MXPA00002654A - Endothelin antagonist and beta receptor blocking agent as combined preparations - Google Patents

Abstract

The invention relates to a combination consisting of endothelin-antagonists and beta receptor blocking agents. Said combination is suitable for the treatment of diseases.

Description

PHARMACEUTICAL PREPARATIONS IN COMBINATION The present invention relates to novel combination pharmaceutical preparations which are suitable for the treatment of vasoconstriction-based conditions and which contain a beta-receptor blocker and an endoletin antagonist. Suitable combination preparations for the treatment of vasoconstriction-based conditions and containing a beta-receptor blocker and an endoletin antagonist have already been described (WO 92/13545). However, the activity of these combinations of active compounds is not satisfactory. Now combinations have been found with improved properties. The present invention offers a combination of an endothelin antagonist of the formula I: wherein the substituents are as defined below: R is C1-C4 alkyl, C1-C4 alkoxy; 2 R is C 1 -C 4 alkyl, C 1 -C 4 alkoxy; R is Ci-Cß alkyl which may be substituted by a phenyl radical which in turn may be substituted by one or two C1-C4 alkoxy radicals, Z is oxygen or a single bond, and a beta receptor blocker.

Preferred endothelin antagonists are those compounds of formula I wherein the substituents are as defined below: R 1: C 1 -C 2 alkyl, C 3 -C 2 alkoxy; R 'C 1 -C 2 alkyl, C 1 -C 2 alkoxy; R C 1 -C 2 alkyl which may be substituted by a phenyl radical which in turn may be substituted by one or two C 1 -C 2 alkoxy radicals, Z is oxygen or a single bond. Particularly suitable endothelin antagonists are the compounds: Suitable beta-receptor blockers are, in particular, acebutolol, alprenolol, atenolol metropolol, bupranolol, penbutolol, propranolol, is olol, bisoprolol, carazolol, talinolol, mepindolol, sotalol, metipranolol, pindolol, carteolol, tetratolol, celipropol, nadolol, oxprenolol and bopindolol In particular, carvedilol and bucindolol can be mentioned. The combination of a β-blocker with an inhibitor of the ET system can be used as a composition for the treatment of diseases that are based on vasoconstriction or are associated with pathological vasoconstriction. Examples are all forms of high blood pressure (including pulmonary hypertension), heart disease, heart failure, renal and myocardial ischemia, acute and chronic renal failure. The diseases that are associated with vasoconstriction or other biological effects of endothelin and / or angiotensin II are, in particular, the control and / or prevention of coronary diseases, cardiovascular diseases such as hypertension, heart failure, ischemia (in heart, brain, gastrointestinal). , liver and / or kidney) or vasospasms. Other examples of diseases that can be treated are renal and myocardial ischaemia, renal failure, dialysis, subarachnoid hemorrhage, Raynaud's syndrome, high portal pressure and high pulmonary pressure and also the treatment of gastric and duodenal ulcers and of staph ulcers where it is involved vasoconstriction. Finally, in patients with asthma, the concentration of endothelin in the bronchial discharge increases. In migraine attacks, increased levels of endothelin are also observed in the blood plasma. The combination can, therefore, also be used in these cases. When the combination according to the invention is administered, there is a significant increase in the antihypertensive properties and the duration of the action in comparison with the individual substances, and this superadditive effect. Accordingly, the dose of the individual active compounds can be reduced considerably. Thus, there is a lower risk of adverse effects during administration. The weight ratio of the β-receptor blocker to the endothelin antagonists is usually in the range from 50: 1 to 1: 500, preferably from 10: 1 to 1: 100 and in particular from 2: 1 to 1: fifty. The combinations according to the invention are generally administered orally, for example, in the form of tablets not covered, plated or covered with sugar, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of solutions for injection. The administration of the active compound can be carried in the form of products containing both active compounds together, such as tablets or capsules or separately as an ad-hoc combination of individual substances that can be administered concurrently or in sequence. To produce uncoated, plated or sugar coated tablets and hard gelatin capsules, a combination according to the invention can be processed with pharmaceutically inert inorganic or organic excipients. - The excipients of these types that can be used for tablets not covered and covered with sugar and hard gelatine capsules are lactose, corn starch, or derivatives thereof, talc, stearic acid or salts thereof. Suitable excipients for soft gelatine capsules are vegetable oils, fatty waxes, semi-solid or liquid polyols. Suitable excipients for producing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable excipients for injection solutions are water alcohols, polyols, glycerol, vegetable oils. Suitable excipients for suppositories are natural or hydrogenated oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers. Wetting agents, emulsifiers, sweeteners, colorants, flavorings. Salts to modify the osmotic pressure, buffer solutions, coating agents and / or antioxidants. The unexpected advantageous properties of the compositions according to the invention are demonstrated by the following tests: In a crossover design, the test substance was administered orally as a capsule to chronically instrumented male beagle dogs (approximately 14 kg). The capsule contained nothing (control N = 5), compound A (10 mg / kg N = 10), bucindolol (0.1 mg / kg); N = 5) or the combination bucindolol plus compound A (0.1 + 10 mg / kg / N = 5). Between the individual administrations, a washing phase of at least one week was observed. Systolic and diastolic blood pressure were measured using a Statham Transducer P 23Db, from which the mean arterial blood pressure was calculated. Blood pressure was recorded for 6 hours 2 (MI, Modular Instrumente, USA). Table 1 shows that the blood pressure in the control group and in the group treated with bucindolol does not decrease. A slight reduction in blood pressure can be observed with compound A. The combination of bucindolol with ET antagonist compound A (0.1 + 10 mg / kg) gave rise to a considerable reduction in blood pressure.

Table 1: Development of the mean arterial blood pressure (mmHg, change with respect to the initial value) in normotensive conscious dogs after oral administration of different substances, which are shown as average values.

The following examples illustrate the invention.

Example 1 Plaque tablets of the following composition were prepared: Compound A 100.0 mg Bucindolol 10.0 mg Lactose anhydrous 30.0 mg Microcrystalline cellulose 30.0 mg Polyvinylpyrrolidone 20.0 mg Magnesium stearate 5.0 mg Polyethylene glycol 6000 0.8 mg Yellow iron oxide 1.2 mg Titanium dioxide 0.3 mg Talc 0.7 mg Compound A, bucindolol, lactose, gelulose and polyvinylpyrrolidone are wet granulated and dried. The sifted granules are mixed with the magnesium stearate, and the mixture ready to be compressed is compressed into oval tablet cores each weighing 190.0 mg. The cores are then covered with lacquer until the lacquer-coated tablets have reached a final weight of 200 mg.

Example 2 Preparation of hard gelatine capsules of the following composition: Compound A 100.0 mg Bucindolol 30.0 mg Crystalline lactose 18.0 mg Polyvinylpyrrolidone 15.0 mg Microcrystalline cellulose 17.5 mg Carboxymethyl sodium starch 10.0 mg Talc 9.0 mg Magnesium stearate 3.0 mg The first five components are wet granulated and dried. The granules are mixed with sodium carboxymethyl starch, talc and magnesium stearate, and the mixture is packed into size 1 hard gelatin capsules.

Claims (4)

1. A combination of an endothelin antagonist of the • formula I: 10 in which the substituents are as defined • continued: R is C 1 -C 4 alkyl, C 1 -C 4 alkoxy; 2 R is C 1 -C 4 alkyl, C 1 -C 4 alkoxy; 3 R is alkyl of -Ci-Cs which may be substituted by 15 a phenyl radical which in turn can be substituted by one or two C1-C4 alkoxy radicals, Z is oxygen or a single bond,

2. A pharmaceutical preparation, containing a combination as mentioned in claim 1. 20

3. A process for preparing a pharmaceutical preparation, which consists in making a mixture of a beta-receptor blocker and an endothelin antagonist as mentioned in claim 1 in a pharmaceutical administration form.

4. The use of a combination of a beta-receptor blocker and an endothelin antagonist as recited in claim 1, or of a pharmaceutical preparation containing a beta-blocker receptor and an endothelin antagonist as recited in claim 1, simultaneous, separate or successive use in the treatment of diseases.