DE1817346A1 - Cardiac preparations based on methylanthines - Google Patents

Description

oasis 1/336 Dr. R. Koenigsbeiger

Dr.Ve/Ba Dipl. Ph _ys . R. Holzbauer

Patent attorneys
Munich 2, Bräuhaussiralje 4 / IH

CH. Boehringer Sohn, Ingelheim am Rhein

Cardiac preparations based on methylxanthines

The invention relates to pharmaceutical preparations based on a Combination of methylxanthine derivatives with ß-receptor blockers.

It is already known that, in addition to other heart diseases, angina pectoris in particular can also be treated with the aid of τοπ ß-receptor blockerii. The thereby entering the application-ß Rezöptorenblocker substances are mostly of the type of l-aryloxy - "" 2 - hydroxy = 3 = · aminopropane with optionally substituted aryl and amino Reference is made to the French BSM patents Mr ₀ 37 32 , 40 57 * 40 61, 41 61, 49 05 and 49 06, the Belgian patents Ir. 640 312, 640 313, 641 133 ₉ ^ i 417 ₉ 652 336, 669 402, 670 364, 675 847, 675 967 _f 676 821 ,. 682 872, 684 271, 686 949 * 692 309, 693 518, 700 460, 708 815, 710 400, .715 and 716 647? Irish Patent Applications No. 946/65? 330/66, 331/66 and 430/66, the South African patents Nos. ₀ 65/4447, 65/5403, 65/5907, 67/0822 and 67/5430, the Dutch applications Mr. 64.10522, 65 = 02705, 65ο03196, 66.07921, 66.08099, 66.09639, 66.09640, 67ο1217O ₅ 67.13400, '67 .13499, 67 = 14892, 68.00038 and 68.01917 as well as the German Auslegeschriften Hr. 1,227,462, 1,236,523 and 1,242,596. But also certain compounds with the chemically similar aryl = -l-liydro3cy-2-aminoethane structure such as the Biehlor- * isoproterenol (US Patent 2,938,921), the Pronethai oil (Lancet 1962, So 311 = 316) , das l = (5r6,7? 8-! retrahydro = ^ naphthyl) = l- = hydroxy - = - 2 = "sec ₀ - 'butylaminoethane (Swiss patent 437 351) see that!» (4-Hitrophenyl) · = ·! · "hyaroxy S isopropylaffiinoäthan (J ₀ medo Chem <, £ ₉ 6 (1966) ₈ S ₀ .823) and the l- {4" Metliansiilf © EylasinQplieayl) "l" hjd3? oxy ~ 2 '= isop2? opylaffliriOätlia.n

009i30 / 1769

BADORlQtNAL

(The Pharmacologist δ, »2 (1964) p. 181) are therapeutically valuable, ß-receptor blockers suitable for angina pectoris treatment.

In the treatment of angina pectoris with such compounds however, there are also undesirable effects. Disadvantages are in particular the blood flow-reducing effect of the ß-receptor blockers in the coronary area, their cardiac inhibitory (negative inotropic) and bronchoconstrictor effects.

It has now been found that the disadvantages mentioned of the ß-receptor blockers, in particular the bronchoconstrictor effect, in the treatment of angina pectoris, can be compensated for by ■ with methylxanthine derivatives such as theophylline, theobromine, öaffeine or paraxanthin and their derivatives are prescribed together. Surprisingly, only the undesirable side effects of the ß-blockers are influenced, while the desired sympathicomilytic ones Effect fully preserved. In particular, come for it the above-mentioned 4 compounds themselves and their salts in question, whereby salts with organic bases such as ethanolamine, choline, diethanolamine, Diethylaminoethanol or ethylenediamine are included. Also derivatives of these 4 substances with better water solubility causing side chains (such as hydroxyalkyl, aminoalkyl or alkyl radicals simultaneously substituted with hydroxyl and amino groups) come into question. The 7-hydroxyalkylated, optionally further substituted theophyllines in the alkyl, furthermore the corresponding 1-hydroxyalkyl-TIieobromine, which (possibly in the amino group still substituted) 7-aminoalkyl-theophyllins or I-aminoalkyl-theobroraine (especially their nearly neutral salts) and the corresponding 7- or 1-hydroxy-aminoalkyl derivatives of Theophyllines and theobromines. Examples of individual substances are called:

Theophylline
Choline theophyllinate

Ethylenediamine ditheophyllinate (aminophylline) G-lycin theophyllinate
W-methylglucamine-theophyllinate 1,1,4,4-tetramethylpiperazinium-ditheopliyllinat 5, 4-Mhydroxy-ephedrine-theophyllinat Xheophylline-ß-amino-isobutanol (butaphyllamine) 7-CB-hydroxypropyl) -theophylline 7- (s-Hydr o : icjäthyl) » the ophyllin jmmno ü ^ _{qq gg 3 Q fy ? ß g} bad originau

7- (β, ^ - dihydroxypropyl) -theophylline

7-diethylamino ethyl-the ophyllin

7 ^ ß-Hydroxy -) - (N-ß-hydroxyethyl-N-methyl -

aminojjDropylJ -theophylline

Paraxanthin

Caffeine ■

Theobromine

1-Cβ-hydroxypropyl) -theobromine

l- (ß-Mäthylaininoäthyl) -the obr omin

l- (ß-hydroxyethyl) -theobromine

l- (ß-Cyelohexylaminoäthyl) -theobromin

1- (ß-Benzylaminoethyl) -theobromine

Iheobromine sodium salicylate

Choline theophyllinate has proven to be particularly valuable, also 7- (ß-hydroxypropyl) -theophylline and aminophylline proven.

Advantageously applicable ß-receptor blockers for the combination with the methylxanthine iDeriYates mentioned above are racemic or optical active compounds of the general formula

Ar-OCH ₂ -CHOH-CH ₂ -NHR " _f 1

or their physiologically acceptable acid addition salts.

In this formula:

Ar is an unsubstituted or a mono- or polysubstituted iso-, homo- or heterocyclic radical with at least one aromatic 6-membered ring which is bonded directly to the residue molecule (preferably the phenyl, ITaphthyl, tetralyl or indanyl radical) with as substituents lower Alkyl--, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkylthio, alkylsulfonyl _r hydroxyalkyl, aminoalkyl, (alkyl or dialkyl) amino, acyl, acyloxy, acylamino, aryl, aryloxy, arylamino, arylthio, arylsulfonyl, arylsulfonylamino, aroylamino-j aralkoxy, haloalkyl ", alkoxyalkyl, mono- or dialkylaminoalkyl, further nitro _s hydroxy, amino or halogen atoms or Oyanogruppen suitable: and

009830/1769

- - ¹ · "■ *" BAD ORfOfNAt

■ ~ 1 81 7 ^ 4 Γ

R is a preferably branched alkyl radical or hydroxyalkyl radical 1-8 carbon atoms, preferably the isopropyl or tert. Means butyl group.

A preferred subgroup consists of compounds of the formula I, in which R has the broad meaning given above and Ar has an unsaturated group, such as an alkenyl, alkynyl, alkenyloxy, Alkinyloxy or cyano group-substituted phenyl radical. Even Compounds in which R has the broad meaning given above and Ar is one with a lower hydroxyalkyl, acylamino or thio «.

a] kyl group-substituted phenyl radical, are in the invention Combination applicable with advantage. The following are named as individual substances:

1- (L-naphthoxy) -2-hydroxy-3-isopropylaminopropane 1- (3-tolyloxy) -2-hydroxy-3-isopropylaminopropane 1- (3 j 5-xylyloxy) -2-hydroxy-3-isopropylaminopropane 1- ( 2-cyano-3-methylphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-methylthiophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (4 -Acetamidophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (4-methanesulfonylamidophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (5,6,7, 8-tetrahydro-1-naphthoxy) -2-hydroxy-3-isopropylaminopropane 1- (4-benzamidophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (4-indanyloxy) -2-hydroxy-3-isopropylaminopropane 1- (2 Bromophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (4-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-ethynylphenoxy) -2 -hydroxy-3-isopropylaminopropane 1- (2-methoxymethylphenoxy) ^ - hydroxy-S-isopropylaminopropane 1- (2-hydroxymethylphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-propargyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-methoxyphenoxy) -2-hydr oxy-3-isopijgpylaminopropane 1- (2-isopropoxyphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2- Methallyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (4-indolyloxy) -2-hydroxy-3-isopropylaminopropane 1- (2-phenylphenoxy) -2-hydroxy-3-isopropylaminopropane ^s 1- (2-phenoxyphenoxy) ^ - hydroxy ^ -isopropylaminopropane 1- (2-chloro-5-methylphenoxy) -2-hydroxy-3-tert-butylaminopropane

009830/1769

OFHGiNAt tfiSPECTED

1- (2-Cyanophenoxy) -2-hydroxy-3-tert-butylaminopropane 1 Ol 7 346 1- (3-Hydroxymethylphenoxy) -2-hydroxy-3-tert-butylaminopropane 1- (2-ethynylphenoxy) -2-hydroxy- 3-tert-butylaminopropane 1- (2-allylphenoxy) -2-hydroxy-3-tert-butylaminopropane 1- (2nd phenylphenoxy) -2-hydroxy-3-tert-butylinopropane 1- (2-methoxymethyl-2 ^ ^ ydroxy ~ 3-tert. butylaminopropane 1- (4-acetainidophenoxy) -2-hydroxy-3-tert-butylaminopropane 1- (2-hydroxymethylphenoxy) -2 ~ hydroxy-3-tert-butylaminopropane l- (2-allyloxyphenoxy ) -2-hydroxy73-tert-butylaminopropane 1- (2-gyanophenoxy) -2-hydroxy-3-tert.pentylaminopropane 1- (2-methoxyphenoxy) -2-hydroxy-3-tert.pentylaminopropane 1- (2 «methoxyphenoxy) -2-hydroxy-3- (1,1-dimethylbutyl) aminopropane

or the physiologically acceptable acid addition salts of these Sub- ™ jam.

Also ß-receptor blockers of the general Iormel

Ar-CHOH-CH-NHa II

wherein Ar is a phenyl, haphthyl, tetralyl or indanyl2353t optionally substituted with lipophilic substituents such as halogen, nitro, alkyl or alkoxy, R is a preferably branched alkyl or hydroxyalkyl radical with 1-8 carbon atoms and R _{1 is} hydrogen or a means lower alkyl radical, and their physiologically acceptable acid addition salts μ can be used in the inventive preparations. Preferred substances from this group are 1- (3> 4-dichlorophenyl) ~ l-hydroxy-2-isopropylaminoethane (dichloroisoproterenol), 1- (1'-naphthyl) -l-hydroxy-2-isopropylaminoethane (pronethalol), the 1- (2, S-Dimethoxyphenyl) -1-hydroxy-2-methyl-2-tert-butylaminoethane, 1- (4-methanesulfonylaminophenyl) -1-hydroxy-2-isopropylaminoethane, 1- (5,6,7> 8- Te trahydro-1-naphthyl) -1-hydroxy-2-sec.butylaminoethane and 1- (4-nitrophenyl) -l-hydroxy-2-isopropylaminopropane or the acid addition salts of these compounds,

Both lormel I and lormel II compounds have at the CHOH group have an asymmetry center and therefore come in the form of Stereoisomers. According to the invention, all of these sterocfeomers can be used be used? In general, however, the Raoemate are used.

Suitable acid components for the production of physiologically compatible Acid addition salts of the compounds of the formulas I and II are hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, lactic acid, Tartaric acid, oxalic acid, or maleic acid.

The active ingredient combinations according to the application can be converted into the usual Application forms such as tablets, coated tablets, solutions, emulsions, powders, Capsules or depot forms are brought, for their production the usual pharmaceutical auxiliaries and the usual Manufacturing methods can be used. Corresponding tablets, can, for example, by mixing the active ingredients with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents for achieving one Depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate.

The tablets can also consist of several layers. Correspondingly, coated tablets can be produced by coating cores produced analogously to tablets with agents usually used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the drag-free casing W can also consist of several layers in order to achieve a depot effect, it being possible to use the auxiliaries mentioned above for the tablets.

Juices of the active ingredients or combinations of active ingredients according to the invention In addition, a sweetener such as saccharin, gyclamate, glycerin or sugar, and a taste-improving agent, e.g. Contains flavorings such as vanillin or orange extract. You can also suspension aids or thickeners, such as sodium carboxymethyl cellulose, Wetting agents, for example condensation products of fatty alcohols with ethylene dioxide, or protective substances such as p-hydroxybenzoates, contain.

Injection solutions are used in the usual way, e.g. with the addition of Preservatives, such as p-hydroxybenzoates, or stabilizers, like complexones »produced and in ejection bottles or ampoules bottled. 00983 0/1769

The active ingredients Tdzw. Capsules containing combinations of active ingredients can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or. Sorbitol, mixes tmd encapsulated in gelatin capsules.

Suitable suppositories can be made, for example, by mixing " of the active ingredients or combinations of active ingredients provided for this purpose with conventional carriers such as neutral fats or polyethylene glycol or its derivatives.

For oral use of the preparations according to the invention, the usual dose recommended in the literature for the substance in question comes into consideration for the methylxanthine component, ie the dose range for the individual treatment is in the range of 30-500 mg, preferably depending on the effectiveness of the substance in question however 100-300 mg. If, for example, the choline theophyllinate preferred in the context of the invention is used, this substance can be dosed at 150-200 mg. If theophylline-ethylenediamine and 7- (ß-hydroxypropyl) -theophylline are used, the same dose range is possible. ? 3 ÜR oral application of the ß-Eezeptorenblocker of formulas I or II is an area for the single dose of I - 500 mg, preferably 10 - 200 mg into consideration. When using the β-receptor blockers lm-Iolyloxy-2-hydroxy-3-isopropylaminopropane, 1- (2-chloro-5-methylphenoxy) -2-hydroxy--3-tert-butylaminopropane and 1- (l-naphthyloxy) -2 -hydroxy-3-isopropylaminopidpan in the form of a physiologically compatible acid addition salt, a single dose in the range of 30-75 mgj preferably -50 mg is suggested; when using l- (2-allylphenoxy) -2-hydroxy-3-isopropylaminopropari, l ~ (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane, stdöK l- (2-cyanophenoxy) -2 ~ hydroxy-3- isopropylaminopropane ^ DZW. the acid addition salts of these compounds is a single dose of: 5 - 60, preferably 15 - 40 mg , while when using 1- (4-acetamidophenoxy) -2-hydroxy-3-isopropylaminopropane the dose is higher, namely in the range of 40 - 80 mg should be. Pur the above-mentioned β-receptor blockers of the arylalkanol type, in particular 1- (5-6-7,8-tetrahydro-1-naphthoxy) -1-hydroxy-2-sec-butylaminoethane, or the acid addition salts of these compounds will be a

+] or 1- (P-cyanophenoxy) -? - hydroxy-3-tert.butylaminopropane

γ · 181734C

Suggested single dose in the range of 40-120 mg.

Purely for parenteral use, i.e. for injection solutions, the methyixanthin derivatives can be used in the same area as above indicated for oral use. For the ß-receptor blockers, however, the dose range must be reduced will. In general, only 1/5 to 1/10 of the amounts given above for the oral single dose are used for the parenteral single dose in question.

The following examples illustrate the invention without restricting it:

Example 1 (coated tablets)

a) core

Choline theophyllinate polyvinylpyrrolidone (PVP) corn starch
Magnesium stearate

220.0, g

Production: The active ingredient is mixed with the excipients. The mixture is then briquetted and granulated in the usual way Cores of 10 mm diameter, arched on both sides, are pressed from the granulate.

b) coat

l- _m _Ioiyioxy-2-hydroxy-3-isopropylaminopropane hydrochloride sec. Calcium phosphate shark starch

colloidal silica polyvinylpyrrolidone soluble starch, magnesium stearate

450.0 g

009830/1769

175.0 G 20.0 G 20.0 G 5.0 ft

50.0 6th 175.0 G 193.0 G 14.0 G 6.0 G 10.0 β 2.0 ft

181734G

Production: The active ingredient is with the entire sec. Calcium phosphate and polyvinylpyrrolidone as well as with 150 g of corn starch and 10 g of colloidal silica -mixed. The mixture is made with the help granulated a solution of the soluble starch in 100 ml of demineralized water and the dried granulate with the remaining colloidal Silicic acid, the remaining corn starch and the magnesium stearate mixed. .

100 coated tablets are made from the core and shell granulate in the usual way each of 670 mg G-ewich.t and 13 mm in diameter.

Example 2 (coated tablets) -

1 dragee contains:

7- (ß-hydroxypropyl) -theophylline 200.0 mg 1- (1'-naphthyloxy) -2-hydroxy-3-isopropyl-

aminopropane hydrochloride 40.0 mg

Milk sugar 100.0 mg

Potato starch 100.0 mg

Polyvinylpyrrolidone 20.0 mg

Magnesium stearate 5 _T 0 mg

; 4-65.0 mg

Production: The mixture of the active ingredients with the milk sugar and the potato starch is made with a 25 $ ethanol solution
of the polyvinylpyrrolidone moistened through a sieve with a
Mesh size of 1.5 mm beaten and dried ^{at 45 0 O.} That
dried granules are again beaten through a sieve with a mesh size of 1 mm and mixed with the magnesium stearate. Drag fairing cores are pressed from this mixture.

The cores obtained in this way are coated in the usual way with a shell consisting essentially of sugar and talc.
The coated tablets obtained in this way are polished with the help of beeswax. Final weight: 700 mg.

/ 17 6 9

181734G

Example 3 (coated tablets) / JO
1 dragee contains:

Theophylline 150.0 mg l- (2-allylphenoxy) -2-hydroxy-3-isopropyl- aminopropane hydrochloride 40.0 mg Lactose 100.0 mg Potato starch 100.0 mg gelatin 10.0 mg Magnesium stearate 5iO mg 405.0 mg

Production: The active ingredients are mixed with milk sugar and the potato starch and then with egg? 10 ^ igen aqueous solution of gelatin granulated (sieve: 1.5 mm mesh size); then at 4O ⁰ O is dried. The dried granules are pressed through the above sieve again and mixed with magnesium stearate. Dragee cores are pressed from the mixture. Core weight: 405 mg

The cores produced in this way are in the usual way with a Covered mainly from sugar and talcum powder. The finished coated tablets are polished with the help of beeswax. Final coated weight: 600 mg.

Instead of the ß-receptor blocker used in this example you can also use l- (4-acetainidophenoxy) - 2-hydroxy-3-isopropylaminopropane use in the form of a physiologically compatible acid addition salt.

0098 3 0/1769

181734C

Example 4 (wafer capsules) '

1 capsule contains:

l- (ß-hydroxyethy / l) -theobromine 175.0 mg

aminopropane hydrochloride ■ 40.0 mg

Lactose sugar (crystalline) 75.0 mg

Talc 20.0 mg

310.0 mg

Production: those sifted through a sieve with 0.75 mm mesh size Active substances are mixed intensively with the auxiliary substances and filled into oblate capsules of a suitable size. Capsule filling: 310 mg

Example 5 (ampoules).

1 ampoule contains:. -

Aminophylline 1- (2 '-]! Iitrilo-phenoxy) -2 hydroxy-3-tert-butylaminapropane hydrochloride Sodium pyrοsulphite

bidist. Water ad

• *

Production: In boiled double distilled water cooled to room temperature. Two active substances are dissolved under nitrogen in succession sodium pyrosulfite and the "The solution is made up to volume and filtered suspended particles bottling:.. In brown ampoules (under nitrogen) Sterilization: 20 minutes at 120 ⁰ O..

200.0 mg 5.0 mg 2.0 mg 2.0 ml

Example 6 (drapes) 180.0 mg 1 dragee contains: Butaphyllamine 60.0 mg l- (2-thiomethylphenoxy) -2-hydroxy-3- 100.0 mg isopropylamino propane hydrochloride 80.0 mg Lactose 3.0 mg Potato starch 2.0 me ! Polyvinylpyrrolidone Magnesium stearate

425.0 mg 009830/1769

1817 34G

The finished drag6es are produced analogously to Example 1.

Instead of the ß-receptor blocker used in this example one can also use 1- (5,6,7,8-tetrahydro-l-naphthoxy) -l-hydroxy-2-sec.butylaminoethane and l- (4-methanesulfonamidophenyl) -lhydroxy-2-isopropylaminoethane use in the form of a physiologically compatible acid addition salt.

Example 7 (suppository)

1 suppository contains:

Caffeine 125.0 mg

1- (4-nitrophenyl) -1-hydroxy-2-isopropyl-. aminoethane hydrochloride 75.0 mg

Suppository mass, e.g. Witepsol H 12 1600.0 mg

1800.0 mg

Preparation: The finely powdered is stirred at 40 ⁰ C of active substance in the molten suppository mass. The mass is homogenized and at about 35 ⁰ Q in Ie
Suppository weight: 1.8 g

and poured into slightly pre-cooled molds at about 35 ^{0 Q.}

The caffeine used in this example can also be replaced by paraxanthin or theobromine.

009830/1769

Claims (10)

P a t en t a η s ρ r ü c h e 1.) Pharmaceutical preparations containing as active ingredients a) at least one methylxanthine derivative of the theophylline type, Theobromines, caffeine or paraxanthines or their salts as well their derivatives with side chains which lead to better water solubility, such as hydroxyalkyl, aminoalkyl or hydroxyamines alkylr es th, ■ b) a ß-receptor blocker of the l-aryloxy ^ -hydroxy ^ - type aminopropane or l-aryl-l-hydroxy-2-aminoethane with optionally substituted Aryl or amino group "or their physiologically compatible Acid addition salts. 2.) Pharmaceutical preparations containing as active ingredients a) at least one methylxanthine derivative of the theophylline type, Theobromines, caffeine or paraxanthin or their salts as well their derivatives with side chains resulting in better water solubility such as hydroxyalkyl, aminoalkyl or hydroxyaminoalkyl radicals, b) a ß-receptor blocker of the general formula Ar-OCH ₂ -CHOH-CH ₂ -NHR I In this formula: Ar is an unsubstituted or a mono- or polysubstituted one iso-, homo- or heterocyclic radical with at least an aromatic 6-membered ring, which is bound directly to the rest of the molecule (preferably the phenyl, naphthyl, setralyl «or Indanyl radical) where lower alkyl, alkoxy, Alkenyl, alkenyloxy, alkynyl · »» alkynyloxy, alkylthio, Alkylfulsonyl-, hydroxyalkyl-, aminoalkyl-, alkyl- or dialkylsmino-, Acyl », acyloxy-, acylamino- *, aryl», aryloxy- »arylamino-, 0098.30 / 1768 Arylthio, arylsulfonyl, arylsulfonylamido, aroylamino, Aralkoxy, haloalkyl, alkoxyalkyl, mono- or dialkylaminoalkyl radicals, also nitro, hydroxy, amino or cyano groups or halogen atoms are possible and H is a preferably branched alkyl radical or hydroxyalkyl radical with 1-8 carbon atoms, preferably the isopropyl or tert. Butyl group means, or -GH- Ar-CHOH-CH-NHR II in which Ar is a phenyl, naphthyl, Tetralyl or indanyl radical, R a preferably branched alkyl or hydroxyalkyl radical with 1-8 carbon atoms and R- ^ hydrogen or denotes a lower alkyl radical, or their physiologically tolerable acid addition salts. 3.) Pharmaceutical preparations containing as active ingredients a- or several substances from the group Theophylline Choline theophyllinate Ethylenediamine ditheophyllinate (aminophylline) glycine theophyllinate N-methylglucamine theophyllinate 1,1,4,4-ietramethylpiperazinium ditheophyllinate 3,4-dihydroxy-ephedrine theophyllinate Theophylline-ß-amino-isobutanol (butaphyllamine) 7- (ß-Hydroxypropyl) -theophylline 7- (ß-Hydroxyethyl) -theophylline 7- (ß, j "-dihydroxypropyl) -theophylline ο 7-CDiethylaminoethyl-theophylline φ 1-Γ (ß-hydroxy-) - (N-ß-hydroxyethyl-N-methyloxamino) -propyl _{> -} 7-" fcheophylline
ο paraxanthin
ü 0affeine
^! Eheobromin
<o 1- (ß-hydroxypropyl) -theobromine 1- (ß-diethylaminoethyl) »theobromine 1- ® -hydroxyethyl) -theobromine 1- (ß-Cyclohexylaminoethyl) -theohromin l- (ß-Benzylaminoäthyl) -theobromin The obromin-sodium-salicylat in amounts of 30 - 500 mg in combination with one or more active ingredients from group ■ 1- (1-Naphthoxy) -2-hydroxy-3-isopropylaminopropane 1- (3-tolyloxy) -2-hydroxy-3-isopropylaminopropane l- (3 »5-xylyloxy) ^ - hydroxy ^ -isopropylaminopropane 1- (2nd -Cyano-3-metliylph.enoxy) -2-liydroxy-3-isopropylaminopropane 1- (2-methylthiophenoxy) -2-llydroxy-3-isopropylaminopropane 1- (2-allylphenoxy) -2-llydroxy-3-isopropylaminopropane 1- (4-acetamidophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-allyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (4-methanesulfonylamidophenoxy) -2-hydroxy-3-i-bopropylaminopropane 1- (5, 6,7,8-tetrahydro-1-naphthooxy) -2-hydroxy-3-isopropylaminopropane 1- (4-benzamidophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (4-indanyloxy) -2-hydroxy-3-isopropylaminopropane 1- (2-bromophenoxy) -2 ~ hydroxy-3-isopropylaminopropane 1- (4-cyanophenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-gyanoplienoxy) -2-hydroxy-3-isopropylaminopropane 1- (2- ÄtMnylph.enoxy) -2-hydroxy-3-isopropylaminopiDpan l- (2-methoxymethy! Phenoxy) ~ 2-hydroxy ~ 3-isopropylaminopropane 1- (2-hydroxymethylphenoxy) - ^ - hydroxy - ^ - isopropylami nopropane 1- (2-propargyloxyphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-methoxyphenoxy) -2-hydroxy-3-isopropylaminopropane 1- (2-isopropoxyphenoxy) -2-hydroxy-3-isopropylaminopropane 1 - (2-Methallyloxyphenoxy) ^ -hydroxy ^ -isopropylaminopropane 1- (4-indolyloxy) -2-hydroxy-3-isopropylaminopropane 1- (2-phenoxy-phenoxy) ~ 2-hydroxy-3-isopropylaminopropane 1- (2-phenoxyphenoxy ) - ^ - hydroxy - ^ - isopropylaminopropane 1- (2-chloro-5-methylphenoxy) -2-hydroxy-3-tert-butylaminopropane 1- (2-cyanophenoxy) -2-hydroxy-3-tert-butylaminopropane 1- ( 3-hydroxymethylphenoxy) -2-hydroxy-3-tert. "butylaminopropane 1- ( 2- ethynylphenoxy) -2-hydroxy-3-tert- butylaminopropane 1- (2-allylphenoxy) -2-hydroxy-3-tert-butylaminopropane 009830/1769 1- (2-phenylphenoxy) -2-hydroxy-2-tert. Butylaminopropane 1- (2-methoxymethylphenoxy) -2-hydroxy-3-tert-butylaminopropane 1- (4-acetamidophenoxy) -2-hydroxy-3 -tert.butylaminopropane 1- (2-hydroxymethylphenoxy) -2-hydroxy-3-tert.butylaminopropane 1- (2-allyloxyphenoxy) -2-hydroxy-3-tert.butylaminopropane 1- (2-0yanophenoxy) -2-hydroxy- 3-tert.pentylaminopropane 1- (2-methoxyphenoxy) -2-hydroxy-3-tert.pentylaminopropane 1_ (2-methoxyphenoxy) -3-hydroxy-3- (l, l-dimethylbutyl) aminopropane 1- ^ 3 _} 4-dichlorophenyl) -l-hydroxy-2-isopropylaminoethane (dichloroisoproterenol), 1- C1'-naphthyl) -1-hydroxy-2-isopropylaminoethane (pronethalol) 1- (2,5-dimethoxyphenyl) -1-hydroxy-2-methyl-2-tert.butyiaminoethane 1- (4-methanesulfonylaminophenyl) -1 -hydroxy-2-isppropylaminoethane 1- (5 _} 6,7,8-tetrahydro-1-naphthyl) -l-hydroxy-P-sec.butylaminoethane (1-f4-nitrophenyl) -l-hydroxy-2-isopropylaminopropane or their physiologically compatible acid addition salts in amounts of 5 - 500 mg. 4.) Method for the treatment of angina pectoris, characterized in, that you give the patient preparation © according to claim 1, 2 or prescribed. 5 ·) Process for the production of pharmaceutical preparations according to Claim 1, characterized in that one or more substances from the two groups of active substances mentioned in claim 1 mixed with customary diluents, disintegrants, binders, lubricants and / or agents to achieve a depot effect and brings it into pharmaceutical application forms in the usual way. 6.) Pharmaceutical preparation containing choline theophyllinate as active ingredient in combination with a physiologically compatible acid addition salt of 1-m-tolyloxy-2-hydroxy-3-isopropylaminopropane. 7.) Process for the production of a pharmaceutical preparation according to Claim 6, characterized in that one choline theophyllinate and a physiologically acceptable acid addition salt of 1-m-tolyloxy-2-hydroxy-3-isopropylaminopropane with common thinners, 009830/1769. Disintegrants, binders, lubricants and / or agents for Achievement of a depot effect mixed and in the usual way in galenic application forms "brings. 8.) A pharmaceutical preparation containing aminophylline as the active ingredient and / or theophylline in combination with a physiologically tolerable one Acid addition salt of l ~ (l ~ laphthyloxy) -2-hydroxy-3-isopropyl aminopropane and / or 1- (4-acetamidophenoxy) -2-hydroxy-3-isopropylaminopropane. 9.) Process for the production of a pharmaceutical preparation according to claim 8, characterized in that, aminophylline and / or theophylline and a physiologically acceptable acid addition salt des! - (l-taphthyloxy / J-Z-hydroxy - ^ - isopropylaminopropane and / or l ~ (4-acetamidophenoxy) -2-hydroxy-3-isopropyl aminopropane with common thinners, disintegrants »binders, Lubricants and / or agents for achieving a depot effect mixed and in the usual way in pharmaceutical application forms brings. ■ - 10.) method of treatment; of angina peetoris with the help of preparations Claim 6 or 8.