TW201000097A - Medicament for the prophylaxis or treament of hypertension - Google Patents

Abstract

The invention relates to a medicament for the prophylaxis or treatment of hypertension or a disease caused by hypertension comprising (A) an angiotensin II receptor blocker, (B) at least one calcium channel blocker and (C) at least one diuretic.

Description

201000097 Λ VI. Description of the Invention: [Technical Field] The present invention relates to a medicament for preventing or treating hypertension, heart disease (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart Hypertrophy), kidney disease (eg diabetic nephropathy, glomerulonephritis and nephrosclerosis), cerebrovascular disease (eg cerebral infarction and cerebral hemorrhage), and/or vascular disease (eg atherosclerosis, PTC posterior stenosis, And terminal vascular circulation disease). 〇 [Prior Art] Nowadays, angiotensin II receptor blockers and calcium channel blockers are widely used as drugs for treating or preventing hypertension, heart disease and the like. The angiotensin II receptor blocker is a renin-angiotensin system inhibitor, is particularly effective for renin-dependent hypertension, and exhibits a protective effect on cardiovascular and renal damage. In addition, since the calcium channel blocker has a sodium diuretic action in addition to the vasodilating action, it is also effective for liquid retention (renin-independent) hypertension. Therefore, if angiotensin II receptor blockers and calcium-incorporated scorpion channel blockers are used together, stable and good treatment and prevention of hypertension can be expected regardless of the disease, because in addition to angiotensin receptors In addition to the inhibitory effect of the renin-angiotensin system of the blocker, the calcium channel blocking effect on the vascular smooth muscle and the secondary sodium excretion effect of the calcium channel blocker make it possible to suppress multiple factors causing hypertension. In addition, diuretics are also widely used as drugs for treating or preventing hypertension, heart disease and the like. Diuretics are effective for the treatment of hypertension because of their diuretic effect. Because lit, if angiotensin-receptor blocker and diuretic combination 201000097 are used, stable and good treatment and prevention of hypertension can be expected regardless of the disease, because in addition to angiotensin II receptor blocker In addition to the inhibitory effect of the renin-angiotensin system, the diuretic effect of the diuretic inhibits multiple factors that cause hypertension. (5-Methyl-2-keto-1,3-dioxol-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1 -[2··(1Η-tetrazol-5-yl)bisphenyl-4-ylmethyl]imidazole-5-carboxylate (hereinafter referred to as "olmesartan medoxomil) is An excellent angiotensin II receptor blocker for use in the treatment or prevention of hypertension, heart disease, etc. (Japanese Patent No. 20825 19 and U.S. Patent No. 5,61,5,99).

0 Olmesartan sulphate is marketed under the trade name Olmetec® or Benicar® and contains 5 mg, 10 mg, 20 mg or 40 mg of olmesartan medoxomil as the active ingredient with low-substituted hydroxypropylcellulose and hydroxyl groups. Propyl cellulose, microcrystalline cellulose, lactose and magnesium stearate are used as additives. 3-ethyl-5-methyl-(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl Azetidin-3,5-dicaprate (hereinafter referred to as "amlo dipine) is an excellent calcium channel blocker and is used to treat or prevent hypertension, heart disease Etc. (Japanese Patent No. 1 40 1 088 and US Special 201000097 Lei No. 4,572,909)

Amlodipine amlodipine is marketed under the trade name Norvasc®, which contains 3.47 mg or 6.93 mg of amlodipine besylate (2.5 mg or 5 mg of amlodipine) as the active ingredient, with microcrystalline cellulose, anhydrous phosphoric acid. Hydrogen calcium, sodium starch glycolate, magnesium stearate, hydroxypropyl cellulose, titanium dioxide, talc and palm wax are used as additives. Further, 6-chloro-3,4-dihydro-2H-1,2,4-benzothiazepine-7-sulfonamide 1,1-dioxide (hereinafter referred to as "hydrochlorothiazide"; (hydrochlorothiazide)) is

An excellent thief diuretic, and is disclosed, for example, in U.S. Patent No. 3,025,292.

CI

• NH 〇2 h2no2s Hydrochlorothiazide is known as a drug containing olmesartan medoxomil and a calcium channel blocker (International Publication No. 2004/067003) and a drug containing olmesartan medoxomil and a diuretic ( International Gazette No. 2002/041 890 Official Gazette). Also known as 201000097 is a solid dosage form containing olmesartan medoxomil, amlodipine and hydrochlorothiazide (Official Gazette of International Publication No. 2003/097045 and International Publication No. 2008/032107). However, the remarkable effects of the drug of the present invention containing a specific angiotensin receptor blocker (e.g., olmesartan medoxomil), a calcium channel blocker, and a diuretic in hypertension and the like are unknown. Disclosure of the Invention Objects of the Invention An object of the present invention is to provide a medicament for preventing and/or treating hypertension or a disease caused by hypertension. More specifically, the object of the present invention is to provide a medicament for preventing or treating hypertension, heart disease (for example, angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart hypertrophy), kidney disease (for example) Diabetic nephropathy, glomerulonephritis and nephrosclerosis, cerebrovascular disease (eg cerebral infarction and cerebral hemorrhage), and/or vascular disease (eg atherosclerosis, restenosis after PTC A, and vascular circulatory disease) Especially for drugs that prevent or treat high blood pressure. The present inventors have now found that there is an excellent blood pressure lowering effect via a combined specific angiotensin II receptor, a blocker, a specific calcium channel blocker, and a specific diuretic. Furthermore, the inventors have found that this drug is useful for preventing and/or treating blood pressure, heart disease (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart hypertrophy), kidney disease (such as diabetic nephropathy, kidney). Small glomerulonephritis and nephrosclerosis, cerebrovascular diseases (such as cerebral infarction and cerebral hemorrhage), and/or vascular diseases (such as atherosclerosis, restenosis after PTCA, and peripheral vascular circulatory disease) are particularly effective. The present invention has been completed based on the above findings. Specifically, the present invention provides: 201000097 (1) A medicament for preventing or treating hypertension or a disease caused by hypertension, comprising: (A) an angiotensin II receptor blocker, Selected from a compound of the formula (I),

(I) a group consisting of a pharmacologically acceptable salt, a pharmacologically acceptable ester thereof, and a pharmacologically acceptable salt of the ester; and q (B) at least one calcium An ion channel blocker selected from the group consisting of a 1,4-dihydropyridine derivative and a pharmacologically acceptable salt thereof; and (C) at least one diuretic. (2) The drug according to (1), wherein the disease is selected from the group consisting of hypertension, heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerulonephritis, kidney a group consisting of sclerosis, cerebrovascular disease, cerebral infarction, cerebral hemorrhage, vascular disease, arteriosclerosis, restenosis after PTCA, and peripheral vascular circulatory disease; (3) Drugs such as (1) or (2) Wherein the drug is a pharmaceutical composition comprising the compound (A), the compound 201000097 (B) and the compound (C) as an active ingredient; (4) the drug according to (1) or (2) wherein the compound (A), The compound (B) and the compound (C) are administered separately or simultaneously at a time interval; (5) The medicament according to any one of (1) to (4), wherein the angiotensin Π receptor blocker Is (5-methyl-2-keto-1,3-dioxol-4-yl)methyl 4-(1.hydroxy-1-methylethyl)-2-propyl-1 -[2·-(1Η-tetrazol-5-yl) bisphenyl-4-ylmethyl]imidazol-5-carboxylate; (6) The drug according to any one of (1) to (5) Calcium channel blocker 〇Free azelnidipine, amlodipine, benidipine, nitrendipine, manidipine, nicardipine, nifedipine nisol Lidoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efenidipine, barnidipine (barnidipine), felodipine, and nilvadipine (nilvadipine); (7) The drug according to any one of (1) to (5), wherein the calcium channel is blocked The drug of any one of (1) to (7), wherein the diuretic is selected from the group consisting of hydrochlorothiazide, methyclothiazide, benzylhydrochlorothiazide (benzylhydro chlorothiazide), trichlormethiazide, cyclopenthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide And hydrogen fluoride (10) The drug of any one of (1) to (7), wherein the diuretic is hydrochlorothiazide; (10) as (1) to (9) The medicament according to any one of the invention, wherein the angiotensin π receptor blocker is (5-methyl-2-keto-1,3-dioxol-4-yl)methyl 4-( 1-hydroxy-1-methylethyl)-2-propyl-1·[2·-(1Η-tetrazol-5-yl)bisphenyl-4-ylmethyl]imidazole-5-carboxylate The calcium ion channel blocker is amlodipine, and the diuretic is hydrochlorothiazide; (d) The drug according to any one of (1) to (10), wherein the drug is a single agent ❹ type. Further, the present invention provides the use of the compounds (A), (Β) and (C) for the preparation of the above-mentioned medicaments; a method for preventing or treating (in particular for treating) diseases, comprising a warm-blooded animal having a need thereof (special It is human) to administer a therapeutically effective amount of each of the I complexes (A), (Β) and (C). According to a preferred embodiment of the present invention, the above medicament is provided as a pharmaceutical composition comprising a compound (Α), a compound (Β) and a compound (C) as an active ingredient. The pharmaceutical composition may contain one or more pharmaceutically acceptable substances. Sex additives. © The drug of the present invention, that is, a drug containing a specific angiotensin II receptor blocker such as olmesartan medoxomil, a calcium channel blocker and a diuretic as an active ingredient, has an excellent blood pressure lowering effect and Low toxicity, the drug is used as a therapeutic [preferably as a prophylactic or therapeutic drug (especially a therapeutic drug) for blood pressure, heart disease (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart Hypertrophy), kidney disease (eg diabetic nephropathy, glomerulonephritis and nephrosclerosis), cerebrovascular disease (eg cerebral infarction and cerebral hemorrhage), and/or vascular disease (eg atherosclerosis, restenosis after PTC A, Or terminal vascular circulatory disease; more preferably, as a prophylactic or therapeutic drug for 201000097 hypertension or heart disease (especially a therapeutic drug); and more preferably, as a prophylactic or therapeutic drug for hypertension (especially therapeutic drugs). Furthermore, the above therapeutics are preferably used in warm-blooded animals, and more preferably in humans. [Embodiment] The medicament of the present invention is characterized by containing (A) an angiotensin II receptor blocker as an active ingredient, which is selected from the group consisting of a compound of the formula (I), a pharmacologically acceptable salt thereof, a group consisting of a pharmacologically acceptable ester and a pharmaceutically acceptable salt thereof; (B) at least one calcium channel blocker selected from the group consisting of 1,4-two a group consisting of a hydropyridine derivative and a pharmacologically acceptable salt thereof; and (C) at least one diuretic" a compound of the above formula (I) [4-(1-hydroxy-1-methylethyl) -2-propyl•1-[2·-(1Η-tetrazol-5-yl)bisphenyl-4-ylmethyl]imidazol-5-carboxylate], which is an active ingredient of the medicament of the present invention, It is conventional and can be easily prepared, for example, according to the method described in Japanese Patent Laid-Open Publication No. 5-783-28. The compound of the above formula (I) can be converted into a desired pharmaceutically acceptable salt by treatment with a base according to a conventional method. For example, the salt can be treated in a solvent (for example, an ether, an ester or an alcohol, and preferably an alcohol), with a suitable base at room temperature for 5 to 30 minutes, and then the precipitated crystals are filtered off or the solvent is distilled off under reduced pressure. The salt may be, for example, an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; a metal salt such as an aluminum salt, an iron salt, a zinc salt, a copper salt or a nickel salt. Salt or cobalt salt; inorganic salt, such as ammonium salt; organic salt, such as t-octylamine salt, benzhydrylamine salt, morpholine salt, glucosamine salt, phenylglycinate alkyl ester salt, ethylene Amine salt, N-methyl reduced glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, hydrazine, hydrazine-diphenylmethylethylenediamine salt, -10 - 201000097 chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, or ginseng (hydroxymethyl) Aminomethane salts, but are not limited to these salts. Preferably, the alkali metal salt 'I Μ sodium salt is particularly preferred. The pharmacologically acceptable ester of the above compound of the formula (I) is one in which the carboxyl moiety of the compound of the formula (1) is esterified. The pharmacologically acceptable esters are not particularly limited and can be selected by those skilled in the art. Preferred are esters which are cleaved by biological methods, for example, hydrolysis in living organisms. The group constituting the ester group (the group represented by R, wherein 0 the ester is represented by -COOR) may be, for example, an alkoxy-CrC alkyl group such as a methoxymethyl group or a 1-ethoxy group. Ethyl, 1-methyl·i-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1·dimethyl 1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; C^-CU alkoxylation alkoxy-Ci-C^alkyl, such as 2-methoxyethoxymethyl; C6-C1Q aryloxy-Ci-CU alkyl, such as phenoxymethyl; halogenated (^- Oxy-CrC4 alkyl, such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxyanthryl)methyl; CrC4 alkoxycarbonylalkyl, such as methoxycarbonylmethyl Cyano G-C4 alkyl, such as cyanomethyl or 2-cyanoethyl; Cl-C4 alkylthiomethyl, such as methylthiomethyl and ethylthiomethyl; C6-C1() a thiomethyl group, such as phenylthiomethyl or naphthylthiomethyl; alkylsulfonyl-Ci-C4 lower alkyl, which may be optionally substituted with a halogen atom, such as 2-methanesulfonylethyl or 2 -Trifluoro Alkylsulfonylethyl; c6-C1()arylsulfonyl_Cl_C4 ortho', such as 2-phenylsulfonylethyl or 2-toluene, ethyl; aliphatic d-Cv C1-C4 hospital base 'e.g., methoxymethyl, ethoxymethyl, propenoxymethyl, butyloxymethyl, trimethylacetoxymethyl, pentaneoxy-11 - 201000097 着 methyl, isoamyloxymethyl, hexamethyleneoxymethyl, 1-methylmethoxyethyl, 1-ethyloxyethyl, 1-propoxyethyl, 1 - butyloxyethyl, 1-trimethylethoxymethoxyethyl, 1-pentyloxyethyl, 1-isopentyloxyethyl, 1-hexyloxyethyl '2- Methoxyethyl, 2-ethoxymethoxyethyl, 2-propoxycarbonylethyl, 2-butoxycarbonylethyl, 2-trimethylethenyloxyethyl, 2-pentanyl Oxyethyl, 2-isopentyloxyethyl, 2-hexyloxyethyl, 1-methoxypropylpropyl 1-ethyloxypropyl, 1-propoxypropyl , 1-butoxypropyl, 1-trimethylethoxypropyl, 1-pentyloxypropyl, 1-isopentyloxypropyl, 1-hexyloxypropyl 1-Ethyloxybutyl, 1-propoxylated butyl , 1-Butyloxybutyl, 1-trimethylacetoxybutyl, 1-ethenyloxypentyl, 1-propenyloxypentyl, 1-butenoxypentyl, 1 · Trimethylacetoxypentyl or 1-trimethylethoxydecyl; c5-c6 cycloalkylcarbonyloxy-Ci-C^alkyl, such as cyclopentylcarbonyloxymethyl, ring Hexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1 - cyclopentylcarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl; c6-c1()arylcarbonyloxyindenyl-CPC4 alkyl, such as benzamidineoxymethyl; C^-Ce alkane Oxycarbonylcarbonyloxyalkyl, such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(methoxy Carbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy) Ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)pentyl 1-(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)propyl, 1-( Propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, 1-isopropyl-12-.201000097 oxycarbonyloxy)ethyl, i-(isopropoxycarbonyloxy)butyl , butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)butyl, Isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)butyl , t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl, pentoxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1 -(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1-(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyloxy)propyl; Q C5- C6 cycloalkoxycarbonyloxy-Ci-CU alkyl, such as cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)B , 1-(cyclohexyloxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)butyl;alkyl)-2-keto-1,3-dioxolane- 4-yl]methyl, for example (5-methyl-2-keto-1,3-dioxol-4-yl)methyl, (5-ethyl-2-keto-1, 3-dioxol-4-yl)methyl, (5-propyl-2-keto-1,3-dioxol-4-yl)methyl, (5-isoindole) Propyl-2-keto-1,3-dioxol-4-yl)methyl or (5-butyl-2-keto-1,3-dioxol-4- Methyl); [5-(phenyl (which may be optionally substituted by CrCU alkyl, CrG alkoxy, or halogen atom)-2-keto-1,3-dioxol-4-yl a methyl group such as (5-phenyl-2-keto-1,3-dioxol-4-yl)methyl, [5-(4-methylphenyl)-2-keto -1,3-dioxol-4yl]methyl, [5-(4-methoxyphenyl)-2-keto-1,3-dioxol-4- Methyl, [5-(4-fluorophenyl)-2-enyl-1,3-di Heterocyclopenten-4-yl]methyl or [5-(4-chlorophenyl)-2-keto-1,3-dioxol-4-yl]methyl; or fluorenyl, It may be optionally substituted by a Cl-C4 alkyl group or a Ci-C* alkoxy group, for example, a fluorenyl group, a -13-201000097 dimethyl fluorenyl group or a dimethoxy fluorenyl group. A preferred ester group is trimethylacetoxymethyl, decyl or (5-methyl-2-keto-1,3-dioxol-4-yl)methyl, more preferably (5-Methyl-2-keto-1,3-1,3-dioxol-4-yl)methyl. The ester of the compound of the above formula (I) can be treated with a base according to a conventional method and can be converted into a desired pharmaceutically acceptable salt (i.e., a pharmacologically acceptable salt of the ester). For example, the salt of the ester can be treated in a solvent (for example, an ether, an ester or an alcohol, and preferably an ether), with a suitable base at room temperature for 5 to 30 minutes, and then the precipitated crystals are filtered off or It was obtained by distilling off a solvent under reduced pressure. The salt class 0 can be, for example, a mineral acid salt such as a hydrofluoric acid salt, a hydrochloric acid salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a perchlorate salt, a sulfate salt or a phosphate salt; For example, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, besylate or P-tosylate; carboxylates such as fumarate, succinate, citrate , tartrate, oxalate or maleate; or an amine salt such as glutamate or aspartate. Preferred salts are hydrochlorides, nitrates, sulfates or phosphates, and are particularly preferred as the hydrochloride. As the angiotensin II receptor blocker, which is used as the compound Ο (A), a compound of the above formula (I) or a pharmaceutically acceptable ester thereof can be preferably used. More preferably, a pharmaceutically acceptable ester of the compound of the above formula (I) can be used, and it is preferably a trimethyl ethoxymethyl ester, a decyl ester or a (5-methyl-2) compound of the above formula (I). - Keto-1,3-dioxol-4-yl)methyl ester. Most preferably (5-methyl-2-keto-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propene 1-[2'-(1H-tetrazol-5-yl)bisphenyl-4-ylmethyl]imidazole-5-carboxylate (olmesartan), and it can be used according to Japanese Patent No. 2082519 It is easily prepared by the method described in the above (U.S. Patent No. 5,6,5,599). And the pharmacologically acceptable salt selected from the group consisting of the compound of the above formula (I), the pharmacologically acceptable salt thereof-14-201000097, the pharmacologically acceptable ester thereof, and the ester thereof The compounds of the group may also be used as hydrates or solvates thereof. If a pharmacologically acceptable ester of a compound of the above formula (I) is used, some of the esterified compounds may have one or more pairs of palmitic carbon. As the compound (A), an optical isomer according to the purification of the palmitic carbon, or a stereoisomer such as a non-image isomer, or a mixture of any stereoisomer or racemate can also be used. a calcium ion channel blocker comprising a 1,4-dihydropyridine derivative, which is used as a compound (B) as a compound having a 1,4-dihydropyridine moiety or a chemically equivalent moiety thereof in a molecule A calcium ion channel blocker characterized. Since various drugs are suggested as calcium ion channel blockers, including 1,4-dihydropyridine derivatives, and are actually used in the clinic, one of ordinary skill in the art can select any suitable compound to exert the present invention. The effect. As the 1,4-dihydropyridine calcium ion channel blocker, for example, adipine, amlodipine, benidipine, nitrendipine, manidipine, nicardipine, nifedipine, nisoldipine can be used. , cilnidipine, lercanidipine, nicotipine, nimodipine, azuridine, effluentine, bainidipine, felodipine or nilvadipine, but the invention is not limited to these compounds. The pharmacologically acceptable salt of the 1,4-dihydropyridine derivative is not particularly limited and can be selected by those having ordinary knowledge in the art. The pharmacologically acceptable salt may be an acid addition salt or a hydrazine addition salt. Such salts may, for example, be base addition salts, including alkali metal salts such as sodium, potassium or lithium salts; alkaline earth metal salts such as calcium or magnesium salts; metal salts such as aluminum, iron, barium salts, a copper salt, a nickel salt or a cobalt salt; an inorganic salt such as an ammonium salt; an organic salt such as t-octylamine salt, benzhydrylamine salt, morpholine salt, glucosamine salt, phenylglycinate alkyl ester -15- 201000097 Salt, ethylenediamine salt, N-methyl reduced glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N, - diphenyl Ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, or hydroxymethyl group An aminomethane salt; or an acid addition salt, including a mineral acid salt such as a hydrofluoric acid salt, a hydrochloric acid salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a perchlorate salt, a sulfate salt or a phosphoric acid salt a salt; a sulfonate such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, besylate or P-toluenesulfonate; a carboxylate such as fumarate, amber Tannic acid A salt, a citrate, a tartrate, an oxalate or a maleate; or an amine salt such as a glutamate or an aspartate, but the invention is not limited to these salts. As the calcium ion channel blocker including the 1,4-dihydropyridine derivative, a hydrate or a solvate of the above compound and a pharmacologically acceptable salt thereof can also be used. Further, the calcium ion channel blocker comprising a 1,4-dihydropyridine derivative may have one or more pairs of palmitic carbon. As the compound (B), an optical isomer according to the purification of the palmitic carbon, or a stereoisomer such as a non-image isomer, or a mixture of any stereoisomer or racemate may also be used. As the compound (B), (±)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridin dicarbonate 3 is preferably used. -(1-Diphenylmethyl azathiazide (azethizine-3-yl) ester 5-isopropyl vinegar. As the calcium ion channel blocker including the 1,4-dihydropyridine derivative, amlodipine is more preferably used. It can be easily prepared according to the method described in Japanese Patent No. 1401088 (U.S. Patent No. 4,5,72,909). Amlodipine may be a pharmacologically acceptable salt thereof, and these salts are included in the present invention. The pharmaceutically acceptable salt may be an acid addition salt or a base addition salt. This salt may, for example, be -16- 201000097 is a besylate, a hydrochloride, a hydrobromide, a fumarate, a citrate, a succinate, a maleate, a dextran A sulfonate, a lactate, a methanesulfonate, a nicotinate, a gluconate or the like, but the present invention is not limited to these salts, and benzenesulfonic acid is preferably used. The use of the diuretic as the compound (C) is a conventional compound, and is disclosed in, for example, U.S. Patent No. 2,554,816, U.S. Patent No. 2,980,679, U.S. Patent No. 2,783,241, British Patent No. 795,174, J. Chem. Soc. 1 25 (1 928), U.S. Patent No. 2,835,702, British Patent No. 851,287, U.S. Patent No. 3,356,692, U.S. Patent No. 3,055,904, U.S. Patent No. 2,976,289, U.S. Patent No. 3,058,882, Helv. Chim. Acta, 45, 23 1 6 (1 962) 'Applied Pharmacology, 21, 607 (1982), U.S. Patent No. 3,183,243, U.S. Patent No. 3,3,60,5,8, U.S. Patent No. 3,567,777, U.S. Patent No. 3,634,583 U.S. Patent No. 3,025,292, J. Am. Chem. Soc., 82, 1132 (1960), U.S. Patent No. 3,108,097, Experientia, 16, 1 1 3 (1 960), J. Org. Chem., 26,2814 (1961), U.S. Patent No. 3,009,9,1, U.S. Patent No. 3,265,573, U.S. Patent No. 3,254,076, U.S. Patent No. 3,255,241, U.S. Patent No. 3,75,506, and Belgian Patent No. 639,386 and the United States The first 3,1 No. 63,645. The diuretic can be a sulfonamide compound such as aceta ζ ο 1 amide, methaz 〇1 amide, ethoxzolamide 'clofenacamine (cl〇) Fenamide), dichlorphenamide, disulfamide 'mefruside', chlorthalidone, quinethazone, fur〇sernide ,lpiperamide-17- 201000097 (clopamide), tripamide, indapamide, cloxarone (c 1 ore χ ο 1 ο ne ), metopula knee (met ο 1 a ζ ο ne ), xipamide, bumetanide, H pitatanide or X-54; a tweezers compound such as hydrochlorothiazide, methyl chloride, benzene Methyl hydrochlorothiazide, triclosan, cyclopentanyl, polythiolin, ethidium, cyclosalt, benzyl fluorothiazide, and hydrofluorothiazepine; phenoxyacetic acid compounds, such as itani Ethacrynic acid, tienilic acid, indacrinone or quincarbate; Am (triamterene); amiloride; spironolactone; Potassium canrenoate; and torasemide; MK-447; or traxanox sodium ). It is preferably a sulfur trap compound, and more preferably hydrochlorothiazide. The chemical name of hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiazepine-7-sulfonamide 1,1-dioxide, and the present invention Hydrochlorothiazide includes its pharmacologically acceptable salts. The salt may, for example, be a hydrohalide salt such as a hydrofluoric acid salt, a hydrochloride, a hydrobromide salt, a hydroiodide salt; a nitrate; a perchlorate; a sulfate; a phosphate iCi-C4 alkane a sulfonate, which may be optionally substituted by a halogen atom, such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; C6-C10 allylsulfonate, which may be optionally subjected to C^-C4 alkane Substituted, for example, besylate or p-toluenesulfonate; Ci-C6 fatty acid salt such as acetate, malate, butyl succinate, citrate, citrate, tartrate, grass An acid salt or a maleate; or an amino acid salt such as a glycinate, a beet salt, a arginine, an alanate, a glutamate or an aspartate. It is preferably a hydrochloride, a nitrate, a sulfate or a phosphate, and particularly preferably a chlorate. Further, if the above compound has one or more pairs of palmitic carbons, the urinary -18-201000097 urine of the present invention also includes optical isomers and mixtures thereof. Further, hydrates of the above compounds are also included. In the present invention, 'simultaneous" administration means that the compound (A), the compound (B) and the compound (C) are substantially simultaneously administered. There is no restriction on the dosage form to be administered, but it is preferred to administer it in a single dosage form. In the present invention, "separate at a certain time interval" means that the compound (A), the compound (B) and the compound (C) are administered alone at different times. There is no limitation on the dosage form to be administered, for example, First administered with angiotensin 11 receptor blocker, 0 and then at a certain time interval, can simultaneously be administered with calcium channel blockers and diuretics (or they can be administered sequentially after a certain time interval) Alternatively, the calcium channel blocker or diuretic may be administered first, and after a certain time interval, the remaining two drugs may be administered in the same manner as described above. As clearly shown in the examples of the present specification, the drug of the present invention is The action of the combined compound (A), the compound (B) and the compound (C) can lower the blood pressure more effectively. According to the above effects, the medicament of the present invention is used as a prophylactic or therapeutic (especially treatment) hypertension, heart disease [such as angina pectoris) , myocardial infarction, heart rate irregularity (including sudden death), heart failure, heart hypertrophy], kidney disease (such as diabetic nephropathy, glomerulonephritis, nephrosclerosis), cerebrovascular disease (such as cerebral infarction, brain Blood), and/or vascular disease (eg, arteriosclerosis, restenosis after PTCA, vascular circulatory disease). Angiotensin II receptor blockers, calcium channel blockers, and diuretics The drug of the present invention can exhibit excellent effects as compared with the individual drug alone. The drug of the present invention comprising an angiotensin II receptor blocker, a calcium channel blocker and a diuretic can be separately formulated. Do not use drugs, make a few separate dosage forms, or make a single physical dosage form by mixing all the drugs. -19- 201000097 The body agent is in the form of a soluble agent. Urine makes the things and medicines of the spleen and the dysfunction of the dysentery and the dysfunction of the dysentery and the dysfunction of the disease. Equilibrium sugar injection or non-injection of eczema ' 接 齐 可 可 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上Fang Anzhi, a habit According to the chemical, the root emulsion IMI' powder agent, etc., the granules, the granules, and the granules Ba, are prepared by the additives. Because the compounds (A), (B) and (C) in the medicament of the invention are generally administered orally. The drug, therefore, the drug of the present invention is more profitable by oral administration. As "excipient", for example, organic excipients including sugar derivatives such as lactose, sucrose, glucose, and nectar can be listed. Sugar alcohol or sorbitol; starch derivatives such as corn starch, potato starch, alpha-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; or pullulan; And inorganic excipients, including phthalate derivatives such as light anhydrous citric acid, synthetic aluminum citrate, calcium citrate or magnesium aluminum silicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; Salt, such as calcium sulfate. 〇 as "lubricants" may, for example, be stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; cerium oxide; waxes such as beeswax and cetyl wax Oil; boric acid; adipic acid; sulfate, such as sodium sulfate; ethylene glycol; fumaric acid; sodium benzoate; DL-leucine; lauryl sulfate, such as sodium lauryl sulfate or magnesium lauryl sulfate; a citrate such as phthalic anhydride and citric acid hydrate; or the above starch derivative. As "bonding agent", for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol or the like can be listed. -20- 201000097 As "disintegrating agent", for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internal cross-linking carboxy can be listed. Sodium methylcellulose; and chemically modified starch/cellulose derivatives such as carboxymethyl starch or sodium carboxymethyl starch. Examples of "emulsifiers" can be listed, such as clay gums, such as bentonite or gelatinous veegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants, for example Sodium lauryl sulfate or calcium stearate; cationic surfactants such as ammonium benzyl chloride; or nonionic cerium surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters Or sucrose esters of fatty acids. As "stabilizer", for example, P-hydroxybenzoic acid esters such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; alcohols, for example, Chlorobutanol, benzyl alcohol or phenylethyl alcohol; ammonium benzyl chloride; phenols such as phenol or cresol; thimerosal; dehydrated acetic acid; or sorbic acid. For example, a sweetener such as sodium saccharin or aspartame; an acidulant such as citric acid, malic acid or tartaric acid; or a perfume, such as menthol, lemon or orange. As "diluent", for example, diluents conventionally used, such as lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, may be listed. Water, ethanol 'polyethylene glycol, propylene glycol, glycerin, starch, polyvinylpyrrolidone, magnesium aluminum silicate or a mixture of these compounds. The dosage of the active ingredient of the medicament of the present invention, angiotensin II receptor blocker, calcium channel blocker and diuretic, can be selected according to various factors, such as the activity of the drug and the symptoms, age, and body weight of the patient. . Although the dose of-21-201000097 varies depending on symptoms, age, etc., for oral administration, the minimum limit for adults is 0.1 mg (preferably 0.5 mg) and the maximum limit is 1 000 mg (compared to Preferably, it is 500 mg), and it can be administered one to six times at the same time or at intervals depending on the symptoms of the patient. For parenteral administration, the minimum limit for adults is 0.01 mg (preferably 0.05 mg) and the maximum limit is 100 mg (preferably 50 mg) and can be daily depending on the patient's symptoms. At the same time or at intervals of one to six times. In addition, the dose ratio of angiotensin II receptor blocker, calcium channel blocker and diuretic of the active ingredient of the medicament of the present invention may also vary widely, but angiotensin II receptor blocker and calcium ion channel The dose ratio of the blocker and the diuretic can be, for example, in the range of weight ratio 1: 1 0, 0 0 0: 1 - 1 〇, 0 0 0 to 10,000: 1: 1-10,000, and preferably 1:1. 000: 1-1, 〇〇〇 to 1,000: 1: 1-1,000, and more preferably 1: 100: 1-100 to 100: 1: 1-100 ° Further, for the active ingredient of the medicament of the present invention, If the angiotensin II receptor blocker is olmesartan medoxomil, the calcium channel blocker is amlodipine and the loop diuretic is hydrochlorothiazide, the dosage may vary depending on various factors, such as the activity of the drug and the patient. Symptoms, age, and weight. Although the dosage varies depending on the symptoms, age, etc., if administered orally, the dose of olmesartan medoxomil is 5 mg to 80 mg (preferably 10 mg to 40 mg) per hour for adults, and clopidogrel ( The dose equivalent to the free radical is 2.5 mg to 20 mg (preferably 5 mg to 1 mg), and the dose of hydrochlorothiazide (equivalent to the free radical) is 5 mg to 50 mg (preferably 12.5 mg) Up to 25 mg), and one to six times per day (preferably once daily) depending on the symptoms of the patient, and may be administered simultaneously or at intervals. In addition, the dose ratio can also vary widely, but the dose ratio of olmesartan medoxomil, amlodipine-22-201000097 and hydrochlorothiazide can be, for example, in a weight ratio of 1: 5 0 : 1 - 5 0 to 50: 1: 1-50, and preferably 1:10: 1-10 to 10: 1: 1-10. The optimal dose ratio of olmesartan medoxomil / amlodipine / hydrochlorothiazide can be 40 mg / 10 mg / 12.5 mg, 40 mg / 5 mg / 12.5 mg, 40 mg / 5 mg / 25 mg, 40 Mg/10 mg/25 mg, 20 mg/10 mg/12.5 mg or 20 mg/5 mg/12.5 mg. In the present invention, in the case of using an angiotensin II receptor blocker or prevention or treatment of hypertension, since the calcium ion channel is used to block the excellent effects of the agent and the diuretic, the ratio can be used. A second dose of angiotensin II receptor blocker at a lower dose. EXAMPLES The present invention will hereinafter be described in more detail in the following Experimental Examples and Preparation Examples, but the scope of the present invention should not be construed as limited to the Examples. Test Example 1: Blood pressure lowering effect of olmesartan medoxomil, amlodipine and hydrochlorothiazide in combination with 20 male SHRs (spontaneously hypertensive rats; SPF grade; source: O Hoshino Laboratory Animals Co., Ltd.) surgically implanted a telemetry transmitter to measure blood pressure (ΤΑ 1 1 PA-C40, Data Sciences, Inc.). After the surgery was resumed, blood pressure monitoring began. Animals were divided into five groups (four in each group) after two days of measurement, so that each group showed a similar mean blood pressure (the composition of the group is shown in Table 1). At the age of 36 weeks, a 0.5% CMC-Na aqueous solution (2 mL/kg; control group) or a solution of the substance to be tested suspended in 0.5% CMC-Na aqueous solution (2 mL/kg) was orally administered. Day (once a day), and blood pressure is measured, and the blood pressure drop range within 24 hours is shown in Figure 1. Table 1 Composition of the group and the substance to be tested -23- 201000097 Ο

Group 1 Control group (0.5% CMC-Na 7jc solution) Group 2 Olmesartan medoxomil (0·1 mg/kg) Group 3 Amlodipine (1 mg/kg) (administered as ammonia benzenesulfonate) Level 4 Group 4 Hydrochlorothiazepine (10 mg/kg) Group 5 Olmesartan vinegar (0.1 mg/kg) + gas-level level (1 mg/kg) (administered as amlodipine besylate) +Hydroxychlorothiazide: (10 mg/kg) Excellent antihypertensive effect was observed in animals in the group co-administered with olmesartan medoxomil + amlodipine + hydrochlorothiazide. Preparation Example 1 Lozenges (combination drugs) RSn Olmesartan 40.0 mg Amlodipine 13.89 mg Hydrochlorothiazide 12.50 mg α-. Starch 1 0 5.00 mg Crystalline cellulose 112.41 mg Carboxymethylcellulose sodium 15.00 mg Magnesium stearate 1.20 mg The powder of the above formula was mixed and compressed into a tablet using a tablet machine to prepare a tablet of 300 mg per tablet. If desired, the tablet can be coated with a sugar coating. Industrial Applicability According to the present invention, a medicament for preventing or treating hypertension or a disease caused by hypertension can be obtained. More beautifully, it can be used to prevent and/or treat high blood pressure, heart disease [eg angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart hypertrophy], kidney disease (eg diabetic nephropathy, small kidney) -24- 201000097 globular glomerulonephritis and nephrosclerosis), cerebrovascular diseases (such as cerebral infarction and cerebral hemorrhage), and/or vascular diseases (such as atherosclerosis, restenosis after PTCA, and peripheral vascular circulatory diseases). [Simple description of the diagram] Figure 1 shows the change in blood pressure range within 24 hours. [Main component symbol description] None.

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Claims (1)

201000097 VII. Patent Application Range: 1. A medicament for preventing or treating hypertension or a disease caused by hypertension, comprising: (A) an angiotensin II receptor blocker selected from the group consisting of a compound of the formula (1), (I) a group consisting of a pharmacologically acceptable salt, a pharmacologically acceptable ester thereof, and a pharmacologically acceptable salt of the ester; and bismuth (B) at least one calcium An ion channel blocker selected from the group consisting of a 1,4-dihydropyridine derivative and a pharmacologically acceptable salt thereof; and (C) at least one diuretic. 2. The medicament according to claim 1, wherein the disease is selected from the group consisting of hypertension, heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, heart hypertrophy, kidney disease 'diabetic nephropathy, glomerulonephritis , a group consisting of nephrosclerosis, cerebrovascular disease, cerebral infarction, cerebral hemorrhage, vascular disease, arteriosclerosis, restenosis after PTCA, and peripheral vascular circulatory diseases. -26- 201000097 3. The pharmaceutical preparation according to claim 1 or 2, wherein the medicament is a pharmaceutical composition comprising the compound (Α), the compound (Β) and the compound (c) as an active ingredient. 4. The medicament of claim i or 2, wherein the compound (Α), the compound (B) and the compound (C) are administered separately or simultaneously at intervals. 5. The medicament according to any one of claims 4 to 4, wherein the angiotensin II receptor blocker is (5. methyl-2-keto-1,3.dioxacyclo) 4--4-yl)methyl 4-(1-hydroxy-1-methylethyl)_2-propyl-1-[2,-(1Η-tetraoxazol-5-yl)bisphenyl-4- Methyl imidazole-5-carboxylate. 6. The medicament according to any one of claims 1 to 5, wherein the calcium channel blocker is selected from the group consisting of azelnidipine, amlodipine, benidipine, and nevi Nitrendipine, manidipine, nicardipine, nifedipine, nisoldipine, cilnidipine, lercanidipine, ny Nig Uldipine, nimodipine, aranidipine, efenidipine, barnidipine, felodipine, and nilvadipine The group that makes up. 7. The medicament according to any one of claims 1 to 5, wherein the calcium ion channel blocker is amlodipine. The drug according to any one of claims 1 to 7, wherein the diuretic is selected from the group consisting of hydrogen hydrothiathiazide, methyclothiazide, benzylhydrochlorothiazide. , Trichloromethiazide, CyCl〇penthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide And a group of hydroflumethiazide. 9. The medicament according to any one of claims 1 to 7, wherein the diuretic is hydrochlorothiazide. 10. The medicament according to any one of claims 1 to 9, wherein the angiotensin II receptor blocker is (5-methyl-2-keto-1,3-dioxane 0 Penten-4-yl)methyl 4-(1-hydroxy-1-methylethyl)_2-propyl•1-W-(1H-tetrazol-5-yl)bisphenyl-4-yl The imidazole-5-carboxylate, the calcium channel blocker is amlodipine, and the diuretic is a hydrochlorothiazide. 11. The medicament of any one of claims 1 to 10, wherein the medicament is in a single dosage form. 12. A method for preventing or treating hypertension or a disease caused by hypertension, which comprises administering a medicinal effective amount to a warm-blooded animal in need thereof, any one of claims 1 to 11 Item of the drug. -28-