IE46629B1 - 2-benzyl-perhydroazepines,process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

This invention relates to 2-benzyl-perhydroazepines of the general formula I (I), in which R1 is a hydrogen atom, an aliphatic or alicyclic hydrocarbon radical, a cycloalkylalkyl group or an aralkyl group, R2, R3, R4 and R5 are the same or different and signify 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, R1 not being methyl if R2, R3, R4 and R5 mean hydrogen, and their acid addition salts. This invention also relates to a process for the preparation of these compounds from known materials. The compounds of formula (I) and their pharmacologically compatible acid addition salts are useful in human and veterinary medicine because they produce central stimulation, an increase in vigilance, promote normal and pathologically inhibited drive of warm-blood animals. In addition some representatives display a strong analgesic action or an action which influences the blood pressure.

Description

The invention relates to 2-benzyl-perhydroazepines which may be substituted one or more times in the phenyl ring, a process for their preparation and pharmaceutical compositions containing them.

In the course of a work on elimination reactions L.P.A. Fery and L. Wilputte-Steinert reported (Bull.SOc.Chim. Belg. 73 (19θ4) 15^-165) regarding the formation of 1methyl-2-benzylhaxamethyleneimine, no activity was disclosed for this compound The compound was formed only in such a small quantity that it could be identified only as a derivative in the form of the picrate and methiodide.

In German Offenlegungsschrift (Published Specification) DE-OS 2 5'i8 053 saturated ci-substituted benzyl-i-benzhydrylazaheterocyclic compounds are claimed, but only ^-substituted benzyl-l-benzhydrylazetidines are described,these are intended for use for the treatment of obesity. It has now been found that optionally substituted 2-benzylperhydroazepineepossess valuable pharmalogical properties which can be utilised commercially.

The invention relates to 2-benzyl-perhydroazepiness of the general formula I (I) /).6 6 29 in which is a hydrogen atom, an aliphatic or alicyclic hydrocarbon radical, a cycloalkylalkyl group or a mono-aryl-alkyl group as herein defined, 3 4 5 and R , R , R and R are the same or different and each signify 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 with R^ not being 2 3 4 5 methyl if R , R , R and R mean hydrogen and their acid addition salts.

As aliphatic hydrocarbon radicals one may use straightchained or branched alkyl radicals with 1 to 7 carbon atoms or alkenyl and alkynyl radicals with 2 to 7 carbon atoms. Straightrchained alkyl radicals are methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl radicals, of which those with 1 to 6, especially those with 1 to 3, carbon atoms are preferred. An alkenyl radical is, e.g., allyl.

An alkynyl radical is, e.g., propynyl. Branched alkyl radicals with 3 to 7 carbon atoms are, for example, isopropyl, isobutyl, sec.-butyl, tert.-butyl, 3-methylbutyl, 2,2-dimethylpropyl, 2-methyl-pentyl, 3,3-dimethyIbutyl or 2-ethyl-3-methylbutyl, of which those with 3 to 5, especially with 3, carbon atoms are preferred. As alicyclic hydrocarbon radicals one may use cycloalkyl radicals with 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, of which those with 5 to 6 carbon atoms are preferred.

As cycloalkylalkyl groups one can use those with 1 to 4 carbon atoms in the alkyl radical and 3 to 7 carbon atoms in the cycloalkyl radical, of which those with 1 to 2 carbon atoms in the alkyl radical and 3 to 5 carbon atoms in the cycloalkyl radical are preferred. Selected cycloalkylalkyl 10 groups are cyclopropylmethyl and cyclobutylmethyl.

A mono-aryl-alkyl group means a group which is unsubstituted or substituted in the aryl radical by halogen atoms or alkyl and/or alkoxy groups with 1 to 4 carbon atoms or in the alkyl radical by hydroxy or oxo groups.

As mono-aryl-alkyl groups one may use those with aryl groups which contain up to 12 carbon atoms and alkyl groups which contain 1 to 4 carbon atoms, of which those with 6 carbons atoms in the aryl radical and 1 to 4 carbon atoms in the alkyl radical, mainly with 1 carbon atom in the alkyl radical, are preferred. By way of example one may mention benzyl, phenethyl and phenylpropyl, of which benzyl is preferred If the mono-aryl-alkyl group is substituted, monosubstitution in the aryl radical ( with a halogen atom or an alkyl or alkoxy group with 1 to 4 carbon atoms) is preferred. Preferred halogen atoms are fluorine, chlorine or bromine. By way of example one may mention p-chlorobenzyl, m-chlorobenzyl, / b p-bromobenzyl, o-fluorobenzyl, p-fluorobenzyl, p-tolyl and p-methoxybenzyl. Mono-aryl-alkyl groups substituted in the alkyl radical are the arylhydroxyalkyl and especially the aryloxoalkyl groups, for example benzoylmethyl, 2-benzoylethyl and 3-benzoylpropyl, with preference for the 3-(ρ-chlorobenzoyl)-propyl, especially the 3-(p-fluorobenzoyl)propyl group. 3 4 5 As halogen atoms R , R , R or R one may have fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, bromine and especially chlorine. As alkyl groups or alkoxy 2 3 4 5 groups R , R , R or R one may mention inter alia those with to 4 carbon atoms, of which those with 1 to 3, and especially those with 1 carbon atom are preferred. As acyloxy groups one 1 1 may have -O-CO-R groups in which R has the meaning given above, of which the alkanoyloxy groups with 1 to 7, especially with 2 to 5, carbon atoms, especially the acetoxy group, are preferred. Besides the unsubstituted amino group one may also have as substituents R2, R3, R4 or R5 substituted amino groups of which for example one may mention alkyl and dialkylamino groups with 1 to 4, preferably 1 or 2, carbon atoms in the alkyl radical and also acylamino groups with the usual acyl groups used to protect amino groups, such as alkanoyl groups with 2 to 5 3 4 5 carbon atoms. As substituents R , R , Π or R one may have besides the unsubstituted phenyl group phenyl groups which are substituted with halogen atoms, hydroxy, alkyl and/or alkoxy groups with i to 4 carbon atoms, of which the p-substituted phenyl groups, such as p-chlorophenyl, p-fluorophenyl, p-hydroxyphenyl, p-methoxyphenyl groups, are preferred.

As salts one may use all acid addition salts. Particular mention is made of the pharmacologically compatible salts 10 of the inorganic and organic acids usually employed in pharmacy. Pharmacologically incompatible salts are converted into pharmacologically compatible salts by processes known in the art. Suitable salts by way of example are water-soluble and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, hydriodide , phosphate, nitrate, sulphate, acetate, citrate, gluconate, benzoate, hibenzate (2-(4-hydroxybenzoyl)-benzoate), fendizoate (o-[(2'-hydroxy-4-biphenylyl)-carbonylj-benzoate), propionate, butyrate, sulphosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate, tartrate, amsonate (4 j 4'-diamino-stilbene-2,2*-disulphonate), embonate (1,1'-methylene-bis-2-hydroxy-3-naphthoate), metembonate, stearate, tosylate (p-toluenesulphonate), 2-hydroxy-3naphthoate, 3-hydroxy-2-naphthoate and mesylate (methanesul4 6 6 2 9 phonate), as well as salts with Bumetanide (3-(butylamino)4-phenoxy-5-sulphamoyl-benzoic acid), Furosemide (4-chloroN-furfuryl-5-sulphamoylanthranilic acid), Besunide (4-benzyl3-(butylamino)-5-sulfamoyl-benzoic acid, Piretanide-45 phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid), Etacrynic acid ([2,3-dichloro-4-(2-methylene-butyryl)-phenoxyjacetic acid and Tienilic acid ([2,3-dichloro-4-(2-thenoyl)~ phenoxy]-acetic acid).

One embodiment of the invention consists of 2-benzyl- 1* in which R signifies a hydrogen atom, a straight-chained or branched aliphatic hydrocarbon radical with 1 to 6 carbon atoms, a cycloalkylalkyl group 'with 1 or 2 carbon atoms in the alkyl radical and 3 to 5 carbon atoms in the cycloalkyl radical, or a phenylalkyl group with 1 to 4 carbon atoms in the alkyl radical which may be monosubstituted in the phenyl radical by a halogen atom, an alkyl or an alkoxy group with 1 to 4 carbon atoms and whioh may be monosubstituted in the alkyl radical by a hydroxy or oxo group, 2* R signifies 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 radical, a nitro group or a phenyl group which may be substituted in the para position, and 3* 4* 5* R , R and R each signify 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 radical or a nitro group with at least one of the two substituents in ortno position· being a hydrogen atom, and their acid addition salts.

Anothor embodiment of the invention consists of 2-benzyl-perhydroazepin3S of the general formula I*‘ »* τ** in which R signifies a hydrogen atom, a straight-chained or branched aliphatic hydrocarbon radical with 2 to 6 carbon atoms, a cycloalkylalkyl group with 1 or 2 carbon atoms in the alkyl radical and 3 to 5 carbon atoms in the cycloalkyl radical, or a phenylalkyl group with 1 to 4 carbon atoms in the alkyl radical which may be monosubstituted in the phenyl radical by a halogen atom, an alkyl or an alkoxy group with 1 to 4 carbon atoms and which may be monsubstituted in the alkyl radical by a hydroxy or' oxo group, and 2** 3** 4** 5** R , R , R and R each signify a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group with 1 to 4 carbon atans, 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 radical, a nitro group or a phenyl group which may be substituted in the para position, at least one of the substituents in ortho position being a hydrogen atom, and their acid addition salts.

Further embodiment of the invention are those * ** 2-benzyl-perhydroazepines of the general formulae I or I 1* 2* 3* 4* 5* 1** ?** 3** in which R , R , R , R and R or R ' R ' R ' 4** * * and R have the meanings given above, in which at least o * 4 * 5 * one, preferably two, of the substituents R° , R or R or 3** ft Ίε Ίε R or R and at least one of the substituents in ortho position signifying a hydrogen atom, and their acid addition salts.

Preferred 2-benzyl-perhydroazepines of the general formula 1* I* are those in which R signifies a hydrogen atom, a straight-chained 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 which may be substituted in the para position by halogen, methyl or methoxy, * R signifies a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, 3* signifies a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, 2* 3* the substituents R and R being located at the 2,3- or 2,4- or 3,4- positions, and 4* 5‘ R and n each signify a hydrogen atom, and their acid addition salts.

Selected 2-benzyl-perhydroazepinesof the formula I* 1* are those in which R signifies a hydrogen atom, a methyl group, an isopropyl group, a cyclopropylmethyl group or a benzyl group , 2* R signifies a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, 3* Π signifies a hydrogen atom, a halogen atom, a hydroxy \2 6 6 2» group, a methoxy group, an amino group or a nitro group, * 3 * the substituents R and R being located at the 2.3- or 2,4- or 3,4- positions, and 4* 5* R and R each signify a hydrogen atom, and their acid addition salts.

Preferred 2-benzyl-perhydroazepines of the general •k4t formula I are those in which 1** R signifies a hydrogen atcm, a straight-chained alkyl radical with 2 to 3 carbon atoms, a branched alkyl radical with Iq 3 to 5 carbon atoms, a cycloalkylmethyl radical with 3 to 5 carbon atoms in the cycloalkyl group, a benzyl radical, a p-halobenzyl radical, a p-methylbenzyl radical or a p-methoxybenzyl radical, 2** 3** R and R are the same or different and each signify a hydrogen atom, a halogen atcm, a hydroxy group, a methoxy group, an amino group or a nitro group, in which the 3 substituents R and R are preferably located atthe2,3- or 2.4- or 3,4- positions, and R and R each signify a hydrogen atom, and their acid addition salts.

Selected 2-benzyl-perhydroazepines of the general formula X are those in which 1** R signifies a hydrogen atom, an ethyl group, an isopropyl group, a cyclopropylmethyl group or a benzyl group, Β Ο · * Ί * * R and RJ are the same or different and each signify a hydrogen atom, a halcgen atan, a hydroxy group, a methoxy group, an amino group or a nitro group, the substituents o* * g* * R and R being located at the 2,3- or 2,4- or 3,45 positions, and /j,* « R* * R and R each signify a hydrogen atom, and their acid addition salts.

Particularly preferred 2-benzyl-perhydroazepines are those of the general formula I*, in which i · R signifies a hydrogen atom, a methyl group, an isopropyl group or a cyclopropylmethyl group, 2* R signifies a chlorine atom at 2, 3 or 4 position, or an amino group at 4 position, and 9* 4* 5· Π , Π and R each signify a hydrogen atom, and their 15 pharmacologically compatible acid addition salts.

Selected representatives of the compounds according to the invention are 2-(2-chlorobenzyl)-l-methyl-perhydroazepine, 2-(4-chlorobenzyl)-perhydroazepine, 2-(4-chlorobenzyl)-1-isopropyl-perhydroazepine, 2-(4-chlorobenzyl) -l-methyl-perhydroazepins, 2-benzyl-l-cyclopropylmethyl-perhydroazepine, 2-benzyl-perhydroazepine, 2-(4-aminobenzyl)-perhydroazepine, and their pharmacologically compatible acid addition salts. The 2-benzyl-perhydroazepines according to the invention possess a chirality centre on the carbon atom marked with a (*). The invention therefore includes both the racemates and also the enantiomers and their mixtures.

. The optionally substituted 2-benzyl-perhydroazepines .according to the invention possess. valuable properties which make them commercially utilisable On the one hand these compounds and 2-benzyl-l-methyl-perhydroazepineas well as their pharmacologically, that is to say biologically, tolerable, salts possess pronounced pharmacological properties, particularly effects on the central nervous system (CNS), on the blood pressure and on the sensation of pain of warm-blooded animals, and on the other hand they can be converted into other 2-benzylperhydroazepins of the general formula I, and therefore represent valuable intermediate products for the production of compounds according to the invention.

The activity on the CNS of 2-benzyl-perhydroazepines and the pharmacologically tolerable salts extends to central stimulation, increase in vigilance, the promotion of the 46628 normal and pathologically inhibited drive of warm-blooded animals. In addition some representatives display a strong analgesic action or an action which influences the blood pressure.

The excellent and broad pharmacological efficacy of the 2-benzyl-perhydroazepines permits their use hotn in human and in veterinary medicine, where they are used for the prophylaxis of disorders or for the treatment of symptoms which have already occured.

As indications for use in human medicine one may mention the lack of drive in men and women, a reduction in vigilance, depression, organic psychosyndromes in cerebral degeneration processes, lack of performance, blood pressure disorders and conditions of exhaustion as well as conditions of pain and in children mental and psychological inhibition of development as well as difficulties in learning.

So far as veterinary medicine is concerned, the indications are drop in performance and conditions of pain.

For example it is possible to treat higher animals, such as farm and domestic animals. 43629 The invention also relates to pharmaceutical compositions which contain cue or more 2-benzyl-perhydroazepines tf the general Formula I in which R1 signifies a hydrogen atom, an aliphatic or alicyclic hydrocarbon radical, a cycloalkylalkyl group or an aralkyl group, ο 3 L 5 R , R , R and R are the same or different and signify 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 pharmacologically tolerated acid addition salts.

Preferred pharmaceutical compositions are those which contain 2-benzyl-perhydroazepines of the formula I* or I** or their preferred representatives and/or the corresponding pharmacologically compatible acid addition salts.

The pharmaceutical compositions are prepared according to known processes. They contain besides the active principles suitable pharmaceutical support substances.

Tne- active principle content of these mixtures is from 5 to 95, preferably 25 to 75, per cent by weight of the total mixture.

It is possible for the active principles to be used, in human and veterinary medicine in any desired form, for example systemic or topical, provided that one ensures the formation or maintenance of adequate blood or tissue levels or local concentrations of 2-benzyl-perhydroazepines. This can be done either by oral, rectal or parenteral administration in suitable doses. However, the new pharmaceutical compositions can also be applied locally. More advantageously the pharmaceutical preparation of the active principle occurs in the form of unit doses, which are designed for the particular administration desired. Λ unit dose may consist, for example, of a tablet, a pill, a capsule, a suppository or a measured volume of a powder, a granulate a solution, an emulsion, a suspension, a sol or a gel.

The term ,runit dosein the specification is used to mean a physically determined unit which contains an individual quantitiy of the active component in combination with a pharmaceutical support, the active principle content of which corresponds to a fraction or a multiple of a therapeutical individual dose. An individual dose preferably contains the quantity of active principle which is dispensed in a single application and which usually corresponds to a whole, a half, a third or a quarter of a dailydose. Xf for an individual therapeutical administration only a fraction, such as a half or a quarter, of the unit dose is required, the unit dose is advantageously divisible, for example in the form of a tablet with a notch.

The pharmaceutical preparations according to the Invention, if they occur in unit doses and are intended for application, for example, to man, contain 1 to 200 mg, advantageously 2.5 to 100 mg, and especially 5 to 50 mg of active principle.

In general it has been found advantageous both in human medicine and also in veterinary medicine to administer the active principle or principles in the case of oral admini46629 ‘9 stration in a daily dose of 0.06 to 12, preferably 0.14 to 5·7, especially 0.3 to 3 mg/kg body weight, possibly in the form of a number, preferably 1 to 3i °f individual doses so as to achieve the desired results. An individual administration contains the active principle or principles in quantities of 0.01 to 3·θ, preferably 0.04 to 1.5, especially 0.07 to 0.7 mg/kg body weight.

In the case of a parenteral treatment, for example of an acute depression or of a strong pain condition, similar dosages can be used. In the case of this therapy, 1 to 50 mg of active principle are applied.

For a local application one can use preparations in a pharmacologically acceptable, for example aqueous, solution, which contain 0.1 to 5, preferably 0.2 to 3, especially 0.5 to 2 per cent by weight of active principle.

The therapeutical administration of the pharmaceutical preparations in the case of long-term medication is carried out generally at fixed times, such as for example 1 to 4 times a day, for example after meals and/or in the evening. 2° In the case of acute attacks the medication is carried out at varying points of time. Under certain circumstances it may be necessary to differ from the dosages mentioned, namely according to the nature, the body weight and the age of the patient under treatment, the nature and severity of the disorder, the nature of the preparation and the application of the pharmaceutical product as well as the interval within which the administration takes place. Thus in a few cases it may be sufficient to manage with less than the quantity of active principle mentioned above, whilst in other cases the abovementioned quantity of active principle will have to be exceeded. The determination of the optimum dose and form of application of the active principles necessary in each case can be carried out at any time by the technician on the basis of his technical knowledge.

The pharmaceutical preparations consist as a rule of the active principles according to the Invention and non-toxic pharmaceutically compatible pharmaceutical supports which are used as an admixture or diluent, in a solid, semi-solid or liquid form or as an enrobing agent, for example in the form of a capsule, a tablet coating, a bag or another container, for the therapeutically active component. A support material can, for example, serve as a medium for absorption of the medicament by the body, as a formulation aid, as a sweetener, as a taste corrector, as a colouring material or as a preservative For oral application one can use, for example, tablets, pills, hard and soft capsules, for example of gelatin, dispersible powder, granulates, aqueous and oily suspensions, emulsions, solutions or syrups. 3 Tablets can contain inert diluents, for example calcium carbonate, calcium phosphate, sodium phosphate or lactose; granulating and distributing agents, for example maize starch or alginates; binders, for example starch, gelatin or acacia gum; and lubricants, for example aluminium or magnesium stearate, talcum or silicone oil. In addition they may be provided with a coating which can also be such that it ensures a delayed dissolution and resorption of the pharmaceutical product in the gastrointestinal tract and consequently, for example, an improved compatibility, protraction or retarding effect. Gelatin capsules can contain the pharmaceutical product mixed with a solid diluent, for example calcium carbonate or kaolin, or an oily diluent, for example olive oil, groundnut oil or liquid paraffin.

Aqueous suspensions can contain suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, gum dragon or acacia gum; dispersants and wetting agents, for example polyoxyethylene stearate, heptadeca46629 ethylene oxycetanol, polyoxyethylene sorbitol monooleate, polyoxyethylene sorbitan monooleate or lecithin; preservatives, for example methyl or propyl hydroxybenzaates; flavourings; car sweeteners, for example saccharose, lactose, sodium cyclamate, dextrose, r>r invert sugar syrup.

Oily suspensions may contain, for example, groundnut oil, olive oil, sesame oil, coconut oil or liquid paraffin and thickeners, such as for example beeswax, hard paraffin wax or cetyl alcohol; they may also contain sweeteners, flavourings and anti-oxidants.

Powders and granulates which are dispersible in water may contain the pharmaceutical products mixed with dispersing, wetting and suspending agents, for example with those mentioned above, as well as with sweeteners, fla15 vourings and colouring materials.

Emulsions may contain, for example, olive oil, groundnut oil or liquid paraffin as well as emulsifiers, such as acacia gum, gum dragon, phosphatides, sorbitan monooleate, or polyoxyethylene sorbitan monooleate , and sweeteners and flavourings.

For rectal administration of the pharmaceutical compositions one uses suppositories which are produced with the aid of binders which melt at rectal temperature, for example cocoa butter or polyethyleneglycols.

For the parenteral application of the pharmaceutical compositions one uses aqueous suspensions for sterile injection, isotonic saline solutions or other solutions which can contain dispersants or wetting agents and/or pharmacologically compatible diluents, for example propyleneglycol or butyleneglycol. dels, sols or tablets which are suitable for local treatment may contain in addition, to the active principle or principles the usual supports, for example animal and vegetable fats, waxes, paraffins, starch, gum dragon, cellulose derivatives, polyethyleneglycols, silicones, bentonites, silica, talcum and zinc oxide or mixtures of these substances.

Powders and sprays may contain, in addition to the active principle or principles, the usual supports such as for example lactose, talcum, silica, aluminium hydroxide, calcium silicate and polyamide powder or mixtures of these substances. In addition, sprays may contain the usual propellants, for example chlorofluorinated hydrocarbons .

If desired, the active principles can also occur in a microencapsulated form with one or more of the abovementioned support materials.

In addition to the 2-benzyl-perhydroazepines the pharmaceutical preparations may contain for example one or more pharmacologically active components belonging to other groups of pharmaceutical products, for example mild stimulants, such as caffeine analgesics, such as aminophenazone, acetyl salicylic acid ard d-propoxyphene; antidepressives such as Dibenzepin, Dcxepin, Maprotiline, Amitriptyline, Nortriptyline, Melitracenej tranquilisers, such as benzodiazepines, e.g. Diazepam, Chlordiazepoxide and Meprobamate, substances for promoting cerebral circulation and/or roborifacients, such as glutamic acid ard vitamins car combinations thereof.

Mammals which are suffering from primary or secondary disorders of the central nervous system from pain, or from pathological variations in the blood pressure, may be treated by a process which is characterised by the fact that the rnanmal in question is given a CNS- or analgesic effective Or a blood pressure-regulating and pharmacologically compatible quantity of one or more 2-benzyl-peehydroazepines and/or their pharmacologically tolerated salts.

The intermediate products uf the general formula I can be converted by known /5 methods into pharmacologically effective compounds of the general formula I, as set out in the following Examples. Thus, inter alia, one obtains from the free bases the acid addition salts by reaction with the corresponding acid. Ethers, that is to say those compounds in which one 2 3 4 5 or more of the substituents R , R , R , R represent an alkoxy group are converted by acid hydrolysis, for example with hydrogen halide, into the free hydroxy canpounds. Esters, that is to say those compounds in which one or more of the substituents X, /, , R** represent an acyloxy group, are converted by alkaline hydrolysis, for example witn sodium hydroxide, into tne free hydroxy compounds.- Thefree hydroxy compounds, that is to say those in which one or 2 3 4 5 more of the substituents R , R , R , R signify an OH group, can be etherified or esterified. <.6 Λ further object of the invention is a process for the production of 2-benzyl-perhydroazepines of the general formula I and their acid addition salts in which A) 2-benzyl-azacycloheptane in which Ru and of the general formula II V Λ k X Z- signifies one of the groupings N CHg-, ^'N^'CH-, . O*^N^CH2- and 'Sj'X, R7 i„ CfI2· (b) (c) I NO (d) R.6 signifies an aliphatic or alicyclic hydrocarbon radical, a cycloalkylalkyl group or an aralkyl group and R signifies a hydrogen atom, an aliphatic or alicyclic hydrocarbon radical,a cycloalkylalkyl radical, cr an aralkyl group is reduced and if desired then N-alkylated or N-de-alkylated and/or functionalised and/or the free base obtained is converted into an acid addition salt oe an acid addition salt is converted into the free base.

B) a 2-benzyl-azacycloheptane of the general formula III (G)_ Ir CH, (Ill), in which id has the meaning given above and G signifies a hydrogen atom or a grcup wnich can be functionalised (as herein defined) and n is a whole number from 1 to 4, preferably 1 to 2, especially 1, is functionalised as herein defined, and if desired is then N-alkylatel or N-de-alkylated and/or the free baseobtained is converted into an acid addition salt or an acid addition salt is converted· into tiie free base, or C) a N-acyl-2-benzyl-azacycloheptane of the general formula IV CO-R (IV), in which R2, R3, R4 and R5 have the meanings given above and o R signifies an aliphatic hydrocarbon radical, a cycloalkyl radical or a cycloalkylalkyl radical, an optionally substituted phenyl radical or phenalkyl radical, to produce compounds in which R3 is other than an alicyclic hydrocarbon radical or methyl, is reduced and if desired is then functionalised as herein defined and/or N-de-alkylated and/or the free base obtained is converted into an acid addition salt or an acid addition salt is converted into the free base. 10 The reduction of.the substituted 2-benzyl-azacycloheptanes of the general formula II is preferably carried out with hydrogen in organic solvents, as known in the art for hydrogenation reactions, for example ethanol, methanol, cyclohexane, isopropanol, dimethylformamide, in the presence of metallic catalysts, for example platinum, platinum on active-carbon, palladium, palladium on active carbon, Raney nickel, under pressures of 1 to 500 atmospheres and at temperatures around room temperature, for example 0 to 50°C. The reduction of the compounds of the formula Ila and lib is alternatively carried out in the form of their acid addition salts in aqueous alcoholic solution with sodium borohydride in the manner usual in the art (cf. Enamines:Synthesis, Structure and Reactions edited by A. Gilbert Cook pages 185 et seqq.; Marcel Dekker, New York and London 1969) . /9 The reduction of the compounds lie is effected with lithium aluminium hydride in inert solvents, such as ethers, e.g. diethyl ether, tetrahydrofuran, dioxan, 1,2-dimethoxyethane or diethyleneglycol diethyl ether, at temperatures between 0°C and the boiling temperature of the solvent, preferably between 20°C and 70°C. The reduction of the compounds lid is effected alternatively by reaction with hydrogen halides, preferably hydrogen chloride, in inert solvents, e.g. benzene, in analogy to the process described in Synthesis 1976, Tha compounds of the general formula Ila·to be used as initial compounds 3 4 5 in which R , R , R and R have the meanings given above, are obtained for example by reacting 2-benzylideneazacycloheptanes of the general formula V 3 4 5 in which Π , R , Π and R have the meanings given above, with strong mineral acids. The hydrolysis and simultaneous decarboxylation of the nitriles V is carried out with mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, preferably concentrated hydrochloric acid, at temperatures between room temperature and 120°C, preferably by heating the relevant solution under a reflux until the evolution of carbon dioxide ceases. The resultant imines Ila are relatively unstable compounds so that it is wise to hydrogenate them to-form the perhydroazepines straight away.

The henzylidene compounds V are obtained for example by the process described by T. Kametami and others (J.Chem.Soc.,Perkin I 1976, 389; Heterocycles 3 [l975] 691)· In this a caprolactam ether, preferably caprolact^mmethyl ether, is reacted with a corresponding arylacetonitrile, for example 4-chlorophenylacetonitrile, in the presence of an auxiliary base, such as diazabicycloundecene, diazabicyclononene, triethylamine, ethyldiisopropylamine, either without solvent or in the presence of an inert solvent such as benzene, toluene, xylene , or cyclohexane, at temperatures of 50 to 150°C, preferably 100 to 130°C, and optionally under an inert gas, for example nitrogen. It is preferable to carry out the reaction without using an inert solvent.

The initial compounds lib can be prepared according to various processes. For example they can be obtained by reacting N-substituted caprolactam derivatives VI with phenylacetic acid derivatives VII to form tho benzylidene compounds VIII follcwed by their hydrolysis ard decarboxylation according to the following reaction scheme VIII lib in which 3 li 5 6 R , R , R , R and R have the meanings given above and 12 R signifies a -0-R group or a ,13 . group, ^•R R signifies a -CN or -CO-O-R ' group, 12 11 14 15 R , R , R , R and R J are the same or different and signify an alkyl radical with 1 to 5 carbon atoms, preferably a methyl or ethyl group, and R also signifies a phenyl radical, or else R and 10 -0-R jointly represent an alkylidenedioxy group with up to 4, preferably 2, carbon atoms.

The reaction of the caprolactam derivative VI with the phenylacetic acid derivatives VII is generally carried out at temperatures of 20 to 150°C, preferably between 40 and 100°C, without or preferably with the addition of inert organic solvents such as aliphatic hydrocarbons, for example petrol ether, light petrol, ligroin, or else cycloaliphatic hydrocarbons for example cyclohexane, or aromatic hydrocarbons, for example benzene, toluene, xylene. The hydrolysis and simultaneous decarboxylation of the benzylidene derivatives VIII (esters or acetonitriles) is carried out by the action of mineral acids, such as hydrochloric acid, hydrobromic acid, preferably concentrated hydrochloric acid, at temperatures between room temperature and 120°C, preferably by heating the corresponding solution under reflux until the evolution of CO^ ceases. The enamines lib resulting from the esters VIII or the corresponding acetonitriles are relatively unstable compounds and are generally further processed immediately, that is to say hydrogenated to form the compounds according to the invention. Because of their stability and their easy accossibility and also because of the instability of the enamines lib the esters VIII or the corresponding acetonitriles constitute interesting and valuable intermediate products for the production of the 2-benzylperhydroazepineS I according to the invention.

The N-substituted caprolactam derivatives VI are known compounds or are obtained by known processes. 12 The acid amideacetals VI (Ic : -O-R ) are obtained for example by reacting N-alkyl-caprolactam with alkylating agents such as dimethylsulphate, diethylsulphate, alkyl p-toluenesulphonates, to form the salts IX (formula below) (R : -O-R ) and their subsequent reaction with alkali metal alccholates, such as sodium methylate or ethylate. Arainal esters VI , Q 13 14 (R : -NR n ) are obtained by reacting the salts IX 9 1 3 l4 (R : -NR ) with alkali metal alcoholates, such as sodium methylate or ethylate, in inert solvents such as benzene. ethers, for example diethyl ether.

The initial compounds lib) are obtained according to a further process by reacting azepinium salts IX with phenylacetic acid derivatives VII in the prestence of strong bases to form the benzylidene compounds VIII and their hydrolysis and decarboxylation in.accordance with the following equation 9 in which R and R have the meanings given above, and L® signifies an 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 solvent in the presence of strong bases, such as solutions of alkali metal alcoholates, for example sodium methylate, potassium methylate, potassium propylate, sodium isopropylate, potassium butylate, • 46629 potassium tert.-butylate, potassium tert-pentylate, arxl especially sodium ethylate, at temperatures of 20 to 150°C, preferably 80 to 100°C. If desired the reaction is carried out whilst passing through an inert gas, such as nitrogen, in order to remove any volatile amine which is formed. However, the reaction can also be carried out with the addition of inert solvents, such as alcohols, for example methanol, ethanol, propanol, isopropanol, butanols, or pentanols; tertiary nitrogen bases, for example pyridine; or hydrocarbons, for example benzene. The hydrolysis and decarboxylation of the benzylidene compounds VIII is carried out analogously to the processes described above.

The production of the salts IX, of which those with 13 14 R in the meaning of a -NR R group are preferred, is carried out for example in analogy to II.Bredereck and others (Chem.Ber. 1964, 3θθΐ) by the reaction of the corresponding N-substituted caprolactams with alkylating agents, such as diethylsulphate, methyliodide and preferably dimethylsulphate, in inert solvents at room temperature up to 120°C, preferably without solvents at temperatures around 80°C and, if in the salts IX / represents a -NR^r*^ 14 group, subsequent reaction with the amines IINR R or also by reacting the corresponding caprolactams with inorganic acid chlorides, such as phosphorus oxychloride,or >46629 14 phosgene followed by reaction with the amines HNR Π in inert solvents, such as benzene, at temperatures between 0 and 100°C, preferably between 20 and 60°C, or without solvents at temperatures between 0 and 100°C, preferably between 40 and 80°C.

The initial compounds lie are obtained according to methods known in the art. Starting compounds lie wherein R signifies a hydrogen atom are obtained, e.g. by rearrangement of the corresponding 2-benzylcyclohexanones according to the process described by T. Duong et al. [Austr.J,Chem. 29 (1976) 2667-82, particularly page 2681]. They are also obtained by functionalisation of 7-benzylhexahydroazepin2-one according to methods described in the following para7 graphs. Starting materials lie wherein R signifies an aliphatic or alicyclic hydrocarbon radical, a cycloalkylalkyl group or an aralkyl group are obtained by N-alkylation of tho corresponding 7-benzyl-hexahydroazepin-2-ones.

A convenient method, e.g. is described by T. Duong et al. [Austr.J.Chem. 29 (1976) 2651-65, particularly page 2660].

The initial compounds lid are obtained for example by lithiation of 1-nitrosoperhydroazepinsand subsequent reaction with corresponding benzyl halides, preferably bromides or iodides, in accordance with the process described in Synthesis 1976, 540-41.

The functionalisation of the 2-benzylperhydroazepinee III dr the optional subsequent functionalisation of the 2-benzylperhydroazepines I obtained by reduction or of the starting materials lie are carried out according to the nature of the substituents ultimately desired in the phenyl group as described in the follcwing six paragraphs.

The nitro group is introduced for example by nitration with nitric acid, nitric acid/sulphuric acid, potassium nitrate/sulphuric acid or an alkyl nitrate at temperatures 1θ from -20 to +50°C, preferably -20 to +30°C. In the initial compounds, e.g. Ill, G then signifies a hydrogen atom and 2 4 5 n =1, and in the end products R , R and R have the 3 meaning of a hydrogen atom and R has the meaning of an NO group in the para position. Under more severe conditions <2 dinitro compounds are obtained, that is to say R and R 2 3 have the meaning of a hydrogen atom and R and R that of a nitro group.

The amino group is introduced by the reduction of the NO group or groups of a corresponding nitro compound 2 with hydrogen over suitable catalysts, such as Pt, Pt/C, Pd, Pd/C or Raney nickel in the usual solvents, such as alcohols or cyclohexane. In the initial ccmpcunds .III, G then means one or two NOg groups and n = 1 (or 2), and 4 5 in the end products R , R have the meaning of a hydrogen 46639 3 atom and R and/or R that of an NHg group.

Halogen atoms, especially chlorine and bromine atoms, are introduced in the usual manner by halogenation of the ring. For the halogenation of the ring one uses as cata5 lysts iron, ferric chloride or bromide, aluminum chloride or bromide or' tin tetrachloride or iodine, the reaction being carried out without or in inert solvents, if desired also in glacial acetic acid without a catalyst at temperatures between 0 and 20°C.

Hydroxy groups are introduced by ether splitting of the corresponding alkoxy groups. In the initial compounds III, G then signifies an. alkoxy group, preferably a methoxy group, and n = 1 to 4, preferably 2, especially 1. The ether splitting is carried out, for example, by boi15 ling with hydriodic acid or hydrobromic acid or mixtures of hydrobromic acid/glacial acetic acid or by reaction with boron tribromide in inert solvents, such as chloroformordichioromethane, at temperatures of from -20 to 20°C.

The Etherification is carried out for example by 2° reacting corresponding hydroxy compounds (G in the initial compounds III then means a hydroxy groupj n = 1 to 4, preferably 2, especially 1) with alkyl halides in the presence of equivalent quantities Of alkali metal alcoholate for example sodium ethylate.

The functionalisation of free hydroxy groups or amino groups in the form of acylation or a possibly successive acylation is carried out according to methods known in the art for example by reaction with the correspon5 ding acid anhydrides or halides (cf. inter alia Houben Weyl, Vol. 8, pages 5^3 et seqq. or 655 et seqq.) The splitting off of acyl groups with the liberation of hydroxy groups or amino groups is carried out in the usual manner by saponification, for example by reaction with suitable ·*·° bases, such as caustic soda or potash.

N-alkylation, in which alkyl also includes cycloalkyl, aralkyl and cycloalkylalkyl, is carried out by methods known in the art . Thus the N-alkylation is carried out with alkylating agents, such as alkyl halides, alkyl sulphonates, for example tosylates, or alkylsulphates, in inert solvents such as acetone, methylethylketone, alcohols, such as methanol, ethanol iso-propanol or dimethylformamide or without solvents, using an auxiliary base, such as sodium carbonate, potassium carbonateortriethylamine, at temperatures from 20 to 100°C.

The N-de-alkylation, in which alkyl also includes cycloalkyl .cycloalkylalkyl and aralkyl, especially benzyl, is carried out according to known methods. The N-de-alkylation is carried out for example with chloroformate esters, such as ethyl chloroformate or β ,6, β,-trichloroethyl chloroformate, without or in the presence of inert solvents such as benzene, toluene, chloroform, at elevated temperature, preferably at the boiling point of the solvent. The intermediate product obtained is reacted with aqueous or alcoholic solutions of bases, such as caustic soda/ethanolorcaustic potash/butanol, at elevated temperature, preferably at the boiling point of the solvent, to form the corresponding de-alkylperhydro10 azepinq ,that is to say to form the compound of the general formula I in which R^ signifies a hydrogen atom.

The N-de-alkylation in the special form of de-benzylatxon, that is to say when using compounds of the formula I in which R = benzyl, is carried out by the hydrogenolysis in the presence of catalysts, preferably palladium on carbon, in solvents such as methanol, ethanol, benzene or cyclohexane, at 0 to 5O°C, preferably room temperature, and a hydrogen pressure of 1 to 300 atmospheres, preferably 1 to 5 atmospheres.

Acid addition salts are obtained by dissolving the free base in a suitable solvent, for example acetone, water, a low-molecular aliphatic alcohol (ethanol or isopropanol) or ether ( diethyl ether or tetrahydrofuran) which contains the desired acid, or to which the desired acid is afterwards 4ί added. The salts are recovered by filtration, precipitation with a non-solvent of the addition salt or by evaporating off the solvent.

The salts obtained, for example the hydrochlorides, can be converted into the free base by neutralisation with aqueous sodium or potassium hydroxide, and the base can then be recovered by solvent extraction using a suitable solvent which is not miscible with water, such as chloroform, dichioromethane, ether, benzene, toluene or cyclohexane. The free bases can also be obtained by neutralisation of an acid addition salt with sodium methylate in methanol and isolation of the base using known processes. Salts can also be converted into other salts, for example pharmacologically compatible acid addition salts, by conversion into the base followed by further reaction with an acid.

Any racemate splitting which may be necessary or desired is carried out in the usual manner, for example by mixing with an optically active acid, such as mandelic acid, tartaric acid, camphorsulphonic acid or dibenzoyltartaric acid, the recrystallisation of the resultant salt until the refractive index is constant and liberating the optically active base with alkalis. From the mother liquors occuring during the recrystallisation one obtains tlie other 466^9 enantiomer in an analogous fashion.

The reduction of the N-acyl-2-benzyl-azacycloheptanes of the general formula IV is carried out according to known methods, for example by reaction with a complex metallic hydride as reducing agent in an anhydrous organic solvent and hydrolytic working up. Suitable reducing agents include lithium aluminium hydride (lithium hydridoaluminate) as well as sodium dihydrido-bis-(2-methoxyethoxy)-aluminate· As solvents one may use inert anhydrous ethers, such as diethylether, tetrahydrofuran, dioxan, 1,2-dimethoxyethane and diethyleneglycoldiethylether, as well as aromatic hydrocarbons, such as benzene and toluene, or mixtures of the said compounds. The temperature of the reaction is not critical and can vary within wide limits, for example from 0 to 100°C. As a rule it is best to carry out the reaction at the reflux temperature of the reaction mixture. The duration-of the reaction depends upon the reaction temperature used and may vary between 1 hour and 24 hours. At the preferred reflux temperature the reaction normally ends in 3 to 4 hours. The reactants can be used in equivalent quantities, but an excess of the reducing agent is preferred. After the reaction with the reactant the reaction product is then processed by treating the reaction mixture with an aqueous medium such as water, dilute aqueous inorganic acids or bases or other media containing water. The product can be isolated as the free base or as acid addition salts by adjusting the pH.

The starting compounds of the general formula III are obtained for example by de-methylation of 2-benzyl-lmethylperhydroazepine (to III wherein Π : -H) and optionally subsequent N-alkylati,on (to III wherein R1: alkyl, cycloalkyl, aralkyl, cycloalkylalkyl).

The production of the initial compounds of the formula 10 IV is also carried out by methods which are known in the art for example by the acylation of the corresponding 2-benzylperhydroazepineSI (R = -II) with carboxylic acid halides, such as Cl-CO-R^, in which R^ has the meaning given above, or carboxylic acid anhydrides in inert solvents, such as benzene, toluene, cyclohexane, chloroform or diohloromethane, in the presence of an auxiliary base, such as pyridine or triethylamine, at temperatures between 0 and 50°C. Suitable carboxylic acid halides, for example, are acetyl chloride, propionyl chloride, butyryl chloride, pivaloyl chloride, cyclopropylcarbonyl chloride, cyclobutyicarbonyl chloride, benzoyl chloride or phenylacetyl chloride.

The following examples explain the invention in greater detail without restricting it. The abbreviation MP signifies melting point, BP signifies boiling point, dec. signifies decomposition. The temperatures are given in °C.

EXAMPLES Example 1 2-dimothylamino-l-methyl-4 ,5,6,7-tetrahydro-3H-azepinium methylsulphate 190 g of N-methylcaprolactam and l89 g of dimethylsulphate are stirred for 3 hours at 80°C , after cooling they are shaken with ether and then freed from solvent residues in vacuo. The light yellow oil so obtained (346 g) of 2-methoxy-l-methyl-4,5,6,7-tetrahydro-3H-azepinium methylsulphate is added drop by drop to a solution of 110 g of dimethylamine in 600 mis of benzene whilst stirring and is boiled under a reflux for 90 minutes.

The heavy phase is collected and extracted several times with ether. The yellowish oil is concentrated in vacuo.

Yield 336 g (93 % of theory).

Example 2 S-jjoC- (ethoxvcarbonyl)-4-chlorobenzvlidene]-ΐ-methvlpcrhydroazepine To a mixture of 53-2 g of 2-dimethylamino-l-methyl/i,5,6,7-tetrahydro-3II-azepinium methylsulphate and 29.8 g of ethyl 4-chlorophenylacetate one adds drop by drop at 90° in a stream of nitrogen a solution of 4.6 g of sodium in 100 mis of ethyl alcohol. When this is done the alcohol is removed from the reaction mixture. It is stirred for a further 4 hours at 90° , the cooled mixture is mixed with 100 mis of water, and 100 mis of ether, the organic phase is collected and dried over sodium sulphate. Any excess ethyl 4-chlorophenylacetate is removed after concentration by distilling off in high vacuum. Crude yield .5 S (34 li of theory), yellow oil.

Example 3 2-[c<- (ethoxycarbonyl)-314-dimethoxybenzylidene]-l-methylperhydroazepine According to the method described in Example 2, one obtains from 53.2 g of 2-dimethylamino-i-methyl-4,516,7tetrahydro-3H-azepinium methylsulphate, 33«6 S °f ethyl 3,4-dimethoxyphenylacetate and a solution of 4.6 g of sodium in 100 mis of ethyl alcohol the title compound as a viscous yellow oil with a BP of 175 to l80° (0.001 mm Hg) Yield 8.6 g (17 % of theory).

Example 4 2-[oC- (ethoxycarbonyl)-4-methoxybenzylidene]-1-methylper. hydroazepine Using the method described in Example 2 one obtains from 53·2 g of 2-dimethylamino-1-methyl-4,5,6,7-tetrahydro -3H-azepinium methylsulphate, 29.1 g of ethyl 4methoxyphenylacetate and a solution of 4.6 g in 100 mis of ethanol, the title compound as a viscous yellow oil with a BP of 1650 (0.001 mm Hg). Yield 15.6 g (34 % of theory).

Example 5 2-[06· (ethoxycarbonyl)-3-methoxybenzylidene]-l-methylperhydroazepins Using the mode of operation described in Example 2 one obtains from 7Α·9 g of 2-diinethylamino-l-methyl~4,5, 6,7-tetrahydro-3H-azepinium methylsulphate, 40 g of ethyl 3-methoxyphenylacetate and a solution of 6.4 g of sodium in l6o mis of ethanol, the title compound as a viscous oil. Yield 38.6 g (62 % of theory).

Example 6 2-(4-chlorobenzyl)-1-tnethylperhydroazepine 13.5 S of 2-[cA-(ethoxycarbonyl)-4-chlorobenzylidene]1 1-methylperhydroazepinfiand 110 mis of concentrated hydro]_5 chloric acid are boiled under a reflux until the evolution of C0o ceases, after cooling it is alkalised with caustic soda solution, whilst cooling with ice, and extracted with ether. The ether phase is concentrated and dried over sodium sulphate. The residual 2-(4-chlorobenzylidene)-1mcthylperhydroazepine(7.44 g) is dissolved in ethyl alcohol and hydrogenated with platinum/active carbon/hydrogen. The product, after filtering off the catalyst and distilling off the solvent is distilled in high vacuum. Yield 4.4 g wi-th a BP of 102 to 110° at 0.003 mm Hg.

The picrato (from ethyl alcohol) melts at 120-121°.

The reaction of the base with the equivalent quantity of the corresponding acid gives the following salts: Hibenzate: Citrate i Fumarate: Benzoate: Maleate: Embonate: colourless oil colourless oil light yellow oil light yellow oil light yellow oil yellow oil Example 7 2-(3,4-dimethoxybenzyl)-1-methyl-perhydroazepine Using the mode of operation described in Example 6 one obtains from 12.28 g 2-[oC-(ethoxycarbonyl)-3,4-dimethoxy benzylidene]-l-methylperhydroazepinethe title compound with a BP of 117° at 0.001 mm Hg.

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

Example 8 2-C (eZ-cyano)-benzylidene]-perhydroazepine 8.1 g of oaprolactan methyl ether, 5.0 g of benzyl cyanide and 0.6 g of 1,5-diazabicyclo[5.4.o]undec-5-ene are agitated under nitrogen for 48 hours at 130°; any excess benzyl cyanide is distilled off in high vacuum and the residue is rubbed down with a little methyl alcohol and filtered off. In this way one obtains the title compound (3.78 g), which is recrystallised from methyl alcohol for further purification. MP 108-113°· Example 9 2-[ (oC-cyano)-4-chlorobonzylidene]-perhydroazepine .0 g of 4-chlorobenzyl cyanide, 5-5 g of caprolactim methyl ether .and 0.5 g of diazabicyclo[5-,l-0]undec-5-ene are agitated under nitrogen for 18 hours at 125°· After cooling, the crystallising residue is rubbed down with 20 inis of methyl alcohol and filtered. In this way one obtains the title compound (5-5 g), which is recrystallised from methyl alcohol. MP 114-117°.

Example 10 2-(4-chlorobenzyl)-perhydroazepine 100 g of 2-[ (οί-cyano)-4-chlorobenzvlidene]-pcrhydroazepine and 1 litre of concentrated hydrochloric acid are boiled under a reflux until the evolution of carbon dioxide ceases, after cooling it is alkalised with caustic soda solution whilst cooling with ice and then extracted with ether. After drying over sodium sulphate, the ether extract is concentrated. The 2-‘(4-chlorobenzyl)-4,5,6,7-tetrahydro-3H-azepineso obtained a) is hydrogenated with platinum/active carbon/hydrogen, filtered off from the catalyst, concentrated and distilled 10 One obtains 61.9 g (68 %) with a BP of 93° at 0.1 nun Hg; or b) is dissolved in diluted hydrochloric acid (pH—'5) and mixed with 200 mis of methyl alcohol. 7 g of sodium borohydride are added in small parts within 20 minutes, the pH-value is kept constant by occasional addition of hydrochloric acid. It is stirred for 1 hour, rendered alkaline with caustic soda solution and extracted with diohloromethane. The organic phase is dried over sodium sulphate, concentrated and distilled. One obtains 58 g with a BP of 93° at 0.1 mm Hg.

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

Example 11 2-benzylperhydroazepine Using the mode of operation described in Example 10, one obtains from 15 g of 2-[(cZ-cyano)-benzylidene]-perhydroazepine and 177 mis of concentrated hydrochloric acid 7.46 g (56 % of theory) of the title compound with > a BP of 88° at 0.007 mm Hg.

The hydrochloride (from methyl alcohol/ether) melts at 164-167°.

Example 12 l-ethyl-2-(4-chlorobenzyl)-perhydroazepine g of 2-(4-chlorobenzyl)-perhydroazepine, 2.5 S of anhydrous potassium carbonate and 2.9 g of ethyl bromide are boiled under a reflux for 26 hours in 30 mis of ethylmethylketone whilst agitating, after cooling it is mixed with water and extracted with ether. The organic phase is dried over sodium sulphate, the ether is withdrawn and the residue distilled. One obtains 5«12 g 5 (70 %) with a BP of 112° at 0.005 mm Hg.

Example 13 l-allyl-2-(4-chlorobenzyl)-perhydroazepine Using the mode of operation described in Example 12 6 6 29 one obtains from 8 g of 2-(4-chlorobenzyl)-perhydroazepine, g of anhydrous potassium carbonate and 8.7 g of allyl bromide, 6.76 g (72 % of theory) of the title compound with a BP of 110° at 0.02 mm Hg.

Example l4 2-(4-chlorobenzyl)-1-isopropylperhydroazepine 5 Using the mode of operation described in Example 12 one obtains from 5·8 g of 2-(4-chlorobenzyl)-perhydroazepine 3.6 g of anhydrous potassium carbonate and 6.6 g of isopropyl iodide 3.9 g of the title compound with a BP of 113° at 0.03 mm Hg (56 % of theory).

Example 15 2-(4-chlorobenzyl)-1-hexylperhydroazepine 10 Using the mode of operation described in Example 12 one obtains from 5 g of 2-(4-chlorobenzyl)-perhydroazepine, 3.1 g of anhydrous potassium carbonate and 4 g of 1-bromohexane, 3·θ7 g (56 % of theory) of the title compound with a BP of 129° at 0.005 mm Hg.

Example 16 2-(4-nitrobenzyl)-perhydroazepine To 43 mis of concentrated sulphuric acid one adds drop by drop whilst stirring at -10° 10 g of 2-benzylperhydroazepine then at the same temperature one adds 33 mis of concentrated nitric acid, it is allowed to heat slowly to room temperature and stirred for a further hour. One pours it into 500 g of ice, alkalises it with 6 N caustic soda solution and extracts it with ether. After drying the organic phase over sodium sulphate the solvent is distilled off. There remain 12.0 g (97 % of theory) of the title compound as a red oil.

Example 17 2-(4-aminobenzyl)-perhydroazepine 12 g of 2-(4-nitrobenzyl)-perhydroazepine are hydrogenated in 300 mis of ethyl alcohol with platinum/hydrogen. After the absorption of hydrogen has ceased, it is filtered off from the catalyst and the filtrate is concentrated. There remains the title compound as a dark brown viscous oil. Yield 10.5 g (100 % of theory).

The benzoate (from isopropanol) melts at l86-190°(dec.).

Example 18 1-sec .-butyl-2-(4-chlorobenzvl)-perhydroazepine Using the mode of operation described in Example 12 one obtains from 5.0 g 2-(4-chlorobenzyl)-perhydroazepine 4.0 g of anhydrous potassium carbonate and 3.0 g of sec.-butyl bromide, 3.2 g of the title compound.

Example 19 2-(4-chlorobenzyl)-1-neopentylperhydroazepiiB· Using the mode of operation described in Example 12 one obtains from 5.0 S of 2-(4-chlorobenzyl)-perhydro5 azepine 4.0 g of anhydrous potassium carbonate and 3.6 S of neopentyl bromide, 3·9 S of the title compound.

Example 20 2-(4-chlorobenzyl)-l-cyclohexylperhydroazepine Using the mode of operation described in Example 12 one obtains from 5 S of 2-(4-chlorobenzyl)-perhydroazepine 3.1 g of anhydrous potassium carbonate and 4 g of cyclo10 hexyl bromide, 2.35 g of the title compound.

Example 21 i-methyl-2-(4-nitrobenzyl)-perhydroazepine Using the mode of operation described in Example 12 one obtains from 2.3¾ S Of 2-(4-nitrobenzyl)-perhydroazepine 1.4 g of anhydrous potassium carbonate and 1.5 g of methyl iodide, 1.9 g of the title compound as a red oil. ;5 Example 22 2-(4-aminobenzyl)-1-me thyl-p erhydroaz ep ine Using the mode of operation described in Example 17 one obtains from 3·45 g of l-methyl-2-(4-nitrobenzyl)perhydroazepiie by hydrogenation with Pt02/hydrogen 2.9 S of the oily title compound.

Example 23 2-(4-diethylaminobenzyl)-1-methyl-perhydroazepine 5 2.18 g of 2-(4-amxnobenzyl)-l-methyl-perhydroazepine 2.0 g of anhydrous potassium carbonate and 3.1 S of diethyl sulphate are stirred at l4o° for 7 hours. After cooling, the suspension is mixed with water and poured into caustic soda solution and extracted with diethyl ether. The organic phase is dried over sodium sulphate and the ether is distilled off. Residue 1.9 S (70 % yield).

Example 24 2-b enzyl-1-me thylp erhydro az ep ine Using the mode of operation described in Example 12 one obtains from 4.0 g of 2-benzyl-perhydroazepine,2.9 S of anhydrous potassium carbonate and 3·3 S of methyl iodide, 2.4 g of the title compound with a BP of 68° at 0.003 mm Hg (56 % of theory). 6 6 29 The picrate melts at 116-118°.

Example 25 2-(4-bromobenzyl)-1-methylperhydroazepine 2.03 g of 2-benzyl-l-methyl-perhydroazepineand 50 mg of iron powder are mixed with 10 mmoles of bromine at room temperature. It is stirred for 2 hours, rendered alkaline with caustic soda solution, and the base is extracted with ether, distilled and in this way one obtains 2-(4-bromobenzyl)-1-methyl-perhydroazepineas an oily and almost colourless liquid with a BP of 108° at 0.003 mm Hg.

Example 26 2-(3,4-dihydroxybenzyl)-1-methyl-perhydroazepine ·0 S of 2-(3,4-dimethoxybenzyl)-1-methyl-perhydroazepineare boiled under a reflux in a mixture of 45 mis of acetic acid and 45 mis of 48 % hydrobromic acid for 40 hours. The bulk of the acid is removed by distillation in vacuo, the residue is taken up with iced water and alkalised L5 with soda solution. After extracting the base for several hours with ether, after distilling off the solvent the residue obtained (4.0 g) is converted into the hydrochloride with methyl alcohol/ethereal hydrochloric acid. Yield 3-0 g.

Example 27 2- [ Using the mode of operation described in Example 2 one obtains from 50 g of 2-dimethylamino-l-methyl-4,5,6,7tetrahydro-3H-azepinium methylsulphate, 35·6 g of ethyl 3,4,5-ti'iine'fcIi.oxyphenyl acetate and a solution of 4.32 g of sodium in 100 mis of ethanol, 14.23 g of the title compound as a viscous oil (28 % of theory).

Example 28 2-benzyl-l-cyclopropylcarbonyl-perhydroazepine To 7-0 g of 2-benzyl-perhydroazepine and 4.1 g of triethylamine in 70 mis of dichloromethane one adds drop cyclopropanecarboxyli c by drop at 0 to 8° 4.3 g of / acid chloride in 40 mis of dichloromethane. The stirring is continued for a further 2 hours at 0°, it is mixed with 300 mis of water, the organic phase is separated, it is extracted again with dichloromethane, the combined organic phases are washed with dilute hydrochloric acid and soda solution, dried over sodium sulphate and concentrated to form a viscous oil. Yield 9·2 g (97 % of theory).

Example 29 2-benzyl-l-cyclopropylmethyl-perhydroazepine 9.0 g of 2-benzyl-l-cyclOpropylcarbonyl-perhydroazepine, dissolved in 80 mis of tetrahydrofuran, is added drop by drop whilst stirring at 0° over a period of 10 minutes to a suspension of i.30 g of lithium aluminium hydride (= lithium hydridoaluminate) in 30 mis of tetrahydrofuran.

Then it is boiled for 1.5 hours under a reflux, a further 2.0 g of lithium aluminium hydride is added, it is boiled for a further 3·5 hours under a reflux and after cooling one adds carefully 300 mis of water and extracts 3 times with 50 mis of ether each time. The combined ether solutions are washed with saturated common salt solution, it is dried over sodium sulphate and the residue is distilled after evaporating off the solvent in vacuo. Yield 5.89 g with a BP of 115° at 0.01 mm Hg.

Example 30 l-acetyl-2-benzyl-perhydroazepine 15 Using the mode of operation described in Example 28 one obtains from 6 g of 2-benzyl-perhydroazepine, 4.14 g of triethylamine and 2.65 g of acetyl chloride, 5·θ g of a viscous oil.

Example 31 1- ethyl-2-benzyl-perhydroazepine Using the mode of operation described in Example 29 one obtains from 2.5 g of l-acetyl-2-benzyl-perhydroazepine and 0.80 g of lithium aluminium hydride 1.2 g of an oil with a BP of 90-95° at 0.008 mm Hg.

Example 32 2- (4-chlorobenzyl)-1-cyclopropylcarbonyl-perhydroazepire ’ Using the mode of operation described in Example 28 one obtains from 6 g of 2-(4-chlorobenzyl)-perhydroazepine 4.14 g of triethylamine and 4.30 g of cyclopropanecarboxylic acid chloride 6.2 g of a viscous light yellow oil.

Example 33 2-(4-chlorobenzyl)-1-cyclopropylmethyl-perhydroazepine Using the mode of operation described in Example 29 one obtains from 5·0 g of 2-(4-chlorobenzyl)-1-cyclopropylcarbonyl-perhydroazepineand 1.4 g of lithium aluminium hydride 3.2 g of a colourless oily liquid with a BP of 100-105° at 0.01 mm Hg. 6 6 2 9 υυ Example 34 2-(4-acetylaminobenzyl)-1-methyl-perhydroazepine To a solution of 1.9 g of 2-(4-aminobenzyl)-1-methylperhydroazepiie and 1 g of triethylamine in 10 mis of benzene one adds drop by drop a solution of 0.75 S of acetyl chloride in 5 mis of benzene. After an hour one 1 concentrates the product, takes it up with water and ether, collects the organic phase and concentrates it.

Example 35 2-(4-methoxybenzyl)-perhydroazepine 6.5 S °f caprolactimmethylether, 5.0 S of 4-methoxybenzyl cyanide and 0.5 S of 1,5-diazabicyclo[5·4.0]undec5-ene are stirred under nitrogen for 18 hours at 125°, volatile components are removed in high vacuum and the viscous dark residue (2-[(<<-cyano)-4-methoxybenzylidene]perhydroazepine) is boiled with 5θ mis of concentrated hydrochloric acid under a reflux until the evolution of carbon dioxide ceases. After cooling, it is alkalised whilst 3 cooling, extracted with ether and the ether extract after drying over sodium sulphate is concentrated. The 2-(4methoxybenzyl)-4,516,7-tetrahydro-3H-azepine so obtained is hydrogenated with platinum/active carbon/hydrogen in ethyl alcohol, filtered off from the catalyst, concentrated 6 29 and distilled. One obtains the title compound with a BP of 100-106° at 0.01 mm Hg.

Example 36 2-(3-methoxybenzyl)-perhydroazepine Using the mode of operation described in Example 35 one obtains from caprolactimmethyl ether, 3"ittethoxybenzyl 5 cyanide and l,5-diazabicyclo[5.4.o]-undec-5-ene the title compound as an oil with a BP of 98-103° at 0.01 mm Hg.

Example 37 2-(4-methoxybenzyl)-i-methyl-perhydroazepins Using the mode of operation described in Example 12 one obtains from 2.19 g of 2-(4-methoxybenzyl)-perhydroazepine,2.9 g of methyl iodide and 2.1 g of anhydrous potassium carbonate the title compound as a light-coloured oil.

Example 38 2-(3-methoxybenzyl)-1-methyl-perhydroazepine Using the mode of operation described in Example 12, one obtains from 2-(3-methoxybenzyl)-perhydroazepine, methyl iodide and potassium carbonate the title compound as an. oil with a BP of 110-115° at 0.01 mm Hg. 6 6^9 Example 39 2-(4-chlorobenzyl)-1-(3-(4-fluorobenzoyl)-propyl]-perhydroazepine g of 2-(4-chlorobenzyl)-perhydroazepine 2.7 g of CJ-chloro-4-fluoro-butyrophenone, 1.89 S of potassium carbonate and 10 mis of methylethylketone are boiled under a reflux for 70 hours and after cooling are mixed with mis of water and 25 mis of ether. The ether phase is collected, dried over sodium sulphate, concentrated and dried in high vacuum at. 80°. Yield 1.0 g of viscous light-brown oil.

Example 40 2-(4-chlorobenzyl)-1-[4-(4-fluorophenyl)-butyl]-perhydroazepine 0.5 g of 2-(4-chlorobenzyl)-1-[3-(4-fluorobenzoyl)10 propyl]-perhydroazepine are heated with 1 ml of hydrazine hydrate, 0.5 g of potassium hydroxide and 5 mis of triglycol for 2 hours at 165° and after cooling are mixed with water and ether. The ether phase is dried over sodium sulphate and then concentrated. Yield 0.3 g of viscous oil Example 4l 1- benZyl-2-(4-chlorobenzyl)-perhydroazepine Using the mode of operation described in Example 12, one obtains from 5 S of 2-(4-chlorobenzyl)-perhydroazepine, 3.2 g of anhydrous potassium carbonate and 2.83 g of benzyl chloride, 3»95 S of the oily title compound.

Example 42 2- (4-chlorobenzyl)-perhydroazepine 3.0 g of l-benzyl-2-(4-chlorobenzyl)-perhydroazepine are hydrogenated in 50 mis of ethyl alcohol with 10 % of palladium on active carbon. After filtering off the catalyst, it is concentrated and the residue is converted into the hydrochloride with ethereal hydrochloric acid, and after this has been recrystallised from methyl alcohol/ ether it melts at 176-178°.

Example 43 2-(4-chlorobenzyl)-perhydroazepine 4.0 g of 2-(4-chlorobenzyl)-l-methylperhydroazepine are boiled under a reflux for 5 hours with 20 mis of ethyl chloroformate, the excess chloroformate ester is distilled off and the residual crude l-ethoxycarbonyl-2-(4-chlorobenzyl)-perhydroazepine is boiled with 100 mis of n-butanol e ο η» 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 diohloromethane. The combined organic phases are concentrated and the oily residue is converted with ethereal hydrochloric acid into the hydrochloride, which is recrystailised from methyl alcohol/ ether. Yield 2.2 g (50 % of theory) with an MP of 177-178°, Analogously, by reacting l-benzyl-2-(4-chlorobenzyl)perhydroazepinewith ethyl chloroformate followed by sa10 ponification with potassium hydroxide in butyl alcohol one obtains the title compound.

Example 44 2-[ (oC-cyano)-2-chlorobenzyiidenel-perhydroazepine Using the mode of operation described in Example 9 one obtains from 5.0 g of 2-chlorobenzyl cyanide, 5*5 g of caprolactimmethyl ether and 0.5 g of diazabicyclo15 [5.4.o]undec-5-ene, 4.5 g of the oily title compound.

Example 45 2-(2-chlorobenzyl)-perhydroazepine Using the mode of operation described in Example 10, one obtains from 4.0 g of 2-[(><-cyano)-2-chlorobenzylidene] perhydroazepine1.9 g (52 %) of the title compound with a tf BP of 100-106° at 0.05 mm Hg.

Example 46 2-[ (o^-cyano)-3-chlorobenzylidene]-perhydroazepine Using the mode of operation described in Example 9 one obtains 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 4.5 g of the oily title compound.

Example 47 2-(3-chlorobenzyl)-perhydroazepine Using the mode of operation described in Example 10, one obtains from 4.0 g of 2-[(Λ-cyano)-3-chlorobenzylidene]perhydroazepine2.2 g (60 %) of the title compound with a BP of 98-103° at 0.01 mm Hg.

Example 48 2-(3-chlorobenzyl)-1-methyl-perhydroazepine Using the mode of operation described in Example 12 one obtains from 2.5 g of 2-(3-chlorobenzyl)-perhydroazepine, 1.5 g of anhydrous potassium carbonate and 1.5 g of methyl iodide 2.0 g of the title compound. υ ϋ Λ σ ζ6 Example 49 2- [οι.- (ethoxycarbonyl) - 2-chlorobenzylidene] -1-me thyl-perhydro azepiis Using the mode of operation described in Example 2, one obtains from 80.2 g of 2-dimethylamino-l-methyl^i5,6,7-tetrahydro-3H-azepinium methylsulphate and 40 g of ethyl 2-chlorophenylacetate the title compound as a dark viscous oil.

Example $0 2-(2-chlorobenzyl)-1-methyl-perhydroazepine Using the mode of operation described in Example 6, one obtains from 2-[X-(ethoxycarbonyl)-2-chlorobenzylidene] 1-methyl-perhydroazepine the title compound as a lightcoloured oil with a BP of 134° at 0.01 mm Hg.

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

Example 51 7-(4-chlorobenzyl)-perhydroazepin-2-one To an ice-cold solution of 4.47 S of 2-(4-chlorobenzyl)cyclohexanone in 100 g of polyphosphoric acid one adds 2.6 g of sodium azide whilst stirring. The mixture is stirred for another 1.5 hours at 0° and for a further 8 hours at room temperature, poured into ice water and extracted with methylene chloride. After drying the organic phase over sodium sulphate the solvent is distilled off. There remain 2.85 g of the title compound as a light brown oil.

Example 52 2-(4-chlorobenzyl)-perhydroazepine 0.5 g of lithium aluminium hydride are added to a solution of 2.8 g 7-(^-chlorobenzyl)-perhydroazepin-2one in 30 ml of tetrahydrofuran. The mixture is boiled under a reflux for i6 hours, cooled and carefully treated with ice-water. After extraction with diethyl ether, drying over sodium sulphate and concentrating the oily residue is distilled in a vacuum. One obtains 1.8 g of the title compound with a BP of 90-92° at 0.05 mm Hg.

Example 53 2-(4-aminobenzyl)-perhydroazepine 3.72 g of 7-(4-nitrobenzyl)-perhydroazepin-2-one are hydrogenated in 50 mis of ethyl alcohol with platinum/ hydrogen. After the absorption of hydrogen has ceased, it is filtered off from the catalyst and the filtrate is concentrated. The thus obtained 7-(4-aminobenzyl)perhydroazepin-2-one is dissolved in tetrahydrofuran, 6 6 29 · 680 mg of lithium aluminium hydride are added and the mixture is boiled under a reflux. After cooling it is treated with ice-water and extracted with diethyl ether. The organic phase is dried over sodium sulphate and con5 centrated. There remain 2.0 g of the brown oily title compound.

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

Example 54 2-(2-methoxybenzyl)-perhydroazepine 10 Using the mode of operation described in Example 52 one obtains from 2.8 g of 7-(2-methoxybenzyl)-perhydroazepin-2-one and 0.5 g of lithium aluminium hydride 1.5 S of ths title compound as oil with a BP of 95-100° at 0.01 mm Hg.

Example 55 2-(4-methylbenzyl)-perhydroazepine Using the mode of operation described in Example 52 one obtains from 2.8 g of 7-(4-methylbenzyl)-perhydroazepin 2-one and 0.5 g of lithium aluminium hydride 1.6 g of the title compound as oil with a BP of 82-85° at 0.01 mm Hg Example 56 2-(4-chlorobenzyl)-perhydroazepine A solution of 10 mmol of n-butyllithium in n-hexane is added to a solution of 1.01 g of diisopropylamine in 100 ml of tetrahydrofuran at -78° and passing argon. The mixture is stirred for 5 minutes at room temperature and then cooled down again to -78°. A solution of 1.28 g of N-nitrosoperhydroazepineis added and stirred for 1 hour.

Then, 4.1 g of 4-chlorobenzyl bromide in a small amount of diethyl ether are added. After stirring for another 5 hours at -780 5 ml of glacial acetic acid are added.

The mixture is warmed up to room temperature poured into 100 ml of dichioromethane saturated sodium chloride solution. The organic phase is freed from the solvent and then dis15 solved in methanol. After addition of 2 g of Raney nickel freshly prepared, hydrogen is passed through the solution whilst stirring vigorously. Catalyst is filtered off and washed with methanol, the methanolic filtrate is concentrated. By treating the oily residue with ethanol/ethereal hydrochloric acid one obtains the hydrochloride of the title compound; m.p. 176-1780.

Example 57 Charge for 100 litres (ampoules) 1. 2-(4-chlorobenzyl)-1-isopropyl-perhydroazepine 2.500 kg 2. Mannitol 4.000 kg 3. Twice-distilled water up to 100 litres is dissolved in 80 litres of water with the addition of the equivalent quantity of hydrochloric acid and then J. is added. The solution is adjusted to a pH of 7·0 - 0.5 and then made up with the rest of the water. The solution is filtered sterile over a filter and packed into 2-ml ampoules under germ-free conditions.

Example 58 Charge for tablets 1. 2-(4-chlorobenzyl)-perhydroazepine hydrochloride 10.0 kg 15 2. Glutamic acid 5.0 kg 3· Maize starch 38.0 kg 4. Milk sugar 37-0 kg n '> 5· Aerosil 1.5 kg 6. Sodium lauryl sulphate 2.0 kg 20 7· Gelatin 2.5 kg 8. Glycerine 0.5 kg 9. Talcum 2.5 kg .Magnesium stearate 1.0 kg ia mixed with 5 kg of 4 and ground finely. This mixture is mixed with 1 and 30 kg of 3, the rest of 4, 5 and 6, and sifted. This mixture is moistened with a solution of 7 and 8 in 35 litres of water and passed through a strainer with a mesh of 1.25 mm. After drying, the granulate is mixed with the rest of 3, 9 and 10, and pressed into tablets of 200 mg. .0 kg 8.5 kg .0 kg 22.2 kg 3.0 kg 8.5 kg 2.5 kg 0.3 kg Example 59 Charge for tablets 1. 2-(4-aminobenzyl)-perhydroazepinebenzoate 2. Cellulose (Rehocel®) 3. Milk sugar 4. Maize starch (¢5) . Polyvinylpyrrolidone (Kollidon4* 25) 15 6. Carboxymethylcellulose (Primojel) 7. Talcum 8. Magnesium stearate 1, 2, 3 and 4 are mixed, moistened with 5 (dissolved in 15 litres of water) and granulated. After this it is 20 pre-dried in the drying oven at 50° and then passed through a sieve. The granulate is dried to a relative humidity of 45 to 50 % and after the addition of 6, 7 and 8 and careful mixing is pressed into tablets with a weight of 100 mg (δΟΟίΐΰ Ο Example 6θ Charge for tablets 2-(4-ohlorobenzyl)-pi erhydroazepine hydrochloride 25.0 kg Cellulose (RehoceJ^) 8.5 kg Milk sugar 30.0 RS Maize starch (Kollidoi^ 25) 22.2 kg Polyvinylpyrrolidone 3.0 kg Carboxymethylcellulo; 3e (Primojel) 8.5 kg Talcum 2.5 Rg Magnesium stearate 0.3 Rg 1, 2, 3 and 4 are mixed, moistened with 5 (dissolved in 15 litres of water) and granulated. After this it is pre-dried in the drying cabinet at 50° and then passed through a sieve. The granulate is dried to a relative humidity of 45 to 50 % and after the addition of 6, 7, and careful mixing is pressed into tablets with a weight of 100 mg.

Aerosil1' is a Registered Trade Hark

Claims (20)

1. 2-benzyl-perhydroazepinesof the general formula I R 5 in which R 1 signifies a hydrogen atom, an aliphatic or 5 alicyclic hydrocarbon radioal, a cycloalkylalkyl group or a mano-aryl-alkyl group as herein defined, and R Z , R 3 , / and R 3 are the same or different and each signify a hydrogen atom, a halogen atom, an alkyl group, a hydroxy group, an alkoxy group, an acyloxy group, an 10 optionally substituted amino group, a nitro group, an optionally substituted phenyl group, with R 1 not being 2 3- 4 5 methyl if R , R , R and R mean hydrogen and their acid addition salts. 4 6 6,3.9 /'4

2. 2-benzyl-perhydroazepines of the general formula I (I*) 1* in which R signifies a hydrogen atom, a straight-chained or branched aliphatic hydrocarbon radical with 1 to 6 carbon 5 atoms, a cycloalkylalkyl group with 1 or 2 carbon atoms in the alkyl radical and 3 to 5 carbon atoms in the cycloalkyl radical, or a phenylalkyl group with 1 to 4 carbon atoms in the alkyl radical which may be monosubstituted in the phenyl radical by a halogen atom, an alkyl or an alkoxy group with 10 1 to 4 carbon atoms and which may be monosubstituted in the alkyl radical by a hydroxy or oxo group, 2* R signifies 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 15 carbon atoms, an amino group, a dialkylamino group with 1 to 2 carbon atoms per alkyl radical, a nitro group or a phenyl group which may be substituted in the para position, and 4 6 6 29 /5

3. * 4* 5* R , R and R each signify a hydrogen atcm, 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 dialkyl5 amino group with 1 or 2 carbon atoms in each alkyl radical or a nitro group,with at least one of the substituents ln ortho position being a hydrogen atan, and their acid addition salts. 3· 2-benzyl-perhydroazepines of the general formula I** 1“ 10 in which R signifies a hydrogen atom, a straightchained or branched aliphatic hydrocarbon radical with 2 to 6 Carbon atoms, a cycloalkylalkyl group with 1 or 2 carbon atoms in the alkyl radical and 3 to 5 carbon atoms

4. 6 6 2 θ in the cycloalkyl radical, or a phenylalkyl group with 1 to 4 carbon atoms in the alkyl radical which may be monosubstituted in the phenyl radical by a halogen atom, an alkyl or an alkoxy group with 1 to 4 carbon atoms and which may be monosubstituted 5. In the alkyl radical by a hydroxy or oxo group, and 2** 3** 4** 5** R , R , R and R each signify a hydrogai atom, a halogen atcm, 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, 10 a dialkylamino group with 1 to 2 carbon atoms per alkyl radical, a nitro group or a phenyl group which may be substituted in the para position, with at least one of the substituents in ortho position being a hydrogen atom, and their acid addition salts. 15 4. 2-benzyl-perhydroazepines in accordance with Claim 2, 1* 2* 3* 4* 5* in which R , R , R , R and R have the meanings given in Claim 2, with the proviso at least one of the substituents 3* 4* 5* R , R or R and at least one of the substituents in ortho position being a hydrogen atom, and their acid addition salts. /7

5. 2-benzyl-perhydroazepiiBS in accordance with Claim 3, 1** o** 3* * 4·* 5* in which R , R ,, R . , R and R have the meanings given in Claim 3, with tne proviso at least one of the substituents 5 kt* c»« R or R and at least one of the substituents 5 in ortho position being a hydrogen atom, and their acid addition salts.

6. V 2-benzyl-perhydroazepiiEs in accordance with Claim 2 . . 1* or 4, in which R signifies a hydrogen atom, a straightchained alkyl radical with 1 to 3 carbon atoms, a branched -*· 0 alkyl radical with 2 to 5 carbon atoms, a cycloalkylmethyl radical with 3 to 5 carbon atoms in the cycloalkyl group or a benzyl radical which may be substituted in the para position by halogen, methyl or methoxy, 2* R signifies a halogen atom, a hydroxy group, a methoxy 15 group, an amino group or a nitro group, 3* R signifies a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, 2* 3* the substituents R and R being located at the 2,3- or 2,4- or 3,4- positions and R 4 *and R 5 *each signify a hydrogen atcm, and their acid addition salts. ,3**

7. 2-benzyl-perhydroazepiiiss in accordance with Claims 2, 4 or 6, in which R signifies a hydrogen atom, a methyl group, an isopropyl group, a cyclopropylmethyl group or a benzyl group, _ 2” - 3 R signifies a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, 3* R signifies a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, 2* 3* the substituents R and R being located at the 2,3- or 2,44* 5* 10 or 3,4- positions, and R and R each signify a hydrogen atcm, and their acid addition salts.

8. 2-benzyl-perhydroazepxnesin accordance with Claims 3 1** -or 5, in which R signifies a hydrogen atom, a straight chained alkyl radical with 2 or 3 carbon atoms, a branched 15 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 vzhich may optionally be substituted in the para position by halogen, methyl or methoxy, R and R J are the same or different and each signify a 20 hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, with the substituents 2* * 3* * R and R being located at the 2,3- or 2,4- or 3,4* positions, jc jc and R and R each signify a hydrogen atom, and their acid addition salts.

9. 2-benzyl-perhydroazepinas in accordance with Claims 3, 5 or 8, in which R signifies a hydrogen atom, an ethyl 5 group, an isopropyl group, a cyclopropylmethyl group or a benzyl group, R 2 and R 3 are the same or different and each signify a hydrogen atom, a halogen atom, a hydroxy group, a methoxy group, an amino group or a nitro group, with the substituents 2** 3** 10. R and R being located the 2,3- or 2,4- or 3,4- positions, and 4** 5** R and R each represent a hydrogen aton, and their acid addition salts.

10. 2-benzyl-perhydroazepinesin accordance with Claims 2, 1* 4,6 or 7, in which R signifies a hydrogen atom, a methyl 15 group, an isopropyl group or a cyclopropylmethyl group, 2* ι R signifies a chlorine atom at 2, 3 or b position, or an amino group at 4 position, R 3 *, R^* and R 3 *each signify a hydrogen atan, and their pharmacologically tolerated acid addition salts.

11. 2-(. 2-chlorobenzyl)-l-methyl-perhydroazepinaand its pharmacologically tolerated acid addition salts.

12. 2-(4-chlorobenzyl)-perhydroazepineand its pharmacologically tolerated acid addition salts. 5 lj. 2-C4-chlorobenzyl)-1-isopropyl-perhydroazepineand its pharmacologically tolerated acid addition salts.

13. 14. 2-(4-chlorobenzyl)-1-methyl-perhydroazepineand its pharmacologically tolerated acid addition salts.

14. 15· 2-(4-aminobenzyl)-perhydroazepineand its pharmacolo10 gically tolerated acid addition salts. ' l6. 2-benzyl-perhydroazepine and its pharmacologically tolerated acid addition salts.

15. 17. 2-benzyl-l-cyclopropylmethyl-perhydroazepineand its pharmacologically tolerated acid addition salts. 15

16. 18. 2-oenzyl-parhydroazepines in accordance with any one of Claims 1 to 17 in the form of .1 ' racemates, enantiomers and their mixtures.

17. 19 · Pharmaceutical canpositions containing as active ingredient one or more 2-benzyl-perhydroazepines in accordance with any one of Claims 1 to 18.

18. 20. of the 2-benzyl-perhydroazepinesaccording to Claims 1 to 18 in the treatment of mammals excluding humans for disorders 5 of the central nervous system of pathological charges of blood pressure and/or of pain states.

19. 21. A process for the production of 2-benzyl-perhydroaze1 2 3 4 5 pinasof the general formula I, where R , R , R ,R and R have the meanings given in Claim 1, and their acid addition salts in which 10 A) a 2-benzyl-azacycloheptane of the general formula II and V A k Λ 15 X Z- signifies one of the groupings N CH 2“’ (/ \ I (a) ^n'Sh-, O^N^CH - and <7 '6 i? 2 - CH,NO * R (b) (C) '» G · CL. R signifies an aliphatic or alicyclic hydrocarbon radical, a cycloalkylalkyl group or an aralkyl group and R? signifies a hydrogen atom, an aliphatic or alicyclic hydrocarbon radical, a cycloalkylalkyl radical, or an aralkyl group is reduced and if desired then N-alkylated or N-de-alkylated and/or functionalised as herein defined and/or the free base obtained is converted into an acid addition salt or an acid addition salt is converted into the free base, or B) a 2-benzyl-azacycloheptane of the general formula III N CH, •O' 1 (III), in which R has the meaning given above and G signifies a hydrogen atom or a grcup which can be functionalised (as herein defined) and n is a whole number fran 1 to 4 is functionalised as herein defined and if desired is then N-alkylated or N-de-alkylated and/or the free base obtained is converted into an acid addition salt or an acid addition salt is converted into the free base, or c) a N-acyl-2-benzyl-azacycloheptane of the general formula IV Ζ (IV), in which R 2 , R 3 , R 4 ,. and R 3 have the meaning given above and Q R signifies and aliphatic hydrocarbon radical, a cycloalkyl radical or a cycloalkylalkyl radical, an optionally substituted phenyl radical or phenalkyl radical, to produce compounds in which R 1 is other than an alicyclic hydrocarbon radical or methyl, is reduded and if desired is then functionalised as herein defined and/or N-de-alkylated and/or the free base obtained is converted into an acid addition salt or an acid addition salt is converted into the free base.

20. 22. A process for the preparation of 2-benzyl-perhydroazepines of the general formula I according to Claim 1 substantially as described with reference to the specific examples hereinbefore set forth.