IE42766B1 - Pharmaceutical preparations for the treatment of coronary heart diseases - Google Patents

Abstract

1510370 Compositions for treating coronary heart disease CIBA - GEIGY AG 31 Dec 1975 [6 Jan 1975] 53300/75 Heading A5B Pharmaceutical preparations for the treatment of coronary heart disease contain (1) a beta - receptor blocking compound of the formula:- wherein Ar 1 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 character R 1 denotes an optionally substituted aliphatic, cycloaliphatic or araliphatic hydrocarbon radical and R 2 represents hydrogen or the acyl radical of an organic carboxylic acid, or a compound of the formula wherein R 1 and R 2 have the abovementioned meanings, Ar 2 represents a monocyclic or polycyclic, carbocyclic radical which contains at least one ring of aromatic character, and R 3 denotes hydrogen or lower alkyl, or a salt of such compounds which can be used pharmaceutically, (2) a compound which regulates the thrombocyte function which is acetylsalicylic acid or a salt thereof with a base which can be used pharmaceutically, 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 pharmacetically or a compound of the formula wherein each of the radicals Ph 1 and Ph 2 independently of one another represents a phenyl radical which is optionally substituted 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, n represents 0, 1 or 2 and Ph 3 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, and optionally (3), an alpha - receptor blocking compound which is 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 addition salts of such compounds which can be used pharmaceutically.

Description

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, optionally, an alpha-receptor5 blocking compound, with the proviso that inclusion in the pharmaceutical preparations of (3) an alpha-receptor-blooking compound which is a hydrogenated ergot alkaloid, or a mixture of such alkaloids or acid addition salts thereof which can be used pharmaceutically, or a N-benzy1-N-halogeno-lower alkyl10 amine, a 2 tert.-aminomethyl-benzodioxane, a N-substituted dibenzazepine or a methyl-2-imidazoline which is substituted in the 2-position, or acid addition salts of such compounds which can be used pharmaceutically is indispensable if such pharmaceutical preparations contain (1) a compound of the formula L5 I. or of the formula XI or a salt of such compounds which can be used pharmaceutically and (2) 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.

The new pharmaceutical preparations are suitable, above all, for the prophylactic and thereapeutic 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 disease, that is .to say angina pectoris, coronary insufficiency and cardiac infarction.

The beta-receptor-blocking component of the new pharmaceutical preparations effects a lowering of the heart rate, a reduction in the cardiac contractility and screening of the heart from subjection to external adrenergic stimuli, which results in a reduction of the myocardial oxygen consumption and, in the case of critical nutrition, has the effect of conserving tissue. Compounds 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 produced and die off, and prolong their survival period, especially when the latter is shortened due to disease.

In addition, they reduce the increase in adhesiveness and aggregation of the blood platelets produced by pathological influ10 ences. These properties reduce or prevent thrombotic processes which play an important part in coronary diseases. As a result of the anti-aggregating action, the flow properties of the blood in the arterioles, capillaries and venules are also decisively improved, which, in turn, leads to an improvement in the oxygen supply.

The alpha-receptor-blocking compound which is optionally added to the combination of a beta-receptor-blocking compound and a compound which regulates the thrombocyte function, has the effect, by means of peripheral vasodilation, of facili2o bating the stroke output and thus relieving the left hand ventricle, with a corresponding additional reduction in the oxygen consumption.

The combined use of the two types of active compound, 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 pharmacologically active components supplement one another in a surprising manner. 43766 These pharmaceutical preparations provide a new principle for the prophylactic and therapeutic treatment of coronary heart diseases. This principle is that the oxygen consumption of the myocardium is reduced by beta-blocking, and thrombotic processes in the coronary arteries are reduced or prevented and the flow properties of the blood are improved because the formation of thrombocyte aggregates is prevented. The combination of these effects leads to an unexpected improvement in the results of treatment. The preparation to be manufactured 43766 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 heta-receptor- blocking properties which are employed in the phaimaceutical preparations of the invention are those of the formula. 0-R„ I 2 „ (I) Arj—0—C1I2— CH—CII2—NH—R]_ wherein Ar-^ 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 character, R^ denotes tn optionally substituted aliphatic, cycloaliphatic or araliphatic hydrocarbon radical and Rg represents hydrogen or the acyl radical of an organic carboxylic acid, as well as salts thereof which can be used pharmaceutically, above all corresponding acid addition salts thereof.

Carbocyclic radicals Ar^ 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 l,2,3»4-tetrahydro-5-naphthyl, benz-lndenyl, for example 4- or 5-indenyl, and also optionally partially saturated polycyclic aromatic hydrocarbon radicals, such as benz-fluorenyl, - 5 43766 for example 4-fluorenyl, partially saturated radicals of the above type heing bonded to the oxygen atom via a ring carbon atom of the aromatic part.

Heterocyclic radicals Ar-^ contain, as ring heteroatoms, above all one or more ring nitrogen atoms as vzell 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, monoazacyclic, six-membered radicals of aromatic character, such as pyridyl, for example 2-, 3- or 4-pyridyl, monocyclic, diazacyclic, six-membe'red radicals of aromatic character, such as pyridazinyl, for example 3-pyridazinyl, pyrimidinyl, for example 2- or- 4-pyrimidinyl, or pyrazinyl, for example 2pyrazinyl, monocyclic, thiadiazacyclic, five-membered radicals of aromatic character, such as thiadiazolyl, for example l,2,5-thiadiazol-3-yl, optionally partially saturated bicyclic, 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-5quinolinyl, or bicyclic monothiacyclic radicals of partially aromatic character, such as 2H-thiochromenyl, for example 2Hthiochromen-8-yl.

The above radicals Ar^ can be unsubstituted or substituted and Ar^ contains, above all, one, or also several, in particular two, substituents. The latter are, above all, 43766 optionally substituted aliphatic or cycloaliphatic hydrocarbon radicals, optionally etherified or esterified hydroxyl or mercapto groups, acyl radicals, optionally functionally modified carboxyl groups, nitro or optionally substituted amino groups. Saturated parts of the group Ar^ can also contain, in addition to the abovementioned substituents, substituents which have two bonds, above all oxo.

As substituents of the radical Ar^, aliphatic hydrocarbon radicals are, in particular, lower alkyl or lower alkenyl, as well as lower alkynyl. 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 functionally 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 organic carboxylic acid or of a carbonic acid half-derivative, as well as of an organic sulphonic acid, such as lower alkanoylamino, lower alkoxy20 carbonylamino or optionally N-substituted ureido, such as N'lower alkylated ureido, for example ureido, Ν'-lower alkylureido or Ν',N'-di-lower alkyl-ureido, and also lower alkylsulphonylamino, Substituted lower alkyl radicals are, above all, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower 25 alkylthio-lower alkyl, halogeno-lower alkyl, optionally Nlower alkylated carbamoyl-lower alkyl, lower alkanoylaminolower alkyl or lower alkoxycarbonylamino-lower alkyl, and also - 7 42766 lower alkanoylamino-lower alkenyl or lower alkoxycarbonylamino lower alkenyl.

Cycloaliphatic hydrocarbon radicals are represented, in particular, by monocyclic and polycyclic eycloalkyl.

As substituents of a radical Ar^, etherified hydroxyl or mercapto groups are, above all, hydroxyl or mercapto which are etherified hy optionally substituted aliphatic hydrocarbon radicals, such as lower alkoxy, lower alkenyloxy or lower alkynyloxy, and also lower alkylthio or lower alkenylthio. 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 optional! 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 Ar^, esterified hydroxyl or mercapto groups are, above all, halogen as well as lower alkanoyloxy.

As substituents of the radical Ar-^, acyl groups represent, above all, lower alkanoyl.

As substituents of Ar·^, optionally functionally modified' carboxyl groups are, in particular, esterified or 43766 amidated carboxyl and also cyano. Esterified carboxyl is, above all, lower alkoxycarbonyl, whilst amidated carboxyl represents optionally substituted carbamoyl, suoh as carbamoyl, N-lower alkyl-carbamoyl or N,N-di-lower alkyl-carbamoyl.

As substituents of groups Ar^, optionally substituted amino groups are, in particular, acylamino, wherein acyl above all represents 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, 10 lower alkoxycarbonylamino or optionally Ν'-lower alkylated ureido, for example ureido, Ν'-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, Ν,Ν-aza-lower alkyleneamino, N,N-oxa-lower alkyleneamino or N,N-thia-lower alkyleneamino.

Aliphatic hydrocarbon radicals are, above all, lower alkyl, especially lower alkyl branched at the linking carbon, and also lower alkenyl or lower alkynyl, whilst cycloali20 phatic hydrocarbon radicals represent, in particular, cycloalkyl, including polycyclic cycloalkyl, and araliphatic hydrocarbon 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 alkyl42766 carbamoyl, or N,N-di-lower alkyl-carbamoyl, or optionally functionally modified carboxyl, such as carboxyl and esterifie carboxyl, for example lower alkoxycarbonyl, amidated carboxyl, such as optionally N-lower alkylated carbamoyl, for example carbamoyl, N-lower alkyl-carbamoyl or N,N-di-lower alkylcarbamoyl, 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 alkylcarbamoyl 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 Nlower alkylated carbamoylpyridyloxy-lower alkyl and also lower alkoxycarbohyl-lower alkyl, optionally N-lower alkylated carbamoyl-lower alkyl or cyano-lower alkyl.

An acyl radical Rg 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 25 used in the preceding and the following text preferably have the following meanings: Lower alkyl is, for example, methyl, ethyl, n-propyl, 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 all, allyl and also vinyl, 2methyl-allyl, 2-butenyl or 3,3-dimethylallyl, whilst lower alkynyl-is, for example, ethynyl or propargyl.

Lower alkoxy is, for example, methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy or tert.-butoxy.

Lower alkylthio is, for example, methylthio, ethylthio, 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 15 carbamoyl and also N-lower alkyl-carbamoyl, such as N-methylcarbamoyl or N-ethyl-carbamoyl, or Ν,Ν-di-lower alkylcarbamoyl, such as Ν,Ν-dimethyl-carbamoyl or N,N-diethylcarbamoyl.

Lower alkanoylamino is, for example, formylamino, 20 acetylamino, propionylamino, butyrylamino or pivaloylamino.

Lower alkoxycarbonylamino is, for example, methoxycarbonylamino, ethoxycarhonylamino or tert.-butoxycarbonylamino, whilst N'-lower alkyl-ureido and Ν',Ν'-di-lower alkylureido are, for example, N'-methylureido, N'-ethylureido, Ν',Ν'-dimethylureido or N*,N'-diethylureido.

Lower alkylsulphonylamino is, for example, methylsulphonylamino or ethylsulphonylamino. - 11 42766 Hydroxy-lower alkyl is, for example, hydroxymethyl or 1- or 2-hydroxyethyl.

Lower alkoxy-lower alkyl is, for example, lower alkox; methyl or, preferably, 2-(lower alkoxy)-ethyl, such as methox; methyl, ethoxymethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl or 2isopropoxy-ethyl.

Lower alkylthio-lower alkyl is, for example, lower alkylthio-methyl or, in particular, 2-(lower alkylthio)-ethyl: for example methylthiomethyl, ethylthiomethyl, 2-mothylthio10 ethyl or 2-ethylthioethyl.

Halogeno-lower alkyl is, in particular, trifluorometh} Optionally N-lower alkylated carbamoyl-lower alkyl is, for example, carbamoylmethyl or 1- or 2-carbamoylethyl and also N-lower alkyl-carbamoyl-lower alkyl, such as N-methyl15 carbamoylmethyl or 1- or 2-N-methylcarbamoyl-ethyl, or N,Ndi-lower alkyl-carbamoyl-lower alkyl, such as N,N-dimethy1carbamoyl-methyl or 1- or 2-N,N-dimethylcarbamoyl-ethyl.

Lower alkanoylamino-lower alkyl is, for example, lower alkanoylaminomethyl or, preferably, 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, 25 ethoxycarbonylaminomethyl, 2-methoxycarbonylaminoethyl, 2ethoxycarbonylaminoethyl or 2-tert.-butoxycarbonylaminoethyl.

Lower alkanoylamino-lower alkenyl is, in particular, 43766 2-lower alkanoylamino-vinyl, for example 2-acetylamino-vinyl, 2-propionylamino-vinyl or 2-pivaloylamino-vinyl, whilst lower alkoxycarbonylamino-lower alkenyl preferably represents 2lower alkoxycarbonylamino-vinyl, such as 2-methoxycarbonylamino5 vinyl, 2-ethoxycarbonylamino-vinyl or 2-tert,-butoxycarbonylamino-vihyl.

Cycloalkyl, including polycyclic cycloalkyl, preferably contains 3-10 ring carbon atoms and denotes cyclopropyl or, in particular, cyclopentyl or cyclohexyl, as well as adamantyl, such as 1-adamantyl.

Lower alkenyloxy is, in particular, allyloxy as well as 2-methylallyloxy, and also vinyloxy, 2-butenyloxy or 3,3dimethylallyloxy, whilst lower alkynyloxy represents, for example, propargyloxy.

Lower alkenylthio is, for example, allyIthio 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, 20 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 cr 3- ethoxy-propoxy.

In a lower alkylthio-lower alkoxy radical the sulphur 25 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 all, 2-(lower alkylthio)-ethoxy, for - 13 42766 example 2-methylthio-ethoxy or 2-ethylthio-ethoxy.

In a lower alkoxy-lower alkylthio radical the oxygen atom and the sulphur atom are likewise preferahly separated from one another by at least 2, for example by 2-3, carbon 5 atoms; such radicals are, above all, 2-(lower alkoxy)-ethylthic for example 2-methoxy-ethylthio or 2-ethoxy-ethylthio.

In lower alkanoylamino-lower alkoxy radical's and lower alkoxycarbonylamino-lower alkoxy radicals the nitrogen atom an the linking oxygen atom are preferahly separated from one 10 another hy 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 2pivaloylamino-ethoxy, or 2-lower alkoxycarbonylamino-ethoxy, for example 2-methoxyoarbonylamino-ethoxy or 2-ethoxycarbonyl15 amino-ethoxy.

Lower alkanoyloxy is, for example, acetyloxy, propicny oxy or pivaloyloxy.

Lower alkanoyl is, in particular, acetyl, propionyl or pivaloyl.

Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxyearbonyl or tert.-butoxycarbonyl.

N-Lower alkylamino and Ν,Ν-di-lower alkylamino are, for example, methylamino, ethylamino, dimethylamino or diethylamino. Ν,Ν-Lower alkyleneamino preferably contains 5-7 ring members and is, in particular, pyrrolidinyl or piperidino, whil Ν,Ν-aza-lower alkyleneamino, Ν,Ν-oxa-lower alkyleneamino and Ν,Ν-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, 4methy1-1-piperazinyl, 4-morpholino or 4-thiomorpholino.

Phenyl-lower alkyl is, for example, benzyl or 1- or 2phenylethyl.

Pyridyloxy is, for example, 2-pyridyloxy, 3-pyridyloxy or 4-pyridyloxy.

In a phenoxy-lower alkyl radical and pyridyloxy-lower alkyl radical Rp 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-(optionally N-lower alkylated carbamoyl-phenoxy)-lower alkyl, for example 2-(2-carbamoylphenoxy)-ethyl, 2-(4-carbamoylphenoxy)ethyl, 2-(2-N-methylcarhamoyl-phenyl)-ethyl or 2-(4-N,N20 dimethylcarbamoyl-phenoxy)-ethyl, and also 2-(optionally Nlower 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 alkoxycarbonyImethyl or 1-lower alkoxycarbony1-2-propyl, for example methoxycarbonylmethyl, ethoxycarbonylmethyl, 1methoxycarbonyl-2-propyl or l-ethoxycarbonyl-2-propyl.

Optionally N-lower alkylated carbamoyl-lower alkyl is. above all, carbamoylmethyl and also N-lower alkylcarbamoylmethyl or N,N-di-lower alkylcarbamoyl-methyl, for example Nmethylcarbamoylmethyl, N-ethylcarbamoylmethyl, N,N-dimethyl5 carbamoylmethyl or Ν,Ν-diethylcarbamoylmethyl, as well as 1Carbamoyl-2-propyl and also 1-N-lower alkyl-carbamoyl-2propyl or 1-N,N-di-lower alkyl-carbamoyl-2-propyl, for example 1- N-methylcarbamoyl-2-propyl, l-N-ethylcarbamoyl-2-propyl, 1N,N-dimethylcarbamoyl-2-propyl or l-N,N-diethylcarbamoyl-210 propyl.

Cyano-lower alkyl is, for example, cyanomethyl or 1cyano-2-propyl.

In the compounds of the formula I, the group Ar^ preferably denotes naphthyl, for example 1-naphthyl, fluorenyl 15 for example 4-fluorenyl, indolyl, for example 4-indolyl, 2H-th chromenyl, for example 2H-8-thiochromenyl, lower alkyl-phenyl, such as methyl-phenyl, for example 2- or 3-methy1-phenyl, halo geno-lower alkyl-phenyl, such as chloromethyl-phenyl, for exam 2- chloro-5-methyl-phenyl, lower alkenyl-phenyl, such as allyl20 phenyl, for example 2-allylphenyl, lower alkynyl-phenyl, such ethynyl-phenyl., for example 2-ethynyl-phenyl, cyc-loalkyl-pheny for example 2-cyclopropyl-phenyl or 2-cyclopentyl-phenyl, hydroxy-lower alkyl-phenyl, for example 2-hydroxymethyl-phcnyl lower alkoxy-lower alkyl-phenyl, such as lower alkoxymethyl-ph nyl or (2-lower alkoxy-ethyl)-phenyl, for example 2-methoxymethyl-phenyl or 4-(2-methoxyethyl)-phenyl, carbamoyl-lower alkyl-phenyl, for example carbamoylmethyl-phenyl, lower alkoxy· 43766 carhonylamino-lower alkyl-phenyl, such as (2-lower alkoxycarbonylamino-ethyl)-phenyl, for example 4-(2-methoxycarbonylamino-ethyl)-phenyl, halogeno-lower alkoxyoarbonylamino-lower alkyl-pyridyl, for example 3-chloro-4-(2-methoxycarbonylamino5 ethyl)-2-pyridyl, lower alkoxycarbonylamino-lower alkenylphenyl, especially (2-lower alkoxycarbonylamino-vinyl)-phenyl, for example 4-(2-methoxycarbonylamino-vinyl)-phenyl, lower alkoxy-phenyl, such as methoxyphenyl, for example 2-methoxyphenyl, lower alkenyloxy-phenyl, such as allyloxy-phenyl, for example 2-allyloxy-plienyl, or methallyloxy-phenyl, for 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-methylthio-ethoxy)-phenyl, lower alkylthio-phenyl, such as methylthio-phenyl, for example 2-methylthiophenyl, halogeno-phenyl, such as chlorophenyl, for example 2-chlorophenyl, lower alkanoyl-lower alkanoylamino-phenyl, for example 2-acetyl-420 n-butyrylamino-phenyl, cyano-phenyl,, for example 2-cyanophenyl, lower alkanoylamino-phenyl, such as acetylaminophenyl, for example 4-acetylamino-phenyl, lower alkylsulphonylamino-phenyl, for example 4-methylsulphonylamino-fhenyl ,(1-pyrryl) phenyl, for example 2-(1-pyrryl)-phenyl, morpholinothia25 diazolyl, for example 4-morpholino-l,2,5-thiadiazol-3-yl> oxo-5,6,7,8-tetrahydro-benz-naphthyl, for example 5-oxo5,6,7,8-tetrahydro-l-naphthyl, or oxo-1.2.5.4-tetrahvdro-benz- 17 43766 quinolyl, for example 2-oxo-l,2,3j4-tetrahydro-5-quinolinyl, Rg represents, in particular, hydrogen or lower alkanoyl, fox· example acetyl or pivaloyl, and is, above all, lower alkyl, especially lower alkyl branched at the linking carbon, for exainple isopropyl or tert.-butyl, and also carbamoylphenoxylower alkyl, such as 2-carbamoylphenoxy-lower alkyl, for example 2-(4-carbamoylphenoxy)-ethyl.

Compounds with beta-receptor-blocking properties, of the above formula I, are, above all, the following compounds in which lower alkyl R^ is branched at the linking carbon atom: l-(naphthyloxy')-3-lower alkylamino-2-propanol, for example 3i sopropylamino-1-(1-naphthyloxy)-2-propanol, 1-(benzfluorenyloxy)-3-lower alkylamino-2-propanol and the corresponding O-esters thereof with lower alkanecarhoxylic acids, for example l-(4-fluorenyloxy)-3-isopropylamino-2-propanol or 3-tert.-butylamin o-l-(4-fluorenyloxy)-2-pivaloyloxy-propane, 1-(benz-indolyloxy)-3-lower alkylamino-2-propanols, for example 1-(4-indolyloxy)-3-isopropylamino-2-propanol, 3-lower alkylamino-l-(2H-benz-thiochromenyloxy)-2-propanols, for example 320 tert.-butylamino-l-(2H-thiochromen-8-yloxy)-2-propanol, 3lower alkylamino-l-(lower alkyl-phenoxy)-2-propanols wherein the phenyl radical can additionally be substituted by halogen, for example 3-isopropylamino-3-(3-methyl-phenoxy)~2-propanol, 1-( 2-chloro-5-methyiphenoxy) -3-isopropylamino-2-propanol or 225 tert.-butylammo-l-(2-chloro-5-methylphenoxy)-2-propanol, 3(carbamoylphenoxy-1ower ’alkylamino)-1-(lower alkyl-phenyl)-2propanols, for example 3-(2-(4-carbamoylphenoxy)-ethylamino]-l-(2 methyl- 18 r ν phenyl)-2-propanol, l-(lower alkenyl-phenoxy)-3-lower alkylanjino-2-propanols, for example l-(2-allyl-phenoxy)-3-isopropylamino-2-propanol, l-(lower alkynyl-phenoxy)-3-lower alkylamino-2propanols, for example l-(2-ethynyl-phenoxy)-3-isopropylamino5 2-propanol, 1-( cycloalky1-phenoxy)-3-lower alkylamino-2-propanols, for example l-(2-cyclopropyl-phenoxy)-3-isopropylamino-2-propanol or 3-tert.-butylamino-1-(2-cyclopentylphenoxy)-2-propanol, 1-(hydroxy-lower alkyl-phenoxy)-3-lower alkylamino-2-propanols, for example l-(2-hydroxymethyl-phenoxy) 3-isopropylamino-2-propanol, 1-(lower alkoxy-lower alkylphenoxy)-3-lower alkylamino-2-propanols, for example 3-isopropylamino-l- (2-me thoxyme thy 1-phenoxy) -2-propanol, 3-tert.butylamino-l-(2-methoxymethyl-phenoxy)-2-propanol or 3-isopropylamino-1-[4-(2-methoxyethyl)-phenoxy]-2-propanol, 115 (carbamoyl-lower alkyl-phenoxy)-3-lower alkylamino-2-propanols, for example l-(4-carbamoylmethyl-phenoxy)-3-isopropylamino-2propanol, l-(lower alkoxycarbonylamino-lower alkyl-phenoxy)-3lower alkylamino-2-propanols, for example 3-isopropylamino-l[4-(2-methoxycarbonylamino-ethyl)-phenoxyJ-2-propanol, 120 (halogeno-lower alkoxycarbonylamino-lower alkyl-pyridyloxy)-3lower alkylamino-2-propanols, for example Ϊ-[3-chlor0-4-(2methoxycarbonylamino-ethyl)-2-pyridyloxy]-3-isopropylamino-2propanol, l-(lower alkoxy-phenoxy)-3-lower alkylamino-2--propanols, for example 3-isopropylamino-l-(2-methoxy-phenoxy)-225 propanol, 1-(lower alkenyloxyphenoxy)-3-lower alkylamino-2-propanols, for example l-(2-allyloxy-phenoxy)-3-isopropylamino-2propanol, 1-(2-allyloxy-phenoxy)-3-tert.-butylamino-2-propanol 427θ6 or 3-isopropylamino-l-(2-methylallyloxy-phenoxy)-2-propano), 1(lower alkynyloxy-phenoxy)-3-lower alkylamino-2-propanols, for example 3-isopropylamino-l-(2-propargyloxy-phenoxy)-2propanol, 3-lower alkylamino-1-(lower alkylthio-lower alkoxy5 phenoxy)-2-propanols, wherein the sulphur atom is separated from the oxygen atom by 2-3 carbon atoms, for example 3isopropylamino-l-[4-(2-methylthioethoxy)-phenoxy]-2-propanol, l-(halogeno-phenoxy)-3-lower alkylamino-2-propanols, for example 3-tert.-butylamino-l-(2-chloro-phenoxy)-2-propanol, ΙΙΟ (lower alkylthio-phenoxy)-3-lower alkylamino-2-propanols, for example 3-isopropylamino-l-(2-methylthio-phenoxy)-2-propanol, 1-(lower alkanoyl-lower alkanoylamino-phenoxy)-3-lower alkylamino-2-propanol, for example l-(2-acetyl-4-n-butyrylaminophenoxy)-3-isopropylemino-2-propanol, l-(cyano-phenoxy)-315 lower alkylamino-2-propanols, for example 3-tert.-butylaminol-(2-cyano-phenoxy)-2-propanol or l-(2-cyano-phenoxy)-5-isopropylamino-2-propanol, l-(lower alkanoylamino-phenoxy)-3lower alkylamino-2-propanols, for example 1-(4-acetylaminophenoxy)-3-isopropylamino-2-propanol, 3-lower alkylamino-120 (lower alkylsulphonylaiiiino-phenoxy)-2-propanols, for example 3isopropylamino-l-(4-methylsulphonylamino-phenoxy)-2-propanol, l-(morpholino-thiadiazolyloxy)-3-lower alkylamino-2-propanol, for example 3-isopropylamino-l-(4-morpholino-l,2,5-thiadiazol3-yloxy)-2-propanol, 3-lower alkylamino-1-(oxo-5,6,7»8-tetra25 hydro-benz-naphthyloxy)-2-propanols, for example 3-isopropylamino-l- (5-oxo-5,6,7,8-tetrahydro-l-naphthyloxy)-2-propanol, or 3-lower alkylamino-1-(oxo-1,2,3,4-te trahydro-benz-quinolinyl_ 20 _ oxy)-2-propanols, for example 3-isopropylamino-1-(2-oxo-l,2,3, 4-tetrahydro-5-quinolinyloxy)-2-propanol or 3-tert.-butylamino1-(2-oxo-l,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-RAr= -CHR, I -CH(II) -NH-R. wherein R1 and Rg have the abovementioned meanings, Ar2 represents a monocyclic or polycyclic, carbocyclic radical which contains at least one ring of aromatic character and Rg denotes hydrogen or lower alkyl, and also comprises the salts thereof which can be used pharmaceutically, above all the corresponding acid addition salts thereof.

A carbocyclic radical Ar2 of aromatic character has, for example, the meaning indicated above for the group Ar^ and is, above all, phenyl, as well as an optionally partially saturated, bicyclic, aromatic hydrocarbon radical, such as naphthyl, for example 1- or 2-naphthyl, 1,2,3,4-tetrahydroben2-naphthyl, or benz-indanyl, for example 4- or 5-indanyl, and such radicals can be substituted, for example like the corresponding groups Ar^, and contain, above all, halogen, lower alkyl, lower alkoxy, lower alkylsulphonylamino and/or nitro, for example the corresponding substituents described above.

A group R-j_ in the above compounds of the formula II 5 is, above all, lower alkyl, especially lower alkyl branched at the linking carbon atoms, above all isopropyl or tert.-butyl.

In addition to hydrogen, Rg also represents lower alkanoyl, for example acetyl or pivaloyl.

The radical R^ denotes hydrogen or lower alkyl, 10 especially methyl.

In the above compounds of the formula II» Arg represents, for example, naphthyl, for example 1-naphthyl, lower alkoxy-phenyl, for example 2,5-dimethoxy-phenyl, halogenophenyl, for example 3,4-dichlorophenyl, nitrophenyl, for example 4-nitrophenyl, lower alkylsulphonylamino-phenyl, for example 4-methylsulphonylamino-phenyl, carbamoyl-hydroxyphenyl, for example 4-carbamoy1-3-hydroxyphenyl, or 1,2,3,4tetrahydro-benz-naphthyl, for example 1,2,3,4-tetrahydro-5naphthyl, Rj denotes, above all, lower alkyl branched at the Uniting carbon atoms, for example isopropyl or tert.-butyl, Rg is, in particular, hydrogen and R^ represents, above all, hydrogen or methyl.

Compounds of the above structural formula II which have beta-receptor-blocking properties are, above all, the follow25 ing compounds in which lower alkyl R^ i-s branched at the linking carbon atom: 1-(naphthyl)-2~lower alkylaminoethanols, for example 2-isopropylamino-I-(l-naphthyl)-ethanol, 43766 1-(lower alkoxyphenyl)-2-lower alkylamino-ethanols, for example 2-tert.-butylamino-1-(2,5,-dimethoxy-phenyl)-ethanol, 1-(halogenophenyl)-2-lower alkylamino-ethanols, for example 1-(3,4-dichlorophenyl)-2-isopropylamino-ethanol, 2-lower alkyl5 amino-1-(nitrophenyl)-2-propanols, for example 2-isopropylamino-1-(4-nitrophenyl)-propanol, 2-lower alkylamino-1-(lower alkylsulphonylamino-phenyl)-ethanols, for example 2-isopropylamino-1- (4-methylsulphonylamino-phenyl)-ethanol, 1-(carbamoylhydroxyphenyl)-2-lower alkylamino-ethanols, for example 1-(410 carbamoyl-3-hydroxyphenyl)-2-isopropylamino-ethanol or 1-(4carbamoyl-3-hydroxyphenyl)-2-tert.-butylamino-ethanol, 2lower alkylamino-1-(1,2,3,4-tetrahydro-benz-naphthyl)ethanols, for example 2-tert.-butylamino-1-(1,2,3,4-tetrahydro5-naphthyl)-ethanol, and acid addition salts thereof which can be used pharmaceutically.

Compounds with thrombocyte-function-regulating properties which are employed in the pharmaceutical preparations of the invention are O-acetyl-salicylic acid, or salts thereof with bases, which can be used pharmaceutically, and 2,6-bis20 [di-(2-hydroxyethyl)-amino]-4,8-di-piperidino-pyrimido [5,4-d]pyrimidine(dipyramidol) or acid addition salts thereof which can be used pharmaceutically, compounds of the formula Ph, N Phj-N^ \=0 (III) 0=C•N C= I I -CH-Alk-S(0)-Ph, n J - 23 43766 wherein each of the radicals Ph^ and Phg independently of one another represents a phenyl radical vzhich is optionally substituted by lower alkyl, for example methyl, hydroxyl, lower alkoxy, for example methoxy, and/or halogen, especially fluorine, chlorine or hromine, Alk denotes a lower alkylene radical vzhich separates the sulphur atom from the ring carbor atom by at least 2 carbon atoms, n represents 0, 1 or 2 and Γ represents a phenyl radical which is optionally substituted hy lower allcyl, for example methyl, lower alkoxy, for example methoxy, and/or halogen, foi- example fluorine, chlorine or bromine, and salts of such compounds with bases, which can be used pharmaceutically. These compounds exhibit pronounced thrombocyte-function-regulating properties, there being no influ or only an insignificant influence on the blood coagulation time.

Lower alkylene Alk in the above compomids preferably contains up to 4 carbon atoms and is, for example, 1- or 2methyl-l,2-ethylene, 1,3-propylene, 2-methyl-l,3-propylene, 1,4-butylene and, above all, 1,2-ethylene.

The thrombocyte-function-regulating properties are particularly pronounced in compounds of the formula III where one of the radicals Ph^ and Phg denotes phenyl or hydroxyphenyl, especially 4-hydroxy-phenyl, and the other denotes phenyl or lower alkyl-phenyl, especially 3-methyl-phenyl, Alk represents lower alkylene with 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 Ph^ represents phenyl, and salts of such - 24 42766 compounds with bases, which can be used pharmaceutically. 1,2-Diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxopyrazolidine and l-(4-hydroxy-phenyl)-2-phenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrasolidine, and salts cf these compounds with bases, which can be used pharmaceutically, arc mentioned in particular as preferred compounds with plateletfunction-regulating properties.

The compounds with alpha-receptor-blocking properties, which may be optionally added to the caiibinaticn, according to the invention, of a beta-receptor-hlocking active compound and an active compound which regulates the thrombocyte function, are hydrogenated ergot alkaloids, for example dihydroergotamine, dihydroergocomine, dihydroergocristine or dihydroergocx'yptine or mixtures thereof, as well as acid addition salts thereof which can he used pharmaceutically, and also N-benzyl-M-halogeno-lower alkylamines, for example N,Ndibenzyl-N-(2-chloroethyl)-amine or N-benzyl~N-(2~chloroethyl)~ N-(l-methyl-2-phenoxy-ethyl)-amine, 2-tert.-aminomethy1-benzcdioxanes, for example 2-piperidinomethyl-benzodioxane or 1,4bis-(2~benzodioxanylmethyl)-piperazine, N-substituted dibenzazepines, for example 6-allyl-6,7-dihydro-5H-dibenz[c,e]azepine, or, in particular, methyl-2-imidazolines which are substituted in the 2-position, such as 2-benzyl-imidazolines and, above all, 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl ]-2-imidazoline , as well as pharmaceutically usable acid addition salts of such compounds.

Acid addition salts, which can he used pharmaceutically, - 25 42766 of the abovementioned compounds are those with inorganic acic 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 acj methylmaleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenxoic acic 2-acetoxy-benzoic acid, emhonic acid, nicotinic acid or .isonicotinic acid, or organic sulphonic acids, for example methanesulphonic acid, ethanesulphonic acid, 2-hydroxy-ethane sulphonic acid, ethane-1,2-disulphonic acid, benzenesulphonic acid, 4-methylbenzenesulphonic acid or naphthalcne-2-sulphoni acid.

Salts of the abovementioned compounds with bases are, above all, metal salts or ammonium salts, such as alkali meta salts and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, as well as ammonium salts vzith ammonia or suitable organic amines, possible bases for salt formation being, above all, aliphatic, cycloaliphati cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiary monoamines, diamines or polyamines, as well as heter cyclic bases, such as lower alkylamines, for example triethyl amine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, his-(2-hydroxyethyl)-amine or tris-(2-hydroxyethyl)ainine, basic aliphatic esters of carboxylic acids, foi' exampl 4-aininohenzoic acid 2-diethylamino ethyl ester, lower alkylen amines, for example 1-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 form of pure isomers, especially of optically active antipodes.

The Invention relates in particular to pharmaceutical preparations which contain a beta-receptar-blocking compound, viz, one of those mentioned above, together with a compound which regulates the thrombocyte-function, viz, one of those mentioned above, and optionally an alpha-receptor-blocking compound, viz, one of those mentioned above, as well as the manufacture of these preparations, which can be used for the prophylactic and therapeutic treatment 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(1-naphthyloxy)-2-propanol, 3-isopropylamino-3-(3-methylphenoxy)-2-propanol, 1-(2-allyl-phenoxy)-3-isopropylamino-2propanol, 1-(4-acetylamino-phenoxy)-3-isopropylamino-2propanol, 1-(4-indolyloxy)-3-isopropylamino-2-propanol,3isopropylamino-1-[4-(2methoxyethyl)-phenoxy]-2-propanol, 3isopropylamino-l-[4-(2-methylthioethoxy)--2-propanol, 1- [2-(3,4-dimethoxyphenyl)-ethylamino]-3-(3-methyl-phenoxy) 2- propanol, l-isopropylamino-3-(l,2,3,4-tetrahydro-l,4ethano-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-indanylo: 3- isopropylamino-2-propanol, l-(5-niethyl-8-cumary].oxy)-3isopropylamino-2-propnnol, 4-(3-isopropylamino-2-bydroxy1-propyloxy)-2-methyl-indole, or above all,- 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component an< 2,6-bis-tdi-(2-hydroxyethyl)-amino] - 4,8-di-piperidinopyrimido[5,4-d]pyrimidine, or an acid addition salt thereof which can be used pharmaceutically, but especially 1-(4hydroxy-phenyl)-2-pheny1-4-(2-phenylsulphinyl-ehtyl)-3,5-dio: pyrazolidine or, above all, 1,2-dipheny1-4-(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, as well as 2-[n-(3hydroxy-phenyl)-M-(4-methyl-phenyl,-aminomethyl]-2-imidazolii or an acid addition salt thereof which can be used pharmaceutically, as the alpha-receptor-blocking component which ii optionally added with the proviso that inclusion in the pharmaceutical preparations of the alpha-receptor-blocking compound 2-/N-(3-hydroxyphenyl)-N-(4-methyl-phenyl)-amino- 28 43786 methyl/-2-imidazoline or an acid addition salt thereof, which can be used pharmaceutically, is indispensable, if such pharmaceutical preparations contain a beta-receptor-blocking compound as defined above and 2,6-bis-/di-(2-hydroxyethyl)-amino/ -4,8-di-piperidino-pyrimido/5,4-4/pyrimidine, or an acid addition salt thereof which can be used pharmaceutically, as the component which regulates the thrombocyte-function.

The invention relates above all to the new pharmaceutical preparations which contain 1-(2-allyloxy-phenoxy)-3-isopropylamino-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-dioxopyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombocyte-function, and which can optionally contain (3-hydroxyphenyl)-N-(4-methy1-phenyl)-aminomethyl/-2-imidazoline, or an acid addition salt thereof which can be used pharmaceutically, as the alpha-receptor-blocking component, and which, because of their low degree of side effects, are particularly suitable for the treatment of coronary heart diseases.

Further preferred pharmaceutical preparations according to the present invention are those which contain 3-isopropylamino-l-/^-(2-methoxy-ethyl)-phenoxy7~2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, and l,2-diphenyl-4-(2phenylsulphinyl-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, or which contain 3 42766 1-(4-indolyloxy)-3-isopropylamino-2-propanol, or an acid additit salt thereof which can be used pharmaceutically, as the betareceptor-blocking component, and O-acetyl-salicylic acid, or a salt thereof with a base, which can be used pharmaceutically, 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-blocking component, and 1,2-diphenj 4-(2-phenylsulphiny1-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. 43766 A further subject of the present invention is the use, for the treatment of coronary heart diseases, of pharmaceutical preparations v/hich contain a beta-receptor-blocking compound, such as one of the abovementioned compounds, especially one of 5 the compounds with this type of action designated above as being preferred, above all l-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol or an acid addition salt thereof which can bs used pharmaceutically, and a compound which regulates the thrombocyte function, such as one of the abovementioned com]_q pounds, especially one of the compounds with this type of action designated above as being preferred, above all 1,2-diphenyl-ά-(2-ph enylsulphinyl-ethyl)-3,5-dioxo-pyrazol.idine, or a salt thereof with a base, which can be used pharmaceutically, and optionally, an alpha-receptor-blocking compound, such as one of the abovementioned compounds, especially one of the '' compounds with this type of action designated above as being preferred, above all 2-[N-(3-hydroxy-phenyl)-N-(4-methylphenyl) -aminomethyl J-2-imidazo3 ine, or an acid addition salt thereof which can be used pharmaceutically, as the pharmaceu20 tical active components.

Further pharmaceutical preparations which may be mentioned as being preferably suitable, within the scope of the present invention, for the treatment of coronary heart diseases are those which contain 3“isopropylamino-l-[4~(225 methoxyethyl)-phenoxy]-2-propanol or an acid addition salt thereof which can be used pharmaceutically, as the betareceptor-blocking component, and I,2-diphcnyl-4-(2-phenyl31 42766 sulphinyl-ethyl)-3,5-dioxo-pyrazolidine, or a salt thereof witfc a base, which can be used pharmaceutically, as the component which regulates the thrombocyte function, or those which contain l-(4-indolyloxy)--3-isopropylamino-25 propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking component, anc O-acetylsalicylic acid, or a salt thereof with a base, which can he used pharmaceutically, as the component which regulates the thrombocyte function, or which contain l-(4-indolyloxy)~ 3-isopropylamino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptorhlocking component, and l,2-diphenyl-4-(2-phenylsulphinyletbyl)-3,5-dioxo-pyrazolidine, or a salt thereof vzith a base, which can be used pharmaceutically, as the component which regulates tho 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 alphareceptor-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 active compound to the active compound which regulates the thrombocyte function, especially an active compound of the 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 compound to the alpha-receptor-blocking active compound, which is optionally present, are preferred.

The absolute dosage of the active components in the new pharmaceutical preparations 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 0.4 g to about 0.8 g, of an active compound which regulates the thrombocyte function, especially of an active compound of the structural formula III, and optionally from about 0.005 g to about 0.2 g, preferably from about 0.01 g to about 0.1 g, of an alpha-receptor-blocking active compound. 2o 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 l-(2-allyloxy~phenoxy)-3-isopropylamino--2propanol, 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 l,2-diphenyl-4(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazol.idine, or of a salt thereof with a base, which can he used pharmaceutically, and 3.3 437BB optionally, about 0.005 g to about 0.2 g, preferably from about 0.01 g to about 0.1 g, of 2-/&-(3-hydroxyphenyl)-N-(4methyl-phenyl)-aminomethyl7-2-imidazoline, or of an acid addition salt thereof which can be used pharmaceutically.

Further preferred pharmaceutical preparations according to the present invention contain from about 0.02 g to about 0.25 g, preferably from 0.05 g to about 0.150 g, of 3-isopropy1amino-1-/3-(2-methoxyethyl)-phenoxy7-2-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 l,2-diphenyl-4-(2-phenylsulphiny1-ethyl)-3,5dioxo-pyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, or from about 0.005 g to about 0.080 g preferably from about 0.015 g to about 0.050 g, of 1-(4-indolyox; 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 0acetyl-salicylic acid, or of a pharmaceutically acceptable salt thereof with a base, or from about 0.005 g to about 0.080 g, preferably from about 0.015 g to about 0.050 g, of 1-(4indolyloxy)-3-isopropylamino-propdnol, 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 l,2-dix>henyl-4-(2-phenylsulphinyl-ethyl)-5»5dioxo-pyrazolidine, or of a pharmaceutically acceptable salt thereof with a base.

In addition to the pharmacological active compounds, the new pharmaceutical preparations usually contain suitable excipients and auxiliaries which facilitate processing of the active compound to give the preparations which can he used pharmaceutically.

Preferably, the preparations, above all preparations which can he administered orally and which can be used for the preferred type of administration, such as tablets, dragees and capsules, and also preparations v/hich 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 invention 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 he obtained by combining the active compounds with solid excipients, optionally granulating a resulting mixture and processing the mix35 ture or granulates, after adding suitable auxiliaries if desirec 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 phosphate, 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, disintegrating agents, such as the abovementionec starches, and also carboxymethyl-starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regTilating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee 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 gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, in order to manufacture 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 themselves have actions oi short duration can be prolonged by incerperating one or more active compounds into a suitable excipient which effects slow release of the active compound or active 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 soft, sealed capsules made of gelatine and a plasticiser, such as glycerol or sorbitol. The push-fit capsules can contain, the active compounds in the form of granules, for example mixed with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, optionally, stabilisers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols, it also being possible to add stabilisers.

Possible pharmaceutical preparations which can be used rectally are, for example, suppositories, which consist of a combination of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. In addition, it is also poss25 ible to use gelatine rectal capsules which consist of a combination of the active compounds with a base; possible base materials are, for example, liquid triglycerides, polyethylene ., 43766 glycols or paraffin hydrocarbons.

Suitable formulations for parenteral administration ar 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 exampl ethyl oleate or triglycerides, are used, or aqueous injection suspensions, which contain substances which increase the viscosity, 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-(2allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride and 0.3 g of l,2-ydiphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxoί pyrazolidine can be manufactured as follows: Composition (for one tablet) 1-(2-allyloxybphenoxy)-3-isopropylamino-2propanol hydrochloride 0.080 g 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5dioxo-pyrazolidine 0.300 g maize starch 0.088 g colloidal silica 0.020 g - 38 43766 magnesium stearate 0.002 stearic acid 0.005 sodium carboxymethyl starch 0.025 water q.s.

The lacquer-coated tablets are manufactured as follows (for 10,000 tablets): A mixture of 800 g of l-(2-allyloxy-phenoxy)-3-iso~ propylamino-2-propanol hydrochloride, 3,000 g of 1,2-diphenyl4-(2-phenylsulphinyl-ethyl)-3,5~dioxo-pyrazolidine, 300 g of 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 forced through a sieve of 3 mm mesh width and dried at 45°C 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 tablets are coated, in’ a dragee-coatingkettle 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 60°C at the same time. , 43766 Example 2: Lacquer-coated tablets containing 0.16 g of 1-(2allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride and 0.4 g of l,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo5 pyrazolidine can be manufactured as follows: Composition (for one tablet): 1-(2-allyloxy-phenoxy)-3-isopropylamino-2propanol hydrochloride 0.160 g 1,2-diphenyl-3-(2-phenylsulphinyl-ethyl)-3,510 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): A mixture of 3,200 g of l-(2-allyloxy-phenoxy)-3-iso20 propylamino-2-propanol hydrochloride, 8,000 g of 1,2-diphenyl4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine, 750'g of 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 45°C for 30 minutes in a fluidised bed drier. The dry granules are forced through a sieve of 1 mm mesh width and mixed with a 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 follows: ,000 of the above pressed tablets are coated, in a drageecoating kettle 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, ty spraying continuously with 1he soLution in the course of 30 minutes; the coating is dried by blowing in warm air at 60°C at the same time.

Example 3: Punctiform tablets containing 0.08 g of l-(2-allyloxyphenoxy)-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-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)20 aminomethyl]-2-imidazoline hydrochloride, the latter heing in a form suitable for slow release, are manufactured as follows: Composition of tablets suitable for the slow release of 2-[N-, (3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-2-imidazoline 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 0.0050 g 0.0005 g hydrogenated cottonseed oil magnesium stearate The tablets containing 2-[N-(3-hydroxy-phenyl)-N-(4methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride are 5 manufactured as follows (for 10,000 tablets): A mixture of 500 g of 2-[N-(3-hydroxy-phenyl)-N-(4methyl-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 granu10 lated through a sieve of 3 mm mesh width, dried at 45°C 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-dioxopyrazolidine are manufactured as follows: The granules described in Example 1 are processed to 20 tablets and the tablet, described above, for the slow release of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl)2- imidazoline hydrochloride is pressed into the former pressed tablet in such away that one surface of the tablet which is pressed in is visible from the outside. A highly domed press tool 11.5 mmi in diameter is used for the outer cover, which has a weight of 0,520 g.

Example 4: / , Punctiform dragees containing 0.08 g of l-(2-allyloxyphenoxy)-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-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)aminomethyl]-2-imidazoline hydrochloride, the latter being in a form suitable for slow release, are manufactured as follows: ,000 g of the tablets obtainable according to the pro10 cess described in Example 3 are placed in a dragee-ccatfcg kettle cm in diameter and provided with a protective lacquer consisting 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 oi lactose and 105 g of talc. This protective lacquer is sprayed on continuously for 30 minutes and dried at the same time with warm air at 60°C. 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 20 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 hy about 0.145 g and a pure sugar syrup is then used until a final dragee weight of about 0.890 g is reached.

Example 5: Punctiform tablets containing 0.08 g of l-(2-allyloxy- 43 -jj 43766 phenoxy)-3-isopropylamino-2-propanol hydrochloride, 0.3 g of 1.2- diphenyl-4-(2-phenylsulphinyl-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 form suitable for slow release, are manufactured as follows: Composition of tablets suitable for the slow release of 2-ΓΝ(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl)-2-imidazoline hydrochloride (for 1 tablet): 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)10 aminomethyl]-2-imidazoline hydrochloride 0.100 g hydroxypropylmethylcellulose (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-(415 methyl-phenyl)-aminomethyl]-2-imidazoline hydrochloride and the punctiform tablets which additionally contain 1-(2allyloxy-phenoxy)-3-isopropylamino-2-propanol hydrochloride and l,2-diphenyl-4-(2-phenylsulphinyl-ethyl) -3,5-dioxopyrazolidine are manufactured according to the process des20 cribed in Example 3. The punctiform tablets can be converted into punctiform dragees by the process described in Example 4.

Example 6: Capsules containing 0.1 g of 3-isopropylamino-l-[425 (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: Composition (for one capsule) 3-isopropylamino-l-[4-(2-methoxyethyl)-phenoxy]2-propanol tartrate 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5dioxo-pyrazolidine colloidal silica hydroxypropylmethylcellulose (low viscosity) gelatine magnesium stearate polyvinylpyrrolidone 0.1 g 0.4 g 0.013 g 0.042 g 0.012 g 0.006 g 0.007 g The capsules are manufactured as follows (for 10,000 capsules): A mixture of 1,000 g of 3-isopropylamino-l-[4-(2methoxyethyl)-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 40°C. 4,000 g of l,2-diphenyl-4-(2-phenylsulphinyl-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 45°C. The two lots of dried granules are combined and mixed with 420 g of hydroxypropylmethylcellulose, g of colloidal silica and 60 g of magnesium stearate and the mixture is filled, by machine, into 10,000 capsules of size 000. - 45 43766 Example 7: Tablets containing 0.020 g of l-(4-indolyloxy)-3isopropylamino-2-propanol and 1.0 g of O-acetylsalicylic acid are manufactured as follows: Composition (for one tablet): l-(4-indolyloxy)-3-isopropylamino-2-propanol 0.020 g O-acetylsalicylic acid 1.0 g rice starch 0.1 g The tablets are manufactured as follows (for 5,000 Ιθ tablets): A mixture of 100 g of l-(4-indolyloxy)-3-isopropylamino-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 crystalline O-acetylsalicylic acid are added to this mixture and the whole is mixed well. The mixture is then pressed to give ,000 tablets.

Example 8: Capsules containing 0.020 g of l-(4-indolyloxy)-3~ isopropylamino-2-propanol and 0.4 g of l,2-diphenyl-4-(220 phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine are manufactured as follows: Composition (for one capsule): l-(4-indolyloxy)-3-isopropylamino-2-propanol 0.020 g 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,525 dioxo-pyrazolidine 0.4 g gelatine 0.015 g magnesium stearate 0.005 g maize starch 0.0S0 g - 46 427 The capsules are manufactured as follows (for 10,000 capsules): A mixture of 200 g of l-(4~indolyloxy)-3-isopropylamino-2-propanol and 400 g of maize starch is forced through a 5 sieve with a mesh width of 0.5 mm, 100 g of l,2-diphenyl-4-(2phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine are added and the whole is mixed. A further 3,000 g of l,2-diphenyl-4(2~phenylsulphinyl-ethyl)-3,5-dioxo-pyrazolidine are added to this mixture and the whole is mixed well. The mixture is 10 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 45°C. 200 g of maize starch and 50 g of magnesium stearate are added to the dried granules and the mixture is filled, hy machine, into ,000 capsules of size 00.

Example .9: In the above Examples 1-8 it is possible to use 3isopropylamino-1-(1-naphthyloxy)-2-propanol, 1-(2-allylphenoxy)-3-isopropylamino-2-propanol, l-(4-acetylamino20 phenoxy)-3-isopropylamino-2-propanol, 3-isopropylamino-l(4-(2-me thyIthioe thoxy)-phenoxy)-2-propano1, 1-(2-(3,4dimethoxyphenyl)-ethylamino]-3-(3-methyl-phenoxy)-2propanol, l-isopropylamino-3-(l,2,3,4-tetrahydro-l, 4ethano-5-naphthyloxy)-2-propanol, 1-tert.-butylamino-325 (1,2,3,4-tetrahydro-2,3-dihydroxy-5-naphthyloxy)-2-propanol, l-(7-indenyloxy)-3-isopropylamino-2-propanol, l-(7-indany]oxy) - 47 4 27 66 3-isopropylamino-2-propanol, l-(5-methyl-8-cumaryloxy)-3isopropylamino-2-propanol, 4-(3-isopropylamino-2-hydroxy1-propyloxy)-2-methyl-indole or 2-tert.-butylamino-1(7-ethyl-2-benzofuranyloxy)-ethanol, preferably in the form of an acid addition salt which can be used pharmaceutically, such as the hydrochloride, in place of the active compounds used in these examples as the beta-

Claims (15)

CLAIMS:

1. Pharmaceutical preparations for the prophylactic and therapeutic treatment of coronary heart diseases which contain, (1) a beta-receptor-blocking compound which is a compound of the formula 0-R„ (I) ΑΓ χ 0 —CH 2 —CH CH 2 -NH R x wherein ΑΓ χ 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 2. - phenyl-4-(2-phenylsulphinyl-ethyl)-3,5-dioxo-pyrazo- 52 43766 lidine or 1,2-diphenyl-4-(2-phenylsulphinyl-ethyl)3,5-dioxo-pyrazolidine, or a salt thereof with a hase, which can be used pharmaceutically, as the component which regulates the thrombocyte function, and 2-[N-(3-hydroxy-phenyl)-N-(4methyl-phenyl)-aminomethyl]-2-imidazoline, or an acid addition salt thereof which can be used pharmaceutically, as the alphareceptor-blocking component which is optionally added, with the proviso that inclusion in the pharmaceutical preparations of (3) an alpha-receptor-blocking compound which is 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 methy1-2-imidazoline which is substituted in the 2-position, or acid addition salts of such compounds which can be used pharmaceutically is indispensable if such pharmaceutical preparations contain (1) a compound of the formula I or of the formula II or a salt of such compounds which can be used pharmaceutically and (2) 2,6-bis-/di-(2-hydroxyethyl)-aminq74,8-di-piperidino-pyrlmido/5,4-d7pyrimidine or an acid addition salt thereof which can be used pharmaceutically.

2. Pharmaceutical preparations according to Claim 1, characterised in that these contain 3-isopropylamino-l-(1naphthyloxy)-2-propanol, 3-isopropylamino-3-(3-methylphenoxy) -2-propanol, l-(2-allyl-phenoxy)-3-isopropylamino5 2-propanol, l-(4-acetylamino-phenoxy)-3-isopropylamino-2propanol, 1-(4-indolyloxy)-3-isopropylamino-2-propanol, 3-isopropylamino-l-C4-(2-methoxyethyl)-phenoxy]-2-propanol, 3-isopropylamino-l-[4-(2-methylthioethoxy)-phenoxy!-2propanol, 1-(2-allyloxy-phenoxy)-3-isopropylamino-2-propanol,

3. Pharmaceutical preparations according to Claim 1, characterised in that these contain 1-(2-allyloxy-phenoxy)-3isopropylamino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor- 53 42766 blocking component, and l,2-diphenyl-

4. -(2-phenylsulphinylethyl)-3,5-dioxo-pyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombocyte-function. S .4. Pharmaceutical preparations according to Claim 1, characterised in that these contain 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 adde< lo 5. Pharmaceutical preparations according to Claim 1, characterised in that these contain 3-isopropylamino-l-[4(2-methoxyethyl)-phenoxy]-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the betareceptor-blocking component, and l,2-diphenyl-4~(2-phenyl15 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.

5. Addition salt thereof which can he 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 O-acetylsalicylic acid, or of a pharmaceutically acceptable salt thereof with a base. 5 active compound. 5 which regulates the thrombocyte function. 5 2,6-bis- (di-(2-hydroxyethyl)-aminol -4,8-di-piperidino-pyrimido [5,4-dJpyrimidine, or an acid addition salt thereof which can be used pharmaceutically, or a compound of the formula / N \ Ph—N C=0 2 I * (iii) 0=C-CH—Aik—S(0) n —Ph 3 wherein each' of 'the radicals Ph^ and Ph 2 independently of one

6. Pharmaceutical preparations according to Claim 1, characterised in that these contain 1-(4-indolyloxy)-3-iso- 54 43766 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

7. Pharmaceutical preparations according to Claim 1, characterised in that these contain 1-(4-indolyloxy)-3-isopropylamino-2-propanol, or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptor-blocking

8. Pharmaceutical preparations according to one of Claims 15 1-7, characterised in that the ratio of the beta-receptorblocking active compound to the active compound which regulates the thrombocyte function, particularly an active compound of the type of the structural formula III, is about 1:1 to about 1:50 (ratio by weight) and the ratio of the beta-receptor20 blocking active compound to the alpha-receptor-blocking active compound, which is optionally present, is about 1:0.1 to about 1:1 (ratio by weight).

9. . Pharmaceutical preparations according to one of Claims 1-7, characterised in that these contain from about 0.00? g to 25 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 0.4 g to about 0.8 g, 43766 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, preferably from about 0.01 g to about 0.1 g, of an alpha-receptor-blockinp 10. Characterised in that these contain from about 0.005 g bo about 0.080 g, preferably from about 0.015 g to about 0.050 g, of l-(4-indolyloxy)-3-isopropylamino-2-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 15 to about 0.8 g, of l,2-diphenyl-4-(2-phenylsulphinyl-ethyl)3,5-dioxo-pyrazolidine, or of a pharmaceutically acceptable salt thereof with a base. 10 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 l,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3/ diojco-pyrazolidine, or of a salt thereof with a base, which car he used pharmaceutically, and, optionally, from about 0.005 g 15 to about 0.2 g, preferably from about 0.01 g to about 0.1 g, of 2-[N-(3-hydroxy-phenyl)-N-(4-methyl-phenyl)-aminomethyl]-?imidazoline, or of an acid addition salt thereof which can housed pharmaceutically.

10. Pharmaceutical preparations according to Claim 3 or 4, characterised in that these contain from about 0.02 g to about 0.25 g, preferably from about 0.04 g to about 0.2 g, of 1-(2allyloxy-phenoxy)-3-isopropylamino-2-propanol, or of an acid 10 component, and l,2-diphenyl-4-(2-phenylsulphinyl-ethyl)-3,5dioxo-pyrazolidine, or a salt thereof with a base, which can be used pharmaceutically, as the component which regulates the thrombocyte function. 10 1- [2-(3,4-dimethylphenyl)-ethylamino]-3-(3-methyl-phenoxy)2-propanol, l-isopropylamino-3-(1,2,3,4-tetrahydro-l,4-ethano5-naphthyloxy)-2-propanol, l-tert.-butylamino-3-(l, 2,3,4tetrahydro-2,3-dihydroxy-5-naphthyloxy)-2-propanol, 1-(7indenyloxy)-3-isopropylamino-2-propanol, 1-(7-indanyloxy)-315 isopropylamino-2-propanol, l-C5-meth.yl-8-cumaryloxy)-3isopropylamino-2-propanol, or 4-(3-isopropylamino-2-hydroxy1- propyloxy)-2-methyl-indole,or an acid addition salt thereof which can be used pharmaceutically, as the beta-receptorblocking component, 2,6-bis-[di-(2-hydroxyethyl)-amino!-4,8-di20 piperidino-pyrimido[5,4-4)pyrimidine, or an acid addition salt thereof which can be used pharmaceutically, l-(4-hydroxy-phenyl) 10 another represents a phenyl radical which is optionally substituted by lower alkyl, hydroxyl, lower alkoxy and/or halogen, Aik 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 Ph 3 represents a phenyl 15 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, and optionally, (3), an alphareceptor-blocking compound which is a hydrogenated ergot alkaloid, or a mixture of such alkaloids or acid addition salts 20 thereof which can be used pharmaceutically, or a N-benzy1-Nhalogeno-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 addition salts of such compounds which can be used pharmaceutically, with the proviso that inclusion in the pharmaceutical preparations of (3, an alpha-receptor-blocking compound which is a hydrogenated ergot alkaloid, or a mixture of such alkaloids or acid addition salts thereof which can be used pharmaceut5 ically, or a N-benzy1-N-halogeno-lower alkylamine, a 2 tert.aminamethyl-benzodioxane, a N-substituted dibenzazepine or a methyl-2-iaiidazoline which is substituted in the 2-position, or acid addition salts of such compounds which can be used pharmaceutically is indispensable if such pharmaceutical pre10 parations contain (1) a compound of the formula I or of the formula II or a salt of such compounds which can be used pharmaceutically and (2) 2,6-bls-/’di-(2-hydroxyethyl)-aminq/4,8-di-piperidino-pyrimido/5,4-d7pyrimidine or an acid addition salt thereof which can be used pharmaceutically. 51 43766 10 character, R^ denotes an optionally substituted aliphatic, cycloaliphatic or araliphatic hydrocarbon radical and R 2 represents hydrogen or the acyl radical of an organic carboxylic acid, or a compound of the formula 0-R, R, | 2 I 3 (ID Ar^-CH-CH—NH-R x 15 wherein R^ and R 2 have the abovementioned meanings, Ar 2 represents a monocyclic or polycyclic, carbocyclic radical which contains at least one ring of aromatic character,and R, denotes □ - 49 ., 42766 / ... hydrogen or lower alkyl, or a salt of such compounds which can be used pharmaceutically, (2) a compound which regulates the thrombocyte function which is O-acetyl-salicylic acid, or a salt thereof with a base, which can be used pharmaceutically,

11. Pharmaceutical, preparations according to Claim 5, 20 characterised in that these contain from about 0.02 g to about 0.25 g,'preferably from 0.05 g to about 0.150 g, of 3isopropylamino-1-[4-(2-methoxyethyl)-phenoxy]-2-propanol, or of an acid addition salt thereof which can he used pharmaceutically, and from about 0.2 g to about 1.0 g, preferably from 25 about 0.4 g to about 0.8 g, of l,2-diphenyl-4-(2-phenylsulphinyl-ethyl )-3,5-dioxo-pyrazolidine, or of a salt thereof with a base, which can be used pharmaceutically. 1ί.

12. Pharmaceutical preparations according to Claim 6, characterised in that these contain from about 0.005 g to' about 0.080 g, preferably from about 0.015 g to about 0.050 g, of l-(4-indolyloxy)-3-isopropylamino-2-propanol, or of an acid

13. Pharmaceutical preparations according to Claim 7,

14. Preparations according to one of Claims 1-13 which - 57 43766 ~v can be administered orally.

15. Pharmaceutical preparations according to claim 1 as hereinbefore described in examples 1-9.