DE2227423A1 - New pharmaceutical preparations - Google Patents

Description

CIBA-GKICV AG, BASEL (ßCIF / JKIZ)

Case 4-7556 / +
Germany

New pharmaceutical preparations

The invention relates to new pharmaceutical preparations for the treatment of hypertension, which are opposite to previous therapy mainly due to the lack of secondary Distinguish effects.

In the previously usual therapy of arterial. Hypertension were substances used in high? Pro zentäatz OCE cases to sedation (for example, reserpine, Metfiyl dopa or Clohidin) to the orthostatic Blutdrue Kst or ungsn

209852/1105

(e.g. with guanethidine, bethanidine and related substances) or lead to hypercirculation and tachycardia (e.g. hydralazine or öuancydine). These disorders are each with linked to the mechanism of action of the substances, from which the great frequency of occurrence of the side effects is derived explains, In addition, these are not the only side effects of the respective preparations.

Arterial hypertension can be adequately controlled in about * \ 0% of cases with an adrenergic beta-blocker (e.g. 1- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride) in daily doses of 120-480%. Diuretics alone (eg hydrochlorothiazide in a daily dose of 20-60 mg) can also have a favorable effect on the blood pressure in about 3O-40 ^ of patients.

It has now been shown that the combined administration of the two types of active ingredients increases the likelihood a therapeutic success can be significantly increased, since the effects of the two combined types of active ingredients Supplement in a surprising way in such a way that this at least corresponds to an addition of the individual effects.

This creates an antihypertensive that is excellently suited for practical purposes, which is none of the above Side effects (sedation, orthostatic disorders, or hypercirculation). There sedation, othostasis or hypercirculation the usual way of life and work «-

20985? / 1105

-if - - ■

impair the patient's ability (e.g. driving a car), the new preparations represent a clear, considerable advance in the therapy of hypertension.

The compounds of the formula I are particularly useful as β-blockers

OH
Ar-O- CH ₂ - CH - CH ₃ - MHR (I)

into consideration, wherein Ar is a homo- or heterocyclic. rest means that contains at least one six-membered aromatic ring (preferably a phenyl, naphthyl, tetrahydronaphthyl, indolyl or indanyl radical) and which is directly connected to the rest of the molecule and through one or more lower Alkyl, alkoxy, alkenyl, alkeriyloxy, alkynyl, alkynyloxy, Alkyl mercapto, alkylsulfonyl, hydroxyalkyl, aminoalkyl, alkylamino, dialkylamino, alkanoyl, alkanoyloxy, benzamido or alkanoylamino, aryl, aryloxy, ary! amino, aryl mercapto, Arylsulfonyl, arylsulfonylamino, arylarnino, Aryl lower alkoxy, lower haloalkyl, alkoxyalkyl, monoalky! Aminoalkyl, Dialkylarninoalkyl, nitro, .Hydroxy-, amino and / or cyano groups and / or halogen atoms substituted can be, and ■ ■ '

R is a lower, in particular branched, alkyl odor HydrOxyalkylrefit, ύογ all the tert. Butyl, sec. "Butyl or precoious iso-propyl rust means.

In the above-mentioned sub-substituents of the remainder

• 2 09ΩΚ9 / 1 10 5

Ar are lower alkyl radicals, especially those with at most 6 carbon atoms, such as methyl / ethyl, propyl, isopropyl> straight or branched butyl, pentyl or hexyl radicals connected in any position.

Lower alkenyl radicals are, for example, those with a maximum of 6 carbon atoms, in particular allyl or metha - Iyl residues.

A particularly suitable lower alkynyl radical is the propargyl radical.

The main alkanoyl radicals are propionyl, or butyryl radicals, but above all the acetyl radical.

Aryl radicals are primarily naphthyl or, in particular, phenyl radicals.

In particular, fluorine or fluorine atoms are used as halogen atoms

Chlorine atoms into consideration;

A preferred group of β-blockers form the

Compounds of the formula Ij in which R has the meanings given and Ar has a through an unsaturated radical, such as' a lower alkenyl, alkynyl, alkenyloxy, alkynyloxy or Cyano group, substituted phenyl radical, and compounds of the formula I, in which R has the meanings given and Ar is a lower hydroxyalkyl, alkanoylamino or mercaptoalkyl group-substituted phenyl group means.

ORIGINAL 209ΠΒ9 / 110 5

- as β-blockers are specifically mentioned: l- (l-naphthyloxy) -2-hydroxy ~ 3-isopropylaniinopropan, l- (3-tolyloxy) -2-hydroxy-3 ~ i ^s ° P ^r opylaminopropan _J 1 ~ (j >, 5-xylyloxy) -2-hydroxy-3-isopropylaminopropane, 1- (2-cyano-3-Tflethylphenoxy) -2-hydroxy-3-isopropylarainopropane, 1- (2-methylmercapt.o-phenoxy) 2-hydroxy- 3-isopropylarninopropane _i l- (2-allylphenoxy) -2-hydroxy-3-isopropylarninopropane ,, 1- (4-acetamidophenoxy) -2-hydroxy-3-isopropylamiriopropane, 1- (2-allyloxyphenoxy) -2-hydroxy- 3-isopropylaminopropane, 1 -Qi. -Methanesulfonylamidophenoxy) -2-hydroxy-3-isopropylamihopropane _J 1 - (5 ₄ 6j ¹ J, 8-tetrahydro -1-naphthoxy) -2-hydroxy ~ 3-isopropylaminopropane, 1- (A -benzamidophenoxy) -2-hydroxy- 3-isopropylamiήopropan _ί 1- (· Ί -Indanyloxy) -2-hydroxy-3-isopropylarainopropan _i l- (2-bromophenoxy) -2-hydroxy-3-isopropylarninopropan, l- (4-cyanophenoxy) -2-hy-. hydroxy-3-isopropylaminopropane, 1- (2-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane, 1- (2-ethynylphenoxy.) -2-hydroxy-3-isopropylarainopropane, 1- (2-methoxymethylphenoxy) -2 -hydroxy-3-isopropylamiriopropane, 1- (2-hydroxymethylphenoxy) -2-hydroxy-3-isopropylaminopropane, 1- (2-propargyloxyphenoxy) -2-hydroxy-3-isopropylinopropane,, 1- (2-methoxyphenoxy) -2 -hydroxy-3-isopropylaminopropane, 1- (2-isopropoxyphenoxy) -2-hydroxy-3-1sopropylarninopropane, 1- (2-methallyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane, 1- ( ^l \ -indolyloxy) - 2-hydroxy-3-isopropylaminopropane ^ 1- (2-phenylphenoxy) -2-hydroxy-3 "i ^£; opropylamino-

BAD'ORiniNAL

209852/1105

propane, 1- (2-phenoxyphenoxy) -2-hydroxy ~ 3-isopropylattiinopropan, l- (2-Chloro-5-rr _i ethylphenoxy) -2.-hydroxy-3-tert. -butylaminopropane, 1- (2 ~ cyancphenoxy) -2-hydroxy ~ 3 ~ kert. -butylaminopropane, 1- (3-hydroxymethy! phenoxy) -2-hydroxy-3-tert.-butylaminopropane, 1- (2-ethynylphenoxy) -2-hydroxy-3-tert.-butylarainopropane, 1- (2- Allylphenoxy) -2-hydroxy-3 ~ tert-butylaminopropane, 1- (2-phenylphenoxy) -2-hydroxy-3 ~ tert-butylaminopropane, 1- (2-methoxymethylphenoxy) -2-hydroxy-3-tert. -butylaminopropane, 1- (4-acetamidophenoxy) -2-hydroxy-3-tert, -butylarainopropane, 1- (2-hydroxymethylphenoxy) -2-hydroxy-3-tert. -butylaminopropane, 1- (2-allyloxyphenoxy) -2-hydroxy-3 ~ ^te ^ t -butylaminopropane, 1- (2-cyanophenoxy) -2-hydroxy-3 ~ tert. -pentylaminopropane., l - (^ - Allyloxyphenoxy) -2-hydroxy-3 ~ i ^s opropy! aminopropane ₎ ! - (4-Methallyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane, 1- (4-propargyloxyphenoxy) -2- hydroxy-3-isopropylaminopropane, 1- (4-allyloxyphenoxy) -2-hydroxy-3-tert-butylaminopropane, 1- (2-methoxyphenoxy) -2-hydroxy-3-tert. -penty! aminopropane. and l- (2-methoxyphenoxy) ^ 2-hydroxy-3- (l, l-diroethylbutyl) aminofiropan.

In addition, those of the formula also come as β-blockers

OH R ₁

Ar-CH CH - Nlffl (II)

into consideration, where Ar is a phenyl, naphthyl, tetrahydronaphthyl - or Indanylrect means that also by lipophxle

20985? / 1105

Substituents such as "halogen atoms, nitro groups, lower alkyl and / or alkoxy radicals, may be substituted, R for a lower, preferably branched; Hydroxyalkyl or alkyl radical and R ^ is a hydrogen atom or a lower alkyl radical means.

Preferred compounds of this group are: 1 ~ (3> 4-dichlorophenyl) -l-hydroxy-2-isopropylaminoethane (dichloroisoproterenol), 1- (I'-naphthyl) -1-hydroxy-2-isopropylaminoethane (pronethalol), 1- ( 2,5-dimethoxyphenyl) -1-hydroxy-2-methyl -2-tert. -butylaminoethane, 1- (4-methanesulfonylaminophenyl) -1-hydroxy-2-isopropylaminoethane, 1- (5, 6, 7,8 tetrahydro-1-naphthyl) -1-hydroxy-2-see-butylaminoethane and 1 - ( ^} i -nitropheny 1) -1-hydroxy -2 -isopropyiaminopropane.

Suitable diuretics are substances that act on the tissues both through renal and extrarenal effects Increase diuresis. Thereby substances come with an inhibiting effect on the reabsorption in the tubule, e.g. especially Saluretica r.ov / ie ethacric acid and its analogues into consideration.

Benzothiadiazine derivatives are particularly suitable, such as thiazides and hydrothiazides, benzenesulfonamides, Phenoxyacetic acids, benzofuran-2-carboxylic acids and benzofuran ^, ^ - dihydro-P-carboxylic acids. . . ,

Particularly suitable thiazides are those of Formci] III · '

• r.

BAD ORIG1NAI 2 0 9 8 K 7 1 1 1 0 S

N \ ^R 3 2227423 Q
I.
NH (III), k / V

wherein R is a hydrogen atom or a phenyl-lower alkylthio-lower alkyl and R ₂ . are a halogen atom or the trifluoromethyl group.

A phenyl-lower alkyl-thio-lower alkyl radical R- is in particular one in which the lower alkyl parts have up to H C atoms and in particular 1 C atoms, and
in which the phenyl part is unsubstituted, like the benzyl-thiomethyl radical.

A halogenator R ^, is a bromine atom, iodine atom,
Fluorine atom and especially a chlorine atom.

Above all, these compounds should be mentioned
of formula III 6-chloro-7-sulfamyl-l, 2,4-benzothiadiazine-l, l-dioxide, 6-trifluoromethyl-7-sulfamyl-l, 2,4-benzothiadiazine-1,1-dioxide and 2-benzylthiomethyl-6 -chlor-7-sulfamyl-1 ', 2, -' J-benzothiadiazine-1,1-dioxide,

Particularly suitable hydrothiazides are such Formula IV

BATH ORIGINAL

20985? / 1105 '

0 It

⁶ (IV)

NR ₅

where R ^ is hydrogen or lower alkyl, R ^ is hydrogen, lower alkyl, Lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, -aryl, Aryl-lower alkyl, halogen-lower ■ alkyl, lower alkylthio-lower alkyl, lower alkenylthio-lower alkyl, Halo-lower alkylthio-lower alkyl, phenyl-lower alkylthio-lower alkyl or heterogycloalkyl-lower alkyl, R is hydrogen or together with R ^ for lower alkylene and Rn is halogen or trifluoromethyl.

A lower alkyl radical R ^ - is in particular one such with up to 7 carbon atoms, especially with up to 4 carbon atoms, such as Ethyl, n-propyl, i-propyl, straight or branched, in butyl, pentyl, hexyl or bonded to any position Heptyl, and especially methyl.

A lower alkyl radical Rg is one such in particular as indicated for R ^ and especially methyl, ethyl or isobutyl.

A lower alkenyl radical Rg is in particular one with up to 7, \ x '(, _K in particular up to k carbon atoms, v / ie allyl.

209852/1105

Rg is cycloalkyl is, in particular one having 3-8 * ^v or particularly 5-7 ring carbon atoms and a total of preferably up to 8, especially up to 7 carbon atoms, such as cyclopentyl and cyclohexyl.

A cycloalkenyl radical R / - is in particular one such with 5-8, especially 5-7 ring carbon atoms and a total of preferably with up to 8, in particular up to 7 carbon atoms, such as cyclopentenyl, Cyclohexenyl or norbornenyl, especially 5-norbornen-2-yl.

A cycloalkyl-lower alkyl radical Rg is in particular one in which the cycloalkyl part and the lower alkyl part have the above meaning, especially cyclopentylmethyl.

An aryl radical R ^ is in particular one with 6 carbon atoms such as phenyl, replaced by lower alkyl, such as Methyl, lower alkoxy such as methoxy, halogen such as chlorine, or Trifluoromethyl can be substituted.

An aryl-lower alkyl radical R ^ is in particular a those in which the lower alkyl part has the above meaning and the aryl part by lower alkyl, such as methyl, lower alkoxy, such as Methoxy, halogen, such as chlorine, or trifluoromethyl-substituted phenyl or, in particular, unsubstituted phenyl is such as benzyl or 1-phenylethyl.

A halo-lower alkyl radical R ^ is in particular a lower alkyl radical bearing one, two or three halogen atoms, where the lower alkyl part in particular has the above meaning

209852/11 OB

has, such as in particular halomethyl, e.g. trifluoromethyl, Chloromethyl, dichloromethyl and trichloromethyl.

A lower alkylthio-lower alkyl radical Rr- is in particular one wherein the lower alkyl portion and the lower alkyl portion of the lower alkylthio tell are those above for lower alkyl have given meanings, such as methylthiomethyl and 2-methylthio-ethyl.

A lower alkenylthio-lower alkyl radical R ^ - contains 2 B. one of the above-mentioned lower alkenyl radicals and is s.B. Aliylthiomethyl.

A halo-lower alkylthio-lower alkyl radical R 1 - is in particular one as indicated for the lower alkylthio-lower alkyl radical R / - which has two or three halogen atoms carries, such as 2,2,2-trifluoroethylthio-methyl.

A phenyl-lower alkylthio-lower alkyl radical Rg is especially one in which the lower alkyl moieties have the above meaning, such as benzylthio-methyl.

A heterocycloalkyl lower alkyl radical is, for example, one with one or more heteroatoms in a 3 to 10-membered ring, in particular a 5-membered ring, such as a furyl radical or a pyrrolyl radical, and a lower alkyl part that has up to 7 carbon atoms, especially up to ¹ I has carbon atoms, such as ethyl, n-propyl, straight or branched butyl, pontyl, iloxyl or ileptyl bonded in any position, and above all methyl ..

A lliederalky-

20985 7/1105 BAD ORIGINAL

lenrest is in particular one with up to 7, above all with up to 6 carbon atoms, and in particular with at least 2, in particular rr.with at least ¹ carbon atoms in the alkylene chain, such as 1,5-pentylene and 3-methyl -l, 5-pentylene.

A halogen atom Rn is bromine, iodine or fluorine and especially chlorine.

Of these, compounds of the formula IV should be mentioned in particular

3-ethyl-6-chloro-7-sulfamyl-3 _i 4-dihydro-l, 2 ^ _i -benzothiadiazin-l, l-dioxide; 3- ^Tr i ^c hlormethyl-6-chloro-7-sulfamyl-3,4-dihydro-l, 2,4-benzothiadiazine-l, 1-dioxide; 3-benzyl-6-

1,1-dioxide; 2-methyl-3- _(2,2-J 2 trifluoräthylthiomethyl) -6-chloro-7-sulfiimyl-3 ^ -dihydro-l ^ _{J J} 2 -benzothiadiazin - l _i 1-dioxide; 3- (2,2, 2-trifluoroethylthiornethyl) -o-chloro-T-sulfamyl ^, 4-dihydro-l ^^ - benzothiadiazine-l, 1-dioxide; 3- (5-norbornen-2-yl) -6-chloro-7-sulfamyl -3, H -dihydro-1, 2, H -benzothiadiazin-1, Ια ioxide; 2-methyl-3-chloromethyl-6-chloro-7-sulfamyl-3, ^ l-dihydro-l ^^ - benzothiadiazine-l, 1-dioxide; 6-chloro-7-sulfamyl-3,4-dihydro-lj2 _J ^ -benzothiadiazine-l _J l-dio>: yd; 3-dichloromiethyl-6-chloro-7-sulfamyl-3, ^ - dihydro-1,2,4-benzothiadiazine-1,2-dioxide; 3-Cyclopentylmethyl-6-chloro-7-sulfarnyl-3, ^ - dihydro-l, 2,4-henzothiadJazir) -l, l-dioxide; 6- trifluoromethyl-7-.su] fair.yl-3, ^} - dihydro-l _J 2 _i ⁱ i-benzothiadiazine-l, l ~ dioxide and 3-isobutyl-

s Kooipjnote Bcu "o], suli'o'jainide ν,. \ ΐιύ huI.cii · '. ·

20985? / 11 06 ΒΑΟ _ΟΒ , _{Θ (ΝΑ} Γ

the For.T.el V

R ₁₀ HKO ₂ S-

where R is halogen, _{lower alkyl or trifluoromethyl, R 10 is} hydrogen, lower alkyl, phenyl-lower alkyl, optionally phenyl or pyrrolidinomethyl, piperidinomethyl, piperazinomethyl, morpholinomethyl or thiomorpholinomethyl, for example, phenyl substituted by lower alkoxy or amino, R is carboxyl, carbamoyl, N-mono- or N-di-substituted carbamoyl, sulfamoyl, N-mono- or N-di-substituted sulfamoyl, lower alkyl sulfonyl, or an isoindolinyl or is linked to the radical R-jP, Rp is hydrogen, lower alkyl, amino, mono- or di-substituted amino and R, _{v is} hydrogen or halogen.

A Nlederalkylrest R, R ₁₀ * or Rp is in particular one of the abovementioned, especially methyl.

An aminophenyl _{radical R 1} is "in particular a monoaminophenyl radical, such as ^ -aminopbenyl.

An N-monosubstituted carbamoyl radical R ₁₁ is in particular an N-lower alkyl-carbamoyl radical, in which lower alkyl has the same meaning as the N-ethyl-carbamoyl radical, or an N-amino-substituted carbamoyl radical, the amino groups in particular di-lower alkylamino, such as dimethy 1-

BATH 20 9852/1105

amino, or lower alkylidenesmino, v.ie pyrrolidino, piperidino or 2,6-dircethylpiperidino, such as the 1-1- (2,6-dimethylpiperidino) -carba rr.oylrest.

An N-di-substituted carbareoyl radical FL is in particular an N-di-lower alkyl-carbohydrate group, v: orin 1-lower alkyl has the above meanings, viie the Ν, Ν-dirnethyl-carbarnoylrest.

An N-monosubstituted sulfamoyl radical R. is

m -LL

in particular an N-lower alkyl-sulfamoyl radical, in which lower alkyl has the above meaning, v.ie N-methyl-sulfamoyl, an N-pu ^ furyl or N-tetrahydrofurfuryl-sulfamoyl radical, viie M-purfuryl-sulfamoyl, N-tetrahyarofurfuryl -sulfarnoyl, N- (2-methyltetrahydrofurfuryl) -sulfatnoyl and N- (2-methyl- ^2- t-oxo-tetrahydrofurfuryl) -sulfamoyl.

An N-di-substituted sulfamoyl radical R ,. is in particular an NjN-di-lower alkyl-sulfamoyl radical, in which lower alkyl has the above meaning, v / ie N, N-dimethyl-sulfamoyl, an N, N-lower alkylene-sulfamoyl radical, v / or lower alkylene in particular has the above meaning, such as piperidino-sulfonyl, öin N-lower alkyl-N-carboxy-lower alkyl-sulfamoyl radical, v / orin the lower alkyl moieties have the above meaning, such as N-methyl-N-carboxymethyl -sulfamoyl, an N-lower alkyl-N-furfuryl-sulfamoyl radical, wherein lower alkyl has the above meaning, v: ie N-Mothyl-K-furfuryl · sulfamoyl, or an N-lower alkyl-N-tetrahydr-ofur-i'uryl-sulfarnoyl radical, where lower alkyl has the above meanings, v / i ο N-

BATH

Kothyl-H- (2-methyl-k- oxo-tetrahydrofurfuryl) -sulfamoyl and N-methyl-H- (2-methyl-k -oxo-tetrahydrofurfuryl) -sulfamoyl.

A _{lower alkylsulphonyl radical R 1} is in particular one in which the lower alkyl part has the above meaning, such as methylsulfonyl, ethy1sulfenyl and η-butylsulphonyl.

- An isoiridolinyl radical R ,, is in particular a 1-isoindolinyl radical with a 3-hydroxy group and a 1-oxo group, like 3 ^ hydroxy-l-oxo-isoindolinyl- (3) ·

The radicals R. ,, connected to the radical Rp are, in particular, carbamoyl radicals R -. ,, which have an amino group R. _? or a lower alkyl group R-. _? such as 1-oxo-2-cyclohexyl-2-aza-propylene- (1,3) and l-0xo-2, ^ - bis-aza-3-ethyl-butylene- (l, ^).

A monosubstituted amino group R, "is in particular a lower alkylamino group wherein lower alkyl has the above Has meaning, such as methylamino, or tetrahydrofurfurylamino or, in particular, purfurylamino or benzylamino.

A di-substituted amino group R ^ p is in particular a di-lower alkylamino group, viorin lower alkyl has the above meaning, such as dimethylamine), or a di- (phenyl-lower alkyl) amino group, wherein the lower alkyl part has the above meaning, such as di-benzyl-amino.

A halogen atom R, - is bromine, iodine, fluorine or in particular Chlorine.

209BK7 / 1105

Of the compounds of the formula V are in particular those to be emphasized, v, 'orin R is chlorine, R Air.ir> op3; enyl,

y -LO

Methyl or in particular 'is hydrogen, R, carboxyl, carbamoyl, N-methyl-carbamoyl, N- (2,6-dimethyl-piperidino) -carbamoyl, 3-I-hydroxyl-l-oxo-isoindolinyl- (3) or N-methyl-I * - (? ~ methyl-tetrahydro-furi'uryl) -sulfa: noyl or together with Rp for l-0xo-2-cyclohexyl-2-aza-propylene- (l, 3) or 1 -Oxo-2, ⁱ l-bis-aza-3-ethyl-butylene - (l, 4), R _1? Is hydrogen or purfurylamino, and R ₁ -. Is hydrogen.

Of these compounds of the formula V, particular mention should be made of them

2-chloro-5-N-methyl-sulphonamido-benzene-sulphonamide; 2-chloro-5-N, N-dimethylsulfonamido-benzene-sulfonaiide; 2-chloro-5-piperidinosulphonyl-benzene-sulfonamide; 2-chloro-5- (N-carboxymethyl-N-diethyl) -sulfonamido-benzene-sulfonamide; 2-chloro-5 - (. N-furfuryl-sulfonamido) -benzene-sulfonamide; 2-chloro-5- (N-tetrahydrofurfuryl-sulfonamido) -benzene-sulfonamide; 2-chloro-5- [N-methyl-N- (2-methyl-4-oxo-tetrahydrofurfuryl) sulfonamido] benzene sulfonamide; 4,5-dichlorobenzene-l _a 3-disulfonamide] ^ ~ chloro-6-methylbenzene-1,3-disulfonamide; ^ -Chlor-6-aininoben; r, ol-1,3-disulfonamide; 2-chloro-5-methylsulphonyl-benzene-sulfonamide; 2-chloro-5-ethylsulphonyl-benzene-su3 formamide; 2-chloro-5-n-buty / sulphonyl-benzene-sulphonate; 2-methyl-5-ethylsulphonyl benzene sul i'oriamide; 2-methyl-5-diethyl sulphonyl-benzene-sulphonamide; 2-methyl - ^ - n-butylsuli) honyl-bcnzol-r>ulfonain.id; 2-chlorine

BATH ORIGINAL 2098S9 / 1105

4- (N, N-dibenzylamino) -5-carboxyl-benzene-sulfonamide; 2-Furfury1-ataino-4-chloro-5-N- (p-aminophenyl) -sulphamoyl-benzoic acid, 2-furfurylamino-4-chloro-5-N- (0-aminophenyl) -sulpharaoyl-benzoic acid and especially 3-sulfonamido-4-chloro-benzoic acid; 3-sulfonamido-4-chlorobenzamide; 3- (N-methylsulphamoyl) -4-chloro-N-methyl ~ benzamide; l-chloro- · '! - [N-methyl-N- (2-irethyltetrahydrofurΓuryl) .- sulfamoyl3benzeneGUlfonaίnid; 1,3-disulfaffioyl-1-chlorobenzene; 2-chloro-5- [j5 ~ hydroxy-1-oxo-isoindolyl- (3)] -berizole-sulfonamide; 2-Aetbyl - ^ - oxo-6-sulfarrtoyl ~ 7 ~ chlorine-l, 2,3.j ^ -tetrahydro-china- · zolin; l-0xo-2-cyclohexyl-5-chloro-6-sulfamoyl-lj 2-dihydroisoindole; 2-ChIoX "-!? - [N- (2,6-dimethylpiperidino) -carbarnoyl] benzene sulf onamide; 2- Chloral-furfury la mino-5-carboxy l-ben2'.ol ~ sulfonamide and 2-chloro- ^ l-benzylamino-5-carboxyl-benzene-sulfonamide.

Particularly suitable phenoxyacetic acid !; are such of formula VI

0-CH ₂ -COOH (VI),

wherein R ₁ Jh is nicderalkyl, R ₁ ^ is halogen or lower alkyl and R ₁ ^ - is hydrogen, _{halogen or lower alkyl or in which R. r} and R, /: together stand for but-l ^ -dienylon-fl, ^).

A Miecieralkylrest JL ^ ^ is in particular one with 2-7, especially 2-Ί C-atoms, v / ie a above Gunanntor residue, and an indispensable one reads like this, vrie n-propyl, η-ΓηιίΛτ ! _Q and especially ethyl.

BATH ORIGINAL

A halogenator. R ..,. or R ^ is bromine, iodine or Fluorine and especially chlorine.

A lower alkyl radical S _{1 n} or R _n ^ is in particular

15 Io

one with up to 7 *, especially up to 4 -C ateurs, v; ie especially Kethyl.

Particularly suitable compounds of the formula VI are [2,3-dimethyl-4- (2-methylene-butyryl) phenoxy] -ess i gic acid, [2 -Ke thy 1 -3 - chlorine --4 - (2-methylene-butyry Ϊ) phenoxy] -e acetic acid, [H - (2-methylen-butyryl) -1-naphthoxy] -acetic acid and especially [2,3-diehlor-'l- (2- ethylene-butyryl) -phenoxy] -acetic acid.

Particularly suitable benzofuran-2-carboxylic acids are those of the formula VII

R ₁₇ -CC

-COOH

(VII),

_{viorin R 1 is} lower alkyl and R ₁ O is lower alkyl or lower alkoxy.

A Nlederalkylrest R ₁₇ is in particular one with 2-7, above all 2- ^} \ C atoms, such as an abovementioned, and preferably an unbranched radical of this type, ie ethyl.

A lower alkyl radical R, ο is in.sbesondore a sol-

209857/1105

rather with up to ' I, especially ir.it up to 4 carbon atoms, v / ie mentioned above, and especially methyl.

A lower alkoxy radical PL is one such in particular , wherein the alkyl part has the above meaning, such as methoxy.

Suitable compounds of the formula VII are in particular

special mention should be made of 5- (2-methylene-butyryl) -6-methyl-benzo-ι

1 furan-2-carboxylic acid, 5- (2-methylene-butyryl) -6-methoxy-benzo-!

füran-2-carboxylic acid and 5- (2-methylen.-propionyl) -6-methyl-

benzofuran-2-carboxylic acid. ^v ι

Particularly suitable benzoxuran-2, j5-dihJΓdro-2-car- i

Bonic acids are those of the formula VIII

RC-CO- ²¹ ill _(VIII)

where R is, hydroxy, alkoxy, cycloalkoxy or arylalkoxy, R is ζν, οΐ hydrogen atoms or Nlederalkyliden. R is _{lower alkyl, Rp 2 is} hydrogen, calogen, lower alkyl or lower alkoxy _{, and R p is hydrogen or lower alkyl}

An alkoxy radical R 1 is in particular one such

with 1-3.8, especially 3.-12 carbon atoms, v; ie one of the above, v.'je in particular methoxy, aotlioxy, η-but oxy, 2-lIe>:;> '3 oxy and'

209852/1105

n-decyloxy.

A cyclcalkoxy radical R ₁ is in particular a sol-

J-y

rather with 3-8 .. in particular 5-7 ring C-atoms and in particular with up to 10, especially up to 8, carbon atoms, v; ie cyclopentyloxy and cyclohexyloxy.

An arylalkoxy radical R .. _o is in particular phenyl-lower alkoxy, in which the lower alkyl part has the above meaning, such as benzyloxy.

A lower alkylidene R _po is especially such with up to '], in particular up to 4 C-Atornen, such as methylene and ethylidene.

A _{lower alkyl radical R pi} is in particular one with up to 7> in particular up to 4 carbon atoms, such as in particular straight-chain such radicals such as methyl, n-propyl, η-butyl and especially ethyl.

A halogen atom R _pp is bromine or iodine and in particular fluorine or very particularly chlorine.

A lower alkyl radical R _go or R is in particular one with up to 7, in particular with up to ^} \ C atoms, such as one mentioned above, especially methyl.

A lower alkoxy radical R _pp is in particular one with up to J, in particular up to h, carbon atoms, such as one mentioned above, especially methoxy.

Of the compounds of the formula VIII are in particular those gec-jgnot, where K is hydroxy, R ,, MothylcMi

209852/1105

or ethylidene, Rp, straight-chain alkyl with 1-4 C atoms: r.en is, R _{00 is} methyl, methoxy, chlorine or fluorine and R "is -, hydrogen or methyl.

Of the compounds of the formula VIII are emphasized

5- (2-methylenebutyryl) -6-methyl-2 _i 3-dihydro-benzofuran-2-carboxylic acid; 5- (2-methylene-butyryl) -6-fluoro-2,3-dihydro-benzofuran-2-carboxylic acid; 5- (2-methylene-butyryl) -6-chloro-2,3-dihydro-benzofuran-2-carboxylic acid; 5- (2-methylenepionyl) -6-methyl -2, 3-dihydro-benzofuran-2-carboxylic acid; 5- (2-methylene-hexanoyl) -6-methyl-2 _J 3-dihydro-benzofuran-2-carboxylic acid; 5- (2-methylen-valeryl) -6-methyl-2 _i 3-dihydrobenzofuran-2-carboxylic acid; 5- (2-methylenepropionyl) -6-methyl-. 2,3-dihydro-benzofuran-2-carboxylic acid; 5- (2-ethylidene-butyryl) -6-methyl-2 _i 3-dihydro-benzofuran-2-carboxylic acid; 5- (2-methylenebutyryl) -6-ir.ethyl-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester; 5- (2-methylenebutyryl) -6-methyl-2,3-dihydrobenzoxuran-2-carboxylic acid ethyl ester; 5- (2-methylenebutyryl) -6-rfiethyl-2 _i 3-dihydro-benzofuran-2-carboxylic acid n-butyl ester; 5- (2-i'iethylenebutyryl) -6-methyl-2,3-dihydro-benzofuran-2-carbpnoic acid-2-hexyl ester .; 5- (2-methylenebutyryl) -β-methyl. ^ 3-dihydro-benzofuran-2-carboxylic acid n-decyl ester; 5- (2-methylenebutyryl) -6-methyl-2,3-dihydro-benzofuran-2-carboxylic acid cyclopentyl ester; ¹ J- (2-methylenebutyryl) -6-methy l) -2,3 -dihydrobenzofuran-2-carbon. ^c 5 acid eyelohexyl ster; 5- (2-methylenebuty-

209852/1108

ryl) -6-methyl-2,3-dihydro-benzofuran-2-carboxylic acid benzyl ester; 5- (2-methylenebutyryl) -7-methyl-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester; 5- (2-methylenebutyryl) -6-chloro-7-methyl-2,3-dihydro-benzofurane-2-carboxylic acid methyl ester; 5- (2-methylenepionyl) -6-methyl-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester; 5_ (2-methylen-valeryl) -6-methyl-2,3-dihydro-benzofuran-2-carboxylic acid methyl esterj 5- (2-methylen-3-methyl-butyryl) -6-methyl-2,3-dihydro- benzofuran-2-carboxylic acid methyl ester; and 5- (2-methylenebutyryl) -6-fluoro-2,3-dihydro-benzofuran-2-carboxylic acid methyl ester, and especially 5- (2-M3thylenebutyryl) -6 _> 7-dimethyl-2,3-dihydro -benzofuran-2-carboxylic acid; 5- (2-methylene-_3.- ^Metn yl- ^{but r} y y ¹⁾ -6-methyl-2 _J 3-dihydro-benzofuran-2-carboxylic acid; 5- (2-methylenebutyryl) -6-chloro-7-methy1-2,3-dihydro-benzofuran-2-carboxylic acid.

The mentioned ß-blockers and diuretics can each according to the number of their asymmetric carbon atoms in the form of isomer mixtures, pure isomers (racemates) or optical antipodes are present. They are preferably used in the form of the more effective or less toxic Isomers or antipodes.

The mentioned ß-blockers and diuretics with Babasic Groups can also be in free form or in form

their non-toxic salts are present. As such salts ■ come in particular salts with organic or inorganic Acids into consideration, such as: Hn Io gc.-nwn.se; or »

209852 / I ₁ OS

chemical acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, amber, glycol, lactic, apple, tartaric, Citric, ascorbic, maleic, hydroxymaleic or pyruvic acid; Phenyl acetic, benzoin, p-aminobenzoic, anthranil, p-Hydroxybenzoic, salicylic or p-aminosalicylic acid, emboxylic acid, Methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid; Halogenbenzenesulfone, toluenesulfone, Naphthalenesulfonic acid or sulfanilic acid; Cyclohexylsulfamic acid, Methionine, tryptophan, lysine or arginine.

The mentioned diuretics with acidic groups can also be used in free form or in the form of their non-toxic Salts are present. Particularly suitable salts are salts with bases, such as, for example, alkali metal, such as sodium or Potassium carbonates, hydrogen carbonates or hydroxides, or corresponding alkaline earth metal, such as calcium or magnesium compounds, or ammonia, as well as amines such as aliphatic, e.g. lower alkylamines, such as trimethylamine or triethylamine. Aluminum salts, e.g. salts of two moles of acid and one mole of aluminum hydroxide, are also suitable, especially because of their slower absorption and odorlessness and minor gastrointestinal disturbances.

The invention therefore relates to pharmaceutical preparations which contain a / i-blocker, in particular one of the above

209857 / im *; bad original

named, together with a Diuretieui®, in particular one of the above, as well as the production of these preparations, furthermore the use of these active ingredients in the form of the preparations mentioned or by combined but separate application for the treatment of hypertension »

The pharmaceutical preparations according to the invention contain as diuretics, especially Saluretlca, in particular from the group of the benzothiadiazine derivatives, such as Tlsiazide and hydrothiazides, benzene sulfonamides, phenoxy © ssigsäuren, Benzofuran-2-carboxylic acids and Benzofuran-2,3-dihydro-2-carbojic acids. Of the thiazides characterized by Forjaael III are to be mentioned 6- (

diazine-lj, 1-dioxide, 6-trifluorosethyl-7-sulfamgrl-l, 2, 4-1 thiadiazine-1,1-dioxide and 2-1
amryl -1,2,4-benzothiadiazine -1, 1-i

Of the hydrothiazides of Fonael IV there are above all 3-ethyl-6-chloro-7-sulfaffisrl-3j "^ - dih3rdr © -l, 2,4-toeJizothiadiazine-1,1-dioxide; 3- {2- [M "- (1,2-Bihydro-1-phthaliziny-" liden) -hydrazones J -propylj »-6-c
2,4-benzothiadiazim-1,1-dioxide; 3- ¹ ^

sulfaisi (yl-3,4-dihydro-l, 2,4-benzothisdiszine-l, ld.i © xyd; 3- (3-phenylethyl) -6-chloro-7-! S ' ^| ! 5lfamiyl-3 # $ -dihyär © -!, 2,4-1 diazine-1,1-dioxide; 3-benzyl-6-1
dihydro-1,2,4-toenzothisdiazijn-l, l- ^ ieocyfäj 2-lfethyl-3-C ^ * S, 2-trif3 taor ethyl thiomce ttoyl) -6-chloro-7-E «i.lfai3tiyi-3, h -ditaydro-l, 2, 4-

■ -3 »

BAD ORIGINAL 209857/11! »$

benzothiodiazine-1,1-dioxydj 3 * 3 '- (spiro-3-ynethyl-cyclohexane) -6-chloro-7-sulfai; iyl-3 _i ⁱ l-dihydro-l _J 2., ^ l-benzothiodiazine-l ,! - · dioxide; 3J3 '- (spiro-3-nr.ethyl-cyclohexane) -6-trifluorniethyl-7-sulfarnyl-3,4-dihydro-l, _2-i 4 benzothiodiazin-l, l-dioxide: 3- (5-norbornene 2-yl) -6-chloro-7-sulfamyl-3 _JI ⁱ } -dihydro-1 _i 2 _J ^; lbenzothiadiazine-l, l-dioxide, and very particularly 2-methyl-3-chloromethyl-6-chloro-7-sulfarnyl-3, ⁱ t-dih3'-dro-l _i 2,4-benz.othiadiazine-l, l -dioxide; o-chloro-T ^^ benzothiadiazine-l ^ l-dioxide;
amyl ^ j ^ -dihydro-l ^ i ^ -benzothiadiazine-l ^ l-dioxydi 3-benzylthiomethyl-6-chloro-7-sulfamyl-1,2,2 - benzothiadiazine-1,2-dioxide; 3-Cyclopentylmethyl-6-chloro-7-sulfamyl-3 _J ^ -dihydrol ^^ - benzo-thiadiazine-l ^ l-dioxide; 6-Trifluoromethyl-7-sulf- amyl-3j ^j t-dihydro-l, 2,4-benzothladiazine-l, l-dioxide and y ~ isobutyl-6-chloro-7-sulfamy1-3 , h -dihydro-! , 2,4-benzothiadiazinljl-dioxide.

The most important compounds of the diuretic benzenesulfonamides of the formula V in the preparations according to the invention are 2-chloro-5-N-ethylsulfonamido-benzenesulfonamide; 2-chloro-5-N _i N-dimethylsulfonamido-benzene-sulfonarnid; 2-chloro-5-piperidiriosulphonyl-benzene-sulFonaraid; 2-chloro-5- (l \ f-carboxytriethyl-N-methyl) -sulfonamido-benzene-sulfonamide; 2-chloro-3- (N-furfury1-sulfonamido) -benzene-sulfonamide; 2-chloro 5 ~ (N-tetrahydrofurfuryl-.oulfonamido) -berizole-sulfonamidi 2-chloro-5- [N-ir.etfiyl -N- (2-methyl -4 -oxo-tetrahydrofuri'uryl) -üu1-

209852/1105

i'onamido] -benzenesulfonamide} H, 5-dichlorobonzene-1,3-disulfonanride; H -chloro-6-methylbenzoi-1 , 3- disulfonarr.id; 4-chloro-6-aminobenzene-1,3-disulfonamidi 2-chloro-5-methylsulphony1-benzene-sulfonarr.id} 2-chloro-5-ethylsulphonyl-benzene-sulfonamide} 2-chloro-5-n-butylsulphony 1 -benzol-sulfonarr.id} 2-methyl-5-ethylsulphonyl-bonzol-sulfonaraid} 2-methyl'-5-rr _i ethylsulphonyl benzene-sulfonamide} 2-methyl-5-n-butylsulphonyl-benzene-sulfonamide} 2-chloro ~ ^ - (N _J N-dibenzylamino) ~ 5-carboxyl-benzene "sulfonamido} 2-purfurylamino- ^f 1-chloro-5-li (p-aminophenyl) -sulphamoylbenzoic acid} and especially 3-sulfonamido-'4 -chlorobenzoic acid 3

sulphamoyl) -4-chloro-N-methylbenzamide} l-chloro-4- [N-methyl-N- (2-methyl-tetrahydrofurfuryl) -sulfamoyl3 -benzenesulphonamide} 2-chloro-5-l3-hydroxy-l-oxo- isoindolyl (3)} - benzene sulfonamide; 2-Ethyl - ^ - oxo-6-sulfamoyl-7-chloro-1,2,3,4-tetrahydro-quinazoline} l-0xo-2-cyclohexyl-5-chloro-6-sulphamoyl-1,2-dibydroisoindole} 2-chloro-5- [N- (2,6-dirnethylpiperidino) -carbamoyl] benzenesulfonamide, 2-chloro- ⁱ t -furfurylamino-5-carboxyl-benzenesulfonamide and 2-chloro-H-benzylamino-5-carboxyl-behzol-sulfonamide .

For the pharmaceutical preparations according to the invention Particularly suitable phenoxyfacids of the formula VI are [2,3-dimethyl-4- (2-methylene-butyryl) -phenoxy] -ecr.i ^ säut-o; [2-methyl-3-chloro - ^ - (2-ir: ethylene-butyryl) -phenoxy l-esnlGBfiuro} [Ju (2-methylene-butyryl) -l-nfjphthoxy] -os «icic acid and [2,3-dichloro'-l - (2-methylene-butyvy3) -PUeI] uL

209852/1105

BATH ORIGINAL

Of the benzofuran-2-carboxylic acids of the formula VII, 5- (2-methyleri-butyryl) -6-rcethyl-benzofuran-2-carboxylic acid are particularly suitable for the present invention; 5- (2-Mefchylen-butyryl) -6-methoxy-benzofuran-2-carboxylic acid and 5- (2-1-ethylene-propionyl) -6-methyl-benzofuran-2-carboxylic acid ₃ of the Ben2ofuran-2,3 -dihydro-2-carboxylic acids of the formula VIII are particularly important 5- (2-methylene-butyryl) -6-ynethyl-2,3-dihydro-benzofuran-2-carboxylic acid 5- (2-methylene-butyryl) -6 -fluoro-2, jJ-dihydro-benzofuran-2-carboxylic acid; 5- (2-methylenebutyryl) -6-chloro-2,3-dihydro-benzofuran-2-carbonsäurej 5- (2-Methylenpropionyl) -6-rnethyl-2,3-dihydroergotamine ⁱ iro-benzofuran-2-carboxylic acid; 5- (2-methylen-hexanoyl) -6-methyl-2,3-dihydro-benzofuran-2-carboxylic acid; 5- (2-methylene-butyryl) -6,7-dimethyl-2,3-dihydro-benzofuran-2-carboxylic acid; 5- (2-Metli3 ^r len-valeryl) -6-me thyl -2.3 dihydro-benz of uranium-2-carboxylic acid; 5- (2-methylerspropionyl) -6-methyl -2, 3-dihydro-benzofurane-2-carboxylic acid; 5- (2-ethylidene-butyryl) -6-methyl -2,3-dibydro-benzofuran-2-carboxylic acid; 5- (2-methylenebutyryl) -6-ynethyl-2 _J 3-dihydrobenzofuran-2-carboxylic acid methyl ester; 5- (2-Methylenbufcyr yl ) 6-jr-ethyl-2,3-dihydro-benzofuran-2-carboxylic acid ethyl ester; 5- (2-methylene-butyryl) -6-rr «ethyl-2,3- ^{ iihyäro-benzofuraii-2-cai" -boxy-n-butyl ester; 5- (2-methylenebufcyryl) -6-raietliyl- 2,3-dihiydro-benzofuran-2-carboxylic acid-2-liexyl ester "; ^ - (2-Mett butyry 1) -6-methyl -2, 3 -d ibyd ro -benzofursn ^ -carboxylic acid -n- &ter; S- (2-MethyJen-butyryl) -6-aceUiyl-2,3 -

209852/1105

benzofuran-2-carboxylic acid eyelopeirtyl ester; 5- (2-methylenebutyryl) -6-rr / sthyl-2,3-dihydro-beriZoi / irari-2-carboxylic acid cyclohexyl ester; i3- (2-methylene-butyryl) -6-methyl-2,3-dihydrobenzofuran-2-carboxylic acid benzyl ester; 5- (2-Kethylene-butyryl) -Y-methyl-1-2,3-dihydro-benz of uran-2-carboxylic acid-non-thy-ester; 5- (2-Methylen-butyryl) -6-chlcr-7-iriethyl-2,3-dihydro-benzofuran-2-carboxylic acid-diethyl ester; 5- (2-methylenopropionyl) -6-methyl-2j 3-dihydro-benzofuran-2-carboxylic acid methyl ester; 5- (2-methylen-valeryl) -6-methyl-2,3- ^< 3ih3 * dro-benzofuran-2-carboxylic acid methyl ester; 5- (2-methylene-3-methyl-butyryl) -6-methy1-2 _t 3-dihydro-benzofuran-2-carboxylic acid methyl ester; 5- (2-methylene-butyryl) -6 - fluoro-2 _i 3-dihydro-benzofuran-2-carboxylic acid methyl ester and especially 5- (2-methylene-butyryl) - 6, 7-dimethyl-2j3-dihydro- benzofuran-2-carboxylic acid; 5 - (2-methylen-3-methyl-butyryl) -6-methyl-2 _J 3-dihydro-benzofuran-2- ^ carboxylic acid j 5- (2-methylen-butyryl) -6-chloro-7-methyl- 2,3-dihydro-benzofirane-2-carboxylic acid.

Particularly valuable are pharmaceutical, preparations, the ß-blocker l- (l-naphthyloxy) -2-hydroxy-3 ~ isopropylaminopropane, l- (3-tolyloxy) -2-hydroxy-3-isopropylaminopropane, the l- (2-allylphenoxy) -2-hyd.roxy-3-isopropylaminopropane, the 1- (4-acetamidophenoxy) -2-hydroxy-3-isopropyl-aminopropiri or above all 1- (2-allyloxyphynoxy) -2-hydroxy-3-IIIOpropylaminopropane or the 1- (Ί-Al IyI oxy ph en oxy) -2-) hydroxy-3 ~ ii; opropyla: iiinopropane and as]). i urc-ticurn 2-chlorine-

2 0 9 8 S ? / 1 1 0 F ^BAD ORIGINAL

5- [3-hydroxy-l-oxo-isoindolyl- (3)] - benzene-sulfonamides 6-

oxide, 3-cyclopentylmethyl-6-chloro-7-sulfamyl-3 _J ⁱ -dihydro- 1 _} 2, k -benzothiadiazine-l, l-dioxide or 5- (2-methylene-butyryl) δ-methyl-benzofuran ^ -carboxylic acid contain.

A very special subject of the invention are therefore preparations containing l- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane, l- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropane or l - (^ - allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane together with l-oxo-3- (3-chloro-phenyl) -3-hydroxyisoindoline or o-Chlo 3 _J 4-dihydro-l, 2,4-benzothiadiazine-l, l-dioxide _J 3-Cyclopentylmethyl-ö-chloro-Y-sulfamyl ^^ - dihydrol _J , 2 _i 4-benzothiadiazine-1,1-dioxide or 5- (2-methylenebutyryl) -6-methyl-benzofuran-2-carbdic acid contain .

The use of these is also correspondingly preferred Preparations or the use of the individual components in a combination therapy is a special subject the invention.

In the new preparations, the ratio of ß-blockers to diuretic vary within wide limits.

The dosage of the new preparations depends, of course, on the effectiveness of the ß-blockers and in question Diuretics and the individual needs of the patient away. You can e.g. for-the β-blocking component between

209857/1105

BATH ORIGINAL

7227423

half and double the single dose, preferably using the half to single dose. For example, the above-mentioned particularly preferred preparations 20 to 100 mg, in particular hO to 80 mg, l- (2-allyloxyphenoxy) -2-h3 ^r hydroxy-3-isopropylair _i inoprGpan hydrochloride or l- (2-allylphenoxy) - 2-h, hydroxy-3-isopropylaminopropane hydrochloride or from 0 to 200 mg, in particular 80 to 160 mg, 1- (4-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride. The dosage of the .Diuretic can be between half and double the single dose, preferably half to single dose is used. For example, the above-mentioned preferred preparations can contain 10 to 25 mg, in particular 10 mg of 2-chloro-5- [3-hydroxy-l-oxo-isoindolyl- (3) 3-benzene sulfonamide, 10 to 25 mg, in particular 10 mg 6-Chloro-7-sulfarnyl-3, ^ -dlhydro-l ^^ l-benzothiadiazine-ljl-dxoxyd, 10 to 25 mg, especially 10 mg 3-Cyclopentylmethyl-6-chloro-7-sulfamyl ~ 3, ^J ldihydro- l, 2,4-benzothiadiazine-l, l-dioxide or 10 to 30, in particular 10 to 20 mg of 5- (2-methylenebutyryl) -6-methyl-benzofuran-2-carboxylic acid.

The new pharmaceutical preparations are main suitable for oral application and as such can use the usual carrier materials, such as lactose, Starch, gelatin, colloidal silica, marysiunintearate, Tall :, Phenylvj ny! Pyrrolidone, and the like. Further

209852/110 "; BATH ORIGINAL

You can also use other therapeutically valuable substances included mixed in. They lie e.g. as tablets, coated tablets or capsules. You will receive it in the usual way. For a rectal application there are the new .pharmaceutical Preparations, especially in the form of suppositories vpr, which are usually obtained. .

The preparations according to the invention, in particular those mentioned as preferred, can advantageously contain potassium chloride contain, preferably 200 to 800 mg, in particular 500 to 700 mg per dose unit (capsule) used will.

The diuretics and ß-blockers used are known or can be produced in a manner known per se.

The invention is described in the following examples without thereby in any way affecting its scope should be limited.

BATH

209857/1105

example 1

Tablets containing 40 mg of 1- (2-allyloxyphenoxy) -2-hydroxy-J-isopropylarodopropane hydrochloride and 10 mg of 6-chloro-7-sulfamyl-5,4-dihydro-1,2,2-benzothiadiazine-1,2-dioxide.

To be together

1- (2-Allyloxyphenoxy) -2-hydroxy-5-isopropylamino-propane hydrochloride 4θ mg

6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide 10 mg

Milk sugar 12J mg

Wheat starch 90 mg

Colloidal silica 10 mg

Polyvinylpyrrolidone 10 mg

Talc 15 mg

Magnesium stearate 2 rng

500 mg

Manufacturing

The two active ingredients are mixed with the milk sugar, the colloidal silica and some of the wheat starch. the Mixture is forced through a sieve and mixed with an aqueous alcoholic Solution of polyvinylpyrrolidone kneaded until a plastic mass has arisen. This is driven through a sieve, dried and the dry granulate is again

—- ■:? -Ys «

209857/1105 -'- ^ ORIGINAL

sifts. The remaining wheat starch, talc and magnesium stearate are placed on top mixed in and the mixture pressed into tablets weighing JOO mg with a score line.

BAD ORlQlNAt

209852/1105

Example'2

Dragees containing 40 mg 1- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylamino-propane hydrochloride, 10 mg 6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide and 600 mg of potassium chloride.

Together set Zung
core

Potassium Chloride 600 mg

Stearyl alcohol 77 mg

Polyvinylpyrrolidone 20 mg

Magnesium stearate 3 mg

700 mg

Protective varnish 20 rng

covering

1- (2-Allyloxyphenoxy) -2-hydroxy - ^ - isopropylamino-propane hydrochloride

6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide

Sugar, talc, coloring, binding agent q.s. ad

40 mg 10 mg 280 mg 1000 mg

209852/1105

• Manufacture ". '

The potassium chloride comes with the stearyl alcohol and a concentrated Polyvxnylpyrrolidonlosung granulated and dried. The received cash register is sieved and made into pellets of 700 mg in weight. These are coated with a protective lacquer layer and then with colored sugar syrup, in which the two active ingredients are dissolved or suspended, coated to a final weight of approx. 1 g.

BAD ORtGlNAL

20985 7/1105

Example .3

Tablets containing 20 rag ll- (2-Aliyloxyphenoxy) 2-hydroxy-3-is ^r ° P ° Pyl ^a mino-propane hydrochloride and 10 mg of 2-chloro-5- [3-hydroxy-oxoisoindolyl- (3)] - benzenesulfonamide .

composition

1- l- (2-Allyloxyphenoxy) -2-hydroxy-3-isopropylamino-propane 20 mg

2-chloro-5- [3-hydroxy-l-oxo-iso-

indolyl (3)] benzenesulfonamide 10 mg

Milk sugar 57

Wheat starch. 45 mg

Colloidal silica 5 mg

Polyvinylpyrrolidone 5 mg

Talc ■ 7 mg

Magnesium stearate 1 mg

I50 mg

Manufacturing

The two active ingredients are with the milk sugar, the colloi dalen silica and part of the wheat starch mixed. The mixture is driven through a sieve and treated with a kneaded aqueous-alcoholic solution of polyvinylpyrrolidone, until a plastic mass is created. This is driven through a sieve, dried and the dry; Degree

209852/1105

sieved again. Then ground the remaining wheat starch, Talc and magnesium stearate are mixed in and the mixture is pressed into tablets weighing 150 mg with a score line.

209852/1 105

- 3ο -

Example 4.

Tablets containing 80 mg of 1- (4-allyloxyphenoxy) -2 hydroxy-J-isopropylamino-propane hydrochloride and 10 mg of 5- (2-methylenebutyryl) -6-raethyl-benzofuran-2-carboxylic acid.

composition

1- (4-Allyloxyphenoxy) -2-hydroxy-3-isopropylamino-propane hydrochloride 8θ rng

5- (2-Methyl-tert-thyryl) -6-methyl-benzofuran-2-carboxylic acid 10 mg

Lactose. . I70 mg

Wheat Starch I35 mg

Colloidal silica 15 mg

Polyvinylpyrrolidone 15 mg

Talc 22 mg

Magnesium stearate 3

^J I50 mg

Manufacture

The two active ingredients are colloidal with the milk sugar Silicic acid and part of the wheat starch mixed. The mixture is forced through a sieve and kneaded with an aqueous alcoholic solution of polyvinylpyrrolidone until a plastic mass has arisen. This is driven through a sieve, dried and the dry granulate is again

208852/1105 bath

sifts. The rest of the wheat starch, talc and foagnesium stearate are then added mixed in and the mixture compressed into tablets weighing 450 mg with a break groove.

209857/1105

Example 5

Tablets containing 40 mg of l- (2-allylphenoxy) -2-hydroxy-5-isopropylamino-propane hydrochloride and 10 mg of 5- (2-methylenebutyryl) -6-methyl-benzofuran-2-carboxylic acid.

composition

1- (2-allylphenoxy) -2-hydroxy-5-

isopropylaminopropane hydrochloride 4θ mg

5- (2-methylenebutyryl) -6-methyl-

benzofuran-2-carboxylic acid 10 mg

Milk sugar 125 mg

Wheat starch 90 mg

Colloidal silica 10 mg

Polyvinyl pyrrolidone. 10 mg

Talc 15 mg

Magnesium stearate 2 mg

500 mg

Manufacturing

The two active ingredients are colloidal with the milk sugar Silicic acid and part of the wheat starch mixed. The mixture is forced through a sieve and mixed with an aqueous-alcoholic Solution of polyvinylpyrrolidone kneaded until a plastic mass is formed. This is through a Sieve driven, dried and the dry granules again

209852/1105

sifted. The remaining wheat starch, talc and Magnesium tistearate admixed with the mixture to tablets of 500 mg weight pressed with a break groove.

209852/1105

Claims (1)

Pa tentaii sayings 1. Pharmaceutical preparation containing a ß-receptor blocker and a diuretic along with a pharmaceutical Carrier material. 2. A pharmaceutical preparation according to claim 1 containing a compound of the formula OH Ar-O- CH ₂ - CH - CH ₂ - NHR, wherein Ar is a homo- or heterocyclic radical which has at least one six-membered aromatic ring and which is directly connected to the rest of the molecule and is replaced by one or more lower alkyl, alkoxy, Alkenyl-, alkenyloxy-, alkynyl-, alkynyloxy-, alkylrnercapto-, Alkylsulfonyl, hydroxyalkyl, aminoalkyl, alkylamino, dialkylamino, Alkanoyl, alkanoyloxy, benzarnido or alkanoylamino radicals aryl, aryloxy, arylamino, ary, mercapto, Arylsulfonyl-; Arylsulfonylarnino, arylamino, aryl lower alkoxy, lower haloalkyl, alkoxyalkyl ,. Mönoalky! Aminoalkyl-, Dialkylaminoalkyl radicals, nitro, hydroxy, amino and / or cyano groups and / or halogen atoms can be substituted, and R- is a lower alkyl or Ilydroxyalkylrost means in free form or in the form of their non-toxic 209852/1105 - = » BATH ORIGINAL Salts, and a benzothiadiazine derivative, a benzenesulfonamide a phenoxyacetic acid, a benzofuran-2-carboxylic acid, · or a benzofuran-2,3-dihydro-2-carboxylic acid in free form or in the form of their non-toxic salts. 3 · Containing pharmaceutical preparation according to claim 1 a compound of the formula OH R ₁ II ¹ Ar-CH- CH> - NHR wherein Ar is a phenyl, naphthyl, tetrahydronaphthyl or indanyl radical, which is also replaced by lipophilic substituents may be substituted, R represents a lower hydroxyalkyl or alkyl radical and R represents a hydrogen atom or a means lower alkyl radical, in free form or in the form of their non-toxic salts, and a benzothiadiazine derivative Benzenesulfonamide, a phenoxyacetic acid, a benzdfuran-2-carboxylic acid or 'a benzofuran-2,3-dihydro-2-carboxylic acid in free form or in the form of its non-toxic salts, 4. A pharmaceutical preparation according to claim 1 containing a compound of the formula OH Ar-O- CH - CH - CH - ONLY where Ar is a phenyl, naphthyl, tetrahydronaphthyl, indolylr 209852/1105 ORIGINAL BATHROOM or indanyl radical which is replaced by one or more lower alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, Alkylrcercapto-, alkylsulfonyl-, hydroxyalkyl-, aminoalkyl-, Alkylamino, dialkylamino, alkanoyl, alkanoyloxy, benzamido or alkanoylamino, aryl, aryloxy, arylamino, Arylmercapto-, Arylsulfonyl-, Arylsulfonylair.ino, arylamino-, aryl-lower alkoxy-, lower haloalkyl-, alkoxyalkyl-, Monoalkylaminoalkyl, dialkylarcinoalkyl radicals, nitro, Hydroxy, amino and / or cyano groups and / or haleto: r, e can be substituted, and R is a lower branched alkyl radical, in free form or in the form of its non-toxic salts, and a benzothiadlazine derivative, a behzenesulfonamide, a phenoxyacetic acid, a benzofuran-2-carboxylic acid or a benzofuran-2,3-dihydro-2-carboxylic acid in free Form or in the form of their non-toxic salts. ' 5. A pharmaceutical preparation according to claim 1 containing a compound of the formula EAR, II ¹ Ar - CH - CH - NHR wherein Ar is phenyl, naphthyl, tetrahydronaphthyl or Indanyl radical means, which is also represented by halogen atoms, nitro groups, lower alkyl and / or alkoxy radicals can be substituted, R stands for a lower branched alkyl radical and R, 209852/1105 BATH ORIGINAL denotes a V / Assstoffatoii or a lower alkyl radical, in free form or in the form of their non-toxic salts, and a benzothiadiazine derivative, a benzenesulfonamide, a Phenoxyacetic acid, a benzofuran-2-carboxylic acid or a benzofuran-2,3-dihydro-2-carboxylic acid in free form or in Form of their non-toxic salts. 6. A pharmaceutical preparation according to claim 1 containing a compound of the formula OH
Ar - O - CH ₂ - CH - CH ₂ - NHR wherein Ar is one by a lower alkenyl, alkynyl, alkenyloxy, Alknyloxy or gyano group-substituted phenyl radical and R denotes the tert-butyl, sec-butyl or isopropyl radical means, in free form or in the form of their non-toxic salts, and a benzothiadiazine derivative of the formula v / orin R, a hydrogen atom or a phenyl-lower alkylthio-lower alkyl and R ₂ , a halogen atom or the trifluorotethyl group. "■ 209852/1105
BATH ORIGINAL 7 · Containing pharmaceutical preparation according to claim 1 a connection of the 'B' formula . . OH Ar-O-CH ₂ - CH - CH ₂ - NHR wherein Ar is one by a lower alkenyl, alkynyl, alkenyloxy, Alkynyloxy or cyano group-substituted phenyl radical and R denotes the tert-butyl, sec-butyl or isopropyl radical means, in free form or in the form of their non-toxic salts, and a benzothiadiazine derivative of the formula HJf-O "S-J where R _{r is} hydrogen or lower alkyl, R ^ hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, aryl, aryl-lower alkyl, halo-lower alkyl, lower alkylthio-lower alkyl, lower alkenylthio-lower alkyl, halo-lower alkylthio-lower alkyl , Is phenyl-lower alkylthio-lower alkyl or heterocycloalkyl-lower alkyl, Ry is hydrogen or together with Rg is lower alkylene, and Rn is halogen or trifluoromethyl. 8. A pharmaceutical preparation according to claim 1 ent- 209852/1105
BATH ORIQMAL holding a compound of the formula OH;.
• Ar - O - CH ₂ - CH - CH ₂ - NHR wherein Ar 'is one by a lower alkenyl, alkynyl, alkenyloxy, Alkynyloxy or cyano group-substituted phenyl radical and R denotes the tert-butyl, sec-butyl or isopropyl radical means, in free form or in the form of their non-toxic salts and a benzenesulfonamide of the formula • R. 11 wherein R _{Q is} halogen, lower alkyl or trifluomethyl, R-, "is hydrogen, lower alkyl, phenyl-lower alkyl, optionally ■ phenyl or pyrrolidinomethyl substituted by lower alkoxy or amino, piperidinomethyl," piperazinomethyl, morpholinomethyl or thiornorpholinomethyl, R ,, carboxyl, carbamoyl, M- is mono- or N-di-substituted carbamoyl, sulfamoyl, N-mono- or N-di-substituted sulfamoyl, lower alkylsulfonyl or an isoindolinyl or is connected to the radical R _{1 ?} , R ^ ₂ hydrogen, ■ lower alkyl, amino , monoodor is di-substituted amino, and R _{1 is} -. Hydrogen or halogen. 209852/1105 BATH ORIGINAL 9 · Containing a pharmaceutical preparation according to claim i a compound of the formula OH _n - CH - CH ₀ - Ar-O-CH ₂ - CH - CH ₂ - KHR wherein Ar is one by a lower alkenyl, alkynyl, alkenyloxy, Alkynyloxy or cyano group-substituted phenyl radical and R denotes the tert-butyl, sec-butyl or isopropyl radical means, in free form or in the form of its non-toxic salts and a phenoxyacetic acid of the formula CH = C-CO- <x y> -0-CH ₀ -COOH ^R 14 where R-, _} , is lower alkyl, R, _ is halogen or lower alkyl and R, ^ is hydrogen, halogen or _{lower alkyl or where R 1} ^ and R, g together for JBut-1,3-dienylene- (l, ^) stands. 10. A pharmaceutical preparation according to claim 1 containing a compound of the formula OH Ar-O-CH ₂ - CH - CH ₂ - NHR wherein Ar is one by a lower alkenyl, alkynyl, alkenyloxy, Alkynyloxy or cyano group substituted phenyl 209852/1105
BAD ORIGiNAU radical and R denotes the tert-butyl, sec, -butyl or isopropyl radical means, in free form or in the form of their non-toxic salts and a benzofuran-2-carboxylic acid of the formula R -G-CO-CH -COÜH wherein R _{17 is} lower alkyl and R, o is lower alkyl or lower alkoxy. 11. A pharmaceutical preparation according to claim 1 containing a compound of the formula OH
Ar - O - CH ₂ - CH - CH ₂ - NHR wherein Ar is one by a lower alkenyl, alkynyl, alkenyloxy, Alkinyloxy or cyano group substituted phenyl and R denotes the tert-butyl, sec-butyl or iso propyl radical means, in free form or in the form of their not toxic salts and a benzofuran-2,3-dihydro-2-carboxylic acid of the formula 209852/1105 R ₂₁ -C-CO wherein R ^ _{Q is} hydroxy, alkoxy, cycloalkoxy or arylalkoxy, Rp _{0 stands} for two hydrogen atoms or lower alkylidene
_{/ Rg 1} is lower alkyl, R _{33 is} hydrogen, halogen, lower alkyl or lower alkoxy and Rp. is hydrogen or lower alkyl. 12. A pharmaceutical preparation according to claim 1 containing as a ß-blocker a compound of the formula OH Ar-O- CH ₂ - CH - - NHR where Ar is a phenyl radical substituted by a lower alkenyl or alkynyloxy group and R is an isopropyl radical means in free form or -in the form of their non-toxic Salts and, as a diuretic, a benzothiadiazine derivative of the formula 209857/1105 C-R- wherein R-. a water substance or a benzylthiomethyl radical and mean the chlorine atom or the trifluoromethyl group. 13. A pharmaceutical preparation according to claim 1 containing as a ß-blocker a compound of the formula OH Ar-O-CH ₂ - CH - CH ₂ - NHR where Ar is a phenyl radical substituted by a lower alkenyl or alkynyloxy group and R is an isopropyl radical means, in free form or in the form of their non-toxic salts and as a diuretic, a benzothiadiazine derivative the formula wherein R ₁ - hydrogen j or is the methyl group, 2098S9 / 11OB
BATH ORIGINAL Hydrogen atom, a lower alkyl radical bearing one, two or three chlorine atoms, the 2,2,2-trifluoroethylthioniethyl radical, the benzyl radical, the 5-norbornen-2-yl radical, the cyclopentylmethyl radical or the isobutyl radical, R _{7 is} the hydrogen atom and Rn is the chlorine atom or the trifluoromethyl group. l4. A pharmaceutical preparation according to claim 1 containing as a ß-blocker a compound of the formula OH Ar-O-CH ₂ - CH - CH ₃ - NHR where Ar is a phenyl radical substituted by a lower alkenyl or alinyloxy group and R is an isopropyl radical means, in free form or in the form of its non-toxic salt and as a diuretic, a benzenesulfonamide of the formula R ₁₀ HNSO ₂ - 12th where R "is the chlorine atom or the methyl group, R" _{Q is} the hydrogen atom, the methyl group or an aminophynyl group, R, .. the carboxyl group, the carboxyl group, the N-methylcarbanyl group, or the N- ( P, 6-1) i tr; ethyIpIjwrid 1 no) - 20985? Mins _B AD ORIGINAL earbamoyl group ,, the SuIfamoy! group, an N-lower alkylsulphonyl radical, the N- (2-Kethyltetrahydrofurfuryl) -sulphamoyl group or the 3-Hy ⁽ 3roxy ~ l-oxo-isoindolinyl- (3) group, R _{12 is} the hydrogen atom, the Methyl group, the amino group, the furfurylamino group or the dibenzylamino group, R ,, and R ₁₂ together -l-0xo-2-cyclohexyl ~ 2-aza-propylene- (1,3) and the l-oxo-2,4-bis -aza-3-ethyl-butylene- (l, 4), R _{12 is} the hydrogen atom, the methyl group, the amino group, the furfurylamino group, the benzylamino group or the dibenzylamino group and R- is the hydrogen atom. 15. * Pharmaceutical preparation according to claim 1 holding a compound of the formula as a ß-blocker OH Ar - O - CH ₂ - CH - CH ₂ '- NHR wherein Ar is represented by a lower alkenyl or alkynyloxy group Substituted phenyl radical and R denotes the isopropyl radical, in free form or "in the form of their non-toxic salts and as a diuretic a phenoxyacetic acid the form]. 115 116 BAD ORlGINAt CH, -C-CO- < _v / VO-OH-COOII 209857/1105 where R, jl is the Ae thy! group, R, ^ the chlorine atom or the Methyl group is / FLg the chlorine atom or the methyl group or R and Rg together for but-l, j5-dienylene- (l, 4) stand. 16. A pharmaceutical preparation according to claim 1 ent-; holding a compound of the formula as a ß-blocker OH Ar-O-CH ₂ - CH - CH ₂ - NHR where Ar is a phenyl radical substituted by a lower alkenyl or alkynyloxy group and R denotes the isopropyl radical means, in free form or in the form of their non-toxic salts and as a diuretic, a benzofuran-2-carboxylic acid the formula wherein R _{17 is} the methyl or ethyl group and R ^ is the methyl or methoxy group. ΐγ. Pharmaceutical preparation according to claim 1 ent holding a compound of the formula as a ß-blocker 20985 2/1105 OH
Ar-O-CH ₂ - CH - CHg - HHR in which Ar is a phenyl radical substituted by a lower alkenyl or alkynyloxy group and R is Isopro pyl radical means, in free form or in the form of its non-toxic salts and as a diuretic, a benzofuran-2, j5-dihydro-2-carboxylic acid the formula ? 20 R ₂₁ -C-CO- 22nd -CO-R. wherein R is the hydroxyl group, an alkoxy group, the cyclohexyloxy group, the cyclopentyloxy group or the benzyloxy group, R 1 is, mefchylidene or ethylidene, R _{1 is} a
Is lower alkyl group, R _{22 is} the hydrogen atom, ■ the methyl group, the chlorine atom or the fluorine atom and Rp, the
Is hydrogen atom or the methyl group. l8. Pharmaceutical preparation according to claim 1 containing as ß-blocker-l- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane, l- (2-allylphenoxy) -2-hydroxy-3-isopropylarninopropane or 1- (H -allyloxyphenoxy) -2-hydroxy-2-isopropyl ~ aminopropari or a nontoxic salt of these compounds and air, diurotiourr, P-Ch] or- [fj- [3-hydroxy-1-oxo-ii: oindolyl- ( 5)] - 2 0 rj Ii 5 2/1105 BATH ORIGINAL benzene-sulfonamide, o-chloro ^ -sulfamyl ^^ - dihydro-l, 2,4-benzothidiazine-l, l-dioxide, ^ -Cyclopentylmethyl-o-chloro-T-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide or 5- (2-methylenebutyryl) -6-methylbenzofuran-2-carboxylic acid. 19 · Pharmaceutical preparation according to claim 1 containing 1- (4-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane or a non-toxic salt thereof and 2-chloro-5- [3-hydroxy-1-oxo-isoindolyl- (3)] -benzenesulfonamide. 20. A pharmaceutical preparation according to claim 1 containing 1- (4-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane or a non-toxic salt thereof and 6-chloro-7-sulfamy1-3,4-dihydro-1,2,4-benzothiadiaζin-l, l-dioxide. 21. A pharmaceutical preparation according to claim 1 containing 1- (4-allyloxyphenoxy) -2-hydroxy ~ 3-isopropylaminopropane or a non-toxic salt thereof and 3-cyclopentylmethyl-6-chloro-7-sulfamyl-3,4-dihydrο-1,2,4-benzothiadiazine-1,1-dioxide. 22. A pharmaceutical preparation according to claim 1 containing 1- (4-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane or a non-toxic salt thereof and 5- (2-methylenebutyryl) -6-methyl-benzofuran-2-carboxylic acid. 209852/1105
BATHROOM QRiGINAL 23. A pharmaceutical preparation according to claim 1 containing l- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopro pan or a non-toxic salt thereof and 2-chloro-5- [3-hydroxy-l _T oxo-isoindolyl- (3)] - benzene sulfonamide. 2H. A pharmaceutical preparation according to claim 1 comprising l- (2-Allyloxypherioxy) -2-hydroxy-3-isopropylaminopro pan or a non-toxic salt thereof and 6-chloro-7-sulfamyl-3 4-dihydro-l _{J J} 2 _J ⁱ i -benzOthiadiazin-l _i l-dioxide. 25.3 Pharmaceutical preparation according to claim 1 containing 1- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane or a non-toxic salt thereof and 3-cyclopentylmethyl-6-chloro-7-sulfarnyl-3 _J 4-dihydro-1 _J 2 _i 4-benzothiadia- -lj1-dioxide. 26. A pharmaceutical preparation according to claim 1 containing l- (2-allyloxyphenoxy) ~ 2-hydroxy-3 ~ isopropylaminopropane or a non-toxic salt thereof and 5- (2-methylenebutyryl) -6-methyl-benzofuran-2-carboxylic acid. 27. A pharmaceutical preparation according to claim 1 containing 1- (2-Allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane or a non-toxic salt thereof and 2-chloro-5-13 ~ hydroxy-l-oxo-isoindolyl- (3)] -benzenesulfonamide. 209852/1105 28. Pharmaceutical preparation according to claim 1 containing l- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropane or a non-toxic salt thereof and 6-chloro-7-sulfamyl-3 _J ⁱ f-dihydro- l _J 2,4-benzothiadlazine-l, l-dioxide. 29. A pharmaceutical preparation according to claim 1 comprising l- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropan or a non-toxic salt thereof, and 3-cyclopentylmethyl-6-chloro-7-sulfamyl-3, 4-dihydro-1 , 2,4-benzothiadiazin-1, Ια i oxy d. 30. A pharmaceutical preparation according to claim 1 containing 1- (2-allylphenoxy) ~ 2-hydroxy-3-isopropylamino propane or a non-toxic salt thereof and 5- (2-methylenebutyryl) · 6-methyl-benzofuran-2- carboxylic acid. 31. A pharmaceutical preparation according to any one of claims 1 to 30 containing half to double the single dose of the ß-blockers and half to double the single dose of the diuretic. 32. A pharmaceutical preparation according to any one of claims 1 to 30 containing half to simple single dumplings ß-blockers and half to simple single doses of the. Dlure-tlcums. 209857/1105 33 · Pharmaceutical preparation according to one of Claims 1 to 30 containing 20 to 100 mg of 1- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 to 25 isg of 2-chloro-5- [3-hydroxy-1-oxo-isoindolyl- (3)) -benzenesulfonamide. 3 ^. Pharmaceutical preparation according to one of the claims 1 to 30 containing 40 to 80 mg of 1- (2- allyloxyphenoxy) -2-. hydroxy-3-isopropylaminopropane hydrochloride and 10 mg of 2-chloro-5- [3-hydroxy-1-oxo-isoindolyl- (3)] -benzenesulfonamide. 35 · Pharmaceutical preparation according to one of Claims 1 to 30 containing 20 to 100 mg of 1- (2-allylphenoxy) -2-hydroxy -3 -isopropylaminopropane hydrochloride. and 10 to 25 mg of 2-chloro-5- [3-hydroxy-1-oxo-isoindolyl- (3)] -benzenesulfonamide. 36. A pharmaceutical preparation according to any one of claims 1 to 30 containing 40 to 80 mg of 1- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 mg of 2-chloro-5_ [3-hydroxy-1-oxo-isoindolyl- (3)] -benzenesulfonamide. 37. A pharmaceutical preparation according to one of claims 1 to 30 containing ho to 200 mg of 1 - (^ - AlIyIoxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 to 25 mg of 2-chloro! 3- [3-hydroxy- l-oxo-isolndolyl- (3)] -benzene-sulfonamide. 20985.7 / 1105 38. Pharmaceutical preparation according to one of claims 1 to J) O containing 80 to 160 mg of l- (4-allyloxypherioxy) -2 ~ hydroxy ^ -isopropylaminopropane hydrochloride and 10 mg of 2-chloro-5- [3-hydroxy-l- oxo-isoindolyl- (5)] -benzenesulfonamide. 39 · Pharmaceutical preparation according to one of Claims 1 to 30 containing 20 to 100 mg of 1- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 to 25 mg of 6-chloro-7-sulfamyl-3 ^ f-dihydro-1,2,4-ben2othiadia2; in-1,2-dioxide. 40. Pharmaceutical preparation according to one of the claims 1 to 30 containing 40 to 80 mg of 1- (2-allyloxyphenoxy) -2 ~ hydroxy-3-isopropylaminopropane hydrochloride and 10 mg 6- i | l. Pharmaceutical preparation according to one of the claims 1 to 30 containing 20 to 100 mg of 1- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 to 25 mg of 6-chloro-7-sulfamyl-3,4-dihydro ~ l _t 2, ^l \ -benzothiadiazin-l, 1- dioxide. 42. Pharmaceutical preparation according to one of the claims 1 to 30 containing ή'ο to 8θ mg 1- (2-Λ3 Iy] phenoxy) -2-hydroxy-3-isopropylaminopropane hyd) 'O ( ⁱ chloride and 10 ν.ψ; 6-chloro 20985? M1flF ^ BATH ORIGINAL 43. Pharmaceutical preparation according to one of the claims 1 to 30 containing 40 to 200 mg of l- (4-allyloxyphenoxy) ~ 2 » hydroxy-3-isopropylaminopropane hydrochloride and 10 to 25 mg dioxide. 44th. A pharmaceutical preparation according to one of claims 1 to 30 containing from 80 to I60 rng l- (4-allyloxyphenoxy) -2-hydroxy-3-i ^so P ^ro Pyl ^ara i ^no P ^r ° Pan hydrochloride and 10 mg of 6-chloro-T -sulfamyl ^^ - dihydro-l ^^ - benzothiadiazine-ljl-dioxide. ■ 45 · Pharmaceutical preparation according to one of the claims 1 to 30 containing 30 to 100 mg of 1- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 to 25 mg of 3-cyclopentylmethyl-6-chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide. 46. A pharmaceutical preparation according to one of claims 1 to 30 containing 40 to 80 mg of l- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 mg of 3-cyclopentyln.ethyl ~ 6-chloro-7-sulfamyl- 3 _i 4-dihydro-l, 2 _i 4-benzothiadiazine-l, l-dioxide. 20985P / 110B 7227423 - 62 - ^ 7 · Pharmaceutical preparation according to one of the claims 1 to 30 containing 20 to 100 mg of 1- (2-allylphenoxy) -2-hydroxy-3-isopropylalinopropane hydrochloride and 10 to 25 rag 3-Cyclopentylir; ethyl-6-chloro-7-sulfarriyl-3 ^} - dihydro-1,2 ^ lbenzothiadiazine-1,1-dioxide. 48. A pharmaceutical preparation according to any one of claims 1 to 30 containing 4θ to 80 mg of l- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 mg of 3-cyclopentylmethyl-6-chl-oro-7-sulfamyl 3j ^ -dihydro-l _J 2 _J 4-benzothiadiazine-lj1-dioxide. ^ 9 · Pharmaceutical preparation according to one of claims 1 to 30 containing 40 to 200 mg of l- (4-allyloxyphenoxy) _- 2 ~ hydroxy-3-isopropylaminopropane hydrochloride and 10 to 25 mg of 3-cyclopentylmethyl-6-chloro-7- sulfarnyl-3 _J 4-dihydro-1 _J 2,4-benzothiadiazine-1,1-dioxide. 50. A pharmaceutical preparation according to any one of claims 1 to 30 containing 80 to 160 mg of l - (^ - allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 mg of 3-cyclopentylmethyl-6-chloro-7-sulfarr _: yl -3 _J ⁱ i -dihydrO-l _i 2 _i ^; l-benzothiadiaziri-1, l-dioxide. 51. Pharmaceutical preparation at nar: h one dor claims 209852/1105 BATH ORIGINAL 7227A23 - 63 - 1 to 30 containing 20 to 100 mg of 1- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 to 30 mg of 5- (2-methylenebutyryl) -6-methyl-benzofuran-2-carboxylic acid. 132. Pharmaceutical preparation according to one of claims 1 up to 30 containing 40 to 80 mg of 1- (2- allyloxyphenoxy) -2-hydroxy-3-isopropylamihopropane hydrochloride and 10 to 20 mg of 5- (methylenebutyryl) -6-methyl-benzofuran-2-carboxylic acid. 53 · Pharmaceutical preparation according to one of Claims 1 to 30 containing 20 to 100 mg of 1- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 to 30 mg of 5- (2-methylenebutyryl) -6-methyl-benzofuran-2-carboxylic acid. 5 ^. Pharmaceutical preparation according to one of claims 1 to 30 containing Ho to 80 mg of l- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and 10 to 20 mg of 5- (2-methylenebutyryl) -6-methyl-benzofuran 2-carboxylic acid. 55. Pharmaceutical preparation according to one of the claims 1 to 30 containing> J0 to 200 mg of 1- (4-allyloxyphenoxy) -2-hydroxy ~ 3-isopropyl aminopropane hydrochloride and 10 to 30 mg 5- (2-methylenebutyryl) -6-methyl-benzofurane-2-carboxylic acid. 56. Pharmaceutical preparation according to one of the claims 209852/1105 1 to 50 containing 80 to 160 mg of 1- (W »llyloxypher.oxy) -2-hydroxy-jj-isopropylaminoprcpan-hydrochloride and 10 to 20 rr.g 5- (2 -! '. ethylenebutyryl) -6-rr.ethyl-benzofurEn-2-carboxylic acid. 57 · Pharmaceutical preparation according to one of the claims 1 to 56 containing potassium chloride. 58. Pharmaceutical preparation according to one of the claims 1 to 56 containing 200 to 800 mg potassium chloride. 59 »Pharmaceutical preparation according to one of the claims 1 to 56 containing 500 to 700 mg of potassium chloride. 60. A method for the production of pharmaceutical preparations according to any one of claims 1 to 59, characterized in that that one of the active ingredients mentioned in one of claims 1 to 59 with a pharmaceutical carrier material processed. ■. BATH ORIGINAL 209852/1105