DD157796A5 - PROCESS FOR THE PREPARATION OF NEW DERIVATIVES OF 2-AMINO-AETHANOL - Google Patents

Abstract

The invention relates to a process for the preparation of novel derivatives of 2-amino-ethanol for use as a medicament. The aim of the invention is the provision of novel compounds for the treatment of insufficient cardiac output and cardiac arrhythmias and asthma and circulatory disorders. According to the invention compounds of formula I are prepared in which, for example, Ar is optionally substituted phenyl, m is a number from 0 to 3, n the number 0 or 1 and alk alkylene having 2-5 carbon atoms, wherein the nitrogen atom and the oxygen atom or, if n is zero, the phenyl radical are separated by at least two carbon atoms, and R deep 1 and R 2 deep independently of each hydrogen or lower alkyl, or together lower alkylene, Oxaniederalkylen, Thianiederalkylen, Azaniederalkylen or N-Niederalkylazaniederalkylen in the form of racemates, racemates, optical antipodes or their salts.

Description

· 4

Eerlin, the 3 · 3. 1981 58 303/18

Process for the preparation of new derivatives of

2 "~ ~ amino ethanol

Area of application of the invention.

The invention relates to a process for the preparation of novel derivatives of 2-amino ethanol ethanol

The compounds according to the invention have valuable effects pharmakolpgisehe ex \ f * They are used as medicinal products on the one hand at the usual for beta-blocker Indications j other part, for the treatment of insufficienten cardiac output, asthma and circulatory disorders "

Characteristics of the known technical solutions

There are no data available on it. Known which compounds were previously used as ß-blockers or "for the treatment of the inadequate cardiac output of asthma, and circulatory disorders"

There is also no information on processes for the preparation of 2-amino-ethanol derivatives known *

Object of the invention

The aim of the invention is the provision of compounds / as stimulators of cardiac J3 ~ receptors for the treatment of insufficient cardiac output and cardiac arrhythmia • as well as stimulators of tracheal and vascular ß-receptors as broncho- and vasodilators for the treatment of asthma, Hei ; insufficiency and circulatory disorders are applicable,

Presentation of the _We sensation of the invention

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

i

According to the invention, derivatives of 2-amino ethanol are of the formula;

! OH

^; 'IR ₁

OH H

in which Ar is unsubstituted or substituted phenyl jm is a number from 0 to 3 _} η is the number 0 or 1 and alk is alkylene having 2-5 carbon atoms, v / o is 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 Rp are each independently hydrogen, or liederalkyl _s or together lower alkylene, Oxaniederalkylen, thia-lower alkylene, Azanieder ~ .alkylen or H-üFi'ederalkylazaniederalkylen with the proviso, if .that m is 0, the phenyl radical Ar contains at least one substituent and a phenyl radical Ar substituted by one or two hydroxyl groups or protected hydroxy groups contains at least one additional substituent other than these.

in the form of mixtures of racemates, racemates, optical antipodes or their salts, in particular acid addition salts, and in particular pharmaceutically acceptable, non-toxic acid addition salts. /

Substituents of the radical Ar, for example, if appropriate, in particular indicated below, substituted lower alkyl,> lower alkenyl or lower alkoxy, further Niederalkenyloxy, Niederalk'inyl, Niederalkinyloxy, Niederalkylidendioxy, cyano and / or nitro and / or directly or a ⁿ aforementioned lower alkyl, lower alkenyl or lower bound / dh a substituting these groups, lower alkanoyl, esterified or amidated carboxyl, in particular lower alkoxycarbonyl or optionally substituted carbamoyl, such as carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, or (HydroxyniederalkyD-carbamoyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl or lower alkylsulfamoyl _s di-lower alkylsulfamoyl, or directly or to the aforesaid lower alkyl or halogen attached to the lower alkoxy higher than the 1-stop, etherified mercapto such as lower alkylthio, optionally substituted amino such as amino, lower alkyl amino, di-lower alkylamino, alkylene or oxaalkyleneamino, pyrrol-1-yl, acylamino, such as lower alkanoylamino or lower alkoxycarbonylamino, if appropriate, especially by one or two lower alkyl, - substituted by hydroxy lower alkyl or cycloalkyl ureido, Niederalkylsulf onylamino or optionally etherified or esterified hydroxy, such as hydroxy , Phenyl-lower alkoxy or lower alkanoyloxy or, as a non-directly bonded substituent, again lower alkoxy, with the proviso that, if m is 0, the aryl group Ar at least one substituent and by one or two hydroxy, 1-Phenylniederalkoxy- or Lower alkanoyloxy substituted phenyl contains at least one additional, other of these substituents.

In connection with the present description with

"lower" designated radicals and compounds preferably contain

to 7 and primarily to 4 carbon atoms.

The general terms used in the enumeration of substituents of the radical Ar can be used, for example. have the following specific meanings. Is lower alkyl .zB methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl or tert-Buty l * _f substituted lower alkyl is in particular methyl .entsprechendes or 1- or 2-substituted ethyl, Lower alkenyl is, for example, vinyl, allyl , 2- or 3-methallyl or 3,3-dimethylsilyl, and substituted lower alkenyl in particular. 2-substituted vinyl or 3-substituted allyl. Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy, _isopropyloxy, n-butyloxy or isobutyloxy, and substituted lower alkoxy, for example substituted 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; Niederalkylidendioxy is, for example Iscpropylidendioxy, Aethylidendioxy ^{un and} in particular methylene dioxy, - and 'alkylenedioxy in particular ethylenedioxy, lower alkanoyl is, for example, acetyl, propionyl or butyryl. Lower alkoxycarbonyl is, for example, methoxycarbonyl or ethoxycarbonyl. Lower alkyl or di-lower alkylcarbamoyl is, for example, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl or diethylcarbamoyl, and hydroxynxederalkylcarbamoyl eg (2-hydroxyethyl) -carbainoyl. Lower alkylthio. is, for example, methylthio, A. 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,

• Dimethy! Amino or diethylamino. Alkyleneamino and oxaalkyleneamino are e.g. Pyrrolidino or piperidino or morpholine). Lower alkanoyland.no. is e.g. Acetylamine or butyrylamino, and lower alkoxycarbonylamino e.g. Methoxycarbonylamino or ethoxycarbonylamino. By one or two lower alkyl, hydroxyalkyl or by. Cycloalkyl, preferably those having 5 to 7 ring members, substituted ureido is e.g. 3-Methylureido, 3,3-dimethylureido, 3- (2-hydroxyethyl) -ureido and 3-cyclohexylureido. Lower alkylsulfonylamino is e.g. Aethylsulfonylamino and especially 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 limiting the possible combinations thereof. Lower alkanoylalkyl is e.g. 2-oxopropyl (acetonyl) or 3-oxobutyl, lower alkanoyl-lower alkenyl e.g. 3-oxo-1-butenyl, and lower alkanoylalkoxy e.g. 2-oxopropoxy (acetonyloxy) or 3-oxo-butoxy. Optionally substituted carbamoyl-lower alkyl is e.g. Carbamoylmethyl or [(hydroxyniederaikyl) carbamoyl)] lower alkyl such as [(2-hydroxyethyl) carbamoyl] methyl. Lower alkoxycarbonyl-lower alkoxy is e.g. Aethoxycarbonyliaethoxy. Optionally substituted carbamoyl-lower alkoxy is e.g. Carbamoyl-lower alkoxy, such as carbamoylmethoxy, or [(hydroxynyl-tetrahydroxy) -carbamoyl] -lower alkoxy, such as [(2-hydroxyethyl) -carbamoyl] -methoxy, halo-lower alkyl is especially halomethyl, eg trifluoromethyl, lower alkylthio-lower alkoxy, eg 2-methylthioethoxy or 2-ethylthioethoxy. Acylamino-lower alkyl is, for example, lower alkanoylamino-lower alkyl, especially lower alkanoylaminomethyl or 1- and especially 2-lower alkanoylaminoethyl, eg acetylaminomethyl, 2-acetylaminoethyl or 2-propionylaminoethyl, or lower alkoxycarbonylamino-lower alkyl, especially lower alkoxycarbonylaminomethyl or 1- and especially 2-lower alkoxycarbonylamino ethyl, eg methoxycarbonylaminomethyl, 2-metho> ^ / carbonylaminoethyl or 2-ethoxy-

carbonylamino-ethyl. Acylaminoniederalkoxy is eg Niederalkanoylaminoniederalkoxy, especially 2-Niederalkanoylaminoäthoxy, eg 2 ~ (Acetylaniino) -ethoxy, or Niederalkoxycarbonylaminoniederalkoxy, in particular 2- _{(Niederalkoxycarbonylaminoäthoxy>} as 2- (methoxy * carbonylamino) -ethoxy or 2- (Aethoxycarbonylamino) -ethoxy. Hydroxy is lower alkoxy-lower alkyl is preferably lower alkoxymethyl or 1- and especially 2-lower alkoxyethyl, eg methoxymethyl, ethoxymethyl, 2-methoxyethyl or 2-ethoxyethyl. 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.

R and R in the meaning of lower alkyl are, for example, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl or heptyl, and especially methyl or ethyl. Together with yours. Nitrogen atom of the amide group are R and R as lower alkylene, for example, 1-aziridinyl, l-azetidinyl, l ~ pyrrolidinyl, piperidino, hexahydro-lH-azepin-1-yl, as Oxaniederalkylen eg morpholino, as Thianiederalkylen example Thiomorpholino; as azan-lower alkylene, for example 1-piperazinyl or hexahydro-lH-1,4-diazepin-1-yl, where the latter two groups correspond to the meaning of N-lower-alkylazo-lower alkylene for R and R in the 4-position, ie, _n- amino group, eg lower alkyl. such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl, may be substituted.

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. bound in the para position to the hydroxy group.

"The novel compounds may be in the form of their salts _/ acid addition salts and, in particular, their pharmaceutically acceptable non-toxic acid addition salts Suitable salts include those with inorganic acids such as hydrohalic acids, eg hydrochloric, hydrobromic, sulfuric or phosphoric acid, or with organic acids, such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulphonic acids, for example formic, acetic, propionic, succinic, glycolic, lactic, acetic, tartaric, citric, maleic, Hydroxymalein, pyruvic, fumaric, benzoin, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, ethabonic, methanesulfonic, ethanesulfonic, 2-hydroxyethylsulfonic, ethylenesulfonic, toluenesulfonic, Naphthalenesulfonic or subilanilic acid, or with other acidic organic substances, such as ascorbic acid.

In particular, the invention relates to compounds of the formula I in which Ar is optionally monosubstituted or polysubstituted, preferably at most 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 directly or indirectly bonded to the aforementioned lower alkyl, lower alkenyl or lower alkoxy, esterified or amidated carboxyl, especially lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or (hydroxy lower alkyl) carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl or lower alkylsulfamoyl, and / or directly or ^- 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 1-Pyrro.l idinyl, piperidino or. Morpholino, pyrrol-1-yl, 'acylamino such as lower alkanoylamino or lower alkoxycarbonylamino, optionally substituted by lower alkyl, hydroxy-lower alkyl or cycloalkyl-substituted ureido, lower alkylsulfonylamino, hydroxy, phenyl-lower alkoxy, eg

Jf β ι g »

Benzyloxy, lower alkanoyloxy or, as. not directly linked substituent may be present turn-lower alkoxy, m is a number from 0 to 3., η represents the number .0 or 1 and alk represents an alkylene radical ^m it 2 to 4 carbon atoms, where the nitrogen atom and the oxygen atom or, if η is 0, the phenyl radical is separated from each other by 2 to 3 carbon atoms of the radicals alk, R and R "are as defined under formula I, but are preferably: hydrogen or lower alkyl, eg methyl or ethyl, or together with form the nitrogen atom of the "amide group" morpholino or alkyleneamino having 5 to 6 ring members, such as 1-pyrrolidinyl or piperidino, with the proviso that, if m is 0, the phenyl radical Ar has at least one substituent and one or two hydroxyl, Ar-1-phenyl-lower alkoxy or lower alkanoyloxy substituted phenyl radical Ar contains at least one additional substituent other than these, in the form of racemic mixtures chen, racemates, optical antipodes, as free compounds or salts thereof, in particular acid addition salts, especially pharmaceutically acceptable, "non-toxic acid addition salts.

The invention preferably relates to compounds of the formula I in which Ar is optionally monosubstituted to trisubstituted, substituents optionally substituted in the manner indicated below being substituted lower alkyl, lower alkenyl or lower alkoxy _, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkylidenedioxy, cyano and / or nitro and / or lower alkanoyl bonded directly or to the abovementioned lower alkyl, lower alkenyl or lower alkoxy. Lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl, lower alkylsulfamoyl, and / or halo directly or to lower alkyl mentioned or lower than 1 to lower alkoxy, lower alkylthio, amino, lower alkylamino, di-lower alkylamino , Alkylen- or Oxaalkylenamino, z. B.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, eg benzyloxy, lower alkanoyloxy or, as non-directly bonded substituent may again be lower alkoxy, m is a number from 0 to 3 and η is the number 0 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 radical alk, R and R are those given under formula I. Are of importance, but are preferably hydrogen or lower alkyl, in particular methyl or ethyl, or together with the nitrogen atom of the amino group form 1-pyrrolidinyl, piperidino or morpholino, with the proviso that _; if m stands for 0 _; Phenyl radical Ar contains 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 , in particular acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

The invention particularly relates to 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 alkylidenedioxy, nitro and / or cyano and / or as substituents optionally indicated below. or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxy lower alkyl) -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 aforesaid lower alkyl or in higher than the 1-position aforesaid lower alkoxy-bonded halogen, lower alkylthio, amino, lower alkylamino,

Di-lower alkylamino, alkylene or oxaalkylene amino, e.g. 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbonylamino, optionally lower alkoxy or cycloalkyl substituted ureido, 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, if m is 0, the phenyl radical Ar at least one substituent, and a by one or two hydroxy-, 1-phenyl-lower-alkoxy- or lower alkanoyloxy-substituted phenyl radical Ar contains at least one additional substituent other than these, η is the number Ό or 1 and alk is an alkylene radical with 2 -la-4 carbon atoms, where 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 are each independently hydrogen or lower alkyl, in particular methyl or ethyl, or together with the nitrogen atom of the amide group form morpholino in the form of mixtures of racemates, racemates, optical antipodes, as free compounds or their salts, in especially acid addition salts, especially pharmaceutically acceptable non-toxic acid addition salts. ,

The invention relates especially to compounds of Formula I wherein Ar is optionally _{e n} £ _ to trisubstituted, suitable substituents being optionally in the manner indicated below substituted lower alkyl or lower alkoxy, more 'lower alkenyl. Lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitro and / or cyano, and / or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkalkylcarbamoyl or (hydroxyloweralkyl) -carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl and / or directly or to the aforesaid lower alkyl or directly or to the aforesaid lower alkyl or lower alkoxy in higher than the 1-position to the aforementioned lower alkoxy bound halogen,

Lower alkylthio, amino, alkylene or oxaalkyleneamino, e.g., 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino or lower alkoxycarbonylamino, or optionally lower alkyl substituted ureido, oxyderalkylsulfonylamino, hydroxy, further phenyl-lower alkoxy, e.g. Benzyloxy, or, as not directly bound '. Substituent, again lower alkoxy may be present, 'm is a number from 0 to 3, with the proviso that, if m is 0, the phenyl radical; Ar 'is at least one substituent, and a phenyl radical Ar substituted by one or two hydroxy, 1-phenyl-lower alkoxy or lower alkanoyloxy groups, at least one additional of these

contains different substituents, η is the number 0 or 1 and 'alk 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 are each independently hydrogen or lower alkyl, but preferably hydrogen or Represent methyl, 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 the first place to compounds of the formula I in which Ar 'is optionally monosubstituted to trisubstituted, whereupon substituents optionally substituted in the manner indicated below substituted lower alkyl, for example methyl, or lower alkoxy, for example methoxy or ethoxy, further lower alkenyl, for example allyl Lower alkenyloxy, eg allyloxy, lower alkynyloxy, eg propargyloxy, nitro _/ lower alkylidenedioxy, eg methylenedioxy. and / or cyano and / or lower alkanoyl directly or to the above-mentioned lower alkyl or lower alkoxy, for example acetyl, carbamoyl, lower alkylcarbamoyl, z..B. N-methylcarbamdyl, or (hydroxy-lower alkyd-carbamoyl, for example N-hydroxymethyl-carbamoyl, lower-alkylsulfonyl, for example methylsulfonyl, sulfamoyl, and / or directly or on

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 alkoxycarbonyl-amino, e.g. Methoxycarbonylamino, or lower alkylsulfonylamino, e.g. Methylsulfonylanino, m is an integer from 0 to 3, with the proviso that when m is 0, the phenyl radical Ar is at least one substituent and a phenyl radical Ar substituted by one or two hydroxy or 1-phenyl-lower alkoxy groups is 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 phenyl radical bearing the amide and the adjacent hydroxy group 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, above all pharmaceutically acceptable, non-toxic acid addition salts.

The invention relates in particular to compounds of the formula I in which Ar is optionally monosubstituted to trisubstituted, the substituents being lower alkyl, lower alkoxy, hydroxy lower alkyl, amino, lower alkanoylamino, lower alkylsulfonylamino, nitro, phenyl-lower alkoxy, ureido, halo-lower alkyl, halogen and hydroxy, and m represents 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, the nitrogen atom being and the oxygen atom, or, if η is zero, the -phenyl radical, are separated by at least two carbon atoms, and R, and R "independently of

each lower alkyl having up to 4 carbon atoms or R and R together are lower alkylene having 4-6 carbon atoms in the unbranched chain, but especially 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 particular to 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 0 and η is the number 0 or 1 and alk is an alkylene radical having 2 to 3 carbon atoms where 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 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 compounds of the formula I in which Ar is substituted by lower alkylsulfonylamino, such as methylsulfonylamino, where appropriate also by halogen, such as chlorine or by sulfamoyl, halogen, such as chlorine, or lower alkoxy, such as methoxy, m is the number 0 and η is the number 0 or 1 and alk is an alkylene radical having 2 to 3 carbon atoms, where 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 " in each case hydrogen, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or salts thereof, in particular acid addition salts, of all pharmaceutically acceptable, non-toxic acid addition salts.

Π η Γ ': j; \ Vl .. '' ι ι \ ί \ Λ: '

The invention relates in particular to 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 are separated by at least two carbon atoms, and R 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 -toxic acid addition salts.

The new derivatives of 2-aminoethanol according to the invention correspond to the above-described formula I 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 are separated by at least two carbon atoms, and R and R are each independently hydrogen or lower alkyl, or together lower alkylene, Oxaniederalkylen, Thianiederalkylen, Azaniederalkylen or N-Niederalkylazaniederalkylen, in the form of racemic mixtures, racemates, optical antipodes or their salts, in particular acid addition salts, and in particular pharmaceutically acceptable non-toxic acid addition salts,

The invention relates in particular to compounds of the formula I in which Ar is optionally monosubstituted or polysubstituted, preferably at most trisubstituted, with substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynylxyxy, as substituents, if appropriate, in particular indicated below. Lower alkylidenedioxy, lower alkylenedioxy, cyano and / or nitro, and / or directly or on

aforesaid lower alkyl, lower alkenyl or lower alkoxy-bonded lower alkanoyl, versed or amidated carboxyl, especially lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or (hydroxy-lower alkyd-carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl or lower alkylsulfamoyl, and / or directly or to the aforesaid lower alkyl or in higher than the 1-position halogeno, lower alkylthio, amino, lower alkylamino, di-lower alkylamino, alkylene- or oxaalkyleneamino, for example 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, acylrino, such as lower alkanoylamino or lower alkoxycarbonylamino, optionally substituted by lower alkyl, hydroxy-lower alkyl or cycloalkyl substituted ureido, Niederalkylsulfonylamxno, hydroxy, Phenylniederalkoxy, eg benzyloxy, lower alkanoyloxy or, as not directly bonded substituent, again lower alkoxy may be present, m.fware a number from 1 to 3, η is the number 0 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 have the meaning given under formula I. but preferably for hydrogen or lower alkyl, eg Methyl or ethyl, or stand together with the nitrogen atom of the amide group, morpholino or alkylene amino with 5 to 6 ring members, such as 1-pyrrolidinyl or piperidino, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or salts thereof, especially acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

The invention preferably relates to compounds of the formula I in which Ar is optionally substituted up to trisubstituted by eirr, where appropriate as sub-substituents in the manner indicated below

.i ^. Λ

substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkylidenedioxy, cyano and / or nitro and / or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxyloweralkyl) carbamoyl, lower alkylsulfinyl, directly or indirectly bonded to the aforesaid lower alkyl, lower alkenyl or lower alkoxy, Lower alkylsulfonyl, sulfamoyl, Niederalkylsulfamoyl, and / or directly or 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 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbonylamino, optionally substituted by lower alkyl, hydroxy lower alkyl or cycloalkyl, ureido, lower alkylsulfonylamino, phenyl-lower alkoxy, e.g. Benzyloxy, lower alkanoyloxy or, as an unsubstituted substituent may again be lower alkoxy, m is a number from 1 to 3 and η is the number 0 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 radical alk, R and R have the meaning given under formula I, but are preferably hydrogen or lower alkyl, in particular methyl or ethyl, or together form with the nitrogen atom of the amino group 1-pyrrolidinyl, piperidino or mopholino, 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 particularly relates to compounds of formula I, wherein Ar is optionally substituted one to three times, wherein

optionally substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitro and / or cyano and / or lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxy lower alkyl) directly or to the aforesaid lower alkyl, lower alkenyl or lower alkoxy -carbamoyl, lower-alkylsulfinyl, lower-alkylsulfonyl, sulfamoyl or lower-alkylsulfamoyl, and / or directly or to the aforesaid lower-alkyl or halogen which is more than 1-connected to the aforementioned lower-alkoxy, lower-alkylthio, amino, lower-alkylamino, -di-lower-alkylamino, alkylene- or oxa-alkylene-amino, for example 1 Pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbonylamino, optionally substituted by lower alkyl or cycloalkyl ureido, lower alkylsulfonylamino, hydroxy, phenyl-lower alkoxy, eg benzyloxy, lower alkanoyloxy or, as not m is a number from 1 to 3, η is the number 0 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 0 is the phenyl radical, are separated by 2 to 3 carbon atoms of the radical alk, and R and R independently represent each hydrogen or lower alkyl, in particular methyl or Aethy1 «, or form together with the nitrogen atom or amide morpholino, in the form of racemate mixtures ₅ racemates, optical antipodes, as free compounds or salts thereof, in particular acid addition salts, especially pharmaceutically acceptable, non-toxic acid addition salts.

The invention relates in particular to compounds of the formula I in which Ar is optionally monosubstituted to trisubstituted by substituted lower alkyl or lower alkoxy, further lower alkenyl, lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitro and / or cyano and / or as substituents optionally indicated below directly or to the aforesaid lower alkyl or

Lower alkoxy-bonded lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkoxycarbamoyl or (hydroxy lower alkyl) carbamoyl, 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 halogen, lower alkylthio, amino, alkylene or oxaalkyleneamino, for example, 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino or lower alkoxycarbonyl, or optionally lower-substituted ureido, lower alkylsulfonylamino, hydroxy, further phenylene, lower alkoxy, for example Benzyloxy, or, as not directly bonded substituent, again lower alkoxy may be present, m is a number from 1 to 3, η is the number 0 or 1 and all an Alkylenr.est having 2 to 4 carbon atoms, wherein the nitrogen atom and the oxygen atom or, if η is 0, the phenyl radical which is separated by 2 to 3 carbon atoms of the radical alk, and R and R are each independently hydrogen or lower alkyl, but preferably hydrogen or methyl, 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 the first place to compounds of the formula I in which Ar is optionally monosubstituted to trisubstituted, with substituted lower alkyl as substituent, optionally substituted as indicated below, e.g. Methyl, or lower alkoxy, e.g. Methoxy or ethoxy, further lower alkenyl, e.g. Allyl, lower alkenyloxy, e.g. Allyloxy, lower alkynyloxy, e.g. Propargyloxy, nitro, lower alkylidenedioxy, e.g. Methylene-dioxy, and / or cyano, and / or lower alkanoyl directly or linked to the aforesaid lower alkyl or lower alkoxy, e.g. Acetyl, carbamoyl, lower alkylcarbamoyl, e.g. N-methylcarbamoyl, 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,

- ie - -

The novel compounds of the formula I have valuable pharmacological properties. In particular, they specifically act on 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. ^ intrinsic sympathomimetic activity, and when expressed more strongly as predominant stimulation of the β-adrenergic receptors. 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 a- [N- [2- (4-carbainoyl-3-hydroxyphenoxy) -l-methylethyl] -aminomethyl] -4- (methylsulfonylamino) -benzyl alcohol, in particular its one enantiomeric pair, mp. 165-167 ° as the main effect of a blocking Effect on β-receptors (with slightly more preferential inhibition of the 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 α- [N- [2- (4-carbamoyl-3-hydroxyphenoxy) -1-methylethyl] -aminomethyl] -4- (methylsulfonylamino) -benzyl alcohol as well as its two pairs of enantiomers, mp. 165-167 ° and 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 distinct 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. These compounds prove their effect on cardiac β-receptors on the one hand in in vitro experiments at sea ¹

In contrast, in piglets, potent blockers with relatively clear ISA, on the other hand predominantly as strong-acting stimulants in in vivo experiments on the anesthetized cat. 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, are substituted, e.g. α- [N- [2-O-carbamoyl-A-hydroxyphenoxy) -1-methylethyl] -aminomethyl] -4-methylbenzyl 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- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -3,4-methylenedioxy-benzyl alcohol, which shows a cardioselective ß-stimulation in in vivo experiments on the cat leaves. As additional effects, e.g. for α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) -1-methylethyl] -aminomethyl] -3,4-methylenedioxy. benzyl alcohol, a decrease 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 isolated guinea pig hearts in a concentration range of about 0.001 to about 11 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 results, if one is linked, from the increase in the basal heart rate

the anesthetized, reserpine pretreated cat when administered intravenously in a dose range of 0.001 to 1 mg / kg. The novel beta-blocking compounds also cause a reduction in arterial blood pressure in the anesthetized cat at a dose range of about 0.1 mg / kg to about 10 mg / kg iv. The additional α-blocking activity, which may favor, for example, a hypotensive effect, for example, results from the antagonization of noradrenaline-induced contraction of the isolated rat vas deferens by such compounds in a concentration of 0.1 μg / ml to about 10 μg . 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 arrhythmia, and as hypotensive agents. The additional diuretic and saluretic effects present in certain types of Formula I compounds, such as those shown above, could lead to a significant enhancement of the antihypertensive effect and eliminate the need for the combination of β-receptor blockers with diuretics.

Pie β-receptor-stimulating compounds of formula I, such as a- [N- [2- (37-carbamoyl-4-hydroxy-phenoxy) -äthy1] -aminomethyl] -3,4-methylenedioxy-benzyl alcohol, cause an increase in heart rate and Myocardial contraction force in the isolated guinea pig atrium in a concentration range of about 0.0001 pgAal to 0.1 μg / 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.sup.- receptors) in comparison to the β receptors in the blood vessels (β.sup.- receptors) and thus differ qualitatively distinctly from isoproterenol, which binds the β receptors of the Heart and the blood vessels stimulated about equally strong. Some of the compounds of formula I also have relatively clear stimulating effects on β-receptors. (Blood vessels, trachea).

  '22,

Accordingly, the novel stimulatory compounds of formula I can be:.

1) as stimulatory agents of cardiac β receptors for the treatment of insufficient cardiac output and cardiac arrhythmia,

2) as stimulatory agents of tracheal and vascular β receptors as broncho- and vasodilators for the treatment of asthma, heart disease

, sufficiency and circulatory disorders are used.

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

Ar- (CH.) -CH - CH. - Z * m 2 1

with a compound of the formula

Z-alk- (O) - ^ - Λ,

wherein one of Z and Z is a reactive esterified

* X. £ r

Represents hydroxy group and the other represents the primary amino group, and X is hydroxyl, or wherein X ₁ and Z ₁ together denote the epoxy group and Z_ stands for the primary amino group, Ar, alk, m and η have the above meaning, and if desired, converting a compound obtained into one, 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 resulting racemate mixture into the racemates or an obtained racemate into the optical antipodes.

A reactive esterified hydroxy group Z or Z is one, in particular a strong acid, in particular a strong Ano'rganische acid, such as a hydrogen halide, in particular

Hydrochloric, hydrobromic or hydroiodic acid, or sulfuric acid, or a strong organic acid, especially a strong organic sulphonic acid, such as an aliphatic or aromatic sulphonic acid, e.g. Methanesulfonic acid, 4-methylbenzenesulfonic acid or 4-bromobenzenesulfonic acid, esterified hydroxy groups, and is primarily halogen, e.g. Chlorine, bromine or iodine, or aliphatically or aromatically substituted sulphonyloxy, e.g. Methylsulfonyloxy or 4-methylphenyl-sulfonyloxy.

The above reaction is carried out in a manner known per se, wherein, especially when using a starting material having a reactive esterified hydroxy group, advantageously in the presence of a basic agent, an inorganic base, sB of an alkali metal or alkaline earth metal carbide or hydroxide, or an organic basic agent, such as an alkali metal lower alkanolate, and / or an excess of the basic reactant, and usually in the presence but, if appropriate, also in the absence of a solvent or solvent mixture and, if necessary, with cooling or heating, Z. B. in a temperature range of about -20 ⁰ C to about +150 ⁰ C, in an open or closed vessel and / or in an inert gas atmosphere, for example in a nitrogen atmosphere works.

Starting materials of Formeh II or III are known or can be prepared in a conventional manner. Thus, to prepare a starting material of formula II in which m is 0, a compound of formula Ar-H, wherein any of the ao or hydroxy groups present may be protected by a protecting group, e.g. any of those described below may be protected with a haloacetyl halide, e.g. Chloroacetyl chloride, in the presence of a suitable Lewis acid, e.g. Aluminum oxide, haloacetylated according to the Friedel-Crafts method on a carbon atom of the radical Ar. And in the Ar-haloacetyl compound thus obtained, e.g. by

Treat with a suitable hydride reducing agent, reduce the carbonyl 'to the carbinol group; if desired, a halogen Z, e.g. by treating with ammonia, or a suitable derivative, such as hexamethylenetetramine and decomposing the resulting compound with dilute mineral acid, or by reacting with an alkali metal salt of the phthalimide and cleaving the resulting N-phthalimide compound, e.g. with hydrazine, into the primary amino group

Convert Z Starting materials of the formula II, in which X and Z together are epoxy, can be prepared, for example, by cyclization of a compound of the formula II in which X is hydroxy and Z is a reactive esterified hydroxy group, for example chlorine or methanesulfonyloxy, by means of alkaline reagents, for example a mixture of dilute Sodium hydroxide and tetrabutylammonium chloride are obtained in a suitable solvent, for example methylene chloride.

Starting materials of the formula II in which m has the above meaning and X and Z ₁ together represent the epoxy group, and any amino or hydroxy groups present are protected by a protective group, for example as indicated below, can be obtained by reacting in a compound of the formula Ar - (CH ") - CH = CH" (Ha), which

2 m 2

Group -CH = CH by introducing the epoxy group into the group

-CE. - CH converted, for example by reaction with a peroxy compound such as hydrogen peroxide, or an organic peracid such as 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 Solvents, such as chloroform. This reaction is carried out in the usual way.

-2K-

Starting materials of the formula III can be prepared, for example, by reacting a hydroxysalicylamide with a dihaloalkane corresponding to the meaning of alk, for example a chlorobromo or dibromoalkane in the presence of an alkaline metal oxide. Condensing agent, such as an alkali carbonate, and, if desired, replacement of the remaining halogen Z in the above for. Z indicated by the primary ayano group _/ . These reactions are carried out in a customary manner, with protection groups present at the amino or hydroxyl groups being split off simultaneously or subsequently, for example as described.

The compounds of the formula I can be further prepared by reacting in a compound of the formula

^{1 year}

OX ₂ X ₃ ^R 2

where Ar. the meaning of Ar or a radical Ar which is substituted by in each case 1 to 2 hydroxy- and / or anino-transferable groups, X ", X- and X are each hydrogen or a substituent substitutable by hydrogen and X" is for R is, or X_ and X and / or X, and X_ zusamtaen a divalent, replaceable by two hydrogen atoms radical, with the proviso that at least one of the radicals X, X_ and X is other than hydrogen -verschieden _0, or at least Ar a Res means Ar substituted by 1 to 2 hydroxyl- and / or amino-substituted groups, respectively, or at least X ₀ and X together or X and X together represent a bivalent radical substitutable by two hydrogen atoms, and m and η are the above meanings

have, or in a salt thereof, other than hydrogen, X, X ₅ , or X, or X and X taken together or X and X together replaced by hydrogen, and / or substituted Ar present in a radical substituted hydroxy and / or amino in converted free hydroxy and / or amino, and if desired, performs the subsequent process steps referred to the first method.

The cleavage of the groups X ", X ₃ or X ₄ or in each case X ₂ and X or X, and X ₁ . together and optionally present in a radical Ar ₁ protecting groups of hydroxy and / or amino substituents is carried out by solvolysis, such as hydrolysis, alcoholysis, aminolysis or acidolysis, or by reduction, including hydrogenolysis.

Particularly suitable cleavable groups X. and X, or · hydroxy and / or amino-protecting groups in an Ar radical are primarily hydrogenolytically removable α-aryl-lower alkyl groups, such as an optionally substituted 1-polyphenyl or 1-phenyl-lower alkyl radical in which in particular of the phenyl part, eg Lower alkyl, such as methyl, or lower alkoxy, such as methoxy, and primarily benzyl. Groups X, and in particular X and X, as well as hydroxyl and / or amino-protecting groups in an Ar radical can also be solvolytic, such as hydrolytic or acidolytic, and also reductive, including hydrogenolytic cleavable radicals, especially corresponding acyl radicals, such as the acyl radical of an organic carboxylic acid, eg Lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, and also the acyl radical of a haloester of carbonic acid, such as lower alkoxycarbonyl, e.g. Methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally substituted 1-phenyl-lower alkoxycarbonyl, e.g. Benzyl oxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. Phenacyloxycarbonyl, further optionally substituted 1-Polyphenylniederalkylgruppen, wherein substituents, primarily the phenyl ·

partly, e.g. have the meaning given above, and represent trityl in the first place.

A cleavable radical formed by X- and X and / or X, and X together is primarily a hydrogenolytically cleavable bivalent group, such as optionally substituted 1-phenyl-lower alkylidene, wherein substituents, in particular of the phenyl moiety, for example, lower alkyl or lower alkoxy, and especially benzylidene, as well as solvolysis, especially hydrolytically cleavable groups such as lower alkylidene, for example methylene or isopropylidene, or-l-phenyl-lower alkylidene, whose phenyl moiety is optionally substituted by lower alkyl, such as methyl _r or Niederalkcxy such as methoxy, substituted, especially benzylidene or cycloalkylidene , eg cyclopentylidene or cyclohexylidene.

Starting materials useful in the form of salts are primarily in the form of acid addition salts, e.g. used with mineral acids, as well as with organic acids.

Hydrogenolytically removable radicals X _2, X, and / or X ,, especially optionally substituted 1-Phenylniederalkylgruppen, furthermore also suitable acyl groups such as optionally substituted 1-phenyl-lower alkoxycarbonyl, swie by the groups X 'and X_, and X, and X. ₁ together formed, optionally substituted 1-Phenylniederalkylidengruppen, as well as existing in a remainder Ar hydroxy and / or amino protecting groups of this type can be prepared by treatment with catalytically activated hydrogen, for example with hydrogen in the presence of a nickel catalyst, such as Raney nickel, or a suitable Precious metal catalyst are eliminated.

Hydrolytically cleavable groups X, X and / or X ^, such as acyl radicals of organic carboxylic acids, e.g. Lower alkanoyl, and half esters of carbonic acid, e.g. Lower alkoxycarbonyl, further e.g. Trityl radicals, and by the radicals X_ and X. and / or X, and X.

co-formed lower alkylidene, 1-phenyl-lower alkylidene or cycloalkylidene groups, and hydroxy and / or amino protecting groups of this type present in an Ar radical can be treated by treatment with water under acidic or basic conditions, e.g. in the presence of a mineral acid such as hydrochloric or sulfuric acid, or an alkali metal or Erdalkalinietallhydroxids or -scrbonats or an amine such as isopropylamine, are cleaved off.

By aminolysis, for example, as protecting groups of hydroxy groups present acyl groups and especially by X ^ and X together formed Niederalkyliden-, 1-Phenylniederalkyliden- or Cycloalkylidengruppen such as the 1-Methyläthylidengruppe be cleaved, for example by reaction with ammonia or, especially in the case of the aforementioned divalent Protecting groups, with primary amines, such as isopropylamine or benzylamine, in a suitable reaction medium, such as isopropanol or dioxane. As a primary amine, a starting material of the formula II for the former manufacturing method for the compounds of formula I can act. Therefore, man-in receives the reaction of compounds of the below angegebenen.Formel IVe in which X and X_ together one of the above-mentioned divalent protecting groups, such as isopropylidene _ 'represent, with twice the molar amount of the corresponding starting materials of formula II, which in turn also fall under the formula IVa, with cleavage of the protecting group formed from X, and X. directly end of the formula I, while said protecting group remains and the corresponding starting material of the formula IV arises when, instead of an excess of the halogenated as a hydrogen halide Compound of formula II or IVa, for example, certain inorganic bases such as alkali metal carbonates used.

Acidolytically removable radicals X, X and / or X, and / or hydroxy and / or amino protecting groups in a radical Ar are in particular

certain acyl radicals of half-esters. of carbon dioxide ,. such as. tert-Niederalkoxycarbonyl or optionally substituted Diphenylmethoxycarbonylreste, further search the tert-butyl radical; such radicals may be cleaved by treatment with suitable strong organic carboxylic acids, such as optionally substituted by halogen, in particular fluorine, substituted lower alkanecarboxylic acids, in the first place with trifluoroacetic acid (if necessary in the presence of an activating agent such as anisole), as well as with formic acid.

By reductively cleavable radicals X., X_ and / or X and / or hydroxy and / or amino protecting groups in a radical Ar are also understood to mean those groups which, when treated with .. a chemical reducing agent (in particular, with a reducing metal or

a reducing metal compound) are split off. Such radicals are especially 2-halo-lower alkoxycarbonyl or arylmethoxycarbonyl, e.g. upon treatment with a reducing heavy metal, such as zinc, or with a reducing heavy metal salt, such as a chromium (II) salt, e.g. chloride or acetate, usually in the presence of an organic carboxylic acid, such as formic acid or acetic acid, and can be cleaved from water.

Protecting groups which are present in an Ar radical optionally present hydroxy and / or amino groups correspond to the aforementioned and can be removed by the methods described and replaced by hydrogen groups, such groups in the course of the process described. Simultaneously with other groups or subsequently in a separate process measure, be split off.

The above reactions are usually carried out in the presence of a solvent or solvent mixture, suitable reactants also functioning as such at the same time.

and, if necessary, cooling or heating, e.g. in, an open or closed vessel and / or in the atmosphere of an inert gas, e.g. Nitrogen.

The starting materials of the formula TV can be obtained inan¬ known manner by preparing a starting material, wherein m is 0, for example, a compound of formula Ar-H with a haloacetyl halide, for example chloroacetyl chloride, in the presence of a suitable Lewis acid, eg. Reacting aluminum chloride, according to the Friedel-Crafts method ,, the carbonyl group in the thus obtained or in other, conventionally obtained Ar-haloacetyl compound, for example by Natfiumborhydrid _/ to Carbinolgruppe- reduced and the resulting compound with an amine of the formula

, (O) _n _- ^ ly _co / 5 (IVa)

-> 2

wherein X has the meaning given, and X. or X. and X_ together are different from hydrogen, is reacted.

Starting materials of the formula 'IV, wherein' m has the above meaning, are obtainable by reacting a compound of the formula II explained above with a compound of the formula IVa. This reaction is carried out in a conventional manner.

It is also possible to e.g. by reacting a compound of the formula

Ar ₁ - (CHj.-CH-CH ₀ -NH "(IVb)

12m Ll

Π η r:;

-JQ-

with a carbonyl compound of the formula

R - (O) -S- ^ A ₅ . / _IV \

η · '»-CON vivc;»

O S =

wherein R represents an alkyl radical corresponding to the alkylene radical alk, an alkyl radical containing a carbonyl group separated from the oxygen atom or phenyl radical by at least one carbon atom, and X or X.

AA

and X ₅ together represent one of the specified protecting groups, Schiff base formed with a stock hydride _s about NstriuHiborhydrid sur sur compound of formula IV reduce. The reduction can also be activated by. Hydrogen in the presence of a Hydx'ierkatalysators, for example, a platinum-on-carbon catalyst done.

Amines of the formula IVb in which X represents hydrogen or a group which can be split off by means of reduction, including hydrogenolysis, and which can be replaced by hydrogen, can be used, for example. by reacting a compound of the formula

, Ar- (CHj - CH - CH ₀ - (Z ₁ IVd),

12m Zl

wherein X and Z have the meaning given under the formula (It), with ammonia or a by reduction including hydrogenolysis, e.g. as indicated, releasable amine containing hydrogen substitutable radical, z.3. Benzylamine, manufactured.

Carbony compounds of formula (IVc), wherein η is the value 1, can be prepared by reacting a compound of the formula

κ4

^H0 - <f "Χ -«, / ⁵ ("β)

I SS ·

with a compound of the formula R-Hal (IVf), wherein R has the above meaning, and a compound (IVf) e.g. a haloketone, e.g. Chloroacetone is obtained in the usual way.

From the abovementioned compounds of the formula (IVe) it is also possible by reaction with non-geminal, in particular vicinal dihalo-lower alkanes, especially dibromo or bromo-chloro-lower alkanes, to have compounds of the formula , , ,

Hal-alk-O / - \ _ _co _ / ^ 5 (IVg) '

in which shark is a bromine or chlorine and R "alk, X, and X have the abovementioned meaning, and these react with compounds of formula IVb to the starting materials of formula IV, wherein, as already erwä-hnt, optionally directly end products of Formula I arise. · · · ·

The novel compounds of the formula I can also be obtained by reacting in a compound of the formula

Ar- (CHJ-Y-X- (O) __Jil- \ A

_ ^{2 2 m 6 n} - ™ ~ T ^ \ «con ( ¹ (ν),

wherein X, a reducible group of the formulas -CH-N-Alk - (Va), or -CH-N = alk - (Vb)

or - C (= X_) - N (X ₀ ) - alk - (Vc) or

- CH- - N (X ₀ ) - C (-X.) - alk. - "(Vd) or a group

-CH- - N (X) - alk - (Ve), where alk is the radical alk 2. ρ 1

corresponding alkyl-ylidene and alk- to a bound to the nitrogen methyl group truncated alk, X is the oxo or thioxo and X is hydrogen or one under the conditions for the reduction of X _c and / or Y by hydrogen

represents a substitutable radical, and Y is a radical of the formula -CO- (Vf) or * -CH (OX ₀ ) - (Vg), in which X _{0 has} the meaning indicated above, Ar. corresponds to a radical Ar, but optionally

instead of in each case one or two hydroxy and / or amino one or two groups-OX ₀ , and / or -N (X ₀ ) -, in which X has the meaning indicated above, m, and η have the above meanings, wherein always X _fi a reducible group Va to Vd undyoder Y is a carbonyl group Vf, this (group (s) is reduced and the non-hydrogen groups X- replaced in the same operation by hydrogen, and, if desired, the additional ^ subsequent to performs the first method steps mentioned.

A hydrogenolytically removable group X ₀ is primarily

an δ-aryl-lower alkyl group such as an optionally substituted 1-phenyl-lower alkyl group, wherein substituents. e.g. Lower alkoxy, such as methoxy, and especially benzyl.

Protecting groups attached to the rest of ar. optionally substituted hydroxy and / or amino groups, correspond to the previous

mentioned for X ₀ and cleavable by the methods described '8

and by hydrogen replaceable groups, such groups vobei during AES method described simultaneously be split off in a separate Verfahrensraassnahme below with other groups or.

Starting materials of the formula V having a group X _{fi of} the formula Vb can also be used in the isomeric form of ring tautomers of the formula

Ar - (CH) --Cl-CH

2 2 m -2

(Vh)

where alk_ is the meaning of alk. and the oxygen and nitrogen of the ring are bonded to the same carbon atom.

5 7 1 »- 39

% ß ff% - ³ ^

An alkyl-ylidene group alk. is e.g. , l-Aethyl-2-ylidene methyl-l-ethyl-2-ylidene, while a Alkylidengi represents methylene, ethylidene or 1-methyl-ethylidene.

or 2-methyl-1-ethyl-2-ylidene, while an alkylidene group alk.

.. The reduction of the nitrogen-carbon double bond in starting materials of the formula V, denoted as X ,. contain a group Va or Vb,

while Ar ₀ , Y, X and η have the meaning given under the formula V (or in the isomeric compounds, the formula Vg of the oxygen-carbon-nitrogen bond) to the nitrogen-carbon single bond can in a conventional manner, eg by treatment with catalytically activated hydrogen, such as hydrogen in the presence of a suitable hydrogenation catalyst, such as a nickel, platinum or palladium catalyst carried out, wherein hydrogenolytically cleavable groups X _{0 are} simultaneously eliminated and replaced by hydrogen ;, or one works with a suitable hydride reducing agent, vie one Alkali metal borohydride, eg sodium borohydride. In all cases, at the same time with the group Va or Vb also, if

present, a carboxyl radical Y reduced to Hydroxyiasthylenrest, and when using Eydridreduktionsmittel also bonded to oxygen acyl radicals of carboxylic acids, such as acetic acid, can be present as radicals X ₀ and cleaved in the same operation.

The reduction of the carbonyl group Y in starting materials of the general formula V, which contain a group Ve as the radical X, while Ar ₀ , X ₀ and η have the meaning given under the formula V, can in the above for the reduction of the groups' Va and Vb indicated manner, which in turn can be split off hydrogenolytically in the catalytic hydrogenation corresponding radicals X ₀ .

Particularly suitable for the reduction of compounds of the formula V with a group 'of the formula Ve or Vd and the meanings defined by the formula V of Ar ₉ , Y and η are hydride reducing agents, such as sodium borohydride or diborane.

Simultaneously with the reduction of a group Vc or Vd is the reduction of a carbonyl group Y, if present, and dj.e elimination of oxygen-bonded acyl groups of carboxylic acids, such as acetic acid, as X _g . On the other hand, by restricting the amount of the reducing agent and appropriately selecting the reducing conditions, it is to be ensured that the aromatic-bonded carboxamide group is not reduced. Groupings of formulas Ve and Vd, wherein each X- represents a thicxo group, are replaced by reductive desulfurization, 2.B. by treatment with a hydrogenation catalyst, such as Raney nickel, into the grouping of the formula -CFL-NR-alk- converted. The above

Reduktionsreaktionen.werden in per se known. Usually, in the presence of an inert solvent and, if necessary, with cooling or heating, e.g. in a temperature range of about -20 ° to about + 150 °, and / or in a closed vessel under pressure and / or in an inert gas, e.g. Nitrogen atmosphere, carried out.

A starting material of the formula V in which m is 0 can be prepared in a manner known per se, if appropriate in situ, ie under the conditions of the process described. Thus, one can acetylate a compound of the formula Ar ₀ - H (Vi) with an acetic acid halide or anhydride in the presence of a Lewis acid and. in the obtained intermediate, the acetyl group is then converted into the glyoxyloyl group, for example by treatment with a suitable oxidizing agent such as selenium dioxide. Such a glyoxyl compound, or, if desired, a suitable derivative thereof, such as an acetal, may then be reacted with an amine of the formula

(Vj)

to a starting material of formula V with group X of formula Va ', wherein Y represents the carbonyl group. One can further

 f

- Pr

a compound of formula (Vi) with a haloacetyl halide, e.g. Chloroacetyl chloride, in the presence of a suitable Lewis acid, e.g. Aluniniumchlorid, according to the Friedel-Crafts Mathode halogenacetylieren to the corresponding Ar ^ -Chloracetyl compound halogeno, in the thus or otherwise obtainable haloacetyl compound by treatment with a suitable hydride reducing agent reduce the carbonyl to carbinol group, and the halogen atom by treatment with ammonia or a suitable derivative thereof, such as hexamethylenetetramine, and decomposing the formed reaction product with dilute acid, such as aqueous hydrochloric acid, into the primary amino group, followed by an intermediate of formula

Ar - (CH) - CH - CH ₀ - NH ₀ (Vk)

/ ζ m. / 2

OH

where m is 0. Amines of the formula VK in turn, wherein m has the above meaning, are e.g. by reacting a compound of the formula

Ar- (CH-) - CH- CH_ - Z ₁ (VI)

Z Z m / 1

wherein X and Z are as defined under formula (II), with ammonia or an ammonia-providing compound, e.g. Hexamethylenetetramine, obtainable in a known manner, wherein compounds of formula (Vl) can be obtained analogously to the procedure described for the preparation of starting materials of the formula (II).

Amines of the formula Vk, wherein m has the above meaning, can'ausdem also by reacting an aldehyde of the formula

Ar - (CH ₀ ) - CHO (Vm) λ m

or a suitable derivative thereof, such as an acetal, e.g. dimethyl acetal, or a bisulfite addition compound, with a suitable organosilicon cyano compound, such as a tri-lower alkyl, e.g. Trimethylsilyicyananid, in the usual manner in the presence of a catalyst such as zinc iodide, to a compound of formula

• CN

Ar - (CH ₀ ) - CH (Vn);

^2m \

P-Si (CH ₃ ) ₃

and their conversion by means of a suitable reducing agent, e.g. a non-noble metal hydride, such as lithium aluminum hydride, in a solvent, usually comprising an ethereal liquid, e.g. Diethyl ether or tetrahydrofuran serves to obtain a compound of the formula Vk. where m has the above meaning.

By reacting an intermediate of the formula Vk with a carbonyl compound of the formula

o - _alki - (O) _n Xco / ^{1 CVo)} '

can be converted to starting materials of the formula V with a group X of

Get formula (Vb). A modification of these reactions is that in the above-described intermediate, instead of replacing the halogen atom with the primary amino group by treatment with ammonia, etc., it reacts with a 1-aryl-lower alkylamine, e.g. Benzylamine or a di- (1-aryl-lower alkyl) -amine e.g. Dibenzylamine is exchanged for the corresponding 1-aryl-lower alkylamino or di- (1-aryl-lower alkyl) -amino group and the compound obtained, for example the corresponding dibenzylamino compound, with the oxo compound of the formula (VI) under the reducing

3-r-

the conditions of the procedure. Here, the reducing agent used is primarily catalytically activated hydrogen, e.g. Hydrogen in the presence of a Schwermetallhydrierkatalysators or a mixture thereof, such as a palladium and / or platinum catalyst. Under such reaction conditions, hydrogenolytically cleavable groups X, e.g. Benzylgruppen. Cleaved, which optionally carbonyl to the carbinol group and at the same time reduces the nitrogen-carbon double bond to the corresponding nitrogen-carbon single bond.

Oxo compounds of formula ⁷ Vo in turn, wherein η is 1, are, for example, by reacting a dihydroxy compound of the formula

with a haloalkanone compound of the above-explained formula R - Hal (IVf), e.g. Chloroacetone, in the presence of an alkaline condensing agent, such as potassium carbonate, or an organic base, such as triethylamine, available.

Starting materials of the formula V with a group X _r of

Formula Vc or Vd can be prepared in a manner known per se, for example by adding a monomeric compound of the formula Ar _n - (CH) -CHO

2 2m

(Vq) is reacted with hydrogen cyanide and in the thus obtainable cyanohydrin intermediate the cyano to the carboxyl group, e.g. under acidic conditions, hydrolyzed. The so or through the intermediates imide chloride,. Ar -2 -hydroxyacetic acid obtained in the presence of a suitable condensing agent, e.g. of a carbodiimide, such as dicyclohexylcarbodiimide, with an amine of the formula (Vj), to give a starting material of the formula V · with the group X.

of formula (Vc).

Furthermore, by reacting a compound of formula Vk with a compound of formula

Hal - C (= 0) -alk - (O) ^ - ~ \ Λ · <* r)

• . ^u \ / V,

wherein Hal represents halogen and in particular chlorine, a starting material of the formula (V) with the group X, the formula (Vd). Further, in the above-mentioned Ar 1 -chloroacetyl compound, the chlorine may be exchanged with the primary amino group by reaction with hexamethylenetetramine, and a compound thus obtained

react with a halogen compound of the formula Vr. In a thus-obtained starting product der.Formel V with a group X ,. of the formula '.Vd and wherein Y represents the carbonyl group, it is possible to simultaneously reduce the carbonyl to the carbinol group and the aliphatically bound carbamoyl group to the group of the formula -CH- -N-alk- _} etv7a

by means of a hydride reducing agent, in particular diborane.

The novel compounds of the formula I can also be obtained by adding a compound of the formula

CB ₂ - H - .Ik - CO) _n

wherein Ar has the meaning of Ar, or represents a radical Ar, which is convertible by 1 to 2 by aminolysis in hydroxy and / or amino and / or substituted by groups of the formula -COOH, X is hydrogen or an aminolysis cleavable group , and m and η have the above meanings, or a reactive derivative of one of the carboxylic acids defined in formula VI, with a compound of the formula HNR R (VII) and optionally present, by means of aminolysis in hydroxy

and / or converts amino-convertible radicals into hydroxy and / or amino, and / or optionally splits off any radicals X present and replaced by hydrogen, and, if desired, carries out the additional process steps referred to in the first process. Hydrolytically and in particular by means of aminolysis in hydroxy and / or amino convertible radicals or radicals cleavable in this way X are acyl radicals of organic carboxylic acids, eg Aroyli, such as benzoyl, or lower alkanoyl, such as acetyl.

Reactive derivatives of the carboxylic acids defined in formula VI are, for example, the halides, such as the chlorides or bromides, furthermore the azides, and acid anhydrides in particular mixed acid anhydrides with, for example, lower alkanecarboxylic acids, such as acetic acid or propionic acid, lower alkoxyalkanecarboxylic acids, such as 2-methoxyacetic acid. Reactive derivatives of carboxylic acids of the formula VI are in particular esters, 2.B. with lower alkanols, such as methanol, ethanol, isopropanol, tert-butanol, furthermore with aryl-lower alkanols, possibly optionally lower alkyl, eg methyl, or lower alkoxy, eg methoxy, substituted benzyl alcohol, or phenols, which are optionally activated by suitable substituents, eg halogen, about 4-halogen, such as' 4-chloro, lower alkoxy, such as 4-lower alkoxy such as 4-methoxy, 4-nitro or 2,4-dinitro, such as 4-chlorophenol, 4 ~ methoxyphenol, 4-nitro or 2 _S 4 -Dinitrophenol, further esters with cycloalkanols, such as cyclopentanol or cyclohexanol, which may optionally be substituted by lower alkyl, eg methyl. The reaction is carried out in a conventional manner, usually in the presence of an inert solvent, for example in a temperature range of about -.10 ° to +50 ⁰ C in a closed vessel.

The starting materials of the formula VI in which m is 0 can be obtained in a manner known per se by reacting a compound of the formula Ar. - COCH brominated, the carbonyl group in the thus obtained

-ACT-

Ar -haloacetyl compound to carbino group, e.g. using diborane, reduced and the resulting compound with an amine of the formula

wherein X has the meaning indicated, or a reactive derivative thereof, is reacted. It is also possible to react the Ar-haloacetyl compounds with the amine of the formula VIa and subsequently convert the carbonylin into the carbino group.

For the preparation of starting materials of the formula VI in which m has the above meaning, it is also possible by reacting a compound of the formula

Ar- (CHj-CH-CH "-NH ₀ (VIb) OH

with a carbonyl compound of the formula

• - / 'S

^ V ^(VIC)

wherein R represents the alkyl radical alk corresponding to a carbonyl group-containing alkyl radical, i. to an oxoalkyl radical, reduce Schiff's base formed with a borohydride, such as sodium hydride.

The reduction can also be carried out by means of activated hydrogen in the presence of a hydrogenation catalyst, e.g. a platinum-on-carbon catalyst. , ,

Compounds of formula -VIb in turn are e.g. by reacting a compound of the formula

Ar ₃ - (CH _{3 m} - CH - CH - Z (VId)

J * -

wherein X and Z together are epoxy, or X is hydroxy and Z is a reactive esterified hydroxy group, e.g. Halogen, such as chlorine, with ammonia, or, if X is hydroxy and Z is e.g. Chlorine, with hexamethylenetetramine and decomposition of the adduct formed with dilute mineral acid, such as dilute hydrochloric acid, obtainable, wherein starting materials of formula VId can be prepared analogously to the method described for the preparation of starting materials of the formula II.

Carbonyl compounds of the formal (VIc) in turn, wherein η 1 be, can be prepared by reacting a compound of formula

HO. / " ^X 9

with a compound of the formula R-Hal (IVf), where Hal is halogen, in particular chlorine, in a manner known per se.

The novel compounds of the formula I in which R and R "each represent a substance, can be a compound of the formula

Hydrogen can also be obtained by placing in

Ar- (CH _{2) m} ^ CH - CH ₂ - N - alk- (O) _n - - ^ \ ^ (VII),

^HN '

OH. , ^{H. N} - '

in which one or both hydroxy groups and / or present in the radical Ar hydroxy and / or amino groups are optionally protected by such auslösaltbaren 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 optionally together with the said protected hydroxy and / or amino groups the group -CN is present, the groups -CN by means of .Hydrolysis in the group -C0NH "and simultaneously optionally protected hydroxy" and / or amino groups in free hydroxy and / or amino groups

converts, and, if desired, performs the additional method steps subsequently referred to the first method.

The starting materials of formula VII can be prepared in a conventional manner by reacting a compound of formula

Ar - (CH) - CH - CH - NH (VIIa)

, ² mj 2 2

^; - OH with a compound of the formula

Hal-alk- (O) -f-

• ce

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

Starting materials of formula (Vila)., In which m has the above meaning, are obtained by reacting a compound of formula (II) wherein X and Z together represent the epoxy group with ammonia, or when X is hydroxy and Z as 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., Available.

Starting materials of the formula (VII) wherein m is 0 can be further prepared in a conventional manner by e.g. a compound of the formula Ar-COCH (VII c) halogenated, ζ..B. brominated, such as by bromine in an inert solvent, such as chloroform, in the resulting Ar-haloacetyl-, z, .B. bromoacetyl compound, the halogen through the amino group, e.g. by. Reacting with hexamethylenetetramine in a solvent, such as a chlorohydrocarbon, as replacing chloroform, the resulting adduct with diluted mineral

acid, ζ.3. Hydrochloric acid is decomposed, in the resulting compound of the formula Ar-CO-CH ₂ -NH ₂ (VIId) the carbonyl group to the carbinol group, for example by means of diborane, reduced and the compound of the formula 1 obtained

Ar -, CH - CH - NH (VIIe)

Ί ² '

OH

reacted with a compound of formula VIIb explained above in the manner indicated there.

In turn, a compound of formula VIIb can be obtained by the action of acetic anhydride on the oxime corresponding to the cyanide. This is conveniently done by boiling under reflux. For my part, the oxime can be refluxed from the corresponding aldehyde by boiling with hydroxylamine hydrochloride in the presence of alcoholic sodium carbonate solution. The corresponding aldehyde in turn can be prepared by reacting 2,4-dihydroxybenzaldehyde with a cc, β, α, γ or α, μJ-dihalo-lower alkane, preferably in the presence of a basic agent. It is also possible in an analogous manner a hydroxysalicylonitrile, such as 2,4-dihydroxybenzonitrile [Chem.Ber. 24, 3657 (1891)] or the 2,5-dihydroxybenzonitrile [HeIv, Chim. Acta JKD 149, 153 (1947)] with a non-geminal dihalo-lower alkane to give a compound of formula VIIb.

The novel compounds of the formula I in which m is 1, 2 or 3 can also be obtained by reacting in a compound of the formula

OH'

• A / ^R l

Ar - X - CH - CH - A - (O) K - Γ °° ^Ν _v (VIII).

OH

A (O) K Γ _v 2 η * · \

V R

where A is the group -N-alk-or -N = alk -, in which alk ^ represents the group having a methyl group which is less alkene, and X is converted into a methylene, 1,2-ethylene by means of reduction, including hydrogenolysis, or 1,3-propylene group, and one or both hydroxy groups and / or optionally present in the radical Ar hydroxy and / or amino groups are protected by such means'reduction, including hydrogenolysis, cleavable and substitutable by hydrogen groups

are, which are cleaved under the conditions of the process and replaced by hydrogen, the group X by reduction including hydrogenolysis in a methylene, 1,2-ethylene or 1,3-propylene group and at the same time an optionally present unsaturated group A in the saturated Group A, and simultaneously optionally present protected hydroxy and / or amino groups in the free hydroxy and / or amino groups, and, if desired, performs the additional method steps subsequently mentioned in the first method.

In particular, a group X represents a carbonyl group instead of a methylene group, which either stands alone according to the meaning of m as 1, 2 or 3 or occupies each of the possible positions together with one or two methylene groups. A group X also provides a di- or triunsaturated group having 2 to 3 carbon atoms, e.g. a 1,2-aethenylene, 1,2-propenylene, 2,3-propenylene or 1,2-ethynylene or 1,3-propynylene group. represents.

The reduction of the group X in the customary manner, for example by means of activated hydrogen, eg hydrogen in the presence of ¹ Hydrxerkatalysators such as a nickel or if appropriate on a carrier material such as activated carbon, the deposited noble metal catalyst such as platinum or _palladium; or a platinum or palladium on carbon catalyst

optionally present hydrogenolytically removable cleavable hydroxy and / or amino protecting groups and replaced by hydrogen. The reduction, including hydrogenolysis, is carried out in a manner known per se, usually in the presence of an inert solvent at normal or elevated pressure and at normal or elevated temperature.

Starting materials of the formula VIII ₅ in which X is a group of the formulas -CO- (VIIIa) ₅ -CO-CH- (VIIIb), or -CO-CH-CH - (VIIIc), and in the radical Ar, as indicated above, protected Hydroxy and / or amino groups are present, can be obtained in a conventional manner by reacting in a compound of formula

Ar - X - CH = CH ₂ (IX)

the group -CH = CH 'epoxidizes to the group -CH - CH ₉ (cf.

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 an optionally substituted, such as halogenated, aliphatic or aromatic peracid, e.g. Peracetic acid or trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid in an anhydrous solvent, e.g. Chloroform or dioxane. Subsequently, the obtained compound or a compound thereof, e.g. by reaction with a hydrohalic acid, e.g. Hydrochloric acid in a solvent such as dioxane, compound of the general formula '

Ar -X-CE-CH ₂ -Z ₃ (X) in which X and Z together are epoxy or X is hydroxyl and Z is halogen, eg chlorine.

means, rait. Ammonia, or if X ₂ and Z .Halogen, with hexamethylenetetramine and subsequent decomposition of the resulting adduct with a dilute mineral acid, for example hydrochloric acids, in a compound of formula

Ar - X - CH - CH - NH ( _XI )

I ^{Z A} OH

convert. From this can be by reaction with a compound of the formula

Hal-alk '- (O)

(XII)

wherein Hal is halogen and in particular chlorine, a starting material of the formula VIII with the group A of the formula -N-alk-, or

by reaction with a compound of the formula

OH

\; - ^CON \

^R 2

wherein alk has the above meaning, a starting material of the formula VIII, wherein the group A of the formula -N = alk -, produce. These reactions are carried out in a manner known per se, e.g. When reacting with a compound of formula XII, an alkaline condensing agent, e.g. an alkali or alkaline earth carbonate, such as sodium or calcium carbonate.

Starting materials of the formula VIII in which X is a di- or triunsaturated group having 2 to 3 carbon atoms, and A has the meaning given can be obtained by reacting a compound of the formula

Ar-X-CHO. (XIV)

wherein X represents a di- or triunsaturated group having 2-3 carbon atoms, or a suitable derivative thereof, such as an acetal, e.g. the dimethyl acetal, or a bisulfite addition compound, with a suitable silicic acid-organic cyano compound, such as a tri-lower alkyl, e.g. trimethylsilyl; in the usual way in the presence of a catalyst such as zinc iodide, in a compound of formula

CN Ar - X - CH (XV)

^{X is} Si (CH ₃ ) ₃

in which the group, -CN by reduction, with simultaneous replacement of the trimethylsilyl by hydroxy in the. 'Group -CH NH transferred. As the reducing agent, e.g. use a non-noble metal hydride, such as lithium aluminum hydride, in a suitable solvent, usually an ethereal liquid, e.g. Diethyl ether or tetrahydrofuran. "The compound of the formula obtained hereinafter

Ar - X - CH - CH - NH (XVI)

I OH '

can then be reacted with a compound of formula XII described above to give a compound of formula (VIII), wherein A represents the group of the formula -N-alk ~ '; or you put one

Η, compound of the formula XVI with a compound of the above-described formula (XIII) in order to obtain a starting material of the formula VIII wherein A is the group of the formula -N = alk -.

These reactions are carried out in the usual way.

- .48 '-

Care must be taken when selecting the appropriate method above for the preparation of compounds of the formula, that existing substituents, in particular the radicals Ar, are not converted or cleaved, if such conversions or splits are not desired. In particular, functionally modified carboxyl groups, such as esterified or amidated carboxyl groups, and cyano groups, as substituents of the radicals Ar during solvolysis, can in particular

special hydrolyses, also involved in reducing the reaction; be and be transformed. On the other hand, simultaneous conversions of substituents may be desired; e.g. may be unsaturated substituents, such as lower alkenyl, under the conditions of a reduction method used according to the invention, e.g. to lower alkyl.

In the compounds obtained, in the context of the definition of the compounds of the formula I, it is possible in the customary manner according to the process to convert the compounds obtained into other end products, e.g. by modifying, introducing or eliminating suitable substituents.

Thus, in obtained compounds in the radical Ar standing unsaturated substituents such as lower alkynyl or .. Niederalkinyloxy, or lower alkenyl or Niederalkenyloxy, 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 transferred by Aimnono-.lyse or aminolysis with ammonia or a primary or secondary • amine in the corresponding Carbamoy! group.

: I D Ό / ϊ -VS-SO-

Compounds having a carbamoyl group in the group Ar and groups other than hydrogen R and R may be prepared in a conventional manner, e.g. by the action of dehydrating agents such as phosphorus pentoxide or phosphorus oxychloride, preferably at higher temperatures dehydrated to the corresponding cyano compounds.

In compounds having a cyano group as substituents in the radical Ar, this can be prepared in the usual way, Z..B. by the addition of alcohols in the presence of an anhydrous acid such as hydrogen chloride, and subsequent hydrolysis of the resulting imido ester are alcoholysiert · to the corresponding compounds with esterified carboxyl groups.

In compounds having a nitro group as a substituent in the radical Ar, it may be reduced to the amino group, e.g. by catalytically activated hydrogen such as hydrogen in the presence of a hydrogenation catalyst, such as Raney-Nicke.1 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 corresponding 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 Methansulfensäureester, conveniently in the presence of a basic agent such as an alkali metal hydroxide or carbonates.

In compounds having a primary amino group in the radical Ar, these can be converted into the ureido, N'-lower alkylureido or Ν, Ν'-di-lower alkyl

ureido group ₁ z ".B. By reaction with cyanic acid or a

25 5

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.

Compounds having a primary amino group in the radical Ar may be converted to a lower alkylsulfonylamino group, e.g. by -translation with a. Lower alkylsulfonyl 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 that undesirable side reactions, which may result in the conversion of additional groupings, do not occur.

The reactions described above may, if desired, be carried out simultaneously or successively, furthermore in any order. If necessary, they are in the presence of diluents, condensing agents and / or catalytic agents, at reduced or elevated temperature, in the \. 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 new compounds or salts thereof to be present as remi, mono, sesquic or polyhydric. 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 with organic or inorganic acids, for example, with the acids mentioned, can form acid addition salts, in particular those for their preparation

"'*" - 31 "- SZ

Acids are used 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 can, due to the physicochemical differences of the diastereoisomers in a known manner, e.g. by chromatography and / or fractional crystallization, are separated into the two stereoisomeric (diasterebmeren) 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 reacting with an optically active substance forming the racemic compound, in particular acids, and separating the salt mixture thus obtained., 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-formates of tartaric acid, di-0,0 '- (p-toluoyl) tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamine

- 52 '- S3

acid, aspartic acid or quinic acid. Advantageously, one isolates the more effective of the two antipodes.

The invention also relates to those embodiments of the method according to which starting from a compound obtainable as an intermediate at any stage of the process and carrying out the missing process steps, or terminating the process at any stage, or wherein forming a starting material under the reaction conditions, or in which a reaction component is optionally present in the form of their 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. New starting materials also form an object of the invention. The invention also provides intermediate process products obtainable by the process.

The new compounds may e.g. in the form of pharmaceutical preparations which contain a pharmacologically effective amount of the active substance, optionally together with pharmaceutically acceptable tracers, 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 glycerin and / or lubricants, for example ' Silica, talc, stearic acid or salts thereof, such as magnesium or

-5a: .-

Calciurnstearat, and / or polyethylene glycol, have. Tablets may also contain binders, e.g. Magnesium aluminosilicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, mathylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, disintegrants, eg 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, for example, 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 osmotic 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, granulating, coating, dissolving or lyophilization processes, and containing from about 0.1% to 100%, in particular from about .1% to about 50%, lyophilisates up to 100% of the active substance.

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 single doses, when administered orally to warm-blooded animals for β-receptor blockers of the formula I are 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 β- receptor stimulants of the formula I 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.

58 303/18

Out of the way s e pi e1

The following examples serve to illustrate the invention; Tempatures are given in degrees Centigrade.

In the case of compounds which have zirconium centers and therefore could exist as mixtures of diastereomers, the relative content of the two diastereomers (enantiomeric

1 °

Couples) by ^ C-IIMR spectroscopy on the relative intensity of the two C ~ methyl signals at 13-3 + 0.1 ppm

T3

and 13.6 + 0.1 ppm, respectively. The C ~ spectra were recorded in DMSO-dg. on a Varian XL-100 instrument at 25.16 MEIz using Tetramethylsilian as an internal standard (digital resolution 0 _s 8 points / Hz) ", salts were investigated as bases with acids (z * B. 1 Equivalent fumaric acid) to achieve separation of the methyl signals _e

A solution of γοη 1.96 g of 5- (2-Aminoäthoxy) ~ salicylamide in 15 ml of anhydrous dimethyl sulfoxide is treated with 2.4 g of 2,4-dichloro-1- (eposyäthyl) benzene and The reaction mixture was stirred for 30 minutes in a bath at 80 ° C., poured into 30 ml of ice-water and extracted with 100 ml of ethyl acetate. The organic phase was separated off, dried over magnesium sulphate and evaporated. The evaporation residue is stirred with 20 ml of petroleum ether, filtered off with suction and the crystals obtained are recrystallized from methanol after which _f dene;, - [tTF [2- (3 ~ ~ 4 ~ hydroxy ~ carbamoyl phenoxy) -äthylj 3iiinomethylj ~ ~ ~ 2.4 dichlorobenzyl, mp _s 139 - HO ⁰ gets "

The 5- (2-aminoethoxy) -salicylamide required as starting material can be prepared as follows:

58 303/15

a) by Irvine et al. Synthesis method described JJ972_ ₅ 568 2 benaoxazin 3-j5 ~ dihydroxy- ^ = ben2i8 iid using an excess of acetone in _2} 3-dihydro-2,2-dimeth3 ^r l ~ 6- "hydroxy-4H-1 ~ ₅ 4 ~ on of the Smp «215 - 216 ° transferred · - ..

~ 57-

b) A mixture of 70 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one, 75 g of dried potassium carbonate and 400 ml of 1,2-dibromoethane is used during 14 Stir under stirring and reflux. The mixture is cooled and filtered, the residue thoroughly stirred with 400 ml of water, filtered off with suction and the residue dried in vacuo at 80 °. This gives crude 6- (2-Bromäthoxy) -2,3-dihydro-2,2-dimethyl-4H-l, 3 ~ benzoxazin-4-one, mp. 190-200 °, which is sufficiently pure for further reactions. Recrystallization from methanol gives a pure product of mp. 205-208 °.

c) A mixture of 60 g of 6- (bromoethoxy) -2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one and 110 ml of benzylamine is placed in a bath of 80 ° for 30 minutes touched. The reaction mixture is then on with ice cooling with conc. Hydrochloric acid brought to pH 3-4 and allowed to crystallize. After 2-4 hours, the crystals are filtered off, washed with 50 ml of water and ethyl acetate and dried. The resulting 5 - [(2-benzylamino) ethoxy] -salicylamide hydrochloride melts at 214-216 °. The liberated base melts at 107-108 ° (from Aet'hylacetst ether).

d) Catalytic debenzylation of .alpha. - [(2-benzylamino) ethyl] salicylamide in methanol by means of a palladium-on-carbon catalyst (5% strength) gives 5- (2-aminoethoxy) -salicylamide of the mp. 140 °.

Example 2 : Analogously to Example 1, 17.4 g of 4-chloro-1f (epoxyethyl) -3-nitrobenzene and 11.4 g of 5- (2-aminoethoxy) salicylamide in 50 ml of dimethyl sulfoxide give the a- [N- [ 2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -4-chloro-3-nitrobenzyl alcohol, m.p. 167-168 ° (from ethyl acetate).

Example 3 8 g of 2-chloro-5- (epoxyethyl) benzenesulfonamide and 5 g of 5- (2-aminoethoxy) salicylamide are dissolved in 40 ml of dimethyl sulfoxide and the solution is heated to 90 ° with stirring for 65 minutes. On-

- SB '

The mixture is then cooled, the reaction mixture poured onto ice-water and extracted with ethyl acetate. The organic phase is then treated with 1-n. Extracted aqueous methanesulfonic acid, the acidic phase made alkaline with ammonia and extracted several times with ethyl acetate. After drying the organic phase over sodium sulfate, the solvent is removed on a rotary evaporator and the residue is recrystallized from isopropanol. After repeated recrystallization from methanol to give the a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethyl] aminomethyl] -3-sulfamoyl-4-chloro-benzyl alcohol of mp. 193-195 °.

, The 2-chloro-5 - (epoxyethyl) benzoisulfonamide required as the starting material can be prepared as follows:

a) A solution of 20 g of 5- (bromoacetyl) -2-chlorobenzenesulfonamide. (DE-OS 26 01 598) in SOO ml of methanol is added portionwise at 0-5 ° within 1 L / 2 hours with 13.5 g of sodium borohydride, «is stirred for 3 hours at room temperature on, removed .The solvent on a rotary evaporator and partition the residue between water and ethyl acetate. The organic phase is dried, evaporated and the residue recrystallized from ethyl acetate / ether to give the 2-chloro-5- (epoxyethyl) -benzenesulfonamide, mp. 126-129 °.

Example 4: A solution of 21.9 g of 4- (2-Aminoäthoxy) -salicylamide and 30.3 g of cr-CBrommethyO ^ -nitrobenzylalkohol in 250 ml of ethanol is added after addition of 20 g of potassium bicarbonate for 12 hours under reflux and. Cooked. After cooling and filtration, the filtrate is evaporated and the residue between 50 ml of 2-n. Hydrochloric acid and 100 ml of ethyl acetate. The aqueous phase is evaporated and the residue is recrystallized from methanol. The a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) ethyl] aminomethyl] -4-nitr © benzyl alcohol is obtained as the hydrochloride; Mp 231-233 ° (from methanol).

The 4- (2-aminoethoxy) -salicylamide required as starting material is obtained as follows:

a) 16.2 g of the example 8b) obtained 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-l, 3-benzoxazin-4-one are analogous to Example Ib) with 84 ml of 1.2 -Dibromäthan reacted and give the 2,3-dihydro-2,2-dinethyl-7- (2-bromoethoxy) -4H-l, 3 ~ benzoxazin-4-one, mp. 156-158 ° (from isopropanol).

b) 53 g of 2,3-dihydro-2,2-dimethyl-7- (2-bromoethoxy) -4H-l, 3-benzoxazin-4-one and 94 g of benzylarain are boiled with stirring for 3 hours. The reaction mixture is treated with conc. Ammonia made alkaline, and the organic phase at max. 50 ° evaporated. The 4- [2- (senzylamino) -ethoxy] -salicylamide thus obtained forms an OeI, whose hydro-chloride melts at 252-254 ° '(from methanol). :

c) Catalytic Deberizylation of 4 - [(2-Benzylamino) -ethoxy] -salicylamide. Example 3 gives the 4- (2-aminoethoxy) -salicylamide of mp. 126-130 ° (from isopropanol).

Example 5: A mixture of 16.4 g of N- [5- (2-bromo-1-hydroxyethyl) -2-chloro-phenyl-methanesulfonamide, 14.7 g of '5- (2-aminoethoxy) -salicylamide and 5 g Potassium bicarbonate in 10.0 ml of isopropanol is boiled for 25 hours with stirring and reflux. The reaction mixture is filtered, the filtrate evaporated and between ether and 2-n. Hydrochloric acid distributed. The aqueous phase is made alkaline with solid potassium bicarbonate and the mixture is extracted with ethyl acetate. From the foam obtained after evaporation gradually crystallized from a little Aethy1- acetate of a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethyl] aminomethyl] -3- (methylsulfonylamino) -4-chloro benzyl alcohol of the mp 139-141 °. He forms a neutral Fuinarat of the Smp. 190-192 ° (from methanol).

The N- [5- (2-bromo-1-hydroxyethyl) -2-chloro-phenyl] -methanesulfonamide required as starting material is prepared in the following manner:

a) While cooling with ice, 110 g of methanesulfonic acid are added to a solution of 162.5 g of 3-amino-4-chloro-acetophenone in 900 ml of pyridine.

chloride dripped. After further stirring at room temperature for 3 hours, the resulting precipitate is filtered off and the filtrate is evaporated. The residue crystallizes on addition of water. The resulting crude N- (2-chloro-5-acetyl-phenyl) -methanesulfonamide is recrystallized from ethanol; Mp. 112-114 °.

b) Bromination of the compound obtained according to Example 5a) with the equivalent amount of bromine in chloroform gives the N ~ (5-bromoacetyl-2-chloro-phenyl) -methanesulfonamide, mp. 120-123 °.

c) Reduction of the compound obtained according to Example 5b) with the equivalent molar amount of sodium borohydride in dioxane-Wassar (9: 1) gives der.d = N = [5 - (2 ~ bromo-1-hydroxyethyl) ~ 2 ~ chloro phenyl] -methanesulfonamide, mp. 130-134 ° ..

Example 6 : 4.7 g of 4-amino-a- (aminomethyl) -3,5-dichloro-benzyl alcohol _s 6.0 g of 5 - (2-bromoethoxy) -salicylamide and 12.9 g of Ν, Ν-diisopropyl-ethylamine are refluxed in a mixture of 20 ml. dimethylformamide and 50 ml dioxane for 3 hours. After evaporation of the solvent der'Rückstand is worked up analogously to Example 5. The a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aluminomethyl] -3,5-dichloro-4-amino-benzyl alcohol is obtained as brownish crystals of mp. 196-201 °.

The 5- (2-bromoethoxy) -salicylamide required as starting material can be obtained as follows:

a) 30.0 g of the obtained according to Example Ib) 6- (2-Bromäthoxy) -2,3-dihydro-2,2-dimethyl-4H-l, 3 ~ benzoxazin-4-one are in a mixture of 100 ml Dioxane and 100 ml of 6-n. Hydrochloric acid with stirring for 1 1/2 hours at reflux. The crystals obtained after evaporation of the reaction mixture are washed with -50 ml of water and dried in vacuo. The resulting 5- (2-Bromäthoxy) -salicylamide melts at 141-143 °.

s W ^v E • g & i «fe ^ J ^ J ξ,

-39'-

The 4-amino-cr- (aminomethyl) -3,5-dichloro-benzyl alcohol required as starting material is prepared in the following manner:

b). A suspension of 17.9 g of phthalimide in 70 ml of dimethylformamide is added in portions with stirring with 6.5 g of sodium hydride suspension (55% in paraffin oil). After one hour, with further stirring and cooling at 10-20 °, a solution of 34.5 g of 4-amino-4) -bromo-3,5-dichloro-acetophenone in 50 ml of dimethylformamide is added dropwise, the reaction mixture is 3-4 Stirred for hours and then poured on 1200 tal water. The precipitated crystals are filtered off and dried in vacuo at 100 °. This gives crude N- [2- (4-amino-3,5-dichlorophenyl) -2-oxo-ethyl] -phthal'imid, mp. 255-260 °.

c) A suspension of 23.6 g of "N- [2- (4-amino-3,5-dichloro-phenyl) -2-oxo-ethyl] -phthalimide in a mixture of 150 ml of dioxane and 20 ml of water is in portions 5.2 g of sodium borohydride are added and the mixture is stirred for 48 hours at 80-90 ° C. After 24 hours, another 5.2 g of sodium borohydride are added.

The excess sodium borohydride is added with 2-n under ice-cooling. Hydrochloric acid decomposes and the reaction mixture is evaporated. The evaporation residue is treated with conc. Ammonia solution made alkaline and extracted with ethyl acetate. After removal of the solvent, the crude 4-amino-3,5-dichloro-a- [N- (2-hydroxymethyl-benzoyl) aminomethylj-benzyl alcohol of mp. 165-170 °, which is further processed without further purification.

d) 19.4 g of the crude product according to Example 6c) and 4.8 g of sodium hydroxide are boiled in 200 ml of ethanol for 5 hours under reflux. By distributing the evaporation residue between 200 ml of ethyl acetate and 30 ml of water and conventional workup gives the 4-amino-a- (aminomethyl) -3,5-dichloro-benzyl alcohol of mp. 124-127 °.

-Gz -Stir-. ,

Example 7: A mixture of 8.7 g of N- [3- (2-amino-1-hydroxy-ethyl) -phenyl] -methanesulfonamide and 9.0 g of 5- (2-3-methylethoxy) -salicylamide in 50 ml of dioxane and 20 ml of triethylamine is boiled for 4 hours with stirring and reflux. The foam obtained by evaporation is stirred with 100 ml of saturated potassium bicarbonate solution and 500 ml of ethyl acetate until complete. The organic phase gives after drying over magnesium sulfate and evaporation 12 g of a greenish foam, from which by dissolving in a mixture of methanol and isopropanol (about 1:10) of a- [N- [2- (3-carbamoyl-4 -hydroxy-phenoxy) -ethyl] "aminomethyl" -3- (methylsulfonylamino) -benzyl alcohol of mp 135-137 ° crystallized.

Example 8 : 23 g of crude a- [N ~ [2- (2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-7-yloxy) -l-methyl-ethyl] -aminomethyl] -4- (methylsulfony1-amino) -benzylalcohol are refluxed for 2 hours in a mixture of 50 ml of isopropylamine and 200 ml of isopropanol and then evaporated, and the residue is stirred with 5 ml of isopropanol and 20 ml of ether. The gradually forming crystals are filtered off with suction and represent the a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -4- (methylsulfonylamino) -benzyl alcohol as a diastereoisomeric mixture A 1: 1 mixture of the diastereoisomers melts at 140-145 °. '

The starting material is prepared in the following manner:

a) A solution of 11.5 g of N- [4- (2-amino-1-hydroxy-ethyl) -phenylj-methanesulfonamide and 12.4 g of 2,3-dihydro-2,2-dimethyl-7- (2 -pxopropoxy) ~ 4H-l, 3-benzoxazin-4-one in 250 ml of methanol after addition of 0.13 g of concentrated sulfuric acid over Ig platinum on carbon catalyst until the calculated amount of hydrogen is hydrogenated under Noraalbedingungen. After filtering off the catalyst, the solution is evaporated, after which the crude a- [N- [2 ~ (2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazine 7-yloxy) -1-methyl-ethyl] -aminomethyl j-4

- te -

(methylsulfonylamino) -benzylalkohol receives as OeI, which is further processed as such;

The 2,3-dihydro-2,2-dimethyl-7- (2-oxo-propoxy) -4H-1,3-benzoxazin-4-one required as another starting material can be obtained as follows:

b) Analogously to Example la) is obtained from 2,4-dihydroxy-benzainide, the 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-l, 3-benzoxazin-4-one of mp. 249-251 °.

c) From 168 g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benzoxazin-4-one, 305 g of potassium carbonate and 88 ml of chloroacetone in 1.2 liters of acetonitrile by boiling during 28 hours and subsequent workup gives the 2,3-dihydro-2,2-dimethyl-7- (2-oxo-propoxy) ~ 4H-l, 3-benzoxazin-4-one, mp. 160-162 ° (from isopropanol).

Example 9 : Analogously to Examples 8 and 8a), α- (aminomethyl) -3: 4-methylenedioxybenzyl alcohol (mp 75-78 °, compare H. Tatsuno et al., J. Med. Chem. 394, 1977) and 2,3-dihydro-2,2-diaethyl-6- (2-oxopropoxy) -4 H -1,3-benzoxazin-4-one are the a- [N- [2- (3-carbamoyl) 4-hydroxyphenoxy) -1-methyl-ethyl] aminomethyl] -3,4-methylenedioxybenzyl alcohol as diastereoisomer mixture. By fractional crystallization of the hydrochloride from methanol-water (4: 1) to obtain a pure enantiomeric pair, mp. 211-212 °.

The 2,3-dihydro-2,2'-2-dimethyl-6- (2-oxo-propoxy) -4 H -1,3-benzoxazin-4-one required as starting material can be obtained as follows:

a) 70 g of the obtained according to Example la) 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-l, 3-benzoxazin-4-one are dissolved in 400 ml of acetonitrile with 100 g of potassium carbonate and 32 ml of chloroacetone Stirred for 30 hours under reflux. After adding another 3.2 ml of chloroacetone is the

-HA-

Reaction mixture heated for a further 15-20 hours. The still warm reaction mixture is filtered, the residue washed thoroughly with acetone and the combined filtrate evaporated. The crystalline residue is recrystallized from toluene to give the 2,3-dihydro-2,2-dimethyl-6- (2-oxo-propoxy) -4H-1,3-benzoxazin-4-one of. Mp. 125-126 ⁵

EXAMPLE 10 Analogously to Example 9, using 2,3-dihydro-2,2-dimethyl-7- (2-oxo-propoxy) -4H-1,3-benzoxazin-4-one, the a- [N " [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-ethyl-ethyl] -aminomethyl] -3,4-methylenedioxybenzyl alcohol as diastereoisomeric mixture (about 1: 1), mp. 164-174 ° It forms a neutral fumarate of the mp.

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

Example 11: A solution of 0.795 g of 1- (3-sulfamoyl-4-chlorophenyl) -2-aminoethanol and 0.707 g of (2,3-dihydro-2,2-dimethyl-4H-1, 3 Benzoxazin-4 ~ on ~ 6-yloxy) -acetaldehyde in 20 ml of methanol is mixed with 2 g of molecular sieves (3 A) and 0.44 g of sodium cyanoborohydride and the suspension is stirred at room temperature. By dropwise addition of methanolic hydrochloric acid, the pH is maintained at 6-7. After 12 hours, filtered, the filtrate to decompose the cyanoborohydride with 1 ml of conc. Hydrochloric acid added, stirred for 10 minutes and then with conc. Ammonia adjusted to pH 9. The suspension is freed from the solvent, the residue is partitioned open with a mixture of chloroform / methanol / ammonia (40: 10: 1), and the filtrate is concentrated again. The residue is chromatographed on 150 g of silica gel with a mixture of chloroform / methanol / ammonia (40: 10: 1), the main fraction is evaporated and the residue is stirred for 15 minutes in a mixture of 20 ml of dioxane and 1 ml conc. Hydrochloric acid heated to 80 °. To. Removal of the solvent, the residue is taken up in ethyl acetate and washed with 2- * n. Extracted ammonia. The organic phase is dried, evaporated and the residue is recrystallized from isopropanol-ethyl acetate, after which the a- [N- [2- (3-carbato)

moyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -3-sulfamoyl-4-chloro-benzyl alcohol, Snip. 193-195 ° .. '

The 2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-on-6-yloxy) acetaldehyde required as the starting material can be obtained as follows:

a) A solution of 9.65 g of the obtained according to Example la) 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-l, 3 ~ benzoxazin-4-one and 9.1 g of allyl bromide in 150th The acetonitrile is stirred under reflux for 5 hours with the addition of 10.3 g of dry potassium carbonate, the reaction mixture is filtered while warm, the filtrate is evaporated and the remaining crystals are filtered off with suction after etherification, after which the crude 2,3-dihydro-2, 2-dimethyl-6-allyloxy-4H-l, 3-benzoxazin-4-one, mp. 137-138 ° receives.

b) A solution of 4.7 g of 2,3-dihydro-2,2-dimethyl-S-allyloxy-4H-l, 3-benzoxazin-4'-one in a mixture of 50 ml of dioxane and 15 ml of water under Stirring with about 20 mg Osmiumtetroxid added. After 15 minutes, 8.6 g of sodium metaperiodate are added in portions, the temperature rising to 45 °. After 2 hours, the reaction mixture is filtered, the filtrate is evaporated and the residue is partitioned between 20 ml of water and 200 ml of ethyl acetate. The organic phase is separated, dried and evaporated. The remaining OeI is chromatographed over 100 g of silica gel. Elution with ethyl acetate and evaporation to dryness gives (2,3-dihydro-2,2-dimethyl-4E-1,3-benzoxazin-4-on-6-yloxy) acetaldehyde of mp 153-163 °.

Example 12 : A solution of 9.2 g of α- (aminomethyl) -4- (methylsulfonyl-amino) -benzyl alcohol and 8.5 g of 4- (2-oxo-propoxy) -salicylamide in 180 ml of methanol is added with addition of 0.1 g conc. Hydrogenated sulfuric acid over Ig platinum-on-carbon catalyst (5 '%). After filtration and evaporation of the filtrate gives a foam, which is from isopropanol

-ΛΑ -

Standing for several days, the a- [N- [2- (4-carbamoyl-3-hydroxyphenoxy) -l-methyl-ethyl] aminomethyl] -4- (methylsulfonylamino) benzyl alcohol as a diastereoisomeric mixture (about 1: 1 ) of the mp 141-152 °. The isolation of the pure diastereomers is in Example 28. described. '

The 4- (2-oxo-propoxy) -salicylamide required as starting material can be prepared as follows;

a): 66 g of crude obtained according to Example 9a) 2,3-dihydro-2,2-dimethyl-6 ^k - (2-oxopropoxy) -4H-l, 3-benzoxazin-4-one is dissolved in a mixture of 150 ml Dioxane and 400 ml of 2-n. Hydrochloric acid hydrolyzed for 1 hour on the boiling water. After evaporation of the solvent and trituration of the residue with water to give crude 4- (2-oxo-propoxy) -salicylamid, mp. 128-140 °. After recrystallization from ethanol, the product melts at 145-148 °.

Example 13 Analogously to Example 12, using the equivalent amount of the 5- (2-oxo-propoxy) -salicylamide obtained according to Example 10a), the a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -i-methylethyl] aminomethylj-4-feathylsulfonylamino) -benzyl alcohol as OeI, which comprises a neutral fumarate as a mixture of the diastereoisomers in the

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

Example . 14: A solution of 24.1 g of 5- (2-amino-1-hydroxy-ethyl) -salicylamide and 25.6 g of 5- (2-oxo-propoxy) -salicylamide is analogously to Example 12 over 2 g'Platin on carbon catalyst (5%), added in 2 portions, until the calculated amount of hydrogen is hydrogenated. The evaporation residue of the filtered solution is dissolved with the addition of fumaric acid in water, the solution extracted with ethyl acetate and the aqueous phase separated. This is made alkaline with saturated potassium bicarbonate solution and the precipitate precipitated is extracted with much ethyl acetate by stirring for 1 hour. From the ethyl acetate solution is obtained after the

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

Example 15 : A solution of 10.0 g of 'a- (amincmethyl) -4- (2-ethoxyethoxy) benzyl alcohol and 9.9 g of 5- (2-oxo-propoxy) -salicylamide is dissolved in 200 ml of methanol analogously to Example 12 hydrogenated and worked up analogously to Example 14. This gives the a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -1-methyl-ethyl] aminomethyl] -4- (2-methoxy-ethoxy) -benzyl alcohol, which after recrystallization from ethyl acetate melts at 100-106 ° and a diastereoisomer mixture in the ratio of about 1: 1 represents.

The a ~ (aminomethyl) -4- (2-methoxyethoxy) benzyl alcohol used as starting material can be prepared in the following manner:

a) A suspension of 21 g of 2 ~ methoxy ~ ethyl bromide, 13.6 g of 4-hydroxy ~ acetophenone and 27.6 g of potassium carbonate in 250 ml of acetone is boiled for 20 hours with stirring and reflux. Uebliches working up and distillation of the crude product at 0.001 Torr gives the 4- (2-methoxy-ethoxy) acetophenone from bp. 113-116 ° / O, OO1 Torr, as a colorless OeI, which solidifies crystalline.

b) Bromination of the compound obtained according to Example a) with the equivalent amount of bromine in chloroform at 20-30 ° for 2 hours gives the i "> - bromo-4- (2-niethox> ^r -ethoxy) acetophenone, which as such is used.

c) A solution of 53 g of the crude, obtained according to Example b) compound in 350 ml of dimethylformamide is cooled to 0-5 ° and treated portionwise with stirring 15.4 g of sodium azide. To

After the exothermic reaction has subsided, the ice cooling is removed and the reaction mixture is stirred for a further 3 hours. The solution is then poured onto 3 liters of ice-water and the precipitating yellow OeI mif ether extracted. The ether solution (500 ml) is washed twice with 100 ml of water, then with 100 ml of saturated sodium chloride solution, dried thoroughly over magnesium sulfate, filtered and the filtrate with a suspension of 35 g of lithium aluminum hydride in 500 ml of ether for 2 hours at 10-12 ° reduced. Routine workup gives crude crude a- (aminomethyl) -4- (2-methoxyethoxy) benzyl alcohol as a yellowish OeI, which can be reused as crude product. In the Kugelrohr distillation it boils at 13O-14O ° / O, O8 Torr.

Example 16 Analogously to the procedure of Example 12 is obtained from 7.5 g of a- (aminomethyl) -4-methyl-benzyl alcohol and 10.45 g of 5- (2-oxopropoxy) -salicylamid the a- [N- [2- (3-Carbamoy1-4-hydroxy-phenoxy) -1-methyl-ethyl] -aminomethyl] -4-methyl-benzyl alcohol of mp. 120-134 ° (from ethyl acetate), which is a mixture of diastereoisomers in the ratio of about 1: 1 represents .. '.

Example 17 : A solution of 6.1 g of α-aminomethyl-4-methoxybenzyl alcohol (SM Albonico et al., J. Chem. Soc. 1967 , 1327) and 7.7 g of 5- (2-oxo-propoxy) -salicylamide in 130 ml of methanol is added with the addition of 0.09 g of conc. Sulfuric acid and 1.2 g platinum-on-carbon catalyst (5%) hydrogenated analogously to Example 12. The crude product is recrystallized from 200 ml of ethyl acetate, then from acetonitrile. The higher melting enantiomeric pair of a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) -1-methyl-ethyl] -aminomethyl] -4-methoxy-benzyl alcohol, mp 144-146, is obtained °. The other enantiomer pair is obtained from the ethyl acetate mother liquor by concentration and purified by crystallization from acetonitrile, mp 129-131 °.

Example IS : A solution of 7 g of a- (aminorocethyl) -3-sulfamoyl-4-chlorobenzyl alcohol and 5.8 g of 5- (2-oxo-propoxy) -salicylamide in 130 ml

Methanol is concentrated with 70 mg. Sulfuric acid and then shaken under nitrogen for 2 hours at room temperature. 0.7 g of platinum-on-carbon catalyst (5 ×) are added and hydrogenation is carried out under normal pressure until the hydrogen uptake is stopped. The catalyst is filtered off, the filtrate is freed from the solvent and the remaining foam is recrystallised from isopropanol, then from methano 1 / isopropanol, after which the a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -methyl] Ethyl] -aminometh'yl] -3-sulfamoyl-4-chloro-benzyl alcohol as approx. 1: 1 diastereomer mixture of mp. 103-106 ° with 0.5 mol of crystalline isopropanol.

The required as starting material a -! (Aminomethyl) -3-sulfamoyl-4-chlorobenzyl alcohol can be obtained as follows:

a) To a solution of 28 g of 5- (bromoacetyl) -2-chlorobenzenesulfonamide (DE-OS 26 01 598) in 40 ml of dimethylformamide are added at 0-5 ° in the course of 30 minutes in portions 8 g of sodium azide. The mixture is stirred for a further 2 hours at. This temperature and the reaction mixture is then poured onto an ice / water mixture. The thereby crystallizing 5- (azidoacetyl) -2-chloro-benzenesulfonamide, which decomposes from 152 °, is filtered off, washed with plenty of water and dried under high vacuum. The resulting crude product is used directly in the next step.

b) A solution of 29.5 g of crude 5- (azidoacetyl) -2-chlorobenzenesulfonamide in 800 ml of methanol and 46.4 ml of hydrochloric acid is added in the presence of 3 g of a platinum on carbon catalyst (5%) Room temperature and normal pressure until hydrogen absorption is complete: hydrogenated. The catalyst is filtered off, the filtrate evaporated and the residue slurried in acetone. The resulting 5- (aminoacetyl) -2-chlorobenzenesulfonamide hydrochloride is filtered off and used as the crude product in the next step.

c) 5 g of 5- (aminoacetyl) -2-chlorobenzenesulfonamide hydrochloride are slurried in 100 ml of methanol and treated portionwise with 1.6 g of sodium borohydride. The solution is stirred for 1/2 hour at room temperature, evaporated on a rotary evaporator and the residue treated with ethyl acetate and water. The organic phase is dried over 'sodium sulfate, evaporated and the residue is recrystallized from ethyl acetate to give the a- (aminomethyl) -3-sulfamoyl-4-chlorobenzyl alcohol of mp. 179-182 °.

Example 19 Analogously to the procedure described in Example 18, the α- [aminomethyl] -3-sulfamoyl-4-chlorobenzyl alcohol and 4- (2-oxo-propoxy) -salicylamide are replaced by the ct [N- [2- (3- Hydroxy-4-carbamoylphenoxy) -l-methyl-ethyl] aminomethyl] -3-sulfamoyl-4-chloro-benzyl alcohol, mp. 112-116 °, which is present as Dxastereomerengemisch (about 1: 1).

Example 20 : A solution of 20 g of crude a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethyl] benzylaminomethyl] -3-sulfamoyl-4-methoxybenzene alcohol in 200 ml of methanol is added Addition of 2 g of palladium on carbon catalyst (5%) hydrogenated until the calculated amount of hydrogen. By filtration and evaporation of the filtrate. a viscous residue is obtained from which, by dissolving in a methanol-isopropanol mixture, the α- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] aminomethyl] -3-sulfamoyl-4-methoxy crystallized benzyl alcohol, which shows the mp. 160-162 ° after recrystallization from methanol. A crystal modification of the mp 191-194 ° "occurs when the compound is recrystallized from acetonitrile.

The starting material can be prepared in the following way:

a) 2-Methoxy-5 - (bromoacetyl) benzoylsulfonamide is reduced in methanol with 5-fold molar amount of sodium borohydride to give 5- (epoxyethyl) -2-methoxy-benzenesulfonamide (mp 158-160 ° from methanol).

b) A solution of 7.7 g of 5- (epoxyethyl) -2-methoxy-benzenesulfonamide and 8.6 g of the obtained according to Example Ic) 5 - [(2-benzylamiro) -ättioxy] -salicylamid in 150 ml of isopropanol · Boiled under reflux for 20 hours. Evaporation of the solution gives the a- [N- [2- (3-carboanioyl-4-hydroxy-phenoxy) -ethyl] -benzylaminomethyl] -3-sulfamoyl-4-inethoxybenzy lalkoho 1 as an orange-colored resin, which without further purification is further processed.

Example 21: A solution of 5.5 g of 1- [N-benzyl-2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4- (2-methoxyphenyl) -2-butanol in 60 ml Methanol is hydrogenated with the addition of 0.6 g of palladium on carbon catalyst (5%) under normal conditions until the hydrogen uptake is complete, the reduction product partially precipitating out of the solution. The suspension is diluted with 400 ml of methanol, heated and filtered through a filter aid. The filtrate is treated with an excess of methanolic hydrochloric acid and freed from the solvent on a rotary evaporator. The residue is recrystallized from acetonitrile / ethyl acetate to give 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4- (2-methoxyphenyl) -2-butanol hydrochloride of mp 124-126 °. Preserves.

The required 1- (N-benzyl) 1- (N-benzyl-1, 4-hydroxy-phenoxy) -ethylamino] -4- (2-methoxyphenyl) -2-butanol can be prepared as follows. "

a) To a solution of 5 g of 1- (3-butenyl) -2-methoxybenzene (see WS Johnson: JACS 1986, (1964) in 25 ml of methylene chloride-d ', a solution of 7 is added with stirring at room temperature After 21/2 hours, the mixture is filtered off, the filtrate is washed with 10% sodium sulfite solution, dried on sodium sulfate and concentrated by evaporation, leaving the crude l- (3,4-epoxybutyl) remaining behind ) -2-methoxybenzene is further processed as such.

b) 2.45 g of crude 1- (3,4-epoxybutyl) -2-methoxybenzene and 3.9 g of the 4- [2- (benzylamino) -atoxy] -salicylamide obtained according to Example 4b are dissolved in 65 ml of isopropanol dissolved and the solution heated to reflux for 80 hours. The solvent is then removed and the residue is chromatographed over 300 g of Kieselge.l with a mixture of chloroform / methanol / ammonia = 350: 50: 1, whereby the l- [N-benzyl-2- (4-hydroxy-3- carbamoyl-phenoxy) ethylamino] -4- (2-methoxyphenyl) -2-butanol as a yellowish OeI, which is further processed as such.

Example 22: To a solution of 2.9 g of 5- (2-aminoethyl) -salicylamide in 10 ml of dimethylsulfoxide is added 2.7 g of (2,3-epoxypropyl) benzene followed by 40 minutes in a ca. This solution is cooled and diluted with 40 ml of water, the precipitated crystals are filtered off with suction, washed with a little water and dried in vacuo to give the 1- [2- (3-carbamoyl-4 -hydroxy-phenoxy) ethylamino] -3-phenyl-2-propanol, m.p. 142-143 ° (as isopropanol).

Example 23: A solution of 11.4 g of 1- [2- (3-carbamoyl-4-hydroxyphenoxy) -N-benzyl-ethylamino] -3- (2-methoxyphenyl) -2-propanol in 130 ml of methanol is added at room temperature hydrogenated in the presence of 1.2 g of palladium on carbon catalyst until hydrogen uptake ceased. The catalyst is filtered off and the filter residue is washed with methanol, the filtrate is evaporated to dryness under reduced pressure, the residue is recrystallized from methanol, the resulting crystals are suspended in methanol and the suspension is combined with methanolic hydrochloric acid, and the solution is evaporated to dryness and the residue is recrystallized from acetonitrile. The 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -3- (2-methoxyphenyl) -2-p.-propanol is obtained as the hydrochloride of mp 152-154 °.

tea »«. «ν & / J ^ -j *

- -73-

The starting material can be prepared as follows: A solution of 5 g of 2-methoxy-1- (2,3-epoxypropyl) benzene (see Compt rendues, 219, 163-64 (1944)) and 8.7 g 5- (2-N-Benzylaminoethoxy) -salicylamide in 130 ml of isopropanol is refluxed for 20 hours, then the solvent is removed on a rotary evaporator, the residue is digested on 500 g of silica gel and treated with a mixture of chloroform: methanol, ammonia 350: The fractions 4-20 are collected, combined and evaporated to dryness, after which the 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -N-benzyl-α-thylamino] -3- (2-methoxyphenyl) -2-propanol as an oily residue.

Example 24: 4.18 g of α-aminomethyl-2-methoxybenzyl alcohol are stirred in 250 ml of methanol and 4.28 ml of 5.9N methanolic hydrochloric acid (-pH6) .The reaction solution is treated with 0.59 g of potassium hydroxide (firmly)

offset (r »» pH9). After addition of 25 g of molecular sieve 3A and 5.60 g of (2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one-6-yloxy) -acetaldehyde. .Wird a solution of 0.59 g of sodium cyanoborohydride in 60 ml of methanol was added dropwise. The reaction mixture is stirred at room temperature for 24 hours, filtered and washed with 50 ml of 5.9-n. methanolic hydrochloric acid refluxed for 1 hour. The reaction solution is freed from the solvent and the residue over 500 g of silica gel with a mixture of chloroform / methanol / ammonia (40: 5: 0.5) chromatographed. The main fraction is evaporated. By crystallization from isopropanol, the a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -2-methoxy-benzyl alcohol of mp. 167-168 °.

The cr-aminomethyl-2-methoxy-benzyl alcohol required as starting material can be obtained as follows:

a) A solution of 13.8 g of a-Brpm-2-methoxy-acetophenone in 30 ml of dimethylformamide is added with stirring at 0-5 ° for 30 minutes with 5.85 g of sodium azide. After stirring for 2 hours at 0 ° is the

The reaction mixture is poured onto 100 ml of ice / water and the crystalline a-azido ~ 2-methoxy-acetophenone is filtered off with suction. The filter residue is dissolved in 300 ml of toluene, the solution dried (MgSO 4) and added dropwise within 1 hour to a suspension of 10 g of lithium aluminum hydride in 200 ml of tetrahydrofuran at 0-5 °. The reaction mixture is stirred for 1 1/2 hours at 0-5 ° and then at 0-5 ° dropwise with 10 ml of water, 10 ml of conc. Sodium hydroxide solution and then mixed with 30 ml of water. The precipitate is filtered off and the filtrate is evaporated. The residue is crystallized from ethyl acetate to give the a-aminomethyl-2-methoxy-benzyl alcohol of mp 122-123 °.

Example 25; A solution of 100 g of crude 2- [N-benzyl-N- [2 ~ (4-carbamoyl-3-hydroxy-phenoxy) -ethyl] -amino] -4-methylsulfonylamino-acetophenone in 1000 ml of methanol is added with the addition of 100 ml of acetic acid and 20 g of palladium-on-carbon catalyst (10 Z) at 30-40 ° under atmospheric pressure to standstill of hydrogen uptake, hydrogenated (80% of theory) After filtration and evaporation of the solvent to obtain an OeI, which after Neutralization to pH 3-4 with 6-n. Hydrochloric acid ":;.. '.': ..... crystallized The crystals are filtered off with suction and recrystallized from water is obtained as the a- [N- [2- (4-carbamoyl-3-hydroxyphenoxy) ethyl].. -aminomethyl] -4-methylsulfonylamino-benzyl alcohol as the hydrochloride, mp. 239-240 °.

The starting material can be prepared in the following way:

a) A mixture of 58.6 g of 2-bromo-4-methylsulfonylamino-acetophenone, 57.2 g of 4- [2-benzylamino-ethoxy] -salicylamide and 30 g of potassium bicarbonate in 400 ml of dioxane for 4 hours at 20-30 °, filtered and evaporated. The evaporation residue is between ethyl acetate and 2-n. Distributed potassium bicarbonate solution, the organic phase separated and with 2 ~ n. Hydrochloric acid extracted three times. Neutralization of the acidic extract with potassium bicarbonate and extraction with ethyl acetate gives crude 2- [N-benzyl-N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -

ethyl] -amino] -4-methylsulfonylamino-acetophenone as a brown oil, which is further processed as such.

Example 26 Analogously to Examples 25 and 25a, using 5- [2-benzylamino-ethoxy] -salicylamide, the a- [N- [2- (3-carbamoyl-4-hydroxyphenoxy) ethyl] -aminomethyl] 4-methanesulfonylamino-benzyl alcohol as the base of mp. 172-174 ° (from ethanol), by reacting the evaporated hydrogenation with 2-n. Ammonia solution is alkaline and. extracted with a lot of ethyl acetate, the base.

Example 27: A solution of 8.5 g of α- (aminomethyl) -4- (N-methylsulfamoyl) -benzyl alcohol and 7.7 g of 4- (2-oxo-propoxy) -salicylamide is hydrogenated and worked up analogously to Example 12 , By fractional recrystallization 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 mp. 136-150 °. Further recrystallization from ethanol gives a pure diastereomer of mp. 138-140 ° (C-NMR signal at 15.3 ppm after addition of fumaric acid).

The starting material can be prepared in the following way:

a) 4-chlorosulfonyl-acetophenone is reacted with an excess of methylamine to 4- (N-methyl-sulfamoyl) -acetophenone: mp 111-112 ° (from isopropanol) *

b) 60 g of the compound obtained are reacted in 1000 ml of acetic acid with the addition of 1 g of aluminum bromide with .44.8 g of bromine to give 2-bromo-4- (N-methylsulfamoyl-acetophenone, a yellowish oil which remains crude.

is used.

c) 80 g of the resulting compound are dissolved in 760 ml of acetone and treated with 109 g of dibenzylamine. The reaction mixture is stirred for 16 hours at 20-30 °. The crystallized dibenzylamine hydrobromide is filtered off and the filtrate is evaporated. The residue is combined with 500 ml of ether, filtered off from the insolubles and the ether solution is evaporated. The crude 2-dibenzylamino-4 - (N-methylsulfamoyl) -acetophenone thus obtained as OeI can be reduced as a crude product with sodium borohydride. By recrystallization from isopropanol, a pure product of mp. 93-94 ° is obtained.

d) 100 g of the crude compound obtained are dissolved in a mixture of 1800 ml of isopropanol and 200 ml of methanol and the solution is added while stirring and cooling at 10-15 ° with 9.5 g of sodium borohydride protion. After 2-3 hours, the reaction mixture is brought to pH 5-6 with acetic acid, evaporated under reduced pressure and partitioned between ethyl acetate and water. The organic phase is separated, washed with water, dried (MgSO.) And evaporated. The verb ~. . '. , permanent oil gradually crystallizes out of little ether. This gives the a- (dibenzylaminomethyl) -4- (N-methylsulfamoyl) -benzyl alcohol, mp. 105-106 °.

e) By catalytic debenzylation of the compound obtained in methanol over palladium-on-carbon catalyst gives the a- (aminomethyl) -4- (N-methylsulfamoyl) benzyl alcohol of mp. 130-132 ° (from methanol-toluene).

Example 28: 110.0 g of α- (aminomethyl) -4- (methylsulfonylamino) -benzyl alcohol are reacted with 100.0 g of 4- (2-oxopropoxy) -salicylamide as described in Example 12. The hydrogenation solution is concentrated to about 300 ml and allowed to crystallize for 15-20 hours.

The crystals of the obtained a- [N- [2- (4-carbamoyl-3-hydroxy-phenoxy) -1-methylethyl] -aminomethyl] -4- (methylsulfonylaminb) -benzyl alcohol are filtered off with suction and show a mp. From 156-162 °. you

13 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. Further, - recrystallization three times from methanol to obtain the enantiomeric pair A of mp 165-167 (> 90% A). It forms a hydrochloride, mp. 219-220 ° (from methanol);

13 ·

^ .CrNMRr -. ,, C-CH signal at 13.15 ppm.

By further concentration of the first mother liquor to obtain a further crystalline fraction of mp. 138-144 °, wherein the diastereomer ratio'-Ί: 1. The mother liquor filtered off from this

Siert. no more. It contains after. .C NMR analysis enriched the enantiomeric pair B to 60-70%. This mother liquor (~ 80 g of brown OeI) is chromatographed over 4 kg of silica gel. With 70 fractions of ethyl acetate a 150 ml, unidentified impurities are eluted. Further elution with methanol (80 fractions of 150 ml) gives a brown OeI which gradually crystallizes in part. Repeated recrystallization from ethanol gives the enantiomeric pair B of the mp 144-145 ° 0.90% B). It forms a hydrochloride of

13 mp 206-209 ° (from ethanol), which shows in ι C-Me thy! Group at 13.65 ppm (^ -95%).

13 mp. 206-209 ° (from ethanol), which in C-NMR the signal of

Example 2 9 _: A solution of 19.6 g of 5- (2-Arainoäthoxy) -salicylamide in 100 ml of dimethyl sulfoxide with. 19.0 g of 3,4-iEpoxybutyl) benzene stirred for 1 hour in a bath of 120 ° and then poured onto 200 ml of ice water. Extraction three times with 400 ml of ethyl acetate, washing the extract with water, drying (MgSO.) and evaporation gives a semi-solid residue from which by recrystallization from a little methanol, the l - [: 2- (3-carbamoyl-4-hydroxyphenoxy ) -ethylamino] -4-phenyl-2-butanol of mp. 159-160 °.

Example 30: A solution of 29 g of crude 1- [N-benzyl-2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4- (2-methylphenyl) -2-butanol in methanol is added 3.0 g of palladium on carbon catalyst (5%) hydrogenated to standstill of hydrogen uptake under normal conditions. Filtration and evaporation give crude 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4- (2-methylphenyl) -2-butanol, which, after recrystallization from isopropanol, melts at 140-142 ° , It forms a hydrochloride of mp. 155-157 ° (from isopropanol).

The starting materials can be obtained in the following way:

a) To 2-methyl-1-benzyl magnesium bromide (prepared from 92.5 g of α-bromo-oxylol, 12.5 g of magnesium spun in 250 ml of absolute ether) is added dropwise a solution of 46.3 g of epichlorohydrin in 175 ml of benzene. Then the ether is distilled off and the reaction mixture after reaching 65 ° internal temperature for 1 hour under reflux boiled. Under ice-cooling, the reaction mixture is first carefully with 50 ml of water

• decomposed and then with 125 ml 2-n. Sulfuric acid acidified. Insolubles are filtered off, the aqueous phase extracted twice with 200 ml of ethyl acetate, the organic phases combined, washed with water, dried (MgSO4) and evaporated. This gives crude 1-chloro-4- (2-niethylphenyl) -2-butanol as a yellow OeI, which is further processed as such.

b) 98 g of the compound obtained are dissolved in 700 ml of dichloromethane, with 16.7 g of tetrabutylammonium hydrogen sulfate and 700 ml of 2-n. Sodium hydroxide solution and the mixture stirred for 7 hours at room temperature. Separation of the layers, drying (MgSO 4) and evaporation of the dichloromethane solution give an OeI which gives two fractions by bulb tube distillation at 135-145 ° C bath pressure and 0.5 mm pressure. The more volatile component shows in the H-NMR spectrum the signals expected for 2- (3,4-epoxy-buty-1-toluene: (CDCl6 in ppm) 1.8 ('m, 2H), 2.3 (s , 3H), 2.45 (q, IH), 2.7 (m, -2H), 2.85 (s, IH)

C \ η r -. ,

2.95 (m, IH); 7.1 (s, 4H).

c) A solution of 15.0 g of the obtained epoxide and 18.6 g of 5 ~ (2-benzylaminoethoxy) salicylamide in 130 ml of isopropanol is refluxed for 24 hours and then evaporated. This gives crude 1- [N-benzyl-2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino] -4- (2-methylphenyl) -2-butanol as a yellow oil, which is further processed as such. '

Example 31; 20 g of crude 1- [N-benzyl-2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4- [4- (2-methoxy-ethoxy) -phenyl] -2-butanol is analogous to Example 30 debenzylated catalytically. The 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino] -4- [4- (2-methoxy-ethoxy) -phenyl] -2-butanol, mp. 151-153 ° (mp. from methanol). It forms a hydrochloride, mp. 207-208 ° (from methanol).

a) 76 g of 4-Hydroxyb.enzoesäure methyl ester are alkylated with 92 g (2-methoxyethyl) -methansulfonat in 1500 ml of acetonitrile in the presence of 138 g of potassium carbonate by boiling for 18 hours under reflux, after which 4- (2-Methoxyäthoxy ) -benzoic acid methyl ester of mp. 35-38 °.

b) 66 g of the compound obtained are reduced with 12 g of lithium aluminum hydride in 700 ml of tetrahydrofuran, after which crude 4- (2-Methoxyäthoxy) benzyl alcohol is obtained as OeI, which is used as such.

c) In a solution of 49 g of the resulting compound in 550 ml of toluene is introduced for 1 hour at about -5 ° hydrogen chloride gas in rapid flow. The reaction mixture is then stirred for 1 hour at about 0 to 5 °, then washed with saturated aqueous sodium chloride solution, dried (MgSO.) And evaporated in vacuo below 50 °. The crude '4- (2-methoxyethoxy) ~ thus obtained

- 38- - - 80- benzyl chloride is further processed without further purification.

d) From 45 g of the compound obtained and 6.5 g of magnesium turnings in a mixture of 100 ml of ether and tetrahydrofuran, the Grignard compound is prepared and then reacted analogously to Example 30a) with 21 g of epichlorohydrin. This gives crude 1-chloro-4- [4- (2-methoxyethoxy) -phenyl] -2-butanol as Oel, which, analogous to Example 30b), gives l- (3,4-epoxybutyl) -4- (2- -methoxy-ethoxy) -benzene is reacted

¹ H-NMR (CDCl3): 1.6-1.8 (m); 2.45 (q) x 2.8-3.0 (m). Based on these signals, an epoxy compound content of 50% is calculated.

e) Equivalent amounts of the resulting compound and 5- (2-Benzylaminoäthoxy) -salicylamid be reacted analogously to Example 30c) and give the 1- [N-Benzy1-2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino] - 4- [4- (2-methoxy-ethoxy) -phenyl] -2-butanol as -OeI which is further processed as such.

Example 32: A solution of 2.1 g of crude a- [N- [2- (4-carbomethoxy-3-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -4- (methylsulfonylamino) -benzyl alcohol in 20 ml Dioxane is concentrated with 40 ml. Ammonia solution allowed to stand for 3 days at 20-30 °. Evaporation of the solution gives a foam which gradually crystallizes from ethanol to give the a- [N- [2- (4-carbamoyl-3-hydroxy-l-phenoxy) -l-methyl-ethyl] -aminomethyl] -4- (Methylsulfonylamino) benzyl alcohol as a diastereoisomeric mixture (about 1: 1), mp. 141-150 °.

The starting material can be prepared in the following manner:

a) A solution of 3.4 g of 2,4-dihydroxybenzoate, 4.0 g of triethylamine and 2.8 g of chloroacetone in 40 ml of acetonitrile is refluxed for 16 hours. After addition of 1.4 g of chloroacetone and 1.3 g of triethylamine, the reaction mixture is boiled for a further 5 hours, then .Vaporated, the residue dissolved in 50 ml of toluene, the solution with

10 ml of water, then washed with 10 ml of saturated aqueous sodium chloride solution and chromatographed over 200 g of silica gel. The first eluted with toluene fractions containing the 4- (2-oxo-propoxy) -salicylaäureaethylester which is recrystallized from isopropanol, and. at 106-108 ° melts. ·

b) A solution of 2.3 g of a-CAminomethyD-A-CmethylsulfonylaminoJ-benzyl alcohol and 1.9 g of 4- (2-0xopropoxy) -salicylic acid methyl ester in 50 ml of methanol is hydrogenated analogously to Example 12. Filtration and evaporation afford crude α- [N- [2- (3-carbomsthoxy-4-hydroxy-phenoxy) -lmethyl-ethyl] -alaiinomethyl-1-yl-4-methylsulfoaylamino) benzyl alcohol as a yellowish oil Crystallized by crystallization, it can be further processed by crude crystallization from urea crystallization from ethyl acetate ether to give msn crystals of mp 113-121 ° (diastereoserene mixture).

_J! £ 2_ £ _{i i} ji, a solution of 10.5 g of crude l- [N-Eenzyl-2- (3 ~ 4-carbamoyl-hydroKy ^ra phanoj2y) ~ äthylaisino] -4- (4-benEylo3 ^ - phenyl) ~ 2-butanol in 55 ml of methanol is debenzylated analogously to Example 30 catalytically. This gives the 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino] -4- (4-hydroxyphenyl) -2-butanol.

The starting material can be prepared in the following way:

a) 18 g of 4-benzyl oxy- "benzyl alcohol is chlorinated with 21 ml of thionyl chloride in 30 ml of pyridine to 4 ~ -Benzyloxy-ban2yl chloride, mp. The raw material 72-78 °;

b) 15 g of the resulting 4-EenzyloKy-benzyl chloride are reacted analogously to Example 3Id) Grignsrd-Verbindisng and this with 7g epichlorohydrin zxwx 1- (3,4-Epo3cybutyl) -4-benzyloxy-benzene.

c) Reaction of 15 g of the resulting epoxide with 18.6 g of 5- (2-Benzylaminoäthoxy) ~ salicylamide analogous to Example 30c) gives the crude 1- [N-benzyl- "2- (3-carbamoyl-4-hydro3cy-phenoxy ) -ethylamino] -4- (4-benzyloxyphenyl) -2-butanol as OeI, which is further processed as such.

Example 34: 8.4 g of α- [N- [2- (4-carbomethoxy-3-hydroxy-phenoxy) -l-methyl-ethyl] -naphthyl-4- (methylsulfonylamino) -benzyl alcohol is dissolved in

EL K

Dissolved 50 ml of dioxane and treated with 200 ml of a 40% aqueous methylamine solution. The solution is allowed to stand for 2-3 days at room temperature. Working up analogously to Example 32 gives the a - [N- [2 - (4-methylcarbamoyl-3-hydroxy-phenoxy) -l-methyl-ethyl] -amino-methyl-4-methylsulfonylamino-benzyl alcohol as diastereoisomeric acid.

 mixture.

EXAMPLE 35 Tablets containing 20 mg of active substance are prepared ss * in the customary manner in the following composition:

Additionally a rsaense estimation: a- [K- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-

ethyl] -afflinomethyl] -3-sulfamoyl-A-chloro-benzylalcohol 20 mg

• Wheat starch. 60 mg

Lactose 50 mg

Colloidal silica. 5 mg

Talk. , 9 mg

Magnesiuiastearat 1 mg

Ra etting ˚:

3-sulfaxoyl-4-chloro-beryl-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 PuI mixture kneaded with this paste until a slightly plastic mass is formed.

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 stearst are added and the mixture is compressed into tablets of 145 mg weight with score.

Example 36 Tablets containing 1 mg of active substance are prepared in the usual way in the following composition:

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

aaflinoiBethyl 3 ~ 3-sulfaffioyl-4-chloro-benzyl alcohol 1 mg

Wheat starch 60 mg

Lactose 50 mg

Colloidal silica 5 mg

Talc '9 mg

Magnesium Stearate I mg

126 mg

production:

a ~ [N - [2- (3-hydroxy-4-carbatsoyl-phenoxy) -l-methyl-ethyl] -anilomethyl] -3-sulfamoyl-4-chloro-benzyl alcohol is mixed with a portion of the wheat starch, mixed with lactose and colloidal silica, and the mixture is passed through a sieve, another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath, and the paste is kneaded with this paste until a slightly plastic mass is formed. ,

The plastic mass is forced through a sieve of about 3 tarn mesh size, dried and the resulting dry granules are again driven through a sieve, then the remaining wheat starch, talc and Magnesiurastearat be mixed and pressed the mixture into tablets of 145. mg weight with score ,

Example 37 : Capsules containing 10 mg of active substance are as. follows in the usual way:

Together mensetzung.

a- [N- {2- (3-carbamoyl-4-hydroxy-phenoxy) -ethyl] -aminoniethyl] -

3-sulfamoyl-4-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 with a mesh size of 0.5 mm and this is filled into portions of 11 mg each into hard gelatine capsules of suitable size.

Example 38: A sterile solution of 5.0 g of α- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -3-sulfamoyl-4-chlorobenzyl alcohol-methanesulfonate 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 39: 3.62 g of ~ (N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -3-sulfamoyl-4-chloro-benzyl alcohol are added with the addition of 100.0 Dissolve Ο-, ΙΟ-η hydrochloric acid in a volume of 18100 ml with 18000 ml of distilled water and pour into sterilized solution in 5.0 ml ampoules containing 1 mg of active substance.

Example 4 0: Instead of in the examples. Compounds 36 to 39 used as the active substance may also be the following compounds of formula I, or their pharmaceutically acceptable non-toxic acid addition salts as active ingredients in tablets, dragees, capsules, ampoule solutions, etc. wercjen used:

a- [N- [2- (3-carbaraoyl-4-hydroxy-phenoxy) -äthyl-aminorylethyl] -2,4-di- • chlorobenzylalcohol,

α- [N- [2- (3-Carbamoy1-4-hydroxy-phenoxy) -ethyl] -aminomethy1] -4-chloro-

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

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

sulfonylamino) -4-chloro-benzyl alcohol, ar [N- [2- (3-carbamoy1-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -3,5-dichloro

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

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

4- (methylsulfonyl-amino) -benzyl alcohol,: a- [N- [2- (3-carbamoyl-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -

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

3,4-methylenedioxybenzyl alcohol, Ct- [N- [2- (3-carbamoy-1-4-hydroxy-4-pheoxy) -l-1-yl] -aminomethyl] -

4- (methylsulfonylamino) -benzyl alcohol, α- [N- [2- (3-carbamoy1-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -

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

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

4-methyl-benzyl alcohol,. '.

α- [N- [2- (3-Carbamoy1-4-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -

, 4-methoxybenzyl alcohol, - 'a- [N- [2- (3-carbamoy1-4-hydroxy-phenoxy) -ethyl] -aminomethyl] -3-sulfonated

Moyles-4-methoxy-benzyl alcohol.

 1- [2- (3-Carbamoy1-4-hydroxy-phenoxy) -äthylamino] -4- (2-methoxyphenyl) -

2-butanol,.

l- [2- (3-Carbamoy1-4-hydroxy-phenoxy) -äthylamino] -3-phenyl-2-propanol,

or the 1- [2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino-3- (2-methoxyphenyl) -2-propanol

- as - -

a- [N- [2-O-carbamoyl-A-hydroxy-phenoxy) -äthy1] -aminomethyl] -2-methoxybenzyl alcohol,

ώ- · [Ν ~ [2- (4 ~ carbamoyl-3-hydroxy-phenoxy) -äthy1] aminomethyl] -4-methy1-sulfonylamino-benzyl alcohol,

a- [N- [2- (3-Carbamoy1-4-hydroxy-phenoxy) -äthy1] -aminomethy1] -4-methanesulfonylamino-benzyl alcohol,

a-tN- [2- (4-carbamoyl-3-hydroxy-phenoxy) -l-methyl-ethyl] -aminomethyl] -4- (methylsulfonylamino) -benzylalcohol as an enantiomeric pair of mp. 165-167 °, or as a pair of enantiomers of Mp 144-145 °,

l- [2- (3-carbamoyl-4-hydroxy-phenoxy) -äthylamino] -4-phenyl-2-butanol,

1- [2- (3-Carbamoy1-4-hydroxy-phenoxy) -äthylamino] - (2-methylphenyl) -2-butanol,

1- [2- (3-carbamoyl-4-hydroxy-phenoxy) -äthylamino] -4- [4- (2-methoxyethoxy) phenyl] -2-butanol.

Claims (1)

~ 88 ~ Right to claim 1. Process for the preparation of novel derivatives of 2-aminoethanol of the formula   , OH Ar- (CH ₀₎ -CH-GHO-H-alk (0)
ά. πι ι ι η OH H in which Ar is optionally substituted phenyl, m is a number from 0 to 3 »η the number 0 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 ₁ and R ₂ independently of one another are each hydrogen or lower alkyl, or together are lower alkylene, oxo lower alkylene, lower alkylene, Azaniederalkylen or H-Mederalkylazaniederalkylen represents, with the proviso that if m is 0, the phenyl radical Ar contains at least one substituent and substituted by one or two hydroxy or protected hydroxy groups phenyl Ar contains at least one additional, different from these substituents, in which Form of racemic mixtures, racemates, optical antipodes or salts thereof, characterized in that a) a compound of the formula. Ar- (OH ₂ > _m -CH - Un ₂ - Zi _{1 (II)} with a compound of the formula OH Z ₂ - alk - (O) _n - ~ - f \ _C01T (in) - z-r - wherein one of Z and Z represents a reactive esterified hydroxy group and the other represents the primary asino group, and X represents hydroxy, or wherein X ₁ and Z 1 together represent the epoxy group and Z 1 represents the primary amine nucleus, Ar , all, m and η have the above meaning, or implements b) in a compound of the formula ^c v «- ^elk " where Ar. the meaning of Ar or iron is Rast Ar, which is substituted by in each case 1 to 2 hydroxyl- and / or amine-transferable groups, X ₂ , X. and X are each hydrogen or a hydrogen-substitutable substituent and X is R , or X_ and X_ and / or X, and Xj. together form a bivalent radical which can be replaced by two hydrogen atoms, Kit means that at least one of the radicals X ", X and X is different from hydrogen or at least Ar is a radical Ar which is each 1 to 2 in hydroxy and / or amino-substituted groups, or at least X, usd X-zurzurner. or X.sup.a, and X.sup.- can represent a bivalent radical which can be replaced by two hydrogen atoms, and in which and .alpha. have the above meanings, or in a salt thereof, different from hydrogen X ", X ,, or X ,, bzv7. X "and X" together or X, and X "together 2. ό u 2 2 4 5 replaced by hydrogen, and / or in a radical Ar substituted hydroxy and / or amino in free hydroxy and / or amino, or c) in a compound of formula ^ . T - X ₆ - (O) _n Vco / i (V). wherein Σ, a reducible group of the Fonssln -CH-N-Alk- (Va), or -CH-N = slk.- (Vb) or - C («X_) - R (X _B ) -. Ik - (Vc) or - CIl ₂ - N (X _g ) - C (-X ₇ ) - elk ₂ - (Vd) or a group -CH- - N (X ₀ ) - filk - (Ve), where alk, for the rest alk ι ö 1 corresponding alkyl-ylidene radical and elk _? an isa is a methyl group which is truncated to the nitrogenate and alk is the oxo or thioxo radical and X is hydrogen or a radical which is displaceable under the conditions for the reduction of X, and / or Y by hydrogen and Y is a radical of the formula CO- (Vf) ODSR -CH (OX _p) - (Vg) is, in the X_ has the meaning given above, ar_ a radical Ar corresponds to, but optionally instead of each eineis gwei or hydroxy and / or amino or a two group OXc, and / or -N (X ₀ ) -, in which X _{n is} the one mentioned above. 8 given meaning, carries, ns and η have the above meanings, where X, a reducing group Va to Vd and / or Y is always a carbonyl group Vf, reduces these (group (s) and in the same operation that of hydrogen different groups X _n replaced by hydrogen, or d) a compound of the formula  wherein Ar, which has the meaning of Ar, or one radical Ar, which is convertible by 1 to 2 by aminolysis in hydroxy and / or amino and / or substituted by groups of the formula -COOH, .X hydrogen or an aminolysis cleavable group means, and m and η have the above meanings, or a reactive derivative of one of the carboxylic acids defined in formula VI, with a compound of the formula HNR R (VII) and simultaneously optionally present, by means of aminolysis in hydroxy and / or amino converted radicals into hydroxy and / or amino, and / or optionally eliminates Xg present and replaced by hydrogen, and and, if desired, converts a compound obtained in another compound of formula I, and / or it is desired to convert a resulting free compound into, a salt or a salt obtained into a free compound, and / or, if desired, to separate an obtained racemate mixture into the racemate or a racemate obtained into the optical antipodes. 2e method according to item 1, characterized in that ö. - / ^ - / 2- (2,3-dihydro-2,2-dichloro-4-oxo-4H-1,3-benzoxazin- -? - yloxy) 1-methylethyl-7-aminomethyl-4-methylsulphonylaminobenzyl alcohol using isopropylamine and isopropanol to give o- / H- / 2- (4-carbamoyl-3-hydroxyphenoxy) -1-methylethyl7-aminomethyl / -4- methylsulfonylaminobenzylalkoho1 hydrolyzed A process according to item 1, characterized in that the Schiff base prepared from o-aminomethyl-4-methylsulphonylaminobenzyl alcohol and 4- (2-oxopropoxy) -salicylamide is converted into ^ - / l-V2- (4-carbamoyl) 3 "hydroxy-phenoxy" -1-methylethyl7 "-aminomethyl7 ~ 4 ~ methylsulfonylamino ~ benzyl ~ alcohol reduced« 4 * Method according to item 1, characterized in that in the form of Ra.cematgemisch.en present cc- / N- / 2- (4-carbampyl-3-hydroxy-phenoxy) -1-methyläthyl7 »aminomethyl7-4 ~ methyl ~ sulfonylamino-benzyl alcohol by fractional crystallization in the Enantioinerenpaare of mp 165-167 and 144- 145 ° separates. Method according to one of the items 1 to 4? characterized in that a compound of the formula I obtained is converted into a pharmaceutically acceptable, non-toxic acid addition salt »... '