DD202692A5 - PROCESS FOR THE PREPARATION OF NEW DERIVATIVES OF 2-AMINO-AETHANOL - Google Patents

Abstract

The present invention relates to a process for the preparation of novel derivatives of 2-aminoethanol for use as a medicament. The aim of the invention is the provision of new compounds for the treatment of insufficient cardiac output and cardiac arrhythmias as well as asthma and circulatory disorders. According to the invention, the compounds of general formula (I) are provided. The novel stimulatory compounds of formula I can be used as stimulators of cardiac beta-receptors for the treatment of insufficient cardiac output and cardiac arrhythmias as stimulators of tracheal and vascular beta receptors as broncho- and vasodilators for the treatment of asthma, cardiac insufficiency and circulatory disorders ,

Description

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Process for the preparation of new derivatives of 2-aminoethanol

Field of application of the invention

The present invention relates to a process for the preparation of novel derivatives of 2-aminoethanol. Such compounds act partly as optionally cardioselective β-receptor blockers and accordingly can be used for the treatment of angina pectoris and cardiac arrhythmias as well as antihypertensive agents. On the other hand, such compounds act as β-receptor stimulators and can accordingly

1) as stimulators of cardiac β-receptors for the treatment of insufficient cardiac output and cardiac arrhythmia,

2) can be used as stimulators of tracheal and vascular β-receptors as broncho- and vasodilators for the treatment of asthma, heart failure and circulatory disorders.

Characteristics of the known technical solutions There are no known details of which compounds have hitherto been used as β-blockers or for the treatment of the insufficient cardiac output of asthma and circulatory disorders.

There are also no data on methods for the preparation of 2-amino-ethanol derivatives known.

Object of the invention

The aim of the invention is the provision of compounds which partly as a blocker of ß-adrenergic receptors for the treatment of angina pectoris and cardiac arrhythmias and as hypotensive agents, partly as stimulators of cardiac ß-receptors for the treatment of insufficiency cardiac output and cardiac arrhythmias, and

2aMl & I982 * O8Q243

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- la -

as stimulators of tracheal and vascular ß-receptors for the treatment of asthma, heart failure and circulatory disorders are applicable.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and to provide methods for their preparation.

The invention relates to a process for the preparation of novel derivatives of 2-aminoethanol of the formula OH

Ar- (CH ₂ ) _m -CH-CH ₂ -N-alk- (O)

OH ^H

in which Ar is optionally substituted phenyl, m is a number from 0 to 3, η is the number 0 or 1 and alk alkylene having 2 to 5 carbon atoms, wherein the nitrogen atom and the oxygen atom or, if η is zero, the phenyl radical by at least two Carbon atoms are separated from each other, and R and R "are each hydrogen, with the proviso that when m is 0, the phenyl radical Ar contains at least one substituent and a phenyl radical Ar substituted by one or two hydroxy or protected hydroxy groups at least one additional one of these various substituents, in the form of racemic mixtures, racemates, optical antipodes or their salts, in particular acid addition salts, and especially pharmaceutically acceptable non-toxic acid addition salts.

As substituents of the radical Ar, for example, optionally, in particular given below, substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, Niederalkylidendioxy, cyano and / or nitro and / or directly or to the above-mentioned lower alkyl, lower alkenyl or lower alkoxy bound, ie one of these groups substituting lower alkanoyl, esterified or amidated carboxyl, in particular

2 (UUG 1982 * 080243

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Lower alkoxycarbonyl or optionally substituted carbamoyl, e.g. Carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, or (hydroxy-lower alkyl) -carbamoyl, lower-alkylthio, lower-alkylsulfinyl, lower-alkylsulfonyl, sulfamoyl or lower-alkylsulfamoyl, di-lower alkylsulfamoyl, or halo directly or to the aforesaid lower alkyl or lower than the 1-position to the aforesaid lower alkoxy, etherified mercapto such as lower alkylthio , optionally substituted amino, such as amino, lower alkylamino, di-lower alkylamino, alkylene- or oxaalkyleneamino, pyrrol-1-yl, acylamino, such as lower alkanoylamino or lower alkoxycarbonylamino, optionally substituted by one or two lower alkyl, by hydroxy-lower alkyl or cycloalkyl-substituted ureido, lower alkylsulfonylamino or optionally etherified or esterified hydroxy, such as hydroxy, phenyl-lower alkoxy or lower alkanoyloxy or, as an unsubstituted substituent, again lower alkoxy, with the proviso that, if m is 0, the aryl radical Ar least ns contains a substituent and a phenyl radical substituted by one or two hydroxy, 1-phenyl-lower alkoxy or lower alkanoyloxy groups contains at least one additional substituent other than these.

The radicals and compounds referred to herein as "lower" preferably contain from 7 to and most preferably up to 4 carbon atoms.

The general terms used in the enumeration of substituents of the radical Ar may be e.g. have the following specific meanings. Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl; Substituted lower alkyl is especially methyl or 1- or 2-substituted ethyl, lower alkenyl is e.g. Vinyl, allyl, 2- or 3-methylallyl or 3,3-dimethylallyl, and substituted lower alkenyl, especially 2-substituted vinyl or 3-substituted allyl. Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy, and substituted lower alkoxy e.g. substituted

λ α α ο « (\ Q π O.U '

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Methoxy or 1- or 2-substituted ethoxy. Lower alkenyloxy is, for example, allyloxy, 2- or 3-methallyloxy or 3,3-dimethylallyloxy. Lower alkynyl is, for example, propargyl, and lower alkynyloxy, in particular, propargyloxy; Lower alkylidenedioxy is, for example, isopropylidenedioxy, ethylidenedioxy and, in particular, methylenedoxy, and alkylenedioxy, in particular ethylenedioxy. Lower alkanoyl is, for example, acetyl, propionyl or butyroyl. Lower alkoxycarbonyl is, for example, methoxycarbonyl or ethoxycarbonyl. Lower alkyl or di-lower alkylcarbamoyl is, for example, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl or diethylcarbamoyl, and hydroxy-lower alkylcarbamoyl eg (2-hydroxyethyl) -carbamoyl. Lower alkylthio is, for example, methylthio, ethylthio, n-propylthio or isopropylthio. Lower alkylsulfinyl is, for example, methyl or ethylsulfinyl, lower alkylsulfonyl, for example methyl, ethyl or n-propylsulfonyl, and lower alkylsulfamoyl, for example methyl, ethyl or Isopropylsulfamoyl, and di-lower alkylsulfamoyl, for example dimethylsulfamoyl. Halogen is bromine or iodine and preferably fluorine or chlorine. Phenyl-lower alkoxy is, for example, benzyloxy or 1- or 2-phenylethoxy, and lower alkanoyloxy, for example formyloxy, acetoxy; Lower alkylamino and di-lower alkylamino are, for example, methylamino, ethylamino, dimethylamino or diethylamino. Alkyleneamino and oxaalkyleneamino are, for example, pyrrolidino or piperidino or morpholino. Lower alkanoylamino is, for example, acetylamino or butyroyl · amino, and lower alkoxycarbonylamino, for example methoxycarbonylamino or ethoxycarbonylamino. Ureido which is substituted by one or two lower alkyl, by hydroxy lower alkyl or by cycloalkyl, preferably by 5 to 7 ring members, is, for example, 3-methylureido, 3,3-dimethylureido, 3- (2-hydroxyethyl) ureido or 3-cyclohexylureido. Lower alkylsulfonylamino is, for example, ethylsulfonylamino and in particular methylsulfonylamino.

As indicated above, substituents of Ar may be one of the aforementioned radicals which is not bound directly but via lower alkyl, lower alkoxy or optionally lower alkenyl. Hereinafter, a selection of such substituents will be generically and specifically exemplified without the possible combinations

λ λ mn

<Ί * ,. l \ <nC \ O L · Tt

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to limit it. Lower alkanoylalkyl is e.g. 2-oxopropyl (acetonyl) or 3-oxobutyl, lower alkanoyl-lower alkenyl e.g. 3-0xo-1-butenyl, and lower alkanoylalkoxy e.g. 2-oxopropoxy (acetonyloxy) or 3-oxobutoxy. Optionally substituted carbamoyl-lower alkyl is e.g. Carbamoylmethyl or [(hydroxy-lower alkyl) -carbamoyl)] lower-alkyl, such as [(2-hydroxyethyl-carbanioyl) -methyl., Lower alkoxycarbonyl-lower alkoxy is, for example, ethoxycarbonylmethoxy. Optionally substituted carbamoyl-lower alkoxy is, for example, carbamoyl-lower alkoxy, such as carbamoylmethoxy, or [(hydroxy-lower alkyl) -carbamoyl] -lower alkoxy halo-lower alkyl is in particular halomethyl, eg trifluoromethyl, lower alkylthio-lower-alkoxy, eg 2-methylthioethoxy or 2-ethylthioethoxy.Acylamino-lower alkyl is, for example, lower alkanoyl-amino-lower alkyl, in particular lower alkanoyl-amino-methyl or 1- and especially 2-. Lower alkanoylaminoethyl, for example acetylaminomethyl, 2-acetylaminoethyl or 2-propionylaminoethyl, or lower alkoxycarbonylamino-lower alkyl, in particular lower alkoxycarbonylaminomethyl or 1- and in the first line 2-lower alkoxycarbonylamino-ethyl, for example methoxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl or 2-ethoxycar carbonylamino-ethyl. Acylamino lower alkoxy is e.g. Lower alkanoylamino lower alkoxy, especially 2-lower alkanoylaminoethoxy, e.g. 2- (acetylamino) ethoxy, or lower alkoxycarbonylaminoloweralkoxy, in particular 2- (lower alkoxycarbonylaminoethylthio, eg 2- (methoxycarbonylamino) ethoxy or 2- (ethoxycarbonylamino) ethoxy.) Hydroxiloweralkyl is preferably hydroxymethyl or 1- and especially 2-hydroxyethyl lower alkoxy-lower alkyl is preferably lower alkoxymethyl or 1- and especially 2-lower alkoxyethyl, eg methoxymethyl, ethoxymethyl, 2-methoxyethyl or 2-ethoxyethyl lower alkoxy-lower alkoxy is especially 2-lower alkoxyethoxy, such as 2-methoxyethoxy or 2-ethoxyethoxy.

Alkylene alk may be straight chain or branched and is e.g. 1,2-ethylene, 1,2-, 2,3- or 1,3-propylene, 1,4- or 2,4-butylene, 2-methyl-2,4-butylene, or 1,1-dimethylethylene.

Λ η * Ii Γ ·

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The phenyl carrying the amide and adjacent hydroxy groups may be attached in any position to the remainder of the molecule, preferably the latter being in the 4-position of said phenyl, i. in the para position to the amide group, and especially in the 5-position of said phenyl, i. in para position to the hydroxy group.

The novel compounds may be in the form of their salts, such as their acid addition salts and, in the first place, their pharmaceutically acceptable non-toxic acid addition salts. Suitable salts are e.g. those with inorganic acids, such as hydrohalic acids, e.g. Hydrochloric or hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulphonic acids, e.g. Ants, acetic, propionic, succinic, glycolic, lactic, acetic, tartaric, citric, maleic, hydroxymalein, pyruvic, pumarric, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, monobutyl, methanesulfonic, ethanesulfonic, 2-hydroxyethylsulfonic, ethylenesulfonic, toluenesulfonic, naphthalenesulfonic or sulphanilic acid, or with other acidic organic substances, such as ascorbic acid.

The invention relates in particular to a process for the preparation of compounds of the formula I in which Ar is optionally monosubstituted or polysubstituted, preferably not more than trisubstituted, substituted or unsubstituted, in particular below, substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, Lower alkynyl, lower alkynyloxy, lower alkylidenedioxy, lower alkylenedioxy, cyano and / or nitro, and / or lower alkanoyl bonded directly or to the aforesaid lower alkyl, lower alkenyl or lower alkoxy, esterified or amidated carboxyl, especially lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or (hydroxyloweralkyl) carbamoyl, loweralkylsulfinyl, loweralkylsulfonyl , Sulfamoyl or lower alkylsulfamoyl, and / or directly or to the aforesaid lower alkyl or in higher than the 1-position

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the aforementioned lower alkoxy-bonded halogen, lower alkylthio, amino, Niederalkylami.no, di-lower alkylamino, alkylene or Oxaalkylenamino, eg 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, acylamino such as Niederalkanoylamino or Niederalkoxycarbonylamino, optionally substituted by lower alkyl, hydroxy lower alkyl or cycloalkyl Ureido, Niederalkylsulfonylamino, hydroxy, Phenylniederalkoxy, eg benzyloxy, lower alkanoyloxy or, as not directly bonded substituent, again lower alkoxy may be present, m is a number from 0 to 3, η is the number 0 or 1 and alk is an alkylene radical with 2 to 4 carbon atoms, wherein the nitrogen atom and the oxygen atom or, if η is 0, the phenyl radical, are separated by 2 to 3 carbon atoms of the radicals alk, R. and R _{2 have} the meaning given under formula I, with the proviso when m is 0, the phenyl radical Ar has at least one substituent, and a through one or two hydroxy, 1-phenyl-lower alkoxy or lower alkanoyloxy substituted phenyl radical Ar contains at least one additional, other of these substituents, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, especially acid addition salts, especially pharmaceutically acceptable , non-toxic acid addition salts.

The invention preferably relates to a process for the preparation of compounds of formula I, wherein Ar is optionally substituted one to three times, as substituents optionally substituted as shown below substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, Niederalkylidendioxy, cyan and or nitro and / or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxyloweralkyl) carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl, lower alkylsulfamoyl directly or to the abovementioned lower alkyl, lower alkenyl or lower alkoxy, and / or directly or to the abovementioned lower alkyl or to higher than the 1-position to the aforementioned lower alkoxy-bonded halogen, lower alkylthio,

2 (U1IL1982 # O3Ü24: I

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Amino, lower alkylamino, di-lower alkylamino, alkylene or oxaalkylene-argino, e.g. 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbonylamino, optionally substituted by lower alkyl, hydroxy lower alkyl or cycloalkyl substituted ureido, lower alkylsulfonylamino, phenyl-lower alkoxy, e.g. Benzyloxy, lower alkanoyloxy or, as an unsubstituted substituent, again lower alkoxy, m is a number from 0 to 3 and η is the number O or 1, and alk is an alkylene radical having 2 to 4 carbon atoms, wherein the nitrogen atom and the oxygen atom, or, if η is O, the phenyl radical is separated by 2 to 3 carbon atoms of the radical alk, R and R "are as defined under formula I, with the proviso that, if m is O, the phenyl radical Ar at least one substituent, and a phenyl radical Ar substituted by one or two hydroxy, 1-phenyl-lower alkoxy or lower alkanoyloxy groups contains at least one additional substituent other than these, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, especially acid addition salts, especially pharmaceutically acceptable non-toxic acid addition salts.

The invention particularly relates to a process for the preparation of compounds of the formula I in which Ar is optionally monosubstituted to trisubstituted, substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyloxy, lower alkyl idendioxy, nitro and / or as substituents optionally indicated below. or cyano and / or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxyloweralkyl) -carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl or lower alkylsulfamoyl directly or to the aforesaid lower alkyl, lower alkenyl or lower alkoxy, and / or directly or to the abovementioned lower alkyl or to higher as the 1-position to the aforementioned lower alkyl or in higher than the 1-position to the aforementioned lower alkoxy bonded halogen, lower alkylthio, amino, lower alkylamino, di-lower alkylamino, alkylene or Oxaalkylenamino, eg

η η me

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1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbony! amino, ureido optionally substituted by lower alkyl or cycloalkyl, lower alkylsulfonylamino, hydroxy, phenyl-lower alkoxy, e.g. Benzyloxy, lower alkanoyloxy or, as an unsubstituted substituent, may again be lower alkoxy, m is a number from 0 to 3, with the proviso that when m is O, the phenyl radical Ar has at least one substituent, and one by one or more two hydroxy, 1-phenyl-lower alkoxy or lower alkanoyloxy substituted phenyl Ar contains at least one additional, other of these substituents, η is the number O or 1 and alk is an alkylene radical having 2 to 4 carbon atoms, wherein the nitrogen atom and the oxygen atom, or, if η is O, the phenyl radical is separated from each other by 2 to 3 carbon atoms of the radical alk, and R.sup.1 and R.sup.2 are each independently hydrogen, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, especially acid addition salts, especially pharmaceutically acceptable non-toxic acid addition salts.

The invention relates in particular to a process for the preparation of compounds of the formula I in which Ar is optionally monosubstituted to trisubstituted, optionally substituted lower alkyl or lower alkoxy, further lower alkenyl, lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitro and / or as substituents in the manner indicated below. or cyano and / or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkalkylcarbamoyl or (hydroxy lower alkylcarbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl and / or directly or to the aforesaid lower alkyl or higher than the 1-position to the aforementioned lower alkoxy bonded directly or to the aforesaid lower alkyl or lower alkoxy bonded halogen, lower alkylthio, amino, alkylene or oxaalkyleneamino, for example 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, the lower alkoxycarbonylamino, or optionally by lower

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alkyl substituted ureido, lower alkylsulfonylamino, hydroxy, further phenyl-lower alkoxy, e.g. Benzyloxy, or »may be present as not directly bonded substituent, again lower alkoxy, m is a number from 0 to 3, with the proviso that, if m is O, the phenyl radical Ar at least one Sübstituenten, and by one or two Aryl, which is substituted by hydroxy, 1-phenyl-lower alkoxy or lower alkanoyloxy, contains at least one additional substituent other than these, η is the number O or 1 and alk is an alkylene radical having 2 to A carbon atoms, the nitrogen atom and the oxygen atom or, if η for Is 0, the phenyl radical, are separated by 2 to 3 carbon atoms of the radical alk, and R "independently represent hydrogen, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, in particular acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

The invention relates in the first place to a process for the preparation of compounds of the formula I in which Ar is optionally mono- to trisubstituted, substituted lower alkyl as substituent, optionally substituted as below, e.g. Methyl, or lower alkoxy, e.g. Methoxy or ethoxy, which may be lower alkenyl, e.g. Allyl, lower alkenyloxy, e.g. Allyloxy, lower alkynyloxy, e.g. Propargyloxy, nitro, lower alkylidenedioxy, e.g. Methylenedioxy, and / or cyano, and / or lower alkanoyl bonded directly or to the aforesaid lower alkyl or lower alkoxy, e.g. Acetyl, carbamoyl, lower alkylcarbamoyl, e.g. N-methyl-carbamoyl, or (hydroxy-lower alkyl) -carbamoyl, e.g. N-hydroxymethylcarbamoyl, lower alkylsulfonyl, e.g. Methylsulfonyl, sulfamoyl, and / or directly or to the aforesaid lower alkyl, e.g. Methyl, bound fluorine or chlorine, e.g. Trifluoromethyl, hydroxy or as directly attached substituents phenyl-lower alkoxy e.g. Benzyloxy, lower alkoxy-lower alkoxy, e.g. 2-methoxyethoxy, benzyloxy, amino, lower alkanoylamino, e.g. Acetylamino, lower alkoxy

2ILMIP. 1932 * 080 243

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carbonylamino, e.g. Methoxycarbohylamino, or lower alkylsulfonylaraino, e.g. Methylsulfonylamino, m is a number from 0 to 3, with the proviso that when m is 0, the phenyl radical Ar has at least one substituent and a phenyl radical Ar substituted by one or two hydroxy or 1-phenyl-lower alkoxy groups at least one additional, of these various substituents, η is the number 1 and alk is an alkylene radical having 2 to 4 carbon atoms, wherein the nitrogen atom and the oxygen atom are separated by 2 to 3 carbon atoms of the radical alk, and R and R are hydrogen, and the the amide and the adjacent hydroxyl bearing phenyl radical is preferably connected in its 4- or 5-position with the remainder of the molecule, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, in particular acid addition salts, especially pharmaceutically acceptable , non-toxic acid addition salts.

The invention relates in particular to a process for the preparation of compounds of the formula I in which Ar is optionally mono- to trisubstituted, where as substituents lower alkyl, lower alkoxy, Hydroxiliederalkyl, amino, Niederalkanoylamino, Niederalkylsulfonylamino, nitro, Phenylniederalkoxy, ureido, halo-lower alkyl, halogen and Hydroxy and m is the number 0, with the proviso that a phenyl radical Ar substituted by one or two hydroxy groups contains at least one additional substituent other than these, η is the number 0 or 1 and alk is an alkylene radical having 2 to 5 carbon atoms wherein the nitrogen atom and the oxygen atom, or, if η is zero, the phenyl radical, are separated by at least two carbon atoms, and R and R "are hydrogen, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, in particular acid addition salts, v or all pharmaceutically acceptable, non-toxic acid addition salts.

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More particularly, the invention relates to a process for the preparation of compounds of the formula I in which Ar is substituted by lower alkylsulfonylamino such as methylsulfonylamino, optionally also by halogen, such as chlorine, m is the number O and η is the number O or 1 and alk is an alkylene radical with 2 to 3 carbon atoms, wherein the nitrogen atom and the oxygen atom, or, if η is zero, the phenyl radical are separated by at least two carbon atoms, and R ₁ and R_ are each hydrogen, in the form of racemate mixtures, racemates, optical Antipodes, as free compounds or their salts, especially acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

The invention relates in particular to a process for the preparation of compounds of the formula I in which Ar is substituted by lower alkylsulfonylamino, such as methylsulfonylamino, optionally also by halogen, such as chlorine or by sulfamoyl, halogen, such as chlorine, or lower alkoxy, such as methoxy, m is the number O, and η is the number 0 or 1 and alk is an alkylene radical having 2 to 3 carbon atoms, wherein the nitrogen atom and the oxygen atom, or if η is zero, the phenyl radical, are separated by at least two carbon atoms, and R and R are each hydrogen, in the form of mixtures of racemates, racemates, optical antipodes, as free compounds or their salts, in particular acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

The invention relates in particular to a process for the preparation of compounds of the formula I in which Ar is substituted by sulfamoyl and halogen, such as chlorine, or lower alkoxy, such as methoxy, m is the number 0 and η is the number 1 and alk is an alkylene radical having 2 to 3 carbon atoms, wherein the nitrogen atom and the oxygen atom separated by at least two carbon atoms

_ -.,., .η ΛΛ-. /> οηο / ι ^f l

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and R and R are each hydrogen, in the form of mixtures of racemates, racemates, optical antipodes, as free compounds or their salts, in particular acid addition salts, especially pharmaceutically acceptable non-toxic acid addition salts.

The new derivatives of 2-aminoethanol prepared according to the invention correspond to the formula I explained above, in which Ar is optionally substituted phenyl, m is a number from 1 to 3, η is the number 0 or 1 and alk is alkylene having 2-5 carbon atoms, where the nitrogen atom and the oxygen atom or, if η is zero, the phenyl radical is separated by at least two carbon atoms, and R and R independently represent hydrogen each, in the form of racemate mixtures, racemates, optical antipodes or their salts, in particular acid addition salts, and all pharmaceutically acceptable non-toxic acid addition salts.

The invention relates in particular to a process for the preparation of compounds of the formula I in which Ar is optionally monosubstituted or polysubstituted, preferably not more than trisubstituted, substituted or unsubstituted, in particular below, substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, Lower alkynyl, lower alkynyloxy, lower alkylidenedioxy, lower alkylenedioxy, cyano and / or nitro, and / or lower alkanoyl bonded directly or to the aforesaid lower alkyl, lower alkenyl or lower alkoxy, esterified or amidated carboxyl, especially lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or (hydroxyloweralkyl) carbamoyl, loweralkylsulfinyl, loweralkylsulfonyl , Sulfamoyl or lower alkylsulfamoyl, and / or directly or to the aforesaid lower alkyl or in a higher than the 1-position to the aforementioned lower alkoxy bonded halogen, lower alkylthio, amino, lower alkylamino, di-lower alkylamino, alkylene od he oxaalkyleneamino, e.g. 1-pyrrolidinyl, piperidino or morpholine, pyrrol-1-yl, acylamino such as lower alkanoylamino or lower alkoxycarbonylamino, optionally substituted by lower alkyl, hydroxy lower alkyl or cycloalkyl

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Ureido, lower alkylsulfonylamino, hydroxy, phenyl-lower alkoxy, e.g. Benzyloxy, lower alkanoyloxy or, as not directly bonded substituent, again lower alkoxy may be present, m is a number from 1 to 3, η is the number O or 1 and alk is an alkylene radical having 2 to 4 carbon atoms, wherein the nitrogen atom and the Oxygen atom or, if η is 0, the phenyl radical, are separated by 2 to 3 carbon atoms of the radicals alk, R and R "are as defined under formula I, in the form of" racemate mixtures, racemates, optical antipodes, as free Compounds or their salts, in particular acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

The invention preferably relates to a process for the preparation of compounds of formula I, wherein Ar is optionally substituted one to three times, as substituents optionally substituted as shown below substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, Niederalkylidendioxy, cyan and or nitro and / or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxyloweralkyl) -carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl, lower alkylsulfamoyl directly or to the abovementioned lower alkyl, lower alkenyl or lower alkoxy, and / or directly or to the abovementioned lower alkyl or to higher as the 1-position to the aforementioned lower alkoxy bound halogen, lower alkylthio, amino, lower alkylamino, di-lower alkylamino, alkylene or Oxaalkylenamino, for example 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, Niederalkoxycarbonylamino, g optionally substituted by lower alkyl, hydroxy lower alkyl or cycloalkyl substituted ureido, Niederalkylsulfonylamino, Phenylniederalkoxy, eg benzyloxy, lower alkanoyloxy or, as non-directly bonded substituent may again be lower alkoxy, m is a number from 1 to 3 and η is the number 0 or 1, and alk a Alkylene radical having 2 to 4 carbon atoms, wherein the nitrogen atom and the oxygen atom, or, if η is 0, the phenyl radical, are separated by 2 to 3 carbon atoms of the radical alk, R ₁ and R

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in the form of racemates, racemates, optical antipodes, as free compounds or their salts, in particular acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

The invention more particularly relates to a process for the preparation of compounds of formula I in which Ar is optionally substituted one to three times, substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitro and / or as substituents optionally indicated below Cyano and / or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxyloweralkyl) -carbamoyl, loweralkylsulfinyl, loweralkylsulfonyl, sulfamoyl or lower alkylsulfamoyl directly or to the aforesaid lower alkyl, lower alkenyl or lower alkoxy, and / or directly or to the aforesaid lower alkyl or higher than the 1 Position to the aforementioned lower alkoxy-bonded halogen, lower alkylthio, amino, lower alkylamino, di-lower alkylamino, alkylene or oxaalkyleneamino, for example 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbonylamino, optionally d by Ⓒ or cycloalkyl-substituted ureido, lower alkylsulfonylamino, hydroxy, phenyl-lower alkoxy, eg benzyloxy, lower alkanoyloxy or, as non-directly attached substituent, again lower alkoxy may be present, m is a number from 1 to 3, η is the number O or 1 and alk is an alkylene radical with 2 to 4 carbon atoms, wherein the nitrogen atom and the oxygen atom, or, if η is 0, the phenyl radical, are separated by 2 to 3 carbon atoms of the radical alk, and R and R ₂ are each independently hydrogen, in the Form of racemic mixtures, racemates, optical antipodes, as free compounds or their salts, in particular acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

239910 1

The invention relates in particular to a process for the preparation of compounds of the formula I in which Ar is optionally monosubstituted to trisubstituted, optionally substituted lower alkyl or lower alkoxy, further lower alkenyl, lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitro and / or as substituents in the manner indicated below. or cyano and / or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkalkylcarbamoyl or (hydroxy lower alkyl) carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl and / or directly or to the aforesaid lower alkyl or in higher than the 1-position bonded to the aforesaid lower alkyl or lower alkoxy Lower alkoxy bonded halogen, lower alkylthio, amino, alkylene or Oxaalkylenamino, eg 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino or lower alkoxycarbonylamino, or optionally lower alkyl substituted ureido, lower alkylsulfonylamino, hydroxy, further phenyl-lower alkoxy, e.g. Benzyloxy, or, as an unsubstituted substituent, may again be lower alkoxy, m is a number from 1 to 3, η is the number O or 1 and alk is an alkylene radical having 2 to 4 carbon atoms, where the nitrogen atom and the oxygen atom or, if η is O, the phenyl radical is separated by 2 to 3 carbon atoms of the radical alk, and R and R independently of one another represent hydrogen, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or salts thereof, in particular Acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

The novel compounds of the formula I have valuable pharmacological properties. In particular, they specifically act on β-adrenergic receptors. This effect is based on the common property of the compounds of the formula I, the affinity for these receptors, which in the absence or very little stimulating effect as pure blockade, with low to moderate stimulatory effect as a blockade with simultaneous ISA, i.

239910 1

intrinsic ^ ympathomimetic activity, and with greater intrinsic activity as predominant stimulation of ß ~ adrenergic receptors expresses. The boundaries between β-receptor blockers without or with at most moderate ISA are fluid, as are the therapeutic applications of these types of compounds. Of the compounds of formula I which act as β-receptor blockers with or without ISA, such as those substituted in the phenyl nucleus by a lower alkylsulfonylamino group, e.g. the α-tN- [2- (4-carbamoyl-3-hydroxyphenoxy) -l-methylethyl] -aminomethyl] -4- (methylsulfonylamino) -benzyl alcohol, in particular its one pair of enantiomers, mp. 165-167 °, has a blocking effect as the main action on β-receptors (with slightly more preferential inhibition of cardiac receptors) to which are added, as additional efficacies, weak antihypertensive and α-receptor blocking effects. Compounds of this type, such as e.g. the said or- [N- [2- (4-carbamoyl-3-hydroxyphenoxy) -l-methylethyl] -aminomethyl] -4- (methylsulfonylamino) -benzyl alcohol as well as its two entaniomer pairs of the mp 165-167 ° or 144, respectively -145 °, or the a- [N- [2- (4-carbamoyl-3-hydroxyphenoxy) ethyl] aminomethyl] -4- (methylsulfonylamino) benzyl alcohol or the a- [N- [2- (3- Carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4- (methylsulfonylamino) benzyl alcohol also show a marked diuretic and saluretic effect, such as after p.o. Administration of 1 or 5 mg / kg of such compounds to the dog.

In other compounds of the formula I can be found clear ß-receptor blocking and ß-receptor-stimulating effects. With respect to their action on cardiac β receptors, these compounds prove to be potent blockers with relatively clear ISA in guinea pig heart in vitro experiments, and on the other hand in the anesthetized cat in vivo as predominantly strong-acting stimulators. With respect to the effect on vascular β-receptors, they are predominantly as a moderator with moderate ISA, while compounds of formula I, which in the phenyl nucleus Ar by lower alkyl, e.g. Methyl, e.g. the

239910 1

a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) -l-methylethyl] -aminomethyl] -4-raethylbenzyl alcohol at tracheal β receptors prove to be potent stimulants.

This latter group includes e.g. also those compounds in which Ar represents an etherified hydroxyphenyl radical, such as e.g. the a- [N- [2- (β-carbamoyl-A-hydroxy-phenoxy) -äthy1] -aminomethy1] -3,4-methylenedioxy-benzyl alcohol, which show a cardioselective ß-stimulation in in vivo experiments on the cat leaves. As additional effects, e.g. in a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) -l-methylethyl] -aminomethyl] -3,4-methylenedioxybenzyl alcohol, a reduction in blood pressure as well as a weak blockade of adrenergic α-receptors.

The above information regarding pharmacological properties is based on the results of corresponding pharmacological tests in standard test procedures. Thus, the novel β-blocking compounds exhibit inhibition of isoproterenol-induced tachycardia on the isolated guinea pig heart in a concentration range of about 0.001 to about 1 μg / ml and on the anesthetized cat in a dose range of about 0.001 mg / kg to about 1 mg / kg when given intravenously. The inhibition of isoproterenol-induced vasodilation in the anesthetized cat with perfusion of the femoral artery is detectable on intravenous administration in a dose range of about 0.003 mg / kg to about 3 mg / kg. The ISA of the β-blocking compounds of formula I, if linked, results from the increase in basal heart rate on the anesthetized reserpine pretreated cat when administered intravenously in a dose range of 0.001 to 1 mg / kg. The novel β-blocking compounds also effect i.v. in a dose range of from about 0.1 mg / kg to about 10 mg / kg. a lowering of the arterial blood pressure in the anesthetized cat. The additional α-blocking activity, e.g. favor a blood pressure lowering effect

239910 1

For example, antagonizing the norepinephrine-induced contraction of the rat's isolated vasodefere can be demonstrated by such compounds in a concentration of 0.1 μg / ml to about 10 μg / ml. The novel beta-blocking active compounds of the formula I can be used as, optionally cardioselective, beta-receptor blockers, for example for the treatment of angina pectoris and cardiac arrhythmias, and as antihypertensive agents. The additional diuretic and saluretic effects present in certain types of compounds of formula I, such as shown above, could lead to a substantial enhancement of the antihypertensive effect and eliminate the need for the combination of β-receptor blockers with diuretics.

The clearly β-receptor-stimulating compounds of the formula I, such as the a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethyl] -aminomethyl] -3,4-methylenedioxy-benzyl alcohol, cause a Increase in heart rate and myocardial contraction force in the isolated guinea pig atrium in a concentration range of about 0.0001 ^ g / ml to 0.1 jig / ml and an increase in heart rate and maximum pressure increase rate in the left ventricle (dp / dt max.) In the anesthetized cat in a dose range of about 0.001 mg / kg to about 1 mg / kg iV. Some of the new compounds selectively stimulate the cardiac β-receptors (β-receptors) in comparison to the β-receptors in the blood vessels (β-receptors) and thus differ qualitatively distinct from isoproterenol, which contains the β-receptors of the heart and the Blood vessels stimulated approximately equally. In part, the compounds of formula I also have relatively clear stimulating effects on β "receptors. (Blood vessels, trachea).

The new stimulatory compounds of formula I can

demanch

1) as stimulators of cardiac β-receptors for the treatment of insufficient cardiac output and cardiac arrhythmia,

20.AUG 1932 * 030243

2399 10 1

2) as stimulators of tracheal and vascular β-receptors as broncho- and vasidilators for the treatment of asthma, heart failure and circulatory disorders »

The novel compounds of the formula I are prepared in a manner known per se. You can use it e.g. obtained by mixing in a compound of the formula

At- (CH ₂ ) _m - CH - CH ₂ - Jj - - »- (O) _n - ^ fVc (I ₁ ),

OH \ mS

in which one or both hydroxy groups and / or present in the radical Ar hydroxy and / or amino groups are optionally protected by such aushydratable by hydrolysis and displaceable by hydrogen groups which are cleaved under the conditions of the process and replaced by hydrogen, or in the radical Ar, if appropriate together with the said protected hydroxyl and / or amino groups, the group -CN is present, which converts -CN groups into the group -CONH ₂ by hydrolysis and simultaneously optionally protected hydroxy and / or amino groups into free hydroxy and / or amino groups, and, if desired, converting a compound obtained into another compound of formula I, and / or, if desired, converting a resulting free compound to a salt or salt in a free compound, and / or, if desired, a derivative obtained Racemat mixture in the racemates or a racemate obtained in the optical antipodes separates.

The starting materials of the formula II can be prepared in the usual manner by reacting a compound of the formula

Ar - (CH ") - CH - CH ₀ --NH ₀ (Ha) I η 2 I

OH with a compound of the formula

1982 * 030 243

»- rt

Hal-alk- (O) - * \ ,

η · ^ «CN (lib),

• ~ «

where Hal is chlorine, bromine or iodine. The reaction is advantageously carried out in the presence of a basic agent in a conventional manner.

Starting materials of the formula Ha in turn _s in which m has the above meaning, are by reacting a compound of the formula

Ar - (CH ₀ ) -CH - CH ₀ - Z ₁ (lic),

2 m / 1

wherein X and Z together represent the epoxy group, with ammonia, or when X is hydroxy and Z as the reactive esterified hydroxy group e.g. Halogen, such as chlorine, means, e.g. with hexamethylenetetramine and subsequent conversion of the resulting adduct with dilute mineral acid, such as dilute hydrochloric acid, obtainable.

A reactive esterified hydroxy group Z is a strong acid, in particular a strong inorganic acid, such as a hydrohalic acid, in particular hydrochloric, hydrobromic or hydroiodic acid, or sulfuric acid, or a strong organic acid, in particular a strong organic sulfonic acid, such as an aliphatic acid aromatic sulfonic acid, eg Methanesulfonic acid, 4-methylbenzenesulfonic acid or 4-bromobenzenesulfonic acid, esterified hydroxy group, and is primarily halogen, e.g. Chlorine, bromine or iodine, or aliphatically or aromatically substituted sulphonyloxy, e.g. Methylsulfonyloxy or 4-methylphenylsulfonyloxy.

Starting materials of the formula II in which m is 0 can furthermore be prepared in a customary manner, by e.g. a compound of the formula Ar-COCH (Id) halogenated, e.g. brominated, such as by bromine in an inert solvent, such as chloroform, in the thus obtained

9 0.

239910 1

Ar-haloacetyl, e.g. bromoacetyl compound, the halogen through the amino group, e.g. by reaction with hexamethylenetetramine in a solvent such as a chlorohydrocarbon such as chloroform, the resulting adduct is treated with dilute mineral acid, e.g. Hydrochloric acid decomposed in the resulting compound of formula

Ar-CO-CH ₂ -NH ₂ (He)

the carbonyl group to the carbinol group, e.g. using diborane, reduced and the resulting compound of the formula

Ar-CH-CH ₉ - NH (Hf)

I ^l

OH

with a compound of the above-described formula Hb in the manner specified therein.

In turn, a compound of formula Hb can be obtained by the action of acetic anhydride on the oxime corresponding to the cyanide. This is conveniently done by boiling under reflux. The oxime, in turn, can be prepared from the corresponding aldehyde by boiling with hydroxylamine hydrochloride in the presence of alcoholic sodium carbonate solution under reflux. The corresponding aldehyde, in turn, can be prepared by reacting 2,4-dihydroxybenzaldehyde with an α, β, α, γ or α, J-dihalo-lower alkane, preferably in the presence of a basic agent. A hydroxy-salicyl nitrile, e.g. the 2,4-dihydroxybenzonitrile [Chem. 24, 3657 (1891)] or the 2,5-dihydroxybenzonitrile [HeIv. Chim. Acta [149, 153 (1947)] with a non-geminal dihalo-lower alkane to give a compound of formula VIIb.

Care must be taken in the selection of the appropriate above process for the preparation of compounds of formula I, that existing substituents, primarily the radicals Ar, are not converted or cleaved, if such conversions or cleavages not

2QAUG1982 * ÜS0243

are desired. Thus, in particular functionally modified carboxyl groups, such as esterified or amidated carboxyl groups, as well as cyano groups, as substituents of the radicals Ar during solvolysis, in particular hydrolyses, also be involved in reducing the reaction and be converted.

In compounds obtained in the context of the definition of the compounds of the formula I can be converted according to the method in a conventional manner compounds obtained in other end products, e.g. by modifying, introducing or eliminating suitable substituents.

Thus, in obtained compounds in the radical Ar, unsaturated substituents, such as lower alkynyl or lower alkynyloxy, or lower alkynyl or lower alkenyloxy, e.g. by treatment with catalytically activated hydrogen.

In compounds having halogen atoms as substituents of the radical Ar, the halogen, e.g. replace with hydrogen by treatment with hydrogen in the presence of a conventional hydrogenation catalyst, such as Raney nickel or palladium on carbon.

In compounds having an esterified carboxyl group as a substituent in the radical Ar, it may be prepared in a conventional manner, e.g. be converted by ammonolysis or aminolysis with ammonia or a primary or secondary amine in the corresponding carbamoyl group.

In compounds having a cyano group as a substituent in the radical Ar, it may be prepared in a conventional manner, e.g. are alcoholysed by addition of alcohols in the presence of an anhydrous acid such as hydrogen chloride, and subsequent hydrolysis of the resulting imido ester to the corresponding compounds with esterified carboxyl groups.

239910 1

In compounds having a nitro group as a substituent in the radical Ar, it may be reduced to the amino group, e.g. by means of catalytically activated hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel or a palladium on carbon catalyst, or by means of a metal, e.g. Iron or optionally amalgamated zinc in an acid, e.g. a mineral acid such as hydrochloric acid or a carboxylic acid such as acetic acid or mixtures thereof.

In compounds having a primary amino group as a substituent in the radical Ar, these can be converted into a lower alkylamino or di-lower alkylamino group, e.g. by reaction with a suitable suitable alkylating agent, such as a reactive esterified lower alkanol, e.g. the halide, such as the chloride, bromide or iodide, or an ester with a strong organic sulfonic acid, e.g. the methanesulfonic acid ester, conveniently in the presence of a basic agent such as an alkali hydroxide or carbonate.

In compounds having a primary amino group in the radical Ar, these may be converted to the ureido, N'-lower alkylureido or N, N'-di-lower alkylureido group, e.g. by reaction with cyanic acid or a salt thereof, such as potassium cyanate, in an acidic medium, such as aqueous hydrochloric acid, or with a lower alkyl or Ν, Din-di-lower alkylurea at elevated temperature.

In compounds having a primary amino group in the radical Ar, it may be converted to a lower alkylsulfonylamino group, e.g. by reaction with a lower alkyl sulfonyl halide in the presence of a basic agent, e.g. Pyridine.

As with the manufacturing processes, care must be taken when carrying out the additional steps to ensure that unwanted side reactions, which may result in the conversion of additional groupings, do not occur.

2 (UUC 1982 * 080243

The reactions described above may, if desired, be carried out simultaneously or successively, furthermore in any order. If necessary, they are carried out in the presence of diluents, condensing agents and / or catalytic agents, at reduced or elevated temperature, in a closed vessel under pressure and / or in an inert gas atmosphere.

Depending on the process conditions and starting materials, the novel compounds are obtained in free form or in the form of their salts also encompassed by the invention, it also being possible for the novel compounds or salts thereof to be present as hemi-, mono-, sesqui- or polyhydrates. Acid addition salts of the novel compounds can be prepared in a manner known per se, e.g. by treatment with basic agents, such as alkali metal hydroxides, carbonates or bicarbonates or ion exchangers are converted into the free compounds. On the other hand, free bases obtained can be treated with organic or inorganic acids, e.g. form with the acids mentioned, acid addition salts, in particular those acids are used for their preparation, which are suitable for the formation of pharmaceutically acceptable salts.

These or other salts, especially acid addition salts of the new compounds, e.g. Oxalates or perchlorates can also be used to purify the resulting free bases by salifying the free bases, separating and purifying them, and releasing the bases from the salts.

Depending on the choice of starting materials and procedures, as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms, the novel compounds may also be present as racemate mixtures. The starting materials can also be used as specific optical antipodes.

Obtained racemate mixtures may, due to the physico-chemical differences of the diastereoisomers in a known manner, e.g. by

239910 1

Chromatography and / or fractional crystallization, are separated into the two stereoisomeric (diastereomeric) racemates.

Obtained racemates can be broken down into the antipodes by methods known per se, e.g. by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance which forms salts with the racemic compound, in particular acids, and separation of the salt mixtures obtained in this way, e.g. due to different solubilities, into the diastereomeric salts from which the free antipodes can be released by the action of suitable agents. Particularly common optically active acids are e.g. the D and L forms of tartaric acid, di-0,0 '- (p-toluoyl) tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid are advantageously isolated the more effective of the two antipodes.

The invention also relates to those embodiments of the method according to which one starts from an intermediate obtainable at any stage of the process, and performs the missing process steps, or terminates the process at any stage, or in which one forms a starting material under the reaction conditions, or in which a reaction component is optionally in the form of its salts.

Appropriately used for carrying out the inventive reactions, such starting materials, which lead to the above-mentioned groups of end products and especially to the specifically described or highlighted end products.

The starting materials are known or, if new, may be prepared by methods known per se, as above, e.g. analogously as described in the examples.

Il AlIH 49 9 3 * ügOQ4

The new compounds may e.g. in the form of pharmaceutical preparations containing a pharmacologically effective amount of the active substance, optionally together with pharmaceutically acceptable excipients, which are enteral, e.g. oral or parenteral administration, and may be inorganic or organic, solid or liquid. Thus, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerol and / or lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol having. Tablets may also contain binders, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Furthermore, one can use the new pharmacologically active compounds in the form of parenterally administered preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, e.g. for lyophilized preparations containing the active ingredient alone or together with a carrier material, e.g. Mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the Ostnotnian pressure and / or buffers. The present pharmaceutical compositions which, if desired, may contain other pharmacologically active substances, are prepared in a manner known per se, e.g. by means of conventional mixing, granulation, coating, solution or lyophilization processes, produced and contained

2 (* ÜÜG1982 Ü3O243

239910 1

from about 0.1% to 100%, more preferably from about 1% to about 50%, lyophilizates up to 100% of the active.

The dosage may depend on various factors, such as route of administration, species, age and / or individual condition. Thus, the doses to be administered daily in one or more, preferably at most 4 individual doses by oral administration to warm-blooded animals for ß-receptor blocker of formula I between 0.03 mg / kg and 3 mg / kg and for warm-blooded animals of about 70 kg body weight Preferably between about 0.004 g and about 0.08 g, and for ß-receptor stimulants of formula 1 between 0.01 mg / kg and 1 mg / kg and for warm-blooded animals of about 70 kg body weight between about 0.002 g and about 0 , 04 g

The following examples serve to illustrate the invention; Temperatures are given in degrees centigrade.

For compounds that have two centers of asymmetry and therefore can exist as diastereomeric mixtures, the relative content

13 of the two diastereomers (enantiomeric pairs) by C-NMR spectroscopy based on the relative intensity of the two C-methyl signals at 13.3 + 0.1 ppm and 13.6 + _ 0.1 ppm found. The C spectra

were in DMSO-d. on a Varian XL-100 instrument at 25.16 MHz 6

taken using tetramethylsilane as an internal standard. (Digital resolution 0.8 points / Hz). Salts were examined as such. Bases must be neutralized with acids (e.g., 1 equivalent of fumaric acid) to achieve separation of the methyl signals.

Example 1 ; 1.2 g of crude a- [N- [2- (4-cyano-3-hydroxy-phenoxy) -ethyl] -aminomethyl] -4-methylsulfonylamino-benzyl alcohol is concentrated in 15 ml of conc. Dissolved hydrochloric acid and the solution allowed to stand for 24 hours at 20-25 °. Evaporation in vacuo gives the a- [N- [2- (4-carbamoyl-3-hydroxyphenoxy) ethyl] aminomethyl] -4-methylsulfonylamino-benzyl alcohol as Hydrochloric !, which after recrystallization from water at 239-240 °

2 (UUG 1982 * 08024

melts.

The starting material can be prepared in the following way:

a) A mixture of 27.4 g of 2,4-dihydroxy-benzonitrile, 30.8 g of potassium carbonate, 1000 ml of 1,2-dibromoethane and 100 ml of dimethylformamide is heated with stirring on descending condenser so that an internal temperature of 127-129 ° is reached. The heating is continued for 6 hours. The distillate is discarded. The reaction mixture is filtered and the filtrate is evaporated in vacuo. By partitioning the residue between ethyl acetate and water, drying (MgSO4), evaporation of the organic phase and crystallization gives the 4- (2-bromoethoxy) -2-hydroxy-benzonitrile, mp. 160-175 ° (from ethyl acetate), which for the following reaction is sufficiently pure.

b) A mixture of 2.8 g of α- (aminomethyl) -4-methylsulfonylaminobenzyl alcohol, 2.4 g of 4- (2-bromoethoxy) -2-hydroxybenzonitrile, 4.1 g of triethylamine and 20 ml of dioxane is heated for 3 hours with stirring and reflux. Work-up gives crude a- [N- [2- (4-cyano-3-hydroxy-phenoxy) -ethyl] -aminomethyl-4-methylsulfonylamino-benzyl alcohol as a brown foam which is further processed crude.

EXAMPLE 2 Analogously to the procedure described in the preceding example, the following compounds of the formula I or salts thereof are obtained using appropriate starting materials:

a) a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -2,4-dichlorobenzyl alcohol of the mp. 139-140 ⁰ (from methanol).

b) a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -4-chloro-3-nitrobenzyl alcohol of the mp 167-168 ° (from ethyl acetate).

c) The residue obtained after working up is recrystallized from isopropanol. After repeated recrystallization from methanol gives the a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -

2399 10 1

aminomethyl] -3-sulfamoyl-4-chlorobenzyl alcohol of mp. 193-195 °.

d) a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -ethyl] -aminomethyl] -4-nitrobenzyl alcohol as hydrochloric! Mp 231-233 ° (from methanol).

e) From the foam obtained after working up, little ethyl acetate is gradually crystallized from the a- [N ~ [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -3- (methylsulfonylard.no) -4-chlorobenzyl alcohol of the mp. 139-141 °. It forms a neutral fumarate of the mp 190-192 ° (from methanol).

f) a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethyl] aminomethyl] -3,5-dichloro-4-aminobenzyl alcohol as brownish crystals of mp. 196-201 °.

g) a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy-ethyl] -aminomethyl] -3- (methylsulfonylamino) -benzyl alcohol of the mp 135-137 ° (from methanol / isopropanol about 1 : 10).

h) a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -3,4-methylenedioxy-benzyl alcohol as a diastereoisomer mixture. By fractional crystallization of the hydrochloride from methanol-water (4: 1) to obtain a pure enantiomeric pair, mp. 211-212 °.

i) a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -3,4-methylenedioxybenzyl alcohol as diastereoisomeric mixture (about 1: 1) from the m. 164-174 °. It forms a neutral

13 Fumarate of mp 193-204 ° (from methanol-water), which is identified by means of C nuclear magnetic resonance spectrum as a mixture of diastereomers (about 1: 1).

2 (* HlI01982 080243

239910

j) a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -4- (methylsulfonylamino) -benzyl alcohol as OeI ₈ which is a neutral fumarate as a mixture of diastereoisomers in the ratio of approx.

13 6: 4 according to C spectroscopy study of mp. 210-215 ° forms.

k) a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -amino-methyl] -3-carbamoyl-4-hydroxybenzyl alcohol, which after recrystallization from ethyl acetate at 143 ° C. 148 ° with decomposition melts and a mixture of diastereoisomers in the ratio of about 1: 1 represents.

1) a- [N- [2- (3-carbamoyl-4-hydroxy ~ phenoxy) -l-methyl-ethyl] ~ aminomethyl] -4- (2-methoxy-ethoxy) benzyl alcohol, after recrystallization from ethyl acetate _$ of at 100-106 ° melts and a diastereoisomer mixture in the ratio of about 1: 1 represents.

m) a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] aminomethyl] -4-methyl-benzyl alcohol of mp. 120-134 ° (from ethyl acetate, which Mixture of diastereoisomers in the ratio of about 1: 1 represents.

n) The crude product obtained after workup is recrystallized from 200 ml of ethyl acetate, then from acetonitrile. The higher melting enantiomeric pair of a- [N- [2 ~ (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -4-methoxybenzyl alcohol is obtained. Mp 144-146 °. From the ethyl acetate mother liquor, the other pair of enantiomers is obtained by concentration and purified by crystallization from acetonitrile, mp. 129-131 °.

o) The foam obtained after working up is recrystallised from isopropanol, then from methanol / isopropanol, after which the a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl ] -3-sulfamoyl-4-chloro-benzyl alcohol as an approximately 1: 1 diastereomer mixture, mp. 103-106 ° with 0.5 mol of crystalline isopropanol.

η η in /? jnefl.u / ifinfti.n

39910 1

ρ) α-fN- [2- (3-hydroxy-4-carbamoyl-phenoxy) -l-methyl-ethyl] -aminomethyl] -3-sulfamoyl-4-chloro-benzyl alcohol, mp. 112-116 ° as a mixture of diastereomers ( about 1: 1).

q) After working up, a viscous residue is obtained from which, by dissolving in a methanol-isopropanol mixture, the α- [N- (2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -3 Crystallization of the mp 191-194 ° is formed when the compound is recrystallized from acetonitrile after crystallization from methanol of the mp 160-162 °.

r) 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4- (2-methoxyphenyl) -2-butanol hydrochloride, m.p. 124-126 °; (from acetonitrile / ethyl acetate).

s) 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -2-phenyl-2-propanol, m.p. 142-153 ° (from a little isopropanol).

t) The residue obtained after working up is chromatographed over 500 g of silica gel with a mixture of chloroform / methanol / ammonia (40: 5: 0.5). The main fraction is evaporated. Crystallization from isopropanol gives a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -2-methoxybenzyl alcohol, mp. 167-168 °.

u) 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -3- (2-methoxyphenyl) -2-propanol as the hydrochloride of mp 152-154 °; (from acetonitrile).

v) or- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -4-methanesulfonylaminobenzyl alcohol as the base, m.p. 172-174 °; (from ethanol).

2I1AI1G 1982 * 030243

23 99

w) By fractional recrystallization of the residue obtained after working up from ethanol and ethyl acetate, 3 crystal fractions are obtained which give uniform spots in the thin-layer chromatogram (system: ethyl acetate, ethanol, concentrated ammonia 24: 12: 4) and which, together with ethanol, recrystallizes the a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -4- (N-methyl-sulfamoyl) -benzyl alcohol as a mixture of diastereomers (3: 1) of the mp 136-150 °. Further recrystallization from ethanol gives a pure diastereomer of

13 m.p. 138-140 ° (C-NMR signal at 15.3 ppm after addition of fumaric acid).

x) The crystals of the a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -4- (methylsulfonylamino) -benzyl alcohol obtained after working up are filtered off with suction and show one

13 m. From 156-162 °. They consist by C-NMR analysis of a mixture of 75% of the higher melting enantiomeric pair A and 25% of the lower melting enantiomeric pair B. By further, three recrystallizations from methanol to obtain the enantiomeric pair A of mp. 165 -167 ° (> 90% A). It forms a hydrochloride of 13.15 ppm.

chloride of mp. 219-220 ° (from methanol); ¹³ C-NMR: C-CH signal at

Further concentration of the first mother liquor gives a further crystalline fraction of mp. 138-144 °, wherein the diastereomer ratio is --- 1: 1. The filtered off mother

13 lye does not crystallize anymore. It contains the enantiomeric pair B enriched to 60-70% according to C-NMR analysis. This mother liquor (~ 80 g of brown OeI) is chromatographed over 4 kg of silica gel. With 70 fractions of ethyl acetate of 150 ml, unidentified impurities are eluted. Further elution with methanol (80 fractions of 150 ml) gives a brown OeI which gradually crystallizes in part. By repeated recrystallization from ethanol to obtain the enantiomeric pair B of mp. 144-145 ° (5 ^ 90% B).

on Ji ti r jni "^ /> ο ι \ η ι. ο

239910

It forms a hydrochloride, mp. 206-209 ° (from ethanol), which ³ C NMR 95%).

- 33 -

13 shows in C-NMR the signal of the C-methyl group at 13.65 ppm

y) 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4-phenyl-2-butanol, m.p. 159-160 ° (from a little methanol).

z) 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -äthyIamino] -4- (2-methylphenyl) -2-butanol, which melts after recrystallization from isopropanol at 140-142 °. It forms a hydrochloride of mp. 155-157 ° (from isopropanol).

a ') 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4- [4- (2-methoxyethoxy) -phenyl] -2-butanol, m.p. 151-153 ° (from methanol ). It forms a hydrochloride, mp. 207-208 ° (from methanol).

b ') 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylaminoy-4- (4-hydroxyphenyl) -2-butanol.

Example 3 : Tablets containing 20 mg of active substance are prepared in the usual manner in the following composition.

Composition; a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-äthylr

aminomethyl] -3-sulfamoyl-4-chloro-benzyl alcohol Wheat starch Milk sugar Colloidal silica talc magnesium stearate

20 mg 60 mg 50 mg 5 mg 9 mg 1 mg

145 mg

Preparation: a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -

0 0 4ΙΙΓ 4Q DO * / ιηι \ Λ>. # »

1 Π 1

S-sulphamoyl-chlorobenzyl alcohol is mixed with a portion of the wheat starch, with lactose and colloidal silica, and the mixture is forced through a sieve. Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture kneaded with this paste until a weakly plastic mass is formed.

The plastic mass is printed through a sieve of about 3 mm mesh size, dried and the resulting dry granules are again driven through a sieve. Then the remaining wheat starch, talc and magnesium stearate are added and the mixture is compressed into tablets of 145 mg weight with score.

Example 4 Tablets containing 1 mg of active substance are prepared in the usual manner in the following composition:

Composition ;

a- [N- [2- (3-hydroxy-4-carbamoyl-phenoxy) -l-methyl-ethyl] -

aminomethyl] -3-sulfamoyl-4-chloro-benzyl alcohol Wheat starch Milk sugar Colloidal silica talc magnesium stearate

1 mg 60 mg 50 mg 5 mg 9 mg 1 mg

126 mg

Production :

a- [N- [2- (3-Hydroxy-4-carbamoyl-phenoxy) -l-methyl-ethyl] -aminomethyl] -3-sulfamoyl-4-chloro-benzyl alcohol is mixed with a portion of the wheat starch, with lactose and colloidal Silica is mixed and the mixture is forced through a sieve. Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture is kneaded with the paste until a slightly plastic mass is formed.

^ 0.AU ^; ΐ9 ^ '> ί · 8Ρ

239910

The plastic mass is forced through a sieve of about 3 mm mesh size, dried and the obtained dry granules are again driven through a sieve. Then the remaining wheat starch, talc and magnesium stearate are added and the mixture is compressed into tablets of 145 mg weight with score.

Example 5 ; Capsules containing 10 mg of active substance are prepared in the usual way as follows:

Z us amme η settlement :

α- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminomethy1] -

S-sulfamoyl-A-chloro-benzyl alcohol 2500 mg

Talc '200 mg

Colloidal silica 50 mg

Production :

The active substance is intimately mixed with talc and colloidal silica, the mixture is forced through a sieve of 0.5 mm mesh size and this is filled into portions of 11 mg each in hard gelatin capsules of suitable size.

Example 6 : A sterile solution of 5.0 g of α- [N- [2- (3-carbarooyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -3-sulfamoyl-4-chlorobenzyl alcohol tjiethansulfonate in 5,000 ml of distilled water is added to 5 ml ampoules containing 5 mg of active substance in 5 ml of solution.

Example 7 : 3.62 g of α- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminopethyl] -3-sulfamoyl-4-chloro-benzyl alcohol are added with the addition of 100, 0 ml of 0.10-n. Hydrochloric acid with 18000 ml of distilled water to a volume of 18100 ml. The sterilized solution is filled into 5.0 ml ampoules containing 1 mg of active ingredient.

now

239

Example 8 ; Instead of the compounds used as active substance in Examples 4 to 7, the following compounds of Formula I, or their pharmaceutically acceptable non-toxic acid addition salts can be used as active ingredients in tablets, dragees, capsules, vial solutions, etc.: a- [N- [ 2- (3-Carbamoy1-4-hydroxy-phenoxy) -äthyi] -aminomethy1] -2 _s 4-di-

chlorobenzyl alcohol, α- [N- [2- (3-carbamoy1-4-hydroxy-phenoxy) -äthy1] -aminomethyl thy1] -4-chloro

3-nitro-benzyl alcohol, α- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -äthy1] -aminomethyl] -4-nitro

benzyl alcohol, a- [N- [2- (3-carbamoy1-4-hydroxy-phenoxy) -äthy1] -aminomethyl] -3- (methyl-

sulfonylamino) -4-chloro-benzyl alcohol, α- [N- [2- (3-carbaraoy1-4-hydroxy-phenoxy) -äthy1] -aminomethyl] -3,5-di-

chloro-4-aminobenzyl alcohol, a- [N- [2- (3-carbamoy1-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -3- (methyl-

sulfonylamino) -benzyl alcohol, a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -1-methyl-1-ethyl] -aminomethyl-1-yl

4- (methylsulfonylamino) -benzyl alcohol, of "[N- [2- (3-carbamoy1-4-hydroxy-phenoxy) -1-methyl-ethyl] -aminomethyl] -

3,4-methylenedioxy-benzyl alcohol, a- [N- [2- (4-Carbamoy1-3-hydroxy-phenoxy) -1-methy1-äthy1] -aminomethyI] -

3,4-methylenedioxybenzyl alcohol, α- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -1-methyl-ethyl] -aminomethyl] -

4- (methylsulfonylamino) -benzyl alcohol, α- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -1-methyl-ethyl] -aminomethyl] -

S ^ -hydroxy-carbamoyl-benzyl alcohol, a- [N- [2- (3-Carbamoy1-4-hydroxy-phenoxy) -1-methy1-äthy1] aminomethyl] -

4- (2-methoxy-ethoxy) -benzyl alcohol, α- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -1-methyl-ethyl-1-aminomethyl] -

4-methylbenzyl alcohol, n- [N- [2- (3-carbamoy1-4-hydroxy-phenoxy) -1-methyl-1-ethyl] -aminomethyl] -4-methoxy-benzyl alcohol;

jr \ O Π

239910 1

a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethyl] aminomethyl] -3-sulfated

Moyl-4-methoxy-benzyl alcohol, 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4- (2-methoxyphenyl) -

2-butanol 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -3-phenyl-2-propanol,

l- [2- (3-carbamoyl-4-hydroxy-phenoxy) -äthylamino-3- (2-methoxyphenyl) -

2-propanol a- [N-t 2 - (3-carbainoyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -2-methoxy

benzyl alcohol, a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -ethyl] -aminomethyl] -4-ethyl

sulfonylamino-benzyl alcohol, α- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -4-methanesulfonylamino-benzyl-alcohol,

a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -4- (methylsulfonylamino) -benzylalcohol as an enantiomeric pair of mp. 165-167 °, or as an enantiomeric pair of the mp. 144-145 °, 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylaminoy-4-phenyl-2-butanol, 1- [2- (3-carbamoyl-4-hydroxy-phenoxy ) -äthylamino] - (2-methylphenyl) -2-

butanol, 1- [2- (3-carbamoy1-4-hydroxy-phenoxy) -ethylamino] -4- [4- (2-methoxyethoxy) -phenyl] -2-butano1.

2HAUai982- * 080243

Claims (6)

2399 10 1 claims 1. A process for the preparation of novel derivatives of 2-aminoethanol of the formula / \ Λ. Ar- (CH ₀₎ -CH-CH "-N-Alk- (O) + - Il ^C ° ^N \ (I), OH H · in which Ar is optionally substituted phenyl, m is a number from 0 to 3, η is the number O or 1 and alk alkylene having 2-5 carbon atoms, wherein the nitrogen atom and the oxygen atom or, if η is zero, the phenyl radical by at least two Carbon atoms are separated from each other, and R and R "are each hydrogen, with the proviso that when m is 0, the phenyl radical Ar contains at least one substituent and a phenyl radical Ar substituted by one or two hydroxy or protected hydroxy groups at least one additional one of these contains ver different substituents, in the form of racemates, racemates, optical antipodes or their salts, characterized in that in a compound of formula / ^0H in which one or both hydroxy groups and / or present in the radical Ar hydroxy and / or amino groups are optionally protected by such aushydratable by hydrolysis and displaceable by hydrogen groups which are cleaved under the conditions of the process and replaced by hydrogen, or in the radical Ar, if appropriate together with said protected hydroxy and / or amino groups, the group -CN is present, the groups -CN converted by hydrolysis into the group -CONH and simultaneously optionally protected hydroxy and / or amino groups in free hydroxyl and / or amino groups, and if desired, a compound obtained in η η »un« in O O * / i Q Π Ο 239910 1 converting another compound of the formula I, and / or, if desired, converting a free compound obtained into a salt or a salt obtained into a free compound, and / or, if desired, a racemate mixture obtained in the racemates or a racemate obtained separates the optical antipodes. 2. The method according to claim 1, characterized in that one carries out the hydrolysis in the presence of a mineral acid. 3. The method according to claim 2, characterized in that one uses a hydrohalic acid. 4. The method according to claim 3, characterized in that the hydrolysis by means of conc. Hydrochloric acid. 5. The method according to any one of claims 1-4, characterized in that one carries out the hydrolysis in a temperature range of 20-25 ⁰ C. 6. The method according to any one of claims 1-5, characterized in that one converts a compound of formula I obtained in a pharmaceutically acceptable, non-toxic acid addition salt.