Oxepine Derivatives Research Articles

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.

Novel Synthesis of Azocine, Azepine, Oxocine, and Oxepine Derivatives by Palladium-catalyzed Medium-Ring Formation from Bromoallenes

Novel and efficient synthesis of medium-sized heterocycles such as azepine, oxepine, and benzo[d]azocine derivatives is described. Treatment of bromoallenes having a nucleophilic moiety with sodium alkoxide and a palladium(0) catalyst in the presence of an alcohol leads to regioselective formation of medium-sized rings at the central position of the allenic carbon.

Separation of cis- and trans-isomers of thioxanthene and dibenz[ b, e]oxepin derivatives on calixarene- and resorcinarene-bonded high-performance liquid chromatography stationary phases

The chromatographic behavior of six calix[ n]arene phases ( n=4, 6, 8) and one calix[4]resorcinarene phase is described for the separation of cis- and trans-isomers of three thioxanthene (flupentixol, clopenthixol, chlorprothixene) and one benz[ b, e]oxepin derivative (doxepin). The influences of two different organic modifiers (MeOH, MeCN) for the separation of the isomers on every column are described. Different selectivities of the stationary phases exist as a function of the ring size of the calixarenes and their substitution at the “upper rim” with p- tert.-butyl groups. Furthermore, the influence of free phenol groups on the resorcinarene phase is discussed. Relations between structural elements of the analytes and the retention behavior on the stationary phases are found. The selectivity of the calixarene and resorcinarene stationary phases is compared with a RP-C 18 phase containing the same base silica. Advantages of the resorcinarene as well as of the calixarene columns exist for the separation of cis- and trans-isomers of three compounds dependent from the substitution in position 2 of the thioxanthenes, respectively the kind of the basic side chain of all substances.

Stereoselective preparation of enantiomerically pure annulated carbohydrates using ring-closing metathesis

Ring-closing metathesis has been applied to a series of glucose derivatives to produce cyclopentene derivatives 5a and 5b, cyclohexene derivatives 8 and 9, cycloheptene 12, and cyclooctene 14. Spirocyclic dihydrofurans 19, 26a, and 26b, along with dihydropyran 22, were also produced. A range of fused oxepine derivatives 29a-c and one oxo-cyclononene 31 were also prepared. Cyclopentene 5b was subjected to a sequence of hydrogenation, NBS bromination, and treatment with powdered zinc to furnish the ring-expanded product 35. No such ring expansion occurred when the cyclohexaannulated compound 8 was treated with NBS followed by powdered zinc, leading to aldehyde 39. The spiro dihydrofuran derivative 19 was converted to the aldehyde 42 via the same reaction sequence used to fragment cyclopentene derivative 5b.

Dibenzoxepines as treatments for neurodegenerative diseases

Abstract

Recent advances in the metabolism of cannabinoids

This review describes recent advances in the metabolism of cannabinoids. Cannabidiol was metabolized to cannabielsoin, 6 β-hydroxymethyl- Δ 9-tetrahydrocannabinol and an oxepine derivative through epoxide intermediates by hepatic microsomal enzymes containing cytochrome P450 of animals. Cannabidiol inactivated cytochrome P450 UT-2 (CYP2C11) ‡ in male rats and a member of 3A subfamily in mouse liver. These inactivations may be very important because serious drug-drug interactions will occur in the case that cannabidiol is co-administered with drugs which are metabolized mainly by the enzyme system containing these P450 isozymes. A member of cytochrome P450 belonging to 2C subfamily was the major isozymes responsible for the cannabinoid metabolism in many experimental animals and that of 3A subfamily made some contribution to the metabolism of cannabinoids by human hepatic microsomes. Microsomal aldehyde oxygenase, a particular isozyme of cytochrome P450 catalyzing the oxidation of 11-oxo-tetrahydrocannabinol to tetrahydrocannabinol-11-oic acid, was found for the first time by the authors. Cytochrome P450 MUT-2 (CYP2C29) is the major isozyme responsible for the microsomal aldehyde oxygenase activity in mouse hepatic microsomes.

Novel angiotensin II receptor antagonists. Design, synthesis, and in vitro evaluation of dibenzo[a,d]cycloheptene and dibenzo[b,f]oxepin derivatives. Searching for bioisosteres of biphenylyltetrazole using a three-dimensional search technique.

Three-dimensional substructure searching (3D search), using the program MACCS-3D, was utilized for designing novel angiotensin II receptor antagonists which contain a bioisostere of the biphenylyltetrazole moiety of DuP 753. A 3D query was prepared from an overlay model of substructures of several potent AII antagonists. The search system retrieved 139 compounds from the database MDDR-3D, which consisted of 29,400 medicinal patent compounds. A tricyclic compound was selected from the retrieved compounds and then evolved by considering steric fitness to the overlay model and synthetic feasibility. Finally, various novel AII antagonists having dibenzo[a,d]cycloheptene or dibenzo[b,f]oxepin were designed and synthesized. The receptor binding activity (Ki) for several members of this series was in the 10(-10) M range, demonstrating the ability of 3D search technique to explore new lead structures.

Dibenzoxepin derivatives: thromboxane A2 synthase inhibition and thromboxane A2 receptor antagonism combined in one molecule.

A new series of 6,11-dihydrodibenz[b,e]oxepin derivatives exerting both thromboxane synthase inhibitory (TXS-I) and thromboxane receptor antagonist (TXRA) activities is described. (-)-11-[(3-Pyridylmethyl)thio]-6,11-dihydrodibenz[b,e]oxepin -2- carboxylic acid [(-)-3] and (E)-11-[2-(3-pyridyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin+ ++-2- carboxylic acid methanesulfonate (11E) exhibited potent inhibitory effects on bovine platelet thromboxane synthase with IC50 values of 4.0 and 14 nM, respectively, and these derivatives also antagonized guinea pig platelet TXA2/PGH2 receptors with Ki values of 85 and 180 nM, respectively. Compound 11E exhibited the dual inhibitory activity in ex vivo experiments and demonstrated a significant protective effect in a rat acute renal failure model.

Valence-bond isomer chemistry. Part 13 . Photochemical oxidation of hexafluorobenzene: formation of hexafluoro-3-oxatricyclo[3.2.0.0 2,4]hept-6-ene and its reactions

Vapour-phase ultraviolet irradiation of hexafluorobenzene in the presence of oxygen slowly yields hexafluoro-3-oxatricyclo[3.2.0.0 2,4]hept-6-ene ( 2) (10%). The CFCF bond in 2 adds (yields of adducts given) the dienes; cyclopentadiene (74%), furan (61%) and 2,5-diphenylisobenzofuran (59%); benzonitrile oxide (58%); chlorine (59%) and bromine (71%) photochemically. Heptene 2 isomerises thermally to hexafluorocyclohexa-2,4-dienone ( 6) (60%) at 50 °C, and reacts with diethyl ether at room temperature yielding ethylfluoride (89%) and 2-ethoxypentafluorocyclohexa-2,5-dienone (21%). The benzonitrile oxide adduct, upon flow pyrolysis at 440 °C, yields an isomeric oxepin derivative and the cyclohexadienone 6 with longer contact times. The chlorine adduct similarly yields a dichloro-oxepin derivative; attempts to dechlorinate this to hexafluoro-oxepin were unsuccessful. Benzonitrile oxide adds tone or both of the CC bonds of hexafluorobicyclo[2.2.0]hexa-2,5-diene; the 1:1 adduct isomerises thermally to the benzonitrile oxide-hexafluorobenzene adduct.

Dibenz[b,e]oxepin derivatives: novel antiallergic agents possessing thromboxane A2 and histamine H1 dual antagonizing activity. 1.

Dibenz[b,e]oxepin derivatives: novel antiallergic agents possessing thromboxane A2 and histamine H1 dual antagonizing activity. 1.

ChemInform Abstract: A New Series of Antiallergic Agents. Part 1. Synthesis and Activity of 11‐(2‐Aminoethyl)thio‐6,11‐dihydrodibenz(b,e)oxepin Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

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.

Electrophile-induced intramolecular cyclization of ortho-(aryloxy)phenylalkynes to dibenz[b,f] oxepines

Reaction of o-(aryloxy)phenylalkynes with electrophiles such as perchloric acid, tetrafluoroboric acid, benzenesulfenyl chloride, and iodine monochloride yielded dibenz[b,f]oxepine derivatives. Cyclization to the dibenz[b,f]oxepines competed with 1,2-addition of the electrophiles. The effect of substituents on the alkyne is also discussed.

A New Series of Antiallergic Agents. I. Synthesis and Activity of 11-(2-Aminoethyl)thio-6,11-dihydrodibenz(b, e)oxepin Derivatives.

A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin derivatives was synthesized and evaluated for antiallergic activity. Convenient methods for the preparation of sulfides from alcohols were developed. Structure-activity relationships are described. Compound 7, 11-[2-(dimethylamin)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylic acid hydrochloride, was the most potent in the rat passive cutaneous anaphylaxis test (ED50 = 0.92 mg/kg p.o.). It had a potent inhibitory effect on anaphylactic bronchoconstriction in guinea pigs (ED50 = 0.029 mg/kg p.o.) and H1 receptor antagonistic effect (Ki = 14 nM) with few central nervous system side effects. Additionally, an antagonistic effect against prostaglandin D2-induced contraction of isolated guinea pig trachea (pA2 = 5.73) was an attractive mechanism of action of the new antiallergic agent. Compound 7 was selected for further evaluation as KW-4994.

Cycloadditionen von 1,3,4‐Oxadiazin‐6‐onen (4,5‐Diaza‐α‐pyronen), 9. 6‐Oxo‐5‐phenyl‐1,3,4‐oxadiazin‐2‐carbonsäure‐methylester — Synthese und Reaktionen mit Norbornen, Norbornadien, Cyclopropenen, Cyclobuten und Benzvalen

Cycloadditions of 1,3,4‐Oxadiazin‐6‐ones (4,5‐Diaza‐a‐pyrones), 9. — Methyl 6‐0xo‐5‐phenyl‐1,3,4‐oxadiazin‐2‐carboxylate — Synthesis and Reactions with Norbornene, Norbornadiene. Cyclopropenes, Cyclobutene. and BenzvaleneMethyl 6‐oxo‐5‐phenyl‐1,3,4‐oxadiazin‐2‐carboxylate (7) was prepared by treatment of hydrazone 6 with dicyclohexylcarbodiimide. The reactions of 7 with norbornene and norbornadiene afforded the Diels‐Alder adducts 8 and 9, respectively, which decomposed in solution at 20°C to give mainly the γ‐oxoketenes 10 and 12 and small amounts of the β‐lactones 11 and 13, respectively. The stable γ‐oxoketenes 10, 12, and the bis(γ‐oxoketene) 14 were obtained directly from solutions of 7 and the respective olefin. Cyclopropene, 1‐methylcyclopropene, and cyclobutene were converted by 7 mainly into the oxepin derivatives 15, 17, 18 and the oxocin derivative 19, respectively. Benzvalene and 7 provided the tetracyclo[3.3.0.02,8.04,6]octanone 21. In these reactions, small quantities of β‐lactones were formed, too, which together with the β‐lactones 11 and 13 give evidence for the dihydropyryliumolates 24 as intermediates in the thermal denitrogenation of the Diels‐Alder adducts of 7, e.g. 8 and 9.

A diels-alder adduct and other constituents from Cineraria species

The investigation of five Cineraria species afforded C11-acetylenes and oxepin derivatives typical for Cineraria species. Furthermore, a dimeric diendiynene and a glucoside of 3β-hydroxymyrtenol were isolated. The structures were elucidated by high field NMR techniques.

Oxepine derivatives and anthraquinones from Asphodeline tenuior and A. Taurica

From the chloroform extracts of Asphodeline taurica and A. tenuior anthraquinones chrysophanol, asphodeline and microcarpin as well as β-sitosterol, sitosteryl 3β-glucoside were isolated. In addition, A. taurica yielded an eudesmanolide 1β-acetoxy-8β-hydroxy-eudesman-4(15),7(11)-dien-8α,12-olide, while aleoemodin and two new oxepine derivatives, tenual and tenucarb, were obtained from A. tenuior.

Synthesis of (±)-senoxepin - the first naturally occurring anti-hückel oxepin derivative

The first total synthesis of (±)-senoxepin3 is described.3 is prepared via an intramolecular [4+2] cycloaddition from a substituted decadienyne7. The resulting hexalin8 was converted to a lactone, which on epoxidation, NBS bromination and elimination with NaI afforded senoxepin.

ChemInform Abstract: Asteroxepin, a New Sulfur‐Containing Oxepine Derivative from Aspergillus terreus.

ChemInformVolume 18, Issue 13 Natural Products ChemInform Abstract: Asteroxepin, a New Sulfur-Containing Oxepine Derivative from Aspergillus terreus. G. W. KIRBY, G. W. KIRBY Dep. Chem., Univ. Glasgow, Glasgow G12 8QQ, UKSearch for more papers by this authorD. J. ROBINS, D. J. ROBINS Dep. Chem., Univ. Glasgow, Glasgow G12 8QQ, UKSearch for more papers by this authorW. M. STARK, W. M. STARK Dep. Chem., Univ. Glasgow, Glasgow G12 8QQ, UKSearch for more papers by this author G. W. KIRBY, G. W. KIRBY Dep. Chem., Univ. Glasgow, Glasgow G12 8QQ, UKSearch for more papers by this authorD. J. ROBINS, D. J. ROBINS Dep. Chem., Univ. Glasgow, Glasgow G12 8QQ, UKSearch for more papers by this authorW. M. STARK, W. M. STARK Dep. Chem., Univ. Glasgow, Glasgow G12 8QQ, UKSearch for more papers by this author First published: March 31, 1987 https://doi.org/10.1002/chin.198713358Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume18, Issue13March 31, 1987 RelatedInformation

Oxepine derivatives from the roots of Smyrnium rotundifolium

Oxepine derivatives from the roots of Smyrnium rotundifolium