GB2101119A

GB2101119A - Substituted 2-aminoethanols

Info

Publication number: GB2101119A
Application number: GB08212611A
Authority: GB
Inventors: Franz Ostermayer; Walter Fuhrer; Markus Zimmermann
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1981-05-08
Filing date: 1982-04-30
Publication date: 1983-01-12
Also published as: FI821573L; ES8400080A1; EP0069838A1; JPS57185243A; FI821573A0; IL65658A0; GR76002B; AU8348682A; NO821510L; ES511969A0; ZA823153B; DD204697A5; DK205082A

Description

SPECIFICATION Substituted 2-aminoethanois The invention relates to novel substituted 2-aminoethanols, processes for the manufacture thereof and pharmaceutical preparations that contain such compounds, and the use thereof for the manufacture of pharmaceutical preparations or as pharmacologically active compounds. The novel compounds according to the invention correspond to the formula

in which R is methyl, methoxy, fluorine, chlorine or bromine, and m is 0 or 3, with the proviso that, if m is 0, R is 2-methyl, 3-methyl, 4-methyl, 4-fluoro, 4-chloro, 4-bromo or 4-methoxy and the basic side chain is bonded by its oxygen atom to the salicylamide radical in the 4-position to the hydroxy group present therein or, if m is 0 and R is 4- methyl, the basic side chain is bonded by its oxygen atom to the salicylamide radical in the 4-position to the carboxamide group present therein or, if m is 3, R is 2-methoxy and the basic side chain is bonded by its oxygen atom to the salicylamide radical in the 4-position to the hydroxy group present therein, in the form of racemates, optical antipodes or salts thereof, especially acid addition salts and, more especially,pharmaceutically acceptable, non-toxic acid addition salts. The novel compounds have valuable pharmacological properties. They act on the central nervous system, which is reflected, for example, in the relief of symptoms of reduced sympathetic functions and in the treatment of lack of drive, as can be seen, for example, from the antagonism towards hypothermia brought about in mice after subcutaneous administration of 2 mg/kg of reserpine (B. Benz, P.G. Waser, Arzneimittelforschung 21, 654-61 (1971) in a dosage range of from approximately 3 mg/kg to approximately 100 mg/kg i.p., or from the antagonism towards hypothermia brought about in mice after subcutaneous administration of 10 mg/kg of apomorphine (P.L. Puech; Europ. J. Pharmacol. 47,125-127 (1978); E.L.Schelkunov: Psychopharmacol. 55, 87-95 (1977)) in a dosage range of from approximately 0.3 mg/kg to approximately 10 mg/kg i.p., or from the antagonism towards hypothermia brought about in mice after intraperitoneal administration of 0.25 mg/kg of clonidine (P.F. Voigtlander et al.: Neuropharmacol. 17, 375-381, (1978)) in a dosage range of from approximately 0.05 mg/kg to approximately 2.5 mg/kg. As a result of these activities, the preparations mentioned appear suitable for the treatment of reactive or endogenous depressions of different degrees of severity, and also neurotic or other psychotropic disorders with lack of drive and depressive psychoses. The compounds can also be used, alone or in combination with other substances having an anti-depressive activity, for short treatment of post-partum or post operative depressions, or of depressions having other origins. Furthermore, the novel compounds of the formula I act in a specific manner on (3-adrenergic receptors. This activity, which is a property common to all compounds of the formula I, can be attributed to their affinity to these receptors, which manifests itself as a pure blockade when the inherent stimulating action of the receptors is absent or very slight, as a blockade with simultaneous ISA, i.e. intrinsic sympathomimetic activity, when the inherent stimulating action of the receptors is slight to moderate, and as pronounced stimulation of the (3-adrenergic receptors when the inherent action of the latter is relatively strong. The boundaries between (3-receptor blockers without ISA or with at most medium-strong ISA are variable, just as are the therapeutic areas of use of these types of compounds. The above information is based on the results of appropriate pharmacological experiments in customary test procedures. Thus, the novel compounds exhibit, on the one hand, a blocking action on cardiac (3-receptors, which can be demonstrated by the inhibition of tachycardia induced by isoproterenol in the isolated hearts of guinea pigs according to Langendorff in a concentration range of from approximately 0.01 Micromol/litre to approximately 10 Micromol/litre, while a blocking action on vascular (3-receptors can be shown by the inhibition of reduction in blood pressure induced by isoproterenol in narcotised cats in a dosage range of from approximately 0.1 mg/kg to approximately 10 mg/kg after intravenous administration.Furthermore, in a dosage range of from approximately 0.1 mg/kg to approximately 10 mg/kg i.v., the novel compounds bring about a reduction in arterial blood pressure in narcotised cats. As a result of these properties, the novel compounds appear suitable, in some cases as cardioselective, -receptor blockers, for example for the treatment of Angina pectoris and cardiac rhythm disorders and also for use as agents for reducing blood pressure. On the other hand, the novel compounds, especially those in which R is a methyl group or a fluorine atom and the basic side chain is bonded by its oxygen atom to the salicylamide radical in the p-position to the aromatic hydroxy group therein, have a stimulating action on cardiac (3-receptors, which can be demonstrated by the positive chronotropic action on the spontaneously beating isolated right atrium of guinea pigs in a concentration range of from approximately 0.01 Micromol/litre to approximately 10 Micromol/litre. As a result, these compounds appear suitable, in some cases as cardioselective, (3-receptor stimulators, on the one hand forthe treatment of insufficient cardiac output and, on the other hand, as broncho- and vaso-dilators for the treatment of asthma and circulatory disorders. The novel compounds of the formula I are manufactured in a manner known perse. They can be obtained, for example, by reacting a compound of the formula

with a compound of the formula

in which one of the groups Z, and Z2 is a reactive esterified hydroxy group and the other is the primary amino group, and X1 is hydroxy, or in which X1 and Z1 together are the epoxy group and Z2 is the primary amino group, and R and m have the meanings given above, and, if desired, converting a resulting free compound into a salt or a resulting salt into a free compound, and or, if desired, separating a resulting racemate into the optical antipodes. A reactive esterified hydroxy group Z, or Z2 is a hydroxy group esterified by a strong acid, especially a strong inorganic acid, such as a hydrohalic acid, especially hydrochloric, hydrobromic or hydriodic acid, or sulphuric acid, or a strong organic acid, especially a strong organic sulphonic acid, such as an aliphatic or aromatic sulphonic acid, for example methanesulphonic acid, 4-methylbenzenesulphonic acid or 4bromobenzenesulphonic acid, and is especially halogen, for example chlorine, bromine or iodine, or aliphatically or aromatically substituted sulphonyloxy, for example methylsulphonyloxy or 4methylphenylsulphonyloxy. The above reaction is carried out in a manner known perse and, especially when using a starting material having a reactive esterified hydroxy group, advantageously in the presence of a basic agent, such as an inorganic base, for example an alkali metal or alkaline earth metal carbonate or hydroxide, or of an organic basic agent, such as an alkali metal lower alkoxide, and or of an excess of the basic reactant and usually in the presence, but optionally also in the absence, of a solvent or solvent mixture and, if necessary, while cooling or heating, for example within a temprature range of from approximately -20[deg] to approximately +150[deg]C, in an open or closed vessel and/or in an inert gas atmosphere, for example in a nitrogen atmosphere. Starting materials of the formula II or III are known or can be manufactured in a manner known perse.Thus, forthe manufacture of a starting material of the formula II in which m is 0, a compound oftheformula

can be haloacetylated, according to the Friedel-Crafts method, at a carbon atom of the aromatic radical with a haloacetyl halide, for example chloroacetyl chloride, in the presence of a suitable Lewis acid, for example aluminium chloride, and, in the corresponding haloacetyl compound so obtained, the carbonyl group can be reduced to the carbinol group, for example by treating with a suitable hydride reducing agent;if desired, a halogen Z1 can be converted into the primary amino group Z1, for example by treating with ammonia or a suitable derivative thereof, such as hexamethylenetetramine, and decomposing the resulting compound with a dilute mineral acid, or by reacting with an alkali metal salt of phthalimide and cleaving the resulting N-phthalimide compound, for example with hydrazine. Starting materials of the formula II in which Xi and Z, together are epoxy can be obtained, for example, by cyclising a compound of the formula II in which X1 is hydroxy and Z1 is a reactive esterified hydroxy group, for example chlorine or methylsulphonyloxy, by means of alkaline reagents, for example a mixture of dilute sodium hydroxide solution and tetrabutylammonium chloride, in a suitable solvent, for example methylene chloride. Starting materials of the formula II in which m has the meaning given above and Xi andZi together are the epoxy group can be obtained by converting the group - CH = CH2 in a compound of the formula

into the group

by epoxidation, for example by reacting with a peroxy compound, such as hydrogen peroxide, or with an organic peracid, such as, for example, an optionally substituted, such as halogenated, aliphatic or aromatic peracid, for example peracetic acid or trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid, in an anhydrous solvent, for example a halo-lower alkane, such as chloroform or methylene chloride. This reaction is carried out in the usual manner. Starting materials of the formula lib in which m is 3 can, for their part, be obtained in the usual manner by reacting a compound of the formula

in which the hydroxy group is reactively esterified, for example in the manner indicated above, and is, for example, halogen, for example bromine, with a Grignard compound, for example with a compound of the formula Br-(CH2)n-CH=CH2 (lid), in which n is 1 or 2. Starting materials of the formula III can be obtained, for example, by reacting a hydroxysalicylamide with 1,2-dihaloethane, for example 1-chloro-2-bromoethane or 1,2-dibromoethane, in the presence of an alkaline condensation agent, such as an alkali metal carbonate and, if desired, replacing the remaining halogen Zz by a primary amino group in the manner described above for Z1. These reactions are carried out in the usual manner. The compounds of the formula I can furthermore be manufactured as follows: in a compound of the formula

in which each of X2, X3, X4 and X5 is hydrogen or a substituent that can be replaced by hydrogen, or X2 and X3 together and/or X4 and X5 together are a bivalent radical that can be replaced by two hydrogen atoms, with the proviso that at least one of the radicals X2, X3, X4 and X5 is other than hydrogen, or at least X2 and X3 together or X4 and X5 together are a bivalent radical that can be replaced by two hydrogen atoms, and R and m have the meanings given above, or in a salt thereof, the X2, X3, X4 or X5 that is other than hydrogen, or the X2 and X3 together, or the X4 and X5 together, is replaced by hydrogen, and, if desired, the additional process steps mentioned in connection with the first process are carried out. The removal of the groups X2, X3, X4 or X5 or of X2 and X3 together or X4 and X5 together is carried out by means of solvolysis, such as hydrolysis, alcoholysis, aminolysis or acidolysis, or by means of reduction, including hydrogenolysis. Especially suitable groups X3 and X4 that can be removed are mainly a-aryl-lower alkyl groups that can be removed by hydrogenolysis, such as an optionally substituted 1-polyphenyl-lower alkyl or 1-phenyl-lower alkyl group, in which the substituents, especially of the phenyl moiety, may be, for example, lower alkyl, such as methyl, or lower alkoxy, such as methoxy, and especially benzyl.Groups X3 and especially X2 and X4 may alternatively be radicals that can be removed by solvolysis, such as hydrolysis or acidolysis, or by reduction, including hydrogenolysis, especially corresponding acyl radicals, such as the acyl radical of an organic carboxylic acid, for example lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, or the acyl radical of a semiester of carbonic acid, such as lower alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl or tert.-butoxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally substituted 1-phenyl-lower alkoxycarbonyl, for example benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, for example phenacyloxycarbonyl, or optionally substituted 1-polyphenyl-lower alkyl groups, in which the substituents, especially, of the phenyl moiety, have,for example, the meaning given above and are especially trityl. A radical that can be removed and is formed by X2 and X3 and/or X4 and X5 together is especially a bivalent group that can be removed by hydrogenolysis, such as optionally substituted 1-phenyl-lower alkylidene, in which the substituents, especially of the phenyl moiety, may be, for example, lower alkyl or lower alkoxy, or especially benzylidene, or groups that can be removed by solvolysis, especially by hydrolysis, such as lower alkylidene, for example methylene or isopropylidene, or 1-phenyl-lower alkylidene in which the phenyl moiety is optionally substituted by lower alkyl, such as methyl, or lower alkoxy, such as methoxy, especially benzylidene, or cycloalkylidene, for example cyclopentylidene or cyclohexylidene. Starting materials that can be used in the form of salts are used especially in the form of acid addition salts, for example with mineral acids, and also with organic acids. Radicals X2, X3 and/or X4 that can be removed by hydrogenolysis, especially optionally substituted 1-phenyl-lower alkyl groups, and suitable acyl groups, such as optionally substituted 1-phenyl-lower alkoxycarbonyl, and optionally substituted 1-phenyl-lower alkylidene groups formed by X2 and X3 and also by X4 and X5 together, can be removed by treating with catalytically activated hydrogen, for example with hydrogen in the presence of a nickel catalyst, such as Raney nickel, or a suitable noble metal catalyst.Groups X2, X3 and/or X4 that can be removed by hydrolysis, such as acyl radicals of organic carboxylic acids, for example lower alkanoyl, and of semiesters of carbonic acid, for example lower alkoxycarbonyl, and also, for example, trityl radicals, and lower alkylidene, 1-phenyl-lower alkylidene or cycloalkylidene groups formed by the radicals X2 and X3 and/or X4 and X5 together can be removed, depending on the nature of such radicals, by treating with water under acidic or basic conditions, for example in the presence of a mineral acid, such as hydrochloric or sulphuric acid, or of an alkali metal or alkaline earth metal hydroxide or carbonate or of an amine, such as isopropylamine. By aminolysis it is possible to remove, for example, acyl radicals present as protecting groups of hydroxy groups, and especially lower alkylidene, 1-phenyl-lower alkylidene or cycloalkylidene groups formed by X4 and X5 together, such as, for example, the 1-methylethylidene group, for example by reacting with ammonia or, especially in the case of the above-mentioned bivalent protecting groups, with primary amines, such as, for example, isopropylamine or benzylamine, in a suitable reaction medium, such as, for example, isopropanol or dioxan. Radicals X2, X3 and.'or X4 that can be removed by acidolysis are especially certain acyl radicals of semiesters of carbonic acid, such as, for example, tert.-lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl radicals, and also the tert.-butyl radical; such radicals can be removed by treating with suitable strong organic carboxylic acids, such as lower alkanecarboxylic acids optionally substituted by halogen, especially fluorine, especially trifluoroacetic acid (if necessary in the presence of an activating agent, such as anisole), and also with formic acid. By radicals X2, X3 and or X4 that can be removed by reduction there are to be understood also those radicals which can be removed by treating with a chemical reducing agent (especially with a reducing metal or a reducing metal compound). Such radicals are especially 2-halo-lower alkoxycarbonyl or arylmethoxycarbonyl, which can be removed, for example, by treating with a reducing heavy metal, such as zinc, or with a reducing heavy metal salt, such as a chromium(II) salt, for example chromium (II) chloride or acetate, usually in the presence of an organic carboxylic acid, such as a formic acid or acetic acid, and water,. The above reactions are usually carried out in the presence of a solvent or solvent mixture, it being possible for suitable reactants to function simultaneously as such, and, if necessary, while cooling or heating, for example in an open or closed vessel and or in the atmosphere of an inert gas, for example nitrogen. The starting materials of the formula IV can be obtained in a manner known perse as follows: for the manufacture of a starting material in which m is 0, for example, a compound of the formula

is reacted, according to the Friedel-Crafts process, with a haloacetyl halide, for example chloroacetyl chloride, in the presence of a suitable Lewis acid, for example aluminium chloride, the carbonyl group in the corresponding haloacetyl compound obtained in this manner or in another usual manner is reduced, for example by means of sodium borohydride, to the carbinol group, and the resulting compound is reacted with an amine of the formula

in which X3 has the meaning given, and X4 or X4 and X5 together are other than hydrogen. Starting materials of the formula IV in which m has the meaning given above can be obtained by reacting a compound of the formula II described above with a compound of the formula IVa. This reaction is carried out in a manner known perse. The Schiff's base formed, for example, by reacting a compound of the formula

with a compound of the formula

in which X4 or X4 and X5 together are one of the mentioned protecting groups, can be reduced with a borohydride, for example sodium borohydride, to a compound of the formula IV. The reduction can also be effected by means of activated hydrogen in the presence of a hydrogenation catalyst, for example a platinum-on-carbon catalyst. Amines of the formula IVb in which X2 is hydrogen or a group that can be removed by reduction, including hydrogenolysis, and replaced by hydrogen can be manufactured, for example, by reacting a compound of the formula

in which X1 and Z1 have the meanings given under formula (II), with ammonia or with an amine, for example benzylamine, that contains a radical which can be removed by means of reduction, including hydrogenolysis, for example as stated, and replaced by hydrogen, and subsequently removing that radical. Starting materials of the formula IVd in which X1 and Z, together are the epoxy group can, fortheir part, be obtained analogously, for example as described for the manufacture of compounds of the formula II, for example starting from compounds of the formula Ila via compounds of the formula lib, for example as described, and subsequent epoxidation. Carbonyl compounds of the formula (lVc) can be obtained in the usual manner by rotating a compound of the formula

with, for example, chloroacetaldehyde (IVf). It is also possible to manufacture from the above-mentioned compounds of the formula (IVe), by reaction with, for example, 1,2-dibromoethane, compounds of the formula

in which X4 and X5 have the meanings given above, and these compounds can be reacted with compounds of the formula (IVb) to form starting materials of the formula IV. The novel compounds of the formula I can also be obtained as follows: in a compound of the formula

in which X6 is a reducible group ofthe formula -CH=N-CH2-CH2- (Va), -CH2-N=CH-CH2- (Vb), -C(=X7)-N(X8)-CH2-CH2- (Vc) or -CH2-N(X8)-X(=X7)-CH2- (Vd), or is a group -CH2-N(X8)-CH2-CH2- (Ve) wherein X7 is the oxo or thioxo radical and X8 is hydrogen or a radical that can be replaced by hydrogen under the conditions for the reduction of X6 and/or Y, and Y is a radical of the formula -CO- (Vf), or -CH(OX8)- (Vg) in which X8 has the meaning given above, and R and m have the meanings given above, wherein, at all times, X6 is a reducible group Va to Vd and/or Y is a carbonyl group Vf, this group or these groups is/are reduced and, in the same operation, the groups X8 that are other than hydrogen are replaced by hydrogen, and, if desired,the additional process steps mentioned subsequent to the first process are carried out. A group X8 that can be removed by hydrogenolysis is espcially an a-aryl-lower alkyl group, such as an optionally substituted 1-phenyl-lower alkyl group, in which the substituents may be, for example, lower alkoxy, such as methoxy, and more especially benzyl. Starting materials of the formula V having a group X6 of the formula Vb may also be in the isomeric form of ring tautomers of the formula

in which the oxygen atom and the nitrogen atom of the ring are bonded to the same carbon atom. The reduction of the nitrogen-carbon double bond in starting materials of the formula V that contain, as the radical X6, a group Va or Vb, while Y and X8 have the meanings given under formula V, (or,in the isomeric compounds of the formula Vh, the reduction of the oxygen-carbon-nitrogen bond) to form a nitrogen-carbon single bond can be effected in a manner known perse, for example by treatment with catalytically activated hydrogen, such as hydrogen in the presence of a suitable hydrogenation catalyst, for example a nickel, platinum or palladium catalyst, the groups X8 that can be removed by hydrogenolysis at the same time being removed and replaced by hydrogen; or a suitable hydride reducing agent is used, such as an alkali metal borohydride, for example sodium borohydride.In all cases, a carbonyl radical Y, if present, is reduced to form the hydroxymethylene radical simultaneously with the reduction of the group Va or Vb and, if a hydride reducing agent is used, also acyl radicals of carboxylic acids, for example acetic acid, bonded to oxygen may be present as radicals X8 and may be removed in the same operation. The reduction of the carbonyl group Y in starting materials of the general formula V that contain, as the radical X6, a group Ve, while X8 has the meanings given underformula V, can be effected in the manner given above for the reduction of the groups Va and Vb, wherein, once again, in the case of catalytic hydrogenation, corresponding radicals X8 can be removed by hydrogenolysis. Especially suitable for the reduction of compounds of the formula V having a group of the formula Ve or Vd and the meanings of Y defined under the formula V are hydride reducing agents, such as, for example, sodium borohydride or diborane. Simultaneously with the reduction of a group Vc or Vd, the reduction of a carbonyl group Y, if present, and also the removal of acyl radicals of carboxylic acids, such as, for example, acetic acid, bonded to oxygen as radicals X8 also takes place. On the other hand, it must be ensured, by limiting the amount of reducing agent and suitable selection of the reduction conditions, that the aromatically bonded carboxamide group is not reduced. Groups of the formulae Vc and Vd, in which X7 is, in each case, a thioxo group, are converted into the group of the formula -CH2-NH-alk- by reductive desulphurization, for example by treating with a hydrogenation catalyst, such as Raney nickel.The above reduction reactions are carried out in a manner known perse, usually in the presence of an inert solvent and, if necessary, while cooling or heating, for example within a temperature range of from approximately -20[deg] to approximately +150[deg]C, and/or in a closed vessel under pressure and/or in an inert gas atmosphere, for example a nitrogen atmosphere. A starting material of the formula V in which m is 0 can be manufactured in a manner known perse, optionally in situ, i.e. under the conditions of the described process. Thus, a compound of the formula

can be acetylated wifth an acetic acid halide or anhydride in the presence of a Lewis acid and, in the resulting intermediate, the acetyl group can then be converted into the glyoxyloyl group, for example by treating with a suitable oxidising agent, such as selenium dioxide. A glyoxyl compound of this kind, or, if desired, a suitable derivative thereof, for example an acetal, can then be reacted with an amine of the formula

to form a starting material of the formula V having the groups X6 of the formula Va, in which Y is the carbonyl group.A compound of the formula (Vi) can also be haloacetylated, according to the Friedel-Crafts method, with a haloacetyl halide, for example chloroacetyl chloride, in the presence of a suitable Lewis acid, for example aluminium chloride, to form the corresponding chloracetyl compound, and, in the haloacetyl compound obtained in this manner or in another usual manner, the carbonyl group can be reduced to the carbinol group by treating with a suitable hydride reducing agent, and the halogen atom can be converted into the primary amino group by treating with ammonia or a suitable derivative thereof, such as hexamethylenetetramine, and deomposing the resulting reaction product with a dilute acid, for example aqueous hydrochloric acid, whereupon an intermdiate of the formula

is obtained in which m is 0.Amines of the formula Vk, in which m has the above meaning, can, for their part, be obtained in known manner, for example by reacting a compound of the formula

in which X, and Z, have the meanings given under the formula (II), with ammonia or a compound that yields ammonia, for example hexamethylenetetramine, it being possible to obtain compounds of the formula (VI) analogously to the process described for the manufacture of starting materials of the formula (II). Amines of the formula Vk in which m has the meaning given above can also be obtained by reacting an aldehyde of the formula

or a suitable derivative thereof, such as an acetal, for example dimethyl acetal, or a bisulphite addition compound, with a suitable organosilicon cyano compound, such as a tri-lower alkylsilyl cyanide, for example trimethylsilyl cyanide, in the usual manner in the presence of a catalyst, such as zinc iodide, to form a compound of the formula

and converting the latter into a compound of the formula Vk in which m has the meaning given above by means of a suitable reducing agent, for example a di-light metal hydride, for example lithium aluminium hydride, in a solvent, this usually being an ethereal liquid, for example diethyl ether or tetrahydrofuran.By reacting an intermediate of the formula Vk with a carbonyl compound of the formula

it is possible to obtain starting materials of the formula V having a group X6 of the formula (Vb). A modification of these reactions is, instead of exchanging the halogen atom in the intermediate described above for the primary amino group by treating with ammonia etc., to exchange it, by reaction with a 1-aryl-lower alkylamine, for example benzylamine or a di-(1-aryl-lower alkyl)-amine, for example dibenzylamine, forthe correspondikng 1-aryl-lower alkylamino or di-(1-aryl-lower alkyl)-amino group and to react the resulting compound, for example the corresponding di-benzylamino compound, with the oxo compound of the formula (Vo) under the reducing conditions of the process.In so doing, there is used as the reducing agent especially catalytically activated hydrogen, for example hydrogen in the presence of a heavy metal hydrogenation catalyst or a mixture thereof, such as a palladium and/or platinum catalyst. Under such reaction conditions, groups X8, for example benzyl groups, that can be removed by hydrogenolysis are removed, and the optionally present carbonyl group is reduced to the carbinol group and, at the same time, the nitrogen-carbon double bond is reduced to the corresponding nitrogen-carbon single bond. Oxo compounds of the formula Vo can, for their part, be obtained, for example, by reacting a dihydroxy compound of the formula

with chloroacetaldehyde in the presence of an alkaline condensation agent, for example potassium carbonate, or of an organic base, such as triethylamine. Starting materials of the formula V having a group X6 of the formula Vc or Vd can be manufactured in a manner known perse, for example by reacting a formyl compound of the formula

with hydrocyanic acid and, in the cyanohydrin intermediate obtained in this manner, hydrolysing the cyano group to form the carboxyl group, for example under acidic conditions.The corresponding 2-hydroxyacetic acid obtained in this manner or via the intermediate stages imide chloride, imido-lower alkyl ester and lower alkyl ester is then reacted in the presence of a suitable condensation agent, for example a carbodiimide, such as dicyclohexylcarbodiimide, with an amine of the formula (Vj), whereupon a starting material of the formula V having the group X6 of the formula (Vc) is obtained. A starting material of the formula (V) having the group X6 of the formula (Vd) can be obtained also by reacting a compound of the formula Vk with a compound ofthe formula

in which Hal is halogen and especially chlorine. Furthermore, in the above-given chloroacetyl compound, the chlorine atom can be exchanged for the primary amino group, for example by reaction with hexamethylenetetramine, and a compound so obtained can be reacted with a halogen compound oftheformula Vr. In a resulting starting material of the formula V having a group X6 of the formula Vd and in whichY is the carbonyl group, the carbonyl group can be reduced to the carbinol group and, at the same time, the aliphatically bonded carbamoyl group can be reduced to the group of the formula

for example by means of a hydride reducing agent, especially diborane. The novel compounds oftheformula I can also be obtained by reacting a compound of the formula

in which Xg is hydrogen or a group that can be removed by ammonolysis, and R and m have the meanings given above, or a reactive derivative of one of the carboxylic acids defined in formula VI, with ammonia and removing optionally present radicals Xg and replacing them by hydrogen, and, if desired, carrying out the additional process steps mentioned subsequent to the first process. Radicals X9 that can be removed by ammonolysis are acyl radicals of organic carboxylic acids, for example aroyl, such as benzoyl, or lower alkanoyl, such as acetyl. Reactive derivatives of the carboxylic acids defined in the formula VI are, for example, the halides, such as the chlorides or bromides, and the azides, and also the acid anhydrides, especially mixed acid anhydrides with, for example, lower alkanecarboxylic acids, such as acetic acid or propionic acid, and lower alkoxyalkanecarboxylic acids, such as 2-methoxyacetic acid.Reactive derivatives of carboxylic acids of the formula VI are especially esters, for example with lower alkanols, such as methanol, ethanol, isopropanol and tert.-butanol, or with aryl-lower alkanols, such as benzyl alcohol optionally substituted by lower alkyl, for example, methyl, or by lower alkoxy, for example methoxy, or phenols which are optionally activated by suitable substituents, for example by halogen, for example 4-halo, such as 4-chloro, lower alkoxy, for example 4-lower alkoxy, such as 4-methoxy, 4-nitro or 2,4-dinitro, such as, for example, 4-chlorophenol, 4-methoxyphenol, 4- nitro- or 2,4-dinitro-phenol, also esters with cycloalkanols, such as, for example, cyclopentanol or cyclohexanol which may optionally be substituted by lower alkyl, for example methyl.The reaction is carried out in a manner known perse, usually in the presence of an inert solvent, for example within a temperature range of from approximately -10[deg] to +50[deg]C in a closed vessel. The starting materials of the formula VI in which m is 0 can be obtained in a manner known perse by brominating a compound of the formula

reducing the carbonyl group in the resulting corresponding haloacetyl compound to the carbinol group, for example by means of diborane, and reacting the resulting compound with an amine of the formula

in which X9 has the meaning given, or with a reactive derivative thereof. The haloacetyl compound mentioned can also be reacted with the amine of the formula Vlb and the carbonyl group converted into the carbinol group subsequently. For the manufacture of starting materials of the formula VI in which m has the meaning given above, it is also possible to reduce the Schiff's base formed by reacting a compound of the formula

with a carbonyl compound of the formula

with a borohydride, for example sodium borohydride. The reduction can also be effected by means of activated hydrogen in the presence of a hydrogenation catalyst, for example a platinum-on-carbon catalyst. Compounds of the formula VIc can, for their part, be obtained, for example, by reacting a compound of the formula

in which X1 and Z1 together are epoxy, or X1 is hydroxy and Z, is a reactive esterified hydroxy group, for example halogen, such as chlorine, with ammonia,or, if X1 is hydroxy and Z1 is, for example, chlorine, with hexamethylenetetramine, and decomposing the resulting adduct with a dilute mineral acid, such as dilute hydrochloric acid, it being possible to manufacture starting materials of the formula Vie analogously to the process described for the manufacture of starting materials of the formula II. Carbonyl compounds of the formula (Vld) can, for their part, be obtained in a manner known perse by reacting a compound of the formula

with chloroacetaldehyde (IVf). The novel compounds of the formula I can also be obtained as follows: in a compound of the formula

in which one or both hydroxy groups are optionally protected by groups that can be removed by hydrolysis and replaced by hydrogen and which are removed and replaced by hydrogen underthe conditions of the process, the group -CN is converted by hydrolysis into the group -CONH2 and, if desired, the additional process steps mentioned subsequent to the first process are carried out. The starting materials of the formula VII can be manufactured in the usual manner by reacting a compound of the formula

with a compound of the formula

in which Hal is chlorine, bromine or iodine. The reaction is carried out in a manner known perse, advantageously in the presence of a basic agent. Starting materials of the formula (Vlla) in which m has the meaning given above can, for their part, be obtained by reacting a compound of the formula (II) in which X1 and Z1 together are the epoxy group with ammonia, or, if X1 is hydroxy and Z1, as a reactive esterified hydroxy group, is, for example, halogen, such as chlorine, for example with hexamethylenetetramine, and subsequently converting the resulting adduct with a dilute mineral acid, such as dilute hydrochloric acid. Starting materials of the formula (VII) in which m is 0 can also be manufactured in the usual manner, for example by halogenating, for example brominating, a compound of the formula

for example by means of bromine in an inert solvent, such as chloroform, and, in the resulting haloacetyl, for example bromoacetyl, compound, replacing the halogen by the amino group, for example, by reacting with hexamethylenetetramine in a solvent, for example a chlorinated hydrocarbon, such as chloroform, decomposing the resulting adduct with a dilute mineral acid, for example hydrochloric acid, reducing the carbonyl group in the resulting compound of the formula

to the carbinol group, for example by means of diborane, and reacting the resulting compound of the formula

with a compound of the above-described formula Vllb in the manner there described. A compound of the formula Vllb can, for its part, be obtained by the action of acetic anhydride on the oxime corresponding to the cyanide. This takes place advantageously by boiling under reflux. The oxime can, for its part, be manufactured from the corresponding aldehyde by boiling under reflux with hydroxylamine hydrochloride in the presence of an alcoholic sodium carbonate solution. The corresponding aldehyde can, in turn, be manufactured by reacting 2,4-dihydroxybenzaldehyde with an alpha , beta -, a,y- or alpha , -dihalo-lower alkane, preferably in the presence of a basic agent. In an analogous manner, a hydroxysalicylonitrile, for example 2,4-dihydroxybenzonitrile [Chem. Ber. 24, 3657 (1891 )] or 2,5dihydroxybenzonitrile [Helv. Chim. Acta 30,149, 153 (1947)] can be reacted with a dihaloethane to form a compound of the formula Vllb. The novel compounds of the formula I in which m is 3 can also be obtained as follows: in a compound of the formula

in which A is the group

X is a group that can be converted into a 1,3-propylene group by means of reduction, including hydrogenolysis, and one or both hydroxy groups are protected by groups that can be removed by means of reduction, including hydrogenolysis, and replaced by hydrogen and which are removed and replaced by hydrogen under the conditions of the process, the group X is converted into a 1,3-propylene group by means of reduction, including hydrogenolysis, and, at the same time, an optionally present unsaturated group A is converted into the saturated group A and, if desired, the additional process steps mentioned subsequent to the first process are carried out. A group X is especially a carbonyl group standing in place of a methylene group and, according to the meaning of m as 3, adopts each of the possible positions together with two methylene groups. A group X also is a group having 3 carbon atoms which has a double or triple bond, for example a 1,2-propenylene, 2,3-propenylene or 1,3-propynylene group. The reduction of the group X is effected in the usual manner, for example by means of activated hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, for example a nickel catalyst or a noble metal catalyst, such as platinum or palladium, optionally precipitated on a carrier, such as activated carbon, or a platinum-on-carbon or palladium-on-carbon catalyst. In this operation, optionally present hydroxyprotecting groups that can be removed by hydrogenolysis are removed and replaced by hydrogen. The reduction, including hydrogenolysis, is carried out in a manner known perse, usually in the presence of an inert solvent at normal or elevated pressure and normal or elevated temperature. Starting materials of the formula VIII in which X is a group of the formula -CO-CH2-CH2- (Villa) can be obtained, in a manner known perse, by epoxidising the group -CH=CH2 in a compound of the formula

to form the group

(cf. in this connection: Cahnmann, Bull. Soc. Chim. France [5], 4, 1937, 226, 230.) for example as described under the starting materials of the formula (II), by reaction with a peroxy compound, such as hydrogen peroxide, or an organic peracid, such as, for example, an optionally substituted, such as halogenated, aliphatic or aromatic peracid, for example peracetic acid or trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid, in an anhydrous solvent, for example chloroform or dioxan.The resulting compound or a compound obtained therefrom, for example by reaction with a hydrohalic acid, for example hydrochloric acid, in a solvent, such as dioxan, having the general formula

in which X1 is hydroxy and Z3 is halogen, for example chlorine, can then be reacted with ammonia or with hexamethylenetetramine and subsequently the resulting adduct can be converted by decomposition with a dilute mineral acid, for example hydrochloric acid, into a compound of the formula

From this, by reaction with a compound of the formula

in which Hal is halogen, especially chlorine, a starting material of the formula VIII having the group A of the formula

can be manufactured or,by reaction with a compound of the formula

a starting material of the formula VIII in which the group A corresponds to the formula -N=CH-CH2- can be manufactured. These reactions are carried out in a manner known perse: for example, in the reaction with a compound of the formula XII, an alkaline condensation agent is used, for example an alkali metal or alkaline earth metal carbonate, such as sodium or calcium carbonate. Starting materials of the formula VIII, in which X is a group having 3 carbon atoms which has a double or triple bond, and A has the meaning given, can be obtained by converting a compound of the formula

in which X is a group having 3 carbon atoms which has a double or triple bond, or a suitable derivative thereof, such as an acetal, for example the dimethyl acetal, or a bisulphite addition compound, with a suitable organosilicon cyano compound, such as a tri-lower alkylsilyl cyanide, for example trimethylsilyl cyanide, in the usual manner in the presence of a catalyst, such as zinc iodide, into a compound of the formula

and, in this compound, converting the group -CN by means of reduction, with the simultaneous replacement of the trimethylsilyl group by hydroxy, into the group -CH2NH2.As reducing agent, there can be used, for example, a di-light metal hydride, such as lithium aluminium hydride, in a suitable solvent, this usuallly being an ethereal liquid, for example diethyl ether or tetrahydrofuran. The compound of the formula

obtained in this manner can then be reacted with a compound of the above-described formula XII to form a compound of the formula (VIII) in which A is the group of the formula

or a compound ofthe formula XVI is reacted with a compound of the above-described formula (XIII), whereupon a starting material of the formula VIII is obtained in which A is the group of the formula -N=CH-CHz-. These reactions are carried out in the usual manner. When selecting the suitable above-mentioned process for the manufacture of compounds of the formula I care must be taken that any substituents present, especially in the aromatic radical substituted by R, are not converted or removed. Depending on the process conditions and the starting materials, the novel compounds are obtained in free form or in the form of their salts which is likewise included in the scope of the invention, it being possible for the novel compounds or salts thereof also to be in the form of hemi-, mono-, sesqui- or poly-hydrates. Acid addition salts of the novel compounds can be converted into the free compounds in a manner known perse, for example by treating with basic agents, such as alkali metal hydroxides, carbonates or bicarbonates, or ion exchangers. On the other hand, resulting free bases may form acid addition salts with organic or inorganic acids, for example with the mentioned acids, there being used for the manufacture thereof especially those acids which are suitable for the formation of pharmaceutically acceptable salts. These or other salts, especially acid addition salts, of the novel compounds such as, for example, oxalates or perchlorates, may also be used to purify the resulting free bases, by converting the free bases into salts, separating and purifying these, and liberating the bases from the salts again. Depending on the starting materials and procedures chosen, the novel compounds may be in the form of optical antipodes or racemates. The starting materials may also be used in the form of specific optical antipodes. Resulting racemates can be resolved into the antipodes according to methods known perse, for example by recrystallisation from an optically active solvent, by treatment with suitable micro-organisms or by reaction with an optically active substance that forms salts with the racemic compound, especially acids, and separating the salt mixture obtained in this manner, for example on the basis of differing solubility, into the diastereoisomeric salts from which the free antipodes can be liberated by the action of suitable agents. Especially customary optically active acids are, for example, the D- and L-forms of tartaric acid, di-0,0'(p-toluoyl)-tartaric acid, malic acid, mandelic acid, camphorsulphinic acid, glutamic acid, aspartic acid or quinic acid. Advantageously, the more active of the two antipodes is isolated. The invention relates also to those embodiments of the process according to which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or the process is discontinued at any stage, or in which a starting material is formed under the reaction conditions, or in which a reactant is optionally in the form of its salts. The starting materials are known or, if new, can be manufactured according to methods known perse, as stated above, for example analogously to the methods described in the Examples. The invention relates also to novel starting materials. The invention relates also to intermediates that can be obtained in accordance with the process. The novel compounds may be used, for example, in the form of pharmaceutical preparations which contain a pharmacologically active amount of the active ingredient, optionally together with pharmaceutically acceptable carriers which are suitable for enteral, for example oral, or parenteral administration, and may be inorganic or organic and solid or liquid. Thus, tablets or gelatin capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerine and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.Tablets may also contain binders, for example magnesium aluminium silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinyl pyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescing mixtures, or adsorbents, colouring substances, flavourings and sweeteners. The novel pharmacologically active compounds can also be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic solutions or suspensions, it being possible to manufacture these before use, for example, in the case of lyophilised preparations which contain the active ingredient on its own or together with a carrier, such as mannitol.The pharmaceutical preparations can be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations which may, if desired, by manufactured in a manner known perse, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, contain from approximately 0.1 % to 100 %, especially from aproximately 1 % to approximately 50%, and, in the case of lyophilisates, up to 100 %, of the active ingredient. The dosage may depend on various factors, such as the manner of administration, the species, age and/or individual condition. Thus, the daily doses to be administered in one or several, but preferably not more than 4, single doses in the case of oral administration to warm-blooded animals of approximately 70 kg body weight are in the range of from approximately 5 to 200 mg for the treatment of depressions, preferably between approximately 0.02 g and approximately 0.2 g for 13-receptor blockers, and between approximately 0.002 g and approximately 0.04 g for (3-receptor stimulators. The following Examples serve to illustrate the invention; temperatures are given in degrees Centigrade.

Example 1 After the addition of 2 g of palladium-on-carbon catalyst (5% strength), a solution of 25 g of crude a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylaminomethyl}-4-fluorobenzyl alcohol in 200 ml of methanol is hydrogenated until the calculated amount of hydrogen has been absorbed. Filtration, and concentration by evaporation of the filtrate, yields a viscous residue from which, by dissolving in methanol and cooling, a-{N-[2-(3-carbamoy-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-fluorobenzyl alcohol crystallises out which, after recrystallisation from dioxane, has melting point of 186-187[deg]. The starting material can be manufactured as follows: 1a) A solution of 8.3 g of 1-(4-fluorophenyl)-oxirane and 14.3 g of 5-[(2-benzylamino)-ethoxy]salicylamide in 100 ml of isopropanol is heated for 18 hours under reflux and then concentrated by evaporation. The a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylaminomethyl}-4-fluorobenzyl alcohol so obtained in theform of an orange oil isfurther processed in thatform.

Example 2 Analogously to the working methods described in Examples 1 a) and 1), a) a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-2-methylbenzyl alcohol having a melting point of 151-152[deg] (recrystallised once in each case from ethyl acetate and dioxane) is obtained using 1-(2-methylphenyl)-oxirane, b) a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-3-methylbenzyl alcohol having a melting point of 180-182[deg] (from dioxane) is obtained using 1-(3-methyl-phenyl)-oxirane, and c) a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-methylbenzyl alcohol having a melting point of 190-191[deg] (from dioxane) is obtained using 1-(4-methylphenyl)-oxirane.

Example 3 18.7 g of 5-(2-aminoethoxy)-salicylamide are dissolved in 100 ml of dimethyl sulphoxide by heating. When the temperature of the solution has reached 80-85[deg], 18.4 g of 1-(4-chlorophenyl)-oxirane are added all at once and the reaction mixture is stirred for 45 minutes at 80-85[deg]. The solution is then poured onto 1500 ml of water and, after the addition of 50 ml of ethyl acetate, the mixture is stirred for 30 minutes. The precipitated crystals are filtered with suction and recrystallised from methanol. After the crystals have been filtered with suction and dried, a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-chlorobenzyl alcohol having a melting point of 189-190[deg] is obtained.

Example 4 Analogously to Example 3, a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-bromobenzyl alcohol having a melting point of 189-190[deg] is obtained using 23.7 g of 1-(4-bromophenyl)-oxirane.

Example 5 A solution of 28 g of crude a-{N-[2-(4-benzyloxy-3-carbamoylphenoxy)-ethyl]-benzylaminomethyl}-4methoxybenzyl alcohol in 300 ml of methanol is hydrogenated under normal conditions, with the addition of 4.0 g of palladium-on-carbon catalyst (10 % strength), until completion, with the absorption of 2 mole equivalents of hydrogen. The product, which has already crystallised out, is dissolved by the addition of dioxane and heating, and catalyst is filtered off and the filtrate is concentrated by evaporation. The resulting crystals are recrystallised from dioxane and yield a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]aminomethyl}-4-methoxybenzyl alcohol having a melting point of 183-184[deg]. The starting material is manufactured as follows:

Example 6 5a) A mixture of 18.8 g of 5-(2-benzylaminoethoxy)-2-benzyloxy-benzamide, 13.8 g of co-bromo-4methoxyacetophenone and 10.5 g of potassium carbonate in 200 ml of dioxane is stirred for 20-24 hours at room temperature. The suspension is filtered and the filtrate is concentrated by evaporation. The oil so obtained is dissolved in 250 ml of methanol and, in the course of approximately 2 hours, while stirring, 9.0 g of sodium borohydride are introduced in portions into the solution, the temperature being maintained at from 20 to 30[deg] by cooling. The mixture is stirred for a further hour and then concentrated by evaporation, and the evaporation residue is partitioned between ethyl acetate and water. The organic phase is washed with water, dried over magnesium sulphate and concentrated by evaporation.Crude a-{N-[2-(4-benzyloxy-3carbamoylphenoxy)-ethyl]-benzylaminomethyl}-4-methoxybenzyl alcohol is obtained in the form of an oil which solidifies into crystals and is further processed in that form; A solution of 25 g of crude a-{N-[2-(4-carbamoyl-3-hydroxyphenoxy)-ethyl]-benzylaminomethyl}-4methylbenzyl alcohol in 400 ml of methanol is hydrogenated with the addition of 3.0 g of palladium-oncarbon catalyst (10 % strength), until 1 mole equivalent of hydrogen has been absorbed, and the mixture is worked up analogously to Example 5. a-{N-[2-(4-carbamoyl-3-hydroxyphenoxy)-ethyl]-aminomethyl}-4methylbenzyl alcohol having a melting point of 160-165[deg] is obtained. By reaction with the calculated amount of hydrochloric acid in methanol, the hydrochloride having a melting point of 243-244[deg] is obtained. The starting material is manufactured as follows: 6a) A solutionof 10 g of 1-(4-methylphenyl)-oxirane in 100 ml of isopropanol is boiled under reflux for 48 hours with 12.0 g of 4-(2-benzylaminoethoxy)-salicylamide. By concentration by evaporation, crude a-{N-[2-(4-carbamoyl-3-hydroxyphenoxy)-ethyl]-benzylaminomethyl}-4-methylbenzyl alcohol is obtained in the form of an oil, which is further processed without additional purification.

Example 7 A solution of 11.1 g of 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-5-(2-methoxyphenyl)2-pentanol in 100 ml of methanol is hydrogenated under normal conditions, with the addition of 1 g of palladium-on-carbon catalyst (5 % strength), until the absorption of hydrogen is complete. The catalyst is filtered off, the solvent is removed from the filtrate in a rotary evaporator and the residue is recrystallised from isopropanol to yield 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-5-(2-methoxyphenyl)-2pentanol. Treatment with excess methanolic hydrochloric acid, removal of the solvent in a rotary evaporator and recrystallisation, from acetonitrile/ether, of the residue, yield the hydrochloride having a melting point of 110-112[deg]. The 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-5-(2-methoxyphenyl)-2-pentanol required as starting material can be manufactured as follows: 7a) 24.3 g of magnesium filings washed with chloroform are suspended under nitrogen in 50 ml of ether and a few drops of a solution of 56.0 g of 4-bromo-1-butene in 40 ml of ether are added. After the reaction has started, the stirrer is switched on, and firstly 200 ml of ether are added, the reaction mixture is cooled in an ice bath and, in the course of 4 hours, the remainder of the bromobutene solution is slowly added. The reaction mixture is stirred in the ice bath for a further 30 minutes and the turbid solution is then filtered under nitrogen through glass wadding into a second flask provided with a stirrer. There is then added dropwise to this solution, in the course of 30 minutes, at 15-20[deg], a solution of 34.2 g of 2-methoxybenzyl bromide in 60 ml of toluene.The reaction mixture is then stirred for 15 hours at room temperature and a further 1 hour under reflux, and subsequently cooled in an ice bath, 20 ml of water are added dropwise and the resulting suspension is filtered through a filtering means, then washed with ether and the filtrate is extracted 3 times with 0.1 N hydrochloric acid. After the organic phase has been dried and the solvent has been removed in a rotary evaporator, the residue is distilled in vacuo to yield 1-(4-pentenyl)-2-methoxybenzene; boiling point: 54-60[deg]/0.03 torr. 7b) A solution of 13.0 g of m-chloroperbenzoic acid (85 % strength) in 120 ml of methylene chloride is slowly added dropwise, while stirring at room temperature, to a solution of 9.7 g of 1-(4-pentenyl)-2methoxybenzene in 50 ml of methylene chloride. After 4 hours, filtration is carried out, and the filtrate is washed with 10 % strength sodium sulphite solution, dried over sodium sulphate and concentrated. The crude 1-(4,5-epoxypentyl)-2-methoxybenzene remaining is further processed in that form. 7c) 6 g of crude 1-(4,5-epoxypentyl)-2-methoxybenzene and 8.1 g of 4-[2-(benzylamino)-ethoxy]salicylamide are dissolved in 150 ml of isopropanol and the solution is heated under reflux for 48 hours. The solvent is then removed and the residue is chromatographed over 450 g of silica gel using a mixture of chloroform/methanol (95/5), 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-5-(2methoxyphenyl)-2-pentanol being obtained from the main fractions in the form of an oil, and further processed in that form.

Example 8 A solution of 3.0 g of a-aminomethyl-4-methylbenzyl alcohol and 4.8 g of (2,3-dihydroxy-2,2-dimethyl-4H1,3-benzoxazin-4-on-6-yloxy)-acetaldehyde in 150 ml of methanol is neutralised with a solution of hydrogen chloride in methanol (pH about 6), and 10 g of molecular sieve (3A) and then 6.2 g of sodium cyanoborohydride are added. The suspension is stirred overnight at a temperature of 20-25[deg], filtered, decomposed with dilute hydrochloric acid while cooling with ice and concentrated by evaporation in vacuo.The evaporation residue is dissolved in water, the solution is filtered until it is clear, and the filtrate is rendered alkaline with concentrated ammonia (pH 8-9), whereupon a-{N-[2-(3-carbamoyl-4hydroxyphenoxy)-ethyl]-aminomethyl}-4-methylbenzyl alcohol gradually crystallises out which, after recrystallisation twice from dioxane, has a melting point of 190-191[deg].

Example 9 4.5 g of a-{N-[2-(3-methoxycarbonyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-methylbenzyl alcohol are dissolved in 20 ml of dioxane, 100 ml of concentrated ammonia are added and the solution is left to stand for 3-4 days in a sealed container at room temperature. Concentration by evaporation of the solution and recrystallisation from dioxane of the evaporation residue yields a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]-aminomethyl}-4-methylbenzyl alcohol having a melting point of 190-191[deg]. The starting material can be manufactured as follows: a) A mixture of 13.4 g of 2,5-dihydroxybenzoic acid methyl ester, 12.0 g of potassium carbonate and 80 g of 1,2-dibromoethane is boiled under reflux, while stirring, for 35 hours. The reaction mixture is filtered, the filtrate is concentrated by evaporation in vacuo and the evaporation residue is dissolved in 200 ml of ethyl acetate.Washing the organic phase twice with water (50 ml each time), drying it over magnesium sulphate and concentrating the solution by evaporation in vacuo yields crude 5-(2-bromoethoxy)-salicylic acid methyl ester in the form of an oil, which gradually crystallises; melting point 53-55[deg] (from isopropanol). b) A mixture of 6.5 g of a-(aminomethyl)-4-methylbenzyl alcohol, 7.7 g of 5-(2-bromoethoxy)-salicylic acid methyl ester and 4.2 g of potassium carbonate is melted, while sitrring, in a bath of 120-130[deg]. After 2 hour, the reaction mixture is cooled and partitioned between 50 ml of water and 100 ml of ethyl acetate. The organic phase is separated off, washed with 50 ml of water, dried over magnesium sulphate and concentrated by

alcohol in the form of an oil, which is further processed without additional purification.

Example 10 Tablets containing 20 mg of active ingredient are manufactured in customary manner in the following composition: Composition:

Manufacture: a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-chlorobenzyl alcohol is mixed with some of the wheat starch, with the lactose and the colloidal silica and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste with 5 times the amount of water on a water bath, and the pulverulent mixture is kneaded with the paste until a slightly plastic mass is formed. The plastic mass is pressed through a sieve having a mesh width of about 3 mm and dried, and the resulting dry granulate is again forced through a sieve. The remaining wheat starch, the talc and the magnesium stearate are then admixed and the mixture is pressed into tablets each weighing 145 mg and having a break groove.

Example 11 Tablets containing 1 mg of active ingredient are manufactured in customary manner in the following composition:

Manufacture: a-{N-[2-(3-hydroxy-4-carbamoylphenoxy)-ethyl]-aminomethyl}-4-methylbenzyl alcohol is mixed with some of the wheat starch, with the lactose and the colloidal silica and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste with 5 times the amount of water on a water bath and the pulverulent mixture is kneaded with the paste until a slightly plastic mass is formed. The plastic mass is pressed through a sieve having a mesh width of about 3 mm and dried, and the resulting dry granulate is again forced through a seive. The remaining wheat starch, the talc and the magnesium stearate are then admixed and the mixture is pressed into tablets each weighing 126 mg and having a break groove.

Example 12 Capsules containing 10 mg of active ingredient are manufactured in customary manner as follows:

Manufacture: The active ingredient is intimately mixed with talc and colloidal silica, the mixture is forced through a sieve having a mesh width of 0.5 mm, and is introduced in 11 mg portions into hard gelatin capsules of suitable size.

Example 13 A sterile solution of 5.0 g of a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-2methylbenzyl alcohol in 5000 ml of distilled water is filled into 5 ml ampoules which contain 5 mg of active ingredient in 5 ml of solution.

Example 14 3.62 g of a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-3-methylbenzyl alcohol are dissolved, with the addition of 100.0 ml of 0.1 ON hydrochloric acid, with 18000 ml of distilled water to a volume of 18100 ml. The sterilised solution is filled into 5 ml ampoules which contain 1 mg of active ingredient.

Example 15 Instead of the compounds used as active ingredients in Examples 10-14, it is alternatively possible to use the following compounds of the formula I, or their pharmaceutically acceptable non-toxic acid addition salts, as active ingredients in tablets, dragees, capsules, ampoule solutions etc.:

Claims

1. Novel substituted 2-aminoethanols of the formula

in which R is methyl, methoxy, fluorine, chlorine or bromine, and m is 0 or 3, with the proviso that if m is 0, R is 2-methyl, 3-methyl, 4-methyl, 4-fluoro, 4-chloro, 4-bromo or 4-methoxy and the basic side chain is bonded by its oxygen atom to the salicylamide radical in the 4-position to the hydroxy group present therein or, if m is 0 and R is 4-methyl, the basic side chain is bonded by its oxygen atom to the salicylamide radical in the 4-position to the carboxamide radical present therein or, if m is 3, R is 2-methoxy and the basic side chain is bonded by its oxygen atom to the salicylamide radical in the 4-position to the hydroxy group present therein, in the form of racemates or optical antipodes.

2. a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-fluorobenzyl alcohol. 3. a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-2-methylbenzyl alcohol.

5. a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-methylbenzyl alcohol.

6. a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-chlorobenzyl alcohol.

7. a-{N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl}-4-bromobenzyl alcohol.

11. Salts of compounds of claims 1 to 10.

12. Pharmaceutically acceptable, non-toxic acid addition salts of compounds of claims 1 to 10.

13. Pharmaceutical preparations containing a compound of any one of claims 1 to 10 and 12 together with inert adjuncts and carriers.

14. Compounds of the formula I for use in a method for the therapeutic treatment of the human or animal body.

15. Compounds of the formula I as anti-depressants.

16. Compounds of the formula I as blockers of cardiac -receptors. 17. Compounds of the formula I as stimulators of cardiac (3-receptors.

18. Use of compounds of the formula I for the manufacture of pharmaceutical preparations.

19. Use of compounds of the formula I to combat reactive or endogenous depressions of different degrees of severity, and also neurotic or other psychotropic disorders with lack of drive and depressive psychoses.

20. Use of compounds of the formula I to combat rhythm disorders (arrhythmiae), Angina pectoris and hypertonia.

21. Use of compounds of the formula I to combat insufficient cardiac output and also asthma and circulatory disorders. 22. Process for the manufacture of novel substituted 2-aminoethanols of the formula

in which R is methyl, methoxy, fluorine, chlorine or bromine, and m is 0 or 3, with the proviso that, if m is 0, R ; is 2-methyl, 3-methyl, 4-methyl, 4-fluoro, 4-chloro, 4-bromo or 4-methoxy and the basic side chain is bonded by its oxygen atom to the salicylamide radical in the 4-position to the hydroxy group present therein or, if m is 0 and R is 4-methyl, the basic side chain is bonded by its oxygen atom to the salicylamide radical in the 4-position to the carboxamide group present therein or, if m is 3, R is 2-methoxy and the basic side chain is bonded by its oxygen atom to the salicylamide radical in the 4-position to the hydroxy group present therein, : in the form of racemates or optical antipodes, characterised in that a) a compound of the formula

is reacted with a compound of the formula

in which one of the groups Zi and Zz is a reactive esterified hydroxy group and the other is a primary amino group, and X1 is hydroxy, or in which X1 and Z1 together are an epoxy group and Z2 is a primary amino group, and R and m have the meanings given above, or b) in a compound of the formula

in which each of X2, X3, X4 and X5 is hydrogen or a substituent that can be replaced by hydrogen, or X2 and X3 and/or X4 and X5 together are a bivalent radical that can be replaced by two hydrogen atoms, with the proviso that at least one of the radicals X2, X3, X4 or X5 is other than hydrogen, or at least X2 and X3 together or X4 and X5 together are a bivalent radical that can be replaced by two hydrogen atoms, and R and m have c) in a compound of the formula

in which X6 is a reducible group of the formula -CH=N-CH2-CH2- (Va), -CH2-N=CH-CH2 (Vb), -C(=X7)-N(X8)-CH2-CH2- (Vc) or-CH2-N(X8)-C(=X7)-CH2- (Vd), or is a group -CH2-N(X8)-CH2-CH2- (Ve), wherein X7 is the oxo or thioxo radical and X8 is hydrogen or a radical that can be replaced by hydrogen under the conditions for the reduction of X6 and/or Y, and Y is a radical of the formula CO (Vf) or CH(OX$) (Vg), in which X8 has the meaning given above, R and m have the meanings given above, wherein, at all times, X6 is a reducible group Va to Vd and/or Y is a carbonyl group Vf, this group or these groups is/are reduced and, in the same operation, the groups X8 that are other than hydrogen are replaced by hydrogen, or d) a compound of the formula

in which Xg is hydrogen or a group that can be removed by ammonolysis and Rand m have the meanings given above, or a reactive derivative of one of the carboxylic acids defined in formula VI is reacted with ammonia and optionally present radicals Xg are removed and replaced by hydrogen, or e) in a compound of the formula

in which one or both hydroxy groups are optionally protected by groups that can be removed by hydrolysis and replaced by hydrogen and which are removed and replaced by hydrogen under the conditions of the process, the group -CN is converted by hydrolysis into the group CONH2, or f) in a compound of the formula

in which A is the group

X is a group that can be converted into a 1,3-propylene group by means of reduction, including hydrogenolysis, and one or both hydroxy groups are protected by groups that can be removed by means of reduction, including hydrogenolysis, and replaced by hydrogen and which are removed and replaced by hydrogen under the conditions of the process, the group X is converted into a 1,3-propylene group by means of reduction, including hydrogenolysis, and, at the same time, an optionally present unsaturated group A is converted into the saturated group A, and, if desired, a resulting free compound is converted into a salt, or a resulting salt is converted into a free compound, and/or, if desired, a resulting racemate is separated into the optical antipodes.

23. The compounds that can be obtained according to the process of claim 22. 24. Pharmaceutical preparations substantially as hereinbefore described with reference to any one of Examples 10 to 15.

25. A process as claimed in claim 22 substantially as hereinbefore described with reference to any one of Examples 1 to 9.