hb S was increased by less than 10% in the presence of 218 micro M cetiedil. The oxygen equilibrium curves of Hb S were not significantly affected by cetiedil. Erythrocytes treated with high concentrations of cetiedil were swollen and became spheroidal. The antisickling effects of cetiedil might be due to an effect on erythrocyte membranes.

Antisickling Agents↗
PubMed1980

The degradation of [14C]molinate in soil under flooded and nonflooded conditions.

The degradation of [14C]molinate in soil under flooded and nonflooded conditions was investigated. In laboratory studies, 50 percent of the applied molinate was lost in 3 weeks under moist soil conditions, while under flooded conditions, dissipation was reduced to 50 percent loss in 10 weeks. Analysis for molinate and its degradation products in the soil and flood water showed that under flooded conditions very little breakdown of molinate occurred, and volatilization was the primary mode of dissipation. However, under nonflooded conditions, hydroxylation of the azepine ring and further oxidation to the respective ketones occurs. Oxidation to form the sulfoxide, cleavage to yield the imine, and acetylation of the imine are also proposed. Other pathways appear to involve desethylation to produce a free thiocarbamic acid derivative followed by S-methylation as well as carboxylation of the S-ethyl group.

Azepines↗
PubMed1985

Effect of cetiedil on the superoxide-generating system of porcine neutrophils.

Cetiedil, alpha-cyclohexyl-3-thiopheneacetic acid 2-(hexahydro-1H-azepin-1-yl)-ethyl ester, was found to inhibit the generation of superoxide (O2-) by porcine neutrophils exposed to various stimulators. The concentration of cetiedil required for 50% inhibition was about 45 microM when neutrophils were stimulated by phorbol myristate acetate. Cetiedil not only decreased the rate of generation of O2-, but prolonged the lag time prior to the production of O2-. The inhibitory effect of cetiedil on the O2(-)-generating activity of the NADPH oxidase in the membrane vesicles was less than that on whole cells; the concentration of cetiedil necessary for 50% inhibition was about 250 microM. To study the mechanism of cetiedil's effect on the membrane, the transmembrane potential of neutrophils and the intracellular free Ca2+ concentration were monitored by using fluorescence probes, diS-C3-(5), and quin-2, respectively. Cetiedil caused depolarization of the membrane potential and increased the intracellular free Ca2+. These results indicate that integrity of ionic distribution is necessary to activate the O2(-)-generating system of neutrophils.

Animals↗
PubMed1982

alpha-Adrenoceptor subtypes in cardiovascular regulation.

A great deal of experimental observations at alpha-adrenoceptors may be explained if two points are considered: (1) the alpha 1-/adrenoceptor ratio (selectivity ratio) of a given drug and (2) the ratio of alpha 1-/adrenoceptors in the target organ or tissue. The alpha 1-/alpha 2-selectivity ratio for 10 agonists was determined in pithed rats by their hypertensive effect in the presence or absence of the antagonists rauwolscine or prazosin, respectively. Treatment with a beta-blocking agent made it possible to test drugs with additional beta-adrenergic potencies (phenylethylamines). Methoxamine exerted the highest alpha 1-/alpha 2-selectivity ratio, the azepine derivative B-HT 920 the lowest ratio, i.e., the highest selectivity for alpha 2-adrenoceptors. Using the two selective agonists methoxamine and B-HT 920, respectively, the alpha 1-/alpha 2-adrenoceptor ratio (importance) in several target systems was estimated (determination of equieffective doses). Results indicated the prevalence of alpha 1-adrenoceptors in the nictitating membrane, and the equal importance of both subtypes at peripheral postsynaptic vascular sites in rats, as well as in cats. At presynaptic sites (cardiac nerve, rats), alpha 2-adrenoceptors are prevalent. A comparison of equieffective doses of B-HT 920 and clonidine in cats indicated the alpha 2-nature of the central adrenoceptors which mediate hypotension.

Adrenergic alpha-Agonists↗
PubMed1985

Effects of cetiedil on the oxidative metabolism of activated polymorphonuclear leucocytes.

Cetiedil, alpha-cyclohexyl-3-thiopheneacetic acid 2-(hexahydro-lH-azepin-l-yl)-ethyl ester, was found to specifically suppress oxygen uptake by polymorphonuclear leucocytes (PMN) that were exposed to myristate or heat-killed E. coli. The chemical had no effect on the basal respiration rate of PMN in the resting state. Inhibition of oxygen uptake by cetiedil was proportionate to the degree of inhibition of the generation of O-2 and H2O2. It was also found that cetiedil suppressed the rate of the phagocytosis by PMN of opsonized oil droplets. Cetiedil had no effect on subcellular NADPH oxidase, an enzyme responsible for the respiratory burst that is activated by the perturbation of PMN plasma membrane with phagocytable particles or stimulators such as myristate. These results suggest that cetiedil affects the trigger mechanism of the plasma membrane to inhibit the activation of NADPH oxidase.

Animals↗
PubMed1980

Preliminary experience of the use of meptazinol as an obstetric analgesic.

Following an open pilot trial, meptazinol [m(3-ethyl-1-methyl-hexahydro-1-H-azepin-3-yl) phenol hydrochloride] was compared to pethidine in a single-blind study in women requiring analgesia during labour. Meptazinol provided significantly better analgesia than pethidine with similar but possibly less distressing maternal side effects. There were no obvious adverse effects in the newborn.

Apgar Score↗
PubMed2006

Evidence against alpha-adrenoceptors mediating relaxation in rat thoracic aortae: alpha-agonists relaxation depends on interaction with alpha-adrenoceptors.

In rat aorta, the presence of functional alpha(2)-adrenoceptors (alpha(2)-AR) was investigated in ring preparations preconstricted with alpha(1)-adrenergic and non- alpha(1)-adrenergic agonists. Particularly, the hypothetical interference of alpha(2)-AR agonists with alpha(1)-AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to alpha(2)-AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 x 10(-6) m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (-log EC(50)) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective alpha(2)-AR antagonist, rauwolscine (< or =1 x 10(-6) m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F(2alpha) (3 x 10(-7) m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration-contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the alpha(1D)-AR selective antagonist, BMY 7378, and rauwolscine. The pA(2) and pK(B) values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the alpha(1D)-AR. The other selective alpha(2)-AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional alpha(2)-AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the alpha(1)-AR), inhibitory and excitatory, interaction with alpha(1)-ARs.

Adrenergic alpha-Agonists↗
PubMed1984

Calcium-dependence and antagonism of responses to alpha 1- and alpha 2-adrenoceptor agonists in vascular tissues from hypertensive and normotensive rats.

Inhibition by D600 (methoxyverapamil) of responses to an alpha 2-adrenoceptor selective agonist, B-HT 920, (6-allyl-2-amino-5, 6, 7, 8-tetrahydro-4H-thiazolo [4, 5-d] azepin dihydrochloride), an alpha 1-adrenoceptor selective agonist, phenylephrine (PE), and a nonselective agonist, noradrenaline (NA), was studied in isolated preparations of the aortae and carotid arteries obtained from young (5-7 weeks) and old (15-17 weeks) hypertensive (SHR) and normotensive (WKY) rats. Maximum responses of WKY tissues to B-HT 920 were the most sensitive, PE-induced responses the least sensitive and maximum responses to NA were intermediate in their sensitivity to inhibition by D600. Sub-maximal responses to NA and PE were not different in their sensitivity to inhibition by D600, but were less sensitive than the responses to B-HT 20. Sub-maximal responses to PE were significantly more sensitive to D600 inhibition than were the maximal responses to this agonist. NA-induced responses of tissues from older SHR were less sensitive to inhibition by D600 when compared to responses in WKY rats. Responses to B-HT 920, in tissues suspended in calcium-free solutions, showed the largest decline compared to NA- and PE-induced responses. We conclude that responses to B-HT 920 largely utilize extracellular calcium. PE- and NA- induced responses mobilize extracellular calcium to varying degrees depending upon the concentration of the agonist employed to elicit the response.

Adrenergic alpha-Agonists↗
PubMed1984

Endothelial mediated inhibition of contraction and increase in cyclic GMP levels evoked by the alpha-adrenoceptor agonist B-HT 920 in rat isolated aorta.

In the presence of endothelium maximal contractions of rat aorta preparations evoked by B-HT 920 were about 10% of those evoked in the absence of endothelium. 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d)azepin dihydrochloride (B-HT 920, 0.1 microM to 0.1 mM) induced concentration-dependent contractions of rat aorta in the absence of endothelium. Maximal contractions were comparable in magnitude to those induced by noradrenaline. In the presence of endothelium but not in its absence B-HT 920 (0.1 mM) stimulated an increase in tissue cyclic GMP levels of about 2 fold. Levels of cyclic AMP were unaffected. Removal of endothelium reduced basal tissue levels of cyclic GMP. The guanylate cyclase inhibitor methylene blue (0.5 microM) potentiated B-HT 920-induced contractions in the presence of endothelium and inhibited increases in cyclic GMP. In the presence of endothelium 5,8,11,14-eicosatetraynoic acid (ETYA; 0.1 mM), an inhibitor of both lipoxygenase and cyclo-oxygenase systems, inhibited the B-HT 920-induced increase in cyclic GMP but did not potentiate B-HT 920-induced contractions. ETYA also antagonized B-HT 920-induced contractions in the absence of endothelium. It is concluded that endothelium continuously releases a product or products which influence the smooth muscle. Inhibition of B-HT 920-induced contractions in the presence of endothelium is associated with increased tissue levels of cyclic GMP.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1986

B-HT 958 lowers blood pressure and heart rate in the rat through stimulation of dopamine receptors.

To investigate whether the hypotensive and bradycardiac effects of B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo-(5,4-d) azepine) are due to the stimulation of peripheral prejunctional alpha2-adrenoceptors, the selective alpha2-adrenoceptor antagonist idazoxan was given either intravenously (i.v.) or intracerebroventricularly (i.c.v.) to anaesthetized rats before the administration of i.v. B-HT 958. Plasma noradrenaline was used as an approximate index of peripheral sympathetic nervous activity. B-HT 958 350 micrograms kg-1 i.v. caused significant falls in blood pressure and heart rate which were maximal 5 min after dosing (-29.25 +/- 3.2 mmHg and - 52 +/- 6.8 beats min-1 respectively, mean of all control animals). The hypotension and bradycardia were accompanied by significant falls in plasma noradrenaline concentration of 30-40%. Idazoxan 300 micrograms kg-1 i.v. caused a marked, but transient tachycardia and a large sustained rise in plasma noradrenaline concentration. Idazoxan 300 micrograms kg-1 and 1000 micrograms kg-1 i.v. did not prevent B-HT 958-induced falls in mean arterial pressure, heart rate and plasma noradrenaline concentration. Responses to B-HT 958 were unaffected by idazoxan 20 micrograms i.c.v. B-HT 958-induced falls in mean arterial pressure, heart rate and plasma noradrenaline concentration were significantly attenuated by i.v. administration of the dopamine receptor antagonist, sulpiride 300 micrograms kg-1. Sulpiride 10 micrograms and 50 micrograms i.c.v. caused inhibition of B-HT 958 hypotension and bradycardia similar to that of intravenous sulpiride. After i.c.v. sulpiride, B-HT 958 did not cause a significant fall in plasma noradrenaline concentration. A combination of idazoxan 1000 micrograms kg-1 i.v. and sulpiride 300 micrograms kg-1 i.v. did not cause further significant inhibition of B-HT 958 hypotension and bradycardia compared with sulpiride 300 micrograms kg-1 i.v. alone. This combination however had a significantly greater effect in inhibiting B-HT 958 hypotension than had idazoxan 1000 micrograms kg-1 alone, and almost completely blocked the B-HT 958-induced fall in plasma noradrenaline concentration. These results suggest that in the anaesthetized rat the cardiovascular effects of B-HT 958 are due to stimulation of dopamine receptors, probably located within the central nervous system, and not to stimulation of peripheral prejunctional alpha2-adrenoceptors.

Animals↗
PubMed1990

The effectiveness of alpha 2-adrenoceptor activation increases from the distal to the proximal part of the veins of canine limbs.

1. The effectiveness of alpha 1- and alpha 2-adrenoceptor activation was compared at different levels of the saphenous and cephalic vein of the dog in vitro. 2. Helically cut strips were used to determine concentration-response curves to phenylephrine, noradrenaline, UK-14,304 (5-bromo-6-(imidazoline-2-ylamino)-quinoxaline) and B-HT 920 (2-amino-6-allyl-5,6,7,8-tetra-hydro-4H-(thiazo)-4,5-d-azepine). The effect of prazosin and yohimbine on these curves was also studied. 3. At the distal level, the maximum response to UK-14,304 amounted to 33 and 50% of those to noradrenaline in the saphenous and cephalic vein, respectively, while at the proximal level the maximum response to UK-14,304 amounted to 72 and 78% of those to noradrenaline, in the saphenous and cephalic vein, respectively. 4. In both vessels, the results obtained with B-HT 920 were very similar to those for UK-14,304. 5. The pD2 values for UK-14,304 - which were identical at the three levels of both vessels - and the pA2 values for the antagonism exerted by either prazosin or yohimbine against the responses to UK-14,304 indicate that the alpha 2-adrenoceptors are identical at the different levels of both vessels. 6. These results show that the effectiveness of alpha 2-adrenoceptor stimulation increases from the distal to the proximal regions of canine limb veins. Apparently, this is due to a greater density of alpha 2-adrenoceptors in the proximal regions. 7. Yohimbine is much more potent against phenylephrine distally than proximally in both vessels. However, after 30 nm phenoxybenzamine - a concentration which eliminates the vast majority of alpha,-adrenoceptors without affecting alpha 2-adrenoceptors - yohimbine became equally potent at both levels, suggesting that the difference existing before phenoxybenzamine depended on alpha,-adrenoceptors. Hence it is concluded that alpha,-adrenoceptors in distal and proximal portions may differ.

Adrenergic alpha-Agonists↗
PubMed1983

Pre-junctional alpha 2-adrenoceptor activity of B-HT920.

An in-vitro study has been carried out on the pre-junctional alpha 2-adrenoceptor activity of the thiazoloazepine derivative B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine) using field-stimulated rat vas deferens and guinea-pig ileum. The alpha 2-selective agonists clonidine (an imidazoline derivative) and alpha-methyl noradrenaline (a beta-phenethylamine derivative) were compared. Results show that B-HT 920 is a potent agonist on pre-junctional alpha 2-adrenoceptors and is competitively antagonized by the selective alpha 2-adrenoceptor antagonist yohimbine. The characteristics of the pharmacological responses obtained with B-HT920 indicate that it interacts with the receptor in an imidazoline-like, rather than a beta-phenethylamine-like, manner.

Adrenergic alpha-Agonists↗
PubMed1984

B-HT 958 stimulates dopamine autoreceptors but blocks noradrenaline autoreceptors in the brain.

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo 5,4-d azepine) blocked the gamma-butyrolactone-induced increase in the synthesis of dopamine and slowed down the alpha-methyltyrosine-induced disappearance of dopamine in the mouse brain by haloperidol-sensitive mechanisms. In reserpine-treated mice, B-HT 958 produced a most a weak locomotion and no change in the apomorphine-induced increase in motor activity. The motor activity of normal mice was reduced by B-HT 958. At high doses, B-HT 958 accelerated the alpha-methyltyrosine-induced disappearance of noradrenaline and it inhibited the effects of clonidine on the turnover and on the synthesis of noradrenaline in the mouse brain. The findings indicate that the dopamine autoreceptors can be selectively stimulated by B-HT 958 but that the alpha 2-adrenoceptors can be blocked following high doses.

Adrenergic alpha-Agonists↗