Pharmaceutical drug

 

(57) Abstract:

The invention relates to a combined preparation. It can be used for the treatment of diseases of the circulatory system. The drug contains the inhibitor system of the renin - angiotensin - cilazapril and antagonist of endothelin - 4-tert. butyl-N- [6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- 2,2'-bipyrimidin-4-yl] benzosulfimide. Their mass ratio of 1:1-1: 100. In particular, the product contains 2.5 to 10 mg of cilazapril and 250 to 1,000 mg of the antagonist of endothelin. The total mass of the two components in the product may be 550 mg Joint introduction of the two components of the drug leads to a synergistic effect. Thanks to this effective dose of both components can be significantly reduced. This reduces side effects. 2 C.p. f-crystals, 4 Il.

The invention relates to a combined pharmaceutical preparations suitable for the treatment of diseases of the circulatory system and containing the inhibitor system of the renin - angiotensin (RAS inhibitor and an endothelin antagonist.

The system renin - angiotensin plays an important role in blood pressure regulation. This system can be represented in the form of a proteolytic cascade, consisting of the following inactive.

2. Angiotensin I is converted by the enzyme ACE (Angiotensin Converting Enzyme - the enzyme that converts angiotensin) to angiotensin II.

3. Angiotensin II binds to receptors in the membrane of effector cells and causes a biological reaction.

Such biological reactions are very diverse. This may occur, for example, in the contraction of the blood vessels, the biosynthesis of aldosterone and stimulating the growth of blood vessels after any damage.

System the renin - angiotensin can inhibit all three of the above stages, namely: in the first stage by applying an inhibitor of renin, the second by applying an ACE inhibitor and at the third, by applying a receptor antagonist of angiotensin II.

In the treatment of high blood pressure and congestive heart failure ACE inhibitors has become of great importance. The prototype of this type of compounds is captopril. The renin inhibitors and receptor antagonists angiotensin II up to the present time is not on sale, however, their creation being conducted around the world.

Endothelin is an outdoor only a few years ago peptide hormone [see Yanagisawa et al., Nature 332. 411-415 (1988)], proavus ilayski the inner surface of blood vessels. Although its concentration in plasma is very low, it can be assumed that the local concentration between the endothelial cells and the neighboring smooth muscle cells of blood vessels is much higher.

Elevated levels of endothelin in plasma is observed at a number of diseases of the cardiovascular system such as hypertension, heart failure, ischemia (heart, brain, gastrointestinal tract, kidneys), or vascular spasm. In patients with asthma, there is increased concentration of endothelin in the secret of the bronchus. Similarly, increased levels of endothelin in plasma during migraine attacks.

Endothelin binds to specific receptors of effector cells. Today, we have a description of at least two subtypes of these receptors, namely the endothelin receptor a and endothelin receptor B [see Lin et al., Proc. Natl. Acad. Sci., USA 88, 3185-3189 (1991) and Sakamoto et al., Biochen. Biophys. Res. Commun. 178. 656-663 (1991)]. Endothelin causes A narrowing of blood vessels, as endothelin B, then its role to date is not yet fully revealed.

As the pathophysiological significance of endothelin large, then there exists a need for an appropriate antagonist and), FEBS 305, 41 (1992) and Biochem. Biophys. Res. Commun. 185, 630 (1992) describes a series of compounds inhibiting the binding of endothelin to its receptor. However, we are talking here or on substances found in fermentation broths, which are obtained by chemical means is practically impossible, or peptides, which, apparently, due to insufficient reliability of biologically unsuitable for oral administration to man. In contrast, described in EPA 510526 and 526708 and in the application WO 93/08799 endothelin antagonists have a simple chemical structure and have the advantage that they can be administered orally.

Combination drug used for treating hypertension containing ACE inhibitor cilazapril and antagonist of calcium ions - nitrendipin (Nitrendipin) described in U.S. patent 4859665.

In the framework of the present invention have found that with the introduction of proposed according to the invention the composition containing the inhibitor system of the renin - angiotensin in combination with an endothelin antagonist, not only summarily improve blood pressure-lowering properties and increases the duration of action of the individual components, but in an unexpected way these factors are amplified, making the effective dose of ateneu has the advantage of that the insertion of a number of biologically active substances can be significantly reduced, and unwanted side effects are completely eliminated or at least significantly limited.

Thanks to this proposed according to the invention, the composition can be used as a tool for the treatment of diseases related to vasoconstriction or due to any other biological effects of endothelin and/or angiotensin II. Examples of such diseases are high blood pressure, coronary disease, cardiac insufficiency, renal and myocardial ischemia, renal failure, dialysis, subarachnoid hemorrhage, Raynaud's syndrome and pulmonary hypertension. This includes the treatment of gastric ulcers and duodenal ulcers, and varicose ulcers, i.e., diseases caused by narrowing of blood vessels.

These agents can also be used with atherosclerosis and to prevent restenosis after induced swelling lung expansion vessels.

According to the present invention features a pharmaceutical preparation containing the inhibitor system of the renin - angiotensin - cilazapril and antagonist of endothelin - 4-tert. - Christ.and respectively 1:1 - 1:100.

Preferably the daily dose of injected composition is 2.5-10 mg of inhibitor of RAS and 250-1000 mg antagonist of endothelin. As a rule, the total number of input RAS inhibitor and an antagonist of endothelin is a maximum of 550 mg / day. When using a hydrate or applicable in the pharmaceutical salts of the above values should be changed accordingly.

The relationship between the mass of the RAS inhibitor and a lot of endothelin antagonist can be selected and in the range from 1:1 to 1:500.

Thus, based on the foregoing, the present invention describes:

- the composition of the RAS inhibitor and an antagonist of endothelin,

pharmaceutical preparation containing a RAS inhibitor and an endothelin antagonist,

- obtaining a pharmaceutical composition of a compound containing a RAS inhibitor and an endothelin antagonist as a therapeutic agent, in the form of galenical forms of the drug,

- the use of a composition of the RAS inhibitor and endothelin antagonist, respectively, of a pharmaceutical product containing a RAS inhibitor and an endothelin antagonist, for simultaneous, separate or at certain intervals of time the treatment of diseases related to vasoconstriction or CMY circulation, especially when therapy, respectively prevention of hypertension and complications caused by it, and in the treatment of heart failure.

As the inhibitor system of the renin - angiotensin can be considered renin inhibitors, ACE inhibitors and antagonists of angiotensin II. It is preferable to apply the ACE inhibitors. Suitable for achieving the present invention aims can be ACE inhibitors such as Alacepril, Benazepril, Captopril, Cilazapril, Cilazaprilat, Delapril, Enalapril, Enalaprilat, Fosinopril, Lisinopril, Perindopril, Quinapril, Ramipril, Spirapril, Zofenopril and MC 838 [calcium salt of (R-(R,S)-1-(3-((2-((cyclohexylcarbonyl)amino)-1-oxopropyl)thio)-2 - methyl-1-oxopropyl)-L-Proline] , and analogues of these compounds is described in European patent publications EPA-7477, 12401, 50800, 51391, 53902, 65301, 72352, 94095, 172552, 211220 and 271795, in U.S. patents 4105776 and 4316906, in the United Kingdom patent 2102412, as well as in Tetrahedron Letters, 23, 1677-1680 (1982). For your preferred ACE inhibitors are compounds that, in the publications highlighted. Especially preferred ACE inhibitors are the above compounds. Most preferred among them Cilazapril, described in DE-OS 2117571.

Suitable for the purposes of the present invention renin inhibitors can bisoprolol] -2-(imidazol-4-yl)ethyl] -3-[1-methyl-1- (morpholine-4-ylcarbonyl)ethylsulfonyl]propionamide;

Ditekiren

Boc-Pro-Phe-N-His-Leu-(CHOH-CH2)-Val-Ile-Asp;

Enalkiren

[1S-(1R*, 2S*,3R*)]-N-(3-amino-3-methyl-1 - oxobutyl)-O-methyl-L-tyrosyl-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexan]-L-histidine;

Remikiren

(S)-2-tert. butylsulfonyl-N-[(S)-1-[(1S,2R,3S)-1 - cyclohexylmethyl-3-cyclopropyl-2,3-dihydroxypropane] -2- (1H-imidazol-4-yl)methyl] -3-phenylpropanamide;

Terlakiren

[R-(R*S*)]-N-(4-morpholinylcarbonyl)-L-i.e. phenylalanyl - N-[1-(cyclohexylmethyl)-2-hydroxy-3-(1-methylethoxy)-3-oxopropyl]- S-methyl-L-cysteine;

A 65 317

1(S)-cyclohexylmethyl-2(R)-hydroxy-2-[3-ethyl-2-oxoacridine - 5(S)-yl] ethylamide N-[2(R)-benzyl-N-[2-[2-(2-methoxyethoxy)methoxy] ethyl] - N-methylsuccinimide]histidine;

A 72 517

1(S)-(cyclohexylmethyl)-2(R) 3(S)-dihydroxy-5-methylhexane N-[2(S)-benzyl-3-(4-methyl-1-piperazinylcarbonyl)propanol] -3-(4 - thiazolyl)-L-alanine;

A 70 461

N-[2(S)-amino-1-cyclohexyl-3(R), 4(S)-dihydroxy-6-methylhept - 1-yl] -2(S)-[1(S)-[4-(methoxyethoxy)piperidine-1-ylcarbonyl] - 2-phenylethane]hexanamide;

A 74 273

6-cyclohexyl-4(S)-hydroxy-2(S)-isopropyl-5(S)-[2(S)-[1 (S)-[4-(methoxyethoxy)piperidine-1-ylcarbonyl]-2-phenylethane] hexanamide]-N-(3-morpholinopropan)hexanamide;

A 82 110

6-cyclohexyl-4(S)-HYDR shall aminopropyl)hexanamide;

WAY 121 604

methyl ester of (3S)-4-cyclohexyl-2-hydroxy-3-[[(2S)-4 - methyl-2-[[(2S)-2-(1-oxo-1,3-dihydroindol-2-yl)-3-phenylpropionyl] amino] pentanoyl]amino]butyric acid;

SQ 31 844

[R-(R*S*)]-N-(4-morpholinylcarbonyl)-L-i.e. phenylalanyl]- N-[1-(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)ethyl]-L - histidine;

SQ 33 800

[1S-[1R*(R*), 2S*, 3S*]]-[2-(tert. butylsulfonyl)-1-oxo-3-phenylpropyl] -N-[4-[(butylamino) sulfonyl] -1-(cyclohexylmethyl)-2,3-dihydroxybutyl]-L-histidine - monoethanesulfonate;

GR 70 982

[1S-(1R*THAT 2R*4S*)] -N-[(1,1-dimethylmethoxy) carbonyl]-L-i.e. phenylalanyl-N-[5-[(4-aminobutyl)amino] -1-(cyclohexylmethyl)- 2-hydroxy-5-oxo-4-(4-pyridinylmethyl)pentyl]-L-histidine;

ICI 219 623

(2S, 4S,5S)-N-butyl-6-cyclohexyl-4-hydroxy-2-isopropyl-5-[2- [8-propyl-6-(3-pyridyl)-1,2,4-triazolo[4,3-a] pyrazin-3-yl] -3-(3-pyridyl) propionamido]-hexanamide;

L 157 119

4-(Boc-Phe-His-ACHPA-Lys-NH-CH2)pyridine;

CP 71 362

[2R-(2R*4S*, 5S*)] -N-[N2-[6-cyclohexyl-5- [[N-[N-[(1,1-dimethylmethoxy)-carbonyl] -L-i.e. phenylalanyl] -L-histidyl] amino]- 4-hydroxy-2-(2-methylpropyl)-1-oxohexyl]-L-lysyl]-L-phenylalanine - diacetate;

ES 8 891

5-cyclohexyl-2,4,5-trideoxy-N-hexyl-4-[[N-[3-(1-naphthas(R*), 2R*, 4[R*(R*)] ] ] - N-[4-[[1-[[(5-amino-6-hydroxyhexyl)amino] -carbonyl]-3 - methylbutyl]amino]-2-hydroxy-1-(2-methylpropyl)- 4-oxobutyl] --[[3-(1 - naphthalenyl)-2-(1-naphthalenyloxy)- 1-oxopropyl]amino] -1H-imidazol-4-propanamide;

PD 132 002

[1S-(1R*, 2S*, 3R*)] -N-(4-morpholinylcarbonyl)- L-i.e. phenylalanyl-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexan] - O-methyl-3-oxo-D - or L-Suriname;

PD 134 674

([1S-(1R*, 2S*, 3R*)] )-N-(4-morpholinylcarbonyl)- L-i.e. phenylalanyl-3-(2-amino-4-thiazolyl)-N-[(cyclohexylmethyl)-2,3 - dihydroxy-5-methylhexan]-L-alaninate;

YM 21 095

N-[2-[[1-(cyclohexylmethyl)-2-hydroxy-3-[(1-methyl-1H - tetrazol-5-yl)thio] propyl] amino] -1-(1H-imidazol-4-ylmethyl)-2 - oxoethyl]--(1-naphthalenyloxy)--oxo-4-morpholinomethyl;

FK 906

1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexane N-methyl-N-[2(S)-[N-methyl-N-[2-[N-methyl-N-(morpholinoethyl)amino] ethyl]carbarnoyl]-3-phenylpropionyl]-L-histidine;

FK 744

ethyl ester of [1S-[1R*[R*(R*)],2R*]]-methyl-[3-(4 - morpholinyl)-3-oxopropyl] -2-[[2-[[1-(cyclohexylmethyl)-2 - hydroxy-5-methylhexan] amino] -1-(1H-imidazol-4-ylmethyl)-2 - oxoethyl] methylamino]-2-oxo-1-(phenylmethyl) carbamino acid;

S 89-2864

1(S)-(cyclohexa, acetate;

MDL 73 323

1-(cyclohexylmethyl)-3,3-Diptera-4-(3-methylbutylamine)-2 - oxobutanamide 3-amino-3-methylbutyryl-(4-O-methyl)-L-tyrosyl-L - Norvaline, hydrochlorizide; and

THERMOWELLS ARE MADE 3 071

1H-indole-2-ylcarbonyl-L-histidine-1(S)-(cyclohexylmethyl)- 2(S),4(S)-dihydroxy-5-methylhexane.

Suitable for the purposes of the present invention, antagonists of angiotensin II are the following:

Losartan

potassium salt of 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)-[1,1'- biphenyl] -4-yl]methyl]-1H-imidazole-5-methanol;

Valsartan< / BR>
N-(1-oxobutyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl] -4-yl] methyl]-L-valine;

BIBS 39

4'-[(2-n-butyl-6-cyclohexylcarbodiimide-1-yl) methyl] biphenyl-2-carboxylic acid;

BIBS 222

2-n-butyl-1-[4-(6-carboxy-2,5-dichloraniline)benzyl] -6 - N-(methylaminomethyl)-n-intraministerial;

BIBR 277

4'-[(1,4'-dimethyl-2'-propyl-[2,6'-bi-1H-benzimidazole] -1'-yl) methyl] -[1,1'-biphenyl]-2-carboxylic acid;

DuP 532

4-(pentafluoroethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylic acid;

EXP 7 711

4'-[[2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl] methyl] -[1,1'-biphenyl]-2-carboxylic acid;

D 6 888

2-ethyl-5,6,7,8-tetrahydro-4-([2'-(1H-tetrazol-5-yl)biphenyl-BR> GR 117 289

1-((3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)-5-benzofuranyl)methyl)- 2-butyl-4-chloro-1H-imidazole-5-carboxylic acid;

GR 138 950

1-[[3-bromo-2-[2-[[(trifluoromethyl)sulfonyl] amino]phenyl]-5 - benzofuranyl] methyl]-4-cyclopropyl-2-ethyl-1H-imidazol-5-carboxamide;

L 158 809

5,7-dimethyl-2-ethyl-3-(2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl) methyl)-3H-imidazo-(4,5-b)pyridine;

SC 50 560

5-[4'-(3,5-dibutil-1,2,4-triazole-1-ylmethyl)biphenyl-2-yl]-1H - tetrazol;

SC 51 895

1,4-dibutil-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl] -2,3-dihydro - 1H-imidazol-2-he;

SR 47 436

2-n-butyl-4-spirocyclopentane-1-[(2'-(1H-tetrazol-5-yl)biphenyl - 4-yl)methyl]-2-imidazolin-5-he;

SKF 108 566

(E)--[[2-butyl-1-[(4-carboxyphenyl)methyl] -1H-imidazol-5-yl] methylene]-2-tofepoopema acid;

TCV 116/CV 11 974

1-[[(cyclohexyloxy)carbonyl] oxy]ethyl ester 2-ethoxy-1-[[2'- (1H-tetrazol-5-yl)-[1,1'-biphenyl] -4-yl] methyl] -1H-benzimidazole - 7-carboxylic acid;

CI 996

2-propyl-4-[(3-TRIFLUOROACETYL)pyrrol-1-yl] -1-[[2'-(2H-tetrazol - 5-yl)[1,1'-biphenyl]4-yl]methyl]-1H-imidazole-5-carboxylic acid; and

YM 358

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.

As endothelin antagonists can be used in a variety of the th derivative, preferred ones derivatives. Particularly preferred among the ones derivatives are those which can be efficiently used orally. Examples of peptide derivatives are the following:

FR 139 317

peligrosas-1-ylcarbonyl-L-leucyl-(1-methyl)-D-tryptophyl- [3-(2-pyridyl)]-D-alanine;

FR 901 367

2-acetamido-3-[[1,4,4 a,5,6,6 a,7,12,12 a,12b-decahydro-4a,8,12 a, 12b-tetrahydroxy-3-methyl-1,7,12-dioxobenzo[]anthracene-6a-yl] thio]propionic acid;

BE 18 257 B

cyclo(-D-Trp-D-Glu-L-Ala-ALLO-D-Ile-L-Leu-);

BQ 123

cyclo(-D-Trp-D-Asp-L-Pro-D-Val-L-Leu-);

peligrosas-1-ylcarbonyl-L-leucyl-D-tryptophyl-D-tryptophan;

Cochinmicin I;

the air merceron-caffeic acid and

PD 142 893

acetyl-(3,3-diphenyl-D-alanyl)-L-Leu-L-Asp-L-Ile-L-Ile-L-Trp.

Suitable for the purposes of the present invention the ones endothelin antagonists are, for example, sulfonamides and derivatives indane and indene, described in the European patent publications EPA 510526 and 526708 and in the application WO 93/08799, in particular the following compounds:

4-tert. butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)- 2,2'-bipyrimidin-4-yl]benzosulfimide (described in EPA 526708);

(1RS, 2SR, 3SR)-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indan-2-carboxylic what RS, 2RS, 3SR)-5-methoxy-3-(4-methoxyphenyl)-1-(3,4 - methylenedioxyphenyl)indan-2-carboxylic acid;

(1RS, 2RS,3SR)-1,3-bis(3,4-methylenedioxyphenyl)-5-hydroxyine - 2-carboxylic acid;

(1RS, 2RS, 3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid;

(1RS, 2RS, 3SR)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(2-methoxy - 4,5-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid;

medicinelexaproca salt (1RS,2RS,3RS)-3-[2-(1-carboxylat - 2-yloxy)-4-methoxyphenyl] -1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy) indan-2-carboxylic acid;

(1RS,2RS,3SR)-[2-[(E)-2-carboxylate-1-yl]-4-methoxyphenyl]-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid;

(1RS, 2RS,3SR)-3-[2-(2-carboxylat-1-yl)-4-methoxyphenyl]-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid; and

(1RS, 2RS,3RS)-3-[2-(3-carboxyphenyl)-4-methoxyphenyl]-1- (3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indan-2-carboxylic acid.

Proposed according to the invention the combination of 4-tert.butyl-N- [6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy) -2,2'-bipyrimidin-4-yl] benzosulfimide (hereinafter referred to as "compound A") and Cilazapril'a is the best.

Thanks to the combined prego and prolonged reduction of blood pressure.

Preferred sverhsummarny effect in reducing blood pressure, as well as increase the duration of action of the composition according to the invention in comparison with the mentioned factors of both components separately is illustrated by the following experiments.

Reduction of blood pressure in spontaneously hypertensive rats.

One of the first series of experiments were conducted on rats. Used rats of the genus SHRSP (weight about 300 g and the age of 18-20 weeks). SHRSP (spontaneously hypertensive rats, stroke prone - spontaneously hypertensive rats, drosterone), the standard name of spontaneously hypertensive rats with age, tendency to bleeding in the brain. At 18 weeks of age, blood pressure in these rats stabilized.

Arterial blood pressure in these rats was measured using telemetry method. The Creator of this telemetry system is the company Data Scienses, Inc., San Paul, Minnesota, USA. Blood pressure measurement was carried out by a fluid-filled catheter, which had previously been implanted in the abdominal aorta. The implantation was performed under General anesthesia brief (15-20 min) with Evipan(100 mg/kg, nutripure the cells, received signals corresponding to the fluctuations of blood pressure. In this way ensured the possibility of continuous measurements on freely moving laboratory animals in a long time.

The experiments were conducted on a group of 9 rats by Cross-Over technique, i.e., each of these rats once did not enter any substances (solvents), once I entered the compound A, once Cilazapril and once the composition of compound A and Cilazapril. The time interval between the individual injections were made at least 48 hours. Dosage was 100 mg/kg orally for compounds A and 1 mg/kg orally for Cilazapril. The introduction was performed using a gastric probe.

In Fig. 1 presents the results of this first series of experiments illustrating the effectiveness of Cilazapril (1 mg/kg orally) and compound A (100 mg/kg orally) administered separately, and the effectiveness of the simultaneous administration of the same doses of both substances (n = 9 rats).

To confirm the reliability of the results was carried out a number of other experiments in which experimental animals were treated with compound a in the other two dosages, namely 10 and 30 mg/kg orally, whereas the dose of Cilazapril sostem data alone Cilazapril, as well as his introduction with 100 mg/kg compound A, is included in Fig. 2 from the previous series.

Shown in Fig. 1 and 2 values represent the average values of blood pressure in 9 experimental animals, stripes borders errors indicate standard error. As further explanation is not required, these bands in Fig. 2B and 2C are omitted.

Connection A slightly reduced mean arterial blood pressure (MAP), and the maximum effect was 20 mm Hg (Fig. 2B). Cilazapril confirmed the expected decrease in pressure, which is approximately 20 hours (maximum effect: reduction in blood pressure of approximately 45 mm Hg (Fig. 2A)). With the introduction of composition, blood pressure was decreased by a maximum of about 60 mm Hg, and it should be noted that after 20 hours it was still possible to observe an obvious effect, and after 40 hours the effect was the same as in 20 hours after administration of one Cilazapril (Fig. 2C). Both lower doses connection And had about the same impact as high dose (Fig. 2B). These data confirm the increased duration of action.

Reduction in blood pressure in abusiv combination with a renin inhibitor Remikiren. In this series of experiments was conducted on monkeys, as Remikiren has a specific action in relation to renino primates and therefore cannot be used on rats. Remikiren is an active renin inhibitor, suitable for oral administration (see Fischli et al., Hypertension 18, 22-31 (1991)).

The measured value was arterial blood pressure was measured by telemetry. Monkey species Saimiri sciureus (saimiri-squirrel or squirrel monkeys) have a weight of from 400 to 700, the removal of sodium reactivity of blood pressure in relation to the RAS inhibitor increases. The excretion of sodium was achieved by subcutaneous injection of 5 mg/kg of furosemide (accutane), which was conducted for 66, 42, and 18 hours before the experiment. The night before the experiment the animals received no food. During the experiments, monkeys were kept in an isolated room for them observed using video cameras, dictated by the necessity to avoid fluctuations in blood pressure, which could be due to stress caused by the experimenters.

In Fig. 3 presents the results of these experiments, and specified the actual changes in average blood pressure, comprising 100 mm P5 monkeys) blood pressure was decreased by approximately 30 mm Hg. The introduction of the composition was achieved significantly greater effect. As the requirements for the protection of animals is not allowed to contain the monkeys in the cage for more than 8 hours, it was not possible to determine the duration of action of drugs.

Cardiac failure.

Because ACE inhibitors currently commonly used in the treatment of patients with heart failure, the connection A and Cilazapril, administered separately and in combination with each other, was also tested on animals in relation to heart failure.

The experiments were conducted on rats, which have 8 weeks after coronary artery ligature (a circumflex) showed complete symptoms of heart failure. Blood pressure was measured above by telemetry. The results of these experiments are presented in Fig. 4. For reasons of greater clarity strip borders errors are presented only for the curve placebo. This animal model also confirmed the higher efficiency of the composition and increase the duration of its validity in comparison with the components entered separately.

Experimental data in an unexpected way suggest finding enter predominantly oral route for example in the form of tablets, lacquered tablets, coated tablets, hard - and megkozeliteni capsules, solutions, emulsions or suspensions. The administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions. The introduction of biologically active substances can be implemented in the form of preparations containing both biologically active substances in the form of dosimetric units, such as tablets or capsules, or separately using the composition in the form of the same dosimetric units, at the same time, or intervals of time.

For the manufacture of tablets, lacquered tablets, coated tablets and terdoslavich capsules composition according to the invention can be added inert pharmaceutical respect, inorganic or organic excipients.

As such, can be used, for example, tablets, pills and terdoslavich capsules are lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. as excipients for megkozeliteni capsules are suitable, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.; however, depending on specificato.

For the manufacture of solutions and syrups as a suitable excipients, for example, water, polyols, sucrose, invert sugar, glucose, etc.

As excipients for injection solutions are suitable, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

As excipients for suppositories are suitable, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

The pharmaceutical compositions can contain, in addition, and preservatives, substances that promote solubility, stabilizers, substances with a high surface activity, emulsifiers, sweet substances, colorants, flavorings, salts for modifying the osmotic pressure, buffers, shell, or antioxidants. They can also contain other valuable in therapeutic relationship substance.

Below the invention is illustrated by examples.

Example 1.

Obtaining a varnish tablets having the following composition mg:

The core of lacquer tablet:

A. Compound a IS a 500,0

B. Cilazapril - 5,0

C. Anhydrous lactose - 30,0

, Microcrystalline cellulose - 30,0

D. Polyvinylpyrrolidone - 20,0

E. Stearate magosa - 3,5

C. Ethylcellulose - 3,5

I. polyethylene Glycol 6000 - 0,8

K. iron Oxide yellow - 1,2

HP titanium Dioxide - 0,3

M. Talc - 0,7

The weight of the lacquer shell - 10,0

Total weight of one lacquered tablets - 600,0

The method of manufacture.

Manufacturer engine lacquer tablets.

Connection A, Cilazapril, lactose, cellulose and polyvinylpyrrolidone are mixed and passed through a sieve. The mixture granularit wet, dried and sieved. The sifted granules are mixed with magnesium stearate, and then from the plastic mass is pressed kernel oval weighing 590,0 mg each.

The manufacture of lacquer shell.

Ingredients W-m prepare aqueous lacquer suspension and appropriately using the method of coating in the drageeing boiler or in any other apparatus for coating cover this suspension kernel to obtain a varnish tablets with the final weight of 600 mg each.

Example 2.

Manufacturer terdoslavich capsules having the following composition mg:

A. The compound A - 250,0

B. Cilazapril - 2,5

C. Crist. lactose - 18,0

, Polyvinylpyrrolidone - 15,0

D. Microcrystalline cellulose is 17.5

that is, NAT is
The method of manufacture.

Connection A, Cilazapril, lactose, polyvinylpyrrolidone and cellulose sift through a sieve and mix. The mixture granularit in the wet state and then dried. The granulate is mixed with a sodium-carboxymethylated starch, talc and magnesium stearate and the resulting mixture is made tverdoplamennoe capsules size 1.

1. The pharmaceutical preparation containing the inhibitor system of the renin - angiotensin - cilazapril, characterized in that it further comprises an antagonist of endothelin - 4-tert.butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl] benzosulfimide at mass ratio of 1 : 1 to 1 : 100.

2. Pharmaceutical drug under item 1, characterized in that it contains 2.5 to 10 mg of the inhibitor system of the renin - angiotensin and 250-1000 mg antagonist of endothelin.

3. Pharmaceutical drug on the PP.1 and 2, characterized in that the total mass of the inhibitor system of the renin - angiotensin and endothelin antagonist is 550 mg

 

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3 ex

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