DE1617336C2 - Medicines for angina pectoris - Google Patents

Description

where for oral administration 10-100 parts by weight a) in addition to 25-120 parts by weight b) and for parenteral administration 10 parts by weight a) and 5 parts by weight b) are used.

The invention relates to a medicament against angina pectoris, characterized by the content of

a) 2,6-bis (diethanolamino) -4,8-dipiperidinopyrimido- [5,4-d] pyrimidine and

b) 1 - (3'-Toloyloxy) -2-hydroxy-3-isopropylaminopropane hydrochloride

being 10-100 parts by weight for oral administration a) next to 25-120 parts by weight b) and for parenteral administration 10 parts by weight a) next to 5 parts by weight b) are used.

It is already known that, in addition to other heart diseases, angina pectoris with the help of j9-adrenolytically active l-aryloxy-2-hydroxy-3-aminopropanes can be treated (see e.g. the French BSM 3 732, 4 057, 4 061 and 4 161, the Belgian patents 6 52 336, 6 70 364, 6 75 967 and 6 76 821, Irish patent applications 946/65, 330 / 66,331 / 66 and 430/66, the South African patents 65/4 447, 65/5 403 and 65/5 907, the Dutch Patent applications 64.10 522 and 65.03 196 as well as DE-AS 12 27 462).

In treating angina pectoris with such compounds, however, there are a few must accept therapeutic disadvantages. This is because compounds of the above-mentioned structure type return the coronary-expanding effect of chemical transmitters in the sympathetic nervous system, Epinephrine and norepinephrine, turn into a vascular constricting effect. It has also been shown that all j3-adrenolytics also have a more or less large coronary constricting effect.

Despite an improvement in the anginal condition, this leads to the overall blood circulation of the heart muscle decreases. Especially in the case of a lack of oxygen and emotional excitement (conditions, which are coupled with an activation of the sympathetic nervous system) it can through this Mechanisms of a current deficiency in blood flow to the heart muscle come about.

It has now been found that the disadvantages of treating angina pectoris with jS-Adrenolytica can fix it if you get it with a medicine

a) the coronary dilator dipyridamole = 2,6-bis- (di-

ethanolamino) -4,8-dipiperidino-pyrimido- [5,4-d] -pyrimidine and

b) the /? - receptor blocker = 1- (3'-tolyloxy) -2-hydroxy-3-isopropylaminopropane hydrochloride

treated, whereby for oral administration 10-100 parts by weight a) as well as 25-120 parts by weight b); and for parenteral administration 10 parts by weight a) and 5 parts by weight b) are used are.

The beneficial effects of the new drug are proven through clinical trials over which is reported in the following references.

ίο 1. »Heart and Circulation« 6th year, No. 5 (May 1974) pp. 271-277,
Author: H. Pozenel

2. "Heart and Circulation", 8th year, No. 1 (Jan. 1976) pp. 27-33,

Authors: G. Hellige, H. Duchanova, K. H. Piesker, H. Prennschütz-Schützenau, H. Vennebusch, H. J. Bretschneider

3. "Therapy of the Present" 114 vol., No. 7 pages 3-9

Authors: Ch. Bibracher, K. Krüger, J. Röhren

These publications demonstrate a beneficial synergism between the coronary dilator and the jS receptor blocker; in the following ways:

1. Decrease in total peripheral resistance by relieving pressure on the heart and avoiding it the cardio-depressive side effect of the / J-blocker.

2. Sensitization of the jS receptors by the coronary dilator and therefore better responsiveness on j3 blocker; Furthermore, the "insufficiency reaction" is weakened when the j3 blocker is administered alone occurs.

3. Antihypertensive effects with a far lower ß- blocker dose than usual, furthermore cholesterol-lowering effects.

The active ingredient combination according to the application of compounds of the formulas a) and b) or of the above specifically mentioned active ingredients can take the usual galenic application forms, such as tablets, dragees, Solutions, emulsions, powders, capsules or depot forms are brought to their Manufacture the usual pharmaceutical auxiliaries and the usual manufacturing methods are used can be, 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 a depot effect, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate. or Polyvinyl acetate can be obtained.

The tablets can also consist of several layers. Dragees can be coated accordingly of cores produced analogously to the tablets with usually used in Dragoe coatings Agents, for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar will. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. The coated tablet shell can also be used in the same way to achieve a depot effect consist of several layers, the excipients mentioned above for the tablets being used

can.

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

Injection solutions are used in the usual way, for. B. with the addition of preservatives such as p-hydroxybenzoates, or stabilizers, such as complexones, prepared and placed in injection bottles or ampoules bottled.

The capsules containing active ingredients or combinations of active ingredients can, for example, be produced by mixing the active ingredients with inert carriers such as lactose or sorbitol and placing them in gelatin capsules encapsulated.

Suitable suppositories can be created, for example, by mixing the active ingredients or Combinations of active ingredients with conventional carriers, such as neutral fats or polyethylene glycol or its Derivatives.

The following examples illustrate the invention without restricting it:

example 1
(Coated tablets)

1 dragee contains:

2,6-bis- (diethanolamino) -4,8-dipipe-

ridinopyrimido [5,4-d] pyrimidine 75.0 mg
1 - (3'-tolyloxy) -2-hydroxy-3-isopro-

pylaminopropane hydrochloride 60.0 mg

Milk sugar 65.0 mg

Potato starch 55.0 mg

Talc 15.0 mg

gelatin
Magnesium stearate

7.0 mg
3.0 mg

280.0 mg

Manufacturing

The active ingredients are mixed with milk sugar, potato starch and talc and then with a 10% strength granulated aqueous solution of gelatin (sieve: 1.5 mm

ίο mesh size); then it is dried at 40.degree. The dried granulate is pressed again through the above sieve and mixed with magnesium stearate. Dragee cores are pressed from the mixture.
Core weight: 280 mg.

The cores produced in this way are coated in the usual way with a shell consisting mainly of sugar and talc. The finished coated tablets are polished with the help of beeswax.
Final coated weight: 480 mg.

Example 2
(Ampoules)

1 ampoule contains:

2,6-bis- (diethanolamino) -4,8-dipipe-

ridinopyrimido [5,4-d] pyrimidine

l- (3'-tolyloxy) -2-hydroxy-3-iso-

propyl aminopropane sulfate

Sodium pyrosulfite

bidist. Water - ad.

Manufacturing

5.0 ml
2.0 ml
2.0 ml

In dried and cooled to room temperature redist. Water, sodium pyrosulphite and the two active ingredients are dissolved one after the other while gassing with nitrogen. The solution is made up to the specified volume and filtered free of suspended particles.
Filling: in brown ampoules (under nitrogen)
Sterilization: 20 minutes at 20 ° C.

Claims (1)

1
Claim: Medicines for angina pectoris, characterized by the content of a) 2,6-bis (diethanolamino) -4,8-dipiperidinopyrimido- [5,4-d] -pyrimidine and b) 1 - (3'-Toloyloxy) -2-hydroxy-3-isopropylaminopropane hydrochloride