NO803653L - PROCEDURE FOR THE PREPARATION OF NEW DERIVATIVES FOR 2-AMINO-ETHANOL. - Google Patents

Description

The invention relates to methods for the production of new derivatives of 2-amino-ethanol with the formula

in which Ar means optionally substituted phenyl, m means a number from 0 to. 3, n means the number 0 or 1 and alk means the alkylene of 2-5 carbon atoms, whereby the nitrogen atom and the oxygen atom or, if n stands for zero, the phenyl residue are separated from each other by means of at least two carbon atoms, and R1 and R2 independently of each other denote each hydrogen or lower alkyl or denotes together the lower alkylene, the oxal lower alkylene, the thial lower alkylene, the aza lower alkylene or the N-lower alkyl-azal lower alkylene with the proviso that if m stands for zero, the phenyl residue Ar contains at least one substituent and a phenyl residue Ar substituted by one or two hydroxy groups or protected hydroxy groups as at least contains a further, of these various substituents, in the form of racemate mixtures, racemates, optical antipodes or their salts, especially acid addition salts and above all pharmaceutically usable, non-toxic acid addition salts.

As substituents, the residue Ar can be optionally present, especially in the manner indicated below, substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkylidenedioxy, cyan and/or nitro and/or bonded directly or to the aforementioned lower alkyl, lower alkenyl or lower alkoxy, i.e. one of these groups can substitute lower alkanoyl, esterified or amidated carboxyl, especially lower alkoxycarbonyl or optionally substituted carbamoyl, e.g. carbamoyl, loweralkylcarbamoyl, diloweralkylcarbamoyl or (hydroxyloweralkyl)-carbamoyl, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, sulfamoyl or loweralkylsulfamoyl, diloweralkylsulfamoyl, or directly or to the aforementioned loweralkyl or in a higher than 1-position to the aforementioned loweralkyl bonded halogen, etherified mercapto, as loweralkylthio, optionally substituted amino, such as amino, lower alkylamino, dilower alkylamino, alkylene- or oxaalkylenamino, pyrrol-l-yl, acylamino, such as lower alkanoylamino or lower alkoxycarbonylamino, optionally, especially of one or two lower alkyl, of hydroxyl lower alkyl or cycloalkyl substituted ureido, lower alkylsulfonylamino or optionally etherified or esterified hydroxy, such as hydroxy, phenyl lower aryl oxy or lower alkanoyloxy or, as a non-directly bonded substituent, further lower alkoxy, with the proviso that, if m stands for zero, the aryl residue Ar contains at least one substituent and one aven or two hy hydroxy, 1-phenyl lower oxy or lower alkanoyloxy groups substituted phenyl radical which contains at least one further, of these different substituents.

The residues designated "lower" in connection with the present description preferably contain up to 7 and primarily up to 4 carbon atoms.

The general designations used in the enumeration of substituents for the residue Ar can e.g. have the following specific meanings. Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; substituted lower alkyl is particularly corresponding to methyl or 1- or 2-substituted ethyl, lower alkenyl is e.g. vinyl, allyl, 2- or 3-methylallyl or 3,3-dimethylallyl, and substituted lower alkenyl, especially 2-substituted vinyl or 3-substituted allyl. Low-area coke is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or iso-butyloxy, and substituted lower alkoxy e.g. substituted methoxy or 1- or 2-substituted ethoxy.. Lower alkenyloxy is e.g. allyloxy, 2- or 3-methylallyloxy or 3,3-dimethylallyloxy. Lower real akynyl is e.g. propargyl,

and lower alkynyloxy is especially propargyloxy; lower alkylidenedioxy is e.g. isopropylidenedioxy, ethylidenedioxy and especially methylenedioxy and alkylenedioxy are special

ethylene dioxide. Lowerealkanoyl is e.g. acetyl, propionyl or butyryl. Lower oxycarbonyl is e.g. methoxycarbonyl or ethoxycarbonyl. Lower alkyl or dilower alkyl carbamoyl is e.g. methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl or diethylcarbamoyl, and hydroxyl lower alkylcarbamoyl are e.g. (2-Hydroxyethyl)-carbamoyl. Lower alkylthio is e.g. methylthio, ethylthio, n-propylthio or isopropylthio. Lower alkylsulfinyl is e.g. methyl- or ethylsulphinyl, lower alkylsulphonyl are e.g. methyl-, ethyl- or n-propylsulfonyl, and lower alkylsulfamoyl are e.g. methyl, ethyl or isopropylsulfamoyl, and dilavealkylsulfamoyl are e.g. dimethylsulfamoyl. Halogen is bromine or iodine and preferably fluorine or chlorine. Phenylvareal oxy is e.g. benzyloxy or 1- or 2-phenylethoxy and lower alkanoyloxy are-e.g. formyloxy, acetoxy; lower alkylamino and dilower alkylamino are e.g. methylamino, ethylamino, dimethylamino or diethylamino. Alkylenamino and oxaalkylene-amineb are e.g. pyrrolidino or piperidino respectively morpholino. Lower alkanoylamino is e.g. acetylamino or butyrylamino, and lower alkoxycarbonylamino is e.g. methoxycarbonylamino or ethoxycarbonylamino. Of one or two lower alkyl, of hydroxyl lower alkyl or of cycloalkyl, preferably those with 5 to 7 ring members, substituted ureido is e.g. 3-methylureido, 3,3-dimethylureido, 3-(2-hydroxyethyl)-ureido and 3-cyclohexylureido respectively. Lower alkyl-sulfonylamino is e.g. ethylsulfonylamino and especially methylsulfonylamino.

As stated above, substituents for Ar can consist of one of the aforementioned residues which are not bonded directly, but via lower alkyl, lower alkoxy or optionally via lower alkenyl. Subsequently, a selection of such substituents is mentioned generally and specifically as examples without limiting the combination possibilities. Lower alkanoyl alkyl is e.g. 2-oxopropyl(acetonyl) or 3-oxobutyl, lower alkanoyl and lower alkenyl are e.g. 3-oxo-1-butenyl, and lower alkanoyl alkoxy are e.g. 2-oxopropoxy(acetonyloxy) or 3-oxobutoxy. Optionally substituted carbamoyl lower alkyl is e.g. carbamoylmethyl or [(hydroxylower alkyl)-carbamoyl)]-lower alkyl such as [(2-hydroxyethyl)-carbamoyl]-methyl. Lower-real oxycarbonyl lower-real oxy is e.g. ethoxycarbonylmethoxy. Optionally substituted carbamoyl lavereal oxy is e.g. carbamoyl lower alkyl, such as carbamoylmethoxy, or [(hydroxylower alkyl)-carbamoyl]-lower alkyl, such as [(2-hydroxyethyl)-carbamoyl]-methoxy. Halolower alkyl is especially halomethyl, e.g. trifluoromethyl. Lower alkyl thiolavereal oxy is e.g. 2-methylthioethoxy or 2-ethylthioethoxy. Acylamino lower alkyl is e.g. lower-alkanoylaminolower alkyl, especially lower alkanoylaminomethyl or 1- and primarily 2-lower alkanoylamino-ethyl,. e.g. acetylaminomethyl, 2-acetylaminoethyl or 2-propionylamino-ethyl or lower alkoxycarbonylamino-lower alkyl, especially lower alkoxycarbonylaminomethyl or 1- and primarily 2-lower alkoxycarbonylamino-ethyl, e.g. methoxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl or 2-ethoxycarbonylaminoethyl. Acylamino lower real oxy is e.g. lower-alkanoylamino-lower-alkyloxy, especially 2-lower-alkanoylamino-ethoxy, e.g. 2-(acetylamino)-ethoxy, or lower alkoxy-carbonylamino-lower-alkyl, especially 2-(lower-alkyl-carbonylamino-ethoxy, e.g. 2-(methoxycarbonylamino)-ethoxy or 2-(ethoxycarbonylamino)-ethoxy. Hydroxyl-lower-alkyl is preferably hydroxymethyl or 1- and primarily 2-hydroxyethyl. Lower oxyalkyl is preferably lower oxymethyl or 1- and primarily 2-lower alkoxyethyl, e.g. methoxymethyl, ethoxymethyl, 2-methoxyethyl or 2-ethoxyethyl. -methoxyethoxy or 2-ethoxy-ethoxy.

The alkylene alk can 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.

and R 2 in the meaning of lower alkyl is, for example, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl or heptyl and rather

all methyl or ethyl. Together with the nitrogen atom of the amide group and R ? as the lower alkylene, for example 1-aziridinyl, 1-azetidinyl, 1-pyrroidinyl, piperidino, hexahydro-1H-azepin-1-yl, as the oxalaverealkylene e.g. morpholino, such as thialaverealkylene e.g. thiomorpholino; such as the azalower alkylene e.g. 1-piperazinyl or hexahydro-1H-1,4-diazepin-1-yl, whereby both of the latter groups corresponding to the meaning of N-lower alkylazal lower alkylene for R^ and R2 can be substituted in the 4-position, i.e. in the imino group with e.g. . lower alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

The amide and adjacent hydroxy group-bearing phenyl group can be bound in any position with the other molecule, preferably the latter is in the 4-position of the said phenyl, i.e. in the para-position to the amide group, and above all bound in the 5-position in the aforementioned phenyl, i.e. in the para position to the hydroxy group.

The new compounds may exist in the form of their salts as their acid addition salts and primarily as pharmaceutically usable, non-toxic acid addition salts. Suitable salts are e.g. those with inorganic acids, such as halogen hydrogen acids, e.g. hydrochloric acids or hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids such as aliphatic, cycloaliphatic, aromatic or heterocyclic carbonic or sulphonic acids, e.g. formic, vinegar, propion, amber, glycol, milk, apple, wine, lemon, maleic, hydroxymaleic, pyrrhotite, fumaric, benzo, 4-aminobenzoic, anthranilic, 4-hydroxybenzo-, salicylic-, embonic-, methanesulfone-, ethanesulfone-, 2-hydroxyethanesulfone-, ethylenesulfone-, toluenesulfone-, naphthalenesulfone or sulfanilic acid or with other acidic organic substances such as ascorbic acid.

The invention relates in particular to compounds of formula I, in which Ar is optionally substituted one or more times, preferably three times at the most, whereby the substituents may optionally be present, especially on below. indicated manner, substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkylidenedioxy, lower alkylene dioxy, cyan and/or nitro, and/or directly or to the aforementioned lower alkyl, lower alkenyl or lower alkoxy bound lower alkanoyl, esterified or amidated carboxyl, in particular lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or (hydroxylower alkyl)-carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl or lower alkylsulfamoyl, and/or directly or to the aforementioned lower alkyl or in the higher than 1-position to the aforementioned lower alkoxy bonded halogen, lower alkylthio, amino, lower alkylamino, dilower alkylamino, alkylene - or oxaalkyleneamino, e.g. 1-pyrrolidinyl, piperidino or morpholino, pyrrole-1, acylamino, such as lower alkanoylamino or lower alkoxycarbonylamino, optionally with lower alkyl, hydroxy lower alkyl or cycloalkyl substituted ureido, lower alkylsulfonylamino, hydroxy, phenyl lower alkyl, e.g. benzyloxy, lower alkanoyloxy or, as a non-directly bonded substituent may again be lower alkoxy, m stands for a number from 0 to 3, n stands for the number 0 or 1 and alk means an alkylene residue with 2-4 carbon atoms, whereby the nitrogen atom and the oxygen atom or, if n stands for zero, the phenyl residue is separated from each other by 2-3 carbon atoms to the residue alk, R, and R2 have the meanings given under formula I, however preferably stand for hydrogen or lower alkyl, e.g. methyl or ethyl, or forms together with the nitrogen atom of the amide group morpholino or alkyleneamino with 5-6 ring members such as 1-pyrrolidinyl or piperidino, with the proviso that, if m stands for zero, the phenyl residue Ar contains at least one substituent and one with one or two hydroxy, 1-phenyl lower oxy or lower alkanoyloxy groups substituted phenyl residue Ar which contains at least one additional substituent different from these, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or as their salts, especially acid addition salts, above all pharmaceutical usable,

non-toxic acid addition salts.

The invention preferably relates to compounds of formula I, in which Ar is optionally substituted one to three times, whereby the substituents may optionally be substituted in the manner indicated below, lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkylidenedioxy, cyan and/or nitro and/or directly or to the aforementioned lower alkyl, lower alkenyl or lower alkoxy bonded lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxylower alkyl)-carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl, lower alkylsulfamoyl, and/or directly or to the aforementioned lower alkyl or in higher than 1- the position of the aforementioned lower alkoxy bonded halogen, lower alkylthio, amino, lower alkylamino, dilower alkylamino, alkylene- or oxaalkyleneamino, e.g. 1-pyrroidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbonylamino, optionally with lower alkyl, hydroxyl lower alkyl or cycloalkyl substituted ureido, lower alkyl sulfonylamino, phenyl lower real oxy, e.g. benzyloxy, lower alkanoyloxy or, as a non-directly bonded substituent may again be lower alkoxy, m stands for a number from 0 to 3 and n stands for the number 0 or 1, and alk means an alkylene residue with 2-4 carbon atoms, whereby the nitrogen atom and the oxygen atom or, if n stands for 0, the phenyl residue is separated from each other by 2-3 carbon atoms to the residue alk, and R^ has the meaning given under formula I, however preferably stands for hydrogen or lower alkyl, especially methyl or ethyl, or forms together with the nitrogen atom to the amino group 1-pyrroidinyl, piperidino or morpholino, with the proviso that, if m stands for zero, the phenyl residue Ar contains at least one substituent and one with one or two hydroxy-, 1-phenylloweraloxy- or loweralkanoyloxy groups substituted phenyl residue Ar containing at least one additional substituent different from these, in the form of racemate mixtures, racemates, optical antipodes, such as free compounds or their salts, especially acid addition salt ter, above all pharmaceutically usable, non-toxic acid addition salts.

The invention relates in particular to compounds of formula I, in which Ar is optionally one to three times substituted, whereby the substituents may be optionally substituted in the manner indicated below lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitro and/or cyan and/or directly or to the aforementioned lower alkyl, lower alkenyl or lower alkoxy bonded lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxylower alkyl)-carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl or lower alkylsulfamoyl, and/or directly or to the aforementioned lower alkyl or in the higher than 1-position of the aforementioned lower alkoxy bonded halogen, lower alkylthio, amino, lower alkylamino, dilower alkylamino, alkylene- or oxaalkyleneamino, e.g. 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbonylamino, optionally with lower alkyl or cycloalkyl substituted ureido, lower alkylsulfonylamino, hydroxy-phenyl lower alkoxy, e.g. benzyloxy, lower alkanoyloxy or, as a non-directly bonded substituent, can again be lower alkoxy, m stands for a number from 0 to 3, with the proviso that, if m stands for zero, the phenyl residue Ar contains at least one substituent and one with one or two hydroxy , 1-phenyl lower oxy or lower alkanoyloxy group substituted phenyl residue Ar which contains at least one additional substituent different from these,

n means the number 0 or 1 and alk means an alkylene residue of 2-4 carbon atoms, whereby the nitrogen atom and the oxygen atom, or, if n stands for zero, the phenyl residue are separated from each other by 2-3 carbon atoms to the residue alk, and R^ and R2

. denotes independently each hydrogen or lower alkyl, especially methyl or ethyl, or together with the nitrogen atom of the amide group morpholino, in the form of racemate mix-

dings, racemates, optical antipodes, such as free compounds or their salts, especially acid addition salts, above all pharmaceutically usable, non-toxic acid addition salts.

The invention relates above all to compounds of formula I, in which Ar is substituted one to three times, whereby the substituents can optionally be substituted in the manner indicated below, lower alkyl or lower alkoxy, further lower alkenyl, lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitr.o and/or cyan and/or directly or to the aforementioned lower alkyl or lower alkoxy bonded lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkaalkylcarbamoyl or (hydroxylower alkyl)-carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl and/or directly or to the aforementioned lower alkyl or in the higher than 1-position to the aforementioned lower alkoxy bonded halogen , lower alkylthio, amino, alkylene-or oxaalkyleneamino, e.g. 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino or lower alkoxycarbonylamino, or optionally with lower alkyl substituted ureido, lower alkylsulfonylamino, hydroxy, further phenyl lower aryloxy, e.g. benzyloxy, or, if no directly bonded substituent can again be lower alkoxy, m stands for a number from 0 to 3, with the proviso that, if m is zero, the phenyl residue Ar contains at least one substituent and one with one or two hydroxy, 1 -phenyl lower oxy or lower alkanoyloxy group substituted phenyl radical Ar containing a further substituent different from these, n means the number 0 or 1 and alk means an alkylene radical with 2-4 carbon atoms, whereby the nitrogen atom and the oxygen atom or, if n is 0, the phenyl radical are separated from each other of 2-3 carbon atoms to the residue alk and R1°^R2an<3ir independently from each other each hydrogen or lower alkyl, however preferably hydrogen or methyl, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, especially acid addition salts , above all pharmaceutical applicable, non-toxic. acid addition salts.

The invention primarily relates to compounds of formula I, in which Ar is optionally substituted one to three times, whereby the substituents may optionally be substituted lower alkyl in the manner specified 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. methylenedioxy and/or cyan and/or directly to the aforementioned lower alkyl or lower alkoxy bound lower alkanoyl,

e.g. acetyl, carbamoyl, lower alkylcarbamoyl, e.g. N-methylcarbamoyl or (hydroxylower alkyl)-carbamoyl, e.g. N-hydroxymethyl-carbamoyl, lower alkylsulfonyl,

e.g. methylsulfonyl, sulfamoyl, and/or directly or to the aforementioned lower alkyl, e.g. methyl, bound fluorine or chlorine, e.g. trifluoromethyl, hydroxy, or as directly bonded substituents phenyl lower real oxy, e.g. benzyloxy, lower alkoxy lower alkyl oxy, e.g. 2-methoxy-ethoxy, benzyloxy, amino, lower alkanoylamino, e.g. acetylamino, lower alkoxycarbonylamino, e.g. methoxycarbonylamino, or lower alkylsulfonylamino, e.g. methylsulfonylamino, m stands for a number from 0 to 3, with the proviso that, if m stands for 0, the phenyl residue Ar contains at least one substituent and a phenyl residue Ar substituted with one or two hydroxy or 1-phenyl-lower oxy groups that contains at least one further substituent which is different from these, n means the number 1 and alk means an alkylene residue with 2-4 carbon atoms, whereby the nitrogen atom and the oxygen atom are separated from each other by 2-3 carbon atoms to the residue alk, and and R^ denotes hydrogen, and the amide-

and nearby hydroxy group bearing phenyl residue is preferably bound in its 4- or 5-position with the rest of the molecule, in the form of racemate mixtures, racemates, optical antipodes, as well as free compounds or their salts, especially acid addition salts, above all pharmaceutical usable, non-toxic acid addition salts .

The invention relates above all to compounds of formula I, in which Ar is optionally substituted one to three times, whereby substituents can be mentioned as lower alkyl, lower alkoxy, hydroxyl lower alkyl, amino, lower alkanoylamino, lower alkylsulfonylamino, nitro, phenyl lower alkyl, ureido, halogen lower alkyl, halogen and hydroxy, and m stands for the number 0 with the proviso that a phenyl radical Ar substituted with one or two hydroxy groups contains at least one additional substituent that is different from these,

n means the number 0 or 1 and alk means an alkylene residue with

2-5 carbon atoms, whereby the nitrogen atom and the oxygen atom, or, if n stands for zero, the phenyl residue are separated from each other by at least two carbon atoms and R, and R^ independently of each other means lower alkyl with up to 4 carbon atoms or R^ and R^ together mean the lower alkyl with 4-6 carbon atoms in the unbranched chain, but especially hydrogen, in the form of racemate mixtures, racemates, optical antipodes as well as free compounds or their salts, especially acid addition salts, above all pharmaceutical tolerable, non-toxic acid addition salts.

The invention relates in particular to compounds

with formula I, in which Ar is substituted with lower alkylsulfonylamino such as methylsulfonylamino, optionally also substituted with halogen, such as chlorine, or is substituted with sulfamoyl, halogen, and chlorine, or lower alkoxy, such as methoxy, m stands for the number 0 and n means the number 0 or 1 and alk means an alkylene residue with 2-3 carbon atoms, whereby the nitrogen atom and the oxygen atom, or if n stands for zero, the phenyl residue are separated from each other by 2 carbon atoms, and R^ and R2 each mean hydrogen, in the form of racemate mixtures, racemates, optical antipodes, as well as free compounds or their salts, especially acid addition salts, above all pharmaceutically acceptable non-toxic acid addition salts.

The invention relates in particular to compounds of formula I, where Ar is substituted with sulfamoyl and halogen as well as chlorine, or lower alkoxy, such as methoxy, m stands for the number 0 and n means the number 1 and alk means an alkylene residue with 2-3 carbon atoms, whereby the nitrogen atom and the oxygen atom are separated from each other by at least two carbon atoms, and R₂ and R₂ each represent hydrogen, in the form of racemate mixtures, racemates, optical antipodes, as well as free compounds or their salts, especially acid addition salts, above all pharmaceutical tolerable, non-toxic acid addition salts.

The new derivatives of 2-amino-ethanol according to the invention correspond to the formula I illustrated above, in which Ar means optionally substituted phenyl, m means a number from 1 to 3, n means the number 0 or 1 and alk means the alkylene with 2- 5 carbon atoms, whereby the nitrogen atom and the oxygen atom or, if n stands for zero, the phenyl residue are separated from each other by at least two carbon atoms, and R^ and R2 independently of each other denote each hydrogen or lower alkyl, or together the lower alkyl, the oxala lower alkyl, the thiala lower alkyl, the aza lower alkyl or N- lower alkylazal lower alkylene, in the form of racemate mixtures, racemates, optical antipodes or their salts, especially acid addition salts, above all pharmaceutically acceptable, non-toxic acid addition salts.

The invention relates in particular to compounds

with formula I, in which Ar is optionally substituted one or more times, preferably no more than three times, whereby the substituents may optionally be present, especially in the manner indicated below, substituted lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkylidenedioxy, lower alkylenedi- oxy, cyan and/or nitro, and/or directly or to the aforementioned lower alkyl, lower alkenyl or lower alkoxy bonded lower alkanoyl, esterified or amidated carboxyl, especially lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or (hydroxylower alkyl)-carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl or lower-alkyl sulfamoyl and/or directly or to the aforementioned lower alkyl or in the higher than 1-position to the aforementioned lower alkoxy bonded halogen, lower alkylthio, amino, lower alkylamino, dilower alkylamino, alkylene- or oxaalkyleneamino, e.g. 1-pyrroidinyl, piperidino or morpholino, pyrrol-l-yl, acylamino, such as lower alkanoylamino or

lower alkoxycarbonylamino, optionally with lower alkyl, hydroxy lower alkyl or cycloalkyl substituted ureido, lower alkylsulfonylamino, hydroxy, phenyl lower alkyl, e.g. benzyloxy, lower alkanoyloxy or, as a non-directly bonded substituent, there may again be lower alkoxy, m stands for a number 1 from 3, n stands for the number 0 or 1 and alk means an alkylene residue with 2-4 carbon atoms, whereby the nitrogen atom and the oxygen atom or, if n stands for zero, the phenyl residue is separated from each other by 2-3 carbon atoms to the residue alk, R, and R2 has the meaning given under formula I, however preferably stands for hydrogen or lower alkyl, e.g. methyl or ethyl, or forms together with the nitrogen atom the amide group, morpholino or alkylenamino with 5-6 ring members such as 1-pyrrolidinyl or piperidino, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, especially acid addition salts, above all pharmaceutical tolerable , non-toxic acid addition salts.

The invention preferably relates to compounds of formula I, in which Ar is optionally substituted one to three times, whereby the substituents can optionally be substituted in the manner indicated below, lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkylidenedioxy, cyan and/or nitro and /or directly or to the aforementioned lower alkyl, lower alkenyl or lower alkoxy bonded lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxylower alkyl)-carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl, lower alkylsulfamoyl, and/or directly or to the aforementioned lower alkyl or in higher than 1 -the position of the aforementioned lower alkoxy bonded halogen, lower alkylthio, amino, lower alkylamino, dilower alkylamino, alkylene- or oxaalkyleneamino, e.g. 1-pyrroidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbonylamino, optionally with lower alkyl, hydroxyl lower alkyl or cycloalkyl substituted ureido, lower alkylsulfonylamino, phenyl lower alkoxy, e.g. benzyloxy, lower alkanoyloxy or, as a non-directly bonded substituent may again be lower alkoxy, m stands for a number from 1 to 3 and n means the number 0 or 1, and alk means an alkylene residue with 2-4 carbon atoms, whereby the nitrogen atom and the oxygen atom, or, if n is zero, the phenyl residue is separated from each other by 2-3 carbon atoms to the residue alk, R, and R^, when they have the meanings given under formula I, preferably stand for hydrogen or lower alkyl, especially methyl or ethyl, or form together with the nitrogen atom to the amino group 1-pyrroiidinyl, piperidino or morpholino, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, especially acid addition salts, above all pharmaceutically acceptable, non-toxic acid addition salts.

The invention relates in particular to compounds of formula I, in which Ar is optionally substituted one to three times, whereby the substituents can be optionally substituted in the ways indicated below, lower alkyl, lower alkenyl or lower alkoxy, further lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitro and/or cyan and/or directly or to the aforementioned lower alkyl, lower alkenyl or lower alkoxy bonded lower alkanoyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, (hydroxylower alkyl)-carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl or lower alkylsulfamoyl and/or directly or to the aforementioned lower alkyl or in the higher than 1-position to the aforementioned lower alkoxy bonded halogen, lower alkylthio, amino, lower alkylamino, dilower alkylamino, alkylene- or oxaalkyleneamino, e.g. 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino, lower alkoxycarbonylamino, optionally with lower alkyl or cycloalkyl substituted ureido, lower alkylsulfonylamino, hydroxy, phenyl lower oxy, e.g. benzyloxy, lower alkanoyloxy or, as a non-directly bonded substituent, lower alkoxy may again be present,

m stands for a number from 1 to 3, n means the number 0 or 1

and alk means an alkylene residue of 2-4 carbon atoms, whereby the nitrogen atom and the oxygen atom, or, if n is zero, the phenyl residue are separated from each other by 2-3 carbon atoms to the residue alk, and R, and R^independently each hydrogen or lower alkyl, especially methyl or ethyl, or forms together with the nitrogen atom or the amido group morpholino, in the form of racemate mixtures, racemates, optical antipodes, as free compounds or their salts, especially acid addition salts, above all pharmaceutically usable, non-toxic acid addition salts.

The invention primarily relates to compounds of formula I, in which Ar is optionally substituted one to three times, whereby the substituents may optionally be present in the ways indicated below substituted lower alkyl, or lower alkoxy, further lower alkenyl, lower alkenyloxy, lower alkynyloxy, lower alkylidenedioxy, nitro and/or cyan and /or directly or to the aforementioned lower alkyl or lower alkoxy bonded to lower alkanoyl, lower-alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or (hydroxylower alkyl)-carbamoyl, lower alkylsulfinyl, lower alkylsulfonyl, sulfamoyl and/or directly or to the aforementioned lower alkyl or in the higher than 1-position of the aforementioned lower alkoxy bonded halogen, lower alkylthio, amino, alkylene- or oxaalkyleneamino, e.g. 1-pyrrolidinyl, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino or lower alkoxycarbonylamino or optionally with lower alkyl substituted ureido, lower alkylsulfonylamino, hydroxy, further phenyl lower aryloxy, e.g. benzyloxy or, as a non-directly bound substituent, can again be lower alkoxy, m stands for a number from 1 to 3,

n means the number 0 or 1 and alk means an alkylene residue with 2-4 carbon atoms, whereby the nitrogen atom and the oxygen atom or, if n stands for 0, the phenyl residue are separated from each other by 2-3 carbon atoms to the residue alk, and R^ and R^

denotes independently each hydrogen or lower alkyl, however preferably hydrogen or methyl, in the form of racemate mixtures, racemates, optical antipodes, as free compounds

deis or their salts, especially acid addition salts, above all pharmaceutically usable, non-toxic acid addition salts.

The invention primarily relates to compounds of formula I, in which Ar is optionally substituted one to three times, whereby the substituents may optionally be present in the manner indicated below substituted lower alkyl, 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. methylenedioxy, and/or cyan and/or directly or to the aforementioned lower alkyl or lower alkoxy bound lower alkanoyl, e.g. acetyl, carbamoyl, lower alkylcarbamoyl, e.g. N-methylcarbamoyl, or (hydroxylower alkyl)-carbamoyl, e.g. N-hydroxymethylcarbamoyl, lower alkylsulfonyl, e.g. methylsulfonyl, sulfamoyl, and/or directly or to the aforementioned lower alkyl, e.g. methyl, bound fluorine or chlorine, e.g. trifluoromethyl, hydroxy.

The new compounds of formula I have valuable pharmacological properties. In particular, they act in a specific way on 3-adrenergic receptors. The basis for this effect is, as a general property of the compounds of formula I, the affinity for these receptors, which manifests itself with a lack of or very little stimulatory intrinsic effect as pure blockade, with a minor to moderately strong stimulatory intrinsic effect as blockade with simultaneous ISA, i.e. intrinsic sym- pathomimetic activity, and in the case of stronger intrinsic effects such as predominantly stimulation of the 3-adrenergic receptors. The boundaries between 3-receptor blockers without or with very medium-strength ISA are fluid, as are the therapeutic areas of application of these compound types. Of the compounds of formula I, which act as 3-receptor blockers without or with ISA, for example those which are substituted in the phenyl nucleus with a lower alkylsulfonylamino group, show e.g. α-1N-[2-(4-carbamoyl-3-hydroxyphenoxy)-1-methylethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol, especially those of an enantiomer pair with a melting point of 165-167° as the main action a blocking effect on 3-receptors (with slightly preferred inhibition of cardiac receptors), to which is added as an additional effect a weak blood pressure-lowering and 3-receptor-blocking effect. Connections of this kind, such as e.g. the aforementioned α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methylethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol as also both enantiomeric pairs of these with melting point 165-167° resp. . 144-145° , or ot-[N-[2-(4-carbamoyl-3-hydroxyphenoxy)-ethyl]-aminomethyl]-4-(methyl-sulfonylamino)-benzyl alcohol or a-[N-[2-( 3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol also shows a clear diuretic and saluretic effect, which can be shown e.g. after p.o. administration of 1 or 5 mg/kg of such compounds to dogs.

In the case of other compounds of formula I, (3-receptor-blocking as well as (3-receptor-stimulating) effects can be clearly established. These compounds are shown with regard to their effect on cardiac 3-receptors on the one hand in in vitro experiments on guinea pig hearts that potently block with relatively clear ISA, on the other hand, in in vivo experiments in the anesthetized cat predominantly as potent stimulators With respect to the action on vascular 3 receptors, they appear predominantly as blockers with medium ISA, while compounds of formula I, which in the phenyl nucleus Ar is substituted with lower alkyl, e.g. methyl, e.g. α-fN-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]-aminomethyl]-4- methylbenzylalcohol on tracheal 3 receptors proves to be strong stimulators.

To the latter group belong e.g. also such compounds, to which Ar denotes an etherified hydroxy-phenyl radical, such as e.g. α-[N-[2-(3-carbamoyl-4-hydroxy-phen-oxy)-ethyl]-aminomethyl]-3,4-methylenedioxy-benzyl alcohol, with which, in in vivo experiments on the cat, a cardio-selective 3-stimulation. As additional effects, e.g. with α-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methyl-ethyl ]-aminomethyl]-3,4-methylenedioxy-benzyl alcohol determine a blood pressure lowering as well as a weak blockade of adrenergic α-receptors.

The above-mentioned indications regarding pharmacological properties are based on the results of corresponding pharmacological tests in normal test procedures. Thus, the new 3-blocking compounds show an inhibition of isoproterenol-induced tachycardia on isolated pig hearts in a concentration range of approx. 0.001 to approx. 1 ug/ml and on anesthetized cats in a dose range of approx. 0.001 mg/kg to approx. 1 mg/kg by intravenous administration. The inhibition of isoproterenol-induced vasodilatation in anesthetized cats with perfusion of the femoral artery is demonstrable, when administered intravenously in a dose range from approx. 0.003 mg/kg to approx. 3 mg/kg. The ISA of B-blocking compounds of formula I results, if such is associated, from the increase in the basal heart rate of the anesthetized, reserpine-treated cat by intravenous administration in a dose range from 0.001 to 1 mg/kg. The new 8-blocking compounds also work in a dose range from approx.

0.1 mg/kg to approx. 10 mg/kg i.v. a lowering of the arterial blood pressure in an anesthetized cat. The further α-blocking effect, which e.g. can favor a blood pressure-lowering effect, appears e.g. of antagonizing the norepinephrine-induced contraction of the isolated rat vas deferens by such compounds at a concentration of 0.1 pg/ml to ca. 10 µg/ml. The new (3-blocking compounds of formula I can be used as possibly cardioselective, 3-receptor blockers, e.g. for the treatment of angina pectoris and heart rhythm disorders, as well as blood pressure-lowering agents. The in the case of certain types of compounds of formula I, for example, as above, the additional diuretic and saluretic effect present can lead to a significant strengthening of the anti-hypertensive effect and make the combination of the 3-receptor blockers with diuretics unavoidable.

The clear 3-receptor stimulating compounds of formula I, such as α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-3,4-methylenedioxy-benzyl alcohol, cause an increase of heart rate and myocardial contraction force on isolated porcine heart .. in a concentration range from approx. 0.0001 yg/ml to 0.1 yg/ml and an increase in heart rate and maximum rate of pressure increase in the left ventricle (dp/dt max.) in anesthetized cat in a dose range from approx. 0.001 mg/kg to approx. 1 mg/kg i.v. The new compounds partially selectively stimulate the cardiac 3-receptors receptors) in comparison to the 3-receptors in the blood vessels (32_resPtors) and thereby differ qualitatively clearly from isoproterenol, which stimulates the 3-receptors of the heart and blood vessels approximately equally strongly. In part, the compounds of formula I also have a relatively clear stimulating effect on 32 receptors• (Blood vessels, trachea).

The new stimulating active compounds of formula I can therefore be used 1) as stimulators for cardiac 3-receptors for the treatment of heart muscle insufficiency and heart rhythm disturbances, 2) as stimulators for tracheal and vascular 3-receptors as broncho- and vasodilators for the treatment of asthma, heart failure and blood flow control travels.

The new compounds of formula I are prepared

in a manner known per se. You can obtain these e.g. when converting a compound with formula

with a compound of formula

in which one of the groups Z^ and Z~ denotes a reactive esterified hydroxy group and the other stands for the primary amino group, and X^ means hydroxy, or in which X, and Z, together mean the epoxy group and Z^ stands for the primary amino group, Ar, alk, m and n have the meaning stated above, and, if desired, convert a compound obtained into another compound of formula I, and/or, if desired, transfer a compound obtained free into a salt or a salt obtained into a free compound, and/or, if desired, separates an obtained racemate mixture into the racemates or an obtained racemate into the optical antipodes.

A reactive esterified hydroxy group Z, resp. Z 2 is one, of a strong acid, especially a strong inorganic acid, such as a hydrohalic acid, especially chloro-,

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 group, and denotes primarily halogen, e.g. chlorine, bromine or iodine, or aliphatic or aromatically substituted sulphonyloxy, e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy.

The above-mentioned reactions are carried out on

per se known manner, whereby, especially when using a starting material with a reactive esterified hydroxy group, it is most advantageous to work in the presence of a basic agent such as an inorganic base, e.g. an alkali metal or alkaline earth metal carbonate or hydroxide, or in the presence of an organic basic agent such as an alkali metal low-alkaline anolate, and/or working in the presence of an excess of the basic reactant and usually in the presence,

but optionally also in the absence of a solvent or solvent mixture and, if necessary, working under cooling or heating, e.g. in a temperature range from approx. -20°C to approx. +150°C, in an open or closed vessel and/or in an inert gas atmosphere, e.g. in a nitrogen atmosphere.

Starting substances with the formulas II or III are known or can be prepared according to methods known per se. Then, for the preparation of a starting material of formula II, in which m stands for zero, a compound of formula Ar-H can be halogen-acetylated, in which any amino or hydroxy groups present can be protected by a protecting group, e.g. one of those described below, with a haloacetyl halide, e.g. chloroacetyl chloride, in the presence of a suitable Lewis acid, e.g. aluminum chloride, according to the Friedel-Crafts method to a carbon atom to the residue Ar and in the thus obtainable Ar haloacetyl compound, e.g. by treatment with a suitable hydride reducing agent, reduce the carbonyl group to carbinol group; if desired, one can convert a halogen Z, e.g. by treatment with ammonia or a suitable derivative thereof, such as hexamethylenetetramine, and cleavage of the obtained compound with dilute mineral acid, or by reaction with an alkali metal salt to phthalimide and cleavage of the obtained N-phthalimide compound, e.g. with hydrazine, in the primary amino group Z^. Starting material f is of formula II, in which Xlog Zlti-lsamiTien means epoxy, can be obtained e.g. by cyclization of a compound of formula II in which X denotes hydroxy and Z denotes a reactive esterified hydroxy group, possibly chlorine or methanesulfonyloxy, by means of alkaline reagents, e.g. a mixture of dilute caustic soda and tetrabutylammonium chloride in a suitable solvent, e.g. methylene chloride.

Starting substances with formula II, in which m has the meaning given above and X^ and Z-^ together mean the epoxy group, and any amino or hydroxy groups present are e.g. as subsequently indicated protected, can be obtained by converting the group -CH=CH2 in a compound of formula Ar-(CH2)m-CH=CH2(Ha) by introducing the epoxy group into the group

e.g. by reaction with a peroxy compound,

such as hydrogen peroxide, or an organic peracid, such as

an optionally substituted halogenated, aliphatic or aromatic peracid, e.g. peracetic acid or trifluoroperacetic acid, perbenzoic acid or m-chloroperbenzoic acid, in an anhydrous solvent, such as chloroform. This turnover is carried out in the usual way.

Starting substances with formula III can be obtained, e.g. by reacting a hydroxysalicylamide with a corresponding dihalide in the sense of alk, possibly a chlorobromo- or dibromoalkane in the presence of an alkaline condensing agent, such as an alkali carbonate, and, if desired, substituting the remaining halogen 7,^ in the above for Z -^ indicated manner by the primary amino group. This turnover is carried out in the usual way, whereby amino or the hydroxy groups standing protective groups simultaneously or subsequently, e.g. as described, is split off.

The compounds of formula I can further be prepared by using a compound of formula

wherein Ar ^ has the meaning of Ar or means a residue Ar, which is substituted by 1-2 in hydroxy and/or amino transferable groups, X^, X^ and X^ each means hydrogen or a hydrogen-exchangeable substituent and X,- stands for , or X^and X^and/or X^and X^ together mean a divalent residue exchangeable with two hydrogen atoms with the proviso that at least one of the residues X^, X^and X^ is different from hydrogen, or at least Ar ^ means a residue At which is substituted by every 1-2 in hydroxy and/or amino transferable groups or at least X^ and X^ together or X^ and X<- together indicates a divalent, with two hydrogen atoms replaceable residue,

and m and n have the meanings given above, or a salt thereof, that of hydrogen different X^, X^ or X^, respectively. X^ and X^ together or X^ and X,- together replace with et

hydrogen, and/or in a residue Ar, transfer the present substituted hydroxy and/or amino into free hydroxy and/or amino, and if desired, carry out the additional procedures mentioned adjacent to the first method.

The splitting of the groups X^ t X^or X^or each X^and X^ or X^and X<- together as well as the possibly

in a residue Ar-^present protective groups of hydroxy and/or amino substituents carry out by means of solvolysis, such as hydroxy, alcoholysis, aminolysis or acidolysis, or by means of reduction including hydrogenolysis.

Particularly suitable cleavable groups X^ and X^ or hydroxy and/or amino protecting groups in a residue Ar^ are primarily hydrogenolytically cleavable α-aryl lower alkyl groups such as an optionally substituted 1-polyphenyl or 1-phenyl lower alkyl group , where i.substituents, especially for the phenyl part, can be e.g. lower alkyl, such as methyl, or lower alkoxy, such as methoxy and primarily benzyl. Group X^and especially X^and X^as well as hydroxy and/or amino protecting groups in a residue Ar-^can also denote solvolytic, such as hydrolytic or acidolytic, further reductive, including hydrogenolytic cleavable residues, especially corresponding acyl residues such as the acyl residue of a organic carbonic acid, e.g. lower alkanoyl, such as acetyl or aroyl, such as benzoyl, further the acyl residue of a half-ester to the carboxylic acid, such as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halo-lower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally substituted 1-phenyl lower oxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, further optionally substituted 1-poly-phenyl lower alkyl groups, in which substituents, primarily to the phenyl part such as e.g. has the above meaning, and primarily trityl.

A cleavable residue formed by X2 and X^ and/or X^ and X^ together is primarily a hydrogenolytically cleavable divalent group as optionally substituted 1-phenyl lower alkylidene, in which substituents, especially for the phenyl part,

can be e.g. lower alkyl or lower alkoxy, and especially benzylidene as well as solvolytic, especially hydrolytically cleavable groups, such as lower alkylidene, e.g. methylene or isopropylidene, or 1-phenyl-lower alkylidene, if phenyl-

part is optionally substituted with lower alkyl, such as methyl or lower alkoxy, such as methoxy, especially benzylidene, or cycloalkylidene, e.g. cyclopentylidene or cyclohexylidene.

In the form of salts usable starting materials

is primarily used in the form of acid addition salts, e.g. with mineral acids as well as with organic acids.

Hydrogenolytically cleavable residues X^ r X^ and/or X^, especially optionally substituted 1-phenyl lower alkyl groups, further also suitable acyl groups, such as optionally substituted 1-phenyl lower alkyl carbonyl, and of the groups X2

and X^ as well as X^ and X,- formed together, optionally substituted 1-phenyl lower alkylidene groups, as well as hydroxy and/or amino protecting groups of this type present in a residue Ar^ can be cleaved off by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a nickel catalyst, such as Raney nickel, or a suitable noble metal catalyst.

Hydrolytically cleavable groups X2, X^ and/or X^j as well as acyl residues of organic carboxylic acids, e.g. lower alkanoyl, and of half-esters to the carboxylic acid, e.g. lower alkoxy car bonyl, further e.g. trityl residues, as well as lower alkylidene, 1-phenyl-lower alkylidene or cycloalkylidene groups formed by the residues X2 and X-j and/or X^ and X, together with hydroxy and/or amino protecting groups present in a residue Ar^ of this species can be split off each according to the nature of such residues 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 in the presence of an alkali metal or alkaline earth metal hydroxide or carbonate or in the presence of an amide such as isopropylamine.

In the case of aminolysis, for example, acyl residues and especially of x. and X,, together formed lower alkylidene, 1-phenyl lower alkylidene or cycloalkylidene groups such as e.g. 1-Methylethylidene groups are split off, for example by reaction with ammonia or especially in the case of the aforementioned divalent protecting groups, with primary amines, such as e.g. isopropylamine or benzylamine, in a suitable reaction medium such as e.g. isopropanol or dioxane. As a primary amine, a starting material of formula II can also function for the first-mentioned preparation method for the compounds of formula I. Therefore, the reaction yields compounds of formula IVe given below, in which X^ and X,- together mean one of the above-mentioned divalent protection groups such as isopropylidene,

with the double molar amount of corresponding starting substances with formula II, which in turn also falls under formula IVa, during cleavage of the protective groups formed by X^ and X^ direct end products with formula I, while the said protective groups remain and the corresponding starting substance with formula IV is formed when, as a halogen hydrogen binding agent, instead of an excess of the compound with formula II or IVa uses e.g. certain inorganic bases, such as alkali metal carbonates.

Acidolytically cleavable residues X2, X^ and/or X^ and/or hydroxy and/or amino protecting groups in a residue Ar^ are particularly defined acyl residues of half-esters of the carboxylic acid, such as e.g. tert.-lower oxycarbonyl or optionally substituted diphenylmethoxycarbonyl residues, furthermore also the tert.-butyl residue; such residues can be split off by treatment with suitable strong organic carbonic acids,

as optionally with halogen, especially fluorine, substituted lower alkanecarboxylic acids, primarily with trifluoroacetic acid (if necessary, in the presence of an activating agent such as anisole), as well as with formic acid.

Under reductively cleavable residues X^, X^and/or X^and/or hydroxy and/or amino protecting groups in a residue Ar^ are also understood such groups as

treatment with a chemical reducing agent (especially with

a reducing metal or a reducing metal compound) splits off. Such residues are especially 2-halo-lower oxycarbonyl or arylmethoxycarbonyl, which can be cleaved off e.g. by 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 or acetic acid, and from water.

Protecting groups, which are bound in a residue Ar^ to which any hydroxy and/or amino groups are bound, correspond to the aforementioned and the groups that can be cleaved and replaced using the described methods, whereby such groups are simultaneously cleaved off during the described methods • together with other groups or is subsequently split off by a special procedural rule.

The above-mentioned reactions are usually carried out in the presence of a solvent or solvent mixture, whereby suitable reaction participants can simultaneously also function as such and, if necessary, during 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 formula IV can be obtained

in a manner known in and of itself, since for the production of a starting material, in which m stands for zero, one converts e.g. a compound of formula Ar^-H with a haloacetyl halide, e.g. chloroacetyl chloride, in the presence of a suitable Lewis acid, e.g. aluminum chloride, by the Friedel-Crafts method, reduces the carbonyl group in the thus obtained or in otherwise obtained Ar^-halogenacety1-for bond, e.g. with the aid of sodium borohydride, to the carbinol group and reacts the resulting compound with an amine of the formula

in which X^has the indicated meaning and X^or X^and. X,.

is different from hydrogen.

Starting substances of formula IV, in which m has the meaning indicated above, are available by reacting a compound of the above-explained formula II with a compound of formula IVa. This turnover is carried out in a manner known per se.

One further e.g. that by reacting a compound with formula

with a carbonyl compound of the formula in which R means an alkylene residue corresponding to alk, one of the oxygen atom or the phenyl residue of at least one carbon atom separated carbonyl groups ing containing an alkyl residue and X^ or X^ and X5 together means one of the specified protecting groups, formed Schiff's base with a borohydride , such as sodium borohydride, reduce to the compound of formula IV. The reduction can also take place using activated hydrogen in the presence of a hydrogenation catalyst, e.g. a platinum-on-carbon catalyst. Amines of formula IVb, in which indicates hydrogen or a group that can be split off by means of reduction including hydrogenolysis and replaceable with hydrogen, can e.g. is produced by reacting a compound of formula

in which X and Z have the meaning given under formula (II),

With ammonia or a residue containing an amine that can be replaced by reduction and with hydrogen, e.g. benzylamine.

Carbonyl compounds of formula (IVc), in which n denotes the value 1, can be obtained by reacting a compound of formula

with a compound of formula R-Hal (IVf), in which R has the above meaning, and a compound (IVf) denotes e.g. et•halo ketone, e.g. chloroacetone, in a known manner. Of the aforementioned compounds of formula (IVe), one can also by reaction with non-geminal, especially vicinal dihalolower alkanes, above all dibromo- or bromo-chloro-lower alkane compounds of formula

in which. Hal means a bromine or chlorine atom and R2alk, X^ and X, have the above meaning, prepare and react these with compounds of formula IVb to starting substances of formula IV, whereby, as already mentioned, possibly directly end products of formula I are formed .

The new compounds of formula I can likewise be obtained by using in a compound of formula in which Xg is a reducible group with the formulas

whereby alk^ stands for a residue alk corresponding to the alkyl-ylidene residue and alk2 corresponds to a shortened residue alk if a methylene group bonded to the nitrogen atom, X^ denotes the oxo or thio-oxo residue and Xg denotes hydrogen or one under the conditions for reduction of Xg and/ or Y with a hydrogen exchangeable residue and Y stands for a residue of formula -CO- (Vf) or

-CH(OXg)-(Vg), in which Xg has the meaning stated above, Ar2 corresponds to a residue Ar, however optionally instead of each one or two hydroxy and/or amino carries one or

two groups -OXg, and/or -N(Xg)-, in which Xg has the above-mentioned meaning, m and n have the above-mentioned meanings, whereby always Xg is a reducible group Va to Vd and/or Y is a carbonyl group Vf, reduce these group(s) and, in the same work operation, replace the hydrogen-different groups Xg with hydrogen, and, if desired, carry out the aforementioned process step further in connection with the first process.

A hydrogenolytically cleavable group Xg is primarily an α-aryl lower alkyl group such as an optionally substituted 1-phenyl lower alkyl group, in which substituents can be e.g. lower alkoxy, such as methoxy, and especially benzyl.

Protective groups which are bound to the group Ar2, which is optionally substituted with hydroxy and/or amino groups, correspond to the groups mentioned above for Xg and which can be split off using the described methods and are exchangeable with hydrogen, whereby such groups during the described method simultaneously with other groups or subsequently in a separate method step are split off.

Starting substances of formula V with a group Xg of formula Vb can also exist in the isomeric form of ring tautomers of formula

in which alk-j corresponds to the meaning of alk^ and the oxygen and nitrogen atoms of the ring are attached to the same carbon atom.

An alkyl-ylidene group alk^ is e.g. 1-ethyl-2-ylidene or 2-methyl-1-ethyl-2-ylidene, while an alkylidene group alk2 indicates e.g. methylene, ethylidene or 1-methyl-ethylidene.

The reduction of the nitrogen-carbon double bond in the starting substances of formula V which as Xg contains a group Va or Vb, while Ar2, Y, Xg and n have the meaning given under formula V (or the oxygen-carbon-nitrogen bond of the isomeric compounds with formula Vg) to nitrogen-carbon single bond can take place in a manner known per se, e.g. by treatment with a catalytically activated hydrogen, such as hydrogen in the presence of a suitable hydrogenation catalyst, e.g. a nickel, platinum or palladium catalyst, whereby hydrogenolytic cleavable groups Xg are simultaneously cleaved off and replaced with hydrogen, or one works with a suitable hydride reducing agent such as an alkali metal borohydride, e.g. sodium borohydride. In all cases, at the same time as the group Va or Vb, a carbonyl residue Y is also reduced, if present, to a hydroxymethylene residue and, by using a hydride reducing agent, acyl residues of carboxylic acids can also be bound to oxygen, such as e.g. acetic acid, present as residues Xg and split off during the same work operation.

The reduction of the carbonyl group Y in starting substances with the general formula V, which as a residue X^ contains a group Ve, while xg 0<3 n has the meaning given under formula V, can take place both above for the reduction of the groups Va and Vb in the manner indicated, whereby, on the other hand, during the catalytic hydrogenation, hydrogenolytically corresponding residues Xg can be split off.

Especially suitable for the reduction of compounds of formula V with a group of formula Ve or Vd and the meanings of Ar, >, Y and n defined under formula V are hydride reducing agents such as e.g. sodium borohydride or d i bo r a n .

At the same time as the reduction of a group Vc or Vd, the reduction of a carbonyl group Y occurs, if this

is present, as well as the cleavage of oxygen-bound acyl residues of carboxylic acids, such as e.g. acetic acid, as residue Xg. On the other hand, by limiting the amount of reducing agent and choosing suitable reduction conditions, it must be ensured that the aromatic bound carboxamide group is not reduced. Groups with the formulas Ve and Vd, in which X-, means a thiooxo group, are converted by reductive desulphurisation, e.g. by treatment with a hydrogenation catalyst such as Raney nickel, in the grouping of formula

-CT^-NH-alk-. The above-mentioned reduction reactions are carried out in a manner known per se, usually in the presence of an inert solvent and, if necessary, during cooling or heating, e.g. in a temperature range from approx. -20° to approx. +150°, and/or in a closed vessel under pressure and/or in an inert gas, e.g. nitrogen atmosphere. A starting material of formula V, in which m stands for zero, can be produced in a manner known per se, possibly in situ, i.e. under the conditions of the described method. Thus, one can acylate a compound of the formula Ar2-H (Vi) with an acetic acid halide or anhydride in the presence of a Lewis acid and then convert the acetyl group in the intermediate product obtained, e.g. by treatment with a suitable oxidizing agent, as well as selenium dioxide, in the glyoxyloyl group. Such a glyoxyl compound, or, if desired, a suitable derivative thereof, such as an acetal, can then be reacted with an amine of the formula

to a starting product of formula V with the group X, of formula Va, in which Y denotes the carbonyl group. You can further halogen-acetylate a compound of formula (Vi) with a halogen acetyl halide, e.g. chloroacetyl chloride, in the presence of a suitable Lewis acid, e.g. aluminum chloride, according to the Friedel-Crafts method to the corresponding Ar2-chloroacetyl compound, in the halogen-acetyl compound obtainable in this way or in other usual ways, reduce the carbonyl group to the carbinol group by treatment with a suitable hydride reducing agent, and convert the halogen atom by treatment with ammonia or a suitable derivative thereof, such as hexamethylenetetramine, and cleavage of the formed reaction product with dilute acid, such as aqueous hydrochloric acid, in the primary amino group, after which one obtains an intermediate of formula in which m stands for zero. Amines of formula Vk, on the other hand, in which m has the meaning given above, are obtainable in a known manner, e.g. by reacting a compound of formula in which X^ and Z-^ have the meaning indicated under formula (II) with ammonia or an ammonia-yielding compound, e.g. hexamethylenetetramine, whereby compounds of formula (VI) can be obtained analogously to the method described for the preparation of starting materials of formula (II). Amines of formula Vk, in which m has the above meaning, can also be obtained by reacting an aldehyde of formula or a suitable derivative thereof, such as an acetal, e.g. dimethyl acetals or a bisulphite addition compound, with a suitable organosilicon cyano compound, such as a trilower alkyl, e.g. trimethylsilyl cyanide, in the usual way in the presence of a catalyst, such as zinc iodide, to a compound of formula and whose conversion takes place by means of a suitable reducing agent, e.g. a dilate metal hydride, such as lithium aluminum hydride in a solvent, usually an ethereal liquid, e.g. diethyl ether or tetrahydrofuran, in a compound of formula Vk, in which m has the meaning given above. In the reaction of an intermediate of formula Vk with a carbonyl compound of formula

starting materials of formula V can be obtained with a group Xg of formula (Vb). A modification of this reaction consists in replacing the halogen atom in the previously described intermediate, instead of replacing it by treatment with

ammonia etc. against the primary amino group by reaction with a 1-aryl-lower acylamine, e.g. benzylamine or a di-(1-aryl-lower alkyl)amine e.g. dibenzylamine against the corresponding 1-aryl lower alkylamino or di-(1-aryl lower alkyl) amino group and reacts the compound obtained, such as the corresponding dibenzylamino compound, with the oxo compound of formula (VI) under the reducing conditions of the process. In this way, catalytically activated hydrogen, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst or a mixture thereof, such as a palladium and/or platinum catalyst. Under such reaction conditions, hydrogenolytically cleavable groups Xg, e.g. benzyl groups, split off, the possibly present carbonyl group is reduced to a carbinol group and at the same time the nitrogen-carbon double bond is reduced to a corresponding nitrogen-carbon single bond.

Oxo compounds with formula Vo, on the other hand, in which n stands for 1, are obtainable, e.g. by reacting a dihydroxy compound of formula

with a haloalkanone compound of the above 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.

Starting products of formula V with a group Xg of formula Vc or Vd can be prepared in a manner known per se, by reacting e.g. a formyl compound of the formula Ar^-(CH^)^-CHO (Vq) with hydrogen cyanide and hydrolyzes in the thus obtainable cyanohydrin intermediate the cyano group to a carboxyl group, e.g. under acidic conditions. The hr^-2-hydroxyacetic acid thus obtained or via the intermediate stage imide chloride, imido-lower alkyl ester and lower alkyl ester was then reacted in the presence of a suitable condensing agent, e.g. a carbodiimide, such as dicyclohexylcarbodiimide, with an amine of formula (Vj), after which a starting material of formula V with the group Xg of formula (Vc) is obtained.

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

in which Hal stands for halogen and especially for chlorine, obtain a starting material of formula (V) with the group Xg of formula (Vd). Furthermore, in the above-mentioned A^-chloro-acetyl compound, the chlorine can be replaced, for example, by reaction with hexamethylenetetramine against the primary amino group and a compound thus obtained is reacted with a halogen compound of formula Vr. In a thus obtained starting product of formula V with a group Xg of formula Vd and in which Y denotes the carbonyl group, one can simultaneously reduce the carbonyl group to the carbinol group and the aliphatic bound carbamoyl group to the group of formula

-CH9- N - alk - , for example by means of a hydride reduction-H

sion agent, especially diborane.

The new compounds of formula I can likewise be obtained by reacting a compound of formula

in which Ar^ has the meaning of Ar or denotes a residue Ar,

which with 1-2 by means of aminolysis are transferable into hydroxy and/or amino and/or are substituted with groups

with the formula -COOH, Xg means hydrogen or a group cleavable by means of aminolysis and m and n have the meanings given above, or a reactive derivative of a carboxylic acid as defined in formula VI, with a compound of formula HNR^T^ (VII ) and simultaneously transfers any present by means of aminolysis in hydroxy and/or amino

transferable residues in hydroxy and/or amino, and/or cleave off any present residues Xg and replace with hydrogen, and, if desired, carry out the additional method steps mentioned in connection with the first method. Hydrolytically and in particular by means of aminolysis in hydroxy and/or amino transferable residues or residues cleavable in this way Xg are acyl residues of organic carboxylic acids, e.g. aroyl, such as benzoyl, or lower alkanoyl such as acetyl.

Reactive derivatives of the carboxylic acids defined in formula VI are e.g. the halides such as the chlorides or bromides, further the azides as well as acid anhydrides, especially mixed acid anhydrides with e.g. lower alkanecarboxylic acids, such as acetic or propionic acid, lower alkoxyalkanecarboxylic acids, such as 2-methoxyacetic acid. Reactive derivatives of carboxylic acids of formula VI are especially esters, e.g.

with lower alkanols such as methanol, ethanol, isopropanol, tert.-butanol, further with aryl lower alkanols, such as optionally with lower alkyl, e.g. methyl, or lower alkoxy, e.g. methoxy, substituted benzyl alcohol or phenols which are optionally activated with suitable substituents, e.g. with halogen, such as 4-halogen, such as 4-chloro, lower alkoxy, such as 4-lower oxy such as 4-methoxy, 4-nitro or 2,4-dinitro, such as for example 4-chlorophenol, 4-methoxyphenol, 4-nitro-

or 2,4-diytrophenol, further esters with cycloalkanols, such as for example cyclopentanol or cyclohexanol which may optionally be substituted with lower alkyl, e.g. methyl. The reaction is carried out in a manner known per se, usually in the presence of an inert solvent, e.g. in a temperature range from approx. -10° to + 50°C in a closed vessel.

The starting materials of formula VI, in which m stands

for zero, can be obtained in a manner known per se, by brominating a compound of the formula Ar^ - COCl- l^, reducing the carbonyl group in the thus obtained Ar^<->haloacetyl compound to a carbinol group, e.g. using diborane, and reacts the resulting compound with an amine of formula

wherein Xg has the above meaning, or a reactive derivative thereof. One can also react the Ar 1 -haloacetyl compound with the amine of formula Via and later convert the carbonyl group into a carbinol group. For the preparation of the starting material of formula VI, in which m has the meaning given above, it can further be obtained by reacting a compound of formula with a carbonyl compound of formula

in which R corresponds to an alkyl residue corresponding to alk, a carbonyl group containing an alkyl residue, i.e. an oxoalkyl residue, the Schiff's base formed reduces with a borohydride, for example sodium borohydride.

The reduction can also take place using activated hydrogen in the presence of a hydrogenation catalyst, e.g. a platinum-on-carbon catalyst.

Compounds of formula VIb are obtainable e.g.

by reacting a compound with formula

in which X^ and Z^ together mean epoxy, or X^ means hydroxy and Z^ means a reactive esterified hydroxy group, e.g. halogen as well as chlorine, with ammonia, or, if X^ means hydroxy and Z^, e.g. means chlorine, with hexamethylenetetramine and cleavage of the adduct formed with dilute mineral acid, such as dilute hydrochloric acid, whereby starting substances of formula Vid can be prepared analogously to the method described for the preparation of starting substances of formula II. Carbonyl compounds of formula (VIc), on the other hand, in which n means 1, can be obtained by reacting a compound of formula with a compound of formula R-Hal.(IVf), in which Hal stands for halogen, especially chlorine, on i and known manner. The new compounds of formula I, in which R 1 and R 2 each mean hydrogen, can likewise be obtained, as in a compound of formula

in which one or both hydroxy groups and/or hydroxy and/or amino groups present in residues Ar are optionally protected by such groups that can be split off by means of hydrolysis and are replaceable with hydrogen, as under the conditions

until the method is split off and replaced with hydrogen or the group -CN is present in the residue Ar optionally together with the aforementioned protected hydroxy and/or amino groups, converts the group -CN by means of hydrolysis into the group -CONH^ and simultaneously converts optionally protected hydroxy and/or or amino groups in free hydroxy and/or amino groups, and, if desired, they carry out in connection with the first method mentioned additional method steps.

The starting materials with formula VII can be prepared in the usual way by reacting a compound with formula

with a compound of formula

where Hal stands for chlorine, bromine or iodine. The conversion is carried out most advantageously in the presence of a basic agent in a manner known per se.

Starting materials of formula (Vila) on the one hand, in which m has the above-mentioned meaning, are obtainable by reacting a compound of formula (II), in which and Z, can together mean the epoxy group, with ammonia, or when X^means hydroxy and Z^means as reactive esterified hydroxy group, e.g. halogen, such as chlorine, e.g. with hexamethylenetetramine and subsequent conversion of the obtained adduct with dilute mineral acid as dilute hydrochloric acid.

Starting substances with formula (VII), in which m stands for zero, can further be prepared in the usual way, e.g. halogenates a compound of formula Ar-COCH^

(VIIc), e.g. bromates, for example by means of bromine i

an inert solvent, such as chloroform, replaces in the Ar haloacetyl compound thus obtained, e.g. Ar-bromoacetyl compound halogenated with the amino group, e.g. by reaction with hexamethylenetetramine in a solvent, for example a chlorohydrocarbon, such as chloroform, the resulting adduct cleaves with dilute mineral acid, e.g. hydrochloric acid, in the obtained compound with the formula Ar-CO-CH2-NH2(VHd) reduces carbonyl groups to carbinol groups, e.g. using diborane, and reacts the obtained compound with formula

with a compound of the above-explained formula VHb in the manner indicated therein.

A compound of formula VHb, on the other hand, can be obtained by the action of acetic anhydride on the oxime corresponding to the cyanide. This happens conveniently when boiling under reflux. On the one hand, the oxime can be prepared from the corresponding aldehyde by boiling with hydroxylamine hydrochloride in the presence of alcoholic sodium carbonate solution under reflux. The corresponding aldehyde, on the other hand, can be prepared by reacting 2,4-dihydroxybenzaldehyde) with an α,3-α,y- or α,αi-dihalolower alkane, preferably in the presence of a basic agent. One can also convert a hydroxy-salicylonitrile in an analogous way, e.g. 2,4-dihydroxybenzonitrile [Chem. Ber. 24, 2657 (189.1)] or 2,5-dihydroxybenzoni tr i 1 [Heiv. Chim. Acta 3^0, 149, 153 (1947)] with a non-geminal diha-. log lower alkane to a compound of formula VHb.

The new compounds of formula I, in which m stands for 1, 2 or 3, can also be obtained when in a compound of formula in which A stands for the group -N-alk- or -N=alk,-, in which alk^ denotes a group containing a methylene group smaller than alk and X denotes a group transferable by means of reduction, including hydrogenolysis, into a methylene, 1,2-ethylene or 1,3-propylene group and one or both hydroxy groups and/ or in the residue Ar any hydroxy and/or amino groups present are protected as such by means of reduction> including hydrogenolysis, of cleavable and by reduction replaceable groups, which under the conditions of the process are cleaved off and replaced with hydrogen, the group X converts by means of reduction including hydrogenolysis in a methylene, 1,2-ethylene or 1,3-propylene group and at the same time converts an optionally present unsaturated group A into a saturated group A and at the same time converts any present protected hydroxy and/or amino groups into free hy hydroxy and/or amino groups, and, if desired, carries out in connection with the first method mentioned further method steps.

A group X specifically indicates instead of a methylene group a carbonyl group which, corresponding to the meaning of m as 1, 2 or 3, either stands alone or together with one or two methylene groups occupies each of the possible positions.

A group X also denotes a doubly or triply unsaturated group with 2-3 carbon atoms, e.g. a 1,2-ethenylene, 1,2-propenylene, 2,3-propenylene or 1,2-ethynylene or 1,3-propynylene group.

The reduction of the group X takes place in the usual way, e.g. by means of activated hydrogen, for example hydrogen in the presence of a hydrogenation catalyst, e.g. a nickel- or optionally on a support material, such as activated carbon, deposited noble metal catalyst such as platinum or palladium, or a platinum or palladium-on-carbon catalyst. In this way, any existing hydrogenolytic cleavable hydroxy and/or amino protecting groups are split off and replaced with 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 substances of formula VIII, in which X means a group of formulas -CO- (VHIa), -CO-CH2- (VHIb) or -CO-CH2-CH2- (VIIIc) and in the residue Ar, as previously indicated, are present protected hydroxy and/or amino groups, can be obtained in a manner known per se, as in a compound of formula

epoxidizes the group -CH=CH2 to the group (cf. here: Cahnmann, Bull.Soc.Chim France [5], 4, 1937, 226, 230.) e.g., as described under the starting substances of formula (II), by reaction with a peroxy compound, such as hydrogen peroxide, or an organic peracid, such as e.g. an optionally substituted, such as halogenated aliphatic or aromatic peracid, e.g. peracetic acid or trifluoroperacetic acid, perbenzoic acid or m-chlorobenzoic acid in an anhydrous solvent, e.g. chloroform or dioxane. In addition, the obtained connection or one of these, e.g. by reaction with a hydrohalic acid, e.g. hydrochloric acid in a solvent, such as dioxane, converts the obtained compound of the general formula in which X^ and Z-. together means epoxy or X^ means hydroxy and Z^ halogen e.g. chlorine, with ammonia, or if X2 and Z^ are halogen, with hexamethylenetetramine and later cleavage of the adduct obtained with a dilute mineral acid, e.g. hydrochloric acid in a compound of formula From this can be prepared by reaction with a compound of formula in which Hal stands for halogen and especially for chlorine, a starting material of formula VIII with the group A of formula -N-alk-or by reaction with a compound of formula H in which alk^ has the meaning given above, a starting material of formula VIII, in which the group A corresponds to the formula -N=alk^-. This turnover is carried out in a manner known per se, e.g. in the reaction with a compound of formula XII, an alkaline condensing agent is used, e.g. an alkali or alkaline earth carbonate such as sodium or calcium carbonate. Starting substances of formula VIII, in which X means doubly or triply unsaturated groups with 2-3 carbon atoms and A has the indicated meaning, can be obtained by converting a compound of formula

in which X means doubly or triply unsaturated groups with 2-3 carbon atoms or a suitable derivative thereof, for example an acetal, e.g. the dimethyl acetal, or a bisulphite addition compound, with a suitable silicon-organic cyan compound, for example a trilower alkyl, e.g. trimethyl-

silyl cyanide, in the usual way in the presence of a catalyst, such as zinc iodide, in a compound of formula and transfers in this group -CN by means of reduction, while simultaneously replacing the trimethylsilyl group with hydroxy in the group -Cr^NP^. As a reducing agent, you can use e.g. a dilate metal hydride, for example lithium aluminum hydride, in a suitable solvent, for which an ethereal liquid can usually be used, e.g. diethyl ether or tetrahydrofuran. The thus obtained compound with formula

can later be reacted with a compound of the above-explained formula XII to a compound of formula (VIII), in which A denotes the group of formula -N-alk-; or one reacts a compound of formula XVI with H a compound of the formula (XIII) explained above, after which a starting material of formula VIII is obtained, in which A means the group of formula -N=alk^-.

These sales are carried out in the usual way.

When selecting the suitable above-mentioned method for preparing compounds of formula I, care must be taken that the present substituents, primarily residues Ar, are not converted or split off, if such conversions or spin-offs are not desired. Thus, especially functionally converted carboxyl groups, such as esterified or amidated carboxyl groups as well as cyan groups, as substituents for residues Ar during the solvolysis, especially the hydrolysis, and also during the reduction can be present in the reaction and converted. On the other hand, simultaneous transformations of substituents may be desired, e.g. of unsaturated substituents such as lower alkenyl, are reduced under the conditions of the reduction method used according to the invention, e.g. to lower alkyl.

In the compounds obtained, within the framework of the definition of the compounds of formula I, compounds obtained by ordinary methods can be transferred into other end products, e.g. while converting, introducing or cleaving suitable substituents.

Then, in the obtained compounds, unsaturated substituents such as lower alkynyl or lower alkynyloxy or lower alkenyl or lower alkenyloxy, reduce e.g. by treatment with catalytically activated hydrogen.

In compounds with halogen atoms as substituents for the residue Ar, the halogen can be replaced, e.g. by treatment with hydrogen in the presence of a common hydrogenation catalyst such as Raney nickel or palladium on carbon, with hydrogen.

In compounds with an esterified carboxyl group as a substituent in the residue Ar, these can be used in the usual way, e.g. by ammonolysis or aminolysis with ammonia or a primary or secondary amine is transferred in the corresponding carbamoyl group.

Compounds with a carbamoyl group in the residue Ar and of hydrogen different groups and R2 can in the usual way, e.g. under the influence of water-binding agents such as phosphorus pentoxide or phosphorus oxychloride, preferably at higher temperatures, are dehydrated to the corresponding cyan compounds.

In compounds with a cyano group as substituents in the residue Ar, these can be used in the usual way, e.g. by addition of alcohols in the presence of an anhydrous acid such as hydrogen chloride, and subsequent hydrolysis of the formed imidoesters alcoholyses to the corresponding compounds with esterified carboxyl groups.

In compounds with a nitro group as substituents in the residue Ar, these can be reduced to an amino group, e.g. by means of catalytically activated hydrogen as hydrogen in the presence of a hydrogenation catalyst, for example Raney nickel or a palladium-on-carbon catalyst or by means of a metal, e.g. iron eels possibly amalgamated zinc in an acid, e.g. a mineral acid such as hydrochloric acid or a carbonic acid such as acetic acid or mixtures thereof.

In compounds with a primary amino group as substituents in the residue Ar, these can be transferred into a lower alkylamino or dilave alkylamino group, e.g. by reaction with a correspondingly suitable alkylating agent, for example a reactive esterified lower alkanol, e.g. the halide, for example the chloride, bromide or iodide, or an ester with a strong organic sulphonic acid, e.g. the methanesulfonic acid ester, suitably in the presence of a basic agent such as an alkali hydroxide or carbonate.

In compounds with a primary amino group in the residue Ar, these can be converted into ureido, N'-lower alkyl ureido or N,N'-dilower alkyl ureido groups, e.g. by reaction with cyanic acid or a salt thereof, for example potassium cyanate, in an acidic medium such as aqueous hydrochloric acid or with a lower alkyl resp. N,N-dilever alkylurea at elevated temperature.

For compounds with a primary amino group in the residue Ar, these can be converted into a lower alkylsulfonylamino group, e.g. by reaction with a lower alkylsulfonyl halide in the presence of a basic agent, e.g. pyridine.

As with the production methods, care is also taken when carrying out the further steps that unwanted side reactions, which may result in the transformation of further groupings, do not occur.

The reactions described above can optionally be carried out simultaneously or one after the other, further in any order. If necessary, they take place in the presence of diluents, condensing agents and/or catalytic agents, at lowered or elevated temperature, in closed vessels under pressure and/or in an inert gas atmosphere.

Depending on the process conditions and the starting compounds, the new compounds are obtained in free form or in the form of their salts, also mentioned in the invention, since the new compounds or salts thereof can also be present as hemi-, mono-, sesqui- or polyhydrates. The acid addition salts of the new compounds can be used in and

in a manner known per se is transferred in the free compounds, e.g. by treatment with basic agents, such as alkali metal hydroxides, carbonates or hydrogen carbonates or ion exchangers. On the other hand, free bases can be obtained with organic or inorganic acids to form acid addition salts, e.g. with the aforementioned acids, in that for their preparation such acids are used in particular which are suitable for the formation of pharmaceutically acceptable salts.

These or other salts, especially acid addition salts of the new compounds, such as e.g. the oxalates or perchlorates, can also serve to purify the free bases formed, as one transfers the free bases into the salt, separates them and purifies them, and from the salts releases the bases again.

Depending on the choice of starting materials and working methods, the new compounds can exist as optical antipodes or racemates, or if they contain two asymmetric carbon atoms, also as racemate mixtures. The starting materials can also be used as specific optical antipodes.

Due to the physico-chemical differences of the diastereoisomers, obtained racemate mixtures can be divided in a known manner into the two stereoisomeric (diastereomeric) racemates, e.g. with chromatography and/or fractional crystal iser ing.

Racemates obtained can be divided into antipodes in a manner known per se, e.g. by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance, which with the racemic compound forms salts, especially acids, and separation of salt mixtures obtained in this way, e.g. due to different solubilities in the diastereomeric salts, of which the free antipodes can be liberated by the action of suitable agents. Particularly common, optically active acids are e.g. The D and re forms of tartaric acid, di-0,0'-(p-toluoyl)-tartaric acid, malic acid, mandelic acid, camphor sulphonic acid, glutamic acid, aspartic acid or quinic acid. Preferably, the most effective of the two antipodes is isolated.

The invention also relates to the embodiments of the method, according to which one starts from a compound obtained as an intermediate in one or another step of the method and carries out the missing method steps, or interrupts the method at one or another step, or where a starting material is formed during the reaction sion conditions, or where a reaction component is possibly present in the form of its salt.

Appropriately, one applies for implementation

of the reaction according to the invention such starting substances which lead to the groups of end substances specifically mentioned at the outset, and in particular to the particularly mentioned or highlighted end substances.

Starting substances are known or, if they are new, can be obtained by methods known per se, as above, e.g. analogous to what is discussed in the examples. New starting materials also form an object of the invention. The invention also relates to intermediate products obtained by the method.

The new connections can e.g. find application

in the form of pharmaceutical preparations, which contain a pharmacologically effective amount of the active substance, possibly together with pharmaceutically usable carriers, which are suitable for enteral administration, e.g. oral or parenteral administration, and may be inorganic and organic, solid or liquid. Thus, tablets or gelatin capsules are used which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol and/or lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.

The tablets may also contain binders, e.g. magnesium aluminum silicate, starch, such as corn, wheat,

rice or arrowroot starches, gelatins, tragacanth, methyl

cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, and, if desired, explosives, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or fizzy mixes, or adsorbents, colourings, flavorings and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, as these e.g. in the case of lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol, can be produced by use. The pharmaceutical preparations can be sterilized and/or excipients, e.g. preservative, stabilizing, wetting and/or emulsifying agents, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which, if desired, may contain further pharmacologically active substances, are prepared in a manner known per se, e.g. by means of usual mixing, granulating, dragging. mitering, dissolving or lyophilization methods, and contains from approx. 0.1% to 100%, especially from approx. 1% to approx. 50% lyophilisates up to 100% of the active substance.

The dosage may depend on various factors, such as method of application, type, age and/or individual condition. Thus, the daily in one or more, preferably a maximum of 4 single doses of the only administered dose by oral application on warm-blooded animals for (3-receptor blockers with formula I between 0.03 mg/kg and 3 mg/kg and for warm-blooded animals of approx. 70 kg preferably between about 0.004 g and about 0.08 g, and for Ø-receptor stimulator with formula I between 0.01 mg/kg and 1 mg/kg respectively for warm-blooded animals with about 70 kg body weight between about 0.002 g and about 0.04 g.

The following examples serve for illustration

of the invention, temperatures are given in degrees Celsius.

In compounds that have two centers of asymmetry

and therefore can exist as diastereomeric mixtures, were

the relative content of both diastereomers (enantiomers-13

par) determined by means of C-NMR spectroscopy due to the relative intensity of both C-methyl signals at 13.3 ± 0.1 ppm resp. 13.6 ± 0.1 ppm. The ^C spectra were recorded in DMSO-dg on a Varian-XL-100 instrument at 25.16 MHz using tetramethylsilane as an internal standard. (Digital resolution 0.8 points/Hz). Salts were examd. as such Bases must be neutralized with acids (eg 1 equivalent of fumaric acid) to achieve a separation of methyl signals.

Example 1

A solution of 1.96 g of 5-(2-aminoethoxy)-salicylamide in 15 ml of anhydrous dimethyl sulfoxide was added with 2.4 g of 2,4-dichloro-1-(epoxyethyl)-benzene and stirred for 30 minutes in a bath of 80°. The reaction mixture was poured into 30 ml of ice water and extracted with 100 ml of ethyl acetate. The organic phase was separated, dried over magnesium sulfate and evaporated. The evaporation residue was taken up with 20 ml of petroleum ether,

the formed crystals were suctioned off and recrystallized from methanol, after which α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-2,4-dichlorobenzyl alcohol with a melting point of 139-140° is obtained .

The 5-(2-amino-ethoxy)-salicylamide required as starting material can be prepared as follows: a) According to the method described by Irvine et al., Synthesis 1972, p. 568, 2,5-dihydroxy-benzamide is over- conducted using an excess of acetone in 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4^one of melting point 215-216°. 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 boiled under 14 hours under stirring and reflux. The mixture is cooled and filtered, the residue is thoroughly stirred with 400 ml of water, suction is applied and the residue is dried in a vacuum at 80°. Crude 6-(2-bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one of melting point 190-200° is obtained, which is sufficiently pure for further reactions. Recrystallization from methanol gives a pure product with a melting point of 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

benzylamine is stirred in a bath of 80° for 30 minutes. The reaction mixture was then cooled under ice

with concentrated hydrochloric acid at pH 3-4 and allowed to crystallize. After 2-4 hours, the crystals are suctioned off, washed with 50 ml of water and 50 ml of ethyl acetate and dried. The 5-[(2-benzylamino)-ethoxy]-salicylamide hydrochloride thus formed melts at 214-216°. The base thus liberated melts at 107-108°

(of ethyl acetate-ether) .

d) Catalytic debenzylation of 5-[(2-benzyl-amino)ethoxy]-salicylamide in methanol using a palladium-on-carbon catalyst (5%-ig) leads to 5-(2-amino-ethoxy)- 'salicylamide with a melting point of 140°.

Example 2

Analogously to example 1, 17.4 g of 4-chloro-1-(epoxyethyl)-3-nitrobenzene and 11.4 g of 5-(2-aminoethoxy)-salicylamide in 50 ml of dimethyl sulfoxide a-[N-[2-( The 3-carbamoyl-4-hydroxy-phenoxy)ethyl]-aminomethyl]-4-chloro-3-nitrobenzyl alcohol of melting point 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 dimethylsulfoxide and the solution is heated with stirring for 65 minutes at 90°. It is then cooled, the reaction mixture is poured onto ice water and extracted with ethyl acetate. The organic phase is then extracted with 1N aqueous methanesulfonic acid solution, the acidic phase is made alkaline with ammonia and extracted several times with ethyl acetate.

After the drying of the organic phase over sodium sulfate, the solvent is removed on the rotary evaporator and the residue is recrystallized from isopropanol. After further recrystallization from methanol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-3-sulfamoyl-4-chloro-

the benzyl alcohol with melting point 193-195°.

The 2-chloro-5-(epoxyethyl)-benzenesulfonamide required as starting material can be prepared as follows: a) A solution of 20 g of 5-(brbmacetyl)-2-chlorobenzenesulfonamide (DE-OS 26 01 598) in 800 ml of methanol is added by 0-5° during 1*2 hours in portions with 13.5 g of sodium borohydride. The mixture is stirred for a further 3 hours at room temperature, the solvent is removed on the rotary evaporator and the residue is distributed between water and ethyl acetate. The organic phase is dried, evaporated and the residue is recrystallized from ethyl acetate-ether, whereby 2-chloro-5-(epoxyethyl)-benzenesulfonamide with a melting point of 126-129° is obtained.

Example 4

A solution of 21.9 g of 4-(2-aminoethoxy)-salicylamide and 30.3 g of α-(bromomethyl)-4-nitrobenzyl alcohol in 250 ml of ethanol is boiled after the addition of 20 g of potassium bicarbonate for 12 hours under reflux and stirring. After cooling and filtering, the filtrate is evaporated and the residue is distributed between 50 ml of 2N hydrochloric acid and 100 ml of ethyl acetate. The aqueous phase is evaporated and the residue is recrystallized from methanol.

The α-[n-t2-(4-carbamoyl-3-hydroxy-phenoxy)-ethyl]-amino-methyl ]-4-nitrobenzyl alcohol is obtained as hydrochloride; mp 231-233° (of methanol).

The 4-(2-amino-ethoxy)-salicylamide required as starting material is obtained as follows: a) 16.2 g of the 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H- 1,3-benzoxain-4-one is reacted analogously to example 1b) with 84 ml of 1,2-dibromoethane and gives 2,3-dihydro-2,2-dimethyl-7-(2-bromoethoxy)-4H-1,3- benzoxazin-4-one with melting point 156-158° (from isopropanol).

b) 53 g of 2,3-dihydro-2,2-dimethyl-7-(2-bromomethoxy)-4H-1,3-benzoxazin-4-one and 94 g of benzylamine are boiled with stirring for 3 hours. The reaction mixture is made alkaline with concentrated ammonia and the organic phase is evaporated at a maximum of 50°. The 4-[2-(benzylamino)-ethoxy]-salicylamide thus formed forms an oil, which hydrochloride

melts at 252-254° (of methanol).

c) Catalytic debenzylation of 4-[(2-benzyl-1-amino)-ethoxy]-salicylamide analogously to example 1 gives the 4-(2-aminoethoxy)-salicylamide with melting point 126-130° (from isopropanol).

Oak sample 5

A mixture of 16.4 g of N-[5-(2-bromo-1-hydroxyethyl)-2-chloro-phenyl]-methanesulfonamide, 14.7 g of 5-(2-amino-ethoxy)-salicylamide and 5 g of potassium bicarbonate in 100 ml isopropanol is boiled for 25 hours with stirring and reflux. The reaction mixture is filtered, the filtrate is evaporated and distributed between ether and 2N hydrochloric acid. The aqueous phase is made alkaline with solid potassium bicarbonate and the mixture is extracted with ethyl acetate. From the foam formed after evaporation, little by little the ethyl acetate of α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-3-(methylsulfonylamino)-4-chloro- the benzyl alcohol with melting point 139-141°. It forms a neutral fumarate with a melting point of 190-192° (from methanol).

The N-[5-(2-bromo-1-hydroxyethyl)-2-chloro-phenyl]-methanesulfonamide required as starting material is prepared as follows: a) Under ice-cooling, add dropwise to a solution of 162.5 g of 3-amino- 4-Chloro-acetophenone in 900 ml pyridine 110 g methanesulfonic acid chloride. After further stirring at room temperature for 3 hours, the precipitate formed is filtered off and the filtrate is evaporated. The residue crystallizes when added with water. The crude N-(2-chloro-5-acetyl-phenyl)-methanesulfonamide obtained is crystallized from ethanol, melting point 112-114°. b) By brominating the compound obtained according to example 5a) with the equivalent amount of bromine in chloroform, N-(5-bromoacetyl-2-chloro-phenyl)-methanesulfonamide is obtained with a melting point of 120-123°. c) By reducing the compound obtained according to example 5b) with the equivalent molar amount of sodium borohydride in dioxane-water (9:1) one obtains N-[5-(2-bromo-1-hydroxyethyl)-2-chloro-phenyl] -the methanesulfonamide with a melting point of 130-134°.

Example 6

4.7 g of 4-amino--(aminomethyl)-3,5-dichloro-benzyl alcohol, 6.0 g of 5-(2-bromoethoxy)-salicylamide and 12.9 g of N,N-diisopropyl-ethylamine are boiled in a mixture of 20 ml of dimethylformamide and 50 ml of dioxane for 3 hours under reflux. After evaporation of the solvent, the residue is worked up analogously to example 5. The α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-3,5-dichloro-4-amino-benzyl alcohol is obtained as brownish crystals with melting point 196-201°.

The 5-(2-bromo-ethoxy)-salicylamide required as starting material can be obtained as follows: a) 30.0 g of the 6-(2-bromoethoxy)-2,3-dihydro-2,2 obtained according to example lb) -dimethyl-4H-1,3-benzoxazin-4-one is boiled in a mixture of 100 ml of dioxane and 100 ml of 6N hydrochloric acid with stirring for 1% hour at reflux. The crystals obtained after evaporation of the reaction mixture are washed with 50 ml of water and dried in a vacuum. The 5-(2-bromoethoxy)-salicylamide thus obtained melts at 141-143°.

The 4-amino-α-(aminomethyl)-3,5-dichlorobenzyl alcohol required as starting material is prepared in the following way: b) A suspension of 17.9 g of phthalimide in 70 ml of dimethylformamide is added portionwise while stirring with 6.5 g of sodium hydride -suspension (55% in paraffin oil). After one hour, a solution of 34.5 g of 4-amino-io-bromo-3,5-dichloro-acetophenone in 50 ml of dimethylformamide is added dropwise with further stirring and cooling at 10-20°, the reaction mixture is then stirred for a further 3-4 hours and then poured into 1200 ml of water. The precipitated crystals are suctioned off and dried in a vacuum at 100°. Crude N-[2-(4-amino-3,5-dichlorophenyl)-2-oxo-ethyl]-phthalimide with melting point 255-260° is obtained. 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.

dioxane and 20 ml of water are added in portions with 5.2 g of sodium borohydride and are then stirred for 48 hours at 80-90°. After 24 hours, a further 5.2 g of sodium borohydride are added.

The excess sodium borohydride is added under ice-cooling with 2N hydrochloric acid and the reaction mixture is evaporated. The evaporation residue is made alkaline with concentrated ammonia solution and extracted with ethyl acetate. After removal of the solvent, the crude 4-amino-3,5-dichloro-a-[N-(2-hydroxymethyl-benzoyl)-aminomethyl]-benzyl alcohol with a melting point of 165-170° is obtained, 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

during reflux. After distribution of the evaporation residue between 200 ml of ethyl acetate and 30 ml of water and usual work-up, 4-amino-a-(aminomethyl)-3,5-dichloro-benzyl alcohol with a melting point of 124-127° is obtained.

Example 7

A mixture of 8.7 g of N-t 3-(2-amino-1-hydroxyethyl)-phenyl]-methanesulfonamide and 9.0 g of 5-(2-bromoethoxy)-salicylamide in 50 ml of dioxane and 20 ml of triethylamine is boiled for 4 hours under agitation and reflux. The foam formed after evaporation is stirred with 100 ml of saturated potassium bicarbonate solution and 500 ml of ethyl acetate until complete dissolution. The organic phase, after drying over magnesium sulfate and evaporation, gives 12 g of a greenish foam, from which upon dissolution in a mixture of methanol and isopropanol (approx. 1:10) a-[N~[2-(3-carbamoy1-4) crystallizes -hydroxy-phenoxy)-ethyl]-aminomethyl]-3-(methylsulfonylamino)-benzyl alcohol with melting point 135-137°.

Example 8

23 g raw α-[N-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-7-yloxy)-1-methyl-ethyl]-aminomethyl] -4-(methylsulfonylamino)-benzyl alcohol is boiled in a mixture of 50 ml of isopropylamine and 200 ml of isopropanol for 2 hours under reflux and then evaporated and the residue is stirred with 5 ml of isopropanol and 20 ml of ether. The little by little forming crystals are sucked off and form α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methylethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol as a diastereoisomer mixture. A 1:1 mixture of the diastereoisomers melts at 140-145°.

The starting material is prepared in the following way: a) A solution of 11.5 g of N-[4-(2-amino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide and 12.4 g of 2,3-dihydro- ■

2,2-dimethyl-7-(2-oxo-propoxy)-4H-1,3-benzoxazin-4-one in 250 ml of methanol is hydrated after adding 0.13 g of concentrated sulfuric acid over 1 g of platinum-on-carbon catalyst until absorption of the calculated amount of hydrogen under normal conditions. After filtering off the catalyst, the solution is evaporated, after which crude α-[N-[2-(2,3-dihydro-2.2-dimethyl-4-oxo-4H-1,3-benzoxaz.in-7-yloxy)- 1-methyl-ethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol as oil, which are further processed as such.

The 2,3-dihydro-2,2-dimethyl-7-(2-oxo-propoxy)-4H-1,3-benzoxa-zin-4-one required as additional starting material can be obtained as follows: b) Analogous to example la) gets one of 2,4-dihydroxy-benzamide 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benz-oxazin-4-one with melting point 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, you get by boiling during 28 hours and subsequent work-up 2,3-dihydro-2,2-dimethyl-7-(2-oxo-propoxy)-4H-1,3-benzoxazine-4-6n with melting point 160-162° (from isopropanol).

Example number 9

Analogous to examples 8 and 8a) is obtained from α-(amino-■ methyl)-3,4-methylenedioxy-benzyl alcohol (melting point 75-78°, cf. H. Tatsuno et al., J. Med. Chem. _20 , 394 , 1977) and 2,3-dihydro-2,2-dimethyl-6-(2-oxo-propoxy)-4H-1,3-benzoxa-zin-4-one) α-[N-[2-(3 -carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-3,4-methylenedioxy-benzyl alcohol as dia stereoisomer mixture. After fractional crystallization of the hydrochloride from methanol-water (4:1), a pure pair of enantiomers with a melting point of 211-212° is obtained.

The 2,3-dihydro-2,2-dimethyl-6-(2-oxo-propoxy)-4H-1,3-benzoxazin-4-one required as starting material can be obtained as follows: a) 70 g of that according to example la) The obtained 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one is stirred in 400 ml of acetonitrile with 100 g of potassium carbonate and 32 ml of chloroacetone for 30 hours under reflux. After adding a further 3.2 ml of chloroacetone, the reaction mixture is heated for a further 15-20 hours. The even hotter reaction mixture is filtered, the residue is washed thoroughly with water and the combined filtrate is evaporated. The crystalline residue is recrystallized from toluene and gives 2,3-dihydro-2,2-dimethyl-6-(2-oxo-propoxy)-4H-1,3-benzoxazin-4-one with a melting point of 125-126°.

Example 10

Analogously to example 9, using 2,3-dihydro-2,2-dimethyl-7-(2-oxo-propoxy)-4H-1,3-benzoxa-zin-4-one a-[N- [2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-3,4-methylenedioxy-benzyl alcohol as diastereoisomer mixture (approx. 1:1) with melting point 164-174°. A neutral fumarate with a melting point of 193-204° was formed

13

(of methanol-water), which is identified by C-nuclear resonance spectrum as a mixture of the diastereomers (approx. 1:1).

Example 11

A solution of 0.795 g of 1-(3-sulfamoyl-4-chloro-phenyl)-2-amino-ethanol and 0.707 g of (2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazine-4 -on-6-yloxy)-acetaldehyde in 20 ml of methanol is added with 2 g of molecular sieves (3 Å) and 0.44 g of sodium cyanoborohydride and the suspension is stirred at room temperature. After dropwise addition of methanolic hydrochloric acid, the pH value is obtained at 6-7. After 12 hours it is filtered, the filtrate is added with 1 ml of concentrated hydrochloric acid to split the cyanoborohydride, stirred for 10 minutes and then adjusted with concentrated ammonia to pH 9. The suspension is freed from the solvent, the residue is slurried with a mixture of chloroform/methanol/ammonia (40:10 :1), is filtered and the filtrate is evaporated 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 heated for 15 minutes in a mixture of 20 ml of dioxane and 1 ml of concentrated hydrochloric acid at 80°. After removal of the solvent, the residue is taken up in ethyl acetate and extracted with 2N ammonia. The organic phase is dried, evaporated and the residue is recrystallized from isopropanol-ethyl acetate, after which α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-3-sulfamoyl-4-chloro is obtained -benzyl alcohol, melting point 193-195°.

The 2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-on-6-yloxy)-acetaldehyde required as starting material can be obtained as follows: a) A solution of 9.65 g of the 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one obtained according to example la) and 9.1 g of allyl bromide in 150 ml of acetonitrile are stirred for 5 hours while adding 10 .3 g dried potassium carbonate■under reflux. The reaction mixture is filtered hot, the filtrate is evaporated and the remaining crystals are filtered off after mixing with ether, after which the crude 2,3-dihydro-2,2-dimethyl-6-allyloxy-4H-1,3-benzoxazin-4-one is obtained with melting point 137-138°. b) A solution of 4.7 g of 2,3-dihydro-2,2-dimethyl-6-allyloxy-4H-1,3-benzoxazin-4-one in a mixture of 50 ml

dioxane and 15 ml of water are added while stirring with approx. 20 mg osmium tetroxide. After 15 minutes, 8.6 g of sodium metaperiodate are added in portions, whereby the temperature rises to 45°. After 2 hours, the reaction mixture is filtered, the filtrate is evaporated and the residue is distributed between 20 ml of water and 200 ml of ethyl acetate. The organic phase is separated, dried and evaporated. The remaining oil is chromatographed over 100 g of silica gel. By elution with ethyl acetate and evaporation to

dryness gives (2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-on-6-yloxy)-acetaldehyde with melting point 153-163°.

Example 12

A solution of 9.2 g of α-(aminomethyl)-4-(methyl-sulfonylamino)-benzyl alcohol and 8.5 g of 4-(2-oxo-propoxy)-salicylamide in 180 ml of methanol is hydrated while adding 0.1 g of concentrated sulfuric acid over 1 g of platinum-on-carbon catalyst (5%). After filtering and evaporating the filtrate, a foam is obtained, which from isopropanol after several days gives α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-4 -(methylsulfonylamino)-benzyl alcohol as diastereoisomer mixture (approx. 1:1) with melting point 141-152°. The isolation of the pure diastereomers is described in example 28.

The 4-(2-oxo-propoxy)-salicylamide required as starting material can be prepared as follows: a) 66 g crude according to example 9a) obtained 2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy) -4H-1,3-benzoxazin-4-one is hydrolysed in a mixture of 150 ml of dioxane and 400 ml of 2N hydrochloric acid for one hour on the boiling water bath. After evaporating the solvent and mixing the residue with water, crude 4-(2-oxo-propoxy)-salicylamide with a melting point of 128-140° is obtained. After recrystallization from ethanol, the product melts at 145-148°.

Example 13

Analogously to example 12, using equivalent amounts of the 5-(2-oxo-propoxy)-salicylamide obtained according to example 10a) a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1 is obtained -methylethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol as an oil, which forms a neutral fumarate as a mixture of the diastereoisomers in the ratio of

13

about. 6:4 according to C-spectroscopy examination with melting point 210-215°.

Example 14

A solution of 24.1 g of 5-(2-amino-1-hydroxyethyl)-salicylamide and 25.6 g of 5-(2-oxo-propoxy)-salicylamide is hydrogenated analogously to example 12 over 2 g of platinum-on-carbon catalyst (5%), which is added in 2 portions, until the calculated amount of hydrogen is absorbed. The evaporation residue from the filtered solution is dissolved with the addition of fumaric acid in water, the solution is extracted with ethyl acetate and the aqueous phase is separated. It is made alkaline with saturated potassium bicarbonate solution and the precipitate is extracted with plenty of ethyl acetate by stirring for one hour. From the ethyl acetate solution, after drying over magnesium sulfate and evaporation, a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-3-carbamoyl-4-hydroxy-benzyl alcohol is obtained , which melt after recrystallization from ethyl acetate at 143-148° during cleavage and form a mixture of the diastereoisomers in the ratio from approx. 1:1.

Example 15

A solution of 10.0 g of α-(aminomethyl)-4-(2-methoxy-ethoxy)-benzyl alcohol and 9.9 g of 5-(2-oxo-propoxy)-salicylamide is hydrated in 200 ml of methanol analogously to example 12

and worked up analogously to example 14. α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-4-(2-methoxy-ethoxy)-benzyl alcohol is obtained as after recrystallization from ethyl acetate melts at 100-106° and forms a diastereoisomer mixture in the ratio from approx. 1:1.

The (aminomethyl)-4-(2-methoxy-ethoxy)-benzyl alcohol used as starting material can be prepared in the following way: a) A suspension of 21 g of 2-methoxy-ethyl bromide, 13.6 g of 4-hydroxy- acetophenone and 27/6 g potassium carbonate i

250 ml of acetone is boiled for 20 hours with stirring and reflux. Usual work-up and distillation of the crude product at 0.001 torr yields 4-(2-methoxy-ethoxy)-acetophenone with a boiling point of 113-116°/0.001 torr as a colorless oil which solidifies into a crystalline mass.

b) Bromination of the compound obtained according to example a) with the equivalent amount of bromine in chloroform by

20-30° for 2 hours gives co-bromo-4-(2-methoxy-ethoxy)-acetophenone, which is used as such.

c) A solution of 53 g of the crude compound obtained according to example b) in 350 ml of dimethylformamide is cooled to 0-5° and added with stirring in portions with 15.4 g of sodium azide. After the exothermic reaction has subsided, the ice cooling is removed and the reaction mixture is stirred for 3 hours. The solution is then poured onto 3

liter of ice water and the yellow oil that separates is extracted with ether. 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 sulphate, filtered and the filtrate is reduced with a suspension of 35 g of lithium aluminum hydride in 500 ml of ether for 2 hours at 10-12° . Usual work-up yields crude α-(aminomethyl)-4-(2-methoxy-ethoxy)-benzyl alcohol as a yellowish oil, which can be further used as a crude product. -During distillation in ball tubes, wood boils. 130-140°/0.08 torr.

Example 16

Analogous to the way of working in example 12, you get

7.5 g of α-(aminomethyl)-4-methyl-benzyl alcohol and 10.45 g of 5-(2-oxo-propoxy)-salicylamide α-[N-[2-(3-carbamoyl-4-hydroxy- phenoxy)-1-methyl-ethyl]-aminomethyl]-4-methyl-benzyl alcohol with melting point 120-134° (from ethyl acetate), which forms a mixture of the diastereoisomers in the ratio of approx. 1:1.

Example 17

A solution of α-aminomethyl-4-methoxybenzyl alcohol (S.M. Albonico et al., J. Chem. Soc. 1967, 1327) and 7.7 g of 5-(2-oxo-propoxy)-salicylamide in 130 ml of methanol is hydrated with the addition of 0.09 g of concentrated sulfuric acid and 1.2 g of platinum-pa-carbon catalyst (5%) analogous to example 12. The crude product is recrystallized from 200 ml of ethyl acetate, then from acetonitrile. The higher-melting enantiomer pair of α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-4-methoxy-benzyl alcohol is obtained, melting point 144-146° . The ethyl acetate mother liquor is obtained by evaporation with other pairs of enantiomers and purified by crystallization from acetonitrile, melting point 129-131°.

Example 18

A solution of 7 g of α-(aminomethyl)-3-sulfamoyl-4-chlorobenzyl alcohol and 5.8 g of 5-(2-oxo-propoxy)-salicylamide in 130 ml of methanol is added with 70 mg of concentrated sulfuric acid and then shaken under nitrogen 2 hours at room temperature. 0.7 g of platinum-on-carbon catalyst (5%) is added and hydrogenated under normal pressure until saturation of hydrogen. The catalyst is filtered off, the filtrate is freed from the solvent and the remaining foam is crystallized from isopropanol, then from methanol/isopropanol, after which a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1- methyl-ethyl]-aminomethyl]-3-sulfamoyl-4-chloro-benzyl alcohol as approx. 1:1 diastereomer mixture with melting point 103-106° with 0.5 mol crystalline isopropanol.

The α-(amino-methyl)-3-sulfamoyl-4-chlorobenzyl alcohol required as starting material 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, 8 g of sodium azide are added in portions at 0-5° over the course of 30 minutes. Stirring continues for 2 hours at this temperature and the reaction mixture is then poured onto an ice/water mixture. The resulting 5-(azido-acetyl)-2-chloro-benzenesulfonamide, which decomposes from 152°, is filtered off with suction, washed with plenty of water and dried under high vacuum. The raw product obtained 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 4.6.4 ml of hydrochloric acid is hydrated in the presence of 3 g of a platinum-on-carbon catalyst (5%) at room temperature under normal pressure until complete hydrogen absorption. The catalyst is filtered off, the filtrate is evaporated and the residue is slurried in acetone. The obtained 5-(aminoacetyl)-2-chlorobenzenesulfonamide hydrochloride is filtered off and used as crude product in the next step. c) 5 g of 5-(aminoacetyl)-2-chlorobenzenesulfonamide hydrochloride are suspended in 100 ml of methanol and 1.6 g of sodium borohydride are added in portions. The solution is stirred for h hour at room temperature, evaporated on the rotary evaporator and the residue is added with ethyl acetate and water. The organic phase is dried over sodium sulfate, evaporated and the residue is recrystallized from ethyl acetate, after which α-(aminomethyl)-3-sulfamoyl-4-chloro-benzyl alcohol with a melting point of 179-182° is obtained.

Example 19

Analogous to the method described in example 18, α-[N-[2-(3-hydroxy -4-carbamoyl-phenoxy)-1-methyl-ethyl]-aminomethyl]-3-sulfamoyl-4-chloro-benzyl alcohol with a melting point of 112-116°, which exists as a mixture of diastereomers (approx. 1:1).

Example 20

A solution of 20 g of crude α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-benzylaminomethyl]-3-sulfamoyl-4-methoxy-benzyl alcohol in 200 ml of methanol is hydrated after adding 2 g palladium-on-carbon catalyst (5%) until absorption of the calculated amount of hydrogen. After filtering and evaporating the filtrate, a viscous residue is obtained from which, when dissolved in a methanol-isopropanol mixture, uncrystallized a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-3 -sulfamoyl-4-methoxy-benzyl alcohol, which after recrystallization from methanol shows a melting point of 160-162°. A crystal modification with melting point 191-194° is formed if the compound is recrystallized from acetonitrile.

The starting material can be prepared in the following way: a) 2-methoxy-5-(bromoacetyl)-benzenesulfonamide is reduced in methanol with the 5-fold molar amount of sodium borohydride to 5-(epoxyethyl)-2-methoxy-benzenesulfonamide (melting point 158 -160° of methanol). b) A solution of 7.7 g of 5-(epoxyethyl)-2-methoxy-benzenesulfonamide and 8.6 g of the 5-[(2-benzylamino)-ethoxy]-salicylamide obtained according to example lc) in 150 ml of isopropanol boiled for 20 hours under reflux. After evaporation of the solution, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-benzylaminomethyl]-3-sulfamoyl-4-methoxy-benzyl alcohol is obtained as an orange-colored resin which is further processed without further purification.

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 of methanol is hydrogenated with the addition of 0.6 g of palladium-on-carbon catalyst (5%) under normal conditions until complete hydrogen absorption, whereby the reduction product is partially precipitated from the solution. The suspension is diluted with 400 ml of methanol, heated and filtered through a filter aid. The filtrate is added with an excess of methanolic hydrochloric acid and freed from the solvent on a rotary evaporator. The residue is recrystallized from acetonitrile-ethyl acetate, after which 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-(2-methoxyphenyl)-2-butanol hydrochloride with a melting point of 124-126° is obtained.

The 1-[N-benzyl-2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-(2-methoxy-phenyl)-2-butanol required as starting material can be prepared as follows: a) To a solution of 5 g of 1-(3-butenyl)-2-meth-poxybenzene (cf. W.S. Johnson: JACS 86, 1975, (1964) in 25 ml of methylene chloride is slowly added dropwise while stirring at room temperature to a solution of 7.3 g m- chloroperbenzoic acid in 60 ml of methylene chloride. After 2 hours, filter off, the filtrate is washed with 10% sodium sulphite solution, dried over sodium sulphate and evaporated. The remaining crude 1-(3,4-epoxybutyl)-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)-ethoxy]-salicylamide obtained according to example 4b) are dissolved in 65 ml of isopropanol and the solution is heated under reflux for 8 hours. The solvent is then removed and the residue is chromatographed over 300 g of silica gel with a mixture of chloroform/methanol/ammonia = 350:50:1, which gives 1-[N-benzyl-2-(4-hydroxy-3-carbamoyl-phenoxy) -ethylamino]-4-(2-methoxyphenyl)-2-butanoic as a yellowish oil, which is further processed as such.

Example 22

A solution of 2.9 g of 5-(2-aminoethoxy)-salicylamide in 10 ml of dimethylsulfoxide is added with 2.7 g of (2,3-epoxypropyl)-benzene and heated here in 40 minutes in an approx. 90° hot bath with stirring. This solution is cooled and diluted with 40 ml of water. The precipitated crystals are suctioned off, washed with a little water and dried in a vacuum. One thus obtains 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-phenyl-2-propanol with a melting point of 142-143° (of some isopropanol).

Example 23

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

The starting material can be prepared as follows: A solution of 5 g of 2-methoxy-1-(2,3-epoxy-propyl)-benzene (cf. Compt. rendues, 219, 163-164 (1944))

and 8.7 g of 5-(2-N-benzylaminoethoxy)-salicylamide in 130 ml of isopropanol are boiled for 20 hours under reflux. The solvent is then removed on the rotary evaporator, the residue is chromatographed on 500 g of silica gel and eluted with a mixture of chloroform:methanol, ammonia 350:50:1. The fractions 4-20'

are collected, combined and evaporated to dryness, after which 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-N-benzyl-ethylamino]-3-(2-methoxyphenyl)-2-propanol is obtained as an oily residue.

Example 24

4.18 g of α-aminomethyl-2-methoxy-benzyl alcohol are stirred in 250 ml of methanol and 4.28 ml of 5.9N methanolic hydrochloric acid (~pH 6). The reaction solution is added with 0.59 g of potassium hydroxide (solid) (~pH 9). After adding 25 g of molecular sieve 3Å and 5.60 g of (2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-on-6-yloxy)-acetaldehyde are added dropwise. a solution of 0.59 g of sodium cyanoborohydride in 60 ml of methanol. The reaction mixture is stirred for 24 hours at room temperature, filtered and boiled with 50 ml of 5.9N methanolic hydrochloric acid for one hour under reflux. The reaction solution is freed from the solvent and the residue is chromatographed over 500 g of silica gel with a mixture of chloroform/methanol/ammonia (40:5:0.5). The main fraction is evaporated. After recrystallization from isopropanol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-2-methoxy-benzyl alcohol with a melting point of 167-168° is obtained.

The α-amino-methyl-2-methoxy-benzyl alcohol required as starting material can be obtained as follows: a) A solution of 13.8 g of α-bromo-2-methoxy-acetophenone in 30 ml of dimethylformamide is added while stirring at 0-5° during 30 minutes with 5.85 g of sodium azide. After stirring for 2 hours at 0°, the reaction mixture is poured into 100 ml of ice/water and the crystalline α-azido-2-methoxy-acetophenone is filtered off with suction. The filter residue is dissolved in 300 ml of toluene, the solution is dried (MgSO4) and added dropwise over the course of one hour to a suspension of 10 g of lithium aluminum hydride in 200 ml of tetrahydrofuran at 0-5°. The reactive ion mixture is stirred for l-j hour at 0-5° and then added dropwise at 0-5° with 10 ml of water, 10 ml of concentrated caustic soda and then with 30 ml of water. The precipitate is filtered off and the filtrate is evaporated. The residue is crystallized from ethyl acetate whereby α-amino-methyl-2-methoxy-benzyl alcohol with a melting point of 122-123° is obtained.

Example 25

A solution of 100 g of crude 2-[N-benzyl-N-[ 2-(yl-carbamoyl-1-3-hydroxy-phenoxy)-ethyl]-amino]-4-methylsulfonylamino-acetophenone in 1000 ml methanol is hydrogenated with the addition of 100 ml of acetic acid and 20 g of palladium-on-carbon catalyst (10%) at 30-40° under normal pressure until complete hydrogen uptake (80% of theory). After filtering and evaporating the solvent, an oil is obtained, which after neutralization to pH 3-4 with 6N hydrochloric acid is crystallized. The crystals are suctioned off and recrystallized from water. Thus a-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-ethyl]-aminomethyl]-4-methylsulfonylamino-benzyl alcohol is obtained as hydrochloride with a melting point of 239-240°.

The starting material can be prepared as follows: 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 is stirred in 400 ml of dioxane for 4 hours at 20-30°, filtered and evaporated. The evaporation residue is distributed between ethyl acetate and 2N potassium bicarbonate solution, the organic phase is separated and extracted three times with 2N hydrochloric acid. After neutralization of the acidic extract with potassium bicarbonate and extraction with ethyl acetate, crude 2-[N-benzyl-N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-ethyl]-amino]-4-methylsulfonylamino-acetophenone is obtained as brown oil, which as such passes on be ides.

Example 26

Analogously to examples 25 and 25a) using 5-[2-benzylamino-ethoxy]-salicylamide a-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-aminomethyl]-4-methanesulfonylamino is obtained -benzyl alcohol as a base with a melting point of 172-174° (of ethanol), making the evaporated hydrator alkaline by mixing with 2N ammonia solution and extracting the base with a lot of ethyl acetate.

Example 27

A solution of 8.5 g of α-(aminomethyl)-4-(N-methyl-sulfamoyl.)-benzyl alcohol and 7.7 g of 4-(2-oxo-propoxy)-salicylamide is hydrated analogously to example 12 and worked up. Fractional recrystallization of ethanol and ethyl acetate yields 3 crystal fractions, which in a thin-layer chromatogram give uniform spots (system: ethyl acetate, ethanol, concentrated ammonia 24:12:4), and which together from ethanol recrystallization gives α-[N-[2 -(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-4-(N-methyl-sulfamoyl)-benzyl alcohol as diastereomer mixture (3:1) with melting point 136-150°. After further recrystallization from ethanol, a pure diastereomer with melting point 138-140° is obtained

13

(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 a excess of methylamine to 4-(N-methyl-sulfamoyl)-acetophenone: mp 111-112° (of isopropanol); b) 60 g of the compound obtained is 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 is further used crude. c) Dissolve 80 g of the compound obtained in 760 ml of acetone and add 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 added with 500 ml of ether, filtered off from undissolved and the ether solution is evaporated.

The crude 2-dibenzylamino-4-(N-methylsulfamoyl)-acetophenone obtained as an oil can be reduced as a crude product with sodium borohydride. After recrystallization from isopropanol, a pure product with a melting point of 93-94° is obtained. d) 100 g of the crude compound obtained is dissolved in a mixture of 1800 ml of isopropanol and 200 ml of methanol and the solution is added portionwise while stirring and cooling at 10-15° with 9.5 g of sodium borohydride. After 2-3 hours, the reaction mixture is brought to pH 5-6 with acetic acid and evaporated under reduced pressure and distributed between ethyl acetate and water. The organic phase is separated, washed with water, dried (MgSO 4 ) and evaporated. The remaining oil crystallizes little by little from a little ether. One thus obtains α-(dibenzylaminomethyl)-4-(N-methyl-sulfamoyl)-benzyl alcohol with a melting point of 105-106°. e) By catalytic debenzylation of the obtained compound in methanol over a palladium-on-carbon catalyst

α-(aminomethyl)-4-(N-methylsulfamoyl)-benzyl alcohol with melting point 130-132° (from methanol-toluene) is obtained.

Example 28

110.0 g of α-(aminomethyl)-4-(methylsulfonylamino)-benzyl alcohol is reacted with 100.0 g of 4-(2-oxopropoxy)-salicylamide, as described in example 12. The hydrogen solution is evaporated to approx. 300 ml and allowed to crystallize for 15-20 hours. )-benzyl alcohol is filtered off and shows a melting point of 156-162°. According to "^C-NMR analysis, they consist of a mixture of 75% of the higher melting enantiomer pair A and 25% of the lower melting enantiomer pair B.

After a further three times of recrystallization from methanol, enantiomer pair A with melting point 165-167° (^ 90% A) is obtained. It forms a hydrochloride with melting point 219-220° (of methanol);<13>C-NMR: C-CH3 signal at 13.15 ppm.

Upon further evaporation of the first mother liquor, a further crystalline fraction with a melting point of 138-144° is obtained, in which the diastereomer ratio amounts to ~1:1. The mother liquor filtered off from there no longer crystallizes.

13

According to C-NMR analysis, it contains the enantiomer pair B enriched to 60-70%. This mother liquor (~80 g of brown oil) is chromatographed on 4 kg of silica gel. No identified contaminants are eluted with 70 fractions of ethyl acetate in 150 ml. Further elution with methanol (80 fractions of 150 ml) gives a brown oil which little by little partially crystallizes. By recrystallization from ethanol several times, the enantiomer pair B is obtained with a melting point of 144-145° (>.90% B). It forms a hydrochloride with melting point 206-209° (of ethanol),

13

which in C-NMR shows the signal of the C-methyl group at . 13.65 ppm { >. 95%).

Example 29

A solution of 19.6 g of 5-(2-aminoethoxy)-salicylamide in 100 ml of dimethylsulfoxide is stirred with 19.0 g of 3,4-(epoxybutyl)-benzene for one hour in a bath at 120° and then poured onto 200 ml ice water. After three extractions with 40.0 ml of ethyl acetate each, washing of the extract with water, drying (MgSO4) and evaporation, a semi-solid residue is obtained, from which 1-[2-(3-carbamoyl-1-4-hydroxyphenoxy) is obtained by recrystallization from a little methanol )-ethylamino]-4-phenyl-2-butanol with melting point 159-160°.

Example 30

A solution of 29 g of crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxy-phenoxy)ethylamino]-4-(2-methyl-phenyl)-2-butanol in methanol is hydrated over 3.0 g palladium-on-carbon catalyst (5%) until cessation of hydrogen uptake under normal conditions. By filtration and evaporation, crude 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-(2-methylphenyl)-2-butanol is obtained which, after recrystallization from isopropanol, melts at 140-142°. It forms a hydrochloride with a melting point of 155-157° (from isopropanol). The starting materials can be obtained in the following way: a) To 2-methyl-benzylmagnesium bromide (prepared from 92.5 g a-bromo-o-xylene, 12.5 g magnesium shavings in 250 ml absolute ether) a solution of 46, 3 g of epichlorohydrin in 175 ml of benzene. The ether is then distilled off and the reaction mixture is boiled after reaching an internal temperature of 65° for a further hour under reflux. Under ice-cooling, the reaction mixture is first carefully decomposed with 50 ml of water and then acidified with 125 ml of 2N sulfuric acid. Undissolved is filtered off, the aqueous phase is extracted twice with 200 ml each of ethyl acetate, the organic phases are combined, washed with water, dried (MgSO4) and evaporated. Crude 1-chloro-4-(2methylphenyl)-2-butanol is obtained as a yellow oil, which is further processed as such.

b) 98 g of the compound obtained is dissolved in

700 ml of dichloromethane are added with 16.7 g of tetrabutylammonium hydrogen sulphate and 700 ml of 2N caustic soda and the mixture is stirred for 7 hours at room temperature. Separation of the layers, drying (MgSO^) and evaporation of the dichloromethane solution gives eh oil, which after bubble tube distillation at 135-145° bath temperature and 0.5 mm pressure gives two fractions. The more volatile component shows in the "'"H-NMR spectrum the signals expected for 2-(3,4-epoxy-butyl)-toluene: (CDCl^; 6 in ppm) 1.8 (m, 2H) ; 2.3 (s, 3H); 2.45 (q, 1H); 2.7 (m, 2H); 2.85 (s; 1H); 2.95 (m. 1H) ; 7.1 (p, 4H) .

c) A solution of 15.0 g of the epoxide obtained and 18.6 g of 5-(2-benzylamino-ethoxy)-salicylamide in 130 ml

isopropanol is boiled for 24 hours under reflux and then evaporated. Crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-(2-methylphenyl)-2-butanol is obtained as a yellow-colored oil, which is further processed as such.

Example 31

20 g crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-[4-(2-methoxy-ethoxy)-phenyl]-2-butanol debenzylates catalytic analogous example 30. One obtains 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-[4-(2-methoxy-ethoxy)-phenyl]-2-butanol with a melting point of 151-153°

(of methanol). It forms a hydrochloride with a melting point of 207-208° (from methanol). a) 76 g of 4-hydroxybenzoic acid methyl ester is alkylated with 92 g of (2-methoxy-ethyl)-methanesulfonate in 1500 ml of acetonitrile in the presence of 138 g of potassium carbonate under reflux for 18 hours, after which 4-(2-methoxy- ethoxy)-benzoic acid methyl ester with melting point 35-38°. b) 66 g of the compound obtained is reduced with 12 g of lithium aluminum hydride in 700 ml of tetrahydrofuran,

after which crude 4-(2-methoxyethoxy)-benzyl alcohol is obtained as oil, which as such is further processed.

c) In a solution of 49 g of the obtained compound in 550 ml of toluene is introduced for one hour at approx. -5°

hydrogen chloride gas in a rapid stream. The reaction mixture

then stirred for a further hour at approx. 0-5°, then washed with saturated aqueous sodium chloride solution, dried (MgSO^) and evaporated in vacuo at a temperature below 50°. The crude 4-(2-methoxyethoxy)-benzyl chloride thus obtained is processed further without further purification.

d) From 45 g of the obtained compound and 6.5 g of magnesium shavings, prepare a mixture of each 100 ml

ether and tetrahydrofuran the Grignard compound and is then reacted analogously to example 30a) with 21 g of epichlorohydrin. Thus, crude l-chloro-4-[4-(2-methoxy-ethoxy)-phenyl]-2-butanol is obtained as an oil, which is converted analogously to example 30b) to l-(3-,4-epoxybutyl)-4- (2-methoxy-ethoxy)-benzene .<1>H-NMR(CDCl 3 ): 1.6-1.8<:>(m); 2.45 (q); 2.8-3.0 (m). On the basis of these signals, a content of epoxy compounds of 50% is calculated. e) Equivalent amounts of the obtained compound and 5-(2-benzylamino-ethoxy)-salicylamide are reacted analogously to example 30c) and gives 1-tN-benzyl-2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]- 4-[4-(2-methoxy-ethoxy)-phenyl]-2-butanol as oil, which as such is further processed.

Example 32

A solution of 2.1 g of crude α-[N-[2-(4-carbomethoxy-3-hydroxy-phenoxy)-1-methyl ethyl]-aminomethyl]-4-(methyl-sulfonylamino)-benzyl alcohol in Leave 20 ml of dioxane

with 40 ml of concentrated ammonia solution for 3 days at 20-30°. After evaporation of the solution, a foam is obtained which little by little crystallizes from ethanol and forms a-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-4-( methylsulfonylamino)-benzyl alcohol as diastereoisomer mixture (approx. 1:1) with melting point 141-150°.

The starting material can be prepared as follows: a) A solution of 3.4 g of 2,4-dihydroxybenzoic acid methyl ester, 4.0 g of triethylamine and 2.8 g of chloroacetone in 40 ml of acetonitrile is boiled for 16 hours under reflux. 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 evaporated, the residue is dissolved in 50 ml of toluene, the solution is washed with 10 ml of water, then with 10 ml of saturated aqueous sodium chloride solution and chromatographed over 200 g of silica gel. The fractions first eluted with toluene contain 4-(2-oxo-propoxy)-salicylic acid methyl ester which is recrystallized from isopropanol and melts at 106-108°. b) A solution of 2.3 g of a-(aminomethyl)-4-(methylsulfonylamino)-benzyl alcohol and 1.9 g of 4-(2-oxoprop-oxy)-salicylic acid methyl ester in 50 ml of methanol is hydrated analogously to example 12. By filtering and evaporation yields crude α-[N-[2-(3-carbonethoxy-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol as a yellow oil, which gradually solidifies as a crystalline mass. It can be further processed raw by recrystallization from ethyl acetate-ether, crystals with melting point 113-121° are obtained (mixture of diastereomers).

Example 3 3

1.2 g of crude α-[N-[2-(4-cyano-3-hydroxy-phenoxy)-ethyl]-aminomethyl]-4-methylsulfonylamino-benzyl alcohol are dissolved in 15 ml of concentrated hydrochloric acid and the solution is left to stand for 24 hours at 20-25°. Evaporation in a vacuum gives α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-ethyl]-aminomethyl]-4-methylsulfonylamino-benzyl alcohol as hydrochloride which, after recrystallization from water, melts at 239-240° .

The starting material can be prepared in the following way: a) A mixture of 27.4 g of 2,4-dihydroxy-benzonitrile, 30.8 g of potassium carbonate, 1000 ml of 1,2-dibromoethane and

100 ml of dimethylformamide is heated with stirring on a descending cooler so that an internal temperature of 127-129° is achieved. Heating continues for less than 6 hours. The distillate is discarded. The reaction mixture is filtered and the filtrate is evaporated under vacuum. By partitioning the residue between ethyl acetate and water, drying (MgSO4), evaporation of the organic phase and crystallisation, 4-(2-bromoethoxy)-2-hydroxy-benzonitrile is obtained with a melting point of 160-175° (of ethyl

acetate), which is sufficiently pure for the following reaction. b) A mixture of 2.8 g of α-(aminomethyl)-4-methylsulfonylamino-benzyl alcohol, 2.4 g of 4-(2-bromomethoxy)-2-hydroxy-benzonitrile, 4.1 g of triethylamine and 20 ml of dioxane is heated 3 hours under stirring and reflux. Workup analogous to example 7 gives crude α-[N-[2-(4-cyano-3-hydroxy-phenoxy)-ethyl]-aminomethyl-4-methylsulfonylamino-benzyl alcohol as a brown foam which is further crudely processed.

Example 34

A solution of 10.5 g of crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-(4-benzyloxy-phenyl)-2-butanol in 55 ml of methanol is debenzylated analogous example 30 catalytic. 1-[2-(3-carbamoyl-1-4-hydroxy-phenoxy)-ethylamino]-4-(4-hydroxyphenyl)-2-butanol is thus obtained.

The starting material can be prepared as follows: a) 18 g of 4-benzyloxy-benzyl alcohol is chlorinated with 21 ml of thionyl chloride in 30 ml of pyridine to form 4-benzyloxy-benzyl chloride, melting point of the crude substance 72-78°; b) 15 g of the obtained 4-benzyloxy-benzyl chloride is reacted analogously to example 31d) to a Grignard compound and

this is reacted with 7 g of epichlorohydrin to 1-(3,4-epoxy-butyl)-4-benzyloxy-benzene.

c) Reaction of 15 g of the obtained epoxide with 18.6 g of 5-(2-benzylaminoethoxy)-salicylamide analogous example

30c) gives crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-(4-benzyloxyphenyl)-2-butanol as oil, which as such is further processed.

Example 35

8.4 g of a-[N-[2-(4-carbonethoxy-3-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol are dissolved in 50 ml of dioxane and added with 200 ml of a 40% aqueous methylamine solution. Leave the solution for 2-3 days at room temperature. Processing analogously

Example 32 gives α-[N-[2-(4-methylcarbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol as diastereomer mixture.

Example 36

Tablets containing 20 mg of active substance are prepared in the following composition in the usual way:

Composition:

Preparation: a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-3-sulfamoyl-4-chloro-benzyl alcohol is mixed with part of the wheat starch, with milk sugar and colloidal silicic acid and the mixture is run through a sieve. A further part of the wheat starch pre-glued with 5 times the amount of water in a water bath and the powder mixture is crushed with this glue until a weak plastic mass is formed.

The plastic mass is pressed through a sieve of approx. 3 mm mesh size, is dried and the formed dry granules are run again through a sieve. The remaining wheat starch, talc and magnesium stearate are then mixed in and the mixture is pressed into tablets of 145 mg weight with an indication of breakage.

Example number 37

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

Composition:

Manufacturing:

a-[N-t2-(3-hydroxy-4-carbamoyl-phenoxy)-1-methyl-ethyl]-aminomethyl]-3-sulfamoyl-4-chloro-benzyl alcohol is mixed with part of the wheat starch, with milk sugar and colloidal silicic acid and the mixture is passed through a sieve. A further part of the wheat starch pre-glued with 5 times the amount of water in a water bath and powder mix no crunch with this glue until a weak plastic mass is formed.

The plastic mass is pressed through a sieve of approx. 3 mm mesh size, is dried and the formed dry granules are run again through a sieve. The remaining wheat starch, talc and magnesium stearate are then mixed and the mixture is pressed into tablets of 145 mg weight with instructions for breaking.

Example number 38

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

Compilation:

Front tillage:

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

Example 39

A sterile solution of 5.0 g of α-[N-[2-β-carbamoyl-β-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-3-sulfa-.moyl-4-chloro- benzyl alcohol-methanesulfonate in 5000 ml of distilled water is filled into ampoules of 5 ml, which in 5 ml of solution contain 5 mg of active substance.

Example 40

3.62 g of a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-3-sulfamoyl-4-chloro-benzyl alcohol are dissolved while adding 100.0 ml of 0.10N hydrochloric acid with 18000 ml of distilled water in a volume of 18100 ml. The sterilized solution is filled in ampoules of 5.0 ml, which contain 1 mg of active substance.

Example 41

Instead of the compounds used as active substances in examples 37 to 40, the following compounds of formula I can also be used, or their pharmaceutically acceptable non-toxic acid addition salts as active substances in tablets, dragees, capsules, ampoule solutions, etc. : a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-2.4- dichlorobenzyl alcohol, a-[N-[2-(3-carbamoyl-4-hydroxy- phenoxy)-ethyl]-aminomethyl]- 4-chloro-3-nitro-benzyl alcohol, α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-ethyl]-aminomethyl]- 4-nitro-benzyl alcohol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]- 3-(Methylsulfonylamino)-4-chloro-benzyl alcohol, a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-3.5-dichloro-4-amino-benzyl alcohol, a -[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-.3-(methylsulfonylamino)-benzyl alcohol, α-[N-[2-(4-carbamoyl-3 -hydroxy-phenoxy)-1-methyl-ethyl]- aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol, α-[N-[2-(3 carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-3,4-methylenedioxy-benzyl alcohol, >■ ct-[W-[ 2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]- aminomethyl]-3,4-methylenedioxy-benzyl alcohol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]- aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]- aminomethyl]-3-carbamoyl-4-hydroxy-benzyl alcohol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]-aminomethyl]-4-(2-methoxy- ethoxy)-benzyl alcohol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]- aminomethyl]-4-methyl-benzyl alcohol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethyl]- aminomethyl]-4-methoxy-benzyl alcohol, α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]- 3-sulfamoyl-4-methoxy-benzyl alcohol, 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-(2- methoxyphenyl)-2-butanol, l-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-phenyl-2-propanol, or 1-t 2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino-3-(2- methoxyphenyl)-2-propanol, a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-3- methoxy-benzyl alcohol, a-[N-[2-(4 -carbamoyl-3-hydroxy-phenoxy)-ethyl]-aminomethyl]-4-methyl-sulfonylamino-benzyl alcohol, a-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]- aminomethyl]- 4-methanesulfonylamino-benzyl alcohol, α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]- aminomethyl]-4-(methylsulfonylamino)-benzyl alcohol as a pair of enantiomers with a melting point of 165-167°, or as a pair of enantiomers with a melting point of 144-145°, 1-1 2-(3-carbamoyl-4-hydroxy-phenoxy) -ethylamino]-4-phenyl- 2-butanol, l-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-(2-methyl- phenyl)-2-butanol,

1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-4-[4-(2-methoxy-ethoxy)-phenyl]-2-butanol.

Claims (1)

1. Process for the production of new derivatives of 2-amino-ethanol with formula in which Ar means optionally substituted phenyl, m means a number from 0 to 3, n means the number 0 or 1 and alk means the alkylene with 2-5 carbon atoms, whereby the nitrogen atom and the oxygen atom or, if n stands for zero, the phenyl residue are separated from each other and of at least two carbon atoms, and and R^ independently of each other denote each hydrogen or lower alkyl, or together the lower alkylene, the oxal lower alkylene, the thial lower alkylene, the aza lower alkylene or the N-lower alkyl aza lower alkylene with the proviso that if m stands for zero, the phenyl residue Ar contains at least one substituent and a of one or two hydroxy groups or protected hydroxy groups substituted phenyl residue Ar which contains at least one further, of this different substituents, in the form of racemate mixtures, racemates, optical antipodes or their salts, characterized by a) reacting a compound of formula with a compound of formula wherein one of the groups Z^ and Z^ represents a reactive esterified hydroxy group and the other represents the primary amino group, and X^ represents hydroxy, or wherein X^ and Z^ together represent the epoxy group and Z^ represents the primary amino group, Ar, alk, m and n have the above meaning, or b) in a compound of formula in which Ar^ has the meaning of Ar or means a residue Ar, which are substituted with each 1 to 2 in hydroxy and/or amino transferable groups, X^, X^ and X^ are each hydrogen or a hydrogen replaceable substituent and X,- stands for , or X^ and X^ and/or X^ and X, together mean a divalent residue replaceable by two hydrogen atoms with the proviso that at least one of the residues X^, X^ and X^ is different from hydrogen, or at least Ar^ means a residue Ar, which is substituted with each 1 to 2 in hydroxy and/or amino transferable groups, or at least X^ and X^ together or X^ and X,. together denotes a divalent residue replaceable by two hydrogen atoms, and m and n have the meanings given above, or in a salt thereof, it is replaced by hydrogen other than X^, X^, or X^, respectively. X^ and X^ together or X^ and X,- together with hydrogen, and/or in a residue Ar^ converts present substituted hydroxy and/or amino into free hydroxy and/or amino, or c) in a compound of formula where Xg is a reducible group with the formulas in which alk^ stands for a residue alk corresponding to an alkyl-ylidene residue and alk2 corresponds to an abbreviated residue alk if a methylene group attached to the nitrogen atom, X^ denotes an oxo- or thio-oxo residue and Xg denotes hydrogen or one under the condition of reduction of Xg and/ or Y with a hydrogen replaceable residue and Y stands for a residue of the formula -CO-(Vf) or -CH(OXg)-(Vg), in which Xg has the above meaning, Ar2 corresponds to a residue Ar, however optionally instead of each one or two hydroxy and/or amino bear one or two groups -OXg, and/or -N(Xg)-, in which Xg has the above-mentioned meaning, m and n have the above-mentioned meanings, whereby Xg is always a reducible group Va to Vd and/or Y is a carbonyl group Vf, reduce these group(s) and, in the same working operation, replace by hydrogen different groups Xg with hydrogen, or d) react a compound of formula in which Ar^ has the meaning of Ar, or indicates a residue Ar, which is substituted by 1 to 2 by means of aminolysis in hydroxy and/or amino transferable and/or with groups of the formula -COOH, -Xg means hydrogen or a by means of by aminolysis cleavable group, and m and n have the meanings given above, or a reactive derivative of a carboxylic acid defined in formula VI, with a compound of formula HNR^F^(VII) and at the same time transfer any present, by means of aminolysis in hydroxy and/or amino transferable residues in hydroxy and/or amino, and/or cleave off any present residues Xg and replace with. hydrogen, or e) for the preparation of compounds of formula (I), in which and R2 each means hydrogen, converts in a compound of formula: in which one or both hydroxy groups and/or hydroxy and/or amino groups present in the residue Ar are optionally protected by groups that can be split off by means of hydrolysis and are replaceable with hydrogen which under the conditions of the process are split off and replaced with hydrogen, or in the residue Ar optionally together with the aforementioned protected hydroxy and/or amino groups, the group -CN is present, the group -CN by means of hydrolysis in the group -CONI-^ and at the same time converts any protected hydroxy and/or amino groups into free hydroxy and/or amino groups, or f) for the preparation of compounds' of formula (I), in which m stands for 1, 2 or 3, in a compound of formula in which A stands for the group -N-alk- or -N=alk,-, in which alk, . H denotes a methylene group less exhibiting group alk, and X denotes a group transferable by means of reduction, including hydrogenolysis, into a methylene-, 1,2-ethylene or 1,3-propylene group and one or both hydroxy groups and / or in the residue Ar any hydroxy and/or amino groups present are protected by such by means of reduction, including hydrogenolysis, cleavable and hydrogen-replaceable groups, which under the conditions of the process are cleaved off and replaced with hydrogen, the group X converts by means of reduction including hydrogenolysis in a methylene, 1,2-ethylene or 1,3-propylene group and at the same time converts an optionally present unsaturated group A into a saturated group A, and at the same time converts any present protected hydroxy and/or amino groups into free hydroxy and/or amino groups, and, if desired, converts an obtained compound into another compound of formula (I), and/or, if desired, transfers an obtained free compound in a salt t or an obtained salt in a free compound, and/or, if desired, separates an obtained racemate mixture into the racemates or separates an obtained racemate into the optical antipodes.