NO773125L - PROCEDURE FOR PREPARING 1-AMINO-2-HYDROXY-3-HETEROCYCLOXYPROPANE - Google Patents

Description

1-amino-2-hydroxy-3-heterocyclyloxy-propane.

The invention relates to 1-amino-2-hydroxy-3-heterocyclyloxy-propane with formula

in which.

Y means the group - CH = or the group - N = ,

R]_ means hydrogen, hydroxy, lower alkyl or

lower alkoxy,

F?2 means hydroxy, lower alkjks.v or the salmen with

o-lower alkylenedioxy or o-lower alkylenedioxy and

R-j means lower alkyl, lower alkoxy, halogen or cyano,

wherein the residues R-^, R2 and R^ are each bound to an arbitrary one of the possible aromatic carbon atoms,

or their salts, methods for their preparation as well as pharmaceutical preparations containing such compounds and their use.

The rest with formula

means the 2-pyridyl residue, in which the group R^ can be in the 3-, 4-, 5-, or 6-position, or the 2-pyrazinyl residue, in which the group R^ can be in the 3-, 5-, or 6-position.

Within the framework of the present description and claims, those with "lower" designated groups and compounds, unless otherwise defined, have up to 7 and primarily up to H carbon atoms.

Lower alkyl is e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, while lower alkeny1 e.g. means vinyl, allyl or methallyl and lower alkynyl e.g. ethynyl or propargyl.

Lower oxy is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy.

Halogen is primarily halogen with an atomic number up to 35, i.e. fluorine, chlorine or bromine.

o-lower alkylidenedioxy and o-lower alkylenedioxy each have 1 to 3 carbon atoms and are e.g. methylenedioxy or isopropylidenedioxy, while lower alkylenedioxy-, e.g.

is 1,2-ethylenedioxy.

Salts of compounds of formula I are primarily acid addition salts and in particular pharmaceutically acceptable, non-toxic acid addition salts with suitable inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with suitable organic ones, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, ^l-hydroxybenzoic acid, salicylic acid, phenylacetic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, L\-chlorobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylaminesulfonic acid and ascorbic acid. Due to the narrow relationship between the new compounds in free form and in the form of their salts, with the free compounds and with the salts possibly also

to understand the corresponding salts resp. free connections.

The invention relates in particular to compounds of formula I, wherein

R-^means hydrogen, hydroxy, lower alkyl or lower alkoxy with each up to ^ C atoms,

R2 means hydroxy, lower alkoxy with up to 4 C atoms and together with R-^o lower alkylidene dioxide with 1 to 2 C atoms and

R-, means lower alkyl or lower alkoxy with each time up to twenty C-atoms, halogen or cyano, R-^ and R^ each being in the 2-, 3- or ^-position and o-lower alkylidenedioxy is in the 2,3_ or 3 ,^-position, R^, in a pyridine ring is in the 3-, ty-, 5- or 6-position, or in a pyrazine ring in the 3-, 5- or 6-position and their' salts, especially their pharmaceutically acceptable ones, non-toxic acid addition salts.

The invention further particularly relates to compounds of formula

in which

R-[_ means hydrogen, hydroxy, methyl or methoxy,

R2 means hydroxy, methoxy or together with o-methylenedioxy and

R 1 means methyl, methoxy, chlorine or cyano, wherein

R-^ and R2 are each in the 3- or ^-position, o-methylenedioxy in the 3,4-position and R^ in the 3-position or ^-position,

as well as their salts, especially their pharmaceutically acceptable non-toxic acid addition salts.

The invention further particularly relates to compounds of formula

in which

R-^butyr is hydrogen, hydroxy, methyl or methoxy,

R 2 means hydroxy, methoxy or together with R 2 o-methylenedioxy and

Rj means methyl, methoxy, chlorine or cyano,

wherein Rj and R2 are each in the 3_ or ^-position, o-methylenedioxy in the 3,^-position and R^ in the 3-position,

as well as their salts, especially their pharmaceutically acceptable, non-toxic acid addition salts.

The invention relates in particular to the following compounds of formula I: 2~1_ 3' - (2 - ( 3, ^J-dimethoxyphenyl)-ethylamino )-2'-hydroxy-propoxy/- 3-cyanopyridine, 1-(3-chloropyrazine -2-yloxy)-~ b~ l_ 2-(3, ^-dimetoxyphenyl)-ethylamino/- 2-propanol, 1- /_ 2 - (3, ^-dimethoxyphenyl)-ethylamino/- 3-(3_methoxypyridine -2-yl-oxy)-2-propanolj2 - (p-methoxyphenyl)-ethylamino/-3~ ( 3-methylpyridin-2-yloxy )-2- propanol, 2 - ( 3, 4-methylenedioxy phenyl )-ethylamino /-3 - ( 3~methylpyridin-2-yloxy)-2-propanol, 2 - ( 3 , ty -methylenedioxy phenyl)-ethylamino/-3 - (^1-methylpyridin-2-yloxy)-2- propanol, 2-( p -hydroxy phenyl)-ethylamino/-3 - ( 3-methylpyridin-2-yloxy )-2-propanol, 1- _/ 2 - (p- hydroxy pheny 1) - ethylamino / - 3~ (^J-methylpyridin-2-yloxy)-2- propanol, l-_/ 2-(3,^-dimethoxyphenyl) - ethylamino / 3 - (3-methoxypyrazin-2-yloxy)-2-propanol , 1-/_ 2-(p-hydroxyphenyl)-ethylamino/-3-(3-methoxypyridin-2-yl-oxy)-2-propanol,

1- _/ 2 - (3-Methoxy-4-hydroxy phenyl)-ethylamino_7- 3~ (3-methylpyridin-2-yloxy)-2-propanol,

and their salts, especially their pharmaceutically acceptable non-toxic acid addition salts.

The new compounds have valuable pharmacological properties. Thus, they have particularly adrenergic beta-receptor-blocking effects which can be demonstrated as inhibition of isoproterenol tachycardia, e.g. on isolated guinea pig heart according to Langen-dorff. The concentrations required for a half-maximal inhibitory effect (EC^q) therefore amount to 0.0J - 0.^1 ug/ml. In addition, e.g. inhibits 2- 1_ 3 ' - ( 2-(3 , ^-dimethoxyphenyl )-ethylamino )-2 ' - hydroxy-propoxy/-3-cyanopyridine as neutral fumarate in anesthetized cat with perfused hind limb isopoterenol tachycardia clearly stronger (ED^ Q= 0.2 mg/kg i.v.) than isopro-terenol vasodilatation (ED^Q = 3 mg/kg i.v.). From this it appears that this compound belongs to the class of cardioselective beta-receptor blockers.

The new compounds also cause an inhibition of adrenergic alpha receptors, which can be detected e.g. as nor- adrenaline antagonism on isolated Vas deferens. The concentrations required for a pA2~value in this test system amount to 0, H - 7.6/UM at corresponding pA2~values of. 6.^0 - 5.12/UM.

The new compounds also have hypotensive properties, which e.g. can be shown by the long-term lowering of the arterial blood pressure in anesthetized cats at doses from 0.1 mg/kg i.v. Due to their properties, the new compounds can be used as beta-receptor blockers with additional alpha-receptor-blocking and hypotensive effects in the treatment of the indications known for beta-receptor blockers, e.g. hypertension, Angina pectoris or heart rhythm disturbances.

The new compounds according to the invention can be prepared in a manner known per se, e.g. since in a connection with formula

wherein Y and R^ have the above-mentioned meaning, R^ has the meaning of R-^ and furthermore means the group -0-X-^, R^ has the meaning of R^ and furthermore means the group - 0 - X^, wherein at least one of the groups X-p X2, X^ and Xjj mean a group replaceable by the hydrogen atom and the others mean hydrogen or a hydrogen-replaceable group, or X-^ and X2 together mean a cleavable by two with the oxygen atom corresponding to the secondary alcohol group resp. nitrogen atom connected hydrogen atom replaceable residue and/or X-j and Xi(together means a replaceable residue that can be split off by means of two hydrogen atoms connected to the oxygen atoms corresponding to the groups - 0 - X^resp. - 0 - X^, or in a salt thereof, the residue X-j is replaced, and/ or X2 or X-^ and X2 together and/or X^. and/or XI) and/or X-^ and X^ together with hydrogen, and if desired, a formed compound of formula I is transferred into another compound of formula I and/ or, if desired, a formed free compound is transferred into a salt or a formed salt into a free compound and /or, if desired, a formed stereoisomeric mixture is divided into the individual stereoisomers or a formed racemate in the optical antipodes.

The removal of the groups X1 and/or X2 and/or X^ and/or X^ is carried out by means of solvolysis or reduction. Thereby, in the aforementioned starting materials of formula II, X- is preferably a hydrogen-replaceable group, while X2, X^ and Xjj primarily mean hydrogen.

A particularly suitable, cleavable group X-^ is primarily a hydrogenolytically cleavable α-aryl lower alkyl group, such as an optionally substituted 1-phenyl lower alkyl group, in which the substituents, especially of the phenyl part can be e.g. lower alkyl, such as methyl or tert.-butyl, hydroxy, lower alkoxy, such as methoxy, halogen, e.g. chlorine or bromine and/or nitro and primarily benzyl. A group X-, can also mean a solvolytic, such as hydrolytic or acidolytic, further a reductive, including hydrogenolytic, cleavable residue, especially a corresponding acyl residue such as the acyl residue of an organic carboxylic acid, e.g. lower alkanoyl, such as acetyl or aroyl, such as benzoyl, further the acyl residue of.a half-ester of carboxylic acid,

as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halolower oxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacyclooxycarbonyl, or the acyl residue of an organic sulfonic acid, such as an aromatic sulfonic acid, primarily an optionally substituted phenyl-sulfonyl residue, in which the substituents e.g. has the meaning given for the above-mentioned 1-phenyl lower alkyl residue and especially 1-methyl-phenylsulfonyl, further an optionally substituted 1-polyphenyl lower alkyl group, in which the substituents in the first row of the phenyl part, e.g. has the above meaning and primarily means trityl.

A hydrogen-replaceable group X2, X^ or X^ is preferably likewise a hydrogenolytically cleavable group, such as one of the aforementioned, optionally substituted in 1-phenyl-lower-alkyl groups and primarily benzyl. They can move on too

be one of the solvolytically, including alcoholitically, or reductively cleavable acyl groups mentioned for the group X-^, further a polybranched, optionally substituted aliphatic or araliphatic hydrocarbon residue at the connecting carbon atom, such as tert.-lower alkyl, e.g. tert-butyl or trityl.

A cleavable residue formed by means of X-^ and X2 or X-z and X^ together is primarily again a hydrogenolytically cleavable group, as optionally substituted 1-phenyl-lower alkylidene, in which the substituents, especially of the phenyl part, e.g. can be lower alkyl, such as tert.-butyl, hydroxy, lower alkoxy, halogen and/or nitro and especially benzylidene, as well as solvolytically, especially hydrolytically cleavable groups, such as lower alkylidene, e.g. methylene or isopropylidene, or cycloalkylidene, e.g. the cyclohexylidene. A further, by means of the groups X]_ and X2 or X^ and X^ together formed residue is the diacyl residue of carboxylic acid or thiocarboxylic acid, i.e. carbonyl or the thiocarbonyl group.

Starting materials usable in the form of salts are primarily used in the form of acid addition salts, e.g. mineral acids, as well as organic acids.

Hydrogenolytically cleavable' residues X-^ and/or X2 and/or X^ and/or X^, especially optionally substituted 1-phenyl lower alkyl groups, further also suitable acyl groups such as optionally substituted 1-phenyl lower alkyl and with the help of the group Xi and X2 and/or X^ and X^ formed together, optionally substituted 1-phenyl lower alkylidene groups, can be split off by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a nickel catalyst, such as Raney nickel or a suitable noble metal catalyst.

Hydrolytically cleavable groups X-^ and/or X 2 and/or X^ and/or X^ such as acyl residues of organic carboxylic acids, e.g. lower alkano1 and half-esters of carboxylic acid, e.g. lower alkoxycarbony1, further e.g. trityl residues, as well as by means of the residues X_| and X2 and/or X^ and X; (lower alkylidene groups or carbonyl groups formed together can, depending on the type of such residues, be split off by treatment with water under acidic and/or basic conditions, e.g. in the presence of a mineral acid, such as hydrogen chloride - or sulfuric acid, or an alkali metal or alkaline earth metal hydroxide or carbonate.

Acidolytically cleavable residues are in particular certain acyl residues of carboxylic acid half-esters, such as e.g. tert.-lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl residues, further also tert.-lower alkyl residues X2, X-^ or X^; they can be cleaved by treatment with suitable strong organic carboxylic acids, such as optionally with halogen, especially fluorine, substituted lower alkane carboxylic acids, primarily with trifluoroacetic acid (if necessary, in the presence of an activating agent, such as anisole) and with formic acid.

Under reductively cleavable residues and/or X2 and/or X^ and/or X^ are also understood such groups which are cleaved off by treatment with a chemical reducing agent (especially with a reducing metal or a reducing metal compound. Such residues are especially 2-halogen- lower alkoxycarbonyl or aroylmethoxycarbonyl, which can, for example, be cleaved by treatment with a reducing heavy metal such as zinc, or with a reducing heavy metal salt, such as a chromium II salt, for example -chloride or -acetate, usually in the presence of an organic carboxylic acid such as formic acid or acetic acid or of water Reductively cleavable arylsulfonyl residues, especially those primarily meaning the residue X^, can, for example, by treatment with an alkali metal, e.g., lithium or sodium, in ammonia or by of electrolytic reduction is replaced by hydrogen. The above-mentioned reactions are carried out in a manner known per se, usually in the presence of a solvent or solvent mixture, with suitable reaction participants at the same time can also function as such and if necessary during - cooling or heating, e.g. in a temperature range from approx. -20°C to approx. +150°C, in an open or closed vessel and/or' in the atmosphere of an inert gas, e.g. nitrogen. The new compounds according to the invention may be similar ledes are obtained when a compound with formula

is reacted with a compound of formula

wherein one of the groups Xg and Xy represents a reactive esterified hydroxy group and the other represents the primary amino group and X^ represents the hydroxy group, or wherein X^ and Xg together represent the epoxy group and X^ represents the primary amino group and Y, R-^, R2

and R-j have the above-mentioned meanings, and if desired, the additional process steps are carried out.

A reactive esterified hydroxy group Xg resp. Xy is a hydroxy group esterified with a strong acid, especially a strong inorganic acid, such as a hydrohalic acid, especially chloro, bromic or hydroiodic acid, or sulfuric acid, or a strong organic acid, especially a strong organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid , e.g. methanesulfonic acid, ^-methylphenylsulfonic acid or<*>J-bromophenylsulfonic acid and is primarily halogen, e.g. chlorine, bromine or iodine, or aliphatic or aromatic substituted sulfonyloxy, e.g. methylsulfonyloxy or ty-methylphenylsulfonyloxy. The above-mentioned reaction is carried out in a manner known per se, particularly when using a starting material with a reactive esterified hydroxy group, preferably working in the presence of a basic agent, such as an inorganic base, e.g. an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent, such as an alkali metal low-alkanolate and/or an excess of the basic reactant and usually in the presence of a solvent, or solvent mixture, and if necessary , during cooling or heating, e.g. in a temperature range from approx. -20°C to approx. +150°C, in an open or closed vessel and/or in an inert gas atmosphere, e.g. in a nitrogen atmosphere. The new compounds can also be obtained, since in a compound with formula; wherein the group -Xg- (Va) means one of the residues of the formulas ; the thioxo group, Y, R]_, R2°g X-^ has the above-mentioned meaning and R-^ has the indicated meaning with the exception of halogen and cyano, the group - Xg - is reduced, possibly above the intermediate step, containing the residue - CH2- N - CH2- CH2 - to the residue with formula - CH~2 - NH - CH2- CH2- and, if desired, the additional process steps are carried out. ;The reductive transfer of a residue with formula;- Xg - (Va) into the desired grouping with formula - CH2- NH -;CH2- CH2- can be carried out in a manner known per se, as the choice of a suitable reducing agent depends on the type of the group of formula Va. Particularly suitable for the reduction of groups of formula (Vb) and (Vc) as well as of groups of formula (Vd) and (Ve), in which the residues of formula -C( = Xg)-N-CH2-CH2- resp. ;<X>l;-CH2~N-C(=X^)-CH2- contain a carbamoyl group, are light- ;metal hydride reducing agents, such as alkali metal aluminum hydrides, e.g. lithium aluminum hydride (which is particularly suitable for the reduction of carbamoyl groups), or alkali metal borohydrides, e.g. sodium borohydride, as well as alkali metal cyanoborohydrides, e.g. sodium cyanoborohydride, or borohydrides, e.g. diborane, (which primarily serves to reduce alkylidene amino groups). Furthermore, groupings with formula (Vd) and (Vc) can be transferred, and possibly simultaneously the hydrogenolytic cleavage of a hydrogen-replaceable residue X-^ by means of hydrogenolysis by treatment with catalytically activated hydrogen, which e.g. with hydrogen in the presence of a heavy metal catalyst, e.g. Raney nickel, platinum oxide or palladium. Groupings of formula (Vd) and (Ve), in which Xg each time means a thiono group and optionally contains a hydrogenolytically cleavable residue X-^ are converted by reductive desulphurisation, e.g. by treatment with a hydrogenation catalyst such as Raney nickel to the grouping with the formula CH2- NH - CH2- CH2~. The above-mentioned reduction reactions are carried out in a manner known per se, usually in the presence of an inert solvent and if necessary during cooling or heating, e.g. in a temperature range from approx. ^20°C to approx. +150°C and/or in a closed vessel under pressure and/or in an inert gas, e.g. nitrogen atmosphere. In the compounds formed, within the framework of the definition of the compounds of formula I, compounds formed according to the method can be transferred in the usual way to other end substances, e.g. by exchanging one suitable substituent for another or introducing a substituent. Thus, in a compound of formula I, in which FU means halogen, which e.g. chlorine, exchanges this by reaction with a to the meaning of R-j as lower alkoxy corresponding to lower alkanol for lower alkoxy. Appropriately, a basic condensation agent such as e.g. an alkali hydroxide, such as sodium or potassium hydroxide or an alkali-lower-alkanolate corresponding to the meaning of the lower alkali coke residue to be introduced, e.g. sodium or potassium methoxide, sodium or potassium ethoxide. Furthermore, in a compound of formula I, in which R 1 and/or R 2 is hydroxy, such hydroxy groups can be converted into the corresponding lower alkoxy groups or a lower alkylene dioxy group. This takes place e.g. by reacting a compound containing a hydroxy group of formula I with a reactive derivative of a lower alkanol corresponding to the meaning of R 2 as lower alkoxy, whose hydroxy group is esterified as indicated above by the groups Xg or ;Xy. As such, there are e.g. considering the corresponding lower alkyl halides, e.g. chloride or bromide. This is preferably done in the presence of a basic agent, such as an inorganic base, e.g. an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent such as an alkali metal laver alkanolate. Appropriately, one can transfer such a hydroxy group-containing compound of formula I in the usual way to a salt, e.g. an alkali metal salt, e.g. a sodium salt, for example by reacting with sodium methoxide and subjecting the salt thus formed to the reaction, e.g. with a lower alkyl bromide, e.g. methyl or ethyl bromide. Usually, a solvent or a solvent mixture is used for this purpose, e.g. a polar solvent, such as a lower alkanol e.g. ethanol, or a fatty acid amide, e.g. dimethylformamide or N-methylacetamide or M,N-dimethylacetamide, or an amide of phosphoric acid, e.g. hexamethylphosphoric acid triamide or sulfolane or mixtures of such solvents. The turnover is carried out in an area from approx. +10 to approx. +160°C; in an open or closed vessel, possibly in an inert gas atmosphere, e.g. under nitrogen. As reactive derivatives of a lower alkanol, the corresponding diazoalkanes also come into consideration, e.g. diazomethane or diazoethane. Their reaction with a compound of formula I containing a hydroxy group is carried out in an organic solvent, e.g. an ether, such as diethyl ether or a chlorohydrocarbon, e.g. methylene chloride. In this way, you work appropriately in a temperature range from approx. -20°C to +50°C, possibly under a protective gas, e.g. nitrogen. Depending on process conditions and starting materials, the new compounds are obtained in free form or in the form of their salts, which is also covered by the invention, since the new compounds or salts thereof can also be present as hemi-, mono-, sesqui- or polyhysrirates thereof. Acid addition salts of the new compounds can in a manner known per se, e.g. when treated with basic agents, such as alkali metal hydroxides, carbonates or hydrogen carbonates or ion exchangers are transferred in the free compounds. On the other hand, free bases formed with organic or inorganic acids, e.g. with the aforementioned acids to form acid addition salts, in particular for their preparation such acids are used which are suitable for the formation of pharmaceutically acceptable salts. These or other salts, especially the acid addition salts of the new compounds, such as e.g. the picrates or perchlorates can also serve to purify the free bases formed, as one transfers the free bases into the salts, separates and purifies them, and frees the bases again from the salts. Depending on the choice of starting materials and working methods, the new compounds can exist as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms, also as racemate mixtures. The starting materials can also be used as optical antipodes. Due to the physico-chemical differences of the diastereoisomers, racemate mixtures formed can in a known manner, e.g. by chromatography and/or fractional crystallization are divided into the two stereoisomeric (diastereomeric) racemates. Formed racemates can be divided into the antipodes according to methods known per se -, e.g. by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance, which with the racemic compound forms salts, especially acids and splitting the salt mixture formed in this way, e.g. due to different solubilities in the diastereomeric salts, of which the free antipodes can be liberated by the action of suitable agents. Particularly common optically active acids are e.g. The D and L form of tartaric acid, di-o-toluyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Preferably, the most effective of the two antipodes is isolated. The invention also relates to the embodiments of the method, according to which one starts from one or other step of the method as an intermediate formed compound and carries out the missing method steps, or interrupts the method at one or the other step, or where a starting substance is formed under the reaction conditions , or where a reaction component is possibly present in the form of their salts. Appropriately, for carrying out the reaction according to the invention, such starting substances are used, which lead to the groups of end substances mentioned at the outset, and in particular to the end substances specifically mentioned or highlighted. The starting materials are known and, if they are new, can be produced according to known methods. Thus, compounds of formula II can be prepared, e.g. by reacting a compound of formula ;Y ;Vr3 VI k N>-OH ;or a salt thereof, in which Y and R3 have the above meaning, with a compound of formula D ;Fli ; ; wherein X-^ has the above meaning and X° means the group X2, with at least one of the groups X-^ and X° being different from hydrogen and Xjq means hydroxy or a reactive esterified hydroxy group or X^ and X-^g together means a carbon -oxygen bond, or in which X-^ and X° together mean a cleavable residue, which is replaceable by two, with oxygen- or nitrogen atoms connected; hydrogen atoms and X-^q means a reactive esterified hydroxy group or analogously one of the above-mentioned method modifications when treating a compound of formula; with a compound of formula ;R i. ; in which X2 has the meaning given above for X2 and one of the groups Xg and X° means a reactive esterified hydroxy group and the other means the group with formula - NHCX-^), in which X^ has the above-mentioned meaning, with the precaution that at least one of the groups X- ^and X2 are different from hydrogen, or in which X2 and X<g>form an oxygen-carbon bond and X° means the group of formula - NH(X^) and X-j, is different from hydrogen. The above-mentioned reactions are carried out in a manner known per se, e.g. as discussed above. Starting substances with formula VIII, in which Y means the group - N =, can e.g. is obtained by reacting a compound of the above-mentioned formula VI or a salt thereof with a compound of formula ; in which X^^means a reactive esterified hydroxy group and, if desired, by splitting the epoxyethyl group in the product formed in a 2-amino-1-hydroxyethyl- resp. 2-reactive esterified hydroxy-1-hydroxy-ethyl group. The reactions can be carried out in a manner known per se. Starting substances with formula VIII, in which Y means the group - CH = can e.g. a compound of formula ; wherein X12 means a suitable leaving group, such as halogen, e.g. chlorine or bromine, nitro or lower alkylsulfonyl, is reacted with 2,2-dimethyl-5-hydroxymethyl-1,3-dioxolane, the compound formed is reacted by means of hydrolysis, e.g. by means of aqueous acids, such as dilute hydrochloric acid to the corresponding 1,2-propanediol derivative, this is transferred by treatment with orthoacetic acid triethyl ester into the corresponding R-^-substituted 2-ethoxy-5-(2-pyridyloxymethyl)-2-methyl -1,3-dioxolane, this is transferred by treatment with trichlorosilane in a chlorohydrocarbon, e.g. dichloromethane, to the corresponding R-^-substituted 2-(2-acetyloxy-3-chloro-propyloxy)-pyridine and. this is converted using a suitable base, e.g. tetrabutylammonium hydrogen sulphate in alkaline solution, e.g. in the presence of sodium hydroxide and a chlorohydrocarbon, such as methylene chloride in combination with formula VIII, in which X^ and Xg represent an oxygen-carbon bond. These sales are carried out in the usual way. Compounds with formula VII again can e.g. is obtained in a manner known per se by reacting a compound of formula with a compound of formula; in which for XI, X° and X^q the specified precautions and meanings apply and X° and Xg mean an oxygen-carbon bond. Starting substances with formula V can be obtained by reacting amino compounds with formula ; in which the hydroxy group may optionally be present in protected, e.g. in esterified or suitably etherified form with oxo compounds of formula or with carboxylic acid compounds of formula or their reactive derivatives, such as the halides e.g. the chlorides, resp. of amino compounds of formula with oxo compounds of formula in which the group -CHO may optionally be present in a suitable etherified form, or with carboxylic acid compounds of formula; in which the hydroxy group may optionally be present in protected, e.g. in esterified or suitable etherified form. In an intermediate with a protected hydroxy group, this is transferred in its free form. The above-mentioned reactions are carried out in a manner known per se. The new connections can e.g. find application; in the form of pharmaceutical preparations, which contain a pharmacologically effective amount of the active substance, possibly together with pharmaceutically usable carriers, which are suitable for enteral administration, e.g. oral or parenteral administration and may be inorganic or organic, solid or liquid. Thus, tablets or gelatin capsules are used, which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol and/or lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Tablets may also contain binders, e.g. magnesium aluminum silicate, starch, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone and, if desired, explosives, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate and/or effervescent mixtures or adsorbents, colourants, preservatives and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, as these e.g. in the case of lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations which, if desired, can contain further pharmacologically active substances are prepared in a manner known per se, e.g. by means of usual mixing, granulating, coating, dissolving or lyophilization methods and contains from approx. 0.1 to 100$, especially from approx. 1% to approx. 50%, lyophilisates up to 100% of the active substance. The dosage may depend on various factors, such as means of application, type, age and/or individual condition. Thus, the daily administrable dose for oral application to warm-blooded animals is between approx. 0.04 g and approx. 2.0 g and for warm-blooded animals with a weight of approx. 70 kg preferably between approx. 0.1 g and 1.0 g. The invention will be explained in more detail with the help of some examples. Example 1. A solution of 75 g of crude 2-/"3'-(2-(3,^-dimethoxyphenyl)-ethyl)-2'-phenyl-oxazolidinyl-(5'_)7-methoxy-3-cyanopyridine in 200 ml of ethanol is mixed with 100 ml of 2 N hydrochloric acid and the solution is allowed to stand for 2-3 hours at 20 - 30° C. The reaction mixture is then evaporated, distributed between 200 ml of ethyl acetate and 300 ml of water, the water phase is clarified with activated carbon, filtered and made alkaline with 2 N caustic soda. The separated oil is extracted with ethyl acetate. The crude product formed by evaporation is dissolved in 1.5 liters of dichloromethane and stirred for \ hour with 300 g of an adsorbent based on magnesium silicate. The mixture is then treated with activated carbon, filtered and the filtrate evaporated, after which crude 2-[3'- (2-;(3,4-dimethoxyphenyl)-ethylamino)-2'-hydroxy-propoxy/-3-cyanopyridine is obtained, which is dissolved in 25 ml of methanol and mixed with a hot solution of 3.0 g of fumaric acid in 20 ml of methanol. On cooling, the neutral fumarate crystallizes in colorless crystals that melt at 160 - 161°C. ;Starting material fat can be produced on. the following way:;a) A mixture of 90.6 g of homoveratrylamine, 75 g of glycerol glycide and 250 ml of isopropanol is kept for 2H hours at an internal temperature of 50°C. By evaporation, a mixture is obtained, which to 75% consists of J>-/_ 2-( 3 , ^-dirnet oxyphenyl)-ethylamine T"-1,2-propanediol and can be further used raw. b) 170 g of the crude product formed is heated together with 80 ml of benzaldehyde, 500 ml of toluene and 1 ml of glacial acetic acid for 7 hours under a water separator under reflux. The solution is then washed once with 100 ml of 1 N caustic soda and twice with each time 100 ml of water, dried over magnesium sulfate and is evaporated. From the evaporation residue, the excess benzaldehyde is separated by distillation under reduced pressure (12 torr). The distillation residue, which cannot be distilled unsplit, consists predominantly of ~ b- 1_ 2-(3,^-dimethoxyphenyl)-ethyl/-5-hydroxymethyl-2- phenyloxazolidine, which is further used as a crude product. c) 56 g of crude 3-/<_>2-(3,<i>J-dimethoxyphenyl)-ethyl7-5-hydroxymethyl-2-phenyl-oxazolidine is reacted in 250 ml of 1,2- dimethoxyethane with 5.7 g of sodium hydride dispersion (55%-ig) and then stirred for 2 hours at ^0° C. After addition of l6, H g of 2-chloro-3-cyano-pyridine vi the reaction mixture is stirred for 2 hours at 0-50°C, filtered over a filter aid based on diatomaceous earth and the filtrate is evaporated. The evaporation residue is divided 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 evaporated, after which crude 2-l_ 3 ' _ ( 2- ( 3, ^-dimethoxy- phenyl)-ethyl 1)-2'-phenyl-oxazolidinyl-(5'2/_thiethoxy-3-cyanopyridine. ;E xample 2. ;A mixture of 9.3 g of 2-chloro-3-(2,3 -epoxy-propoxy)-pyrazine and 9.0 g of 2-(3,'1-dimethoxyphenyl)-ethylamine in 100 ml of isopropanol are stirred for 18 hours at 20 - 30°C, after which the solvent is evaporated, the evaporation residue is dissolved in 50 ml of 2 N hydrochloric acid and the solutions are extracted with 50 ml of ether. The hydrochloric acid phase is separated and made 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 after each extraction, after which an oil is finally obtained which eventually crystallizes. The thus formed crude 1-(3~chloro-pyrazin-2-yloxy)-3-_/~2-(3,^-dimethoxypheny 1)-ethyl-amino /- 2- propane l melts at 62 - 70°C. It forms a hydrochloride which, after recrystallization from methanol, melts at 18° - 187°C. Example 3 A solution of 932 g of 2-(2,3-epoxy-propoxy)-3-methoxy-pyridine and 9.0 g of 2-(3,'-1-dimethoxy-phenyl 1 )- ethylamine in 100 ml of isopropanol is stirred for 6 hours at room temperature. Workup analogous to example 2 yields 7.5 g of crude base, which is chromatographed as a solution in ethyl acetate over a column of 300 g of silica gel. After washing with ethyl acetate, the by-products are eluted. By elution with from 1-5% increasing amounts of ethanol-containing ethyl acetate and finally with an ethyl acetate-ethanol mixture ^:1, one obtains 1-/~2-(3,4-dimethoxyphenyl)-ethylamino?-3~ (3- methoxy-pyridin-2-yloxy)-2-propanol, which after evaporation of the solvent forms a yellow oil, whose acid oxalate after recrystallization from methanol-acetone melts at 132 - 13<i>1°C. ;The starting material can be prepared as follows:';a) A mixture of 161 g of 3-methoxy-2-nitro-pyridine and 100 g of 2,2-dimethyl-5-hydroxymethyl-1,3-dioxolane in 1000 ml of hexamethylphosphoric acid triamide is mixed with stirring during of one hour with 26.5 g of sodium hydride; upon cooling, the temperature during the addition is kept at 0 - 10°C. The reaction mixture is stirred for a further 5 hours under ice cooling and then 15 hours at room temperature. The reaction mixture is poured onto ice and extracted with diethyl ether. The organic extract is washed with a concentrated aqueous sodium chloride solution, dried and evaporated. The residue is dissolved in 1000 ml of ethanol, mixed with 100 ml of 2 N hydrochloric acid and allowed to stand for 8 hours. After the solvent has evaporated, the residue is made alkaline with a concentrated solution of sodium hydroxide in water and extracted with acetic acid ethyl ester. When the solvent is evaporated, a crude product is obtained where, after addition of diethyl ether, the crystalline 3~(3-methoxy-2-pyridyloxy)-1,2-propanediol is obtained, which melts at 62 - 65°C. b) A solution of 62 g of 3-(3_methoxy-2-pyridyloxy)-1,2-propanediol in 350 ml of orthoacetic acid triethyl ester is mixed with 2 drops of trifluoroacetic acid and allowed to stand for 3 hours at 20 - 30°C. Evaporation gives the crude 2-ethoxy-5-(3-methoxy-2-pyridy1-oxymethyl)-2-methyl-1,3-dioxolane as an oil, which is used without further purification. ;c) A mixture of 85 g of 2-ethoxy-5-(3_methoxy-2-pyridyloxymethyl)-2-methyl-1,3-dioxolane in 500 ml of dichloromethane; is mixed with 5 ml of trimethylchlorosilane and stirred for one hour at 20 - 30°C. By complete evaporation and under reduced pressure, the crude 2-(2-acetyloxy-3_chloro-propyloxy)-3-methoxy-pyridine is obtained as an oil, which is used without purification. ;d) A mixture of 80 g of 2-(2-acetyloxy-3-chloro-propoxy)-3-methoxy-pyridine, 900 ml of methylene chloride, 500 ml of ;a 2 N aqueous sodium hydroxide solution and 9.5 g of tetrabutyl ammonium hydrogen sulfate is stirred vigorous for 16 hours at 20-30°C. The organic phase is then separated and evaporated. The remaining oil is dissolved in diethyl ether, the solution is filtered, treated with activated carbon and evaporated, after which 2-(2,3-epoxy-propyloxy)-3-methoxypyridine is obtained, which melts at 63 - 65°C. E xample ty . ;A mixture of 9.1 g of 1-amino-3-(3-niethyl-pyridin-2-yloxy)-2-propanol, 10.8 g of 2-(p-methoxy-phenyl)-ethyl bromide, ;10 g of potassium carbonate and 100 ml of absolute ethanol are boiled for 20 hours with stirring and reflux. The reaction mixture is filtered after cooling, evaporated in vacuo and the evaporation residue dissolved in 200 ml of ethyl acetate. The solution is washed once with 50 ml of water and then extracted with 1 N acetic acid. From the acetic acid aqueous solution, the base is liberated with concentrated caustic soda, this is extracted with ethyl acetate and the solvent is completely evaporated, after which crude 2-(p-methoxy-phenyl)-ethylamino7-3-(3-methyl-pyridin-2-yloxy) is obtained )-2-propanol as eventually crystallizing oil, which after recrystallization from isopropanol melts at 80 - 81°C. Example 5 A solution of 6.65 g of 1-amino-3-(3-methyl-pyridin-2-yloxy)-2-propanol in 100 ml of methanol is neutralized with an approx. ;ty N solution of hydrogen chloride in methanol and stirred after adding 5.0 g of 3,4-methylenedioxy-phenylacetaldehyde and 2.0 g of sodium cyanoborohydride for approx. 30 hours at 20 - 30°C. The reaction mixture is evaporated in vacuo and the residue is distributed between 100 ml of 2 N hydrochloric acid and 50 ml of ethyl acetate. The hydrochloric acid phase is made alkaline with concentrated caustic soda, after which crude 1-_/~2-(3, [1-methylenedioxy-phenyl 1)-ethylamino?- 3~ (3-methyl 1-pyridin-2-yloxy) is obtained -2-propanol, whose hydrochloride after recrystallization from isopropanol ether melts at 123 - 125°C. Example 6. A solution of 8.4 g of crude 1-f~N-benzyl-N-_/ 2-( 3 , ty-tue tylendioxy-phenyl)-ethyl _1/-amino/-3- ( 4-methyl-pyridin-2-yloxy)-2-propanol in 100 ml of methanol is hydrogenated with the addition of 1 g of palladium-on-charcoal catalyst (5%) under normal conditions until the calculated amount of hydrogen is taken up. By filtering off the catalyst and evaporating the solvent, crude 1-[2-(3,4-methylenedioxyphenyl)-ethylamino7-3-(4-methyl-pyridin-2-yloxy)-2-propanol is obtained as a crystalline compound, which after recrystallization from isopropanol melts at 80 - 81°C. ;The starting material is obtained in the following way:;a) Glyceringlyeide and benzylamine are converted in a known manner to 3-benzylamino-1,2-propanediol (boiling point l60 - 170°C/ ;0.01 torr.;b) 3-benzylamino-1, 2-propanediol is transferred with benzaldehyde by azeotropic distillation with benzene in a known manner to 3-benzyl-5-hydroxymethyl-2-phenyl-oxazolidine, boiling point 168-171°C/0.005 torr. ;c) From 134 g of this compound, 50.9 g of 2-chloro-4-methyl-pyridine and 1931 g of sodium hydride dispersion, 1-benzylamino-3-(4-methyl-pyridin-2-yloxy) is prepared in the usual way )-2-propanol, which after recrystallization from cyclohexane melts at 70 - 71°C. ;d) A solution of 10.9 g of 1-benzylamino-3-(4-methyl-pyridin-2-yloxy)-2-propanol and 7.0 g of triethylamine in 50 ml of chloroform is formed while stirring with a solution of 9>6 g of 3,4-methylenedioxy-phenylacetyl chloride in 50 ml of chloroform dropwise and the reaction mixture is stirred for 2 hours. The reaction solution is washed each time with 20 ml of 2 N hydrochloric acid, then with 2 N caustic soda and finally with water, dried over sodium sulfate and the solvent is evaporated, after which an oil is obtained in the form of N-benzyl-N- /_ 2-hydroxy-3 - (4-methyl-pyridin-2-yloxy)-propyl/-(3,4-methylenedioxyphenyl)-acetamide, which is further used without further purification. e) A solution of 12 g of the compound formed in 50 ml of 1,2-dimethoxyethane is added dropwise under ice-cooling and stirring to a suspension of 2.0 g of lithium aluminum hydride in 100 ml of 1,2-dimethoxyethane. The reaction mixture is then stirred for 3 hours at an internal temperature of 48 - 55°C and split under ice-cooling with 10 ml of water. The organic phase is separated, evaporated in a vacuum and dissolved in approx. 200 ml ethyl acetate. The solution is extracted with 50 ml of 2 N hydrochloric acid, the acidic, aqueous phase is separated and the base is liberated with concentrated caustic soda. By extracting with ethyl acetate and evaporating the solvent, N-benzyl 1-N-_/ 2-(3,4-methylenedioxy-phenyl)-ethyl_1/-amino/-3-(4-methyl-pyridine-2 -yloxy) - 2-propanol as oil, which is further processed as such. Example 1. A solution of 8 g of crude M-(2-hydroxy-3-(3-methylpyridin-2-yloxy)-propyl)-(3,4-methylene-dioxy-phenyl)-acetamide in 100 ml of tetrahydrofuran is mixed under ice-cooling with 100 ml of a 1 molar solution of diborane in tetrahydrofuran and allowed to stand for 5 hours at room temperature. The solution is then evaporated, mixed with 100 ml of 2 N hydrochloric acid and allowed to stand for approx. 1 hour. The solution is extracted with 50 ml of ether, the acidic, aqueous phase is separated and made alkaline with concentrated caustic soda. Extraction with ethyl acetate and evaporation of the solvent gives crude !-_/ 2-(3, '4-methylenedioxyphenyl-ethylamino/ 3-(3-methylpyridin-2-yloxy)-2-propanol as an oil, the hydrochloride of which after recrystallization from methanol-ether melts at 123-125° C. The starting material is obtained analogously to example 6b) from: 10 g (3,4-methylenedioxyphenyl)-acetyl chloride, 8.2 g 1-amino-3-(3-methyl- pyridin-2-yloxy)-2-propanol and 6.1 g of triethylamine as an oily product. Example 8. A mixture of 8.8 g of 3-cyano-2-(2,3-epoxy-propoxy)-pyridine and 9.0 g of 2-(3,4-dimethoxy-phenyl)-ethylamine in 100 ml of isopropanol stirred for 18 hours at room temperature. Workup analogous to example 2 gives the crude 3_cyan-2-/_ 3~(2-(3,4-dimethoxy-phenyl)-ethyl)-2-hydroxy-propoxy/-pyridine, whose neutral fumarate after recrystallization from methanol melts at 160 - 161°C. ;The starting material required 3-cyano-2-(2,3-epoxy-propoxy)-pyridine is prepared analogously to examples ;3a) - 3d) using 2-chloro-3-cyano-pyridine, obtaining the following crystalline intermediate products: ;a) 5"/.(3_cyan-pyridin-2-yloxy)-methoxy/-2,2-dimethyl-1,3-dioxolane, which after recrystallization from ether-petroleum ether melts at 68 - 71°C ; b) 3-cyano-2-(2,3-epoxy-propoxy.)-pyridine, which after recrystallization from ether melts at 55 - 58° C. ;Example 9-;A solution of 23 g of crude l-/ _ N-benzyl-N-_/ 2-(p-benzyloxy phenyl)-ethyl _1/-amino7- 3~ (3-methyl-pyridin-2-yloxy) - 2-propanol in 300 ml of methanol is hydrogenated analogously example 6 to take up 2 mole equivalents of hydrogen and work up, after which one obtains 1-_/ 2-(p-hydroxypheny 1)-ethylamino/-3-( 3-methylpyridin-2-yloxy)-2-propanol, if neutral fumarate after recrystallization from isopropanol melts at 182 - 183° C. The starting material is obtained as follows: a) A solution of 13.6 g of 1-benzylamino-3-(3-methyl-pyridine) -2-yloxy)-2-propanol, which melts at 77-82°C and 7.6 g of triethylamine in 150 ml of chloroform are mixed over 10 minutes with a solution of 16.0 g of (p-benzyloxyphenyl) -acetyl chloride in 100 ml of chloroform, the temperature increasing to 40°C. The reaction mixture is stirred for another 2 hours and then worked up analogously to example 6b), after which the crude N-benzyl-N-1_2-;hydroxy-3~(3-methyl-pyridin-2-yloxy)-<p>ropyl/ -(p-benzyloxy-phenyl)-acetamide as a brown oil, which is further processed without further purification. ;b) 24 g of the compound formed is dissolved in 200 ml of tetrahydrofuran, mixed under ice-cooling with 150 ml of a 1 molar solution of diborane in tetrahydrofuran and the mixture is allowed to stand for 24 hours at room temperature. Preparation analogous to example 6c) gives crude N-benzyl-N-[2-(p-benzyl-oxyphenyl)-ethyl]-amino[-3-(3-methyl-pyridin-2-yl-oxy)-2-propanol ^ølTT^b^Lui^t^yktf ly tened oil, which is further processed without further reirsing. Example 10. 22 g of crude 1-[N-benzyl-N-[2-(p-benzyloxy-phenyl)-ethyl]-amino]-3-(4-methyl-pyridine-2 -yloxy)-2-propanol is debenzylated analogously to example 9 to !-_/_ 2-(p-hydroxyphenyl)-ethylamino/-3-(4-methyl-pyridin-2-yloxy)-2-propanol, which after recrystallization from isopropanol melts at 104 - 105°C. The starting material is prepared analogously to examples 9a - b from 1-benzylamino-3-(4-methyl-pyridin-2-yloxy)-2-propanol. ;Example 11. ;Analogous to example 1, using 48 g of crude 2-/<_>3,-(2-(3,4-dimethoxy-phenyl)-ethyl)-2'-phenyloxa-zolidinyl-(5 ' )-methoxy/-3~ ( 3-methoxy-pyrazine get 2-(3,4-dimetoxyphenyl)-ethylamino/-3-(3-methoxy-pyrazin-2-yloxy)-2-propanol, whose hydrochloride melts at 167-170° C. The starting material is prepared analogously to example lc) using 17.1 g of 2-chloro-3-methoxy-pyrazine, obtaining crude, oily 2-/~3'-2-(3,4-dimethoxy -phenyl)-ethyl)-2'-phenyl-oxazolidinyl-(5')-methoxy/-3-methoxy-pyrazine. Example 12. Analogous to example 1, using 52 g of crude 2-chloro-3-[3*-(2-(3,4-dimethoxy-phenyl)-ethyl)-2'-phenyl-oxazolidinyl -(5')-methoxy/-pyrazine get 1-(3-chloropyrazin-2-yloxy) ~ 3-/_ 2 - ( 3 , 4 -di ime toc sy-phenyl)-ethylamino/-2-propanol, whose hydrochloride melts at 183~l87°C.

The starting material is prepared analogously to example 1c) using 17.6 g of 2,3-dichloropyrazine. The thus formed 2-chloro-3-[3'-(2-(3,4-dimethoxy-phenyl)-ethyl)-2'-phenyl-oxazolidinyl-(5')-methoxy]-pyrazine is further processed crudely.

Example 15.

A solution of 4.5 g of sodium methoxide and 9.0 g of crude 1-(3-chloro-pyrazin-2-yloxy)-3-/. 2-(3, 4-dimethoxyphenyl)-ethylamino/-2-propanol in 200 ml of methanol is boiled for 5 hours under reflux. After filtering and evaporating the solvent, crude 1-/_ 2-(3,4-dimethoxyphenyl)-ethylamino/- 3-(3-inethoxy-pyrazin-2-yloxy)-2-propanol is obtained as a yellow oil, if hydrochloride after recrystallization from methanol melts at 167 - 170°C.

Example 14.

A solution of 13 g of crude N-/_ 2-hydroxy-3-(3-methylpyridin-2-yloxy)-propyl/-(p-hydroxy-phenyl)-acetamide 1,200 ml of tetrahydrofuran is mixed dropwise under ice-cooling at 5-10 °C with 250 ml of a 1 molar solution of diborane in tetrahydrofuran and stirred for 20 hours at room temperature. After the solvent has evaporated, the residue is carefully mixed with 100 ml of 2 N hydrochloric acid and stirred for 1 hour. The separated crystals are filtered off and the solution is extracted with 50 ml of ether. The aqueous phase is then brought to pH 8 - 9 with solid sodium carbonate and extracted twice with 100 ml of ethyl acetate each time. Evaporation of the organic phase gives crude 1- / 2-(p-hydroxyphenyl)-ethylamino/-3_(3-methyl-pyridin-2-yl-oxy)-2-propanol as a yellowish oil, whose neutral fumarate after recrystallization from isopropanol melts at 182 - 183°C.

Starting substances are produced in the following way:

To a solution of 7.6 g of p-hydroxyphenylacetic acid and 6.6 g of triethylamine in 200 ml of dioxane, while cooling and stirring at 0-5°C, a solution of 7.23 g of trimethylacetyl chloride in 100 ml of dichloromethane is added dropwise . The colorless suspension is stirred for 4 hours at 0-5°C and then at this temperature a solution of 8.2 g of 1-amino-3-(3-methyl-pyridin-2-yloxy)-2-propanol in 50 ml of dioxane is added dropwise . The suspension is stirred for 2 hours at 0-5°C and then 15 hours at room temperature. After the solvent has evaporated in vacuo, the residue is distributed between 200 ml of ethyl acetate and 100 ml of water, the organic phase is extracted twice with each time 200 ml of 1 N hydrochloric acid, the acidic extracts are combined and brought to a pH of approx. 8. The precipitated oil is extracted with dichloromethane. After evaporation of the dichloromethane, crude N-(2-hydroxy-3-(3-methyl-pyridin-2-yloxy)-propyl-(p-hydroxyphenyl)-acetamide is obtained as light yellow viscous oil which is used without further purification.

Example 15.

Analogous to the procedure mentioned in example 2

by using 356 g of 2-(2,3-epoxypropoxy)-3-methoxy-pyridine and 2.5 g of p-hydroxyphenethylamine, 2-(p-hydroxyphenyl)-ethylamino/-3-(3-methoxy-pyridine) -2-yloxy)-2-propanol, whose - neutral fumarate after recrystallization from methanol-acetone melts at 175-176°C.

Example 16.

A solution of 7.3 g l-/. 2-(p-benzyloxy-phenyl)-ethylamino/-3~(3-methoxy-pyridin-2-yloxy)-2-propanol in 100 ml of ethanol is hydrated in the presence of 1.5 g of palladium-on-charcoal catalyst ( 5%) to uptake of 1 mole equivalent of hydrogen at atmospheric pressure. After filtration from the catalyst and evaporation of the filtrate, 2-(p-hydroxyphenyl)-ethylamino/-3-(3-methoxy-pyridin-2-yloxy)-2-propanol is obtained, whose neutral fumarate after recrystallization from methanol-acetone melts at 175 - 176°C.

The starting substance is obtained by reacting 5.4 g of 2-(2,3-epoxy-propoxy)-3-methoxy-pyridine and 6.5 g of (p-benzyl-oxy-phenyl)-ethylamine in 150 ml of isopropanol analogous example 2; after recrystallization from dichloromethane ether melts at 85-86°C.

Example 17.

A mixture of 400 mg of 2-(p-hydroxyphenylmethyl bromide, 500 mg of 1-amino-3-(3~methyl-pyridin-2-yloxy)-2-propa-

nol and 200 mg of potassium bicarbonate are stirred in 10 ml of isopropanol for 5 hours under reflux. Preparation analogous to example 4

gives the oily l-_/ 2-(p-hydroxyphenyl)-ethyl lamino/-3~ ( 3-methyl-pyridin-2-yloxy)-2-propanol, whose neutral fumarate after recrystallization from isopropanol melts at 182 - 183 °C. Example 18.

A solution of 14 g of crude 1-_/N-benzyl-N-_ 12-(4-benzyloxy-3-methyloxy-phenyl)-ethyl_/-amino/- 3-(3-methyl-- pyr i-din-2-yloxy)-2-propanol in 200 ml of methanol is hydrogenated with the addition of 4.0 g of palladium-on-charcoal catalyst (5%) until uptake of 2 mole equivalents of hydrogen under normal conditions. After filtration from the catalyst and evaporation of the filtrate by evaporation of the solvent, the evaporation residue is distributed between 200 ml of ether and 100 ml of 2 N hydrochloric acid, the acidic, aqueous solution is separated, made alkaline with concentrated ammonia solution and extracted with 200 ml of ethyl acetate. Evaporation of the dried ethyl acetate solution gives crude 1-_/ 2-(4-hydroxy-3_methoxy-phenyl)-ethylamino/-3-(3-methyl-pyridin-2-yloxy)-2-propanol as a yellowish oil, which dissolved with the half-equivalent amount of fumaric acid in methanol, forms a neutral fumarate which melts at 181 - 183°C.

The starting material can be obtained in the following way:

a) 4-benzyloxy-3-methoxy-phenylacetic acid (melting point 87 - 90°C) is transferred with thionyl chloride in dichloromethane into the acid chloride and this is reacted analogously to example 6 b) with 1-benzylamino-3-(3-niethyl-pyridine- 2-yloxy)-2-propanol to N-benzyl-N-(2-hydroxy-3-(3-methyl-1-pyridin-2-yloxy)-propyl 1/(4-benzyloxy-3-methoxy- phenyl)-acetamide. It forms an oil which is further used raw. b) 22 g of the crude amide formed is reduced analogously to example 9 b) with diborane and gives the crude 1-/N-benzyl-N-_/ 2-(4-benzyloxy-3-methoxy-phenyl)-ethyl_/- amino/ - 3-(3_methyl 1-pyridin-2-yloxy)-2-propanol as a yellow oil, which is further processed as such.

E xample 19-

Tablets containing 0.1 g of 2-(3,4-dimethoxyphenyl)-ethylamino)-2'-hydroxy-propoxy/-3-cyanopyridine as neutral fumarate are prepared as follows:

S composition (for 10,000 tablets): 2-/~3'-(2-(3,4-dimethoxyphenyl)-ethylamino)-2'-hydroxy-propoxy/-3-cyanopyridine as neutral

Front position.

2- Ty-(2-(3,4-dimethoxyphenyl)-ethylamino)-2'-hydroxy-propoxy/-3-cyanopyridine as neutral fumarate is mixed with the milk sugar, part of the corn starch and with colloidal silicic acid and the mixture is run through a term. A further part of the cornstarch is pasted with five times the amount of water

water bath and the powder mixture is crushed with this paste until a weak plastic mass is formed. This is printed through a sieve of approx. 3 mm mesh size, is dried and the dry granules are run through a sieve again. Then mix in the rest

corn starch, talc and magnesium stearate and the resulting mixture is pressed into tablets of 0.250 g weight (with breaking instructions).

Claims (29)

1. Process for the preparation of 1-amino-2-hydroxy-3-heterocyclyloxy-propane with formula in which Y means the group - CH = or the group - N =, R-^ means hydrogen, hydroxy, lower alkyl or lower alkoxy, R2 means hydroxy, lower alkoxy or together with R-^ o-lower alkylidenedioxy or o-lower alkylenedioxy and R^ means lower alkyl, lower alkoxy, halogen or cyano, in that the residues R-^ , R 2 and R-^ are each bound to an arbitrary one of the possible aromatic carbon atoms, characterized in that in a connection with formula wherein Y and R^ have the above meanings, R^ has the meaning of R^ and furthermore means the group -0-X^, R^ has the meaning of R2 and moreover means the group - 0 - X^ , at least one of the groups X-^ , X2 , X^ and X^| means a hydrogen-replaceable group and the others mean hydrogen or a hydrogen-replaceable group, or X-^ and X2 together mean a cleavable, by means of two with to the secondary alcohol group corresponding oxygen atom resp. nitrogen atom connected hydrogen atoms, replaceable residue and/or X2 and X^ together mean a cleavable with two with that of the group- 0 - X-j resp. - 0 - X[j corresponding oxygen atoms connected hydrogen atoms replaceable residue, or in a salt thereof, the residue X-^ and/or X2 or X-^ and X2 together and/or X^ and/or X^ and/or X-^ are replaced and X^ together with hydrogen, or a compound with formula is reacted with a compound of formula wherein one of the groups Xg and Xy means a reactive esterified hydroxy group and the other means the primary amino group and Xc; means the hydroxy group, or in which X^ and Xg together mean the epoxy group and X^ means the primary amino group and Y, R-p R2 and R-j have the above meanings, or in a connection with formula wherein the group "Xg" (Va) means one of the residues of formulas - CH = N - C <H>2 - CI 12 - (Vb), or - CH2 - N = CH - CH2 - (Vc), or -C( = Xg) - N - CH2 - CH2 - (Vd) or K - CH2 - N - C ( = Xg) - CH2 - (Ve)', in which Xg means oxo- or XL the thioxo group, Y, R^, R2 and X-^ have the above-mentioned meanings and R^ has the stated meaning with the exception of halogen and cyano, the group -Xg- is optionally reduced over the intermediate steps containing the residue -CH2 - N - CH2 - CH2 - to the rest with a formula xl - CH2 - NH CH2 - CH2 , and if desired, a formed compound of formula I is transferred into another compound of formula I and/or, if desired, a formed free compound is transferred into a salt or a formed salt into a free compound and/or if desired, a formed isomer mixture is divided into the individual isomers or a formed racemate in the optical antipodes. 2. Method according to claim 1, characterized in that X-^ and/or X2 and/or X^ and/or X^ are split off by means of solvolysis or reduction. 3. Method according to claims 1 to 2, characterized in that the cleavable group X-^ is a hydrogenolytically cleavable α-aryl lower alkyl group and primarily benzyl. 4. Process according to claims 1 to 2, characterized in that a cleavable group X^ means a solvolytic, such as hydrolytically or acidolytically or reductively cleavable acyl residue, such as an acyl residue of an organic carboxylic acid or sulfonic acid or optionally substituted 1-polyphenyl-lower alkyl residue. 5. Method according to claims 1 to 2, characterized in that a cleavable group X 2 , X 1 and X 2 is a hydrogenolytically cleavable α-aryl lower alkyl group and primarily benzyl. 6. Process according to claims 1 to 2, characterized in that the cleavable group X2, X^ and X^ is a solvolytically, such as hydrolytically, alcohololytically or acidolytically cleavable acyl residue or a polybranched, optionally substituted aliphatic or araliphatic hydrocarbon residue at the linking carbon atom. 7. Process according to claims 1 to 2, characterized in that and together and X^ and Xj( together form a hydrogenolytically cleavable, optionally substituted 1-phenyl-lower alkylidene residue. 8. Method according to claim 1 to 2, characterized in that X-j_ and X2 together as well as X^ and X^' together form a solvolytically cleavable lower alkylidene or cycloalkylidene residue, further the carbonyl or thiocarbonyl group. 9- Method according to one of claims 3, 5 and 7, characterized in that the starting material is treated with catalytically activated hydrogen. 10. Method according to one of claims 4, 6 and 8, characterized in that the starting material is hydrolyzed, alcoholized, acidolyzed or reduced. 11. Process according to claim 1, characterized in that starting materials with formula V, in which the group with formula Va means the residues with the formulas Vb or Vc, as well as Vd or Ve, in which the groups -C(=X^ )-NH- resp. -NH-C(=X^ )-means the carbamoyl group, is treated with a light metal hydride or a borohydride. 12. Process according to claim 1, characterized in that starting substances of formula V, in which the group of formula Va means residues of formula Vb or Vc, are treated with catalytically activated hydrogen. 13. Process according to claim 1, characterized in that starting materials of formula V, in which the group of formula Va means residues with the formulas (Vd) or (Ve), in which Xn means the thioxo group, are reductively desulphurised. 14. A method according to one of claims 1-13, characterized in that it starts from one or other step of the method as an intermediate formed compound and the missing method steps are carried out, or the method is interrupted at one or the other step. 15. Method according to one of claims 1-14, characterized in that a starting substance is formed under the reaction conditions or that a reaction component is optionally present in the form of its salt. 16. Method according to one of claims 1-15, characterized in that compounds of formula I according to claim 1 or their salts are prepared, wherein means hydrogen, hydroxy, lower alkyl or lower alkoxy with every v time up to 4 C atoms, R 2 means hydroxy, lower alkoxy with up to 4 C atoms and together with R-j. means o-lower alkylidenedioxy with 1 to 2 C atoms and R^ means lower alkyl or lower alkoxy with each time up to 4 C atoms, halogen or cyano, R-^<p> g R 2 each standing in 2-, 3- or 4 -position and o-lower alkylidenedioxy or o-lower alkylenedioxy is in the 2,3- or 3,4-position and R^ in a pyridine ring is in the 3", 4-, 5^ or 6-position or in a pyrazine ring in the 3-, 5~ or 6-position. 17. Method according to one of claims 1-15, characterized in that compounds are produced else with a formula or their salts, in which R-^ means hydrogen, hydroxy, methyl or methoxy, R 2 means hydroxy, methoxy or together with R^ o-methylenedioxy and- R^ means methyl, methoxy, chlorine or cyano, wherein R-^ and R2 are each in the 3- or 4-position, o-methylenedioxy in the 3,4-position and R^ in the 3- or 4-position. l8. Method according to one of claims 1-15, characterized by the fact that -compounds are produced- else with a formula or its salts, wherein R-j_ means hydrogen, hydroxy, methyl or methoxy, R2 means hydroxy, methoxy or together with R]_ o-methylenedioxy and R^ means methyl, methoxy, chlorine or cyano, R-^ and R2 each time is in the 3- or 4-position, o-methylenedioxy in the 3,4-position and R-^ in the 3-position and their salts. 19. Method according to one of claims 1-15, characterized in that 2-1_ 3'-(2-(3,4-dimethoxyphenyl)-ethylamino)-2'-hydroxy-propoxy/-3-cyanopyridine or salts thereof are prepared . 20. Method according to one of claims 1-15> characterized in that 1-(3-chloropyrazin-2-yloxy)-3-/ is produced. 2-(3,4-dimethoxyphenyl)-ethylamino I-2-propanol or salts thereof. 21. Process according to one of claims 1-15, characterized in that 1-(2-(3,4-dimethoxyphenyl)-ethylamino)-3-(3-methoxypyridin-2-yloxy)-2-propanol or salts are produced of this. 22. Method according to one of claims 1-15, characterized in that 1-(p-methoxyphenyl)-ethylamino/-3-(3-methylpyridin-2-yloxy)-2-propanol or salts thereof are produced. 23. Method according to one of claims 1-153, characterized in that 1-(2-(3,4-methylenedioxyphenyl)-ethylamino)-3-(3-methylpyridin-2-yloxy)-2-propanol or salts thereof are produced. 24. Method according to one of claims 1-15, characterized in that 1-/2-(3,4-methylenedioxyphenyl)-ethylamino/-3-(4-methylpyridin-2-yl-oxy)-2-propanol is produced or salts thereof. 25. Process according to one of claims 1-15, characterized in that 1-(p-hydroxyphenyl)-ethylamino/-3-(3-methylpyridin-2-yloxy)-2-propanol or salts thereof are produced. 26. Method according to one of claims 1-153, characterized in that 2-(p-hydroxyphenyl)-ethylamino/-3-(4-methylpyridin-2-yloxy)-2-propanol or salts thereof are produced. 27. Process according to one of claims 1-153, characterized in that 1-[2-3j 4-dimethoxy-phenyl)-ethylamino]-3-(3-methoxypyrazin-2-yloxy)-2-propanol or salts thereof are produced . 28. Method according to one of claims 1-15> characterized in that 2-(p-hydroxyphenyl)-ethylamino/-3-(3-methoxypyridin-2-yloxy)-2-propanol or salts thereof are produced. 29. Method according to one of the claims 1-15, characterized in that it is prepared -yloxy)-2-propanol or salts thereof.