CH644517A5 - MEDICINAL PRODUCT CONTAINING 3- (BETA-HYDROXY-ALPHA-METHYL-PHENAETHYLAMINO) -3-METHOXY-PROPIOPHENONE AND THEOPHYLLINE OR THEOPHYLLINE COMPOUNDS. - Google Patents

Description

The invention relates to the objects characterized by the claims.

The 3- (β-hydroxy-a-methyl-phenethylamino) -3'-methoxy-propiophenone can be used in an optically active form or as a racemate. In general, the L or DL form (depending on whether left-handed or racemic norephedrine was used in the production) is used.

Furthermore, the 3- (β-hydroxy-cc-methyl-phenethyl-amino-3'-methoxy-propiophenone is preferably used as an acid addition salt, in particular in the form of the hydrochloride. However, the salts of 3- (β-hydroxy-a -methyl-phenethylamino) -3'-methoxy-propiophenone can be used with other pharmacologically usable acids, such as: halogen acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, organic mono-, di- or tricarboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series and sulfonic acids, examples of which are: ant, vinegar, propion, amber, glycol, milk, apple, wine, lemon, ascorbic, maleic, fumaric -, hydroxymaleic or pyruvic acid; s phenylacetic, benzoic, p-amino-benzoic, anthranil, p-hy-hydroxy-benzoic, salicylic or p-aminosalicylic acid -, ethylene sulfonic acid; halobenzenesulfonic, toluenesu Iphonic, naphthalenesulfonic acid or sulfanilic acid or also 8-lo chloro-theophylline.

If the radical R in the formula I is a C2-C4-alkyl group, this can be straight or branched. Examples of compounds of the formula I are theophylline, 7- (2-hydroxyethyl) theophylline (abbreviated: oxyethyl theophylline), 7- (2-15 hydroxypropyl) theophylline, 7- (2,3-dihydroxypropyl) theo -phylline and caffeine. One or more compounds of the formula I can be combined with the 3- (β-hydroxy-a-methylphenäthylamino) -3'-methoxy-propiophenone.

20 The active ingredient combination according to claim 1 has the same direction of action as the 3- (ß-hydroxy-a-methyl-phenethylamino) -3'-methoxy-propiophenone (for example the oxyfedrine), but the positive inotropic effect is considerably enhanced.

25 The indications for which the combination of active substances described are suitable are, for. B. the same as for oxyfedrine: coronary insufficiency, angina pectoris, myocardial infarction, condition after myocardial infarction, especially if there are symptoms of cardiac insufficiency or beginning heart failure at the same time and an improvement in cardiac strength is to be sought.

The combination of active ingredients described is suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or drugs contain as active ingredient the combination according to claim 1, optionally in a mixture with other pharmacologically or pharmaceutically active substances. The pharmaceuticals are produced in a known manner, it being possible to use the known and customary pharmaceutical auxiliaries and other customary excipients and diluents.

Such carriers and auxiliaries such. For example, those substances are recommended that are recommended or indicated in the following literature as auxiliary substances for pharmacy, cosmetics and related areas: Ullmanns Encyklopä-die der technical chemistry, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 u. ff .; H.v. Czetsch-Lindenwald, auxiliaries for pharmacy and neighboring areas; Pharm. Ind., Issue 2,1961, see page 72 u. ff .; Dr. H.P. Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas, Cantor KG. Aulendorf in Württemberg 1971.

Examples include gelatin, natural sugars such as cane sugar or milk sugar, lecithin, pectin, starch 55 (e.g. corn starch), alginic acid, tylose, talc, lycopodium, silicic acid (e.g. colloidal), cellulose, cellulose derivatives (e.g. cellulose ethers in which the cellulose hydroxyl groups are partially etherified with lower saturated aliphatic alcohols and / or lower saturated aliphatic oxyal-6o alcohols, e.g. methyloxypropyl cellulose), stearates, magnesium and calcium salts of fatty acids 12 to 22 carbon atoms, in particular saturated (e.g. stearates), emulsifiers, oils and fats, in particular vegetable (e.g. peanut oil, castor oil, olive oil, sesame oil, cotton 65 saatö}, corn oil, wheat germ oil, sunflower seed oil , Ka-beljau liver oil, mono-, di- and triglycerides of saturated fatty acids C12H2402 to C18H3602 and their mixtures), pharmaceutically acceptable mono- or polyhydric alcohols

3rd

644517

and polyglycols such as polyethylene glycols and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 C atoms), in particular 10 to 18 C atoms) with monohydric aliphatic alcohols (1 to 20 C atoms) or polyhydric alcohols such as glycols, Glycerin, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc., which may also be etherified, benzyl benzoate, dioxolanes, glycerin formals, tetrahydrofurfuryl alcohol, polyglycol ethers with C 1 -C 4 -alcohols, dimethylacetamide, lactamyl, lactate, lactate, lactate, lactate, lactate, lactate, lactate, lactate, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactates, lactate, lactates, lactate, lactate, lactate, lactate, lactate, lactate, lactate, lactate, lactate, lactate, lactate, lactate Dimethylpolysiloxanes) magnesium carbonate and the like.

For the preparation of solutions, for example, water or physiologically compatible organic solvents, such as. B. ethanol, 1,2-propylene glycol, polyglycols and their derivatives, dimethyl sulfoxide, fatty alcohols, triglycerides, partial esters of glycerol, paraffins and the like.

Known and customary solubilizers or emulsifiers can be used in the preparation of the preparations. Possible solubilizers and emulsifiers are, for example: polyvinylpyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolized polyethyl fatty acids, fatty acid alkylene fatty acids, fatty acid alkylene fatty acids, fatty acid alkylene fatty acids, fatty acid alkoxylates, fatty acid alkylene fatty acids, fatty acid alkoxylates, fatty acid alkylene fatty acids, fatty acid fatty acids Poly-oxyethylated here means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which is generally between 2 and 40 and in particular between 10 and 20.

Such polyoxyethylated substances can be obtained, for example, by reacting hydroxyl-containing compounds (for example mono- or diglycerides or unsaturated compounds such as, for example, those which contain oleic acid residues) with ethylene oxide (for example 40 moles of ethylene oxide per mole of glyceride).

Examples of oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil (see also Dr. H.P. Fiedler "Lexicon of auxiliaries for pharmacy, cosmetics and related areas", 1971, pages 191 to 195).

In addition, the addition of preservatives, stabilizers, buffer substances, e.g. As calcium hyphosphate, colloidal aluminum hydroxide, taste corrections, antioxidants and complexing agents (e.g. ethylenediaminotetraacetic acid) u. Like possible. If necessary, to stabilize the active substance molecule with physiologically compatible acids or buffers, a pH range of about 3 to 7 should be set. In general, a pH that is as neutral as possible to weakly acidic (up to pH 5) is preferred.

The antioxidants used are, for example, sodium metabisulfite, ascorbic acid, gallic acid, alkyl callusate, butylated hydroxyanisole, nordihydroguajaretic acid, tocopherols and tocopherols + synergists (substances which bind heavy metals through complex formation, for example lecithin, ascorbic acid, phosphoric acid). The addition of the synergists increases the antioxidant effect of the tocopherols considerably.

Examples of suitable preservatives are sorbic acid, p-hydroxybenzoic acid esters (e.g. lower alkyl esters), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride and formalin derivatives.

The pharmacological and pharmaceutical handling of the combination of active ingredients described can be carried out according to the customary standard methods. For example, active ingredients and excipients or carriers are stirred or

Homogenization mixed well, generally at temperatures between 20 and 80 C, preferably 20 to 50 ° C.

In particular, the addition of other active pharmaceutical ingredients is also possible or inexpensive.

The synergistic effect of the combination of active ingredients described can be, for. B. by examinations of papillary larval muscles of guinea pigs: Such tests are carried out on isolated papillary muscles with a diameter <1 mm from the right ventricle of young guinea pigs (270-330 g); the muscles contract isometrically in a two-chamber organ bath with a capacity of 50 ml. Details of this experimental setup are described in Reiter, M., Arzneimittel-Forschung (Drug. Res.) 17, 1249-1253 (1967). The temperature is 35 ° C, the muscles are stimulated by rectangular pulses of 1 ms duration at 1 Hz with a current strength just above the threshold. A resting force of 3.9 mN is kept constant during the experiment. The bathroom solution has z. B. the following composition (mmol / 1): NaCl 114.9; NaHC03 24.9; KCl 4.7; KH2P04 1.2; CaCl2 3.2; MgS04 1.2; Glucose 10.0. The solution is continuously gassed with a mixture of 95% 02 and 5% CO 2 and stirred; pH 7.4.

With the help of an electromechanical force transducer (Hottinger Baldwin Messtechnik, type Q 11), isometric contraction curves are displayed on an oscillograph or recorded by a recorder. The increase or contraction force results from these curves.

Such tests show that the positive inotropic effect of 3 x 10 "6 mol / liter oxyfedrine in the presence of 10-4 mol / liter theophylline or 5 x 10-4 mol / liter 7- (2-hydroxyethyl) - theophylline is almost doubled.

Likewise, the described combination of active substances in anesthetized dogs shows a clear, potentiating effect on the contractility of the left ventricle compared to the individual compounds (in the same dosage). B. is evaluated according to the rate of pressure increase (dp / dt max) of the left ventricle. To determine this parameter, the pressure profile in the left ventricle is continuously electronically measured and registered. The electronic signal is differentiated via an analog computing amplifier, so that a second signal (dp / dt) indicates the changes in pressure against time (Schaper et al, Archiv für Kreislaufforschung 46, 27-41 (1965)). In the table below, А% max denotes the maximum change in the measured variable dp / dt compared to the initial value before substance administration in percent. In the last column (D%, 60 min), the mean change in the measured variable dp / dt during an hour (starting with substance administration) is also given in% (mean increase over an hour).

Substance dose increase in

Contractility (dp / dt max)

À% max D%, 60 min

A = oxyfedrine

0.1

+ 80

+ 53

B = theophylline

(Monohydrate)

3.0

+ 24

+ 9

C = oxyethyl

theophylline

20.0

+ 49

+ 26

A + B

0.1 + 3.0

+ 185

+ 114

A + C

0.1 + 20.0

+ 185

+ 120

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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The lowest already positive inotropic (= increasing contractility) combination doses in the animal experiment mentioned are, for example (in mg / kg body weight / dog).

inside intravenously

Oxyfedrine in combination 0.1 0.03

with theophylline (monohydrate) 4- 3.0 +0.3 or with oxyethyltheophylline +30 +3.0

In the animal experiment given above, the general dose range for the positive inotropic effect is, for example (mg / kg body weight / dog):

inside intravenously

Oxyfedrine in combination

0.1 to 5,

0.03 to 1.0,

especially especially

0.5 to 2

0.1 to 0.5

with theophylline

1.0 to 50,

0.1 to 10,

(Monohydrate)

especially especially

5 to 20

1 to 5

with oxyethyl theophylline

5 to 200,

1 to 50,

especially especially

20 to 60

10 to 30

The pharmaceutical preparations for oral administration contain, for example, between 2 to 24 mg of oxyfedrine, for parenteral administration (injection ampoule), for example, 4-8 mg of oxyfedrine.

The second theophylline component can be present in such preparations in an amount which is, for example, 2 to 200 times, in particular 5 to 100 times, preferably 10 to 20 times the respective amount by weight of oxyfedrine.

The theophylline component can be a single compound of the formula I or a mixture of different compounds of the formula I. However, it is also possible that the quantitative ratio of theophylline component to oxyfedrine given above applies separately to each individual theophylline compound of the formula I, so that B. in the event that the preparation contains oxyfedrine, theophylline and oxyethyl theophylline, this can contain, for example, 5 to 10 parts by weight of theophylline and 10 to 50 parts by weight of oxyethyl theophylline per 1 part by weight of oxyfedrine.

In the event that a different salt of 3- (ß-hydroxy-a-methyl-phenethylamino) -3'-methoxy-propiophenone is used as the hydrochloride, all quantities relating to the oxyfedrine are to be changed in accordance with the molecular weight of the other acid ester that the amount of free aminoketone drug is always the same.

The administration can take place, for example, in the form of tablets, capsules, pills, dragées, suppositories, ointments, jellies, creams, powders, dusting powder, aerosols or in liquid form. As liquid application forms come e.g. B. in question: oily or alcoholic or aqueous solutions as well as suspensions and emulsions. Preferred forms of use are, for example, tablets which contain between 8 and 16 mg of oxyfedrine and 80 to 600 mg of the theophylline component of the formula I or solutions which contain between 0.1 and 10% of the individual active compounds.

For example, 1 to 2 tablets containing 4 to 16 mg oxyfedrine and 50 to 100 mg theophylline or 4 to 16 mg oxyfedrine and 200 to 400 mg oxyethyltheophylline or z. B. With intravenous injection 1 to 3 times a day, an ampoule of 2 to 10 ml content with s 4 mg oxyfedrine and 50 mg theophylline or 4 mg oxyfedrine and 100 mg oxyethyl theophylline are recommended. When administered orally, the minimum daily dose can be seen, for example, 16 mg oxyfedrine and 160 mg theophylline or 16 mg oxyfedrine and 600 mg oxyethyl theophylline angelo.

The maximum daily dose for oral administration should not exceed 96 mg of oxyfedrine and, for example, 1 g of theophylline or 4 g of hydroxyethyl theophylline. For other theophyllin derivatives of the formula I, for example, the same quantitative data apply as given above for theophylline or oxyethyl theophylline.

The acute toxicity of the combination of active substances described on the rat (expressed by the LD 50 mg / kg; method according to Miller and Tainter: Proc. Soc. Exper. Biol. A. 20 Med. 57 (1944) 261) lies between, for example, peroral administration 450 and 1500 mg / kg.

The medicinal products can be used in human medicine, veterinary medicine and agriculture alone or in a mixture with other pharmacologically active substances.

The active ingredients or the medicaments can be applied to the skin or mucous membrane or into the interior of the body, for example orally, enterai, pulmonoal, rectal, nasal, vaginal, lingual, intravenous, iritraarterial, intracar-30 dial, intramuscular, intraperitoneal, intracutaneous, subcutaneous.

example 1

Tablet with an active ingredient dosage of 100.0 mg theophylline. 1 H20 and 35 4.0 mg oxyfedrine (hydrochloride)

Working instructions for the production of 100,000 tablets: 10.0 kg of theophylline. 1 H20 are mixed with 0.4 kg of oxyfedrine (hydrochloride), 5 kg of milk sugar and 3 kg of microcrystalline cellulose and granulated in the usual way with a solution of 0.3 kg of Polyvi-40 nylpyrrolidone in 1.2 kg of water. After adding 4.05 kg of microcrystalline cellulose,

2 kg of corn starch, 0.05 kg of highly disperse silica and 0.2 kg of magnesium stearate are tablets with a weight of 250 mg, a diameter of 9 mm and a

45 exercise radius of 13.5 mm pressed. The breaking strength of the tablets is 6-8 kg (Heberlein breaking strength tester).

Each tablet contains 100 mg theophylline. 1 H20 and 4 mg oxyfedrine (hydrochloride).

50 Example 2

Tablet with an active ingredient dose of 10 mg oxyfedrine (hydrochloride) and 200 mg 7- (2-hydroxypropyl) theophylline

55 Working instructions for the production of 100,000 tablets: 20.0 kg of 7- (2-hydroxypropyl) theophylline are mixed with 1 kg of oxyfedrine, 7 kg of milk sugar and 4 kg of microcrystalline cellulose and with a solution of 0.3 kg of polyvinylpyrrolidone in 1.5 kg of water granulated in the usual way. 60 After adding 4.32 kg of microcrystalline cellulose,

3 kg of corn starch and 0.08 kg of highly disperse silica and 0.3 kg of magnesium stearate are pressed into tablets weighing 400 mg, with a diameter of 10 mm and a radius of curvature of 10 mm.

65 The breaking strength of the tablets is 70-100 Newtons (Heberlein breaking strength tester).

Each tablet contains 200 mg 7- (2-hydroxypropyl) theophylline and 10 mg oxyfedrine.

Claims (2)

644 517 PATENT CLAIMS I. Medicament containing an active ingredient combination of 3- (ß-hydroxy-a-methylphenäthyIamino) -3'-methoxy-propiophenone or a pharmacologically acceptable salt thereof and at least one compound of the formula 0 wherein R is hydrogen, methyl or optionally substituted with one or two hydroxyl group (s) alkyl having 2-4 carbon atoms. 2. Medicament according to claim 1, characterized in that it contains the active ingredient combination together with pharmacological carriers and / or diluents. The compound 3- (ß-hydroxy-a-methyl-phenäthylamino-no) -3'-methoxy-propiophenone is an active pharmaceutical ingredient and is used for the treatment of coronary heart disease. The hydrochloride of the L-form is known under the name oxyfedrine hydrochloride. An essential property of 3- (ß-hydroxy-a-methyl-phenäthylamino) -3'-methoxy-propiophenone is that this substance causes an increase in the contraction force of the heart (positive inotropic effect). It has now been found that this positive inotropic action of 3- (β-hydroxy- <x-methyl-phenethylamino) -3'-methoxy-propiophenone and its acid addition salts by adding theophylline or theophyllin derivatives of the formula I in a synergistic manner is increased. For example, the positive inotropic effect of 3- (β-hydroxy-a-methyl-phenethylamino) -3'-methoxy-propio-phenone can be achieved by a substance of formula I such as theophylline or 7- (2-hydroxyethyl) - theophylline in the organ test (papillary muscle of the guinea pig) can be almost doubled.