CH618416A5 - Process for the preparation of novel hydroxyamines - Google Patents

Description

The present invention relates to a process for the preparation of new hydroxyamines which are active / 3-receptor-blocking compounds. When administered to mammals, particularly humans, these compounds block the heart's / 3 receptors and are therefore valuable remedies for treating the symptoms and features of cardiovascular diseases.

In the above formula, R1 stands for an unsubstituted alkyl of 1 to 10 carbon atoms, for unsubstituted cycloalkyl with 3 to 8 carbon atoms or for alkyl with 1 to 6 carbon atoms, the 45 with hydroxy, phenyl, halophenyl or Alkoxyphenyl may be substituted; R2 stands for hydrogen or alkyl with 1 to 4 carbon atoms, R3 stands for acyl with 1 to 10 carbon atoms and R4 finally stands for hydrogen, halogen, —OH, nitro, cyano, acetamide, trifluoromethyl, alkyl, alkoxyalkyl, see above Phenylalkyl, phenylalkoxy, aryl or aryloxy, where all of the radicals mentioned can have 1 to 10 C atoms, or for cycloalkyl with 3 to 8 C atoms or hydroxyalkyl, alkoxy, alkenyloxy, alkynyloxy, alkenyl, alkylthio, alkanoyl or alkoxycarbonyl each with 1 to 5 carbon atoms. Also possible are the esters of the above-mentioned compounds with aliphatic carboxylic acids or aromatic carboxylic acids or other condensation products thereof. However, these compounds also do not show any of the important a-receptor activities.

GB Patent No. 1,344,976 describes compounds of the formula or 3

In the formula, Z represents chlorine, alkoxy, cyano, hydroxymethyl, acetyl, alkyl in the meta position or alkyl in the ortho position.

However, none of the meta-substituted compounds mentioned shows any a-receptor activity. The ortho-substituted compounds of said British patent show side activities in combination with their beta-receptor blocking selectivity which are not desired.

The new compounds obtainable according to the invention have valuable pharmacological properties. So they block z. B. the cardial ß-receptors, which can be shown by determining the antagonism of tachycardia after intravenous injection of 0.5 fim / kg of d / l-isoproterenol sulfate in an anesthetized cat after intravenous injection of 0.002 to 2 mg / kg. The compounds obtainable according to the invention also block the vascular β-receptors, which can be determined by determining the antagonism of the vasodilation after intravenous injection of 0.5 wm / kg of d / l-isoproterenol sulfate in an anesthetized cat by intravenous administration of 0.002 to 2 mg / kg or more is shown. The compounds obtainable according to the invention also have stimulating properties on / J receptors, i. H. they show a specific effectiveness (intrinsic activity). This characteristic is particularly pronounced with regard to the vascular / 3 receptors which cause dilation of the peripheral blood vessels.

The new compounds obtainable according to the invention can be used for the treatment of arrhythmias, angina pectoris and hypertension. Peripheral vasodilation is particularly valuable for the latter two indications. The compounds can also be used as intermediates for the preparation of other valuable compounds with pharmacological properties.

The process according to the invention for the preparation of new hydroxyamines of the formula (I) is defined in the patent claim.

Preferred compounds are the following: 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-methyl-

phenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-ethyl-

phenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-pro-

pylphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-allyl-

phenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-pro-

pargyloxyphenoxypropanol- (2), 3- [2- (4-HydroxyphenyI) -l-methyIäthyIamino] -l-o-cyano-

phenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l, l-dimethylethylamino] -l-o-me-

thylphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l, l-dimethylethylamino] -l-o-ethyl-

phenoxypropanol- (2),

3 - [2 - (4-hydroxyphenyl) -1,1 -dimethylethylamino] -1 -o-pro-

pylphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l, l-dimethyläthyIamino] -l-o-allyl-

phenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l, l-dimethylethylamino] -l-o-pro-

pargyloxyphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -1,1-dimethylethylamino] -1 -o-

cyanophenoxypropanol- (2), 3-ethyl-3- [2- (4-hydroxyphenyl) -l-methylethylamino] -

1-o-allylphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o, m-dime-

thy lphenoxypropanol- (2), 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-methoxy-

phenoxypropanol- (2), 3-methyl-3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-ethylphenoxypropanol- (2),

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3-methyl-3- [2- (4-hydroxyphenyl) -l-methylethylamino] -

1-o-cyanophenoxypropanol- (2), 3-methyl-3- [2- (4-hydroxyphenyl-l, l-dimethylethylamino] -

1-o-methylphenoxypropanol- (2), 3-methyl-3- [2- (4-hydroxyphenyl) -l, 1 -dimethylethylamino] -

l-o-allylphenoxypropanol- (2) and 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-m-methyl-

phenoxypropanol- (2).

Salt-forming acids can be used to prepare therapeutically permissible salts of the compounds obtainable according to the invention, for example hydrohalic acids, sulfuric, phosphoric, nitric and perchloric acids, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, for example formic, acetic, propionic -, amber, glycol, milk, apple, wine, citronene, ascorbic, maleic, hydroxymalein, pyruvate, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p- Hydroxybenzoic, salicylic, p-aminosalicyl, embon, methansulfone, ethanesulfone, hydroxyethanesulfonic, ethylene sulfonic, ha-logenobenzenesulfonic, toluenesulfonic, naphthylsulfonic or sulfanilic acid, methanine, tryin or arginine.

The compounds obtainable according to the invention can be used orally or parenterally for acute and chronic treatment of the above-mentioned cardiovascular diseases. The biological effects of the new compounds obtainable according to the invention were tested and the various tests carried out with the compounds mentioned are indicated and explained below.

Z, the reactive, esterified hydroxyl group is in particular one with a strong, inorganic or organic acid, preferably a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, or sulfuric acid or a strong organic sulfonic acid, such as, for. B. benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid, esterified hydroxyl group.

When using a reactive ester as the starting material, the reaction is preferably carried out in the presence of a basic condensing agent and / or with an excess of amine. Suitable basic condensing agents are u. a. Alkali hydroxides, preferably sodium or potassium hydroxide, alkali carbonates, preferably potassium carbonate, and alkali alcoholates, preferably sodium methylate, potassium ethylate or potassium tert-butoxide.

This radical can be eliminated from a compound of the basic formula (I) in which the nitrogen atom of the amino group and / or the hydroxyl groups additionally contain a radical which can be removed.

Such cleavable residues are in particular those which can be cleaved by solvolysis, reduction, pyrolysis or fermentation.

Residues that can be split off by solvolysis are preferably residues that can be split off by hydrolysis or ammonolysis.

Residues which can be split off by hydrolysis are, for example, an acyl residue which, if present, represents functionally modified carboxyl groups, for example oxycarbonyl residues, such as alkoxycarbonyl residues, e.g. B. tert-butoxycarbonyl or Äthoxycarbonylrest, Ar alkoxycarbonylreste, such as Phenylnied-rig-alkoxycarbonylreste, z. B. a carbobenzyloxy, halo-gencarbonylrest, z. B. a chlorocarbonyl radical, also arylsulfonyl, such as toluenesulfonyl or bromobenzenesulfonyl and possibly halogenated, for. B. fluorinated, lower alkanoyl, such as formyl, acetyl or trifluoroacetyl, or a benzyl or cyano groups or silyl, such as. B. trimethylsilyl.

Of the abovementioned residues on the hydroxyl groups which can be split off by hydrolysis, 3

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4th

which preferably uses the oxycarbonyl radicals and the lower alkane-oyl radicals or the benzoyl radicals.

In addition to the radicals mentioned above, double-bonded radicals on the amino group which can be split off, e.g. B. alkylidene or benzylidene radical or a phosphorylidene group, such as. B. a triphenylphosphorylide group, which then gives the nitrogen atom a positive charge. Residues which can be split off by hydrolysis on the hydroxyl group and the amino group are also divalent residues which, if appropriate, can be substituted methylene. Any organic radicals can be used as the substituent on the methylene radicals, it being irrelevant in the hydrolysis which compound is the substituent on the methylene group. As a methylene substituent, for example aliphatic or aromatic radicals, such as 5 z. B. the above-mentioned alkyl, aryl, e.g. B. phenyl or pyridyl. The hydrolysis can be carried out in any customary manner, for example in a basic or - preferably - in an acidic medium.

The compounds which have radicals which can be eliminated by hydrolysis are, for example, the compounds of the formula (VII)

OCH ^ CH-0

R I

EH

R '

N -C-CH; 'I CH.

"OH

(vii)

wherein R \ R2, R3 and R4 have the meanings given above and Y is a carbonyl or thiocarbonyl radical.

The hydrolysis can be carried out in an analogous manner, e.g. B. in the presence of a hydrolyzing agent, e.g. B. in the presence of an acidic agent such as dilute mineral acids such as sulfuric acid or hydrohalic acid, or in the presence of basic agents such as. B. alkali metal hydroxides, such as sodium hydroxide. Oxycarbonyl radicals, arylsulfonyl radicals and cyano groups can be removed in a suitable manner by acidic means, for example by means of a hydrohalic acid, preferably hydrobromic acid. The cleavage is preferably carried out using dilute hydrobromic acid, preferably in a mixture with acetic acid. Cyano groups are preferably cleaved with hydrobromic acid at elevated temperature, for example in boiling hydrobromic acid, using the “bromine cyanide method” (von Braun). Furthermore, for example, a tert-butoxycarbonyl radical can be split off under anhydrous conditions by treatment with a suitable acid, for example trifluoroacetic acid.

Residues which can be split off by ammonolysis are, in particular, the halocarbonyl radicals, such as, for example, the chlorocarbonyl radical. The ammonolysis can be carried out in a conventional manner, e.g. B. by means of an amine containing at least one hydrogen atom bound to the nitrogen atom, for example a mono- or di-lower alkylamine, e.g. B. methylamine or dimethylamine, or in particular ammonia, preferably at elevated temperature. Instead of ammonia, one can use an agent that cleaves ammonia, for example hexamethylenetetramine.

Residues that can be split off by reduction are e.g. B. an a-aryl-alkyl radical, such as. B. a benzyl radical or an a-aralkoxycarbonyl radical, such as. B. a benzyloxycarbonyl radical which can be split off in the usual way by hydrogenolysis, in particular by catalytically excited hydrogen, such as by hydrogen in the presence of a hydrogenation catalyst, for. B. Raney nickel. Other residues that can be split off by hydrogenolysis include: a. 2-haloalkoxycarbonyl residues, such as 2,2,2-trichloroethoxycarbonyl residues or 2-iodoethoxy or 2,2,2-tribromoethoxycarbonyl residues, which can be cleaved in a conventional manner, in particular by metal reduction (so-called nascent hydrogen). Nascent hydrogen can be obtained by the action of a metal or a metal alloy such as amalgam on compounds which release hydrogen, for example carboxylic acids, alcohols or water, in particular zinc or zinc alloys can be used together with acetic acid. Hydrogenolysis of 2-haloalkoxycarbonyl radicals can also be carried out using chromium or chromium (II) compounds, such as chromium (II) chloride or chromium (II) acetate.

A residue that can be removed by reduction can also be an arylsulfonyl group, for example a toluenesulfonyl group, which can be removed in a conventional manner by reduction using nascent hydrogen, for example using an alkali metal such as lithium or sodium in liquid ammonia; the cleavage can preferably take place on a nitrogen atom. When carrying out the reduction, care must be taken that 35 other reducible groups are not influenced.

Pyrolysis, in particular radicals which can be split off from the nitrogen atom, are, where appropriate, substituted or preferably unsubstituted carbamoyl groups. Suitable substituents are e.g. B. lower alkyl or aryl-lower alkyl, e.g. B. 40 methyl or benzyl, or aryl, such as. B. phenyl; The pyrolysis is carried out in the usual way, taking care that other groups sensitive to the effects of heat are not affected.

Residues which can be split off from the nitrogen atom by fermentation are, where appropriate, substituted, but preferably unsubstituted, carbamoyl groups. Suitable substituents are, for example, lower alkyl or aryl-lower alkyl, such as methyl or benzyl, or aryl, such as phenyl. The fermentation can be carried out in the usual way, e.g. B. by means of the enzyme urease or with soybean extract at a temperature of 20 ° C or at a slightly elevated temperature.

Furthermore, a Sehiff base of the formula (VIII) or (IX)

55

□ H R1

I '// V \

QCH2CH-Ç = N-Ç-CH .—, '/ \\ - OH

1 3 1

RJ-- CH.

65

ÜH Rx

'J ^ V-ÜCH ^ H-CH - N = C-CH2

1 3

CH.,

(viii)

-OH

(IX)

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

wherein R \ R2, R3 and R4 have the meanings given above, but R1 is not methyl, and the compounds of the formulas (IX) and (X) can coexist. This reduction can be carried out in the usual way, e.g. B. using a light metal hydride such. As sodium borohydride, lithium aluminum hydride, using a hydride such as boranate with formic acid, or by means of catalytic hydrogenation, such as. B. with hydrogen in the presence of Raney nickel. With the 25 reduction, care must be taken that other reducible groups are not influenced.

The oxo group of a compound of the formula (XI)

rv 0 c H o 1 ~ H N H - ü - C H - / - 13 i

2 R C, 13

CJI

GCH2CHOHÇH NH-j-CH ^

35

(XI)

40

wherein R1, R2, R3 and R4 have the meanings given above, are reduced to a hydroxyl group. This reduction can be carried out in a customary manner, preferably using a light metal hydride, as already mentioned above, or according to the “Meerwein-Pondorf-Ver-ley method” or a modification thereof, preferably an alkanol as reaction component and is used as a solvent, for example isopropanol, further preferably a metal alkoxide, such as metal isopropanolate, e.g. B. aluminum isopropoxide is used.

You can also in a compound of formula (XII)

OH

55

CH

■ J

(XII)

where R \ R3 and R4 have the meanings given above and where X2 is a radical which can be converted into a radical R2, convert the radical X2 into R2.

Furthermore, the oxo group of a compound which corresponds to that of the formula (I) and which is on a carbon atom which is bonded to a nitrogen atom can be reduced to a CH 2 group.

Such compounds are, for example, those of the formula (XIII)

wherein R \ R2 and R4 have the meanings given above and R3 is hydrogen.

The reduction can be carried out in the manner described above, complex metal hydrides, e.g. As lithium aluminum hydride or diisobutyl aluminum hydride can be used. The reaction is preferably carried out in an inert solvent, for example an ether, preferably diethyl ether or tetrahydrofuran.

Depending on the conditions which are observed in the process according to the invention and the starting materials used, the end product is obtained either in free form or in the form of its acid addition salt. For example, basic, neutral or mixed salts can be obtained, as can hemiamino, sesgui or polyhydrates. The acid addition salts of the new compounds can be converted into the free compounds in a manner known per se, basic agents, such as alkalis, or ion exchangers being used. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In the production of acid addition salts, preference is given to using those acids which form suitable therapeutically permissible salts. Such acids are, for example, hydrohalic acids, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carbon or sulfonic acid, such as, for example, formic, acetic, propionic, amber, glycolic, lactic , Apple, wine, lemon, ascorbic, maleic, hydroxymalein, amber, phenylacetic, benzoic, p-aminobenzoe, anthranil, p-hyroxybenzoic, salicyl, p-aminosalicyl or embonic acid, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic or ethylenesulfonic acids, halobenzenesulfonic, toluenesulfonic or naphthylsulfonic acids or sulfanilic acid; Methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds, for example picrates, can be used to purify the free bases obtained by converting the bases into salts, separating them and releasing the bases from the salts. Because of the close relationship between the new compounds in free form and in the form of their salts, it is understood from the foregoing and below that, if possible, the corresponding salts can also be used if the free compounds are mentioned.

This description also includes those embodiments of the process in which one starts from any compound obtained as an intermediate in any process step and carries out the remaining process steps or in which the process is stopped at any process step or in which a starting material is allowed to form under the reaction conditions or where a reaction component may be in the form of its salt.

For example, an aldehyde of the formula (XIX)

(/ y-ÜCH2CH0HCH0

4 ^ ^ 2

R R

(XIX)

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wherein R2 and R4 have the meanings given above and R3 represents hydrogen, in the presence of a suitable reducing agent, for example one of the abovementioned, with an amine of the formula

OH

where R1 has the meaning given above. This gives a compound of formula (VII) as an intermediate.

Furthermore, an amine of the formula (III) can be prepared in a manner known per se in the presence of a suitable reducing agent, for example one of the abovementioned, with an aldehyde or a ketone of the formula

0 = C-CH

to compounds in which R1 is hydrogen. This gives a compound of formula (IX) or (X) as an intermediate.

Depending on the choice of starting materials and the process, the new compounds can be present as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms, they can be present in the form of an isomeric mixture (racemate mixture).

The isomeric mixtures obtained (racemate mixtures) can be separated into the two stereoisomeric (diastereomeric) pure racemates, for example by means of chromatography and / or by fractional crystallization, depending on the physico-chemical differences between the components.

The racemates obtained can be separated by methods known per se, for. B. by recrystallization from an optically active solvent, by means of microorganisms or by reaction with optically active acids, salts of the compounds being formed, which are then separated, for example because of their different solubility, into the diastereomeric forms from which the antipodes are then separated by suitable means Freedom. Suitable optically active acids are, for example, the L and D forms 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.

In the process according to the invention, preference is given to using starting materials which lead to groups of end products which are primarily particularly desirable and in particular lead to the specifically described and preferred end products.

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

In clinical use, the compounds obtainable according to the invention can normally be administered orally, rectally or by injection in the form of a pharmaceutical preparation which contains an active component either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, e.g. B. which contains hydrochloride, lactate, acetate, sulfamate or the like, in combination with a pharmaceutical carrier.

The mention of the new compounds obtainable according to the invention relates either to the free amine base or to the acid addition salts of the free base, even if the compounds are generally or specifically described, provided that the context in which such terms are used, e.g. B. in the examples, does not agree with the broad meaning. The carrier can be a solid, semi-solid or liquid diluent or a capsule. The amount of active compound is usually between 0.1 and 95% by weight of the preparation, preferably between 0.5 and 20% by weight for preparations for injection and between 2 and 50% by weight for preparations for oral administration.

In the manufacture of pharmaceutical preparations for oral administration, the compound obtainable according to the invention can be mixed with a solid, powdery carrier, for example with lactose, sucrose, sorbitol, mannitol, starch, for example potato starch, corn starch or amylopectin, cellulose derivatives or gelatin, or together with a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol waxes or the like; the mass can then be compressed into tablets. If dragées are to be produced, the cores prepared as above can be coated with concentrated solutions of sugar. These solutions can also contain, for example, gum arabic, gelatin, talc, titanium dioxide or the like. In addition, the dragées can be coated with a lacquer dissolved in a volatile organic solvent or mixture of solvents. A dye can be added to these coatings to enable easy distinction between tablets with different active compounds or with different amounts of active compound.

In the production of soft gelatin capsules (pearl-shaped, closed capsules) consisting of gelatin and, for example, glycerol, or in the production of similar closed capsules, the active compound can be mixed with a vegetable oil. Hard gelatin capsules can contain granules of the active compound in combination with a solid, powdery carrier, for example with lactose, sucrose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin.

Unit dosage forms for rectal administration can be prepared in the form of suppositories containing the active substance in admixture with a neutral fat base, or in the form of gelatin rectal capsules containing the active substance in admixture with a vegetable oil or paraffin oil.

Liquid preparations for oral administration can be in the form of syrups or suspensions, e.g. B. solutions containing about 0.2 to about 20 wt.% Of active substance, the remainder consisting of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations can contain colorants, flavorings, saccharin and / or carboxymethyl cellulose as thickeners.

Solutions for parenteral administration by injection can be prepared in the form of an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration of about 0.5 to about 10.0% by weight. These solutions can also contain stabilizing agents and / or buffer substances and can be obtained in ampoules with different doses.

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Preferred embodiments of the method according to the invention are explained in more detail below with the aid of examples. The temperatures are given in ° C.

example 1

Preparation of 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-methylphenoxypropanol- (2)

2.5 g of 2-epoxy-3-o-methylphenoxypropane was mixed with 1.5 g of l- (4-hydroxyphenyl) -2-aminopropane and 25 ml of isopropanol, and the whole solution was under for 1.5 hours Reflux cooling heated to boiling. The solution was then evaporated in vacuo. The base thus obtained was dissolved in acetone and the hydrochloride was precipitated with ether in hydrogen chloride. The hydrochloride was filtered off and washed with acetonitrile. The yield of 3- [2- (4-hydroxyphenyl) -l-methylethylamino] -l-o-methyl-phenoxypropanol- (2) was 1.4 g; Mp 112 ° C. The structure was determined by NMR spectrum.

Example 2

3- [2- (4-Hydroxyphenyl) -l-methylethylamino] -lo-ethyl-phenoxypropanol- (2) was prepared by the process according to Example 1, with 1,3-epoxy-3- (o-ethyl) -phenoxypro -pan and l- (4-hydroxyphenyl) -2-aminopropane were used as starting materials. The melting point of the hydrochloride was 143 ° C. The structure was determined by means of the NMR spectrum and the equivalent weight.

Example 3

3- [2- (4-Hydroxyphenyl) -1-methylethylamino] -1-o-allylphenoxypropa-nol- (2) was prepared by the process according to Example 1, 1,2-epoxy-3-o-allylphenoxypropane and l- (4-hydroxyphenyl) -2-aminopropane were used as starting materials. The melting point of the tartrate was 71 ° C. The structure was determined by NMR spectrum and the equivalent.

Example 4

3- [2- (4-Hydroxyphenyl) -1-methylethylamino] -lo-propargyloxyphenoxypropanol- (2) was prepared by the process according to Example 1, 1,2-epoxy-3-o-propargyloxyphenoxy propane and 1- (4-hydroxyphenyl-2-aminopropane were used as starting materials. The p-hydroxybenzoate was prepared.

Example 5

3- [2- (4-Hydroxyphenyl) -l-methylethylamino] -lo-cy-anophenoxypropanol- (2) was prepared from 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4- Hydroxyphenyl) -l-methylethylamine prepared as starting materials. The hydrochloride was obtained as a water-soluble oil and its structure was determined by NMR spectrum.

Example 6

According to the process according to Example 1, 3- [2- (4-hydroxyphenyl) -1, l-dimethylethylamino] -lo-methylphenoxy-propanol- (2) was made from 1,2-epoxy-3-o-methylphenoxypropane and 2 - (4-Hydroxyphenyl) -l, l-dimethylethylamine prepared. The hydrochloride was obtained as a water-soluble oil and its structure was determined by NMR spectrum.

Example 7

3- [2- (4-Hydroxyphenyl) -1, l-dimethylethylamino] -lo-ethylphenoxypropanol- (2) was prepared by the process according to Example 1, with 1,2-epoxy-3-o-ethylphenoxypropane and 2 - (4-Hydroxyphenyl) -l, l-dimethylethylamine were used as starting materials. The melting point of the hydrochloride was 154 ° C.

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Example 8

The procedure according to Example 1 was used to prepare 3- [2- (4-hydroxyphenyl) -1,1-dimethylethylamino] -1-o-allylphenoxypro-pan- (2), 1,2-epoxy-3- o-allylphenoxypropane and 2- (4-hydroxyphenyl) -l, l-dimethylethylamine were used as starting materials. The melting point of the hydrochloride was 140 ° C.

Example 9

3- [2- (4-Hydroxyphenyl) -1, l-dimethylethylamino] -3-o-propargyloxyphenoxypropanol- (2) was prepared according to the procedure of Example 1 using 1,2-epoxy-3-o-pro-pargyloxyphenoxypropane and 2- (4-hydroxyphenyl) -l, l-dimethylethylamine as starting materials.

Example 10

3 - [2- (4-Hydroxyphenyl) -1, 1 -dimethylethylamino] -1-o-cy-anophenoxypropanol- (2) was prepared by the process according to Example 1, using 1,2-epoxy-3-o-cyanophenoxy -propane and 2- (4-hydroxyphenyl) -l, l-dimethylethylamine were used as starting materials. The melting point was 144 ° C (HCl).

Example 11

3- [2- (4-Hydroxyphenyl) -1-methylethylamino] -lo, m ~ dimethylphenoxy-propanol- (2) was prepared by the process according to Example 1, l, 2-epoxy-3-o, m -dimethyl-phenoxypropane and 2- (4-hydroxyphenyl) -l-methylethylamine were used as starting materials; F. 125 ° C (HCl).

Example 12

3- [2- (4-Hydroxyphenyl) -1-methylethylamino-lo-methoxyphenoxypro-panol- (2) was prepared by the process according to Example 1, 1,2-epoxy-3-o-methoxyphenoxypropane and 2- (4-hydroxyphenyl) -l-methylethylamine were used as starting materials; Mp 114 ° C (HCl).

Example 13

3-Methyl-3- [2- (4-hydroxyphenyl) -1-methylethylamino-lo-ethylphenoxypropanol- (2) was prepared by the process according to Example 1, where 1,2-epoxy-1-methyl-3- o-ethylphenoxypropane and 2- (4-hydroxyphenyl) -l-methyl-ethylamine were used as starting materials. The hydrochloride was obtained as a water-soluble oil and its structure was determined by NMR spectrum.

Example 14

3-Methyl-3- [2- (4-hydroxyphenyl) -1-methylethylamino] -1-o-cyano-phenoxypropanoI- (2) was prepared by the process according to Example 1, 1,2-epoxy-l-methyl -3-o-cyanophenoxypropane and 2- (4-hydroxyphenyl) -l-methylethylamine were used as starting materials. The hydrochloride was obtained as a water-soluble oil and its structure was determined by NMR spectrum.

Example 15

3-Ethyl-3- [2- (4-hydroxyphenyl) -l-methylethylamino-lo-allylphenoxy-propanol- (2) was prepared by the process according to Example 1, where 1,2-epoxy-l-ethyl-3- o-allyl-phenoxypropane and 2- (4-hydroxyphenyl) -l-methylethylamine were used as starting materials. The hydrochloride was obtained as a water-soluble oil and its structure was determined by NMR spectrum.

Example 16

3-Methyl-3- [2- (4-hydroxyphenyl) -1, l-dimethylethylamino] -lo-methyl-phenoxypropanol- (2) was prepared by the process according to Example 1, 1,2-epoxy-l-methyl -

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618 416

8th

3-o-methylphenoxypropane and 2- (4-hydroxyphenyl) -l, l-dimethylethylamine were used as starting materials. The hydrochloride was obtained as a water-soluble oil and its structure was determined by NMR spectrum.

Example 17

3-Methyl-3- [2- (4-hydroxyphenyl) -1, l-dimethylethylamino] -lo-allyl-phenoxypropanol- (2) was prepared by the process according to Example 1, 1,2-epoxy-l-methyl -3-o-allylphenoxypropane and 2- (4-hydroxyphenyl) -l, l-dimethylethylamine were used as starting materials; Mp 162 ° C (HCl).

Example 18

3- [2- (4-Hydroxyphenyl) -1-methylethylamino] -lm-methylphenoxypro-panol- (2) was prepared by the process according to Example 1, 1,2-epoxy-3-m-methylphenoxypropane being used and 2- (4-hydroxyphenyl) -l-methylethylamine were used as starting materials. The melting point of the hydrochloride was 150 ° C.

10th

15

20th

25th

35

Example 19

Preparation of 3- [l-methyl-2- (4-hydroxyphenyl) ethylamino] -l-o-allylphenoxybutanol- (2)

2.5 g of 2,3-epoxy-lo-allylphenoxybutane was mixed with 1.5 g of l-methyl-2- (4-hydroxyphenyl) ethylamine and 25 ml of isopropanol, and the entire solution was refluxed for 100 hours heated to boiling. The solution was then evaporated in vacuo. The base thus obtained was dissolved in trichlorethylene, and the hydrochloride was precipitated with hydrogen chloride dissolved in ether. Water was added and the mixture was titrated with 1N hydrochloric acid. The pH was measured with a glass electrode and the values were plotted against the consumption of hydrochloric acid in ml. For one band in the curve, the aqueous phase was separated, fresh water was added and the process was repeated until the next band appeared in the curve. The aqueous phase was separated, made alkaline with ammonium hydroxide and extracted with methylene chloride. The organic phase was washed with water, dried and evaporated. The hydrochloride would be precipitated with ether + HCl. The ether was decanted off and the product solidified on evaporation under high vacuum. The yield of 3- [l-methyl-2- (4-hydroxyphenyl) ethylamino] -l-o-allylphenoxybutanol-2HCl was 1.6 g; F. 70 ° C. The structure was determined by the NMR spectrum.

The β-receptor blocking agents obtainable according to the invention were tested with regard to their biological properties. All compounds were pretreated on anesthetized cats (male and female weighing 2.5 to 3.5 kg) that had been pretreated with re-serpin (5 mg / kg body weight, administered intramuscularly) approximately 16 hours before the experiments , tested. The animals were with

45

50

Reserpine pretreated to eliminate endogenous sympathetic heartbeat control and vascular smooth muscle tone. The cats were anesthetized with pentobarbital (30 mg / kg body weight, administered intraperitoneally) and artificially ventilated with room air. A bilateral vagotomy was performed on the neck. Blood pressure was measured with a cannula in the carotid artery and the heartbeat was recorded with a cardiotachometer triggered by the electrocardiogram (ECG). The actual beta-mimetic effectiveness on the heart was indicated by an increased heartbeat after the administration of the agent. The test compounds were administered intravenously in logarithmically increased doses. The values obtained were recorded as dose-effect curves, from which the effectiveness values (ED50) (affinity values) were determined. At the end of each trial, high doses of isoprenaline were given to get the maximum heartbeat effect.

The compounds were also tested on conscious dogs. Beagles were trained to lie still and to stand upright for 2 minutes by placing their front paws on a table. Arterial blood pressure was recorded using a blood pressure transmitter attached to the heart. The heartbeat was determined by the EKG. All dogs were pretreated with methylscopolamine to eliminate vagus effects. Recordings were made before and 15 and 75 minutes after test compound administration, first with the dogs on their backs for 2 minutes and in an upright position for 2 minutes. The test compounds were administered at 2 hour intervals in increasing doses.

Table 1 below shows the effective amounts (affinity values) and the real (intrinsic) β-mimetic activity of the compounds obtainable according to the invention on reserpined cats and the effects on the blood pressure of dogs that were conscious. For comparison, corresponding values for propanolol, [1-isopropylamino-3- (1-naphthoxy) propanol (2) and metoprolol, (1-isopropylamino-3- [4- (2-methoxyethyl) phenoxy] - propanol- (2).

Table 1 also shows pA2 values measured in rats. pA2 is the negative logarithm of the concentration of an antagonist, leading to the fact that the dose of norepinephrine has to be doubled in order to achieve the same noradrenaline effect obtained without the antagonist, or pA2 = log (dr-l) -log (antagonist), where dr is the dose-

EDS0 from norepinephrine (antagonist)

Ratio =: - is,

ED50 of noradrenaline (comparison)

where all concentrations are given in mol / 1.

pA2 is therefore a measure of the a receptor effect, with higher pA2 - * higher a effect.

Table 1

connection

Reserpine cat isoprene block ED0 mg / kg HR PR

Conscious dogs Blood pressure in torr after activity, 1.5 mg / kg IV

Beats / min. lying upright pA2

Propanolol Metoprolol Example 1 Example 2 Example 3 Example 5

0.1

0.2

0.07

0.11

0.7

0.04

0.1

4.7

0.07

0.15

1.1

0.1

0 0

+ 16 +32 +33 +33

+ 5 - 5 -22 -40

-40

0

- 3 -19 -35

-19

6.8 7.2 7.2 6.7

9 618 416

Table 1 (continued)

connection

Reserpine cat isoprene block EDjo mg / kg HR PR

Activity beats / min.

Conscious dogs Blood pressure in torr after 1.5 mg / kg IV

lying upright pA2

Example 6

0.06

0.3

+62

--16

-25

5.8

Example 7

0.05

0.04

+38

-

-

6.8

Example 8

0.11

0.09

+39

c-40

-20

6.4

Example 10

0.025

0.04

+42

6.3

Example 11

0.24

0.2

+ 6

-

Example 12

0.04

0.5

+40

-

Example 13

0.12

0.5

+ 18

6.2

Example 14

0.3

1.0

+40

6.0

Example 15

5.1

3.3

+ 2

6.6

Example 16

1.3 »

8.5

+ 9

6.2

Example 17

2.5

0.6

+ 3

7.4

Example 18

0.2

0.4

+ 10

-

Example 19

0.5

0.6

+28

-33

-45

-

The tests prove that the compounds investigated are active /? - receptor antagonists, with or without real ß-mimetic activity. The compounds also lower blood pressure in conscious dogs significantly more than propranolol and metoprolol. The pronounced hypotensive effect of the compounds obtainable according to the invention on dogs that are conscious is based on a vasodilatory effect in combination with cardiac /? - receptor blocking.

s

Claims (3)

618 416 2nd PATENT CLAIM Process for the preparation of new hydroxyamines of the formula (I) The new compounds obtainable according to the invention have the formula (1) r ~ R och 2chohchnhc-ch2 ch_ R * R ' (I) 10th nCHnCH0HCHNHC-CH, 7 j i., ' (I) Ì wherein R1 is hydrogen or methyl, R2 is hydrogen, methyl, ethyl, propyl, allyl, cyano, methoxy or propargyloxy, R3 is hydrogen or methyl and R4 is hydrogen or methyl, where R2 and R4 are not simultaneously hydrogen, and the acid addition salts of these compounds, thereby characterized in that a compound of formula (II) X och-chchz r3 (II) wherein R2, R3 and R4 have the meanings given above, X1 is the hydroxyl group and Z is a reactive, esterified hydroxyl group or X1 and Z together form an epoxy group, with an amine of the formula R h2n-c-ch2 ch. in which R1 has the meaning given above, is implemented and that isomer mixtures obtained are separated into the pure isomers and free bases obtained are converted into their therapeutically permissible salt. wherein R1 is hydrogen or methyl, R2 is hydrogen, methyl, ethyl, propyl, allyl, cyano, methoxy or propargyloxy, R3 is hydrogen or methyl and R4 is hydrogen or methyl, where R2 and R4 are not simultaneously hydrogen. 20 The state of the art can be demonstrated using the following publications: U.S. Patent No. 3,328,424 - Schenker et al. - describes the compound l-isopropylamino-3- (o-isopropoxy-phenoxy) -propanol-2, which, however, is not a clinically valuable a- 25 has receptor activity. However, the compounds made in accordance with this invention show both a-receptor activity and β-receptor blocking activity. U.S. Patent No. 3,852,468 - Howe et al. - Compounds of the formula 30th 35 40 3 2 r r n och2chohch2nhr