Derivatives of 3-aminopropane-1,2-diol

Derivatives of 3-aminopropane-1,2-diol of the formula ##STR1## in which Ar represents optionally substituted aryl, PA1 n represents the number 0 or 1, and PA1 alk represents alkylene having 2 to 5 carbon atoms, the nitrogen atom and the oxygen atom, or, if n is zero, the phenyl radical, being separated from one another by at least two carbon atoms, and PA1 R.sub.1 and R.sub.2, independently of one another, each represents hydrogen or lower alkyl, or together they represent lower alkylene, oxa-lower alkylene, thia-lower alkylene, aza-lower alkylene or N-lower alkyl-aza-lower alkylene, and salts of such compounds, processes for their manufacture, medicaments containing the new compounds and their use for the treatment of Angina pectoris and cardiac arrhythmia, and as blood pressure-reducing agents, as well as for the treatment of reactive or endogenic states of depression.

The invention relates to new derivatives of 3-aminopropane-1,2-diol, 
processes for their preparation, pharmaceutical preparations containing 
such compounds and their use for the manufacture of pharmaceutical 
preparations or as pharmacologically active compounds. 
The new derivatives of 3-aminopropane-1,2-diol according to the invention 
corresponds to the formula 
##STR2## 
in which 
Ar represents optionally substituted aryl, 
n represents the integer 0 or 1, and 
alk represents alkylene having from 2 to 5 carbon atoms, the nitrogen atom 
and the oxygen atom, or if n is zero, the phenyl radical, being separated 
from one another by at least two carbon atoms, and 
R.sub.1 and R.sub.2, independently of one another, each represents hydrogen 
or lower alkyl, or together they represent lower alkylene, oxa-lower 
alkylene, thia-lower alkylene, aza-lower alkylene or N-lower 
alkyl-aza-lower alkylene. 
The invention also relates to salts of these compounds. 
An aryl radical Ar is a carbocyclic or heterocyclic aryl radical. 
Preferably, Ar is monocyclic or bicyclic carbocyclic aryl or monocyclic or 
bicyclic heteroaryl bonded by a ring carbon atom and containing as ring 
members a maximum of two nitrogen atoms and/or one oxygen or sulphur atom. 
These radicals may be unsubstituted or substituted one or more times, 
preferably at most three times, and in bicyclic radicals Ar, the ring not 
directly bonded to the ether group may be at least partially hydrogenated 
and in this case may be substituted especially by oxo. Ar is especially 
phenyl, or also naphthyl, such as 1-naphthyl, or partially saturated 
naphthyl, such as 1,2,3,4-tetrahydro-5-naphthyl; when Ar represents 
monocyclic or bicyclic heteroaryl it is especially pyridyl, for example, 
pyrid-2-yl, pyrid-3-yl or pyrid-4-yl, pyridazinyl, for example 
pyridazin-3-yl, pyrimidinyl, for example pyrimidin-2-yl or pyrimidin-4-yl, 
pyrazinyl, e.g. pyrazin-2-yl, thienyl, for example thien-3-yl, thiazolyl, 
e.g. thiazol-2-yl, thiadiazolyl, e.g. 1,2,4-thiadiazol-3-yl or -5-yl or 
1,2,5-thiadiazol-3-yl, ndolyl, e.g. indol-4-yl, quinolinyl, e.g. 
quinolin-2-yl, isoquinolinyl, e.g. isoquinolin-1-yl, 
2-oxobenzimidazol-4-yl, naphthyridinyl, e.g. 1,8-naphthyridin-2-yl, or 
benzofuranyl, for example benzofuran-4-yl or benzofuran-5-yl. 
Possible substituents of radicals Ar, for example of the radicals defined 
in detail above and of the radicals mentioned hereinbefore as examples, 
are, for example, optionally substituted, especially in the manner 
specified hereinafter, lower alkyl, lower alkenyl or lower alkoxy, also 
lower alkenyloxy, lower alkynyl, lower alkynyloxy, cyano and/or nitro, 
and/or, as substituents bonded directly or to the above-mentioned lower 
alkyl, lower alkenyl or lower alkoxy, one or more of lower alkanoyl, 
cycloalkyl, esterified or amidated carboxyl, especially lower 
alkoxycarbonyl or optionally substituted carbamoyl, for example carbamoyl, 
lower alkylcarbamoyl, di-lower alkylcarbamoyl or (hydroxy-lower alkyl) 
carbamoyl, lower alkylsulphinyl, lower alkylsulphonyl, sulphamoyl or lower 
alkylsulphamoyl; or halogen bonded directly or halogen bonded to the 
above-mentioned lower alkyl or, in a position higher than the 1-position, 
halogen bonded to the above-mentioned lower alkoxy; or optionally 
etherified or esterified hydroxy, such as hydroxy, bonded directly or 
bonded to the above mentioned lower alkyl such as hydroxy-lower alkyl or 
polyhydroxy-lower alkyl, substituents not directly bonded are, again, 
lower alkoxy, cycloalkyl-lower alkoxy, also phenyl-lower alkoxy, or lower 
alkanoyloxy, etherified mercapto, such as lower alkylthio, optionally 
substituted amino, such as amino, lower alkylamino, di-lower alkylamino, 
alkyleneamino or oxa-alkyleneamino, pyrrol-1-yl, acylamino, such as lower 
alkanoylamino, lower alkoxycarbonylamino, optionally substituted ureido, 
especially ureido substituted by one or two lower alkyl radicals, by 
hydroxy-lower alkyl or by cycloalkyl, lower alkylsulphonylamino or N-lower 
alkyl lower alkylsulphonylamino. 
The radicals and compounds denoted by "lower" in connection with the 
present description contain preferably up to 7, and especially up to 4, 
carbon atoms. 
The general terms used in the enumeration of substituents of the radical Ar 
may have, for example, the following specific meanings. Lower alkyl is, 
for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or 
tert.-butyl; substituted lower alkyl is especially corresponding methyl or 
1- or 2-substituted ethyl. Lower alkenyl is, for example, vinyl, allyl, 2- 
or 3-methallyl or 3,3-dimethallyl, and substituted lower alkenyl is 
especially 2-substituted vinyl or 3-substituted allyl. Cycloalkyl has from 
3 to 7 ring members and is for example, cyclopropyl. Lower alkoxy is, for 
example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy, 
and substituted lower alkoxy is, for example, substituted methoxy or 1- or 
2-substituted ethoxy. Lower alkenyloxy is, for example, allyloxy, 2- or 
3-methallyloxy or 3,3-dimethallyloxy. Lower alkynyl is, for example, 
propargyl, and lower alkynyloxy is especially propargyloxy. Lower alkanoyl 
is, for example, acetyl, propionyl or butyryl. Lower alkoxycarbonyl is, 
for example, methoxycarbonyl or ethoxycarbonyl. Lower alkylcarbamoyl or 
di-lower alkylcarbamoyl is, for example, methylcarbamoyl, 
dimethylcarbamoyl ethylcarbamoyl or diethylcarbamoyl, and hydroxy-lower 
alkylcarbamoyl is, for example, (2-hydroxyethyl)carbamoyl. Lower 
alkylsulphinyl is, for example, methyl- or ethylsulphinyl, lower 
alkylsulphonyl is, for example, methyl-, ethyl- or propylsulphonyl, and 
lower alkylsulphamoyl is, for example, methyl-, ethyl- or 
isopropylsulphamoyl. Halogen may be bromine or iodine, but is preferably 
fluorine or chlorine. Cycloalkyl-lower alkoxy is for example 
cyclopropylmethoxy or 1- or 2-cyclopropylethoxy. Phenyl-lower alkoxy is, 
for example, benzyloxy or 1- or 2-phenylethoxy, and lower alkanoyloxy is, 
for example, formyloxy, acetoxy, propionyloxy, butyryloxy or 
isobutyryloxy. Lower alkylthio is, for example, methylthio, n-propylthio 
or isopropylthio. Lower alkylamino and di-lower alkylamino are, for 
example, methylamino, ethylamino, dimethylamino or diethylamino. 
Alkyleneamino and oxa-alkyleneamino are, e.g., pyrrolidino, piperidino or 
morpholino. Lower alkanoylamino is, for example, acetylamino or 
butyrylamino, and lower alkoxycarbonylamino is, for example, 
methoxycarbonylamino or ethoxycarbonylamino. Ureido substituted by one or 
two lower alkyl radicals, by hydroxy-lower alkyl or by cycloalkyl 
preferably having 5 to 7 ring members, is e.g. 3-methylureido, 
3,3-dimethylureido, 3-(2-hydroxyethyl)ureido, or 3-cyclohexylureido. Lower 
alkylsulphonylamino is e.g. ethylsulphonylamino and especially 
methylsulphonylamino, N-lower alkyl lower alkylsulphonylamino is e.g. 
N-methyl methylsulphonylamino. 
As stated above, substituents of Ar may be one of the above-mentioned 
radicals which is bonded not directly but through lower alkyl, lower 
alkoxy or optionally also through lower alkenyl. General and specific 
examples of such substituents are given in the following but the possible 
combinations are not limited thereto. Lower alkanoylalkyl is e.g. 
2-oxopropyl (acetonyl) or 3-oxobutyl; lower alkanoyl-lower alkenyl is e.g. 
3-oxobut-1-enyl, and lower alkanoylalkoxy is e.g. 2-oxopropoxy 
(acetonyloxy) or 3-oxobutoxy. Optionally substituted carbamoyl-lower alkyl 
is e.g. carbamoylmethyl or [(hydroxy-lower alkyl)carbamoyl)]-lower alkyl, 
such as [(2-hydroxyethyl)carbamoyl)]methyl. Lower alkoxycarbonyl-lower 
alkoxy is e.g. ethoxycarbonylmethoxy. Optionally substituted 
carbamoyl-lower alkoxy is, for example, carbamoyl-lower alkoxy, such as 
carbamoylmethoxy, or [(hydroxy-lower alkyl)carbamoyl]lower alkoxy, such as 
[(2-hydroxyethyl)carbamoyl]methoxy. Halo-lower alkyl is especially 
halomethyl, e.g. trifluoromethyl. Hydroxy-lower alkyl is preferably 
hydroxymethyl, or 1- or especially 2-hydroxyethyl. Polyhydroxy-lower alkyl 
is, for example, di- or trihydroxy-lower alkyl such as 1,2-dihydroxy- or 
2,3-dihydroxy-lower alkyl for example 1,2-dihydroxy- or 
2,3-dihydroxypropyl. Lower alkoxy-lower alkyl is preferably lower 
alkoxymethyl or 1- or especially 2-lower alkoxyethyl, e.g. methoxymethyl, 
ethoxymethyl, 2-methoxyethyl or 2-ethoxyethyl. Cycloalkyl- lower 
alkoxy-lower alkyl is preferably cycloalkyl-lower alkoxy methyl or 1- or 
2-(cycloalkyl-lower alkoxy)-ethyl e.g. 1- or 2-(cyclopropylmethoxy)-ethyl. 
Lower alkoxy-lower alkoxy is especially 2-lower alkoxyethoxy, such as 
2-methoxyethoxy or 2-ethoxyethoxy; lower alkylthio-lower alkoxy is e.g. 
2-methylthioethoxy or 2-ethylthioethoxy. Acylamino-lower alkyl is e.g. 
lower alkanoylamino-lower alkyl, especially lower alkanoylaminomethyl, or 
1- or especially 2-lower alkanoylaminoethyl, e.g. acetylaminomethyl, 
2-acetylaminoethyl or 2-propionylaminoethyl; or lower 
alkoxycarbonylamino-lower alkyl, especially lower 
alkoxycarbonylaminomethyl, or 1- or especially 2-lower 
alkoxycarbonylaminoethyl e.g. methoxycarbonylaminomethyl, 
2-methoxycarbonylaminoethyl or 2-ethoxycarbonylaminoethyl. Acylamino-lower 
alkoxy is e.g. lower alkanoylamino-lower alkoxy, especially 2-lower 
alkanoylaminoethoxy, e.g. 2-(acetylamino)ethoxy, or lower 
alkoxycarbonylamino-lower alkoxy, especially 2-(lower 
alkoxycarbonylamino)ethoxy, e.g. 2-(methoxycarbonylamino)ethoxy or 
2-(ethoxycarbonylamino)ethoxy. Lower alkylcarbamoyl lower alkenyl is, for 
example, N-methylcarbamoyl lower alkenyl such as N-methylcarbamoyl vinyl. 
Alkylene alk may be straight chain or branched and is, for example, 
ethylene, trimethylene, propylene, tetramethylene, 1-methyltrimethylene, 
1,1-dimethyltrimethylene or 1,1-dimethylethylene. 
R.sub.1 and R.sub.2 having the meaning lower alkyl are, for example, 
propyl, isopropyl, butyl, isobutyl, sec.-butyl, pentyl, isopentyl, 
neopentyl, hexyl or heptyl, and especially methyl or ethyl. Together with 
the nitrogen atom of the amide group, R.sub.1 and R.sub.2 as lower 
alkylene are, for example, aziridin-1-yl, azetidin-1-yl, pyrrolidino, 
piperidino, hexahydro-1H-azepin-1-yl; as oxa-lower alkylene e.g. 
morpholino; as thia-lower alkylene e.g. thiomorpholino; as aza-lower 
alkylene e.g. piperazin-1-yl or hexahydro-1H-1,4-diazepin-1-yl, wherein 
the two last-mentioned groups, corresponding to the meaning N-lower 
alkyl-aza-lower alkylene for R.sub.1 and R.sub.2 in the 4-position, that 
is in the imino group, may be substituted, for example, by lower alkyl, 
such as methyl, ethyl, propyl, isopropyl, butyl or isobutyl. 
The phenyl radical carrying the amide and the hydroxy group may be bonded 
in any position to the remainder of the molecule; preferably, the latter 
is bonded in the 4-position of the said phenyl radical, that is, in the 
position para to the amide group, and is bonded especially in the 
5-position of the said phenyl radical, (that is, in the position para to 
the hydroxy group). 
The new compounds may exist in the form of their salts, such as their acid 
addition salts, and especially in the form of their pharmaceutically 
acceptable, non-toxic acid addition salts. Suitable salts are e.g. those 
with inorganic acids, such as hydrohalic acids, e.g. hydrochloric acid or 
hydrobromic acid, sulphuric acid or phosphoric acid, or with organic 
acids, such as aliphatic, cycloaliphatic, aromatic or heterocyclic 
carboxylic or sulphonic acids, e.g. formic, acetic, propionic, succinic, 
glycolic, lactic, malic, tartaric, citric, maleic, hydroxymaleic, pyruvic, 
fumaric, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, 
salicyclic, embonic, methanesulphonic, ethanesulphonic, 
2-hydroxyethanesulphonic, ethylenesulphonic, toluenesulphonic, 
naphthalenesulphonic or sulphanilic acids, or with other acidic organic 
substances, such as ascorbic acid. 
The new compounds have valuable pharmacological properties. In particular, 
they act in a specific manner on .beta.-adrenergic receptors. This action 
is attributed to the affinity for these receptors, which is a property 
common to the compounds of the formula I. With no or only very slight 
inherent stimulating action this affinity is reflected as a pure blocking, 
and with slight to moderate inherent stimulating action is reflected as a 
blocking with simultaneous ISA (i.e. intrinsic sympathomimetic activity), 
and, with relatively strong inherent action, as actual stimulation of the 
.beta.-adrenergic receptors. Pronounced .beta.-receptor-stimulating and at 
the same time cardioselective activity is found especially with those 
compounds of formula I in which Ar represents a hydroxyphenyl radical. Of 
the remaining compounds of the formula I, the .beta.-receptor-blockers 
with or without ISA, those having a substituent in the p-position, such as 
especially 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(2-methoxyethoxy)phen 
oxy]propan-2-ol, exhibit a more or less pronounced cardioselectivity. This 
action is less clear, or lacking, however, in compounds with 
ortho-substitution in the broadest sense, that is, the presence of a 
single substituent or a fused ring in the position ortho to the ether 
group. On the other hand, such compounds in addition have .alpha.-receptor 
blocking properties. An example of such a compound is especially 
1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propan 
-2-ol. 
The above details referring to pharmacological properties are based on the 
results of appropriate pharmacological experiments in conventional test 
methods. Thus, in a concentration range of from approximately 0.001 
.mu.g/ml to approximately 1 .mu.g/ml the new .beta.-blocking compounds 
inhibit tachycardia induced by isoproterenol in isolated guinea pig hearts 
and in a dosage range of from approximately 0.001 mg/kg to approximately 3 
mg/kg, they inhibit the same condition in anaesthetised cats when 
administered intravenously. In the same dosage range, in anaesthetised 
cats the .beta.-blocking compounds of the formula I also inhibit an 
increase in heart rate induced by electrical stimulation of the 
sympathetic nerves. The inhibition of vasodilation induced by 
isoproterenol in anaesthetised cats with perfusion of the arteria 
femoralis can be demonstrated with cardioselective compounds of the 
formula I when administered intravenously in a dosage range of from 
approximately 0.1 mg/kg to approximately 30 mg/kg, and with 
non-cardioselective compounds in a dosage range of from 0.001 to 1 mg/kg. 
The ISA of the .beta.-blocking compounds of the formula I is shown by the 
increase in the basal heart rate in anaesthetised cats previously treated 
with reserpine, when the compounds are administered intravenously in a 
dosage range of from 0.001 to 1 mg/kg. The new .beta.-blocking compounds 
also cause a reduction in arterial blood pressure of anaesthetised cats in 
a dosage range of from approxmately 0.01 mg/kg to approximately 10 mg/kg 
i.v. The additional .alpha.-blocking activity of the non-cardioselective 
.beta.-receptor-blockers which may, for example, promote a blood 
pressure-reducing action, is shown, for example, in the antagonisation of 
the noradrenalin-induced contraction of the isolated vas deferens of rats 
by such compounds in a concentration of from 0.01-3 .mu.g/ml. The new 
.beta.-blocking compounds of the formula I may be used as optionally 
cardioselective .beta.-receptor-blockers, for example for the treatment of 
angina pectoris and cardiac arrhythmia, and as blood pressure-reducing 
agents. 
The .beta.-stimulating compounds of the formula I, such as 
1-(4-hydroxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamin 
o]propan-2-ol, for example that racemate of which the neutral fumarate 
melts at 195.degree.-198.degree., cause an increase in heart rate and 
myocardial contraction force in the isolated guinea pig auricle in a 
concentration range of from approximately 0.0001 to 0.1 .mu.g/ml, and 
cause an increase in heart rate and maximum pressure increase speed in the 
left ventricle (dp/dt max), in anaesthetised cats in a dosage range of 
from approximately 0.0001 to approximately 0.1 mg/kg i.v. On the other 
hand, higher doses, corresponding to a dosage range of from approximately 
0.001 to approximately 1 mg/kg i.v., are required to reduce arterial blood 
pressure in anaesthetised cats, that is to say, the new compounds 
stimulate specifically the cardial .beta.-receptors (.beta..sub.1 
-receptors) compared with the .beta.-receptors in the blood vessels 
(.beta..sub.2 -receptors) and are thereby qualitatively clearly 
distinguished from isoproterenol which stimulates the .beta.-receptors of 
the heart and the blood vessels approximately equally strongly. The new 
compounds may therefore be used as positively inotropically acting agents, 
especially as cardiotonic agents for the treatment of myocardial 
insufficiency, either alone or in combination with other preparations, 
such as cardiac glycosides, and also for the treatment of certain 
disturbances in cardiac rhythm. 
Compounds of the formula I, in which Ar is phenyl unsubstituted or 
substituted one to three times by hydroxy exhibit effects on the central 
nervous system, which are reflected for example in the suppression of the 
symptoms of impaired sympathetic functions and in the suppression of lack 
of initiative, as can be demonstrated for example by virtue of the 
antagonism against hypothermia induced in mice after s.c.-administration 
of 2 mg/kg of reserpine (B. Benz et al,: Arzneimittelforschung 21, 654-61 
(1971)) in a dose of about 3 mg/kg to about 100 mg/kg i.p., or by virtue 
of the antagonism against hypothermia induced in mice after 
s.c.-administration of 10 mg/kg of apomorphine (Puech A. L.: Europ. J. of 
Pharmacol. 47, 127-27 (1978); Schelkunov E. L.: Psychopharmacol. 55, 87-95 
(1977)) in a dose range of about 0,03 mg/kg to about 1 mg/kg i.p., or by 
virtue of the antagonism against hypothermia induced in mice after 
i.p.-administration of 0,25 mg/kg of clonidine (Voigtlaender P. F. et al,: 
Neuropharmacol. 17, 375-81 (1978)) in a dose range of about 0,01 mg/kg to 
about 0,3 mg/kg i.p. With respect to these results such compounds of the 
formula I can be used for the treatment of reactive or endogenic states of 
depression of varying degrees of severity, and also for the treatment of 
neurotic or other psychic disturbances involving loss of initiative and 
depressive disorders. Such compounds can also be used for the short-term 
treatment of post-partum or postoperative depression, or of depression of 
different origin. Such compounds of the formula I can be used on their own 
or in combination with other antidepressants. 
The compounds of the general formula I may also be used as valuable 
intermediates for the preparation of other more valuable compounds, 
especially compounds that are pharmaceutically more effective. 
The invention relates in particular to compounds of the formula I in which 
Ar represents monocyclic or bicyclic carbocyclic aryl or monocyclic or 
bicyclic heteroaryl bonded by a ring carbon atom and containing as ring 
members a maximum of two nitrogen atoms and/or one oxygen or sulphur atom, 
which radicals may be unsubstituted or substituted one or more times, 
preferably at most three times, wherein as substituents there may be 
present optionally substituted, especially in the manner specified 
hereinafter, lower alkyl, lower alkenyl or lower alkoxy, also lower 
alkenyloxy, lower alkynyl, lower alkynyloxy, cyano and/or nitro, and/or, 
as substituents bonded directly or to the above-mentioned lower alkyl, 
lower alkenyl or lower alkoxy, one or more of lower alkanoyl, cycloalkyl, 
esterified or amidated carboxyl, especially lower alkoxycarbonyl, 
carbamoyl, lower alkylcarbamoyl or (hydroxy-lower alkyl)carbamoyl, lower 
alkylsulphinyl, lower alkylsulphonyl, sulphamoyl or lower alkylsulphamoyl; 
and/or, halogen bonded directly or halogen bonded to the above-mentioned 
lower alkyl or, in a position higher than the 1-position, halogen bonded 
to the above-mentioned lower alkoxy; optionally etherified or esterified 
hydroxy, such as hydroxy bonded directly or bonded to the above-mentioned 
lower alkyl or, as substituent not directly bonded, again lower alkoxy, 
cycloalkyl-lower alkoxy, also phenyl-lower alkoxy, for example benzyloxy, 
or lower alkenyloxy, etherified mercapto, such as lower alkylthio, 
optionally substituted amino, such as amino, lower alkylamino, di-lower 
alkylamino, alkyleneamino or oxaalkyleneamino, for example, pyrrolidino, 
piperidino or morpholino, pyrrol-1-yl, acylamino, such as lower 
alkanoylamino, lower alkoxycarbonylamino, ureido optionallyl substituted 
by lower alkyl, by hydroxy-lower alkyl or by cycloalkyl, lower 
alkylsulphonylamino or N-lower alkyl lower alkylsulphonylamino, and in 
bicyclic radicals Ar, the ring not directly bonded to the ether group is 
also at least partially hydrogenated and in this case may also be 
substituted by oxo; and in which n is the number 0 or 1, alk is an 
alkylene radical having from 2 to 4 carbon atoms, the nitrogen atom and 
the oxygen atom or, if n is 0, the phenyl radical, being separated from 
one another by 2 or 3 carbon atoms, and R.sub.1 and R.sub.2 have the 
meanings given under formula I but preferably represent hydrogen or lower 
alkyl, for example methyl or ethyl, or together with the nitrogen atom of 
the amide group, form morpholino or alkyleneamino having 5 or 6 ring 
members, such as pyrrolidino or piperidino; and salts thereof, especially 
acid addition salts, more especially pharmaceutically acceptable non-toxic 
acid addition salts. 
The invention relates preferably to compounds of the formula I in which Ar 
represents monocyclic or bicyclic carbocyclic aryl or monocyclic or 
bicyclic heteroaryl bonded by a ring carbon atom and containing as ring 
members a maximum of two nitrogen atoms and/or one oxygen or sulphur atom, 
which radicals may be unsubstituted or substituted one to three times, 
wherein as substituents there may be present, optionally substituted in 
the manner specified hereinafter, lower alkyl, lower alkenyl or lower 
alkoxy, also lower alkenyloxy, lower alkynyl, lower alkynyloxy, cyano 
and/or nitro, and/or, as substituents bonded directly or to the 
above-mentioned lower alkyl, lower alkenyl or lower alkoxy, one or more of 
lower alkanoyl, cycloalkyl, lower alkoxycarbonyl, carbamoyl, lower 
alkylcarbamoyl or (hydroxy-lower alkyl)-carbamoyl, lower alkylsulphinyl, 
lower alkylsulphonyl, sulphamoyl or lower alkylsulphamoyl; and/or halogen 
bonded directly or halogen bonded to the above-mentioned lower alkyl or, 
in a position higher than the 1-position, halogen bonded to the 
above-mentioned lower alkoxy; hydroxy, hydroxy-lower alkyl or 
polyhydroxy-lower alkyl, or, as substituent not directly bonded, again 
lower alkoxy, cycloalkyl-lower alkoxy phenyl-lower alkoxy, for example 
benzyloxy, lower alkanoyloxy, lower alkylthio, amino, lower alkylamino, 
di-lower alkylamino, alkyleneamino or oxaalkyleneamino, for example 
pyrrolidino, piperidino or morpholino, pyrrol-1-yl, lower alkanoylamino or 
lower alkoxycarbonylamino, ureido optionally substituted by lower alkyl, 
by hydroxy-lower alkyl or by cycloalkyl, lower alkylsulphonylamino or 
N-lower alkyl lower alkylsulphonylamino, and, in bicyclic radicals Ar, the 
ring not directly bonded to the ether group is also at least partially 
hydrogenated and in this case may also be substituted by oxo; and in which 
n represents the number 0 or 1, alk represents an alkylene radical having 
from 2 to 4 carbon atoms, the nitrogen atom and the oxygen atom or, if n 
is 0, the phenyl radical, being separated from one another by 2 or 3 
carbon atoms, and R.sub.1 and R.sub.2 have the meanings given under 
formula I but preferably represent hydrogen or lower alkyl, especially 
methyl or ethyl, or, together with the nitrogen atom of the amide group, 
form pyrrolidino, piperidino or morpholino; and salts thereof, especially 
acid addition salts, more especially pharmaceutically acceptable, 
non-toxic acid addition salts. 
The invention relates especially to compounds of the formula I in which Ar 
represents phenyl, naphthyl or 1,2,3,4-tetrahydro-5-naphthyl, which 
radicals may be unsubstituted or substituted one to three times, wherein 
as substituents there may be present, optionally substituted in the manner 
specified hereinafter, lower alkyl, lower alkenyl or lower alkoxy, also 
lower alkenyloxy, lower alkynyloxy, and/or cyano, and/or, as substituents 
bonded directly or to the above-mentioned lower alkyl, lower alkenyl or 
lower alkoxy, one or more of lower alkanoyl, lower alkoxycarbonyl, 
cycloalkyl, carbamoyl, lower alkylcarbamoyl or (hydroxy-lower 
alkyl)carbamoyl, lower alkylsulphinyl, lower alkylsulphonyl, sulphamoyl or 
lower alkylsulphamoyl; and/or halogen bonded directly or halogen bonded to 
the above-mentioned lower alkyl or, in a position higher than the 
1-position, halogen bonded to the above-mentioned lower alkoxy; hydroxy, 
hydroxy-lower alkyl or polyhydroxy-lower alkyl, or, as substituent not 
directly bonded, again lower alkoxy, cycloalkyl-lower alkoxy, also 
phenoxy-lower alkoxy, for example benzyloxy, lower alkanoyloxy, lower 
alkylthio, amino, lower alkylamino, di-lower alkylamino, alkyleneamino or 
oxa-alkyleneamino, for example pyrrolidino, piperidino or morpholino, 
pyrrol-1-yl, lower alkanoylamino or lower alkoxycarbonylamino, ureido 
optionally substituted by lower alkyl or cycloalkyl, lower 
alkylsulphonylamino or N-lower alkyl lower alkylsulphonylamino, and in 
which n represents the number 0 or 1, alk represents an alkylene radical 
having from 2 to 4 carbon atoms, the nitrogen atom and the oxygen atom or, 
if n is 0, the phenyl radical, being separated from one other by 2 or 3 
carbon atoms, and R.sub.1 and R.sub.2, independently of one another, each 
represents hydrogen or lower alkyl, especially methyl or ethyl, or, 
together with the nitrogen atom of the amide group, form morpholino; and 
salts thereof, especially acid addition salts, more especially 
pharmaceutically acceptable non-toxic acid addition salts. 
The invention relates especially to compounds of the formula I in which Ar 
represents phenyl which may be unsubstituted or substituted one to three 
times, wherein as substituents there may be present, optionally 
substituted in the manner specified hereinafter, lower alkyl or lower 
alkoxy, also lower alkenyl, lower alkenyloxy, lower alkynyloxy, and/or 
cyano, and/or, as substituents bonded directly or to the above-mentioned 
lower alkyl, lower alkoxy or lower alkenyl, one or more of lower alkanoyl, 
cycloalkyl, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or 
(hydroxy-lower alkyl)carbamoyl, lower alkylsulphinyl or lower 
alkylsulphonyl; and/or halogen bonded directly or halogen bonded to the 
above-mentioned lower alkyl or, in a position higher than the 1-position 
halogen bonded to the above-mentioned lower alkoxy; hydroxy, hydroxy-lower 
alkyl or polyhydroxy-lower alkyl, or, as substituent not directly bonded, 
again lower alkoxy, cycloalkyl-lower alkoxy, also phenyl-lower alkoxy, for 
example benzyloxy, lower alkylthio, alkyleneamino, or oxaalkyleneamino, 
for example pyrrolidino, piperidino or morpholino, pyrrol-1-yl, lower 
alkanoylamino or lower alkoxycarbonylamino, or ureido optionally 
substituted by lower alkyl, lower alkylsulphonylamino or N-lower alkyl 
lower alkylsulphonylamino; and in which n represents the number 0 or 1, 
alk represents an alkylene radical having from 2 to 4 carbon atoms, the 
nitrogen atom and the oxygen atom or, if n is 0, the phenyl radical, being 
separated from one another by 2 or 3 carbon atoms, and R.sub.1 and R.sub.2 
independently of one another each represents hydrogen or lower alkyl, but 
preferably hydrogen or methyl; and salts thereof, especially acid addition 
salts, more especially pharmaceutically acceptable non-toxic acid addition 
salts. 
The invention relates especially to compounds of the formula I in which Ar 
represents phenyl which may be unsubstituted or substituted one to three 
times, wherein as substituents there may be present, optionally 
substituted in the manner specified hereinafter, lower alkyl or lower 
alkoxy, also lower alkenyl, lower alkenyloxy, lower alkynyloxy, and/or 
cyano, and/or as substituents bonded directly or to the above-mentioned 
lower alkyl, lower alkoxy or lower alkenyl, one or more of lower alkanoyl, 
cycloalkyl, carbamoyl, lower alkylcarbamoyl or (hydroxy-lower 
alkyl)-carbamoyl, lower alkylsulphinyl and lower alkylsulphonyl; and/or 
fluorine or chlorine bonded directly or to the above-mentioned lower alkyl 
or, in a position higher than the 1-position, to the above-mentioned lower 
alkoxy; hydroxy, hydroxy-lower alkyl or 1,2-dihydroxy- or 
2,3,-dihydroxy-lower alkyl, such as 2,3-dihydroxypropyl, or, as 
substituent not directly bonded, again lower alkoxy, cycloalkyl-lower 
alkoxy such as cyclopropylmethoxy, also phenyl-lower alkoxy, for example 
benzyloxy, lower alkylthio, pyrrol-1-yl, lower alkanoylamino, lower 
alkoxycarbonylamino, ureido, lower alkylsulphonylamino such as 
methylsulphonylamino, N-lower alkyl lower alkylsulphonylamino such as 
N-methyl methylsulphonylamino; and in which n represents the integer 1, 
alk represents an alkylene radical having from 2 to 4 carbon atoms, the 
nitrogen atom and the oxygen atom being separated from one another by 2 
carbon atoms, and R.sub.1 and R.sub.2 represent hydrogen, and the phenyl 
radical carrying the amide and the hydroxy group is bonded preferably in 
its 4-position, and especially in its 5-position, to the remainder of the 
molecule; and salts thereof, especially acid addition salts, more 
especially pharmaceutically acceptable non-toxic acid addition salts. 
The invention relates especially to compounds of the formula I in which Ar 
represents phenyl unsubstituted or substituted one or three times by 
hydroxy, n represents the integer 1, alk represents an alkylene radical 
having from 2 to 4 carbon atoms, the nitrogen atom and the oxygen atom 
being separated from one another by 2 carbon atoms, R.sub.1 and R.sub.2 
represent hydrogen or lower alkyl, such as methyl, and the phenyl radical 
carrying the amide and the hydroxy group is bonded preferably in its 
4-position, and especially in its 5-position to the remainder of the 
molecule, and salts thereof, especially acid addition salts, more 
especially pharmaceutically acceptable non-toxic acid addition salts. 
The new compounds of the formula I are prepared in a manner known per se. 
They may be obtained, for example by reacting a compound of the formula 
##STR3## 
with a compound of the formula 
##STR4## 
in which 
one of the groups Z.sub.1 and Z.sub.2 represents a reactive esterified 
hydroxy group and the other represents the primary amino group, and 
X.sub.1 represents hydroxy, 
or in which 
X.sub.1 and Z.sub.1 together represent the epoxy group and 
Z.sub.2 represents the primary amino group, and Ar, n, alk, R.sub.1 and 
R.sub.2 have the meanings given above, and, if desired, converting a 
compound which may be thus obtained into a different compound of the 
formula I and/or if desired, converting a resulting free compound into a 
salt or a resulting salt into a free compound and/or, if desired, 
separating a resulting isomeric mixture into its isomers or a resulting 
racemate into its antipodes. 
A reactive esterified hydroxy group Z.sub.1 or Z.sub.2 is a hydroxy group 
esterified by a strong acid, especially a strong inorganic acid, such as a 
hydrohalic acid, especially hydrochloric, hydrobromic or hydriodic acid, 
or sulphuric acid, or by a strong organic acid, especially a strong 
organic sulphonic acid, such as an aliphatic or aromatic sulphonic acid, 
for example methanesulphonic acid, 4-methylphenylsulphonic acid or 
4-bromophenylsulphonic acid, and is especially halogen, for example 
chlorine, bromine or iodine, or aliphatically or aromatically substituted 
sulphonyloxy, for example methylsulphonyloxy or 
4-methylphenylsulphonyloxy. 
The above reaction is carried out in a manner known per se, wherein, 
especially when using a starting material having a reactive esterified 
hydroxy group, the reaction is carried out advantageously in the presence 
of a basic medium, such as an inorganic base, for example an alkali metal 
or alkaline earth metal carbonate or hydroxide, or in the presence of an 
organic basic medium, such as an alkali metal lower alkanolate, and/or an 
excess of the basic reactant, and usually in the presence of a solvent or 
mixture of solvents, and, if necessary, whilst cooling or heating, for 
example in a temperature range of from approximately -20.degree. C. to 
approximately 150.degree. C., in an open or closed vessel and/or in an 
inert gas atmosphere, for example a nitrogen atmosphere. 
Starting materials of the formula II are known or can be prepared in a 
manner known per se. 
Starting materials of the formula III may be obtained, for example, by 
reacting a hydroxysalicylic amide with a dihaloalkane corresponding to the 
meaning of alk, for instance a chloro-bromoalkane or dibromoalkane, in the 
presence of an alkaline condensing agent, such as an alkali metal 
carbonate. These reactions are carried out in the customary manner, 
protecting groups at the hydroxy groups being simultaneously or, as 
described hereinafter, subsequently split off. 
The compounds of the formula I may also be prepared by a process which is 
characterised in that in a compound of the formula 
##STR5## 
in which 
Ar.sub.1 has the same meaning as Ar or represents a radical Ar that is 
substituted by 1 or 2 groups that may be converted into hydroxy, 
X.sub.2, X.sub.3 and X.sub.4 each represents hydrogen or a substituent that 
may be replaced by hydrogen, and 
X.sub.5 represents R.sub.1, or 
X.sub.2 and X.sub.3 and/or 
X.sub.4 and X.sub.5 together represent a divalent radical that may be 
replaced by two hydrogen atoms, provided that at least one of the radicals 
X.sub.2, X.sub.3 and X.sub.4 is different from hydrogen, or at least 
Ar.sub.1 represents a radical Ar that is substituted by 1 or 2 groups that 
may be converted into hydroxy, or at least X.sub.2 and X.sub.3 together or 
X.sub.4 and X.sub.5 together represent a divalent radical that may be 
replaced by two hydrogen atoms, 
or in a salt of the compound of the formula (IV) those of the groups 
X.sub.2, X.sub.3 and X.sub.4, or X.sub.2 and X.sub.3 together, or X.sub.4 
and X.sub.5 together, which are other than hydrogen are replaced by 
hydrogen atoms, and/or substituted hydroxy present in a radical Ar.sub.1 
is converted into free hydroxy and, if desired, the additional process 
steps following the first process are subsequently carried out. 
The splitting off of the groups X.sub.2, X.sub.3 or X.sub.4 X.sub.2 and 
X.sub.3 together or X.sub.4 and X.sub.5 together, and of the hydroxy 
substituents present in a radical Ar.sub.1 is effected by solvolysis for 
example by hydrolysis, alcoholysis, or by reduction including 
hydrogenolysis. 
An especially suitable group X.sub.3 or X.sub.4 that is capable of being 
split off, or a hydroxy-protecting group in a radical Ar.sub.1 is 
especially a .alpha.-aryl-lower alkyl group that is capable of being split 
off by hydrogenolysis, such as an optionally substituted 
1-polyphenyl-lower alkyl group or 1-phenyl-lower alkyl group, in which 
substituents, especially of the phenyl moiety, may be, for example, lower 
alkyl, such as methyl, or lower alkoxy, such as methoxy, and especially 
benzyl. A group X.sub.3 and especially X.sub.2 and X.sub.4 and also 
hydroxy-protecting groups in a radical Ar.sub.1 may also be radicals 
capable of being split off by solvolysis, such as by hydrolysis or 
acidolysis, or radicals capable of being split off by reduction, including 
hydrogenolysis, especially a corresponding acyl radical, such as the acyl 
radical of an organic carboxylic acid, for example lower alkanoyl, such as 
acetyl, or aroyl, such as benzoyl, the acyl radical of a semi-ester of 
carbonic acid, such as lower alkoxycarbonyl, for example methoxycarbonyl, 
ethoxycarbonyl, or tert.-butoxycarbonyl, 2-halo-lower alkoxycarbonyl, for 
example 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, optionally 
substituted 1-phenyl-lower alkoxycarbonyl, for example benzyloxycarbonyl 
or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, for example 
phenacyloxycarbonyl, or an optionally substituted 1-polyphenyl-lower alkyl 
group, in which substituents, especially of the phenyl moiety, for example 
have the meaning given above, and represent especially trityl. 
A radical capable of being split off and formed by X.sub.2 and X.sub.3 
and/or X.sub.4 and X.sub.5 together, is especially a group that can be 
split off by hydrogenolysis, such as optionally substituted 1-phenyl-lower 
alkylidene, in which substituents, especially of the phenyl moiety, may 
be, for example, lower alkyl or lower alkoxy, and especially benzylidene, 
and also groups that can be split off by solvolysis, especially by 
hydrolysis, such as lower alkylidene, for example methylene or 
isopropylidene, or 1-phenyl-lower alkylidene or which the phenyl moiety is 
optionally substituted by lower alkyl, such as methyl, or lower alkoxy, 
such as methoxy, especially benzylidene, or cycloalkylidene, for example 
cyclopentylidene or cyclohexylidene. 
Starting materials that may be used in the form of salts are used 
especially in the form of acid addition salts, for example with mineral 
acids, and with organic acids. 
Radicals X.sub.2, X.sub.3 and/or X.sub.4 that can be split off by 
hydrogenolysis, especially optionally substituted 1-phenyl-lower alkyl 
groups, also suitable acyl groups, such as optionally substituted 
1-phenyl-lower alkoxycarbonyl, and optionally substituted 1-phenyl-lower 
alkylidene groups formed by the groups X.sub.2 and X.sub.3 and by X.sub.4 
and X.sub.5 together, and also hydroxy-protecting groups of this kind 
present in a radical Ar.sub.1, can be split off by treating with 
catalytically activated hydrogen, for example hydrogen in the presence of 
a nickel catalyst, such as Raney nickel, or a suitable noble metal 
catalyst. 
Groups X.sub.2, X.sub.3 and/or X.sub.4 that can be split off by hydrolysis, 
such as acyl radicals of organic carboxylic acids, for example lower 
alkanoyl, and of semi-esters of carbonic acid, for example lower 
alkoxycarbonyl, also for example trityl radicals, and also lower 
alkylidene, 1-phenyl-lower alkylidene or cycloalkylidene groups formed by 
the radicals X.sub.2 and X.sub.3 and/or X.sub.4 and X.sub.5 together, and 
also hydroxy-protecting groups of this kind present in a radical Ar.sub.1, 
may, depending on the nature of such radicals, be split off by treating 
with water under acidic or basic conditions, for example in the presence 
of a mineral acid, such as hydrochloric acid or sulphuric acid, or an 
alkali metal or alkaline earth metal hydroxide or carbonate, or an amine, 
such as isopropylamine. 
Radicals X.sub.2, X.sub.3 and/or X.sub.4 and/or hydroxy-protecting groups 
in a radical Ar.sub.1 that can be split off by acidolysis are especially 
certain acyl radicals of semi-esters of carbonic acid, such as, for 
example, tert.-lower alkoxycarbonyl or optionally substituted 
diphenylmethoxycarbonyl radicals, and the tert.-lower alkyl radical; such 
radicals can be split off by treating with suitable strong organic 
carboxylic acids, such as lower alkanecarboxylic acids optionally 
substituted by halogen, especially fluorine, or especially with 
trifluoroacetic acid (if necessary in the presence of an activating agent, 
such as anisole), and with formic acid. 
Radicals X.sub.2, X.sub.3 and/or X.sub.4 and/or hydroxy-protecting groups 
in a radical Ar.sub.1 that can be split off by reduction shall also 
include those groups which are split off when treated with a chemical 
reducing agent (especially with a reducing metal or a reducing metal 
compound). Such radicals are, in particular, 2-halo-lower alkoxycarbonyl 
or arylmethoxycarbonyl, which can be split off, for example, by treating 
with a reducing heavy metal such as zinc, or with a reducing heavy metal 
salt, such as a chromium(II) salt, for example chromium chloride or 
acetate, usually in the presence of an organic carboxylic acid, such as 
formic acid or acetic acid, and water. 
Protecting groups positioned at the hydroxy groups optionally present in a 
radical Ar.sub.1 correspond to the previously mentioned groups that can be 
split off by means of the described methods and replaced by hydrogen, such 
groups being split off in the course of the described process at the same 
time as other groups or subsequently in a separate process step. 
The above reactions are usually carried out in the presence of a solvent, 
or a mixture of solvents, wherein suitable reactants may also act 
simultaneously as such, and, if necessary, whilst cooling or heating, for 
example in an open or closed vessel, and/or in the atmosphere of an inert 
gas, for example nitrogen. 
The starting material of the formula IV can be obtained analogously to the 
above described process modifications, for example by treating a compound 
of the formula Ar.sub.1 OH or a salt thereof with a compound of the 
formula 
##STR6## 
in which 
X.sub.2.sup.o represents the group X.sub.2, wherein at least one of the 
groups X.sub.3 and X.sub.2.sup.o does not represent hydrogen, and 
X.sup.o represents a reactive esterified hydroxy group, or 
X.sub.2.sup.o and X.sup.o together represent a carbon-oxygen bond, 
or in which 
X.sub.3 and X.sub.2.sup.o together represent a radical that is capable of 
being split off and can be replaced by two hydrogen atoms bonded to the 
oxygen or nitrogen atom, and 
X.sup.o represents a reactive esterified hydroxy group, 
or by treating a compound of the formula 
##STR7## 
with a compound of the formula 
##STR8## 
in which 
X.sub.2.sup.o has the meaning given above for X.sub.2, and 
one of the groups Y.sub.1 and Y.sub.2 represents a reactive esterified 
hydroxy group and the other represents the group of the formula 
--NH(X.sub.3), in which X.sub.3 has the meaning given above, provided that 
at least one of the groups X.sub.3 and X.sub.2 does not represent 
hydrogen, 
or in which 
X.sub.2.sup.o and Y.sub.1 form an oxygen-carbon bond and 
Y.sub.2 represents the group of the formula --NH(X.sub.3) and X.sub.3 does 
not represents hydrogen. 
The above reactions are carried out in a manner known per se, for example 
as described under the first process according to the invention. 
Furthermore, the Schiff's base formed by reacting a compound of the formula 
##STR9## 
with a carbonyl compound of the formula 
##STR10## 
in which 
R represents an alkyl radical corresponding to the alkylene radical alk and 
containing a carbonyl grouping that is separated from the oxygen atom or 
phenyl radical by at least one carbon atom, and 
X.sub.4 or 
X.sub.4 and X.sub.5 together represent one of the mentioned protecting 
groups, 
may be reduced, for example, with a borohydride, for instance sodium 
borohydride, to the compound of the formula IV. The reduction can also be 
carried out by means of activated hydrogen in the presence of a 
hydrogenating catalyst, for example a platinum-on-carbon catalyst. 
Carbonyl compounds of the formula (IVe) in which n is 1, may in turn be 
obtained in the customary manner by reacting a compound of the formula 
##STR11## 
with a compound of the formula R-Hal (IVg) in which R has the meaning 
given above, for example a haloketone, for example chloroacetone. 
The new compounds of the formula I may likewise be obtained by a process 
which is characterised in that, in a compound of the formula 
##STR12## 
in which 
X.sub.6 is a reducible group of the formula --CH=N-alk-(Va) or --CH.sub.2 
-N=alk.sub.1 -(Vb) in which alk.sub.1 represents an alkylylidene radical 
corresponding to the radical alk, and 
X.sub.7 represents hydrogen or a radical that may be replaced by hydrogen 
under the conditions for the reduction of X.sub.6, 
Ar.sub.2 corresponds to a radical Ar, but optionally, instead of carrying 
one or two hydroxy groups carries one or two OX.sub.7 groups in which 
X.sub.7 has the meaning given above, and 
n is 0 or 1, wherein X.sub.6 is always a reducible group Va or Vb, 
the X.sub.6 group is reduced, and simultaneously the X.sub.7 group other 
than hydrogen is replaced by hydrogen and, if desired, the additional 
process steps following the first process are carried out. 
A X.sub.7 group that can be split off by hydrogenolysis is especially an 
.alpha.-aryl-lower alkyl group, such as an optionally substituted 
1-phenyl-lower alkyl group, in which the substituents may be, for example, 
lower alkoxy, such as methoxy, and more especially benzyl. 
Protecting groups that are positioned at the hydroxy groups optionally 
substituting the radical Ar.sub.2 are the same as the groups mentioned 
previously for X.sub.7 that can be split off by the described methods and 
replaced by hydrogen, wherein such groups are split off during the course 
of the described process at the same time as other groups, or split off 
subsequently in a separate process step. 
Starting substances of the formula V having a X.sub.6 group of the formula 
Vb may also exist in the isomeric form of ring tautomers of the formula 
##STR13## 
in which alk.sub.2 has the same meaning as alk.sub.1 and the oxygen and 
nitrogen atoms of the ring are bonded to the same carbon atom. 
An alkylylidene group alk.sub.1 is, for example ethylyidene, whilst an 
alkylidene group alk.sub.2 represents, for example methylene, ethylidene 
or 1-methylethylidene. 
The reduction of the nitrogen-carbon double bond in starting substances of 
the formula V that contain a Va or Vb group as X.sub.6, whilst Ar.sub.2, 
X.sub.7 and n have the meanings given under formula V, to form the 
nitrogen-carbon single bond can be carried out in a manner known per se, 
for example by treating with catalytically activated hydrogen, such as 
hydrogen in the presence of a suitable hydrogenating catalyst, for example 
a nickel, platinum or palladium catalyst, wherein X.sub.7 groups capable 
of being split off by hydrogenolysis are simultaneously split off and 
replaced by hydrogen; alternatively, the reaction is carried out with a 
suitable hydride reducing agent, such as an alkali metal borohydride, e.g. 
sodium borohydride. When using a hydride reducing agent, acyl radicals of 
carboxylic acids, such as, for example, acetic acid, bonded also to 
oxygen, may be present as X.sub.7 radicals and may be split off in the 
same operation. 
A starting material of the formula V may be prepared in a manner known per 
se, optionally in situ, that is to say, under the conditions of the 
process described. Thus, a compound of the formula 
##STR14## 
can be reacted with an amine of the formula 
##STR15## 
to give a starting product of the formula V with the X.sub.6 group of the 
formula Va. 
By reacting a compound of the formula 
##STR16## 
with a carbonyl compound of the formula 
##STR17## 
starting substances of the formula V can be obtained with a X.sub.6 group 
of the formula (Vb). A modification of these reactions consists in 
reacting a dibenzylamino compound corresponding to a compound of the 
formula (Vh) with the oxo compound of the formula (Vi) under the reducing 
conditions of the process. In this reaction the reducing agent used is 
especially catalytically activated hydrogen, for example hydrogen in the 
presence of a heavy metal hydrogenating catalyst or a mixture thereof, 
such as a palladium and/or platinum catalyst. Under these reaction 
conditions, X.sub.7 groups which may be split off by hydrogenolysis, for 
example benzyl groups, are split off, and at the same time the 
nitrogen-carbon double bond is reduced to the corresponding 
nitrogen-carbon single bond. 
Oxo compounds of the formula (Vi), in which n is 1, are in their turn 
obtained, for example, by reacting a dihydroxy compound of the formula 
##STR18## 
with a haloalkanone compound of the above-mentioned formula R-Hal (IVf), 
for example chloroacetone, in the presence of an alkaline condensing 
agent, for instance potassium carbonate, or of an organic base, such as 
triethylamine. 
The new compounds of the formula I may likewise be obtained by reacting a 
compound of the formula 
##STR19## 
in which 
Ar.sub.3 has the same meaning as Ar, or represents a radical Ar that is 
substituted by 1 or 2 groups that may be converted into hydroxy by 
aminolysis, 
X.sub.8 represents hydrogen or a group that can be split off by aminolysis, 
or a reactive derivative of one of the carboxylic acids defined in formula 
VI, with a compound of the formula 
EQU HNR.sub.1 R.sub.2 (VII) 
and at the same time splitting off optionally present X.sub.8 radicals and 
replacing them by hydrogen, and, if desired, carrying out the additional 
process steps mentioned following the first process. 
X.sub.8 radicals that can be split off by aminolysis and especially by 
ammonolysis are acyl radicals 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, for 
example, the halides, such as the chlorides or bromides, the azides, and 
also acid anhydrides, especially mixed acid anhydrides with, for example, 
lower alkanecarboxylic acids, such as acetic acid or propionic acid, or 
lower alkoxyalkanecarboxylic acids, such as 2-methoxyacetic acid. Reactive 
derivatives of carboxylic acids of the formula VI are especially esters, 
for example with lower alkanols, such as methanol, ethanol, isopropanol or 
tert.-butanol, also with aryl lower alkanols, for instance benzyl alcohol 
optionally substituted by lower alkyl, for example methyl, or lower 
alkoxy, for example methoxy, or with phenols which are optionally 
activated by suitable substituents, for example by halogen, for instance 
4-halo, such as 4-chloro; lower alkoxy, for instance 4-lower alkoxy, such 
as 4-methoxy; 4-nitro; or 2,4-dinitro; for instance 4-chlorophenol, 
4-methoxyphenol, 4-nitrophenol or 2,4-dinitrophenol; furthermore with 
cycloalkanols such as cyclopentanol or cyclohexanol, which may optionally 
be substituted by lower alkyl, for example methyl. The reaction is carried 
out in a manner known per se, usually in the presence of an inert solvent, 
for example in a temperature range of from approximately -10.degree. to 
50.degree. C. in a closed vessel. 
The starting substances of the formula VI may be obtained in a manner known 
per se by reacting a compound of the formula (II), in which X.sub.1 and 
Z.sub.1 together represent the epoxy group, with an amino compound of the 
formula 
##STR20## 
in which X.sub.8 has the meaning given, or with a reactive derivative 
thereof. 
The Schiff's base formed by reacting a compound of the formula 
##STR21## 
with a carbonyl compound of the formula 
##STR22## 
in which R represents the alkyl radical corresponding to an alkylene 
radical alk and containing an oxo radical in place of the free valency 
thereof, 
may also be reduced with a borohydride, for instance sodium borohydride. 
The reduction can also be carried out by means of activated hydrogen in 
the presence of a hydrogenating catalyst, for example a platinum-on-carbon 
catalyst. 
Carbonyl compounds of the formula (VIc), in which n is 1, may in turn be 
obtained in a manner known per se by reacting a compound of the formula 
##STR23## 
with a compound of the formula 
EQU R--Hal (IVg) 
in which Hal represents halogen, especially chlorine. 
The new compounds of the formula I may likewise be obtained by a process 
which is characterised in that, in a compound of the formula 
##STR24## 
in which one or both hydroxy groups and/or hydroxy groups optionally 
present in the radical Ar are protected by those groups that can be split 
off by hydrolysis and replaced by hydrogen, which are split off under the 
conditions of the process and are replaced by hydrogen, 
the --CN group is converted by hydrolysis into the --CONH.sub.2 group and, 
at the same time, optionally protected hydroxy groups are converted into 
free hydroxy groups, and, if desired, the additional process steps 
following the first process are carried out. 
The above reactions are carried out in a manner known per se. The 
hydrolysis is effected in a basic, or, advantageously, in an acidic 
medium, especially in the presence of concentrated aqueous mineral acids, 
such as, for example, concentrated hydrochloric acid, and, if necessary, 
whilst cooling or heating, for example in a temperature range of from 
approximately 0.degree. to 60.degree., preferably from approximately 
40.degree.-50.degree., in an open or closed vessel and/or in an inert gas 
atmosphere, for example in a nitrogen atmosphere. 
The starting substances of the formula VIII may be obtained, for example, 
by reacting a compound of the formula 
##STR25## 
with a compound of the formula 
##STR26## 
in which Hal represents chlorine, bromine or iodine. The reaction is 
advantageously carried out in the presence of a basic medium in a manner 
known per se. 
The compound VIIIb may in turn be obtained by the action of acetic 
anhydride on the oxime corresponding to the cyanide. This is expediently 
carried out by refluxing. The oxime may in its turn be prepared from the 
corresponding aldehyde by refluxing with hydroxylamine hydrochloride in 
the presence of alcoholic soda solution. The corresponding aldehyde may in 
turn be prepared by reacting 2,4-dihydroxybenzaldehyde with a 
.alpha.,.omega.-dihalo-lower alkane, preferably in the presence of a basic 
medium. Alternatively, however, a hydroxysalicylonitrile, for example 
2,4-dihydroxybenzonitrile [Chem. Ber. 24, 3657 (1891)] or 
2,5-dihydroxybenzonitrile [(Helv. Chim. Acta 30, 149, 153 (1947)] may be 
reacted in an analogous manner with a non-geminal dihalo-lower alkane to 
form a compound of the formula VIIIb. 
The new compounds of the formula I wherein Ar is substituted by 
hydroxy-lower alkyl or by polyhydroxy-lower alkyl, for example 
1,2-dihydroxy- or 2,3-dihydroxy-lower alkyl, such as 1,2-dihydroxy- or 
2,3-dihydroxypropyl, can be obtained by a process which is characterised 
in that in a compound of the formula 
##STR27## 
wherein Ar.sub.4 represents a radical Ar which is substituted by a 
hydroxy-lower alkyl group of which the hydroxy group is substituted by a 
radical that can be split off and replaced by hydrogen, or is substituted 
by a polyhydroxylower alkyl group, for example by one of those mentioned, 
whereby at least one hydroxy group, or two hydroxy groups together, each 
of which is located at one of two adjacent hydrocarbon atoms, is (are) 
protected by a radical that can be split off and replaced by hydrogen, or 
in a salt thereof, these protecting groups, which can be identical or 
different, as well as optionally further protecting groups located at the 
nitrogen atom and/or at the oxygen atoms, are split off, and replaced by 
hydrogen, and, if desired, the additional process steps described 
subsequent to the first process are then carried out. Groups which can be 
split off, and replaced by hydrogen, for example groups that can be split 
off by means of solvolysis, such as hydrolysis, alcoholysis or acidolysis, 
or by means of reduction, including hydrogenolysis, for instance as 
described above, are for example the radicals X.sub.2 or X.sub.4 described 
above. Radicals X.sub.2 or X.sub.4 that can be split off by solvolysis, 
such as by hydrolysis or acidolysis, are for example acyl radicals, such 
as acyl radicals of organic carboxylic acids, for example lower alkanoyl, 
such as acetyl, or aroyl, such as benzoyl, also for example lower-alkoxy 
carbonyl, optionally substituted 1-phenyl-lower alkoxycarbonyl, for 
example benzyloxycarbonyl, also an optionally substituted 
1-polyphenyl-lower alkyl group, for example trityl, and furthermore the 
tetrahydropyranyl radical. Protecting groups located together at two 
adjacent hydroxy groups are for example: lower alkylidene, for example 
methylene or isopropylidene, or 1-phenyl-lower alkylidene, of which the 
phenyl moiety is optionally substituted by lower alkyl, such as by methyl 
or lower alkoxy, such as methoxy, particularly benzylidene, or 
cycloalkylidene, for example cyclopentylidene or cyclohexylidene, also the 
carbonyl group. 
Groups of the stated types which can be split off by hydrolysis, for 
example acyl radicals of organic carboxylic acids, for example 
lower-alkanoyl radicals, also for example lower-alkoxycarbonyl or trityl 
radicals, also tetrahydropyranyl radicals, also lower-alkylidene, 
1-phenyl-lower alkylidene or cycloalkylidene groups located together at 
two hydroxy groups, as well as optionally further protecting groups of 
this kind located at the nitrogen atom and/or at the oxygen atoms, can be 
split off, depending on the nature of such radicals, by treatment with 
water under acidic or basic conditions, for example in the presence of a 
mineral acid, such as hydrochloric acid of sulfuric acid, or of an 
hydroxide or carbonate of an alkali metal or alkaline-earth metal. A 
carbonyl group located at one of two adjacent hydroxy groups is 
advantageously split off by means of basic agents, for instance an alkali 
hydroxide, such as potassium hydroxide, or by means of an alkali metal 
alcoholate, such as sodium ethylate or potassium tert.-butylate, whilst 
for example tetrahydropyranyl radicals are split off by means of acid 
agents, for instance such as those mentioned. Radicals which can be split 
off by acidolysis are for example those mentioned above for X.sub.2 and/or 
X.sub.4, and are for example lower-alkoxycarbonyl or tert.-lower alkyl 
radicals. Radicals of this kind can be split off, for example as described 
above, by treatment with suitable strong organic carboxylic acids, such as 
by lower-alkane-carboxylic acids optionally substituted by halogen, 
especially fluorine, particularly by treatment with trifluoroacetic acid 
(if necessary in the presence of an activating agent, such as anisole), as 
well as with formic acid. These reactions are performed in a manner known 
per se. 
A particularly suitable hydroxy protecting group that can be split off by 
hydrogenolysis is above all an .alpha.-aryl-lower alkyl group which can be 
split off by hydrogenolysis, such as an optionally substituted 
1-polyphenyl-lower alkyl or 1-phenyl-lower alkyl group, wherein 
substituents, especially of the phenyl moiety, can be for example lower 
alkyl such as methyl, or lower alkoxy such as methoxy, and in particular 
benzyl. A group which is located at two adjacent hydroxyl groups together 
and which can be split off by hydrogenolysis is for example optionally 
substituted 1-phenyl-lower alkylidene, wherein substituents, especially of 
the phenyl moiety, can be for example lower alkyl such as methyl, or lower 
alkoxy such as methoxy, and particularly benzylidene. Groups of the stated 
type which can be split off by hydrogenolysis can be split off in the 
customary manner by treatment with catalytically activated hydrogen, for 
example with hydrogen in the presence of a nickel catalyst, such as Raney 
nickel, or of a suitable noble metal catalyst. 
Protective groups which are located at one or two hydroxyl groups and which 
can be split off by means of reduction are for example those groups which 
are split off on being treated with a chemical reducing agent, for 
instance as described above, for example 2-halo-lower-alkoxycarbonyl or 
arylmethoxycarbonyl. Splitting off is effected for instance by the methods 
described above, for example by means of zinc, or of a chromium(II) salt, 
or by means of an organic carboxylic acid, such as formic acid. 
Further protecting groups optionally present at the nitrogen atom and/or at 
the oxygen atoms correspond to the aforementioned groups that can be split 
off and replaced by hydrogen by the methods mentioned, whereby such groups 
can be split off in the course of the described process simultaneously 
with other groups or subsequently in a separate process step. 
Starting materials of the formula IX wherein Ar.sub.4 is substituted by a 
radical which can be converted into a hydroxy-lower alkyl group or 
polyhydroxy-lower alkyl group, such as 1,2- or 2,3-dihydroxy-lower alkyl 
group, for example a 2,3-dihydroxypropyl group, can be obtained for 
example by a process wherein a compound which optionally carries 
protecting groups on the nitrogen atom and/or on the oxygen atoms and 
which corresponds to the formula IX in which Ar.sub.4 is a group of the 
formula 
EQU --R.sub.9 --CH.sub.2 --Z.sub.3 (IXa) or of the 
formula 
##STR28## 
wherein R.sub.9 corresponds to a lower alkyl radical containing one carbon 
atom less, and R.sub.10 to a lower alkyl radical containing two carbon 
atoms less, and Z.sub.3 and Z.sub.4, which can be identical or different, 
are each a reactive esterified hydroxy group, for example halogen, such as 
chlorine and particularly bromine, is reacted with a salt of a carboxylic 
acid, for example with an alkali metal salt, for instance the potassium 
salt, of a lower alkanecarboxylic acid, for example acetic acid, or of an 
aromatic carboxylic acid, such as benzoic acid, to give the corresponding 
compound of the formula IX containing one or two acyloxy groups in the 
lower alkyl group located at the radical Ar.sub.4. Starting materials of 
the formula IX having a group IXa can be obtained by an addition reaction 
of for example hydrogen halide with an alkenyl radical bonded to the 
radical Ar, whereas starting materials having a group IXb are obtainable 
by an addition reaction of halogen, for example bromine, with an 
appropriate alkenyl radical. 
Starting materials of the formula IX wherein Ar.sub.4 is substituted for 
example by a group of the formula 
##STR29## 
in which X.degree..sub.10 represents a radical which can be split off by 
hydrolysis, including alcoholysis or acidolysis, or by means of reduction, 
including hydrogenolysis, for example one of such radicals mentioned 
above, and R.sub.10 has the meaning already defined, can be obtained by 
reacting for example a compound of the formula 
##STR30## 
with epichlorohydrin, and reacting the resulting compound of the formula 
##STR31## 
for example with a 5-(2-aminoethoxy)-salicylamide, which is optionally 
N-protected, such as N-benzylated, to obtain a compound of the formula IX 
wherein Ar.sub.4 contains the group IXc. 
These reactions are performed in the customary manner, optionally with 
cooling or heating, and in a suitable solvent. 
When selecting one of the above suitable processes for the preparation of 
compounds of the formula I, care must be taken that substituents present, 
especially of the Ar radicals, are not converted or split off, should such 
conversions or splitting off be undesirable. Thus, especially functionally 
modified carboxyl groups, such as esterified or amidated carboxyl groups, 
and also cyano groups, as substituents of Ar radicals during solvolysis 
reactions, especially hydrolysis reactions, and also during reducing 
operations, may participate in the reaction and be converted. On the other 
hand, simultaneous conversion of substituents may be desirable; for 
example, unsaturated substituents, such as lower alkenyl, may be reduced, 
for example to lower alkyl, under the conditions of a reducing process 
used according to the invention. 
Within the scope of the definition of the compounds of the formula I, 
compounds obtained in the usual manner according to the invention can be 
converted into other final products, for example by modifying introducing 
or splitting off suitable substituents in resulting compounds. 
For instance, unsaturated substituents, for example lower alkenyl, in 
resulting compounds may be reduced, for example by treating with 
catalytically activated hydrogen. 
Furthermore, in resulting compounds having halogen-substituted radicals of 
an aromatic nature, the halogen may be replaced by hydrogen, for example 
by treating with hydrogen in the presence of a customary hydrogenating 
catalyst, such as Raney nickel, or palladium on carbon. 
Free carboxyl groups in the Ar radicals, may be esterified in the customary 
manner, for example by reacting with an appropriate alcohol, 
advantageously in the presence of an acid, such as a mineral acid, for 
example sulphuric acid or hydrochloric acid, or in the presence of a 
dehydrating agent, such as dicyclohexylcarbodiimide, or by reacting with a 
corresponding diazo compound, for example diazomethane. The esterification 
may also be carried out by reacting a salt, preferably an alkali metal 
salt of the acid, with a reactive esterified alcohol, for example an 
appropriate halide, such as chloride. 
Free carboxyl groups may be amidated in the usual manner, for example by 
reaction with ammonia, or with a primary or secondary amine, 
advantageously in the presence of a dehydrating agent, such as 
dicyclohexyl carbodiimide or by converting the carboxyl group into a 
halocarbonyl group, for example a chlorocarbonyl group, and then reacting 
with ammonia or with a primary or secondary amine. 
In compounds that contain an esterified carboxyl group, the latter may be 
converted into a free carboxyl group in the customary manner, for example 
by hydrolysis, preferably in the presence of strong bases, such as an 
alkali metal hydroxide, for example sodium or potassium hydroxide, or in 
the presence of strong acids, for example a strong mineral acid, such as a 
hydrohalic acid, for example hydrochloric acid, or sulphuric acid. 
In compounds having an esterified carboxyl group as substituent, the latter 
may be converted into the corresponding carbamoyl group in the customary 
manner, for example by ammonolysis or aminolysis with ammonia or a primary 
or secondary amine. 
Compounds having a carbamoyl group and preferably R.sub.1 and R.sub.2 
radicals that do not represent hydrogen may be dehydrated to the 
corresponding cyano compounds in the customary manner, for example by the 
action of dehydrating agents, such as phosphorus pentoxide or phosphorus 
oxychloride, preferably at relatively high temperatures. 
Compounds that contain a cyano substituent may be hydrolysed in the 
customary manner, for example in the presence of concentrated aqueous 
mineral acids, or alkali metal hydroxides, to the corresponding carbamoyl 
compounds, or directly to the carboxyl compounds. 
Compounds having a cyano group as substituent may be alcoholysed to the 
corresponding compounds having esterified carboxyl groups in the customary 
manner, for example by the addition of alcohols in the presence of an 
anhydrous acid, such as hydrogen chloride, and by subsequent hydrolysis of 
the resulting imido ester. 
As in the preparation processes, care must also be taken when carrying out 
the additional steps that undesirable side reactions that may result in 
the conversion of additional groupings, do not occur. 
The above-described reactions may optionally be carried out at the same 
time or in succession, or in any sequence. If necessary, they are carried 
out in the presence of diluents, condensing agents and/or catalytically 
active agents, at reduced or elevated temperature, in a closed vessel 
under pressure and/or in an inert gas atmosphere. 
Depending on the process conditions and starting substances, the new 
compounds are obtained in free form or in the form of their salts, also 
covered by the invention, wherein the new compounds or salts thereof may 
also be in the form of hemi-, mono-, sesqui- or polyhydrates. Acid 
addition salts of the new compounds may be converted into the free 
compounds in a manner known per se, for example by treating with basic 
agents, such as alkali metal hydroxides, carbonates or bicarbonates, or 
with ion-exchangers. On the other hand, resulting free bases with organic 
or inorganic acids, for example with the acids mentioned, may form acid 
addition salts, wherein the acids used for their preparation are 
especially those that are suitable for the formation of pharmaceutically 
acceptable salts. 
These or different salts, especially acid addition salts of the new 
compounds, such as, for example, oxalates or perchlorates, may also be 
used for the purification of the resulting free bases, by converting the 
free bases into salts, separating them off and purifying them and 
liberating the bases from the free salts. 
Depending on the choice of starting substances and working methods, the new 
compounds may be obtained as optical antipodes or racemates, or, provided 
they contain at least two asymmetric carbon atoms, as mixtures of 
racemates. The starting substances can also be used as specific optical 
antipodes. 
Resulting mixtures of racemates may be separated into the two 
stereoisomeric (diastereoisomeric) racemates on the basis of 
physical-chemical differences in the diastereoisomers in known manner, for 
example by chromatography and/or fractional crystallisation. 
Resulting racemates may be decomposed into the antipodes by methods known 
per se, for example by recrystallisation from an optically active solvent, 
by treating with suitable microorganisms, or by reacting with an optically 
active substance forming salts with the racemic compound, especially 
acids, and separating the salt mixture obtained in this manner, for 
example on the basis of different solubilities, into the diasteroisomeric 
salts, from which the free antipodes may be liberated by the action of 
suitable agents. Especially useful, optically active acids are, for 
example, the D- and L-forms of tartaric acid, di-O,O'-(p-toluoyl)tartaric 
acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, 
aspartic acid or quinic acid. Advantageously, the more active of the two 
antipodes is isolated. 
The invention relates also to those forms of the process according to which 
a compound that may be obtained as intermediate at any stage of the 
process is used as starting material, and the remaining process steps are 
carried out or the process is interrupted at any stage, or in which a 
starting substance is formed under the reaction conditions or in which a 
reactant is optionally present in the form of its salts. 
Advantageously, the starting materials used for carrying out the reactions 
according to the invention are those which yield the groups of final 
substances mentioned initially, and especially those which lead to the 
specifically described or emphasized final substances. 
The starting materials are known, or if they are new, can be prepared 
according to methods known per se, as described above, for example 
analogously to the Examples. The invention relates also to the new 
starting materials and to intermediates that may be obtained according to 
the process. 
The new compounds may, for example, be used in the form of pharmaceutical 
preparations which contain a pharmacologically active amount of active 
substance, optionally together with pharmaceutically acceptable carriers 
that are suitable for enteral, for example oral, or parenteral, 
administration, and that may be organic or inorganic, solid or liquid. 
Thus, tablets or gelatin capsules are used which contain the active 
substance together with diluents, for example lactose, dextrose, sucrose, 
mannitol, sorbitol or cellulose and/or glycerin and/or lubricants, for 
example silica, talc, stearic acid or salts thereof, such as magnesium or 
calcium stearate, and/or polyethylene glycol. Tablets may likewise contain 
binders, for example magnesium aluminium silicate, starches, such as 
maize, corn, rice or arrowroot starches, gelatin, tragacanth, 
methylcellulose, sodium carboxymethylcellulose and/or 
polyvinylpyrrolidone, and, if desired, disintegrating agents, for example 
starches, agar, alginic acid, or a salt thereof, such as sodium alginate, 
and/or effervescing mixtures, or adsorption agents, colorants, flavouring 
substances and sweeteners. Furthermore, the new pharmacologically active 
compounds may be used in the form of parenterally administerable 
preparations or infusion solutions. Such solutions are preferably 
isotonic, aqueous solutions or suspensions, wherein these, for example in 
the case of lyophilised preparations that contain the active substance 
alone or together with a carrier, for example mannitol, can be prepared 
before use. The pharmaceutical preparations may be sterilised and/or 
contain auxiliaries, for example preservatives, stabilisers, wetting 
and/or emulsifying agents, solubilisers, salts for regulating the osmotic 
pressure and/or buffers. The present pharmaceutical preparations which, if 
desired, may contain other pharmacologically active substances, are 
prepared in a manner known per se, for example by means of conventional 
mixing, granulating, coating, dissolving, or lyophilising processes, and 
contain from approximately 0.1% to 100%, especially from approximately 1% 
to approximately 50%, and in the case of lyophilisates up to 100%, of the 
active substances. 
The dosage may be dependent on various factors, such as the method of 
administration, species, age and individual condition. Thus, the doses to 
be administered orally to warm-blooded animals daily in one or more, 
preferably at most 4 individual doses, lie between 0.03 and 3 mg/kg for 
.beta.-receptor blockers of the formula I, and, for warm-blooded animals 
of approximately 70 kg body weight, preferably between approximately 0.004 
and approximately 0.08 g, and for .beta.-receptor stimulators of the 
formula I, between 0.01 and 1 mg/kg and between approximately 0.002 and 
0.04 g, respectively.

The following Examples serve to illustrate the invention; temperatures are 
given in degrees Centigrade. 
EXAMPLE 1 
21 g of crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-[4-(2- 
methoxyethoxy)phenoxy]-propan-2-ol, dissolved in 170 ml of methanol, are 
hydrogenated with the addition of 2 g of Pd/C-catalyst (5%) under normal 
conditions until hydrogen absorption ceases. By filtration and 
concentration of the solution by evaporation, an oil is obtained which 
crystallises when triturated with toluene. After recrystallisation of the 
crystalline residue from ethyl acetate, the resulting 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-[4-(2-methoxyeth 
oxy)phenoxy]propan-2-ol melts at 117.degree.-125.degree., (mixture of the 
diastereoisomers). 
The starting material is prepared as follows: 
(1a) In accordance with the method described by Irvine et al., Synthesis 
1972, 568, using an excess of acetone, 2,5-dihydroxybenzamide is converted 
into 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one having a 
melting point of 215.degree.-216.degree.. 
(1b) 70 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazine-4-one 
are refluxed for 30 hours, whilst stirring, in 400 ml of acetonitrile with 
100 g of potassium carbonate and 32 ml of chloroacetone. After the 
addition of a further 3.2 ml of chloroacetone, the reaction mixture is 
heated for a further 15 to 20 hours. The still warm reaction mixture is 
filtered, the residue thoroughly washed with acetone and the combined 
filtrate is concentrated by evaporation. The crystalline residue is 
recrystallised from toluene and yields 
2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one having a 
melting point of 125.degree.-126.degree.. 
(1c) 74 g of crude 
2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one obtained 
according to Example 1b) are heated in a mixture of 150 ml of dioxan and 
450 ml of 2N hydrochloric acid for 45 minutes on a water bath. The solvent 
is evaporated off and the crystalline residue triturated with water and 
then suction-filtered. By recrystallisation from isopropanol, 
5-(2-oxopropoxy)salicylamide having a melting point of 
152.degree.-154.degree. is obtained. 
(1d) 55 g of benzylamine and 1.25 g of concentrated sulphuric acid are 
added to a solution of 104.5 g of 5-(2-oxopropoxy)salicylamide in 1000 ml 
of methanol and hydrogenated in the presence of 3.0 g of Pt/C-catalyst at 
room temperature and atmospheric pressure until 1 equivalent of hydrogen 
has been absorbed. The catalyst is filtered off, approximately 10 g of 
powdered calcium carbonate are stirred into the solution and the solution 
is filtered again and concentrated by evaporation. The oil remaining 
crystallises from isopropanol. Repeated recrystallisation from isopropanol 
yields 5-[2-(benzylamino)propoxy]salicylamide having a melting point of 
102.degree.-104.degree.. 
(1e) A solution of 10.2 g of 
1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene and 11.0 g of 
5-[2-(benzylamino)-propoxy]salicylamide in 200 ml of isopropanol is 
refluxed for 24 hours. By concentration of the solution by evaporation, 
crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-[4-(2- 
methoxyethoxy)phenoxy]-propan-2-ol is obtained as an oil which is used in 
its crude state for debenzylation. 
EXAMPLE 2 
6.1 g of crude 
1-[N-[2-(4-carbamoyl-3-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-[4-(2- 
methoxyethoxy)phenoxy]-propan-2-ol are hydrogenated and worked up 
analogously to Example 1. After recrystallisation from isopropanol, 
1-[2-(4-carbamoyl-3-hydroxyphenoxy)-1-methylethylamino]-3-[4-(2-methoxyeth 
oxy)phenoxy]propan-2-ol is obtained as a diastereoisomeric mixture having a 
melting point of 120.degree.-121.degree.. 
The starting material is prepared as follows: 
(2a) Analogously to Example (1a), from 2,4-dihydroxybenzamide there is 
obtained 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benzoxazin-4-one having 
a melting point of 249.degree.-251.degree.. 
(2b) Analogously to Example (1b), 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, there is obtained by boiling for 28 hours and subsequent 
working up, 
2,3-dihydro-2,2-dimethyl-7-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one having a 
melting point of 160.degree.-162.degree. (from isopropanol). 
(2c) 75 g of crude 
2,3-dihydro-2,2-dimethyl-7-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one and 32 g 
of benzylamine, dissolved in 1000 ml of methanol, are hydrogenated under 
normal conditions with the addition of 0.75 g of concentrated sulphuric 
acid and 1.6 g of Pt/C-catalyst (5%) until hydrogen absorption ceases. 
After filtering off the catalyst and evaporating off the solvent, the oily 
residue is divided between 300 ml of ethyl acetate and 500 ml of 2N 
hydrochloric acid. Crude 
2,3-dihydro-2,2-dimethyl-7-[(2-benzylamino)propoxy]-4H-1,3-benzoxazin-4-on 
e is isolated as an oil from the aqueous phase by rendering alkaline with 
concentrated ammonia (whilst cooling with ice) and extracting with ethyl 
acetate, and this oil can be put to further use in its crude state. 
(2d) A mixture of 100 g of crude 
2,3-dihydro-2,2-dimethyl-7-[(2-benzylamino)propoxy]-4H-1,3-benzoxazin-4-on 
e, 100 ml of isopropanol and 100 ml of isopropylamine is refluxed for 1 
hour and then concentrated by evaporation. The oil remaining crystallises 
when triturated with ether. The crystals are suction-filtered and washed 
with a little isopropanol. In this manner, 
4-[2-benzylamino)propoxy]-salicylamide having a melting point of 
121.degree.-123.degree. is obtained. 
(2e) Analogously to Example (1e), using 
4-[2-(benzylamino)propoxy]salicylamide instead of the 5-derivative, 
1-[N-[2-(4-carbamoyl-3-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-[4-(2- 
methoxyethoxy)phenoxy]propan-2-ol is obtained as an oil which is used in 
its crude state for debenzylation. 
EXAMPLE 3 
Analogously to Example 2, by debenzylation of 22 g of crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]-benzylamino]-3-[2-[N-(2-hydro 
xyethyl)carbamoylmethoxy]-phenoxy]propan-2-ol there is obtained 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-[N-(2-hydroxyethyl)-ca 
rbamoylmethoxy]phenoxy]propan-2-ol having a melting point of 
157.degree.-159.degree.. A hydrochloride is formed having a melting point 
of 126.degree.-127.degree. (from isopropanol/water 1:1). 
The starting material is obtained in the following manner: 
(3a) A mixture of 48.2 g of 
2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one, 70 g of 
potassium carbonate and 250 ml of 1,2-dibromoethane is refluxed for 4 
hours whilst stirring. The semi-liquid reaction mixture is extracted 3 to 
4 times whilst hot with 1 liter of methanol each time; the combined 
methanol extracts are concentrated by evaporation and the residue is 
recrystallised from methanol. 
6-(2-Bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one having 
a melting point of 190.degree.-195.degree. is obtained. 
(3b) A mixture of 60 g of 
6-(2-bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazine-4-one and 
110 ml of benzylamine is stirred for 30 minutes in a bath at 80.degree.. 
The reaction mixture is then brought to pH 3-4 with concentrated 
hydrochloric acid, whilst cooling with ice, and left to crystallise. After 
2-4 hours, the crystals are suction-filtered, washed with 50 ml of water 
and 50 ml of ethyl acetate and dried. The resulting 
5-[(2-benzylamino)ethoxy]salicylamide hydrochloride melts at 
214.degree.-216.degree.. The base liberated therefrom melts at 
107.degree.-108.degree. (from ethyl acetate/ether). 
(3c) 12 g of [2-(2,3-epoxypropoxy)phenoxy]-N-(2-hydroxyethyl)acetamide and 
11.5 g of 5-[(2-benzylamino)-ethoxy]salicylamide are refluxed in 70 ml of 
isopropanol for 18-24 hours. The oily residue of evaporation is used for 
debenzylation in its crude state. 
EXAMPLE 4 
21 g of crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]benzylamino]-3-[4-(2-methoxye 
thoxy)phenoxy]propan-2-ol are hydrogenated analogously to Example 1. After 
hydrogen absorption has ceased, the product is dissolved in hot methanol 
and the catalyst is filtered off. By concentration of the methanolic 
solution by evaporation, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol is obtained as crystals having a melting point of 
157.degree.-158.degree.. A neutral fumarate is formed having a melting 
point of 150.degree.-151.degree. (from methanol/acetone). 
The starting material may be prepared as follows: 
(4a) A solution of 9 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene 
and 8.6 g of 5-[(2-benzylamino)ethoxy]-salicylamide in 60 ml of 
isopropanol is refluxed for 24 hours. The crude product obtained by 
concentration by evaporation is divided between 50 ml of 2N hydrochloric 
acid and 100 ml of ether. The aqueous phase is separated off, and rendered 
alkaline with concentrated ammonia solution whilst cooling with ice. By 
extraction with approximately 300 ml of ethyl acetate, drying 
(MgSO.sub.4), and concentration by evaporation, the crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]benzylamino]-3-[4-(2-methoxyet 
hoxy)phenoxy]-propan-2-ol is isolated as an oil and used without further 
purification for debenzylation. 
EXAMPLE 5 
The following are prepared in a manner analogous to Examples 4 and 4a): 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-phenoxypropan-2-ol, 
melting point 154.degree.-156.degree., (from methanol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-[2-(methoxycarbonylamin 
o)ethoxy]phenoxy]propan-2-ol, melting point 150.degree.-151.degree., (from 
methanol), 
1-(4-acetamidophenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propan 
-2-ol, melting point 185.degree. (from methanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-methylphenoxy)propan-2- 
ol, melting point 129.degree.-130.degree., (from isopropanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methylphenoxy)propan-2- 
ol, melting point 154.degree.-155.degree. (from methanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-5-ethylamino]-3-(2-methylindol-4-yloxy) 
propan-2-ol, melting point 180.degree.-194.degree. (from ethyl acetate), 
5-[3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-2-hydroxypropoxy]-1,2,3,4 
-tetrahydro-2,3-cis-naphthalenediol as diastereoisomeric mixture, melting 
point 108.degree.-118.degree. (from methanol), 
4-[2-hydroxy-3-[(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]propoxy]phenylace 
tamide, melting point 149.degree.-151.degree. (from methanol); a different 
crystal modification has a melting point of 181.degree.-182.degree. (from 
dimethylformamide/water), 
4-[2-hydroxy-3-[(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]propoxy]phenoxyac 
etamide melting point 168.degree.-170.degree. (from DMF/water), 
N-[4-[2-hydroxy-3-[(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]propoxy]phenyl 
]-N',N'-dimethyl urea, melting point 140.degree.-142.degree. (with 
decomposition) (from methanol), 
1-(4-butyroylamino-2-acetylphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethy 
lamino]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-methoxyphenoxy)propan-2 
-ol, melting point 125.degree.-126.degree., (from methanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2,3-dimethylphenoxy)propa 
n-2-ol, melting point 129.degree.-131.degree. (from methanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-(2-methoxyethoxy)phenox 
y]propan-2-ol, melting point of the hydrochloride 157.degree.-160.degree. 
(from methanol-acetone), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[3-(2-methoxyethoxy)phenox 
y]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-(pyrrol-1-yl)phenoxy]pr 
opan-2-ol, melting point 138.degree.-140.degree. (sinters at temperatures 
of 135.degree. and above), 
1-(2-carbamoylphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]propa 
n-2-ol, melting point of hydrochloride 149.degree.-152.degree. (from 
methanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-trifluoromethylphenoxy) 
propan-2-ol, melting point 195.degree.-196.degree. (from methanol), 
1-(2-acetylphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propan-2- 
ol, melting point 122.degree.-124.degree. (from isopropanol), 
1-[4-[2-(acetamido)ethoxy]phenoxy]-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl 
amino]propan-2-ol as a hydrochloride, melting point 191.degree.-192.degree. 
(from methanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methylpyridin-2-yloxy)p 
ropan-2-ol, melting point 147.degree.-148.degree. (from methanol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methyl-4-methylsulphony 
lphenoxy)propan-2-ol, melting point 128.degree.-131.degree. (from 
acetonitrile), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(1-naphthyloxy)propan-2-ol 
, melting point 131.degree.-134.degree. (from isopropanol). 
EXAMPLE 6 
Analogously to Examples 2 and (2e), from 10.5 g of 
4-[(2-benzylamino)propoxy]salicylamide and 8.5 g of 
3,4-dihydro-5-(2,3-epoxypropoxy)-2-(1H)-quinolinone and by debenzylating 
the reaction product, there is obtained 
5-[3-[2-(4-carbamoyl-3-hydroxyphenoxy)-1-methylethylamino]-2-hydroxypropox 
y]-3,4-dihydro-2-(1H)-quinolinone as a diastereoisomeric mixture which 
forms a hydrochloride having a melting point of 239.degree.-245.degree. 
(from methanol). 
EXAMPLE 7 
A solution of 16 g of crude 
1-[N-[3-(3-carbamoyl-4-hydroxyphenyl)propyl]benzylamino]-3-[4-(2-methoxyet 
hoxy)-phenoxy]propan-2-ol is hydrogenated analogously to Example 1. The 
hydrogenating solution is neutralised with a solution of hydrochloric acid 
gas in methanol, concentrated by evaporation and crystallised from 
acetone. In this manner 
1-[3-(3-carbamoyl-4-hydroxyphenyl)propylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol is obtained as a hydrochloride having a melting point of 
194.degree.-200.degree.. 
The starting material may be prepared as follows: 
(7a) 3-(4-hydroxyphenyl)propionic acid is converted into the mixed 
anhydride and then, with benzylamine, into the 
3-(4-hydroxyphenyl)propionic acid N-benzylamide (m.p. 
115.degree.-116.degree.). 
(7b) Flask-synthesis (CO.sub.2, 180.degree., 4 hours, 55 bar) with the 
sodium salt of the compound prepared according to (7a) yields 
3-(3-carboxy-4-hydroxyphenyl)propionic acid N-benzylamide having a melting 
point of 180.degree.-181.degree.. 
(7c) Esterification with methanol/sulphuric acid while refluxing for 48 
hours yields 3-(3-methoxycarbonyl-4-hydroxyphenyl)propionic acid 
N-benzylamide having a melting point of 139.degree.-140.degree. (from 
ethyl acetate). 
(7d) Reacting with benzyl bromide/potassium carbonate in acetone (refluxing 
for 15 hours) yields 3-(4-benzyloxy-3-methoxycarbonylphenyl)propionic acid 
N-benzylamide as a yellowish oil. 
(7e) Selective reduction of the amide group with diborane in 
tetrahydrofuran (for 48 hours, 20.degree.-25.degree.) with gentle 
catalytic debenzylation of the product (Pd/C-catalyst 5%, 
15.degree.-20.degree. in methanol) yield 
N-[3-(4-hydroxy-3-methoxy-carbonylphenyl)propyl]benzylamine having a 
melting point of 75.degree.-77.degree. (from isopropanol). 
(7f) 200 ml of concentrated ammonia are added to a solution of 27 g of 
N-[2-(4-hydroxy-3-methoxycarbonylphenyl)propyl]benzylamine in 100 ml of 
dioxan and the solution is left to stand for 3-4 days at 
20.degree.-30.degree.. The reaction mixture is concentrated by 
evaporation, divided between water and ethyl acetate and the organic phase 
is separated. Usual working up yields crude 
N-[3-(3-carbamoyl-4-hydroxyphenyl)propyl]benzylamine as an oil which is 
processed further without further purification. 
(7g) A solution of 6.7 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene 
and 8.5 g of N-[3-(3-carbamoyl-4-hydroxyphenyl)propyl]benzylamine in 70 ml 
of isopropanol is refluxed for 18 hours and then concentrated by 
evaporation. The resulting crude 
1-[N-[3-(3-carbamoyl-4-hydroxyphenyl)propyl]benzylamino]-3-[4-(2-methoxyet 
hoxy)-phenoxy]propan-2-ol is used in its crude state for debenzylation. 
EXAMPLE 8 
A solution of 5 g of crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-(4-ben 
zyloxyphenoxy)propan-2-ol (with diastereoisomer pair A present in greater 
amount) in 50 ml of methanol is hydrogenated under normal conditions in 
the presence of 0.5 g of Pd/C-catalyst (5%) until 2 equivalents of 
hydrogen have been absorbed, whereupon the hydrogenation ceases. The 
reaction mixture is filtered, 0.52 g of fumaric acid is dissolved in the 
filtrate and the solution is concentrated to approximately 10 ml. After 
standing for a relatively long period of time, crystals of the neutral 
fumarate of 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-(4-hydroxyphenox 
y)propan-2-ol form, having a melting point of 195.degree.-198.degree. (pure 
enantiomer pair A). 
In an analogous manner, by debenzylation of the enantiomer pair B present 
in greater amount the fumarate of the pure enantiomer pair B having a 
melting point of 181.degree.-185.degree. can be prepared. 
The starting materials can be prepared as follows: 
(8a) A solution of 49.8 g of 
2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one and 21.4 
g of benzylamine in 700 ml of methanol is hydrogenated with the addition 
of 0.5 g of concentrated sulphuric acid and 3 g of Pt/C-catalyst (5%) 
until the equivalent amount of hydrogen has been asborbed. Working up 
analogously to Example (1d) yields 
6-(2-benzylaminopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one 
having a melting point of 127.degree.-129.degree. (from isopropanol). 
(8b) A solution of 15.4 g of benzyl [4-(2,3-epoxypropoxy)-phenyl]ether and 
17.0 g of 
6-(2-benzylaminopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one 
in 100 ml of isopropanol is refluxed for 24 hours, filtered and 
concentrated by evaporation. Trituration of the residue with approximately 
200 ml of ether results in crystallisation of 
1-[N-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methy 
lethyl]benzylamino]-3-(4-benzyloxyphenoxy)propan-2-ol having a melting 
point of 149.degree.-160.degree. (in which the enantiomer pair A is 
present in greater amount). 
By concentrating the ether solution by evaporation and recrystallising from 
a little isopropanol, after standing for several days crystals having a 
melting point of 59.degree.-62.degree. (rest up to 140.degree.) are 
obtained. The mother liquor which no longer crystallises is separated off. 
It contains the enantiomer pair B in greater amount. 
(8c) 5.2 g of the crystals having a melting point of 
149.degree.-160.degree. mentioned under (8b) are refluxed in a mixture of 
20 ml of isopropylamine and 40 ml of isopropanol for 1 hour and then 
concentrated by evaporation. The resulting crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]-benzylamino]-3-(4-be 
nzyloxyphenoxy)propan-2-ol (5g) obtained as an oil contains the enantiomer 
pair A in greater amount and is used without further purification for 
debenzylation. 
The procedure with the oil from Example (8b) containing the enantiomer pair 
B in greater amount is analogous. 
EXAMPLE 9 
80 ml of isopropylamine are added to a solution of 18.0 g of crude 
1-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methylet 
hylamino]-3-(4-methylcarbamoylphenoxy)propan-2-ol in 300 ml of methanol and 
the solution is refluxed for 1 hour. The reaction mixture is concentrated 
by evaporation and the oil remaining is crystallised from 80 ml of 
isopropanol. 
1-[2-(3-Carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-(4-methylcarbamo 
ylphenoxy)propan-2-ol having a melting point of 172.degree.-175.degree. 
(diastereoisomeric mixture) is obtained. 
The starting materials can be obtained as follows: 
(9a) A solution of 13.6 g of 
6-(2-benzylaminopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one 
and 10.4 g of 4-(2,3-epoxypropoxy)-N-methylbenzamide in 80 ml of 
isopropanol is refluxed for 30 hours. The residue remaining after the 
solvent has been evaporated off is divided between ether and 2N 
hydrochloric acid. The acidic, aqueous phase is separated off, and, whilst 
cooling with ice, rendered alkaline with approximately 10% aqueous ammonia 
solution and extracted with ethyl acetate. By separating off, drying 
(MgSO.sub.4) and concentrating the ethyl acetate extract by evaporation, 
the crude 
1-[N-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methy 
lethyl]benzylamino]-3-(4-methylcarbamoylphenoxy)propan-2-ol is obtained as 
an oil which may be used without further purification for catalytic 
debenzylation. 
(9b) The product obtained according to (9a) is dissolved in 300 ml of 
methanol and, with the addition of 2.8 g of Pd/C-catalyst (5%) and a 
further addition of 1.4 g of catalyst, is hydrogenated until hydrogen 
absorption ceases. The methanolic solution of 
1-[2-(2,3-dihydro-2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-6-yloxy)-1-methylet 
hylamino]-3-(4-methylcarbamoylphenoxy)propan-2-ol obtained after the 
catalyst has been filtered off is further processed directly. 
EXAMPLE 10 
Exactly in accordance with the method described in Example 9, using 
4-(2,3-epoxypropoxy)-(2-methoxyethyl)-benzene, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-[4-(2-methoxyeth 
yl)phenoxy]propan-2-ol is obtained as a diastereoisomeric mixture having a 
melting point of 139.degree.-142.degree. (from ethyl acetate). 
EXAMPLE 11 
A mixture of 9.0 g of 
6-(2-bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one and 
14.5 g of 1-(2-allyloxyphenoxy)-3-aminopropan-2-ol is stirred for 1 hour 
in a bath at 110.degree.-120.degree.. The melt is then extracted by 
boiling with 100 ml of isopropanol, the solution is filtered and 
concentrated by evaporation. The residue is divided between 400 ml of 
ethyl acetate and 50 ml of 2N potassium bicarbonate solution. By 
concentration by evaporation and fractional crystallisation, 
1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-propa 
n-2-ol having a melting point of 147.degree.-148.degree. (from isopropanol) 
is obtained from the ethyl acetate solution. The neutral fumarate of the 
compound melts at 136.degree.-137.degree. (from methanol). 
EXAMPLE 12 
A mixture of 11.2 g of 1-(2-allyloxyphenoxy)-3-aminopropan-2-ol and 10.5 g 
of 5-(2-oxopropoxy)salicylamide is boiled using a water separator in 200 
ml of toluene with the addition of a few drops of acetic acid. After the 
splitting off of water has ceased (after about 2-3 hours), the solution is 
concentrated by evaporation, the dark red residue is dissolved in 300 ml 
of ethanol and a total of 5.7 g of sodium borohydride is added in portions 
whilst stirring. The temperature increases during this operation to 
36.degree.. The reaction mixture is stirred for a further 2 hours at 
20.degree.-30.degree., and left to stand overnight. Whilst cooling with 
ice, it is then brought to pH 3-4 with approximately 6N hydrochloric acid, 
filtered and concentrated by evaporation. The residue is divided between 
100 ml of water and 100 ml of ethyl acetate, the aqueous phase is 
separated off, rendered alkaline with concentrated ammonia and extracted 
with 200 ml of ethyl acetate. Working up of the organic phase yields crude 
oily 
1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylami 
no]propan-2-ol as an enantiomer mixture. By slow crystallisation from 
isopropanol the two pure enantiomer pairs having melting points of 
123.degree.-125.degree. and 98.degree.-102.degree. respectively are 
obtained. 
EXAMPLE 13 
A mixture of 6.5 g of 5-(2-bromoethoxy)salicylamide and 8.9 g of 
1-(2-allyloxyphenoxy)-3-aminopropan-2-ol is melted in an oil bath at 
100.degree. and stirred for 1 hour using a magnetic stirrer. The working 
up is carried out analogously to Example 11 and yields 
1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-propa 
n-2-ol having a melting point of 147.degree.-148.degree. (from 
isopropanol). 
The salicylamide compound used as starting material may be obtained as 
follows: 
(13a) 30.0 g of 
6-(2-bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one are 
refluxed in a mixture of 100 ml of dioxan and 100 ml of 6N hydrochloric 
acid, whilst stirring, for 1.5 hours. The crystals obtained after 
concentrating the reaction mixture by evaporation are washed with 50 ml of 
water and dried in vacuo. The resulting 5-(2-bromoethoxy)salicylamide 
melts at 141.degree.-143.degree.. 
EXAMPLE 14 
By using the corresponding 1-aryloxy-3-aminopropan-2-ols the following 
compounds are obtained in a manner analogous to Example 13: 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-cyanophenoxy)propan-2-o 
l, melting point 121.degree.-124.degree. (from ethanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)phenox 
y]propan-2-ol, melting point 157.degree.-158.degree. (from isopropanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-(prop-2-ynyloxy)phenoxy 
]propan-2-ol, melting point 140.degree.-141.degree. (from ethanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methylthioethoxy)phe 
noxy]propan-2-ol, which forms a hydrochloride having a melting point of 
202.degree.-204.degree. (from methanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-allylphenoxy]propan-2-o 
l, which forms a neutral fumarate having a melting point of 
165.degree.-166.degree. (from ethanol). 
EXAMPLE 15 
Analogously to Example 1, by debenzylation of 16 g of crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-[4-(ca 
rbamoylmethoxy)phenoxy]propan-2-ol, after crystallisation from dioxan the 
pure 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-[4-(carbamoylmet 
hoxy)phenoxy]propan-2-ol having a melting point of 145.degree.-149.degree. 
is obtained (sinters at a temperature of 140.degree.) (mixture of the 
diastereoisomers). 
EXAMPLE 16 
Analogously to Example 3, by debenzylation of 18 g of crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylbenzylamino]-3-[2-[N'-(2-hydrox 
yethyl)ureidomethyl]phenoxy]propan-2-ol, after crystallisation from 
dimethylformamide/ether 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-[N'-(2-hydroxyethyl)ur 
eidomethyl]phenoxy]propan-2-ol is obtained having a melting point of 
164.degree.-166.degree.. 
The starting material can be prepared as follows: 
2-benzyloxybenzylamine 
In a Soxhlet apparatus 18.4 g of lithium aluminium hydride in 1800 ml of 
dry ether are boiled under a nitrogen atmosphere at a bath temperature of 
70.degree., 5.3 g of 2-benzyloxybenzamide being introduced into the 
Soxhlet thimble. After 21 hours the reaction mixture is immersed in an ice 
bath, and 18.4 ml of water, 18.4 ml of 15% sodium hydroxide solution and 
55 ml of water are added dropwise in succession, whilst stirring. The 
temperature may be allowed to rise to a maximum of +10.degree.. Stirring 
of the mixture is then continued at 20.degree. and the resulting 
precipitate is suction-filtered and washed with ether. The filtrate is 
concentrated by evaporation in vacuo and the oil remaining is stirred with 
500 ml of 10% hydrochloric acid and 400 ml of ether for 2 hours, whilst 
cooling with ice. The precipitated 2-benzyloxybenzylamine hydrochloride is 
suction-filtered, washed with water and ether and dried in vacuo. Melting 
point 190.degree.-191.degree.. 
2 -benzyloxybenzyl isocyanate 
38.5 g of 2-benzyloxybenzylamine hydrochloride are suspended in 400 ml of 
distilled toluene and heated at a bath temperature of 140.degree.. Whilst 
stirring, phosgene is introduced and after about 50 minutes the solution 
becomes clear. After a further 10 minutes, the addition of phosgene is 
interrupted and boiling is continued for a further hour. The solution is 
then left to cool a little and the toluene is distilled off in vacuo. A 
sample of the oil remaining was distilled in a bulb tube: Boiling point, 
bath temperature 120.degree./0.06 torr. 
N-(2-hydroxyethyl)-N'-(2-benzyloxybenzyl)urea 
A solution of 73.6 g of crude 2-benzyloxybenzyl isocyanate in 120 ml of 
methylene chloride is added dropwise in the course of 50 minutes to a 
solution of 36.8 ml of ethanolamine in 370 ml of methylene chloride. The 
reaction is slightly exothermic. After 2 hours the reaction solution is 
washed three times with 200 ml of water each time and dried using sodium 
sulphate. Methylene chloride is distilled off and the residue is 
recrystallised from isopropanol. The resulting product melts at 
92.degree.-94.degree.. 
N-(2-hydroxyethyl)-N'-(2-hydroxybenzyl)urea 
59.6 g of N-(2-hydroxyethyl)-N'-(2-benzyloxybenzyl)-urea are dissolved in 
600 ml of methanol and hydrogenated in the presence of 6 g of 
Pd/C-catalyst (5%). After 2 hours the hydrogenation ceases. The catalyst 
is suction-filtered, and the filtrate concentrated by evaporation in 
vacuo. The residue is recrystallised from 350 ml of ethyl acetate; the 
pure product melts at 100.degree.-101.degree.. 
N-[2-(2,3-epoxypropoxy)benzyl]-N'-(2-hydroxyethyl)urea 
A mixture of 29.2 g of N-(2-hydroxyethyl)-N'-(2-hydroxybenzyl)urea, 440 ml 
of epichlorohydrin and 38.9 g of potassium carbonate is stirred for 6 
hours at 90.degree.. The solids are then suction-filtered whilst hot, 
washed with acetonitrile and the filtrate is concentrated by evaporation 
in vacuo. The oil remaining crystallises when left to stand and is 
recrystallised from 320 ml of ethyl acetate, with carbon treatment. The 
resulting epoxide melts at 96.degree.-99.degree.. 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]benzylamino]-3-[2-[N'-(2-hydrox 
yethyl)ureidomethyl]phenoxy]propan-2-ol 
A solution of 9.75 g of the above epoxide and 9.4 g of 
N-[(3-carbamoyl-4-hydroxyphenoxy)ethyl]benzylamine in 100 ml of 
isopropanol is stirred for 7 hours at a bath temperature of 95.degree.. 
The solution is concentrated by evaporation in vacuo. The resulting crude 
product can be subjected directly to hydrogenolysis. 
EXAMPLE 17 
A mixture of 10.2 g of [2-(2,3-epoxypropoxy)phenyl]-prop-2-ynyl ether, 7.8 
g of 5-(2-aminoethoxy)salicylamide and 25 ml of isopropanol is refluxed 
for 1 hour whilst stirring. The residue remaining after concentrating the 
reaction mixture by evaporation is dissolved in 30 ml of ethyl acetate. 
The 1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-(prop-2-ynyloxy)ph 
enoxy]-propan-2-ol crystallising out melts after recrystallisation from 
ethanol at 140.degree.-141.degree.. 
(17a) The 5-(2-aminoethoxy)salicylamide required as starting material can 
be prepared by debenzylation, using hydrogen in the presence of a 
Pd/C-catalyst (5%), of the corresponding N-benzyl compound (analogously to 
Example (3b) in methanol; it melts at 140.degree.. 
EXAMPLE 18 
Analogously to Example 17, by using the correspondingly substituted 
epoxides, the following compounds are obtained: 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-cyanophenoxy)propan-2-o 
l, melting point 121.degree.-124.degree. (from ethanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-chlorophenoxy)propan-2- 
ol, melting point 140.degree.-141.degree. (from ethanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methylthioethoxy)phe 
noxy]propan-2-ol, which forms a hydrochloride, melting point 
202.degree.-204.degree., (from methanol), 
1-(2-allylphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propan-2-o 
l, the neutral fumarate of which melts at 165.degree.-166.degree. (from 
ethanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)phenox 
y]propan-2-ol, melting point 157.degree.-158.degree. (from methanol), 
1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propan- 
2-ol, melting point 147.degree.-148.degree. (from methanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methyl-4-methylthiophen 
oxy)propan-2-ol, melting point 139.degree.-141.degree. (from acetonitrile), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methyl-4-methylsulphiny 
lphenoxy)propan-2-ol with double melting point 92.degree. and 140.degree., 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methyl-1,2,4-thiadiazol 
-5-yloxy)propan-2-ol, after chromatography on silica gel, as an amorphous 
powder having a melting point of 132.degree. after sintering. 
EXAMPLE 19 
3.09 g of 4-(2,3-epoxypropoxy)benzimidazol-2-one and 4.29 g of 
5-[2-(benzylamino)ethoxy]salicylamide are refluxed for 3 hours in 80 ml of 
isopropanol. The solvent is then removed under reduced pressure. The crude 
N-[2-(4-hydroxy-3-carbamoylphenoxy)ethyl]-N-[3-(2-oxobenzimidazol-4-yloxy) 
-2-hydroxypropyl]-N-benzylamine remaining is dissolved in 80 ml of 
methanol, 3 ml of a 5N methanolic hydrogen chloride solution are added 
thereto, and the whole is then shaken with the addition of 0.8 g of 
Pd/C-catalyst (5%) in a hydrogenating apparatus under a hydrogen 
atmosphere. When the hydrogen absorption corresponding to the calculated 
amount has ceased, the catalyst is filtered off, and the filtrate is 
concentrated under reduced pressure. As the concentrate cools, 
4-[3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-2-hydroxypropoxy]benzimi 
dazol-2-one hydrochloride crystallises, melting point 
148.degree.-152.degree. (after recrystallisation from methanol). 
EXAMPLE 20 
By catalytic debenzylation of 
1-[N-[2-(4-carbamoyl-3-hydroxyphenoxy)ethyl-benzylamino]-3-[4-(2-methoxyet 
hoxy)-phenoxy]propan-2-ol, analogously to Example 1 there is obtained 
1-[2-(4-carbamoyl-3-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol having a melting point of 151.degree.-152.degree. (from 
methanol). 
The starting material is prepared as follows: 
(20a) 16.2 g of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benzoxazin-4-one 
are reacted analogously to Example (3a) with 84 ml of 1,2-dibromomethane 
and yield 
2,3-dihydro-2,2-dimethyl-7-(2-bromoethoxy)-4H-1,3-benzoxazin-4-one having 
a melting point of 156.degree.-158.degree. (from isopropanol). 
(20b) 53 g of 
2,3-dihydro-2,2-dimethyl-7-(2-bromoethoxy)-4H-1,3-benzoxazin-4-one and 94 
g of benzylamine are boiled for 3 hours whilst stirring. The reaction 
mixture is rendered alkaline with concentrated ammonia, and the organic 
phase is concentrated by evaporation at a maximum temperature of 
50.degree.. 
The 4-[2-(benzylamino)ethoxy]salicylamide obtained in this manner forms an 
oil, the hydrochloride of which melts at 252.degree.-254.degree. (from 
methanol). 
(20c) Analogously to Example (4a), using 
4-[2-(benzylamino)-ethoxy]salicylamide, 
1-[N-[2-(4-carbamoyl-3-hydroxyphenoxy)-ethyl]benzylamino]-3-[4-(2-methoxye 
thoxy)phenoxy]propan-2-ol is obtained as an oil which is debenzylated in 
its crude state. 
EXAMPLE 21 
Analogously to Example 8, by debenzylation of crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]benzylamino]-3-(4-benzyloxyphe 
noxy)propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(4-hydroxyphenoxy)propan- 
2-ol having a melting point of 130.degree.-131.degree. (from isopropanol), 
and, using the 4-carbamoyl-3-hydroxy isomer, 
1-[2-(4-carbamoyl-3-hydroxyphenoxy)ethylamino]-3-(4-hydroxyphenoxy)propan- 
2-ol having a melting point of 148.degree.-151.degree. (from methanol) are 
obtained, the hydrochloride salt of which melts at 
224.degree.-226.degree.. 
(21a) The starting materials may be obtained by reacting 
benzyl-[4-(2,3-epoxypropoxy)phenyl]ether with 5- or 
4-[2-(benzylamino)ethoxy]salicylamide respectively analogously to Example 
8b. 
EXAMPLE 22 
Analogously to Example 13, using 6-(2-bromoethoxy)-salicylamide, 
1-[2-(2-carbamoyl-3-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol is obtained; melting point 176.degree.-179.degree. (from 
methanol). 
(22a) The starting material may be prepared as follows: 
A mixture of 23.0 g of 2,6-dihydroxybenzamide, 20.7 g of potassium 
carbonate and 28.2 g of 1,2-dibromoethane is refluxed, whilst stirring, 
for 2-3 hours in 300 ml of acetonitrile. The reaction mixture is filtered 
whilst still warm, the filtrate concentrated by evaporation and the 
residue recrystallised from a little methanol. 
6-(2-Bromoethoxy)salicylamide having a melting point of 
120.degree.-121.degree. is obtained. 
EXAMPLE 23 
The solution of 2.24 g of 5-(2-amino-2-methylpropoxy)salicylamide in 30 ml 
of dioxan is refluxed for 7 hours after the addition of 2.3 g of 
2-(2,3-epoxypropoxy)-benzonitrile, and then concentrated by evaporation. 
The residue is divided between 10 ml of 2N hydrochloric acid and 100 ml of 
ethyl acetate. The acidic aqueous phase is rendered alkaline with 
concentrated ammonia solution, the base is extracted with ethyl acetate 
and the solvent is evaporated off, whereupon an oil is obtained from 
which, by crystallisation from isopropanol and recrystallisation from 
ethyl acetate, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1,1-dimethylethylamino]-3-(2-cyanophen 
oxy)propan-2-ol having a melting point of 125.degree.-126.degree. is 
obtained. 
The starting material may be obtained as follows: 
(23a) A mixture of 84.3 g of 
2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one, 144.2 g of 
methanesulphonic acid (2-methyl-2-nitropropyl)ester and 121 g of dry 
potassium carbonate in 440 ml of diethylene glycol dimethyl ether is 
stirred for 9 hours in a bath at approximately 150.degree.. The reaction 
mixture is cooled, poured into 4000 ml of water and extracted with 3000 ml 
of ethyl acetate. The oil obtained by concentrating the organic phase by 
evaporation is dissolved in 250 ml of dioxan, and approximately 750 ml of 
2N hydrochloric acid are added until the reaction mixture turns acidic. 
The solution is maintained at 80.degree.-100.degree. for one and a half 
hours, then concentrated to half the volume under reduced pressure and 
extracted 3 times with 500 ml of ethyl acetate each time. The combined 
organic phases are washed with 200 ml of water, then with saturated sodium 
carbonate solution and finally with saturated sodium chloride solution, 
dried over magnesium sulphate and concentrated by evaporation. The dark 
brown oil obtained in this manner is chromatographed on 500 g of silica 
gel. By elution with ether crystalline 
5-(2-methyl-2-nitropropoxy)salicylamide having a melting point of 
145.degree.-148.degree. is obtained. 
(23b) 11.5 g of 5-(2-methyl-2-nitropropoxy)salicylamide are hydrogenated in 
150 ml of methanol at 40.degree.-50.degree. and 80 bar over 5 g of Raney 
nickel until hydrogen absorption ceases. By filtration and concentration 
of the filtrate by evaporation, crude 
5-(2-amino-2-methylpropoxy)salicylamide is obtained, which, after standing 
for a relatively long period, crystallises from isopropanol and melts at 
115.degree.-117.degree.. 
EXAMPLE 24 
A mixture of 50 ml of dioxan and 500 ml of concentrated ammonia solution is 
added to 21.5 g of 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-(3-hydroxy-4-met 
hoxycarbonylphenoxy)propan-2-ol. The reaction mixture is stirred for 1-2 
hours, and as soon as it is homogeneous, left to stand for 3 days at 
20.degree.-30.degree.. By concentration by evaporation, 20 g of crude, 
crystalline 
1-(4-carbamoyl-3-hydroxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-met 
hylethylamino]propan-2-ol is obtained as a diastereoisomeric mixture having 
a melting point of 180.degree.-190.degree.. A hydrochloride is formed 
which melts at 238.degree.-243.degree. (from ethanol/methanol). 
The starting material may be prepared in the following manner: 
(24a) By refluxing 34 g of 2,4-dihydroxybenzoic acid methyl ester with 185 
g of epichlorohydrin and 35 g of potassium carbonate for 2 to 3 hours, and 
chromatographing the crude product on 100 g of silica gel (elution with 
toluene), 4-(2,3-epoxypropoxy)salicylic acid methyl ester having a melting 
point of 53.degree.-55.degree. is obtained. 
(24b) After 40 hours' boiling and working up analogously to Example (4a), 
22.4 g of 4-(2,3-epoxypropoxy)salicylic acid methyl ester and 30 g of 
5-(2-benzylaminopropoxy)-salicylamide in 200 ml of isopropanol yield crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-(3-hyd 
roxy-4-methoxycarbonylphenoxy)propan-2-ol as a light-coloured foam which is 
further processed as a crude product. 
(24c) A solution of 46 g of 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-(3-hyd 
roxy-4-methoxycarbonylphenoxy)propan-2-ol in 500 ml of methanol is 
hydrogenated with the addition of 5 g of Pd/C-catalyst (5%) under normal 
conditions until 1 equivalent of hydrogen has been absorbed. The product, 
which has partially crystallised out, is dissolved in about 2000 ml of hot 
methanol and the catalyst is filtered off. By concentrating the filtrate, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-(3-hydroxy-4-met 
hoxycarbonylphenoxy)propan-2-ol having a melting point of 
168.degree.-172.degree. is obtained as a diastereoisomeric mixture. 
EXAMPLE 25 
5.2 g of crude 
1-[N-[2-(3-carbamoyl-2-hydroxyphenoxy)-ethyl]benzylamino]-3-[4-(2-methoxye 
thoxy)phenoxy]propan-2-ol are hydrogenated and worked up analogously to 
Example 4. After recrystallisation from isopropanol, 
1-[2-(3-carbamoyl-2-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)-phen 
oxy]propan-2-ol having a melting point of 125.degree.-129.degree. is 
obtained. 
The starting material is prepared as follows: 
(25a) 2,3-dihydroxybenzoic acid methyl ester is reacted in the presence of 
potassium carbonate in acetonitrile with 1.1 equivalents of 
1-dibenzylamino-2-chloroethane for 18 hours at 82.degree.. The crude 
3-(2-dibenzylaminoethoxy)-salicylic acid methyl ester obtained after 
working up is put to further use without further purification. 
(25b) The compound obtained in accordance with Example (25a) is dissolved 
in methanol and, after the addition of palladium-on-carbon catalyst, is 
hydrogenated until 1.1 equivalents of hydrogen have been absorbed. The 
catalyst is filtered off, the solvent evaporated off, the residue taken up 
in ethyl acetate, the organic phase washed with water and concentrated by 
evaporation, after which the crude 3-(2-benzylaminoethoxy)salicylic acid 
methyl ester is obtained as a honey-coloured oil. 
(25c) The product obtained in accordance with Example (25b) is stirred with 
10 times the amount by weight of concentrated ammonia, and when 
dissolution has occurred, is left to stand for 4 to 5 days at room 
temperature. The solution is then concentrated by evaporation, the residue 
is divided between water and ethyl acetate, the organic phase is dried 
over magnesium sulphate and concentrated by evaporation, after which 
3-(2-benzylaminoethoxy)salicylamide is obtained as a yellowish oil. 
(25d) By reacting 2.5 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene 
with 2.9 g of crude 3-(2-benzylaminoethoxy)salicylamide obtained according 
to Example (25c), analogously to Example (4a), 
1-[N-[2-(3-carbamoyl-2-hydroxyphenoxy)ethyl]benzylamino]-3-[4-(2-methoxyet 
hoxy)-phenoxy]propan-2-ol is obtained as an oil which is further processed 
in this state. 
EXAMPLE 26 
A solution of 2.5 g of 1-amino-3-[4-(2-methoxyethoxy)-phenoxy]propan-2-ol 
and 2.23 g of 
(2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-on-6-yloxy)acetaldehyde in 
20 ml of ethanol is refluxed for 3 hours. After cooling, 0.8 g of sodium 
borohydride is added in portions, whilst stirring, and stirring is 
continued for a further 3-4 hours at room temperature. 
By adding 2N hydrochloric acid, the excess sodium borohydride is 
decomposed, the solution is then concentrated by evaporation, the residue 
rendered alkaline with ammonia solution and extracted 3 times with 300 ml 
of ethyl acetate each time. By concentrating by evaporation the combined 
ethyl acetate solutions dried over magnesium sulphate, a brown residue is 
obtained, from which, by repeated recrystallisation from isopropanol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol having a melting point of 157.degree.-158.degree. is 
obtained. 
The starting material is prepared as follows: 
(26a) A solution of 9.65 g of 
2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one and 9.1 g of 
allyl bromide in 150 ml of acetonitrile is refluxed for 5 hours, whilst 
stirring, with the addition of 10.3 g of dry potassium carbonate. The 
reaction mixture is filtered whilst warm, the filtrate is concentrated by 
evaporation and the remaining crystals are suction-filtered after 
trituration with ether. The crude 
2,3-dihydro-2,2-dimethyl-6-(1-propen-3-yloxy)-4H-1,3-benzoxazin-4-one 
obtained in this manner melts at 137.degree.-138.degree.. 
(26b) Approximately 20 mg of osmium tetroxide are added to a solution of 
4.7 g of 
2,3-dihydro-2,2-dimethyl-6-(1-propen-3-yloxy)-4H-1,3-benzoxazin-4-one in a 
mixture of 50 ml of dioxan and 15 ml of water whilst stirring. After 15 
minutes 8.6 g of sodium metaperiodate are added in portions, the 
temperature rising to 45.degree.. After 2 hours the reaction mixture is 
filtered, the filtrate concentrated by evaporation and the residue divided 
between 20 ml of water and 200 ml of ethyl acetate. The organic phase is 
separated off, dried over sodium sulphate and concentrated by evaporation, 
and the resulting oil is chromatographed on 100 g of silica gel. By 
elution with ethyl acetate and concentration by evaporation, 
(2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-on-6-yloxy)acetaldehyde 
having a melting point of 153.degree.-163.degree. is obtained. 
EXAMPLE 27 
After the addition of 0.2 g of palladium-on-carbon catalyst, a solution of 
4.1 g of 
1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propan 
-2-ol in 100 ml of methanol is hydrogenated under normal conditions until 1 
equivalent of hydrogen has been absorbed. By filtration and concentration 
of the solution by evaporation, colourless crystals are obtained which 
melt at 142.degree.-143.degree. after recrystallisation from methanol and 
consist of 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-propoxyphenoxy)propan- 
2-ol. 
EXAMPLE 28 
Analogously to Example 8, using 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]benzylamino]-3-(2-benzyloxyphe 
noxy)propan-2-ol as starting material, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-hydroxyphenoxy)propan- 
2-ol is obtained which forms a neutral fumarate having a melting point of 
178.degree.-180.degree. (from ethanol). 
The starting material can be obtained analogously to (Example 8b) from 
benzyl-[2-(2,3-epoxypropoxy)phenyl]ether and 
5-[2-(benzylamino)ethoxy]salicylamide. 
EXAMPLE 29 
Analogously to Example 4, 
(a) from 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]-benzylamino]-3-(3-carbamoyl-4 
-hydroxyphenoxy)propan-2-ol there is obtained 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-carbamoyl-4-hydroxyphe 
noxy)-propan-2-ol, melting point 212.degree.-215.degree., (from methanol); 
(b) from 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)ethyl]-benzylamino]-3-[4-(2-oxopropo 
xy)phenoxy[propan-2-ol there is obtained 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(2-oxopropoxy)phenoxy 
]propan-2-ol, melting point 118.degree.-120.degree. (from acetonitrile). 
EXAMPLE 30 
Analogously to Example 17, the following compounds are obtained using the 
correspondingly substituted epoxides: 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-acetamidoethyl)pheno 
xy]propan-2-ol; melting point of the hydrochloride 223.degree.-224.degree. 
(from methanol), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(4-acetamidomethylphenoxy) 
propan-2-ol, melting point 173.degree.-176.degree. (from Methyl 
Cellosolve), 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(4-carbamoylmethylphenoxy) 
propan-2-ol, melting point 181.degree.-182.degree., (from 
dimethylformamide/water). 
EXAMPLE 31 
A solution of 25 g of crude 
1-[N-[4-(3-carbamoyl-4-hydroxyphenoxy)butyl]benzylamino]-3-[4-(2-methoxyet 
hoxy)-phenoxy]propan-2-ol in 250 ml of methanol is hydrogenated and worked 
up analogously to Example 4. The resulting crystalline crude product is 
recrystallised from isopropanol and yields 
1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol having a melting point of 122.degree.-124.degree.. 
The starting material is prepared as follows: 
(31a) A suspension of 96.5 g of 
2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one and 76 g of 
potassium carbonate in 300 ml of 1,4-dibromobutane is stirred for 5 hours 
in a bath at 120.degree.-130.degree.. The reaction mixture is filtered and 
the excess 1,4-dibromobutane is distilled off at about 1 torr. The 
crystalline residue is triturated with ether and suction-filtered. In this 
manner crude 
2,3-dihydro-2,2-dimethyl-6-(4-bromobutoxy)-4H-1,3-benzoxazin-4-one having 
a melting point of 139.degree.-142.degree., which is sufficiently pure for 
further reaction, is obtained. 
(31b) A mixture of 65.6 g of 
2,3-dihydro-2,2-dimethyl-6-(4-bromobutoxy)-4H-1,3-benzoxazin-4-one, 85 g 
of benzylamine and 100 ml of water is heated at 110.degree.-120.degree. 
for 1 hour, whilst stirring. Whilst cooling with ice, the reaction mixture 
is then acidified with concentrated hydrochloric acid, a salt mixture of 
5-(4-benzylaminoethoxy)salicylamide crystallising out after a few hours. 
The base liberated therefrom by means of 20% ammonia is extracted with 
ethyl acetate and the organic phase is evaporated off. The residue forms 
an oil which crystallises gradually, (melting point 
103.degree.-106.degree., sinters at a temperature of 86.degree. and 
above). 
(31c) A solution of 15.7 g of the compound obtained according to Example 
23b and 13.4 g of 1-(2,3-epoxypropoxy)-4-(2-methoxyethoxy)benzene is 
reacted analogously to (Example 4a) to give 
1-[N-[4-(3-carbamoyl-4-hydroxyphenoxy)-butyl]benzylamino]-3-[4-(2-methoxye 
thoxy)phenoxy]propan-2-ol and is further processed in this state. 
EXAMPLE 32 
A mixture of 8.4 g of 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol and 30 ml of n-butylamine is heated in a rotating closed 
vessel for 17 hours at 160.degree.-170.degree.. After evaporating off the 
butylamine, a crystalline residue is left which is recrystallised from 
methanol and yields 
1-[2-(3-N-n-butylcarbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyeth 
oxy)phenoxy]propan-2-ol having a melting point of 118.degree.-119.degree.. 
EXAMPLE 33 
A mixture of 8.1 g of 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-propoxyphenoxy)propan- 
2-ol and 50 ml of a 33% solution of methylamine in ethanol is reacted 
analogously to Example 32 in a closed vessel. 
By concentrating the resulting solution by evaporation, an oil is obtained 
which is neutralised by adding a 5N solution of hydrochloric acid in 
methanol. After adding ether until the solution starts turning turbid, 
1-[2-[3-(N-methylcarbamoyl)-4-hydroxyphenoxy]ethylamino]-3-(2-propoxypheno 
xy)propan-2-ol gradually crystallises out as a hydrochloride having a 
melting point of 114.degree.-116.degree.. 
In an analogous manner, using piperidine 
1-[2-[3-(N-piperidinocarbonyl)-4-hydroxyphenoxy]ethylamino]-3-(2-propoxyph 
enoxy)propan-2-ol is obtained as a viscous oil, the IR- and .sup.1 
H-NMR-spectra of which are in concordance with the assumed structure and 
the Rf-value of which is 0,70 according to thin-layer-chromatography on 
silicagel using a mixture of ethylacetate-ethanol-conc. ammonia 24:12:4 as 
the eluent. 
EXAMPLE 34 
7.3 g of 2-(2,3-epoxypropoxy)benzonitrile are added to a solution of 6.7 g 
of 5-(4-aminobutoxy)salicylamide in 60 ml of dimethyl sulphoxide and the 
mixture is stirred for 1 hour in a bath at 90.degree.. The reaction 
mixture is poured into 300 ml of water and extracted twice with 200 ml of 
ethyl acetate each time. Working up analogously to Example 23 yields crude 
1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-(2-cyanophenoxy)propan-2- 
ol as a viscous oil, the IR- and .sup.1 H-NMR-spectra of which are in 
concordance with the assumed structure and the Rf-value of which is 0,51 
according to thin-layer-chromatography on silicagel using a mixture of 
ethylacetate-ethanol-conc. ammonia 24:12:4 as the eluent. 
5-(4-Aminobutoxy)salicylamide needed as starting material is obtained by 
catalytic debenzylation of 5-[4-(benzylamino)butoxy]salicylamide in 
methanol using a palladium-on-carbon catalyst (5%), melting point 
78.degree.-81.degree. (from ethanol). 
EXAMPLE 35 
A solution of 3.5 g of 
1-[2-(3-cyano-4-hydroxyphenoxy)-ethylamino]-3-[4-(2-methoxyethoxy)phenoxy] 
propan-2-ol in a mixture of 15 ml of concentrated hydrochloric acid and 20 
ml of dioxan is stirred for 15 hours at 20.degree.-25.degree.. The 
reaction mixture is then concentrated by evaporation and rendered alkaline 
with 10% aqueous ammonia solution. The crude 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol which is precipitated after standing for a few hours is 
filtered off and recrystallised from a mixture of dioxan/methanol (1:1). 
Melting point 157.degree.-158.degree.. 
1-[2-(3-cyano-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)phenoxy]pr 
opan-2-ol needed as starting material is obtainable in a manner analogous 
to the method described in Example 13 from 
1-[4-(2-methoxyethoxy)-phenoxy]-3-aminopropan-2-ol and 
5-(2-bromoethoxy)-2-hydroxybenzonitrile. The crude product obtained after 
working up is put to further use in this state. 
EXAMPLE 36 
Tablets containing 20 mg of active substance are manufactured in the 
following composition in the customary manner. 
______________________________________ 
Composition: 
______________________________________ 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)- 
20 mg 
ethylamino]-3-[4-(2-methoxyethoxy)- -phenoxy]propan-2-ol 
wheat starch 60 mg 
lactose 50 mg 
colloidal silica 5 mg 
talc 9 mg 
magnesium stearate 1 mg 
145 mg 
______________________________________ 
MANUFACTURE 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)phenox 
y]propan-2-ol is mixed with part of the wheat starch, with the lactose and 
colloidal silica and the mixture is pressed through a sieve. A further 
portion of the wheat starch is made into a paste using a water bath with 5 
times the amount of water and the powder mixture is kneaded with this 
paste until a slightly plastic composition has formed. 
The plastic composition is pressed through a sieve having a mesh width of 
approximately 3 mm, dried, and the resulting dry granulate is again 
pressed through a sieve. The remaining wheat starch, the talc and 
magnesium stearate are then admixed and the mixture is compressed to form 
tablets of 145 mg weight having a breaking groove. 
EXAMPLE 37 
Tablets containing 1 mg of active substance are manufactured in the 
following composition in the customary manner: 
______________________________________ 
Composition: 
______________________________________ 
1-(4-hydroxyphenoxy)-3-[2-(3-carbamoyl- 
1 mg 
4-hydroxyphenoxy)-1-methylethylamino]propan- 
2-ol 
wheat starch 60 mg 
lactose 50 mg 
colloidal silica 5 mg 
talc 9 mg 
magnesium stearate 1 mg 
126 mg 
______________________________________ 
MANUFACTURE 
1-(4-Hydroxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino 
]propan-2-ol is mixed with part of the wheat starch, with the lactose and 
colloidal silica and the mixture is pressed through a sieve. A further 
portion of the wheat starch is made into a paste using a water bath with 5 
times the amount of water, and the powder mixture is kneaded with this 
paste until a slightly plastic composition has formed. 
The plastic composition is pressed through a sieve having a mesh width of 
approximately 3 mm, dried, and the resulting dry granulate is again 
pressed through a sieve. The remaining wheat starch, the talc and 
magnesium stearate are then admixed, and the mixture is compressed to form 
tablets of 145 mg weight having a breaking groove. 
EXAMPLE 38 
Capsules containing 10 mg of active substance are manufactured in the 
customary manner as follows: 
______________________________________ 
Composition: 
______________________________________ 
1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4- 
2500 mg 
hydroxyphenoxy)ethylamino]propan-2-ol 
talc 200 mg 
colloidal silica 50 mg 
______________________________________ 
MANUFACTURE 
The active substance is intimately mixed with the talc and colloidal 
silica, the mixture is pressed through a sieve having a mesh width of 0.5 
mm, and introduced in 11 mg portions into hard gelatin capsules of 
suitable size. 
EXAMPLE 39 
A sterile solution of 5.0 g of 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol methane sulphonate in 5000 ml of distilled water is 
introduced into 5 ml ampoules which contain 5 mg of active substance in 5 
ml of solution. 
EXAMPLE 40 
3.62 g of 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(4-hydroxyphenoxy)propan- 
2-ol are dissolved, with the addition of 100.0 ml of 0.10N hydrochloric 
acid, in 18000 ml of distilled water to a volume of 18100 ml. The 
sterilised solution is introduced into 5.0 ml ampoules containing 1 mg of 
active substance. 
EXAMPLE 41 
Instead of the compounds used as the active substances in Examples 36 to 
40, the following compounds of the formula I, or the pharmaceutically 
acceptable non-toxic acid addition salts thereof, may also be used as 
active substances in tablets, dragees, capsules, ampoule solutions etc.: 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-[4-(2-methoxyetho 
xy)phenoxy]propan-2-ol, 
1-[2-(4-carbamoyl-3-hydroxyphenoxy)-1-methylethylamino]-3-[4-(2-methoxyeth 
oxy)phenoxy]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-[N-(2-hydroxyethyl)-ca 
rbamoylmethoxy]phenoxy]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-phenoxypropan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-[2-(methoxycarbonyl)et 
hoxy]phenoxy]propan-2-ol, 
1-(4-acetamidophenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-prop 
an-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-methylphenoxy)propan-2 
-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methylphenoxy)propan-2 
-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-methylindol-4-yloxy)pr 
opan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-(trifluoromethylphenoxy) 
propan-2-ol, 1-(2-acetylphenoxy)-3-[ 
2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propan-2-ol, 
1-[4-[2-(acetamido)ethoxy]phenoxy]-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethy 
lamino]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methylpyridin-2-yloxy) 
propan-2-ol, 
5-[3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-2-hydroxypropoxy]-1,2,3, 
4-tetrahydro-2,3-cis-naphthalene diol, 
4-[2-hydroxy-3-[(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propoxy]phenylace 
tamide, 
4-[2-hydroxy-3-[(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]propoxy]phenoxya 
cetamide, 
N-[4-[2-hydroxy-3-[(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propoxy]-pheny 
l]-N',N'-dimethyl urea, 
1-(4-butyroylamino-2-acetylphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)eth 
ylamino]-propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-methoxyphenoxy)propan- 
2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2,3-dimethylphenoxy)prop 
an-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[3-(2-methoxyethoxy)pheno 
xy]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-(pyrrol-1-yl)phenoxy]- 
propan-2-ol, 1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-( 
3-methyl-4-methylsulphonylphenoxy)propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(1-naphthyloxy)-propan-2- 
ol, 
5-[3-[2-(4-carbamoyl-3-hydroxyphenoxy)-1-methylethylamino]-2-hydroxypropox 
y]-3,4-dihydro-2(1H)-quinolinone, 
1-[3-(3-carbamoyl-4-hydroxyphenyl)propylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-(4-methylcarbamo 
ylphenoxy)propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-[4-(2-methoxyeth 
yl)phenoxy]propan-2-ol, 
1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylami 
no]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-cyanophenoxy)propan-2- 
ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-(prop-2-ynyloxy)phenox 
y]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methylthioethoxy)ph 
enoxy]propan-2-ol, 1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]- 
3-[2-allylphenoxy]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-[4-(carbamoylmet 
hoxy)-phenoxy]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[2-[N'-(hydroxyethyl)ure 
idomethyl]phenoxy]-propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-(prop-2-nyloxy)phenoxy 
]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-cyanophenoxy)-propan-2 
-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-chlorophenoxy)propan-2 
-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-methylthioethoxy)-p 
henoxy]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-(methyl-4-methylthiophen 
oxy)propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methyl-4-methylsulphin 
ylphenoxy)propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-methyl-1,2,4-thiadiazo 
l-5-yloxy)propan-2-ol, 
4-[3-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-2-hydroxypropoxy]benzim 
idazol-2-one hydrochloride, 
1-[2-(4-carbamoyl-3-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol, 
1-[2-(2-carbamoyl-3-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)-phen 
oxy]propan-2-ol, 1-[ 
2-(3-carbamoyl-4-hydroxyphenoxy)-1,1-dimethylethylamino]-3-[4-(methylcarba 
moyl)phenoxy]-propan-2-ol, 
1-(4-carbamoyl-3-hydroxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-met 
hylethylamino]propan-2-ol as a diastereoisomeric mixture, 
1-[2-(3-carbamoyl-2-hydroxyphenoxy)ethylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]-propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-propoxyphenoxy)propan- 
2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-hydroxyphenoxy)propan- 
2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(3-carbamoyl-4-hydroxyphe 
noxy)propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(2-carbamoylphenoxy)propa 
n-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[4-(2-oxopropoxy)phenoxy] 
propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino[4-3-[-(2-acetamidoethyl)phen 
oxy]propan-2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(acetamidomethyl)phen 
oxy]propan-2-ol, 1-[2-( 
3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-(4-carbamoylmethylphenoxy)propan 
-2-ol, 
1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-[4-(2-methoxyethoxy)pheno 
xy]propan-2-ol, 
1-[2-[3-(N-n-butylcarbamoyl)-4-hydroxyphenoxy]ethylamino]-3-[4-(2-methoxye 
thoxy)phenoxy]propan-2-ol, 
1-[2-[3-(N-methylcarbamoyl)-4-hydroxyphenoxy]ethylamino]-3-(2-propoxypheno 
xy)propan-2-ol, 
1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-(2-cyanophenoxy)propan-2- 
ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-[2-(2-methoxy-ethoxy)phen 
oxy]propan-2-ol, 
1-(2-carbamoylphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]prop 
an-2-ol, 
1-[2-(4-carbamoyl-3-hydroxyphenoxy)ethylamino]-3-(4-hydroxyphenoxy)propan- 
2-ol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[2-(2,3-dihydroxypropyl) 
-phenoxy]-2-propanol, 
1-[2-(4-carbamoyl-3-hydroxyphenoxy)-1-methylethylamino]-3-(methansulphonyl 
aminophenoxy)-2-propanol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[2-(cyclopropylmethox 
y)-ethyl]-phenoxy]-2-propanol, 1-[ 
2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-(4-methanesulphonylamino-ph 
enoxy)-2-propanol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methyl-ethylamino]-3-(4-methanesulph 
onylamino-phenoxy)-2-propanol, 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(N-methyl-methanesulp 
honylamino)-phenoxy]-2-propanol or 
4-[3-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-2-hydroxy-propoxy]-N-m 
ethylcinnamic acid amide. 
EXAMPLE 42 
A solution of 6.9 g of 
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[2-(2,2-dimethyl-dioxola 
n-4-yl)-methyl]-phenoxy]-2-propanol in 165 ml of 0.1N hydrochloric acid is 
left to stand at 20.degree. for 5 hours. It is then washed twice with 
ether; the aqueous phase is filtered, and is subsequently concentrated in 
vacuo with a bath-temperature of 40.degree.. The aqueous solution obtained 
is lyophilised to yield 
1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-[2-(2,3-dihydroxy-propy 
l)-phenoxy]-2-propanol hydrochloride in the form of colourless amorphous 
powder. 
The starting material can be produced in the following manner: 
(a) A mixture of 76.8 g of 4-(2-hydroxybenzyl)-2,2-dimethyl-1,3-dioxolane, 
248 ml of epichlorohydrin and 69.7 g of potassium carbonate is stirred for 
7 hours at a bath-temperature of 130.degree.. 
The reaction mixture is filtered, and concentrated in vacuo to dryness. The 
residue is dissolved in ether; the solution is washed with 2N sodium 
hydroxide solution and then with water; it is dried over sodium sulfate 
and subsequently concentrated by evaporation. The resulting crude 
4-[2-(2,3-epoxy-propoxy)-benzyl]-2,2-dimethyl-1,3-dioxolane is further 
processed as such. 
(b) A mixture of 17.4 g of the crude compound obtained and 17.1 g of 
5-(2-benzylamino-ethoxy)-salicylamide in 60 ml of dimethyl sulfoxide is 
stirred for 20 hours at a bath-temperature of 80.degree.. The reaction 
mixture is poured into ice and water, and extracted with ethyl acetate. 
The organic phase is diluted with ether, and successively washed with 0.1N 
hydrochloric acid (at pH 4-5) and then with aqueous saturated potassium 
carbonate solution, and dried over sodium sulfate. Concentration by 
evaporation leaves an oil, which is chromatographed through silica gel 
with methylene chloride/methanol. Further processing yields 
1-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-benzyl-amino]-3-[2-[(2,2-di 
methyl-dioxolan-4-yl)-methyl]-phenoxy]-2-propanol as thick oil. 
(c) A solution of 23.5 g of the resulting compound in 240 ml of methanol is 
hydrogenated with the addition of 2.4 g of palladium-on-charcoal catalyst 
under normal conditions. The reaction product is dissolved in ethyl 
acetate, and precipitated in crystalline form by the addition of petroleum 
ether. The crystals are again dissolved in ethyl acetate, and the solution 
is stirred with 4.5 g of silica gel for 1/2 hour. Petroleum ether is added 
portionwise to the filtrated solution to thus obtain 
1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-[2-[(2,2-dimethyl-dioxo 
lan-4-yl)-methyl]-phenoxy]-2-propanol, m.p. 91.degree.-93.degree.. 
EXAMPLE 43 
A solution of 20.0 g of crude 
1-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-benzylamino]-3-(4- 
methane-sulfonylamino-phenoxy)-2-propanol in 250 ml of methanol is 
hydrogenated, after the addition of 2.5 g of Pd/C catalyst (5%), under 
normal conditions until debenzylation is completed (DC control), for which 
an addition of a further 1.0 g of catalyst is required. The catalyst is 
filtered off; the filtrate is concentrated by evaporation, and the oil 
remaining behind is dissolved in a small amount of hot isopropanol. On 
cooling is obtained crystalline 
1-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethylamino]-3-(4-methanesulf 
onylamino-phenoxy)-2-propanol, m.p. 147.degree.-150.degree. 
(diastereoisomeric mixture). 
The starting material is obtained in the following manner: 
(43a) According to the method described by Irvine et al., Synthesis 1972, 
568, 2,4-dihydroxybenzamide is converted, using an excess of acetone, into 
2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benzoxazin-4-one, m.p. 
249.degree.-251.degree.. 
(43b) 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 is obtained, by boiling for 28 hours and subsequent 
processing, 
2,3-dihydro-2,2-dimethyl-7-(2-oxo-propoxy)-4H-1,3-benzoxazin-4-one, m.p. 
160.degree.-162.degree. (from isopropanol). 
(43c) A solution of 75 g of crude 
2,3-dihydro-2,2-dimethyl-7-(2-oxo-propoxy)-4H-1,3-benzoxazin-4-one and 32 
g of benzylamine in 1000 ml of methanol is hydrogenated, with the addition 
of 0.75 g of conc. sulfuric acid and 1.6 g of a Pt/C catalyst (5%), under 
normal condition until the absorption of hydrogen has ceased. After 
removal of the catalyst by filtration and of the solvent by evaporation, 
the oily residue is distributed between 300 ml of ethyl acetate and 500 ml 
of 2N hydrochloric acid. There is then isolated from the aqueous phase, by 
rendering alkaline with concentrated ammonia (ice-cooling) and extracting 
with ethyl acetate, crude 
2,3-dihydro-2,2-dimethyl-7-[(2-benzylamino)-propoxy]-4H-1,3-benzoxazin-4-o 
ne in the form of oil, which can be further processed in the crude state. 
(43d) A mixture of 100 g of crude 
2,3-dihydro-2,2-dimethyl-7-[(2-benzylamino)-propoxy]-4H-1,3-benzoxazin-4-o 
ne, 100 ml of isopropanol and 100 ml of isopropylamine is refluxed for 1 
hour, and then concentrated by evaporation. The oil remaining behind 
crystallises on trituration with ether. The crystals are filtered off with 
suction, and washed with a small amount of isopropanol to thus yield 
4-[2-(benzylamino)-propoxy]-salicylamide, m.p. 121.degree.-123.degree.. 
(43e) A solution of 19.0 g of 4-[2-(benzylamino)-propoxy]-salicylamide and 
12.4 g of 4-(2,3-epoxypropoxy)-nitrobenzene in 300 ml of isopropanol is 
refluxed for 20 hours. After the addition of a further 1.2 g of 
4-(2,3-epoxypropoxy)-nitrobenzene, refluxing is continued for a further 20 
hours. The solvent is subsequently partially evaporated off, whereupon 
1-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-benzylamino]-3-(4- 
nitrophenoxy)-2-propanol, m.p. 160.degree.-164.degree. (diastereoisomeric 
mixture) crystallises out. 
(43f) A solution of 19.0 g of the resulting compound in 380 ml of dioxane 
is hydrogenated, with the addition of 18 g of Raney nickel in 4 portions, 
under normal conditions, until 3 mol-equivalents of hydrogen have been 
absorbed. After filtration and subsequent concentration by evaporation of 
the filtrate, there remains behind crude 
1-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-benzylamino]-3-(4- 
amino-phenoxy)-2-propanol in the form of orange-brown oil, which can be 
further processed without additional purification. 
(43g) 16 g of the compound obtained are dissolved in 90 ml of anhydrous 
pyridine, and to the solution are added dropwise, with cooling to 
5.degree.-10.degree., 4.4 g of methanesulfonic acid chloride. The reaction 
mixture is stirred for 4 hours at room temperature; the solvent is then 
evaporated off, and the residue is distributed between 400 ml of ethyl 
acetate and 50 ml of water. The organic phase is washed three times with 
50 ml of water each time and dried over magnesium sulfate; it is 
subsequently treated with charcoal, and concentrated by evaporation to 
yield crude 
1-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl]-benzylamino]-3-(4- 
methanesulfonylamino-phenoxy)-2-propanol in the form of orange-coloured 
oil, which can be further processed without additional purification. 
EXAMPLE 44 
A solution of 30 g of crude 
1-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-benzylamino]-3-[4-[2-(cyclo 
propylmethoxy)-ethyl]-phenoxy]-2-propanol in 600 ml of methanol is 
hydrogenated, with the addition of 4 g of a Pd/C catalyst (5%), under 
normal conditions until 1 mol-equivalent of hydrogen has been absorbed. By 
the addition of dioxane and by heating, the product which has already 
crystallised out is taken into solution; the catalyst is filtered off and 
the filtrate is concentrated by evaporation. Recrystallisation from 
isopropanol and then from methanol yields pure 
1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-[4-[2-(cyclopropylmetho 
xy)-ethyl]-phenoxy]-2-propanol, m.p. 149.degree.-150.degree.. 
The starting material is produced in the following manner: 
(44a) By application of the method described by Irvine et al., Synthesis 
1972, 568, 2,5-dihydroxy-benzamide is converted, using an excess of 
acetone, into 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one, 
m.p. 215.degree.-216.degree.. 
(44b) 70 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazin-4-one in 
400 ml of acetonitrile with 100 g of potassium carbonate and 32 ml of 
chloroacetone are stirred under reflux for 30 hours. After the addition of 
a further 3.2 ml of chloroacetone, the reaction mixture is refluxed for a 
further 15-20 hours. The reaction mixture is filtered whilst still warm; 
the residue is thoroughly washed with acetone, and the combined filtrate 
is concentrated by evaporation. The crystalline residue is recrystallised 
from toluene and yields 
2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one, m.p. 
125.degree.-126.degree.. 
(44c) 74 g of the resulting 
2,3-dihydro-2,2-dimethyl-6-(2-oxo-propoxy)-4H-1,3-benzoxazin-4-one in a 
mixture of 150 ml of dioxane and 450 ml of 2N hydrochloric acid are heated 
for 45 minutes on a water bath. The solvent is evaporated off, and the 
crystalline residue is triturated with water and then filtered off with 
suction. Recrystallisation from isopropanol yields 
5-(2-oxo-propoxy)-salicylamide, which has a melting point of 
152.degree.-154.degree.. 
(44d) 55 g of benzylamine and 1.25 g of conc. sulfuric acid are added to a 
solution of 104.5 g of 5-(2-oxo-propoxy)-salicylamide in 1000 ml of 
methanol, and the mixture is hydrogenated, in the presence of 3.0 g of a 
Pt/C catalyst under normal conditions until 1 equivalent of hydrogen has 
been absorbed. The catalyst is filtered off, and the solution is then 
stirred up with about 10 g of pulverised calcium carbonate; the mixture is 
again filtered, and concentrated by evaporation. The oil remaining behind 
crystallises from isopropanol. Repeated recrystallisation from isopropanol 
yields 5-[2-(benzylamino)-propoxy]-salicylamide, m.p. 
102.degree.-104.degree.. 
(44e) A solution of 14.3 g of 
1-[2-(cyclopropyl-methoxy)-ethyl]-4-(2,3-epoxypropoxy)-benzene (German 
Offenlegungsschrift No. 2,649,605) and 16.3 g of 
5-[2-(benzylamino)-propoxy]-salicylamide in 200 ml of isopropanol is 
refluxed for 18 hours. The reaction mixture is concentrated by evaporation 
to leave crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylamino]-3-[4-[2-(cyclop 
ropylmethoxy)-ethyl]-phenoxy]-2-propanol in the form of brown oil, which 
can be further processed without additional purification. 
EXAMPLE 45 
The following compounds are prepared in a manner analogous to Example 43: 
1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-(4-methanesulphonylamino 
-phenoxy)-2-propanol; 
1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-1-methyl-ethylamino]-3-(4-methanesulph 
onylamino-phenoxy)-2-propanol. 
EXAMPLE 46 
A mixture of 11.5 g of 4-(2,3-epoxy-propoxy)-cinnamic acid-N-methylamide 
and 7.4 g of 5-(2-aminoethoxy)-salicylamide is dissolved in 50 ml of 
dimethyl sulfoxide heated to about 80.degree.; the solution is stirred for 
1 hour at 75.degree.-85.degree., and is then poured into 500 ml of water. 
The resinous product which precipitates is separated and stirred up with 
150 ml of ethyl acetate. The precipitating crystals are filtered off with 
suction, and recrystallised from a small amount of isopropanol to thus 
obtain 
4-[3-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-2-hydroxypropoxy]-N-me 
thylcinnamic acid amide, m.p. 170.degree.-171.degree. (sinters from 
148.degree.). 
EXAMPLE 47 
A solution of 41 g of crude 
1-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-benzylamino]-3-[4-N-methyl- 
methanesulfonylamino)-phenoxy]-2-propanol in 410 ml of methanol is 
hydrogenated, in a manner analogous to that described in Example 4, in the 
presence of 4 g of palladium-on-charcoal catalyst and subsequently 
processed. The product obtained after recrystallisation from ethanol and 
methanol is 
1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-[4-(N-methyl-methanesul 
phonylamino)-phenoxy]-2-propanol, m.p. 120.degree.-121.degree.. 
The starting material is produced in the following manner: 
(47a) 77 ml of methanesulfonic acid chloride are added dropwise in the 
course of about 30 minutes, with ice-cooling and stirring, to a solution 
of 103.7 g of 4-methylaminophenol sulfate in 330 ml of pyridine and 102 ml 
of N,N-diisopropylethylamine, and the mixture is stirred overnight at room 
temperature. The volatile constituents are evaporated off, and the residue 
is distributed between ethyl acetate and water; the organic phase is 
subsequently separated and concentrated by evaporation, and the 
crystalline residue is heated with 300 ml of 6N sodium hydroxide solution 
on a water-bath until completely dissolved. The solution is filtered, and 
the pH-value is adjusted to 2 with concentrated hydrochloric acid, 
whereupon 4-(N-methylsulfonylamino)-phenol precipitates in crystalline 
form. It is filtered off with suction and dried in vacuo at 80.degree., 
m.p. 135.degree.-136.degree.. 
(47b) A mixture of 34.2 g of the compound obtained according to Example 
(47a) 35.2 g of potassium carbonate and 125 ml of epichlorohydrin is 
stirred and refluxed for 2 hours. The suspension is filtered, the filtrate 
is concentrated by evaporation and distributed between ethyl acetate and 
water; the organic phase is then separated, dried over magnesium sulfate, 
and concentrated by evaporation to thus obtain 
4-(2,3-epoxy-propoxy)-N-methylmethanesulfonanilide, m.p. 
96.degree.-100.degree. (from methanol). 
(47c) A solution of 19.0 g of the compound obtained according to Example 
(47b) and 21.4 g of 5-(2-benzylaminoethoxy)-salicylamide in 350 ml of 
isopropanol is refluxed for 5 hours. The product obtained after 
concentrating by evaporation is crude 
1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylamino]-3-[4-(N-methyl- 
methanesulfonylamino)-phenoxy]-2-propanol in the form of viscous oil, which 
is further processed as such.