CS225106B2 - The production of new tetrahyro-and hexahydro-aza-tetra cyclic compounds - Google Patents

Abstract

Azatetracyclic compounds of formula I <IMAGE> are obtained by reaction of a reactive diester of a diethanol of formula II <IMAGE> with a compound of formula III <IMAGE> The meaning of the individual symbols is given in Claim 1. The novel compounds may be used as tranquillizing, antipsychotic and sedative compounds for the treatment of anxiety (agitation) states.

Description

The invention relates to a process for the preparation of novel tetrahydro- and hexahydroazatetracyclic compounds and their acid addition salts, which compounds have valuable pharmacological properties and can be used as active ingredients of a medicament.

The tetrahydro- and hexehydroazatetrecyclic compounds of the invention correspond to the general formula I,

R

(i) in which:

R 1 is hydrogen, C 1 -C 8 alkyl, C 4 -C 10 cycloalkylalkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 4 -C 10 dialkyleminoalkyl, hydroxyalkyl C 2 -C 8 radical, C 3 -C 10 alkoxyalkyl, C 3 -C 10 alkylthioalkyl or, optionally, chlorine, methyl or methoxy substituted C 7 -C 12 phenylalkyl, and ring A is unsubstituted or substituted a halogen having an atomic number of up to 35, an alkyl® radical having 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms or a cyano group,

X represents an epoxy group, an epithio group, a methylene group, a direct bond or a divalent radical of partial formula Ia;

Κ

I (Ie) ^B 3 wherein hydrogen or C 1 -C 4 alkyl and one of X and Ϊ is vinylan or epithio and the other is a direct bond.

The invention also relates to the acid addition salts of the compounds of the formula I, in particular the pharmaceutically acceptable acid addition salts.

By lower radicals is meant radicals having at most 8 and preferably at most 4 carbon atoms.

R 1 preferably contains 1 to 6 carbon atoms as the alkyl radical. Such alkyl groups which may have a straight or branched chain are, for example, methyl, ethyl, propyl, isopropyl, bityl, isobutyl or tert-butyl.

As the cycloalkylalkyl radical, the radical R1 preferably contains 4 to 8 carbon atoms. Thus, the cycloelkylaltyl radical is, for example, cyclopropylmethyl, cyclobitylmethyl and in particular cyclopentyl, cyclohexylmethyl, furthermore, for example, cyclopentyl, cyclolylmethyl, cyclopentylethyl,

As alkenyl, the radical R contains preferably 3 to 4 carbon atoms, and in particular 3 carbon atoms. Alkenyl is, for example, allyl or 2-methylphalyl.

A propargyl radical is particularly suitable as the radical R in the meaning of the symbol R.

In the di-alkylamino radical R, the nitrogen atom is separated from the ring nitrogen atom by at least 2 carbon atoms. The radical preferably contains 4 to 6 carbon atoms.

The alkyl radicals in this substituent are preferably straight chain. The rest is constituted for example rest dietyteiinobutylo'ýi, dietytmmnnoIr · opyloýi or dittylθminoet1lovým, _{diiet1laiinobutylo5ýi)} dLiet1laiinoetyloýi and especially diietylθiinoproρylooým.

In the hydroxy radical R, the hydroxyl group is separated from the ring nitrogen atom by at least 2 carbon atoms. This residue preferably contains 2 to 6 carbon atoms. Hyydooy A stylish residue, which may be straight or branched, is represented, for example, by 1-8-41-41-41X1111- ^ 2-hydroxypropyl, 1- or 2-mmyl-2-oxoxypropyl, and in particular by 2-hydroxypropyl. hydroxyethyl and 3-hydroxypropyl.

In the lower alkoxyalkyl group R, the oxygen atom is separated from the ring nitrogen atom by at least 2 Vil atoms. This residue preferably contains 3 to 6 carbon atoms. This alkoxyalkyl radical is represented, for example, by 2-ethoxypropylthio, 2- or 3-hexopropyl, 2- or 3-propoxypropylthi, 3-isoxypropylpropyl, and in particular by 2-methoxy or 2-ethoxyphenyl, and in particular 3-imoxypropylthio.

In an alkylthioalkyl group of the radical R @ 1 is a sulfur atom separated by a bd nitrogen atom in the ring of at least 2 carbon atoms. This radical contains, for example, 3 to 10 and preferably 3 to 6 carbon atoms. The alkylthioalkyl radical is, for example, methylthiothyl or 3-ethylthiopropyl.

R | contains in the meaning of an optionally substituted phenyl alkyl radical in the phenyl ring a chlorine, methyl or methoxy group.

Ring A may be substituted one or more times. Nevertheless, the ring is preferably most mono-substituted by halogen having an atomic number of more than 35, in particular chlorine, an alkyl radical of up to 4 carbon atoms, such as ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl and especially methyl, hydroxy, alkoxy. from 1 to 4 carbon atoms such as ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and in particular methoxy, allylthioeloipine and 1-4 carbon atoms, such as ethylthiocipine, propylthio; iso-propylthioCo80upioiu, butylthi o group and especially melylthi o pinc group.

If X is not a divalent radical of the partial formula Ie, (Ie) then R1 is preferably hydrogen or an alkyl radical having 1 to 4 carbon atoms, such as propyl, bityl, isobutyl and especially methyl or ethyl.

Preferably, Y is a direct bond and Z is an oinylenic group or epp shaking.

The salts of the compounds of the formula I are in particular acid addition salts, in particular pharmacologically acid addition salts with acids, for example with inorganic acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acids, or with organic acids such as organic carboxylic acids and sulfonic acids, such as melanosufco, etenesulfokn, 2-hydroxyetosulfos, acetic, cider, vinous, lemon, milk, oxalic, amber, 8alicylio, Dmiar, meleio, benzo, feoylicУio, almond oebc.

The novel 10-cyclic compounds of the formula I and their acid addition salts have valuable pharmacological properties, for example properties of the central nervous system. Thus, they have centrally depressant effects as well as suppressive effects (e.g. Thus, these compounds have been tested in the rat for the anticoagulant effect of emphetamine (Nilmlgeers and Jeossen, Amoemittelfirsch., Vol. 24, p. 45 (1974)) in the dose range from 0.1 The cataleptic effect of the amphetamine antagonist is relatively modest compared to the amphetamine antagonist activity of the novel novel tricyclic compounds of formula (I) and their phimacologically useful acid addition sodium may therefore be reduced. to be used as compounds with traoccultant, antipsychotic and stimulant-depressant effects for the treatment of conditions of excitement.

The invention is. in particular, it relates to compounds of the formula I in which R @ 1 represents hydrogen, C1 -C8 alkyl radical, for example methyl, ethyl, isopripyl and o-butyl, C4 -C8 cycloalkyl radical, for example cyclopentyamelya and cycachexyl. melting, a 3 to 8 carbon atom of 10 to 10 carbon atoms, for example allyl, 11 to 10 carbon atoms, such as a 3 to 8 carbon atom, such as propyptargyl, a 4 to 10 carbon atom, a 4 to 10 carbon atom, such as dimethylaminoctyl and 3-dimethylaminopropyl; a (C 2 -C 6) hydroxyalkyl radical, for example a C 2 -C 6 -cycloalkyl and a 3-hydroxyl radical having from 3 to 10 carbon atoms, for example 3-methoxy- and 3-itixylpropyl, (3-10-thioyl) alkyl radicals having from 3 to 10 atoms 2-methyl-2-ethyl-2-ethylthioethyl, 3-ethyl-3-ethyl-3-propyl or 7 to 12 carbon atoms such as benzyl in phenylethyl, a ring A is unsubstituted or substituted by halogen having an atomic number of up to 35, alkyl of 1 to 4 carbon atoms, hydroxy, C1-C4alkoxy, C1-C4anoyloxy, C1-C4haloalkyl of 1 to 4 carbon atoms , trifluoromethyl X is an epoxy group, an epiyl group, a melyleo group, a direct bond or a bivalent radical, the remainder of the partial formula Ia,

(Ie)

in which

R3 represents hydrogen or an alkyl radical having from 1 to 4 carbon atoms, preferably methyl or ethyl, and one of the radicals Y and Z represents a viral group or an epithiocup and the other represents a direct bond, and a salt, in particular acid addition salts, in particular pharmaceutically usable acid addition salts.

More particularly, the invention relates to compounds of formula I in which R1 represents hydrogen, an alkyl radical of 1 to 6 carbon ethers, for example a methyl or a stylish radical, a cycloelkylalkyl radical of 4 to 8 carbon atoms, for example a cyclopentylmethyl radical or a cyclohexylmethyl radical; from 1 to 6 carbon atoms, for example allyl, an alkynyl radical and from 3 to 6. carbon atoms, for example pyrrolidyl, (C1 -C4) alkyl- (4-8) -alkyl, e.g., dimethylaminolyl and 3-dimethylaminolpeoppl, a saturated alkyl radical and 2 to 6 carbon atoms, such as 2-hydroxyethyl-3-hydroxy-OPpy, . an alkoxyalkyl radical having from 3 to 6 carbon atoms, e.g. (C 3 -C 6) ethyl, for example, ethyl 3-methylthienyl or phenylalkyl of 7 to 10 carbon atoms, for example benzyl or phenylethyl, ring A - is unsubstituted or substituted by chlorine, bromine, methyl, hydroxy, methoxyme, mmeylthiamine or cyenosine, X represents epoxyslnipine, a p moiety, a methylene group or a divalent radical of the formula Ia, (Ie)

or epithiocult, and so, in particular. acids, especially pharmacologically orthopedic salts of acids.

In particular, the invention relates to compounds of formula I wherein R 1 represents an alkyl radical having 1. and the ring A is unsubstituted or substituted by chlorine, methyl, mm toxy or cyano, preferably at the 7-position of the ring A of compounds in which Z is X is an epoxystopine, epithio or methylene group or a bivalent radical of the formula Ie, (Ie) wherein R 3 is hydrogen, methyl or ethyl, β Y is a direct bond and Z - is a vinylene or epithia group, JEKO 3-ιnetyУ-2,3,4,5-tr) eeehydro-1H-dibenzo04,3,6,77thiepino [4,5-01] ^^^, ^{3-methyl-y -2, 3,} 4, H -dibenzof ^2.3: 57J oxepino no ^p [4.М гр ^ ^ ^{3-methyl-7-yl-2,3,4,5-kyun} teeuhlУy (r? o-1 H dibunzo ^[2, 3: 6, 7] thiepine-4,5,5-djazepine, 3-methyl-1,2,3,4,5,10-huxahloro-dibeerolf3 4: S, 77cУkllhepPap or 3- (2,3,4,5-eetrhydero-1 H-dlb) [2,3: 6,7] Thiepine [4,5-d] epepin-3-yl) pentanol, and salts of these compounds, in particular the acid addition salts thereof, in particular pharmacotherapeutic use the salts of these compounds with acids.

The compounds of formula I are prepared in a manner known per se.

According to the invention, the compounds of formula (I) are produced by producing a compound of formula (IV),

in which

A, X, Y, Z and Rj are not as defined above and, at least one of both symbols and Q? represents an oxygen atom and the other optionally represents two hydrogen atoms, reduces.

The reduction is preferably carried out with a complex hydride such as lithium aluminum hydride or diborane or with aluminum hydride. The solvents used are preferably ethereal liquids such as diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether. The reaction temperature is preferably between about 0 to 100, optionally at the boiling point of the reaction medium used.

Diborene may be produced separately and introduced into the reaction mixture or may be formed in situ from sodium borohydride and boron trifluoride etherate. An activator such as aluminum chloride can also be used for the reaction with lithium aluminum hydride.

N-substituted lactam derivatives and imidoderivatives as starting materials of formula IV may be prepared by substitution of the corresponding compounds of formula IV which are not substituted on nitrogen. This N-substitution may be carried out according to known methods, for example by treatment with a reactive ester of the corresponding hydroxy compound of formula R 1 -OH; wherein R1 is as defined above except hydrogen.

Imides of formula IV which are not substituted on a nitrogen atom can be obtained from the corresponding diacetonitriles by forming an ezepine ring with hydrogen bromide followed by water and dimethylformamide. From these imides, the corresponding lactams can be produced by partial reduction with a complex hydride of an ethereal solvent such as diethyl ether or tetrahydrofuran.

The reactions according to the invention can optionally be followed by various conversions in which the compounds of the formula I are converted into other compounds of the formula I.

Optionally, a compound of formula I wherein R 1 is hydrogen can be converted to a reaction product wherein R 1 has any of the other meanings.

Thus, for example, substitution may be made on a nitrogen atom either by treatment with a reactive ester of the corresponding alcohol of formula R1 -OH, in which R1 is the same meaning as R1; in formula I, with the exception of hydrogen, or by reaction of 8 with the appropriate aldehydes or ketones under reducing conditions.

The reaction of compounds of formula I wherein R is hydrogen with a reactive ester of the hydroxy compound of formula ^V R-OH, is preferably carried out in a solvent at a reaction temperature of 20-130 ° C, especially at the boiling point of the solvent.

As reactive esters, for example, halides such as chlorides or bromides, longer sulfonic acid esters such as methyl or ethyl o- or p-toluenesulfonic acid esters, or sulfuric acid esters such as dimethyl sulfate or diethyl sulfate can be used. Suitable acid-binding agents are, for example, alkali metal carbonates such as potassium carbonate or alkali metal hydroxides such as sodium hydroxide, or tertiary organic bases such as pyridine or N-ethyldiisopropylamine.

б

Suitable solvents are those which are inert under the reaction conditions, for example hydrocarbons such as benzene or toluene, furthermore alkanols such as methanol or ethanol, or alkanones such as an oetone or methyl ethyl ketone.

IV

Aldehydes and ketones which correspond to alcohols of the formula R 1 -OH are represented, for example, by lower aliphatic aldehydes or ketones, by lower free, eaterified oxoelkencarboxylic acids. The reaction product obtained in the reaction of these aldehydes or ketones with said compounds of formula I can be reduced in the same process or thereafter.

Aldehydes, for example formeldehyde or acetaldehyde, or ketones, for example acetone, and, for example, with said compounds of formula I, are heated in an inert solvent to a temperature of 30 to 100 ° C and simultaneously or thereafter. Suitable solvents are, for example, alkanols, such as methanol or ethanol, and suitable catalysts are noble metal catalysts, such as palladium on carbon, or aline catalysts, such as Raney nickel.

Other reducing agents, such as formic acid, may also be used in place of hydrogen in the presence of a catalyst for reductive alkylation. According to this process variant, said compounds of formula (I) are heated with formic acid and the aldehydes or ketones of said type, in particular formaldehyde, preferably without solvent.

However, this substitution at the disk atom by an alkyl radical may also be carried out by first acylating the reaction product in which R @ 1 is hydrogen and reducing the carbonyl group. This reaction is preferably carried out by treatment with a complex hydride such as lithium aluminum hydride or diborane. The solvent used is preferably an ethereal liquid such as diethyl ether, tetrahydrofuran-dioxane, dimethyl ether, ethylene glycol or diethylene glycol dimethyl ether. The reaction temperature is preferably between about 0 ° C and 100 ° C, or it is about the pM boiling point of the reaction medium used. Diborene can be produced separately and introduced into the reaction mixture or formed in situ from sodium borohydride and boron trifluoride etherate.

Further, optionally, a compound of formula (I) wherein R 1 is hydroxy (lower) alkyl may be a compound of formula (1) wherein hydroxy is lower (lower) alkyl.

Aoylation can be carried out, for example, by treatment with a carboxylic acid anhydride or with an appropriate carbonyl halide at a reaction temperature between about 20 and 100 ° C. Since the condensation proceeds from the cleavage of the acid, it is expedient to add to the reaction mixture an acid-binding agent, for example a tertiary organic base, such as pyridine. Excess tertiary organic base can also serve as a solvent. In addition, hydrocarbons such as benzene or toluene or halogenated hydrocarbons such as chloroform can also be used as solvents.

Further optionally, compounds of formula X &apos; wherein R1 is phenyl (lower) alkyl may be hydrogenolyzed to a compound in which R1 is hydrogen.

Hydrogenolysis ae can be carried out using conventional hydrogenation catalysts, such as noble metal catalysts such as palladium on carbon or platinum dioxide, rhodium catalysts such as rhodium on carbon or non-alumina or alloys such as Raney nickel, in an inert organic solvent such as methanol, ethanol or dioxane, at room temperature and atmospheric pressure or at moderately elevated temperatures up to about 100 ° C and / or under elevated pressure to about 100 bar.

Further, optionally, a compound of formula I wherein X is a bivalent radical of partial formula Ie, (Ia) wherein R 1 is hydrogen may be converted to another reaction product wherein R 6 is a lower alkyl moiety. .

This conversion is preferably carried out by reacting the above reaction product with a reactive lower alkyl ester in the presence of a solvent and a basic condensing agent.

As reactive esters, for example, halides such as chlorides or bromides, sulfonic acid esters such as methyl or ethyl esters of o- or p-toluenesulfonic acid, or sulfuric acid esters such as dimethylesulfate or diethyl sulfate can be used. Alkali metal alkoxides, such as potassium tert-butoxide or the corresponding amides, such as sodium amide, or metal hydrides, such as sodium hydride or lithium hydride, are suitable as the basic condensing agent. Suitable solvents are those which are inert from the reaction conditions, for example, hydrocarbons such as benzene or toluene, and ethereal liquids such as tetrahydrofuron, dodoxane, ethyl ether glycol ether or amides such as phosphoric hexameyl triamide or dimethyforreamide.

This conversion can also be carried out by first acylating the above-mentioned reaction product and then reducing the corbonyl group.

The reduction is preferably carried out with a hydride. The hydride used is preferably diborene, in an ethereal reaction medium such as tetrahydrofuran, dioxane, dimethyl ethylene glycol.^Noor diethyl ether diethyl ether. The reaction temperature is at^pr^kland^d mmzi -^{20 May} and^of +8⁰ ° C, preferably between 0 ° C and room temperature. The necessary dlboren will mercury to produce either from^bo ^^r^ t ^^r.fl ^ uo ^! td ether and sodium hydride in particular, for example, in a solvent which is used for the reaction and can be used in the form of a solution, or is formed, for example, in dimethylether dimethyl ether and introduced as a gas into the reaction network, or is also formed in situ.

Depending on the reaction conditions and the dispensing materials used, the reaction products are optionally obtained in free form or in the form of their salts, which can be converted in a conventional manner with each other. or get converted to other salts. Thus, the free compounds of the formula I are formed from the acid addition salts obtained, for example by treatment with bases or basic ionic salts, whereas the free bases of the formula I are converted into the β-acid addition salts, for example by reaction with organic or inorganic acids, which are suitable for the production of pharmaceutically acceptable salts as mentioned above.

Salts of the novel compounds can also be viewed for purification, for example, by converting the free compounds into their salts, isolating them and optionally purifying them, and converting them into the free compounds again. As a result of the close relationship between the novel compounds in free form and in the form of their salts, the free and the corresponding salts are understood to mean the free compounds according to the purpose and the purpose.

The invention also relates to those embodiments of the process, wherein the starting material is a compound which is obtained at an arbitrary stage of the process, such as that for the absence of the retention steps, or of such embodiments of the process, in which the starting material is formed under the reaction conditions or in which the reactants are used in the form of a salt.

Suitably, starting materials are used for carrying out the process according to the invention, leading to the groups of reaction products which have been particularly emphasized above, and in particular to the particularly described or emphasized reaction products.

New compounds can be seen. for example in the form of pharmaceutical preparations containing an effective amount of the active ingredient, optionally together with inorganic or organic, solid or liquid, pharmaceutically usable substances which are suitable for enteric, for example oral, or enteral administration. Thus, it uses tablets or gelatine capsules which contain the active ingredient together with diluents, for example and lactose, dextrose, aacharose, mucosa, aorbit, cellulose and / or glycine, and lubricants such as baptism, mothers, atearic acid. or an adi thereof, such as the magnesium or calcium salt of atearic acid, and / or polyethylene glycols.

The tablets also contain binders, for example, magnesium aluminum silicate, starches such as cristal, peanut or rice. The starch, gelatin, tregttite, methylcellulose, netrlimcarboxyl ethylcellulose and / or polyvinylpyrrolidone, and optionally the substances allow for the use of the starch. disintegration of tablets such as starches, agar, acid. . alginic acid or an adi thereof, such as alginate stabbing and / or effervescent alpha, or edaorbing agents, barium, flavorings, and aladdla. Further, the novel pharmacologically active compounds can be used in the form of an injectable, e.g. in the case of injectable preparations or ifusion solutions.

Such anionic solutions are preferably isotonic aqueous solutions or auapensions, and such solutions or suspensions, for example as photophilic formulations, which contain an active substance and / or an apol and a compound, for example, may be prepared before. using. The pharmaceutical preparations ae may be atrilotate and / or may contain adjuvants such as preservatives, licking agents, wetting agents and / or emulators, auxiliary solvents, oamotic pressure control agents and / or buffers. other pharmacologically valuable substances that are produced in a manner known per se, for example by means of conventional mixing, granulating, dragee, dissolving or hydrophilic processes and having a range of about 0.1 to 100%. in particular about 1 to 50%, 10 to 100% active ingredient.

The dose depends on the method of application, type, age and individual status. The free dosage of the free bases or pharmaceutically acceptable salts thereof is between 0.1 mg / kg and 10 mg / kg for warm-blooded in general and between 0.01 g and 0.5 g for warm-blooded weight. about 70 kg.

Here are some examples to НШт! The invention is based on Cdsia.

Peak IbIB

Slaptnzi To 14.6 g (0.38 mol) of ^y lilhlmιel'minllml -ridu in 1 liter of absolute -1ι0ι140ιπ ae stirring under nitrogen a0iOttfárol added over 20 minutes auapenze 32.1 g (0.1 mol) of 3-1-ietyl ^, 5-di ^LYD ro-2H- ^(d bbtiz ^{2.3: a} 7 ⁷ - <. ^{1 iepiio-4,} 5-d aztpLi _^J-2) 4 ^(H) -dione in ⁰⁰ ml of 5 abaoluta ^ o pMče ^ e ^ coated is maintained at 20 ^and 30 °. After ^the reaction was allowed om e auditorium for ^{15 h} in a Vario ^{d 0} under zpilým tuner ^ - after ⁰ M e is cooled to ^0-5 °. Carefully mix with 75 ml. of acetic acid. and then with 150 ml of water and decompose the excess lhminolaminamine. The organic phases are then separated and extracted several times with 5% aqueous acid. 1

The acidic extracts are basified with concentrated ammonia to pheno- phthaline, whereby auric 3-ethanol-2, 3,4,5-tetraalkyl (1 _H -dibenzo [2,3,3,07]) is obtained as an oil. 4,5,5-07azepli · Crude base ae extracted with ether, the organic phase ae separated, washed ae with water and after thalatine. and completely evaporate.

Residual ae rozpiutí ^to 5 ⁰ ml petardám ™ and the cooled ^and says .ae at ⁰ ° ^F NACE conducting training zmaluje ^CIA and a base, mp 83-86 °. Melting point (methanesulphate: 256 to 256 °,

Default ^AOK l and, ^for j. ^{T 3 -methyl-1-yl, 5-2H-} -dltψdrc ^d i ^b enzc ^£ 2, ^{3, 6,} 77 ^{7 1} e ^and h inc] ^{4, 5} - <? 2 azepli 4 (3H) -dione can be produced in the following manner. To a solution of 30.7 g (0.1 mol) of ^1,5-d-2H- dilydrc lbbtio ^cf 23: 6,7 / t ¹ iepino ⁴ 4.5 - ^^ ^ 1 ^ -2,4 (^) 1-one ^(b vlro TNE ¹ on ^p ccording ^{Observe the} reading in the case ^of _ ⁶⁾ а 16.6 g (0.12 mol) of methyl iodide in 1 liter of methylene chloride, with stirring under nitrogen dropwise over 30 minutes a solution of 28.5 g (0.11 mol) tetrabutyleaone fluoride hydroxide in 45 [mu] l of water, raising the temperature from 20 to 25 [deg.] C. The reaction mixture is then allowed to stir at 100 [deg.] C. at room temperature and 250 ml of water are added. The organic phase is now separated, washed with water and, after drying over sodium sulfate, completely evaporated. The crystalline residue is stirred with 50 ml of absolute ethanol, then the mixture is filtered and the residue on the filter is washed with absolute ethanol. The product, i.e. 3-methyl-1,5-dihydro-2H-dibenzof2,3: 6,7 / thiepino-4,5,5-dipazepine-2,4 (3H) dione, melts after drying at 216-222 °.

At. clade 2

To an ice-cooled solution of 4 g (0.03 mol) of aluminum chloride in 100 ml of absolute diethyl ether is left stirring and excluding moisture in (0.03 mol) of lithium aluminum hydride in 75 ml of absolute diethyl ether so that the reaction temperature does not exceed 5 °. Then, 2.93 g (0.01 mol) of 1,3,4,5-tetrehydro-2H-dibenzof2,3,16,7-thiepinof4,5-djazepin-2-one in is added to the suspension; 50 ml of absolute diethyl ether and refluxed for 24 hours. After cooling to 0 to 5 °, excess aluminum chloride is carefully decomposed by dropwise addition of 10 ml of water. The organic phase is then separated, washed twice with 30 ml of water each time, dried over sodium sulphate and evaporated. 2,3,4,5-Tetrehydro-1H-dibenzof2,3: 6,7-thlepinof4,5-dezepine is obtained as a residue, which melts at 142-143 ° after recrystallization from methanol. melting point: 305-307 °.

The starting material, i.e. 1,3,4,5-tetrahydro-2H-dlbenzof2,3: 6,71thiepinof4,5-d] azepin-2-one, can be produced as follows:

198 g (0.5 mol) of 10,11-bis (bromomethyl) dibenzophobifthiepine are dissolved under stirring in a nitrogen atmosphere at 50 DEG C. in 2.5 liters of acetonitrile. To this solution was added dropwise a solution of 59 g of sodium cyanide in 180 ml of distilled water over 10 minutes, while maintaining the internal temperature at 50 ° with gentle cooling. The reaction mixture is then allowed to stir for a further 30 minutes at this temperature, and then 1.5 liters of ice water are added, crystallizing out the dibenzophobium, phthiepine-10,11-diacetetritrile. The gray crystals are filtered off, washed with water, then with acetonitrile and finally dried under vacuum at 50 °, mp 205-207 °.

145 g (0.5 mol) of dibenzo [b, f] thiepine-10,11-diacetonitrile are dissolved from 2.75 l of methylene chloride by stirring. Dry hydrogen bromide was removed from the reaction mixture over a period of 30 minutes from ice-cooling at 5 to 7 ° C, after which time yellow crystals began to precipitate out of the reaction mixture. Thereafter, the hydrogen bromide feed was discontinued and the mixture was further stirred for 30 minutes at 5-7 °. Then, the reaction mixture was distilled off. half of the solvent in vacuo, the remaining crystalline slurry was filtered off, washed well with methylene chloride and the slightly yellow crystals were dried under reduced pressure at 60 °. The 2-amino-4-bromo-1H-dibenzof2,3: 6,7-thiepino / 4 thus obtained, The 5-azepine hydrobromide is further processed as a crude product.

g (0.2 mol) of 2-amino-4-bromo-1H-dibenzof2,3: 6,7-thiepino-6,5-dazepine hydrobromide,

1.5 liters of DMF and 1.3 liters of water are heated under reflux for 2 hours under nitrogen. Then the reaction mixture is diluted with water at 90-100 ° C and then cooled to 5 ° on ice, crystallizing 1,5-dlhydro-2H-dibenzo [2,3: 6] thiepino [4,5-d] ] ezepine-2,4 (3H) dione, which is filtered off and washed with water and acetone. After drying at 100 ° under reduced pressure, the crude product melts at 253-256 °.

To a suspension of 22.8 g (0.6 mol) of lithium aluminum hydride in 3.5 liters of absolute diethyl ether and 350 ml of absolute tetrahydrofuran under stirring under a nitrogen atmosphere, a suspension of 61.4 g (0.2 mol) of 1,5-dihydro- 2H-dibenzof2,3: 6,7] thiepinof4,5-dasepine-2,4 (3H) dione in 200 mL absolute diethyl ether, maintaining the temperature at 20-30 °.

The reaction mixture was then refluxed for 24 hours and then cooled to 0-5 °. Carefully dropwise addition of 150 ml of ethyl acetate and then 300 ml of water decompose the excess lithium aluminum hydride.

The organic phase was separated, washed first with 2N hydrochloric acid solution and then several times with water, dried over sodium sulfate and then evaporated completely. As the residue, zi ^ ská ¹ 3> 4,5-tetahhyč ^{r-2H-dibenzo about} 2.3: 6.7 thiepinl ^j £ ^4, 5-d ^{j pi} Aze-2-yn melting ^{melting 19} 5 to 198 °.

Example 3

8.38 g ^{(0, 0} 3 ^of RNO) H-dbeenz ^^ Oj ^ thiepino £ 4, from stirring dissolved in 6 ml of 85% formic acid at 40 ° to 50 °. 2.4 ml of a 35% formeldehyde solution are now added to this solution and then the mixture is further stirred at 95-100 ° C for 12 hours. The reaction mixture was cooled to 20, diluted with 100 mL of water and this solution was concentrated ammonia zslkallzuje not fenooftalein, whereby an oil precipitated crude ³ -OC ^{2 et} _l-> 3, ^{4, 5} -tetreh ^yd * L ^-1H-d beezzΓ2, Зп тНм.ер ^! ^ ^f4, 5 ^e djezepin. The crude base is extracted with ether, the organic phase is separated, washed with 200 ml of water and, after drying with sodium sulfate, completely evaporated. The base is n ^y it 'not converted in the following manner:

8.4 g of the crude base was dissolved in acetone 40 mm а к opparně solution was added 2.6 g of metensulfonové, followed vytarystaluje mee ^3-yl 1l2, ^3, 4,5-tetrθh DRL ^{yl-1H-děbenzo02 3:} 6,7-β-piperidine-4,5-di-ezepinoethanesulfate, which, after recrystallization from absolute ethanol, melts at a pH of 256 to 2513 °.

EXAMPLE 4 ^8.38 g (0.0 RNM ^{3 o) 2, 3, 4 e} 5 ♦ eaгe ^ ydrl-Ш-dibtnzo ^{L2, 3: 6,} 7_Jthiepinlí ^4, 5 ^of Jtztplnu with stirring in 80 ml rozpussí 50% acetic acid. To this solution was added 8.16 g (0.08 mol) in one portion. The reaction mixture was completely rotary evaporated, the residue dissolved in ether, the ethereal solution washed once with hydrochloric acid, once with 2N sodium hydroxide solution, and the dihydrate with water. After drying over sodium sulfate, the ethereal solution is completely odpaaí, ^price in the form ^of oil žatého ZBUD ³ ation ^e yl- ^{2, 3,} 4,5- ^t ttral ^y d ^r o ^{1H- l} 2.3 ^dL Beni 6 , 7 ⁷ thiepine-β-dJezepine. 9.4 g of the crude acetyl derivative are dissolved in 150 ml of absolute diethyl ether, and this solution is added dropwise over 30 minutes to a suspension of 1.6 g (0.042 molar of tert-butylaluminum monohydride) in 50 ml of absolute diethyl ether, bringing the reaction mixture to boiling. After cooling to 0-5 DEG C., 40 ml of water are added dropwise to the reaction mixture, the organic phase is separated off, the organic phase is washed with water and, after drying with sodium sulphate, completely evaporated to dryness. was dissolved in 10 ml acetone and cooled · is not 10 °, then vykny-complains,. ..3 TTYL-2, ^{3, 4,5-d} tetrθhy ro-1H- ^di benzof2, ^{3: 6,} 7jthespino [4,5-dJazepin melting "point Ю ^{6 and} 107 °. MeeanBulfonát obtained by the method according to the 17th příttad temperatures © ^ i ^212-214 ° ^(from absolute ethanol).

Example 5

Analogously JEKO described in Example 2 was prepared iáβtedulící reaction product: 30 g (0.1 idoD tttгahydrl- mixture of ^{1,3,4,5-2H-thieeiO 2} *, 3 2, ^3] fjbenioltie ^p ino [ 4,5, -dJazepin-2-one and 1,2, ³⁾ 5-4H-tttrahydo thiLeil ² *, 3 *: 2.31. benioltietinofé ^ -djazepin-4-one was obtained ^2-3.4.0-1H tetaвhydl - hieei0 ² ', 3': 2,3 [(J benizlhiepino0 ^4, 5-dJaztpin, mp 119-120 ° ( from diet bars).

And Výchzzí ^{^^,} i. A mixture of ^{1, 3,4,} 5- ^d · ^t ttrθhy ro- ^{2H-thieno L} 2 ', ^{з: 2} JJ ^J 1 ^b einzcιthieρiil £ 4,5-dJazep N- ^ -one and ^{1, 2,} 3,5- ^t ttrahydl- ^{4H-thieno LL2 *} 3 ^J 1 ^{f JT} hitpinl ^{(4, 4} 5ddJaztpLn- -ziu, may yyro & T substance analogously to Example 12 as follows:

of ^{201 g (0 5} mol) of 4,5-bis (br <tetramethyl) thieno [2,3-b] p] is obtained tenzothiepinu thienop, 3 ^"b JflJ eNom ^ ^, 556 ^ 810 ° t ^ L, mp ¹⁷⁰ ° EŽ 17 ^{2 (from} ecetoliiril ^u)} of 147 g (0.5 mol) thitnof2,3 b] flbtBnzothitpin 4 * i5-dletetoiitrilu · gave a mixture of 2-AMNOTE-4-bromo-1H-ttdenol23 *: 2,3] f) J-benzothienyl [4,5-d] zeppinyl (methyl [4-amino-2-thiol] -1H-thienophene ² , ³ : 2,3 ⁾ beozo lapioo ^ ^£ 4,5-d] aze in ^{p h} y ^d r chromium as a crude product. from a mixture of 92 g (0.2 mol) of 2-aιdnio-4-roliLH thihnoi0 ', 3''2 ^ зJ LJ beozoOhiepioo £ ^4, 5-dJaze pinhydrochloridu · 1 and 4-amino-2-0 ^ · (lm5H-thlenif, 3 *: 2,3jf)] b «ozooMepioo24, '5id] azepinhydrobromita detects the ^1,5 -d l ^{d ih} 'o · 1 ² H ^H tl .tno ^L2 * У: ^2, 33 ^{2 R} Enio ^0tl ep ^p £ amino-4,5 UJβzepPn- ² 4 ² 3 J ^Н ion ^{with mp} 21> Jk 218 * (from my thin); and 62.6 ^{g (0 2} mol) of ^{1, 5-di h} y ^<d, o ^{- HT} iieif ^o2, 3 * ² 3j flJ ^b tnzo hit ^{by p} ino {4 ', 5-dJazt ^beta-2,4 (H) -dione gave a mixture of' 1,3,4,5-tetΓ8l1Ur (o2H - hleeol22 3 ^2: 2J3Jfϊ (tβnzotl ^{overvoltages p-iof4,5} u7aztpin ^-2- oou and ^{1,2, 3,} 5- ^t OTE lУ * ^s d · oτ4H ^p-th TNO ^{222 з2 3 »3] and} lol ΐei ^{β 1e} Pi ^and 02o ² 5 Ud] ^TPE-n-0-flax crude product. .

Example 6

In an analogous manner to that of Example 3, a non-seeded reaction product is prepared:

Λ 14.3 g (0.05 moo) -2,3,4,5-1H-terrahidro - hitnoo2 ', 3': 2,3] pJbenzothiepioof4 ₃ 5-d ₈ zepiou give 3-mtt-L-2 , 3,4,5-tttrehidro thitnoo ^1H-22, 3 *: 2,31217benzothiepioo24,5 d] ezepio as a crude product; methanesulfonate has 0. 0. 206-209 ° (from absolute ethanol):

Example 7

The following reaction product was prepared in an analogous manner to Example 4:

14.3 ^{g (0} ^ ⁵ mo ^{o) 2,3,} 4, ⁵ -tetaahl ^d ro- ^{1 -0h} EEI 1H- ^{022, 3} ': ^2,3 J ^{P7 (b} nfrom · ^o h. ^I e ^{when 4-NO2} J51 dJazepinu of ^ka ^ ^l l- 3TT ² 3,4,5oto ^r ee ^ ^y dro ^- 1 H ^-0h .eno ^{L22, з2: 2, 3]} / ^ib and ^l ie inzot ^p ino ^{2 u} 4,5] aze ^p io ^o t ^p lo ° of the ^{127 th} and ^from 129 DEG ^(from acetone); ineeealainďonát 0. 0. ²⁰⁹ and ^{from 21} ° (from abs. ethanol).

Example

The following compounds can be prepared in an analogous manner to that described in Example 1, using the appropriate starting materials:

from 39 ^{3 g (0 »4} MO 3 ²³ ^ - ^(l dimt0 amino)] p? L ¹ of ^{the op-1,5-UIH l <u} Ό- ² H ^- Ubieiz £ 2,3: 6, 7jthie ^P th ~ ino flaztpin ^ - ^^ ^ rr Don and 14.6 ^{grams (0.36} mo ^ _ l ^of th ^{l l} MM1 ШL lLUш ⁱ ^ h l ^{d ld} rl absolute diethyl -. ethen give 3 -3- (((δ »β-β-α-β-propionyl) -2,3,4,5-tetrahydro-1H-dibenzimidazole, 3: 6,7] Ohpino 24,5-U] azepia in 2 ore of crude product; (.Alpha., Chlorine, 0.25 DEG to 265 DEG C. with decomposition;

X ^{39.9 g (0.1} mol) of N, N-dimethylamino-amino- ¹¹ -diene; 5- ih ^{IU u} ro- ^{2H-thitnoΓ2 ',} 3 ^{2: 2} £ 3J í7benzo0hiepino24,5-dJazepin-dione and 14.6 g (0.36 mol) 10lhlmnβlmloLluщhy (RIDL dietil in absolute ether to give 3 - £ 3-d ^dp mttyemino) propi1J · 2, ^3, 4,5-tetrahydro 1uro ^P) H-thilLeo ^ l ² 3 ² 2.37 ^{2 2} lJteřnzo0hie ^p ino ^{4, 5-d] p} in of eze in the form of a crude product ^; McldorM 0. ²⁶ 0. 5 ^{and 2} 7 °° zs decomposition;

z 37.4 g (0.1 mol) 3-231 '('<Lioβ011βmiio)β-β-β-5,10-> dichlorodibenzo [3,4]: 6,7 cyclohepoa ^{ ^ - ^ aztpin- ² ^ 1 ^H d ^ Mi-one and H ^»(6 g, ^0.36 mo ^ ^ Mun mdminium ^ d ^ u va ^b solutním chtVk.éten of ^ s ^ ^{ka 3} - ^2з - ^(d imtty ^e θm ⁱ no) -prop; l] J-1, ^2, 3,4, ^5, 1 ⁰ -hθXθl · ^hl to ^{Lu biniofЗ:} 4: 6,7jcyklo ^HE p ^{<0E '2)} ^ - (^ ζορ! ^{0, the 0th 0th 60} e ⁶² ° ^(from pentane), d ^ toochlorid ^{0th 0th} about ³ ° 15 ^(for ^ née Lafo).

The starting material can be produced as follows:

aa) to a suspension of 30.7 · ^'g (0.1 mol) of 1,5-di-hy ^d ^ ro- ² ^ -C ^ IT BE ^ from ^about 23 2: 66r7t ^t ^ l (^] ^ i ^ i ^ (^ f4, ⁵ -dJeze ^beta-2,4 (3H) dione in 14.6 g (0.12 mol) of freshly destiOovaného 3- (dimetyleminp) piOpylchloridu and 600 ml of absolute toluene under stirring under reflux for e A suspension of 2.3 g (0.1 mol) of lihliwamide in 6.9 ml of abs. toluene was added dropwise to the reflux condenser over 2 hours, and the reaction mixture was then refluxed for 20 hours and then cooled to room temperature. After the addition of 100 ml of water, the organic phase is separated and extracted three times with 50 ml of 10% methanesulphonic acid each, and the acidic extracts are basified with concentrated ammonia and not pheno-phthalein, whereby 3- [3- (dimethylemino) pyl] -1-1 is obtained in crystalline form. ^5-yl & dihydropyrimidine-2H-dibbezo ^of 3: 6,7jthiepinof4,5 ^{dJezep-i-2,4 (H)} d ^and on which, after přelkrystalování from ether e.. Tiye pentane at I ⁰² ° to Н ³ °.

Mte ^ r ^ ns ^ uLfo ^ i ^ -t is prepared as follows:

g of base (0.076 mol) was rozpudí in 75 ml ecetonu ek solution was carefully added 7.3 g of methanesulfonic acid (0.076 mol, followed vylkyšteluje 3-f3Mdimetylaon.no) jp? ooyyl-1 ^{»5-2H-dlhyiro-} dibbnnoOf , 3:, 6,7tthlepinofl, 5idJorepnn 3,4:)) (dloIтаetenβulfonát which, when recrystallized from methanol to ^t and is at ²⁷⁰ to ²⁷ ° for 5 rpzklata ·.

The following compounds can be produced in an analogous manner:

bb) ^{31.2 g} (0.1 mol) of ^1, 5-IIh ^with <f · {ooí2 - · thleenO2 ', 3': 2,3.ftJlrмloothLβpLLn ^{[4,5-IT-2,43H} oepLn ) -dione, 14.6 g (0.12 mol) of 3- (IIIm · ts1cmino) proppSchloriiu and 2.3 g (0.1 mole) of L ^ Hulu amide to give 3- ^f 3 ^(iL Lmrt l · ^{s м} .no)] p! · Jb PPE ^{with 5 .mu.l} hУ ^{i '<O 2-thio Eno} 2 *, 3 ^{*: 2} з] ^[L f | benw ^^ pi. amino ^^ - ^ azepine ^^ DJs lHHion by ^counting at ^{17 and} 1. 119 DEG ^(from acetone) tyfrooUorM ^b from mp 224-227 ° (from absolute ethanol) and ^{cc) of} 23 ^{9 g (0} 1 mole) of ^5, 10 iih ^y (R odibbenoOЗ 4: 6,7tc ^with clohepta [1'-dmMn- ² , 411 (3)] dLone, 14.6 g (0.12 mol) of 3- (trans -emino) meth-chloride and 2.3 g (0.1 mol) of Ιϋ ^ ΙϋβΜ. ^ ^e gave> [ '3- ^{(iimetylaminn))} after ^{the IP} У ^L - ¹ 0-di- y ^{h (i: Oi} Ό bbenoOЗ, 4: ^{6, l} o ^h 7tcsk EPTA ^^ - ^ rnzepin-2 41 (1H, 3H), mp 113-115 ° (from hexane) hydrochloride, mp 265-269 ° (from α).

5110- (r01brnoЪeзz4 3,4 3,4sá, k] cheltaepta1,0rd] asepine-H, 3 (1 H, 03) Mon was prepared analogously to the starting materials in Example 14:

¹⁸ 9 ^{g (0 5} mol) of N, N-O-methyl tt.s ^ ^^ ^ dihmzofe .Jcyklobeptanu (DOS ^{no. 2125654} in 2,5-Hu Lita acetone and 59 g (1.2 mol) of sodium cyanide ae obtained 5H- dtbmno £ ¢ a, d] csk1ohet ~. TM-10 J-1 díeceroontгil t. it ^217-2 20 ^(Z οΗ οζ ^ ^ ^ ηί) 135 g (0.5. MOO) 5H -dibbenzOa * bb - rklohepttn-10,11-diacceton ^<Lrilu 2.75 Lita metyΙηοΗ Ι ^ ^ ae dry HBr gives 2-βmino-4-bromo-1,10-dLhyώroiibβnzo £ 3.4: 6,7Jcsklohbppafi ^ ^ n ^ -djeze drobroald crude product; ^{86 5 g (0} 2 mol) of ² -cmnno ^- 4lb'oo-1 ^{(10far hy} d ⁱ h>_dibenznfO> 4sб ⁷ JtyklL tf1 ^{O t} he ² - ⁱ i ^{- 1} corp nhydrobromidu, 1.5 and 1.3 titre cast AE water afforded 5,10-dihsirodibenoo 3.4 ^{F: 6} 7.70 10 ^ ^^^ ² - ^D- czetin- ^2, 4 ^{(1 H, H) and} ion it to 265 ^DEG-268 DEG ^(from acetone).

Example. 9

In the same way as in Example 1, the following compounds can be prepared from the use of drop-off starting materials:

3 ^"b ltyl- ² · ^c 3,4,5rte and ^Sir ro11 ^H - ⁱ i ^b rnooΓ ^2, 3: ^6, 7 ^t thienyl ^{pn 4} ,, amino 5idbcze in ^t, 't.. t. W7 e ^ž

108 DEG (from acetone), mp ^{218 and 220} ° ^(from the ATA. Ethano ^);

3-cl · 1 ^s l- ^2: 3,4., 5rteegeh ^id o-11 ^H - ^iib rnoo ^f2 , ³ : ⁶ , 7J thie ^p ino ⁴ , 5id ⁷ eoe ^pL n ^is a crude protact; methyl sulfonate Tiye ^ s ^p e 225 ²² 7 ° ^(from dnaoluto ^ o ^ methanol);

^ kpfvo

3-propynyl-2,3,4,5-tetrahydro-1 H -dibenzof 2,3,3,7-thiepinof 4,5,5-djazepine as a crude product; methanesulfonate, mp 218-221 ° (from absolute ethanol);

3- (cyclopentylmethyl) -2,3,4,5-tetrahydro-1H-dibenzof2,3: 6,7] thienyl-4,5-azepine,

mp 113-115 ° (from absolute ethanol); methanesulfonates mp 246-252 ° (from absolute ethanol);

3- (cyclohexylmethyl) -2,3,4,5-tetrahydro-1 H -benzoyl 2,3,3,7,7-epino-4,5,5-d] azepine, mp 113-115 ° (from acetone); methanesulfonate, m.p. 256-256 ° (from absolute ethanol);

1.2.4.5- tetrahydro-ЗЙ-dibenzo ² 3s6,7.Ithlepinof4,5-d] azepin-3-ethanol, mp 157 EŽ 159 DEG (from acetone); methanesulfonate, mp 194-198 ° (from absolute ethanol);

1,2.4,5-Tetrehydro-3H-dibenzof2,3 * 6,7-thiepinof4,5-djazepine-3-propenol, m.p. mp 120-132 ° (from acetone); methanesulfonet, mp 181-183 ° (from absolute ethanol);

3- (3-methoxypropyl) -2,3,4,5-tetrahydro-1H-dibenzo ^2, 3: 4,5-6,7jthieplno £ dJazepin as a crude product, methanesulfonate, mp 213 EŽ 216 DEG (from ethanol absolute );

3- [3- (methylthio) propyl] -2,3,4,5-tetrahydro-1 H -dibenzof 2,3,3,7-thiepinof 4,5,5-djazepine _; in the form of a crude product; methanesulfonet, mp 212-214 ° (from absolute ethanol);

3- [2- (methylthlo) ethyl] -2,3,4,5-tetrahydro-1 H -dibenzof 2,3,3,7,7-thiepinof 4,5,5-dezepine, mp 91-92 ° (from pentane); methanesulfonate, m.p. 216 DEG-220 DEG (from absolute ethanol);

7-chloro-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo-2,3,6,6,7-thiepino-4,5-djazepine as a crude product; hydrochloride, m.p. 266-268 ° (from absolute ethanol);

7-chloro-3- (cyclopentylmethyl) -2,3,4,5-tetrehydro-1H-dibenzo [2,3-b] thipin-4,5-d] azepine, mp 123-126 [deg.] (From acetone); methanesulfonate, m.p. 195-196 ° (from absolute ethanol) ·

Example 10

Analogously to Example 1, the following compounds can be prepared from the corresponding starting materials: 3-ethyl-1,2,3,4,5,10-hexahydro-benzo [eta] &lt; 3,4 &gt;: 6,7-cyclohepte [1,2-d] azepine hydrochloride; 296 to 299 °;

mp methanesulfonate: 220 to 221 °. ·

They did

A suspension of 19.4 g (0.05 mol) of 3-benzyl-1,2,3,4,5,10,10-hexahydro-dibenzo [3,4,4,7] cyclohepte-1,2-dazepine hydrochloride and 2 g of 59-palladium-on-carbon in 900 ml of methanol are hydrogenated at atmospheric pressure and 40 to 50 ° C until 770 ml of hydrogen are consumed. The catalyst is then filtered off and the filtrate is evaporated in a water pump vacuum.

The remaining crude 1,2,3,4,5,10-hexahydro-dibenzof 3,4,4,7,7-cyclophtheptafl, 2-dazepine hydrochloride was recrystallized from ethanol. Mp 295-300 °.

To release the base, the hydrochloride is suspended in 250 ml of methylene chloride and the suspension is shaken with 100 ml of concentrated ammonia solution. The methylene chloride solution is separated and concentrated until crystallization begins. Hexane was then added and crystallized

1,2,3,4,5,1O-hexahydrodibenzof3,4: 6,7] cyclohepte-1,2-dazepine, m.p. 190-191 °.

For conversion into the methanesulphonate, the free base is dissolved in methylene chloride and treated with the theoretical amount of acid and 1,2,3,4 _{metensulfonové>} 5,10-3,4 hexahydrodlbenz © _6> 77cykloheptafl 2-dJezepinmetansulfonát is precipitated with ether. Melting point 269-271 °.

AT

225Ю6

Example 12

Analogously to Example 1 and using the starting materials, the following compounds were prepared:

3- (cyclopentylmethyl) -1,2,3,4,5,10-hexahydrodibenzof 3,4,4,7,7-cyclohepta [1,2-d] asepl. Mp 141-142 °. To convert to the aethenesulfonate, the base is dissolved in methylene chloride, the theoretical amounts of methanesulfonic acid and 3- (cyclopentylmethyl) -1,2,3,4,5} 10-hexahydrodibenso £ 3,4: 6,7cyclohepta are added [1,2] - <5a8epinaethane sulphonate and precipitates the terrain. Mp 248-249 °.

Example li

26,1 g (0,1 aol) 1,2,3,4,5> 10-hexahydrodibenzo £ 3,4: 6,71 cyclohepta β, 2-dlazepine (produced according to example 11) ее sa announcement January mixed with addition 92 g (2 mol) of moleic acid and 20 g (0.2 mol) of 30% formaldehyde are added and the mixture is stirred for 1 hour at 95-100 °. The reaction mixture was then poured onto ice and water and basified with 10M sodium hydroxide solution. The precipitated base is taken up with aethylene chloride and the aylene chloride solution is concentrated to the beginning of the cryatalysis.

Then. hexane is added, whereby 3-methyl-1,2,3,4,5,10-hexahydrodibensor 3,4: 6,7] cycloheptafl, 2-desepin crystallizes, m.p. 144-146 °. To convert to the aethenesulfonate, the base is dissolved in aethylene chloride, the theoretical amounts of aethenesulfonic acid and 3-aethyl-1,2,3,4,5,10-hexahydrodibenso-3,4,4,7,7-cycloheptap-4-aaepinactene sulfonate are precipitated with ether. · Melting point 189-191 ° ·

Přikladli *

Analogous to Example 1 and using the corresponding starting materials, 3-bonzyl-2,3,4,5-tetrahydro-1 H -dibenao [2,3: 6,7] thiepino [4,5- d] asopine is obtained having a melting point of 149 to 145 DEG C. 150 °.

To convert to the hydrochloride, 3.0 g of the base in 100 l of acetone are dissolved and 2.2 l of a 4M solution of hydrogen chloride in ether are added with stirring and so much ether is added until the solution becomes cloudy ♦ 3-benzyl-2,3 4,5,5-tetrahydro-1H-dibenzof2,3: 6,7} thlepino [4,5-d] asepinhydro chloride is crystallized; mp 241-242 °.

Example 15

The following compounds can be prepared in analogy to the procedure described in Example 1 using the appropriate starting materials:

3- (2-Phenylotyl) -2,3,4,5-tetrahydro-1 H -dibenso [2,3: 6,7] triazino-4,5-dasepinine, m.p. 96-99 ° (with acetonitrile); aetensulfonate, mp 161-164 ° (with absolute ethanol);

7 * methoxy-methyl-2,3,4,5-tetrahydro-1H-dibensof2,3: 6,77thiepinof4,5-daBopine, mp 108-112 ° (with acetone);

hydrochloride, m.p. 220-224 ° (from absolute methanol);

7-methylthio-3- (cyclopentylaethyl) -2,3,4,5-tetrahydro-1 H -dibensof 2,3: 6, thiophenone, 5-d asepine, crude product; methanesulfonate, m.p. 206-209 ° (with absolute ethanol);

3,7-dimethyl-2,3,4,5-tetrehydro-1H-dibenzo [3, 6,7] thienyl] -4,5-djezepine, crude product; hydrochloride, m.p. 265-266 ° (from absolute ethanol);

7-bromo-3-methyl-2,3,4,5-tetrahydro-1 H -dibenzop, 3: 6: thiepino C 4, 5-d] azepine, crude product; Hydrochloride, m.p. 280 DEG (dec.) (from absolute ethanol);

3-methyl-2,3,4,5-tetrahydro-1H-phenanthro [9,10-djazepine, m.p. 142-145 ° (from acetone), netanaulfonate, mp 242-244 ° (from methanol)

3-ethyl-2,3,4,5-tetrahydro-1H-thlenof2 *, 3 *: 1,21 naphtol, 5-palzepine, crude product; m.p. 273 DEG-280 DEG C. with decomposition (from methanol);

3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine, m.p. 147-149 [deg.] (From acetonitrile); Hydrochloride, m.p. 282-289 ° (from absolute ethanol);

3-Isopropyl-2,3,4,5-tetrahydro-1H-dibenzo {2,3: 6,7-oxepinof4,5-d] zepine, m.p. 125-128 ° (from acetonitrile); maleate, mp 175-177 ° (with acetone);

3-methyl-10-ethyl-1,2,3,4,5,10-hexahydro-dibenzofb, fezepino44,5-d7aBepin, m.p. 99-100 ° (from toluene); oxalate, m.p. 180-183 ° (from absolute ethanol);

3-allyl-10-ethyl-1,2,3,4,5,10-hexahydrodibensophb, phazepino [4,5-d] azepine, m.p. 100-101 ° (from hexane); hydrochloride, m.p. 245-248 ° (from a mixture of absolute ethanol and acetone);

3-methyl-1,2,3,4,5,10-hexahydrodibenzo (b, phasepino-4,5-dasaspine, mp 121-124 ° (from methanol); methanesulfonate, mp 263-266 °) (with a mixture of absolute ethanol and acetone) and

3- (cyclopentylmethyl) -1,2,3,4,5,10-hexahydrodibenzofb, phesepine [4,5-djazepine, mp 72-75 ° (from pentane); m.p. 271-274 ° (with methanol).

Example 1 a d 16

A mixture of ¹⁶ 2 ^{g (0. 0} 5 mol) of B ^^ - tetrahydro-N-dtenzofz ^ io ^ jthiepinor4,5-djBzepinu (prepared - according to example 15) and 140 ml of 48% aqueous hydrobromic tyeeliny, boiled for 2 hours under stirring and then cooled to 20 °. The precipitated hydrobromide 7-hyd'toχl - mrtyl- З ² _{l, 4-1} 5-1H- tetrehldro · dibrnzo £ ^2, 3: 6,7jjzrpin filtered and rozpiutí in 160 ml of 60% aqueous methanol. Basified with concentrated aqueous amoortaku to fenooftelein then mounts an talus-free 7-hydroxy-E.S -meeyl ^^ ^ drahytao-dibenzoate H ^ ^ LSE Jthiepinuf ^{4, 5-beta} in DBrightness. Product ^p · taj of ^fc ekrystalovění from acetonitrile at 216 DEG-218 DEG.

9.3 g (0.03 mol) of the base in 380 ml of acetone are dissolved to convert to meenenephthonate and a solution of 2.88 g (0.03 mol) of meeannulfonic acid is added from the solution to the solution, followed by stirring. ^ 1 ^ <^^ luje hyddtoyl-7-ethyl-з -, 3, ^4, 5-trt'ehldto-1 - (! ldbbrzz0f »3: 6 _l 7] thirpino [4,5-d] ^p AZR inmerensulfonát tt about ²⁸² and ^from 286 °.

Example 17

A mixture of 18.6 g (0.05 md) of 7-bt-α-etrl-, 3, ⁴ , 5-tetramethyl-1H- (dbeta2,3: 6,7) thiepino [4,5] - ^ d ^ azepine (made according to Example 15), 10.7 g (0.12 mol) of mercuric cyanide in 20 ml measuring dimetylfrramidu the zehřívá atmooféře nitrogen at 22 hours of stirring at 180 ° no. Ree ^CZK Then the mixture was cooled on ЭД ⁰ zfcd 100 ml re ^e ylenchlori ^d ua bow ^and 5 DEG ml 5 ^0% aqueous ι ^ Ιθ ^ Ι amine. fr ^ DCKA phase is odddlí for ^ them with water, vyauěení sodium sulfate odppří. The crystalline residue, i.e. 7-klβn mrtyl-3 - 2 3,4,5-tetrв ^ y dtd-1H-di enno0 ^{b f} 3: 6,7jthiep ^and nO 4,5- ^f rzrpin ^d7, melting ^p o přefryštelování ^8г г 81 of hexane and ethyl acetate at 154 to 157 °.

9.6 g (0.03 md) of base is dissolved in 50 ml of acetone and a solution of 2.88 g (0 g) of is added from the stirring solution to convert it into the methanol. 3 mol) thyadines, 8-fluorophenone, whereupon 7-cyano-3-mrtyl-, 3,4,5-tetrehldro-1H- (3-bromo-4-ol) is crystallized, 3: 6 &_gt; - ^d Ieze ^p ^ i ^ n ^ € ^ 1 ^ i ^ r ^ i ^ 8 ^] ^ ^f tt sulfonates of ² 47 ^{and 2} 50 ^o.

Example 18

In an analogous manner to Example 1, using the corresponding starting materials, the following title compound was prepared: (3-г ^ 1-2,3,4,5 - ^^ 8 ^^ 0 - ^ - ^^^ 0 ^ 2,3: 6 , 7jthieoindf4,5-d7rzrolnt. ^t «m ^e t ^ r ^ i ^ 8 ^] ^ ^f he ^ate at ²¹² and ²¹ 4 °.

Example 19 ’

27.6 g (0.1 mol) of _3-rertl-1> 2,3, ^4), 510 - rexвhldtodlЫrlπfb f] ezroinof4,5 djazroinu the breakdown-8 also in 8гГ & hexametapdu 1130 ml and 130 ml absdutního - toluene míelháií. To this solution was added dropwise over 15 g of a suspension of 7.8 g (0.2 md) of sodium amide in 24 ml of absolute toluene, maintaining the temperature at 18-20 ° with gentle cooling; at the same time, a stream of dry nitrogen is introduced into the reaction solution to expel the releasing amodac. After completion of the dropwise addition, the reaction mixture was stirred jeltl 30 minutes and then a solution of 14.2 g (0.1 mol) of methyl ^ y iodide in 100 ml of dry toluene over 15 minutes while cooling with ice and heat ^{t d} ELE maintained ^{18 to 2} 0 ^o . ^p o ^t <m rukCní further mícM mixture is ≤ 15 minutes, ^and poured Strikes and not a mixture of 2 liters of water and 400 ml of toluene, FR-DCKA oddděí phase and the aqueous phase was extracted with toluene. The combined organic solutions were washed. water and evaporated to dryness after drying with potassium carbonate in vacuo. Crystalline residue, which is 3,10- ^ μ · ^ -1,2,3, · -

4,5,10-11 ejθ ^l y ^t genus benz ^{b £} b, f ^j zeolnof ⁴ 4,5-d ^{r t} ezopin ^EXAMPLE »Ilk» ^r -taluje from ethanol and melted ^p s ¹ 97-199 °; the metnuffonate melts at 231 to 233 ° (z - absolute ethanol). Yield of strontium is - 83%

The starting material can be produced as follows:

from 42.1 g (0.1 mol) of 5-acetyl-10,11-bis (bromomethyl) -5H-dibenzobenzazepine and 11.6 g (0.24 mol) of sodium cyanide in 500 ml of acetonitrile were prepared 5-ethyl-5H-dibenzyl ,azepine-10,11-diacetonitrile, mp 183-185 ° (from benzene);

5-acetyl-5H-dibenzyl ester was obtained from 31.3 g (0.1 mol) of 5-ethyl-5H-dibenzyl, phazepine-10,11-diacetoxdtril, 400 ml of methanol, 3.8 ml of water from absolute hydrogen chloride. b, ezepine-10,11-diacetic acid, mp 123-124 ° (from toluene);

from 37.9 g (0.1 mol) of 5-ethyl-5H-dibenz [b, f] azepine-10,11-diacetic acid dimethyl ester and 7.6 g of lithium aluminum hydride in 150 ml of absolute tetrahydrofuran gave 5-ethyl-5H- dibenzfb, phazepine-10,11-diethanol, mp 102-105 ° (from ether):

from 30.9 g (0.1 mol) of 5-ethyl-5H-dibenz [b, f] -azepine-10,11-diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine were added. 10.11-bis (2- (methylsulfonyloxy) ethyl) -5-ethyl-5H-dibenz [b] f] azepine, mp 140-143 [deg.] (from toluene:

starting from 37.9 g (0.1 mol) of 5-acetyl-5H-dibenz-b, f-azepine-10,11-diacetic acid dimethyl ester and 7.6 g of tert-butylamine hydride in 1 liter of absolute diethyl ether gave 5H-dibenz-b, fjazepine -10.11-diethanol, mp 180-182 ° (from acetone);

starting from 28.1 g (0.1 mol) of 5H-dibenzfb, β-azepine-10,11-diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine gave 10,11-bisf2- (methylsulfonyloxy) 1-ethyl-5H-dibenz [b, f] ezepine, m.p. 140-142 ° (from toluene);

from 21.9 g (0.05 mol) 10,11-bis [2- (methylsulfonyloxy) ethyl] -5H-dibenz [b] phazepine, 1.85 g (0.06 mol) methylamine and 16.25 g (0.125 mol) diisopropylethylamine yields 3-methyl-1,2,3,4-

5,10-hexahydrodibenz [b, fjezepinof4,5-d] azepine, mp 121-124 ° (from methanol); the methanesulfonate has a melting point of 263-266 ° (from a mixture of absolute ethanol and acetone).

Example 20

In analogy to Example 1, the following compounds can be prepared from the corresponding starting materials;

3-propyl-2,3,4,5-tetrahydro-1 H -dibenzof 2,3,3,7,7-thiepine-4,6-dezepine, mp 128-130 ° (from acetone); methanesulfonate. mp 181-183 ° (from absolute ethanol);

7-Bromo-3- (cyclopentylmethyl) -1,2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] esepine, mp 120-123 ° ( ethanol);

7-bromo-3-ethyl-2,3,4,5-tetrahydro-1H-dibenzof2,3: 6,7] thiepino-4,5-dezepine, crude product.

Example 21

A mixture of 19.3 g (0.05 mol) of 7-bromo-3-ethyl-2,3,4,5'-tetrehydro-1H-dibenzof2,3: 6,7-thiophenol-4,5-palzepine, 10.7 g (0, 12 M) of cyanide in 20 ml of DMF was heated to 180 DEG C. under stirring under nitrogen for 22 hours. The mixture was then cooled to 30 °, diluted with 100 mL of methylene chloride and 50 mL of a 50% aqueous ethylenediamine solution was added. The organic phase is then separated, washed with water and dried over sodium sulphate and evaporated. The crystalline residue, i.e. 7-cyano-3-ethyl-2,3,4,5-tetrshydro-1H-dibenzo [2,3]: 6,7-thieno [4,5-djazepine] melts after recrystallization from a mixture of hexane and ethyl acetate at 154 ° C. to 156 °. Yield 57% ·

To convert to the methanesulfonate, 10 g (0.03 mol) of the base is dissolved in 50 ml of acetone and 2.88 g (0.03 mol) of methanesulfonic acid are added with stirring, followed by crystallization of 7-cyam-3-ethyl -2,3,4,5-tetrehydro-1H-dibenz [2,3,3,7] thiepino [4,5-d] asepinmethanesulfonate, mp 220-223 °.

In an analogous way it is possible to produce:

from 22 g (0.05 mol) of 7-bromo-3- (cyclopentylmethyl) -2,3,4,6-tetr8hydro-1H-dibenzo / 2,3: 6,7-thiepinof4,5-djazepine, 10.7 g ( 0.12 mol of cuprous cyanide in 20 ml of dimethylformamide is obtained

7-cyeno-3 (cyclopentylaethyl) -2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino-4,5-d] azepine; 170-172 ° (from methoo); yield 60%; methensulfonate, -. -. 203-206 ° (from absolute e-eno 0u).

Example 22

Tablets containing 0.02 g of 3-methyl-h-2,3,4,5-ethyl-1H-dibenzo [[2,3: 6,7] thiopino [4,5-d] azepinomethensulfonate] are prepared as follows:

Ingredients' (for 10 000 tablets):

3-mee-h- 2,3,4,5 -ee-rahhd o-1H-di-benzo [2,3: 6,71-full [4,5-d] ezepine methanesulfonate lactose potato Starch · s-earic acid talc magnesium stearate colloidal silica e-anol

200.00 g 200.80 g 354.70 g

10.00 g 200.00 g

2.50 g 32.00 g as needed

Зио mixture of ^1-1 - ^{2 '3,} 4,5- ^e e ^e' and ^{r l} d r - d ^b 1H-benzo ^{[2,3: 6,} 7] th ^{s t} ep No ^{4 4} -DD ^t Dichlorotin sulphonate, lactose and 194.70 g of potato starch are moistened with an enenolic stearic acid solution and the mixture is granulated with a sieve. After drying, the starch, starch, magnesium sulphate and colloidal silicon dioxide were mixed and compressed to 0.1 g, optionally with grooves to finely adjust the dosage.

Example 23

Dragees, containing 0.005 g · 3-Meeth ^klβn--7-2, 3,4,5-tttrahydro-1H-dibtnzo [2,3: 6,7] -hlepinor4,5 d] azepiimeten8ulfonátu was prepared as follows:

Ingredients (for 10,000 dragees):

3-Methyl-7-cylene-2,3,4,5-e-methyl-2H-dithenzoic acid [2,3: 6,]] -hiepine £ 4,5-d] hzepinmeeaníalf oné -u 50.00 G lactose 175.90 G stearic acid 10.00 G colloidal silicon dioxide 56.60 G talc 165.00 G potato starch 20,00 G magnesium s-eerene 2.50 G Sucurose (crystalline) 502.28 G Selek 6.00 G arabic gum 10.00 G dye 0.22 G oxide 1, 50 G eeanol as required

From 3-metyll7 ^hernia-2-3, 4,5-H-tttrθhhdrc dibtnzo £ 2.3: 6]) íthtepíno [4,5día8tepínmtetísulfonétu, lactose and e-anolického-extended mesh ¹ 'acid-g are prepared earové After drying, colloidal silicon dioxide, meat, potato starch and magnesium tartar are admixed to the cream, and the mixture is pressed into dragee cores. The dragee cores are then opaque coated with a concentrated syrup of sucrose, shellac, acacia, dye and ammonium oxide and dried. Thus, a dragee of 0.10.0 g was obtained.

♦

A capsule containing 0.02 g of 3-methyl-2,3,4,5-tetrehydro-1H-dibenzo [2,3,6,7] oxepin-4,5-djazepine hydrochloride is prepared as follows:

Composition (for 1000 capsules):

Example 24

3-methyl-2,3,4,5-tetrahydro-1H-di-benzo [2,3: 6,7] oxepin-4,5-dihydrochloride lactose hydrochloride gelatine corn starch talc water 20.00 g 253.00 g 2,00 g 10,00 g 15.00 g as needed

3-Methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3-a]: 6,7-oxepino [4,5] -dezepine hydrochloride is mixed with lactose moistened evenly with an aqueous gelatin solution and granulated with a suitable sieve ( a sieve with a mesh size of 1.2 to 1.5 mm). The granulate is mixed with dry corn starch and talc and filled into hard gelatin capsules (size 1).

Example 25 An aqueous injection solution containing 0.01 g / ml of 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino-4,5-djazepine methanesulfonate was prepared as follows: :

Composition (for 1000 ampoules):

3-Methyl-2,3,4,5-1-threhydro-1H-di-benzo [2,3: 6,7] thi epino-4,5-d] azepinomethanesulfonate vpde 10.00 g as needed

A solution of 3-methyl-2,3 _{L of} 4,5-tetrahydro-1H-dibenzof2,3: 6,7-thiepinoft, 5-di-azepine-methanesulfonate in 1000 ml of water is filled into ampoules and sterilized. The ampoule contains a 1% solution of the active ingredient.

Claims (9)

A process for the preparation of novel tetrahydro- and hexahydro-azetetracyclic compounds of the general formula I, wherein: R 1 represents hydrogen, C 1 -C 8 alkyl radical, C 4 -C 10 cycloelkylalkyl radical, C 3 -C 8 alkenyl radical, C 3 -C 8 alkynyl radical, C 4 -C 10 dialkyleminoalkyl radical, hydroxyalkyl radical C 2 -C 8 radical, C 3 -C 10 alkoxyalkyl, C 3 -C 10 alkylthioalkyl or optionally chlorine, methyl 225-6 or methoxy substituted phenylalkyl of 7 to 12 carbon atoms, and ring A is unsubstituted or substituted by halogen having atomic number up to 35, alkyl radical having 1 to 4 carbon atoms, hydroxy, alkoxy having 1 to 4 carbon atoms, alkylthio and 1 up to 4 carbon atoms or cyano, X represents an epoxy group, an epithio group, a methylene group, a direct bond or a bivalent radical of partial formula Ia, N (Ia) wherein hydrogen or (C1-C4) -alkyl and one of Y and Z is vinylene or eplthio and the other is a direct bond, and their acid addition salts, characterized in that of formula IV, wherein at least one of both Q ₁ and Q ₂ is an oxygen atom and the other one is two hydrogen atoms, is reduced, whereupon any compound obtained is converted to another compound of formula I, and / or the free compound obtained is optionally converted the salt, and / or the salt obtained is optionally converted into the free compound or not another salt, and / or the resulting mixture of isomers is optionally separated into individual isomers. 2. The process of item 1 for producing the novel azepine derivatives of formula I, wherein: R 1 represents hydrogen, the alkyl radical β | azorný to 8 atoms, a cycloalkylalkyl radical containing 4 to 6 carbon atoms, an alkenyl radical having 3-8 carbon atoms, alkynyl radical of 3 to 8 carbon atoms, dialkylamlnoalkylový radical with 4 to 10 carbon atoms, hydroxy alkyl radical O- _iy above with C 2 to 8 carbon atoms, C 3 to C 10 alkoxyalkyl C 3 to C 10 alkylthloalkyl or C 7 to C 12 phenylalkyl, ring A is unsubstituted or substituted by halogen with an atomic number of up to 35, alkyl radical 8 1 C 1 -C 4 alkoxy, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyloxy, C 1 -C 4 alkylthio, hydroxy, trifluoromethyl or cyano, X represents an epoxy group, an eplthio group, a methylene group, a direct bond or a divalent radical of partial formula Ia, (Ie) in which: R @ 1 is a hydrogen or C1 -C4 alkyl radical, and one of X and Z is a vinylene group or an epothio group and the other is a direct bond. The method of claim 1, wherein the compound of formula IV is reduced. wherein Q, Q2 are as defined in 1, and R, A, X, X and Z are as defined. mentioned in this point above. A process according to bpdu '1 for the preparation of novel azepine derivatives of the general formula I, in which R 1 represents hydrogen, C 1 -C 6 alkyl, C 4 -C 8 -cycloalkyl, C 4 -C 8 -alkyl, alkenyl. (C 3 -C 6) alkynyl, (C 3 -C 6) alkynyl, (C 4 -C 8) alkylaminoalkyl radical, hydroxy (C 2 -C 6) alkyl, (C 1 -C 6) alkyl; C 3 -C 6 alkyl, C 3 -C 6 alkylthioalkyl or C 7 -C 10 phenylalkyl, ring A is optionally substituted with chlorine, bromine, methyl, hydroxy, methoxy, methylthio or cyano , X represents an epoxy ^p-well, epithioslrapinu, a methylene group or a bivalent radical of partial formula Ia \ / '(Ia) wherein ^R 3 represents hydrogen ,. methyl or ethyl, and X denoted by a straight mandrel a Z is a vinyl group or an epithio group, characterized in that a compound of the general formula is reduced. IV wherein Q, Q2 are not as defined in 1, and R, A, X, X and Z are as defined above. 4. The process of item 1 for the preparation of novel azepine derivatives of formula I wherein R1 is C1 -C6 alkyl or cyclopentyl-butyl and ring A is optionally substituted with chloro, methyl, ethyl, cyano or cyano. X represents an ipc, s, a group, a butterfly group, or a divalent radical of the parole Ia, (Ia) wherein: Hj represents a hydrogen group or a minor group ltylioik ¹ X stands for рМтои of ligament. and Z is a viral group or epithioscipine, which is distinguished by reducing a compound of formula IV wherein Q and Q2 are as defined in point 1, and Rp A, X, X and Z are as defined in point above. 5. The method of claim 1 к production.>_{-Methylcarbamate-2,3>} 4,5 · teteahydri-1 H-dibel about 2.35 ^and 6.77 t ^{t p} il ino £ 4,5-dJazepiim, oyетlnjující by The method according to claim 1, wherein A, X, Ϊ, Z, Q and Q2 8 R 1 are as defined above. Sixth Úsobí ^{Zp p} ccording to claim ¹ · k · IE produce ^3-lty _-2> ³ · 4.5 ^"L-1 etethydrO' ^- diblnzi ^{£ 2} ^ 3 6.7 .mu.l ^{j p} ino [4,5- d) a compound which is reduced by reducing a compound of formula IV in which: A, X, X, Z, Qp Q2 with R1 are as defined above. 225106 22 7. A process according to claim 1 for the preparation of 3-methyl-7-cyano-2,3,4,5-tetrahydro-1H-dibenzo [1,3: 6,7] -lepino [4,5-d] azepine, characterized in that: reduces a compound of formula IV wherein A, X, Y, Z, Qp, Q _2, and R 6 are as defined above. 8. A process according to claim 1 for the preparation of 3-methyl-1,2,3,4,5,10-hexahydrodibenzo [1,4]: 6,7-cycloheptafl, 2-dazazine, characterized in that the compound of formula (IV) is reduced in: wherein A, X, Y, Z, Qp Qg and Rj are as defined above. 9. A process according to claim 1 for the preparation of 3- (2,3,4,5-tetrahydro-1H-dibenzof2,3: 6,7-thiepino [4,5-d] azepin-3-yl) propenol, characterized in that the compound of the general formula is reduced. of formula IV wherein A, X, Y, Z, Qp, Qg and R6 are as defined above.