DE2623314A1 - NEW 1-ARYLOXY-2-HYDROXY-3-AMINOPROPANES AND THE METHOD FOR THEIR PRODUCTION - Google Patents

Description

HOECHST AKTIENGESELLSCHAFT

File number:

Date: May 21, 1976

HOE 76 / F 115 Dr.La/Rp

NEW 1-ARYLOXY-2-HYDROXY-3-AMINOPROPANES AND PROCEDURES FOR ITS

MANUFACTURING

The present invention relates to new basic substituted phenol ethers of the formula I.

OH
OCH ₂ - CH _{- CH 2} - N

wherein R ¹ and R ¹ 'are identical or different and are hydrogen,

709849/0235

- Ύ -

an alkyl or alkoxy radical with 1-4 carbon atoms, the

2 represent a halogen atom or the nitro group, R an acrylic acid residue or Acrylic Acid Nitrxlrest of the formulas

R ⁵ R ⁶ R ⁵ R ⁶

I I 7 Il

-C = C-C- OR or - C = C - CN

in which R is hydrogen, a C. - C ₅ -alkyl radical, an unsubstituted or aryl or aryl-lower alkyl radical which is unsubstituted or substituted by lower alkyl or alkoxy, R is hydrogen or an alkyl radical having 1-8 C atoms, .R is hydrogen, a lower one Mean alkyl or an aryl-lower alkyl radical,

3 4

R and R together with the nitrogen atom form a heterocyclic ring with 5-7 which is optionally substituted with C.-C.-alkyl Represent members in which a carbon atom is replaced by an oxygen, sulfur atom or another nitrogen atom may be, the latter may be substituted with an alkyl, alkoxy, oxalkyl, acyl or carbalkoxy radical with each 1-5 carbon atoms, a pyridyl radical or a phenyl radical, which in turn can be substituted one or more times by the Hydroxyl group, halogen or an alkyl or alkoxy group with 1-4 C atoms, or

3 4

R is hydrogen and R is a straight-chain or branched alkyl or oxalkyl radical with 1-8 C atoms, a straight-chain or branched unsaturated aliphatic hydrocarbon radical with 2-6 carbon atoms, a cycloaliphatic hydrocarbon radical with 3-6 carbon atoms or a phenylalkylene or Phenylalkylidene radical of the formula

R ^9/3

709S49 / 023f

ORIGINAL INSPECTED

8 9

mean in which η is a number from 1-3 and R and R are identical or different and are hydrogen, an alkoxy radical with

Q g

1-3 carbon atoms or the benzyloxy radical or R and R together represent the bismethylenedioxy radical,

as well as the physiologically acceptable acid addition salts.

The invention includes both the racemic mixtures and the individual optically active isomers of the formula I.

The present invention also relates to a method of manufacture of compounds of the formula I, which is characterized in that one

a) a compound of the formula II

\\ / OCH ₂ - CH - CH ₂ II

R ²

11 '2
wherein R, R and R have the meaning given for formula I, with an amine of formula III

HN I ₁₁

3 4
in which R and R have the meaning given for formula I, converts or

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b) a compound of the formula IV

OCH ₂ - CH - CH ₂ X IV OH

1 1 '2 wherein R, R and R have the meaning given for formula I and

X is a halogen atom, which is sulfuric acid or a sulfonic acid radical, is reacted with an amine of the formula III or

c) a compound of the formula V.

R ¹ '1

V ⁴ V.-

_x . / w CH ₀ - CH - CH ₀ - NH ₀ V

\ l / 2 ι 2

\ ^ OH

R ²

11 '2 wherein R, R _and ar have the meaning given for formula I,

with a compound of the formula VI

XR ⁴ VI

4 wherein R is the formula I and X is the formula IV

Have meaning, converts, or d) a phenol of the formula VII

VII

1 1 «2 where R, R and R have the meaning given for formula I,

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with a compound of the formula VIII

X - CH ₀ - CH - CH- - N VIII

2 ι 2 \ μ

3 4

in which R and R are as defined for formula I and X as defined for formula IV, in the presence of an acid-binding agent, or

e) a compound of the formula V or IX

OCH ₂ - CO - CH ₂ - NH ₂ IX

11 * 2

R, R _and R have the meaning given for formula I,

Reacts with a suitable ketone and reduces the condensation product or

f) a compound of the formula X

OCH ₂ - CO - CH ₂ - NHR ₄ X

11 * 9 Λ

wherein R, R, r and R have the meaning given for formula I, reduced or

g) a compound of the formula XI

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χ -

O - CH _n - CH ₀ XI

I I 4

O N-R

1 1 '9 &

wherein R, R, R and R have the meaning given for formula I and Z is a carbonyl group or optionally with one Phenyl group or one or two lower alkyl radicals Represents methylene group, hydrolyzed or

h) in a compound of the formula XII

0 - CH ₂ - CH - CH ₂ - N - R ³ i ¹⁰ R ¹¹

R ²

1 1 '2 3
in which R, R, R and R have the meaning given for formula I, R is hydrogen, a lower acyl radical or the benzyl radical

11 10

and R denotes hydrogen or the benzyl radical, but R and R cannot both denote hydrogen at the same time, the benzyl groups are split off by catalytic hydrogenation in the presence of noble metal and / or the acyl group is hydrolyzed

and the compounds obtained by processes a) to h), if appropriate converted into the physiologically acceptable acid addition salts.

Of the substituents mentioned, the following are preferred: For R ⁴ (if R ³ = H): alkyl, alkoxy or oxalkyl radicals having 15 carbon atoms, in particular branched radicals such as the isopropyl or tert-butyl radical, and also unbranched unsaturated ones aliphatic hydrocarbons with 2-4 carbon atoms, especially the

/ 7

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-7-

' ⁵ 26233H

Allyl radical, cycloaliphatic hydrocarbons with 4 or 5 carbon atoms, in particular the cyclopentyl radical, as well as dialkoxyphenylethylidene, especially the 5 ', 4'-dimethoxyphenylethylidene and the 1-methyl-2-3 ', 4' -Dimethoxyphenyläthylidenrest.

3 4

If R and R together with the nitrogen atom form a heterocyclic Ring form / are preferred as ring systems those with 5 or 6 members, e.g. pyrrolidine, piperidine and morpholine, which with lower alkyl radical one to two times or can be substituted by the pyridyl radical. The piperazine ring is particularly preferred, which can be substituted on the second nitrogen atom with a Alkyl, alkoxy, oxyalkyl or acyl groups with 1-4 carbon atoms, with a carbalkoxy group with 1-5 carbon atoms, with a pyridyl radical or with an optionally substituted phenyl radical.

For R: hydrogen, an unbranched alkyl radical with 1-4 C atoms, in particular the methyl, ethyl and phenyl radicals,

For R: hydrogen, an alkyl radical with 1-4 carbon atoms,

For R: an alkyl radical with 1-4 carbon atoms, in particular the methyl, ethyl and tert-butyl radical as well as the benzyl radical.

1 1 '

For R and R: hydrogen _} alkyl and alkoxy radicals with 1 - 3 C-

Atoms, fluorine, chlorine and the nitro group.

The amines of the formula III are used for the reactions according to the procedures a) and b) in question:

1. Primary amines, such as: methylamine, ethylamine, isopropylamine, isobutylamine, sec. Butylamine, tert-butylamine, 1-methylpropylamine, 2-aminoethanol, 2-methoxyethylamine, 1-methyl-3-hydroxypropylamine, Allylamine, 3-dimethylaminopropylamine, Phenylethylamine, 3-phenylpropylamine, 1-phenylethylamine, 1-methyl-2-phenylethylamine, i-methyl-2- (4-methoxy) -phenylethylamine, 1-methyl-2- (3,4-dimethoxy) -phenylethylamine, 3,4-dimethoxyphenylethylamine, 3-methoxy-4-ethoxyphenylethylamine, S-methoxy ^ -hydroxyphenylethylamine, 3-methoxy-4-benzyloxy-

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phenylethylamine, S-benzyloxy ^ -methoxy-phenylethylamine, 3,4-methylenedioxy-phenylethylamine, 2,5-dimethoxyphenylethylamine, 2/4-dimethoxyphenylethylamine, 2,3-dimethoxyphenylethylamine, 3,4,5-trimethoxyphenylethylamine, 2-methoxyphenylethylamine, 3-methoxyphenylethylamine, 4-methoxyphenylethylamine, 3,4-dimethoxyphenyl-methylamine, 2-hydroxy-2-phenylethylamine, 1-methyl-2-hydroxy-2-phenylethylamine, 3,4-dimethylphenylethylamine, 4-chlorophenylethylamine, 3,4-dichlorophenylethylamine, 4-hydroxyphenylethylamine, heptaminol, cyclopropylamine, Cyclopentylamine, cyclohexylamine, 2-adamantylamine. As special The use of isopropylamine and tert-butylamine, furthermore homoveratrylamine, has proven advantageous.

2. 5-6 membered cyclic secondary amines such as: N-phenylpiperazine, N-2'-methylphenylpiperazine, N-3'-methylphenylpiperazine, N-4'-methylphenylpiperazine, N-2'-methoxyphenylpiperazine, N-3'-methoxyphenylpiperazine, N-4'-methoxyphenylpiperazine, N-2'-chlorophenylpiperazine, N-3'-chlorophenylpiperazine, N-4'-chlorophenylpiperazine, N-2'-pyridylpiperazine, N-3'-pyridylpiperazine, N-4'-pyridylpiperazine, N-2'-hydroxyphenylpiperazine, N-3'-hydroxyphenylpiperazine, N-4'-hydroxyphenylpiperazine, N-Oxyäthylpiperazin, N-Methylpiperazin, N-Ethylpiperazine, N-Carbmethoxypiperazine, N-Carbethoxypiperazine, N-carb- (2-hydroxy-2-methyl) -propoxypiperazine, 2-methylpiperazine, 2,6-dimethylpiperazine, 2,6-dimethylpiperidine, 3-ß-pyridy! Piperidine, piperidine, morpholine, and pyrrolidine.

709 & 49 / 023S

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The amine residue is introduced according to procedure a) by reacting the two components, optionally in the presence of organic solvents such as alcohols, e.g. Methanol, ethanol, isopropanol, aromatic solvents such as benzene, toluene or ethers such as dioxane, tetrahydrofuran or Carboxamides, especially dimethylformamide. According to a preferred embodiment, the two components are left in alcohol dissolved react with each other at elevated temperature. The reaction temperatures are temperatures from room temperature to the boiling point of the solvent in question.

The glycidic ethers used as starting materials in procedure a) of the formula II can be obtained according to patent specification (patent application P / HOE 76 / F 116).

According to the procedure described under b) are used as starting materials the o ° -halogen-ß-hydroxypropyl ethers of the formula IV used. Instead of the halogen atom, preferably chlorine or bromine, in the oO-position, the corresponding esters of Sulfuric acid or esters of sulfonic acids can be used.

The starting materials can also be prepared by splitting the epoxide of the formula II with a hydrohalic acid or sulfuric acid or sulfonic acid. For reaction with an amine of formula III one works in the presence or absence of suitable organic solvents, such as alcohols e.g. methanol, Ethanol, isopropanol, aromatic solvents such as benzene, toluene or ethers such as dioxane, tetrahydrofuran, or carboxamides, especially dimethylformamide. The reaction can take place at temperatures between room temperature and the boiling point of the solvent take place, it is preferably carried out at an elevated temperature. To bind the liberated acid, e.g. Hydrogen halide can be used in the presence of acid-binding agents, for example tert-amines, such as triethylamine, pyridine . or alkali or alkaline earth hydroxides, carbonates or bicarbonates work. The amine used can advantageously also be used in

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Use excess, e.g. in twice the molar amount, for the reaction.

The phenoxy-2-hydroxy-1-aminopropane derivative is used for the procedure mentioned under c) of the formula V used.

This can also be in the form of a salt. The reaction with a reactive ester of the formula VI takes place under the Procedure b) mentioned reaction conditions. The amine of the formula V used as starting material is for example by Implementation of the epoxide of the formula II with ammonia accessible. It can also be obtained from the halogen compound IV with ammonia will.

The production of the process products succeeds even after the d) designated procedure in which the abovementioned phenol of the formula VII is used. The phenol can also be in the form its alkali metal salt, such as sodium or potassium salt, can be used. As reaction components of the formula VIII are 1-halo-2-hydroxy-3-alkylaminopropanes are used. One can also of sulfuric acid or sulfonic acid esters of 1,2-dihydroxy-3-alkylaminopropanes go out. The reaction is advantageously carried out in the presence of an acid-binding agent, such as alkali hydroxide. In The 1-halo-2-hydroxy-3-alkylaminopropane used can be used in an alkaline environment intermediate in the corresponding 1,2-epoxypropane, which reacts with the phenol. The implementation can be used in the presence or absence of solvents such as alcohols, e.g. methanol, ethanol, isopropanol, aromatic solvents, such as benzene, toluene or ethers such as dioxane, tetrahydrofuran or carboxamides, especially dimethylformamide, at normal or up to the boiling point of the solvent used increased temperature. The compounds of formula VIII used as starting materials are for example accessible by reacting an amine of the formula III with epichlorohydrin at low temperatures.

709848 / 023F

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According to the procedure described under e), the amine of the formula V with a ketone corresponding to the meaning of R. is in Hydrogenated in the presence of catalytically excited hydrogen. Examples of ketones are acetone, methyl ethyl ketone and cyclopropanone and called cyclohexanone. Raney nickel, platinum or palladium, for example, are used as catalysts. Man generally works in the presence of an inert solvent such as methanol, ethanol or isopropanol. You can also first the amine of the formula III with the abovementioned ketone condense and then reduce the Schiff base obtained, optionally without isolating it, as above. the Reduction of the azomethine can also be done with sodium boranate, lithium alanate or other complex metal hydrides, as well as with aluminum amalgam in the usual way.

In process e) only those compounds of the formula I are obtained in which the radical R. is represented by a secondary carbon atom connected to the nitrogen atom.

The process, as referred to under e), can also be carried out in such a way that the aminoketone of the formula IX is used. the The reaction is carried out in the same way as with the aminopropanol of the formula V, since in the reduction, either in a reaction stage or after preparation and optionally Isolation of the azomethine, the keto group is reduced simultaneously with the azomethine double bond. The production of the als Aminoketones used as the starting material can be effected, for example, by mild oxidation of the aminopropanol of the formula V.

The procedure referred to under f), the reduction of aminoketones of the formula X can in turn in the already in the Process e) described manner carried out by catalytic hydrogenation. The reduction of the keto group can also be carried out with lithium alanate or other complex metal hydrides are carried out or, according to Meerwein-Ponndorf, with aluminum isopropylate. The gentlemen

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position of the ketones of the formula X can, for example, by reaction of corresponding 1-halo-2-oxo-3- (phenoxy) propane with an amine of the formula III.

Another embodiment of the method according to the invention is in the hydrolysis of an oxazolidone or oxazoiidine of the formula XI according to procedure g). One can get such oxazolidones obtained, for example, by using the corresponding 1-amino-2-hydroxy-3- (phenoxy) propane with a reactive derivative of carbonic acid, such as diethyl carbonate, chlorocarbonic acid methyl ester or phosgene, or if a 5-hydroxymethyl-oxazolidone- (2) optionally substituted in the 3-position in the form of a hydrohalic acid, sulfuric acid or sulfonic acid ester with a corresponding alkali metal phenolate implements. Suitable oxazolidines can be prepared, for example, by using corresponding 1-amino-2-hydroxy-3-phenoxy-propanes of the formula V reacts with aldehydes or ketones. Not on the nitrogen atom Substituted oxazolidones or oxazolidines can be used with compounds of the formula VI as described under procedure c) be alkylated. The hydrolysis of these oxazolidone or oxazolidine derivatives can be carried out in an acidic or alkaline medium be, for example by means of dilute hydrochloric acid, dilute sulfuric acid, dilute sodium hydroxide solution or dilute Potassium hydroxide. It is advantageous to heat to accelerate the hydrolysis. The hydrolysis can also be water-soluble in the presence Solvents, e.g. lower alcohols. The products of the process can also be obtained by from Compounds of the formula XII in which the hydroxyl and / or the secondary amino group are protected by the radicals R and R, respectively is to split off these protective groups. Acyl radicals or the benzyl radical are suitable as protective groups. The splitting off of the Benzyl radical is carried out by catalytic hydrogenation in the presence of noble metals such as palladium or platinum. Will Acyl compounds used, the AcyIrest preferably a lower aliphatic acyl radical, such as the acetyl or propionyir radical, is, the cleavage takes place hydrolytically

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either in an acidic or alkaline aqueous medium. The corresponding benzyl or acyl compounds of the formula XII can be prepared by one of the methods described above, using the corresponding acylated or benzylated starting materials. If starting materials of the formula XII in which R _{2 is} an acyl radical are to be prepared, then, for example, the compound of the formula III can be acylated, whereupon the corresponding acyl compounds are then converted to compounds of the formula XII by method b).

1 0 The same applies to compounds in which R is the eenzyl

means remainder, whereby the benzy] ation instead of the acylation

the corresponding hydroxy compounds occurs. Do you want to

11 bonds of the formula XII start in which R is the benzyl radical means, you can use procedures a), b), c), f) or d) instead of the primary amines, the corresponding N-benzyl compounds insert. If you have acyl and benzyl radicals as

R and R next to one another, this group can be split off one after the other in the manner described.

It can sometimes be used in procedures a), b), d) or h) of It may be advantageous to combine the production of the starting compounds directly with the further conversion, i.e. the starting materials not to be isolated separately.

The products of the process can be used as the free base or in the form of their Salts are obtained and, if necessary, by the usual work-up methods, for example by recrystallization or optionally conversion into the free base and then Treatment with a suitable acid. The products of the process can optionally be converted into the salts physiologically compatible organic or inorganic acids are converted.

Examples of organic acids are:

Acetic acid, malonic acid, propionic acid, lactic acid, succinic acid,

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Tartaric acid, maleic acid, fumaric acid, citric acid, malic acid, Benzoic acid, salicylic acid, oxyethanesulfonic acid, aceturic acid, ethylenediaminetetraacetic acid, emboxylic acid and acidic groups synthetic resins.

Inorganic acids that can be used are, for example: Hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid and sulfamic acid.

You can obtain the optically active isomers of the racemic basic substituted phenol ethers of the formula I if one the latter is broken down into its components with optically active acids.

The following acids may be mentioned, for example, for the preparation of optically active salts according to the invention: (+) - and (-) - tartaric acid, (+) - and (-) - dibenzoyltartaric acid, (+) - and (-) - ditoluyltartaric acid, (+) - and (-) - mandelic acid, (+) - and (-) "camphoric acid, (+) - camphor-ß-sulfonic acid, (+) - o ^ - Bromcamphor-o ^ sulfonic acid and N- (p-nitrobenzoyl) - (+) -glutamic acid. The preparation of the optically active salts can be carried out in water, hydrous or anhydrous organic solvents. The use of alcohols or of Esters of organic carboxylic acids.

To prepare optically active compounds, the base racemate is preferably used in a molar amount in a solvent Amount ratios with an optically active acid and isolate the optically active salt of the compounds of the formula I. Man can in certain cases only use half an equivalent of the optically active acid to remove the one optically active acid To remove antipodes from the racemate, as you can also use excess amounts of optically active acid.

Depending on the type of optically active acid, the desired antipode can be either directly or from the mother liquor of the first

$ 709849/023

Crystals are obtained. The optically active base can then be set free from the salt in the usual way and this optically active base into a salt of one of the aforementioned physiologically compatible organic or inorganic acids convict.

The compounds of the formula I or their physiologically tolerable ones In animal experiments on dogs, acid addition salts have valuable therapeutic, in particular ß-adrenolytic, B ..- adrenolytic, and / or antihypertensive and / or antiarrhythmic properties shown and therefore know, for example for the treatment or prophylaxis of diseases of the coronary arteries, for the treatment of cardiac arrhythmias and for the treatment of high blood pressure can be used in human medicine.

The following should be emphasized in particular: A therapeutically favorable split between B ₁ - and ß _? -Receptors blocking effect, the B "receptors are not blocked, show in particular the compounds of formula I,

4 3
in which R, when R = 11, denotes a phenylalkylene radical. For example, the product according to Example 15 shows a significantly stronger B. sympathicolytic (in the absence of β ₉ -sympathicolytic) effect than the already known 1 - / (3,4-dimethoxyphenethyl) amino-3-aryloxy-2-propanols such as the 1 - / (3, 4-D.imethoxyphenothyl) -amino-3- (m-tolyloxy) -2-propanol hydrochloride (ML Hoefle et. Al., J. Med. Chem. Jj? (1975), 148).

The products of the process can be in the form of the free bases or their Oral salts in the form of tablets or dragees, optionally mixed with conventional pharmaceutical carriers and / or stabilizers or administered parenterally in the form of solutions in ampoules. Carriers for tablets are, for example Lactose, starch, tragacanth and / or magnesium stearate in question.

For injections, a dosage of 2-20 mg comes in

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Consider, while the oral dosage is between 6 and 150 mg: a single tablet or a dragee can be about Contains 5 to 50 mg of active ingredient.

A long-lasting significant one that is also therapeutically desirable The compounds of the formula I, in which R to-

4th
together with R and the N atom represent a heterocycle, such as the unsubstituted or substituted on the second N atom piperazino, piperidino or morpholino radical.

3 4

Compounds of the formula I in which R = H and R is a branched one aliphatic or cycloaliphatic hydrocarbons are characterized by a general very strong blockage of the ß-receptors.

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Bexspxel Ii * ■ *

φ, O -3- / 2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl) crotonic acid nitrile hydrochloride

7.0 g φ <L / -3- / 2- (2, 3-Qxido-propoxy) -phenyl) -crotononitrile in a mixture of 80 ml of ethanol (98%) and 15 ml of tert. Butylamine heated to boiling under reflux for 1 1/4 hours. Then i. V. concentrated to dryness and several times with toluene i. V. evaporated. The oily distillation residue (free base) is dissolved in 50 ml of ethanol and adjusted to pH 4 by the dropwise addition of concentrated hydrochloric acid and then i. V. to
Evaporated dry. By repeated evaporation i. V. The distillation residue is dried with toluene and then recrystallized from a little ethanol and ether and then again from ethanol.

7.1 g of (d, ly-3- / 2- (3-tert-butylamino-2-hydroxypropoxy) phenyl) crotononitrile hydrochloride were obtained obtained from m.p. 155-156 °.

Example 2:

\ D, l) -3- (2- (3-Morpholino-2-hydroxy-propoxy) -phenyl) -crotononitrile hydrochloride

15 g of (D, L) -3- {2- (2 _l 3-oxido-propoxy) -phenyl) -crotononitrile are in a mixture of 90 ml of ethanol and 6.1 g of morpholine

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Heated to boiling under reflux for 2 1/4 hours. Afterward is worked up as described in Example 1 and converted into the hydrochloric.

There were 12.9 g of (d, L) -3- ^ 2- (3-morpholino-2-hydroxypropoxy) phenyl) crotononitrile hydrochloride from Schrnp. 184.5 185 ° obtained.

Example 3:

\ D, i) -3- ^ 2- (3-N-phenyl-piperazino-2-hydroxy-propoxy) -phenyl) -crotonic acid nitrxl-hydrochloride

15 g of (d, l) -3- (2- (2,3-oxido-propoxy) -phenyl ^ -crotonic acid nitrile are refluxed for 1 1/2 hours in 90 ml of ethanol and 11.4 g of N-phenylpiperazine. Then how described in Example 1, worked up and converted into the hydrochloride convicted.

14.0 g (D _t L) -3- (2- (3-N-phenyl-piperazino-2-hydroxypropoxy) -phenyl) -crotononitrile hydrochloride with a melting point of 177 ° 178 ° were obtained.

Example 4:

\ D, L / -3- ^ 2- (3-isopropylamino-2-hydroxy-propoxy) -phenyl-crotonic acid nitrile-hydrochlor id

27 g \ D, L) -3- ^ 2- (2,3-oxido-propoxy) -phenyl ^ -crotonic acid nitrile are in a mixture of 270 ml of ethanol and 60 ml of isopropyl

/ 19th

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xiessend wx

arain refluxed for 1 hour. Then becomes as described in Example 1, worked up and converted into the hydrochloride.

There were 21.5 g of (d, L) -3- (2- (3-isopropylamino-2-hydroxypropoxy) -phenyl ^ -crotonic acid nitrile hydrochloride at the front, m.p. 145-146 °.

Example 5:

{d, I ^ -3- {2- [3-2, 6 -D imethy! piperidino-2-hydroxy- propoxy) -phenyl) -crotonic acid nitrile hydrochloride

15 g ^ D, L ^ -3- / 2- (2,3-oxido-propoxy) -phenyl) ~ ci "otonic acid nitrile are refluxed for 13 hours in a mixture of 90 ml of ethanol and 8.0 g of 2,6-dimethylpiperidine and as described in Example 1, worked up and converted into the hydrochloride.

There are 12.4 g of {d, ^ -3- / 2- [3-2, 6 -dimethylpiperidino-2-hydroxypropoxy J-phenylY-crotonic acid nitrile hydrochloride obtained from m.p. 157-158.

Example 6:

^ D, Ly-3- / 2- (3-3, 4 -dimethoxyphenethylamino-2-hydroxypropoxy) -phenyl-crotononitrile-hydrochloride

19 g ^ D, L ^ -3- / 2- (2,3-oxido-propoxy) -phenyiy-crotonic acid nitrile are refluxed for 5 hours in a mixture of 100 ml of ethanol and 12.7 g of homoveratrylamine.

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It is then worked up as described in Example 1 and converted into the hydrochloride.

10.8 g ^ D ₁ L ^ -3- ^ 2- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydroxy-propoxy) -phenyly-crotononitrile hydrochloride of melting point 164-165 ^ are obtained.

The free base is isolated from the mother liquor in the usual way (alkaline sites, extract with toluene, con. and by recrystallization from toluene / diisopropyl ether 1.2 g of the same with a melting point of 88 ° -89 ° were obtained.

Example 7:

\ Ό, ΐΛ-3- / 2- (3-N- (2 *) - pyridino-piperazino-2-hydroxy ~ propoxy) -phenyl ^ -crotonitrile trihydrochloride

7 g ^ D, Iy-3-i2- (2,3-oxido-propoxy) -phenylN-crotonic acid nitrile are in a mixture of 70 ml of ethanol and 6 g of N- (2-pyridino) piperazine Boiled under reflux for 3 hours. It is then worked up as described in Example 1 and converted into the trihydrochloride.

5.1 g ^ D, l) -3- / 2- (3-N- ^ 2 * V-pyridino-piperazino-2-hydroxy-propoxy) -phenyl ^ -crotonsaurenitrile-trihydrochloride of melting point 121 are obtained.

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Example 0:

Cd , l) - 3- (2- (3-N- (4-acetylphenyl) -piperazino-2-hydroxypropoxy) -phenyl) -crotonitrile-dihydrochloride

7 g ^ D, l) -3- ^ 2- (2,3-oxido-propoxy) -phenyl) -crotonic acid nitrile are in a solution of 6.8 g of N- (4-piperazino) acetophenone refluxed in 70 ml of ethanol for 3 hours. After that i. V. evaporated to dryness. The oily still residue crystallizes through after a few hours. Then it is rubbed with a little ether and sucked off. The filter residue was dissolved in just sufficient amount of chloroform and added in portions while stirring with saturated hydrochloric acid / chloroform solution added until the acidic reaction.

After a short time, the dihydrochloride separates out of the clear solution.

After suctioning off, washing with a little chloroform / acetone and 9 g of (d, l) -3- ^ 2- (3-N- (4-acetylphenyl) piperazino-2-hydroxypropoxy) phenyl) crotonic acid nitrile dihydrochloride are dried obtained with a melting point of 151 °.

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Example 9:

(θ, Iy-3- / 2- (3-N- ^ 2-methoxyphenyl) -piperazino-2-hydroxypropoxy) -plieny l) -crotononitrile dihydrochloride

6 g <D, L ^ -3- (2- (2, 3-oxido-propoxy) -pheny ±> -crotonic acid nitrile are in a solution of 5.5 g of N- (2-methoxyphenyl) piperazine refluxed in 60 ml of ethanol for 3 hours. Then i. V. z. Narrowed, in Dissolved chloroform and acidified with hydrochloric acid / chloroform. Then i. V. z. Tr. And brought to crystallization by rubbing with a little ether. To suctioning off and drying 10.5 g ^ D, ΐΛ-3- ^ 2- (3-N- / 2-methoxyphenyl ^ -piperazino-2-hydroxy-propoxy) -phenyl) -crotonic acid nitr il-dihydrochloride obtained with a melting point of 171 °.

Example 10:

, L / -3- ^ 2- (3-N- ^ 2-methylphenyl ^ -piperazino-2-hydroxypropoxy) -phenyl V-crotononitrile dihydrochloride

7 g \ Ό, L / -3- (2- (2,3-oxido-propoxy) -phenyl) -crotononitrile are in a mixture 6.5 g of N- (o-tolyl) -piperazine and 70 ml of ethanol, such as described in Example 9 implemented and worked up.

There are 10 g of (d, l) -3- ^ 2- (3-N- (2-methylphenyl) -piperazino-2-hydroxy-propoxy) -phenyl ^ -crotonitrile dihydrochloride obtained with a melting point of 138 °.

709 & 4Θ / 023Ϊ

Example 11:

, l) -3- (2- (3-N - (methylpiperazino) -2-hydroxy-propoxy) -phenyl) -

crotonic acid nitrile dihydrochloride

7 g ^ D.l) -3- / 2- (2,3-oxido-propnxy) -phenyl) -crotonic acid nitrile are reacted with 3 g of N-methylpiperazine in 60 ml of absolute ethanol as described in Example 9 and worked up. That The crude dihydrochloride is dissolved in 50 ml of Viasser and filtered through 3 g of activated charcoal. The filtrate is concentrated to dryness finally in a high vacuum. The resulting foam is rubbed with ether, filtered off with suction and dried. This gives 4.9 g of strongly hygroscopic (d, l) -3- / 2- (3-N- (methylpiperazino) -2-hydroxypropoxy) phenyl) -crotonic acid nitrile dihydrochloride.

The compound shows characteristic bands in the IR at 2203, 1590, 1435, 1235 and 745 cm " ¹ .

Example 12:

d, l) -3- (2- (3-N- (2 - hydroxyethyl) --piperazirio-2-hydroxy ~ propoxy) phenyl) crotononitrile dihydrochloride

7 g of (D, L) -3- (2- (2,3-oxido-propoxy) -phenyl) -crotonic acid nitrile are with 4.7 g of N- (2-hydroxyethyl) piperazine in 70 ml asolute ethanol as described in Example 9 and worked up.

There are 8.5 g of (d, l) -3- (2- (3-N- ^ 2-hydroxyethyl) piperazino-2-hydroxypropoxy) phenyl) crotononitrile dihydrochloride obtained with a melting point of 146 °.

/ 24

709S49 / 023S

Example 13:

2ί -

30 2823314

(D ₁ L.) - 3- ^ 4- (3-N-Phenylpiperazino-2-hydroxy-propoxy) -phenyl ^ -crotonic acid nitrile hydrochloride

10.75 g \ D, l) -3- ^ 4- (2,3-oxido-propoxy) -phenyl) -crotonic acid nitrile are refluxed for 3 hours in a solution of 8.1 g of phenylpiperazine in 60 ml of ethanol. The reaction mixture is then cooled with ice and, after standing for a while, the crystals which have separated out are filtered off with suction and recrystallized from a little ethanol. 12.9 g of free base with a melting point of 133 ° -134 ° are obtained. The base is dissolved in just enough acetone at room temperature and then added dropwise with stirring conc. Hydrochloric acid added up to pH - 4.5. The hydrochloride precipitates after a short time. It is suctioned off and dried.

13.9 g of crude hydrochloride are obtained with a melting point of 158 -

160 °.

By recrystallizing once from a lot of ethanol, 13.3 g of ^ D, Iy-3- (4- (3-N-phenylpiperazino-2-hydroxy-propoxy) - pheny ^ -crotononitrile hydrochloride with a melting point of 160-161 °

obtain.

/ 25

70984970235

\ Ώ, Ly-3- ^ 4- (3-morpholino-2-hydroxy ~ propoxy) -phenyl) -crotonic acid enitrile hydrochloride

15.0 g of {d, l) -3- ^ 4- (2,3-oxido-propoxy) -phenyl) -crotonic acid nitrile are in a solution of 6.1 g of morpholine in 100 ml Ethanol heated to 80 ° for 4 1/2 hours. After standing for another 12 hours at room temperature. Afterward will i. V. concentrated to dryness and evaporated 3 more times with toluene. The distillation residue is in a little toluene dissolved and brought to crystallization by adding diisopropyl ester. After filtering off with suction and drying, 18.0 g are obtained free base of melting point 79-80 °.

It is then converted into the hydrochloride as described in Example 1.

There are 16.4 g of ^ D, l) -3- (4- (3-morpholino-2-hydroxy-propoxy) -phenyl ^ -crotononitrile hydrochloride obtained with a melting point of 121 ° -122 °.

Example 15:

\ D, L / -3- (4- (3-2 *, 6 * -Dimethylpiperidino-2-hydroxy-propoxy) -phenyl) -crotonitrile-hydrochloride

15 g of (D, L) -3- (4- (2,3-oxido-propoxy) -phenyl) -crotonic acid nitrile are refluxed for 6 1/2 hours in a solution of 8.0 g of 2,6-dimethylpiperidine in 100 ml of ethanol. Then i. V. evaporated to dryness, the distillery

/ 26

709849/0235

lation residue dissolved in 80 ml of toluene. After adding 300 ml of water is mixed with conc. Hydrochloric acid adjusted to pH 4 with thorough shaking. The aqueous phase is with 80 ml of fresh toluene are added and the pH is adjusted to 10 with sodium hydroxide solution while shaking.

It is extracted twice with 50 ml of toluene each time and the combined organic extracts are washed with water over sodium sulfate dried and i. V. concentrated to dryness. By rubbing with diisopropyl ether, suction off the resulting Crystals and drying give 15.0 g of free base with a melting point of 98 °.

From this, as described in Example 1, 14.5 g of (d, l) -3- (4- (3-2 *, 6 * -dimethylpiperidino-2-hydroxypropoxy) phenyl) crotononitrile hydrochloride obtained from m.p. 168-169.

Example 16:

3- (4- (3-3 *, 4 * -Dimethoxyphenäthylamino ~ 2-hydroxy-propoxy) -phenyl) -crotonitrile hydrochloride

17 * 5 g (D, l) -3- (4- {2,3-oxido-propoxy) -phenyl ^ -crotonic acid nitrile are in a solution of 15.0 g of homoveratrylamine in 100 ml of ethanol heated to boiling under reflux for 5 hours. After the usual work-up (see Example 1), the Free crude base from ethanol / diisopropyl ether and recrystallized again from ethanol.

/ 27

709849/0235

- * ~ 2g233U

16.1 g of free base with a melting point of 141.5-142 are obtained. From this, 13.6 g are obtained in a manner analogous to that described in Example 1

-3- (Α- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl ^ -crotononitrile hydrochloride of melting point 148-149.

Example 17:

(D, L) -3- (4- (3-N-2 * -pyridyl-piperazino-2-hydroxy-propoxy) -phenyl) -crotonitrile dihydrochloride

10.75 g (d, l) -3 ~ ^ 4- (2,3-0xido-propoxy) -phenyl) -crotonic acid nitrile are refluxed for 3 hours in a solution of 8.2 g of pyridylpiperazine in 60 ml of ethanol. Thereafter is cooled with ice, the precipitated crystals are collected and dried. The 17.1 g of free base thus obtained with a melting point of 131-132 ° are converted into 15.1 g of (d, l) -3-Y4- (3-N-2 * -Pyridyl-piperazino ~ 2-hydroxy- propoxy) phenylycrotonitrile dihydrochloride transferred from melting point 259-160 °.

Example 18:

D, L) -3- ^ 4- (3-N - 4 * -acetyl-phenyl-piperazino-2-hydroxy-propoxy) -phenyl) -crotonitrile hydrochloride

10.75 g ^ D, L) -3 - / 4- (2,3-0xido-propoxy) -phenyl) -crotonic acid nitrile are refluxed for 4 hours in a solution of 10.2 g of p-piperazinoacetophenone. The one after cooling down

/ 28

709849/0235

crystallized, filtered off and dried base (20.1 g, Mp. 160-161 °) is in 100 ml of abs. Ethanol and 30 ml Dimethylformamide with conc. Hydrochloric acid adjusted to pH 5. The crystallized hydrochloride is collected and extracted from ethanol / Recrystallized hot water.

There are 17.7 g ^ D, L) -3- (4- (3-N-4 * -acetyl-phenyl-piperazino-2-hydroxy-propoxy) -phenyl) -crotononitrile hydrochloride with a melting point of 221-222 °.

Example 19:

(D, L) -3- (4- (3-N-2 * -methoxyphenylpiperazino-2-hydroxypropoxy) ~ phenyl) crotononitrile hydrochloride

10.75 g (D, L) -3- (4- (2,3-0xido-propoxy) -phenyl) -crotonic acid nitrile are in a solution of 10.3 g of N- (2-methoxyphenyl) piperazine dihydrochloride in a mixture of 14.0 ml of triethylamine and boiled ml of ethanol for 5 hours under reflux. Then i. V. constricted to the trocne and through Addition of ethanol caused the RonDase to crystallize. By suctioning off, then washing with ethanol and water, 15.0 g of free base with a melting point of 102 103 ° are obtained after drying obtain. It is then converted into the hydrochloride as usual (see Example 1). After recrystallizing twice 13.3 g of (D, L) -3- (4- (3-N-2 * -methoxyphenylpiperazino-2-hydroxy-propoxy) -phenyl) -crotonic acid nitrile hydrochloride are obtained from ethanol obtained from m.p. 198-199 °.

/ 29

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- 26233U

Example 20: **

/ d, L ^ -3- ^ 4- (3-N-2 * -Methyl-pb.enyl-piperazino-2-hydroxy-propoxyj-phenyl ^ -crotonitrile hydrochloride

10.95 g ^ D _l L ^ -3- (4- (2,3-oxido-propoxy) -phenyl) -crotononitrile are in a solution of 8.8 g of o-tolylpiperazine
Boiled under reflux for 3 hours. After cooling down
16.5 g of free base of melting point 104-105 crystallize
the end. They are converted into the hydrochloride as described in Example 1. After final recrystallization twice from ethanol 10.0 g of (D, L) -3-6ä- (3-N-2 * -methylphenyl-piperazino-2-hydroxy ~ propoxy) -phenyl) -crotononitrile hydrochloride with a melting point of 233 - 234 ° received.

Example 21:

\ D, L / -3- (4- (3-N-3 * -Methyl-phenyl-piperazino-2-hydroxy-propoxy) -phenyl) -crotonic acid enitrile hydrochloride

10.75 g of ^ D, L) -3- ^ 4- (2,3-0xido-propoxy) -phenyl) -crotonic acid nitrile are reacted as described in Example 19 with 8.8 g of m-tolylpiperazine.

After the same work-up, 16.4 g of free base with a melting point of 108-109 °, 14.6 g of (D, L> -3- (4- (3-N-3 * -Methyl-phenylpiperazino-2-hydroxy- propoxy) phenyl crotonic acid nitrile hydrochloride id obtained from melting point 151-152 °.

/ 30

7098A9 / 023F

26233H

Example 22:

\ D, L / - 3- Λϊ- (3-Ν- methyl-piper azino-2-hydroxy-propoxy) -pheny Iy-

crotonsäurenitr il-dihydrochloride

10.75 g of ^ D, L) -3- ^ 4- (2,3-oxido-propoxy-phenyl) -crotonic acid nitrile are reacted as described in Example 19 with 5.0 g of N-methylpiperazine in 60 ml of ethanol and Worked up as described in Example 1 and converted into the dihydrochloride convicted.

There are 11.8 g of ^ D, L ^ -3- ^ 4- (3-N-methyl-piperazino-2-hydroxy-propoxy) -phenyl ^ -crotonsäuritril-dihydrochloride of melting point 217-218 ° obtained.

Example 23:

^ D, L / -3- ^ 4- (3-N-2 * -oxyethyl-piperazino-2-hydroxy-propoxy) -phenyl) -crotonic acid nitr il-dihydrochloride

5.0 g \ D, l) -3- (4- (2, 3-oxido-propoxy) -phenyl) -crotonic acid nitrile v / earth in a solution of 3.5 g of hydroxyethylpiperazine refluxed in 50 ml of ethanol for 2 hours. After evaporation i. V. z. Tr. Is crystallized from toluene. the obtained 5.7 g of free base of melting point 101-102 ° are described in Example 1 in 6.7 g of (d, l) -3- (4- (3-N-2 * - Oxyäthyl-piperazino-2-hydroxy-propoxy) -phenyl) -crotonsäurenitr il-dihydrochloride with a melting point of 204 ° -205 °.

709 & 49/0235

zl 26233U

Example 24:

, l) -3- (4- {3-7 *, 5 * -Dimethyl-5 * -hydroxy-hexylamino-2-hydroxypropoxy) -phenyl / -crotonic acid nitrile oxalate

8.5 g «D ₄ L ' - 3—' 4— (2 _φ 3 — Oxide — propoxy) —phenyl) —crotononitrile are dissolved in a solution of 1.6 g of sodium hydroxide and 7.2 g of heptamoxnol hydrochloride in 50 ml of ethanol 2 Boiled under reflux for hours, then i. V. concentrated, the distillation residue was taken up in 85 ml of water and adjusted to pH 7 with hydrochloric acid. It is washed twice with toluene and ethyl acetate and the aqueous phase is made alkaline to pH 10 with sodium hydroxide solution. The mixture is then extracted with ethyl acetate / toluene (1: 1), the organic extracts are dried and concentrated i. V. z. Evaporated to dryness. The crude base is taken up in ethanol and treated with a conc. Solution of oxalic acid in ethanol exnosed to pH 4. After suctioning off and drying, 1.1 g of (d, l) -3 - / 4- (3- / *, 5 * - Dxrnethyl-b * -nydroxy-hexylamxno-2-hydroxy-propoxy) -phenyl) crotonic acid xtrxl from Ax to a melting point of 155 °.

Example 2b:

\ D, l) -3- ^ 2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl) -

acrylonitrile hydrochloride

7.0 g iD, L / -3- (2- (2,3-oxido-propoxy) -phenyl) -acrylic acid nitrile are in a solution of 15 ml of tert-butylamine in 80 ml of abs. Ethanol refluxed for 1 hour. It is processed as described in Example 1 and transferred to the

709849/0235

Hydrochloric! convicted. 5.3 g of (d, L) -3- (2- (3-tert-butylamino-2-hydroxypropoxy) are obtained ) -pheny].) - Acrylic acid nitrile hydrochloride of melting point 155.

Example 26;

(ρ , L V-3- (2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyIy-

acrylic acid tert-butyl ester hydrochloride

30.0 g ^ D, L / -3- ^ 2- (2,3-0xido-propoxy) -phenyl) -acrylic acid-tert. butyl esters are in a mixture of 30 ml of tert-butylamine and 150 ml of ethanol refluxed for 3 hours. After the usual work-up (see. Example 1) the crude hydrochloride is dissolved in water, the aqueous solution extracted twice with toluene and the aqueous phase then with conc. aqueous saline solution added. The ^ D, Iy -3- ^ 2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl) -acrylic acid-tert-butyl ester hydrochloride crystallizes the end. It is sucked off, i. V. dried and recrystallized twice from isopropanol. 13.8 g of (d, l) -3- / 2- (3 - tert-butylamino-2-hydroxypropoxy) phenyl are obtained -acrylic acid tert-butyl ester hydrochloride of melting point 186 ° -187 °.

/ 33

709S49 / 023S

Example 27:

-ß - ^ - (3-3 *, 4 * -Dimethoxy-phenäthylamino-2-hydroxy-propoxy) -

phenyl) acrylic acid tert-butyl ester hydrochloride

30.0 g of (D, L) -3- (2- (2,3-oxido-propoxy) -phenyl) -acrylic acid-tert-butyl ester are in a solution of 20.0 g of homoveratrylamine in 60 ml of ethanol for 2 hours heated to boiling under reflux. After the usual work-up (comp. Example 1) 15.9 g \ Ό, Ly-3- (2- (3-3 * 4 * dimethoxy-phenäthylamino-2-hydroxy-propoxy) -phenyl) -aerylsäure- tert-butyl ester hydrochloride with a melting point of 167 ° -168 °.

Example 28:

- (3-N-2 * -oxyethyl-piperazino ~ 2-hydroxy-propoxy) -phenyl) -acrylic acid-tert-butyl ester-dihydrochloride

11.0 g \ D, l) - 3- (2- (2, ^r 3-0xidopropoxy) -phenyl) -acrylic acid-tert. butyl esters are refluxed for 2 hours in a mixture of 55 g of N-hydroxyethylpiperazine and 60 ml of ethanol. It is then worked up as described in Example 14, but here pH = 3 instead of pH = 4. 6.4 g of (d, L) -3- (2- (3-N-2 * -oxyethyl-piperazino-2-hydroxypropoxy) -phenyly-acrylic acid-tert-butyl ester-dihydrochloride of mp. 168 ° (decomp.)

/ 34

709849/0235

£ 26233U

Example 29:

(d, l) -3- (2- (3-N-phenylpj.perazino-2-hydroxypropoxy) -phenyl) acrylic acid tert-butyl ester hydrochloride

11.0 g of ^ D, l) -3- {2- (2,3-Cxido propoxy) phenyl) acrylic acid tert-butyl ester are refluxed for 1 hour in a mixture of 6.5 g of phenylpiperazine and 50 ml of ethanol and as in Example 1 described, worked up. The hydrochloride will finally recrystallized here 2 times from ethanol. 6.2 g of (d, l) -3- (2- (3-N-Bhenylpiperazino-2-hydroxypropoxy) phenyl) acrylic acid tert-butyl ester hydrochloride are obtained of m.p. 200 - 201 ° (decomp.)

Example 30:

(d, Iy-3- (4- (3-tert-butylamino-2-hydroxypropoxy) -phenyl) -acrylic acid-tert-butyl ester-hydrochloride

15.0 g of (d, l) -3- (4- (2,3-oxidopropoxy) phenyl) acrylic acid tert-butyl ester are in a mixture of 25 ml of tert-butylamine and 100 ml of ethanol (98%) refluxed for 2 hours. Then i. V. concentrated to dryness, the distillation residue is evaporated twice with toluene (iv.) and finally made to crystallize with diisopropyl ether. 16.7 g of free base with a melting point of 107-108 ° are obtained. From this, as described in Example 28, 12.3 g are obtained (d, l) -3- (4- (3-tert-Butylarnino-2-hydroxypropoxy) phenyl) acrylic acid tert-butyl ester hydrochloride of m.p. 192 - 193 ° (decomp.).

/ 35

709849/0235

'S "26233U

Example 31: '^

(d, L) -3- (4- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl) -acrylic acid tert-butyl ester hydrochloride

15.0 g {d, l) ~ 3- (4- (2,3-Cxidopropoxy) -phenyl) -acrylic acid-tert-butyl ester are refluxed for 8 hours in a solution of 10.5 g of homoveratrylamine. Then it is worked up as usual and the crude hydrochloride dissolved in (6 1) water, extracted several times with toluene and the aqueous phase with Sodium hydroxide solution adjusted to pH 9. It is then extracted with toluene and ethyl acetate. The combined organic extracts will i. V. evaporated to dryness and crystallized with diisopropyl ether. 6.95 g of free base are obtained from m.p. 100 - 101. This gives 7.4 g of (d, l) -3- (4- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl) as described in Example 1 -acrylic acid tert-butyl ester hydrochloride of melting point 176-177, which was finally recrystallized twice from ethanol.

Example 32;

(d, l) -S-phenyl-S- (2- (3-tert-butylamino-2-hydroxypropoxy) phenyl) acrylonitrile hydrochloride

5.4 g (D, L) -3-phenyl ~ 3- / 2- (2,3-oxidopropoxy / pheny ^ -acrylic acid nitrile are refluxed for 2 hours in a mixture of 15 ml of tert-butylamine. Then wxrd i. V. to Concentrated dry and twice i. V. steamed with toluene. The distillation residue is caused to crystallize by digestion with toluene / petroleum ether. 6.4 g / 35 are obtained

709849/0235

"- * - 26233U

free base of m.p. 92-93. This becomes like in example 1 described 5.5 g ^ D, l} -3-phenyl-3- (2- (3-tert-butylamino ~ 2-hydroxy-propoxy) -phenyl) -acrylic acid nitrile hydrochloride obtained from melting point 171-172 °.

Example 33:

ό, Ly-3-phenyl-3- (2- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxypropoxy) -phenyl) -acrylic acid nitrile-haloalate

5.4 g \ Ώ, Iy-3-Pheny 1-3- \ 2- (2, 3-Oxidopropoxy) -phenyl / -acrylsäurenitril are refluxed for 3 hours in a solution of 3.7g homoveratrylamine in 50 ml ethanol. Then as described in Example 30, worked up. The oily free base is then converted into the oxalate as described in Example 23. However, a pH of 6.5 must be set when the oxalic acid is added. The raw Halboxalat is not crystallized twice from ethanol and one receives 4.1 g (l), L) -3-phenyl-3- ^ 2- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydroxy-propoxy) -phenyl) -acrylic acid nitrile haloalate with a melting point of 172-173 °.

Example 34:

\ D, L / -3-Phenyl-3- ^ 2- (3-N-Phenylpiperazino-2-hydroxy-propoxy) -phenyl) -acrylic acid nitrile hydrochloride

6.0 g (D, Ii) -3-phenyl-3- ^ 2- (2, 3-oxidopropoxy) phenyl) acrylonitrile are refluxed for 2 hours in a solution of 3.5 g of phenylpiperazine in 50 ml of ethanol. Then like described in Example 1, worked up and in the hydro

/ 37

709849 / 023F

chloride transferred. For further cleaning as in example 30 proceeded. The free base was purified by crystallization using toluene / diisopropyl ether. You get 4.1 g of m.p. 102-103 °. The free base is again converted into the hydrochloride as described in Example 1. 4.4 g of double melting point are obtained. 85 ° / 184 °.

Example 35:

(d, l) -3-phenyl-3- (4- (3-tert.-butylamino-2-hydroxy-propoxy) -phenyl) -acrylic acid nitrile hydrochloride

10.0 g (d, L ^ -3-phenyl-3- ^ 4- (2,3-oxido-propoxy) -phenyl) -acrylic acid nitrile are refluxed for 2 hours in a mixture of 20 ml of tert-butylamine and 50 ml of ethanol heated. Then as described in Example 1, worked up and converted into the hydrochloride. The crude hydrochloride was finally recrystallized twice from ethanol. 4.6 g of (D, L / -3-phenyl-3- / 4- (3-tert.-butylamino-2-hydroxypropoxy) phenyl) are obtained -acrylic acid nitrile hydrochloride from

Mp. 233-234. The ethanolic mother liquor from the second recrystallization is i. V. concentrated to dryness and analogous converted into the free base as in Example 30. After the crude base has crystallized by triturating with diisopropyl ether 1.1 g of free base with a melting point of 112 ° -114 ° are still obtained.

709849/0235

'%' 26233 U

Example 36:

UD, L ^ -3-phenyl-3- (4- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxypropoxy) phenyl) acrylonitrile oxalate

JLU t \ * ^ \ Lj ι ju i— »j» - riicti ^ j. ~ * ^ - V ~ r— \ 6f j — w-rv-i-dw — jt ^ · * - w] jw ^ w ^ / —Jjiiciiy i / -

Acrylic acid nitrile is in a mixture of 6.5 ml homoveratrylamine and 50 ml of ethanol refluxed for 2 hours. Then as described in Example 30, worked up. the The oily free base is then converted into the oxalate as described in Example 23. 4.9 g of ^ D, I,) -3-phenyl-3- (4- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxypropoxy) phenyl) acrylonitrile oxalate are obtained from melting point 124 - 125 ° ..

Example 37:

vD, L) -3-Phenyl-3- ^ 4- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl ^ -acrylic acid nitrile dihydrochloride

10, Og (d, L) -3-phenyl-3- (4- (2,3-oxido-propoxy) -phenyl) -acrylic acid nitrile are refluxed for 2 hours in a solution of 5.9 g of phenylpiperazine in 50 ml of ethanol. After Working up as in Example 1, 6.8 g / d, L) -3-phenyl-3- \ 4- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl) -acrylic acid nitrile dihydrochloride obtained from melting point 189-190 °.

709049/023 ^

Example 38: "»? 262331 A

(υ, L) -3-Phenyl-3- [4- (3-N- (2-hydroxyethyl) -piperazino-2-hydroxy-propoxy) -phenyl) -acrylonitrile-dihydrochloride

10.0 g <D, L) -3-phenyl-3- (4- (2,3-oxido-propoxy) -phenyl) -acrylic acid nitrile are reacted with 4.7 g of N-hydroxyethyl piperazine in 50 ml of ethanol analogously to Example 3b and worked up. 9.8 g of (D, L) -3-phenyl-3 ~ <4- (3-N- ^ 2-hydroxyethyl) ^ are obtained -piperazino-2-hydroxy-propoxy) -phenyl) -acrylic acid nitrxl-dxhyürochlorici from m.p. Ib4 - lbS °.

Example 39:

D, l) -3- (4- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydroxy-prop-

oxy) -phenyl ^ -acrylic acid methyl ester hydrochloride

6 g of (d, l) -3- ^ 4- (2,3-oxido-propoxy) -phenyl) -acrylic acid methyl ester v / ground in a solution of 4.7 g of homoveratrylamine in 60 ml of absolute ethanol refluxed for 2 1/2 hours and then as described in Example 1, worked up. 6.2 g of (d, l) -3- (4- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydroxy-propoxy) -phenyl) are obtained methyl acrylate hydrochloride with a melting point of 162 °.

/ 40

709849/0235

Bezspiel 40: ^ ⁹

(d, l) -3- ^ 4- (3- 1,5-dimethyl-5-hydroxy) -hexylamino-2-hydroxypropoxy) -phenyl) acrylic acid methyl ester hydrochloride

5.5 g (d, l) -3- (4- (2,3-0xido-propoxy) -phenyl) -acrylic acid methyl ester are in a solution of 4.6 g of 6-amino-2-methyl-2-heptanol hydrochloride (Heptaminol hydrochloride) and 1.02 g Sodium hydroxide in 70 ml of abs. Ethanol refluxed for 4 hours. Then as described in Example 1, worked up. Ether is used to recrystallize the free base and crystallize the hydrochloride. 1.2 g of (D, L) -3- (4- (3- (l, 5-dimethyl-5-hydroxy) -hexylamino-2-hydroxy-propoxy) -phenyl) -acrylic acid methyl ester hydrochloride obtained from m.p.

Example 41:

d, l) -3- (4- (3-N-2 * -methoxyphenyl-piperazino-2-hydroxy-propoxv) ~

phenyl) acrylic acid methyl ester dihydrochloride

4.5 g of {D, L) -3- ^ 4- (2,3-0xido-propoxy) -phenyl) -acrylic acid-methyl esters are in a solution of 4.0 g of N- (2-methoxyphenyl) piperazine in 60 ml abs. Ethanol refluxed for 3 hours. After the usual work-up (see Example 39), ground 6.05g (d, l) -3- (4- (3-K-2 * -Methoxyphenyl-piperazino-2-hydroxypropoxy) -phenyl) Acrylic acid methyl ester dihydrochloride with a melting point of 204 °.

/ 41

709849/023?

- (3-3 *, 4 * -Dimethoxyphenäthylaminu-2-hydroxy-propcxy) -

phenyl ^ -acrylic acid ethyl ester hydrochloride

10, 0 g (d, L ^ -3 ~ r2- (2,3-oxido-propoxy) -phenyl ^ -acrylic acid ethyl ester are refluxed for 4 hours in a solution of 7.3 g of homoveratrylamine in 60 ml of ethanol. Afterward will i. V. concentrated to dryness. The oily distillation residue is caused to crystallize by digestion with hexane. After filtering off and drying, 9.8 g of free base with a melting point of 80-82 are obtained. It becomes, as in example 1 described the hydrochloride produced, which for Finally it is recrystallized again from ethanol / water and finally from isopropanol. 8.1 g of (d, l) -3-2- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl ^ are obtained ethyl acrylate hydrochloride with a melting point of 161-162 °.

Example ^43:

(d, l) -3- \ 2- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl) -acrylic acid ethyl ester hydrochloride

10.0 g of ^ D, LV3- (2- (2,3-oxido-propoxy) -phenyl ^ -acrylic acid ethyl ester are boiled in a solution of 6.54 g of N-phenyl-piperazine in 60 ml of ethanol for 4 1/2 hours. Then it becomes like in Example 1 described, worked up and converted into the hydrochloride. The hydrochloride obtained is finally still recrystallized once from isopropanol and then from ethanol / water. 10.2 g of (D, L) -3- (2- (3-N-phenylpiperazino-2-hydroxypropoxy) -pheny ^ -acrylic acid ethyl ester hydrochloride are obtained from melting point 186 - 187 °.

/ 42

7099-49 / 023?

Example 44:

(d, l) -3- ^ 2- (3-tert-butylamino-2-hydroxypropoxy) phenyl) acrylic acid ethyl ester hydrochloride

10.0 g of (d, l) -3- / 2- ( 2, 3-oxido-propoxy) -phenyl) -acrylic acid ethyester are in a mixture of 4.25 m ± tert-butylamine and 60 ml of ethanol " The mixture is then worked up as described in Example 1. The crude hydrochloride obtained, which is precipitated from ethanol / hydrochloric acid as usual and then evaporated with toluene, is recrystallized from ethanol / diisopropyl ether 30 is purified again via the free base. Here, it is sufficient to slurry the hydrochloride in about 100 ml of water before adding the sodium hydroxide solution. After recrystallization from isopropanol, 5.8 g of D, l) -3- (2- (3-tert .-Butylamino-2-hydroxypropoxy) phenyl) acrylic acid ethyl ester hydrochloride with a melting point of 133 ° -134 °.

Example 45:

D, l) -3- (A- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl) -3-

ethyl acrylonitrile hydrochloride

10.0 g (d, l) -3- (4- (2, 3-0xido-propoxy) -phenyl) -3-ethyl-acrylonitrile are refluxed for 2 hours in a mixture of 15 ml of tert-butylamine and 50 ml of ethanol. It is then worked up as described in Example 1. The initially obtained crude base is converted from toluene / hexane

709849/0235

£ \ 26233H

crystallized. "J

The obtained 7.0 g of melting point 73-75 ° is also, converted into the hydrochloride as described in Example 1. 3.4 g of (d, l) -3- (4- (3-tert-butylamino-2-hydroxy ~) are obtained propoxy) phenyl) -3-ethyl-acrylonitrile hydrochloride from M.p. 170-171 °.

Example 46:

(d, l) -3- (4- (3-3 *, 4 * -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl) -3-ethyl-acrylonitrile hydrochloride

15.0 g (d, L) -3- / 4- (2,3-oxido-propoxy) -phenyl) -3-ethyl-acrylonitrile are boiled in a solution of 12.0 g of homoveratrylamine in 100 ml of ethanol for 2 hours and v / ie in example 30 described, worked up. First 10.3 g of free base with a melting point of 103-104 are obtained. From it one obtains v / ie in Example 1 described 7.5 g of (d, l) -3- (4- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl) -3-ethyl-acrylonitrile hydrochloride with a melting point of 120 - 121 °.

Example 47:

(d, l) -3- (4- (3-N-phenyl-piperazino-2-hydroxy-propoxy) -phenyl) -S-ethyl-acrylonitrile-dihydrochloride

10.0 g of (D, L) -3- (4- (2,3-oxido-propoxy) -phenyl) -3-ethyl-acrylonitrile are refluxed for 2 hours in a solution of 11.0 g of Phenylpiperazxn in 50 ml of iithanol. Then it will be

709849/0235

the reaction mixture was cooled to 5 °, the free base crystallizing out. 8.2 g of free base with a melting point of 110 ° -115 ° are obtained from the base as described in Example 1, using 4.19 ml of 10% hydrochloric acid, 8.1 g of ^ D, L ^ -3- / 4-ON-phenyl -piperazino- -propoxy) -phenyl) -a-ethyl-acrylonitrile-dihydro-

chloride of m.p. 202-204 can be obtained

Example 48:

(d, l) -3- (4- (3-N- (2-hydroxyethyl) piperazino-2-hydroxy-prop oxy) -phenyl) -S-ethyl-acrylonitrile dihydrochloride

10 , Og (d, l) -3- (4- (2,3-oxido-propoxy) -phenyl) -3-ethyl-acrylonitrile are in a solution of 6.0 g of N-hydroxyethylpiperazine as in Example 45 or 30 (2.0 1 water) implemented and worked up. 6.4 g of free base with a melting point of 80-81 ° are initially obtained and 7.2 g of this with 3.57 ml of 10 η hydrochloric acid

d, l) -3- (4- (3-N- / 2-hydroxyethyl) -piperazino-2-hydroxy-propoxy) phenyl) -S-ethyl-acrylonitrile dihydrochloride with a melting point of 181 ° -182 °.

Example 49:

-3- ^ 2- (3-3 *, 4 * -Dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl) -3-ethyl-acrylic acid methyl ester hydrochloride

8 g of (d, l) -3- (2- (2,3-oxidopropoxy) -phenyl--3-ethyl-acrylic acid ~ methyl ester hydrochloride are in a solution of 5.7g Hcrnoveratrylamin in 80 ml of absolute ethanol for 3 hours under back

/ 45

709849/0235

river boiled. Then v.-ird as in Example 45 BeschTa.eessen, worked up. 4.3 g of (D, L ^ -3- (2- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxypropoxy) phenyl) -3-ethy1-acrylic acid methyl ester hydrochloride are obtained Base shows characteristic IR bands at 2920, 1710, 1630, 1585, 1505, 1437, 1225, 1145, 1015, 798 and 748 cm " ¹ .

Example 50:

(d, l) -3- (2- (3-N-2 * -methoxy-phenyl-piperazino-2-hydroxypropoxy) -phenyl) -3-ethyl-acrylic acid methyl ester dihydrochloride

8 g ^ D, l) -3- ^ 2- (2,3-oxido-propoxy) -phenyl) -3-ethy1-acrylic acid methyl ester with a solution of 6.8 g N- (2-methoxyphenyl) - piperazine in 80 ml of absolute ethanol as described in Example 41, reacted and worked up. 4.4 g of ^ D, l) -3- ^ 2- (3-N-2 * -methoxyphenyl-piperazino-2-hydroxypropoxy) -phenyl) -3-ethyl-acrylic acid methyl ester dihydrochloride of melting point 120 are obtained - 122 °.

Example 51:

Ethyl 3- (2- (3-tert-butylamino-2-hydroxypropoxy) phenyl) crotonic acid, hydrochloride

10.5 g (d, l) -3- (2- (2,3-0xido-propoxy) -phenyl) -crctonic acid ethyl ester are in a mixture of 20 ml tert-butylamine and 50 ml ethanol for 16 hours at 20 - Stirred at 25 °. Then, as described in Example 1, "worked up. The hydrochloride

/ 46

709849/0235

is recrystallized here twice from isopropanol / ether. 5.4 g of (d, l) ~ 3- / 2- (3-tert-butylamino-2-hydroxypropoxy) phenyl are obtained -crotonic acid ethyl ester hydrochloride from Schinp. 118-119 °.

Example 52:

^ D, l) -3- (l- (3-3 *, 4 * -dimethoxy-phenethylamino-2-hydroxypropoxy) -phenyl) -crotonic acid ethyl ester-oxalate

12.0 g / D, L) -3- ^ 2- (2,3-oxido-propoxy) -phenyJ ^ -crotonic acid ethyl ester are dissolved in a solution of 7.2 g Horaoveratrylamin in 100 ml ethanol for 16 hours at 20-25 stirred and then as described in Example 24, worked up. There are 4.5 g ^ D, l) -3- (2- (3-3 *, 4 * -dimethoxy-phenethylamino-2-hydroxypropoxy) -phenyl) -crotonic acid ethyl ester oxalate with a melting point of 115 ° -117 ° (Decomp.) Obtained.

Example 53;

d, 17-3- (2- (3-N-2 * -methoxyphenylpiperazino-2-hydroxypropoxy) phenyl) -crotonic acid ethyl ester dihydrochloride

7.9 g (d, l) -3- / 2- (2,3-oxido-propoxy) -phenyl) -crotonic acid ethyl ester are in a solution of 5.8 g of N-2-methoxyphenylpiperazine stirred in 100 ml of ethanol for 48 hours at room temperature. Then as described in Example 1 to the raw base worked up. It is dissolved in a little ethyl acetate and chromatographed on a column of 240 g of silica gel (silica gel 60 · Merck). Exclusive elution and ethyl acetate gave 4.4 g

/ 47

709849/0235

purified base as an oil. It is as usual (see Example 1) in 2.9 g of (p, L) -3- / 2- (3-N-2 * -methoxyphenylpiperazino-2-hydroxy propoxy) -phenyl) -crotonic acid ethyl ester dihydrochloride transferred from melting point 134-136 °.

Example 54:

(d, l) -3- (3- (3-tert-butylamino-2-hydroxypropoxy) phenyl) acrylonitrile hydrochloride

15 g of (d, l) -3- (3- (3- (2, 3-oxido-propoxy) -phenyl) -acrylic acid nitrile are refluxed for 1 hour in a mixture of 40 ml of tert-butylamine and 200 ml of ethanol After the usual work-up, 8.3 g of strongly hygroscopic (D, l) -3- (3- (3-tert-butylamino-2-hydroxypropoxy) phenyl) acrylonitrile hydrochloride are shown Characteristic IR bands at 3300, 2950, 2208, 1608 (shoulder), 1590 (shoulder), 1570, 1473, 1435, 1372 and 743 cm " ¹ .

Example 55:

(p, l) -3- ^ 3- (3-N-2 * -methoxy-phenyl-piperazino-2-hydroxypropoxy) -phenyl) -acrylic acid nitrile dihydrochloride

12, o g \ D, L) -3- (3- (2,3-Oxido-propoxy) -phenyl) -acrylic acid nitrile are in a solution of 11.5 g of N-2-methoxyphenylpiperazine refluxed in 50 ml of ethanol for 1 hour. Then it is described in the same way as in Example 31 (but here 4 1 water, Sodalsg. instead of NaGl) worked up. The crude free base

/ 43

70984970235

- {β- 26233Ί4

is oily and is described in Example 1 in 15.7 g ^ D, L) -3- (3- (3-M ~ 2 * -Methoxy-phenyl-piperazino-2-hydroxy-propoxy) -phenyl ^ -acrylic acid nitrile- dihydrochloride transferred from mp. 210 (decomp.).

Example 56:

\ D, l) -3- (3- (3-N- (2-hydroxyethyl) piperazino-2-hydroxypropoxy) phenyl) acrylonitrile dihydrochloride

12 _£ o g ^ D, l) -3- ^ 3- (2,3-oxido-propoxy) -phenyl) -acrylic acid nitrile are mixed with 20.0 g of N-2-hydroxyethylpiperazine in 50 ml of ethanol as in Example 55 described, implemented and processed. There are 13.5 g of (D ₁ l) -3- (3- (3-N- ^ 2-hydroxyethyl) piperazino-2-hydroxypropoxy) phenyl) acrylonitrile dihydrochloride with a melting point of 180 ° -182 ° obtain.

Example 57:

- (3-3 *, 4 * -Dimethoxyphenäthylamino-2 ~ hydroxy-propoxy} -phenyl) -acrylic acid nitrile hydrochloride

12.0 g of (D, l) -3- ^ 3-2,3-0xido-propoxy) -phenyl) -acrylic acid nitrile are reacted as in Example 55 with 20.0 g of N-2-hydroxyethylpiperazine in 50 ml of ethanol and worked up to 13.5 g of (D, l) -3- ^ 3- (3-3 *, 4 * - dimethoxyphenethylamino-2-hydroxy-propoxy) phenyl) acrylonitrile hydrochloride with a melting point of 180-182.

70984970235

% 26233U

Example 58:

^ D, l) -3- {j- (j-tert-Butylamino-2-hydroxy-propoxy) -phenyl) crotonic acid nitrile hydrochloride

15 g of (p. ^} -3- {3- (2, 3-oxido-propoxy) -phenyl) -crotononitrile are as described in Example 55, reacted with 40 ml of tert-butylamine in 200 ml of ethanol and worked up. 13.8 g of (d, l) -3- (3- (3-tert-butylamino-2-hydroxypropoxy) phenyl) crotononitrile hydrochloride with characteristic IR bands at 3320, 2960, 2205, 1668, 1570, 1473, 1430, 1370 and 772 cm ~ l.

Example 59:

\ D, l) -3- (3- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl) -acrylic acid ethyl ester hydrochloride

6.0g (d, l) -3- / 3- (2,3-oxido-propoxy) -phenyl) -acrylic acid ethyl ester are stirred in a solution of 3.6g homoveratylamine in 30 ml ethanol for 16 hours at room temperature and then as in Example 24 described worked up to the raw base. This is implemented as described in Example 1, 3.6 g of (D ₁ l) -3- (3- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxy-propoxy) phenyl) -acrylic acid ethyl ester hydrochloride, 128-129 °.

/ 50

709849/0235

Example 60:

- (3- (3-N-2 * -methoxyphenyl-piperazino-2-hydroxy-propoxy) -phenyl) -acrylic acid ethyl ester-dihydrochloride

6.0 g ^ D. ϊΛ ~ 3- ^ 3- (2. 3-oxido-pronoxy) -phenyl.) -Acrylic be sänriiäfhylester g in a solution of 3.9 N-2-methoxy-phenylpiperazine stirred for 48 hours at room temperature. After working up analogously to Example 1, 3.4 g of (d, l) ~ 3- (3- (3-N-2 * -methoxyphenyl-piperazino-2-hydroxy-propoxy) -phenyl) -acrylic acid ethyl ester dihydrochloride of mp · 164 - 165 received.

Example 61:?

(d, l) -3- {3- (3-N- (2-hydroxyethyl) -piperazino-2-hydroxypropoxy ) -phenyl) -acrylic acid ethyl ester-dihydrochloride

12.0 g (d, L) -3- ^ 3- (2,3-oxido-propoxy) -phenyl) -acrylic acid ethyl ester are in a solution of N-2-Hydroxyäthylpiperazin in 60 ml of ethanol stirred for 24 hours at 20-24 °. After working up as in Example 59, 9.3 g of (d, l) -3- (3- (3-N- ^ 2-hydroxyethyl) piperazino-2-hydroxypropoxy) phenyl) ethyl acrylate dihydrochloride with a melting point of 189-190 °.

Example 62:

(D, l) -3- (Phenyl-3- (4- (3-N-2 * -methoxyphenyl-piperazino-2-hydroxypropoxy) -phenyl) -acrylic acid methyl ester, dihydrochloride

15.0 g (d, L) -2-phenyl-3- (4- (2,3-oxido-propoxy) ~ phenyl) -acxylic acid methyl ester are in a solution of 9.3 g of N-2-methoxy

/ 51

70994970235

phenylpiperazine in 150 ml of methanol for 16 hours at 20-24 °
touched. It is as described in Example 31 for free
Base worked up. The purified base obtained as an oil
is converted into the hydrochloride as described in Example 1. After recrystallization from methanol / ether and
Finally, from methanol, 13.8 g of ^ D, L) -2-phenyl-3- / 4- (3 ~ N-2 * -methoxyphenyl-piperazino-2-hydroxypropoxy) -phenyl) -acrylic acid methyl ester dihydrochloride from M.p. 168 170 ° (decomp.)

Example 63:

(d, l) - 3-phenyl-3- (4- (3-N- (2-hydroxyethyl) -piperazino-2-hydroxypropoxy) -phenyl) -acrylic acid diethyl ester-dihydrochloride

15.0 g of ^ D, L) -2-phenyl-3- ^ 4- (2,3-oxido-propoxy) -phenyl) -acrylic acid methyl ester are as described in Example 62 with
6.3 g of N-2-hydroxyethyl piperazine reacted in 150 ml of methanol and worked up. 16.4 g of (d, I,) - 2-phenyl-3 - (4- (3-N-2-hydroxyethyl) -piper azino-2-hydroxy-propoxy) -phenyl) -acryl- are obtained

acid methyl ester dihydrochloride with a melting point of 218 ° -220 °

709849/0235

Example 64

(d, L) -3-PtIeIIyI-S- <! 4- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydroxy-propoxy) -phenyl / '-acrylic acid methyl ester 15 g ^ DL / -2-phenyl-3- <^ 4- (2,3-oxido- propoxy) -phenyl> -acrylic acid methyl ester are stirred in a solution of 8.22 g homoveratrylamine for 24 hours at room temperature. The crude hydrochloride obtained analogously to that described in Example 1, this time by adjusting to ρ 6, is first recrystallized from isopropanol / diisopropyl ether and finally from toluene / methylene chloride. There are 4.1 g <^ D, L ^ -2-phenyl-3- <^ 4- (3-3 *, 4 * - dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl / acrylic acid methyl ester with a melting point of 145-147 ° C received.

Example 65

^ .D, L V-3- Q- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydroxy-propoxy) -phenyl ^ -crotonitrile-hydrochloride 15 g \ p, li / -3- <^ 3- ( 2,3-Oxido-propoxy) -phenyl / "-crotonsäurenitril are refluxed for 2 1/2 hours in a solution of 12-62 g of homoveratrylamine in 150 ml of ethanol and worked up as described in Example 31. The so prepurified oily free base is finally, as described in Example 1, in 6.5 g of pure \ D, L "^ -3- <C 3- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydroxypropoxy) -phenyl ^ -crotonitrile hydrochloride of melting point 135 138 ⁰ C transferred.

Example 66 \ D, L ^ -3- <C3- (3-N-2 * -Methoxyphenyl-piperazino-2-hydroxy-propoxy) phenyl / '- crotononitrile hydrochloride

709949/0235

26233Ί4

15 g <^ D, L ^ -3- <3- {2 _r 3-oxido-propoxy) -phenyl / '- crotonsäurenitril are in a solution of 3.9 g N-2-methoxyphenylpiperazine in 150 ml ethanol 1 1 / Boiled under reflux for 2 hours. After working up analogously to Example 1, 17.1 y ^ D ₇ L / -3- \, 3- {3-N-2 * -Methoxypheny 1-piperaζino-2-hydroxy-propoxy} -phenyl / crotononitrile hydrochloride of mp 160-162 ° C obtained.

Example 67

<.-> - and Q> -3- <! 4- (3-3 *, 4 * -Dime thox yphenäthylamino-2-hydroxypropoxy) -phenyl * ^> -crotononitrile hydrochloride A solution of 50 g <Cj> r L ^ -3- <^ 4- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydr oxy-pr opoxy) -phenyly'-crotononitrile in 200 ml of ethanol is mixed with a solution of 19.2 g of D - (-) - Mandelic acid mixed in 150 ml of ethanol. After standing for a while, the precipitated crystals are filtered off with suction. After washing with a little ethanol and drying in vacuo, 32.8 g of <y - "7 -3 - <^ 4- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydroxy-propoxy) -phenyl are sparingly soluble in ethanol ^ -crotononitrile-D- (-) -mandelate of melting point 114-116, / "^ 77 ° =" 35.4 ° (c = 0.6, methanol). After recrystallization from 200 ml of hot ethanol, 28.9 g of pure mandelate are obtained with a Melting point of 118-119 ° C. and a rotation value of β * J_ / = -38.2 ° (c = 0.6, methanol) obtained, yield 83.5%.

To a mixture of 23 g of the above levorotatory almond paste, 230 ml of water and 100 ml, which is quickly stirred while cooling with ice A mixture of 3.15 ml of concentrated aqueous ammonia solution and 30 ml of water is added dropwise to chloroform. The organic phase is separated, washed with a little water and after drying

709 * 43/023?

- 2633914

it?

concentrated to dryness over sodium sulfate in vacuo. The hydrochloride described in Example 1 is obtained from the (-) -3- ^ 4- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl J -erotonic acid nitrile, which is obtained after recrystallization Ethanol / ether melts at 166 - 167 ° C and has a rotation value of / pl / 7 = -12.8 ° (c = 0.5. Methanol), final yield 17.5 g (96%).

Evaporation of the ethanolic mother liquors of the above resolution gives the ^ ⁺ / * - 3 - <^ 4- (3-3 *, 4 * -Dimethoxyphenäthylamino-2-hydroxy-propoxy) -phenyl ^> -crotonic acid nitrile, which is very easily soluble in ethanol D - (-) - almond paste. From this, as described above, the <^ + "/> -3- / 4- (3-3 *, 4 * -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl ^ -crotononitrile is prepared. After recrystallization from toluene / Petroleum ether 25.4 g of the nitrile are obtained from Schinp. 132-135 ° C. This is converted into the dextrorotatory hydrochloride, as already described for the (-) - antipode. After recrystallization from ethanol / ether, 25.5 g (93%) are not quite Optically pure <{. + /> -3- / ^ 4- (3-3 *, 4 * - Diir.ethoxyphenäthylamino-2-hydroxy-propoxy) -phenyl-crotononitrile hydrochloride of melting point 162-164 ° C with a Rotation value of el = + 9.7 ° (c = 0.6, methanol) was obtained.

/ 55

709849/0235

Claims (5)

PATENT CLAIMS: 2623314 OCH ₀ - CH _{- CH 0} - N wherein R ¹ and R ^{1 are the} same or different and hydrogen, an alkyl or alkoxy radical with 1 ~ 4 C-atoirs, the AJJylgruppe, 2 represent a halogen atom or the nitrate group, R an acrylic acid residue or acrylonitrile radical of the formulas R ⁵ R ⁶ R ⁵ R ⁶ Il 7 It -CC-C-O, * .. -C = C-C, in which R is hydrogen, a C. - C ₅ -alkyl radical, an unsubstituted or substituted by lower alkyl or alkoxy Aryl or aryl lower alkyl radical, R is hydrogen or an alkyl 7th
.rest with 1-8 carbon atoms, R is hydrogen, a lower alkyl or an aryl lower alkyl radical, 3 4 R and R together with the nitrogen atom represent a _{heterocyclic ring with 5-7 members which is optionally substituted by C 1} -C alkyl, in which one carbon atom can be replaced by an oxygen, sulfur atom or another nitrogen atom, which latter can be substituted with an alkyl, alkoxy, oxalkyl, acyl or carbalkoxy radical each having 1-5 carbon atoms, a pyridyl radical or a phenyl radical, which in turn can be substituted one or more times by the hydroxyl group, halogen or an alkyl or alkoxy radical with 1-4 carbon atoms, or 703849/0235 / 56 "i HOE 7ό / Ρ 115 it . . 26233H 3 4 R is hydrogen and R is a straight-chain or branched one Alkyl or oxalkyl radical with 1-8 carbon atoms, a straight-chain or branched unsaturated aliphatic hydrocarbon radical with 2-6 carbon atoms, a cycloaliphatic carbon residue with 3-6 carbon atoms or a phenylalkylene or phenylalkylidene radical of the formula .8th - (CH ₀ ) 8 mean 9, where η is a number from 1-3 and R and R are the same or are different and are hydrogen, an alkoxy radical with 8 9 mean 1-3 carbon atoms or the benzyloxy radical or R and R together represent the bismethylenedioxy radical, as well as the physiologically acceptable acid addition salts. 2. Process for the preparation of compounds of the formula I, thereby marked that one a) a compound of the formula II - CH - CH ₂ II 1 "1 * 2
wherein R, R _{un <} 3 r have the meaning given for formula I, with an amine of formula III 708849/0238 / 57 HOE 76 / F 115 ^ R " 3 4
wherein R and R have the meaning given for formula I, implements or
b) a compound of the formula IV OCH ₀ - CH - CH ₀ X
² OH ² IV 1 ν ₂ wherein R ι R and R have the meaning given for formula I and X is a halogen atom, the 'sulfuric acid or a sulfonic acid radical, with an amine of the formula III or reacts c) a compound of the formula V.
J ¹ - CH - CH ₀ - NH A ² Ah 1 1 '2
wherein R, R and R have the meaning given for formula I, with a compound of the formula VI X-R VI 4th
wherein R is the formula I and X is the formula IV Have meaning, or 709849/0235 / 58 HOE 76 / P 115 d) a phenol of the formula VII
»Τ VII 1 1 * 2
wherein R, R and R have the meaning given for formula I, with a compound of the formula VIII X - CH "- CH - CH ₀ - N
OH VIII wherein R and R are those for formula I and X those for formula IV Have meaning, reacts in the presence of an acid-binding agent, or e) a compound of the formula V or IX OCH ₂ - CO - CH ₂ - NH ₂ IX 11 2 wherein RfR and R have the meaning given for formula I, Reacts with a suitable ketone and reduces the condensation product or f) a compound of the formula X 709849/023 * / 59 KOE 76 / Ρ.115 28233U- OCH ₂ - CO - CH ₂ - NHR ₄ 1 1 '2 4 wherein R, R ι R and R have the meaning given for formula I, reduced or g) a compound of the formula Xx VK-O- _ο - CH ₀
2. ι / NO" XI 1 Ί 0 A in which R , R / R and R have the meanings given for formula I and Z represents a carbonyl group or a methylene group optionally substituted by a phenyl group or one or two lower alkyl radicals, hydrolyzed or h) in a compound of the formula XII - CH ₀ - CH - CH ₀ - N - R ' XII where R, R, R and R have the meaning given for formula I, R is hydrogen, a lower acyl radical or the benzyl radical 11 10 and R is hydrogen or the benzyl radical, R and P. but not both can mean water at the same time?> toff, 709849/0235 "δ *" HOE 76 / P 115 26233Η the benzyl groups by catalytic hydrogenation in the present " cleaved from noble metal and / or hydrolyzed the acyl group and the compounds obtained by processes a) to h), if appropriate converted into the physiologically acceptable acid addition salts. 3. Process for the production of pharmaceuticals, characterized in that that a compound of the formula I mentioned in claim 1, optionally with conventional pharmaceutical carriers and / or stabilizers, in a therapeutically suitable application form. 4. Medicines, characterized by a content of a compound of the formula I mentioned in claim 1 or consisting of such a compound. 5. Use of a compound of the formula I mentioned in claim 1 in medicaments or as medicaments. 709849/0235