CA1093096A - Heart active derivatives of 1-amino-2,3-dihydroxy propane - Google Patents

Abstract

Abstract of the Disclosure Compounds of the general formula

Description

10930~

The present invention relates to new potent ~-receptor blocking compounds as well as their preparation and a method for treating symptoms and signs of cardiovascular disorders by block-ing the ~-receptors of the heart by administering to mammals, including man, these new compounds.
The new compounds are those of the general formula ~ 2CHOHCH2NH- (CH2) 2-X ~g~R3 (I) wherein R is selected from the group consisting of methyl, ethyl, propyl, cyano, methoxy, cyanomethyl, hydroxymethyl, and CH3OC2H4 NHCOCH2O-, R2 and R3 are the same or different and are each selec-ted from the group consisting of hydrogen hydroxy, methoxy and hydroxymethyl provided that R2 and R3 are not both hydrogen, and X i~ -0- or -S-.
The new compounds have valuable pharmacological properties.
Thus they block cardiac ~-receptors, which is shown at the determination of the antagonism of tachycardia after an intra-venous injection of 0.5 ~g/kg of d/l-isopropterenol sulphate on an anaesthetized cat at an intravenous dose of 0.002 to 2 mg/kg.
They also block the vascular ~-receptors which is shown at the determination of the antagonism of vasodilation after an intra-venous injection of 0.5 ~g/kg of d/l-isoproterenol sulphate on an anaesthetized cat at an intravenous dose of 0.002 to 2 mg/kg or more. The compounds have also stimulating properties on ~-receptors, i.e. they show intrinsic activity. This property is especially pronounced concerning vascular ~-receptors causing dilatation of peripheral blood vessels.
The new compounds can be used at the treatment of arryth-mias, angina pectoris and hypertension. The peripheral vasodila-tation is especially valuable for the two last mentioned indica-10~3~9~;
tions. One may also use them as intermediates for the prepara-tion of other valuable pharmaceutical compounds.
Compounds according to the present invention are:
3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2;
3-[2-(4-hydroxyphenoxy)-ethylamino~-1-o-ethylphenoxy-propanol-2;
3-L2-(4-hydroxyphenoxy)-ethylamino~-1-o-propylphenoxy-propanol-2;
3-L2-(4-hydroxyphenoxy)-ethylamino]-1-o-allylphenoxy-propanol-2;
3-L2-(4-hydroxyphenoxy)-ethylamino~-1-o-propargyloxyphenoxy-pro-panol-2;
3-L2-(4-hydroxyphenoxy)-ethylamino~-1-o-cyanophenoxy-propanol-2;
3-[2-~4-hydroxyphenoxy)-ethylaminol-1-o-allyloxyphenoxy-propanol-

2;

3-L2-(4-hydroxyphenoxy)-ethylamino]-1-o-propargylphenoxy-propanol-2;
3-[2-(4-hydroxyphenoxy)-ethylamino~-1 o-cyanomethylphenoxy-pro-panol-2;
3-L2-(4-hydroxyphenoxy)-ethylamino~-1-o-acetylphenoxy-propanol-2;
3-L2-(4-hydroxyphenoxy)-ethylamino]-1-o-hydroxymethyloxyphenoxy-propanol-2;
3-[2-(4-hydroxyphenylthio)-ethylamino~-1-o-cyanophenoxy-propanol-~ ,.

10~30~

3-[2-(4-hydroxyphenylthio)-ethylamino]-1-o-methylphenoxy-propanol-2;
3-[2-(3-methoxy-4-methoxyphenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2;
3-[2-(3-bromo-4-hydroxyphenoxy)-ethylamino]-o-methoxyphenoxy-propanol-2;
3-[2-(3-hydroxymethyl-4-hydroxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2;
3-[2-(3,4-dihydroxyphenylthio)-ethylamino]-1-o-cyanophenoxy-propanol-2;
3-[3-(4-hydroxyphenoxy)-propylamino]-1-o-methylphenoxy-propanol-2;
3-[4-(4-hydroxyphenoxy)-butylamino]-1-o-allylphenoxy-propanol-2; and 3-[2-(2-chloro-4-hydroxyphenylthio)-ethylamino]-1-o-allyloxyphenoxy-propanol-2.
3-[2-(4-methoxyphenoxy)-ethylamino- 1-o-cyanophenoxy-propanol-2;
3-[2-(2-hydroxyphenoxy)-ethylamino-1-o-cyanophenoxy-propanol-2;
3-[2-(4-hydroxy-3-methoxyphenoxy)ethylamino]-1-o-cyanophenoxy-propanol-2;
3-[2-(3,5-dimethoxyphenoxy)ethylamino]-1-o-cyanophenoxy-propanol-2;
3-[2-(4-hydroxyphenoxy)ethylamino-1-o-pyrrolylphenoxy-propanol-2;
3-[2-(4-hydroxyphenoxy)ethylamino]-1-o-methoxyethylaminocarbonylmethoxy-phenoxy-propanol-2.
Salt forming acids may be used in preparing therapeutically acceptable salts of the compo~tnds. These are: hydrohalogen acids, sulfuric acid, phosphoric acid9 nitric acid, perchloric acid, aliphatic, alicyclic, 2.0 aromatic or heterocyclic carboxy or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, or pyrovic acid, phenylacetic, benzoi.c, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicyclic or p-amino-salicyclic acid, embonic acid, methanesulfonic, ethanesulfonic, hydroxyethane sulfonic, ethylene-sulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthylsulfonic, or sulfanilic acid, methionine, tryptophane, lysine or arginine.
The substances are intended to be administered orally or parenter-ally for acute and chronic treatment of above mentioned cardiovascular dis-orders.
The biological effects of the ne~ compounds have been tested, and i~3~V~6 the different tests carried out will be shown and explained below.
The new compounds are obtained according to methods known per se. Thus, a compound of formula II

~ Xl ~ OC 2 CH II

wherein Rl has the meaning given above, Xl is a hydroxy group, z is a reactive, esterified hydroxy group, or Xl and Z together form an epoxy group, is reacted with an amine of the formula H2N- (CH2) 2-~R

wherein R2, R3, and X have the same meanings as given above.
A reactive, esterified hydroxy group is particularly a hydroxy group esterified with a strong, inorganic or organic acid, preferably a hydrohalogen acid, as hydrochloric acid, hydrobromic acid, or hydroiodic acid, further sulfuric acid or a strong organic sulfonic acid, e.g. benzenesulfonic acid, 4-bromobenzene-sulfonic acid, or 4-toluenesulfonic acid. Thus, Z is preferably chloro, bromo or iodo.
This reaction is carried out in a common way. At the use of a reactive ester as a starting material the preparation takes place preferably in the presence of a basic condensating agent and/or with an excess of an amine. Suitable basic condensating agents are e.g. alkalimetal hydroxides as sodium or potassium hy-droxide, alkalimetal carbonates as potassium carbonate and alkali-metal alcoholates as sodium methylate, potassium ethylate and potassium tert.-butylate.
The reaction is carried out in an alkanol having 1 to 4 1~93096 carbon atoms by refluxing the reactants in said solvent for a time long enough to give the compound of formula I, generally 1 to 12 hrs.
Further,a compound of formula III

~ OCH2CHOHCH2NH2 (III) wherein Rl has the meaning given above, is reacted with a compound of the formula Z (CH2)2 X ~

wherein R2, R3, X, and Z have the same meanings as given above.
This reaction is carried out in a common way, preferably in the presence of a basic condensating agent and/or an excess of an amine. Suitable basic condensating agents are e.g. alkaline alcoholates, preferably sodium or potassium alcoholate, or also alkaline carbonates as sodium or potassium carbonate.
This reaction is carried out in an alkanol having 1 to 3 . carbon atoms in an autoelave being heated to 100 to 130C for 5 to 15 hrs.
Further, a eompound of formula IV

~ OH (IV~
~C
~1 wherein Rl has the same meaning as given above is reaeted with a eompound of formula V

Z-cH2cHcH2-NH (CH2J 2~R (V) D

1(~9309~;

wherein Z, Xl, R2, R3, and X have the same meanings as given above.
This reaction is carried out in a common way. In those cases where reactive esters are used as starting material, the compound of formula IV may suitably be used in the form of its metalphenolate as alkalimetalphenolate, preferably sodiumpheno-late, or one works in the presence of an acid binding agent, pre-ferably a condensating agent, which can form a salt of the compound of formula IV as an alkalimetal alcoholate.
This reaction is carried out in an alkanol having 1 to 3 carbon atoms in an autoclave being heated to 80 to 100C for 5 to 15 hrs.
Further, a compound of formula Va ~ 2CHOHCH2NH(CH2)2z (Va) wherein Rl, and Z have the meanings given above, is reacted with a compound of formula IVa HX ~ (IVa) wherein R2, R3 and X have the same meanings as given above.
This reaction is carried out in the same way as the re-action between compounds of formula IV and V above.
Further, a compound of formula IV

~ OH (IV) wherein Rl has the same meaning as given above, is reacted with ~-J= -6-10~30~6 a compound of formula VI

CH2 - N - (CH2)2-X ~ (VI) OH
wherein R2, R3, and X have the same meanings as given above.
This reaction is carried out in a common way. Thus, the reaction is carried out under alkaline conditions in a suit-able solvent, as benzyl-alcohol by boiling the reaction mixture for some hours. Thereby the phenol is primarily converted to its metalphenolate as alkalimetalphenolate before it is added to the acetidinol of formula VI.
Further, one may split off a residue from a compound of formula I

-6a-B

above, in which the nitrogen atom of the amino group and/or the hydroxy groups have attached thereto a splitable residue.
Such splitable residues are especially those which are splitable by solvolysis, reduction, pyrolysis or fermentation.
Residues splitable by solvolysis are preferably residues splitable by hydrolysis or a~monolysis.
Residues splitable by means of hydrolysis are e.g. an acyl residue, which, when present, are functionally varied carboxy groups, e.g. oxycarbonyl residues, as alkoxycarbonyl residues, e.g. tert.-butoxycarbonyl residue, or ethoxycarbonyl residue, aralkoxycarbonyl residues as phenylloweralkoxy-carbonyl residues, e.g. a carbobenzyloxy residue halogencarbonyl residue, e.g.
a chlorocarbon residue further arylsulphonyl residues as toluenesulfonyl or bromobenzenesulfonyl residues and possibly as halogenated, as fluorinated loweralkanoyl residues as formyl-, acetyl- or trifluoroacetyl residues or a benzyl residue or cyano groups or silyl residues, as trimethylsilyl residue.
O the above mentioned residues present at the hydroxy groups, which residues are splitable by hydrolysis, preferably the oxycarbonyl residues and the loweralkanoyl residues or the benzoyl residues are used.
Besides the above mentioned also double-bound residues, which are splitable at the amino group by hydrolysis are used, e.g. alkylidene or benzylidene residue or a phosphorylidene group as a triphenylphosphorylidene group, whereby the nitrogen atom then obtains a positive charge.
Residues splitable at the hydroxy group and the amlno group by hydrolysis are furthermore divalent residues as in occurring cases substituted methylene. As substituents on the methylene residues any organic residue may be used, whereby it does not matter at the hydrolysis which compound is the substituent to the methylene residue. As methylene subs~ituents e.g. alip~
hatic or aromatic residues as alkyl as mentioned above, aryl, e.g. phenyl or pyridyl may be used. The hydrolysis may be carried out in any common way, suitably in a basis or preferably in an acid medium.

.
- 7 ~

1~93096 Compounds having residues being splittable by hydrolysis are also the compounds according to formula VII

~ OCH2CH--------CIH2 ~ R2 (VII) wherein Rl, R2, R3, and X have the same meanings as given above and Y is a carbonyl or thiocarbonyl residue.
The hydrolysis is carried out in an analogous way. e.g. in the presence of a hydrolysing agent, e.g. in the presence of an acidic agent as e.g. diluted mineral acids, as sulfuric acid or hydrohalogen acid, or in the presence of basic agents as e.g. al-kalimetal hydroxides, as sodium hydroxide. Oxycarbonyl residues,aryl sulfonyl residues and cyano groups may in a suitable way be split off by means of acidic agents as by means of a hydrohalogen acid, suitably hydrobromic acid. Preferably the splitting may take place using diluted hydrobromic acid, possibly in a mixture with acetic acid. Cyano groups are preferably split off by means of hydrobromic acid at an elevated temperature, as in boiling hydrobromic acid, according to the "bromocyano method" (v. Braun).
Further, e.g. a tert.-butoxycarbonyl residue may be split off under anhydrous conditions by means of a treatment with a suitable acid, as trifluoroacetic acid. Acidic agents are preferably used at a hydrolysis of compounds of ~ormula VI.
Residues splittable by ammonolysis are especially the halo-gencarbonyl residues, as the chlorocarbonyl residues. The ammono-lysis may be carried out in a common way, e.g. by means of an amine containing at least one hydrogen atom bounded to the nitrogen atom, as a mono- or diloweralkylamine e.g. methylamine or dimethylamine, or especially ammonia, preferably at an elevated temperature.
Instead of ammonia one may use an agent which gives ammonia as hexamethylene tetraamine.

B~

10~ 96 Residues splittable by means of a reduction are e.g. an ~-aryl--8a-C~
.~ .

, 10~3096 alkyl residue, as a benzyl residue or an ~-aralkoxycarbonyl residue as a benzyloxycarbonyl residue, which in a common way may be split off by means of a hydrogenolysis, especially by catalytically activated hydrogen, as by hydrogen in the presence of hydrogenating catalysts, e.g. Raney-nickel.
Further residues splitable by means of hydrogenolysis are 2-halogenalkoxy-carbonyl residues as 2,2,2-trichloroethoxycarbonyl residues or 2-iodoethoxy-or 2,2,2-tribromoethoxycarbonyl residues, which may be split off in a common way, suitably by means of a metallic reduction (so called nascerating hydro-gen). Nascerating hydrogen may be obtained by the influence of metal or metal alloys, as amalgam on compounds which give hydrogen as carboxy acids, alcohols or water, whereby especially zink or zinkalloys together with acetic acid may be used. Hydrogenolysis of 2-halogenalkoxycarbonyl residues may further take place using chromium or chromium ~II) compounds as chromium (II) chloride or chromium (II) acetate.
A residue splitable by reduc~ion may also be an arylsulfonyl group as a toluenesulfonyl group, which in a common way may be split off by reduc-tion using nascerating hydrogen, e.g. by means of an alkalimetal, as lithium or sodium in liquid ammonia, and suitably may be split off from a nitrogen atom. At the carrying out of the reduction one has to take care of the fact that other reducing groups are not influenced.
Residues splitable by means of pyrolysis, especially residues splitable from the nitrogen atom, are in occurring cases substituted suitably unsubstituted carbamoyl groups. Suitable substituents are e.g. loweralkyl or arylloweralkyl as methyl or benzyl or aryl, as phenyl, the pyrolysis is carried out in a common way, whereby one may have to take care of other thermically susceptible groups.
Residues splitable by means of fermentation, especially residues splitable from the nitrogen atom are in occurring cases substituted, however suitably unsubstituted carbamoyl groups. Suitable substituents are e.g.
loweralkyl or arylloweralkyl, as methyl or benzyl, or aryl as phenyl. The _ g _ 1093(396 fermentation is carried out in a common way, e.g. by means of the enzyme urease or soy bean extract at about 20C or slightly elevated temperature.
Further, a Shiff's base of formula VIII or IX

OCH2CH-CH=N-(CH2)2-X ~ R (VIII) OH ~ R
OCH CH-CH -N=CH-CH2-X ~ R3 (IX) R

or a cyclic tautomer corresponding to formula IX or formula X
,~ 2f 1 2 O NH (X) \C

3 CH2-X ~ R3 can be reduced, wherein Rl, R2, R3, and X have the same meanings as given above, and whereby the compounds of formula IX and X may exist together, too. This reduction is carried out in a common way, e.g. using a di-lightmetalhydride, as sodiumborohydride, lithiumaluminiumhydride, using a hydride as Boran with formic acid, or by means of a catalytic hydrogenation, as with hydrogen in the presence of Raney-nickel. At the reduction one has to take care of the fact that other groups are not affected.
Further, the oxo group in the compound of formula XI

t:~ _J:

10~3~96 ~ 2 2 ( 2)2 ~ R23 (XI) wherein Rl, R2, R3, and X have the same meanings as given above, can be reduced to a hydroxy group. This reduction is carried out in a common way, especially using a di-lightmetalhydride, as men-tioned above, or according to the "Meerwein-Pondorf-Verley method"
or a modification thereof/ suitably using an alkanol as a reaction component and as solvent, as isopropanol, and using a metalalkano-late, as metalisopropanolate, e.g. aluminium isopropanolate.
Further, in a compound of formula XII

0cH2cHoHcH2NH-(cH2)2-x ~ R3 (XII) X R

wherein R2, R3, and X have the same meanings as given above, and wherein x2 is a residue, which is able to be transformed to a re-sidue R , one transforms X to R .
Further, the oxo group in a compound corresponding to these of formula I and which carries an oxo group at a carbon atom bound to a nitrogen atom may be reduced by two hydrogen atoms.
Said compounds are e.g. such of the formula XIII

OCH2CHO~CNH-(CH2)2-X ~ R2 (XIII) Rl R

20 wherein Rl, R , R , and X have the meaning as given above.
The reduction can be carried out according to the above described manner using complex metalhydrides, e.g. lithiumaluminium-hydride or diisobutylaluminiumhydride. Suitably the reaction takes place in an inert solvent as an ether, e.g. diethylether or tetra-~()93096 hydrofuran.
In a common way the substituents may be varied from the compounds obtained within the end product as well as the compounds obtained may be introduced, split off or transformed into other end products in a common way.
Depending on the process conditions and the starting material the end product is obtained either in free form or in the form of its acid addition salt, which is included in the scope of the invention~ Thus, for example,basic, neutral or mixed salts may be obtained as well as hemiamino, sesqui--lla-B

10~3096 or polyhydrates. The acid addition salts of the new compounds may in a manner known per se be transformed into free compounds using e.g. basic agents as alka]Li or ion exchanger. On the other hand, the free bases obtained may form salts with organic or inorganic acids. In the preparation of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts. Such acids are e.g. hydrohalogen acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic, carboxy or sulfonic acids, as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxy-ma]eic or pyruvic acid, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methane-sulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic acids, halogenbenzenesulfonic, toluenesulfonic, naphthylsulphonic acids, or sul-fanilic acid; methionine, tryptophane, lysine or arginine.
These or other salts of the new compounds as e.g. picrates may serve as purifying agents or the free bases obtained as the free bases are transformed into salts, these are separated and the bases are then set free rom the salts again. According to the close relationship between the new compounds in free form and in the form of their salts it will be understood from the above and the below that, if possible, the corresponding salts are included in the free compound.
The invention also relates to any embodiment of the process of which one starts from any compound obtained as an intermediate in any process step and one carries out the lacking process step, or one breaks off the process at any step, or at which one forms a starting material under the reaction conditions, or at which a reaction component possibly in the form of its salt is present.
Thus, one may react an aldehyde of the formula XIX

~ OCH2CHOHCHO ~XTX) R

~0~93(~96 wherein Rl has the same meaning as given above, with an amine of the formula H2N- (CH2) 2-X ~

wherein R2, R3, and X have the same meaning as given above, in the presence of a suitable reducing agent, as one of the above mentioned. Thereby a compound of formula VII is obtained as an intermediate, which then is reduced according to the invention.
Further, one may in a manner known per se react an amine of the formula III with an aldehyde or a keton of the formula R

O=CH-CH - ~

in the presence of a suitable reducing agent, as one of the a~ove mentioned to produce compounds of formula IX or X as an intermediate, which then is reduced according to the invention.
The new compounds may, depending on the choice of starting materials and process, be present as optical antipodes or race-mate, or, if they contain at least two asymmetric carbon atoms, be present as an isomer mixture (racemate mixture).
The isomer mixtures (racemate mixtures) obtained may, de-pending on physical-chemical differences of the component, be separated into the both stereoisomeric (diastereomeric) pure racemate e.g. by means of chromatography and/or fractionated crystallizatîon.
The racemates obtained can be separated according to known methods, e.g. by means of recrystallization from an optical active solvent, by means of microorganisms, or by a reaction with opti-cally active acids forming salts of the compound and separating !~, -13-the salts thus obtained, e.g. by means of their different solu-bility in the diastereomers, from which the antipodes by the influence of a suitable agent may be set free. Suitably useable optically active acids are e.g. the L- and D-forms of tartaric acid, di-o-tolyl-tartaric -13a ~-~,., acid, malic acid, mandelic acid, camphersulfonic acid or china acid. Prefer-ably the more active part of the two antipodes is isolated.
Suitably such starting materials are used for carrying out the reactions of the invention, which material leads to groups of end products ~
primarily especially desired and especially to the specifically described and preferred end products.
The starting materials are known or may, if they should be new, be obtained according to processes known per se.
In clinical use the compounds of the invention are administered normally orally, rectally or by injection in the form of a pharmaceutical preparation, which contains an active component either as free base or as pharmaceutically acceptable, non-toxic acid addition salts, e.g. the hydro-chloride lactate, acetate, sulphamate or the like in combination with a pharmaceutical carrier.
Thereby the mentioning of the new compounds of the invention is here related to either the free amine base or the acid addition salts of the free base, even if the compounds are generally or specifically described, pro-vided that the context in which such expressions are used, e.g. in the ex-amples, with this broad meaning should not correspond. The carrier may be a solid, semisolid or liquid diluent or a capsule. These pharmaceutical pre-parations are a further object of the invention. Usually the amount of active compound is between 0.1 to 99% by weight of the preparation, suitably between 0.5 to 20% by weight in preparations for injection and between 2 to 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical preparations containing a compound of the present invention in the form of dosage units for oral ad-ministration the compound elected may be mixed with a solid, pulverulent carrier, as e.g. with lactose, saccharose, sorbitol, manitol, starch, as pota-toe starch, corn starch, amylopectin, cellulose derivatives or gelatine~ as well as with an antifriction agent as magnesium stearate, calcium stearate, polyethyleneglycol waxes or the like, and be pressed into tablets. If coated - 14 ~

10~ 096 tablets are wanted, the above prepared core may be coated with concentrated solut:ion of sugar, which solution may contain e.g. gum arabicum, gelatine, talc, titandioxide or the like. Furthermore, the tablets may be coated with a lacquer dissolved in an easily volatile organic solvent or mixture of sol-vents. To this coating a dye may be added in order to easily distinguish between tablets with different active compounds or with different amounts of the active compound present.
IJI the preparation of soft gelatine capsules ~pearl-shaped, closed capsules), which consist of gelatine and e.g. glycerine or in the preparation of similar closed capsules the active compound is mixed with a vegetable oil.
Hard gelatine capsules may contain granules of the active compo~md in combina-tion with a solid, pulverulent carrier as lactose, saccharose~ sorbitol, mannitol, starch (as e.g. potatoe starch, corn starch or amylopectin), cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared in the form of suppositories, which contain the active substance in a mixture with a neutral fat base, or they may be prepared in the form of gelatine-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin oil.
Liquid preparations for oral administration may be present in the form of syrups or suspensions, e.g. solutions containing from about 0.2% by weight to about 20% by weight of the active substance described, whereby the residue consists of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thicken-ing agent.
Solutions for parenteral administration by injection may be pre-pared as an aqueous solution of a watersoluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from about 0.5% by weight to about 10% by weight. These solutions may also contain stabilizing ~0~3096 agents and/or buffering agents and may suitably be available in different dosage unit ampoules.
The preparation of pharmaceutically tablets for peroral use is carried out in accordance with the following method:
The solid substances included are ground or sieved to a certain particle size. The binding agent is homogenized and suspended in a certain amount of solvent. The therapeutic compound and necessary auxiliary agents are mixed during a continuous and constantly mixing with the binding agent solution and are moistened so that the solution is uniformly divided in the mass without overmoistening any parts. The amount of solvent is usually so adapted that the mass obtains a consistency reminding of wet snow. The moisten-ing of the pulverulent mixture with the binding agent solution causes the particles to gather together slightly to aggregates and the real granulating process is carried out in such a way that the mass is pressed through a sieve in the form of a net of stainless steel having a mesh size of about 1 mm.
The mass is then placed in thin layers on a tray to be dried in a drying cabinet. This drying takes place during 10 hours and has to be standardized carefully as the damp degree of the granulate is of utmost importance for the following process and for the feature of the tablets. Drying in a fluid bed may possibly be used. In this case the mass is not put on a tray but is poured into a container having a net bottom.
After the drying step the granules are sieved so that the particle size wanted is obtained. Under certain circumstances powder has to be removed.
To the so called final mixture, disintegrating, antifriction agents and antiadhesive agents are added. After this mixture the mass shall have its right composition for the tabletting step.
The cleaned tablet punching machine is provided with a certain set of punches and dies, whereupon the suitable adjustment for the weight of the tablets and the degree of compression is tested out. The weight of the tablet is decisive for the size of the dose in each tablet and is calculated 10!~3~96 start:ing from the amount of therapeutic agent in the granules. The degree of compression affects the size of the tablet, its strength and its ability to disintegrate in water. Especially as regards the two later properties the choice of compression pressure ~0.5 to 5 ton) means something of a balance-step. When the right adjustment is set, the preparation of tablets is started which is carried out with a rate of 20,000 to 200,000 tablets per hour. The pressing of the tablets requires different timesand depends on the size of the batch.
The tablets are freed from adhering pulver in a specific apparatus and are then stored in closed packages until they are delivered.
Many tablets, especially these which are rough or bitter, are coated with a coating. This means that these are coated with a layer of sugar or some other suitable coating.
The tablets are usually packed by machines having an electronic counting device. The different types of packages consist of glass or plastic gallipots but also boxes, tubes and specific dosage adapted packages.
The daily dose of the active substance varies and is depending on the type of administration, but as a general rule it is 100 to 400 mg/day of active substance at peroral administration and 5 to 20 mg/day at intravenous administration.
~e following illustrates the principle and the adaptation of the invention, however, without being limited thereto. Temperature is given in degrees Celsius.
Example 1 Preparatlon of 3-[2-~4-hydroxyphenoxy)-ethylamino]-1-o-methyl ph0noxy-propanol-2 _ _ _ 2.5 g of 1,2-epoxy-3-o-methylphenoxy propane were mixed with 1.5 g of 2-~4-hydroxyphenoxy)-ethylamine and 25 ml of isopropanol and the total solution was refluxed for 1.5 hours. The solution was thereupon evaporated in vacuo. Ihe base thus obtained was dissolved in acetone and the hydro-chloride was precipitated using HCl in ether. The hydrochloride was filtered off and washed with acetonitril. The yield of 3-[2-(4-hydroxyphenoxy)-ethyl-amino]-l-o-methylphenoxy-propanol-2 was 1.5 g. Melting point 150~C (HCl).
The structure was determined using NMR.
Example 2 3-[2-(2-hydroxyphenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-(o-methyl)-phenoxy-propane and 2-(2-hydroxyphenoxy)-ethylamine as starting materials. Melting point of its hydrochloride is 80C. Its structure was determined by NMR and equivalent weightO
Example 3 3-[2-(2-methoxyphenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methylphenoxy-propane and 2-(2-methoxyphenoxy)-ethylamine as starting material. Melting point of tartrate is 91C. Its structure was determined by NMR and equivalent weight.
Example 4 3-[2-(4-ethylphenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methylphenoxy-propane and 2-(4-ethylphenoxy)-ethylamine as starting material. The hydrochloride melted at 127C~
Example S
3-[2-t4-methoxyphenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methylphenoxy-propane and 2-~4-methoxyphenyl)-ethylamine as starting materials. The hydrochloride melted at 168C.
Example 6 3 [2-(3,4-dimethoxyphenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2 was prepared according to Example 1, using 1,2-epoxy-3-o-methylphenoxy-propane and 2-~3,4-dimethoxyphenoxy)-ethylamine as starting materials. The hydrochloride melted at 160C.

93~6 Example 7 3-[2-(4-cyanophenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methylphenoxy-propane and 2-(4-cyanophenoxy)-ethylamine as starting materials. The melting point of the hydrochloride is 126C.
Example 8 3-[2-(4-methoxyethoxyphenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-methyl-phenoxy-propane and 2-(4-methoxyethoxyphenoxy)-ethylamine as starting materials.The melting point of the hydrochloride is 149C.
Example 9 3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-cyanophenoxypropanol-2 was prepared according to Example 1 using 112-epoxy-3-o-cyanophenoxy-propane and 2-(4-hydroxyphenoxy)-ethylamine as starting materials. The tartrate melted at 52C.
Example 10 3-~2-~4-hydroxyphenoxy)-ethylamino]-1-o-allyloxyphenoxy-propanol-2 was prepared according to Example 1, using 1,2-epoxy-3-o-allyloxyphenoxy-; propane and 2-~4-hydroxyphenoxy)-ethylamine as starting materials. Melting point lOSC (tartrate).
Example 11 3-[2-(4 hydroxyphenoxy)-ethylamino]-1-o-allylphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-allylphenoxy-; propane and 2-(4-hydroxyphenoxy)-ethylamine as starting materials.
Exa~ple 12 3-[2-~4-hydroxyphenoxy)-ethylamino]-1-o-methoxyphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-methoxyphenoxy-propane and 2-(4-hydroxyphenoxy)-ethylamine as starting materials.
Example 13 3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-ethylphenoxy-propanol-2 ~0~3V96 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-ethylphenoxy-propane and 2-(4-hydroxyphenoxy)-ethylamine as starting materials.
Example 14 3-[2-~4-hydroxyphenylthio)-ethylamino]-1-o-cyanophenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epoxy-3-o-cyano-phenoxy-propane and 2-(4-hydroxyphenylthio)-ethylamine as starting materials.
Example 15 3-[3-(4-hydroxyphenoxy)-propylamino-1-o-allylphenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epoxy-3-o-allyl-phenoxy-propane and 3-(4-hydroxyphenoxy)-propylamine as starting materials.
Example 16 3-[2-(3,4-dimethoxyphenoxy)-ethylamino]-1-o-allyloxyphenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epoxy-3-o-allyloxyphenoxy-propane and 2-(3,4-dimethoxyphenoxy)-ethylamine as starting materials.
Example 17 3-~2-(2-chlorophenoxy)-ethylamino]-l-o-allylphenoxy-propanol-2 was prepared in accordance with Example 1 above using 1,2-epoxy-3-o-allylphenoxy-propane and 2-(2-chlorophenoxy)-ethylamine as starting materials.
Example 18 3-[2-(4-hydroxyphenoxy)-ethylamino~-1-o-propargyloxyphenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-propargyloxyphenoxypropane and 2-(4-hydroxyphenoxy)-ethylamine as starting materials.
Example 19 3-[2-(4-methoxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 was prepared in accordance with Example l using 1,2-epoxy-3-o-cyanophenoxy-propane and 2-~4-methoxyphenoxy)-ethylamine as starting materials. Mp. 134C
as hydrochloride.

1093~96 Example 20 3-[2-(2-hydroxyphenoxy~-ethylamino]-1-o-cyanophenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(2-hydroxyphenoxy) ethylamine as starting materials. Mp. 1$1C
as hydrochloride.
Example 21 3-[2-(4-hydroxy-3-methoxyphenoxy)ethylamino]-1-o-cyanophenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2-~4-hydroxy-3-methoxyphenoxy)ethylamine as starting materials. Mp. 78C hydrochloride.
Example 22 3-[2-(3,5-dimethoxyphenoxy)ethylamino]-1-o-cyanophenoxy-propanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(3,5-dimethoxyphenoxy)ethylamine as starting materials. Mp.
159C as hydrochloride.
Example 23 3-[2-(4-hydroxyphenoxy)ethylamino]-1-o-pyrrolylphenoxypropanol-2 was prepared in accordance with Example 1 using 1,2-epoxy-3-o-pyrrolylphenoxy-propane and 2-(4-hydroxyphenoxy)ethylamine as starting materials. Mp. 150C
as succinic acid addition salt.
Example 24 A syrup containing 2% (weight per volume) of active substance was prepared from the following ingredients:

3-[2-(4-hydroxyphenyl)-1-methylethylamino]-l-o-methylphenoxy-propanol-2 HCl 2.0 g Saccharlne 0.6 g Sugar 30.0 g Glycerine 5.0 g Plavouring agent 0.1 g Ethanol 96% 10.0 g Distilled water ad 100.0 ml 1093~96 Sugar, saccharine and the ethersalt were dissolved in 60 g of warm water. After cooling, glycerine and solution av flavouring agents dissolved in ethanol were added. To the mixture water was then added to 100 ml.
The above given active substance may be replaced with other pharmaceutically acceptable acid addition salts.
Example 25 3-[2-(4-hydroxyphenyl)-1,1-dimethylethyla~ino-1-o-allylphenoxy]-propanol-2 hydrochloride (250 g) was mixed with lactose (175.8 g) potatoe starch (169.7 g) and colloidal silicic acid (32 g). The mixture was moistened with a 10% solution of gelatine and was granulated through a 12-mesh sieve.
After drying potatoe starch (160 g), talc (50 g) and magnesium stearate (5 g) were admixed and the mixture thus obtained was pressed into tablets (10,000) which contain 25 mg of substance. The tablets are sold on the market provided with a breaking score to give another dose than 25 mg or to give multiples thereof when broken.
Example 26 ; GTanules were prepared from 3-[2-(4-hydroxyphenyl)-1-methylethyl-amino]-l-o-propargyloxyphenoxy-propanol-2-p-hydroxybenzoate (250 g), lactose (175.9 g) and an alcoholic solution of polyvinyl pyrrolidone (25 g). After the drying step the granules were mixed with talc (25 g), potatoe starch ~40 g) and magnesium stearate (2.50 g) and was pressed into 10,000 tablets being biconvex. These tablets are primarily coated with a 10% alcoholic solution of shellac and thereupon with an aqueous solution containing saccharose ~45%), gum arabicum (5%), gelatine (4%) and dyestuff (0.2%). Talc and powder sugar were used for powdering after the first ive coatings. The coating was then coated with a 66% sugar syrup and polished with a 10% carnauba wax solution in carbon tetrachloride.
Example 27 3-r2-(4-hydroxyphenyl)-1,1-dimethylethylamino]-3-o-ethylphenoxy-propanol-2-h~drochloride ~1 g), sodiumchloride (0.8 g) and ascorbic acid (0.1 10~309~i g) we:re dissolved in sufficient amount of distilled water ~o give 100 ml of solut:ion. The solution, which contains 10 mg of active substance on each ml, was used in filling ampoules, which were sterilized by heating at 120C for m;nutes.
Example 28 ~method b + e) 10 g of o-methylphenylglycidylether in 100 ml of ethanol were saturated with gaseous ammonia and the mixture was heated in an autoclave on a boiling waterbath for 4 hours. The solvent was evaporated and the residue was dissolved in ethylacetate and HCl-gas was introduced. The hydrochloride then precipitated and it was filtered off and dissolved in 50 ml of ethanol to which 2-(4-methoxy-methoxy)-phenoxy-ethylchloride and 15 g of K2CO3 had been added. The mixture was heated in an autoclave at 130C for 10 hours whereupon the solvent was evaporated and the residue was treated with 100 ml of 2N HCl for 1 h at ambient temperature. The aqueous phase was made alkaline with ammonia and extracted with ethyl acetate. The solvent phase was dried over K2C03, whereupon-3-12 (4-hydroxy)-phenoxy-ethylamino]-1-(o-methylphenoxy)-propanol-2 was obtained. The base obtained was converted to its hydrochloride, 3-[2-(4-hydroxy)-phenoxy-ethylamino]-1-(o-methylphenoxy)-propanol-2 hydro-chloride. Melting point 150C.
Exam~le 29 ~method c ~ e) 2.4 g of Na were dissolved in 100 ml of ethanol, whereupon 10.8 g of o-methylphenol and then 22.9 g of 3-[2-(4-methoxymethoxy)-phenoxy-ethyl-amino]-l-chloropropanol-2 were added. The mixture was heated in an autoclave on a boiling waterbath for 10 hours. Thereupon it was filtered and the fil-trate was evaporated to dryness. The residue was treated with 2N HCl for 1 h ; at ambient temperature and extracted with ether, whereupon the aqueous phase was made alkaline with ammonia and extracted with etherO The ether phase was dried over MgS04 and 3-[2-~4-hydroxy)-phenoxy-ethylamino]-1-(o-methylphenoxy)-propanol-2 was obtained and was converted to its hydrochloride and isolated.
3a Melting point 150C.

~0~3~

Example 30 (method d) 0.116 moles of o-methylphenol were mixed with 0.080 moles of 1-[2-(4-methoxymethoxyphenoxy)ethyl]-3-acetidinol, 0.500 moles of benzylalcohol and 0.003 moles of KOH. The mixture was refluxed while stirring for 6 hrs at 140C and was then cooled and extracted with 2N HCl. The aqueous phase was allowed to stand for 1 h at ambient temperature, was then made alkaline, and was finally extracted with chloroform. After drying and evaporation the residue was dissolved in ether and to the solution HCl in ether was added.
The hydrochloride was filtered off and was washed with acetone. The hydro-chloride of 3-[2-(4-hydroxyphenoxy)ethylamino]-1-(o-methylphenoxy)-propanol-2 melted at 150C.
Example 31 (method f) In accordance with Example 23 above 1-amino-3-(o-methylphenoxy)-propanol-2 was prepared. 5 g of this compound were dissolved in 50 ml of methanol and 15 g of 4-hydroxyphenoxy-acetaldehyde were added, whereby 3-[2-C4_hydroxyphenoxy)-eth~limino]-1-o-methylphenoxy-propanol-2 was obtained. The solution was cooled to 0C and at this temperature 5 g of sodium borohydride were added little by little, whereby the imino compound was reduced. The temperature was then allowed to rise to ambient temperature and after 1 h 150 ml of H20 were added and the total mixture was extracted with ether. The ether phase was dried over MgSO4 and was evaporated. The residue was trans-formed into its hydrochloride. In this way 3-[2-(4-hydroxyphenoxy)-ethyl-amino]-l-(o-methylphenoxy)-propanol-2 HCl was obtained. Melting point 150C.
Example 32 Cmethod g) 1.0 g of 3-o-methylphenoxy-1-[2-(4-hydroxyphenoxy)-ethylamino]-propanone 2 was dissolved in 25 mls of methanol and the solution was cooled to 0C on an ice-bath. 0.25 g of NaBH4 were added little by little while stirring first at 0C for 1 h and them at ambient temperature for 0.5 h. The solution thus obtained was evaporated whereupon 50 ml of H20 were added. The _ 24 -10~3C~96 aqueous phase was extracted 3 times with 50 ml chloroform, the collected chloroform phase was dried and evaporated. The hydrochloride was precipitated from an ether solution of the residue by adding ether containing HCl. Recry-stallization was made from aceton. The hydrochloride o~ 3-[2-(4-hydroxy-phenoxy)-ethylamino]-l-(o-methylphenoxy)-propanol-2 melted at 150C.
Example 33 (method h) 3-[2-(4-hydroxyphenoxy)ethylamino]-1-(o-propynylphenoxy)-propanol-2 was prepared in accordance with Example 1 above from 1,2-epoxy-1-o-propynyl-phenoxypropane and 2-(4-hydroxyphenoxy)-ethylamine. The hydrochloride was dissolved in ethanol and a Pd/C-catalyst was added and the compound was hydro-genated until calculated amount of H2 had been absorbed. After filtration the filtrate was evaporated to dryness and the residue was recrystallized from ethylacetate. In this way 3-[2-(4-hydroxyphenoxy)-ethylamino]-1-(o-allyl-phenoxy)-propanol~2 HCl was obtained.
Biolbgical efects The ~receptor blocking agents of the present invention were tested as regards their biological properties. All compounds were thereby tested in anaesthetized cats (males and females weighing 2.5-3.5 kg) pretreat-ed with reserpine (5 mg/kg bodyweight administered intramusculary)about 16 hours beore the experiments. The animals were pretreated with reserpine in order to eliminate the endogenous sympathetic control of heart rate and vascular smooth muscle tone. The cats were anaesthetized with pentobarbital (30 mg/kg bodyweight administered i.p.) and artificially ventilated with room air. A bilateral vagotomy was performed in the neck. Blood pressure was obtained rom a cannulated carotid artery and heaTt rate was registered from a cardiotachometer, triggered by the electrocardiogram (ECG). Intrinsic beta mimetic activity on the heart was seen as increased heart rate after drug administration. The test compounds were given intravenously in logarithmical-ly increasing doses. The values obtained were plotted on dose-response curves, rom which af~inity values CED50) were estimated. At the end of each experi-10~3~396 ment high doses of isoprenaline were given in order to obtain the maximal heart rate response.
The compounds were also tested on conscious dogs. Beagle dogs were trained to be lying quietly and to be lifted to an errect position by placing their forelegs on a table for 2 minutes. Arterial blood pressure was registered via a blood pressure transducer attached to the dog at the heart level. Heart rate was triggered from the ECG. All dogs were pretreated with methylscopolamine to avoid vagal influences. Recordings were taken be-fore and 15 and 75 min after administration of the test compound, first in supine position for 2 min and then in the errect position for 2 minutes. The test compounds were given in increasing doses with 2 hours intervals.
PA2 was also measured on rats. PA2 is -log of the concentration of an antagonist which leads to the fact that the dose of noradrenaline has to be doubled in order to obtain the same effect of noradrenaline as one obtains without the antagonist or ~A2 ~ log Cdr-l)-log (antagonist) ED of noradrenaline ~antagonist) wherein dr is dose ratio = 50 ED50 of noradrenaline (control) and all concentrations are given in mol/l. PA2 is thus a measure of ~-receptor effect where higher PA2 higher ~-effect.
The experiments demonstrate that the compounds tested are potent ~-receptor antagonists being cardioselective and with or without intrinsic ~-mimetic activity. The compounds also decrease blood pressure in conscious dogs significantly. The pronounced hypotensive effect in conscious dogs of the new compounds depends on a vasodilating effect in combination with cardiac beta-receptor blockade. Results obtained in above given tests are given in Table I below.

10~3C~96 ~~ Ln L~ oo ~ o o Oo oo ~ ~ o .U~DV~

o~ ~
o\~r1 ~ ~ I` o ~ N Lt~ ~ O

~CY ~
~3 ~ ~ ~ oO O O oO Ln ~

3~ ,~

_~ Z ~ ~
~ _ ~X ~ j 1 3 N N o ~ D ~ O `D
N--I ~ h O O O --~ O N --I ~ O --I 1~
:CI V) ~ ~
Oca.,lrC u.~

~ ~ z N :~ ~
q o O O O Ln ~t O 0 01 C~ C~ 0 0~
N ~ ~ ~ N ~ ~ ~ ~ ~ N

~ ~ ~:
_~ Z ~Z ~ Z X ~ Z ~3 27 - `

Claims (28)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of new amines of the formula (I) wherein R1 is selected from the group consisting of methyl, ethyl, propyl, cyano, methoxy, cyanomethyl, hydroxymethyl, and CH3OC2H4NHCOCH2O-, R2 and R3 are the same or different and are each selected from the group consisting of hydrogen hydroxy, methoxy and hydroxymethyl provided that R2 and R3 are not both hydrogen, and X is -O- or -S-, characterized in that a) a compound of the formula II

(II) wherein R1 has the same meaning as given above, X1 is a hydroxy group and Z
is a reactive, esterified hydroxy group, or X1 and Z together form an epoxy group, is reacted with an amine of the formula wherein R2, R3, and X have the same meaning as given above, or b) a compound of the formula III

(III) wherein R1 has the same meaning as given above, is reacted with a compound of the formula wherein R2, R3, X and Z have the same meanings as given above, c) a compound of the formula IV

(IV) wherein R1 has the same meaning as given above, is reacted with a compound of formula V

(V) wherein Z, X1, R2, R3 and X have the same meanings as given above, or d) a compound of the formula IV

(IV) wherein R1 has the same meaning as given above, is reacted with a compound of the formula VI

(VI) wherein R2, R3 and X have the same meanings as given above, e) from a compound of the formula I wherein R1, R2, R3 and X
have the same meanings as above, and which compound has a splitable residue at the nitrogen atom of the amino group and/or at the hydroxy groups, which residue is splitable by means of solvolysis, reduction, pyrolysis or fermentation, this residue is split off, f) a Schiff's base of the formula VIII or IX

(VIII) (IX) or a cyclic tautomer of formula X corresponding to the compound of formula IX

(X) wherein R1, R2, R3 and X have the same meanings as above, whereby the compounds IX and X may be present simultaneously, is reduced, or g) in a compound of the formula XI

(XI) wherein R1, R2, R3 and X have the same meanings as above, the oxo group is reduced to a hydroxy group, h) in a compound of the formula XII

wherein R2, R3 and X have the same meanings as above and wherein x2 is a residue transformable into R1 having the above meanings by hydrogenation, X is hydrogenated into R1, or i) reacting a compound of formula Va (Va) wherein R1 and Z have the same meanings as above with a compound of formula IVa wherein R2, R3 and X have the same meanings as above; or k) in a compound corresponding to the one of formula I having an oxo group at a C-atom close to the N-atom, this oxo group is reduced to two hydrogen atoms and, if desired, isomer mixtures obtained are separated into pure isomers, and/or racemates obtained are separated into optical antipodes and/or free bases obtained are transformed into their therapeutically acceptable salt or salts obtained are transformed into their free bases.

2. A process according to claim 1 wherein R1 is selected from the group consisting of methyl, ethyl and cyano,

3. A process according to claim 1 wherein R3 is hydrogen and R2 is selected from the group consisting of hydroxy and methoxy.

4. A process according to claim 1 wherein R is hydrogen and R2 is selected from the group consisting of 2-hydroxy, 4-hydroxy and 4-methoxy.

5. A process according to claim 1 wherein R3 is a methoxy group and R2 is chosen from the group consisting of hydroxy and methoxy.

6. A process according to claim 1 wherein R3 is a 3-methoxy group and R2 is chosen from the group consisting of 4-hydroxy and 5-methoxy.

7. Compounds of the formula I

wherein R1 is selected from the group consisting of methyl, ethyl, propyl, cyano, methoxy, cyanomethyl, hydroxymethyl and CH3OC2H4NHCOCH2O-; R2 and R3 are the same or different and are each selected from the group consisting of hydrogen, hydroxy, methoxy and hydroxymethyl, provided that R2 and R3 are not both hydrogen; X represents -O- or -S-; and the therapeutically acceptable salts thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

8. A compound of the formula I as defined in claim 7 wherein R1 is selected from the group consisting of methyl, ethyl and cyano, whenever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

9. A compound of the formula I as defined in claim 7 wherein R3 is hydrogen and R2 is selected from the group consisting of hydroxy and methoxy, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

10, A compound of the formula I as defined in claim 7 wherein R3 is hydrogen and R2 is selected from the group consisting of 2-hydroxy, 4-hydroxy and 4-methoxy, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

11. A compound of the formula I as defined in claim 7 wherein R3 is a methoxy group and R2 is chosen from the group consisting of hydroxy and methoxy, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

12. A compound of the formula I as defined in claim 7 wherein R3 is a 3-methoxy group and R2 is chosen from the group consisting of 4-hydroxy and 5-methoxy, whenever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.

13. Process for the preparation of 3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-methylphenoxy propanol-2 hydrochloride, which process comprises reacting 1,2-epoxy-3-o-methylphenoxy propane with 2-(4-hydroxyphenoxy)-ethylamine, and recovering the product as its hydrochloride salt.

14, 3-[2-(4-Hydroxyphenoxy)-ethylamino]-1-o-methylphenoxy-propanol-2 hydrochloride, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof,

Process for the preparation of 3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-ethylphenoxy-propanol-2 hydrochloride, which process comprises reacting 1,2-epoxy-3-o-ethylphenoxy propane with 2-(4-hydroxyphenoxy)-ethylamine, and recovering the product as its hydrochloride salt.

16. 3-[2-(4-Hydroxyphenoxy)-ethylamino]-1-o-ethylphenoxy-propanol-2 hydrochloride, whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

17. Process for the preparation of 3-[2-(4-hydroxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 tartrate, which process comprises reacting 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(4-hydroxyphenoxy-ethylamine, and recovering the product as its tartrate salt

18. 3-[2-(4-Hydroxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 tartrate, whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.

19. Process for the preparation of 3-[2-(4-hydroxyphenylthio)-ethyl-amino]-1-o-cyanophenoxy-propanol-2, which process comprises reacting together 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(4-hydroxyphenylthio)-ethylamine.

20. 3-[2-(4-Hydroxyphenylthio)-ethylamino]-1-o-cyanophenoxy-propanol-2, whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.

21. Process for the preparation of 3-[2-(4-methoxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 hydrochloride, which process comprises reacting together 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(4-methoxyphenoxy)-ethylamine, and recovering the product as its hydrochloride salt.

22. 3-[2-(4-Methoxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 hydrochloride, whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.

23. Process for the preparation of 3-[2-(2-hydroxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 hydrochloride, which process comprises reacting together 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(2-hydroxyphenoxy)-ethylamine, and recovering the product as its hydrochloride salt.

24. 3-[2-(2-Hydroxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 hydrochloride, whenever prepared by the process of claim 23 or by an obvious chemical equivalent thereof.

25. Process for the preparation of 3-[2-(4-hydroxy-3-methoxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 hydrochloride, which process comprises reacting together 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(4-hydroxy-3-methoxyphenoxy)-ethylamine, and recovering the product as its hydrochloride salt.

26. 3-[2-(4-Hydroxy-3-methoxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 hydrochloride, whenever prepared by the process of claim 25 or by an obvious chemical equivalent thereof.

27. Process for the preparation of 3-[2-(3,5-dimethoxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 hydrochloride, which process comprises reacting together 1,2-epoxy-3-o-cyanophenoxy-propane and 2-(3,5-dimethoxyphenoxy)-ethylamine, and recovering the product as its hydrochloride salt.

28. 3-[2-(3,5-Dimethoxyphenoxy)-ethylamino]-1-o-cyanophenoxy-propanol-2 hydrochloride, whenever prepared by the process of claim 27 or by an obvious chemical equivalent thereof.