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At least 19 recordsLinked to original sources
PubMed1992

Synthesis of a dibenz[b,e]oxepin-bovine serum albumin conjugate for radioimmunoassay of KW-4679 ((Z)-11-[3-(dimethylamino)propylidene]-6,11- dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride).

(Z)-11-[3-(Dimethylamino)propylidene]-2-(methoxycarbonyl)methyl-6, 11- dihydrodibenz[b,e]oxepin-9-acrylic acid (5) was prepared for application to the radioimmunoassay of KW-4679 (1, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e ] oxepin-2-acetic acid hydrochloride). The acrylic acid moiety in the 9-position of 5 was employed for coupling with an amino group of bovine serum albumin (BSA) to provide 17. Subsequently, the conjugate 17 was treated with aqueous NaOH to hydrolyze the terminal methoxycarbonyl group in the 2-position of the BSA conjugated 5. Antiserum raised against the antigenic BSA-conjugate 4 finally obtained was specific for 1.

Antigens↗
PubMed1996

Structure-activity relationships in the mutagenicity and cytotoxicity of putative metabolites and related analogs of benzene derived from the valence tautomers benzene oxide and oxepin.

A series of putative metabolites and related analogs of benzene, derived from the valence tautomers benzene oxide and oxepin, was tested for mutagenicity (reversions to histidine prototrophy and forward mutations to resistance to 8-azaguanine) and for cytotoxicity by the Ames Salmonella mutagenicity test. Benzene was not mutagenic in either assay. The benzene oxide-oxepin system and benzene dihydrodiol induced point mutations but not frameshifts. 4,5-sym-Oxepin oxide, which is a putative metabolite of the oxepin valence tautomer; 3,6-diazo-cyclohexane-1,6-3,4-dioxide, a synthetic precursor of sym-oxepin oxide; and transoid-4,11-dioxatricyclo(5.1 0)undeca-1,6-diene, a stable bridge-head diene analog of sym-oxepin oxide, were toxic but not mutagenic in both assays. 4H-Pyran-4-carboxaldehyde, a stable acid catalyzed rearrangement product of sym-oxepin oxide, was not mutagenic and much less cytotoxic than sym-oxepin oxide. Stable analogs of the valence tautomer benzene oxide, namely syn-indan-3a,7a-oxide and syn-2-hydroxyindan-3a,7a-oxide, were mutagenic and induced point mutations. All compounds were cytotoxic to Salmonella. Firstly, the apparent decay times of these chemicals, especially that of sym-oxepin oxide, were surprisingly longer than expected, as judged by quantitative plate diffusion assays. Secondly, it is concluded that if benzene oxide is further metabolized in its oxepin tautomeric form, toxic but not mutagenic products are formed. Thirdly, the relatively weak mutagenicity of benzene oxide may be mainly due to its instability and corresponding low probability to reach intracellular polynucleotide targets, whereas stable analogs of benzene oxide are relatively more potent mutagens.

Benzene Derivatives↗
PubMed1985

Hashish: synthesis and central nervous system activity of some novel analogues of cannabidiol and oxepin derivatives of delta 9-tetrahydrocannabinol.

Several C-10 substituted cannabidiol (CBD) derivatives and novel oxepin derivatives of delta 9-tetrahydrocannabinol (delta 9-THC) were synthesized and evaluated for biological activity in mice and dogs. Treatment of 10-bromocannabidiol diacetate (3) with various amines in Me2SO gave the corresponding 10-aminocannabidiol derivatives 4-6. Similarly, treatment of 3 with NaN3 gave the azido compound 7, which with LiA1H4 afforded the 10-aminocannabidiol 9. However, reduction of 7 with CrCl2 formed the amide 8, which on further reduction with LiA1H4 gave the N-ethyl analogue 10. Coupling of 9 with 11 in the presence of dicyclohexylcarbodiimide formed 12, which was then deprotected with HCl to give the analogue 13. The oxepin analogue 14a was synthesized from 3 by treatment with Na2CO3 in CH3OH/H2O at room temperature. The dimethylheptyl analogue 14b was similarly prepared. Incorporation of N-ethyl (10), N-methyl-N-propargyl (6), and morpholino (4) groups in CBD at position 10 resulted in analogues that were more potent than CBD in producing hypoactivity in mice. These analogues had relatively little effect on rectal temperature. Selected substitutions at C-10 also resulted in analogues that were partially effective in blocking delta 9-THC antinociceptive activity. This blockade was observed particularly in compound 10, which also showed unusually toxic properties. Incorporation of a seven-membered oxepin in the delta 9-THC structure eliminated cannabinoid activity although substitution of the pentyl side chain with a 1,2-dimethylheptyl in the oxepin 14b resulted in CNS depression in mice.

Analgesics↗
PubMed2005

Sequential cyclization-elimination route to carbohydrate-based oxepines.

A five-step preparation of carbohydrate-based oxepines from hept-1-enitols is presented. The hept-1-enitols were subjected to silyl protection and hydroboration/oxidation to give the protected heptan-1-itols. Swern oxidation of the homologated alcohols followed by sequential acetal formation/cyclization provided methyl 2-deoxyseptanosides that underwent elimination reactions to give the carbohydrate-based oxepines. The new sequence is an alternative to the ring-closing metathesis for the synthesis of carbohydrate-based oxepines from protected pyranose sugars. The product oxepines can serve as glycosyl donors in the synthesis of novel septanose carbohydrates. In addition, C-methylenealdehydo arabinofuranoside 16 was formed from 2-deoxyseptanoside 10 as the only product during protic acid mediated elimination reactions. This novel ring contraction complements other reported preparations of C-methylenaldehydo furanosides and underscores the acid-mediated reactivity introduced by competing eliminations between the C-1/C-2 and C-2/C-3 bonds.

Carbohydrates↗
PubMed1997

Dimethyldioxirane converts benzene oxide/oxepin into (Z,Z)-muconaldehyde and sym-oxepin oxide: modeling the metabolism of benzene and its photooxidative degradation.

Oxidation of 7-oxabicyclo[4.1.0]hepta-2,4-diene (benzene oxide)/oxepin with dimethyldioxirane (DMDO) gave mainly (Z,Z)-muconaldehyde, with complete diastereoselectivity. Similarly, 2-methyl-7-oxabicyclo[4.1.0]hepta-2,4-diene (toluene 1,2-epoxide)/2-methyloxepin gave (Z,Z)-1,6-dioxohepta-2,4-diene, while 2,6-dimethyl-7-oxabicyclo[4.1.0]hepta-2,4-diene (1,2-dimethylbenzene 1,2-epoxide)/2,7-dimethyloxepin gave (Z,Z)-2,7-dioxo-3,5-octadiene. By monitoring the DMDO oxidation of benzene oxide/oxepin by 1H NMR spectroscopy, a significant byproduct was identified as 4,8-dioxabicyclo[5.1.0]octa-2,5-diene (sym-oxepin oxide). This observation supports the hypothesis that the route to (Z,Z)-muconaldehyde proceeds from oxepin via 6,8-dioxabicyclo[5.1.0]octa-2,4-diene (oxepin 2,3-oxide), with a minor pathway leading to sym-oxepin oxide. The DMDO oxidations described provide model systems for the cytochrome P450-dependent metabolism of benzene and for the atmospheric photooxidation of benzenoid hydrocarbons.

Aldehydes↗
PubMed2003

Structure-based drug design: synthesis, crystal structure, biological evaluation and docking studies of mono- and bis-benzo[b]oxepines as non-steroidal estrogens.

Mono- and bis-benzo[b]oxepine derivatives have been rationally synthesized to meet the molecular requirement for interaction with estrogen receptor. Bis-benzo[b]oxepines (7 and 9) and mono-benzo[b]oxepine (10) acquire geometry with phenolic groups disposed in a fashion to stimulate estrogen receptor. Structure-based investigation, in vivo activity and docking studies have been described and correlated to demonstrate a practical approach for suitable ligand design.

Drug Design↗
PubMed1994

Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Synthesis and hypocholesterolemic activity of dibenz[b,e]oxepin-11-carboxanilides.

A series of N-phenyl-6,11-dihydrodibenz[b,e]oxepin-11-carboxamides and related derivatives were prepared on the basis of structures of the reported inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). These compounds were tested for their ability to inhibit ACAT (liver microsomes from cholesterol-fed rabbits) in vitro and to decrease serum total cholesterol in cholesterol-fed golden hamsters in vivo. The structure-activity relationships in vitro were as follows. Substitution at positions 2 and 6 in the anilide resulted in potent inhibitory activity, and the potency increased with increasing size of the substituents, with maximum potency being obtained with a 2,6-diisopropyl substitution. The position of the substituent on the dibenz[b,e]oxepin ring system influenced the activity, and substitution at position 2 was critical for potent activity. The electronic effect of the substituent at position 2 does not influence activity, but bulkiness seems to be a significant factor. The lipophilicity of the compounds also plays an important role in determining ACAT inhibitory activity. Among the compounds tested, 2-bromo-N-(2,6-diisopropylphenyl)-6,11-dihydrodibenz-[b,e]++ +oxepin-11- carboxamide (33, KF17828) showed significant in vitro activity (rabbit liver microsomes IC50 = 23 nM) and the most potent in vivo activity (complete reduction in elevated serum total cholesterol levels at a dose of 10 mg/kg in hamsters).

Animals↗
PubMed1992

Synthesis and antiallergic activity of 11-(aminoalkylidene)-6,11-dihydrodibenz[b,e]oxepin derivatives.

A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid derivatives was synthesized and demonstrated to be orally active antiallergic agents. These compounds are structurally related to 1 (KW-4994), which we had reported previously to be a new antiallergic agent. Most compounds synthesized exhibited potent inhibitory effects on 48-h homologous passive cutaneous anaphylaxis (PCA) in rats and on IgG1-mediated bronchoconstriction in guinea pigs. Additionally, compounds possessing a terminal carboxyl group at the 2-position of the dibenz[b,e]oxepin ring system exhibited inhibitory effects on specific [3H]pyrilamine binding to guinea pig cerebellum histamine H1 receptors, whereas these demonstrated negligible effects on specific [3H]QNB binding to rat striatum muscarinic acetylcholine M1 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced antiallergic activities: (1) a 3-(dimethylamino)propylidene group as the side chain at the 11-position, (2) a terminal carboxyl moiety at the 2-position, and (3) a dibenzoxepin ring system. Among the compounds synthesized, (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride (16) was selected for further evaluation. It had an ED50 value of 0.049 mg/kg po in the PCA test in rats and an ID50 value of 0.030 mg/kg po in inhibiting anaphylactic bronchoconstriction in guinea pigs. Furthermore, it had a Ki value of 16 +/- 0.35 nM for the histamine H1 receptor, while it exhibited negligible CNS side effects up to a dose of 600 mg/kg po. Compound 16 is now under clinical evaluation as KW-4679.

Animals↗
PubMed1977

Dibenz[b,e]oxepinalkanoic acids as nonsteroidal antiinflammatory agents. 1. 6,11-Dihydro-11-oxodibenz]b,e]oxepin-2-acetic acids.

A series of 6,11-dihydrodibenz[b,e]oxepin-2-acetic acids has been evaluated for both antiinflammatory and analgetic activity in the carrageenan paw edema and phenylquinone writhing assays. The requirements for optimal activity in this series appear rather specific: (a) an unsubstituted 6,11-dihydrodibenz[b,e]oxepin nucleus and (b) a carbonyl group in the 11 position. One derivative, 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid (11), has been selected for further study.

Animals↗
PubMed1982

Affinity of 10-(4-methylpiperazino)dibenz[b,f]oxepins for clozapine and spiroperidol binding sites in rat brain.

10-(4-Methylpiperazino)dibenz[b,f]oxepins were prepared and evaluated as potential antipsychotic agents using specific clozapine [8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine] binding sites in rat forebrain that are noncholinergic and nondopaminergic in nature and from which [3H]clozapine is displaced by known antipsychotic agents. [3H]Clozapine binding in the presence of atropine represents nonmuscarinic binding, while binding in the absence of atropine represents muscarinic (cholinergic) plus nonmuscarinic binding. The relative affinity for dopamine binding sites was determined by displacement of [3H]spiroperidol from binding sites in rat caudate nuclei. Thus, clozapine, its 2-chloro isomer, its dechloro analogue, and their 5H-dibenzo[a,d]cycloheptene and dibenz[b,f]oxepine analogues have about the same relative affinity for the nonmuscarinic clozapine binding sites. At the spiroperidol (dopaminergic) sites, both the nature of the tricyclic system and the presence of a chlorine atom on the tricyclic system have a substantial effect on the binding affinity. Within each series, shift or a chlorine atom from the position distal to the piperazino group to the proximal position increases the binding affinity by a factor of about nine, but removal of the chlorine atom substantially decreases the binding affinity. Nevertheless, 10-(4-methylpiperazino)dibenz[b,f]oxepin has a threefold greater affinity for the dopaminergic binding sites than does clozapine itself.

Animals↗
PubMed2004

Synthesis, crystal structure, and reactivity of a D-xylose based oxepine.

The synthesis and X-ray crystal structure of a D-xylose-based oxepine are reported. The oxepine was prepared from 2,3,4-tri-O-benzyl-D-xylose by the three-step sequence (Wittig olefination, vinyl ether formation, and ring closing metathesis) we recently reported. Epoxidation of this cyclic enol ether using dimethyldioxirane (DMDO) gave 1,2-anhydro-beta-D-idoseptanose, which was trapped by a number of nucleophiles to give alpha-idoseptanosides. The stereochemistry of epoxidation was assigned based on product analysis. Spectroscopic data of methyl 2,3,4,5-tetra-O-acetyl-alpha-D-idoseptanoside, derived from the methanolysis product 11, was compared to data of its enantiomer, the known methyl 2,3,4,5-tetra-O-acetyl-alpha-L-idoseptanoside.

Carbohydrate Conformation↗
PubMed2005

Synthesis of 2-N,N-dimethylaminomethyl-2,3,3a,12b-tetrahydrodibenzo[b,f]furo[2,3-d]oxepine derivatives as potential anxiolytic agents. Part 2: substitutions by methyl groups on the tetrahydrofuran ring.

New synthesis approaches that have led to a series of novel tetrahydrodibenzo[b,f]furo[2,3-d]oxepine derivatives are described. A systematic synthetic approach for the introduction of small carbon substituents (methyl groups) around the tetrahydrofuran moiety of tetrahydrodibenzo[b,f]furo[2,3-d]oxepine derivatives is reported. Preliminary pharmacological data of the newly synthesised compounds are also communicated.

Anti-Anxiety Agents↗
PubMed1995

A novel metabolite, an oxepin formed from cannabidiol with guinea-pig hepatic microsomes.

The metabolic formation of an oxepin derivative, 3-pentyl-6,7,7a,8,9,11a-hexahydro-1,7-dihydroxy-7,10- dimethyldibenzo-[b,d]-oxepin, from cannabidiol was studied in-vitro using guinea-pig hepatic microsomes. The hepatic microsomes catalysed the formation of the metabolite from cannabidiol and 8S, 9-epoxycannabidiol in the presence of an NADPH-generating system and 3, 3, 3-trichloropropene-1, 2-oxide. 8S, 9-Epoxycannabidiol was thought to be an intermediate in the formation of the metabolite, which was identified by gas chromatography-mass spectrometry. The metabolite synthesized from 8S, 9-epoxycannabidiol diacetate exhibited catalepsy, hypothermia and pentobarbitone-induced sleep prolongation in mice, although the pharmacological effect was less potent than that of delta 9-tetrahydrocannabinol.

Animals↗
PubMed2003

Separation of (Z)- and (E)-isomers of thioxanthene and dibenz[b,e]oxepin derivatives with calixarenes and resorcinarenes as additives in nonaqueous capillary electrophoresis.

Five acidic calix[4]arenes with carboxylic or sulfonic groups at either the upper or lower rim of the cavity and one resorc[4]arene were investigated to separate three thioxanthenes (flupentixol, clopenthixol, chlorprothixene) and a dibenz[b,e]oxepin derivative (doxepin) with cis-/trans-isomerism by nonaqueous capillary electrophoresis (NACE). Partial filling of the capillary with the UV-absorbing selectors led to a low detection limit and an advantageous signal-to-noise ratio (S/N). A sufficient electrophoretic mobility of the calixarenes towards the anode was necessary to outweigh the oppositely directed electroosmotic flow (EOF). This depended from the functional groups, the dissociation and the hydrodynamic radius of the cyclophanes. In contrast, the resorcinarene was useable only by addition of sodium dodecyl sulfate (SDS) because only the complex of the two selectors had an anodic apparent electrophoretic mobility. p-Sulfonyl-calix[4]arene (ss-a1) was the most capable selector for all E/Z-isomers with maximal alpha-values ranging from 1.056 for doxepin to 1.224 for chlorprothixene. This was due to the sufficient migration in reversed direction to the EOF even at low pH* values of 3.0. Otherwise, electrostatic as well as hydrophobic interactions with the positively charged isomers seem to contribute to a superior recognition. Increasing the concentration up to 15 mM ss-a1 and using acidic media (pH* 5.0) led to high separation efficiency. Changing the organic solvent provides a powerful tool to improve selectivity with N,N-dimethylformamide-methanol (DMF-MeOH)-mixtures for thioxanthenes. Further electrophoretic parameters were optimized, such as the concentration of the electrolytes, the addition of SDS, the kind of electrolytes and the voltage. Distinct differences in selectivities were found between the derivatives with thioxanthene and dibenzo[b,e]oxepin ring system, respectively. Further, the different basic side chain was responsible for the different selectivity at higher pH* values. In contrast, the substitution at position 2 of the thioxanthenes played a secondary role. Based on the studies of single parameters a method for a simultaneous separation of the four pairs of isomers within 13 min was developed.

Calixarenes↗
PubMed1995

Binding of 5H-dibenzo[a,d]cycloheptene and dibenz[b,f]oxepin analogues of clozapine to dopamine and serotonin receptors.

Series of 5,11-dicarbo- and 11-carbo-5-oxy-10-(1-alkyl-1,2,3,6-tetrahydro-4 pyridinyl) analogues and a 11-carbo-5-oxy-10-(1-methyl-4-piperidinyl) analogue of the atypical antipsychotic agent clozapine were prepared and tested for binding to the dopamine D-2L and D-4 and serotonin S-2A and S-2C receptors. Some of these analogues were found to have dopamine D-2L and D-4 and serotonin S-2A and S-2C receptor binding activities as high as or higher than those of clozapine, indicating that neither the diazepine structure nor the piperazine ring present in clozapine is essential for high antidopamine activity and or for high dopamine D-4 selectivity (Ki for the dopamine D-2L receptor/Ki for the dopamine D-4 receptor). Increasing in the effective size of the alkyl substituent at the tertiary amine nitrogen atom in the 1,2,3,6-tetrahydro-4-pyridinyl moiety in the 5H-dibenzo[a,d]cycloheptene series reduces the affinity for the dopamine D-4 receptor, but in the dibenz[b,f]oxepin series, no significant change in binding affinity to the dopamine D-4 receptor was observed. Equal or slightly higher affinity for the serotonin S-2A and S-2C receptors was observed for the 10-(1-ethyl-1,2,3,6-tetrahydro-4- pyridinyl) analogues in both series, but for the 10-[1,2,3,6-tetrahydro-1-(2-propenyl)-4- pyridinyl] analogues, any favourable steric factor is overshadowed by an unfavorable electronic effect as a result of change in the basicity of the tertiary amino group in the pyridinyl moiety. Replacement of three of the four nitrogen atoms in clozapine with three carbon or two carbon atoms and an oxygen atom and removal of the chlorine atoms gives 10-(1,2,3,6-tetrahydro-1- methyl-4-pyridinyl)dibenzo[a,d]cycloheptene and 10-(1-methyl-4-piperidinyl)dibenz[b,f]oxepin, each having twice the binding activity to the dopamine D-4 receptor as does clozapine and a dopamine D-4 selectivity equal to that of clozapine.

Binding Sites↗
PubMed1978

Nonsteroidal antiinflammatory agents. 2. Derivatives/analogues of dibenz[b,e]oxepin-3-acetic acid.

6,11-Dhydro-11-oxodibenz[b,e]oxepins and some related compounds have been synthesized and evaluated for antiinflammatory effect according to the carrageenan paw edema method in rats. The structure-activity relationships have been discussed among acetic acid, carboxylic acid, alcohol, and tetrazole derivatives of dibenzoxepins and acetic acid derivatives of thienobenzoxepins and of the corresponding thiepins. The 3-isopropyl alcohol 9 and 11-deoxo-3-propionic acid (49) were more active than indomethacin but not as active as the title compound (i.e., 43). Carboxylic acids, tetrazoles, esters, amides, and ketones were less active than the corresponding acetic acids. Three compounds (31, 33, and 34) were evaluated for ulcerogenicity and lethality but none surpassed 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-acetic acid (41) in therapeutic ratio.

Animals↗
PubMed1991

Synthesis and biological activity of 11-[4-(cinnamyl)-1-piperazinyl]- 6,11-dihydrodibenz[b,e]oxepin derivatives, potential agents for the treatment of cerebrovascular disorders.

A series of 11-[4-(cinnamyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e] oxepins and related compounds were synthesized and evaluated for their protective activities against complete ischemia, normobaric hypoxia, lipidperoxidation and convulsion. Structure-activity relationship studies of this series led to the finding of (E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-yl)-4-(3- phenyl-2-propenyl)piperazine dimaleate (50), AJ-3941 with the most appropriate property for combined pharmacological activities. Compound 50 also shows an inhibitory effect against cerebral edema as well when orally given to rats.

Animals↗