IL29340A - Dibenzoazepine derivatives and their preparation - Google Patents

Description

DEKIVATIVES AHD THEIR PREPARATION THIS INVENTION relates to dibenzazepine derivatives and their The present invention provides the azepine derivatives of the and their acid addition salts and quaternary in which R and are the same or different and represent of 1 to carbon of 1 to carbon alkyl 1 1 of 1 to carbon atoms in the alkyl in phonyl nuolouo io or mora of alkyl of uf 1 to 5 carbon OP and is on atoms in the alkyl or phonyl alkyl of 1 to in in which by af of to of 1 In accordance with the the compounds of formula I are prepared by one of the following The compounds of formula I in which R and are both hydrogen may be prepared by reducing a compound of the general II in which is as hereinbefore preferably by the action of in a saturated primary aliphatic alcohol of 2 to 6 carbon for example or by the action of sodium The compounds of formula I in which in which R is alkyl of 1 to 4 carbon of 1 to 4 carbon 1 to in of 1 to 4 carbon atoms in the alkyl Qlltyl 1 to a in the the to and is alkyl of 1 to carbon henylalkyl of 1 to carbon atoms in the alkyl 1 carbon in whieh the nucleus ia u Gd by one of of 1 to may be prepared by reducing a compound of the in which and are as hereinbefore by any method suitable for reducing a group to a As reducing agent it is advantageous to employ lithium aluminium hydride and to carry out the operation in an inert organic solvent such as an for example diethyl ether or The compounds of formula I in which is as previously defined and is of 1 to carbon hydroxyalkyl of 1 to 5 carbon of 1 to in alkyl c l l f i t c b t in the alkyl alkyl of to in in which ia oubatituted one of allcyl of 1 to of 1 carbon may be prepared by reacting compound of the R CHO IV in which R is as previously and hydrogen in the presence a hydrogenation on a compound of the in which and are as hereinbefore 1 When this process is applied to compounds of V in which is a hydrogen and two molecular proportions or more of the aldehyde of formula IV and hydrogen are compounds of I are in which In all it is advantageous to operate in a saturated lower primary aliphatic alcohol such as ethanol and to employ Raney nickel or Adams platinum as hydrogenation In some when it is desired to produce a compound in which is it may be advantageous to react the aldehyde of formula IV and the hydrogen with a compound of the in which Ac represents an acyl radical nay be readily by acid hydrolysis and is as previously and then to the Ac radical by of I in which R is hereinbefore and is alkyl of 1 to 5 carbon of 1 to carbon off phenylalkyl of 1 to carbon atoms in the alkyl or to jy carbon in in by or of may be prepared by reacting a compound of the R X 5 in which is as hereinbefore defined and X represents a reactive ester 5 residue such as a halogen atom or a sulphuric or sulphonic ester residue example a or with a compound of the in which R and are as hereinbefore When this process is applied to of formula VII in which R is and molecular proportions or more of the compound of formula VI are compounds of formula I are in which R is of the 52 It is advantageous to operate in an inert organic solvent such as and in the presence of sodium preferably at the boiling temperature of the compounds of formula I in which in which is as hereinbefore may be prepared by in a compound of the in which and are as hereinbefore defined and Y is alkanesulphonyl or arylsulphonyl the radical Y a hydrogen The replacement of the radical Y by hydrogen may be carried out by the usual methods specific to each of the meanings of The compounds of formula I in which hydrogen or of 1 to 5 carbon may be prepared by reducing compound of the in which is of 1 to 5 carbon and and are as hereinbefore preferably the operation being carried out in an inert organic solvent such as an for diethyl ether or When a base of I is obtained by any of the foregoing methods to it may optionally be converted into an acid addition salt or quaternary ammonium derivative The compounds of formula which are novel may be prepared from the corresponding ketones of the by any method per se for the preparation of from The compounds of formula X in which is other than may be prepared in accordance German Patent This method consists in alkylating a compound of the with a compound of the XII in which is the as but not and X is as hereinbefore followed by hydrolysing the of the thus The of formula III in which and are as before defined nay be prepared from cocipounds of the in which and are as hereinbefore by any method of acylation known per It appears particularly advantageous to employ a chloride or anhydride of an acid of is as hereinbefore and to operate in an inert organic solvent such as benzene or with reflux of the solvent and in the presence or absence of a base such as a tertiary for example When R in formula III is it is particularly advantageous to carry out the acylation with ethyl formate and to operate o o an autoclave at a temperature between and 150 The compounds of formula in which and are as before defined may be prepared by any method known se for the preparation of urethanes from compounds of the in which is as hereinbefore The compounds of VII and in which and are as hereinbefore but are not be prepared by successive application of one or more of the methods to described herein to compounds of the in which is as previously The compounds of VIII be obtained by one of the following By the action of cyanogen of an or of an aliphatic or aromatic sulphonyl chloride on a compound of the formula Villa in and are as hereinbefore By alkylation of a compound of the ill which and Y are as hereinbefore defined with reactive ester of the fornula VI in the presence of an alkaline condensation agent The compounds of may be obtained conpounds of the VIIIc in which is as hereinbefore defined by the action of cyanogen bromide an alkyl chloroformate an acid halide or an aliphatic or aromatic sulphonyl chloride The compounds of formula I may optionally be purified by physical methods as crystallisation or chromatography or by chemical methods such as formation of salts crystallisation of the latter and decomposition in alkaline In these operations the nature of the anion of the salt is immaterial the only condition being that the salt should be and readi ly The compounds of fornula I may be converted into acid addition salts and quaternary ammonium derivatives The acid addition salts may be obtained by the action of the bases on acids in appropriate solvents The solvents employed may be for example alcohols ethers ketones or chlorinated The salt formed precipit ates after optional concentration of its solution and is separated by filtration or The quaternary derivatives may be obtained by the action of the bases on esters optionally in an organic solvent at ambient temperature or more rapidly with moderate heating The compounds of formula I and their acid addition salts and quaternary ammonium derivatives have interesting pharmacodynamic properties They are very active on the central nervous system as antidepressants and They also have good activity as convulsants and They have given good results in physiological tests on animals in doses of per of animal The aost interesting compounds are those of formula I in which R R and which are identical or represent hydrogen atom or of I to 5 carbon especially raethyl For medicinal the new compounds may be employed either as bases or as pharmaceutically acceptable acid addition salts or quaternary ammonium salts and derivatives which are in the doses in which they are As examples of pharmaceutically acceptable acid addition there may be mentioned salts of mineral acids as nitrates and and salts of organic acids as propionates theophyllineacet t y phenolphthalinates and substitution derivatives of these examples of pharnaceutica acceptable quaternary derivatives there may be mentioned of mineral or organic esters such as the ylchlorides benzyl benzyliodides the and the sulphonates and substitution derivatives of these The following Examples illustrate the EXAMPLE I To a solution of 19 of fjazepine in 200 of butanol at of sodium are added in portions in 90 The reaction mixture is then heated under reflux of the butanol for 20 minutes until the sodium completely After l60 cm of distilled water are added and of the solvents is evaporated under reduced pressure cm of distilled water are added and the residual butanol is evaporated under normal The aqueous suspension obtained is diluted with 700 cm 3 of distilled 3 water and extracted with 150 cm of diethyl The separated aqueous solution is then twice washed a total of 200 cm of diethyl The combined ethereal solutions are extracted 6 times with a total of 300 cm of aqueous 2N methanesulphonic acid 3 The combined aqueous acid solutions are made alkaline with 100 cm of ION sodium hydroxide solution and extracted 3 times with a total 3 of cm of diethyl The combined ethereal solutions are 3 washed times to neutrality with a total of 300 cm of distilled dried over anhydrous sodium sulphate and The residue is dissolved in 20 of boiling diisopropyl After cooling at for 4 the crystals which have appeared are twice washed with a total of 20 cm diisopropyl ether and dried under reduced pressure of are The pure product may be obtained by preparing the hydrochloride in ethanol and then converting it into the base and recrystallising the latter from The starting may be prepared as is prepared by the method of German Patent The reaction of an excess of hydroxylam on 60 of in aqueous ethanolic medium under reflux gives fjazepine EXAMPLE A solution of of in 360 cm of ethanol and 40 of aqueous formaldehyde is in the presence of 18 of Raney nickel at normal temperature under a hydrogen pressure of 50 bars for 7 After the catalyst has been filtered off and washed with the clear filtrate is evaporated under reduced pressure The residue is treated with 1 0 cm 3 of diethyl The insoluble matter which appears is filtered off and washed with diethyl The ethereal solution obtained is extracted 4 times with a total of 3 200 cm of an 2N aqueous methanesulphonic acid and the combined acid solutions are made alkaline in the cold with 3 cm of ION sodium hydroxide The oil which separates out is extracted 3 times with a total of 300 cm of diethyl The combined ethereal solutions are twice washed with a total of 3 200 cm of distilled dried over anhydrous potassium and The residue is dissolved at boiling point 3 3 in 14 cm of ethanol and 3 of distilled On cooling to about and crystals The crystallisation is continued at for 2 The crystals are washed with 3 11 cm of aqueous ethanol and dried under reduced pressure of are EXAMPLE III 2 of azepine are added in small portions in 2 minutes to a suspension of 3 1 of lithium aluminium hydride in l80 cm of anhydrous dxethyl 5 and the mixture is refluxed for 5 The cooled to is hydrolysed in 20 minutes by adding successively 3 3 cm of distilled of sodium hydroxide solution and cm of distilled After stirring for 1 hour at ambient the precipitate formed is separated and washed 3 times with a total of 120 of boiling methylene The filtrate 3 is evaporated and the residue dissolved in 250 cm of diethyl The ethereal solution obtained is extracted times with a total of 3 cm of aqueous 2N methanesulphonic The combined 3 acid solutions are made alkaline in the cold with 40 cm of 5 ION sodium hydroxide The oil which separates out is 3 extracted 3 times with a total of 300 cm of diethyl The 3 combined ethereal solutions are twice washed with a total of 200 cm of distilled dried over anhydrous sodium sulphate and 3 To the residue in solution in 10 cm of isopropanol are added 2 of an anhydrous solution of hydrogen chloride in diethyl ether 4 of acid per litre of After cooling for 1 hour at the crystals formed are washed with an mixture of 4 cm 3 of isopropanol and 3 3 of anhydrous diethyl ether and dried under reduced pressure 11 are The starting is prepared as 2 of 10 are obtained by heating 25 of and EXAMPLE IV 205 of sodium amalgam containing of sodium and of are brought into contact at a temperature between and in 76 cm of ethanol until the sodium of the amalgam is completely In the course of this the pH of the reaction medium is maintained in the neighbourhood of 6 by the addition of 3 a total of l8 cm of acetic The reaction mixture is diluted with 76Ο cm of distilled The mercury regenerated in the course of the reaction is eliminated by The aqueous phase is made alkaline with 25 cm of sodxura hydroxide and 3 extracted three times with a total of 750 cm of diethyl The combined ethereal solutions are twice extracted with a total of 200 cm of aqueous 2N methanesulphonic acid The 3 combined aqueous acid solutions are washed with 40 cm of diethyl 3 ether and then made alkaline with 5 cm of sodium hydroxide The oil which separates out is extracted three times with 3 a total of cm of diethyl The ethereal extracts are washed five times with total of 50 cm of distilled dried over potassium carbonate and The product obtained is chromatographed on 42 of alumina eluting with a mixture of benzene and ethyl The chromatographed product is dissolved in 30 cm of a boiling mixture of hexane and benzene After cooling for 1 hour at the crystals which have appeared are washed twice with 3 a total of 8 cm of a mixture of cyclohexane and benzene by and dried under reduced pressure To a boiling solution of of purified product in 8 of acetone is added a boiling solution of of anhydrous oxalic acid in of After cooling for half an hour at the crystals have appeared are washed twice with a total of 3 10 cm of and then with 8 cm of anhydrous diethyl and dried under reduced pressure of fjazepine are The starting azepine may be prepared as prepared by the method of Swiss Patent The action of dilute hydrochloric acid on of gives of The action of an excess of hydroxylamine on 8 of in aqueous ethanolic medium under reflux gives of EXAMPLE V 335 of sodium amalgam containing of sodium and 10 of are brought into contact at in 320 of ethanol until the sodium of the amalgam has been completely In the course of this the pH of the reaction medium is maintained in the neighbourhood of 6 by the addition of a total of 30 cm of acetic When the reaction has the regenerated mercury is eliminated by The aqueous ethanol phase is concentrated under reduced pressure to a volume of about cm and then diluted with cm of distilled water and made alkaline with aqueous sodium carbonate The oil in suspension is extracted 3 three times with a total of 300 cm of diethyl ether and the combined ethereal solutions are extracted five times with 500 cm of aqueous 2N methanesulphonic acid The aqueous acid solutions are 3 made alkaline with 100 cm of 10 N sodium hydroxide and the oil which separates out is extracted three times with a total of of diethyl The ethereal extracts are twice washed 3 with a total of 200 cm of distilled dried over anhydrous sodium and The residue obtained 5 dissolved in 20 cm of boiling After cooling for 24 hours at the crystals which have appeared are washed with 10 cm of heptane and dried under reduced pressure 20 The product obtained is purified by conversion into the fumarate which is recrystallised from ethanol 2 and reconverted into the which is then crystallised from of are The starting may be prepared as azepine is prepared as indicated in Example The reaction of sodamide and then of ethyl iodide in hexamethylphosphotriamxde on 20 of gives of The action of dilute hydrochloric acid on 7 of gives of 10 fjazepine 120 The action of an excess of hydroxylamine on of gives of VI 327 of sodium amalgam containing of sodium and of are brought into contact at in 320 of ethanol until the sodium of the amalgam has been completely In the course of this the pH of the reaction medium is maintained in the neighbourhood of 6 by the addition of a total of 25 cm of acetic The mercury regenerated in the course of the reaction is eliminated by The aqueous ethanol phase is concentrated under reduced pressure 20 to a volume of about 3 3 100 cm and then diluted with 600 cm of distilled water and made alkaline with aqueous sodium carbonate The oil in suspension is extracted three times with a total of 600 cm of diethyl The combined ethereal solutions are extracted four times with a total of 400 cm of an aqueous 2N acid The aqueous acid solutions are made alkaline with of ION sodium hydroxide and the oil which separates out is extracted three times with a total of cm of diethyl 3 The ethereal extracts are twice washed with a total of 200 cm of distilled dried over anhydrous sodium and The residue obtained is dissolved in 28 cm of anhydrous ethanol and the solution is filtered and treated at o 3 cm of a methanesulphonic acid solution in After cooling for 1 hour at the crystals which have 3 appeared are washed with 10 cm of anhydrous 3 ethanol and then 10 cm of anhydrous diethyl ether and dried under reduced pressure 20 of are The starting may be prepared as azepine 1 is prepared by the method of German Patent 1 The action of an excess of on of gives of azepine EXAMPLE VII of are added in small portions in 2 minutes to a suspension 3 of lithium aluminium hydride in 700 cm of anhydrous diethyl The mixture is heated under reflux for 5 hours and the suspension is then cooled to and hydrolysed by the addition of of distilled followed by cm of sodium and finally 25 cm of distilled After stirring for 1 hour at the precipitate formed is separated and twice 3 washed with a total of 100 cm of boiling methylene The filtrate is extractedYwith a total of 90 cm of aqueous 2N methanesulphonic acid The aqueous acid solutions are washed with 40 cm of diethyl ether and then made alkaline 3 18 cm of 10N sodium hydroxide The oil which separates out is twice extracted with a total of 100 cm of diethyl ether and 3 the ethereal extracts are washed three times with a total of 120 cm of distilled dried over potassium carbonate and The residue obtained is purified by conversion into the fumarate which is crystallised from ethanol and reconversion into the The purified product 3 dissolved 30 cm of anhydrous diethyl ether and the solution is treated at with of a methanesulphonic acid solution in ethanolo After cooling for 2 hours at the crystals which have appeared are twice washed with a total of of anhydrous diethyl and dried under reduced pressure 2 of are The starting may be prepared as fJazepine is prepared as described The action of acetic anhydride in pyridine on of gives of fJazepine EXAMPLE VIII A solution of of in 40 cm of anhydrous diethyl ether is added in 7 minutes to a suspension of 4 of lithium aluminium hydride in 160 of anhydrous diethyl ether at After heating under reflux for the suspension is cooled to and hydrolysed by the addition of cm of distilled followed 3 3 by cm of sodium and finally 2 cm of distilled After stirring for 1 hour at ambient the precipitate formed is separated and twice washed with a total of 3 70 cm of boiling methylene The filtrate is evaporated under reduced pressure 20 The residue 5 dissolved 3 in 30 cm of diethyl ether and the ethereal solution obtained 3 twice extracted with a total of 70 cm of aqueous 2N methanesulphonic acid The combined aqueous acid solutions are made alkaline at with 18 of ION sodium hydroxide solution and the oil which separates out is extracted three times with a total of 130 of diethyl The extracts are twice washed 3 a total of 200 cm of distilled dried over anhydrous magnesium and The residue obtained 1 is 3 dissolved in 20 cm of boiling petroleum After cooling for minutes at the crystals which have appeared are 3 o washed with 10 cm of petroleum ether at and dried under reduced pressure 20 of are The starting dihydr may be prepared as fJazepine gives of fjazepine a crude oily EXAMPLE IX A solution of 10 of 3 fjazepine in 200 cm of anhydrous diethyl ether is added in 10 minutes to a suspension of 1 of lithium aluminium hydride in 200 of anhydrous diethyl ether at After heating under reflux for 4 the suspension is cooled to and hydrolysed by the 3 3 addition of cm of distilled followed by 3 cm of sodium and finally cm of distilled After stirring for 15 minutes at the precipitate formed is separated and twice washed 3 with a total of 200 cm of boiling methylene The filtrate 3 twice extracted with a total of 200 cm of aqueous 2 methanesulphonic 3 acid solution and three times with a total of cm of distilled 3 The combined aqueous acid solutions are made alkaline with 70 cm of 3 sodium hydroxide and the which separates out is extracted with 100 cm of diethyl The aqueous alkaline phase is saturated with sodium 3 chloride and then again twice extracted a total of 200 cm of diethyl The combined ethereal solutions are dried over potassium carbonate 3 and evaporatedo The residue obtained is dissolved in 4 cm of boiling ethyl acetate and the solution obtained is treated with a boiling 3 solution of 3 of acid in 25 cm of ethyl After cooling o at 3 for 2 the crystals which have appeared are 3 twice washed with a total of 10 cm of ethyl acetate and then twice with a 3 total of 20 cm of anhydrous diethyl ether and dried under reduced pressure 20 of fJazepine are The starting may be prepared as 10 fjazepine is prepared as described in Example The action of an excess of formylacetic anhydride at ambient temperature on 1 of gives EXAMPLE X To a solution of of azepine in 10 cm of anhydrous containing of sod a solution of of 3 dimethylsulphate in anhydrous dimethylformaniide is added stirred in the course of 4 The suspension obtained is agitated at ambient temperature for cm of distilled water 3 and 10 of ION sodium hydroxide solution are and the mixture 3 is extracted three times with a total of l80 era of diethyl The united ethereal solutions are extracted twice a total of 3 60 cm of aqueous The aqueous acid solutions 3 are united and made alkaline with 10 of sodium hydroxide and the alkaline mixture is extracted three times with a 3 total of 120 cm of diethyl The ethereal solutions are dried over potassium and The residue is converted into the in and then reconverted into the base which is recrystallised from aqueous ethanol to give of EXAMPLE XI A solution of of in 10 of is heated under reflux for 8 hours in the presence of of 3 potassium After 100 cm of distilled water are 3 and the mixture is extracted twice with a total of 100 cm of 3 diethyl The united ethereal extracts are washed with cm of 3 distilled and then extracted twice with a total of 100 cm of aqueous N methanesulphonic The united aqueous acid solutions are made alkaline 25 cm of 10 solution and 3 extracted three times with a total of 120 cm of diethyl The 3 united ethereal extracts are washed 20 of distilled dried over anhydrous magnesium and The residue obtained is converted in isopropanol into the hydrochloride of EXAMPLE A solution of of Jazepine in of is heated under reflux for 4 hours in the 3 presence of of potassium After 100 era of distilled water are and the is extracted twice with a 3 total of 120 of diethyl The united ethereal extracts are 3 washed with of distilled water and then extracted twice a 3 total of 100 cm of aqueous N methanesulphonic The 3 aqueous solutions are and made alkaline with of 10 N hydroxide and extracted twice with a total of 3 120 cm of diethyl The united ethereal extracts are washed 3 20 cm of distilled dried over anhydrous sodium and The residue is converted in isopropanol into the hydrochloride of azepine EXAMPLE XIII A solution of of amino jazepine in 10 of is heated under reflux for 8 hours in the presence of of potassium 3 After 100 cm of distilled water are and the mixture is 3 extracted twice with a total of 100 cm of diethyl The united 3 ethereal extracts are washed with 25 cm of distilled and then 3 extracted twice with a total of cm of aqueous N sulphonic The united aqueous acid solutions are made alkaline of 10 N sodium hydroxide and three 3 times with total of 120 en of diethyl The united ethereal 3 extracts are washed with of distilled dried over anhydrous magnesium and The residue obtained is converted in isopropanol into the hydrochloride of The used as starting material can be prepared as is prepared in the manner described in Example 3y the action of followed by dimethyl at ambient temperature in anhydrous on of of 95 are EXAMPLE XIV of sodium is added in portions over 8 minutes to a suspension of of in 15 of at The reaction mixture is then heated under reflux for minutes until the sodium 3 has completely After 100 cm of distilled water 3 are and the mixture extracted a total of 100 cm of diethyl The united ethereal extracts are extracted twice 3 a total of 80 cm of aqueous N The 3 united aqueous acid solutions are made alkaline 20 cm of 10 N 3 sodium hydroxide and extracted twice a total of 120 cm of diethyl The united ethereal extracts are dried over potassium carbonate and The residue is dissolved in a mixture of 3 cm 3 of isopropanol and 3 cm 3 of diethyl cm 3 of a anhydrous solution of hydrogen chloride in diethyl ether is and after cooling for 1 hour at crystals formed are washed with 2 of a mixture of isopropanol and diethyl 3 ether then twice with a total of of diethyl and finally dried under reduced pressure of the chloride of o are obtainede osyl used as starting can be prepared as Jazepine is prepared by the method of Example The reaction of of toluenesulphonyl chloride on of Jazepine in pyridine at ambient tenperature gives 2 of The reaction of of dimethyl sulphate on of in ethanol in the presence of an agent gives of XV A solution of of Jazepine in 75 of anhydrous diethyl ether is added in 25 minutes to a suspension of of lithium aluminium hydride in 75 of anhydrous diethyl The mixture is refluxed for The suspension is then cooled to and hydrolysed in 1 hour by the successive addition of 3 3 of distilled cm of 5 N sodium hydroxide and of distilled The precipitate formed is filtered off and washed 3 four times with a total of 200 cm of diethyl The filtrate 3 extracted twice with a total of 100 cm of aqueous 2 3 sulphonic and then with cm of distilled The united aqueous acid solutions are made alkaline with 40 cm of 10 N sodium hydroxide solution and then extracted three times with a total of 240 cm of ethereal arc t of distilled over and obtained is solved in 7 err of l of distilled After 16 hours cooling of of distilled water and dried under reduced used is prepared by od of action of c in the p on of of In a as 2 the appropriate following of the of oxalate within eoope in with a acceptable carrier or of X or a acid or in or oral include or the active is vit one or inert diluents ouch as Xu such Liquid oral pharmaceutically acceptable syrups and elixirs containing inert diluents such as water or paraffin These coqpositions also comprise substances other than for example wetting sweetening perfumes and preservative The compositions according to the invention for parenteral administration be aqueous or sterile As solvent or there may be employed propylene polyethylene vegetable more particularly olive and injectable organic for example ethyl These compositions also contain more particularly wetting and dispersing The sterilisation may be effected in various for example with the aid of a bacteriological by incorporating sterilising agents in the by irradiation or by The compositions may also be prepared in the form of sterile solid compositions which nay be dissolved at the time of use in sterile water or any other sterile injectable The compositions for rectal administration are suppositories which in addition to the active excipients such as butter or suppository The dose employed depends upon the desired therapeutic the route of administration and the duration of orally generally between 10 and per day of active product is administered to an The following Examples illustrate pharmaceutical compositions according to the Tablets having the following composition are prepared by the usual technique 11 10 starch 105 colloidal silica 32 nagnesiun stearate 3 EXAMPLE B Tablets having the following coinposition are prepared by the usual f J azepine hydrochloride starch colloidal silica 32 nagnesiun stearate 3 insufficientOCRQuality

Claims (1)

1. particularly described and ascertained the nature of our said invention and manner the same is we declare that wo claim is 10 ivatives of the and their acid addition salts and quaternary ammonium in which R and are the same or different and represent of 1 to 5 carbon of 1 to 5 carbon alkyl of l of 1 to 5 carbon atoms in the alkyl 1 to atone in is by one is alkyl of 1 to toms in the alkyl phon 1 nuolouo io alkyl 1 to derivatives as claimed in claim 1 and their acid addition salts and quaternary ammonium derivatives in which is other than derivatives as claimed in claim 1 and their acid addition salts and quaternary ammonium derivatives in which R and are each hydrogen or alkyl of 1 to 5 carbon atoms and is alkyl of 1 to 5 carbon derivatives as claimed in claim 1 and their acid addition salts and quaternary ammonium derivatives in which R and are each hydrogen or alkyl of 1 to 5 carbon atoms and and its acid addition salts and quaternary ammonium f azepine and its acid addition salts and quaternary ammonium azepine and its acid addition salts and quaternary ammonium and its acid addition salts and quaternary ammonium and its acid addition salts and quaternary ammonium and its acid addition salts and quaternary ammonium and its acid addition salts a d quaternary ammonium and its acid addition salts and quaternary ammonium its acid addition salts and quaternary ammonium Process for the preparation of a derivative as claimed in claim 1 in which and are both or an acid addition salt or quaternary ammonium derivative which comprises reducing a compound of the in which is as defined in claim and optionally converting a base Process according to claim 14 in which is not Process for the preparation of a derivative as claimed in claim 1 or an acid addition salt or quaternary ammonium derivative thereof in which is of the in which is alkyl of 1 to 4 carbon hydroxyalkyl of 1 to 4 carbon to in phenylalkyl of 1 to 4 carbon atoms in the alkyl nf in of and is alkyl of 1 to 5 carbon phenylalkyl of 1 to 5 carbon atoms in the alkyl nf nf 1 to comprises reducing a compound of the in which is as defined in claim 1 and and are as hereinbefore and optionally converting a base obtained into an acid addition salt or quaternary ammonium derivative Process according to claim 16 in which is not Process for the preparation of a azepine derivative as claimed in claim 1 or an acid addition salt or R quaternary ammonium derivative thereof in which is of the in which R is as defined in claim 16 and is alkyl n Γ of 1 to 5 carbon atoms in the phony 1 or of of 1 which comprises reacting a compound of the formula and in the presence of a hydrogenation with a compound of the in which R is as defined in claim 1 and is as hereinbefore and 1 optionally converting a base obtained into an acid addition salt or quaternary derivative Process according to claim 18 in which is hydrogen and the product is one in which is of the formula Process according to claim 18 or 19 in which is not Process for the preparation of a azepine derivative claimed in claim 1 or an acid addition salt or quaternary ammonium derivative thereof in which is hydrogen and 1 of 1 to 5 carbon atoms in the of to in in of 1 ailcoay of which comprises reacting a compound ι of the formula and in the presence of a hydrogenation with a compound of the Ac in which Ac is an acyl radical and is as hereinbefore removing the radical Ac by and optionally converting a base obtained into an acid addition salt or quaternary ammonium derivative thereof Process according to claim 21 in which is hydrogen and the product is one in which is of the Process for the preparation of a azepine derivative as claimed in claim 1 or an acid addition salt or carbon atoms hydroxyalkyl of 1 to 5 carbon of 1 to 5 carbon atoms in the alkyl or 1 to atomo in tho which 1 to of 1 to 5 which comprises reacting a compound of the where X represents a reactive ester residue and is as hereinbefore with a compound of the formula in which R and are as defined in claim and optionally converting a base obtained into an acid addition salt or quaternary ammonium derivative Process according to claim in which R is hydrogen and the product is one in which Process according to claim 23 or 24 in which is not Process for the preparation of a azepine derivative as claimed in claim 1 or an acid addition salt or quaternary ammonium derivative thereof in which is of the in which is as defined in claim 23 which comprises in a compound of the in Y is or is as defined in claim 1 and is as defined in claim 23 radical Y by a hydrogen optionally converting a obtained into an acid addition salt or quaternary ammonium derivative Process according to claim 26 in which is not Process for the preparation of a azepine derivative as claimed in claim 1 or acid addition salt or R quaternary ammonium derivative thereof in which is of the in which Rg is hydrogen or of 1 to 5 carbon which comprises reducing a compound of the in which is alkyl of 1 to carbon is as defined in claim and is as hereinbefore and optionally converting a base obtained into an acid addition salt or quaternary ommonium derivative Process according to claim 28 in which is not Process according to claim 15 substantially as described in Process according to claim 20 substantially as described in Example Process according to claim 17 substantially as described in Example Process according to claim 14 substantially as described in Example or Process according to claim 16 substantially as described in Example VIII or Process according to any of claims 26 or 28 substantially as described in any one of Examples X to derivatives as claimed in claim 1 and their acid addition salts and quaternary ammonium when prepared by the process claimed in any of claims 33 or derivatives as claimed in 2 and their acid addition salts and quaternary ammonium when prepared by the process claimed in any of claims azepine derivatives as claimed in claim 1 and their acid addition salts and quaternary ammonium derivatives when prepared by the process claimed in claim A pharmaceutical composition in association with a pharmaceutically acceptable carrier or at least one derivative as claimed in any of claims or 3ί or a acid addition salt or quaternary ammonium derivative A pharmaceutical composition in association with a pharmaceutically acceptable carrier or at least one derivative as claimed in any of or or a acid addition salt or quaternary dorivativo cal according to claim substantial as Dated this Seventeenth day of January for insufficientOCRQuality