IL43457A - Benzylamines a process for their preparation and pharmaceutical products containing them - Google Patents

Description

omtt o' aen mnpiT '- wani Hovel beaaylamines, a process for their preparation and pharaiaccutical products containing them DR. KARL ΦΗΟΚΑΕ GMBH..

C/ 41562 This invention relates to new benzylamines having interesting pharmacological properties and to processes for their preparation.

According to one feature of the present invention there are provided compounds of general formula [wherein Hal represents a chlorine or bromine atom; represents a hydrogen, chlorine or bromine atom; Ίλ^ represents a morpholinocarbonylmethyl group, a branched alkyl group containing from 3 to 5 carbon atoms optionally substituted by from 1 to 3 hydroxyl groups, or a group of formula A (wherein R^ represents a hydrogen atom, a hydroxyl group or an alkyl group containing from 1 to 4 carbon atoms , n represents the integer 0, 1 or 2 , and the radicals A and B either both represent hydrogen atoms or together represent the group I (R- - C - R ) 5 J 5 m ■A (wherein the groups which may be the same or different represent hydrogen atoms or alkyl groups containing 1 or 2 carbon atoms and m represents the integer 1 or 2); represents a straight or branched alkyl group containing from 1 to 4 carbon atoms , an alkenyl group containing from '2 to 4 carbon atoms , a cycloalkyl group containing 3 or 4 carbon atoms or (if is other than hydrogen or R2 represents a branched alkyl group containing 3 to 5 carbon atoms optionally substituted by from 1 to 3 hydroxyl groups) a hydrogen atom; and 1 represents the integer 1 or 2] and acid addition salts thereof.

Aminorbenzylamine .analogues -of—those -phenols — of formula I in which R2 is hydroxycyclohexyl and R4 is methyl, influencing the respiratory function and having antipyretic, secretolytic and antitussive activity/ were described in U.S. Patent Specification No. 3,536,713 (corresponding to Israel Patent Specification No. 2.7908).

In general the compounds of general formula I and their physiologically compatible acid addition salts with inorganic t organic acids possess valuable pharmacological properties, in- particular a secretolytic and antitussive effect as well as a stimulating effect on the production of the surfactant or antiatelectasis factor of the alveoli.

Preferred compounds of general formula I by virtue of their particularly favourable pharmacological properties are those wherein Hal represents a chlorine or bromine atom; represents a hydrogen, chlorine or bromine atom; represents a branched alkyl group containing from 3 to 5 carbon atoms optionally substituted by from 1 to 3 hydroxyl groups, or a cyclohexyl or hydroxycyclohexyl group; represents a straight-chain or branched alkyl group containing 1 to 4 carbon atoms or(if represents a hydroxycyclohexyl group or a branched alkyl group containing from 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxy groups) a hydrogen atom, and 1 represents the integer l;and physiologically compatible acid addition salts thereof. Especially preferred are the following compounds: N-ethyl-N-cyclohexyl-3 , 5-dibromo-2-hydroxy-benzylamine , 3 , 5-dibromo-4-hydroxy- - (trans-3-hydroxy-eyelohexy1 )- benzylamine , 3 , 5-dibromo-N-(dihydroxy-tert .butyl)-2-hydroxy-benzylamine , 3 , 5-dibromo-2-hydroxy-N- (trans-4-hydroxy-eyelohexy1)- benzylamine , 3 , 5-dichloro-N-(dihydroxy-tert .butyl)-4-hydroxy-benzylamine and physiologically compatible acid addition salts thereof. The compounds according to the invention may be prepared according to the following processes, which processes constitute further features of the invention: a) Reaction of a compound of formula (wherein R^ , Hal and 1 are as hereinbefore defined and R& represents a hydroxyl group, a chlorine, bromine or iodine atom, or an acyloxy, sulfonyloxy, alkoxy, aryloxy or aralkoxy group) with a compound of formula (wherein R„ and R. are as hereinbefore defined). 2. 4 The reaction is conveniently performed in the presence of a solvent, suitable solvents being acetone, carbon tetrachloride, chloroform, ethanol, tetrahydrofuran, benzene, toluene, dioxane and tetralin, or in the presence of an excess of the amine of general formula III used. The reaction may however, if desired also be carried out in the absence of a solvent.

The reaction is preferably carried out at temperatures from -70 to 200°C, depending on the nature of the group R^.

If Rg represents a halogen atom the reaction is preferably carried out at temperatures from 0° to 150°C, e.g. at the boiling point of the solvent used. In this case the reaction is with advantage performed in the presence of a hydrogen halide binding agent, for example an inorganic base such as sodium carbonate or sodium hydroxide, or in the presence of an ion exchanger or a tertiary organic base, e.g. triethylamine or pyridine. The latter may conveniently at the same time V If Rg represents a sulfonyloxy group, for example the --methyl^phenyl-sulfonyloxy group, the reaction is preferably performed at temperatures from-70° to 50°C.

If represents an acyloxy group, for example the acetoxy or benzoyloxy group, or an alkoxy, aryloxy or aralkoxy group, the reaction may if desired be carried out in the presence of an acid catalyst such as ammonium chloride, preferably at temperatures from 0° to 200°C.

If ^ represents a hydroxyl group, the reaction is advantageously performed in the presence of an acid catalyst, e.g„ hydrobromic acid, p_-toluene-sulfonic acid or butyric acid, or in the presence of an alkaline catalyst, e.g. potassium hydroxide or magnesium oxide, preferably at temperatures from 120° to 180°C. The reaction may, however if desired also be performed in the absence of a solvent, b) Reacion of a compound of formula (wherein R^ , Hal and 1 are as hereinbefore defined) with a compound of formul (wherein R„ and R. are as hereinbefore defined) or with 4 a corresponding formamide in the presence of formic acid.

The reductive amination is preferably carried out at temperatures from 50° to 250°C, optionally in the presence of a solvent and optionally whilst distilling off at the same time the water which forms 0 It is of special advantage however, to use an excess of the amine of formula II and/or the formic acid during the reaction as solvent. If ^ in the compound of formula III represents a hydrogen atom, the reaction mixture obtained is refluxed after the reaction with a dilute acid, e.g. 2N hydrochloric acid, c) For preparation of compounds of generaly formula I wherein R^ represents a hydrogen atom: Reduction of a compound of formula or of a compound of formula (Va) (wherein R^, Ti^, Hal and 1 are as hereinbefore 'defined , Z represents a cyclohexylidene group optionally substituted by a hydroxy group or an alkyl group with 1 to 4 carbon atoms , a branched alkylidene group with 3 to 5 carbon atoms or a morpholinocarbonylmethylidene group and R^ represents a hydrogen atom or an organic acyl group.) If a compound of formula V or Va wherein R.. represents a hydrogen atom is used the reduction is conveniently effected by means of catalytically activated hydrogen (e.g. hydrogen in the presence of Raney nickel or Raney cobalt) , nascent hydrogen (e.g. activated metallic aluminium and water, sodium amalgam and ethanol or zinc and hydrochloric acid), or advantageously a complex metallic hydride (e.g. lithium aluminium hydride or sodium borohydride) in the presence of an appropriate solvent, for example methanol, ethanol, ethanol/water , tetrahydrofuran, dioxane, dioxane/water pyridine or ether, and at temperatures up to the boiling point of the solvent used, for example temperatures from -50° to 100°C.

If a compound of formula V or Va wherein represents an organic acyl group is used, the latter is split off during the reduction with nascent hydrogen or with a complex metallic hydride. d) For the preparation of compounds of generaly formula I as hereinbefore defined with the proviso that R is other than a hydrogen atom and and R^ do not represent radicals substituted by a hydroxyl group: Alk lation of a compound of formula (wherein R^ , Hal and 1 are as hereinbefore defined and R2' represents a hydrogen atom, an alkyl group containing from 1 to 4 carbon atoms or one of the groups represented by R2 as hereinbefore defined but not a branched alkyl group containing from 3 to 5 carbon atoms or a radical substituted by a hydroxyl group) with a compound of formula R,' - W (VII) 4 (wherein R^' represents a branched alkyl group containing from 3 to 5 carbon atoms , a cyclohexyl group or one of the groups represented by R^ but not a hydrogen atom, and W represents a halogen atom or a sulfonic acid group).

The reaction is advantageously carried out in the presence of a solvent, for example methanol, dioxane or dimethylformamide , conveniently at temperatures from -20° to 150°C, preferably, however, at the boiling point of the solvent used. A methylation may also be effected using e) Reaction of a phenol of formula (wherein R^, Hal and 1 are as hereinbefore defined with the proviso that (one of) the radical(s) Hal is in the 2-position) with formaldehyde or paraformaldehyde and a compound of formula H - 2 (III) (wherein and R^ are as hereinbefore defined).

The reaction is advantageously carried out in the presence of a solvent such as water, methanol, ethanol or dioxane, at temperatures from 0 to 100 °C, preferably, however at the boiling point of the solvent used.

Alternatively a compound of formula (wherein R„ and R, are as hereinbefore defined and Alk i 4 represents a lower alkyl group) formed optionally in situ, may be used in the place of the fomaldehyde or paraformaldehyde and amine. f) Halogenation of a compound of formula (wherein , and R^ are as hereinbefore defined).

The halogenation is effected by means of a halogenating agent, e.g. with chlorine, bromine, iodosobenzene dichloride or tribromophenolbromine , preferably in the presence of a solvent, for example in 50-100% acetic acid, in methylene chloride or in tetrahydrofuran. The reaction is advantageously effected in the presence of a tertiary organic base, and conveniently at temperatures from -20° to 50°C. 1 or 2 moles of the halogenating agent or a slight excess thereof are generally used per mole of the compound of formula IX present as the base or as a salt, for example as the hydrochloride. If a hydrohalic acid salt is formed during the reaction it may be isolated as such or, if desired, be further purified via the base. g) Removal of one or two protecting groups from a compound of formula X (wherein , , Hal and 1 are as hereinbefore defined, X represents a protecting group for an amino group or is as hereinbefore defined for R^, and Y represents a protecting group for a hydroxyl group or, in the case where X represents a protecting group for an amino group, a hydrogen atom).

If X and/or Y in the compound of formula X represents an acyl group, for example an acetyl, benzoyl or p-toluene-sulfonyl group, these groups are preferably split off hydrolytically in the presence of a solvent, e.g. with ethanolic hydrochloric acid or with aqueous alcoholic sodium hydroxide solution, at temperatures up to the boiling point of the solvent used.

If X and/or Y in the compound of formula X represents a benzyl group, this group is preferably split off by hydrogenation, for example using hydrogen in the presence of a catalyst, preferably in the presence of a solvent, such as ethanol, methanol/hydrochloric acid, water/ hydrochloric acid, and at room temperature. During the reaction any alkenyl group present in the starting material may be converted into the corresponding alkyl group.

If Y in the compound of formula X represents an alkyl , aryl or aralkyl group, these groups are preferably split off with hydrobromic acid or hydroiodic acid at elevated V temperatures. These protecting groups may also be removed with acid halides , phosphoryl halides, phosphorus pentahalides , aluminium halides , with sulfuric acid or with organometallic compounds .

If Y in the compound of formula X represents an acyl group, for example an acetyl or benzoyl group, this group may be split off with a complex metal hydride , e.g. sodium borohydride in pyridine, or with lithium aluminium hydride in an inert solvent such as either or tetrahydrofuran, conveniently at temperatures from 0°C to the boiling point of the solvent used. If X represents a formyl or acetyl group, this group is simultaneously reduced to a methyl or ethyl group respectively, h) Reduction of a compound of formula (Hal)l OR (wherein ^ , 2 , Hal and 1 are as hereinbefore defined with the proviso that does not represent a morpholinocarbonyl-methyl group, R " represents a formyl or acetyl group or one of the groups represented by R^ as hereinbefore defined and R^ represents a hydrogen atom or an organic acyl group) .

The reduction is conveniently effected using catalytically activated hydrogen, or nascent hydrogen, (for example using an alkali metal in an alcohol such as sodium in ethanol) preferably at temperatures from room temperature up to the boiling point of the solvent used. It is of special advantage, however, to perform the reaction with a complex metal hydride, for example with sodium borohydride in pyridine or with lithium aluminium hydride in ether or tetrahydrofuran. If R^" in the compound of formula XI represents a formyl or acetyl group this group is reduced at the same time to the corresponding alkyl group. Where R-. in the compound of formula XI represents an organic acyl group, the reaction is effected with nascent hydrogen or with a complex metal hydride, whereby the organic acyl group is simultaneously removed . i) For the preparation of compounds of general formula I wherein the hydroxy1 group is in the 2-position and represents a hydrogen atom: Hydrolysis of a compound of formula V. (wherein , , Hal and 1 are as hereinbefore defined The hydrolysis is conveniently performed in the presence of an acid such as hydrochloric acid or sulfuric acid or advantageously in the presence of a base such as sodium hydroxide or potassium hydroxide. The reaction is preferably carried out in the presence of a solvent, e.g. ethanol, isopropanol, tert.-butanol , acetone or dioxane, and at temperatures up to the boiling point of the solvent used. j ) Reaction of a compound of formula (wherein R^ , Hal and 1 are as hereinbefore defined and Rg represents an organic acyl group) with an amine of formula (wherein R and R are as hereinbefore defined).

V The reaction is conveniently carried out in the presence of a solvent, for example tetraline, or in an excess of the amine of formula III used, at temperatures from 100° to 220°C, preferably, however, at temperatures from 120° to 180°C. The reaction may also be carried out in the absence of a solvent.

The organic acyl group represented by Rg is preferably acetyl, butyryl, benzoyl or 4-chlorobenzoyl group, k) For the preparation of compounds of general formula I wherein the hydroxyl group is in the 2-position: Reaction of a compound of formula (wherein R^ , Hal and 1 are as hereinbefore defined and Rg represents an alkyl , aryl or aralkyl group) with an amine of formula (wherein and R^ are as hereinbefore defined) and the subsequent hydrolysis of the reaction product.

- - The reaction is conveniently carried out in the presence of a solvent such as tetraline or in an excess of the amine of formula III used, and preferably at temperatures from 100° to 200°C, ideally, however, at temperatures from 120° to 180°C. The reaction may, however, also be performed in the absence of a solvent.

The subsequent hydrolysis is preferably carried out in the presence of an acid such as sulfuric acid or hydrochloric acid in a polar solvent, e.g. water, ethanol/ water or dioxane/water and at temperatures up to boiling point of the solvent used.

The group Rg in the compound of formula XIV used is preferably a methyl, phenyl or benzyl group. 1) For the preparation of compounds of general formula I (wherein R^ , R^ , Hal and 1 are as hereinbefore defined, R, represents a hydrogen atom and the hydroxyl group is in the 2-position): Hydrolysis of a compound of formula (wherein R , R_ , Hal and 1 are as hereinbefore defined).

The hydrolysis may if desired be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid, but is conveniently effected however, without any acid, but in the presence of a polar solvent, e.g. water, methanol/water or dioxane/water. The hydrolysis is preferably effected at temperatures from 0° up to the boiling point of the solvent used. m) For the preparation of compounds of general formula I (wherein , Hal and 1 are as hereinbefore defined, represents a cyclohexyl group and represents a methyl group) ; Reaction of a compound of formula (wherein R^ , Hal and 1 are as hereinbefore defined)with an amide of formula V or with an amide of formula (wherein R and R, are as hereinbefore defined and i 4 represents an alk l , aryl or aralkyl group).

The reaction is conveniently carried out in the presence of a solvent such as tetraline ,and at temperatures from 100° to 250°C, preferably, however, from 120° to 180°C. The reaction may, if desired, be performed in the absence of a solvent.

The compounds of general formulae II - XVIa used as starting materials in processes a - m are partly known from the literature and may be prepared according to processes known from the literature.

The benzyl halides of general formula II, for example, may be prepared from the corresponding toluene derivatives by reaction with halogen or with N-bromo-succinimide under ultraviolet irradiation.

The benzyl alcohol derivatives of general formula II may, for example, be obtained by reaction of the corresponding benzyl alcohol with the corresponding acid in the presence of hydrochloric acid, or by reaction of the corresponding benzyl halide with the corresponding alcohol in the presence of barium carbonate. A benzyl alcohol of formula II may be prepared by halogenation of the corresponding benzyl alcohol.

The aldehydes of general formula IV may be obtained, for example, by halogenation of the corresponding benzaldehydes and the imines of general formulae V and Va may be obtained from the corresponding primary amines and the corresponding carbonyl compounds. A compound of formula VI may be prepared by reduction of a compound of formula V or Va, for example using sodium borohydride.

The benzylamines of general formula IX and X may for example , be prepared by reaction of the corresponding benzyl halides with the corresponding amines optionally with subsequent acylation.

The benzamides of general formula XI used as starting materials .may for example, be prepared by reaction of the corresponding acid halides with the corresponding amines optionally with subsequent acylation.

The compounds of general formula XII used as starting materials may be obtained for example, by halogenation of the corresponding benzoxazines .

V A compound of formula XIII may, for example, be obtained by reduction of the corresponding benzaldehyde with hydrogen and Raney nickel as catalyst.

A compound of formula XIV may be prepared, for example by halogenation of the corresponding compound of formula XIV wherein 1 is zero.

A compound of formula XV may for example be obtained by condensation of the corresponding phenol and an amine of formula III with an excess of formaldehyde.

An acid amide of formula XVI or XVIa may be obtained by reacting the corresponding acid halide with a corresponding amine in the presence of pyridine.

The compounds of general formula I thus obtained may if desired by converted into their acid addition salts, preferably their physiologically compatible acid addition salts, by means of inorganic or organic acids. Hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid or maleic acid have proved to be suitable for this purpose.

As stated above, the novel compounds of general formula I in general possess valuable pharmacological properties. Besides a stimulating effect on the production of the surfactant or the antiatelectasis factor they particularly show a secretolytic and antitussive activity.

The compounds A = N-ethyl-N-cyclohexyl-3 , 5-dibromo-2-hydroxy-benzylamine hydrochloride , B = N-ethyl-N-cyclohexyl-3 ,5-dibromo-4-hydroxy-benzylamine- hydrochloride , C = 3 ,5-dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine hydrochloride , D = 3-bromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine hydrochloride , E = 3-bromo-5-chloro-N-eyelohexy1-4-hydroxy-N-methy1-benzylamine hydrochloride , F = 3 ,5-dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)- benzylamine hydrochloride , G = 3 , 5-dibromo-N-(dihydroxy-tert .-butyl )-2-hydroxy- benzylamine hydrochloride , H = 3 ,5-dichloro-N-(dihydroxy-tert.-butyl)-4-hydroxy-benzyl- amine hydrochloride and I = 3 ,5-dibromo-2-hydroxy-N-tert. -pentyl-benzylamine hydrochloride, for example, have been investigated with regard to their biological activities , and the results of these tests are given hereinbelow. 1) Antitussive activity 50 rag/kg of each of the substances to be investigated were administered orally to several groups of 10 awake white rats . Coughing spasms were induced in these rats by means of a spray containing 7.5% aqueous citric acid. 30 minutes after the application of the substance under investigation the average percentage alteration in the number of cough attacks was determined and compared with the result from a control group of 10 animals (see Engelhorn and Pilschmann In Arzneimittelforschung 13 , 474-480 (1963)).

Substance Average percentage alteration in the number of cough attacks 30 minutes after oral application to 50 mg/kg A -38 B -34 C -35 2) Expectorant effect The expectoration tests were carried out on 8-10 narcotized rabbits or 5 narcotized guinea pigs after oral application of 8 mg/kg of each of the substances to be investigated.

The increase of secretion within 2 hours of application of the substance was calculated (see Perry and Boyd in Pharmakol. exp. Therap. 73, 65 (1941)).

The circulatory effect of the substances on cats was determined under chloralose-urethane narcosis after intravenous application of the compounds (size of test group: 3 animals).

Tests in rabbits : Tests in guinea pigs: Substance Increase of secretion D + 66 % E + 65 % F + 70 % G + 88 % H + 88 % 3) Acute toxicity The orientational acute toxicity was determined in groups of 5 white mice after oral application to each animal of a dose ranging in size from 500 mg/kg to 5000 mg/kg (time of observation: 72 hours).

Substance acute toxicity A >1000 mg/kg, p.o. (0 of 5 animals dead) B >1000 mg/kg, p.o. (0 of 5 animals dead) C >1000 mg/kg, p.o. (0 of 5 animals dead) D >500 mg/kg, p.o. (0 of 5 animals dead) E >500 mg/kg, p.o. (0 of 5 animals dead) F >5000 mg/kg, p.o. (0 of 5 animals dead) G >5000 mg/kg, p.o. (0 of 5 animals dead) H I 5000 mg/kg, p.o. (0 of 5 animals dead) According to a further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient a compound of formula I as hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.

The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral administration. Thus for example compositions for oral administration may be solid or liquid and may take the form of juices, drops, tablets or coated tablets, such compositions comprising carriers or excipients conventionally used in the pharmaceutical art.

For parenteral administration, the carrier may be a sterile parenterally acceptable liquid such as sterile water, or a parenterally acceptable oil, e.g. arachis oil, contained. in ampoules. Compositions for rectal administration may take the form of suppositories, the carrier comprising a suppository base.

Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Each dosage unit preferably contains from 1 to 20 mg preferably however from 2 to 10 mg of active ingredient.

The following Examples sense to illustrate the preparation of compounds according to the invention and also of pharmaceutical compositions containing the same.

V E in^le 1 N-E.thyl-N-cyclohe yl-3 > 5-dibrono-2-hydroxy-benzylamine hydro-chloride 17 S of 3 > 5-dibrono-2-hvdroxy-benzy bromide and 12,7 g of N-ethyl-cyclohexylanine were heated for 3 hours whilst refluxing in 50 ml of ethanol. Subsequently the reaction mixture was evaporated to dryness. The residue was shaken with 150 ml of chloroform and 200 ml of water. The chloroform layer was separated, filtered and evaporated to dryness. The residue was dissolved in ethanol and acidified with ethanolic hydrochloric acid.

In doing so the N-ethyl-N-cyclohexyl-3>5-dibromo-2-hydroxy-benzylamine hydrochloride crystallized out. .p.: 193 - 1 ^°C (decomposition).

Example 2 N-G.yclohexyl-3 » 5-dibromo-2-hydroxy-M-methyl-benzylamine..hydrochloride 21 g of j -dibromo-salicylaldehyde , 56,5 g of N-methyl-cyclo-hexylamine and 23 g of formic acid were heated for 6 hours at■< 70-00°C. After cooling the reaction product was shaken with chloroform and dilute ammonia. The chloroform layer was separated and evaporated to dryness . The residue was purified by means of chromatography over 000 g of silica gel with ethyl acetate/chloroform (1:1).The first0,5 1 of eluent were discarded and tine renHin±¾ 0,5 1 were collected and evaporated to dryness. The residue was dissolved in 50 ml of ethanol and acidified with ethanolic hydrochloric acid. The N-cyclohexyl- , 5-dibromo-2-hydroxy-N-methyl-benzylamine hydrochloride , melting point:- 189-19 °C (decomposition)) crystallized out. 27 / Example Λ 3 , 5-Pi¾romo- -hydro y-H- (cis-3-hydroxy-cyclohexyl )-ben2yl£,ino hydrochloride 19 g of N-(3,5-dibromo-4—hydroxy-benzylidene)-cis-3-amino-cyclo-hexanol (m.p.: 231-233°C, decomposition) were suspended in 0,5 1 of ethanol and mixed with 2 g of sodium borohydride. The mixture was stirred for 1,5 hours at room temperature. Subsequently 200 ml of 2N sodium hydroxide solution were added to the mixture and the ethanol was distilled off in vacuo . The remaining solution was mixed with ammonium chloride. In doing so a cri-stalline precipitate was obtained. The latter was sucked off, washed with v/ater and dissolved in 100 ml of 2 hydrochloric acid whilst heating. After a short time the 3>5-dibromo-4-hyd-roxy-M-(cis-3-hydroxy-cyclohexyl)-benzylamine hydrochloride crystallized out and was then sucked off and washed with acetone.

M.p.: 216-218°C (decomp.) Example N-Cyclohexyl-5.5-dibromo-2-hydroxy-N-methyl-benzylamine hydrochloride 3#6 g of N-cyclohexyl-3 » 5-dibromo-2-hydroxy-benzylamine , 3»6 g of sodium hydrogen carbonate and 3*6 g of methyl iodide were re-fluxed for 16 hours in 25 ml of tetrahydrofuran and 50 ml of methanol. Subsequently the reaction mixture was filtered and evaporated to dryness. The residue was shaken with chloroform and dilute ammonia and the chloroform layer was evaporated to dryness. The remaining residue was boiled with ethyl acetate and after cooling the undissolved material was "filtered" off._^. The filtrate..was acidified with ethanolic hydrochloric acid, thus precipitating' the hydrochloride.

M.p.: 189-191°C (decomposition).

E ompl e 5 V N-Cyc] ohe.xyl- .5- ibromo-4-hydroxy- -mgthyl-bcnzylanine, hydrochloride 7,2 g of N-cyclohexyl- ?-dibromo- -hydroxy-benzylamine were dissolved in 20 ml of formic acid and mixed with 2 ml of 0% formaldehyde. The solution was heated for 3 hours over the boiling water bath, subsequently diluted with water and made alkaline with concentrated ammonia. The precipitated base was sucked off, washed with water and the hydrochloride recrystallized from ethanol by addition of a, little.

M.p.: 168-170°C (decomposition).

Example 6 N-Ethyl-N-cvclohexyI- » 5-dibromo~2-hydroxy-benzylamine-hydrochloride 51 g of N-ethyl-cyclohexylamine and 12 g of paraformaldehyde were dissolved whilst warming in 200 ml of ethanol. After cooling 100 g of ,4-dibromo-phenol were added. The reaction mixture was left to stand for 1 hour at room temperature and was then refluxed for 7 hours. The solution was evaporated to dryness. The residue was dissolved in ether and shaken with 2N ammonia solution and subsequently with water. The ether layer was mixed with 2 hydrochloric acid whilst stirring vigorously until the mixture showed a strong acid reaction. After a short time the hydrochloride crystallized. Th latter was sucked off and washed in turn -with water and acetone. After recrystallization from me-thanol/ether it had a melting point of 193-19^°C (decomposition).

Example 7 Λ N-(4-tort . -Batyl-cyc~lohexyl)- , 5-dibromo- -hydroxy-benzylamine M.p. of the hydrochloride: 229 - 231°C (decomposition) Prepared from 3 » 5-dibromo-4-hydroxy-benzy, brcmide and 4-tert.-butyl-cyclohexylamine analogously to Example 1.

Example 8 3 , 5-E-Lbromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared from 3 > 5-dibromo-2-hydroxy-benzyl .bromide and trans-4-amino-cyclohexanol analogously to Example 1.

Example 9 3 » 5-Dibromo-2-hydroxy-N-(cis-3-hydroxy-cyclohexyl )-benzylamine M.p. of the hydrochloride: 128 - 136°C (decomposition) Prepared from 3 > 5-dibromo-2-hydroxy-benzyl bromide and cis-3-a ino-cyclohexanol analogously to Example 1.

Example 0 ^ 5- Dibromo-2-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-benzylamine M.p.: 203 - 204, 5°C (decomposition) Prepared from , 5-dibromo-2-hydroxy-benzyl bromide and trans-3-arnino-cyclohexanol analogously to Example 1.

Exanpl e 11 V , -Di¾rono-?-hydro::y-N-(trans-4-hydroyy-cyclohe yl )-N-r.othyl-benzyl amine M.p. of the hydrochloride: 120°C (decomposition) Prepared analogously to Example 2 from 3 » 5-dibromo-salicylalde-hyde, trans- -methyl-amino-cyclohexanol and formic acid.

Example 2 3 ? 5-.Dibromo-2-hydroxy-M- (ci?.-3-hydroxy-cyclohexyl)-N-methyl-benzylamine M.p. of the hydrochloride: SO - 83°C (decomposition) Prepared analogously to Example 1 from 3> 5-dibromo-2-hydroxy-benzyl bromide and cis-3-methyl-amino-cyclohexanol .

Example 13 N- Ethyl-3 » 5-dibromo-2-hydroxy-N-(trans- -hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride as ethanolate: 135 - 137°C (decomposition) .

Prepared analogously to Example 1 from 3 > 5-dibromo-2-hydroxy-benzylbromide and trans-4-ethylamino-cyclohexanol .

Example 14 N- Cyclohexyl-3.5-dibromo-2-hydroxy-N-propyl-benzylamine M.p. of the hydrochloride: 178 - 180°C Prepared analogously to Example 1 from 3»5-dibrorao-2-hydroxy-benzyl bromide and N-propyl-cyclohexylamine .

Example 15. "V..

N- Al1y1-N-cyc1ohe>:y1-3 > 5-dibromo-2-hydroxy-benzylamine M.p. of the hydrochloride: 176 - 178°C (decomposition) Prepared from 3 » 5-dibromo-2-hydroxy-benzyIbromide and N-allyl-cyclohexylamine analogously to E xample 1.

Example 6 N- Cyclohexyl-3 > 5-dibromo-2-hydroxy-N-isopropyl-benzylamine M.p.: 108 - 110°C Prepared analogously to Example 1 from 3 » 5-dibromo-2-hydroxy-benzyl bromide and N-isopropyl-cyclohexylamine .

Example 17 N-Cyclohexyl-N-cyclopropyl-3.5-dibromo-2-hydroxy-benzylamine M.p. of the hydrochloride: 204 - 208°C (decomposition) Prepared analogously to Example 1 from 3 > 5-dibromo-2-hydroxy-benzy] bromide and N-cyclopropyl-cyclohexylamine .

Example 18 N- (4-tert . -Butyl-cyclohexyl)- » 5-dibromo-2-hydrox - -methyl-benzylamine M.p. of the hydrochloride: 209 - 211°C (decomposition) Prepared analogously to Example 1 from 3 » 5-dibromo-2-hydroxy-benzyl bromide and N-methyl-4-tert . -butyl-cyclohexylamine .

Exam le 19 N-E.thy1.-N- (trans-4-tcrt . -butyl-cyclo exyl ) -3 > 5-dibromo-2-hydr;:xy benzylamine M.p. of the hydrochloride: 175 - 176°C (decomposition) Prepared analogously to. Example 1 from » 5-dibromo-2-hydroxy-benzy] bromide and N-ethyl-4-tert . -butyl-cyclohexylanine . The mixture of isomers was separated by means of column chromatography.

Example 20 N- Ethyl-N- (cis-4-tert . -butyl-cyclohexyl ) -3 ? 5-dibrono-2-hydro::v-bcnz^lamlne M.p. of the hydrochloride: 168 - 169°C (decomposition) Prepared analogously to Example 19 from 3 , 5-dibromo-2-hydroxy-benzy] bromide and N-ethyl-4-tert . -butyl-cyclohexylanine.

Example 21 N- (trans-4-ter . -Butyl-cyclohexyl)-3.5-dibromo-2-hydroxy-N-pro-pyl-benzylamine M.p. of the hydrochloride: 173 - 174°C (decomposition) Prepared analogously to Example 19 from 3 » 5-dibromo-2-hydroxy-benzyl bromide and N-propyl-4-tert. -butyl-cyclohexylamine .

Example 22 N- (cis-4-tert . -Butyl-cyclohexyl)-3.5-dibromo-2-hydroxy-N-propyl-benzylamine M.p. of the hydrochloride: 148 - 1.50°C (decomposition).

Prepared analogously to Example 19 from 3»5-dibromo-2-hydroxy-benzyl bromide and N-propyl-4-tert. -butyl-cyclohexylamine .

Example 23 N- ( -tert . -¾utyl-cyclohexyl)-3 , 5-dibromo-2-hydroxy-N-lsopropyl-bcnzylamine M.p. of the hydrochloride: 152 - 15/+°C (decomposition) Prepared analogously to Example 1 from 3 , -dibromo-2-hydroxy-benzyl romide and N-isopropyl-4-tert.-butyl-cyclohexylamine.

Example 24 N- Cyclopentyl- , 5-dibromo-2-hvdroxy-TI-methyl-benzylamine M.p.: 61 - 63°C Prepared from 3 > 5-dibromo-2-hydroxy-benzyl bromide and N-methyl-cyclopentylamine analogously to Example 1.

Example 25 N-.Ethyl-N-cyclopentyl- » -dibromo-2-hydroxy-benzylamine M.p. of the hydrochloride: 124 - 128°C (decomposition) Prepared from 3»5-dibromo- 2-hydroxy-benzyl bromide and N-ethyl-cyclopentylamine analogously to Example 1.

Example 26 N- Cyclopenty -3 > 5-dibromo-2-hydroxy-N-propyl-benzylamine M.p. of the hydrochloride: 113 - 120°C Prepared from 3 i -dibromo-2-hydroxy-benzyl bromide and N-propyl-cycl.opentylamine analogously to Example .

E p.P le 27 N-Cycl opentyl-? , 5- ibroino-2-hydroxy-N-isopropyl-bcnzylar,. n M.p. of the hydrochloride: 154 - 157 C (decomposition) Prepared from 3 » dibromo-2-hydroxy-benzy bromide and N-isopro-pyl-cyclopentylamine analogously to E-xample 1.

E sir.r)le .28 N-Cycl oheptyl- . -dibromo-2-hydroxy-N-methyl-benzylamine M.p. of the hydrochloride: 196 - 193°C (decomposition) Prepared from 3 > -dibromo- 2-hydroxy-benzyl bromide and N-methyl-cycloheptylamine analogously to Example 1. .

Example 29 N- Ethyl-N-cycloheptyl-3 » 5-dibromo-2^hydroxy-benzylamine M.p. of the hydrochloride: 180 - 183°C (decomposition) Prepared from 3»5-dibromo-2-hydroxy-benzyl bromide and N-ethyl-cycloheptylamine analogously to Example 1.

Example 30 N- Cycloheptyl-3 , -dibromo-2-hydroxy~N-propyl-benzylamine M.p. of the hydrochloride: 134 - 139°C Prepared analogously to Example 1 from 3» 5-dibromo-2-hydroxy-benzyl bromide and -propyl-cycloheptylamine .

Example 31 N-Cycloheptyl-3 > 5-d.ibromo-2-hydroxy-N-lsopropyl-benzylamine .p. of the hydrochloride: 156 - 1 59°C (decomposition) Prepared from 3 » 5-dibromo-2-hydroxy-benzyl bromide and N-isopro-pyl-cycloheptylamine analogously to Example 1 .

Example 32 3 , 5-.Qibrono-4-hydroxy-N-( trans- -hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 220 - 225°C (decomposition) Prepared analogously to Example 1 from 3 , 5-dibromo- -hydroxy-benzyl bromide and trans-4-amino-cyclohexanol .

Example 33 3 , 5-PibroTno-A-hydroxy-N- (trans-3-hydroxy-cyclohexyl ) -benzylamine M.p. of the hydrochloride: 215 - 215# 5°C (decomposition) Prepared analogously to Example 1 from 3 > 5-dibromo- -hydroxy-benzy] bromide and trans-3-amino-cyclohexanol .

Example N-Cyclohexyl-3 > 5-dibromo-4-hydroxy-N-methyl-benzylamine o .

M.p. of the hydrochloride: 168 - 170 C (decomposition) Prepared analogously to Example 1 from 3 » 5-dibromo-4-hydroxy-benzyl bromide and N-methyl-cyclohexylamine .

Example 35 ^ .5-.D-ibromo-4-hydroxy-N- ( trans-4-hydroxy-cyclohexyl ) -N-methyl- M.p. of the hydrochloride: 160 - 162°C (decomposition) Prepared analogously to Example 1 from 3 » 5-dibromo-4-hydroxy-benzyl bromide and trans-4-methylamino-cyclohexanol .

E>:.°n?le 36 3.5-J) i rorno-A-hydroxy-M-(cis-3-hydroxy-cyc1 ohexyl)-N-methyl-benzy amine M.p.: 133 - 136°C Prepared analogously to Example 1 from 3 * 3-dibromo-A-hydroxy-benzyl bromide and cis-3-methy] amino-cyclohexanol .

Example 37 N- Ethyl-3 > 5-dibromo-4-hydroxy-N- ( trans-4-hydroxy-cyclohexyl ) -benzylamine M.p. of the hydrochloride: 176 - 178°C (decomposition) Prepared analogously to Example 1 from 3 , 5-dibromo-4-hydroxy-benzyl .bromide and trans-4-ethylamino-cyclohexanol .

Example 8 N- B:hyl-3 > 5-dibrOmo-4-hydroxy-M-(cis-3-hydroxy~cyclohexyl )-benzylamine M.p.: 134 - 136°C (decomposition) Prepared analogously to Example 1 from 3 » 5-dibromo-4-hydroxy-benzyl bromide and cis-3-ethylamino-cyclohexanol .

Exampl e 39 M-Cyclohexyl- » 5-dibromo-4-hydroxy-N-r)ropyl-benzylamine M.p.: 1 15 - 116°C (decomposition) Prepared from 3 , 5-dibromo-4-hydroxy-benzyl bromide and N-propyl-cyclohexylamine analogously to Example 1 .

Example AO N-.Allyl-N-cyclohexyl-3 » 5-dibromo-4-hydroxy-benzylamine M.p. of the hydrochloride: 134 - 186°C (decomposition) Prepared from.3 , 5-dibromo-4-hydroxy-benzyl bromide and N-allyl-cyclohexylamine analogously to Example 1 .

Example 41 N- Cyclohexyl-N-cyclopropyl- > 5-dibromo-4-hydroxy-benzylamine M.p. of the hydrochloride: 197 - 198°C (decomposition) Prepared from 3 » 5-dibromo-4-hydroxy-benzy] bromide and N-cyclo-propyl-cyclohexylamine analogously to Example 1 .

Example 42 N- (4-tert .-Butyl-cyclohexyl) -3 » 5-dibromo-4-hydroxy-N-methyl-benzylamine M.p. of the hydrochloride: 158 - 159°C (decomposition) Prepared analogously to xample 1 from 3 » 5-dibromo-4-hydroxy-benzy] bromide and N-methyl-4-tert.-butyl-cyclohexylamine.

Example 43 N-Ethyl-N- (4-tert . -butyl-cyclohexyl ) -3 > 5-dibromo-4-hydroxy-bensv an;ine M.p. of the hydrochloride: 170 - 170, 5°C (decomposition) Prepared from 3 > 5-dibromo-4-hydroxy-benzyl bromide and N-ethyl-4-tert . -butyl-cyclohexylamine analogously to Example 1.

Example 44 N- (4-tert . -Butyl-cyclohexyl )-3 > 5-dibromo-4-hydroxy-N-propyl-benzylamine M.p. of the hydrochloride: 159 - 160°C (decomposition) Prepared from 3>5-dibromo-4-hydroxy-benzy] bromide and N-propyl 4-tert. -butyl-cyclohexylamine analogously to Example 1.

Example 45 N- Cyclopentyl-3 > 5-dibromo-4-hydroxy-N-methyl-benzylamine M.p. of the hydrochloride: 185 - 188°C (decomposition) Prepared analogously to Example 1 from 3»5-dibromo-4-hydroxy-benzyl bromide and N-methyl-cyclopentylamine .

Example 46 N-Ethyl-N-cycbpentyl- » 5-d-romo-4-hydroxy-benzylamine M.p. of the hydrochloride: 164 - 165°C (decomposition) Prepared from 3 > 5^dibromo-4-hydroxy-benzyl bromitie and N-ethyl-cyclopentylamine . analogously to Example 1.

Example 47 -* N-Cyclopentyl-3 * 5-dibromo-4-hyriroxy- -propyl-benzylaminc M.p. of the hydrochloride: 156 - 15S C (decomposition) Prepared from 3 > 5-dibromo-4-hydroxy-benzy] bromide and N-propyl-cyclopentylamine analogously to Example .

Example 48 N-Cyclopentyl- , 5-dibromo-4-hydroxy-N-isopropyl-benzylamine M.p. of the hydrochloride: 151 - 152°C (decomposition) Prepared from 3 » 5-dibromo-4-hydroxy-benzy. bromide and N-isopro-pyl-cyclopentylamine analogously to Example 1 .

Example 49 N- Cycloheptyl-3 > 5-dibromo-4-hydroxy-N-methyl-benzylamine M.p. of the hydrochloride: 175 - 179°C (decomposition) Prepared from 3 , -dibromo-4-hydroxy-benzyl bromide and N-methyl-cycloheptylamine analogously to Example .1 .

Example 0 N- Ethyl-N-cycloheptyl-3 > 5 -dibromo-4-hydroxy-benzylamine M.p. of the hydrochloride: 176 - 177°C (decomposition) Prepared analogously to Example 1 from 3 » -dibrorao-4-hydroxy-benzyl bromide and N-ethyl-cycloheptylamine .

Example 51 »' N-Cycl ohe tyl-3 » 5-di rono-4-hydroxy-N-propyl-bcnzylamine M.p. of the hydrochloride: 35 - 136°C Prepared analogously to Example 1 from 3,5-dibromo-4-hydroxy-benzyl bromide and N-propyl-cycloheptylamine .

Example 2 N- (2-Bicyclo/.. , 2 , l7heptyl)-3 > 5-dibromo-fr-hydroxy-N-methyl-ben-zylfimine M.p. of the hydrochloride: 181 - 182°C (decomposition) Prepared analogously to Example 1 from 3 » 5-dibromo-4-hydroxy-benzyl bromide and 2-methyl-amino-bicyclo 2,2,i1J-heptane.

Example 53 N-Cyclohexyl-3 > 5-dichloro-2-hydroxy-N-methyl-benzylamine M.p. of the hydrochloride: 174 - 170°C Prepared analogously to Example 1 from 3 > 5-dichloro-2-hydroxy-benzy bromide and N-methyl-cyclohexylamine .

Example 54 N-E thyl-N-cyclohcxyl- , 5-dichloro-2-hydroxy-benzy].amine M.p. of the hydrochloride: 135 - 183°C (decomposition) Prepared analogously to Example 1 from 3 » 5-dichloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine .

Example 55 N- Ethy - » 5-dichloro-2-hydroxy-N-( trans-4-hydroyy-cyclohexyl ) - enzylamine M.p. of the hydrochloride: 147 - 152°C Prepared analogously to Example 1 from 3>5-dichloro-2-hydroxy-benzyl bromide and trans-4-ethylamino-cyclohexanol .

Example 56 N-Cyclohexyl-3, 5-dichloro-2-hydroxy-N-propyl-benzylamine M.p. of the hydrochloride: 168 - 170°C Prepared analogously tc Example 1 from 3 , 5-dichloro-2-hydroxy-benzyl .bromide and N-propyl-cyclohexylamine .

Example 57 N-Cyclohexyl-3 > -dichloro~2-hydroxy- -isopropyl-benzylamine M.p. : 36 - 89°C Prepared analogously to Example 1 from 3 , 5-dichloro-2-hydroxy-benzyl bromide and N-isopropyl-cyclohexylamine .

Exam e 58 TT-E t y -M-cyclohe::yl- · 5-dichloro-4-hydroxy-benzylaraine M.p. of the hydrochloride: 190 - 191°C (decomposition) Prepared from 3 » -dichloro-4-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine analogously to Example 1.

E anrole 59 -4 M- Ethyl-3-bronQ-5-c.h oro-N-cvclohgxyl-2-h\rdroxy-benzylarnine 11 . p . of the hydrochloride: 1 - 197°C (decomposition) Prepared from 3-bromo-5-chloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine analogously to Example 1.

Example 60 N- Ethyl-5-bromo-3-ch].oro- -cyc].ohexyl-2-hydroxy-benzyla:r.irie M.p. of the hydrochloride: S3 - 191°C (decomposition) Prepared from 5-bromo-3-chloro-2-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine analogously to Example 1.

Example 61 5-¾romo-N-cyclohexyl-2-hydroxy-N-methyl-benzylamine M.p. of the hydrochloride: 19 - 197°C Prepared from 5-bromo-salicylaldehyde , N-methyl-cyclohexylamine and formic acid analogously to Example 2.

Example 62 N ·,Ethyl-5-bronio-N-cyclohexyl-2-hydroxy-benzylamine M.p. of the hydrochloride: 175 - 178°C Prepared from 5-bromo-salicylaldehyde, N-ethyl-cyclohexylamine and formic acid analogously to Example 2.

}.'.."'P. inn .. Θ 4.' N-Ethyl-5-bromo-2-hydroxy-N-(trans- -hydroxy-cyclohexyl)-ben-zylamine M.p. of the hydrochloride: 190 - 193°C (decomposition) Prepared from 5-brorao-salicylaldehyde , trans-4-ethylamino-cyclohexanol and formic acid analogously to Example 2.

Example 64 5-Bromo-N-cyclohexyl-2-hydroxy-N-propyl-benzylamine M.p. of the hydrochloride: 166 - 169°C (decomposition) Prepared from 5-bromo-salicylaldehyde, N-propyl-cyclohexyl-amine and formic acid analogously to Example 2.

Example 65 5-Bromo-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamlne M.p.: 90 - 93°C Prepared from 5-bromo-salicylaldehyde, N-isopropyl-cyclohexyl-amine and formic acid analogously to Example 2.

Example 66 5- Qiloro-N-cyclohexyl-2-hydroxy-N-methyl-benzylamine M.p. of the hydrochloride: 194 - 198°C Prepared from 5-chloro-salicylaldehyde , N-methyl-cyclohexyl-amine and formic acid analogously to Example 2.

Example 67 N-Ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine M.p. of the hydrochloride: 169 - 171°C Prepared from 5-chloro-salicylaldehyde, N-ethyl-cyclohexyl-amine and formic acid analogously to Example 2.

Example 68 5-Chloro-N-cyclohexyl-2-hydroxy-N-propyl-benzylamine M.p. of the hydrochloride: 140 - 142°C Prepared from 5-chloro-salicylaldehyde, N-propyl-cyclohexyl-amine and formic acid analogously to Example 2.

Example 69 5-Chloro-N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine M.p.: 85 - 8S°C Prepared from 5-chloro-salicylaldehyde, N-isopropyl-cyclohexyl-amine and formic acid analogously to Example 2.

Example 70 ?-¾romo-N-cyclohexyl-4-hydroxy-N- nethyl-benzylamine M.p. of the hydrochloride: 165 - 169°C (decomposition) Prepared analogously to Example 1 from 3-bromo-4-hydroxy-benzyl bromide and N-methyl-cyclohexylamine.

Example 71 N- (4-tert . -Sutyl-cyclohexyl )-3, 5-dibromo-2-hydroxy-benzylamine M.p.: 188 - 191°C Prepared analogously to Example 1 from 3>5-dibromo-2-hydroxy-benzyl bromide and 4-tert. -butyl-cyclohexylamine .

Example 72 N- Ethyl-N-cyclohexyl-5 » 5-dibromo-4-hydroxy-benzylamine M.p. of the hydrochloride: 180 - 181°C (decomposition) Prepared from » 5-dibromo-4-hydroxy-benzy!l bromide and N-ethyl-cyclohexylamine analogously to Example .

Example 73 N-Ethyl-2-bromo-N-cyclohexyl-5-hydroxy-benzylamine 54 g of 2-bromo-5-hydroxy-benzyl bromide in 800 ml of carbon tetrachloride were mixed with 51 g of N-ethyl-cyclohexylamine and refluxed for 1 hour. Subsequently the reaction mixture was shaken twice with water and the organic phase was dried over sodium sulfate and evaporated. The residue was purified by means of column chromatography over silica gel with ethyl acetate as eluent. The crude base was dissolved in ethyl acetate and acidified with absolute ethanolic hydrochloric acid. In doing so the N-ethyl-2-bromo-N-cyclohexyl-5-hydroxy-benzyl-amine . hydrochloride crystallized out.

M.p.: 183 - 188°C (decomposition) Example 74 £ 2 ,4-Dibromo-5-hydroxy-N-(trans-4-hydroxy-cvclohexyl)-benzylamine 3.5 g of N-(2,4-dibromo-5-hydroxy-benzylidene)-trans-4-amino- cyclohexanol in 70 ml of ethanol were added' dropwise to a solution of 0,4 g of sodium borohydride in 5 ml of water whilst stirring. After stirring for 1 hour 10 ml of 2Ν· sodium hydroxide solution and 30 ml of water were added to the solution which was then evaporated to half its volume. Subsequently the solution was mixed with saturated ammonium chloride solution thus precipitating the 2 , 4-dibromo-5-hydroxy-N- (trans-4-hydroxy-cyclo- hexyl)-benzylamine . The precipitate was sucked off, suspended in acetone, warmed and acidified with absolute ethanolic hydrochloric acid. In doing so the base dissolved and the hydrochloride crystallized out immediately.

M.p.: 268 - 270°C (decomposition) Example 75 5-Bromo-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine 3.6 g of 3-bromo-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine-hydrochloride were dissolved in 50 ml of 90 % acetic acid and mixed with a solution of 0,75 g of chlorine in 15 ml of glacial acetic acid whilst cooling with ice-water. After stirring for a short time the solution was poured into a mixture of ice and 10N sodium hydroxide solution and extracted three times with methylene chloride. The organic phase was evaporated to dryness. The residue was purified by means of column chromatography over silica gel with ethyl acetate as eluent. The 3-bromo-5-chloro- -cyclohexyl-4-hydro y-N-methyl-benzylamine was recrystallized from ethanol/ether.

M.p.: 136-138°C.

Example 76 > N~Ethyl-5-bromo--N-cyclohexyl-3-chloro-- -hydroxy--ben2ylamine 2,3 g of N-ethyl-3-chloro-N-cyclohexyl- -hydroxy-benzylamine were dissolved in 20 ml of 75% acetic acid and mixed dropwise whilst stirring with 1,6 g of bromine. The solution was diluted with water, made alkaline with concentrated ammonia and shaken twice with chloroform. The organic phase was dried over sodium sulfate and evaporated. The residue was dissolved in absolute ethanol and acidified with absolute ethanolic hydrochloric acid. On addition of ether the N-ethyl-5-bromo-N-cyclo-hexyl-3-chloro- -hydroxy-benzylamine hydrochloride crystallized out.

M.p.: 165 - 168°C (decomposition) Example 77 N-Ethyl-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine 13 g of N-ethyl-eyelohexylamine and 3 g of paraformaldehyde were dissolved whilst heating in- 100 ml of ethanol. The -mixture was -then cooled mixed with 13 g of 2-chloro phenol, left to stand for 1 5 hours at room temperature and finally refluxed for 3 hours. Subsequently the solution was evaporated and the residue purified with ethyl acetate over a column of silica gel. The crude base was dissolved in absolute ethanol and acidified with absolute ethanolic hydrochloric acid. The N-ethyl-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine-hydrochloride crystallized out on addition of ethyl acetate .

M.p.: 177 - 178°C (decomposition) Example 78 3.5-J3ichloro-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl) -benzyl-amine M.p. of the hydrochloride: 216 - 222°C (decomposition) Prepared by reduction of N-(3 » 5-dichloro-2-hydroxy-benzylidene)-trans-4-amino-cyclohexanol with sodium borohydride analogously, to Example 74.

Example 79 , 5- Dichloro-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylr-amine M.p. of the hydrochloride: 222 - 225°C (decomposition) Prepared by reduction of N-(3»5-dichloro-4-hydroxy-benzylidene) trans-4-amino-cyclohexanol with sodium borohydride .· analogously to Example 74.

Example 80 3-Bromo-5-chloro-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-ben-zylamine M.p. of the hydrochloride: 214 - 221°C (decomposition) Prepared analogously to Example 74 by reduction of N-(3-bromo-5-chloro-2-hydroxy-benzylidene)-trans-4-amino-cyclohexanol with sodium borohydride.

Example 81 5-Bromo-3-chloro-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-ben-zylamine M.p. of the hydrochloride: 193 - 197°C (decomposition) Prepared analogously to Example 74 by reduction of N-(5-bromo- 3-chloro-2-hydroxy-benzylidene ) -trans-4-amino-cyclohexanol wlfth sodium borohydride.

Example 82 5-Bromo-3-chloro-4-hydroxy-N- ( trans-4-hydroxy-cyclohexyl ) -ben-zylamine M.p. of the hydrochloride: 220 - 226°C (decomposition) Prepared analogously to Example 74 by reduction of N-(5-bromo-3-chloro-4-hydroxy-benzylidene ) -trans-4-amino-cyclohexanol with sodium borohydride.

Example 83 -¾romo-2-hydroxy-N-(trans~4-hydroxy-cyclohexyl)^benzylamine M.p. of the hydrochloride: 222 - 230°C (decomposition) Prepared analogously to Example 74 by reduction of N-(5-bromo-2-hydroxy-benzylidene)-trans- —araino-cyclohexanol with sodium borohydride . vi.

Example 84 2-¾romo-5-hydroxy-N-(trans-4-hydroxy-cyclohexyl)»benzylamine M.p. of the hydrochloride: 220 - 225°C (decomposition) Prepared analogously to Example 73 from 2-bromo-5-hydroxy-ben-zyl bromide and trans-4-amino-cyclohexanql.

Example 85 j5-Bromo-4-hydroxy-N^trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 225 - 227°C (decomposition) Prepared by reduction of N-(3-bromo-4-hydroxy-benzylidene)-trans-4-amino-cyclohexanol with sodium borohydride " analogously to Example 74.

Example 86 g-Bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl)^benzylamine M.p. of the hydrochloride: 194 - 196°C (decomposition) Prepared by reduction of N-(3-bromo-2-hydroxy-benzylidene)-trans-4-amino-cyclohexanol with sodium borohydride analogously to Example 74.

Example 37 2 , 6-.Dibromo-3-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 269 - 271°C (decomposition) Prepared by reduction of N-(2,6-dibromo-3-hydroxy-benzylidene)-trans-4-amino-cyclohexanol analogously to Example 74.

Example 88 >,5-.Dichloro-2-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 209 - 214°C (decomposi-tion) Prepared analogously to Example 74 by reduction of N-(3»5-di-chloro-2-hydroxy-benzylidene)-cis-3-amino-cyclohexanol .

Example 89 , 5-Dichloro-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl ) -benzylamine M.p. of the hydrochloride: 219 - 224°C (decomposition) Prepared by reduction of N-(3i 5-dichloro-4-hydroxy-benzylidene)-cis-3-amino-cyclohexanol analogously to Example 74.

Example 90 3-Bromo-5-chloro-2-hydrbxy-N-(cis-3-hydroxy-cyclohexyl -benzylamine M.p. of the hydrochloride: 197 - 201°C (decomposition) Prepared by reduction of N-(3-bromo-5-chloro-2-hydroxy-benzyli-dene)-cis-3-amino-cyclohexanol analogously to Example 74.

Example 91 5-Bromo-3-chloro-2-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 219 - 222°C (decomposition) Prepared analogously to Example 74 by reduction of N-(5-bromo-3-chloro-2-hydroxy-benzylidene ) -cis-3-amino-cyclohexanol .

Example 92 -Bromo-3-chloro-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 216 - 218°C (decomposition) Prepared analogously to Example 74 by reduction of N-(5-bromo-3-chloro-4-hydroxy-benzylidene)-cis-3-amino-cyclohexanol .

Example 93 5-Bromo-2-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 148 - 151°C (decomposition) Prepared by reduction of N-(5-bromo-2-hydroxy-benzylidene)-3-araino-cyclohexanol analogously to Example 74.

Example 94 2-Bromo-^-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 245 - 250°C (decomposition) Prepared by reduction of N-(2-bromo-5-hydroxy-benzylidene)- 3-amino-cyclohexanol analogously to Example 74.

Example 95 2 , 4- Dibromo-5-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamlne M.p. of the hydrochloride: 278 - 280°C (decomposition) Prepared by reduction of N-(2 ,4-dibromo-5-hydroxy-benzylidene)-cis-3-amino-cyclohexanol analogously to Example 74.

Example 96 3-Bromo-4-hydroxy-N-(cis-?-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 214 - 220°C (decomposition) Prepared by bromination of 4-hydroxy-N-(cls-3-hydroxy-cyclohexyl)-benzylamine analogously to Example 76.

Example 97 . ^\ j3-Bromo-2-hydroxy-N- ( cis-3-hydroxy-cyclohexyl) -benzylamine M.p. of the hydrochloride: 163 - 167°C (decomposition) Prepared analogously to Example 74 by reduction of N- (3-bromo- 2-hydroxy-benzylidene)-cis-3-amino-cyclohexanol .

Example 98 2 > 6-Dibromo-3-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 255 - 259°C (decomposition) Prepared analogously to Example 74 by reduction of N- ( 2 , 6-di-bromo-3-hydroxy-benzylidene)-cis-3-amino-cyclohexanol .

Example 99 N-Ethyl-2-bromo-4-chloro- -cyclohexyl-5-hydroxy-benzylamine M.p. of the hydrochloride: 132, 5 - 137°C (decomposition) Prepared analogously to Example 76 by bromination of N-ethyl-4^chloro-N-cyclohexyl-5-hydroxy-benzylamine .

Example 100 N- Ethyl-4-chloro-N-cyclohexyl-3-hydroxy-benzylamire M.p. of the hydrochloride: 128 - 132°C (decomposition) Prepared analogously to Example 73 from 4-chloro-3-hydroxy-ben-zy] bromide and N-ethyl-cyclohexylamine .

Example 101 N-Ethyl-2-chloro-N-cyclohexyl-5-hydroxy-benzylamine M.p. of the hydrochloride: 210 - 211°C Prepared analogously to Example 73 from 2-chloro-5-hydroxy-benzyl bromide and N-ethyl-cyclohexylamine .

Example 102 N- Ethyl-N-cyc hexyl-2 , 4-dichloro-5-hydroxy-benzylamine M.p. of the hydrochloride: 179 - 186°C (decomposition) Prepared analogously to Example 75 by chlorinatlon of N-ethyl-N-cyclohexyl-5-hydroxy-benzylamine .

Example 03 N-Ethyl-3-bromo-N-cyclohexyl-4-hydroxy-benzylamlne M.p. of the hydrochloride: 185 - 190°C (decomposition) Prepared analogously to Example 77 from 2-bromophenol, „ paraformaldehyde and N-ethyl-cyclohexylamine.

Example 104 N-Ethyl-4-chloro-N-cyclohexyl-2-hydroxy-benzylamine M.p. of the hydrochloride: 144 - 146°C Prepared from 3-chlorophenol , paraformaldehyde and N-ethyl-cyclohexylamine analogously to Example 77.

Example 105 N-Ethyl-3-bromo-N-cyclohexyl-2-hydroxy-benzylamlne M.p. of the hydrochloride: 171 - 173°C Prepared analogously to Bcample 77 from 2-bromohydride formaldehyde and N-ethyl-cyclohexylamine .

Example 106 N- Ethyl-4-bromo-N-cyclohexyl-2-hydroxyr-benzylamine M.p. of the hydrochloride: 175 - 177°C Prepared from 3-bromohydride paraformaldehyde and N-ethyl-cyclohexylamine analogously to Example 77.

Example 107 N-Ethyl-3-chloro-N-cyclohexyl-4-hydroxy-benzylamine M.p. of the hydrochloride: 181 - 183°C Prepared analogously to Example 75 by chlorination of N-ethyl-N-cyclohexyl-4-hydroxy-benzylamine .

Example 108 N-Ethyl-2-chloro-N-cyclohcxyl-4-hydroxy-benzylamine M.p. of the hydrochloride: 165 - 166,5°C Prepared analogously to Example 77 from 3-chlorophenol paraformaldehyde and N-ethyl-cyclohexylamine.

Example 109 . .

N-Ethyl-2-bromo- -chloro-N-cyclohexyl-3-hydroxy-benzylamlne M.p. of the hydrochloride: 130 - 137°C (decomposition) Prepared analogously to Example 76 by bromination of N-ethyl- -chloro-N-cyclohexyl-3-hydroxy-benzylamine .

Example 1 0 N-Ethyl-N-cyclohexyl-2 , 6-dibromo-3-hydroxy-benzylamine M.p.: 123 - 126°C Prepared analogously to Example 76 by bromination of N-ethyl-N-cyclohexyl-3-hydroxy-benzylamine.

Example 111 N-Ethyl-N-cyclohexyl-2 , -dichloro-3-hydroxy-benzylamine M.p. of the hydrochloride: 127 - 132°C (decomposition) Prepared analogously to Example 75 by chlorination of N-ethyl-N-cyclohexyl-3-hydroxy-benzylamine .

Example 112 3 5-Xtibromo-2-hydroxy-N-methyl-N-morpholinocarbonylmethyl-ben-zylamine M.p. of the hydrochloride: 196 - 201°C Prepared analogously to Example 73 from 3 » -dibromo-2-hydroxy-benzy] bromide and sarcosine morpholide.

Example 113 ^ j » 5-Dibromo-4-hydroxy--N-methyl-N-morpholinocarbonylmethyl-benzylamine M.p. of the hydrochloride: 214 - 218°C Prepared analogously to Example 73 from 3f 5-dibromo-4-hydroxy-benzyl bromide and sarcosine morpholide.

Example 4 4-Chloro-2-hydroxy-H-methyl-N-morpholinocarbonylmethyl-benzyl-amine M.p. of the hydrochloride: 210 - 213°C (decomposition) Prepared analogously to Example 77 from 3-chloro phenol , , paraformaldehyde and sarcosine morpholide.

Example 115 2-Chloro-4-hvdroxy-N-methyl-N-morpholinocarbonylmethyl-benzyl-amine M.p. of the hydrochloride: 216 - 217°C (decomposition) Prepared analogously to Example 77 from 3-chlbro phenol , paraformaldehyde and sarcosine morpholide.

Example 116 N- Ethyl-N-cyclohexyl- 5-dibromo-4-hydroxy-benzylamine M.p. of the hydrochloride: 180 - 181°C (decomposition) Prepared analogously to Example 76 from N-ethyl-N-cyclohexyl-4-hydroxy-benzylamine and bromine.

Example 1 7. . /- .

N-Ethyl-6-chloro-N-cyclohexyl-2 > -dibromo-3-hydroxy-benzylamine M.p.: 138 - 140°C Prepared analogously to Example 76 from N-ethyl-2-chloro-N-cyclohexyl-5-hydroxy-benzylamine hydrochloride and bromine.

Example 8 N- Ethyl-4-chloro-N-cyclohexyl-2 , 6-dibromo-3-hydroxy-benzylamine M.p. of the hydrochloride: 189 - 190°C (decomposition) Prepared analogously to Example 76 from N-ethyl-4-chloro-N-cyclohexyl-3-hydroxy-benzylamine hydrochloride and bromine.

Example 119 N-E thyl- -cyclohexyl-3-hydroxy-2 , , 6-tribromo-benzylamine M.p.: 172 - 175°C Prepared analogously to Example 76 from N-ethyl-2-bromo-N-cyclohexyl-5--hydroxy-benzylamine and bromine.

Example 120 ^-Hydroxy-N-(cis-3-hydroxy-cyclohexyl)-2 ,4, 6-tribromo-benzylamine M.p. of the hydrochloride: 228 - 228#5°C (decomposition) Prepared analogously to Example 74 by reduction of N-(3-hydroxy-2,4,6-tribromo-benzylidene)-cis-3-amino-cyclohexanol with sodium borohydride.

Example 21 3- Hydroxy-N- (trans-4-hydroxy-cyclohexyl ) -2 , , 6-tribrono-benzyl-amine M.p. of the hydrochloride: 259 - 261°C (decomposition) Prepared analogously to Example 7 by reduction of N-(3-hydroxy-2,4,6-tribromo-benzylidene)-trans-4-amino-cyclohexanol with sodium borohydride.

Example 22 N- Ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylarnine 3,5 g of N-ethyl-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride v.rere dissolved in 50 ml of glacial acetic acid. Whilst stirring vl^prousJ a solution of 0,85 g of chlorine in 10 ml of glacial acetic acid was poured into the reaction mixture, which was stirred for 1 minute and then poured onto ice. Subsequently 10N sodium hydroxide solution was added until a slightly alkaline reaction could be observed and the mixture was extracted twice with 100 ml of chloroform. The combined chloroform solutions were washed with water, dried over sodium sulfate and evaporated to dryness in vacuo . The oily residue was dissolved in a little absolute ethanol. On gradual addition Of etheral hydrochloric acid until the solution was clearly acid colourless crystals precipitated. The hydrochloride was sucked off and re-crystallized twice from isopropanol.

M.p. : 169 - 171°C Example 123 N-Ethyl-N-cyclohexyl- » -dichloro-2-hydroxy-benzylamine 3,1 g of N-ethyl-N-cyclohexyl-2-hydroxy-benzylamine were dissolved in 100 ml of absolute tetrahydrofuran and 4 ml of pyridine. The solution was cooled to -5°C. At that temperature 7.2 g of iodosobenzene dichloride were added portionwise to the^^ reaction mixture which was stirred for a further 2 hours at -5 -0°C. Subsequently the reaction mixture was evaporated to dryness in vacuo and the residue was distributed between chloroform and water. The chloroform solution was separated and the aqueous solution was extracted further with chloroform. The combined chloroform layers were dried over sodium sulfate and evaporated to dryness in vacuo . The oily residue was dissolved in a little absolute ethanol. On addition of ethereal hydrochloride acid until an acid reaction could clearly be observed colourless crystals precipitated which were then sucked off and recrystallized from isopropanol.

M.p. of the hydrochloride: 185 - 188 °C (decomposition) Example 124 j N-Ethyl-N-cyclohexyl-3 , 5-dfcbromo-2-hydroxy-benzylamine 2.7 g of N-ethyl-N-cyclohyexyl-2-hydroxy-benzylamine were dissolved in 50 ml of glacial acetic acid. Whilst stirring vigorously at room temperature a solution of 1 ml of bromine in 10 ml of glacial acetic acid was dropped slowly into the reaction mixture . The reaction mixture was then poured onto ice, made alkaline with ION sodium hydroxide solution and extracted three times with 100 ml portions of chloroform. The combined chloroform solutions were washed v/ith water, dried over sodium sulfate and evaporated to dryness in vacuo . The oily residue v:as dissolved in . absolute ethanol. On addition of. etherealhydrochloric acid until* an acid reaction could be observed clearly colourless crystals precipitated which were sucked off and recrystallized from absolute ethanol.

M.p. of the hydrochloride: 193 - 9 °C (decomposition) Example 125 At that temperature a solution of 10.6 g of tribromophenol- I i bromine in 200 ml of methylene chloride was slowly added dropwise and with vigorous stirring to the reaction mixture which was then stirred for a further 2 hours and evaporated to dryness in vacuo. The residue was purified by means of column chromatography over silica gel using chloroform as eluent. When the fractionation was completed the solvent was evaporated in vacuo . The residue was dissolved in a little absolute ethanol. Ethereal hydrochloric acid was added until a clearly acid reaction was observed and colourless crystals precipitated which were sucked off and re- crystallized from absolute ethanol.

M.p. of the hydrochloride: 193 - 19 °C (decomposition) Example 126 N- Ethyl-N-cvclohexyl-5 , 5-dibromo-2--hvdroxy-benzylamlne 0,15 g of 2-acetoxy-N-ethyl-N-cyclohexyl-3,5-dibromo-benzyl- amine were boiled for 1 hour with 10 ml of 4N .-ethanolic hydro.- chlor c acid. The reaction mixture was cooled, poured onto ice, made alkaline with concentrated ammonia and shaken out with chloroform. The chloroform extract was dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in ethanol, and -ethanolic hydrochloric acid was added thus, crystallizing out the hydrochloride.

M.p.: 193 - 194°C (decomposition) Example 127 3 5--Dibror,o-2-hvdroxy-N- (trans-4-hydroxy-cyclohexyl ) -benzylamine 4,7 g of -benzyl-3,5-dibrono-2-hydroxy-N-(trans-4-hydroxy-cyclo-hexyl)-benzylamine were dissolved in 350 ml of methanol and 6 ml of 2N hydrochloric acid and hydrogenated in the presence of 350 mg of palladium (10 %) on coal. The hydrogenation was stopped as soon as 1 mol of. hydrogen had been .absorbed. ' The catalyst -was filtered off from the reaction mixture and the filtrate was evaporated in vacuo. he residue was recrystallized from ethanol. 3» 5- ibromo-2-hydroxv-N- (trans-4-hydroxy-cyclohexyl)-benzylamine ·hydrochloride was obtained with a melting point of 212 - 218°C (decomposition).

Example 28 N-Ethyl-N-cyclohexyl- , 5-dibromo-2-hydroxy-be'nzylamlne 0,2 g of N-ethyl-N-cyclohexyl-3 , 5-dibromo-2-methoxy-benzylamine < hydrochloride were boiled for 3 hours with 3 ml of a 40% solution of hydrobromic acid in glacial acetic acid. The reaction mixture was cooled, poured onto ice,made alkaline with ammonia and extracted with chloroform. The chloroform extract was dried over sodium sulfate and evaporated i£ vacuo, The residue was dissolved in ethanol. By addition of ethanolic hydrochloric acid the hydrochloride was crystallized out.

M.p.: 193 - 194°C (decomposition) Example 129 N- (4-tert . -Butyl-cyclohexyl)-3 > 5-dibromo-2-hydroxy-benzylamine 2,8 g of 3»5-dibromo-2-hydroxy-benzylamine and 1#6 g of 4-tert.-butyl-cyclohexanonewere refluxed for 4 hours in 250 ml of toluene . After cooling the reaction mixture was diluted with 250 ml of methanol and mixed portionwise whilst stirring with 2,8 g of sodium borohydride . After one hour the mixture was evaporated to dryness in vacuo . The residue was shaken with 2N sodium hydroxide solution. The substance was sucked off, washed with water and recrystallized from methanol. The mixture of isomers could be separated by means of column chromatography over silica gel with chloroform/ethyl acetate (2:1).

M.p. of the. cis-form: 159 - 160°C M.p. of the trans-form: 186 - 189°C (decomposition) Example 130 M-Ethyl-N-cyclohexyl-3 » 5-dibromo-2-hydroxy-benzylamine 0, g of N-ethyl-N-cyclohexyl-3 , 5-dibromo-2-hydroxy-benzamide v/ere boiled for 5 hours with 0,12 g of sodium borohydride in 20 ml of dry pyridine. In order to destroy the excess of sodium borohydride, - acetone was added and the pyridine was removed jn. vac_ o . The residue .was distributed between water and chloroform ,and the combined chloroform layers were dried over sodium sulfate and evaporated in vacuo . The residue was purified o'ver a column of silica gel with ethyl acetate. An oil was obtained which was dissolved in ethanol and converted into the N-ethyl-N-cyclohexyl-3 » 5-dibromo-2-hydroxy-benzylamine hydrochloride by addition of ethanolic hydrochloric acid.

M.p.: 193 - 19 °C (decomposition) Example 131 N- Ethyl-N-cyclohexyl-3 , 5-dibromo-2-hydroxy-benzylamine 1 g of N-ethyl-N-cyclohexyl-3 >5-dibromo-2-hydroxy-benzamide was boiled for 1 hour with 0,17 g of lithium aluminium . hydride in 80 ml of absolute tetrahydrofuran. The reaction product was cooled and cautiously mixed with water. The precipitate was separated and boiled ~ with tetrahydrofuran. The combined tetrahydrofuran solutions were evaporated in, vacuo . the. residue was distributed between water and chloroform and the combined chloroform layers were dried over sodium sulfate and evaporated .in vacuo. An oil was obtained which was dissolved in ethanol and converted into the N-ethyl-N-cyclohexyl-3 , 5-dibromo-2-hydroxy-benzylamine hydrochloride by means of ethanolic hydrochloric acid.

M.p.: 193 - 19 °C (decomposition) Example 32.

N-Ethyl-N-cyclohexyl-3 > 5-dibromo-2-hydroxy-benzylamine 2# 25 g * of 2-acetoxy-N-ethyl-M-cyclohexyl-3 » 5-dibromo-benzamide were dissolved in 30 ml of absolute tetrahydrofuran and dropped whilst stirring into a suspension of 0,8 g of lithium aluminium hydride in 120 ml of absolute tetrahydrofuran. The mixture was boiled for 75 minutes, then cooled to about 10°C and mixed with water. The precipitate was separated and washed once with tetrahydrofuran . The combined tetrahydrofuran solutions containing water were evaporated in order to remove the organic solvent. The aqueous solution thus obtained was extracted three times with chloroform and the combined chloroform extracts were dried over sodium sulfate and evaporated. The N-ethyl-N-cyclo-hexyl-3 , 5-dibromo-2-hydroxy-benzylamine was obtained as an oil which was then dissolved in ethanol and converted into its hydrochloride with ethanolic hydrochloric acid.

M.p.: 193 - 9^°C (decomposition) Example 33 - Ethyl-N-cyclohexyl- , -dibromo-2-hydroxy-benzylamine 1 # 2 g of 2-acetoxy-N-acetyl-N-cyclohexyl-3 , 5-dibromo-benzyl-amine were boiled for about 1 hour with 0, 5 g of lithium aluminium hydride in 100 ml of absolute tetrahydrofuran. The excess of lithium aluminium hydride was decomposed by cautious addition of water. The precipitate which formed was sucked off and washed with tetrahydrofuran . The combined tetrahydrofuran solutions containing water were evaporated and the remaining aqueous residue was extracted with chloroform. The chloroform solution was dried over sodium sulfate and evaporated. The oil thus obtained was dissolved in ethanol and converted into the N-ethyl-N-cyclohexyl-3 , 5-dibromo-2-hydroxy-benzylamine hydrochloride by addition of ethanolic hydrochloric acid.

M.p.: 193 - 94°C (decomposition) Example 134 31 5-.Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl )-benzylamine 1, 0 g of 6,8-dibromo-3-(trans-4-hydroxy-cyclohexyl) -3 > 4-dihydro-2H-1 , 3-benzoxazin- 2-one .. was refluxed for 1 hour in a mixture of 30 ml of tert.-butanol and 25 ml of 2: sodium hydroxide solution. The reaction mixture was cooled and mixed in turn with 30 ml of 2N hydrochloric acid and as excess ofsodium hydrogen carbonate solution. The alcohol was distilled off i vacuo and the aqueous phase was extracted twice with a mixture of tetrahydro-furan and ether (1:1). The organic extracts were dried over magnesium sulfate and evaporated in vacuo to a small volume. Petroleum ether was added whilst heating until the reaction mixture became turbid. The desired end product which melted at 191 -193°C was recrystallized whilst cooling.

M.p. of the hydrochloride: 212 - 218°C (decomposition) Example 135 N-.Ethyi-5-bromo-N-cyclohexyl-2-hydroxy-benzylamine M.p. of the hydrochloride: 175 - 178°C Prepared analogously to Example 124 from N-ethyl-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride and bromine.

Example 136 N-Ethyl-3-bromo-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine M.p. of the hydrochloride: 194 - 197°C (decomposition) Prepared analogously to. Example 124 from N-ethyl-5-chloro-N-cyclohexyl-2-hydroxy-benzylamine hydrochloride and bromine.

Example 137.

N-Ethyl-N-cyclohexyl-5 , 5-dichloro-4-hydroxy-benzylamine M.p. of the hydrochloride: 190 - 1 1°C (decomposition) Prepared analogously to Example 122 from N-ethyl-N-cyclohexyl-4-hydroxy-benzylaraine and chlorine.

Example 138 3.5-D-ibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamlne M.p. of the hydrochloride: 216 - 218°C (decomposition) Prepared analogously to Example 124 from 4-h'ydroxy-N-(cis-3-hydro y-cyclohexyl)-benzylamine hydrochloride and bromine.

Example 139 3 j 5-P.ibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl benzylamine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared analogously to Example 124 from 2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine hydrochloride and bromine.

Example 140 3 , 5-Jlibromo-4-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 215 - 215t5°C (decomposition) Prepared analogously to Example 124 from 4-hydroxy-N-(trans-3-hydro y-cyclohexyl)-benzylamine hydrochloride and bromine.

Example 1 1 3 i 5-Dipromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl ) -benzylamine M.p.' of the hydrochloride: 212 - 218°C (decomposition) Prepared analogously to Example 128 by clearage of 3>5-dibromo-N-(trans-4-hydroxy-cyclohexyl)-2-methoxy-benzylamine hydrochloride with h hydrobromic acid solution in glacial acetic acid.

Example 142 3.5-.Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl )-benzylamine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared analogously to Example 129 from 3 , 5-dibromo-2-hydroxy-benzylamine, 4-hydroxy-cyclohexanoneand sodium borohydride.

Example 143 > 5 D ibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine M.p. of the. hydrochloride: 212 - 218°C (decomposition) Prepared analogously to Example 131 by reduction of 3>5-dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzamide with lithium · aluminium hydride.

Example 144 3 f 5-.Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared analogously to Example 132 by reduction of 2-acetoxy-3,5-dibrorao-N-(trans-4-hydroxy-cyclohexyl)-benzamide with lithium aluminium hydride.

Example 145 3 , 5- Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 216 - 218°C (decomposition) .

Prepared analogously to Example 127 by debenzylation of N-ben-zyl-3 , 5-dibromo- -hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine hydrochloride with hydrogen in the presence of palladium on activated charcoal.

Example 146 3 . 5-^Ilbromo-4-hydroxy-H-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 216 - 218°C (decomposition) Prepared analogously to Example 128 by splitting of 3 i 5-dibromo-N-(cis-3-hydroxy-cyclohexyl) -4-methoxy-benzylamine hydrochloride with h0% hydrobromic acid solution in glacial acetic acid.

Example 147 3 > 5-.Dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of. the hydrochloride: 216 - 218°C (decomposition) Prepared analogously to Example 129 from 3 » 5-dibromo-4-hydroxy-benzylamine, 3-hydroxy-cyclohexanontand sodium borohydride.

Example 148 3 > 5-D.ibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl) -benzylamine M.p. of the hydrochloride: 216 - 218°C (decomposition) Prepared analogously to Example 131 by reduction of 3 > 5-dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzamide with lithium aluminium hydride.

- Example 149 3, 5-Pibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 216 - 218°C (decomposition) Prepared analogously to Example 132 by reduction of 4-acetoxy- , 5-dibromo-N-(cis-3-hydroxy-cyclohexyl)-benzamide with lithium aluminium hydride .

Example 1 0 ^ , -J)ibromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-benzylamine .

M.p. of the hydrochloride: 215 - 215*5°C (decomposition) Prepared analogously to Example 127 by debenzylation of N-benzyl-3 , 5-dibrorao-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-benzylamin'e hydrochloride v/ith hydrogen in the presence of palladium on activated charcoal.

Example 151 3? 5--¾bromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 215 - 215,5°C (decomposition) Prepared analogously to Example 128 by cleavage of 3 , 5-dibromo-N- ( rans-3-hydroxy-cyclohexyl ) -4-methoxy-benzylamine hydrochloride with O°/o hydrobromic acid solution in glacial acetic acid.

Example ^2 3 > 5-Hibromo-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl ) -benzylanine M.p. of the hydrochloride: 215 - 215.5°C (decomposition) Prepared analogously to Example 129 from 3 , 5-dibromo-4-hydroxy-benzylamine, 3-hydroxy-cyclohexanon and sodium borohydride.

Example 153 ? , 5- Dibromo-4-hydroxy- - (trans-3-hydroxy-cyclohexyl ) -benzylamine M.p. of the hydrochloride: 215 - 215#5°C (decomposition) Prepared analogously to Example 131 by reduction of 3>5-dibromo-4-hydroxy-N-(trans-4-hydroxy-cyclohexyl)rbenzamide with lithium aluminium hydride.

Example 1 3 , 5--Pibromo-4-hydroxy-N-(trans-3-hydroxy-cyc-lphexyl) -benzylamine M.p. of the hydrochloride: 215 - 2 5«5°C (decomposition) Prepared analogously to Example 132 by reduction of 4-acetoxy-3,5-dibromo-N-(trans-3-hydroxy-cyclohexyl)-benzamide with lithium aluminium hydride.

Example 155 , 5-D ibromo-4-hydroxy-N- (trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 220 - 225°C (decomposition) Prepared analogously to Example 124 from 4-hydroxy-N-(trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine.

Example 156 315- Dibromo-4-hydroxy-N-(trans-4-hydroxy-cyclohexyl) -N-methyl-benzylamine M.p. of the hydrochloride: 160 - 162°C (decomposition) Prepared analogously to Example 124 from 4-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-N-methyl-benzylamine hydrochloride and bromine .

Example 157 N- Ethyl-5-bromo-3-chloro-N-cyclohexyl-2-hydroxy-benzylamine M.p. of the hydrochloride: 188 - 191°C (decomposition) Prepared analogously to Example 122 from N-ethyl-5-bromo-N-cyclo hexyl-2-hydroxy-benzylamine hydrochloride and chlorine .

Example 158 N-Ethyl-3 5-dichloro-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 147 - 152°C Prepared analogously to Example 123 from N-ethyl^-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl)-benzylamine and iodosobenzene dl-chloride .

Example 159 N- (4-tert . -Butyl-cyclohexyl ) -3 , 5-dibromo-4-hydroxy-benzylamine M.p. of the hydrochloride: 158 - 159°C (decomposition) Prepared analogously to Example 124 from N- (4-tert. -butyl-cyclo-hexyl)-4-hydroxy-benzylamine hydrochloride and bromine.

Example 160 N-Ethyl-5-bromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl) -benzylamine M.p. of the hydrochloride: 190 - 193°C (decomposition) Prepared analogously to Example 124 from N-ethyl-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl) -benzylamine hydrochloride and bromine.

Example 161 ^ -Bromo-N-cyclohexyl-2-hydroxy-N-lsopropyl-benzylamlne M.p.: 90 - 93°C Prepared analogously to Example 124 from N-cyclohexyl-2-hydroxy-N-isopropyl-benzylamine and bromine.

Example 162 N-Cyclopentyl-3 » 5-dibromo-4-hydroxy-N-methyl-benzylamlne M.p. of the hydrochloride: 185 - 188°C (decomposition) Prepared analogously to Example 124 from N-cyclopentyl-4-hydroxy- N-methyl-benzylamine hydrochloride and bromine.

Example 163 N-Ethyl-N-cyclopentyl- i 5-dibromo-2-hydroxy-benzylamine Prepared analogously to Example 124 from N-ethyl-N-cyclopentyl- 2-hydroxy-benzylamine hydrochloride and bromine.

M.p. of the hydrochloride: 124 - 128°C (decomposition) Example 164 N-Cycloheptyl-315-dibromo-4-hydroxy~N~propyl-benzylamine M.p. of the hydrochloride: 176 - 177°C (decomposition) Prepared analogously to Example 124 from N-cycloheptyl-4-hydroxy- N-propyl-benzylaraine hydrochloride and bromine.

Example 165 N- Cycloheptyl-3 5-dibromo-2-hydroxy-N-lsopropyl-benzylamlne M.p. of the hydrochloride: 1 56 - 159°C (decomposition) Prepared analogously to Example 124 from N-cycloheptyl-2-hydroxy- N-isopropyl-benzylamine hydrochloride and bromine.

Example 66 N-Ethyl-N~cyclohexyl-3 t ^-dibromo-2-hydroxy-benzylamine 6 g of 3,5-dibromo-2-hydroxy-benzyl acetate and 7 g of N-ethyl-cyclohexylamine were heated for 1 hour at 140 °C. 2N hydrochloric acid and ether were added to the reaction mixture with stirring thus crystallizing out the N-ethyl-N-cyclohexyl-3 ,5-dibromo-2-hydroxy-benzylamine hydrchloride . The crystals were sucked off and washed with water and acetone .

M.p.: 193 - 194°C (decomposition) Example 167 N-Ethyl-N-cvclohexyl-3 , 5-dibromo-2-hydroxy-benzylamlne 7 g of 3 » 5-dibromo-2-hydroxy-benzyl alcohol and 2, 8 g of sodium hydride dispersion (50% in oil) were refluxed for 6 hours in 150 ml of absolute tetrahydrofuran. Subsequently the reaction mixture was cooled to -60 to -70°C and 9, 5 g of p-toluene-sul- ~f.onyl„ - chloride in 100 ml of absolute tetrahydrofuran; were added dropwise with... stirring. When the reaction mixture had reached a temperature of -30°C it was again cooled to -70°C .

Subsequently 12, 7 g of N-ethyl-cyclohexylamine in 100 ml of ether were dropped into the reaction mixture whilst stirring. Slowly the mixture was allowed to reach room temperature and was then extracted twice with 200 ml of water. The combined aqueous phases were e.xtrac ted once with chloroform. The chloroform layer was combined wi^Ja the ether-tetrahydrofuran layer and the mixture was evaporated to dryness. Subsequently it was purified over a column of silica gel with chloroform/ethyl acetate (9:1). The corresponding fractions were combined and evaporated to dryness. The residue was stirred with 2N hydrchloric acid and ether, thus crystallizing out the N-ethyl-N-cyclohexyl-3 ,5-dibromo-2-hydroxy-benzylamine hydrochloride . The crystals were sucked off and washed with water and acetone.

M.p.: 193 - 194°C (decomposition) Example 168 N- Ethyl-N-cyclohexyl-3 , 5-dibromo-2-hvdroxy-benzylamine 1,3 g of 2-benzoyloxy-3>5-dibromo-benzyl alcohol and 1,3 g of N-ethyl-cyclohexylamine were heated for 1 hour at 1 0°C. The reaction product was stirred with 2N hydrochloric acid and ether thus crystallizing out the N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride. The crystals sucked off and washed with water and acetone.

M.p.: 193 - 19 °C (decomposition) Example 69 N-E.thyl-N-cyclohexyl-3 » 5-dibromo-2-hydroxy-benzylamine 2,8 g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 3,8 g of N-ethyl-cyclohexylamine were heated for 1 hour at 140°C. The reaction product was stirred with 2 hydrochloric acid and ether thus crystallizing out the N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride which was sucked off and washed with water and acetone.

M.p.: 193 - 194°C (decomposition) Example 170 Ν- Ethyl-N-cyclohexyl-3 ι 5-dibromo-2-hydroxy-benzylamine 2,8 g of 3>5-dibromo-2-hydroxy-benzyl alcohol, 3.8 g of N-ethyl-cyclohexylamine and 1,2 ml of 8 hydrobromic acid were heated oJb. Q for 1 hour at 140 C. The reaction mixture was shaken with chloroform and water. The chloroform layer was separated and evaporated to dryness. The residue was stirred with 2N hydrochloric acid and ether thus crystallizing out the N-ethyl-N-cyclohexyl-3>5-dibromo-2-hydroxy-benzylamine hydrochloride which was sucked off and washed with water and acetone.

M.p.: 193 - 194°C (decomposition) Example 171 N- Ethyl-N-cyclohexyl-3, 5-dibromo-2-hydroxy-benzylamine 5#6 g of 3 » 5-dibromo-2-hydroxy-benzyl alcohol, 8,8 g of butyric acid and 12,7 g of N-ethyl-cyclohexylamine were heated for one hour at 140°C, then cooled, dissolved in 200 ml of ether and extracted four times with water. The organic phase was dried over sodium sulfate and evaporated. The residue was dissolved in a' little absolute ethanol. This solution was acidified with ethanolic hydrochloric acid and mixed with ether so that the N-ethyl-N-cyclohexyl-3 , 5-dibromo-2-hydroxy-benzylamine hydrochloride crystallized out.

M.p.: 193 - 194°C (decomposition) Example 172 N-Ethyl- -cyclohexyl-3t 5-dibromo-2-hydroxy-benzylamine 5,6 g of 3,5-dibromo-2-hydroxy-benzyl alcohol, 12,7 g of N-ethyl-cyclohexylamine and 0,4 g of magnesium oxide were heated for 8 hour* at 120 °C. The reaction mixture was then mixed tgh ether em* vater acidified with 2N hydrochloric acid and subsequently made alkaline with with 2N hydrochloric acid and subsequently made alkaline with concentrated ammonia. The mixture was shaken and the organic phase was separated, washed four times with water, dried over sodium sulfate and evaporated. The residue was dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid. On addition of ether the N-ethyl-N-cyclohexyl-3» 5-dibromo-2-hydroxy-benzylamine hydrochloride crystallized out.

M.p.: 193 - 194°C (decompositition) Example 173 315-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine . 0,9 g of 6,8-dibromo-2-methyl- ,3-benzdioxane and 1,0 g of trans-4-amino-cyclohexanol were heated for 17 hours afc 140°C. Subsequently the reaction product was boiled with 100 ml of dilute, hydrochloric acid. The solution was treated with activated charcoal and evaporated in vacuo to a volume of about 5 ml, thus crystalliz ing out the 3>5-dibromo-2-hydroxy-N-(trans-4-hvdroxy-cyclohexyl)-benzylamine hydrochloride.:. The crystats were - sucked off, washed with water and acetone and dried in vacuo at 80°C.

M.p.: 212 - 218°C (decomposition) Example 174 N-Ethyl-N-cyclohexyl-3 , 5-dibromo-2-hvdroxy-benzylamine 2,9 g of 3»5-dibromo-a-methoxy-o-cresol and 3»8 g of N-ethyl-cyclohexylamine were heated for 1 hour at 140°C. The reaction product was stirred with 2N hydrochloric acid and ether thus crystallizing out the N-ethyl-N-cyclohexyl-3»5-dibromo-2-hydroxy-benzylamine hydrochloride which was sucked off and washed with water and acetone.

M.p.: 193 - 194°C (decomposition) Example 175 N-Cyclohexyl-315-dibromo-2-hydroxy-N-methyl-benzylamine 1,4 g of 3»5-dibromo-2-hydroxy-benzyl alcohol and 11#5 g of Ν,Ν' fN"-tricyclohexyl-N,N' ,N"-trimethyl-phosphoric acid tri-amide were heated for 10 hours at 150°C. The reaction product was purified over a column of silica gel with chloroform/ethyl acetate (1:1). The corresponding fractions were combined and evaporated. The residue was dissolved in petroleum ether, acidified with ethanolic hydrochloric acid and shaken, the solution was decanted. The oily residue was dissolved in a little absolute ethanol and mixed with ether thus crystallizing out the N-cyclohexyl-3 i 5-dibromo-2-hydroxy-N-methyl-benzylamihe hydrochloride.

M.p.: 189 - 191° C Example 176 3.5- Dibromo-2-hydroxy-N- (trans-4-hydroxy cyclohexyl) -benzylamine 2 g of 6,8-dibromo-3»4-dihydro-3-(trans-4-hydroxy-cyclohexyl)-2H-1 ,3-benzoxazine were dissolved at room temperature in 20 ml of methanol and mixed with 5 ml of water. After 15 minutes another 10 ml of methanol were added forming a crystalline precipitate which was sucked off and washed with methanol. The base was dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid. In doing so the 3»5-dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-ben^ylamine hydrochloride crystallized out. M.p.: 212 - 218°C (decomposition) Example 77 ^,5-.Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzyl-amine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared analogously to Example 166 from 3,5-dibromo-2-hydroxy-benzyl acetate and trans-4-amino-cyclohexanol.

Example 176 N-Ethyl-N-cyclohexyl-3 5-dibromo-4-hydroxy-benzylamlne M.p. of the hydrochloride: 180 - 181°C (decomposition) Prepared analogously to Example 166 from 3,5-dibromo-4-hydroxy-benzyl acetate and N-ethyl-cyclohexylamine .

Example 179 3, 5^Dlbromo-4-hydroxy-N-(cis-3--hydroxy-cvclohexyl)-benzylamine M.p. of the hydrochloride: 215 - 215#5°C (decomposition) Prepared analogously to Example 166 from 3» 5-dibromo-4-hydroxy-benzyl acetate and cis-3-amino-cyclohexanol .

Example 180 N-Ethyl-N-cyclohexyl-3.5-dlbromo-2-hydroxy-benzylamine M.p. of the hydrochloride: 193 - 194°C (decomposition) Prepared analogously to Example 166 from 3,5-dibromo-2-hydroxy-benzyl benzoate and N-ethyl-cyclohexylamine.

Example 181 3 , 5- Dibromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl )-benzyl-amine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared from 2-benzoyloxy-3>5-dibromo-benzyl alcohol and trans- 4-amino-cyclohexanol analogously to Example 168.

Example 182 N- Ethyl-N-cyclohexyl-3» 5-dlbromo-4-hydroxy-benzylamlne M.p. of the hydrochloride: 180 - 181°C (decomposition) Prepared from 4-acetoxy-3»5-dibromo-benzyl alcohol and N-ethyl-cyclohexylamine analogously to Example 168.

Example 183 , 5~Dibromo-4-hydroxy-N-(cis-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 215 - 215#5°C (decomposition) Prepared from 4-acetoxy-3»5-dibromo-benzyl alcohol and cis-3-amino-cyclohexanol analogously to Example 168.

Example 184 3t5~.Dibromo-2~hy.droxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared from 3»5-dibromo-2-hydroxy-benzyl alcohol and trans-4-amino-cyclohexanol analogously to Example 169.

Example 185 3 5-d3ibromo-4-hydroxy-N-(cls-3-hydroxy-cyclohexyl)-benzylamine M.p. of the hydrochloride: 215 - 215#5°C (decomposition) Prepared analogously to Example 169 from 3»5-dibromo-4-hydroxy-benzyl alcohol and cis-3-amino-cyclohexanol.

Example 186 N-Ethyl-N-cyclohexyl-3 > 5-dibromo-2-hydroxy-benzylamine M.p. of the hydrochloride: 1S3 - 194°C (decomposition) Prepared analogously to Example 170 from 3 » 5-dibromo-2-hydroxy-benzyl alcohol, N-ethyl-cyclohexylamine and p-toluene-sulfonic acid.

Example 187 N-Ethyl-N-cyclohexyl-3 » 5-dlbromo- -hydroxy-benzylamine M.p. of the hydrochloride: 180 - 181°C (decomposition) Prepared analogously to Example 171 from 3>5-dlbromo-4-hydroxy-benzyl alcohol, N-ethyl-cyclohexylamine and butyric acid.

Example 188 5"Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzyl-amine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared analogously to Example 171 from 3 » 5-dibromo-2-hydroxy-benzyl alcohol, butyric acid and trans-4-amino-cyclohexanol.

Example 189 3.5- Dibromo-4-hydroxy-N- (cis-3-hvdroxy-cvclohexyl )-benzylamine M.p. of the hydrochloride: 215 - 21 »5°C (decomposition) Prepared analogously to Example 171 from 3 » 5-dibromo-4-hydroxy-benzyl alcohol, cis-3-amino-cyclohexanol and butyric acid.

Example 190 3.5·. Dibromo-2-hydroxy-N- (trans-4-hvdroxy-cyclohexyl ) -benzyl-amine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared analogously to Example 172 from 3»5-dibromo-2-hydroxy-benzyl alcohol, trans-4-amino-cyclohexanol and magnesium oxide.

Example 191 N- Ethyl-N-cyclohexyl-3 » 5-dibromo-2-hydroxy-benzylamlne M.p. of the hydrochloride: 193 - 194°C (decomposition) Prepared analogously to Example 172 from 3,5-dibromo-2-hydroxy-benzyl alcohol, N-ethyl-cyclohexylamine and potassium hydroxide.

Example 192 3 , -.Dibromo-4-hydroxy-N- (cis-3-hvdroxy-cyclohexyl) -benzylamine M.p. of the hydrochloride: 215 - 215.5°C (decomposition) Prepared analogously to Example 172 from 3,5-dibromo-4-hydroxy-benzyl alcohol, cis-3-amino-cyclphexanol and magnesium oxide.

Example 193 N-Ethyl-N-cyclohexyl- , 5-dlbromo-2-hydroxy-benzylamine M.p. of the hydrochloride: 193 - 194°C (decomposition) Prepared analogously to Example 173 from 6,8-dibromo-2-methyl- ,3-benzdioxane and N-ethyl-cyclohexylamine .

Example 194 ^ , 5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzyl-amine M.p. of the hydrochloride: 212 - 218°C (decomposition) Prepared analogously to Example 174 from 3,5-dibromo-a-methoxy-o-cresol and trans-4-amino-cyclohexanol.

Example 195 N-Ethyl-N-cyclohexyl-315-dibromo-4-hydroxy-benzylamine M.p. of the hydrochloride: 180 - 181°C (decomposition) Prepared analogously to Example 174 from 3»5-dibromo-a-methoxy-p-cresol and N-ethyl-cyclohexylamine.

Example 196 31 -.Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine M.p. of the hydrochloride: 215 - 215«5°C (decomposition) Prepared analogously to Example 174 from 3, 5-dibromo-oc-methoxy-p-cresol and cis-3-amino-cyclohexanol.

Example 197 N-Cvclohexyl-3.5-dibromo-2-hvdroxy-N-methyl-benzylamine M.p. of the hydrochloride: 189 - 191°C Prepared analogously to Example 175 from 3 , 5-dibromo-2-hydroxy-benzyl alcohol and N-cyclohexyl-N-methyl-acetamide.- .

Example 198 3.5-Dibromo-N- (dihydroxy-tert. -butyl)-2-hydroxy-benzylamine 5*6 g of 3,5-dibromo-2-hydroxy-benzyl alcohol and 6,3 g of dihydroxy-tert.-butylamine were heated for 1 hour at . 140°C, The molten mas was then, dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid. The 3,5-dibromo-N-(dihydroxy-tert. -butyl)-2-hydroxy-benzylamine hydrochloride crystallized out on addition of ether.

Recrystallization from absolute ethanol, m.p.: 187-189°C Example 199 3 -.Dibromo-N- (dihydroxy-tert. -butyl)-2-hydroxy-benzylamine 21,6 g of 3»5-dibromo-2-hydroxy-benzyl bromide dissolved in 0,5 1 of carbon tetrachloride were mixed with a solution of 26,4 g of dihydroxy-tert.-butylamine in 100.ml of ethanol and refluxed for 30 minutes. The precipitate which formed was sucked off and washed with carbon tetrachloride and water. The crude product was dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid. The 3, -dibromo-N-(dihydroxy-tert.-butyl)-2-hydroxy-benzylamine hydrochloride crystallized out on addition of ether.

M.p.: 187-189°C Example 200 5.5-Dibromo-N- ( dihydroxy-tert .-butfl)-2-hvdroxy-benzylamine 4, 0 g of 3 , 5-dibromo-2-hydroxy-benzyl acetate and 4, 0 g of dihydroxy-tert. -butylamine were heated for 1 hour at , 140°C .

The reaction product was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and crystallized out on addition of ether.

M.p.: 137- 1 B9°C .

Example 201 3 . 5- Dibromo-2-hvdroxy-N-tert. -pentyl-benzylamine 3· 5 g of 3 , 5-dibromo-2-hydroxy-benzyl alcohol and 1 , 4 g of sodium hydride dispersion ( 50 % in oil) were refluxed for 6 hours in 100 ml of absolute tetrahydrofuran . Subsequently the reaction mixture was cooled to -60 to -70°C and 4, 8 g of p-toluene-sulfonyl .... chloride in 50 ml of absolute tetrahydrofura were added dropwise. The mixture was then lertito stand until a-tempaca-ture of -30°C was reached and was again cooled to -70°C . 4, 4 g of tertrpentylamine in, 50 ml of ether were added dropwise to _ the stirred reaction mixture until it slowly reached room temperature. Subsequently the mixture WEB shaken twice with water, the aqueous layer was extracted with chloroform and the combined organic phases were evaporated. After purification over a column of silica gel with chloroform/ethyl acetate ( 2/1 ) the 3 i 5-dibromo-2-hydroxy-N-tert.-pentyl-benzylamine hydrochloride was recrystallized from acetone/ether after having been acidified with ethanolic hydrochloric acid.

Recrystallization from water, m.p.: 202-206°C (decomposition).

Example 202 3 ♦ 5-J).ibromo-N- (dihvdroxy-tert. -butyl )-2-hvdroxy-benzylamine 2,9 g of 3, 5-dibromo-2-hydroxy-benzyl methyl ether and 3.3 g of dlhydroxy-tert.-butylamine were heated for 1 hour at 140°C.

The crude product was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and mixed with ether until the , 5-dibroino-N-(dihydroxy-tert. -butyl )-2-hydroxy-benzylamine hydrochloride crystallized out. .p.: 137 - 189°C.

Example 205 3.5-iDibromo-N- (dihvdroxy-tert. -butyl )-2-hvdroxy-benzylamine 7 g of 3,5-dibromo-salicylaldehyde, 17,5 g of dihydroxy-tert.-butylamine and 7,7 g of formic acid were heated for 6 hours at 70-80°C. Subsequently the reaction mixture was mixed with ammonia and shaken vigorously. -The precipitate which formed was sucked off. The residue was dissolved in ethanol, acidified with ethanolic hydrochloric acid and mixed with ether whereby the product stallized out.

Recrystallization from absolute ethanol/ether , m.p.: 187-189°C.

Example 204 3.5-.Dibromo-N- (dihvdroxy-tert. -butyl)-2-hvdroxy-benzylamine 7,3 g of N-(3.5-dibromo-2-hydroxy-benzylidene)-dihydroxy-tert.- butylamine were stirred for 2 hours with 1 g of sodium borohydride in 200 ml of ethanol. Some acetone was added to the reaction mixture in order to decompose the excess of sodium borohydride. The mixture was: acidified with 2.N hydrochloric acid and evaporated to a small volume. After addition of 2 ammonia until an alkaline reaction was- observed the yellowish precipitate was sucked off. The residue was dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid. Ether was added to crystallize out the 3>5-dibromo-N-(dihydroxy-tert.- butyl)-2-hydroxy-benzylamine hydrochloride.

M.p.: 187-189°C.

Example 205 3 « 5-J bromo-2-hvdroxy-N-lsopropyl-benzylamine 16 g of N-isopropylidene-(3>5-dibromo-2-hydroxy-benzylamine) in 120 ml of ethanol were mixed with 2 g of sodium borohydride the mixture BB stirred for 3 hours, then filtered, mixed with 40 ml of 2N sodium hydroxide solution and 200 ml of water and evaporated to about half the total volume.The solution was then mixed with saturated ammonium chloride solution thus precipitating the crude base. The precipitate was sucked off and washed thoroughly with water. The product was dissolved in acetone and acidified with ethanolic hydrochloric acid. In doing so the 3»5-dibromo-2-hy-droxy-N-isopropyl-benzylamine hydrochloride crystallized out immediately.

M.p.: 195-199°C (decomposition).

Example 206 , 5-D.ibromo-N- (dihydroxy-tert. -butyl )-2-hydroxy-benzylamine P2 g of dihydroxy-tert. -butylamine and 1,2 g of paraformaldehyde were dissolved in 20 ml of absolute ethanol whilst warming. The solution was mixed at room temperature- with"" iG .O g^of 2,4-dibromo-phenol and-aftex standing, .for_l h ur was- jrefluxed for a further 7 hours. he reaction solution was subsequently acidified with ethanolic hydrochloric acid and mixed with ether, thus crystallizing out the 3, 5-dibromo-N- (dihydroxy-tert. -butyl )-2-hydroxy-benzylamine hydrochloride.

Recrystallization from absolute ethanol/ether; m.p.: 187-189°C.

Example 207 3.5-.Dibromo-N- (dihydroxy-tert. -butyl )-2-hydroxy-benzylamine 2,5 g of N-(dihydroxy-tert-butyl)-2-hydroxy-benzylamine hydro- - - A chloride were dissolved in 50 ml of glacial acetic acid and 5 ml of water and 3_2 g of bromine in 10 ml of glacial acetic acid were added dropwise whilst stirring. Subsequently the reaction mixture was diluted with water- and made alkaline with concentrated ammonia. The precipitated crude base was sucked off, dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid. Ether was added until the 3, 5-dibromo-N-(dihydroxy-tert. -butyl )-2-hydroxy-benzylamine hydrochloride crystallized out.

Recrystallization from absolute ethanol/ether; m.p. : 187-189°C.

Example 208 3. - Dibromo-N- (dihvdroxy-tert. -butyl )-2-hvdroxy-benzylamine 2.5 g of N-benzyl-3,5-dibromo-N-(dihydroxy-tert.-butyl)-2-hy- droxy-benzylaraine hydrochloride were dissolved in 200 ml of methanol and hydrogenated in the presence of about 0,1 g of palladium (10 %) on coal. As soon 3 the calculated quantity of hydrogen was absorbed the hydrogenation was stopped, the catalyst filtered off and the solution evaporated. After recry- stallizing twice from absolute ethanol/ether pure 3,5-dibromo-N- (dihydroxy-tert. -butyl)-2-hydroxy-benzylamine hydrochloride was obtained.

M.p. : 187-189°C.

Example 209 3. -.Dibromo-2-hvdroxy-tert. -pentyl-benzylamine 0,8 g of 3»5-dibromo-2-hydroxy-N-tert.-pentyl-benzamide were refluxed for 5 hours with 0,3 g of sodium borqhydride- , in 30 ml of dry pyridine. In order to decompose the -excess of sodium borohydride, acetone was added and the pyridine was distilled off in vacuo. The residue was dissolved in hot 2 hydrochloric acid, filtered,made alkaline with 2N ammonia and shaken '" three times with chloroform. The organic layer was dried ,4 over sodium sulfate and evaporated. Further purification was effected by means of column chromatography over silica gel with chloroform/ethyl acetate (2/1). The base obtained was dissolved in a little acetone and acidified with ethanolic hydrochloric acid. The 3,5-dibromo-2-hydroxy-tert.-pentyl-benzylamine hydrochloride was crystallized out by addition of ether.

RecrystaUization from water; m.p.: 202-206°C (decomposition).

Example 210 3.5-. Dibromo-N- (dihvdroxy-tert . -butyl )-2-hydroxy-benzylamine 1#8 g of 6,8-dibromo-3, -dihydro-3-(dihydroxy -tert. -butyl)-2H-1 ,3-benzoxazine-2-one in 50 ml of tert . -butanol and 40 ml of 2N sodium hydroxide solution were refluxed for 1 hour. The reaction mixture was cooled, mixed with 50 ml of 2i hydrochloric acid and the alcohol was distilled off _in vacuo. An. excess ofsodium hydrogen carbonate solution was added, the precipitated base was sucked off and washed with water. The residue was dissolved in absolute ethanol and acidified with ethanolic hydrochloric acid. On addition of ether the 3,5-di-bromo-N- (dihydroxy-tert. -butyl )-2-hydroxy-benzylamine hydrochloride was crystallized out.

M.p. : 187-189°C Example 2 1 3 , 5-Dibromo-N- (dihydroxy-tert. -butyl )-2-hydroxy-benzylamine 0,9 g of 2-benzoyloxy-3,5-dibromo-benzyl alcohol and 0,6 g of dihydroxy-tert. -butylamine were heated for 1 hour at . 1 0°C. The reaction product was dissolved in absolute ethanol, acidified with ethanolic hydrochloric acid and mixed with ether in order to crystallize out the 3, 5-dibromo-N-(dihydroxy-tert. -butyl )-2-hydroxy-benzylamine ^hydrochloride.

RecrystaUization from absolute ethanol/ether; m.p.: 187-189°C.

Example 212 3.5-Dibromo-N-(dihvdroxy-tert.-butyl)-2-hydroxy-benzylamine 1,8 g of 6,8-dibromo-2-methyl-1 ,3-benz-dioxane and 1,8 g of di-hydroxy-tert.-butylamine were heated for 20 hours v at^, 140°C.

Subsequently the reaction product was boiled with 100 ml of 2 hydrochloric acid, mixed with activated charcoal filtered and the solvent was" evaporated .The residue was recrystallized twice from absolute ethanol/ether in order to purify the 3,5-dibromo-N- (dihydroxy-tert. -butyl)-2-hydroxy-benzylamine hydrochloride.

M.p. : 187 - 189°C.

Example 213 315-Dibromo-N- (dihvdroxy-tert. -butyl )-2-hvdroxy-benzylamine 3 g of 6,8-dibromo-3,4-dihydro-3-(dihydroxy-tert.-butyl)-2H-1 ,3-benzoxazine were dissolved in 30 ml of methanol and mixed with 10 ml of water. The precipitate which formed" . was sucked off after 1 hour and washed with a little -methanol. The base was dissolved in a little absolute ethanol, acidified with ethanolic hydrochloric acid and mixed with ether, thus crystallizing out the 3,5-dibromo-N-(dihydroxy-tert.-butyl)-2-hydroxy-benzylamine , hydrochloride.

M.p.: 187-189°C.

Example 214 3.5-Dichloro-2-hvdroxy-N-isopropyl-benzylamine M.p. of the hydrochloride: 188-189r5°C Prepared from 3f5-dichloro-2-hydroxy-benzyl bromide^ and isopropyl-amine analogously to Example 199.

Example 215 N-tert. -Butyl-3.5-dibromo-4-hvdroxy-benzylamlne M.p. of the hydrochloride: 234-236°C (decomposition).

Prepared from 315-dibromo-4-hydroxy-benzyr bromide and tert.- butylamine analogously to Example 199.

Example 216 N-tert. -»¾utyl-3.5-dichloro-2-hvdroxy-benzylamine M.p.: 172-174°C.

Prepared from 3 ,5-dichloro-2-hydroxy-benzyl bromide and tert. butylamine analogously to Example 199.

Example 217 N-tert. -"Butyl-3 5-dichloro-4-hydroxy--benzylamine M.p. of the hydrochloride: 222-223°C (decomposition) Prepared from 3 , 5-dichloro-4-hydroxy-benzy.l bromide and tert. butylamine analogously to Example 199.

Example 218 3.5--Dlbromo-4-hvdroxy-»N-tort. -pentyl-benzylamine M.p. of the hydrochloride: 176-180°C (decomposition).

Prepared from 3 , 5-dibromo-4-hydroxy-benzyl bromide and tert.-pertylamine analogously to Example 199.

Example 219 3.5-I)ichloro-4-hvdroxy-N-tert. -pentyl-benzylamine M.p. of the hydrochloride: 203-207°C (decomposition).

Prepared from 3>5-dichloro-4-hydroxy-benzyl bromide and tert.-pentylamine analogously to Example 199.

Example 220 3.5-Qibromo-»2-»hvdroxy-N-(hvdroxy-tert.-»butyl)~benzylamine M.p. of the hydrochloride: 189-191°C Prepared from 3, 5-dibromo-2-hydroxy-benzyl. bromide and hydroxy- tert. -butylamine analogously to Example 199.

Example 221 3 5-Dibromo-4-hvdroxy-N- (hydroxy-tert. -butyl)-benzylamine M.p. of the hydrochloride: 200-202°C.

Prepared from 3 , 5-dibromo-4-hydroxy-benzy] bromide and hydroxy- tert. -butylamine analogously to Example 199.

Example 222 3.5- Dichloro-4-hvdroxy-N- (hvdroxy-tert. -butyl )-benzylamine M.p. of the hydrochloride: 208-212°C (decomposition) Prepared from 3 , 5-dichloro-4-hydroxy-benzyl bromide and hydroxy tert. -butylamine analogously to Example 199.

Example 223 3, 5-Dibromo-N-(dihydroxy-tert. -butyl)-4-hydroxy-benzylamine M.p. of the hydrochloride: 182-183,5°C Prepared from 3>5-dibromo-4-hydroxy-benzyl bromide and dihydroxy-tert.-butylamine analogously to Example 199.

Example 224 3 5~. PLbromo-4-hydroxy-N- (trihydroxy-tert. -butyl )-benzylamine M.p. of the hydrochloride: 1S9-191»5°C Prepared from 3>5-dibromo-4-hydroxy-benzyl bromide and trihydroxy-tert.-butylamine analogously to Example 199.

Example 225 3 5-. Dichloro-N- (dihydroxy-tert. -butyl )-4-hydroxy-benzylamine M.p. of the hydrochloride: 166-169°C (decomposition).

Prepared from 3 > 5-dtehloro-4-hydroxy-benzyl bromide and dihydroxy-tert.-butylamine analogously to Example 199.

Example 226 3 5-Dibromo-2-hvdroxy-N- (trihydroxy-tert. -butyl )-benzylamine M.p. of the hydrochloride: 185-187°C (decomposition).

Prepared from 3»5-dibromo-2-hydroxy-benzyl bromide and trihydroxy-tert.-butylamine analogously to Example 199.

Example 227 3.5-! I¾chloro-4-hvdroxy-N- (trihvdroxy-ter . -butyl)-benzylamine .p. of the hydrochloride: 170-174°C (decomposition).

Prepared from 3 » 5-dichloro-4-hydroxy-benzyl bromide and trihy-droxy-tert.-butylamine analogously to Example 199.

Example 228 N-tert. -Dutyl- . -dibromo-2-hvdroxy-benzylamlne M.p. of the hydrochloride: 216-220°C (decomposition).

Prepared from 3>5-dibromo-salicylaldehyde, tert.-butylamine and formic acid analogously to Example 203.

Example 229 3.5- Dibromo-4-hvdroxy-N-isopropyl-benzylamine M.p. of the hydrochloride: 229-233°C (decomposition).

Prepared by reduction of N-(3»5-dibromo-4-hydroxy-benzylidene)-isopropylamine with sodium borohydride analogously to Example 204.

Example 230 3. -Dlchloro-4-hvdroxy-N-isopropyl-benzylamine M.p. of the hydrochloride: 223-231°C (decomposition).

Prepared by reduction of N-(315-dichloro-4-hydroxy-benzylidene)-isopropylamine with sodium borohydride analogously to Example 204.

Example 231 . 5-tD.ichloro-2-hvdroxy-N-ter . -pentyl-benzylamine .p. of the hydrochloride: 211 -213°C (decomposition).

Prepared by reduction of N- ( 3 , 5-dichloro-2-hydroxy-benzylidene)- tert.-pentylamine with sodium boro hydride analogously to Example 204.

Example 232 3 .5-Dlchloro-2-hvdroxy-N- (hvdroxy-tert. -butyl )-ben2ylamlne M.p. of the hydrochloride: 200-204# 5°C (decomposition) Prepared by reduction of N- (3 , 5-dichloro-2-hydroxy-benzylidene)-hydroxy-tert.-butylamine with sodium borohydride analogously to Example 204.

Example 233 3.5T-Dichloro-N- (dlhvdroxy-tert. -butyl )-2-hvdroxy-benzylamine M.p. of the hydrochloride: 184 - 188°C (decomposition).

Prepared by reduction of N- ( 3 » 5-dichloro-2-hydroxy-benzylidene)-dihydroxy-tert.-butylamine with sodium borohydride analogously to Example 204.

Example 234 3.5-Dichloro-2-hvdroxy-N-(trlhvdroxy-tert. -butyl )-benzylamine M.p. of the hydrochloride: 172-176°C (decomposition).

Prepared by reduction of N- (3 i 5-dichloro-2-hydroxy-benzylidene)-trihydroxy-tert.-butylamine with sodium borohydride analogously to Example 204.

Example 235 5-Bromo-N-tert. -butyl-2-hvdroxy-benzylamine M.p. of the hydrochloride: 255-258°C (decomposition).

Prepared by reduction of N-(5-bromo-2-hydroxy-benzylidene)- tert.-butylamine with sodium borohydride analogously to Bc- ample 204.

Example 236 Juice containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4- hydroxy-benzylamine hydrochloride per 10 ml.

Composition: 100 ml of juice contain active ingredient 0,04 g tartaric acid 0,50 g benzoic acid 0,20 g ammonium chloride 0,40 g glycerine 10,00 g sorbitol 50.00 g naphthol red S 0,01 g raspberry flavouring 4824 (Messrs. Do ke, Roberts & Co.) 0,25 g ethanol 10,00 g distilled water ad 100,00 ml Preparation: 45 g approximately of distilled water were heated to 80°C.

The tartaric acid, , benzoic acid, active substance, naphthol red S and sorbitol were then dissolved in turn in the water which was subsequently mixed with glycerine and a 20 % solution of the ammonium chloride. After cooling to room temperature, ethanol and the raspberry flavouring were stirred into the mixture. The juice was filled up to the indicated volume and filtered in an appropriate manner.

Composition: 1 tablet contains active ingredient lactose potato starch polyvinylpyrrolidone magnesium stearate 1 10, 0 mg Preparation: The active ingredient was mixed with lactose and with potato starch. and granulated through a screen of 1 mm mesh-size with a 20 % aqueous solution of polyvinylpyrrolidone. The moist granulate was dried at 40°C , again passed through the above mentioned screen and mixed with magnesium stearate. The mixture was pressed into tablets.

Weight of tablet: 1 10 mg Punch: 7 mm Example 239 Coated tablets containing 4 mg of N-ethyl-N-cyclohexyl-3 i 5-di-bromo-4-hydroxy-benzylamine hydrochloride The tablets prepared according to Example 238 were coated according to conventional methods with a shell consisting essentially of sugar and talcum. The finished coated tablets were polished with beeswax.

Weight of coated tablet: 200 mg Example 240 Suppositories containing 4 mg of N-ethyl-N-cyclohexyl-3 » 5-di-bromo-4-hydroxy-benzylamine hydrochloride 10 ml of juice contain 4 mg of N-ethyl-N-cyclohexyl- 3 , 5-dibromo-4-hydroxy-benzylamine-hydrochloride .

Example 237 Drops containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4 hydroxy-benzylamine hydrochloride per ml.

Composition: 100 ml of drop solution contain active ingredient 0,40 g methyl p^hydroxv-benzoate 0,07 g propyl p-hydroxy benzoate 0,03 g polyvinylpyrrolidone 5,00 g aniseed oil 0,01 g fennel oil 0,001g ethanol 10,00 g distilled water ad 100,00 ml Preparation: The p-hydroxy-benzoic acid esters, polyvinylpyrrolidone and active ingredient were dissolved in turn in the distilled water warmed to 80°C. The solution was cooled and subsequently mixed with a mixture of the aromatic substances and ethanol. The solution was made up to the indicated volume with distilled water and filtered through an appropriate screen. 1 ml of drop solution contain 4 mg of N-ethyl-N-cyclo- hexyl-3 , 5-dibromo-4-hydroxy-benzylamine hydrochloride .

Example 238 Tablets containing 4 mg of N-ethyl-N-cyclohexyl-3,5-dibromo-4-hydroxy-benzylamine hydrochloride . \ / Compos: :.on: 1 suppository contains active ingredient 4to mg suppository mass (e.g. V.'itepsol W 45) 1696,0 mg 1700,0 mg Preparation : The finely pulverized active ingredient waff" stirred into- the molten suppository mass cooled to 4u°C and homogenized. The mass was poured into slightly pre-cool ,d moulds at about 35°C Example 241 Ampoules containing 4 mg of N-et!;.,l-N-cyclohexyl-315-dibromo-4-hydroxy-benzylamine hydrochloride Composition: 1 ampoule contains active ingredient 4,0 mg tartaric acid 2,0 mg glucose 95,0 mg distilled water ad 2,0 ml Preparation: The distilled water was heated to 80°C and the tartaric- acid—"-and active ingredient were dissolved therein whilst stirring.

After cooling to room temperature the glucose was dissolved and the solution was.Jnade up to the indicated volume. " The solution was then filtered sterile.

Filling: into white 2 ml-ampoules Sterilisation: 20 minutes at 1Z0°C

Claims (44)

1. Compounds of general formula [wherein Hal represents a chlorine or bromine atom; represents a hydrogen, chlorine or bromine atom; represents a morpholinocarbonylmethyl group, a branched aIkyl group containing from 3 to 5 carbon atoms optionally substituted by from 1 to 3 hydroxy1 groups, or a group of formula A (wherein represents a hydrogen atom, a hydroxyl group or an alkyl group containing from 1 to 4 carbon atoms, n represents the integer 0, 1 or 2, and the radicals A and B either both represent hydrogen atoms or together represent the group I wherein the group R,. which may be the same or different represent hydrogen atoms or alkyl groups containing 1 or 2 carbon atoms and m represents the integer 1 or 2); represents a straight or branched alkyl group containing from 1 to 4 carbon atoms, an alkenyl group containing from 2 to 4 carbon atoms, a cycloalkyl group containing 3 or 4 carbon atoms or (if R^ is other than hydrogen or 2 represents a branched alkyl group containing 3 to 5 carbon atoms optionally substituted by from 1 to 3 hydroxy1 groups) a hydrogen atom; and 1 represents the integer 1 or 2] and acid addition salts thereof.

2. Compounds of general formula I according to claim 1 [wherein Hal represents a chlorine or bromine atom; R^ represents a hydrogen, chlorine or bromine atom; R2 represents a branched alkyl group containing from 3 to 5 carbon atoms optionally substituted by from 1 to 3 hydroxyl groups, or a cyclohexyl or hydroxycyclohexyl group; R. represents a straight-chain or branched alkyl group containing 1 to 4 carbon atoms or (if represents a hydroxycyclohexyl group or a branched alkyl group containing from 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxyl groups) a hydrogen atom, and 1 represents represents the integer 1] and physiologically compatible acid addition salts thereof.

3. Compounds of general formula [wherein Hal represents a chlorine or bromine atom; 1 represents the integer 1; represents a hydrogen, chlorine or bromine atom; represents a hydrogen atom, a hydroxyl group or an alkyl group containing from 1 to 4 carbon atoms; R^ represents a straight-chain or branched alkyl group containing from 1 to 4 carbon atoms, an alkenyl group containing from 2 to 4 carbon atoms, a cycloalkyl group containing 3 or 4 carbon atoms or (if R~ is other than hydrogen) a hydrogen atom; n represents the integer 0, 1 or 2, and the radicals A and B together represent the group (R.. - C - RJ 5 J 5'm (wherein represents a hydrogen atom or an alkyl group with 1 or 2 carbon atoms and m represents the integer 1 or 2) or A and B each represent hydrogen atoms] and physiologically compatible acid addition salts thereof.

4. Compounds of general formula [wherein represents a hydrogen, chlorine or bromine atom; Hal represents a chlorine or bromine atom; R^ represents a hydrogen atom or a methyl or ethyl group; R2 represents a cyclohexyl, hydroxy- cyclohexyl or morpholinocarbonylmethyl group, and 1 represents the integer 1 or 2] and physiologically compatible acid addition salts thereof.

5. Compounds of general formula [wherein Hal represents a chlorine or bromine atom; represents a hydrogen, chlorine or bromine atom, represents a branched alkyl group containing 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxyl groups; and 1 represents the integer 1 or 2] and physiologically compatible acid addition salts thereof.

6. N-Ethyl-N-cyclohexyl-3, 5-dibromo-2-hydroxy-benzylamine and physiologically compatible acid addition salts thereof.

7. 3 , 5-Dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl)-benzylamine and physiologically compatible acid addition salts thereof.

8. 3 , 5-Dibromo-4-hydroxy-N-(trans-3-hydroxy-cyclohexyl)-benzylamine and physiologically compatible acid addition i salts thereof.

9. 3,5-Dibromo-N-(dihydroxy-tert.butyl)-2 hydroxy-benzylamine and physiologically compatible acid addition salts thereof.

10. 3, 5-Dibromo-2-hydroxy-N-(trans-4-hydroxy-cyclohexyl)-benzylamine and physiologically compatible acid addition salts thereof.

11. 3 , 5-Dichloro-N-(dihydroxy-tert. butyl )-4-hydroxy-benzylamine and physiologically compatible acid addition salts thereof.

12. Compounds as claimed in claim 1 other than those claimed in claims 6 to 11 as herein specifically disclosed.

13. Compounds as claimed in claim 3 other than those claimed in claims 6 to 8 as herein specifically disclosed.

14. Compounds as claimed in claim 4 as herein specifically disclosed.

15. Compounds as claimed in claim 5 other than those claimed in claims 9 to 11 as herein specifically disclosed.

16. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula (wherein R^, Hal and 1 are as defined in claim 1 and represents a hydroxy1 group, a chlorine, bromine or iodine atom, or an acyloxy, sulfonyloxy, alkoxy, aryloxy or aralkoxy group) with a compound of formula (wherein R2 and R^ are as defined in claim 1).

17. A process as claimed in claim 16 wherein the reaction is effected in the presence of a solvent.

18. A process as claimed in claim 16 or claim 17 wherein the reaction is effected at temperatures from -70 to 200°C.

19. A process as claimed in any of claims 16 to 18 wherein a compound of formula II wherein R^ represents a halogen atom is used and the reaction is effected at temperatures from 0 to 150°C.

20. A process as claimed in claim 19 wherein the reaction is effected in the presence of a hydrogen halide binding agent or in the presence of an ion exchanger.

21. A process as claimed in any of claims 16 to 18 wherein a compound of formula II wherein represents a sulfonyloxy group is used and the reaction is effected at temperatures from -70 to 50°C.

22. A process as claimed in any of claims 16 to 18 wherein a compound of formula II wherein represents an acyloxy, alkoxy, aryloxy or aralkoxy group is used and the reaction is effected at temperatures from 0 to 200°C.

23. A process as claimed in claim 22 wherein the reaction is effected in the presence of an acid catalyst.

24. A process as claimed in claim 23 wherein the acid catalyst comprises ammonium chloride.

25. A process as claimed in any of claims 16 to 18 wherein a compound of formula II wherein represents a hydroxyl group is used and the reaction is effected at temperatures from 120 to 180°C.

26. A process as claimed in claim 25 wherein the reaction is effected in the presence of an acid or basic catalyst.

27. A process for the preparation of compounds of general formula la as defined in claim 3 which comprises reacting a compound of formula (wherein R^, 1 and Hal are as defined in claim 3 and Hal' represents a chlorine, bromine or iodine atom) with a compound of formula (wherein R, , A and B are as defined in claim

28. A process for the preparation of compounds of general formula I as defined in claim 4 which comprises reacting a compound of formula (wherein R^, Hal and 1 are as defined in claim 4 and Hal' represents a chlorine, bromine or iodine atom) with a compound of formula (wherein and are as defined in claim 4).

29. A process for the preparation of compounds of general formula lb as defined in claim 5 which comprises reacting a compound of formula (wherein R^ Hal and 1 are as defined in claim 5 and represents a hydroxy1 group, a chlorine, bromine or iodine atom, or an acyloxy, sulfonyloxy, alkoxy, aryloxy or aralkoxy group) with a compound of formula (wherein R2 is as defined in claim 5).

30. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula (wherein R-^, Hal and 1 are as defined in claim 1) with a compound of formula (wherein R0 and R. are as defined in claim 1) or with a Δ 4 corresponding formamide in the presence of formic acid.

31. A process as claimed in claim 30 wherein the reaction is effected in the presence of a solvent. A process as claimed in claim 30 or claim 31 wherein the reaction is effected at temperatures from 50 to 250°C. 33. A process as claimed in any of claims 30 to 32 wherein a compound of formula III wherein R^ represents a hydrogen atom is used and the reaction mixture is subsequently heated with a dilute acid. 34. A process for the preparation of compounds of general formula la as defined in claim 3 which comprises reacting a compound of formula (wherein Hal and 1 are as defined in claim 3) with a compound of formula (wherein R^, R^, A and B are as defined in claim 3) or with a corresponding formamide in the presence of formic acid. 35. A process for the preparation of compounds of general formula I as defined in claim 4 which comprises reacting a compound of formula (wherein R^, Hal and 1 are as defined in claim 4) with a compound of formula (wherein and are as defined in claim 4) or with a corresponding formamide in the presence of formic acid. 36. A process for the preparation of compounds of general formula lb as defined in claim 5 which comprises reacting a compound of formula (wherein R, , Hal and 1 are as defined in claim 5) with a • compound of formula (wherein R2 is as defined in claim 5) or with a corresponding formamide in the presence of formic acid. 37. A process for the preparation of compounds of general formula I (wherein R^, and 1 are as defined in claim 1 and represents a hydrogen atom) which comprises reducing a compound of formula or a compound of formula (wherein R^, I^, Hal and 1 are as defined in claim 1, Z represents a cyclohexylidene group optionally substituted by a hydroxy group or by an alkyl group containing from 1 to 4 carbon atoms, a branched alkylidene group containing from 3 to 5 carbon atoms or a morpholin-carbonylmethylidene group, and represents a hydrogen atom or an organic acyl group). 38. A process as claimed in claim 37 wherein the reaction is effected in the presence of a solvent. 39. A process as claimed in claim 37 or claim 38 wherein a compound of formula V or Va wherein represents a hydrogen atom is used and the reduction is effected by means of catalytically activated hydrogen, nascent hydrogen or a complex metal hydride. 40. A process as claimed in claim 37 or claim 38 wherein a compound of formula V or Va wherein represents an organic acyl group is used and the reduction is effected by means of nascent hydrogen or a complex metal hydride. 41. A process as claimed in any of claims 37 to 40 wherein the reduction is effected at temperatures from -50 to 100°C. 42. A process for the preparation of compounds of general formula la (wherein R^, Hal, 1, n, A and B are as defined in claim 3, represents a hydrogen atom and R^ represents a hydroxy! group or an alkyl group containing from 1 to 4 carbon atoms) which comprises reducing a compound of formula A (wherein R^, Hal, 1 and n are as defined in claim 3 and R represents a hydroxy group or an alkyl group containing from 1 to 4 carbon atoms) . 43. A process for the preparation of compounds of general formula la (wherein R^, R^, Hal, A, B, n and 1 are as defined in claim 3 and R^ represents a hydrogen atom) which comprises reducing a compound of formula (wherein R, , R~, A, B, Hal, 1 and n are as defined in claim 3 and R^ represents a hydrogen atom or an organic acyl group). 44. A process for the preparation of compounds of general formula I (wherein R^, R^, Hal and 1 are as defined in claim 4 and R2 represents a hydrogen atom) which comprises reducing a compound of formula or a compound of formula (wherein R^, R^t Hal and 1 are as defined in claim 4, Z represents a cyclohexylidene, hydroxycyclohexylidene or morpholinocarbonyl- methylidene group, and R^ represents a hydrogen atom or an organic acyl group). 45. A process for the preparation of compounds of general formula lb as defined in claim 5 which comprises reducing a compound of formula or a compound o ormula (Hal) OR (wherein R^, R2, Hal and 1 are as defined in claim 5, Z represents a branched alkylidene group containing from 3 to 5 carbon. atoms and R^ represents a hydrogen atom or an organic acyl group). / 46. A process for the preparation of compounds of general formula I as defined in claim 1 with the proviso that R^ is other than a hydrogen atom and R2 and R^ do not represent radicals substituted by a hydroxyl group which comprises alkylating a compound of formula (wherein R^, Hal and 1 are as defined in claim 1 and R2 represents a hydrogen atom, an alkyl group containing from 1 to 4 carbon atoms or one of the groups represented by R2 as defined in claim 1 but not a branched alkyl group containing from 3 to 5 carbon atoms or a radical substituted by a hydroxyl group) with a compound of formula R ' - W (VII) (wherein R^' represents a branched alkyl group containing from 3 to 5 carbon atoms, a cyclohexyl group or one of the groups represented by R, but not a hydrogen atom, and W represents a halogen atom or a sulfonic acid group). 47. A process as claimed in claim 46 wherein the reaction is effected in the presence of a solvent. 48. A process as claimed in claim 46 or claim 47 wherein the reaction is effected at temperatures from -20 to 150°C. 49. A process as claimed in any of claims 46 to 48 wherein the alkylation is a methylation and is effected by means of formaldehyde in the presence of formic acid. 50. A process for the preparation of compounds of general formula la as defined in claim 3 with the proviso that does not represent a hydrogen atom which comprises alkylating a (wherein R, , P , Hal, 1, A, B and n are as defined in 1 3 claim 3) with a compound of formula R. - W (Vila) r (wherein R^ is as defined in claim 3 and represents a halogen atom or a sulfonic acid group). 51. A process for the preparation of compounds of general formula I as defined in claim 4 with the proviso that R^ does not represent a hydrogen atom which comprises alkylating a compound of formula (wherein R^, Hal and 1 are as defined in claim 4 and R'2 represents one of the groups represented by R2 and R^ as defined in claim 4 with the exception of the hydrogen atom) with a compound of formula R*. - W (VII) 4 (wherein R1^ represents one of the groups represented by R^ as defined in claim 4 or a methyl or ethyl group, and W represents a halogen atom or a sulfonic acid group). 52. A process for the preparation of compounds of general formula lb as defined in claim 5 with the proviso that R2 does not represent a radical substituted by a hydroxyl group) which comprises alkylating a compound of formula (wherein R^, Hal and 1 are as defined in claim 5) with a compound of formula R ' - W (VII) 4 (wherein R^1 represents an alkyl group containing from 3 to 5 carbon atoms and W represents a halogen atom or a sulfonic acid group). 53. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a phenol of formula (wherein R, , Hal and 1 are as defined in claim 1 with the proviso that (one of) the radical(s) Hal is in the 2-position) with formaldehyde or paraformaldehyde and a compound of formula (wherein and are as defined in claim 1) . 54. A process as claimed in claim 53 wherein the reaction is performed in the presence of a solvent. 55. A process as claimed in claim 53 or claim 54 wherein the reaction is performed at temperatures from 0 to 100°C. 56. A process for the preparation of compounds of general formula la as defined in claim 3 which comprises reacting a phenol of formula (Villa) (wherein and Hal are as defined in claim 3) with formaldehyde or paraformaldehyde and an amine of general formula (wherein R^, R^, A, B and n are as defined in claim 3). 57. A process for the preparation of compounds of general formula I as defined in claim 4 which comprises reacting a phenol of formula (wherein R^, Hal and 1 are as defined in claim 1 with the proviso that (one of) the radical(s) that is in the 2-position) with formaldehyde or paraformaldehyde and an amine of formula H - N (III) \ R, (wherein R_ and R are as defined in claim 4,). 58. A process for the preparation of compounds of general formula lb as defined in claim 5 which comprises reacting (wherein R^f Hal and 1 are as defined in claim 5 with the proviso that (one of) the radical(s) Hal is in the 2-position) with formaldehyde or paraformaldehyde and a compound of formula (wherein is as defined in claim 5). 59. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a phenol of formula (wherein R^, Hal and 1 are as defined in claim 1 with the proviso that (one of) the radical(s) that is in the 2- position) with a compound of formula (wherein R2 and are as defined in claim 1 and Alk represents a lower alkyl group), optionally prepared in situ. 60. A process as claimed in claim 59 wherein the reaction is performed in the presence of a solvent. 61. A process as claimed in claim 59 or claim 60 wherein the reaction is performed at temperatures from 0 to 100°C. 62. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises halogenating a compound of formula (wherein R^, R2 and R^ are as defined in claim 1 ) . 63. A process as claimed in claim 62 wherein the halogenation is performed in the presence of a solvent. 64. A process as claimed in claim 62 or claim 63 wherein the halogenation is effected by means of chlorine, bromine, iodoaebenzene dichloride or ribromophenol bromine. 65. A process as claimed in any of claims 62 to 64 wherein the halogenation is performed at temperatures from -20 to 50°C . 66. A process for the preparation of compounds of general formula la as defined in claim 3 which comprises halogenating a compound of fornula i Ί (wherein R^, R^, R^, A, B and n are as defined in claim 3). 67. A process for the preparation of compounds of general formula I as defined in claim 4 which comprises halogenating a compound of formula (wherein R, , R and R. are as defined in claim 4). 1 2 4· 68. A process for the preparation of compounds of general formula lb as defined in claim 5 which comprises halogenating a compound of formula (wherein R^ and R are as defined in claim 5). 69. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises splitting off one or two protecting groups from a compound of formula (wherein R^, R2, Hal and 1 are as defined in claim 1, X represents a protecting group for an amino group or is as hereinbefore defined for R^, and Y represents a protecting group for a hydroxy1 group or, in the case were X represents a protecting group for an amino groqp, a hydrogen atom). 70. A process as claimed in claim 69 wherein the reaction is performed in the presence of a solvent. 71. A process as claimed in claim 69 or claim 70 wherein X and/or Y in the compound formula X represent acyl groups which are split off hydrolytically. 72. A process as claimed in claim 69 or claim 70 wherein X and/or Y in the compound of formula X represent benzyl groups which are split off hydrogenolitically. 73. A process as claimed in claim 69 or claim 70 wherein Y in the compound of formula X represents an alkyl, aryl or aralkyl group and is split off by means of hydrobromic acid, Hydroiodic acid, an acyl halide, a phosphoryl halide, a phosphorus pentahalide, an aluminium halide, sulfuric acid or an organometallie compound . 74. A process as claimed in claim 69 or claim 70 wherein Y in the compound of formula X represents an organic acyl group which is split off by means of a complex metal hydride. 75. A process for the preparation of compounds of general formula la as defined in claim 3 which comprises splitting off one or two protecting groups from a compound of formula (wherein R^, R^, A, B, Hal,l and n are as defined in claim 3, X represents a protecting group for an amino group or is as hereinbefore defined for R^, and Y represents a protecting group for a hydroxy1 group or, in the case where X represents a protecting group for an amino group, a hydrogen the preparation of compounds of general ed in claim 4 which comprises splitting tecting groups from a compound of formula (wherein R^, , Hal and 1 arenas defined in claim 4, X represents a protecting group for an amino group or is as hereinbefore defined for R^, and Y represents a protecting group for a hydroxyl group or, in the case where X represents a protecting group for an amino group, a hydrogen atom). 77. A process for the preparation of compounds of general formula lb as defined in claim 5 which comprises splitting off one or two protecting groups from a compound of formula (wherein R^, I^, Hal and 1 are as defined in claim 5, X represents a protecting group for an amino group or a hydrogen atom, and Y represents a protecting group for a hydroxy1 group or, in the case where X represents a protecting group for an amino group, a hydrogen atom). 78. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reducing a compound of formula (wherein R^, R , Hal and 1 are as defined in claim 1 with the proviso that R2 does not represent a mor holinocarbonylmethyl group, R^" represents a formyl or acetyl group or one of the groups represented by R^ as defined in claim 1 and R^ represents a hydrogen atom or an organic acyl group). 79. A process as claimed in claim 78 wherein the reduction is effected in the presence of a solvent. 80. A process as claimed in claim 78 or claim 79 wherein the reduction is effected at temperatures from room temperature up to the boiling temperature, of the solvent used. 81. A process as claimed in any of claims 78 to 80 wherein a compound of formula XI wherein represents a hydrogen atom is used and the reduction is effected by means of catalytically activated hydrogen, 82. A process as claimed in any of claims 78 to 80 wherein the reduction is effected by means of nascent hydrogen or a complex metal hydride. 83. A process for the preparation of compounds of general formula la as defined in claim 3 which comprises reducing a compound of formula (wherein R^, R^, A, B, Hal, 1 and n are as defined in claim 3, R," represents an aliphatic acyl group containing from 1 to 4 carbon atoms or one of the groups represented by as defined in claim 3, and represents a hydrogen atom or an organic acyl group). 84. A process for the preparation of compounds of general formula I as defined in claim 4 which comprises reducing a compound of formula (wherein R^, I^, Hal and 1 are as defined in claim 4, R^" represents a formyl or acetyl group or one of the groups represented by as defined in claim 4, and R^ represents a hydrogen atom or a organic acyl group). 85. A process for the preparation of compounds of general formula lb as defined in claim 5 which comprises reducing a compound of formula (wherein R^, R2, Hal and 1 are as defined in claim 5 and represents a hydrogen atom or an organic acyl group). 86. A process for the preparation of compounds of general formula I (wherein R^, R^t HaI and 1 are as defined in claim 1, R^ represents a hydrogen atom and the hydroxyl group is in the 2-position) which comprises hydrolysing a compound of formula (wherein R^, I^, Hal and 1 are as defined in claim 1). 87. A process as claimed in claim 86 wherein the reaction is effected in the presence of a solvent. 88. A process as claimed in claim 86 or claim 87 wherein the reaction is effected at temperatures up to the boiling point of the solvent used. 89. A process as claimed in any of claims 86 to 88 wherein the reaction is effected in the presence of an acid or base. 90. A process for the preparation of compounds of general formula la (wherein R^, R^, Hal, A, B, 1 and n are as defined in claim 3,R^ represents a hydrogen atom and the hydroxyl group is in the 2-position) which comprises hydrolysing a compound of formula A r (wherein R^, R^, A, B, Hal, 1 and n are as defined in claim 3). 91. A process for the preparation of compounds of general formula I (wherein R^, Hal and 1 are as defined in claim 4, R^ represents a hydrogen atom and the hydroxyl group is in the 2-position) which comprises hydrolysing a compound of formula (wherein R^, ^t Hal and 1 are as defined in claim 4). 92. A process for the preparation of compounds of general formula lb as defined in claim 5 with the proviso that the hydroxyl group is in the 2-position which comprises hydrolysing a compound of formula ■» (wherein R^, ^t Hal and 1 are as defined in claim 5). 93. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula (wherein R^, Hal and 1 are as defined in claim 1 and R represents an organic acyl group) with a compound of formula . H N (III) R, (wherein R^, R^t Hal and 1 are as defined in claim 5). 93. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula (wherein R^, Hal and 1 are as defined in claim 1 and R represents an organic acyl group) with a compound of formula .R, l2 / H N (III) R, 139 (wherein and are as defined in claim 1). 94. A process as claimed in claim 93 wherein the reaction is performed in the presence of a solvent. 95. A process as claimed in claim 93 or claim 94 wherein the reaction is effected at temperatures from 100 to 220°C. 96. A process as claimed in claim 95 wherein the reaction is effected at temperatures from 120 to 180°C. 97. A process for the preparation of compounds of general formula I (wherein R^, R^, Hal and 1 are as defined in claim 1 and R is as defined in claim 1 with the proviso that it does not represent a branched alkyl group containing from 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxyl groups) which comprises reacting a compound of formula 140 (wherein R^, Hal and 1 are as hereinbefore defined and R represents an organic acyl group) with a compound of formula (wherein R2 and R^ are as hereinbefore defined). 98. A process for the preparation of compounds of general formula lb as defined in claim 5 which comprises reacting a compound of formula (wherein R. , Hal and 1 are as defined in claim 5 and R0 represents an organic acyl group) with an amine of formula 141 (wherein is as defined in claim 5). 99. A process for the preparation of compounds of general formula I as defined in claim 1 but wherein the hydroxyl group is in the 2-position which comprises reacting a compound of formula (wherein R , Hal and 1 are as defined in claim 1 and 1 Rg represents an alkyl, aryl or aralkyl group) with a compound of formula (wherein R2 and R^ are as defined in claim 1), and subsequently hydrolysing the reaction product obtained. 142 100. A process as claimed in claim 99 wherein the reaction is effected in the presence of a polar solvent. 101. A process as claimed in claim 99 or claim 100 wherein the reaction is effected at temperatures from 100 to 200°C. 102. A process as claimed in claim 101 wherein the reaction is effected at temperatures from 120 to 180°C. 103. A process as claimed in any of claims 99 to 102 wherein the reaction is effected in the presence of an acid. 104. A process for the preparation of compounds of general formula I as defined in claim 97 but wherein the hydroxyl group is in the 2-position which comprises reacting a compound of formula (wherein R^, Hal and 1 are as defined in claim 97 and Rg represents an alkyl, aryl or aralkyl group) with a compound 143 of formula H— (III) (wherein and are as defined in claim 97) and subsequently hydrolysing the reaction product. 105. A process for the preparation of compounds of general formula lb as defined in claim 5 but wherein the hydroxyl group is in the 2-position which comprises reacting a compound of formula (wherein R^, Hal and 1 are as defined in claim 5 and represents an alkyl, aryl or aralkyl group) with a compound of formula (wherein R2 is as defined in claim 5) and subsequently hydrolysing the reaction product. 106. A process for the preparation of compounds of general formula I (wherein R^, Ι^» anc 1 are as defined in claim 1, represents a hydrogen atom and the hydroxyl group is in the 2-position) which comprises hydrolysing a compound of formula (wherein R Hal anc* 1 are as defined in claim 1). 107. A process as claimed in claim 106 wherein the hydrolysis is effected in the presence of a solvent. 108. A process as claimed in claim 106 or claim 107 wherein the hydrolysis is effected in the presence of an acid. 109. A process as claimed in any of claims 106 to 108 wherein the hydrolysis is effected at temperatures from 0°C up the boiling temperature of the solvent used. 110. A process for the preparation of compounds of general formula I (wherein R^, R2, Hal and 1 are as defined in claim 97, R, represents a hydrogen atom and the ( hydroxyl group is in the 2-position) which comprises hydrolysing a compound of formula (Hal)1 (wherein R^, ^t anc* 1 are as defined in claim 97). 111. A process for the preparation of compounds of general formula lb as defined in claim 5 but wherein the hydroxyl group is in the 2-position which comprises hydrolysing a compound of formula (wherein R^, I^, Hal and 1 are as defined in claim 5). 112. A process for the preparation of compounds of general formula I (wherein R^, Hal and 1 are as defined in claim 1, R9 represents a cyclohexyl group and R, 146 represents a methyl group) which comprises reacting a compound of formula (wherein R^ Hal and 1 are as defined in claim 1) with amide of formula or with an amide of formula 0 .R2 R 113. A process as claimed in claim 112 wherein the reaction is effected in the presence of a solvent. 114. A process as claimed in claim 112 or claim 113 wherein the reaction is effected at temperatures from 100 to 250°C. 115. A process as claimed in claim 114 wherein the reaction is effected at temperatures from 120 to 180°C.. 116. A process as claimed in any of claims 16 to 115 where the compound of formula I obtained is subsequently converted into an acid addition salt thereof. 117. A process as claimed in any of claims 16 to 116 substantially as herein described. 118. A process as claimed in any of claims 27, 34, 42, 50 and 56 substantially as herein described. 119. A process as claimed in any of claims 43, 66,75, 83 and 90 substantially as herein described. 120. A process as claimed in any of claims 28, 35, 44, 51, 57, 67,76, 84 and 91 substantially as herein described. 121. A process as claimed in any of claims 97, 104, 110 and 112 substantially as herein described. 148 122. A process as claimed in any of claims 29, 36, 45, 52, 58, 68, 77, 85, 92, 98, 105 and 111 substantially as herein described. 123. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any of Examples 1 to 235. 124. A process for the preparation of compounds as claimed in claim 3 substantially as herein described in any of Examples 1 to 71. 125. A process for the preparation of compounds as claimed in claim 3 substantially as herein described in any of Examples 122 to 165. 126. A process for the preparation of compounds as claimed in claim 4 substantiallly as herein described in any of Examples 73 to 121. 127. A process for the preparation of compounds as claimed in claim 3 or claim 4 substantially as herein described in any of Examples 166 to 197. 128. A process for the preparation of compounds as claimed in claim 5 substantially as herein described in any of Examples 198 to 235. 149 129. Compounds as claimed in claim 1 when prepared by a process as claimed in any of claims 16 to 123. 130. Compounds as claimed in claim 3 when prepared by a process as claimed in any of claims 27, 34, 42, 50, 56, 118 and 124. 131. Compounds as claimed in claim 3 when prepared by a process as claimed in any of claims 43, 66, 75, 83, 90, 119 and 125. 1

32. Compounds as claimed in claim 4 when prepared by a process as claimed in any of claims 28, 35, 44, 51, 57, 67, 76, 84, 91, 120 and 126. 1

33. Compounds as claimed in claim 3 or claim 4 when prepared by a process as claimed in any of claims 97, 104, 110, 112, 121 and 127. 1

34. Compounds as claimed in claim 5 when prepared by a process as claimed in any of claims 29, 36, 45, 52, 58, 68, 77, 85, 92, 98, 105, 111, 122 and 128. 1

35. Pharmaceutical compositions comprising as active ingredient a compound of formula I as defined in claim 1 or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient. 150 1

36. Compositions as claimed in claim 135 in a form suitable for oral, rectal or parenteral administration. 1

37. Compositions as claimed in claim 135 or claim 136 in the form of dosage units. 1

38. Compositions as claimed in claim 137 wherein each dosage unit contains from 1 to 20 mg of active ingredient. 1

39. Compositions as claimed in claim 138 wherein each dosage unit contains from 2 to 10 mg of active ingredient. 1

40. Compositions as claimed in any of claims 135 to 139 wherein the active ingredient is a compound as claimed in claim 3. 1

41. Compositions as claimed in any of claims 135 to 139 wherein the active ingredient is a compound as claimed in claim 4. 1

42. Compositions as claimed in any of claims 135 to 139 wherein the active ingredient is a compound as described in claim 5. 151 43457/2 1

43. Pharmaceutical compositions substantially as herein described. 1

44. Pharmaceutical compositions substantially as herein described with reference to Examples 236 to 241. - 152 -