Benzimidazole derivative and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to a medicinal agent for antagonistic action on angiotensin II, which contains a compound of formula (I) , in which R1 is a group of formula or , in which R2, R3, R4, R5, R6, R7 and R8, each independently, denote a hydrogen atom or a C1-6alkyl or salt thereof, which is intended for preventing or treating blood circulation disorders such as diabetes and diseases caused by insulin resistance. The invention relates to a medicinal agent which further contains a calcium antagonist and diuretic. The invention relates to use of said medicinal agents to treat said diseases, as well as methods of treating and preventing said diseases and disorders.

EFFECT: high efficiency of using said compounds.

17 cl, 2 tbl, 9 ex

 

The present invention relates to a new derivative of benzimidazole with better pharmacological properties. In particular, the present invention relates to a precursor drugs benzimidazole series with a special structure, which is an antagonist of angiotensin II, shows a strong and long-lasting hypotensive effect and insulin-sensitizing activity and is effective for the prophylaxis or treatment of circulatory disorders such as hypertension, cardiac diseases (cardiac hypertrophy, cardiac insufficiency, myocardial infarction and the like), nephritis, stroke and the like, as well as metabolic disorders such as diabetes, etc. and to use this connection.

Angiotensin II, acting through the receptor of angiotensin II on the cell membrane that causes narrowing of blood vessels and increases blood pressure. Therefore, the receptor antagonist of angiotensin II may be an effective therapeutic tool for the treatment of circulatory disorders such as hypertension, etc.

It is known that as the preferred chemical structure having a high antagonistic activity against angiotensin II, in clinical practice used compounds containing an acid group, such as tetrataenia group, carboxyl group, etc. with the Biff the safe side chain; as pharmacologically active compounds such structural characteristics used losartan (losartan, candesartan, cilexetil (candesartan cilexetil), olmesartan medoxomil (olmesartan medoxomil), etc. (Ruth R. Wexler et al., Journal of Medicinal Chemistry, vol. 39, p. 625 (1996), JP-A-4-364171, JP-A-5-78328 etc). Patent JP-A-5-271228 indicates that the compound in which the acid 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-ilen group is associated with biphenylenes side chain, manifests in oral long-term administration of high antagonistic activity against angiotensin II and hypotensive action. In addition, patent WO 03/047573 indicates that one described in the patent JP-A-5-271228 compounds - derivatives of benzimidazole - 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (compound A) along with antagonistic activity against angiotensin II also has insulin-sensitizing activity.

It is known that one way to increase the practical value of a pharmaceutical product is to make connections with some pharmacological activity, the precursor drug (prodrug). For example, earlier in the development of pharmaceutical products based on compounds exhibiting insufficient pronounced activity when administered orally, ka is este prodrugs based on the carboxylic acid is widely used alkylcarboxylic ether, 1-alkylcarboxylic ether, allyloxycarbonyl ether, 1-alkoxycarbonylmethyl ester and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester. In addition, it is known that ester of farnesol, which is a fat-soluble component of indometacin, and complex ethyl ester - ACE inhibitor (angiotensin converting enzyme) have the ability to make preparations sustainable activity, etc.

As esters of the compounds And in the patent JP-A-5-271228, in particular, it is stated methyl ester (compound B), 1-(cyclohexyloxycarbonyloxy)ethyl ester (compound C) and acetoxymethyl ester (compound D).

The present invention is to create a new connection, which is the best agent for the prophylaxis or treatment of circulatory disorders such as hypertension and similar diseases, and metabolic disorders such as diabetes, etc.

The applicants of the present invention conducted intensive research to find new potent compounds with longer acting oral introduction, in order to obtain more useful in the clinic pharmacological drug for the prophylaxis or treatment of circulatory disorders such as hypertension and the like and metabolic disorders such as diabetes, etc.

In the Nai is Yong predecessor medicine with a special structure, which is converted in the body to the connection And is the most safe and has excellent pharmaceutical properties, as evidenced by the unexpectedly strong and long-lasting hypotensive effect, the possibility of sustainable management of blood pressure for a long time, etc.

Accordingly, the present invention relates to

(1) to the compound of formula (I)

(I)

in which R1represents a group of the formula

in which each of R2, R3, R4, R5, R6, R7and R8independently represents a hydrogen atom or a C1-6alkyl or its salt;

(2) the above compound (1), which is a salt;

(3) the above compound (1)in which R1represented by the formula

in which R2defined above;

(4) the compound selected from the group consisting of

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate,

2-oxo-1,3-dioxolane-4-yl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate,

4-methyl-2-oxo-1,3-dioxolane-4-yl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol the-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate and

5-exoterica-2-furanyl 2 ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate or its salt;

(5) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate potassium;

(6) the method of obtaining the compounds of formula

where R2is a hydrogen or C1-6the alkyl, or salts thereof, which lies in the interaction of a reactive derivative of 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid or a salt thereof with the compound of the formula

in which R2defined above, or its salt;

(7) a medicinal product comprising the above compound (1);

(8) the above medicinal product (7), which is an antagonist of angiotensin II;

(9) the above medicinal product (7), which is an insulin sensitizer;

(10) the above medicinal product (7), which is an agent for the prophylaxis or treatment of circulatory disorders;

(11) a medicinal product comprising the above compound (1) in combination with a calcium antagonist or diuretic;

(12) the above drugs is (7), which is an agent for the prophylaxis or treatment of circulatory disorders;

(13) the method antagonizing effects on angiotensin II in mammals, which is an introduction to the specified mammal an effective amount of the above compounds (1);

(14) the method for improving insulin resistance in a mammal, which provides an introduction to the specified mammal an effective amount of the above compounds (1);

(15) the method for the prevention or treatment of circulatory disorders in mammals, which is an introduction to the specified mammal an effective amount of the above compounds (1);

(16) the method for the prevention or treatment of circulatory disorders in mammals, which is an introduction to the specified mammal an effective amount of the above compound (1) in combination with a calcium antagonist or a diuretic;

(17) application of the above compounds (1) to obtain the antagonist of angiotensin II;

(18) the use of the above compounds (1) to receive an insulin sensitizer;

(19) application of the above compounds (1) to obtain the prophylaxis or treatment of circulatory disorders;

(20) the use of the above compound (1) in combination with antagonistically to receive prophylaxis or treatment of circulatory disorders; etc.

In the above formula, R1represents a group

in which each of R2, R3, R4, R5, R6, R7and R8independently is a hydrogen or C1-6the alkyl and as C1-6the alkyl can be, for example, methyl, ethyl,n-propyl, isopropyl,n-butyl, isobutyl,Deut-butyl,tert-butyl,npencil, isopentyl, neopentyl,n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylpropyl etc.

In the group R1represented by the formula

defined above, the group R2is preferred, and for R2preferred is methyl.

In the above formula is a group represented by the formula

(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-ilen group), includes three tautomer (a', b' and c')

and 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-ilen group includes all three of the above tautomer a', b' and c'.

Preferred compounds of formula (I) of the present invention are

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate,

2-oxo-1,3-dioxolane-4-yl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-ox is diazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate,

4-methyl-2-oxo-1,3-dioxolane-4-yl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate,

5-exoterica-2-furanyl 2 ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate and the like is particularly preferable to use (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate.

Salt of the compounds of formula (I) may be any, provided that this salt is pharmaceutically acceptable. As such salts can be salts of the compounds of formula (I) with inorganic bases (e.g. alkali metal salts, such as sodium, potassium and the like; salts of alkaline earth metals such as calcium, magnesium and the like), organic bases (for example, salts of organic amines, such as tromethamine [Tris(hydroxymethyl)methylamine], ethanolamine, trimethylamine, triethylamine,tert-butylamine, pyridine, picoline, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenziletilendiaminom and the like; salts ό amino acids such as arginine, lysine, ornithine and the like), ammonia, etc.

As salts of the compounds of formula (I) are preferred alkali metal salts. Of these the most preferred salt is potassium.

The compound of formula (I) may contain isotopic label (e.g.,3 H,14C,35S125I and the like), etc.

As the compounds of formula (I) or its salt (hereinafter referred to as compound (I) or the compound of the present invention, particularly preferred is a salt of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate potassium.

Ways to get

The compound (I) can be obtained, for example, in accordance with the following method or a similar method and similar.

The yield of compound (I)obtained in the following way, may vary depending on the reaction conditions, however, the compound (I) of high purity can be easily isolated from the reaction products using conventional methods of isolation and purification (for example, recrystallization, column chromatography and the like).

The compound (I) can be obtained by reacting a reactive derivative (for example, mixed acid anhydride, galodamadruga etc.) the compounds of formula (II) (compound A) or its salt (hereinafter sometimes referred to as a compound (II)) with the corresponding alcohol (IV) (HO-R1) or its salt.

Waya

where X represents a halogen atom (chlorine, bromine, iodine and the like), Et represents ethyl, R12represents alkyl, (e.g. the, C1-6alkyl, such as methyl, ethyl, propyl,tert-butyl and the like), alkoxy (for example, C1-6alkoxy, such as methoxy, ethoxy, isobutoxy etc) or phenyl, optionally substituted by a halogen atom, a C1-6the alkyl or nitro-group and the like, and R1defined above.

Wayathis involves reacting a compound (II) with allermuir agent (III) in the presence of a base, and the obtained mixed acid anhydride and then atrificial the corresponding alcohol (IV) (HO-R1in the presence of a base.

The mixed acid anhydride receive in solution using about 1-3 moles of the base and about 1-3 moles Alliluyeva agent per 1 mol of compound (II) in the solvent. Before you can add the appropriate alcohol, filtered salt (salt of the base with H-X), the filtrate concentrated, the residue is diluted with solvent and then add the corresponding alcohol and base and carry out the esterification.

As a basis you can use triethylamine, Diisopropylamine, DBU, 4-dimethylaminopyridine, sodium hydride,tert-butyl potassium, potassium carbonate and sodium carbonate, etc.

As Alliluyeva agent use pualeilani, ethylchloride, isobutylparaben or 2,4,6-trichlorobenzoyl, 2,6-dichlorobenzophenone, 2,4,6-tribromaniline, 2,3,6-trimethyl-4,5-dinitrobenzophenone and p is such connection, described in Bulletin of the Chemical Society of Japan, vol. 52, pages 1989-1993 (1979).

The solvent can usually be used dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, toluene, acetonitrile, acetone, methyl ethyl ketone, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc.

Reaction conditions to obtain a mixed anhydride can vary depending on the combination of the base, Alliluyeva reagent and solvent; typically the reaction is preferably carried out at a temperature from about-30ºC to room for about 1-10 hours. The conditions of the esterification reaction vary depending on the combination of the received anhydride and solvent; typically the reaction is preferably carried out at a temperature of from about -30 ºC to the boiling point of the solvent under reflux for about 1-10 hours.

Wayb

where the group R1above.

Waybthis involves reacting a compound (II) or its salt with thionyl chloride or oxalylamino in the presence of a catalyst such as DMF and the like, and the resulting acid chloride is then atrificial the corresponding alcohol (IV) in the presence of a base.

Upon receipt of the acid chloride used about 1-3 mole of thionyl chloride or oxalicacid on 1 mol of compound (II) when outstay of catalytic amounts of DMF; if necessary, the reaction is carried out in a solvent. The mixture is then concentrated, add solvent and the appropriate alcohol (HO-R1and carry out the esterification.

As the base used for reasons similar to those used in methodaand so on

As the solvent used solvents similar to those used in methodaand so on

Reaction conditions to obtain the acid chloride can vary depending on the solvent used; typically the reaction is preferably carried out at a temperature of from about -30 ºC to the boiling point under reflux for from about 10 minutes to 5 hours. The conditions of the esterification reaction may vary depending on the combination of the obtained acid chloride and solvent; typically the reaction is preferably carried out at a temperature of from about -30 ºC to the boiling point under reflux for from about 1 to 10 hours.

Wayc

where X' is a halogen atom (chlorine, bromine, iodine and the like) and R1defined above.

Waycincludes esterification of compound (II) or its salt (for example, salt of an alkali metal such as sodium, potassium and the like; salt with alkaline earth metal such as calcium, magnesium and the like), with an alkylating agent (X'-R1) when it is Timoti in the presence of a base.

The etherification is carried out in a solvent using about 1-3 mole of base and about 1-3 mol of alkylating agent per 1 mol of compound (II).

As the base used for reasons similar to those used in methodaand so on

As the solvent used solvents similar to those used in methoda,etc.

The conditions of the esterification reaction may vary depending on the combination of the base, alkylating agent and a solvent; typically the reaction is preferably carried out at a temperature of from about -30 ºC to the boiling point under reflux for about 30 min to 10 hours.

Wayd

where the group R1defined above.

Waydincludes esterification of compound (II) corresponding alcohol (IV) in the presence of a condensing agent.

The etherification is carried out in a solvent using about 1-3 mol of the corresponding alcohol (IV) on 1 mol of compound (II).

As the condensing agent used DCC, WSC, the Mitsunobu reagent, etc.

As the solvent used solvents similar to those used in methodaand so on

The conditions of the esterification reaction may vary depending on the combination of the condensing agent and rest is rites; usually the reaction is preferably carried out at a temperature of from about -30 ºC to the boiling point under reflux for about 30 min to 24 hours.

The compound (II) can be obtained according to the method described in patent JP-A-5-271228, etc.

When compound (I) are obtained in a free form, it can be converted into the corresponding salt, the famousper seway or a similar way. On the contrary, if the connection is obtained as a salt, it can be converted into a free form or in another substance, knownper semethod, or similar method.

If there are optical isomers of compound (I), all these individual optical isomers and their mixtures are naturally included in the scope of the present invention.

The compound (I) may be crystalline and may be in the form of single crystal or a mixture of many crystals. Crystals can be obtained by a crystallization method knownper se. Preferably, the compound (I) was in the form of a crystal.

The compound (I) may be a MES (e.g., hydrate etc), and as MES, and MES (e.g., hydrate etc) included in the scope of the present invention.

Thus obtained compound allatoxin and safe (in other words, it has the best pharmaceutical properties from the point of view of acute toxicity, hronicheskoi toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, interaction with other drugs, Carcinogenicity and the like) and is rapidly converted to the compound A in the body of an animal, particularly a mammal (e.g. human, monkey, cat, pig, horse, cow, mouse, rat, Guinea pig, dog, rabbit etc).

Because the connection normalizes A transmission mechanism of intracellular insulin signal, which basically causes insulin resistance, decreased insulin resistance and increased insulin action, it thus facilitates the sugar load. Thus, the connection of the present invention can be used for mammals (for example, human, monkey, cat, pig, horse, cow, mouse, rat, Guinea pig, dog, rabbit and the like) as a means to improve the condition or prophylaxis and/or treatment of diseases associated with insulin resistance. Among such diseases include, for example, insulin resistance, reduced glucose tolerance; such forms of diabetes as insulin-independent diabetes; type II diabetes; type II diabetes associated with insulin resistance; type II diabetes is associated with reduced glucose tolerance, and the like; various complications, such as hyperinsulinemia hypertension, associated with insulin resistance; hypertension associated with reduced glucose tolerance; hypertension associated with diabetes (e.g. type II diabetes and the like), hypertension associated with hyperinsulinemia, insulin resistance associated with hypertension; reduced glucose tolerance associated with hypertension; diabetes associated with hypertension; hyperinsulinemia associated with hypertension; complications in diabetes [e.g., microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cataract, diseases of the large vessels, osteoporosis, diabetic hyperosmolar coma, infectious diseases (e.g., respiratory infection, urinary tract, infection of the digestive tract, infection of the soft skin tissues, infections of the lower limbs and the like), diabetic gangrene, dry mouth, hearing loss, diabetic cerebrovascular disorders, diabetic disorders peripheral vascular, diabetic hypertension, etc.], the total depletion in diabetes and the like, the Compound of the present invention can also be used to treat patients with high normal blood pressure in diabetes.

Because the connection has A strong antagonistic activity against angiotensin II, the connection N. the present invention is useful as a means of prevention or treatment of a disease (or early manifestations of the disease), develops as a result of narrowing or widening of the blood vessels or disorders of the organs, which is transmitted through the receptor of angiotensin II, due to the presence of angiotensin II, or due to factors due to the presence of angiotensin II in mammals (e.g. human, monkey, cat, pig, horse, cow, mouse, rat, Guinea pig, dog, rabbit etc).

As such diseases include, for example, hypertension, abnormality of circadian rhythm of blood pressure, heart disease (e.g., cardiac hypertrophy, acute heart failure and chronic heart failure including congestive heart failure, cardiac myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, myocardial infarction and the like), cerebrovascular disorders (e.g., asymptomatic cerebrovascular disorders, transient cerebral ischemia, apoplexy, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction and the like), cerebral edema, cerebrovascular disease, relapse and consequences of cerebrovascular disorders (e.g., neurotic symptom, psychic symptom, subjective symptom, violation of life activities, and the like), ischemic peripheral circulatory disorders, myocardial ishem the Yu, venous insufficiency, progression of cardiac insufficiency after myocardial infarction, renal disorders (e.g., nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic vasculopathies, complications of dialysis, organ dysfunction, including nephropathy as a consequence of irradiation, and the like), arteriosclerosis including atherosclerosis (e.g., aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis and the like), vascular hypertrophy, vascular hypertrophy or obliteration and violations of the bodies after the intervention (e.g., after percutaneous transluminal coronary angioplasty, stenting, coronary angioscopy, intravascular ultrasound, thrombolytic therapy for Downs etc), vascular realliteral and restenosis after bypass, polycythemia, hypertension, disorders of organs and vascular hypertrophy after transplantation, rejection after transplantation, diseases of the eye (e.g. glaucoma, ocular hypertension, and the like), thrombosis, multiple violations of organs, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (e.g., deep vein thrombosis, obstructive peripheral vascular disease, obliterative arteriosclerosis, pulmonary, tromba is HIIT, ischemic disease of the cerebral circulation, Raynaud's disease, a disease Berger, etc.), metabolic disorders and/or diseases caused by defects of power (e.g., obesity, hyperlipidemia, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatremia etc), degenerative diseases of the nervous system (for example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, encephalography AIDS etc), diseases of the Central nervous system (e.g., brain hemorrhage, brain infarction, their consequences and complications, head injury, spinal injury, brain swelling, loss of sensation, functional and sensory impairment disorders of autonomic nervous system, distance autonomic nervous system, multiple sclerosis etc), dementia, defects of memory, disorder of consciousness, amnesia, symptom of anxiety, catatonic symptom, discomfort mental state, psychopathy (e.g., depression, epilepsy, alcoholism and the like), inflammatory diseases (e.g. arthritis, including rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis etc; postoperative inflammation and injury; remission of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory putting in diseases such as Crohn's disease, ulcerative colitis and the like; meningi is; inflammatory eye disease; inflammatory lung diseases, such as pneumonia, silicosis of the lung, sarcoidosis of lungs, tuberculosis, and the like), allergic diseases (e.g. allergic rhinitis, conjunctivitis, gastrointestinal Allergy, pollinosis, anaphylactic and the like), chronic obstructive pulmonary disease, interstitial pneumonia, pnevmaticheskaja pneumonia, collagen diseases (eg, systemic lupus erythematosus, scleroderma, polyarteritis and the like), liver disease (e.g. hepatitis, including chronic hepatitis, liver cirrhosis and so on), portal hypertension, diseases of the digestive system (e.g., gastritis, ulcer stomach, stomach cancer, postoperative gastritis, dyspepsia, esophageal ulcer, pancreatitis, intestinal polyps, cholecystitis, hemorrhoids, hernia of the esophagus and stomach etc), diseases of the blood and/or myelopathy (e.g., erythrocytosis, vascular purpura, autoimmune hemolytic anemia, symptoms of diffuse intravascular coagulation, multiple myelopathy etc), diseases of the skeleton (for example, fractures of bones, re-fracture, osteoporosis, osteomalacia, bone Paget's disease, scleroticonyxis myelitis, rheumatoid arthritis, osteoarthritis of the knee and dysfunction of the joint tissues and other caused similar disease, etc), solid tumor, tumors (e.g the measures malignant melanoma, malignant lymphoma, cancer of digestive organs (e.g., stomach, intestine and the like), etc.), cancer and cancer after total exhaustion, cancer metastasis, endocrinopathy (e.g., Addison disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism etc), a disease of Creutzfeldt-Jakob disease, diseases of the urinary and/or genital system (e.g., cystitis, hypertrophic prostate, prostate cancer, genital infections, etc.), gynecological diseases (e.g., climacteric disorder, gestosis, endometriosis, hysteromyoma, ovarian disease, disease of the breast, genital infections, etc.), diseases associated with environmental and occupational disease (for example, the effects of radiation, effects of ultraviolet irradiation, the effects of the laser beam, altitude sickness etc), respiratory diseases (e.g., syndrome of cold, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary embolism etc), infectious diseases (such as viral infections caused by cytomegalovirus, influenza virus, herpes etc., rickettsias, disease, bacterial infections, etc), toxicosis (e.g., sepsis, septic shock, endotoxin shock, gram negative sepsis, toxic shock syndrome etc), otorhinolaryngological diseases the project (for example, the Meniere's syndrome, tinnitus, taste perversion, vertigo, disequilibrium, dysphagia etc), skin diseases (e.g., kelaidi, hemangioma, psoriasis etc), intradialytic hypotension, myasthenia gravis, systemic diseases such as chronic fatigue syndrome, etc.

Because the connection of the present invention can maintain a constant hypotensive activity day and night, may reduce the dose and frequency of intake compared with the introduction of compound A. in Addition, it effectively reduces, in particular, the problematic rise in blood pressure before and after raising the pressure in patients with hypertension.

In addition, due to the prolonged suppression of the action of angiotensin II, a compound of the present invention softens violation or deviation from the norm in biofunction and physiological activity, or inhibits their development, which leads to age-related disorders, adults, etc. that in turn gives primary or secondary prevention related disorders or clinical manifestations and stop their progression. You can call the following violations or deviations from the norm in biofunction and physiological action, for example, breach or deviation from the norm in the automatic regulation of the ability of the cerebral circulation and/or renal the circulation, violation of circulation (for example, peripheral, cerebral, microcirculation and so on), disruption of the blood-brain barrier, sensitivity to salt, the abnormal state of the systems of coagulation and fibrinolysis, the abnormal condition of blood components and blood cells (e.g., increased activity in platelet aggregation, erythrocyte deformability, increased adhesion of leukocytes, increased blood viscosity, etc.), education and functional enhancement of growth factor and cytokines (e.g., PDGF, VEGF, FGF, interleukin, TNF-α, MCP-1 etc), increased proliferation and infiltration of inflammatory cells, increased formation of free radicals the strengthening of lipostatin, impaired endothelial function, endothelial dysfunction, cell and organ, swelling, changes in cellular morphogenesis smooth muscles, etc. (from morphogenesis to proliferation and the like), education and the strengthening of the functions vasoactive substances and inductors thrombosis (e.g., endothelin, thromboxane A2etc), abnormal narrowing of blood vessels, etc., metabolic disorders (e.g., an abnormality of serum lipids, dysglycemia etc), abnormal growth of cells, etc., angiogenesis (including abnormal vasculogenesis during the formation of abnormal reticular formations in adventitia arteriosclerosis), etc. of the Present invention can use the diamonds as a tool for primary and secondary prevention or treatment of disorders of the organs as a result of various diseases (for example, violations of cerebral circulation and related organs, disorders in the organs in the cardiovascular diseases, disorders of the organs caused by diabetes, abnormalities in the organs after surgery and so on). In particular, because the connection And has inhibitory activity against proteinuria, the compound of the present invention can be used as a means to protect the kidneys. Therefore, the compound of the present invention is better to use patients with insulin resistance, reduced glucose tolerance, diabetes or hyperinsulinemia, which are the treatment of the above diseases or clinical conditions.

As the compound A is active in the inhibition of weight gain, the compound of the present invention can be used as an inhibitor of growth in body mass in mammals. This applies to mammals for which you want to avoid weight gain. Mammals can be affected by genetic risk of weight gain or may suffer from diseases caused by lifestyle, such as diabetes, hypertension and/or hyperlipidemia and the like, the weight Gain can be caused by excessive or newbalancewomen power or may be due to a combination of drugs, in the example, the insulin sensitizers, which are antagonists of PPARγ, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc. in Addition, the increase in body mass may be preceded by obesity or can occur in obese patients. Here, obesity is determined by measuring BMI (body mass index; body weight (kg)/[height (m)]2), which for the Japanese equal to at least twenty-five (criteria of the Japanese society for the study of obesity) or at least thirty for Westerners (WHO criteria).

In 1999, the Japanese diabetes society published new criteria in connection with the criteria for diabetes.

According to this publication, diabetes is a condition in which the glucose level in the blood, measured on an empty stomach (glucose concentration in venous plasma)of not lower than 126 mg/DL, a value of 2 hours (glucose concentration in venous plasma) after ingestion of 75 g oral tolerance test glucose (75 g OGTT) is not less than 200 mg/DL and random glucose levels in the blood (glucose concentration in venous plasma) is not less than 200 mg/DL. In addition, a state that does not fall under the above description of diabetes and which is not a "condition in which the glucose level in the blood, measured on an empty stomach (glucose concentration in venous plasma)of less than 110 mg/DL or is 2 hours (Konzentrat what I glucose in venous plasma) after ingestion of 75 g oral tolerance test glucose (75 g OGTT) below 140 mg/DL" (normal type) called "edge type".

In addition, the ADA (American diabetes Association) in 1997 and WHO in 1998 published the new diagnostic criteria based on the diagnostic criteria for diabetes.

According to these publications, diabetes is a condition in which the glucose level in the blood, measured on an empty stomach (glucose concentration in venous plasma)of not lower than 126 mg/DL and the value after 2 hours (glucose concentration in venous plasma) after ingestion of 75 g oral tolerance test glucose is not lower than 200 mg/DL.

In addition, according to the above publications, impaired glucose tolerance is a condition in which the level of fasting blood glucose (glucose concentration in venous plasma) below 126 mg/DL and 2 hours (glucose concentration in venous plasma) after ingestion of 75 g oral tolerance test the glucose is not less than 140 mg/DL and less than 200 mg/DL. Moreover, according to the ADA, a condition in which the level of fasting blood glucose (glucose concentration in venous plasma) is not less than 110 mg/DL and below 126 mg/DL is called IFG (impaired fasting glucose). On the other hand, according to the WHO regarding state IFG (impaired fasting glucose), a condition in which the value after 2 hours (glucose concentration in venous plasma) after ingestion of 75 g oral test n the tolerance to glucose below 140 mg/DL, is called IFG (impaired fasting glucose).

The compound of the present invention can be used as a means of relief, prevention or treatment of diabetes, borderline type, impaired glucose tolerance, IFG (impaired fasting glucose) and IFG (impaired fasting glucose)defined by the above diagnostic criteria. Moreover, the connection of the present invention can also be used as a therapeutic antihypertensive tools for patients with hypertension, providing a level not less than the above diagnostic criteria (e.g., blood glucose fasting 126 mg/DL). Moreover, the connection of the present invention can also be used to stop the progression of diabetes, borderline type, impaired glucose tolerance, IFG (impaired fasting glucose) or IFG (impaired fasting glucose).

The compound of the present invention is used as a means of prevention or treatment of metabolic syndrome. As patients with metabolic syndrome are highly susceptible to cardiovascular disease compared with patients with a single disease caused by lifestyle, prevention or treatment of metabolic syndrome is very important for the prevention of cardiovascular disease

Criteria for diagnosis of metabolic syndrome WHO formulated in 1999 and NCEP in 2001, According to the WHO criteria, patients suffering from at least two of diseases - obesity, dyslipidemia (high levels of serum triglycerides or low HDL cholesterol), hypertension in combination with hyperinsulinemia or impaired fasting glucose - diagnosed as patients with metabolic syndrome (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999). According to the criterion of the Stand III adult treatment National training program on cholesterol, which is an indicator of treatment of coronary heart disease in America, patients with at least three symptoms - abdominal obesity, high triglycerides, low content of HDL cholesterol, hypertension and glucose in fasting blood - diagnosed as patients with metabolic syndrome (national training programme cholesterol: guidance summary of the Third report of the National training program on cholesterol (NCEP)expert stand by definition, evaluation and treatment of high blood cholesterol in adults (Booth III for the treatment of adults). Journal of the American Medical Association, Vol. 285, 2486-2497, 2001).

The compound of the present invention can use the with to treat patients with high blood pressure and metabolic syndrome.

Because the connection And has anti-inflammatory action, the compound of the present invention can be used as an anti-inflammatory agent for the prevention or treatment of inflammatory diseases. Examples of inflammatory diseases include arthritis (e.g. rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, synovitis), asthma, allergic diseases, arteriosclerosis including atherosclerosis (aneurysm, coronary sclerosis, cerebral arterial sclerosis, peripheral arterial sclerosis etc), diseases of the digestive tract, such as inflammation of the bowel (such as Crohn's disease, ulcerative colitis), diabetes complications (breakdown by diabetes, vascular disorders by diabetes), atopic dermatitis, chronic obstructive pulmonary disease, systemic lupus erythematosus, visceral inflammatory diseases (nephritis, hepatitis), autoimmune hemolytic anemia, psoriasis, degenerative diseases of the nervous system (for example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, encephalopathy because of AIDS), diseases of the Central nervous system (e.g., cerebral vascular hemorrhage and cerebral infarction, head trauma, spinal injury, cerebral edema, multiple scle the lake), meningitis, angina, cardiac infarction, congestive heart failure, vascular hypertrophy or occlusion, and violations of the bodies after the intervention (percutaneous coronary plastic endoprosthesis vessels, coronary endoscopy, intravascular ultrasound, intracoronary thrombosis and the like), vascular reocclusion or restenosis after bypass surgery, functional diseases of the endothelium, and other diseases of the circulatory system (intermittent claudication, obstructive peripheral vascular disease, obstructive arteriosclerosis, pulmonary thrombotic vasculitis, ischemic cerebral circulation, Raynaud's disease, a disease Berger), inflammatory diseases of the eye, inflammation of the lungs (e.g., chronic pneumonia, silicosis, sarcoidosis lungs tuberculosis of the lungs) endometritis, toxicosis (e.g., sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome), depletion (e.g., depletion as a result of infection, depletion in cancer, exhaustion as a result of acquired immune deficiency syndrome), cancer, Addison's disease a disease of Creutzfeldt-Jakob disease, viral infection (such as viral infections caused by cytomegalovirus, influenza virus, herpes etc), disseminated intravascular coagulation.

Chrome is also because the connection And has an analgesic effect, the compound of the present invention can also be used as an analgesic for the prevention or treatment of pain. Examples of pain include acute pain in the bones as a result of inflammation, pain associated with chronic inflammation, pain associated with acute inflammation, pain after surgery (incisional pain, deep pain, pain in the body, chronic pain after surgery, and the like), pain in the muscles (pain in the muscles associated with chronic pain, stiffness of the shoulders, etc.) arthralgia, toothache, jaw pain, headache (migraine, catatonic headache, headache with fever, headache hypertension), pain in the organs (heart pain, angina, abdominal pain, pain in the kidneys, pains in the urinary tract, pain in the bladder), gynecological pain (pain in the intermenstrual period, dysmenorrhea, pain in childbirth), pain (herniated disc, pain in the nerve roots, neuralgia after shingles, trigeminal neuralgia), pain, cancer, reflex sympathetic atropia, complex local pain syndrome, etc. Compound of the present invention efficiently removes aches and pains such as pain of nervous origin, pain in cancer and inflammation, and has an excellent analgesic effect on the patient is in low pain threshold in different pathologies.

The compound of the present invention is particularly suitable as an analgesic for pain associated with chronic inflammation or hypertension, or as a means of prevention or treatment of inflammatory diseases or pain caused (1) arteriosclerosis, including atherosclerosis, (2) hypertrophy of vascular obstruction or disruption of the bodies after the intervention, (3) reocclusion, restenosis or functional disease of the endothelium after bypass surgery, (4) intermittent claudication, (5) occlusal human peripheral blood circulation, (6) occlusive arteriosclerosis.

The compound of the present invention can be used as a safe pharmaceutical agents for mammals (e.g. human, monkey, cat, pig, horse, cow, mouse, rat, Guinea pig, dog, rabbit and the like) in the form of compounds as such or in the form of a pharmaceutical composition after mixing with a pharmaceutically acceptable carrier according to a method knownper se.

As shown in the description, as the pharmacologically acceptable carrier can be used various organic or inorganic substances that are traditionally used for the manufacture of drugs. For example, you can call excipient, lubricant, binder and disintegrity reagent for the manufacture of solid p is aparatow; the solvent substances that contribute to the dissolution suspendisse agent, isotonic component and buffer solution for liquid medications, etc. If required for preparation, you can also use additives, such as preservatives, antioxidants, colorants, sweeteners, etc.

Preferred examples of the excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, reptitiously starch, dextrin, crystalline cellulose, slabosalenuyu hydroxypropylcellulose, sodium carboxymethylcellulose, gum Arabic, pullulan, white silicic acid anhydride, synthetic aluminum silicate, alumosilicate magnesium, etc.

Preferred examples of the lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, etc.

Preferred examples of the binder include reptitiously starch, sucrose, gelatin, gum Arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, saccharose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, etc.

Preferred examples dezintegriruetsja reagents include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, sodium carboximetilkrahmal, Ely the silicic acid anhydride, slabosalenuyu hydroxypropylcellulose etc.

Preferred examples of the solvent include water for injection, physiological saturated sodium chloride solution, ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cotton seeds, etc.

Preferred examples of substances that promote dissolution, include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, etc.

Preferred examples suspendida reagents include surfactants, such as steartrimonium, sodium lauryl sulfate, lauramidopropyl, lecithin, benzylaniline, benzenehexachloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose etc.; Polysorbate, polyoxyethylene, gidrirovannoe castor oil, etc.

Preferred examples of the isotonic component include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like,

Preferred examples of the buffer solutions include solutions based on f is state, acetate, carbonate, citrate, etc.

Preferred examples of the preservatives includep-oxybenzoic, chlorbutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid, sorbic acid, etc.

Preferred examples of the antioxidant include sulfite, ascorbate, etc.

Preferred examples of the dyes include water-soluble dyes from food grade resin (for example, food dyes type of Food Red No. 2 and No. 3, Food Yellow No. 4 and 5, Food Blue No. 1 and 2 and the like), water insoluble lacquers (e.g., aluminum salts of the above water-soluble resinous food dyes and the like), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide and the like), etc.

Preferred examples of the sweeteners include sodium saccharin, dialogicality, aspartame, stevia, etc.

The dosage forms of the pharmaceutical compositions include, for example, oral forms such as tablet, capsule (including soft capsule and microcapsule), granule, powder, syrup, emulsion, suspension, the drug delayed allocation and the like, each of which safe is administered orally.

The pharmaceutical composition can be manufactured by conventional methods known in the field of pharmaceutical production, for example, methods described in Japanese Pharmacopoeia, and other Special methods of manufacture of such preparations detail is written below.

For example, the tablet is prepared by adding, for example, excipients (e.g. lactose, sucrose, starch, D-mannitol and the like), dezintegriruetsja reagents (e.g., calcium carboxymethylcellulose and the like), binders (for example, pepsirefresh starch, gum Arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and the like), lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000 and the like), etc. to the active ingredient, by extrusion-molding and, if necessary, by drawing the shell method, knownper seusing the basics of shell knownper sewith the purpose of taste masking, dissolution in the intestine or delayed allocation.

The capsule can be a solid, filled with powder or granular pharmaceutical agent, or soft, filled with a liquid or liquid suspension. Hard capsule produced by mixing and/or granulating the active ingredient with, for example, excipients (for example, lactose, sucrose, starch, crystalline cellulose, D-mannitol and the like), dezintegriraat reagent (slabosalenuyu hydroxypropylcellulose, calcium-carmellose, corn starch, sodium croscarmellose and the like), binders (hydroxypropylcellulose, polyvinylpyrrolidone, hypromellose, and the like), lubricant (Starata magnesium, and so what.) etc. and filling the mixture or granules, capsules made from the above-mentioned gelatin, hydroxypropylmethylcellulose etc. Soft capsule is made by dissolving or suspendirovanie active ingredient in the base material (soybean oil, oil seeds, cotton, triglycerides of fatty acids with medium chain length, waxes and the like) and sealed in a solution or a suspension in gelatin shell, using, for example, rotary filling machine, etc.

If the compound (I) is a salt and it is desirable to avoid contact of the compound (I) in the form of a salt with water, it is preferable to mix the compound (I) in a dry form with excipients, etc. to obtain a hard capsule.

The content of the compound (I) in the pharmaceutical composition is usually from about 0.01 to about 99.9 wt.%, preferably from about 0.1 to about 50 wt.% by weight of the total preparation.

The dose of compound (I) is determined taking into account age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs, the extent of disease, from which treated the patient, and other factors.

As the dose varies depending on the type of disease, condition, form of administration, route of administration and the like, preferably a daily dose of 0.1 to 100 mg for oral administration as Ter is non-therapeutic tools for adult patients with hypertension in a lump sum or in the form of 2-3 servings.

In addition, since the compound of the present invention is completely safe, you can assign it for a long period.

The compound of the present invention can be used in combination with other pharmaceuticals, for example, drugs for diabetes, diabetic complications, anti-hyperlipidemia, anti-arteriosclerotic agents, drugs for hypertension, anti-obesity, diuretics, anti-gout, anti thrombotic, anti-inflammatory drugs, chemotherapeutics, immunotherapy means of therapies for osteoporosis, dementia, erectile dysfunction, therapeutic means from urinary incontinence and frequent urination, etc. (following they will be referred to as a combination drug). In such cases, the time of introduction of the compounds of the present invention and the combination drug is not limited, because the connection of the present invention and the combination drug combined. As the method of such introduction can be called, for example, (1) administration of a single preparation obtained by simultaneous preparation of compounds of the present invention and the combination drug, (2) simultaneous administration of drugs of two types, the obtained partition is the principal preparation of compounds of the present invention and the combination drug, in one act of introduction, (3) separated in time the introduction of two types of drugs prepared separate preparation of the compounds of the present invention and the combination drug, with the same method of administration, (4) simultaneous introduction of two types of drugs prepared separate preparation of the compounds of the present invention and combinations of drugs with different routes of administration, (5) separated in time the introduction of two types of drugs prepared separate preparation of the compounds of the present invention and the combination drug, the separate introduction of, for example, the introduction in such a manner that first enter the compound of the present invention and the combination drug funds, or in reverse order, etc. Dose combinations of drugs can be determined on the basis of the dose used in the clinical trial. The ratio in the mixture of the compounds of the present invention to the combination of drugs can be selected depending on the object of administration, method of administration, type of disease, condition, combination, and other factors. When administered to humans, for example, a combination of drugs can be used in amounts of from 0.01 to 100 parts by weight per part by weight of compounds of the present invention.

As those who appenticeship anti-diabetes can be called, for example, insulin preparations (e.g., animal insulin preparations extracted from the pancreas of cows or pigs; preparations of human insulin synthesized by genetic engineering methods with the use ofE. colior yeast and the like), other synthetic drugs insulin (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, FK-614, etc.), inhibitors of α-glucosidase (e.g., voglibose, acarbose, miglitol, emiglitate and the like), biguanides (e.g., phenformin, Metformin, buformin and the like), stimulants of insulin secretion [for example, sulfonylureas (e.g. tolbutamide, glibenclamide, gliclazide, hlorpropamid, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole etc.), Repaglinide, sinapinic, nateglinide, mitiglinide or hydrate of its calcium salt, GLP-1, etc.], agonists of amerina (for example, pramlintide etc.), inhibitors phosphoribosyltransferase (for example, vanadium acid and the like), inhibitors dipeptidylpeptidase IV (for example, NVP-DPP-278, PT-100, P32/98 and so on), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc.), inhibitors of gluconeogenesis (e.g., glycogen phosphorylase inhibitor, an inhibitor of glucose-6-phosphatase, the glucagon antagonist and the like), SGLT inhibitors (superelastic sodium-glucose) (e.g., T-1095 etc) and so on

As a therapeutic cf the of funds against the complications of diabetes can be called, for example, inhibitors aldesleukin (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-112 etc), neurotrophic factors (e.g., NGF, NT-3, BDNF, etc), PKC inhibitors (e.g., LY-333531 and the like), AGE inhibitors (e.g., ALT946, pimagedine, paroxetin, N-phenacylthiazolium (ALT766), EXO-226, and so on), trap active oxygen (e.g., thioctic acid and the like), cerebral vasodilator (e.g., tiaprid, meksiletin and the like), etc.

As protivoepidemicheskih means include, for example, statins, inhibitors of cholesterol synthesis (e.g., tseriwastatina, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their salts (e.g. sodium salt and the like), and the like), inhibitors stvalentines (for example, TAK-475 and the like) or fibrate connection, reducing the concentration of triglycerides (for example, bezafibrat, clofibrate, simfibrate, clinofibrate and the like), etc.

As anti-arteriosclerosis can be called, for example, the inhibitor acylcoenzyme cholesterolesterase (ACAT) (for example, melinamide, CS-505 and the like) and to contribute to the resorption of fatty plaques (for example, compounds described in WO 02/06264, WO 03/059900 etc), etc.

As protivogipertonicheskoe means include, for example, enzyme inhibitors transformation angioten is in (for example, captopril, enalapril, delapril etc.), antagonists of angiotensin II (e.g., candesartan, cilexetil, candesartan, losartan potassium-losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil and the like), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine and the like), β-blockers (e.g. metoprolol, atenolol, propranolol, carvedilol, pindolol, etc.), clonidine etc.

As anti-obesity can be called, for example, means acting on the Central nervous system (for example, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamfetamine, mazindol, phenylpropanolamine, clobenzorex etc.), inhibitors of pancreatic lipase (e.g., orlistat and the like), a β3 agonist (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc.), anorectic peptides (e.g., leptin, CNTF (ciliary neurotropic factor) and the like), cholecystokinin antagonists (for example, lintitript, FPL-15849 etc), etc.

As diuretics can lead, for example, xanthine derivatives (e.g., theobromine and sodium salicylate, theobromine and calcium salicylate and the like), drugs thiazide (for example, atiase, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydroxylamine, panflutes, poly 5 teased, methyclothiazide and p), drugs antialdosterone (e.g., spironolactone, triamterene etc.), carbonic anhydrase inhibitors (eg, acetazolamide and the like), drugs chlorobenzenesulfonamide (e.g., chlorthalidone, mefruside, indapamide etc), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide, etc.

As anti-gout you can specify, for example, allopurinol, probenecid, colchicine, benzbromarone, febuxostat, citrate, etc.

As anti-thrombosis can be called, for example, anticoagulants [e.g., sodium heparin, potassium heparin, potassium warfarin (warfarin), inhibitors of factor X activated blood coagulation (e.g., compounds described in WO 2004/048363 etc.)], thrombolytic tools [e.g., tPA, urokinase], antiplatelet tools [e.g., aspirin, sulfinpirazon (anturan), dipyridamole (persantin), ticlopidine (panaldine), Cilostazol (pletal), antagonist of GPIIb/IIIa (ReoPro), clopidogel etc.] etc.

As anti-inflammatory drugs can lead, for example, nonsteroidal anti-inflammatory drugs, such as acetaminophen, phenacetin, ethenzamide, calponin, antipyrine, Amigrenin, aspirin, mefenamovaya acid, flufenamic acid, sodium diclofenac, sodium loxoprofen, phenylbutazone, indomethacin, ibuprofen, Ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen is, pranoprofen, floctafenine, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesilate, chemostat mesilate, ulinastatin, colchicine, probenecid, sulfinpirazon, benzbromarone, allopurinol, sodium-gold-thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, Levorphanol, Ketoprofen, naproxen, Oxymorphone, and their salts, etc.

As chemotherapeutic agents include, for example, alkylating agents (e.g. cyclophosphamide, ifosfamide, etc.), antagonists of metabolism (e.g., methotrexate, 5-fluorouracil and the like), anticancer antibiotics (e.g., mitomycin, adriamycin and the like), anti-cancer agents of vegetable origin (e.g., vincristine, vindesine, Taxol etc), cisplatin, carboplatin, etoposide, etc. Among them, preferred are furtulon, neopentylene etc. which are derivatives of 5-fluorouracil.

As immunotherapy can be called, for example, a microorganism or bacterial components (e.g., derivatives of muramyldipeptide, picibanil and the like), polysaccharides with immunostimulatory activity (e.g., lentinan, sizofiran, christenings and the like), cytokines obtained by genetic engineering methods (e.g., interferon, interleukin (IL) etc.), colony-stimulating factor (e.g. factor stimulating colonies of granulocytes, erythropoietin and the like), etc. and preferred are IL-1, IL-2, IL-12, etc.

As therapeutic agents against osteoporosis can lead, for example, alpha-calcidiol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, encadrant disodium etc.

As anti-dementia you can specify, for example, taken, donepezil, rivastigmine, galantamine, etc.

As a means against erectile dysfunction can be called, for example, apomorphine, sildenafilcitrate etc.

Therapeutic anti-incontinence/frequent urination are, for example, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride etc.

Moreover, in combination with a pharmaceutical agent of the present invention can be used pharmaceuticals to combat exhaustion, tested in animal models and in the clinic, which include cyclo-oxygenase inhibitors (e.g., indomethacin etc) [Cancer ResearchVol. 49, 5935-5939 pages, 1989], the derivatives of progesterone (for example, magistralata) [Journal of Clinical OncologyVol. 12, pages 213-225, 1994], glucosteroid (for example, dexamethasone and the like), pharmaceutical drugs metoclopramide pharmaceuticals tetrahydrocannabinol), tools that improve the metabolism of fats (for example, eicosapentanoic acid, etc.) [British Journal of CancerVol. 68, pp. 314-318, 1993], growth hormones, IGF-1, and antibodies to TNF-α, LIF, IL-6 and oncostatin M, which causes the depletion etc.

Combined drug preferably includes a diuretic, a drug is insulin, an insulin sensitizer, an inhibitor of α-glucosidase, biguanides, tools that enhance insulin secretion (preferably a sulfonylurea), etc. In particular, the preferred diuretic type of hydrochlorothiazide, etc. and an insulin sensitizer type pioglitazone hydrochloride etc.

The above combined drug can be a combination of two or more types of drugs combined in the appropriate ratios.

Because the connection of the present invention increases the hypoglycemic activity of other insulin sensitizers, sharing compounds of the present invention and other insulin sensitizers (preferably pioglitazone hydrochloride) significantly enhances the prophylactic and/or therapeutic effect in the treatment of diseases where insulin resistance, such as type II diabetes, etc.

The compound of the present invention is highly effective in the prevention and treatment of circulatory disorders such as hypertension is so, and metabolic disorders such as diabetes, etc.

Examples

The present invention is explained with the help of the following examples of the preparation examples and experimental examples. However, these examples are merely practical options and do not limit the present invention. The present invention can be modified to the extent that it does not deviate from the scope of the invention.

The elution method of column chromatography in the examples

conducted with control by TLC (thin layer chromatography). In experiments on TLC used plates 60F254(Merck), eluting the solvent was the same as manifesting the solvent in column chromatography for detection used a UV detector. As silica gel for the column used kieselgel 60 (70-230 mesh) or kieselgel 60 (230-400 mesh mesh) from Merck. An NMR spectrum was recorded with tetramethylsilane was as an internal or external standard, chemical shifts are given in δ units and constants involved in Hz. In the examples used the following notation:

q:
s:the singlet
d:doublet
t:triplet
Quartet
dd:double doublet
m:multiplet
J:constant STV
THF:tetrahydrofuran

DMF:dimethylformamide
DMSO:the sulfoxide
DBU:1,8-diazabicyclo[5.4.0]-7-undecene

Example 1

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

To a solution of disodium 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (2.0 g) in DMF (20 ml) was added 4-chloromethyl-5-methyl-1,3-dioxol-2-it (0,99 g) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and the residue was dissolved in chloroform and 1 N hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silicagel and got the connection, specified in the header (0.26 g, 14%), as colourless solid.

1H NMR (300 MHz, CDCl3) δ: USD 1.43 (3H, t, J=7,1 Hz), and 2.14 (3H, s), 4,46 (2H, square, J=7,1 Hz), to 4.87 (2H, s), 5,63 (2H, s), 6,93 (2H, d, J=8,3 Hz), 7,07 (1H, t, J=7.9 Hz), 7,16 (2H, d, J=8.1 Hz), 7,32-7,37 (2H, m), 7,53-to 7.64 (3H, m), 7,83 (1H, DD, J=1.4 Hz and 7.6 Hz).

Example 2

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

To a solution of 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5.0 g) and triethylamine (1,69 ml) in THF (50 ml) was added dropwise 2,4,6-trichlorobenzoyl (1,81 ml) under cooling with ice. After stirring the mixture at room temperature for 12 hours, filtered nerastvorimaya substance and the filtrate was concentrated. The residue was dissolved in methylene chloride (50 ml) and added 4-hydroxymethyl-5-methyl-1,3-dioxol-2-he (1,72 g) and N,N-dimethylaminopyridine (1,61 g) under cooling with ice. After stirring the mixture at room temperature for 4 h, the reaction mixture was diluted with chloroform (150 ml), washed with water, saturated aqueous sodium bicarbonate solution, 1 N hydrochloric acid and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallize from diisopropyl ether and the obtained crude crystals. Cheese is e crystals were dissolved in ethanol (18 ml) by boiling under reflux. To the solution was added activated charcoal (0.1 g) and the mixture was stirred while boiling under reflux for 30 minutes Nerastvorimaya substance was filtered and the filtrate allowed to cool to room temperature. After 12 hours, filtered, the crystals formed, washed with cooled in ice with ethanol and dried under reduced pressure at room temperature, has received the connection specified in the header (3.0 g, 50%). 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-he synthesized according to the method described in Alpegiani, M.; Zarini, F.; Perrone, E. Synthetic Communication, Vol. 22, pp. 1277-1282 (1992).

1H NMR (300 MHz, DMSO-d6) δ: of 1.37 (3H, t, J=7,2 Hz), and 2.14 (3H, s), 4,58 (2H, square, J=7,2 Hz), 5,10 (2H, s), of 5.53 (2H, s), 6,97 (2H, d, J=7.8 Hz), 7,17-7,22 (3H, m), 7,44-7,53 (3H, m), to 7.61-7,73 (3H, m).

Example 3

2-oxo-1,3-dioxolane-4-yl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

A solution of 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (1.0 g), 4-chloro-1,3-dioxolane-2-it (0,41 g) and triethylamine in DMF was stirred at 90°C for 12 hours. The reaction mixture was concentrated and the residue was dissolved in chloroform and 1 N hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel and got the link is, specified in the header (0.20 g, 22%), as colourless solid.

1H NMR (300 MHz, DMSO-d6) δ: of 1.39 (3H, t, J=7,1 Hz), to 4.52 with 4.65 (3H, m), 4,78 (1H, DD, J=5.8 Hz, 10.1 Hz), of 5.55 (2H, d, J=2.6 Hz), at 6.84 (1H, DD, J=2.1 Hz, 5.6 Hz), 7,03 (2H, d, J=8,3 Hz), 7,20-of 7.25 (3H, m), 7,43-EUR 7.57 (2H, m), 7,60-7,69 (3H, m), to 7.77 (1H, DD, J=1.0 Hz, 7.8 Hz).

Example 4

4-methyl-2-oxo-1,3-dioxolane-4-yl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

The connection specified in the header (0.21 g, 11%)was obtained from 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (2.0 g) and 4-chloro-4-methyl-1,3-dioxolane-2-she (1.2 g) by the method similar to the method of example 3. 4-Chloro-4-methyl-1,3-dioxolane-2-he synthesized according to the method described in JP-A-62-290071.

1H NMR (300 MHz, CDCl3) δ: of 1.41 (3H, t, J=7,1 Hz ), is 1.81 (3H, s), a 4.53 (2H, d, J=3.6 Hz), 4,63 (2H, square, J=7,1 Hz), to 5.57 (2H, d, J=6.4 Hz), of 6.96 (2H, d, J=8.1 Hz), 7,20-7,28 (3H, m), 7,46 (1H, d, J=7.9 Hz), 7,54-of 7.69 (4H, m), for 7.78 (1H, d, J=7.9 Hz).

Example 5

Potassium salt of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid

The compound (0.55 g)obtained in examples 1 or 2 was dissolved in acetone (10 ml) at 50°C. the Solution was cooled in ice and added dropwise a solution of 2-ethylhexanoate potassium (0.17 g) in acetone (2 ml). The mixture is left overnight in the fridge and what was filtrowanie the precipitated crystals, dried under reduced pressure at room temperature and has received the connection specified in the header (0,37 g, 63%). Melting point: 196°C (decomp.).

1H NMR (300 MHz, DMSO-d6) δ: of 1.42 (3H, t, J=7,1 Hz), 2,17 (3H, s), to 4.62 (2H, square, J=7,1 Hz), 5,11 (2H, s), the 5.51 (2H, s), 6,85 (2H, d, J=8,3 Hz), 7,16-7,27 (4H, m), 7,30-7,42 (2H, m), 7,44-7,52 (2H, m), 7,72 (1H, DD, J=1.1 Hz, 7.9 Hz).

Example 6

Sodium salt of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid

The compound (10 g)obtained in examples 1 or 2 was dissolved in THF (200 ml) at 50°C. the Solution was cooled with ice and added dropwise a solution of 2-ethylhexanoate potassium (2,93 g) in THF (2 ml). The reaction mixture was concentrated, the residue was washed with diethyl ether and the crystals were filtered. The crystals were dried under reduced pressure at 50°C and received the connection specified in the header (charged 8.52 g, 82%), as colourless solid.

1H NMR (300 MHz, DMSO-d6) δ: of 1.41 (3H, t, J=7,1 Hz)of 2.16 (3H, s), br4.61 (2H, square, J=7,1 Hz), 5,11 (2H, s), of 5.53 (2H, s)6,91 (2H, d, J=8,4 Hz), 7,19-7,28 (4H, m), 7,29-to 7.68 (4H, m), 7,76 (1H, m).

Example 7

Adduct the calcium salt of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid and acetate calcium

The compound (1.0 g)obtained in example 6, was dissolved in ACE is onitrile (10 ml) at room temperature. To the solution was added dropwise at room temperature a solution of the monohydrate calcium acetate (0.26 g) in acetonitrile (10 ml). The reaction mixture was stirred overnight and the precipitated crystals were filtered. The crystals were dried under reduced pressure at 50°C and received the connection specified in the header (0,78 g, 56%) as a colourless solid.

1H NMR (300 MHz, DMSO-d6) δ: of 1.42 (3H, t, J=7.2 Hz), 1,78 (9H, s), 2,17 (3H, s), to 4.62 (2H, square, J=7,2 Hz), 5,11 (1H, s), the 5.51 (1H, s), at 6.84 (2H, d, J=7.4 Hz), 7.18 in-of 7.23 (4H, m), 7,28-7,40 (2H, m), 7,47-to 7.50 (2H, m), 7,69-7,74 (1H, m).

Example 8

5-exoterica-2-furanyl 2 ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

To a solution of 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (4.0 g) and triethylamine (1.3 ml) in THF (50 ml) was added dropwise 2,4,6-trichlorobenzoyl (1,4 ml) under cooling with ice. After stirring at room temperature for 12 h was filtered nerastvorimaya substance and the filtrate was concentrated. The residue was dissolved in methylene chloride (50 ml) and added 5-exoterica-2-furanyl (0,67 g) and N,N-dimethylaminopyridine (1.0 g) under cooling with ice. After stirring at room temperature for 4 h, the reaction mixture was diluted with chloroform (150 ml), washed with water, saturated aqueous solution of the m sodium bicarbonate, 1 N hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel and got the connection specified in the header (0.16 g, 3,3%), as colourless solid.

1H NMR (300 MHz, CDCl3) δ: 1,48 (3H, t, J=7,1 Hz), 2,31-2,39 (1H, m), 2,45-of 2.66 (2H, m), 2,67-and 2.79 (1H, m), 4,63 (2H, square, J=7,1 Hz), 5,61 (1H, d, J=18 Hz), of 5.81 (1H, d, J=18 Hz), of 6.71-6.73 x (1H, m), 6,98-7,01 (2H, m), 7,16-7,25 (3H, m), of 7.36-7,38 (1H, m), of 7.48-to 7.59 (3H, m), 7,69-7,80 (2H, m).

Example 9

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

To a solution of 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (9.0 g) and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-it is 3.08 g) in N,N-dimethylacetamide (100 ml) addedp-toluensulfonate (4,13 g), N,N-dimethylaminopyridine (0,48 g) and potassium carbonate (3.54 in) under ice cooling and the mixture was stirred at about 10ºC for 3 hours. After the establishment of about pH 5 the mixture was led by addition of water (72 ml) and obtained crystals of the solvate. The precipitated crystals suspended in a mixture of water (63 ml) and acetone (27 ml) and the suspension was stirred at about 35ºC for 2 hours. After stirring with ice cooling for 2 hours, the crystals were filtered, the, washed with water (18 ml), dried under reduced pressure at 40°C and has received the connection specified in the header (10.6 g, 95%).

1H NMR (300 MHz, DMSO-d6) δ: of 1.39 (3H, t, J=6.4 Hz), 2,17 (3H, s), 4,60 (2H, square, J=6.4 Hz), 5,12 (2H, s)to 5.56 (2H, s)to 7.00 (2H, d, J=7,0 Hz), 7,22-7,24 (3H, m), 7,46-EUR 7.57 (3H, m), of 7.64 to 7.75 (3H, m).

Examples of cooking

When using the compounds of the present invention as a therapeutic agent for the treatment of circulatory diseases such as hypertension, heart disease, stroke, jade, etc. can be applied, for example, the following preparation method.

The next time you prepare as components (additives)other than the active ingredient, it is possible to use compounds listed in Japanese Pharmacopoeia, Japanese Pharmacopoeia quasi drugs, or Standard additives to pharmaceutical products.

1. Tablet
(1)The compound obtained in example 110 mg
(2)Lactose35 mg
(3)Corn starch150 mg
(4)Microcrystal the ical pulp 30 mg
(5)Magnesium stearate5 mg
1 tablet230 mg

(1), (2), (3) and 2/3 of (4) were mixed and granulated. Added the remaining components (4) and (5), and the mixture was pressed into tablets.

2. Capsule
(1)The compound obtained in example 510 mg
(2)Lactose69,5 mg
(3)White silicic acid anhydride0.2 mg

(4)Magnesium stearate0.3 mg
1 capsule80 mg

(1), (2), (3) and (4) are mixed in dry form and fill HPMC capsule (No. 3).

3. Tablet
(1)The is a group of obtained in example 110 mg
(2)Amlodipine, besylate5 mg
(3)Lactose30 mg
(4)Corn starch150 mg
(5)Microcrystalline cellulose30 mg
(6)Magnesium stearate5 mg
1 tablet230 mg

(1), (2), (3), (4) and 2/3 from (5) are mixed and granularit. Add the remaining (5) and (6), and the mixture is pressed into tablets.

4. Capsule
(1)The compound obtained in example 510 mg
(2)Amlodipine, besylate5 mg
(3)Lactose64,5 mg
(4) White silicic acid anhydride0.2 mg
(5)Magnesium stearate0.3 mg
1 capsule80 mg

(1), (2), (3), (4) and (5) are mixed in dry form and fill HPMC capsule (No. 3).

5. Tablet
(1)The compound obtained in example 110 mg
(2)Hydrochlorothiazide12.5 mg

(3)Lactose22,5 mg
(4)Corn starch150 mg
(5)Microcrystalline cellulose30 mg
(6)Magnesium stearate5 mg
1 tablet230 mg

(1), (2), (3), (4) and 2/3 from (5) is mesilat and granularit. Add the remaining (5) and (6), and the mixture is pressed into tablets.

6. Capsule
(1)The compound obtained in example 510 mg
(2)Hydrochlorothiazide12.5 mg
(3)Lactose57 mg
(4)White silicic acid anhydride0.2 mg
(5)Magnesium stearate0.3 mg
1 capsule80 mg

(1), (2), (3), (4) and (5) are mixed in dry form and fill HPMC capsule (No. 3).

Experimental example 1

The inhibitory activity of the compounds of the present invention in terms of pressure in rats induced by angiotensin II

Male rats Sprague-Dawley (age 9-11 weeks old, CLEA Japan, Inc.) was anestesiologi phenobarbital (50 mg/kg, intraperitoneally); femoral artery and vein were removed and they were inserted plastic tube filled with saline solution, with the holding heparin (200 U/ml). Subcutaneously injected with a catheter in the neck and fixed them. After recovery, the rats were injected in the experience. The arterial catheter was connected to a pressure transducer, connected to a tonometer (2238, NEC San-ei Instruments), and the pressure was recorded on a recorder (RECTI-HORIZ 8K, NEC San-ei Instruments). After receiving the response of the pressure rise induced by angiotensin II (AII, 100 ng/kg, i.v.), were administered the test compound in a dose corresponding equimolar quantity of compound A (2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid). After 24 hours was introduced AII and measured the rise in blood pressure, according to which the expected rate of inhibition of values before the introduction. All compounds were suspended in 0.5% methylcellulose and administered orally in a volume of 2 ml/kg

The results are shown as average ± average statistical deviation (table 1). Statistical significance between the group with the compound obtained in example 5, and other groups were analyzed using Studentttest (**: p>0,01, *: p>0,05).

Table 1
24 hours
after introduction
Example 5 [0.13 mg/kg, orally (n=5)] 32,7±4,6
Compound B [0,10 mg/kg, orally (n=3)]0,8±4,9**
Connection C [0.14 mg/kg, orally (n=5)]9,3±8,6*
Connection D [0,12 mg/kg, orally (n=4)]10,9±5,6*

ConnectionB:methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

ConnectionC:1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

ConnectionD:acetoxymethyl 2 ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate.

As follows from the obtained results, the compound of the present invention provides oral introduction of a long and strong pharmacological effect compared to the esters described in JP-A-5-271228.

Experimental example 2

The inhibitory effect of the compounds of the present invention in terms of pressure in dogs induced by angiotensin II

For experience have used a dog breed Beagle (body mass 12,0-14,7 kg, KITAYAMA LABES Co., LTD.). They were anestesiologi sodium phenobarbital (50 mg/kg, intraperitoneally) and were inserted Proc. of the BKU into the trachea to regulate air flow. The thigh and the neck shaved and disinfected (solution isodine, MEIJI SEIKA KAISHA, LTD.). The dog was fixed in position on the back and made an incision in the femoral region. In the femoral artery was injected mirror catheter (5F, MILLER INDUSTRIES)and in the femoral vein was injected polyurethane tube. The catheter and the tube was passed subcutaneously and recorded on the back. Then the incision was sewn up and was injected intramuscularly potassium salt of penicillin G (MEIJI SEIKA KAISHA, LTD., 40000 units) to prevent infection. Starting from the next day, the potassium salt of penicillin G (40,000 units) was administered once a day for 3 days. 3 days after recovery, the dog was put into the experience.

During the experiment, the dog was placed in a small metabolic cage. For measurement mirror catheter inserted into the femoral artery was connected with the sensor (MILLER INDUSTRIES), and systematically recorded blood pressure (mean blood pressure) recorder (RECTI-HORIZ 8K, NEC San-ei Instruments) through a DC amplifier (N4777, NEC San-ei Instruments) and the tonometer with amplifier (N4441, NEC San-ei Instruments). Polyurethane tube, introduced into the femoral vein, recorded outside the cells and used for the introduction of AII (PEPTIDE INSTITUTE, INC.). The experiment was carried out on an empty stomach and was introduced AII (100 ng/kg, intravenously) 3-4 times before the introduction of the test connection to confirm the stabilizing response to increased pressure. The dose and pitamaha connection the corresponding equimolar quantity of compound A, suspended in 0.5% methylcellulose and administered orally in a volume of 2 ml/kg After administration of the medicinal product was administered AII in each moment of time during the measurement and the measured rise in blood pressure, according to which the expected rate of inhibition of the values obtained before the introduction.

The results are shown as average ± average statistical deviation (table 2). Statistical significance between the group with the compound obtained in example 5, and the group entered the compound And were analyzed using Studentt-test adjusted Bonferroni (**: p>0,01, *: p>0,05).

Table 2
10 hours
after introduction
24 hour
after introduction
Connection A [1 mg/kg, orally (n=6)]27,0±3,219,6±3,7
Example 2 [1.25 mg/kg, orally (n=6)]35,9±4,828,6±4,7
Example 5 [of 1.33 mg/kg, orally (n=5)]55,6±3,4**40,3±5,1*

As SL is blowing from these results, the compound of the present invention when administered orally, has a long and strong pharmacological action.

APPLICATION IN INDUSTRY.

The compound of the present invention is applicable as a means for prevention or treatment of circulatory disorders such as hypertension and the like, and metabolic disorders such as diabetes, etc.

This application is based on patent application No. 2004-048928, filed in Japan patent application U.S. - SN. 11/031057, the contents of which are included in the description by reference.

1. Drug for antagonistic effects on angiotensin II, including the compound of formula (I)

in which R1represents a group of the formula

in which R2, R3, R4, R5, R6, R7and R8each independently represents a hydrogen atom or a C1-6alkyl, or its salt.

2. The drug according to claim 1, which is intended for the prevention or treatment of hypertension.

3. Drug intended for the prevention or treatment of circulatory disorders, which includes a compound of the formula I

in which R1represents a group of the formula

in which R2, R3, R 4, R5, R6, R7and R8each independently represents a hydrogen atom or a C1-6alkyl, or its salt.

4. A drug intended for the prevention or treatment of circulatory disorders, comprising a compound of formula (I)

in which R1represents a group of the formula

in which R2, R3, R4, R5, R6, R7and R8each independently represents a hydrogen atom or a C1-6alkyl, or its salt, in combination with a calcium antagonist.

5. The drug according to claim 4, where the calcium antagonist is a amlodipine or its salt.

6. A drug intended for the prevention or treatment of circulatory disorders, comprising a compound of formula (I)

in which R1represents a group of the formula

in which R2, R3, R4, R5, R6, R7and R8each independently represents a hydrogen atom or a C1-6alkyl, or its salt, in combination with a diuretic.

7. The drug according to claim 6, where a is a diuretic chlorthalidone.

8. Method for the prevention or treatment of circulatory disorders in a mammal, which VK is uchet introduction to the specified mammal an effective amount of a medicinal product according to claim 1 in combination with a calcium antagonist.

9. The method of claim 8, where the calcium antagonist is a amlodipine or its salt.

10. Method for the prevention or treatment of circulatory disorders in a mammal, which includes an introduction to the specified mammal an effective amount of a medicinal product according to claim 1 in combination with a diuretic.

11. The method according to claim 10, where a is a diuretic chlorthalidone.

12. The use of the drug according to claim 1 in combination with a calcium antagonist for the prevention or treatment of circulatory disorders.

13. The application indicated in paragraph 12, where the calcium antagonist is a amlodipine or its salt.

14. The use of the drug according to claim 1 in combination with a diuretic for the prophylaxis or treatment of circulatory disorders.

15. The application 14, where a is a diuretic chlorthalidone.

16. A drug intended for the prevention or treatment of hypertension comprising a compound of formula (I)

in which R1represents a group of the formula

in which R2, R3, R4, R5, R6, R7and R8each independently represents a hydrogen atom or a C1-6alkyl, or its salt, in combination with a calcium antagonist.

17. A drug intended for the prevention the IKI or treatment of hypertension, comprising the compound of formula (I)

in which R1represents a group of the formula

in which R2, R3, R4, R5, R6, R7and R8each independently represents a hydrogen atom or a C1-6alkyl, or its salt, in combination with a diuretic.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyridin-2-one and pyridazin-3-one derivatives, having Btk inhibiting activity. In formulae I-IV:

,

R denotes -R1-R2-R3 or -R2-R3; R1 denotes a heteroaryl containing 6 ring atoms, including one N heteroatom; R2 denotes -C(=O), -C(=O)N(R2'), where R2' denotes H; R3 denotes R4; where R4 is a lower alkyl, heterocycloalkyl, (lower alkyl) heterocycloalkyl or heterocycloalkyl (lower alkyl), where the heterocycloalkyl contains 6 ring atoms, including two heteroatoms selected from N and O; and where R4 can be substituted with one or more substitutes selected from lower alkyl, oxo group and lower alkoxy group; X denotes CH or N; Y1 denotes lower alkyl; n and m are equal to 0; values of radicals Y2, Y4 are given in the claim.

EFFECT: improved properties of compounds.

6 cl, 2 tbl, 42 ex

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenylaminopyrimidine compounds of formula I, which are JAK kinase inhibitors. In particular, these compounds selectively act on JAK2 kinase. The compounds can be used to treat diseases such as immunological and inflammatory diseases; hyperproliferative diseases, myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases. In the compound of formula I , Q and Z are independently selected from N and CR1; R1 is independently selected from hydrogen, halogen, R2, OR2, OH, R4, OR4, CN, CF3, (CH2)nN(R2)2, where n equals 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3 and OR5R4; or two substitutes R1 together with carbon atoms with which they are bonded form an unsaturated 5- or 6-member heterocyclic ring containing 1-4 N atoms; R2 is C1-4alkyl; R4 is R2, C2-4alkenyl or phenyl; R4 is NH2, NHR2, N(R1)2, substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or tetrahydrofuranyl unsubstituted and substituted or unsubstituted tetrahydropyranyl; R5 is C2-4alkylene; R6-R9 are independently selected from H, RXCN, halogen, substituted or unsubstituted C1-4alkyl, OR1, CO2R1, N(R1)2, NO2 and CON(R1)2, wherein at least one of R6-R9 is RXCN; the rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of treatment.

29 cl, 7 dwg, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to nitro-derivatives of polycyclic heterocyclic compounds, more specifically to a heterocyclic compound containing two nitrofurazan rings, directly bonded to a furazan ring, and specifically to 3,4-bis(4-nitrofurazan-3-yl)-furazan .

EFFECT: 3,4-bis(4-nitrofurazan-3-yl)-furazan as an energy-rich compound.

1 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula (I) wherein A, R1, R2, R3, R4, R5, R6 and R7 are presented in the description, preparing and using them as pharmaceutically active compounds possessing SP1/EDG1 receptor agonist activity.

EFFECT: using the declared compounds or pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition for preventing or treating the diseases or disorders associated with the activated immune system.

13 cl, 76 ex, 2 tbl

Azole compounds // 2493154

FIELD: chemistry.

SUBSTANCE: invention relates to compounds which are pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[3-(4-fluoromethyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[5-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate, 2,6-dimethylpyridin-3-yl 4-[5-(3,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[3-(2-fluorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[5-(3-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate and 6-methylpyridin-3-yl 4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate or to a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having inhibiting effect on fatty acid amide hydrolase (FAAH).

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for treating neuropathic pain.

13 cl, 38 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel of 2,4-pyrimidine diamine compounds of formula I, which inhibit degranulation of immune cells and can be used in treating cell reactions mediated by FcεRI or FcγRl receptors. In formula (I) each R2 and R4 is independently phenyl substituted with one or more R8 groups or a heteroaryl selected from a group consisting of , where the heteroaryl is optionally substituted with one or more R8 groups and at least one of R2 and R4 is a heteroaryl; R5 is selected from a group consisting of (C1-C6)alkyl, optionally substituted with one or more identical or different R8 groups, -ORd, -SRd, fluorine, (C1-C3)halogenalkyloxy, (C1-C3)perhalogenalkyloxy, -NRcRc, (C1-C3)halogenalkyl, -CN, -NO2, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc; -OC(NH)NRcRc, - [NHC(O)]nORd, R35 is hydrogen or R8; each Y is independently selected from a group consisting of O, S and NH; each Y1 is independently selected from a group consisting of O, S and NH; each Y2 is independently selected from a group consisting of CH, CH2, S, N, NH and NR37. Other values of radicals are given in the claim.

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to antibacterial compounds of formula (I) , where one or two of U, V, W and X represent N, the remaining ones represent CH or, in case X, can also represent CRa, where Ra represents fluorine; R1 represents alcoxygroup, halogen or cyanogroup; R2 represents H, CH2OH, CH2N3, CH2NH2, alkylcarbonylaminomethyl or triazol-1-ylmethyl; R3 represents H or, when n=1, R3 can also represent OH, NH2, NHCOR6 or triazol-1-yl; A represents CR4; K represents O, NH, OCH2, NHCO, NHCH2; CH2NH5 CH2CH2, CH=CH, CHOHCHOH or CHR5; R3 represents H or together with R5 forms bond, or R4 can also represent OH, when K is not O, NH, OCH2 or NHCO; R5 represents OH or together with R4 forms bond; R6 represents alkyl; m=0 or 1 and n=0 or 1; and G is specified in i.1 of the formula; and to salt of such compound.

EFFECT: obtaining antibacterial compounds.

19 cl, 1 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyridine derivatives pyridine1-A-pyridine2 of formula (1), where pyridine1 represents

, , or , ,

where asterisks stand for bond, which contains pyridine1 ring with A; R1 represents C1-5alkyl, C1-4alkoxygroup, C3-6-cycloalkyl, hydroxymethyl or NR1aR1b, R1a represents C1-4alkyl; R1b represents hydrogen or C1-3alkyl; or R1a and R1b, together with nitrogen atom, which is bound to pyridine, form pyrrolidine ring; R2 represents hydrogen or C1-4alkyl, or in case, when R1 represents C1-5alkyl or C3-6-cycloalkyl, R2 can additionally represent methoxygroup; R3 represents C1-4alkyl, C1-4alkoxygroup, C3-6-cycloalkyl or NR3aR3b; R3a represents C1-4alkyl; R3b represents hydrogen or C1-3alkyl; R4 represents C1-4alkyl or hydrogen; R5 represents C1-5alkyl, methoxygroup or NR5aR5b; and R6 represents C1-2alkyl; R5a represents C1-4alkyl; R5 represents hydrogen or C1-3alkyl; or R5 represents C1-2alkyl or methoxygroup; and R6 represents C1-5alkyl or NR6aR6b; R6a represents C1-4alkyl; R6b represents hydrogen or C1-3alkyl; R7 represents C1-5alkyl; R8 represents C1-2alkyl or methoxygroup; R9 represents C1-5alkyl; R10 represents C1-2alkyl; A represents

, , or ,

where asterisks stand for bond, binding pyridine1 ring with A; pyridine2 represents

, , or , ,

where asterisks stand for bond, which binds pyridine ring with A; R11 represents C1-4alkyl; C1-3alkyloxy group, hydroxymethyl or NR11aR11b; R,1a represents C1-3alkyl; R11b represents hydrogen or C1-2alkyl; R12 represents hydrogen or C1-4alkyl; R13 represents C1-4alkyl or NR13aR13b; R13a represents C1-4alkyl; R13b represents hydrogen or C1-2alkyl; R14 represents C1-2alkyl; R15 represents C1-4alkyl or NR15aR15b; and R16 represents C1-2alkyl; R15a represents C1-3alkyl; R15b represents hydrogen or C1-3alkyl; or R15 represents C1-2alkyl; and R16 represents C1-4alkyl or NR16aR16b; R16a represents C1-3alkyl; R16b represents hydrogen or C1-2alkyl; R17 represents C1-4alkyl; R18 represents C1-2alkyl or methoxygroup; R19 represents C1-4alkyl; and R20 represents C1-2alkyl; with exception of 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole; or pharmaceutically acceptable salt of such compound.

EFFECT: obtaining pyridine derivatives, which possess agonistic activity with respect to S1P1/EDG1.

15 cl, 2 tbl, 131 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, namely using an aqueous-alcohol solution of Hymenocardia acida leaves for preparing a pharmaceutical composition for treating hypertension.

EFFECT: using the aqueous-alcohol solution of Hymenocardia acida leaves enables preparing the composition for treating hypertension which is well-tolerated by the patients if administered regularly and continuously.

10 cl, 4 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (1) or salts thereof, where in formula (1) R1 is a lower C1-C6alkyl group, a lower C3-C6cycloalkyl group, a phenyl group, a heterocyclic group, which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom and a sulphur atom, or a phenyl(C1-C6alkyl) group; in cases when R1 is a lower C1-C6alkyl group, that lower C1-C6alkyl group can have, as substitute(s), one, two or three groups selected from a halogen atom, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one or two heteroatoms in the ring, selected from a nitrogen atom and an oxygen atom, a carboxyl group, a lower C1-C6alkoxycarbonyl group, a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a lower C1-C6alkylamino group, a lower C1-C6alkylamino group, substituted with a phenyl group; in cases when R1 is a phenyl group, a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated or unsaturated monocyclic heterocyclic ring containing one, two or three heteroatoms in the ring, selected from a nitrogen atom, an oxygen atom or a sulphur atom, or a phenyl(C1-C6alkyl) group, that phenyl, heterocyclic or phenyl(C1-C6alkyl) group can contain, as substitute(s), one, two or three groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group or a lower C1-C6alkoxy group; R2 is a hydrogen atom or a lower C1-C6alkyl group; R3 is a hydrogen atom or a lower C1-C6alkyl group; R4 and R5 can be identical or different and are a hydrogen atom or a lower C1-C6alkyl group; R6 is a hydrogen atom or a lower C1-C6alkyl group; R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom; in cases where R7 is a phenyl group or a heterocyclic group which relates to a residue formed by removing a hydrogen atom from a saturated monocyclic heterocyclic ring containing one heteroatom in the ring, selected from an oxygen atom and a sulphur atom, that phenyl or heterocyclic group can contain, as substitute(s), one or two groups selected from a halogen atom, a lower C1-C6alkyl group, a hydroxyl group, a lower C1-C6alkoxy group and a nitro group; W is an oxygen atom or NR8; R8 is a hydrogen atom or a lower C1-C6alkyl group; X is an oxygen atom or a sulphur atom; Y is a lower C1-C6alkylene group; Z is an oxygen atom, a sulphur atom, NR9 or OCO; R9 is a hydrogen atom or a lower C1-C6alkyl group. The invention also relates to a pharmaceutical composition based on said compounds, having GR binding activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine as glucocorticoid receptor modulators.

10 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention aims at a composition for treating pulmonary hypertension which contains an active agent consisting of 0.001 mg/ml to 20 mg/ml of an ACE inhibitor and additionally containing at least one humidifier. It is isotonic and has the pH value within 3 to 8. It is acceptable to administer the composition by inhalations into a mammal in need thereof. According to the invention, the compositions can represent a solution or a suspension, and preferentially, it is acceptable to administer them by spraying. The present invention also aims at a kit for treating a mammal suffering pulmonary hypertension. 2 primary claims, 12 secondary claims.

EFFECT: preparing the composition for treating pulmonary hypertension.

1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to a liquid oral solution for treating angiotensin II mediated disorders and conditions, and to a method for preparing it. The liquid oral solution contains valsartan in the concentration of 5 mg/ml or less, a wetting agent, a preserving agent, a flavouring agent, a buffer system and water with pH of the solution making 4.5-5.9. The wetting agent is poloxamer 188 described by the structure HO(CH2CH2O)a(CH(CH3)CH2OH)b(CH2CH2O)cH, wherein a is equal to 75, b is equal to 30, and c is equal to 75, with average molecular weight 8350. The buffer system contains alkali citrates and citric acid, alkali acetates and acetic acid, alkali succinates and succinic acid, or any mixtures thereof. The method for preparing the above solution involves mixing the ingredients added then with valsartan when heated.

EFFECT: group of inventions provides preparing the liquid solution of valsartan with an extended storage period.

8 cl, 12 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cyclic azaindole-3-carboxamides of formula (I) in any of its stereoisomeric forms or in the form of a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable salt thereof or a physiologically acceptable solvate of any of them: wherein A is specified in O, S and C(Ra)2; Ra is specified in hydrogen and (C1-C4)-alkyl wherein the two groups Ra are independent from each other and may be identical or different; R is specified from hydrogen, (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, phenyl-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-CO-CuH2u- and R1-NH-CO-CuH2u-, wherein all the groups R are independent from each other and may be identical or different; R1 is specified from hydrogen, (C1-C4)-alkyl and H2N-CO-(C1-C4)-alkyl-; R10 is specified from hydrogen, (C1-C6)-alkyl-O-CO-; R20 is specified from phenyl which is optionally substituted by one or more identical or different substitutes specified in halogen, (C1-C4)-alkyl and (C1-C4)-alkyl-O-; R30 is specified from (C3-C7)-cycloalkyl and phenyl, wherein phenyl is optionaly substituted by one or more identical or different substitutes specified in halogen and (C1-C6)-alkyl; R40 is specified in halogen, (C1-C4)-alkyl, phenyl-(C1-C4)-alkyl-, hydroxy, (C1-C4)-alkyl-O-, HO-CO-(C1-C4)-alkyl-O- and (C1-C4)-alkyl-O-CO-(C1-C4)-alkyl-O-, wherein all the substitutes R40 are independent from each other and may be identical or different; one of the groups Y1, Y2, Y3 and Y4 represents N, while the others are identical or different groups CH or CR40; n is specified in 0, 1, 2 and 3; p and q which are independent from each other and may be identical or different being specified in 2 and 3; n is specified in 0, 1 and 2, wherein all the values are independent from each other and may be identical or different; wherein all the alkyl groups are independently from each other optionally substituted by one or more fluorine atoms; wherein all the phenyl groups found in R and R40 are independently from each other optionally substituted by one or more identical or different substitutes specified in halogen and (C1-C4)-alkyl. Besides, the invention describes a method for preparing a compound of formula I, a pharmaceutical compositions having renin inhibitory activity and containing the compound of formula I and to using the compound of formula I for making a therapeutic preparation.

EFFECT: described and prepared are the new compounds that inhibit the enzyme renin, and modulate activity of the renin-angiotensin system, and are effective for treating the diseases such as, eg hypertension.

7 cl, 141 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition the form of an oral suspension consisting of valsartan or a pharmaceutically acceptable salt thereof and at least one or two or more ingredients specified in glycerol or a syrup or a mixture thereof, a preserving agent, a buffer system, a suspending/stabilising agent and anti-foaming agent. The buffer system is specified in sodium citrate, potassium citrate, sodium bicarbonate, sodium dihydrophosphate and potassium dihydrophosphate, and maintains pH of the composition within the range of 3.0 to 5.0. Further, the present invention refers to using the pharmaceutical composition for preparing a drug.

EFFECT: orally administered valsartan suspension provides high bioavailability and reduced variability of response to the administered dose when administered to different subjects or one subject.

10 cl, 4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a selective thiazolidinedione analogue to be used in treating and preventing diabetes and dyslipidemia, representing 5-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)benzyl)thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof. Also, the invention refers to a pharmaceutical composition for diabetes and dyslipidemia, containing an effective amount of 5-(4-(2-(3-methoxyphenyl)-2-oxoethoxy)benzyl)thiazolidine-2,4-dione or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. .

EFFECT: what is produced is the selective thiazolidinedione analogue decreasing binding and activating of the PPARγ nuclear transcription factor.

4 cl, 2 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cyclic indole-3-carboxamide of formula (I) or physiologically acceptable salts thereof of formula (I): wherein the values A, R, R10, R20, R30, R40, n, p and q are specified in clause 1 of the patent claim. A method for preparing them is described.

EFFECT: compounds have renin-inhibitory activity that allows using them for preparing a pharmaceutical composition and a drug preparation for treating the diseases associated with renin activity.

11 cl, 4 tbl, 127 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combined antihypertensive drug containing an agent presented by Amlodipine besilate and Lisinopril dehydrate mixed with an excipient. As the excipient, the specified antihypertensive drug contains microcrystalline cellulose of an average particle size of 90-100 mcm and a bulk density of 0.28-0.33 g/ml; as additives, it contains colloidal silicon dioxide, magnesium stearate and sodium carboxymethyl starch. The invention also refers to a method for preparing the mentioned antihypertensive drug by direct compression.

EFFECT: providing a stable drug preparation, more storage-stable, having high producibility, active substance distribution uniformity and bioavailability.

8 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to medicine, namely to solid peroral dosage form, obtained by rotation pressing, which includes therapeutically effective quantity of aliskiren or its pharmaceutically acceptable salt, and active ingredient is present in said dosage form in amount higher than 38% by weight of peroral dosage form, as well as to method of obtaining said solid peroral dosage form.

EFFECT: method with application of rotational pressing makes it possible to exclude application of solvent, requires for wet granulation, method ensures high content of drug agent in composition.

23 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine and concerns antagonising the hedgehog signalling pathway in a cell by using the methods of treating cancer with a cyclopamide derivative of general formula (1).

EFFECT: developing the new method of treating cancer.

34 cl, 5 tbl, 35 ex

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