DK150301B - METHOD OF ANALOGUE FOR PREPARING AZATETRACYCLIC COMPOUNDS OR ACID ADDITION SALTS - Google Patents

Description

; V i 150301

The present invention relates to an analogous process for the preparation of novel azatetracyclic compounds of general formula I

A

• ·

I I

.

^ \ / \ / N

• · · · ...

R-I I II II II (I) 2 · · · ·

'·' Ν 'V

Wherein R ^ is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of not more than 10 carbon atoms, alkenyl of 3-4. carbon atoms, propargyl, dialkylaminoalkyl of not more than 10 carbon atoms, hydroxyalkyl of 2-8 carbon atoms, alkoxyalkyl of 3-10 carbon atoms, alkanoyloxyalkyl of 10-11 carbon atoms, alkylthioalkyl of 3-11 carbon atoms or phenylalkyl of 7 or 8 carbon atoms, means hydrogen, fluorine , chlorine, bromine, alkyl of not more than 4 carbon atoms, hydroxy, alkoxy of not more than 4 carbon atoms, alkanoyl-oxy of 1-4 carbon atoms, alkylthio of not more than 4 carbon atoms, trifluoromethyl or cyano, X means epoxy, epithio, methylene , a direct bond or a divalent group of formula hi, wherein hydrogen or alkyl having not more than 4 carbon atoms and one of the groups Y and Z means vinyl or epithick and the other means a direct bond, or acid addition salts thereof.

The process according to the invention is characterized in that in reacting a reactive diester of a diethanol of the formula

HO-CH2 CH2-OH

kl Ml s \ / * = \ / y \ R -— ί— I * II i * (II) 2 ·. V · v ν'x ° 'wherein x, y, z and R 2 have the above meanings, with a compound of the formula

Wherein R 1 is as defined above, or b) for the preparation of compounds of formula I wherein R 1 represents the group R 5 having the same meaning as R 1, except for alkanoyloxyalkyl of 4-11 carbon atoms, reduces a compound of formula i1 ° 2o κ \ a

• · = · Y

s \ / \ / N

t · · ·

II II II

2 ·. · · ·

V \ / V

wherein R 1, R 2, X, Y and Z have the above meanings, and one of the two symbols and Q 2 is an oxygen atom and the other is an oxygen atom or 2 hydrogen atoms and, if desired, converts a compound prepared with Formula I wherein R 1 represents hydrogen to a compound of Formula I wherein R 1 has one of the other meanings set forth above acylates a formed compound of Formula I wherein R 2 represents a hydroxyalkyl group of 2-8 carbon atoms, to represents a compound of formula I wherein R 1 represents an alkanoyloxyalkyl group of 3-11 carbon atoms, hydrogenolyses a readily prepared compound of formula I, wherein means a phenylalkyl group of 7 or G carbon atoms, to a compound of formula 1 / wherein is hydrogen, alkylates a compound of formula I wherein X represents a divalent group of the formula

N

wherein R 2 represents hydrogen, to a compound of formula I wherein R 2 represents alkyl of not more than 4 carbon atoms, employs a formed compound of formula I wherein alkoxy of not more than 4 carbon atoms means hydrogen hydrobronic acid to form a compound of formula I, wherein 112 represents hydroxy, forms a prepared compound of formula I wherein R 2 is different from cyan, alkyl of not more than 4 carbon atoms and trifluoromethyl to a compound of formula I wherein R 2 represents cyano and / or cm a prepared free compound to an acid addition salt thereof and / or, if desired, forms a prepared acid addition salt to the free compound or to another acid addition salt and / or, if desired, to a prepared isomer mixture in the individual isomers.

BE Patent Specification No. 814,467 and DE Publication No. 2,503,407 disclose certain tetracyclic piperidine compounds which, in contrast to the present compounds of Formula I, which contain a 7-membered N-ring, contain a corresponding 6-membered N-ring. The present compounds of formula I have a depressive effect on the central nervous system, whereas the above-mentioned known compounds have the opposite effect.

Alkyl groups may be straight-chain 'branches and are e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl. 2 2

Cycloalkylalkyl groups preferably contain 4-8 carbon atoms. Cycloalkylalkyl is e.g. cyclopropylmethyl, cyclobutylmethyl and especially cyclopentylmethyl, cyclohexylmethyl, further, e.g. cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl.

Alkenyl groups R1 contain 3-4 carbon atoms, especially 3 carbon atoms. Alkenyl is e.g. allyl or 2-methylallyl.

In dialkylamyralkyl groups, the nitrogen atom is preferably separated from the ring nitrogen atom by at least 2 carbon atoms. This group contains up to 10 carbon atoms, especially 4-6 carbon atoms. The alkyl groups of these substituents are preferably straight-chain. The whole group is e.g. diethylamino-butyl, 10-propyl or -ethyl, dimethylamino-butyl, -ethyl and especially dimethylaminopropyl.

In hydroxyalkyl groups R 1, the hydroxyl group is preferably separated from the ring nitrogen atom by at least 2 carbon atoms. This group preferably contains 2-6 carbon atoms. The hydroxyalkyl group may be straight chain or branched and is e.g. 1-methyl-2-hydroxyethyl, 2-hydroxypropyl, 1- or 2-methyl-2-hydroxypropyl, especially 2-hydroxyethyl and 3-hydroxypropyl.

In alkoxyalkyl groups, the oxygen atom is preferably separated from the ring nitrogen atom by at least 2 carbon atoms. This group preferably contains from 3 to 6 carbon atoms. Alkoxyalkyl is e.g.

2-methoxypropyl, 2- or 3-ethoxypropyl, 2- or 3-prop-oxypropyl, 3-isopropoxypropyl, especially 2-methoxy- or 2-ethoxyethyl, especially 3-methoxypropyl.

In the alkanoyloxyalkyl groups R 1, the oxygen atom is preferably separated from the ring nitrogen atom by at least 2 carbon atoms. This group is e.g. 2-acetyloxyethyl, 2-propionyloxyethyl, 2-acetyloxypropyl, 2-methyl-3-acetyloxypropyl or 2- or 3-propionyloxypropyl, especially 3-acetyloxypropyl and 3-octanoyloxypropyl.

30 in alkylthioalkyl groups R 1 is preferably separated from the ring nitrogen atom by at least 2 carbon atoms. This group preferably contains from 3 to 6 carbon atoms and is especially methylthio-1-methyl (3-methylthiopropyl).

R 2 in the sense alkyl is e.g. ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, especially methyl. Alkoxy R2 is e.g. ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, especially methoxy. Alkanoyloxy R2 is e.g. formyloxy, propionyloxy, especially acetyloxy, and alkylthio R2 are e.g. ethylthio, propylthio, isopropylthio, butylthio, especially methylthio.

R 1 in the sense alkyl is e.g. propyl, butyl, isobutyl, especially methyl or ethyl.

. Preferably, Y is a direct bond and Z is vinylene or epithio.

Salts of compounds of formula I are pharmaceutically useful acid addition salts, e.g. with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid or phosphoric acid, or with organic acids such as organic carboxylic and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic acid, malic acid, tartaric acid, lactic acid, lactic acid , oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid or embonic acid.

The present azatetracyclic compounds of general formula I and their acid addition salts have valuable pharmacological properties and act e.g. on the central nervous system. They are first and foremost distinguished by centrally attenuating, amphetamine antagonistic effects, which can be demonstrated by pharmacological tests. Thus, in rats in the amphetamine antagonism test (Niemegeers and Janssen, Arzneimittelforsch., Vol. 24, p. 45 (1974)), they show a dose range of 0.1 to 25 mg / kg i.p. or per 30 ounces an inhibitory effect. The cataleptic effect is relatively poor relative to the amphetamine antagonistic effect. Accordingly, the aforementioned azatetracyclic compounds of general formula I and their pharmaceutically useful acid addition salts can be used as tranquilizers, antipsychotics and mood inhibitors to treat mood states.

The amphetamine antagonistic action of the compounds of the present invention is determined by the method of Niemegeers and Janssen, Arzneimittelforsch-, Vol. 24, p. 45 (1974). The results are given in the table below.

Table 10 Compound Amphetamine antagonism in rats i.p.

RcgAg I 3-Methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] -thiepino [4,5-d] -azepine methanesulfonate 0.7 II 3-Methyl-2 3,4,5-tetrahydro-1H-dibenz [2,3: 6,7] oxepino [4,5-d] azepine hydrochloride 0.55 III 3-Ethyl-2,3,4,5- tetrahydro-1H-dibenzo (3,4: 6,7] -cyclohepta [1,2-d] azepinamethanes ul femate 1,4 IV 3-Methyl-1,2,3,4,5,10-hexahydro -dibenz [b, f] - azepino [4,5-d] azepine methanesulfonate 0.7 V 3-Methyl-2,3,4,5-tetrahydro-1H-dibenzo [3,4: 6,7] - Cyclchepta [1,2-d] azepine methanesulfonate hemihydrate 0.6 VI 3-Methyl-7-chloro-2,3,4,5-tetrahydro-1H-dibenzo- [2,3: 6,7] thiepino [4,5-d] azepine hydrochloride 0.16 VII 3-Methyl-2,3,4,5-tetrahydro-1H-thieno (2 ', 31: 2,3] - [1] benzothiepino [4,5 -d] azepine methanesulfonate 0.55 VIII 3-Cyclopentylmethyl-2,3,4,5-tetrahydro-1H-di benzo- (2,3: 6,7] thiepino [4,5-d] azepine methanesulfonate 1.3 IX 3- (2,3,4,5-Tetrahydro-1H-dibenzo [2,3: 6,7] Thiepino [4,5-d] azepin-3-yl) propanol methanesulfonate 1.2 X 3-Methyl 1-7-cyano-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5] -Dazazepine Methanesulfanate 0.18 XI 3,10-Dimethyl 1-1,2,3,4,5,10-hexahydro-dibenz [b, f] azepino [4,5-d] azepine methanesulfonate 0.7 XII (3-Methyl) - (7-chloro) -2,3,4,5-tetrahydro-1H-dibenz [2,3: 6,7] oxepino (4,5-d] azepine hydrochloride 0.08 . \ * · · 7 150301

Compound in Nphetamine Antagonism in Rats i.p.

-XIII 3-Cyclopentylmethyl-7-cyano-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine methanesulfonate 0.75 XIV 3- Propyl 2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] 5 thiepino [4,5-d] azepine methanesulfonate 2,4 XV 3-Ethyl-7-cyano-2 , 3,4,5-tetrahydro-1H-di benzo [2,3: 6,7] thiepino [4,5-d] azepine 1,3

In particular, the process of the invention prepares compounds of formula I wherein hydrogen, alkyl, methyl or ethyl, cycloalkylalkyl of 4-8 carbon atoms, e.g. cyclopentylmethyl and cyclohexylmethyl, allyl, propargyl, dialkylaminoalkyl, e.g. dimethylaminoethyl and 3-dimethylaminopropyl, hydroxyalkyl, e.g. 2-hydroxyethyl and 3-hydroxypropyl, alkoxyalkyl, e.g. 3-15 methoxypropyl, alkanoyloxyalkyl, e.g. acetoxypropyl and octanoyloxypropyl, alkylthioalkyl, e.g. 2-methylthioethyl and 3-methylthiopropyl, benzyl or phenylethyl, R 2 is H, chlorine, bromine, methyl, hydroxy, methoxy, methylthio or cyan, X means epoxy, epithio, methylene or the divalent group of partial formula (la) R 3 wherein R 1 is hydrogen, methyl or ethyl, Y is a direct bond, and z is vinylene or epithio, and pharmaceutically useful acid addition salts thereof. 1 2 3 4 5 5

Above all, compounds of formula I are prepared wherein 2 is methyl, ethyl or cyclopentylmethyl, R 2 is H, chloro, 3

methyl, methoxy or cyano, preferably in the 7-position, X

4 is epoxy, epithio or methylene or the divalent group 5 of partial formula 8 150301

V

In (1a) R 3 wherein is hydrogen, methyl or ethyl, Y is a direct bond and Z is vinylene or epithio such as 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6 , 7] thiepino [4,5-d] -5 azepine, 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine, 3-methyl-7-cyano-2,3,4,5-tetrahydro-ΙΗ-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, 3-methyl-1,2, 3, 4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [1,2-d] azepine or 3- (2,3,4,5-tetrahydro-1H-dibenzo [2,3 : 6,7] thiepino-10 [4,5-d] azepin-3-yl) propanol, and pharmaceutically useful acid addition salts thereof.

In process a), as reactive diesters of a diethanol of formula II, esters of strong inorganic acids such as the bis-hydrogen chloride or bis-hydrogen iodide ester or especially the bis-hydrogen bromide ester or hydrogen bromide-hydrogen chloride ester can be used. Furthermore, similar diesters of strong organic acids, e.g. of sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-chloro- or p-bromo-benzenesulfonic acid or 20 p-toluenesulfonic acid. These diesters of compounds of formula II are preferably reacted in a suitable inert solvent at a reaction temperature of 20 to 130 ° C. For example, as inert solvents are hydrocarbons such as benzene or toluene, halohydrocarbons such as chloroform, lower alcohols such as ethanol and especially methanol, ether-like liquids such as ether or dioxane, and lower alkanones, e.g. acetone, methyl ethyl ketone or diethyl ketone, or mixtures of such solvents, e.g. benzene-methanol. 1 by reacting a molar equivalent diester of a diethanol of formula II with a molar equivalent free base of formula III, two molar equivalent of acid, which is preferably bound to an acid binding agent, is cleaved. Suitable as acid binding agents, e.g. alkali metal carbonates such as potassium carbonate, or e.g. alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, or excess base of formula III, and further tertiary organic bases such as pyridine and especially triethylamine or N-ethyl diisopropylamine.

The immediate starting substances, i.e., the reactive diesters of formula II, can be prepared from the corresponding diethanols by esterification or replacement of hydroxyl groups 10 with halogen by conventional methods. The diethanols can be prepared from the corresponding diacetic acid methyl esters by reduction with lithium aluminum hydride. The acetic acid methyl esters can be prepared from the corresponding diacetonitriles with methanol and 2 molar equivalents of water with the addition of hydrogen chloride. The diacetonitriles can be obtained from the corresponding bis (bromomethyl) compounds and sodium cyanide.

In process b), the reduction of a compound of formula IV is advantageously carried out by a complex hydride such as lithium aluminum hydride or diborane or aluminum hydride. As an solvent, an ethereal liquid such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether are preferably used. The reaction temperature is preferably between ca. 0 and 100 ° C, respectively, at the boiling temperature of the reaction medium used. The diborane can either be prepared separately and fed or formed in situ by sodium, borohydride and boron trifluoride etherate. An activator such as aluminum chloride may also be used for the reaction with lithium aluminum hydride.

N-Substituted lactam and imide compounds as starting substances of formula IV can be prepared by substituting the corresponding compounds of formula IV which are not N-substituted.

This N substitution can be done by known methods, e.g. with a reactive ester of a corresponding hydroxyl compound of formula R R -OH wherein R R | has the above meaning with the exception of hydrogen.

150301 ίο

The imides of formula IV, which are not N-substituted, can be prepared from the corresponding diacetonitriles by forming the azepine ring with hydrogen bromide and subsequent treatment with water and dimethylformamide. Of these, however, by partial reduction by means of a complex hydride in an ethereal solvent such as diethyl ether or tetrahydrofuran, the corresponding lactams can be prepared.

In addition to the reactions, the following conversions may be made which transfer the compounds of formula I to other compounds of formula I.

Optionally, a compound of formula I wherein the group is hydrogen may be converted to a compound of formula I wherein the group R 1 has one of the other meanings.

Thus, e.g. an N-substitution occurs, either with a reactive ester of a corresponding alcohol of formula R ^ IV-OH, wherein R ^ IV bears the same meaning as R ^ in formula I, except hydrogen, or by reaction with corresponding aldehydes or ketones under reducing conditions.

The reaction of compounds of formula I wherein R 1 is hydrogen with a reactive ester of a hydroxyl compound of formula RIV-OH is preferably carried out in a solvent at a reaction temperature of 20-130 ° C, especially at the boiling temperature of the solvent. 1 2 3 4 5 6

As reactive esters, e.g. halides such as chlorides or bromides, sulfonic acid esters, 3 such as o- or p-toluenesulfonic acid methyl ester or ethyl ester, or sulfuric acid esters such as dimethyl or diethyl sulfate are used. Suitable as acid binding agents are alkali metal carbonates such as potassium carbonate or alkali metal hydroxides such as sodium hydroxide or tertiary organic bases such as pyridine or N-ethyl diisopropylamine. Suitable solvents are those solvents which are inert under the reaction conditions, for example hydrocarbons such as benzene or toluene, further alkanols such as methanol or ethanol, or alkanones such as acetone or methyl ethyl ketone.

Aldehydes and ketones corresponding to the alcohols of Form IV

5 R len -OH, for example, are similar aliphatic aldehydes or ketones, corresponding to free, esterified or etherified hydroxyaxoalkanes or esterified oxoalkanecarboxylic acids. The reaction product obtained by reacting these aldehydes or ketones with said compounds of formula I can be reduced in the same operation or in connection therewith.

The aldehydes, e.g. formaldehyde or acetaldehyde, or the ketones, e.g. acetone, is heated, for example, with said compounds of formula I in an inert solvent to ca. The reaction mixture is hydrogenated with hydrogen in the presence of a catalyst. Suitable solvents are e.g. alkanols such as methanol or ethanol, and suitable catalysts precious metal catalysts such as palladium-on-carbon, or alloy skeletal catalysts such as Raney nickel.

Instead of hydrogen in the presence of a catalyst, other reducing agents, e.g. formic acid, for the reductive alkylation. According to this variant of the process, said compounds of formula I are heated with formic acid and said types of aldehydes or ketones, especially formaldehyde, preferably without solvent.

However, this N-substitution with alkyl can also be done by first acylating the process product in which the group R 1 represents hydrogen and then reducing the carbonyl group. This reduction is advantageously accomplished by a complex hydride such as lithium aluminum hydride or diborane. As an solvent, an ethereal liquid such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether is preferably used. The reaction temperature is preferably between ca. 0 and 100 ° C respectively.

in the boiling temperature of the reaction medium used. The diborane can either be prepared separately and fed or formed in situ by sodium borohydride and boron trifluoride etherate.

Furthermore, a compound of formula I, whose group 5 is a hydroxyalkyl group, may optionally be acylated to a compound whose group means an esterified hydroxyalkyl group.

The acylation may e.g. is carried out with a carboxylic anhydride or with a corresponding carbonyl halide at a reaction temperature of between ca. 20 and 100 ° C. Since the condensation takes place during acid decomposition, it is convenient to add an acid binding agent to the reaction mixture, e.g. a tertiary organic base such as pyridine. Excess tertiary organic bases can also be used as a solvent. Furthermore, as a solvent, hydrocarbons may be used, e.g. benzene or toluene, or halohydrocarbons, e.g. chloroform.

Further, a compound of formula I, whose group R 1 is a phenylalkyl group, may be optionally hydrogenolysed to a process product wherein R 1 is hydrogen.

The hydrogenolysis can be carried out using conventional hydrogenation catalysts, for example, precious metal catalysts such as palladium on carbon or platinum oxide, rhodium catalysts such as rhodium on coal or on alumina, or alloy skeletal catalysts such as Raney nickel, in an inert organic solution. , such as methanol, ethanol or dioxane, at room temperature and normal pressure or moderately elevated temperatures up to approx. 100 ° C and / or elevated pressure until approx. 100 atmosphere.

Further, a compound of formula I wherein X is a 30 divalent group of partial formula Λ / (1a) R 3 \ 13 150301 and wherein hydrogen is optionally transferred to another process product of formula I wherein R 1 is alkyl.

This conversion is preferably done by reacting the above process product in the presence of solvents and basic condensing agents with a reactive corresponding alkyl ester.

As reactive esters, e.g. halides such as chlorides or bromides, sulfonic acid esters such as o- or p-toluenesulfonic acid methyl ester or ethyl ester, or sulfuric acid esters such as dimethyl or diethyl sulfate are used. Suitable alkaline condensing agents are alkali metal alkanolates such as potassium tert-butylate or similar amides such as sodium amide or metal hydrides such as sodium or lithium hydride. Suitable solvents are such solvents which are inert under the reaction conditions, for example hydrocarbons such as benzene or toluene, in addition ether-like liquids, e.g. tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, or amides such as phosphoric acid hexamethyl triamide or dimethylformamide.

However, this conversion can also be done by first acylating the above process product and then reducing the carbonyl group.

This reduction is preferably carried out by means of a hydride.

As the hydride, diborane is preferably used in an ethereal reaction medium, such as tetrahydrofuran, dioxane, ethylene glycoliraethyl ether or diethylene glycol dimethyl ether. The reaction temperature is, for example, at -20 to 80 ° C, preferably between 0 ° C and room temperature. The required diborane is formed, for example, from boron trifluoride etherate and sodium borohydride either separately, e.g. in the solvent used for the reduction, and is used as a solution, or is formed, for example, in diethylene glycol dimethyl ether and is fed to the reaction mixture as a gas, or it is formed in situ.

14 150301

Depending on the process conditions and the starting materials, the final products are optionally obtained in free form or in the form of their salts, which can be converted into each other or into other salts in the usual way. Thus, free compounds of formula I are formed of acid addition salts obtained, e.g. by treatment with bases or basic ion exchangers, while e.g. transfer free bases of formula I to acid addition salts by reaction with organic or inorganic acids suitable for the formation of pharmaceutically useful salts such as those mentioned above.

Due to the close connection between the compounds in question in free form and in the form of their salts, in the foregoing and hereafter, compounds with regard to meaning and purpose may also mean the corresponding salts.

Conveniently, the starting materials are used for carrying out the process according to the invention, which leads to the groups of end products specifically mentioned in the introduction and in particular to the specially described or highlighted end products.

The compounds of the invention may e.g. find use in the form of pharmaceutical compositions containing an effective amount of the active substance, optionally together with inorganic or organic, solid or liquid pharmaceutically useful carriers, and suitable for enteral, e.g. oral or parenteral administration. The dosage depends on the mode of application and on the nature, age and individual condition. The daily doses of the free bases or of pharmaceutically usable salts thereof range between approx. 0.1 and 10 mg / kg for 30 warm-blooded animals or humans in general and approx.

0.01 g to 0.5 g for warm blooded animals or humans weighing approx. 70 kg.

The process according to the invention is illustrated in more detail in the following examples.

· '/.

15 150301

Example 1

To a solution of 21.8 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenzo [a, d] cyclohepten in 200 ml of absolute ethanol is added 35 ml (2.6 g, 0.06 mol) of a 7.4% ethanolic ethylamine solution and 15.5 g (0.125 mol) of diisopropylethylamine are boiled under reflux for 18 hours. The reaction mixture is then evaporated in water jet vacuum, the residue is dissolved in 300 ml of methylene chloride and the solution is washed with 100 ml of 2 N 10 sodium hydroxide solution and then with 100 ml of water. The methylene chloride solution is evaporated in water jet vacuum to ca.

50 ml, and 15 ml of 4 N ethereal hydrogen chloride solution are added, whereby 3-ethyl-1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [1, 2-d] azepine hydrochloride, m.p.

15 296-299 ° C crystallizes.

f2H5 / x ΑΑΛ

Mp. of the methanesulfonate: 220-221 ° c.

The starting material can be prepared as follows, namely by analogy with the statements of Example 5: 20 Of 27 g (0.1 mole) of 5H-dibenzo [a, d] cyclohepten-10,11-diacetonitrile, 400 ml of methanol, 3, 8 ml of water and dry hydrogen chloride 5H-dibenzo [a, d] cyclohepten-10,11-acetic acid dimethyl ester, m.p. 104-106 ° C (from hexane).

Of 33.6 g (0.1 mole) of 5H-dibenzo [a, d] cyclohepten-10,11-diacetic acid dimethyl ester and 7.6 g (0.2 mole) of lithium aluminum hydride in 1 liter of absolute diethyl ether 5H-dibenzo [a, d] cyclo-hepten-10,11-diethanol, m.p. 154-156 ° C (from acetone).

To a solution of 28.0 g (0.10 mol) of 5H-dibenzo [a, d] cyclo-hepten-10,11-diethanol in 120 ml of pyridine is added dropwise at a reaction temperature of -5 ° C 16.8 ml (25.2 g, 0.22 mol) of methanesulfonic acid chloride. Then stir for 30 minutes at 0 ° C and for 1 hour at 15-25 ° C. The reaction mixture together with 600 ml of methylene chloride is shaken in a separatory funnel with 400 ml of 5 N hydrochloric acid and then with 400 ml of ice water. The methylene chloride solution is separated, dried over magnesium sulfate and evaporated in water jet vacuum. As the residue, 10,11-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenzo [a, d] cyclohepten remains as a colorless viscous oil.

Analogously can be prepared: 3-Methyl-1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta- [1,2-d] azepine methanesulfonate, m.p. 189-191 ° C, from 21.8 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenzo [a, d] cycloheptane, 30 ml (1 , 9 g, 0.06 mol) of a 6.3% ethanolic methylamine solution and 15.5 g (0.125 mol) of di-isopropylethylamine.

3-Benzyl-1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta- [1,2-d] azepine hydrochloride, m.p. 265-270 ° C, from 21.8 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenzo [a, d] cyclohepten, 6.2 g (0.06 mol) benzylamine and 15.5 g (0.125 mol) diisopropylethylamine.

Example 2

A suspension of 19.4 g (0.05 mol) of 3-benzyl-1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [1,2-d] azepine hydrochloride and 2 g of 5% Palladium-on-coal in 900 ml of methanol are hydrogenated at normal pressure and 40-50 ° C to take up 770 ml of hydrogen.

The catalyst is then filtered off under suction and the filtrate is evaporated in water jet vacuum.

17 150301

The residual crude 1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [1,2-d] azepine hydrochloride is recrystallized from ethanol. Mp. 295-300 ° C.

To release the base, the hydrochloride is suspended in 250 ml of 5 methylene chloride and shaken with 100 ml of wife. ammonia solution. The methylene chloride solution is separated and evaporated to begin crystallization. Hexane is then added to give 1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta- [1,2-d] azepine, m.p. 190-191 ° C crystallizes.

10 For transfer to methanesulfonate, the free base is dissolved in methylene chloride added to the theoretical amount of methane: sulfonic acid and 1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclo hepta [1 , 2-D] azepine-methanesulfonate is precipitated with ether, m.p. 269-271 ° C.

Example 3

To a solution of 43.6 g (0.1 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenzo [a, d] cycloheptane in 400 ml of absolute ethanol is added 11, 9 g (0.12 mol) (aminomethyl) cyclopentane and 32.3 g (0.25 mol) diisopropyl-ethylamine, and the reaction mixture is refluxed for 20 hours. The reaction mixture is then evaporated in a water-jet vacuum, the residue is dissolved in 150 ml of methylene chloride and 500 ml of pentane, and this solution is washed with 200 ml of 2 N sodium hydroxide solution and then with 200 ml of water. Then, 200 ml of 2N hydrochloric acid are added to the organic phase, whereby the hydrochloride is separated into grains. The crystals are filtered off with suction and to release the base, the hydrochloride is suspended in 300 ml of methylene chloride and shaken with 100 ml of wife. ammonia solution. The methylene chloride solution is separated and evaporated to begin crystallization. Hexane is then added to give 3- (cyclopentylmethyl) -1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [1,2-d] azepine, m.p. 141-142 ° C crystallizes. For transfer to the methanesulfonate, the base is dissolved in methylene. in chloride, the theoretical amount of methanesulfonic acid is added and 3- (cyclopentylmethyl) -1,2,3,4,5,10-hexahydro-dibenzo- [3,4: 6,7] cyclohepta [1,2-d ] azepine methanesulfonate precipitates with ether, m.p. 248-249 ° C.

Example 4

To 26.1 g (0.1 mole) of 1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] -cyclohepta [1,2-d] azepine (prepared according to Example 2 ), under ice-cooling, 92 g (2 moles) of formic acid and 20 g (0.2 moles) of 30% formaldehyde are added and stirred for one hour at 95-100 ° C.

10 Then the mixture is poured onto ice water and made alkaline with 10 N sodium hydroxide solution. The separated base is taken up in methylene chloride and the methylene chloride solution is evaporated to begin crystallization. Hexane is then added to give 3-methyl-1,2,3,4,5,10-hexahydro-dibenzo-15 [3,4: 6,7] cyclohepta [1,2-d] azepine, m.p. 144-146 ° C out stall. For transfer to methanesulfonate, the base is dissolved in methylene chloride, the theoretical amount of methanesulfonic acid is added and 3-methyl-1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [1,2 -d] azepine methanesulfonate is precipitated with ether, 20 m.p. 189-191 ° C.

Example 5

To a solution of 4.56 g (0.01 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -dibenzo [b, f] thiepine in 50 ml of absolute ethanol is added 1.3 g (0.012 mol) benzylamine and 3.25 g (0.025 mol) diisopropyl-ethylamine, and the reaction mixture is refluxed for 18 hours. After cooling by an ice bath, crystals are filtered off which are filtered off under suction and washed with a little 2-propanol and pentane. The filtered material is 3-benzyl-2,3,4,5-30 tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, m.p. 149-150 ° C.

t.

19: '19 150301

P

CH ~

N

('Ί ccc \ Jy Γ r. 1' 1) To transfer to hydrochloric acid, dissolve 3.0 g of the base in 100 ml of acetone and add, while stirring, 2.2 ml of a

4 N solution of hydrogen chloride in ether and then add 5 much ether to make the solution slightly cloudy. 3-Benzyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino- [4,5-d] azepine hydrochloride is allowed to crystallize, m.p. 241-242 ° C

The starting material can be prepared as follows: 58 g (0.2 mole) of dibenzo [b, f] thiepin-10,11-diacetonitrile is suspended with stirring in 800 ml of methanol and 7.5 ml of water and cooled in an ice bath to 0-5 ° C. Then, for 1 hour, dry hydrogen chloride is allowed to give a clear solution.

The temperature must be kept at 5-20 ° C during the supply. Then, the reaction mixture is stirred for 1 hour at room temperature. 15 hours and then for 4 hours under reflux, then evaporate completely on rotary evaporator. The residue is dissolved in ether and the ether solution is washed with water and 2N sodium carbonate solution and evaporated completely after drying over sodium sulfate. The oily residue is dissolved in methanol and cooled to 0 ° C, then dibenzo [b, f] thiepin-10,11-diacetic acid methyl ester crystallizes, which after filtration is filtered off under suction and dried at 50 ° C under reduced pressure at 84 -86 ° C.

. i, - / 5 • 1 "» 150201 20

To a suspension of 7.6 g (0.2 mole) of lithium aluminum hydride in 400 ml of absolute diethyl ether, a solution of 35.4 g (0.1 mole) is added dropwise with stirring and exclusion of moisture and in a nitrogen atmosphere. dibenzo [b, f] -5 thiepin-10,11-diacetic acid dimethyl ester in 1 liter of absolute diethyl ether and then reflux the reaction mixture for 16 hours. After cooling to 0-5 ° C, 130 ml of water is added dropwise to the reaction mixture and the organic phase is then separated. It is washed with water 10 and evaporated after drying over sodium sulfate to a small volume, whereby dibenzo [b, f] thiepin-10,11-diethanol with m.p. 131-133 ° C crystallizes.

15 g (0.05 mole) of dibenzo [b, f] thiepin-10,11-diethanol are dissolved at room temperature in 60 ml of pyridine and added under stirring in an ice-sodium chloride bath at a reaction temperature of -5 ° C dropwise 8.4 ml (12.6 g, 0.11 mol) of methanesulfonic acid chloride. The reaction mixture is then stirred for 30 minutes at 0 ° C and then for 1 hour at 15-25 ° C. The mixture is then shaken with 500 ml of methylene chloride in a separating funnel 20 with 400 ml of 2N hydrochloric acid and then with 400 ml of water. The methylene chloride solution is separated, dried over magnesium sulfate and evaporated in water jet vacuum. As the residue, 10,11-bis- [2- (methylsulfonyloxy) -ethyl] -dibenzo [b, f] -thiepine remains with m.p. 107-108 ° C.

Example 6

Analogously to Example 5, the following compounds can be prepared using the corresponding starting materials: A) of 22.7 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) -ethyl] dibenzo [b, f] thiepine, 7.3 g (0.06 mol) of 2-phenylethyl-amine and 16.25 g (0.125 mol) of diisopropylethylamine in absolute ethanol 3- (2-phenylethyl) -2,3,4,5-tetrahydro-1H -dibenzo- [2,3: 6,7] thiepino {4,5-d] azepine, m.p. 96-99 ° C (from acetonitrile), methanesulfonate m.p. 161-164 ° C (from absolute ethanol), 21.2 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-methoxy-dibenzo [b, f] thiepine, 1.85 gm of methylamine (0.06 mole) and 16.25 g (0.125 mole) of diisopropylethylamine in absolute ethanol 7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, m.p. 108-112 ° C (from acetone), hydrochloride m.p. 220-224 ° C (from absolute ethanol), C) of 25.0 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-methylthio-dibenzo [b, f] thiepin, 6.0 g (0.06 mol) of 10 (aminomethyl) -cydopentane and 16.25 g (0.125 mol) of diisopropylethylamine in absolute ethanol 7-methylthio-3- (cyclopentylmethyl) -2,3,4,5 -tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, crude product, methanesulfonate m.p. 206-209 ° C (from absolute ethanol),

D) of 23.4 g (0.05 mol) of 10, II-bis- [2- (methylsulfonyloxy) ethyl] -2-methyl-dibenzo [b, f] thiepine, 1.85 g (0.06 mole) methylamine and 16.25 g (0.125 mole) diisopropylethylamine in absolute ethanol 3,7-dimethyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] -thiepino [4,5 -d] azepine, crude product, hydrochloride m.p. 265-268 ° C

20 (from absolute ethanol), E) of 26.7 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-bromo-dibenzo [b, f] thiepine, 1, 85 g (0.06 mole) of methylamine and 16.25 g (0.125 mole) of diisopropylethylamine in absolute ethanol 7-bromo-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6, 7] - 25 thiepino [4,5-d] azepine, crude product, hydrochloride m.p. 280 ° C (under decomposition) (from absolute ethanol), F) of 21.1 g (0.05 mole) of 9,10-bis [2- (methylsulfonyloxy) ethyl] phenanthrene, 1.85 g (0) , 06 mol) of methylamine and 16.25 g (0.125 mol) of diisopropylethylamine in absolute ethanol 3-methyl-2,3,4,5-tetrahydro-1H-phenanthro (9,10-d] azepine, mp 142-145 ° C (from acetone), methanesulfonate, mp 242-244 ° C (from ethanol), i.f. 22 CH (/ G) of 21.4 g (0.05 mole) of 4,5-bis- 2- (methylsulfonyloxy) -ethyl] -naphtho [1,2-b] thiophene, 1.85 g (0.06 mol) of methylamine © g 16.25 g (0.12'S mol) of diisopropylethylamine 3-methyl-2, 3,4, 5 5-Tetrahydro-1H-thieno [2 ', 3': 1,2] naphtho [4,5-d] azepine, crude product, hydrochloride m.p. 273-280 ° C (under decomposition) (from methanol), CHO I 3

A

<Z> <7> H) of 21.9 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) -10 ethyl J-dibenzo [b, floxepine, 1.85 g (0.06 mole) ) methylamine and ~ Y 16.25 g (0.125 mol) of diisopropylethylamine 3-methyl-2,3,4,5-. tetrahydro-1H-dibenz [2,3: 6,7] oxepino [4,5-d] azepine, m.p.

147-149 ° C (from acetonitrile), hydrochloride m.p. 282-285 ° C (from absolute ethanol), CH

A

15 aKa

M

of 21.9 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -dibenz [b, f] oxepine, 3.5 g (0.06) isopropylamine and 16.25 g (0.125 mol) diisopropylethylamine 3-isopropyl-2,3,4,5-tetrahydro-1H-dibenz [2,3: 6,7] oxepino [4,5-d] azepine, 5 mp. 125-128 ° C (from acetonitrile), maleate m.p. 175-177 ° C (from acetone), K) of 23.3 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -5-ethyl-5H-dibenz [b, f ] azepine, 1.85 g (0.006 mol) of methylamine and 16.25 g (0.125 mol) of diisopropylethylamine 3- 10 methyl-10-ethyl-1,2,3,4,5,10-hexahydro-dibenz [b, f ] azepino- [4,5-d] azepine, m.p. 99-100 ° C (from toluene), oxalate m.p. 180-183 ° C (from absolute ethanol), CH, 11 µL 1 / c 2 H 5 L) of 23.3 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) -; Ethyl] -5-ethyl-5H-dibenz [b, f] azepine, 3.4 g (0.06 mole) of allyl amine and 16.25 g (0.125 mole) of diisopropylethylamine 3-allyl-10-ethyl-1 , 2,3,4,5,10-hexahydro-dibenz [b, f] azepino [4,5-d] azepine,

mp. 100-101 ° C (from hexane), hydrochloride m.p. 245-248 ° C

(from absolute ethanol / acetone), 1 2 3 4 5 6 M) of 21.9 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) -2 ethyl] -5H-dibenz [b, f] azepine, 1.85 g (0.06 mol) of methylamine and 3.25.25 g (0.125 mol) of diisopropylethylamine 3-methyl-1,2,3,4,5,4

10-hexahydro-dibenz [b, f] azepino [4,5-d] azepine, m.p. 121-124 ° C

5 (from methanol), methanesulfonate m.p. 263-266 ° C (from absolutely 6 ethanol / acetone), and 24 150301 N) of 21.9 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenz [ b, f] azepine, 6.0 g (0.06 mol) (aminomethyl) cyclopentane and 16.25 g (0.125 mol) diisopropylethylamine 3- (cyclopentylmethyl) -1,2,3,4,5,10-hexahydro -dibenz [b, f] aze-pino [4,5-d] azepine, m.p. 72-75 ° C (from pentane), methanesulfonate m.p. 271-274 ° C (from methanol).

The starting materials can be prepared as follows:

To B) of 42.3 g (0.1 mole) of 2-methoxy-10,11-bis (bromomethyl) dibenzo [b, f] thiepine and 11.8 g (0.24 mole) of sodium cyanide in 10,500 ml of acetonitrile 2-methoxy-dibenzo [b, f] thiepin-10,11-diacetonitrile, m.p. 198-200 ° C (from acetonitrile), of 31.8 g (0.1 mole) of 2-methoxy-dibenzo [b, f] thiepin-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride 2-methoxy-dibenzo [b, f] thiepin-10,11-diacetic acid dimethyl ester, m.p. 96-98 ° C (from toluene), of 38.5 g (0.1 mole) of 2-methoxy-dibenzo [b, f] thiepin-10,11-diacetic acid dimethyl ester and 7.6 g (0.2 mole) ) lithium aluminum hydride in 1 liter of absolute diethyl ether 2-methoxy-dibenzo [b, f] thiepin-10,11-diethanol, m.p. 116-119 ° C (from 20 ethyl acetate / hexane), of 32.8 (0.1 mol) of 2-methoxy-dibenzo [b, f] thiepin-10,11-diethanol, 25.2 g (0.22 mol ) methanesulfonic acid chloride in 120 ml of pyridine 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-methoxy-dibenzo [b, f] thiepine, crude product, 25 to C) of 44.2 g (0, 1 mole) of 2-methylthio-10,11-bis- (bromomethyl) -dibenzo [b, f] thiepine and 11.8 g (0.24 mole) of sodium cyanide in 500 ml of acetonitrile 2-methylthio-dibenzo [b, f] -thiepin-10,11-diacetonitrile, m.p. 204-206 ° C (from ethyl acetate), 1 of 33.4 g (0.1 mole) of 2-methylthio-dibenzo [b, f] thiepin-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml water and dry hydrogen chloride 2-methylthio-dibenzo [b, f] thiepin-10,11-diacetic acid dimethyl ester, m.p. 85-86 ° C (from pentane), of 40.0 g (0.1 mole) of 2-methylthio-dibenzo [b, f] thiepin-10,11-diacetic acid dimethyl ester and 7.6 g (0.2 mole) ) lithium aluminum hydride in 1 liter of absolute diethyl ether 2-methylthio-dibenzo [b, f] thiepin-10,11-diethanol, m.p. 58-60 ° C (from diethyl ether), of 34.5 g (0.1 mole) of 2-methylthio-dibenzo [b, f] thiepin-10,11-diethyl, 25.2 g (0.22 mole) of methanesulfonic acid chloride in 120 ml of 10 pyridine 10,11-bis- (2- (methylsulfonyloxy) ethyl] -2-methylthio-dibenzo [b, f] thiepine, crude product, to D) of 41.0 g (0.1 mol ) 2-methyl-10,11-bis (bromomethyl) -dibenzo [b, f] thiepine and 11.8 g (0.24 mol) of sodium cyanide in 500 ml of acetonitrile 2-methyl-dibenzo [b, f] thiepin 10,11-diace-15 tonitrile, m.p. 198-200 ° C (from acetonitrile), of 30.2 g (0.1 mole) of 2-methyl-dibenzo (b, f] thiepin-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride 2-methyl-dibenzo [b, f] thiepin-10,11-diacetic acid dimethyl ester, mp 76-77 ° C (from methanol), 20 of 36.9 g (0.1 mole) 2 -methyl-dibenzo [b, f] thiepin-10,11-acetic acid dimethyl ester and 7.6 g (0.2 mole) of lithium aluminum hydride in 1 liter of absolute diethyl ether 2-methyl-dibenzo [b, f] - / in thiepin-10,11-diethanol, mp 126-129 ° C (from acetonitrile), of 31.2 g (0.01 mol) of 2-methyl-dibenzo [b, thiepin-10, 11-di -25 ethanol, 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-methyl-dibenzo [b, f] thiepine, crude product, to E) of 47.5 g (0.1 mole) of 2-bromo-10,11-bis (bromomethyl) di-benzo [b, f] thiepine and 11.8 g (0.24 mole) of sodium cyanide in 500 30 ml of acetonitrile 2-bromo-dibenzo [b, f] thiepin-10,11-diacetonitrile, m.p. 200-204 ° C (from acetonitrile), 2 vs · W / * 26 150 g of 36.7 g (0.1 mole) of 2-bromo-dibenzo [b, f] thiepin-10,11-diaceto-nitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride 2-bromo-dibenzo (b, f] thiepin-10,11-diacetic acid dimethyl ester, mp 90-93 ° C (from absolute ethanol), 5 of 34.3 g (0.1 mole) of 2-bromo-dibenzo [b, f] thiepin-10,11-diacetic acid dimethyl ester and 7.6 g (0.2 mole) of lithium aluminum hydride in 1 liter of absolute diethyl ether 2-bromo-dibenzo [b, f] -thiepin-10,11-diethanol, mp 166-169 ° C (from diethyl ether), of 37.7 g (0.1 mole) of 2-bromo-dibenzo [b, f] thiepin-10 11-di-10-ethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-bromo-dibenzo [b, f] thiepine , mp 94-96 ° C (from benzene ether), to F) of 25.6 g (0.1 mole) of phenanthrene-9,10-diacetonitrile (cf. S. Hauptmann, Chem. Ber. 93 2604 (1960)), 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride phenanthrene-9,10-diacetic acid dimethyl ester, m.p. 143-145 ° C (from methanol), of 32.2 g (0.1 mole) of phenanthrene-9,10-diacetic acid dimethyl ester and 7.6 g (0.2 mole) of lithium aluminum hydride in 1 liter of absolute diethyl ether phenanthryl -9,10-diethanol, m.p. 175-177 ° C 20 (from methanol), of 26.6 g (0.1 mole) of phenanthrene-9,10-diethanol and 25.2 g (0.22 mole) of methanesulfonic acid chloride in 120 ml of pyridine 9,10-bis - [2- (methylsulfonyloxy) -ethyl] -phenanthrene, m.p. 157-159 ° C (from acetonitrile), 1 2 3 4 5 6 to G) 122 g (0.5 mole) of 4,5-dimethylbenzo [f] thieno [2,3-b] - 2 thiepin (cf. (Danish Patent No. 124,689), 980 ml of 3 ethylene glycol and 100 g of potassium hydroxide are boiled under stirring 4 and in a nitrogen atom for 2 hours under reflux.

5

The mixture is then cooled to 20 ° C: diluted with 6,800 ml of water and extracted with petroleum ether. The organic phase is separated, washed with water, dried over sodium sulfate and evaporated. The residue 4,5-dimethyl-naphtho- [1,2-b] thiophene melts after recrystallization from methanol at 88-90 ° C, 106 g (0.5 mole) of 4,5-dimethyl-naphtho [1, Dissolve 2-b] thiophene in 2.5 liters of carbon tetrachloride and 178 g (1 mole) of N-bromosuccinimide are added. With stirring and in a nitrogen atom, the mixture is heated under illumination with a UV lamp for 5 boiling. It is kept boiling until all the N-succinimide lying on the bottom of the container is converted into the succinimide swimming on the solution, duration approx. 20 minutes.

400 ml of water are then added to the mixture and the crystallized 4,5-bis- (bromomethyl) -naphtho [1,2-b] thio-10-filtrate is filtered off, m.p. 202-204 ° C; of 37.0 g (0.1 mole) of 4,5-bis-bromomethyl-naphtho [1,2-b] thio

phen, and 11.8 g (0.24 mol) of sodium cyanide in 500 ml of acetonitrile. naphtho [1,2-b] thiophene-4,5-diacetonitrile, m.p. 250-251 ° C

(from acetone) γ of 26.2 g (0.1 mole) of naphtho [1,2-b] thiophene-4,5-diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride naphtho [1, 2-b] thiophene-4,5-diacetic acid dimethyl ester, m.p. 136-138 ° C (from methanol), of 32.8 g (0.1 mole) of naphtho [1,2-b] thiophene-4,5-diacetic acid dimethyl ester and 7.6 g (0.2 mole) lithium aluminum hydride in 1 liter of absolute diethyl ether naphtho [1,2-b] thiophene-4,5-diethanol, m.p. 163-166 ° C (from acetone),. of 27.2 g (0.1 mole) of naphtho [1,2-b] thiophene-4,5-diethanol and 25.2 g (0.22 mole) of 120 ml of pyridine 4,5- [2- (methylsulfonyloxy) ) -25 ethyl] -naphtho [1,2-b] thiophene, m.p. 132-135 ° C (from methylene chloride), to Η + I) of 38 g (0.1 mole) of 10,11-bis (bromomethyl) di-benz [b, f] oxepine and 11.8 g (0.24 mol) sodium cyanide in 500 ml of acetonitrile dibenz [b, f] oxepin-10,11-diacetonitrile, m.p.

176-178 ° C (from methanol), of 27.2 g (0.1 mole) of dibenz [b, f] oxepin-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride dibenz. >, 1 28 150301 [b, f] oxepin-10,11-diacetic acid dimethyl ester, m.p. 65-67 ° C (from pentane), of 33.8 g (0.1 mole) of dibenz [b, f] oxepin-10,11-diacetic acid dimethyl ester and 7.6 g (0.2 mole) of lithium aluminum hydride in 5 1 liter of absolute diethyl ether dibenz [b, f] oxepin-10,11-diethanol, m.p. 138-140 ° C (from acetone), of 28.2 g of dibenz [b, f] oxepine-10,11-diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine 10,11-bis [2- (methylsulfonyloxy) -ethyl] -dibenz [b, f] oxepine, m.p.

112-114 ° C (from methylene chloride), to K + L) of 42.1 g (0.1 mole) of 5-acetyl-10,11-bis- (bromomethyl) -5H-dibenz [b, f ] azepine and 11.8 g (0.24 mol) of sodium cyanide in 500 ml of acetonitrile 5-acetyl-5H-dibenz [b, f] azepine-10,11-diacetonitrile, m.p. 183-185 ° C (from benzene), 15 of 31.3 g (0.1 mole) of 5-acetyl-5H-dibenz [b, f] azepine-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml water and dry hydrogen chloride 5-acetyl-5H-dibenz [b, f] azepine-10,11-diacetic acid dimethyl ester, m.p. 123-124 ° C (from toluene), of 37.9 g (0.1 mole) of 5-acetyl-5H-dibenz [b, f] azepine-10,11-diacetic acid dimethyl ester and 7.6 g lithium aluminum hydride in 150 ml of absolute tetrahydrofuran 5-ethyl-5H-dibenz [b, f] azepine-10,11-diethanol, m.p. 102-105 ° C (from ether), of 30.9 g (0.1 mole) of 5-ethyl-5H-dibenz [b, f] azepine-10,11-diethanol and 25.2 g (0, 22 moles) of methanesulfonic acid chloride in 120 ml of pyridine 10,11-bis- [2- (methylsulfonyloxy) ethyl] -5-ethyl-5H-dibenz [b, f] azepine, m.p. 140-143 ° C (from toluene), to M + N) of 37.9 g (0.1 mole) of 5-acetyl-5H-dibenz [b, f] azepine-10, 11-diacetic acid dimethyl ester and 7, 6 g of lithium aluminum hydride in 1 liter of absolute diethyl ether 5H-dibenz-30 (b, f] azepine-10,11-diethanol, mp 180-182 ° C (from acetone, '' 1 '') 29 29301 of 28 , 1 g (0.1 mole) of 5H-dibenz [b, f] azepine-10,11-diethanol and 25.2 g (0.22 mole) of methanesulfonic acid chloride in 120 ml of pyrididine 10,11-bis- [2 - (methylsulfonyloxy) ethyl] -5H-dibenz [b, f] -azepine, mp 140-142 ° C (from toluene).

Example 7

A mixture of 16.2 g (0.05 mol) of 7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d ] azepine (prepared according to Example 6) and 140 ml of 48% aqueous hydrogen bromide solution are boiled for 2 hours with stirring and reflux and then cooled to 20 ° C. The precipitated hydrobromide of 7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo-yl [2,3: 6,7] thiepino (4,5-d] azepine is filtered off and Dissolve v; in 160 ml of 60% aqueous methanol solution. The solution is made by adding concentrated aqueous ammonia solution to phenolphthalein alkaline, on which the free 7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2.3: 6.7] thiepino [4,5-b] azepine crystallizes The product melts after recrystallization from acetonitrile at 216-218 ° C.

To transfer to methanesulfonate, 9.3 g (0.03 20 moles) of base are dissolved in 380 ml of acetone and stirred with stirring 2.88 g (0.03 moles) of methanesulfonic acid, to which 7-hydroxy-3-methyl 2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] -thiepino [4,5-d] azepine methanesulfonate, m.p. 282-286 ° C crystallizes.

..A

Example 8

A mixture of 18.6 g (0.05 mol) of 7-bromo-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d ] azepine (prepared according to Example 6), 10.7 g (0.12 mol) of copper I-cyanide in 20 ml of dimethylformamide is heated in a nitrogen atmosphere for 22 hours with stirring to 180 ° C. The mixture is then cooled to 30 ° C and diluted with 100 ml of methylene chloride and 50 ml of a 50% aqueous ethylenediamine solution is added. The organic phase is then separated, washed with water and evaporated after drying over sodium sulfate. The 7-cyano-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine crystalline residue melts after recrystallization from hexane / ethyl acetate at 154-157 ° C.

To transfer to methanesulfonate, 9.6 g (0.03 5 moles) of base are dissolved in 50 ml of acetone and to this solution is added with stirring 2.88 g (0.03 moles) of methanesulfonic acid, whereupon 7-cyano-3-methyl 2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thienpino [4,5-d] azepine methanesulfonate, m.p. 247-250 ° C crystallizes.

Example 9

To a solution of 16.9 g (0.05 mol) of 2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-3-propanol in 50 ml of absolute pyridine is dropped over 15 minutes with stirring 12.2 g (0.075 mole) of octanoyl chloride, keeping the temperature between 0 and 5 ° C. Then stir for another 20 hours at room temperature. The reaction mixture is then poured onto ice water and extracted with ether. The organic phase is separated, washed with water and evaporated completely after drying over sodium sulfate. As oily residue, 3-octanoyloxy-propyl-2,3,4,5-tetrahydro-1H-dibenzo-2,3: 6,7] -thiepino [4,5-d] azepine remains.

21.5 g of crude base are dissolved in 150 ml of acetone, and a solution of 4.2 g (0.047 mole) of anhydrous oxalic acid is added in 22 ml of absolute alcohol, upon which 3-octanoyloxypropyl-3 5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine oxalate, which after recrystallization from absolute ethanol melts at 157-162 ° C.

By analogy can be prepared:

Of 16.9 g (0.05 mol) of 2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] -30 thiepino [4,5-d] azepine-3-propanol in 50 of absolute pyridine and 5.9 g (0.075 mol) of acetyl chloride 3-acetoxypropyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine. The oxalate has a m.p. at 156-160 ° C (from absolute ethanol).

31 150301

Example 10

To 75 ml of a 7.4% ethylamine solution in absolute ethanol (corresponding to 0.012 mol) is added 3.25 g (0.025 mol) of diisopropylethylamine, 50 ml of absolute ethanol and 4.5 g (0.01 mol) 5,11-bis- (2- (methylsulfonyloxy) -ethyl] -dibenzo [b, f] thiepin (prepared according to Example 5) and the mixture is heated in a closed tube for 20 hours at 85-90 ° C. the reaction mixture together with 250 ml of methylene chloride in a separatory funnel with 50 ml of 2N sodium hydroxide solution and then with 50 ml of water. dibenzo [2,3: 6,7] thiepino [4,5-d] azepine is transferred to hydrochloride as follows: 3.1 g of residue, a brown viscous oil, is dissolved in 25 ml of methylene chloride and 3 ml is added 4 N ethereal hydrogen chloride solution 3-Ethyl-2,3,4,5-tetrahydro-1H-di-benzo [2,3: 6,7] thiepino [4,5-d] azepine hydrochloride is precipitated with ether, filter off under suction and recrystallize once from ethano l-ether, m.p. of the methanesulfonate 212-214 ° C.

Example 11

To a suspension of 14.6 g (0.38 mole) of lithium aluminum hydride in 1 liter of absolute diethyl ether, a suspension of 32.1 g (0.1 mole) of 3-methyl is added over 20 minutes with stirring in a nitrogen atmosphere. 1,5-dihydro-2H-dibenzo [2,3: 6,7] - 25 thiepino [4,5-d] azepine-2,4 (3H) -dione in 500 ml of absolute diethyl ether, keeping the temperature at 20 -30 ° C. The reaction mixture is then allowed to boil for another 15 hours under reflux and then cooled to 0-5 ° C. By gently adding 75 ml of ethyl acetate and then 150 ml of water, the excess lithium aluminum hydride is decomposed. The organic phase is then separated and extracted several times with 5% methanesulfonic acid. The acidic extracts are made phenolphthalein-alkaline with wife. ammonia, whereby the crude 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thi-pino [4,5-d] azepine is excreted as an oil. The crude base is extracted with ether, separated from the organic phase, washed with water and evaporated completely after drying over sodium sulfate. The residue is dissolved in 50 ml of petroleum ether and cooled to 0 ° C, then the pure base with m.p.

5 83-86 ° C crystallizes. Mp. of the methanesulfonate: 256-258 ° C.

The starting material 3-methyl-1,5-dihydro-2H-dibenzo [2,3: 6,7] thienpino [4,5-d] azepine-2,4 (3H) -dione can be prepared as follows:

To a solution of 30.7 g (0.1 mole) of 1,5-dihydro-2H-dibenzo- [2,3: 6,7] thiepino [4,5-d] azepine-2,4 (3H) - dione (prepared 10 according to the example of Example 12) and 16.6 g (0.12 mol) of methyl iodide in 1 liter of methylene chloride are added dropwise with stirring in a nitrogen atmosphere over a 30 minute solution of 28.5 g (0.11 mol tetrabutylammonium hydroxide in 45 ml of water, raising the temperature from 20 to 25 ° C. The reaction mixture is then allowed to stir for another 5 hours at room temperature and then 250 ml of water is added. The organic phase is separated, washed with water and evaporated completely after drying over sodium sulfate. The crystalline residue is stirred with 50 ml of absolute ethanol and then filtered off under suction and washed with absolute ethanol. The product 3-methyl-1,5-dihydro-2H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-2,4 (3H) -dione melts after drying at 216-222 ° C .

Example 12

To an ice-cooled solution of 4 g (0.03 mole) of aluminum chloride 25 in 100 ml of absolute diethyl ether, a suspension of 1.14 g (0.03 mole) of lithium aluminum hydride in 75 ml of absolute water is slowly allowed to stir. diethyl ether flows so that the reaction temperature does not exceed 5 ° C. Then a suspension of 2.93 g (0.01 mole) of 1,3,4,5-tetrahydro-2H-di-benzo [2,3: 6,7] thiepino [4,5-d] azepine is added. 2-ounce in 50 ml of absolute diethyl ether and the mixture is refluxed for 24 hours. After cooling to 0-5 ° C, the excess aluminum hydride is gently decomposed by dropwise addition of 10 ml of water. The organic phase is then separated and washed twice, each time with 30 ml of water, dried over sodium sulfate and evaporated. As the residue, 2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine remains, which after recrystallization from methanol melts at 142-143 ° C.

Mp. of the methanesulfonate: 305-307 ° C.

The starting substance 1,3,4,5-tetrahydro-2H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepin-2-one can be prepared as follows: 198 g (0.5 mol) , 11-bis (bromomethyl) -dibenzo [b, f] thiepin 10 is dissolved under stirring in a nitrogen atmosphere at 50 ° C in; -V; 2.5 liters of acetonitrile. To this solution, a solution of 59 g of sodium cyanide in 180 ml of distilled water is dropped over 10 minutes, keeping the internal temperature at 50 ° C with low cooling. Then, the reaction mixture is stirred for another 30 minutes at this temperature and then 1.5 liters of ice water are added, whereupon dibenzo [b, f] thiepin-10,11-diacetonitrile crystallizes. The gray crystals are filtered off under suction, washed with water and then with acetonitrile and then dried in vacuo at 50 ° C, m.p. 205-207 ° C.

145 g (0.5 mole) of dibenzofb, f] thiepin-10,11-diacetonitrile are dissolved with stirring in 2.75 liters of methylene chloride. To this solution is led under ice-cooling at 5 to 7 ° C for 30 minutes dry hydrogen bromide, after which yellow crystals are separated from the reaction mixture after some time. Then the hydrogen bromide feed is stopped and stirred for another 30 minutes at 5 to 7 ° C. The reaction mixture is then distilled off for approx. half of the solvent in vacuo, filtering off the residual crystal mass during suction, thoroughly washing with methylene chloride and drying the slightly 30 yellow crystals under reduced pressure at 60 ° C. The 2-amino-4-bromo-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] -azepine hydrobromide thus obtained is further processed as a crude product.

90 g (0.2 mole) of 2-amino-4-bromo-1H-dibenzo [2,3: 6,7] thiepino- (4,5-d] azepine hydrobromide, 1.5 liters of dimethylformamide and

». 'J

1.3 liters of 1.3 liters of water are boiled under stirring in a nitrogen atmosphere for 2 hours under reflux. Then, the reaction mixture is diluted at 90-100 ° C with 800 ml of water and then cooled with ice to 5 ° C to give 1,5-dihydro-2H-dibenzo-5 [2,3: 6,7] thiepino [4, 5-d] azepine-2,4 (3H) -dione crystallizes, this is filtered off under suction and washed thoroughly with water and acetone. After drying at 100 ° C under reduced pressure, the crude product melts at 253-256 ° C.

To a suspension of 22.8 g (0.6 mol) of lithium aluminum hydride .V 10 in 3.5 liters of absolute diethyl ether and 350 ml of absolute tetrahydrofuran is added under stirring in a nitrogen atmosphere for one year. over 30 minutes a suspension of 61.4 g (0.2 mole) of 1,5-dihydro-2H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-2,4 (3H) ) -dione in 200 ml of absolute diethyl ether, keeping the temperature at 20-30 ° C. The reaction mixture is then allowed to boil for another 24 hours at reflux and then cooled to 0-5 ° C. By gently dripping 150 ml of ethyl acetate and then 300 ml of water, the excess lithium aluminum hydride is decomposed. The organic phase is separated, washed with 2N hydrochloric acid and then several times with water, dried over sodium sulfate and then evaporated completely. As the residue, 1,3,4,5-tetrahydro-2H-dibenzo (2,3: 6,7) thiepino [4,5-d] -azepin-2-one remains, mp 195-198 ° C.

Example 13 8.38 g (0.03 mole) of 2,3,4,5-tetrahydro-1H-dibenzoth2,3: 6,7] - thiepino (4,5-d] azepine are dissolved in stirring in 6 ml of 85 % formic acid at 40-50 ° C. To this solution is now added 2.4 ml of 35% formaldehyde solution and it is then stirred for another 12 hours at an internal temperature of 95-100 ° C. the reaction mixture is diluted to 20 ° C and diluted with 100 ml of water and this solution is made phenolphthalein-alkaline with wife ammonia to give the crude 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2 , 3: 6,7] Thiepino (4,5-d] azepine is excreted as an oil. The crude base is extracted with ether, the organic phase is separated, washed twice with water Λ 35 35301 and It is completely evaporated after drying over sodium sulfate. The base is transferred as follows to the methanesulfonate: Dissolve 8.4 g of crude base in 40 ml of acetone and cautiously add 2.6 g of methanesulfonic acid, to which 3-methyl-2,3,4, 5-tetra-5-hydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine-methanesulfonate crystallizes, this melts after recrystallization from absolute ethanol at 256-258 ° C.

Example 14 8.38 g (0.03 mole) of 2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] -10 thiepino [4,5-d] azepine are dissolved under stirring for 80 minutes. ml of 50% acetic acid. To this solution is now added at once 8.16 g of V (0.08 mole) of acetic anhydride and allowed to stand for 12 hours at room temperature. Then the reaction mixture is completely evaporated on rotary evaporator, the residue is dissolved in ether and the ether solution is washed once with hydrochloric acid, once with 2N sodium hydroxide solution and twice with water. After drying over sodium sulfate, the ether solution is evaporated completely, leaving 3-acetyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine as a yellow oil . The 20.9.4 g crude acetyl compound is dissolved in 150 ml of absolute diethyl ether and this solution is dropped over 1 hour to a suspension of 1.6 g (0.042 mole) of lithium aluminum hydride in 50 ml of absolute diethyl ether, bringing the reaction mixture to a boil. . Then, the mixture is refluxed for another 6 hours per hour. After cooling to 0-5 ° C, 40 ml of water is added dropwise to the reaction mixture and the organic phase is separated, washed with water and evaporated completely after drying over sodium sulfate. The oily residue is dissolved in 10 ml of acetone and cooled to -10 ° C, whereupon 3-ethyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5- d] azepine with m.p. 106-107 ° C crystallizes. The methanesulfonate is prepared by the procedure of Example 7, m.p. 212-214 ° C (from absolute ethanol).

36 150301

Example 15

Analogously to Example 12, the following final product is prepared:

Of 30 g (0.1 mole) of a mixture of 1,3,4,5-tetrahydro-2H-thieno [2 ', 3': 2,3] [1] benzothiepino [4,5-d] azepine 2-one and 5 1,2,3,5-tetrahydro-4H-thieno [2 ', 3': 2,3] [1] benzothiepino- [4,5-d] azepin-4-one, 2,3 , 4,5-tetrahydro-1H-thieno (2 ', 3': 2,3] - [1] benzothiepino [4,5-d] azepine, mp 119-120 ° C (from diethyl ether).

H

Λ: λΚ-.

CXSJU

The starting substance, the mixture of 1,3,4,5-tetrahydro-2H-thieno- [2 ', 3': 2,3] [1] benzothiepino [4,5-d] azepin-2-one and 1,2 , 3,5-Tetrahydro-4H-thieno (2 ', 3': 2,3] [1] benzothiepino [4,5-d] -azepin-4-one can be prepared analogously to the starting material of Example 12 as follows: 15 of 201 g (0.5 mole) of 4,5-bis (bromomethyl) thieno [2,3-b] [1] benzothiepine thieno [2,3-b] [1] benzothiepin-4,5 diacetonitrile, mp 170-172 ° C (from acetonitrile), of 147 g (0.5 mole) of thieno [2,3-b] [1] benzothiepine-4,5-diacetonitrile a mixture of 2-amino-4- bromo-1H-thieno [2 ', 3': 2,3] [1] benzothiepino [4,5-d] azepine hydrobromide and 4-amino-2-bromo-5H-thieno [2 ', 3': 2,3] [1] benzothiepino [4,5-d] azepine hydrochloride as a crude product, of a mixture of 92 g (0.2 mole) of 2-amino-4-bromo-1H-thieno- [2 ', 3 ': 2,3] [1] benzothiepino [4,5-d] azepine hydrobromide and 4-amino-2-bromo-5H-thieno [2', 3 ': 2,3] [1] benzothiepino [4 , 5-d] - .1Λ in _- * 37 150301 azepine hydrobromide 1,5 dihydro-2H-thieno [21,31: 2,3] [1] -benzothiepino [4,5-d] azepine-2 , 4 (3H) -dione, mp 215-218 C ( of methanol), of 62.6 g (0.2 mole) of 1,5-dihydro-2H-thieno [21,3 ': 2,3] [1] -5-benzothiepino [4,5-d] azepine-2 , 4 (3H) -dione a mixture of 1,3,4,5-tetrahydro-2H-thieno [21,3 '; 2,3] [1] benzothiepino [4,5-d] azepin-2-one and 1,2,3,5-tetrahydro-4H-thieno [2 ', 3': 2.3] [1] benzothiepino [4,5-d] azepin-4-one, crude product.

Example 16.

Analogously to Example 13, the following final product is prepared: of 14.3 g (0.05 mole) of 2,3,4,5-tetrahydro-1H-thieno [2 ', 3': 2.3] [1] benzothiepino [ 4,5-d] azepine 3-methyl-2,3,4,5-tetrahydro-1H-thieno [2 ', 3': 2,3] [1] benzothiepino [4,5-d] azepine 15 as crude product, methanesulfonate m.p. 208-209 ° C (from absolute ethanol).

Example 17

Analogously to Example 14, the following final product is prepared: 20 of 14.3 g (0.05 mole) of 2,3,4,5-tetrahydro-1H-thieno [21,3 ':

2.3] [1] benzothiepino [4,5-d] azepine 3-ethyl-2,3,4,5-tetrahydro-1H-thieno [2 ', 3': 2,3] [1] benzothiepino [4 , 5-d] azepine, m.p. 127-129 ° C (from acetone), methanesulfonate m.p. 209-211 ° C

r - (from absolute ethanol).

Example 18.

Analogously to Example 11, the following compounds can be prepared using the appropriate starting materials: of 39.3 g (0.1 mole) of 3- [3- (dimethylamino) propyl] -1,5-dihydro-2H-dibenzo [2 , 3: 6.7] thiepino [4,5-d] azepine-2,4 (3H) -dione, and 14.6 g (0.38 mol) of lithium aluminum hydride in absolute diethyl ether 3- [3- (dimethylamino) propyl) -2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine as a crude product, dihydrochloride m.p. . 285-289 ° C under decomposition, 5 of 39.9 g (0.1 mole) of 3- [3- (dimethylamino) propyl] -1,5-dihydro-2H-thieno [2 ', 3': 2, 3] [1] benzothiepino [4,5-d] azepine-2,4 (3H) -dione and 14.6 q (0.38 mol) of lithium aluminum hydride in absolute diethyl ether 3- [3- (dimethylamino) propyl] - 2,3,4,5-tetrahydro-1H-thieno [2 ', 3': 2,3] [1] benzothiepino (4,5-d] azepine as a crude product, dihydrochloride mp 265-270 ° C under decomposition, of 37.4 g (0.1 mole) of 3- [3- (dimethylamino) propyl] -5,10-dihydro-dibenzo [3,4: 6,7] cyclohepta [1,2-d] azepine-2,4 (1H, 3H) -dione and 14.6 g (0.38 mol) of lithium aluminum hydride in absolute diethyl ether 3- [3- (dimethylamino) propyl] -1,2,3,4,5,10-hexahydro 15 dibenzo [3,4: 6,7] cyclohepta [1,2-d] azepine, mp 80-82 ° C (from pentane), dihydrochloride mp about 315 ° C (under decomposition).

The starting material can be prepared as follows: aa) To a suspension of 30.7 g (0.1 mole) of 1,5-dihydro-2H-di-benzo [2,3: 6,7] thiepino [4,5-d ] azepine-2,4 (3H) -dione in 14.6 g of 20 (0.12 mole) of freshly distilled 3- (dimethylamino) propyl chloride and 600 ml of absolute toluene are dripped with stirring and refluxing under a nitrogen atmosphere over two hours a suspension of 2.3 g (0.1 mole) of lithium amide in 6.9 ml of absolute toluene. The reaction mixture is then allowed to boil for another 20 hours under reflux and then cooled to room temperature. After adding 100 ml of water, the organic phase is separated and extracted three times, each time with 50 ml of 10% methanesulfonic acid. The acidic extracts are made phenol-phthalein alkaline with concentrated ammonia, whereby 3- [3- (dimethylamino) propyl] -1,5-dihydro-2H-dibenzo [2,3: 6,7] thiepino [ 4,5-d] azepine-2,4 (3H) -dione is crystalline, which melts after recrystallization from ether / pentane at 102-103 ° C.

39 150301

The methanesulfonate is prepared as follows: Dissolve 30 g of base (0.076 mole) in 75 ml of acetone and gently add 7.3 g of methanesulfonic acid (0.076 mole), then 3- [3- (dimethylamino) propyl] -1,5-dihydro -2H-dibenzo (2,3: 6,7) -5 thiepino [4,5-d] azepine-2,4 (3H) -dione methanesulfonate crystallizes, which melts after recrystallization from methanol at 270-275 ° C. decomposition.

Analogously, the following compounds may be prepared: bb) of 31.2 g (0.1 mole) of 1,5-dihydro-2H-thieno [2 ', 3': 2,3] [1] -10 benzothiepino [4, 5-d] azepine-2,4 (3H) -dione, 14.6 g (0.12 mole) of 3- (dimethylamino) propyl chloride and 2.3 g (0.1 mole) of lithium amide 3- [3 - (dimethylamino) propyl] -1,5-dihydro-2H-thieno [2 ', 3': 2,3] [1] benzothiepino [4,5-d] azepine-2,4 (3H) -dione , m.p. 117-119 ° C (from acetone), hydrochloride m.p. 224-227 ° C (from 15 absolute ethanol) and cc) of 28.9 g (0.1 mole) of 5,10-dihydro-dibenzo [3,4: 6,7] cyclohepta [1,2-d ] azepine-2,4 (1H, 3H) -dione, 14.6 g (0.12 mol) of 3- (dimethylamino) propyl chloride and 2.3 g (0.1 mol) of lithium amide 3- [3- (dimethylamino) ) -propyl] -5,10-dihydro-dibenzo [3,4: 6,7] -20 cycloheptafl, 2-diazepine-2,4 (1H, 3H) -dione, m.p. 113-115 ° C (from hexane), hydrochloride m.p. 265-268 ° C (from ethanol).

5,10-Dihydro-dibenzo [3,4: 5,7] cyclohepta [1,2-d] azepine-2,4- (1H, 3H) -dione is prepared analogously to the starting materials of Example 14: 25 of 189 g (0.5 mol) of 10,11-bis (bromomethyl) -5H-dibenzo [a, d] cyclohepten (German Publication No. 2,125,654) in 2.5 liters of acetonitrile and 59 g (1 , 2 mol) sodium cyanide 5H-dibenzo [a, d] cyclohepten-10,11-diacetonitrile, m.p. 217-220 ° C (from acetonitrile), 30 of 135 g (0.5 mole) of 5H-dibenzo [a, b] cyclohepten-10,11-diaceto-y ·. with dry hydrogen bromide 2-amino-4-bromo-1,10-dihydro-dibenzo [3,4: 6,7] cyclohepta [1,2- d] azepine hydrobromide, crude product, of 86.5 g (0.2 mole) 2-amino-4-bromo-1,10-dihydro-dibenzo [3,4: 5,7] cyclohepta [1,2-d] azepine hydrobromide, 1.5 liters of dimethylformamide and 1.3 liter of water 5,10-dihydro-dibenzo [3,4: 6,7] cyclohepta [1,2-d] azepine-2,4 (1H, 3H) -dione, m.p. 265-268 ° C (from acetone).

Example 19.

Analogously to Example 5, using the corresponding starting materials, the following compounds can be prepared: from 22.7 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -dibenzo [b, f] thiepine, 4.4 g (0.06 mol) of n-butylamine and 16.25 g (0.125 mol) of diisopropylethylamine in absolute ethanol 3-butyl-2,3,4,5-tetrahydro-1H-dibenzo [2 , 3: 6.7] thiepino [4,5-d] azepine, m.p. 107-108 ° C (from acetone), methanesulfonate m.p. 218-220 ° C (absolute ethanol), of 22.7 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -dibenzo [b, f] thiepine, 3.4 g ( 0.06 mole) of allylamine and 16.25 g (0.125 mole) of diisopropylethylamine in absolute ethanol 3-allyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4, 5-d] azepine as a crude product, methanesulfonate m.p. 225-227 ° C (from absolute ethanol),

• I

of 22.7 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -25 dibenzo [b, f] thiepine, 3.3 g (0.06 mole) of propargylamine, and 16, 25 g (0.125 mol) of diisopropylethylamine in absolute ethanol 3-propynyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino- [4,5-d] azepine as a crude product, methanesulfonate mp. 218-221 ° C (from absolute ethanol), 1 '.7 of 22.7 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) -ethyl] -dibenzo [b, f] thiepine, 6.0 g (0.06 mol) (aminomethyl) cyclo-pentane and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol 3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1 dibenzo- [2,3: 6,7] thiepino [4,5-d] azepine, m.p. 113-115 ° C (from absolute ethanol), methanesulfonate m.p. 248-252 ° C (from absolute ethanol), 5 of 22.7 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) -ethyl] -dibenzo [b, f] thiepine, 6.7 g (0.06 mol) (aminomethyl) -cyclohexane and 16.5 g (0.125 mol) diisopropylethylamine in absolute ethanol 3- (cyclohexylmethyl) -2,3,4,5-tetrahydro-1H-dibenzo- [2, 3: 6.7] thiepino [4,5-d] azepine, m.p. 113-115 ° C (from acetone), methanesulfonate m.p. 256-258 ° C (from absolute ethanol), of 22.7 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] - dibenzo [b, f] thiepine, 3.7 (0.06 mole) ethanolamine and 16.25 g (0.125 mole) diisopropylethylamine in absolute ethanol 1,2,4,5-tetrahydro-3H-dibenzo [2,3: 6,7] thiepino [4,5-d ] azepine-3-ethanol, m.p. 157-159 ° C (from acetone), methanesulfonate m.p. 194-198 ° C (from absolute ethanol), of 22.7 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -dibenzo [b, f] thiepine, 4.5 g (0.06 mole) of 3-aminopropanol and 16.25 g (0.125 mole) of diisopropylethylamine in absolute ethanol 1,2,4,5-tetrahydro-3H-dibenzo [2,3: 6,7] thiepino [4,5 -d] azepine-3-propanol, m.p. 120-132 ° C (from acetone), methanesulfonate m.p. 181-183 ° C (from absolute ethanol), of 22.7 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -l] dibenzo [b, f] thiepine, 5.4 g (0.06 mol) of 3-methoxypropylamine and 16.25 g (0.125 mol) of diisopropylethylamine in absolute ethanol 3- (3-methoxypropyl) -2,3,4,5- tetrahydro-1H-dibenzo [2,3: 6,7) -thiepino [4,5-d] azepine as a crude product, methanesulfonate m.p.

213-216 ° C (from absolute ethanol), of 22.7 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -30 dibenzo [b, f] thiepine, 6.3 g (0.06 mol) of 3- (methylthio) propylamine and 16.25 g (0.125 mol) of diisopropylethylamine in absolute ethanol 3- [3- (methylthio) propyl] -2,3,4,5-tetrahydro -1H-di-benzo [2,3: 6,7] thiepino [4,5-d] azepine as a crude product, methane-V ·.

Sulfonate m.p. 212-214 ° C (from absolute ethanol), of 22.7 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -dibenzo [b, f] thiepine, 5.5 g (0.06 mol) of 2- (methylthio) ethylamine and 16.25 g (0.125 mol) of diisopropylethylamine in absolute ethanol 3- [2- (methylthio) ethyl] -2,3,4,5-tetrahydro -1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, m.p. 91-92 ° C (from pentane), methanesulfonate m.p. 218-220 ° C (from absolute ethanol), of 24.5 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-chloro-dibenzo [b, f] thiepine, 1.85 g of methylamine (0.06 mole) and 16.25 g (0.125 mole) of diisopropylethylamine in methanol 7-chloro-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-diazepine as a crude product, hydrochloride m.p. 266-268 ° C (from absolute ethanol), of 24.5 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -15 2-chloro-dibenzo [b, f] thiepine 6.7 g (0.06 mol) (aminomethyl) cyclopentane and 16.25 g (0.125 mol) diisopropylethylamine in absolute ethanol 7-chloro-3- (cyclopentylmethyl) -2,3,4,5-tetrahydro -1H-dibenzo [2,3: 6,7] thiepin [4,5-d] azepine, m.p. 123-126 ° C (from acetone), methanesulfonate m.p. 195-198 ° C (from absolute ethanol),

Analogously to Examples 5 and 12, respectively, the starting material for the two latter end products can be prepared: "A" of 43.1 g (0.1 mole) of 2-chloro-10,11-bis- (bromomethyl) -dibenzo [b, f] thiepin and 11.8 g of sodium cyanide in 500 ml of acetonitrile 25 2-chloro-dibenzo [b, f] thiepin-10,11-diacetonitrile, mp 207-210 ° C (from chloroform), of 32.3 g ( 0.1 mole) of 2-chloro-dibenzo [b, f] thiepin-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml of water and dry hydrogen chloride 2-chloro-dibenzo [b, f] thiepin-10,11 -acetic acid dimethyl ester, 30 mp 111-113 ° C (from methanol), of 38.9 g (0.1 mole) of 2-chloro-dibenzo [b, f] thiepin-10,11-diacetic acid 43 150301 acid dimethyl ester and 7.6 g (0.2 mole) of lithium aluminum hydride in 1 liter of absolute diethyl ether 2-chloro-dibenzo [b, f] thiepin-10,11-diethanol, mp 152-154 ° C (from ethyl acetate), of 33.3 g (0.1 mole) of 2-chloro-dibenzo [b, f] thiepin-10,11-diethanol, 25.2 g (0.22 mole) of methanesulfonic acid chloride in 120 ml of pyridine 10.11 -bis- [2- (methylsulfonyloxy) ethyl] -2-chloro-dibenzo [b, f] thiepin, mp 118-120 ° C (f diethyl ether).

Example 20

To a solution of 21.9 g (0.05 mol) of 10,11-bis [2- (methylsulfonyloxy) ethyl] -dibenzo [b, f] oxepine in 250 ml of absolute ethanol is added 6 g (0 , 06 mol) of aminomethyl-cyclopentane and 16.25 g (0.125 mol) of diisopropyl-ethylamine, and the reaction mixture is refluxed for 18 hours. After cooling by means of an ice bath, crystals are extracted which are extracted and washed with a little isopropanol and pentane. The substance on the filter is 3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-dibenzo (2,3: 6,7] oxepino [4,5-d] azepine, mp 99-101 ° C, mp for the methanesulfonate: 280 ° C (dec.).

Similarly, from 21.9 g (0.05 mole) of 10,11-bis- (2- (methylsulfonyloxy) ethyl] -dibenz [b, f] oxepine, 4.5 g (0.06 mole) is prepared from 3-Aminopropanol and 16.25 g (0.125 mole) of diisopropyl-ethylamine in absolute ethanol 1,2,4,5-tetrahydro- [3H-dibenz [2,3: 6,7] oxepino [4,5 -d] azepine-3-propanol, m.p.

j / r ·; 59-61 ° C (from pentane), methanesulfonate, m.p. 188-192 ° C (from 25 absolute ethanol).

Example 21.

27.6 g (0.1 mole) of 3-methyl-1,2,3,4,5,10-hexahydro-dibenz [b, f] -azepino (4,5-d] azepine are dissolved in a mixture of 130 To this solution, a suspension of 7.8 g (0.2 mole) of sodium amide in 24 ml of absolute toluene is added dropwise over a period of 18 to 20 minutes, maintaining the temperature of 18-20 ml. ° C at low cooling, at the same time a dry nitrogen stream is passed through * · i * v. J

J

.. t. .

44 150301 the reaction solution to expel the ammonia formed.

After the addition is complete, the mixture is stirred for 30 minutes, then a solution of 14.2 g (0.1 mole) of methyl iodide in 100 ml of absolute toluene is added dropwise over 15 minutes, keeping the temperature again at 18-20 ° C. cooling with ice. The mixture is then stirred for an additional 15 minutes, then slowly poured into a mixture of 2 liters of water and 400 ml of toluene. The organic phase is isolated and the aqueous phase is extracted with toluene. The combined organic solutions are washed with water, dried with potassium carbonate and completely evaporated in vacuo. The crystallized residue, 3,10-dimethyl-1,2,3,4,5,10-hexahydro-dibenz [b, f] azepino- [4,5-dlazepine, is recrystallized from ethanol and melts at 197-199 ° C , the methanesulfonate melts at 231-233 ° C (from absolute 15 ethanol).

The starting material is prepared analogously to the procedure described in Example 6K from 42.1 g (0.1 mole) of 5-acetyl-10.11-bis (bromomethyl) -5H-dibenz [b, f] azepine and 11.8 g (0 , 24 mol) sodium cyanide in 500 ml of acetonitrile 5-acetyl-5H-dibenz [b, f] azepine-10,11-diacetonitrile, m.p. 183-185 ° C (from benzene), from 31.3 g (0.1 mole) of 5-acetyl-5H-dibenz [b, f] azepine-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml water and dry hydrogen chloride 5-acetyl-5H-dibenz [b, f] azepine-10,11-diacetic acid dimethyl ester, m.p. 123-124 ° C (from toluene), from 37.9 g (0.1 mole) of 5-acetyl-5H-dibenz [b, f] azepine-10,11-diacetic acid dimethyl ester and 7.6 g of lithium aluminum hydride in 1 liter of absolute diethyl ether 5H-dibenz [b, f] azepine-10,11-diethanol, m.p. 180-182 ° C (from acetone), from 28.1 g (0.1 mole) of 5H-dibenz [b, f] azepine-10,11-diethanol and 25.2 g (0.22 mole) of methanesulfonic acid chloride in 120 ml of pyridine 10.11-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenz [b, fazepine, m.p. 140-142 ° C (from toluene), 150,301 in 45 from 21.9 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -5H-dibenz [b, f] azepine , 1.85 g (0.06 mol) of methylamine and 16.25 g (0.125 mol) of diisopropyl-ethylamine 3-methyl-1,2,3,4,5,10-hexahydro-dibenz [b, f] azepino [ 4,5-d] azepine, 5 m.p. 121-124 ° C (from methanol), methanesulfonate m.p. 263-266 ° C (from absolute ethanol / acetone).

> Example 22.

Analogous to the procedure described in Example 6H, using the same starting materials, the following compounds are prepared: v-v'1 from 23.6 g (0.05 mole) of 10,11-bis- (2- methylsulfonyloxy) ethyl] -2-chloro-dibenz [b, f] oxepine, 1.85 g (0.06 mol) of methylamine and 16.25 g of diisopropylethylamine in absolute ethanol 7-chloro-3-methyl 2,3,4,5-tetrahydro-1H-dibenz [2,3: 6,7] oxepino-15 [4,5-d] azepine, mp 174-176 ° C (from toluene), the hydrochloride melts at 279 -281 ° C (from absolute ethanol).

The starting material, 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-chloro-dibenz [b, f] oxepine can be prepared by analogy to the procedure described in Example 6H as follows: 20 a) from 20.7 (0.05 mole) of 10,11-bis (bromomethyl) -2-chloro-dibenz [b, f] oxepine and 5.9 g (0.12 mole) of sodium cyanide in 250 ml of acetonitrile, 2-chloro-dibenz [b, f] oxepin-10,11-diacetonitrile, m.p. 227-230 ° C (from methanol),

.; JV

1b) from 15.3 g (0.05 mole) of 2-chloro-dibenz [b, f] oxepine-10,11-diacetonitrile, 200 ml of methanol, 1.9 ml of water and dry hydrogen chloride 2 -chloro-dibenz (b, f] oxepin-10,11-diacetic acid dimethyl ester, crude product (oil), c) from 18.7 g] (0.05 mole) of 2-chloro-dibenz [b, f ] oxepin-10,11-diacetic acid dimethyl ester and 3.8 g (0.1 mole) of lithium aluminum hydride in 500 ml of diethyl ether 2-chloro-dibenz [b, f] oxepin-10,11-diethanol, crude product (oil ), and F " . 4 livestock; *. d) from 15.8 g (0.05 mole) of 2-chloro-dibenz [b, f] oxepine-10,11-diethanol and 12.6 g (0.11 mole) of methanesulfonic acid chloride in 60 ml of pyridine, 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-chloro-dibenz [b, f] oxepine, crude product (oil).

Example 23.

Analogous to the process described in Examples 5 and 6E, the following compounds can be prepared using similar starting materials: <a) from 22.7 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) - 10 ethyl ] -dibenzo [b, f] thiepine, 3.3 g (0.06 mol) of propylamine and 16.25 g of diisopropyl-ethylamine in absolute ethanol 3-propyl-2,3,4,5-tetrahydro-1 dibenzo [2,3: 6,7] thiepin [4,5-d] azepine, m.p. 128-130 ° C (from acetone), methanesulfonate m.p. 181-183 ° C (from absolute ethanol), 15 b) from 26.7 g (0.05 mol) of 10,11-bis- [2- (methylsulfonyloxy) ethyl] -2-bromo-dibenzo [b, f] thiepine, 6.0 g (0.06 mol) (amino-methyl) cyclopentane and 16.25 g (0.125 mol) diisopropylethylamine 7-bromo-3- (cyclopentylmethyl) -2,3,4,5 -tetrahydro-1H-di-benzo [2,3: 6,7] thiepino [4,5-d] azepine, m.p. 120-123 ° C (from 20 ethanol), c) from 26.7 g (0.05 mole) of 10,11-bis- [2- (methylsulfonyloxy) -ethyl] -2-bromo-dibenzo [b , f] thiepine, 2.7 g (0.06 mole) of ethylamine and 16.25 g (0.125 mole) of diisopropyl-ethylamine 7-bromo-3-ethyl-2,3,4,5-tetrahydro-1 dibenzo [2,3: 6,7] thiepino [4,5-d] -25 azepine, crude product.

Example 24.

A mixture of 19.3 g (0.05 mol) of 7-bromo-3-ethyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d ] azepine and 10.7 g (0.12 mol) of copper I-cyanide in 20 ml of dimethylformamide 30 are heated in a nitrogen atmosphere for 22 hours with stirring to 180 ° C. The mixture is then cooled to 30 ° C, diluted with 100 ml of methylene chloride and 50 ml of 50% aqueous ethylene diamine solution is added. The organic phase is isolated, washed with water and dried over sodium sulfate and then evaporated. The crystalline residue, 5 7-cyano-3-ethyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] - thiepino [4,5-d] azepine melts after recrystallization from hexane / ethyl acetate at 154-156 ° C.

* To convert to the methanesulfonate, 10 g (0.03 mole) of the base is dissolved in 50 ml of acetone and to this solution V is added. 2.88 g with stirring 2.88 g (0.03 mole) of methanesulfonic acid, on which 7β-cyano-3-ethyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] -

Thiepino [4,5-d] azepine methanesulfonate, m.p. 220-223 ° C

.A ,; crystallizes.

Analogously, 22 g of X0.05 mol) of 7-bromo-3-15 (cyclopentylmethyl) -2,3,4,6-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4 , 5-d] azepine, 10.7 g (0.12 mol) of copper I-cyanide in 20 ml of dimethylformamide, 7-cyano-3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, m.p. 170-172 ° C (from methanol), methanesulfonate: m.p. 203-206 ° C (from absolute ethanol).

'V- *', i> *> · ^ '. ·; Li

Claims (8)

150301 1. Analogous Process for the Preparation of Azetetracyclic Compounds of the General Formula i1 Λ \ / v · · s · Y s \ / \ / \ R - + - II li il (I) r Vx / Y- 5 wherein hydrogen , alkyl of 1-6 carbon atoms, 4'-cycloalkylalkyl of not more than 10 carbon atoms, alkenyl of 3-4 carbon atoms, propargyl, dialkylaminoalkyl of not more than 10 carbon atoms, hydroxyalkyl of 2-8 carbon atoms, alkoxyalkyl of 3-10 carbon atoms, alkanoyloxyalkyl of 3-11 carbon atoms, alkylthioalkyl of 3-11 carbon atoms or phenylalkyl of 7 or 8 carbon atoms, R5 means hydrogen, fluorine, chlorine, bromine, alkyl of not more than 4 carbon atoms, hydroxy, alkoxy of not more than 4 carbon atoms, alkanoyl-oxy of 1 -4 represents carbon atoms, alkylthio having not more than 4 carbon atoms, trifluoromethyl or cyano, X means epoxy, epithio, methylene, a direct bond or a divalent group of formula 1 'in </ S: t wherein R or alkyl · having a maximum of 4 carbon atoms and one of the groups Y and Z means vinyl or epithicy and the other means a direct bond, or acid addition salts thereof, characterized by a) reacting a reactive diester of a diethanol of formula 150301 ν '·' · 49 v τ; · H ° -CH2 CH2 · · = · .. ^ \ / \ / y \ R, - + - i * ίΐ ii (ii) '•' V'V wherein X, Y, Z and Rj have the above meanings, with a compound having. wherein R 1 has the meaning given above, or • in * b) for the preparation of compounds of formula I wherein R 2 the group R R, which has the same meaning as R R, with the exception of alkanoyloxyalkyl of 4-11 carbon atoms, reduces a compound of formula Γ1 Q2 * / \ /> l 10 \ /! v (IV> ^ \ / \ / * R 1 -H- II II II νΝ / 'ν wherein R 2, R 5, X, Y and Z have the meanings given above and one of the two symbols and Q 2 is an oxygen atom and the other is an oxygen atom or 2 hydrogen atoms, and, if desired, converting a compound of formula I wherein R 1 represents hydrogen into a compound of formula I wherein R 2 has one of the other meanings given above, acylating a formed compound of formula I, wherein R 2 represents a hydroxyalkyl group of 2-8 carbon atoms, to a compound of formula I wherein R 1 represents an alkanoyloxyalkyl group of 3 to 11 carbon atoms, hydrogenates a prepared compound see is a phenylalkyl group having 7 or 8 carbon atoms, to a compound of formula I wherein R 1 represents hydrogen, alkylates a compound of formula I wherein X represents a divalent group of the partial formula N 'R 3 wherein hydrogen represents a compound of formula 5 wherein alkyl of not more than 4 carbon atoms employs a formed compound of formula I wherein R2 represents alkoxy of not more than 4 carbon atoms with hydrogen hydrochloric acid to form a compound of formula I wherein R 2 represents hydroxy converts a compound of formula I wherein is different from cyano, alkyl of not more than 4 carbon-10 ethers and trifluoromethyl, to a compound of formula I wherein; means cyano, and / or, cm desired, forming a prepared free compound for an acid addition salt thereof and / or, cm desired, forming a prepared acid addition salt for the free compound or to another acid addition salt and / or, if desired, separating a produced isomer mixture in the individual isomers. Process according to claim 1, characterized in that 3-methyl-2,3,4,5-tetrahydro-1H-di-benzo [2,3: 6,7] thiepino [4,5-d] azepine is prepared. or acid addition salts thereof. Process according to claim 1, characterized in that 3-methyl-2,3,4,5-tetrahydro-1H-di-benzo [2,3: 6,7] oxepino [4,5-d] azepine is prepared. or acid addition salts' V1 thereof. Process according to claim 1, characterized in that 3-methyl-7-cyano-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5- d] azepine or acid addition salts thereof. Process according to claim 1, characterized in that 3-methyl-1,2,3,4,5,10-hexahydro-dibenzo [3,4: 6,7] cyclohepta [1,2- d] azepine or acid addition salts thereof. 150301 Process according to claim 1, characterized in that 3- (2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine 3-yl) propanol or acid addition salts thereof. Process according to claim 1, characterized in. net by preparing 3-methyl-7-chloro-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine or acid addition salts thereof. Process according to claim 1, characterized in that 3-methyl-7-chloro-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino is prepared. [4,5-d] azepine or acid addition salts thereof. Published publications: DK application no. 6149/69 (Pat.130214), 661/75 (forwarding 145652) CH patent no. 518961 DE publication no.