HU177638B - Process for producing 3-bracket-2-phenoxy-ethyl-amino-bracket-1-phenoxy-propanoles - Google Patents

Abstract

The process is used for preparing the novel amines of the formula (I) <IMAGE> R<1>, R<2> and R<3> are defined in Patent Claim 1. The reactions for preparing the said compounds always take place between primary amines and compounds having a reactive, esterified hydroxyl group or an epoxy group. The novel compounds effectively block beta receptors.

Description

The present invention relates to novel potent β-receptor blocking aminopropanol derivatives and their salts and to pharmaceutical compositions containing these compounds as active ingredients. The new compounds block the β-receptors of the heart and are thus useful in the treatment of cardiovascular disease.

According to the invention, 3- (2-phenoxyethylamino) -1-phenoxypropanols of formula I and their salts are prepared.

In this formula

R ^{1 is} cyano, cyanomethyl, hydroxymethyl or -OCH ₂ -C-NH-C ₂ H ₄ -OCH ₃ ;

II

R ² and R ³ are each independently hydroxy, methoxy or hydroxymethyl, and R ₃ may also be hydrogen, n being 2, 3 or 4.

German Patent Publication No. 2,438,077 discloses 3- (2-phenoxyethylamino) -1-phenoxypropanol-2 derivatives having a phenoxy group at the 1-position with hydrogen, halogen, alkyl, alkenyl, alkoxy or and the phenoxy group attached to the 2-position of the ethylene chain may be disubstituted and one of the substituents is hydrogen or halogen or alkyl or alkoxy, the other substituent is attached via a methylene or ethylene group to a polar group, i.e. carboxy, alkoxycarbonyl; , phonyl, alkenyl, carbamoyl, sulfo, alkoxysulfonyl, sulfamoyl, cyano, azido, nitro or trifluoromethyl.

German Patent Publication No. 2,531,312 discloses 2-propanol derivatives having substantially similar basic structures, but with nine different substituents and meanings.

The novel compounds have valuable pharmacological properties. The compounds block cardiac β-receptors, which are demonstrated by determining the inhibitory effect on tachycardia following intravenous injection of 0.5 pg / kg d / l-isoproterenenesulfate intravenously at an intravenous dose of 0.002-2.0 mg / kg. . The novel compounds also block vascular β-receptors, which are demonstrated by administering intravenous doses of 0.002 to 2 mg / kg or more after intravenous injection of 0.5 pg / kg d / l-isoproterenol sulfate in anesthetized cats. vasodilator effect. The compounds also have a stimulatory effect on β-receptors, i.e. they exhibit intrinsic activity. This property is mainly related to those β-receptors in the vascular system that cause dilation of peripheral vessels.

The novel compounds are useful in the treatment of arrhythmia, angina pectoris and hypertension. Peripheral vasodilation is mainly useful in the latter two indications. The novel compounds can also be used as intermediates for the preparation of other valuable therapeutic compounds.

For example, the following compounds of formula I can be prepared according to the invention:

3- [2- (4-hydroxy-phenoxy) ethylamino] -l- (p-cyano-phenoxy) propan-2:

3- [2- (4-hydroxy-phenoxy) ethylamino] -l- (p-cyano-phenoxy) propanol-2:

3- [2- (4-Hydroxy-phenoxy) -ethylamino] -1- (o-hydroxymethoxy-phenoxy) -propanol;

3- [2- (3-hydroxymethyl-4-hydroxy-phenoxy) ethylamino] -l- (p-cyano-phenoxy) -propanol-2;

3_ [2- (4-methoxyphenoxy) ethylamino] -l- (p-cyano-phenoxy) -propanol-2;

3- [2- (2-hydroxy-phenoxy) ethylamino] -l- (p-cyano-phenoxy) -propanol-2;

3- [2- (4-hydroxy-3-methoxy-phenoxy) ethylamino] -l- (p-cyano-phenoxy) -propanol-2;

3- [2- (3,5-Dimethoxy-phenoxy) -ethylamino] -1- (o-cyano-phenoxy) -propanol-2;

3- [2- (4-hydroxy-phenoxy) ethylamino] -l- [o- (methoxy-ethyl-aminocarbonyl) phenoxy] propanol-second

Pharmaceutically acceptable salts of the compounds are prepared using salt forming acids. Such acids include hydrogen halides, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, citric, tartaric, -, ascorbine, malein, hydroxymalein or pyrosol, phenylacetate, benzo, ρ-aminobenzo, anthranil, ρ-hydroxybenzo, salicyl or ρ-amino-salicyl, embon, methanesulfone- , ethanesulfonic, hydroxyethanesulfone, ethylene sulfone, halobenzenesulfonic, toluenesulfonic, naphthylsulfonic or sulfonyl acids, methionine, tryptophan, lysine or arginine.

The compounds may be used orally or parenterally for the acute and chronic treatment of the aforementioned cardiovascular disorders.

The biological effects of the new compounds have been investigated, and the various assays performed will be described later.

The novel compounds of formula I may be prepared by the following processes:

a) A compound of formula II wherein R ^{1 is} as defined above, X ^{1 is a} hydroxy group, Z is a reactive esterified hydroxy group, or X ¹ and Z together form an epoxy group, with an amine of formula a wherein R ² , R ³ , meaning - we react.

The reactive esterified hydroxyl group is preferably a strong inorganic or organic acid esterified hydroxyl group, the acid being preferably a hydrogen halide such as hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid or a strong organic sulfonic acid such as benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-bromo-sulfonic acid. Thus, Z is preferably chlorine, bromine or iodine.

The above reaction is carried out in the usual manner. When reactive ester is used as starting material, the synthesis is preferably carried out in the presence of a basic condensing agent and / or in the presence of an excess of amine. Suitable basic condensing agents are, for example, 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.

The reaction is carried out in a C 1 -C 4 alkanol by refluxing the reagents in the solvent for a period of time to form a compound of Formula I, which is usually from 1 to 12 hours.

b) Alternatively, reacting a compound of Formula III wherein R ^{1 is} as defined above with a compound of Formula b wherein R ² , R ³ , n and Z are as defined above.

The reaction is carried out in the usual manner, preferably in the presence of a basic condensing agent and / or in excess of the amine. Suitable basic condensing agents are, for example, alkali metal alcoholates, preferably sodium or potassium alcoholate, or alkali metal carbonates, such as sodium or potassium carbonate.

The reaction is carried out in a C 1-3 alkanol in an autoclave heated to 100-130 ° C for 5-15 hours.

c) Further, a compound of formula IV wherein R ^{1 is} as defined above is reacted with a compound of formula V wherein Z, X ¹ , R ² , R ^{3 are} as defined above.

The reaction is carried out in the usual manner. In cases where reactive esters are used as starting materials, the compounds of formula IV are preferably used in the form of a metal phenolate such as an alkali metal phenolate, preferably sodium phenolate, or in the presence of an acid scavenger, preferably a condensing agent.

The reaction is carried out in a C 1-3 alkanol in an autoclave heated to 80-100 ° C for 5-15 hours.

d) A compound of formula Va wherein R ¹ , Z and na are as defined above is reacted with a compound of formula IVa wherein R ² , R ^{3 are} as defined above.

e) A compound of formula IV wherein R * is as defined above is reacted with a compound of formula VI wherein R ² , R ³ , na are as defined above.

The reaction is carried out in the usual manner, and the reaction mixture is refluxed under alkaline conditions in a suitable solvent such as benzyl alcohol for several hours. In this way, the phenol is first converted to a metal phenolate, such as an alkali metal phenolate, before being added to the azetidinol of formula VI.

f) Alternatively, a compound of Formula I wherein a cleavable group is attached to the nitrogen atom and / or the hydroxy group of the amino group may be cleaved.

Such cleavable groups are, in particular, those which can be cleaved by solvol tasting, reduction, pyrolysis or fermentation.

The groups which can be cleaved by solvolysis are preferably those which can be cleaved by hydrolysis or ammonolysis.

Examples of hydrolysis cleavable groups are acyl groups which, when present, are carboxyl groups which are functionally modified, such as oxycarbonyl groups such as alkoxycarbonyl groups such as tert-butoxycarbonyl or ethoxycarbonyl groups, aralkoxycarbonyl groups such as phenyl-lowercarbonyl, such as chlorocarbonyl, and arylsulfonyl groups such as toluenesulfonyl or bromobenzenesulfonyl groups, and optionally halogenated lower fluoroalkanoyl groups such as formyl, acetyl or trifluoroacetyl, or benzyl or cyano groups or silyl groups such as trimethylsilyl.

Of the aforementioned groups on the hydroxyl group which can be cleaved by hydrolysis, oxycarbonyl groups and lower alkanoyl groups or benzoyl groups are preferred.

In addition, double bonded groups which may be cleaved from the amino group by hydrolysis, such as an alkylidene or benzylidene group, or a phosphorylidene group such as a triphenylphosphorylidene group, can be used to give a positive charge to the nitrogen atom.

Further, the groups which can be cleaved by hydrolysis from the hydroxyl group and the amino group are divalent groups, such as optionally substituted methylene groups. As the substituents of the methylene groups, any organic group may be used, since it is of no interest to hydrolysis what compound is substituted for the methylene group. Substituents for the methylene group include, for example, aliphatic or aromatic groups such as the alkyl groups mentioned above, or phenyl or pyridyl groups. The hydrolysis may be carried out in a conventional manner, preferably in a basic or preferably acidic medium.

Compounds having hydrolysis cleavable groups are also compounds of formula VII wherein R ¹ , R ² , R ³ , na are as defined above and Y is a carbonyl or thiocarbonyl group.

The hydrolysis is carried out in a similar manner, for example in the presence of a hydrolysis promoter such as an acidic material, such as a dilute mineral acid such as sulfuric acid or hydrogen halide, or a basic material such as an alkali metal hydroxide such as sodium hydroxide. The oxycarbonyl, arylsulfonyl and cyano groups may conveniently be cleaved with acidic agents such as hydrogen halides, preferably hydrobromic acid. The cleavage of the above groups is preferably carried out with dilute hydrogen bromide, optionally with acetic acid. Preferably, the cyano groups are cleaved with hydrogen bromide at a higher temperature, such as boiling hydrogen bromide, by the "bromination process" [Braun]. For example, a tert-butoxycarbonyl group may be cleaved under anhydrous conditions by treatment with a suitable acid such as trifluoroacetic acid. The acidic agents are preferably used to hydrolyze the compounds of formula VI.

The groups which can be cleaved by ammonolysis are mainly halocarbonyl groups such as chlorocarbonyl groups. Ammonolysis may be carried out in a conventional manner, for example with an amine containing at least one hydrogen atom on the nitrogen atom, such as mono- or di- (lower) alkylamines, such as methylamine or dimethylamine, or especially ammonia, preferably at elevated temperatures. Instead of ammonia, an ammonia-releasing agent such as hexamethylenetetramine can be used.

g) Compounds of formula I can also be prepared by reducing a Schiff base of formula VIII or IX or a compound of formula X, which is a cyclic tautomer of the corresponding compound of formula IX. In the formulas, R ¹ , R ² , R ³ , na have the meanings given above, and the compounds of the formulas IX and X may also be present together. The reduction is carried out in a conventional manner, for example using di-light metal hydrides such as sodium borohydride or lithium aluminum hydride or borane with formic acid or by catalytic hydrogenation such as hydrogen in the presence of Raney nickel. Care must be taken when reducing! not to touch other groups.

h) Alternatively, in a compound of formula XI wherein R ', R ² , R ³ , na are as defined above, the oxo group can be reduced to a hydroxy group. The reduction is carried out in the usual manner, in particular using the aforementioned di-light metal hydride, or according to the Meerwein-Pondorf-Verley process, or a modified version thereof, preferably using an alkanol such as isopropanol and a metal alkanolate such as metal isopropanol. using aluminum isopropanolate.

Depending on the reaction conditions and the starting material, the final products are obtained in free form or in the form of acid addition salts, which are also within the scope of the invention. For example, basic, neutral or mixed salts, as well as hemiamino compounds, sesqui or polyhydrates, may be prepared. The acid addition salts of the novel compounds can be converted into the free compounds in a manner known per se, for example by using basic agents such as bases or ion exchangers. On the other hand, the free bases obtained may form salts with organic or inorganic acids. Acid addition salts are preferably prepared from acids which form the therapeutically acceptable corresponding salts. Examples of such acids are hydrogen halides, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carbonic and sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, , lemon, ascorbine, maleic, hydroxymalein, pyrosuccinic, phenylacetic, benzoic, ρ-aminobenzoic, anthranilic, ρ-hydroxybenzoic, salicylic or ρ-amino-salicylic, methanesulfone, ethanesulfonic, hydroxyethanesulfonic, ethylene sulfonic, halobenzenesulfonic, toluenesulfonic, naphthylsulfonic or sulfanylic acids; and methionine, tryptophan, lysine or arginine.

The above and other salts of the novel compounds, such as picrates, can be used to purify the free bases obtained by converting the free bases into salts, isolating them and releasing the bases from the salts. Because of the close relationship between the free forms and the novel forms of the novel compounds, it is clear from the above and the following that, when possible, the free compound also includes the corresponding salt.

Thus, an aldehyde of formula XIX, wherein R ^{1 is} as defined above, can be reacted with an amine of formula (a), wherein R ² , R ³ , na are as defined above, in the presence of a suitable reducing agent, for example. Thus, a compound of formula VII is obtained as an intermediate which is then reduced according to the process of the invention.

Alternatively, an amine of Formula III may be reacted with an aldehyde or ketone of Formula c in the presence of a suitable reducing agent, for example. Thus, a compound of formula IX or X is prepared as an intermediate which is then reduced according to the process of the invention.

The novel compounds may be present in the form of optical antipodes or racemates, or, if they contain at least two asymmetric carbon atoms, in the form of isomer mixtures (racemate mixtures), depending on the starting materials and the method chosen.

The resulting isomer mixtures (racemate mixtures) can be separated into the two stereoisomers (diastereomers) on the basis of the physicochemical differences of the components, for example by chromatography and / or fractional crystallization.

The racemates prepared can be separated into diastereomers by known methods, for example by recrystallization from an optically active solvent, microorganisms, or optically active acids to form a salt of the compound, for example, according to their different solubilities. From these diastereomers, the antipodes are liberated with the aid of a suitable agent. Suitable optically active acids are, for example, the L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid or chinese acid. Preferably, the more active of the two antipodes is isolated.

In carrying out the reactions of the present invention, it is convenient to use starting materials which result in a group of final products which are primarily intended to be produced, and in particular the specific and preferred final products.

The starting compounds are known or, if new, can be prepared in a manner known per se.

In clinical practice, the novel compounds may be administered orally, rectally or by injection in the form of a pharmaceutical composition containing the active compound in free base or pharmaceutically acceptable non-toxic acid addition salt form, for example hydrochloride, lactate, acetate, sulfamate or the like, in combination with a pharmaceutical carrier.

When the novel compounds of the invention are mentioned, this applies to both the free amino bases and the acid addition salts of the free bases, both generally and specifically, provided that the texts in which such terms are used, e.g. they are not contrary to a broad interpretation.

The carrier may be a solid, semi-solid, or liquid diluent or capsule. These pharmaceutical compositions also form part of the invention. The active ingredient is generally present in an amount of from 0.1 to 99% by weight, preferably from 0.5 to 20% by weight in injection formulations and from 2 to 50% by weight in formulations for oral administration.

For the preparation of pharmaceutical compositions for oral administration containing the compounds of the invention in unit dosage form, the selected compound may be admixed with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, starch such as potato starch, cereal starch, amylopectin, cellulose derivatives, gelatin, magnesium stearate, calcium stearate, polyethylene glycol wax and the like, and the mixture is compressed into tablets. If coated tablets are to be prepared, the core prepared as above is coated with a concentrated sugar solution which may contain gum arabic, gelatin, talc, titanium dioxide and the like. The tablets may also be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of solvents. Dyes may also be added to this coating in order to distinguish between tablets containing different active ingredients or different amounts of active ingredient present.

In the manufacture of soft gelatine capsules (bead-shaped closed capsules) consisting of gelatin and, for example, glycerol, or the like, the active ingredient is mixed with vegetable oil. Hard gelatine capsules contain granules consisting of a mixture of the active ingredient and solid powdered carriers, such as lactose, sucrose, sorbitol, mannitol, starch such as potato starch, cereal starch or amylopectin, cellulose derivatives or gelatin.

Dosage units for rectal administration may be presented as suppositories containing the active ingredient in admixture with a neutral fatty base, or in the form of rectal gelatin capsules containing the active ingredient in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral administration may be in the form of syrups or suspensions, e.g. They contain from 0.2 to 20% by weight of the active ingredient, the remainder being a mixture of sugar and ethanol, water, glycerol and propylene glycol. These liquid formulations may optionally contain coloring and flavoring agents, saccharin and a carboxymethylcellulose thickener.

An injection solution for parenteral administration may be formulated as an aqueous solution of a pharmaceutically acceptable water-soluble salt of the active ingredient, wherein the concentration of the active ingredient is about 10%. 0.5-10% by weight. These solutions may contain stabilizers and / or powders. Preferably, ampoules containing different dosage units are prepared.

Tablets for oral administration are prepared as follows:

The solids are comminuted or screened to a suitable particle size. The binder is homogenized in a certain amount of solvent and suspended. The therapeutic compound and the necessary excipients are mixed with the binder solution by continuous and constant mixing and moistened so as to distribute the solution evenly throughout the mass, without wetting certain portions. The amount of solvent is chosen so that the mass is consistent with wet snow. Moistening the powdery mixture with the binder solution causes the particles to form loose aggregates. The real granulation process is carried out with a mass of approx. Sift through a 1 mm mesh stainless steel screen. The mass is then placed in a thin layer on a tray and dried in an oven. Drying is carried out for 10 hours, carefully and standardized, since the moisture content of the granulate is very important for the next step and the properties of the tablets. Drying can also be carried out on a fluidized bed. In this case, the mass is not placed on a tray, but is poured into a perforated bottom container.

After the drying step, the granulate is sieved to obtain the required particle size. In some cases, the port may need to be removed.

The so-called. disintegrants, lubricants and anti-adhesives are added to the final mixture. After mixing, the paste has the proper composition for the tabletting process.

The cleaned tabletting machine is provided with the appropriate tool set, and then the tablet weight and degree of compression are adjusted. The weight of the tablets is decisive for the dosage size of each tablet, calculated from the amount of therapeutic agent present in the granulate. The degree of compression affects the tablet size, strength and disintegration in water. Particularly in view of the latter two characteristics, the choice of pressure (0.5 to 5 tonnes) is crucial. Once the machine is set with 177638 needles, we start to make tablets at a speed of 20,000 to 200,000 tablets / hour. The compression time of the tablets varies and depends on the size of the batch produced.

The tablets are freed from the powder adhering to them in a special machine and stored in a sealed packaging until transport.

Many tablets are coated, especially if they are rough or bitter. This means that the tablets are coated with a sugar coating or other suitable coating.

The tablets are usually packaged by a machine with an electronic counter. Packaging methods are various, such as glass or plastic jars or boxes, vials, and packaging for specific doses.

The daily dose of the active ingredient will vary and will depend on the route of administration, but will generally be 100 to 400 mg daily for oral administration and 5 to 20 mg daily for intravenous administration.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

In the examples, temperatures are in degrees Celsius.

Example 1

3- [2- (4-Hydroxy-phenoxy) -ethylamino] -1- (o-cyanophenoxy) -propanol-2 (a)

2.6 g of 2-epoxy-3- (o-cyanophenoxy) propane are mixed with 1.5 g of 2- (4-hydroxyphenoxy) ethylamine and 25 ml of isopropanol and the resulting solution is stirred for 1.5 hours. reflux for 1 hour and then evaporate in vacuo. The resulting base is dissolved in acetone and the hydrochloride salt is separated off with ethereal hydrogen chloride. The hydrochloride salt was filtered off and washed with acetonitrile. The yield of the title compound is 1.6 g. Its tartrate has a melting point of 52 ° C. The structure of the compound was verified by NMR spectroscopy.

Example 2

3- [2- (4-Hydroxy-phenoxy) ethylamino] -l- (p-cyano-methyl-phenoxy) propanol-2

Prepared from 1,2-epoxy-3- (o-cyanomethyl-phenoxy) -propane and 2- (4-hydroxy-phenoxy) -ethylamine according to example 1. The neutral oxalate has a melting point of 168 ° C.

Example 3

3- [2- (4-Hydroxymethyl-phenoxy) ethylamino] -l- (p-cyanophenoxy) - (> 2-ropanol

Prepared from 1,2-epoxy-3- (o-cyano-o-phenoxy) -propane and 2- (4-hydroxymethyl-phenoxy) -ethylamine as in Example 1. M.p. 86 ° C.

Example 4

3- [2- (4-Methoxy-phenoxy) ethylamino] -l- (p-cyano-phenoxy) propanol-2

Prepared from 1,2-epoxy-3- (o-cyanophenoxy) propane and 2- (4-methoxyphenoxy) ethylamine according to Example 1. The hydrochloride has a melting point of 134 ° C.

Example 5

2- [2- (2-Hydroxy-phenoxy) -ethylamino] -1- (o-cyanophenoxy) -propanol-2

Prepared from 1,2-epoxy-3- (o-cyanophenoxy) propane and 2- (2-hydroxyphenoxy) ethylamine according to Example 1. Mp 181 ° C.

Example 6

3- [2- (4-Hydroxy-3-methoxy-phenoxy) -ethylamino] -1- (o-cyano-phenoxy) -propanol-2

Prepared from 1,2-epoxy-3- (o-cyanophenoxy) propane and starting from 2- (4-hydroxy-3-methoxyphenoxy) ethylamine.

Example 1. The hydrochloride has a melting point of 78 ° C.

Example 7

3- (2- (3,5-Dimethoxy-phenoxy) -ethylamino] -1- (o-cyanophenoxy) -propanol-2)

Prepared from 1,2-epoxy-3- (o-cyanophenoxy) propane and 2- (3,5-dimethoxyphenoxy) ethylamine according to Example 1. The hydrochloride has a melting point of 159 ° C.

Example 8

3- [2- (4-oxopentanoic-phenoxy) ethylamino] -l- [o- (methoxy-ethyl-aminocarbonyl) phenoxy] propanol-2

Prepared from 1,2-epoxy-3- (o- (methoxy-ethylaminocarbonyl-methoxy) -phenoxy] -propane and 2- (4-hydroxy-phenoxy) -ethylamine according to example 1. mp 150 ° C.

Example 9 1- [2- (4-Hydroxy-phenoxy) -ethylamino] -3- (o-cyano-phenoxy) -propanol-2 (b) and (e) Process variants g (o-Cyano-phenyl) glycidyl ether was saturated with ammonia gas in 100 ml of ethanol and the reaction mixture was heated in an autoclave on a hot water bath for 4 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and hydrogen chloride gas was added to the solution. The precipitated hydrochloride is filtered off, dissolved in 50 ml of ethanol and 2- (4-methoxymethoxy) phenoxyethyl chloride and 15 g of potassium carbonate are added. The reaction mixture was heated in an autoclave for 10 hours at 130 ° C. The aqueous phase was made basic with ammonium hydroxide and extracted with ethyl acetate. The organic phase is dried over potassium carbonate. The resulting title compound is converted to its tartrate; mp 52 ° C.

Example 10 1- [2- (4-Hydroxy-phenoxy) -ethylamino] -3- (o-cyanophenoxy) -propanol-2 (c) and variant (e)

2.4 g of sodium are dissolved in 100 ml of ethanol and 11.9 g of o-cyanophenol are added followed by 22.9 g of 1- [2- (4-methoxymethoxyphenoxy) ethylamino] -3-chloro. propanol-2. The reaction mixture was heated in an autoclave in hot water on a water bath for 10 hours, then filtered and the filtrate evaporated to dryness. To the residue was added 2N hydrochloric acid, allowed to stand at room temperature for 1 hour, then extracted with ether, basified with aqueous ammonium hydroxide and extracted with ether. The ether layer was dried over magnesium sulfate to give the title compound, which was converted to the tartrate and then isolated. 52 ° C.

In a similar manner, steps 2-8 can be prepared. and the compounds of Example III.

II. example

3- (2- (4-Hydroxy-phenoxy) -cyl-amino] -1- (o-cyanophenoxy) -propanol-2 (d))

0.116 mol of o-cyanophenol are mixed with 0.080 mol of 1- [2- (4-methoxymethoxyphenoxy) ethyl] -3-azetidinol, 0.500 mol of benzyl alcohol and 0.003 mol of potassium hydroxide. The reaction mixture was stirred at 140 ° C for 6 hours, then cooled and extracted with 2N hydrochloric acid. The aqueous phase was allowed to stand at room temperature for 1 hour, then basified and extracted with chloroform. After drying and evaporation, the residue is dissolved in ether and hydrogen chloride in ether is added. The hydrochloride salt was filtered off and washed with acetone. The hydrochloride of the title compound was converted to the tartrate: mp 52 ° C.

In a similar manner, steps 2-8 can be prepared. and the compounds of Example III.

Example 12

3- [2- (4-Hydroxy-phenoxy) -ethylamino] -1- (o-cyanophenoxy) -propanol-2 (fi variant)

In the same manner as in Example 9, 1-amino-3- (o-cyanophenoxy) propanol-2 was prepared, 6 g was dissolved in 50 ml of methanol and 15 g of (4-hydroxyphenoxy) acetaldehyde were added. . The resulting solution containing 3- [2- (4-hydroxy-phenoxy) -ethylimino] -1- (o-cyanophenoxy) -propanol-2 was cooled to 0 ° C and 5 g of sodium borohydride is added. The reaction mixture was allowed to warm to room temperature and after 1 hour water (150 mL) was added and the reaction mixture was extracted with ether. The ether layer was dried over magnesium sulfate and evaporated.

The residual title compound is converted to its tartrate. 52 ° C.

In a similar manner, steps 2-8 can be prepared. and the compounds of Example III.

Example 13

3- [2- (4-Hydroxy-phenoxy) -ethylamino] -1- (o-cyanophenoxy) -propanol-2 (g)

1- [2- (4-Hydroxy-phenoxy) -ethylamino] -3- (o-cyanophenoxy) -propanone-1.0 g is dissolved in 25 ml of methanol and the solution is cooled to 0 ° C in an ice bath. After cooling to 0.25 g sodium borohydride was added in portions with stirring at 0 ° C for 1 hour and at room temperature for 0.5 hour. The resulting solution was evaporated and water (50 mL) was added. The aqueous phase was extracted with chloroform (3 x 50 mL) and the combined chloroform layer was dried and evaporated. To the ethereal solution of the residue, ethereal hydrogen chloride was added to isolate the hydrochloride of the title compound and recrystallize from acetone. The tartrate salt has a melting point of 52 ° C.

In a similar manner, steps 2-8 can be prepared. and the compounds of Example III.

Example 14

1- (2- (4-Methoxy-phenoxy) -ethylamino] -3- (2-cyanophenoxy) -propanol-2 (h)

To a solution of 2.4 g of sodium in 100 ml of ethanol was added 12.4 g of 4-methoxyphenol, followed by 25.3 g of 1- (2-chloroethylamino) -3- (2-cyanophenoxy) propanol- 2. The reaction mixture was heated in an autoclave on a hot water bath for 10 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was treated with 2N hydrochloric acid for 1 hour at room temperature, extracted with ether, and the aqueous phase was made basic with ammonium hydroxide and extracted with ether. The ether layer was dried over magnesium sulfate to give the title compound, which was converted to its hydrochloride and then isolated. 134 ° C.

In a similar manner, steps 2-8 can be prepared. and the compounds of Example III.

Example 15 A syrup containing by weight of active ingredient is prepared from the following components: 3- [2- (4-hydroxyphenoxy) ethylamino] '1- (o-

-cyanophenoxy) -propanol-2-tartrate2.0 g saccharin0.6 g sugar 30.0 g glycerol5.0 g flavoring 0.1 g

96% ethanol 10.0 g distilled water to 100.0 ml.

The sugar, saccharin and active ingredient are dissolved in 60 g of warm water. The solution is cooled and glycerol and flavoring in ethanol are added and the mixture is made up to 100 ml with water.

The above active ingredient may be replaced by other pharmaceutically acceptable acid addition salts.

Example 16

250 g of 3- [2- (4-hydroxy-phenoxy) -ethylamino] -1- (o-cyanomethyl-phenoxy) -propanol-2-hydrochloride with 175.8 g of lactose, 169.7 g of potato starch and g of colloidal silica. The mixture was moistened with 10% gelatin solution and granulated through a 12 mesh sieve. The granulate is dried, then 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate are added and the mixture is compressed into tablets. 10,000 tablets each containing 25 mg of active ingredient are prepared. The tablets are provided with a fracture notch so that a dose other than 25 mg is obtained when the tablets are broken.

Example 17

250 g of a mixture of 3- [2- (4-hydroxy-3-methoxy-phenoxy) -ethylamino] -1- (o-cyanophenoxy) -propanol-2, 175.9 g of milk sugar and 25 g of polyvinylpyrrolidone making granules. The granulate is dried, then with 25 g of talc, 40 g of potato starch and

2.50 g of magnesium stearate are mixed and 10,000 biconvex tablets are compressed. The tablets are first coated with 10% alcoholic shellac solution and then with an aqueous solution containing 45% sucrose and 5% gum arabic, 4% gelatin and 0.2% dyes. After the first five coatings, talc and powdered sugar are used to dust the tablets. The coating is then coated with 66% sugar syrup and polished with 10% carbon tetrachloride carnauba wax solution.

Example 18 g 3- [2- (3,5-Dimethoxy-phenoxy) -ethylamino] -1- (o-cyanophenoxy) -propanol-2-hydrochloride, 0.8 g of sodium chloride and 0.1 g of the title compound. ascorbic acid is dissolved in enough distilled water to give 100 ml of solution. This solution, containing 10 mg of active ingredient per ml, is used to fill ampoules. The vials were sterilized at 120 ° C for 20 minutes.

Example 19

3- [2- (4-Hydroxy-phenoxy) ethylamino] -l- (p-hydroxymethyl-phenoxy) propanol-2

The title compound was prepared as described in Example 1 from 1,2-epoxy-3- (o-hydroxymethylphenoxy) propane and 2- (4-hydroxyphenoxy) ethylamine. The citrate has a melting point of 68 ° C.

Biological effects of the new compounds

The biological properties of the β-receptor blocking compounds of the present invention were tested. The effects of each compound were tested on anesthetized cats (male and female, 2.5-3.5 kg), which were exposed to ca. After 16 hours, reserpine was administered at 5 mg / kg body weight im. Animals were pretreated with reserpine to eliminate endogenous sympathetic heart rate control and vascular smooth muscle tone. Cats were anesthetized with pentobarbital at 30 mg / kg i.p. and artificially ventilated with room air. The animals underwent bilateral vagatomy. Blood pressure was measured from the cannulated carotid artery and heart rate recorded on the electrocardiogram was recorded with a cardiotachometer. Intrinsic beta mimetic activity in the heart has been shown to increase heart rate after drug administration. The test compounds were administered intravenously at increasing logarithmic doses. The values obtained are plotted on the dose response curve from which the affinity values (ED _W ) are determined. At the end of each experiment, a very high dose of isoprenaline was administered to the animals to determine the maximal effect on heart rate.

The compounds were also tested on conscious dogs. Hunting dogs were trained to lie down and then put their forelegs upright on a table for 2 minutes. Arterial blood pressure was measured using a blood pressure transducer connected to the dog at the height of the heart. Heart rate was recorded by ECG. All dogs were pretreated with methylscopolamine to avoid planetary nerve influences. Observations were made prior to administration of the test compounds and 15 and 75 minutes after administration, first in supine position for 2 minutes and then in upright position for 2 minutes. Test compounds were administered in increasing doses at 2 hour intervals.

PA ₂ was also measured in rats. The _pA2 is a negative logarithm of the inhibitor, which causes that the norepinephrine dose should be doubled in order to get the same effect of norepinephrine, as without the inhibitor, or pA ₂ = log (DR-I) -log (inhibitor compound), where dr is the dose ratio -

ED _J0 of noradrenaline (in the presence of an inhibitor)

Norepinephrine ED _J0 (control)

All concentrations are expressed in moles / liter. Thus, pA _{2 is a} measure of the α-receptor effect, if pA _{2 is} greater, the effect is greater.

The experiments show that the new compounds are potent β-receptor blocking compounds, are cardioselective and, if appropriate, have intrinsic β-mimetic activity. The compounds significantly reduce blood pressure in conscious dogs. The specific antihypertensive activity of the new compounds in conscious dogs depends on the vasodilatory effect associated with cardiac β-receptor blockade.

The results of the above experiments are illustrated in the following table.

The test compounds are compounds of formula I wherein n = 2 and R *. R ² , R ³ are as follows:

i R * i i R ¹ es R ' anaesthetized cat PA Isoprenaline pulse & block ^ block ED "| Amol / kg The 3-bladate of isoprenaline ¹ peripheral resistance is EDnPJnóbkg Intrinsic activity Δ heart rate / min isoprenaline —CN ' 4 — OCH ₃ , H 0.22 2.7 7 7 6.4 —OCH ₂ CONHC ₂ H ₄ 1 OCH ₃ 4 — OH, H 0:05 1.8 0 0 5.5 CN 2-OH. H 1.7 17 35 39 6.5 CN 3 — OCH ₃ , 4 — OH 0.3 3.4 17 27 6.8 CN 3,5-di-OCH 2.9 11 15 17 6.5 CN 4 — OH, H 0.08 5.5 13 15 6.3 CN 4 - CH ₂ OH, H 0.2 0 10 10 5.8 —Ch ₂ cn 4 — OH, H '0.05 1.6 20 6.6 —Ch ₂ oh 4 — OH, H 0:02 0.05 17 6.3

Patent claims

Claims (10)

Patent claims A process for the preparation of new aminopropanol derivatives of the formula I and their salts, wherein R ^{1 is} cyano, cyanomethyl or hydroxymethyl or CH ₃ OC ₂ H ₄ NHCCH ₂ O— O bottom, R ² and R ³ are each independently hydroxy, methoxy or hydroxymethyl, but R ^{3 may be} hydrogen and n is a number from 2 to 4, characterized in that a) a compound of formula II wherein R ^{1 is} as defined above, X * is hydroxy and Z is a reactive esterified hydroxy group, preferably halogen, or X ¹ and Z together form an epoxy group with an amine of formula a wherein R ² , R ³ , with the meaning given above - or b) reacting a compound of formula III wherein R ^{1 is} as defined in the scope of the invention with a compound of formula b wherein R ² , R ³ , na and Z are as defined above in variant a), or c) reacting a compound of Formula IV wherein R ^{1 is} as defined in the scope of the invention with a compound of Formula V wherein Z, X ^{1 is as} defined in Variant a), R ² , R ³ , na as defined herein; or d) reacting a compound of Formula IV wherein R ^{1 has} the meaning given in the parent compound with a compound of the Formula VI wherein R ² , R ³ has the same meaning as defined in the preamble; e) a compound of formula I wherein R ¹ , R ² , R ³ , na are as defined above, wherein the amino and / or hydroxyl groups of the amino group have a protecting group, preferably lower alkyl, which is preferably cleaved by hydrolysis; obsession f) reducing a Schiff base of formula VIII or IX or a cyclic tautomer of formula X in equilibrium with the corresponding compound of formula IX, wherein R ¹ , R ² , R ³ , na are as defined herein; or g) in a compound of formula XI - wherein R ¹ , R ² , R ³ , N are as defined in the foregoing - the oxo group is reduced to a hydroxy group, preferably with an alkali metal borohydride - or h) reacting a compound of formula Va wherein R ¹ , na in the scope and Z in the variant a) with a compound of the general formula IVa wherein R ² , R ^{3 in} the present invention, and optionally, obtaining the resulting I converting the compound of formula (II) into its salt. Process for the preparation of process variant a) -g) according to claim 1 for the preparation of 3- [2- (4-hydroxyphenoxy) ethylamino] -1- (o-cyanophenoxy) propanol-2, characterized in that: by reacting appropriately substituted starting compounds. 3. A process for the preparation of a live variant a) according to claim 1 for the preparation of 3- [2- (4-hydroxyphenoxy) ethylamino] -1- (o-cyanomethylphenoxy) propanol-2 to react appropriately substituted starting materials. 4. A process for the preparation of process variant a) according to claim 1 for the preparation of 3- [2- (4-hydroxymethylphenoxy) ethylamino] -1- (o-cyanophenoxy) propanol, characterized in that it is suitably substituted starting material. compounds. 5. A process for the preparation of process variant a) according to claim 1 for the preparation of 3- [2- (4-methoxyphenoxy) ethylamino] -1- (o-cyanophenoxy) propanol-2 characterized in that it is suitably substituted. starting compounds. 6. A process for the preparation of process variant a) according to claim 1 for the preparation of 2- [2- (2-hydroxyphenoxy) ethylamino] -1- (o-cyanophenoxy) propanol-2 characterized in that it is suitably substituted. starting compounds. 7. A process according to claim 1 for the preparation of 3- [2- (4-hydroxy-3-methoxyphenoxy) ethylamino] -1- (o-cyanophenoxy) propanol-2 to react appropriately substituted starting materials. 8. A process for the preparation of process variant a) according to claim 1 for the preparation of 3- [2- (3,5-dimethoxyphenoxy) ethylamino] -1- (o-cyanophenoxy) propanol-2, characterized in that: reacting appropriately substituted starting materials. The process of variant (a) according to claim 1, wherein 3- [2- (4-hydroxyphenoxy) ethylamino] -1- [o- (methoxyethylaminocarbonylmethoxy) phenoxy] propanol is used. -2 by reacting appropriately substituted starting materials. The further development of any method of claim 1 for the manufacture of a medicament containing a compound of formula I or a salt thereof, wherein R ¹ , R ² , R ³ , X and n are as defined in claim 1, wherein The active ingredient is formulated together with the 5 customary excipients, diluents, fillers and / or other excipients of the pharmaceutical compositions.