MXPA06009260A - Benzimidazole derivative and use thereof - Google Patents

Abstract

The present invention relates to a compound represented by the formula (I) wherein R1 is a group represented by the formula wherein R2, R3, R4, R5, R6, R7 and R8 are each independently a hydrogen atom or a C6 - 1 alkyl, or a salt thereof. The compound of the present invention is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and the like.

Description

DERIVATIVE OF BENCIMIDAZOL AND USE OF THE SAME FIELD OF THE INVENTION The present invention relates to a novel benzimidazole derivative possessing the superior properties of a pharmaceutical agent. More particularly, the present invention relates to a prodrug of a benzimidazole derivative having a particular structure, which has a strong and prolonged angiotensin II antagonist activity and hypotensive action and an insulin sensitizing activity; it is also useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension, heart diseases (cardiac hypertrophy, heart failure, cardiac infarction and the like), nephritis, stroke, and the like and metabolic diseases such as diabetes and the like, and the use thereof. BACKGROUND OF THE INVENTION Angiotensin II causes vasoconstriction through an angiotensin II receptor in the cell membrane and raises blood pressure. Accordingly, an angiotensin II receptor antagonist may constitute a drug of therapeutic utility for circulatory diseases such as hypertension and the like. As a preferred chemical structure for expressing a strong angiotensin II antagonist REF.173839 activity is known a structure possessing an acid group such as a tetrazolyl group, a carboxyl group and the like in a biphenyl side chain, while, as a pharmaceutical compound with such structural features, clinically, losartan, candesartan cilexetil, olmesartan medoxomil and the like have been used (Ruth R. Wexler et al., Journal of Medicinal Chemistry, vol.39, "p.625 (1996), JP-A-4-364171 , JP-A5-78328 and the like.) JP-A-5-271228 discloses that a compound in which an acidic group on a biphenyl side chain is a 5-oxo-4,5-dihydroyl group, 2,4-oxadiazol-3-yl exhibits a strong and prolonged angiotensin II antagonist activity and hypotensive action by oral administration In addition, OO3 / 047573 discloses that, among the benzimidazole derivatives described in JP-A- 5-271228, a compound parti cular (2-ethoxy-l- acid. { [2 '- (5-oxo-4,5-dihydro-l, 2, -oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid: compound A) possesses insulin sensitization activity in addition to the angiotensin II antagonist activity. As a means for improving the practical use of a pharmaceutical agent, it is known to convert a compound having some pharmacological activity to a prodrug. For example, in the development of pharmaceutical products, in the case of compounds that show an insufficient expression of activity when administered orally, such as a carboxylic acid prodrug, alkylcarbonyloxymethyl ester, 1-alkylcarbonyloxyethyl ester, alkyloxycarbonyloxymethyl ester, have been used to a large extent, 1-Alkyloxycarbonyloxyethi? Ester and (5-methyl-2-oxo-l, 3-dioxol-4-yl) ethyl ester. In addition, among others, Farnesol ester, which is a liposoluble substance of indomethacin, and ethyl ester as an ACE inhibitor are known to achieve sustained activity. JP-A-5-271228 specifically discloses esters of compound A, methyl ester (compound B), 1- (cyclohexyloxycarbonyloxy) ethyl ester (compound C) and acetoxymethylester (compound D). The present invention has for its object to provide a new superior compound as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and the like. BRIEF DESCRIPTION OF THE INVENTION The inventors of the present have carried out intensive studies to discover a new compound that is more powerful and effective in terms of the duration of its action when administered orally, through which an agent is provided. pharmaceutically more useful from the clinical point of view as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and the like. As a result they have discovered that a prodrug compound that has some structure, which becomes a compound A in the body, shows that it is excellently safe and has extremely superior properties as a pharmaceutical agent, as evidenced by the unexpectedly strong and long-lasting hypotensive action, and the possible stabilization of blood pressure over a long period of time. time and the like, having implemented the present invention. Accordingly, the present invention relates to (1) a compound represented by the formula (1) in which R1 is a group represented by the formula wherein R2, R3, R4, R5, R6, R7 and R8 are each independently a hydrogen atom or C? alkyl? 6, or salt thereof; (2) the above-mentioned compound (1), which is a salt; (3) the above-mentioned compound (1), in which R1 is a group represented by the formula R2 in which R2. maintains the previous definition; (4) a compound selected from the group consisting of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2, -oxadiazol-3-i1) biphenyl-1-yl] methyl} - l-benzimidazole-7-carboxylate, 2-oxo-l, 3-dioxolan-4-yl-2-ethoxy-1 -. { [2'- (5-oxo-4, 5-dihydro-1,2,4,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate, 4-methyl-2-oxo-l, 3-dioxolan-4-yl-2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-- benzimidazole-7-carboxylate and 5-oxotetrahydro-2-furanyl 2-ethoxy-1-. { [2 '- (5-oxo-4, 5-dihydro-1, 2, -oxadiazol-3-yl) ifenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate, or salts thereof; (5) Potassium salt of (5-methyl-2-oxo-l, 3-dioxol-4-yl) ethyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2, -oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate (6) A process for producing a compound represented by the formula Wherein R2 is a hydrogen atom or C alquilo alkyl? 6, or one thereof, which comprises reacting a reagent derived from 2-ethoxy-1- acid. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid or a salt thereof with a compound represented by the formula wherein R2 maintains the above definition, or a salt thereof; (7) a medicament comprising the compound of the aforementioned (1); (8) the aforementioned medicament (7), which is an angiotensin II antagonist; (9) the aforementioned medicament (7), which is an insulin sensitizer; (10) the aforementioned medicament (7), which is an agent for the prophylaxis or treatment of circulatory diseases; (11) a medicament comprising the aforementioned compound (1) in combination with a calcium antagonist or a diuretic agent; (12) the aforementioned medicament (11), which is an agent for the prophylaxis or treatment of circulatory diseases; (13) a method for antagonizing angiotensin II in a mammal, comprising administering an effective amount of the compound of the aforementioned (1) to said mammal; (14) a method for improving the resistance of insulin in a mammal, which comprises administering an effective amount of the aforementioned compound (1) to said mammal; (15) a method for preventing or treating circulatory diseases in a mammal, comprising administering an effective amount of the aforementioned compound (1) to said mammal; (16) a method for preventing or treating circulatory diseases in a mammal, comprising administering an effective amount of the aforementioned compound (1) in combination with a calcium antagonist or a diuretic agent to said mammal; (17) use of the aforementioned compound (1) for the manufacture of an angiotensin II antagonist; (18) use of the aforementioned compound (1) for the manufacture of an insulin sensitizer; (19) use of the aforementioned compound (1) for the manufacture of an agent intended for the prophylaxis or treatment of circulatory diseases; (20) use of the aforementioned compound (1) in combination with a calcium antagonist or diuretic agent for the manufacture of an agent intended for the prophylaxis or treatment of circulatory diseases; and similar. DETAILED DESCRIPTION OF THE INVENTION In the above formula, R1 is a group represented wherein R2, R3, R4, R5, R6, R7 and R8 are each independently a hydrogen atom or C? -6 alkyl, such as C? _6 alkyl it is possible to mention, for example, methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3, 3-dimethylbutyl, 2 -ethylpropyl and the like. For R1, a group represented by the formula is preferred where R2 is preferred as the above definition, while methyl is preferred for R2. In the previous formula, the group represented by the formula (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl group) includes three tautomers (a1, b 'and c') represented by the formulas a * V C while a 5-oxo-4,5-dihydro-l, 2-oxadiazol-3-yl group embraces the aforementioned a ', b' and e '. As a compound represented by the formula (I) of the present invention, it is preferable to use (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] ethyl} - lH-benzimidazole-7-carboxylate, 2-oxo-l, 3-dioxolan-4-yl-2-ethoxy-1 -. { [2.1 - (5-oxo-4, 5- "dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl.}. -IH-benzimidazole-7-carboxylate, 4-methyl- 2-oxo-l, 3-dioxolan-4-yl 2-ethoxy-l- { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl -4-yl] methyl.}. - lH-benzimidazole-7-carboxylate, 5-oxotetrahydro-2-furanyl 2-ethoxy-l- { [2 '- (5-oxo-4, 5-dihydro-l , 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} - lH-benzimidazole-7-carboxylate, and the like, Among them, (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl 2-ethoxy-l- { [2 '- (5-oxo-4,5-dihydro-l, 2, -oxadiazol-3-yl) biphenyl-4-yl] methyl.}. -lH-benzimidazole-7-carboxylate The salt of a compound represented by the formula (1) can be any to the extent that it is pharmaceutically acceptable. As it is possible to mention salts of a compound represented by the formula (1) with an inorganic base (for example, alkali metals such as sodium, potassium and the like, alkaline earth metals such as calcium, magnesium and the like, etc.), a organic base (e.g., organic amines such as tromethamine [tris (hydroxymethyl) methylamine], ethanolamine, trimethylamine, triethylamine, t-butylamine, pyridine, picoline, diethanolainine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like; such as arginine, lysine, ornithine and the like, etc.), ammonia and the like. As the salt of the compound represented by the formula (1), the alkali metal salts of the compound represented by the formula (I) are preferred. Among these, potassium salt is particularly preferred. The compound represented by the formula (I) can be labeled with an isotope (for example, 3 H, 14 C, 35 S, 125 I and the like), and the like. As a compound represented by the formula (I) or a salt thereof (hereinafter in some cases referred to as compound (1) or compound of the present invention), the potassium salt of (5-methyl-2-oxo-1) is particularly preferred. , 3-dioxol-4-yl) methyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2, -oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate. Methods of Preparation The compound (I) can be produced, for example, by the method shown in the following or a method analogous thereto, and the like. However, the yield of the compound (I) obtained in the following method can vary according to the reaction conditions used, the compound (I) can be easily obtained with a high degree of purity through conventional means of separation or purification (eg, recrystallization, column chromatography and the like) from the product by such methods. The compound (I) can be produced by subjecting a reaction to a reactive derivative (eg, a mixed acid anhydride, acid halide and the like) of the compound represented by the formula (II) (compound A) or a salt thereof (hereinafter in some cases "called as a compound (II)) with a corresponding alcohol (IV) (HO-R1) or a salt thereof. Method a (H) (I) where X is a halogen atom (chlorine, bromine, iodine, etc.), Et is an ethyl, R12 is alkyl (for example C6_6 alkyl such as methyl, ethyl, propyl, t-butyl, and the like), alkoxy ( for example, C6-C6 alkoxy such as methoxy, ethoxy, isobutyloxy, and the like) or phenyl optionally substituted by a halogen atom, alkyl C? _6 or a nitro group and the like, R1 maintains the above definition. The method a comprises reacting the compound (II) with an acylating agent (III) in the presence of a base to obtain a mixed acid anhydride and reacting the resulting compound with a corresponding alcohol (IV) (HO-R1) in the presence of a base to allow esterification. The mixed acid anhydride is produced using between about 1 and 3 moles of a base and between about 1 and 3 moles of an acylating agent relative to 1 mole of the compound (II) in a solvent. Subsequently, the corresponding alcohol is incorporated to allow the reaction, or after the salt is filtered (salt of the base with HX), the filtrate is concentrated, the residue is diluted with a solvent and the corresponding alcohol and a base are added to allow that the reaction carries out the esterification. As a base, it is possible to employ triethylamine, diisopropylethylamine, DBU, 4-dimethylaminopyridine, sodium hydride, potassium t-butoxide, calcium carbonate and sodium carbonate. As the acylating agent, pivaloyl chloride, ethyl chlorocarbonate, isobutyl chlorocarbonate, or 2,4,6-trichlorobenzoyl chloride, 2,6-dichlorobenzoyl chloride, 2,4,6-tribromobenzoyl chloride, 2-chlorocarbonyl chloride, , 3, 6-trimethyl-4,5-dinitrobenzoyl and the like described in Bulletin of the Chemical Society of Japan, vol. 52, 1989-1993 page (1979).

As a solvent, it is generally possible to use dichloromethane, chloroform / 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, toluene, acetonitrile, acetone, ethyl methyl ketone, dioxane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like. Although the reaction conditions for the production of a mixed acid anhydride vary according to the combination of the base, the acylating agent and the solvent to be used, the reaction in general is preferably carried out at a temperature ranging from approximately - 30 ° C at room temperature for between about 1 and 10 The reaction conditions for the esterification vary according to the combination of the obtained mixed acid anhydride and a solvent, the reaction is preferably preferably carried out at a temperature ranging from about -30 ° C. Reflux temperature of the solvent for between about 1 and 10 hours. Method b (p) (I) where R1 maintains the previous definition.

Method b comprises subjecting a reaction represented by formula (II) or a salt thereof with thionyl chloride or oxalyl chloride in the presence of a catalyst such as DMF and the like to obtain an acid chloride, and subjecting the chloride to a reaction. acid to a reaction with the corresponding alcohol (IV) in the presence of a base to allow esterification. The acid chloride is prepared using between about 1 and 3 moles of thionyl chloride or oxalyl chloride relative to 1 mole of the compound (II) in the presence of a catalytic amount of DMF, in a solvent as necessary. After the subsequent concentration, a solvent is added and then the corresponding alcohol (HO-R1) and the base to allow the reaction to carry out the esterification. As a base, it is possible to use those similar to the bases used in methods A and the like. As a solvent, it is possible to use those similar to the solvents used in Method a and the like. Although the reaction conditions for producing an acid chloride vary according to the solvent to be used, in general the reaction is preferably carried out at a temperature ranging from about -30 ° C to reflux temperature for between about 10 minutes and 5 minutes. hours . The reaction conditions for the esterification vary according to the combination of the acid chloride produced and the solvent, the reaction is preferably preferably carried out at a temperature ranging from about -30 ° C to the reflux temperature of the solvent for about 1 hour. to 10 hours. Method c (fl) (I) in which X 'is a halogen atom (chlorine, bromine, iodine, etc.) and R1 maintains the above definition. Method c comprises subjecting a reaction represented by formula (II) or a salt thereof to a reaction. (for example, a salt with an alkali metal such as sodium, potassium and the like; salt with an alkaline earth metal such as calcium, magnesium and the like, etc.) with an alkylating agent (X'-R1) as necessary in the presence of a base to allow esterification. The esterification is carried out using between about 1 and 3 moles of a base and between about 1 and 3 moles of an alkylating agent relative to 1 mole of the compound (II) in a solvent. As a base, it is possible to use those similar to the bases used in Method a and the like. As a solvent, it is possible to use those similar to the solvents used in Method a and the like. However the reaction conditions for the esterification vary according to the combination of the base, alkylating agent and solvent to be used, the reaction in general and preferably is carried out at a temperature ranging from about -30 ° C to a temperature of reflux for between about 30 minutes and 10 hours. Method d cp) (i) where R1 maintains the previous definition. The method d comprises reacting the compound (II) with the corresponding alcohol (IV) in the presence of a condensing agent to carry out the esterification. The esterification is carried out using between about 1 and 3 moles of the condensing agent and between about 1 and 3 moles of the corresponding alcohol (IV) relative to 1 mole of the compound (II) in a solvent. DCC is used as the condensing agent, WSC, Mitsunobu reagents and the like. As a solvent, it is possible to use those similar to the solvents used in Method a and the like. Although the reaction conditions for the esterification vary according to the combination of the condensing agent and the solvent to be used, in general and preferably the reaction is carried out at a temperature ranging from about -30 ° C to reflux temperature during between approximately 30 minutes and 24 hours. The compound (II) can be prepared by the method described in JP-A-5-271228 and the like. When the compound (I) is obtained as a free form, it can be converted into an object salt through a method known per se or a method analogous thereto. Reciprocally, when it is obtained as a salt, it can be converted into a free form or another salt of a different object through a method known per se or analogous to it. If optical isomers of the compound (I) exist, such optical isomers and mixtures thereof of course all fall within the scope of the present invention. The compound (I) can be a crystal, and can take the form of a single crystal or a mixture of multiple crystals. The crystals can be produced by crystallization according to a crystallization method known per se. The compound (I) is preferably a crystal. The compound (I) can be a solvate (eg, hydrate, etc.) and both the solvate and the non-solvate (eg, non-hydrate, etc.) fall within the scope of the present invention. The compound of the present invention thus produced shows less toxicity and is safe (in other words, it constitutes a more superior pharmaceutical agent considering the aspects of acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, interaction with other drugs. , carcinogenicity, and the like), and rapidly becomes compound A in the living body of an animal, particularly a mammal (e.g., human, monkey, cat, pig, horse, bovine, mouse, rat, guinea pig, dog , rabbit, etc.). Whereas compound A normalizes the transduction mechanism of the intracellular insulin signal, which primarily causes insulin resistance, consequently reduces insulin resistance and improves its action, and has an improved action of glucose tolerance . Therefore, the compound of the present invention can be used in mammals (e.g., human, monkey, cat, pig, horse, bovine, mouse, rat, guinea pig, dog, rabbit, etc.) as an enhancing agent or a agent for the prophylaxis and / or treatment of diseases in which insulin resistance is involved. As such diseases, it is possible to mention, for example, insulin resistance, impaired glucose tolerance; diabetes such as non-insulin dependent diabetes, type II diabetes, type II diabetes associated with insulin resistance, type II diabetes associated with impaired glucose tolerance, etc .; various complications such as hyperinsulinemia, hypertension associated with insulin resistance, hypertension associated with impaired glucose tolerance, hypertension associated with diabetes (eg, type II diabetes, etc.), hypertension occurs in association with hyperinsulinemia, resistance to insulin occurs in association with hypertension, impaired glucose tolerance that occurs in association with hypertension, diabetes that occurs in association with hypertension, hyperinsulinemia that occurs in association with hypertension, diabetic complications (eg, microangiopathy, diabetic neuropathy, diabetic nephropathy , diabetic retinopathy, diabetic cataract, large vessel disease, osteopenia, diabetic hyperosmolar coma, infectious diseases (eg, infectious respiratory disease, infectious disease of the urinary tract, digestive infectious disease, infectious soft tissue disease, in infectious disease of the lower limb, etc.), diabetic gangrene, dry mouth, decreased auditory sensitivity, diabetic cerebrovascular disorder, diabetic peripheral hematogenic disorder, diabetic hypertension, and the like), diabetic cachexia and the like. The compound of the present invention can also be used to treat patients with normal high blood pressure with diabetes. Since compound A exerts a strong angiotensin II antagonist activity, the compound of the present invention is useful as an agent for the prophylaxis or treatment of a disease (or a disease whose onset is stimulated) developed by the contraction or growth of blood vessels or organic disorder, which is expressed through an angiotensin II receptor, or due to the presence of angiotensin II, or a factor induced by the presence of angiotensin II, in mammals (eg, human, monkey, cat , pig, horse, bovine, mouse, rat, guinea pig, dog, rabbit, etc.). Among such diseases, it is possible to mention, for example, hypertension, abnormality of the blood pressure cycardian, heart diseases (eg, cardiac hypertrophy, acute heart failure and chronic heart failure including congestive heart failure, cardiac myopathy, angina pectoris, myocarditis , atrial fibrillation, arrhythmia, tachycardia, cardiac infarction, etc.), cerebrovascular disorders (for example, asymptomatic cerebrovascular disorder, transient cerebral ischemia, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.), cerebral edema, cerebral circulatory disorder, recurrence and sequelae of cerebrovascular disorders (eg, neurotic symptoms, psychic symptoms, subjective symptoms, disruption of daily activities, etc.), peripheral ischemic circulation disorder, myocardial ischemia, venous insufficiency, progress of heart failure after e cardiac infarction, renal diseases (eg, nefritts, glomerulonephritis-, glomerulosclerosis, renal insufficiency, thrombotic vasculopathy, dialysis complication, organic dysfunction including nephropathy derived from radiation damage, etc.), arteriosclerosis including atherosclerosis (e.g. , aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriesclerosis, etc.), vascular hypertrophy, vascular hypertrophy or obliteration and organic dysfunctions after an intervention (for example, percutaneous transluminal coronary angioplasty, stenting, coronary angioscopy, intravascular ultrasound, therapy thrombolytic, etc.), vascular reobliteration and restenosis after bypass, polycythemia, hypertension, organic disorder and vascular hypertrophy after transplantation, rejection after transplant, eye diseases (eg, glaucoma, ocular hypertension, etc.), thrombosis, multiple organ dysfunction, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (eg, deep vein thrombosis, peripheral obstructive circulatory disease, arteriosclerosis obliterated, obstructive thromboangiitis, cerebral ischemic circulatory disease, Raynaud's disease, Berger's disease, etc.), metabolic and / or nutritional disorders (for example, "obesity, -hyperlipidemia, hypercholesterolemia, hyperuricacidemia, hyperkalemia, hypernatremia, etc.), "nerve" degenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.), diseases of the central nervous system (eg, cerebral hemorrhage, cerebral infarction, its sequelae and complications, damage cerebral, spinal cord damage, cerebral edema, disfu sensorial disorders, sensory functional disorder, autonomic nervous system disorder, autonomic nervous system malfunction, multiple sclerosis, etc.), dementia, memory failure, consciousness disorder, amnesia, anxiety symptom, catatonic symptom, altered mental state , psychopathies (eg, depression, epilepsy, alcoholism, etc.), inflammatory diseases (eg, arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis, etc.).; inflammation after surgery and injuries; swelling remission; pharyngitis; cystitis; pneumonia; atopic dermatitis; Inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, etc .; meningitis; ocular inflammatory disease; inflammatory lung disease such as pneumonia, pulmonary silicosis, pulmonary sarcosidosis, pulmonary tuberculosis, etc.), allergic diseases (eg, allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis, etc.), chronic obstructive pulmonary disease, interstitial pneumonia pneumonia Carinni pneumocitis, collagen diseases (eg, systemic lupus erythematosus, scleroderma, polyarteritis, etc.), liver diseases (eg, hepatitis, including chronic hepatitis, liver cirrhosis, etc.), portal hypertension, diseases of the digestive system (for example, gastritis, gastric ulcer, gastric cancer, gastric disorder after surgery, dyspepsia, esophageal ulcer, pancreatitis, colon polyps, cholelithiasis, hemorrhoidal disease, esophagus and stomach varices rupture, etc.), diseases of the blood and / or myelopoietic (eg, erythrocytosis, vascular purpura, autoimmune hemolytic anemia) mune, disseminated intravascular coagulation syndrome, multiple myelopathy, etc.), bone diseases (eg, fracture, refracture, osteoporosis, osteomalacia, Paget's disease, sclerosing myelitis, rheumatoid arthritis, osteoarthritis of the knee and tissue dysfunction of joints and "like" caused by diseases similar to these, etc.), "solid tumor, tumors (eg, malignant melanoma, malignant lymphoma, cancer of the digestive organs (eg, stomach, intestine, etc.), cancer and cachexia after cancer, cancer of metastasis, endocrinopathies (eg, Addison's disease). "Cushing syndrome", pheochromocytoma, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, organ diseases urinals and / or male genitalia (for example, - _ cystitis, prostatic hypertrophy, prostate cancer, sexual infectious disease, etc.), female disorders (eg, climacteric disorder, gestos, endometriosis, hysteromyoma, ovarian disease, breast disease, infectious sexually transmitted disease), disease related to the environment and occupational factors (for example, exposure to radiation, exposure to UV rays, infrared or lasers, altitude sickness, etc.), respiratory diseases (eg, colds, pneumonia, asthma, pulmonary hypertension, thrombosis pulmonary, and pulmonary embolism, etc.), infectious diseases (eg, viral infectious diseases with cytomegalovirus, influenza virus, herpes virus, etc., rickettsia, bacterial infectious disease, etc.); toxemias (eg, sepsis, septic shock, endotoxin shock, Gram-negative 5 sepsis, toxic shock syndrome, etc.), otorhinolaryngological diseases (eg, Meniere's syndrome, tinnitus, dysgenesis, vertigo, imbalance, dysphagia, etc.) , skin diseases (eg, keloid, hemangioma, psoriasis, etc.), intradialitic hypotension, myasthenia gravis, systemic diseases such as chronic fatigue syndrome. Since the compound of the present invention is capable of maintaining a constant hypotensive action both day and night, it is possible to reduce its dose and frequency of administration in relation to the administration of the compound A. In addition, it can effectively suppress the increase particularly problematic of blood pressure before and after rising in the case of hypertensive patients. Furthermore, through the sustained suppression during a longer period of the action of angiotensin II, the compound of the present invention improves the disorders or abnormalities or suppresses its generation in the biofunctional and physiological action, which causes disorders and several diseases in adults. associated with aging, and the like, which in turn leads to the primary and secondary prophylaxis of diseases or clinical conditions caused as a consequence or suppression of their progress. Among the disorders or abnormalities in biofunction and physiological action, it is possible to mention, for example, disorder or abnormality in the capacity of automatic control of the cerebral circulation and / or renal circulation, disorders in the circulation (for example, peripheral, cerebral, microcirculation, etc.), bleeding barrier disorder, salt susceptibility, abnormal coagulation status and fibrinolysis system, abnormal state of blood and cellular components of the blood (eg, accentuation of platelet accumulation activity , capacity of deformation of erythrocytes, accentuation of the adhesion of leukocytes, increase of blood viscosity, etc.), production and accentuation of the function of growth factors and cytokines (for example, PDGF, VEGF, interleukin, TNF-a, MCP-1, etc.), accentuation of the proliferation and infliltration of inflammatory cells, accentuation of radical production is free, accentuation of liposteatosis, endothelial function disorder, endothelium dysfunction, cells and organs, edema, change in cell morphogenesis of smooth muscles, etc. (morphogenesis at type of proliferation, etc.), accentuation of the production and function of vasoactive substances and inducers of thrombosis (for example, endothelin, thromboxane A2, etc.), abnormal constriction of blood vessels, etc., metabolic disorder ( for example, serum lipid abnormalities, dysglicemia, etc.), abnormal growth of cells, etc., angiogenesis (including abnormal vasculogenesis during abnormal capillary reticular formation in the adventitial plaque of arteriosclerosis) and the like. Among these, the present invention can be used as an agent for the primary and secondary prophylaxis or treatment of organic disorders linked to various diseases (e.g., cerebrovascular and organic disorders linked to them, organic disorders associated with cardiovascular disease, organic disorders after an intervention, etc.). In particular, since compound A has a proteinuria inhibitory activity, the compound of the present invention can be used as an agent for the protection of the kidneys. Accordingly, the compound of the present invention can be conveniently used when patients with insulin resistance, impaired glucose tolerance, diabetes or hyperinsulinemia have concurrently developed the aforementioned diseases or clinical conditions. Considering that compound A is capable of inhibiting body weight gain, the compound of the present invention can be employed as an inhibitor of weight gain in mammals. The mammals subject to this treatment can be any mammal in which the increase in body weight should be avoided. Mammals may have a genetic tendency to gain weight or suffer from diseases related to life habits such as diabetes, hypertension and / or hyperlipidemia, etc. Weight gain can be caused by excessive feeding or a diet without a balance of nutrients, or be linked to the administration of certain drugs, for example, insulin sensitizers that have PPAR agonistic activity? such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc., and the like. In addition, weight gain may precede obesity, or occur in obese patients. In this case, obesity is defined through a BMI (body mass index); body weight (kg) / (height (m)] 2) of at least 25 in the case of Japanese (criterion of Japan Society for the Study of Obesity), or of at least 30 in the case of Westerners ( WHO criteria). The new criteria were reported with respect to the criteria of diabetes in 1999 by the Japan Diabetes Society. According to this report, diabetes is a condition in which the fasting blood glucose level (glucose concentration in venous plasma) is not lower than 126 mg / dl, while the value of 2 hours (concentration of venous plasma glucose) of the oral glucose tolerance test for 75 g (OGTT 75g) is not less than 200 mg / dl, or the casual blood glucose level (glucose concentration of venous plasma) is not less than 200 mg / dl. In addition, that condition that does not fall within the aforementioned diabetes classification, and which is not a "condition where the fasting blood glucose level (venous plasma glucose concentration) is less than 100 mg / dl, or the value of 2 hours (glucose concentration in venous plasma) of the oral glucose tolerance test for 75 g (OGTT 75g) is less than 140 mg / dl "is called" border type ". In addition, regarding the diagnostic criteria for diabetes, ADA (The American Diabetes Association) has reported new criteria in 1997, the WHO having done the same in 1998. According to these reports, diabetes is a condition in which the fasting blood glucose level (concentration "of plasma venous glucose) is not lower than 126 mg / dl, while the value of 2 hours (venous plasma glucose concentration) of the oral glucose tolerance test per 75 g is not lower than 200 mg / dl Furthermore, according to the aforementioned reports, impaired glucose tolerance is a condition in which the fasting blood glucose level (glucose concentration in venous plasma) is lower at 126 mg / dl, while the 2-hour value (glucose concentration in venous plasma) of the oral glucose tolerance test for 75 g is not lower than 140 mg / dl but lower than 200 mg / dl. according to the ADA report, that condition in the which the fasting blood glucose level, (glucose concentration in venous plasma) is not lower than 110 mg / dl but lower than 126 mg / df is called IFG (Impaired Fasting Glucose). On the other hand, according to the WHO report, when the value of 2 hours (glucose concentration in venous plasma) in the oral glucose tolerance test for 75 g is lower than 140 mg / dl, is called IFG '(I'mpampading Fasting Glycemia). The compound of the present invention can be used as an enhancing agent or agent for the prophylaxis or treatment of diabetes, border type condition, IFG (Impaired Fasting Glucose), and IFG (Impaired Fasting Glycemia) according to the definition of the new diagnostic criteria mentioned above. In addition, the compound of the present invention can also be used as a therapeutic agent for hypertension of hypertensive patients who do not exhibit a level below the aforementioned diagnostic criteria (e.g., fasting blood glucose level of 126 mg. / dl). On the other hand, the compound of the present invention can also be used to prevent the advance of the border type condition, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glicemia) of diabetes. The compound of the present invention is useful as an agent for the prophylaxis or treatment of the metabolic syndrome. Given that patients with metabolic syndrome have an extremely high incidence of cardiovascular diseases with respect to patients suffering from diseases related to simple life habits, the prophylaxis or treatment of the metabolic syndrome is of paramount importance to avoid cardiovascular diseases. The criteria for the diagnosis of metabolic syndrome were announced by the WHO in 1999 and by NCEP 2001. According to the WHO criterion, patients with at least two of abdominal obesity, dyslipidemia (high triglyceride content in serum or low cholesterol) HDL), hypertension in addition to hyperinsulinemia or fasting blood glucose suffer from metabolic syndrome (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications.) Part I: Diagnosis and Classification of Diabetes Mellitus, World Healt Organization, Geneva, 1999 ). According to the criterion of Adult Treatment Panel III of the National Cholesterol Education Program, which is an indicator to control ischemic heart disease in the United States of America, patients with at least 3 abdominal obesity, high triglycerides, low HDL cholesterol, Hypertension and Fasting Blood Glucose Suffer Metabolic Syndrome (National Cholesterol Education Program: Executive Summary of the Third National Report Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel III The Journal of the American Medical Association, Vol. 285, 2486-2497, 2001).

The compound of the present invention can be used to treat high blood pressure patients with metabolic syndrome. Since compound A possesses anti-inflammatory action, the compound of the present invention can be used as an anti-inflammatory agent - intended to prevent or treat inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases due to various diseases such as arthritis (eg, rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, synovitis), asthma, allergic diseases, arteriosclerosis including atherosclerosis (aneurysm, coronary sclerosis, sclerosis cerebral arterial, peripheral arterial sclerosis, etc.), diseases of the digestive tract such as inflammatory bowel diseases (for example, Crohn's disease, ulcerative colitis), diabetic complications (diabetic nervous disorder, diabetic vascular disorder), atopic dermatitis, pulmonary disease chronic obstructive, systemic lupus erythematosus, visceral inflammatory disease (nephritis, hepatitis), autoimmune hemolytic anemia, psoriasis, nervous degenerative diseases (for example, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy), diseases of the central nervous system (for example, cerebrovascular disorders such as cerebral hemorrhage, cerebral infarction, head trauma, spinal cord damage, cerebral edema, multiple sclerosis), meningitis, angina, cardiac infarction, congestive heart failure, vascular hypertrophy or occlusion and organic disorders after an intervention (transdermal coronary plasty, stent placement, coronary endoscopy, intravascular ultrasound, intracoronary thrombolysis, etc.), ocular reocclusion or restenosis after a bypass operation, endothelial functional disorder, other circulatory diseases (intermittent claudication, peripheral obstructive circulatory disorder, obstructive arteriosclerosis, obstructive thrombotic angitis, cerebral ischemic circulatory disorder, Raynaud's disease, Berger's disease), inflammatory eye disease, inflammatory lung disease (eg, chronic pneumonia, silicosis, pulmonary sarcosidosis, pulmonary tuberculosis), endometritis, toxemia (eg, sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, etc.) , cachexia (eg, cachexia by infection, carcinomatous cachexia, cachexia due to AIDS), cancer, Addison's disease, Creutzfeldt-Jakob disease, viral infections (eg, infection of viruses such as cytomegalovirus, influenza virus, herpes) , etc.), disseminated intravascular coagulation.

In addition, since compound A possesses analgesic action, the compound of the present invention can also be used as an analgesic agent to prevent or treat pain. Examples of painful • diseases include acute pain from inflammation, pain associated with chronic inflammation, pain associated with acute inflammation, pain after surgery (pain in the incision, deep pain, organic pain, chronic pain after surgery, etc.), muscle pain (muscle pain associated with chronic pain, stiff shoulders, etc.), arthralgia, toothache, gnaticartralgia, headache (migraine, catatonic headache, headache associated with fever, pain headache associated with hypertension), organic pain (heart pain, angina pain, abdominal pain, kidney pain, ureteral pain, bladder pain), pain in the obstetric area (mittelshmerz, dysmenorrhea, labor pain), neuralgia, (disk hernia, nerve root pain, neuralgia after shingles, trigeminal neuralgia), carcinomatous pain, reflex sympathetic atrophy, complex local pain syndrome, and the like. The compound of the present invention is effective in the direct and rapid relief of various pains such as nerve pain, carcinomatous pain and inflammatory pain, and exhibits a particularly excellent analgesic effect in patients and on pathologies where the threshold of the sense of pain descends.

The compound of the present invention is of particular utility as an analgesic agent for pain associated with chronic inflammation or pain associated with hypertension, or as an agent to prevent or treat an inflammatory disease or pain due to (1) arteriosclerosis including atherosclerosis, (2) vascular hypertrophy, occlusion and organic disorder after an intervention, (3) reocclusion, restenosis or endothelial functional disorder after a bypass operation, (4) intermittent claudication, (5) peripheral occlusive circulatory disorder, (6) occlusive arteriosclerosis. The compound of the present invention can be used as a safe pharmaceutical agent in mammals (eg, human, monkey, cat, pig, horse, bovine, mouse, rat, guinea pig, dog, rabbit and the like) in the form of a compound such as such or a pharmaceutical composition after mixing it with a pharmaceutically acceptable carrier according to a method known per se. As used herein, various organic or inorganic carrier substances conventionally used as materials for the preparation can be used as the pharmaceutically acceptable carrier. For example, it is possible to mention excipients, lubricants, binders and disintegrants for solid preparations; solvents, dissolving aids, suspending agents, isotonizing agents and buffers for liquid preparations; and similar. To the extent necessary, it is also possible to use additives for the preparation, such as preservatives, antioxidants, coloring agents, sweeteners and the like. Preferred examples of excipients include lactose, sucrose, D-mannitol, O-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, swarm, mild silicic anhydride, synthetic aluminum silicate, aluminometasilicate of magnesium and the like. Preferred examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, and the like. Preferred examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pululan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferred examples of disintegrants include lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, carboxymethyl sodium starch, mild silicic anhydride, low substituted hydroxypropyl cellulose, and the like.

Preferred examples of solvents include water for injections, physiological saline solution, Ringer, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, and the like. Preferred examples of dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like. Preferred examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc .; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc .; polysorbates, polyoxyethylene, hydrogenated castor oil, and the like. Preferred examples of isotonizing agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like. Preferred examples of buffers include buffers such as phosphate, acetate, carbonate, citrate, etc., and the like. Preferred examples of preservatives include p-oxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferred examples of antioxidants include sulfite, ascorbate and the like. Preferred examples of coloring agents include water-soluble edible tar-based dyes (for example, food dyes such as Food Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, Food Blue Nos. 1 and 2, etc. .), water-insoluble lacquer-based dyes (for example, aluminum salts of water-soluble edible tar-based dyes mentioned above), natural colors (e.g., β-carotene, chlorophyll, red iron oxide, etc.) .) and similar. Preferred examples of sweetening agents include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like. The dosage form of the pharmaceutical composition includes, for example, oral agents such as tablet, capsule (including a soft capsule and microcapsule), granule, powder, syrup, emulsion, suspension, prolonged-release preparation and the like, which can be administered each one with safety orally. The pharmaceutical composition can be prepared by conventional methods in the field of pharmaceutical art, such as methods described in the Japanese Pharmacopeia, and the like. Hereinafter, specific production methods for such preparations are described in detail. For example, a tablet is produced by adding, for example, excipients (e.g., lactose, sucrose, starch, D-mannitol, etc.), disintegrants (e.g., calcium carboxymethylcellulose, etc.), binders (e.g., pregelatinized starch). , gum arabic, carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc.), lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), and the like, to the active ingredient, are compression molded, and where necessary, are applies a coating through a method known per se using a coating base known per se for the purpose of achieving taste masking, enteric dissolution or sustained release. The capsule can be prepared as a hard capsule filled with a powder or granular pharmaceutical agent, or as a soft capsule filled with a liquid or liquid suspension. The hard capsule is produced by mixing and / or granulating an active ingredient with, for example, an excipient (eg, lactose, sucrose, starch, crystalline cellulose, D-mannitol, and the like), a disintegrant (low substituted hydroxypropyl cellulose). , carmellose calcica, corn starch, croscarmellose sodium, and the like), binder (hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), lubricant (magnesium stearate and the like) and the like, and filling the mixture or granule into a capsule made of the aforementioned gelatin, hydroxypropylmethylcellulose and the like . The soft capsule is produced by dissolving or suspending the active ingredient in a base (soybean oil, cottonseed oil, medium chain fatty acid triglyceride, beeswax, and the like) and sealing the solution or suspension prepared in a foil. of gelatin using, for example, a rotary filling machine and the like. When the compound (I) is a salt and it is preferred to avoid contact of the compound (I) in the form of a salt with water, preferably the compound is mixed dry with an excipient and the like to obtain a hard capsule. The content of compound (I) in a pharmaceutical composition in general ranges from about 0.01 to 99.9% by weight, preferably between about 0.1 and 50% by weight, relative to the entire preparation. The dose of the compound (I) is determined considering the age, weight, general health status, sex, diet, time of administration, method of administration, rate of clearance, combination of drugs, level of the disease to be treated in the patient, and other factors.

However, the "dose varies according to the disease object, condition, subject of administration, method of administration and the like, in the case of oral administration as a therapeutic agent for essential hypertension in adults, the daily dose of between 0.1 and 100 mg preferably it is administered in a single dose or in two or three doses.Also, considering that the compound of the present invention is highly safe, it can be administered for a prolonged period of time.The compound of the present invention can be used in combination with pharmaceutical agents such as a therapeutic agent for diabetes, therapeutic agent for diabetic complications, anti-hyperlipidemic agent, anti-arteriosclerotic agent, anti-hypertensive agent, anti-obesity agent, diuretic, anti-gout agent, antithrombotic agent, anti-inflammatory agent, agent chemotherapeutic agent, immunotherapeutic agent, therapeutic agent for osteoporosis, age Anti-dementia, agent for improving erectile dysfunction, therapeutic agent for urinary incontinence / urinary frequency, and the like (hereinafter abbreviated as combination drug), On such occasions, the time of administration of the compound of the present invention and the of the combination drug is not limited to the extent that the compound of the present invention and the combination drug are combined. As administration mode it is possible to mention, among others, for example (1) administration of a simple preparation obtained by the simultaneous formulation of the compound of the present invention and a combination drug, (2) simultaneous administration of two classes of preparations obtained at Through the separate formulation of the compound of the present invention and a combination drug, "through a single route of administration, (3) stepwise administration of two classes of preparations obtained through the separate formulation of the compound of the present invention and a combination drug, by the same route of administration, (4) simultaneous administration of two classes of preparations obtained by the separate formulation of the compound of the present invention and a combination drug, through different routes of administration, (5) stepped administration of time of two kinds of preparation s obtained by the separate formulation of the compound of the present invention and a combination drug, through different routes of administration, such as administration in the order of the compound of the present invention and then the combination drug, or administration in an order inverse, and similar. The dose of the combination drug can be suitably determined based on the clinically used dose. The mixing ratio of the compound of the present invention and the combination drug can be suitably selected according to the subject of administration, route of administration, target disease, condition, combination and other factors. In case the subject of administration is human, for example, the combination drug can be used in an amount ranging from 0.01 to 100 parts by weight per part by weight of the compound of the present invention. As a therapeutic agent for diabetes, it is possible to mention, for example, insulin preparations (for example, animal insulin preparations extracted from the pancreas of bovines or pigs; human insulin preparations synthesized by a genetic engineering technique using E. coli or yeast, and the like), other insulin sensitizers (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone, GI-262570, JTT-501, MCC-555, YM-440, RP-297, CS-011, FK-614, etc.). ), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformim, etc.), insulin secretors (eg, sulfonylureas (e.g., tolbutamide, glibenzylamide, gliclazide, elorpropamide, tolazamide, acetohexami, glieopyramide, glimepiride, glipizide, glibuzol, etc.), repaglinide, senaglinide, nateglinide, mitiglinide, or its calcium salt hydrate, GLP-l, etc.), agonists of andrin (eg, pramlintide, etc.), phosphotyrosine phosphatase inhibitors (eg, vanadic acid), dipeptidylpeptidase IV inhibitors (eg, NVP-DPP-278, PT-100, P32 / 98 etc.), agonists of ß3 (for example, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc.), glycogenesis inhibitors (e.g., glycogen phosphorylase inhibitor) , glucose-6-phosphatase inhibitor, glucagon antagonist, etc.), inhibitors of SGLT (sodium-glucose cotransporter) (e.g., T-1095 etc.) and the like. As therapeutic agents for diabetic complications it is possible to mention, for example, aldose reductase inhibitors (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-112 etc.), neurotrophic factors (e.g. ? GF,? T-3, BD? F etc.), PKC inhibitors (for example, LY-333531 etc.), AGE inhibitors (for example, AL T946, pimagedine, piratoxatin,? -phenacylthiazolium bromide (AL T766 ), EXO-226 etc.), active oxygen purifiers (e.g., thioctic acid, etc.), cerebral vasodilators (e.g., thiapride, mexiletine etc.), and the like. As anti-hyperlipidemia agents it is possible to mention, for example, statin compounds which are inhibitors of cholesterol synthesis (for example, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or salts thereof (eg salt of sodium, etc.), etc.), asqualene synthetase inhibitors (eg, TAK-475 etc.) or fibrate compounds that have the effect of decreasing triglycerides (eg, bezafibrate, clofibrate, simfibrate, clinofibrate etc.) and the like. As anti-arteriosclerotic agents, it is possible to mention, for example, an inhibitor of acyl-Coenzyme A cholesterol acyltransferase (ACAT) (for example, melinamide, CS-505, etc.) and a lipid-rich plaque regression agent ( for example, the compounds described in WO 02/06264, WO 03/059900 etc.) and the like. As antihypertensive agents it is possible to mention, for example, angiotensin-converting enzyme inhibitors (for example, captopril, enalapril, delapril etc.), angiotensin II antagonists (for example, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, 'termisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil etc.), calcium antagonists (for example, manidipine, nifedipine, amlodipine, efonidipine, nicardipine etc.), ß-blocker (for example, metoprolol, atenolol, propranolol, carvedilol, pindolol etc.), clonidine, and the like. As anti-obesity agents, for example, it is possible to mention a centrally acting anti-obesity agent (for example, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamfetamine, mazindol, phenylpropanolamine, clobenzorex etc.), pancreatic lipase inhibitors ( for example, orlistat etc.), ß3 agonist (for example, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc.), anorectic peptides (eg, leptin, CNTF (ciliary neurotropic factor) etc.), cholecystokinin agonists (eg, lintitript, FPL-15849 etc.) and the like. As diuretics, it is possible to mention, for example, xanthine derivatives (for example, theobromine and sodium salicylate, theobromine and calcium salicylate, etc.), thiazide preparations (for example, etiazide, cyclopentiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide , benzylhydrochlorothiazide, penflutiazide, poly 5 thiazide, methiclothiazide etc.), anti-aldosterone preparations (eg spironolactone, triamterene etc.), carbonic anhydrase inhibitors (eg acetazolamide etc.), chlorobenzensulfonamide preparations (eg, chlorthalidone, mefruside, indapamide etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide, and the like. As anti-drop agents it is possible to mention, for example, allopurinol, probenecid, colchicine, benzbrornarone, febuxostat, citrate and the like. As antithrombotic agents it is possible to mention, for example, an anticoagulant agent [for example, heparin sodium, heparin potassium, warfarin potassium (warfarin), inhibitor of factor X blood coagulation (for example, the compounds described in WO 2004/048363 etc.)], thrombolytic agent [eg, tPA, urokinase], antiplatelet agent [eg, aspirin, sulfinpyrazone (anturan), dipyridamole (persantin), ticlopidine (panaldin), cilostazol (pletal), GPllb / IIIa antagonist (ReoPro ), clopidogrel etc.], and the like. As anti-inflammatory agents, it is possible to mention, for example, nonsteroidal antiinflammatory agents such as acetaminophen, phenacetin, etenzamide, sulpirin, antipyrin, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenin, epirizol, thiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, sodium gold thiomalate, sodium hyaluronate, salicylate sodium, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, oxymorphone and its salts, etc., and the like. As chemotherapeutic agents, it is possible to mention, for example, alkylating agents (for example, cyclophosphamide, ifosfamide, etc.), metabolic antagonists (for example, methotrexate, 5-fluorouracil etc.), anticancer antibiotics (for example, mitomycin, adriamycin etc.). .), anti-cancer agents derived from plants (for example, vincristine, vindesine, taxol etc.), cisplatin, carboplatin, etoposide and the like. Among these, furtulon, neofurtulon etc., which are 5-fluorouracil derivatives and the like are preferred. As immunotherapeutic agents it is possible to mention, for example, microorganism or bacterial components (for example, derivative of muramyl dipeptide, picibanil etc.), polysaccharides with immunostimulatory activity (for example, lentinan, schizophyllan, krestin etc.), cytokines obtained by immunoassay techniques. genetic engineering (e.g., interferon, interleukin (IL) etc.), colony-stimulating factor (e.g., granulocyte colony stimulation factor, erythropoyentin etc.) and the like, with IL-1, IL-2, IL being preferred. -12 And similar. As therapeutic agents for osteoporosis it is possible to mention, for example, alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium and the like. As anti-dementia agents it is possible to mention, for example, tacrine, donepezil, rivastigmine, galantamine and the like. As erectile dysfunction improving agents it is possible to mention, for example, apomorphine, sildenafil citrate and the like. As therapeutic agents for urinary incontinence / urinary frequency, it is possible to mention, for example, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like. On the other hand, it is also possible to use, in combination with the pharmaceutical agent of the present invention, pharmaceutical agents with a cachexia-enhancing effect recognized in animal models and clinical situations, including cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, Vol. 49, 5935-5939 pages, 1989], progesterone derivatives (eg, megestrol acetate) [Journal of Clinical Oncology, Vol. 12, 213-225 pages, 1994], glucosteroids (for example, dexamethasone etc.), metoclopramide pharmaceutical agents, pharmaceutical tetrahydrocannabinol agents (the publications are the same as above), fat metabolism improving agents (e.g., eicosapentaenoic acid etc.) [British Journal of Cancer, Vol. 68, pp. 314-318, 1993], growth hormone, IGF-1, and antibodies against TNF-a. , LIF, IL-6 and oncostatin M, which induce cachexia, and the like.

The combination drug preferably includes a diuretic, insulin preparation, insulin sensitizer, α-glucosidase inhibitor, a biguanide agent, an insulin secretion activator (preferably a sulfonylurea agent) and the like. Particularly preferred is a diuretic such as hydrochlorothiazide and the like and insulin sensitizers-such as pioglitazone hydrochloride and the like. The aforementioned combination drug can be a combination of two or more classes thereof which are related under suitable proportions. Since the compound of the present invention potentiates the hypoglycemic activity of other insulin sensitizers, the combined use of the compound of the present invention and other insulin sensitizers (preferably pioglitazone hydrochloride) markedly improves the prophylactic and / or therapeutic effect against diseases in the which insulin resistance is involved, such as type II diabetes and the like. The compound of the present invention exhibits a superior prophylactic or therapeutic effect against circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and the like. EXAMPLES The present invention will be explained in detail with reference to the following Examples, Preparation Examples and Experimental Examples. However, these examples are mere practical embodiments and do not limit the present invention. The present invention can be modified to the extent that the scope thereof is not modified. The elution by column chromatography in the Examples was carried out under observation by TLC (thin layer chromatography). In the observation by TLC, 60F25 (Merck) was used as a TLC plate, the solvent used as an elution solvent in the column chromatography was used as a developing solvent, and a detector was used for the detection purposes. of UV As silica gel for the column, Kieselgel 60 (70-230 mesh) or Kieselgel 60 (230-400 mesh) manufactured by Merck was used The NMR spectrum was measured using tetramethylsilane as internal or external standard, while the change chemical is expressed in value d while the coupling constant is expressed in Hz. The symbols in the examples mean the following: s: simple d: doublet t: triplet q: quartet dd: double doublet m: multiplet J: constant coupling THF: tetrahydrofuran DMF: dimethylformamide DMSO: dimethyl sulfoxide DSU: 1,8-diazabicyclo [5.4.0] -7-undecene Example 1 - (5-methyl-2-oxo-l, 3-dioxol-4-yl) ethyl 2 -etoxy-l- { [2 '- (5-oxo-4, 5-dihydro-l, 2, -oxadiazol-3-yl) biphenyl-4-yl] methyl.} - lH-benzimidazole-7 -carboxylate To a solution of 2-ethoxy-l- { [2 '-. {5-oxo-4,5-dihydro-1,2,4-oxadiazol-3yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate disodium (2.0 g) in DMF (20 ml) was added 4'-chloromethyl-5-methyl-1,3-dioxol-2-one (0.99 g) and the mixture was stirred at room temperature. environment for 12 hours. The reaction mixture was concentrated and the residue was dissolved in chloroform and 1N hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (0.26 g, 14%) as a colorless solid. X H NMR (300 MHz, CDCl 3) d: 1.43 (3 H, t, J = 7.1 Hz), 2. 14 (3H, s), 4.46 (2H, q, J = 7.1 Hz), 4.87 (2H, s), 5.63 (2H, s), 6.93 (2H, d, J = 8.3Hz), 7.07 (1H, t, J = 7.9Hz), 7.16 (2H, d, J = 8.1Hz), 7.32-7.37 (2H, m), 7.53-7.64 (3H, m), 7.83 (1H, dd, J = 104Hz, 7.6Hz ). * Example 2 (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxa-diazol-3-yl) biphenyl-4-yl} methyl } - lH-benzimidazole-7-carboxylate To a solution of 2-ethoxy-l- acid. { [2 '- (5-oxo-4,4-dihydro-1,2,4,4-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., 4,6-trichlorobenzoyl chloride (1.81 ml) under cooling with ice. After stirring the mixture at room temperature for 12 hours, the insoluble material was filtered and the filtrate was concentrated. The residue was dissolved in methylene chloride (50 ml), and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (1.72 g) and N, N-dimethylaminopyridine (1.61 g) were added under cooling with ice. After stirring the mixture at room temperature for 4 hours, the reaction mixture was diluted with chloroform (150 ml), washed with water, saturated aqueous sodium hydrogen carbonate, 1 N hydrochloric acid and saturated saline, dried over sodium sulfate. anhydrous and concentrated. The residue was crystallized from diisopropyl ether in ethanol (18 ml) with reflux. Activated carbon (0.1 g) was added to the solution and the mixture was stirred under reflux for 30 minutes. The insoluble material was filtered and the filtrate was allowed to cool to room temperature. After 12 hours, the precipitated crystals were collected by filtration and washed with ice-cold ethanol and dried under reduced pressure at room temperature to obtain the title compound (3.0 g, 50%). 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-one was synthesized by the method described in Alpegiani, M.; Zarini, F .; Perrone, E. Synthetic Communication, Vol. 22, pages 1277-1282 (1992). XH NMR (300 MHz DMSO-d6) d: 1.37 (3H, t, J = 7.2Hz), 2.14 (3H, s), 4.58 (2H, q, J = 7.2Hz), 5.10 (2H, s), 5.53 (2H, s), 6.97 (2H, d, J 7.8Hz), 7.17-7.22 (3H, m), 7.44-7.53 (3H, m), 7.61-7.73 (3H, m). Example 3 2-oxo-l, 3-dioxolan-4-yl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-1,2-oxadiazol-3-yl) biphenyl-4-yl) ethyl} -1H-benzimidazole-7-carboxylate A solution of 2-ethoxy-l- acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] ethyl} -1H-benzimidazole-7-carboxylic acid (1.0 g), 4-chloro-l, 3-dioxolan-2-one (0.41 g) and triethylamine in DMF was stirred at 90 ° C for 12 hours. The reaction mixture was concentrated, and the residue dissolved in chloroform and 1 N hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (0.20 g, 22%) as a colorless solid. XH RM? (300 MHz DMS0-d6) d: 1.39 (3H, t, J = 7.1Hz), 4.52-4.65 (3H, m), 4.78 (1H, dd, J = 5.8Hz, 10.1Hz), 5.55 (2H, d, J = 2.6Hz), 6.84 (1H, dd, J = 2.1Hz, 5.6Hz), 7.03 (2H, d, J = 8.3Hz), 7.20-7.25 (3H, m), 7.43-7.57 (2H , m), 7.60-7.69 (3H, m), 7.77 (1 H, dd, J = 1.0Hz, 7.8Hz). Use 4 4-methyl-2-oxo-l, 3-dioxolan-4-yl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2, -oxadiazol-3-yl) biphenyl-4-yl} methyl } -lH-benzimidazole-7-carboxylate The title compound (0.21 g, 11%) was obtained from 2-ethoxy-l- acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] ethyl} -lH-benzimidazole-7-carboxylic acid (2.0 g) and 4-chloro-4-methyl-l, 3-dioxolan-2-one (1.2 g) according to a method similar to that of Example 3. 4-chlorine was synthesized -4-methyl-l, 3-dioxolan-2-one according to the method described in JP-A-62-290071. XB NMR (300 MHz, CDCl3) d: 1.41 (3H, t, J = 7.1Hz), 1.81 (3H, s), 4.53 (2H, d, J = 3.6Hz), 4.63 (2H, q, J = 7.1Hz ), 5.57 (2H, d, J, = 604Hz), 6.96 (2H, d, J = 8.1Hz), 7.20-7.28 (3H, m), 7.46 (1H, d, J = 7.9Hz), 7.54-7.69 (4H, m), 7.78 (1H, d, J = 7.9Hz). Example 5 Potassium salt of 5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2, -oxadiazol-3-yl) biphenyl-4-yl] ethyl} -lH-benzimidazole-7-carboxylate The compound (0.55 g) obtained in Example 1 or 2 was dissolved in acetone (10 ml) at 50 ° C. The solution was cooled with ice and a solution of potassium 2-ethylhexanoate (0.17 g) in acetone (2 ml) was added dropwise. The mixture was allowed to stand overnight in a refrigerator, and the precipitated crystals were collected by filtration and dried under reduced pressure at room temperature to obtain the title compound (0.37 g, 63%), melting point: 196 ° C ( dec). XH NMR (300 MHz DMSO-d5) d: 1.42 (3H, t, J = 7.1Hz), 2.17 (3H, s), 4.62 (2H, q, J = 7.1Hz), 5.11 (2H, s), 5.51 (2H, s), 6.85 (2H, d, J 8.3Hz), 7.16-7.27 (4H, m), 7.30-7.42 (2H, m), 7.44-7.52 (2H,), 7.72 (1H, dd, J = 1.1Hz, 7.9Hz). Example 6 Sodium salt of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl 2-etoxia-l-. { [2 '- (5-oxo-4,5-dihydro-l, 2, -oxadiazol-3-yl) ifenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate The compound (10 g) obtained in Example 1 or 2 was dissolved in THF (200 ml) at 50 ° C. The solution was cooled with ice and a solution of potassium 2-ethylhexanoate (2.93 g) in THF (2 ml) was added dropwise. The reaction mixture was concentrated, the residue was washed with diethyl ether and the crystals were collected by filtration. The crystals were dried under reduced pressure at 50 ° C to obtain the title compound (8.52 g, 82%), as a colorless solid. XH NMR (300 MHz DMSO-d6) d: 1.41 (3H, t, J = 7.1Hz), 2.16 (3H, s), 4.61 (2H, q, J = 7.1Hz), 5.11 (2H, s), 5.53 (2H, s), 6.91 (2H, d, J = 8.4Hz), 7.19-7.28 (4H, m), 7.29-7.68 (4H, m), 7.76 (1H, m). Example 7 Calcium salt adduct with calcium acetate (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-1,2, -oxadiazol-3-yl) biphenyl-4-yl] ethyl} -1H-benzimidazole-7-carboxylate The compound (1.0 g) obtained in Example 6 was dissolved in acetonitrile (10 ml) at room temperature. A solution of calcium acetate monohydrate (0.26 g) in acetonitrile (10 ml) was incorporated by dripping into the solution at room temperature. The reaction mixture was stirred overnight and the precipitated crystals were collected by filtration. The crystals were dried under reduced pressure at 50 ° C to obtain the title compound (0.78 g, 56%) as a colorless solid. XH NMR (300 MHz DMSO-de) d: 1.42 (3H, t, J = 7.2Hz), 1.78 (9H, s), 2.17 (3H, s), 4.62 (2H, q, J = 7.2Hz), 5.11 (1H, s), 5.51 (1H, s), 6.84 (2H, d, J = 7.4Hz), 7.18-7.23 (4H, m), 7.28-7.40 (2H, m), 7.47-7.50 (2H, m ), 7.69-7.74 (1H,).

Example 8 5-Oxotetrahydro-2-furanyl 2-ethoxy-1-. { [2 '- (5-oxo-4, 5-dihydro-1,2,4,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate To a solution of 2-ethoxy-1- acid. { [2 '- (5-oxo-4, 5-dihydro-1,2, -oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid (4.0 g) and triethylamine (1.3 ml) in THF (50 ml) were added dropwise to 2,4,6-trichlorobenzoyl chloride (1.4 ml) under ice-cooling. After stirring at room temperature for 12 hours, the insoluble material was filtered and the filtrate was concentrated. The residue was dissolved in methylene chloride (50 ml) and 5-oxotetrahydro-2-furanyl (0.67 g) and N, N-dimethylaminopyridine (1.0 g) under cooling with ice. After stirring at room temperature for 4 hours, the reaction mixture was diluted with chloroform (150 ml), washed with water, saturated aqueous sodium hydrogen carbonate, 1 N hydrochloric acid and saturated saline, dried over sodium sulfate. anhydrous and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (0.16 g, 3.3%) as a colorless solid. aH NMR (300 MHz, CDC13) d: 1.48 (3H, t, J = 7.1Hz), 2.31-2.39 (1H,), 2.45-2.66 (2H,), 2.67-2.79 (1H, m), 4.63 (2H , q, J = 7.1Hz), 5.61 (1H, d, J = 18Hz), 5.81 (1H, d, J = 18Hz), 6.71-6.73 (1H, m), 6.98-7.01 (2H, m), 7.16 -7.25 (3H, m), 7.36-7.38 (1H, m), 7.48-7.59 (3H, m), 7.69-7.80 (2H, m). Example 9- (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl 2-ethoxy-1-. { [2'- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} - lH-benzimidazole-7-carboxylate To a solution of 2-ethoxy-l- acid. { [2 '- (5-oxo-4, 5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid (9.0 g) and 4-hydroxymethyl-5-methyl, 3-dioxol-2-one (3.08 g) in N, N-dimethylacetamide (100 ml) were added "p-toluenesulfonyl chloride" (4.13 g), N, N-dimethylaminopyridine (0.48 g) and potassium carbonate (3.54 g) under ice-cooling and the mixture was stirred at about 10 ° C for 3 hours, after adjusting the pH of the mixture to approximately 5, the mixture was crystallized by adding water (72 ml) to obtain crystals as a solvate.The isolated crystals were suspended in a mixture of water (63 ml) and acetone (27 ml) and the suspension was stirred at about 35 ° C during After stirring under ice-cooling for 2 hours, the crystals were collected by filtration and washed with water (18 ml) and dried under reduced pressure at 0 ° C to obtain the title compound (10.6 g, 95%). XH R \ T (300 MHz DMSO-de) d: 1.39 (3H, t, J = 6.4Hz), 2.17 (3H, s), 4.60 (2H, q, J = 6.4Hz), 5.12 (2H, s), 5.56 (2H, s) , 7.00 (2H, d, J = 7.0Hz), 7.22-7.24 (3H, m), 7. 46-7.57 (3H, m), 7.64-7.75 (3H, m). Formulation Examples When the compound of the present invention is used as a therapeutic agent for circulatory diseases such as hypertension, heart disease, stroke, nephritis and the like, for example, it is possible to use the following formulations. In the following formulations, it is possible to use as components (additive) in addition to the active ingredient, those listed in the Japanese Pharmacopeia, the quasi-drugs of Japanese Pharmacopeia or standard pharmaceutical product additive, and the like. 1. Tablet (1) Compound obtained in Example 1 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) , (2), (3) and 2/3 of (4) are mixed and granulated. To these are added the remaining (4) and (5), and the mixture is compression molded to obtain the tablets. 2. Capsule (1) Compound obtained in Example 5 10 mg (2) Lactose 69.5 mg (3) Soft silicic anhydride - 0.2 mg (4) Magnesium stearate 0.3 mg 1 capsule 80 mg (1), (2), (3) and (4) were mixed dry and incorporated into an HPMC capsule (No. 3). 3. Tablet (1) Compound obtained in Example 1 10 mg (2) Amlodipine besylate 5 mg (3) Lactose 30 mg (4) Corn starch 150 mg (5) Microcrystalline cellulose 30 mg (6) Magnesium stearate 5 mg 1 tablet 230 mg (1), (2), (3), (4) and 2/3 of (5) are mixed and granulated. The remaining (5) and (6) are added thereto, and the mixture is compression molded to obtain the tablets. 4. Capsule (1) Compound obtained in Example 5 10 mg (2) Amlodipine besylate 5 mg (3) Lactose 64.5 mg (4) Soft silicic anhydride 0.2 mg (5) Magnesium stearate 0.3 mg 1 capsule. _ 80 mg (1), (2), (3), (4) and (5) were mixed dry and incorporated into an HPMC capsule (No. 3). 5. Tablet (1) Compound obtained in Example 1 10 mg (2) Hydrochlorothiazide 12.5 mg (3) Lactose 22.5 mg (4) Corn starch 150 mg (5) Microcrystalline cellulose - 30 mg (6) Magnesium stearate 5 mg 1 tablet 230 mg (1), (2), (3), (4) and 2/3 of (5) are mixed and granulated. To these the remaining (5) and (6) were added, and the mixture was compression molded to obtain the tablets. 6. Capsule (1) Compound obtained in Example 5 10 mg (2) Hydrochlorothiazide 12.5 mg (3) Lactose 57 mg (4) Soft silicic anhydride 0.2 mg (5) Magnesium stearate 0.3 mg 1 capsule 80 mg (1), (2), (3), (4) and (5) were mixed dry and incorporated into an HPMC capsule (No. 3). Experimental Example 1 Inhibitory effects of the compounds of the present invention against the induced blood pressure response of angiotensin II in rats. Male Sprague-Dawley rats (9-11 weeks old, CLEA Japan, Inc.) were anesthetized with pentobarbital (50 mg / kg, ip) and the femoral artery and vein were separated and cannulated with polyethylene tubes filled with saline solution which -contains heparin (200 U / ml). The catheters were subcutaneously inserted at a point at the back of the neck and fixed. After a period of recovery, the rat was subjected to the experiment. The arterial catheter was connected to a pressure transducer attached to a blood pressure monitoring amplifier (2238, NEC Sanei Instruments) and the pressure was recorded on a recorder (RECTI-HORIZ 8K, NEC San-ei Instruments). After establishing the angiotensin II induced blood pressure responses (AII, 100 ng / kg, iv), a test compound was administered at a dose corresponding to an equimolar amount of compound A (2-ethoxy-l-. . [2 '- (5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl]} - lH-benzimidazole-7-carboxylic acid). AII was administered after 24 hours and the increase in blood pressure was measured, based on which the inhibition index was calculated from the value prior to administration. All compounds were suspended in 0.5% methylcellulose and administered orally at a volume of 2 ml / kg. The results are listed in Table 1 (average +/- SEM). The importance between the group administered with the compound obtained in Example 5 and the other groups was analyzed by Student's t-test. (**: p> 0.01, *: p> 0.05). Table 1 Compound B: methyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-1,2-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate Compound C: 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-. { [2 '- (5-oxo-4, 5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl} methyl } -lH-benzimidazole-7-carboxylate Compound D: acetoxymethyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-1,2, -oxadiazol-3-yl) biphenyl-4-yl} methyl } -1H-benzimidazole-7-carboxylate As clearly emerges from the results, the compound of the present invention shows a significantly prolonged and potent pharmacological action when administered orally, in relation to the esters described in JP-A- 271228. Experimental Example 2 Inhibitory effects of the compounds of the present invention against the induced blood pressure response of angiotensin II in dogs. For the experiment, male Beagles (weight 12.0-14.7 kg, KITAYAMA LABES CO, LTD) were used. They were anesthetized with sodium pentobarbital (50 mg / kg, ip), and a tracheal tube was inserted to manage the airway. The femoral region and the back of the neck were shaved and a disinfectant was applied (isodine solution, MEIJI SEIKA KAISHA LTD). The dog was immobilized in a dorsal position and a cut was made in the right femoral region. A mirror catheter (5F MILLER INDUSTRIES) was inserted and placed in the femoral artery and a polyurethane tube in the femoral vein. The catheter and the tube were passed subcutaneously and fixed in the posterior region. The cut region was sutured and then intramuscularly administered penicillin G potassium (MEIJI SEIKA KAISHA LTD, 40000 units) to avoid an infection. Beginning the next day, penicillin G potassium (40000 units) was administered once a day for 3 days. After 3 days of recovery, the dog was subjected to the experiment.

During the experiment, the dog was placed in a small metabolic cage. For the measurement, the mirror catheter inserted in the femoral vein was connected to a transducer unit (MILLER INDUSTRIES), and the systemic blood pressure (average blood pressure) was recorded in a recorder (RECTI-HORIZ 8K, NEC San-ei Instruments) through a DC amplifier (N4777, NEC San-ei Instruments) and a blood pressure monitoring amplifier (N4441, NEC San-ei Instruments). The polyurethane tube inserted into the femoral vein was fixed outside the cage and used for administration of AII (PEPTIDE I? STITUTE, I? C). The experiment was conducted on an empty stomach and AII (100 ng / kg, i.v.) was administered 3 or 4 times before the administration of a test compound to confirm the stabilization of the vasopressor response. A dose of the test compound corresponding to an equimolar amount of compound A was suspended in 0.5% methylcellulose and orally administered at a volume of 2 ml / kg. After administering the drug, AII was administered at each time of measurement, the increase in blood pressure was recorded, with which the inhibition index was calculated from the value prior to administration. The results are listed in Table 2 (average +/- SEM). The importance between the group administered with the compound obtained in Example 5 and the group administered with compound A was analyzed by Student's t-test with Bonferroni correction (**: p> 0.01, *: p> 0.05 ). Table 2 As it clearly emerges. of the results, the compound of the present invention * shows a significantly prolonged and potent pharmacological action when administered orally. Industrial Applicability The compound of the present invention is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and the like. This application is based on a Patent Application No. 2004-048928 filed in Japan and in U.S. Patent Application No. 11/031057 whose contents are incorporated herein by reference. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (18)

2. Having described the invention as above, the content of the following claims is claimed as property: 1. Compound represented by the formula (I) characterized in that R1 is a group represented by the formula wherein R2, R3, R4, R5, R6, R7 and R8 are each independently a hydrogen atom or C? _6 alkyl, or salt thereof; 2. Compound according to claim 1, characterized in that it is a salt.
3. 3. Compound according to claim 1, characterized in that R1 is a group represented by the formula where R2 remains as in the previous definition.
4. 4. Compound characterized in that it is selected from the group consisting of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl 2-ethoxy-1-. { [21- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} ~ 1H-benzimidazole-7-carboxylate, 2-oxo-l, -3-dioxolan-4-yl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate, 4-methyl-2-oxo-l, 3-dioxolan-4-yl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate and 5-oxotetraidro-2-furanyl-2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-1,2, -oxadlazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate, or salts thereof;
5. 5. Compound characterized in that it is potassium salt of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl 2-ethoxy-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate.
6. 6. Process for the preparation of a compound represented by the formula characterized in that R2 is a hydrogen atom or C? -6 alkyl, or a salt thereof, which comprises reacting a reagent derived from 2-ethoxy-l- acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid or a salt thereof with a compound represented by the formula wherein R2 maintains the above definition, or a salt thereof;
7. 7. Medicament characterized in that it comprises the compound according to claim 1.
8. 8. A drug according to claim 7, characterized in that it is an angiotensin II antagonist.
9. 9. Medication in accordance with the claim 7, characterized in that it is an insulin sensitizer.
10. 10. Medicament according to claim 7, characterized in that it is an agent for the prophylaxis or treatment of circulatory diseases;
11. 11. Medicament characterized in that it comprises the compound according to claim 1 in combination with a calcium antagonist. .
12. 12. Medicament characterized in that it comprises the compound according to claim 1 in combination with a diuretic agent.
13. 13. Medicament according to claim 11, characterized in that it is an agent for the prophylaxis or treatment of circulatory diseases.
14. 14. Use of the compound according to claim 1 for the manufacture of an angiotensin II antagonist.
15. 15. Use of the compound according to claim 1 for the manufacture of an insulin sensitizer.
16. 16. Use of the compound according to claim 1 for the manufacture of an agent for the prophylaxis or treatment of circulatory diseases.
17. 17. Use of the compound according to claim 1 in combination with a calcium antagonist for the manufacture of an agent for the prophylaxis or treatment of circulatory diseases.
18. 18. Use of the compound according to claim 1 in combination with a diuretic agent for the manufacture of an agent for the prophylaxis or treatment of circulatory diseases.