NO812736L - DERIVATIVES OF 3-AMINO-1,2-PROPANDIOL. - Google Patents

Description

The invention relates to new derivatives of 3-amino-1,2-propanediol, methods for their preparation, pharmaceutical preparations containing such compounds, and their use for the preparation of pharmaceutical preparations

rates, or as pharmacologically active compounds.

The invention has a formula

in which R.j.| means polyhydroxy lower alkyl, cycloalkyl lower - alkoxy lower alkyl, in the ^--position bonded lower alkyl sulfonyl - amino or in the 4--position bonded in a lower alkylcarbamoyl-2-vinyl, and alk means residues with the formulas -CHp-CHp or

The invention also includes salts of such compounds.

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

Cycloalkyl has 3-7, especially 3-5 carbon atoms as ring members. Lower alkyl is e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl. Polyhydroxy lower alkyl can occupy any of the possible positions in the phenyl ring, and is e.g. dj- or trihydroxy lower alkyl,

as 1,2-dihydroxy- or 2,3-dihydroxy lower alkyl, e.g. 1,2-dihydroxy or 2,3-dihydroxypropyl.

Cycloalkyl lower alkyl lower alkyl can substitute each of the possible positions in the phenyl ring, and is e.g. cycloalkyllower oxymethyl or 1- or 2-(cycloalkyllower-

alkoxy ) -ethyl.

Lower alkyl sulfonylamino corresponds to the formula lower alkyl-SO2-N(R^2)-, in which R^2 means hydrogen or lower alkyl, and consequently means e.g. ethyl sulfonylamino and in particular means sulfonylamino, further, however, also N-methyl-methyl sulfonylamino. 1-lower alkylcarbamoyl-2-vinyl is e.g. 1-ethylcarbamoyl- and especially 1-methylcarbamoyl-2-vinyl.

Phenyl which has the amide and hydroxy group is connected to the remaining molecule so that the latter is bound in the 4- position of said phenyl, i.e. in the para-position to the amide group, and above all in the 5-position of said phenyl, (i.e. para-position to the hydroxy group).

New compounds may exist in the form of salts such as their acid addition salts, and primarily their pharmaceutically usable non-toxic acid addition salts. Suitable salts are e.g. those with inorganic acids, such as haldgen - hydrogenic acid, e.g. hydrochloric acid, or hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, hydroxymaleic acid, d>rue acid, fumaric acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, embonic acid, methanesulfonic acid , ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethylenesulfonic acid, toluenesulfonic acid, naphthalene sulfonic acid, or sulfanilic acid, or with other acidic organic substances such as ascorbic acid.

The new compounds have valuable pharmacological properties. In particular, they act in a specific way on 3-adrenergic receptors. The basis for this effect is, as a general property of the compound of formula I, the affinity of these receptors, which manifests as a lack or very little stimulating intrinsic effect as pure blockade, with a small to moderate stimulating intrinsic effect as blockade, with simultaneous ISA, i.e. intrinsic sympathomimetric activity.

Compound of formula I has a blocking effect on adrenergic 3-reseptors with pronounced cardio-selectivity, which can be determined in particular with such substances which are substituted in the 4-position of the phenyl ring with lower alkyl sulfonylamino-, e.g. methylsulfonylamino or with 1-lower alkylcarbamoyl-2-vinyl, e.g. 1-methylcarbamoyl-2-vinyl, while such substances whose phenyl ring is substituted with cycloalkyl lower oxy-1 averealkyl, e.g. cyclopropylmethoxyethyl, has a less pronounced cardioselectivity. The compounds of formula I further cause a blockade of vascular 3-receptors, which can be determined in particular with those substances whose phenyl ring is substituted with polyhydroxy lower alkyl, e.g. 2,3-dihydroxypropyl, or with cycloalkyl lower oxy -lower alkyl, e.g. cyclopropylmethyloxyethyl, as both with these compounds and also with those which have a lower alkylsulfonyamino-, e.g. a methylsulfonylamino group, or a 1-1 averealkyl-carbamoyl-2-vinyl-, e.g. a 1-methylcarbamoyl-2-vinyl group, is present as an additional effect one more. or less pronounced blockade of tracheal 3 receptors.

Compound of formula I with a polyhydroxy lower alkyl, e.g. a 2, 3-dihydroxypropyl group also shows a more or less pronounced ISA, the additional effect being a blood pressure reduction. This latter effect can also be demonstrated on compounds with a lower alkyl sulfonylamino -, e.g. a methylsulfonylamino group in the phenyl ring.

The above-mentioned indications regarding pharmacological properties are based on the results of corresponding pharmacological tests in the usual test procedure. Thus, the new 3-blocking compounds show an inhibition, which with the help of isoproterenol induces tachycardia on isolated guinea pig hearts in a concentration range from approx. 0.001 ug/ml to approx. 3Ug/

ml, and on a cat drugged with reserpine pre-treated in a dose range from approx. 0.001 mg/kg to approx. 10 mg/kg by intravenous administration. The blockade of vascular 3-receptors is demonstrable by inhibition of the isoproterenol-induced vasodilatation in the vascular area of the A. femoralis in anesthetized with reserpine pre-treated cats by intravenous administration

in a dose range from approx. 0.003 mg/kg to approx. 30 mg/kg.

The blockade of tracheal 3 receptors caused by a compound of formula I can be demonstrated by means of inhibition of the relaxation induced by isoprenaline on the isolated guinea pig trachea in a concentration range from approx.

0.001u Mol/liter to approx. 30u Mol/liter.

ISA of the 3-blocking compound of formula

I is shown when the increase in the basal heart rate in cats pretreated with narcotized reserpine, which e.g. can be shown by intravenous administration of 1-l_ 2 - (3 ( -carbamoyl -4--hydroxy -phenoxy) -ethyl amino /- 3-/2 - (2, 3-dihydroxypropyl) -phenoxy_/ -2-propanol in a dose range of about 0.001 mg/kg to about 1 mg/kg.

The new 3-blocking compounds work further

in a dose range of approx. 0.03 mg/kg to approx. 30 mg/kg i.v., a lowering of the arterial blood pressure in anesthetized cats.

The new compounds of formula I can consequently be used as partially cardioselectively active 3-receptor blockers, e.g. for the treatment of heart rhythm disorders, angina pectoris, and hypertension.

The compounds with the general formula I can also be used as valuable intermediates for the production of other valuable, especially pharmaceutical active compounds.

The invention relates in particular to a compound of formula I, in which R,... means di- or trihydroxy lower alkyl, cycloalkyl lower alkyl with up to 4 carbon atoms in the lower alkyl part, in the 4-position bonded lower alkylsulfonylamino- or W-lower alkyl -lower alkyl sulf onylamino with up to 4 carbon atoms in each lower alkyl part, or in the 4-position bonded 1-lower alkylcarbamoyl-2-vinyl with up to 4 carbon atoms in the lower alkyl part and alk means residues with formula

-CH 2 -CH 2 - or CH 2

-CH-CH2-

or salts, especially acid addition salts, above all pharma-

cosmetically usable non-toxic acid addition salts thereof.

The invention relates in particular to the compounds of formula I in which R... denotes 1,2-dihydroxy- or 2,3-dihydroxylower alkyl, cycloalkyllower oxymethyl or 1- or 2-(cycloalkyllower oxy)-ethyl, in the 4-position bonded lower alkyl sulfonylamino with up to 4-carbon atoms where R.J2 means hydrogen, or in the 4-position bonded 1-ethylcarbamoyl-2-vinyl or 1-methylcarbamoyl-2-vinyl and alk means

the remainders with formula

or salts, especially acid addition salts, above all pharmaceutically usable non-toxic acid addition salts thereof. The invention relates in particular to compounds of formula I in which R.,,, means 1,2-dihydroxy or 2,3-dihydroxylower alkyl with up to 4 carbon atoms, e.g. 1,2-dihydroxy-or 2,3-dihydroxypropyl, 1- or 2-(cycloalkyllower oxy)-ethyl with 3-5 carbon atoms in the cycloalkyl part, e.g. 1- or 2- (cyclopropylmethoxy)-ethyl in the 4-position bonded lower alkyl sulfonylamino with up to 4- carbon atoms, where R^2 means hydrogen, e.g. methylsulfonylamino, or 1-methylcarbamoyl-2-vinyl, and alk means residues with the formulas

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

The new compounds of formula I are prepared on

in and of itself known manner. They can e.g. is produced as a compound of formula

is reacted with a compound of formula

in which one of the groups Z., and Zr, means a reactive esterified hydroxy group, and the other means the primary amino group, and X.j means hydroxy, or in which and Z^ together means the epoxy group, and Z^ means the primary amino group,

and if desired, a formed free compound is transferred to a salt, or a formed salt to a free compound, and/or if desired, a formed isomer mixture is divided into the isomers or a formed racemate in the antipode.

A reactive esterified hydroxy group Z^resp, Z2 is a hydroxy group esterified\ with a strong acid, especially a strong inorganic acid such as a hydrohalic acid, especially chlorobromic or hydroiodic acid or sulfuric acid, or a strong organic acid, especially a strong organic sulfonic acid which an aliphatic or aromatic sulphonic acid, e.g. methanesulfonic acid, 4,-methylphenylsulfonic acid or 4-bromophenylsulfonic acid, and primarily means halogen, e.g. chlorine, bromine or iodine, or aliphatic or aromatic substituted sulfonyloxy, e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy.

The above-mentioned reaction is carried out in a manner known per se, particularly when using starting material with a reactive esterified hydroxy group, work is preferably carried out in the presence of a basic agent such as an inorganic base, e.g. an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent such as an alkali metal lower-area alkanolate, and/or an excess of the basic reactant, and usually in the presence of a solvent or solvent mixture, and if necessary under cooling or heating, e.g. in a temperature range from approx. -2 0UC to approx. +150 C in an open or closed vessel, and/or in an inert gas atmosphere, e.g. in nitro-

genatmo sphere.

Starting material f f is of formula II is combed,, or

can be produced in a manner known per se.

Starting substances with formula III can e.g. is obtained by reacting a hydroxysalicylamide with a dihaloalkalan corresponding to the meaning of alk, e.g. a chlorobromo or dibromoalkane in the presence of an alkaline condensing agent such as an alkali carbonate. The setups are carried out in the usual way, with protective groups placed at the hydroxy group being cleaved at the same time or, as discussed below, afterwards.

The compounds of formula I can further be prepared as a compound of formula

in which R.|!j has the meaning of R-|-|>or means in the ^--position bonded at nitrogen by means of a with hydrogen replaced-

bare substituent, substituted lower alkylsulfonylamino,

X2, J- y X^ and X^ each represent hydrogen, or one with hydro-

gene replaceable substituent, or X2 and X^ and/or X^ and X^ together means a 2-valent with 2-hydrogen atoms replaceable residue, with the precaution that at least one of the residues X^» f'

\ y X^,: and X^ is different from hydrogen, or at least R^ means in the ^.-position bonded to the nitrogen atom with a hydrogen-replaceable substituent, substituted lower alkylsulfonylamino, or at least X2 and X^ together or X ^ and X^together with a 2-valent residue replaceable by 2 hydrogen atoms, or a salt thereof, they are split off from hydrogen or separate groups, X2, ly X^and X^resp. X2and X^together and/or X^and X^together must be replaced by hydrogen atoms and/or one with the nitrogen atom of bonded in the 4- position

in lower alkyl sulfonylamino R^ |)>placed with hydrogen eratable substituent is replaced with hydrogen, and if desired, the aforementioned in connection with the first method are carried out

extra progress baby steps.

Cleavage of the groups Xg, Xy X^or X^ or each time and X^and/or X^ and X^together, as well as of the 1

a 4- -lower alkyl sulfonylamino group at nitrogen atom-placed substituent is carried out by means of solvolysis, such as hydrolysis, alcoholysis or acidolysis, or by means of reduction including hydrogenolysis.

A particularly suitable cleavable group X^or

X^falls one in a 4- -lower alkyl sulfonylamino group at the nitrogen atom bound protecting group, is in the first row a hydrogenolytically cleavable α-aryl lower alkyl group, as an optionally substituted 1-polyphenyl lower alkyl or 1-phenyl lower alkyl group, in which the substituents especially of the phenyl part can be e.g. lower alkyl, such as methyl or lower alkoxy such as methoxy, and primarily benzyl. A group X^ and especially X2 and X^, as well as a nitrogen protecting group in a 4- -lower alkyl sulfonylamino group, can also be-

ty a solvolytic, such as hydrolytic, or acidolytic, further a reductive including hydrogenolytically cleavable residue, especially an acyl residue corresponding to the acyl residue of an organic carboxylic acid, e.g. lower alkanoyl such as acetyl or aryl such as benzoyl, further the acyl residue of a half-ester of carbon-

acid such as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl, or tert-butyloxycarbonyl, 2-halo-lower oxycarbonyl, e.g. 2, 2, 2-trichloroethoxy carbonyl or 2-iodoethoxycarbonyl, optionally substituted 1-phenyl lower oxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyloxycarbonyl, further an optionally substituted 1-polyphenyl lower alkyl group, in which the substituents in the first row of the phenyl part, e.g. has the above meaning, and primarily means trityl.

A cleavable residue formed with X2°S and/or X^ and X^ together is primarily a hydrogenolytically cleavable group which is optionally substituted 1 -phenyl -lower alkyli-, the one in which the substituents especially of the phenyl part, e.g. can be lower alkyl or lower alkoxy, and especially benzylidene, as well as solvolytically, especially hydrolytically cleavable groups such as lower alkylidene, e.g. methylene or isopropylidene, or 1-phenyl-lower alkylidene, whose phenyl part is optionally substituted with lower alkyl, such as methyl or lower alkoxy,

such as methoxy, especially benzylidene or cycloalkylidene, e.g.

e.g. cyclopentylidene or cyclohexylidene.

In the form of salts, usable starting materials f are, used primarily in the form of acid addition salts, e.g.

e.g., with mineral acid, as well as with organic acids.

Hydrogenolytically cleavable residues X^, Xy X^ and/or Xy especially optionally substituted 1-phenyl lower - alkyl group, further also suitable acyl groups, such as optionally substituted 1-phenyl lower real oxycarbonyl, as well as with the help of the groups X^ and X^ as well as X^ and X^ optionally substituted 1-phenyllower alkylidene groups formed together, as well as in a 4-lower alkylsulfonylamino group placed at the nitrogen protecting group, this type can be cleaved by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a nickel catalyst such as Raney nickel, or a suitable noble metal catalyst.

Hydrolytically cleavable groups X2>Xy X^and/or Xy as acyl residues of organic carboxylic acids, e.g. lower alanoyl, and of half-esters of carboxylic acid, e.g. lower alkoxy car bonyl, further e.g. trityl residues, as well as with the help of the residues X2 and X^ and/or X^ and X^ together formed lower alkylidene, 1-phenyl-lower alkylidene or cycloalkylidene groups, as well as the nitrogen protecting groups present in a 4--lower alkyl sulfonylamino group of this type, depending on the type, such residues can be split off by treatment with water under acidic or basic conditions, e.g. in the near-

be of a mineral acid, such as hydrochloric or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or

-carbonate, or an amine such as isopropylamine.

Acidolytically cleavable residues X2, Xy X^and/or X^and/or a nitrogen protecting group present in a 4. -lower alkyl sulfonylamino group are in particular certain acyl residues and half-esters of carboxylic acid, such as e.g. tert.-1 avereal oxycarbonyl or optionally substituted diphenyl-methoxycarbonyl residues, furthermore also a tert.-lower alkyl residue, such residues can be cleaved by treatment with suitable strong organic carboxylic acids, such as optionally with halogen, especially fluorine, substituted lower alkane carboxylic acids, primarily with trifluoroacetic acid, ( if necessary in the presence of an altivating agent such as anisole), as well as with formic acid.

By reductively cleavable residues X,-,, X^>X^ and/or X<-, and/or a nitrogen-protecting group in a 4--lower alkylsulfonylamino group, are also understood such groups which are cleaved by treatment with a chemical reducing agent (especially with a reducing metal, or a reducing metal compound see ). Such residues are in particular 2-halogen lower oxycarbonyl or arylmethoxycarbonyl, such as e.g. can be split off by treatment with a reducing heavy metal such as zinc, or with a reducing heavy metal salt, such as met chromium (II) salt, e.g. -chloride or -acetate, usually in the presence of an organic carboxylic acid, such as formic or acetic acid, and of water.

Nitrogen protecting groups that stand at the nitrogen atom of a 4- -lower alkyl sulfonylamino group R !j ^ correspond to the previously mentioned, and with the help of the mentioned methods, groups that can be removed and replaced with hydrogen, as such groups during the mentioned method, are removed at the same time with other groups, or later, in a separate progression, gradually entered.

The above-mentioned reactions are usually carried out in the presence of a solvent, or solvent-mixture, since suitable reaction participants can also act as such at the same time, and if necessary during cooling or heating, e.g. in an open or closed vessel, and/or in an inert gas atmosphere, e.g. nitrogen.

Starting substances with formula IV can be formed analogously to the above-mentioned process modifications, e.g. when treating a compound of formula

or a salt thereof, with a compound of formula in which X^ represents the group X^, at least one of the groups X^ and X^ being different from hydrogen, and X° means a reactive esterified hydroxy group, or X^ and X° together mean a carbon-oxygen bond, or in which X^and X^together mean a separable two, with oxygen- or hydrogen atoms connected to the nitrogen atom replaceable residue, and X° means a reactive esterified hydroxy group, or by treating a compound of formula with a compound of formula

in which X^ has the meaning given above for X^, and one of the groups and Y2 means a reactive esterified hydroxy group, and the other means the group of formula -NH(X^), in which X^ has the above-mentioned meaning, with the precaution that at least

one of the groups X^ and X2 is different from hydrogen, or in which X2 and Y- means an oxygen-carbon bond and Y2 means the group of formula -NH(X^), and X^ is different from hydrogen. The above-mentioned reactions are carried out in a manner known per se

e.g. as discussed under the first method alternative according to the invention.

You can further e.g. reduce it with turnover of compound with formula

with a carbonyl compound of formula

in which R means a to the allylene residue alk corresponding to a carbonyl group separated from an oxygen atom by a carbon atom formed alkyl residue and X^ and X^ or X^ and X^ together means one of the indicated protecting groups, formed Schiff's base with a borohydride , e.g. sodium borohydride to compound of formula IV. The reduction can also take place using activated hydrogen in the presence of a hydrogenation catalyst,

e.g. a platinum on charcoal catalyst.

Carbonyl compounds of formula IVe can again be obtained in the usual way by reaction with a compound with

for flour

with a compound of formula R-Hal (IVg), in which R has the above meaning, and e.g. means a halogen ketone, e.g. at oraceton.

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

where X^means a reducible group of formulas

-CH = N - alk - (Va), resp.

-CH2- N = alk1- (Vb)

where alk means an alkyl ylidene residue corresponding to the residue alk,

and Xy means hydrogen or a residue replaceable by hydrogen under the conditions for reduction of X^, R^ has the meaning of R-j-j» or means in the 4-position bonded with a nitrogen atom a hydrogen-replaceable substituent, Xy substituted lower alkyl sulfonylamino, in which Xy has the above-mentioned meaning, since X^ always means a reducible group Va or Vb, this group is reduced, and at the same time it is cleaved from hydrogen different groups Xy, and replaced with hydrogen, if desired, in connection with the first method, the aforementioned X from method step .

A hydrogenolytically cleavable group Xy is primarily an α-aryl lower alkyl group, such as an optionally substituted 1-phenyl lower alkyl group, in which the substituents of the phenyl part, for example, can be lower alkoxy, such as methoxy, and especially benzyl.

Nitrogen protecting groups Xy in a 4--lower alkyl sulfonylamino group R!^ correspond to those previously mentioned for Xy, and with the help of the mentioned methods, groups that can be removed, and groups that can be replaced with hydrogen, as such groups are removed during the described procedure at the same time with other groups, or later in a separate 'progressive step'.

Output s substance is with f or meil V with a group X^

of formula Vb can also exist in the isomeric form of ring tautomers of formula

in which alkg corresponds to the meaning of alk.], and oxygen-

and the nitrogen atom of the ring is bonded to the same carbon atom.

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

The reduction of the nitrogen-carbon double bond in the starting substances of formula V, which as X^ contains a group Va or Vb, while Xy has the meaning given under formula V to nitrogen-carbon single bond, can take place on

in and of itself known way, e.g. by treatment with catalytically activated hydrogen, such as hydrogen in the presence of a suitable hydrogenation catalyst, e.g. a nickel-platinum or palladium catalyst, with hydrogenolytically cleavable groups Xy being cleaved off at the same time, and replaced with hydrogen, or one works with a suitable hydride reducing agent, such as an alkali metal borohydride, e.g. sodium borohydride. When using hydride reducing agents, acyl residues of carboxylic acids such as e.g. of acetic acid are present as residues Xy, and are split off in the same work step.

A starting material of formula V can be produced in a manner known per se, possibly in situ, i.e. under the conditions of the described procedure. Thus, a compound with formula can

is reacted with an amine of formula

to a starting product of formula V with the group X^ of formula Va.

When reacting a compound with formula

with a carbonyl compound of formula

can one arrive at starting material f et with formula V, with a group X^ of formula Vb,. A modification of these reactions consists in reacting a dibenzylamino compound corresponding to the compound of formula Vh with the oxo compound of formula Vi under the reducing conditions of the process. In this way, catalytically activated hydrogen is primarily used as reducing agents, e.g. hydrogen in the presence of a heavy metal hydrogenation catalyst or a mixture thereof, such as a palladium and/or platinum catalyst. Under such reaction conditions, hydrogenolytically cleavable groups Xy, e.g. benzyl groups, and at the same time the nitrogen-carbon double bond is reduced to the corresponding nitrogen-carbon single bond.

Oxo-compounds with formula We are on the other handODDnåelio- e.g. by turnover with a compound of formula

with a haloalkanone compound of the above-mentioned formula R-Hal (IVf), e.g. chloroacetone in the presence of an alkaline condensing agent, e.g. potassium carbonate or an organic base such as triethylamine;... The new compounds of formula I can also be obtained as a compound of formula

in which R<!>j^ has the meaning of R-]-]»or means in the 4-position optionally bonded at the nitrogen atom with a cleavable by means of ammonolysis or with a hydrogen-replaceable substituent, substituted lower alkylsulfonylamino, Xg means hydrogen, or by by means of ammonolysis, a group that can be split off, or a reactive derivative of a carboxylic acid defined in formula VI is reacted with ammonia, (VII) and at the same time any remaining residues Xg are split off,

or at the nitrogen of a 4- -lower alkyl sulfonylamiho group placed substituent, is replaced with hydrogen, and if desired they are then carried out in connection with the first process^-

manner mentioned additional method steps.

Ammonolytically cleavable substituents and residues

Xg are acyl residues of organic carboxylic acids, e.g. aroyl

such as benzoyl or lower alkanoyl such as acetyl.

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

Reactive derivatives of carboxylic acids of formula VI are especially esters, e.g. with lower alkanols such as methanol, ethanol, isopropanol, tert.-butanol, further with aryl lower alkanols, e.g. optionally with lower alkyl, e.g. methyl, or lower alkoxy, e.g. methoxy, substituted benzyl alcohol, or phenols, which are optionally activated with suitable substituents, e.g. with halogen, e.g. 4-halogen such as 4-chloro, lower alkoxy, e.g. 4-lower oxy, such as 4-methoxy, 4-nitro, or 2,4-dinitro, such as e.g. 4-chlorophenol, 4-methoxy enol, 4-nitino- or 2,4-dinitro-phenol, further with cycloalkanols, such as e.g. cyclopentanol or cyclohexanol, which may optionally be substituted with lower alkyl, e.g. methyl. The reaction is carried out in a manner known per se, usually in the presence of an inert solvent, e.g. in the temperature range from approx. -10° to + 50°C in a closed vessel.

The starting substances of formula VI can be formed in a manner known per se, as a compound of formula II in which and together means the epoxy group is reacted with an amino compound of formula

wherein Xg has indicated meaning, or a reactive derivative thereof. Furthermore, it can by reacting a compound of formula with a carbonyl compound of formula

in which R means a to an alkylene residue Alk corresponding instead of its free valence to an oxo residue containing an alkyl residue formed Schiff's base, is reduced with a borohydride, e.g. sodium

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

a platinum on charcoal catalyst.

Carbonyl compounds of formula VIc can again be obtained by reacting a compound of formula

with a compound of the above-mentioned formula in which Hal means halogen, especially chlorine, in a manner known per se. The new compounds of formula I can likewise be obtained in that in a compound of formula in which one or all hydroxy groups and/or secondary nitrogen atoms and/or lower alkyl sulfonyl-amino R^ bound in the 4-position is substituted at the nitrogen atom optionally by means of such by means of hydrolysis-cleavable and hydrogen-replaceable groups, which are cleaved off under process conditions, and replaced with hydrogen, the group -CN is converted by means of hydrolysis to the group -CONH2, and at the same time a lower alkyl sulfonylamino group bonded in the 4- position is optionally cleaved off at the nitrogen atom and/or with one or all. - hydroxy groups and/or protective groups placed on secondary nitrogen atoms are split off and replaced with hydrogen, if desired, the extra progress mentioned in connection with the first method is carried out.

The above-mentioned reactions are carried out in a manner known per se. The hydrolysis is carried out in a basic or stepwise in an acidic medium, especially in the presence of a concentrated aqueous mineral acid, such as e.g. concentrated hydrochloric acid, and if necessary during cooling or heating, e.g.

in a temperature range of approx. 0 to 60°C, preferably on

about. 4-0-$0°C in an open or closed vessel, and/or in an inert gas atmosphere, e.g. in a nitrogen atmosphere.

Starting substances with formula VII can be e.g. obtained by reaction of compound with formula

with a compound of formula

where Hal means chlorine, bromine or iodine. The reaction is preferably carried out in the presence of a basic agent in a manner known per se. The compound with Vllb can again be obtained by the action of acetic anhydride on the oxime corresponding to the cyanide. It is conveniently done by boiling under reflux. The oxime, on the other hand, can be obtained from the corresponding aldehyde by boiling with hydroxylamine hydrochloride in the presence of alcoholic soda solution under reflux. The corresponding aldehyde can in turn be obtained by reacting 2,4-dihydroxybenzaldehyde with an a,co-dihalolower alkane, preferably in the presence of a basic agent. However, it is also possible to convert a hydroxy salicylonitrile in an analogous way, e.g. 2,4-dihydroxybenzonitrile /_Chem. Pray. 24-, 3657 (1 89.1 )7 or 2,5-dihydroxybenzonitrile /Heiv. Chem. Acta 30, 14-9, 153 (1 94-8)/ with a non-geminal dihalolower alkane to a compound of formula Vllb.

The new compounds of formula I in which R 1 means polyhydroxy lower alkyl, e.g. 1,2-dihydroxy- or 2,3-dihydroxy lower alkyl such as e.g. 1,2-dihydroxy- or 2,3-dihydroxypropyl or can be obtained by using in a compound of formulaOTT

in which R<!j!>|means a polyhydroxy lower alkyl group, e.g.

one of the aforementioned, in which at least one or two hydroxy groups together, each of which stands at two neighboring carbon atoms, is protected with a cleavable and hydrogen-replaceable residue, or a salt thereof, these protective groups, which may be the same or different, are cleaved off and even

tually further, protective groups placed at the nitrogen atom and/or at the oxygen atom are replaced with hydrogen and, if desired, the additional method steps mentioned in connection with the first method are carried out. Cleavable and replaceable with hydrogen, e.g. by means of solvolysis such as hydrolysis, alcoholysis or acidolysis, or by reduction including hydrogenolysis, e.g. as mentioned above., cleavable groups, are e.g. the above-mentioned residues Xg or X^. Solvolytically or hydrolytically or acidolytically cleavable residues. X^ or X^ are, for example, acyl residues such as acyl residues of organic carboxylic acids, e.g. lower alkanoyl, such as acetyl or aroyl, such as benzoyl, further e.g. lower alkoxy carbonyl, optionally substituted 1-phenyl lower oxycarbonyl, e.g. benzyloxycarbonyl, further an optionally substituted 1-polyphenyl lower alkyl group, e.g. trityl,

and furthermore the tetrahydropyranyl residue. In the case of two neighboring hydroxy groups consisting of shuttle groups, e.g. the lower alkylidene, e.g. methylene or isopropylidene, or 1-phenyl lower alkylidene, whose phenyl part is optionally substituted with lower alkyl, such as methyl or lower alkoxy such as methoxy, especially benzylidene or cycloalkylidene, e.g. cyclopentyl i -

the or cyclohexylidene, further the carbonyl group.

Hydrolytically cleavable groups of indicated

type, e.g. acyl residues >of organic carboxylic acids, e.g. 1averealkanoyl residues, further e.g. lower alkoxycarbonyl or trityl residues, further tetrahydropyranyl residues, further to two lower alkylidene-1-phenyl-lower alkylidene or cycloalkylidene groups linked by the hydroxy group, as well as possibly additional protective groups of this type placed at the nitrogen atom and/or at the oxygen atoms, depending on the type of such residues, can be cleaved by treatment with water under acid or basic conditions, e.g. in the presence of a mineral acid such as hydrochloric or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonate. A carbonyl group consisting of two adjacent hydroxy groups is appropriately cleaved off with the aid of basic agents, e.g. an alkali hydroxide such as potassium hydroxide, or an alkali metal alcoholate such as sodium methylate! or potassium tert.-butylate, while e.g. tetrahydrofuranyl residues are cleaved off with acidic agents, e.g. as indicated. Acidolytically cleavable residues are e.g.<;>. mentioned above for Xg and/or X^ and is, for example, low is al/coc sy carbonyl or also tert-lower alkyl residues. Such residues can be split off as mentioned above by treatment with suitable strong organic carboxylic acids, such as optionally with halogen, especially fluorine, substituted lower alkane carboxylic acids, primarily with trifluoroacetic acid (when necessary in the presence of an activating agent such as anisole), as well as with formic acid. These transactions are carried out in a manner known per se.

A particularly suitable hydrogenolytically cleavable hydroxy protecting group is primarily a hydrogenolytically cleavable α-aryl lower alkyl group, as an even

tually substituted 1-polyphenyl lower alkyl or 1-phenyl lower alkyl group, in which the substituents especially of the phenyl part can be e.g. lower alkyl such as methyl or lower alkoxy such as methoxy, and primarily benzyl. In one of two neighboring hydroxy groups standing together hydrogenolytically de-

cleavable group, is e.g. optionally substituted 1-phenyl - lower alkylidene, in which the substituents.*especially of the phenyl part, e.g. can be lower alkyl, such as methyl, or lower alkoxy, such as methoxy, especially benzylidene. Hydrogenolytically cleavable groups of the aforementioned type can be cleaved off in the usual way by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a nickel catalyst, such as Raney^nickel or a suitable noble metal catalyst. Protecting groups that can be removed by reduction from one or both hydroxy groups are e.g. such as are split off by treatment with a chemical reducing agent, e.g. as mentioned above, e.g. 2-halogen lower oxycarbonyl or arylmethoxycarbonyl. ;The spin-off takes place e.g. using the above-mentioned methods, e.g. by means of zinc or a chromium (Il) salt or an organic carboxylic acid such as formic acid. ;Furthermore, any protective groups present at the nitrogen atom and/or the oxygen atom correspond to the previously mentioned groups that can be cleaved off using the methods mentioned, and groups that can be replaced with hydrogen, such groups being cleaved off simultaneously with other groups or later, in the course of the described method a separate progress in small steps. Starting substance f is of formula VIII in which R! yes! jmeans a polyhydroxy-lower alkyl, such as 1,2- or 2,3-dihydroxy-lower alkyl group, e.g. a 2,3-dihydroxypropyl group transferable residue, can e.g. a protective group-containing compound with formula VIII, where R! J^ for example corresponds to a group of formula ; ; in which R^q corresponds to a 1-averealkyl residue containing two less carbon atoms, and at least one of the groups and Z^, which may be the same or different, means a react ionizable esterified hydroxy group, e.g. halogen such as chlorine, and especially bromine, and the other means hydroxy is reacted with a salt of a carboxylic acid, e.g. an alkali metal salt, e.g. the potassium salt of a lower alkane carboxylic acid, e.g. acetic acid, or aromatic carboxylic acids such as benzoic acid to a corresponding compound containing 1 or 2 acyloxy groups in the group Villa. Starting substances of formula VIII with a group Villa can again be obtained by addition of halogen, e.g. bromine, or a halogen compound of the formula Hal-OH, e.g. under chlorine acidification or under bromine acidification, to an alkenyl residue containing the group Illa. These transactions are carried out in the usual way. ;Starting substance f is of formula VIII, in which R l» ! j for example means a group of formula ; in which X°0 means hydrolytically including alcohololytically or acidolytically or by means of reduction including hydrogenolysis cleavable residue, e.g. one of the: mentioned above, and R^q has the stated meaning can be obtained as e.g. a compound of formula is reacted with epichlorohydride and the formed compound of formula ; is traded, e.g. with an optionally N-protected such as N-benzylated 5-(2-aminoethoxy)salicylamide to a compound of formula VIII in which R! yes! j means the group Vlllb. This conversion is carried out in the usual way, possibly during cooling or heating, and in a suitable solvent. ;The new compounds of formula I, in which R^ means a k-lower alkyl sulfonylamino group, can likewise be obtained when, in a compound of formula qjj ; ; in which R^g means hydrogen or lower alkyl, introduces the lower alkyl sulfonyl group, and if desired, carries out the additional process steps mentioned in connection with the first method. The introduction of a lower alkylsulfonyl group takes place by reaction with a corresponding lower alkanesulfonic acid, e.g. e.g. methanesulfonic acid, eventixed in the presence of a suitable condensing agent, e.g. N,N'-Dicyclohexylcarbodiimide. Instead of a lower alkanesulfonic acid, a reactive derivative thereof can also be used, e.g. a halide such as the chloride or bromide, further an azide, or an acid anhydride, e.g. one with a lower alkane carboxylic acid such as acetic acid. Reactive derivatives are lower alkane sulfone - acids are especially also esters, e.g. those with lower alkanols such as methanol, ethanol, isopropanol, tert.-butanol, further with aryl lower alkanols, e.g. optionally with lower alkyl, e.g. methyl or lower alkoxy, e.g. methoxy, substituted benzyl alcohol, or with phenols, which are optionally activated with suitable substituents, such as 4-halogen, e.g. 4-chloro, k- ;nitro or 4-_methoxy, and consequently means e.g. 4--methoxy-4-nitro-2,4--nitro-, 4--chlorophenol. Most conveniently, the secondary amino groups placed in the side chain are present in reduced reactivity, e.g. protonated form, as the conversion is carried out in a pH range of approx. 4-, 0-5, 0, for example in the presence of an acid, such as acetic acid. These turnovers are carried out in a manner known per se, e.g. at elevated or reduced temperature, in the absence or in the presence of a suitable solvent, possibly in a protective gas atmosphere, e.g. under nitrogen. Starting substances with formula IX are available in the usual way, for example by reacting the compound with reacting the compound se^with formula ; with a compound of formula ; in which the primary amino group and/or the hydroxy group may be protected with a hydrogenolytically cleavable hydrogen replaceable group, e.g. benzyl. By subsequent reduction of the nitro group to the amino group, and at the same time or in a separate reduction step, cleavage of a hydrogenolytically cleavable N- and/or 0-protecting group present in the compound formed yields the starting material; with formula IX. This reduction is carried out in the usual way, e.g. by means of activated hydrogen, e.g. hydrogen in the presence of a catalyst such as nickel, or a noble metal catalyst, such as platinum or palladium, optionally on a suitable support material such as coal. ;Output sstof f is of formula IX in which R^ ? means lower alkyl, can be obtained by reacting a compound with formula ; with a lower alkanesulfonic acid or a reactive derivative, e.g. the chloride thereof, reaction of the formed compound of formula wherein R.J2 is lower alkyl with epichlorohydrin to the corresponding compound of formula and reaction with a compound of formula IXb. This reaction is carried out in and of itself kj a t way. i> The new compounds of formula I can likewise be obtained with a compound of formula reacted with a compound of formula; in which Z^ means a reactive esterified hydroxy group, and X^ means hydroxy, or in which and X^ together means the epoxy group, or is reacted with a corresponding ring-closed compound of formula ; ; in which R... and alk each have the indicated meaning, and X..., means hydrogen, or a group that can be left under the process conditions which, with the hydroxy group of a compound of formula X, is capable of forming the ether bond, and if desired, the in connection with the first method mentioned method step. On said cleavable groups, which are capable of forming an ether bond, are e.g. aryl ether alkyl groups, in which aryl e.g. means naphthyl, ;f. e.g. 1-naphthyl, and especially phenyl, which is optionally substituted with lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl and/or nitro. Groups X₂ defined in the above-mentioned manner are consequently particularly benzyl, further lower alkoxy-methyl, e.g. methoxymethyl. ;A reactive esterified hydroxy group;is a hydroxy group esterified with a strong acid, especially a strong inorganic acid such as a hydrohalic acid, especially hydrochloric, bromic or iodic acid, or sulfuric acid, or a strong organic acid, especially a strong organic sulfonic acid, such as a aliphatic or aromatic sulphonic acid, e.g. methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid, and is primarily halogen, e.g. chlorine, bromine or iodine, or aliphatic or aromatically substituted sul-phenyloxy, e.g. methyl sulfonyloxy or 4-methylphenylsulfonyloxy. The reaction of a compound of formula X to a compound of formula XI is carried out in a manner known per se, particularly when reacting a starting material of formula XI with a reactive esterified hydroxy group, preferably working in the presence of a basic agent, such as an inorganic base, e.g. an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent, such as an alkali metal low-alkaline alkoxide, and/or an excess of the basic reactant. The compound of formula X can also be present as a salt, e.g. as alkali salt, e.g. sodium salt. The reaction of ::.a compound of formula X with a compound of formula XII usually takes place in the presence of a basic catalyst, such as an alkali hydroxide, e.g. potassium hydroxide or an organic base, such as triethylamine, or an acid catalyst such as trifluoroacetic acid. This reaction is carried out in a manner known per se, and usually in the presence of a solvent or solvent mixture, and if necessary during cooling or heating, e.g. in a temperature range from approx. 20°C to approx. 200°C, preferably from approx. 100 to approx. 180°C in an open or closed vessel, and/or in an inert gas atmosphere, e.g. in a ni tr and a at oma sphere . Starting substances of formula XI in which Z is a reactive esterified hydroxy group, e.g. chlorine, and X^ means hydroxy, is available in the usual way by reacting an amine, optionally protected hydroxy group of formula ; ; with epichlorohydride, while a starting material of formula XI in which Z^ and X^ together form the epoxy group, can be obtained from an amine of formula Xla with epichlorohydride in the presence of a basic agent, e.g. e.g. an alkali or alkaline earth hydroxide or carbonate such as sodium hydroxide or carbonate, or calcium hydroxide or carbonate. A protected hydroxy group is e.g. a group which is cleavable by an intermediate reduction including hydrogenolysis, e.g. an α-aryl lower alkyl group, such as an optionally mentioned above substituted 1-phenyl lower alkyl group, e.g. a benzyl group or by means of hydrolysis 'and replaceable by hydrogen, e.g. an acyl residue such as a lower alkanoyl residue, such as an acetyl group, substituted hydroxy group. Such protecting groups are removed by means of reduction, including hydrogenolysis or hydrolysis, in the usual way, simultaneously or in a separate reaction step, f, e.g. as mentioned, and is replaced by hydrogen. Starting substances of formula XII can be obtained in a manner known per se by reaction of a compound of formula ; in which the two hydroxy groups can preferably be present in a reactive esterified form, e.g. as halogen, as chlorine or as sulfonyloxy- as methanesulfonyloxy group, and X^ is preferably different from hydrogen, and e.g. can mean, as mentioned, an optionally substituted benzyl group, with a compound of formula in which alk has the indicated meaning. These reactions are usually carried out in a solvent or solvent mixture, and if necessary during cooling or heating, e.g. in a temperature range from approx. -20° to +150°C, preferably from approx. 60° to 100°C in an open or closed vessel, and/or an inert gas atmosphere, e.g. e.g. in a nitrogen atmosphere. Means a in a thus formed starting material with formula XII the group X^ a possibly e.g. as described substituted benzyl group, then this can be split off in the usual way, e.g. by means of catalytically activated hydrogen, such as hydrogen in the presence of a noble metal catalyst, such as a palladium on charcoal catalyst and replaced by hydrogen, obtaining a starting material of formula XII in which X^ means hydrogen. The above-mentioned reactions can possibly be carried out simultaneously or one after the other, further in the desired order. If necessary, they take place in the presence of diluents, condensation agents and/or catalytic agents at reduced or increased temperature in a closed vessel under pressure and/or in an inert gas atmosphere. Depending on the process conditions and starting materials, the new compounds are obtained in free form, or the form likewise covered by the invention and their salts, since the new compounds or salts thereof can be present as hemi-, mono-, sesqui- or polyhydrates. Acid addition salts of the new compounds can in a manner known per se, e.g. when treated with basic agents such as alkali metal hydroxides, carbonates or hydrogen carbonates or ion exchangers are transferred in the free compounds. On the other hand, free bases formed with organic or inorganic acids, e.g. with the aforementioned acids to form acid addition salts, using in particular such acids which are suitable for the formation of pharmaceutically acceptable salts. ;These or other salts, especially acid addition salts of the new compounds such as e.g. oxalates or perchlorate, can also serve to purify the formed free bases, as the free bases are transferred into salts, separated and purified, and the base is again liberated from the salts. Depending on choice and starting material and working methods, the new compounds can exist as optical antipodes or racemates or, if they contain at least ten asymmetric carbon atoms, also as racemate mixtures. The starting materials can also be used as specific optical antipodes. Formed racemate mixtures can, due to the physico-chemical differences of the diastereomers in a known manner, e.g. by chromatography and/or fractional crystallization are divided into the two stereoisomeric (diastereomeric) racemates. Formed racemates can be divided into antipodes according to 1 and per se known methods, e.g. by recrystallization from an optically active solvent by treatment with suitable microorganisms, or addition with an optically active substance that forms salts with racemic compounds, especially acids, and separation of the salt mixture formed in this way, e.g. due to different solubilities diastereomeric salts from which free antipodes can be liberated by the action of suitable agents. Particularly common optically active acids are e.g. The D and L form of tartaric acid, Di-0,0-(p-toluoyl)-cinic acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Preferably isolates with the most effective of the two antipodes. The connection also relates to the embodiments of the method according to which one starts from a compound formed at one or other step of the method as an intermediate, and carries out the missing method steps or interrupts the method at one or other step, or where a starting substance is formed under reaction conditions -sene or where a reaction component is possibly present in the form of its salt. Appropriately, for carrying out the reaction according to the invention, such starting substances are used which lead to the groups of end substances specifically mentioned at the beginning, and in particular to the end substances specifically mentioned and emphasized. The starting materials are known, or, if they are new, can be obtained by methods known per se, as above, e.g. analogous to those mentioned in the examples. The starting materials with formulas II - IX and XI - XII which were developed specifically for the production of the compound according to the invention with formula I are also new, and are likewise covered by the invention. The invention also relates to intermediate products obtained according to the method. The new connections can e.g. find use in the form of pharmaceutical preparations, which contain a pharmacologically effective amount of the active substance, possibly together with pharmaceutical usable carriers, which are suitable for enteral administration, e.g. oral or parenteral administration, and may be inorganic or organic, solid or liquid. Thus, tablets or gelatin capsules are used, which contain the active substances together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol and/or lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets may also contain binders, e.g. magnesium aluminum silicate, starches, such as corn, wheat, rice and arrowroot starch, gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and if desired explosives, e.g. starches, agar, alginic acid or a salt thereof, such as sodium algenate, and/or soda mixtures, or adsorbents, colourings, flavorings and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, as these e.g. in the case of lyophilized preparations containing the active substance alone or together: i with a carrier material, e.g. mannitol, can be produced by use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilizers, wetting agents, and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure, and/or buffers. The present pharmaceutical preparations which, if desired, can contain further pharmacologically active substances are prepared in a manner known per se, e.g. by means of usual mixing-granulating, coating-dissolving or lyophilization methods, and containing from 0.1% to 100%, especially from approx. 1% to approx. 50% lyophilisates; up to 100% of the active substance. The dosage may depend on various factors, such as method of application, type, age and/or the individual condition. Thus, the daily dose to be administered in one or more preferably a maximum of four single doses by oral application to warm-blooded animals, for 6-receptor blockers with formula I is between 0.03 and 3 mk/kg and for warm-blooded animals of approx. 70 kg, preferably between approx. 0.005 and approx. 0.3 g- ;The invention shall be explained in more detail with the help of some examples. ;Example 1;A solution of 6.9 g of 1/2-(3-carbamoyl-4--hydroxy-phenoxy)-ethylamino_7-3-/2(2,2-dimethyl-diocholan-4--yl)- methyl_/-phenoxy_7-2-propanol in 165 ml of 0.1 N hydrochloric acid is left at 20°C for 5 hours, then washed twice with ether, the aqueous phase is filtered, and then concentrated in vacuum with a bath temperature of 4-0 °C. The aqueous solution formed is lyophilized, after which 1-1_ 2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino_7-3-/2-(2,3-dihydroxy-propyl)-phenoxy7-2-propanol hydrochloride is obtained as colorless amorphous powder. Starting material can be prepared as follows: 1a) A mixture of 76.8 g of 4.-(2-hydroxybenzyl)-2, 2-dimethyl-1, 3-dioxolane, 24-8 ml of epichlorohydrin and 69.7 g of potassium carbonate stirred at a bath temperature of 130°C for 7 hours. The reaction mixture is filtered and evaporated to dryness under vacuum. The residue is dissolved in ether, the solution is washed with 2N caustic soda, then water, dried over sodium sulfate, and then evaporated. The crude 4-(2-(2,3-epoxypropoxy)-benzyl7-2,2-dimethyl-1,3-dioxolane formed is further processed as such. ;1b) A mixture of 17.4 g of the crude compound formed and 17.1 g of 5-(2-benzylamino-ethoxy)-salicylamide in 60 ml of dimethylsulfoxide is stirred at a bath temperature of ;80UC for 20 hours. The reaction mixture is poured onto ice and water and extracted with ethyl acetate. The organic phase is diluted with ether, and washed successively with 0.1N hydrochloric acid (at pH 4.-5), then with aqueous saturated potassium carbonate solution, and dried over sodium sulfate. After evaporation, an oil remains which is ornotographed over silica gel with methylene chloride-methanol. After work-up, T-/W-/2 - (3-carbamoyl-4-hydroxy-phenoxy)-ethyl7-benzylamino/-3-/^2» 2-dimethyl -dioxalan-4--yl)-methyl7 -f enoxy/- 2-propanol as thick oil. ;1c) A solution of 23.5 g of the compound formed in 24-0 ml of methanol is hydrogenated with the addition of 2.4 g of palladium on a charcoal catalyst under normal conditions. The reaction product is dissolved in acetic acid ethyl ester, and is precipitated crystalline with the addition of petroleum ether. The crystals are dissolved again in acetic acid ethyl ester, and stirred with 4->5 g of silica gel for 1/2 hour. The filtered solution is mixed in portions with petroleum ether, after which 1-/2-(3-carbamoyl-.4-hydroxy-phenoxy)-ethylamino 7-3-/~2-/J,2.dimethyl-dioxalan-4 is obtained - -yl ) - methyl/-phenoxy/-2-propanol of m.p. 91-93°C. ;Example 2;A solution of 20.0 f crude 1 -/N-/2- U -carbamoyl -3-hydroxy -phenoxy )-1 -methyl -ethyl/-benzylamino/-3- (4--methanesulfonylamino- phenoxy)-2-propanol in 250 ml of methanol, is hydrogenated by adding 2.5 g of Pd/C catalyst (5%) under normal conditions until the debenzylation is finished. ;(DC control), for which an addition of a further 1.0 g of the catalyst is also required. The catalyst is filtered off, the filtrate is evaporated, and the remaining oil is dissolved in slightly warm isopropanol. After cooling, crystalline 1-/2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethylamino/-3-(4--methane sulfonylamino-phenoxy)-2-propanol is obtained , of sm.p. 14-7-150°C (diastereomer mixture). ;The starting material is obtained in the following way:;2a) According to the one by Irvine et;.al. Synthsis 1,972, 568 described methods, 2,4-dihydroxybenzamide using an excess of acetone is converted to 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-1,3-benzoxazin-4-one of sm.p. 249-251°C. 2b) From 168 g of 2, 3-dihydro-2, 2-dimethyl-7-hydroxy-4-H-1, 3-benzoaxazine-4-> 305 g of potassium carbonate and 88 ml of chloroacetone in 1.2 liters acetonitrile is obtained by boiling for 28 hours and subsequent work-up 2,3-dihydro-2,2-dimethyl-7-(2-oxopropoxy)-4-H-1, 3-benzoaxazin-4--one of m.p. 160-162°C (from isopropanol). ;2c) A solution of 75 g of crude 2,3-dihydro-2,2-dimethyl-7-(2-oxopropoxy)-4-H-1,3-benzoxazin-4-one and 32 g of benzylamine in 1000 ml methanol is hydrogenated with the addition of 0.75 g of concentrated sulfuric acid and 1.6 g of Pt/C catalyst (5%) until standstill of the hydrogen uptake under normal conditions. After filtering off the catalyst and evaporation of the solvent, the oily residue is distributed between 300 ml of ethyl acetate and 500 ml of 2-n hydrochloric acid. Crude 2,3-dihydro-2,2-dimethyl-7-(2-benzylamino)-propoxy7-4-H-1 is isolated from the aqueous phase by mixing with isolated ammonia (ice cooling) and extraction with ethyl acetate , 3-benzoxåzin-4-one as an oil, which can be further used crude. ;2d) A mixture of 100 g crude 2,3-dihydro-2,2-dimethyl-7-/ (2-benzylamino )-propoxy/-4H-1, 3-benzoxazin-4--one, 100 ml isopropanol and 100 ml of isopropylamine is boiled for 1 hour under reflux, and then evaporated. The remaining oil is crystallized by extraction with ether. The crystals are suctioned off and washed with a little isopropanol. One thus obtains 4-(2-(benzylamino)-propoxy/-salicylamide of m.p. 121-123°C. ;2e ) 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 boiled for 20 hours and refluxed - ;run. After adding a further 1.2 g of 4-(2,3-epoxy-propoxy)-nitrobenzene, the mixture is heated under reflux for a further 20 hours. The solvent is then partially evaporated, whereupon 1-/N-/2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl/-benzylamino/7-3-(4-nitrofenoxy)-2- propanol of m.p. 160-164-°C (diaster omer rbl anding ).;2f ) A solution of 19»0 g of the formed compound in 380 ml of dioxane is hydrogenated with the addition of 18 g of Raney nickel in 4 portions at normal conditions for absorption of 3 mol-equivalent hydrogen. After filtration and evaporation of the filtrate, crude 1-/N-/2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethyl/-benzylamine o7-3 -(4 -amino-phenoxy)-2-propanol as an orange-brown oil, which is further processed without further purification. ;2g) 16 g of the compound formed is dissolved in 90 ml of anhydrous pyridine and to this is added dropwise while cooling 5- ;10°C L, L g of methanesulphonic acid chloride. The reaction mixture is stirred for 4 hours at room temperature, the solvent is evaporated in a ladle, and the residue is distributed between 400 ml of ethyl acetate and 50 ml of water. The organic phase is washed 3 more times with 50 ml of water each time, dried over magnesium sulfate, treated with charcoal and evaporated, after which crude 1-/N-/2-(4--carbamoyl-3-hydroxy-phenoxy)- 1-methyl-ethyl_7-benzyl amino/-3-(4--methanesulfonylamino-phenoxy)-2-propanol as an orange oil; which is further processed without further purification. ;Example 3;A solution of 30 g of crude 1-/N-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl_7-phenoxy7~2-propanol in 600 ml of methanol is hydrogenated while adding 4 g Pd/C catalyst (5%) for uptake of 1-mol-equivalent hydrogen under normal conditions. By adding dioxane and heating, the already crystallized product is brought into solution, the catalyst is filtered off, and the filtrate is evaporated. After recrystallization from isopropanol, then from methanol, pure 1-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino_7-3-/4--/2-(cyclo-propylmethoxy)-ethyl7- f enoxy_/-2-propanol of m.p. 14-9-150°C. ;Starting substances are prepared in the following way:;3a) According to the one by Irvin et al. Synthesis 1972, 568 mentioned method, 2,5-dihydroxy-benzamide using excess acetone is transferred to 2,3-dihydro-2,2-dimethyl-;6-hydroxy-4-H-1,3-benzoxazine-4 --on-off sm.p. 215-216°C.; 3b) 70 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4-H-1,3-benzoxazin-4--one are stirred in 4-00 ml of acetonitrile with 100 g of potassium carbonate and 32 ml of chloroacetone for 30 hours under reflux. After adding a further 3.2 ml of chloroacetone, the reaction mixture is further heated for 15-20 hours. The still warm reaction mixture is filtered, the residue is washed thoroughly with acetone and the combined filtrate is evaporated. The crystalline residue is recrystallized from toluene to give 2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one of m.p. 125-126°C. ;3c) 74 g of the formed 2,3-dihydro-2,2-dimethyl-6-(2-oxo-propoxy)-4-H-1,3-benzoxazin-4-one are heated in a mixture of 150 ml dioxane and 4-50 ml 2-n hydrochloric acid for 4-5 minutes in a water bath. The solvent is evaporated, and the crystalline residue is expelled with water and then suctioned off. Recrystallization from isopropanol gives 5-(2-oxo-propoxy)-sal icylamide ac m.p. 152-154-°C. ;3d ) A solution of 104-, 5 g of 5 - (2-oxo-propoxy)-sal i -sylamide in 1000 ml of methanol is mixed with 55 g of benzylamine and . 1.25 g of concentrated sulfuric acid is hydrogenated in the presence of 3.0 g of Pt/C catalyst under normal conditions until the absorption of 1 equivalent of hydrogen. The catalyst is filtered off and the solution is stirred with approx. 10 g of powdered calcium carbonate are filtered again and evaporated. The remaining oil crystallizes from isopropanol. Repeated recrystallization from isopropanol gives 5-(2-(benzylamino)-propoxy7-salicylamide of sm. at 102-104°C. ;3e ) A solution of 14-» 3 g of 1-/2-(cyclopropyl-methoxy)-ethyl_7-4--(2,3-epoxypropoxy)-benzene (DE-OS 26 4-9 605) and 16.3 g of 5-(benzylamino)-propoxy/-salicylamide in 200 ml of isopropanol is boiled for 18 hours under reflux. After evaporation of the reaction mixture, a crude 1-/N-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl7-benzylamino/-3-/4--/2-(cyclopropylmethoxy)-ethyl7 is obtained -pheno ksy7-2-propanol as brown oil; which is further processed without further purification. ;Example 4-;A solution of 50 g of crude 1-/N-/2-(3-carbamoyl-4- -hydroxy -phenoxy )-ethyl / -benzyl amino_/-3-(4--methane sul phonylamino-phenoxy)-2-propanol in 550 ml of methanol, is hydrogenated after adding 6 g of palladium on charcoal catalyst (5%) under normal conditions until the hydrogen uptake has come to a standstill. The already crystallized product is brought into solution by adding dioxane and heating, the catalyst is filtered off, and the filtrate is evaporated. The crystalline evaporation residue gives after recrystallization from ethanol. and then from methanol with the addition of activated carbon 1 -/_ 2 - (3-carbamoyl-4-hydroxy-phenoxy)-ethylamino/-3-(4-.methanesulfonamino-phenoxy)-2-propanol of sm. p. 152-153°C. Starting material is prepared in the following way: 4.a) 19»5 g of 4-(2,3-epoxypropoxy)-nitrobenzene and 28.6 g of 5-(2-benzylaminoethoxy)-salicylamide are boiled in 4-00 ml of isopropanol in 20 hours under reflux. After evaporation, from the reaction mixture.. as a viscous oil formed crude 1-/N-/2-(3-carbamoyl -4--hydroxy -phenoxy )-ethyl/-benzylamino_/-3- ( 4-nitro-phenoxy)-2-propanol is further processed as such. 4-b) 50 g of the crude compound formed according to example 4a is dissolved in 500 ml of ethanol and hydrogenated in the presence of 5 g of Raney-Nickel. It is required in addition, two additions of 10 g each of Raney-Nickel until the calculated amount (3 mol equivalents) of hydrogen is taken up. After filtering off and evaporating the filtrate, crude 1-/N-/2-(3-carbamoyl-4-hydroxy -phenoxy)-ethyl/-benzylamino7-3-(4-amino-phenoxy)-2-propanol as brown oil. 4c) 44 g of the crude compound formed according to example 4b are dissolved in 300 ml of anhydrous pyridine and mixed while stirring ag cooling at 10-20°C dripping water ice with 11.4 g of methanesulfonic acid chloride. The reaction mixture is stirred overnight at room temperature, evaporated and distributed between 500 ml of ethyl acetate and 100 ml of water. The organic phase is separated, washed twice with 100 ml of water each time, dried over magnesium sulphate and evaporated. The crude 1-[N-(2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl-7-benzylamino]-3-(4-methane-sulfonylamino-phenoxy) thus formed is further processed without further purification. ;Example 5';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 to approx. dimethyl sulphoxide heated to 80°C, the solution is stirred for one hour at 75 - 85°C, and then poured into 500 ml of water. The resinous product which separates is separated and stirred with 150 ml of ethyl acetate. The crystals that separate are suctioned off, recrystallized from a little isopropanol, after which 4-/3-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino/-2-hydroxy-propoxy7-N-meth< y>lkannamic acid - amide of m.p. 170-171°C, (sinters from U8°C). ;Example 6;A solution of 41 g of crude 1-/N-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl_7-benzylamino_7-3-/4-(N-methyl-methanesulfonylamino)-f Enoxy_7-2-propanol in 410 ml of methanol is hydrogenated analogously to example 4 in the presence of 4 g of palladium on a charcoal catalyst, and worked up. After recrystallization from ethanol and methanol, 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino_7-3-/4-(N-methylmethanesulfonylamino)-phenoxy/-2-propanol of m.p. . 120-121°C. The starting material is prepared as follows: 6a) A solution of 103.7 g of 4-methylaminophenol sulfate in 330 ml of pyridine and 102 ml of N,N-diisopropylethylamine is mixed dropwise under ice-cooling and stirring with 77 ml of methanesulfonic acid chloride during approx. 30 minutes, and stirred at room temperature overnight. The volatile parts are evaporated, the evaporation residue is distributed between ethyl acetate and water, the organic phase is separated and evaporated, and the crystalline residue is heated on a water bath with 300 ml of 6-n sodium hydroxide solution until complete dissolution. The solution is filtered and adjusted with concentrated hydrochloric acid to pH 2. This precipitates crystalline 4-(N-methylsulfonylamino)-phenol. It is sucked off and dried in a vacuum at 86°C, m.p. 135-136°C.

6b) A mixture of 34.2 g of the compound formed according to example 6a, 35.2 g of potassium carbonate and 125 ml of epichlorohydride is boiled for 2 hours with stirring and reflux. The suspension is filtered, the filtrate is evaporated, distributed between ethyl acetate and water, the organic phase is separated, dried over magnesium sulfate and evaporated. 4-(2, 3-epoxy-propoxy)-N-methyl-methanesulfonanilide of m.p. 96-100°C

(from methanol).

6c), A solution of 19.0 g of the compound formed according to example 6b, and 21.4 g of 5-(2-benzylaminoethoxy)-salicylamide in 350 ml of isopropanol is boiled for 5 hours under reflux. After evaporation, crude 1-/N-/2-(3-carbamoyl-4--hydroxy-phenoxy)-ethyl/-benzylamino/-3-/4--(N-methyl-methane-sulfonylamino)- phenoxy7~2-propanol as viscous oil,

which is further processed as such.

Example 7

A mixture of 5 g of methanesulfonyl chloride, 5 g of 1-/2-(3-carbamoyl-4--hydroxy-phenoxy)-ethylamino/-3-(4-amino-phenoxy)-2-propanol 1, 5 g of acetic acid and 100 ml of water are heated in a boiling water bath while stirring for 5 minutes. After cooling, the pH is adjusted to 9.0-12.0 by adding concentrated caustic soda, and the mixture is extracted exhaustively with ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate and evaporated to dryness. The evaporation residue is recrystallized from ethanol, then from methanol to give 1-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino/- 3-(4-methanesulfonylamino-phenoxy)-2-propanol of sm. p. 152°C.

The starting material can be prepared in the following way: 7a) A solution of 10 g of the 1-/N-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl_7-benzyl-aminoq7~ formed according to example 4-b 3-(4--Amino-phenoxy)-2-propanol in 100 ml of ethanol, hydrogenated after adding 0.5 g of palladium on charcoal catalyst (5%-ig) until complete hydrogen absorption (1 mol-equivalent) After filtering off the catalyst, the filtrate is evaporated

to dryness, after which 1 - fz - (3-carbamoyl-4-hydroxy-phenoxy)-ethylamino7-3-(4-aminophenoxy)-2-propanol is obtained as a crude product which is further processed as such.

Example 8

A mixture of 13.9 g of 1-(4-methanesulfonylamino-phenoxy-3-amino-2-propanol and 10.5 g of 4-(2-oxo-propoxy)-salicylamide is boiled in 200 ml of toluene with the addition of some drops of acetic acid under the water separator . After the water separation has stopped (approx. 2-3 hours) the solution is evaporated,

the dark red residue is dissolved in 100 ml of ethanol, and mixed in portions while stirring with a total of 5.7 g of sodium borohydride. The temperature thereby rises to 36°C. The reaction mixture is stirred for a further 2 hours at 20-30°C, and allowed to stand overnight. Under ice cooling, it is brought there-

after with approx. 6n hydrochloric acid to pH 3-4, filtered and evaporated. The evaporation residue is distributed between 100 ml of water each time

and ethyl acetate, the water phase is separated, made alkaline with concentrated ammonia and extracted with 200 ml of ethyl acetate. After washing the organic phase with water, drying over sodium sulfate and evaporating the solvent, 1-/2-(4-carbamoyl-3-hydroxy-phenoxy)-1-methyl-ethylamino7-3-(4-methanesulfonylamino-phenoxy )-2-propanol as diastereomer mixture which is recrystallized from slightly warm isopropanol of m.p., 147-150°C.

The required starting material 1 - (4-methanesulfonylamino-phenoxy)-3-amino-2-propanol is prepared as follows: 8a) A mixture of 18.7 g of 4-methanesulfonylaminophenol, 8.5 g of epichlorohydrin, 7 g of potassium carbonate and 70 ml isopropanol is stirred for 2.5 hours at 90°C. The reaction mixture is filtered hot, the residue is washed with isopropanol and the filtrate is evaporated under reduced pressure finally at 0.03 torr on a water bath, after which -4-methanesulfonylamino-(2, 3-epoxypropoxy)phenol is obtained as a residue.

A solution of 24-, 3 g of the product formed

in 170 ml of dioxane, mixed with a solution of approx. 2 g of dry ammonia gas in 110 ml of dioxane, and the reaction mixture is left in a closed vessel for 24 hours at room temperature. After removal of excess ammonia and evaporation of the solvent under reduced pressure, crude 1-3-methanesulfonylaminophenoxy)-3-amino-2-propanol is obtained, which is further processed as such.

Example'9

2.3 g of 1-/2- (4--methoxycarbonyl-3-hydroxy-phenoxy)-1-methyl-ethylamineq/-3-(4--methanesulfonylamino-phenoxy)-2-propanol is mixed with a mixture of 50 ml of dioxane and 500 ml of concentrated ammonia solution. The reaction mixture is stirred for 1-2 hours and set aside as soon as it has become homogeneous yet

for 3 days at 20-30°C. Evaporation yields crude 1-(4--carbamoyl-3-hydroxy-phenoxy)-3-/2- (4--methanesulfonylamino-phenoxy). - 1-methyl-ethylamino/-2-propanol as diastereomer mixture. This is dissolved in slightly warm isopropanol and then cooled in the ladle while the compound is obtained pure with m.p. 14-7-150°C.

The starting material can be prepared in the following way: 9a) A solution of 2.4-» 3 g of 4--(2, 3-epoxy-propoxy)-methanesulfonylaminophenol and 30 g of 4--(2-benzylamino-propoxy)-methoxycarbonyl- 3-hydroxybenzene in 200 ml of isopropanol, heated for 24 hours under reflux. The crude product formed after evaporation is distributed between 2N hydrochloric acid and ether, the aqueous phase is separated, and made alkaline with concentrated ammonia solution. By exhaustive extraction with ethyl acetate, washing of the organic phase with water, drying over magnesium sulfate and evaporation, crude 1-/N-/2 - (4- — carbome toxy - 3-hydroxy -phenoxy )- is obtained 1-methyl-ethyl 7-benzyl-amino7-3-(4--methanesulfonylamino-phenoxy)-2-propanol, which is further processed as such to the next step.

9b) A solution of 4-6 g of 1 - (N-/2- (4--methoxycarbonyl -

3-hydroxy-phenoxy)-1-methylethyl_7-benzylamino/-3-(4--methanesulfonylamino-phenoxy)-2-propanol in 500 ml of methanol is hydrogenated with the addition of 5 g of palladium on charcoal catalyst (5% under normal conditions until uptake of 1 mol equivalent of hydrogen. The solution is filtered off from the catalyst, and the filtrate is evaporated to dryness, after which crude 1- /2- (4--methoxycarbonyl-3-hydroxy-phenoxy)-1-methyl- ethyl-amino_7-3-(4-methanesulfonylamino-phenoxy)-2-propanol, which is further processed as such.

Example 10

A solution of 3.7 g of 1-/2-(3-cyano-4-hydroxyphenoxy)-ethylamineq/-3-(4-methanesulfonylamino-phenoxy_7-2-propanol) in a mixture of 15 ml of concentrated hydrochloric acid and 25 ml of dioxane, stirred for 15 hours at a temperature of 20-25°C. The reaction mixture is then evaporated and made alkaline with a 10% aqueous ammonia solution. The crude 1-/2-(3-carbamoyl-4-hydroxy-phenoxy)-et<y>lamino/-3<->/4-methanesulfonylamino-phenoxy/-2-propanol separated after a few hours' rest is filtered off and recrystallized from ethanol, then from methanol and has m.p. 152-153°C.

The 1-/2-(3-cyano-4-hydroxy-phenoxy)-ethylamino/-3-/4-methanesulfonylamino-phenoxy/-2-propanol required as starting material can be obtained as follows: 10a) A mixture of 6.5 g of 5-(2-bromomethoxy)-2-hydroxy-benzonitrile and 9.7 g of the 1-(4-methanesulfonylaminophenoxy)-3-amino-2-propanol formed according to example 8a are melted in an oil bath at 100°C , and magnetically stirred for 1 hour. The mixture is then boiled off with 100 ml of isopropanol, and the solution is filtered, and the filtrate is evaporated. The evaporation residue is distributed between 400 ml of ethyl acetate and 50 ml of 2N potassium bicarbonate solution, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated, after which crude 1-/2-(3-cyano-4-hydroxy- phenoxy)-ethylamino/-3-(4-methanesulfonylamino-phenoxy/-2-propanol, which is further processed as such.

Example 11

2.3 g of sodium metal are reacted with 45 ml of methanol.

After the reaction has ended, the solution .19" 2 g of 4-(2-cyclopropylmethoxyethyl)phenol (DE-OS 26 49 605) in 100 ml, methanol is added and the mixture is heated for 1 hour on a water bath under reflux. The reaction mixture is then evaporated under reduced pressure to dryness, and the sodium salt formed is slurried in 100 ml of dimethylformamide. To this, a solution of 28.85 g of 5-/N-(3-chloro-2-hydroxy-propyl)/-amino-ethoxysalicylamide in 170 ml of dimethylformamide is added, and the mixture is heated for 3 hours while stirring in a boiling water bath. The solvent is removed under reduced pressure, and the residue is treated with 200 ml of water, filtered off and the filter residue is crystallized from isoproanol, then from methanol, whereby pure 1-(2-(3-carbamoyl-4-hydroxy-phenoxy) is obtained )-ethyl - amino/-3-/4-/2-(cyclopropylmethoxy)-ethyl7-phenoxy7-2-propanol of m.p. 149-150°C.

The necessary starting material 5-(N-(3-chloro-2-hydroxypropyl)-7aminoethoxy-salicylamide can be prepared as follows: 11a) 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 are boiled with stirring and under reflux for 4 hours. The mushy reaction mixture is extracted hot, three

to four times with 1 liter of methanol each time, the combined methanol extracts are evaporated, and the residue is recrystallized from methanol. 6-(2-bromoethoxy-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoaxizine of m.p. 190-195°C is obtained.

11b) A mixture of 60 g of 6-(2-bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one and 110 ml of benzylamine is stirred in a bath of 80 °C for 30 minutes. The reaction mixture is then ice-cooled with concentrated hydrochloric acid to pH 3-4" and crystallized. After 2-4 hours, the crystals are suctioned off, washed each time with 50 ml of water and ethyl acetate. Thus formed 5-(2-benzylamino-ethoxy)-salicylamide hydrochloride melts at 214-216°C. The base released therefrom melts at 107-108°c (from ethyl acetate-ether).

11c) 5-(2-aminoethoxy)-salicylamide can be prepared by debenzylation using hydrogen in the presence of Pd/C catalyst (5%-ig) of the N-benzyl compound formed correspondingly according to example 11b in methanol, sm. p. 14-0°C.

11d) A solution of 19.6 g of 5-(2-aminoethoxy)-salicylamide in 80 ml of methanol is slowly added to a solution of 9.25 g of epichlorohydrin in 30 ml of methanol and the reaction mixture is stirred for 3 hours at 25°C . After ■ up scoop s cv. Evaporation of the agent gives crude 5-/N-(3-chloro-2-hydroxypropyl./)_7-aminoethoxy-salicylamide, which is further processed as such.

Example 12

To a mixture of 19.2 g of 4-(2-cyclopropylmethoxy-ethyl)phenol and 25.2 g of 1-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl_7-3-azetidinol 0.4 g of solid calcium hydroxide is added and the mixture is heated for 22 hours at 150°C in a nitrogen atmosphere. After cooling, the reaction mixture is made neutral with 2N hydrochloric acid, extracted with 100 ml of ether, and the ether phase is separated and extracted with 2N hydrochloric acid. The aqueous phase is separated, made neutral with concentrated sodium hydroxide solution, and the mixture is extracted with methylene chloride. After washing the organic phase with water and evaporating the solvent, the residue formed is recrystallized from isopropanol, then from methanol, after which 1 -/2-(3-carbamoyl-4- -hydroxy -phenoxy ) -ethyl - aminc_7 is obtained -3-/4--/2 - (cycl opyl methoxy )-ethyl/-phenoxy/-2-propanol, with m.p. U9-150°C.

The starting material required 1 -/2-(3-carbamoyl -4- -hydroxy-phenoxy)-ethyl/-3-azetidinol is obtained in the following way: 12a) To a heated to <80°C solution of 4-0 g 4-(2-Aminoethoxy)-2-benzyloxy-benzamide in 250 ml of 80% ethanol is allowed to add dropwise with stirring over the course of 1 hour a solution of 15.4 g of 2-benzyloxy-1,3-dibromopropane in 95% ethanol, and continues stirring at the specified temperature for another 12 hours. Then as much solvent as possible is removed, the residue is made alkaline with 2N sodium hydroxide solution, and the mixture is extracted with ethyl acetate. The ethyl acetate solution is extracted with 2N hydrochloric acid, until

acid reaction, the organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness, after which crude 1-[ 2- (3-carbamoyl-4--benzyloxy-phenoxy)-ethylaminoq_7-3-benzylazetidinol is obtained.

By hydrogenolysis with the aid of hydrogen in the presence of a palladium on charcoal catalyst in methanolic solution until uptake of 2 mol equivalent hydrogen, one obtains from said compound 1 -/2- (3-carbamoyl -4- -hydroxy-phenoxy )-ethylamino_7- 3-azetidinol, which is further processed as such.

Example 13

Tablets containing 20 ml of active substance are produced in the usual way in the following composition:

Preparation: 1-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino 7-3-/4.-/2-(cyclopropylmethoxy)-ethyl_7-phenoxy7-2-propanol is mixed with part of the wheat starch with milk sugar and colloidal silicic acid, and the mixture is run through a sieve.

A further part of the wheat stiff ice is pasted with wood

times the amount of water in a water bath, and the powder mixture is crushed with this paste until a weak plastic mass is formed.

The plastic mass is pressed through a sieve, of approx. 3 mm mesh size, dried, and the formed dry granules are driven through a sieve again. The remaining wheat starch, talc and magnesium stearate are then mixed in, and the mixture is pressed into tablets of 14-5 mg weight with a break pattern.

Example 14-

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

Manufacturing:

1 -/2 - (4-- carbamoyl -3-hydroxy -phenoxy ) -1 - methyl - ethylamino_7 - 3-(4-methanesulfonylamino -phenoxy ) -2-propanol is mixed with part of the wheat starch with milk sugar and colloidal silicic acid, and the mixture is passed through a sieve.

A further part of the wheat starch is pasted. with five times the amount of water, in a water bath, and the powder mixture is crushed with this paste until a weak plastic mass is formed.

The plastic mass is pressed through a sieve

about. 3 mm mesh size, is dried, and the formed dry granules are again driven through a sieve. The remaining wheat starch, talc and magnesium stearate are then mixed in, and the mixture is pressed into tablets of 126 mg weight with instructions for breaking.

Example 15

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

Manufacture:

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

Example 16

A sterile solution of 5.0 g of 1-/2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl amino/-3-/2-(2,3-dihydroxy propyl)-phenoxy/-2- propanol hydrochloride in 5000 ml of distilled water is filled into ampoules to 5 ml, which in 5 ml of solution contain 5 mg of active substance.

Example 17

Instead of the substances used in examples 13 to 16 as active substances, the following compound with formula I or their pharmaceutically usable non-toxic acid addition salts can also be used as active substances in tablets, dragees, capsules, ampoule solutions, etc.: 1- /2-(3-carbamoyl -4--hydroxy -phenoxy ) -ethyl amino / -3 - (4--methyl sulfonyl - amino) -phenoxy -2 -propanol, 4-~/3- /2 - (3-carbamoyl - 4-hydroxy - phenoxy ) -ethyl amino 7-2 -hydroxy -propoxy_/ - N-methyl -zimmic acid amide or 1 -/2 - (3-carbamoyl -4- - hydroxy -phenoxy)-ethylamino/-3-(4-(N-methyl-methanesulfonylamino)-phenoxy7-2-propanol.

Claims (1)

1. Process for the preparation of derivatives of 3-amino-1,2-propanediol with formula in which R... means polyhydroxy lower alkyl, cycloalkyl lower alkyl lower alkyl lower alkyl sulf onylamino in the 4 position or 1-lower alkyl carbamoyl-2-vinyl attached in the 4 position and alk means residues of the formula -CHg-CHg- or CH^ -CH-CH2 characterized by ata) a compound of formula is reacted with a compound of formula in which one of the groups Z-, and Z^ means a reactive esterified hydroxy group, and the other means a primary amino group, and X.j means hydroxy or in which X^ and Z^ together mean the epoxy group, and Z^ means the primary amino group, and R. ].j and. alk has the above meaning, or b) in a connection with formula IN in which R.,., the meaning of R-j-j» or means in the 4,-position bonded at the nitrogen atom with a hydrogen-replaceable substituent substituted lower alkylsulfonylamino, Xg, Xy X^ and X^ each means hydrogen or a hydrogen-replaceable substituent or Xg and X^ and/or X^ and X^ together mean a 2-valent radical with 2 hydrogen atoms replaceable with the precaution that at least one of the radicals Xg» X^» X^ and X^ is different from hydrogen, or at least R .,., means in the 4- position bonded at the nitrogen atom with a hydrogen-replaceable substituent, substituted lower alkylsulfonylamino, or at least Xg and X^ together or X^ and X^ together means a 2-valent residue with 2 hydrogen atoms replaceable, or a salt thereof, is cleaved those from hydrogen different groups, Xg, Xy X^ and X^ resp. Xg and X^ together, and/or X^ and X^ together, and are replaced by hydrogen atoms, and/or one with the nitrogen atom of in the 4--position in bonded lower alkyl sulf onylamino R,,., placed with hydrogen replaceable substituent is replaced by hydrogen, or c) in a compound of formula in which X^ means a reducible group with the formulas -CH = N - alk - (Va), resp. -CHg - N = alk.,- (Vb) where alk,, means an alkylylidene residue corresponding to the residue alk, and X^ ' means hydrogen, or a sub / <be> t <i> ngtel sen for reduction of X^ with hydrogen replaceable residue, R.,., has the meaning of R.,.,, or means in the 4--position bonded to the nitrogen atom with a hydrogen-replaceable substituent, Xy substituted lower alkylsulfonylamino, in which Xy has the above meaning, X^ always means a reducible group Va or Vb, this group is reduced and at the same time they are split off from hydrogen different groups Xy, and replaced with hydrogen ord) A compound with formula it in which R.,., has the meaning of R-]-]» or means in the 4--position bonded with the nitrogen atom with a by means of ammonolysis with a hydrogen-replaceable substituent substituted lower alkylsulfonylamino, Xg means hydrogen, or a by means of ammonolysis cleavable group, or a reactive derivative of one of the carboxylic acids defined in formula VI is reacted with ammonia (VII) and at the same time any remaining residues Xg are cleaved off and replaced with hydrogen or) in a compound of formula in which one or all hydroxy groups and/or the secondary nitrogen atom and/or lower alkyl sulfonylamino R^ bonded in the 4-position is substituted with the nitrogen atom, optionally with such groups that can be split off by means of hydrolysis and can be replaced with hydrogen, which are split off under the process conditions and replaced with hydrogen, the group's is converted -CN by means of hydrolysis to the group -CONHg, and at the same time optionally split off at the nitrogen atom of a lower alkylsulfonylamino group bound in the ^- position, and/or with one or all hydroxy groups and/or at the secondary nitrogen atom placed protecting groups are replaced with hydrogen orf) for preparation of a compound of formula I in which R... means polyhydroxy lower alkyl becomes in a compound of formula it i wherein R 1 means a polyhydroxy lower alkyl group, e.g. one of the aforementioned, in which at least one or two hydroxy groups together, each of which stands at two neighboring carbon atoms, is protected with a residue that can be removed and replaced by hydrogen, or a salt thereof, - these protective groups, which may be the same or different, are removed, as well as possibly further by the nitrogen atom and/or protective groups placed at the oxygen atom, and is replaced by hydrogen or g) for the preparation of a compound of formula I in which R.,., means a 4--1 aver ealkyl sulfonyl- aminoeruDoe. is introduced in a connection with formula in which R 1 g means hydrogen or lower alkyl, the lower alkyl sulfonyl group, or h) a compound of formula is traded with a compound with.formula in which Z^ means a reactive esterified hydroxy group, and X., means hydroxy or in which Z^ and X^ together mean an epoxy group, or reacted with a corresponding ring-closed compound of formula in which R.,., and alk each have the indicated meaning, and X.,., means hydrogen or a cleavable under the process conditions, and with the hydroxy group of a compound with X for the formation of an ether bond suitable group, and if desired, a formed free compound is transferred in a salt or in a formed dalt in a free compound and/or if desired divide the formed isomer mixture into the isomers or a formed racemate into the antipodes.