Note: Descriptions are shown in the official language in which they were submitted.
~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)
- CH2 - LH CH2 - NH R
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::: : : . : ' ' ' . ' : , ' .. ', , , . ~ :
1063516
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,
. .
- 4 -
" ,,
. ~; .
.. . . .... . .. . . . .. .. . . . . .
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
, .
- . : -
., . .. ~ , .~, - .
. ~
.
1063516
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.- ~ .
. ~
~; ,. ' ": . . : .. , ... ; .
1063516
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.
-- 10 --
~. `
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
:,
- 12 -
~ .
,''' ~ . ;. ' '' ~ '~ ',.
-: . ' . .' ' . ' . : . . . . . ' .. . . ' ~ , '
1063516
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
- 13 -
.
.. . . ~ ~ '
;; ' 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.
- 14 -
.' , , - . ,
.. 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-
-- 19 --
.
.
.
~ - .
, 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, -
. . .
- 21 -
,
~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
- 23 -
'~` 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
- 24 -
.
. . ., - , ~ ,
.
. :' . - . :. : .
' '. '- ' ,,', '- . . :
- . . . . .
1063S16
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-
~!
1063S16
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
- 31 -
i... ~... , ,,, , ~ . ....... .. . ,. ,., .. .. .. ,...... - ~ ... .. . . .. .
, , , , , : , . , ,,, ~ -.. . , . : . , .:
; .. .:. .. . . . . . .. . :, .... . - . . ., . . . ~,.... . . . ... .
. . . . . .. .: . . , ,: ,....... .. , - ., . . : .. . . -
- 1063S16
~` 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
::
., ,
.
; ~ : ' : .. ' . . . -.'' ' ' ' ~ ,: ' ' ~ : - :
,, , ~.. , , ,, . ... ,.; ~ , ~ , ... ..
1063516
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.
- 37 -
,. - . . , . ,......... ~ . . , ,, .. ... ,., ~ . - . . - ...
. . . . -, . . . , ,. .... : , , .. ; .
. . . . .. . . .... . . . . .
i '." ' '." ' ':~''-' ,"'','".,.,''""' "''' ~,:; ;;'''
1063516
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 " ,,,, ,, , , ,, ,,, ", . . . ....
,. ~ . . . .:: ..
,.~, . ~ . .
,. .... ~. ,
1063S16
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
, :
.
i. ",. ', ' ' ,. i.' . ' ' , . ' '' ' ': ' ' ' ':
"' ' ' ' ' ' ' ' ' , ' ' ' , ' : ' ' - ' ' " , ~
:, . . : ,' '' ' ' ' ". , . ' ': '. ,'' ':, ,' ', ', , :' ' ' ., , ,' . ' ' '- ' ' . . .
" ' . : ' ' '. . ' , ,' , ,, ~ . , . ~ , . :
~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.
... .
- 40 -
f
~ . . - . . ~
:, . ,. ,.,.~.. , ,-
'
~' . ' . -
-`` 11~6351f~
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-
- 41 -
': -.. :
. ,,. ~ - ... , . ~ , , . . -
-~ ~ 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.
,'~
.,~ . .
.. . . .
1063S16
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.
- 44 -
... . . . . . . . . .. . .
' ' ', ' . ~ ' ' . ~ , ~ - . ` : ' . .
~, ' : , , ' ' .: ` .
'.': ' ' ' : , ' ' ': ' '
,
' 1~)6351~ ~ ~
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.
.
