IE45692B1 - 1-amino-2-hydroxy-3-heterocyclyloxy-propanes - Google Patents

Abstract

Novel 2-[3'-(2-(3,4-dimethoxyphenyl)ethylamino)- 2'-hydroxypropoxy]-3-cyanopyridine of the formula and its acid addition salts are prepared by hydrolysis of [3'-(2-(3,4-dimethoxyphenyl)ethyl)-2'-phenyloxazolidin-5'-yl]methoxy-3 -cyanopyridine. The compound and its salts are cardioselective beta receptor blockers having additional alpha receptor-blocking and hypertensive properties, by virtue of which they can be used in the treatment of the indications known for beta receptor blockers, e.g. angina pectoris and cardiac arrhythmias, in particular hypertension.

Description

The present invention relates to 1 - amino - 2 - hydroxy3 - heterooyclyloxy - propanes, prooess for the preparation thereof and pharmaceutical preparations comprising them.

The present invention provides a compound of the general 5 formula wherein Y represents the group—CH= or the group —N=, R^ represents hydrogen, hydroxyl, lower alkyl or lower alkoxy, Rg represents hydroxyl, lower alkoxy or, together with R^, o - (lower alkylidene) - dioxy or o - (lower alkylene)dioxy, and Rg represents lower alkyl, lower alkoxy, halogen or cyano, 15 and wherein each of the radicals R , Rg and Rg may be bound to any one of the aromatic carbon atoms, or a salt thereof.

:The radical of the formula represents the 2 - pyridyl radical wherein the group R3 may be in the 3-, 4-, 5- or 6-position, or the 2 - pyrazinyl radical wherein the group R3 may be in the 3-, 5- or 6-position.

The term lower whenever used herein in relation to a radical except where otherwise defined, represents a radical having from 1 to 7 carbon atoms and especially from 1 to 4 carbon atoms.

Lower alkyl may be, for example, methyl, ethyl, npropyl, iso - propyl, n - butyl, isobutyl, see. - butyl, tert.butyl, n - pentyl, neopentyl, n - hexyl or n - heptyl; whilst lower alkenyl may be, for example, vinyl, allyl or methallyl; and lower alkynyl ethynyl or propargyl.

Lower alkoxy may be, for example, methoxy ethoxy, npropyloxy, isopropyloxy, n - butyloxy. isobutyloxy or tert.butyloxy.

Halogen, represented by Rg, is preferably one having an atomic number of up to 35, i.e. fluorine, chlorine or bromine. o - (lower alkylidene) - dioxy and o - (lower alkylene)dioxy may each have from 1 to 3 carbon atoms and are for example, methylenedioxy isopropylidenedioxy and 1,2 - ethylenedioxy.

Salts of compounds of the general formula I are preferably acid addition salts, especially pharmaceutically suitable, physiologically tolerable acid addition salts with suitable - 4 30 inorganic acids, for example hydrochloric acid hydrobromic acid, sulphuric acid or phosphoric acid; or with suitable organic acids, for example aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carboxylic acids or sulphonic acids, for example formic acid, acetic acid, propionic aeid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid pyruvic acid, benzoic acid, anthranilic acid, 4 - hydroxybenzoic acid, salicylic acid, phenylacetic acid, enibonic acid, methanesul10 phonic acid, ethanesulphonic acid, hydroxyethanesulphonic acid, ethylenesulphonic acid, 4 - chlorobenzenesulphonic acid, toluenesulphonic acid, naphthalene - sulphonic acid, sulphanilic acid or cyclohexylaminesulphonic acid, and also ascorbic acid.

By virtue of the close relationships between the new compounds in the free form and in the form of their salts, it is to be understood that by free compounds and by salts are accordingly meant with the appropriate modifications, optionally also the corresponding salts and free compounds, respectively.

The invention preferably provides compounds of the general formula I wherein R^ represents hydrogen, hydroxyl, lower alkyl or lower alkoxy having from 1 to 4 carbon atoms, R2 represents hydroxyl, lower alkoxy having from 1 to 4 oarbon atoms, or, together with R^, o - (lower alkylidene) - dioxy having 1 or 2 carbon atoms, and R3 represents lower alkyl or lower alkoxy having from 1 to 4 carbon atoms, halogen or cyano, wherein each of R^ and R2 is in the 2-, 3- or 4-position or o - (lower alkylidene) - dioxy is in the 2,3- or 3.4-position and R^ is in the 3-, 4-, 5- or 6-position of a pyridine 43692 - 5 ring or in the 3-, 5- or 6-position of a pyrazine ring, and their salts, especially their pharmaceutically suitable, physiologically tolerable acid addition salts.

The invention provides especially compounds of the general 5 formula wherein represents hydrogen, hydroxyl, methyl or methoxy, R^ represents hydroxyl, methoxy or, together with R , o10 methylenedioxy, and R^ represents methyl, methoxy, chlorine or cyano, wherein R^ and R2 are in the 3- and 4-position- or o - methylenedioxy is in the 3, 4 - position, and is in the 3- or 4position; and their salts, especially their pharmaceutically suitable, physiologically tolerable acid addition salts.

The invention provides more especially · · compounds of the general formula N wherein 8 692 - 6 represents hydrogen/ hydroxyl, methyl or methoxy, R2 represents hydroxyl, methoxy, or, together with R , omethylenedioxy, and.

R3 represents methyl, methoxy, chlorine or cyano, wherein 5 and R,> are in the 3- and 4-position, or o - methylenedioxy is in the 3,4-positioh, and R3 is in the 3-position; and ' · their salts, especially their pharmaceutically suitable, physiologically tolerable acid additLon salts.

The invention more especially provides the following 10 compounds of the general formula Is - [3 * - (2 - (3,4 - dimethoxyphenyl) - ethylamino) - 2'hydroxypropoxy/ - 3 - cyanopyridine, 1-(3- chloropyrazin - 2 - yloxy) - 3 - [2 - (3,4dimethoxyphenyl) - ethylamino] - propan - 2 - ol, 1 - [2 — (3,4 - dimethoxyphenyl) - ethylamino] - 3 - (3methoxypyridin -2-yl - oxy) - propan - 2 - ol, - [2 - (£- methoxyphenyl) - ethylamino] - 3 - (3methylpyridin - 2 - yloxy) - propan - 2 - ol, - [2 - (3,4 - methylenedioxyphenyl) - ethylamino] - 320 (3 - methylpyridin - 2 - yloxy) - propan - 2 - ol, - [2 - (3,4 - methylenedioxyphenyl) - ethylamino] - 3(4 - methylpyridin - 2 - yloxy) - propan - 2 - ol, - [2 - (£- hydroxyphenyl) - ethylamino] - 3 - (3methylpyridin - 2 - yloxy) - propan - 2 τ ol, 1 - [2 - (£- hydroxyphenyl) - ethylamino] - 3 - (4methylpyridin - 2 - yloxy) - propan - 2 - ol, - [2 - (3,4 - dimethoxyphenyl) - ethylamino] - 3 - (3methoxypyrazin -2-yl - oxy) - propan - 2 - ol, - 7 1 - [2 - (p- hydroxyphenyl) - ethylamino] - 3 - (3methoxypyridin - 2 - yloxy, - propan - 2 - ol, - [2 - (3 - methoxy - 4 - hydroxyphenyl) - ethylamino] 3-(3- methylpyridin - 2 - yloxy) - propan - 2 - ol; and > their salts, especially their pharmaceutically suitable, physiologically tolerable acid addition salts.

The compounds of the invention possess useful pharmacological properties. They possess, in particular, an adrenergic beta-receptor-blocking action; this can be verified as inhibition of the isoproterenol tachycardia, for example on an isolated guinea-pig heart according to Langendorff. The concentrations required for a half-maximum inhibitory effect (EC_„j are in this case in the range of from 0.04 to 0.44 μg/ml. 50 Furthermore 2 - [3' - (2 - (3,4 - dimethoxyphenyl) - ethylamino)2' - hydroxypropoxy] - 3 - cyanopyridine, for example, as neutral fumarate, inhibits the isoproterenol tachycardia of an anaesthetised cat having perfused back extremity more (ED_ =0.2 □o mg/kg i.v·) than it does the isoproterenol vasodilation (ED5Q=3 mg/kg i.v.) From this it follows that this compound belongs to the cardioselective beta-receptor-blocker class.

The compounds produce, moreover, an inhibition of the adrenergic alpha receptors; this effect can be verified, for example, as noradrenalin antagonism on the isolated vas deferens in a rat. The concentrations necessary for a pAg value are, in this test system, in the range 0.4 to 7.6 μΜ, with corresponding pAg values of in the range of from 6.40 to 5.12 μ,Μ.

The compounds of the invention additionally possess hypotensive properties, which can be shown, for example, by the long-lasting lowering of the arterial blood pressure in an anaesthetised cat using doses of 0.1 mg/kg i.v. and upwards. - 8 By virtue of their properties as beta-receptor blockers with additional alpha - receptor - blocking and hypotensive effects, the compounds of the invention can be used in the treatment of the indications known for beta-receptor blockers, for example hypertonia, Angina pectoris or disturbances of the cardiac rhythm.

The compounds of the present invention may be produced in a manner known per se, for example by a process wherein in a compound of the general formula wherein Y and Rg have the meanings given above, R^ has the meaning of given above or may represent the group —0—Xg, R_ has the meaning of R_ given above or may represent the 5 Z group —O—X^, and wherein at least one of the groups X^, Xg, Xg and X^ represents a group replaceable by hydrogen, and the others represent hydrogen or a group replaceable by hydrogen, or X^ and Xg together represent a radical which is capable of being split off and which is replaceable by two hydrogen atoms one bound to the oxygen atom of the secondary alcohol group and one to the ^nitrogen atom, and/or Xg and X^ together represent a radical which is capable of being split off and which is replaceable by two hydrogen atoms bound to the oxygen atoms of the groups —0—Xg or —or in a salt thereof, the radical X^ and/or Xg or X^ and Xg together and/or Xg and/or X^ and/or Xg and X^ together are replaced by hydrogen; and, if desired, a resulting compound of the general formula I is 45632 - 9 converted into another compound of the general formula I? and/or, if desired, a free compound obtained is converted into a salt, or a salt obtained is converted into a free compound; and/or, if desired, a stereoisomeric mixture obtained is separated into the individual stereoisomers, or a racemate obtained is separated into the optical antipodes.

The groups X^ and/or and/or and/or X^ are split off by means of solvolysis or reduction. In the starting materials of the general formula II, X^ is preferably a group which is replaceable by hydrogen, whilst X_, X and X especially repred 3 4 sent hydrogen.

An especially suitable group represented by X^ capable of being split off is an a - aryl - (lower alkyl) group which can be split off by hydrogenolysis, for example as an optionally substituted 1 - phenyl - (lower alkyl) group, wherein substituents, especially of the phenyl moiety, may be, for example, lower alkyl e.g. methyl or tert. - butyl, hydroxyl, lower alkoxy e.g. methoxy, halogen, e.g. chlorine or bromine, and/or nitro, and especially benzyl. X^ may also be a radical capable of being split off by solvolysis, e.g. by hydrolysis or acidolysis, and also by reduction, including hydrogenolysis, especially a corresponding acyl radical, e.g. the acyl radical of an organic carboxylic acid, for example lower alkanoyl e.g. acetyl, or aroyl e.g. benzoyl, also the acyl radical of a semi-ester of carbonic acid, e.g. lower alkoxyearbonyl, for example methoxycarbonyl, ethoxycarbonyl or tert. - butyloxycarbonyl, - halogeno - (lower alkoxy) - carbonyl, for example 2,2,2trichloroethoxycarbonyl or 2 - iodoethoxycarbonyl, for example benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, for example phenacyloxycarbonyl, or the acyl radical of an organic sulphonic acid, e.g. an aromatic sulphonic acid, - 10 particularly an optionally substituted phenylsulphonyl radical wherein substituents have, for example, the meaning given above for the 1 - phenyl - (lower alkyl) radical, and especially 4methylphenylsulphonyl, also an optionally substituted 1polyphenyl - (lower alkyl) group wherein substituents particularly of the phenyl moiety have, for example, the meaning given above, and especially represent trityl, A group represented by X2< X3 or X^ replaceable by hydrogen is also preferably a group capable of being split off by hydrogenolysis, e.g. one of thaunsubstituted or substituted, - phenyl - (lower alkyl) groups given above, and especially benzyl. It can also be one of the acyl groups, mentioned for the group X^, which are capable of being split off by solvolysis, including alcoholysis, or by reduction; also an unsubstituted or substituted aliphatic or araliphatic hydrocarbon radical polybranched on the linking carbon atom, e.g. tert. - (lower alkyl), for example tert. - butyl or trityl.

A radical formed by Χη and X^ or X3 and X^ together and capable of being split off, is again especially a group capable of being split off by hydrogenolysis, e.g. unsubstituted or substituted 1 - phenyl - (lower alkylidene), wherein substituents especially of the phenyl moiety, may be, e.g., lower alkyl such as tert. - butyl, hydroxyl, lower alkoxy, halogen and/or nitro, and especially benzylidene; also groups capable of being split off by solvolysis, especially by hydrolysis, e.g. lower alkylidene, for example methylene or isopropylidene, or cycloallylidene, for example cyclohexylidene. A further radical formed by the groups X^ and X2 or X3 and X^ together is the diacyl radical of carbonic aoid or thiocarbonic aoid, i.e. the carbonyl or thiocarbonyl group.

Starting materials usable in the form of salts are used - 11 45692 principally in the form of acid addition salts, for example with mineral acids, and also with organic acids.

Radicals X^ and/or and/or and/or capable of being split off by hydrogenolysis, especially unsubstituted or substituted 1 - phenyl - (lower alkyl) groups, also suitable acyl groups e.g. optionally substituted 1 - phenyldower alkoxy) - carbonyl, and also optionally substituted I - phenyl - (lower alkylidene) groups formed by the groups X^ and X2 and/or X3 and X^ together, may be split off by treatment with catalytically activated hydrogen, for example with hydrogen in the presence of a nickel catalyst, e.g.

Raney nickel, or of a suitable noble metal catalyst.

Groups X and/or X , and/or X and/or X , such as acyl X 2 3 4 radicals of organic carboxylic acids, e.g. lower alkanoyl, and semi-esters of carbonic acid, e g. lower alkoxyearbonyl, also, e.g., trityl radicals,and also lower alkylidene groups or carbonyl groups formed by the radicals X^ and X2 and/or Xg and X^ together, can be split off, depending on the type of such radicals, by treatment with water under acid and/or basic conditions, for example in the presence of a mineral acid, e.g. hydrochloric acid or sulphuric acid, or in the presence of a hydroxide or carbonate of an alkali metal or an alkaline earth metal.

Radicals which can be split off by acidolysis are especially certain acyl radicals of semi-esters of carbonic acid, e.g. tert. - (lower alkoxy) - carbonyl or unsubstituted or substituted diphenylmethoxycarbonyl radicals, also tert.(lower alkyl) radicals X^, X3 or X^? they can be split off by treatment with suitable strong organic carboxylic acids, such as (lower alkane) - carboxylic acids unsubstituted or substituted by halogen, especially by fluorine, especially - 12 with trifluoroacetic acid {if necessary in the presence of an activating agent, e.g. anisole), and also with formic acid.

By radicals Χχ and/or Xg and/or Xg. and/or X4-capable of being split off by reduction are meant also those groups which are split off by treatment with a chemical reducing agent (particularly with a reducing metal or a reducing metal compound). Such radicals are especially 2 - halogeno - (lower alkoxy) - carbonyl or aroylmethoxycarbonyl, which can be split off, for example, by treatment with a reducing heavy metal e.g. zinc or with a reducing heavy metal salt e.g. with a chromium (II) salt, e.g. chromium (II, chloride or chromium (II) acetate, usually in the presence of an organic carboxylic acid, e.g. formic aeid or acetic acid, and water. Arylsulphonyl radicals capable of being split off by reduction, especially those represented by X^, can be replaced by hydrogen by treatment with an alkali metal, e.g. lithium or sodium, in ammonia, or by means of electrolytic reduction.

The above reactions are performed in a manner known per se, usually'in the presence of a solvent Or solvent mixture, with suitable reactants are able to simultaneously function as such, and, if necessary, with cooling or heating, e.g. in a temperature range of -20°C to +150°C, in an open or closed vessel and/or in an inert gas atmosphere, e.g. under nitrogen.

The compounds of the present invention can also be obtained by reacting a compound of the general formula Y (III) O-CH. -CH-CH. - X, 2 ι 2 6 48692 - 13 with a compound of the general formula wherein one of the groups X. and X_ represents a reactive 6 7 esterified hydroxyl group, and the other represents a primary amino group, and X_ represents a hydroxyl group, or wherein 5 X and X together represent an epoxy group, and X represents 5 6 7 a primary amino group, and Y, R , R2 and R3 have the meanings given above; and, if desired, performing the optional steps of the process given above.

A reactive esterified hydroxyl group represented by X, Ό or X? is a hydroxyl group esterified by a strong acid, especially a strong inorganic acid such as ahydrohalic acid, especially hydrochloric acid, hydrobromic acid or hydriodic acid, or sulphuric acid, or by a strong organic aoid, particularly a strong organic sulphonic acid, e.g. an aliphatic or aromatic sulphonic acid, for example methanesulphonic acid, - methylphenylsulphonic acid or 4 - bromophenylsulphonic acid, and is above all halogen, e.g. chlorine, bromine or iodine, or aliphatically or aromatically substituted sulphonyloxy, for example methylsulphonyloxy or 4 - methylphenylsulphonyloxy.

The above reaotion is performed in a manner known per se, and is performed, especially with the use of a starting material having a reactive esterified hydroxyl group, advantageously in the presence of a basic agent, e.g- an inorgani: base, for example in the presence of a carbonate or hydroxide X 43692 of an alkali metal or of an alkaline earth metal, or in the presence of an organic base agent, e.g. an alkali metal lower alkanolate, and/or with an excess of the basic reactant, and usually in the presence of a solvent or solvent mixture, and, if necessary, with cooling or heating, e.g. in a temperature range of -20°C to +150°C, in an open or closed vessel and/or in an inert-gas atmosphere, e.g. in a nitrogen atmosphere.

The compounds of the invention can also be obtained by a process wherein in a compound of the general formula in which the group '—X_—(Va) represents one of the radicals 8 of the formulae or —CH=N—CHg—CHg— (Vb), 15 or —CHg—N=CH—CHg— (VC), “C (=Xg) —N—CHg—CHg— 1 (Vd), orxi —CHg—N—C (=Xg) —CHg— (Ve) wherein Xg represents the oxo- or thiooxo group, Y, R^, Rg and X^ have the meanings given above and Rg has the meaning given above with the exception of halogen and cyano, the group —Xo— is reduced, optionally by way of the intermediate containing the radical - 15 —CH2-'-ir-CH2—CH2—, X1 to the radical of the formula —CH2—NH—CH2—CH2—; and, if desired, the optional steps of the first process given above are performed.

The reductive conversion of a radical of the formula —X—(Va) into the desired group of the formula —CH„—NH—· 8 2 CH2—CH2— can be performed in a manner known per se, with the choice of suitable reducing agents depending on the nature of the groups of the formula Va. Especially suitable for the reduction of groups of the formulae Vb and Vc, and also of groups of the general formulae Vd and Ve, wherein the radicals of the formula —C(=Xg)—Ν—OH2“-CH2— or —CH -N—C(=Xq)-CH_I 9 2 X. contain a carbamoyl group, are light metal hydride reducing agents e.g. alkali metal aluminum hydrides, e.g. lithium aluminium hydride (which are especially suitable for the reduction of carbamoyl groups), or alkali metal boron hydrides, e.g. sodium boron hydride, and also alkali metal cyanoboron hydrides, e.g. sodium cyanoboron hydride, or boron hydrides, e.g. diborane, (which especially serve to reduce aikylideneamino groups). Furthermore, groups of the formulae Vb and Vc can be converted, optionally with simultaneous hydrogenolytic splitting-off of a radical X^ replaceable by hydrogen by means of hydrogenolysis, by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a heavy metal catalyst, e.g. Raney nickel. - 16 platinum oxide or palladium, into the group of the formula —CHg—NH—CHg—CHg—. Groups of the general formulae Vd and Ve, wherein, in each case Χθ represents a thiono group and optionally contains a radical X^ which can be split off by hydrogenolysis, are converted by reductive disulphurisation, e.g. by treatment with a hydrogenation catalyst, such as Raney nickel, into a group of the formula —CHg—NH—CHg— CHg—. The above reducing reactions are performed in a manner known per se, customarily in. the presence of an inert solvent and, if necessary, with cooling or heating, e.g. in a temperature range of -20°C to +150°C, and/or in a closed vessel under reduced pressure and/or in an inert-gas atmosphere, e.g. in a nitrogen atmosphere.

Within the scope of the definition of the compounds of the general formula I, compounds obtained according to the process of the present invention can be converted In the usual manner into other final materials, for example by exchanging a suitable substituent for another or by introducing a substituent. Thus, in a compound of the general formula I wherein R^ represents halogen, e.g. chlorine, this can be exchanged, by reaction with a lower alkanol which corresponds to the meaning of R as lower alkoxy, for lower alkoxy. For this there is advantageously used a basic condensing agent such as an alkali hydroxide, for instance sodium hydroxide or potassium hydroxide, or an alkali lower alkanolate corresponding to the meaning of the lower alkoxy radical to be introduced, e.g. sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide.

Furthermore, it is possible in a compound of the general formula I wherein and/or Rg represent(s) hydroxyl to convert such hydroxyl groups into the corresponding lower alkoxy groups or into a lower alkylidenedioxy group. This is performed, for example, by reacting a compound of the general formula I containing a hydroxyl group with a reactive derivative of a lower alkanol corresponding to the meaning of R^ as lower alkoxy, the hydroxyl group of which, as stated above in the case of the groups X. and X , is esterified. Suitable as such are, e.g., the corresponding lower alkyl halides, e.g. the chloride or bromide. The process here is advantageously performed in the presence of a basic agent, such as an inorganic base, e.g. in the presence of a carbonate or hydroxide of an alkali metal or alkaline-earth metal, or in the presence of an organic basic agent, such as an alkali metal lower alkanolate. Such a compound of the general formula I containing hydroxyl groups can advantageously be converted, in the customary manner, into a salt, e.g. into an alkali metal salt, such as a sodium salt, for example by reaction with sodium methoxide? and the salt prepared in this manner subjected to a reaction with for instance a lower alkyl bromide, e.g. with methyl bromide or ethyl bromide. There is customarily used for this purpose a solvent or solvent mixture, for example a polar solvent such as a lower alkanol, e.g. ethanol, or a fatty acid amide, e.g. dimethylformamide or N-methylacetamide or N,N - dimethylacetamide, or an amide of phosphoric acid, such as hexamethylphosphoric acid triamide, or sulpholane, or mixtures of such solvents. The reaction is carried out in a range of from +10° to +160°C in an open or closed vessel, optionally in an inert gas atmosphere, e.g. under nitrogen.

Suitable reactive derivatives of a lower alkanol are also the corresponding diazoalkanes e.g. dia2omethane or diazoethane. Their reaction with a compound of the general formula I containing hydroxyl groups is performed in an organic solvent, for instance in an ether such as diethyl ether, or 69 3 - - 18 in a chlorinated hydrocarbon, such as methylene chloride.

The reaction is in this case advantageously performed in a temperature range of from -20° to +50°C, optionally under a protective gas, e.g. under nitrogen.

Depending on the process conditions and on the starting materials, the compounds of the invention are obtained in the free form or in the form, likewise embraced by the invention, Of their salts, and compounds or salts thereof can also be in the form of hemi-, mono-, sesgui- or poly-hydrates thereof.

Acid addition salts of the new compounds can be converted, in a manner known per se, for example by treatment with basic agents e.g. hydroxides, carbonates or hydrogen carbonates of alkali metals, or ion exchangers, into the free compounds. Alternatively, resulting free bases can form with organic or inorganic acids, e.g. with the acids mentioned above, acid addition salts, for the production of which are used in particular those acids that are suitable for the formation of pharmaceutically acceptable salts.

These or other salts, especially acid addition salts, of the compounds of the present invention, e.g. picrates or perchlorates, can also serve to purify the resulting free bases by converting the free bases into salts, separating and purifying them, and again liberating the bases from the salts.

Depending on the choice of starting materials and procedures, the compounds of the invention can be obtained in the form of optical antipodes or racemates or, provided they contain at least two asymmetrical carbon atoms, also in the form of mixtures of racemates. The starting materials can be employed also in the form of optical antipodes.

Racemate mixtures obtained can, by virtue of the physical-chemical differences in the diastereoisomers, be 43692 - 19 separated in a known manner, e.g. by chromatography and/or fractional crystallisation, into the two stereoisomeric (diastereomeric) racemates.

Racemates obtained can be resolved by known methods, into the antipodes, e.g. by recrystallisation from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance, especially an acid, which forms salts with the racemic compound, and separation of the salt mixture obtained in this manner, e.g. by virtue of differing solubilities, into the diastereomeric salts from which the free antipodes can be liberated by the action of suitable agents. Particularly suitable optically active acids are, for example, the D-and L-forms of tartaric acid, di - o - toluyltartaric acid, malic acid, mandelic acid, oamphorsulphonic acid, glutamic acid, aspartic acid or quinic aoid. It is advantageous to isolate the meet active of the two antipodes.

If desired, a starting material is formed under the reaction conditions or a reactant is present in the form of a salt thereof.

For carrying out the reactions according to the invention there are advantageously used those starting naterials which lead to the groups of final materials especially mentioned at the beginning of the text, and especially to the final materials that have been specifically described or emphasised.

The starting materials are known or can be obtained by methods known per se.

Compounds of the general formula II can thus be obtained, for example, by reaction of a compound of the general formula - 20 (VI) /\ or of a salt thereof, wherein Y and R^ have the meanings given above with a compound of the general formula wherein R^, R^ and X^ have the meaning given above, and X°2 represents the group Xg given above, with at least one of the groups X^ and X°2 having a meaning other than hydrogen, and Χ^θ represents hydroxyl or a reactive esterified hydroxyl group, or X 2 and X^Q together represent a carbon-oxygen bond, or wherein X and X 2 together represent a radical which is capable of being split off and which is replaceable by two • hydrogen atoms one bound to the oxygen and the other to the nitrogen atom, and Χ^θ represents a reactive esterified hydroxyl group; or analogously by a modification of a process described above by treatment of a compound of the general formula (VIII) - CH. - CH - CH. - X“ 2 ι 2 6 ° - X 2 vzith a compound of the general formula 8 b a Ji - 21 10 X°7 - CHg (IX) wherein Y, R^, R^ and have the meanings given above X°2 has the meaning given above for X , and one of the groups X° and o 2d X 7 represents a reactive esterified hydroxyl group and the other represents the group of the formula NHiX^), wherein X^ has the meanings given above, provided that at least one of the groups X·^ and Xg has a meaning other than hydrogen, or wherein X° and X° together form an oxygen-carbon bond, and X° represents 2 6 Z the group of the formula —NH(X^), and X^ has a meaning other than hydrogen. The above reactions are performed in a manner known per se, for example as described above.

Starting material of the general formula VIII wherein Y represents the group —N= can be obtained, for example by reacting a compound of the general formula VI described above, or a salt thereof, with a compound of the general formula X - CH - CH - CH 11 2 , 2 (X) wherein X^ represents a reactive esterified hydroxyl group, and, if desired, by splitting the epoxyethyl group in the product obtained to give a 2 - amino - 1 - hydroxyethyl group or a 2 - reactive esterified hydroxy - 1 - hydroxyethyl group. These reactions can be performed in a manner known per, se.

Starting material of the general formula VIII wherein Y represents the group —CH= can be obtained, for example, by reacting a compound of the general formula - 22 10 Ν wherein Χ^2 represents a group capable of being split off, e.g. halogen, e.g. chlorine or bromine, nitro or lower alkylsulphonyl·, with 2,2 - dimethyl - 5 - hydroxymethyl - 1,3dioxolane; reacting the resulting compound by means of hydrolysis, for instance with the aid of aqueous acids e.g. dilute hydrochloric acid, to give the corresponding propane - 1,2diol derivative; converting this by treatment with triethyl orthoacetate into the corresponding R^ - substituted - 2ethoxy - 5 - (2 - pyridyloxymethyl) - 2 - methyl - 1,3dioxolane; converting this by treatment with trichlorosilane in a chlorinated hydrocarbon, e,g. diehloromethane, into the corresponding R^ - substituted 2-(2- acetyloxy - 3 - chloropropyloxy) - pyridine; and converting this by means of a suitable base, e.g. tetrabutylammonium hydrogen sulphate in an alkaline solution, for example in the presence of sodium hydroxide and a chlorinated hydrocarbon e.g. methylene chloride, into the compound of the general formula VIII wherein X° and θ £ X together represent a oxygen-carbon bond. These reactions o are performed in the customary manner. Compounds of the general formula VII can in their turn be obtained, in a manner known per se, by for example reacting a compound of the general formula XlQ—CH^—CH—CH2—Xg (XII) o-x2 with a compound Of the general formula (XIII) wherein R., R_, 4 5 are as defined above and X°, x6 and Xlo X° and X° together represent an oxygen-carbon bond. 2 Ό Starting materials of the general formula V can be obtained by reacting amino compounds of the general formula (Ilia), wherein Y and Rg are as defined above, and wherein the hydroxyl group can optionally be in a protected form, e.g. in an esterified or suitably etherified form, with oxo compounds of the general formula (XIV), wherein and acid compounds Rg are as defined above,or with of the general formula defined above, wherein R^ and Rg are as carboxylic (Xlva), or with their reactive - 24 45692 derivatives, e.g. their halides, e.g. their chlorides; or byreacting amino groups of the general formula R! R„ H2N ~ CH2 CH, (iva) wherein R^ and R2 have the meanings given above with oxo compounds of the general formula Y H / CH- - CH - C 2 X (xv), wherein Y and R^ have the meanings given above, and wherein the group —CHO can optionally be in a suitably etherified form, or with carboxylic acid compounds of the general formula (XVa), wherein Y and R3 have the meanings given above, and wherein the hydroxyl group can optionally be in a protected form, e.g. in the esterified form or xn a suitably etherified form. In an intermediate having a protected hydroxyl group, this group is converted into the free form. The aforementioned reactions are performed in a manner known per se.

The present invention further provides a pharmaceutical preparation which comprises a compound of the general formula I 43692 - 25 or a physiologically tolerable salt thereof in admixture or conjunction with a pharmaceutically suitable carrier.

The compounds can be used, for example, in the form of pharmaceutical preparations which contain a pharmacologically effective amount of the active substance, optionally together with pharmaceutically suitable carrier substances which are suitable for enteral administration, e.g. oral or parenteral administration, and which can be inorganic or organic and solid or liquid. There are thus used tablets or gelatine capsules which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose,mannitol, sorbitol, cellulose and/or glycerin, and/or lubricants, e.g. diatomaceous earth, talcum, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets can also contain binders, e.g. magnesium aluminium silicate, starches such as maize starch, wheat starch, rice starch or arrowroot starch, gelatine, tragacanth, methylcellulose, sodium carboxymethyl - cellulose and/or polyvinylpyrrolidone, and, if desired, effervescent agents, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyestuffs, flavourings and sweetening agents. Furthermore, the pharmacologically effective compounds of the invention can be used in the form Of preparations which can be administered parenterally, or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, and these, e.g. in the case of lyophilised preparations which contain the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use. The pharmaceutical preparations can be sterilised and/or can contain auxiliaries, e.g. preservatives, stabilisers, wetting agents and/or emulsifying agents, agents promoting solubility, salts for - 26 456θ^ regulating the osmotic pressure and/or buffers. The pharmaceutical preparations of the invention which can if desired contain further pharmacologically active substances, are produced in a manner known per se, e.g. by means of con5 ventional mixing, granulating, coating, dissolving or lyophilising processes, and they may contain in the range of from 0.1% to 100%, especially from 1% to 50%,of active substance, with lyophilised preparations containing up to 100% of active substance.

The present invention also provides a method of treating hypertonia. Angina pectoris and other disturbances of the cardiac rhythm, which comprises administering a compound of the general formula I, or a physiologically tolerable salt thereof, or a pharmaceutical preparation of the invention to a non-human animal.

The dosage amount can depend on various factors, such as on mode of application, species and age and/or on the individual conditions. Thus, the daily dosage amounts to be administered to warm-blooded animals in the case of oral administration are in the range of from 0.04 g to 2.0 g, and for warm-blooded animals having a weight of about 70 kg the dosage amounts are preferably in the range of from 0.1 g to 1.0 g.

The following Examples illustrate the invention. Temperatures are given in degrees Centigrade.

Example 1 100 ml of 2 N hydrochloric acid is added to a solution of 75 g of crude 2 - [3' - (2 - (3,4 - dimethoxyphenyl)ethyl) - 21 - phenyloxazolidin - 5' - yl] - methoxy - 3cysnopyridine in 200 ml of ethanol, and the solution is left to stand for 2 to 3 hours at 20—30°. The reaction mixture 48692 - 27 is subsequently concentrated by evaporation and distributed between 200 ml of ethyl acetate and 300 ml of water; the water phase is clarified with active charcoal, filtered, and rendered alkaline with 2 N sodium hydroxide solution. The oil which has precipitated is extracted with ethyl acetate. The crude product, obtained by concentration by evaporation, is dissolved in 1.5 litres of dichloromethane, and the solution is stirred for % hour with 300 g of an adsorption agent based on magnesium silicate. The mixture is then treated with active charcoal and filtered, and the filtrate is concentrated by evaporation to yield crude 2 - [3' - (2 - (3,4 - dimethoxyphenyl) - ethylamino) - 2' - hydroxypropoxy] - 3 - cyanopyridine; this is dissolved in 25 ml of methanol, and a hot solution of 3.0 g of fumarie aeid in 20 ml of methanol is added. On cooling, the neutral fumarate crystallises out in the form of colourless crystals which melt at 160—161°.

The starting material can be produced in the following manner: a) A mixture of 90.6 g of homoveratrylamine, 75 g of glycerin glycide and 250 ml of isopropanol is held for 24 hours at 50° internal temperature. Concentration by evaporation yields a mixture which consists to an extent of 75% of - [2 - (3,4 - dimethoxyphenyl) - ethylamino] - propane - 1,2diol, and which can be used further in the crude form. b) 170 g of the crude product obtained is refluxed together with 80 ml of benzaldehyde, 500 ml of toluene and 1 ml of glacial acetic acid for 7 hours on a water separator.

The solution is then washed once with 100 ml of 1 N sodium hydroxide solution and twice with 100 ml of water each time; it is subsequently dried over magnesium sulphate and concentrated by evaporation. The unreacted benzaldehyde is removed - 28 4 56 from the residue by distillation under reduced pressure (12 Torr). The distillation residue, which cannot be distilled undecomposed, consists principally of 3 - [2 - (3,4 - dimethoxy phenyl) - ethyl] - 5 - hydroxymethyl - 2 - phenyl - oxazolidine which can be further used as crude product. c) 56 g of crude 3 - [2 - (3,4 - dimethoxyphenyl)ethyl] - 5 - hydroxymethyl - 2 --phenyl - oxazolidine is reacted in 250 ml of 1,2 - dimethoxyethane with 5.7 g of a sodium hydride dispersion (55%), and stirring is maintained for 2 hours at 40°. After the addition of 16.4 g of 2 - chloro - 3cyanopyridine, the reaction mixture is stirred at 40—’50° for a further 2 hours; it is subsequently filtered through a filtering auxiliary based on diatomaceous earth, and the filtrate is concentrated by evaporation. The resulting residue is distribu ted between 500 ml of ethyl acetate and 100 ml of water; the organic phase is washed twice with 100 ml of water each time, dried over magnesium sulphate, and concentrated by evaporation to yield crude 2 - [3' - (2 - (3,4 - dimethoxy - phenyl)ethyl) - 2' - phenyl - oxasolidin - 5' - yl] - methoxy - 320 cyanopyridine.

Example 2 A mixture of 9.3 g of 2 - chloro - 3 - (2,3 - epoxypropoxy) - pyrazine and 9.0 g of 2 - (3,4 - dimethoxyphenyl)ethylamine in 100 ml of isopropanol is stirred for 18 hours at —30°; the solvent is then.evaporated off, the residue is dissolved in 50 ml of 2 N hydrochloric acid, and the solution is extracted with 50 ml of ether. The acidified phase is separated, and is rendered alkaline with concentrated ammonia solution. The crude base is extracted 3 times with 100 ml of ethyl acetate each time, and the solvent is evaporated off after each extraction, and in this way there is finally - 29 obtained an oil which gradually crystallises. The crude ΙΟ - chloropyrazin - 2 - yloxy) - 3 - [2 - (3,4 - dimethoxyphenyl) - ethylamino] - propan - 2 - ol thus obtained melts at 62—70°. It farms a hydrochloride which, after recrystallisation from methanol, melts at 184—187°.

Example 3 A solution of 9.2 g of 2 - (2,3 - epoxypropoxy) - 3methoxypyridine and 9.0 g of 2 - (3,4- dimethoxyphenyl)ethylamine in 100 ml of isopropanol is stirred for 6 hours at room temperature. Processing analogously to Example 2 yields 7.5 g of crude base, which is chromatographed, as a solution in ethyl acetate, through a column of 300 g of silica gel The by-products are extracted by subsequent washing with ethyl acetate. By elution with ethyl acetate containing amounts of ethanol rising frcm 1-5%, and finally with an ethyl acetate/ethanol mixture of 4:1, there is obtained 1-/2-(3,4-dimethcxyphenyl)“ethyl£rniro/- 3 (3-methaxy-pyridin-2-ylcKy)-propan-2-ol, which, after renewal of the solvent by evaporation, is a yellow oil of.which the acid oxalate, after recrystallisation frcm methanol/acetate, melts at 132 - 134 .

The starting material can be produced in the following manner: a) 26.5 g of sodium hydride is added with stirring, in the course of one hour, to a mixture of 161 g of 3 - methoxy2 - nitropyridine and 144 g of 2,2 - dimethyl - 5 - hydroxymethyl - 1,3 - dioxolane in 1000 ml of hexamethylphosphoric acid triamide,· the temperature during the addition is maintained at 0—10° by cooling. The reaction mixture is stirred for a further 5 hours with ice cooling, and then for 15 hours at room temperature. The reaction mixture is poured onto ice, and extracted with diethyl ether. The organic extract is - 30 washed with a concentrated aqueous sodium chloride solution, dried, and concentrated by evaporation. The residue is dissolved in 1000 ml of ethanol; 100 ml of 2 N hydrochloric acid is then added and the whole is allowed to stand for 8 hours. After removal of the solvent by evaporation, the residue is made alkaline with a concentrated solution of sodium hydroxide in water, and extracted with ethyl acetate. Removal of the solvent by evaporation yields a crude product from which is obtained, after the addition of diethyl ether, crystalline 3(3 - methoxy - 2 - pyridyloxy) - propane - 1,2 - diol which melts at 52—^55°. b) To a solution of 62 g of 3 - (3 - methoxy - 2pyridyloxy) - propane - 1,2 - diol in 350 ml of triethyl orthoacetate are added 2 drops of trifluoroacetic acid, and the mixture is allowed to stand for 3 hours at 20—30°. concentration by evaporation yields crude 2 - ethoxy - 5 - (3methoxy - 2 -pyridyioxymethyl) - 2 - methyl - 1,3 - dioxolane in the form of oil, whioh is used without further purification. c) To a mixture of 85 g of 2 - ethoxy -5-(3- methoxy2 - pyridyloxy) - methyl) - 2 - methyl - 1,3 - dioxolane in 500 ml of diehloromethane is added 45 ml of trimethylchlorosilane, and stirring is performed at 20—30° for one hour. Complete concentration by evaporation under reduced pressure yields crude 2 -(2 - acetyloxy - 3 - chloropropyloxy) - 3 - methoxypyridine in the form of oil, which is used without purification. d) A mixture of 80 g Of 2 - (2 - acetyloxy - 3 - ohloropropoxy) - 3 - methoxypyridine, 900 ml of methylene chloride, 500 ml of a 2 N aqueous sodium hydroxide solution and 9.5 g of tetrabutylammonium hydrogen sulphate is vigorously stirred for 16 hours at 20—30°. The organic phase is then separated 45892 - 31 and concentrated by evaporation. The oil remaining is dissolved in diethyl ether; the solution is filtered, treated with active charcoal, and concentrated by evaporation to give 2 - (2,3 - epoxypropoxy) - 3 - methoxypyridine, which melts at 63—65°.

Example 4 A mixture of 9.1 g of 1 - amino - 3 - (3 - methylpyridin2 - yloxy) - propan - 2 - ol, 10.8 g of 2 - (p - methoxyphenyl)ethyl bromide, 10 g of potassium carbonate and 100 ml of absolute ethanol is refluxed for 20 hours with stirring. The reaction mixture is filtered after cooling, concentrated in vacuo, and the residue is dissolved in 200 ml of ethyl acetate. The solution is washed once with 50 ml of water, and then extracted with 50 nil of 1 N acetic acid. From the acidified aqueous solution is liberated the base with concentrated sodium hydroxide solution; it is then extracted with ethyl acetate, and the solvent is completely removed by evaporation to leave crude 1 - [2 - (jj - methoxyphenyl) - ethylamino] - 3 - (3 - methylpyridin - 2 - yloxy) - propan - 2 - ol in the form of a gradually crystallising oil which, after recrystallisation from isopropanol, melts at 80—81°.

Example 5 A solution of 6.65 g of 1 - amino - 3 - (3 - methylpyridin - 2 - yloxy) - propan - 2 - ol in 100 ml of methanol is neutralised with an approximately 4 N solution of hydrogen chloride in methanol, and after the addition of 5.0-.g of 3,4methylenedioxyphenylacetaldehyde and 2.0 g Of sodium cyanoboron hydride it is stirred for about 30 hours at 20—30°.

The reaction mixture is concentrated in vacuo, and the residue is distributed between 100 ml of 2 N hydrochloric acid and 50 ml of ethyl acetate. The acidified phase is rendered alkaline - 32 4St»aa with concentrated sodium hydroxide solution and there is thus obtained crude 1 - [2 - (3,4 - methylenedioxyphenyl)ethylamino] - 3 - (3 - methylpyridin - 2 - yloxy) - propan2 - ol, the hydrochloride of which melts at 123—125° after recrystallisation from isopropanol/ether.

Example 6 A solution of 8.4 g of crude 1 - [N - benzyl - N - [2(3,4 - methylenedioxyphenyl) - ethyl] - amino] - 3 - (4methylpyridin - 2 -yloxy) - propan - 2 - ol in 100 ml of methanol is hydrogenated, with the addition of 1 g of palladium, charcoal catalyst (5%), under normal conditions until the calculated amount of hydrogen has been absorbed. Removal of the catalyst by filtration and of the solvent by evaporation yields crude 1 - [2 - (3,4 - methylenedioxyphenyl) - ethylamino]15 3-(4- methylpyridin - 2 - yloxy) - propan - 2 - ol as a crystalline compound, which melts at 80—81° after recrystallisation from isopropanol.

The starting material is obtained in the following manner: a) Glycerin glycide and benzylamine are reacted, in a manner known, to give 3 - benzylamino - propane - 1,2 - diol (b.p. 160—170°/0.01 Torr). b) 3 - Benzylamino - propane - 1,2 - diol is converted with benzaldehyde,by azeotropic distillation with benzene in a manner known per se, into 3 - benzyl - 5 - hydroxymethyl25 2 - phenyloxazolidine, b.p. 168—L71°/0.Q05 Torr. c) From 134 g of this compound, 50.9 g of 2 - chloro4 - methyl - pyridine and 19.1 g of a sodium hydride dispersion is produced, in the usual manner, 1 - benzylamino - 3 - (4raethylpyridin - 2 - yloxy) - propan -2 - ol, which melts at 70—71° after recrystallisation from cyclohexane. 4SG92 - 33 d) To a solution of 10.9 g of 1 - benzylamino - 3 - (4methylpyridin - 2 - yloxy) - propan- 2 - ol and 7.0 g of triethylamine in 50 ml of chloroform is added dropwise, with stirring, a solution of 9.6 g of 3,4 - methylenedioxyphenylacetyl chloride in 50 ml of chloroform, and the reaction mixture is subsequently stirred for 2 hours. The reaction solution is washed with 20 ml of 2 N hydrochloric acid, then with 2 N sodium hydroxide solution, and finally with water,· it is dried over sodium sulphate, and the solvent is evaporated off to obtain oily N - benzyl - N - [2 - hydroxy - 3 - (4methylpyridin - 2 - yloxy) - propyl] - (3,4 - methylenedioxyphenyl) - acetamide, which is further used without additional purification. e) A solution of 12 g of the resulting compound in 50 ml of 1,2 - dimethoxyethane is added dropwise, with ice cooling and with stirring, to a suspension of 2.0 g of lithium aluminium hydride in 100 ml of 1,2 - dimethoxyethane. The reaction mixture is then stirred for 3 hours at an internal temperature of 48—55°, and subsequently decomposed with 10 ml of water whilst cooling with ice. The organic phase is separated, concentrated in vacuo and dissolved in about 200 ml of ethyl acetate. The solution is extracted with 50 ml of 2 N hydrochloric acid? the acid aqueous phase is separated, and the base is liberated with concentrated sodium hydroxide solution. Extraction with ethyl acetate and removal of the solvent by evaporation yield 1 - [N - benzyl - N - [2 - (3,4methylenedioxyphenyl) - ethyl] - amino] - 3 - (4 - methylpyridin - 2 - yloxy) - propan - 2 - ol as oil, which is further processed as auch.

Example 7 100 ml of a 1 M solution of diborane in tetrahydrofuran , 48692 - 34 is added, while cooling with ice, to a solution of 8 g of crude N - [2 - hydroxy - 3 - {3 - methylpyridin - 2 - yloxy)propyl] - (3,4 - methylenedioxyphenyl) - acetamide in 100 ml of tetrahydrofuran, and the whole is allowed to stand for 5 hours at room temperature. The solution is then concentrated by evaporation; an addition of 100 ml of 2 N hydrochloric acid is made, and the solution is left to stand for about 1 hour.

It is then extracted with 50 ml of ether, the acid aqueous phase is separated, and rendered alkaline with concentrated sodium hydroxide solution. Extraction with ethylaeetate and removal of the solvent by evaporation yield crude 1 - [2(3,4 - methylenedioxyphenylethylamino] - 3 - (3 - methylpyridin2 - yloxy) - propan - 2 - ol in the form of oil, the hydrochloride of which melts at 123—125° after recrystallisation from methanol/ether.

The starting material is obtained, analogously to Example 6b), from 10 g of (3,4 - methylenedioxyphenyl)acetyl chloride 8.2 g of 1 - amino - 3 - (3 - methylpyridin2 - yloxy) - propan - 2 - ol and 6.1 g of triethylamine, in the form of an oily product..

Example 8 A mixture of 8.8 g of 3 - cyano - 2 - (2,3 - epoxypropoxy) - pyridine and 9.0 g of 2 - (3,4 - dimethoxyphenyl)ethylamine in 100 ml of isopropanol is stirred for 18 hours at room temperature. Working up analogously to Example 2 yields crude 3 - cyano 2- [3- (2 - (3,4- dimethoxyphenyl)ethylamino) - 2 - hydroxypropoxy] - pyridine, the neutral· fumarate of which melts at 160—161° after recrystallisation from methanol. 6 9 2 - 35 The 3 - cyano - 2 - (2,3 - epoxypropoxy) - pyridine required as starting material is produced, in a manner analogous to that of the Examples 3a)—3d), using 2 - chloro3 - cyanopyridine, with the following crystalline intermediate products being obtained: a) 5 - [(3 - cyanopyridin - 2 - yloxy) - methoxy] - 2,2dimethyl - 1,3 - dioxolane, which melts at 68—71° after recrystallisation from ether/petroleum ether? and b) 3 - cyano - 2 - (2,3 - epoxypropoxy) - pyridine, which melts at 55—58° after recrystallisation from ether.

Example 9 A solution of 23 g of crude 1 - [N - benzyl - N - [2(£ - benzyloxyphenyl) - ethyl] - amino -3-(3- methylpyridine-2-ylaxy)-prqpan-2-ol in 300 ml of methanol is hydrogenated analogously to Example 6, until 2 malar equivalents of hydrogen have been absorb•yj, aid subsequently processed to obtain 1-/2-(£-hydrcKyjhenyl)-ethylamino/3-(3-methylpyridin-2-yloxy)-prcpan-2-ol, the neutral funarate of which melts at 182—183° after recrystallisation from isopropanol.

The starting material is obtained in the following manner: a) A solution of 16.0 g of (£ - benzyloxyphenyl)acetyl chloride in 100 ml of chloroform is added, in the course of 10 minutes, to a solution of 13.6 g of 1 - benzylamino -3 - (3 - methylpyridin - 2 - yloxy) - propan - 2 - ol, which melts at 77—82°, and 7.6 g of triethylamine in 150 ml of chloroform, with the temperature rising to about 40°. The reaction mixture is stirred for a further 2 hours, and is subsequently worked up analogously to Example 6b) to obtain crude N - benzyl - KT - [2 - hydroxy - 3 - (3 - methylpyridin2 - yloxy) propyl] - (£ - benzyloxyphenyl) - acetamide in the - 36 4 5 6 9« form of brown oil, which is further processed without additional purification. b) 24 g of the compound obtained is dissolved in 200 ml of tetrahydrofuran; 150 ml of a 1 M solution of diborane in tetrahydrofuran is added whilst cooling with ice, and the mixture is allowed to stand for 24 hours at room temperature. Working up analogously to Example 6c) yields crude 1 - [Nbenzyl - N - [2 - (p - benzyloxyphenyl) - ethyl] - amino]3-(3- methyIpyridin - 2 - yloxy) - propan - 2 - ol in the form of brown viscous oil, which can be further used without additional purification.

Example 10 g of crude 1 - [N - benzyl - N - [2 - (p - benzyloxyphenyl) - ethyl] - amino] - 3 - (4 - methylpyridin - 2 - yloxy)15 propan - 2 - oi is debenzylated, analogously to Example 9, to give 1 - [2 - (p - hydroxyphenyl) - ethylamino] - 3 - (4methyIpyridin - 2 - yloxy) - propan - 2 - ol, which melts at 104—105° after recrystallisation from isopropariol.

The starting material is produced, analogously to Example 9a and b, from 1 - benzylamino - 3-(4- methylpyridin - 2 - yloxy) - propan - 2 - ol.

Example 11 Analogously to Example 1 is obtained, using 48 g of crude 2 - [3' -(2- (3,4 - dimethoxyphenyl) - ethyl - 2'25 phenyloxazolidin - 5' - yl - methoxy - 3 - methoxypyrazine, - [2 - (3,4 - dimethoxyphenyl) - ethylamino] - 3 - (3methoxypyrazin - 2 - yloxy) - propan - 2 - ol, of which the hydrochloride melts at 167—170°.

The starting material is produced, analogously to Example le), using 17.1 g of 2 - chloro - 3 - methoxypyrazine. 4569® - 37 with crude oily 2 - [3' - (2 - (3,4 - dimethoxyphenyl)ethyl) - 2' - phenyl - oxazolidin - 5’ - yl - methoxy] - 3methoxypyrazine being obtained.

Example 12 Analogously to Example 1 is obtained, using 52 g of crude 2 - chloro - 3 - [3' - (2 - (3,4 - dimethoxyphenyl)ethyl) - 2' - phenyl - oxazolidin - 51 - yl - methoxy] pyrazine, 1-(3- ohloropyrazin - 2 - yloxy) - 3 - [2 - (3,4dimethoxyphenyl) - ethylamino] - propan - 2 - ol, of which the hydrochloride melts at 183—187°.

The starting material is produced, analogously to Example lc), with the use of 17.6 g of 2,3 - dichloropyrazine. The resulting 2 - chloro - 3 - [3' - (2 - (3,4 - dimethoxyphenyl) - ethyl) - 2' - phenyl - oxazolidin - 5' - ylmethoxy] - pyrazine is further processed in the crude form.

Example 13 A solution of 4.5 g of sodium methoxide and 9.0 g of crude 1-(3- ohloropyrazin - 2 - yloxy) - 3 - [2 - (3,4dimethoxyphenyl) - ethylamino] - propan - 2 - ol in 200 ml of methanol is refluxed for 5 hours. There is obtained, after filtration and then removal of the solvent by evaporation, crude 1 - [2 - (3,4 - dimethoxyphenyl) - ethylamino]3-(3- methoxypyrazin - 2 - yloxy) - propan - 2 - ol in the form of yellow oil, the hydrochloride of which melts at 167— 170° after recrystallisation from methanol.

Example 14 250 ml of a 1 M solution of diborane in tetrahydrofuran is added dropwise at 5—10°, whilst cooling with ice, to a solution of 13 g of crude N - [2 - hydroxy - 3 - (3methylpyridin - 2 - yloxy) - propyl] - (f> - hydroxyphenyl)4369 3 - 38 acetamide in 200 ml of tetrahydrofuran, and the mixture is stirred for 20 hours at room temperature- After removal of the solvent by evaporation, there is carefully added to the residue 100 ml of 2 N hydrochloric acid, and stirring is continued for 1 hour. The crystals which have been precipitated are filtered off, and the solution is extracted with 50 ml of ether. The aqueous phase is then brought to pH 8 to 9 with solid sodium bicarbonate, and extracted twice with 100 ml of ethyl acetate, each time. Concentration of the organic phase by evaporation yields crude 1 - [2 - (£ - hydroxyphenyl)ethylamino] - 3 - (3 - methylpyridin - 2 - yloxy) - propan2-01 in the form of yellowish oil, the neutral fumarate of which melts at 182—183° after recrystallisation from isopropanol.

The starting material is produced in the following manner: A solution of 7.23 g of trimethylacetyl chloride in 100 ml of diehloromethane is added dropwise at 0—5°, with cooling and stirring, to a solution of 7.6 g of £ - hydroxyphenyl20 acetic acid and 6.6 g of triethylamine in 200 ml of dioxan.

The colourless suspension is stirred for 4 hours at 0—5°, and then at this temperature is added dropwise a solution of 8.2 g of 1 - amino - 3 - (3 - methylpyridin - 2 - yloxy)propan - 2 - ol in 50 ml of dioxan. The suspension is stir25 red for 2 hours at 0—5° and then for 15 hours at room temperature. After the solvent has been evaporated off in vacuo, the residue is distributed between 200 ml of ethyl acetate and 100 ml of water; the organic phase is extracted with twice with 200 ml of 1 N hydrochloric acid each time, the acid extracts are combined, and the pH value thereof,is 4-36 9 2 - 39 adjusted to about 8 with solid sodium bicarbonate. The oil which has been precipitated is extracted with dichloromethane. The dichloromethane is evaporated off to leave crude N - [2hydroxy - 3 - (3 - methylpyridin - 2 - yloxy) propyl] - (fi5 hydroxyphenyl) - acetamide in the form of light-yellow viscous oil, which can be used without further purification.

Example 15 By a procedure analogous to that described in Example 2 is obtained, using 3.6 g of 2 - (2,3 — epoxypropoxy) - 310 methoxy - pyridine and 2.5 g of p - hydroxyphenylethylamine, - [2 - (j=> — hydroxyphenyl) - ethylamino] - 3 - (3 - methoxypyridin - 2 - yloxy) - propan - 2 - ol, the neutral fumarate of which melts at 175—176° after recrystallisation from methanol/acetone.

Example 16 A solution of 7.3 g of 1 - [2 - (fi - benzyloxyphenyl)ethylamino] - 3 - (3 - methoxypyridin - 2 - yloxy) - propan2-01 in 100 ml of ethanol is hydrogenated, in the presence of 1.5 g of a palladium charcoal catalyst (5%) and at 2o atmospheric pressure, until 1 molar equivalent of hydrogen has been absorbed. After removal of the catalyst by filtration and concentration of the filtrate by evaporation, there remains 1 - [2 - (fi - hydroxyphenyl) - ethylamino] - 3 - (3methoxypyridin - 2 - yloxy) - propan - 2 - ol, of which the neutral fumarate melts at 175—176° after recrystallisation from methanol/acetone.

The starting material is obtained by reaction of 5.4 g of 2 - (2,3 - epoxypropoxy) - 3 - methoxypyridine and 6.5 g of (fi - benzyloxyphenyl) - ethylamine in 150 ml of isopropanol, analogously to Example 2; after recrystallisation from dichlor omethane/ether, it melts at 85—36°. 4369 2 - 40 Example 17 A mixture of 400 g of 2 - (p - hydroxyphenyi) - ethyl bromide, 500 mg of I - amino -3-(3- methylpyridin - 2yloxy) - propan - 2 - ol and 200 mg of potassium bicarbonate in 10 ml of isopropanol is refluxed for 5 hours. Processing analogously to Example 4 yields oily 1 - [2 - (p - hydroxyphenyi) - ethylamino] - 3 - (3 - methylpyridin - 2 - yloxy) propan - 2 - ol, the neutral fumarate of which melts at 182— 183° after recrystallisation from isopropanol.

Example 18 A solution of 14 g of crude 1 - [N - benzyl - N - [2(4 - benzyloxy - 3 - methoxyphenyl) - ethyl] - amino] - 3(3 -methylpyridin - 2 - yloxy) - propan - 2 - ol in 200 ml of methanol is hydrogenated under normal conditions, with the addition of 4.0 g of a palladium charcoal catalyst (5%), until 2 molar equivalents of hydrogen have been absorbed. After removal of the catalyst by filtration and concentration of the filtrate by evaporating Off the solvent, the residue is distributed between 200 ml of ether and 100 ml of 2 N hydro20 chloric acid; the acid aqueous solution is separated, made alkaline with concentrated ammonia solution and extracted with 200 ml of ethyl acetate. Concentration of the dried ethyl acetate solution by evaporation yields crude 1 - [2(4 - hydroxy - 3 - msthoxyphenyl) - ethylamino] - 3 - (325 methylpyridin - 2 - yloxy) - propan - 2 - ol in the form of yellow oil which, dissolved with half the equivalent amount of fumaric acid in methanol, forms a neutral fumarate, which malts at 181-183°.

The starting material can be produced in the following manner; . a) 4 - Benzyloxy - 3 - methoxyphenylacetic acid (m.p. 6 9 2 - 41 87—90°) is converted with thionyl chloride in diehloromethane into the acid chloride; and this is reacted, analogously to Example 6 b), with 1 - benzylamino - 3 - (3 - methylpyridin2 - yloxy) - propan - 2 - ol to give N - benzyl - N - [25 hydroxy -3-(3- methylpyridin - 2 - yloxy) - propyl](4 - benzyloxy - 3 - methoxyphenyl) - acetamide. This forms an oil which can be further used in the crude form. b) 22 g of the crude amide obtained is reduced, analogously to Example 9 b), with diborane, and yields crude 1 - [N - benzyl - N - [2 - (4 - benzyloxy - 3 - methoxyphenyl) - ethyl] - amino] - 3 - (3 - methylpyridin - 2yloxy) - propan - 2 - ol in the form of yellow oil, which can be further used as such.

Example 19 j_5 Tablets containing 0.1 g of 2 - [3' - (2 - (3,4 - di;?ethoxyphenyl) - ethylamino) - 2' - hydroxypropoxy] - 3cyanopyridine as a neutral fumarate are produced as follows: Composition (for 10,000 tablets): -[3' - (2- (3,4- dimethoxy20 phenyl) - ethylamino) - 2'hydroxypropoxy] - 3 - cyanopyridine as a neutral fumarate 1000.00 9 lactose 580.00 9 maize starch 750.00 9 colloidal silicic acid 80.00 9 taleum 80.00 9 magnesium stearate 10.00 9 water q.s.

Production The 2 - [3' - (2 - (3,4 - dimethoxyphenyl) - ethylamino)2' - hydroxypropoxy] - 3 - cyanopyridine as a neutral fumarate - 42 is mixed with the lactose, a portion of the maize starch and with the colloidal silicic acid, and the mixture is put through a sieve. A further portion of maize starch is made into a paste with the five-fold amount of water on a water-bath, and 5 the powder mixture is kneaded with this paste until a slightly plastic mass is formed. This is pressed through a sieve having a mesh size of about 3 mm? it is then dried and the dry granulate is again put through a sieve. The remainder of the maize starch, the talcum and the magnesium stearate are thereupon mixed in and the resulting mixture is pressed to form tablets each weighing 0.250 g (with breaking groove).

Claims (61)

1. A process for producing 1 - amino - 2 - hydroxy - 3heterocyclyloxy - propanes of the general formula 5 wherein Y represents the group —CH= or the group —11=, R. represents hydrogen, hydroxyl, lower alkyl or lower 1 alkoxy, R^ represents hydroxyl, lower alkoxy or, together with 10 R^, o - (lower alkylidene) - dioxy or o - (lower alkylene) - dioxy, and r^ represents lower alkyl, lower alkoxy, halogen or cyano, with the radicals Ry R 2 and R 3 each being bound to any one of the aromatic carbon atoms, characterised in that 15 in a compound of the general formula Y wherein Y and R 3 have the above meanings, R^ has the meaning of R^ above or may represent the group —0—Xy R^ has the meaning of R 2 above or may represent the group —0—X^, with at least one of the groups X^, X 2 < X^ and X^ representing a group replaceable by hydrogen, and the others representing hydrogen or a group replaceable by hydrogen, or X^ and X^ together represent a radical which is capable of being split off and which is replaceable by two hydrogen atoms one bound to the oxygen atom of the secondary alcohol group and the other to the nitrogen atom, and/or X^ and X^ together represent a radical which is capable of being split off and whioh is replaceable by two hydrogen atoms bound to the oxygen atoms of the groups or in a salt thereof, the radical X^ and/or X 2 and X^ and together 'and/or .and/or X^ and/ or X 3 and X^ together are replaced by hydrogen; or a compound or the general formula 0 - CH, - CH - CH, - X, 2 . 2 6 (III) is reacted with a compound of the general formula wherein one of the groups X, and X, represents a reactive o 7 esterified hydroxyl group and the other represents a primary amino group, and X^ represents a hydroxyl group, or wherein X, and X, together represent a epoxy group, and X, represents 3 0 / a primary amino group, and Ϋ, R^, R 2 and R^ have the meanings given above; or in a compound of the general formula 4 5 6 9 2 - 45 Υ wherein the group —X— (Va) represents one of the radicals 8 of the formulae —CH=N—CH 2 —CH 2 — (Vb) —CH 2 —N=CH—CH 2 — (Vc) —1C (=Xg) —KT—CH 2 —CH 2 — (va) 1 X, 1 ~CH 2 —-n—C (=X g ) —CH 2 — (Ve) wherein X represents an oxo or thioxo group, Y, R., R- and X 9 J. £> 1 have the meanings given above and R^ has the meaning given above with the exception of halogen and cyano, the group —X— is reduced, optionally by way of the intermediate 8 containing the radical —CH '—N—-CH„—CH —, 2. | 2 2 x i 15 to the radical of the formula —CH^—NH—CH^—CH^—; and, if desired, a resulting compound of the general formula I is converted into another compound of the general formula I? and/or, if desired, a free compound obtained is converted into a salt, or a salt obtained is converted into a free compound; and/or, - 46 4S692 if desired, an isomeric mixture obtained is separated into the individual isomers, or a racemate obtained is separated into the optical antipodes.

2. A process as claimed in Claim 1, wherein X^ and/or Xg 5 and/or Xg and/or X^ are split off by means of solvolysis or reduction.

3. A process as claimed in claims 1 or claim 2, wherein a group X^ which is capable of being split off is an a - arylflower alkyl) group capable of being split off by hydrogenoly10 sis.

4. A process as claimed in Claim 3, wherein X^ is a benzyl group.

5. A process as claimed in Claim 1 or Claim 2, wherein a group X^ which is capable of being split off is an acyl radical 15 capable of being split off by solvolysis or reduction, or an unsubstituted or substituted 1 - polyphenyl - (lower alkyl) radical.

6. A process as claimed in Claim 5, wherein X^ is an acyl radical capable of being split off by hydrolysis, acidolysis or 20 reduction.

7. A process as claimed in Claim 6, wherein X^ is an acyl radical of an organic carboxylic or sulphonic acid.

8. A process as claimed in Claim 1 or Claim 2, wherein a group Xg, Xg or X^ capable of being split off is an a - aryl25 (lower alkyl) group capable of being split off by hydrogenolysis.

9. A process as claimed in Claim 8, wherein X^, Xg or X^ is a benzyl group.

10. A process as claimed in Claim 1 or Claim 2, wherein a - 47 group X 2 , X 3 or X^ capable of being split off is an acyl radical which is capable of being split off by solvolysis or an unsubstituted or substituted aliphatic or araliphatic hydrocarbon radical polybranched on the linking carbon atom.

11. A process as claimed in Claim 10, wherein X^, X 3 or X^ is an acyl radical capable of being split off by hydrolysis, alcoholysis or acidolysis.

12. A process as claimed in Claim 1 or Claim 2, wherein X^ and X 2 together and X 3 and X& together represent an unsubstituted or substituted 1 - phenyl - (lower alkylidene! radical which is capable of being split off by hydrogenolysis.

13. A process as claimed in Claim 1 or Claim 2, wherein X^ and X together and X and X together represents a lower 2 3 4 alkylidene or cycloalkylidene radical capable of being split off by solvolysis, or a carbonyl or thiocarbonyl group.

14. » A process as claimed in any one of Claims 3, 4, 8, 9 and 12, wherein the starting material is treated with catalytically activated hydrogen.

15. A process as claimed in any one of Claims 5 to 7, 10, 11 and 13, wherein the starting material is hydrolysed, aleoholised, aoidolised or reduced.

16. A process as claimed in Claim 1, wherein a starting material of the general formula V, wherein the group of the formula Va represents one of the radicals of the formulae Vb, Vc Vd or Ve in which the groups —C(=X g )—NH— and —NH—C(=X g )-, wherein Χθ has the meaning given in claim 1 represent a carbamoyl group, is treated with a light metal hydride or a boron hydride.

17. A process as claimed in Claim 1, wherein a starting material of the general formula V, wherein the group of the - 48 general formula Va represents one of the radicals of the formula Vb or Vc, is treated with catalytically activated hydrogen.

18. A process as claimed in Claim 1, wherein a starting 5 naterial of the general formula V, wherein the group of the general formula Va represents one of the radicals of the general formula Vd or Ve in which X_ represents a thioxo y group. Is reductively desulphurised.

19. A process as claimed in any one of Claims 1 to 18, 10 wherein a starting material is formed under the reaction conditions, or a reactant is present in the form of a salt thereof.

20. A process as claimed in any one of Claims 1 to 19, wherein there is produced a compound of the general formula I 15 given in Claim 1, or a salt thereof, wherein R^ represents hydrogen, hydroxyl, lower alkyl or lower alkoxy each having from 1 to 4 carbon atoms, R 2 represents hydroxyl, lower alkoxy having from 1 to 4 carbon atoms, or together with R^ represents o - (lower alkylidene) - dioxy or o - (lower alkylene)20 dioxy having 1 or 2 carbon atoms, and R^ represents lower alkyl or lower alkoxy each having from 1 to 4 carbon atoms, halogen or cyano, and wherein each of R and R. is in-the 2-, X 4. 3- or 4-position, o - (lower alkylidene) - dioxy or o - (lower alkylene) - dioxy is in the 2,3- or 3,4-position, and R^ is 25 in the 3-, 4-, 5- or 6-position of a pyridine ring or in the 3-, 5- or 6-position of a pyrazine ring.

21. A process as claimed in any one of claims 1 to 19, wherein there is produced a compound of the general formula 43692 or a salt thereof, wherein R^ represents hydrogen hydroxyl, methyl or methoxy, Rg represents hydroxyl, methoxy or, together with R^, represents o - methylenedioxy, and Rg represents 5 methyl, methoxy, chlorine or cyano, and wherein R^ and Rg are in the 3- and 4-position, o - methylenedioxy is in the 3,4position and Rg is in the 3- or 4-position.

22. A process as claimed in any one of Claims 1 to 19, wherein there is produced a compound of the general formula or a salt thereof, wherein R^ represents hydrogen, hydroxyl, methyl or methoxy, Rg represents hydroxyl, methoxy or, together with R^, represents o - methylenedioxy,and Rg represents methyl, methoxy, chlorine or cyano, and wherein R^ and Rg are 15 in the 3- and 4-position, o - methylenedioxy is in the 3,4position and Rg is in the 3-position.

23. A process as claimed in any one of Claims 1 to 19, wherein 2 - [3' - (2 - (3,4 - dimethoxyphenyl) - ethylamino)2' - hydroxypropoxy] - 3 - cyanopyridine or a salt thereof 20 is produced. .45692 - 50

24. A process as claimed in any one of Claims 1 to 19, wherein 1 - (3 - ohloropyrazin - 2 - yloxy) - 3 - [2 - (3,4dimethoxyphenyl) - ethylamino] - propan - 2 - ol or a salt thereof is produced. 5

25. A process as claimed in any one of Claims 1 to 19, wherein 1 - [2 -(3,4- dimethoxyphenyl) - ethylamino] - 3(3 - methoxypyridin - 2 - yloxy) - propan - 2 - ol or a salt thereof is produced.

26. A process as claimed in any one of Claims 1 to 19, wherein 1 - [2 - (£ - methoxyphenyl) - ethylamino] - 3 - (310 methylpyridin - 2 - yloxy) - propan - 2 - ol or a salt thereof is produced.

27. A process as claimed in any one of Claims 1 to 19, wherein 1 - [2 - (3,4 - methylenedioxyphenyl) - ethylamino] 3-(3- methylpyridin - 2 - yloxy) - propan - 2 - ol or a 15 salt thereof is'produced.

28. A process as claimed in any one of Claims 1 to 19, wherein, 1 - [2 - (3,4 - methylenedioxyphenyl) - ethylamino] 3-(4- methylpyridin - 2 - yloxy) - propan - 2 - ol or a salt thereof is produced. 20

29. A process'as claimed in any one of Claims 1 to 19, wherein 1 - [2 - (£- hydroxyphenyl) - ethylamino] - 3 - (3methylpyridin - 2 - yloxy) - propan - 2 - ol or a salt thereof is produced.

30. A process as claimed in any one of Claims 1 to 19, 25. Wherein 1 - [2 - (£ - hydroxyphenyl) - ethylamino] - 3 - (4methylpyridin - 2 - yloxy) - propan - 2 - ol or a salt.thereof is produced.

31. A process as claimed in any one of Claims 1 to 19, wherein 1 - [2 - (3,4 - dimethoxyphenyl) - ethylamino] - 34569 i - 51 (3 - methoxypyrazin - 2 - yloxy) - propan - 2 - ol or a salt thereof is produced.

32. A process as claimed in any one of Claims 1 to 19, wherein 1 - [2 - (fi - hydroxyphenyl) - ethylamino] - 3 - (35 methoxypyridin r 2 - yloxy) - propan - 2 - ol or a salt thereof is produced.

33. A process as claimed in any one of claims 1 to 19, wherein 1 - [2 - (3 - methoxy - 4 - hydroxyphenyl) - ethylamino] - 3 - (3 - methylpyridin - 2 - yloxy) - propan - 210 ol or a salt thereof is produced.

34. A process as claimed in Claim 1, carried out substantially as described in any one of Examples 1 to 18 herein.

35. A 1 - amino - 2 - hydroxy - 3 - heterocyclyloxypropane of the general formula wherein Y represents the group —CH= or the group —N=, R^ represents hydrogen, hydroxyl, lower alkyl or lower alkoxy, 20 Rj represents hydroxyl, or lower alkoxy or, together with R , o - (lower alkylidene) - dioxy or o - (lower alkylene) - dioxy, and R^ represents lower alkyl, lower alkoxy, halogen or cyano, and wherein each of the radicals R , Rg and Rg may be - 52 45692 bound to any one of the aromatic carbon atoms.

36. A compound as claimed in Claim 35, wherein R^ represents hydrogen, hydroxyl, alkyl having from 1 to 4 carbon atcms or alkoxy having from 1 to 4 carbon atoms, R 2 represents hydroxyl, or lower alkoxy having up to 4 carbon atoms, or, together with R^, represents o - (lower alkylidene) - dioxy Or o - (lower alkylene) - dioxy having 1 or 2 carbon atoms, and R^ represents lower alkyl or lower alkoxy each having from 1 to 4 carbon atoms, halogen or cyano, and wherein R^ and R 2 are in the 2-, 3- or 4-position, o(lower alkylidene) - dioxy or o - (lower alkylene) - dioxy is in the 2,3- or 3,4-position, and R^ in the 3-, 4-, 5- or 6position. of a pyridine ring in the 3-, 5- or 6-position of a pyrazine ring.

37. A compound of the general formula wherein R^ represents hydrogen, hydroxyl, methyl or methoxy, R 2 represents hydroxyl, methoxy or, together with R^, represents o -methylenedioxy, and R 3 represents methyl, methoxy, chlorine or cyano, and wherein R^ and R 2 are in the 3- and 4-position, or omethylenedioxy in the 3,4 - position and R 3 is in the 3- or 4-position.

38. A compound of the general formula - 53 43692 wherein represents hydrogen, hydroxyl, methyl or methoxy, Rg represents hydroxyl, methoxy or, together with R , represents o - methylenedioxy, and Rg represents methyl, methoxy, chlorine or cyano, and wherein R^ and Rg are in the 3- and 4-position, or omethylenedioxy is in the 3,4 - position, and Rg is in the 3-position. 10

39. ft 2 - [3' (2 - (3,4 - Dimethoxyphenyl) - ethylamino)2' - hydroxypropoxy] - 3 - cyanopyridine.

40. 1-(3- Chloropyrazin - 2 - yloxy) - 3 - [2 - (3,4dimethoxyphenyl) - ethylamino] - propan - 2 - ol.

41. 1 - [2 - (3,4 - Dimethoxyphenyl) - ethylamino] - 3 - (315 methoxypyridin - 2 - yloxy) - propan - 2 - ol.

42. 1 - [2 - (£ - Methoxyphenyl) - ethylamino] -3-(3methylpyridin - 2 - yloxy) - propan - 2 - ol.

43. 1- [2 - (3,4 - Methylenedioxyphenyl) - ethylamino] 3-(3- methylpyridin - 2 - yloxy) - propan - 2 - ol. 20

44. 1 - [2 - (3,4 - Methylenedioxyphenyl) - ethylamino] - 3(4 - methylpyridin - 2 - yloxy) - propan - 2 - ol.

45. 1 - [2 - (£ - Hydroxyphenyl) - ethylamino] - 3 - (3methylpyridin - 2 - yloxy) - propan - 2 - ol. 43692 - 54

46. 1 - [2 - Qo - Hydroxyphenyi) - ethylamino] - 3 - (4methylpyridin - 2 - yloxy) - propan - 2 - ol.

47. 1 - [2 - (3,4 - Dimethoxyphenyl) - ethylamino]. - 3(3 - methoxypyrazin - 2 - yloxy) - propan - 2 - ol. 5

48. I - [2 - (fi - Hydroxyphenyi) - ethylamino] - 3 - (3methoxy - pyridin - 2 - yloxy) - propan - 2 - ol.

49. 1 - [2 - (3 - Methoxy - 4 - hydroxyphenyi) - ethylamino]3 - (3 - methylpyridin - 2 - yloxy) - propan - 2 - ol.

50. A salt of a compound as claimed in any one of Claims 35 10 to 49.

51. An acid addition salt of a compound as claimed in any one of Claims 35 to 49,

52. A pharmaceutically tolerable acid addition salt of a compound as claimed in any one of claims 35 to 49. 15

53. A compound as claimed in Claim 35, or a salt thereof, whenever prepared by a process as claimed in any one of Claims 1 to 34.

54. A compound as claimed in Claim 53, whenever obtained by a process carried out substantially as described in any one 20 of the Examples herein.

55. A ptermaceutical preparation which comprises a compound aa claimed in any one of Claims 35 to 49 and 52 to 54 in admixture or conjunction with a pharmaceutically suitable carrier. 25

56. A pharmaceutical preparation as claimed in Claim 55, which is suitable for enteral administration.

57. A pharmaceutical preparation as claimed in Claim 56, which is suitable for oral administration. - 55

58. A pharmaceutical preparation as claimed in any one of Claims 55 to 57, which contains in the range of from 0.1% to 100% by weight of active substance.

59. A pharmaceutical preparation as claimed in Claim 58, 5 which contains in the range of from 1% to 50% by weight of active substance.

60. A pharmaceutical preparation as claimed in Claim 55, which is described in Example 19 herein.

61. A method of treating hypertonia, Angina pectoris and 10 other disturbances of the cardiac rhythm which comprises administering a compound as claimed in any one of Claims 35 to 49 and 52 to 54 or a pharmaceutical preparation as claimed in any one of Claims 55 to 60 to a non-human animal.