CS225103B2 - The production of new tetrahydro-and hexahydro-aza-tetracyclic 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 present invention relates to a process for the preparation of novel tetrahydro- and hexsulfuratetric compounds and their acid addition salts, which compounds have valuable pharmacological properties and can be used as active ingredients of a medicament.

The compounds of formula (I) according to the invention correspond to the general formula (I):

in which

R 1 is hydrogen, C 1 -C 8 alkyl, C 4 -C 10 cycloalkyl, C 3 -C 8 alkenyl, C 1 -C 8 alkynyl, and C 1 -C 8 alkynyl (C až-C 10 hydrox), (C až-C hydrox hydrox) hydroxyalkyl, (C až-C zl zl) alkoxy, (C až-C alk alk) (C / alk alk) alkoxy (Cioskyl-C zlkyl) alkyl group or, optionally, C 7 -C 12 phenylalkyl substituted by chlorine, methyl or methoxy-alkoxy, and * ring A is unsubstituted or substituted by halogen having an atomic number of up to 35, an alkyl radical and 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms , (C1-C4) alkylthio or cyano,

X is an epoxy group, an epithio group, a methylene group, a direct bond or a bivalent radical of partial formula Ia, (Ia) wherein it is hydrogen or a (C1-C4) alkyl radical and one of I and Z is vinylene or epithio; direct link ·

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

Lower radicals are understood to be those having a maximum of 8 and preferably a maximum of 4 carbon atoms, preferably having 1 to 6 carbon atoms as the alkyl radical. These alkyl groups which may have a straight or branched chain are, for example, methyl, ethyl, propyl, isopropyl, butyl , isobutyl or tert-butyl.

As a cycloalkylalkyl radical containing radical R _{1 is} preferably 4 to 8 carbon atoms, cycloalkylalkyl radical · Thus, for example, cyclopropylmethyl, cyclobutylmethyl, in particular cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl further example, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl ·

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

The alkynyl radical R @ 1 is, in particular, the propargyl radical.

In the dialkylaminoalkyl radical, 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 preferably have a straight chain. The entire radical is, for example, diethylaminobutyl, diethylaminopropyl or diethylaminoethyl, dimethylaminobutyl, dimethylaminoethyl and in particular dimethylaminopropyl.

In the hydroxyalkyl radical R1, 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. A hydroxyalkyl radical which may be straight or branched is, for example, 1-methyl-2-hydroxyethyl, 2-hydroxypropyl, 1- or 2-methyl-2-hydroxypropyl, and in particular 2-hydroxyethyl and 3-hydroxypropyl.

In the alkoxyalkyl group R @ 1, the oxygen atom is separated from the ring nitrogen atom by at least 2 carbon atoms. This residue preferably contains 3 to 6 carbon atoms. This alkoxyalkyl radical is, for example, 2-methoxypropyl, 2- or 3-ethoxypropyl,

2- or 3-propoxypropyl, 3-isopropoxypropyl, and in particular 2-methoxy- or 2-ethoxyethyl, and in particular 3-methoxypropyl.

In the alkanoyloxyalkyl radical R @ 1, the oxygen atom is separated from the ring nitrogen atom by at least 2 carbon atoms. This residue preferably contains 4 to 11 carbon atoms. This residue is, for example, 2-formylethyl, 2-acetyloxyethyl, 2-propionyloxyethyl, 2-acetyloxypropyl, 2-methyl-3-acetyloxypropyl or 2- or 3-propionyloxypropyl, and in particular 3-acetyloxypropyl and 3-octanoyloxypropyl.

In an alkylthioalkyl radical R @ 1, the sulfur atom is separated from the ring nitrogen atom by at least 2 carbon atoms. This radical contains, for example, 3 to 10a, preferably 3 to 6 carbon atoms. This alkylthioalkyl radical is represented, for example, by methylthioethyl or 3-methylthiopropyl.

R 1 contains, as an optionally substituted C 7 -C 12 phenylalkyl radical, chloro, methyl or methoxy.

Ring a can be substituted one or more times. Nevertheless, this ring is preferably most monosubstituted with halogen having an atomic number of up to 35, in particular chlorine, an alkyl group having 1 to 4 carbon atoms, such as ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, and especially methyl, hydroxy, alkoxy having 1 up to 4 carbon atoms, such as ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and in particular methoxy, C 1 -C 4 alkylthio, such as ethylthio, propylthio, isopropylthio, butylthio, and especially methylthio.

If X is a divalent radical of partial formula Ia,

(Ia) R @ 1 is preferably hydrogen or C1 -C4 alkyl, such as propyl, butyl, isobutyl, and especially methyl or ethyl.

Y is preferably a direct bond and Z is a vinylene or epithio group.

The salts of the compounds of the formula I are in particular acid addition salts, in particular pharmaceutically usable acid addition salts, for example with inorganic acids such as hydrochloric, hydrobromic, sulfuric or phosphoric acids, or with organic acids such as organic carboxylic and sulphonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, acetic, malic, tartar, citric, lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic, mandelic or embonic.

The novel azatetracyclic compounds of the formula I and their acid addition salts have valuable pharmacological properties, for example those acting on the central nervous system. Thus, they are characterized in particular by centrally depressant effects, further by suppressive effects (amphetamine antagonistic effects), as evidenced by pharmacological tests. Thus, these compounds in the rat in an amphetamine antagonist effect test (Niemegeers and Janssen, Arzneimittelforsch., Vol. 24, p. 45 (1974)) at a dosage range of from 0.1 to 25 mg / kg i.p. or per os suppress excitement. The cataleptic effect is relatively small compared to the antagonistic effect of amphetamine. The novel azatetracyclic compounds of formula I and their pharmaceutically usable acid addition salts can therefore be used as compounds with tranquilizing, antipsychotic and stimulant-suppressing effects for the treatment of conditions of excitement.

In particular, the invention relates to compounds of the formula I in which R ^ represents hydrogen, an alkyl radical of 1 to 8 carbon atoms, for example methyl ethyl, isopropyl and n-butyl, a cycloalkylalkyl radical of 4 to 8 carbon atoms, for example cyclopentylmethyl and cyclohexylmethyl, alkenyl C 3 -C 8 radical, for example allyl, C 3 -C 8 alkynyl radical, for example propargyl, C 4 -C 10 dialkylaminoalkyl radical, for example dimethylaminoethyl and 3-dimethylaminopropyl, C 2 -C 8 hydroxyalkyl radical, for example 2 hydroxyethyl and 3-hydroxypropyl, C 3 -C 10 alkoxyalkyl, for example 3-methoxy- and 3-ethoxypropyl, C 4 -C 11 alkanoyloxyalkyl, for example 3-acetyloxypropyl and 3-octanoyloxypropyl, C 3 alkylthioalkyl up to 10 carbon atoms, for example 2-methylthio- and 2-ethylthioethyl, 3-methylthio and 3-ethylthiopropyl or phenylalkyl radicals of 7 to 10 carbon atoms; 12 carbon atoms, such as benzyl and phenylethyl, ring A is unsubstituted or substituted by halogen having an atomic number of 1 to 4 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an alkanoyloxy group having 1 to 4 carbon atoms, (C 1 -C 4) alkylthio, trifluoromethyl or cyano, X represents an epoxy group, an epithio group, a methylene group, a direct bond or a bivalent radical of partial formula (Ia),

(Ia) in which hydrogen or a C1-C4 alkyl radical, preferably methyl or ethyl, and one of the radicals Ϊ and Z represents a vinylene or epithio group and the other represents a direct bond, and salts, in particular acid addition salts, in particular of pharmaceutically usable acid salts ·

In particular, the invention relates to compounds of formula I in which R ₁ represents hydrogen, a C 1 -C 6 alkyl radical, for example a methyl or ethyl radical, a C 4 -C 8 cycloalkylalkyl radical, for example a cyclopentylmethyl radical and a cyclohexylmethyl radical, a 3-alkenyl radical. up to 6 carbon atoms, for example allyl, alkynyl of 3 to 6 carbon atoms, for example propargyl, dialkylaminoalkyl of 4 to 8 carbon atoms, for example dimethylaminomethyl and 3-dimethylaminopropyl, hydroxyalkyl of 2 to 6 carbon atoms, for example 2-hydroxyethyl and 3-hydroxypropyl, C 3 -C 6 alkoxyalkyl, e.g. 3-methoxypropyl, C 4 -C 11 alkanoyloxyalkyl (e.g. acetoxypropyl and octanoyloxypropyl, C 3-6 alkylthioalkyl, e.g. 2-methylthioethyl and 3-methylthiopropyl, or a 7 to 10 carbon phenylalkyl radical, for example a benzyl or phenylethyl radical, a ring A is unsubstituted or substituted by chlorine, bromine, methyl, hydroxy, methoxy, methylthio or cyano, X is epoxy, epithio, methylene or the bivalent radical of partial formula Ia,

(Ia) in which it represents hydrogen, methyl or ethyl, and Y represents a direct bond and Z represents a vinylene group or an epithio group, and salts, in particular acid addition salts, in particular pharmaceutically usable acid addition salts;

More particularly, the present invention relates to compounds of formula I wherein R 1 is C 1 -C 6 alkyl, for example methyl or ethyl or cyclopentylmethyl and ring A is unsubstituted or substituted by chlorine, methyl, methoxy or Xyloxy,

225ЮЗ, preferably at position 7 in the ring A of compounds in which Z is a vinylene group, X is an epoxy group, an epithio group or a methylene group, or a divalent radical of partial formula Ia,

(Ia) wherein R 1 is hydrogen, methyl or ethyl, and Y is a direct bond and Z is a vinylene or epithio group, such as 3-methyl-2,3,4,5-tetrahydro-1 H -dibenzo [2,3: 6, R] thiepino [4,5-d] 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-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, 3-methyl-1,2, -

3,4,5,10-hexahydrodibenzo [3,4: 6,7] cycloheptalpha, 2-d] azepine or 3- <2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] 1-thiepino [4,5-d] azepin-3-yl) propanol and salts thereof, especially acid addition salts, in particular pharmaceutically usable acid salts thereof.

The compounds of formula I are prepared in a manner known per se. Thus, they are obtained, for example, by reacting a diester of a strong inorganic or organic acid and a diethanol of the formula II

HO - CH ₂ CH _{2 -} OH

(IX) wherein

X, Y, Z and A are as defined above and reacted with a compound of formula III

I ¹

N / \

Wherein H is as defined above.

As the reactive diesters of the diethyl alcohol of formula II, esters of strong inorganic acids, such as, for example, an ester derived from bis-hydrochloric acid, bis-hydroiodic acid or especially bis-hydrobromic acid or an ester derived from one mole of hydrobromic acid and one mole of hydrochloric acid. Furthermore, corresponding diesters of strong organic acids, for example sulfonic acids, such as methanesulfonic, benzenesulfonic, p-chloro- or p-bromobenzenesulfonic or p-toluenesulfonic acids, can also be used. These diesters of the compounds of formula (II) are preferably reacted in a suitable inert solvent at a reaction temperature of from 20 to 130 ° C. Suitable inert solvents are, for example, hydrocarbons such as benzene or toluene, halogenated hydrocarbons such as chloroform, lower alcohols such as ethanol and especially methanol, etheric liquids such as ether or dioxane, as well as lower alkanones such as acetone, methyl ethyl ketone or diethyl ketone, or mixtures such solvents, for example a mixture of benzene and methanol.

In the reaction according to the invention, where one mole equivalent of diethyl alcohol diester of formula II is reacted with 8 mole equivalent of the free base of formula III, two mole equivalents of the acid are cleaved off, which preferably binds with an acid binding agent. potassium carbonate or, for example, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, or an excess of the base of the formula III, furthermore tertiary organic bases such as pyridine and in particular triethylamine or N-ethyldiisopropylamine;

Directly used starting materials, i.e. reactive diesters of formula II, can be prepared from the corresponding diethanes by esterification or halogen substitution of hydroxyl groups according to conventional methods. Dietanols can then be prepared from the corresponding acetic acid dimethyl esters by reduction with lithium aluminum hydride. Diacetate methyl esters can be prepared from the corresponding diacetonitriles by reaction with methanol and 2 mol equivalents of water while introducing hydrogen chloride. Diacetonitriles can then be obtained from the corresponding bis- (bromomethyl) derivatives by reaction with sodium cyanide.

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 the reactive ester IV of the corresponding alcohol of formula R1 -OH, in which R1 has the same meaning as R1 in formula I, except for hydrogen, or by reaction with the corresponding aldehydes or ketones under reducing conditions.

The reaction of compounds of formula I wherein R ₁ is hydrogen with a reactive ester hydroxyslouIV substituting Compound of formula R-OH, is preferably carried out in a solvent at a reaction temperature from 20 to 130 C, especially at the boiling point of the solvent.

As reactive esters, for example, halides such as chlorides or bromides, esters of sulfonic acids such as methyl or ethyl esters of o- or p-toluenesulfonic acid, 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. 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 acetone or methyl ethyl ketone.

Aldehydes and ketones which correspond to alcohols of formula R * ^V -OH are, for example, lower aliphatic aldehydes or ketones, lower free, esterified or etherified hydroxyoxoalkanes, or esterified oxoalkanecarboxylic acids. The reaction product obtained in the reaction of these aldehydes or ketones with the compounds of the formula I can be reduced in the same step or thereafter.

Aldehydes, for example formaldehyde or acetaldehyde, or ketones, for example acetone, are heated with, for example, the compounds of formula I in an inert solvent to a temperature of about 30 to 100 ° C and simultaneously or thereafter the reaction mixture is hydrogenated with hydrogen in the presence of a catalyst. Suitable solvents are, for example, alkanols, such as methanol or ethanol, and suitable noble metal catalysts, such as palladium on carbon, or alloys such as Raney nickel.

Instead of hydrogen in the presence of a catalyst, other reducing agents, for example formic acid, may also be used for the purpose of reductive alkyls. According to this process variant, the compounds of the formula I are heated with formic acid and with aldehydes or ketones of the type mentioned, in particular with formaldehyde, preferably without solvent.

However, this substitution on the nitrogen atom by an alkyl radical can also be carried out in such a way that:

225ЮЗ is the reaction product in which the residue R | means hydrogen, first acylated and then the carbonyl group is reduced · This reduction is preferably carried out by treatment with a complex hydride such as lithium aluminum hydride or diborane · Preferably, an ethereal liquid such as diethyl ether, tetrahydrofuran, dioxane, dimethyl ether of ethylene glycol or dimethyl ether of diethylene glycol is used it is preferably between about 0 ° C and 100 ° C, or lies at the boiling point of the reaction medium to be used. Diborane can be made special 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 acylated to a compound wherein hydroxy is lower (lower) alkyl.

The acylation can be carried out, for example, by treatment with a carboxylic acid anhydride or by treatment with an appropriate carbonyl halide at a reaction temperature between about 20 and 100 ° C. Since condensation takes place with acid elimination, it is expedient to add an acid-binding agent, e.g. an excess of a tertiary organic base can also serve as a solvent. In addition, hydrocarbons such as benzene or toluene or halogenated hydrocarbons such as chloroform can be used as solvents.

Further, optionally compounds of formula 1 wherein R 1 is phenyl (lower) alkyl may be hydrogenolyzed to a compound wherein R ₁ is hydrogen.

Hydrogenolysis can be carried out using conventional hydrogenation catalysts, for example noble metal catalysts such as palladium on carbon or platinum oxide, rhodium catalysts such as rhodium on carbon or aluminum oxide, 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 at elevated pressure up to about 100 bar.

Further, optionally, a compound of formula (I) wherein X is a divalent radical of partial formula (Ia, Z) may also be used

N (Ia) wherein ^R ₃ is hydrogen, can be converted to another reaction product wherein R 3 is lower alkyl.

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

As reactive esters, for example, halides, such as chlorides or bromides, 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 may be used. metals such as potassium tert-butoxide or the corresponding amides, such as sodium amide, or metal hydrides, such as sodium hydride or lithium hydride · Suitable solvents are those which are inert under the reaction conditions, for example hydrocarbons such as benzene or toluene; , for example tetrahydrofuran, diaxane, dimethyl ether, ethylene glycol, or amides such as hexamethylphosphoric triamide or dimethylformamide.

J

This conversion can also be carried out by first agglomerating the above reaction product and then reducing the carbonyl group.

The reduction is preferably carried out with hydride · As the hydride and preferably using diborane, in an ethereal reaction medium such as tetrahydrofuran, dioxane »ethylene glycol dimethylate or diethylene glycol dimethyl ether · Reaction temperature ее is, for example, between -20 ° C to 4 * 80 ° C, preferably between 0 ° C and room temperature · The required diboron can be produced either from boron trifluoride etherate and sodium borohydride especially, for example in a solvent which is used for the reaction and can be used as a solution, or is formed in diethylene glycol dimethyl ether for example. into the reaction mixture, or else formed in situ.

Depending on the reaction conditions and the starting materials used, the reaction products are optionally obtained in free form or in the form of their free salts, which can be converted into one another in the usual manner or can be converted into. Thus, the free compounds of formula I are formed from the acid addition salts obtained, for example by treatment with bases or basic ion exchangers, while the free bases of formula X are converted into acid addition salts and acids, for example by reaction with organic or inorganic acids, particularly those suitable for the formation of pharmaceutically usable salts as mentioned above ·

Salts of the novel compounds can also be used for purification, for example by converting the free compounds into their salts, isolating them and optionally purifying them, and converting them again into the free compounds. their salts in the preceding and following parts are understood to be the free compounds according to the meaning and purpose and possibly also the corresponding salts.

The invention also relates to those process embodiments wherein the starting material is a compound obtained at any stage of the process as an intermediate and the missing reaction steps are carried out, or those process embodiments wherein the starting material is formed under the reaction conditions, or where the reactants are used in the form of a salt ·

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

The novel compounds can be used, for example, in the form of pharmaceutical preparations containing an effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for enteral, for example oral or parenteral administration. or gelatin capsules which contain the active ingredient together with diluents, for example α.actose _r dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants such as diatomaceous earth, talc, stearic acid or its salts, such as magnesium or calcium stearic acid and / or polyethylene glycols ·

Tablets also contain binders such as magnesium aluminum silicate, starches such as corn, wheat, rice or maranth starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and optionally tablet disintegrants such as starches, agar, acid alginic acid or its salts, such as sodium alginate and / or effervescent mixtures »or adsorption agents» dyes, flavorings and sweeteners · Furthermore, the new pharmacologically active compounds can be used in the form of injectable, for example intravenously administrable preparations or infusion solutions. isotonic aqueous solutions or suspensions, these solutions or suspensions, for example as lyophilized preparations, containing the active ingredient alone or together with a carrier, for example mannitol, may be prepared before use. The preparations may be sterilized and / or contain adjuvants »e.g. preservatives» stabilizers »wetting agents and / or emulsifiers, co-solvents, salts for influencing the osmotic pressure and / or buffers. Said pharmaceutical preparations, which may optionally contain other pharmacologically valuable substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, draining, dissolving or lyophilizing processes, and contain about 0.1 to 100%, in particular about 1 to about 50 up to 100% of active ingredient.

The dosage depends on the mode of administration, the type, the age and the individual condition. The daily dose of the free bases or the pharmacologically usable salts of these compounds is less than about 0.1 m / kg and about 10 mg / kg for warm-blooded in general and about 0.01 g to about 0.5 g for warm-blooded with about 70 kg.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius.

Example I ^{To a} solution of 21.8 g ^(0.0 5 ^{0.11 1} OOD -bil- [2- (melylsu onylóxy ^tf) etyϊJ -SH-dibenzo ^ J cycloheptene absooutního 200 ml of ethanol was added 35 ml (2.6 g 0.065% of a 7.4% solution of ethylamine in ethanol and 15.5 g (0.125 moo) of isopropyl ether and the reaction mixture was heated under reflux for 118 hours. dissolved in 300 ml of meltlene chloride and this solution was washed successively with 100 ml of 2N sodium hydroxide solution and water in succession.

about 50 ml, and to the residue was added 15 ml of 4N ethereal hydrogen chloride piHemž you -et.yl crystallized ^{3-1,2,3,35, 1 0} - ^{h LX} yddo ^0d benoz З ^{about 4} _l o ^ cyld- talfl ol ^ ^ - ^ azepiohydrochlorid the ^{b th} the ODU ^{296 and 2 0th}

Melting point ^tf oelεaos sulfonate: ^220-22 1 ^O.

The starting material can be prepared in the following manner, i.e. analogously to Example 51

Z ² 7 ^{g (0J} 5H-Mod ^II enmoOa d] ^yk c ^h lo lptln- ^10, 11-D ^and _J 4 aaclooittilt ⁰⁰ ml όοΙ ^:)! ^ ^3.8 ml of water and hydrochloric toiho abso ^ ^ ku the ZIS ^ka dimethyl-5H d ⁱ Beno; o0a, d] c loeeptln ^yk-1 10.1 -di CTC ^ o ^ ^ v ^ s acid, melting point 104 DEG-106 · ^o (from hexane).

^{33 »6 g (0 1} MOD-methyl-N-5H ERU dibenooJ ^ and ^ ^ lo ^ JCY pteo- ^{10, 11} - ^d ioctov ^E k ^{y y} Selin and 7.6 g. (0.2 mole) liehiomatuointuoe ^y driit in 1 liter of absolute diethyl ether was afforded ^ ⁱ i ⁱ 5H- enoo [a, ^{i] cyclo- e} lo lp ^t yn-1 ^0, 11-die ^ NCL, the ^th point ^{154-1560 (from} acetone) .

^{To a} solution of 28.0 ^{g (0} ^ ⁰ mod 5H-di ⁱ enoo ^of _a> d] ^p c ^yk lohl tlo- ¹⁰ 1 ¹ - ^id ltaoolt in ¹²⁰ ml pyridine přilcapu ^p s rea rises ^to -5 ° ^ jnlotě ^{16, 8} ml ^{(25.2 g,} 0.22 mod ^alkyl chloride Selim oelansslfooov ^{y s. p} Otom allowed ^and the mixture stirred ³⁰ min at 0 ° s and ^p Otom ¹ hour at ^15-25 °. Realcční mixture together with 600 ml oeltléncheoriiu shaken in a separatory funnel always 400 milllitry 5N hydrochloric acid and ice water. Meetrlénchloridový solution oddděí dried Slaney magnesium odppaí in a water-jet vacuum. as residue ^{e from} Iška 1 0, ¹ 1-bis ^[2 - ^(t OEL llulfoo ^yloxy) ethyl] - H-tobenzo ^^ ^^ cyclohexylmethyl, as follows: ^e ^ z ^ r ^ in ^ he lcozoíto ^OLE.

Atalogioiý / m manner may be prepared: ^3-тег у, 1- ^1, 2,3,4 ^₍₁ 0-5-dibenzo hexehydro ^»4: ÍbjYjcykloheptalfl -dJazepin ^ methanesulfonate, m.p. nd ^b 9 to ¹⁸ ^ L ^{0, 21.8 g (0.0} 5 MOO) ¹ 0.11 ^ь ь-8- [Z CMEE ulfo ^ ^ ^ lox ethyl HH ^ d ^ enoofajd] cydoheptanu 3 ⁰ ml ^(1, 9 ^g, 0 6.0 mol% of 6.3% ethanol stream of matylamizi and 15.5 g (0.125 mol) of diisopoopiletylminine.

3-Tenn ^01-1 ^ j ^{3, 4, 5} ^ ⁰ - ^ ^ χι too ^{ditenzot-3, 4:} 6,7] cyclo ^y e ^{pt [2- d]} ioep ^p n ~ ^{y yy} ydioo ooii ^b on u ^{dy 2} 65 and ²⁷⁰ ° ^j o. ^{21.8 g (0j05} mo ^o) 1 ⁰ 11 ^"II ^ s ^ - ^{2 [- m} ^ ^y ^ ^I0 e ^ i ^ u ^ n ^ ^{i 0fo} io ^ ^ ⁱ r) e! ^{Io 1].} ] - ^ 5 ^{[di IE} ^ r ^ o ^ o [l, ^d] cikloh ^e p ^y ene, ^6.2 g ^{(0, 06 m} o ⁰⁾ bezzylamizi and ^{15.5 g (0.12} 5 mo ^s) dso ^ o ^ etAmtau.

Example 2

Sus ^p enoe ^19.4 g ^(0.0 5.mo ^o) 3- Enz ^{ol i -1, 2, 3, 4,5,} 1 ⁰ - ^h y ^{d y} exa parental ^b enoo ^[3,4: 6, ^7] cyclo ^y e ^py l [ijiSid ^ ozepřintydoochlor ^ u and ^{2 g of} 5% ^p ala ^d IA u ^yy in ^900ml mmturolu the ^h y ^d oogenuje ^p ri ^s mos ^f áoickém tleto ^{40 and} 5 ⁰ ° ^and with ^p to ^y of ^b SOLUTION CONTRARY tO 77 ⁰ ml in ^d s ^to u. Then total átoo odfiltuije ^ and the filtrate was concentrated under water pump vacuum.

The residual crude ^{1, 2, 3, 4,} 51-cyclohexyl-TOO tbezof 3,4: 6, ⁷ Jc ^IKL about the ^y e ^p [i ^ - ^ ^ NH ^ aoe hydrochloride with ^{Pla to} rystaluje of ethanol. Mp ²⁹ 5 ^and 3 ^of 0 °.

In order to release the broth, the hydrochloride ^is suspended in 250 ml of methylene chloride and the suspension is shaken with 100 ml of concentrated ammonia stream. The methylene chloride stream was separated and purified until further crystallization occurred. Hexane was then added, whereupon the ¹ H 2 H 2 O-hexahydrodibenone [3 H: 6, H 2 O] and 13 H ⁽ mp) had a melting point of ^{190 to} 191 °.

For conversion into the free meetaizulfozát báoe ooopustí in mettlénnyhoridu added to the theoretical mwlžteí ^ Eliz mmtazsulfozové ¹ and ^{1, 2,3,4,} 5 ¹ 1 ⁰ - ^{y y} ltxah Clit ^0ib ieto [3,4: ^{6, 7} JcyklohУ ^e tt ^J 1 ^{, 2} - ^d ] to ep ^{d e e} azazsu ^lf ozate is ^{produced by} ether. Paragraph ^{269 th} September and ^{27 0th}

PPíklad 3 ^{to the} stream ^{43.6 g} C ^{0 1} mo ^{o). 1} 0 ¹ t ^id 1- ^[2 - (meth ^yl TUL ozylox ^{f l)} tt ^l l ^[55H-IE d ezoo [N cykloheptazi in 400 ml of absolute including ^ lu was added 11.9 g (0.12 mmol ) (amizomít ^y 1) ^y c1kloptn LZL and 32.3 g (0.25 mol) DIIB-drowning-Etna-nu oeakčzí and the mixture is boiled for 20 hours under a condenser again. The pressurized mixture was then vacuum cleaned in a vacuum pump, the residue was taken up in 150 ml of methylene chloride and 500 ml of pentas, and this stream was washed successively with 200 ml of 2N sodium hydroxide and water. Then, 200 ml of 2N hydrochloric acid is added to the organic phase, which is then eliminated in the acid phase. Crystals were oOdiltoijí OA to release the báoe УydгocУУor ^d and suspended in 300 ml metyléncУУoriiu and tluptzot with pootřepává with 100 ml of concentrated oootoku umonzaki. The motorcycle is separated and purified until the crystallization begins. Then hexane přieemž vikrystalije 3- (ciklopeetylmetyl) - ^{1,2,3, 4, 5,} 1 ⁰ -htxlУydrodibtnzo ^[3,4: 6, ^7] cykloУУ ^{t and} the 1 ^ ^ iz -íJio the NDI ^b t ^and Z ^141-142 °. For ^ Ely Take the ^ her on mstt ^ lts ^LF sulfonate ^b AOE ooo ^p usability, the methyl-jchdoribi ^p ri ^gives the theoretical mzOssví kiselizi m ^ e ^ i ^ r ^ i ^ i ^ where ^ o ^ t ^ o ^ é a, [(cl ^k ] ^ opn ^ 1Уll ^ m ^ ty ^].) [^ 12,3J: 4 _J í »0-yne: ^ J У ro dro ^ benzo ⁰³³⁴ : ⁶ , ⁷ ] c ^lk lo TPTA ^{y [1 2 l} id bundle mt ^{t t f} azuul ot ^Whether in r ^ i ^ fter. Bo ^{d th} September ²⁴⁸ and ^from 249 °. ,

EXAMPLE 4 ^{26.1 g (0j1} MO0) ^{1,2, 3, 4,5,} 1 ⁰ - ^h ydro TXL ^{d y} i ⁱ tnoo ^{[з, 4:} 6, ⁷ Jc lo ^{o p y} t ta ^[12 ^ - ^ (11 ^ 5 ^ ^ пр1 п1 ^(v ^ oobezého according to Example 2) is cycloalkyl сУХюпп! přddavkem ice mixed with 92 g (MoO 2) kyselizi mravezčí and ^{20 g (0 2} mol of ⁰⁾ 30% ^^ ^^ ιΟ ι and the mixture ball ^{hook 1H} Odin ^p s ^{95 and 10} ° 0. ^ 'that protrudes poppy-VI mixture under ice-conductors and the mixture oalkaLioljt oootokam 10N NaOH

The precipitated base is taken up in methylene chloride and the methylene chloride solution is concentrated. . Hexane is then added to crystallize

5, ^{10 and} -heirO ^<i btdibcnzo [3,4- ^{c k} '] ^and cyclo ^EPTA', 2-d] azepine by Mu point ^{144 and} Мб ^0th In order to convert the ^m ^ e ^ m ^ u ^ íaic Ulfo ^ i ^ -t will burst at the base meeylénchhoriiu added the theoretical amount of acid, methane 8Ul ^{f é} -ones and 3-methyl-l- ^{NT 1, 2,} 3.4, 5,10- EAA ^{n) yd} dro ⁱ i ^{i ъ} enzc 3.4: 6,7Jc ^{y p} klchn taC1,2 dJaznpinmetшl8uUfcnát-precipitated with ether. . Melting point 189 to

Example 5

To a solution of 4.56 g (0.01 M) of 0.11-cis-12-methylsulfonyl-yetyldibenzo [b, f] thiepine in 50 ml of absolute ethanol was added 1.3 g (0.012 mole) of benzylamine a. 3.25 g <0.025 molar) for 1 min and the reaction mixture was refluxed for 18 hours. crystals are deposited in the ice bath, these are filtered off and washed with a small amount of isopropane and pentene. The residue on the filter is 3-benzene-2,3,4,5-triethylamine-1H-dibenzoyl 2,3,3,7] thiepino. [4,5-d] azepine, m.p. 149-150 °.

To convert to the hydrochloride, 3.0 g of base in 100 ml of acetone are dissolved and 2.2 ml of 4N hydrogen chloride in ether are added with stirring, and so much ether is added until the solution becomes slightly cloudy. 4,5-п1, г 1у £ ^ о ~ 1 2,3: 6,7] thiepind4,5 i] aonpinhy <drcchlorta allowed vyki eltalovalL ^ · melting point 2 ^41-2 42 ⁰ ·

The starting material can be produced as follows:

g (0.2 mol) of dibenzzobbf flth.eppn-10,11-diaflucitrile is suspended in 800 ml of methanol and 7.5 ml of water with stirring and the suspension is cooled to 0-5 ° C in an ice bath. one hour introducing dry hydrogen chloride, whereupon a clear solution · temperature my Whem ZAVA ^d & her chlorovdíku maintained at ^5-2 0 ^<° · ^p Otom reaction mixture was further stirred for 1 hour at ROOM ^ and then refluxed for 4 h under The residue is dissolved in ether, the ether solution is washed with water and 2N sodium hydroxide solution and dried over sodium sulphate. The oily residue is swirled in methanol and cooled to ^{0, then the} methyl ester of benzene, 10-thipin-10,11-acetic acid crystallizes, melting after filtration and drying at 50 ° under reduced printing. , at 84 to 86 ⁰ ·

To a suspension of 7.6 g < 0.2 molaritumo-aluminumum hydride in 400 ml of absolute diethyl ether, a solution of 35.4 g < 0.1 molarimethylnitrile (II) benzene was added dropwise over 1 hour under stirring and exclusion of moisture and under nitrogen. thiepin-10,11-iioctové acid in 1 liter of absolute diethyl ether and then the reaction mixture VA ^: i 16 hours under reflux, the ^walk-p at ^0-5 °, ^the reaction mixture ^{of p} s and ^p e ^{to 130} m. in and ^{dy p} ot ^t the phases were separated ohmic · PROM with water and sodium vysuěení sírinnem from PAI on ^p moles of a volume, wherein vykystaluje ^ъ ennz ⁱ i ^c b, f] thienyl ^p-yn-1 0, ¹¹ - ^{t i} Ie ancle of ice on the 131 ^th and ^{f 0} · МЗ '15 g <0.05 moo) iiЪenzoCb, f] thiepin-10,11-iintanclu to burst the at RT

225ЮЗ in 60 ml of pyridine and 8.4 ml (12.6 g; 0.11 mol) of methanesulfonic acid chloride are added dropwise with stirring at -5 ° C in a bath of ice / sodium chloride. Thereafter, the reaction mixture was stirred at 0 ° for 30 minutes and then stirred at 15-25 ° for 1 hour. Then the mixture is mixed together with 8 500 ml of methylene chloride in a separatory funnel successively with 400 ml of 2N hydrochloric acid and water. The methylene chloride solution was separated, dried over magnesium sulfate and evaporated in a water pump vacuum. 10.11-bie [2- (methylsulfonyloxy) ethyl] dibenzo [b] f] thiepine is obtained as a residue, m.p.

Example 6

The following compounds can be prepared in an analogous manner to that described in Example 5 using the appropriate starting materials:

A. from 22.7 g (0.05 mol) of 10,11-bis [2- (methylaulfonyloxy) ethyl] dibenzo [b, f] thiepine, 7.3 g (0.06 mol) of 2-phenylethylamine and 16.25 g (0.125 mol) dlisopropylethylamine in absolute ethanol gave 3- (2-phenylethyl) -2,3,4,5-tetrahydro-1H-dlbenzo [2,3: 6,7] thiepino {4,5-djazepine,

m.p. 96-99 ° (from acetonitrile; methanesulfonate, mp 161-164 ° (from absolute ethanol);

B. from 24.2 g (0.05 mol) 10,11-bis [2- (methylsulfonyloxy) ethyl] -2-methoxydibenzofb, phthiepine, 1.85 g methylamine (0.06 mol) and 16.25 g ( 0.125 mol) dlisopropylethylamine in absolute ethanol gave 7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, bt 108-112 ° (from acetone); hydrochloride, m.p. 220-224 ° (from absolute methanol);

C. from 25.0 g <0.05 mol) 10,11-bis {2- (methyl8-sulfonyloxy) ethyl] -2-methylthi-dibenzo [b, phthiepine, 6.0 g (0.06 mol) (aminomethyl) cyclopentane and 16.25 g (0.125 mol) of diisopropylethylamine in absolute methanol gave 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 ° (from absolute ethanol);

O. from 23.4 g (0.05 mol) 10,11-blat 2- (methylsulfonyloxy) ethyl] -2-methyl-dibenzo [b, f] thiepine, 1.85 g (0.06 mol) methylamine and 16 25 g (0.125 mol) of dlisopropylethylamine in absolute ethanol gave 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 ° (from absolute ethanol);

E. from 26.7 g (0.05 mol) 10,11-bis [2- (methylsulfonyloxy) ethyl] -2-bromodibenzo [b, f] thiepine, 1.85 g (0.06 mol) methylamine and 16.25 g (0.125 mol) of dlisopropylethylamine in absolute ethanol gave 7-bromo-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5] -d] azepine, crude; hydroohlorid b _f t. 280 ° (dec) (from absolute ethanol);

F. from 21.1 g (0.05 mol) of 9,10-bis [2- (methylsulfonyloxy) ethyl] phenanthrene, 1.85 g (0.06 mol) of methylamine and 16.25 g (0.125 mol) of dlisopropylethylamine in absolute methanol to give 3-methyl-2,3,4,5-tetrahydro-1H-phenanthro [9,10-d] azepine, bt. 142-145 ° (from acetone), methanesulfonate, m.p. 242-244 ° (from methanol);

? ^H 3

N.

G. 2 21.4 g (0.05 mol) 4,5-bis- (methylsulfonyloxy) ethyl] naphtho [1,2-b] thiophene, 1.85 g (0.06 mol) methylamine and 16.25 έ (0.125 mol) of diisopropylethylamine gave 3-methyl-2,3,4,5-tetrahydro-1H-thieno [2 *, 3 *: 1,2] naphtho [4,5-d] azepine, crude product; hydrochloride, m.p. 273 DEG-280 DEG with decomposition (from methanol);

H. from 21.9 g (0.05 mol) 10,11-bis [2- (methylsulfonyloxy) ethyl] dibenzo [b, phloxepine, 1.85 g (0.06 mol) methylamine and 16.25 g (0.125) mol) of diisopropylethylamine gives 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino (4,5-d) azepine, mp 147-149 ° (from acetonitrile) hydrochloride, mp 282-285 ° (from absolute ethanol);

1. from 21.9 g (0.05 mol) 10,11-bis [2- (methylsulfonyloxy) ethyl] dibenzo [b, floxepine, 3.5 g (0.06 mol) isopropylamine and 16.25 g (0.125) mol) diisopropylethylamine gives 3-isopropyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino (4,5-d] azepine, mp 125-128 ° (from acetonitrile); maleate, mp 175-177 ° (from acetone);

K. from 23.3 g (0.05 mol) 10,11-bis [2- (methylsulfonyloxy) ethyl] -5-ethyl-5H-dibenzo [b, f] azepine, 1.95 g (0.006 mol) methylamine and 16.25 g (0.125 mol) of diisopropylethylamine gave 3-methyl-10-ethyl-1,2,3,4,5,1-hexahydrodibenzo [b _} fjazepino [4,5- d] azepine, bt 99-100 ° (from toluene); oxalate, mp 180-183 ° (from absolute ethanol);

L. from 23.3 g (0.05 mol) 10,11-bis [2- (methylsulfonyloxy) ethyl] -5-ethyl-5H-dibenzo [b, f] azepine, 3.4 g (0.06 mol) of allylamine and 16.25 g (0.125 mol) of diisopropylethylamine gave 3-allyl-10-ethyl-1,2,3,4,5,10-hexahydrodibenzo [b, f] azepino [4,5-d] azepine, bt 100-101 ° (from hexane); hydrochloride, m.p. 245-248 ° (from a mixture of absolute ethanol and acetone);

AT

Μ. from 21.9 g (0.05 mol) 10,11-b18 [2- (methyl-3-sulfonyloxy) ethyl] -5H-dibenzo [b, f] azepine, 1.85 g (0.06 mol) methylamine and 16.25 g (0.125 mol) dlisopropyletylminu afforded ^{3-meetl-1 2>} 3> ¹ 10 ^4,5-b hexe ^h ydrodi enzz [BTF] azepinoí'.4 | 5-d) ^azepine, mp ^121-12 ° 4 ( metianou of Me ^ ^e irnsu ^with sulfonate 26 ³ to ²⁶⁶ ° (from a mixture of ethanol and acetone abdutního); and

N. from 21.9 g (0.05 md) 10.11-biu [2- (methylsulfonyloxy) ethyl] 55H-dibeszo [b, f] azepine, 6.0 g, (0.06 md) (amnomeeyy4). yklopentmu and 16.25 g (0.125 md) diisopropyletylminu ^ tion of ³ - ^(LTB c ^{y s} y ^{y e} ylmethyl) - ^1, 2, ^{3, 4, 5,10-b} HESA У ^l ro ^d iЬenzs [V f] AAE nS4,5-- ^{a i] p} in ^BZE, mp ^{72-750 (from} Pantano) ee ^with tbls ^{t methanesulfonate,} Ut. 27 ^{1-2740 (from} my ^ · nL).

Starting materials can be produced as follows:

with B. from 42.3 g (0.1 md) 2 eetoзql-10,11-bis ^(b rvшnetylLdi ^b Esso | * b, f] ihispist and 11.8 g (0.24 md) of sodium cyanide in 500 m gave 2-eeSolylibbSso [b, f] this ^p-well 10, ¹¹ -diaccttlitril, mp. 198 °, ^from 2 ° ^{0 (z} ^ ACCET ttilu);

31.8 g (0.1 md) 2 eeetlydidebes [l, b] thienyl ^p-Pns10,11 diiactolittrlu 400m of methanol, and 3.8 ой vocty abbsoutního cChorovoodk gave dimmeylisstr 2 ^ ι ^ ϋ £ θ5χ ηζο 1b, f] thiepinz-W, U-acetic ^ 861 ^, ^b #t. ⁹⁶ and ^{Z 9} 8 ^{O (toluene} ^ of 38.5 g (0.1 md) dieeSylestsru 2-eeeolylitbeso [b, f] thiepin-10,11-dioctlvé acid and 7.6 g (0.2 mol) of L .iht ^ i ^ m ^ aum: ^ m ^ ^ nu; idiiidu in 1 liter of absolute diethyl ^ ^ initial yield 2-dibenz ^b metoJX ^bb, f] this ^and tS ^{10, 11} - ^{d isiasol,} Ы. ¹¹⁶ to ^{1190 (} from ethyl acetate and hexane);

from 32.8 g (0.1 md) of 2-ethoxydibs (b, f) thiis-10,11-iisiasdt, 25.2 g (0.22 mol) of ethanesulfonic acid chloride in 120 ml of pyridine gave 10.11 -bisb2- (εSilsulfonyl) rrlethyl] 2-eeto: χ 1 ^{d b} esoCb, f] thiepis, crude product;

to C. from 44.2 g (0.1 mol) of 2-eSilthiv-10,11-bis (bromomethyl-ll dibesso [b, f] thiepist) and 11.8 g (0.24 md) of sodium cyanide in 500 ml of bisStrStriL were obtained 2-ethylthiibensophb, phthiopin-10,11-dibCsStrii, mp 204-206 (from dylacdate);

starting from 33.4 g (0.1 md) of 2-eephthyl-iibsnzo [ ^b , f] ihisiis-10,11-iLaceSooStrilt, 400 ml of methanol, 3.8 mL of water and absolute hydrogen chloride gave 2-eeilthildibenzo [b, f] 1'-bis-10,11-diodic acid, bt. 85-86 ° (from pentane);

from 40.0 g (0.1 mol) of 2-dieeSylsstsru eeSilthivdibessoCb, f] thisiis-10,11-iioctové acid and 7.6 g - (0.2 moles) in 1 liter of absolute iisilléisrt gave ^m silyltliodbSsnlo ^b f _l f] tei4L L1-1 ⁿ ^^ - diethanolamino !, ^b t. ^58-6 ° ^{0 (z i l} ist ⁱ srt ^treatment);

from 34.5 g (0.1 md) of 2-methylthio [b, f] thiis-10,11-diethyl, 25.2 g - (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine to give 10.11 -bisb2- (eeSilвutfllnУ.! xyletyl] 2 eetyl ^t h ⁱ l ⁱ i ^b enzo [biíj t-depn crude Kiukt ^;

to D of 41.0 g (0.1 mol) of 2-eeeil-10,11-BI8 ^(b roeeeeyl) dibenzl [b, f] thiβiist and 11.8 g (0.24 md) of sodium cyanide in 500 d aceSooSirilt was obtained 2-eSildi ^b bSSo [b, f] thLepin-10,11-dibCstostria, bt. 198 DEG-200 DEG (from accSt) (filter);

of 30.2 g (0.1 md) of 2-eeildibbssoCb, f-thiepis-10,11-dibCcOto-Stil, 400 ml of SiO2, 3.8MM, always in the form of a water. zssád dieetylesSes 2-estyddbSslo [b] t ^t LlSipSn-Ю, ^11- diode К ^ сИп ^ bt. 7 ^{6-770 (of e} TBSD ee);

from 36.9 g (0.1 mol) of diethyl ester of 2-ethylbenzo [b, f] ihisiine-10,11-diacetic acid and 7.6 g (0.2 md) of lithium tert-butyl ether in 1 liter of absolute diethyl ether gave ² -methylbenzo [b, f] thiis-10,11-iistanol, mp 126-129 ° (from acdioStiilt);

from 31.2 ^g (0.01 mol) of 2-methyldibenzo [b, f] thiepine-10,11-diethanol, 25.2 ^g (0.22 mol) of uelaisulfonic acid chloride in 120 i pyridine gave 10.11 --is [2- (UEE 1sulObb ^y ^ ^yloxy Tyll-and-uetyld-enzo [b, f] thiepin and the crude ^product, to the E. 47.5 g (0.1 COO) 2-EROEI IOjll- bis (erometnt) diienzo [o ffthiepinu and 11.8 g ^{(0, 2 of} the fourth ^MO) solution in ⁵⁰⁰ tyanidu ^ACC ^ sn oittilu ^the OIS and Z toonráibenzo [a, e ^{f thiepin-10,} 11 - ^d iace tbitril ^{e e} t. ^200-204 DEG ^{(aceeooitrilu} ^ of ^36.7 g ^{(0-> 1} mc> ^{a) 2-bromo d} ibnnoo | .b, f1th ^e e ^p-1 in ^0.1 ^^ ation ^^ three-year, ⁴⁰⁰ ml · uu ^e a'iolu,

3.8 ml odly and absolu ^ n ^ o chbroobddí ^to un · zssáá dimltylesner brbmmdbnnzoo ² b, ^{naphth-1-d 10.1} lpLOn- ioctové tyseHo ^e ^ .t. ⁹⁰ and ⁹³ ° ^(the absolute ^ o ^ etaooli of 43.3 g (0.1 moo) diieeylesteru 2-brbmefbenob [b, fithiepib-10,11-dioetové acid and 7.6 g (0.2 moo) ltthiemaluiiniuihydridu in 1 liter of absblutant is obtained

2 ^of rbmd benob ^{e [e, e} e flth] ⁿ n-1 ^0, 11 ^diethanol, BT ¹⁶⁶ and ^{1690 F (^} o ^ ru ^ be ethylene of ^{37.7 g (0} 1 mo ^o) 2- rou ^{b f b} and ^{ENOB, b, f] thiepin-1} -f ⁱ etinbll ^0.11 and 25.2 ^{g (0,} 22 mul) of acid chloride uelaisulfonové vn sn 120 ml of pyridine give cis-1 0.11 ^[2 - ^{(ueeylsulfbnylbxy) ethyl]} -2- Obudu ^{b b bb} enoo ^f.] t ^{p h} ie in ^e .T · ⁹⁴ and ⁹⁶ ° ^(Z direction can toss ^m and ^{eT ERI)} from 25.6 to F. g (0.1 moo) of phthalene-9,10-diaceetobtril (cf. S. Hauptuabn, Chem. Ber. 21, 2 604 (1960)), 400 ml of methanol, 3.8 ml of water, and ahsulphuric hydrogen chloride are obtained. IMEI-ester ^F-enaithren 9 ^ - ^ ^ bt tyseHo acid 143 and ^from 145 DEG ^{(from about} ueetaio ^u) from 32.2 g (0.1 Muo) diueeylesterl f ^ n ^ RM ⁹ ^ - diode acid and 7.6 g (0.2 mol) ΙίίΙύϋΒϋίηΙϋΙ ^^ ι in 1 liter of absolute ^ ^ е Шеи sn-Cietanol fenanhry1-9,10 obtained, mp ¹⁷⁵ and ^{1 77} ° ^{(from about} ue1taio ^u) of 26 6 g · (a 1 mmol) fenenthren-9,1O-diethanolamino !! and 25.2 g (0.22 mole) of acid chloride ¹²⁰ ml uelansulfonové knows ^ yri-pyrrolidine from ^KA-9, cis-1 ^ alkenyloxy ieVylsul ^^ ^ ^ L ^ ^ m onan bt ⁰ 15 ⁷ and ^{from 159} DEG ^(from ACC ^ CN ^ oi.trili G. ^{122 g (0, 5} mo ^o) 4.5 diethylbenzo- ^f] thieno [ ^{2,3- e]} thiourea, ⁹⁸⁰ ml of ethylene glycol, and 100 g of potassium hydroxide are refluxed under stirring under nitrogen for 2 hours. The mixture was then cooled to 20, diluted with ⁸⁰⁰ mL of ^Dy in the provicti extratoe ^ olétereu pet. The organic phase is separated, washed with water, dried over sodium sulphate and evaporated. The residue i.e. 4,5- ^f iie ^Weyl nn ⁱ 0 t ^{- 1 2} - ^e] l ^ H ^ C ^ ^ e ^ o ^p o melts the uninstallation ^ ob ^ i ^e from the UE 88 and aioli at ^≥ 90 ° .

1 ^{06 g (0,} 5 mo ^o) _4> 5 diuee lnΜ'tofl ^{yl, 2-b]} thib ^e eni rozpuutí vn sn ^2, 5 ..itru Teti ^ ^ achlo methane and added a solution of 178 g (1 mole ) N-bromiulseniuid1. The mixture is heated to boiling under stirring and under a nitrogen atmosphere, while irradiating the lamp with a lamp. The mixture is continued at the point floss until all N broInssUsCniuid, which lies on the bottom of containers ^Y, converts it succinate. iuid floating on solution. This takes about 20 minutes. Then sn CN mixture was added 400 ml water and 'in ^^ Raindance Connect 8 (bbouue ^{ey l) of} NIF f [. ¹ ^ - ^ thiophene ^b on the ODU ²⁰² and ^a point ²⁰⁴ ° from ^one was filtered ^(37.0 g, ^{0 »1} mol) of 4,5-bi p omne t ^{y i} 0o Lnn ^{of [1} ^ - ^ ¹ 1 Hhiofenu 8 ^{g (0.2} mo ^of 4) tyanidu sodium in 500 ml · iceeob0trill gave top naphthoquinone, 2-Ъ.] trio0een4,55 ^d faietenbtril et 250-251 ° ^{(from acetone);} from 26.2 g (0.1 .mu.o) of naphtho (1,2-e) thiboene-4,5-diacephobitrile, 400 .mu.l of methanol, 3.8 .mu.l of water, and absolute hydrogen chloride yielded dLu (1). ^ -eHhiofen-E 5-fioetové tyse ≤ n ≤ mp ¹ 36 to ^ 8 ° ^(molasses);

from 32.6 g (0.1 mol) of naphtho [1,2-b] thiophone [1,2-b] thiophene-4,5-diacetic acid dimethyl ester and 7.6 g (0.2 mol) of lithium aluminum hydride in 1 liter of absolute diethyl ether gives naphtho [1,2-b] thiophene-4,5-diethanol, bt 163-166 ° (from acetone);

from 27.2 g (0.1 mol) of naphthofl, 2-b] thiophene-4,5-diethanol and 25.2 g (0.22 mol) in 120 ml of pyridine gave 4,5- [2- (methylsulfonyloxy) Ethyl] naphtho [1,2-b] thiophene, bt 132-135 ° (from methylene chloride);

to H. + ϊ. dibenzo [b, f] oxepine-10 is obtained from 38 g (0.1 mol) of 10,11- (1-bromomethyl) dibenzo [b, f] oxepine and 11.8 g (0.24 mol) of sodium cyanide in 500 ml of acetonitrile, 11-diacetonitrile, bt 176-178 ° (from methanol);

from 27.2 g (0.1 mol) of dibenzo [b, f] oxepine-10,11-diacetonitrile, 400 ml of methanol, 3.6 ml of water and absolute hydrogen chloride yielded dimethyl dibenz [b, f] oxepin-10, 11-diacetic acid, bt 65-67 ° (from pentane);

from 33.8 g (0.1 mol) of dibenz [b, f] oxepine-10,11-diacetic acid dimethyl ester and 7.6 g (0.2 mol) of lithium aluminum hydride in 1 liter of absolute diethyl ether, dibenz [b, f] is obtained Oxepine-10,11-Diethanol, bt 138-140 ° (from acetone);

from 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 gave 10,11-bis [2- (methylsulfonyloxy) ethyl] dibenz [b, foxoxin, bt 112-114 ° (from methylene chloride);

to para + L. from 42.1 g (0.1 mol) 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 there is obtained 5-acetyl-5H-dibenz [b, f] -> azepine-10,11-diacetonitrile, bt 183-185 ° (from benzene);

from 31.3 g (0.1 mol) of 5 * acetyl-5H-dibenz [b, phazepine-10,11-diacetonitrile, 400 ml of methanol, 3.8 ml of water and absolute hydrogen chloride gave 5-acetyl-5H- dimethyl ester. dibenz [b, f] azepine-10,11-diacetic acid, bt 123-124 ° (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 lithium aluminum hydride in 150 ml of absolute tetrahydrofuran gave 5-ethyl-5H -dibenz (b, f) azepine-10,11-diethanol, mp 102-105 ° (from ether);

starting 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 gave 10,11-bis [2 * (methylsulfonyloxy) ethyl] -5-ethyl-5H-dibenz [b, f] azepine, bt 140-143 ° (from toluene);

to paragraph M. + N. 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 lithium aluminum hydride in 1 liter of absolute diethyl ether to give 5H-dibenz [b, f] azepine-10,11-diethanol, bt 180-182 * (from acetone);

from 28.1 g (0.1 mol) of 5H-dibenz [b, f] azepine-10,11-diethanol and 25.2 g (0.22 mol) of methanesulfonic acid chloride in 120 ml of pyridine gave 10.11- bis [2- (methyl8-sulfonyloxy) ethyl] -5H-dibenz [b, f] azepine, bt 140-142 ° (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 (produced according to Example 6) and 140 ml of 48% aqueous hydrobromic acid are refluxed for 2 hours and then cooled to 20 °. The precipitated 7-hydroxy-3-methyl-2,3,4 hydrobromide is formed. The 5-tetrahydro-1 H -dibenzo [2,3- b, 6,1] azepine is filtered off and dissolved in 160 ml of 60% aqueous methanol. The solution was made basic by the addition of concentrate. 17 225103 of aqueous ammonia to phenolphthalein, whereupon the free 7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5- dlazepin. Sell melts after the transfer of ^the trait ^t alování about ²¹⁶ .When acetooitrilu at 21 · 8 °.

To convert to mercaphoronate, 9.3 g (0.03 md) of base is dissolved in 380 ml of acetone and a solution of 2.88 g (0.03 mole) of methanesulfonic acid is added to the solution while stirring. 2,3,4,5-tttrahydro-1H-dibeeioO [3: 6.7] ehiepino [4,5-DAA: eэpirmetrnsul ^{f b} ODU casting of m.p. ²⁸² DEG 2Θ6 ^0th

Example 8

Smet 18.6 g (0.05 mol) of 7-broImЗзmetyl- ^2, 3,4,5-tetrahldro-1H-dibtnzo ^[2, 3: 6,7] thlepino ^[4,5- 1azepinu ^{in (b ANNUAL} Ene ^h o ^p ccording example 6) H), ^{7 g (0 2} mol of J) in tyanidu měánéto ² 0 N 'dimethyl-amide te yHorni heated in a nitrogen atmosphere for 22 hours of stirring at 180 °. Then cool the reaction bar to 30 °, dilute with 100 ml of methylene peroxide and add 50 ml of a 50% aqueous solution of teylenedirmin. The organic phase is then separated off, washed with water and evaporated after drying at room temperature. The crystalline residue, i.e. 7-kyωinЗ ^mrtyl--2, 3,4,5-1 · tetrhyěro ^ěibtnool-2, 3: 6,71thiepino. [4,5-ějaotpin melts after překryttalování TMES of hexane and ethyl acetate at 154 to 157 °.

To convert to methaneselfonate te, 9.6 g (0.03 mol) of the base is dissolved in 50 ml of acetone and a solution of 2.88 g (0.03 moD of meto-sulfonic acid) is added to this solution with stirring, followed by crystallization of 7-methyl- _{^{3-methyl-2,3-d}} tetahyUro ^4,5-1H-b enzo di [2.3: 6.71 the switches [4,5-4rotpiime εmsulfonát ^{e d} by bo ^th in the ²⁴⁷ to 250 °.

Example 9

To a solution of 16.9 g (0.05 mol) 2,3,4,5etetra] Yedra-1H-ěibtizol2,3: 6, ^7] thitpino [4,5-3-ěJrotpin propriolu in 50 mi absolute pyridine TE blhem stirring for 15 minutes was added dropwise, with stirring 12.2 ^{g (0, 5} ° 7 ^of MO) -octane-chlori.d all, while maintaining the temperature ^of that MEEI ⁰ ° ^{and 5} °. The reaction was then allowed to stir for 20 hours at room temperature. Then pour the reaction string into ice water and extract with ether. · The organic phase is separated, washed with water and, after curing with shade of sodium, completely evaporated. As dejovitý residue left on the ^3-n (onyl ^^ 01 ^ 0 12 2.3> ^4, 5 · γι ^^ ^ (1γο- 1 ^ ^ ~ dt of benzo [2,3: ^6,7] thi. E ^when no ^{[4, 5]} rot ^P II.

21.5 g of tur base are dissolved in 150 ml of acetone and a solution of 4.2 g (0.047 md) of anhydrous stearic acid in 22 ml of absolute alcohol is added to the solution, and then filtered out. 2,3,4-5 ettrr ^Hyu ro-1H-ditenzo Ь, ^{3: 6} hiepino ^^ ^{[4, 5} - ^{d] r} rotpiioxa sulfate, after which the absolute přtkrystrlování of ethanedisulfonic melts at 157-162 °.

The following compounds are produced in an aidogical manner:

^{16.9 g (0.0} 5 mol) of ^2, 3 ^, ^ - d ^ of benzo azepine ^^ - ^ ³ -propnndu azepine in 50 ml of absolute pyridine and 5.9 g (0.075 md) acetyl te yolk 3 -rcttoxypro ^of y ^y - ^{2,3, 4, 5} - ^t TTR ^HLD ro-1 ^H - ^d i ^b tioo ^{[2, 3: 6, 7]} ino thit ^{p (4,} 5 ^u] rotpii. Todat a point m.p. 156-160 ° (from absolute temperature).

Example · 10

Κ 75 ml Ί ₉ 4% ethyl amine in absolute ethanol (corresponding to 0.012 mol) add 3.25 g (0.025 mol) of diisopropylethylamine, 50 ml of absolute ethanol and 4.5 g (0.4 (^ 1 mol)) , 11, bis (^ - (^ metylsulfoityloaqOetylldl.benzol byflthie ^ nu ^(p vyrotjenéto ccording nitrobenzonitrile clade ^P '5) and the whole was' heated in a sealed tube dobu.20 hours at 85-90 ° .. after oclh.azení The reaction mixture, together with 250 ml of methylene chloride, is shaken in a separatory funnel and shaken successively with 50 ml of 2N sodium hydroxide solution and water in each case, and the methylene chloride solution is removed in a water pump vacuum and 3-ethyl-2,3,4,5-tetreyydoo 1H-dbbenzo [2,3: 6,7] thiepinoL4,5-d] azepine, which precipitates in the crude state, is converted to the tydrochtoride as follows: 3.1 g of residue, ie · brown viscous oil, · dissolved in 25 ml of methylene chloride and add 3 ml of a 4N solution of ethereal hydrogen chloride 3-ethyl-2,3,3,5,5-tetrahydro-1H-dibinzo [2,3: ^6,7] thiepino [4,5- d ^and azepine hydrochloride The id is precipitated with ether, filtered off and recrystallized once from ethanol and ethanol. Melting point of methisulfonate 212 to 214 ⁰ ·

Pi k.ai И '. In a manner analogous to that of Example 10, the following compounds can be prepared in the absence of the depleting of starting materials:

3-ϋ6-1-1 _l of 5 · ^- IH ^1d DO ² Hd ^- bbino ^of 2,4: 6,7] ^TTI IPIN ^^ - ^ «zípIí- ,, ^{31 2)} - ^- ^^ ^b of ^d · 216 to 222 °.

² .3.4.5- ^^ «^ - γο- Hd ^{1 -b} biio ^2.3: 6 ^7Ί iipino t ^{t [4,5o -]} tzipin ^{b d} a point ¹⁴² and ¹ 43 ° (after překrystalovAií z mmewinou); meet melting point 305 to 307 ° ·

2.3.4.5- titгthy-гo-1Hothiβiю [2 ^ 3 ^ 3 ^ 0 ^^ 0 ^^^ ^^ zeptn 14 ^b of ^d Toni 11 9-120 ° (from -Ι ι ^ ^^ ™).

⁸ Example 12 ^{36 g} (0.0 ιηοΌ ³ 2, ^{3, 4, 5, and} E t ^{t e yd} roo ^{1H- -ib} INZO ^2.3: 6 ^Ί1tti i ^oi No ^[4,5o · ^- ] tzio ^and also for míchdní rozpist d 6 ^{m 8} 5% formic acid at ^t ep ^l of ^{thickness 40 from} 50 degrees. К this solution now intermarry 2.4 ml of 35% sodium foemaldetydu and then the mixture was stirred The reaction mixture is cooled to 20 °, diluted with 100 ml of water, and this solution is quenched with concentrated ammonia to give a solution of crude 3-beta-1-2 as an oil. 3J4,5-1H-itettlyčlro - Иbinzo0 ² З ^d 6 Ί3ttLieoiilo ^[4-5o 3tzipii · the crude base was extracted with ether, the organic phase by-El dvíhkrát rubs with water, dried over sodium sulfate completely pM ^ I. The base is now converted to mmiιalEuU.foiate as follows:

8.4 g of the crude base is dissolved in EA E0 om acetone а к ooparně solution was added 2.6 g of sulfonic metшiβul ^{f, f} NACE vylkystOtoje ^{3-methyl 1-2, 3, 4,} 5-te t ^e COO ^{Week 1} H ^- ibenzo ^{[ 1,4]} : 6,7 ^- thio [4,5-dimethoxymine sulfonate, which melts at ^256-258 ° C after recrystallization from absolute ethanol. ·

Peak la dJ ⁸ 3 ^{8 g (0 3} mol ^{of O) 2, 3, 4,} 5-teet ^TY DOO ^{1H- -} IBIN ^{2 _0,} 3: ^{6, Ί3} t ^t ie ^about io [4 5- ^d Lazi ^oИ Iz rozpissí with stirring in 80 ml of 50% acetic acid. To this solution, 8.16 grams (0.08 moD acetic anhydride) was added in one portion and the mixture was allowed to stand at room temperature for 12 hours. The reaction mixture was then completely removed on a rotary evaporator, the residue was dissolved in ether. The ethereal solution is washed once with hydrochloric acid, once with 2N sodium hydroxide solution and twice with water. After drying with sodium sulfate, the ethereal solution is completely evaporated,

225103>

wherein in the left a yellow oil of _3-acetyl-2> 3.4 _t 5-tetra} ydro-lH-dibenzo _[2,3í6> .7] thiepino [4,5-dJazepin. 9.4 ^g crude acetate-erivátu was dissolved in ¹ 5 ⁰ ml of abs. of diethyl ether. This solution was added dropwise over 30 minutes to a suspension of 1.6 g (0.042 md). Alimim aluminum aluminum oxide in 50 m of absolute diethyl ether, the reaction mixture is fed to cotton wool. Then the reaction mixture was further refluxed for 6 hours. After cooling to 0-5 °, 40 m of water are added dropwise to the reaction mixture, and the organic phase is separated. The organic phase is washed with water and, after drying with sodium sulphate, completely evaporated to dryness. The oily residue was extended ^beta results in ¹⁰ ml acetone and dedicated to -1 ⁰ °, and ^{C o u} ^ crystallized ethyl ^^^^ - ^ ro ^ pull-1H-dibenzo [2,3: 6,7] thiepino [ 4,5- ^ djazephn of melting point 106 to Ю7 ⁰ . The methestersiphonate was prepared as described in Example 7. Melting point 212-214 ° (from absolute stand).

Example 14

The following reaction product was prepared in an analogous manner to Example 12:

^{14.3 g} of ⁽⁰ ^ ⁵ mo ^o) 2, ^3,4, 5-tetrahydro ^y dr [- ^1o -t ^and thieno ^{[2 ', 3':} 2 з] [l lbenzothiepino ^[4,5-ά ] azepine be tempted ³ -Me ^e y ^y L 2, ^{3, 4, 5} - ^{t y} etrah DDT-1-th ^and Heo ^{[[^,} ^: 2.31 - (?] Beno [t ^h e ^p in [- 24,5-d] azepine as a crude product, the meeansulfonate has a melting point of 208-209 ° (from absolute ethanol).

Analogous. The following reaction product was prepared as in Example 13:

from ¹⁴ 3 ^{g (0} ° ^-5 mol) of ^{2, 3, 4,} 5-tetra ^AYD r [- ¹ H ^and thieno ^[2 ', 3': ^{2, з1 2H]} Beno [t ^and IE ^p in ^[24 , 5-d] azene. Zia is ^y ^ ³ -e3 l- ^{2, 3,} 4,5e etraУi ^{t e?} t ^DAA-1H- thieno ^[2 * ³ * ^{2 3)} M bennztdednoo ^4, 5- ^d Jazee ^p in the bo ^{d melt 12} 7 to ¹² 9 ^{O (} from acetone); mettrnsdiFonát bo ^th the ^{d 209} d ²¹¹ DEG ^(from ethanol whom you).

Example 16.

In a similar manner to that described in Example 10, successors to the compound can be prepared using appropriate starting materials:

Ьз 3- ^{((methyl d e} y ^y ιamno ^[p pr ^TPY] - ,,, 3 ² 1 H-dibennz L ² idedno, 5d] i ^ 2 ^ a ^ ^e ^ ^p ^^ -hI rm ^of crude ^ odúktu; dtyfroddor ^b ^ of the ^{d th 28 5-289} ° behind lighted.

Ь- 3- (dmetylomno ^ r ^ -yl ^{1-2, 3,} 4, FR-teintytoo-lH-week ^[2 *, ^{3 ό: 2,} 3j ^[1 ^ J ^^ пго р! ^ As ^ surovtao odUktu; dtyfroddor ^dt ^ bo u ^26, 5 and ²⁷⁰ ° with decomposition.

3- teimetylamno fa ^ ^^ ι ΐ) - ^{1,2, 3, 4,} 5 ^»1 0- ^and exa ^HYI ro ⁱ i ^b enzo ^{23, 4:} 6, ^7] cyclo-pta ^[2 - ^d azepin melting point ⁸⁰ to ⁸² ° ^{(from p} entanu); melting point about 3 ¹ 5 ° (with decomposition).

Example 17

AnaLoglckým manner as in Example 5 may povuihí tdpptíddeícíca as starting materials to produce compound successors' of ^22, 7 ^{g (0.0} 5 mol) ¹ 0 ¹¹ - ^{22 b} it d ^(y here ^yl methyl onl <o ^χ) β ^ethyl l ⁱ i ⁱ enoo ^{[2: 3 pull} tp L ^{h OI. 4.4} g (0.06 md) ndbutyltmhnu and 16.25 g (0.125 moo) diiз [prtp; y ^{y y} tty ιmhnu in absdutním eanoplu of i-3 ^{with a} Ka ^{of the} IUI - ^2, 3, ^4, 5-theta ^ayi rt- ^1H - ^d i ^b toot ^22,3 : ^6,7 l ^traction tp ^h no ^[ 4, ^^^ ipío ^b o ^d 'Uní 107 to 10 ^ο (from acetone); m.p. 218 DEG-220 DEG (from absolute ethanol);

225103 20 from 22.7 g. ^(0.05 mo ¹ ^ 0 _l ¹¹ -bÍ8 [2- ^{(methylsulfonyl x} and ^y ethyl] dibenzo [b, f] t iepinu ^h, 3.4 ^g (0.06 mol ) allyaiminu and 16.25 g (0.125 mol) in absolute ethanol diisopropyletyamlnu ^gave ^ tí.lil-dddS tetrÉhitoo--1H-dibenzo ^[b, ^ O ^^^ azepine ^ - ^ ^p aze in JEKO crude protakt; ^e Me tMinul ^{sulfonate t 2} when a is 25 to ²² 7 ° (from absolute etanoW;

^{of 22 7} g ⁽⁰ ° ⁵ ° ^{m ^.)} 10,11-bis ^[2 - ^{(Me e} yl8ul olцy.o ^f: f ^{χ) e'tyl] d} · ib noo [Ъ ^f] thienyl ^pi nu ^, 3.3 ^g (0.06 mol). propargyl CM and 16.25 g (0.125 mol). of diisopropylethylml in absolute ethanol. ^gave l- ^ ^ -propionic ^{2, 3, 4,} 5 ^et tlaУd ^d ro- ^dd beeoz ^1H- [2,3: 6, ^'7] thie ^p ioo ^[4,5 - ^d] can ^pi n ^- jtóo raw prodict; mernosulfonate melting point 218-221 ° (from absolute ethanol); * from ^22.7 g. ⁽⁰ ° ^-5 mol) ¹ 0! - bist ² - (mstylsulí ^^ ^ lo yetyl ^3d ibenoz [b, f ^{6.0 g} (0.06 mol) lri.noIn · eyУcy) k.opentaou and 16, 25 g (0.125 mol) ^{of p} diLL80 ropyletylадlou absolute yes ^ e ^ u ^ka Zia 3- ^{(c lk} llpen ^{of ylmethyl)} -2, ^{3, 4, 5} - ^y etrι ^hl drl- ^1H -dibenoo [2,3- : 6,7JthL.epiou [4,5'-4] azepine bo ^d mp ^113-15 DEG ^(from ethanol absolute ^); methralphonate melting point 248-252 ° (from absolute ethanol);

of ^{22 7} g ^{(0, 05} mo ° J 0 ^{1, 11 2} -Me -bieΓ ^{e l} y ^f ol 8el ^мl O2 ^{χ) ethyl] d} ibenoo [b, ^f] thienyl ou ^pi, 6.7 ^g (0 06 moo) (eminomeeyDcykl (hexane and 16.5 g (0.125 mol) in absolute diLLaoproplletylшlou et.enolu the ZIS ^ka ^^ ^^ Ή χ ¹ ^ ¹¹⁾ - ^{2, 3,} 4 ,, ^ ^d 1.6taH- lbenzo ^2,3: б 7] Уli ^e ploo ^[4, 5-d] ^ ^ epi ¹¹³ and a melting point ^{from 11} 5 ° ^(from acetone); meeιmoul LNA ^{f y,} mp 256-258 ^ (from absolute ethanol );

from ^22.7 g ^(0.05 mo ^{o) 1} 0,11-Bis ^[2 - ^{(methylsulfonyl f} LO2 of ^{Ol χ} r) ^{ethyl] di} benzo [b, ^f] У ^{hi pi} e ou ^{33 g} (0, 06 mol) and 16.25 g (0.125 mol) in absolute ethanol dilsopropiletyamlnu of M ^ ^1,2,4, 5- tУa ^{hy e} r ^d d ^d ro- ^3H Beno ^{[2, 3:} б ^{7] thi} e ^when no ^[4, 5- ^dd · ^P can be in- -eУano ³ · ^0, bo ^d mp ^{157-159 (from} acetonitrile ^s one); ^e cauul methyl ^sulfonate, bo ^th the ^{d 194} and ¹⁹⁸ DEG ^(from ethanol absolutníto);

from 22.7 g. (0,05 moo) 10,11-blu | 2- (methylsulphonyl: χr) ethyl] dibeozo [b, f] thiepLLol, 4.5 g (0.06 mol) of 3-amino-propanol and 16.25 g (0.125) mole) in absolute dilsopropiletyaminu - ethanol ZIS ^{ka 1, 2, 4,} 5 ^{e d} ttaaУ dro- ^3H - ^dd Beno [2, ^3, 6, ^7] EP ^{d thi} no [4,5-d azepine ^{l d} N- ³ -pгoplOol bo ^{d th} and the ^{120! 132} ° ⁽ from ace.on); Met ^ su ^ bo ^d sulfonate mp ^181-18 ° 3 ^(from absolute ethanol); .

of - 22.7 g (0.05 mol) of 10,11-Bio [2- (metylsllfoцll <oχfl · butyl] diЪenzo [b, f] thiepiol, 5.4 g (0.06 mol) of methyl ^3-yl lχypropyllmiou and 16,25- g (0.125 mol) in absolute ethanol dlLLeopropiletyamlnu gave 3- (3-m · ^y L: χlprooyl) -2,3,4,5yee αllddroн1H ^y-dibenzo [2,3: 6,7] thiepnnoC4 5-d] aze ^p in. in the form of crude ^p ro ^d also in ^{y, f} meeaeoul <ooát ^{bo d} point 213 and ^{from 216} ° - ^(from absolute ethanol-it);

of - 22.7 g (0.05 mol) of 10,11-bis--Cmetylsulfomyloxl) eУll] ^d lbeozo CbjfJttii.epinui 6.3 g (0.06 mol) - 3- (metilthio) ^p ropyarainu and 16.25 g (0.125 mol) in dilsopropyletyamlnu absolením ethanol to give 3- [3- ¢ Me yltlio ^yl) propyl) <- 2.3, ^4, 5tey allddro ^{yl-1H-diЪeeoz} [3.3: 6.71 · ^y ЫL full aze ^f ^ n Orme crude proďuldtu; We ^e taloul LNA ^{f y, d} bo ^th the ^{212-2 14} ° ^(z - ^y absolu whom you ethano-lu);

from 22.7 g (0.05 mol) of 10,11-biu [2 - ((methylphenyl) oxy) ethyl] dlbenzo DbfHMepine, 5.5 g (0.06 mol) of 2- (methylthio) ethyl] 16 25 - g (0.125 mol) - in absolute dlisopropilytyaminu etanUu from ^ k ^and 3- ^[2 - ^(y we ylУ ^h io) et ϊ ^l] -2,3,4, tetellι ^yd dl н1 ^Hd ibeozo ^[2 3: бЗ] ^y hiypinot4, ⁵ - ^d] azepine, ^b o ^d Tenia Iz 91 ^{- 92} ° ^(from Entente ^-p); We ^e íааoul sulfonates ^{y f, - d} t bo u-218 ^{and 22} 0 ^{(a - b} solutního ethanol);

from 24.5 g (0.05 mol) of 10,11-bis [2- (1-chloro-8-fluorophenoxy) -elide] -2-chloro-benzo [b] f, tliepiou,

1.85 grams of methyl amine (0.06 mol) and 16.25 mol) dliвoproplletyαвдiou - in - methanol gave 7-chloro-3-meeyl- ^2, 3,4,5-УetríΛydro-1H-diЬenoz [2,3- : 6,7Hthiepino [4,5-d ^ benzodiazepine as a crude ^p ro ^{d uktu;} Hydrochloride ^- bo ^ i ^d t from 266 to ^{2689 (from} absolutaího ^ et ^ ol of 24.5 g (0.05 mol) of bis-10JI -ímetylsulfonyloxy Tyll ^ Z-chlorodibenzo lb flthi spin,

6.7 g (0.06 mol) of (aminommtyl) cyclopentane 16.25 g (0.125 mol). diisopropyletylminu in absolute ethanol se.získá 7-chloro-3- (cyklópentylmeeyl) -2,3,4,5-telrhlydoo-lH-dlbenzoPjSi ^ ^ VHhíe nfAjS ^{dlizep-1 d} ^ bo mp ^{123 DEG-126} DEG ^(from acetone); M.p. 195 DEG-1913 DEG (from absolute ethanol).

Aidogically as in Examples 5 and 12 respectively, the starting material can be prepared for both of the following reaction products:

from 43.1 g (0.1 mol) of 2-chloro-10,11-bis (bromomethyl those Hlibenotb 1,:,] thiepin and 11.8 g of cyanide ^with copper in 500 ml of icetorátrilu ^ ka 2-c ^h ^ ^l ORD betzz [b, f] ^ t ^{h e} .e lnn10,1 ^{1-5 liters} ILC's ^{t n} _J ^b tril o'd ttoí ^207-210 ° ^(ZC lorofoimu ^h);

from 32 ^{3 g (0} 1 mo ^{O) 2-di} -cW.or ^b enzz ° b fltřepin- ^{10 1} -dilcetooiirill 400 caliber methanol

3rd ^{8 m} in the ^soil and drought ^é it. chlorovofóku gave RAMET ^ ster 2 chLžrd bbtzo ^{L of} B, R thitpin- ^10.11 -dioctové acid, melting point 111 DEG-113 DEG (from methanol);

38.9 ^g of ^{(0, 1} mol.l meeyles ^ ru ^ ² c ^{h l} i ^b Lžr- enzz [b, ^f] thitpiZ5 ^{10, 11} - ^L ižctžv tyeel ^{s i} n ^g, and 7.6 g (0.2 mol) ltthlmnalmJinl mh ^ ^y lithium aluminiumhydride in 1 l. of absolute ether Hety ee gave ² -c01orditzozo ^[b, f] Heienin-! 0.11-diethanolamino !, mp 152-154 ° (from etylicetátu);

from 33.3 g (0.1 mole) of 2-chloro-libenzz [b, f] thitpiz-10,11-lithium) and 25.2 g (0.22 mole) of mithiol sulphonic acid chloride in 120 ml of pyridine gave 10 , 11tyIsulfonyloxy) ttll) - ² -chlorlibtnzoíb f] thiepiz m.p. 118-120 ° (from ether Hety).

Example 18 ^{To a} solution of ²¹ 9 ^{g (0.0} 5 ¹ 0,11metylsul mo ^ ^fO n ^yloxy) e ^tl l ^l dibenoo ^[b, f ^{0 p} oxe Izu in 250 ml of absolute ethanol was added 6 g (0.06 mol) arázomet Уc ^{y y]} klžptztazu and 16.25 g (0.125 mol) dii80pIюpllθtylедinu and the mixture is boiled for 18 hours under reflux. After cooling the porn ice bath, crystals precipitate which are filtered off and washed with a small amount of isopropanol and pentane. The filter residue is 3- (cyclo entllee ^p ~ l t ^l) -2,3,4,5-tIlr8lιydo5n1 H5libtnzo ⁽² _L 3í6, ^{7J p} oxe ino ^{[4,5-l] p} LOE in the temperatures ⁹⁹ and ^{Counting from} 101 °. The melting point is 280 ° eetдеsulfžndtu (dec) *

AruHogic way you can produce:

from 21.9 ^{g (0.0} 5 mol) of ¹ 0, ¹ 1-bis [2- ^(l EET lsulfžz zxy ^yl) eth ^yl] di ^b enz b floxepinu, 4.5 ^g (0.06 mol) 3-lm.nopropιшzolu and 16.25 g (0.125 mol) dii8opropllet ^y Lmin absolute pmol gave 1,2,4,5-eeIaaly <r * o-ЗH libenz | ₍₂ '3: 6,7] oxtpizž [4,5-d] -3- azepiz * propαzol mp '59 and ⁶¹ ° ^(from pentane) eetaιzzsll: methanesulfonate melts at ^188, and ^{from 192} DEG ^(from ethanol absolráráhio).

Example 19

27.6 g (0.1 mol) of 3-eee ^{yl-1, 2-3,4,5115} teahydrodibenz [b, f] aotpino (N is -djazepin. SMMS dissolved in 130 and 130 htxlmetapoll ck ck absolute Rachan toluene. to this solution was added dropwise over 15 min a suspension of 7.8 g (0.2 mol) of the amide. solution. in 24 ml of absolute toluene at ^a temperature ^from SE Rice slightly ^ 'cooling maintained at ¹⁸ and ²⁰ °; simultaneously introducing the reaction solution into a stream of dry nitrogen was LBY vypuzovhl vonZkaljcí imoráak. After completion of the dropwise addition, the reaction mixture was stirred for 30 min and then a solution. 14.2 g (0.1 mol) ^y eee ljolilu in 100 ml of absolute toluene during 15 ránut while cooling with ice the temperature is further uώ ^ ί ^ l ^; jt at ^18-20 °. ^p Otom Rea ^ the mixture ftéle RACH is ^{ETE 15} ránut and pi ¹ was slowly poured into 2 liters water and 400 ml The organic phase is separated and the aqueous phase is extracted with toluene, the combined organic solutions are washed with water and evaporated after drying The crystalline residue, 3,10,10-dimethyl-1,2,3,4,5,10-hexahydro-benzo [b, f] azeePno [4,5-d] azepine, is crystallized from ethanol and melts at 197-199 °; the melting agent melts at 231-233 °. (from absolute ethanoia).

The starting material can be produced by a method analogous to that described in Example 6K as follows:

from 42.1 g (0.1 mol) of 5-teceyl-10,11-bis (bromoethyl) -5H-ribtin [b, f] azepine and 11.8 g (0.24 mol) of sodium cyanide in 500 ml of acetone are prepared 5-tert-ethyl-5H-ribeno [b, f] thepepia-10,11-diaccetoitrile, m.p. 183-185 ° (from benzene);

from 31.3 g (0.1 moo) of 5-tert-ethyl-5H-ribeno [b, f] thio-10,11-ritetto-Otil, 400 ml of methanol, 3.8 ml of water and absolute hydrogen chloride gave rioethylphenyl-5-α-ethyl. -5H-ribeno [b, f] azepine-10, 11-Acetic acids, m.p. 123-124 ° (from toluene);

starting from 37.9 g (0.1 molar) of methyl methyl-5-methyl-5H-pyrrolo [b, f] aztpia-10,11-di-acetic acid and 7.6 g of triethylmine / mhydrir in 150 ml of absolute tetrahydrofuran yielded 5- ethyl 5H-ribeno [b, f] thiazepia-10,11-rithiaol, m.p. 102-105 ° (from ether); .

with 30.9 g (0.1 MOO) of 5-Eille-5H-ribenz _[b> f] tmeiio-10,11-diettaolu and 25.2 g (0.22 mol) of mett08ulfoaové acid in 120 mi of pyridine afforded ee 10,11-bis- [2- (olyl-fluoro-10 &apos; 2-ethyl) -5-tris] 5H-ribtaz [b, f] methyl, mp 140-143 [deg.] (From toluene);

starting from 37.9 g (0.1 -moO) of riteeyleuter of 5-tert-butyl-5H-ribtin (b, f] aztpia-10111-dioic acid and 7.6 g in 1 liter of absolute diethyl ether gave 5H-dibenz ( ^b , f) aze ^{p IA-10,} 1 ¹ - ^r ltitaol, ^T-180 and Lot ttaí ^Z ^ 2 ^{0 (from} acetone);

from 28.1 g (0.1 moo) of 5H-drbeeo [b, f] dark ^p io-10,11-diet mol and 25.2 g (0.22 moo) of methanesulfonic acid chloride in 120 ml of pyridine gave 10 , 11-bis [2- (teeylmUfploloJχ) Ettl] - ^5Н - ^{г, ь 6ПО} [b, f] αzt ^{p i,} t ^ ^th the Iota ^{140 DEG-2} DEG ^{(from heating); 2.9 g (0.0} mo ^{of 5) 1} 0 ¹ ~ ^b U ^[2 -me ^t yluulfoayloJ ^χ 'letyl] -5 ^{H IB} TAZ -R ^b, f ^{t p} iau AZT, ^1.8 5 ^g (0.06 moo) mm tylamine and 16.25 g (0.125 mol) of dlisopropylethylamine gave 3-trans-1, 2, 3, 4, 4, 6-hexamethylethyl ^and 54d] rzαp ^t and te ^ ^^ PTO 12 ^1-124 DEG (from my Ομο1ο) ι; ι2 tseisulfonát mp 263-266 ° (from a mixture of absolute ethanol class, acetone).

Example 20

Following the procedure described in Example 6H, the following compounds can be prepared using the corresponding starting materials:

23.6 g (0.05 mol) of 10,11-bis [2- (tetyluUifoaylP2ýletyl] -2-chloro-D ^b where [b, f] oxepiau,

1.85 g (0.06 moo) mm of laminate and 16.25 g of dihydropropylamine in absolute ethanol yielded 7-chloro-m-ethyl-2,4,4,4-diol-2,4-diol. beoen2 [2: 3: ₇ beta] eieoin4 [4 _l-r tmeiθoin, mp 174-176 ° (from toluene); ГУ'ГгосЬГоЛГ melts at 279 to 281 ° (from absolute ethanol).

The starting material, i.e., 10.11-bis [2- (tethyl8-sulfonyl) ethyl] -2-7-propylbenzo [b, f] oxppi, can be prepared in a manner analogous to Example 6H as follows:

* a) of 20.7 g (0.05 moo) of 10 -4-biu (broyl) -2-chrordibeno [b, fpepepiou] and 5.9 g (0.12 moo) of sodium cyanide in 250 ml. ^ HrHu gave 2-7rlorribenz (b fJpχepin riα7etpnitrii-10,11-te ^ ^ OTA eye 7 and ^{22 for 23} °° (zm TTA ^ c ^ ^o ^ i ^);

b) from 15.3 g (0.05 mol) of 2-chlorodibenzyl, f] oxepine-10,11-diacetonitrile, 200 ml of methanol, 1.9 ml of water and absolute hydrogen chloride, dimethyl ester of 2-chlorodibenzo [b, f] was obtained. loxtpine-10,11-diacetic acids, crude product (oltj);

(c) from 18.7 g (0.05 mol) of 2-chlorodibratic [b, f] oxtpine-10,11-diacetic acid dimethyl ester and 3.8 g (0.1 mol) of 10-dimethylaminimide hydride in 500 ml of dittyl ether are obtained 2 ' Chhordibeti [b, f '] ^p ~ in-oxa 10.11 dittanoo crude product (oltj); and ^d) from ^{15.8 g (0, 05} mo ^o) 2-chloro-D ^b TNI ^[b, f ^{p of} oxt in-1 ^0,11 - ^di ttanolu and ^{12 6 g (0,} · И mol) chloride metiansulfonové acid in 60 ml of pyridine gave b0,11 st "bi ^ s [2 ^ -m ^ 1 ^; ^ ^^ lsulf onyl-oxy) tiylj - ^ - ^ chlordibtnzí ftaxtjnu crude ^p ro ^d uct ^(oltj) _e

Example 21

Following the procedure described in Examples 5 and 6E, the following compounds can be produced using appropriate starting materials:

(a) of 22,7 g (0,05 moo) of 10,11-bis [ ^2- o (retylbuthoxylloo) -fluorobenzoyl, 4 [mu] m of propylumine, 3.3 g (0.06 moo) of propylumine and 16, 25 g diisopropylttyaminu absolute ttanolu st to give 3-yl ^p "2,3,4,5 rotates ^{t y d} y ^oo-lH-d i ^b tnzo [2,3: ^6,7] th ^t ep ^and NC4, ⁶ - ^{d] aztpin, O} and Otplo Oání ¹²⁸ and ¹ 3 ⁰ ° ^(from acetone); Rr · ^e olliul ^sulfonate ajt at ^{about 181-183} ° ^(from absolute TTA ^ ^lu);

(b) from 26,7 g (0,05 moo) of 0,11-bis [2- (retylsulphonyl) oxyl) 22-oxo-dibisol, 4] Olitpinj,

6.0 g (0.06 moo) of φmJnoneeyccyclopenoate and 16.25 g (0.125 moo) of diisopropylttylamine are obtained

7-bromo-3- ^(p eeiolmёtyl cyclo) -2,3,4,5-OtOrlhydro-1H-dibtnzo [2,3: 6,7] Ohi tpinoÍ4,5 'd] azepine OtploOa Oání ^120-12 3 ^{O (} from ttanol ^ ·

c.) from 26.7 g (0.05 moo) 1 0,11-bis [2- (retylsulfonyloχ)) TTYL] - ² -brordibeeizO johitpinu ^b _i F, 2.7 g (0.06 moo) amine TTYL and 16.25 g (0.125 mol) dilsopropylttyaminu obtained 7-bromo-3-2,3,4,5 tOyl2 "1 € 1γ« ^^ ο-1H-dibtnzo ^2, 3: 6,7] thiepino [ 4.5 ”· U] aztpin, crude product.

Example.2

A mixture of 19.3 g (0.05 moo) of ^7-bromo-2 Ззetyl-, 3,4,5-tttlíllydro-1H- ^d iЪeeiz02,4,6 ^7] tlitpino [4,5-dJaztpinu, 10.7 g (0.12 molar) of cyanide cyanide in 20 ml of DMF was heated under stirring for ²² hours under stirring to WO ⁰ . Then cooled to 30 ° ZRT ^{d 4} I ST mettlénchloridu 100 ml and add 50 ml of 50 st% aqueous etylénUilminu. The organic phase is then separated, washed with water and dried over sodium sulphate and evaporated. Crystalline zbyOtk, kttrým jt 7 kyía: NO-otylo2,3,4,5o · eetllhydro 1HoUiitnzL ² _J-3: 6,7] ^p Ohita ino [4,5-d] ^p in AZT, TAJTI ^P O ^{P O} řtkrys alování ZT mixtures htxanu and tty ^ -t ^ ru ^to, acetic acid ^p s ¹ 54 and ^from 156 °.

For účtlem ^p řeveUení to reeía isUfonát rozpuusí st ^ 10 g (0.03 mol) in 50 ml bázt Ado-one and O Omuta rozOoku st marks stirring with 2.88 g (0.03 mol) of methane sulfonic cid retrieves vykrystaLujt 7 ~ kyεalnO Ottl · o2,3,4,5 Ottrahydro-1H-dibtnz [2,3: 6,7-divided hitcpnnot4, Ou ^d latρ irmt0ansulfonát ^p o 't.tploO Oání ^{1 220 and 2} 23 ^O.

In an analogous manner, the following can be produced: · from 22 g (0.05 mol) of 7-bromo-0 (chloro-oylmethyl) -2,3,4,5-triazole-o-1H-dibeio02,4: 6,7] ^{. d p} lazt ⁴ yne ^{10.7 g (0, 12} mo ^o) ýrn mESNA t ^ u ^ ²⁰ ml of methyl-rnumdu Hyan-3- ^(p eniylmtyl hyclate)) - 2,3,4,5-1H-Ottaehydro -dibtnzo [2,3: 6,7 ^ Hi pího [4,5-d] aztpln, OipIoOi Oání ¹⁷⁰ and ^{1 72} ° ^(from methane). O ^and the temperature rrtanis ^{uf ON, and} the ²⁰³ and 206 ° ^{F (from} absolute tianolu).

Example 23

a) 15 g (0.05 mol) of dibenzo-1b, flthiepin-1, ^0.11- diethanol are dissolved in ²⁰ ml of chloroform with stirring. Ee To this solution was added dropwise over 30 minutes with ice cooling at a reaction -íepLo ^ 5 to ¹⁰ ^ ° extended to L3,5 ^{g (0.0} mo 5 romi ^b ^ ^d with phosphorous in ¹⁰⁰ ml of chloroform. The mixture is stirred for 15 The organic phase is washed with water, dried over sodium sulphate and evaporated. The residue, i.e. 10,11-bis [2-bromoethyl dibenzz [b, f] thiepine, remains in the water at room temperature. of the raw product.

(b) 21.2 g (0.05 mol) of the crude product obtained under (a) is stirred with a solution of 15.5 g (0.5 mol) of meeylamine in 150 ml of ethanol at room temperature for 5 hours at a temperature of 65 to 70 °. The reaction mixture is then evaporated in vacuo and 100 ml of water are added to the residue, whereupon 3-methyl-2,3,4,5-errhedodo-1H-dibenzo [2,3: 6,7] thitpino [4,5] crystallizes. -d '.lazepin, which after drying and ^p o ^p CONTRARY tO recrystallized from ^1-Trol ^^ u ^p s m.p. ^83-86 °.

Example 24

Tablets obsahhjící 0.02 g of 3-methyl-2,3,4,5-tttaíhlydrl-1H-dibetzo ^[2, 3: 6,7] thiepinl ^^ - djazepirmetansulfonátu are prepared as follows:

Ingredients (for 10,000 tablets):

Meet-3-2,3,4,5-tetrιhlydrl-1H-di-Nzoia 2, ^{3: 6,7]} thi switches ^b4, 5- ^d J-

azepinmeeteisuufonát 200,00 g lectose 200,80 g potato starch 354,70 g stearic acid 10,00 g talc 200,00 g magnesium stearate 2.50 g colloidal silicon dioxide 32,00 g ethanol as required

A mixture of 3-methyl-2,3,4,5-tetratidro-1H-dibenzo [2,3: 6,7] thiepino U, 5-d] diazepine methanesulfonate, lactose and 194.70 g of potato starch is moistened with ethanolic stearic acid solution and the mixture is granulated with a sieve. After drying, the remaining potato starch, talc, magnesium stearate and colloidal silicon dioxide are admixed, and the mixture is compressed into tablets having a thickness of about 0.1 g, optionally scored to finely adjust the dosage.

Example 25

Dragees, sewn ^ h compounding ^0.00 5 ^{g 3-methyl-e-7-yl} kyia-2, ^{3, 4, 5} -teta dlro ^{hl-1 H} - ^d i ^b enzo [2,3: 6, ⁷ hhiepino [4,5-djozep-Imethanesulfoate] was prepared as follows:

Composition (for 10,000 dragee): 3-meeyl-7-cyano-2,3,4,5-t * tahyrdro> -1H--ďLtanzo ^[2, 31 ^6, 7 Lime ^ nu ^[4,5-d ] -

aoepi-methnicillufoate 50,00 g lactose 175.90 g

Ingredients (for 10,000 dragees):

eteeric acid colloidal quartz oxide 10,00 g 56,60 g . talc 165,00 g potato starch 20,00 g itearan sucrose stearate ^(for R ^{i for} it ^and Lic ^s) shellac 2.50. G. 502.28 g 6,00 g arabic gum 10,00 g dye 0.22 g titanium dioxide 1.50 g ethanol * as required

^From 3-methyl-7-cyano-2,3,4,5-tetrahydro-1H-dibenzo [-2,3: 6,7-thiopyridine-5-d] azepiimethane-

After drying, colloidal silicon dioxide, magnesium sulfate, and the mixture are pressed into the dragee cores. The cores of dragee iirup of iacharose, shellac, arabic gum, dye are dried. So it is dragees about helens! 0.100 g. ^é IE ANNUAL ^b i ^G hurt Seremo · ^e k, potato starch and then itearnn oppaří coating concen- Tysl and the ^ ^ ^ Ιζ ιμΙ Λ ^ ^1! r ™ and vy-

Example · 26

Capsules containing 0.02 g of 3-methyl-2,3,4, oxepino [4,5] -palzepine hydrochloride are prepared as follows: 5-te ^ 1H tahydro- (JLB ^ ^ r ^ NZF ^2! 2 :: 5 7í-

Ingredients (for 1,000 capsules): 3-methyl-2,3,4-tetrahydro-

. tydro-W-dibennz [2,3: 6, ⁷ Jooejino- [4,5-dOazepine] 20,00 g laktc ^ 253,00 g gelatin · 2,00 g cornstarch 10,00 g talc 15,00 g water as required

^HH ldroh ^h orid З-тееу ¹ - ² ,, ^, 5-eetahtydooil ^H - ^d ibenzo [ ² , ³ : 6, ⁷ Joxepino ⁴ , ⁵ Jazepin ie imi-

with lactose, moistened evenly by mixing the aqueous solution with a suitable sieve (for example, sieve and aperture size of 1.2 to 1-hour corn starch and grease) and filled into hard veins gelatin and granules, 5 mm). Girnuate ie immission is iuatin cappias (size 1).

P Píkl a d '27

Aqueous injection solution containing 0,01 g / m 3 “mete1-2 fe, 3: 6,7 3thiepino | ^, .4,5-d] azepinmeeenilUfonátu IE Prepare * NO , 3,4,5-tetrilyl-11H-dibenzene, as follows:

Composition (for 1000 empulses):

3-methyl-2> 3,4,5-tetrahydro-1 H -dibenzo-

(2,3: 6,7Ithiepino [4,5-d] azepine methanesulfonet 10,00 g water as required

A solution of 3-methyl-2,3,4,5-tetrahydro-1H-dibenzole-2,3: 6,7-thiepino [4,5,5-d] azepine methanesulfonate in 1000 ml of water is filled into ampoules and sterilized. 1% active substance solution ·

Claims (9)

SUBJECT OF THE INVENTION A process for the preparation of the novel tetrahydrofuran I, and the hexahydroazatetracyclic compounds of general formula (I) in which R ^ 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) dialkylaminoalkyl, (C 2 -C 6) hydroxyalkyl, (C 3 -C 10) alkoxyalkyl, (C 3 -C 11) alkanoyloxyalkyl, (C 3 -C 10) alkylthioalkyl or, optionally, chlorine, methyl or methoxy substituted phenylalkyl (C 7 -C 12) and ring A is unsubstituted or substituted by halogen having an atomic number of up to 35, an alkyl group 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, (Ia) in which: R ^ is hydrogen or (C až-C zbytek) alkyl, and one of Ϊ and Z is a vinylene or epithio group and the other is a direct bond, and their acid addition salts, characterized in that the reactive diester is a strong inorganic or organic acids and diethanol of the formula II-но сн ₂ сн -он ₂ (II) wherein X, Y, Z and A are as defined above, reacted with a compound of formula III, N (III) / \ HH in which it is as defined above, whereupon the optionally obtained compound is converted to another compound of formula I, and / or the obtained compound is optionally converted into a salt, and / and the obtained salt is optionally converted into a free compound or into another salt, 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: R1 is hydrogen, C1-C8aliphenyl, C4-C8cycloalkylalkyl, C3-C8alkenyl, C3-C8alkynyl, C4-C10alkylaminoalkyl, C 2 -C 8 hydroxyalkyl, C 3 -C 10 alkoxyalkyl, C 4 -C 11 alkanoyloxyalkyl, C 3 -C 10 alkylthioalkyl or C 7 -C 12 phenylalkyl, ring A is unsubstituted or is substituted by halogen having an atomic number of up to 35, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an alkanoyloxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, hydroxy, trifluoromethyl or cyano; X represents an epoxy group, an epithio group, a methylene group, a direct bond or a divalent radical of partial formula Ia X / N | (Ia) ^R 3 wherein R 1 is hydrogen or C 1 -C 4 alkyl, and one of Y and Z is vinylene or epithio, and the other is a direct bond, characterized in that it is reacted with a reactive diester of a diethanol of formula II wherein X, Y , Z and A are as defined above at this point; wherein R is as defined above 3. A process according to item 1 for the preparation of novel azepine derivatives of the general formula I, wherein: R 1 is hydrogen, C 1 -C 6 alkyl, C 4 -C 8 cycloalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 4 -C 8 dialkylminoalkyl C 2 -C 6 alkyl, C 3 -C 6 alkoxyalkyl, C 4 -C 11 alkanoyloxyalkyl, C 3 -C 6 alkylthioalkyl or C 7 -C 10 phenylalkyl is optionally substituted by chlorine, bromine, methyl, hydroxystopine, mercapto, methylthiostopine or cyano, X is an epic stopin, epithio, methylene or bivalent radical of partial formula Ia, X z N (Ia) wherein R 3 is hydrogen, mm tulle, or stylish Ϊ means a direct bond and Z is a vinylene trace or epithio group, characterized in that a reactive diethanol ester of formula (II) in which X, Y, Z and A are as defined above is treated with a compound of formula (III) in which R 1 has at this point. 4. The process of item 1 for producing the novel azepine derivatives of formula I, wherein: R1 is C1-C6alkyl or cyclopentylmethyl and the ring A is optionally substituted with chloro, methyl, methoxystopine or cyano; X is epoxystopine, epithio, mmtylene trace, or the divalent radical of partial formula Ia, X / N I (.Ia) R ₃ in which R 3 is hydrogen, methyl or ethyl, J v Y represents a direct bond, · a Z is a vinylene trace or epithio group, characterized in that a reactive diethanol ester of formula (II) in which X, Y, Z and A is as defined above is treated with a compound of formula (III): R 1 is as defined above. 5. The method of item 1 for producing 3-methyl-2,3,4,5-tetrahydro-1H-dibenz (2,3: 6,7] thiepino [4,5] azepine, characterized in that the reactive diester of diethanol II, wherein A, X, Y and Z are as defined above, is treated with a compound of formula III, wherein R 1 represents a methyl group. 6. A process according to claim 1 for the preparation of 3-methyl-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] oxepino [4,5-d] azepine, characterized in that: and ee is reacted with a reactive diester of a diethanol of formula (II) in which A, X, Y and Z are as defined above with a compound of formula (III) in which R1 is a methyl group. 7. The method of item 1 for the preparation of 3-methyl-7-cyano-2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiepino [4,5-d] azepine, The method of claim 1, wherein the reactive diethanol diester of formula (II) in which A, X, Y and Z are as defined above is treated with a compound of formula (III) in which R1 is a methyl group. 8. A process according to claim 1 for the preparation of 3-methyl-1, 2,3,4,5, 10-hexahydrodibenzo [3,4: 6,7] cyclohepta [1,2-d] azepine, characterized in that: the reactive diester of diethanol II, wherein A, X, Y and Z are as defined above, is treated with a compound of formula III wherein R 1 is methyl. 9. A process according to claim 1 for the preparation of 3- (2,3,4,5-tetrahydro-1H-dibenzo [2,3: 6,7] thiopino-4,5-palladepin-3-yl) propanol, characterized in that the reactive diester of diethanol II, wherein A, X, Y and Z are as defined above, is reacted with a compound of formula III wherein R 1 is hydrogen.