A new series of antiallergic agents. II. Synthesis and activity of new 6,11-dihydrodibenz[b,e]oxepin-carboxylic acid derivatives.

New methods for the preparation of multi-functionalized-6,11-dihydrodibenz[b,e]oxepins were developed. The structural requirements of KW-4994 (1), a promising orally active antiallergic agent, were defined. A carboxyl group at C-2 was critical for enhanced antiallergic activity of 1. The introduction of bromine atom at C-9 of 1 could elongate the duration of the action of the parent. Antiplatelet activity, a new pharmacological property of this series of compounds, was observed in one of the derivatives of 1.     

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.     

Dibenzo[b,e][1,4]diazepin-1-Ones,Synthesis and Derivatization

Several linearly fused tricyclic 6,7,6-systems were prepared. Reaction of 1,2-diamino-4-nitrobenzene with 5,5-dimethylcyclohexan-1,3-dione gave 3-(2-amino-5-nitroaniIino)-5,5-dimethylcyclohex-2-en-1-one (8) . Reaction of 8 and its analogue 6 with various aldehydes gave 2,3,4₎5,10,11-hexahydro-3,3-dimethyl-11-substituted-1H-dibenzo[b,e][1,4]diazepin-1-ones 9 and 10 . Acetylation of 9 and 10 gave the corresponding N-acetyl derivatives. Spectral data of the products are discussed.     

Neurotrope und psychotrope Substanzen, 6. Mitt.: Synthese neuer Aminoderivate von 6,11-Dihydrodibenzo[b,e]thiepin

Zusammenfassung Ausgehend vom 6,11-Dihydrodibenzo[b,e]thiepin-11-on (II) wurde über den Alkohol III das Chlorid V gewonnen, das durch übliche Umsetzungen die Amine VI–VIII, das Phthalimidoderivat IX, das primäre Amin X und das Nitril XI lieferte. Bei der Reaktion mit 3-Dimethylaminopropylmagnesiumchlorid ergab es das antireserpin-wirksame 11-(3-Dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]thiepin (XII), das zum ebenfalls antireserpin-aktiven sekundären Amin XIV partiell demethyliert wurde.

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The preparation of 11-chloro-6,11-dihydrodibenzo[b,e]thiepine (V) from the ketone II via III is described. Usual transformations gave amines VI–VIII, the phthalimido derivative IX, the primary amine X, and the nitrile XI. Treatment of V with 3-dimethylaminopropylmagnesium chloride resulted in 11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]thiepine (XII), having antireserpine activity. Partial demethylation of XII gave the secondary amine XIV, which had the same type of pharmacodynamic activity.

     

Potential antidepressants. Synthesis of 6,11-dihydrodibenzo[b,e]thiepin-11-yl 4-(dimethylamino-methyl)phenyl ketone and of some related compounds

Reactions of dibenzo[b,e]thiepin-11(6H)-one (4) with 2-, 3- and 4-(dimethylaminomethyl)phenylmagnesium bromide afforded the tertiary alcohols 5a,b,c. The aldehydes 7 and 8 gave similarly the secondary alcohols 9a,b,c and 10c . Numerous attempts to prepare the corresponding ketones, especially by oxidation of 9a,b,c and 10c were unsuccessful. Only the oxidation of 9c with tetrabutylammonium chromate in chloroform afforded the desired ketone 16 . Its formation was accompanied by an important side reaction consisting in a cleavage of the “retro-ene-reaction” type leading to compound 11 and the aldehyde 13c which reacted with the chloroform present to give the alcohol 17 . Compounds 5a,b,c, 9a,b,c and 16 were tested as potential antidepressants but with the exception of some effects in the test of potentiation of yohimbine toxicity in mice, they proved inactive in this line.     

Structural specificity of electrophilic substitution of reaction of 2-phenylbenzo[b]cyclopenta[e]pyran

2-Phenyl- and 1,2-diphenylbenzo[b]cyclopenta[e]pyrans were subjected to formylation, nitration, and phenylsufonylation. It was shown by PMR spectroscopy that 2-phenylbenzo[b]cyclopenta[e]pyran undergoes substitution exclusively in the 1 position. The effect of the spatial orientation and the degree of electron-acceptor character of the introduced substituents on the chemical shift of the 9-H proton was studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 902–905, July, 1977.     

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.     

Synthesis and properties of some tetracyclic derivatives of 9H-carbazole, 10,11-dihydro-5H-dibenz[b,f]azepine,and 5,11-dihydrodibenz[b,e] [1,4]oxazepine

The behavior of 5,6-dihydro-4H-pyrido[3,2,1-jk]carbazol-4-one (10) , 1,2,7,8-tetrahydro-3H-quino[1,8-ab][1]benzazepin-3-one (11) , 1,2-dihydro-9H-[1]benzazepino[1,9-ab] [4,1]benzoxazepin-4 (3H)one (13) , and 1,2-dihydro-8H-[1]benzazepino[1,9-cd] [1,5]benzoxazepin-4(3H)one (14) towards the Schmidt reaction has been determined in polyphosphoric acid and in benzeneor chloroform-sulfuric acid. Evidence for the structure of the new heterocyclic systems obtained from these four compounds is presented.     

Synthesis and acylation of 2-nitro-11H-dibenzo[b,e][1,4]dioxepin

A one-pot synthesis of the 11H-dibenzo[b,e]1,4]dioxepin ring system from catechol and an o-chlorobenzyl chloride is described. Friedel-Crafts acylation occurs at the 7-position as shown by X-ray analysis.     

Novel polycyclic heterocycles. VIII. 6,11-dihydro-12H-dibenzo[b,f] [1,4]thiazocines and their derivatives

6,11-Dihydro-12H-dibenzo[b,f][1,4]thiazocine, 4 , and its 2-chloro, 7 , and 2-(trifluoromethyl)-, 1 , derivatives, were prepared by the reaction of an o-aminobenzenethiol and α,α-dibromo-o-xylene. Acylation and alkylation at position-12 gave a series of ω-haloacyl-, ω-amino-acyl, and ω-aminoalkyl derivatives of these heterocycles. The conformations, proton magnetic resonance spectra, and x-ray crystallographic studies of these compounds are discussed.