Method of treating patients suffering chronic cardiac failure compromised type 2 diabetes
SUBSTANCE: invention refers to medicine, namely to cardiology and endocrinology, and concerns treating the patients with chronic cardiac failure compromised by type 2 diabetes. That is ensured by the additional introduction of the selective β1 adrenoceptor antagonist nebivolol in a single dose 5-7.5 mg/day within 12 months with underlying ACE inhibitor and diuretic therapy in the patients with a higher level of basal glycemia by more than 4.5 mmol/l and preserved LVEF by more than 52 %.
EFFECT: method provides effective treatment in the given group of patients due to ability of nebivolol to improve nitrogen oxide synthesis by a vascular endothelium and to provide normalising haemodynamic, metabolic, anti-ischemic and immune-correcting action.
1 ex, 3 tbl
The invention relates to medicine and can be used in cardiology, endocrinology, rehabilitation, transplantation for the treatment of chronic heart failure (CHF), aggravated diabetes mellitus (DM) type 2.
There is a method of treatment of chronic heart failure in patients without disorders of carbohydrate metabolism in which for the treatment of comorbidity to reduce the side effects of therapy using β-blocker, a diuretic and an ACE inhibitor, titrated to maximum tolerated doses .
This method is the closest to the claimed technical essence and the achieved clinical results and selected as a prototype. Proposed therapy provides an implementation of the complex effects of antianginal, anti-ischemic and hemodynamic.
The disadvantage of this method is that in patients with chronic heart failure, aggravated diabetes mellitus type 2, it does not give influence on the major pathogenetic mechanisms of chronic heart failure (neuroendocrine and immune activation, nonspecific inflammation), which are weakly enforced traditionally conservative therapy [2-5].
The task of the invention is to improve the efficiency of the method of treatment of chronic heart failure associated with type 2 diabetes.
The problem is solved the way the medical treatment of patients with CHF FC I-III according to NYHA, associated with type 2 diabetes (with elevated basal glucose 4.5 mmol/l and LV EF 52%), new superselective β1-the blocker nebivolol (firm "BERLIN-CHENIE AG/MENARINI GROUP, Germany), titrated, starting with a dose of 5 mg/day. to 7.5 mg/day.(average dose of 6.25±1.25 mg/day.) once within 12 months on therapy with ACE inhibitors and diuretics.
New in the proposed method is the assignment in complex therapy of chronic heart failure, burdened with type 2 diabetes, high selective β1-blocker III generation of nebivolol, modulating vascular endothelial synthesis of nitric oxide (NO) and causes endothelium-dependent vasodilation, which leads to the realization antiatherogenic, hemodynamic, metabolic, anti-ischemic and immunokorrektiruyuschie effects of the drug that is prescribed only to patients with elevated basal glucose 4.5 mmol/l and preserved LVEF more than 52%at a dose of 5-7 .5 mg/day, once daily for 12 months.
The proposed method of treatment of chronic heart failure associated with type 2 diabetes, using nebivolol based on the fact that it is based on the impact on the main pathological mechanism HSN - remodeling of the myocardium by improving the system and intracardiac hemodynamics, increased ejection fraction, reduced post - and preload. Remodeling of the myocardium JW is aetsa not only a result of scarring after transferred, but the consequence of neurohormonal activation and systemic inflammatory process, characterized by apoptosis of smooth muscle cells, hypertrophy of the walls of the heart, hyperplasia and activation of fibroblasts, diffuse interstitial fibrosis of the tissues of the myocardium. The rate of progression of CKD largely determines hyperactivation RAAS (hypercoagulability), and it induced toxic effects on cardiomyocytes (CMC), the development of T-cell suppression, cytokine activation and hyperproduce immune complexes makes theoretically justified the use in the treatment of CHF blockade of β-adrenergic receptors. The presence of additional effects - normalize the sensitivity of peripheral tissues of patients with diabetes to insulin due to specific NO-modulating effect provides for nebivolol its neutrality in respect of carbohydrate and fat metabolism, and its ability to endothelial and peripheral vasodilation underlies the reduction of the severity of tissue injury and disorders of microcirculation, reduce blood triglycerides, improve the quality of life and survival in patients with diabetes , which makes use of nebivolol attractive and reasonable.
Therefore, an additional purpose of superselective β1-blocker (NO-adjuvant action is) nebivolol for primary therapy of chronic heart failure II-IV according to NYHA FC, including ACE inhibitors and diuretics, it allows to approach the solution of the following tasks:
- build new (more effective and safe approaches to diagnosis, prevention and treatment of severe, including asthma, chronic heart failure due to implementation: 1) myocardial protection against the toxic effects of high levels of catecholamines in the blood, reduce death CMC (path necrosis and apoptosis); 2) anti-ischemic actions - improve both systolic and diastolic LV function; 3) antiarrhythmic actions - increase threshold for the development of ventricular fibrillation, the reduction of the electrical instability of the myocardium, which leads to reducing the risk of sudden death; 4) ensure recovery of sensitivity CMC to β-stimulation due to the increase in their surface density of β-receptors; 5) reduce fibrosis of the myocardium and degradation of the collagen matrix; 6) reduce damage to the endothelium under the influence of stress hemodynamic effects and increased production of prostacyclin, reduce the adhesion of platelets to the endothelium of arteries and binding of LDL to proteoglycans vascular wall .
to ensure stabilization and reverse the development of LV remodeling on the background of chronic heart failure, including after a previous Q-wave myocardial infarction;
- optimize modern effective ways medicamentos the treatment, aimed at improving the quality of life and improve survival of patients with chronic heart failure, aggravated diabetes mellitus type 2.
Distinctive features showed in the inventive combination of new properties that are not explicitly derived from the prior art in this field and not obvious to the expert. Identical set of features analyzed in the literature were not found. The present invention can be used in health care.
Based on the foregoing, it should be considered an invention relevant to the patentability of "Novelty", "Inventive step", "Industrial applicability".
The method is as follows:
Examined 30 patients with CHF FC I-III according to NYHA and type 2 diabetes mild and moderate severity (n=30) at the age of 54.1±5,6 with elevated basal glycemia (>4.5 mmol/l) and preserved LV EF (>52%). Before inclusion in the study were prescribed therapy, which included ACE, diuretics, hypoglycemic agents. The hospital was appointed an additional nebivolol (firm "BERLIN-CHENIE AG/MENARINI GROUP, Germany), titrated, starting with a dose of 5 mg/day. to 7.5 mg/day. (average dose of 6.25±1.25 mg/day.) once within 12 months. All patients endocrinologist picked up an adequate individualized hypoglycemic therapy (drugs of the group is sulfanilamide: diabecon-MV 1 so or maninil at a dose of 1.75 to 5 mg, biguanides: siofor 500-100 mg). Assessment criteria good antiischemic and hemodynamic effects considered: regression of CHF symptoms, reduce the frequency and severity of angina, lower daily requirement of nitrates, increase physical tolerance of at least 10%, maintaining stable blood, in the absence of deterioration of the metabolic condition, and without any obvious allergic or worsening of immune disorders.
To assess the studied parameters were collected blood from the cubital vein on an empty stomach a glass tube containing 70-100 IU of heparin in the amount of 7-10 ml of blood, carefully mixing in order to prevent the formation of clots. Determination of glucose in capillary fasting blood produced at the beginning and at the end of the study enzymatic (glucose oxydase) method on the automated analyzer "Biosen 5030" (Germany). Definition HbA1 conducted at the beginning and at the end of the study on the automated analyzer "Glycomat DS-5 (UK) using the reagents of the firm "HUMAN" (Germany) and with the use of control material HbA1 Control Kit Level 1 and HbA1 Control Kit Level 2. For the separation of hemoglobin and its derivatives "Glycomat DS-5" used cation-exchange chromatography of low pressure. Haemoglobin fractions were detected photometricinterpretation detector at a wavelength of 415 nm. Whole blood prior to analysis pre demolishable. Blood lipid profile was determined at the beginning and at the end of the study on the automated analyzer "Synchron CX-7" firm "Beckman (USA) using reagents firm "HUMAN" (Germany). The lipid parameters were evaluated in accordance with the recommendations of GFCF, 2004, the Contents of the CEC in the serum was determined by a standard method in the test with complement . Determination of IG in serum was performed by radial immunodiffusion in gel according to Mancini . Determination of Auto-antibodies to CL was performed using enzyme-linked immunosorbent assay (ELISA) on a standard dice on a technique "Biohimik". The optical density was determined on spectrophotometer Reader Pasteur LP-400", wavelength 450 nm, the results of which were built calibration curve . Studies of the content of cytokines in serum was performed by the method of solid-phase ELISA system bideterminant determine the antigen with the use of horseradish peroxidase as indicator enzyme . To determine the concentrations of IL-1α, IL-2, IL-6, IL-8, TNF-α, if α used test systems produced by LLC "Cytokine" (Saint-Petersburg) with the threshold for IL-1α-5 PG/ml, IL-2, IL-6, IL-8 to 10 PG/ml, TNF-α 20 ng/ml, IGF-α - 10 PG/ml, IGF-β - 10 PCs/ml Optical density was determined on spectrophotometer Reader Paster LP-400" (the length in the wave 450 nm), the results of which were built calibration curve .
Statistical analysis of the received digital data was performed using STATISTICA 6.
Source according to the ECHO KG, against the background of diastolic dysfunction of the left ventricle was increased CSR LV (table 1). After 6 and 12 months of taking nebivolol was observed a significant reduction in the CSR LV (16.2%)actually state was normalized diastolic LV function: peak E/A has reached 1±0,2, an increase of 25% (p=0,05-0,01).
Analysis of the lipid spectrum of blood serum in patients source revealed a clear manifestation of atherogenic dyslipidemia (table 2). Course therapy with nebivolol provided positive dynamics of lipid and carbohydrate metabolism: total cholesterol after 6 and 12 months of taking nebivolol decreased by 9.5% and 14.3% (p=0.05). The decrease statistically significantly elevated in comparison with donors TG and LDL (p=0.05) at 12 months occurred in 17.4% and 18.4% respectively. The atherogenic index decreased 23.2% after 6 months (p=0.001) and 43.5% through 12 months (p=0.001)compared with baseline in the group, and by the end of treatment was 3.9 $
The original was statistically significant (in comparison with donors) increased basal glycemia (p=0.001) after 6 and 12 months of taking nebivolol decreased by 8.7% and 10.9%, respectively, and reached by the end of the follow - up of 8.2±0.8 mmol/l (p=0.001), postprandial g is ikemiya (p=0.001) - 11.3% after 6 months and 13.2% in 12 months, amounting to 9.2±0.9 mmol/l, Hb levels in Als (p=0.05) by the end of therapy decreased by 4.8%.
Changes of humoral immunity in a dynamic 12-month observation are presented in table 3. Compared with a group of donors source revealed a pronounced increase in the content of IgA (p=0.001), AutoIt to CL (p=0.001). By the end of the annual treatment with nebivolol any decreased significantly - by 39.7% (p=0.001) and 10% respectively.
Initial level of cytokines in blood were statistically significantly increased in comparison with the group of donors (p=0,05-0,001). The emerging decline to 6-month course of therapy with nebivolol content of cytokines at the end of the 12-month observation was greatest in relation to IL-1α (29.2%), IL-6 (32%), IL-8 (25%), TNF-α (23%).
Thus, it is established that superselective β1-adrenergic new generation with additional No-modulating effect of nebivolol is well tolerated by patients of IHD with type 2 diabetes (mild or moderate severity, with long-term (12 months) course therapy prevents and hemodynamic ischemic cardiac remodeling and improves the metabolic profile and provides the immunosuppressive effects by reducing cytokine activation. Any negative immune, coronarienne or hemodynamic effects set the e was.
EXAMPLE: Patient W, 57 years. Pensioner. Admitted with complaints of shortness of breath when climbing to the 3rd floor, while walking at 400-500 m, the AD up to 160/90 mm RT. Art., constricting pain in the chest with irradiation to the left hand, occur with little exertion, intractable nitroglycerin under the tongue (need up to 5 tablets/day). Suffering from diabetes for 8 years. Before admission to the hospital took aspirin, gipotiazid, Enap, monocycle-retard, sublingual nitroglycerin in angina pain, diabeton.
Clinical diagnosis: ischemic heart disease. Angina II FC. Postinfarction (1996) cardiosclerosis. Atherosclerosis of the aorta. Arterial hypertension stage III, II degree increase AD risk 4. NC 1 tbsp., II class according to NYHA. Diabetes mellitus type II, moderate severity, compensation.
ECG: sinus Rhythm right, 72/min Deviation e. axis of the heart to the left. Ischemia of the anterior-septal-apical region and the lateral wall of the left ventricle.
In hospital to previously accept added nebilet 5 mg 1 time per day.
The dynamics of clinical and laboratory parameters of the patient ø:
|Indicators||Source||After 6 months.||After 12 months.|
|The BPA rest, mm RT. Art.||160||130||130|
|Add rest, mm RT. Art.||90||90||80|
|The thickness Skid, mm||1,0||1,2||1,1|
|The thickness Mgpd, mm||1,1||1,2||1,0|
|Peak E, m/s||0,6||0,7||0,7|
|Peak And m/s||0,8||0,8||0,8|
Dynamics of immunological indexes of the patient ø:
|Indicators||Source||After 6 months||Δ source / 6 months.||After 12 months.||Δ 6 months. / 12 months.|
|Ig A, g/l||5,9||5,5||-6,78||3,4||-38,18|
|The CEC of 4.17%, cu||62||76||+22,58||66||-13,16|
|AutoIt to CL, honey/ml||41||34||-17||29||-14,17|
By the end of 6 months. therapy nebilet significant increase TFN (up to 150 W), ischemia angina pain to 1-2 attacks and daily needs for nitroglycerin to 0-2 tab./day. Heart rate 60/min Objectively the patient felt satisfactory. Improved exercise tolerance, stabilized HELL, correction dose of nebivolol was not required.
Thus, in CKD patients, burdened with type 2 diabetes, the clinical effect of treatment with nebivolol was shown by regression of the symptoms of chronic heart failure, to reduce the severity of FC HSN, reducing the frequency and severity of angina and the need for nitroglycerin, the improvement of physical tolerance, stabilization of blood pressure and intracardiac hemodynamics. The drug is well tolerated by patients with long-term therapy, preventing and hemodynamic ischemic cardiac remodeling and improving metabolic and cytokine profile.
The proposed method is applied in 30 patients and improves the efficiency of treatment of patients with chronic heart failure associated with diabetes mellitus type 2.
Sources of information
1. Maliszewski M.V., Smurov VA, Klevtsova T., Sokolov, S. and others : the b treatment of patients with chronic heart failure on the background of coronary heart disease. Patent RU 2213559 C2, 10.10.2003.
2. Albanska LI Metabolic syndrome in patients with chronic heart failure: approaches to treatment. Heart failure, 2003: 1(17), 4.:12-14.
3. Sliver V.B. have been, Yeshatova. Diabetes mellitus type 2 and hypertension. Heart 2004; 1(13):13-16.
4. Nasonov EL Immunopathology of congestive heart failure: role of cytokines. Elenasnow, Musasino, Unibanco, DI Fuchs. Cardiology, 1999: 3; 66-73.
5. Nagornov, VA, zhota Mrs x, cytokines, immune inflammation and atherosclerosis. The successes of modern biology, 1996; 111:48-59.
6. The Roytberg G. Metabolic syndrome. M: Medpress-inform, 2007: S.
7. Karpov Y.A., Shubin A.T. the Use of β-blockers in the treatment of patients with arterial hypertension: new opportunities and prospects. Russian medical journal, 2005; No. 19. So 13: 1265-1268.
8. Khaitov R.M P.M., Pinegin B.V., Islamov HI Ecological immunology. Rmitv. - M.: VNIRO, 1995. - 218 S.
|The influence of 6-, 12-month nebivolol on hemodynamics in patients with ischemic heart disease with type 2 diabetes (M±m)|
|Index||Source (n=30)||p||After 6 months (n=24)||12 months (n=16)||p||Δ% 6 months/ 12 months||The donor group (n=20)|
|The LV EDV, ml||122±5,5||nd||126±3,7||nd||118±4,1||nd||+3.3V/-3,3||118±11|
|CSR LV, ml||68±6,6||P1=0,005||57±2,3||R 1=0,05||56±3,1||P1=0,05||-16,2/-17,6||42±5,7|
|Mm index, g/m2||144±8,1||nd||137±5,5||nd||128±6,3||nd||-4,9/-11,1|
|The influence of 6-, 12 - month therapy with nebivolol on the dynamics of lipid and carbohydrate metabolism in patients with ischemic heart disease with type 2 diabetes (M±m)|
|Index||Source (n=30)||p||After 6 months||p||After 12 months||p||Δ% 6 months. / 12 months.||The donor group (n=20)|
|Total cholesterol, mmol/l||6,3±0,4||the 1=0,001||5,7±0,4||P1=0,005||5,4±0,5||nd||-9,5/-14,3||4,4±0,1|
|IA, USD||6,9±0,4||P1=0,001||5,3±0,4||P1=0,001; R2=0,01||3,9±0,5||P2=0,001||-23,2/-43,5||2,5±0,5|
|Postprandial glycemia, mmol/l||10,6±0,7||P1=0,001||9,4±1,1||nd||9,2±0,9||nd||or 11.3/-13,2||7,8±0,1|
|Hb A1 C %||8,4±1||P1=0,05||8,3±0,6||P1=0,001||8±0,6||R 1=0,005||-1,2/-4,8||6,1±0,1|
|Note: P1 - for comparison, in the group with donors; P2 - for comparison group before and after treatment; nd implausible differences|
|the influence of 6-, A 12 - month course of therapy with nebivolol on parameters of humoral immunity and cytokine status in patients with ischemic heart disease with CHF III-IV according to NYHA FC associated with diabetes mellitus type 2 (M±M)|
|Index||Source (n=30)||p||After 6 months (n=24)||p||12 months (n=16)||p||Δ% 6 months. / 12 months.||The donor group (n=20)|
|IgA, g/l||5,8±0,4||P1=0,001||3,8±0,4||P1=0,01; P2=0,001||3,5±0,2||P1=0,01; P2=0,001||-34,5/-39,7||2,0±0,5|
|CEC $||60±6,0||nd||64±5,8||nd||68±5,1||R 1=0,05||+6,7/++13||35±15|
Antibodies to CL, IU/ml
|IL-2, PCG/ml||88±4||P1=0,001||76±3,6||P1=0,001; R2=0,05||72±2,6||P1=0,005; p2-0,005||-13,6/-18,2||30±12|
|IL-8, PCG/ml||48±6||P1=0,01||38±2,6||P1=0,05||36±2,1||P1=0,05||20, 8C/-25||31±0,8|
|If α, PCG/ml||102±9||P1=0,01||93±2,7||nd||94±2,1||nd||-8,8/vs.-7.9bn||94±3,2|
|Note: P1 - for comparison, in the group with donors; P2 - for comparison group before and after treatment; nd - false distinction; the comparison group - a group of patients, per the carrying krupnooptovyj THEM older 6 months or more who to include in the study had no signs of heart failure and received basic antiischemic therapy without β-blockers, a group of donors - a group of practically healthy persons|
A method for the treatment of patients with chronic heart failure, aggravated diabetes mellitus type 2, including the appointment of β1-blockers, diuretics and ACE inhibitors, characterized in that as β-blocker prescribed nebivolol only patients with elevated basal glucose 4.5 mmol/l and preserved LVEF more than 52%at a dose of 5-7 .5 mg/day, once daily for 12 months.
SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),
(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.
EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.
7 cl, 19 tbl, 37 ex
SUBSTANCE: invention relates to field of medicine, namely, to therapy and cardiology, and deals with treatment of arterial hypertension. For this purpose into complex of conventional therapy additionally introduced is prostaglandin E2 in form of 0.0008% solution. Prostaglandin is introduced intravenously, starting with rate 50-100 ng/kg/min, increasing rate of introduction each 10 minutes on 20-40 ng/kg/min, bringing rate to 150-300 ng/kg/min during 40-60, minutes. Altogether there are three introductions per a course with 1-2 day intervals between them.
EFFECT: additional introduction of prostaglandin E2 in elaborated doses and regimen ensures efficient normalisation of arterial pressure during long term due to enhance of excretion of prostaglandins by kidneys, expressed vasodilation of vessels of kidneys, heart and brain, as well as normalisation of functional activity of platelets.
SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.
EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.
27 cl, 160 ex, 2 tbl
SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.
EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.
11 cl, 8 ex, 1 tbl
SUBSTANCE: compounds are suitable for use as kinase 1β-adrenergic receptor (βARK-1) inhibitors. The invention also relates to compositions containing such compounds and to use of compounds of formula to treat and prevent chronic heart failure, hypertension myocardial ischemia and hepatitis C viral infections (HCV) and for preventing opiate addiction. The invention also pertains to methods of producing formula (I) compounds.
EFFECT: more effective use of the compounds.
11 cl, 2 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.
EFFECT: production of the compounds for therapy of the disease which depends on renin activity.
28 cl, 1 tbl, 375 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: agent for treating systemic hypertension contains as an active ingredient a compound presented by formula (1): or its pharmaceutically acceptable salt.
EFFECT: preparation of the new agent for treating systemic hypertension.
12 cl, 7 ex, 7 dwg
SUBSTANCE: invention relates to novel compounds of general formula (I) , where the dotted line is either absent or denotes a double bond; R1 denotes H or C1-6-alkyl, possibly substituted with a CN group, or denotes a phenyl or sulphonyl phenyl, substituted with one or more B groups, or denotes -(CH2)m-Ra, where Ra denotes: NRiRii, C3-6-cycloalkyl, 6-member heterocycloalkyl, which denotes a univalent saturated group which contains one nitrogen heteroatom, the rest are carbon atoms, aryl, which can be substituted with one or more B groups, or denotes -(CH2)n-(CO)-Rb or -(CH2)n-(SO2)-Rb, where Rb denotes: NRiRii, 5-6-member heterocycloalkyl, which denotes a univalent saturated group containing one or more heteroatoms selected from nitrogen, oxygen, the rest are carbon atoms, aryl or 5- or 6-member heteroaryl, which denotes an aromatic ring containing two heteroatoms as ring members, the said heteroatoms selected from N or O, the rest are carbon atoms; which can possibly be substituted with one or more B groups, R2 denotes one or more H, halo, C1-6-alkyl, C1-6-alkoxy, R3 denotes H or-(CO)-Rc, where Rc denotes: C1-6-alkyl, 5-member heterocycloalkyl, which denotes a univalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms possibly substituted with C1-6-alkyl, or denotes C1-6-alkyl; R4 denotes H; R5 denotes H, C1-6-alkyl, -(CH2)m-NRiRii, -(CH2)n-(CO)-Rb, where Rb denotes NRiRii or a 6-member heterocycloalkyl which denotes a univalent saturated group which contains one nitrogen heteroatom, the rest are carbon atoms, when the dotted line is absent or is absent when the dotted line denotes a double bond; R6 is absent, when the dotted line denotes a double bond; R7 denotes Cl or NReRf, where Re and Rf denotes H or C1-6-alkyl, or Re and Rf together with the nitrogen atom to which they are bonded form a 6-member heterocycloalkyl which denotes a univalent saturated group containing one or two heteroatoms selected from nitrogen, oxygen, the rest are carbon atoms; which can be substituted with C1-6-alkyl, or R6 and R7 together form a C=O group, when the dotted line is absent; B denotes halogen, C1-6-alkoxy, (CRiiiRiv)n-phenyl; Ri and Rii denote H, C1-6-alkyl -C(O)-C1-6-alkyl; Riii and Riv denote C1-6-alkyl; m equals to 1 or 2, n equals 0 or 1; as well as to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, as well as to use of compounds of formula (I), (I-a) or (1-b).
EFFECT: obtaining novel biologically active compounds having activity on V1a receptor.
12 cl, 48 ex
SUBSTANCE: invention refers to medicine and concerns methods of treating diseases with using VEGF antagonists. Substance of the invention involves application of a VEGF antagonist containing VEGFR1R2-FcΔ C1 (a) SEQ ID NO:4 in preparing a drug for hypertension reduction, in treating the diseases associated with administering the VEGF antagonist where the treatment is conducted by subcutaneous introduction.
EFFECT: advantage of the invention consists in reducing side effects associated with treating the diseases by administering the VEGF antagonist.
8 cl, 3 ex, 1 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, namely to an agent exhibiting antihypertensive activity which represents 1-alkyl-2-alkylcarbamoylglycerins of general formula I . In formula I R means hydrocarbon radical -(CH2)nCH3 (n=10-18), R1 means methyl or ethyl. Also, the invention refers to a method for preparing the compounds of formula I. The method consists in the fact that parent 1-alkylglycerins of general formula II react with trimethylchlorosilane with using triethylamine in toluene medium at temperature -20°C to 0°C, then the reaction mass is added with appropriate alkylisocyanate and processed with ammonium bifluoride in methanol medium at room temperature.
EFFECT: preparation of the agent exhibiting antihypertensive activity.
2 cl, 7 ex
SUBSTANCE: invention is related to alimentation, in particular - to a method and composition for improvement of glucose and insulin balance. Proposed is a compound that includes: a protein source, a fat source and a carbohydrate source, the protein source to the fat source ratio being approximately 1:1:1, each source accounting for 15% - 45% of the total calorie content of the compound. The fat source accounts for approximately over 2% of the total calorie content of the composition in the form of linoleic acid (18:2). According to an alternative version, the food compound for normalisation of insulin and glucose in the organism contains a protein source, a fat source and a carbohydrate source at a ratio of 1:1:1, each of these components accounting for approximately a third of the total calorie content of the compound. Additionally proposed are a diet for enhancement of sensitivity to insulin, a method to reduce resistivity to insulin, a method to reduce insulin levels in the plasma during after dinner time, a method to delay occurrence of insulin in one's blood and a method to increase fat clearance during after dinner time envisaging usage of the above food compound.
EFFECT: invention allows to improve glucose regulation and insulin effect.
68 cl, 34 dwg, 38 tbl
SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.
EFFECT: compounds of the invention exhibit properties of a glucokinase activator.
33 cl, 1499 ex
SUBSTANCE: invention relates to novel compounds - benzoquinone derivatives of formula (I): , where each of R1 and R2 is O-C(O)phenyl; where the phenyl is substituted with 1 substitute selected from halide, nitro, C1-C6 alkyl or C1-C6 alkoxy, and pharmaceutically acceptable salts thereof.
EFFECT: low activity of pancreatic lipase based on compounds of the said formula.
6 cl, 3 tbl, 23 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: claimed is application of biologically active substance for production of medication for treatment of syndrome of resistance to insulin, diabetes, including type I diabetes and type II diabetes, syndrome of ovary polycystosis, treatment or reduction of probability of atheroslerosis development, arterioslerosis, obesity, hypertension, hyperlipidemia, fatty infiltration of liver, nephropathy, neuropathy or retinopathy, feet ulceration or cataracts associated with diabetes, where medication represents compound of formula , as well as corresponding treatment method, pharmaceutical composition and biologically active substance of the same purpose.
EFFECT: increase of compound activity: 75% reduction of glucose level with loading in contrast to 10% reduction for analogues known before, as well as reduction of level of triglycerides in blood serum.
17 cl, 1 dwg, 2 tbl, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to compounds of formula
wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.
EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.
31 cl, 4 ex
SUBSTANCE: invention relates to a compound having structure
, radicals are as described in the formula of invention, as well as pharmaceutically-acceptable salt, prodrug, tautomer and stereoisomer thereof. The invention also relates to a composition, a set for modulating PPAR based on said compound, a method of treating a patient suffering from a disease or condition or at risk of a disease or condition, for which PPAR modulation is therapeutically useful.
EFFECT: novel compounds which are active towards PPAR are obtained and described.
41 cl, 622 ex, 8 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to a compound of formula
where X represents OR1, SR1 or NR1R2 where R1 and R2 independently represent C1-C5 lower alkyl, and R1 and R2 in NR1R2 can form a 5-7-members ring including an O heteroatom; or to its stereoisomer, to a pharmaceutically acceptable salt, hydrate or solvate. Besides, the invention refers to a method for making thereof and to a based pharmaceutical composition exhibiting DPP-IV inhibitor activity.
EFFECT: new compounds which can find application in medicine for prevention or treatment of the DPP-IV associated diseases, such as diabetes or obesity are produced.
12 cl, 1 tbl, 2 dwg, 18 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention aims at a pharmaceutical composition in the form of a clear solution or a water mixture, a suspension or a semisolid composition containing at least one peptide compound of water solubility more than 1 mg/ml at room temperature and pH value within 4.0 to 6.0 selected from the group consisting of hGLP-1 (7-36)-NH2, as well as its analogues and derivatives, hGLP-1 (7-37)-OH, as well as its analogues and derivatives and/or exendin-4, as well as its analogues and derivatives, zinc and a solvent where less than 95 % of said peptide compound are dissolved by the solvent.
EFFECT: invention provides a long-term effect of the preparation with lower initial plasma concentrations.
20 cl, 1 dwg
SUBSTANCE: invention relates to field of pharmacology, medicine and food industry and deals with medicine for reduction of visceral fatty tissue accumulation, which contains compounds of formula or extract of plant Liliaceae, which includes these compounds, application of said compounds or extracts for inhibition of visceral fatty tissue accumulation as well as product on their basis.
EFFECT: invention insures efficient reduction of visceral fatty tissue accumulation.
19 cl, 2 tbl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to pharmacology and is intended for extension of nomenclature of herbal medications for treatment of diabetes mellitus. Medication, representing bog bilberry shoots, demonstrates activation of glucose absorption by ischemic brain in treatment of type II diabetes mellitus. Studies were Indices of glucose-tolerant test at initial level, 30, 60, 120 minutes after glucose loading, as well as level of glucosuric activity. At the background of experimental DM utilisation of glucose by ischemic brain was determined by arterial-venous difference.
EFFECT: obtained results substantiate possibility of bog bilberry shoots application in clinic.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, namely to oncohematology and can be used for treatment of diffuse large B-cell lymphosarcomas (DLBCL) of lymphoid organs in adults. The method involves pre-phase chemotherapy of sequential 6-fold block radical chemotherapy A-B-A-B-C-A or A-B-A-B-A-B. The block A is performed by the intravenous introduction of: methotrexate 1500 mg/m2 and vincristine 2 mg on the 1st day, doxorubicine 25 mg/m2 on the 1st and 2nd days, vepezide 100 mg/m2 and cytosar 150 mg/m2 on the 4th and 5th days only, and iphosphamide 800 mg/m2 intravenously, dexamethasone 20 mg in tablets on the 1-5th days. Further, the block B follows by the intravenous introduction of: methotrexate 1500 mg/m2 and vincristine 2 mg on the 1st day, doxorubicine 25 mg/m2 on the 4th and 5th days only, cyclophosphan 200 mg/m2 and dexamethasone 20 mg in tablets on the 1-5th days, then another 2 blocks A and B follow. In the presence of a complete remission, another 2 blocks A-B are required, and in the absence thereof, the block C is performed by the intravenous introduction: methotrexate 1500 mg/m2 and vinblastine 10 mg on the 1st day, cytosar 2000 mg/m2 2 times a day on the 2nd and 3rd days, vepezide 150 mg/m2 on the 3rd, 4th and 5th days, dexamethasone 20 mg in tablets on the 1-5th days, and then in the presence of the complete remission, the block A is performed. The therapeutic course is 4.5-5 months, every 21 days.
EFFECT: method allows higher clinical effectiveness in DLBCL, reduced recurrent cases, higher survival rate.
2 dwg, 3 ex