WO2009145358A2

WO2009145358A2 - Medicament for the prophylaxis or treatment of hypertension

Info

Publication number: WO2009145358A2
Application number: PCT/JP2009/060295
Authority: WO
Inventors: Makoto Mizuno
Original assignee: Daiichi Sankyo Company, Limited
Priority date: 2008-05-30
Filing date: 2009-05-29
Publication date: 2009-12-03
Also published as: TW201000097A; WO2009145358A3

Abstract

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

Description

DESCRIPTION

Medicament for the prophylaxis or treatment of hypertension

[Technical Field of the Invention]

The present invention relates to a medicament for the prophylaxis or treatment of hypertension, heart diseases (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and cardiac hypertrophy), renal diseases (such as diabetic nephropathy, glomerulonephritis and nephrosclerosis), cerebrovascular diseases (such as cerebral infarction and cerebral hemorrhage), and/or vascular disorders (such as arteriosclerosis, post-PTCA restenosis, and peripheral circulatory disorders)

[Background of the Invention]

Currently angiotensin Il receptor blockers and calcium channel blockers are widely used as medicaments for the treatment or prophylaxis of hypertension, heart diseases and the like. The angiotensin Il receptor blocker, which is a renin angiotensin system inhibitor, is particularly effective for renin dependent hypertension and shows protective effects on cardiovascular and renal impairment. Furthermore, since the calcium channel blocker possesses natriuretic action in addition to vasodilative action, it is also effective on fluid retentive (renin independent) hypertension. Accordingly, if an angiotensin Il receptor blocker and a calcium channel blocker are used in combination, stable and satisfactory treatment and prophylaxis of hypertension can be expected without regard to the cause of the disease since the calcium channel blocking effect in vascular smooth muscles and the secondary sodium excretion effect of the calcium channel blocker in addition to the renin angiotensin system inhibiting effect of the angiotensin Il receptor blocker make it possible to suppress multiple factors of the cause of hypertension.

Furthermore, diuretics are also widely used as medicaments for the treatment or prophylaxis of hypertension, heart diseases and the like. Diuretics are effective for the treatment of hypertension because of their diuretic effect. Accordingly, if an angiotensin Il receptor blocker and a diuretic are used in combination, stable and satisfactory treatment and prophylaxis of hypertension can be expected without regard to the cause of the disease since the diuretic effect of the diuretic in addition to the renin angiotensin system inhibiting effect of the angiotensin Il receptor blocker make it possible to suppress multiple factors of the cause of hypertension. (5-methyl~2-oxo-1 ,3-dioxolen-4-yl) methyl 4-(1 -hydroxy-1 -methylethyl)-2-propyl-1 -[2¹- (1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate (hereafter, referred to as "olmesartan medoxomil") is a superior angiotensin Il receptor blocker and is useful for the treatment or prophylaxis of hypertension, heart diseases and the like (Japanese Patent Number 2082519 and U.S. Patent Number 5,616,599).

Olmesartan Medoxomil

Olmesartan medoxomil is marketed under the trade name Olmetec® or Benicar i which contains 5 mg, 10 mg, 20 mg, or 40 mg of olmesartan medoxomil as the active ingredient and low-substituted hydroxypropylcellulose, hydroxypropylcellulose, microcrystalline cellulose, lactose, and magnesium stearate as additives.

3-ethyl-5-methyl-(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1 ,4-dihydro-6- methy!pyridine-3,5-dicarboxylate (hereafter, referred to as "amlodipine") is a superior calcium channel blocker and is useful for the treatment or prophylaxis of hypertension, heart diseases and the like (Japanese Patent Number 1401088 and U.S. Patent Number 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 as amlodipine) as the active ingredient and microcrystalline cellulose, anhydrous calcium hydrogen phosphate, sodium starch glycolate, magnesium stearate, hydroxypropylcellulose, titanium oxide, talc, and camauba wax as additives.

Furthermore, 6-chloro-3,4-dihydro-2H-1 ,2,4- benzothiadiazin-7-sulfonamide 1 ,1- dioxide (hereafter, referred to as "hydrochlorothiazide") is a superior thiazide diuretic and is disclosed, for example, in U.S. Patent Number 3,025,292 and the like.

Hydrochlorothiazide

A medicament containing olmesartan medoxomil and a calcium channel blocker (International Publication Number 2004/067003 Official Gazette) and a medicament containing olmesartan medoxomil and a diuretic (International Publication Number 2002/041890 Official Gazette) are known. A solid dosage form containing olmesartan medoxomil, amlodipine and hydrochlorothiazide (International Publication Number 2003/097045 Official Gazette and International Publication Number 2008/032107 Official Gazette) is also known. However, remarkable effects on hypertension and the like of medicaments containing a specific angiotensin Il receptor blocker, such as olmesartan medoxomil, a calcium channel blocker and a diuretic of the present invention are not known.

[Objects of the Invention]

The object of the present invention is to provide medicaments for the prophylaxis and/or treatment of hypertension or diseases caused by hypertension. More specifically, it is the object of the present invention to provide medicaments for the prophylaxis or treatment of hypertension, heart diseases (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and cardiac hypertrophy), renal diseases (such as diabetic nephropathy, glomerulonephritis and nephrosclerosis), cerebrovascular diseases (such as cerebral infarction and cerebral hemorrhage), and/or vascular disorders (such as arteriosclerosis, post-PTCA restenosis, and peripheral circulatory disorders), particularly medicaments for the prophylaxis or treatment of hypertension.

[Summary of the Invention]

The present inventors have now found that by combining a specific angiotensin Il receptor blocker, a specific calcium channel blocker, and a specific diuretic, there is a superior hypotensive effect. Moreover, the present inventors have found that this medicament is extremely effective for the prophylaxis and/or the treatment of hypertension, heart diseases (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and cardiac hypertrophy), renal diseases (such as diabetic nephropathy, glomerulonephritis and nephrosclerosis), cerebrovascular diseases (such as cerebral infarction and cerebral hemorrhage), and/or vascular disorders (such as arteriosclerosis, post-PTCA restenosis, and peripheral circulatory disorders). The present invention was completed based on these findings described above.

Specifically, the present invention provides:

(1 ) A medicament for the prophylaxis or treatment of hypertension or a disease caused by hypertension comprising:

(A) an angiotensin Il receptor blocker selected from the group consisting of a compound having a general formula (I),

(I)

pharmacologically acceptable salts thereof, pharmacologically acceptable esters thereof and pharmacologically acceptable salts of said esters thereof; and

(B) at least one calcium channel blocker selected from the group consisting of 1 ,4- dihydropyridine derivatives and pharmacologically acceptable salts thereof; and

(C) at least one diuretic

(2) A medicament according to (1), wherein the disease selected from the group consisting of hypertension, heart diseases, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, renal diseases, diabetic nephropathy, glomerulonephritis, nephrosclerosis, cerebrovascular diseases, cerebral infarction, cerebral hemorrhage, vascular disorders, arteriosclerosis, post-PTCA restenosis, and peripheral circulatory disorders;

(3) A medicament according to (1) or (2), wherein the medicament is a pharmaceutical composition comprising compound (A), compound (B), and compound (C) as active ingredients;

(4) A medicament according to (1) or (2), wherein compound (A), compound (B), and compound (C) are administered at the same time or separately at certain intervals; (5) A medicament according to any one of (1) to (4), wherein the angiotensin Il receptor blocker is (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1- [2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate;

(6) A medicament according to any one of (1) to (5), wherein the calcium channel blocker is selected from the group consisting of azelnidipine, amlodipine, benidipine, nitrendipine, manidipine, nicardipine, nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, bamidipine, felodipine, and nilvadipine;

(7) A medicament according to any one of (1) to (5), wherein the calcium channel blocker is amlodipine;

(8) A medicament according to any one of (1) to (7), wherein the diuretic is selected from the group consisting of hydrochlorothiazide, methyclothiazide, benzylhydrochlorothiazide, trichlormethiazide, cyclopenthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide, and hydroflumethiazide;

(9) A medicament according to any one of (1) to (7), wherein the diuretic is hydrochlorothiazide;

(10) A medicament according to any one of (1) to (9), wherein the angiotensin Il receptor blocker is (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1- [2'-(1 H-tetrazoI-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate, the calcium channel blocker is amlodipine, and the diuretic is hydrochlorothiazide;

(11) A medicament according to any one of (1) to (10), wherein medicament is a single dosage form.

Furthermore, the present invention provides: the use of compounds (A), (B) and (C) in the manufacture of the medicament described above; a method for preventing or treating (particularly treating) diseases comprising administering to a warm-blooded animal (particularly a human) in need thereof a pharmaceutically effective amount of each of compounds (A), (B), and (C). According to a preferred embodiment of the invention, the medicament described above is provided as a pharmaceutical composition comprising compound (A), compound (B), and compound (C) as active ingredients. This pharmaceutical composition may contain one or more pharmaceutically acceptable additives.

Since the medicament of the present invention, i.e., the medicament comprising a specific angiotensin Il receptor blocker such as olmesartan medoxomil, a calcium channel blocker and a diuretic as active ingredients, has superior hypotensive effects and low toxicity, the medicament is useful as a remedy [preferably as a preventive or therapeutic agent (particularly a therapeutic agent) for hypertension, heart diseases (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and cardiac hypertrophy), renal diseases (such as diabetic nephropathy, glomerulonephritis and nephrosclerosis), cerebrovascular diseases (such as cerebral infarction and cerebral hemorrhage), and/or vascular disorders (such as arteriosclerosis, post-PTCA restenosis, or peripheral circulatory disorders); more preferably as a preventive or therapeutic agent (particularly a therapeutic agent) for hypertension or heart diseases; and most preferably as a preventive or therapeutic agent (particularly a therapeutic agent) for hypertension. Furthermore, the remedies described above are preferably for use in warm blooded animals and more preferably for use in humans.

[Detailed Description of the Invention]

The medicaments of the present invention are characterized by containing (A) an angiotensin Il receptor blocker selected from the group consisting of a compound having a general formula (I), pharmacologically acceptable salts thereof, pharmacologically acceptable esters thereof and pharmacologically acceptable salts of said esters thereof; (B) at least one calcium channel blocker selected from the group consisting of 1 ,4- dihydropyridine derivatives and pharmacologically acceptable salts thereof; and (C) at least one diuretic as active ingredients.

The compound having the formula (I) described above [4-(1-hydroxy-1-methylethyl)~ 2-propyl-i-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate], which is an active ingredient of the medicament of the present invention, is commonly known and can be easily prepared , for example, according to the methods disclosed in Japanese Patent Publication (Kokai) Number Hei 5-78328 and the like. The compound having the formula (I) described above can be converted to the corresponding pharmaceutically acceptable salts as desired by treating with a base according to conventional methods. For example, salts can be obtained by treating with a suitable base in a solvent (for example, ethers, esters, or alcohol can be used and preferably alcohols can be used) for five to 30 minutes at room temperature, and then filtering out the precipitated crystals or distilling off the solvent under reduced pressure. Such salts can be, for example, an alkali metal salt such as a sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as a calcium salt or magnesium salt; a metal salt such as an aluminum salt, iron salt, zinc salt, copper salt, nickel salt, or cobalt salt; an inorganic salt such as an ammonium salt; an organic salt such as a t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamide salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylene diamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethyl amine salt, piperazine salt, tetramethylammonium salt, or tris(hydroxymethyl)aminomethane salt, but are not restricted to these salts. Alkaline metal salts are preferred and the sodium salt is particularly preferred.

The pharmacologically acceptable esters of the compound having the formula (I) described above are compounds having the formula (I) in which the carboxyl moiety is esterified. The pharmacologically acceptable esters are not particularly restricted, and can be selected by a person of ordinary skill in the art. It is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo. The group constituting said esters (the group shown as R wherein said esters thereof are expressed as -COOR) can be, for example, a C₁-C₄ 8IkOXy-C₁-C₄ alkyl group such as methoxymethyl, 1 -ethoxyethyl, 1 -methyl- 1 -methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1 ,1-dimethyl- 1 -methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t- butoxymethyl; a C₁-C₄ alkoxylated C₁-C₄ 8IkOXy-C₁ -C₄ alkyl group such as 2- methoxyethoxymethyl; a C₆-C₁₀ aryloxy-Cr^ alkyl group such as phenoxymethyl; a halogenated C₁-C₄ alkoxy-CrC₄ alkyl group such as 2,2,2-trichloroethoxymethyl or bis(2- chloroethoxy) methyl; a C₁-C₄ alkoxycarbonyl-CrC₄ alkyl group such as methoxycarbonylmethyl; a cyano C₁-C₄ alkyl group such as cyanomethyl or 2-cyanoethyl; a C₁-C₄ alkylthiomethyl group such as methylthiomethyl and ethylthio methyl; a C₆-C₁₀ arylthiomethyl group such as phenylthiomethyl or naphthylthiomethyl; a C₁-C₄ alkylsulfonyl- C₁-C₄ lower alkyl group, which may be optionally substituted with halogen atom(s) such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; a C₆-C₁₀ arylsulfonyl-C₁-C₄ alkyl group such as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; an aliphatic C₁-C₇ acyloxy- C₁-C₄ alkyl group such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1 -acetoxyethyl, 1 -propionyloxyethyl, 1- butyryloxyethyl, 1 -pivaloyloxyethyl, 1 -valeryloxyethyl, 1 -isovaleryloxyethyl, 1 - hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1- ^•formyloxypropyl, 1-acetoxypropyl, 1 -propionyloxypropyl, 1-butyryloxypropyl, 1- pivaloyloxypropyl, 1 -valeryloxypropyi, 1 -isovaleryloxypropyl, 1-hexanoyloxypropyl, 1- acetoxybutyl, 1 -propionyloxybutyl, 1 -butyryloxybutyl, 1 -pivaloyloxybutyl, 1 -acetoxypentyl, 1 - propionyloxypentyl, 1 -butyryloxypentyl, 1 -pivaloyloxypentyl or 1 -pivaloyloxyhexyl; a C₅-C₆ cycloalkylcarbonyloxy-C₁-C₄ alkyl group such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1 -cyclopentylcarbonyloxyethyl, 1 -cyclohexylcarbonyloxyethyl, 1 -cyclopentylcarbonyloxypropyl, 1 -cyclohexylcarbonyloxypropyl, 1 - cyclopentylcarbonyloxybutyl or 1 -cyclohexylcarbonyloxybutyl; a C₆-C₁₀ arylcarbonyloxy-d- C₄ alkyl group such as benzoyloxymethyl; a C₁-C₆ alkoxycarbonyloxy C₁-C₄ alkyl group such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1- (methoxycarbonyloxy)propyl, 1 -(methoxycarbonyloxy)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 -isopropoxycarbonyloxy)ethyl, 1 -(isopropoxycarbonyloxy) butyl, butoxycarbonyloxymethyl, 1 -(butoxycarbonyloxy)ethyl, 1 -(butoxycarbonyloxy)propyl, 1 -(butoxycarbonyloxy) butyl, isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy)ethyl, 1 -

(isobutoxycarbonyloxy) propyl, 1 -(isobutoxcarbonyloxy)butyl, t-butoxycarbonyloxymethyl, 1- (t-butoxycarbonyloxy)ethyl, pentyloxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1- (pentyloxycarbonyloxy) propyl, hexyloxycarbonyloxymethyl, 1 -(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyloxy)propyl; a C₅-C₆ cycloalkyloxycarbonyloxy- C₁-C₄ alkyl group such as cyclopentyloxycarbonyloxymethyl, 1 -(cyclopentyloxycarbonyloxy)ethyl, 1- (cyclopentyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1 -(cyclohexyloxycarbonyloxy) ethyl, 1 - (cyclohexyloxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)butyl; a [5-(C₁-C₄ alkyl)- 2-0X0-1 ,3-dioxolen-4-yl]methyl group such as (5-methyl-2-oxo-1 ,3-dioxolen-4-yl) methyl, (5- ethyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1 ,3-dioxolen-4-yl) methyl, (5-isopropyl- 2-0X0-1 ,3-dioxolen-4-yl) methyl or (5-butyl-2-oxo-1 ,3-dioxolen-4-yl) methyl; a [5-(phenyl, which may be optionally substituted with a C^-C₄ alky!, C₁-C₄ alkoxy, or halogen atom(s))-2- oxo-1 ,3-dioxolen-4-yl]methyl such as (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl) methyl, [5-(4- methylphenyl) -2-0X0-1 ,3-dioxolen-4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1 ,3-dioxolen-4- yljmethyl, [5-(4-fluorophenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl or [5-(4-chlorophenyl)-2-oxo- 1 ,3-dioxolen-4-yl]methyl; or a phthalidyl group, which may be optionally substituted with a C₁-C₄ alkyl or C₁-C₄ alkoxy group(s) such as phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl. Preferred ester groups are a pivaloyloxymethyl group, a phthalidyl group or a (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl group, and more preferably a (5- methyl-2-oxo-1 ,3-dioxolen-4-yl) methyl group.

The esters of the compounds having the formula (I) described above can be converted to the corresponding pharmaceutically acceptable salts (i.e. pharmacologically acceptable salts of said esters) as desired by treating with a base according to conventional methods. For example, such salts of the esters can be obtained by treating with a suitable base in solvent (for example, ethers, esters, or alcohol can be used and preferably ethers can be used) for five to 30 minutes at room temperature, and then filtering out the precipitated crystals or distilling off the solvent under reduced pressure. Such salts can be, for example, a mineral acid salt such as a hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulphate or phosphate; a sulfonate such as a methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p- toluenesulfonate; a carboxylate such as a fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as a glutamate or aspartate. Preferred salts are hydrochloride, nitrate, sulphate, or phosphate and the hydrochloride is especially preferred.

As the angiotensin Il receptor blocker, which is used as the compound (A), the compound having the formula (I) described above or pharmaceutically acceptable esters thereof can preferably be used. More preferably, a pharmaceutically acceptable ester of the compound having the formula (I) described above can be used and, even more preferably, a pivaloyloxymethyl ester, phthalidyl ester or (5-methyl-2-oxo-1 ,3-dioxolen-4- yl)methyl ester of the compound having the formula (I) described above can be used. Most preferably (5-methyl-2-oxo-1 ,3-dioxolen-4-yl) methyl 4-(1-hydroxy-1 -methylethyl)-2-propyl-1 - [2"-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate (olmesartan medoxomil) can be used, and it can be easily prepared according to the methods disclosed in Japanese Patent Number 2082519 (U.S. Patent Number 5,616,599) and the like. As the compound selected from the group consisting of a compound having the formula (I) described above, pharmacologically acceptable salts thereof, pharmacologically acceptable esters thereof and pharmacologically acceptable salts of said esters thereof, their hydrates or solvates can also be used. In cases where the pharmacologically acceptable esters of the compound having the formula (I) described above are used, some esterified compounds may have one or more chiral carbons. Purified optical isomers based on the said chiral carbons or stereoisomers such as diastereoisomers or any mixtures of stereoisomers or racemates can also be used as compound (A).

The calcium channel blocker including 1 ,4-dihydropyridine derivatives, which is used as compound (B), is a calcium channel blocker characterized by having a 1 ,4- dihydropyridine moiety or chemically equivalent structural moiety thereof in the molecule. Since various medicaments are proposed as calcium channel blockers, including the 1 ,4- dihydropyridine derivatives and are actually used clinically, a person of ordinary skill in the art can select any suitable compounds exerting the effects of the present invention. As 1 ,4- dihydropyridine calcium channel blockers, for example, azelnidipine, amlodipine, benidipine, nitrendipine, manidipine, nicardipine, nifedipine, nisoldipine, cilnidipine, lercanidipine^ . niguldipine, nimodipine, aranidipine, efonidipine, barnidipine, felodipine or nilvadipine can be used, but the invention is not restricted to these compounds.

The pharmacologically acceptable salts of the 1 ,4-dihydropyridine derivatives are not specifically restricted, and can be selected by a person of ordinary skill in the art. The pharmacologically acceptable salts can be acid addition salts or base addition salts. Such salts can be, for example, base addition salts including an alkali metal salt such as a sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as a calcium salt or magnesium salt; a metal salt such as an aluminum salt, iron salt, zinc salt, copper salt, nickel salt or cobalt salt; an inorganic salt such as an ammonium salt; an organic salt such as a t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylene diamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethyl amine salt, piperazine salt, tetramethylammonium salt, or tris(hydroxym ethyl) aminomethane salt; or acid addition salts including a mineral acid salt such as a hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulphate or phosphate; a sulfonate such as a methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate or p- toluenesulfonate; a carboxylate such as a fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as a glutamate or aspartate, but the invention is not restricted to these salts.

As a calcium channel blocker including the 1 ,4-dihydropyridine derivatives, hydrates or solvates of the compounds described above and pharmacologically acceptable salts thereof can also be used. Furthermore, the calcium channel blocker including the 1 ,4- dihydropyridine derivatives may have one or more chiral carbons. Purified optical isomers based on the said chiral carbons or stereoisomers such as diastereoisomers or any mixtures of stereoisomers or racemates can also be used as the compound (B). As the compound (B), (±)-2-amino-1 ,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyrizine dicarbonic acid 3-(1-diphenyl methyl azethizine-3-yl) ester 5-isopropyl ester is preferably used.

As the calcium channel blocker including the 1 ,4-dihydropyridine derivatives, more preferably amlodipine is used. It is easily prepared according to the methods disclosed in Japanese Patent Number 1401088 (U.S. Patent Number 4,572,909) and the like. The amlodipine can be a pharmacologically acceptable salt thereof, and these salts are included in the present invention. The pharmacologically acceptable salts can be acid, addition salts or base addition salts. Such salts can be, for example, besylate, hydrochloride, hydrobromide, fumarate, citrate, succinate, maleate, camsylate, lactate, mesylate, nicotinate, gluconate, and the like, but the invention is not restricted to these salts. Preferably, the besylate is used.

The diuretic used as compound (C) is a commonly known compound, and disclosed in, for example, U.S. Patent Number 2,554,816, U.S. Patent Number 2,980,679, U.S. Patent Number 2,783,241 , GB Patent Number 795,174, J. Chem. Soc. 1125 (1928), U.S. Patent Number 2,835,702, GB Patent Number 851 ,287, U.S. Patent Number 3,356,692, U.S. Patent Number 3,055,904, U.S. Patent Number 2,976,289, U.S. Patent Number 3,058,882, HeIv. Chim. Acta, 45, 2316 (1962), Applied Pharmacology, 21 , 607 (1982), U.S. Patent Number 3,183,243, U.S. Patent Number 3,360,518, U.S. Patent Number 3,567,777, U.S. Patent Number 3,634,583, U.S. Patent Number 3,025,292, J. Am. Chem. Soc, 82 , 1132 (1960), U.S. Patent Number 3,108,097, Experientia, 16, 113 (1960), J. Org. Chem., 26, 2814 (1961), U.S. Patent Number 3,009,911 , U.S. Patent Number 3,265,573, U.S. Patent Number 3,254,076, U.S. Patent Number 3,255,241 , U.S. Patent Number 3,758,506, BE Patent Number 639,386, and U.S. Patent Number 3,163,645. The diuretics can be a sulfonamide compound such as acetazolamide, methazolamide, ethoxzolamide, clofenamide, dichlorphenamide, disulfamide, mefruside, chlorthalidone, quinethazone, furosemide, clopamide, tripamide, indapamide, clorexolone, metolazone, xipamide, bumetanide, piretanide or X-54; a thiazide compound such as hydrochlorothiazide, methyclothiazide, benzylhydrochlorothiazide, trichloromethiazide, cyclopenthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide or hydroflumethiazide; a phenoxyacetic acid compound such as ethacrynic acid, tienilic acid, indacrinone or quincarbate; triamterene; amiloride; spironolactone; potassium canrenoate; and torasemide; MK-447; or traxanox sodium. The thiazide compounds are preferred, and hydrochlorothiazide is more preferred.

The chemical name of hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1 ,2,4- benzothiadiazin-7-sulfonamide 1 ,1 -dioxide and the hydrochlorothiazide of the present invention includes pharmacologically acceptable salts thereof. Such salts can be, for example, a hydrohalide salt such as a hydrofluoride, hydrochloride, hydrobromide or hydroiodide; nitrate; perchlorate; sulphate; phosphate; a C₁-C₄ alkane sulfonate, which may be optionally substituted with halogen atom(s), such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; a C₆-Ci₀ allyl sulfonate, which may be optionally substituted with C₁-C₄ alkyl, such as benzenesulfonate or p-toluenesulfonate; a. C₁-C₆ fatty acid salt such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate or maleate; or an amino acid salt such as glycine salt, lycine salt, arginine salt, ornithine salt, glutamate or aspartate. The hydrochloride, nitrate, sulfate or phosphate is preferred, and the hydrochloride is especially preferred.

Furthermore, in cases where the compounds described above have one or more chiral carbons, the diuretic of the present invention also includes the optical isomers and mixtures thereof. Moreover, the hydrates of the compounds described above are also included.

In the present invention, administration "at the same time" means that compound (A), compound (B) and compound (C) are to be administered at roughly the same time. There are no restrictions on the dosage forms for administration, but administration as a single dosage form is preferred.

In the present invention, administration "separately at certain intervals" means that compound (A), compound (B) and compound (C) are to be administered independently at different times. There are no restrictions on the dosage forms for administration. For example, first an angiotensin Il receptor blocker may be administered and then, after a certain interval, a calcium channel blocker and a diuretic may be administered at the same time (or they can be administered in order after a certain interval). Alternatively, a calcium channel blocker or a diuretic may be administered first and then, after a certain interval, the remaining two agents may be administered in the same manner as described above.

As clearly shown in the Examples of the present Specification, the medicament of the present invention can lower blood pressure more effectively since by combined actions of compound (A), compound (B), and compound (C). Based on the actions described above, the medicament of the present invention can be used for the prophylaxis or treatment (especially the treatment) of hypertension, heart diseases [such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure, cardiac hypertrophy], renal diseases (such as diabetic nephropathy, glomerulonephritis, nephrosclerosis), cerebrovascular diseases (such as cerebral infarction, cerebral hemorrhage), and/or vascular disorders (such as arteriosclerosis, post-PTCA restenosis, peripheral circulatory disorders). The medicament of the present invention comprising an angiotensin Il receptor blocker, a calcium channel blocker and a diuretic used in combination can show superior effects in comparison with the case in which each of the agents has been administered alone.

The medicament of the present invention comprising an angiotensin Il receptor blocker, a calcium channel blocker and a diuretic can be prepared as several independent dosage forms by formulating each of the agents separately or as a single physical dosage form by mixing all of the agents together.

In cases where the medicament of the present invention is used as a preventive or therapeutic agent for the diseases described above, an angiotensin Il receptor blocker, a calcium channel blocker, and a diuretic, which are the active ingredients of the medicament of the present invention, can be administered each respectively as itself or orally in the form of tablets, capsules, granules, powders, syrups and the like, or parenterally in the form of injections, suppositories and the like. Such dosage forms are manufactured according to commonly known methods by using pharmacologically acceptable additives such as excipients, lubricants, binders, disintegrants, demulsifiers, stabilizers, flavours, diluents, and the like. Since compounds (A), (B) and (C) in the medicament of the present invention are agents which are generally administered orally, the medicament of the present invention is favorable to be administered orally. As "excipients", for instance, organic excipients including sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; or pullulan; and inorganic excipients including silicate derivatives such as light anhydrous silicic acid, synthetic aluminium silicate, calcium silicate or magnesium aluminometasilicate; phosphates such as calcium hydrogenphosphate; carbonates such as calcium carbonate; or sulfates such as calcium sulfate can be listed.

As "lubricants", for instance, stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; laurylsulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as silicic anhydride and silicic hydrate; or the starch derivatives described above can be listed.

As "binders", for instance, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or similar excipients to those described above can be listed.

As "disintegrants", for instance, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose or internally crosslinked sodium carboxymethylcellulose; and chemically modified starch/cellulose derivatives such as carboxymethylstarch or sodium carboxymethylstarch can be listed.

As "demulsifiers", for instance, colloidal clay such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminium hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; or nonionic surfactants such as polyoxyethylenealkylether, polyoxyethylene sorbitan fatty acid ester or sucrose esters of fatty acids can be listed.

As "stabilizers", for instance, p-hydroxybenzoate esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; or sorbic acid can be listed.

As "flavours", for instance, sweeteners such as saccharin sodium or aspartame; acidifiers such as citric acid, malic acid or tartaric acid; or flavours such as menthol, lemon or orange can be listed.

As "diluents", conventionally used diluents, for instance, lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethyleneglycol, propyleneglycol, glycerol, starch, polyvinylpyrrolidone, magnesium aluminometasilicate or a mixture of these compounds can be listed.

Dosage of an angiotensin Il receptor blocker, a calcium channel blocker and a diuretic, which are active ingredients of the medicament of the present invention, can be selected in a suitable manner depending on various factors such as the drugs' activities and symptoms, age and body weight of the patients. Although the dosage varies depending on symptoms, age and the like, in the case of oral administration, 0.1 mg (preferably 0.5 mg) as a lower limit and 1000 mg (preferably 500 mg) as an upper limit per one time for a human adult and one to six times per day depending on the symptoms of the patients can be administered, at the same time or separately at certain intervals. In the case of parenteral administration, 0.01 mg (preferably 0.05 mg) as a lower limit and 100 mg (preferably 50 mg) as an upper limit per one time for a human adult and one to six times per day depending on the symptoms of the patients, at the same time or separately at certain intervals, can be administered.

Furthermore, dosing ratios of an angiotensin Il receptor blocker, a calcium channel blocker and a diuretic, which are active ingredients of the medicament of the present invention, can also vary greatly but the dosing ratio of an angiotensin Il receptor blocker, a calcium channel blocker and a diuretic may be, for instance, in the range of 1 :10,000:1- 10,000 through 10,000:1 :1 -10,000 in weight ratios, and preferably 1 :1 , 000:1 -1 ,000 through 1 ,000:1 :1 -1 ,000, and more preferably 1 :100:1-100 through 100:1 :1-100.

Moreover, in cases where, for the active ingredients of the medicament of the present invention, an angiotensin Il receptor blocker is olmesartan medoxomil, a calcium channel blocker is amlodipine and a diuretic is hydrochlorothiazide, the dosage can be changed depending on various factors such as the drugs' activities and symptoms, age and body weight of the patients. Although the dosage varies depending on symptoms, age and the like, in the case of oral administration, the dosage of olmesartan medoxomil is from 5 mg to 80 mg (preferably 10 mg to 40 mg), the dosage of amlodipine (equivalent to the free base) is from 2.5 mg to 20 mg (preferably 5 mg to 10 mg) and the dosage of hydrochlorothiazide (equivalent to the free base) is from 5 mg to 50 mg (preferably 12.5 mg to 25 mg) per one time for a human adult and one to six times per day (preferably one time per day) depending on the symptoms of the patients, and can be administered at the same time or separately at certain intervals,.

Furthermore, the dosing ratios can also vary greatly but the dosing ratios of olmesartan medoxomil, amlodipine and hydrochlorothiazide may be, for instance, in the range of 1:50:1-50 through 50:1 :1-50 in weight ratios and preferably 1 :10:1 -10 through 10:1 :1 -10. Most preferably, the dosing 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 cases where an angiotensin Il receptor blocker is used or the prophylaxis or treatment of hypertension, due to superior efficacy by using in combination with a calcium channel blocker and a diuretic, a lower dosage of the angiotensin Il receptor blocker can be used than the dosage ordinarily used in monotherapy.

[Examples]

The present invention will be hereinafter described in more detail by way of the Test Example and Preparation Example described below, the scope of the present invention should not be limited to these examples.

Test Example 1 : Hypotensive effects due to the use of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in combination.

Surgery to implant telemetry transmitters for measuring blood pressure (TA11 PA-C40, Data Sciences, Inc.) was carried out on 20 male SHR (spontaneously hypertensive rats; SPF grade; origin: Hoshino Laboratory Animals Co., Ltd.). After recovery from the surgery, the monitoring of blood pressure was started. The animals were divided into five groups (four in each group) so that each group showed a similar mean value of blood pressures based on the measured values for two days (the composition of the groups is shown in Table 1). From the age of 36 weeks, a 0.5% CMC-Na aqueous solution (2 mL/kg; the control group) or a solution in which the substance to be tested was suspended in a 0.5% CMC-Na aqueous solution (2 mlVkg) was administered orally for 14 days (once a day) and blood pressures were measured. Changes in the 24 hour hypotensive area value are shown in Rg. 1.

Table 1 Group composition and administration of the substance to be tested

Group 1 Control group (0.5% CMC-Na aqueous solution)

Group 2 Olmesartan medoxomil (0.1 mg/kg)

Group 3 Amlodipine (1 mg/kg) (administered as amlodipine besylate)

Group 4 Hydrochlorothiazide (10 mg/kg)

Group 5 Olmesartan medoxomil (0.1 mg/kg) + amlodipine (1 mg/kg) (administered as amlodipine besylate) + hydrochlorothiazide (10 mg/kg)

Excellent hypotensive effects were observed in animals in the group co-administered olmesartan medoxomil + amlodipine + hydrochlorothiazide.

Preparation Example 1

Tablets (combination drug)

Olmesartan medoxomil 40.0 mg

Amlodipine 13.89 mg

Hydrochlorothiazide 12.50 mg a-starch 105.00 mg

Crystalline cellulose 112.41 mg

Carmellose sodium 15.00 mg

Magnesium stearate 1.20 mg

A powder of the formula described above is mixed, compressed into tablets using a tableting machine, and made into tablets of 300 mg each. It is possible to coat the tablets with a sugar coating as required.

[Industrial Applicability]

According to the present invention, a medicament for the prophylaxis or treatment of hypertension or a disease caused by hypertension is obtained. More specifically, a medicament for the prophylaxis and/or treatment of hypertension, heart diseases [such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and cardiac hypertrophy], renal diseases (such as diabetic nephropathy, glomerulonephritis and nephrosclerosis), cerebrovascular diseases (such as cerebral infarction and cerebral hemorrhage), and/or vascular disorders (such as arteriosclerosis, post-PTCA restenosis, and peripheral circulatory disorders) is obtained.

[Brief Description of Drawings]

Fig. 1 shows the changes in 24 hour hypotensive area value

Claims

1. A medicament for the prophylaxis or treatment of hypertension or a disease caused by hypertension comprising:

(I)

(C) at least one diuretic.

2. A medicament according to claim 1 , wherein the disease is selected from the group consisting of hypertension, heart diseases, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, renal diseases, diabetic nephropathy, glomerulonephritis, nephrosclerosis, cerebrovascular diseases, cerebral infarction, cerebral hemorrhage, vascular disorders, arteriosclerosis, post-PTCA restenosis and peripheral circulatory disorders.

3. A medicament according to Claim 1 or 2, wherein the medicament is a pharmaceutical composition comprising compound (A), compound (B), and compound (C) as active ingredients.

4. A medicament according to Claim 1 or 2, wherein compound (A), compound (B), and compound (C) are administered at the same time or separately at certain intervals.

5. A medicament according to any one of Claims 1 to 4, wherein the angiotensin Il receptor blocker is (5-methyl-2-oxo-1 ,3-dioxolen-4-yl) methyl 4-(1-hydroxy-1 -methylethyl)-2- propyl-1-[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate.

6. A 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, nitrendipine, manidipine, nicardipine, nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, barnidipine, felodipine, and nilvadipine.

7. A medicament according to any one of Claims 1 to 5, wherein the calcium channel blocker is amlodipine.

8. A medicament according to any one of Claims 1 to 7, wherein the diuretic is selected from the group consisting of hydrochlorothiazide, methyclothiazide, benzylhydrochlorothiazide, trichlormethiazide, cyclopenthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide, and hydroflumethiazide.

9. A medicament according to any one of Claims 1 to 7, wherein the diuretic is hydrochlorothiazide.

10. A medicament according to any one of Claims 1 to 9, wherein the angiotensin Il receptor blocker is (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1 -methylethyl)-2- propyl-1 -[2'-(1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate, the calcium channel blocker is amlodipine, and the diuretic is hydrochlorothiazide.

11. A medicament according to any one of Claims 1 to 10, wherein the medicament is a single dosage form.

12. A method for preventing or treating hypertension or a disease caused by hypertension which comprises administering to a warm-blooded animal in need thereof a pharmaceutically effective amount of a medicament according to any one of Claims 1 to 11.