MXPA00002655A - Endothelin antagonist and a renin-angiotensin system inhibitor as a combined preparation - Google Patents

Abstract

The invention relates to a combination consisting of endothelin-antagonists and RAS inhibitors. Said combination is suitable for the treatment of diseases.

Description

PHARMACEUTICAL PRODUCTS IN COMBINATION The present invention relates to novel combination pharmaceutical products suitable for the treatment of cardiovascular disorders and contains an inhibitor of the renin-angiotensin system (RAS inhibitor) and an endoletin antagonist. Suitable combination products for the treatment of cardiovascular diseases and containing an inhibitor of the renin / angiotensin system (RAS inhibitor) and an endothelin antagonist have been described (EP-A-634, 175, EP-A-617, 001) . However, the effect of these mixtures of active ingredients is not satisfactory. Now combinations have been found with improved properties. The present invention relates to a combination of an endothelin antagonist of the formula I: wherein the substituents have the following meanings: R C? -C4 alkyl / C? -C4 alkoxy; R C? -C alkyl, C1-C4 alkoxy; R Ci-Cs 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 RAS inhibitor. Preferred endothelin antagonists are those compounds of formula I wherein the substituents have the following meanings: R: C 1 -C 2 alkyl, C 1 -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 oxygen or a single bond, Particularly suitable endothelin antagonists are the following compounds: Suitable inhibitors of the renin-angiotensin system are, in particular, the angiotensin II antagonists and very particularly, the ACE inhibitors. ACE inhibitors suitable for the purpose of the present invention are alacepril, benazepril, captropil, cilazapril, cilazaprilat, delapril, enalapril, enalaprilat, fosinopril, lisinopril, perindropyl, quinapril, ramipril, spirapril, trandolapril, and zofenopril. Among these, preference is given to ramipril and, in particular, trandolapril. Angiotensin II antagonists suitable for the purpose of the present invention are: losartan, the potassium salt of 2-butyl-4-chloro-1 - [[2 '- (1H-tetrazol-5-yl) [1, 1] '-biphenyl] -4-yl] -methyl-lH-imidazole-5-methanol; valsartan, N- (1-oxopentyl) -N [[2 '- (lH-tetrazol-5-yl) [1, 1' -biphenyl-4-yl] methyl-L-valine; candesartan, 2-ethoxy-l- [[2 '- (lH-tetrazol-5-yl) [1, 1' -biphenyl] -4-yl] methyl] -lH-benzimidazole-7-carboxylic acid; 4 '- [(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazol-1-yl) methyl] biphenyl-2-carboxylic acid 2-n-butyl-1- [4- (6-carboxy-2, 5-dichlorobenzoylamino ) benzyl] -6-N- (methylaminocarbonyl) -n-pentylaminobenzimidazole; 4 '- [(1,4' -dimethyl-2'-propyl- [2,6 '-bi-lH-benzimidazole] -1' -yl) -methyl] - [1,1'-biphenyl] -2 -carboxylic; 4- (pentafluoroethyl) -2-propyl-l- [[2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4-yl] methyl] -lH-imidazole-5-carboxylic acid; 4 '- [[2-butyl-4-chloro-5- (hydroxymethyl) -IH-imidazol-1-yl] methyl] - [1,1'-bifenyl] -2-carboxylic acid; 2-ethyl-5, 6, 7, 8-tetrahydro-4- ([2'- (H-tetrazol-5-yl) biphenyl-4-yl] methoxy) quinoline; 2-ethyl-4- [(2 '- (lH-tetrazol-5-yl) ifenyl-4-yl) ethoxy] quinoline hydrochloride; l- [[3-Bromo-2- (2- (lH-tetrazol-5-yl) phenyl) -5-benzofuranyl] -methyl] -2-butyl-4-chloro-lH-imidazole-5-carboxylic acid; 1- [[3-bromo-2- [2- [(trifluoromethyl) sulfonyl] amino] phenyl-5-benzofuranyl] ethyl] -4-cyclopropyl-2-ethyl-lH-imidazole-5-carboxamide; 5,7-dimethyl-2-ethyl-3- (2 '- (1H-tetrazol-5-yl) (1, 1'-biphenyl) -4-yl) ethyl) -3H-imidazo- (4, 5) b) pyridine; 5- [4'- (3,5-dibutyl-l, 2,4-triazol-l-ylmethyl) biphenyl-2-yl] -lH-tetrazole; 1,4-dibutyl-3- [2 '- (lH-tetrazol-5-yl) biphenyl-4-ylmethyl] -2,3-dihydro-lH-imidazol-2-one; 2-n-butyl-4-spirocyclopentan-1 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -2-imidazolin-5-one; (E) -a- [[2-Butyl-l- [(4-carboxyphenyl) methyl] -lH-imidazol-5-yl] -methylene] -2-thiophenepropanoic acid; 2-ethoxy-l- [[2 '- (lH-tetrazol-5-yl) [1, 1' -biphenyl] -4-yl] ethyl] -lH-benzimidazole-7-carboxylic acid 1- [[(cyclohexyloxy)] carbonyl] oxy] ethyl ester; 2-propyl-4- [(3-trifluoroacetyl) pyrrol-1-yl) -l- [[2 '(2 H -tetrazol-5-yl) [1, 1' -biphenyl] -4-yl] methyl] -lH-imidazole-5-carboxylic acid; and the potassium salt of 2,7-diethyl-5- [[2 '- (1H-tetrazol-5-yl) [1, 1-biphenyl] -4-yl] methyl] -5H-pyrazolo [1, 5-b] [1,2,4] -triazole. The conditions associated with vasoconstriction and other biological effects of endothelin and / or angiotensin II that can be particularly mentioned are the control or prevention of coronary diseases, cardiovascular diseases such as hypertension, heart failure, ischemia (in the heart, brain, gastrointestinal tract, liver). and / or kidney) or vasospasm. Other examples of diseases that can be treated are renal failure and renal failure, dialysis, subarachnoid hemorrhage, Raynaud's syndrome, portal hypertension and pulmonary hypertension, and the treatment of gastric and duodenal ulcers and leg ulcers in which vasoconstriction is involved . These can also be used for atherosclerosis and to prevent restenosis after balloon-induced vasodilation. Finally, the concentration of endothelin is increased in the bronchial secretion of patients with asthma. Increases in endothelin in blood plasma are also found during migraine attacks. The combination, therefore, can also be used in these cases. With the administration of the combination according to the invention, there is a considerable, rather than an additive, improvement in the blood pressure and action reducing properties compared to the individual substances. The dose of the individual active ingredients can thus be considerably reduced. This means that fewer side effects should be expected with administration. The weight ratio of the renin / angiotensin system inhibitor to endothelin antagonist is usually in the range from 50: 1 to 1: 500, preferably 10: 1 to 1: 100 and, in particular, 2: 1 to 1:50. . The combinations according to the invention are generally administered orally, for example, in the form of tablets, lacquered tablets, sugar-coated tablets, hard and soft gelatin 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 active ingredients may be administered in the form of products containing both active ingredients together, such as tablets or capsules, or separately as an ad-hoc combination of individual substances, which may be administered concurrently or in sequence. To produce tablets, lacquered tablets, sugar-coated tablets and hard gelatin capsules, it is possible to produce a combination according to the invention, with inorganic or organic, pharmaceutically inert excipients. The excipients that can be used for tablets, coated tablets and hard gelatine capsules are lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof. Suitable excipients for such gelatin capsules are vegetable oils, waxes, fats, 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 hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. 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 following tests show the unexpected advantageous properties of the combinations according to the invention. The test substance was administered orally as a capsule to chronically instrumented male beagle dogs (approximately 14 kg) in a crossover design. The capsules contained nothing (control N = 10), trandolapril (2 mg / kg N = 10), compound A (10 mg / kg); N = 10) or combinations of trandolapril plus compound A (2 + 10 mg / kg, N = 10, and 2 + 0.5 mg / kg, N = 5). There was a period of elimination of at least one week between the individual administrations. The change in blood pressure was recorded for 6 hours. The systolic (SAP) and diastolic (DBH) blood pressure in the abdominal artery [irutiHg] was measured, from which the mean arterial blood pressure was determined. (MAP). The heart rate [min ~] was calculated from the systolic peak of the blood pressure signal. Table 1 shows that there is no fall in blood pressure in the control group and in the group treated with trandolapril. A slight drop in blood pressure can be observed with compound A and is significant at some points in time. The combination of trandolapril with ET antagonist compound A (2 + 10 mg / kg) shows a marked drop in blood pressure, which is still pronounced even in the second combination group with proportion with smaller proportion of the ETA antagonist (only 0.5 mg / kg instead of 2 mg / kg).

Table 1: Changes in mean arterial blood pressure (MAP, mmHg) in normotensive dogs, aware after administration of different substances, the averages are shown.

There is no change in heart rate in the control group during the observation period (Table 2). With compound A there is an increase of about 11 beats in the rhythm, which can be interpreted as a reflex response to the drop in blood pressure. Trandolapril in the same way gives rise to an increase in the pulse, despite the lack of an effect on blood pressure, and this is even more pronounced in the groups in combination.

Table 2: changes in heart rate (min) in conscious normotensive dogs after administration of various substances, the averages are shown.

The following examples illustrate the invention.

Example 1 Lacquered tablets of the following composition were produced: Compound A 200.0 mg Trandolapril 2.0 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 Iron oxide, yellow 1.2 mg Titanium dioxide 0.3 mg Talc 0.7 mg Compound A, trandolapril, lactose , cellulose and polyvinylpyrrolidone were wet granulated and dried. The sieved granules are mixed with magnesium stearate, and the mixture is now ready for compression in each oval tablet cores of 290.0 mg. The cores are then coated with lacquer until the lacquered tablets have reached a final weight of 300 mg.

Example 2 Production of hard gelatine capsules of the following composition: Compound A 250.0 mg Ramipril 2.5 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 ingredients are wet granulated and dried. The granules are mixed with sodium carboxymethyl starch, talc and magnesium stearate, and the mixture is packed in size 1 hard gelatin capsules.

Claims (1)

CLAIMS A combination of an endothelin antagonist of formula I: wherein the substituents are as defined below: C 1 -C 4 alkyl, C 1 -C 4 alkoxy; R 'C 1 -C 4 alkyl, C 1 -C 4 alkoxy; R C 1 -C 4 alkyl which may be substituted by a phenyl radical which in turn may be substituted or by one or two C

1 -C 4 alkoxy radicals, Z is oxygen or a single bond, and a RAS inhibitor. A pharmaceutical preparation containing a combination as claimed in claim 1. The production of a pharmaceutical preparation, which consists of converting a mixture of a RAS inhibitor and an endothelin antagonist as set forth in claim 1 into a dosage form. pharmaceutical The use of a combination of a RAS inhibitor and an endothelin antagonist as set forth in claim 1, or of a pharmaceutical preparation containing a RAS inhibitor and an endothelin antagonist as set forth in claim 1 for concurrent, separate or in sequence to treat conditions associated with vasoconstriction or other biological effects of endothelin and / or angiotensin II.