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At least 19 recordsLinked to original sources
PubMed1976

8-chloro-(S)- and -(R)-10-((S)-and -(R)-3'-methylethylaminopyrrolidino)- 10,11-dihydrodibenzo(b,f)thiepins. Synthesis and pharmacological studies.

The synthesis for 8-chloro-(S)- and -(R)-10-[(S)- and -(R)-3'-methylethylaminopyrrolidino]-10,11-dihydrodibenzo[b,f]thiepins is presented. The absolute configuration at position 3' of the aminopyrrolidino side chain is known from synthesis and corresponds to the asymmetric carbon atom in (S)- or (R)-aspartic acid. The absolute configuration at C-10 of the dihydrodibenzo[b,f]thiepin ring system was deduced from ORD-CD analysis coupled with degradation of partially resolved (+)-8-chloro-10-amino-10,11-dihydrodibenzo[b,f]thiepin to (+)-(S)-1,2-diphenylethylamine. The four isomers were studied in mice for their ability to block conditioned avoidance responding, antagonize oxotremorine, and act as analgetics and anticonvulsants. These compounds were found to be nonselective antagonists of histamine, acetylcholine, and BaCl2 in vitro. The compounds exerted effects similar to those of chlorpromazine. Stereoselective differences in activity between diastereoisomers, rather than between enantiomorphs, were generally observed.

Analgesics↗
PubMed1991

A new class of calcium antagonists. Synthesis and biological activity of 11-[(omega-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo [b,e]thiepin derivatives.

A series of 11-[(omega-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11- octahydrodibenzo[b,e]thiepin derivatives were prepared and found to be a structurally new class of calcium antagonists. The structure-activity relationship studies indicated that the optimum was (6aR*,10aR*,11R*)-11-[[4-[4-(4-fluorophenyl)-1- piperazinyl]butyryl] amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo[b,e]thiepin (31,pA2 8.16), which was superior to diltiazem (pA2 7.42) in calcium antagonistic activity. Compound 31 showed antihypertensive activity in anesthetized rats, without a significant effect on the heart rate. It had also antianginal effects in vasopressin-induced ST-depression and methacholine-induced ST-elevation testings in rats. These potencies of 31 were essentially equal to those of diltiazem.

Animals↗
PubMed1991

A new class of calcium antagonists. 2. Synthesis and biological activity of 11-[[4-[4-(4-fluorophenyl)-1-piperazinyl]butyryl]amino]-6,11- dihydrodibenzo[b,e]-thiepin maleate and related compounds.

A series of [(epsilon-aminoalkanoyl)amino]-6,11- dihydrodibenzo[b,e]thiepins and -5H-dibenzo[a,d]cycloheptenes and related compounds were synthesized and evaluated for calcium antagonistic activity by calcium-induced constriction of potassium-depolarized rat aorta. Semiempirical molecular orbital calculations of the dibenzotricyclic systems indicated that calcium antagonistic activity increased with a decrease of the angle between the planes of the two phenyl rings. AM1 net charge calculations showed that a neutral or positive charge distribution in the bridge portion was necessary for activity. 11-[[4-[4-(4-Fluorophenyl)-1- piperazinyl]butyryl]amino]-6,11-dihydrodibenzo[b,e]thiepin maleate (16, AJ-2615) showed a more gradual and longer lasting antihypertensive effect than diltiazem and nifedipine in spontaneously hypertensive rats (SHR) administered orally. Compound 16 also possessed antianginal effects in methacholine-induced ST elevation and vasopressin-induced ST depression tests in rats. The alteration of the dibenzotricyclic system of 16 to 5H-dibenzo[a,d]cycloheptene (19, 5-[[4-[4-(4-fluorophenyl)-1-piperazinyl]-butyryl]amino]-5H- dibenzo[a,d]cycloheptene) resulted in selectivity for cardiac tissue over vascular tissue, thereby conferring antianginal activity without an effect on blood pressure. Antianginal potencies of 16 and 19 were equal to or somewhat more potent than those of diltiazem.

Animals↗
PubMed1987

High-performance liquid chromatographic assay of a new non-steroidal anti-inflammatory agent, 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid, in human plasma and urine.

A high-performance liquid chromatographic method for the quantitation of a new anti-inflammatory agent, 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid (CN-100; I), has been developed. The assay consists in extracting samples containing I and mefenamic acid, the internal standard, under acidic conditions and analysis by reversed-phase chromatography using ultraviolet detection at 330 nm. Preliminary plasma concentration-time and cumulative urinary excretion profiles from a healthy subject following oral administration of the tablet formulation are presented. This method is simple, sensitive and reproducible and is applicable to studies of the pharmacokinetic behaviour of I in humans.

Administration, Oral↗
PubMed1982

Tricyclics with analgesic and antidepressant activity. 2. [[(Alkylamino)ethyl]thio]dibenzo[b,f]thiepins and 10,11-dihydro derivatives.

A series of [[(alkylamino)ethyl]thio]dibenz[b,f]thiepins (III) and their 10,11-dihydro derivatives (IV) was synthesized and subjected to broad analgesic/CNS screening. Preliminary results indicated a combination of analgesic/antidepressant profiles, similar to that observed for the [[(alkylamino)ethyl]thio]dibenz[b,f]oxepins (I) and their corresponding dihydro derivatives (II). The most active congener from the present series, 10b, shows an antinociceptive potency in the pentazocine range as assessed by phenyl-p-quinone-induced writhing (PQW) and tail flick in mice. It is also more than twice as active as imipramine in preventing tetrabenazine-induced ptosis (TBZ), a test widely recognized to be of predictive value for clinically efficacious antidepressants.

5-Hydroxytryptophan↗
PubMed1983

Tricyclic triarylethylene antiestrogens: dibenz[b,f]oxepins, dibenzo[b,f]thiepins, dibenzo[a,e]cyclooctenes, and dibenzo[b,f]thiocins.

The bridging groups O, S, CH2CH2, and SCH2 were used to produce a series of 26 tricyclic triarylethylenes. Their in vitro binding to rat uterine estrogen receptor was measured in a competitive binding assay. Antifertility and uterotrophic tests in rats showed that antiestrogenic activity was present. The most interesting series had a basic side chain, and the most potent compounds were 3-[2-(dimethylamino)ethoxy] -10-ethyl-11-(4-hydroxyphenyl)dibenzo[b,f]thiepin (7b) and 3-[2-(dimethylamino)ethoxy]-11-ethyl-12-(4-hydroxyphenyl)-5,6-dihydrodibenzo[a,e]-cyclooctene (7c), which had good binding (approximately 50% relative to estradiol) and good antiestrogenic activity (ca. one-half of the potency of tamoxifen, III). In this series, the O-bridged compound was the least active, and this is interpreted in terms of the flatness of the dibenzoxepin ring system. Sedative activity was found in some of the compounds.

Animals↗
PubMed1987

L-641,953 (R-8-fluoro-dibenzo[b, f]thiepin-3-carboxylic acid-5-oxide): a novel thromboxane-prostaglandin endoperoxide antagonist.

The effects of L-641,953 (R-8-fluoro-dibenzo[b, f]thiepin-3-carboxylic acid-5-oxide) have been studied on pulmonary and other smooth muscle preparations in vitro and in vivo. When studied in vitro on guinea-pig tracheal chains, L-641,933 produced significant shifts in the dose-response curves to the prostaglandin endoperoxide analogues, U-44069 (pA2 7.06) and U-46619 (pA2 7.14), and prostaglandin (PG) F2 alpha (pA2 6.33) had minimal activity against contractions induced by histamine (pA2 4.38), 5-hydroxytryptamine (pA2 4.63), and acetylcholine (pA2 4.56) and slightly enhanced relaxation induced by PGE2. When tested on the guinea-pig gall bladder strip in vitro, L-641,953 antagonized contractions induced by U-44069 (pA2 7.03) but was less active against those induced by PGF2 alpha (pA2 6.03), PGE1 (pA2 5.62), and histamine (pA2 4.84). When tested in vitro on the guinea-pig pulmonary artery, L-651-953 significantly antagonized contractions induced by U-44069 (pA2 7.04), U-46619 (pA2 7.14), and PGF2 alpha (pA2 7.16) but was less effective against contractions induced by histamine (pA2 4.19). Schild analysis indicated that L-641,953 was fully competitive against contractions of either the guinea-pig tracheal chain induced by U-46619 or the guinea-pig pulmonary artery induced by U-44069 and U-46619. When tested on human platelets in vitro L-641,953 inhibited aggregation induced by U-44069 (IC50 1.3 X 10(-6) M) but not ADP.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Effect of a novel anti-inflammatory drug, 2-(10, 11-dihydro-10-oxo-dibenzo[b,f]-thiepin-2-yl)propionic acid (CN-100), on the proteoglycan biosynthesis in articular chondrocytes and prostaglandin E2 production in synovial fibroblasts.

The effect of a novel nonsteroidal anti-inflammatory drug, 2-(10,11-dihydro-10-oxo-dibenzo[b,f]thiepin-2-yl)propionic acid (CN-100), on the biosynthesis of proteoglycans in chondrocytes of rat femoral head articular cartilage was studied. Sodium salicylate and hydrocortisone inhibited significantly the biosynthesis proteoglycans, but CN-100 did not affect the biosynthesis of glycosaminoglycan chains nor their sulfation. The effect of CN-100 on the interleukin 1-induced biosynthesis of prostaglandin E2 (PGE2) and tissue collagenase in rabbit and human rheumatoid synovial fibroblasts was also examined. CN-100 did not inhibited directly the collagenase production, but significantly prevent the biosynthesis of PGE2 known as an inflammatory mediator. The 50% inhibitory concentration (IC50) of CN-100 on PGE2 of rabbit and human fibroblasts were 3.8 x 10(-9) M and 2.4 x 10(-8) M, respectively; an inhibitory effect of CN-100 was equivalent to that of a control drug, hydrocortisone (2.0 x 10(-9) M and 1.7 x 10(-8) M, respectively). These results indicate that CN-100 is a potent anti-inflammatory drug without affecting the proteoglycan biosynthesis.

Animals↗
PubMed1986

Pharmacological investigations of the new antiinflammatory agent 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid. 2nd communication: inhibitory effects on acute inflammation and prostaglandin-related reactions.

Since a newly synthesized nonsteroidal antiinflammatory drug (NSAID) having weaker effects on gastrointestinal tract, 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid (CN-100), was found to markedly inhibit rat paw edema induced by carrageenin and other phlogists, the effects of the drug on other acute inflammatory reactions and prostaglandins (PGs)-related reactions were compared with those of known NSAID in this study. At even a large dose of CN-100, 20 mg/kg, the drug did not significantly inhibit the increased vascular permeability induced by histamine in rat skin, but CN-100 could dose-dependently inhibit the increased vascular permeability induced by acetic acid in mouse peritoneum. The inhibitory activity of CN-100 in the latter was equivalent to that of pranoprofen and indometacin. CN-100 exerted a potent inhibitory action on erythema induced by UV irradiation, which was equal to and 3 times stronger than pranoprofen and indometacin in activity, respectively. Since PGs participate in these acute inflammatory reactions, the effects of CN-100 on reactions relevant to PGs were examined. The drug at dose levels lower than antiinflammatory doses could prevent acute death and diarrhea induced by i.v. injection of arachidonic acid in rabbits and endotoxin in mice, respectively, suggesting that the drug had a potent inhibitory action on biosynthesis of PGs. The adverse effects of CN-100 on gastric and small intestinal mucosa was very weak, the activity being about one-tenth of that of pranoprofen and indometacin.

Animals↗
PubMed1987

Analgesic and antiinflammatory effects of 2-(10,11-dihydro-10-oxo-dibenzo[b,f]thiepin-2-yl)propionic acid in rat and mouse.

Analgesic and antiinflammatory effects of 2-(10,11-dihydro-10-oxo-dibenzo[b,f]thiepin-2-yl)propionic acid (CN-100) have been investigated pharmacologically in rats and mice. With bradykinin-induced pain responses, CN-100 proved to be the most potent of the commercial non-steroidal antiinflammatory drugs which were tested in rats: The potency of CN-100 was 4 times stronger than that of indometacin. The analgesic effect of CN-100 on writhing induced by acetic acid, adjuvant-induced hyperalgesia, and carrageenin-induced hyperalgesia, and the effect on AgNO3-induced arthralgia were equipotent to or a little weaker than those of indometacin, but stronger than that of diclofenac sodium. In mice, CN-100 was found to be as active as indometacin against peritonitis induced by acetic acid and pain responses induced by mechanical stimulus (pressure). Against the peritonitis induced by acetylcholine and phenyl-quinone, CN-100 showed inhibitory actions and its potencies were much stronger than those of aminophenazone (amino-pyrine) in mice. However, all the drugs tested failed to increase pain thresholds induced by thermal stimulus in rats and mice. CN-100 exerted potent inhibitory effects on carrageenin-induced acute inflammatory edema and adjuvant-induced arthritis. The antiinflammatory effect of CN-100 on the former was equal to that of indometacin, but weaker on the latter. The ulcerogenic activity of CN-100 was less potent than that of indometacin. These results indicate that CN-100 may produce its analgesic effects through a peripheral mechanism and be preferable for clinical use, especially for the treatment of inflammatory conditions accompanied by pain.

Acetylcholine↗
PubMed1986

Pharmacological investigations of the new antiinflammatory agent 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid. 3rd communication: inhibitory effects on leucocyte emigration and proliferation of granulation.

The effects of 2-(10,11-dihydro-10-oxodibenzo [b,f]thiepin-2-yl)propionic acid (CN-100), which has a significant inhibitory effect on acute inflammatory reactions, on leucocyte emigration and proliferation of granulation were examined in this study. The compound obviously inhibited the protein exudation and polymorph emigration 6 h after application of carboxymethylcellulose pouch method. It also definitely inhibited the monocyte emigration occurring 24 h after carrageenin pleurisy, and the inhibitory activity of the compound was nearly equal to that of pranoprofen and weaker than that of indometacin. CN-100 inhibited the proliferation of granulation in the test by paper disk method, i.e., the compound inhibited wound healing. The antigranulation activity of CN-100 was also nearly equal to that of pranoprofen and weaker than that of indometacin. These results proved that CN-100 should definitely inhibit the reactions of the second and third inflammatory phases of the whole reactions from the exudative phase throughout proliferative phase, suggesting that the compound is a useful antiinflammatory drug.

Animals↗
PubMed1986

Pharmacological investigations of the new antiinflammatory agent 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl]propionic acid. 4th communication: inhibitory effects on rat adjuvant arthritis.

The preventive and therapeutic effects of 2-(10,11-dihydro-10-oxodibenzo [b,f]thiepin-2-yl)propionic acid (CN-100) on local and systemic changes of rats with adjuvant arthritis being used frequently as experimental model of rheumatoid arthritis were investigated in comparison with those of reference drugs, indometacin and pranoprofen. Preventively and therapeutically CN-100 showed potent inhibitory effects on adjuvant primary inflammation and secondary lesion. CN-100 also exerted an evident preventive effect on destruction of foot bone, improved the changes in organ weight, and stimulated weight gain. These effects were dose-dependent, and the effects at 5.0 mg/kg were almost the same as those of indometacin and pranoprofen at 1.25 and 2.5 mg/kg, respectively. The mode of action of CN-100 resembled that of reference compounds. Although CN-100 improved the change in albumin/globulin ratio, which was a parameter of systemic inflammatory reactions, the effect was more remarkable in therapeutic administration than in preventive one. This suggests that CN-100 is suitable for clinical application.

Animals↗
PubMed1986

Pharmacological investigations of the new antiinflammatory agent 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid. 5th communication: antiplatelet effect of the drug and antiinflammatory effect of its main metabolite.

Since nonsteroidal antiinflammatory drugs (NSAID) usually have an antiplatelet effect, the inhibitory effect of 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl) propionic acid (CN-100), which exerts a potent antiinflammatory effect, was compared with those of reference drugs, indometacin and pranoprofen, in this study. Indometacin at 10(-5) mol/l inhibited completely (100%) rat and rabbit platelet aggregation induced by collagen and arachidonic acid. Pranoprofen at 10(-5) mol/l also entirely inhibited rat platelet aggregation induced by the two aggregators, but an about 10 times higher concentration was required to produce 100% inhibition of rabbit platelet aggregation. CN-100 at 10(-5) mol/l exerted 100% inhibition of rat platelet aggregation induced by collagen, whereas more than 10(-4) mol/l was needed to exhibit 100% inhibition of aggregation induced by arachidonic acid and ADP. The inhibitory activity of CN-100 on aggregation of rat platelets ex vivo was weaker than those of reference NSAID, i.e., the antiplatelet effect of CN-100 was found to be weak. The main metabolite of CN-100 also had a weak antiplatelet effect, and its antiinflammatory effect on carrageenin edema and UV erythema was apparently weaker than that of CN-100. The inhibitory effect of the metabolite on endotoxin diarrhea was weak. The ulcerogenic effect of the metabolite on gastric mucosa was similar to that of CN-100, but the effect rarely seemed to be a clinical problem because it was basically weak.

Animals↗
PubMed1979

Pharmacological study of [2-chloro-11-(2-dimethylaminoethoxy) dibenzo[b,f]thiepine] (zotepine), a new neuroleptic drug.

2-Chloro-11-(2-dimethyl-aminoethoxy)dibenzo [b,f]thiepine (zotepine) is a new neuroleptic drug with a chemical structure different from known neuroleptics. The psychopharmacological effects of zotepine in mice, rats and dogs were studied and compared with those of commercially available neuroleptics. Haloperidol and perphenazine were the most active and thioridazine was the least active in hibiting apomorphine-induced gnawing and circling movement, methamphetamine-induced gnawing and circling movement, conditioned avoidance response, motor activity, dopamine-induced pancreatic secretion and apomorphine-induced vomiting. These drugs also had the same order of potency in inducing catalepsy and increasing dopamine turnover and prolactin release. Chlorpromazine, propericiazine and thiothixene were intermediate in potency. Zotepine equalled chlorpromazine in most activities, however, it was clearly less active than chlorpromazine in potentiation of barbiturate sleep and cardiovascular effect.

Animals↗
PubMed1979

Pharmacokinetics and metabolism of 2-chloro-11-(2-dimethylaminoethoxy)-dibenzo[b,f]thiepine (zotepine) in rat, mouse, dog and man.

The absorption, distribution, metabolism and excretion of 2-chloro-11-(2-dimethylaminoethoxy)dibenzo [b,f]thiepine (zotepine), a new neuroleptic agent, were investigated in rat, mouse, dog and man. Zotepine was absorbed rapidly and almost completely from the gastrointestinal tract in all species after oral dosing. The serum level of the unchanged drug in man was comparatively higher than in animals. The serum half-lives of zotepine after i.v. dosing were approximately 3.2 h in rats, 1.5 h in mice and 3.0 h in dogs. The drug and radioactive metabolites were rapidly distributed to the tissues of rats and mice, and the brain levels of the unchanged drug were about 20 to 30 times higher than the serum levels. Only small amounts of the unchanged drug were excreted in the urine in all species; faecal excretion through the bile was the main route of elimination of the drug and metabolites. Extensive biliary excretion and enterohepatic circulation of the radioactive compound were observed in rats. Zotepine was well metabolized in the body. Besides N-demethylation and oxygenation of the N and/or S atoms, hydroxylation of the aromatic ring and consecutive conjugation were important metabolic pathways of zotepine.

Adult↗
PubMed1979

Toxicological and teratological studies of 2-chloro-11-(2-dimethylaminoethoxy)-dibenzo[b,f]thiepine (zotepine), a new neuroleptic drug.

Toxicological and teratological studies of 2-chloro-11-(2-dimethylaminoethoxy)dibenzo[b,f]thiepine (zotepine) were performed in mice, rats, rabbits and dogs. There was no essential difference among mice, rats, rabbits and dogs in the acute toxicity of i.v. given zotepine. The rather small variation between intravenous and oral acute toxicity suggests the good absorption of zotepine from the gastrointestinal tract. In the subacute and chronic toxicity studies in rats, significant changes attributed to the drug were impairment of growth, alveolar proliferation in the mammary gland, decrease in uterine weight and increased number of diestrous rats. These changes were dose-dependent in the animals given 16 mg/kg or higher. Incidence of tumor in the treated groups in the 12-month study was almost the same as that in the control. In the subacute and chronic toxicity studies in dogs, abnormal quietness and abnormal gait occurred. Enlarged breasts and galactorrhea also occurred in females given 16 and 64 mg/kg in the 6-month study. Apart from these changes, one dog given 64 mg/kg had reversible hepatic dysfunction. In the teratological studies, zotepine had no adverse effects on pregnant animals and their fetuses in rats and rabbits, or reproductive performance of the F1 rats.

Animals↗