DD202691A5 - PROCESS FOR THE PREPARATION OF DERIVATIVES OF 3-AMINO-1,2-PROPANDIOL - Google Patents

Abstract

The invention relates to a process for the preparation of novel 3-amino-1,2-propanediols with pharmacological activity, which can be used in medicine as a remedy. The aim of the invention is the enrichment of the prior art by new drugs with betha receptors blocking effect for the treatment of angina pectoris and cardiac arrhythmias and for lowering blood pressure. The invention has for its object to develop a process for the preparation of derivatives of 3-amino-1,2-propanediol. The novel compounds of the formula I in which R is polyhydroxy-lower alkyl and alk radicals of the formula -CH 2 -CH 2, deep or -CH 2, and Salts of such compounds are prepared by cleaving off the corresponding starting compound with R "'instead of R d.

Description

2Λ2604 2

Process for the preparation of derivatives of 3-amino-1,2-propanediol

 Field of application of the invention

The invention relates to a process for the preparation of novel 3-amino-1,2-propanediols ₉ which, owing to their β-receptor blocking action, can be used in the treatment of heart diseases and, moreover, also as antihypertensive agents in medicine.

Characteristic of the known technical solutions

For the treatment of angina pectori β, cardiac arrhythmia or hypertension a variety of compounds have become known · However, the known compounds are not always satisfactory

Object of the invention

It is the object of the invention to provide the prior art with new pharmacologically active compounds in the aforementioned direction of action.

Presentation of the nature of

The object of the invention is to develop a process for the preparation of derivatives of 3-amino-1,2-propanediol.

According to the invention are prepared new derivatives of 3-amino-1,2-propanediol of the formula

61 105 12

242604 2 - ² -

OH

, i -O-CH ^ CH-CHg-H'-alk-O - {- OH H

in which R Polyhyaroxyniederalkyl and alk radicals of the formulas -CH ₂ -CH ₂ - or CH. means, and their salts ·

-CH-CH ₂ -

They in the context of the present description with "lower" designated radicals and compounds preferably contain up to 7 and primarily up to 4 carbon atoms »

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl. Polyhydroxy-lower alkyl may occupy any of the possible positions in the phenyl ring and is, for example, benzoic or trihydroxy-lower alkyl, such as 1,2-dihydroxy- or 2,3-dihydroxy-lower alkyl, e.g. For example, 1,2-dihydroxy or 2,3-dihydroxypropyl.

The phenyl carrying the amide and hydroxy groups is linked to the remainder of the molecule in such a way that the latter is in the 4-position of said phenyl, ie. in the para-position to the amide group, and especially in the 5-position of said phenyl (d · h # in para-position to the hydroxy group) is bound ·

The novel compounds may be present in the form of their salts, such as their acid addition salts and, in particular, their pharmaceutically usable, non-toxic acid addition salts. Suitable salts are, for example, those with inorganic acids, such as hydrohalic acids, .alpha.

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242604 2

hydrazoic or hydrobromic acid, sulfuric acid, or phosphoric acid, or with organic acids, such as aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, for example, formic, acetic, propionic, succinic, glycolic, lactic, and apple , Tartaric, citric, maleic, hydrozymalein, pyruvic, fumaric, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, embonebyric, methanesulphonic, ethanesulphonic, 2- Hydroxyäthansulfon-, Äthyl en aul Fön-, toluene sulfone, Uaphthalinsulfon- or sulphanilic acid, or with other acidic organic substances, such as ascorbic acid ·

The novel compounds have valuable pharmacological properties. In particular, they have a specific effect on .beta.-adrenergic receptors. This action is based on the common property of the compounds of the formula I of affinity for these receptors, which in the absence of or very little stimulating intrinsic activity is pure blockade , with low to moderate stimulatory effect as a blockade with simultaneous ISA, d. H. intrinsic sympathomimetic activity, expresses

The compounds of the formula I show a blocking activity on adrenergic β-receptors with pronounced cardioselectivity, which can be ascertained especially in the case of such substances. The compounds of the formula I furthermore bring about a blockade of vascular β-receptors which can be detected, in particular, with the substances , whose phenyl ring by Polyhydrozyniederalkyl, z. B. 2,3-dihydroxypropyl is substituted, with these compounds as additional effect a more or less pronounced blockade of tracheal ß-receptors is present ·

Compounds of the formula I with a polyhydroxy-lower

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alkyl, such as a 2i3-Diiydro2ypropylgruppe, also show a more or less pronounced ISA ₉ with an additional effect is to call a © blood pressure reduction ·

The above statements regarding pliannacological properties are based on the results of corresponding pharmacological tests in customary test procedures. Thus, the novel β-blocking compounds show inhibition of isoproterenol-induced tachycardia in isolated guinea pig hearts in a concentration range of about 0.001 / μg / ml to about 3 / Ug / ml, and on the anesthetized, reserpine-pretreated cat in a dose range of about 0.001 mg / kg to about 10 mg / kg when given intravenously. Blockade of vascular β receptors is by inhibition of isoproterenol-induced vasodilation in the vascular area the A * femoralie on the anesthetized reserpine pretreated cat when administered intravenously in a dose range of about 0.003 mg / kg to about 30 mg / kg.

The caused by the compounds of formula I block the tracheal ß-receptors can be by means of the inhibition induced by isoprenaline relaxation at the iso "profiled guinea pig trachea in a concentration range of about 0.001 ax mol / Iiter to about 30 Al mol / liter demonstrate ·

The ISA of the β-blocking compounds of the formula I results from the increase in the basal heart rate in the anesthetized cat pretreated with reserpine, which results, for example, in intravenous administration of 1- / 2- (3-carbamoyl-4-hydroxy phenoxy) ethylamino / -3-Z2- (2,3-dihydrosopropyl) phenoxy / -2-propanol in a dose range of from about 0.001 mg / kg to about 1 mg / kg. »

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New beta-blocking compounds cause fexner in a dose range of about 0.03 mg / kg to about 30 mg / kg i.v. a lowering of the arterial blood pressure in the anesthetized cat.

Accordingly, the novel compounds of the formula I can be used as partially cardioselective β-receptor blockers z. B. used for the treatment of cardiac arrhythmias, angina peotoris and hypertension «

The compounds of the general formula I can also be used as valuable intermediates for the preparation of other valuable, in particular pharmaceutically active compounds.

The novel compounds of the formula I are prepared in a manner known per se.

The novel compounds of the formula I wherein R is folyhydrocyl-lower alkyl, e.g. For example, 1,2-dihydroxy or 2,3-Dihydroacyniederalkyl, such as 1,2-dihydroxy or 2,3-dihydroxypropyl, can be obtained by reacting in a compound of formula

* j

₂ ] J4! OH H

wherein R ¹ "represents a polyhydroxy-lower alkyl group, for example one of those mentioned, in which at least one or two hydroxy groups together, one of each on two adjacent carbon atoms, is represented by a cleavable and

_r 61 105 12

60 4 2 - ⁶ -

Protected by hydrogen substitutable Best, or in a salt thereof, these Schutagmppen, which may be identical or different, and optionally further on the nitrogen atom and / or on the oxygen atoms protecting protecting groups and replaced by hydrogen, and, if desired, a resulting free Converted compound into a salt or a salt obtained in a free compound, and / or, if desired, a mixture of isomers obtained in the isomers or a racemate obtained in the antipodes separated ·

Cleavable and hydrogen-substituted groups are z * B. by solvolysis such as hydrolysis, alcoholysis or acidolysis, or by reduction, including hydrogenolysis, cleavable groups · solvolytic such as hydrolytic or acidolytic cleavable best example, acyl radicals such as acyl radicals of organic carboxylic acids, eg. B. lower alkanoyl such as acetyl, or aroyl such as benzoyl, also z. B # lower alkoxycarbonyl, optionally substituted 1-phenyl-lower alkoxycarbonyl, eg B, benzyloxycarbonyl, furthermore an optionally substituted 1-polyphenyl-lower alkyl group, eg trityl, and furthermore the tetrahydropyranyl radical protecting groups which are present on two adjacent hydroxy groups are, for example, lower alkylidene, Methylene or isopropylidene, or 1-phenyl-lower 'alkylidene, the phenyl portion of which is optionally substituted by lower alkyl, such as methyl, or lower alkoxy, such as methoxy, in particular benzylidene, or cycloalkylidene, e.g. B. cyclopentylidene or cyclohexylidene, furthermore the carbonyl group ·

Hydrolytically cleavable groups of the type indicated, z "B" acyl radicals of organic carboxylic acids, for example, "lower alkanoyl radicals, also z. B. lower alkoxycarbonyi or trityl residues,

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furthermore Tetrahydropyranylreste, further bonded to two hydroxy groups liiederalkyliden-, 1-phenyl-niederalkyliden- or Cycloalkylidengruppen and optionally further standing on the nitrogen atom and / or the oxygen atoms protecting groups of this type can, depending on the nature of such radicals by treatment with water under acidic or basic conditions For example, a carbonyl group which is present on two adjacent hydroxy groups is conveniently removed by means of a basic agent, such as an alkali hydroxide, such as, for example, an alkali metal hydroxide such as hydrochloric acid or hydrochloric acid or an alkali metal or alkaline earth metal hydroxide or carbonates Potassium hydroxide or an alkali metal alcoholate, such as sodium ethylate or potassium tert-butylate, while z. B. tetrahydropyranyl groups are eliminated by acidic means, as indicated.

Acidolytically cleavable radicals are, for example, lower alkoxycarbonyl or tert-lower alkyl radicals. Such radicals can be cleaved, for example, by treatment with suitable organic carboxylic acids, such as optionally halogen, in particular fluorine, substituted lower alkanecarboxylic acids, primarily trifluoroacetic acid (if necessary in the presence of an activating agent such as anisole) and formic acid Reactions are carried out in a manner known per se ·

A particularly suitable hydrogenolytically removable hydroxy protecting group is primarily a hydrogenolytically cleavable οέ aryl-lower alkyl group, such as an optionally substituted 1-Polyphenylniederalkyl- or 1-Phenylniederalkylgruppe, wherein substituents, in particular of the phenyl moiety, eg B * lower alkyl, such as methyl or lower alkoxy such as methoxy can, and primarily benzyl ·

24 2 6 O Λ 2 egg los 12

A hydrogenolytically cleavable group which is present on two adjacent hydroxy groups is · & · B · optionally substituted 1-phenyl-lower alkylidene, in which sub-substituents, in particular of the phenyl moiety, eg lower alkyl, such as methyl or lower alkoxy, may be methoxy, and in particular benzylidene · Hydrogenolytically cleavable Groups of the type mentioned can be split off in the customary manner by treatment with catalytically activated hydrogen, z * B * with hydrogen in the presence of a nickel catalyst such as Raney nickel or a suitable noble metal catalyst.

Protective groups which can be split off by means of reduction and / or two hydroxyl groups are, for example, those which are eliminated on treatment with a chemical reducing agent, for example as described above, for example 2-halo-lower alkoxycarbonyl or arylmethoxycarbonyl.

The cleavage takes place for example by means of the methods described above, for example by means of zinc, or a chromium (II) salt or an organic carboxylic acid, such as formic acid.

Further protective groups optionally present on the nitrogen atom and / or the oxygen atoms correspond to the abovementioned groups that can be eliminated by hydrogen atoms and replaced by hydrogen. In the course of the process described, such groups are split off simultaneously with other groups or subsequently in a separate process.

Starting materials of the formula II in which R " ^{1 is} a radical convertible into a polyhydroxy-lower alkyl, such as 1,2- or 2,3-dihydroxy-lower alkyl group, for example a 2,3-dihydroxypropyl group, can be obtained, for example

61 105 12

2Λ2 60Λ 2

by carrying a compound of the formula II which optionally carries protective groups on the nitrogen atom and / or the oxygen atoms, in which R ^{Mt.tbd.Z is} a group of the formula

-R ₁ -CH-CH ₀ -Z- (Ha) ¹ I ^{2 3} Z ₄

in which R- corresponds to a lower alkyl group having two fewer carbon atoms, and at least one of Z.sup.2 and Z.sup. *, which may be the same or different, is a reactive esterified hydroxy group, e.g. B represents halogen, such as chlorine and especially bromine, and the other represents hydroxy, with a salt of a carboxylic acid, eg an alkali metal salt, such as the potassium salt, a lower alkanecarboxylic acid, benzic acid, or an aromatic carboxylic acid, such as benzoic acid to the corresponding compounds containing one or two acyloxy groups in the group Ha. Starting materials of the formula II with a group Ha in turn can be obtained by addition of halogen, for example bromine, or a halogen compound of the formula Hal-OH _9, for example hypochlorous or hypobromous acid, are obtained on an alkenyl radical corresponding to the group Ha. These reactions are carried out in the customary manner.

Starting materials of the formula II, wherein R ^nf z. B. a group of the formula

(Hb)

where X ° is a radical which can be split hydrolytically, including alcoholytically or acidolytically or by means of reduction, including hydrogenolysis, for example

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242604 2

_ ₁₀ _

represents the above, and E- has the meaning given, can be obtained, for example, by adding a compound of the formula

OH-OH ₂

reacted with epichlorohydrin, and the resulting compound of the formula

0-CH ₀ -CH - CH ₀

² V

z. B. reacted with an optionally N-protected, such as N-benzylated 5- (2-Aminoäthoxy) salicylamide to give a compound of formula II, wherein R ¹ "is the group Ub ·

These reactions are carried out in a customary manner, if appropriate with cooling or heating and in a suitable solvent.

If necessary, they are carried out in the presence of diluents, condensing agents and / or catalytic agents, at reduced or elevated temperature, in a closed vessel under pressure and / or in the closed vessel an inert gas atmosphere ·

242604 2

. ".

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

These or other salts, in particular acid addition salts of the novel compounds, such as oxalates or perchlorates, can also be used to purify the free bases obtained by salts, separating and purifying the free bases, and from the salts Releases bases ·

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

Resulting Racematgemische can due to the physicochemical differences of the diastereoisomers in a known manner, for example by chromatography and / or fractional crystallization, in the two stereoiso-

242604 2 ^6i1O5ia

- 12 me re η (diastereomeric) racemates are separated ·

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

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and carries out the missing process steps, or terminates the process at any stage, or in which a starting material is formed under the reaction conditions, or in which a reaction component is optionally present in the form of its salts ·

The starting materials are known or, if they are new, can be obtained by methods known per se, as above, for example analogously to the examples described.

The novel compounds can be used, for example, in the form of pharmaceutical preparations which contain a pharmacologically effective amount of the active substance, if appropriate

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- 13 -

contained together with pharmaceutically acceptable excipients which are suitable for enteral, eg oral or parenteral administration and which may be inorganic or organic, solid or liquid. Thus tablets or gelatine capsules containing the active ingredient together with diluents, eg. B · lactose, dextrose, sucrose, MaTiTii.tol, sorbitol, cellulose and / or glycerol and / or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol, have tablets may also include binders, for example, magnesium aluminum silicate, starches such as corn, wheat, rice and arrowroot, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, disintegrants, e.g. starches, agar , Alginic acid or a salt thereof, such as sodium alginate and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners It is also possible to use the novel pharmacologically active compounds in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these being z. B. for lyophilised preparations containing the active substance alone or together with a carrier material The pharmaceutical preparations may be sterilized and / or auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic Pressure and / or buffer containing · The present pharmaceutical preparations, which, if desired, may contain other pharmacologically active substances are in a conventional manner, for. B · by conventional mixing, granulation, coating, solution or lyophilization process, prepared and contain from about 0.1 % to 100 %, in particular

242604 2

from about 1 % to about 50 % _t lyophilisates up to 100 % of the active ingredient

Dosage may depend on various factors, such as route of administration, species, age and / or individual condition. For example, the doses to be administered daily in one or more, preferably at most 4, single doses to warm-blooded animals for β-receptor blocker of formula I are oral between 0.03 and 3 mg / kg and for warm-blooded animals of about 70 kg, preferably between about 0.005 and about 0.3 g.

The following examples serve to illustrate the invention; Temperatures are given in degrees Centigrade ·

example 1

A solution of 6.9 g of 1- ^ 2- (3-carbamoyl-4-hydroxy-pheno-3-cy) ethylamine q / -3- / 2 - / (2,2-dimethyl-dioxolan-4-yl) -methyl. / phenoxy7-2-propanol in 165 ml of O, 1-n. hydrochloric acid is allowed to stand at 20 ° for 5 hours, then washed twice with ither, the aqueous phase is filtered and then concentrated in vacuo at a bath temperature of 40 ° aqueous solution is lyophilized, followed by 1- / 2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamine Q7-3 - ^ - (2,3-dihydroxy-propyl) -phenoxx7-2-propanol hydrochloride ale colorless amorphous powder is obtained ·

The starting material can be produced on the following catfish:

1a) A mixture of 76.8 g of 4 "(2-hydrozybenzyl) -2,2" dimethyl-1,3-dioxolane, 248 ml of epichlorohydrin and 69.7 g of potassium carbonate is heated at a bath temperature of 130 °

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242604 2 -15-

Stirred for 7 hours. The reaction mixture is filtered and concentrated to dryness in vacuo. The kickstand is dissolved in ether, the solution is washed with 2N sodium hydroxide solution, then with water, dried over sodium sulphate and then concentrated. The crude 4-Z 2 (2,3-Epoxypropoxy) benzyl-2,2-dimethyl-1,3-dioxolane is further processed as such.

1b) A mixture of 17.4 g of the crude compound obtained and 17.1 g of 5- (2 = Benzylajnino-ethoxy) -salicylamid in 60 ml Dime thyl sulf oxide is stirred at a bath temperature of 80 ° for 20 hours · The reaction mixture is poured onto water 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 remains an oil which is chromatographed on silica gel with methylene chloride-methanol · After working up gives 1-25sf- ^ 2- (3-carbamoyl-4-hydroxy-phenoxy) -äthy ^ -benzylamino / ^ - Z ^ Zi 2, 2-dimethyl-dioxolan-4-yl) methyl], / phenoxex / 2-propanol as a thick oil

1c) A solution of 23> 5 g of the resulting Terbindung in 240 ml of methanol is hydrogenated with the addition of 2.4 g of palladium on carbon catalyst under normal conditions. The reaction product is dissolved in ethyl acetate and precipitated by addition of petroleum ether crystalline. The crystals are again dissolved in Esslgsäureäthylester and stirred with 4.5 g of silica gel for 1/2 hour · The filtered solution is added in portions with petroleum ether, followed by 1- / 2- (3-carbamoyl-4-hydroxy-phenoxy) ethylamino / ^ - ^ i »- ^ 2,2-dimethyl-dioxolan-4-yl) -methyl7-phenoxy / -2-propanol, mp. 91 to 93 ° receives ·

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24 2 60 4 2 - «-

Example 2;

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

Composition :

1- / 2- (3-carbamoyl-4-hydroxyphenoxy) -ethylamino-7-3-Z2- (2,3-dihydroxy-propyl) -

Phenoxx-2-propanol hydrochloride Wheat Starch Milk Sugar Colloidal Silica Talc

magnesium stearate

145 mg Production:

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

1 - ^ 2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylaminq7-3- / 2- (2,3-dihydroxy-propyl) -phenoxx7-2-propanol hydrochloride is blended with a portion of the wheat starch, with lactose and colloidal silica are mixed and the mixture is driven through a sieve. Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture is kneaded with this paste until a slightly plastic mass has formed.

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

242604 2 -η- ^6i1O5ia

Example 3:

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

Composition:

- (2,3-dihydroxypropyl) -phenoxy-2-propanol hydrochloride 2500 mg

Talcum 200 mg

Colloidal silica 50 mg

manufacture;

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

Example 4:

A sterile solution of 5 * 0 g of 1- / 2- (3-carbamoyl-4-hydroxy-phenoxy) -ethylamino J-OZ ^ - (2,3-dihydroxypropyl) phenoxy-7-2-propanol hydrochloride in 5000 ml of distilled water filled into 5 ml ampoules containing 5 mg of active ingredient in 5 ml of solution.

Claims (3)

invention claim 1 · Process for the preparation of derivatives of 3-amino-1,2-propanediol of the formula OH U • M_n Λττ OH-CH _O -N '' - ^Λ - -J- * * -O-CHg-CH-CHg-N-alk-O-1- | l (I) OH H ^ ^{# /} in which R is polyhydroxy-lower alkyl, and alk is radicals of the formulas -CH ₂ -CH ₀ - or CH- -CH-CH ₂
in that in a compound of formula wherein H ¹ "means a Polyhydrozyniederalkylgruppe wherein at least one or two hydroxy groups together, each one of two adjacent carbon atoms, is protected by a removable and hydrogen-displaceable radical, or in a salt thereof, these protecting groups, which may be identical or different and, optionally, further protecting groups attached to the nitrogen atom and / or to the oxygen atoms and replaced by hydrogen, and, if desired, converting a free compound obtained into a salt or a salt obtained into a free compound, and / or, if desired, a preserved one  · 61 105 12 6 (H 2 -Μ- Isomer mixture in the isomers or a received
Racemate separates into the antipodes · 2 · The method of item 1, characterized in that from 1 - (3 ^{<^} arbamoyl-4-hydrosy-phenoxy) -äthylaminq7-3- £ {2- (2,2-dimethyl-dioxolan-4-yl - ^ ) -methyl-2-phenoxy-2-propanol by hydrolysis of 1- / 2- (3-carbamoyl-4-hydroxyphenoxy) -ethyl-amino / -3- / ² -methyl-2,3-dihydroxy-propylphenoxx-2-propanol manufactures · Method according to one of the items 1 to 2, characterized in that a compound of the formula I obtained is converted into a pharmaceutically acceptable, non-toxic
Acid addition salt transferred ·