ES2350948T3 - DERIVED FROM BENCIMIDAZOL AND ITS USE. - Google Patents

Abstract

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

Description

TECHNICAL FIELD

The present invention relates to a new benzimidazole derivative with superior properties as a pharmaceutical agent, a method of production thereof and the use thereof. More specifically, the present invention relates to a prodrug of a benzimidazole derivative with a specific structure, which exhibits superior pharmacological actions (eg, a potent and sustained hypotensive action, insulin sensitizing activity and the like) and superior properties (e.g. eg, crystallinity, stability and the like) and which is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension, heart disease (heart hypertrophy, heart failure, heart attack and the like), nephritis, stroke and the like and diseases metabolic, such as diabetes and the like, to a method of production thereof, to the use thereof and the like.

Prior art

Angiotensin II produces vasoconstriction by an angiotensin II receptor in the cell membrane and raises blood pressure. Accordingly, an angiotensin II receptor antagonist may be an effective therapeutic drug for circulatory diseases such as for hypertension and the like.

As a preferable chemical structure for expressing the strong antagonistic activity of angiotensin II, a structure is known which has an acid group such as a tetrazolyl group, a carboxyl group and the like in a biphenyl side chain, and, as a pharmaceutical compound with said structural characteristics. Losartan, eprosartan, candesartan, cilexetil, olmesartan medoxomil and the like have been used clinically (Ruth R. Wexler et al., Journal of Medicinal Chemistry, vol. 39, p. 625 (1966), JP-A-4-364171 , JP-A-5-78328 and the like). JP-A-5-271228 describes that 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro1,2,4-oxadiazol-3-yl) biphenyl-4-yl acid ] methyl} -1H-benzimidazol-7-carboxylic acid (compound A) and a methyl ester thereof (compound B), which are compounds in which an acidic group in a biphenyl side chain is the 5-oxo-4 group, 5-dihydro-1,2,4-oxadiazol-3yl, has a strong antagonistic activity of angiotensin II and hypotensive action by oral administration. Furthermore, WO 03/047573 describes that, of the benzimidazole derivatives described in JP-A-5-271228, a specific compound (2-ethoxy-1 - {[2 '- (5-oxo-4, 5-dihydro-1,2,4-oxadiazol-3-yl) -1,1'-biphenyl-4-yl] methyl} -1H-benzimidazol-7-carboxylic acid: compound C) has an insulin sensitizing activity in addition to an activity angiotensin II antagonist.

As one of the means to increase the practical use as a pharmaceutical agent, the conversion of a compound having a certain pharmacological activity for a prodrug is known. For example, as the carboxylic acid prodrug, the alkylcarbonyloxymethyl ester, 1-alkylcarbonyloxyethyl ester, alkyloxycarbonyloxymethyl ester, 1-alkyloxycarbonyloxyethyl ester and ester (5-methyl-2-oxo-1,3-dioxol-4-) have been widely used il) methyl (i.e., medoxomyl ester) for a compound that exhibits insufficient activity expression by oral administration in the development of pharmaceuticals herein. In addition, Farnesol ester, which is a liposoluble substance of indomethacin; and the ethyl ester of an ACE inhibitor are known to provide sustained and similar activity.

WO 2005/080384 describes the medoxomyl ester of the compound

C.

From the aspects of ease of isolation and purification, stability in the formulation and the like, the compounds are preferably in the form of crystals. However, it is generally unpredictable if a compound crystallizes, and it is not known until the compound is in fact synthesized and isolated. On the other hand, crystallization generally decreases the solubility of the compounds, which in turn generally degrades the oral absorption capacity. Therefore, it is not possible to predict whether a crystal with superior properties (a correct balance of stability and solubility) can be obtained as a pharmaceutical compound.

Description of the invention

The present invention aims to provide a new superior compound as a pharmaceutical agent for the prophylaxis or treatment of circulatory diseases such as hypertension or the like and metabolic diseases such as diabetes and the like, and the like.

The present inventors have carried out intensive studies in an attempt to find a new compound with superior pharmacological action and superior physicochemical properties in order to provide a more useful pharmaceutical agent as an agent for prophylaxis or the treatment of circulatory diseases such as hypertension. or the like and metabolic diseases such as diabetes and the like and the like.

As a result, they have discovered that a prodrug compound that has a specific structure and capable of converting a compound A in the living body has extremely superior properties as a pharmaceutical agent because it has unexpectedly superior properties (e.g., physicochemical properties such as crystallinity, stability and the like), unexpectedly strong and sustained hypotensive action and the like, which results in the achievement of the present invention.

Accordingly, the present invention relates to:

one.

2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1Hbenzimidazol-7-carboxylate ( 5-methyl-2-oxo-1,3-dioxol-4-yl) methyl.

2.

A 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazol-7- salt (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carboxylate.

3.

Potassium salt of 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3yl) biphenyl-4-yl] methyl} -1H-benzimidazol-7- (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carboxylate.

Four.

A 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazol-7- solvate (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carboxylate.

5. A crystal of the compound of any one of claims 1 to 4.

6.

A method for producing 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazol-7 (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carboxylate or a salt thereof, which comprises reacting a reactive derivative of 2-cyclopropyl-1 - {[2 '- (5-oxo -4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} 1H-benzimidazol-7-carboxylate (5-methyl-2-oxo-1,3-dioxol-) 4-yl) methyl, or a salt thereof, with 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one or one of its salts.

7.

A pharmaceutical agent comprising the compound of any one of claims 1 to 4.

8.

The pharmaceutical agent of claim 7, which is an angiotensin II antagonist.

9.

The pharmaceutical agent of claim 7, which is an agent for the prophylaxis or treatment of circulatory diseases.

10.

An insulin sensitiser comprising the compound of any one of claims 1 to 4.

eleven.

A hypoglycemic activity enhancer of an insulin sensitizer, comprising the compound of any one of claims 1 to 4.

12.

A compound according to claims 1 to 4 for use to antagonize angiotensin II in a mammal.

13.

Use of the compound of any one of claims 1 to 4 for the production of an angiotensin II antagonist.

14.

A compound according to any one of claims 1 to 4 for use to prevent or treat circulatory diseases in a mammal.

fifteen.

Use of the compound of any one of claims 1 to 4 for the production of an agent for the prophylaxis or treatment of circulatory diseases.

16.

A compound of any one of claims 1 to 4 for use to produce an insulin sensitizer.

17.

Use of the compound of any of claims 1 to 4 for the production of an insulin sensitizer.

18.

A compound of any one of claims 1 to 4 for use to produce a hypoglycemic activity enhancer of an insulin sensitizer.

19.

Use of the compound of any of claims 1 to 4 for the production of a hypoglycemic activity enhancer of an insulin sensitizer.

The compound of the present invention has a prophylactic or therapeutic effect on circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and the like.

Brief description of the drawings

10

Fig. 1 shows a powder X-ray crystal diffraction model of the crystal obtained in Example 3.

Best mode for carrying out the invention

fifteen

2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1Hbenzimidazol-7-carboxylate ( 5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (hereinafter sometimes referred to as compound (I)) is represented by the formula:

image 1

In the formula, a group represented by the formula:

image 1

(group 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) includes three tautomers (a ’, b’ and c ’) represented by the formulas:

image 1

and a 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl group comprises all the a, b, and c mentioned above.

A salt of the compound (I) may be any provided it is a pharmacologically acceptable salt. As such salt, the salts of compound (I) with an inorganic base (e.g., alkali metals such as sodium, potassium and the like; alkaline earth metals such as calcium, magnesium and the like; etc.), an organic base may be mentioned. (eg, organic amines such as tromethamine [tris (hydroxymethyl) methylamine], ethanolamine, trimethylamine, triethylamine, tert-butylamine, pyridine, picoline, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like; amino acids; such as arginine, lysine, ornithine and the like, etc.), ammonia and the like.

As the salt of the compound (I), alkali metal salts of the compound (I) are preferable. Of these, a potassium salt is particularly preferable.

The compound (I) may be labeled with an isotope (e.g., 3H, 14C, 35S, 125I and the like) and the like.

The compound (I) can be a crystal, and can be in the form of a single crystal or a mixture of several crystals. The crystals can be produced by crystallization according to a crystallization process known per se.

The compound (I) is preferably a crystal and particularly, the crystal of form A which has a good balance of stability and solubility and is suitable for industrial manufacturing is preferable.

The compound (I) can be a solvate (e.g., hydrate, etc.) and the compound (I) comprises both the solvate and the non-solvate (e.g., no hydrate, etc.).

Method of production

The compound (I) can be produced according to, for example, the methods shown below, a method analogous to it and the like.

Although the yield of the compound (I) obtained by the following method may vary depending on the reaction conditions used, the compound (I) can be easily obtained with high purity by conventional means of

separation or purification (eg, recrystallization, column chromatography and the like) from the product by said methods. The compound (I) can be produced by reacting a reactive derivative (for example, a mixed acid anhydride, an acid halide and the like) of a

5 compound represented by formula (II) (compound A) or one of its salts (hereinafter sometimes referred to as compound (II)) with the corresponding alcohol (IV) (HO-R2) or one of its salts.

Method a

10

image 1

where X is a halogen atom (chlorine, bromine, iodine, etc.), R2 is a (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, R12 is an alkyl group (e.g., a C1-6 alkyl group such as methyl, ethyl, propyl, tert-butyl, and the like), an alkoxy group (e.g., a group

C 1-6 alkoxy such as methoxy, ethoxy, isobutyloxy and the like) or a phenyl group optionally substituted by a halogen atom, a C 1-6 alkyl group, a nitro group and the like, and R 12 is an alkyl group (e.g. ., a C1-6 alkyl group such as methyl, ethyl, propyl, tert-butyl and the like), or a phenyl group optionally substituted by a halogen atom, a C1-6 alkyl group, a nitro group and the like.

The method to comprise reacting the compound (II) with the 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 base to allow esterification. The mixed acid anhydride is produced in a solvent that uses

About 1 to 3 moles of a base and about 1 to 3 moles of acylating agent (III), with respect to 1 mole of compound (II). Subsequently the alcohol (IV) is added to allow the reaction or after once the salt is filtered (salt of the base with HX), concentrating the filtrate and diluting the residue with a solvent, alcohol (IV) and a base are added for allow the reaction, with which to carry out the esterification. In the esterification, the amount of alcohol (IV) to be used is approximately 1 to 3 moles relative to 1 mole of compound (II), and the amount of the base to be used is approximately 1 to 3 moles relative to to 1 mole of compound (II).

As a base, triethylamine, diisopropylethylamine, DBU, 4-dimethiaminopyridine, sodium hydride, potassium tert-butoxide, potassium carbonate, sodium carbonate and the like can be used.

As acylating agent (III), pivaloyl chloride, ethyl chlorocarbonate, isobutyl chlorocarbonate, or acid halides such as 2,4,6-trichlorobenzoyl chloride, 2,4-dichlorobenzoyl chloride, 2,4,6- chloride are used. 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 the Bulletin of the Chemical Society of Japan, vol. 52, p. 1989-1993 (1979).

As the solvent, dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, toluene, acetonitrile, acetone, ethylmethyl ketone, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, can generally be used. dimethyl sulfoxide and the like.

Although the reaction conditions for producing 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 to room temperature for 1 to 10 h. Although the reaction conditions for esterification vary depending on the combination of the mixed acid anhydride produced and the solvent to be used, the reaction is generally carried out preferably at about -30 ° C to the reflux temperature of the solvent for about 1 to 10 h.

Method b in which R2 is as defined above.

image 1

Method b comprises reacting 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 esterification.

The acid chloride is produced using about 1 to 3 moles of thionyl chloride or oxalyl chloride in relation to 1 mole of the compound (II) in the presence of a catalytic amount of DMF, in a solvent when necessary. After further concentration, a solvent is added and then alcohol (IV) and the base are added to allow the reaction to carry out the esterification. In the esterification, the amount of alcohol (IV) to be used is approximately 1 to 3 moles relative to 1 mole of the compound (II), and the amount of the base to be used is approximately 1 to 3 moles relative to to 1 mol of the compound (II).

As a basis, similar to the bases used in Method a and the like are used.

As the solvent, similar to the solvents used in Method a and the like are used.

Although the reaction conditions for producing the acid chloride vary depending on the solvent to be used, the reaction is generally carried out preferably at about -30 ° C to the reflux temperature of the solvent for about 10 min. up to 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 generally carried out preferably at about -30 ° C to the reflux temperature of the solvent for about 1 to 10 h .

Method c

image 1

in which X ’is a halogen atom (chromium, bromine, iodine, etc.) and R2 is as defined above.

Method c comprises 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; and the like) with the alkylating agent (V) (X'-R2) in the presence of a base to allow

10 esterification

The esterification is carried out in a solvent using about 1 to 3 moles of a base and about 1 to 3 moles of alkylating agent (V), relative to 1 mole of the compound (II).

As a basis, similar to the bases used in Method a and similar are used. As the solvent, similar to the solvents used in Method a and the like are used. Although the reaction conditions for esterification vary depending on the combination of the base, the alkylating agent (V) and the solvent to be

When used, the reaction is generally carried out preferably at about 30 ° C to the reflux temperature of the solvent for about 30 min. at 10 h.

25

D method

image 1

in which R2 is as defined above. 5 Method d comprises reacting compound (II) with alcohol (IV) (HO-R2) in the presence of a condensing agent to perform esterification.

The esterification is carried out in a solvent using about 1 to 3 moles of the condensing agent and about 1 to 3 moles of alcohol (IV), relative to 1 mole of the compound (II).

10 DCC, WSC, Mitsunobu reagents and the like are used as condensing agent. As a solvent, similar to the solvents used in Method a and the like are used. Although the reaction conditions for esterification vary depending

From the combination of the condensing agent and the solvent to be used, the reaction is generally carried out preferably at about -30 ° C to the reflux temperature of the solvent for about 30 min. at 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 method known per se or a method analogous to it. Conversely, when obtained as salt, it can be converted into a free form or a different objective salt according to a method known to itself or a method analogous to it.

When the compound (I) is obtained as amorphous, it can be crystallized according to the crystallization method known per se or a method analogous to it.

The crystalline form A of the compound (I) can be produced by recrystallizing the compound (I) in a single solvent of a low molecular weight aprotic solvent

(e.g., acetonitrile, acetone and the like) or a mixed solvent thereof with water to give a crystalline solvate of compound (I), and drying the crystalline solvate at room temperature to about 150 ° C, preferably about 80 ° C to about 120 ° C, for 5 h up to 3 days, preferably 8 h up to 15 h, under reduced pressure.

The compound (I) and a salt thereof (sometimes referred to as the compound of the present invention) thus produced have lower toxicity and are safe (in other words, more superior as a pharmaceutical agent from the aspects of acute toxicity, toxicity chronic, genetic toxicity, reproductive toxicity, cardiac toxicity, drug interaction, carcinogenicity and the like), and quickly become compound A in the living body of an animal, particularly a mammal (e.g., male, monkey, cat , pig, horse, cattle, mouse, rat, guinea pig, dog, rabbit, etc.).

Compound A or a salt thereof or a prodrug thereof has insulin sensitizing activity.

The salt of compound A can be any, as long as it is a pharmacologically acceptable salt, and those similar to the salts illustrated for compound (I) can be mentioned.

A prodrug of compound A is a compound that is converted to compound A due to the reaction by enzymes, gastric acid and the like in physiological conditions in the body, that is, a compound that is converted to compound A by enzymatic oxidation, reduction, hydrolysis and the like, and a compound that is converted to compound A by hydrolysis and the like by gastric acid and the like.

Examples of prodrugs of compound A include a compound in which an amino group of compound A is acylated, alkylated or phosphorylated (eg, a compound where an amino group of compound A is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl -2-oxo-1,3-dioxol-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated, and the like); a compound in which a hydroxy group of compound A is acylated, alkylated, phosphorylated or borated, (e.g., a compound in which a hydroxy group of compound A is acylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarate, alanylated or dimethylaminomethylcarbonylated, and the like); a compound in which a carboxyl group of compound A is esterified or amidated (e.g., a compound in which a carboxyl group of compound A is esterified with ethyl, esterified with phenyl, esterified with carboxymethyl, esterified with dimethiaminomethyl, esterified with pivaloyloxymethyl, esterified with ethoxycarbonyloxyethyl, esterified with phthalidyl, esterified with (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, esterified or methylamidated with cyclohexyloxycarbonylethyl or methylamidated, and the like) and the like. These compounds can be produced from compound A according to a method known per se.

A prodrug of compound A may be a compound that 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 in which a carboxyl group of compound A is esterified with (5-methyl-2-oxo-1,3-dioxol-4yl) methyl (ie, compound (I)) is preferable .

When a prodrug of compound A contains an optical isomer, a stereoisomer, a position isomer or a rotation isomer, they are also comprised in a prodrug of compound A. For example, when a prodrug of compound A has an optical isomer, an isomer Optical solution derived from a racemic compound is also comprised in a prodrug of compound A. These isomers can be obtained as an isolated product according to the synthesis method and the separation method known per se (eg, concentration, extraction, chromatography in column, recrystallization and the like).

A prodrug of compound A may be a crystal, and may be in the form of a single crystal or a mixture of several crystals. The crystals can be produced by crystallization according to a procedure known per se.

Since compound A normalizes the signal transduction mechanism of intracellular insulin, which mainly produces insulin resistance, thereby reducing insulin resistance and enhancing the action of insulin, and has an action to improve glucose tolerance Accordingly, compound A, one of its salts or one of its prodrugs containing the compound of the present invention can be used for mammals (e.g., man, monkey, cat, pig, horse, cattle, mouse, rat , guinea pig, dog, rabbit, etc.) as an improving agent or an agent for the prophylaxis and / or treatment of diseases in which insulin resistance is involved. As such diseases, there can be mentioned, for example, insulin resistance, impaired glucose tolerance; diabetes such as non-insulin-dependent diabetes, type II diabetes, type II diabetes associated with insulin resistance, type II diabetes associated with impaired glucose tolerance, etc .; various complications such as hyperinsulinemia, hypertension associated with insulin resistance, hypertension associated with impaired glucose tolerance, hypertension associated with diabetes (eg, type II diabetes, etc.), association of hypertension with hyperinsulinemia, insulin resistance that occurs in association with hypertension, impaired glucose tolerance that occurs in association with hypertension, diabetes that occurs in association with hypertension, hyperinsulinemia that occurs in association with hypertension , diabetic complications [p. eg, microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cataract, macroangiopathy, osteopenia, diabetic hyperosmolar coma, infectious diseases (eg, infectious respiratory disease, infectious urinary syndrome, infectious digestive disease, infectious skin tissue disease soft, infectious disease of the lower limb, etc.), diabetic gangrene, xerostomia, decreased sense of hearing, diabetic cerebrovascular disorder, diabetic peripheral hematogenous disorder, diabetic hypertension and the like], diabetic cachexia and the like; and the like Compound A, one of its salts or one of its prodrugs can be used to treat patients with high normal blood pressure who developed diabetes.

Since compound A has a potent angiotensin II antagonistic activity, the compound of the present invention is useful as an agent for the prophylaxis or treatment of diseases (or diseases whose onset is stimulated) developed by the contraction or growth of blood vessels. or the organic disorder, which is expressed by 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., man, monkey, cat, pig, horse, Cattle, mouse, rat, guinea pig, dog, rabbit, etc.).

As such diseases, for example, hypertension, abnormality in the circadian rhythm of blood pressure, heart disease (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, altered vasodilation, myopathy may be mentioned heart, angina, myocarditis, atrial fibrillation, arrhythmia, tachycardia, heart attack, etc.), cerebrovascular disorders (eg, asymptomatic cerebrovascular disorder, temporal cerebral ischemia, stroke, cerebrovascular dementia, encephalopathy hypertensive, cerebral infarction, etc.), cerebral edema, cerebral circulatory disorder, relapse and sequelae of cerebrovascular disorders (e.g., neurotic symptom, psychic symptom, subjective symptoms, disorder in daily life activities, etc.), ischemic disorder of the peripheral circulation, myocardial ischemia, venous insufficiency, evolution of heart failure after heart attack, kidney diseases (p. eg, nephritis, glomerulonephritis, glomerulosclerosis, renal insufficiency, thrombotic vasculopathy, dialysis complication, organic dysfunction including radiation damage nephropathy, etc.), arteriosclerosis including atherosclerosis (eg, aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis , peripheral arteriosclerosis, etc.), vascular hypertrophy, vascular hypertrophy or obliteration and organic disorders after the intervention

(p.

e.g., percutaneous transluminal coronary angioplasty, stent graft, coronary angioscopy, intravascular echocardiography, dounce thrombolytic therapy, etc.), vascular reobliteration and restenosis after shunt, polycythemia, hypertension, organic disorder and hypertrophy after transplantation, rejection after transplantation , eye diseases (e.g., glaucoma, ocular hypertension, etc.), thrombosis, multiple organ disorder, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (e.g., deep vein thrombosis, obstructive peripheral circulatory disorder, arteriosclerosis obliterans, obstructive thromboangeitis, ischemic cerebral circulatory disorder, Raynaud's disease, Berger's disease, etc.), metabolic and / or nutritional disorders (e.g., obesity, hyperlipidemia, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatriemia, etc.), degenerative nerve diseases (e.g., nurse Alzheimer's disease, Parkinson's syndrome, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.), central nervous system disorders (e.g. eg, cerebral hemorrhage, cerebral infarction, its sequelae and complications, head trauma, spinal trauma, cerebral edema, sensory dysfunction, sensory functional disorder, autonomic nervous system disorder, autonomic nervous system dysfunction, multiple sclerosis, etc.), dementia , memory defects, knowledge disorders, amnesia, anxiety symptom, catatonic symptom, mental state of restlessness, psychopathies (eg, depression, epilepsy, alcoholism, etc.), inflammatory diseases

(p.

eg, arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis, etc .; inflammation after the operation and trauma; remission of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, etc .; meningitis; inflammatory eye disease; inflammatory lung diseases such as pneumonia,

pulmonary silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, etc.), allergic diseases (eg, allergic rhinitis, conjunctivitis, gastrointestinal allergy, polenosis, anaphylaxis, etc.), chronic obstructive pneumopathy, interstitial pneumonia, Pneumocystis carinnii pneumonia, diseases of collagen (e.g., disseminated lupus erythematosus, scleroderma, panarteritis, etc.), liver diseases (e.g., hepatitis including chronic hepatitis, liver cirrhosis, etc.), portal hypertension, digestive system disorders (p e.g., gastritis, gastric ulcer, gastric cancer, postoperative gastric disorder, dyspepsia, esophageal ulcer, pancreatitis, colon polyps, cholelithiasis, hemorrhoids, ruptures of varicose veins of the esophagus and stomach, etc.), blood diseases and / or myelopoietic (eg, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelopathy, etc.), in bone diseases (e.g., fractures, refractures, osteoporosis, osteomalacia, Paget's bone disease, sclerosing myelitis, rheumatoid arthritis, knee osteoarthritis and joint tissue dysfunction and the like caused by diseases similar to these, etc.), solid tumor, tumors (e.g. eg, malignant melanoma, malignant lymphoma, cancer of digestive organs (eg, stomach, intestine, etc.) etc.), cancer and cachexia after cancer, cancer with metastasis, endocrinopathy (e.g., Addison's disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism, etc.), Creutzfeldt-Jacob disease, male urinary and / or genital diseases (eg, cystitis, prostatic hypertrophy, prostate cancer, infectious sexual disease , etc.), female disorders (e.g., climacteric disorder, gestosis, endometriosis, hysteromioma, ovarian disease, breast disease, infectious sexual disease, etc.), diseases related to environmental and occupational factors (e.g. ., radiation risk, risk of ultraviolet, infrared or laser rays, altitude sickness, etc.), respiratory diseases (eg, cold, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary embolism, etc.), infectious diseases goddesses (eg, viral infectious diseases with cytomegalovirus, influenza virus, herpes virus, etc.), rickettsiosis, infectious bacterial disease, etc.), toxemias (p. e.g., septicemia, septic shock, endotoxin shock, Gram-negative septicemia, toxic shock syndrome, etc.), ENT diseases (e.g., Meniere syndrome, tinnitus, dysgeusia, vertigo, imbalance, dysphagia, etc. ), skin diseases (eg, keloid, hemangioma, psoriasis, etc.), intradialitic hypotension, myasthenia gravis, generalized diseases such as chronic fatigue syndrome and the like.

Since the compound of the present invention can maintain a constant hypotensive action both day and night, dose and frequency reduction is possible compared to the administration of compound A. In addition, it can effectively suppress in particular the problem increase in blood pressure before and after appearing in patients with hypertension.

Furthermore, by maintaining the longer-term suppression of the action of angiotensin II, the compound of the present invention improves the disorder or anomaly.

or suppresses its stimulation in biofunction and physiological action, which produces disorders in adults and various diseases linked to aging and the like, which in turn leads to primary and secondary prophylaxis of diseases or clinical conditions produced by it or the suppression of its evolution. As a disorder or anomaly in biofunction and in physiological action, for example, the disorder or abnormality in the ability to automatically control cerebral circulation and / or renal circulation, circulation disorder (e.g., peripheral, cerebral, microcirculation, etc.), blood-brain barrier disorder, salt sensitivity, abnormal state of coagulation and fibrinolysis system, abnormal state of blood and blood cell components

(e.g., accentuation of platelet agglomeration activity, erythrocyte deformation, leukocyte adhesive accentuation, blood viscosity increase, etc.), function production and accentuation of growth factor and cytokines (e.g., PDGF, VEGF, FGF, interleukin, TNF-�, MCP-1, etc.), the accentuation of proliferation and infiltration of inflammatory cells, the accentuation of the production of free radicals, accentuation of lipoesteatosis, functional disorder of the endothelium, dysfunction of the endothelium, of cells and organs, edema, change of smooth muscle cell morphogeny, etc. (proliferation type morphogenesis, etc.), production and accentuation of the function of the vasoactive substance and thrombosis inducers (e.g., endothelin, thromboxane A2, etc.), abnormal constriction of blood vessels, etc. , metabolic disorder (e.g., serum lipid abnormalities, dysglycemia, etc.), abnormal cell growth, etc., angiogenesis (including abnormal vasculogenesis during abnormal capillary reticular formation in the adventitial layer of arteriosclerosis ) and the like can be mentioned. Of these, the present invention can be used as an agent for primary and secondary prophylaxis or the treatment of organic disorders associated with various diseases (e.g., cerebrovascular disorder and the associated organic disorder thereof, the organic disorder associated with the disease cardiovascular, the organic disorder associated with diabetes, the organic disorder after the intervention, etc.). In particular, since compound A has an activity of inhibiting proteinuria, the compound of the present invention can be used as an agent for kidney protection. Accordingly, the compound of the present invention can be used advantageously when patients with insulin resistance, impaired glucose tolerance, diabetes or hyperinsulinemia have simultaneously developed the above-mentioned clinical diseases or conditions.

Since compound A has an activity of inhibiting body weight gain, the compound of the present invention can be used as an inhibitor of body weight gain for mammals. Target mammals may be some mammals whose body weight gain should be avoided. Mammals may be at risk of genetic weight gain or may suffer from lifestyle-related diseases, such as diabetes, hypertension and / or hyperlipidemia, etc. The body weight gain can be caused by excessive feeding or diet without nutrient balance, or it can come from the combination of drugs, for example, insulin sensitizers that have agonistic activity of PPAR� such as troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone , etc., and the like. In addition, body weight gain may be preliminary to obesity, or it may be body weight gain from patients with obesity. Hereby, obesity is defined as the BMI (body mass index; body weight (kg) / [height (m)] 2) is at least twenty-five for the Japanese (Japan Society for the Study of Obesity criteria) , or at least thirty for Westerners (WHO criteria).

The Japan Diabetes Society published a report on the new diabetic criteria in 1999.

According to this report, diabetes is a disease in which the fasting blood glucose concentration (venous plasma glucose concentration) is less than 126 mg / dl, the value at 2 hours (venous plasma glucose concentration) of the 75 g oral glucose tolerance test (75 g OGTT) is less than 200 mg / dl, or the casual blood glucose concentration (venous plasma glucose concentration) is less than 200 mg / dl. In addition, a condition that is not included in the diabetes mentioned above, and that is not a condition in which the fasting blood glucose concentration (venous plasma glucose concentration) is less than 110 mg / dL or the value a The 2 hours (concentration of venous plasma glucose) of the 75 g oral glucose tolerance test (75 g OGTT) is less than 140 mg / dL (normal type) is called a "limit type".

In addition, with respect to the diagnostic criteria for diabetes, new diagnostic criteria were published by ADA (The American Diabetes Association) in 1997 and by WHO in 1998.

According to these reports, diabetes is a disease in which the fasting glucose concentration (venous plasma glucose concentration) is not less than 126 mg / dl and the 2-hour value (venous plasma glucose concentration) of The 75g oral glucose tolerance test is not less than 200 mg / dl.

In addition, according to previous reports, impaired glucose tolerance is a condition in which the fasting blood glucose concentration (venous plasma glucose concentration) is less than 126 mg / dL and the value at 2 hours (concentration of venous plasma glucose) of the 75 g oral glucose tolerance test is not less than 140 mg / dl, and the 2-hour value (concentration of venous plasma glucose) of the glucose tolerance test 75 g buccal is not less than 140 mg / dl and less than 200 mg / dl. In addition, according to the ADA report, a condition in which the fasting blood glucose concentration (venous plasma glucose concentration) is not less than 110 mg / dl and less than 126 mg / dl, is called IFG ( fasting impaired glucose). Moreover, according to the WHO report of the conditions of IFG (unchanged fasting glucose), a condition in which the value at 2 hours (concentration of venous plasma glucose) of the oral glucose tolerance test of 75 g is less than 140 mg / dl, it is called IFG (fasting blood glucose).

The compound of the present invention can be used as an improving agent or an agent for the prophylaxis or treatment of diabetes, borderline type, of impaired glucose tolerance IFG (impaired fasting glucose) and IFG (unchanged fasting blood glucose) defined by 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 having a concentration not lower than the diagnostic criteria mentioned above (eg, fasting blood glucose concentration of 126 mg / dl). In addition, the compound of the present invention can also be used to prevent the evolution of the limit type, the tolerance to unchanged glucose IFG (unchanged fasting glucose) or IFG (impaired fasting blood glucose) to diabetes.

The compound of the present invention is useful as an agent for the suppression or improvement of cardiac depression, the evolution of cardiac restructuring and the worsening of symptoms, or an agent for the suppression of the decrease in the survival rate of the heart disease patients (e.g., heart hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, altered vasodilation, heart myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, heart attack, etc.) along with diabetes. The compound of the present invention is effective for preventing the onset of heart disease (e.g., heart hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, altered vasodilation, cardiac myopathy, angina pectoris, myocarditis , atrial fibrillation, arrhythmia, tachycardia, myocardial infarction, etc.) and cerebrovascular disorders (eg, asymptomatic cerebrovascular disorder, temporal 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 prophylaxis or treatment of metabolic syndrome. Because patients with metabolic syndrome have an extremely high frequency of cardiovascular diseases compared to patients with diseases related to a single lifestyle, prophylaxis or treatment of metabolic syndrome is very important to prevent cardiovascular disease.

The criteria for the diagnosis of metabolic syndrome were announced by WHO in 1999, and by NCEP in 2001. According to WHO criteria, patients with at least two of abdominal obesity, dyslipidemia (high serum triglycerides or HDL cholesterol low), hypertension in addition to hyperinsulinemia or fasting blood glucose, are diagnosed as metabolic syndrome (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999). According to the criteria of the Adult Treatment Panel III of National Cholesterol Education Program, which is an indicator to direct ischemic heart disease in America, patients with at least three of abdominal obesity, high triglycerides, low HDL cholesterol, hypertension and blood glucose fasting, are diagnosed as metabolic syndrome (National Cholesterol Education Program: Executive Summary of the Third Report of National

Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel III). The Journal of the American Medical Association, Vol. 285, 2486-2497, 2001).

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

Since compound A has an inflammatory action, the compound of the present invention can be used as an inflammatory agent to prevent or treat inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases due to various diseases such as arthritis.

(e.g., rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis, synovitis), asthma, allergic diseases, arteriosclerosis including atherosclerosis (aneurysm, coronary sclerosis, cerebral arterial sclerosis, peripheral arterial sclerosis, etc.), apparatus disease such as inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), diabetic complication (diabetic nerve disorder, vascular diabetic disorder), atopic dermatitis, chronic obstructive pneumonia, disseminated lupus erythematosus, inflammatory disease of the viscera (nephritic, hepatitis), autoimmune hemolytic anemia, psoriasis, degenerative nerve disease (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy), central system disorder (e.g. , cerebrovascular disorder such as cerebral hemorrhage and cerebral infarction, head trauma, trauma spinal cord, cerebral edema, multiple sclerosis), meningitis, angina pectoris, heart attack, congestive heart failure, vascular hypertrophy or occlusion and organ disorder after the intervention (transdermal coronary plasty, permanent stent, coronary endoscopy, intravascular echocardiography, intracoronary thrombolysis , etc.); vascular reocclusion or restenosis after shunt operation, endothelial functional disorder, other circulatory diseases (intermittent claudication, obstructive peripheral circulatory disorder, obstructive arteriosclerosis, obstructive thrombotic angitis, ischemic cerebral circulatory disorder, Leiner's disease, Buerger's disease), inflammatory eye disease , inflammatory pulmonary disease (eg, chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis), endometritis, toxemia (eg, septicemia, septic shock, endotoxin shock, septicemia, gram-negative, shock syndrome) toxins), cachexia (e.g., cachexia due to infection, carcinomatous cachexia, cachexia due to acquired immunodeficiency syndrome), cancer, Addison's disease, Creutzfeldt-Jacob disease, viral infection (e.g., virus infection such as cytomegalovirus, influenza virus, herpes, etc.), intravascular coagulation di Seminated

In addition, since compound A has an analgesic action, the compound of the present invention can also be used as an analgesic agent for the impediment or treatment of pain. Examples of diseases with pain include acute pain due to inflammation, pain associated with chronic inflammation, pain associated with acute inflammation, postoperative pain (incision pain, acute pain, organic pain, chronic postoperative pain, etc.), pain muscle (muscle pain associated with chronic pain disease, shoulder stiffness, etc.), arthralgia, toothache, mandibular arthralgia, headache (migraine, catatonic headache, fever associated headache, hypertension associated headache), organic pain ( cardiac pain, angina pectoris pain, abdominal pain, kidney pain, ureteral pain, bladder pain), pain in the delivery room (intermenstrual pelvic pain, dysmenorrheal, labor pains), neuralgia (disc herniation, root pain nerve, postherpetic neuralgia, trigeminal neuralgia), carcinomatous pain, reflex sympathetic atrophy, complex local pain syndrome and the like. The compound of the present invention is effective for directly and rapidly relieving various pains such as nerve pain, carcinomatous pain and inflammatory pain, and has the particularly excellent analgesic effect for patients and pathologies in which the sensitive pain threshold is reduced.

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 for preventing or treating inflammatory disease or pain due to (1) arteriosclerosis including atherosclerosis, (2) vascular hypertrophy, occlusion

or organic disorder after the intervention, (3) reocclusion, restenosis or endothelial functional disorder after the shunt operation, (4) intermittent claudication, (5) occlusive peripheral circulatory disorder, (6) occlusive arteriosclerosis.

The compound of the present invention can be used as a safe pharmaceutical agent in mammals (e.g., man, monkey, cat, pig, horse, cattle, mouse, rat, guinea pig, dog, rabbit and the like) in the form of the compound such which

or in a pharmaceutical composition after mixing a pharmacologically acceptable carrier according to a method known per se.

As used herein, as a pharmacologically acceptable carrier, various organic or inorganic carrier substances can be used as materials for the preparations. For example, excipient, lubricant, binder and disintegrator for solid preparations; solvent, dissolution aids, suspending agents, isotonic agent and buffer for liquid preparations; and the like When necessary, preparation additives may also be used, such as preservatives, antioxidants, coloring agents, sweetening agents and the like.

Preferable examples of excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, pullullan, light silicic anhydride, synthetic aluminum silicate, alumina silicate magnesium and the like

Preferable examples of lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

Preferable examples of binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullullan, hydroxypropylcellulose, hydroxypropylmethylcellulose.

Preferable examples of disintegrator include lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, carboxymethyl sodium starch, light silicic anhydride, low substituted hydroxypropyl cellulose and the like.

Preferred examples of solvent include water for injections, physiological brine, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

Preferable examples of dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, tris-aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.

Preferable examples of suspending agents include surfactants such as stearyltrietanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc .; hydrophilic polymers such as polyvinyl alcohol, polyvinyl, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc .; polysorbates, castor oil hydrogenated with polyoxyethylene and the like.

Preferable examples of isotonic agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.

Preferable examples of buffer include buffers such as phosphate, acetate, carbonate, citrate, etc., and the like.

Preferable examples of preservative include p-oxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

Preferable examples of antioxidant include sulfite, ascorbate and the like.

Preferable examples of coloring agents include water-soluble edible pitch dyes (e.g., food dyes such as food reds # 2 and # 3, food yellows # 4 and # 5, food blues # 1 and # 2, etc. ), water-insoluble lacquer dyes (e.g., aluminum salts of the water-soluble edible pitch dyes mentioned above, etc.), natural dyes (e.g., �-carotene, chlorophyll, iron oxide red, etc.) and the like.

Preferable examples of sweetening agent include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like.

The pharmaceutical form of the pharmaceutical composition includes, for example, oral agents such as tablets, capsules (including soft capsule and microcapsule), granules, powders, syrups, emulsions, suspensions, sustained release preparation and the like, which can each be administered by orally safely.

The pharmaceutical composition can be prepared by conventional methods in the field of pharmaceutical preparation technique, such as the methods described in the Japanese Pharmacopoeia, and the like. Specific production methods for such preparations are described in detail below.

For example, a tablet is produced by adding, for example, an excipient

(e.g., lactose, sucrose, starch, D-mannitol, etc.), a disintegrator (e.g., calcium carboxymethylcellulose, etc.), a binder (e.g., pregelatinized starch, gum arabic, carboxymethylcellulose , hydroxypropylcellulose, polyvinyl, etc.), a lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000, etc.) and the like, to the active ingredient, compression-sizing, and, when necessary, apply a coating by a method known per se using a coating base known per se in order to achieve taste masking, enteric dissolution or sustained release.

The capsule can be prepared as a hard capsule filled with a powder or granular pharmaceutical agent, or as a soft capsule filled with a liquid or liquid suspension. The hard capsule is produced by mixing and / or granulating an active ingredient, e.g. eg, with an excipient (e.g., lactose, sucrose, starch, crystalline cellulose, D-mannitol and the like), a disintegrator (low substituted hydroxypropylcellulose, calcium carmellose, corn starch, croscarmellose sodium and the like), a binder (hydroxypropylcellulose, polyvinyl, hydroxypropyl methylcellulose and the like), a lubricant (magnesium stearate and the like) and the like, and filling the mixture or granule in a capsule formed by the aforementioned gelatin, hydroxypropyl methylcellulose and the like. The soft capsule is produced by dissolving or suspending the active ingredient in a base (soybean oil, corn seed oil, medium chain fatty acid triglyceride, beeswax and the like) and sealing the prepared solution or suspension in a sheet of gelatin using, for example, a rotary filling machine and the like.

When the compound of the present invention is a salt and it is preferable to avoid contact of the compound of the present invention as a salt with water, the compound of the present invention is preferably dry mixed with an excipient and the like to give a hard capsule. .

The content of the compound of the present invention in a pharmaceutical composition is generally about 0.01 to about 99.9% by weight, preferably about 0.1 to about 50% by weight, relative to the entire preparation.

The dose of the compound of the present invention is determined in consideration of age, body weight, general health status, sex, diet, duration of administration, method of administration, elimination rate, combination of drugs, level of disease for which The patient is under treatment then, and other factors.

Although the dose varies depending on the target disease, the disease, the administration patient, the method of administration and the like, for oral administration as a therapeutic agent for essential hypertension in adults, the daily dose of 0.1 to 100 mg is preferably administered in a single dose or in 2 or 3 fractions.

In addition, because the compound of the present invention is superior in safety, it can be administered over a long 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 agent against hyperlipidemia, an anti-arteriosclerotic agent, an anti-hypertensive agent, an anti-hypertensive agent. obesity, a diuretic, an agent against gout, an antithrombotic agent, an anti-inflammatory agent, a chemotherapeutic agent an immunotherapeutic agent, a therapeutic agent for osteoporosis, an agent against dementia, an agent for the improvement of erectile dysfunction, an agent Therapeutic for urinary incontinence / urinary frequency and the like (hereinafter it will be abbreviated as a combination drug). On such occasions, the administration schedule of the compound of the present invention and that of the pharmaceutical combination is not limited, provided that the compound of the present invention and the pharmaceutical combination are combined. As a way of such administration, for example, (1) the administration of a single preparation obtained by simultaneous formulation of the compound of the present invention and a combination drug, (2) simultaneous administration of two types of preparations obtained by the formulation can be mentioned separately from the compound of the present invention and a combination drug, by a single route of administration, (3) alternate time administration of two types of preparations obtained by separately formulating the compound of the present invention and a combination drug , by the same route of administration, (4) simultaneous administration of two types of preparations obtained by separate formulations of the compound of the present invention and a combination drug, by different routes of administration, (5) alternate administration at the time of two types of preparations obtained by formulation separately from the com since the present invention and a combination drug, by different routes of administration, such as administration in order of the compound of the present invention and then the combination of drugs, or administration in reverse order, and the like. The dose of the combination drug can be determined appropriately based on the clinically employed dose. The mixing ratio of the compound of the present invention and the combination of drugs can be appropriately selected according to the patient for administration, route of administration, target disease, condition, combination, and other factors. In cases where the patient for administration is a human being, for example, the pharmaceutical combination can 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 a therapeutic agent for diabetes there can be mentioned, for example, insulin preparations (e.g., insulin preparations of animals extracted from the bovine or porcine pancreas; human insulin preparations 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, CS-011, FK-614 , etc.), �-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (e.g., fenformin, metformin, buformin, etc.), insulin secretagogues [p . e.g., sulfonylureas (e.g., tolbutamide, glibenclamide, glycylazide, chlorpropamide, tolazamide, acetoxamide, glycylpyramide, glimepiride, glipizide, glibuzole, etc.), repaglinide, senaglinide, nateglinide, mitiglinida, saliglide etc.], amirin agonists (e.g., pramlintide, etc.), phosphotyrosine phosphatase inhibitors (e.g., vanadic acid, etc.), dipeptidylpeptidase IV inhibitors (e.g., NVP-DPP- 278, PT-100, P32 / 98, etc.), agonists of �3 (e.g. CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085 , AZ-40140, etc.), gluconeogeny inhibitors (e.g., glycogen phosphorylase inhibitor, glucose-6 phosphatase inhibitor, glucagon antagonist, etc.), SGLT inhibitors (sodium-glucose cotransporter) (p e.g., T-1095, etc.) and the like.

As therapeutic agents for diabetic complications there may be mentioned, for example, aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-112, etc.), neurotrophic factors (e.g., NGF, NT-3, BDNF, etc.), PKC inhibitors (e.g., LY-333531, etc.), AGE inhibitors (e.g., ALT946, pimagedine, piratoxatin, N-phenacylthiazolium bromide (ALT766), EXO-226, etc.), active oxygen antioxidants

(e.g., thioctic acid, etc.), cerebral vasodilators (e.g., thiapride, mexiletine, etc.) and the like.

As agents against hyperlipidemia, there may be mentioned, for example, statin compounds that are inhibitors of cholesterol synthesis (e.g., cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or its salts (e.g. ., sodium salt, etc.) etc.), squalene synthesis inhibitors (e.g., TAK-475, etc.), fibrate compounds with a triglyceride reducing effect (e.g., bezafibrate, clofibrate , simfibrate, clinofobrate, etc.), EPA, DHA and the like.

As anti-arteriosclerotic agents, for example, an acyl-coenzyme A cholesterol-acyltransferase (ACAT) inhibitor (e.g., melinamide, CS-505, etc.), a lipid-rich plaque regressive agent (e.g. eg, the compounds described in WO 02/06264, WO 03/059900, etc.) and the like.

As antihypertensive agents may be mentioned, for example, converting enzyme inhibitors in angiotensin (e.g., captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, termisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, etc.), �-blocker (p. eg, metoprolol, atenolol, propranolol, carvedilol, pindolol, etc.), clonidine and the like.

As agents against obesity there may be mentioned, for example, the central action agent against obesity (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine, amphepramone, dexamfetamine, mazindole, pheipropanolamine, clobenzorex, etc.), inhibitors of pancreatic lipase (e.g., orlistat, etc.), agonist of

�3 (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140, etc.), anorexic peptides (e.g., leptin, CNTF (ciliary factor), etc.), cholescistocinin agonists (e.g., lintitript, FPL-15849, etc.) and the like.

As diuretics, there may be mentioned, for example, xanthine derivatives

(P. G., Theobromine and sodium salicylate, theobromine and calcium salicylate etc.), thiazide preparations (p. G., Ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutiazida, polythiazide, methyclothiazide, etc.) , anti-aldosterone preparations (e.g., spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (e.g., acetazolamide, etc.), chlorobenzenesulfonamide preparations (e.g., chlorthalidone, mephruside, indapamide , etc.), azosemide, isosorbide, ethacrynic acid, pyretanide, bumetanide, furosemide and the like.

As anti-gout agents, for example, allopurinol, probenecid, colchicine, benzobromarone, febuxostat, citrate and the like can be mentioned.

As antithrombotic agents there can be mentioned, for example, anticoagulant agents [e.g. eg, sodium heparin, potassium heparin, potassium warfarin (warfarin), activated blood coagulation factor X inhibitor (eg, the compounds described in WO 2004/048363, etc.)], trobolitic agent

[p. eg, tPA, urokinase], antiplatelet agent [p. eg, aspirin, sulfinpyrazone (Anturan), dipyridamole (Persantin), ticlopirin (Panaldina), cilostazol (Pletal), GPIIb / IIIa antagonist (ReoPro), clopidogrel, etc.] and the like.

As anti-inflammatory agents there can be mentioned, for example, non-steroidal anti-inflammatory agents, such as acetaminophen, phenacetin, ethenzamide, sulpirin, antipyrine, migrenine, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethatazone ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, epirizole, hydrochloride tiaramide, zaltoprofen, mesylate gabexate, camostat mesilate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, sodium gold thiomalate, sodium hyaluronate , sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, oxymorphone and its salts, etc., and the like.

As chemotherapeutic agents there may be mentioned, for example, alkylating agents (e.g., cyclophosphamide, ifosfamide, etc.), metabolic antagonists (e.g., methotrexate, 5-fluorouracil, etc.), anti-cancer antibiotics (e.g. , mitomycin, adriamycin, etc.), anticancer agents from plants (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide and the like. Of these, furtulon, neofurtulon, etc.), which are derivatives of 5-fluorouracil, and the like are preferable.

As immunotherapeutic agents, there may be mentioned, for example, components of microorganisms or bacteria (e.g., derived from muramyl dipeptide, picibanyl, etc.), polysaccharides with immunostimulatory activity (e.g., lentinan, schizophilan, krestin, etc. .), cytokines obtained by genetic modification techniques (e.g., interferon, interleukin (IL), etc.), colony stimulating factor (e.g., granulocyte colony stimulating factor, erythropoietin, etc.) and similar, preferably for IL-1, IL-2, IL-12 and the like.

As therapeutic agents for osteoporosis there may be mentioned, for example, alphacalcidol, calcitriol, elcaltonin, salmon calcitonin, estriol, ipriflavone, disodium pamidronate, hydrated sodium alendronate, disodium incadronate and the like.

As agents against dementia, there may be mentioned, for example, tacrine, donepezil, rivastigmine, galantamine and the like.

As agents for the improvement of erectile dysfunction can be mentioned, for example, apomorphine, sildenafil citrate and the like.

As therapeutic agents for urinary incontinence / urinary frequency, for example, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like can be mentioned.

In addition, pharmaceutical agents that have a recognized cachexia enhancing effect in animal models and clinical situations, including cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, vol. 49, p. 5935-5939, 1989], progesterone derivatives (eg, megestrol acetate) [Journal of Clinical Oncology, vol. 12, p. 213-225, 1994], glucosteroids (eg, dexamethasone, etc.), pharmaceutical agents of metoclopramide, pharmaceutical agent of tetrahydrocannabinol (publications are the same as above), fat metabolism enhancing agent (e.g. ., eicosapentanoic acid, etc.) [British Journal of Cancer, vol. 68, p. 314-318, 1993], growth hormone, IGF-1 and antibodies against TNF-�, LIF, IL-6 and oncostatin M, which induce cachexia, and the like, can also be used in combination with the pharmaceutical agent of the present invention .

The pharmaceutical combination preferably includes a diuretic, an insulin preparation, an insulin sensitizer, an �-glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably sulfonylurea agent) and the like. In particular, a diuretic such as hydrochlorothiazide and the like and insulin sensitizers such as pioglitazone hydrochloride and the like are preferable.

The pharmaceutical combination mentioned above may be a combination of two or more types thereof combined in appropriate ratios.

Since compound A increases the hypoglycemic activity of other insulin sensitizers, a combined use of compound A, a salt thereof or a prodrug thereof (particularly the compound of the present invention) and other insulin sensitizers, (preferably hydrochloride of pioglitazone) significantly improves a prophylactic and / or therapeutic effect against diseases in which insulin resistance is involved, such as diabetes II and the like.

Examples

The present invention is explained in detail with reference to the following Examples, Preparation Examples and Experimental Examples. However, these Examples are mere practical embodiments and do not limit the present invention. The present invention can be modified as long as it does not deviate the scope of the invention.

Elution by column chromatography in the Examples was performed under observation by TLC (thin layer chromatography). In the TLC observation, 60F254 (manufactured by Merck) was used as the TLC plate, the solvent used as elution solvent in the chromatographic column was used as the developing solvent, and UV detector was used for detection. As silica gel for column chromatography, Kieselgel 60 (70-230 mesh) or Kieselgel 60 (230 400 mesh) manufactured by Merck was used. As a basic silica gel, Chromatorex (NH) (100-200 mesh) manufactured by FUJI SILSIA CHEMICAL LTD was used. The NMR spectrum was measured with Bruker AVANCE 300 (300 MHz) using tetramethylsilane as internal or external standard, and the chemical shift is expressed in value � and the coupling constant is expressed in Hz. The diffraction of the powder X-ray crystal It was measured using RINT2100 Ultima + / PC [CuK rays (� = 1.5418 Å)] manufactured by Rigaku Corporation. The symbols in the Examples mean the following.

s

: singlet

d

: double

t

: triplet

that

: quartet

dd

: double double

m

: multiplet

j

: coupling constant

THF

: tetrahydrofuran

DMF

: N, N-dimethylformamide

DMSO

: dimethyl sulfoxide

DBU

: 1,8-diazabicyclo [5.4.0] -7-undecene

DMAP

: 4-dimethylaminopyridine

JP1

: Solution 1 of the Pharmacopoeia disintegration test of

Japan (fourteenth edition).

JP2: Solution 2 of the disintegration test of the Pharmacopoeia of Japan (fourteenth edition).

GCDC / JP2: Solution 2 of the disintegration test of the Pharmacopoeia of Japan containing glucokenodeoxycholic acid.

Reference Example 1

1 - [(2’-cyanobiphenyl-4-yl) methyl] -2-cyclopropyl-1 H -benzimidazol-7-methyl carboxylate

image 1

Methyl 3-amino-2 - {[(2'-cyanobiphenyl-4-yl) methyl] amino} benzoate (42 g) was dissolved in ethyl acetate (420 ml) and triethylamine (19.7 ml) was added. Cyclopropanecarbonyl chloride (12.2 ml) was added 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

5 successively with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated. The residue was dissolved in ethanol (380 ml) and then concentrated hydrochloric acid (42 ml) was added, and the mixture was stirred at 80 ° C for 5 h. Aqueous sodium hydroxide solution was added, to neutralize the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed

10 successively with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated. The crystals obtained were washed with diisopropyl ether to give the title compound (46.2 g, 96%). 1 H NMR (300 MHz, CDCl 3) � 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),

15 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

2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H20 benzimidazol-7-carboxylate methyl

image 1

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 chromatography on basic silica gel to give the title compound (44.0 g, 83%).

5 1 H NMR (300 MHz, DMSO-d6) � 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

10 2-Cyclopropyl-1 - {[2 ’- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1Hbenzimidazol-7-carboxylic acid

image 1

The compound (31.8 g) obtained in Reference Example 2 was dissolved in

Aqueous solution (0.4 N) of sodium hydroxide (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%). 1 H NMR (300 MHz, DMSO-d6) � 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 ,

20 J = 7.91 Hz, 1.13 Hz, 1 H).

Example 1

2-cyclopropyl-1 - {[2 ’- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H

(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl benzimidazol-7-carboxylate.

25

image 1

The compound (4.20 g) obtained in Reference Example 3 was dissolved in THF (42 ml), and triethylamine (1.42 ml) and 2,4,6-trichlorobenzoyl chloride (1.52 ml) were added , and the mixture was stirred for 12 h. Insoluble materials were separated by

5 filtration, and the filtrate was concentrated. The residue was dissolved in dichloromethane (42 ml), and medoxomyl alcohol (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

10 title compound (3.08 g, 59%). 1 H NMR (300 MHz, DMSO-d6) � 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 Hz, 1.04 Hz, 1 H), 12.38 (s, 1 H).

15 Example 2

3- {4 ’- [(2-cyclopropyl-7 - {[(5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl} -1H-benzimidazole

1-yl) methyl] biphenyl-2-yl} -1,2,4-oxadiazol-5-ato potassium

image 1

The compound (1.00 g) obtained in Example 1 was dissolved in acetone (20 ml), and potassium 2-ethylhexanoate (0.323 g) was added and the mixture was stirred for 4 h and

30 min. Precipitated crystals were collected by filtration to give the compound. of the title (0.581 g, 54%). 1 H NMR (300 MHz, DMSO-d6) � 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),

5 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

Crystal of 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} 10 1H-benzimidazol-7 (5-methyl-2-oxo-1,3-dioxol-4-yl) methylcarboxylate

The compound obtained in Example 1 was recrystallized from acetonitrile to give the solvate crystal containing acetonitrile. This was dried overnight at 100 ° C under reduced pressure to give crystal form A, which is heat stable and practical. The crystal obtained presented a powder X-ray diffraction model

15 shown in Fig. 1, and approximately the following diffraction angles.

Table 1

Diffraction angle (2 �)

Relative intensity

5.08

3. 4

10.10

62

11.52

38

11.62

38

14.76

fifty

15.56

41

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

fifty

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-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} 5 1H-benzimidazol-7 (5-methyl-2-oxo-1,3-dioxol-4-yl) methylcarboxylate

2-Cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1 H -benzimidazole-7- acid was dissolved carboxylic (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 no

10 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 no more than 20 ° C for approximately 3 h. 0.5 N hydrochloric acid was added to adjust the pH to 4, 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

15 dimethylacetamide (2 L) and acetone containing 70% water (2 L). The isolated crystals were suspended in acetone containing 14% water (6 L) and the suspension was dissolved by heating at 50 ° C. Activated carbon (30 g) was added and the mixture was stirred for 10 min. Activated carbon was filtered off and washed with acetone containing 14% water (1 L). The filtrate was cooled to approximately 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 stirring for 1 h. The mixture was cooled to no more than 10 ° C and stirred further for 1 h. The precipitated crystals were isolated and washed with acetone containing 70% water (6 L) to give a solvate crystal containing acetone. The crystal was dried at 90 ° C under reduced pressure to give a

25 crystal in form A (903 g, yield: 80%).

Example 5

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

2-Cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1 H -benzimidazole-7- acid was dissolved carboxylic (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 approximately 3 h. 0.5 N hydrochloric acid was added to adjust the pH 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 acetone containing 70% water (30 L). The isolated crystals were suspended in acetone containing 40% water (225 L) and the suspension was dissolved by heating at 50 ° C. The solution was decontaminated by filtration and washed with acetone containing 50% water (30 L). The filtrate was cooled to approximately 25 ° C to allow precipitation of crystals, and the mixture was stirred at the same temperature for 1 h. Water (45 L) was added and the mixture was further stirred for 1 h. The mixture was cooled to no more than 10 ° C and stirred further for 1 h. The precipitated crystals were isolated and washed with acetone containing 50% water (30 L) to give a solvate crystal containing acetone. The crystal was dried at 95 ° C under reduced pressure to give a crystal in A form (15.73 kg, yield: 84%).

Formulation Examples

When the compound of the present invention should 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, as components (additives), apart from the active ingredient, those related to the Japanese Pharmacopoeia, the Parapharmaceutical products of the Japanese Pharmacopoeia or the conventional pharmaceutical product additive 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

(1), (2), (3), 2/3 of (4) and 1/2 of (5) are mixed and granulated. The rest (4) and (5) are added thereto and the mixture is compressed to give tablets.

2. Capsule 5 1) Compound obtained in Example 2 10 mg

(2)

Lactose 69.5 mg

(3)

0.2 mg light silicic anhydride

(4)

Magnesium Stearate 0.3 mg

10 1 capsule 80 mg (1), (2), (3) and (4) were dry mixed and filled in HPMC capsule (# 1)

3. Compressed

The compound (I) (17.24 g), mannitol (3342 g) and microcrystalline cellulose (663 g) were mixed evenly in a fluidized bed granulation dryer, and the mixture was granulated in the dryer by spraying an aqueous solution of hydroxypropyl cellulose (132.6 g) and dried therein. The granules obtained were sprayed with a 1.5 mm perforated sieve using an electric mill to

20 give a powder classified by size. To the powder classified by size (3788 g), closcarmellose sodium (Ac-Di-Sol) (201.5 g) and magnesium stearate (40.3 g) were added and mixed to give granules for tabletting. The granules were compressed with a tablet making machine with a 7.0 mm perforation � to give flat tablets weighing 130 mg per

25 tablet A solution of hydroxypropyl methylcellulose 2910 obtained by dispersing titanium oxide and yellow ferric oxide and dissolving polyethylene glycol 8000 was atomized onto the flat tablets obtained in a film coating machine to give approximately 25,000 film-coated tablets having the theoretical formulation shown in Table 2 , containing 0.5 mg of compound (I)

30 per tablet

35

Table 2

Composition Amount added (mg)

Compound (I) 0.5 Mannitol 98.3 Microcrystalline cellulose 19.5 Hydroxypropylcellulose 3.9 Croscarmellose sodium 6.5 Magnesium stearate 1.3

Flat tablet 130

Hydroxypropyl methylcellulose 2910 3.735 Polyethylene glycol 8000 0.75 Titanium oxide 0.5 Yellow ferric oxide 0.015

Total 135

4. Tablet Compound (I) (172.4 g), mannitol (3187 g) and

5 microcrystalline cellulose (663 g) in a fluidized bed granulation dryer, and the mixture was granulated in the dryer by spraying an aqueous solution of hydroxypropyl cellulose (132.6 g) and dried therein. The granules obtained were sprayed with a 1.5 mm perforated sieve using an electric mill to give a powder classified by size. The powder classified by size (3788 g) is

10 added closcarmellose sodium (Ac-Di-Sol) (201.5 g) and magnesium stearate (40.3 g) and mixed to give granules for tabletting. The granules were compressed with a tablet making machine with a 7.0 mm perforation � to give flat tablets weighing 130 mg per tablet. A solution of hydroxypropyl methylcellulose 2910 obtained by dispersing

15 titanium oxide and yellow ferric oxide and dissolving polyethylene glycol 8000 was sprayed onto the flat tablets obtained in a film coating machine to give approximately 25,000 film-coated tablets having the theoretical formulation shown in Table 3, containing 5 mg of the compound (I) per tablet.

twenty

Table 3

Composition Amount added (mg)

Compound (I) 5 Mannitol 93.8 Microcrystalline cellulose 19.5 Hydroxypropylcellulose 3.9 Croscarmellose sodium 6.5 Magnesium stearate 1.3

Flat tablet 130

Hydroxypropyl methylcellulose 2910 3.735 Polyethylene glycol 8000 0.75 Titanium oxide 0.5 Yellow ferric oxide 0.015

Total 135

5. Tablet Compound (I) (689.7 g), mannitol (2670 g) and

5 microcrystalline cellulose (663 g) in a fluidized bed granulation dryer, and the mixture was granulated in the dryer by spraying an aqueous solution of hydroxypropyl cellulose (132.6 g) and dried therein. The granules obtained were sprayed with a 1.5 mm perforated sieve using an electric mill to give a powder classified by size. The powder classified by size (3788 g) is

10 added closcarmellose sodium (Ac-Di-Sol) (201.5 g) and magnesium stearate (40.3 g) and mixed to give granules for tabletting. The granules were compressed with a tablet making machine with a 7.0 mm perforation � to give flat tablets weighing 130 mg per tablet. A solution of hydroxypropyl methylcellulose 2910 obtained by dispersing

15 titanium oxide and yellow ferric oxide and dissolving polyethylene glycol 8000 was atomized onto the flat tablets obtained in a film coating machine to give approximately 25,000 film-coated tablets having the theoretical formulation shown in Table 4, containing 20 mg of the compound (I) per tablet.

twenty

Table 4

Composition Amount added (mg)

Compound (I) 20 Mannitol 78.8 Microcrystalline cellulose 19.5 Hydroxypropylcellulose 3.9 Croscarmellose sodium 6.5 Magnesium stearate 1.3

Flat tablet 130

Hydroxypropyl methylcellulose 2910 3.735 Polyethylene glycol 8000 0.75 Titanium oxide 0.5 Yellow ferric oxide 0.015

Total 135

6. Tablet Compound (I) (3.4 g), lactose (311.4 g) and

5 cornstarch (88.4 g) in a fluidized bed granulation dryer, and the mixture was granulated in the dryer by spraying an aqueous solution of hydroxypropyl cellulose (13.26 g) and dried therein. The granules obtained were sprayed with a 1.5 mm perforated sieve using an electric mill to give a powder classified by size. To the powder classified by size (306.3 g) closcarmellose sodium was added

10 (Ac-Di-Sol) (16.25 g) and magnesium stearate (2.5 g) and mixed to give granules for tabletting. The granules were compressed with a tablet making machine with a 7.0 mm perforation � to give flat tablets weighing 130 mg per tablet. A solution of hydroxypropyl methylcellulose 2910 obtained by dispersing titanium oxide and ferric oxide

Yellowing and dissolving polyethylene glycol 8000 was sprayed onto flat tablets obtained in a film coating machine to give approximately 900 film-coated tablets having the theoretical formulation shown in Table 5, containing 1 mg of compound (I) per tablet. .

twenty

Table 5

Composition Amount added (mg)

Compound (I) 1 Lactose 91.6 Corn starch 26 Hydroxypropylcellulose 3.9 Croscarmellose sodium 6.5 Magnesium stearate 1

Flat tablet 130

Hydroxypropyl methylcellulose 2910 3.735 Polyethylene glycol 8000 0.75 Titanium oxide 0.5 Yellow ferric oxide 0.015

Total 135

Experimental Example 1

Inhibitory effect of the compound of the present invention on vasopressor 5 caused by angiotensin II (AII) in rat

11 week old male SD rats (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 was placed in it filled with physiological saline

10 containing heparin (200 U / ml). The catheter was fixed subcutaneously at the back of the neck. After the recovery period, the rats were tested.

The arterial catheter was connected to a pressure transducer (2238, Nec San-ei Instruments) and the signals were recorded in a pen register (RECTI-HORIZ 8K, 15 Nec San-ei Instruments) by means of a blood pressure amplifier. Once the vasopressor action of AII (100 ng / kg, iv) was stabilized, a test compound was administered in an equimolar dose to that of compound A. After 24 h, AII was administered, an increase in blood pressure was measured , and an inhibition rate was calculated with respect to the value before drug administration. All the

20 components were suspended in 0.5% methylcellulose and administered orally at a volume of 2 ml / kg.

The results are presented on average ± SEM (Table 6). The significance between the

administration group of compound (I) and another administration group of

Compound was determined by the Student's t test (**: p <0.01, *: p <0.025).

Table 6

Suppression rate at 24 h after administration

Compound (I) [0.12 mg / kg, p.o. (n = 5)]

20.2 ± 3.2%

Compound (A) [0.10 mg / kg, p.o. (n = 5)]

-6.0 ± 3.5% **

Compound (B) [0.10 mg / kg, p.o. (n = 5)]

2.6 ± 4.8% *

As is evident from the results, the compound of the present invention has a sustained and strong pharmacological action by oral administration.

Experimental Example 2

Enhancer effect of the compound of the present invention on insulin sensitivity in rats

15 Spontaneously hypertensive male rats of 24 weeks of age were used (SLC: SHR / Izm, Japon SLC, Inc.). Body weight, systolic blood pressure, fasting blood glucose concentration, plasma insulin concentration and plasma triglyceride concentration in rats were measured, and the rats were divided into an administration group. of vehicle (0.5% solution of

20 methylcellulose) and administration groups of compound (I) (0.12, 0.37 and 1.23 mg / kg) using them as indices. Compound (I) was suspended in 0.5% methylcellulose and administered orally at a volume of 2 ml / kg for 2 weeks. Insulin sensitivity was assessed by the glucose stocks technique. To be specific, rats after fasting all night were anesthetized with

25 sodium pentobarbital (Nembutal injection, Dainippon Pharmaceutical Co., Ltd., 50 mg / kg ip), and catheters (SP45, Natume Seisakusho Co., Ltd.) for blood sampling, insulin infusion (novolin R- 100, Novo Nordisk Pharma Co., Ltd.) and glucose infusion (Otsuka Glucose Injection 50%, Otsuka Pharmaceutical Co., Ltd.) were each placed in the right common carotid artery, the femoral vein

left and right femoral vein. After a single intravenous injection of 25 mU / kg of insulin, the high insulin status was maintained by infusion using an infusion pump (KDS100, KDS) at an injection rate of 4 mU / kg / min. In addition, glucose was infused intravenously in an amount necessary to maintain the normal blood glucose concentration using a different infusion pump (KDS100, KDS). Intravenous glucose injection was started from 10 min after the start of insulin injection, and the glucose injection rate was changed after blood glucose measurement was performed every 5 min. Blood glucose concentration was measured rapidly using a simple device.

10 blood glucose measurement (ACCU-CHEK Comfort, Roche diagnostics). Glucose was infused for 90 min., The mean value of the amount of glucose injection was calculated for 40 min (50 min to 90 min after the start of the injection) and was used as an index (M value) of insulin sensitivity . The results are presented as mean ± SEM (Table 7). For comparison

15 of the vehicle administration group and the compound administration group

(I) the Williams test was used (*: p <0.025).

Table 7

M value

Vehicle management group (n = 11)

6.7 ± 0.7

Compound (I) [0.12 mg / kg, p.o. (n = 12)]

8.2 ± 0.8

Compound (I) [0.37 mg / kg, p.o. (n = 12)]

9.0 ± 0.6 *

Compound (I) [1.23 mg / kg, p.o. (n = 11)]

9.8 ± 0.8 *

twenty

As is evident from the results, the compound of the present invention has a strong potentiating action on insulin sensitivity by oral administration.

25 Experimental Example 3 Evaluation of the solubility and permeability of the membrane by means of the artificial membrane penetration test (Parallel Artificial Membrane Permeability Assay; PAMPA).

(1) Solubility

30 Approximately 2 mg of samples were suspended in 2 ml of JP1, JP2 and 20 mmol / l of GCDC / JP2. The suspension was equilibrated at 37 ° C for 2 h and filtered. The concentration in the solutions was determined by HPLC under the following conditions. HPLC conditions

5 Detector: UV 254 nm Column: CAPCELLPAK C18 MG 75x4.6 mm Phase A mobile 0.05 mol / l ammonium formate buffer (pH3) / MeCN = 9: 1 Phase B mobile 0.05 mol / l buffer ammonium formate (pH3) / MeCN = 1: 9 Gradient program: 0�10min 0�100% B)

10 10�15 min 100% B)

15.1�20min 0% B) Temp. of the column: 40 ° C Flow rate: 1 ml / min Vol. Injection point: 10 µl

fifteen

(2) Permeability of the membrane Permeability with the artificial membrane was determined by PAMPA in the

twenty

following conditions. lipid membrane: measurement wavelength: incubation duration: GIT mode (pION) 250-400 nm 3 h

25

incubation temperature: Donor: pH: compound concentration: 25 ° C buffer containing 10% DMSO 3 points of 7.4, 6.0, 5.5 50 µmol / l

The results of the solubility and permeability of compound X (crystalline form A of compound (Y)), compound A and compound B are shown in Table 8.

30 Table 8

T-No

Solubility (µg / ml) PAMPA (nm / s)

JP1

JP2 GCDC / JP2 pH 7.4 pH 6.2 pH 5.5

Compound X

27 8.3 52 95 190 210

Compound A

130 470 680 0 6.3 130

Compound B

160 2.8 27 89 200 460

Compared to 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 little oral absorption due to low

5 permeability. Compound B is also considered to produce little oral absorption due to the amount that limits low solubility. Therefore, it is expected that compound X will achieve greater oral absorption compared to compound A and compound B.

10 Industrial Application The compound of the present invention is useful as a drug for the prophylaxis or treatment of circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and the like, and the like.

fifteen

Claims (19)

one.

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

2.

A 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazol-7- salt (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carboxylate.

3.

Potassium salt of 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3yl) biphenyl-4-yl] methyl} -1H-benzimidazol-7- (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carboxylate.

Four.

A 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazol-7- solvate (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carboxylate.

5. A crystal of the compound of any one of claims 1 to 4.

6.

A method for producing 2-cyclopropyl-1 - {[2 '- (5-oxo-4,5-dihydro-1,2,4oxadiazol-3-yl) biphenyl-4-yl] methyl} -1H-benzimidazol-7 (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl carboxylate or a salt thereof, which comprises reacting a reactive derivative of 2-cyclopropyl-1 - {[2 '- (5-oxo -4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} 1H-benzimidazol-7-carboxylate (5-methyl-2-oxo-1,3-dioxol-) 4-yl) methyl, or a salt thereof, with 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one or one of its salts.

7.

A pharmaceutical agent comprising the compound of any one of claims 1 to 4.

8.

The pharmaceutical agent of claim 7, which is an angiotensin II antagonist.

9.

The pharmaceutical agent of claim 7, which is an agent for the prophylaxis or treatment of circulatory diseases.

10.

An insulin sensitiser comprising the compound of any one of claims 1 to 4.

eleven.

A hypoglycemic activity enhancer of an insulin sensitizer, comprising the compound of any one of claims 1 to 4.

12.

A compound according to any one of claims 1 to 4 for use to antagonize angiotensin II in a mammal.

13.

Use of the compound of any one of claims 1 to 4 for the production of an angiotensin II antagonist.

14.

A compound according to any one of claims 1 to 4 for use to prevent or treat circulatory diseases in a mammal.

fifteen.

Use of the compound of any one of claims 1 to 4 for the production of an agent for the prophylaxis or treatment of circulatory diseases.

16.

A compound of any one of claims 1 to 4 for use to produce an insulin sensitizer.

17.

Use of the compound of any of claims 1 to 4 for the production of an insulin sensitizer.

18.

A compound of any one of claims 1 to 4 for use to produce a hypoglycemic activity enhancer of an insulin sensitizer.

19.

Use of the compound of any of claims 1 to 4 for the production of a hypoglycemic activity enhancer of an insulin sensitizer.