CA1108633A - 1-aryloxy-2-hydroxy-3-aminopropanes and process for preparing same - Google Patents

Abstract

FOR PREPARING SAME

Abstract of the disclosure:

Compounds of formula I

I

wherein R1 and R1' are identical or different and represent hy-drogen, an alkyl radical or alkoxy radical having 1 - 4 carbon atoms, the allyl group, a halogen atom or the nitro group, R2 represents an acrylic acid radical or an acrylic acid nitrile radical of the formulae or wherein R5 represents hydrogen, an alkyl radical having 1 - 5 carbon atoms, an aryl radical or aryl-lower alkyl radical either unsubstituted or substituted by lower alkyl or alkoxy, R6 re-presents hydrogen or an alkyl radical having 1 - 8 carbon atoms, R7 represents hydrogen, a lower alkyl radical or an aryl-lower alkyl radical, R3 and R4 represent together with the nitrogen atom a hetero-cyclic ring with 5 - 7 members being optionally substituted by C1-C4 alkyl, in which ring one carbon atom may be replaced by one oxygen atom, sulfur atom or one further nitrogen atom, the latter may be substituted, or wherein R3 represents hydrogen and R4 represents a straight-chain or branched alkyl radical or oxalkyl radical having 1 - 8 carbon atoms, a straight-chain or branched unsaturated alipha-tic hydrocarbon radical having 2 - 6 carbon atoms, a cyclo ali-phatic hydrocarbon radical having 3 - 6 carbon atoms or a phenylalkylene radical or phenylalkylidene radical of formula wherein n is a figure from 1 - 3 and R8 and R9 are identical or different and represent hydrogen, an alkoxy radical having 1 - 3 carbon atoms or the benzoyl radical or R8 and R9 represent to-gether the bismethylene dioxy radical, as well as the physiologically compatible acid addition salts and a process for preparing these compounds.

- 1a -

Description

~ he present invention i~ co~cerned with new basically substituted phenol ethers of the formula I

1 ~ . 3 H / R
OC~ - c;~- CH2 - N

in which ~1 and R1 are ident~cal or different and represent hty~rogen, an alkyl or alkoxy r~dical contain~ng 1 - 4 carbon atoms, the allyl group, a halogen atom or the nitro group, R2 represents an acryl~c acid radical or acrylic acid nitrile radical ha~ing respectively the ~ormulae - C = C - ~ - oR7 and - C = C - C~l in which R5 represents 4ydro~en, a C1 - C5-alk~l radical, an aryl or aryl-lower alkyl radical which is unsubst tuted or substituted by lower alkyl or al~ox~, R6 represents hydro-ge~ or an alk~l radical contai~ing 1 - 8 carbon atoms, and R represents hydrogen, a lower alk~l rad~ cal or an aryl-lo~-er alkyl radical, R~ a~d R4 together with the nitrogen atom represent a hetero-cyclic ring containing 5 - 7 members optionally substituted b~ C1 - C4-alkyl, in which ri~g a carbon atom may be replaccd by an oxyge~ atom, sulphur atom or a further nitrogen atom, and the latter may be qubstituted by an alkyl, alkoxy, ox-alkyl, ac~l or carbalkoxy residue i~ each case containing 1 to 5 carbon a~oms, a pyridyl radical or a phenyl radical, t which may itself be substituted one or more times b~ the .

hydroxyl group, halogen or an alkyl or alkoxy radical containing 1 to 4 carbon atoms, or R3 represents hydrogen and ~4 represents a straight-chained or branched ~1k~l or o~alXyl radical containing 1 - 8 carbon atoms, a straight-chained or branched unsaturated aliphatic h~drocarbon radical containing 2 to 6 carbon atoms, a c~clo-aliphatic hydrocarbon radical containing 3 to 6 carbon atoms or a phen~l-alkylene or phenyl-alkylidene radical of the formula ~(CH2~n in which n is a number from 1 to 3, and R and R9 are iden-tic~1 or differe~t and represent hydrogen, an alkoxy radical containing 1 to 3 c æbon atoms or the benzyloxy radical, or R8 and R9 together represent a bismeth~lene-dio~ radical, and also physiologically tolerable acid addition salts thereof.
~he invention includes both the racemic mixtures and the individual opticall~ active isomers of the formula I.
The present invention is also concerned with a process for the production of compounds of the formula I, which is characterised in that (a) a compound Or the formula II

R1 ' ~ OCH2 - CY. - CH2 II

! ' in which ~1, R1 and R2 have the meanings gi~en for formula I, is reacted with an amine of the fo~mula III

HN III
~4 in which R3 and R4 have the meaning~ glven for formula I, or (b) a c~mp~u~a o~ the ~ormula I~

in which ~1, R~1 and R2 have the ~eani~gs ~i~en for formula I, and x represents a halogen atom, the sulphuric acid r~dic~l or a sulphonic acid radical~ is reacted with a~
amine of the general formula III, or (c) a compound of the formula V

R ~ - CH2 - CIH - CH2 ~H2 in which R1, R1 and R2 ha~e the meanings ~i~en for formula I, is reacted with a compound of the formula ~I

in which R4 has the meaning given for formula I and ~ has the meaning given for formula IV, or (d) a phenol of the formula VII

,:

,, ' '' , ' ' ,:
'', ~ ' ,' ' ~OH VII.
: ' :

in which R1, ~1 ~nd R2 have the me~i~gs given for formula I, is reacted with a ~ompound of the formula VIII

/
- GH2 - ~ - C~2 VIII
O~I \ *
in which R3 and R4 have the meanings given for formula I
and X has the me~ning given for formula IV, in the presence of an acid-binding agent, or (e) a compound of the formula V or I~

OCH2 - C0 - C~2 - N~2 IX

R

in which R1, R1 and R2 have the meanings given for formula I, is reacted with a suitable ketone and the condensation ~roduct is reduced, or (f) a compound of the formula X

1 ' R~ OCR2 - CO - CH2 ~lRR4 ~2 , ~ 33 in which R1, Rl , R2 ana R4 have the meanings given for formula I, is reduced, or.
(g) a compound of the formula ~1 ` 1 .R1 ~ ~ CH2 ~ CN XI

R2 \ /

in which R1, R1 , ~2 and R4 have the meaning~ given for formula I and Z represents a carbo~yl group or a methylene group optionally substituted b~ a phen~l group o~ one or two lower alk~l radicals, is h~drolysea, or (h) in a compound of the formula XII

1 ' ' R1~ - C~2 - f~' ~ C~2 ~ N - R3 XII

in which R1, R1 , R2 and R3 have the meanin~s given for formula I, ~10 represe~ts ~drogen, a lower ac~l radical or the be~zyl radical, and R11 represents hyaroge~ or the be~zyl radical, but R10 and R11 cannot both simultaneously represent hydro~en, the be~zyl groups are split off by catal~tic hydrogenation in the presence o~ ~ noble metal ~nd/or the acyl group is h~drol~sed, . ~ . .

~ 3 ~
a~d the compounds obtained in accordance with methods (a) to (h) are optionally converted into physiolog~cally tolerable acid addition ~alts.
Among the substituents mentioned the following are - 5 preferred:
~or R4 (when R3 - H): alkyl, alko~y or oxalkyl radicals conta~ning 1 - 5 carbon atoms, especiall~ branched radicals such a the isopropyl or tert.-butyl radical, also non-branched unsaturated aliphatic hydrocarbons containing 2 - 4 ~9 carbon atoms, especially the allyl ~adical, c~cloaliphat$c hydrocarbon radicals containing 4 or 5 carbon atoms, espec-ially the cyclopentyl radical, and also dialkoxyphenyl-ethylidene radicals, especially the 5',4'-dimethoxyphenyl-ethylidene radical or the 1-methyl-2-3',4'-dimethoxyphen~l-' 1~ ethylidene radical.
~Jhen R3 and R4 together with the nitrog~n atom form a heterocyclic ring, there are preferred as ring systems those containing 5 or 6 members, ~or exa~ple, pyrrolidine, piperidine and morpholine, which may be substituted once or twice by a lower alkyl radi¢al or substituted by the pyridyl radical. Especially pre~erred is the piperazine ring, which may be substituted at the second nitrogen atom b~ an alkyl, alkoxy, oxalk~l or acyl group containing 1 - 4 carbon atoms, by a carbal~oxy group containing 1 - 5 carbon atoms, ~5 by a pyridyl radical or by an optionally substituted phenyl radical.
For R5: hydrogen, an unbranched alkyl radical containing l - 4 carbon atoms, especially the methyl, ethyl radical, and the phenyl radical, For R6: hydrogen, an alkyl radical containing 1 - 4 carbon atcms, , .: -. .
- .... .
. . -~i8633 For R7: an alkyl radical containing 1 to 4 carbon atoms, especially the methyl, ethyl and tert.-butyl radical, and also the benzyl radical.
For Rl and Rl : hydrogen, alkyl or alkoxy radicals containing 1 - 3 carbon atoms, fluorine, chlorine and also the nitro group.
As amine~ of the formula III there come into consider-ation for the reac~Dns according to methods (a) and (b):
1. Primary amines, such, for e~ample, as: ~ethyla~ne, ethylamine, isopropyl~mine, isobutylamiDe, sec.-butylamine, tert.-butylamine, 1-methylpropylamine, 2-aminoethanol,

2-metho~y-ethylamine~ 1-methyl-3-h~droxy-propylamine, ~llylamine, 3-dimethylP~ino-propyl~mine, phenylethylamine,

3-~henyl-propyl~mine, 1-phenyl-ethylamine, 1-methyl-2-15 phenyl-ethyl~mine, 1-methyl-2-(4-metho~y)~pkenylethyl~ine, 1-methyl-2-(3,4-dimethoxy)-phenylethylamine, 3,4-dimethoxy-phenylethylamine, 3-methoxy-4 ethox~-phenylethylamine, 3-methoxy-4-hydroxy-phenylethylamlne, 3-methoxy-4-benzyl-ox~phe~ylethylamine, 3-benzyloxy-4-methoxy-phenylethyl-amine, 3~4-methylenedioxy-phenylethylamine, 2,5-dimethoxy-phènylethylamine, 2,4-dimethoxyphenylethylamine, 2,3-dimethoxyphenylethylamine., 3,4,5-trimethoxy-phenylethyl-amine, 2-~tho~henylethylamine, 3~methoxyphenylethyl-amine, 4-methoxyphenylethylamine, 3,4-dimethoxyphenyl-methylami~e, 2-h~dro~y-2-phenyl-ethylamine~ 1-methyl-2-hydroxy-2-phenylethylamine, 3,4-dimethylphenyleth~lamine,

4-chlorophenylethylamine, 3,4-dichlorophenylethylamine, 4-h;ydroxyphenylethylamine, heptaminol, cyclopropylamine, cyclopentylamine, cyclohexylamine, 2-adamantylamine.
~G ~he use of isopropyl~m~ne and tert.-butylamine and also ~a . . ~ ~ . .. ... , . .~ - . .. . ...
.

` 1SL~8633 homoveratrylamine, has been found especially advantageous.
2. 5 - 6 Membered c~clic secondary amines such, for example, as:
Phenylpiperazine, N-2'-methylphenylpiperaz~ne, ~-3'-methyl-phenylpiperazine, ~-4'-methylph~nylp~perazine, ~-2'-methcxy-phen~lpiperazine, ~-~'-methoxyphenylpiperazine, N 4'-methoxy-phenylpiperazine, ~-2'-chlorophenylpiperazine, N-~'-chloro-phenylpiperazine, ~-4'-chlorophenylpiperazine, N-2'-p~ridyl-piperazine, N-3'-pyridylpiperazine, N 'I'-pyridylpiperazine, N-2'-hydroxyphenylpiperazine, N-3'-hydroxyphenylpiperazi~e, O ~-4'-h~droxyphenylpiperazine, N-oxyethylpiperazine, N-methyl-piper~zine, N-ethylpiperazine, N-carbQmetho2ypiperazi~e, N-carbethoxypiperazine, N-carbo-(2-h~droxy-2-methyl)-propoxy-piperazine, 2-methylpiperazine, 2,6-dimethylpiperazine, 2,6-dimeth~lpiperidine, 3-~-pyridylpiperidine, piperidine, ~5 mor holine and also p~rrolidine.
~he introduction of the amine radical according to method (a) is carried out by reaction of the two compone~ts, optionally in the presence of organic solvents such as alcohols, for example, methanol, ethanol, isopropanol, aromatic solvents such as benzene, toluene or ethers such as dioYane, tetrahydrofurane or carboxylic acid amides, especially dimethylformamide. In a preferred modification the two components dissolved in alcohol may be reacted with one another at a raised temperature. ~s reaction temperatures there come into consideration temperatures from room temper-ature up to the boiling point of the solvent.
~he glycidyl ethers of the formula II used as starting materials in method (a) can be obtained in accordance with our co-pendinq Patent Application Serlal No.

. .: , .; :

In the method described under (b) the a-haloge~
hydroxy-propyl ethers of the formula IV are used as starting materiàls. I stead of the halogen atom, preferably chlori~e or bromine, in the ~-positio~ there may be used the corres-ponding esters of sulphuric ~cid or esters of sulphonic acids.
~he starting substances can also be obuained by splitting the epoxide of the formula II with a hydrohalic acid, sulphur-ic acid or sulphonic acid. ~he reaction with an amine of the formula III is carr~ed out in the presence or absence of o sultable organlc solvents, such as alcohols, ~or e~ample, methanol, ethanol, isopropanol, aromatic solvents such as benzene, toluene, or ethers such as dioxane, tetrahydrofurane, or carbox~lic acid amides, especially dimethylfor~amide.
~he reaction may be carried out at temperatures between room 1~ te~p~r2~ure ~nd the boiling point of the ol~ent, and is preferably c2rried out at a raised temperature. ~or bind- -~
ing the liberated acid, for ex~mple halogen hydride, the operation may be carried out in the presence of acid-binding agents, for example, tert.-amines, such as triethylamine, pyridine or alkali or alkali~e earth metal hydroxides, carbonates or bicarbonates. ~he amine used can advantage-ously be used for the reaction in e~ces~, for example, in twioe the molar quantity.
~or the m~thod described under (c) there is used 'he pheno~y-2-hydroxy-1-aminoprop~ne derivative of the formula V.
The latter ~ay also be present in the form of a salt.
~he reaction with a reactive ester of the formula VI is carried out under the reaction conditions mentioned in method (b). ~he amine of the formula V used as starting ~.' 10 ~.: ,~, material can be obtained, for example, by reactin~ the epoxide of the formula II with ammonia. It can also be obtained from the halogen compound IV with ammonia.
~he preparation of the products of the process is also effected in accordance with the method described under (d), in which the above-mentioned phenol of the formula VII is used. ~he phenol may also be used in the form of its alkali metal salts, such as the sodium or potassium salt.
As reaction components of the formula VIII there are used ~-halogeno-2-h~droxy-3-al~ylam~nopropanes. It is al~o possible to start from sulphuric or ~ulphonic acid esters of the 1,2-dihydroxy-~-al~ylaminopropanes. ~he reaction is advantageously carried ou~ in the presence of an acid-binding agent, such as an alk~limetal hydro~de. In an a ~ line medium the 1-halogeno-2-hydroxy-3-alkylaminopropane used can change intermediately into the corresponding 1,2-epoxy-propane, which reacts with the phenol. ~he reaction may be carried out in the presence or absence of solvents such, for example, as alcohols, for eYample, methanol, ethanol, isopropanol, aro~atic solvents such a3 benzene or toluene, or ethers such as dioxane, tetrah~drofurane, or carboxylic acid am~des, especiall~ dimeth~lformamide, at normal tem-perature or a raised temperature up to the boiling point of the solvent used. ~he compounds of the formula VIII used as starting materials are obtainable, Por example, b~ the reaction of an a~ine of the formula III with epichlorh~drin at low temperatures.
In the method described under (e) the amine of the formula v is hydrogenated with a ketone appropriate for the meaning of R4 in the presence of catalytically activated ,, .- ;.. .. , . .; -; , :
. . . . . . - .. . . .
... ..

1~8633 h~drogen. As ketones th-ere may be mentioned, for example, acetone, methyl ethyl ketone, cyclopropanone and cyclohexanone.
~s catalysts there are used, for example, Raney nickel, platinum or palladium. Generally, the operation i8 carried out in the presence of an inert solvent such as methanol, ethanol or isopropanol. It is also poss~ble first to condense the amine of the formula ITI with the abo~e mentioned ketone and ~hen to reduce as above the Schiff'~ base so obtained, optionally without isolating it. ~he reduction the aæomethine may also be carried out in the usual manner with sodium boranate, lithium alanate or other complex metal hydrides, and also with aluminium amalgam.
By the method (e) there are obtai~e~ only those compounds of the formula I in wnich the radical R,l is connected to the ~i~ nitrogen atom by a secondary carbon atom.
The mathod described under (e) c~n also be carried out by using the ~minoketone of the formula I~. The reaction is carried out in the same manner as in the case of the aminopropanol of the formula V, since in the reduction, either in one reaction stage or after preparinga~d optionally isolating the azomethine, the keto group is simultaneously reduced with the azomethine double bond. ~he preparation of the aminoketone used as starting materi~l may be carried out, for example, by mild oxidation of the aminopropanol of the formula V.
The method described under (f), namely the reduction of aminoketones of the formula X can also be carried out by catalytic hydrogenation in the manner already described for method (e). The reduction of the keto group can also be carried out with lighium alanate or other complex metal .

.. : : .. . ~: :
~. .~ . ~ :, .

6;~3 hydrides or by the Meerwein-Ponndorf method with aluminium isopropylate. The preparation of the ketones of the formula X can be carried out, for example, by reacting appropriate l-halogen-2-oxo-3-~phenoxy)-propanes with an amine of the formula III.
A further modification of the process of the invention is the hydrolysis of an oxazolidone or oxazolidine of the formula XI by method (g). Such oxazolidones can be obtained, for example, by reacting the corresponding l-amino-2-hydroxy-3-tphenoxy)-propanes with a reactive derivative of carbonic acid, such as diethyl carbonate, chlorocarbonic acid methyl ester or phosgene, or by reacting a 5-hydroxymethyl-oxazoli-done-(2) optionally appropriately substituted in the 3-position and in the form of a hydrohalic acid-, sulphuric acid- or sulphonic acid ester with an appropriate alkyl phenolate. Suitable oxazolidines can be prepared, for example, by reacting the corresponding l-amino-2-hydroxy-3-phenoxy-propanes of the formula V with aldehydes or ketones. Oxazolidones or oxazolidines not substituted at the nitrogen atom may be alkylated with compounds of the formula VI as described undex method (c). The hydrolysis of these oxazolidone derivatives or oxazolidine derivatives may be carried out in an acid or alkaline medium, for example, by means of dilute hydrochloric acid, dilute sulphuric acid, dilute sodium hydroxide solution or dilute potassium hydroxide solution. It is of advantage to apply heat in order to accelerate the hydrolysis. The hydrolysis may also be carried out in water-soluble solvents, for example, lower alcohols. The products of the process can also be 30;~i; obtained from compounds of the formula XII, in which the ,, ~, .~, -: ~ . ` . : "
~ ':
,, ~ ~: , - ~ .

h~drox~l and/or the secondary amino group is protected by the radical R10 or R11 respectively, by splitting off the~e protecting groups. As protecting groups there come into consideration acyl radicals or the benzyl radical. ~he splittin~ off of the benzyl radical is carried out by cata-lytic hydrogenation in the presence of noble metals, such as palladium or platinum. If acyl-compounds are used, the acyl radical preferably being a lower aliphatic acyl radicæl, such as the acetyl or propion~l radical, the split-ting is carried out hydrolytically either in an acid or alkal~ne aqueous medium. The preparation of the corres-ponding benzyl- or acyl-compounds of the formula XII may be carried out by one of the methods described above, the correspo~ding acylated or benzylated startin~ ma~erials being use~. ~Jhen starting materials of the for~ula XII
ar~ to be prepPred, in which R2 represe~ts an acyl radical, there may be acylated, for exa~ple, the compound of the formula III, a~d then the corre~ponding acyl-compounds are reacted by method (b) to form compounds of the formula ~II.
~his applies correspondingly for compounds in which R10 represents a benzyl radic~l, the corresponding hydroxy-compounds being benzylated, instead of acylated. If it is desired to start from compound~ of the formula ~II, in which R11 represents a be~zyl radical, there can be used in accordance with method~ (a), (b), (c), (f) or (d), instead of the primary amines, the correspo~ding ~-benzyl-compounds. When a~ acyl radical and ~ benzyl radical a~e in juxtaposition as R10 and R11, these groups can be split off in succession in the manner described.
It may sometimes be of advantage ~n methods (a), (b), i~ 14 , . ~

-' , ~ `. ~ . '., ~"

..
, -:- , , - ; ,,, . - , ~ .:

(d) or (h) to combine the preparation of the starting compounds directly with the furtber reaction, that is to 5ay~ not to isol~te the starting materials separately.
The product~ of the process may be obtained in the form of the base or in the form of salts thereof, and when nece~sary they are purified by the usual method~, for example, by recr~stallisation or optio~ally conversio~
into the free base and subsequent treatment with a suitable acid. The products of the process may, if desired, be converted into salts of phy~iologically tolerated or~anic or inorganic acids.
As organic acids there may be mentioned, for example, acetic acid, malonic acid, propionic acid, lactic acid, succinic acid, tartaric acid, maleic acid; Lumaric acid, citric acid, malic acid, benzoic acid, salicylic acid, oxyethane sulphonic acid, aceturic acid, ethylene diamine tetracetic acid, embonic acid and also synthetic resins containing acid ~roups.
As inorganic acids there come into co~sideration, for example, hydrohalic acids such as h~drochloric acid or hydrobromic acid, sulphuric acid, phosphoric acid and amido-sulphonic acid.
~he optically active isomers of the racemic basically substituted phenol ethers of the formula I can be obtained by splitting the latter into their components with optically acti~e acids.
As acids there come into consideration for the prepara-tion of optically acti~e salts in accordance with the invention, for example, (+)- and (-)-tartaric acid, (+)-~ and (-)-dibenzoyl-tartaric acid, (+)- and (-)-ditoluyl-r 8fi33 tartaric acid, (+)- and (-)-mandelic acid, (f)- and (-)-camphoric acid, (f)-camphor-~-sulphonic acid, (+)--bromo-camphor-x-sulphonic acid and N-(para-nitrobenzovl)-(+~-glutamic acid. ~he preparation of the optically active salt~ may be carried out in water or a~ueous or anhydrous org~nic solvents. The use of alcohols or esters of organic carboxylic acids has been found advantageous.
For the prep~ration of optically active compounds the racemate of the base is reac~ed in a solvent, preferably in molar proportions, with a~ optically active acid, and the optically active salt of the compound of the formula I is isolated. In certai~ cases i~ is also possible to use only one half of an equivalent of the optically active acid in order to remove o~e of the optically active antipodes from the racemate, and also quantities of optically active acid in excess may be used.
Depending on the nature of the optically active acid the desired ~ntipodes can be obtained either directly or from the mother liquor of the first crystallizate.
Subse~uentl~, the opticall~ active base may be liberated from the salt in the usual manner~ and this optically active base oan be converted into a salt of one of the physiolog-ically tolerable organic or inorganic acids mentioned above.
~he compoun~s of the formula I and physiolo~ically tolerable acid addition salts thereof have been found in animal tests o~ dogs to have valuable therapeutic, especially ~-adrenol~tic, ~1-adrenolytic, and/or blood pressure-lowering and/or anti-arrhythm~c~ properties, and can therefore be used, for e~ample, for the treatment or prophylaxis of disorders of the coronary ~essels, for the treatment of ~ 16 ,.

~i3633 cardiac arrhythmia and for the treatment of high blood pressure in human medicine.
Special emphasis may be given to the follow~ng:
A therapeutically fa~ourable split between ~1- and ~2-receptor blocking action, the ~2-receptors not being blocked, is exhibited by compou~ds o~ the formula I in which R4, when R3 = E, represen~s a phen~l-alkylene radical. For example, the product according to Example 15 ~hibits a substantiall~
stronger ~l-sy~pathicolytic (in the absence o. ~2-symp~thico-0 lytic) action than do the known 1-[(3,4-dimethoxypheneth~l)-amino-~-aryloxy-2-propanols such, for example, as 1-t(3,4-dimetho~henethyl)-amino-3-(meta-tolyloxy)-2-p~opanol hydrochloride (M.L. ~oefle et. al., J. Med. Chem. 18 (1975), 148).
'~ The products of the process may be administered in the form of free bases or salts ~hereof orall~ in the form of ~ablets or dragees, optionally mixed with the usual pharm-aceutical carrier subst~nces and/or st~bilizers or parenter-ally in the form o~ solutions in ampoules. As carrier substances for tablets there come into consideration, for example, lactose, starche , tragacanth a~d/or magnesium stearate.
For in~ection purposes there comes into consideration a dosage of about 2 - 20 mg, and for peroral dosage between about 6 and 150 mg. A single tablet or a dragee may contain about 5 to 50 mg of active substance.
A therapeutic similarly desired long-lasting significant lowering of the blood pressure with only little or no ~- receptor blocking is exhibited by compounds of the formula I, in which R3 together with R4 and the N-atom ..
. .

- ~
. . . .

re.present a hetexocycle, such as the unsubstituted or substituted at the second M-atom piperazino, piperidino or morpholino radical.
Compounds of the formula I, in ~which R3 = H and R4 represents a branched aliphatic or cycloaliphatic hydrocar-bon radical, are distinguished by a generally very strong blocking of the ~-receptors.
~he following Examples illustrate the in~ention.

~i 1 8 . . .

. . --- ,.
. - . , ,, .... ~ ... . ...

~ 3 ExamPle 1 [D,T]-3-~2-(3-tert -but~lamino-2-hydroxy-~ropoxy)-phenyl]-crotonic acid nitrile hydrochloride.
7.0 Grams of [D,~]-3-~2-~2,3-oxido-propoxy)-phenyl~-cro-tonic ao~d nitrile are heated under re~lux at the boil in a mixture of 80 ml of ethanol (98% strength) and 15 ml of tert.-butylamine for 1 1/4 hours. Concentrating to dry-ness in acuo is then carried out and e~aporation with toluene in ~acuo is carried out several times. ~he oily distillation residue (free base) is dissolved in 50 ml of ethanol, and the mix~ure is adjusted to a pH-value of 4 by the dropwise addition of concentrated hydrochloric acid and then evaporated to dryness in vacuo. . By e~aporation in vacuo with ~oluene several times the distillation residue is dried, and then recrystallised f-o~ a s~all amoun~ of eth~nol and ether and again from ethanol.
~here were obtained 7~1 grams of ~D,~]-3-t2-~3-tert.-butyl~mino-2-hydroxypropoxy)-phenyl]-crotonic acid nitrile hydrochloride melting at 155-156C.
Example 1 a.
2-(~-tert;.-butylamino-2-h~dro~y-propoxy)-4-fluoro-~en~l]-crotonic acid nitrile h~drochloride.
14.0 Grams of ~D,~]-3-~2-(2,3-oxido-propoxy)-4-fluoro-phenyl]-crotonic acid nitrile in 50 ml of ethanol and 100 ml of tert.-butylamine are heated on a stesm bath under reflux for 2 hours. ~y working up as described in Example 1 8.6 grams of ~D,~-3-~2-(3-tert.-butylsmi~o-2-hydroxy-prop-oxy)-4-fluorophenyl]-crotonic acid nitrile hydrochloride melting at 158-159C. were obtained.

. . ~ ...... , ; ;: : : .

.. ~ , , - ~

Example 1 b tD,L]-3-~2-(3-3~,4~-Dimethoxy-pheneth~l-ami~o-2-hydroxy-~ropoxy)-4-fluoro-phen~l~-crotonic acid nitrile hydrochloride 14.0 Grams of tD~-3-[2-(2,3-oxido-propo~y)-4-fluoro-phenyl~-crotonic acid nitrile i~ 15 ml of ethanol are heated with 20.0 grams of homoveratryl~mine for 2 hours on a steam bath ~nder reflux, working up is carried out as desGribed in Example 6, and the hydrochloride is recrystallised ~rom isopropanol/ether.
Yield: 11.4 grams of [D,L~-3-~2-(3-3*,4~-dimethoxy-phenethyl-~minG-2-hydroxy-propoxy)-4-fluorophenyl~-crotonic Pcid nitrile hydrochloride melting at 153 - 155C~
Example 1 c ~D,~-3-~2-(~-~*t4~-D~methox~-~hen~t~ ino-2-h~lro~-propoxy)-5-1uorophenyl]-crotonic acid nitrile hydrochloride 12~0 Grams of tD,L]-3-~2-(2,3-oxido-propoxy)-5-Lluoro-phe~yl]-crotonic acid nitrile in 15 ml o~ etkanol are react-ed with 12.0 grams o~ homoveratrylamine ln ~he mann~r des-cribed in Example 16 e. The 10.6 grams of ~ree base melting at 105-107C. f~r~t obtained are con~erted i~ the usual manner (analogous to Example 1) into 8.8 gram~ of ~D,L]-3-~2-(3-3*,4*-dimethoxy-pheneth~l-ami~o-2-hydro-~y-propoxy)-

5-fluoro-phenyl~-crotonic acid nitrile hydrochloride melting at 145-147C.
: 25 . Example 1 d [D,L]-3-[2(3-tert.-butylamino-2-hydroxy-propoxy)-5-fluoro-: phenyl]-crotonic acid nitrile hydrochloride.
12.0 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-5-fluoro-phenyl]-crotonic acid nitrile hydrochloride in 50 ml of ethanol are heated at the boil under reflux for 2 hours with .
~,~ 20 :: -: ~ . i - :
- .: ~ . :
.. . . -. .. .

~ 63~
too ml of tert.-butylamine. Working up is carried out in the usual manner (Example 1). ~he crude hydrochloride is recr~stallised from isopropanol/ether and again from isopropanol.
Yield: 9.7 grams of [D,~]-3-t2-(~-tert.-butylamino-2-hydroxypropoxy)-5-~luorophenyl~-crotonic acid ni~rile hydrochloride meltins at 134 - 135C.
Exam~le 2 ~D~-3-[2-(3-Morpholino-2-h~droxy-propoxy)-phen~l]-crotonic acid nitrile h~drochloride.
15 Grams of [D.,L]-3-[2-(.2,~-oxido-propo~y)-phenyl]-crotonic acid nitrile in a mixture of 90 ml of ethanol and

6.1 gram~ of morpholine are heated at the boil under reflux for 2 1/4 hours. Working up is then carried out as des-cribed in ~xample 1, and ~he product is converted into the hydrochloride.
There were obtained 12.9 grams of [D,L]-3-[2-(3-morpho-lino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile h~dro-chloride melting at 184.5 - 18~C.
Example 3 tD,L]-3-t2-(3-N-Phenyl-piperazino-2-hydroxy-~ropoxy)-phenyl~-crotonic acid nitrile hydrochloride.
15 Grams o~ tD,~ 2-(2,3-Oxido-propoxy)-phenyl]-crotonic acid nitrile in 90 ml of ethanol and 11.4 grams of ~-phenylpiperazine are boiled under re~lux for 1 1/2 hours.
Working up and conversion into the hydrochloride are then carrled out as described in Example 1.
~here were obtained 14.0 grams of tD,~-3-t2-(3-~-phenyl-piperazino-2-hydroxy-propoxy)-phenyl~-crotonic acid .~trile h~drochlor~de melting at 177-178C.
...~ 21 . . .

~ 3 Example 4 ~D,~]-3-[2-t3-Isopro~ylamino-2-hydrox;r-propo ~)-pheayl~-cro-tonic acid nitrile hydrochloride.
27 Grams of [D,L~-3-[2-(2,3-oxido-propoxy)-phenyl]-cro-tonic acid nitrile in a mixture of 270 ml of ethanol and 60 ml of isopropylamine are boiled under reflux for one hour.
Working -~p and conversion into the hydrochloride are then carried out as described in Example 1.
~here were obtai~ed 21~5 grams of tD,L~-3-C2-(3-iso-.propylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride melting at 145 - 146C.
Example 5 CD,~]-3-~2-(3-2~,6~-Dimethylpiperidino-2-hydroxy-propox~
henyl]-crotonic acid nitrile hydrochloride.
15 Grams of [D,~-3-[2-(2,3-oxido-propo~y)-phenyl]-crotonic acid nitrile in a mixture of 90 ml of ethanol and 8.0 gr~ms of 2,6-dimetkylpiperidine are boiled under reflux for 13 hours, and working up and conversion i~to the hydro-chloride are carried out as described in Example 1.
~here were obtained 12.4 grams of [D,~-3-t2-(~-2*,6~-dimethylpiperidino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride melting at 157 - 158C.
Example 6~ -CD ,~] -3-~2-(3-3*,4*-dimethoxyphenethylamino-2-hydro~y-~ oxy)-Phenyl]-crotonic acid nitrile hydrochloride.
19 Grams of [D,~]-3-t2-(2,3-Oxido-propoxy)-phenyl]-crotonic acid ni~rile in a mixture of 100 ml of ethanol and ~ 12.7 grams of homoveratrylamine are boiled under reflu~ for ; 5 hours. Worki~g up and conver~ion into the hydrochloride are then carried out as described in Example 1.
;` ~ 22 ~ . ,~ .. - - . -:, - ~ . , - :, - .

. ,, . ,, . ,.. , ~ :
., - . .... . . .
., ; .

3~3 There were obtained 10.8 grams of [D,L]-3-[2-(3-3*,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride melting at 164 - 156C.
The free base is isolated from the mother liquor in the 5 usual manner (rendering al~aline, extracting with toluene, concentrating to dryness in vacuo) and there were obtained by recrystallisation from toluene/diisopropyl ether 1.2 grams thereof melting at 88 to 89C.
Example 6 a [D,L]-3-[2-(3-3*,4*-Dimethoxy-phenethyl-amino-2-hydroxy-propoxy)-4-methoxy-phenyl]-crotonic acid nitrile hydrochloride

7.0 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-4-methoxy-phenyl]-crotonic acid nitrile in a mixture of 7.0 grams of homoveratrylamine and 7.0 ml of ethanol are heated on a steam bath (while refluxing) for one hour. The reaction mixture is cautiously adjusted with concentrated hydrochloric acid to a pH-value of 3.5, stirred into 1 1 of water and extracted three times with toluene/ethyl acetate. The aqueous phase is then adjusted to a pH-value of 8 to 8.5 with sodium hydrogen carbonate and is again extracted with toluene. The basic extracts are dried, rotated and the crude base is converted into the hydrochloride in the manner described in Example 1.
There were obtained 9.4 grams of [D,L]-3-[2-(3-3*,4*-dimethoxy-phenethylamino-2-hydroxy-propoxy)-4-methoxy-phenyl]-crotonic acid nitrile hydxochloride melting at 169 - 170 C.
~xample 7 [D,L]-3-[2-(3-N-[2*]-Pyridino-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile trihydrochloride 7 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]--.: , .

l~g8633 crotonic acid nitrile in a mixture of 70 ml of ethanol and 6 grams of N-(2-pyridino)-piperazine are boiled under reflux for 3 hours. Working up and conversion into the trihydro-chloride is then carried out as described in Example 1.
5.1 Grams of [D,L]-3-[2-(3-N-[2*]-pyridino-piperazino-]-hydroxy-propoxy)-phenyl]-crotonic acid nitrile trihydro-chlorid~ melting at 121C are obtained.
Example 8 [D,L]-3-[2-(3-N-[4-Acetylphenyl]-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile dihydrochloride 7 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile in a solution of 6.8 grams of N-(4-piperazino)-acetophenone in 70 ml of ethanol are boiled under reflux for 3 hours. Evaporation to dryness in vacuo is then carried out. The oily distillation residue crystallises after a few hours. Trituration with a small amount of ether and filtering off with suction are then carried out. The filter residue was dissolved in exactly the sufficient quantity of chloroform, and a saturated solution of hydro-chloric acid/chloroform is added in portions, while stirring, until the reaction is acid. After a short time the dihydro-chloride separates from the clear solution.
By filtering off with suction, washing with a small amount of chloroform/acetone and drying there are obtained 9 grams of [D,L]-3-[2-(3-N-[4-acetylphenyl]-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile dihydrochlor-ide melting at 151C.
^ Example 9 [D,L]-3-[2-(3-N[2-Methoxyphenyl]-piperazino-2-hydroxy-30 ~ propoxy)-phenyl]-crotonic acid nitrile dihydrochloride :: -. : : , : . : - -:: :

6 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile in a solution of 5.5 grams of N-(2-methoxy-phenyl)-piperazine in 60 ml of ethanol are boiled under reflux for 3 hours. Concentration to dryness in vacuo is then carried out, the residue is dissolved in chloroform and the solution is rendered acid with hydro-chloric acid/chloroform. Rotation to dryness in vacuo is then carried out, and crystallisation is brought about by trituration with a small amount of ether. By filtering off with suction and drying there are obtained 10.5 grams of [D,L]-3-[2-(3-N-[2-methoxyphenyl]-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile dihydrochloride melting at 171°C.
Example 10 [D,L]-3-[2-(3-N-[2-Methylphenyl]-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile dihydrochloride, 7 Grams of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile in a mixture of 6.5 grams of N-(ortho-tolyl)-piperazine and 70 ml of ethanol are reacted and worked up as described in Example 9.
There are obtained 10 grams of [D,L]-3-[2-(3-N-[2-methylphenyl]-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile dihydrochloride melting at 138°C.
Example 11 [D,L]-3-[2-(3-N-[Methylpiperazino]-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile dihydrochloride, 7 Grams of [D,L]3-2-[2-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile are reacted with 3 grams of N-methyl-piperazine in 60 ml of absolute ethanol and worked up, as described in Example 9. The crude dihydrochloride is dissolved in 50 ml of water and filtered over 3 grams of active carbon. The filtrate is concentrated to dryness ~8633 finally under a high vacuum. ~he resulting fo~m is tritur-ated with ether, filtered off with suction and dried.
~here are obtained 4~9 grams of strongly hygroscopic [D,L~-3-C2-(3-N-[methylpiperazino~-2-hydroæy-propoxy)-phenyl~-crotonic acid nitrile dihydrochloride.
~he compound exhibits in the IR characterist~c bands at 2203, ~599, 1435, 1235 and 745 cm 1.
Exam~le 12 - [D.L~-3-[2-(~-N-~2-$Iydroxyethyl~-piperazino-2-hsrdro~-proP
oxy)-vhenyl~-crotonic acid nitrile dihydrochloride.
7 Grams of [D,L~-3-~2-(2,3-Oxido-propoxy)-phenyl~-crotonic acid nitrile are reacted with 4.7 grams o~ ~-(2-hydroxyethyl)-piperazine in 70 ml of absolute ethanol are reacted and wor~ed up, as described in Example 9.
~here are obtained 8.5 grams of [D,L]-3-~2-(3-N-[2-hydroxyethyl]-piperazino-2-hydrox~-propox~)-phenyl~-crotonic acid nitrile dihydrochloride melting at 146C.
Example 12 a ~D.L~-3-[4- -tert.-Butylamino-2-hydroxy-propox~ henyl~-crotonic acid nitrile hydrochloride.
6.0 Grams of [D,~-3-[4-(2,3-Oxido-propoxy)-phenyl~-crotonic acid nitrile in 40 ml of ethanol are reacted with i 40 ml of tert.-butylamine and worked up, as described in Example 1.
Yield: 6.0 grams of [D,L~-3-[4-(3-tert.-butylamino-2-hydroxypropoxy)-phenyl]-crotonic acid nitrile hyarochloride ` melting at 186-187C.

, 1~8633 ~xample 12 b [D,L~-3-~2-Methoxy~ (3-teru.-3u~ylamino-2-h~dro~-propoxy)-phenyl~-crotonic acid nitrile hydrochloride.
3.4 Grams o~ [D,~]-3-[2-Metho~-4-(2,3-oxido-propoxy)-phenyl~-croto~ic acid ~itrile are boiled under reflux for 2 1/2 hours with 20 ml of ethahol and 40 ml of tert.-butyl~m-ine and worked up as described i~ E~ample 1.
Yield: 4.0 Grams of [~,L1-3-[2-Metho~y-4-(3-tert.-butylamino-2-hydroxy-propoxy)-phe~yl~-cro~onic acid nitrile h~drochlor-ide melting at ~45-146C.
Example t2 c -[D,L~-3-[2-(3-tert.-Butylamino-2-h;~dro~;Y-propo~y)-4-methox~-phenJl~-croto~ic acid ni~rile h~drochloride.
5.0 Grams of tD,L]-3-[2-(2,3-oxido-propoxy)-4-methoyy-phe~yl]-crotonic acid nitrile dissolved in 20 ml of eth~nol ~ ^
are, after the addition o~ 50 ml of tert butylamine5 heated at the boil under reflux ror 3 hours, and the~ wor~ing up is carried out as described in Example 1.
Yield: 4,3 grams of ~D,L]-3-[2-(3-tert.-bu~la~ino-2-hydrox~-propoxy)-4-methoYy-phenyl~-crotonic acid ~itrile hydrochlor-ide melting at 144 - 145C.
Exam~le 1~
[D?L]-3-[4-(3-N-Pken~lpiperazino-2-h;s~d-ox;~-proQox~ hen~l]-- crotonic acid nitrile h~drochloride 10.75 Grams of [D,~-3-~4-(2,3-oxido-propox~)-phenyl]-crotonic acid nitrile in a solution of 8.1 ~rams of ~hen~l-piperazine in 60 ml of ethanol are boiled under re~lux for 3 hours. ~he reaction mixture is the~ cooled with ice and, after standing for a short time, the crystals that - ;. , - ., -,. ~ ,. : - .

., .

separate are filtered off with suction and recrystallised from a small ~mount of ethanol.
12.9 Grams of the free base melting at 133 - 134C. are obtained. ~he base is dissolvsd at room temperature in ju~t the sufficient quantity of acetone, and then concentrated h~drochloric acid is added dropwise, while stirring, u2til the pH-value is 4.5. After a short time the hydrochloride ; precipitates. It is filtered off with suction and dried.
There are obtained 13.9 ~ra~s of crude hydrcchloride meltin~
at 158 - 160C.
By recrystallisation once from a large amount of ethanol 13.3 grams of [D,~-3-~4-(3-N-phenylpiperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride melting at 160-161C, are obtained.
Exam~le 14 - [D,L]-3-[4-(3-Morpholino-2-hydroxy-propoxy)-phenyl]-crotonic ;"
acid nitrile h~drochloride 15.0 GramQ of tD~]-3-[4-(2~3-oxido-propoxy)-phenyl]
crotonic acid nitrile in a solution of 6.1 grams of morpholine .~.
~ 20 in 100 ml of ethanol are heated at 80C. for 4 1/2 hours.
. ., ~he mixture i5 allowed to stand for a further 12 hours at ;- room temperature. ~he mi~ure is then concentrated to dry-ness in vacuo and evaporated three times with toluene.
~he distillation residue is dissolved in a small amount of toluene, and caused to cryatallise by the addition of diisopropyl ester. ~y filtering off with suction and drying, ~; 18.0 grams of the free base melting at 79-80C. æ e obtained.
,:
Conversion into the hydrochloride is then carried out ` as de~cribed in Example 1.
3o There are obtained 16.4 grams of [D,~]-3-t4-(3-.

~, : . . :
- -- : ~ : -,.. , , . , . ~ -, ..
- - : : : , .. .
,- - . . ..

~8633 morpholino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitriie h~drochloride melting at 121 - 122C.
Example 15 ~D,L]-3-t4-(~-2~,6*-Dimethylpiperidino-2-hydroxy-proPox~)-S _he~yl]-crotonic acid nitrile h~drochloride.
15 Gra~s of ~D,L]-3-[4-(2,3-oxido-propoxy)-~henyl]-crotonic acid nitrile in a solution Or 8.0 grams of 2,6-dimethylpiperidine i~ 100 ml of ethanol are boiled under reflux for 6 1/2 hou~s. The mixture is the~ evaporated to dryness in acuo, and the dist_llation residue is dissol~-ed i~ 80 ml of tolue~e. After the additio~ o~ 300 ml o~
water, the mixture is adju6ted to a pH-value of 4 with concentrated hydrochloric acid with good agitation.
~o the aqueous phase are added 80 ml of fresh tolue~e and the p~-value is adjusted to 10 by agitation with sodium hydroxide solution. Extraction is carried out twice with 50 ml of toluene each time, a~d the combined organic ; extracts are washed with water, dried over sodium sulphate and concentrated to dryness i~ vacuo. By trituration with diisopropyl ether, filtering off the resulting cr~stals with 6uction and dr~ing there are obtained 15.0 grams of ~ the free base melting at 97 - 98C.
; ~rom the latter there are obtained in a manner described in Example 1 14.5 grams of ~D,L]-3-t4-(3-2~,6~-dimethyl-piperidi~o-2-hydroxy-propoxy)-phenyl~-crotonic acid nitrile hydrochloride melting at 168 - 169C.
Example 16 [D~]-3-[~3-3~,4~-Dimetho~gPhenethylamino-2-hg~rox~-~roPox~)-phen~l~-crotonic cid nitrile h~drochloride.
17.5 gr~ms of [D,L]-3-[4-(2~3-oxido-propoxy)-phenyl]-.

: :
- , .. ~ :

~8633 crotonic acid nitrile in a solution of 15.0 grams of homo-veratrylamine in 100 ml o ethanol are heated at the boil under reflux for 5 hours. After the usual working up (see ~xample 1) the free crude base is recr~stallised from ethanol/diisopropyl ether and again from ethanol.
~here are obtained 15.1 grams of free base melting at 141.5-142C. From the latter there are obtained in a manner analogous to that i~ Example 1 13.6 grams of [D,L]-3-[4-(3-3~,4~-dimethoxyphenethylamino-2-ny~roxy-propoxy)-phenyl]-crotonic acid ~itrile hydrochloride melting at 148-149 C.
Example 16 a ~D,L~-~-[2-Methoxy-4-(3,3~,4~-dimeth_xy-pheneth~l-amino-2-hydrox~-pro~ox~)-phenyl~-crotonic acid nitrile hydrochloride 6.7 Grams of [D,L]-3-[2-Methoxy-4-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile in 7 ml of e~hanol are boiled under reflux for one hour with 7.0 grams of homoveratrylamine and reacted as described in Example 16.
Yield: 6.6 grams of ~D,L]-3-~2-methoxy-4-(3-3~,4~-dimethoxy-phenethyl-amino-2-hydroxy-propoxy)-phenyl]-croto~ic acid nitrile hydrochloride melting at 131 - 132C.
~xample 16 b [~,L]-3-~3-Chloro-4-(~-3~,4~-dimethoxy-pheneth~l-amino-2-hydrox~-propoxy)-phenyl]-crotonic acid nitrile h~drochloride 5.0 Grams of tD,L~-3-~3-Chloro-4-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile are boiled u~der reflux with 15 ml of ethanol and 5 grams of homoveratrylamine for 4 hours.
50 Grams of ethanol are then added, and the mixture is adjusted to a pH-value of 3.5 with concentrated hydrochloric 3o acid t and the r~action mixture is poured into 5 litres of : . : : . : . : , ~ , :: . .

. ~

water. After extraction o the neutral fraction with ethyl acetate/toluene ~2 : 1), the aqueous phase is rendered we~kly alkaline with sodiu~ hydrogen carbonate. Extraction ~ -is carr ed out w th toluene/ethyl ac~tate (2 : 1) and the organic phase is dried and rotated. By crystallisation with toluene/diisopropyl ether there are obt~ined 5.1 ~rams of free base me1ting at 117 - 1t9C. ~he latter is convert-ed into the h~drochloride as described n Example 1.
Yield: 4.7 grams of [D,L]-3-~3-chloro-4-(3-3~4~-dimetho~y-phenethyl-amino-2-hydroxy-propoy.y)-phen~l]-crotonic acid nitrile hydrochloride melting at 146 - 148C.
Example 16 c [D,~]-3-t3-Chloro 4-(3-tert.-butylamino-2-hydroxy-~ropox~)--crotonic acid nitrile hydrochloride.
4.5 Grams oI [D,L]-3-[3-chloro-4-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile in 15 ml of ethanol ~e reacted for 3 hours, as described in Example 6 a, with 50 ml of tert.-butylamine, and wor~ed up in the manner described in Example 1.
Yield: 6.0 grams o~ [D,~]-3-~3-chloro-4-(3-tert.-but~lamino-2-h~droxy-propoxy)-phenyl]-crotonic acid nitrib hydrochlcride melting at 188 - 189C.
Example 16 d ~ ~]-3-[3-~luoro-4-(3-tert.-butylamino-2-hydro~r-proPoxy~-- phen~l]-crotonic acid nitrile hydrochloride 5.0 Grams of ~D,~]-3-[3-fluoro-4-(2,3-oxido-propox~)-phenyl]-crotonic acid nitrile in 15 ml of etha~ol ~re boiled under reflux for 3 1/2 hours with 50 ml of tert.-butylamine ~nd worked up as described in Example 1.
Yield: 6.9 Grams of [D,~-3-[3-~luoro-4-(3-tert.-butyl~mino-: . . .. . .

' ' ' ;': , ~'; ' ~ '' , :

11~8633 - 2-hydroxy-propox~)-phenyl]-crotonic acid nitrile h~drochloride melting at 190-191C.
Example 16 e [~?~]-3-[Z-Fluoro-4-(3-3*,4*~dimethoxy-Phenethgl-amino-2-hydroxy-propox~)-phenyl]-crotonic acid nitrile hydrochloride 10 Grams of ~D,L~-3-[3-fluoro-4-(2,3-oxido-pr~pox~)-phenyl]
-crotonic acid nitrile in 20 ml of ethanol a~d ~0.0 grams of homoveratrylamine are heated under reflux on a steam bath ; for 3 1/2 hours. Working up is then carried out as in Example 16 b. 7.9 Grams of the free base so obtained melting at 111 - 112C. are converted as described in Example 1 into 7.3 grams of ~D,~]-3-[3-fluoro-4-(3-3*,4~-di~ethoxy-phenethyl-amino-2-hydroxy-propoxy)-phenyl]-crotonic acid ~itrile hydrochloride melting at 163 - 164C.
Example 16 f tD,L]-3-[3-methoxy-4-(3-3~4~-dimethoxy-phenethyl-amino-2-~` hydrox~-Propox~)-phen~l]-crotonic acid nitrile hydrochloride.
i 9.8 Grams of [D,L]-3-~3-methoxy-4-(2,3-oxido-propoxy)-phe~yl]-crotonic acid nitrile are heated for 2 hours on a steam bath under reflux.
~he mixture is then diluted with about 50 ml of ethanol, ad~usted to a pH-value of 1 with concentrated hydrochloric acid, and the reaction mixture is poured into 5 litres of water. The neutral constituents are extracted with toluene/
ethyl acetate. The aqueous phase is rendered weakly basic with sodium hydrogen carbonate, extracted with toluene and the basic extracts are dried by rotation, and recrystallised from toluene/ether and then from ethanol.
~ Yield: 7.6 gram~ of free base melting at 115 - 116C. It is 3o con~erted in the usual manner (see Example 1) into the hydro-chloride, and the latter is recrystallised from ethanol/ether - . i, . ...
. :
- . .
. ~ , ... :, .... .
t : .
:` . :.'' . `. '~.' ... . ':

~ ~38~33 and ethanol.
Yield: 6.4 gr~ms of LD9~-3-~3-mathoxy-4-(3-3~,4~-dimethoxy-phenathyl-amino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloriae melting at 110 - 112C.
Example 16 [D,~]-3-[3-Metho~-4-(3-tert.-but~lamino-2-h~droxy-pro~oxy)-ph~nyl]-crotonic acid nitrile h~drochloride~
7.0 Grams of [D,L3-3-[3-methoxy-4-(2,3-oxido-propox~)-phenyl~-crotonic scid nitrile in a mixture of 28 ml o~ ethanol and 70 ml of tert.-butylamine are heated at the boil under reflux for one hour. Workins up is then carried out as described in Exam-ple 1.
Yield: 7.1 ~rams of [D~]-3-~3-methox~-4-(3-tert.-butyl~min 2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile h~drochloride melting at 157 - 158C.
Example 17 ", [D,L3-3-[4-(3-N-2~-pyridyl-piPerazino-2-h~droxy-~ropo~
., phe~ -crotonic acid nitrile dihydrochloride.
10.75 Grams of tD,~-3-~4-t2,3-oxido-propoxy)-phenyl]-cro-tonic acid nitrile in a solution of 8.2 grams of pyridyl-pip-erazine in 60 ml of ethanol are boiled under reflux for 3 hours. ~he mixture is then cooled with ice, and the pre-cipltated cr~6tals are collected and dried. ~he resulting 17.1 grams of free base melting at 131 - 132C. are converted in the usual manner into 15.1 grams of [D,~]-3-[4-(3-~-2~-pyridyl-piperazino-2-hydroxy-propoxy)-phenyl3-crotonic acid nitrile dihydrochloride melting at 259-260C.
Example 18 ~D,L~-3-[4-(3-~-4~-Acetyl-phenyl-piperazino-2-h~droxy-~roPox~) ~henyl3-crotonic acid nitrile hydrochloride.
10.75 Grams of [D,~]-3-[4-(2,3-oxido-propoxy)-phenyl~-. . , ~' -' ' ., ' ~-, . : - .
.

;33 crotonic acid nitrile are boiled under reflux in a solution of 10.2 grams of para-piperazinoacetophenone for 4 hours.
The base, obtained by cooling, crystallising, filtering off with suction and drying (20.1 grams, melting at 160-- 161C.) is adjusted in 100 ml of absolute ethanol and 30 ml of dimethyl-formamide with concentrated hydrochloric acid to a pH-value of 5. The hydrochloride that crystallises out is collected and recrystallised hot from ethanol/water.
There are obtained 17.7 grams of [D,L]-3-[4-(3-N-4*-acetyl-phenyl-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride melting at 221 - 222C.
Example 19 [D,L]-3-[4-(3-N-2*-Methoxy-phenylpiperazino-2-hYdroxy-propoxy)-phenyl]-crotonic acid nitrlle hydrochloride 10.75 Grams of [D,L]-3-[4-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile are boiled under reflux for 5 hours in a solution of 10.3 grams of N-(2-methoxyphenyl)-piperazine dihydrochloride in a mixture of 14.0 ml of triethylamine and 60 ml of ethanol. Concentration to dryness is then carried out ln vacuo, and the crude base is caused to cryst-allise by the addition of ethanol. By filtering off with suction, subsequently washing with ethanol and water there are obtained, after drying, 15.0 grams of free base melting at 102 - 103C. It is then converted in the usual manner (see Example 1) into the hydrochloride. By recrystallisa-tion twice from ethanol there are obtained 13.3 grams of [D,L]-3-[4-(3-N-2*-methoxy-phenylpiperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride melting at 198-199C.
~ 34 ,~....
.~, ::: . .. ;.

~ 3 3 E~ample 20 [D,~]-3-[4-(3~N-?~-Methyl-phenyl-piperazino-2-hyaroxy-propoy~)-phenyl3-crotonic acid nitrils hydrochloride~
10.95 Grams of [D,L]-3-[4-(2,3-oxido-propoY.~)-phenyl]- -crotonic acid nitrile are boiled under reflux for 3 hours in a solution of 8.8 grams of ortho-tolyl-piperazine.
After cooling, 15.5 g~ams of the free base crystallise out, melting at 104 - 105C. It is converted into the hydro-chloride as described in Example 1. 3y fi~lly recrystall-ising twice from ethanol there are obtained 10.0 grams o tD,L]-3-[4-(3-N-2~-methylphenyl-piperazino-2-h~droxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride melting at 233-234C.
Exam~le 21 tD,~]-3-[4-(3-~-3~-Methyl-phenyl-piPerazino-2-hydroYy-Propox~
phenyl]-crotonic acid nitrile hydrochloride-10.75 Grams of [D,L]-3-[4-(2,3-oxido-propoxy)-phenyl~-crotonic acid nitrile are reacted as described in Example 19 with 8.8 grams of meta-tolyl-piperazine.
By working up in the same manner there are obtained from 16.4 grams of the free base melting at 108 - 109C., 14.6 grams of [D,L]-3-~4-(3-~-3~-methyl-phenyl-piperazin~-2-hydroxy-propoxy)-phen~l]-crotonic acid nitrile hydrochloride meltin~ at 151 - 152C.
ExamPle 22 [D,~-3-[4-(3-N-Methyl-piperazi o-?-hydroxy-propoxy)-pkenyl]-croto~ic acid nitrile dih~drochloride, 10.75 Grams of [D,L]-3-[4-(2,3-oxido-propoxy-phenyl]-croto~ic acid nitrile are reacted as described in Ex~mple 19 3o with 5.0 grams of N-methylpiperazine in 60 ml of ethanol, - . . ~ : ';

and, as described i~ Example 1, worked up and converted into the dihydrochloride.
There are obtained 11.8 grams of [D,~]-3-[4-(3-N-methyl-piperasino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile dihydrochloride meltin~ at 217 - 218~.
Example 23 [D,L]-3-[4-(3-N-2*-oxyethyl-piperazino-2-hydroxy-propo ~en~l]-crotonic acid nitrile dihydrochloride~
5.0 Gr~s of [D,~]-3-[4-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile are boiled under reflux for 2 hours in a solution of 3.5 grams of hy~roxyethyl-piperazine in 50 ml of ethanol. After evaporation to drynes~ in vacuo, crystallisation frsm toluene is carried out. The result-in~ 5.7 grams of ~ree base melting at 101 - 102C. are converted as described in Example 1 into 6.7 grams of ~D,~]-3-[4-(3-N-2~-oxyethyl-piperazino-2-hydroxy-propox~)-phenyl]-crotonic acid nitrile dihydrochloride mslting at 204 - 205C.

[D~ 3-[4-(3-7~5~-Dimethyl-5~-h~droxy-hexylamino-2-hydroxy-~roPox~ henyl]-crotonic acid nitrile oxalate.

8.5 Grams of [D,~]-3-[4-(2,3-oxido-propoxy) -phenyl~-crotonic acid nitrile are boiled under reflux for 2 hours in a solution of 1.6 grams of sodium hydroxide and 7.2 grams f heptaminol hydrochloride in 50 ml of ethanol. ~he mix-ture is then concentrated in ~acuo, the distillation residue is taken up in 85 ml of water and adausted to a pH-value o~
7 with hydrochloric acid. Washing with toluene and ethyl acetate is carried out twice each time, and the aqueous ~o phase i9 rendered alkaline at a pE-value of 10 with sodium -.

: . .
: ' '':'' :"' ,, : . ' : ` .
- - :, ' ` :

: ~~ . . , ' ., hydrox~de solution. Extraction with ethyl acetate/toluene (1:1) is then carried out, the organic extracts are dried and evaporated to dryness in vacuo. ~he crude base is take~ r up in ethanol, and the mixture is adjusted to a pH-value o~
4 with a concentrated solution of oxalic acid in ethanol.
3y filtering off with suction and drying there are obtained 7 ? grams of [D,~]-3-[4-(3-7~,5~-dimethyl-5~-hydroxy-hexyl-amino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile melting at 155C.
~xam~le 25 [D,L]-3-[2-(3-tert.-butylamino-2-h~dro~y-propoxy)-phenyl]-acrylic acid nitrile hydrochloride.
7.0 Grams of [D,~]-3-[2-(2,3-oxido-propoxy)-phenyl]-acrylic acid nitrile in a solution of 15 ml o~ tert.-butylam-i~e in 80 ml of absolute ethanol are boiled under reflux for one hour. In the manner described in Example 1, working up and conversion into the hydrochloride are carried ; out. ~here are obtained 5.3 grams of ~D,L]-3-[2-(3-tert.-; butylamino-2-hydroxy-propoxy)-phenyl]-acrylic acid nitrile hydrochloride melting at 155C.
Example 26 [D,~]-3-t2-(3-tert.-butylamino-2-hydrox~-propoxy)-~henyl]-acrylic acid tert.-butyl ester hydrochloride.
30.0 Grams of [~,~]-3-[2-(2,3-oxido-propoxy)-phenyl]-acrylic acid tert.-butyl ester are boiled under reflux for 3 hours in a mixture of 30 ml of tert.-butyl~mine and 150 ml of ethanol. After working up in the usual manner (see Exampla 1), the crude hydrochloride is dissolved in water, the aqueous solutiou is extracted twice with toluene, and a concentrated aqueous solution of sodium chloride is then added to the a~ueous pha~e. In this way the [D~]-3-[2-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-acr~lic acid tert.-butylester hydrochloride crystallises out.
The product is filtered off with suction, dried in vacuo, ~ and again recr~stallised twice from isopropanol. ~here are - 5 obtained 13.8 grams of [D,L]-3-[2-(3-tert-butylamino-2-hydroxy-propoxy)-phenyl]-ac~ylic acid tert.-buty~ ester hydrochloride melting at 186 - 187C.
xamPle 27 [D,h]-3-[2-(3-3~,4~-Dimethox~-pheneth~lamino-2-hydrox~-~ro~ox~-phenyl]-acrylic acid tert.-but~l ester hydrochlor~de 30.0 Grams of CD,L~-3-C2-(2,3-oxido-propoxy)-phen~l]-acrylic acid tert.-butyl ester are heated at the boil under reflux for 2 hours in a solution of 20.0 gram3 of homovera-trylamine in 60 ml of ethanol. After wor~ing up in th e usual manner (see Example 1) 15.9 grams of tD,L)-3-t2-(3-3~,4~-dimethoxy-phenethylamino-2-hydroxy-propoxy)-phenyl]-acr~lic acid tert.-butyl ester hydrochloride melti~g at 167 - 168C. are obtained.
Example 28 ; 20 tD~L2~3-[2-(3-N-2~-oxyet~l-piperazino-2-hydrox~-propoxy)-_henyl]-acrylic acid tert.-but~l ester dihydrochlorlde.
11.0 Gram~ of [D,L]-3-[2-(2,3-oxidopropoxy)-phenyl]-acrylic acid tert.-butyl ester are boiled u~der reflux for 2 hours in a mixture of 55 grams of ~-hydroxyethyl-piperazine and 60 ml of ethanol. Working up is then carried out as in Example 14, but in this case the pH-value is 3 instead of 4. 5.4 Grams of CD,L]-3-[2-(3-~-2~-oxyethyl-piperazino-2-hydroxy-propoxy)-phenyl~-acrylic acid tert.-butylester dihydrochloride melting at 168C. (with decomposition~ are obtained.

.. . .. . ...
.

,: ~, -xample 29 tD,L~-3-t2-(3-~-phen~lpi~erazino-2-hydrox~ ~ropo~)-phen~l]-acr~lic acid tert.-but~l ester hy~rochloride.
11.0 Grams of tD~-3-[2-(2,3-oxidoPropoxY)-phenyl]-acr~lic acid tert.-butyl ester are boiled under reflux for one hour in a ~ixture of 6.5 grams of phenylpiperazine and 50 ml of ethanol, and working up is carried out as described in E~ample 1. In this case the h-~drochloride is finally recrystallised twice from ethanol. 6.2 Grams o~ [D,L]-3-[2-(3-~;-phenylpiperazino-2-hydroxy-propoxy)-phen~l]-ac~ylic acid tert.-butyl ester hydrochloride melting at 200 - 201C.
(with decomposition) are obtained.
Example 30 [D~T ~ -3-[4-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl~-acr~lic acid tert.-butyl ester hydrochloride.
15.0 Grams of [D,L]-3-[4-(2,3-oxidopropoxy)-phen~l]-acr~lic acid tert.-butyl ester are boiled under reflux for 2 hours in a mixture o~ 25 ml of tert.-butylamine and 100 ml of ethanol (98% strength). The mixture is then concentrated to dr~-ness in vacuo, the distillation residue is evaporated twice with to;uene (in vacuo) and finally caused to crystal-lise with diisopropyl ether. 16.7 grams of free base melting at 107 - 108C. are obtained. ~rom the l~tter there are obtzined as described in ~xample 28 12.3 grams of [D,~]-3-[4-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-acrylic scid tert.-butylester hydrochloride melting at 192 - 193C. (with decomposition).
Exa_ple 31 [D,L~-3-[4-(3-3*,4*-Dimethox~phenethylamino-2-hydrox~-~roPo~y~enyl]-acrylic acid tert.-butyl ester h~drochloride, , : ~

~8~

15.0 Gra s of [D,L~-3-t4-(2,3-oxidopropoxy)-phenyl]-acryl-ic acid tert.-bu~yl ester a-e boiled under reflux for 8 hours in a solution of 10.5 grams of homoveratryl~mine. Working Up i9 carried out in the usual manner, and the crude hydro-chloride is dissolved in 6 litres of water, ~xtracted several times with ~oluene and the aqueous phase is adjusted to a p~-value of 9 wi~h sodium hydroxide solution. ~he mixture is then e~tracted with toluene and eth~l acatate. ~he com-bined organic extracts are e~aporated to dryness in vacuo, and crystallisation is caused with diisopropyl ether.
6.95 Grams of free base are obtained melting at 100 - 101C.
From the latter are obtained as described in Example 1 7.4 grams of [D,L]-3-t4-(3-3~,4~-dimethoxyphenethyla~ino-2-hydroxy-propo~y)-phenyl]-Gcrylic acid tert.-butyl esver hydrochloride melting at 176 - 177C., which W2S finally recrystallised twice from ethanol.
Example 32 [D.L3-3-Phen~1-3-[2-(3-ter'.-butylami~o-2-hydroxy-~ropo~)-~ 3-acrylic acid nitrile hydrochloride, 5.4 Grams of ~D,L~-3-phen~1-3-~2-(2,3-oxidopropox~)-phe~yl]-acrylic acid ~itrile are boiled under reflux for 2 hours i~ a mix-ture of 15 ml of tert.-butylamine. ~ha mix-ture is then eva~orated to dryness in vacuo, and e~aporated twice with toluene in ~acuo. ~he distilla~ion residue is caused to crystallise by digestion with toluene/petroleum ether. 6.4 Grams of free base melting at 92 - 93C. are obtained. From the latter are obtained as described i~
Example 1,5.5 ~ra~s of [D,L]-3-phenyl-3-[2-(3-tert.-butyl-amino~2-hydrox~-propoxy)-phenyl]-acrylic acid nitrile hydrochloride melting at 171 - 172C.
; ,,, ~ ~ 40 , - . .
, : , -. . ; ~ : ~

~8633 :ExamPle 33 [D,I,]-3-Phe~ 3-r.? (~ s4~-Dimetho~y~he~eth;ylamino-2-nydrox;
propox~)-phen~l]-acrv~lic acid nitrile semi-oxalate~
5.4 Grams of [D,~]-3-phenyl-3-[2-(2,3-oxidopropoxy)-phenyl~-acrylic acid nit~ile are boiled under re~lux for 3 hours in a solution of 3~7 grams of homoveratrylamine i~
50 ml of ethanol. Wor~ing up is then carried out as des-cribed in Example 30. ~he oily free base is then converted as described in Ex~mple 23 into the oxalate, but in this case it is adjusted to a p~-value of 6.5 by the addition of oxalic acid. The crude semi-oxalate is again recrystallised twice from ethanol, and 4.1 gramæ of tD,L]-3-phenyl~3-[2-(3-3#,4~-dimethoxyphenethylamino-2-hydrox~-propo~y)-phen~l]-acrylic acid nitrile semioxalate melting at 172-173C. are obtained.
Example 34 [D,L]-~-Phenyl-3-~2-(3-N-phenylpiPerazino-2-hydroxy-propo~)-phenyl]-acr~lic acid nitrile hydrochloride, 6.0 grams of tD,L] 3-phenyl-3-[2-(2,3-o~idopropoxy)-phenyl]-acrylic acid nitrile are boiled under reflux for 2 hours in a solution of 3.5 grams of phenyl-piperazine in 50 ml of ethanol. ~hen, as described in E~ample 1, working up and converaion into the hydrochloride are carried out.
For further purification the procedure is as described i~
Example 30. ~he free base was purified by crystallisation with toluene/dii~opropyl ether~ 4.1 Grams melting at 102 - 103C. are obtained. ~he free base is again as described in Example 1 converted into the hydrochloride.
~here are obtained 4.4 grams having the double melting point 85C./184C.

, . ~ .
.:

. .

~ 3 ~

[D ~]-3-Phenyl-j~[4-(3-tert_-butylamino-?-hydroxy-~
phen~l]-acr~]ic acid nitrile_n~ochloride 10.0 Grams of [D~L]-~-phenyl-3-[4-~2,~-oxido-~propoxy)-phenyl~-acrylic acid nitrile are heated at the boil under reflux for 2 hours in a ~lixture of 20 ml of tert.-butylamine a~d 50 ml of ethanol. ~hen, as described in ~xample 1, working up and conversion into the hydrochloride are carried out, he crude hydrochloride ~as finally recrystallised again twice from e~hanol. 4.6 Grams of [D~-3~phenyl-3--L4-(~-tert.~butylamino-2-hydroxy-propoxy)-phenyl~-ac~lic acid nitrile hydrochloride melting at ~33 - 234C. ale obt~ined.
~he ethanolic mother liquor from the second recr~stallisat~on is concentrated to dr~ness ~n ~acuo, and con~erted into the free base in a manner a~alogous to that in Exa2ple 30~
After crystallisation of the crude base by trit~ration with diisopropyl ether 1~1 grams of the free base melti~g at 112 - 114C. are obtained.
~xample 36 ~D~I.]-3-Phenyl-3-[4-(3-3 ,4~-Dimethox~heneth~lamino-2 ~rox~-propoxy)-phenyl]-acxylic acid nitrile oxalate.
10.0 Grams of [D,~]-3-phenyl-3-[4-(2,3-oxido-propoxy)-phen~l]-acrylic acid nitrile are boiled under ~e~lux for 2 hours in a mixture of 6.5 ml of homoveratrylamine and 50 ml of ethano'. Working up is then carried out as described in Example 30. ~he oily free base is then converted into the oxalate as described in Example 23. 4.9 Gr~ms of [D,L]-3-phen~ [4-(7-3~,4~-dimethoxy-phenethylamino-2-hydrogy-p~opox~)-phe~yl] acrylic aci d nitri le oxal ate melt~ng at 124 - 125C. are obtai~ed.

- . .. -.

;, :: ,. . :. . ;

,. . :~:,. :

6~3 ~Z
CD~ 3- Phenyl-~-[4-~3-N-phen~lpipera ~henyl]-acr~lic acid nitrile_d h drocnloride.
10.0 Grams of [D,~1-3-phenyl-3-[4-(2,3-o~ido-propoxy)-phenyl]-acrylic acid nitrile are boiled under reflux for 2 hours in a solution of 5.9 grams of phenyl-piperazine in 50 ml of ethanol. ~y working up in a manner analogous to that in Example 1 6.8 grams o~ [D,~-3-phenyl-3~4-(3-N-phenylpiperazino-2-hydrox~-propoxy)-phenyl~-acrylic acid nitrile dihydrochloride melting at 189-190C. are obtained.
xample 38 [D~L]-3-Phen~1-3-~4-(3-~-~2-h~droxyeth~l]-piperazi~o-2-h~drox~-~ropoxy)-phenyl~-acrylic acid nitrile dip~drochloride In a man~er analogous to that in Example 36, 10.0 grams f [D,L]-3-phen~1-3-[4-(2,3-oxido-propoxy)-phenyl]-acr~lic acid ni~rile are r~acted with 4.7 grams of ~-hydroxyethyl-piperazine in 50 ml of ethanol a~d worked up. 9.8 Grams of tD,L]-3-phenyl-3-[4-(3-N-[2-hydroxyethyl]-piperazino-2-hydroxy-propoxy)-phenyl~-acr71ic acid nitrile dihydrochloride melting at 164 - 165C. are obtained.

[D,L]-3-[4-(3-3~,4~-Dimethoxyphenethylamino-2-h~drox~-prop-ox~)-phenyl]-acrylic acid methyl ester h drochloride.
6 Grams of [D,L]-3-[4-(2,3-oxido-propoxy)-phe~yl]-~5 ~cr~lic acid methyl ester are boiled under reflux for 2 1J2 hours in a solution o~ 4.7 grams of homo~eratryl~mine in 60 ml of absolute ethanol, and then working up is carried out as described in Example 1. 6.2 Grams o~ [D,L]-3-[4-(3-3~,4~-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-acrylic acid methyl ester h~drochloride melting at 162C.
are obtained.

,, ,, . " ~ , . ~ - , ..
: ~ ' ;

[D?L~-3- [4-(3-1 ~ 5-Dimeth~rl-5-hydro~ -hex~lamino-2-h~drox,~7 -5.~ ~rams of ED,L]-3-[4-(2,3-oxido-propox~)-phenyl]-acryl-ic acid met~yl ester are boiled under refll~ for 4 hours in a solution of 4~6 grams of 6-amino-2-methyl-2-heptanol hydro-chloride (heptaminol h~droehloride) a~d 1.02 grams of sodium hydroxide in 70 ml of absolute ethanol. Wor~ing up is ~hen carried out a~ described in Example 1. Ether is used ~or recrystailisation of the free base and for recr~stallisation of the hydrochloride. 1.2 Grams of [D~L]-3-~4-(3- [1,5-dimethyl-5~hydro~y]-hexyla~ino-2-h~droxy-propo~y)-phenyl]-acrylic acid methyl ester h~drochloride melting at 110C.
are obtained.
~xample 40 a [D~L]-3-[4-(3-N-2~-methoxv~hen~l-E~ azino-2-h~drox~-pr?~oxy)-~henyl]-crotonic acid meth~l ester.
15.0 Grams of [D,L~-3-~4~(2,3-oxido-propoxy)-phenyl]-croto~ic acîd methyl est~r are heated for ono hour on a ste~m bath in 50 ml of ethanol and 10 gram~ of 2-metho~y-phen~l-piperazine. Worki.ng up is the~ carried out as described in Example 1. 6.2 Grams of [D,LJ-3-[4-(3-~-2~-methox~phenyl-piperazino-2-hydroxy-propox~)-phen~l]-crotonic acid meth~l ester melting at 183 - 184C. are obtained.
Example_41 [D~L~-3-[4-(3-N-2~-Methoxyphen~l-pi~erazino-2-hyaroxy-propoæ~)-phen~l]-acrylic acid methyl ester dihydrochlorid~.
4.5 Grams of [D,L]-3-[4-(2,~-oxido-propoxy)-phenyl~-acrylic acid methyl ester are boiled under reflux for 3 hGurs in a solution of 4.0 6rams of N-(2-metho~y-phenyl)-pi~erazine .:,: - ,.., ~ :

- : :: : , ~ :- :
, ~ , .

~ 6 3 ~

in 60 ml O.L absolute eth~nol. By the usual working up (see E~ample 39j 6.05 grams of [D,L~-3-[4-(3-N-2~-methoxy-phenyl-piperazlno-2-hydroxy-propoxy)~phenyl]-acrylic acid methyl ester dihydrochloride melting at 204C. are obtained.
Example 42 ~3~L]-3- [?-(3-3~,4~-Dimetho}~-phenethylamino-2-hydro~y-prop ~) ~enyl]-acrylic acid eth~l ester _ ~drochloride.
10.0 Grams o~ [D,L~-3-~2-(2,3-oxido-propo~y)-phenyl]-acr~lic acid eth~l ester are boiled under reflux for 4 hours in a solution of 7.3 grams of homoveratrylamine in 60 ml of ethanol. The mixture is then concentrated to dryness ~n vacuo. B~ digestion with hexane the oily distillation residue is caused to cr~stallise. After ~iltering of~ snd drying 9.8 grams Or free base melting at 80 - 82C. are ob-tained. From the lattsr is prepared as described in E~ample 1 the hyd~ochloride, which is once a~ain recrystallised from ethanol/water and finally from isopropanol. 8.1 Grams of tD,L]-3-2-(3-3~,4~-dimethoxy-phenethylamino-2-hydroxy-propoxy)-phenyl]-acrylic acid ethyl ester hydrochloride melting at 161 - 162~C. are obtain~d.
Example 43 [D,L~-3-t2-(~-N-phenylpiperazino-2-h~droxy-propox ~-Phenyl]
acr~lic hcid ethyl ester hydrochloride.
10.0 Grams of [D,L]-~-~2-(2,3-oxido-propoxy)-phenyl]-acry-lic acid ethyl ester are voiled for 4 1~2 hours in a solution of 6.54 grams of N-phenyl-piperazine in 60 ml of ethanol.
l'hen, as described in ~xample 1, working up a~d con~ersion into the hydrochloride are carried out. ~he hydrochloride once so obtained is finally recrystallised agai~yfrom isopropanol and then lrom ethanol/water. 10.2 Grams of [D,L]-3-[2-- . : , , . ~ :
- ~ , . . .

(3-~-phen;s~lpiperazi.no-2-h~dro~xy-propoxy)-,phenyl~-ac~ylic obt~ined.
acid ethyl ester hydrochloride melti~ at 185 - 187G. ~re /
E~ampl~ 44 [D,L]-3-[2-(3-tert.-bu~yl~ino-2-hydrox~-prouox~)-phenyl~-acr~lic acid eth~l ester h~drochloride.
10.0 Grams of [D~I,]-3-[2-(2.3-oxido-propo2y)-phenyl]-ac~ylic acid eth~i ester are boiled for 5 1/2 hours in a mixture of 4 25 ml of tert.-butylamine and 60 ml of ethanol.
'~hen, as described in Example 1, working up is carried out and the crude h~drochloride obtained, which is precipitated in the usual manner from ethanol/h~drochloric acid and i5 then evaporated with toluene, is recrystallised from ethanoi/di-isopropyl ether. As described in Example 30, the hydrochlor-ide is then purified again via the free base. I~ this case suspensio~ of the hydrochloride in about 100 ml o~ water b~
the addition o~ sodium nydroxide solution is sufficient.
B~ recr~stallisation from isopropanol 5.8 grams of [D,L]-3-t2-(3-tert.-butylamino-2-hydro~y-propoxy)-phenyl~-acrylic asid ethyl ester hydrochloride melti~g at 133 - 134C are obtained.

[D,~] 3-~4-(3-tert.-but~lamino-2-h~drox~-~ropo~ phenyl~-3-eth~l-acrylic acid nitrile hydrochloride.
10.0 Grams of [D,L~-3-[4-(2,3-oxido-propoxy)-phen~l]-3-ethyl-acrylic acid nitrile are boiled under reflux for 2 hours in a mixture of 15 ml of tert.-butyl~mine and 50 ml of etha~ol. Working up is then carried out as describad in ~xample 1. The crude free base first obtained is recryst-allised from toluene/hexane. '~he 7.0 ~rams so obtained - melting at 73 - 75C. are converted as described in ~xample 1 into the hydrochloride. 3.4 Grams of [D~L~-3-[4 4~

.:. : - ....... :. . :

: ::,, . :: - :
- :. .. :, ::: . ~ ::. :

:

~863~

tert.-but~lamino-2-hydroxy-propoxy)-phenyl~-3-ethyi-acrylic acid nitrile hyd~ochloride melting at 170 ~ 171Co are obtained.
Example 46 [D~L]~3-[4-~3-3~,4~-Dimetho~-phenethylam ~o-2-hydroxy-prop~
oxy)-phenyl]-3-eth~l-acr~lic acid nitrile hydrochloride.
15.0 Grams of [D 9 ~] -~ -[4-(2,3-oxido-propoxy)-phenyl]-3-ethyl-acrylic acid nitrile are boiled for 2 hours in a solution of 12.0 grams of homoveratrylamine in 100 ml of ethanol~ and wor~ing up i~ carried ou~ as dsscr bed in Example 30. ~here are obtained first 10.3 grams of the free base melting at 103 - 104C. ~rom the latter are ob-tained as described in ~xample 1,7.5 grams of [D,L]-3-[4-(3-3~,4~-dimethoxy-phenethylamino-2-hydroxy-propoxy)-phenyl]-3-etnyl-acrylic acid nitrile hydrochloride melting at 120 -121C.
Example 47 [D,L~-3-[4~ N-Phenyl-piperazino-2-hydroxy-Propoxy)-p~enyll-; 3-ethyl-acrylic acid ~itrile dihydrochloride.
10.0 Grams of [D,~]-3-[4-(2,3-oxido-propoxy)-phen~
3-ethyl-acrylic acid nitrile are boiled u~der reflux for 2 hours in a solution of 11.0 grams of phe~ylpiperazine in 50 ml of ethanol. ~he reaction mixture is then cooled to 5~C., and the free base crystallises out. 8.2 Grams of the free base melting at 110 - 115C. are obtained, from which there are obtained, as described in Example 1 by means of 4.19 ml of 10 N-hydrochloric acid, 8.1 grams of ~D,~]-3-[4-(3-N-phenyl-piperazino-2-hydroxy-propoxy)-phenyl]-3-ethyl-acrylic acid nitrile dihydrochloride melti~g at 202 -~0 204oc 863~

Examnle 48 [D~l~-3-[4~t3-N-~2-~I;Ydrox~eth~l~-niperazino-2-hydr ~e~yl~-3~eth l-acrylic_acid nitrile dihydrochloriae.
10.0 Grams of [D,L~-3-~4-(2,3-oxido-propoxy)-phenyl]-3-ethyl acrylic acid nitrile in a solution of 6.0 grams of N-hydroæyethyl-pipe-azine are, as in Example 45 or 30 (2.0 litres of water) reacted and wor~ed up. ~here are obtained first 6.4 grams of ~he lree base melting at 80 -81C. and therefrom by mea~s o~ 3.57 ml o~ 10N-hydrochloric acid, 7.2 grams of ~D,~]-3-[4-(3-N-[2-hydroxyethyll-piperazino-2-hydroxy-propoxy)-phenyl]-3-ethyl-acrylic acid nitrile dihydrochloride melting at 181 - 182C.
_xamPle 49 [D,L~-3-~2-(3~ 4*-Dimethoxy-phenethylamino-2-h~droxy-propoxy) he~yl~-3-ethyl-acrylic acid methyl ester hydrochloride.
8 Grams of [D,L]-3-[2-(2,3-oYidopropoY~)-pheny~]-3-ethyl-acrylic acid meth~l ester h~d-ochloride are boiled under reflux for 3 hours in a solution of 5.7 grams of homo-reratryl-amine in 80 ml of absolute ethanol. Working up is then carried out as described in Example 45. 4.3 Gr~ms of ~D,L~-3-[2-(3-3~,4~-dimethoxy-pheneth~lamino-2-hydro~y-Propoxy)-phenyl~-3-ethyl-acrylic acid methyl ester hydrochloride are ob~ained ~he free base shows characte~is~ic ~R-bands ~t 2920, 171~ 1630, 1585, 1505, 1437, 1225, 1145, 1015, 793 and 748 cm 1 Exam~le 50 [D~]-3-[2-(3-~J-2~-MethoY~y-phen~yl-pi~erazino-2-h2~dro~-proPoxy)-~henyl~-3-et~yl-acrylic acid meth~ ester_dih~ro-chloride.
8 Gr~ms of [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-3-~ 48 ~: : : :: :: : : ::

e~nyl-acrylic ac~d methyl esver are reacted, as ~escribed ~n Example 41, with a solution of 6.8 ~rams o~ ~-(2-methoxy-phenyl)-piperaæine in 80 ml of absolute ethanol, and worked up, 4.4 G ~ms of ~D,L]-3-[2-(3-~ 2~-methoxy-~hen71-piper-azino-2-'nydroxy-propox~ phenyl~-~-e'hyl-acrylic acid me~hy~
es~er dihyd~ochloride melting at 120 - 122C. ~re cbtained.
Ex~le 51 [D,~]-3-[2-(3-~ert.-Bu~lami~o-2-hydroxy-propQx~)-phenyl]-crotonic acid ethyl ester h~drochloride~
10.5 Grans of [D,~]-3-[2-(2,3-oxjdo-~ropo~y)~pheny']-crotonic acid ethyl ester are st~re~ for 16 hours at 20 -25C. in a mixture of 20 ml of tert.-butylamine and 50 ml of ethano~. Working up is then carried out as described ~n E~ample 1. ~he hydrochloride s in this case rec~stallisea from isopropa~ol/ether twice. 5.4 Grams o~ [D,L3-3-[2-(~-tert.-butylamino-2-h~droxy--propoxy)-phenyl~-crotonic aci~
ethyl ester hydrochloride melting at 118 - 119C. are obtained.
Exa~ple_52 [D,~-3-~2-(3-3~,4~Dimetho~ Pheneth~lamino-2-hydrox~-pro~oxy)-phenyl~-crotonic acid ethyl ester oxalate.
12 0 Grams of [D,~]-3-[2-(2,3-oxido~propoxy)-phen~
crotonic acid eth~l ester are stirred fvr 16 hours at 20 to 25C. in ~ solutio~ of 7.2 grams of homove-atrylamine in 100 ml of ethanol, and then worki~g up is ca~ried out as described in E~.ample 24. 4.5 Grams of [D,~3-3-~2-(3-~,4~-dimethoxy-phenethylamino-2-hyd~ox~-propoxy)-phe~yl]-croto~ic acid ethyl ester oxalate melting at 115 - 117C. (with decompositio~) are obt~ined.
Example 53 [D,L]-3-[2-(3-N-2*-Methoxy-phenylpiperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid ethyl ester dihydrochloride.
}
~ 49 .

,. : ~ ;~ . .~ , ,.
.
.. ~ . . ,. . - . ...
~. . - . , .
.

~8633 7.9 Grams of tD~L]-3-[2-(2.3-oxido-propoxy)-phen~
crotonic acid eth~l ester ~re stirred at room temperatnre for 48 hours in a solution of 5.8 grams of N-2-methoxy-phenyl-piperazine in 10C ml of ethanol. ~hen workin~ up to the crude base is then carried out as described in Example 1.
It is dissolved in a small amount of ethyl acetate and chromatographed over a column of 240 grams of silica gel (Silica gel 60, Merck). ~inally elution with ethyl acetate yielded 4.4 grams of purified base i~ the form o~ an oil.
~; 10 It is then converted in the usual manner (see Example 1) into 2.9 grams o~ ~D,L~-3-~2-(3-N-2~-methox~-phen~lpiperazino-2-hydroxy-propo~y)-phenyl]-crotonic acid ethyl ester dihydro-chloride melting at 134 - 136C.
; Exam~le 54 [D~L~-3-t3-(3-tert.-b~t~lamino-2-h~droxy-propox~-phen~l]-acrylic acid nitrile h~drochloride.
15 Grams of [D,L]-3-t3-(3-(2,3-oxido-propoxy)-phenyl]-acrylic acid nitrile are boiled under reflu~ for ons hour in a mixture of 40 ml of tert.-butylamine and 200 ml of ethanol.
By the usual working up, 8.3 graLs of stron~ly h~groscopic [D,~-3-~3-(3-tert.-butylam$no-2-hydroxy-propox7)-phenyl]-acr~lic acid nitrile hydrochloride are obtained. ~he free base exhibits characteristic IR bands at 3300, 2950, 2208, 1608 (shoulder), 1590 (shoulder), 1570, 14?3, 1435, 1372 and 743 cm 1.
Example 55 [D~L~-3-[3-(3-N-2~-Methoxy-phen~ iperazino-2-hydroxy-ro~ox~-phen~l~-acrylic acid nitrile dinydrochloride.
12.0 Grams of ~D,L]-3-~3-(2,3-oxido-propcxy)-phenyl]-l~j, - .~

acrylic acid nitrile are boiled under xeflux for one hour in a solution of 11.5 grams of N-2-methoxy-phenylpiperazine in 50 ml of ethanol. ~hen working up is carried out in a manner analogous to that in Example 31 (but in this case 4 litres of water, soda solution, instead Or NaCl). ~he crude free base is oily and is con~erted as described in Example 1 into 15.7 grams of [D,L]-3-[3-(3-N-2~-methoxy-phenyl-piperazino-2-hydroxy-propox~)-phenyl]-acrylic acid nitrile dihydrochloride melting at 210C. (with decompositio~).
gxamPle 56 [D.~]-3-~3-(3-N-[2-~ydroxyeth~l]-piperaæino-2-hydrox~-~opoxy)-phenyl]-acrylic acid nitrile dihydrochloride.
12.0 Grams of [D,L]-3-[3-(2,3-oxido-propoxy)-phenyl]-acrylic acid nitrile are, as de3cribed in Example 55, reacted with 20.0 grams of ~-2-hydroxy-ethylpiperazine in 50 ml of ethanol and worked up. 13.5 Grams of [D,~-3-[3-(3-~-[2-hydroxyethyl]-piperazino-2-hydroxy-propoxy)-phenyl]-acrylic acid nitrile dihydrochloride melting at 180 - 182C. are obtained.
Example_57 ~D,L]-3-~3-(3-3~,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl?-acr~lic acid nitrile hydrochloride.
12.0 Grams of [D,L]-3-~3-2,3-oxido-propoxy)-phenyl~-acrylic acid nitrile are reacted as in Example 55 with 20.0 grams of N-2-hydroxyethyl-piperazine in 50 ml of ethanol, and worked up to 13.5 grams of [D,L]-3-[3-(3-3~,4~-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl~-acrylic acid nitrile hydrochloride melting at 180 - 182C.

.. . . .. . . .. . .. . . . . . . .
,,, , ,, . ,, ,:
- ,: :: ,, . , ;, ., : . ,, :,, . . , . : : ~ ,>, ..
. , - .. : .. " ,.: ::: -: ..
. ~. .. , . : ,- , . , ~- ..

., , :. .: . . - - . , :.
, :.- ; . , . ~ :, :. - : . , ~

11~8633 Example 58 ~D,L]-3-[3-(3-tert.-but~lamino-2-hydroAyy propox~)-phenyl]-crotonic acid nitrile h~drochloride.
15 Grams OA~ [D,lA]-3-[3-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile are, as described in Example 55, reacted with 40 ml of tert.-butylamine in 200 ml of ethanol and worked up. 13.8 Grams of [D~L]-3~[3-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride are obtained having characteristic IR-bands at 3320, 2960, 2205, 1668, 1570, 1473, 1430, 1370, and 772 cm 1.
ExamPle 59 ~D,Ll-3-[3-(3-3~,4*-Dimethoxy-pheneth~lamino-2-h~droxy-propoxy)~
phenyl]-acrylic acid ethyl ester hydrochloride.
6.0 Grams of [D,L]-3-[3-(2,3-oxido-propoxy)-phenyl]-acrylic acid ethyl ester are stirred for 16 hours at room temperature in a solution of 3.6 grams of homoveratrylamine in 30 ml of ethanol, and then worked up to the crude base as described in Example 24. ~he latter is reacted as described in Example 1 to yield 3.6 grams of [D,L]-3-[3-(3-3~,4~-dimethoxy-phenethylamino-2-hydroxy-propoxy)-phenyl~-acrylic acid ethyl ester melting at 128 - 129C.
Example 60 [D,~-3-[3-(3-N-2~-Methoxg~henyl-piperazino-2-hydrox~-propoxy)-phenyl]-acr~lic acid eth~l ester dih~drochloride.
6.0 Grams of [D,~]-3-[3-(2,3-oxido-propoxy)-phenyl~-acrylic acid ethyl ester are stirred for 48 hours at room temperature in a solution of 3.9 grams of N-2-methoxy-phenyl-piperazine. By working up in a manner analogous to that in Example 1 3.4 grams of [D,L]-3-~3-(3-N-2~-methoxyphenyl-piperazino-2-hydroxy-propoxy)-phenyl]-ac~ylic acid ethyl ester dihydrochloride melting at 164 - 165C. are obtained.

.

86~

xample 61 ~D~-3-[3-(3-N-[2-Eydrox~eth;yl~-piperazino-2~h;~droxy-~ropoxy) ~hen~ acr~lic acid ethyl ester dih~drochloride.
12.0 Grams of [D,L~-3-[3-(2,3-o2ido-propoxy)-phenyl]-acrylic acid ethyl ester are stirred for 48 hours at 20 to 24C. in a solution of N-2-hydroxyethyl-piperazine in 60 ml of ethanol. By working up in a manner analogous to that in Example 59 9.3 grams of [D,L]-3-[3-(3-~-~2-h~dro~yethyl]-piperaz no-2-hydroxy-propox~)-phenyl]-acrylic acid eth~l ester dihydrochloride melting at 189 - 190C. are obtained.
ExamPle 62 ~D,L]-3-[Phenyl-3-[4-(3~-2~-metho~Yyphenyl-piperazino-2-h~droxy-propoxy)-phenyl]-acrylic acid methyl ester dihydro-chloride.
:
15.0 Grams of [D,L]-2-phenyl-3-[4-(2,3-oxido-propoxy)-- phenyl]-acrylic acid methyl ester are stirred for 16 hours at 20 to 24C. in a solution of 9.3 grams of N-2-methoxy-phenyl-piperazine in 150 ml of methanol. Working up to the free base is carried out as desoribed in Example 31.
~he purif~ed base obtained as an oil is converted into the hydrochloride as described in Example 1. By recrystall-isation from methanol/ether and finally from methanol 13.8 grams of [D,L]-2-phenyl-3-[4-(3-~J-2~-methoxyphe~yl-piperazino-2-hydroxy-propoxy)-phenyl]-acrylic acid meth~l ester dih~drochloride meltin~ at 168 - 170C. (with decom-position) are obtained.
Example 63 [D,L]-3-Phen~1-3-[4-(3-N-[2-hyd~ox~ethyl~-~iperazino-2-h~droxy-propo~y)-phen~l]-acrylic acid meth 1 ester dihydro-chloride.
15.0 Grams of [D,L]-2-phe~yl-3-[4-(2,3-oxido-propoxy~-, .. .
~;
. ~ .
.. .: .. : : ~ :
, : :

...

i33 phenyl]-acrylic ~cid methyl ester are reacted as described in ~xample 62 with 6.3 grams of N-2-hydro} yethyl-piperazine in 150 ml of methanol and l"orked up. 16.4 grams of [D,L~--2-phenyl-3-[4-(3-N-[2-hydroxyethyl~-piperazino-2-hydrox;y-propo}~)-phenyl]-acrylic acid methyl ester dihydrochloride melti~g at 218 - 220C. are obtained.
~{ample 64 tD,L]-3-Phenyl-3-~4-~-3*~4~-Dimetho}ypheneth;~lamino-2-hydroxy-propoxy)-phenyl~-acrylic acid methyl est_r.
15 Grams of tD,I.]-2-phenyl-3-[4-(2,3~oxido-propoxy)-phenyl]-acrylic acid methyl ester are stirred at room temper-ature for 24 hours in a solution of 8.22 grams of homovera-trylamine. ~he crude hydrochloride obtained in a manner analoE;ous to that in l~xample 1, this time by adjusting the pH value to 6, is recrystallised first from isopropanol/di-isopropyl ether and finally from toluene/met hylen e chloride.
4.1 Grams of CD,I.]-2-phenyl-3-~4-(3-3*,4~-dimethoxyphenethyl-amino-2-hydroxy-propoxy)-phenyl]-acrylic acid methyl ester melting at 145 - 147C. are obtained.
Example 67 [D,L]-3-[3-(3-3~,4~-Dimethoxyphenethylamino-2-hydroxy-~ropoxy?-~hen;~l]-crotonic acid nitrile hydrochloride.
15 Grams of [D,L]-3-[3-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile are boiled under reflux for 2 1/2 ho~rs in a solution of 12.62 grams of homoveratrylamine in 150 ml of ethanol, and worked up as described in Example 31. ~he oily free base so purified is finally converted, as described in Example 1, into 6.5 grams of pure [D,lj]-3-~3-(3-3~,4*-dimethox;yphenethylamino-2-hydrox;y-propoxy)-phenyl]-crotonic acid nitrile hydrochloride melting at 135 - 138C.

-: .~ : ., , . . .
, ,.,, , ExamPle 66 [D,~-3-~3-(3-N-2~-Methox~phen~l-piperazino-2-~ydroxy-pro~oxy~
phenyl]-crotonie acid nitrile h~drochloride.
15 Grams of ~D,L]-3 [3-(2,3-oxido-propox~)-phenyl]-crotonic acid nit~i le are boiled under reflux for 1 1/2 hours in a solution of 3.9 grams of ~-2-methoxy-phenylpiperazine ; in 150 ml of ethanol. By working up in a manner analogou~
to that in Example 1 17.1 grams of [D,L]-3-[3-(3-N-2~-methoxyphenyl-piperazino-2-hydrox~-propox~)-phenyl]-crotonic acid nitrile hydrochloride melting at 160 - 162C. are obtained.
Example 67 [-]- and [+]-3-[4-(3-3~,4~-Dimethoxy~he~eth!Ylamino-2-hydrox~-propoxy)-phenyl]-crotonic acid nitrile h~drochloride.
A solution of 50 grams of ~D,1]-3-~4-(3-3~,4~-dimethox~-phenethyl-amino-2-hydroxy-propoxy)-phenyl]-crotonic acid ni~rile in 200 ~l of ethanol is mixed with a solution of 19.2 grams of D-(-)-mandelic acid in 150 ml cf ethanol~
After standing for a short time, the crystals that separate are filtered o~f with suction. By washing with a small amount of ethanol and drying in vacuo there are isolated 32.8 grams of [-]-3-~4-(3-3~,4~-dimethox7phenethylamino-2-hydro~y-propo~y)-phenyl~-crotonic acid nitrile-D-9-)-mandelate melting at 114 - 116C. which is sparingl~ soluble in ethanol, ~ ~ ]3 = -35.4~ (c = 0.6, methanol). By recryst-allisation from 200 ml of hot ethanol 28.9 grams of the pure mandelate are obtained melti~g at 118 - 119C. and having a rotation value of [~]D = -38.2 ~c = 0.6, methanol), yield 83. 50~G .
~o a rapidl~ stirred mix~ure of 23 grams of the above - ,, :.
.. . . , :, : . -, . - . :: :.
. , :. . - ~, : . . ,-: . . . . , . , , . . .,: . ..
- . - . : .. .- ..... . ..
.. - ,, : : .: . . ... ~ ~. .
-, 63~

laevo-rotatory mandelate, 230 ml of water a~d 100 ml of chloroform is added dropwise, while cooling with ice, a mixture of 3.15 ml of concentrated aqueous ammonia solution and ~0 ml of water. ~he organic phase is separated, ~Jashed ~ith some water, and, after being dried over sodium sulphate, is concentrated to dryness in vacuo.
~`rom the resulting ~ 3-[4-(3-3~,4~-dimethoxyphenethyl-amino-2-hydro~y-propoxy)-phe~yl]-crotonic acid nitrile is obtained the h~drochloride described in Example 1, which, after recrystallisation from ethanol/ether, melts at 166 - 167C. and has a rotation value of [a~D = -12.8 (c = 0.5 .
methanol), final yield 17.5 grams (96%).
By evaporation of the ethanolic mother liquor~ of the abo~e racema~e splitting there is obtained the t+]-3-[4-t3-3*,4~-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile-D-(-)-mandelate, which is very readily soluble in ethanol. ~rom the latter the [+]-3-[4-(3-3~,4~-dimethoxyphenethylamino-2-hydroxy-propox~)-phenyl]-crotonic acid nitrile can be prepared as described above.
3y recrystallisation from toluene/petroleum ether 25.4 grams of the nitrile melting at 132 - 135C. are obtained. ~he latter, as in the case of the (-)-antipodes already described, is converted into the dextro-rotatory hydrochloride.
By recrystallisation from ethsnol/ether there are obtained 25.5 grams (930/G) of not quite optically pure [+]-3-[4-(3-3~,4~-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl-crotonic acid nitrile hydrochloride melting at 162 - 164C.
having a rotational value of aD = +9~7O (c = 0.6, methanol).

. .
.. ; , .

Claims (26)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the formula I

I

wherein R1 and R1' are identical or different and represent hydrogen, an alkyl or alkoxy radical containing 1 - 4 carbon atoms, the allyl group, a halogen atom or the nitro group, R2 represents an acrylic acid radical or acrylic acid nitrile radical of the formulae or wherein R5 represents hydrogen, a C1 - C5-alkyl radical, an aryl or aryl-lower alkyl radical which is unsubstituted or substituted by lower alkyl or alkoxy, R6 represents hydro-gen or an alkyl radical containing 1 to 8 carbon atoms, R7 represents hydrogen, a lower alkyl or aryl-lower alkyl radical, R3 and R4, together with the nitrogen atom represent a hetero-cyclic ring containing 5 to 7 members which may be substituted by C1 - C4-alkyl, in which ring one carbon atom may be replaced by an oxygen atom, sulphur atom or a further nitrogen atom, and the latter may be substituted by an alkyl, alkoxy, oxalkyl, acyl or carbalkoxy radical in each case containing 1 to 5 carbon atoms, a pyridyl radical or a phenyl radical, which may itself be substituted one or more times by a hydroxyl group, halogen or an alkyl or alkoxy radical containing 1 to 4 carbon atoms, or R3 represents hydrogen and R4 represents a straight-chained or branched alkyl or oxalkyl radical containing 1 to 8 carbon atoms, a straight-chained or branched unsaturated aliphatic hydrocarbon radical containing 2 to 6 carbon atoms, a cyclo-aliphatic hydrocarbon radical containing 3 to 6 carbon atoms or a phenyl alkylene or phenyl alkylidene radical of the formula wherein n is a number from 1 - 3, and R8 and R9 are identical or different and represent hydrogen, an alkoxy radical containing 1-3 carbon atoms or the benzyloxy radical or R8 and R9 together represent the bis-methylene-dioxy radical, and the physiologically tolerable acid addition salts thereof, in which (a) a compound of the formula II

II

wherein R1, R1' and R2 are as defined above, is reacted with an amine of the formula III

III

wherein R3 and R4 are as defined above, or (b) a compound of the formula IV

IV

wherein R1, R1' and R2 are as defined above and X represents a halogen atom, the sulphuric acid or a sulphonic acid radical, is reacted with an amine of the formula III, or (c) a compound of the formula V

V

wherein R1, R1' and R2 are as defined above, is reacted with a compound of the formula VI

wherein R4 is as defined above and X has the meaning given for the formula IV, and the compound so obtained according to methods (a) to (c) may be converted into a physiologically tolerable acid addition salt thereof by reaction with a physiologically tolerable acid.

2. A process as claimed in claim 1 in which the prepara-tion is carried out according to reaction (a) in the presence of an organic solvent.

3. A process as claimed in claim 1 in which the prepara-tion is carried out according to reaction (b) in the presence of an organic solvent at an elevated temperature and in the presence of an acid-binding agent.

4. A compound of the formula I as defined in claim 1, and the physiologically tolerable acid addition salts thereof, whenever obtained according to a process as claimed in claim 1, claim 2 or claim 3 or by an obvious chemical equivalent thereof.

5. A process as claimed in claim 1 in which the prepara-tion is carried out according to reaction (c) and the presence of an organic solvent at an elevated temperature and in the presence of an acid-binding agent.

6. A compound of the formula I as defined in claim 1 and the physiologically tolerable acid addition salts thereof, when-ever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.

7. A process as claimed in claim 1 for the preparation of [D,L]-3-[2-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride in which [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile is heated under reflux in ethanol with tert.-butylamine, the product is separated, reacted with hydrochloric acid and the resultant product is sub-sequently isolated.

8. [D,L]-3-[2-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride, whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.

9. A process as claimed in claim 1 for the preparation of [D,L]-3-[2-(3-isopropylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride in which [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile is heated under reflux in ethanol with isopropylamine, the product is separated, reacted with hydrochloric acid and the resultant product is subsequently isolated.

10. [D,L]-3-[2-(3-isopropylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.

11. A process as claimed in claim 1 for the preparation of [D,L]-3-[4-(3-N-phenylpiperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride in which [D,L]-3-[4-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile is heated under reflux in ethanol with phenylpiperazine, the product is sepa-rated, reacted with hydrochloric acid and the resultant product is subsequently isolated.

12. [D,L]-3-[4-(3-N-phenylpiperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride, whenever obtained according to a process as claimed in claim 11 or by an obvious chemical equivalent thereof.

13. A process as claimed in claim 1 for the preparation of [D,L]-3-[4-(3-3*,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride, in which [D,L]-3-[4-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile is heated under reflux in ethanol with homoveratrylamine, the pro-duct is separated, reacted with hydrochloric acid and the result-ant product is subsequently isolated.

14. [D,L]-3-[4-(3-3*,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride, whenever obtained according to a process as claimed in claim 14 or by an obvious chemical equivalent thereof.

15. A process as claimed in claim 1 for the preparation of [D,L]-3-[3-chloro-4-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride in which [D,L]-3-[3-chloro-4-(2,3-oxido-propoxy)-phenyl]-crotonic acid nitrile is heated under reflux in ethanol with tert.-butylamine, the product is separated, reacted with hydrochloric acid and the resultant product is subsequently isolated.

16. [D,L]-3-[3-chloro-4-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride, whenever obtained according to a process as claimed in claim 15 or by an chemical equivalent thereof.

17. A process as claimed in claim 1 for the preparation of [D,L]-3-[2-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-acrylic acid nitrile hydrochloride in which [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-acrylic acid nitrile is heated under reflux in ethanol with tert.-butylamine, the product is separated, reacted with hydrochloric acid, and the resultant product is subsequently isolated.

18. [D,L]-3-[2-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-acrylic acid nitrile hydrochloride, whenever obtained according to a process as claimed in claim 17 or by an obvious chemical equivalent thereof.

19. A process as claimed in claim 1 for the preparation of [D,L]-3-[4-(3-N-2*-methoxyphenyl-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid methyl ester in which [D,L]-3-[4-(2,3-oxido-propoxy)-phenyl]-crotonic acid methyl ester in ethanol is heated on a steam bath with 2-methoxy-phenyl-piperazine and the resultant product is subsequently isolated.

20. [D,L]-3-[4-(3-N-2*-methoxyphenyl-piperazino-2-hydroxy-propoxy)-phenyl]-crotonic acid methyl ester, whenever obtained according to a process as claimed in claim 19 or by an obvious chemical equivalent thereof.

21. A process as claimed in claim 1 for the preparation of [D,L]-3-[2-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid ethyl ester hydrochloride in which [D,L]-3-[2-(2,3-oxido-propoxy)-phenyl]-crotonic acid ethyl ester is heated for 16 hours at 20 to 25°C in a mixture of tert.-butylamine and ethanol, the product is separated, reacted with hydrochloric acid and the resultant product is subsequently isolated.

22. [D,L]-3-[2-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid ethyl ester hydrochloride, whenever obtained according to a process as claimed in claim 21, or by an obvious chemical equivalent thereof.

23. A process as claimed in claim 1 for the preparation of [D,L]-3-[3-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-acrylic acid nitrile hydrochloride, in which [D,L]-3-[3-(3-(2,3-oxido-propoxy)-phenyl]-acrylic acid nitrile is refluxed in ethanol in the presence of tert.-butylamine, the product is separated, reacted with hydrochloric acid and the resultant product is subsequently isolated.

24. [D,L]-3-[3-(3-tert.-butylamino-2-hydroxy-propoxy)-phenyl]-acrylic acid nitrile hydrochloride, whenever obtained according to a process as claimed in claim 23 or by an obvious chemical equivalent thereof.

25. A process as claimed in claim 1 for the preparation of [-]- and [+]-3-[4-(3-3*,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride in which [D,L]-3-[4-(3-3*,4*-dimethoxyphenethyl-amino-2-hydroxy-propoxy)-phenyl]-crotonic acid in solution in methanol is mixed with a solution of D-(-)-mandelic acid in ethanol, the resultant cry-stals are separated, washed and dried to produce [-]-3-[4-(3-3*,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile-D-9-)-mandelate, [-]-3-[4-(3-3*,4*-dimethoxyphen-ethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile-D-9)-mandelate is isolated by recrystallization from hot ethanol;
water, chloroform and concentrated aqueous ammonia are added to the crystals, the product is separated, reacted with hydrochloric acid and (-)-3-[4-(3-3*,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile is obtained; the hot ethanol liquor from the recrystallization step is evaporated to produce [+]-3-[4-(3-3*,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile-D-(-)-mandelate, this is then treated with water, chloroform and concentrated aqueous ammonia, [+]-3-[4-(3-3*,4*-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile is obtained, treated with hydrochloric acid and [+]-3-[4-(3-3*,4*dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride is subsequently isolated.

26. [-]- and [+]-3-[4-(3-3*,4*,-dimethoxyphenethylamino-2-hydroxy-propoxy)-phenyl]-crotonic acid nitrile hydrochloride, whenever obtained according to a process as claimed in claim 25 or by an obvious chemical equivalent thereof.