DK145375B - METHOD OF ANALOGUE FOR THE PREPARATION OF PHENOXYPROPANOLAMINALS SALTS THEREOF - Google Patents

Description

(19) DENMARK

lp in) PUBLICATION OF 145375 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 4431/77 (51) IntCI * C 07 C 93/06 (22) Filing date 6 · Oct. 1977 C 07 C 121/75 (24) Running day 6 Oct. 1977 C 07 C 103/38 (41) Aim. available Apr 8 1 978 (44) Submitted Nov. 8; 1982 (86) International application no.

(86) International filing day (85) Continuation day (62) Stock application no.

(30) Priority 7 Oct. 1976, 7611125, SE

(71) Applicant SHARE COMPANY HAESSLE, S-431 20 Moelndal, SE.

(72) Inventor Enar Ingemar Carlsson, SE: Gustav Benny Roger Samuele = son, SE: Bo Torsten Lundgren, SE.

(74) Clerk of the Office of Industrial Excellence v. Svend Schønning.

(54) Analogous process for preparing phenoxypropanolamines or salts thereof.

The present invention relates to an analogous method for the preparation of novel, potent 3-receptor blocking phenoxypropanolamines or therapeutically acceptable salts thereof, which are suitable for treating symptoms and signs of cardiovascular disorders by blocking the 6-receptors of the heart and having the The preamble of claim 1 showed general formula I, wherein R, R, and 3 "" R have the same meanings stated.

0 2 3 Γ) R and R are attached at positions 2, 3, 4 or 5 and preferably at positions 3 or 4 of the phenoxy group; preferably R 2 is hydrogen and R hydroxy, or R and R 3,4-dimethoxy.

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The compounds of the present invention have valuable pharmacological properties. Thus, they block the β-receptors of the heart, as evidenced by the determination of antagonism to tachycardia after intravenous injection of 0.5 µg / kg d / l isoproterenol sulfate on an anesthetized cat at an intravenous dose of 0.002 - 2 mg / kg. They also block vascular β-receptors, which is evidenced by the determination of the antagonism for vasodilation following intravenous injection of 0.5 µg / kg to d / l isoproterenol sulfate on an anesthetized cat at an intravenous dose of 0.002 - 2 mg / kg or more. . The compounds also have stimulatory properties on β-receptors, ie they exhibit intrinsic effect. This property is particularly pronounced with respect to vascular β-receptors which cause peripheral blood vessel expansion. The properties are elucidated at the end of the description.

The present compounds can be used to treat arrhythmias, angina pectoris and hypertension. The peripheral vasodilatation is particularly valuable in the latter two indications.

A number of related phenoxypropanolamines with similar pharmacological effects are known, but none of the aforementioned publications mentioning such compounds discloses any of the compounds prepared by the process of the invention.

Thus, from British Patent Specification No. 902,617 compounds of the formula R4OCH2CH2NR5CH2CHR6CH2OR7 wherein R4 is a hydroxy, methyl or methoxy optionally substituted phenyl group, R hydrogen, methyl or monocarboxylic are known. acyl, R hydrogen, hydroxy, methoxy or alkanoyloxy and R 1 -C 6 alkyl, C 2 -C 6 alkenyl, alkynyl, alkoxyalkynyl or hydroxyalkynyl or certain cycloalkyl or alkenyl groups or optionally substituted phenyl groups. Compounds very similar to these are known from British Patent No. 1,264. 128; they have the formula o g · 9 i

Ph-O-CH2 CHOH.CH2 .NR .CR R - (CH2) n-O-Ph, where Ph is phenyl optionally substituted with halogen, alkyl, alkoxy, trifluoromethyl or benzyloxy, Ph

o Q 1 Q

or alkoxy, R, R and R are hydrogen or alkyl and n is 2 or 3. These compounds differ from those prepared by the present process by being higher homologous.

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British Patent No. 1,433,920 discloses compounds of the formula R10-O-CH2CHOHCH2NH-AX-R11 wherein R10 is phenyl optionally substituted with halogen, cyano, nitro, alkyl, alkenyl or alkenyloxy, R4 is alkyl, cycloalkyl, aryl or aralkyl, A is C2-6 alkylene and X is -S-, -SO- or -SO2 ~.

German Patent Publication No. 25 03 222 discloses compounds of the formula Ph 1 -OCH 2 - (CHOR 3) -C'H 2 -NHR 2, where Ph 2 is phenyl substituted with R 14 and optionally also R 1 and R 2, 14 where R Among other things, may be halogen, alkyl, alkenyl or alkylene, 15

carboxy, alkylammo, cyano, aminoalkyl or hydroxyalkyl, R

has a similar meaning; may be halogen, alkyl or 12 13

alkoxy, R is hydrogen, acyl or tetrahydropyranyl and R

alkyl optionally substituted by hydroxy or halogen, or alkylcycloalkyl, cycloalkyl, aralkyl or aralkyloxy.

Finally, from Danish Patent Application No. 4444/75 compounds of the formula Ar-O-CHo.CHOH.CHR17NR18.C (R17) + (CEL) -1 2 2 2 n Y-Ar wherein Ar is phenyl substituted with a substituent are known. which include

may be alkyl, alkoxyalkyl, alkoxyalkoxyl alkenyloxy or alkyloxy and optionally also with halogen or additional alkyl 17 18 or alkoxy, R is hydrogen or alkyl, R is hydrogen, alkanoyl or benzyl, n is 0-5, Y is - O- or -CH-- and Ar1 are phenyl substituted with R, R and (CH9) R, where R and R are hydrogen, halogen, alkyl or alkoxy, m is 0-2 and R 1a. a. may be hydrogen, alkoxycarbonylaminoalkyl, alkanoyl, sulfo, cyano and certain alkylamido groups.

Representatives of the compounds thus known have been subjected to experiments comparing their action with the action of the compounds prepared by the present process. The results of these experiments, described later in this specification, are presented in Table 2 and show that the known compounds have weaker and partly different effects than the compounds prepared by the process according to the invention.

Salt-forming acids may be used to prepare therapeutically acceptable salts of the compounds of the present invention. Examples of suitable acids include hydrohalogenic acids, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids and sulfonic acids, for example, formic acid maleic acid, hydroxy-maleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-amino-benzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid and p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyacetic acid, hydroxyethanesulfonic acid, tryptophan, lysine and arginine.

The drugs are suitable for oral or parenteral administration for acute or chronic treatment of the above cardiovascular disorders.

The process according to the invention is characterized by the characterizing part of claim 1. Most effective according to the invention is the compounds of claim 3 and the compounds of claim 3, which it is therefore preferred to prepare.

Proceeding according to reaction a), i.e. reacting a compound of formula II with the amine XIII, is used as a reactive esterified hydroxy group, in particular a hydroxy group esterified with a strong inorganic or organic acid, preferably a haloacetic acid such as hydrochloric acid. hydrochloric acid or iodine hydrochloric acid, or with sulfuric acid or a stronger organic sulfonic acid, for example benzenesulfonic acid, 4-bromobenzene sulfonic acid or 4-toluenesulfonic acid. Thus, Z is preferably chlorine, bromine or iodine.

This reaction is carried out in a conventional manner.

Using a reactive ester as a starting material, the fabricator. 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 metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as potassium carbonate, or alkali metal alcoholates such as sodium methylate, potassium ethylate or potassium 1-butyl tate.

The reaction is carried out in an alkanol of 1-4 carbon atoms by refluxing the reactants in this solvent for a sufficient time to give a compound of formula I, generally 1-12 hours.

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Reaction b), reaction of the amine III with a compound XIV, is carried out in a conventional manner, preferably in the presence of a basic condensing agent and / or an excess of an amine. Suitable basic condensing agents are, for example, alkali alcoholates * preferably sodium or potassium alcoholate, or alkali carbonates such as sodium or potassium carbonate.

This reaction is carried out in an alkanol having 1-3 carbon atoms pg in an autoclave heated to 100-130 ° C, for 5-15 hours.

The reaction of the compound IV with the amine V is carried out in the usual manner. In dp cases where reactive esters are used as starting material, the compound of formula IV may conveniently be used in the form of the metal phenolate thereof such as an alkali metal phenolate, preferably sodium phenolate, or one may work in the presence of an acid binding agent, preferably a condensing agent which can form a salt of compound IV as an alkali metal alcoholate.

This reaction is carried out in an alkanol having 1-3 carbon atoms in an autoclave nail heated to 80-100 ° C for 5-15 hours.

Reaction i), where instead an amine Va is reacted with a compound of the general formula IVa, is carried out in the same manner as the reaction just described between the compounds of formula IV and V.

Instead of compound V, a compound of formula IV can be reacted with a compound of general formula VI, and this reaction is also carried out in the usual manner. Thus, the reaction is carried out under alkaline conditions in a suitable solvent such as benzyl alcohol, boiling the reaction mixture for a few hours. Thereby, the phenol is primarily converted to a metal phenolate such as an alkali metal phenolate thereof before being added to the azetidinol of formula VI.

In reaction e), a residue is cleaved from a compound of the general formula I shown above, wherein the nitrogen atom of the amino group and / or the hydroxy groups has a cleaved residue attached.

Examples of such cleavable residues are in particular those cleaved by solvolysis, reduction, pyrolysis or fermentation.

Residues that can be cleaved by solvolysis are preferably tests that can be cleaved by hydrolysis or ammonolysis.

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Residues that can be cleaved by hydrolysis are, for example, an acyl residue which, when present, is functionally varied carboxy groups, for example oxycarbonyl residues such as alkoxycarbonyl residues, eg a t-butoxycarbonyl residue; or ethoxycarbonyl residues, aralkoxycarbonyl residues such as phenyllavalkoxycarbonyl residues, e.g., a carbobenzyloxy residue, halogen carbonyl residue such as a chlorocarbon residue, further arylsulfonyl residues such as toluene sulfonyl or bromobenzene sulfonyl groups and the like. halogenated, for example, fluorinated lower alkanoyl residues such as formyl, acetyl or trifluoroacetyl groups or a benzyl residue or a cyano group or silyl residue, eg a trimethylsilyl residue.

Of the above residues present on hydroxy groups, residues which can be cleaved by hydrolysis, the oxycarbonyl residue and the lower alkanoyl or benzoyl residues are preferably used. rest.

In addition to the above, double bonded residues can also be used which can be cleaved off by the amino group by hydrolysis, for example 1 alkylidene or benzylidene residue or a phosphorylidene group such as a triphenylphosphorylidene group, whereby the nitrogen atom obtains a positive charge.

Furthermore, residues which can be cleaved from the hydroxy group and the amino group by hydrolysis are divalent to residues such as methylene or substituted methylene. As substituents on the methylene group, any organic residue may be present and it is of no importance in the hydrolysis which compound is substituent on the methylene residue. As methylene residues, for example, aliphatic or aromatic residues can be used, such as alkyl groups as mentioned above, or aryl groups such as phenyl or pyridyl. The hydrolysis may be carried out in any manner known per se, conveniently in a basic or preferably in an acidic medium.

Furthermore, compounds containing residues which can be cleaved off by hydrolysis are compounds of the general formula VII

in y-OCHOCH-CH, .-- r2 3 VI1

R

Wherein R, R and R are as defined above and Y is a carbonyl group or thiocarbonyl group.

The hydrolysis is carried out in an analogous manner, i.e., in the presence of a hydrolyzing agent, for example in the presence of an acidic agent such as a dilute mineral acid such as sulfuric acid or a hydrochloric acid, or in the presence of a basic agent such as an alkali metal hydroxide such as sodium hydroxide. Oxycarbonyl residues, arylsulfonyl residues and cyano groups can be conveniently cleaved by acidic means, for example by hydrocarbon acid and appropriate hydrobronic acid. Preferably, the cleavage can take place by means of dilute hydrochloric acid, optionally. in admixture with acetic acid. Cyan groups are preferably cleaved by hydrochloric acid at elevated temperature, for example in boiling hydrochloric acid, according to the so-called "bromocyanine method" (v. Braun). Acidic agents are preferably used for the hydrolysis of compounds of formula VII.

Residues that can be cleaved by ammonolysis are especially halocarbonyl residues such as a chlorocarbonyl residue. The ammonolysis can be carried out in the usual manner, for example by means of an amine containing at least one hydrogen atom attached to the nitrogen atom, for example a mono- or di-lower alkylamine such as methylene nip / dimethylamine, or in particular by means of ammonia, preferably at elevated temperature. Instead of ammonia, an ammonia-releasing agent can be used, for example, hexamethylenetetramine.

Residues which can be cleaved off by reduction are, for example, an α-aryl alkyl residue and such as a benzyl residue or an α-aralkoxycarbonyl residue such as a benzyloxycarbonyl residue which can be cleaved in the usual manner by hydrogenolysis, in particular by catalytically activated hydrogen such as by the presence of hydrogen. of a hydrogenation catalyst, e.g., rane nickel. Other residues which can be cleaved off by hydrogenolysis are 2-haloalkoxycarbonyl residues such as the 2,2,2-trichloroethoxycarbonyl residue or the 2-iodoethoxy or 2,2,2-tribromoethoxycarbonyl residue which can be cleaved in the usual manner, conveniently by metallic reduction (with so-called nascent hydrogen). Nascent hydrogen can be obtained by the influence of metal or metal alloys such as amalgams on compounds giving hydrogen, for example carboxylic acids, alcohol or water, whereby in particular zinc or zinc alloys can be used with acetic acid. In addition, hydrogenolysis of 2-haloalkoxycarbonyl residues may take place using chromium or chromium (II) compounds such as chromium (II) chloride or chromium diacetate.

A residue which can be cleaved off by reduction can also be an arylsulfonyl group such as a toluene sulphonyl group which can be cleaved in the usual manner by reduction by nascent hydrogen, for example by means of an alkali metal such as lithium or sodium in liquid ammonia, and suitably it can be cleaved from a nitrogen atom. When performing the reduction, care must be taken to ensure that other reductive groups are not affected.

Residues that can be cleaved by pyrolysis, especially residues. which can be cleaved from the nitrogen atom is possibly. substituted but suitably unsubstituted carbamoyl groups. Suitable substituents are, for example, lower alkyl groups or aryl lower alkyl groups such as methyl or benzyl, or aryl such as phenyl; the pyrolysis is carried out in the usual way whereby must take care not to damage other thermally sensitive groups.

Residues that can be cleaved by fermentation, in particular the residues that can be cleaved from the nitrogen atom, are possible. substituted but especially 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 is carried out in the usual manner, for example by the enzyme urease or by means of soybean extract at approx. 20 ° C or slightly elevated temperature.

Reduction of Schiffe bases of formula VIII or IX or a cyclic tautomer of formula X (reaction f)) can be carried out in the usual manner, for example, by a dile metal hydride such as sodium borohydride or lithium aluminum hydride, using a hydride such as borane with formic acid or by catalytic hydrogenation, for example with hydrogen in the presence of rane nickel. During the reduction care must be taken to ensure that other groups are not affected.

Reduction of the oxo group in a compound of general formula XI (reaction g)) is carried out in the usual manner, in particular by means of a diethyl metal hydride as mentioned above, or according to the Meerwein-Pondorf-Verley method or a modification thereof, conveniently under using an alkanol as a reaction component and as a solvent, for example isopropanol, and by means of a metal alkanolate such as a metal isopropanolate, for example aluminum isopropanolate.

Depending on the process conditions and the starting material, the final product is obtained either in free form or in the form of an acid addition salt, and the latter is also within the scope of the compounds which can be prepared by the process of the invention. Thus, for example, basic, neutral or mixed salts as well as hemiamino, sesquilized polyhydrates can be obtained. Acid addition salts of the subject compounds can be converted into the free compounds in a manner known per se, for example by means of basic agents such as alkali or by means of ion exchangers. On the other hand, a won free base can form salts with organic or inorganic acids. In the preparation of acid addition salts, such acids are preferably used which form suitable therapeutically acceptable salts. Examples of such acids are halo, hydrochloric, phosphoric, nitric, perchloric, aliphatic, alicyclic, aromatic and heterocyclic carboxylic and sulfonic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, lactic acid, lactic acid, lactic acid, lactic acid maleic and pyruvic acid, phenylacetic acid, benzoic acid, p-amino-benzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid and p-aminosalicylic acid, embonic acid, methanesulfonic acid, lysanesulfonic acid, hydroxyacetic acid sulfonic acid, ethylene sulfonic acid, arginine.

Salts with these acids or other salts of the subject compounds, for example picrates, can serve as detergents for the free bases, whereby a free base is first converted into a salt thereof, after which the salt is separated and the base is again released from the salt. Because of the close relationship between the present novel compounds in free form and in the form of their salts, it will be appreciated that the preparation of the salts is part of the process of the invention.

The compounds of the invention may, depending on the choice of starting materials and the process of choice, be available as optical antipodes or racemates, and if they contain at least two asymmetric carbon atoms, they may be present as isomer blend (racemate blend).

145376 ίο

The obtained isomer mixture (racemate mixture) can be separated into the two stereoisomeric (diasteromeric) pure racemates, for example by chromatography and / or fractional crystallization, depending on physico-chemical differences.

The obtained racemates can be separated by known methods, for example, by recrystallization from an optically active solvent or by microorganisms, or by reaction with optically active acids to form salts of the compound and separation of the salts thus formed, e.g. their different solubility, in the diastereomers, and from here the antipodes can be released by a suitable agent. Suitable usable optically active acids are, for example, the L and D forms of tartaric acid, d-o-tolyl tartaric acid, malic acid, almond acid, camphor sulfonic acid or quinic acid. Preferably, the most active of the two antipodes is isolated.

Conveniently, such materials are used to carry out the reaction of the invention which leads to groups in the end products which are particularly desired, i.e., which leads to the particularly described and preferred end products.

The starting materials are known or, in cases where they may be new, can be obtained by processes known per se.

For clinical use, the subject compounds are usually administered orally, rectally or by injection in the form of pharmaceutical compositions containing the active substance either as free base or as pharmaceutically acceptable, non-toxic acid addition salts such as hydrochlorides, lactates, acetates, sulfamates or the like and in combination with appropriate pharmaceutical carrier.

The daily dose of the active substance varies and depends on the type of administration, but as a general rule, a daily dose of 100-400 mg / day of the active substance for oral administration and 5-20 mg per day for intravenous administration must be expected.

Some examples serve to elucidate the method of the invention.

Example 1 11 3- [2- (4-Hydroxyphenoxy) ethylamino] -1-o-methylphenoxypropanol-2 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 isoppopanol and the whole solution refluxed for 1.5 hours. The solution is then evaporated in vacuo. The base thus obtained was dissolved in acetone and the hydrochloride precipitated by addition of HCl in ether. The hydrochloride was filtered off and washed with acetonitrile. The yield of 3- [2- (4-hydroxyphenoxy) ethylamino] -1-o-methylphenoxypropanol-2 was 1.5 g. The hydrochloride melting point was 150 ° C. The structure was determined by NMR:

Example 2 3- [2- (2-Hydroxyphenoxy) ethylamino] -1-o-methylphenoxypropanol-2 was prepared in the manner described in Example 1 using 1,2-epoxy-3- (o-methyl) phenoxypropane and 2- (2-hydroxyphenoxy) ethylamine as starting materials. The melting point of the hydrochloride is Q Q ° C. The structure was determined by NMR and equivalent weight.

Example 3-7 In the manner described in Example 1, the following compounds were prepared: 3) 3- [2- (4-hydroxyphenoxy) ethylamino] -1-o-propylphenoxypropanol-2-. The hydrochloride m.p. 135 ° C.

4) 3- [2- (4-hydroxyphenoxy) -ethylamino] -1-o-cyanomethylphenoxypropanol-2. The neutral oxalate m.p. 168 ° C.

5) 3- [2- (4-hydroxymethylphenoxy) -ethylamino] -1-o-cyanophenoxypropanol-2. Base m.p. 86 ° C.

6) 3- [2- (4-hydroxyphenoxy) ethylamino] -1-o-hydroxymethylphenoxypropanol-2. The citrate m.p. 68 ° C.

7) 3- [2- (4-hydroxyphenoxy) -ethylamino] -1-o-methoxyethyl-aminocarbonylmethoxyphenoxypropanol-2: m.p. 150 ° C.

Example 8 12 3- [2- (4-Hydroxyphenoxy) ethylamino] -3-o-cyanophenoxypropanol-2 was prepared according to Example 1 with 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4 -hydroxyphenoxy) -ethylamine as starting materials. The tartrate of the compound melts at 52 ° C.

Example 9 3- [2- (4-Hydroxyphenoxy) -ethylamino] -lo-ethylphenoxypropanol-2 was prepared according to Example 1 from 1,2-epoxy-3-o-ethylphenoxypropane and 2- (4-hydroxyphenoxy) -ethylamine as starting materials. The hydrochloride m.p. 140 ° C.

Example 10 3- [2- (4-Methoxyphenoxy) -ethylamino] -lo-cyanophenoxypropanol-2 was prepared according to Example 1 from 1,2-epoxy-3-o-cyanophenoxypropane and 2- (4-methoxyphenoxy) -ethylamine as starting materials. The hydrochloride has a melting point of 134 ° C.

Example 11 3- [2- (2-Hydroxyphenoxy) ethylamino] -lo-cyanophenoxypropanol-2 was prepared according to Example 1 from 1,2-epoxy-3-o-cyanophenoxypropane and 2- (2-hydroxyphenoxy) -ethylamine as starting materials. The melting point of the hydrochloride is 181 ° C.

Example 12 3- [2- (4-Hydroxy-3-methoxyphenoxy) ethylamino] -1-o-cyanophenoxy-propanol-2 was prepared according to Example 1 from 1,2-epoxy-3-o-cyanophenoxypropane and 2 - (4-hydroxy-3-methoxyphenoxy) ethylamine as starting materials. Mp. 78 ° C for the hydrochloride.

Example 13 3- [2- (3,5-Dimethoxyphenoxy) -ethylamino] -1-o-cyanophenoxypropanol-2 was prepared according to Example 1 from 1,2-epoxy-3-o-cyanophenoxypropane and 2- ( 3,5-dimethoxyphenoxy) -ethylamine as starting materials. Melting point of the hydrochloride 159 C.

Example 14 (Method b + e) 10 g of o-methylphenylglycidyl 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. Then the hydrochloride precipitated and it was filtered off and dissolved in 50 ml of ethanol to which was added 2- (4-methoxymethoxy) phenoxyethyl chloride and 15 g of CO 2. The mixture was heated in an autoclave to 130 ° C for 10 hours, then the solvent was evaporated and the residue was treated with 100 ml of 2N HCl for 1 hour at room temperature. The vane phase was made alkaline with ammonia and extracted with ethyl acetate. The solvent phase was dried over K 2 CO 3 and then 1- [2- (4-hydroxy) -phenoxyethylamino] -3- (o-methylphenoxy) -propanol-2 was obtained. The base formed was converted to the hydrochloride, 1- (2- (4-hydroxy) -phenoxyethylamino] -3- (o-methylphenoxy) -propanol-2, hydrochloride, mp 150 ° C.

Example 15 (Method c + e) 2.4 g of Na was dissolved in 100 ml of ethanol, to which was added 10.8 g of o-methylphenol and then 22.9 g of 1- [2- (4-methoxymethoxy) phenoxyethylamino] -3- chloropropanol -2. The mixture was heated in an autoclave on a boiling water bath for 10 hours. Then filtered and the filtrate evaporated to dryness. The residue was treated with 2N HCl for 1 hour at room temperature and extracted with ether, then the aqueous phase was made alkaline with ammonia and extracted with ether. The ethereal phase was dried over MgSO 4 and 1 - [2- (4-hydroxy) -phenoxyethylamino] -3- (o-methylphenoxy) -propanol-2 was obtained; this compound was converted to the hydrochloride and isolated and had a melting point of 150 ° C.

Example 16 (Method d) 0.116 moles of o-methylphenol were mixed with 0.080 moles of 1- [2- (4-methoxymethoxyphenoxy) ethyl] -3-azetidinol, 0.500 moles of benzyl alcohol and 0.003 moles of KOH. The mixture was refluxed with stirring for 6 hours at 140 ° C and then cooled and extracted with 2N HCl. The aqueous phase was left at room temperature for 1 hour and then made alkaline; finally it is shredded with chloroform. After drying and evaporation, the residue was dissolved in ether and to the solution HCl was added in ether. The hydrochloride formed was filtered off and washed with acetone. The hydrochloride of 3- [2- (4-hydroxyphenoxy) ethylamino] -1- (o-methylphenoxy) propanol-2 melted at 150 ° C.

Example 17 (Method f) 1-Amino-3- (o-methylphenoxy) propanol-2 was prepared in accordance with the above Example 23. 5 g of this compound was dissolved in 50 ml of methanol and 15 g of 4-hydroxyphenoxyacetaldehyde was added, to give 3- [2- (4-hydroxyphenoxy) -ethylimino] -lo-methylphenoxypropanol-2. The solution was cooled to 0 ° C and at this temperature little by little 5 g of sodium borohydride was added, thereby reducing the imino compound. The temperature was then allowed to rise to room temperature and after 1 hour 150 ml of 0 0 were added and the combined mixture was shaken with ether. The ether phase was dried over MgSO4 and evaporated. The residue was converted to the hydrochloride. In this way, 3- [2- (4-hydroxyphenoxy) ethylamino] -1- (o-methylphenoxy) propanol-2, HCl was obtained. Mp. 150 ° C.

Example 18 (Method g) 1.0 g of 3-o-methylphenoxy-1- [2- (4-hydroxyphenoxy) -ethylamino] -propanone-2 was dissolved in 25 ml of methanol and the solution cooled to 0 ° C in an ice bath. Gradually, 0.25 g of NaBH 2 was added with stirring, first at Q ° C for 1 hour and then at room temperature for 1/2 hour. The solution thus obtained was evaporated and then 50 ml of H₂O was added. The aqueous phase was extracted 3 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 the addition of ether containing HCl. Recrystallization occurred from acetone. The hydrochloride of 3- [2- (4-hydroxyphenoxy) ethylamino] -1- (o-methylphenoxy) propanol-2 melted at 150 ° C.

Example 19 (Method h) 3- [2- (4-Hydroxyphenoxy) -ethylamino] -1- (o-propynylphenoxy) propanol-2 was prepared according to Example 1 from 1,2-epoxy-lo-propynylphenoxypropane and 2- (4-hydroxyfenoxy) -ætylåmin. The hydrochloride was dissolved in ethanol and a Pd / C catalyst was added and the compound was hydrogenated until the calculated amount was absorbed. After filtration, the filtrate was evaporated to dryness and the residue was recrystallized from ethyl acetate.

In this way, 3- [2- (4-hydroxyphenoxy) ethylamino] -1- (o-propylphenoxy) propanol-2 was obtained. The hydrochloride m.p. 135 ° C.

Example 20 (Method i) 25.4 g of 2- [3-o-cyanophenoxy-2-hydroxypropylamino] ethyl chloride, 10.8 g of 4-hydroxyphenol and 20.7 g of potassium carbonate are refluxed for 8 hours with stirring in acetonitrile. Then, the reaction mixture was filtered, evaporated, acidified with HCl and extracted with ether. The aqueous phase was made alkaline and extracted again with ether. The ether phase was dried over MgSO 4 and evaporated to give the free base 1- [2- (4-hydroxy-phenoxy) -ethylamino] -3-o-cyanophenoxypropanol-2. M.p.

42 ° C. Yield 13.7 g (42%).

Biological action

The β-receptor blocking agents prepared by the process of the invention were tested for biological properties.

All the compounds were then tested on anesthetized cats (males and females weighing 2.5-3.5 kg), pre-treated with reserpine (5 mg / kg body weight intramuscularly administered) for approx. 16 hours before the trial. The animals were pretreated with reserpine to eliminate the endogenous sympathetic control of heart rate and vascular smooth muscle tone. The cats were anesthetized with pentobarbital (30 mg / kg body weight, administered i.p. (intraperitoneally)) and artificially ventilated with stool air. Bilateral vagotomy was performed in the throat. Blood pressure was found on a cannulated carotid artery, and the heart rate was recorded from a cardiotakometer triggered by the electrocardiogram (ECG). The β-mimetic intrinsic effect on the heart was observed as increased heart rate after the drug is administered. The test compounds were administered intravenously (i.v.) at logarithmically increasing doses. The values found were plotted on dose-response curves from which an estimate of the affinity values (ED + g) was obtained. At the end, each trial was given high doses of isoprenaline to obtain maximum heart rate response.

the compounds were also tested on dogs by consciousness. Beagle dogs were trained to lie still and to stand in an upright position by placing the forelegs on a table for 2 minutes. The arterial blood pressure was recorded via a blood pressure transducer attached to the dog at heart level. The heart rate was triggered by RCG. All dogs were pretreated with methyl scopolamine to ward off vagal influences. Recordings were taken before as well as 15 minutes and 75 minutes after the administration of the test compound, first in the supine position for 2 minutes and then in the upright position for 2 minutes. The test compounds were administered in increasing doses at 2 hour intervals.

pA2 was also measured in rats. pA2 is -log to the concentration of an antagonist which causes the dose of noradrenaline to be doubled to achieve the same effect of noradrenaline as obtained without the antagonist, or pA2 = log (dr-l) -log (antagonic) EDcn of noradrenaline (antagonist) ) where dr is the dose ratio: ^ noradreraliii "(control) with all concentrations being expressed in moles / liter. pA2 is thus a measure of α receptor effect where higher pA2 means higher α effect.

The experiments show that the compounds tested are potent β-reoeptor antagonists that are cardioselective, with or without β-mimetic intrinsic effect. The compounds also significantly reduce blood pressure in dogs by consciousness. The pronounced hypotensive effect in dogs upon awareness of the subject compounds is due to a vasodilatory effect in combination with cardiac β-receptor blockade. Results obtained from the experiments described above are shown in Table 1.

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By the same test technique as described above, some of the compounds prepared by the process of the invention were compared with compounds known from the patent descriptions mentioned in the preamble of the specification. The results are shown in Table 2 below. The compounds prepared by the process of the invention are identified by the above examples in which they are mentioned, while the known compounds are identified by code letters representing compounds as follows: A) 1- (2-methoxyphenoxy -3- [2- (2-methoxyphenoxy) ethylamino] -propanol-2B) 1- (2-hydroxyphenoxy) -3- [2- (methoxyphenoxy) -ethylamino] -propanol-2C) 1- (2- methylphenoxy) -3- (2-phenylthioethylamino) -propanol-2D) 1- (2-cyanophenoxy) -3- [2- (4-methylphenylthio) -ethylamino] -propanol-2E) 1- (2-cyanophenoxy) -3- [2- (3-methyl-6-chlorophenoxy) -1,1-dimethylethylamino] -propanol-2F) 1-phenoxy-3- [2- (3-methyl-6-chlorophenoxy) -1,1 -dimethylethyl-aminopropanol-2G) 1- (2-methylphenoxy) -3- [2- (4-ethylphenoxy) -ethylamino] -propanol-2H) 1- (2-allylphenoxy) -3- [1-methylphenoxy) 2- (2-methylphenoxy) -ethylamino] -propanol-2

Of these, compounds A and B are known from British Patent Specification No. 902,617, C and D from British Patent Specification No. 1,433,920, E and F from German Pat.

25 03 222 and G and H from Danish Patent Application No. 4444/75.

The results in Table 2 show that the compounds prepared by the process of the invention are significantly more potent than the known compounds. Compounds A-C also have an intrinsic effect that far exceeds clinically appropriate values, and the compounds are as much or more 3-receptor stimulating in chronotropy than 3-receptor blocking. Compounds E-F are not heart-selective and have no α-receptor blocking effect.

145375 19

Table 2

Combine _Reserpine-treated cat_pA2 part 3-blockade of 3-blockade of self-efficacy isoprenaline; isoprenaline; beating / min |% of heart rate peripheral 3 max ig (> ED, μιηοΐ / kg resistance prenaline ED50, pmol / kg ^ ex .1 0.1 3.4 ..... 8 5.8 ex. 2 0.6 17 30 29 6.0 Ex 3 0.2 0.5 0 0 6.9 Ex 4 0.1 2.7 17 22 6.3 Ex 5 0.2 10 .10 10 5.8 Ex. 6 0.02 0.05 17 6.3 Ex. 7 0.05 1.8 "0 0 5.5 Ex. 8 0.08 5.5 13 5 6.3 Ex. 9 0.2 '0.9 5 6 6.6 Ex 10 0.22 2.7 7 7 6.4 Ex 12 0.3 3.4 17 27 6.8 A 0.27 5.6 51 49 6.8 B 0.7 6 , 3 67 55 6.7 C 2 17.5 60 67 4.0 D 5.3> 68 28 33 6.3 E> 4.2> 4.2 0 0 - F> 17> 17 0 0> 4, 0 G 7.9> 68 15 5.6 H 1.3 1.3 15 6.0

Claims (3)

1Λ5375 20 An analogous process for the preparation of phenoxypropanolamines of the general formula C 0-CH₂CHOHCH₂NH- wherein R and R 2, which are the same or different, each represent hydrogen, hydroxy, methoxy or hydroxymethyl, however, R and R cannot both be hydrogen and R 2 and / or R 3 cannot be methoxy groups if R methyl, or therapeutically acceptable salts thereof, characterized in that: a) reacting a compound of general formula II, X1 / V OCH2CHCH2Z II Nr1 wherein R hydroxy group, or wherein X and Z are together an epoxy group, with an amine of the general formula r OCH 2 CHOHCH 2 NH 2 III, where R 1 has the meaning given above, m ed a compound of general formula XIV R2,. · · .. '. Z'-CH "CH_-O_C · XIV 23 where R and R have the above meanings and Z 'are. or c) reacting a compound of general formula IV. : Where R 1 - has the meaning given above, having a compound of the general formula V f 1 CH2C.HCH2NH-CH2CH2-0-h ^, v R -; ... ··. . · ;; 12, wherein Z, X, R and R have the meanings given above, or d) react a compound of the general formula IV / J \ _H IV ^^ R1 where R · has the meaning given above, with a compound with the general formula VI / -VR 2 CH 2 - | -CH 2 CH 2 - O / vi CH - CH 2 OH i:. Wherein R 4 and R have the above meanings or e) from a compound of the general formula I wherein R 2 3 · R and R have the meanings set forth above and, as a supplement, contain a leaving residue at the nitrogen atom of the amino group and / or a leaving residue on one or more hydroxy groups, leaving any such residue, or f) reducing a Schiff's base of the general formula VIII or XX _ _ r2 ^ _och2crohch = n-ch2ch2-o - <^^ VIII R3 9 / -V / -vR <f V 0CH2CH0HCH2N; = CH-CH2-0 ......... IX or a cyclic tautomer of formula X, corresponding to the compound of formula IX V_OC82CH-_ch2 O \ NH \ - X 'r2 XH CH2-0- ^ X R3 12 3 in which formulas R ^ R' and RM have the above meanings, IX and X may be present at the same time, or g) in a compound of the general formula XI ^ oqh2S: ch 2nh- ch 2ch XI V ~ r3 12 3 where R, R and R have the meanings given above reduce the pxg group to a hydroxy group, or h) in a compound of general formula XII