CA1063516A - Pharmaceutical preparations for the treatment of coronary heart diseases - Google Patents

Abstract

Abstract of the Disclosure Pharmaceutical preparations for the treatment of coronary heart diseases containing as pharmacological active comp-ounds a betareceptor-blocking compound and a compound which regulates the thrombocyte function,and, optionally, an alpha-receptor-blocking agent.

Description

~063S~6 The present invention relates to new pharmaceutical preparations which contain, as pharmacological active compounds, a beta-receptor-blocking compound and a compound which regulates the thrombocyte function and, option-ally, an alpha-receptor-blocking compound.
According to the present invention there are provided pharmsceutical preparations for the treatment of coronary heart diseases which contain, as pharmaceutical active compounds, a beta-receptor-blocking compound of the formula O - R2 tI) I 10 wherein Arl represents a monocyclic or polycyclic, carbocyclic or heterocyclic ¦ radical which contains at least one ring of aromatic character and which is , bonded to the oxygen atom vla a ring carbon atom of the ring of aromatic character, Rl denotes an optionally substituted aliphatic, cycloaliphatic or ~ araliphatic hydrocarbon radical and R2 represents hydrogen or the acyl radical :~ of an organic carboxylic acid, or a compound of the formula Ar - qCH - CH - NH - Rl ~II) wherein Rl and R2 have the abovementioned meanings, Ar2 represents a monocyclic . or polycyclic, carbocyclic radical which contains at least one ring of aromatic character, and R3 denotes hydrogen or lower alkyl, or a salt of such compounds : 20 which can be used pharmaceutically, as the beta-receptor-blocking active com-pound, O-acetyl-salicyclic acid, or a salt thereof with a base, which can be ~ used pharmaceutically, 2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-1 pyrimido[5,4-d]pyrimidine, or an acid addition salt thereof which can be used ~ pharmaceutically, or a compound of the formula ii J~
.1 ~

. ' . : . : . : , , . .:: . : ... , .. . . ~ -i .. ,, , . . ... ,. , : , , : ,: ,,, ,., ,:

. :: : . ': ... . . ' .. i :': . . ' : :. ' 1063~6 . :
Ph~
/ N \ ~III) ., Ph2 ~ =
O = C - CH - Alk - S()n - Ph3 wherein each of the radicals Phl and Ph2 independently of one another re-~ presents a phenyl radical which is optionally substituted by lower alkyl, ; hydroxyl, lower alkoxy and/or halogen, Alk tenotes a lower alkylene radical which separates the sulphur atom from the ring carbon atom by at least 2 carbon atoms, n represents 0, 1 or 2 and Ph3 represents a phenyl radical which is optionally substituted by lower alkyl, lower alkoxy and/or halogen, or a salt thereof with a base, which can be used pharmacologically, as the active com-pound which regulates the thrombocyte function, and a hydrogenated ergot alkaloid, or a mixture of such alkaloids or acid addition salts thereof which can be used pharmaceutically, or a N-benzyl-N-halogeno-lower alkylamine, a ; 2-tert.-aminomethyl-benzodioxane, a N-substituted dibenzazepine or a methyl-2-imidazoline which is substituted in the 2-position, or acid adtition salts of such compounds which can be used pharmaceutically, as the alpha-receptor-block-ing active compound which is optionally present, wherein the ratio of the beta-receptor-blocking active compound to the active compound which regulates the thrombocyte function, especially an active compound of the type of the structural formula (III) is about 1:1 to about 1:50 (by weight) and the ratio of the beta-` receptor-blocking active compound to the alpha-receptor-blocking active com-; pount which is optionally present, is about 1:0,1 to 1:1 (by weight).
~ The new pharmaceutical preparations are suitable, above all, for the i~ ~ prophylactic and therapeutic treatment of coronary heart diseases, especially of an arteriosclerotic nature, which can also be accompanied by thrombosis.
` They can be used in the various stages of arteriosclerotic coronary heart :i :
~ -2a-.. , ,: , . ~ ,, . . . . ................... ,, :
. ~ .- , ., :: , . :. .. . ,. . :

~--` 1063S16 disease, that is to say angina pectoris, coronary insufficiency and cardiac infarction.
The beta-receptor-blocking component of the new pharmaceutical pre-parations effects a lowering of the heart rate, a reduction in the cartiac contractility and screening of the heart from subjection to external adrenergic stimuli, which results in a retuction of the myocardial oxygen consumption ant, in the case of critical nutrition, has the effect of conserving tissue. Com-pounts which have thrombocyte function-regulating properties effect a reduction in the metabolic rate of the thrombocytes, that is to say in the rate at which the thrombocytes are protucet ant die off, ant prolong their survival periot, especially when the latter is shortened due to disease. In adtition, they ; retuce the increase in adhesiveness ant aggregation of the blood platelets producet by pathologicsl influences. These properties reduce or prevent thrombotic processes which play an important part in coronary diseases. As a result : :
~'~
, , :
~ . .
:' :
, .
, . .. ..
~ .

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

:~ .

-2b-:

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

1063~i~6 of the anti-aggregatîng action, the flow properties of the blood in the arterioles, capillaries and venules are also deci-sively improved, which, in turn, leads to an improvement in the oxygen supply.
The alpha-receptor-blocking compound which is option-ally added to the combination of beta-receptor-blocking compound and a compound which regulates the thrombocyte function, has the effect, by means of peripheral vasodilatation, of facili-~ tating the stroke output and thus relieving the left hand ven-,~ 10 tricle, with a corresponding additional reduction in the oxygen !
I consumption.
!~ The combined use of the two types of active co pound, to which a compound with an alpha-receptor-blocking action can also optionally be added, considerably increases the probability of the therapeutic success, since the actions of the pharmacol-ogically active components supplement one another in a surpri-sing manner in such a way that the combined action corresponds at least to a summation of the intividual actions.
These pharmaceutical preparations provide a new principle :,:
; 20 ~ for the prophylactic and therapeutic treatment of coronary heart diseases. This principle is that the oxygen consumption of the myocardium lS reduced by beta-blocking, and thrombotic processes in the coronary arteries are reduced or preventet by a compound which . , regulates the thrombocyte function and the flow properties of the blood are~improved because the formation of thrombocyte aggregates is prevent-et. The combination of these effects leads to an unexpected improvement ; in the results of treatment. The preparation to be manufactured J ~ 3 -i::: : : . : ' ' ' . ' : , ' .. ', , , . ~ :

according to the invention display a good long-term toleration, cause no troublesome side effects and, in particular due to the reduction in the frequency of cardiac infarction, represent a distinct and considerable advance in the therapy of coronary heart diseases.
Compounds with beta-receptor-blocking properties are, in particular, those of the formula 1 0--C~12 CH--C~12--NH--Rl (I) wherein Arl represents a monocyclic or polycyclic, carbocyclic or heterocyclic radical which contains at least one ring of aromatic character and which is bonded to the oxygen atom via a ring carbon atom, preferably of the ring of aromatic charac-ter, Rl denotes an optionally substituted aliphatic, cyclo-aliphatic or araliphatic hydrocarbon radical and R2 represents .
hydrogen or the acyl radical of an organic carboxylic acid, as well as salts thereof which can be used pharmaceutica?ly, above all corresponding acid addition salts thereof.
Carbocyclic radicals Arl of aromatic character are,above all, phenyl,:as well as optionally partially saturated bicyclic aromatic hydrocarbon radicals, such as naphthyl, for :-.
, example 1- or 2-naphthyl, 1,2,3,4-tetrahydro-benz-naphthyl, for example 1,2,3,4-tetrahydro-5-naphthyl, benz-indenyl, for example 4- or 5-indenyl, and also optionally partially saturated polycycllc aromatic hydrocarbon radicals, such as benz-fluorenyl, . .

" ,, . ~; .

.. . . .... . .. . . . .. .. . . . . .

1(~63516 for example 4-fluorenyl, partially saturated radicals of the above type being bonded to the oxygen atom via a ring carbon atom of the aromatic part .
Heterocyclic radicals Arl contain, as ring hetero-atoms, above all one or more ring nitrogen atoms as well as, preferably in addition to a ring nitrogen atom, a ring oxygen atom or ring sulphur atom. Such radicals are, in particular, monocyclic, five~membered or six-membered, mono-, di- or tri-azacyclic radicals, above all monocyclic, monoaza-cyclic, six-membered radicals of aromatic character, such as pyridyl, for example 2-, 3- or 4-pyridyl, monocyclic, diaza-cyclic, six-membered radicals of aromatic character, such as pyridazinyl, for example 3-pyridazinyl, pyrimidinyl, for example 2- or 4-pyri~idinyl, or pyrazinyl, for example 2-pyrazinyl, monocyclic, thiadiazacyclic, five-membered radicals of aromatic character, such as thiadiazolyl, for example 1,2,5-thiadiazol-3-yl, optionally partially saturated bi-cyclic, monoazacyclic radicals of aromatic character with a five-membered or six-membered heterocyclic ring, such as indolyl, for example 4-indolyl, or optionally partially saturated quinolinyl, for example 1,2,3,4-tetrahydro-5-quinolinyl, or bicyclic monothiacyclic radicals of partially aromatic character, such as 2H-thiochromenyl, for example 2H-thiochromen-8-yl..
The above radicals Arl can be unsubstituted or sub-stituted and Arl contains,above all,one, or also several, in particular two, substituents. me latter are, above all, ...

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

,r ~~ ' 3~ 16 . optionally substituted aliphatic or cycloaliphatic hydrocarbon radicals, optionally etherified or esterified hydroxyl or mercapto groups, acyl radicals, optionally functionally modlfied carboxyl groups, nitro or optionally substituted amino groups. Saturated parts of the group Arl can also contain, in addition to the abovementioned substituents, substituents which have two bonds, above all oxo.
- As substituents of the radical Arl, aliphatic hydro-carbon radicals are, in particular, lower alkyl or lower alkenyl, as well as lower alkinyl Substituents of such ~ radicals, especially of lower alkyl, as well as lower alkenyl, / are optionally etherified or esterified hydroxyl, for example .~. lower alkoxy, lower alkylthio or halogen, optionally function-ally modified carboxyl, especially optionally N-substituted carbamoyl such as N-lower alkylated carbamoyl, or optionally ~ substituted amino, especially acylamino, wherein acyl : represents the radical of an o.rganic carboxylic acid or of a carbonic acid half-derivative, as well as of an organic . sulphonic acid, such as lower alkanoylamino, lower alkoxy-carbonylamino or optionally N-substituted ureido, such as N'-;~;, lower alkylated ureido, for example ureido, N'-lower alkyl-ureido or N',N'-di-lower alkyl-ureido, and also lower alkyl-. sulphonylamino. Substituted lower alkyl radicals are, above 3 all, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylthio-lower alkyl, halogeno-lower alkyl, optionally N-.~ lower alkylated carbamoyl-lower alkyl, lower alkanoylamino-lower alkyl or lower alkoxycarbonylamino-lower alkyl, and also " , .1 . . .

- '` 1(~63~16 ~ ' .
lower alkanoylamino-lower alkenyl or lower alkoxycarbonylamino-lower alkenyl.
Cycloaliphatic hydrocarbon radicals are represented, in particular, by monocyclic and polycyclic cycloalkyl.
.~
As substituents of a radical Arl, etheri~ied hydroxyl or mercapto groups are, above all, hydroxyl or mercapto which are etherified by optionally substituted aliphatic hydro-carbon radicals, such as lower alkoxy, lower alkenyloxy or lower alkinyloxy, and also lower alkylthio or lower alkenyl-thio. Substituents of such etherifying aliphatic hydrocarbon radicals, especially of etherifying lower alkyl, are, above all, optionally etherified or esterified hydroxyl or mercapto, such as lower alkoxy, lower alkylthio or halogen, or optionally substituted amino, such as acylamino, for example lower alkanoylamino or lower alkoxycarbonylamino. Hydroxyl or mercapto etherified by correspondingly substituted aliphatic hydrocarbon radicals is, in particular, lower alkoxy-lower alkoxy, lower alkylthio-lower alkoxy or lower alkoxy-lower alkylthio and also lower alkanoylamino-lower alkoxy or lower alkoxycarbonylamino-lower alkoxy.
As substituents of groups Arl, esterified hydroxyl or mercapto groups are, above all, halogen as well as lower alkanoyloxy.
As substituents of the radical Arl, acyl groups represent, above all, lower alkanoyl.
As substituents of Arl, optionally functionally modi-fied carboxyl groups are, in particular, esterified or , .

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

. ~
.

amidated carboxyl and also cyano. Esterified carboxyl is, above all, lower alkoxycarbonyl, whilst amidated carboxyl represents optionally substituted carbamoyl, such as carbamoyl, N-lower alkyl-carbamoyl or N,N-di-lower alkyl-carbamoyl.
As substituents of groups Arl, optionally substituted amino groups are, in particular, acylamino, wherein acyl above all represen-ts the corresponding radical of an organic carboxylic acid or of a half-derivative of carbonic acid, and also of an organic sulphonic acid, such as lower alkanoylamino, lower alkoxycarbonylamino or optionally N'-lower alkylated .
ureido, for example ureido, N'-lower alkyl-ureido or N',N'-di-lower alkyl-ureido, and also lower alkylsulphonylamino as well as N-lower alkylated amino, such as N-lower alkylamino or -N,N-di-lower alkylamino, and furthermore, N,N-lower alkyleneamino, N,N-aza-lower alkyleneamino, N,N-oxa-lower alkyleneamino or N,N-thia-lower alkyleneamino, Aliphatic hydrocarbon radicals Rl are, above all, lower ..
alkyl, especially lower alkyl branched at the linking carbon, and also lower alkenyl or lower alkinyl, whilst cycloali- .
phatic hydrocarbon radicals represent, in particular, cyclo-alkyl, including polycyclic cycloalkyl, and araliphatic hydro-carbon radicals represent, above all, phenyl-lower alkyl.
Substituents of such hydrocarbon radicals are, for example for lower alkyl, etherified hydroxyl, especially phenoxy or pyridyloxy which are optionally substituted, for example by functionally modified carboxyl, such as optionally N-lower alkylated carbamoyl, for example carbamoyl, N-lower alkyl-- 8.- ~ .

. ~

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

carbamoyl, or N,N-di-lower alkyl-carbamoyl, or optionally functionally modified carboxyl, such as carboxyl and esterified carboxyl, for example lower alkoxycarbonyl, amidated carboxyl, such as optionally N-lower alkylated carbiamoyl, for exiample carbamoyl, N-lower alkyl-carbamoyl or N,N-di-lower alkyl-carbamoyl, or cyano, and, for example for the aromatic part of phenyl-lower alkyl, optionally functionally modified carboxyl, above all amidated carboxyl, such as carbamoyl,N-lower alkyl-carbamoyl or N,N-di-lower alkylcarbamoyl. Lower alkyl radicals substituted in this way are phenoxy-lower alkyl or preferably optionally N-alkylated carbamoylphenoxy-lower alkyl, and also pyridyloxy-lower alkyl or preferably optionally N-lower alkylated carbamoylpyridyloxy-lower alkyl and also lower alkoxycarbonyl-lower alkyl, optionally N-lower alkylated carbamoyl-lower alkyl or cyano-lower alkyl.
An acyl radical R2 is, above all, the corresponding radical of an organic carboxylic acid, especially lower ;
alkanoyl or benzoyl.
Unless specific data are given, the radicals and ,.~.:: : ' compounds designated "lower" in the preceding and following text preferably contain up to 7 carbon atoms, monovalent ; radicals contain above all up to 5 carbon atoms and divalent radicals contain 3 to 6, above all 4 or 5, carbon atoms.
Unless specific data are given, the general concepts j: :
used in the preceding and the following text preferably have the foIlowing meanings:
Lower al~yl is, for example, methyl, ethyl, n-propyl, ,1, .
g _ :~, ,, . , , . . . ~ ., . ., ` ., . -; ~ , .. .

lQ63S~6 :
isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl as ;~ well as n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl or ;; n-heptyl. Lower alkyl branched at the linking carbon atom is, above all, isopropyl or tert.-butyl.
~! Lower alkenyl is,above al~ allyl and also vinyl, 2- -methyl-allyl, 2-butenyl or 3,3-dimethylallyl, whilst lower -alkinyl is, for example, ethinyl or propargyl.
Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy.
i Lower alkylthio is, for example, methylthio, ethyl-thio, isopropylthio or n-butylthio.
Halogen is, for example, chlorine or bromine and also fluorine as well as iodine.
Optionally N-lower alkylated carbamoyl is, for example carbamoyl and also N-lower alkyl-carbamoyl, such as N-methyl-carbamoyl or N-ethyl-carbamoyl, or N,N-di-lower alkyl-carbamoyl, such as N,N-dimethyl-carbamoyl or N,N-diethyl-.,1 .
carbamoyl.
Lower alkanoylamino is, for example, formylamino,acetylamino, propionylamino, butyrylamino or pivaloylamino.
Lower alkoxycarbonylamino is, for example, methoxy-carbonylamino, ethoxycarbonylamino or tert.-butoxycarbonyl-amino, whilst N'-lower alkyl-ureido and N',N'-di-lower alkyl-ureido are, for example, N'-methylureido, N'-ethylureido, N',N'-dimethylureido or N',N'-diethylureido.
Lower alkylsulphonylamino is, for example, methyl-sulphonylamino or ethylsulphonylamino.

~. `

6 3~ 16 Hydroxy-lower alkyl is, for example, hydroxymethyl or l- or 2-hydroxyethyl.
Lower alkoxy-lower alkyl is, for example, lower alkoxy-methyl or, preferably, 2-(lower alkoxy)-ethyl, such as methoxy-methyl, ethoxymethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl or 2-isopropoxy-ethyl.
Lower alkylthio-lower alkyl is, for example, lower alkylthio-methyl or, in particular, 2-(lower alkylthio)-ethyl, for example methylthiomethyl, ethylthiomethyl, 2-methylthio-ethyl or 2-ethylthioethyl.
Halogeno-lower alkyl is, in particular, trifluoromethyl.
Optionally N-lower alkylated carbamoyl-lower alkyl is, ~or example, carbamoylmethyl or l- or 2-carbamoylethyl and also N-lower alkyl-carbamoyl-lower alkyl, such as N-methyl-carbamoylmethyl or l- or 2-N-methylcarbamoyl-ethyl, or N,N-di-lower alkyl-carbamoyl-lower alkyl, such as N,N~dimethyl-carbamoyl-methyl or l- or 2-N,N-dimethylcarbamoyl-ethyl.
~ ower alkanoylamino-lower alkyl is, for example, lower alkanoylaminomethyl or, pre~erably, 2-lower alkanoylaminoethyl, such as acetylaminomethyl, propionylaminomethyl, 2-acetylamino-ethyl, 2-propionylaminoethyl or 2-pivaloylaminoethyl, whilst lower alkoxycarbonylamino-lower alkyl represents, for example, lower alkoxycarbonylamino-methyl or, preferably, 2-lower alkoxycarbonylamino-ethyl, such as methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl, 2-ethoxycarbonylaminoethyl or 2-tert.-butoxycarbonylaminoethyl.
Lower alkanoylamino-lower alkenyl is, in particular, ... .
~ -- 11 --,, ; - ' : 1~a63516

2-lower alkanoylamino-uinyl, for example 2-acetylamino-vinyl, 2-propionylamino-vinyl or 2-pivaloyli~mino-vinyl, whilst lower alkoxycarbonylamino-lower alkenyl preferably represents 2-lower alkoxycarbonylamino-vinyl, such as 2-methoxycarbonylamino-vinyl, 2-ethoxycarbonylamino-vinyl or 2-tert.-butoxycarbonyl-amino-vinyl.
' Cycloalkyl, including polycyclic cycloalkyl, pre~er-ably contains 3-10 ring carbon atoms and denotes cyclopropyl or, in particular, cyclopentyl or cyclohexyl, as well as adamantyl, such as l-adamantyl.
,j Lower alkenyloxy is, in particular, allyloxy as well as 2-methylallyloxy, and also vinyloxy, 2-butenyloxy or 3,3-~s dimethylallyloxy, whilst lower alkinyloxy represents, for example, propargyloxy.
J Lower alkenylthio i.s, for example, allylthio and also 2-methyl-allylthio or 2-butenylthio.
In a lower alkoxy-lower alkoxy radical the two oXygen atoms are preferably separated by at least 2, for example by 2-3, carbon atoms; such radicals are thus, for example, ~, methoxymethoxy or ethoxymethoxy but above all 2-(lower alkoxy)-ethoxy, for example 2-methoxyethoxy or 2-ethoxyethoxy, as well as 3-(lower alkoxy)-propoxy, for example 3-methoxy-propoxy or i:! 3-ethoxy-propoxy.
!~5~ In a lower alkylthio-lower alkoxy radical the sulphur atom and the oxygen atom are preferably separated from one another by at least 2, for example by 2-3, carbon atoms; such radicals are thus,above al~ 2-(lower alkylthio)-ethoxy, for :, ~ .
,''' ~ . ;. ' '' ~ '~ ',.
-: . ' . .' ' . ' . : . . . . . ' .. . . ' ~ , ' example 2-methylthio-ethoxy or 2-ethylthio-ethoxy.
In a lower alkoxy-lower alkylthio radical the oxygen atom and the sulphur atom are likewise preferably separated from one another by at least 2, for example by 2-3, carbon atoms; such radicals are,above al~ 2-(lower alkoxy)-ethylthio, for example 2-methoxy-ethylthio or 2-ethoxy-ethylthio.
In lower alkanoylamino-lower alkoxy radicals and lower alkoxycarbonylamino-lower alkoxy radicals the nitrogen atom and the linking oxygen atom are preferably separated from one another by at least 2, for example 2-3, carbon atoms; these radicals are,above all,2-lower alkanoylamino-ethoxy, for example 2-acetylamino-ethoxy, 2-propionylamino-ethoxy or 2-pivaloylamino-ethoxy, or 2-lower alkoxycarbonylamino-ethoxy, for example 2-methoxycarbonylamino-ethoxy or 2-ethoxycarbonyl-amino-ethoxy Lower alkanoyloxy is, for example, acetyloxy, propionyl-. . . .
oxy or pivaloyloxy.
Lower alkanoyl is, in particular, acetyl, propionyl orpivaloyl.
; Lower alkoxycarbonyl is, ~or example, methoxycarbonyl, '.3 ethoxycarbonyl or tert.-butoxycarbonyl.
~-` N-Lower alkylamino and N,N-di-lower alkylamino are, for example, methylamino, ethylamino, dimethylamino or diethyl-amino.
N,N-Lower alkyleneamino preferably contains 5-7 ring !~ members and is, in particular, pyrrolidino or piperidino, whilst N,N-aza-lower alkyleneamino, N,N-oxa-lower alkyleneamino and .

.. . . ~ ~ ' ;; ' 1063516 N,N-thia-lower alkyleneamino preferably contain 6 ring members, the second ring hetero-atom being separated from the linking nitrogen atom by 2 carbon atoms and, in the N,N-aza-lower alkyleneamino radical, being optionally substituted, for example by lower alkyl; such radicals are, for example, 4-methyl-l-piperazinyl, 4-morpholino or 4-thiomorpholino, ; Phenyl-lower alkyl is, for example, benzyl or 1- or 2-phenylethyl.
Pyridyloxy is, for example, 2-pyridyloxy, ~-pyridyloxy or 4-pyridyloxy.
In a phenoxy-lower alkyl radical and pyridyloxy-lower alkyl radical Rl, which preferably contain optionally N-lower alkylated carbamoyl as substituents, the oxygen atom and the linking carbon atom bonded to the nitrogen atom are preferably separated from one another by at least 2, for example by 2-3, carbon atoms. Such substituents are, in particular, 2-(option-i , ; ally N-lower alkylated carbamoyl-phenoxy)-lower alkyl, for example 2-(2-carbamoylphenoxy)-ethyl, 2-(4-carbamoylphenoxy)-ethyl, 2-(2-N-methylcarbamoyl-phenyl)-ethyl or 2-(4-N,N-dimethylcarbamoyl-phenoxy)-ethyl, and also 2-(optionally N-lower alkylated carbamoyl-pyridyloxy)-lower alkyl, for example 2-(4-carbamoyl-2-pyridyloxy)-ethyl, 2-(2-carbamoyl-4-pyridyloxy)-; ethyl or 2-(3-carbamoyl-2-pyridyloxy)-ethyl.
~! Lower alkoxycarbonyl-lower alkyl is, for example, lower alkoxycarbonylmethyl or l-lower alkoxycarbonyl-2-propyl, for example methoxycarbonylmethyl, ethoxycarbonylmethyl, 1-~ ~ .
methoxycarbonyl-2-propyl or 1-ethoxycarbonyl-2-propyl.

.' , , - . , .. j .
. . .

c~ ,, . ., . -. ~. , . . "

1(~63516 ~`

Optionally N-lower alkylated carbamoyl-lower alkyl is, above all, carbamoylmethyl and also N-lower alkylcarbamoyl-methyl or N,N-di-lower alkylcarbamoyl-methyl, for example N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N,N-dimethyl-carbamoylmethyl or N,N-diethylcarbamoylmethyl, as well as 1-carbamoyl-2-propyl and also l-N-lower alkyl-carb~moyl-2-'A propyl or l-N,~-di-lower alkyl-carbamoyl-2-propyl, for example l-N-methylcarbamoyl-2-propyl, 1-N-ethylcarbamoyl-2-propyl, 1-N,N-dimethylcarbamoyl-2-propyl or 1-N,N-diethylcarbamoyl-2 propyl.
Cyano-lower alkyl is, for example, cyanomethyl or 1-cyano-2-propyl, In the compounds of the ~ormula I, the group Arl preferably denotes naphthyl, ~or example l-naphthyl, fluorenyl, . for example 4-fluorenyl, indolyl, for example 4-indolyl, 2~-thio-chromenyl, for example 2H-8-thiochromenyl, lower alkyl-phenyl, such as methyl-phenyl, for example 2- or 3-methyl-phenyl, halo-geno-lower alkyl-phenyl, such as chloromethyl-phenyl, ~or example 2-chloro-5-methyl-phenyl, lower alkenyl-phenyl, such as allyl-.,, phenyl, for example 2-allylphenyl, lower alkinyl-phenyl, such as ethinyl-phenyl, for example 2-ethinyl-phenyl, cycloalkyl-phenyl, for example 2-cyclopropyl-phenyl or 2-cyclopentyl-phenyl, hydroxy-lower alkyl-phenyl, for example 2-hydroxymethyl-phenyl, lower alkoxy-lower alkyl-phenyl, such as lower alkoxymethyl-phe-nyl or (2-lower alkoxy-ethyl)-phenyl, for example 2-methoxy- -methyl-phenyl or 4-(2-methoxyethyl)-phenyl, carbamoyl-lower alkyl-phenyl, for example carbamoyimethyl-phenyl, lower alkoxy-~ , ~s - 15 ,, .
,. . .

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

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

i3~:16 :- carbonylamino-lower alkyl-phenyl, such as (2-lower alkoxy-carbonylamino-ethyl)-phenyl, for example 4-(2-methoxycarbonyl-amino-ethyl)-phenyl, halogeno-lower alkoxycarbonylamino-lower ~:.alkyl-pyridyl, for example 3-chloro-4-(2-methoxycarbonylamino-- ethyl)-2-pyridyl, lower alkoxycarbonylamino-lower alkenyl-phenyl, especially (2-lower alkoxycarbonylamino-vinyl)-phenyl, :; for example 4-(2-methoxycarbonylamino-vinyl)-phenyl, lower ~ alkoxy-phenyl, such as methoxyphenyl, for example 2-methoxy-; phenyl, lower alkenyloxy-phenyl, such as allyloxy-phenyl, for : example 2-allyloxy-phenyl, or methallyloxy-phenyl, ~or example ;- 2-(2-methylallyloxy)-phenyl, lower alkinyloxy-phenyl, such as . propargyloxy-phenyl, for example 2-propargyloxy-phenyl, lower alkylthio-lower alkoxy-phenyl wherein the sulphur atom is ; separated from the oxygen atom by 2-3 carbon atoms, such as (2-lower alkylthio-ethoxy)-phenyl, for example 4-(2-methyl-thio-ethoxy)-phenyl, lower alkylthio-phenyl, such as m~thyl-. thio-phenyl, for example 2-methylthiophenyl, halogeno-phenyl, ` such as chlorophenyl, for example 2-chlorophenyl, lower alkanoyl-lower alkanoylamino-phenyl, for example 2-acetyl-4-. n-butyrylamino-phenyl, cyano-phenyl, for example 2-cyano-, . . .
. phenyl, lower alkanoylamino-phenyl, such as acetylamino-, phenyl, for example 4-acetylamino-phenyl, lower alkylsulphonyl-amino-phenyl, for example 4-methylsulphonyl~no-~eny1,(1-py ~ ~-phenyl, for example 2-(1-pyrryl)-phenyl, morpholinothia-diazolyl, for example 4-morpholino-1,2,5-thiadiazol-3-yl, .
~`4 oxo-5,6,7,8-tetrahydro-benz-naphthyl, for example 5-oxo-5,6,7,8-tetrahydro-1-naphthyl, or oxo-1,2,3,4-tetrahydro-benz-,. . ..
, ~.
~ . - 16 -.. : .

. .A
1,:' ' :~' ' ' .' '' ' ' ,. .' '.' .' ., " . ` ., ,, . . ' ' ' ~ . . '' ' ,' ,'.' , 1~i63~16 quinolyl, for example 2-oxo-1,2,3,4-tetrahydro-5-quinolinyl, R2 represents, in particular, hydrogen or lower alkanoyl, for example acetyl or pivaloyl, and Rl is, above all, lower alkyl, especially lower alkyl branched at the linking carbon, for example isopropyl or tert.-butyl, and also carbamoylphenoxy-lower alkyl, such as 2-carbamoylphenoxy-lower alkyl, for example 2-(4-carbamoyl-phenoxy)-ethyl.
Compounds with beta-receptor-blocking properties, of the above ~
~ formula I, zre, above all, the following compounds in which lower alkyl Rl is , .1 ~, branched at the linking carbon atom: l-(naphthyloxy)-3-lower alkylamino-2-,..;1 propanol, for example 3-isopropylamino-1-(1-naphthyloxy)-2-propanol, l-(benz-fluorenyloxy)-3-lower alkylamino-2-propanol and the corresponding O-esters ; thereof with lower alkanecarboxylic acids, for example 1-(4-fluorenyloxy)-3-~ isopropylamino-2-propanol or 3-tert.-butylamino-1-(4-f1uorenyloxy)-2-pivaloyloxy-;~, propane, l-(benz-indolyloxy)-3-lower alkylamino-2-propanols, for example ~ 4-indolyloxy)-3-isopropylamino-2-propanol, 3-lower alkylamino-1-(2H-benz-;~ thiochromenyloxy)-2-propanols, for example 3-tert.-butylamino-1-(2H-thiochromen-8-yloxy)-2-propanol, 3-lower alkylamino-l-(lower alkyl-phenoxy)-2-propanols wherein the phenyl ratical can adtitionally be substituted by halogen, for example 3-isopropylamino-1-(3-methyl-phenoxy)-2-propanol, 1-(2-chloro-S-methyl-phenoxy)-3-isopropylamino-2-propanol or 2-tert.-butylamino-1-~2-chloro-5-methyl-, ~ phenoxy)-2-propanol, 7,'~
,: :'i ' ' ',J'-,,~.

: .
' ~ . ' 1(~63S16 phe~yl)~ p~4~a~e~ (lower alkenyl-phenoxy)-3-lower alkylami-no-2-propanols, for example 1-(2-allyl-phenoxy) 3-isopropylami-no-2-propanol, l-(lower alkinyl-phenoxy)-3-lower alkylamino-2-propanols, for example 1-(2-ethinyl-phenoxy)-3-isopropylamino-2-propanol, 1-(cycloalkyl-phenoxy)-3-lower alkylamino-2-pro-panols, for example 1-(2-cyclopropyl-phenoxy)-3-isopropyl-amino-2-propanol or 3--tert.-butylamino-1-(2-cyclopentyl-. phenoxy)-2-propanol, l-(hydroxy-lower alkyl-phenoxy)-3-lower ^ alkylamino-2-propanols, for example 1-(2-hydroxymethyl-phenoxy)-

3-isopropylamino-2-propanol, l-(lower alkoxy-lower alkyl-phenoxy)-3-lower alkylamino-2-propanols, for example 3-iso-propylamino-1-(2-methoxymethyl-phenoxy)-2-propanol, 3-tert.-~i butylamino-1-(2-methoxymethyl-phenoxy)-2-propanol or 3-iso-~ propylamino-1-[4-(2-methoxyethyl)-phenoxy~-2-propanol, 1-j (carbamoyl-lower alkyl-phenoxy)-3-lower alkylamino-2-propanols, . for example 1-(4-carbamoylmethyl-phenoxy)-3-isopropylamino-2-propanol, l-(lower alkoxycarbonylamino-lower alkyl-phenoxy)-3-lower alkylamino-2-propanols, for example 3-isopropylamino-1-i~ [4-(2-methoxycarbonylamino-ethyl)-phenoxy~-2-propanol, 1- :
1 (halogeno-lower alkoxycarbonylamino-lower alkyl-pyridyloxy)-3-lower alkylamino-2-propanols, for example 3-t3-chloro-4-(2-methoxycarbonylamino-ethyl)-2-pyridyloxy]-3-isopropylamino-2-propanol, l-(lower alkoxy-phenoxy)-3-lower alkylamino-2-propa-nols, for example 3-isopropylamino-1-(2-methoxy-phenoxy)-2-propanol, l-(lower alkenyloxyphenoxy)-3-lower alkylamino-2-pro-panols, for example 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol, 1-(2-allyloxy-phenoxy)-3-tert.-butylamino-2-propanol , . . . .
. - 18 -.... , , ,~ . . .... .
.~ - - .. ..

,j~ . . . .
, ; ~ , . .,. ~. .
: ' . !, , .. . . . . , ' .
:. ~ . ' , '' ' ,, , ' ' , ' ' " , ' ' 1063~

or 3-isopropylamino-1-(2-methylallyloxy-phenoxy)-2-propanol, 1-(lower alkinyloxy-phenoxy)-3-lower alkylamino-2-propanols, for example 3-isopropylamino-1-(2-propargyloxy-phenoxy)-2-propanol, 3-lower alkylamino-l-(lower alkylthio-lower alkoxy-phenoxy)-2-propanols, wherein ~he sulphur atom is separated from the oxygen atom by 2-3 carbon atoms, for example 3-isopropylamino-1-[4-(2-methylthioe~thoxy)-phenoxy]-2-propanol, l-(halogeno-phenoxy)-3-lower alkylamino-2-propanols, ~or example 3-tert -butylamino-1-(2-chloro-phenoxy)-2-propanol, 1- .
(lower alkylthio-phenoxy)-3-lower alkylamino-2-propanols, for example 3-isopropylamino-1-(2-methylthio-phenoxy)-2-propanol, l-(lower alkanoyl-lower alkanoylamino-phenoxy)-3-lower alkyl-amino-2-propanol, ~or example 1-(2-acetyl-4-n-butyrylamino-phenoxy)-3-isopropylamino-2-propanol, 1-(cyano-phenoxy)-3-lower alkylamino-2-propanols, for example 3-tert.-butylamino-1-(2-cyano-phenoxy)-2-propanol or 1-(2-cyano-phenoxy)-3-iso-propylamino-2-propanol, l-(lower alkanoylamino-phenoxy)-3- .
lower alkyla~ino-2-propanols, for example 1-(4-acetylamino-phenoxy)-3-isopropylamino-2-propanol, 3-lower alkylamino-l-(lower alkylsulphonylamino-phenoxy)-2-propanols, for example 3-isopropylamino-1-(4-methylsulphonylamino-phenoxy)-2-propanol, l-(morpholino-thiadiazolyloxy)-3-lower alkylamino-2-propanol, for example 3-isopropylamino-1-t4-morpholino-1,2,5-thiadiazol-3-yloxy)-2-propanol, 3-lower alkylamino-1-(oxo-5,6,7,8-tetra-hydro-benz-naphthyloxy)-2-propanols, for example 3-isopropyl-amino-1-(5-oxo-5,6,7,8-tetrahydro-1-naphthyloxy)-2-propanol, or 3-lower alkylamino-1-(oxo-1,2,3,4-tetrahydro-benz-quinolinyl-.
.
.

~ - .
, la63sl~
: oxy)-2-propanols, for example 3-isopropylamino-1-~2-oxo-1,2,3,

4-tetrahydro-5-quinolinyloxy~-2-propanol or 3-tert.-butylamino-1-(2-oxo-1,2,3,4-tetrahydro-5-quinolinyloxy~-2-propanol, and acid addition salts thereof which can be used pharmaceutically.
-A further group of beta-receptor-blocking compounds can be represented by the formula ; 0-R2 3 .~ Ar2 CH - CH - NH R (II) .< :

wherein Rl and R2 have the abovementioned meanings, Ar2 represents a monocyclic or polycyclic, carbocyclic radical :~: :
which contains at least one ring of aromaticcharacter and R3 tenotes hytrogen or lower alkyl, ant also comprises the salts thereof which can be used pharmaceutically, above all the cor-responting acit attition salts thereof.
A carbocyclic ratical Ar2 of aromatic character has, for example, the meaning inticated above for the group Arl ant is, above all, phenyl, as well as an optionally partially ,j :
l saturated, bicyclic, aromatic hytrocarbon radical, such as .
naphthyl, for example 1- or 2-naphthyl, 1,2,3,4-tetrahytro-benz-naphthyl, or benz-intanyl, for example 4- or 5-intanyl, and such raticals can be substitutet, for example like the corresponting groups Arl, ant contain, above all, halogen, ) .'':
l - 2Q -. ' ".' 1. ~ ' ' , . ' ' ': .: ' , s~ :

lower alkyl, lower alkoxy, lower alkylsulphonylamino and/or nitro, for example the corresponding substituents described above.
A group Rl in the above compounds of the formula II
is, above all, lower alkyl, especially lower alkyl branched at the linking carbon atoms, above all isopropyl or tert.-butyl.
In addition to hydrogen, R2 also represen-ts lower alkanoyl, for example acetyl or pivaloyl The radical R3 denotes hydrogen or lower alkyl, especially methyl.
; In the above compounds of the formula II, Ar2 repre-sents, for example, naphthyl, for example l-naphthyl, lower alkoxy-phenyl, for example 2,5-dimethoxy-phenyl, halogeno-phenyl, for example 3,4-dichlorophenyl, nitrophenyl, for - example 4-nitrophenyl, lower alkylsulphonylamino-phenyl, for example 4-methylsulphonylamino-phenyl, carbamoyl-hydroxy-phenyl, for example 4-carbamoyl-3-hydroxyphenyl, or 1,2,3,4-r tetrahydro-benz-naphthyl, for example 1,2,3,4-tetrahydro~5-~i naphthyl, Rl denotes, above all, lower alkyl branched at the ;i! linking carbon atoms, for example isopropyl or ter-t -butyl, R2 is, in particular, hydrogen and R3 represents, above all, hydrogen or methyl.
~ Compounds of the above structural formula II which have :;! beta-receptor-blocking properties are, above all, the follow-ing compounds in which lower alkyl Rl is branched at the linking carbon atom: l-(naphthyl)-2-lower alkylamino-ethanols, for example 2-isopropylamino-l-(1-naphthyl)-ethanol, -. . .

, ~63S~6 l-(lower alkoxyphenyl)-2-lower alkylamino-ethanols, for .example 2-tert.-butylamino-1-(2,5-dimeth~xy-phenyl)-ethanol, l-(halogenophenyl)-2-lower alkylamino-ethanols, for example ~ 1-(3,4-dichlorophenyl)-2-isopropylamino-ethanol, 2-lower alkyl-., amino-l-(nitrophenyl)-2-propanols, for example 2-isopropyl-. amino-1-(4-nitrophenyl)-propanol, 2-lower alkylamino-l-(lower alkylsulphonylamino-phenyl)-ethanols, for example 2-isopropyl-amino-1-(4-methylsulphonylamino-phenyl)-ethanol, l-(carbamoyl-hydroxyphenyl)-2-lower alkylamino-ethanols, for example 1-(4~
. carbamoyl-3-hydroxyphenyl)-2-isopropylamino-ethanol or 1-(4-carbamoyl-3-hydroxyphenyl)-2-tert.-butylamino-ethanol, 2-lower alkylamino-1-(1,2,3,4-tetrahydro-benz-naphthyl)- ~
ethanols, for example 2-tert.-butylamino-1-(1,2,3,4-tetrahydro-

5-naphthyl)-ethanol,and acid addi-tion salts thereof which can be used pharmaceutically.
. Compounds with throm~yte-function-regulating properties .j which may be mentioned are O-acetyl-salicylic acid, or salts ~ thereof with bases, which can be used pharmaceutically, and 2,6-bis-[di-(2-hydroxyethyl)-amino3-4,8-di-piperidino-pyrimido[5,4-d3pyrimidine (dipyramidol) or acid addition salts thereof which can be used pharmaceutically.
Above all, compounds of the formula ~` . .
.~ N . (III) ,j , Ph2 C_ O
0 ~ C - Cl~ llc- S()n - Ph3 ~ - 22 -.. . .
; : .
,~

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

~0635~6 , ~:
wherein each of the radicals Phl and Ph2 independently of one another represents a phenyl radical which is optionally sub- :
stituted by lower alkyl, for example methyl, hydroxyl, lower alkoxy, for example methoxy, andtor halogen, especially fluorine, chlorine or bromine, Alk denotes a lower alkylene :
radical which separates the sulphur atom from the ring carbon atom by at least 2 carbon atoms, n represents 0, 1 or 2 and Ph3 :
represents a phenyl radical which is optionally substituted by lower alkyl, for example methyl, lower alkoxy, for example methoxy, and/or halogen, for example fluorine, chlorine or bromine, and salts of such compounds with bases, which can be used pharmaceutically, exhibit pronounced thrombocyte-function-regulating properties, there being no influence or only an insignificant influence on the blood coagulation time.
Lower alkylene Alk in the above compounds preferably contains up to 4 carbon atoms and is, for example, 1- or 2-methyl-1,2-ethylene, 1,3-propylene, 2-methyl-1,3-propyl~ne, 1,4-butylene and, above all, 1,2-ethylene.
The thrombocyte-function-regulating properties are particularly pronounced in compounds of the formula III wherein one of the radicals Phl and Ph2 denotes phenyl or hydroxy-phenyl, especially 4-hydroxy-phenyl, and the other denotes phenyl or lower alkyl-phenyl, especially 3-methyl-phenyl, Alk represents lower alkylene wi-th up to 4 carbon atoms, which separatesthe sulphur atom from the ring nitrogen atom by 2 to 4 carbon atoms, especially 1,2-ethylene, n denotes 0, 1. or 2, especially 1, and Ph3 represents phenyl, and salts of such '~` 1063S16 . ' ,. .
comp~unds with bases, which can be used pharmaceutically 1,2-Diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine and 1-(4-hydroxy-phenyl)-2-phenyl-4-(2-phenyl-sulphinyl-ethyl)-3,5-dioxo-pyrazolidine, and salts of these - compounds with bases, which can be used pharmaceutically, are - mentioned in particular as preferred compounds with platele-t-function-regulating properties.
Compounds with alpha-receptor-blocking properties, hich are optionally added to the combination, according to the invention, of a beta-receptor-blocking active compound and an active compound which regulates the thrombocyte function, are, i in particular, hydrogenated ergot alkaloids, for example dihydroergotamine, dihydroergocornine, dihydroergocristine or dihydroergocryptine or mixtures thereo~, as well as acid addition salts thereo~ which can be used pharmaceutically, and also N-benzyl-N-halogeno-lower alkylamines, ~or example N,N-dibenzyl-N-(2-chloroethyl)-amine or N-benzyl-N-(2-chloroethyl)-N-(1-methyl-2-phenoxy-ethyl)-amine, 2-tert.-aminomethyl-benzo-dioxanes, for example 2-piperidinomethyl-benzodioxane or 1,4-l bis-(2-benzodioxanylmethyl)-piperazine, N-substituted dibenz-j azepines, for example 6-allyl-6,7-dihydro-5H-dibenz[c,e]aze-pine, or, in particular, methyl-2-imidazolines which are sub-, stituted in the 2-position, such as 2-benzyl-imidazolines and, I above all, 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-amino-methyl]-2-imidazoline, as well as pharmaceutically usable acid addition salts of such compounds.
Acid addition salts, which can be used pharmaceutically, J

.

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

of the abovementioned compounds are those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulphuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example acetic acid, propionic acid, glycollic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenxoic acid, .
.............. 2-acetoxy-benzoic acid, embonic acid, nicotinic acid or iso-nicotinic acid, or organic sulphonic acids, for example methanesulphonic acid, ethanesulphonic acid, Z-hydroxy-ethane-i~ sulphonic acid, ethane-1,2-disulphoni.c acid, benzenesulphonic acid, 4-methylbenzenesulphonic acid or naphthalene-2-sulphonic acid.
Sal~s of the abovementioned compounds with bases are, above all, m~tal salts or ammonium salt~, such as alkali m~tal salts and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, possible bases . for salt formation being, above all, aliphatic, cycloaliphatic, .............. cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary monoamines, diamines or polyamines, as well as he-tero-,! cyclic bases, suc~l as lower alkylamines, for example triethyl-amine, hydroxy-lower alkylamines, for example 2-hydroxyethyl-amine, bis-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)-amine, basic aliphatic esters of carboxylic acids, for example ' 4-aminobenzoic acid 2-diethylamino ethyl ester, lower alkylene-`i -- 25 --.~

~3~6 amines, for example l-ethyl-piperidine, cycloalkylamines, for example dicyclohexylamine, or benzylamines,for example N,N'-dibenzyl-ethylenediamine, and also bases of the pyridine type, .. . .
for example pyridine, collidine or quinoline.
The abovementioned compounds, which contain centres of asymmetry, can be used in the form of mixtures of isomers, especially of racemates, or in the forrn o~ pure isomers, especially of optically active antipodes.
The invention relates in particular to pharmaceutical preparations which contain a beta-receptor-blocking compolmd, especially one of those mentioned above, together with a com-pound which regulates the thrombocyte-function, especially one of those mentioned above, and optionally an alpha-receptor-blocking compound, especially one of those mentioned above, as well as the manufacture of these preparations, and also the use of the above combination of active compounds in the form of the said preparations for the prophylactic and therapeutic treat-ment of coronary heart diseases, such as angina pectoris, coronary insufficiency or cardiac infarction.
The invention relates in particular to the new pharmaceutical preparations which contain 3-isopropylamino-1-(l-naphthyloxy)-2-propanol, 3-isopropylamino-3-(3-methyl-phenoxy)-2-propanol, 1-(2-allyl-phenoxy)-3-isopropylami.no-2-propanol, 1-(4-acetylamino-phenoxy)-3-isopropylamino-2-propanol, 1-(4-indolyloxy)-3-isopropylamino-2-propanol, 3-isopropylamino-1-[4-(2-methoxyethyl)-phenoxy]-2-propanol, 3-isopropylamino-1-[4-(2-methylthioethoxy)-phenoxy]-2-propanol, .
~ - ~ - 26 -~, .

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

. . . . .. ... .
. .

.
1-[2-(3,4-dimethoxyphenyl)-ethylamino]-3-~3-methyl-phenoxy)-2-propanol, l-isopropylamino-3-(1,2,3,4-tetrahydro-1,4-ethano-5-naphthyloxy)-2-propanol, ,. .
l-tert.-butylamino-3-(1,2,3,4-tetrahydro-2,3-dihydroxy-5-naphthyloxy)-2-propanol, 1-(7-indenyloxy)-3-isopropylamino-2-propanol, 1-(7-indanyloxy)-3-isopropylamino-2-propanol, 1-(5-methyl-8-cumaryloxy)-3-isopropylamino-2-- propanol or 4-(3-isopropylamino-2-hydroxy-1-propyloxy)-2-methyl-indole, . . .
:::

;?~

.'', : ..
-.'.:

,,:

d .~ .
.; : .'.' ,.i ~,~ . . .
:: :
,j -. . .
,~

.
., ~ . '.

~ 26a-~!

or, above all, 1-(2-allyloxy-phenoxy)-3-isopropylamino~2-pro-panol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component and 2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-pyrimido[5,4-d]pyrimidine, or an acid addition salt thereof which can be used pharmaceutically, but especially 1-(4-hydroxy-phenyl)-2-phenyl-4-(2-phenylsulphinyl-ethyl)-3,5-clioxo-pyrazolidine or, above all, 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a salt thereo~ with a base, which can be used pharmaceutically, as the component w~lich regulates the thrombocyte-function, as well as 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline, or an acid addition salt thereof which can be used pharma-ceutically, as the alpha-receptor-blocking component which is optionally added.
The invention relates above all to the new pharrnaceutical preparations which contain 1-(2-allyloxy-phenoxy)-3-isopropyl-amino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombo-cyte-function, and which can optionally contain 2-[N-(3-hydroxyphenyl)-N-(4-methyl-phenyl)-aminomethyl~-2-imidazoline, or an acid addition salt thereof which can be used pharmaceuti-cally, as the alpha-receptor-blocking component, and which, because of their low degree of side effects, are particularly . .
., .. 27 ,, ,~
., ,~ , , . .: .. , . . :
,i .: ~ - . .:
~.

... . . . . . . . .

1(~635i6 . .
suitable ~or the treatment of coronary heart diseases.
Further preferred pharmaceutical preparations according to the present invention are those which contain 3-isopropyl-amino-l [4-(2-methoxy-ethyl)-phenoxy~-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the be-ta-receptor-blocking component, and 1,2-diphenyl-4-(2--. phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a sa].t thereof with a base, which can be used pharmaceu-tically, as the com~
ponent which regulates the thrombocyte function, or which contain ~-isopropylamino-1~(3-methylphenoxy)-2-propanol, or an acid addition salt thereof which can be used pharmaceuti.cally, as the beta-receptor-blocking component, and 2,6-bis-[di-(2-hydroxy-ethyl)-amino~-4,8-di-piperidinopyrimido[5,4-d~pyrimidine, or an acid addition salt thereof which can be used pharmaceuti-I cally, as the component which regulates the thrombocyte I function, or which contain 1-(4-indolyloxy)-3-i~opropylamino-2-propanol, or an acid addition salt -thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and ' O-acetyl-salicylic acid, or a salt thereof with a base, which can be used ph~rmaceutically, as the component which regulates the thrombocyte function, or which contain 1-(4-indolyloxy)-3-isopropylamino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-~3 blocking component, and 1,2-diphenyl-4-(2-phenylsulphinyl-~ ethyl)-3,5-dioxo-pyrazolidine, or a salt thereof with a b~se, ',3 which can be used pharmaceutically, as the component which .~! regulates the thrombocyte function.

' ~ - 28 -~ .

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

~ ~)63S~6 -A further subject of the presen-t invention is the use, for the treatment of coronary heart diseases,.of pharmaceutical preparations which contain a beta-receptor-blocking compound, :. such as one of the abovementioned compounds, especially one of the compounds with this type of action designated above as ~eing pre~erred, above all 1-(2-allyloxy-phenoxy)-3-isopropyl-amino-2-propanol or an acid addition salt thereof which can be used pharmaceutically, and a compound which regulates the thrombocyte func-tion, such as one of the abovementioned com-pounds, especially one of the compounds with this type of action designated above as being preferred, above all 1,2-di-phenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or . a salt thereof with a base, which can be used pharmaceutically, and optionally, an alpha-receptor-blocking compound, such as one o~ the abovementioned compounds, especially one of the compounds with this type o~ action design~ted above as b~i.ng . preferred, above all 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline, or an acid additlon salt thereof which can be used pharmaceutically, as the pharmaceu-tical active components.
~. Further pharmaceutical preparations which may be . mentioned as being preferably suitable, within the scope of .i the present invention, for the treatment of coronary heart dis-eases are those which contain 3-isopropylamino-1-[4-(2-methoxyethyl)-phenoxy]-2-propanol or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and 1,Z-diphenyl-4-(2-phenyl-;~ - 29 -.

1~)63516 sulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, as the componen-t which regulates the thrombocyte function, or those which contain . 3-isopropylamino-1-(3-methylphenoxy)-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-bloc.king component, and 2,6-bis-~di-(2-hydroxyethyl)-amino]-4,~-di-piperidinopyrimido~5,4-d]pyrimidine, or an acid addition salt thereof which can be used pharmaceuti-cally, as the component which regulates the thrombocyte function, or those which contain 1-(4-indolyloxy)-3-isopropyalm.ino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and O-acetylsalicylic acid, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombocyte function, or which contain l-(L~-indolyloxy)-3-isopropylamino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking componen-t, and 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a salt thereof with a base, d , which can be used pharmaceutically, as the component which regulates the thrombocyte function.
In the new pharmaceutical preparations, the ratio of the beta-receptor-blocking compound to the compound which regulates the thrombocyte function, as well as to the alpha-receptor-blocking compound which is optionally present, can vary within wide limits. In general, a ratio of about 1:1 to about 1:50 (by weight) of the beta-receptor-blocking ,~ , . ..
. - 30 -.

:
` I063~16 active compound to the active compound which regulates the thrombocyte f~mction, especially an active compound of th~
type of the structural formula III, and a ratio of about 1:0.1 to 1:1 (by weight~ of the beta-receptor-blocking active compoun~ to the alpha-receptor-blocking active compound, which is optionally present, are preferred.
The absolute dosage of the active components in the new pharmaceutical prepara-tions also varies greatly and depends, above all, on the individual degree of response to the active components to be used according to the invention. In general, the new preparations contain from about 0.002 g to about 0.3 g, preferably from about 0.005 g to about 0.2 g,of the beta-receptor-blocking active compound and from about 0.2 g to about 1.0 g, preferably from about 0.~ g to about 0.8 g, of an active compound which regu~ates the thrombocyte func-tion, especially of an active compound of the structural formula III, and optionally from about 0.005 g to abou~ 0.2 g, preferably from about 0.01 g to about 0.1 g, of an alpha-receptor-blocking active compound.
' - Thus, the preferred pharmaceutical preparations contain from about 0.02 g to about 0.25 g, preferably from 0.04 g to about 0.2 g, of 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol, or of an acid addition salt thereof which can be used pharmaceutically, and from about 0.2 g to about 1.0 g, preferably from about 0.4 g to about 0.8 g, of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or of a ~alt thereof with a base, which can be used pharmaceutically, and i... ~... , ,,, , ~ . ....... .. . ,. ,., .. .. .. ,...... - ~ ... .. . . .. .
, , , , , : , . , ,,, ~ -.. . , . : . , .:

; .. .:. .. . . . . . .. . :, .... . - . . ., . . . ~,.... . . . ... .
. . . . . .. .: . . , ,: ,....... .. , - ., . . : .. . . -~` optionally, abou-t 0.005 g to about 0.2 g, preferably from about 0.01 g to about 0.1 g, of 2-[N-(3-hydroxyphenyl)-N-(4-.,,~
methyl-phenyl)-aminomethyl~-2-imidazoline, or of an acid addition salt thereof which can be used pharmaceutically.
Further preferred pharmaceutical preparations according to the present invention con-tain from about 0.02 g to about 0.25 g, preferably from 0.05 g to about 0 150 g, of 3-isopropyl- -amino-1-[4-(2-methoxyethyl)-phenoxy]~2-propanol, or of an acid addition salt thereof which can be used pharmaceutically, and from about 0.2 g to about 1.0 g, preferably from about 0.4 g to about 0.8 g, of 1,2-diphenyl-4-(2~phenylsulphinyl-ethyl)-3,5-; dioxo-pyrazolidine, or of a salt thereof with a base, which ... .
can be used pharmaceutically, or from about 0.050 g to about ` 0.250 g, preferably from about 0.060 g to about 0.150 g, of 3-isopropylamino-1-(3-methyl-phenoxy)-2-propanol, or of an acid `::
~: addition salt thereof which can be used pharmaceutically, and from about 0.020 g to about 0.2 g, preferably from about 0.050 g to about 0.150 g, of 2,6-bis-[di-(2-hydroxyethyl)-} amino]-4,8-di-piperidino-pyrimido[5,4-d~pyrimidine, or of an i acid addition salt thereof which can be used pharmaceutically, ~; or from about 0.005gbD about 0.080 g, preferably from about 0.015 g to about 0.050 g, of 1-(4-indolyoxy)-3-isopropylamino-2-propanol, or of an acid addition salt thereof which can be . used pharmaceutically, and from about 0.7 g to about 2.0 g, ~ preferably from about 1.0 g to about 1.5 g, of 0-acetyl-; salicylic acid, or of a pharmaceutically acceptable salt ..... .
~ thereof with a base, or from about 0.005 g to about 0.080 g, . .
~ ~. 32 .
,1 .

, . ` ., . .. .~ . ~ . . ~ ... . .. .. . .. . .. .
.~ , ........ ... ..... .... . ... .. .. ... . . . . .

. ~ , . . . . ., . , . ~ . . . . ... . .

~ 63~16 preferably from about 0.015 g to abou-t 0.050 g, of 1-(4-indolyloxy)-3-isopropylamino-propanol, or of an acid addition salt thereof which can be used pharmaceutically, and from about 0.1 g to about 1.0 g, preferably from about 0.2 g to about 0.8 g, of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or of a pharmaceutically acceptable salt thereof wi-th a base.
In addition to the pharmacological active compounds, the new pharmaceuticalpreparationsusually contain suitable excipients and auxiliaries ~Jhich facilitate processing of the active compound to give the preparations which can be used pharmaceutically.
Preferably, the preparations, above all preparations which can be administered orally and which can be used for the pre~erred type of administration, such as tablets, dragees and capsules, and also preparatlons which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 20% to 100%, preferably from about 50% to about 90%, of active compound together with the excipient.
The pharmaceutical preparations of the present inven-tion are manufactured in a manner which is in itself known, for example by means of conventional mixing, granulating, dragee-making, dissolving or lyophilising processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, option-ally granulating a resulting mixture and processing the mix-.

~ - 33 -',',' .

.. . . . . . . . .: ,. . . . . ...... . . :. -" ' ' . ' . ' ~ ' '. ' ' ' '`, " . ~ 1 ' ' ' ' . ' ' ' ' - ' ' . ' ' -- -- --- 1063~16 ,, .:
ture or granules, after adding suitable auxiliaries if desired or necessary, to give tablets or dragee cores.
Suitable excipients are, in particular, fillers, such : as sugars, for example lactose or sucrose, mannitol or sorbitol, -:
cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosp~late, as well as `~
binders, such as starch paste using, for example, maize starch, wheat starch, rice starch or potato starch, gelatine, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/
or, if desired, disint~ra~g agents, such as the abovementioned starches, and also carboxymethyl-starch, cross- ~
y linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above 1 all, flow-regulating agents and lubricants, ~or example silica, i talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. DraKée cores are provided with suitable coatings, which, if desired, are resistant to gastric juices, and for this purpose, inter ~ alia, concentrated sugar solutions, which optionally contain ;1 gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol ~ and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, in order to manufacture .i coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. The ~, period of action of one or more components which in themaelves - 34 - :
... . . .

, ., , . . . ., . . . , . ~

.. ~ , . . . . . .

lV63S16 have ac-tions of short duration can be prolonged by incorpora-ting one or more active compounds into a suitable excipient which effects slow release of the active compound or acti~e compounds Dyestuffs or pigments can be added to the tablets or dragee coatings, for example for identification or in order to characterise different combinations of active compound doses.
Other pharmaceutical preparations which can be used orally are push fit capsules made of gelatine, as well as i~ soft, sealed capsules made of gelatine and a plasticiser, such as glycerol or sorbitol. The push-fit capsules can contain the active compoundsin the form of granules, for example mixed with fillers, such as lac-tose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, ~7 optionally, stabilisers. In soft capsules, the active com-pounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid para~in or liquid poly-ethylene glycols, it also being possiblè to add stabilisers.
Possible pharmaceutical preparations which can be used rectally are, for example, suppositories, which consist of a combination of the active compoundswith a suppository base.
Suitable suppository bases are, for example, natural or syn-thetic triglycerides, paraf~in hydrocarbons, polyethylene glycols or higher alkanols. In addition, it is also poss-ible to use gelatine rectal capsules which consist o~ a , combination of the active compounds with a base; possible base materials are, for example, liquid triglycerides, polyethylene ::

., , .

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

glycols or paraffin hydrocarbons.
- Suitable formulations for parenteral administration are, above all, aqueous solutions of the active compounds in a water-soluble form, for example in the form of water-soluble . . .
salts, and also suspensions of the active compounds, such as appropriate oily injection suspensions, for which suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example .
ethyl oleate or triglycerides, are used, or aqueous injection suspensions, which contain substances which increase the ~is-cosity, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also contain stabilisers.
The examples which follow illustrate the invention described above; however, they are not intended to restrict the scope of the invention in any way.
Example 1:
Lacquer--coated tablets containing 0.08 g of 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride and 0.3 g of 1,2--diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine can be manufactured as follows:
, .
Com~osition (for one tablet) - ( 2-allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride 0.080 g 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine 0.300 g .
maize starch 0.088 g colloidal silica 0.020 g "
~ 36 , .
.~ ,.,, :
~ . .

, .. .. . . ... ..... . .. . .. . . .. . . . . . . .. . .
`,' `'` ' ': ' : ' ' ' " . ' ,~ '.' '' ' . ~' " " . ' , ~ , . , . - . , : ~
- '' : ': ' . . ' . ~ '; ' .: , , ' ' '- ~ ' . :' ' , ' . :-, ,, 1~63516 magnesium s-tearate 0.002 g stearic acid 0.005 g sodium carboxymethyl starch 0.025 g water q.s.
.j , , The lacquer-coated tablets are manufactured as follows (for 10,000 tablets):
A mix-ture of 800 g of 1-(2-allyloxy-phenoxy)-3-iso-propylamino-2-propanol hydrochloride, 3,000 g of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, ~00 g o~
maize starch and 200 g of colloidal silica is worked into a moist mass with a starch paste consisting of 450 g of maize starch and 2.2 kg of demineralised water. This mass is ;I forced through a sieve of 3 mm mesh width and dried at 45C
for 30 minutes in a fluidised bed drier. The dry granules are pressed through a sieve of 1 mm mesh width and mixed with a previously sieved mixture (1 mm sieve) of 130 g of maize starch, 20 g of magnesium stearate, 50 g of stearic acid and 250 g of sodium carboxymethyl-starch and the mixture is pressed to give slighly domed tablets 11.5 mm in diameter.
The tablets which can be manufactured according to the , above process are provided with a lacquer coating as follows:
,~ The pressed ta-blets are coated, in a dragée-co2tingket~e 45 cm in diameter, with a solution of 20 g of shellac and 40 g -of hydroxypropylmethylcellulose (low viscosity) in 110 g of methanol and 1,350 g of methylene chloride, by spraying evenly with the solution in the course of 30 minutes; the coating is dried by blowing in air at 60C at the same time.

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

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

i '." ' '." ' ':~''-' ,"'','".,.,''""' "''' ~,:; ;;''' Exampl e 2:
Lacquer-coated tablets containing 0.16 g of 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride and 0.4 g of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine can be manufactured as follows:
Composition (for one tablet):
(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride 0.160 g 1,2-diphenyl-3-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine 0.400 g maize starch 0.120 g colloidal silica 0.030 g magnesium stearate 0.003 g stearic acid 0.007 g sodium carboxymethyl-starch 0.035 g water q.s.
The lacquer-coated tablets are manufactured as follows (for 20,000 tablets):
, I . .
~ A mixture of 3,200 g of 1-(2-allyloxy-phenoxy)-3-iso-: propylamino-2-propanol hydrochloride, 8,000 g of 1,2-diphenyl-: 4-(2-phenylsu~phinyl-ethyl)-3,5-dioxo-pyrazolidine, 750 g of ~5 ~ maize starch and 600 g of colloidal silica is worked into a moist mass with a starch paste consisting of 1,250 g of ~. . maize starch and 6.4 kg of demineralised water. This mass ,~
~ is forced through a sieve of 3 mm mesh width and dried at s~j 45C for 30 minutes in a f~ised bed drier. The dry granules ii .
are forced through a sieve of 1 mm mesh width and mixed with a ~ .
~ - 38 -.~ç ~' ,;
.j .i " ,,,, ,, , , ,, ,,, ", . . . ....
,. ~ . . . .:: ..

,.~, . ~ . .

,. .... ~. , previously sieved mixture (1 mm sieve) of 400 g of maize starch, 60 g of magnesium stearate, 140 g of stearic acid and 700 g of sodium carboxymethyl-starch and the mixture is pressed to give domed tablets in the shape of small rods 16.4 mm in length and 8.6 mm in width.
The lacquer coating is applied to the tablets, thus :;
obtainable, as ~ollows:
5,000 of the above pressed tabletsare coatel,in a dragée-coating kettle 45 cm in diameter, with a solution of 20 g of shellac and 40 g of hydroxypropylmethylcellulose (iow vis-cosity) in 110 g of methanol and 1,350 g of methylene chloride, ~yspraying continuously with the s~ution in the course of 30 minutes;
~ . .
the coa~g isdried by blowing in warm air at 60C at the same time.
~ Example ~:
'! Punctiform tablets containing 0.08 g of 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride, 0.3 g of , 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine .< and 0.05 g of 2~[N-(~-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl~-2-imidazoline hydrochloride, the latter being in a form suitable for slow release, are manufactured as follows:
,~, .
r~ ~ Composition of tablets suitable for the slow release of 2-rN-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl~-2-imidazo-line hydrochloride (for 1 tablet):
' 2-~N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride 0.0500 g hydroxypropylmethylcellulose (low viscosity) 0.0015 g , . .
;-. 39 , :
.

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~5 1 6 hydrogenated cottonseed oil 0.0050 g magnesium stearate 0.0005 g ; The tablets containing 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride are manufactured as follows (for 10,000 tablets):
A mixture of 500 g of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride and ; 15 g of hydroxypropylmethylcellulose is worked into a moist mass with 150 g of demineralised water and this mass is granu-lated through a sieve of 3 mm mesh width, dried at 45C for 30 minutes and comminuted through a 0.6-0.8 mm sieve. After admixing 50 g of hydrogenated cottonseed oil in pulverulent form and 5 g of magnesium stearate, the mass is pressed to :
give slighly domed tablets 6 mm in diameter.
The punctiform tablets which additionally contain 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride ` and 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-. pyrazolidine are manufactured as follows: The granules described in Example 1 are processed to tablets and the tablet, described above, for the slow release of 2-[N-(~-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride is pressed into the former pressed tab-let in su~h awaythat one surface of the tablet which is pressed ~ in is visible from the outside. A highly domed press ~ tool 11.5 mm in diameter is used for the outer cover, w~ich has a wbight of 0.520 g.

... .

f ~ . . - . . ~
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Example 4:
Punc-tiform dragees containing 0.08 g of 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride, 0.3 g of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-~,5-dioxo-pyrazolidine and 0.05 g of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride, the latter being in a ~orm suitable for slow release, are manu~actured a~
~ollows:
5,000 g of the tablets obtainable according to the pro-cess described in Exa~lple 3 are placed in a dragée~coat~ke~
45 cm in diameter and provided with a protective lacquer con-sisting of a dispersion of 350 g of a copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester (70:30) in demineralised water containing 105 g of lactose and 105 g of talc This protective lacquer is sprayed on continuously for 30 minutes and drled at the same time with warm air at 60C. The increase in weight is about 0,01 g, The cores which have been lacquer-coated in this way, are further coated with a sugar solution. For this purpose a sugar syrup consisting of two parts of sugar and one part of water, with the addition of talc (18%), polyvinylpyrrolidone (1.5%) and polyethylene glycol 6000 (1%), is first used until the weight of the tablets has increased by about 0.145 g and a pure sugar ~, syrup is then used until a final dragée weight of about 0.890 g is reached.
Example 5:
Punctiform tablets containing 0.08 g of 1-(2-allyloxy-': -.. :

. ,,. ~ - ... , . ~ , , . . --~ ~ 1063516 .
~ phenoxy)-3-isopropylamino-2-propanol hydrochloride, 0.3 g of .
1,2-diphenyl-4-(2-phenylsulphLnyl-ethyl)-3,5-dioxo-pyrazolidine and 0.1 g of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride, the latter being in a iorm suitable for slow release, are manufactured as follows:
Composition of tablets suitable for the slow release of 2-rN-(3-hydroxY-Phenyl)-N-(4-methyl-Phen~1)-aminometh~ 2-imidazo-line hydrochloride (for 1 tablet):
2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride 0.100 g , ,' hydrox,ypropylmethylcellulose (low viscosity) 0.003 g ,' hydrogenated cottonseed oil 0.010 g magnesium stearate ' 0.001 g The tablets containing 2-[N-(3-hydroxy-phenyl)-N-(4- ' , methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride and the punctiform tablets which additionally contain 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride and 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)~3,5-dioxo-pyrazolidine are manufactured according to the process des-orlbed in Example 3. The punctiform tablets can be con-, ~
verted into punctiform dragees by the process described in Ex~ple 4.
ExamPle 6:
''~ , Capsules containing 0.1 g of 3-isopropylamino-1-[4-(2-methoxyethyl)-phenoxy]-2-propanol tartrate and 0.4 g of 1,,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine ; :: ~
~ can be manufactured as follows: ' ~J : ~
~ 42 -~, , ~ ~, .: ' : . . . :
'.: ' ' ~ . ; ", ' , ' :

5.063516 ~-Composition (for one capsule) 3-isopropylamino~ 4-(2-methoxyethyl)-phenoxy]-2-propanol tartrate 0 1 g 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5- ~ :
dioxo-pyrazolidine 0.4 g -colloidal silica 0.013 g hydroxypropylmethylcellulose (low vi.scosity) 0.042 g gelatine 0.012 g magnesium stearate 0.006 g polyvinylpyrrolidone 0.007 g The capsules are manufactured as follows (for 10,000 capsules):
A mixture of 1,000 g of 3-isopropylamino-1-~4-(2-methoxyethyl)-phenoxy]-2-propanol tartrate and 80 g of .:
colloidal silica is sieved through a sieve with a mesh width of 1.6 mm and granulated, in a fluidised bed, with an aqueous solution of 70 g of polyvinylpyrrolidone and the granules are then dried at 40C. 4,000 g of 1,2-diphenyl-4-(2-phenyl-sulphinyl-ethyl)-3,5-dioxo-pyrazolidine are moistened with an aqueous solution of 120 g of gelatine, dried and converted into a granular state by means of extrusion and the granules are dried at 45C. The two lots of dried granules are com- ..
bined and mixed with 420 g of hydroxypropylmethylcellulose, 50 g of colloidal silica and 60 g of magnesium stearate and the mixture is filled, by machine, into 10,000 capsules of size 000.
,'~

.,~ . .
.. . . .

Example 7:
Dragées containing 0.075 g of 3-isopropylamino-1-(3-methyl-phenoxy)-2-propanol hydrochloride and 0.1 g of 2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-pyrimido [5,4-d]pyrimidine are manufactured as follows:
Composition (for one dragee):
3-isopropylamino-1-(3-methyl-phenoxy)-2-propanol hydrochloride 0.075 g 2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-pyrimido[5,4-d]pyrimidine 0.1 g magnesium stearate 0.003 g maize starch 0.085 g polyvi~ylpyrrolidone 0.009 g The dragees are manufactured as follows (for 10,000 dragees):
A mixture of 750 g of 3-isopropylamino-1-(3-methyl-phenoxy)-2-propanol hydrochloride, 1,000 g of 2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-pyrimido[5,4-d]pyri-midine, 830 g of lactose and 550 g of maize starch is moistened with an aqueous solution of 90 g of polyvinylpyrroli-done, the moist mixture is kneaded and granulated and the granules are dried at 45C. The dried granules are forced through a sieve with a mesh width of 1.2 mm and mixed with 300 g of maize starch and 30 g of magnesium stearate and the mixture is pressed to give 10,000 dragée cores. These are coated with a sugar coating in the customary way.

... . . . . . . . . .. . .

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~, ' : , , ' ' .: ` .

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Example 8:
Tablets containing 0.020 g of 1-(4-indolyloxy)-3-isopropylamino-2-propanol and 1.0 g of 0-acetylsalicylic acid are manufactured as follows:
Composition (for one tablet):
1-(4-indolyloxy)-~-isopropylamino-2-propanol 0.020 g 0-acetylsalicylic acid 1.0 g rice starch 0.1 g The tablets are manufactured as follows (for 5,000 tablets):
A mixture of 100 g of 1-(4-indolyloxy)-3-isopropyl-amino-2-propanol and 500 g of rice starch is forced through a sieve with a mesh width of 0.5 mm. 5,000.0 g of crystal-line 0-acetylsalicylic acid are added to this mixture and the whole is mixed well. The mixture is then pressed to give 5,000 tablets.
Example 9:
Capsules containing 0.020 g of 1-(4-indolyloxy)-3-isopropylamino-2-propanol and 0.4 g of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine àre manufactured ; as follows:
comPosition (for one capsule):
1-(4-indolyloxy)-3-isopropylamino-2-propanol 0.020 g , 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine 0.4 g gelatine 0.015 g magnesium stearate 0.005 g maize starch 0.060 g ' .
_ 45 _ . : - . . : ~ ~ - ,, .. ,. . . . . .. . :

~ 1(363S~
.

The capsules are manu~actured as follows (for 10,000 capsules):
A mixture of 200 g of 1-(4-indolyloxy)-~-isopropy]- - .
amino-2-propanol and 400 g of maize starch is forced through a sieve with a mesh width of 0.5 mm, 100 g of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-~,5-dioxo-pyrazolidine are added and the whole is mixed. A further 3,000 g of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine are added to this mixture and the whole is mixed well. The mixture is then moistened with an aqueous solution of 150 g of gelatine, kneaded and converted to a granular state by means of extrusion and the granules are dried at 45C. 200 g of maize starch and 50 g of magnesium stearate are added to the dried granules and the mixture is filled, by machine, into 10,000 capsules of size 00.
Example 10:
In the above Examples 1-9 it is possible to use 3-isoprop~lamino-l-(l-naphthyloxy)-2-propanol, 1-(2-allyl-phenoxy)-3-isopropylamino-2-propanol, 1-(4-acetylamino-phenoxy)-~-isopropylamino-2-propanol, 3-isopropylamino-1-14-(2-methylthioethoxy)-phenoxyl-2-propanol, 1-12-(3,4-dimethoxyphenyl)-ethylaminol-3-(3-methyl-phenoxy)-2-propanol, l-isopropylamino-3-(1,2,3,4-tetrahydro-1,4-ethano-5-naphthyloxy)-2-propanol, 1-tert.-butylamino-3-(1,2,3,4-tetrahydro-2,3-dihydroxy-5-naphthyloxy)-2-propanol, 1-(7-indenyloxy)-3-isopropylamino-2-propanol, 1-(7-indany]oxy)-~ - 46 -.

.. . .
.. . . .

.. : .; . ~ ~ ' ~
.
. .
.

Slf~

3-isopropylamino-2-propanol, 1-(5-methyl-8-cu..aryloxy)-3-isopropylamino-2-propanol, 4-(3-isopropylaminc-2-hydroxy-l-propyloxy)-2-methyl-indole or 2-tert.-butylemino-1-(7-ethyl-2-benzofuranyloxy)-ethanol, preferably in the form of an acid addition salt which can be used pharma-ceutically, such as the hydrochloride, in place of the active compounds used in these examples as the beta-receptor-blocking component.

.

Claims

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

1. Pharmaceutical preparations for the treatment of coronary heart diseases which contain, as pharmaceutical active compounds, a beta-receptor-blocking compound of the formula (I) wherein Ar1 represents a monocyclic or polycycllo, carbocyclic or heterocyclic radical which contains at least one ring of aromatic character and which is bonded to the oxygen atom via a ring carbon atom of the ring of aromatic character, R1 denotes an optionally substituted aliphatic, cycloaliphatic or araliphatic hydrocarbon radical and R2 represents hydrogen or the acyl radical of an organic carboxy-lic acid, or a compound of the formula (II) wherein R1 and R2 have the abovementioned meanings, Ar2 represents a monocyclic or polycyclic, carbocyclic radical which contains at least one ring of aromatic character!
and R3 denotes hydrogen or lower alkyl, or a salt of such compounds which can be used pharmaceutically, as the beta-receptor-blocking active compound, O-acetyl-salicyclic acid, or a salt thereof with a base, which can be used pharmaceuti-cally,2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-pyrimido[5,4-d]pyrimidine, or an acid addition salt thereof which can be used pharmaceutically, or a compound of the formula (III) wherein each of the radicals Ph1 and Ph2 independently of one another represents a phenyl radical which 18 optionally sub-stituted by lower alkyl, hydroxyl, lower alkoxy and/or halogen, Alk denotes a lower alkylene radical which separates the sulphur atom from the ring carbon atom by at least 2 carbon atoms, a represents O, 1 or 2 and Ph3 represents a phenyl radical which is optionally substituted by lower alkyl, lower alkoxy and/or halogen, or a salt thereof with a base, which can be used pharmacologically, as the active compound which regulates the thrombocyte function, and a hydrogenated ergot alkaloid, or a mixture of such alkaloids or acid addition salts thereof which can be used pharmaceutically, or a N-benzyl-N-halogeno-lower alkylamine, a 2-tert.-aminomethyl-benzodioxane, a N-substituted dibenzazepine or a methyl-2-imliazoline which is substituted in the 2-position, or acid addition salts of such compoundswhich can be used pharmaceutically, as the alpha-receptor-blocking active compound which is optionally present, wherein the ratio of the beta-receptor-blocking active compound to the active compound which regulates the thrombocyte function, especially an active compound of the type of the structural formula (III) is about 1:1 to about 1:50 (by weight) and the ratio of the beta-receptor-blocking active compound to the alpha-receptor-blocking active compound which is optionally present, is about 1:0,1 to 1:1 (by weight).

2. Pharmaceutical preparations according to Clalm 1, characterised in that these contain 3-isopropylamino-1-(1-naphthyloxy)-2-propanol, 3-isopropylamino-1-(3-methyl-phenoxy)-2-propanol, 1-(2-allyl-phenoxy)-3-isopropylamino-2-propanol, 1-(4-acetylamino-phenoxy)-3-isopropylamino-2-propanol, 1-(4-indo1yloxy)-3-isopropylamino-2-propanol, 3-isopropylamino-1-[4-(2-methoxyethyl)- phenoxy]-2-propanol, 3-isopropylamino-1-[4-(2-methy1thioethoxy)-phenoxy]-2-propanol, 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol, 1-[2-(3,4-dimethylphenyl)-ethy1amino]-3-(3-methyl-phenoxy)-2-propanol, 1-isopropylamino-3-(1,2,3,4-tetrahydro-1,4-ethano-5-naphthyloxy)-2-propanol, 1-tert.-butylamino-3-(1,2,3,4-tetrahydro-2,3-dihydroxy-5-nalphthyloxy)-2-propanol, 1-(7-indenyloxy)-3-isopropylamino-2-propano1, 1-(7-indanyloxy)-3-isopropylamino-2-propanol or 1-(5-methyl-8-cumary1oxy)-3-isopropylamino-2-propanol, 4-(3-isopropylamino-2-hydroxy-1-propyloxy)-2-methyl-indole, or an acid addition salt thereof which can be used pharma-ceutically, as the betareceptor-blocking component, 2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-pyri-mido[5,4-d]pyrimidine, or an acid addition salt thereof which can be used pharmaceutically, 1-(4-hydroxy-phenyl)-2-phenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazo-lidine or 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombocyte function, and 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline, or an acid addition salt thereof which can be used pharmaceutically, as the alpha-receptor-blocking component which is optionally added.
3. Pharmaceutical preparations according to Claim 1, characterised in that these contain 1-(2-allyloxy-phenoxy)-3-isoproylamino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombocyte-function. -Pharmaceutical preparations according to Claim 3 characterised in that these contain 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline, or an acid additlon salt thereof which can be used pharmaceutically, as the alpha-receptor-blocking component which is optionally added.
5. Pharmaceutical preparations according to Claim 1, characterised in that these contain 3-isopropylamino-1-[4-(2-methoxyethyl)-phenoxy]-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and 1,2-diphenyl-4-(2-phenyl-sulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombocyte function.
6. Pharmaceutical preparations according to Claim 1, characterised in that these contain 3-isopropylamino-1-(3-methyl-phenoxy)-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and 2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-pyrimido[5,4-d]pyrimidine, or an acid addition salt thereof which can be used pharmaceutically, as the component which regulates the thrombocyte function.
7. Pharmaceutical preparations according to Claim 1, characterised in that these contain 1-(4-indolyloxy)-3-iso-propylamino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and O-acetylsalicylic acid, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombocyte function.
8. Pharmaceutical preparations according to Claim 1, characterised in that these contain 1-(4-indolyloxy)-3-iso-propylamino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombocyte function, 9. Pharmaceutical preparations according to Claim 1, characterised in that these contain from about 0.002 g to about 0.3 g, of the beta-receptor-blocking active compound and from about 0.2 g to about 1.0 g, of an active compound which regulates the thrombocyte function, especially an active compound of the structural formula III, and, optionally, from about 0.005 g to about 0.2 g, of an alpha-receptor-blocking active compound.

10. Pharmaceutical preparations according to claim 1, characterised in that these contain from about 0.005 g about 0,2 g of the beta-receptor-blocking active compound and from about 0.4 g to about 0.8 g of an active compound which regulates the thrombocyte function, especially an active compound of the structural formula (III) and optionally from about 0.01 g to about 0.1 g of an alpha-receptor-blocking active compound.

11. Pharmaceutical preparations according to Claim 3, characterised in that these contain from about 0.02 g to about 0.25 g, of 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol, or of an acid addition salt thereof which can be used pharmaceutically, and from about 0.2 g to about 1.0 g, of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyra-zolidine, or of a salt thereof with a base, which can be used pharmaceutically, and, optionally, from about 0.005 g to about 0.2 g, of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline, or of an acid addition salt thereof which can be used pharmaceutically.

12. Pharmaceutical preparations according to claim 3, characterised in that these contain from about 0,04 g to about 0,2 g of 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol or of an acid addition salt thereof which can be used pharmaceutically, and from about 0,4 g to about 0,8 g of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or of a salt thereof with a base, which can be used pharmaceutically, and optionally from about 0,01 g to about 0,1 g of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazolidine, or of an acid addition salt thereof which can be used pharmaceutically.

13. Pharmaceutical preparations according to Claim 5, characterised in that these contain from about 0,02 g to about 0.25 g, of 3-isopropylamino-1-[4-(2-methoxyethyl)-phenoxy]-2-propanol, or of an acid addition salt thereof which can be used pharmaceutically, and from about 0.2 g to about 1.0 g of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or of a salt thereof with a base, which can be used pharmaceutically.

14. Pharmaceutical preparations according to Claim 5, characterised in that these contain from about 0.05 g to about 0.150 g, of 3-isopropylamino-1-[4-(2-methoxyethyl)-phenoxy]-2-propanol, or of an acid addition salt thereof which can be used pharmaceutically, and from about 0.4 g to about 0.8 g, of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or of a salt thereof with a base, with can be used pharmaceutically.

15. Pharmaceutical preparations according to Claim 6, characterised in that these contain from about 0.050 g to about 0.250 g, of 3-isopropylamino-1-(3-methyl-phenoxy)-2-propanol, or of an acid addition salt thereof which can be used pharmaceutically, and from about 0.020 g to about 0.2 g, of2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperi--dino-pyrimido[5,4-d]pyrimidine, or of an acid addition salt thereof which can be used pharmaceutically.

16. Pharmaceutical preparations according to Claim 6, characterised in that these contain from about 0.060 g to about 0.150 g, of 3-isopropylamino-1-(3-methyl-phenoxy)-2-propanol, or of an acid addition salt thereof which can be used pharmaceutically, and from about 0.050 g to about 0.150 g, of 2,6-bis-[di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-pyrimido[5,4-d]pyrimidine, or of an acid addition salt thereof which can be used pharmaceutically 17. Pharmaceutical preparations according to Claim 7, characterised in that these contain from about 0.005 g to about 0.080 g of 1-(4-indolyloxy)-3-isopropylamino-2-propanol, or of an acid addition salt thereof which can be used pharma-ceutically, and from about 0.7 g to about 2.0 g of O-acetyl-salicyclic acid, or of a pharmaceutically acceptable salt thereof with a base.

18. Pharmaceutical preparations according to Claim 7, characterised in that these contain from about 0.015 g to about 0.050 g, of 1-(4-indolyloxy)-3-isopropylamino-2-propanol, or of an acid addition salt thereof which can be used pharma-ceutically, and from about 1.0 g to about 1.5 g, of O-acetyl-salicylic acid, or of a pharmaceutically acceptable salt thereof with a base.

19. Pharmaceutical preparation according to Claim 8, characterised in that these contain from about 0.005 g to about 0.080 g of 1-(4-indolyloxy)-3-isopropylamino-propanol, or of an acid addition salt thereof which can be used pharma-ceutically, and from about 0.1 g to about 1.0 g of 1,2-di-phenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or of a pharmaceutically acceptable salt thereof with a base.

20. Pharmaceutical preparations according to Claim 8, characterised in that these contain from about 0.015 g to about 0.050 g, of 1-(4-indolyloxy-3-isopropylamino-2-propanol, or of an acid addition salt thereof which can be used pharmaceutically, and from about 0.2 g to about 0.8 g, of 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or of a pharmaceutically acceptable salt thereof with a base.

21. Pharmaceutical preparations according to claim 1 which contain one or more active compounds incorporated into a suitable excipient which effects a slow release of the active compound or active compounds.

22. Pharmaceutical preparations according to claim 1 characterized in that these contain the 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline or an acid ad-dition salt thereof which can be used pharmaceutically as the alpha-receptor-blocking component in a slow release form.

23. Pharmaceutical preparations according to claim 1 in unit dosage form.

24. Pharmaceutical preparations according to claim 23 in the form of tablets, dragees and capsules.

25. Pharmaceutical preparations according to claim 24 characterized in that these contain from about 50% to about 90%
of active compound together with the excipient.

26. Pharmaceutical preparations according to claim 24 which can be administered orally.