MX2007011834A - Benzimidazole derivative and use as angiotensin ii antagonist. - Google Patents

Abstract

The present invention provides (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-cyclopropyl-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate represented by the formula: which has superior properties as a pharmaceutical agent, a salt thereof, a crystal thereof, a pharmaceutical agent containing the compound, and the like.

Description

DERIVATIVE OF BENCIMIDAZOL AND ITS USE AS AN ANTAGONIST OF ANGIOTENSIN II FIELD OF THE INVENTION The present invention relates to a novel benzimidazole derivative having superior properties than a pharmaceutical agent, a method of producing same and the use thereof. More particularly, the present invention relates to a prodrug of a benzimidazole derivative having a particular structure, which exhibits superior pharmacological effects (for example, a strong and prolonged hypotensive action, insulin sensitizing activity and the like) and superior properties ( for example, crystallinity, stability and the like), and which is useful as an agent for the prevention or treatment of circulatory diseases such as hypertension, heart diseases (cardiac hypertrophy, cardiac dysfunction, cardiac infarction and the like), nephritis, apoplexy and the like and metabolic diseases such as diabetes and the like, with a method of production thereof, the use thereof and others.

BACKGROUND OF THE INVENTION Angiotensin II produces vasoconstriction through an angiotensin II receptor in the cell membrane and raises blood pressure. Therefore, an antagonist of REF. : 185678 Angiotensin II receptor can be an effective therapeutic drug for circulatory diseases such as hypertension and others. It is known as a preferred chemical structure to express a strong angiotensin II antagonist activity, a structure having an acid group, such as a tetrazolyl group, a carboxyl group and the like in a biphenyl side chain, and, as a pharmaceutical compound having such characteristics In structural studies, losartan, eprosartan, candesartan cilexetil, olmesartan medoxomil, and the like were clinically used (Ruth R. exler et al., Journal of Medicinal Chemistry, vol 39, p.625 (1996), JP-A-4-364171, JP -A-5-78328 and the like). In JP-A-5-271228 it is described that 2-cyclopropyl-1- acid. { [2 '- (5-oxo-4,5-dihydro-1,2, -oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid (compound A) and its methyl ester (compound B), which are compounds, wherein an acidic group on a biphenyl side chain is a 5-oxo-4,5-dihydro-1, 2 group , 4-oxadiazol-3-yl, present a strong angiotensin II antagonist action and a hypotensive action through oral administration. In addition, WO 03/047573 discloses the benzimidazole derivatives described in JP-A-5-271228, a particular acid compound (2-ethoxy-1-. [2 '- (5- oxo-4, 5-dihydro-1,2,4-oxadiazol-3-yl) -1, '-biphenyl-4-yl] methyl.} - lH-benzimidazole-7- carboxylic: compound C) exhibits an insulin sensitizing activity in addition to an angiotensin II antagonist activity. As one of the means to enhance practical use as a pharmaceutical agent, the conversion of a compound having a certain pharmacological activity is known. For example, they were widely used as a prodrug of carboxylic acid, alkylcarbonyloxymethylester, 1-alkylaccarbonyloxyethyl, alkyloxycarbonyloxymethyl ester, 1-alkyloxycarbonyloxyethyl ester and (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester (ie , medoxomyl ester) for a compound that shows up to now insufficient expression of activity through oral administration in the development of pharmaceutical products. In addition, it is known that the Farnesol ester, which is a liposoluble substance of indomethacin, and the ethyl ester of an ACE inhibitor provide sustained activity and others. In WO 2005/080384 a medoxomyl ester of compound C is described. Taking into account aspects of ease of isolation and purification, stability in the formulation and the like, the compounds are preferably presented in the form of crystals. Anyway, and since it is generally not possible to predict if a compound crystallizes and this is unknown until it is in fact synthesized and isolates On the other hand, crystallization usually reduces the solubility of compounds, which in turn usually degrades oral absorbability. Therefore, it is not possible to predict whether a crystal having superior properties (a good balance of stability and solubility) can be obtained as a pharmaceutical compound.

BRIEF DESCRIPTION OF THE INVENTION The objective of the present invention is to provide a new superior compound as a pharmaceutical agent for the prevention or treatment of circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and the like and others. The present inventors of the invention have carried out intensive studies trying to find a new compound that has a greater pharmacological action and better physicochemical properties, so as to provide a pharmaceutical agent more useful as an agent for the prevention or treatment of circulatory diseases such as hypertension. and the like and metabolic diseases such as diabetes and the like, and others. As a result, they found that a prodrug compound that has a particular structure and the ability to become a compound A in a living organism, has properties far superior to a pharmaceutical agent, given that it has unexpected superior properties (for example, physicochemical properties, such as crystallinity, stability and the like), an unexpectedly strong and sustained hypotensive action and the like, which resulted in the fulfillment of the objective of the present invention. Therefore, the present invention relates to: (1) 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester; (2) a salt of 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester; (3) potassium salt of 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester; (4) a solvate of 2-cyclopropyl-1-. { [2 '- (5-oxo-, 5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester; (5) a crystal of the compound of any of items (1) to (4) that were previously mentioned; (6) a method to produce 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4- il) methyl or one of its salts, which includes the reaction of a reactive derivative of 2-cyclopropyl-1-acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid, or one of its salts, with 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one or one of its salts; (7) a pharmaceutical agent that includes the compound of any of items (1) to (4) that were previously mentioned; (8) the pharmaceutical agent of those mentioned above (7), which is an angiotensin II antagonist; (9) the pharmaceutical agent of item (7) mentioned above, which is an agent for the prevention or treatment of circulatory diseases; (10) an insulin sensitizer that includes 2-cyclopropyl-1- acid. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs; (11) an enhancer of a hypoglycemic activity of an insulin sensitizer, which includes 2-cyclopropyl-1- acid. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs; (12) a method for antagonizing angiotensin II in a mammal, which includes administering an effective amount of the compound of any one of items (1) to (4) that is previously mentioned said mammal; (13) a method for preventing or treating circulatory diseases in a mammal, which includes administering an effective amount of the compound of any one of items (1) to (4) that were previously mentioned to said mammal; (14) a method for improving the resistance of insulin in a mammal, including administering an effective amount of 2-cyclopropyl-1-acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) bipheni-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs to said mammal; (15) a method for increasing the hypoglycemic activity of an insulin sensitizer in a mammal, which includes administering an effective amount of a 2-cyclopropyl-1- acid. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs to such a mammal; (16) the use of the compound of any of items (1) to (4) that were previously mentioned for the production of an angiotensin II antagonist; (17) the use of the compound of any of items (1) to (4) that were previously mentioned for the production of an agent for the prevention or treatment of circulatory diseases; (18) the use of 2-cyclopropyl-l- acid. { [2 '- (5-oxo-4, 5- dihydro-1, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs for the production of an insulin sensitizer; (19) the use of 2-cyclopropyl-1- acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs for the production of an enhancer of a hypoglycemic activity of an insulin sensitizer; and others. The compound of the present invention shows a superior therapeutic or prophylactic effect in circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and others.

BRIEF DESCRIPTION OF THE FIGURE Fig. 1 shows a X-ray powder crystal diffraction pattern obtained in Example 3.

DETAILED DESCRIPTION OF THE INVENTION The 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl (sometimes referred to hereinbefore as compound (I)) is represented by the formula: In the formula, a group represented by the formula: (5-OXO-4, 5-dihydro-1,2,4-oxadiazol-3-yl group) includes three tautomers (a ', b' and e ') represented by the formulas: b ' and a 5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl group includes all of the above-mentioned a ', b' and e '. A salt of the compound (I) can be any as long as it is an acceptable salt for pharmaceutical use. As such salts may be mentioned the salts of the compound (I) 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.), an organic base (for example, organic amines such as tromethamine [tris (hydroxymethyl) -methylamine], ethanolamine, trimethylamine, triethylamine, tert-butylamine, pyridine, picoline, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like; basic amino acids such as arginine, lysine, ornithine and the like;, etc.), ammonia and others. As a salt of the compound (I), the alkali metal salts of the compound (I) are preferably. Of these, a potassium salt is preferably particular. The compound (I) can be labeled with an isotope (for example, 3H, 14C, 35S, 125I and the like) and others. The compound (I) can be a crystal, and it can have a single crystal shape or a form of a mixture of several crystals. The crystals can be produced by crystallization according to a commonly known crystallization method. The compound (I) is preferably a crystal, and particularly, a form A crystal having a good balance of stability and solubility and suitable for industrial production is preferred. The compound (I) can be a solvate (eg, hydrate, etc.) and compound (I) includes both the solvates and the non-solvates (eg, not hydrate, etc.).

PRODUCTION METHOD The compound (I) can be produced, for example, according to the methods indicated below, a method analogous to them and others. While the yield of the compound (I) obtained by the following method can vary depending on the reaction conditions employed, a compound (I) can be easily obtained in high purity, using conventional separation or purification means (eg, recrystallization). , column chromatography and the like) from the product by such methods. The compound (I) can be produced by the reaction of a reactive derivative (eg, a mixed acid anhydride, an acid halide and the like) of a compound represented by the formula (II) (compound A) or a salt thereof (in occasions hereinafter referred to as compound (II)) with the corresponding alcohol (IV) (HO-R2) or one of its salts.

METHOD a wherein X is a halogen atom (chlorine, bromine, iodine, etc.), R2 is a group (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl, R12 is an alkyl group ( for example, a C x 6 alkyl group such as methyl, ethyl, propyl, tert-butyl and the like), an alkoxy group (e.g., a C 1-6 alkoxy group such as methoxy, ethoxy, isobutyloxy and the like) or a group phenyl optionally substituted with a halogen atom, a C 6 -6 alkoyl group, a nitro group and the like, and R 12 'is an alkyl group (e.g., an Ci-β alkoyl group such as methyl, ethyl, propyl, tert-butyl) and the like), or a phenyl group optionally substituted with a halogen atom, an alkoyl group Ci-6, a nitro group and others. The method a includes reacting a compound (II) with an acylating agent (III) in the presence of a base to give a mixed acid anhydride and reacting the acid anhydride mixed with alcohol (IV) (HO-R2) in the presence of a basis to allow esterification. The mixed acid anhydride is produced in a solvent using about 1-3 mole of a base and about 1-3 mole of an acylating agent (III), relative to 1 mole of compound (II). Next, alcohol (IV) is added to allow the reaction or after filtering out the salt (salt of the base with HX), concentrating the filtrate and diluting the residue with a solvent, alcohol (IV) and a base are added. to allow the reaction, and thus lead to out the esterification. In the esterification, the amount of alcohol (IV) to be used is about 1-3 mole relative to 1 mole of compound (II), and the amount of base to be used is about 1-3 mole relative to 1. mol of compound (II). As the base, triethylamine, diisopropylethylamine, DBU, 4-dimethylaminopyridine, sodium hydride, potassium tert-butoxide, potassium carbonate, sodium carbonate and others can be used. As an acylating agent (III), pivaloyl chloride, ethyl chlorocarbonate, isobutyl chlorocarbonate, or acid halides such as 2,4,6-trichlorobenzoyl chloride, 2,4-dichlorobenzoyl chloride, 2-chloride, are used. 4,6-tribromobenzoyl, 2,3-, 6-trimethyl-4,5-dinitrobenzoyl chloride and the like; sulfonyl halides such as p-toluenesulfonyl chloride, methanesulfonyl chloride and the like, which are described in Bulletin of the Chemical Society of Japan, vol. 52, pp. 1989-1993 (1979). As a solvent, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, toluene, acetonitrile, acetone, ethylmethylketone, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide are generally used. , dimethyl sulfoxide and others. While the reaction conditions to produce the mixed acid anhydride vary depending on the combination of the base, the acylating agent (III) and the solvent to be used, the reaction is preferably carried out at about -30 ° C at room temperature for about 1-10 h. While the reaction conditions for the esterification vary depending on the combination of the mixed acid anhydride produced and the solvent to be used, the reaction is generally preferably carried out at about -30 ° C at the reflux temperature of the solvent for about 1 -10 h.

METHOD b (II) (i) where R is as previously defined. Method b includes reacting the compound (II) with thionyl chloride or oxalyl chloride in the presence of a catalyst such as DMF and the like to give an acid chloride, and reacting the acid chloride with alcohol (IV) (HO-R2 in the presence of a base to allow the esterification. The acid chloride is produced using about 1-3 moles of thionyl chloride or oxalyl chloride relative to 1 mole of compound (II) in the presence of a catalytic amount of DMF, in a solvent where necessary. After the subsequent concentration, a solvent is added and then alcohol (IV) and base are added to allow the reaction to carry out the esterification. In the esterification, the amount of alcohol (IV) to be used is about 1-3 mole relative to 1 mole of compound (II), and the amount of the base to be used is about 1-3 mole. to 1 mol of compound (II). As the base, those similar to the bases used in Method a and others are used. As a solvent, those similar to the solvents used in Method a and others are used. While the reaction conditions for producing the acid chloride vary depending on the solvent to be used, the reaction is generally preferably carried out at about -30 ° C at the reflux temperature of the solvent for about 10 min. 5 h. The reaction conditions for the esterification vary depending on the combination of the acid chloride produced and the solvent to be used, the reaction is usually carried out at about -30 ° C at the reflux temperature of the solvent for about 1 to 10 h METHOD c (H) (l) where X 'is a halogen atom (chlorine, bromine, iodine, etc.) and R2 is as previously defined. Method c includes reacting compound (II) (when it is a salt, preferably a salt with an alkali metal, such as sodium, potassium and the like; a salt with an alkaline earth metal such as calcium, magnesium and the like; ) with an alkylating agent (V) (X '-R2) in the presence of a base to allow esterification. The esterification is carried out in a solvent using about 1-3 mole of a base and about 1-3 mole of the alkylating agent (V), relative to 1 mole of compound (II). As the base, those similar to the bases used in Method a and others are used.

As a solvent, those similar to the solvents used in Method a and others are used. While the reaction conditions for the esterification vary depending on the combination of the base, the alkylating agent (V) and the solvent to be used, the reaction is preferably preferably carried out at about -30 ° C to the Reflux temperature of the solvent for about 30 min. to 10 h.

METHOD d where R is as previously defined. The method d comprises reacting the compound (II) with alcohol (IV) (HO-R2) in the presence of a condensing agent to produce the esterification. The esterification is carried out in a solvent using about 1-3 mole of the condensing agent and about 1-3 moles of alcohol (IV), relative to 1 mole of compound (II).

As the condensing agent, DCC, WSC, Mitsunobu reagents and others are used. As a solvent, those similar to the solvents used in Method a and others are used. While the reaction conditions for the esterification vary depending on the combination of the condensing agent and the solvent to be used, the reaction is usually preferably carried out at about -30 ° C at the reflux temperature of the solvent for about from 30 min to 24 h. The compound (II) can be produced according to 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 objective salt according to a usually known method or a method analogous thereto. As opposed, when obtained as a salt, it can be converted into a free form or a different objective salt according to a usually known method or an analogous method. When the compound (I) is obtained as an amorphous, it can be crystallized according to a commonly known crystallization method or an analogous method. A Form A crystal of the compound (I) can be produced by recrystallization of the compound (I) from a individual solvent of a low molecular weight aprotic solvent (e.g. acetonitrile, acetone and the like) or a solvent mixed therewith with water to give a solvate crystal of compound (I), and drying the solvate crystal at room temperature - around 150 ° C, preferably around 80 ° C - about 120 ° C, for 5 h - 3 days, preferably 8 h - 15 h, under reduced pressure. The compound (I) and one of its salts (sometimes referred to hereafter as the compound of the present invention) thus produced show less toxicity and is safe (in other words, it is superior to a pharmaceutical agent with respect to the acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, drug interaction, carcinogenicity and the like), and rapidly becomes compound A in the living organism of an animal, particularly a mammal (e.g., humans, monkeys, cats, pigs, equines, cattle, mice, rats, guinea pigs, dogs, rabbits, etc.). Compound A or one of its salts or one of its prodrugs exhibits an insulin sensitizing activity. The salt of compound A may be any as long as it is an acceptable salt for pharmaceutical use, and may be mentioned those similar to the salts exemplified for the compound (I) • A prodrug of compound A is a compound that is converted to compound A due to the reaction through enzymes, gastric acid and the like under physiological conditions in the organism; that is, a compound that is converted to compound A through enzymatic oxidation, reduction, hydrolysis and the like, and a compound that is converted to compound A by hydrolysis and the like through gastric acid and others. Examples of a prodrug of compound A include a compound wherein an amino group of compound A is acylated, alkylated or phosphorylated (for example, a compound wherein an amino group of compound A is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2) -oxo-l, 3-dioxol-4-yl) methoxycarbonylated, tetrahydrofuranoylated, pyrrolidylmethyl, pivaloyloxymethyl or tert-butylated and the like); a compound wherein a hydroxy group of compound A is acylated, alkylated, phosphorylated or borated (for example, a compound wherein a hydroxy group of compound A is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumedylated, alanylated or dimethylaminomethylcarbonylated and the like); a compound wherein a carboxyl group of compound A is esterified or amidated (for example, a compound wherein a carboxyl group of the Compound A is ethylesterified, phenylsterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl ester, cyclohexyloxycarbonylethyl esterified or methylamide and the like) and others. These compounds can be produced from compound A according to a commonly known method. A prodrug of compound A can be a compound which is converted to compound A under physiological conditions as described in Development of Pharmaceutical Products, vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990). As a prodrug of compound A, a compound is preferred wherein a carboxyl group of compound A is (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl esterified (ie, compound (I)). When a prodrug of compound A includes an optical isomer, a stereoisomer, a positional isomer or a rotational isomer, these are also included in a prodrug of compound A. For example, when a prodrug of compound A has an optical isomer, it is also included an optical isomer resolved from a racemic compound, in a prodrug of compound A. These isomers can be obtained as an individual product according to a synthesis method and a known separation method (for example, example, concentration, extraction, column chromatography, recrystallization and the like). A prodrug of compound A can be a crystal and can have a single crystal form or a form of a mixture of several crystals. The crystals may have been produced by crystallization according to a commonly known method. Since compound A normalizes the mechanism of intracellular insulin signal transduction, which mainly causes insulin resistance, thereby reducing insulin resistance and increasing the action of insulin and has an effect by which tolerance is improved to glucose. Therefore, compound A, one of its salts, or one of its prodrugs containing the compound of the present invention can be used for mammals (eg, humans, monkeys, cats, pigs, horses, cattle, mice, rats, guinea pigs, dogs, rabbits, etc.) as an improving agent or an agent for the prevention and / or treatment of diseases, in which insulin resistance is important. Mention may be made of such diseases, for example, insulin resistance, lower glucose tolerance; diabetes such as non-insulin-dependent diabetes, type II diabetes, type II diabetes associated with insulin resistance, type II diabetes associated with lower glucose tolerance, etc .; different complications such as hyperinsulinemia, hypertension associated with insulin resistance, hypertension associated with lower glucose tolerance, hypertension associated with diabetes (for example, type II diabetes, etc.), hypertension in association with hyperinsulinemia, insulin resistance that occurs associated with hypertension, lower tolerance to glucose that is associated with hypertension, diabetes that is associated with hypertension, hyperinsulinemia that is associated with hypertension, diabetic complications [for example, microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataract Diabetic disease, large vessel disease, osteopenia, diabetic hyperosmolar coma, infectious diseases (eg, infectious respiratory disease, infectious disease of the urinary tract, digestive infectious disease, infectious disease of smooth dermal tissue, infectious disease of the extremities inf eriores, etc.), diabetic gangrene, dry mouth, decreased sense of hearing, diabetic cerebrovascular disorder, diabetic peripheral hematogenous disorder, diabetic hypertension and the like], diabetic cachexia and the like; and others. Compound A, one of its salts or one of its prodrugs can also be used to treat patients with high normal blood pressure who developed diabetes.

Since compound A exhibits strong antagonistic activity to angiotensin II, the compound of the present invention is useful as an agent for the prevention or treatment of diseases (or diseases, of which initiation is promoted) developed by contraction. or the growth of blood vessels or organic disorders, which are 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 (e.g., humans, monkeys, cats, pigs, equines, cattle, mice, rats, guinea pigs, dogs, rabbits, etc.). As such diseases may be mentioned, for example, hypertension, abnormality of the circadian rhythm of blood pressure, cardiac diseases (eg, cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, poor vasodilation, cardiac myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, taguicardia, cardiac infarction, etc.), cerebrovascu lar disorders (for example, asymptomatic cerebrovascular disorder, transient cerebral ischemia, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.), cerebral edema, circulatory disorder cerebral, recurrence and sequelae of cerebrovascular disorders (eg, symptom of neurosis, symptom psychic, subjective symptoms, disorders in the activities of daily life, etc.), peripheral ischemic circulation disorder, myocardial ischemia, venous insufficiency, progression of heart failure after myocardial infarction, kidney diseases (eg, nephritis, glomerulonephritis) , glomerulosclerosis, renal failure, thrombotic vasculopathy, dialysis complication, organic dysfunction including nephropathy due to radiation damage, etc.), arteriosclerosis including atherosclerosis (for example, aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular hypertrophy , vascular hypertrophy or obliteration and organic disorders after an intervention (for example, percutaneous transluminal coronary angioplasty, stenting, coronary angioscopy, intravascular ultrasound, thrombolytic Dounce treatment, etc.), vascular reobliteration and restenosis after viation (bypass), polycythemia, hypertension, organic disorders and vascular hypertrophy after transplant, rejection after transplant, eye diseases (for example, glaucoma, ocular hypertension, etc.), thrombosis, multiple organ disorders, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (eg, deep vein thrombosis, peripheral obstructive circulatory disorders, arteriosclerosis obliterans, thromboangiitis obstructive, ischemic cerebral circulatory disorder, Raynaud's disease, Berger's disease, etc.), metabolic and / or nutritional disorders (for example, obesity, hyperlipidemia, hypercholesterolemia, hyperuricalcidemia, hyperkalemia, hypernatremia, etc.), nervous degeneration diseases ( for example, Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, AIDS, encephalopathy, etc.), central nervous system disorders (for example, cerebral hemorrhage, cerebral infarction, its sequelae and complications, cranial injury, spinal injury, edema cerebral, sensory dysfunction, sensory functional disorder, autonomic nervous system disorder, autonomic nervous system dysfunction, multiple sclerosis, etc.), dementia, memory failure, consciousness disorders, amnesia, anxiety symptom, catatonic symptom, mental state of bewilderment, psychopathies (for example, depression, epilepsy, alcoholism, etc.), inf diseases lamatorias (for example, arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis, etc .; inflammation after surgery and injury; 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 such as pneumonia, pulmonary silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, etc.), allergic diseases (for example, allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis, etc.), chronic obstructive pulmonary disease, interstitial pneumonia, pneumonia carini pneumocystis, collagen diseases (e.g., systemic lupus erythematosus, scleroderma, polyarteritis, etc.), liver diseases (e.g., hepatitis, including chronic hepatitis, liver cirrhosis, etc.), portal hypertension, digestive system disorders (e.g., gastritis, gastric ulcer, gastric cancer, gastric disorder after surgery, dyspepsia, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoidal disease, esophagus and stomach varicose ruptures, etc.), blood and / or myelopoetic diseases ( for example, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, coagul syndrome disseminated intravascular ation, multiple myelopathy, etc.), bone diseases (eg, fracture, refracture, osteoporosis, osteomalacia, Paget's disease of the bones, sclerosing myelitis, rheumatoid arthritis, osteoarthritis of the knee and dysfunction of the tissue of union and the like caused by diseases similar to these, etc.), solid tumor, tumors (eg, malignant melanoma, malignant lymphoma, cancer of digestive organs (eg, stomach, intestine, etc.), cancer and cachexia followed by cancer, cancer metastasis, endocrinopathy (eg, Addison's disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, organ urinary and / or male genital diseases (eg, cystitis, prostatic hypertrophy, prostate cancer, sexual infectious disease, etc.), female disorders (eg, climacteric disorder, gestosis, endometriosis, hysteromyoma, ovarian disease, breast, sexual infectious disease, etc.), disease related to environmental and occupational factors (for example, risk of radiation, risk of laser radiation, infrared or ultraviolet radiation, discomfort due to altitude, etc.), respiratory diseases (for example, of cold, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary embolism, etc.), infectious diseases (for example, viral infectious diseases with citom egalovirus, influenza virus, herpes virus, etc., rickettsiosis, bacterial infectious disease, etc.), toxemias (eg, sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome, etc.) , otorhinolaryngological diseases (for example, Meniere's syndrome, tinnitus, dysgeusia, vertigo, imbalance, dysphagia, etc.), skin diseases (for example, keloids, hemangioma, psoriasis, etc.), intradialitic hypotension, myasthenia gravis, diseases systemic, such as chronic fatigue syndrome and others. Since the compound of the present invention can maintain a constant hypotensive action during the day and night, it is possible to reduce the dose and frequency in comparison with the administration of the compound A. In addition, it can effectively suppress particularly the problematic increase in pressure blood pressure before and after increasing in patients with hypertension. Furthermore, in cases of sustained suppression for longer periods of the action of angiotensin II, the compound of the present invention improves the disorders or abnormality or suppresses the promotion thereof in the biofunction and the physiological action that produces disorders in adults. and different diseases related to aging and the like, which in turn generates the primary and secondary prevention of diseases or clinical conditions caused by them or represses their progression. It can be mentioned as a disorder or abnormality in the biofunction and physiological action, for example, the disorder or the abnormality in the automatic control of cerebral and / or renal circulation capacity, circulation disorder (for example, peripheral, cerebral, microcirculation, etc.). .), blood-brain barrier disorder, salt susceptibility, abnormal coagulation and fibrinolysis system, abnormal state of blood and blood blood cell components (eg, exacerbation of platelet aggregation activity, erythrocyte deformability, increased leukocyte adhesiveness, increased blood viscosity, etc.), production and exacerbation of factor growth factor and cytokines (eg. example, PDGF, VEGF, FGF, interleukin, TNF-a, MCP-1, etc.), exacerbation of proliferation and infiltration of inflammatory cells, exacerbation of free radical production, exacerbation of lipoesteatosis, impaired endothelial function, dysfunction of the endothelium, cells and organs, edema, change of the cellular morphogenesis of the smooth muscles, etc. (morphogenesis to proliferation type, etc.), increased production and function of vasoactive substance and inducers of thrombosis (eg, endothelin, thromboxane A2, etc.), abnormal constriction of blood vessels, etc., metabolic disorder (eg example, serum lipid abnormalities, dysglicemia, etc.), abnormal cell growth, etc., angiogenesis (including abnormal vasculogenesis during abnormal capillary reticular formation in the adventitial layer of arteriosclerosis), and others. Of these, the present invention can be used as an agent for the primary and secondary prevention or treatment of organic disorders associated with various diseases (e.g., cerebrovascular disorder and organic disorders associated therewith, disorders organic substances associated with cardiovascular disease, organic disorders associated with diabetes, organic disorders after surgical intervention, etc.). In particular, since compound A exhibits an inhibitory activity of proteinuria, the compound of the present invention can be used as an agent to protect the kidney. Therefore, the compound of the present invention can be used advantageously, when patients with insulin resistance, lower glucose tolerance, diabetes or hyperinsulinemia concurrently developed the diseases or clinical condition that were previously mentioned. Since compound A exhibits an inhibitory activity of body weight gain, the compound of the present invention can be used as an inhibitor of body weight gain in mammals. White mammals can be any mammals, in which the increase in body weight should be avoided. Mammals may present a genetic risk of increased body weight or may suffer from lifestyle-related diseases such as diabetes, hypertension and / or hyperlipidemia, etc. The increase in body weight can be caused by excessive feeding or by a diet without balance of nutrients or it can be derived from the combination of medications, for example, insulin sensitizers that present an activity PPARγ antagonist, such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc., and others. In addition, the increase in body weight may be prior to obesity, or it may be an increase in body weight of obese patients. Here it is defined as obesity, when the BMl (index of body weight, body weight (kg) / [height (m)] 2) is at least twenty-five for Japanese (criteria of the Japanese Association for the Study of Obesity), or at least thirty for Westerners (WHO criteria). The Association for Diabetes in Japan issued a report on the new criteria for diabetes in 1999. According to this report, diabetes is a condition where the fasting blood glucose level (glucose concentration of venous plasma) is not lower than 126 mg / dl, the value of 2 hours (venous plasma glucose concentration) the oral glucose tolerance test of 75 g (75 g OGTT) is not less than 200 mg / dl, or the casual level of blood glucose (venous plasma glucose concentration) is not lower than 200 mg / dl. In addition, it is termed a "borderline type" condition, a condition that is not included in the types of diabetes that were previously mentioned and that is not "a condition where the fasting blood glucose level (venous plasma glucose concentration) is less than 110 mg / dL or the value of 2 hours (venous plasma glucose concentration) in the test oral glucose tolerance of 75 g (75 g of OGTT) is less than 140 mg / dl "(normal type) .In addition, of the diagnostic criteria for diabetes mentioned, ADA (The American Diabetes Association) reported new diagnostic criteria in 1997 and WHO in 1998.

According to these reports, diabetes is a condition where the fasting blood glucose level (glucose concentration in venous plasma) is not lower than 126 mg / dl and the value of 2 hours (venous plasma glucose concentration) in The oral glucose tolerance test of 75 g is not less than 200 mg / dl. Furthermore, according to previous reports, the lower glucose tolerance is a condition where the fasting blood glucose level (glucose concentration in venous plasma) is lower than 126 mg / dl and the value of 2 hours (glucose concentration in venous plasma) in the oral glucose tolerance test of 75 g is not lower than 140 mg / dl and is lower than 200 mg / dl. In addition, according to the ADA report, a condition where the fasting blood glucose level (glucose concentration in venous plasma) is not less than 110 mg / dL and lower than 126 mg / dL, is called IFG (glucose in Altered fasting.} On the other hand, according to the WHO report, the conditions of IFG (altered fasting glucose), a condition where the value of 2 hours (concentration of glucose in venous plasma) in the test from oral glucose tolerance of 75 g is less than 140 mg / dl, it is called IFG (altered fasting glycemia). The compound of the present invention can be used as an improving agent or an agent for the prevention or treatment of diabetes, borderline type, lower glucose tolerance, IFG (altered fasting glucose) and IFG (altered fasting glycemia) as defined in 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 presenting a level no lower than the diagnostic criteria mentioned above. (for example, fasting blood glucose level of 126 mg / dL). Moreover, the compound of the present invention can also be used to prevent progression of the borderline type, lower glucose tolerance, IFG (altered fasting glucose) or IFG (altered fasting blood glucose) to diabetes. The compound of the present invention is useful as an agent for the suppression or improvement of cardiac depression, progression of cardiac remodeling and exacerbation of symptoms, or an agent for suppressing the reduction of the survival rate, of patients with cardiac disease ( for example, cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, poor vasodilation, cardiac myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, cardiac infarction, etc.) in association with diabetes. The compound of the present invention is effective for preventing the onset of cardiac diseases (eg, cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, deficient vasodilation, cardiac myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia , tachycardia, cardiac infarction, etc.) and cerebrovascu lar disorders (for example, asymptomatic cerebrovascular disorder, transient cerebral ischemia, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.) of diabetic patients. The compound of the present invention is useful as an agent for the prevention or treatment of metabolic syndrome. Because patients with metabolic syndrome have an extremely high incidence of cardiovascular diseases compared to patients with diseases related to a simple lifestyle, the prevention or treatment of metabolic syndrome is of paramount importance to prevent cardiovascular diseases.

The criteria for the diagnosis of the metabolic syndrome were indicated by the WHO in 1999 and by NCEP in 2001. According to the WHO criteria, patients with at least two of the following: abdominal obesity, dyslipidemia (high serum triglyceride value or low HDL cholesterol), hypertension in addition to hyperinsulinemia or fasting blood glucose were diagnosed as a syndrome metabolic (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and its complications, Part 1: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999). According to the criteria of the Adult Treatment Panel III of the National Cholesterol Education Program, which is an indicator for the control of ischemic heart disease in America, patients with at least three of the following: abdominal obesity, triglycerides elevated, low HDL cholesterol, hypertension and fasting blood glucose were diagnosed as metabolic syndrome (National Cholesterol Education Program: Main Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult 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 patients with high blood pressure with syndrome metabolic. Since compound A has an anti-inflammatory action, the compound of the present invention can be used as an anti-inflammatory agent to prevent or treat inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases due to various diseases such as arthritis (for example rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, synovitis), asthma, allergic diseases, arteriosclerosis including atherosclerosis (aneurysm, coronary sclerosis, cerebral arterial sclerosis, sclerosis peripheral arterial, etc.), digestive tract disease such as inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), diabetic complication (diabetic nervous disorder, diabetic vascular disorder), atopic dermatitis, chronic obstructive pulmonary disease, systemic lupus erythematosus , visceral inflammation disease (nephritis, hepatitis), autoimmune hemolytic anemia, psoriasis, degenerative nerve disease (eg Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS, encephalopathy), central nervous disorder (for example, cerebrovascular disorder such as cerebral hemorrhage and cerebral infarction, cranial trauma, spinal damage, cerebral edema, multiple scleritis), meningitis, angina, cardiac infarction, congestive heart failure, vascular hypertrophy or occlusion and organic disorders after surgery (transdermal coronary plasty, incorporated stent, coronary endoscopy, intravascular ultrasound, intracoronary thrombolysis, etc.), vascular reocclusion or restenosis after a bypass intervention, functional disorder endothelial, other circulatory diseases (intermittent claudication, peripheral obstructive circulatory disorder, obstructive arteriosclerosis, obstructive thrombotic angiitis, cerebral ischemic circulatory disorder, Leiner's disease, Buerger's disease), inflammatory eye disease, inflammatory lung disease (eg, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis), endometritis, toxemia (eg, sepsis, septic shock, endotoxic shock, gram-negative sepsis, toxin shock syndrome), cachexia (eg, cachexia due to infection, cachexia carche cytomatose, cachexia due to acquired immunodeficiency syndrome), cancer, Addison's disease, Creutzfeldt-Jakob disease, viral infection (for example virus infection such as cytomegalovirus, influenza virus, herpes, etc.), disseminated intravascular coagulation. In addition, since compound A exhibits an analgesic action, the compound of the present invention also It can be used as an analgesic agent to prevent or treat pain. Examples of painful conditions include acute pain due to inflammation, pain associated with chronic inflammation, pain associated with acute inflammation, pain after surgery (incision pain, deep pain, organic pain, chronic pain after operation, etc.), muscle pain (muscle pain associated with chronic pain disease, stiffness of the shoulder joint, etc.), arthralgia, toothache, gnaticartralgia, headache (migraine, catatonic headache, headache associated with fever, headache associated with hypertension), organ pain (heart pain, angina pain, abdominal pain, kidney pain, urethral pain, bladder pain), pain in the obstetric area (intermenstrual pain, dysmenorrhea, labor pain), neuralgia, (herniated disc, nerve pain of the radicular nerve , neuralgia after herpes zoster, trigeminal neuralgia), carcinomatous pain, atrophy of the sympathetic reflex, complex local pain syndrome and others. The compound of the present invention is effective in alleviating various pains directly and rapidly, such as nerve pain, carcinomatous pain and inflammatory pain, and has a particularly good analgesic effect in patients and pathologies, in which the threshold of the sensation of pain. The compound of the present invention is particularly useful as an analgesic agent for pain associated with chronic inflammation or pain associated with hypertension, or as an agent to prevent or treat inflammatory diseases or pain due to (1) arteriosclerosis including atherosclerosis, (2) vascular hypertrophy, occlusion or organic disorders after a surgical intervention, (3) reocclusion, restenosis or endothelial functional disorder after a bypass intervention, (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 for mammals (e.g., humans, monkeys, cats, pigs, horses, cattle, mice, rats, guinea pigs, dogs, rabbits, etc.) in the form of the compound as is or a pharmaceutical composition after mixing it with a vehicle acceptable for pharmaceutical use according to a commonly known method. As used herein, as an acceptable vehicle for pharmacological use, various organic or inorganic carrier substances may be used as materials for preparations. For example, excipients, lubricants, binders and disintegrants for solid preparations may be mentioned; solvents, dissolving agents, suspending agents, isotonicity agents and buffers for liquid preparations; and others. When necessary, additives may also be used for the preparation, such as preservatives, antioxidants, coloring agents, sweetening agents, and others. Preferred examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light silicic anhydride, synthetic aluminum silicate. , magnesium aluminometasilicate and others. Preferred examples of lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and others. Preferred examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and others. Preferred examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light silicic anhydride, low substituted hydroxypropylcellulose and others. Preferred examples of solvents include water for injectables, physiological brine, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, flax seed oil and others. Preferred examples of dissolution adjuvants include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and others. 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, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc .; polysorbates, polyoxyethylenated hydrogenated castor oil, and others. Preferred examples of isotonicity agents include sodium chloride, glycerin, O-mannitol, O-sorbitol, glucose and others. Preferred examples of buffers include buffers such as phosphate, acetate, carbonate, citrate, etc. and others. Preferred examples of conservatives include p- oxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and others. Preferred examples of antioxidants include sulfite, ascorbate and others. Preferred examples of coloring agents include edible water-soluble tar inks (eg, edible dyes such as Food Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, Food Blue Nos. 1 and 2, etc.), Water-insoluble lake dyes (for example, aluminum salts of water-soluble edible tar dyes mentioned above, etc.), natural colors (e.g., carotene, chlorophyll, red iron oxide, etc.) and others . Preferred examples of sweetening agents include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and others. The form of presentation of the pharmaceutical composition includes, for example, oral agents such as tablet, capsule (including soft capsule and microcapsule), granule, powder, syrup, emulsion, suspension, slow-release preparation and the like, which can each be administered orally in a safe way. The pharmaceutical composition can be prepared by conventional methods in the technical field of the pharmaceutical production area, such as the methods describe in the Japanese Pharmacopoeia and others. The production methods for such preparations are described in more detail below. For example, a tablet is produced by the addition of, for example, an excipient (e.g., lactose, sucrose, starch, O-mannitol, etc.), a disintegrant (e.g., calcium carboxymethylcellulose, etc.), a binder (eg, pregelatinized starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) and similar to the active ingredient, is formed by compression and where necessary, a coating is applied by a usually known method using a coating base usually known for the purpose of concealing the taste, the enteric solution or the slow release. The capsule can be prepared as a hard capsule filled with a powdered pharmaceutical agent or granules, or a soft capsule filled with a liquid or a 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, 0-mannitol and the like), a disintegrant (low substituted hydroxypropylcellulose, carmellose calcica, corn starch, croscarmellose sodium and the like), a binder (hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), a lubricant (magnesium stearate and the like) and the like and filling the mixture or granule in a capsule formed from the gelatin, hydroxypropylmethylcellulose mentioned above and others. The soft capsule is produced by dissolving or suspending the principle in a base (soybean oil, flaxseed oil, medium chain fatty acid triglycerides, beeswax oil and the like) and sealing the solution or suspension prepared in a sheet of gelatin using, for example, a rotary packaging machine and the like. When the compound of the present invention is a salt and it is preferable to avoid contacting the compound of the present invention in the form of a salt with water, the compound of the present invention is preferably dry blended with a carrier and the like to obtain a hard capsule The content of the compound of the present invention in a pharmaceutical composition is generally about 0.01 - about 99.9% by weight, preferably about 0.1 - about 50% by weight, relative to the entire preparation. The dose of the compound of the present invention is determined taking into consideration the age, the body weight, the general physical condition, the sex, the diet, time of administration, method of administration, elimination index, combination of medications, the level of disease for which the patient is treated and other factors. While the dose varies depending on the target disease, condition, subject of administration, method of administration and the like, for oral administration as a therapeutic agent to treat essential hypertension in adults, the daily dose of 0.1-100 mg it is preferably administered in a single dose or in 2 or 3 portions. In addition, and because the use of the compound of the present invention has superior safety, it can be administered for a prolonged period. The compound of the present invention can be used in combination with pharmaceutical agents such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antiarteriosclerotic agent, an antihypertensive agent, an anti-obesity agent, a diuretic, an agent anti-gout, an anti-thrombotic agent, an anti-inflammatory agent, a chemotherapeutic agent, an immunotherapeutic agent, a therapeutic agent for osteoporosis, an anti-dementia agent, an erectile dysfunction-improving agent, a therapeutic agent for urinary incontinence / frequency and similar (from now on the abbreviation of combined medication is used). On such occasions, the posology for the administration of the compound of the present invention and that of the combined medicament is not limited, as long as the compound of the present invention and the combined medicament are combined. As the form of such administration, there may be mentioned, for example, (1) the administration of an individual preparation obtained by simultaneous formulation of the compound of the present invention and the combined drug, (2) the simultaneous administration of two types of preparations obtained by separate formulation of the compound of the present invention and a combined medicament, through a single route of administration, (3) the stepwise administration of two types of preparations obtained by separate formulation of the compound of the present invention and a medicament combined, by the same route of administration, (4) the simultaneous administration of two types of preparations obtained by separate formulation of the compound of the present invention and a combined drug by different routes of administration, (5) administration stepwise in time of Two types of preparations obtained by separate formulations of the of the present invention and a combination drug by different routes of administration, such as an administration in the order of composed of the present invention and then the combined medicament, or an administration in reverse order and the like. The dose of the combination medication can be appropriately determined on the basis of the dose used for the treatment. The mixing ratio of the compound of the present invention and the combined medicament can be appropriately selected according to the subject of administration, the route of administration, the target disease, the condition, the combination and other factors. In cases, where the subject of administration is a human being, the combined medicament, for example, may be used in an amount of 0.01 to 100 parts by weight per part by weight of the compound of the present invention. As the therapeutic agent for diabetes, there may be mentioned, for example, insulin preparations (for example, animal insulin preparations extracted from the bovine and porcine pancreas; preparations of human insulins synthesized by a genetic engineering technique using E. coli or a yeast and the like; ), other insulin sensitizers (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS011, FK-614, etc.), inhibitors of α-glucosidase (eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [e.g., sulfonylureas (e.g., toibutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glibuzol, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or their calcium salt hydrate , GLP-1, etc.], amirin agonists (eg, pramlintide, etc.), phosphotyrosine phosphatase inhibitors (eg, vanadic acid, etc.), dipeptidylpeptidase IV inhibitors (eg, NVP-OPP-278 , PT-100, P32 / 98, etc.), ß3 agonists (for example, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc. .), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, etc.), SGLT inhibitors (sodium-glucose cotransporters) (eg, T1095, etc.) and Similar. As therapeutic agents for diabetic complications there may be mentioned, for example, aldose reductase inhibitors (for example, tolrestate, epalrestate, zenarestate, zopolrestate, minalrestate, fidarestate, SNK-860, CT-112, etc.), neurotrophic factors (e.g., NGF). , NT-3, BONF, etc.), PKC inhibitors (eg, LY-333531, etc.), AGE inhibitors (eg, ALT946, pimagedin, piratoxatin, N-phenacylthiazole bromide (ALT766), EXO-226, etc.), active oxygen purifiers (for example, acid thioctic, etc.), cerebral vasodilators (e.g., thiapride, mexiletin, etc.) and the like. As antihyperlipidemic agents there may be mentioned, for example, statin compounds which are inhibitors of cholesterol synthesis (for example, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or salts thereof (eg, sodium salt, etc.), etc.), squalene synthase inhibitors (eg TAK-475, etc.), fibrate compounds that have a triglyceride reducing effect (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.), EPA , DHA and others. As anti-atherosclerotic agents, there may be mentioned, for example, a cholesterol acyltransferase coenzyme A (ACAT) inhibitor (e.g., melinamide, CS-505, etc.), a lipid-rich plaque regression agent (e.g. which are described in WO 02/06264, WO 03/059900, etc.) and the like. As antihypertensive agents there may be mentioned, for example, angiotensin-converting enzyme inhibitors (for example, captopril, enalapril, delapril, etc.), angiotensin II antagonists (for example, candesartan cilexetil, candesartan, losartan, potassium losartan, eprosartan, valsartan) , termisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), β-blockers (eg, metoprolol, atenolol, propranolol, carvedilol, pindolol, etc.), clonidine and the like. Anti-obesity agents which may be mentioned are, for example, centrally acting anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamfetamine, mazindol, phenylpropanolamine, clobenzorex, etc.), pancreatic lipase inhibitors (eg. example, orlistat, etc.), ß3 agonist (eg, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc.), anorectic peptides (for example, leptin, CNTF (ciliary neurotrophic factor), etc.), cholescistokinin agonists (for example, lintitript, FPL-15849, etc.) and others. As diuretics there may be mentioned, for example, xanthine derivatives (for example, theobromine and sodium salicylate, theobromine and calcium salicylate, etc.), thiazide preparations (for example, etiazide, cyclopentiazide, trichlormethiazide, thiazide hydrochloride, hydroflumethiazide, thiazide benzyl hydrochloride, penflutiazide, polythiazide, methyclothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg , chlorthalidone, mefruside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and others. As anti-drop agents there may be mentioned, for example, allopurinol, probenecid, colchicine, benzbromarone, febuxostate, citrate and others. As antithrombotic agents, there may be mentioned, for example, anticoagulant agents [for example, heparin sodium, potassium heparin, warfarin potassium (warfarin), inhibitor of activated blood coagulation factor X (for example, the compounds described in WO 2004 / 048363, etc.)], thrombolytic agents [e.g., tPA, urokinase], antiplatelet agent [e.g., aspirin, sulfinpyrazone (anthurium), dipyridamole (persantine), ticlopidine (panaldin), cilostazol (pletal), GPIIb / IIIa antagonist (ReoPro), clopidogrel, etc.] and others. As the antiinflammatory agents there may be mentioned, for example, nonsteroidal inflammatory 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, camostate mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, gold and sodium thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, oxymorphone and its salts, etc. and similar. As chemotherapeutic agents there may be mentioned, for example, alkylating agents (e.g., cyclophosphamide, ifosfamide, etc.), metabolic antagonists (e.g., methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (e.g., mitomycin, adriamycin, etc.), anti-cancer agents derived from plants (for example, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide and others. Of these, furtulon, neofurtulon, etc., which are 5-fluorouracil derivatives and the like, are preferably. As immunotherapeutic agents, there may be mentioned, for example, microorganism or bacterial components (for example, muramyl dipeptide, picibanyl derivative, etc.), polysaccharides having immunostimulatory activity (for example, lentinan, schizophyllan, crestin, etc.), cytosines obtained by genetic engineering techniques (e.g., interferon, interleukin (IL), etc.), colony stimulation factor (e.g., granulocyte colony stimulation factor, erythropoietin, etc.) and the like, preferably IL-1 , IL-2, IL-12 and the like. As therapeutic agents for osteoporosis they can mention may be made, for example, of alfacalcidol, calcitriol, elcaltonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, disodium incadronate and others. As the anti-dementia agents there may be mentioned, for example, tacrine, donepezil, rivastigmine, galantamine and the like. As the agents that improve erectile dysfunction can be mentioned for example, apomorphine, sildenafil citrate and others. As the therapeutic agent for urinary incontinence / frequency may be mentioned, for example, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like. In addition, pharmaceutical agents that exhibit a cachexia-enhancing effect recognized in animal models and clinical situations, including cyclooxygenase inhibitors (e.g., indomethacin, etc.) [Cancer Research, Vol. 49, p. 5935-5939, 1989], progesterone derivatives (e.g., megestrol acetate) [Journal of Clinical Oncology, Vol. 12, p. 213-225, 1994], glucocorticoids (e.g., dexamethasone, etc.), metoclopramide pharmaceutical agents, tetrahydrocannabinol pharmaceutical agents (publications are the same as indicated above), metabolism improving agents of fat (eg, eicosapentaenoic acid, etc.) [British Journal of Cancer, Vol. 68, pp. 314-318, 1993], growth hormones, IGF-1 and antibodies against TNF-α, LIF, IL-6 and oncoestatin M, which induces cachexia and the like, can also be used in combination with the pharmaceutical agent of the present invention. The combined drug preferably includes a diuretic, an insulin preparation, an insulin sensitizer, an α-glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonylurea agent), and the like. In particular, a diuretic such as thiazide hydrochloride and the like and an insulin sensitizer such as pioglitazone hydrochloride and others are preferred. The combined drug mentioned above can be a combination of two or more types of these combined in suitable proportions. Since compound A improves the hypoglycemic activity of other insulin sensitizers, a combined use of compound A, one of its salts, or one of its prodrugs (particularly the compound of the present invention) and other insulin sensitizers (preferably hydrochloride of pioglitazone) markedly improves a prophylactic and / or therapeutic effect against diseases, in which insulin resistance has a part, like type II diabetes and others.

EXAMPLES The present invention is explained in detail with reference to the following Examples, Preparation Examples and Experimental Examples. In any case, these Examples are merely practical embodiments and do not limit the present invention. The present invention can be modified as long as the scope of the invention is not altered. Elution by column chromatography in the Examples was carried out under observation by TLC (thin layer chromatography). In TLC observation, 60F25 (produced by Merck) was used as the TLC plate, the solvent used as an elution solvent in the column chromatography was used as a developing solvent, and a UV detector was used for detection. As silica gel for column chromatography, Kieselgel 60 (70-230 mesh) or Kieselgel 60 (230-400 mesh) produced by Merck was used. As the basic silica gel, Chromatorex (NH) (100-200 mesh) produced by FUJI SILSIA CHEMICAL LTD. Was used. The NMR spectrum was measured by Bruker AVANCE 300 (300 MHz) using tetramethylsilane as an internal or external standard and the chemical shift is expressed at a value d, and the coupling constant is expressed in Hz. The diffraction of the crystal was measured by X-rays using RINT2100 Ultima + / PC [rays CuKa (? = L, 5418 Á)] produced by Rigaku Corporation. The symbols in the Examples mean the following. s: singlet d: doublet t: triplet q: quartet dd: double double m: multiplet J: coupling constant THF: tetrahydrofuran DMF: N, N-dimethylformamide DMSO: dimethylsulfoxide DBU: 1,8-diazabicyclo [5, 4, 0 ] -7-undecane DMAP: 4-dimethylaminopyridine JP1: Japan Pharmacopoeia (14th edition) solution 1 of the disintegration test JP2: Japan Pharmacopoeia (14th edition) solution 2 of the disintegration test GCDC / JP2: solution 2 of the Japan Pharmacopoeia disintegration test containing glycokenedeoxycholic acid Reference Example 1 1- [(2'-Cyanobiphenyl-4-yl) methyl] -2-cyclopropy1-1H-benzimidazole-7-carboxylic acid methyl ester 3-amino-2- was dissolved. { [(2'-cyclobiphenyl-4-yl) methyl] amino} Methyl benzoate (42 g) in ethyl acetate (420 mL), and triethylamine (19.7 mL) was added. Cyclopropancarbonyl chloride (12.2 mL) dropwise at 0 ° C, and the mixture was stirred for 6 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in ethanol (380 mL), then concentrated hydrochloric acid (42 mL) was added and the mixture was stirred at 80 ° C for 5 h. An aqueous solution of sodium hydroxide was added to neutralize the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated. The obtained crystals were washed with diisopropyl ether to give the title compound (46.2 g, 96%). XH NMR (300 MHz, CDC13) d ppm 1.05-1.14 (m, 2 H), 1.22-1.30 (m, 2 H), 1.93-2.05 (m, 1 H), 3.73 (s, 3 H), 5.97 ( s, 2 H), 7.06 (d, J = 8.48 Hz, 2 H), 7.19 - 7.29 (m, 1 H), 7. 38-7.50 (m, 4 H), 7.57-7.69 (m, 2 H), 7.72-7.78 (m, 1 H), 7.89 (dd, J = 7.91, 1.13 Hz, 1 H).

Reference Example 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} Methyl-1H-benzimidazole-7-carboxylate Hydroxylamine hydrochloride (78.8 g) was dissolved in DMSO (500 mL), and sodium bicarbonate (114 g) was added and the mixture was stirred at 50 ° C for 50 min. The compound (46.2 g) obtained in Reference Example 1 was added and the mixture was stirred at 80 ° C for 12 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The residue was dissolved in THF (436 mL), and carbonyldiimidazole (19.3 g) and DBU (11.9 mL) were added and the mixture was stirred for 30 min. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by basic chromatography on silica gel to give the title compound (44.0 g, 83%). X H NMR (300 MHz, DMSO-d 6) d ppm 0.99-1.12 (m, 4 H), 2.20-2.32 (m, 1 H), 3.67 (s, 3 H), 5.86 (s, 2 H), 6.96 ( d, J = 8.10 Hz, 2 H), 7.18 - 7.29 (m, 3 H), 7.44 - 7.59 (m, 3 H), 7.62 - 7.71 (m, 2 H), 7.79 (d, J = 7.91 Hz, 1 H), 12.39 (s, 1 H).

Reference Example 3 2-cyclopropyl-1-acid. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid The compound (31.8 g) obtained in Reference Example 2 was dissolved in 0.4 N aqueous sodium hydroxide solution (673 mL), and the mixture was stirred at 70 ° C for 5 h. 1 N Hydrochloric acid (270 mL) was added dropwise, and the precipitated crystals were collected by filtration to give the title compound (30.8 g, 97%). H NMR (300 MHz, DMSO-d6) d ppm 0.95 - 1.08 (m, 4 H), 2.17 - 2.30 (m, 1 H), 6.03 (s, 2 H), 6.99 (d, J = 8.29 Hz, 2 H), 7.19 - 7.26 (m, 3 H), 7.43 - 7.70 (m, 5 H), 7.76 (dd, J 7.91, 1.13 Hz, 1 H).

Example 1 2-cyclopropy1-1-. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl The compound (4.20 g) obtained in Reference Example 3 was dissolved in THF (42 mL), and triethylamine was added. (1.42 mL) and 2,4,6-trichlorobenzoyl chloride (1.52 mL) and the mixture was stirred for 12 h. The insoluble materials were removed by filtration, and the filtrate was concentrated. The residue was dissolved in dichloromethane (42 mL) and alcohol medoxomil (1.45 g) and DMAP (1.36 g) were added and the mixture was stirred for 12 h. The reaction mixture was diluted with chloroform, washed successively with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over magnesium sulfate and concentrated to give the title compound (3.08 g, 59%). X H NMR (300 MHz, DMSO-d 6) d ppm 0.97-1.10 (m, 4 H), 2.14 (s, 3 H), 2.18-2.31 (m, 1 H), 5.11 (s, 2 H), 5.89 ( s, 2 H), 6.96 (d, J = 8.29 Hz, 2 H), 7.18 - 7.31 (m, 3 H), 7.44 - 7.71 (m, 5 H), 7.82 (dd, J = 8.01, 1.04 Hz, 1 H), 12.38 (s, 1 H).

Example 2 3-. { 4 '- [(2-cyclopropyl-7-. {[[(5-methyl-2-oxo-l, 3-dioxol-4-yl) methoxy] carbonyl} - lH-benzimidazol-1-yl) methyl ] -biphenyl-2-il} -1, 2, -oxadiazole-5-ato potassium The compound (1.00 g) obtained in Example 1 was dissolved in acetone (20 mL) and 2-ethylhexanoate potassium (0.323 g) was added and the mixture was stirred for 4 h and 30 min. The precipitated crystals were collected by filtration to give the title compound (0.581 g, 54%). X H NMR (300 MHz, DMSO-d 6) d ppm 1.08 (d, 4 H, J = 6.2 Hz), 2.15 (s, 3 H), 2.25-2.34 (m, 1 H), 5.09 (s, 2 H) , 5.84 (s, 2 H), 6.82 (d, 2 H, J = 8.3 Hz), 7.18 - 7.28 (m, 4 H), 7.29 - 7.42 (m, 2 H), 7.45 - 7.50 (m, 1 H ), 7.53 (dd, 1 H, J = 7.5, 1.1 Hz), 7.80 (dd, 1 H, J = 7.9, 1.1 Hz).

EXAMPLE 3 2-Cyclopropyl-l- crystal. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) bipheni-4-yl] methyl} -lH-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl The compound obtained in Example 1 was recrystallized from acetonitrile to give a solvate crystal containing acetonitrile . This dried until the next day at 100 ° C under reduced pressure to give a form A crystal, which is stable to heat and handling. The crystal obtained presented the X-ray crystal diffraction pattern shown in Fig. 1, and approximately the following diffraction angles.

Table 1 Angle of Intensity diffraction (Relative 2Tj 5.08 34 10.10 62 11.52 38 11.62 38 14.76 50 15.56 41 Angle of Intensity diffraction (2T) relative 15.68 59 17.10 100 17.20 76 19.74 46 21.00 59 21.18 60 21.30 63 23.50 51 23.82 41 23.94 50 24.12 63 24.20 44 25.02 43 25.44 60 25.76 42 25.86 51 Example 4 Crystal of 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl The 2-cyclopropyl-l- acid was dissolved. { [2 '- (5-oxo-4, 5- dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid (1 kg) in N, N-dimethylacetamide (10 L), and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (345 g) was added. After cooling to not more than 10 ° C, p-toluenesulfonyl chloride (463 g), 4-dimethylaminopyridine (54 g) and potassium carbonate (397 g) were added and the mixture was stirred at not more than 20 ° C. for about 3 h. 0.5 N hydrochloric acid was added to adjust the pH value to, and water (10 L) was added to allow crystallization. The precipitated crystals were collected by filtration under reduced pressure and washed successively with N, N-dimethylacetamide (2 L) and 70% acetone with water content (2 L). The isolated crystals were suspended in 14% acetone with water content (6 L), and the suspension was dissolved on heating at 50 ° C. Activated charcoal (30 g) was added and the mixture was stirred for 10 min. The activated carbon was removed by filtration and washed with 14% acetone containing water (1 L). The filtrate was cooled to about 25 ° C to allow the precipitation of crystals and the mixture was stirred at the same temperature for 1 h. Water (13 L) was added and the mixture was continued to stir for 1 h. The mixture was cooled to no more than 10 ° C and stirring was continued for 1 h. The precipitated crystals were isolated and washed with 70% acetone with water content (6 L) to give a solvate crystal containing acetone. The glass was dried at 90 ° C under pressure reduced to give a form A crystal (903 g, yield: 80%).

Example 5 Crystal of 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl The 2-cyclopropyl-l- acid was dissolved. { [2 '- (5-oxo-4,5-dihydro-1, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzoimidazole-7-carboxylic acid (15.00 kg) in N, N-dimethylacetamide (150 L), and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (5.18 kg) was added. After cooling to no more than 10 ° C, p-toluenesulfonyl chloride (6.95 kg), 4-dimethylaminopyridine (0.81 kg) and potassium carbonate (5.96 kg) were added and the mixture was stirred at no more than 20 ° C. for about 3 h. 0.5 N hydrochloric acid was added to adjust the pH value to 4, and water (150 L) was added to allow crystallization. The crystallized solvate crystals were collected by filtration under reduced pressure and washed successively with N, N-dimethylacetamide (30 L) and 70% acetone with water content (30 L). The isolated crystals were suspended in 40% acetone with water content (225 L), and the suspension was dissolved on heating at 50 ° C. The solution was decontaminated by filtration and washed with 50% acetone with water content (30 L). The filtrate was cooled to around 25 ° C to allow the precipitation of crystals and the mixture was stirred at the same temperature for 1 h. Water (45 L) was added and the mixture was continued stirring for 1 h. The mixture was cooled to no more than 10 ° C and further stirred for 1 h. The precipitated crystals were isolated and washed with 50% acetone with water content (30 L) to give a solvate crystal containing acetone. The crystal was dried at 95 ° C under reduced pressure to give a Form A crystal (15.73 kg, yield: 84%).

Formulation Examples When the compound of the present invention is to be used as a therapeutic agent for circulatory diseases such as hypertension, heart disease, stroke, nephritis and the like, the following formulation can be used, for example. In the following formulation, since the components (addition) are different from the active ingredient, those indicated in the Japanese Pharmacopoeia, the quasi-drugs of the Japanese Pharmacopoeia or the standard of addition of pharmaceutical products, and the like can be used. 1. Tablet (1) Compound obtained in Example 4 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 Mix and granulate (1), (2), (3), 2/3 of (4) ) and 1/2 of (5). To this is added the remaining (4) and (5), and the mixture is compressed to give tablets. 2. Capsule (1) The compound obtained in Example 2 10 mg (2) Lactose 69.5 mg (3) Light silicic anhydride 0.2 mg (4) Magnesium stearate 0.3 mg 1 capsule 80 mg They were mixed dry (1), (2), (3) and (4) and packed in an HPMC capsule (No. 1). 3. Tablet Compound (I) (17.24 g), mannitol (3342 g) and microcrystalline cellulose (663 g) were mixed uniformly in a fluid bed granulator dryer, and the mixture was granulated in the dryer by spraying a solution aqueous hydroxypropyl cellulose (132.6 g) and dried there. The obtained granules were sprayed with a 1.5 mm screen of 0 using a force mill to give a powder of adequate granulometry. To the powder of suitable granulometry (3788 g), croscarmellose sodium (Ac-Di-Sol) (201.5 g) and magnesium stearate (40.3 g) were added and mixed to give pellets for the preparation of tablets. The granules were compressed in a press machine with a 7.0 mm screen of 0 to give pure tablets weighing 130 mg per tablet. A solution of hydroxypropylmethylcellulose 2910 obtained by the dispersion of titanium oxide and yellow ferric oxide and the solution of polyethylene glycol 8000 was sprayed on the pure tablets obtained in a coating machine to give about 25000 coated tablets having the theoretical formulation shown in Table 2 , which contains 0.5 mg of compound (I) per tablet.

Table 2 4. Tablet Compound (I) (172.4 g), mannitol (3187 g) and microcrystalline cellulose (663 g) were mixed uniformly in a fluidized bed granulator dryer, and the mixture was granulated in the dryer by spraying a solution aqueous hydroxypropyl cellulose (132.6 g) and dried there. The obtained granules were sprayed with a 1.5 mm-0 sieve using a force mill to give a powder of suitable granulometry. To the powder of suitable granulometry (3788 g), croscarmellose sodium (Ac-Di-Sol) (201.5 g) and magnesium stearate (40.3 g) were added and mixed to give pellets for the preparation of tablets. The granules were compressed in a press machine with a sieve of 7.0 mm of 0 to give pure tablets weighing 130 mg per tablet. A solution of hydroxypropylmethylcellulose 2910 obtained by the dispersion of titanium oxide and yellow ferric oxide and the polyethylene glycol 8000 solution on the pure tablets obtained in a coater to give about 25000 coated tablets having the theoretical formulation shown in Table 3, containing 5 mg of compound (I) per tablet.

Table 3 . Tablet Compound (I) (689.7 g), mannitol (2670 g) and microcrystalline cellulose (663 g) were mixed uniformly in a fluidized bed granulator dryer, and the mixture was granulated in the dryer by spraying a solution aqueous hydroxypropyl cellulose (132.6 g) and dried there. The obtained granules were pulverized with a sieve of 1.5 mm of 0 using a force mill to give a powder of suitable granulometry. To the powder of suitable granulometry (3788 g), croscarmellose sodium (Ac-Di-Sol) (201.5 g) and magnesium stearate (40.3 g) were added and mixed to give granules for the preparation of tablets. The granules were compressed in a press machine with a 7.0 mm screen or to give pure tablets weighing 130 mg per tablet. A solution of hydroxypropylmethylcellulose 2910 obtained by the dispersion of titanium oxide and yellow ferric oxide and the solution of polyethylene glycol 8000 was sprayed onto the pure tablets obtained in a coating machine to give about 25000 coated tablets having the theoretical formulation shown in Table 4 , which contains 20 mg of compound (I) per tablet.

Table 4 6. Tablet Compound (I) (3.4 g), lactose (311.4 g) and corn starch (88.4 g) were mixed uniformly in a fluidized bed granulator dryer, and the mixture was granulated in the dryer by spraying a aqueous solution of hydroxypropylcellulose (13.26 g) and dried there. The obtained granules were sprayed with a 1.5 mm-0 sieve using a force mill to give a powder of suitable granulometry. To the powder of suitable granulometry (306.3 g) they added croscarmellose sodium (Ac-Di-Sol) (16.25 g) and magnesium stearate (2.5 g) and mixed to give pellets for the preparation of tablets. The granules were compressed in a press machine with a 7.0 mm 0 sieve to give the pure tablets weighing 130 mg per tablet. A solution of hydroxypropylmethylcellulose 2910 obtained by the dispersion of titanium oxide and yellow ferric oxide and the polyethylene glycol 8000 solution on the pure tablets obtained in a coating machine was sprayed to give about 900 coated tablets having the theoretical formulation shown in Table 5 , which contains 1 mg of compound (I) per tablet.

Table 5 EXPERIMENTAL EXAMPLE 1 Inhibitory effect of the compound of the present invention on an angiotensin II-induced vasoconstrictor action (AII) in rats Male SD rats aged 11 weeks (JCL: SD, CLEA Japan, Inc.) were anesthetized with pentobarbital (50 mg / kg, ip), the femoral artery and the femoral vein were isolated, and a polyethylene tube filled with physiological saline containing heparin (200 U / mL) was placed. The catheter was fixed subcutaneously at the back of the neck. After the recovery period, the rats were subjected to the test. The arterial catheter was connected to a pressure transducer (2238, NEC San-ei Instruments) and the signals were transmitted to a recorder (RECTI-HORIZ 8K, NEC San-ei Instruments) through an amplifier for arterial pressure. After having stabilized the vasoconstrictor action of AII (100 ng / kg, i.v.), a test compound in an equimolar dose to compound A. After 24 hours of administering AII, an increase in blood pressure was measured and an inhibition index was calculated from the value prior to administration. All compounds were suspended in 0.5% methylcellulose and orally administered in a volume of 2 ml / kg. The results are shown as mean ± SEM (Table 6). The significance between the administration group of the compound (I) and another administration group of the compound is determined by Student's t test (**: p <0.01, *: p <0.05).

Table 6 As is evident from the results, the compound of the present invention shows a strong and sustained pharmacological action through oral administration.

EXPERIMENTAL EXAMPLE 2 Enhancing Effect of the Compound of the Present Invention on Insulin Sensitivity in Rats Male rats of 24 weeks of age were used to present hypertension spontaneously (SLC: SHR / Izm, Japan SLC, Inc.). The body weight, systolic blood pressure, fasting blood glucose level, plasma insulin level and plasma triglyceride level of the rats were measured, and the rats were divided into a vehicle administration group ( 05% methylcellulose) and the compound administration group (I) (0.12, 0.37 and 1.23 mg / kg), using them as indexes. Compound (I) was suspended in 0.5% methylcellulose solution and administered orally in a volume of 2 ml / kg for 2 weeks. Insulin sensitivity was evaluated by the glucose fixation technique. Specifically, the rats were anaesthetized with sodium pentobarbital after fasting overnight (injection of Nembutal, Dainippon Pharmaceutical Co., Ltd., 50 mg / kg ip), and catheters were placed (SP45, Natume Seisakusho Co., Ltd .) to collect blood samples, for insulin infusion (novolin R / 100, Novo Nordisk Pharma Co., Ltd.) and glucose infusion (glucose injection Otsuka 50%, Otsuka Pharmaceutical Co., Ltd.) in the common carotid artery right, in the left femoral vein and the right femoral vein. After a single intravenous injection of 25 mU / kg of insulin, the high insulin level was maintained through the infusion, using an infusion pump (KDS100, KDS) with an injection rate of 4 mU / kg / min. furtherIntravenously, glucose was infused in an amount necessary to maintain normal blood glucose level using a different infusion pump (KDS100, KDS). Intravenous glucose injection was started 10 min after the insulin injection started, and the glucose injection rate was modified after measuring blood glucose every 5 min. The blood glucose level was then measured rapidly using a simple blood glucose measuring device (ACCU-CHEK Comfort, Roche Diagnostics). Glucose was infused for 90 min, the average value of the glucose injection rate was calculated for 40 min (from 50 min to 90 min after the start of the injection) and used as an index (M value) of the insulin sensitivity. The results are shown as mean ± SEM (Table 7). For the comparison of the vehicle administration group and the compound (I) administration group, the Williams test (*: p <was used.; 0.025).

Table 7 As is evident from the results, the compound of the present invention shows a strong insulin sensitivity enhancing action through oral administration.

Experimental Example 3 Evaluation of membrane solubility and permeability by the artificial membrane permeation test (Parallel Artificial Membrane Permeability Assay Parallel-Permeability Parallel Test) (1) Solubility About 2 mg of samples were suspended in 2 ml of JPl, JP2 and 20 mmol / l of GCDC / JP2. The suspension was equilibrated at 37 ° C for 2 h and filtered. The concentration was determined in the solutions by HPLC under the following conditions.

HPLC conditions Detector: UV 254 nm Column: CAPCELLPAK C18 MG 75x4.6mm Mobile phase A: 0.05 mol / 1 buffer ammonium format (pH 3) / MeCN = 9: 1 Mobile phase B: 0.05 mol / 1 buffer ammonium format (pH 3) / MeCN = 1: 9 Gradient program: 0 -.10 min 0? 100% B) 10-.15 min 100% B) 15.1-20 min 0% B) Temp. of column: 40 ° C Flow rate: 1 ml / min Injection volume: 10 μL (2) Membrane Permeability The permeability with the artificial membrane was determined by means of PAMPA under the following conditions. Lipid membrane: GIT mode (pION) Measurement of long. Wavelength: 250-400 nm Incubation time: 3 h Incubation temperature: 25 ° C Donor: DMSO-containing buffer % pH: 3 points of 7.4, 6.0, 5.5 Compound concentration: 50 μmol / 1 The results of the solubility and permeability of compound X (crystal form A of compound (I)), compound A and compound B were show in Table 8.

Table 8 Compared with compound X, compound A was more soluble but less permeable and compound B was more permeable, but less soluble. Compound A is considered to produce poor oral absorption, due to its low permeability. It is also considered that compound B produces a low oral absorption, due to the low solubility that limits the index.

Therefore, it is expected that compound X achieves higher oral absorption compared to compound A and compound B.

Industrial Applicability The compound of the present invention is useful as a medicament for the prevention or treatment of circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and others. This application is based on patent applications Nros. 2005-099788 and 2005-198014 registered in Japan, 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 (15)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. 2-Cyclopropyl-1 -. { [2'- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl.
2. 2. A salt of 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl.
3. 3. Potassium salt of 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl.
4. 4. A solvate of 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} (5-Methyl-2-oxo-l, 3-dioxol-4-yl) methyl-1H-benzimidazole-7-carboxylate.
5. 5. A crystal of the compound according to any of claims 1 to 4.
6. 6. A method for producing 2-cyclopropyl-1-. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate of (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl or one of its salts, characterized in that it includes the reaction of a reactive derivative of 2-cyclopropyl- l- . { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid, or one of its salts, with 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one or one of its salts.
7. 7. A pharmaceutical agent, characterized in that it includes the compound according to any of claims 1 to 4.
8. 8. The pharmaceutical agent according to claim 7, characterized in that it is an angiotensin II antagonist.
9. 9. The pharmaceutical agent according to claim 7, characterized in that it is an agent for the prevention or treatment of circulatory diseases.
10. 10. An insulin sensitizer, characterized in that it includes 2-cyclopropyl-1- acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs.
11. 11. An enhancer of a hypoglycemic activity of an insulin sensitizer, characterized in that it includes 2-cyclopropyl-1- acid. { [2 '- (5-oxo-4,5-dihydro-l, 2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -IH-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs.
12. 12. Use of the compound according to any of claims 1 to 4 for the production of an angiotensin II antagonist.
13. 13. Use of the compound according to any of claims 1 to 4 for the production of an agent for the prevention or treatment of circulatory diseases.
14. 14. Use of 2-cyclopropyl-l- acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs for the production of an insulin sensitizer.
15. 15. Use of 2-cyclopropyl-l- acid. { [2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] ethyl} -1H-benzimidazole-7-carboxylic acid or one of its salts or one of its prodrugs for the production of an enhancer of a hypoglycemic activity of an insulin sensitizer.