US 2008O176909A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0176909 A1 Horiuchi et al. (43) Pub. Date: Jul. 24, 2008

(54) METHODS FOR PREVENTION AND (52) U.S. Cl...... S14/356 TREATMENT OF ARTERIOSCLEROSIS, HYPERTENSION AND RESTENOSIS (57) ABSTRACT (75) Inventors: Masatsugu Horiuchi, Ehime (JP); Methods for the prophylaxis and/or treatment of arterioscle Masaru Iwai, Ehime (JP); Toshio rosis, hypertension, restenosis, heart diseases, renal diseases Sada, Tokyo (JP); Makoto Mizuno, and cerebrovascular diseases by administering a pharmaceu Chiba (JP) tical composition comprising the following active ingredi ents: (A) an angiotensin II receptor antagonist selected from Correspondence Address: the group consisting of a compound having a formula (I), a FRISHAUF, HOLTZ, GOODMAN & CHICK, PC pharmacologically acceptable ester thereof and a pharmaco 220 Fifth Avenue, 16TH Floor logically acceptable salt thereof (for example, olmesartan NEW YORK, NY 10001-7708 medoxomil), the compound having the following formula: (73) Assignee: DAIICHI SANKYO COMPANY., LIMITED, Tokyo (JP) (I) (21) Appl. No.: 12/074,778 (22) Filed: Mar. 6, 2008 Related U.S. Application Data (60) Division of application No. 1 1/484,417, filed on Jul. 11, 2006, which is a continuation of application No. 11/188,275, filed on Jul. 22, 2005, which is a continu ation-in-part of application No. PCT/JP2004/000861, filed on Jan. 29, 2004. N (30) Foreign Application Priority Data N Jan. 31, 2003 (JP) ...... 2003-022990 Y-NH Feb. 7, 2003 (JP) ...... 2003-O3O830 and (B) a calcium channel blocker selected from the group Publication Classification consisting of a 1,4-dihydropyridine compound and a pharma (51) Int. Cl. cologically acceptable Salt thereof (for example, azelnid A6 IK 3/4422 (2006.01) ipine), wherein the composition does not include the combi A6IP 9/12 (2006.01) nation of olmesartan medoxomil and amlodipine or A6IP 9/10 (2006.01) amlodipine besylate. Media 30

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METHODS FOR PREVENTION AND Number 01/76632 Official Gazette, International Publication TREATMENT OF ARTERIOSCLEROSIS, Number 01/74390 Official Gazette, Japanese Patent Publica HYPERTENSION AND RESTENOSIS tion (Kohyo) Number 2002-524408, International Publica tion Number 92/10097 Official Gazette, Japanese Patent Pub CROSS-REFERENCE TO RELATED lication (Kokoku) Number Hei 7-035372, United Kingdom APPLICATIONS Patent Application Publication Number 2268743, Japanese 0001. This application is a divisional application of appli Patent Publication (Kokai) Number Hei 6-56789, Japanese cation Ser. No. 1 1/484,417, filed Jul. 11, 2006, which is a Patent Publication (Kokai) Number Hei 5-155867, United continuation application of application Ser. No. 1 1/188,275, States Patent Application Publication Number 2001/ filed Jul. 22, 2005, which is a continuation-in-part application 0004640, U.S. Pat. No. 6,204.281, Japanese Patent Number 3057471, Japanese Patent Number 2930252, Japanese Patent of International application PCT/JP2004/000861, filed Jan. Publication (Kohyo) Number 2002-507213, Japanese Patent 29, 2004, the entire contents of all of the aforesaid applica Publication (Kohyo) Number 2001-513498, Japanese Patent tions are incorporated by reference herein. Publication (Kohyo) Number 2000-508632, Japanese Patent Publication (Kokoku) Number Hei 7-91299, Japanese Patent BACKGROUND OF THE INVENTION Publication (Kokoku) Number Hei 7-14939, Japanese Patent 0002 1. Field of the Invention Publication (Kokai) Number Hei 6-65207, Japanese Patent 0003. The present invention relates to a medicament for Publication (Kokai) Number Hei 5-213894, Japanese Patent the prophylaxis and/or treatment of arteriosclerosis. In addi Publication (Kohyo) Number 2002-518417, Japanese Patent tion, the present invention relates to a medicament for the Publication (Kohyo) Number 2002-506010, and Japanese prophylaxis and/or medical treatment of diseases such as Patent Publication (Kohyo) Number 2001-522872), and it is hypertension, heart diseases (angina pectoris, myocardial inf disclosed that optimum antihypertensive effects are achieved arction, arrhythmia (including Sudden death), cardiac failure by combined administration of a specific calcium channel or cardiac hypertrophy), renal diseases (diabetic nephropa blocker and a specific angiotensin II receptor antagonist in thy, glomerulonephritis or nephrosclerosis) or cerebrovascu some of these publications described above. However, the lar diseases (cerebral infarction or cerebral hemorrhage). effects of combined administration of a specific angiotensin 0004 2. Background Art II receptor antagonist and a specific calcium channel blocker 0005. Currently, calcium channel blockers and inhibitors of the present invention are not known. of the renin-angiotensin system are widely used clinically for 0008. On the other hand, characteristics of pathological the prophylaxis and treatment of hypertension. Various types changes at the early stages of arteriosclerosis are abnormal of calcium channel blockers are used, and among them 1,4- thickening of the middle arteries or large arteries, and the dihydropyridine derivatives such as amlodipine, benidipine, pathological changes at the early stage of arteriosclerosis are nitrendipine, manidipine, nicardipine, nifedipine, nisol characterized by injury of the endothelium, migration of vas dipine, cilnidipine, lercanidipine, niguldipine, nimodipine, cular smooth muscle cells (VSMC) to the tunica intima of the aranidipine, efonidipine, barnidipine, felodipine, nilvadipine, blood vessels, proliferation of vascular smooth muscle cells, aZelnidipine and the like are long-lasting calcium channel accumulation of lipids within the cells (foam cells), and the blockers and are widely used clinically as first-choice antihy like. In addition, under hypertensive conditions, which are pertensive agents. Furthermore, as inhibitors of the renin associated with progression of arteriosclerosis, it is known angiotensin System, clinical use of angiotensin II receptor that vascular cytoarchitecture is changed by responding to antagonists is growing larger and larger since, first, angio various loading factors to the vessels and remodeling of the tensin II receptor antagonists lack side effects such as cough, vessels occurs. Remodeling of the vessels indicates structural which has been a cause of troubles elicited by angiotensin changes in the vessels caused by hemodynamic changes such converting enzyme (ACE) inhibitors, and second, they exert as changes of blood flow and tension of blood vessel walls. In protective effects on the cardiovascular and renal systems. addition to Substances such as growth factors and cytokines, However, the blood pressure of patients with hypertension vasoactive Substances are Suggested to contribute to the cannot be fully controlled by only one kind of these drugs in development processes. For example, it is known that angio many cases. tensin II facilitates proliferation of vascular smooth muscle 0006. Since calcium channel blockers exert natriuretic cells (Medical Clinics of Japan, Vol. 21, 1924, 1995), and also action in addition to vasodilative action, they are also effec facilitates remodeling of vessels (Journal of Clinical and tive against hypertension caused by retention of fluid (renin Experimental Medicine (IGAKU NO AYUMI), Vol. 193, independent hypertension). On the other hand, angiotensin II 361, 2000). receptor antagonists are particularly effective against renin 0009. However, detailed mechanisms of progression of dependent hypertension, and in addition, they exert excellent arteriosclerosis from pathogenesis to advanced disease are protective activities in several organs. Therefore stable and not sufficiently clarified. In addition, detailed mechanisms of significantantihypertensive effects are expected by combined vascular remodeling are also unknown. Although there are administration of a calcium channel blocker and an angio Some reports describing relationships between angiotensin II tensin II receptor antagonist, no matter what the cause of receptor antagonists and vascular remodeling (Circulation, hypertension. 104, 2716, 2001), the effects of calcium channel blockers on 0007. Many combination drugs comprising a calcium pathological changes in arteriosclerosis and vascular damage channel blocker and an angiotensin II receptor antagonist as well as their mechanisms are littleknown. Furthermore, the have been proposed (for example, International Publication prophylactic and therapeutic effects of combined administra Number 01/15674. Official Gazette, International Publication tion of a calcium channel blocker and an angiotensin II recep Number 01/78699 Official Gazette, International Publication tor antagonist againstarteriosclerosis are little reported, if at Number 02/43807 Official Gazette, International Publication all. Particularly, the effects of calcium channel blockers on US 2008/0176909 A1 Jul. 24, 2008 the renin-angiotensin System and the Synergistic effects of a and the specific angiotensin II receptor antagonist described calcium channel blocker and an angiotensin II receptor above could achieve excellent antihypertensive action. In antagonist are little known, despite the fact that they are addition, the present inventors found that the present medi important Subjects in therapeutic aspects of arteriosclerosis. cament is remarkably effective for the prophylaxis and/or 0010 Furthermore, since percutaneous coronary interven treatment of hypertension, heart diseases angina pectoris, tion (PCI) including percutaneous transluminal coronary myocardial infarction, arrhythmia (including Sudden death), angioplasty (PTCA) and stent implantation have low inva cardiac failure or cardiac hypertrophy, renal diseases (dia siveness, they occupy the central position in current therapeu betic nephropathy, glomerulonephritis or nephrosclerosis) or tic strategies against ischemic heart diseases. However, rest cerebrovascular disorders (cerebral infarction or cerebral enosis appearing within several months after Surgery in hemorrhage). Thus the present invention was completed 30-45% patients undergoing these Surgical procedures is a based on these findings described above. major problem. As for the mechanisms of restenosis follow 0015 The present invention provides a medicament for ing PCI, decreases in the diameters of whole vessels in the late the prevention and/or treatment of arteriosclerosis, compris period after PCI (that is, remodeling) are considered impor ing the following composition: tant, in addition to hyperplasia and hypertrophy of neointima (A) an angiotensin II receptor antagonist selected from the caused by proliferation of Smooth muscle cells and accumu group consisting of a compound having a general formula (I), lation of extracellular matrix, which is produced by the smooth muscle cells (Coronary Intervention, Vol. 1, 12, 2005; Medical Clinics of Japan, Vol. 21, 1924, 1995). Under these (I) circumstances, development of new medicaments that can effectively prevent restenosis of vessels following PCI is CH3 needed. Nevertheless, no medicaments with high efficacy have so far been developed. N OH SUMMARY OF THE INVENTION --> 0011. The subject of the present invention is to provide medicaments for the prevention (the terms “prevention' or “prophylaxis' as used herein include the delaying of the onset of a disease or condition) and/or treatment of arteriosclerosis. More concretely, it is the subject of the present invention to provide medicaments to prevent or to inhibit the proliferation of vascular Smooth muscles and neointima formation in blood vessels. Furthermore, another subject of the present invention N is to provide medicaments that effectively inhibit remodeling Y-NH of vessels and prevent progression of arteriosclerosis as well as restenosis of vessels following PCI. pharmacologically acceptable esters thereof and pharmaco 0012. Furthermore, the other subject of the present inven logically acceptable salts thereof, and tion is to provide medicaments for the prophylaxis or treat ment of hypertension or diseases caused by hypertension. (B) a calcium channel blocker selected from the group con More concretely, the subject is to provide medicaments for sisting of 1,4-dihydropyridine derivatives and pharmacologi the prophylaxis and/or medical treatment of hypertension, cally acceptable salts thereofas active ingredients. heart diseases angina pectoris, myocardial infarction, 0016 Furthermore, from another different point of view of arrhythmia (including Sudden death), cardiac failure or car the present invention, it provides a medicament for the inhi diac hypertrophy, renal diseases (diabetic nephropathy, bition of the proliferation of vascular smooth muscle cells glomerulonephritis or nephrosclerosis) or cerebrovascular comprising the compound (A) and the compound (B) as diseases (cerebral infarction or cerebral hemorrhage) (par active ingredients; a medicament for the inhibition of neoin ticularly medicaments for the prevention or treatment of tima formation in blood vessels comprising the compound hypertension). (A) and the compound (B) as active ingredients; and a medi 0013 The present inventors have fastidiously studied the cament for the inhibition of vascular remodeling comprising subjects described above, and found that combined adminis the compound (A) and the compound (B) as the active ingre tration of a specific calcium channel blocker and a specific dients. These medicaments can be used, for example, as a angiotensin II receptor antagonist potently prevents prolifera prophylactic agent for restenosis following percutaneous tion of vascular Smooth muscle cells as well as neointima coronary intervention. From this point of view, a medicament formation in blood vessels, and that the inhibitory action of for the prevention of restenosis following percutaneous coro the combined administration of the two kinds of agents was nary intervention comprising the compound (A) and the com discovered to be synergistic, and also found that the inhibitory pound (B) is provided by the present invention. action was potently observed at lower doses than their effec 0017. Furthermore, the present invention provides a medi tive doses when they were administered alone. Moreover, the cament for the prevention and/or treatment of hypertension or present inventors found that combined administration as diseases caused by hypertension comprising the following described above remarkably prevented vascular remodeling compounds as active ingredients: and that the medicament effectively inhibited restenosis fol (A) an angiotensin II receptor antagonist selected from the lowing PCI. group consisting of a compound having the formula (I) 0014 Furthermore, the present inventors found that com described above, pharmacologically acceptable esters thereof bined administration of the specific calcium channel blocker and pharmacologically acceptable salts thereof, and US 2008/0176909 A1 Jul. 24, 2008

(B) a calcium channel blocker selected from the group con mals including humans; methods for the inhibition of neoin sisting of 1,4-dihydropyridine derivatives and pharmacologi tima formation of blood vessels, comprising any process of cally acceptable salts thereof, and a medicament for the pre administration of effective doses of said compound (A) and vention and/or treatment of heart diseases angina pectoris, said compound (B) to mammals including humans; methods myocardial infarction, arrhythmia (including Sudden death), for the inhibition of vascular remodeling, comprising any cardiac failure, cardiac hypertrophy and the like, renal dis process of administration of effective doses of said compound eases (diabetic nephropathy, glomerulonephritis, nephroscle (A) and said compound (B) to mammals including humans; rosis and the like), or cerebrovascular disorders (cerebral and methods for the inhibition of restenosis following percu infarction, cerebral hemorrhage and the like comprising the taneous coronary intervention, comprising any process of following compounds as active ingredients: administration of effective doses of said compound (A) and (A) an angiotensin II receptor antagonist selected from the said compound (B) to mammals including humans. Prefer group consisting of a compound having the formula (I) ably, in the present invention the effective dose of each com described above, pharmacologically acceptable esters thereof position comprising the compound (A) and the compound (B) and pharmacologically acceptable salts thereof, and is around the lowest limit or below the lowest limit of the (B) a calcium channel blocker selected from the group con effective dose of the compound (A) or the compound (B) sisting of 1,4-dihydropyridine derivatives and pharmacologi when administered alone. cally acceptable salts thereof. 0022. Furthermore, the present invention provides meth 0018. According to a preferred embodiment of the inven ods for the prophylaxis and/or treatment of hypertension or tion, the medicament described above is provided as a phar diseases caused by hypertension, comprising any process of maceutical composition comprising the compound (A) and administration of effective doses of said compound (A) and the compound (B) as active ingredients. This pharmaceutical said compound (B) to mammals including humans; methods composition may contain one or more excipients for formu for the prophylaxis or treatment of hypertension, comprising lation. According to another preferred embodiment of the any process of administration of effective doses of said com invention, a medicament described above to administer the pound (A) and said compound (B) to mammals including compound (A) and the compound (B) at the same time or humans; methods for the prophylaxis or treatment of heart separately at certain intervals is provided. diseases, comprising any process of administration of effec 0019. Furthermore, according to a more preferred tive doses of said compound (A) and said compound (B) to embodiment of the invention, the medicament described mammals including humans; methods for the prophylaxis or above is provided as a pharmaceutical composition compris treatment of angina pectoris, comprising any process of ing an angiotensin II receptor antagonist and a calcium chan administration of effective doses of said compound (A) and nel blocker, wherein said angiotensin II receptor antagonist is said compound (B) to mammals including humans; methods (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- for the prophylaxis or treatment of myocardial infarction, methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- comprising any process of administration of effective doses yl)methyl)imidazol-5-carboxylate (hereinafter it is referred of said compound (A) and said compound (B) to mammals to as “olmesartan medoxomil in some parts of the present including humans; methods for the prophylaxis or treatment specification) and said calcium channel blocker is any one of arrhythmia, comprising any process of administration of selected from the group of calcium channel blockers com effective doses of said compound (A) and said compound (B) prising (t)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophe to mammals including humans; methods for the prophylaxis nyl)-3,5-pyridine-dicarboxylate-3-(1-diphenylmethylazeti of sudden death, comprising any process of administration of din-3-yl)ester 5-isopropylester (hereinafter it is referred to as effective doses of said compound (A) and said compound (B) “aZelnidipine' in some parts of the present specification); to mammals including humans; methods for the prophylaxis amlodipine, benidipine, nitrendipine, manidipine, nicar or treatment of heart failure, comprising any process of dipine, nifedipine, nisoldipine, cilnidipine, lercanidipine, administration of effective doses of said compound (A) and niguldipine, nimodipine, aranidipine, efonidipine, barnid said compound (B) to mammals including humans; methods ipine, felodipine, and nilvadipine; and the preferred calcium for the prophylaxis or treatment of cardiac hypertrophy, com channel blocker is azelnidipine. prising any process of administration of effective doses of 0020. From another aspect of the present invention, the said compound (A) and said compound (B) to mammals present invention provides the use of an angiotensin II recep including humans; methods for the prophylaxis or treatment tor antagonist selected from the group consisting of a com of renal diseases, comprising any process of administration of pound having the formula (I) described above, pharmacologi effective doses of said compound (A) and said compound (B) cally acceptable esters thereof and pharmacologically to mammals including humans; methods for the prophylaxis acceptable salts thereof to manufacture the medicament or treatment of diabetic nephropathy, comprising any process described above; and the use of a calcium channel blocker of administration of effective doses of said compound(A) and selected from the group consisting of 1,4-dihydropyridine said compound (B) to mammals including humans; methods derivatives and pharmacologically acceptable salts thereof to for the prophylaxis or treatment of glomerulonephritis, com manufacture the medicament described above. prising any process of administration of effective doses of 0021. Furthermore, the present invention provides meth said compound (A) and said compound (B) to mammals ods for the prophylaxis and/or treatment of arteriosclerosis, including humans; methods for the prophylaxis or treatment comprising any process of administration of pharmaceuti of nephrosclerosis, comprising any process of administration cally effective doses of said compound (A) and said com of effective doses of said compound (A) and said compound pound (B) to mammals including humans; methods for the (B) to mammals including humans; methods for the prophy inhibition of the proliferation of vascular smooth muscle laxis or treatment of cerebrovascular diseases, comprising cells, comprising any process of administration of effective any process of administration of effective doses of said com doses of said compound (A) and said compound (B) to mam pound (A) and said compound (B) to mammals including US 2008/0176909 A1 Jul. 24, 2008

humans; methods for the prophylaxis or treatment of cerebral (Kokai) Number Hei5-78328 (U.S. Pat. No. 5,616,599), and infarction, comprising any process of administration of effec the like. The pharmacologically acceptable salts of the com tive doses of said compound (A) and said compound (B) to pound having the formula (I) described above are not specifi mammals including humans; and/or methods for the prophy cally restricted and these salts can be selected by a person laxis or treatment of cerebral hemorrhage, comprising any with an ordinary skill in the art. As pharmacologically accept process of administration of effective doses of said compound able salts of the compound having the formula (I) described (A) and said compound (B) to mammals including humans. above, Such salts are, for example, an alkaline metal salt Such as sodium salt, potassium salt or lithium salt; an alkaline earth BRIEF DESCRIPTION OF THE DRAWINGS metal salt Such as calcium salt or magnesium salt; a metal salt 0023 FIG. 1A and FIG. 1B are graphs which indicate the Such as aluminium salt, iron salt, Zinc salt, copper salt, nickel results for the inhibition of DNA synthesis invascular smooth salt or cobalt salt; an amine Salt such as an ammonium salt, muscle cells by a calcium channel blocker, azelnidipine, at a t-octylamine salt, dibenzylamine salt, morpholine salt, glu dose range of 0.1 to 1.0 mg/kg/day. cosamine salt, phenylglycine alkyl ester salt, ethylenedi 0024 FIG. 2A and FIG. 2B are graphs which show the amine salt, N-methylglucamine salt, guanidine salt, diethy results for inhibition of neointima formation in blood vessels lamine salt, triethylamine salt, dicyclohexylamine salt, N,N'- by a calcium channel blocker, azelnidipine, at a dose range of dibenzylethylenediamine salt, chloroprocaine salt, procaine 0.1 to 1.0 mg/kg/day. salt, diethanolamine salt, N-benzyl-phenethylamine salt, pip 0025 FIG.3A and FIG.3B are graphs which represent the erazine salt, tetramethylammonium salt or tris(hydroxym results for inhibition of DNA synthesis in vascular smooth ethyl)aminomethane salt, but not restricted to these salts. muscle cells by an angiotensin II receptor antagonist, olm Preferably alkaline metal salts can be used, and particularly esartan, at a dose range of 0.5 to 3.0 mg/kg/day. preferably the sodium salt can be used. 0026 FIG. 4A and FIG. 4B are graphs which indicate the 0033. The pharmacologically acceptable esters of the results for inhibition of neointima formation in blood vessels compound having the formula (I) comprise the compound by an angiotensin II receptorantagonist, olmesartan, at a dose having the formula (I) of which a carboxyl moiety is esteri range of 0.5 to 3.0 mg/kg/day. fied. The pharmacologically acceptable esters are not particu 0027 FIG. 5A and FIG. 5B are graphs which show the larly restricted, and can be selected by a person with an results for inhibition of DNA synthesis in vascular smooth ordinary skill in the art. In the case of said esters, it is prefer muscle cells by simultaneous administration of azelnidipine able that such esters can be cleaved by a biological process andolmesartan at doses of 0.1 mg/kg/day and 0.5 mg/kg/day, such as hydrolysis in vivo. The group constituting the said respectively (at which doses they did not elicit any significant esters (the group shown as R when the esters thereof are effects by each of these drugs alone). expressed as —COOR) can be, for example, a C-C alkoxy 0028 FIG.6A and FIG. 6B are graphs which represent the C-C alkyl group such as methoxyethyl, 1-ethoxyethyl, results for inhibition of neointima formation in blood vessels 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxy by simultaneous administration of azelnidipine and olm ethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, esartan at doses of 0.1 mg/kg/day and 0.5 mg/kg/day, respec ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxym tively (at which doses they did not elicitany significant effects ethyl or t-butoxymethyl; a C-C alkoxylated C-C alkoxy by each of these drugs alone). C-C alkyl group such as 2-methoxyethoxymethyl; a Co-Co 0029 FIG. 7 is a graph which indicates the results for aryloxy C-C alkyl group Such as phenoxymethyl; a haloge inhibition of potentiation of DNA synthesis in cultured rat nated C-C alkoxy C-C alkyl group such as 2.2.2-trichlo vascular Smooth muscle cells following stimulation of angio roethoxymethyl or bis(2-chloroethoxy)methyl; a C-C, tensin II receptors by azelnidipine in a concentration-depen alkoxycarbonyl C-C alkyl group Such as methoxycarbon dent manner. ylmethyl; a cyano C-C alkyl group Such as cyanomethyl or 0030 FIG. 8 is a graph which shows the results for sig 2-cyanoethyl, a C-C alkylthiomethyl group Such as meth nificant inhibition of DNA synthesis in cultured vascular ylthiomethyl or ethylthiomethyl; a C-C arylthiomethyl Smooth muscle cells by co-administration of azelnidipine and group Such as phenylthiomethyl or naphthylthiomethyl; a olmesartan at low concentrations, at which concentrations C-C alkylsulfonyl C-C lower alkyl group, which may be they did not elicit any significant effects by each of these optionally substituted with a halogenatom(s) such as 2-meth drugs alone. anesulfonylethyl or 2-trifluoromethanesulfonylethyl; a C-Clo arylsulfonyl C-C, alkyl group such as 2-benzene DETAILED DESCRIPTION OF THE INVENTION sulfonylethyl or 2-toluenesulfonylethyl; a C-C, aliphatic acyloxy C-C alkyl group such as formyloxymethyl, 0031. The medicaments of the present invention are char acetoxymethyl, propionyloxymethyl, butyryloxymethyl, piv acterized by containing (A) an angiotensin II receptorantago aloyloxymethyl, Valeryloxymethyl, isovaleryloxymethyl, nist selected from the group consisting of a compound having hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, the formula (I) described above, pharmacologically accept 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, able esters thereof and pharmacologically acceptable salts 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxy thereof; and (B) a calcium channel blocker selected from the ethyl, 2-formyloxyethyl, 2-acetoxyethyl 2-propionyloxy group consisting of 1,4-dihydropyridine derivatives and phar ethyl, 2-butyryloxyethyl 2-pivaloyloxyethyl, 2-valeryloxy macologically acceptable salts thereof as active ingredients. ethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 0032. The compound having the formula (I) described 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypro above, 4-(1-hydroxy-1-methylethyl)-2-propyl-1-2'-(1H pyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valerylox tetrazol-5-yl)biphenyl-4-yl)methyl)imidazol-5-carboxylic ypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-ac acid is a known compound, and for example, it is easily etoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, obtained by methods disclosed in Japanese Patent Publication 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, US 2008/0176909 A1 Jul. 24, 2008

1-butyryloxypentyl, 1-pivaloyloxypentyl or 1-pivaloyloxy optionally Substituted with a C-C alkyl group(s). Such as a hexyl, a C-C cycloalkylcarbonyloxy C-C alkyl group benzenesulfonate or p-toluenesulfonate; a C-C aliphatic Such as cyclopentylcarbonyloxymethyl, cyclohexylcarbony acid salt such as an acetate, malate, fumarate. Succinate, cit loxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexyl rate, tartrate, oxalate or maleate; oranamino acid salt such as carbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cy a glycine salt, lysine salt, arginine salt, ornithine salt, clohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl glutamic acid salt or aspartic acid salt, and is preferably a or 1-cyclohexylcarbonyloxybutyl; a Co-Co arylcarbonyloxy hydrochloride, nitrate, Sulfate or phosphate, and is particu C-C alkyl group Such as benzoyloxymethyl; a C-C, larly preferably a hydrochloride. alkoxycarbonyloxy C-C alkyl group Such as methoxycar 0035. The angiotensin II receptor antagonist, which is bonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(meth used as the compound (A), is preferably the compound hav oxycarbonyloxy)propyl. 1-(methoxycarbonyloxy)butyl, ing the formula (I) described above or a pharmacologically 1-(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy) acceptable ester thereof, more preferably a pharmacologi hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy) cally acceptable ester of said compound having the formula ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy) (I), and further more preferably a pivaloyloxymethyl ester, butyl, 1-(ethoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy) phthalidyl ester or (5-methyl-2-oxo-1,3-dioxolen-4-yl)me hexyl, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy) thyl ester of the compound having the formula (I). Most ethyl, 1-(propoxycarbonyloxy)propyl. preferably, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1- 1-(propoxycarbonyloxy)butyl, isopropoxycarbonyloxym hydroxy-1-methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl) ethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(isopropoxycarbo biphenyl-4-yl)methyl)imidazol-5-carboxylate can be used. nyloxy)butyl, butoxycarbonyloxymethyl, 1-(butoxycarbony 0036. As the compound selected from the group consist loxy)ethyl, 1-(butoxycarbonyloxy)propyl. ing of a compound having the formula (I) described above, 1-(butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, pharmacologically acceptable esters thereof and pharmaco 1-(isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy) logically acceptable salts thereof, their hydrates or solvates propyl, 1-(isobutoxycarbonyloxy)butyl, t-butoxycarbony can also be used. In the case that the pharmacologically loxymethyl, 1-(t-butoxycarbonyloxy)ethyl, pentyloxycarbo acceptable esters of the compound having the formula (I) are nyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, used. Some esterified compounds may have one or more 1-(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxym asymmetric carbons, but optical isomers purified based on the ethyl, 1-(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbo said asymmetric carbons or Stereoisomers such as diastereoi nyloxy)propyl; a C-C cycloalkyloxycarbonyloxy C-C, Somers or any mixtures of these stereoisomers or racemates alkyl group Such as cyclopentyloxycarbonyloxymethyl, can also be used as the compound (A). 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycar 0037. A calcium channel blocker including 1,4-dihydro bonyloxy)propyl. 1-(cyclopentyloxycarbonyloxy)butyl, pyridine derivatives, which is used as the compound (B), is a cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbo calcium channel blocker characterized by having the 1,4- nyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)propyl or 1-(cy dihydropyridine moiety or chemically equivalent structural clohexyloxycarbonyloxy)butyl; a 5-(C-C alkyl)-2-oxo-1, moiety to the 1,4-dihydropyridine moiety in the molecule. 3-dioxolen-4-yl)methyl group Such as (5-methyl-2-oxo-1,3- Many medicaments are proposed as calcium channel block dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) ers including the 1,4-dihydropyridine derivatives and are methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, actually used clinically, and a person with an ordinary skill in (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl or (5-butyl-2- the art can select any suitable compounds exerting the effects oxo-1,3-dioxolen-4-yl)methyl; a 5-(phenyl, which may be of the present invention. As 1,4-dihydropyridine calcium optionally substituted with a C-C alkyl, C-C alkoxy or channel blockers, for example, azelnidipine, amlodipine, halogen atom(s))-2-oxo-1,3-dioxolen-4-yl)methyl group benidipine, nitrendipine, manidipine, nicardipine, nifedipine, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, 5-(4- nisoldipine, cilnidipine, lercanidipine, niguldipine, nimo methylphenyl)-2-oxo-1,3-dioxolen-4-yl)methyl, 5-(4- dipine, aranidipine, efonidipine, bamidipine, felodipine, or methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl)methyl, 5-(4- nilvadipine can be used, but the scope of the present invention fluorophenyl)-2-oxo-1,3-dioxolen-4-yl)methyl or 5-(4- should not be limited to these calcium channel blockers chlorophenyl)-2-oxo-1,3-dioxolen-4-yl)methyl: O a exemplified. In addition, azelnidipine can be easily manufac phthalidyl group, which may be optionally substituted with a tured according to the methods disclosed in Japanese Patent C-C alkyl or C-C alkoxy group(s), Such as phthalidyl, Publication (Kokai) Number Sho 63-253082 (U.S. Pat. No. dimethylphthalidylor dimethoxyphthalidyl, and is preferably 4,772.596) and the like. Furthermore, amlodipine can be eas a pivaloyloxymethyl group, phthalidyl group or (5-methyl-2- ily manufactured according to the methods disclosed in U.S. oXo-1,3-dioxolen-4-yl)methyl group, and more preferably a Pat. No. 4,572,909 or U.S. Pat. No. 4,879,303. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group. 0038 Since the pharmacologically acceptable salts of 1,4- 0034. In the case that the esters of the compound of for dihydropyridine derivatives are not specifically restricted, mula (I) described above form pharmacologically acceptable any salts thereof can be selected by a person with an ordinary salts, the pharmacologically acceptable salts can be selected skill in the art. The pharmacologically acceptable salts can be by a person with an ordinary skill in the art, and are not acid addition salts or base addition salts. These salts can be, particularly restricted. Such salts can be, for example, a for example, an alkaline metal salt such as a sodium salt, hydrohalogenic acid salt Such as a hydrofluoride, hydrochlo potassium salt or lithium salt; an alkaline earth metal salt Such ride, hydrobromide or hydroiodide; a nitrate; a perchlorate; a as a calcium salt or magnesium salt; a metal salt Such as an Sulfate; a phosphate; a C-C alkanesulfonic acid salt, which aluminum salt, iron salt, Zinc salt, copper salt, nickel Salt or may be optionally Substituted with a halogenatom(s) such as cobalt salt; or a base addition salt, for example, an amine salt a methanesulfonate, trifluoromethanesulfonate or ethane Such as an ammonium salt, t-octylamine salt, dibenzylamine Sulfonate; a Co-Co arylsulfonic acid salt, which may be salt, morpholine salt, glucosamine salt, phenylglycine alkyl US 2008/0176909 A1 Jul. 24, 2008

ester salt, ethylenediamine salt, N-methylglucamine salt, cardiac hypertrophy and the like), renal diseases (diabetic guanidine salt, diethylamine salt, triethylamine salt, dicyclo nephropathy, glomerulonephritis, nephrosclerosis and the hexylamine salt, N,N'-dibenzylethylenediamine salt, chloro like) or cerebrovascular disorders (cerebral infarction, cere procaine salt, procaine salt, diethanolamine salt, N-ben bral hemorrhage and the like), and preferably for the treat Zylphenethylamine salt, piperazine salt, ment. The medicament of the present invention comprising an tetramethylammonium salt or tris(hydroxymethyl)ami angiotensin II receptor antagonist and a calcium channel nomethane salt; oran acid addition salt, for example, a hydro blocker exerts more excellent effects by combined adminis halide such as a hydrofluoride, hydrochloride, hydrobromide tration of an angiotensin II receptor antagonist and a calcium or hydroiodide; a nitrate; a perchlorate; a sulfate; a phosphate: channel blocker than either one of these agents administered a C-C alkanesulfonate, which may be optionally Substituted alone. with a halogen atom(s) such as a methanesulfonate, trifluo 0043. The medicament of the present invention may be romethanesulfonate or ethanesulfonate; a Co-Co arylsul prepared as a pharmaceutical composition (so-called as a fonate, which may be optionally substituted with a C-C, mode of a “combination drug') comprising the compound alkyl group(s) such as a benzenesulfonate or p-toluene (A) and the compound (B) as the active ingredients. For Sulfonate; a C-C aliphatic acid salt Such as an acetate, example, each active ingredient may be mixed together and malate, fumarate. Succinate, citrate, tartrate, oxalate or male may be prepared as a physically single formulation. In addi ate; or an amino acid salt such as a glycine salt, lysine salt, tion, the compound (A) and the compound (B) may be pre arginine salt, ornithine salt, glutamic acid salt or aspartic acid pared separately as an independent formulation and can be salt, but the scope of the present invention should not be provided as a medicament containing a combination of each restricted to these salts described above. mode of formulation. The latter medicament can be used as a 0039. As a calcium channel blocker including 1,4-dihy medicament to administer the compound (A) and the com dropyridine derivatives, hydrates or solvates of the com pound (B) at the same time or separately at certain intervals. pounds described above and pharmacologically acceptable 0044 Administration of the compound (A) and the com salts thereof can be used. In addition, some calcium channel pound (B) “at the same time' described in the present speci blockers including 1,4-dihydropyridine derivatives contain fication includes administration of the compound (A) and the one or more asymmetric carbons in their molecules. In these compound (B) roughly at the same time and not just restricted cases, optical isomers purified based on the asymmetric car to exactly the same time. There is no restriction of the dosage bons or stereoisomers such as diastereoisomers, or any mix form for administration at the same time; for example, it is tures of stereoisomers, or racemates can also be used as the included that either one of the compositions is orally admin compound (B). As the compound (B), (E)-2-amino-1,4-dihy istered and the other composition is non-orally administered. dro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic Nevertheless, it is favourable to prepare the invention as a acid 3-(1-diphenylmethylazetidin-3-yl)ester 5-isopropyl single pharmaceutical composition and to take the both com ester, (R)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)- positions simultaneously. 3.5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidin 0045 Independent administration of the compound (A) 3-yl)ester 5-isopropyl ester, amlodipine besylate, or amlo and the compound (B) “at certain intervals’ described in the dipine maleate is preferred. present specification means that the compound (A) and the 0040. As concretely shown in the Test Examples of the compound (B) described in the present invention are to be present specification, the medicament of the present inven taken independently at different times by administering one tion consisting of the compound (A) and the compound (B) of the active compounds (Compound (A) or Compound (B)) works synergistically and inhibits neointima formation of when the other active compound is in a patient's bloodstream blood vessels and proliferation of vascular smooth muscle and/or is active. The mode of administration for separate cells and, as a result, inhibits vascular remodeling. Based on administration at certain intervals has no restriction. For the actions described above, the medicaments of the present instance, it includes that first an angiotensin II receptor invention can be used for the prophylaxis of restenosis fol antagonist is administered, and then after a certain interval, a lowing percutaneous coronary intervention in addition to the calcium channel blocker is administered, or first a calcium prophylaxis and/or treatment of arteriosclerosis. channel blocker is administered, and then after a certain inter 0041. The medicament of the present invention is charac val, an angiotensin II receptor antagonist is administered, but terized by exerting excellent inhibitory effects on neointima the dosage form has no restriction. formation of blood vessels and proliferation of vascular 0046. The present medicament is manufactured by previ smooth muscle cells due to combined administration of the ously known methods in a suitable dosage form, Such as compound (A) and the compound (B) at their lowest limit tablets, capsules, granules, powders or syrups for oral admin doses or lower than their lowest limit doses of each compo istration, or injections or Suppositories for parenteral admin sition administered alone. Particularly, it is preferable to co istration, by using pharmacologically acceptable and Suitable administer the compound (A) and the compound (B) at low additive agents (carriers) such as excipients, lubricants, bind doses at which no effects are elicited on administration of ers, disintegrants, demulsifiers, stabilizers, flavours, diluents, each composition alone. and the like, if necessary, in addition to the compound (A) and 0042. As concretely shown in Test Examples of the the compound (B), which are the active ingredients, and can present specification, the medicament of the present inven be administered. Since the compound (A) and the compound tion lowers blood pressure more effectively by the synergistic (B) contained in the medicament of the present invention are action of the compound (A) and the compound (B). Based on compounds to be orally administered in general, the medica these actions described above, the medicament of the present ment of the present invention is favourable to be orally admin invention can be used for the prophylaxis and/or treatment of istered. hypertension, heart diseases (angina pectoris, myocardial inf 0047. As “excipients', for instance, organic excipients arction, arrhythmia (including Sudden death), cardiac failure, including Sugar derivatives such as lactose, Sucrose, glucose, US 2008/0176909 A1 Jul. 24, 2008

mannitol or Sorbitol; starch derivatives such as corn starch, depending on the symptoms of the patients can be adminis potato starch, C-Starch or dextrin; cellulose derivatives Such tered. In the case of parenteral administration, 0.00016 mg/kg as crystalline cellulose; gum arabic; dextran; or pullulan; and (preferably 0.00008 mg/kg) as a lower limit and 1.7 mg/kg inorganic excipients including silicate derivatives such as (preferably 0.85 mg/kg) as an upper limit for a mammal, for light anhydrous silicic acid, synthetic aluminium silicate, example, 0.01 mg (preferably 0.05 mg) as a lower limit and calcium silicate or magnesium aluminometasilicate; phos 100 mg (preferably 50 mg) as an upper limit per one time for phates such as calcium hydrogenphosphate; carbonates Such a human adult and one to six times per day depending on the as calcium carbonate; or Sulfates such as calcium sulfate can symptoms of the patients, can be administered. For instance, be used. the dosing ratio of the compound (A) and the compound (B) 0.048. As “lubricants', for instance, stearic acid; metal can range from 1:10000 to 10000:1 in weight ratios, prefer salts of Stearic acid such as calcium Stearate and magnesium ably it can be in the range of 1:1000 to 1000:1, and more Stearate; talc, colloidal silica, waxes such as beeswax and preferably it can be in the range of 1:100 to 100:1 and still spermaceti; boric acid; adipic acid; Sulfates such as sodium more preferably 1:10 to 10:1. Sulfate; glycol, fumaric acid; sodium benzoate; DL-leucine; 0056. When the two active compounds are not adminis laurylsulfates such as Sodium lauryl Sulfate or magnesium tered in the same composition, each active compound should lauryl Sulfate; silicates Such as silicic anhydride and silicic be administered within the dosage ranges and dosing ratios hydrate; or the starch derivatives described above can be used. set forth in the preceding paragraph. 0049. As “binders', for instance, hydroxypropylcellulose, 0057 When the medicament of the present invention is hydroxypropylmethylcellulose, polyvinylpyrrolidone, mac used for the prophylaxis and/or treatment of arteriosclerosis, rogol, or similar excipients to those described above can be it is desirable, in general, that the blood concentration of the used. compound (A) and the compound (B) after administration is 0050. As “disintegrants', for instance, cellulose deriva properly adjusted so as to be around the lowest limit or below tives Such as low-substituted hydroxypropylcellulose, car the lowest limit of the compound (A) or the compound (B) boxymethylcellulose, calcium carboxymethylcellulose or when administered alone. internally crosslinked sodium carboxymethylcellulose; and 0.058 When the medicament of the present invention is chemically modified starch/cellulose derivatives such as car used for the prophylaxis and/or treatment of hypertension, the boxymethylstarch or sodium carboxymethylstarch can be dosage of angiotensin II receptorantagonist can be prescribed used. at lower doses than the dosage of the angiotensin II receptor 0051. As “demulsifiers', for instance, colloidal clay such antagonist when the angiotensin II receptorantagonist is used as bentonite or veegum; metal hydroxides such as magnesium alone as a hypotensive agent, which is its original use, and the hydroxides or aluminium hydroxide; anionic Surfactants such dosage of the angiotensin II receptor antagonist can be enor as Sodium lauryl Sulfate or calcium Stearate; cationic Surfac mously reduced, because excellent antihypertensive action tants such as benzalkonium chloride; or nonionic Surfactants can be achieved by combined administration of an angio Such as polyoxyethylenealkylether, polyoxyethylene Sorbitan tensin II receptor antagonist with a calcium channel blocker. fatty acid ester or Sucrose esters of fatty acids can be used. 0052. As “stabilizers', for instance, p-hydroxybenzoate EXAMPLES esters such as methylparabenor propylparaben; alcohols such 0059. The present invention will be hereinafter described as chlorobutanol, benzyl alcohol orphenylethyl alcohol; ben in more detail by way of the Examples and Test Examples Zalkonium chloride; phenols such as phenol or cresol; thime described below, but the scope of the present invention should rosal; dehydroacetic acid; or Sorbic acid can be used. not be limited to these examples. In the Test Examples, “olm 0053 As “flavours”, for instance, sweeteners such as sac esartan medoxomil is simply called “olmesartan’. charin sodium or aspartame; acidifiers such as citric acid, malic acid or tartaric acid; or flavours such as menthol, lemon Test Example 1 or orange can be used. 0054 As “diluents”, conventionally used diluents, for Inhibitory Effects Against Arteriosclerosis instance, lactose, mannitol, glucose, Sucrose, calcium Sulfate, calcium phosphate, hydroxypropylcellulose, microcrystal (A) Materials and Methods line cellulose, water, ethanol, polyethyleneglycol, propyle (1) Cuff-Induced Vascular Injury Model neglycol, glycerol, starch, polyvinyl-pyrrolidone, magne sium aluminometasilicate or a mixture of these compounds 0060 C57BL/6 mice aged 10 weeks were used. Inapart of can be used. this study, AT1a receptor gene knock out (AT1aKO) mice 0055 Doses of an angiotensin II receptor antagonist (com were also used. Inflammatory vascular damage was induced pound A) and a calcium channel blocker (compound B). in mice by loosely placing a polyethylene tube which was cut which are active ingredients, and their dosing ratio can be longitudinally to open the tube, around the femoral artery of selected in a Suitable manner depending on various factors mice. In the damaged artery, the following observations were Such as the drugs activities and symptoms, age and body determined. The usefulness of this model of vascular damage weight of the patients. Although the total dosage of com to analyze vascular remodeling has been previously reported pound A and compound B combined varies depending on (Physiol. Genomics., 2, pp. 13-30, 2000; Circulation, 104, pp. symptoms, age and the like, in the case of oral administration, 2716-2721, 2001; Circulation, 106, pp. 847-853, 2002). 0.0016 mg/kg (preferably 0.008 mg/kg) as a lower limit and (2) Neointima Formation in the Blood Vessels and DNA 16.7 mg/kg (preferably 8.35 mg/kg) as a lower limit for a Synthesis mammal, for example, 0.1 mg (preferably 0.5 mg) as a lower limit and 1000 mg (preferably 500 mg) as an upper limit per 0061 A paraffin-embedded section of the damaged artery one time for a human adult, and one to six times per day was prepared 14 days after cuff placement, Elastica Van Gie US 2008/0176909 A1 Jul. 24, 2008

son staining was carried out, and the cross-sectional area of vascular Smooth muscle cells following stimulation by angio the neointima and tunica media of the blood vessels was tensin II was suppressed by administration of azelnidipine in determined by image analysis Software. For quantification of a concentration-dependent manner. When low-doses of DNA synthesis, bromodeoxyuridine (BrdU) was injected into aZelnidipine and olmesartan insufficient to elicit any effects the mice 7 days after cuff placement and BrdU index calcu alone were co-administered, DNA synthesis of cultured rat lated from incorporation into the nuclei of the cells was cal vascular Smooth muscle cells was significantly suppressed culated. (FIG. 8). (3) Olmesartan, an AT1 receptor blocker, was intraperito Test Example 2 neally injected into wild-type mice by an osmotic minipump, Antihypertensive Activity and the dose-dependency of olmesartan was investigated as 0063 Surgical operations were carried out in 56 sponta described in (2). Oral administration of azelnidipine to the neously hypertensive rats (SHRs, SPF grade, Breeder: wild-type mice was started after cuff placement, and dose Hoshino Laboratory Animals) aged 20 weeks to implant dependency of azelnidipine was investigated as described in transmitters for recording their blood pressures. After recov (2). ery from the Surgical operations, their blood pressure was (4) Both olmesartan and azelnidipine were simultaneously monitored starting at 24 weeks of age. 0.5% carboxymethyl administered to wild-type mice, and the effects of co-admin cellulose sodium (CMC Na) solution (2 ml/kg) was orally istration of olmesartan and azelnidipine were compared with administered for 7 Successive days (once daily) by a dosing those of administration of either olmesartan or azelnidipine cannula. The animals were divided into 7 groups (8 rats per alone as described in (2). Effects of olmesartan and azelnid group) with homogenous blood pressure in each group-based ipine were investigated at effective doses of either olmesartan on their blood pressure determined on the 5th and 6th days oraZelnidipine alone and at insufficient doses to elicit signifi from initiation of blood pressure monitoring (the constitution cant effects by either olmesartan oraZelnidipine alone, so as of each group is illustrated in Table 1). Then either 0.5% to determine synergistic effects of these two agents. CMC Na Solution (2 ml/kg: control group) or test drug (5) By using cultured rat vascular Smooth muscle cells, the Solution (2 ml/kg) in which the test Substance was suspended effects of co-treatment of olmesartan and azelnidipine on in 0.5% CMC Nasolution was administered from 25 weeks facilitation of DNA synthesis following stimulation by angio of age for 14 Successive days (once daily) and changes in tensin II (determined by incorporation of Hithymidine) blood pressure were observed. Changes in the blood pressure were investigated. of group 6 and group 7 are shown in Table 2. (Values in the tables represent meantS.D.) Excellent antihypertensive (B) Results effects were observed in animals in the group co-adminis 0062 (1) In the cuff-induced vascular damage model of tered olmesartan plus azelnidipine. wild-type mice, DNA synthesis of vascular smooth muscle cells was increased and neointima formation in the blood TABLE 1 vessels was potentiated. These changes were inhibited by Group 1 Control group (0.5% CMC-Nasolution) aZelnidipine in a dose-dependent manner at a dose range of Group 2 Olmesartan medoxomil (0.2 mg/kg) 0.1 to 1.0 mg/kg/day, without any effects on blood pressure Group 3 Olmesartan medoxomil (1.0 mg/kg) Group 4 AZelnidipine (2.0 mg/kg) (FIGS. 1A, 1B, 2A and 2B). In addition, olmesartan exhibited Group 5 AZelnidipine (5.0 mg/kg) similar inhibitory effects in a dose-dependent manner at a Group 6 Olmesartan medoxomil (0.2 mg/kg) + azelnidipine (2.0 mg/kg) dose range of 0.5 to 3.0 mg/kg/day, without any effects on Group 7 Olmesartan medoxomil (1.0 mg/kg) + azelnidipine (5.0 mg/kg) blood pressure (FIGS. 3A, 3B, 4A and 4B). When 0.1 mg/kg/ day of azelnidipine and 0.5 mg/kg/day of olmesartan (both of

TABLE 2 Blood Pressure (minHg Test Substance l 1st Day 2nd Day 5th Day 13th Day Control Group 8 169.2 23.8 167.O. 20.6 1704 21.1 1730 21.2 Group 6 8 1503 - 11.7 14459.8 147.2 10.1. 145.988 Group 7 8 1242. 13.2 122:38.4 127.89.O 1259, 10.0 these drugs did not elicit any significant effects at these doses) Test Example 3 were administered at the same time, the increase in DNA synthesis of vascular Smooth muscle cells and potentiation of Antihypertensive Effects neointima formation in the blood vessels were significantly suppressed (FIGS.5A, 5B, 6A and 6B). From these results, it 0064. Male apolipoprotein E (ApoE) knockout mice aged was clearly demonstrated in vivo that co-administration of 12 weeks were divided into 4 groups (15 mice per group) as aZelnidipine and olmesartan works Synergistically, inhibits following: control group (0.5% carboxymethylcellulose proliferation of the vascular smooth muscle cells and (CMC) Solution administered group), olmesartan medoxomil improves vascular remodeling. (3 mg/kg) administered group, azelnidipine (3 mg/kg) admin (2) The Synergistic action of azelnidipine and olmesartan istered group, and olmesartan medoxomil (3 mg/kg) plus described above was investigated in an in vitro study. As aZelnidipine (3 mg/kg) administered group. Either test Sub shown in FIG. 7, facilitation of DNA synthesis in cultured rat stance or vehicle (0.5% CMC solution) was orally adminis US 2008/0176909 A1 Jul. 24, 2008

tered to animals for 24 Successive weeks. A high fatty diet (containing 0.15% cholesterol and 15% unsalted butter) was given to all mice in all groups following the start of test agent (I) administration (12 weeks of age). The systolic blood pressure of all mice was measured by a non-preheating type blood CH pressure monitor (BP MONITOR FOR RATS & MICE, N OH Model MK-2000, Muromachi Kikai Co., Ltd.) at 21 to 24 hours after drug administration in the 23rd week. The results are shown in Table 3 (values in the table indicate meant S.E.). --> TABLE 3 Systolic blood Administration Group pressures (mmHg) N Control group 1293 Olmesartan medoxomil administered group 1214 N AZelnidipine administered group 1274 Y-NH Olmesartan medoxomil and azelnidipine co- 1123 administered group and (B) a calcium channel blocker selected from the group consisting of a 1,4-dihydropyridine compound and a pharmacologically acceptable salt thereof, with the pro 0065. As the results show above, remarkable hypotensive Viso that the composition does not include the compo effects (p=0.0063; Dunnett's multiple comparison test) were sition wherein the angiotensin II receptor antagonist is observed in the olmesartan medoxomil and azelnidipine co (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hy administered group, at which doses either agent alone did not droxy-1-methylethyl)-2-propyl-1-2'-(1H-tetrazol-5- elicit any significant effects, and the effects elicited by co yl)biphenyl-4-yl)methyl-imidazol-5-carboxylate and administration of olmesartan medoxomil and azelnidipine the calcium channel blocker is amlodipine or amlo were synergistic (p=0.0065; two-way analysis of variance). dipine besylate. 2. The method according to claim 1, wherein the mammal Preparation Example is a human; the angiotensin II receptor antagonist is (5-me thyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-meth 0066 ylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl) methyl)imidazol-5-carboxylate; and a weight ratio of the angiotensin II receptor antagonist to the calcium channel blocker is 1:10 to 10:1. Tablets (Combination Drug) 3. The method according to claim 1, wherein the mammal Olmesartan medoxomil 10.0 mg is a human, the calcium channel blocker is selected from the AZelnidipine 10.0 mg group consisting of azelnidipine, amlodipine, amlodipine Lactose 278.0 mg besylate, benidipine, nitrendipine, manidipine, nicardipine, Corn Starch 50.0 mg nifedipine, nisoldipine, cilnidipine, lercanidipine, nigul Magnesium Stearate 2.0 mg dipine, nimodipine, aranidipine, efonidipine, barnidipine, felodipine and nilvadipine; and a weight ratio of the angio 0067. The powders of above prescription are mixed and tensin II receptor antagonist to the calcium channel blocker is tableted with a tableting machine to prepare a tablet compris 1:10 to 10:1. ing 350 mg of the composition. The tablets can be Sugar 4. The method according to claim 1, wherein the mammal coated, when it is necessary. is a human, the angiotensin II receptor antagonist is (5-me 0068. The medicament of the present invention is useful as thyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-meth a prophylactic and/or therapeutic agent againstarteriosclero ylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl) sis and hypertension. methyl-imidazol-5-carboxylate and the calcium channel blocker is azelnidipine. 5. The method according to claim 4, wherein a weight ratio of the angiotensin II receptor antagonist to the calcium chan What is claimed is: nel blocker is 1:10 to 10:1. 1. A method for the prevention and/or treatment of arterio 6. A method for the prevention and/or treatment of hyper Sclerosis comprising administering to a mammal in need tension comprising administering to a mammal in need thereof a pharmaceutically effective amount of a pharmaceu thereof a pharmaceutically effective amount of a pharmaceu tical composition comprising pharmaceutically effective tical composition comprising pharmaceutically effective amounts of the following active ingredients: amounts of the following active ingredients: (A) an angiotensin II receptor antagonist selected from the (A) an angiotensin II receptor antagonist selected from the group consisting of a compound having a formula (I), a group consisting of a compound having a formula (I), a pharmacologically acceptable ester thereof and a phar pharmacologically acceptable ester thereof and a phar macologically acceptable salt thereof, said compound macologically acceptable salt thereof, said compound having the following formula: having the following formula: US 2008/0176909 A1 Jul. 24, 2008

(A) an angiotensin II receptor antagonist selected from the group consisting of a compound having a formula (I), a (I) pharmacologically acceptable ester thereof and a phar macologically acceptable salt thereof, said compound CH having the following formula: N OH

(I) H3C

fN \ HC N COOH 3 NY-NH

and (B) a calcium channel blocker selected from the group consisting of a 1,4-dihydropyridine compound and a N pharmacologically acceptable salt thereof, with the pro Viso that the composition does not include the compo Y-NH sition wherein the angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hy droxy-1-methylethyl)-2-propyl-1-2'-(1H-tetrazol-5- and (B) a calcium channel blocker selected from the group yl)biphenyl-4-yl)methyl-imidazol-5-carboxylate and consisting of a 1.4-dihydropyridine compound and a the calcium channel blocker is amlodipine or amlo dipine besylate. pharmacologically acceptable salt thereof, with the pro Viso that the composition does not include the compo 7. The method according to claim 6, wherein the mammal sition wherein the angiotensin II receptor antagonist is is a human; the angiotensin II receptor antagonist is (5-me (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hy thyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-meth ylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl) droxy-1-methylethyl)-2-propyl-1-2'-(1H-tetrazol-5- methyl)imidazol-5-carboxylate; and a weight ratio of the yl)biphenyl-4-yl)methyl-imidazol-5-carboxylate and angiotensin II receptor antagonist to the calcium channel the calcium channel blocker is amlodipine or amlo blocker is 1:10 to 10:1. dipine besylate. 8. The method according to claim 6, wherein the mammal 12. The method according to claim 11, wherein the mam is a human; the calcium channel blocker is selected from the mal is a human. group consisting of azelnidipine, amlodipine, amlodipoine 13. The method according to claim 12, wherein the angio besylate, benidipine, nitrendipine, manidipine, nicardipine, tensin II receptor antagonist is (5-methyl-2-oxo-1,3-diox nifedipine, nisoldipine, cilnidipine, lercanidipine, nigul olen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1- dipine, nimodipine, aranidipine, efonidipine, barnidipine, 2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl-imidazol-5- felodipine and nilvadipine; and a weight ratio of the angio carboxylate and the calcium channel blocker is aZelnidipine; tensin II receptor antagonist to the calcium channel blocker is and a weight ratio of the angiotensin II receptor antagonist to 1:10 to 10:1. the calcium channel blocker is 1:10 to 10:1. 9. The method according to claim 6, wherein the mammal 14. A method for the prevention and/or treatment of a is a human, the angiotensin II receptor antagonist is (5-me disease selected from the group consisting of a heart disease, thyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-meth angina pectoris, myocardial infarction, arrhythmia, heart fail ylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl) ure, cardiac hypertrophy, a renal disease, diabetic nephropa methyl-imidazol-5-carboxylate and the calcium channel thy, glomerulonephritis, nephrosclerosis, a cerebrovascular blocker is azelnidipine. disease, cerebral infarction and cerebral hemorrhage com 10. The method according to claim 9, wherein a weight prising administering to a mammal in need thereof a pharma ratio of the angiotensin II receptor antagonist to the calcium ceutically effective amount of a pharmaceutical composition channel blocker is 1:10 to 10:1. comprising pharmaceutically effective amounts of the fol 11. A method for the prevention and/or treatment of a lowing active ingredients: disease caused by hypertension comprising administering to (A) an angiotensin II receptor antagonist selected from the a mammal in need thereof a pharmaceutically effective group consisting of a compound having a formula (I), a amount of a pharmaceutical composition comprising phar pharmacologically acceptable ester thereof and a phar maceutically effective amounts of the following active ingre macologically acceptable salt thereof, said compound dients: having the following formula: US 2008/0176909 A1 Jul. 24, 2008 11

(I) (I)

CH CH N OH -->N OH

NY-NH NY-NH

and (B) a calcium channel blocker selected from the group and (B) a calcium channel blocker selected from the group consisting of a 1,4-dihydropyridine compound and a consisting of a 1,4-dihydropyridine compound and a pharmacologically acceptable salt thereof, with the pro pharmacologically acceptable salt thereof, with the pro Viso that the composition does not include the compo Viso that the composition does not include the compo sition wherein the angiotensin II receptor antagonist is sition wherein the angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hy (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hy droxy-1-methylethyl)-2-propyl-1-2'-(1H-tetrazol-5- droxy-1-methylethyl)-2-propyl-1-2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl-imidazol-5-carboxylate and yl)biphenyl-4-yl)methyl-imidazol-5-carboxylate and the calcium channel blocker is amlodipine or amlo the calcium channel blocker is amlodipine or amlo dipine besylate. dipine besylate. 15. The method according to claim 14, wherein the mam 20. The method according to claim 19, wherein the mam mal is a human and the angiotensin II receptor antagonist is mal is a human and the angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl)imidazol-5-carboxylate. yl)methyl)imidazol-5-carboxylate. 16. The method according to claim 14, wherein the mam 21. The method according to claim 19, wherein the mam mal is a human and the calcium channel blocker is selected mal is a human and the calcium channel blocker is selected from the group consisting of azelnidipine, amlodipine, amlo from the group consisting of azelnidipine, amlodipine, amlo dipine besylate, benidipine, nitrendipine, manidipine, nicar dipine besylate, benidipine, nitrendipine, manidipine, nicar dipine, nifedipine, nisoldipine, cilnidipine, lercanidipine, dipine, nifedipine, nisoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efonidipine, barnid niguldipine, nimodipine, aranidipine, efonidipine, bamid ipine, felodipine and nilvadipine. ipine, felodipine and nilvadipine. 22. The method according to claim 19, wherein the mam 17. The method according to claim 14, wherein the mam mal is a human, the angiotensin II receptor antagonist is mal is a human, the angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl-imidazol-5-carboxylate and the calcium channel yl)methyl-imidazol-5-carboxylate and the calcium channel blocker is azelnidipine. blocker is azelnidipine. 23. The method according to claim 22, wherein a weight 18. The method according to claim 17, wherein a weight ratio of the angiotensin II receptor antagonist to the calcium ratio of the angiotensin II receptor antagonist to the calcium channel blocker is 1:10 to 10:1 channel blocker is 1:10 to 10:1. 24. A method for the inhibition of vascular smooth muscle 19. A method for the prevention of restenosis following cells, the inhibition of neointima formation of blood vessels percutaneous coronary intervention or Sudden death compris or the inhibition of vascular remodeling comprising admin ing administering to a mammal in need thereof a pharmaceu istering to a mammal in need thereof a pharmaceutically tically effective amount of a pharmaceutical composition effective amount of a pharmaceutical composition compris comprising pharmaceutically effective amounts of the fol ing pharmaceutically effective amounts of the following lowing active ingredients: active ingredients: (A) an angiotensin II receptor antagonist selected from the (A) an angiotensin II receptor antagonist selected from the group consisting of a compound having a formula (I), a group consisting of a compound having a formula (I), a pharmacologically acceptable ester thereof and a phar pharmacologically acceptable ester thereof and a phar macologically acceptable salt thereof, said compound macologically acceptable salt thereof, said compound having the following formula: having the following formula: US 2008/0176909 A1 Jul. 24, 2008 12

(I) (I) H3C

and (B) a calcium channel blocker selected from the group consisting of a 1,4-dihydropyridine compound and a and (B) a calcium channel blocker selected from the group pharmacologically acceptable salt thereof, with the pro consisting of a 1,4-dihydropyridine compound and a Viso that the composition does not include the compo pharmacologically acceptable salt thereof, wherein the sition wherein the angiotensin II receptor antagonist is angiotensin II receptor antagonist and the calcium chan (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hy nel blocker are administered separately at the same time droxy-1-methylethyl)-2-propyl-1-2'-(1H-tetrazol-5- or at a certain interval, with the proviso that if the angio yl)biphenyl-4-yl)methyl-imidazol-5-carboxylate and tensin II receptor antagonist is (5-methyl-2-oxo-1,3-di the calcium channel blocker is amlodipine or amlo oxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2- dipine besylate. propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl 25. The method according to claim 24, wherein the mam imidazol-5-carboxylate, then the calcium channel mal is a human and the angiotensin II receptor antagonist is blocker is not amlodipine or amlodipine besylate. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- 30. A method according to claim 29, wherein the mammal methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- is a human and the angiotensin II receptor antagonist is yl)methyl)imidazol-5-carboxylate. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- 26. The method according to claim 24, wherein the mam methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- mal is a human and the calcium channel blocker is selected yl)methyl)imidazol-5-carboxylate. from the group consisting of azelnidipine, amlodipine, amlo 31. The method according to claim 30, wherein the calcium dipine besylate, benidipine, nitrendipine, manidipine, nicar channel blocker is selected from the group consisting of dipine, nifedipine, nisoldipine, cilnidipine, lercanidipine, aZelnidipine, amlodipine, amlodipine besylate, benidipine, niguldipine, nimodipine, aranidipine, efonidipine, bamid nitrendipine, manidipine, nicardipine, nifedipine, nisol ipine, felodipine and nilvadipine. dipine, cilnidipine, lercanidipine, niguldipine, nimodipine, 27. The method according to claim 24, wherein the mam aranidipine, efonidipine, bamidipine, felodipine and nilvad mal is a human, the angiotensin II receptor antagonist is (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- ipine. methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- 32. The method according to claim 29, wherein the mam yl)methyl-imidazol-5-carboxylate and the calcium channel mal is a human, the angiotensin II receptor antagonist is blocker is azelnidipine. (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- 28. The method according to claim 27, wherein a weight methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- ratio of the angiotensin II receptor antagonist to the calcium yl)methyl-imidazol-5-carboxylate and the calcium channel channel blocker is 1:10 to 10:1. blocker is azelnidipine. 29. A method for the prevention and/or treatment of arte 33. A method for the prevention and/or treatment of hyper riosclerosis comprising administering to a mammal in need tension comprising administering to a mammal in need thereof pharmaceutically effective amounts of: thereof pharmaceutically effective amounts of: (A) an angiotensin II receptor antagonist selected from the (A) an angiotensin II receptor antagonist selected from the group consisting of a compound having a formula (I), a group consisting of a compound having a formula (I), a pharmacologically acceptable ester thereof and a phar pharmacologically acceptable ester thereof and a phar macologically acceptable salt thereof, said compound macologically acceptable salt thereof, said compound having the following formula: having the following formula: US 2008/0176909 A1 Jul. 24, 2008 13

(I) (I)

N NY-NH and (B) a calcium channel blocker selected from the group consisting of a 1,4-dihydropyridine compound and a pharmacologically acceptable salt thereof, wherein the and (B) a calcium channel blocker selected from the group angiotensin II receptor antagonist and the calcium chan consisting of a 1,4-dihydropyridine compound and a nel blocker are administered separately at the same time pharmacologically acceptable salt thereof, wherein the or at a certain interval, with the proviso that if the angio angiotensin II receptor antagonist and the calcium chan tensin II receptor antagonist is (5-methyl-2-oxo-1,3-di nel blocker are administered separately at the same time oxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2- or at a certain interval, with the proviso that if the angio propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl tensin II receptor antagonist is (5-methyl-2-oxo-1,3-di imidazol-5-carboxylate, then the calcium channel oxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2- blocker is not amlodipine or amlodipine besylate. propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl 38. The method according to claim 37, wherein the mam imidazol-5-carboxylate, then the calcium channel mal is a human. blocker is not amlodipine or amlodipine besylate. 39. A method for the prevention and/or treatment of a disease selected from the group consisting of a heart disease, 34. The method according to claim 33, wherein the mam angina pectoris, myocardial infarction, arrhythmia, heart fail mal is a human and the angiotensin II receptor antagonist is ure, cardiac hypertrophy, a renal disease, diabetic nephropa (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- thy, glomerulonephritis, nephrosclerosis, a cerebrovascular methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- disease, cerebral infarction and cerebral hemorrhage com yl)methyl)imidazol-5-carboxylate. prising administering to a mammal in need thereof pharma 35. The method according to claim 34, wherein the calcium ceutically effective amounts of: channel blocker is selected from the group consisting of (A) an angiotensin II receptor antagonist selected from the aZelnidipine, amlodipine, amlodipine besylate, benidipine, group consisting of a compound having a formula (I), a nitrendipine, manidipine, nicardipine, nifedipine, nisol pharmacologically acceptable ester thereof and a phar dipine, cilnidipine, lercanidipine, niguldipine, nimodipine, macologically acceptable salt thereof, said compound aranidipine, efonidipine, bamidipine, felodipine and nilvad having the following formula: ipine. (I) 36. The method according to claim 33, wherein the mam H3C mal is a human, the angiotensin II receptor antagonist is 5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl-imidazol-5-carboxylate and the calcium channel blocker is azelnidipine. 37. A method for the prevention and/or treatment of a disease caused by hypertension comprising administering to a mammal in need thereof pharmaceutically effective amounts of: (A) an angiotensin II receptor antagonist selected from the group consisting of a compound having a formula (I), a pharmacologically acceptable ester thereof and a phar macologically acceptable salt thereof, said compound having the following formula: US 2008/0176909 A1 Jul. 24, 2008 14

and (B) a calcium channel blocker selected from the group imidazol-5-carboxylate, then the calcium channel consisting of a 1,4-dihydropyridine compound and a blocker is not amlodipine or amlodipine besylate. pharmacologically acceptable salt thereof, wherein the 44. The method according to claim 43, wherein the mam angiotensin II receptor antagonist and the calcium chan mal is a human and the angiotensin II receptor antagonist is nel blocker are administered separately at the same time (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- or at a certain interval, with the proviso that if the angio methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- tensin II receptor antagonist is (5-methyl-2-oxo-1,3-di yl)methyl)imidazol-5-carboxylate. oxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2- 45. The method according to claim 44, wherein the calcium propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl channel blocker is selected from the group consisting of imidazol-5-carboxylate, then the calcium channel aZelnidipine, amlodipine, amlodipine besylate, benidipine, blocker is not amlodipine or amlodipine besylate. nitrendipine, manidipine, nicardipine, nifedipine, nisol 40. The method according to claim 39, wherein the mam dipine, cilnidipine, lercanidipine, niguldipine, nimodipine, mal is a human and the angiotensin II receptor antagonist is aranidipine, efonidipine, barnidipine, felodipine and nilvad (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- ipine. methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- 46. The method according to claim 43, wherein the mam yl)methyl)imidazol-5-carboxylate. mal is a human, the angiotensin II receptor antagonist is 41. The method according to claim 40, wherein the calcium (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-4-(1-hydroxy-1- channel blocker is selected from the group consisting of aZelnidipine, amlodipine, amlodipine besylate, benidipine, methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- nitrendipine, manidipine, nicardipine, nifedipine, nisol yl)methyl-imidazol-5-carboxylate and the calcium channel dipine, cilnidipine, lercanidipine, niguldipine, nimodipine, blocker is azelnidipine. aranidipine, efonidipine, barnidipine, felodipine and nilvad 47. A method for the inhibition of vascular smooth muscle 1p1.ne. cells, the inhibition of neointima formation of blood vessels 42. The method according to claim 39, wherein the mam or the inhibition of vascular remodeling comprising admin mal is a human, the angiotensin II receptor antagonist is istering to a mammal in need thereofpharmaceutically effec (5-methyl-2 oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- tive amounts of: methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- (A) an angiotensin II receptor antagonist selected from the yl)methyl-imidazol-5-carboxylate and the calcium channel group consisting of a compound having a formula (I), a blocker is azelnidipine. pharmacologically acceptable ester thereof and a phar 43. A method for the prevention of restenosis following macologically acceptable salt thereof, said compound percutaneous coronary intervention or Sudden death compris having the following formula: ing administering to a mammal in need thereof pharmaceuti cally effective amounts of: (A) an angiotensin II receptor antagonist selected from the group consisting of a compound having a formula (I), a pharmacologically acceptable ester thereof and a phar macologically acceptable salt thereof, said compound CH3 having the following formula: N OH (I) HC - CH – N OH N NY-NH and (B) a calcium channel blocker selected from the group N consisting of a 1,4-dihydropyridine compound and a N pharmacologically acceptable salt thereof, wherein the angiotensin II receptor antagonist and the calcium chan Y-NH nel blocker are administered separately at the same time and (B) a calcium channel blocker selected from the group or at a certain interval, with the proviso that if the angio consisting of a 1,4-dihydropyridine compound and a tensin II receptor antagonist is (5-methyl-2-oxo-1,3-di pharmacologically acceptable salt thereof, wherein the oxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2- angiotensin II receptor antagonist and the calcium chan propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl nel blocker are administered separately at the same time imidazol-5-carboxylate, then the calcium channel or at a certain interval, with the proviso that if the angio blocker is not amlodipine or amlodipine besylate. tensin II receptor antagonist is (5-methyl-2-oxo-1,3-di 48. The method according to claim 47, wherein the mam oxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2- mal is a human and the angiotensin II receptor antagonist is propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1- US 2008/0176909 A1 Jul. 24, 2008 15 methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- 50. The method according to claim 47, wherein the mam yl)methyl)imidazol-5-carboxylate. mal is a human, the angiotensin II receptor antagonist is 49. The method according to claim 48, wherein the calcium (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-4-(1-hydroxy-1- channel blocker is selected from the group consisting of aZelnidipine, amlodipine, amlodipine besylate, benidipine, methylethyl)-2-propyl-1-2'-(1H-tetrazol-5-yl)biphenyl-4- nitrendipine, manidipine, nicardipine, nifedipine, nisol- yl)methyl-imidazol-5-carboxylate and the calcium channel dipine, cilnidipine, lercanidipine, niguldipine, nimodipine, blocker is azelnidipine. aranidipine, efonidipine, barnidipine, felodipine, and nilvad ipine. ck