NO750098L - - Google Patents

Description

New amines and their process

manufacture.

The invention relates to new amines of formula I

wherein R means methyl or ethyl, as well as a process for their preparation.

The new compounds have valuable pharmacological properties. Thus, they block cardiac B receptors shown by

.the determination' of the antagonism of tachycardia after an intravenous injec-

tion of 0.5/Ug/kg of d/l-isoprotereriosulfate to anesthetized cat at an intravenous dose of 0.002 to 2 mg/kg. Thus, they block the vascular 3-receptors, which is shown on the determination of the antagonism of vasodilation after an: intravenous injection, of 0.5/Ug/kg of d/1-isoproterenol sulfate in anesthetized cat an intravenous dose of 3 mg/kg or more.

The new compounds can be used as cardioselective antagonists of adrenergic B-receptor stimulators, e.g. in the treatment of arrhythmias and angina pectoris. They can also be used as valuable intermediates in the production of other useful compounds, especially pharmaceutically active compounds.

The new compounds can be produced in and of themselves

known methods.

(Method a) A compound of formula II

in which R has the above meaning, X1 means a hydroxy group, Z is a reactive, esterified hydroxy group or X1 and Z together mean an epoxy group are reacted with isopropylamine.

A reactive esterified hydroxy group is in particular a hydroxy group 'esterified with a strong inorganic or organic acid',

preferably a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, further sulfuric acid or a strong organic sulphonic acid, such as a strong aromatic sulphonic acid, e.g. benzenesulfonic acid, k-bromobenzenesulfonic acid or 4-toluenesulfonic acid. Thus Z is preferably chlorine, bromine or iodine.

This reaction is carried out in the usual way. When using a reactive ester as a starting material, the preparation preferably takes place in the presence of a basic condensation agent and/or with an excess of an amine. Suitable basic condensation substances are e.g. alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as potassium carbonate and alkali metal alcoholates such as sodium methylate, potassium ethylate and potassium tert.-butylate.

(Method b).. A compound of formula III

in which R has the above meaning, is reacted with a compound of formula IV

This turnover is carried out in the usual way, preferably

in the presence of a basic condensing agent and/or an excess of an amine. Suitable basic condensation substances are e.g. alkali alcoholates, preferably sodium or potassium alcoholates., or also alkali carbonates such as sodium or potassium carbonate..

(Method c). A compound of formula V

in which R has the above meaning is reacted with a compound of formula VI

where X<1>and Z have the same meaning.

This reaction is carried out in the usual way.- In de. cases where reactive esters are used as starting material, the compound of formula V can conveniently be used in the form of the metal phenolate or the alkali metal phenolate, preferably sodium phenolate, or it is worked in the presence of an acid-binding substance, preferably a condensing agent, which can form a salt of the compound of formula V as alkali metal alcoholate.

(Method d). A compound of formula V can be reacted

with a compound of formula VII

(Method e). A residue can be cleaved from a compound of formula I above, in which R has the above meaning and in which the nitrogen atom (s) of the amino group (s) and/or the hydroxy group is connected to a cleavable residue.

Such decomposable residues are in particular those which can be decomposed by means of solvolysis, reduction, pyrolysis or fermentation.

Residues that are cleavable by solvolysis are preferably residues that are cleavable by hydrolysis or ammonolysis.

Residues that can be split by hydrolysis are e.g. an acyl residue, which, when present, are functionally modified carboxy groups,<!>eg. oxycarbonyl radicals, such as alkoxycarbonyl radicals, e.g. tert-butoxycarbonyl radicals or ethoxycarbonyl radicals, aral-oxycarbonyl radicals such as phenyl lower oxycarbonyl radicals, e.g. a carbobenzyloxy acid residue, halogenocarbonyl residue3 e.g. a chlorocarbon residue, further arylsulfonyl residues such as toluenesulfonyl or bromobenzenesulfonyl residues and possibly as halogenated or fluorinated lower alkanoyl residues such as formyl-j acetyl or trifluoroacetyl residue or a benzyl residue or cyano groups or silyl residues such as trimethylsilyl residue.

Of the above-mentioned residues present at the hydroxy groups, which residues are cleavable by hydrolysis, the oxycarbonyl residues and the lower alkanoyl residues and the benzoyl residues are preferably used.

In addition to the above, double-bonded residues, which are cleavable at the amino group during hydrolysis, are used e.g. alkylidene or benzylidene residue or a phosphorylidene group such as a triphenylphosphorylidene group, in which the nitrogen atom acquires a positive charge.

The cleavable residue at the hydroxy group and the amino group

by means of hydrolysis are further divalent residues such as substituted methylene. As substituents on the methylene residues, any organic residue can be used, whereby it does not play any role in the hydrolysis which compound is a substituent of the methylene residue. As methylene substituents, it can e.g. aliphatic or aromatic residues such as alkyl as mentioned above, aryl e.g. phenyl or pyridyl. The hydrolysis can be carried out in any suitable manner in a basic or preferably acidic medium.

Compounds which have residues which can be split by hydrolysis are also compounds according to formula VIII

wherein R has the same meaning as above and Y means a carbonyl or thiocarbonyl residue.

The hydrolysis is carried out in an analogous way, i.e. in the presence of a hydrolyzing agent. agent, e.g. in the presence of an acidic agent, such as dilute mineral acid such as sulfuric acid or hydrohalic acid, or in the presence of basic substances such as e.g. alkali metal hydroxides, such as sodium hydroxide. Oxycarbonyl residues, arylsulfonyl residues and cyano groups can be suitably cleaved off by means of acidic agents, such as by means of hydrohalic acid. suitable hydrobromic acid. Preferably, the cleavage can take place using diluted hydrobromic acid, if possible a mixture with acetic acid. Cyano groups are preferably split off using hydrobromic acid at an elevated temperature such as in boiling hydrobromic acid according to the "bromocyano method" (von Braun). Furthermore, e.g. a tert.-butoxycarbonyl residue is cleaved off under anhydrous conditions by means of a treatment with a suitable acid such as trifluoroacetic acid. Acidic agents are preferably used in the hydrolysis of compounds of formula VIII.

Residues that can be split off by ammonolysis are especially the halogenocarbonyl residues, such as the chlorocarbonyl residue. The ammonolysis can be carried out in the usual way, e.g. by means of an amine, containing at least one hydrogen atom bound to the nitrogen atom, which. a mono- or di-alkylamine, e.g. methylamine or dimethylamine or especially ammonia, preferably at elevated temperature. Instead of ammonia, you can use an agent that forms ammonia such as hexamethylene tetraamine.

Residues that can be split off using reduction are e.g. an α-arylalkyl residue, such as a benzyl residue or an α-araloxycarbonyl residue, such as a benzyloxycarbonyl residue, which can be cleaved in the usual way by means of hydrogenolysis, especially by catalytically activated hydrogen, such as by hydrogen in the presence of a hydrogenation catalyst, e.g. Raney nod1. Other residues which can be cleaved by means of hydrogenolysis are 2-halogeno alkoxycarbonyl residues such as 2,2,2-trichloroethoxycarbonyl residues are 2-iodoethoxy or 2,2,2-tri-bromomethoxycarbonyl residues, which can be cleaved off in the usual way, suitably by means of metallic reduction (so-called nascent hydrogen). Nascent hydrogen can be obtained by the impact of metal or metal alloys such as amalgam on compounds that give hydrogen such as carboxylic acids, alcohols or water, zinc or zinc alloys in particular together with acetic acid can be used. Hydrogenolysis of 2-halogen alkoxycarbonyl residues can also take place using chromium or chromium (II) compounds such as chromium (II) chloride or chromium (II) acetate.

A residue that can be split off by reduction can also be

an arylsulfonyl group such as a toluenesulfonyl group, as usual

can be split off by reduction, using nascent hydrogen, e.g. by means of an alkali metal such as lithium elier'sodium i

■liquid ammonia and can conveniently be split off from a nitrogen atom. When carrying out the reduction, care must be taken that other reducing groups are not affected. Residues which are cleavable by means of pyrolysis, in particular residues which are cleavable from nitrogen atoms are in the case substituted, suitably unsubstituted carbamoyl groups. Suitable substituents are e.g. lower alkyl or aryl lower alkyl such as methyl or benzyl or aryl, such as phenyl, the pyrolysis being carried out in the usual way, as other thermally susceptible groups must be protected.

Leftovers that are. cleavable by fermentation, in particular residues cleavable from the nitrogen atom are in the appropriate case substituted, however preferably unsubstituted carbamoyl groups. Suitable substituents are e.g. lower alkyl or aryl lower alkyl, such as methyl or benzyl or aryl such as phenyl. Fermentation is carried out in the usual way, i.e. with the help of the enzyme urease or soybean extract at approx. 20°C or a slightly elevated temperature.

(Method f). A ship base with formula IX or X

or a cyclic tautomer corresponding to formula X with formula XI

can be reduced, in which R has the same meaning as stated above, and in that the compounds of formula X and XI can also co-exist. This reduction is carried out in the usual way, e.g. using a dilett metal hydride such as sodium borohydride, lithium aluminum hydride, with a hydride such as borane, with formic acid, or by means of a catalytic

hydrogenation, as with hydrogen in the presence of Raney nod1. During the reduction, it must be ensured that no other groups are attacked.

(Method g). In a connection with formula XII

in which X 2 is a residue transferable in a residue R0C0NHCHpCHp0 with the above-mentioned 2 2 meaning, X is transferred to ROCONHCHPCHPO. A residue X that is transferable in ROCONHCH2C<H>2<0> is e.g. a residue Z-CH2CH20, Z having the above meaning. A compound XII which has such a residue Z-CH2CH20 as X2 can be reacted with a compound ROCONH2 in a known manner. Thus, a compound of formula XIII can be reacted with a compound ROCONH2, in which R and Z have the above meaning. The reaction is carried out in the usual way, i.e. as the reaction according to method a) of a compound of formula II with isopropylamine. A residue X<2> which is transferable ROCONHCH'2 CH20 is e.g. the remainder H2NCH2'CH2O. A compound XII having such a residue H2NCH2CH20 as X<2> must be reacted in the usual way with a compound R0C0C1. Thus, a compound of formula XIV

is treated with a compound R0C0C1, in which R has the above-mentioned meaning. This reaction is carried out in the usual way, i.e. as the reaction according to method a) of a compound of formula II with isopropylamine.

A residue X<2>transferable in ROCONHCH2CH20 is e.g. a residue Z1-CONHCHpCH?0. A compound XII which has such a residue Z<1->C0NHCH?CH?0 can be reacted in the usual way with a compound R-Z 2 , one of Z 1 and

2

Z is hydroxy and the other is Z having the above meaning.

Thus, a compound of formula XV can be reacted

with a compound R-OH, in which R and Z have the above meaning. The turnover is carried out in the usual way, i.e. as the turnover according to method

a) of a compound of formula II with isopropylamine.

A compound of formula XII having a hydroxy group

as residue X 2 can be converted in the usual way with a compound ROCONHCHpCtp-Zjhvori Z has the above meaning. Thus, a compound of formula XVI

is reacted with a compound ROCONHCHpCfp-Z, in which R and Z have the above meaning. The reaction is carried out in the usual way, i.e. as the reaction according to method a) of a compound of formula II with isopropylamine.

(Method h). In a suitable way, it can also be hydrogenated et

amine of formula XVII

In the usual way, the substituents can be varied from the products obtained within the end product, as well as the compounds obtained can be introduced, split off or transferred into other end products in the usual way..'

Thus, it is possible to catalytically hydrogenate C=C double bonds or OC triple bonds to C-C single bonds using hydrogen in the presence of hydrogenation catalysts. eg .P'latina, palladium or nickel such as Raney nickel. It must be ensured that other reducible groups are not reduced.

Compounds obtained containing a CsC triple bond can further be transferred into a C=C double bond and, if desired, hydrogenated stereospecifically to a C=C-cis or C=C-trans double bond. The hydrogenation of the C=C triple bond to a C=C double bond can be carried out, for example, using 1 mol of hydrogen in the presence of a less active hydrogenation catalyst, such as iron or palladium, for example Raney iron or palladium with barium sulphate, preferably at an elevated temperature . The hydrogenation to a C = C double bond can e.g. take place between 1 mol of hydrogen and a less activated catalyst such as palladium on activated carbon and in the presence of quinoline, palladium on calcium carbonate in the presence of lead salts or Raney nickel1. The hydrogenation to a C=C-trans double bond can take place with the help of sodium in liquid ammonia, with regard to other reducible groups, short reaction times are used

and no excess of reducing agent, possibly an ammonium halide such as ammonium chloride is added as a catalyst..

In the case of the above-mentioned reduction, care must be taken that no further reducible groups are reduced.

The above-mentioned reactions can optionally be carried out simultaneously or in any order.

The above-mentioned reactions are carried out in a manner known per se

in the presence or absence of diluting, condensing and/or catalysing substances at low or elevated room temperature, possibly in a closed vessel.

Depending on the reaction conditions and starting material, the end product is obtained either in free form or in the form of the acid addition salt, which falls within the scope of the invention. Thus, for example, basic, neutral or mixed salts can be obtained as well as hemiamino, sesqui- or polyhydrates. The acid addition salts of the new compounds can be transferred to free compounds in a manner known per se, using e.g. basic agents such as alkali or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In the preparation of acid addition salts, such acids are preferably used which form suitable therapeutically acceptable salts. Such acids are e.g. hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glucolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, phenylacetic acid,

• benzoic acid, p-aminobenzoic acid,, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid?, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halogen-benzenesulfonic acid, toluenesulfonic acid naphthylsulfonic acid or sulfanil-

acid, methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, such as e.g. the picrates can serve as cleaning agents for the free bases that have been obtained when the free bases are transferred into salts, these are separated and the bases are released again from the salts. Due to the close relationship between the new compounds in free form and in the form of their salt, it is to be understood that corresponding salts are covered by the invention in the same way as the free compound.

The invention also relates to any embodiment of the method, where one starts from a compound formed as an intermediate product of a step in the method and the remaining method steps are carried out or the method is interrupted at a step, or where a starting material is formed under the reaction conditions or where a reaction component is present in the form of the salt. Thus, an aldehyde of formula XVIII

wherein R has the above meaning, is reacted with isopropylamine in the presence of a suitable reducing agent, such as one of the above. Thereby a compound of formula IX is obtained as an intermediate which is then reduced according to the invention.

Furthermore, in a manner known per se, amine of formula III can be reacted with acetone in the presence of a suitable reducing agent with one of the above. Thereby a compound of formula X or XI is obtained as an intermediate, which is then reduced according to the invention.

The new compounds can, depending on the choice of starting material and method, be present as optical antipodes or racemates, or, if they contain at least two asymmetric carbon atoms, be present as an isomeric mixture (racemate mixture).

The isomeric mixtures (racemate mixtures) that are obtained can, depending on the physico-chemical differences in the components, be separated into the two stereoisomers (diastereomeric) pure racemates, e.g. by means of chromatography and/or fractional crystallization.

The racemates formed can be separated according to known methods, e.g. by recrystallization from an optically active solvent1 with the help of microorganisms or with an optically active acid that forms salts with the compounds and separation of the salts which thus e.g. by means of their different solubility in the diastereomers, from which the antipodes can be released by the action of a suitable agent. Suitable usable optically active acids are e.g. The L and D forms of tartaric acid, di-o-tolyl tartaric acid, malic acid, maleic acid, camphor sulphonic acid or quinic acid. Preferably, the most active of the two antipodes is isolated.

Such starting materials are preferably used for carrying out the method according to the invention which belong to groups of end products which are primarily particularly desired and especially to the particularly mentioned and preferred end products.

The starting materials are known, or may, if new,

are produced according to methods known per se.

In clinical use, the compounds according to the invention are normally administered orally, rectally or by injection in the form of

pharmaceutical preparations, which contain an active component, either as a free base or as a pharmaceutically acceptable, non-toxic acid additive

sion salt, such as the hydrochloride, lactate, acetate, sulfamate or the like in combination with a pharmaceutically acceptable carrier. At the mention of them. new compounds according to the invention, it is here either about free amine bases or acid addition salts of the free bases, even if the compound is generally or specifically mentioned, provided that the compound is used as such expressions, e.g. in the examples, - should not correspond to this broad meaning. The carrier can be a solid, semi-solid or liquid diluent or a capsule. These pharmaceutical preparations are a further object of the invention. Generally, the amount of active compound is between 0.1 and 95% by weight of the preparation, suitably between 0.5 and 20% by weight in injection preparations and between 2 and 50% by weight in preparations for oral administration.

When preparing pharmaceutical preparations containing a compound according to the invention in the form of a dosage unit for oral administration, the selected compound can be mixed with a solid powdered carrier, such as e.g. lactose, sucrose, sorbitol, mannthiol, starch such as potato starch, corn starch, amylopectin, cellulose derivatives or gelatin, as well as with a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol wax or the like and pressed into tablets. If coated tablets are desired, the above-mentioned prepared core can be coated with a "concentrated solution of sugar. This solution can contain, for example, gum arabic, gelatin, talc, titanium dioxide or the like. Furthermore, the tablets can be coated with a varnish which readily dissolves in volatile organic solvents or solvent mixtures.To this coating a dye can be added to easily distinguish between tablets with different active compounds or different amounts of active compound present.

In the production of soft gelatin capsules (bead-shaped closed capsules), which consist of gelatin and e.g. glycerol or when producing corresponding closed capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules may contain granules of active compound in combination with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Dosage units for rectal administration can be prepared

in the form of suppositories containing the active substance in a mixture with a neutral fatty base, or they can be produced in the form of gelatin rectal capsules containing the active substance in a mixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration may be in the form of syrups or suspensions, e.g. solutions containing from approx. 0.2% by weight to approx. 20% by weight of active substance, whereby the rest consists of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations can contain colourants, flavourings, saccharin and carboxymethyl cellulose as a thickener.

Solutions for parenteral administration by injection can be prepared as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from approx. 0.5% by weight to approx. 0.10% by weight. These solutions may also contain stabilizers and/or buffers and may thus be available in different dosage unit ampoules.

The production of pharmaceutical tablets for oral use is carried out according to the following methods: The solid substances are ground or sieved to a specific particle size. The binder is homogenized and suspended in a ■ certain amount of solvent. - The therapeutic compound and necessary auxiliary substances are mixed by continuous and constant mixing with the binder solution and moistened so that the solution is evenly distributed in the mass without overwetting any parts. The amount of solvent is usually adjusted so that the mass achieves a consistency similar to moist snow. The wetting of the powdered mixture with the binder solution causes the particles to stick together to form aggregates and the granulation process itself is carried out in such a way that the mass is pressed through a sieve in the form of a stainless steel mesh which has a mesh size of approx. 1 mm. The pulp is then placed in thin layers on a tray to be dried in a drying oven. The drying takes place within 10 hours, must be carefully standardized as the degree of vaporization of the granulate is very important for the subsequent process

and for the characteristics of the tablets. Drying in a fluidized bed can optionally be used. • In this case, the mass is not placed on a tray, but poured into a container that has a mesh bottom.

After the drying step, the granules are sieved so that the desired particle size is achieved. Under certain conditions dust must be removed.

Explosives, lubricants and anti-adhesion substances are added to the so-called final mixture. After this mixing, the mass must have the correct composition for the tableting step.

The cleaned tablet-piston machine is equipped with a certain set of pistons, and is lowered, after which a suitable setting for the tablet's weight and degree of compression is determined. The weight of the tablets is responsible for the size of the dose in each tablet and is calculated based on the amount of therapeutic substance in the granules. The degree of compression affects the tablet size, strength and ability to break down in water. Especially with regard to the last two properties, the choice of compression pressure (0.5 to 5 tonnes) means something of a challenge. Once the correct alignment has been found, tablet production is started, which is carried out at a rate of 20,000 to 200,000 tablets per hour. Pressing the tablets requires different time and depends on the portion size.

The tablets are freed of adhering powder in a special device and are then stored in closed packaging until they are handed out.

Many tablets, especially those that are sharp and bitter, are coated with a coating. This means that these are coated with a layer of sugar or other suitable coating.

The tablets are usually packed on machines that have an electronic counting device. The different types of packaging consist of glass or plastic containers, but also cans, tubes and special dose-matched packages.

The daily dose of the active substance varies and depends on the type of administration, but as a general rule it is 100 to 400 mg/day active substance as peroral administration and 5 to 20 mg/day as intravenous administration.

The invention shall be explained in more detail by means of some non-limiting examples.

Example 1.

4.1 g of 1,2-epoxy-3-[4'-(methoxycarbonylaminoethoxy)-phenoxy-propane is mixed with 4.1 ml of isopropylamine and 2.5 ml of isopropanol. The mixture is refluxed for 3 hours and evaporated to dryness. The residue was dissolved in 2 molar hydrochloric acid and the mixture was washed twice with ether. The aqueous phase was made alkaline with sodium hydroxide

and extracted with methylene chloride. After drying and evaporation, the residue was dissolved in ethyl acetate and ether containing HCl was added to pH 4. The hydrochloride was filtered off and isolated after being recrystallized<:>from acetone, obtaining 2.6 g of 1-isopropylaamino-3-/ _~4' - (2-Methoxycarbonylaminoethoxy)-phenoxy/-propanol-2 hydrochloride. Melting point 108°C. The structure was determined using NMR.

Example 2.

The raw material indicated in example 1 was produced in the following way. 20.0 g of N,N-dibenzyl-2-chloroethylamine hydrochloride and 27.6 g of potassium carbonate are mixed in 250 ml of acetonitrile. The mixture is refluxed for 15 minutes and 13.8 g of 4-benzyloxyphenol is added, after which the mixture is refluxed for 5 hours with stirring. After filtration and evaporation, the residue was recrystallized from petroleum ether.

18.4 g of 1-(N,N-dibenzylamino)-2-(4'-benzyloxyphenoxy)-ethane were formed. The structure was determined by NMR.

The product formed was dissolved in 185 ml of 95% ethanol

and 5.5 ml of concentrated HCT. After hydrogenation over Pd/C catalyst, filtration, evaporation and recrystallization from isopropanol/

1o

ether, 5.8 g of 4-aminoethoxyphenol were obtained. Melting point 175 C. The structure was determined by NMR.

The 4-aminoethoxyphenol formed and 6.3 g of sodium bicarbonate were mixed in 25 ml of water and cooled in an ice bath. 5.3 g of chloroform methyl ester were added with stirring. The mixture was stirred at room temperature for 3 hours and then extracted with methylene chloride. The methylene chloride phase was dried and evaporated. The diacylated product formed was then hydrolyzed overnight with a

2 molar sodium hydroxide solution. The mixture was acidified with

hydrochloric acid and extracted with methylene chloride. After drying and evaporation, 3.9 g of 4-methoxycarbonylaminoethoxyphenol was formed as a yellow oil. The structure was determined by NMR.

The p-methoxycarbonylaminoethoxyphenol thus formed was dissolved in 30 ml of epichlorohydrin and 1.8 g of potassium carbonate was added.

■The mixture was refluxed for 2 hours. After filtration and evaporation, 4.1 g of 1,2-epoxy-3-(4'-methoxycarbonylamino-ethoxyphenoxy)-propanol-2 was formed as an oil which crystallizes. Melting point 65°C. The structure was determined by NMR.

Example 3- (Method B).

10 g of 4-(2-methoxycarbonylaminoethoxy)-phenylglycidyl ether in 1,100 ml of ethanol was saturated with gaseous ammonia and the mixture was

heated in an autoclave on a boiling water bath for 4 hours. The solvent was evaporated and the residue dissolved in ethyl acetate and HCl gas was introduced. The precipitated hydrochloride was filtered off and dissolved in 50 ml of ethanol, to which was added isopropylamine and 15 g of K^CO-^.

The mixture was heated in an autoclave at 130°C for 10 hours, after which the solvent was evaporated and the residue was mixed with 100 ml of 2 normal HCl and 100 ml of ether. The aqueous phase was separated and made alkaline with 2N NaOH and extracted with ethyl acetate. The solvent phase was dried over 1 2 CO 2 , whereupon 1-isopropylamino-3-4-(2-methoxycarbonylaminoethoxy)-phenoxy-7-propanol-2 was transferred to the hydrochloride by introducing ether containing HCl to pH 4 and recrystallization from .acetone'.- Melting point 108°C.

Example 4. (Method C).

2.4 g of Na was dissolved in .100 ml of ethanol, whereupon it became

added 19.0 g of 4-(2-methoxycarbonylaminoethoxy)phenol and 15.5 g of 1-isopropylamino-3-chloropropanol-2. The mixture was heated in an autoclave on a boiling water bath for 15 hours. It was then filtered and the filtrate was evaporated to dryness. The residue was acidified with 2N HCl and extracted with ether, after which the aqueous phase was

made alkaline with 2 normal NaOH and extracted with ethyl acetate. The ethyl acetate was dried over MgSO4 and 1-(isopropylamino-3-[4-(2-methoxycarbonylaminoethoxy)-phenoxy]-propanol-2) was transferred to the hydrochloride in accordance with Example 1. Melting point 107°C. Example 5- ( Method E).

Consistent with Example 4 above, N-benzyl-1-isopropylamino-3~_/ 4-(2-methoxycarbonylaminoethoxy)-phenoxy/propanol-2 was prepared from 4(2-methoxycarbonylaminoethoxy)phenol and N-benzyl-1-1-isopropylamino- 3-Chloropropanol-2 p-hydroxybenzoate, 10 g of compounds thus formed were dissolved in 100 ml of ethanol, 0.5 g of Pd/C (10%) catalyst was added and hydrogenation was carried out until the calculated amount of H2 was absorbed. After filtration, the mixture was evaporated to dryness and the residue 1-isopropylamino-3-/. 4-(2-Methoxycarbonylaminoethoxy)phenoxy/-propanol-2 was transferred to the hydrochloride in accordance with Example 1 above. Melting point 108°C.

Example 6. (Method F).

11 g of 1-amino-3-H. 4-(2-Methoxycarbonylaminoethoxy)phenoxy/-propanol-2 prepared in accordance with Example 3 was dissolved in 80 ml of ethanol containing 5 g of acetone. The solution was cooled in an ice bath and 10 g of sodium borohydride was gradually added. The temperature was increased to room temperature and after 1 hour 2.00 ml H 2 O was added and the mixture was extracted with ethyl acetate. The ethyl acetate phase was dried over K 2 CO 3 and the compound 1-isopropyl-amino-3-[_ 4-(2-methoxycarbonylaminoethoxy)-phenoxy /-propanol-2 was transferred to the hydrochloride by introducing ether containing HCl to pH 4, isolating the precipitate and recrystallization from acetone. Melting point 108°C.

Example 7- (Method G).

10 g of 1-isopropylamino-3_/_ 4-(2-chloroethoxyphenoxy_)_/_ propanol-2, 8 g of methoxycarbonylamine and 15 g of PpCO-^ were mixed in 100 ml of a.etonitrile and ^refluxed for 5 hours with stirring. Filtration and evaporation gave crude 1-isopropylamino-3'', 4-(2-methoxycarbonylaminoethoxy)phenoxy/-propanol which was dissolved in ethyl acetate and transferred into the hydrochloride by introduction of ether containing HCl and recrystallization of the precipitate from acetone .Melting point 108° C. Example 8. (Method D).

0.116 mol of 4-methoxycarbonylaminoethoxyphenol was mixed with 0.080 mol of 11-isopropyl-3-acetidinol, 0.500 mol of benzyl alcohol and 0.003 mol of KOH. The mixture was refluxed at 140°C for 6 hours with stirring and then cooled and extracted with 2 molar HCl. The aqueous phase was made alkaline and then extracted with chloroform. After drying and evaporation, the residue was dissolved in ether and ether containing HCl was added to the solution. The hydrochloride was filtered off and washed with acetone. Hydrochloride of 1-isopropylamino-3-/ was formed. 4' - (2-methoxycarb ony laminoethoxy)-phenoxyT-propanol-2 with melting point 108°C.

Example 9•

A syrup containing 2% (weight per volume) of active substance was prepared from the following substances:

Sugar, ■saccharin and the ether salt were dissolved in 60 g of warm water. After cooling, glycerol and a solution of flavoring dissolved in ethanol were added. 100 ml of water was then added to the mixture.

The above-mentioned active substance can be replaced with other pharmaceutically acceptable acid addition salts.

Example 10.

1-isopropylamino-3-/. 4'-(2-Methoxycarbonylaminoethoxy)-phenoxy/-propanol-2 hydrochloride (250 g) was mixed with lactose (175.8 g), potato starch (169.7 g) and colloidal silicic acid (32 g). The mixture was moistened with .10% solution of gelatin and was granulated through a 12 mesh sieve. After drying, potato starch (160 g), talc (50 g) and magnesium stearate (5 g) were mixed and the resulting mixture was pressed into tablets (10,000) containing 25 mg of substance. The tablets are sold on the market equipped with a refractive

, line to give doses other than 25 mg or to give a multiple thereof when they are broken.

Example 11.

Granules were. prepared from 1-isopropylamino-3-[4-(2-methoxycarbonylaminoethoxy)-phenoxy]-propanol-2-hydrochloride (250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After the drying step, the granules were mixed with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) and pressed into 10,000 biconvex tablets. These tablets are coated primarily with a 10% alcoholic solution of shellac and then the aqueous solution containing sucrose (45%), gum arabic (5%), gelatin (4%) and a dye (0.2%). Talc and icing sugar were used for dusting after the first five coats. The coating was then coated with 66% sugar syrup and polished with 10% carnauba wax solution in carbon tetrachloride.

Example 12. ;

1-isopropylamino-3~/_"4~-(2-metocy carbonylaminoethoxy)phenoxy/-propanol-2-hydrochloride (1 g), sodium chloride (0.8 g) and ascorbic acid (0.1 g ) was dissolved in a sufficient amount of distilled water to give 100 ml of solution.This solution containing 10 mg of active substance in each ml was used to fill ampoules which were sterilized by heating at 120°C for 20 minutes.

Claims (11)

1. Process for the preparation of new amines of formula I in which R means methyl or ethyl, characterized in that either a) a compound of formula II wherein R has the above meaning, X<1> means hydroxy group and Z is one reactive, esterified hydroxy group or X <1> and Z together form an epoxy group, reacted with isopropylamine, or b) a compound of formula III in which R has the above-mentioned meaning, is reacted with a compound of "formula IV wherein Z has the above meaning, or c) a compound of formula V in which R has the above-mentioned meaning, is reacted with a compound of formula VI in which Z and X <1> have the above meaning, or d) a compound of formula V in which R has the above-mentioned meaning, is reacted with a compound of formula VII or e) a residue is cleaved from a compound of formula I, in which R has the above-mentioned meaning and in which the nitrogen atom or atoms in the amino group or groups and/or hydroxy groups connected by a cleavable residue, or f) ' ■ a Schiff's base with the formulas IX is reduced. or X or a cyclic tautomer of formula XI corresponding to formula X wherein R has the above-mentioned meaning and^ whereby the compounds of the formulas X and XI may exist together or g) ■ transfer in a connection with formula XII in which X 2 is a residue transferable into a residue ROCONHCHpCHpO ■ with the above meaning, X 2 to ROCONHCHpCtpO, .or h) hydrogenation of a compound of formula XVII and if desired, substituents are introduced or removed or reacted in the compounds within the definition of the end products, or compounds formed are transferred into other end products and/or isomer mixtures formed are separated into pure isomers, and/or racemates formed are separated into optical antipodes and/or free bases formed are transferred to their therapeutically tolerable salt or salts formed are transferred in the free base. 2. Method according to claim 1, characterized in that the starting point is a compound formed as an intermediate at one or other step in the method and the remaining method steps are carried out or the method is interrupted at one step, or a starting material is formed under the reaction conditions, or a reaction component is introduced if possible in the form of its salt. 3. Amine of formula I wherein R is methyl or ethyl. 4. 1-isopropylamino-3-/4'-(2-methoxycarbonylaminoethoxy)-phenoxy/-propanol-2.. 5. Compound according to one of claims 3 and 4 in the form of its dextro-rotating optical antipode. 6. Compound according to one of claims 3 and 4 in the form of its levo-rotating optical antipode. 7. Compound according to one of claims 3-6 in the form of the free base. 8. Compound according to one of claims 3-6 in the form of a salt. 9. Compound according to one of claims 3-6 in the form of a therapeutically tolerable salt. 10. Pharmaceutical preparation containing as active substance a compound according to one of claims 3-7 and 9 together with a therapeutically acceptable carrier. 11. Method for the treatment of cardiovascular diseases, characterized by the administration to mammals including humans of a therapeutically active amount of at least one compound according to one of claims 3-9-