Pharmaceutical preparations and their using for prophylaxis of stroke, diabetes and/or congestive cardiac insufficiency

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical preparation based on angiotensin-converting enzyme inhibitor, its using in prophylaxis of insult, diabetes and/or congestive cardiac insufficiency and corresponding methods for its using in patient with maintenance heart function and subjected for risk of cardiovascular attack due to previous history of ischemic disease, insult or peripheral arterial disease. In particular, inhibitor of angiotensin-converting enzyme can be chosen from ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Invention promotes to reducing the total lethality of patients group in case of cardiovascular diseases, cardiac attacks and insults, the necessity for carrying out procedures for revascularization (such as surgery operation for coronary shunt, angioplasty with using balloon and so on) and diabetic complication are diminished.

EFFECT: improved and valuable medicinal properties of preparations.

19 cl, 1 ex

 

The scope of the invention

This invention relates to the use of the inhibitor system of the renin-angiotensin (RAS) or its pharmaceutically acceptable derivative in the manufacture of a medicinal product for the prevention of stroke, diabetes and/or congestive heart failure (CHF). This invention also relates to a method for prevention and/or treatment of stroke, diabetes and/or CHF, introducing a therapeutically effective amount of an inhibitor of RAS or its pharmaceutically acceptable derivative to a patient in need of such prevention and/or treatment.

Prerequisites to the creation of inventions

Compounds that affect the RAS, are well known and are used for the treatment of cardiovascular diseases, in particular hypertension and heart failure. Mainly affect RAS by inhibiting enzymes that synthesize angiotensins, or by blocking of the receptors on the effector sites. Currently available inhibitors of angiotensin-converting enzyme (ACE) and antagonists of the receptor type 1 angiotensin II (AT II).

The ACE inhibitors are compounds that inhibit the conversion of angiotensin I to active angiotensin II, as well as the destruction of the active vasodilator bradykinin. Both mechanisms lead to the extension to wenonah vessels (vasodilation). Such compounds are described, for example, in EP 158927, EP 317878, US 4743450 and US 4857520.

Ramipril (described in EP-A-079022) is an ACE inhibitor long term. Its active metabolite is ramiprilat free decollate, which is formed in vivo upon administration of ramipril. It is known that patients-hypertension introduction ramipril causes a reduction in peripheral arterial resistance and hence reducing blood pressure without compensatory increase in heart rate. It is currently used in the treatment of hypertension and CHF. Moreover, it was shown that ramipril reduces the mortality of patients with clinical signs of congestive heart failure after acute myocardial infarction. It is assumed that ramipril has the additional advantage in comparison with many other ACE inhibitors through the apparent inhibition of ACE them in tissues, resulting in a protective effect on organs such as the heart, kidneys and blood vessels.

Compounds that affect the RAS, including ACE inhibitors and antagonists AT II, currently used for the treatment of various cardiovascular diseases, especially in patients with high blood pressure. The use of these compounds for the prevention of cardiovascular zabolevania.patienta less common, and the use of these compounds for the prevention of stroke, diabetes and/or CHF is still unknown.

Brief description of the invention

This invention relates to the use of RAS inhibitor or its pharmaceutically acceptable derivative in the manufacture of a medicinal product for the prevention of stroke, particularly in patients with normal or low blood pressure.

This invention also relates to the application of RAS inhibitor or its pharmaceutically acceptable derivative in the manufacture of a medicine for the prevention of diabetes.

This invention relates also to the use of RAS inhibitor or its pharmaceutically acceptable derivative in the manufacture of a medicinal product for the prevention of the development of CHF in patients who previously had no CHF, i.e. no signs or symptoms of CHF.

Another aspect of the invention is a method for preventing stroke, diabetes and/or CHF, including the introduction of a therapeutically effective amount of an inhibitor of RAS or its pharmaceutically acceptable derivative to a patient in need of such prevention.

Another aspect of the invention is a pharmaceutical formulation for use for the prevention of stroke, diabetes and/or CHF, comprising a therapeutically effective amount of a RAS inhibitor or its pharmaceutically acceptable p is vizvolnogo.

An additional aspect of the invention is the use of RAS inhibitor or its pharmaceutically acceptable derivative for the prevention of stroke, diabetes and/or CHF, by the introduction of a RAS inhibitor or its pharmaceutically acceptable derivative to a patient in need of such prevention.

Detailed description of the invention

Unexpectedly, it was found that the cardiovascular and metabolic disorders, such as stroke, diabetes and CHF, can be prevented by the application of a RAS inhibitor, in particular an inhibitor of ACE, which affects the synthesis of angiotensin II. This invention mainly surprising that especially patients with preserved cardiac function and/or detecting normal or low blood pressure derive significant benefit from preventive actions of RAS inhibitors. The invention relates to a new method of prevention of disorders such as stroke, diabetes and/or CHF, by introducing an inhibitor of RAS.

Patients with normal or low blood pressure is known as normotensive patients. Examples of methodological recommendations for determining the values of blood pressure for different groups of patients, including different age groups, include guidance issued by WHO and JNC (USA). With regard to the present invention, a suitable definition of normal or decreased what about the blood pressure can be found in JNC VI, included in the description by reference.

In the context of this invention "strike" includes a shot fatal fatal and non-fatal.

In the context of this invention "diabetes" includes mellitus type I, also known as insulin-dependent diabetes mellitus (DMM), and type II diabetes, also known as non-insulin dependent diabetes mellitus (NIDMM).

[In the context of this invention, the inhibitor system of the renin-angiotensin (RAS) or its pharmaceutically acceptable derivative" includes any compound which, by their nature or by the insertion blocks the negative effects of angiotensin II on vascular network by reducing the synthesis of angiotensin II or blocking its action at the receptor.

In the context of this invention the inhibitor of the angiotensin-converting enzyme or its pharmaceutically acceptable derivative" includes any compound which, by their nature or by the insertion affects the synthesis of angiotensin II.

When the RAS inhibitor used in this invention have several asymmetric carbon atoms, they can therefore exist in several stereochemical forms. This invention comprises a mixture of isomers, as well as individual stereoisomers. The invention also includes geometric isomers, rotational isomers, enantiomers, racemates and diastereomeric.

Inhibitors of RAS can be used in neutral form, such as carboxylic acid or in the form of salts, preferably pharmaceutically acceptable salts, such as sodium, potassium, ammonium, calcium or magnesium specified connection. The above compounds may be used in hydrolyzable ester form.

In the context of this invention, the inhibitors of RAS include all their proletarienne forms, whether active or inactive in vitro. Thus, although such protected derivatives may not possess pharmacological activity as such, they can be introduced, for example, parenterally or orally, and thereafter metabolized in vivo to the formation of the pharmacologically active RAS inhibitors. Preferred examples are ramipril, which is metabolized to ramiprilat, and the candesartan cilexetil, which is metabolized in the candesartan].

Inhibitors of RAS include ACE inhibitors, antagonists AT II, also known as receptor blockers angiotensin (ARBs), antagonists renin and inhibitors vasopeptidase (VPIs).

The term "inhibitors vasopeptidase covers the so-called inhibitors of NEP/ACE (also referred to as inhibitors of neutral endopeptidase selective or double action), which have activity of inhibiting neutral endopeptidase (NEP) and what aktivnosti inhibition of angiotensin-converting enzyme (ACE).

The expression "antagonists renin covers inhibitors of renin.

In this invention, the inhibitors of RAS can be a long-term effect, the average duration of action or short action.

The ACE inhibitors or their pharmaceutically acceptable derivatives, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF, include, but are not limited to the above, the following connections: alacepril, elatioris, Altiris calcium, uncovered, benazepril, hydrochloride benazepril, benazeprilat, benzoyltartaric, captopril, captopril-cysteine, captopril-glutathione, ceronapril, ceronapril, ceronapril, cilazapril, zilazaprilata, delapril, dallapiccola, enalapril, enalaprilat, enapril, epilatory, proximity, fosinopril, fosinopril, fosinopril sodium, fosinopril, fosinopril sodium fosinoprilat, fosinoprilat acid, glycopeel, hamartin-4, atapryl, imidapril, indrapuri, indrapala, dibenzepin, lisinopril, licien And, licien In, missapril, moexipril, moeksiprilat, multiperil, mortein And, Murzin In, Murzin With, pentopril, perindopril, perindoprilat, pivaloyl, pivotal, inapril, hydrochloride inapril, FinePrint, ramipril, ramiprilat, spirapril, inhibitor spirapril hydrochloride, spirapril, spirapril, hydrochlor is on spirapril, temocapril, hydrochloride of temocapril, carotid, trandolapril, trandolaprilat, ulibarri, saucepan, sailpilot, zofenopril and zofenoprilat.

Preferred ACE inhibitors for use in this invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Preferred ACE inhibitors for use in this invention are ramipril and ramiprilat. Information about the ramipril and ramiprilata can be found, for example, in the Merck index., 12th ed., 1996, str-1395.

Antagonists AT II or their pharmaceutically acceptable derivatives, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF, include, but without limiting the above, those described in European patent applications, publications

253310, 323841, 324377, 399731, 400974, 401030, 403158, 403159, 407102, 407342, 409332, 411507, 411766, 412594, 412848, 415886, 419048, 420237, 424317, 425211, 425921, 426021, 427463, 429257, 430300, 430709, 432737, 434038, 434249, 435827, 437103, 438869, 442473, 443568, 443983, 445811, 446062, 449699, 450566, 453210, 454511, 454831, 456442, 456442, 456510, 459136, 461039, 461040, 465323, 465368, 467207, 467715, 468372, 468470, 470543, 475206, 475898, 479479, 480204, 480659, 481448, 481614, 483683, 485929, 487252, 487745, 488532, 490587, 490820, 492105, 497121, 497150, 497516, 498721, 498722, 498723, 499414, 499415, 499416, 500297, 500409, 501269, 501892, 502314, 502575, 502725, 503162, 503785, 503838, 504888, 505098, 505111, 505893, 505954, 507594, 508393, 508445, 508723, 510812, 510813, 511767, 511791, 512675, 512676, 512870, 513533, 513979, 514192, 514193, 514197, 514198, 514216, 514217, 515265, 515357, 515535, 515546, 515548, 516392, 517357, 517812,518033, 518931, 520423, 520723, 520724, 521768, 522038, 523141, 526001, 527534 and 528762.

Other antagonists of the Academy of Sciences include those described in international patent applications numbers of publications

WO 91/00277, WO 91/00281, WO 91/11909, WO 91/11999, WO 91/12001, WO 91/12002, WO 91/13063, 91/15209, WO 91/15479, WO 91/16313, WO 91/17148, WO 91/18888, WO 91/19697, WO 91/19715, WO 92/00067, WO 92/00068, WO 92/00977, WO 92/02510, WO 92/04335, WO 92/04343, WO 92/05161, WO 92/06081, WO 92/07834, WO 92/07852, WO 92/09278, WO 92/09600, WO 92/10189, WO 92/11255, WO 92/14714, WO 92/16523, WO 92/16552, WO 92/17469, WO 92/18092, WO 92/19211 WO 92/20651, WO 92/20660, WO 92/20687, WO 92/21666, WO 92/22533, WO 93/00341, WO 93/01177, WO 93/03018, WO 93/03033 and WO 93/03040.

The content of these European and international patent applications included in the description as references.

Preferred antagonists AT II or their pharmaceutically acceptable derivatives for use in this invention include, but without limiting the above, the compounds of the following generic name: candesartan, candesartan, cilexetil, losartan, valsartan, irbesartan, tasosartan, telmisartan and eprosartan.

Particularly preferred antagonists AT II or their pharmaceutically acceptable derivatives for use in this invention are candesartan and candesartan cilexetil. Candesartan and candesartan cilexetil described in European patent No. 459136 B1, U.S. patent 5196444 and U.S. patent 5703110, Takeda Chemical Idustries. Candesartan cilexetil currently produced and sold on the world market and AstraZeneca Tkeda, e.g., under trademarks Atacand®, Amias® and Blopress®.

NEP/ACE inhibitors or their pharmaceutically acceptable derivatives, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF, include, but without limiting the above, those compounds which are disclosed in U.S. patentsâ„–5508272, 5362727, 5366973, 5225401, 4722810, 5223516, 5552397, 4749688, 5504080, 5612359, 5525723, 5430145 and 5679671 and in European patent applications 0481522, 0534263, 0534396, 0534492 and 0671172.

Preferred NEP/ACE inhibitors for use in this invention are those listed as preferred in the above U.S. patents and European patent applications and are included as references. Especially preferred is a NEP/ACE-inhibitor omapatrilat (disclosed in U.S. patent No. 5508272) or MDL100240 (disclosed in U.S. patent No. 5430145).

Inhibitors of renin or their pharmaceutically acceptable derivatives, including active metabolites, which can be used for the prevention of stroke, diabetes and/or CHF, include, but without limiting the above, the following connections: Anacreon, RO 42-5892, 65317, WED 80794, ES 1005, ES 8891, SQ 34017, CGP 29287, CGP 38560, SR 43845, U-71038, A 62198 and 64662.

Pharmaceutical

In one aspect this invention relates to pharmaceutical preparations, containing as active ingredient an inhibitor of RAS or the pharmacist who Cesky acceptable derivative or prodrug, including metabolites, for use for the prevention of stroke, diabetes and/or congestive heart failure (CHF).

For clinical application of the RAS inhibitor is administered in a pharmaceutical composition for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, cheek, rectal, parenteral or any other way of introduction. The pharmaceutical preparation may contain the inhibitor in a mixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.

When the pharmaceutical preparation of the present invention the active ingredient may be mixed with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with dezinfeciruyuhimi agents and lubricating agents such as magnesium stearate, calcium stearate, sodium fumarate and waxes based on polyethylene glycol. The mixture can then be processed into granules or compressed into tablets.

The active ingredient may be separately pre-mixed with other inactive ingredients before mixing to prepare the drug.

Soft gelatin capsules can be obtained with capsules containing a mixture of Akti the aqueous ingredient according to the invention, vegetable oil, fat, or other suitable media for soft gelatin capsules. Hard gelatin capsules may contain granules of the active ingredients. Hard gelatin capsules may contain the active ingredients in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

The standard dose for rectal injection can be prepared (i) in the form of suppositories which contain the active substance is mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable media for gelatin rectal capsules; (iii) in the form of ready-to-use micro or (iv) in the form of a dry preparation for micro, which must be recovered in a suitable solvent just before the introduction.

Liquid preparations can be prepared in the form of syrups or suspensions, for example solutions or suspensions containing the active ingredients and the rest, consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations which may contain dyes, the corrigentov, preservatives, saccharin and carboxymethyl cellulose or other thickeners. Liquid preparations can also be prepared in the form of a dry powder to restore a suitable solvent before use.

Solutions for parenteral administration can be prepared as a solution of the drug according to the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffer ingredients. Solutions for parenteral administration can be prepared as a dry product for restore suitable solvent before use.

The total amount of the active ingredient is in the range from about 0.1% (wt./wt.) to about 95% (wt./wt.) drug, acceptable from 0.5% to 50% (wt./wt.) and preferably from 1% to 25% (wt./wt.).

The pharmaceutical preparations can contain between about 0.1 mg and about 1000 mg of active ingredient, preferably between 1 mg and 100 mg of the active ingredient.

The dose of the active ingredient for administration will depend on the indication, age, weight and sex of the patient and can be determined by the attending physician. The dose will be from about 0.01 mg/kg to about 20 mg/kg, preferably between 0.1 mg/kg and 10 mg/kg

A typical daily dose of the active ingredients varies over a wide range and will depend on various factors, such as indication, route of administration, age, weight and sex of the patient, and may be determined by the attending physician. Typically, doses and especially doses for oral and parenteral administration will be in the range from about 0.1 to about 100 mg of active ingredient per day, preferably between 1 and 50 mg of active ingredient per day.

The following example is intended to illustrate but not to limit the scope of the invention.

Example

Large-scale clinical trial was designed to study the effect of the ACE inhibitor ramipril versus placebo in reducing cardiovascular cases.

The study was conducted in 267 centers in 19 countries in the six-year period and covered 9541 party of those who were at high risk of cardiovascular cases due to the prior history of coronary heart disease, stroke, peripheral arterial disease, or individuals with diabetes.

Systolic blood pressure in the inclusion of patients in the trial had, on average, 138 mm Hg and, therefore, patients were normotensive at baseline. After one month of therapy either ramipril or placebo, systolic blood pressure decreased by 5.48 mm Hg and 1.59 mm Hg, respectively.

The main end of the study were myocardial infarction (MI), UDA and from cardiovascular disease (CV) death (mortality).

The study was terminated prematurely due to the apparent reduction in overall mortality from cardiovascular diseases, heart attacks and strokes in patients taking ramipril. In addition to these advantages also observed reduction reduce the need for revascularization procedures (such as surgery coronary bypass surgery, angioplasty using balloon and the like) and diabetic complications in every fourth or fifth of patients.

In the ramipril group was explicit 32%reduction in the number of patients who developed hit, and this is surprising because patients were normotensive, when they began the study.

The number of patients who developed CHF was reduced by 21% in the ramipril group, which is unexpected, because the patients had no signs or symptoms of CHF at the beginning of the study.

Also amazing is significant 36%reduction in the number of patients in the ramipril group who had developed diabetes.

REDUCTION

ACE = angiotensin-converting enzyme

AT II = receptor type 1 angiotensin II

CHF = congestive heart failure

IDMM = insulin-dependent diabetes mellitus

JNC = joint national Committee

MI = myocardial infarction

NIDDM = non-insulin dependent diabetes mellitus

WHO = world Organization of ZV is amokrane

1. The use of angiotensin-converting enzyme (ACE) or its pharmaceutically acceptable salt for the manufacture of a medicinal product for preventing or reducing the risk of stroke in a patient who has essentially supported the function of the heart, and the patient is at high risk of cardiovascular attack due to the previous history of coronary disease, stroke or peripheral arterial disease.

2. The use of angiotensin-converting enzyme (ACE) or its pharmaceutically acceptable salt for the manufacture of drugs to prevent or reduce the risk of diabetes in patients at high risk of cardiovascular attack due to previous history of coronary heart disease, stroke or peripheral arterial disease.

3. The use of angiotensin-converting enzyme (ACE) or its pharmaceutically acceptable salt for the manufacture of a medicinal product for preventing or reducing the risk of congestive heart failure (CHF) in a patient who previously had no CHF and which has essentially supported the function of the heart, where the patient is at high risk of cardiovascular attack due to a history of previous coronary heart disease, stroke or peripheral Arte the territorial sickness.

4. The use according to any one of claims 1 to 3, characterized in that the patient has normal or low blood pressure.

5. The use according to any one of claims 1 to 3, characterized in that the patient suffers from diabetes.

6. The use according to any one of claims 1 to 5, where the inhibitor of angiotensin-converting enzyme or its pharmaceutically acceptable salt selected from the group consisting of alacepril, altropane, altiopia calcium, uncovering, benazepril, hydrochloride benazepril, benazeprilat, benzoylchloride, captopril, captopril-cysteine, captopril-glutathione, ceronapril, ceronapril, ceronapril, cilazapril, zilazaprilata, delapril, dilapidation, enalapril, enalaprilat, enapril, epicopal, proximity, fosinopril, fosinopril, fosinopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilat acid, glicorisa, Georgina-4, drapela, imidapril, indrapala, Indraprastha, obenzaprine, lisinopril, lelumena And lelumena In, exanple, moeksiprila, moeksiprilat, Multiprise, muraina And, Murzina, muraina With, pentopril, perindopril, perindoprilat, pivaloyl, piophila, inapril, hydrochloride inapril, chinabrief, ramipril, ramiprilata, inhibitor spirapril, inhibitor spirapril hydrochloride, spirapril, spirapril, hydrochloride of spirapril, temocapril, hydrochloride t is makapela, teprotide, trandolapril, trandolaprilat, utibapril, tabelbala, Zubizarreta, zofenopril and zofenoprilat.

7. The use according to claim 6, where the inhibitor of angiotensin-converting enzyme selected from the group consisting of ramipril, ramiprilata, lisinopril, enalapril and enalaprilat.

8. The use according to claim 1, where the inhibitor of angiotensin-converting enzyme is ramipril or ramiprilat.

9. The way to prevent stroke, involving the introduction of a therapeutically effective amount of angiotensin-converting enzyme (ACE) or its pharmaceutically acceptable salt to a patient that has, in essence, support the function of the heart and are at high risk of cardiovascular attack due to the previous history of coronary disease, stroke or peripheral arterial disease.

10. The way to prevent punch according to claim 9, characterized in that the patient has normal or low blood pressure.

11. The way to prevent diabetes, including the introduction of a therapeutically effective amount of angiotensin-converting enzyme or its pharmaceutically acceptable salt to a patient that has, in essence, support the function of the heart and are at high risk of cardiovascular attack due to the previous history of coronary disease, stroke isopreference arterial disease.

12. The way to prevent the development of CHF in patients who previously had no CHF, including the introduction of a therapeutically effective amount of angiotensin-converting enzyme or its pharmaceutically acceptable salt to a patient that has, in essence, support the function of the heart, and the patient is at high risk of cardiovascular attack due to the previous history of coronary disease, stroke or peripheral arterial disease.

13. The method according to any of PP-12, in which the ACE inhibitor or its pharmaceutically acceptable salt selected from the group consisting of alacepril, altropane, altiopia calcium, uncovering, benazepril, hydrochloride benazepril, benazeprilat, benzoylchloride, captopril, captopril-cysteine, captopril-glutathione, ceronapril, ceronapril, ceronapril, cilazapril, zilazaprilata, delapril, dilapidation, enalapril, enalaprilat, enapril, epicopal, proximity, fosinopril, fosinopril, fosinopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilat acid, glicorisa, Georgina-4, drapela, imidapril, indrapala, Indraprastha, obenzaprine, lisinopril, lelumena And lelumena In, exanple, moeksiprila, moeksiprilat, Multiprise, muraina And, Murzina, muraina With, pentopril, perindopril, p is endopilot, pivaloyl, piophila, inapril, hydrochloride inapril, chinabrief, ramipril, ramiprilata, inhibitor spirapril, inhibitor spirapril hydrochloride, spirapril, spirapril, hydrochloride of spirapril, temocapril, hydrochloride of temocapril, teprotide, trandolapril, trandolaprilat, utibapril, tabelbala, Zubizarreta, zofenopril and zofenoprilat.

14. The way to prevent in item 13, in which the ACE inhibitor is selected from the group consisting of ramipril, ramiprilata, lisinopril, enalapril and enalaprilat.

15. The way to prevent in item 13, in which the ACE inhibitor is ramipril or ramiprilat.

16. Pharmaceutical formulation for use for the prevention of stroke, diabetes and/or CHF in a patient who has essentially supported the function of the heart and are at high risk of cardiovascular attack due to the previous history of coronary disease, stroke or peripheral arterial disease, containing a therapeutically effective amount of an ACE inhibitor or its pharmaceutically acceptable salt.

17. The pharmaceutical preparation according to item 16, in which the ACE inhibitor is selected from the group consisting of ramipril, ramiprilata, lisinopril, enalapril and enalaprilat.

18. The pharmaceutical preparation according to any one of p and 17 in a mixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier

19. The pharmaceutical preparation according to any one of p-18 in the form of a standard dosage forms.



 

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7 cl, 11 tbl, 18 ex, 5 dwg

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for treatment of diseases, associated with alterations of blood extracellular DNA, such as generalized infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. Method includes administering of blood extracellular DNA destroying agent into blood. As such agent DNAase is used, in particular in doses providing alteration of electrophoretic profile of blood extracellular DNA, detectable by pulse gel electrophoresis. DNAase may be administrated in doses and regimes providing exceeded levels of blood plasma DNA-hydrolytic activity, namely 150 Kuntz/l of plasma, during 12 h/day in total.

EFFECT: effective method for treatment of abovementioned diseases without side effects.

4 cl, 14 tbl, 15 ex, 5 dwg

FIELD: medicine, cardiology.

SUBSTANCE: the complex of medicinal therapy includes nibentane to be injected at the dosage of 0.125 mg/kg intravenously. Moreover, one should pre-inject magnesium sulfate solution at the dosage of 2.5 g about 10-15 min before nibentane injection. The innovation provides quick restoration of sinus rhythm in case of no therapeutic complications observed.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, medicine, cardiology, biochemistry.

SUBSTANCE: invention relates to benzoyl guanidines of the formula (I): wherein R1 means -CF3; R2 means -Y-para-(C6H4)-R11, -Y-meta-(C6H4)-R11 or -Y-ortho-(C6H4)-R11 wherein R11 means (C1-C9)-heteroaryl comprising two or more nitrogen atoms adjoining across nitrogen (N) atom; Y means oxygen atom; R3 means hydrogen atom; R4 means (C1-C4)-alkyl, and to their pharmaceutically acceptable salts. Indicated compounds elicit very high activity with respect to inhibition of Na+/H+ exchange and improved water solubility and therefore they can be used as anti-arrhythmic medicinal agents with cardioprotective component for prophylaxis of infarction and treatment of infarction and for treatment of stenocardia. Also, proposed compounds inhibit pathophysiological processes in arising disorders induced by ischemia, in particular, in treatment of cardiac arrhythmia induced by ischemia.

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

17 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves applying intracoronary phosphocreatine introduction into infarction-responsible artery when carrying out coronary angioplasty. Phosphocreatine solution is injected after reperfusing the infarction-responsible artery at constant volume rate of 0.1-4 ml/s with introduced phosphocreatine dose being equal to 0.5-4 g.

EFFECT: reduced myocardium necrosis zone; prevented cardiac insufficiency and cardiac rhythm disorders.

4 cl

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

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: method involves administration of amlodipine in the dose 5 mg, once in the same time and metformin in the dose 500 mg, 2 times per 24 h in patients at the background of individually selected hypocaloric diet. Treatment is carried out for 8 weeks, not less. Method provides optimization of intravascular activity of platelets due to correction of primary homeostasis and the level of their antioxidant protection. Invention can be used for rapid optimization of functions of platelets at metabolic syndrome.

EFFECT: improved and enhanced method for optimization.

2 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to new derivatives of acylphenylurea of the formula (I) and to their physiologically acceptable salts possessing property of glycogen phosphorylase inhibitors. In compound of the formula (I) A means phenyl and phenyl residue can be substituted three times with fluorine (F), chlorine (Cl), bromine (Br) atoms, -CF3, -NO2, -O-(C1-C6)-alkyl, -SO2-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R1 means hydrogen atom (H), (C1-C6)-alkyl; R2 means H, (C1-C6(-alkyl, -CO-(C1-C6)-alkyl; 3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -O(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, -COOH, -COO-(C1-C6)-alkyl; X means oxygen (O), sulfur (S) atom; R7 means (C1-C10)-alkylene-COOH, (C1-C10)-alkylene-COO-(C1-C6)-alkyl, (C1-C10)-alkylene-NH2, (C1-C10)-alkylene-NH-(C1-C6)-alkyl, (C1-C10)-alkylene-N-[(C1-C6)-alkyl]2, (C1-C10)-alkylene-B wherein B means piperidinyl or furyl. Also, invention relates to a pharmaceutical composition and a method for preparing the pharmaceutical composition. Proposed compounds can be used for preparing pharmaceutical composition useful for declining level of blood glucose and for treatment of diabetes mellitus type II.

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

7 cl, 2 sch, 2 tbl, 1 ex

FIELD: medicine, endocrinology.

SUBSTANCE: treatment involves prescription to patient light water as drinking water with the total mineralization 200-500 mg/l, the deuterium content 100 ppm, not above, and the oxygen-18 content 1800 ppm, not above, on the background of dietetic therapy and insulin therapy or intake of hypoglycemic preparations in the daily dose 1000-1500 ml. The first intake is carried out before eating in the morning in the dose 200-250 ml and the remaining amount for a day, 30-40 min before eating or in breaks of eating every day. The curative course is from 28 to 45 days. Method provides declining the blood glucose content and to improve metabolic processes.

EFFECT: improved treatment method.

2 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to O-arylglucoside inhibitors of SGLT2 of the formula (I): wherein Y means compounds of formulae: A means -O(CH2)m, sulfur atom (S), -NH(CH2)m or -(CH2)n wherein n = 0-3; m = 0-2; R1-R6 are determined above, and to a pharmaceutical composition based on thereof, and to methods for treatment of diabetes mellitus type 2, and micro- and macrovascular diabetic complications.

EFFECT: valuable medicinal properties of inhibitors.

15 cl, 1 tbl, 99 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for prophylaxis of oncological diseases, or infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. In the first embodiment of invention blood extracellular DNA destroying agent, such as DNAase, is administered into blood. In the second embodiment agent, binding to blood extracellular DNA, such as anti-DNA antibody is administered into blood. According to the third embodiment enzyme altering of blood extracellular DNA chemical structure is administered into blood. According to the forth embodiment agent, stimulating synthesis and/or activity of endogenic deoxyribonuclease or agent stimulating synthesis of antibody binding to blood extracellular DNA are administered into blood.

EFFECT: effective method for treatment of abovementioned diseases without side effects when prolonged using of preparation affected on blood extracellular DNA.

7 cl, 11 tbl, 18 ex, 5 dwg

FIELD: medicine and veterinary.

SUBSTANCE: invention relates to method for treatment of diseases, associated with alterations of blood extracellular DNA, such as generalized infections mordibidized by bacteria or fungi and protozoa, or arteriosclerosis, or diabetes mellitus, or diseases mediated by delayed hyperresponsiveness reaction, or diseases mediated by somatic cell gene mutations. Method includes administering of blood extracellular DNA destroying agent into blood. As such agent DNAase is used, in particular in doses providing alteration of electrophoretic profile of blood extracellular DNA, detectable by pulse gel electrophoresis. DNAase may be administrated in doses and regimes providing exceeded levels of blood plasma DNA-hydrolytic activity, namely 150 Kuntz/l of plasma, during 12 h/day in total.

EFFECT: effective method for treatment of abovementioned diseases without side effects.

4 cl, 14 tbl, 15 ex, 5 dwg

FIELD: medicine.

SUBSTANCE: one should apply anticonvulsive derivatives in mammalians such as topiramate for preventing the development of non-insulin dependent diabetes mellitus and syndrome X, treating and preventing skin diseases associated with these diseases. The innovation suggested enables to prevent increased blood levels of glucose, triglycerides and insulin despite patient's body weight and, thus, avoid the development of the above-mentioned states.

EFFECT: higher efficiency of prophylaxis.

19 cl, 5 ex, 11 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to derivatives of dihydronaphthalene represented by the formula (I):

wherein radical values are determined in the description and to its nontoxic salts. The proposed compound is a regulator of receptors activated by a peroxisome proliferator (PPAR) of α- and γ-type. The agent can be useful as a hypoglycemic agent, hypolipidemic agent, agent for prophylaxis and/or treatment of diseases associated with metabolic disturbances, agent increasing the content of HDL-cholesterol and reducing the content of LDL-cholesterol and/or VLDL-cholesterol and agent for weakening diabetes mellitus factor risk, and/or X-syndrome. Also, invention claims derivative of dihydronaphthalene representing 3-{5-{2-[2-(4-methylphenyl)-5-methyloxazol-4-yl]ethoxy}-3,4-dihydronaphthalen-1-yl}propanoic acid.

EFFECT: valuable medicinal properties of compounds and agent.

21 cl, 15 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: method involves administering pancreatine and/or a digestive enzyme mixture acting like pancreatine, in addition to insulin therapy. The remedy is introduced at a dose of 40000 lipase units when eating and 20000 lipase units between food intakes. Enzyme treatment is carried out on the background of patient fecal elastase-1 level not exceeding 100 mcg/g of patient stool.

EFFECT: enhanced effectiveness of glycemia control.

4 cl, 5 tbl

FIELD: medicine.

SUBSTANCE: method involves introducing solutions into articulation to inhibit cartilage destruction. The solutions contain: (a) therapeutically effective amount of anabolic chondroprotective agent selected from a group composed of interleukine antagonists stimulating anabolic processes in cartilage, members of superfamily transforming growth β-factor including TGF-β agonists and agonists of morphogenous bone proteins stimulating anabolic processes in cartilage, insulin-like fibroblast growth factors stimulating anabolic processes in cartilage; (b) therapeutically effective amount of a cartilage catabolism inhibitor selected from a group composed of antagonists of interleukine-1-receptors, antagonists of TGF-α-receptors, specific cyclo-oxygenase-2 inhibitors, nitrogen oxide synthase inhibitors, nuclear kB factor inhibitors, matrix metalloproteinase inhibitors, cell adhesion molecules including integrin agonists and integrin antagonists, anti-chemotaxis agents, intracellular signal transmission inhibitors including protein kinase C inhibitors and tyrosine protein kinase inhibitors, intracellular (protein-tyrosine)-phosphatases and SH2-domain inhibitors inhibiting cartilage catabolism. The solution is locally supplied.

EFFECT: stimulated integration and modulation of anti-inflammatory synoviocyte and chondrocyte responses.

54 cl, 9 dwg, 30 tbl

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