Pharmaceutical composition

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment or prophylaxis of hypertension, heart diseases, vascular disorders and kidney diseases. The composition comprises compound of the formula (1) as antagonist of angiotensin II receptors and one or some diuretics. The composition shows enhanced effectiveness.

EFFECT: valuable medicinal properties of composition.

23 cl, 2 tbl, 1 ex

 

Technical field of invention

This invention relates to a pharmaceutical composition containing a specific receptor antagonist of angiotensin II and one or more diuretics as active ingredients (in particular, to a pharmaceutical composition for preventing or treating hypertension), the use of a specific receptor antagonist of angiotensin II and one or more diuretics to obtain a pharmaceutical composition (particularly, a pharmaceutical composition for preventing or treating hypertension) and to a method of prevention or treatment (especially of medicine) of disease (particularly hypertension) administration of pharmaceutical compositions comprising an effective dose of a specific receptor antagonist of angiotensin II and one or more diuretics, warm-blooded animals (in particular, people).

Background of the invention

It is known that the introduction of joint receptor antagonist of angiotensin II and diuretic therapy is an effective therapeutic method to prevent or treat hypertension (especially treatment). Such pharmaceutical compositions are described, for example, in WO89/6233, in the patent application of Japan Kokai No. Hei 3-27362 etc.

However, actions farmatsevticheskii composition containing a specific receptor antagonist of angiotensin II, such as CS-866, is diuretic remain unknown.

Description of the invention

Given the importance of preventing and/or treating hypertension, the authors of this invention have investigated a combination of various medications and found that a pharmaceutical composition comprising a specific receptor antagonist of angiotensin II, such as CS-866, and one or more diuretics, shows the excellent antihypertensive properties and, therefore, can be used as a preventive and/or therapeutic agent for the treatment of hypertension.

This invention provides a pharmaceutical composition comprising a specific receptor antagonist of angiotensin II and one or more diuretics as active ingredients (in particular, a pharmaceutical composition for preventing or treating hypertension), the use of specific antagonists of the angiotensin II receptor and one or more diuretics to obtain pharmaceutical compositions (in particular, pharmaceutical compositions for preventing or treating hypertension), method of prevention or treatment (especially of medicine) of disease (particularly hypertension) the introduction of specific receptor antagonist of angiotensin II and one or more diuretics warm-blooded animals (particularly humans) in effective doses, and the pharmaceutical composition is Yu for administration simultaneously or sequentially a specific receptor antagonist of angiotensin II and one or more diuretics for preventing or treating hypertension.

The active ingredients of the pharmaceutical compositions of this invention include antagonist acceptor angiotensin II selected from the group comprising a compound represented by following formula (I), its pharmaceutically acceptable salts, pharmaceutically acceptable esters and pharmaceutically acceptable salts of these esters; and one or more diuretics.

The compound of formula (I), its salt, etc. are known compounds, for example, described in the patent application of Japan Kokai No. Hei 5-78328 etc. and chemical name of the compounds of formula (I) is 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylic acid.

The term "pharmaceutically acceptable salt" of the compound of formula (I), which is the active ingredient of the present invention includes a salt of an alkali metal, e.g. sodium salt, potassium salt or lithium salt; a salt of alkaline earth metal such as calcium salt or magnesium salt; a salt of metal such as an aluminium salt, iron salt, zinc salt, copper salt, Nickel salt, cobalt salt; or an amine salt such as ammonium salt, a salt of tert-octylamine, salt dibenzylamine, salt of the research, salt of glucosamine, salt complex Olkiluoto phenylglycine ester, salt Ethylenediamine salt, N-methylglucamine, salt gua is Idina, salt diethylamine, salt, triethylamine salt of dicyclohexylamine, salt N,N'-dibenziletilendiaminom, salt chloroprocaine, salt of procaine, diethanolamine salt, a salt of N-benzylpenicillin, salt, piperazine salt of Tetramethylammonium or Tris(hydroxymethyl)aminomethane salt. Salt of an alkali metal is preferred, and sodium salt is particularly preferred.

The term "pharmaceutically acceptable ester" of the compounds of formula (I), which is the active ingredient of the present invention, includes connection, esterified on the carboxyl fragment of the compounds of formula (I). The group, forming a specified ester, is a group that can be cleaved by a biological method such as hydrolysis in vivo. Such groups include, for example, (C1-C4)alkoxy(C1-C4)alkyl group, such as methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxyphenyl, butoxymethyl or tert-butoxymethyl; and (C1-C4)alkoxycarbonyl (C1-C4)alkoxy(C1-C4)alkyl group, such as 2-methoxyethoxymethyl; and (C6-C10)aryloxy(C1-C4)alkyl group, such as phenoxymethyl; halogenated (C1-sub> 4)alkoxy(C1-C4)alkyl group, such as 2,2,2-trichloroacetyl or bis(2-chloroethoxy)methyl; (C1-C4)alkoxycarbonyl(C1-C4)alkyl group, such as methoxycarbonylmethyl; cyano(C1-C4)alkyl group, such as cyanomethyl or 2-cyanoethyl; and (C1-C4)alkylthiomethyl group, such as methylthiomethyl or ethylthiomethyl; and (C6-C10)arithimetic, such as phenylthiomethyl or Aftertime; and (C1-C4)alkylsulfonyl(C1-C4)a lower alkyl group which may be optionally substituted atom(s) halogen, such as 2-methansulfonate or 2-triftormetilfullerenov; and (C6-C10)arylsulfonyl(C1-C4)alkyl group, such as 2-benzosulfimide or 2-toluensulfonate; aliphatic (C1-C7)acyloxy(C1-C4)alkyl group, such as formyloxyethyl, acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl, valerolactone, isovalerylglycine, hexaniacinate, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-valeriansee, 1-isovalerianic, 1-hexaniacinate, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionylacetate, 2-butyrylacetate, 2-pivaloyloxymethyl, 2-valeriansee, 2-from valeriansee, 2-hexaniacinate, 1-formylacetate, 1-acetoxymethyl, 1-propionyloxy, 1-butyryloxy, 1-pivaloyloxymethyl, 1-alariaceae, 1-isovalerylglycine, 1-hexanolactone, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl, 1-acetoxyethyl, 1-propionylacetate, 1-butyrylacetate, 1-pivaloyloxymethyl or 1-pivaloyloxymethyl; and (C5-C6)cycloalkylcarbonyl(C1-C4)alkyl group, such as cyclopentanecarboxylate, cyclohexylcarbodiimide, 1-cyclopentanecarboxylate, 1-cyclohexylcarbodiimide, 1-cyclopentanecarboxylate, 1-cyclohexylcarbodiimide, 1-cyclopentanecarboxylate or 1-cyclohexyloxycarbonyloxy; and (C6-C10)arylcarboxylic(C1-C4)alkyl group, such as benzoyloxymethyl; and (C1-C6)alkoxycarbonyl(C1-C4)alkyl group, such as methoxycarbonylmethyl, 1-(methoxycarbonylamino)ethyl, 1-(methoxycarbonylamino)propyl, 1-(methoxycarbonyl)butyl, 1-(methoxycarbonylamino)pentyl, 1-(methoxycarbonyl)hexyl, ethoxycarbonylmethyl, 1-(ethoxycarbonyl)ethyl, 1-(ethoxycarbonyl)propyl, 1-(ethoxycarbonyl)butyl, 1-(ethoxycarbonyl)pentyl, 1-(ethoxycarbonyl)hexyl, propoxycarbonyl, 1-(proposter is enyloxy)ethyl, 1-(propoxycarbonyl)propyl, 1-(propoxycarbonyl)butyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyl)ethyl, 1-(isopropoxycarbonyl)butyl, butoxycarbonylmethyl, 1-(butoxycarbonylamino)ethyl, 1-(butoxycarbonylamino)propyl, 1-(butoxycarbonylamino)butyl, msobuttoniconandcaption, 1-(isobutoxyethene)ethyl, 1-(isobutoxyethene)propyl, 1-(isobutoxyethene)butyl, tert-butoxycarbonylmethyl, 1-(tert-butoxycarbonylamino)ethyl, ventilatsioonisusteemi, 1-(ventilatsioonile)ethyl, 1-(ventilatsioonile)propyl, hexyloxybenzoyl, 1-(hexyloxyethoxy)ethyl or 1-(hexyloxyethoxy)propyl; and (C5-C6)cycloalkylcarbonyl(C1-C4)alkyl group, such as cyclopentanecarboxylate, 1-(cyclopentanecarbonyl)ethyl, 1-(cyclopentanecarbonyl)propyl, 1-(cyclopentanecarbonyl)butyl, cyclohexyloxycarbonyloxy, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)butyl; [5-(C1-C4)alkyl-2-oxo-1,3-dioxolan-4-yl]methyl group, such as (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolan-4-yl)methyl, (5-butyl-2-oxo-1,3-di is Xalan-4-yl)methyl; [5-(phenyl which may be optionally substituted (C1-C4)alkyl, (C1-C4)alkoxygroup(s) or atom(s) halogen)-2-oxo-1,3-dioxolan-4-yl]methyl group, such as (5-phenyl-2-oxo-1,3-dioxolan-4-yl)methyl, [5-(4-were)-2-oxo-1,3-dioxolan-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolan-4-yl]methyl, [5-(4-forfinal)-2-oxo-1,3-dioxolan-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolan-4-yl]methyl; or teledrama group which may be optionally substituted (C1-C4)alkyl or (C1-C4)alkoxygroup(s), such as phthalidyl, dimethylphthalate or dimethoxytrityl. Preferred ester groups are pivaloyloxymethyl group, felicilda group or (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl group, and more preferred ester group is (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl group.

"Pharmacologically acceptable salt of the pharmacologically acceptable complex ester" of the compounds of formula (I), which is the active ingredient of the present invention includes the pharmacologically acceptable salt of the pharmacologically acceptable ether complex"described above, for example, salt halogen acids, such as hydroptere, hydrochloride, hydrobromide or hydroiodide; nitrate; perchlorate; sulfate; phosphate; salt With1-C 4alkanesulphonic acid, which may be optionally substituted atom(s) halogen, such as methanesulfonate, triftorbyenzola or econsultant; Sol6-C10arylsulfonic acid, which may be optionally substituted C1-C4alkyl(s) group(s), such as bansilalpet or p-toluensulfonate; Sol1-C6aliphatic acids, such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or a salt of the amino acids, such as salt of glycine, lysine salt, salt arginine, salt, ornithine salt of glutamic acid or salt asparginase acid. The preferred salts are the hydrochloride, nitrate, sulfate or phosphate, and especially preferred salt is the hydrochloride.

Antagonist acceptor of angiotensin II, which is the active ingredient of the present invention, preferable is a compound of formula (I) or its pharmacologically acceptable ester, more preferably a pharmacologically acceptable ester of the compound of formula (I), and even more preferably complex pivaloyloxymethyl, complex Caligraphy or complex (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester compounds of formula (I). The most preferred compound is (5-methyl-2-oxo-1,3-dioxolan-4-yl)mate the new ester of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylic acid (CS-866).

The compound of formula (I), which is the active ingredient of this invention may absorb water or organic solvent with the formation of a hydrate or of MES, and the invention includes such a hydrate and a solvate.

Diuretics, which are the second active ingredient of the present invention, are known compounds and include, for example, sulfonamidnuyu compounds such as acetazolamide, methazolamide, ethoxzolamide, clopramide, dichlorphenamide, disulfid, mefruside, chlorthalidone, quinethazone (quinethazone), furosemide, clopamide, tripamide, indapamide, chloroxuron, metolazone, xipamide, bumetanide, piretanide and X-54; derivatives thiazide, such as hydrochlorothiazide, methylclothiazide, benzylhydroxylamine, trichlormethiazide, cyclopenthiazide, polythiazide, atiase, cyclothiazide, bendroflumethiazide and hydroflumethiazide; derivatives phenoxyalkanoic acid, such as ethacrynic acid (ethacrynic acid), tanilba acid (tienilic acid), endocrine (indacrinone) and quinkert (quincarbate); triamterene (triamterene); amiloride; spironolactone; canrenoate (canrenoate) potassium; torsemide; MK-447; traxex (traxanox) sodium, which were described in U.S. patent No. 2554816, U.S. patent No. 2980679, U.S. patent No. 2783241, GB 795174, J. Chem. Soc., 1125 (1928), U.S. patent No. 2835702, GB 851287, U.S. patent No. 3356692, U.S. patent No. 3055904, U.S. patent No. 2976289, U.S. patent No. 3058882, Helv. Chim. Act, 45, 2316 (1962), Pharmacometrics, 21, 607 (1982), U.S. patent No. 3183243, U.S. patent No. 3360518, U.S. patent No. 3567777, U.S. patent No. 3634583, U.S. patent No. 3025292, J. Am. Chem. Soc., 82, 1132 (1960), U.S. patent No. 3108097, Experientia, 16, 113 (1960), J. Org. Chem., 26, 2814 (1961), U.S. patent No. 3009911, U.S. patent No. 3265573, U.S. patent No. 3254076, U.S. patent No. 3255241, U.S. patent No. 3758506, VE 639386 and U.S. patent No. 3163645. The preferred diuretic is derived thiazide, and more preferred is hydrochlorothiazide.

The chemical formulas of common diuretics are presented below:

Connection name hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. The term "hydrochlorothiazide of the present invention includes its pharmaceutically acceptable salts, for example, salt halogen acids, such as hydroptere, hydrochloride, hydrobromide or hydroiodide; nitrate; perchlorate; sulfate; phosphate; salt With1-C4alkanesulphonic acid, which may be optionally substituted atom(s) halogen), such as methanesulfonate, triftorbyenzola or econsultant; Sol1-C10arylsulfonic acid, which may be optionally substituted C1-C4alkyl(s) group(s), such as bansilalpet or p-toluensulfonate; Sol1-C6aliphatic acids, such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or a salt of the amino acids, such as salt of glycine, lysine salt, salt arginine, salt, ornithine salt of glutamic acid or salt asparginase acid. The preferred salts are the hydrochloride, nitrate, sulfate or phosphate, and especially preferred salt is the hydrochloride.

When diuretic, described above, contains asymmetric the output(s) atom(s), this invention includes a separate optical isomers and their mixtures. The invention also includes hydrates of the compounds described above.

Diuretic of the present invention is selected from one or more of the compounds described above, and are preferably chosen one diuretic that is used in combination with a receptor antagonist of angiotensin II, such as CS-866.

Preferred pharmaceutical compositions of this invention are the following songs:

1) a pharmaceutical composition in which the diuretic is a sulfonamide-derived phenoxyalkanoic acid, or a derivative thiazide;

2) the pharmaceutical composition in which the diuretic is derived thiazide;

3) the pharmaceutical composition in which the diuretic is selected from the group consisting of hydrochlorothiazide, methylclothiazide, benzylhydroxylamine, trichlormethiazide, cyclopenthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide and hydroflumethiazide; or

4) the pharmaceutical composition in which the diuretic is hydrochlorothiazide.

Industrial applicability

Since this invention is pharmaceutical compositions containing specific receptor antagonist of angiotensin II, such as CS-866, and one or more diuretics, are beautiful antigipertenzivny the properties and have low toxicity, these pharmaceutical compositions are useful as medicines [preferably, a prophylactic or therapeutic medicines for the treatment of hypertension, heart disease (angina, heart failure, cardiac hypertrophy), vascular disorders (arteriosclerosis, restenosis after percutaneous catheter coronaroplasty, disorders of the peripheral blood vessels), renal diseases (diabetic nephropathy, glomerular nephritis, nephrosclerosis); more preferably a prophylactic and/or therapeutic drugs (especially therapeutic drugs) for the treatment of hypertension and heart disease; and most preferably a prophylactic or therapeutic drugs (especially therapeutic drugs) for the treatment of hypertension]. The drugs described above, preferably used warm-blooded animals, particularly humans.

In accordance with this invention a specific receptor antagonist of angiotensin II, such as CS-866, and diuretics in the joint introduction exhibit better therapeutic efficacy than the introduction of separately. In addition, these drugs have shown great effectiveness when introduced into the same body at different times. Site is planned, when connecting two groups used in this invention, are absorbed in the body, they cause the signals in the respective receptors, which cause their pharmaceutical action. Therefore, even when their concentration in the plasma is reduced to a level below the threshold concentrations that can cause each of the medicines, the signals generated at their receptors, are already in place, so there is a prophylactic or therapeutic anti-hypertensive effect caused by the first drug. The act of bonding, which is introduced later, is folded by the action of the first drug. Thus, the actions of these two drugs are additive and can be beautiful effects. As for clinical applications it is convenient if these two medicinal tools are introduced at the same time, the specific receptor antagonist of angiotensin II, such as CS-866, and diuretics can be entered at the same time in the same pharmaceutical composition. If these medicines do not physically can be mixed appropriately the methods used to obtain pharmaceutical preparations, each connection can be administered separately at the same time. In addition, as described above, since these two groups of Lekarstvo the x means do not need to be entered at the same time to obtain wonderful therapeutic efficacy, the compounds can be administered at appropriate intervals of time. The maximum time interval that is suitable for administration of the compounds of these two groups by obtaining an excellent therapeutic or prophylactic effect, can be set using clinical or pre-clinical trials.

The usual method of administration of specific antagonists of receptors of angiotensin II, such as CS-866, and diuretics is the oral route of administration. Therefore, these two groups of compounds can be prepared as a separate pharmaceutical preparations for each group or as a single pharmaceutical drug, physical mixture of these two groups of compounds. The pharmaceutical preparations are, for example, powder, granules, tablets, capsules, etc. Available compounds or their pharmaceutically acceptable salts or esters are mixed with other components, diluents, etc. and pharmaceutical preparations are manufactured according to traditional methods of obtaining, as described below.

In particular, the pharmaceutical preparations described above are made known standard methods using standard additives, such as diluents (e.g., organic diluents, including derivatives of sugars, such as lactose, sucrose, glucose, mannitol, SOR is it; derivatives of starch such as corn starch, potato starch, α-starch and dextrin, cellulose derivatives such as crystalline cellulose; Arabian gum; dextran; pullulan; and inorganic diluents, including silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, alumosilicate magnesium; phosphate derivatives such as primary calcium phosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate), lubricating agents (as examples can be mentioned metal salts of stearic acid such as calcium stearate and magnesium stearate; tal; waxes, such as beeswax, spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; laurilsulfate, such as nutriceuticals, magnipapillata; silicates, such as anhydrous silicic acid, silicic acid hydrate; and starch derivatives described above), binders (for example, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, macrogol and the like diluents described above), disintegrators (e.g., cellulose derivatives, such as nizkozameshhennoj hydroxypropylcellulose, carboxymethylcellulose, sodium is th carboxymethylcellulose and sodium carboxymethylcellulose with internal stitching; derivatives chemically modified starch/cellulose, such as carboximetilkrahmal, natrocarbonatite, crosslinked polyvinylpyrrolidone; and the starch derivatives described above), demulsifier (for example, colloidal clay, such as bentonite and veegum; metal hydroxides such as magnesium hydroxide, aluminum hydroxide; anionic surfactants such as nutriceuticals, calcium stearate; cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylenated, complex polyoxyethylenesorbitan fatty acid esters of sucrose and fatty acids), stabilisers (for example, parahydroxybenzoate, such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid and sorbic acid), flavorings (for example, podslastiteli, podnikatel and commonly used food additives and thinners, etc.

Dose and frequency of introduction of specific receptor antagonist of angiotensin II, such as CS-866, and diuretics depends on various factors, such as activity of drugs, symptoms, age and body weight of patients. However, in General, d is serowka for adult patient (mg intake/admission) specific receptor antagonist angiotensin II and diuretics is from 0.5 to 1000 mg (preferably from 1 to 100 mg) and from about 0.05 to 1500 mg, preferably from 5 to 300 mg), respectively. The compounds are injected once or a few times a day depending on the symptoms of the disease in patients.

The ratio of doses of medication two categories can also vary. In General, however, the dose ratio of specific receptor antagonist of angiotensin II, such as CS-866, and diuretics is from 1:200 to 200:1 based on weight.

In this invention a specific receptor antagonist of angiotensin II, such as CS-866, and diuretics are entered simultaneously, separately or sequentially, at the doses described above.

Best mode for carrying out the present invention

The invention is described in more detail using the following examples. However, the invention is not limited to these examples.

Example 1

Hypotensive effect obtained by the joint introduction of CS-866 and hydrochlorothiazide.

For the experiment using twenty-eight male spontaneously hypertensive rats (spontaneously hypertensive rats - SHRs) age 20 weeks (breed SPF purchased in the laboratory Hoshino Laboratory Animals). Transmitter remote sensor (TA11PA-C40, DATA SCIEMCES Inc.) implanted each individual to record readings of blood pressure. After rehabilitation from surgery blood pressure recording in rats at the age of 24 weeks. In accordance with the ie 7 days daily to rats orally using enteral feeding impose a 0.5% solution of carboxymethyl cellulose (CMC, 2 ml/kg) once a day. Animals are divided into 4 groups (7 animals SHRs group) to obtain approximately equal to the average value of blood pressure in the group based on blood pressure, recorded on the 5th and 6th days after the first injection of a solution of CMC. Then rats orally administered CMC solution (2 ml/mg, control group) or the test compound suspended in 0.5% CMC solution (2 ml/kg) over the next 14 days (once a day). Blood pressure recorded 1 day before injection of the medicinal product and on the 7th and 14th days after the start of injection drugs. Group test substance dosing and blood pressure (mean blood pressure within 24 hours±standard deviation in the corresponding day of the measurement) are shown in tables 1 and 2.

The test compounds are hydrochlorothiazide (HCTZ), CS-866 and the mixture HCTZ and CS-866. HCTZ prepared with 0.5% solution of CMC thus, to obtain a final concentration of 10 mg/2 ml CS-866 suspended in 0.5% CMC solution so that the final concentration was 10 mg/2 ml Solution of CS-866 and HCTZ prepared with 0.5% CMC solution so that the final concentration was [10 mg (HCTZ)+1 mg (CS-866)]/2 ml

Table 1

The composition of the groups and the introduction of IP is Tyvaenergo substance
Group 1Control0.5% solution of CMC
Group 2HCTZHCTZ (10 mg/kg)
Group 3CS-866CS-866 (1 mg/kg)
Group 4HCTZ and CS-866HCTZ (10 mg/kg)+CS-866 (1 mg/kg)

As shown in table 2, the joint introduction of CS-866 and HCTZ (group 4) leads to more pronounced hypotensive action than in separate introduction of CS-866 and HCTZ (group 2 or 3).

A composition of example 1

Tablets
CS-86610.0 mg
Hydrochlorothiazide12.6 mg
Lactose275,5 mg
Corn starch50.0 mg
Magnesium stearate2.0 mg
Only350 mg

The powders described above are thoroughly mixed and tabletirujut using for tabletting machine to obtain tablets containing 350 mg. Tablets may optionally be coated with sugar.

1. Pharmaceutical composition for prevention or treatment of a disease selected from the group consisting of hypertension, Zab is diseases of the heart (angina, heart failure and hypertrophy of the heart), vascular disorders (arteriosclerosis, post-RTSA restenosis (restenosis after percutaneous catheter coronaroplasty), human peripheral blood vessels) and renal diseases (diabetic nephropathy, glomerular nephritis, sclerosis of the kidneys), containing a receptor antagonist of angiotensin II, a compound of General formula (I)

its pharmacologically acceptable salt, pharmaceutically acceptable ester or pharmacologically acceptable salt of the specified complex ester, and one or more diuretics as active components at a mass ratio of the compounds of formula I, its pharmaceutically acceptable salts, its pharmaceutically acceptable complex ester or pharmacologically acceptable salt of the specified complex ester to the specified one or more diuretics is from 1:200 to 200:1.

2. The pharmaceutical composition according to claim 1, where the receptor antagonist of angiotensin II is a compound of General formula (I) or its pharmacologically acceptable ester.

3. The pharmaceutical composition according to claim 1, where the receptor antagonist of angiotensin II is a pharmacologically acceptable ester compounds of General formula (I).

4. The pharmaceutical composition according to claim 1, where the ant is honest receptor of angiotensin II is a complex pivaloyloxymethyl ether, complex Caligraphy ether or complex (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester compounds of General formula (I).

5. The pharmaceutical composition according to claim 1, where the receptor antagonist of angiotensin II is a complex (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester compounds of General formula (I).

6. The pharmaceutical composition according to claims 1-5, where the diuretic is a sulfonamidnuyu derived derived phenoxyalkanoic acid or derivative thiazide.

7. The pharmaceutical composition according to claims 1-5, where the diuretic is a derivative thiazide.

8. The pharmaceutical composition according to claims 1-5, where a is a diuretic hydrochlorothiazide, methylclothiazide, benzylhydroxylamine, trichlormethiazide, cyclopenthiazide, polythiazide, atiase, cyclothiazide, bendroflumethiazide or hydroflumethiazide.

9. The pharmaceutical composition according to any one of claims 1 to 5, where a is a diuretic hydrochlorothiazide.

10. The pharmaceutical composition according to any one of claims 1 to 9, where the composition is intended for preventing or treating hypertension in warm-blooded animals.

11. The pharmaceutical composition according to claims 1-9, where the composition is intended for the prevention or treatment of hypertension in humans.

12. The use of a composition according to any one of claims 1 to 9 for the manufacture of a medicinal product for preventing or mechanizable, selected from the group consisting of hypertension, heart disease (angina, heart failure and hypertrophy of the heart), vascular disorders (arteriosclerosis, post-RTSA restenosis (restenosis after percutaneous catheter coronaroplasty), human peripheral blood vessels) and renal diseases (diabetic nephropathy, glomerular nephritis, sclerosis of the kidneys) in a warm-blooded animal.

13. The application indicated in paragraph 12, where the disease is hypertension, and these warm-blooded animals are people.

14. A method of preventing or treating diseases selected from the group consisting of hypertension, heart disease (angina, heart failure and hypertrophy of the heart), vascular disorders (arteriosclerosis, post-RTSA restenosis (restenosis after percutaneous catheter coronaroplasty), human peripheral blood vessels) and renal diseases (diabetic nephropathy, glomerular nephritis, sclerosis of the kidneys) by administration of a composition containing receptor antagonist of angiotensin II, the General formula (I)

its pharmacologically acceptable salt, pharmaceutically acceptable complex ester or pharmacologically acceptable salt of the specified complex ester, and one or more diuretics as an effective compound is, warm-blooded animals in need, at a weight ratio of the compounds of formula I, its pharmaceutically acceptable salts, its pharmaceutically acceptable complex ester or pharmacologically acceptable salt of the specified complex ester to the specified one or more diuretics is from 1:200 to 200:1.

15. The method according to 14, where receptor antagonist of angiotensin II is a compound of General formula (I) or its pharmacologically acceptable ester.

16. The method according to 14, where receptor antagonist of angiotensin II is a pharmacologically acceptable ester compounds of General formula (I).

17. The method according to 14, where receptor antagonist of angiotensin II is a complex pivaloyloxymethyl ether complex Caligraphy ether or complex (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester compounds of General formula (I).

18. The method according to 14, where receptor antagonist of angiotensin II is a complex (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester compounds of General formula (I).

19. The method according to any of PP-18 diuretic is a sulfonamidnuyu derived derived phenoxyalkanoic acid or derivative thiazide.

20. The method according to any of PP-18 diuretic is a derivative thiazide.

21. The method according to any of PP-18 diuretic presented yet a hydrochlorothiazide, methylclothiazide, benzylhydroxylamine, trichlormethiazide, cyclopenthiazide, polythiazide, atiase, cyclothiazide, bendroflumethiazide or hydroflumethiazide.

22. The method according to any of PP-18, where a is a diuretic hydrochlorothiazide.

23. The method according to any of PP-22, where the disease is hypertension and introduced to people along with other warm-blooded animals.



 

Same patents:

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a solid medicinal formulation eliciting an antihypertensive, anti-anginal, vasodilating, antioxidant and antiproliferative effect. The solid medicinal formulation comprises the following components: carvedilol, disaccharide, magnesium stearate, starch, calcium phosphate, hydroxypropylmethylcellulose, aerosil and carboxymethylcellulose sodium salt. Also, invention discloses a method for preparing this formulation. Invention provides preparing the formulation eliciting high rate and fullness in releasing an active substance in the human body, stability of quality indices for all fitness period and allowing the effective usage in manufacturing the medicinal agent. Invention can be used in treatment hypertension, stenocardia, myocardium ischemia and chronic cardiac insufficiency.

EFFECT: improved preparing method, valuable medicinal properties of formulation.

5 cl, 1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

21 cl, 70 ex

FIELD: medicine.

SUBSTANCE: vaccine is high molecular weight protein conjugate with angiotensine II taken in high molecular weight protein : angiotensine II proportion of 1:12-55 in % by weight. The conjugate is modified with equilibrium quantity of immunocompetent polyelectrolyte like polyoxydonium.

EFFECT: stable physiological response within prolonged period of 6-12 months.

3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: medicine, cardiology, gastroenterology.

SUBSTANCE: invention relates to a method for treatment of ulcer-erosion injures in gastroduodenal region in patients with arterial hypertension. Method involves detection of immune disturbances and carrying out the combined immunomodulating therapy and hypotensive therapy. Immunocorrecting complex consists of licopide, cortexinum, vetoronum TK in arterial hypertension of I-II degree and comprises superlymph additionally in arterial hypertension of III degree. Method provides attaining optimal results in treatment for relatively short time due to adequate immunocorrection in such patients.

EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: medicine.

SUBSTANCE: method involves administering Noliprelum in postoperative period for reducing left ventricle hypertrophy.

EFFECT: enhanced effectiveness of treatment in early postoperative period.

FIELD: medicine, endocrinology, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 3 tbl

The invention relates to pharmaceutical industry and relates to pharmaceutical compositions containing 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate, to prevent, treatment or inhibition of the development of a simple retinopathy or preproliferative retinopathy; the method of preventing, treating or inhibiting the development of a simple retinopathy or preproliferative retinopathy; and applying the 2-ethoxy-1-[[2'-(1 N-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]the benzimidazole-7-carboxylate

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to new applying EP4 receptors agonist for treatment and/or prophylaxis of diseases associated with loss of osseous mass. Agonists of EP4 receptors show high effectiveness in treatment of diseases associated with loss of osseous mass, among the, as osteoporosis of different genesis. Agonists of EP4 receptors involve prostaglandin skeleton base.

EFFECT: valuable medicinal properties of pharmaceutical composition.

16 cl, 3 tbl, 5 ex

FIELD: medicine, biochemistry.

SUBSTANCE: invention relates to a method for treatment of pathology or disorder taken among inflammatory diseases. Method involves using the simultaneous, separating or distributed by time at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2. Also, invention relates to the composition comprising at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2 for using in the method for treatment of pathology or disorder taken among inflammatory diseases.

EFFECT: improved method for treatment.

21 cl, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in treatment or prophylaxis of HIV-infection in humans that comprises effective amount of β-D-D4FC or its pharmaceutically acceptable salts or a prodrug being optionally in a pharmaceutically acceptable carrier in combination with effective amount of compound being optionally in pharmaceutically acceptable carrier that is taken among the group consisting of indinavir, nelfinavir, saquinavir, amprenavir, efaverenza, delavirdin, nevirapin and abacavir as a single preparation and to a method for treatment or prophylaxis of HIV-infection in humans that involves administration of effective amount of this composition. Pharmaceutical composition elicits the preferred or improved pharmacokinetic parameters, parameters of biological distribution, metabolic parameters, parameters of resistance and other parameters as compared with administration of β-D-D4FC only.

EFFECT: improved method for treatment and prophylaxis, valuable properties of composition.

17 cl, 6 tbl, 2 dwg

FIELD: pharmacology and pharmacotherapy.

SUBSTANCE: invention resides in use of activated form of drug in low and ultralow dose, which activated form is obtained by way of multiple consecutive dilution and external action according to homeopathic technology, as agent for potentiation of therapeutical effects of the same drug used in therapeutical dose.

EFFECT: enhanced therapeutical effects of drug.

16 ex

FIELD: pharmacology and pharmacotherapy.

SUBSTANCE: invention resides in that therapeutic dose of drug is supplemented by activated form of the same substance obtained by way of multiple consecutive dilution and external action according to homeopathic technology, in low and ultralow dose, preferably at volume ratio from 1:1 to 1:1000.

EFFECT: enhanced specific effects of drug.

7 tbl, 16 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

FIELD: medicine.

SUBSTANCE: invention relates to application of NO-releasing non-steroid antiinflammation agent as wall as pharmaceutically acceptable salt or enantiomer thereof for production of drug useful in treating of disorders associates or mediated with Helicobacter pylory; pharmaceutical composition for treating of bacterial infections, including NO-releasing non-steroid antiinflammation agent as main ingredient; and similar composition including additionally inhibitor of acid-sensitive proton pump.

EFFECT: effective agents and pharmaceutical compositions for treating of bacterial infections.

19 cl, 4 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compositions eliciting an antilipidemic effect and comprising inhibitor of bile acid transport in jejunum of the general formula (I): and inhibitor of HMG-CoA-reductase. Also, invention relates to a method for carrying out the combined therapy.

EFFECT: improved treatment method, valuable medicinal properties of compositions.

15 cl, 9 tbl, 1401 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention proposes the composition comprising xenon as NMDA-antagonist and alpha-2-adrenergic agonist used for treatment of tetanus or narcotics (alcohol) withdrawal syndrome, states with chronic pain syndrome. Also, invention relates to the anesthetic composition comprising xenon and alpha-2-adrenergic agonist and to a method for anesthesia. The synergistic interaction of xenon as NMDA-antagonist and alpha-2-adrenergic agonist provides reducing the dose and to maintain the prolonged effectiveness by prevention for arising the drug habitation to the claimed preparation.

EFFECT: valuable medicinal properties of composition.

9 cl, 6 dwg, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.

19 cl, 4 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

Up!