NO160296B

NO160296B - APPLICATION OF A BINDING MIXTURE CONTAINING CEMENT, THERMOPLASTIC BINDING AND FILLING FOR FIBER-ARMED RUBBER COATING ON FACE SURFACE INSULATION PLATES.

Info

Publication number: NO160296B
Application number: NO823024A
Authority: NO
Inventors: Martin Bjurvald
Original assignee: Casco Nobel Ab
Priority date: 1981-09-08
Filing date: 1982-09-07
Publication date: 1988-12-27
Also published as: NO823024L; SE433742B; SE8105345L; FI823069L; NO160296C; DK157449C; FI72963B; DK394882A; FR2512439A1; DK157449B; FI823069A0; FI72963C

Description

Fremgangsmåte for fremstilling av nittil ukjente, terapeutisk virksomme dibenzo [b,f] thiepin- og oxepinderivater. Process for the production of hitherto unknown, therapeutically active dibenzo [b,f] thiepine and oxepine derivatives.

Nærværende oppfinnelse vedrører en The present invention relates to a

fremgangsmåte for fremstilling av hittil ukjente thiepin- og oxepinderivater med verdifulle farmakologiske egenskaper, og med den generelle formel I, process for the production of hitherto unknown thiepine and oxepine derivatives with valuable pharmacological properties, and with the general formula I,

hvor X og Y uavhengig av hverandre betyr hydrogen, klor- eller bromatomer, lavere alkyl- eller lavere alkoxyrester, where X and Y independently of each other mean hydrogen, chlorine or bromine atoms, lower alkyl or lower alkoxy residues,

Z svovel eller oxygen, Z sulfur or oxygen,

R, hydrogen eller methylresten, R, hydrogen or the methyl residue,

R„ hydrogen eller en lavere alkylrest, R„ hydrogen or a lower alkyl residue,

R., hydrogen eller en lavere alkylrest eller R2 og R., danner sammen med det tilstøt-ende nitrogen og eventuelt inklusiv, iminogruppen eller en lavere alkylimino-, hydr-oxyalkylimino- eller alkanoyloxyalkyliminogruppe som ringledd en mettet heterocyklisk rest med 5—7 ringledd. R., hydrogen or a lower alkyl residue or R 2 and R., together with the adjacent nitrogen and optionally inclusive, the imino group or a lower alkylimino, hydroxyalkylimino or alkanoyloxyalkylimino group as a ring member form a saturated heterocyclic residue with 5-7 ring members .

Som det nå ble funnet, innehar disse As it was now found, these hold

forbindelser og deres salter med uorganiske og organiske syrer verdifulle farmakologiske egenskaper, i særdeleshet adreno-lytiske og sentraldempende, som f.eks. se- compounds and their salts with inorganic and organic acids valuable pharmacological properties, in particular adrenolytic and centrally depressant, such as e.g. see-

dative og narkosepotenserende virkning. De kan anvendes oralt eller i form av vandige oppløsninger av deres farmasøy-tiske aksepterbare salter også parenteralt, f.eks. for behandling av spennings- og irritasjonstilstander. De lar seg også kom-binere med andre farmaka, f.eks. med antidepressiva. dative and anesthetic potentiating effect. They can be used orally or in the form of aqueous solutions of their pharmaceutically acceptable salts also parenterally, e.g. for the treatment of states of tension and irritation. They can also be combined with other pharmaceuticals, e.g. with antidepressants.

Fra det amerikanske patent nr. 3 100 207 er det allerede kjent at dibenzo-[b,f]thiepin- og oxepinderivater, hvilke i 10-stilling oppviser en minst to CH0-broer inneholdende aminoalkylensidekjede, innehar en god narkosepotenserende effekt. Det ble nå funnet at fremgangsmåten ifølge nærværende krav, som skiller seg fra de tidligere nevnte forbindelser ved at det i 10-stilling i den basiske sidekjede bare er en CH,-bro, i sammenligning med de mest like, kjente forbindelser fra dette amerikanske patent oppviser en ganske betydelig sterkere narkosepotensering, som for noen av fremgangsmåteproduktene sogar er be-dre enn det 10-dobbelte enn ved de nevnte sammenligningsforbindelser. It is already known from American patent no. 3,100,207 that dibenzo-[b,f]thiepine and oxepine derivatives, which in the 10-position show at least two CH0 bridges containing an aminoalkylene side chain, have a good anesthetic potentiating effect. It was now found that the method according to the present claim, which differs from the previously mentioned compounds in that in the 10 position in the basic side chain there is only a CH, bridge, in comparison with the most similar, known compounds from this US patent exhibits a rather significantly stronger anesthetic potentiation, which for some of the process products is even better than 10-fold than with the aforementioned comparison compounds.

I forbindelsene med den generelle formel I er X fortrinnsvis i 2- eller 3-stilling, og Y fortrinnsvis i 7- eller 8-stilling. Som alkylrester er X og Y f.eks. methyl-, ethyl- og isopropylgruppene, videre som alkoxyrester methoxy-, ethoxy- og isopro-poxygruppene. R2 er f.eks. hydrogen, en methyl-, ethyl-, n-propyl-, n-butylrest og R., hydrogen eller en av de for R., nevnte alkylrester. Innbyrdes forbundne rester R2 og R., kan sammen med det tilstøtende nitrogenatom danne f. eks. 1-pyrro-lidinyl-,piperidino-,1 -hexa-hydroazepinyl-, 1-piperazinyl-, 4-methyl-l-piperazinyl-, 4- (2'-hydroxy-ethyl)-1-piperazinyl-, 4-(2'-acetoxyethyl)-l-piperazinyl-, 4-(2'-pivaloyloxy-ethyl)-l-piperazinyl- eller 4-methyl-l-homopipera-zinyl-resten. In the compounds of the general formula I, X is preferably in the 2- or 3-position, and Y is preferably in the 7- or 8-position. As alkyl residues, X and Y are e.g. the methyl-, ethyl- and isopropyl-groups, further as alkoxy residues the methoxy-, ethoxy- and isopropoxy-groups. R2 is e.g. hydrogen, a methyl, ethyl, n-propyl, n-butyl residue and R., hydrogen or one of the alkyl residues mentioned for R. Interlinked residues R2 and R., together with the adjacent nitrogen atom can form e.g. 1-pyrro-lidinyl-,piperidino-,1-hexa-hydroazepinyl-, 1-piperazinyl-, 4-methyl-1-piperazinyl-, 4-(2'-hydroxy-ethyl)-1-piperazinyl-, 4-( 2'-acetoxyethyl)-1-piperazinyl, 4-(2'-pivaloyloxyethyl)-1-piperazinyl or 4-methyl-1-homopiperazinyl residue.

Etter fremgangsmåten ifølge oppfinnelsen for fremstilling av forbindelser med den generelle formel I omsetter man en dibromforbindelse med den generelle formel II, According to the method according to the invention for the preparation of compounds of the general formula I, a dibromo compound of the general formula II is reacted,

hvor Rp X, Y og Z har den ovenfor angitte betydning, med minst den dobbelt-molare mengde mengde av en forbindelse med den generelle formel III, where Rp X, Y and Z have the meaning given above, with at least the double-molar amount amount of a compound of the general formula III,

hvor Rj, og R., har den ovenfor angitte betydning, eller med minst den dobbelt-molare mengde av en metallforbindelse av et N-acylderivat av et lavere alkylamin, underkaster, hvis nødvendig, reaksjonspro-duktet en hydrolyse for avspaltning av en eventuelt ved nitrogenatomet i sidekjeden bundet acylrest, behandler, hvis ønsket, en forbindelse med den generelle formel I med iminogruppen som ringledd med et lavere alkylenoxyd, med en reaksjonsdyktig mo-noester av en lavere alkandiol eller med en reaksjonsdyktig ester av et lavere alkanoyl-oxyalkanol, acylerer, hvis ønsket, en forbindelse med den generelle formel I, som inneholder en lavere hydroxyalkyliminogruppe som ringledd, til en slik med en lavere alkanoyloxyalkyliminogruppe, og overfører, hvis ønsket, en forbindelse med den generelle formel I med en uorganisk eller organisk syre til et salt. where Rj, and R., have the meaning stated above, or with at least the double-molar amount of a metal compound of an N-acyl derivative of a lower alkylamine, subjecting, if necessary, the reaction product to a hydrolysis for splitting off a possibly by the nitrogen atom in the side chain bound acyl residue, if desired, treats a compound of the general formula I with the imino group as ring member with a lower alkylene oxide, with a reactive monoester of a lower alkanediol or with a reactive ester of a lower alkanoyloxyalkanol, acylates , if desired, a compound of the general formula I, containing a lower hydroxyalkylimino group as a ring member, to one with a lower alkanoyloxyalkylimino group, and transfer, if desired, a compound of the general formula I with an inorganic or organic acid to a salt .

Ved omsetningen ifølge oppfinnelsen inntrer i samme arbeidsoperasjon hydro- In the turnover according to the invention, in the same work operation, hydro-

genbromidavspaltning og erstatning av det ikke-tertiært bundne brom med en ifølge definisjonen nitrogenholdig gruppe. Den andre nevnte reaksjon fremskyndes ved anvendelse av en forbindelse med den generelle formel III som utgangsstoff eventuelt gen bromide cleavage and replacement of the non-tertiary bound bromine with a nitrogen-containing group according to the definition. The second mentioned reaction is accelerated by using a compound of the general formula III as a starting material, if necessary

med et overskudd av den samme, dvs. ved with a surplus of the same, i.e. wood

anvendelse av totalt minst den tredobbelte-molare mengde, beregnet på dibromfor-bindelsen. Omsetningene utføres f.eks. i inerte oppløsningsmidler som f.eks. benzol, toluol, lavere alkanoler eller alkanoner. Alt etter betydningen av R,, R., og R.t er re-aksjonen mer eller mindre eksoterm. Hvis nødvendig fullstendiggjøres den ved oppvarmning av reaksjonsblandingen. Forbindelsene med den generelle formel II kan f.eks. omsettes med di-methylamin, methylethylamin, diethylamin, di-n-propylamin, ammoniak, methylamin, ethyla-min, n-propylamin, isopropylamin, n-but-ylamin, isobutylamin, pyrrolidin, piperidin, hexamethylenimin, 1-methyl-piperazin, 1-(p-hydroxy-ethyl)-piperazin, l-((3-acetoxy-ethyl) -piperazin, 1 - (p-pivaloyloxyethyl) - piperazin eller 1-methylhomopiperazin. using a total of at least three times the molar amount calculated for the dibromo compound. The sales are carried out e.g. in inert solvents such as e.g. benzene, toluene, lower alkanols or alkanones. Depending on the meaning of R,, R., and R.t, the reaction is more or less exothermic. If necessary, it is completed by heating the reaction mixture. The compounds with the general formula II can e.g. reacts with di-methylamine, methylethylamine, diethylamine, di-n-propylamine, ammonia, methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, pyrrolidine, piperidine, hexamethyleneimine, 1-methyl-piperazine, 1-(p-hydroxy-ethyl)-piperazine, 1-((3-acetoxy-ethyl)-piperazine, 1-(p-pivaloyloxyethyl)-piperazine or 1-methylhomopiperazine.

Omsetningen av en forbindelse med den generelle formel II med en metallforbindelse av et N-acylderivat av et lavere alkylamin, f.eks. med natriumforbindelsen av et lavere N-formyl- eller N-alkoxycar-bonyl-alkylamin, finner f.eks. sted i et inert organisk oppløsningsmiddel som benzol eller toluol under vannfrie betingelser i varme. Avspaltningen av den i reaksjonsproduk-tet ved nitrogenatomet i sidekjeden bundne acylrest finner f.eks. sted ved behandling av fremgangsmåteproduktet med et alkali-metallhydroxyd ved forhøyet temperatur enten i et høyt kokende hydroxylgruppe-holdig organisk oppløsningsmiddel, som f.eks. ethylenglykol eller diethylenglykol, eller en av dets lavere monoalkylethere eller i en lavere alkanol, i siste tilfelle fortrinnsvis i lukket kar. Videre kan hydrolysen f.eks. også finne sted ved koking med alkanolisk saltsyre. The reaction of a compound of the general formula II with a metal compound of an N-acyl derivative of a lower alkylamine, e.g. with the sodium compound of a lower N-formyl- or N-alkoxycarbonyl-alkylamine, find e.g. place in an inert organic solvent such as benzene or toluene under anhydrous conditions in heat. The cleavage of the acyl residue bound in the reaction product at the nitrogen atom in the side chain finds e.g. place by treating the process product with an alkali metal hydroxide at elevated temperature either in a high-boiling hydroxyl group-containing organic solvent, such as e.g. ethylene glycol or diethylene glycol, or one of its lower monoalkyl ethers or in a lower alkanol, in the latter case preferably in a closed vessel. Furthermore, the hydrolysis can e.g. also take place by boiling with alkanol hydrochloric acid.

Når i forbindelser med den generelle formel I R2 og R:! sammen med det til-støtende nitrogen og en iminogruppe danner en heterocyklisk rest, da dreier det seg - fortrinnsvis om 1-piperazinyl-eller 1-homo-piperazinyl-rest. Slike forbindelser omsettes for innføring av en lavere hydrox-yalkyl- eller alkanoyloxyalkylrest i den frie iminogruppen, d.v.s. f.eks. i 4-stilling i piperazin- henholdsvis homopiperazin-ringen, f.eks. p-bromethanol, p-(p-toluol-sulfonyloxy)-etanol, (p-bromethyl)-acetat i nærvær av et egnet syrebindemiddel som f.eks. kaliumcarbonat eller natriumcarbonat i et organisk oppløsningsmiddel, som f. eks. benzol, toluol, aceton eller butanon eller behandler med ethylenoxyd eller propyl-lenoxyd i et inert organisk oppløsnings-middel. When in compounds of the general formula I R2 and R:! together with the adjacent nitrogen and an imino group form a heterocyclic residue, then it is - preferably a 1-piperazinyl or 1-homo-piperazinyl residue. Such compounds are reacted to introduce a lower hydroxyalkyl or alkanoyloxyalkyl residue into the free imino group, i.e. e.g. in the 4-position in the piperazine or homopiperazine ring, e.g. p-bromoethanol, p-(p-toluene-sulfonyloxy)-ethanol, (p-bromomethyl)-acetate in the presence of a suitable acid binder such as e.g. potassium carbonate or sodium carbonate in an organic solvent, such as e.g. benzene, toluene, acetone or butanone or treated with ethylene oxide or propylene oxide in an inert organic solvent.

Acyleringen av 10- henholdsvis 11-(4'-hydroxyalkyl-r-pi<p>erazin<y>lmeth<y>l) - og 10- henholdsvis ll-[r-(4"-hydroxylalkyl-1 "-piper azinyl)-ethyl-] -(dibenzo[b,f ]thie-piner eller -dibenz[b,f] oxepiner eller tilsvarende homopiperazinylforbindelser finner f.eks. sted ved oppvarmning av disse stoffer i anhydrid av en lavere alkansyre som eddiksyre, propionsyre, smørsyre eller pivalinsyre eller ved behandling med de tilsvarende syrehalogenider i en tertiær nitrogenbase, som pyridin eller dets homo-loge eller ved omsetning av den tilsvarende natriumforbindelse med et syreklorid. The acylation of 10- respectively 11-(4'-hydroxyalkyl-r-pi<p>erazin<y>lmeth<y>l) - and 10- respectively ll-[r-(4"-hydroxylalkyl-1 "-piper azinyl )-ethyl-] -(dibenzo[b,f]thie-pines or -dibenz[b,f] oxepines or similar homopiperazinyl compounds take place, for example, by heating these substances in the anhydride of a lower alkanoic acid such as acetic acid, propionic acid, butyric acid or pivalic acid or by treatment with the corresponding acid halides in a tertiary nitrogen base, such as pyridine or its homologue or by reacting the corresponding sodium compound with an acid chloride.

Utgangsstoffer med den generelle formel II er f. eks. oppnåelige med utgang fra kjent dibenzo[b,f]thiepin-10(HH)-on henholdsvis fra dibenz[b,f]oxepin-10(HH)-on og tilsvarende definisjonen av X og Y subs-tituerte derivater av de samme. Disse oxo-forbindelser med den generelle formel IV, Starting substances with the general formula II are e.g. obtainable starting from known dibenzo[b,f]thiepin-10(HH)-one respectively from dibenz[b,f]oxepin-10(HH)-one and corresponding to the definition of X and Y substituted derivatives of the same. These oxo compounds of the general formula IV,

hvor X, Y og Z har den ovenfor angitte betydning, kondenseres med metllorganiske methyl- eller ethylforbindelser, f.eks. med methyl- eller ethylmagnesiumhalogenider, i ether eller et etherlignende oppløsnings-middel, som diethylether eller tetrahydro-furan, som eventuelt er blandet med et inert organisk oppløsningsmiddel, som f. eks. benzol henholdsvis toluol, til hydroxy-forbindelser med den generelle formel V, hvor R,, X, Y og Z har den ovenfor angitte betydning, og behandler de sistnevnte med vannavspaltende midler henholdsvis utsetter for vannavspaltende betingelser. F.eks. koker man hydroxyforbindelsene noen tid med sterkt fortynnet, f.eks. 0,2-n saltsyre. Derved oppnår man blandinger av en forbindelse med den generelle formel VI, og den isomere forbindelse med endocyc-lisk dobbeltbinding tilsvarende den generelle formel VII, where X, Y and Z have the meaning stated above, are condensed with organometallic methyl or ethyl compounds, e.g. with methyl or ethylmagnesium halides, in ether or an ether-like solvent, such as diethyl ether or tetrahydrofuran, which is optionally mixed with an inert organic solvent, such as e.g. benzene or toluene, respectively, to hydroxy compounds of the general formula V, where R, X, Y and Z have the meaning indicated above, and treating the latter with water-releasing agents or subjecting them to water-releasing conditions. E.g. the hydroxy compounds are boiled for some time with highly diluted, e.g. 0.2-n hydrochloric acid. This results in mixtures of a compound with the general formula VI, and the isomeric compound with an endocyclic double bond corresponding to the general formula VII,

Andelen av den ønskede forbindelse med den generelle formel VI kan økes ved skånende reaksjonsbetingelser og unngåelse av unødvendig lange reaksjonstider. Ved behandlingen av forbindelser med den generelle formel VI henholdsvis råproduk-ter som inneholder disse, med brom i egnede inerte organiske oppløsningsmidler, som f. f.eks. karbondisulfid eller karbontetraklorid, i kulde oppnår man de ønskede utgangsstoffer med den generelle formel II, mens de isomere forbindelser med den generelle formel VII blir uforandret. Fortrinnsvis renses ikke det rå bromaddisjonsprodukt, men omsettes direkte med den mengde av en forbindelse med den generelle formel III som tilsvarer dets innhold — under-søkt fra bromforbruket — av forbindelsen med den generelle formel II. En derved dannet basisk forbindelse med den generelle formel I kan lett på vanlig måte skilles fra nøytralt ledsagerstoff med den generelle formel VII. Analogt finner adskillelsen av ledsagerstoffet sted når i stedet for en forbindelse med den generelle formel III en metallforbindelse av et N-acylderivat av et lavere alkylamin kommer til omsetning, bare må i dette tilfelle basen med den generelle formel I først frisettes ved hydrolyse. The proportion of the desired compound with the general formula VI can be increased by gentle reaction conditions and avoidance of unnecessarily long reaction times. In the treatment of compounds with the general formula VI or raw products containing these, with bromine in suitable inert organic solvents, such as e.g. carbon disulphide or carbon tetrachloride, in the cold one obtains the desired starting substances with the general formula II, while the isomeric compounds with the general formula VII remain unchanged. Preferably, the crude bromine addition product is not purified, but reacted directly with the amount of a compound of the general formula III which corresponds to its content — examined from the bromine consumption — of the compound of the general formula II. A thereby formed basic compound with the general formula I can easily be separated in the usual way from the neutral companion substance with the general formula VII. Analogously, the separation of the companion substance takes place when, instead of a compound of the general formula III, a metal compound of an N-acyl derivative of a lower alkylamine is reacted, only in this case the base of the general formula I must first be released by hydrolysis.

Med uorganiske og organiske syrer, som saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, With inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,

methansulfonsyre, ethandisulfonsyre, p-hydroxyethansulfonsyre, eddiksyre, melke-syre, oxalsyre, ravsyre, fumarsyre, malein-syre, eplesyre, vinsyre, sitronsyre, benzoe-syre, salicylsyre, fenyleddiksyre og mandel-syre danner de nye forbindelser med den generelle formel I salter, hvilke tildels er vannoppløselige. Methanesulfonic acid, ethanedisulfonic acid, p-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid form the new compounds of the general formula I salts, some of which are water-soluble.

De etterfølgende eksempler redegjør nærmere for den nye fremgangsmåten for fremstilling av forbindelser med den generelle formel I, samt for fremstilling av utgangsstoffene. Temperaturene er angitt i Celsiusgrader. The following examples explain in more detail the new method for the preparation of compounds of the general formula I, as well as for the preparation of the starting materials. The temperatures are indicated in degrees Celsius.

Eksempel 1. Example 1.

a) Til en av 29,4 g magnesium, 170 g methyljodid og 350 ml absolutt ether tilbe-redt Grignardoppløsning lar man tildryppe under sterk røring ved en temperatur på a) A Grignard solution prepared from 29.4 g of magnesium, 170 g of methyl iodide and 350 ml of absolute ether is added dropwise with vigorous stirring at a temperature of

—15° til —10° i løpet av 2y2 time en opp-løsning av 135,5 g dibenzo[b,f] thiepin-10 (HH)-on med smeltepunkt 68° i 300 ml absolutt benzol. Under disse betingelsene er methanutviklingen (Zerewitinoff-reaksjon med enolformen av ketonet) med ca. 500 ml praktisk talt uten betydning. Reaksjons-oppløsningen bringes i løpet av 2 timer til 0° og i løpet av ytterligere 1 time til værelsetemperatur. Deretter i-øres den videre ennå 20 timer ved 40° innetemperatur under tilbakeløp, hvorved et grått bunnfall felles ut. Etter avkjøling innrøres reaksjonsblandingen i en oppløsning av 300 g ammoniumklorid i 400 ml isvann. Den organiske fasen skilles fra, og den vandige fase ekstraheres ennå en gang med benzol. De forente oppløsninger vaskes to ganger med vann og tørkes over kaliumcarbonat. Oppløsningsmidlet avdampes fullstendig i vakuum, hvorved 10-methyl-10,ll-dihydro-dibenzo[b,f] thiepin-10-ol krystalliseres. Ved krystallisasjon fra 400 ml cyklohexan, under henstand i isskap, oppnås det rent. Smeltepunkt 109—111°. b) 50 g 10-methyl-lO, 11-dihydro-dibenzo[b,f]-thiepin-lO-ol kokes med 300 ml 0,2-n saltsyre under tilbakeløp 12 timer. Herpå avkjøles blandingen ved 20° og ekstraheres med petrolether; den organiske fase vaskes med vann, tørkes over kaliumcarbonat og inndampes. Som rest blir 10-methylen-10,11 -dihydro-dibenzo[b,f] thiepin tilbake. Sammenlign dertil j), som kommer nedenfor. c) 8,9 g rå 10-methylen-10,ll-dihydro-dibenzo[b,f] thiepin oppløses i 25 ml karbondisulfid. Ved 5—10° tildryppes under røring en oppløsning av brom i karbondisulfid (1 vektdel til 5 volumdeler), inntil ikke noe bromforbruk mer kan konsta-teres. (F. eks. forbruk av 3,18 g brom = 50 pst. av teorien ved en y2 times tildryp-ning). Herpå inndampes oppløsningsmid-let i vakuum ved en temperatur på høyst 40°. Som rest forblir f. eks. 12 g av en blanding av 10-brom-10-brommetyl-10,ll-dihydro-dibenzo[b,f] thiepin og 10-methyl-dibenzo[b,f] thiepin. d) 12 g råprodukt etter c) oppløses i 20 ml absolutt benzol og tildryppes i løpet av -15° to -10° during 2y2 hours a solution of 135.5 g of dibenzo[b,f] thiepin-10 (HH)-one with melting point 68° in 300 ml of absolute benzene. Under these conditions, methane evolution (Zerewitinoff reaction with the enol form of the ketone) is with approx. 500 ml practically insignificant. The reaction solution is brought to 0° within 2 hours and to room temperature within a further 1 hour. It is then stirred for a further 20 hours at an internal temperature of 40° under reflux, whereby a gray precipitate precipitates out. After cooling, the reaction mixture is stirred into a solution of 300 g of ammonium chloride in 400 ml of ice water. The organic phase is separated, and the aqueous phase is extracted once more with benzene. The combined solutions are washed twice with water and dried over potassium carbonate. The solvent is completely evaporated in vacuo, whereby 10-methyl-10,11-dihydro-dibenzo[b,f] thiepin-10-ol is crystallized. By crystallization from 400 ml of cyclohexane, while standing in an icebox, it is obtained pure. Melting point 109-111°. b) 50 g of 10-methyl-10,11-dihydro-dibenzo[b,f]-thiepin-10-ol are boiled with 300 ml of 0.2-n hydrochloric acid under reflux for 12 hours. The mixture is then cooled at 20° and extracted with petroleum ether; the organic phase is washed with water, dried over potassium carbonate and evaporated. As a residue, 10-methylene-10,11-dihydro-dibenzo[b,f] thiepine remains. Compare thereto j), which comes below. c) 8.9 g of crude 10-methylene-10,11-dihydro-dibenzo[b,f] thiepine are dissolved in 25 ml of carbon disulphide. At 5-10°, a solution of bromine in carbon disulphide (1 part by weight to 5 parts by volume) is added dropwise while stirring, until no more consumption of bromine can be detected. (E.g. consumption of 3.18 g of bromine = 50 per cent of the theory at a y2 hour instillation). The solvent is then evaporated in vacuum at a temperature of no more than 40°. As a remainder, e.g. 12 g of a mixture of 10-bromo-10-bromomethyl-10,11-dihydro-dibenzo[b,f] thiepine and 10-methyl-dibenzo[b,f] thiepine. d) 12 g of crude product from c) are dissolved in 20 ml of absolute benzene and added dropwise during

30 minutter under røring til en oppløsning 30 minutes while stirring until a solution

av 5 g dimetylamin i 25 ml absolutt benzol. Herpå røres reaksjonsblandingen videre 2 timer ved værelsetemperatur. Etter til-setning av 10 ml vann skilles den organiske fase fra og ekstraheres tre ganger med 2-n saltsyre. De sure ekstrakter innstilles fe-nolfthalein-alkalisk med konsentrert van-dig ammoniakk og utrystes med ether. Den etheriske oppløsning vaskes med vann, tørkes over kaliumcarbonat og heretter av-destilleres oppløsningsmidlet. Som rest blir 10-dimethylaminomethyl-dibenzo[b,f] thiepin tilbake, smeltepunkt 112°. of 5 g of dimethylamine in 25 ml of absolute benzene. The reaction mixture is then stirred for a further 2 hours at room temperature. After adding 10 ml of water, the organic phase is separated and extracted three times with 2-N hydrochloric acid. The acidic extracts are made phenolphthalein-alkaline with concentrated aqueous ammonia and shaken out with ether. The ethereal solution is washed with water, dried over potassium carbonate and then the solvent is distilled off. As a residue, 10-dimethylaminomethyl-dibenzo[b,f] thiepine remains, melting point 112°.

e) Analogt d) oppnår man ved anvendelse av monomethylamin i stedet for di-methylamin fra rå 10-brom-lO-bromme-thyl-10,11-dihydro-dibenzo [b,f ] thiepin e) Analogous to d) by using monomethylamine instead of dimethylamine from crude 10-bromo-10-bromo-ethyl-10,11-dihydro-dibenzo [b,f ] thiepine

som 10-monomethylaminomethyl-dibenzo such as 10-monomethylaminomethyl-dibenzo

[b,f]thiepin, hvis hydroklorid smelter ved 234—237°. [b,f]thiepine, whose hydrochloride melts at 234—237°.

Under anvendelse av tilsvarende baser oppnår man videre på analog måte: f) 10-[4'-p-hydroxyethyl-l'-piperazinyl) -methyl] -dibenzo [b,f] thiepin, smeltepunkt for dihydrokloridet 235—242°; g) 10-[(4'-p-pivaloyloxyethyl-l'-piperazinyl) -methyl] -dibenzo [b,f] thiepin, smeltepunkt for dihydrokloridet 199—200°; h) 10- [ (4'-methyl-l'-piperazinyl)-methyl]-dibenzo [b,f] thiepin, smeltepunkt for Using corresponding bases, one further obtains in an analogous manner: f) 10-[4'-p-hydroxyethyl-1'-piperazinyl)-methyl]-dibenzo [b,f] thiepine, melting point for the dihydrochloride 235-242°; g) 10-[(4'-p-pivaloyloxyethyl-1'-piperazinyl)-methyl]-dibenzo [b,f] thiepine, melting point of the dihydrochloride 199-200°; h) 10- [ (4'-methyl-1'-piperazinyl)-methyl]-dibenzo [b,f] thiepine, melting point for

dihydrokloridet 225—228°; the dihydrochloride 225-228°;

i) 10-aminomethyl-dibenzo[b,f] thiepin, hvis krystallvannholdige hydroklorid smelter ved 228—231°. i) 10-aminomethyl-dibenzo[b,f] thiepine, whose water-of-crystal hydrochloride melts at 228-231°.

j) Gjennomføres vannavspaltningen i trinnet b) under mer energirike betingelser, f.eks. 20 timers koking med 5-n saltsyre under sterk røring, så oppstår kvantitativt isomeret 10-methyl-dibenzo [b,f ] thiepin. j) Is the water splitting in step b) carried out under more energetic conditions, e.g. After 20 hours of boiling with 5-n hydrochloric acid under vigorous stirring, the isomer 10-methyl-dibenzo [b,f] thiepine is produced quantitatively.

Det skilles fra saltsyren ved to gangers ekstraksjon med cyklohexan. Cyklohexan-oppløsningen vaskes med vann, tørkes og inndampes, hvorved 10-methyl-dibenzo [b, f] thiepin langsomt krystalliserer, smeltepunkt ca. 45—48°. Etter omkrystallisasjon fra pentan smelter den rene substans ved 50—51°. It is separated from the hydrochloric acid by two extractions with cyclohexane. The cyclohexane solution is washed with water, dried and evaporated, whereby 10-methyl-dibenzo [b, f] thiepine slowly crystallizes, melting point approx. 45-48°. After recrystallization from pentane, the pure substance melts at 50-51°.

Eksempel 2 Example 2

Analogt dibenzo [b,f ] thiepin-10 (11H) - onet fremstilles 8-klor-dibenzo[b,f]thiepin-10(llH)-on med smeltepunkt 119—120° Analogous to dibenzo [b,f]thiepin-10 (11H)-one, 8-chloro-dibenzo[b,f]thiepin-10(llH)-one is produced with melting point 119-120°

(fra ether). Fra dette fremstilles f. eks. over mellomproduktene 8-klor-l0-methyl-l0,11 - dihydro-dibenzo[b,f]thiepin-10-ol (råprodukt), 2-klor-l 1 -methylen-10,11 -dihydro-dibenzo[b,f]thiepin (råprodukt) og 10-brom-10-brommethyl-8-klor-10,ll-dihydrodi-benzo[b,f]thiepin (råprodukt), sluttproduktene (from ether). From this, e.g. over the intermediates 8-chloro-10-methyl-10,11 - dihydro-dibenzo[b,f]thiepin-10-ol (crude product), 2-chloro-1 1 -methylene-10,11 -dihydro-dibenzo[b, f]thiepine (crude product) and 10-bromo-10-bromomethyl-8-chloro-10,11-dihydrodi-benzo[b,f]thiepine (crude product), the final products

a) 2-klor-11 -dimethylaminoethyl-dibenzo[b,f]thiepin, smeltepunkt 116° (fra a) 2-chloro-11-dimethylaminoethyl-dibenzo[b,f]thiepine, melting point 116° (from

petrolether) og petroleum ether) and

b) 2-klor-ll-(4'-methyl-r-piperazinyl-methyl)-dibenzo [b,f]thiepin, smeltepunkt b) 2-chloro-11-(4'-methyl-r-piperazinyl-methyl)-dibenzo [b,f]thiepine, melting point

111—112° (fra petrolether). 111—112° (from petroleum ether).

Eksempel 3 Example 3

Analogt dibenzo[b,f]thiepin-10 (11H)-on fremstilles 2-klor-dibenzo[b,f]-thiepin-10(llH)-on med smeltepunkt 141°. Fra dette oppnås f. eks. over 2-klor-10-methyl-10,11-dihydrodibenzo [b,f ] -thiepin- lO-ol Analogous to dibenzo[b,f]thiepin-10 (11H)-one, 2-chloro-dibenzo[b,f]-thiepin-10(11H)-one is prepared with a melting point of 141°. From this, e.g. above 2-chloro-10-methyl-10,11-dihydrodibenzo [b,f]-thiepin-10-ol

(råprodukt), 2-klor-10-methylen-10,11-dihydro-dibenzo[b,f] thiepin (råprodukt) og 10-brom-10-brommethyl-2-klor-10,ll-dihydro-dibenzo [b,f ] thiepin (råprodukt), sluttproduktene (crude product), 2-chloro-10-methylene-10,11-dihydro-dibenzo[b,f] thiepine (crude product) and 10-bromo-10-bromomethyl-2-chloro-10,11-dihydro-dibenzo [b ,f ] thiepin (raw product), the final products

a) 2-klor-10-dimethylaminoethyl)-dibenzo[b,f]thiepin, smeltepunkt 76—77° (fra a) 2-chloro-10-dimethylaminoethyl)-dibenzo[b,f]thiepine, melting point 76-77° (from

petrolether) og petroleum ether) and

b) 2-klor-10-piperidinomethyl-dibenzo [b,f]thiepin, smeltepunkt, 118° (fra ben-sin). b) 2-chloro-10-piperidinomethyl-dibenzo [b,f]thiepine, melting point, 118° (from gasoline).

Eksempel 4 Example 4

Analogt dibenzo[b,f]thiepin-10 (11H)-on fremstilles 8-methoxy-dibenzo[b,f]thiepin-10(llH)-on. Fra dette fremstilles f.eks. over mellomproduktene 8-methoxy-10-methyl-10,ll-dihydrodibenzo[b,f]thiepin-10-ol, 2-methoxy-ll-methylen-10-ll-dihydro-dibenzo[b,f] thiepin, 10-brom-lO-bromme-thyl-8-methoxy-10,ll-dihydro-dibenzo [b,f]thiepin (råprodukt), sluttproduktet 8-methoxy-10-dimethylaminomethyl-dibenzo[b,f]thiepin (= 2-methoxy-ll-dimethyl-aminomethyl-dibenzo[b,f] thiepin), kokepunkt 151°/0,01 Torr, smeltepunkt 92,5°. Hydrokloridet av dette sluttproduktet smelter ved 230—231° (delvis spaltning). Analogous to dibenzo[b,f]thiepin-10 (11H)-one, 8-methoxy-dibenzo[b,f]thiepin-10(11H)-one is prepared. From this, e.g. over the intermediates 8-methoxy-10-methyl-10,ll-dihydrodibenzo[b,f]thiepin-10-ol, 2-methoxy-ll-methylene-10-ll-dihydro-dibenzo[b,f]thiepin, 10- bromo-10-bromo-thyl-8-methoxy-10,11-dihydro-dibenzo [b,f]thiepine (crude product), the final product 8-methoxy-10-dimethylaminomethyl-dibenzo[b,f]thiepine (= 2-methoxy -ll-dimethyl-aminomethyl-dibenzo[b,f] thiepine), boiling point 151°/0.01 Torr, melting point 92.5°. The hydrochloride of this end product melts at 230-231° (partial decomposition).

Eksempel 5 Example 5

Analogt dibenzo[b,f]thiepin-10 (11H)-on fremstilles 2-methyl-dibenzo[b,f]thiepin-10(HH)-on. Fra dette fremstilles f.eks. over mellomproduktene 2,10-dimethyl-10, ll-dihydro-dibenzo[b,f]thiepin-10-ol råprodukt), 2-methyl-10-methylen-10,ll-di-hydro-dibenzo[b,f]thiepin (råprodukt) og 10-brom-10-brommethyl-2-methyl-10,ll-dihydro-dibenzo [b,f ] thiepin (råprodukt), sluttproduktet 2-methyl-10-dimethylami-nometyl-dibenzo[b,f] thiepin, smeltepunkt 245—248°. Analogous to dibenzo[b,f]thiepin-10 (11H)-one, 2-methyl-dibenzo[b,f]thiepin-10(HH)-one is prepared. From this, e.g. over the intermediates 2,10-dimethyl-10,ll-dihydro-dibenzo[b,f]thiepin-10-ol crude product), 2-methyl-10-methylene-10,ll-dihydro-dibenzo[b,f] thiepine (crude product) and 10-bromo-10-bromomethyl-2-methyl-10,11-dihydro-dibenzo [b,f ] thiepine (crude product), the final product 2-methyl-10-dimethylaminomethyl-dibenzo[b,f ] thiepin, melting point 245—248°.

Eksempel 6 Example 6

Analogt dibenzo[b,f]thiepin-10 (11H)-on fremstilles 7-klor-dibenzo[b,f] thiepin - 10(llH)-on. Fra dette fremstilles f. eks. over mellomproduktene 7-klor-10-methyl-10,11 -dihydro-dibenzo [b,f ] thiepin-10-ol (råprodukt), 3-klor-ll-methylen-10,ll-di-hydro-dibenzo[b,f]thiepin (råprodukt) og 10-brom-10-brommethyl-7-klor-10,ll-dihydro-dibenzo[b,f]thiepin (råprodukt), sluttproduktene Analogous to dibenzo[b,f]thiepin-10 (11H)-one, 7-chloro-dibenzo[b,f]thiepin-10(11H)-one is prepared. From this, e.g. over the intermediates 7-chloro-10-methyl-10,11-dihydro-dibenzo [b,f ] thiepin-10-ol (crude product), 3-chloro-11-methylene-10,11-dihydro-dibenzo[b ,f]thiepine (crude product) and 10-bromo-10-bromomethyl-7-chloro-10,11-dihydro-dibenzo[b,f]thiepine (crude product), the final products

a) 3-klor-11 -dimethylaminomethyl-dibenzo[b,f]thiepin, smeltepunkt 70°, så vel a) 3-chloro-11-dimethylaminomethyl-dibenzo[b,f]thiepine, melting point 70°, as well

som as

b) 3-klor-l 1 - (1 '-pyrrolidinylmethyl)-dibenzo[b,f]thiepin, kokepunkt 172—175°/ b) 3-chloro-1 1 -(1'-pyrrolidinylmethyl)-dibenzo[b,f]thiepine, boiling point 172-175°/

0,001 Torr, hydroklorid, smeltepunkt 265— 268° (spaltning). 0.001 Torr, hydrochloride, melting point 265— 268° (decomposition).

Eksempel 7 Example 7

a) Gåes det analogt eksempel la) under anvendelse av Grignardoppløsningen ut a) If the analogous example la) is carried out using the Grignard solution

fra den ekvimolare mengde ethyljodid i stedet for methyljodid, så får man 10-ethyl-10,ll-dihydrodibenzo[b,f]thiepin-lO-ol, smeltepunkt 93—95° (omkrystallisert fra cyklohexan). from the equimolar amount of ethyl iodide instead of methyl iodide, 10-ethyl-10,11-dihydrodibenzo[b,f]thiepin-10-ol is obtained, melting point 93-95° (recrystallized from cyclohexane).

b) Analogt eksempel lb) foretas fra 7a) vannavspaltningen, hvorved ved anvendelse b) Analogous example lb) is carried out from 7a) the water separation, whereby by application

av 2-n saltsyre reaksjonstiden begrenses til 1 time. 10-ethyliden-10,ll-dihydro-dibenzo of 2-n hydrochloric acid, the reaction time is limited to 1 hour. 10-ethylidene-10,11-dihydro-dibenzo

[b,f]thiepin smelter ved 90—92° (fra pentan). [b,f]thiepine melts at 90-92° (from pentane).

c) Bromeringen foretas analogt eksempel lc) og fører til 10-brom-10-(l-brome-thyl)-10,ll-dihydro-dibenzo[b,f] thiepin, smeltepunkt 102 — 103° (fra petrolether). Ved omsetning med de tilsvarende aminer oppnås f.eks. de følgende sluttprodukter: d) 10- (1-dimethylamino-ethyl) -dibenzo[bf]thiepin, kokepunkt 160°/0,012 c) The bromination is carried out analogously to example 1c) and leads to 10-bromo-10-(1-bromoethyl)-10,11-dihydro-dibenzo[b,f] thiepine, melting point 102 — 103° (from petroleum ether). By reaction with the corresponding amines, e.g. the following end products: d) 10-(1-dimethylamino-ethyl)-dibenzo[bf]thiepine, boiling point 160°/0.012

Torr; Dry;

e) 10-(l-monomethylamino-ethyl)-di- e) 10-(1-monomethylamino-ethyl)-di-

benzo [b,f] thiepin, smeltepunkt for hydro- benzo [b,f] thiepine, melting point of hydro-

kloridet 251—252°; the chloride 251-252°;

f) 10-(l-pyrrolidino-ethyl)-dibenzo[b, f) 10-(1-pyrrolidino-ethyl)-dibenzo[b,

f]thiepin, smeltepunkt 84—85° (fra pentan; f]thiepine, melting point 84-85° (from pentane;

g) 10-[l-(4-methyl-piperazinyl)-ethyl] -dibenzo [b,f]thiepin, smeltepunkt for dihydrokloridet 245—249° (fra ethanol). g) 10-[1-(4-methyl-piperazinyl)-ethyl]-dibenzo [b,f]thiepine, melting point for the dihydrochloride 245-249° (from ethanol).

Eksempel 8. Example 8.

a) — d) Anvendes i eksempel la) i stedet for dibenzo[b,f]thiepin-10(HH)-on a) — d) Used in example la) instead of dibenzo[b,f]thiepin-10(HH)-one

126,0 g dibenz[b,f]-oxepin-10(HH)-on, opp- 126.0 g dibenz[b,f]-oxepin-10(HH)-one, up-

når man ved forøvrig lik arbeidsmåte 10-methyl-10,ll-dihydrodibenz[b,f]oxepin- when, with an otherwise identical working method, 10-methyl-10,11-dihydrodibenz[b,f]oxepin-

lO-ol. Dette lar seg omvandle analogt eksempel lb) og c) over 10-methylen-10,ll-dihydro-dibenz[b,f]oxepin til 10-brom-lO-brommethyl-10,ll-dihydro-dibenz[b,f] oxe- lO-ol. This can be converted analogously to examples lb) and c) via 10-methylene-10,11-dihydro-dibenz[b,f]oxepine to 10-bromo-10-bromomethyl-10,11-dihydro-dibenz[b,f] ox-

pin (råprodukt). Omsetning med dimethyl- pin (raw product). Reaction with dimethyl-

amin analogt eksempel ld) gir det rå 10-dimethylaminomethyl-dibenz [b,f] oxepin. amine analog example ld) gives the crude 10-dimethylaminomethyl-dibenz [b,f]oxepine.

Dette lar seg destillere i høyvakuum, koke- This can be distilled in high vacuum, boiled

punkt 128—130°/0,004 Torr. Det fra basen ved hjelp av ethanolisk saltsyre tilberedte hydroklorid smelter etter omkrystallisasjon fra ethanol ved 234 — 136.° point 128—130°/0.004 Torr. The hydrochloride prepared from the base using ethanolic hydrochloric acid melts after recrystallization from ethanol at 234 — 136.°

e) Analogt eksemplene ld) og 8d) opp- e) Analogous to examples ld) and 8d) up-

nås fra 10-brom-10-brommethyl-10,ll-di-hydro-dibenz[b,f]oxepin (råprodukt) is reached from 10-bromo-10-bromomethyl-10,11-dihydro-dibenz[b,f]oxepine (crude product)

e<1>) med methylamin 10-methyl-aminomethyl-dibenz [b,f ] oxepin, kokepunkt 145°/0,004 Torr, hydroklorid, smeltepunkt 185—188° fra absolutt ethanol, e<1>) with methylamine 10-methyl-aminomethyl-dibenz [b,f ] oxepin, boiling point 145°/0.004 Torr, hydrochloride, melting point 185-188° from absolute ethanol,

e<2>) med piperazin-l-ethanol 10-[4'-(2"-hy-droxy-ethyl) -1 '-piperazinylmethyl] -di-benz [b,f ] oxepin,dihydroklorid, smeltepunkt 220 — 225° fra absolutt ethanol, e<2>) with piperazine-1-ethanol 10-[4'-(2"-hydroxy-ethyl)-1 '-piperazinylmethyl]-di-benz [b,f ] oxepin, dihydrochloride, melting point 220 — 225 ° from absolute ethanol,

e<s>) med pyrrolidin 10-pyrrolidinomet-hyl-dibenz[b,f]oxepin, kokepunkt 150 — e<s>) with pyrrolidine 10-pyrrolidinomethyl-dibenz[b,f]oxepine, boiling point 150 —

155°/0,01 Torr, hydroklorid, smeltepunkt 193 — 196° fra absolutt ethanol, og e<4>) med 1-methyl-piperazin 10-(4'-methyl-l'-piperazinylmethyl)-dibenz[b,f] 155°/0.01 Torr, hydrochloride, m.p. 193 — 196° from absolute ethanol, and e<4>) with 1-methyl-piperazine 10-(4'-methyl-1'-piperazinylmethyl)-dibenz[b,f ]

oxepin, smeltepunkt 82 — 83° fra pentan, dihydroklorid, smeltepunkt 210 — 215° fra absolutt ethanol. oxepin, melting point 82 — 83° from pentane, dihydrochloride, melting point 210 — 215° from absolute ethanol.

Eksempel 9. Example 9.

a) Man oppløser 3,7 g N-methyl-aceta- a) 3.7 g of N-methyl-aceta-

mid i 50 ml abs. benzol, tilsetter oppløs- mid in 50 ml abs. benzene, add solvent

ningen 2 g natriumamid og koker blandin- addition of 2 g of sodium amide and boil the mixture

ken i 1 time under tilbakeløp. Deretter av- ken for 1 hour under reflux. Then off-

kjøles den til værelsestemperatur, og en oppløsning av 19 g 10-brom-lO-brom-methyl-10,ll-dihydro-dibenzo[b,f] thiepin i 50 ml absolutt benzol i løpet av 1/2 time tildryppes, og suspensjonen kokes ennå i it is cooled to room temperature, and a solution of 19 g of 10-bromo-10-bromo-methyl-10,11-dihydro-dibenzo[b,f] thiepine in 50 ml of absolute benzene is added dropwise over the course of 1/2 hour, and the suspension still cooked in

14 timer under tilbakeløp. Deretter avkjøler man reaksjonsblandingen til værelsestem- 14 hours during reflux. The reaction mixture is then cooled to room temperature.

peratur og tilsetter den vann. Man skiller den organiske fase fra, vasker den med vann, tørker den over natriumsulfat og inndamper den i vakuum. Resten, N-acetyl-10-methylaminomethyl-dibenzo[b,f] thie- perature and adds water to it. The organic phase is separated, washed with water, dried over sodium sulphate and evaporated in a vacuum. The remainder, N-acetyl-10-methylaminomethyl-dibenzo[b,f] thie-

pin, anvendes som råprodukt. pin, used as a raw product.

b) 15 g rå N-acetyl-10-methylamino-methyl-dibenzo[b,f]thiepin kokes i en opp- b) Boil 15 g of raw N-acetyl-10-methylamino-methyl-dibenzo[b,f]thiepine in a

løsning av 10 g kaliumhydroxyd i 200 ml absolutt ethanol i 24 timer under tilbake- solution of 10 g of potassium hydroxide in 200 ml of absolute ethanol for 24 hours under reflux

løp. Man konsentrerer reaksjonsblandingen, run. The reaction mixture is concentrated,

heller den på vann og ekstraherer den ut- pour it on water and extract it out-

skilte olje med ether. Etheroppløsningen ekstraheres med 2-n saltsyre, og det salt- separated oil with ether. The ether solution is extracted with 2-n hydrochloric acid, and the salt

sure ekstrakt innstilles alkalisk med kon- acidic extract is adjusted alkaline with con-

sentrert ammoniakk. Man ekstraherer den utskilte olje med ether, vasker etheropp- concentrated ammonia. The separated oil is extracted with ether, washed with ether

løsningen med vann, tørker den over na- the solution with water, it dries over na-

triumsulfat og inndamper den. Man over- triium sulfate and evaporates it. One over-

fører resten, det rå 10-methylaminomethyl-dibenzo[b,f]thiepin, med ethanolisk salt- treats the residue, the crude 10-methylaminomethyl-dibenzo[b,f]thiepine, with ethanolic salt-

syre til hydrokloridet, som smelter ved 234 — 237°. acid to the hydrochloride, which melts at 234 — 237°.

Claims

Process for the production of previously unknown, therapeutically active dibenzo [b,f]thiepine and oxepine derivatives of the general formula (I),

where X and Y independently of each other mean hydrogen, chlorine or bromine atoms, lower alkyl or lower alkoxy residues, Z sulfur or oxygen, R{ hydrogen or the methyl residue, Ro hydrogen or a lower alkyl residue, R3 hydrogen or a lower alkyl radical or R., and R3 together with the adjacent nitrogen and possibly including the imino group or a lower alkylimino, hydroxyalkylimino or alkanoyloxyalkylimino group as ring members form a saturated heterocyclic radical with 5-7 ring members, and their salts with inorganic and organic acids, characterized by reacting a dibromo compound with the general formula (II), where R, X, Y and Z have the above-mentioned meaning, with at least the double-molar amount of a compound of the general formula (III), where R, and R., have the meaning stated above, or with at least the double- A trial report of 11 May 1966 was In molar amount of a metal compound of • an N-acyl derivative of a lower alkylamine, if necessary, subject the reaction product to a hydrolysis to split off an acyl residue possibly bound to the nitrogen atom in the side chain, treat, if desired, a compound with the general formula (I) with the imino group as ring member with a lower alkylene oxide, with a reactive monoester of a lower alkanediol or with a reactive ester of a lower alkanoylalkanol, acylates, if desired, a compound of the general formula (I) with a lower hydroxyalkylimino group as a ring member to one with a lower alkanoyloxyalkylimino group and transfers, if desired, a compound of the general formula (I) with an inorganic or organic acid to a salt.