FI67698C - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC MEDICINAL PRODUCTS 1-ARYLOXI-2-HYDROXI-3-AMINOPROPANER - Google Patents

Description

I- .j- ~ 1 _ (JJ ANNOUNCEMENT snsqq B 11 UTLÄGGNINGSSKRIFT 6/698 C (45) ·. 3 lj ° ^ '' (51) Kv.ik.4 / lnt.ci. «C 07 D 295/08 , C 07 C 121/70, 93/06 SUOMI FINLAND (21) Patent application - Patentansökning 771630 (22) Filing date - Ansöknlngsdag 23.05-77 (EN) (23) Starting date - Giltighetsdag 23 · 05 · 77 (41) Published public - Blivit offentiig 26.11 .77

National Board of Patents and Registration / 44) Date of issue and month of glare— 3i.OI.85

Patent and registration authorities' Ansökan utlagd och utl.skriften publieerad (32) (33) (31) Privilege requested - Begärd priority 25.05 * 76 Federal Republic of Germany Förbundsrepubliken Tyskland (DE) P 262331 ^ -7 (71) Hoechst Aktienges Postfach 80 03 20, 6230 Frankfurt / Main 80, Federal Republic of Germany1 (Förbundsrepubliken Tyskland (DE) (72) Werner Fritsch, Bad Soden am Taunus, Ulrich Stache, Hofheim am Taunus, Ernst Lindner, Frankfurt / Main, Federal Republic of Germany1ta-Förbundsrepubliken DE) (74) Oy Kolster Ab (54) Process for the preparation of new therapeutically useful 1-aryloxy-2-hydroxy-3-aminopropanes - For the preparation of new therapeutically useful 1-aryloxy-2-hydroxy-3-aminopropanes

The invention relates to a process for the preparation of new therapeutically useful 1-aryloxy-2-hydroxy-3-aminopropanes of the formula I and to their physiologically tolerable acid addition salts,

\ TjV-och2 ch - ch2 - I

'-' 4 1 .....

wherein R represents hydrogen, an alkoxy group 1 having 1 to 4 carbon atoms or a halogen atom, R represents a group of the formula: 2,67698 f R 6 R 5 R 6 I 7 i |

"c = c" C "0R or - C = C - CN

O

• · 5 ι r 7 in which R represents a C 1 -C 4 alkyl group, R represents hydrogen, K 'represents a lower alkyl group, R 1 and p 1 * together with the working atom form a heterocyclic ring optionally containing a C 1 -C 4 alkyl substituent, in which has 5 to 7 members in which one carbon atom may be replaced by an oxygen atom or an additional nitrogen atom, the latter being substituted by an alkyl, alkoxy, oxalkyl, acyl or carbalkoxy group each having 1 to 5 carbon atoms, a phenyl group or a phenyl group, which in turn may be substituted by one or more hydroxyl groups, halogen or alkyl or alkyl.

O

an oxy group having 1 to 4 carbon atoms, or R represents a hydrogen and R4 represents a phenylalkylene group having the formula:

R

- <CH2> n- ^ 9

R

«. q.

in which n is a number from 1 to 3 and R 1 and R 1 are the same or different and represent hydrogen, an alkoxy group having 1 to 3 C atoms, or a benzyloxy-89 group, or R and R together form a bismethylenedioxy group.

The invention includes both racemic mixtures of formula I as well as individual optically active isomers.

Compounds of formula I are prepared by: a) preparing a compound of formula (II):

Va a

\ i / 0CH2 'CH "CH2 II

R2

II

67698 • 1.2, in which R and R: 11a have the meaning given in connection with formula I, is reacted with an amine of formula (III): / Π3 ττχ. 3 4 wherein R: 11a 3a R has the meaning given in connection with formula I, 1: ·; ; b) a compound of formula (IV): rS £ ~ a_ \ T_y ~~ ° ch2 - cr - ch2x iv

17 OH

RZ

• 1 2 wherein R and R 11a are mentioned in connection with formula I, the meaning -'a X represents a halogen atom, a sulfuric acid or sulfonic acid residue ", is reacted with an amine of formula III, or c) a compound of formula (V) is : R ^ / - \ yt y ~ ° - ch2 - ch - ch2 - κή2 v

¥ ° H

12 ... wherein R and R: 11a have the meanings given in the context of formula I, the reaction with a compound of formula (VI) is:

X - R VJ

4 ....

wherein R is as defined in formula I and X is as defined in formula IV, or d) a phenol of formula (VII) is: “67698

R OH

O

1 2 wherein R and R 11a have the meaning given in connection with formula I, are reacted with a compound of formula (VIII): R 3

X - CH0 - CH - CH0 - VIII

z I 1 I 4

OH R

wherein R 3 and R 6 in the context of formula I and, X in the context of formula IV, have the meaning given in the presence of an acid scavenger, or e) a compound of formula (X):

x> -OCH2 - CO - CH2 - NHR4 X

R 2 wherein R 1, R 2 and R 4 have the meanings given in the context of formula I are reduced, or f) a compound of formula (XI): R 1 -v 2 -o 2 -ch 2 -ch 2

0 o N - R

R2 \ / z - 1 2 4 ...

wherein R, R 11a and R have the meanings given in the context of formula I and Z represents a carbonyl group or a methylene group optionally substituted by a phenyl group or one or two lower alkyl groups, is hydrolysed, or g) a compound of formula (XII) is: 67698

O - CH2 - CH - CH2 - N - R3 XII

OR10 R11

K

f 1 2. 3 wherein the substituents R, R and R are mentioned in connection with formula I.

Ί. C

meaning, R represents hydrogen, a lower acyl group or a benzyl group. 11, 1n 11 and R is hydrogen or a benzyl group, however, R and R cannot simultaneously denote hydrogen, the benzyl groups are cleaved by catalytic hydrogenation in the presence of a noble metal and / or the acyl group is hydrolyzed, and the compounds obtained by methods a) to g) are converted to physiologically acceptable

Of the above substituents, the following are preferred:. 4

If R and R together with the nitrogen atom form a heterocyclic ring, the preferred ring systems are rings having 5 or 6 members, e.g. pyrrolidine, piperidine and morpholine, which may be substituted by one or two lower alkyl residues or a pyridyl residue. Particularly preferred is a piperazine ring which may have an alkyl, alkoxy, oxyalkyl or acyl group having 1 to 4 carbon atoms, a carbazoxy group having 1 to 5 carbon atoms, a pyridyl residue or an optionally substituted phenyl residue as a substituent on the second nitrogen atom.

The coupling of the amine residue according to process a) is carried out by reacting both 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 carboxylic acid amides, in particular dimethyl acid amides. According to a preferred embodiment, the two components are allowed to react with each other dissolved in alcohol at a higher than normal temperature. Suitable reaction temperatures are those between room temperature and the boiling point of the solvent.

6 67698

The glycide ethers of the formula II used as starting materials in process a) can be prepared as described in FI application 771 631.

In the process indicated in b), β-halo-β-hydroxypropyl ethers of the formula IV are used as starting materials.

Instead of the halogen atom, preferably chlorine or bromine, the corresponding sulfuric acid esters or sulfonic acid esters can also be used.

The starting materials can also be obtained by cleavage of the epoxy compound of formula II with hydrohalic acid, sulfuric acid or sulfonic acid. The reaction with an amine of formula III is carried out either in the presence 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 carboxylic acid amides, especially dimethylformamide. The reaction can take place at a temperature between room temperature and the boiling point of the solvent, mainly at higher temperatures. To scavenge the liberated acid, e.g. hydrogen halide, the reaction may also be carried out in the presence of acid scavengers, for example tert-amines, such as triethylamine, pyridine or alkali or alkaline earth metal hydroxides, carbonates or bicarbonates. The germinating amine used can also advantageously be used in excess in the reaction, e.g. in double molar amounts.

The process mentioned in c) uses a phenoxy-2-hydroxy-1-aminopropane derivative of formula V.

This can also be in the form of a salt. The reaction with the reactive ester of formula VI is carried out under the reaction conditions mentioned in process b). The starting amine of formula V is obtained, for example, by reacting an epoxide of formula II with ammonia. It can also be obtained from the halogen compound IV with ammonia.

The process products can also be prepared by the process mentioned in d) using the above-mentioned phenol of formula VII. Phenol can also be used in the form of its alkali metal salt such as the sodium or potassium salt. The reaction components of the formula VIII used are 1-ha-iogen-2-hydroxy-3-alkyl Haminoin

II

7,67698 propanes. Sulfuric acid or sulfonic acid esters of 1,2-dihydroxy-3-alkylaminopropanes can also be used as starting materials. The reaction is preferably carried out in the presence of an acid scavenger such as alkali metal hydroxide. 1-Halo-2-hydroxy-3-alkylaminopropane used in an alkaline environment can be converted to the corresponding intermediate 1,2-epoxypropane, which reacts with phenol. The reaction can be carried out without the use of solvents or in the presence of solvents such as alcohols, e.g. methanol, ethanol, isopropanol, aromatic solvents such as benzene, toluene or ethers such as dioxin, tetrahydrofuran or carboxylic acid amides, especially di-methylformamide at room temperature or at room temperature. The compounds of formula VIII used as starting materials are prepared, for example, by reacting an amine of formula lii with epichlorohydride at low temperatures.

In the procedure mentioned in e), the reduction of the aminoketones of formula X can be carried out by hydrogenation from a catalytic process. The reduction of the keto group can also be carried out with lithium alanate or other metal hydride complexes or, according to the Meerwein-Ponndorf method, with aluminum isopropylate. The preparation of ketones of formula X can be carried out, for example, by reacting the corresponding 1-halo-2-oxo-3- (phenoxypropanes) with an amine of formula ITT.

A further embodiment of the method according to the invention is the formula.

Hydrolysis of oxazolidone or oxazolidine according to XI according to process f). Such oxazolidones can be obtained, for example, by reacting the corresponding 1-amino-2-hydroxy-3- (phenoxy) propanes with reactive carbonic acid derivatives such as diethyl carbonate, chlorocarbonic acid methyl ester or phosgene, or optionally by reacting the corresponding substituent 5-hydroxymethyl in the 3-position. -oxazolidone- (2) in the form of a halogenated hydrochloric acid, sulfuric acid or sulfonic acid ester with the corresponding alkali enolate. Suitable branches ring idines and can be prepared, e.g. by reacting the corresponding 1-amino-2-hydroxy-3-phenoxypropanes of formula V with aldehydes or ketones. Oxazolidones or oxazolidines having no substituents on the nitrogen atom can be alkylated by the compounds of formula VI described in process c): 8 67698. The hydrolysis of these oxazolidone or oxazolidine derivatives can be carried out in an acidic or alkaline environment, for example with dilute hydrochloric acid, dilute sulfuric acid, or dilute sodium or potassium hydroxide. In order to accelerate the hydrolysis, it is preferable to use heating. The hydrolysis can also be carried out in the presence of water-soluble solvents, e.g. low molecular weight alcohols. The products of the process can also be obtained from compounds of the formula XII in which the hydroxy and / or secondary amino groups • 10. 11 are protected by residues R and R, these protecting groups are cleaved. Suitable protecting groups are acyl radicals or benzyl radicals. Cleavage of the benzyl residue is accomplished by catalytic hydrogenation in the presence of noble metals such as palladium or platinum. When acyl compounds are used, wherein the acyl residue is preferably a lower aliphatic acyl residue such as an acetyl or propionyl residue, the cleavage is carried out hydrolytically in either an acidic or alkaline aqueous medium. The preparation of the corresponding benzyl or acyl compounds of the formula XII can be carried out according to one of the methods described above, using acylated or benzylated starting materials, respectively. If starting materials of the formula XII in which an acyl residue is to be prepared can be acylated, for example, a compound of the formula III, after which the corresponding acyl compounds can be reacted according to method b) to give compounds of the formula XII. The same applies to compounds in which R represents a benzyl residue, the acylation of which corresponds to the benzylation of the corresponding hydroxy compounds. If it is desired to use as starting materials compounds of the formula XII in which 11 R represents a benzyl residue, the corresponding N-benzyl compounds can be used instead of the primary amines in accordance with methods a), b), c), e) or d). If the residues R "^ and R ^ are a parallel acyl residue and a benzyl residue, these groups can be cleaved in succession as described.

In the case of processes a), b), d) or g) it may sometimes be advantageous to combine the preparation of the starting compounds directly with the further reaction, i.e. the starting materials are not separated.

The process products can be obtained as free bases or their salts and, if necessary, can be purified by conventional 3,676,98 working methods, for example by recrystallization or possibly conversion to the free base and subsequent treatment with appropriate acids. If desired, the process products can be converted into salts of physiologically acceptable organic or inorganic acids.

Examples of organic acids are: acetic acid, malonic acid, propionic acid, lactic acid, succinic acid, tartaric acid, maleic acid, fumaric acid, citric acid, malic acid, acidic acid, benzoic acid, salicylic acid, acetic acid, acetic acid sulfonic acid, oxethanesulfonic acid, acetic acid sulfonic acid,

Examples of suitable inorganic acids are: hydrohalic acids, such as hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid and amidosulfonic acid.

The optically active isomers of the racemic base-substituted phenol ethers of the formula I can be obtained by resolving the former into their components with optically active acids.

Examples of acids which can be used in the preparation of the optically active salts according to the invention are: (+) - and (-) - tartaric acid, (+) - and (-) - dibenzoyltartaric acid, (+) - and (-) - ditolyltartaric acid, (+ ) and (-) - mandelic acid, (+) - and (-) -camphoric acid, (+) - camphor-sulfonic acid, (+) - bromocamphor-o-sulfonic acid and N- (p-nitrobenzosyl) - (+ ) -Glu-tamiinihappo. The preparation of optically active salts can take place in water, aqueous or non-aqueous organic solvents. The use of esters of alcohols or organic carboxylic acids has proved advantageous.

In preparing optically active compounds, the racemic mixture of bases is reacted in a solvent, preferably in equimolar proportions, with an optically active acid, and the optically active salt of the compounds of formula I is isolated. In certain cases, only half an equivalent of the optically active acid may be used to remove the second optically active antipode from the racemate, as is the possibility of adding an excess of optically active acid.

10 67698

Depending on the nature of the optically active acid, the desired antipode can be obtained either directly or from the mother liquor of the first crystallization. The optically active base can then be liberated from the salt in the usual manner, and this optically active base can be converted into a salt of one of said physiologically acceptable organic or inorganic acids.

The compounds of the formula I or their physiologically acceptable acid addition salts have been shown in animal experiments to be of valuable therapeutic, in particular β-adrenolytic, β 2 -adreonolytic, and / or antihypertensive and / or antiarrhythmic properties. for the treatment or prevention of coronary heart disease, the prevention of irregular heartbeat and the treatment of hypertension.

In particular, the following should be emphasized:

A therapeutically advantageous phenomenon with respect to the blocking effect of β and β receptors, in which β 3 receptors are not blocked, occurs in particular with the compounds of the formula I in which R, if 3. .

R = H, denotes a phenylalkylene residue. For example, the product of Example 15 has a substantially stronger β 2 -sympatholytic (in the absence of a β-cytolytic effect) effect than the already known 1- (3,4-dimethoxyphenethyl) -amino-3-aryl -oxy-2-propanols, such as, for example, 1-ZT (3,4-di-ethoxyphenyl) -amino-3- (m-tolyloxy) -2-propanol hydrochloride (ML Hoefle et al., J. Med. Chem. 18 (1975), 1487.

The products of the process may be administered as free bases or their salts orally in the form of tablets or granules, optionally mixed with conventional pharmaceutical carriers and / or stabilizers, or parenterally in ampoules. Suitable carriers for tablets are, for example, milk sugar, starch, tragacanth and / or magnesium stearate.

For injection purposes, a dose of about 2 to 20 mg is possible, while an oral dose is in the range of about 6 to 15 mg; a private tablet or medicament may contain about 5-50 mg of active ingredient.

e

II

11 67698

Likewise, a therapeutically desirable, long-lasting, significant antihypertensive effect, with little or no β-receptor blocking effect, is a compound of formula 1!] -, 3 4 ..

wherein R together with R and the N atom correspond to a heterocyclic residue such as a piperazino, piperidino or morpholine residue which has no substituent or which has a subs: 'support on the other N atom.

. . . . 3. I:

The compounds of formula I in which R = H and R correspond to a branched aliphatic or cycloaliphatic hydrocarbon have the general very potent β-receptor blocking effect.

The following Tables I and II show the results of teraneat comparative experiments comparing Ο, ΙΟ-3-.A- + + (3,4-dimethoxyphenylethylamino-2-hydroxypropoxy) -phenyl] -Crotonic acid nitrile hydrochloride (Compound 1) and Therapeutic properties of 1-p-carbamoylmethyl'-phenoxy-3-isopropylamino-2-propanol (Compound 2).

Compound 1 of the present invention is described in Example 16, and Compound 2 is described in Example 1 of FR Patent 2,034,661 and U.S. Patent Nos. 3,663,607 and 3,836,671 and is known as a commercial product called "Atenolol" (ICI). It appears that Compound 1 has a remarkably high activity as a beta-blocker, but not as a beta-blocker, and it is of great importance in this sense that the beta-blocker has an effect. This can cause, for example, asthma attacks in patients ♦

Instead, the compound of the present application has been shown to have a peripheral vasodilating effect as well as an antihypertensive effect.

12 67698

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Table III also shows the effect of some other compounds of the present application (compounds of Examples 12a, 1e, 13, 6 and 66) on the circulation. The compound known from Example 8 of U.S. Patent 3,836,671 has been used as a reference compound. In these experiments, male dogs anesthetized with nembutal (35 mg / kg) were administered test compounds as 2-¾ aqueous solutions, possibly with the addition of a solubilizer. Blood pressure was measured after the time indicated in the table after administration of the compounds. Compound 2 in the table (Example 12a) is no longer within the scope of the limited claims, but is included for comparison because it closely resembles compound 1 known from U.S. Pat. No. 3,836,671 (the hydrogen group is replaced by a methyl group).

The results in the table show that at a dose of 1 mg / kg of the test compound, a decrease in blood pressure is observed in all cases (compound 4 was not tested at this dose). At a dose of 2 mg / kg, Compound 1 is observed to cause a sudden, severe, uncontrollable decrease in blood pressure and cause death in the test animal. With the compounds of the present application, the reduction in blood pressure is still controllable at a dose of 2 mg / kg or 3 mg / kg, whereby the initial blood pressure value returns 2 hours after the administration of the compound. The ECG trace is normal with the compounds of the invention and no additional beats of toxicity have been observed. In contrast, with Compound Compound 1 at a dose of 2 mg / kg, additional beats were observed one minute after compound administration, and after two minutes, the compound caused the death of the test animal.

From the therapeutic test results described above can be drawn. . 5

the conclusion that the novel compounds of the invention wherein R

means other than hydrogen, are much more suitable for 5

For the treatment of dainitis as compounds in which R is hydrogen.

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LO uo 67698 18

Example 1/1), 1- (7-3- [2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -1-crotonic acid nitrile hydrochloride (G g ZT), L17-3- Z-2- (2,3-Oxido-propoxy) -phenyl-7-crotonic acid nitrile is refluxed for 1 IM in a mixture of 80 ml of ethanol (98%) and 15 ml of tert-butylamine. It is then evaporated to dryness in vacuo, and then evaporated to dryness several times with toluene in vacuo. the oily distillation residue (free base) is dissolved in 50 ml of ethanol and the pH is adjusted to 4 by dropwise addition of concentrated hydrochloric acid, followed by evaporation to dryness in vacuo. The residue is dried by evaporation to dryness several times in vacuo with toluene and then crystallized from a small amount of ethanol and ether and again once more from ethanol.

7.1 g of [U}, 3-Z7- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -chrotonic acid nitrile hydrochloride are obtained, m.p. was 155-155 °.

Example 1a: [L, L7-3- / 2- (3-tert-Butylamino-2-hydroxy-propoxy) -4-fluoro-phenyl] -crotonic acid nitrile hydrochloride 14.0 g / E, 17-3- / 2- (2,3-Oxido-propoxy) -4-fluoro-phenyldj-crotonic acid nitrile is heated under reflux for 2 hours with 50 ml of ethanol and 100 ml of tert-butylamine. After further work-up as described in Example 1, 8.5 g of t-D, L7-3- / 2- (3-tert-butylamino-2-hydroxy-propoxy) -4-fluoro-phenyl-crotonic acid nitrile hydrochloride were obtained, m.p. was 158-159 °.

Example Ib: / Tl j Lj3-3 / 2- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -4-fluoro-phenyl-crotonic acid nitrile hydrochloride 14.0 g ZD, U- 3- [2- (2,3-Oxido-propoxy) -4-fluorophenyl] -chrotonic acid nitrile is heated at reflux in a water bath for 2 hours in 15 ml of ethanol with 23.0 g of homoveratrylamine and worked up as in Example 1. 6 and the hydrochloride is recrystallized from isopropanol / ether.

Yield: 11.4 g of D, L7-3- [2- (3-3,4-dimethoxy-phenethylamino-? -Hydroxypropoxy) -4-fluoro-phenyl] -crotonic acid nitrile hydrochloride, m.p. is 153-155 °.

il 19 67698

Example 1e: D, 17-3-Z-2- (3-3 +, 4 + -dimethoxy-phenethylamino, amino-2-hydroxy-propoxy-5-fluoro-phenyl) -7-crotonic acid nitrile hydrochloride 12, C g of CD, 1 * 7-3- [2- (2,3-oxido-propoxy) -5-fluorophenyl] -ct-tonic acid nitrile is reacted as described in Example 16e in 15 ml of ethanol to give 12.0 g of with homoveratrylamine.

First, 10.6 g of the free base were obtained, m.p. is 105-107 °, is converted in the usual manner (according to Example 1) to 8.3 grams of E, D7-3-ol2- (3-3 +, 4 + -dimethoxy-phenyl-amino-2-hydroxy) -propoxy) -5-fluoro-phenyl-7-crotonic acid nitrile hydrochloride, m.p. is 1 ^ 5-14 /.

Example Id: ZD, Ε7-3-Ζ-2- (3-tert-butylamino-2-hydroxy-propoxy) -5-f] oyl-1-phenyl-17-crotonic acid nitrile hydrochloride

A mixture of 12.0 g of ZD, L17-3-Z-2- (2,3-oxido-propoxy) -5-fluoro-phenyl-7-crotonic acid nitrile hydrochloride in 50 ml of ethanol and ICO ml of tert-butylamine, heated to reflux for 2 hours. Further processing is performed in the usual way (Example 1). The crude hydrochloride is recrystallized from isopropanol / ether and once again from isopropanol.

Yield: 9.7 g of D, L7-3- [2- (3-tert-butylamino-2-hydroxy-propoxy) -5-fluoro-phenyl] -crotonic acid nitrile hydrochloride, m.p. is 134-135 °.

Example 2 Ethyl hydrochloride of E, D7-3- [2- (3-morpholine-2-hydroxy-propoxy) -phenyl] 17-crotonic acid

A mixture of 15 g of D, 13-3-72- (2,3-oxido-propoxy) -phenyl-7-crotonic acid nitrile, 90 ml of ethanol and 6.1 g of morpholine is heated at reflux for 2 1/4 hours. Further work-up is then carried out as described in Example 1 and the compound is converted into the hydrochloride.

12.9 g of ZD, h7-3-Z "2- (3-morpholino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride, m.p. 134.5-185 °, were obtained.

Example 3 ZD, Ε7-3-Cl- (3-N-phenyl-piperazino-2-hydroxy-propoxy) -phenyl17-crotonic acid nitrile hydrochloride 20 67698

A mixture of 15 g of ID, 17-3-12- (2,3-oxido-propoxy) -phenyl-7-crotonic acid nitrile, 90 ml of ethanol and 11.4 g of N-phenylpiperazine is refluxed under 1 1/2 hours. The work-up is then carried out as described in Example 1, and the compound is converted to the hydrochloride.

14.0 g of ID, 17-3-12- (3-N-phenyl-piperazino-2-hydroxy-propoxy-phenyl) -crotonic acid nitrile hydrochloride, m.p. 177-178 °, were obtained.

Example 4 jD, 17-3-12- (3-Isopropylamino-2-hydroxy-propoxy) -phenyl] -7-crotonic acid nitrile hydrochloride

A mixture of 27 g), 17-3-12- (2,3-oxido-propoxy) -phenyl / crotonic acid nitrile in 27 ml of ethanol and 60 ml of isopropylamine is refluxed. for an hour. Further work-up is then carried out as described in Example 1 and the product is converted into the hydrochloride.

21.5 g of ZP, 17-3-12- (3-isopropylamino-2-hydroxy-propoxy) -phenyl-7-crotonic acid nitrile hydrochloride were obtained, m.p. was 145-146 °.

Example 5 ZD, 17-3-12- (3-2 +, 6 + -dimethylpiperidine-2-hydroxy-propoxy) -phenyl17-crotonic acid nitrile hydrochloride

A mixture of 15 g of ID, 17-3-12- (2,3-oxido-propoxy) -phenyl-crotonic acid nitrile, 90 ml of ethanol and 8.0 g of 2,6-dimethylpiperidine is refluxed for 13 hours. and further work-up is carried out as described in Example 1, and the product is converted into the hydrochloride.

12.4 g of ID, 17-3-12- (3-2 +, 6 + -dimethylpiperidine-2-hydroxypropoxy) -phenyl-7-crotonic acid nitrile hydrochloride are obtained, m.p. is 157-158 °.

Example 6 ID, 17-3-12- (3-3 +, 4+ -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride 19 g ID, 17-3-12- (2,3- oxido-propoxy) -phenyl] -crotonic acid nitrile is boiled for 5 hours in a mixture of 100 ml of ethanol and 12.7 g of homoveratrylamine. Further work-up is then carried out as described in Example 1 and the product is converted into the hydrochloride.

21 67698

10.8 g of iT>, L7-3-Z2- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxypropoxy) -phenyl-7-crotonic acid nitrile hydrochloride are obtained, m.p. is 164-165 °.

The free base is isolated in the usual manner from the mother liquor (made alkaline, extracted with toluene, evaporated to dryness in vacuo) and recrystallized from toluene-diisopropyl ether to give 1.2 g of the same product, m.p. is 88-89 °.

Example 6a ΖΡ, Ε7-3- [2- (3-3 +, 4 + -Dimethoxy-phenethylamino-2-hydroxy-propoxy) -4-methoxy-phenyl] -crotonic acid nitrile hydrochloride 7.0 g ZD, L7-3-Cl- (2,3-oxido-propoxy) -4-methoxy-phenyl-7-chrononic acid nitrile is heated on a water bath for one hour (boiling) with a mixture of 7.0 g of homoveratrylamine and 7.0 ml of ethanol . The pH of the reaction mixture is carefully adjusted to 3.5 with concentrated hydrochloric acid, stirred in 5 liters of water and extracted 3 times with a toluene / ethyl acetate mixture. The pH of the aqueous phase is then adjusted to between 8-8.5 with sodium hydrogen carbonate and repeatedly extracted with toluene. The basic extracts are dried, evaporated to dryness and the crude base is converted to the hydrochloride as described in Example 1.

9.4 g of JD, 17-3- [1- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxypropoxy) -4-methoxy-phenyl] -7-crotonic acid nitrile hydrochloride were obtained, by sp. was 169-170 °.

Example 7 ZI), L7-3- [2-C3-NZ-2 + (7-pyridino-piperazino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile trihydrochloride 7 g ZD, L17-3- / 2 - (2,3-Oxido-propoxy) -phenyl-7-crotonic acid.it-tile is boiled for 3 hours in a mixture of 73 ml of ethanol and 6 g of N- (2-pyridinino) -piperazine. 1 is described and the product is converted to the trihydrochloride.

5.1 g of ZD, L17-3-Z "2- (3-N-Z-2 + -7-pyridino-piperazino-2-hydroxypropoxy) -phenyl] -crotonic acid nitrile trihydrochloride, m.p.

Example 8

Zt>, h7-3-Z2- (3-N-acetylphenyl-7-piperazino-2-hydroxypropoxy) -phenyl-crotonic acid nitrile dihydrochloride 22 67698 7 g / l), 17-3-, 72- (2, 3- Oxido-propoxy) -phenyl-7-crotonic acid nitrile is refluxed for 3 hours in a solution of 6.8 g of N- (H-piperazino) -acetophenone in 70 ml of ethanol.

It is then evaporated to dryness in vacuo. the oily distillation residue crystallizes thoroughly after a few hours. It is then triturated with a small portion of ether and filtered. The filter residue was dissolved in just enough chloroform, and saturated hydrochloric acid / chloroform solution was added portionwise with stirring until the mixture was acidic. After a short time, dihydrochloride is released from the clear solution.

After filtration, washing with a small amount of chloroform / acetone and drying, 9 g of .alpha.,. Alpha.-p-acyrazine-2-hydroxy-1. propoxy) -phenyl-7-crotonic acid nitrile dihydrochloride, m.p. is 151 °.

Example 9 / f, L.7-3-Cl- (3-NZ-2-methoxyphenyl-7-piperazine-2-hydroxypropoxy) phenyl17-crotonic acid nitrile dihydrochloride 6 g TD, L7-3-Cl- ( 2,3-Oxido-propoxy) -phenyl-crotonic acid nitrile is boiled for 3 hours in a solution of 5.5 g of N- (2-methoxyphenyl) -piperazine in 60 ml of ethanol. It is then evaporated to dryness in vacuo, dissolved in chloroform and acidified with hydrochloric acid / chloroform. It is then evaporated to dryness in vacuo and crystallized by trituration with a small amount of ether. After filtration and drying, 10.5 g / l are obtained, 17-3-P_ _ (3-pr [[2-methoxyphenyl] 17-piperazino-2-hydroproxypropoxy) -phenyl - li./-crotonic acid nitrile dihydrochloride, m.p. is 171.

Example 10 TD, L7-3- [7 :- (3-N-T2-methylphenyl] -piperazino-2-hydroxy-4-oxoxyl) -phenyl] -crotonic acid nitrile dihydrochloride 7 g, Ia / -3-72 - (2,3-Oxido-propoxy) -phenyl-7-crotonic acid.it-tile is reacted as described in Example 9 in a mixture of 6.5 g of K- (o-tolyl) -piperazine and 70 ml of the ethanol obtained in Example 9. further processing will also take place.

10 g of TD, L7-3-72- (3-N-72-methylphenyl-7-piperazino-2-hydroxy-propoxy) -phenyl17-crotonic acid nitrile dihydrochloride are obtained, m.p. is 13 8 °.

67698 2 3 Example 11/1), LJ - 3- (3 - K - / jn ethyl 1 ipxperazxx7-2-hydr ok sd -propoxy) -phenyl-crotonic acid nitrile dihydrochloride 7 g, 17-3- ΖΓ2 - (2,3-oxido-propoxy) -phenyl-17-crotonic acid nitrile is reacted with 3 g of N-netylperazine 6 in 3 ml of absolute ethanol as described in Example 9, which is also followed by further work-up. The crude dihydrochloride is filtered through a 3 g activated carbon layer dissolved in 50 ml of water. The filtrate is evaporated to dryness, finally under high vacuum. The resulting foam is triturated with ether, filtered and dried.

This gives 4.3 g of a strongly hygroscopic £ 1, U-3-12 - (? -! \ '- Zm e t y y 1 i p i ρ e r n t s 11 n o7 - 2 - h y d r o k s x - ρ r o n o k s 1) -; f e n y y 117 - k r o t o n i h α p p υ n 't -riil-d.i hydrochloride.

The compound has characteristic peaks in the IR curve at 2203, 1590, 1435 and 745 cm ”1.

Example 12E), E7-3-Z2- (3-N-Y2-hydroxyethyl-piperazinexino-2-hydroxy-P-propoxy) -phenylZ-crotonic acid nitrile dihydrochloride 7 g Zt> .117-3-Z "2 - (2,3-oxo-do-propoxy) -phenyl 17-Chronic acid nitrile is reacted with 4.7 g of N- (2-hydroxyethyl) -piperazine in 70 ml of absolute ethanol in the example 9, according to which the partitioning also follows.

8.5 g of (1), 17-3- [2- (3 ') -Z2-hydroxyethyl-7-piperazine-nx-2-hydroxy-porpoxy) -phenyl-17-crotonic acid are obtained. hydrochloride i-dia, m.p. is 146 °.

Example 12a ZD, 17-3- / 4- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl-7-crotonic acid nitrile dihydrochloride 5, 0 g of β3,17-3- [1- (2,3-oxido-propoxy) -phenyl] -crotonic acid nitrile are reacted in 40 ml of ethanol with 40 ml of tert-butylamine in the same manner as in Example 1, further processing will also take place.

24 67698

Yield: 6.0 g of D, 17-3-A- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl-t'-crotonic acid nitrile hydrochloride, m.p. is 186-187 °.

Example 12b, Lty-3-E-2-Methoxy-4- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -cotonic acid nitrile hydrochloride 3.4 g ZC3, L7-3-IT -methoxy-4- (2,3-oxido-propoxy) -phenyl-7-crotonic acid dononitrile is refluxed for 2 1/2 hours with 20 ml of ethanol and 40 ml of tert-butylamine and worked up as described in Example 1. way.

Yield: 4.0 g of D, 17-3-Z '2-methoxy-4- (3-tert-butylamino-2-hydroxypropoxy) -phenyl-crotonic acid nitrile hydrochloride, m.p. is 145-146 °.

Example 12c ϋ, 1 + 7-3-Ζ-2- (3-tert-butylamino-2-hydroxy-propoxy) -4-methoxy-phenyl-17-crotonic acid nitrile hydrochloride 5.0 g of β, 17- 3- [2- (2,3-Oxido-propoxy) -4-methoxy-phenyl] -crotonic acid nitrile dissolved in 20 ml of ethanol, after the addition of 50 ml of tert-butylamine, is heated under reflux for 3 hours and then then further processing is performed as described in Example 1.

Yield: 4.3 g of ID, 17-3-, t2- (3-tert-butylamino-2-hydroxy-propoxy) -4-methoxy-phenyl-17-crotonic acid nitrile hydrochloride, m.p. is 144-145 °.

Example 13 ID, 17-3- / 74- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl U-Krot is the trile hydrochloride of my acid 10.75 g ID, 17-3-Z4-C2 The 3-oxido-propoxy) -phenyl-crotonic acid nitrile is boiled for 3 hours in a solution of 8.1 g of phenylpiperazine in 60 ml of ethanol. The reaction mixture is then cooled on ice and, after standing, , time, the separated crystals are filtered off and recrystallized from a small amount of ethanol.

12.9 g of the free base are obtained, m.p. is 133-134 °. The base is dissolved in just enough acetone at room temperature and then concentrated dropwise is added dropwise with concentrated hydrochloric acid until pH = 4.5. The hydrochloride precipitates off after a short time. It is filtered off and dried.

13.9 g of crude hydrochloride are obtained, m.p. is 158-163 ^. Recrystallization once from a large amount of ethanol gives 13.3 g of N, N7-3-N- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl-7-crotonic acid nitrile hydrochloride, m.p. is 160-161 °.

Example 14

ZjD, L7-3-Z-4- (3-morpholino-2-hydroxy-propoxy) -phenyl / crotonic acid nitrile hydrochloride 15.0 g ZT), L7-3- / T4- (2 The 3-oxido-propoxy) -phenyl-7-crotonic acid nitrile is heated for 4 1/2 hours at 80 ° in a solution of 6.1 g of morpholine in 100 ml of ethanol. After standing at room temperature for a further 12 hours, the mixture is evaporated to dryness in vacuo and evaporated to dryness 3 more times with toluene. The residue is dissolved in a small amount of toluene and crystallized by adding diisopropyl ether. After filtration and drying, 18 g of free base are obtained, m.p. is 79-80 °.

The product is then converted to the hydrochloride as described in Example 1.

16.4 g of Ζΐ, L7-3- [4- (3-morpholino-2-hydroxy-propoxy) -phenyl] -Z-crotonic acid nitrile hydrochloride are obtained, m.p. is 121-122 °.

Example 15 / D, 11-7-3-N- (3- 2+, 6+ -dimethylpiperidine-2-hydroxy-propoxy-phenyl) -crotonic acid nitrile hydrochloride 15 g Z1), L7-3-Z - (2,3-Oxido-propoxy) -phenyl-7-crotonic acid nitrile is boiled for 6 1/2 hours under reflux in a solution of 67698 g of δ, Ο g of 2,6-dimethylpiperidine in ΪΟϋ ml of ethanol. to dryness in vacuo, the distillation residue is dissolved in 8C of toluene, after the addition of 300 ml of water, the pH is adjusted to 4 by shaking well with concentrated hydrochloric acid and 80 ml of fresh toluene are added to the aqueous phase. The combined organic extracts are washed with water, dried over sodium sulphate and evaporated to dryness in vacuo, triturated with diisopropyl ether, filtered off and filtered to give 15.0 g of the free base, m.p.

This gives, as described in Example 1, 14.5 g of [0.1,7-3- [4- (3-2 +, 6+ -dimethylpiperidin-2-hydroxy-propoxy) -phenyl] -Z-crotonic acid nitrile hydrochloride, by sp. Oh; 108-169 °.

Example 16 ZD, L17-3-3- [4- (3-3,4-Dimethoxyphenethylamino-2-hydroxy-proxy-phenyl) -phenyl] -crotonic acid nitrile hydrochloride 17.5 g / 0.1 / -3- / 4- (2,3-Oxido-propoxy) -phenyl-7-crotonic acid nitrile is heated at reflux for 5 hours in a solution of 15.0 g of homoveratrylamine in 100 ml of ethanol. After the usual work-up (see example), the free crude base is recrystallized from ethanol / diisopropyl ether and once again from ethanol. 16.1 g of the free base are obtained, m.p. is 1-1.5-142 °. From this, 13.6 g of ZD, Lj-3- / 4- (3-3 * * dimethoxyethylamino-2-hydroxy-propoxy) -phenyl-7-crotonic acid-r are obtained as described in Example 1. nitrile-hydro] crid ia, m.p. is 14 3-149 ”.

Example IGa_ _ ^ ^f + ZD, h7-3-Z2-methoxy-4- (3-3-dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl7-crotonic acid nitrate 111-hydrochloride b, 7 g ZD, The N-3-Z2-methoxy-4- (2,3-oxido-propionic) phenyl-crotonic acid nitrile is boiled for one hour in 7 ml of ethanol with 7.0 g of homoveratrylamine and given react with the procedure described in Example 15,

Yield: 6.6 g of ZD, L / -3-Z2-methoxy-4- (3, 3,4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl-17-crotonic acid nitrile hydrochloride, by sp. is 131-132 °.

Il 67698 2 7

Example 16b / D, Ly-3-Z.3-chloro-4- (3-3 +, 4 + -dimethoxy-phenethyl-an, amino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride 5.0 g LD, L_7 - 3-73-Chloro-4- (2,3-oxo-propoxy) -xenyl-17-crotonic acid nitrile is boiled for 4 hours in 15 ml of ethanol with 5 g of homoveratrylamine. Then 50 ml of ethanol are added. The pH is adjusted to 3.5 with concentrated hydrochloric acid and the reaction mixture is poured into 5 liters of water. After extraction of the neutral fraction with ethyl acetate / toluene (2: 1), the aqueous phase is made weakly alkaline with sodium hydrogen carbonate. Extract with a toluene / ethyl ester mixture. 1 a (2: 1) and evaporate the organic phase to dryness. Crystallization from toluene / diisopropyl ether gives 5.1 g of the free base, m.p. is 1] 7-119 °, which is converted to the hydrochloride as described in Example 1.

Yield: k, 7 g £ d, L7-3-Z "3-chloro-4- (3-3 +, 4 + -dimethoxyphenylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid.itil hydrochloride, mp 146-148 °.

Example 16c ZD, L7-3- [-3-chloro-4- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -7-crotonic acid nitrile hydrochloride 4.5 g of 1D, L7-3- Z-3-chloro-4- (2,3-oxido-propoxy) -phenyl] -ctononic acid nitrile is reacted for 3 hours in 15 ml of ethanol as described in Example 5a with 50 ml of tert-butyl lamine and further work-up is performed as described in Example 1.

Yield: 6.0 g of ZXVm7-3- [3-chloro-4- (3-tert-butylamino-hydroxypropoxy) -phenyl] -7-crotonic acid nitrile hydrochloride, m.p. is 188-189 °.

Example 16d ZD, 1.7-3-Z-3-Fluoro-4- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride 5.0 g CD, E / - 3-7 * 3-Fluoro-β- (2,3-oxido-propoxy) -fert-yl: <7-crotonic acid nitrile is boiled in 15 ml of ethanol for 3 1/2 hours with 50 ml of tert-butylamine and further processing is performed as described in Example 1.

Yield: 6.9 g of ZjD, 17-3-73-fluoro--4- (3-tert-butylamino-2-hydroxypropoxy) -phenyl-7-crotonic acid nitrile hydrochloride, m.p. is 130-191 °.

67698 28

Example 16e (D, L) -3-3-3-Fluoro-4- (3-3 +, 4 * -dimethoxy-phenethylamino-2-hydroxypropoxy) -phenyl_7-crotonic acid nitrile hydrochloride 10 g / T), L.7-3- [f-Fluoro-4- (2,3-oxido-propoxy) -phenyl] -crotonic acid nitrile is heated in a water bath under reflux in 20 ml of ethanol with 10.0 g of homoveratrylamine for 3 1/2 hours. Further work-up is then carried out according to Example 16b. 7.9 g of the free base obtained, m.p. is 111-112 °, is converted as in Example 1 to 7.3 grams of L7-3-73-fluoro-4- (3-3,4-dimethoxy-phenethylamino-2-hydroxypropoxy) -phenyl] -crotonic acid nitrile hydrochloride by sp. is 163-164 °.

Example 16f / D, L7-3- [3-Methoxy-4- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride 9.8 g of 7D, L7- 3- [3-Methoxy-4- (2,3-oxido-propoxy) -phenyl] -chrotonic acid nitrile is heated for 2 hours in a water bath under reflux. It is then diluted with about 50 ml of ethanol, the pH is adjusted to 1 with concentrated hydrochloric acid and the reaction mixture is poured into 5 liters of water. The neutral parts are extracted with a toluene / ethyl acetate mixture. The aqueous phase is then weakly basified with sodium hydrogen carbonate, extracted with toluene and the basic extracts are evaporated to dryness, crystallized from toluene / ether and then again from ethanol. Yield: 7.6 g of free base, m.p. is 115-116 °. It is converted in the usual manner (see Example 1) into the hydrochloride and this is recrystallized from ethanol / ether and ethanol.

Yield: 6.4 g, I./-3-ZZ3-3-methoxy-4- (3-3 +, 4 + -dimethoxyethylamino-2-hydroxy-propoxy) -phenyl7- chronitonic acid nitrile hydrochloride, m.p. is 110-112 °.

Example 16g / b, L7-3- [3-Methoxy-4- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride 7.0 g / -D, L7-3- [3-methoxy-4- (2,3-oxido-propoxy) -phenyl] -crotonic acid nitrile is heated under reflux for 1 hour in a mixture of 28 ml of ethanol and 70 ml of tert-butylamine. Thereafter, further processing is performed as described in Example 1.

11 29 67698

Yield: 7.1 g of ZD, 17-3- [3-methoxy-4- [(3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride, m.p. is 157-158 °.

Example 17 ZD, Ε7-3-Ζ-4- (3-N-2 + -pyridyl-piperazino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile dihydrochloride 10.75 g Z-D jL_7-3-Z-+ - (2,3-Oxido-propoxy) -phenyl-7-crotonic acid nitrile is boiled for 3 hours in a solution of 8.2 g of pyridylpiperazine in 60 ml of ethanol. After cooling with ice, the crystals separated are collected and dried. The base thus obtained, 17.1 g, m.p. 131-132 °, is converted in the usual manner to 15.1 grams of Z-D, L7-3-Z-4- (3-N-2 + -pyridyl-piperazino-2-hydroxy-propoxy) -phenyl-4-crotonic acid nitrile dihydrochloride by sp. is 159-160 °.

Example 18 ZD, 1 + 7- 3- - (3-N-4 * -acetyl-phenyl-piperazino-2-hydroxy-propoxy) -phenyl-7-crotonic acid nitrile hydrochloride 10.75 g of ZD, L7-3-Z'4- ( 2,3-Oxido-propoxy) -phenyl] -crotonic acid nitrile is boiled for 4 hours in a solution of 10.2 g of p-piperazinoacetophenone. On cooling, a solution of the crystallized, filtered and dried base (20.1 g, m.p. 160-161 °) with 100 ml of abs. ethanol and 30 ml of dimethylformamide, the pH is adjusted to 5 with concentrated hydrochloric acid. The separated crystallized hydrochloride is combined and recrystallized from hot ethanol / water.

17.7 g of Z-D, 17-3- [4- (3-N-4 + -acetyl-phenyl-piperazine-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride are obtained, by sp. is 221-222 °.

Example 19 ZD, 17-3- [4- (3-N-2 + -methoxy-phenylpiperazino-2-hydroxy-phenyl] -crotonic acid nitrile hydrochloride 10.75 g of 7D, L7-3-A- (2,3-oxide) -propoxy) -phenyl-7-crotonic acid nitrile is refluxed in a solution of 10.3 g of N- (2-methoxyphenyl) -piperazine dihydrochloride in a mixture of 14.0 ml of triethylamine and 60 ml of ethanol for 5 hours. After evaporation to dryness in vacuo and crystallization of the crude base by the addition of ethanol, filtration followed by washing with ethanol and water gives, after drying, 15.0 g of the free base, mp 102-103 DEG C. The product is then converted in the usual manner (cf. Recrystallization twice from ethanol gives 13.3 g of / D, L7-3-A- (3-N-2 + -methoxyphenylpiperazino-2-hydroxy-propoxy) -phenyl-7-crotonic acid nitrile hydrochloride , mp 198-199 °.

Example 20 CD, L7-3-N- (3-N-2 + -methyl-phenyl-piperazino-2-hydroxy-propoxy) -phenyl-7-crotonic acid nitrile hydrochloride 10.95 g / D, Lj-3-7 * 4- (2,3-Oxido-propoxy) -phenyl / crotor, i-acid nitrile is boiled for 3 hours in a solution of 8.8 g of o-tolylioiperazine in 60 ml of ethanol. On cooling, the bellows crystallize xb.5 g of a base with a m.p. is 104-105. It is converted to the hydrochloride as described in Example 1. After recrystallization twice from ethanol, 1 .mu.g, N, N-3-N- (3-K-2-methyl-phenyl-piperazino-2-hydroxy-propoxy) -phenyl-117-crotonic acid nitrile hydrochloride is then obtained. by so. is 233-234 °.

Example 21 / D, L7-3-A- (3-N-3 + -methyl-phenyl-piperazino-2-hydroxy-oropoxy) -phenyl-7-crotonic acid nitrile hydrochloride 10.75 g / "D, L7-3- / 4 - (2,3-Oxido-propoxy) phenyl] -crotonic acid nitrile is reacted as described in Example 19 with 8.8 grams of m-tolylpiperazine.

After further treatment in the same manner, 16.4 g of free base, m.p. 108-109 °, 14.6 g of ZD, L7-3- [4- (3-N-3-methyl-phenyl-piperazino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride are obtained, m.p. is 151-152 °,

Example 22 / D, L7-3- [4- (3-N-methyl-piperazino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile dihydrochloride 10.75 g / D, L7-3-A- (2 The 3-oxido-propoxy) -phenyl-117-crotonic acid nitrile is reacted as described in Example 19 with 5.0 g of N-methylpiperazine in 60 ml of ethanol and further worked up as described in Example 1 and the product is converted into the dihydrochloride. . 11.8 g of (1), N--3-N- (3-N-methyl-piperazino-2-hydroxy-propoxy) -phenyl-7-cromophenitrile dihydrochloride, m.p. is 217-218 °.

il 31 67698

Example 23 fb, L--3- [N4- (3-N-2-oxyethyl-piperazino-2-hydroxy-DrG-poxy) -phenyl] -crotonic acid nitrile dihydrochloride 5.0 g / D, L7-3 - / "4- (2,3-Oxido-propoxy) -phenyl over-crude acid pipelines are boiled for 2 hours in a solution of 3.5 g of hydroxyethylpiperazine in 53 ml of ethanol, after evaporation to dryness in vacuo, recrystallization from toluene. 5.7 g of the free base, m.p. 101-102 °, obtained are converted, as described in Example 1, into 6.7 g of ZD, L7-3-A- (3-N-2 + -oxy-ethyl-piperazino-2 -hydroxy-propoxy) phenyl / crotonic acid nitrile dihydrochloride, mp 204-205 °.

Example 24 ΖΊ), u7-3-ZÖ4- (3-7,5-dimethyl-5 + -hydroxy-hexylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile oxalate 8.5 g / T), L7-3 -Z "4- (2,3-Oxido-propoxy) -phenyl-7-chronophenaponitrile is refluxed for 2 hours in a solution of 1.6 g of sodium hydroxide and 7.2 g of heptaminol hydrochloride in 50 ml of ethanol. It is then evaporated to dryness in vacuo, the distillation residue is dissolved in 85 ml of water and the pH is adjusted to 7 with hydrochloric acid. Wash twice with toluene and twice with ethyl acetate and make the aqueous phase alkaline by adding sodium hydroxide until pH 10. Then extract with ethyl acetate / toluene. 1: 1), the organic extracts are dried and evaporated to dryness in vacuo.

The crude base is dissolved in ethanol and the pH is adjusted to 4 with a concentrated ethanolic solution of oxalic acid. After filtration and drying, 7.7 g / D, L7-3- / 4- (3-7 +, 5 + -dimethyl-5 + -hydroxy-hex) are obtained. · -Cylamino-2-hydroxypropoxy) -phenyl / crotonic acid nitrile, m.p. is 155 °.

Example 25 7β-α-N- [2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -7,7-acrylic acid nitrile hydrochloride 7.0 g / T3, L-7-3 - [7- (2,3-Oxido-propoxy) -phenyl] -acrylic acid-ponitrile is boiled for one hour in a solution of 15 ml of n-n-butylamine in 80 ml of abs. ethanol.

Further work-up is carried out as described in Example 1 and the product is converted into the hydrochloride. 5.3 g (1) of L7-3 - [* 2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid are obtained. by sp. is 155 °.

32 67698

Example 26 “N- [3 - Z-2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid tert-butyl ester hydrochloride 30.0 g / D, L.7-3- ["2- (2,3-Oxido-propoxy) -phenyl] -acrylic acid tert-butyl ester is refluxed for 3 hours in a mixture of 30 ml of tert-butylamine and 150 ml of ethanol. After the usual work-up (cf. to Example 1) the crude hydrochloride is dissolved in water, the aqueous solution is extracted twice with toluene and then a concentrated aqueous brine is added to the aqueous phase, in which case / ~ D, L7-3-/2-(3-tert-butylamino-2-hydroxypropoxy ) -phenyl-7-acrylic acid tert-butyl ester hydrochloride crystallizes out, filtered, dried in vacuo and crystallized twice more from isopropanol to give 13.8 g of [D, L7-3-/2-(3-tert-butylamino-2]. -hydroxy-propoxy) -phenyl-7-acrylic acid tert-butyl ester hydrochloride, mp 186-187 °.

Example 27 / D, L_7-3- [2- (3-3 +, 4 + -Dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid tert-butyl ester hydrochloride 30.0 g / D, b7- 3- [2- (2,3-Oxido-propoxy) -phenyl] -acrylic acid tert-butyl ester is heated at reflux for 2 hours in a solution of 20.0 g of homoveratrylamine in 60 parts of ethanol. After the usual work-up (cf. Example 1), 15.9 g of D, L7-3-72- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl / -acrylic acid-tert .-butyl tert-hydrochloride, m.p. is 167-168 °.

Example 28 / 10,1 -, 7-3-72- (3-N-2 + -oxyethyl-piperazino-2-hydroxy-propoxy) -phenyl-117-acrylic acid tert-butyl ester dihydrochloride 11.0 g / D , L7-3- [2- (2,3-Oxidopropoxy) -phenyl] -acrylic acid tert-butyl ester is boiled for 2 hours in a mixture of 55 g of N-hydroxyethylpiperazine and 60 ml of ethanol. Then proceed as described in Example 14, but now pH = 3, after 4.

6.4 g of / D, 1-, 7-3- [7- (3-N-2 + -oxyethyl-piperazino-2-hydroxypropoxy) -phenyl] -acrylic acid tert-butyl ester dihydrochloride are obtained, m.p. . is 168 ° (dec.).

33 67698

Example 29 / D, L_7-3-Z-2- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl] -acrylic acid tert-butyl ester hydrochloride 11.0 g of ZD, 17-3-Z2- (2, 3-Oxidopropoxy) -phenyl-7-acrylic acid-p-tert-butyl ester is refluxed for 1 hour in a mixture of 6.5 g of phenylpiperazine and 50 ml of ethanol and further worked up as described in Example 1. In this case, the hydrochloride is finally recrystallized twice from ethanol. 6.2 g of [D, U7-3-Z2-(3-N-phenylpiperazine-2-hydroxy-propoxy) -phenyl] -acrylic acid tert-butyl ester hydrochloride are obtained, m.p. is 200-201 ° (dec.).

Example 30 ZD, L7- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl-7-acrylic acid tert-butyl ester hydrochloride 15.0 g of ZD, L7-3- [h- (2,3- oxidopropoxy) -phenyl-7-acrylic acid tert-butyl ester is refluxed for 2 hours in a mixture of 25 ml of tert-butylamine and 100 ml of ethanol (98%). It is then evaporated to dryness in vacuo, the distillation residue is evaporated to dryness twice with toluene (in vacuo) and finally crystallized from diisopropyl ether. 16.7 g of the free base are obtained, m.p. is 107-108 °. This gives, as described in Example 28, 12.3 g of [D,L7~3-A-(3-tert-butylamino-2-hydroxy-propoxy) -phenyl] acrylic acid tert-butyl ester hydrochloride, m.p. is 192-193 ° (dec.).

Example 31 7D, L7-3-Zh- (3-3 *, H + -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl7-acrylic acid tert-butyl ester hydrochloride 15.0 g ZTD, L7-3-ZH- ( 2,3-Oxidopropoxy) -phenyl] -acrylic acid tert-butyl ester is refluxed for 8 hours in a solution of 10.5 g of homoverazrylamine in 80 ml of ethanol. The work-up is then carried out as usual and the crude hydrochloride is dissolved in water (6 L), extracted several times with toluene and the pH of the aqueous phase is adjusted to 9 with sodium hydroxide solution. It is then extracted with toluene and ethyl acetate. The combined organic extracts are evaporated to dryness in vacuo and crystallized from diisopropyl ether. 6.95 g of free base are obtained, m.p. is 100-101 °. This gives, as described in Example 1, 7 (g / D, 17-3-Z) 4- (3-3 +, * 4 + -dimethoxyphenyl) -1,67698-methylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid. tert-butyl ester hydrochloride, m.p. is 176-177 °, and which was finally crystallized twice more from ethanol.

Example 32 Z-D, L--3-phenyl-3- [2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid nitrile hydrochloride 5.4 g ZT), L. 7-3-Phenyl-3 - [[2- (2S-oxidopropoxy] -phenyl] acrylic acid nitrile is refluxed for two hours in a mixture of 15 ml of tert-butylamine, then evaporated to dryness in vacuo and then evaporated to dryness with toluene. The residue is crystallized by digestion with toluene / petroleum ether to give 6.4 g of the free base, mp 92-93, which gives 5.5 g of CD, L7-3-phenyl-3-72- (3) as described in Example 1. -tert-butylamino-2-hydroxy-propoxy) -O-phenyl-7-acrylic acid nitrile hydrochloride, mp 171-172 Example 33 CD, ij-3-phenyl-3- [2- (3-3 +, 4 + -Dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl7-acrylic acid nitrile half-oxalate 5.4 g of TD, L / -3-phenyl-3- [2- (2,3-oxidopropoxy) -phenyl] -acrylic acid nitrile are refluxed for 3 hours. a in a solution of 3.7 g of homoveratrylamine in 50 ml of ethanol. Thereafter, further work is performed as described in Example 30. the oily free base is then converted to the oxalate as described in Example 23. However, the pH must then be adjusted to 6.5 by adding oxalic acid. The crude half-oxalate is recrystallized twice more from ethanol to give 4.1 g / D, L7- + + 3-phenyl-3- [2- (3-3,4-dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid nitrile half oxalate, m.p. on 172— ·>

± / S

Example 34 CD, h7-3-Phenyl-3- [2- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl] -acrylic acid nitrile hydrochloride 6.0 g / D, L / -3-phenyl- 3- [2- (2,3-Oxydropoxy) -phenyl] -acrylic acid nitrile is refluxed for 2 hours in a solution of 3.5 g of phenylpiperazine in 50 ml of ethanol. The work-up is then continued as described in Example 1 and the product is converted into the hydrochloride. For further purification, the procedure is as in Example 30. The free base was purified by crystallization from toluene / diisopropyl ether. 4.1 g of product are obtained, m.p. is 102-103 °. The free base is reconverted to the hydrochloride as described in Example 1. 4. g of product with a double melting point of 85 ° / 184 ° are obtained.

Example 35 / D,17-3-Phenyl-3- [3- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid nitrile hydrochloride 10.0 g of 7 "D, L7-3-phenyl- 3- [4- (2,3-Oxido-propoxy) -phenyl] -acrylic acid nitrile is refluxed for 2 hours in a mixture of 20 ml of tert-butylamine and 50 ml of ethanol, followed by further work-up as described in Example 1 and the product. The crude hydrochloride was finally recrystallized 2 more times from ethanol to give 4.6 g of [D, L17 -3-phenyl-3- [4- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl]. N-acrylic acid nitrile hydrochloride, mp 233-234 DEG C. The ethanol solution obtained after the second recrystallization is evaporated to dryness in vacuo and converted into the free base according to Example 30. After crystallization of the crude base by trituration with diisopropyl ether, a further 1.1 g are obtained. free base with a mp of 112-114 °.

Example 36 ΓΡ, L7-3-Phenyl-3-Z-4- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid nitrile oxalate 10.0 g of ZD, 17-3-phenyl -3-Z4- (2,3-Oxido-propoxy) -phenyl-7-acrylic acid nitrile is refluxed for 2 hours in a mixture of 6.5 ml of homoveratrylamine and 50 ml of ethanol.

It is then continued as described in Example 30. The oily free base is then converted to the oxalate as described in Example 23. 4.9 g of D, L7-3-phenyl-3-Z-4- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxypropoxy) -phenyl-7-acrylic acid nitrile oxalate are obtained, m.p. is 124-125 °.

Example 37 ZD, E7-3-phenyl-3-Z-4- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl-7-acrylic acid nitrile dihydrochloride 10.0 g ZD, E7-3-phenyl-3- [ N- [2,3-oxido-propoxy) -phenyl] -acrylic acid nitrile is refluxed for 2 hours in a solution of 5.9 g of phenylpiperazine in 50 ml of ethanol. After further treatment according to Example 1, 6.8 g of Tt ·, L7-3-phenyl-3-Z "4- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl are obtained. N-acrylic acid nitrate dihydrochloride, mp 189-190 °.

Example 38 ZD, L7-3-Phenyl-3-A- (3-N- (2-hydroxyethyl) piperazine-2-hydroxypropoxy) -phenyl] -acrylic acid nitrile dihydrochloride 10.0 g Z "D, L7 - 3-phenyl-3- [4- (2,3-oxido-propoxy) -phenyl] -acrylic acid nitrile is reacted according to Example 36 in 50 ml of ethanol with 4.7 g of N-hydroxyethylpiperazine 9.8 g of Z-D, 17-3-phenyl-3-Z4- (3-N- [2-hydroxyethyl-7-piperazino-2-hydroxy-prop-p / a) are obtained. -phenyl-7-acrylic acid nitrile dihydrochloride, mp 164-165 °.

Example 39 ZD, L7-3-Z-4- (3-3 +, 4-dimethoxyphenethylamino-2-hydroxy-propoxy) -phenylZ-acrylic acid methyl ester hydrochloride 5 g Z1), L.7-3-Z 4-4- (2,3-Oxido-propoxy) -phenyl-acrylic acid methyl ester is refluxed for 2 1/2 hours in a solution of 4.7 g of homoveratrylanine in 60 ml of absolute ethanol, followed by further work-up as described in Example 1. . 6.2 g of ZD, 17-3- [74- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid methyl ester hydrochloride with a melting point of 162 ° are obtained.

Example 40 ZD, 17-3-Z-4- (3-Z1,5-Dimethyl-5-hydroxy-7-hexylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid methyl ester hydrochloride 5.5 g ZD, L7-3-74- (2,3-Oxido-propoxy) -phenyl-7-acrylic acid methyl ester is refluxed for 4 hours in a solution of 4.6 g of 5-amino-2-methyl-2-heptanol hydrochloride (heptaminol- hydrochloride) and 1.02 g of sodium hydroxide in 70 ml of abs. ethanol. Thereafter, further processing is performed as described in Example 1. Ether is used to recrystallize the free base and recrystallize the hydrochloride.

1.2 g of ZD, L7-3-Z "4- (3-Z" 1,5-dimethyl-5-hydroxy-7-hexylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid methyl ester hydrochloride are obtained. by sp. is 110 °.

Example 40a Z7), L7-3-Z-4- (3-N-2''-methoxyphenyl-piperazino-2-hydroxy-propoxy) -phenylZ-crotonic acid meryl ester 15.0 g, L7-3- / 4- ( 2,3-Oxido-propoxy) -phenyl-7-croton-37,67698 acid methyl ester is heated on a water bath for 1 hour in a mixture of 50 ml of ethanol and 10 g of 2-methoxy-phenyl-piperazine. Further work-up is carried out as described in Example 1; 6.2 g of / D, L7-3- [4- (3-N-2 + -methoxyphenyl-piperazine-2-hydroxy-propoxy) -phenyl] -chrotonic acid methyl ester are obtained, m.p. is 183-184 °.

Example 41 TD, 17-3-74- (3-N-2 + -methoxyphenyl-piperazino-2-hydroxy-propoxy) -phenyl] -acrylic acid methyl ester dihydrochloride 4.5 g Z-D, h] -3 -Z "4- (2,3-Oxido-propoxy) -phenyl-7-acrylic acid methyl ester is refluxed for 3 hours in a solution of 4.0 g of N- (2-methoxy-phenyl) - piperazine in 60 ml of absolute ethanol After the usual further treatment (see

Example 39) 6.05 g of D, 17-3-Z-4- (3-N-2 + -methoxyphenyl-piperazino-2-hydroxy-propoxy) -phenyl-7-acrylic acid methyl ester dihydrochloride are obtained, by sp. is 204.

Example 42 7D, L7-3-Z "2- (3-3 +, 4 + -Dimethoxy-phenylamino-2-hydroxy-propoxy) -phenyl-7-acrylic acid ethyl ester hydrochloride 10.0 g £ D, L7-3 2- [2,3-Oxido-propoxy) -phenyl] -acrylic acid-polyethyl ester is refluxed for 4 hours in a solution of 7.3 g of homoveratrylamine in 60 ml of ethanol. It is then evaporated to dryness in vacuo. The oily distillation residue is crystallized by digestion with hexane. After filtration and drying, 9.8 g of the free base are obtained, m.p. is 80-82 °.

From this, the hydrochloride is prepared as described in Example 1, which is recrystallized once more from an ethanol / water mixture and finally recrystallized from isopropanol. 8.1 g of (D, L7-3-Z "2- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid ethyl ester hydrochloride with a m.p. -162 °.

Example 43 TD, L7-3- [2- (3-N-phenylpiperazine-2-hydroxypropoxy) -phenyl] -acrylic acid ethyl ether hydrochloride 10.0 g of Z-D, L7-3-T2- (2 (3-Oxido-propoxy) -phenyl-7-acrylic acid polyethyl ester is boiled for 4 1/2 hours in a solution of 6.54 g of N-phenylpiperazine in 60 ml of ethanol. The work-up is then carried out as described in Example 1 and the product is converted into the hydrochloride. The hydrochloride obtained is finally recrystallized once more from 38 67698 isopropanol and then again from ethanol / water. 10.2 g of Z "D, L7-3- [2- (3-N-phenylpiperazino-2-hydroxy-propoxy) -phenyl] -acrylic acid ethyl ester hydrochloride, m.p. 186-187 °, are obtained.

Example / D, 17-3- [2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid ethyl ester hydrochloride 10.0 g / D, L7-3- / 2- (2 The 3-oxido-propoxy) -phenyl] -acrylic acid ethyl ester is boiled for 5 1/2 hours in a mixture of 4.25 ml of tert-butylamine in 60 ml of ethanol. The work-up is then carried out as described in Example 1 and the crude hydrochloride obtained, which is precipitated in the usual manner from an ethanol / hydrochloric acid mixture and then evaporated to dryness with toluene, is recrystallized from an ethanol / diisopropyl ether mixture. The hydrochloride is then purified once more as described in Example 1 as the free base. For this, it is sufficient to slurry the hydrochloride in about 100 ml of water and add sodium hydroxide solution. After recrystallization from isopropanol, 5.8 g of D, 17-3-Z '2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl-7-acrylic acid ethyl ester hydrochloride are obtained, m.p. is 133-134 °.

Example 45 / D, L7 -3- [4- (3-tert-Butylamino-2-hydroxy-propoxy) -phenyl-117-3-ethyl-acrylic acid nitrile hydrochloride 10.0 g / D, L7-3- / 4- ( 2,3-Oxido-propoxy) -phenyl] -3-ethyl-acrylic acid nitrile is refluxed for 2 hours in a mixture of 15 ml of tert-butylamine and 50 ml of ethanol.

Thereafter, further processing is performed as described in Example 1. The crude base first obtained is recrystallized from toluene / hexane.

The product obtained, 7.0 g, m.p. 73-75 °, is converted to the hydrochloride as described in Example 1. 3.4 g of ZD, L7-3-74- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl--3-ethyl-acrylic acid nitrile hydrochloride are obtained, m.p. is 170-171 °.

Example 46 Z-D, L7-3- [4- (3-3 *, 4 + -Dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -3-ethyl-acrylic acid nitrile hydrochloride 15.0 g / D, 17-3- [1 + - (2,3-Oxido-propoxy) -phenyl] 117-3-ethyl-acrylic acid nitrile is boiled for 2 hours in a solution of

II

s 39 67698 12.0 g of homoveratrylamine in 100 ml of ethanol and further work-up is carried out as described in Example 30. 10.3 g of the free base are first obtained, m.p. is 103-104 °. 7.5 g of (D, E7-3- / h- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl) -3-ethyl-acrylic acid nitrile are obtained as described in Example 1. hydrochloride, m.p. is 120-121 °.

Example 47 Z-D, L7-3-Z-4- (3-N-phenyl-piperazino-2-hydroxy-propoxy) -phenyl] -3-ethyl-acrylic acid nitrile dihydrochloride 10.0 g of ZD, L_7-3-Z> - (2,3-Oxido-propoxy) -phenyl-3-ethyl-acrylic acid nitrile is refluxed for 2 hours in a solution of 11.0 g of phenylpiperazine in 50 ml of ethanol.

The reaction mixture is then cooled to 5 °, whereupon the free base crystallizes out. 8.2 g of the free base are obtained, m.p. is 110-115 ° to give 8.1 g / D, L7-3 - / "4- (3-N-phenylpiperazine-2-hydroxy) with 4.19 ml of 10 N hydrochloric acid as described in Example 1. -propoxy) -phenyl-3-ethyl-acrylic acid nitrile dihydrochloride, mp 202-204 °.

Example 48 Z-D, L7-3-Z4- (3-N- [2-hydroxyethyl-7-piperazino-2-hydroxy-propoxy) -phenyl] -3-ethyl-acrylic acid nitrile dihydrochloride 10.0 g / D, L / -3 [4- (2,3-Oxido-propoxy) -phenyl] -3-ethyl-acrylic acid nitrile is reacted in a solution of 6.0 g of N-hydroxyethylpiperazine in 50 ml of ethanol as described in Example 45 or 30 (2.0 liters of water) and further treated in the same way. 6.4 g of the free base are first obtained, m.p. is 80-81 ° and is obtained by treatment with 3.57 ml of 10-norm. hydrochloric acid (7.2 g of ZI), L7-3- [4- (3-N- [2-hydroxyethyl] -7-piperazino-2-hydroxy-propoxy) -phenyl] -3-ethyl-acrylic acid nitrile dihydrochloride, m.p. is 181-182 °.

Example 49 / D, 17-3-ZT2- (3-3 *, 4 * -Dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -3-ethyl-acrylic acid methyl ester hydrochloride 8 g / D, L7- 3- [2- (2,3-Oxidopropoxy) -phenyl] -3-ethyl-acrylic acid methyl ester hydrochloride is refluxed for 3 hours in a solution of 5.7 g of homoveratrylamine in 80 ml of absolute ethanol. Further work-up is carried out as described in Example 45 of its residue. 4.3 g of D, L7-3- [2- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -3-ethyl-acrylic acid methyl ester hydrochloride are obtained. The free base has characteristic IR peaks at 2920, 1710, 1630, 1585, 1505, 1437, 1225, 1145, 1015, 798 and 748 cm-1.

Example 50 Z-D, L7-3-Z-2- (3-N-2 + -methoxy-phenyl-piperazino-2-hydroxy-propoxy) -phenyl-S-ethyl-acrylic acid methyl ester dihydrochloride 8 g TD, L7-3-L2- (2,3-Oxido-propoxy) -phenyl] -3-ethyl-acrylic acid methyl ester is reacted as described in Example 41 with a solution of 6.8 g of N- (2-methoxy-phenyl). ) -piperazine in 80 ml of absolute ethanol and further treated in the same manner. 4.4 g of ZD, 17-3- [2- (3-N-2 + -methoxy-phenyl-piperazino-2-hydroxypropoxy) -phenyl] -3-ethyl-acrylic acid methyl ester dihydrochloride are obtained, m.p. . is 120-122 °.

Example 51 / P, 1 / -3- [2- (3-tert-Butylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid ethyl ester hydrochloride 10.5 g ZD, 17-3- / 2- (2 The 3-oxido-propoxy) -phenyl-7-crotonic acid ethyl ester is stirred for 16 hours at 20-25 ° in a mixture of 20 ml of tert-butylamine and 50 ml of ethanol. Thereafter, further processing is performed as described in Example 1. In this case, the hydrochloride is recrystallized from the isopropanol / ether mixture twice. 5.4 g of [7,17-3- / 2- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -chrotonic acid ethyl ester hydrochloride are obtained, m.p. is 118-119 °.

Example 52 ZTD, E7-3-Z2- (3-3 +, 4+ -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid ethyl terioxalate 12.0 g / D, L / ~ 3 [2- (2,3-Oxido-propoxy) -phenyl] -crotonic acid ethyl ester is stirred for 16 hours at 20-25 ° C in a solution of 7.2 g of homoveratrylamine in 100 ml of ethanol and then worked up in Example 1. 24 as described. 4.5 g of D, L7-3- [2- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid ethyl ester oxalate are obtained, m.p. is 115-117 ° (dec.).

Il 41 67698

Example 53 ZJD, N-3- [2- (3-N-2 + -methoxy-phenylpiperazino-2-hydroxy-propoxy) -phenyl] -chrotonic acid ethyl ester dihydrochloride 7.9 g LO, Lj-3- 2- (2,3-Oxido-propoxy) -phenyl} -crotonic acid ethyl ester is stirred at room temperature for 48 hours in a solution of 5.8 g of N-2-methoxy-phenyl-piperazine in 100 ml of ethanol. Thereafter, further work-up is carried out as described in Example 1 until a crude base is obtained. It is dissolved in a small amount of ethyl acetate and chromatographed on a column of 240 g of silica gel (Kieselgel 60, Merck). Elution with ethyl acetate alone gave 4.4 g of purified base as an oil. It is converted in the usual manner (see Example 1) to 2.9 grams of ZD, L / -3-Z'2- (3-N-2 + -methoxy-phenyl-piperazino-2-hydroxy-propoxy) -phenyl7 -crotonic acid ethyl ester dihydrochloride, m.p. is 134-136 °.

Example 54 Z-D, L7--3-z-3- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl-7-acrylic acid (hydrochloride 15 g TT), Lj-3-Z ~ 3- (3- (2,3-oxido-propoxy) -phenyl] -acrylic acid nitrile is refluxed for one hour in a mixture of 40 ml of tert-butylamine and 200 ml of ethanol. .3 g of strongly hydroscopic ZD, L7-3-ZT3- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid nitrile hydrochloride The free base has typical IR peaks at 3300, 2950, 2208, 1508 (shoulder), 1590 (shoulder), 1570, 1473, 1435, 1372 and 743 cm -1.

Example 55 ZD, L7-3-Z-3- (3-N-2 + -methoxy-phenyl-piperazino-2-hydroxy-propoxy) -phenyl] -acrylic acid nitrile dihydrochloride 12.0 g ZD, L7-3-Z 3- (2,3-Oxido-propoxy) -phenyl-7-acrylic acid-nitrile is refluxed for 1 hour in a solution of 11.5 g of N-2-methoxy-phenylpiperazine in 50 ml of ethanol. Thereafter, further work-up is carried out as described in Example 31 (however, using 4 l of water, soda solution instead of NaCl). The crude free base is oily and is converted as described in Example 1 to 15.7 grams of Zd, 17-3-Z'3- (3-N-2 + -methoxy-phenyl-piperazino-2-hydroxy-propoxy) -phenyl-7-acrylic -aconitrile dihydrochloride, m.p. is 210 ° (dec.).

4 2 67698

Example 56 Z-D, L7-3-Z-3- (3-N- (2-hydroxyethyl) -piperazlino-2-hydroxy-propoxy) -phenyl] -acrylic acid nitrile dihydrochloride 12.0 g Z "D, L.7- 3-ZT3- (2,3-oxido-propoxy) -phenyl-7-acrylic acid is reacted as described in Example 55 with 20.0 grams of N-2-hydroxyethylpiperazine in 50 ml of ethanol, and further work-up is carried out in the same manner. 13.5 g of Z 6,17-3-Z3- (3-N- [2-hydroxyethyl-7-piperazino-2-hydroxy-propoxy) -phenyl] -acrylic acid powder dihydrochloride are obtained, m.p. is 180-182 °.

Example 57 / D, L17-3-Z-3- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl-acrylic acid nitrile hydrochloride 12.0 g of ZD, 17-3-Z3-2, 3-Oxido-propoxy) -phenyl] -acrylaminaponitrile is reacted as described in Example 55 with 20.0 grams of N-2-hydroxyethyl-piperazine in 50 ml of ethanol and further treated to give 13.5 g of Z-D, 17-3-Z3- (3-3 +, 4 + -dimethoxyethylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid nitrile hydrochloride, m.p. is 180-182 °.

Example 58

Zb, L7-3- [3- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride 15 g / D, 17-3-73- (2,3-oxido-propoxy) ) -phenyl-7-crotonic acid nitrile is reacted as described in Example 55 with 40 ml of tert-butylamine in 200 ml of ethanol, and further work-up is carried out in the same manner. 13.5 g of fD, Ly-3-Z-3- (3-tert-butylamino-2-hydroxy-propoxy) -phenyl-7-crotonic acid nitrile-1-hydrochloride with characteristic IR peaks at 3320, 2960, 2205 are obtained. , 1668, 1570, 1473, 1430, 1370 and 772 cm -1.

Example 59 ZD, L7-3-Z3- (3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxy-propoxy) -phenyl] -7-acrylic acid ethyl ester hydrochloride 6.0 g of ZD, L7-3-Z "3- ( 2,3-Oxido-propoxy) -phenyl-7-acrylic acid ethyl ester is stirred at room temperature for 16 hours in a solution of 3.6 g of homoveratrylamine in 30 ml of ethanol and then further treated as described in Example 24 to give 1.3 67698 to give This is reacted as described in Example 1 to give 3.6 grams of / D, L7-3-Zβ- (3-3 +, 4+ -dimethoxy-phenylphenylamino-2-hydroxypropoxy) -phenyl] -acrylic acid ethyl acetate. ter-hydrochloride, mp 128-129 °.

Example 60 Z-D, L--3-Z-3- (3-N-2 + -methoxy-phenyl-piperazino-2-hydroxy-1-propoxy) -phenyl] -7-acrylic acid ethyl ester dihydrochloride 6.0 g / D, L / -3 -Z "3- (2,3-Oxido-propoxy) -phenyl] -acrylic acid polyethyl ester is stirred at room temperature for 48 hours in a solution of 3.9 g of N-2-methoxy-phenyl-piperazine for 30 ml. After further work-up according to the example ", 3.4 g of ZTo Jk? - 3 - Z "3 - k 3 - N-2" * - methoxyphenyl-piperazino-2-hydroxy-propoxy) -phenyl-acrylic acid ethyl ester dihydrochloride, m.p. is 164-165 °.

Example 61 CP, L7-3-Z-3- (3-NZ-2-hydroxyethyl-7-piperazine-G-2-hydroxy-propoxy) -phenyl] -acrylic acid ethyl ester hydrochloride 12.0 g / D, L7-3- The 3- (2,3-oxido-propoxy) -phenyl-7-acrylic polyethylene mixture is stirred for 24 hours at 20-24 ° in solution, 01l ~ -; Qrj 7 gN-2- hydroxyethylpiperazine in 60 ml of ethanol After further work-up as in Example 3, 9.3 g of [P, N, N- [Z- (3 - N - (hydroxyethyl) 7-piperazino-2-hydroxy-propoxy) -phenyl] -acrylic acid ethyl ester dihydrochlorides, mp 189-190 °.

Example 62 ZD, L7 -3-Phenyl-3- [4- (3-N-2 + -methoxyphenyl-piperazine-N, N-hydroxypropoxy) -phenyl] -acrylic acid methyl ester dihydrochloride]. -5.0 g of CP, L7 -2-phenyl-3- / 4- (2,3-oxido-propoxy) -phenyl 33 7__ Acrylic acid methyl ester is stirred at 20-24 ° for 15 hours in a solution in which is 9.3 g of N-2-methoxy-phenyl-piperazine 150 n; 1; S3 methanol. Further work-up is carried out to obtain the free base as described in Example 31, and the formed base obtained as an oil is converted to the hydrochloride as described in Example 1. After recrystallization from a methanol / ether mixture and finally from methanol, 13.8 g of E, P] h] -2-phenyl-Z4- (3-N-2 + -methoxyphenyl) are obtained. Iino-2-hydroxy-propoxy) -phenyl β-acrylic acid methyl ester dihydrochloride, m.p. is 168-170 ° (dec.).

44 67698

Example 63 / D, L7-3-Phenyl-3-A- (3-NZ-2-hydroxyethyl-7-piperazino-2-hydroxy-propoxy) -phenyl-7-acrylic acid methyl ester dihydrochloride 15.0 g of ZD, L7-2- phenyl 3- [4- (2,3-oxido-propoxy) -phenyl] -acrylic acid methyl ester is reacted as described in Example 62 with 6.3 g of N-2-hydroxyethylpiperazine in 150 ml of methanol and the work-up is carried out in the same manner.

16.4 g of Z "D, L7-2-phenyl-3 - ['4- (3-NZ" 2-hydroxyethyl LiZ-piperazino-2-hydroxy-propoxy) -phenyl are obtained. .7-acrylic acid methyl ester dihydrochloride, m.p. is 218-220 °.

Example 64 Z-D, L7-3-Phenyl-3- [4- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -acrylic acid methyl ester hydrochloride 15 g / E, L7-2-phenyl-3-Z-4- (2,3-oxido-propoxy) -phenyl-acrylic acid methyl ester is stirred for 24 hours at room temperature in a solution of 8.22 g of homoveratrylamine in 60 ml of ethanol. As described in Example 1, but this time by adjusting the pH to 6, the crude hydrochloride obtained is recrystallized first from isopropanol / diisopropyl ether and finally from toluene / methylene chloride. 4.1 g of ZD, L7-2-phenyl-3-Z'4- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxypropoxy) -phenyl-7-acrylic acid methyl ester hydrochloride are obtained, m.p. is 145-147 ° C.

Example 65 ZTD, L7-3-Z-3- (3-3 +, 4+ -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -cotonic acid nitrile hydrochloride 15 g E, 17-3-Z "3 - (2,3-Oxido-propoxy) -phenyl-7-crotonic acid nitrile is refluxed for 2 1/2 hours in a solution of 12.62 g of homoveratrylamine in 150 ml of ethanol and further worked up as described in Example 31. The purified oily free base is finally converted as described in Example 1 to 6.5 grams of pure ZD, L7-3-Z'3- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl-7-crotomic acid. to nitrile hydrochloride, mp 135-138 ° C.

Example 66 Ζΐ> Ε7-3-Ζ-3- (3-N-2 + -methoxyphenyl-piperazino-2-hydroxypropoxy) -phenyl7-crotonic acid nitrile hydrochloride 15 g Z17, L7-3-Z'3- The nitrile of (2,3-oxido-propoxy) -phenyl / -chrotonic acid 145 6 7 6 9 8 is refluxed for 1 1/2 hours in a solution of 3.9 g of N-2-methoxy-phenylpiperazine in 150 ml of ethanol. After further treatment according to Example 1, 17.1 g of D, L7-3- [3- (3-N-2 + -methoxyphenyl-piperazino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride are obtained, m.p. is 160-162 ° C.

Example 67 E-7- and E + 7-3- / 4- (3-3 +, 4+ -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -cotonic acid nitrile hydrochloride

A solution of 50 g of D, 17-3- [4- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -chrotonic acid nitrile in 200 ml of ethanol is mixed with the solution. with 19.2 g of D - (-) - manteic acid in 150 ml of ethanol. After the mixture has been in place for some time, the separated crystals are filtered off. After washing with a small amount of ethanol and drying in vacuo, 32.8 g of the sparingly soluble E -7-3- [4- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -crool of ethanol are isolated. -tononic nitrile D- ε-7-mandelate, m.p. 114-116 °, [α] D -35.4 ° (c = 0.6 in methanol). After recrystallization from 200 ml of hot ethanol, 28.9 g of pure mandelate are obtained, m.p. is 118-119 ° C and the rotation value / <* 7 ^ = -38.2 ° (c = 0.6, in methanol). Yield 83.5%.

To an ice-cooled, rapidly stirred mixture of 23 g of the above levorotatory mandelate, 230 ml of water and 100 ml of chloroform is added dropwise a mixture of 3.15 ml of concentrated aqueous ammonia solution and 30 ml of water. The organic phase is separated, washed with a small amount of water and, after drying over sodium sulphate, evaporated to dryness in vacuo.

The (-) - 3- / 4- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxypropoxy) -phenyl-7-crotonic acid nitrile thus obtained, as described in Example 1, gives the hydrochloride which, after recrystallization from ethanol / ether, melts 166 At -167 ° C and having a rotation value [° <J = -12.8 ° (c = 0.5 in methanol).

Evaporation to dryness of the mother liquor obtained in the racemate separation above gives a very easily soluble in ethanol E + 7-3- E4- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile-D- (-) - mandelate. From this, as described above, E + 7-3- [4- (3-3 +, 4 + -dimethoxyphenethyl- [6,67698 amino-2-hydroxy-propoxy) -phenyl] -chrotonic acid nitrile is prepared. After recrystallization from toluene / petroleum ether, 25.4 g of nitrile are obtained, m.p. is 132-135 ° C. This is converted to dextrorotatory hydrochloride as already described for (-) antipodes. After recrystallization from an ethanol / ether mixture, 25.5 g (93%) of / + 7-3 - [- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -7-crotonic acid nitrile hydrochloride are obtained. an idia which is not optically completely pure and whose m.p. is 162-164 °, with a rotation value of ^ = + 9.7 ° (c = 0.6 in methanol).

Example 67 b / Ρ, Ε7-3- [4- (3-3 +, 4 + -dimethoxyphenylethylamino-2-hydroxypropoxy) -phenyl-17-crotonic acid nitrile] hydrochloride 10.0 g ZD, 17-3- / 4- (2-Hydroxy-3-chloropropoxy) -phenyl-4-crotonic acid nitrile is added to a mixture of 16.0 g of honoveratrylamine and 20 ml of ethanol, and the mixture is stirred for 5 hours in a water bath at 70 ° C. The mixture is then left to stand at room temperature for 14 hours, after which it is cooled to 0 ° and 20 ml of ice-cold ethanol are added. The separated crystals are then filtered off with suction, washed with ethanol and petroleum ether and dried. 6.4 g of the free base with a melting point of 138-139 [deg.] C. are obtained, which is then converted into the hydrochloride (5.7 g) in the same manner as described in Example 1, m.p. 148-149 ° C.

The starting D, L / -3-N- (2-hydroxy-3-chloropropoxy) -phenyl-crotonic acid nitrile is preferably prepared as follows: 12 g of 3- (4-hydroxyphenyl) -crotonic acid nitrile are added to a mixture of 12 ml of epichloro ihydrin and 0.1 ml of piperidine, and the mixture is stirred for 5 hours at 100 ° C. The excess epichlorohydrim is evaporated on a rotary evaporator in a vacuum water bath. The residue is cooled and the same volume of chloroform is added. The solution is washed with concentrated hydrochloric acid and water and evaporated twice to dryness in vacuo. The residue is recrystallized from toluene to give 11.4 g of D, L7-3- [4- (2-hydroxy-3-chloropropoxy) phenyl] crotonic acid nitrile, m.p. 91-92 ° C. .

Example 67 c ib, hj-3- / 4- (3-3 +, 4 + -Dimethoxyphenylethylamino-2-hydroxypropoxy) -phenyl] crotonic acid nitronitrile hydrochloride 4.36 g of crude ib, hj-3- / 4- (3 -amino-2-hydroxy-propoxy) -phenyl-7-croton- [4 "· acid nitrile is added to a solution of 5.18 g of 1-bromo-2-3,4-dimethoxyphenylethane and 2, 14 g of diisopropylamine in 100 ml of methyl 1,767,698 iketone, and the mixture is heated under reflux with stirring for 24 hours, then the reaction mixture is evaporated to dryness in vacuo and converted into the hydrochloride obtained in Examples 1 and 16 to give 3.7 g ( mp 148-149 ° C).

The starting 3- [4- (3-amino-2-hydroxypropoxy) -phenyl] -chrotonic acid nitrile is prepared as follows: 10 g / b, L7-3- / 4- (2,3-oxopropoxy) -f enyl N-chronic acid powder in 100 ml of methanol is added to a solution of 34 g of ammonia in 200 ml of methanol, and the mixture is stirred for 2 hours in an autoclave at 60 ° C. The mixture is then evaporated to dryness in vacuo.

The crude amine thus obtained is used as a starting material in the reaction described above.

Example 67 e), N - [[4- (3,3+, 9+ -dimethoxy-phenylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride

To a solution of 4.16 g of 3- [4- (2-oxo-3-chloropropoxy) -phenyl] -chrotonic acid nitrile in 12 ml of methylene chloride is added dropwise, with stirring, 10.5 g of 3,4-dimethoxyphenethylamine 15-20 ° C. The mixture is then heated to reflux for one hour. The 3- [4- (3- + 4, 4+ -dimethoxyphenethylamino-2-oxo-propoxy) -phenyl] -crotonic acid nitrile formed in the reaction can be further treated without isolating it from the reaction mixture. The reaction mixture is cooled to 0 [deg.] C., then 10 ml of ethanol are added thereto with stirring and ice-cooling, followed by a solution of 0.9 g of sodium hydroxide in 1 ml of water. 1.0 g of sodium borohydride are then added in small portions. The mixture is then stirred for a further 30 minutes under ice-cooling and then stirred for a further 1 1/2 hours at room temperature.

The solvent is evaporated off under vacuum, after which the distillation residue is dissolved in methylene chloride and washed with water. The organic extract is evaporated to dryness in vacuo and then evaporated to dryness several times with toluene. The residue is dissolved in a small amount of ethanol and further treated as described in Example 1 or Example 16 (14). 2.05 g of ZD, LT-3- / 4- (3-3 +, 4 + -dimethoxyphenethylamino-2-hydroxypropoxy) -phenyl] -cotonic acid nitrile hydrochloride dia, m.p. 148-149 ° C.

The starting 3- [4- (2-oxo-3-chloropropyl) -phenyl] -crotonic acid nitrile can be prepared by oxidizing with chromic acid 3- [4- (2-hydroxy-3-chloropropoxy) -phenyl] -crotonic acid nitrile (preparation described in Example 67 b as follows: 1.8 67698

To a solution of 6.85 g of sodium dichromate in a mixture of 30 ml of water, 9 ml of concentrated sulfuric acid and 5 ml of glacial acetic acid is slowly added dropwise, under ice-cooling and with good stirring, a solution of 3.27 g of 3- ^ 4 - (2-hydroxy-3-chloropropoxy) -phenyl-7-crotonic acid nitrile in 50 ml of benzene, the mixture is stirred for 5 hours at 20-25 ° C, after which the organic phase is separated, washed with water and evaporated to dryness in vacuo.

Example 67 f / D, L7-3-A-3-3 +, 4 + -dimethoxy-phenethylamino-2-hydroxypropoxy-phenyl-7-crotonic acid nitrile hydrochloride 0.32 g of sodium is dissolved in 6 ml of anhydrous glycol monoethyl ether under nitrogen gas. . 3.5 g of 5- (p-1 + -methyl-2 + -cyano-phenoxymethyl) -2-oxazolidone and 3.4 g of 1-bromo-2-3 +, 4 + -dimethoxyphenylethane are then added to the solution with stirring, followed by the mixture is refluxed to exclude moisture in nitrogen gas for 1 1/2 hours. The mixture is then made slightly acidic with a small amount of glacial acetic acid and the solvent is evaporated in vacuo. The residue is dissolved in 25 ml of methanol, 0.60 g of sodium hydroxide dissolved in 2 ml of water are added to the solution, after which the mixture is refluxed for 30 minutes. The mixture is then treated as described in Example 1.

2.1 g of / D, L7-3-Z4-3-3 +, 4 + -dimethoxyphenylethylamino-2-hydroxypropoxy) -phenyl-7-crotonic acid nitrile hydrochloride are obtained, m.p.

14 8-149 ° C.

Example 67 g / D, L7-3- / 9-3-3 +, 4 + -dimethoxyphenethyl-benzylamino-2-hydroxypropoxy) -phenyl] -crotonic acid nitrile hydrochloride

A solution of 5.42 g of Zb, L7-3- (4-3-3 +, 4+ -dimethoxyphenethyl-benzylamino-2-hydroxypropoxy) -phenyl / -chrotonic acid nitrile in 100 ml of methanol is hydrogenated with 1.0 g prehydrated in the presence of 10% palladium (activated carbon catalyst). The hydrogenation is stopped when 450 ml of hydrogen have elapsed. The catalyst is filtered off, the filtrate is evaporated to dryness and the residue is treated as described in Example 1. The hydrochloride is recrystallized several times to give 1.47 g of sufficiently pure [b, L7-3- (k-3-3 +, 4+ -dimethoxyphenethylamino-2-hydroxy-propoxy) -phenyl] -crotonic acid nitrile hydrochloride, m.p. . 148-149 ° C.

The starting Cb, 17-3- [4- (3-3 +, 4 + -dimethoxyphenethyl-benzylamino-2-hydroxypropoxy) -phenyl] -crotonic acid nitrile is prepared in the same manner as described in Example 67b to give 10 g of Zt>, L7 -3- (4-Hydroxy-3-chloropropoxy) -phenyl] -crotonic acid nitrile reacted with 24 g of benzyl homoveratrylamine.

49 67698

Example 68 d jb, L7-3-Z.3-N-2 + -methoxy-phenyl-piperazino-2-hydroxy-propoxy) -phenyl-7-acrylic acid nitrile dihydrochloride 14.5 g of m-coumarin acid nitrile in 25 ml of ethanol are added with stirring to a solution of 2.3 g of sodium in 25 ml of ethanol. 25.5 g of 1-2+ -methoxyphenyl-4- (2-hydroxy-3-chloropropyl) -piperazine are added to the mixture, followed by heating to 65 ° C with stirring. The mixture is further stirred for 3 hours, then the ethanol is distilled off in vacuo, and the distillation residue is dissolved in methylene chloride and washed with dilute sodium hydroxide and water. The extract is dried over sodium sulfate, then evaporated to dryness, the residue is dissolved in as little ethanol as possible, and the pH of the ethanol solution is adjusted to 2-2.5 with hydrochloric acid. 5 l of water are added to the solution and it is extracted several times with toluene.

The pH of the clear aqueous phase is then adjusted to alkaline with concentrated sodium carbonate solution and extracted thoroughly with toluene / ethyl acetate. The organic extracts are combined and evaporated to dryness in vacuo, after which the crude free base is converted into LD-1β-13- (3-N-2-methoxyphenylpiperazino-2-hydroxypropoxy) -phenyl] -acrylic acid nitrile dihydrochloride as described in Example 1. (12.5 g, m.p. 210 ° C, dec.).

The starting 1-2-methoxyphenyl-4- (2-hydroxy-3-chloropropyl) piperazine is prepared as follows:

A solution of 9.2 g of epichlorohydride and 19.2 g of 2 + -methoxyphenylpiperazine in 60 ml of diisopropyl ether is stirred for 30 hours at 35-40 ° C. The solvent is then evaporated off in vacuo and the crystals formed are recrystallized from isopropanol / hexane. 2 3.4 g of 1-2-2-methoxyphenyl-4- (2-hydroxy-3-chloropropyl) piperazine are obtained, m.p. 104-105 ° C.

Claims (3)

A process for the preparation of new therapeutically useful 1-aryloxy-2-hydroxy-3-aminopropanes of the formula I and their physiologically tolerable acid addition salts, wherein R represents hydrogen, 1-4 carbon atoms; containing an alkoxy group 2 or a halogen atom, R represents a group of the formula: R 5 R 6 R 5 R 6 II 7 - c = C - C - OR or -C = C - CN II 0. . 5 g 7 wherein R represents a C 1 -C 6 alkyl group, R represents hydrogen, R 'represents a. 3-4 of the lower alkyl group, R and R together with the nitrogen atom optionally form a heterocyclic ring having 5 to 7 members containing a C 1 -C 4 alkyl substituent, one carbon atom of which may be replaced by an oxygen atom or an additional nitrogen atom, the latter may be substituted by an alkyl, alkoxy, oxalkyl, acyl or carbalkoxy group each having 1 to 5 carbon atoms, a pyridyl group or a phenyl group, which in turn may be substituted by one or more hydroxyl groups, halogen or alkyl - or an alkoxy group having 1 to 4 carbon atoms, or R represents hydrogen and R 'represents a phenylalkylene group of the formula: - <Ch> n- <U / R9 il 51 67698 8 9. . ... wherein n is a number from 1 to 3 and R and R are the same or different and represent hydrogen, an alkoxy group having 1 to 3 C atoms, or a benzyloxy group or R 1 a R together form bismethylenedioxyrin, characterized in that a) a compound of formula (II): wherein R and R 11a have the meaning given in connection with formula I, is reacted with an amine with formula (III): R 3 ΗΝ (Γ III XR 4 3 k .... wherein R 11a and R have the meaning given in connection with formula I, or b) a compound of formula (IV): rVv_ M -OCH 2 - CK - CH 2 X IV-OH -m RZ 12 .... wherein R and R 11a have the meaning given in the context of formula I and X represents a halogen atom, a sulfuric acid or sulfonic acid residue, is reacted with an amine of formula III, or c) a compound of formula (V): - O - CH0 - CH - CH2 - NH9 V \ u = y 2 i | 7 OH K 52 67698 1 · 2 wherein R: 11a 3a R: 11a is in the context of formula I said meaning, is allowed to react with y with a compound of formula (VI): wherein R is as defined in formula I and X is as defined in formula IV, or d) a phenol of formula (VII): 0H VII R2 1.2. . wherein R and R 11a are as defined in formula I, are reacted with a compound of formula (VIII): / r 3 X - CHO - CH - CHO - N (VIII 2 I 2 \ 4 OH R 3 4 wherein R 11a and R in the context of formula I and X in the context of formula IV, in the presence of an acid scavenger, or e) a compound of formula (X) is: (/ y - och2 - co - ch2 - nhr4 X? R "wherein R1, R2 and R4 have the meanings given in connection with formula I is reduced, or f) a compound of formula (XI): ti 67698 53 XI R \ r— \ // \\ - 0 - ch2 - ch2 R2 0 N - R4 \ / 1 .. 4. · · where R, R: 11a and R have the meaning given in connection with formula I and Z corresponding to a carbonyl group or a methylene group optionally substituted by a phenyl group or one or two lower alkyl groups is hydrolyzed, or g) a compound of formula (XII) is: R 1 0. CH2 - ch - CH2 - n - R3 XII ”~ 2 OR10 R11 12 3 ... · Wherein the substituents R, R and R have the meaning given in connection with the formula I, R represents hydrogen, a lower acyl group or a benzyl group. . .10.11 · .. and R is hydrogen or a benzyl group, however, R and R cannot simultaneously denote hydrogen, the benzyl groups are cleaved by catalytic hydrogenation in the presence of a noble metal] a / 'or the acyl group is hydrolyzed and the compounds obtained by methods a) to g) are physiologically acceptable acid addition salts. 54 67698 For the preparation of a therapeutically active compound l-aryloxy-2-hydroxy-3-aminopropane in the form of a pharmaceutical form of a physiologically acceptable sugar addition salt, e.g., Rv OH Rd 0CH2 - CH - CH2 - 1 2. RU R is an intermediate having 1 to 4 alkoxy groups having 1 to 4 cholaters or halogen, R 5 is a group having the formula: R 5 R 6 R 5 R 6 Il 7 II -C = CC-OR or - C = C - CN 0 o 0 7 i vilka R betyder en C.-C „-alkylgrupp, R ° betyder väte, R betyder 3. y 4 en lägre alkylgrupp, R och R tillsammans med kväveatomen bildar en heterocyclisk ring, somamult innehäller en C ^ -C 1-4 alkylsubstituted and preferably 5-7 liters, which may be substituted by a substituent or a hydrogen atom, may be substituted by alkyl, alkoxy, oxalkyl, acyl or carbalkoxy groups , a single ring having 1 to 5 carbon atoms, a pyridyl group or a phenyl group, some of which may be substituted with a hydroxyl group, halogen having an alkyl or alkoxy group, 3 4 groups, a single ring having 1 to 4 carbon atoms atom, or R is a member and R is a phenylalkenyl group having the formula: R8 - <CH2h- (p) Ra n 55 67698 8 9 from 1 to 3 or R and R or lika ooh betyder väte, en alkoxy group with 1-3 C-atoms against en benzyloxy groups or with R and R is the same as the bismethylenedioxy group, which is a) to give (a) a mixture of compounds of formula II p 1/0> <Γ ~ λ / \ ^ n— och2 - ch - ch2 ii R2 1 / of R-1 and Rz are selected from the group consisting of Formula I and the Amine of Formula III 3 .R HN ^ III is R3 and R4 are selected from the group consisting of compounds of formula IV, or b) a mixture of compounds of formula IV RV \ V / Λ \ V_ 0CH ^ „CK _ CH ^ X IV R2 0H 1 2 R and R haren in the same form as formula 1 and X in the halogen atom, in the form of a mixture or a sulfonyl group, with an amine in the form of formula III or c) a mixture of the formulation V κ1νΓΧ I 7 ~ ° ”CH2 - CH - CH2 - NH2 V • 2 OH R 56 6 7 6 9 8 .. 1 2 for R and R har for the same formula as in English, for the preparation of formula VI X - R4 VI 4 for R har Samples of Formula I and X of the Samples of Formula IV, or d) entsätter en phenol med of Formula VII 0H VII RZ 1 2 of R ~ and R har den of the Samples of Formula I of Formula VIII, for the purposes of Formulation VIII R3 X - CH2 - CH - CH2 - n .. VIII OH ^ r "3 4 d R R and R har den ι samband med formulaeln I och X den i samband med formula IV engivna betydelsen, i närvaro av ett syrabindande me or (e) reducers in the formulation of formula X V 7-0CH2 - CO - CH2 - NHRU X R2 12 4 in which R, R and R are selected from the group consisting of formula I, or (f) hydrolysis in the formulation of formula XI