DE2740678A1 - 1-AMINO-2-HYDROXY-3-HETEROCYCLOXYPROPANE - Google Patents

Description

l-amino-Z-hydroxy-S-heterocyclyloxy-propane.

The present invention relates to 1-amino-Z-hydroxy-S-heterocycloxy-propane the formula

^R l

^ NO - CH ₂ - CH (OH) - CH ₂ - NH - ^CH 2 ~ ^CH 2 \ _ / "

where Y stands for the group - CH = or the group -N =,

R. hydrogen, hydroxy, lower alkyl or lower alkoxy, R ~ hydroxy, lower alkoxy or together with R, o-lower-

alkylidendioxy or o-lower alkylenedioxy and R ~ mean lower alkyl, lower alkoxy, halogen or cyano, where the radicals R ,, R ₂ and R- are each bonded to any of the possible aromatic carbon atoms, or their salts, processes for their preparation and pharmaceutical preparations containing such compounds and their use.

The rest of the formula

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4057

-A

means the 2-pyridyl radical, in which the group R- in 3-, 4-, 5- or 6-position, or the 2-pyrazinyl radical, in which the group R 1 can be in the 3-, 5- or 6-position.

In the context of the present application, the groups and compounds labeled “lower” have, if not defined differently, up to 7 and primarily up to 4 carbon atoms.

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, while lower alkenyl e.g. for vinyl, allyl or methallyl, and lower alkynyl e.g. for Ethynyl or propargyl.

Lower alkoxy is e.g. 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 is, for example, methylenedioxy or isopropylidenedioxy, while lower alkylenedioxy, e.g. 1,2-ethylenedioxy is.

Salts of compounds of formula I are primarily acid addition salts, and especially pharmaceutical 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, 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, Brown grape acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, Salicylic acid, phenylacetic acid, emboxylic acid, methanesulfonic acid

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acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylene sulfonic acid, 4-chlorobenzenesulphonic acid, toluenesulphonic acid, Naphthalenesulfonic acid, sulfanilic acid or cyclohexylaminesulfonic acid, as well as ascorbic acid. As a result of the close relationships between the new connections in free form and in form Their salts are among the free compounds and among the salts meaningfully and expediently also the corresponding ones, if appropriate To understand salts or free compounds.

The invention relates in particular to compounds of the formula I in which
R, hydrogen, hydroxy, lower alkyl or lower alkoxy with

up to 4 carbon atoms each,
Rj is hydroxy, lower alkoxy with up to 4 carbon atoms and together with R, o-lower alkylidendioxy with 1 to 2 carbon atoms and R- is lower alkyl or lower alkoxy with up to 4 carbon atoms each, halogen or cyano, where R, and R2 is in the 2-, 3- or 4-position and o-lower alkylidenedioxy is in the 2,3- or in the 3,4-position, R- is in a pyridine ring in the 3-, 4-, 5- or 6-position, or in a pyrazine ring in the 3-, 5- or 6-position, as well as their salts, in particular their pharmaceutically acceptable, non-toxic acid addition salts.

The invention also relates in particular to compounds of the formula

O - CH ₂ - CH (OH) - CH ₂ - NH - CH ₂ -CH ₂ "C ^ ^ ( ^Ia )>

wherein

R, hydrogen, hydroxy, methyl or methoxy, Rj is hydroxy, methoxy or together with R, o-methylenedioxy and R- is methyl, methoxy, chlorine or cyano, where R, and R _{2 are} each in the 3- or 4-position, o -Methylenedioxy is in the 3,4-position and R- in the 3- or 4-position, as well as their salts, in particular their pharmaceutically acceptable, non-toxic acid addition salts.

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27A0678

The invention also relates in particular to compounds of the formula

it ^R 3 CH ₉ - CH (OH) - CH ₉ -NH - CH ₀ -CH ₉ - < K O - 2 L. Z L. L /

R, hydrogen, hydroxy, methyl or methoxy, R ₉ hydroxy, methoxy or together with R, o-methylenedioxy and R "denotes methyl, methoxy, chlorine or cyano, where R and R _{9 are} each in the 3- or 4-position, o-Methylenedioxy is in the 3,4-position and R "is 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 the formula I:
2- [3 '- (2- (3,4-Dimethoxyphenyl) -ethylamino) -2'-hydroxy-propoxy] -

3-cyanopyridine,
1- (3-chloropyrazin-2-yloxy) -3- [2- (3,4-dimethoxyphenyl) ethylamino] -

2-propanol,
1- [2- (3,4-Dimethoxyphenyl) -äthylaminoJ-3- (3-methoxypyridin-2-yl-

oxy) -2-propanol,
1- [2- (p-methoxyphenyl) ethylamino] -3- (3-methylpyridin-2-yloxy) -

2-propanol,
1- [2- (3,4-methylenedioxyphenyl) ethylamino] -3- (3-methylpyridine-2-

yloxy) -2-propanol,
1- [2- (3,4-methylenedioxyphenyl) ethylamino] -3- (4-methylpyridine-2-

yloxy) -2-propanol,
1- [2- (p-Hydroxyphenyl) ethylamino] -3- (3-methylpyridin-2-yloxy) -2-

propanol,
1- [2- (p-hydroxyphenyl) ethylamino] -3- (4-methylpyridin-2-yloxy) -2-propanol,

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1- [2- (3,4-Dimethoxyphenyl) ethylamino] -3- (3-methoxypyrazine-2-

yloxy) -2-propanol,
1- [2- (p-Ilydroxyphenyl) -äthylamino] -3- (3-methoxypyridin-2-yloxy) -

2-propane oil,
1- [2- (3-methoxy-4-hydroxyphenyl) ethylamino] -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. In particular, they have adrenergic beta-receptor-blocking effects, which can be demonstrated as an inhibition of isoproterenol tachycardia, for example in isolated guinea pig hearts according to Langendorf f. The concentrations (EC ₅₀₎ fllr a half-maximum inhibitory effect required are in this case from 0.04 to 0.44 _y ug / ml. In addition, for example, 2- [3 ¹ - (2- (3,4-dimethoxyphenyl) -äthylamino) -2'-hydroxy-propoxy] -3-cyanopyridine, as a neutral fumarate, inhibits isopoterenol tachycardia in an anesthetized cat with a perfused rear extremity significantly stronger (EDc ₀ = 0.2 mg / kg iv) than isoproterenol vasodilation (ED ₅₀ = 3 tng / kg iv). It follows that this compound belongs to the class of cardioselective beta-receptor blockers.

The new compounds also inhibit adrenergic alpha receptors, which can be demonstrated, for example, as noradrenaline antagonism on the isolated vas deferens of the rat. The fllr a pA2 value ~ required concentrations are in this test system from 0.4 to 7.6 _y uM at PAJ corresponding values of 6.40 to 5.12 y

The new compounds also have hypotensive properties, such as the long-term lowering of the arterial blood pressure in the anesthetized cat at doses from 0.1 mg / kg i.v. can be shown. The new compounds can act as beta-receptor blockers due to their properties

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with additional alpha-blocking and hypotensive receptors Effects in the treatment of beta-receptor blockers known indications, e.g. hypertension, angina pectoris or cardiac arrhythmias can be used.

The novel compounds of the present invention can be prepared in a manner known per se, for example by using in a compound of the formula

CH ₂ - CH - CH ₂ - N - CH ₂ - CH ₂ - (' * ■) (H)

where Y and R "have the above meanings, R, has the meaning of R, and also represents the group -OX-, R, - has the meaning of R ₂ and also represents the group - O - X, where at least one of the groups X ₁ , X 2, X 1 and X denotes a group which can be replaced by hydrogen and the others are hydrogen or a group which can be replaced by hydrogen, or X. and X ₂ together are one which can be split off by two with that of the secondary group Oxygen atom corresponding to the alcohol group or hydrogen atoms connected to the nitrogen atom denote a residue that can be replaced, and / or Xo and X together represent a detachable residue which can be replaced by two hydrogen atoms connected to the oxygen atoms corresponding to the groups - O - X - or - O - X, or in a salt thereof, the radical X, and / or X ₂ or X, and X ₂ together and / or X- and / or X, and / or X 1 and X, together replaced by hydrogen, and if desired, a compound obtained of formula I in e Converted to another compound of the formula I, and / or, if desired,

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a free compound obtained is converted into a salt or a salt obtained is converted into a free compound, and / or, if desired, a mixture of stereoisomers obtained into the individual stereoisomers or a racemate obtained into the optical ones Antipodes separates.

The splitting off of groups X, and / or X _? and / or X- and / or X, is carried out by means of solvolysis or reduction. In this case, in the starting materials of the formula II mentioned, X is preferably a group which can be replaced by hydrogen, while Xy, X ^ and X are primarily hydrogen.

A particularly suitable, removable group X is primarily a hydrogenolytically removable oc-aryl-lower alkyl group, such as an optionally substituted 1-phenyl-lower alkyl group, wherein substituents, especially of the phenyl part, 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 be a solvolytic, like hydrolytically or acidolytically, also a reductively, including hydrogenolytically, cleavable radical, in particular a corresponding acyl radical, such as the acyl radical of an organic carboxylic acid, e.g. lower alkanoyl, such as acetyl, or aroyl, such as benzoyl, also the acyl radical of a half ester of carbonic acid, such as lower alkoxycarbonyl, e.g. methoxycarbonyl, ethoxycarbonyl or tert-butyloxycarbonyl, 2-halo-lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, e.g. benzyloxycarbonyl or diphenylmethoxycarbonyl, or aroylmethoxycarbonyl, e.g. phenacycloxycarbonyl, or the acyl radical an organic sulfonic acid, such as an aromatic sulfonic acid, primarily an optionally substituted phenylsulfonyl radical, in which substituents are e.g. 1-Phenyl-lower alkyl radical have given meaning, and in particular

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special 4-methylphenylsulfonyl, also one if necessary substituted 1-polyphenyl-lower alkyl group, in which substituents, primarily of the phenyl moiety, e.g. have the meaning given above, and are primarily trityl.

A hydrogen-replaceable group X2, Xo or X, is preferably likewise a group which can be split off hydrogenolytically, such as one of the above-mentioned, optionally substituted 1-phenyl-lower alkyl groups and primarily benzyl. she can also be one of the group X, named solvolytic, including alcoholytically or reductively cleavable acyl groups, furthermore a polybranched at the linking five carbon atom, optionally substituted aliphatic or araliphatic hydrocarbon radical, such as tert-lower alkyl, e.g. tert-butyl, or trityl.

A radical which can be split off and formed together by X, and X "or X" and X, is primarily in turn a group which can be split off hydrogenolytically, such as optionally substituted 1-phenyl-lower alkylidene, in which substituents, in particular of the phenyl moiety, for example lower alkyl, such as tert. -Butyl, hydroxy, lower alkoxy, halogen and / or nitro, and especially benzylidene, and solvolytically, especially hydrolytically cleavable groups, such as lower alkylidene, for example methylene or isopropylidene, or cycloalkylidene, for example cyclohexylidene. Another radical formed by the groups X ₁ and X ~ or X «and X together is the diacyl radical of carbonic acid or thiocarbonic acid, ie the carbonyl or thiocarbonyl group.

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

Hydrogenolytically cleavable radicals X ·, and / or X2 and / or X ~ and / or X ,, in particular optionally substituted 1-phenyl lower alkyl groups, also suitable acyl groups, such as optionally substituted 1-phenyl-lower alkoxycarbonyl, as well as by the groups X, and X "and / or X- and X, optionally substituted 1-phenyl lower alkylidene groups formed together, can, by treating with catalytically active

fourth hydrogen, e.g. with hydrogen in the presence of a Nickel catalyst, such as Raney nickel, or a suitable noble metal catalyst are split off.

Groups X ₁ and / or X ~, and / or X „and / or X which can be split off hydrolytically, such as acyl radicals of organic carboxylic acids, e.g. lower alkcinoyl, and carbonic acid half-esters, e.g. lower alkoxycarbonyl, also e.g. trityl radicals, as well as through the radicals X and X "And / or X" and X, lower alkylidene groups or carbonyl groups formed together, can, depending on the nature of such radicals, by treatment with water under acidic and / or basic conditions, for example in the presence of a mineral acid, such as hydrochloric or sulfuric acid, or an alkali metal or Alkaline earth metal hydroxide or carbonate are split off.

Residues that can be split off acidolytically are, in particular, certain acyl radicals of half-esters of carbonic acid, such as tert.-lower alkoxycarbonyl or optionally substituted diphenylmethoxycarbonyl radicals, and also tert-lower alkyl radicals X «, Xq or X ,; they can by treatment with suitable strong organic carboxylic acids, such as optionally with halogen, in particular Fluorine, substituted lower alkanecarboxylic acids, primarily with trifluoroacetic acid (if necessary, in the presence of a activating agent, such as anisole), as well as with formic acid.

Reductively split off radicals X and / or X 1 and / or X 1 and / or X are also understood to mean groups which are split off on treatment with a chemical reducing agent (in particular with a reducing metal or a reducing metal compound). Such radicals are in particular 2-halo-lower alkoxycarbonyl or aroylmethoxycarbonyl, which, for example, when treating with a reducing heavy metal, such as zinc, or with a reducing heavy metal salt, such as a chromium (II) salt, e.g., chloride or acetate, usually in the presence of an organic Carboxylic acid, such as ant

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acid or acetic acid, and can be split off from water. Arylsulfonyl radicals which can be split off reductively, especially those which primarily represent the radical X, can, for example, be replaced by hydrogen during treatment with an alkali metal, for example lithium or sodium, in ammonia or by means of electrolytic reduction.

The above reactions are carried out in a manner known per se, usually in the presence of a solvent or solvent mixture, suitable reactants may simultaneously function as such, and if necessary under hollows or heating, for example in a temperature range of about -20 ⁰ C up to about -1-150 ° C, in an open or closed vessel and / or in the atmosphere of an inert gas, eg nitrogen.

The novel compounds of the present invention can also be obtained by using a compound the formula

- CII ₉ - CII - CH ₉ - X

(III)

with a compound of the formula

X ₇ - CH ₂ - CH ₂

wherein one of the groups X, - and X _{7 represents} a reactive esterified hydroxyl group and the other represents the primary amino group and X _{5 represents} the hydroxyl group, or wherein Xj. and X, together denote the epoxy group and X ₇ denotes the primary amino group, and Y, R., R ₉ and R _{3 have the} above meanings, and, if desired, carry out the additional process steps.

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A reactive esterified hydroxyl group X or X-, is one made by a strong acid, especially one strong inorganic acid, such as a hydrohalic acid, in particular hydrochloric, bromic or hydroiodic acid, or Sulfuric acid, or a strong organic acid, especially a strong organic sulfonic acid such as an aliphatic acid or aromatic sulfonic acid, e.g. methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid, esterified Hydroxyl group, and is primarily halogen, e.g. chlorine, bromine or iodine, or aliphatic or aromatic substituted sulfonyloxy, e.g. methylsulfonyloxy or 4-methylphenylsulfonyloxy represents.

The above reaction is carried out in a manner known per se, particularly when using a starting material with a reactive esterified hydroxyl group, advantageously in the presence of a basic agent such as an inorganic base, for example an alkali metal or alkaline earth metal carbonate or hydroxide, or an organic basic agent such as an alkali metal niederalkanolats, and / or an excess of the basic reactant and usually in the presence of a solvent or solvent mixture and, if necessary, while cooling or heating, for example in a temperature range of about -20 ⁰ C to about +150 ⁰ C, in an open or closed vessel and / or in an inert gas atmosphere, for example in a nitrogen atmosphere, for example in a nitrogen atmosphere.

The new compounds can also be obtained by looking at a compound of the formula

0 - CH ₂ - CH (OH) - X ₈ -Ρ Ά (V)

wherein the group -X _g - (Va) is one of the radicals of the formulas

- CH = N - CH ₂ - CH ₂ - (Vb), or - CH ₂ -N-CH- CH ₂ - (Vc),

or -C (- X ₉ ) - N - CH ₂ - CH ₂ - (Vd) or

^X i 809 & U / 0601

- CH ₂ - N - C (= X _g ) - CH ₂ - (Ve) signifies, wherein X _g

represents the oxo or thioxo group, Y, R ,, R ^ and X, have the above meanings, and R ~ has the meaning given with the exception of halogen and cyano, the group -Xo- optionally via the radical - CH ₂ - N - CH ₂ - ClI ₂ - containing

Intermediate stage to the remainder of the formula - CH ₂ - NH - CH ₂ - CH ₂ reduced, and, if desired, the additional process steps carried out.

The reductive conversion of a radical of the formula

- X _ft - (Va) into the desired grouping of the formula

- CH ₂ - NH - CH ₂ - CH ₂ - can be carried out in a manner known per se, the choice of suitable reducing agents depending on the nature of the groups of the formula (Va). Particularly suitable for the reduction of groups of the formula (Vb) and (Vc), and of groups of the formula (Vd) and (Ve), in which the radicals of the formula - C (= X _g ) -N-CH ₂ -CH ₂ - or - CH ₂ -NC (= X _g ) -CH ₂ ~,

X ₁ X ₁

contain a carbamoyl group, are light metal hydride reducing agents, such as alkali metal aluminum hydrides, e.g. lithium aluminum hydride (which are particularly suitable for the reduction of carbamoyl groups suitable), or alkali metal borohydrides, e.g. sodium borohydride, as well as alkali metal cyanoborohydrides, e.g. sodium cyanoborohydride, or borohydrides, e.g. diborane, (which are primarily used to reduce alkylidene amino groups). Furthermore can one groupings of the formulas (Vb) and (Vc) and optionally at the same time the hydrogenolytic cleavage of a residue X which can be replaced by hydrogen by means of hydrogenolysis, by treatment with catalytically activated hydrogen, such as hydrogen in the presence of a heavy metal catalyst, e.g. Raney nickel, platinum oxide or palladium, transfer. Groupings of the formulas (Vd) and (Ve), in which Xg is in each case a thiono group and optionally contains a hydrogenolytically cleavable radical X, are removed by reductive desulfurization, e.g.

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by treatment with a hydrogenation catalyst, such as Raney Nickel, into the grouping of the formula - ClI ₂ - NH - CH ₂ - CH _? converted. The above reduction reactions are performed in per se known V / else, usually in the presence of an inert solvent, and, if necessary, under Klihlen or heating, for example in a temperature range of about -20 ⁰ C to about +150 ⁰ C, and / in a closed vessel under pressure and / or in an inert gas, for example nitrogen, atmosphere.

In the compounds obtained, one can proceed in a customary manner within the scope of the definition of the compounds of the formula (1) Transferring the compounds obtained into other end products, e.g. by exchanging a suitable substituent for another, or introducing a substituent. Thus, in a compound of the formula (I) in which R. is halogen, such as chlorine, this means by reaction with one of the Meaning of R "as lower alkoxy corresponding lower alkanol exchange for lower alkoxy. It is advisable to use a basic condensation agent such as an alkali hydroxide, for example sodium or potassium hydroxide or one corresponding to the importance of the lower alkoxy radical to be introduced Alkali lower alkoxide, such as sodium or potassium methoxide, sodium or potassium ethoxide.

In addition, in a compound of the formula (i) in which R 1 and / or R ″ denotes hydroxyl, such hydroxyl groups can be used convert into the corresponding lower alkoxy groups or a lower alkylidenedioxy group. This happens, for example, by that one contains a hydroxyl group-containing compound of the formula I with one of the meaning of R, as lower alkoxy corresponding converts reactive derivative of a lower alkanol, its hydroxyl group as above for the groups X ^ or X_ indicated is esterified. As such, e.g.

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the corresponding Ni ed era Iky], halo ρ, a de, about dii s chloride or bromide into consideration. Here, one works in an advantageous manner in the presence of a basic agent such as an inorganic base e.g. or hydroxide or an organic basic agent, such as an alkali metal lower alkanolate. Appropriately such a hydroxyl-containing compound of the formula I can be converted into a salt, e.g. Alkali metal salt, such as a sodium salt, for example by Reaction with sodium methoxide, transferring and the pre-formed salt of the reaction, for example, with a lower alkylbroinide, e.g. methyl or ethyl bromide. Usually a solvent or a solvent is used for this purpose, e.g. a polar solvent, such as a lower alkanol such as ethanol, or a fatty acid amide, e.g. dimethylformamide or N-methylacetamide or Ν, Ν-dimethylacetamide, or an amide of Phosphoric acid, such as hexamethylphosphoric triamide, or suI-folane or mixtures of such solvents. The implementation is in a range of about + 10 ° to about + 160 ° in an open or closed vessel, if necessary in an inert gas atmosphere, e.g. under nitrogen.

As reactive derivatives of a lower alkanol come also the corresponding diazoalkanes such as diazomethane or diazoethane into consideration. Their reaction with a containing hydroxyl groups Compound of formula (I) is in an organic solvent, such as an ether such as diethyl ether, or a Chlorinated hydrocarbons, such as methylene chloride. It is expedient to work in a temperature range here from about -20 ° to + 50 °, optionally under a protective gas, such as nitrogen.

Depending on the process conditions and starting materials the new compounds are obtained in free form or in the form of their salts likewise encompassed by the invention, with the new compounds or salts thereof also as ilei, mono-,

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Scsqui- odor polyhydrates chi of may be present. Acid addition salts the new compounds can be known per se Way, e.g. by treatment with basic agents such as A] ka]! .Metal hydroxides, carbonates or hydrogen carbonates or ion exchangers, converted into the free compounds will. On the other hand, the free bases obtained can be mixed with organic or inorganic acids, for example with those mentioned Acids, acid addition salts form, with their production in particular those acids are used which lead to the formation of pharmaceutically acceptable salts suitable.

These or other jellies, especially acid addition salts the new compounds, such as picrates or perchlorates, can also be used to purify the free Bases are used by converting the free bases into salts, separating them and purifying them, and the salts in turn Releases bases.

Depending on the choice of starting materials and working methods, the new compounds can act as optical antipodes or racemates, or if they contain at least two asymmetric carbon atoms, they are also present as mixtures of racemates. The starting materials can also be used as optical antipodes.

Racemic mixtures obtained can be based on the physico-chemical Differences in the diastereoisomers in a known manner, e.g. by chromatography and / or fractionated Crystallization into which the two stereoisomeric (diastereomeric) racemates are separated.

Racemates obtained can be broken down into the antipodes by methods known per se, zj, by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with a, optically active salts forming with the racemic compound Substance »in particular acid, and separation of the salt mixture obtained in this way, e.g. on the basis of different solvents

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opportunities, in the dia st ereoniovt η Sa] ze, from which the free Antipodes released by the action of appropriate means can be. Optically active acids that are particularly common are e.g. the D- and L-forms of tartaric acid, di-o-toluyltartaric acid, Malic acid, mandelic acid, camphorsulphonic acid, Glutamic acid, aspartic acid, or quinic acid. Advantageous one isolates the more effective of the two antipodes.

The invention also relates to those embodiments of the process, according to which one obtainable as an intermediate product at any stage of the process Connection goes out and carries out the missing procedural steps, or the process is terminated at any stage, or in which a starting material is formed under the reaction conditions, or in which a reaction component optionally in the form of their salts.

Expediently one uses for the implementation of the inventive reactions those starting materials that to the groups of end products particularly mentioned at the beginning and especially to those specifically described or emphasized Lead end materials.

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

For example, compounds of the formula (II) can be prepared by reacting a compound of the formula

(VI)

or a salt thereof, in which Y and R. have the above meanings, with a compound of the formula

X _1n - CH ₀ - CH - CH ₀ -N- CH ₀ - CH ₀ ■ </ *> (VII)

ο - x ° X ₁

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in which X _{1 has} the meaning given above, and Xl stands for the group Xy , at least one of the groups X, and Xy being different from hydrogen, and X,,. Hydroxy or a reactive esterified hydroxyl group, or Xy and X-, together represent a carbon-oxygen bond, or in which X, and X ^ together represent a removable radical which can be replaced by two hydrogen atoms connected to the oxygen or nitrogen atom, and X _{1n denotes} a reactive esterified hydroxyl group, or analogously to a process modification described above by treating a compound of the formula

" ^R 3

O - CH ₂ - CH - CH ₂ - X ° ₆ (VIII)

O - X ₂

with a compound of the formula

R /

X ° - CH ₂ - CH ₂ ^ / - \) _(IX)

in which X «has the meaning given above for Xy , and one of the groups X ^ and X ^ represents a reactive esterified hydroxyl group, and the other represents the group of the formula - NH (X,), in which X, has the meaning given above , with the proviso that at least one of the groups X ₁ and Χ «is different from hydrogen, or in which X ~ and X ^ form an oxygen-carbon bond and XZ stands for the group of the formula - NH (X,) and X , is different from hydrogen. The above reactions are carried out in a manner known per se, for example as described above.

Starting materials of the formula (VIII), in which Y stands for the group -N =, can be obtained, for example, by reacting a compound of the formula (VI) explained above or a salt thereof with a compound of the formula

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X ₁₁ - CH ₀ - CH - CH ₀ (X)

where X ,, for a reactive esterified hydroxy group is, and, if desired, by splitting the epoxy äthylgruppierung in the product obtained in a 2-Ar.iino-lhydroxyäthyl- or 2-reactive esterified hydroxyl ~ hydroxy-ethyl group obtain. These reactions can be carried out in a manner known per se.

Starting materials of the formula (VIII), wherein Y is the Group - CH = can be obtained, for example, by adding a compound of the formula

(XI)

wherein X, ~ represents a suitable removable group, such as halogen, for example chlorine or bromine, nitro or lower alkylsulfonyl, with 2,2-dimethyl-5-hydroxymethyl-1,3-dioxolane, the compound obtained by means of hydrolysis, for example by means of aqueous acids how dilute hydrochloric acid is converted to the corresponding 1,2-propanediol derivative, this is converted into the corresponding Ro-substituted 2-ethoxy-5- (2-pyridyloxymethyl) -2-methyl-1,3-dioxolane by treatment with triethyl orthoacetate , this by treatment with trichlorosilane in a chlorinated hydrocarbon, such as dichloromethane, converted into the corresponding Ro-substituted 2- (2-acetyloxy-3-chloro-propyloxy) pyridine and this using a suitable base, such as tetrabutylammonium hydrogen sulfate in alkaline solution, for example The presence of sodium hydroxide and a chlorinated hydrocarbon, such as methylene chloride, is converted into the compound of the formula (VIII), in which X ~ and XZ represent an oxygen-carbon bond. These reactions are carried out in the usual way. Compounds of the formula (VIl) in turn know, for example, by reacting a compound of the formula

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X _1n - CH ₀ - CH - ClI ₀ - X, IU Zj Zo

⁰ " ^X 2

with a compound of the formula

R,

ItN - CH, - CU.

I ²

^X l

(XII)

(XIII)

which fllr X, X ^ and X provisos and meanings are valid, and X ^ XZ and represent an oxygen-carbon bond · can be obtained in a conventional manner.

Starting materials of the formula (V) can by reaction of amino compounds of the formula

O - CH ₂ - CH - CH ₂ OH

(IHa)

wherein the llydroxy group can optionally be present in a split, e.g. in an esterified or suitably etherified form, with oxo compounds of the formula

^R l

0 = CH - CH - "^ ²

(XIV),

or with carboxylic acid compounds of the formula

HO

CC ₂

(XIVa)

or their reactive derivatives, such as the halides, for example the chlorides, or of amino compounds of the formula

R ₁

H ₂ N - CH ₂

(IVa)

8098U / 0601

with; Oxo compounds of the formula

O - CH ₂ - CH - C

- CH ₀ - CH - C

(XV) O

wherein the group -CIIO optionally in a suitably etherified May be in form, or with carboxylic acid compounds of the formula

(XVa)

wherein the hydroxy group is optionally in slotted, e.g. may be in esterified or suitably etherified form, can be obtained. In an intermediate product with: protected Hydroxy group this is converted into the free form. the The above reactions are carried out in a manner known per se.

The new compounds can be used, for example, in the form of pharmaceutical preparations, which have a pharmacological effective amount of the active substance, optionally together with pharmaceutically acceptable carriers, which are suitable for enteral, e.g. oral, or parenteral administration, and inorganic or organic, solid or can be liquid. How to use tablets or gelatin capsules, polygamy the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycerin and / or lubricants, e.g. silica, Talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Tablets can also contain binding agents, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, Gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired,

8098U / 0601

Disintegrants, e.g. starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or louse mixtures, or Adsorbents, colors, flavors and sweeteners contain. The new pharmacologically active compounds can also be administered parenterally in the form of Use preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these e.g. in the case of lyophilized preparations, which contain the active substance alone or together with a carrier material, e.g. mannitol, prepared before use can be. The pharmaceutical preparations can be sterilized and / or auxiliary substances, e.g. preservatives, stabilizers, Wetting and / or emulsifying agents, solubilizers, salts for regulating the osmotic pressure and / or buffers contain. The present pharmaceutical preparations which, if desired, contain other pharmacologically active substances can, are in a manner known per se, e.g. by means of conventional mixing, granulating, coating, dissolving or Lyophilization processes produced and containing from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient.

The dosage can depend on various factors, such as mode of application, species, age and / or individual condition depend. The doses to be administered daily for oral administration to warm-blooded animals are between about 0.04 g and about 2.0 g, and for warm-blooded animals weighing about 70 kg, preferably between about 0.1 g and 1.0 g.

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

8098U / 0601

example 1

A solution of 75 g of crude 2- [3 ¹ - (2- (3,4-dirnethoxyphenyl) ethyl) -2'-phenyl-oxazo] idynyl- (5 ')] methoxy-3-cyanopyridine in 200 ml of ethanol is with 100 ml 2-n. Hydrochloric acid is added and the solution is left to stand for 2-3 hours at 20-30 °. 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 charcoal, filtered and with 2-n. Sodium hydroxide solution made alkaline. The deposited oil is extracted with ethyl acetate. The crude product obtained by evaporation is dissolved in 1.5 liters of dichloromethane and stirred for 1/2 hour with 300 g of an adsorbent based on magnesium silicate. The mixture is then treated with activated charcoal, filtered and the filtrate evaporated, after which crude 2- [3 '- (2- (3,4-Dimethoxyphenyl) ethylamino) -2'-hydroxy-propoxyJ-3-cyanopyridine is obtained, which dissolved in 25 ml of methanol and treated with a hot solution of 3.0 g of fumaric acid in 20 ml of methanol. On cooling, the neutral fumarate crystallizes out in colorless crystals, which melt at 160 - 161 °.

The starting material can be produced in the following manner will:

a) A mixture of 90.6 g of homoveratrylamine, 75 g of glyceryl glycide and 250 ml of isopropanol is heated for 24 hours at an internal temperature of 50 ° held. Evaporation gives a mixture which consists of 75% 3- [2- (3,4-dimethoxyphenyl) ethylamino] -1,2-propanediol exists and can be used raw.

b) 170 g of the crude product obtained together with 80 ml of benzaldehyde, 500 ml of toluene and 1 ml of glacial acetic acid for 7 hours heated under reflux on the water separator. The solution is then once with 100 ml of 1-n. Caustic soda and 2 times with each Washed 100 ml of water, dried over magnesium sulfate and evaporated. The excess becomes from the evaporation residue

8098U / 06Q1

Benzaldehyde by distillation under reduced pressure (12 Torr) separated. The distillation residue, which cannot be distilled undecomposed, consists mainly of 3- [2- (3,4-dirne thoxy phenyl) -a "thy IJ -5-hydroxy methyl -2-phenyl oxazolidine, which is used as a raw product.

c) 56 g of crude 3- [2- (3,4-dimethoxyphenyl) ethyl] -5-hydroxymethyl-2-phenyl-oxazolidine are in 250 ml of 1,2-üimethoxyäthan with 5.7 g of sodium hydride dispersion (55%) reacted and then stirred for 2 hours at 40 °. To Addition of 16.4 g of 2-chloro-3-cyano-pyridine, the reaction mixture is stirred for a further 2 hours at 40-50 °, using a filter aid filtered on the basis of diatomaceous earth and the filtrate evaporated. The evaporation residue is distributed between 500 ral ethyl acetate and 100 ml water, the organic phase washed twice with 100 ml of water each time, dried over magnesium sulfate and evaporated, after which one crude 2- [3 '- (2- (3,4-dimethoxyphenyl) -ethyl) -2 ■ -phenyl-oxazolidinyl- (5') J-methoxy-3-cyanopyridine receives.

Example 2

A mixture of 9.3 g of 2-chloro-3- (2,3-epoxy'-propoxy) pyrazine and 9.0 g of 2- (3,4-dimethoxyphenyl) ethylamine in 100 ml of isopropanol is stirred for 18 hours at 20-30 °, the solvent then evaporated, the evaporation residue in 50 ml of 2-n. Dissolved hydrochloric acid and extracted the solution with 50 ml of ether. The hydrochloric acid phase is separated off and acidified with conc. Ammonia solution made alkaline. The crude base is extracted 3 times with 100 ml of ethyl acetate each time and the solvent is added evaporated with each extraction, after which an oil is finally obtained, which gradually crystallizes. The crude 1- (3-chloro-pyrazin-2-yloxy) -3- [2- (3,4-dimethoxyphenyl) ethyl- amino] -2-propanol melts at 62-70 °. It forms a hydrochloride, which after recrystallization from methanol at 184-18rsch.il «.

Example 3

A solution of 9.2 g of 2- (2,3-epoxy-propoxy) -3-methoxy-pyridine and 9.0 g of 2- (3, 4-Dimet: hoxyphenyl) -ethylamine in 100 ml of isopropanol is Stirred for 6 hours at room temperature. Working up as in Example 2 gives 7.5 g of crude base, which is chromatographed as a solution in ethyl acetate over a column of 300 g of silica gel. The by-products are eluted by washing with ethyl acetate. By elution with ethyl acetate containing increasing amounts of ethanol from 1 to 57 _O , and finally with an ethyl acetate · ethanol mixture 4: 1, 1- [2- (3,4-dimethoxyphenyl) ethylamino] -3- (3- methoxypyridin-2-yloxy) -2-propanol, which after evaporation of the solvent is a yellow oil, the acidic oxalate of which melts at 132-134 ° after recrystallization from methanol-acetone.

The starting material can be produced in the following ways:

a) A mixture of 161 g of 3-methoxy-2-nitro-pyridine and 144 g of 2,2-dimethyl-5-hydroxymethyl-1,3-dioxolane in 1000 ml of hexamethylphosphoric triamide are admixed with 26.5 g of sodium hydride over the course of one hour while stirring; by Cooling, the temperature is kept at 0-10 ° during the addition. The reaction mixture is stirred for a further 5 hours with 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 made with a concentrated aqueous sodium chloride solution, dried and evaporated. The residue is dissolved in 1000 ml of ethanol dissolved, with 100 ml 2-n. Hydrochloric acid is added and the mixture is left to stand for 8 hours. After evaporation of the solvent is the residue made alkaline with a concentrated solution of sodium hydroxide in water and made with ethyl acetate extracted. Obtained by evaporation of the solvent

8098U / 0601

27A0678

one a crude product, from which after the addition of diethyl ether crystalline 3- (3-methoxy-2-pyridyloxy) -1,2-propanediol was obtained which melts at 62 - 65 °.

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 3 hours at Left at 20 - 30 °. The crude 2-ethoxy-5- (3-methoxy-2-pyridyloxymethyl) -2-methyl-1,3-dioxolane is obtained by evaporation as an oil that is used without further purification.

c) A mixture of 85 g of 2-ethoxy-5- (3-methoxy-2-pyridyloxymethyl) -2-methyl-1,3-dioxolane 45 ml of trimethylchlorosilane are added to 500 ml of dichlorotnethane and the mixture is stirred at 20-30 ° for one hour. By complete Evaporation under reduced pressure gives the crude 2- (2-acetyloxy-3-chloro-propyloxy) -3-methoxypyridine as OeI, which is used without purification.

d) A mixture of 80 g of 2- (2-acetyloxy-3-chloropropoxy) -3-methoxypyridine, 900 ml of methylene chloride, 500 ml of a 2-n. aqueous sodium hydroxide solution and 9.5 g of tetrabutylammonium hydrogen sulfate is stirred vigorously for 16 hours at 20-30 °. The organic phase is then separated off and evaporated. The remaining oil is dissolved in diethyl ether dissolved, the solution filtered, treated with activated charcoal and evaporated, after which the 2- (2,3-epoxy-propyloxy) -3-methoxypyridine obtained, which melts at 63 - 65 °.

Example 4

A mixture of 9.1 g of l-amino-3- (3-methyl-pyridin-2-yloxy) -2-propanol, 10.8 g of 2- (p-methoxyphenyl) ethyl bromide, 10 g of potassium carbonate and 100 ml of absolute ethanol is boiled for 20 hours with stirring and reflux. After cooling, the reaction mixture is filtered, evaporated in vacuo and the evaporation residue is dissolved in 200 ml of ethyl acetate. The solution is washed once with 50 ml of water and then with 50 ml

809814/0601

l-n. Acetic acid extracted. From the acetic acidic watery Solution is the base with conc. Sodium hydroxide solution was released, extracted with ethyl acetate and the solvent completely evaporated, after which crude 1- [2- (p-methoxyphenyl) .ethylamino] -3- (3-methyl-pyridin-2-yloxy) -2-propanol as gradually Crystallizing oil is obtained which, after recrystallization from isopropanol, melts at 80-81 °.

Example 5

A solution of 6.65 g of l-amino-3- (3-methyl-pyridin-2-yloxy) -2-propanol in 100 ml of methanol is treated with an approx. Solution of hydrogen chloride in methanol neutralized and, after addition of 5.0 g of 3,4-methylenedioxy-pheny / acetaldehyde and 2.0 g of sodium cyanoborohydride, stirred for about 30 hours at 20.degree.-30.degree. The reaction mixture is evaporated in vacuo and the residue between 100 ml of 2-n. Hydrochloric acid and 50 ml of ethyl acetate distributed. The hydrochloric acid phase is concentrated with. Sodium hydroxide solution adjusted to alkaline, after which crude 1- [2- (3,4-methylenedioxy-phenyl) ethylamino] -3- (3-methylpyridin-2-yloxy) -2-propanol is obtained, the hydrochloride of which after recrystallization from isopropanol Aether melts at 123 - 125 °.

Example 6

A solution of 8.4 g of crude 1- [N-benzyl-N- [2- (3,4-methylenedioxy-phenyl) -ethyl] -amino] -3- (4-methyl-pyridin-2-yloxy) - 2-propanol in 100 ml of wild methanol with the addition of 1 g of palladium-on-charcoal catalyst (57%) under normal conditions hydrogenated until the calculated amount of hydrogen is absorbed. By filtration from the catalyst and evaporation the solvent gives crude 1- [2- (3,4-methylenedioxyphenyl) -äthylamino] -3- (4-raethyl-pyridin-2-yloxy) -2-propanol as a crystalline compound, which after recrystallization Isopropanol melts at 80-81 °.

8098U / 0601

The starting material is obtained in the following way:

a) Glycerine glycide and benzylamine are converted in a known manner to 3-benzylamino-1,2-propanediol (bp.

160-170 ° / 0.01 Torr.

b) 3-Benzylamino-1,2-propanediol is mixed with benzaldehyde by azeotropic distillation with benzene in a manner known per se into 3-benzyl-5-hydroxymethyl-2-phenyl-oxazolidine Transferred, b.p. 168-171 ° / 0.005 Torr ..

c) From 134 g of this compound, 50.9 g of 2-chloro-4-methyl-pyridine and 19.1 g of sodium hydride dispersion is usually 1-benzylamino-3- (4-methyl-pyridin-2-yloxy) -2-propanol produced, which melts after recrystallization from cyclohexane at 70-71 °.

d) A solution of 10.9 g of l-benzylamino-3- (4-methy1-pyridin-2-yloxy) -2-propanol and 7.0 g of triethylamine in 50 ml of chloroform is stirred with a solution of 9.6 g 3,4-methylenedioxy-phenylacetyl chloride in 50 ml of chloroform added dropwise and the reaction mixture stirred for 2 hours. The reaction solution is in each case, 20 ml 2-n. Hydrochloric acid, then with 2-n. Sodium hydroxide solution and finally washed with water, dried over sodium sulfate and that The solvent is evaporated off, after which the oily N-benzyl-N- [2-hydroxy-3- (4-methyl-pyridin-2-yloxy) -propyl] - (3,4-methylenedioxyphenyl) -acetamide obtained, which is used without further purification.

e) A solution of 12 g of the compound obtained in 50 ml of 1,2-dimethoxyethane is added with ice cooling and stirring a suspension of 2.0 g of lithium aluminum hydride in 100 ml of 1,2-dimethoxyethane was added dropwise. The reaction mixture is then Stirred for 3 hours at 48 - 55 ° internal temperature and decomposed with 10 ml of water while cooling with ice. The organic phase will separated, evaporated in vacuo and dissolved in about 200 ml of ethyl acetate. The solution is with 50 ml of 2-n. Hydrochloric acid extracted, the acidic, aqueous phase separated and with conc. Sodium hydroxide solution releases the base. By extraction with ethyl acetate and

8098U / 0601

? 7AÜ678

Evaporation of the solvent gives the 1- [N-benzyl-N- [2- (3,4-methylenedioxy-phenyl) -ethyl] -amino] -3- (4-methyl-pyridin-2-yloxy) -2- propanol as an OeI, which is further processed as such.

Example 7

A solution of 8 g of crude N- [2-hydroxy-3- (3-methylpyridin-2-yloxy) propyl] - (3,4-methylen-dioxy-phenyl) -acetamide in 100 ml of tetrahydrofuran with ice cooling with 100 ml a 1-m. Solution of diborane in tetrahydrofuran added and Left to stand at room temperature for 5 hours. The solution is then evaporated with 100 ml of 2-n. Hydrochloric acid is added and approx. Left to stand for 1 hour. The solution is extracted with 50 ml of ether, the acidic, aqueous phase is separated off and washed with conc. Caustic soda made alkaline. Extraction with ethyl acetate and evaporation of the solvent are obtained crude 1- [2- (3,4-methylenedioxy-phenyl-ethylamino] -3- (3-methylpyridin-2-yloxy) -2-propanol as oil, its hydrochloride after recrystallization from methanol-ether at 123-125 ° melts.

The starting material is obtained analogously to Example 6b) from 10 g (3,4-methylenedioxyphenyl) acetyl chloride and 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 3-cyano-2- (2,3-epoxy-propoxy) -pyridine and 9.0 g of 2- (3,4-dimethoxyphenyl) -ethylamine in 100 ml of isopropanol is stirred for 18 hours at room temperature. Work-up analogous to the example 2 gives the crude 3-cyano-2- (3- (2- (3,4-dimethoxy-phenyl) -ethyl) -2-hydroxy-propoxy] -pyridine, the neutral fumarate of which melts at 160-161 ° after recrystallization from methanol.

8098U / 0601

The 3-cyano-2- (2,3-epoxypropoxy) pyridine required as starting material is prepared in analogy to Examples 3a) 3d) using 2-chloro-3-cyano-pyridine, whereby the following crystalline intermediates are obtained:

a) 5 - [(3-Cyano-pyridin-2-yloxy) -methoxy] -2,2-dimethyl-1,3-dioxolane, which after recrystallization from ether-petroleum ether melts at 68-71 °;

b) 3-cyano-2- (2,3-epoxy-propoxy) -pyridine, which according to the recrystallization from ether at 55-58 ° melts.

Example 9

A solution of 23 g of crude 1- {N-benzyl-N- [2- (p-benzyloxyphenyl) ethyl] amino] -3- (3-methyl-pyridin-2-yloxy) -2-propanol in 300 ml of methanol is hydrogenated and worked up analogously to Example 6 until 2 molar equivalents of hydrogen are absorbed, after which the 1- [2- (p-hydroxyphenyl) ethylamino] -3- (3-methylpyridin-2-yloxy) -2-propanol obtained whose neutral fumarate after recrystallization from isopropanol at 182-183 ° melts.

The starting material is obtained in the following way: a) A solution of 13.6 g of l-benzylamino-3- (3-methylpyridin-2-yloxy) -2-propanol, which melts at 77-82 °, and 7.6 g of triethylamine in 150 ml of chloroform is in the course of 10 minutes with a solution of 16.0 g (p-benzyloxyphenyl) acetyl chloride added in 100 ml of chloroform, the temperature rising to about 40 °. The reaction mixture is still 2 hours Stirred and then worked up analogously to Example 6b), after which the crude N-benzyl-N- [2-hydroxy-3- (3-methyl-pyridin-2-yloxy) -propyl- (p-benzyloxyphenyl) -acetamide is added obtained as a brown oil, which is processed further without further purification.

8098U / 0601

- 3JÖ- -44

b) 24 g of the compound obtained are dissolved in 200 ml of tetrahydrofuran, while cooling with 150 ml of a
1-m. A solution of diborane in tetrahydrofuran was added and the mixture was left to stand at room temperature for 24 hours. Working up as in Example 6c) gives crude 1- [N-benzyl-N- [2- (p-benzyloxyphenyl) ethyl] amino] -3- (3-methyl-pyridin-2-yloxy) -2-propanol as brown viscous oil, which is processed further without further cleaning.

Example 10

22 g of crude 1- [N-benzyl-N- [2- (p-benzyloxy-phenyl) -a'thyl] -amino] -3- (4-methyl-pyridin-2-yloxy) -2-propanol is analogous Example 9 debenzylated to 1- [2- (p-hydroxyphenyl) ethylamino] -3- (4-methyl-pyridin-2-yloxy) -2-propanol, which after recrystallization from isopropanol at 104-105 °
melts.

The starting material is analogous to the examples
9a - b from l-benzylamino-3- (4-methyl-pyridin-2-yloxy) -2-
propanol produced.

Example 11

Analogously to Example 1, using 48 g of crude 2- [3 '- (2- (3,4-dimethoxyphenyl) ethyl) -2 ¹ -phenyloxazolidinyl- (5') -methoxy] -3-methoxy- Pyrazine l- [2- (3,4-Dimethoxyphenyl) ethylaraino] -3- (3-methoxy-pyrazin-2-yloxy) -2-propanol, the hydrochloride of which melts at 167-170 °.

The starting material is prepared analogously to Example Ic) using 17.1 g of 2-chloro-3-methoxy-pyrazin give crude oily 2- [3'-2- (3,4-dimethoxy-phenyl) ethyl ) -2 '-phenyl-oxazolidiny> lj (5') -methoxy] -3-methoxy-pyrazine is obtained.

8098U / 0601

Example 12

Analogously to Example 1, using 52 g of crude 2-chloro-3- [3 ¹ - (2- (3,4 ~ dimethoxyphenyl) ethyl) -2 '-phenyl-oxazolidinyl-CS ^ -methoxyJ-pyrazine is obtained l- (3-chloropyrazin-2-yloxy) -3- [2- (3,4-dimethoxyphenyl) ethylamino] -2-propanol, the hydrochloride of which melts at 183-187 °.

The starting material is analogous to Example Ic) under Using 17.6 g of 2,3-dichloro-pyrazine produced. The 2-chloro-3-f3 '- (2- (3,4-dimethoxyphenyl) ethyl) -2'-phenyl-oxazolidinyl- (5') methoxy] pyrazine thus obtained is processed further raw.

Example 13

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 Methanol is refluxed for 5 hours. After filtration and evaporation of the solvent, crude 1- [2- (3,4-dimethoxyphenyl) ethylamino] 3- (3-methoxy-pyrazin-2-yloxy) -2-propanol is obtained as a yellow oil, the hydrochloride of which is after Recrystallization from methanol at 167-170 ° melts.

Example 14

A solution of 13 g of crude N- [2-hydroxy-3- (3-methylpyridin-2-yloxy) propyl] - (p-hydroxyphenyl) acetamide in 200 ml of tetrahydrofuran is added dropwise at 5-10 ° while cooling with ice with 250 ml of a 1-m. A solution of diborane in tetrahydrofuran is added and the mixture is stirred at room temperature for 20 hours. After evaporation of the solvent, the residue is carefully mixed with 100 ml of 2-n. Hydrochloric acid is added and the mixture is stirred for 1 hour. The deposited crystals are filtered off and the solution with

8098U / 0601

-Mi

50 ml of ether extracted. The aqueous phase is then brought to pH 8-9 with solid sodium bicarbonate and each with 100 ml of ethyl acetate extracted twice. Evaporation of the organic phase gives crude 1- [2- (p-hydroxyphenyl) ethylamino] -3- (3-methyl-pyridin-2-yloxy) -2-propanol as a yellowish oil, its neutral fumarate after recrystallization from isopropanol melts at 182-183 °.

The raw material is produced in the following way: A solution of 7.6 g of p-hydroxyphenylacetic acid and 6.6 g of triethylamine in 200 ml of dioxane is added with cooling and stirring at 0-5 °, a solution of 7.23 g of trimethylacetyl chloride in 100 ml of dichloromethane was added dropwise. The colorless suspension is stirred for 4 hours at 0-5 ° and then a solution of 8.2 g of l-amino-3- (3-methyl-pyridin-2-yloxy) -2-propanol at this temperature added dropwise in 50 ml of dioxane. The suspension is 2 hours at 0-5 ° and then 15 hours at room temperature stirred. After evaporation of the solvent in vacuo, the residue is between 200 ml of ethyl acetate and 100 ml of water distributed, the organic phase 2 times with 200 ml of 1-n. Hydrochloric acid extracted, the acidic extracts combined and brought to pH approx. 8 with solid sodium bicarbonate. The precipitated oil is extracted with dichloromethane. To evaporation of the dichloromethane gives crude N- [2-hydroxy-3- (3-methyl-pyridin-2-yloxy) propyl] - (p-hydroxyphenyl) acetamide as a light yellow, viscous oil that can be cleaned without further cleaning is used.

Example 15

Analogously to the procedure described in Example 2, using 3.6 g of 2- (2,3-epoxypropoxy) r3-methoxypyridine is obtained and 2.5 g of p-hydroxyphenethylamine l- [2- (p-hydroxyphenyl) ethylamino] -3- (3-methoxypyridin-2-yloxy) -2-propanol, the neutral fumarate of which melts at 175-176 ° after recrystallization from methanol-acetone.

8098U / 0601

Example 16

A solution of 7.3 g of 1- [2- (p-benzyloxyphenyl) ethylamino] -3- (3-methoxypyridir-2-yloxy) -2-propanol in 100 ml of ethanol in the presence of 1.5 g of palladium on carbon catalyst (5%) hydrogenated until 1 mol equivalent of hydrogen is absorbed at atmospheric pressure. After filtering off the catalyst and evaporating the filtrate, 1- [2- (p-hydroxyphenyl) ethylamino] -3- (3.-methoxypyridin-2-yloxy) is obtained -2-propanol, whose neutral fumarate after recrystallization from methanol-acetone at 175 - 176 ° melts.

The starting material is obtained by reacting 5.4 g of 2- (2,3-epoxypropoxy) -3-methoxypyridine and 6.5 g (p-benzyloxyphenyl) ethylamine in 150 ml of isopropanol analogous to Example 2; after recrystallization from dichloromethane ether it melts at 85-86 °.

Example 17

A mixture of 400 mg 2- (p-hydroxyphenyl) ethyl bromide, 500 mg of l-amino-3- (3-methyl-pyridin-2-yloxy) -2-propanol, and 200 mg of potassium bicarbonate are dissolved in 10 ml of isopropanol Stirred under reflux for 5 hours. Work-up analogous to the example 4 gives the oily 1- [2- (p-hydroxyphenyl) ethylaminoj-3- (3-methyl-pyridin-2-yloxy) -2-propanol, the neutral fumarate of which melts at 182-183 ° after recrystallization from isopropanol.

Example 18

A solution of 14 g of crude 1- [N-benzyl-N- [2- (4-benzyloxy-3-methoxyphenyl) ethyl] amino] -3- (3-methyl-pyridin-2-yloxy) -2 -propanol in 200 ml of methanol with the addition of 4.0 g of palladium-on-charcoal catalyst (5%) until it is absorbed

8098U / 0601

of 2 molar equivalents of hydrogen under normal conditions hydrogenated. After filtering off the catalyst and concentrating the filtrate by evaporating off the solvent, the Evaporation residue between 200 ml of ether and 100 ml of 2-n. Hydrochloric acid distributed, the acidic, aqueous solution separated, with conc. Ammonia solution made alkaline and extracted with 200 ml of ethyl acetate. By evaporating the dried Ethyl acetate solution gives crude 1- [2- (4-hydroxy-3-methoxyphenyl) ethylamino] -3- (3-methyl-pyridin-2-yloxy) -2-propanol as a yellow oil, which is dissolved in methanol with half the equivalent amount of fumaric acid, a neutral one Forms fumarate, which melts at 181-183 °.

The starting material can be produced in the following manner will:

a) 4-Benzyloxy-3-methoxyphenylacetic acid (melting point 87-90 °) is converted into the acid chloride with thionyl chloride in dichloromethane Transferred and this analogously to Example 6 b) with 1-benzylamino-3- (3-methyl-pyridin-2-yloxy) -2-propanol to N-benzyl-N- [2-hydroxy-3- (3-methyl-pyridin-2-yloxy) -propyl] - (4-benzyloxy-3-methoxyphenyl) -acetamide implemented. It forms an OeI, which is used raw.

b) 22 g of the crude amide obtained are reduced with diborane analogously to Example 9 b) and give the crude 1-IN-Benzyl-N- [2- (4-benzyloxy-3-methoxyphenyl) -ethyl] -amino] -3- (3-methyl-pyridin-2-yloxy) -2-propanol as a yellow oil, which is further processed as such.

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Example 19

Tablets containing 0.1 g of 2-f3 ^f - (2- (3,4-dimethoxyphenyl) ethylamino) -2'-hydroxy-propoxyJ-3-cyanopyridine as a neutral fumarate are prepared as follows:

Composition (fllr 10 ¹ OOO tablets):

2- [3 * - (2- (3,4-Dimethoxyphenyl) ethylamino) -2'-hydroxy-

propoxy] -3-cyanopyridine as neutral fumarate 1000.00 g

Milk sugar 580.00 g

Corn starch 750.00 g

Colloidal silica 80.00 g

Talc 80.00 g

Magnesium stearate 10.00 g water q.s.

Manufacturing

2- [3 '- (2- (3,4-Dimethoxyphenyl) ethylamino) -2'-hydroxypropoxy] -3-cyanopyridine as a neutral fumarate is with the lactose, part of the corn starch and with colloidal silica mixed and the mixture forced through a sieve. Another portion of the cornstarch is made with five times the amount of water on the water bath and knead the powder mixture with this paste until a weakly plastic mass is created. This is pressed through a sieve with a mesh size of about 3 mm, dried and that dry granules driven through a sieve again. The remaining corn starch, talc and magnesium stearate are then placed on top and the mixture obtained is compressed into tablets weighing 0.250 g (with a breaking notch).

S0IIU / 0S01

Claims (8)

Claims 27 A UP / 8 1. Process for the preparation of l-amino-2-hydroxy-3-heterocyclyloxy-propanes the formula 0 - CH ₂ - CH (OH) - CH ₂ - NH - CH ₂ -CH ₂ -f ^% (I), where Y is the group - CH = or the group -N =, Rj is hydrogen, hydroxy, lower alkyl or lower alkoxy, R "hydroxy, lower alkoxy or together with R, o-lower alkylidendioxy or o-lower alkylenedioxy and R- mean lower alkyl, lower alkoxy, halogen or cyano, where the radicals R ,, R ₂ and R- are each bonded to any of the possible aromatic carbon atoms, characterized in that in a compound of the formula cm - cn - cm - ν - cm - cn in which Y and R- have the above meanings, R, has the meaning of R, and in addition for the group -0-X ^, R, - has the meaning of R ₂ and also represents the group - 0 - X, where at least one of the groups X ₁ , X 2, X and X is a hydrogen-replaceable group and the others are hydrogen or a hydrogen-replaceable group, or X 'and X' together are one detachable by two with the the oxygen atom corresponding to the secondary alcohol group 8098U / 060 1 ORIGINAL INSPECTED wise denote hydrogen atoms connected to the nitrogen atom, and / or X- and X, together represent a detachable group replaceable by two hydrogen atoms connected to the oxygen atoms corresponding to the groups - O - X - or - O - X, or in one Salt thereof, the radical X, and / or X ₂ or X, and X ₂ together and / or X- and / or X, and / or X- and X, together replaced by hydrogen, or a compound of the formula - CH ₂ - CH - CH ₂ - X ₆ (III) ^X 5 with a compound of the formula R ₁ X ₇ - CH ₂ - CH ₂ - {'A) (IV) wherein one of the groups X ₆ and X _{7 represents} a reactive esterified hydroxyl group and the other represents the primary amino group and X _{5 represents} the hydroxyl group, or wherein X ₅ and X ₆ together represent the epoxy group and X ₇ represents the primary amino group, and Y, R ₁ , R ₂ and R _{3 have the} above meanings, converts, or in a compound of the formula ₀ ³ - CH ₂ - CH (OH) - X ₈ -P% (V) wherein the group -Xg- (Va) is one of the radicals of the formulas -CH-N- CH ₂ - CH ₂ - (Vb), or - CH ₂ - N - CH - CH ₂ - (Vc), or -C (- X ₉ ) - N - CH ₂ - CH ₂ - (Vd) or 8098U / 0601 274Q678 N - C (= Xg) - CH ₂ - (Ve) is where X _g X ₁ l
represents the oxo or thioxo group, Y, R ,, R ₂ and X. have the above meanings, and R «has the meaning given with the exception of halogen and cyano, the group - X _R - optionally via the radical - CH ₂ - Containing N - CH ₂ - CH ₂ - Intermediate to the remainder of the formula - CH ₂ - NH - CII ₂ - CH ₂ - reduced, and, if desired, a compound obtained from the Formula I converted into another compound of formula 1, and / or, if desired, a free compound obtained in A salt or a salt obtained is converted into a free compound, and / or, if desired, a mixture of isomers obtained separates into the individual isomers or a racemate obtained into the optical antipodes. 2. The method according to claim 1, characterized in that one _{splits off X, and / or X 2} and / or X-, and / or X, by means of solvolysis or reduction. 3. The method according to claim 1 to 2, characterized in that a cleavable group X, a hydrogenolytically cleavable a-aryl lower alkyl group and primarily benzyl. 4. The method according to claim 1 to 2, characterized in that a cleavable group X, a solvolytic, such as hydrolytic or acidolytically or reductively cleavable acyl radical, such as the acyl radical of an organic carboxylic acid or sulfonic acid, or optionally substituted 1-polyphenyl-lower alkyl radical represents. 5. The method according to claim 1 to 2, characterized in that a removable group X ₂ , Xo and X, a hydrogenolytically removable ot-aryl-lower alkyl group and primarily benzyl 809814/0601 -Jl- 27-067 6. The method according to claim 1 to 2, characterized in that a removable group X ₂ , Xq ^unc ^ X /. represents an acyl radical which can be split off solvolytically, such as hydrolytically, alcoholytically or acidolytically, or an optionally substituted aliphatic or araliphatic hydrocarbon radical which is polybranched at the linking carbon atom. 7. The method according to claim 1 to 2, characterized in that X, and X ₂ together and X- and X, together represent a hydrogenolytically cleavable, optionally substituted 1-phenyl-lower alkylidene radical. 8. The method according to claim 1 to 2, characterized in that X, and X «together and X ₃ and X, together represent a solvolytically cleavable lower alkylidene or cycloalkylidene radical, furthermore the carbonyl or thiocarbonyl group. 9. The method according to any one of claims 3, 5 and 7, characterized characterized in that the starting material is treated with catalytically activated hydrogen. 10. The method according to any one of claims 4, 6 and 8, characterized characterized in that the starting material is hydrolyzed, alcoholized, acidolyzed or reduced. 11. The method according to claim 1, characterized in that starting materials of the formula (V), in which the group of the formula (Va) are the radicals of the formulas (Vb) or (Vc), and (Vd) or (Ve), in which the groups -C (= X ") - NH- or -NH-C (= X _g ) - represent a carbatnoyl group, means treated with a light metal hydride or a borohydride. 8098U / 0601 12. The method according to claim L, characterized in that starting materials of the formula (V), wherein the group of Formula (Va) denotes the radicals of the formulas (Vb) or (Vc), treated with catalytically activated hydrogen. 13. The method according to claim 1, characterized in that starting materials of the formula (V), wherein the group of the formula (Va) denotes the radicals of the formulas (Vd) or (Ve) in which Xq represents the thioxo group, reductively desulfurized. 14. The method according to any one of claims 1-13, characterized in, that one starts from a compound obtainable as an intermediate at any stage of the process and the carries out the missing procedural steps, or terminates the procedure at any stage. 15. The method according to any one of claims 1-14, characterized in that that one forms a starting material under the reaction conditions, or that a reaction component optionally in the form of their salts. 16. The method according to any one of claims 1-15, characterized in that compounds of the formula (I) according to claim 1 or their salts are prepared in which R, hydrogen, hydroxy, lower alkyl or lower alkoxy each having up to 4 carbon atoms, R ^ Hydroxy, lower alkoxy with up to 4 carbon atoms and together with R, o-Niederalkylidendioxy with 1 to 2 carbon atoms and R-lower alkyl or lower alkoxy each with up to 4 carbon atoms, halogen or cyano, where R, and R «are in the 2-, 3- or 4-position and o-lower alkylidenedioxy or o-lower alkylenedioxy in 2,3- or in 3,4-position and R_ in a pyridine ring in 3-, 4-, 5- or 6-position Position or in a pyrazine ring in the 3-, 5- or 6-position. 80981 A / 0601 17. The method according to any one of claims 1-15, characterized characterized in that one compounds of the formula O - CH ₉ - CH (OH) - CH ₉ - NH - CH _{9 - CH 9} (Ia), or their salts, in which R, hydrogen, hydroxy, methyl or methoxy, R _{9 is} hydroxy, methoxy or together with R, o-methylenedioxy and R-methyl, methoxy, chlorine or cyano, where R, and R _{9 in} each case in 3 - or 4-position, o-methylenedioxy in the 3,4-position and R ₃ in the 3- or 4-position. 18. The method according to any one of claims 1-15, characterized in that compounds of the formula - CH ₂ - CH (OH) - CH ₂ -NH - (Ib) or their salts, in which R, hydrogen, hydroxy, methyl or methoxy, R _{9 is} hydroxy, methoxy or together with R, o-methylenedioxy and R ~ is methyl, methoxy, chlorine or cyano, where R, and R _{9 are} each in 3 - Or 4-position o-methylenedioxy is in the 3,4-position and R _{3 is} in the 3-position, as well as their salts. 19. The method according to any one of claims 1-15, characterized in, that you have 2- £ 3 '- (2- (3,4-Dimethoxyphenyl) ethylamino) -2'-hydroxy-propoxyJ-3-cyanopyridine or making salts thereof. 809814/0601 .3. 20. The method according to any one of claims 1-15, characterized characterized in that 1- (ß-chloropyrazine ^ -yloxy) -3- [2- (3,4-dimethoxyphenyl) ethylamino] -2-propanol or making salts thereof. 21. The method according to any one of claims 1-15, characterized in that 1- [2- (3,4-dimethoxyphenyl) ethylamino] -3- (3-methoxypyridin-2-yloxy) -2-propanol or salts thereof. 22. The method according to any one of claims 1-15, characterized characterized in that 1- [2- (p-methoxyphenyl) -ethylamino] -3- (3-methylpyridin-2-yloxy) -2-propanol or making salts thereof. 23. The method according to any one of claims 1-15, characterized characterized in that 1- [2- (3,4-methylenedioxyphenyl) ethylamino] -3- (3-methylpyridin-2-yloxy) -2-propanol or making salts thereof. 24. The method according to any one of claims 1-15, characterized in that that 1- [2- (3,4-methylenedioxyphenyl) ethylamino] -3- (4-methylpyridin-2-yloxy) -2-propanol or salts thereof. 25. The method according to any one of claims 1-15, characterized in that that 1- [2- (p-hydroxyphenyl) -ethylamino] -3- (3-methylpyridin-2-yloxy) -2-propanol or making salts thereof. 26. The method according to any one of claims 1-15, characterized characterized in that 1- [2- (p- ^ lydroxyphenyl) -EthylaminoJ-3- (4-methylpyridin-2-yloxy) -2-propanol or making salts thereof. 8098U / 0601 27. The method according to any one of claims 1-15, characterized characterized in that one l- [2- (3,4-Dimethoxyphenyl) ethylamino] -3- (3-methoxypyrazin ~ 2-yloxy) -2-propanol or making salts thereof. 28. The method according to any one of claims 1-15, characterized in that 1- {2- (p-IIydroxyphenyl) ethylamino] 3- (3-methoxypyridin-2-yloxy) -2-propanol or making salts thereof. 29. The method according to any one of claims 1-15, characterized characterized in that l- [2- (3-methoxy-4-hydroxyphenyl) ethylaminoj-3- (3-methylpyridin-2-yloxy) -2-propanol or making salts thereof. 30. l-Amino-2-hydroxy-3-heterocyclyloxy-propane of the formula O - CH ₂ - CH (OH) - CH ₂ - NH - where Y stands for the group - CH - or the group - N -, R _{1 is} hydrogen, hydroxy, lower alkyl or lower alkoxy, R _{2 is} hydroxy, lower alkoxy or together with R _{1 is} o-lower alkylldenoxy or lower alkylenedloxy and R ₃ signifies lower alkyl, lower alkoxy, halogen or cyano, where the radicals R _{1, R 1 and R 3 are} each bonded to any of the possible aromatic carbon tones. 31. Compounds of the formula I ge mass claim 3 0, wherein R, hydrogen, hydroxy, lower alkyl or lower alkoxy each with up to 4 carbon atoms, R ₂ hydroxy, lower alkoxy with up to 8098U / 0601 to 4 carbon atoms and together with: R, o-Niederalkylidendioxy with 1 to 2 carbon atoms and R- lower alkyl or alkoxyalkoxy in each case up to 4 carbon atoms, halogen or cyano, where R- and R2 are each In 2-, 3- or 4-position and o-Niederalkylidendioxy or o-Niederalkylen-dioxy in 2,3- or in 3,4- Position and R- in a pyridine ring in the 3-, 4-, 5- or 6-position, or in a pyrazine ring in the 3-, 5- or 6-position stands. Compounds of the formula O - CH ₂ - CH (OH) - CH ₂ - NH - CH ₂ -CH ₂ wherein Hydrogen, hydroxy, methyl or methoxy, hydroxy, methoxy or together with R, o-methylenedioxy and methyl, methoxy, chlorine or cyano, where R ₁ and R _{2 are} each in the 3- or 4-position, o-methylenedioxy in 3, 4 position and R ₃ in 3 or 4 position » Compounds of the formula O $ - CH ₂ - CH (OH) - CH ₂ -NH - (Ib) wherein R. is hydrogen, hydroxy, methyl or methoxy, R _{2 is} hydroxy, methoxy or together with R, o-methylenedioxy and R- is methyl, methoxy, chlorine or cyano, where R and R _{2 are} each in the 3- or 4-position, o-Methylenedioxy is in the 3,4-position and R- in the 3-position. 809814/0601 34. 2- [3 '- (2- (3,4-Dimethoxyphenyl) -athylami.no) -2 · -hydroxypropoxyJ -3-cyanopyridine. 35. 1- (3-Chlorpyrazin-2-yloxy) -3- [2- (3 _f 4-dimethoxyphenyl) -ethylamino] -2-propanol. 36. 1-12- (3,4-Ditnathoxyphenyl) -ethylamine-3- (3-methoxypyridin-2-yloxy) -2-propanol. ψ / 37. 1- [2- (p-Methoxyphenyl) ethylamino] -3- (3-methylpyridln-2-yloxy) -2-propanol. 38. 1-2- (3,4-methylenedioxyphenyl) -ethylaminoJ-3- (3-methylpyridin-2-yloxy) -2-propanol. 39. 1-12- (3,4-Methylendloxyphenyl) -ethylaminoJ-3- (4-methylpyrldln-2-yloxy) -2-propanol. 40. 1- [2- (p-Hydroxyphenyl) ethylamino] -3- (3-methylpyrldln-2-yloxy) -2-propanol. 41. 1- [2- (p-Hydroxyphenyl) ethylamino] -3- (4-methylpyrldin-2-yloxy) -2-propanol. 42. l-i2- (3,4-Dlmethoxyphenyl) - * lthylaininoJ-3- (3-methoxypyra zln-2-yloxy) -2-propanol. 43. 1- [2- (p-Hydroxyphenyl) ethylamino] -3- (3-raeChoxypyrIdin-2-yloxy) -2-propanol. 44. 1- [2- (3-Methoxy-4-hydroxyphenyl) ethylamino] -3- (3-methylpyridin-2-yloxy) -2-propanol. 809 8.U / 0601 46 - 45. Salts of compounds of claims 30-44. 46. Acid addition salts of compounds of claims 30-44. 47. Pharmaceutically acceptable, non-toxic acid addition salts of compounds of claims 30-44. 48. Pharmaceutical preparations containing a compound of claims 30-44 and 47. 49. Use of the compounds of claims 30-44 and 47 in the form of pharmaceutical preparations. 8098U / 0601