NO781530L - 2-BENZYL-PERHYDROAZEPINES, PROCEDURES FOR THE PREPARATION OF THESE AND THE MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

The present invention relates to 2-benzyl-perhydroazepines

which is optionally also substituted one or more times in the phenyl ring, method for producing these and medical

funds containing them.

Within the framework of a work on elimination reactions

reports L.P.A. Fery and L. Wilputte-Steinert [Bull.Soc.Chim.

Bell. 73 (1964) 154-165] on the formation of 1-methyl-2-benzyl-hexamethyleneimine without this compound being described as active. The preparation of the compound took place in so

small amount that it could only be identified as a derivative in the form of the picrate and the methyl iodide.1 DOS 2,548,053 describes saturated α-substituted benzyl-l-benzhydrylazheterocycles,

however, only α-substituted benzyl-l-benzhydrylazeti-

diner that will serve as a treatment against obesity. It is now

found that optionally substituted 2-benzylperhydroazepines have valuable pharmacological properties that enable them to be exploited economically.

The object of the present invention is 2-benzyl-perhydro-

azepines of the creneryl formula I

where R1 means a hydrogen atom, an aliphatic or alicyclic hydrocarbon residue, a cycloalkylalkyl group or an aralkyl-

group, R<2>, R<3>, R and R are the same or different and mean a

hydrogen atom, a halogen atom, an alkyl group, one hydroxy group, an alkoxy group, an acyloxy group, an optionally substituted amino group, a nitro group, an optionally substituted phenyl group, whereby R 1 is not methyl when R 2 , R 3 , R and R means hydrogen and their acid addition salts.

Relevant aliphatic hydrocarbon residues are linear or branched alkyl residues with 1 to 7 carbon atoms. Straight alkyl residues are methyl, ethyl, propyl, allyl, propynyl, butyl, pentyl, hexyl or heptyl residues, of which those with 1 to 6, especially those with 1 to 3 carbon atoms are preferred. Branched alkyl residues with 3 to 7 carbon atoms are e.g. isopropyl-, isobutyl-, sec-butyl-, tert-butyl-, 3-methyl-butyl-, 2,:2-dimethylpropyl, 2-methylpentyl-, 3,3-dimethylbutyl- or 2-ethyl-3- the methyl-butyl residue of which those with 3 to 5, above all with 3 carbon atoms are preferred. Relevant alicyclic hydrocarbons are above all cycloalkyl residues with 3 to 7 carbon atoms, e.g. the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical, of which those with 5 to 6 carbon atoms are preferred.

As cycloalkylalkyl groups, those with 1 to 4 carbon atoms in the alkyl residue and 3 to 7 carbon atoms in the cycloalkyl residue come into consideration, of which those with 1 to 2 carbon atoms in the alkyl residue and 3 to 5 carbon atoms in the cycloalkyl residue are preferred. Particularly preferred cycloalkylalkyl groups are the cyclopropylmethyl and cyclobutylmethyl groups.

Aralkyl groups include those with aryl groups containing up to 12 carbon atoms and alkyl groups containing 1 to 4 carbon atoms, of which those with 6 carbon atoms in

the aryl residue and 1 to 4 carbon atoms in the alkyl residue, above all

1 carbon atom in the alkyl residue is preferred. For example

mention is made of the benzyl, phenethyl and phenylpropyl group, of which the benzyl group is preferred. The aralkyl groups are optionally also substituted, of which those monosubstituted in the <:>aryl residue are preferred, i.a. with halogen atoms such as fluorine, chlorine or bromine atoms, alkyl and/or alkoxy groups with 1 to 4 carbon atoms.

Examples include p-chlorobenzyl-, m-chlorobenzyl-, p-bromobenzyl-| o-fluorobenzyl-, p-fluorobenzyl-, p-methylbenzyl-, p<->metboxy-benzyl group. Among the aralkyl<:> groups substituted in the alkyl group, the arylhydroxyalkyl and especially the aryloxyalkyl groups are preferred, examples of which are benzoylmethyl-, 2-benzoyl-ethyl-, 3-benzoylpropyl-, preferably 3-(p-chlorobenzoyl)-propyl-, especially the 3-(p-fluorobenzoyl)-propyl group. As halogen atoms

234 5

R , R , R or R is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, bromine, especially chlorine in consideration. As

2 3 4 5 alkyl groups respectively alkoxy groups R , R , R or R are mentioned i.a. those with 1 to 4 carbon atoms of which those with 1 to 3, above all those with 1 carbon atom are preferred. As acyl-oxy groups, e.g. -O-CO-R^ groups in consideration where R"*" has the above meaning, of which those with 1 to 7, especially with 2 to 5 carbon atoms, above all the acetyl group are preferred. Next to the unsubstituted amine group, substituted amino groups also come into consideration as substi-2 3 4 5

tuents R , R , R or R , under which for example alkyl and dialkylamino groups with 1 to 4, preferably 1 or 2 carbon atoms in the alkyl residue and acylamino groups with the usual acyl groups used to protect amino groups such as alkanoyl groups with 2 to 5 carbon atoms are mentioned. As

2 3 4_ 5

substituents R , R , R or R come next to the unsubstituted phenyl group also phenyl groups in consideration which are substituted with halogen atoms, hydroxy, alkyl and/or alkoxy groups with 1 to 4 carbon atoms, of which the p-substituted phenyl groups such as p-chlorophenyl -, p-fluorophenyl, p-hydroxyphenyl, p-methoxyphenyl group is preferred.

As salts come all. acid addition salts into account. Special mention should be made of the pharmacologically tolerable salts

of the inorganic and organic acids frequently used by Galen. Pharmacologically intolerable salts are transferred by methods known to a person skilled in the art into pharmacologically tolerable•salts. Suitable as such are, for example, water-soluble and water-insoluble acid addition salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, glyconate, benzoate, hibenzate. (2-(4-hydroxybenzoyl)-benzoate, fendizoate (o-[(2'-hydroxy-4-biphenylyl)-carbonyl]-benzoate), propionate, j

butyrate, sulfosalicylate, maleate, laurate, rnalate, fumarate, succinate, oxalate, tartrate, amsonate. (4,4'-diamino-stilbene-2,2'-disulfonate), embonate (1,1<1->methylene-bis-2-hydroxy-3-naphthoate), methembonate, stearate, tosilate (p-toluenesulfonate) , 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate, mesylate (raethane-sulfonate) , further salts with bumetanide (3-(butyl.amino)-4-phenoxy-5-sulfamoyl-benzoic acid), furosemide ( 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid), besunide (4-benzyl-3-(butylamine)-5-sulfamoyl-benzoic acid), piretanide (4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl- benzoic acid)-ethacrynic acid ([2,3-dichloro-4-(2-methylene-butyryl)-phenoxy]-acetic acid), thienilic acid ([2,3-dichloro-4-(2-thenoyl)-phenoxy]-acetic acid) etc.

One embodiment of the invention is 2-benzyl-perhydroazepines of the general formula IX

lx where R is a hydrogen atom, a linear or branched aliphatic hydrocarbon residue with 1 to 6 carbon atoms, a cycloalkylalkyl group with 1 to 2 carbon atoms in the alkyl residue and 3 to 5 carbon atoms in the cycloalkyl residue or an optional

monosubstituted phenylalkyl group with 1 to 4 carbon atoms in the alkyl residue,

2x

R is a halogen atom, a hydroxy group, an alkyl group with

1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, an amino group, a dialkylamino group with 1 to 2 carbon atoms per alkyl residue or a nitro group, an optionally para-position substituted phenyl group,

3X 4X 5X

R , R and R are a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, an alkanoyloxy group of 2 to 5 carbon atoms, an amino group, a dialkylamino group of 1 to 2 carbon atoms per . alkyl radical or a nitro group, whereby at least one of the substituents in the 2- or 6-position in the benzyl group is a hydrogen atom, and their acid addition salts.

Another embodiment of the invention is 2-benzyl-perhydroazepines of the general formula I<XX>

where R is a hydrogen atom, a straight or branched aliphatic hydrocarbon residue with 2 to 6 carbon atoms, a cycloalkylalkyl group with 1 to 2 carbon atoms in the alkyl residue and 3 to 5 carbon atoms in the cycloalkyl residue or an optionally

monosubstituted phenalkyl group with 1 to 4 carbon atoms in the alkyl residue,

2xx -^xx ^ xx ^xx

R , R , R and R mean a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, an alkanoyloxy group of 2 to 5 carbon atoms, an amino group, a dialkylamino group of 1 to 2 carbon atoms per alkyl residue, a nitro group or an optionally substituted phenyl group in the para-position, whereby at least one of the substituents in the 2- or 6-position in the benzyl group is a hydrogen atom, and their acid addition salts.

Further embodiments of the invention are such 2-benzyl-perhydroazepines with the general formulas I x according to-xx l<x><2>X 3X 4X 5X ix<x>

show I where R , R , R , R and R respectively R ,

2xx 3xx xx xx

R , R , R and R 5 have the aforementioned meaning, 3X 4X whereby at least one, preferably two of the substituents R R

rX3XX 4XX 5XX .

1 or R respectively R , R or R and at least one of the substituents in the 2- or 6-position in the benzyl group of a hydrogen atom and their acid addition salts.

Preferred 2-benzyl-perhydroazepines of the general formula x<lx>hydrogen atom,

I are those where R means a hydrogen atom, a straight-chain alkyl radical with 1 to 3 carbon atoms, a branched alkyl radical with 3 to 5 carbon atoms, a cycloalkylmethyl radical with 3 to 5 carbon atoms in the cycloalkyl group or an ebentual in the para-position with halogen, methyl or methoxy substituted benzyl-2X

residue, R a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group,

R 3x a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, whereby

2X 3X

the substituents R and R are preferably in the 2-, 3- and/or 4-position,

<4>X 5X

R' and R are a hydrogen atom and their acid addition salts•

Preferred 2-benzyl-perhydroazepines of formula I are those in which R 1X means a hydrogen atom, a methyl group, an isopropyl group, a cyclopropylmethyl group or a benzyl group,

2X

R a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group,

3X

R a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, where

2X 3X

the substituents R and R<3>x are preferably in the 2-, 3- and/or 4-position,

4X 5X

R and R are a hydrogen atom and their acid addition salts.

Preferred 2-benzyl-perhydroazepines of the general formula I xx are those where

^<xx>hydrogen atom, R means a hydrogen atom, a linear alkyl residue of 2 to 3 carbon atoms, a branched alkyl residue of 3 to 5 carbon atoms, a cycloalkylmethyl residue of 3 to 5 carbon atoms in cycloalkyl-.

groups or an optionally substituted benzyl residue in p-position with halogen, methyl or methoxy,

2XX^ XX'

R and R are the same or different and mean a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, whereby the sub-2XX 3XX sistuents R' and R preferably in 2-, 3- and/or 4- score,

^XXj-XX

R and R are a hydrogen atom, and their acid addition salts.

Selected 2-benzyl-perhydroazepines of the general formula

xx

You are such where

^xx

R means a hydrogen atom, an ethyl group, an isopropyl group, a cyclopropylmethyl group or a benzyl group,

R and R are the same or different and mean a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, whereby the substituent

2XX oXX" R and R preferably sit in the 2, 3 and/or 4 position,

R 4 .XX and R o,<-XX>is a hydrogen atom, and their acid addition salts.

Particularly preferred 2-benzyl-perhydroazepines are those with it

x

general formula I where

l<x>

R means a hydrogen atom, a methyl group, an isopropyl group or a cyclopropylmethyl group,

2X

R means a chlorine atom in the 2-, 3- or 4-position or an amino group in the 4-position,

3X 4X 5X

R , R , and R are one hydrogen atom and their pharmacologically acceptable acid addition salts.

Selected representatives of the compounds according to the invention are 2-(2-chlorobenzyl)-i-methyl-perhydroazepine, 2-(4-chlorobenzyl)-perhydroazepine,

2-(4-chlorobenzyl)-1-isopropyl-perhydroazepine,

2-(4-chlorobenzyl)-1-methyl-perhydroazepine,

2-benzyl-l-cyclopropyl Ime tyl-perhydroazepine,

2-benzyl-perhydroazepine,

2-(4-aminobenzyl)-perhydroazepine,

and their pharmacologically tolerable acid addition ion salts'.

2-benzyl-perhydroazepines with the general formula I respectively I X and I XX have a chiral center on the carbonate group which is denoted by ( The invention therefore encompasses both racemates and the enantiomers and mixtures thereof.

The optionally substituted 2-benzyl-perhydroazepines of the • general formula I respectively the embodiments I X and I XX have valuable properties which make them economically exploitable.

On the one hand, these compounds and 2-benzyl-1-methyl-perhydroazepine as well as their pharmacologically, i.e. biologically tolerable, salts have distinct pharmacological properties, particularly effects on the central nervous system, on blood pressure and on pain sensation in warm-blooded animals, and secondly, they allow transfer into other 2-benzyl-perhydroazepines of the general formula I, i.e. the valuable intermediates in the preparation of pharmacologically active compounds of the general formula I, respectively the embodiments I X and ' I XX as well as their biologically tolerable salts.

The central nervous system effects of 2-benzyl-perhydroazepines

and the pharmacologically tolerable salts involve central stimulation, virility enhancement, stimulation of normal and pathologically inhibited activity in warm-blooded animals. In addition, some representatives have a strong analgesic effect or they affect blood pressure.

The excellent and broad pharmacological action of the 2-benzyl-perhydroazepines makes it possible to use them both in human and veterinary medicine, where they are used for prophylaxis before diseases or for the treatment of

Symptoms that are already occurring.

As indications in the human medical area are mentioned

for men and women lack of activity, reduced virility, depressions, organic psychosyndromes in cerebral decay processes, lack of performance, blood pressure disturbances or states of exhaustion as well as pain states,

and in children spiritual and mental retardation as well as learning difficulties.

In the field of veterinary medicine, impaired performance and pain conditions are mentioned as indications. For example, taller animals such as livestock and farm animals can be treated.

Subject matter of the invention are also medicinal products containing 2-benzyl-perhydroazepines of the general formula I

where R"*" means a hydrogen atom, an aliphatic or alicyclic hydrocarbon residue, a cycloalkylalkyl group or an aralkyl group,

2 3 4 5

R , R , R and R are the same or different, and mean a hydrogen atom, a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, an acyloxy group, an optionally substituted amino group, a nitro group, an optionally substituted phenyl group, and/or their pharmacological tolerable acid addition salts.

Preferred drugs are those containing 2-benzyl-per-hydrazepines in the embodiments I X or I XX, respectively their preferred representatives and/or the corresponding pharmacologically tolerable acid addition salts.

The medicines are produced according to known methods. As pharmaceuticals, the new compounds can be used as such or possibly in combination with suitable pharmaceutical carriers. If the new pharmaceutical preparations contain the active ingredients with pharmaceutical carriers, the active ingredient content in these mixtures is 5 to 95, preferably 25 to 75% by weight of the entire mixture.

According to the invention, the active substances can be used in both the human and veterinary medical fields in any desired form, e.g. systemic or topical under the condition that the formation or maintenance of sufficient blood or tissue levels or local concentration of 2-benzyl-perhydroazepines is satisfactory. This can either be achieved by oral, rectal or parenteral administration in suitable doses. However, the new drugs can also be used locally. Advantageously, the pharmaceutical formula is available

ring of the active substance in the form of unit dosages that are adapted to the desired administration. A unit charge can e.g. be a tablet, a dragee, a capsule, a suppository or a measured volume amount of a powder, a granule, a solution, an emulsion, a suspension, a sol or a gel.

By "unit dosage" in the present invention is understood

a physically defined unit containing an individual amount of the active ingredient in combination with a pharmaceutical carrier whose active substance content corresponds to a fraction or several times a therapeutic single dosage. A single dosage preferably contains an amount of active substance which is given in one application and which normally corresponds to a full, half, a third or a quarter of the daily dose. When for a single therapeutic administration only a fraction is required, i.e. half or a quarter of the unit dosage, the unit dosage is advantageously divisible, e.g. in the form of a

tablet with breaking drill.

The pharmaceutical formulations according to the invention contain ! when they are available in unit dosages and are intended for use, e.g. on humans, approx. 1 to 200 mg, incl

distribute 2.5 to 100 mg and especially 5 to 50 mg of active ingredient.

In general, both in human and veterinary medicine it has been shown to be advantageous to give the active ingredient or active ingredients orally in a daily dose of approx. 0.06 to approx. 12, preferably 0.14 to 5.7, especially 0.3 to 3 mg per kg body weight, possibly in the form of several, preferably 1 to 3

single dosages to achieve the desired result. A single dosage contains the active substance or substances in amounts of approx. 0.01 to approx. 3.0, preferably 0.04 to 1.5, especially 0.07 to 0.7 mg per kg body weight.

In a parenteral treatment, e.g. an acute depression or a severe pain condition can use similar dosages. In this therapy, approx. l. to approx.

50 mg active ingredient.

For a local application, formulations come in pharmacologically tolerable, e.g. aqueous solution of speech containing approx. 0.1 to 5, preferably 0.2 to 3, especially 0.5 to 2 weight-% active substance.

The therapeutic administration of the pharmaceutical formulation takes place by continuous treatment generally at fixed times such as 1 to 4 times a day, e.g. after meals and/or in the evening. In the case of acute attacks, the treatment takes place at varying times. Under special circumstances, it may be necessary to deviate from the above-mentioned dosages depending on the type, body weight and age of the object to be treated, the nature and degree of the disease, the type of formulation and the use of the medicine as well as the period of time respectively the interval during which the administration takes place. Thus, in some cases it may be sufficient to use less than the above-mentioned amount of active substance, while in other cases the above-mentioned amount of active substance must be exceeded. The determination of the simply necessary optimal dosage and type of application of the active substance can be carried out by the expert at any time on the basis of his professional knowledge.

The pharmaceutical formulations usually consist of the active substances according to the invention and non-toxic, pharmacologically tolerable drug carriers which can be used as an additive or diluent in solid, semi-solid or liquid form or as an encapsulating agent, e.g. in the form of a capsule, a tablet coating, a bag or other container for the therapeutically active ingredient. A carrier can e.g. serve as a mediator for drug absorption through the body, as a formulation aid, as a sweetener, as a flavoring agent, as a coloring agent or as a preservative.

For use orally, e.g. tablets, dragées, hard and soft capsules, e.g. of gelatin, dispersible powders, granules, aqueous and oily suspensions, emulsions, solutions or syrups are used.

Tablets may contain inert diluents, e.g. calcium carbonate, calcium phosphate, sodium phosphate or lactose, granulating and dispersing agents, e.g. corn starch or alginates, binders, e.g. starch, gelatin or acacia gum, and lubricants, e.g. aluminum or magnesium stearate, talc or silicone oil. They can also be provided with a coating which can also be so arranged that it results in a delayed dissolution and resorption of the drug in the digestive tract and thus e.g. an improved tolerability, accelerated absorption or a retardation. The gelatin capsules may contain the drug mixed with a solid diluent, e.g. calcium carbonate or kaolin or an oily diluent, e.g. olive, peanut or paraffin oil.

Aqueous suspensions may contain suspending agents, e.g. sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate, polyyinylpyrrolidine, tragacanth gum or acacia gum, dispersing and wetting agents, e.g.

polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxy-

ethylene sorbitol monooleate, polyoxyethylene sorbita monooleate and lecithin, preservatives, e.g. methyl or propyl hydroxybenzoate, flavoring agents, sweeteners, e.g.

sucrose, lactose, sodium cyclamate, dextrose, invert sugar syrup.

Oily suspensions can e.g. contain peanut, olive, sesame, coconut or paraffin oil and thickeners, e.g. beeswax, hard paraffin or cetyl alcohol, further sweeteners, flavoring agents and antioxidants..

Powders and granules that are dispersible in water can contain medicinal substances in admixture with dispersing, wetting and suspending agents, e.g. those mentioned above as well as sweeteners, flavoring agents and coloring agents.

Emulsions can contain e.g. olive, peanut or paraffin oil next to emulsifiers, such as e.g. acacia gum, tragacanth gum, phosphatides, sorbitan monoolear, polyoxyethylene sorbitan monooleate and sweeteners and flavourings.

For rectal application of the medicinal substances, suppositories are used which are produced using binders which melt at rectal temperature, e.g. cocoa butter or polyethylene glycols.

For parenteral application of the medicinal substances, sterile injectable aqueous suspensions, isotonic salt solutions or other solutions which may contain dispersing or wetting agents and/or pharmacologically tolerable diluents, e.g. propylene or butylene glycol.

Suitable gels, soles or tablets for local treatment may contain the usual carriers, e.g. eg animal or vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays can, in addition to the active substance or substances, contain the usual carriers, e.g. milk sugar, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also contain the usual propellants, e.g. chlorofluorocarbons.

The active ingredients may possibly be present in the microcapsule

form with one or more of the carriers specified above.

Next to 2-benzyl-perhydroazepines, they can pharma-

tical formulations, for example, contain one or more pharmacologically active ingredients from other drug groups, for example mild stimulants such as caffeine, analgesics such as aminophenazone, acetylsalicylic acid, d-propoxyphene>antidepressants such as dibenzepine, doxepin, maprotiline, amitriptyline, nortriptyline, melitracene, tranquilizers such as diazepam, chlordiazepoxide, meprobamate, cerebral blood flow stimulating agents and/or roborants such as glutamic acid, vitamins or combinations thereof.

A further object of the invention is a method for the treatment of mammals suffering from primary or secondary disturbances in the central nervous system during pathological changes of. the blood pressure and/or pain which is characterized by giving the attacked mammal a central nervous system-acting blood pressure-regulating and/or analgesic-acting and pharmacologically tolerable amount of one or more 2-benzyl-perhydroazepines and/or their pharmacologically tolerable salts.

The intermediates with the general formula I or the embodiments I X or I XX can be transferred by known methods into pharmacologically active compounds with the general formula I as shown in the following examples. Thus, you get, among other things, from the free bases acid addition salts by reaction with the corresponding acid. Ethers, i.e. such compounds where one or more of the substituents R 2 , R 3,

R<4>, R<5>is an alkoxy group or two adjacent substituents-2 3 4 5 *

tuents R , R , R , R together form an alkylidene dioxy group is transferred by acid hydrolysis, e.g. with the hydrogen halogen in the free hydroxy bonds. Esters, i.e. such compounds where one or more of the substituents R 2 , R 3,

4 5

R and R is an acyloxy group are transferred by alkaline hydrolysis, e.g. with sodium hydroxide in the free hydroxy compounds. The free hydroxy compounds, i.e. such where

2 3 4 5

one or more of the substituents R , R , R and R is an OH group can be etherified or esterified.

The subject of the invention is further a process for the production of 2-benzyl-perhydroazepines of the general formula I and their embodiments I X and I XX respectively, as well as salts thereof characterized by

A) reduces a 2-benzyl-azacycloheptane of the general formula II

2 3 4 5 where R , R , R and R have the above meaning and R 6 is an aliphatic or alicyclic hydrocarbon residue, a cycloalkylalkyl group or an aralkyl group and R 7 is a hydrogen atom, an aliphatic or alicyclic hydrocarbon residue or a cycloalkylalkyl residue and optionally then N-alkylates or N-dealkylates and/or functionalizes and/or transfers the obtained free base into acid addition salts thereof in the usual manner in each other or B) functionalizes a,2-benzyl-azacycloheptane with the general formula III where R 7 has the above meaning and G means a hydrogen atom or an advantage of a functional group and n an integer from 1 to 4, preferably 1 to 2, especially 1, and optionally then N-alkylates or N-dealkylates and/or transfers the obtained free base or acid addition salts thereof onto usual way in each other or C) reduces an N-acyl-2-benzyl-azacycloheptane of the general formula IV

2 3 4 5

where R , R , R and R have the above meaning and

R 8 means an aliphatic or alicyclic hydrocarbon residue, a cycloalkylalkyl residue, an optionally substituted phenyl residue or phenalkyl residue, and optionally then functionalizes and/or |

1

IN

N-dealkylates and/or transfers the obtained base or acid addition salts thereof in the usual way into each other.

The reduction of substituted 2-benzyl-azacycloheptanes with

the general formula IIa, b and d preferably occur with hydrogen in organic solvents common to hydrogenation reactions, e.g. ethanol, methanol, cyclohexane, isopropanol, dimethylformamide in the presence of metal catalysts, e.g. platinum, platinum on activated carbon, palladium, palladium on activated carbon, Raney nickel at pressures from approx. 1

to 500 atmospheres and temperatures below room temperature, for example 0 to 50°C. The reduction of the compounds with formulas Ia and b takes place alternatively in the form of their acid addition ion salts in aqueous-alcoholic solution with sodium borohydride in the usual way (compare "Enamines: Synthesis, Structure and Reactions" published by A.Gilbert Cook page 185ff, Marcel Dékker, New York and London 1969). The reduction of the compounds lic takes place with lithium aluminum hydride in inert solvents such as ethers, e.g. diethyl ether, tetrahydrofuran, dioxane, 2-2-dimethoxyethane or diethylene glycol diethyl ether at temperatures between 0°C and the boiling temperature of the solvent, preferably between 20° and 70°C. The reduction of the compounds with fire takes place alternatively by reaction with hydrohalides, preferably hydrogen chloride in inert solvents, e.g. benzene analogously to the method described in Synthesis 1976, 540-41.

The compounds used as starting materials of the general formula IIa

2 3 4 5 I where R , R , R and R have the above meaning is obtained, for example, by reacting 2-benzylidenazacyclo-1 heptanes with the general formula V 1

2 3 4 5

where R , R , R and R have the meaning given above with strong mineral acids. The hydrolysis and simultaneous decarboxylation of the nitriles V takes place with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc., preferably concentrated hydrochloric acid at temperatures between room temperature and 120°C, preferably by heating the corresponding solution under reflux until the evolution of carbon dioxide ceases. The formed imines Ila are relatively unstable compounds so that they are suitably converted immediately. i.e. hydrogenated

to the perhydroazepines.

The benzylidene compounds V are obtained, for example, similarly to the method described by T. Kametami et al. (J. Chem. Soc, Perkin I 1976 , 339 , Heterocycles 3 [1975) 691). Hereby, a caprolactimeter, preferably caprolactim methyl ether, is reacted with a corresponding arylacetonitrile, for example 4-chlorophenylacetonitrile, in the presence of an auxiliary base such as diazabicycloundecene, diazabicyclononene, triethylamine, ethyldiisopropylamine without a solvent or in the presence of an inert solvent such as benzene, toluene, xylene, cyclohexane by temperatures from 50 to 150°C, preferably 100 to 130°C, optionally under an irradiated gas atmosphere, e.g. nitrogen. Reaction without the use of an inert solvent is preferred.

The starting materials Ilb can be prepared according to different methods. For example, they are obtained by reacting N-substituted caprolactam derivatives VI with phenylacetic acid derivatives IV with phenylacetic acid derivatives VII to the benzylidene compounds VIII, hydrolysis thereof and decarboxylation after |

where R<2>, R3, R^, R^ and R^ have the above meaning and 9 12 R means an -O-R group or a

11 15

R a -CN or -CO-0-R group,

10 12 „13 14 15 .. , .... ,u

R , R , R , R and R are the same or different and mean an alkyl radical with 1 to 5 carbon atoms, preferably a methyl or ethyl group and R 14 also a phenyl radical, or R<9> and O-R<10> together form a alkylidenedioxy group with up to 4, preferably carbon atoms.

The reaction of the caprolactam derivatives VI with the phenylacetic acid derivatives VII is generally carried out at temperatures from 20 to 150°C, preferably between 40 and 100°C without or preferably with the addition of inert organic solvents such as aliphatic, e.g. petroleum ether, light petrol, naphtha or cycloaliphatic, e.g. cyclohexane or aromatic, e.g. benzene, toluene, xylol, hydrocarbons. The hydrolysis and simultaneous decarboxylation of the benzylidene derivatives VIII (esters and acetonitrile respectively) takes place by the action of mineral acids such as hydrochloric acid, hydrobromic acid etc., preferably concentrated hydrochloric acid, at temperatures between room temperature and 102°C, preferably by heating the corresponding solution under reflux up to C ^ development ends. The enamines Ilb formed from the esters VIII and the corresponding acetonitrile are relatively unstable compounds and are generally reacted immediately further, i.e. hydrogenated to the compounds according to the present invention. Due to its stability and easy availability as well as due to the 1

the enamines Ilb instability is estererie VIII respectively de

corresponding acetonitrile interesting and valuable intermediates for the production of . The 2-benzylperhydroazepines I according to the present invention.

The N-substituted caprolactam derivatives VI are known compounds or are obtained according to known methods.

9 12

Acid amidacetal VI (R: -O-R) is obtained, e.g. by conversion of N-alkyl-caprolactam. with alkylating agents such as dimethylsulphate, diethylsulphate, p-toluenesulfonic acid alkyl esters

9 12

to the salts IX (R : -O-R ) and the subsequent reaction

of these with alkali metal alcoholates such as sodium methanolate,

-ethanolate etc. Aminal esters VI (R^: -NR^R1<4>) are obtained by

9 13 14

that one reacts the salts IX (R : -NR R ) with alkali metal alcoholates such as sodium methanolate, -ethanolate etc., in indifferent solvents such as benzene, ethers, e.g. diethyl ethers.

The starting compounds Ilb) are obtained according to a further method by reacting azepinium salts IX with phenylacetic acid derivatives VII in the presence of strong bases to the benzylidene compounds VIII and hydrolysis and decarboxylation of these according to the following reaction core

6 9th

where R and R have the above meaning and L means one equivalent of an anion of an organic or inorganic acid.

The reaction of the azepinium salts IX with the phenylacetic acid derivatives VII usually takes place without the addition of further

In !■ solvents in the presence of strong bases which solution'er of. alkali metal alcoholates, e.g. sodium methanolate, potassium methanolate, potassium propanol, sodium isopropanol, potassium butanol, potassium tert-butanol, potassium tert-pentanol, especially sodium ethanolate at temperatures from 20 to 150°C, preferably 80-100°C. Optionally, the reaction is carried out while blowing through an inert gas such as nitrogen to remove any volatile amines that may have arisen. However, the conversion can also take place with the addition of inert solvents such as alcohols, e.g. methanol, ethanol, propano.l, isopropanol, butanols, pentanols, tert. nitrogen bases, e.g. pyridine or hydrocarbons, e.g. benzene. The hydrolysis and decarboxylation of the benzylidene compounds VIII is carried out analogously, with the previously described method.

The preparation of salts IX of which those with R 9 in the meaning of

13 14

-NR R group is preferred e.g. in analogy with H. Bredereck et al. (Chem.Ber. 1964, 3081) by turnover of

the corresponding N-substituted caprolactams with alkylating agents such as diethyl sulfate, methyl iodide, preferably dimethyl sulfate in inert solvents at room temperature to 120°C, preferably without solvent at temperatures around 80°C, and when R 9 in the salts IX is a -NR 13 R<14 ->group consecutive

13 14

reaction with the amines HNR R . or also by reaction of the corresponding caprolactams with inorganic acid chlorides such as phosphorus oxychloride, phosgene and subsequent reaction with

13 14

the amines HNR R in inert solvents such as benzene at temperatures between 0 and 100°C, preferably 20 to 60°C or without solvent at temperatures between 0 and 100°C, preferably 40 to 80°C.

The starting compounds lic are obtained according to methods known per se. The precursors lic where R means -a hydrogen atom are prepared e.g. by rearrangement of the corresponding 2-benzylcyclohexanones according to that of T. Duong [Austr.J.Chem. 29 (1976) 2657-82, especially page 2681] method described.

Alternatively, they are obtained by functionalizing 7-benzyl-hexahydroazepin-2-one according to the method described in the following sections. The precursors lic where R 7 means an aliphatic or alicyclic hydrocarbon residue, a cycloalkylalkyl group or an aralkyl group are obtained by N-alkylation corresponding to 2-benzylhexahydroazepin-2-ones where R"*" has 2 3 4 5 the meaning a hydrogen atom and R , R , R and R have the meanings given above. The starting compounds Ild are obtained, for example, by reaction with lithium of 1-nitrosoperhydroazepine and subsequent reaction with corresponding benzyl halides, preferably -bromides or -iodides in the same way as the method described in Synthesis 1976, 540-41.

The functionalization of 2-benzylperhydroazepines III or

the possibly subsequent functionalization of the 2-benzylperhydroazepines I obtained during reduction is carried out depending on the type of the final substituent in the phenyl group.

The nitro group is introduced, for example, by nitration with nitric acid, nitric acid/sulfuric acid, potassium nitrate/sulfuric acid, alkyl nitrate at temperatures from -20 to +50°, preferably -20

to +30°. In the starting compounds III, G then means a hydrogen-2 4 5

atom and n = 1, in the final products R , R and R have the meaning 3

of a hydrogen atom and R an NO1^ group in the p-position. Under drastic conditions, dinitrotrophic bonds are formed, i.e. R and

5 2 3

R has the meaning of a hydrogen atom and R and R a nitro group.

The amino group is introduced by reduction of the NO^ group(s). in a corresponding nitro compound with hydrogen on corresponding catalysts such as Pt, Pt/C, Pd, Pd/C, Raney nickel, etc. in aqueous solvents such as alcohols, cyclohexane, etc. In the starting compounds III, G then means one or two N09~grup<p >er and n = 1 (or 2), and in the final products R<4>and R<5>mean-2 3

ning a hydrogen atom and R and/or R an NH2~ group.

Halogen atoms, especially chlorine and bromine atoms, are introduced in the usual way by nuclear halogenation. For core halogenation is used

as catalysts iron, iron (III) chloride or bromide, aluminum chloride or bromide, tin tetrachloride or iodine, wherebyj

the reaction is carried out without or in inert solvents,

possibly also in glacial acetic acid without catalyst at temperatures between 0 and 20°C.

Hydroxy groups are introduced by ether cleavage of the corresponding alkoxy groups. In the starting compounds III, G then means an alkoxy group, preferably a methosky group, and n = 1 to 4, preferably 2, especially 1. The ether cleavage is carried out e.g. by boiling with hydrogen iodide or hydrogen bromide or mixtures of hydrogen bromide/glacial vinegar or by reaction with boron tribromide in inert solvents such as chloroform, dichloromethane, at temperatures from -20 to 20°C.

The etherification takes place, for example, by reaction of corresponding hydroxy compounds [G then means in the starting compounds III a hydroxy group, n = 1 to 4, preferably 2, especially 1] with alkyl halides in the presence of equivalent amounts of alkali metal alcoholate, e.g. sodium ethylate.

The functionalization of free hydroxy groups or amino groups in the form of acylation is carried out according to methods known to the person skilled in the art, e.g. by reaction with the corresponding acid anhydrides or -halides, (compare, among other things, Houben-Weyl, volume 8, page 543 onwards and 655 onwards respectively). The cleavage of the acyl groups during the release of the hydroxy groups, respectively the amino groups, takes place in the usual way by saponification, e.g. by reaction with a suitable base such as caustic soda or caustic soda.

The N-alkylation whereby alkyl also includes the meaning cycloalkyl, aralkyl and cycloalkylalkyl, is carried out according to methods known to the person skilled in the art. Thus, the N-alkylation is carried out by alkylating agents such as alkyl halides, alkyl sulphonates, e.g. -tosylates, alkyl sulfates in inert solvents such as acetone, methyl ethyl ketone, alcohols such as methanol, ethanol, isopropanol, dimethylformamide etc. or without solvents under

application of an auxiliary base such as sodium carbonate, potassium carbonate, triethylamine at temperatures from approx. 20 - 100°C.

in

The N-dealkylation where alkyl also includes the meaning of cycloalkyl, cycloalkylalkyl and aralkyl, especially benzyl, is carried out according to methods known per se. N-dealkylation takes place, for example, with chloroformic acid esters such as chloroformic acid ethyl ester, chloroformic acid-0,3,3,-trichloroethyl ester without or in the presence of inert solvents such as benzene, toluene, chloroform at a higher temperature, preferably at the solvent's boiling temperature. The intermediate product obtained is reacted with aqueous or alcoholic solutions of bases such as caustic soda/ethanol, caustic soda/butanol at a higher temperature, preferably at the boiling temperature of the solvent, to the corresponding dealkyl-perhydroazepine, i.e. to the compound of the general formula I where R"*" means a hydrogen atom.

The N-dealkylation in the special form of debenzylation, i.e.

when using compounds of formula I with R"<*>" = benzyl, takes place alternatively by hydrogenolysis in the presence of catalysts, preferably palladium on carbon in solvents such as methanol, ethanol, benzene, cyclohexane at 0 to 50°, preferably room temperature and a hydrogen pressure of 1 to 300 atmospheres, preferably - to 5 atmospheres.

Acid addition salts are obtained by dissolving the free base

in a suitable solvent, e.g. acetone, water, a low molecular weight aliphatic alcohol (ethanol, isopropanol) or ether (diethyl ether, tetrahydrofuran) containing the desired acid or to which the desired acid is added afterwards - The salts are isolated by filtration, precipitation with a non-solvent for the addition salts or by evaporation of the solvent.

The obtained salts, e.g. the hydrochlorides can be converted by neutralization, with aqueous sodium or potassium hydroxide in the free base which is then recovered by solvent extraction with a suitable, water-immiscible solvent such as chloroform,

dichloromethane, ether, benzene, toluene, cyclohexane etc. The free bases can also be recovered by neutralizing an acid addition salt with sodium methylate in methanol and isolating the base according to known procedures. Salts can also be transferred in others

in

salts by transfer of the base and further reaction with an acid,

e.g. pharmacologically tolerable acid addition salts.

Any necessary or desired racemate cleavage is carried out in the usual way, e.g. by mixing with an optically active acid such as mandelic acid, tartaric acid, camphorsulfonic acid, dibenzoyl-tartaric acid, etc., recrystallization of the formed salt with constant rotation and liberation of the optically active base with lye. The other enantiomer is obtained in an analogous way from the mother liquors formed during the recrystallization.

The reduction of N-acyl-2-benzyl-azacycloheptanes with the general formula IV takes place according to methods known per se, e.g. by reaction with a complex metal hydride as reducing agent in an anhydrous organic solvent and hydrolytic processing. Suitable reducing agents are i.a. lithium aluminum hydride (lithium hydride aluminate) and sodium dihydro-bis-(2-methoxyethoxy)-aluminate. As a solvent, inert anhydrous esters such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diethylene glycol diethyl ether are suitable and likewise aromatic hydrocarbons such as benzene and toluene or mixtures of the aforementioned compounds. The reaction temperature is not critical and can vary within wide limits, such as from 0 to 100°C. Normally, it is most appropriate to carry out the reaction at the reflux temperature of the reaction mixture. Reaction duration depends on the reaction temperature used and can vary between 1 hour and 24 hours.

At the preferred reflux temperature, the reaction is normally completed in 3 to 4 hours. The reaction partners can be used in equivalent amounts, but an excess of the reducing agent is preferable. After the reaction with the reducing agent, the reaction product is worked up by treating the reaction mixture with an aqueous medium such as water, dilute aqueous inorganic acids or bases and other aqueous media. The product can be isolated by adjusting the pH value as a free base or as an acid addition salt.

The output connections III can e.g. obtained by demethylation of 2-benzyl-1-methylperhydroazepine (to III with R"<*>" = H)

and optionally subsequent N-alkylation (to III with R"*" = alkyl, cycloalkyl, aralkyl, cycloalkylalkyl).

The preparation of starting compounds with formula IV likewise takes place according to methods known to the person skilled in the art, for example by acylation of the corresponding 2-benzylperhydroazepines I (R 1 = -H) with carboxylic acid halides such as Cl-CO- -R where R has the above meaning or carbonic anhydrides in inert solvents such as benzene, toluene, cyclohexane, chloroform, dichloromethane in the presence of an auxiliary base such as pyridine, triethylamine etc., at temperatures between 0 to 50°C. Suitable carboxylic acid halides are, for example, acetyl chloride, propionyl chloride, butyryl chloride, pivaloyl chloride, cyclopropylcarbonyl chloride, cyclobutylcarbonyl chloride, benzoyl chloride, phenylacetyl chloride.

The following examples illustrate the invention in more detail without limiting it. The abbreviation m.p. means melting point, kp. means boiling point, sp. means cleavage, temperature indications are in C.

in

r

1 r EXAMPLE1

2- dimethylamino- 1- methyl- 4, 5, 6, 7- tetrahydro- 3H- azepinium methyl sulfate

190 g of N-methylcaprolactam and 189 g of dimethylsulphate are stirred for 3 hours at 80 oC, shaken after cooling with ether and freed from solvent residues in a vacuum. The thus obtained pale yellow oil (346 g) of 2-methoxy-1-methyl-4,5,6,7-tetrahydro-3H-azepinium methylsulfate is added dropwise to a solution of 110 g of dimethylamine in 600 ml of benzene with stirring and boiled for 90 minutes during reflux. The heavy phase is kept and extracted three times with ether. The pale yellow oil is evaporated in a vacuum. Yield 336 g (93% of theoretical yield).

EXAMPLE 2

2[ a-(ethoxycarbonyl)- 4- chlorobenzylidene]- 1- methylperhydroazepine

To a mixture of 53.2 g of 2-dimethylamino-1-methyl-4,5,6,7-tetrahydro-3H-azepinium methylsulfate and 29.3 g of 4-chloropheyl-acetic acid ethyl ester, a solution is added dropwise at 90° in a stream of nitrogen of 4.6 g of sodium in 100 ml of ethanol. This removes the alcohol from the reaction mixture. The mixture is stirred for a further 4 hours at 90°, and the cooled reaction mixture is mixed in

100 ml of water and 100 ml of ether, take care of the organic phase and dry over sodium sulphate. Excess 4-chlorophenylacetic acid ethyl ester is removed after evaporation by distillation under high vacuum. Crude yield 15.5 g (34% of theoretical yield) yellow oil.

EXAMPLE 3

2-[ α-(ethoxycarbonyl)- 3, 4- dimethoxybenzylidene]- 1- methyl-perhydroazepine

!

With the working method described in example 2, you get | from 53.2 g of 2-dimethylamino-1-methyl-4,5,6,7-tetrahydro-3H-azepinium methyl sulfate, 33.6 g of 3,4-dimethoxyphenylacetic acid ethyl ester and a solution of 4.6 g of sodium in 100 ml of ethanol the tin compound as a tough, yellow oil with bp. 175 -

180° (0.001 Torr). Yield 8.6 g (17% of theoretical yield).

EXAMPLE 4

2-[ α-(ethoxycarbonyl)- 4- methoxybenzylidene]- 1- methylperhydroazepine

With the working method described in example 2, you get

from 53.2 g of 2-dimethylamino-1-methyl-4,5,6,7-tetrahydro-3H-azepinium methylsulfate, 29.1 g of 4-methoxyphenylacetic acid ethyl ester and a solution of 4.6 g of sodium in 100 ml of ethanol the tin compound as a viscous, yellow oil with bp. 165° (0.001 Torr). Yield 15.6 g (34% of theoretical yield).

EXAMPLE 5

2-[ g-(ethoxycarbonyl)- 3- methoxybenzylidene]- 1- methylperhydroazepine

Using the working method described in example 2, 74.9 g of 2-dimethylamino-1-methyl-4,5,6,7-tetrahydro-3H-azepinium methylsulfate, 40 g of 3-methoxyphenylacetic acid ethyl ester and a solution of 6.4 g sodium in 160 ml ethanol the title compound as a viscous oil. Yield 38.6 d (62% of theoretical yield).....

EXAMPLE 6

2-(4-Chlorobenzyl)-1-methylperhydroazepine

15.5 g of 2-[α-(ethoxycarbonyl)-4-chlorobenzylidene]-1-methylperhydroazepine and 10 ml of concentrated hydrochloric acid are boiled until complete I

CC^evolution during reflux, is made alkaline after

cooling with caustic soda under ice cooling and extracted with

ether. The ether phase is evaporated and dried over sodium sulfate.

The remaining 2-(4-chlorobenzylidene)-1-methylperhydroazepine (7.44 g) is dissolved in ethanol and platinum/active carbon/hydrogen is hydrogenated. The product is distilled in high vacuum after filtering off catalysts and distilling off the solvent. Yield 4.4 g with b.p. 102 -

110° at 0.003 Torr.

The picrate (from ethanol) melts at 120 - 121°.

By reacting the base with the equivalent amount of the corresponding acid, the following salts are obtained:

hibenzate: colorless oil

citrate: colorless oil

fumarate:. pale yellow oil

benzoate: pale yellow oil

maleinate: pale yellow oil embonate: yellow oil

EXAMPLE 7

2-(3,4-dimethoxybenzyl)-1-methyl- perhydroazepine

Using the working method described in example 6, the title compound with b.p. 117° at 0.001 Torr.

The picrate (from ethanol) melts at 127 - 129°.

EXAMPLE 8

2-[(g-cyano)-benzylidene]-perhydroazepine

8.1 g caprolactim methyl ether, 5.0 g benzyl cyanide and 0.6 g

1,5-diazabicyclo[5.4.0]undec-5-ene is stirred under nitrogen for 48 hours at 130°, excess benzyl cyanide is distilled off in high vacuum and the residue is triturated with a little methanol and filtered off. The title compound (3.78 g) is thus obtained, which is recrystallized from methanol for further purification. Temp. 108 113°.

EXAMPLE 9

2-[(α~cyano)-4-chlorobenzylidene]-perhydroazepine

5.0 g of 4-chlorobenzyl cyanide, 5.5 g of caprolactim methyl ether and 0.5 g of diazabicyclo[5.4.0]undec-5-ene are stirred under nitrogen for 18 hours at 125°. After cooling, the crystallizing residue is triturated with 20 ml of methanol and filtered. The title compound (5.5 g) is thus obtained, which is recrystallized from methanol. Temp. 114 - 117°.

EXAMPLE 10

2-(4-Chlorobenzyl)-perhydroazepine

100 g of 2-[(α-cyano-)-4-chlorobenzylidene]-perhydroazepine and 1 liter of concentrated hydrochloric acid are boiled until complete evolution of carbon dioxide under reflux, made alkaline after cooling under ice-cooling with caustic soda and extracted with ether. The ether extract is evaporated after drying over. sodium sulfate. The thus obtained 2-(4-chlorobenzyl)-4,5,6,7-tetrahydro-3H-azepine is hydrogenated

a) with platinum/active carbon/hydrogen, filtered from the catalyst, evaporated and distilled. You get 61.9 g

(68%) with c.p. 93° at 0.1 Torr, or

b) dissolve in dilute hydrochloric acid (pH approx. 5) and mix with 200 ml of methanol. Then 7 g of sodium borohydride are added in portions over the course of 20 minutes. The pH is kept constant at

instillation of hydrochloric acid. The mixture is stirred for a further 1 hour, rendered alkaline with caustic soda and extracted with dichloromethane.

The organic phase is evaporated after drying over sodium sulphate and distilled. You get 58 g with kp. 93° at

0.1 Torr.

The hydrochloride (from methanol/ether) melts at 177 - 178°.

EXAMPLE 11

2- benzylperhydroazepine

Using a working method described in example 10, 15 g of 2-[(α-cyano)-benzylidene]-perhydroazepine and 177 ml of concentrated hydrochloric acid yield 7.46 g (56% of theoretical yield) of the title compound with bp 88° vedo, 007 Torr.

The hydrochloride (from methanol/ether) melts at 164 - 167°C.

EXAMPLE 12

1-ethyl-2-(4-chlorobenzyl)-perhydroazepine

4 g of 2-(4-chlorobenzyl-perhydroazepine, 2.5 g of anhydrous potassium carbonate and 2.9 g of ethyl bromide are boiled for 26 hours in 30 ml of ethyl methyl ketone with stirring and reflux, mixed after cooling with water and extracted with ether. The organic phase dried over sodium sulfate, the ether is distilled off and the residue is distilled.5.12 g (70%) with bp 112° at 0.005 Torr are obtained.

EXAMPLE 13

1-allyl-2-(4-chlorobenzyl)-perhydroazepine

With the working method described in example 12, you get

from 8 g of 2-(4-chlorobenzyl)-perhydroazepine, 5 g of anhydrous potassium carbonate and 8.7 g of allyl bromide 6.76 g (72% of theo-

j retical dividend) of the title compound with kp. 110° at 0.02

Dry..

EXAMPLE 14

2-(4-Chlorobenzyl)-1-isopropylperhydroazepine

Using the working method described in example 12, 5.8 g of 2-(4-chlorobenzyl)-perhydroazepine, 3.6 g of anhydrous potassium carbonate and 6.6 g of isopropyl iodide yield 3.9 g of the title compound with b.p. 113° at 0.03 Torr (56% of theoretical yield).

EXAMPLE 15

2-(4-Chlorobenzyl)-1-hexylperhydroazepine

Using the working method described in example 12, 5 g of 2-(4-chlorobenzyl)-perhydroazepine, 3.1 g of anhydrous potassium carbonate and 4 g of 1-bromohexane yield 3.87 g (56% of theoretical yield) of the title compound at kp. 129° at 0.005 Torr.

EXAMPLE 16

2-(4-nitrobenzyl)-perhydroazepine

To 4 3 ml of concentrated sulfuric acid, while stirring at -10°, add 10 g of 2-benzylperhydroazepine, then at the same temperature 33 ml of concentrated nitric acid, allow to slowly warm to room temperature and stir again for an hour. This is poured onto 500 g of ice, rendered alkaline with 6 N caustic soda and extracted with ether. After drying the organic phase over sodium sulphate, the solvent is distilled off. 12.0 g (97% of theoretical yield) of the title compound remains as a red oil.

IN

EXAMPLE 17

2-(4-aminobenzy1)-perhydroazepine

12 g of 2-(4-nitrobenzyl)-perhydroazepine are hydrogenated in 300

ml ethanol with platinum/hydrogen. After complete hydrogen absorption, the catalyst is filtered off and the filtrate is evaporated.

The title compound returns as a dark brown, viscous oil. Yield 10.5 g (100% of theoretical yield).

The benzoate (from isopropanol) melts at 186 - 190°. (fission) .

EXAMPLE 18

1- sec.- butyl- 2-( 4- chlorobenzyl)- perhydroazepine

Using the working method described in example 12, 3.2 g of the title compound is obtained from 5.0 g of 2-(4-chlorobenzyl)-perhydroazepine, 4.0 g of anhydrous potassium carbonate and 3.0 sec.-butyl bromide.

EXAMPLE 19

2-(4-Chlorobenzyl)-1-neopentylperhydroazepine

Using the working method described in example 12, 5.0 g of 2-(4-chloroberizyl)-perhydroazepine, 4.0 g of anhydrous potassium carbonate and 3.6 g of neopentyl bromide yield 3.9 g of the title compound.

EXAMPLE 20

2-(4-chlorobenzyl)-1-cyclohexylperhydroazepine

Using the working method described in example 12, 2.35 g of the title compound is obtained from 5 g of 2-(4-chlorobenzyl)-perhydroazepine, 3.1 g of anhydrous potassium carbonate and 4 g of cyclohexyl bromide.

EXAMPLE 21

1- methyl- 2-( 4- nitrobenzyl)- perhydroazepine

By the working method described in example 12 you get

from 2.34 g of 2-(4-nitrobenzyl)-perhydroazepine, 1.4 g of anhydrous potassium carbonate and 1.5 g of methyl iodide, 1.5 g of the title compound is obtained as a red oil.

EXAMPLE 2 2

2-(4-aminobenzyl)-1-methyl-perhydroazepine

By the working method described in example 17 you get

from 3.45 g of 1-methyl-2-(4-nitrobenzyl)-perhydroazepine by hydrogenation with PtCl 2 /hydrogen 2.9 g of the oily title compound.

EXAMPLE 2 3

2-(4-diethylarainobenzyl)-1-methyl-perhydroazepine

2.18 g of 2-(4-aminobenzyl)-1-methyl-perhydroazepine, 2.0 g of anhydrous potassium carbonate and 3.1 g of diethyl sulfate are stirred 7

hours at 140°. After cooling, the suspension is mixed with water and caustic soda and extracted with diethyl ether. The organic phase is dried over sodium sulphate and the ether is distilled off. Residue 1.9 g (70% yield).

EXAMPLE 2 4

2- benzyl-l- methylperhydroazepine

With the working method described in example 12. get

from 4.0 g of 2-benzyl-perhydroazepine, 2.9 g of anhydrous potassium carbonate and 3.3 g of methyl iodide, 2.4 g of the title compound with b.p. 68° at 0.003 Torr (56% of theoretical yield).

The picrate melts at 116 - 118°.

EXAMPLE 2 5

2-(4-bromobenzyl)-1-methylperhydroazepine

2.03 g of 2-benzyl-1-methyl-perhydroazepine and 50 mg. iron powder is mixed with 10 mmol of bromine at room temperature. One touches 2

hours, make alkaline with caustic soda, extract the base with ether, distil and obtain 2-(4-bromobenzyl)-1-methyl-perhydroazepine as an oily almost colorless liquid of b.p. 108° at 0.003 Torr.

EXAMPLE 2 6

2-(3,4-Dihydroxybenzyl)-1-methyl-perhydroazepine

5.0 g of 2-(3,4-dimethoxybenzyl)-1-methyl-perhydroazepine is refluxed in a mixture of 45 ml of acetic acid and 45 ml of 48% hydrobromic acid for 40 hours. The main amount of acid is removed by vacuum distillation, the remainder is taken up with ice water and made alkaline with soda solution. After several hours of extraction of the base with ether, after distilling off the solvent, the obtained residue (4.0 g) is transferred with methanol/ ethereal hydrochloric acid into the hydrochloride. Yield 3.0 g.

IN

in ,

'- L _ ■ ' ' ' ■ 1

.EXAMPLE27

2-[ α-(ethoxycarbonyl)- 3, 4, 5- trimethoxybenzylidene]- 1- methyl-perhydroazepine

Using the working method described in example 2, 35.6 g of 3,4,5-trimethoxyphenyl -acetic acid and a solution of 4.32 g sodium in 100 ml ethanol 14.23 g of the title compound as a viscous oil (28 of theoretical yield).

EXAMPLE 28

2- benzy1- 1- cyclopropylkcarbonyl- perhydroazepine

To 7.0 g of 2-benzyl-perhydroazepine and 4.1 g of triethylamine in 70 ml of dichloromethane are added dropwise at 0 to 8° 4.3 g of cyclopropane carbonic acid chloride in 40 ml of dichloromethane. It is stirred for a further 2 hours at 0°, mixed with 300 ml of water, the organic phase separated, extracted again with dichloromethane. washes the combined organic phases with dilute hydrochloric acid and soda solution, dries over sodium sulfate and evaporates to a viscous oil. Yield 9.2 g (97% of theoretical yield).

EXAMPLE 2 9

2- benzyl1- 1- cyclopropylImethyl1- perhydroazepine

9.0 g of 2-benzyl-1-cyclopropylcarbonyl-perhydroazepine dissolved

in 80 ml of tetrahydrofuran is added dropwise with stirring at 0° over the course of 10 minutes to a suspension of 1.30 g of lithium aluminum hydride (=lithium hydridoaluminate) in 30 ml of tetrahydrofuran. Then boil for 1.5 hours at reflux, add a further 2.0 g of lithium aluminum hydride, boil for a further 3.5 hours at reflux and, after cooling, carefully add 300 ml of water and extract three times with 50 ml!

ether. The combined ether solutions are washed with saturated sodium chloride solution, dried over sodium sulphate and the residue distilled after evaporating the solvent in vacuo. Yield 5.89 g with bp. 115° at 0.01 Torr.

EXAMPLE 3 0

1- acetyl- 2- benzyl- perhydroazepine

By the working method described in example 8,

5.8 g of a viscous oil is obtained from 6 g of 2-benzyl-perhydroazepine, 4.14 g of triethylamine and 2.65 g of acetyl chloride.

EXAMPLE 31

1- eth1- 2- benzyl- perhydroazepine

By the working method described in example 29 you get

one white from 2.5 g of 1-acetyl-2-benzyl-perhydroazepine and 0.80

g lithium aluminum hydride 1.2 g of an oil with kp..90 - 95°

at 0.008 Torr.

EXAMPLE 3 2

2-(4-Chlorobenzyl)-1-cyclopropylcarbonyl-perhydroazepine

By the working method described in example 28 you get

from 6 g of 2-(4-chlorobenzyl)-perhydroazepine>4.14 g of triethylamine and 4.30 g of cyclopropane carbonic acid chloride 6.2

g of a tenacious pale yellow oil.

i ■ I

EXAMPLE 33

2- ( 4- chloro benzyl ).- l- cyclopropyl Ime ty 1- perhydroazepine

Using the working method described in example 29, 5.0 g of 2-(4-chlorobenzyl)-1-cyclopropylcarbonyl-perhydroazepine and 1.4 g of lithium aluminum hydride yield 3.2 g of a colorless oily liquid with bp. 100 - .105° at 0.01 Torr.

EXAMPLE 34

2-(4-Acetylaminobenzyl)-1-methyl-perhydroazepine

A solution of 0.75 g of acetyl chloride in 5 ml of benzene is added dropwise to a solution of 1.9 g of 2-(4-aminobenzyl)-1-methyl-perhydroazepine and 1 g of triethylamine in 100 ml of benzene. After one hour, evaporate, take up with water and ether, collect the organic phase and evaporate.

EXAMPLE 3 5

2-(4-Methoxybenzyl)-perhydroazepine

6.5 g of caprolactim methyl ether, 5.0 g of 4-methoxybenzyl cyanide and 0.5 g of 1,5-diazabicyclo[5.4.0]undec-5-ene are stirred under nitrogen for 18 hours at 125°, volatile components are removed under high vacuum and the viscous the dark residue (2-[α-cyano)-4-methoxy-benzylidene]-perhydorazepine) is boiled with 50 ml of concentrated hydrochloric acid until carbon dioxide evolution is complete under reflux. After cooling, it is made alkaline under cooling, extracted with ether and the ether extract is evaporated after drying over sodium sulphate. The thus obtained 2-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-3H-azepine is hydrogenated with platinum/active carbon/hydrogen in ethanol, filtered from cata-

In the lysator, evaporate and distill. Mon.gets the title connection with kp. 100 - 106° at 0.01 Torr. in

EXAMPLE 36

2-(3-Methoxybenzyl)-perhydroazepine

By the working method described in example 35 you get

starting from caprolactim methyl ether, 3-methoxybenzyl cyanide and 1,5-diazabicyclo5.4.0]undec-5-ene the title compound as oil with b.p. 98 - 103° at 0.01 Torr.

EXAMPLE 37

2-(4-Methoxybenzyl)-1-methyl-perhydroazepine

Using the working method described in example 12, the title compound is obtained as a light oil from 2.19 g of 2-(4-methoxybenzyl)-perhydroazepine, 2.9 g of methyl iodide and 2.1 g of anhydrous potassium carbonate.

EXAMPLE 38

2-(3-Methoxybenzyl)-1-methyl-perhydroazepine

Using the working method described in example 12, the title compound is obtained as an oil with b.p. from 2-(3-methoxybehzyl)-perhydroazepine, methyl iodide and potassium carbonate. 110 - 115° at 0.01 Torr.

EXAMPLE 3 9

2-( 4- chlorobenzyl)- 1-[ 3-( 3- fluorobenzyl)- propyl]- perhydroazepine

2 g of 2-(4-chlorobenzyl)-perhydroazepine, 2.7 g of u/-chloro-4-fluoro-butyrophenone, 1.89 g of potassium carbonate and 10 ml of methyl ethyl ketone I are boiled for 70 hours under reflux and mixed after cooling j with 25 ml of water and 25 ml of ether. The ether phase is collected, dried |

! over sodium sulfate, evaporated and dried in high vacuum at 80°• Yield 1.0 g tough, light brown oil.

EXAMPLE 4 0

2- ( 4- chlorobenzyl) - 1- [ 4- ( 4- fluoro. enyl) - butyl] - perhydroazepine

0.5 g of 2-(4-chlorobenzyl)-1-[3-(4-fluorobenzoyl)-propyl]-perhydroazepine is heated with 1 ml of hydrazine hydrate, 0.5 g of potassium hydroxide and 5 ml of triglycol for 2 hours at 165° and mixed after cooling with water and ether. The ether phase is dried over sodium sulphate and then evaporated. Yield 0.3 g viscous oil.

EXAMPLE 41.

1- benzyl- 2-( 4- chlorobenzyl)- perhydroazepine

By the working method described in example 12 you get

3.95 g of the oily title compound are obtained from 5 g of 2-(4-chlorobenzyl)-perhydroazepine, 3.2 g of anhydrous potassium carbonate and 2.83 g of benzyl chloride.

EXAMPLE 4-2

2-(4-Chlorobenzyl)-perhydroazepine

3.0 g of 1-benzyl-2-(4-chlorobenzyl.)-perhydroazepine are hydrogenated in 50 ml of ethanol with 10% palladium on active carbon. After filtering off the catalyst, it is evaporated and the residue is treated with ethereal hydrochloric acid in the hydrochloride which, after recrystallization from methanol/ether, melts at 176 - 178°.

j I

EXAMPLE 4 3

2- ( 4- chlorobenzyl)^ perhydroazepine

4.0 g of 2-(4-chlorobenzyl)-1-methylperhydroazepine are boiled with 20 ml ethyl chloroformate for 5 hours under reflux, the excess of chloroformate is distilled off and the remaining crude 1-ethoxycarbonyl-2-(4-chlorobenzyl)- perhydroazepine is boiled with 100 ml of n-butanol and 8 g of potassium hydroxide for 20 hours. After mixing with water, the organic phase is separated and

the aqueous phase is extracted with dichloromethane. The combined organic phase is evaporated and the oily residue is transferred with ethereal hydrochloric acid into the hydrochloride, which is recrystallized from methanol/ether. Yield 2.2 g (50% of theoretical yield) with melting point 177 - 178°.

An analogy is obtained by reacting 1-benzyl-2-(4-chlorobenzyl)-perhydroazepine with chloroformate ethyl ester and subsequent saponification with potassium hydroxide in the butanol title compound.

EXAMPLE 4 4

2-[(α-cyano)-2-chlorobenzylidene]-perhydroazepine

Using the working method described in example 9, 5.0 g of 2-chlorobenzyl cyanide, 5.5 g of carolactim methyl ether and 0.5 g of diazabicyclo[5.4.0]uhdec-5-ene are obtained 4.5 g of the oily title compound.

EXAMPLE 4 5

2-(2-Chlorobenzyl)-perhydroazepine

With the working method described in example 10, you get

from 4.0 g of 2-[(g<->cyano)-2-chlorobenzylidene]-perhydroazepine

In 1.9 g (52%) of the title compound with b.p. 100 - 106° at 0.05 Torr. f

EXAMPLE 4 6

2-[(g-cyano)-3-chlorobenzylidene]-perhydroazepine

Using the working method described in example 9, 4.5 g of the oily title compound is obtained from 5.0 g of 3-chlorobenzyl cyanide, 5.5 g of caprolactim methyl ether and 0.5 g of diazabicyclo [5.4.0]undec-5-ene .

EXAMPLE 4 7

2-(3-Chlorobenzyl)-perhydroazepine

Using the working method described in example 10, 2.2 g (60%) of the title compound with bp. 98 - 103° at 0.01 Torr.

EXAMPLE 4 8

2-(3-Chlorobenzyl)-1-methyl-perhydroazepine

Using the working method described in example 12, 2.5 g of 2-(3-chlorobenzyl)-perhydroazepine, 1.5 g of anhydrous potassium carbonate and 1.5 g of methyl iodide yield 2.0 g of the title compound.

EXAMPLE 4 9

2-[ g-(ethoxycarbonyl)- 2- chlorobenzylidene]- 1- methylperhydroazepine

Using the working method described in example 2, 80.2 g of 2-dimethylamino-1-methyl-4,5,6,7-tetrahydro-3H-azepinium methylsulfate and 40 g of 2-chlorophenylacetic acid ethyl ester are obtained

^ the title compound which is a viscous oil.

in

EXAMPLE 50 I

2-(2-Chlorobenzyl)-1-methylperhydroazenine

Using the working method described in the example, 2-[a-(ethoxycarbonyl)-2-chlorobenzylidene]-1-methylperhydroazepine gives the title compound as a light oil with b.p. 134° at 0.01 Torr.

The picrate (from ethanol) melts at 123 - 126°.

EXAMPLE 51

7-(4-ChlorobenZyl)-perhydroazepin-2-one

To an ice-cold solution of 4.47 g of 2-(4-chlorobenzyl)-cyclohexanone in 100 g of polyphosphoric acid, 2.6 g of sodium azide are added while stirring, stirred for 1.5 hours at 0° and 8 hours at room temperature. Pour into ice water and extract with methylene chloride. After drying over sodium sulfate and distilling off the solvent, 2.85 g of the title compound are obtained as a light brown oil.

EXAMPLE 52

2-(4-Chlorobenzyl)-perhydroazepine

0.5 g of lithium aluminum hydride is added to 2.8 g of 7-(4-chlorobenzyl)-perhydroazepin-2-one in 30 ml of tetrahydrofuran and refluxed for 16 hours. Mix with ice water and extract with diethyl ether. After drying over sodium sulphate, the oily residue is evaporated and distilled in a vacuum. 1.8 g of the title compound with bp is obtained. 90 - 92° at 0.05 Torr.

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EXAMPLE 53

2-(4-aminobenzyl)-perhydroazepine

3.72 g of 7-(4-nitrobenzyl)-perhydroazepin-2-one are hydrogenated in 50 ml of ethanol with platinum/hydrogen. After completion of hydrogen uptake, the catalyst is filtered off, the filtrate is evaporated

and the crude 7-(4-aminobenzyl)-perhydroazepin-2-one thus obtained is dissolved in 30 ml of tetrahydrofuran, and after the addition of 680 mg of lithium aluminum hydride, it is refluxed for 20 hours. Mix with ice water, extract with ether, dry the organic phase over sodium sulphate and evaporate. 2.0 g of the brown, oily title compound is obtained.

The benzoate (from isopropanol) melts at 186 - 189° (decomposition).

EXAMPLE 54

2-(2-Methoxybenzyl)-perhydroazepine

Using the working method described in example 2, 2.8 g of 7-(2-methoxybenzyl)-perhydroazepin-2-one and 0.5

g lithium aluminum hydride 1.5 g of the title compound as an oily liquid with b.p. 95 - 100° at 0.01 Torr.

EXAMPLE 5 5

2-(4-methylbenzyl)-perhydroazepine

By the working method described in example 52. you get

from 2.8 g of 7-(4-methylbenzyl)-perhydroazpin-2-one and 0.5 g

lithium aluminum nydride 1.6 g of the title compound as an oily liquid with bp. 82 - 85° at 0.01 Torr.

! • . in

1<1>EXAMPLE 5 6 . 1

2-(4-Chlorobenzyl)-perhydroazepine

To a solution of 1.01 g of diisopropylamine in 100 ml of tetrahydrofuran, a solution of 10 mmol of n-butyllithium in hexane is added at -78° under argon, stirred for 5 minutes at room temperature and cooled again to -78°. After adding 1.28 g of N-nitrosperhydroazepine, one stirs for 1 hour at this temperature, then adds 4.1 g of 4-chlorobenzyl bromide in a little diethyl ether, stirs for 5 hours at -78°, adds 5 ml of glacial acetic acid, allows the temperature to rise to room temperature and pour this onto 100 ml of dichloromethane/saturated sodium chloride solution.

The organic phase is dissolved after distilling off the solvent in methanol. After adding 2 g of freshly prepared Raney nickel, hydrogen gas is passed through the solution with vigorous stirring. After the reduction is complete, the catalyst is filtered off, washed with methanol and evaporated. The oily residue is transferred by treatment with methanol/etheric hydrochloric acid in the hydrochloride of the title compound which melts at 176 - 178°.

EXAMPLE 57

Rate for 100 liters (ampoules)

1 dissolves in approx. 80 liters of water while adding the equivalent amount of hydrochloric acid, then add 2. The solution is adjusted to a pH of 7.0 + 0.5 and filled up with the rest of the water. The solution is sterile filtered through a filter and filled under germ-free conditions into 2 ml ampoules.

IN

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EXAMPLE 58

2 is mixed with 5 kg 4 and finely ground. This mixture is mixed

with 1 and 30 kg 3, the rest of 4, 5 and 6 and sieved. This mixture is moistened with one solution of 7 and 8 in 35 ml of water and pressed through a sieve with a mesh size of 1.25 mm. After drying, the granulate is mixed well with the rest of 3,9 and 10

and pressed into tablets of 200 mg.

EXAMPLE 59

1, 2, 3, 4 are mixed, moistened with 5 (dissolved in 15 liters of water) and granulated. It is then dried in a drying cabinet at 50° and the product is then sieved through a sieve. The granulate is dried.!

to a relative humidity of 45 - 50% and pressed after adding 6, 7 and 8 and thoroughly mixing into tablets of

100 mg weight.

EXAMPLE 60

1, 2, 3, 4 are mixed/moistened with 5 (dissolved in 15 liters of water) and granulated. It is then dried in a drying cabinet at 50° and then sifted through a sieve. The granulate is dried to a relative humidity of 45 - 50% and pressed after the addition of 6, 7, 8 and the priming mixture into tablets of 100 mg weight.

Claims (1)

1. 2-Benzyl-perhydroazepines of the general formula I characterized in that R means a hydrogen atom, an aliphatic or alicyclic hydrocarbon residue, a cycloalkylalkyl group or an aralkyl group, 2 3 4 5 R , R , R and R are the same or different and mean a hydrogen atom, a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, an acyloxy group, an optionally substituted amino group, a nitro group, an optionally substituted 1 2 3 4 substituted phenyl group where R is not methyl when R, R, R and R~* means hydrogen and their acid addition ionic salts.2. 2-benzyl-perhydroazepines of the general formula I lx characterized in that R means a hydrogen atom, a straight or branched aliphatic hydrocarbon residue of 1 to 6 carbon atoms, a cycloalkylalkyl group of 1 to 2 carbon atoms in the alkyl residue and 3 to 5 carbon atoms. in the cycloalkyl residue, or an optionally substituted phenylalkyl group with 1 to 4 carbon atoms in the alkyl residue, R 2x a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, an amino group, a dialkylamino group with 1 to 2 carbon atoms per alkyl residue, a nitro group or a phenyl group optionally substituted in the p-position, R3<*> , R <4*> and R<5> a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, an amino group, a dialkylamino group with 1 to 2 carbon atoms per alkyl residue or a nitro group, whereby at least one of the substituents in the 2- or 6-position in the benzyl group is a hydrogen atom and acid addition salts thereof. <!> . <!>13. 2-benzyl-perhydoazepines of the general formula I XX I characterized in that R means a hydrogen atom, a linear or branched aliphatic hydrocarbon residue with 2 to 6 carbon atoms, a cycloalkylalkyl group with 1 to 2 carbon atoms in the alkyl residue and 3 to 5 carbon atoms in the alkyl residue or an optionally singly substituted phenylalkyl group with 1 to 4 carbon atoms in the alkyl residue , 9XX iXX A XX 5XX R <2xx> , R/ R and R a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group of 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, an alkanoyloxy group with 2 to 5 carbon atoms, an amino group, a dialkylamino group with 1 to 2 carbon atoms per alkyl residue, a nitro group or a phenyl group optionally substituted in the p-position, whereby at least one of the substituents in the 2- or 6-position in the benzyl group is a hydrogen atom, and acid addition salts thereof. 4. 2-Benzyl-perhydroazepines according to claim 2., k a r a k- ix 0x oX 4X 5x terized in that R , Rz , R , R . and R has it before mentioned meaning whereby at least one, preferably two of a 4x 5x the substituents R-* , R or R and at least one of the substituents in the 2- or 6-position in the benzyl group means a hydrogen atom, and acid addition salts thereof. 5. 2-benzyl-perhydroazepines according to claim 3, k a r a k- oXx 4x 4XX rXX terized in that R , R ,..R and R3 have the previously stated meaning, whereby at least one, preferably two of "3XX Xv the substituents R , R 4 or R and at least one of the substituents in the 2- or 6-position in the benzyl group means a hydrogen atom, and acid addition salts thereof. IN 6. 2-benzyl-perhydroazepines according to claims 2 and 4, characterized in that R lx means a hydrogen atom, a linear alkyl radical with 1 to 3 carbon atoms, a branched alkyl radical with 3 to 5 carbon atoms, a cycloalkylmethyl radical with 3 to 5 carbon atoms in the cycloalkyl group or a benzyl radical optionally substituted in the p-position with halogen, methyl or methoxy, 2X R a halogen atom, a hydroxy group, a methoxy group, a amino group or a nitro group, 3X RJ a hydrogen atom, a halogen atom, a hydroxy group, eh methoxy group, an amino group or a nitro group, whereby the substituents R^ and R^ are preferably in the 2-, 3-bg./ or 4-position, 4x c-x R and RD are a hydrogen atom, and acid addition salts thereof. 7. 2-benzyl-perhydroazepines according to claims 2, 4 and 6 l<x> characterized in that R means a hydrogen atom, a methyl group, an isopropyl group, a cyclopropylmethyl group or a benzyl group, 2X R a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, RJ a hydrogen atom, a halogen atom, a hydroxy group <p> pe, a methoxy group, an amino group or a nitro group, whereby the substituent R and RJ are preferably in the 2-, 3- and/or 4-position, 4X 5X R and R is a hydrogen atom, and acid addition salts thereof. 8. 2-benzyl-perhydroazepines according to claims 3 and 5, -in XX characterized in that R means a hydrogen atom, a linear alkyl residue with 2 to 3 carbon atoms, a branched alkyl radical with 3 to 5 carbon atoms, a cycloalkylmethyl radical with 3 to 5 carbon atoms in the cycloalkyl group or a benzyl radical optionally substituted in p-position with halogen, methyl or methoxy, ?xx iXX R and R are the same or different and mean a hydrogen atom, a halogen atom, a hydroxy group <p> pe, a methoxy group, an amino group or a nitro group, whereby the substituents 2XX -,xx R and RJ are preferably in the 2-, 3- and/or 4-position, I4<x> x5<x> x in IR and R is a hydrogen atom, and acid addition salts thereof; 9. 2-benzyl-perhydroazepines according to claims 3, 5 and 8, in xx characterized in that R means a hydrogen atom, an ethyl group, an isopropyl group, a cyclopropyl methyl group or a benzyl group, *jXx x x R and R are the same or different and mean a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, eR n amoing andR ruppe foretlrleinr nesvn ins itsriotgtreur ppi e2, -h, vo3r- veod g/esulblesr tit4u-esnttielnleing, 4Xx and c <xx> is a hydrogen atom, and hence. R and R are a hydrogen atom, and acid addition salts thereof. 10. 2-benzyl-perhydroazepines according to claims 2, 4, 6 and 7, characterized in that R lx means a hydrogen atom, a methyl group, an isopropyl group or a cyclopropyl methyl group, R means a chlorine atom in the 2-, 3- or 4-position or a 2X amino group in the 4-position, iX .jr r-X R , R , and R are a hydrogen atom, and pharmacologically tolerable acid addition salts thereof. o 11. 2-(2-chlorobenzyl)-1-methyl-perhydroazepine and pharmacologically tolerable acid addition salts thereof. 12. 2-(4-chlorobenzyl)-perhydroazepine and pharmacologically tolerable acid addition salts thereof. 13. 2-(4-chlorobenzyl)-1-isopropyl-perhydroazpine and pharmacologically tolerable acid addition salts thereof. 14. 2-(4-Chlorobenzyl)-1-methyl-perhydfQazpine and pharmacologically tolerable acid addition salts thereof. 15. 2-(benzyl)-1-cyclopropylmethyl-perhydroazpine and pharmacologically tolerable acid addition salts thereof. 16. 2-benzyl-perhydroazpine and pharmacologically tolerable acid addition salts thereof. 17. 2-(4-aminobenzyl)-<p>erhydroazepine and pharmacologically tolerable acid addition salts thereof. in 18. 2-benzyl-perhydorazpines according to claims 1 to 17, characterized in that they exist as racemates, enantiomers or mixtures thereof. 19. Medicine. characterized in that it contains one or more 2-benzyl-perhydroazepines according to claims 1 to 18. 20. Use of 2-benzyl-perhydroazepines according to claims 1 to 18 in combating disturbances of the central nervous system, morbid changes in blood pressure and/or pain. 21. Process for the production of 2-benzyl-perhydroazepines with the general formula I and their embodiments I X respectively I <XX> and their salts characterized by A) transfers et.2-benzyl-azacycloheptane with the general formula II 2 3 4 5 where R , R , R and R have the above meaning and the grouping in and R an aliphatic or alicyclic hydrocarbon residue, a cycloalkylalkyl group or an aralkyl group <p> e and R <7> a hydrogen atom, an aliphatic or alicyclic hydrocarbon residue or a cycloalkylalkyl residue, and optionally then N-alkylates or N-dealkylates and/or functionalizes and/or transfer the obtained free base or their acid addition salts in the usual way into each other, or B) functionalizes a 2-benzyl-azacycloheptane with the general formula III where R 2 has the meaning given above and G a hydrogen atom or a preference of a functional group and n an integer from 1 to 4, preferably 1 to 2, especially 1, and optionally then N-alkylates or N-dealkylates and/or transfer the obtained free base or their acid addition salts in the usual way into each other or C) reduces an N-acyl-2-benzyl-azacycloheptane with it general formula IV 2 3 4 5 where R , R , R and R have the above meaning and R 8 an aliphatic or alicyclic hydrocarbon residue, a cycloalkylalkyl residue, an optionally substituted phenyl residue or phenyl-i in alkyl residue, and optionally then functionalizes and/or in I dealkylates and/or transfers the obtained free base or its acid addition salts in the usual way into each other.