DE2743493A1 - AMINES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME - Google Patents

Description

The invention relates to new effective, ß-receptor blocking compounds, their production and their use in the Treating symptoms and signs of cardiovascular disease or disorders by blocking the heart's ß-receptors by administering these new compounds to mammals including humans.

The new compounds are those of the general formula

₀ ) -X
2 η

wherein R is methyl, ethyl, propyl, methoxy, propargyloxy, cyano, allyloxy, acetyl, cyanomethyl, hydroxymethyl, CH ₃ OCH ₂ H NHCOCH ₂ O, morpholino, pyrrolidino or pyrrolyl -

2 3

group means, R and R are identical or different and are each hydrogen atoms or alkoxyalkoxy, alkyl, cyano or Hydroxyl groups, halogen atoms or alkoxy or hydroxymethyl

2 3
groups where R and R are not both hydrogen atoms at the same time, η is 2, 3 or 4 and X is -0- or -S-.

Halogen atoms r 'and R are chlorine, bromine, iodine or fluorine atoms, preferably chlorine or bromine atoms.

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Alkoxy groups R and R have up to 7 carbon atoms in their Alkyl part, preferably up to 4 carbon atoms, and are for example methoxy, ethoxy, isopropoxy, propoxy or butoxy groups, preferably methoxy and A "thoxy groups.

2 3

Alkyl groups R and R have up to 7 carbon atoms, preferably up to 4 carbon atoms, and are, for example, methyl, ethyl and isopropyl groups.

2 3
Alkoxyalkoxy groups R and R have up to 7 carbon atoms in each alkyl part, preferably up to 4 carbon atoms, and are, for example, methoxymethoxy groups, methoxyathoxy groups, ethoxyethoxy groups or isopropoxymethoxy groups.

η is 2, 3 or 4, preferably 2.

X is an oxygen or sulfur atom, preferably oxygen.

2 3

R and R are in the 2-, 3- or 4-position and preferably in 3- or 4-position on the alkylene side chain on the phenoxy

or phenylthio group, where preferably R is a water

3 2

is hydrogen atom and R is a hydroxyl group, R and

3 2 3

R are 3,4-dimethoxy groups, R and R are 3,4-dichloro

2 3

ten or R is a chlorine atom and R is a hydroxyl group.

The new compounds have valuable pharmacological properties. Thus , they block ß-receptors of the heart, which is useful in determining the antagonism of tachycardia after an intravenous injection of 0.5, ug / kg of d / 1-isoproterenol sulfate to an anesthetized cat at an intravenous dose of 0.002 to 2 mg / kg is to be shown. They also block the ß-receptors of the blood vessels, which is useful in determining the antagonistic

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nism of vasodilation after an intravenous injection of 0.5, ug / kg of d / 1-isoproterenol sulfate to an anesthetized Cat with an intravenous dose of 0.002 to 2 mg / kg or more. The compounds also have stimulatory properties Properties on the ß-receptors, i.e. they show their own activity. This property is particularly clear with regard to the ß-receptors of the blood vessels, so that an expansion of the peripheral blood vessels.

The new compounds can be used in the treatment of arrhythmias, angina pectoris and high blood pressure. the peripheral vasodilation is particularly valuable for the last two indications mentioned. You can make the connections also use as intermediates in the manufacture of other valuable pharmaceutical compounds.

Compounds according to the present invention are as follows:

3- / 5- (4-hydroxyphenoxy) -äthylamino / -1-o-methylphenoxypropanol-2 3- ^ 2- (4-hydroxyphenoxy) -ä thy lamino / -1 -o-ethylphenoxypropanol-2 3- / 2- ( 4-hydroxyphenoxy) ethylamino7-1-o-propylphenoxypropanol-2 3- / 5- (4-hydroxyphenoxy) -ethyIamino / -1-o-allylphenoxypropanol-2 3- / 5- (4-hydroxyphenoxy) -ethylamino / -1 -o-propargyloxyphenoxy-

propanol-2

3- / 5- (4-hydroxyphenoxy) -ethylamino / -1-o-cyanophenoxypropanol-2 3- / 2- (4-hydroxyphenoxy) -ethylaminoZ-io-allyloxyphenoxypropanol-3- / 5- (4-hydroxyphenoxy) -ethy1amino / -1-o-propargylphenoxypropa-

nol-2

3- / 5- (4-Hydroxyphenoxy) -äthylamino / - 1 -o-cyanomethylphenoxypro-

panol-2

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3- / 2- (4-hydroxyphenoxy) ethylamino-i -o-acetylphenoxypropanol-2 2- / 2- (4-hydroxyphenoxy) ethylamino / -1-o-hydroxymethyloxyphenoxypropanol-2

3- / 2- (4-hydroxyphenylthio) ethylaminoZ-io-cyanophenoxypropanol-2 3- / 2- (4-hydroxyphenylthio) -ethylaminoZ-io-methylphenoxypropanol-2

3- / 2- (3-methoxy-4-methoxyphenoxy) -ethylamino7-1-o-methylphenoxypropanol-2

3- / 2- (3-Bromo-4-hydroxyphenoxy) -ethylaminoy-o-methoxyphenoxypropanol-2

3- / 2- (3-Hydroxymethyl-4-hydroxyphenoxy) -ethylaminoZ-1-o-cyanophenoxypropanol-2

3- / 2- (3,4-Dihydroxyphenylthio) ethylamino? -1-o-cyanophenoxypropanol-2

3- / 3- (4-Hydroxyphenoxy) -propylamino? -1-o-methylphenoxypropanol-2 3 - / _ A- (4-Hydroxyphenoxy) -butylamino / -! -o-ally l-phenoxypropanol-2 and

3- / 2- (2-chloro-4-hydroxyphenylthio) ethylamino / -! - o-allyloxyphenoxypropanol-2

3 - / ^ 2- (4-methoxyphenoxy) ethylaminoZ-i -o-cyanophenoxypropanol-2 3 - / ^ 2- (2-hydroxyphenoxy) ethylaminoZ-i -o-cyanophenoxypropanol-2 3- / 2- (4-Hydroxy-3-methoxyphenoxy) -ethylaminoj-i-o-cyanophenoxypropanol-2

3 - / _ 2- (3/5-dimethoxyphenoxy) -ethylamino / -1 -o-cyanophenoxypropanol-2

3- / 2- (4-hydroxyphenoxy) -ethylamino / -1-o-pyrrolysis-1- phenoxypropanol-2 3- / 2- (4-hydroxyphenoxy) -ethylaminoZ-i -o- methoxyethylaminocarbonylmethoxyphenoxypropanol-2.

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Salt-forming acids can be used in the preparation of therapeutically acceptable salts of the compounds. These are hydrohalic acids, sulfuric acid, phosphoric acid, Nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, such as Formic acid, acetic acid, propionic acid, succinic acid, glycolic 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, Emboxylic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, Ethylene sulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, Naphthylsulfonic acid or sulfanilic acid, methionine, tryptophan, lysine or arginine.

The substances are intended, orally or parenterally, for acute and chronic treatment of the cardiovascular diseases mentioned above to be administered.

The biological effects of the new compounds were tested and the various experiments carried out are described below shown and explained.

The new compounds are obtained by methods known per se. So a compound of the general formula II

where R has the above meaning, X is a hydroxyl group, Z is a reactive esterified hydroxyl group or

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i form an epoxy group, with a general formula

X and Z together form an epoxy group with an amine

R ²

2 3
wherein R, R, η and X have the above meaning, implemented.

A reactive esterified hydroxyl group is especially a hydroxyl group, those with a strong, inorganic or organic acid, preferably a hydrohalic acid, such as Hydrochloric acid, hydrobromic acid or hydroiodic acid, with sulfuric acid or a strong organic sulfonic acid, such as benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid, is esterified. Z is preferably chlorine, Bromine or iodine.

This conversion is carried out in a usual manner. When using a reactive ester as a starting material the preparation takes place preferably in the presence of a basic condensing agent and / or with an excess of an amine. Suitable basic condensing agents are, for example, alkali hydroxides, such as sodium or potassium hydroxide, alkali carbonates, such as potassium carbonate, and alkali alcoholates such as sodium methylate, Potassium ethylate and potassium tertiary butylate.

The reaction is carried out in an alkanol with 1 to 4 carbon atoms by refluxing the reactants in this solvent for a sufficiently long time to complete the compound of the Formula I to give, generally performed for 1 to 12 hours.

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In addition, a compound of the general formula III

R ¹

wherein R has the above meaning with a compound of the general formula

R ²

3? ³

2 3
wherein R, R, n, X and Z have the above meaning, are reacted.

This reaction takes place in the customary manner, preferably in the presence of a basic condensing agent and / or one Excess of an amine. Suitable basic condensing agents are, for example, alkaline alcoholates, such as alkali metal alcoholates, preferably sodium or potassium alcoholate, or also alkaline carbonates, such as alkali carbonates, e.g. sodium or potassium carbonate.

This reaction takes place in an alkanol with 1 to 3 carbon atoms in an autoclave, which is heated to 100 to 130 ° C, carried out for 5 to 15 hours.

In addition, a compound of the formula IV

(IV)

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wherein R has the above meaning with a compound of the general Formula V

X ¹

12 3

wherein Z, X, R, R, η and X have the above meaning, implemented will.

This reaction is carried out in the usual way. In those cases where reactive esters are used as starting material, the compound of the formula IV can expediently in the form of its metal phenolate, such as an alkali metal phenolate, preferably sodium phenolate, be used, or one works in the presence of an acid-binding agent, preferably a condensing agent, which can form a salt of the compound of formula IV, such as an alkali alcoholate.

This reaction is carried out in an alkanol with 1 to 3 carbon atoms in an autoclave which takes 5 to 15 hours to 80 to
100 ° C is heated.

In addition, a compound of the general formula Va

-OCH ₂ CHOHCH ₂ NHiCH ₂ J _n Z (Va)

wherein R, Z and η have the above meanings with a compound of the general formula IVa

"2

(IVa)
-R ³

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wherein R, R and X have the above meaning, are reacted. This reaction takes place in the same way as the reaction between compounds of the above formulas IV and V.

In addition, a compound of the formula IV

(IV)

wherein R has the same meaning as above with a compound of the general formula VI

I ^{2 2 n} \ V "(VI)

CH CH ₂

OH

2 3
wherein R, R, η and X have the above meaning, implemented

will.

This implementation takes place in the usual way. The reaction is carried out under alkaline conditions in a suitable solvent, such as benzyl alcohol, carried out by boiling the reaction mixture for a few hours. This is where the phenol converted primarily to its metal phenate, such as alkali phenate, before it is added to the acetidinol of Formula VI.

You can also use a radical of a compound of the above formula I in which the nitrogen atom of the amino group and / or the hydroxyl groups carry a cleavable radical attached to them, cleave off.

Such cleavable residues are especially those that are produced by solvolysis, Reduction, pyrolysis or fermentation can be split off.

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Residues that can be split off by solvolysis are those that are produced by hydrolysis or Ainmono Iy se can be split off.

Residues that can be split off by hydrolysis are, for example, acyl residues, which, if they are present, functionally altered carboxy groups, such as oxycarbonyl radicals, e.g. alkoxycarbonyl radicals, such as the tertiary butoxycarbonyl radical or ethoxycarbonyl radical, aralkoxycarbonyl radical, such as phenyl-lower alkoxycarbonyl radical, e.g. a carbobenzyloxy radical, Halocarbonyl radicals, such as a chlorocarbonyl radical, also arylsulfonyl radicals, such as toluenesulfonyl or bromobenzenesulf onyl radicals, and optionally halogenated, such as fluorinated lower alkanoyl radicals, such as formyl, acetyl or trifluoroacetyl radicals, or a benzyl radical or cyano groups or silyl radicals, such as a trimethylsilyl radical.

Of the above-mentioned residues present on the hydroxyl groups and which can be split off by hydrolysis are preferably the oxycarbonyl radicals and the lower alkanoyl radicals or the benzoyl radicals are used.

In addition to those mentioned above, double-bonded radicals that can be split off at the amino group by hydrolysis are also used, such as alkylidene or benzylidene radicals or a phosphorylidene group, such as a triphenylphosphorylidene group, where the Nitrogen atom then receives a positive charge.

Cleavable at the hydroxyl group and the amino group by hydrolysis In addition, radicals are double-bonded radicals, such as substituted methylene. As substituents on the methylene radicals can any organic residues occur, it being during hydrolysis does not matter how the substituent on the methylene

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rest looks. For example, aliphatic or aromatic radicals, such as those mentioned above, can be used as methylene substituents Alkyl groups or aryl radicals, such as phenyl, or pyridyl radicals can be used. The hydrolysis can be carried out in the usual way, expediently in a basic or preferably in an acidic medium.

Compounds with residues which can be split off by hydrolysis are also the compounds according to the formula VII

(/ Vv-OCH ₂ CH

0 N - (CH ₉ ) -XV V (VII) \ /

12 1
in which R, R, R, η and X have the above meanings and Y is a carbonyl or thiocarbonyl radical.

The hydrolysis is carried out in a manner analogous to that in the presence of a hydrolyzing agent, such as in the presence of an acidic agent, for example dilute mineral acids such as sulfuric acid or hydrohalic acid, or in the presence of basic agents, for example alkali metal hydroxides such as sodium hydroxide. Oxycarbonyl radicals, arylsulfonyl radicals and cyano groups can be cleaved off in a suitable manner with the aid of acidic agents, such as with the aid of a hydrohalic acid, expediently from hydrobromic acid. The cleavage can preferably take place using dilute hydrobromic acid, if appropriate in a mixture with acetic acid. Cyano groups are preferably split off with the aid of hydrobromic acid at an elevated temperature, such as in boiling hydrobromic acid, according to the "cyanogen bromide method" (von Braun). In addition, for example

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a tertiary butoxycarbonyl radical under anhydrous conditions by treatment with a suitable acid such as trifluoroacetic acid, be split off. Acidic agents are preferably used in hydrolysis of compounds of formula VI.

Residues that can be split off by ammonolysis are in particular the halogenocarbonyl radicals, like the chlorocarbonyl radical. The ammonolysis can be carried out in a conventional manner, such as with the aid of a Amine, which is at least one hydrogen bonded to the nitrogen atom atom contains, such as a mono- or di-lower alkylamine, such as methylamine or dimethylamine, or specifically with the help of Ammonia, preferably at an elevated temperature.- Instead of ammonia one can also use an agent called ammonia results, such as hexamethylenetetramine.

Residues which can be split off by reduction are, for example, an ol-arylalkyl radical, such as a benzyl radical, or an o (-Ar alkoxy carbonyl radical, such as a benzyloxycarbonyl radical, which is produced in the usual way by hydrogenolysis, especially by catalytically activated hydrogen, such as by hydrogen in the presence of hydrogenation catalysts, Such as Raney nickel, can be split off. Further radicals which can be split off by hydrogenolysis are haloalkoxycarbonyl radicals, such as 2,2,2-trichloroethoxycarbonyl radicals or 2-iodoethoxy or 2,2,2-tribromathoxycarbonyl radicals, which are usually obtained by reduction with metals ( so-called nascent hydrogen) can be cleaved off. nascent hydrogen may be by the action of metal or metal alloys, as amalgam on compounds which give hydrogen, such as carboxylic acids, alcohols or water, are obtained, in particular zinc or zinc alloys comparable with acetic acid

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can be turned. Hydrogenolysis of 2-haloalkoxycarbonyl radicals can also take place using chromium or chromium (II) compounds, such as chromium (II) chloride or chromium (I]) acetate.

A residue that can be split off by reduction can also be an arylsulfonyl group, such as a toluenesulfonyl group, which can be obtained in the usual way by reduction using nascent hydrogen, as can be split off with the aid of an alkali metal, such as lithium or sodium in liquid ammonia, and is expedient is split off from a nitrogen atom. When carrying out the reduction, one has to bear in mind that other reducing agents Groups are not affected.

Residues that can be split off by pyrolysis, especially from the nitrogen atom Removable radicals are optionally substituted, but expediently unsubstituted carbamoyl groups. Suitable substituents are, for example, low molecular weight alkyl groups or aryl lower alkyl groups, such as methyl or benzyl groups, or Aryl groups such as phenyl groups. The pyrolysis is carried out in the usual way carried out, whereby one must consider other thermally sensitive groups.

Residues that can be split off by fermentation, especially from the nitrogen atom Removable radicals are optionally substituted, but expediently unsubstituted carbamoyl groups. Suitable Substituents are, for example, low molecular weight alkyl groups or aryl lower alkyl groups, such as methyl or benzyl groups, or aryl radicals, such as phenyl radicals. The fermentation takes place in the usual way, such as with the help of the enzyme urease or with soybean extract at about 20 ° C or slightly higher temperature.

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In addition, a Schiff base of the general formula VIII or IX

/ y OH r ν R '

' W-OCH ₂ CH-CH = N- (CH ₂ J _n -X- /' ^ V

OH

OCH CH-CH ₇ -N = CH- (CH ₀ ), - / ^ ^z 2 n-1

(VIII.)

(IX)

or a cyclic tautomer according to formula IX or of formula X

OCH ₂ CH

(X)

12 3
are reduced, where R, R, R, η and X have the above meaning and where the compounds of the formulas IX and X can also be present with one another. This reduction is carried out in a conventional manner, such as using a light metal hydride such as sodium borohydride, lithium aluminum hydride, using a hydride such as borane, with formic acid, or with the aid of catalytic hydrogenation, such as with hydrogen in the presence of Raney nickel. With the reduction one has to make sure that other groups are not impaired.

In addition, the oxo groups in the compound of the general formula XI

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12 3
wherein R, R, R, η and X are as defined above, are reduced to a hydroxyl group. This reduction is carried out in the usual way, especially using a Dileichtmetallhydride, as mentioned above, or according to the "Meerwein-Ponndorf-Verley method" or a modification thereof, expediently using an alkanol as a reaction component and as a solvent, such as isopropanol, and using a metal alkoxide such as metal isopropoxide, for example aluminum isopropoxide.

In addition, in a compound of the general formula XII y — OCH ₂ CHOHCH ₂ NH- (CH ₂ J _n -X- ^ V (XII)

2 3 2

in which R, R, η and X have the above meaning and in which X

1 2 1

is a residue that can be converted into a residue R, X is in R

convict.

In addition, the oxo group in a compound corresponding to those of the formula I, but which has an oxo group on the carbon, which is bonded to one nitrogen atom, carries, through two hydrogen reduce atoms.

These compounds are, for example, those of the formula XIII

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(CH ₂ J _n -XT ^) (XU!)

12 3
wherein R, R, R, η and X have the above meanings.

The reduction can be carried out in the manner described above using complex metal hydrides such as lithium aluminum hydride or diisobutyl aluminum hydride. The reaction expediently takes place in an inert solvent such as an ether, e.g. diethyl ether or tetrahydrofuran.

The substituents on the compounds obtained in the end product and the compounds obtained can be varied in a customary manner can be introduced into other end products in the usual way, split off from them or converted into them.

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 within the scope of the invention lies. For example, basic, neutral or mixed salts as well as hemiamino-, sesqui- or polyhydrates can be used can be obtained. The acid addition salts of the new compounds can be converted into free compounds in a manner known per se using basic agents such as alkali or ion exchangers. On the other hand, the The resulting free bases form salts with organic or inorganic acids. In the production of acid addition salts those acids are preferably used which form suitable therapeutically acceptable salts. Such acids are for example Hydrohalic acids, sulfuric acid, phosphorus

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acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, Glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, kydroxymaleic acid or pyruvic acid, Phenylacetic acid, benzoic acid, p-aminobenzoic acid> anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, Emboxylic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, Ethylene sulfonic acids, halobenzenesulfonic acid, Toluenesulphonic acid, naphthysulphonic acids or sulphanilic acid, Methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, such as picrates, can be used as agents for purifying the free bases obtained serve by converting the free bases into their salts, separating them and then releasing the bases from the salts again. In view of the close relationship between the new compounds in the free form and in the form of their salts, it goes without saying that that in the above statements and also below, when talking about the free connections, below the corresponding salts are also understood.

The invention also relates to any embodiment of the method, in which one starts from any compound obtained as an intermediate in any process stage and performing the missing process step or by discontinuing the process at any stage or by using a starting material forms under reaction conditions or in which a reactant may be in the form of its salt is present.

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So you can use an aldehyde of the general formula XIX

OCH ₂ CHuHCHO

wherein R has the above meaning with an amine of the general formula

- (CH ₂ J _n -X - //

R ³

2 3
wherein R, R, η and X have the above meaning, react in the presence of a suitable reducing agent, such as one of the reducing agents mentioned above. A compound of the general formula VII is obtained as an intermediate product which is then reduced according to the invention.

An amine of the general can also be used in a manner known per se Formula III with an aldehyde or a ketone of the formula

in the presence of a suitable reducing agent, such as one of the above-mentioned reducing agents, to convert compounds of the Formula IX or X to be obtained as an intermediate product, which is then reduced according to the invention.

The new compounds can be made depending on the choice of starting materials and the process as optical antipodes or race

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mat are present, or if they have at least two asymmetric carbon contain atoms, they can exist as a mixture of isomers (mixture of racemates).

The isomer mixtures obtained (mixtures of racemates) can, depending on the physico-chemical differences between the components separated into the two stereoisomeric (diastereomeric) pure raceemates such as by chromatography and / or fractional crystallization.

The racemates obtained can be separated by known methods be, as by recrystallization from an optically active solvent, with the help of microorganisms or by a reaction with optically active acids, which form salts of the compound, and separation of the salts thus obtained, as with Help their different solubility in the diastereomers, from which the antipodes are released with a suitable agent can be. Optically active acids that can be used well are, for example, the L- and D-form of tartaric acid, di-o-tolyltartaric acid, Malic acid, mandelic acid, camphor sulfonic acid or quinic acid. The more active part of the two antipodes is preferably isolated.

Appropriately, those starting materials are used for carrying out the reactions according to the invention which give rise to groups lead to end products that are particularly desirable primarily and specifically to the end products specifically described and preferred.

The starting materials are known or, if they should be new , can be prepared by methods known per se.

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In clinical use, the compounds of the invention will normally be administered orally, rectally or by injection into administered in the form of a pharmaceutical preparation containing an active component either as a free base or as a pharmaceutical Compatible, non-toxic acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate or the like, in Contains combination with a pharmaceutical carrier material.

Therefore, the mention of the new compounds according to the invention here relates to either the free amine base or the acid addition salts the free base, even if the compounds are described generally or specifically, provided that the accompanying text, using such expressions as in the examples is consistent with this broad meaning. The carrier can be a solid, semi-solid, or liquid diluent, or a capsule. These are pharmaceutical preparations another subject of the invention. Usually the amount of active compound is between 0.1 and 99% by weight of the active compound Preparation, expediently between 0.5 and 20% by weight for preparations for injections and between 2 and 50% by weight for preparations for oral administration.

In the manufacture of pharmaceutical preparations containing a compound according to the present invention in the form of dosage units for oral administration, the selected compound can be mixed with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, starch such as potato starch, corn starch , Amylopectin, cellulose derivatives or gelatin, and with an anti-friction agent such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like

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mixed and compressed into tablets. When coated tablets are desired, the core prepared as above can be coated with a concentrated sugar solution such as May contain gum arabic, gelatin, talc, titanium dioxide or the like. You can also use the tablets a varnish that is dissolved in a volatile organic solvent or solvent mixture. A coloring agent can be added to this coating to easily distinguish between tablets with different active compounds or with different amounts of the active compound present.

When making soft gelatin capsules (pearl-shaped closed Capsules), which consist of gelatin and, for example, glycerine, or in the production of similar closed ones Capsules, the active compound is mixed with a vegetable oil. Hard gelatin capsules can contain granules of the active Compound in combination with a solid, powdery carrier material such as lactose, sucrose, sorbitol, mannitol, starch (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.

Dosage units for rectal administration can be found in the Are made in the form of suppositories, which contain the active substance in a mixture with a neutral fat base, or they can be made in the form of gelatin rectal capsules which contain the active substance in admixture with contain a vegetable oil or paraffin oil. '

Liquid preparations for oral administration may be in the form of syrups or suspensions, such as

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Solutions containing from about 0.2% to about 20% by weight of the active substance described, with the remainder being off Sugar and a mixture of ethanol, water, glycerine and propylene glycol. If necessary, such liquid Preparations colorants, flavorings, saccharin and carboxymethyl cellulose Contained as a thickener.

Solutions for parenteral administration by injection can be used as an aqueous solution of a water-soluble pharmaceutical compatible salt of the active compound, preferably in a concentration of about 0.5% by weight to about 10% by weight getting produced. These solutions can also contain stabilizers and / or buffering agents and are expedient be accommodated in ampoules of different dosage units.

The manufacture of pharmaceutical tablets for oral use is done according to the following method:

The solid substances used are ground or sieved to a certain particle size. The binder is in a certain amount of solvent homogenized and suspended. The therapeutic connection and resources required are mixed with the binder solution with continuous and constant mixing and moistened in such a way that the solution is evenly distributed in the mass without over-moistening any part of it. The amount of solution is usually adjusted so that the mass has a consistency that is reminiscent of wet snow. Moistening the powdery Mixture with the binder solution causes the particles to adhere to one another to form aggregates, and the effective

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The granulation process is carried out in such a way that the Mass is pressed through a sieve in the form of a stainless steel net with a mesh size of about 1 mm. the Mass is then spread in thin layers on a floor to dry in a drying chamber. This drying takes place takes place over 10 hours and must be carefully standardized, since the degree of moistening of the granulate is of the utmost importance for the subsequent procedure and for the characteristics of the tablets. Drying in a fluidized bed can usually be used. In this case, the mass is not placed on a floor, but in a container with a Poured mesh bottom.

After the drying step, the granules are sieved to obtain the desired particle size. Under certain Under certain circumstances, energy must be supplied.

The so-called ready-mix is made up of decomposing, friction-reducing Agents and anti-stick agents added. After this admixture the mass should have its correct composition for the tableting stage.

The cleaned tablet punching machine is provided with a certain set of punches and molding tools, whereupon the appropriate setting for the weight of the tablets and the degree of compression is tested. The weight of the tablet determines the size of the dose in each tablet and is calculated based on the amount of therapeutic agent in the granules. The degree of compression Affects the size of the tablet, its strength and its ability to dissolve in water. Especially with regard to the latter two properties

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ten means the selection of the compression pressure (0.5 to 5 t) something of a balancing level. When the correct setting is reached, the production of tablets is started, which takes place at a rate of 20,000 to 200,000 tablets per hour. The pressing of the tablets requires different Times and depends on the size of the approach.

The tablets are freed from adhering powder in a special device and then stored in closed packs. until they are shipped.

Many tablets, especially those that are rough or bitter, are coated. This means that they are using coated with a layer of sugar or any other suitable coating. The tablets become ordinary packed with machines with an electronic counter. The different types of packaging are made of glass or Plastic stoppers, but also from boxes, tubes and packs for special dosages.

The daily dose of the active substance varies and depends on the mode of administration. As a rule of thumb, however, it can be said that the daily dose is 100 to 400 mg per day of the active substance in the case of oral administration and 5 to 20 mg per day in the case of intravenous administration Administration is.

The following examples serve to further illustrate the invention. Temperatures are given in degrees Celsius.

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example 1

2.5 g of 1,2-epoxy-3-o-methylphenoxypropane were mixed with 1.5 g of 2- (4-hydroxyphenoxy) ethylamine and 25 ml of isopropanol, and the entire solution was refluxed for 1.5 hours. The solution was then evaporated in vacuo. The base so obtained was dissolved in acetone and the hydrochloride was precipitated in ether using HCl. The hydrochloride was filtered off and washed with acetonitrile. The yield of 3- / 2- (4-hydroxyphenoxy) ethylaminoZ-io-methylphenoxypropanol-2 was 1.5 g. The melting point was 150 ° C (HCl). The structure was determined by NMR spectroscopy.

Example 2

3- / 1- (2-Hydroxyphenoxy) -äthylairiimV-i -o-methylphanoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3- (o-methyl) -phenoxypropane and 2- (2-hydroxyphenoxy) -ethylamine produced as starting materials. The melting point of this hydrochloride was 80 ° C. Its structure was determined by NMR spectroscopy and by the equivalent weight.

Example 3

3- / 2- (2-methoxyphenoxy) ethylamino7-1-o-methylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-methylphenoxypropane and 2- ^ (2-methoxyphenoxy) ethylamine as a starting material manufactured. The melting point of the tartrate was 91 C. Its structure was determined by NMR spectroscopy and with the Equivalent weight determined.

• 09815 / 061A

Example 4

3- / 2- (4-Ethylphenoxy) ethylaminoZ-i-o-methylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-methylphenoxypropane and 2- (4-ethylphenoxy) ethylamine prepared as the starting material. The hydrochloride melted at 127 ° C.

Example 5

3- / 2- (4-methoxyphenoxy) ethylamino7-1-o-methylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-methylphenoxypropane and 2- (4-methoxyphenyl) ethylamine prepared as starting materials. The hydrochloride melted at 168 ° C.

Example 6

3- / 2- (3,4-Dimethoxyphenoxy) ethylamino7-1-o-methylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-methylphenoxypropane and 2- (3,4-dimethoxyphenoxy) ethylamine prepared as starting materials. The hydrochloride melted at 160 ° C.

Example 7

3- / 2- (4-cyanophenoxy) -ethylamino / -1-o-methylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-methylphenoxypropane and 2- (4-cyanophenoxy) ethylamine prepared as starting materials. The melting point of the hydrochloride was 126 ° C.

Example 8

3- / 2- (4-methoxyethoxyphenoxy) ethylamino7-1-o-methylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy

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3-o-methylphenoxypropane and 2- (4-methoxyethoxyphenoxy) ethylamine produced as raw materials. The melting point of the hydrochloride was 149 ° C.

Example 9

3- / 2- (4-hydroxyphenoxy) ethylamino / -3-o-cyanophenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-hydroxyphenoxy) ethylamine prepared as starting materials. The tartrate melted at 52 ° C.

Example 10

3- / 2- (4-hydroxyphenoxy) ethylamino / -1-o-allyloxyphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-allyloxyphenoxypropane and 2- (4-hydroxyphenoxy) ethylamine prepared as starting materials. The melting point of the tartrate was at 105 ° C.

Example 11

3- / J2- (4-hydroxyphenoxy) -äthylamino7-1-o-allylphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-allylphenoxypropane and 2- (4-hydroxyphenoxy) ethylamine as starting materials manufactured.

Example 12

2 - / ^ 2- (4-hydroxyphenoxy) ethylamino / -! -o-methoxyphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-methoxyphenoxypropane and 2- (4-hydroxyphenoxy) ethylamine prepared as starting materials.

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Example 13

3 - / _ 2 - (4-Hydroxyphenoxy) -äthylaminoZ-i -o-ethylphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-ethylphenoxypropane and 2- (4-hydroxyphenoxy) ethylamine as Raw materials produced.

Example 14

3- / 2- (4-Hydroxyphenylthio) -äthylaminoZ-i-o-cyanophenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-hydroxyphenylthio) ethylamine as Raw materials produced.

Example 15

3- / 3- (4-Hydroxyphenoxy) propylaminoZ-i-o-allylphenoxypropanol-2 was prepared according to Example 1 using 1 ^ -epoxy-S-o-allylphenoxypropane and 3- (4-hydroxyphenoxy) propylamine as starting materials.

Example 16

3- / 2- (3,4-Dimethoxyphenoxy) ethylamino / -1-o-allyloxyphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-allyloxyphenoxypropane and 2- (3,4-dimethoxyphenoxy ) ethylamine produced as raw materials.

Example 17

3- / 5- (2-Chlorophenoxy) -äthylamino7-1-o-allylphenoxypropanol-2 was prepared according to Example 1 using 1 _# 2-epoxy-3-o-allylphenoxypropane and 2- (2-chlorophenoxy) ethylamine as starting materials manufactured.

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Example 18

3- / 2- (4-hydroxyphenoxy) ethylaminoZ-i-o-propargyloxyphenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-propargyloxyphenoxypropane and 2- (4-hydroxyphenoxy) ethylamine produced as raw materials.

Example 19

3- / 2- (4-methoxyphenoxy) ethylamino7-1-o-cyanophenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-methoxyphenoxy) ethylamine prepared as starting materials. M.p. = 134 ° C as hydrochloride.

Example 20

3- / 2- (2-Hydroxyphenoxy) -äthylamino / -1 -o-cyanophenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (2-hydroxyphenoxy) ethylamine as Raw materials produced. M. - 181 ° C as hydrochloride.

Example 21

3- / 2- (4-Hydroxy-3-methoxyphenoxy) -ethylamino7-1 ~ o-cyanophenoxypropanol-2 was according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-hydroxy-3-methoxyphenoxy) ethylamine prepared as starting materials. M.p. = 78 C as the hydrochloride.

Example 22

3- / 2- (3,5-Dimethoxyphenoxy) -ethylamino / -1-o-cyanophenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-cyanophenoxypropane and 2- (3,5-dimethoxyphenoxy ) -ethylamine produced as starting materials. M.p. = 159 ° C as hydrochloride.

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Example 23

3- / 2- (4-Hydroxyphenoxy) -athylanu.no/-1-o-pyrrolylphenoxypropanol-2 was prepared according to Example 1 using 1,2-epoxy-3-o-pyrrolylphenoxypropane and 2- (4-hydroxyphenoxy) - ethylamine produced as starting materials. F. = 150 ° C as succinic acid addition salt.

Example 24

A syrup with a content of 2% (weight per volume) active substance was prepared from the following ingredients:

3 - / _ 2- (4-hydroxyphenyl) -i-methylethylamino / -i-o-methylphenoxypropanol-2 · HCl 2.0 g

Saccharin 0.6 g

Sugar 30.0 g

Glycerin 5.0 g

Flavor 0.1 g

Ethanol 96% strength 10.0 g

Distilled water to 100.0 ml

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

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

Example 25

3- / 2- (4-Hydroxyphenyl) -1., 1 -dime thy läthylamino-1 -o-allylphenoxy_ / propanol-2-hydrochloride (250 g) was mixed with lactose (175.8 g),

809815 / 06U

Potato starch (169.7 g) and colloidal silica (32 g) mixed together. The mixture was washed with a 10% solution of Gelatin moistened and granulated through a 12-mesh sieve. After drying, potato starch (160 g), talc (50 g) and magnesium stearate (5 g) were admixed, and the mixture thus obtained was compressed into tablets (10,000) containing 25 mg of the substance contained. The tablets were marketed with break lines to break a dose other than 25 mg or a multiple thereof.

Example 26

Granules were made from 3- £ 2- (4-hydroxyphenyl) -i-methyläthylaminejl-o-propargyloxyphenoxypropanol-2-p-hydroxybenzoate (250), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After the drying stage, the granules were made with talc (25 g), potato starch (40 g) and magnesium stearate (2.50 g) mixed and compressed into 10 0OO biconvex tablets. These tablets were initially made with a 10% strength alcoholic solution of shellac and then with an aqueous solution containing sucrose (45%), gum arabic (5%), gelatin (4%) and dye (0.2%) coated. Talc and powdered sugar were used after the first five coatings to be powdered. The coating was then coated with a 66% sugar syrup and with a 10% carnauba wax solution Polished in carbon tetrachloride.

Example 27

3- / 2- (4-hydroxyphenyl) -1,1-dimethylethylaminoZ-S-o -ethylphenoxypropanol-2-hydrochloride (1 g), sodium chloride (0.8 g) and ascor-

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2743A93

Bic acid (0.1 g) was distilled in a sufficient amount Dissolved water to give 100 ml of solution. This solution, which contained 10 mg of active substance per milliliter, was used to fill ampoules which have been sterilized by heating at 120 ° C for 20 minutes.

Example 28 (method b + e)

10 g of o-methylphenyl glycidyl ether in 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 was dissolved in ethyl acetate and HCl gas was introduced. The hydrochloride precipitated and was filtered off and dissolved in 50 ml of ethanol, to which 2- (4-methoxymethoxy) phenoxyethyl chloride and 15 g of K ₂ CO- had been added. The mixture was heated in an autoclave at 130 ° C for 10 hours, after which the solvent was evaporated and the residue treated with 100 ml of 2N HCl for 1 hour at ambient temperature. The aqueous phase was made alkaline with ammonia and extracted with ethyl acetate. The solvent _{phase was dried over K 2} ^CO 3, 1- / 2- (4-hydroxy) -phenoxyethylamino7-3- (o-methylphenoxy) -propanol-2 being obtained. The base obtained was converted into its hydrochloride, 1- / 2- (4-hydroxy) -phenoxyethylamino7-3- (o-methylphenoxy) -propanol-2-hydrochloride. F. = 150 ° C.

Example 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 1- / 5- (4-methoxymethoxy) phenoxyethylamino7-3-chloropropanol-2 were added. The mixture was in

809815 / 06U

heated in an autoclave on a boiling water bath for 10 hours. It was then filtered and the filtrate was evaporated to dryness. The residue was washed with 2N HCl for 1 hour treated at ambient temperature and extracted with ether, whereupon the aqueous phase is made alkaline with ammonia and washed with Ether was extracted. The ether phase was over MgSO. dried, and it became 1 - / _ 2- (4-hydroxy) -phenoxyethylaminoy-S- (o-methylphenoxy) -propanol-2 obtained and converted into the hydrochloride and isolated. F. = 150 ° C.

Example 30 (method d)

0.116 mol of o-methylphenol were mixed with 0.080 mol of 1- / 2- (4-methoxymethoxyphenoxy) ethyl / ^ - acetidinol, 0.500 moles of benzyl alcohol and 0.003 moles of KOH mixed. The mixture was stirred Heated under reflux for 6 hours at 140 ° C. and then cooled and extracted with 2 N HCl. The aqueous phase was left for 1 hour stand at ambient temperature, then it was made alkaline and extracted well with chloroform. After drying and Evaporation, the residue was dissolved in ether and HCl in ether was added to the solution. The hydrochloride was filtered off and washed with acetone. The hydrochloride of 3- / 2- (4-hydroxyphenoxy) -ethylamine-p / -1- (o-methylphenoxy) -propanol-2 melted at 150 ° C.

Example 31 (method f)

1-Amino-3- (o-methylphenoxy) -propanol-2 was prepared according to Example 23. 5 g of this compound were dissolved in 50 ml of methanol, and 15 g of 4-hydroxyphenoxyacetaldehyde were added, with 3- / 2- (4-hydroxyphenoxy) -äthyliminoZ-io-methylphenoxypropa-

The solution was

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nol-2 was obtained. The solution was cooled to 0 C, and

at this temperature 5 g of sodium borohydride were added in small portions, whereby the imino compound was reduced. The temperature was then allowed to rise to ambient temperature and after 1 hour 150 ml of H_0 were added, and the total mixture was extracted with ether. The ether phase was over MgSO. dried and evaporated. The residue was in the Hydrochloride transferred. In this way, 3- / 2- (4-hydroxyphenoxy) -äthylamino7-1- (o-methylphenoxy) -propanol-2 · Obtained HCl. F. = 150 ° C.

Example 32 (method g)

1.0 g of 3-o-methylphenoxy-1- / 2- (4-hydroxyphenoxy) -ethylamino / -propanon-2 was dissolved in 25 ml of methanol and the solution was cooled to 0 C on an ice bath. 0.25 NaBH. were in small Portions were added with stirring initially at 0 ° C. for 1 hour and then at ambient temperature for 0.5 hour. The resulting solution was evaporated and 50 ml of H ~ 0 added became. The aqueous phase was extracted three times with 50 ml of chloroform, and the collected chloroform phase was dried and evaporated. The hydrochloride was precipitated from an ether solution of the residue by adding HCl-containing ether. Recrystallization took place from acetone. The hydrochloride of 3- / 2- (4-hydroxyphenoxy) -äthylamino7-1- (o-methylphenoxy) propanol-2 melted at 150 ° C.

Example 33 (method h)

3 - / ^ 2- (4-hydroxyphenoxy) ethylamino / -! - (o-Propynylphenoxy) -propanol-2 was made according to Example 1 from 1,2-epoxy-i-o-propynylphenoxypropane and 2- (4-hydroxyphenoxy) ethylamine prepared. The hydro

809815 / 06U

chloride was dissolved in ethanol and a Pd / C catalyst was used was added and the compound was hydrogenated until the calculated amount of H_ was absorbed. After filtration, the filtrate was released evaporated to dryness and the residue was recrystallized from ethyl acetate. In this way was 3- / 2- (4-hydroxyphenoxy) -äthylaminp_7-1- (o-allylphenoxy) -propanol-2 · Obtained HCl.

Biological effects

The β-receptor blocking agents according to the present invention were tested for their biological properties. All compounds were tested with anesthetized cats (male and female weighing 2.5 to 3.5 kg) that had been pretreated with reserpine (5 mg / kg body weight intramuscularly) about 16 hours before the experiments. The animals were pretreated with reserpine in order to switch off the endogenous sympathetic regulation of the heart rate and the vascular tone of the smooth muscles. The cats were anesthetized with pentobarbital (30 mg / kg body weight, administered ip) and artificially ventilated with room air. A bilateral vagotomy was performed on the neck. The blood pressure was taken on a cannulated carotid artery and the heart rate was recorded with a cardiotachometer via the electrocardiogram (EKG). The own ß-mimetic activity on the heart was seen in the increased heart rate after the administration of the agent. The test compounds were administered intravenously in logarithmically increasing doses. The values obtained were plotted on Dosisan speaking curves from which ER affinity values (ED ₅₎

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were averaged. At the end of each experiment, the doses were high Isoprenaline administered to respond to maximum heart rate to obtain.

The compounds were also tested with conscious dogs. Beagle dogs were trained to lie quietly and could be raised to an erect position by placing their front paws on a table for two minutes. The arterial blood pressure was registered by a blood pressure transducer that was connected to the dog at heart level. The heart rate was determined on the basis of the EKG. All dogs were pretreated with methylscopolamine to prevent vagal effects avoid. Recordings were made before, 15 and 75 minutes after administration of the test compound, first in the lying position for 2 minutes and then in the upright position for 2 minutes. The test compounds were administered in increasing doses with an interval of 2 hours.

The pA ₂ were also measured in rats. pA_ is -log the concentration of an antagonist which leads to the fact that the noradrenaline dose must be doubled in order to get the same effect of noradrenaline as one would get without the antagonist.

pA ~ = log (dr - 1) - log (antagonist), where dr is the dose ratio

«4- SDc ^ of noradrenaline (antagonist) _Ab . "- _all . v ««, «,, *. ^»

nis = ϊγ ^ 50 —-— r = 3 - = ~ 3 γζζ - -τ * —τϊ -? - is and all concentrations

ED ₅₀ of norepinephrine (control)

tions are given in moles per liter. The pA ~ is thus a measure of the <t-receptor effect, the greater the pA ~, the higher this d-effect is.

The experiments demonstrate that the compounds tested are potent β-receptor antagonists that are cardiac selective and

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27434J93

have no ß-mimetic activity of their own. The connections also greatly lower blood pressure in conscious dogs. The powerful antihypertensive effects of the new compounds in dogs consciously depends on a vasodilator effect in connection with the cardiac ß-receptor blockade. The ones in the Results obtained in the above tests are shown in the table below.

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Tabel Cat treated with reserpine

O - 4-OH Isoprenaline-ß-
Blockade
Lich the her
speed
ED ₅₀ µmoles / kg Isoprenaline-ß-
Blockade
after the peri-
pheric cons
state
ED _r ^, µmol / kg Δ-beats /
minute % Iso
prenalin 6.4 -J O
CD
oa -CN 4-OCH ₃ 0.25 1.0 13th 18th 5.5 co -OCH ₂ CONHC ₄ H ₄ OCh ₃ 4-OH 0.22 2.7 7th 7th 6.5 CD cn -CN 2-OH 0.05 1.8 O O 6.8 CO O -CN 3-OCH ₃ , 4-OH 1.7 17th 35 39 6.5 -CN 3,5-diOCH ₃ 0.3 3.4 17th 27 6.0 -CH ₃ 3,4-diOCH ₃ • 2.9 11 15th 17th 7.0 -CH ₃ 2-OCH ₃ 1.5 5.8 8th 11 5.8 -CH ₃ 4-OCH ₃ 4.5 11 8th 8th 5.8 -CH ₃ 4-OCH ₂ CH ₂ OCH ₃ 0.5 8.2 17th 22nd ⁵ ' ⁹ -CH ₃ 4-CN 0.6 10.3 25th 29 5.6 -CH ₃ 4-C ₂ H ₅ 1.6 30th 12th 17th 6.3 -CN 4-OH 7.9 68 15th 17th 6.0 -CH ₃ 2-OH 0.08 5.5 13th 15th 0.6 17th 30th 29

Claims (28)

Dr. Hans-Heinrich Willrath t Dr. Dieter Weber Dipl.-Phys. Klaus Seiffert PATENTANWÄLTE ['-6! WIESBADEN 23 Sep 1977 PoMla * 6145 Gu511V-Fftyi · »str.ie u Dr. We / Wh Tt (O61H | 37J7SO TflrK, .mm.H - ^^, WILLPATENT Telex: 4-186 (47 / / 4 ο HJ j KH 523-1 Aktiebolaget Hässle, Kärragatan 5, S-431 20 Mölndal Amine, proceedings for their manufacture and pharmaceuticals containing them Priority: Swedish patent application No. 7611125-1 dated October 7, 1976 Claims 1. Amines of the general formula OCH ₂ CHOHCh ₂ NH 80981 5 / 0G1 4 ORlQiNAL WSPECTEQ wherein R is methyl, ethyl, propyl, methoxy, propargyloxy, cyano, allyloxy, acetyl, cyanomethyl, hydroxymethyl, CH ₃ OC ₂ H ₄ NHCOCH ₂ O, morpholino, pyrrolidino or Pyrrolyl group 2 3
pe denotes, R and R are identical or different and each denotes hydrogen atoms, alkoxyalkoxy, cyano, alkyl, hydroxyl, alkoxy or hydroxymethyl groups or halogen atoms, where 2 3 when R and R are not both hydrogen atoms at the same time, η denotes an integer from 2 to 4 and X denotes -0- or -S-, and their therapeutically acceptable salts. 2. Amines according to claim 1 in the form of their right-handed or left-handed optical antipodes. 3. 3- / 2- (4-Hydroxyphenoxy) ethylamino / -1-o-methylphenoxypropanol-2 and its therapeutically acceptable salts. 4. 3- / 2- (4-Hydroxyphenoxy) ethylamino7-1-o-ethylphenoxypropanol-2 and its therapeutically acceptable salts. 5. 3- / 2- (4-Hydroxyphenoxy) ethylamino / -1-o-propylphenoxypropanol-2 and its therapeutically acceptable salts. 6. 3- / 2- (4-Hydroxyphenoxy) ethylaminoZ-i-o-propargyloxyphenoxypropanol-2 and its therapeutically acceptable salts. 7. 3- / 5- (4-Hydroxyphenoxy) ethylamino / -1-o-cyanophenoxypropanol-2 and its therapeutically acceptable salts. 8. 3- / 3- (4-Hydroxyphenoxy) ethylamino / -1 -o-allyloxyphenoxypropanol-2 and its therapeutically acceptable salts. 9. 3- / 2- (4-Hydroxyphenoxy) ethylamino / -1-o-cyanomethylphenoxypropanol-2 and its therapeutically acceptable salts. 10. 3- / 2- (4-Hydroxyphenoxy) -ethylamine-7-1 -o-acetylphenoxypropanol-2 and its therapeutically acceptable salts. .809815 / 0614 11. 3- / 2- (4-Hydroxyphenox /) - Ethylamino / -1-o-Hydroxymethylphenoxypropanol-2 and its therapeutically acceptable salts. 2. 3- / 2- (4-Hydroxyphenylthio) -ethylaminocy-i-o-cyanophenoxypropanol-2 and its therapeutically acceptable salts. 13. 3- / 2- (4-Hydroxyphenylthio) ethy1amino? -1-o-methylphenoxypropanol and its therapeutically acceptable salts. 14. 3- / 2- (3-Methoxy-4-hydroxyphenoxy) -ethylamino7-1-o-methylphenoxypropanol-2 and its therapeutically acceptable salts. 5. 3- / 2- (3-Bromo-4-hydroxyphenoxy) -ethylamineV-i-o-methoxyphenoxypropanol-2 and its therapeutically acceptable salts. 16. 3- / 5- (3-Hydroxymethyl-4-hydroxyphenoxy) -ethylamino-1-o-cyanophenoxypropanol-2 and its therapeutically acceptable salts. 17. 3- / 2- (3,4-Dihydroxyphenylthio) ethylamino / -1-o-cyanophenoxypropanol-2 and its therapeutically acceptable salts. 8. 3- / 2- (4-Hydroxyphenoxy) -propylamine) / -1 -o-methylphenoxypropanol-2 and its therapeutically acceptable salts. 19. 3- / 2- (2-Chloro-4-hydroxyphenylthio) -ethylaminoy-ethylamino-i-oallyloxyphenoxypropanol-2 and its therapeutically acceptable salts. 20. 3- / 2- (4-methoxyphenoxy) ethylamino / -1-o-cyanophenoxypropanol-2 and its therapeutically acceptable salts. 21. 3- / 2- (2-Hydroxyphenoxy) ethylamine V-i-o-cyanophenoxypropanol ^ and its therapeutically acceptable salts. 22. 3- / 2- (4-Hydroxy-3-methoxyphenoxy) -ethylaminoy-i-o-cyanophenoxypropanol-2 and its therapeutically acceptable salts. 0 9 8 1 5/0 6 U 2743 * 93 23. 3- / S- (3,5-dimethoxyphenoxy) -ethylamino / -1-o-cyanophenoxypropanol-2 and its therapeutically acceptable salts. 24. 3 - / _ 2- (4-Hydroxyphenoxy) -ethylaminoy-1 -o-pyrrolylphenoxypropanol-2 and its therapeutically acceptable salts. 25. 3- / 5- (4-Hydroxyphenoxy) ethylamincy-i-o-methoxyethylaminocarbonylmethoxyphenoxypropanol-2 and its therapeutically acceptable salts. 26. Process for the preparation of amines and their salts according to claim 1 to 25, characterized in that one a) a compound of the general formula II Γ \ - X ¹ ₂ CHCH ₂ Z wherein R has the above meaning, X is a hydroxyl group denotes and Z denotes a reactive esterified hydroxyl group or X and Z taken together form an epoxy group, with an amine of the general formula 2 3
in which R, R, η and X have the above meaning or
b) a compound of the general formula III OCH ₂ CHOHCh ₂ NH ₂ • 09815/0814 wherein R has the above meaning with a compound of the general formula , 2 R ³ 2 3 wherein R, R, η, X and Z have the above meaning, reacts or
c) a compound of the general formula IV OH (IV) wherein R has the above meaning with a compound of the general formula V x ^{1 r2} Z-CH ₂ CHCH ₂ NH-ICH ₂ J _n -X- ^ ^) _(v) 12 3 wherein Z, X, R, R, η and X have the above meaning, converts or
d) a compound of the general formula IV wherein R has the above meaning with a compound of the general formula VI IÖ9815 / 06U 2743 ^ 93 CH - CH ₂ OH 2 3
in which R, R, η and X have the above meaning or e) of a compound of the general formula I in which R, R, R and η and X have the above meanings, but in which the Nitrogen atom of the amino group and / or the hydroxyl groups can be split off Carrying residues, splitting off these residues, or f) a Schiff base of the general formula VIII or IX R ² (VIII) or a cyclic tautomer of the form]. X corresponding to the compound of the formula IX // M-OCH ^ CH ² II 0 N 0 NH ^R \ v / 12 3
in which R, R, R, η and X have the above meaning, where the compounds IX and X can also be present at the same time, reduced or _10981S / 06U " ⁷ " · 2743 ^ 93 g) in a compound of the general formula XI OCH ₂ CCH ₂ NH- (CH ₂ J _n -XA ^) (XI) 12 3
wherein R, R, R, η and X have the above meaning, the Oxo group reduced to a hydroxyl group or h) in a compound of the general formula XII f / ^ -DCh ₀ CHOHCH ₀ NH- (CH-) -x- r vT ^{2 2 2 n} \ Si τ (XU) 2 3
wherein R, R, η and X have the above meaning and wherein 2 1 2 1 X is a residue that can be converted into R, X converts to R. or
i) a compound of the general formula Va - OCH., CHOHCH-NH (CH.,) Z 2 2 2 η _(Va) wherein R, η and Z have the above meaning with a compound of the general formula IVa wherein R _f R have the above meaning _to j _χ ^^ e, or k) in a compound corresponding to the formula I with an oxo group on the carbon adjacent to the nitrogen atom 809815/0614 atom reduces this oxo group to 2 hydrogen atoms and in these methods, if appropriate, introducing or splitting off or exchanging substituents and / or the compounds obtained converted into other end products and / or the isomer mixtures obtained are separated into pure isomers and / or the obtained isomers Separates racemates into optical antipodes and / or separates the free bases obtained into their therapeutically acceptable salts or the salts obtained are converted into their free bases. 27. Medicaments containing at least one amine or its salt according to claim 1 to 25, preferably in a conventional pharmaceutical compatible carrier material. 28. Use of at least one amine or its salt according to claim 1 to 25 in blocking the ß-receptors of the heart. 809815 / 06U