201000097 Λ 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種藥物，其用於預防或治療高血壓、心 臟病（例如心絞痛、心肌梗塞、心率不整（包括猝死）、心臟衰 竭及心肥大）、腎臟病（例如糖尿病腎病、腎小球性腎炎及腎 硬化症）、腦血管疾病（例如大腦梗塞及大腦出血）、及/或血 管疾病（例如動脈硬化症、PTC Α後再狹窄、及末稍血管循環 疾病）。 〇 【先前技術】 現今，血管收縮素II受體阻斷劑及鈣離子通道阻斷劑 廣泛地使用作爲治療或預防高血壓、心臟病等之藥物。血管 收縮素II受體阻斷劑爲一種腎素血管收縮素系統抑制劑， 對於腎素依賴型高血壓特別有效，並且在心血管及腎損傷上 顯示保護效果。此外，由於鈣離子通道阻斷劑除了血管舒張 作用之外具有鈉利尿作用，其亦對於液體滯留性（腎素獨立 型）高血壓有效。因此，若血管收縮素II受體阻斷劑及鈣離 〇 子通道阻斷劑合倂使用，不論疾病之原因可預期到安定及良 好的高血壓治療與預防，因爲除了血管收縮素Π受體阻斷 劑之腎素血管收縮素系統抑制效果之外’在血管平滑肌上鈣 離子通道阻斷效果及鈣離子通道阻斷劑之二次鈉排泄效果 使其可抑制引起高血壓之多重因子。 此外，利尿劑亦廣泛地被使用作爲治療或預防高血壓、 心臟病等之藥物。利尿劑因爲其利尿的效果而有效用於治療 高血壓。因lit，若血管收縮素Π受體阻斷劑及利尿劑合倂 201000097 使用，不論疾病之原因可預期到安定及良好的高血壓治療與 預防，因爲除了血管收縮素II受體阻斷劑之腎素血管收縮 素系統抑制效果之外，利尿劑之利尿效果可抑制引起高血壓 之多重因子。 (5-甲基-2-酮基-1，3-二氧雜環戊烯-4-基）甲基-4-(1-羥 基-1-甲基乙基）-2-丙基-1-[2··(1Η-四唑-5-基）雙苯基-4-基甲 基]咪唑-5-羧酸酯（下文稱爲"奧美沙坦酯"（olmesartan medoxomil))爲一種優異的血管收縮素II受體阻斷劑，且用 〇 於治療或預防高血壓、心臟病等（日本專利第20825 1 9號及 美國專利第5,6 1 6,5 99號）。201000097 Λ VI. Description of the Invention: [Technical Field] The present invention relates to a medicament for preventing or treating hypertension, heart disease (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart Hypertrophy), kidney disease (eg diabetic nephropathy, glomerulonephritis and nephrosclerosis), cerebrovascular disease (eg cerebral infarction and cerebral hemorrhage), and/or vascular disease (eg atherosclerosis, PTC posterior stenosis, And terminal vascular circulation disease). 〇 [Prior Art] Nowadays, angiotensin II receptor blockers and calcium channel blockers are widely used as drugs for treating or preventing hypertension, heart disease and the like. The angiotensin II receptor blocker is a renin-angiotensin system inhibitor, is particularly effective for renin-dependent hypertension, and exhibits a protective effect on cardiovascular and renal damage. In addition, since the calcium channel blocker has a sodium diuretic action in addition to the vasodilating action, it is also effective for liquid retention (renin-independent) hypertension. Therefore, if angiotensin II receptor blockers and calcium-incorporated scorpion channel blockers are used together, stable and good treatment and prevention of hypertension can be expected regardless of the disease, because in addition to angiotensin receptors In addition to the inhibitory effect of the renin-angiotensin system of the blocker, the calcium channel blocking effect on the vascular smooth muscle and the secondary sodium excretion effect of the calcium channel blocker make it possible to suppress multiple factors causing hypertension. In addition, diuretics are also widely used as drugs for treating or preventing hypertension, heart disease and the like. Diuretics are effective for the treatment of hypertension because of their diuretic effect. Because lit, if angiotensin-receptor blocker and diuretic combination 201000097 are used, stable and good treatment and prevention of hypertension can be expected regardless of the disease, because in addition to angiotensin II receptor blocker In addition to the inhibitory effect of the renin-angiotensin system, the diuretic effect of the diuretic inhibits multiple factors that cause hypertension. (5-Methyl-2-keto-1,3-dioxol-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1 -[2··(1Η-tetrazol-5-yl)bisphenyl-4-ylmethyl]imidazole-5-carboxylate (hereinafter referred to as "olmesartan medoxomil) is An excellent angiotensin II receptor blocker for use in the treatment or prevention of hypertension, heart disease, etc. (Japanese Patent No. 20825 19 and U.S. Patent No. 5,61,5,99).
0 奧美沙坦酯 奧美沙坦酯以商品名Olmetec®或Benicar®銷售，其含有 5 mg、10 mg、20 mg或40 mg之奧美沙坦酯作爲活性成分 與低取代羥基丙基纖維素、羥基丙基纖維素、微晶纖維素、 乳糖及硬脂酸鎂作爲添加劑。 3-乙基-5-甲基-(±)-2-[(2-胺基乙氧基）甲基]-4-(2-氯苯 基）-1，4-二氫-6-甲基毗啶-3,5-二竣酸酯（下文稱爲"氨氯地平 "(amlo dipine))爲一種優異的鈣離子通道阻斷劑，且用於治療 或預防高血壓、心臟病等（日本專利第1 40 1 088號及美國專 201000097 利第 4,572,909 號）》0 Olmesartan sulphate is marketed under the trade name Olmetec® or Benicar® and contains 5 mg, 10 mg, 20 mg or 40 mg of olmesartan medoxomil as the active ingredient with low-substituted hydroxypropylcellulose and hydroxyl groups. Propyl cellulose, microcrystalline cellulose, lactose and magnesium stearate are used as additives. 3-ethyl-5-methyl-(±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl Azetidin-3,5-dicaprate (hereinafter referred to as "amlo dipine) is an excellent calcium channel blocker and is used to treat or prevent hypertension, heart disease Etc. (Japanese Patent No. 1 40 1 088 and US Special 201000097 Lei No. 4,572,909)
氨氯地平 氨氯地平以商品名Norvasc®銷售，其含有3.47 mg或 6.93 mg之苯磺酸氨氯地平（2.5 mg或5 mg之氨氯地平）作爲 活性成分，與微晶纖維素、無水磷酸氫鈣、乙醇酸澱粉鈉、 硬脂酸鎂、羥基丙基纖維素、二氧化鈦、滑石及棕櫚蠟作爲 添加劑。 此外，6-氯-3,4-二氫-2H-1，2,4-苯并噻二阱-7-磺醯胺 1,1-二氧化物（下文稱爲"氫氯噻哄"（hydrochlorothiazide))爲Amlodipine amlodipine is marketed under the trade name Norvasc®, which contains 3.47 mg or 6.93 mg of amlodipine besylate (2.5 mg or 5 mg of amlodipine) as the active ingredient, with microcrystalline cellulose, anhydrous phosphoric acid. Hydrogen calcium, sodium starch glycolate, magnesium stearate, hydroxypropyl cellulose, titanium dioxide, talc and palm wax are used as additives. Further, 6-chloro-3,4-dihydro-2H-1,2,4-benzothiazepine-7-sulfonamide 1,1-dioxide (hereinafter referred to as "hydrochlorothiazide"; (hydrochlorothiazide)) is
—種優異之噻畊利尿劑，並被揭露於例如美國專利第 3,025,292 號等。An excellent thief diuretic, and is disclosed, for example, in U.S. Patent No. 3,025,292.
CICI
• NH 〇2 h2no2s 氫氯噻阱 已知一種含奧美沙坦酯及鈣離子通道阻斷劑之藥物（國 際公開第2004/067003號官方公報）及一種含奧美沙坦酯及 利尿劑之藥物（國際公開第2002/041 890號官方公報）。亦已 201000097 知一種含奧美沙坦酯、氨氯地平及氫氯噻阱之固體劑型（國 際公開第 2003/097045號官方公報及國際公開第 2008/032107號官方公報）。然而，本發明之含特定血管收縮 素Π受體阻斷劑（例如奧美沙坦酯）、鈣離子通道阻斷劑及 利尿劑的藥物在高血壓等之顯著效果則爲未知。 【發明內容】 發明目的 本發明之目的在提供一種用於預防及/或治療高血壓或 〇 由高血壓引起之疾病的藥物。更具體而言，本發明之目的在 提供一種藥物’其用於預防或治療高血壓、心臟病（例如心 絞痛、心肌梗塞、心率不整（包括猝死）、心臟衰竭及心肥大）、 腎臟病（例如糖尿病腎病、腎小球性腎炎及腎硬化症）、腦血 管疾病（例如大腦梗塞及大腦出血）、及/或血管疾病（例如動 脈硬化症、PTC A後再狹窄、及末稍血管循環疾病），特別是 用於預防或治療高血壓之藥物。 本發明人現已發現，經由合倂特定血管收縮素II受體 © 阻斷劑、特定鈣離子通道阻斷劑、及特定利尿劑，具有優異 之降血壓效果。此外，本發明人已發現，此藥物對於預防及 /或治療筒血壓、心臟病（例如心絞痛、心肌梗塞、心率不整（包 括猝死）、心臟衰竭及心肥大）、腎臟病（例如糖尿病腎病、腎 小球性腎炎及腎硬化症）、腦血管疾病（例如大腦梗塞及大腦 出血）、及/或血管疾病（例如動脈硬化症、PTCA後再狹窄、 及末稍血管循環疾病）特別有效。基於上述之發現而完成本 發明。 具體而言，本發明提供： 201000097 (1) 一種用於預防或治療高血壓或由高血壓所引起的疾病之 藥物，其包含： (A) —種血管收縮素II受體阻斷劑，其選自具有通式（I)化合 物、• NH 〇2 h2no2s Hydrochlorothiazide is known as a drug containing olmesartan medoxomil and a calcium channel blocker (International Publication No. 2004/067003) and a drug containing olmesartan medoxomil and a diuretic ( International Gazette No. 2002/041 890 Official Gazette). Also known as 201000097 is a solid dosage form containing olmesartan medoxomil, amlodipine and hydrochlorothiazide (Official Gazette of International Publication No. 2003/097045 and International Publication No. 2008/032107). However, the remarkable effects of the drug of the present invention containing a specific angiotensin receptor blocker (e.g., olmesartan medoxomil), a calcium channel blocker, and a diuretic in hypertension and the like are unknown. Disclosure of the Invention Objects of the Invention An object of the present invention is to provide a medicament for preventing and/or treating hypertension or a disease caused by hypertension. More specifically, the object of the present invention is to provide a medicament for preventing or treating hypertension, heart disease (for example, angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart hypertrophy), kidney disease (for example) Diabetic nephropathy, glomerulonephritis and nephrosclerosis, cerebrovascular disease (eg cerebral infarction and cerebral hemorrhage), and/or vascular disease (eg atherosclerosis, restenosis after PTC A, and vascular circulatory disease) Especially for drugs that prevent or treat high blood pressure. The present inventors have now found that there is an excellent blood pressure lowering effect via a combined specific angiotensin II receptor, a blocker, a specific calcium channel blocker, and a specific diuretic. Furthermore, the inventors have found that this drug is useful for preventing and/or treating blood pressure, heart disease (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart hypertrophy), kidney disease (such as diabetic nephropathy, kidney). Small glomerulonephritis and nephrosclerosis, cerebrovascular diseases (such as cerebral infarction and cerebral hemorrhage), and/or vascular diseases (such as atherosclerosis, restenosis after PTCA, and peripheral vascular circulatory disease) are particularly effective. The present invention has been completed based on the above findings. Specifically, the present invention provides: 201000097 (1) A medicament for preventing or treating hypertension or a disease caused by hypertension, comprising: (A) an angiotensin II receptor blocker, Selected from a compound of the formula (I),
(I) 其藥理學上可接受之鹽類、其藥理學上可接受之酯類及該酯 類之其藥理學上可接受之鹽類所組成之群組；及 q (B)至少一種鈣離子通道阻斷劑，其選自由1，4-二氫吡啶衍 生物及其藥理學上可接受之鹽類所組成之群組；及 (C)至少一種利尿劑。 (2) 如（1)之藥物，其中該疾病選自由高血壓、心臟病、心絞 痛、心肌梗塞、心率不整、猝死、心臟衰竭、心肥大、腎臟 病、糖尿病腎病、腎小球性腎炎、腎硬化症、腦血管疾病、 大腦梗塞、大腦出血、血管疾病、動脈硬化症、PTCA後再 狹窄、及末稍血管循環疾病所組成之群組； (3) 如（1)或（2)之藥物，其中該藥物爲包含化合物（A)、化合 201000097 物（B)及化合物（C)作爲活性成分之醫藥組成物； (4) 如（1)或（2)之藥物’其中化合物（A)、化合物（B)及化合物 (C)被同時或以某一時間間隔分開投與； (5) 如（1)至（4)中任一項之藥物，其中該血管收縮素Π受體阻 斷劑爲（5-甲基-2-酮基-1，3-二氧雜環戊烯-4-基）甲基 4-(1· 羥基-1-甲基乙基）-2-丙基-1-[2·-(1Η-四唑-5-基）雙苯基-4_基 甲基]咪唑-5-羧酸酯； (6) 如（1)至（5)中任一者之藥物，其中該鈣離子通道阻斷劑選 〇 自由阿折地平（azelnidipine)、氨氯地平、貝尼地平 (benidipine)、尼群地平（nitrendipine)、馬尼地平 (manidipine)、尼卡第平（nicardipine)、硝苯地平 (nifedipine) 尼索地平（nisoldipine)、西尼地平 (cilnidipine)、樂卡地平（lercanidipine)、尼古地平 (niguldipine)、尼莫地平（nimodipine)、阿雷地平 (aranidipine)、依福地平（efonidipine)、巴尼地平 (barnidipine)、 非洛地平（felodipine)、及尼伐地平 ® (nilvadipine)所組成之群組； (7) 如（1)至（5)中任一項之藥物，其中該鈣離子通道阻斷劑爲 氨氯地平； (8) 如（1)至（7)中任一項之藥物，其中該利尿劑選自由氫氯噻 哄、甲氯噻哄（methyclothiazide)、苯甲基氫氯噻哄 (benzylhydro chlorothiazide) 、 三 氯噻哄 (trichlormethiazide)、環戊噻哄（cyclopenthiazide)、聚噻哄 (polythiazide)、乙噻哄（ethiazide)、環唾哄（cyclothiazide)、 卞氟噻明1 (bendroflumethiazide)、 及氫氟噻哄 201000097 (hydroflumethiazide)所組成之群組； (9) 如（1)至（7)中任一項之藥物，其中該利尿劑爲氫氯噻畊； (10) 如（1)至（9)中任一項之藥物，其中該血管收縮素π受 體阻斷劑爲（5-甲基-2-酮基-1,3-二氧雜環戊烯·4-基）甲基 4-(1-羥基-1-甲基乙基）-2-丙基-1·[2·-(1Η-四唑-5-基）雙苯基 -4-基甲基]咪唑-5-羧酸酯，該鈣離子通道阻斷劑爲氨氯地 平，且該利尿劑爲氫氯噻畊； (Π) 如（1)至（10)中任一項之藥物，其中該藥物爲單一劑 ❹ 型。 此外，本發明提供：化合物（A)、（Β)及（C)在製備上述藥 物上之用途；一種預防或治療（特別是治療）疾病之方法，包 含對有其需要之溫血動物（特別是人類）投與醫藥有效量之 各I匕合物（A)、（Β)及（C)。 根據本發明較佳之具體實施例，上述藥物被提供作爲醫 藥組成物，其含化合物（Α)、化合物（Β)及化合物（C)作爲活性 成分’此醫藥組成物可含有一或多種醫藥可接受性添加劑。 © 由於本發明藥物，即含一種特定血管收縮素II受體阻 斷劑’例如奧美沙坦酯，一種鈣離子通道阻斷劑及一種利尿 劑作爲活性成分之藥物，具有優異之降血壓效果及低毒性， 該藥物使用作爲一種治療物[較佳爲預防或治療藥物（特別 是治療藥物），用於髙血壓、心臟病（例如心絞痛、心肌梗塞、 心率不整（包括猝死）、心臟衰竭及心肥大）、腎臟病（例如糖 尿病腎病、腎小球性腎炎及腎硬化症）、腦血管疾病（例如大 腦梗塞及大腦出血）、及/或血管疾病（例如動脈硬化症、PTC A 後再狹窄、或末稍血管循環疾病）；更佳地，作爲一種用於 201000097 高血壓或心臟病之預防或治療藥物（特別是治療藥物）；且更 佳地，作爲一種用於高血壓之預防或治療藥物（特別是治療 藥物）。此外，上述治療物較佳地用於溫血動物，且更佳地 用於人類。 【實施方式】 本發明藥物之特徵爲含有作爲活性成分之（A)—種血管 收縮素II受體阻斷劑，其選自由通式（I)化合物、其藥理學 上可接受之鹽類、其藥理學上可接受之酯類及該酯類之其藥 0 理學上可接受之鹽類所組成之群組；（B)至少一種鈣離子通 道阻斷劑，其選自由1,4-二氫吡啶衍生物及其藥理學上可接 受之鹽類所組成之群組；及（C)至少一種利尿劑》 上述式（I)化合物[4-(1-羥基-1-甲基乙基）-2-丙基 • 1-[2·-(1Η-四唑-5-基）雙苯基-4-基甲基]咪唑-5-羧酸酯]，其 爲本發明藥物之活性成分，係爲習知且可輕易製備，例如根 據日本專利公開案（特公（平））第5-783 28號等所述之方法。 上述式（I)化合物可根據習知方法以鹼處理，被轉換成所 〇 欲之對應醫藥可接受性鹽類。例如鹽可在溶劑（可使用例如 醚、酯或醇，且較佳可使用醇）中，以適當之鹼於室溫處理5 至30分鐘，然後濾出沉澱結晶或在減壓下餾除溶劑而獲得》 此鹽可例如爲鹼金屬鹽，例如鈉鹽、鉀鹽或鋰鹽；鹼土金屬 鹽，例如鈣鹽或鎂鹽；金屬鹽，例如鋁鹽、鐵鹽、鋅鹽、銅 鹽、鎳鹽或鈷鹽；無機鹽，例如銨鹽；有機鹽，例如t-辛胺 鹽、二苯甲基胺鹽、嗎啉鹽、葡萄糖胺鹽、苯基甘胺酸鹽烷 基酯鹽、乙二胺鹽、N-甲基還原葡糖胺鹽、胍鹽、二乙基胺 鹽、三乙基胺鹽、二環己基胺鹽、Ν，Ν·-二苯甲基乙二胺鹽、 -10- 201000097 氯普魯卡因（chloroprocaine)鹽、普魯卡因鹽、二乙醇胺鹽、 N-苯甲基苯乙基胺鹽、哌阱鹽、四甲基銨鹽、或參（羥基甲基） 胺基甲烷鹽，但並不限於這些鹽類。較佳爲鹼金屬鹽’ I Μ 鈉鹽特佳。 上述式（I)化合物之藥理學上可接受之酯類爲式⑴化合 物中羧基部分被酯化者。藥理學上可接受之酯類並未被特別 限制，且可被熟悉技術者選擇。較佳者爲可被生物方法裂解 之酯類，例如於活體之水解。組成該酯類的基（R所示之基， 0 其中該酯類表示爲-COOR)之基團可爲例如烷氧基 -CrC^烷基，例如甲氧基甲基、1-乙氧基乙基、1-甲基·i-甲氧基乙基、1-(異丙氧基）乙基、2-甲氧基乙基、2-乙氧基 乙基、1，1·二甲基-1-甲氧基甲基、乙氧基甲基、丙氧基甲基、 異丙氧基甲基、丁氧基甲基或t-丁氧基甲基；C^-CU烷氧基 化烷氧基-Ci-C^烷基，例如2-甲氧基乙氧基甲基； C6-C1Q芳氧基-Ci-CU烷基，例如苯氧基甲基；鹵化（^ — (^烷 氧基-CrC4烷基，例如2,2,2-三氯乙氧基甲基或雙（2-氯乙氧 〇 基）甲基；CrC4烷氧基羰基烷基，例如甲氧基羰基甲 基；氰基G-C4烷基，例如氰基甲基或2-氰基乙基；Cl-C4 烷基硫甲基，例如甲基硫甲基及乙基硫甲基；C6-C1()芳基硫 甲基，例如苯基硫甲基或萘基硫甲基；烷基磺醯基 -Ci-C4低烷基，其可任意經鹵原子取代，例如2_甲烷磺醯基 乙基或2-三氟甲烷磺醯基乙基；c6-C1()芳基磺醯基_Cl_C4 院基’例如2 -苯磺醯基乙基或2 -甲苯擴酿基乙基；脂族d-Cv 酿氧基-C1-C4院基’例如甲酿氧基甲基、乙酿氧基甲基、丙 醯氧基甲基、丁醯氧基甲基、三甲基乙醯氧基甲基、戊醯氧 -11 - 201000097 着 基甲基、異戊醯氧基甲基、己醯氧基甲基、1-甲醯氧基乙基、 1-乙醯氧基乙基、1-丙醯氧基乙基、1-丁醯氧基乙基、1-三 甲基乙醯氧基乙基、1-戊醯氧基乙基、1-異戊醯氧基乙基、 1-己醯氧基乙基' 2-甲醯氧基乙基、2-乙醯氧基乙基、2-丙 醯氧基乙基、2-丁醯氧基乙基、2-三甲基乙醯氧基乙基、2-戊醯氧基乙基、2-異戊醯氧基乙基、2-己醯氧基乙基、1-甲 醯氧基丙基' 1-乙醯氧基丙基、1-丙醯氧基丙基、1-丁醯氧 基丙基、1-三甲基乙醯氧基丙基、1-戊醯氧基丙基、1-異戊 〇 醯氧基丙基、1-己醯氧基丙基、1-乙醯氧基丁基、1-丙醯 氧基丁基、1-丁醯氧基丁基、1-三甲基乙醯氧基丁基、1-乙 醯氧基戊基、1-丙醯氧基戊基、1-丁醯氧基戊基、1·三甲基 乙醯氧基戊基或1-三甲基乙醯氧基己基；c5-c6環烷基羰基 氧基-Ci-C^烷基，例如環戊基羰基氧基甲基、環己基羰基氧 基甲基、1-環戊基羰基氧基乙基、1-環己基羰基氧基乙基、 1-環戊基羰基氧基丙基、1-環己基羰基氧基丙基、1-環戊基 羰基氧基丁基或1-環己基羰基氧基丁基；c6-c1()芳基羰基氧 ❹ 基-CPC4烷基，例如苯甲醯氧基甲基；C^-Ce烷氧基羰基氧 基烷基，例如甲氧基羰基氧基甲基、1-(甲氧基羰基氧 基）乙基、1-(甲氧基羰基氧基）丙基、1-(甲氧基羰基氧基）丁 基、1-(甲氧基羰基氧基）戊基、1-(甲氧基羰基氧基）己基、 乙氧基羰基氧基甲基、1-(乙氧基羰基氧基）乙基、1-(乙氧基 羰基氧基）丙基、1-(乙氧基羰基氧基）丁基、1-(乙氧基羰基 氧基）戊基、1-(乙氧基羰基氧基）己基、丙氧基羰基氧基甲 基、1-(丙氧基羰基氧基）乙基、1-(丙氧基羰基氧基）丙基、 1-(丙氧基羰基氧基）丁基、異丙氧基羰基氧基甲基、1-異丙 -12- .201000097 氧基羰基氧基）乙基、ι-(異丙氧基羰基氧基）丁基、丁氧基羰 基氧基甲基、1-( 丁氧基羰基氧基）乙基、1-( 丁氧基羰基氧基） 丙基、1-(丁氧基羰基氧基）丁基、異丁氧基羰基氧基甲基、 1-(異丁氧基羰基氧基）乙基、1-(異丁氧基羰基氧基）丙基、 1-(異丁氧羰基氧基）丁基、t-丁氧基羰基氧基甲基、l-(t-丁 氧基羰基氧基）乙基、戊氧基羰基氧基甲基、1-(戊氧基羰基 氧基）乙基、1-(戊氧基羰基氧基）丙基、己氧基羰基氧基甲 基、1-(己氧基羰基氧基）乙基或1-(己氧基羰基氧基）丙基； Q C5-C6環烷氧基羰基氧基-Ci-CU烷基，例如環戊氧基羰基氧 基甲基、1-(環戊氧基羰基氧基）乙基、1-(環戊氧基羰基氧基） 丙基、1-(環戊氧基羰基氧基）丁基、環己氧基羰基氧基甲基、 1-(環己氧基羰基氧基）乙基、1-(環己氧基羰基氧基）丙基或 1-(環己氧基羰基氧基）丁基；烷基）-2-酮基-1，3-二 氧雜環戊烯-4-基]甲基，例如（5 -甲基-2-酮基-1，3-二氧雜環 戊烯-4-基）甲基、（5-乙基-2-酮基-1,3-二氧雜環戊烯-4-基） 甲基、（5-丙基-2-酮基-1，3-二氧雜環戊烯-4-基）甲基、（5-異 Ο 丙基-2-酮基-1，3-二氧雜環戊烯-4-基）甲基或（5-丁基-2-酮基 -1,3-二氧雜環戊烯-4-基）甲基；[5-(苯基（其可任意經CrCU 烷基、CrG烷氧基、或鹵原子取代）-2-酮基-1，3-二氧雜環 戊烯-4-基]甲基，例如（5-苯基-2-酮基-1,3-二氧雜環戊烯-4-基）甲基、[5-(4-甲基苯基）-2-酮基-1，3-二氧雜環戊烯-4·基] 甲基、[5-(4-甲氧基苯基）-2-酮基-1，3-二氧雜環戊烯-4-基] 甲基、[5-(4-氟苯基）-2-萌基-1,3-二氧雜環戊烯-4-基]甲基或 [5-(4-氯苯基）-2-酮基·1，3-二氧雜環戊烯-4-基]甲基；或酞 基，其可任意經Cl-C4烷基或Ci-C*烷氧基取代，例如酞基、 -13- 201000097 二甲基酞基或二甲氧基酞基。較佳之酯基爲三甲基乙醯氧基 甲基、酞基或（5-甲基-2-酮基-1，3-二氧雜環戊烯-4-基）甲 基，更佳爲（5-甲基-2-酮基-1,3-二氧雜環戊烯-4-基）甲基。 上述式（I)化合物之酯類可根據習知方法以鹼處理，可轉 換成所欲對應醫藥可接受性鹽類(即該酯類之藥理學上可接 受之鹽）。例如，此酯類之鹽類可在溶劑（可使用例如醚、酯 或醇，且較佳可使用醚）中，以適當之鹼於室溫處理5至30 分鐘，然後濾出沉澱結晶或在減壓下餾除溶劑而獲得。此鹽 0 類可例如爲無機酸鹽，例如氫氟酸鹽、氫氯酸鹽、氫溴酸鹽、 氫碘酸鹽、硝酸鹽、過氯酸鹽、硫酸鹽或磷酸鹽；磺酸鹽， 例如甲烷磺酸鹽、三氟甲烷磺酸鹽、乙烷磺酸鹽、苯磺酸鹽 或P-甲苯磺酸鹽；羧酸鹽，例如反丁烯二酸鹽、琥珀酸鹽、 檸檬酸鹽、酒石酸鹽、草酸鹽或順丁烯二酸鹽；或胺基酸鹽， 例如麩胺酸鹽或天冬胺酸鹽。較佳之鹽類爲氫氯酸鹽、硝酸 鹽、硫酸鹽或磷酸鹽，且以氫氯酸鹽特佳。 作爲血管收縮素II受體阻斷劑，其使用作爲化合物 Ο (A)，較佳可使用上述式（I)化合物或其醫藥可接受性酯類。 更佳可使用上述式（I)化合物之醫藥可接受性酯，甚佳可爲上 述式（I)化合物之三甲基乙醯氧基甲基酯、酞基酯或（5-甲基 -2-酮基-1,3-二氧雜環戊烯-4-基）甲基酯。最佳可使用（5-甲基-2-酮基-1，3-二氧雜環戊烯-4-基）甲基 4-(1-羥基-1-甲 基乙基）-2-丙基-1-[2'-(1H-四唑-5-基）雙苯基-4-基甲基]咪唑 -5-羧酸酯（奧美沙坦酯），且其可根據日本專利第2082519號 (美國專利第5,6 16,5 99號）等所述之方法而輕易製備。 作爲選自由上述式（I)化合物、其藥理學上可接受之鹽 -14- 201000097 類、其藥理學上可接受之酯類及該酯類之其藥理學上可接受 之鹽類所組成之群組之化合物，亦可使用其之水合物或溶劑 化物。若使用上述式（I)化合物之藥理學上可接受之酯類，一 些酯化化合物可具有一或多個對掌性碳。亦可使用根據該對 掌性碳之純化的光學異構物，或例如非鏡像異構物之立體異 構物，或任何立體異構物或外消旋物之混合物作爲化合物 (A)。 包括1，4-二氫吡啶衍生物之鈣離子通道阻斷劑，其被使 Q 用作爲化合物（B)’爲一種在分子中具有1，4 -二氫吡啶部分 或其化學等價結構部分爲特徵之鈣離子通道阻斷劑。因爲各 種藥物被建議作爲鈣離子通道阻斷劑，包括1,4-二氫吡啶衍 生物，且事實上被使用於臨床，此項技術中具有通常知識者 可選擇任何適當之化合物而發揮本發明之效果。作爲1,4-二氫吡啶鈣離子通道阻斷劑，可使用例如阿折地平、氨氯地 平、貝尼地平、尼群地平、馬尼地平、尼卡第平、硝苯地平、 尼索地平、西尼地平、樂卡地平、尼古地平、尼莫地平、阿 〇 雷地平、依福地平、巴尼地平、非洛地平或尼伐地平，但本 發明並不限於這些化合物。 1，4-二氫吡啶衍生物之藥理學上可接受之鹽並不受特別 限制，且可被此項技術中具有通常知識者選擇。藥理學上可 接受之鹽可爲酸加成鹽或鹸加成鹽。此鹽類可例如爲鹼加成 鹽，包括鹼金屬鹽，例如鈉鹽、鉀鹽或鋰鹽；鹼土金屬鹽， 例如鈣鹽或鎂鹽；金屬鹽，例如鋁鹽、鐵鹽、綷鹽、銅鹽、 鎳鹽或鈷鹽；無機鹽’例如銨鹽；有機鹽，例如t-辛胺鹽、 二苯甲基胺鹽、嗎啉鹽、葡萄糖胺鹽、苯基甘胺酸鹽烷基酯 -15- 201000097 鹽、乙二胺鹽、N-甲基還原葡糖胺鹽、胍鹽、二乙基胺鹽、 三乙基胺鹽、二環己基胺鹽、N，N，-二苯甲基乙二胺鹽、氯 普魯卡因鹽、普魯卡因鹽、二乙醇胺鹽、N-苯甲基苯乙基胺 鹽、哌阱鹽、四甲基銨鹽、或參（羥基甲基）胺基甲烷鹽；或 酸加成鹽，包括無機酸鹽，例如氫氟酸鹽、氫氯酸鹽、氫溴 酸鹽、氫碘酸鹽、硝酸鹽、過氯酸鹽、硫酸鹽或磷酸鹽；磺 酸鹽’例如甲烷磺酸鹽、三氟甲烷磺酸鹽、乙烷磺酸鹽、苯 磺酸鹽或P-甲苯磺酸鹽；羧酸酯，例如反丁烯二酸鹽、琥珀 〇 酸鹽、檸檬酸鹽、酒石酸鹽、草酸鹽或順丁烯二酸鹽；或胺 基酸鹽’例如麩胺酸鹽或天冬胺酸鹽，但本發明並不限於這 些鹽類。 作爲包括1 ,4-二氫吡啶衍生物之鈣離子通道阻斷劑，亦 可使用上述化合物之水合物或溶劑化物及其藥理學上可接 受之鹽類。此外，包括1，4-二氫吡啶衍生物之鈣離子通道阻 斷劑可具有一或多個對掌性碳。亦可使用根據該對掌性碳之 純化的光學異構物，或例如非鏡像異構物之立體異構物，或 〇 任何立體異構物或外消旋物之混合物作爲化合物（B)。關於 化合物（B)，較佳使用（±)-2-胺基-1，4-二氫-6-甲基- 4-(3-硝基 苯基）-3,5-吡阱二碳酸 3-(1-二苯基甲基氮雜噻阱 (azethizine)-3-基）酯 5-異丙基醋。 作爲包括1，4-二氫吡啶衍生物之鈣離子通道阻斷劑，更 佳地使用氨氯地平。其可根據日本專利第1401088號（美國 專利第4,5 72,909號）等所述之方法輕易製備。氨氯地平可爲 其之藥理學上可接受之鹽，且這些鹽類包含於本發明中。藥 理學上可接受之鹽可爲酸加成鹽或鹼加成鹽。此鹽類可例如 -16- 201000097 爲苯磺酸鹽、氫氯酸鹽、氫溴酸鹽、反丁烯二酸鹽、檸檬酸 鹽、琥珀酸鹽、順丁烯二酸鹽、右旋樟腦磺酸鹽、乳酸鹽、 甲磺酸鹽、菸酸鹽、葡萄糖酸鹽等，但本發明並不限於這些 鹽類，較佳爲使用苯磺酸。 使用作爲化合物（C)之利尿劑爲一習知化合物，且揭示 於例如美國專利第2,554,816號、美國專利第2,980,679號、 美國專利第2,783,241號、英國專利第795,174號、J.Chem. Soc. 1 1 25 ( 1 928)、美國專利第2,835,702號、英國專利第 〇 851,287號、美國專利第3,356,692號、美國專利第3,055,904 號、美國專利第2,976,289號、美國專利第3,058,882號、 Helv. Chim. Acta, 45 , 23 1 6 (1 962) ' Applied Pharmacology, 21，607 (1982)、美國專利第3,183,243號、美國專利第 3,3 60,5 1 8號、美國專利第3,567,777號、美國專利第 3,634,583 號、美國專利第 3,025,292 號、J. Am. Chem. Soc·， 82，1132 (1960)、美國專利第 3，108,097 號、Experientia, 16, 1 1 3 ( 1 960)、J· Org. Chem.，26，2814 (1961)、美國專利第 ® 3,009,9 1 1號、美國專利第3,265,573號、美國專利第 3,254,076號、美國專利第3,255,24 1號、美國專利第 3,75 8,506號、比利時專利第639,386號及美國專利第 3,1 63，645號。利尿劑可爲—種磺醯胺化合物，例如乙醋唑 肢（a c e t a ζ ο 1 a m i d e )、甲醋哩胺（m e t h a z 〇 1 a m i d e )、依索哩胺 (ethoxzolamide) ' 氯非那胺（cl〇fenamide)、雙氯非那胺 (dichlorphenamide)、二磺法胺（disulfamide) ' 美呋西特 (mefruside)、氯噻嗣（chlorthalidone)、唾噻酮 (quinethazone)、咲苯胺酸（fur〇sernide)、氯哌酰胺 -17- 201000097 (clopamide)、曲帕胺（tripamide)、Π引達帕胺（indapamide)、 氯索隆（c 1 o r e χ ο 1 ο n e )、美托拉膝（m e t ο 1 a ζ ο n e )、希帕胺 (xipamide)、布美他尼（bumetanide)、H比略他尼（piretanide) 或X-54 ;噻阱化合物，例如氫氯噻肼、甲氯噻畊、苯甲基氫 氯噻畊、三氯噻畊、環戊噻畊、聚噻畊、乙噻畊、環噻畊、苄 氟噻阱、及氫氟噻畊；苯氧基乙酸化合物，例如依他尼酸 (ethacrynic acid)、替尼酸（tienilic acid)、0 達立酮 (indacrinone)或喹卡醋（quincarbate);三氛蝶陡 ❾ (triamterene);阿米洛利（amiloride)；螺內醋 (spironolactone);坎利酸紳（Potassium canrenoate);及托拉 塞米（torasemide); MK-447;或曲咕諾鈉（traxanox sodium)。 較佳爲噻阱化合物，且更佳爲氫氯噻哄。 氫氯噻畊之化學名稱爲6-氯- 3,4-二氫-2H-1，2,4-苯并噻 二哄-7-磺醯胺1，1-二氧化物，且本發明之氫氯噻阱包括其藥 理學上可接受之鹽類。此鹽類可例如爲氫鹵酸鹽，例如氫氟 酸鹽、氫氯酸鹽、氫溴酸鹽、氫碘酸鹽；硝酸鹽；過氯酸鹽； © 硫酸鹽；磷酸鹽iCi-C4烷磺酸鹽，其可任意經鹵原子取代， 例如甲烷磺酸鹽、三氟甲烷磺酸鹽或乙烷磺酸鹽；C6-C10烯 丙基磺酸鹽’其可任意經C^-C4烷基取代，例如苯磺酸鹽或 p -甲苯磺酸鹽；Ci-C6脂肪酸鹽’例如乙酸鹽、蘋果酸鹽、 反丁嫌二酸鹽、號拍酸鹽、檸檬酸鹽、酒石酸鹽、草酸鹽或 順丁烯二酸鹽；或胺基酸鹽’例如甘胺酸鹽、甜菜鹸鹽、精 胺酸鹽、鳥胺酸鹽、麩胺酸鹽或天冬胺酸鹽。以氫氯酸鹽、 硝酸鹽、硫酸鹽或磷酸鹽較佳，且以氣氯酸鹽爲特佳。 此外’若上述化合物具有一或多個對掌性碳，本發明利 -18- 201000097 尿劑亦包括光學異構物及其混合物。此外，亦包括上述化合 物之水合物。 本發明中’"同時"投與意指化合物（A)、化合物（B)及化 合物（C)大致上被同時投與。在投與之劑型上並無限制，但 以單一劑型投與較佳。 本發明中，"以某一時間間隔分開”投與意指化合物 (A)、化合物（B)及化合物（C)獨自於不同時間投與。在投與之 劑型上並無限制，例如可先投與血管收縮素11受體阻斷劑， 0 然後在某一時間間隔後，可同時投與鈣離子通道阻斷劑及利 尿劑（或其可在某一時間間隔後依序投與）。或者是，可先投 與鈣離子通道阻斷劑或利尿劑，在某一時間間隔後，可以上 述相同方法投與剩餘二種藥物。 如本說明書實施例中清楚所示，本發明藥物因爲合倂化 合物（A)、化合物（B)及化合物（C)之作用，可更有效降低血 壓。根據上述作用，本發明藥物使用作爲預防或治療（尤其 是治療）高血壓、心臟病[例如心絞痛、心肌梗塞、心率不整 © (包括猝死）、心臟衰竭、心肥大]、腎臟病（例如糖尿病腎病、 腎小球性腎炎、腎硬化症）、腦血管疾病（例如大腦梗塞、大 腦出血）、及/或血管疾病（例如動脈硬化症、PTCA後再狹窄、 末稍血管循環疾病）。包含合倂使用之血管收縮素II受體阻 斷劑、鈣離子通道阻斷劑及利尿劑的本發明藥物與個別藥物 單獨投與相較之下，可顯示優異的效果。 包含血管收縮素II受體阻斷劑、鈣離子通道阻斷劑及 利尿劑之本發明藥物可經由分別調配各別藥物，製成數個單 獨之劑型，或經由混合所有藥物，製成單一物理劑型。 -19- 201000097 體劑 受錠 II以 素或 縮與 收投 管別 血個 分被 成可 性劑 活尿 使之利 物物及 藥藥劑 明明斷 發發阻 本本道 於，通 形子 情離 防 預 之 病 疾 述 上 爲 作 用 的錦 物、 藥劑 療斷 治阻 或 顆 ' 囊 膠 型 艮 月 Ρ 等 漿 糖 射 注 或 冒 腸 非 等 劑 ' 接 式齊可 型結上 道黏學 mil 理 藥 等 劑 劑釋 栓形稀 • 陚 、 如劑 例味 ， 用風 式使!!' ’ 劑 法定 方安 知、 習劑 據化 . 根乳 末IMI' 粉劑劑 、 等解 粒此崩 、 劑 滑 Ba， 受之添加劑製備。因爲本發明藥物中化合物（A)、（B)及（C) 一般爲經口投與之藥物，因此本發明藥物以經口投與較爲有 〇 利。 作爲"賦形劑"，可列出的例如爲有機賦形劑，包括糖衍 生物，例如乳糖、蔗糖、葡萄糖、甘露糖醇或山梨糖醇；澱 粉衍生物，例如玉米澱粉、馬鈴薯澱粉、α-澱粉或糊精；纖 維素衍生物，例如結晶纖維素；阿拉伯膠；葡萄聚糖；或普 路蘭（pullulan);及無機賦形劑，包括矽酸鹽衍生物，例如 輕無水矽酸、合成矽酸鋁、矽酸鈣或矽酸鎂鋁；磷酸鹽，例 如磷酸氫鈣；碳酸鹽，例如碳酸鈣；或硫酸鹽，例如硫酸鈣。 〇 作爲"潤滑劑"，可列出的例如爲硬脂酸；硬脂酸之金屬 鹽，例如硬脂酸鈣及硬脂酸鎂；滑石；二氧化矽膠；蠟，例 如蜂蠟及鯨蠟油；硼酸；己二酸；硫酸鹽，例如硫酸鈉；乙 二醇；反丁烯二酸；苯甲酸鈉；DL-白胺酸；月桂基硫酸鹽， 例如月桂基硫酸鈉或月桂基硫酸鎂；矽酸鹽，例如矽酸酐及 矽酸水合物；或上述澱粉衍生物。 作爲"黏結劑"，可列出的例如爲羥基丙基纖維素、羥基 丙基甲基纖維素、聚乙烯吡咯啶酮、聚乙二醇（macrogol)或 上述之類似賦形劑。 -20- 201000097 作爲"崩解劑"，可列出的例如爲纖維素衍生物，例如低 取代羥基丙基纖維素、羧甲基纖維素、羧甲基纖維素鈣或內 交聯羧甲基纖維素鈉；及化學改質澱粉/纖維素衍生物，例 如羧甲基澱粉或羧甲基澱粉鈉。 作爲”乳化劑"可列出的例.如爲黏土膠質，例如膨潤土或 膠狀矽酸鎂鋁（veegum);金屬氫氧化物，例如氫氧化鎂或氫 氧化鋁；陰離子表面活性劑，例如月桂基硫酸鈉或硬脂酸 鈣；陽離子表面活性劑，例如氯化苯二甲烴銨；或非離子性 〇 表面活性劑，例如聚氧乙烯烷醚、聚氧乙烯山梨糖醇酐脂肪 酸酯或脂肪酸之蔗糖酯類。 作爲"安定劑"，可列出的例如爲P-羥基苯甲酸酯類，例 如對羥基苯甲酸甲基酯或對羥基苯甲酸丙基酯；醇類，例如 氯丁醇、苯甲醇或苯乙醇；氯化苯二甲烴銨；酚類，例如酚 或甲酚；硫柳汞（thimerosal);去水乙酸；或山梨酸。 作爲"風味劑”，可列出的例如爲增甜劑，例如糖精鈉或 阿斯巴糖；酸化劑，例如檸檬酸、蘋果酸或酒石酸；或香料， © 例如薄荷醇、檸檬或柳橙。 作爲"稀釋劑"，可列出的例如爲習知所使用之稀釋劑， 例如乳糖、甘露糖醇、葡萄糖、蔗糖、硫酸鈣、磷酸鈣、羥 基丙基纖維素、微晶纖維素、水、乙醇 '聚乙二醇、丙二醇、 甘油、澱粉、聚乙烯吡咯啶酮、矽酸鎂鋁或這些化合物知混 合物。 本發明藥物之活性成分血管收縮素II受體阻斷劑、鈣離 子通道阻斷劑及利尿劑的劑量可根據不同因素以適當方式 選擇，例如藥物之活性及病患之症狀、年齡、及體重。雖然 -21- 201000097 劑量根據症狀、年齡等有所變化，就經口投與而言，對於成 年人一次之最低限制爲0.1 mg(較佳爲0.5 mg)，且最高限制 爲1 000 mg(較佳爲5 00 mg)，且根據病患症狀每日可同時或 間隔投與一至六次。就非經腸胃道投與而言，對於成年人一 次之最低限制爲0.01 mg(較佳爲0.05 mg)，且最高限制爲100 mg(較佳爲50 mg)’且根據病患症狀每日可同時或間隔投與 一至六次。 此外，本發明藥物之活性成分血管收縮素II受體阻斷 〇 劑、鈣離子通道阻斷劑及利尿劑之劑量比例亦可廣泛變化， 但血管收縮素II受體阻斷劑、鈣離子通道阻斷劑及利尿劑 之劑量比例可例如在重量比例1 : 1 0，0 0 0 : 1 - 1 〇，0 0 0至 10,000: 1: 1-10,000 之範圍，且較佳爲 1: 1，000: 1-1，〇〇〇 至 1,000: 1: 1-1，000，且更佳爲 1: 100: 1-100 至 100: 1: 1-100 ° 此外，對於本發明藥物之活性成分，若血管收縮素II 受體阻斷劑爲奧美沙坦酯，鈣離子通道阻斷劑爲氨氯地平且 〇 利尿劑爲氫氯噻阱，劑量可根據不同因素變化，例如藥物之 活性及病患之症狀、年齡、及體重。雖然劑量根據症狀、年 齡等有所變化，若經口投與，對於成年人每次之奧美沙坦酯 之劑量爲5 mg至80 mg(較佳爲10 mg至40 mg)，氣氯地平 (相當於游離基）之劑量爲2.5 mg至20 mg(較佳爲5 mg至1〇 mg)，且氫氯噻畊（相當於游離基）之劑量爲5 mg至50 mg (較 佳爲12.5 mg至25 mg)，且根據病患症狀每日一至六次（較 佳爲每日一次），並可同時或間隔投與。 此外，劑量比例亦可廣泛變化，但奧美沙坦酯、氨氯地 -22- 201000097 平及氫氯噻畊之劑量比例可例如在重量比例1 : 5 0 : 1 - 5 0至 50: 1: 1-50，且較佳爲 1: 10: 1-10 至 10: 1: 1-10。最佳 爲奧美沙坦酯/氨氯地平/氫氯噻阱之劑量比例可爲40 mg/1 0 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 或 20 mg/5 mg/12.5 mg。 在本發明中，於使用血管收縮素II受體阻斷劑或高血 壓之預防或治療的情形，因爲經由合倂使用鈣離子通道阻斷 0 劑及利尿劑的優異效果，可使用比一般單次治療劑量更低之 劑量的血管收縮素II受體阻斷劑。 實施例 本發明於下文中將以下述試驗實施例及製備實施例之 方式更詳細說明，但本發明之範圍不應限於這些實施例。 試驗實施例1:因合倂使用奧美沙坦酯、氨氯地平及氫氯噻 阱之降血壓效果 於20隻雄性SHR(自發高血壓大鼠；SPF級；來源： O Hoshino Laboratory Animals Co·，Ltd.)進行手術植入遙測發 送機以量測血壓（ΤΑ 1 1 PA-C40, Data Sciences，Inc.)。手術復 原後，開始監測血壓。根據量測二日之値，將動物分成五組 (每組四隻），以便各組顯示相似之血壓平均値（組別之組成顯 示於表1)。於36週齡起，將0.5% CMC-Na水溶液（2 mL/kg ; 對照組）或懸浮於0.5% CMC-Na水溶液（2 mL/kg)中之欲測試 物質之溶液，經口投與14日（每日一次），並量測血壓，24 小時內之降血壓範圍値變化顯示於第1圖。 表1 組別組成及投與之欲測試物質 -23- 201000097 Ο(I) a group consisting of a pharmacologically acceptable salt, a pharmacologically acceptable ester thereof, and a pharmacologically acceptable salt of the ester; and q (B) at least one calcium An ion channel blocker selected from the group consisting of a 1,4-dihydropyridine derivative and a pharmacologically acceptable salt thereof; and (C) at least one diuretic. (2) The drug according to (1), wherein the disease is selected from the group consisting of hypertension, heart disease, angina pectoris, myocardial infarction, arrhythmia, sudden death, heart failure, cardiac hypertrophy, kidney disease, diabetic nephropathy, glomerulonephritis, kidney a group consisting of sclerosis, cerebrovascular disease, cerebral infarction, cerebral hemorrhage, vascular disease, arteriosclerosis, restenosis after PTCA, and peripheral vascular circulatory disease; (3) Drugs such as (1) or (2) Wherein the drug is a pharmaceutical composition comprising the compound (A), the compound 201000097 (B) and the compound (C) as an active ingredient; (4) the drug according to (1) or (2) wherein the compound (A), The compound (B) and the compound (C) are administered separately or simultaneously at a time interval; (5) The medicament according to any one of (1) to (4), wherein the angiotensin Π receptor blocker Is (5-methyl-2-keto-1,3-dioxol-4-yl)methyl 4-(1.hydroxy-1-methylethyl)-2-propyl-1 -[2·-(1Η-tetrazol-5-yl) bisphenyl-4-ylmethyl]imidazol-5-carboxylate; (6) The drug according to any one of (1) to (5) Calcium channel blocker 〇Free azelnidipine, amlodipine, benidipine, nitrendipine, manidipine, nicardipine, nifedipine nisol Lidoldipine, cilnidipine, lercanidipine, niguldipine, nimodipine, aranidipine, efenidipine, barnidipine (barnidipine), felodipine, and nilvadipine (nilvadipine); (7) The drug according to any one of (1) to (5), wherein the calcium channel is blocked The drug of any one of (1) to (7), wherein the diuretic is selected from the group consisting of hydrochlorothiazide, methyclothiazide, benzylhydrochlorothiazide (benzylhydro chlorothiazide), trichlormethiazide, cyclopenthiazide, polythiazide, ethiazide, cyclothiazide, bendroflumethiazide And hydrogen fluoride (10) The drug of any one of (1) to (7), wherein the diuretic is hydrochlorothiazide; (10) as (1) to (9) The medicament according to any one of the invention, wherein the angiotensin π receptor blocker is (5-methyl-2-keto-1,3-dioxol-4-yl)methyl 4-( 1-hydroxy-1-methylethyl)-2-propyl-1·[2·-(1Η-tetrazol-5-yl)bisphenyl-4-ylmethyl]imidazole-5-carboxylate The calcium ion channel blocker is amlodipine, and the diuretic is hydrochlorothiazide; (d) The drug according to any one of (1) to (10), wherein the drug is a single agent ❹ type. Further, the present invention provides the use of the compounds (A), (Β) and (C) for the preparation of the above-mentioned medicaments; a method for preventing or treating (in particular for treating) diseases, comprising a warm-blooded animal having a need thereof (special It is human) to administer a therapeutically effective amount of each of the I complexes (A), (Β) and (C). According to a preferred embodiment of the present invention, the above medicament is provided as a pharmaceutical composition comprising a compound (Α), a compound (Β) and a compound (C) as an active ingredient. The pharmaceutical composition may contain one or more pharmaceutically acceptable substances. Sex additives. © The drug of the present invention, that is, a drug containing a specific angiotensin II receptor blocker such as olmesartan medoxomil, a calcium channel blocker and a diuretic as an active ingredient, has an excellent blood pressure lowering effect and Low toxicity, the drug is used as a therapeutic [preferably as a prophylactic or therapeutic drug (especially a therapeutic drug) for blood pressure, heart disease (such as angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart Hypertrophy), kidney disease (eg diabetic nephropathy, glomerulonephritis and nephrosclerosis), cerebrovascular disease (eg cerebral infarction and cerebral hemorrhage), and/or vascular disease (eg atherosclerosis, restenosis after PTC A, Or terminal vascular circulatory disease; more preferably, as a prophylactic or therapeutic drug for 201000097 hypertension or heart disease (especially a therapeutic drug); and more preferably, as a prophylactic or therapeutic drug for hypertension (especially therapeutic drugs). Furthermore, the above therapeutics are preferably used in warm-blooded animals, and more preferably in humans. [Embodiment] The medicament of the present invention is characterized by containing (A) an angiotensin II receptor blocker as an active ingredient, which is selected from the group consisting of a compound of the formula (I), a pharmacologically acceptable salt thereof, a group consisting of a pharmacologically acceptable ester and a pharmaceutically acceptable salt thereof; (B) at least one calcium channel blocker selected from the group consisting of 1,4-two a group consisting of a hydropyridine derivative and a pharmacologically acceptable salt thereof; and (C) at least one diuretic" a compound of the above formula (I) [4-(1-hydroxy-1-methylethyl) -2-propyl•1-[2·-(1Η-tetrazol-5-yl)bisphenyl-4-ylmethyl]imidazol-5-carboxylate], which is an active ingredient of the medicament of the present invention, It is conventional and can be easily prepared, for example, according to the method described in Japanese Patent Laid-Open Publication No. 5-783-28. The compound of the above formula (I) can be converted into a desired pharmaceutically acceptable salt by treatment with a base according to a conventional method. For example, the salt can be treated in a solvent (for example, an ether, an ester or an alcohol, and preferably an alcohol), with a suitable base at room temperature for 5 to 30 minutes, and then the precipitated crystals are filtered off or the solvent is distilled off under reduced pressure. The salt may be, for example, an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; a metal salt such as an aluminum salt, an iron salt, a zinc salt, a copper salt or a nickel salt. Salt or cobalt salt; inorganic salt, such as ammonium salt; organic salt, such as t-octylamine salt, benzhydrylamine salt, morpholine salt, glucosamine salt, phenylglycinate alkyl ester salt, ethylene Amine salt, N-methyl reduced glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, hydrazine, hydrazine-diphenylmethylethylenediamine salt, -10 - 201000097 chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, or ginseng (hydroxymethyl) Aminomethane salts, but are not limited to these salts. Preferably, the alkali metal salt 'I Μ sodium salt is particularly preferred. The pharmacologically acceptable ester of the above compound of the formula (I) is one in which the carboxyl moiety of the compound of the formula (1) is esterified. The pharmacologically acceptable esters are not particularly limited and can be selected by those skilled in the art. Preferred are esters which are cleaved by biological methods, for example, hydrolysis in living organisms. The group constituting the ester group (the group represented by R, wherein 0 the ester is represented by -COOR) may be, for example, an alkoxy-CrC alkyl group such as a methoxymethyl group or a 1-ethoxy group. Ethyl, 1-methyl·i-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1·dimethyl 1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; C^-CU alkoxylation alkoxy-Ci-C^alkyl, such as 2-methoxyethoxymethyl; C6-C1Q aryloxy-Ci-CU alkyl, such as phenoxymethyl; halogenated (^- Oxy-CrC4 alkyl, such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxyanthryl)methyl; CrC4 alkoxycarbonylalkyl, such as methoxycarbonylmethyl Cyano G-C4 alkyl, such as cyanomethyl or 2-cyanoethyl; Cl-C4 alkylthiomethyl, such as methylthiomethyl and ethylthiomethyl; C6-C1() a thiomethyl group, such as phenylthiomethyl or naphthylthiomethyl; alkylsulfonyl-Ci-C4 lower alkyl, which may be optionally substituted with a halogen atom, such as 2-methanesulfonylethyl or 2 -Trifluoro Alkylsulfonylethyl; c6-C1()arylsulfonyl_Cl_C4 ortho', such as 2-phenylsulfonylethyl or 2-toluene, ethyl; aliphatic d-Cv C1-C4 hospital base 'e.g., methoxymethyl, ethoxymethyl, propenoxymethyl, butyloxymethyl, trimethylacetoxymethyl, pentaneoxy-11 - 201000097 着 methyl, isoamyloxymethyl, hexamethyleneoxymethyl, 1-methylmethoxyethyl, 1-ethyloxyethyl, 1-propoxyethyl, 1 - butyloxyethyl, 1-trimethylethoxymethoxyethyl, 1-pentyloxyethyl, 1-isopentyloxyethyl, 1-hexyloxyethyl '2- Methoxyethyl, 2-ethoxymethoxyethyl, 2-propoxycarbonylethyl, 2-butoxycarbonylethyl, 2-trimethylethenyloxyethyl, 2-pentanyl Oxyethyl, 2-isopentyloxyethyl, 2-hexyloxyethyl, 1-methoxypropylpropyl 1-ethyloxypropyl, 1-propoxypropyl , 1-butoxypropyl, 1-trimethylethoxypropyl, 1-pentyloxypropyl, 1-isopentyloxypropyl, 1-hexyloxypropyl 1-Ethyloxybutyl, 1-propoxylated butyl , 1-Butyloxybutyl, 1-trimethylacetoxybutyl, 1-ethenyloxypentyl, 1-propenyloxypentyl, 1-butenoxypentyl, 1 · Trimethylacetoxypentyl or 1-trimethylethoxydecyl; c5-c6 cycloalkylcarbonyloxy-Ci-C^alkyl, such as cyclopentylcarbonyloxymethyl, ring Hexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1 - cyclopentylcarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl; c6-c1()arylcarbonyloxyindenyl-CPC4 alkyl, such as benzamidineoxymethyl; C^-Ce alkane Oxycarbonylcarbonyloxyalkyl, such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(methoxy Carbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy) Ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)pentyl 1-(ethoxycarbonyloxy)hexyl, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)propyl, 1-( Propoxycarbonyloxy)butyl, isopropoxycarbonyloxymethyl, 1-isopropyl-12-.201000097 oxycarbonyloxy)ethyl, i-(isopropoxycarbonyloxy)butyl , butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)butyl, Isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)butyl , t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl, pentoxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1 -(pentyloxycarbonyloxy)propyl, hexyloxycarbonyloxymethyl, 1-(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyloxy)propyl; Q C5- C6 cycloalkoxycarbonyloxy-Ci-CU alkyl, such as cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)B , 1-(cyclohexyloxycarbonyloxy)propyl or 1-(cyclohexyloxycarbonyloxy)butyl;alkyl)-2-keto-1,3-dioxolane- 4-yl]methyl, for example (5-methyl-2-keto-1,3-dioxol-4-yl)methyl, (5-ethyl-2-keto-1, 3-dioxol-4-yl)methyl, (5-propyl-2-keto-1,3-dioxol-4-yl)methyl, (5-isoindole) Propyl-2-keto-1,3-dioxol-4-yl)methyl or (5-butyl-2-keto-1,3-dioxol-4- Methyl); [5-(phenyl (which may be optionally substituted by CrCU alkyl, CrG alkoxy, or halogen atom)-2-keto-1,3-dioxol-4-yl a methyl group such as (5-phenyl-2-keto-1,3-dioxol-4-yl)methyl, [5-(4-methylphenyl)-2-keto -1,3-dioxol-4yl]methyl, [5-(4-methoxyphenyl)-2-keto-1,3-dioxol-4- Methyl, [5-(4-fluorophenyl)-2-enyl-1,3-di Heterocyclopenten-4-yl]methyl or [5-(4-chlorophenyl)-2-keto-1,3-dioxol-4-yl]methyl; or fluorenyl, It may be optionally substituted by a Cl-C4 alkyl group or a Ci-C* alkoxy group, for example, a fluorenyl group, a -13-201000097 dimethyl fluorenyl group or a dimethoxy fluorenyl group. A preferred ester group is trimethylacetoxymethyl, decyl or (5-methyl-2-keto-1,3-dioxol-4-yl)methyl, more preferably (5-Methyl-2-keto-1,3-1,3-dioxol-4-yl)methyl. The ester of the compound of the above formula (I) can be treated with a base according to a conventional method and can be converted into a desired pharmaceutically acceptable salt (i.e., a pharmacologically acceptable salt of the ester). For example, the salt of the ester can be treated in a solvent (for example, an ether, an ester or an alcohol, and preferably an ether), with a suitable base at room temperature for 5 to 30 minutes, and then the precipitated crystals are filtered off or It was obtained by distilling off a solvent under reduced pressure. The salt class 0 can be, for example, a mineral acid salt such as a hydrofluoric acid salt, a hydrochloric acid salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a perchlorate salt, a sulfate salt or a phosphate salt; For example, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, besylate or P-tosylate; carboxylates such as fumarate, succinate, citrate , tartrate, oxalate or maleate; or an amine salt such as glutamate or aspartate. Preferred salts are hydrochlorides, nitrates, sulfates or phosphates, and are particularly preferred as the hydrochloride. As the angiotensin II receptor blocker, which is used as the compound Ο (A), a compound of the above formula (I) or a pharmaceutically acceptable ester thereof can be preferably used. More preferably, a pharmaceutically acceptable ester of the compound of the above formula (I) can be used, and it is preferably a trimethyl ethoxymethyl ester, a decyl ester or a (5-methyl-2) compound of the above formula (I). - Keto-1,3-dioxol-4-yl)methyl ester. Most preferably (5-methyl-2-keto-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propene 1-[2'-(1H-tetrazol-5-yl)bisphenyl-4-ylmethyl]imidazole-5-carboxylate (olmesartan), and it can be used according to Japanese Patent No. 2082519 It is easily prepared by the method described in the above (U.S. Patent No. 5,6,5,599). And the pharmacologically acceptable salt selected from the group consisting of the compound of the above formula (I), the pharmacologically acceptable salt thereof-14-201000097, the pharmacologically acceptable ester thereof, and the ester thereof The compounds of the group may also be used as hydrates or solvates thereof. If a pharmacologically acceptable ester of a compound of the above formula (I) is used, some of the esterified compounds may have one or more pairs of palmitic carbon. As the compound (A), an optical isomer according to the purification of the palmitic carbon, or a stereoisomer such as a non-image isomer, or a mixture of any stereoisomer or racemate can also be used. a calcium ion channel blocker comprising a 1,4-dihydropyridine derivative, which is used as a compound (B) as a compound having a 1,4-dihydropyridine moiety or a chemically equivalent moiety thereof in a molecule A calcium ion channel blocker characterized. Since various drugs are suggested as calcium ion channel blockers, including 1,4-dihydropyridine derivatives, and are actually used in the clinic, one of ordinary skill in the art can select any suitable compound to exert the present invention. The effect. As the 1,4-dihydropyridine calcium ion channel blocker, for example, adipine, amlodipine, benidipine, nitrendipine, manidipine, nicardipine, nifedipine, nisoldipine can be used. , cilnidipine, lercanidipine, nicotipine, nimodipine, azuridine, effluentine, bainidipine, felodipine or nilvadipine, but the invention is not limited to these compounds. The pharmacologically acceptable salt of the 1,4-dihydropyridine derivative is not particularly limited and can be selected by those having ordinary knowledge in the art. The pharmacologically acceptable salt may be an acid addition salt or a hydrazine addition salt. Such salts may, for example, be base addition salts, including alkali metal salts such as sodium, potassium or lithium salts; alkaline earth metal salts such as calcium or magnesium salts; metal salts such as aluminum, iron, barium salts, a copper salt, a nickel salt or a cobalt salt; an inorganic salt such as an ammonium salt; an organic salt such as t-octylamine salt, benzhydrylamine salt, morpholine salt, glucosamine salt, phenylglycinate alkyl ester -15- 201000097 Salt, ethylenediamine salt, N-methyl reduced glucosamine salt, sulfonium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N, - diphenyl Ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, or hydroxymethyl group An aminomethane salt; or an acid addition salt, including a mineral acid salt such as a hydrofluoric acid salt, a hydrochloric acid salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a perchlorate salt, a sulfate salt or a phosphoric acid salt a salt; a sulfonate such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, besylate or P-toluenesulfonate; a carboxylate such as fumarate, amber Tannic acid A salt, a citrate, a tartrate, an oxalate or a maleate; or an amine salt such as a glutamate or an aspartate, but the invention is not limited to these salts. As the calcium ion channel blocker including the 1,4-dihydropyridine derivative, a hydrate or a solvate of the above compound and a pharmacologically acceptable salt thereof can also be used. Further, the calcium ion channel blocker comprising a 1,4-dihydropyridine derivative may have one or more pairs of palmitic carbon. As the compound (B), an optical isomer according to the purification of the palmitic carbon, or a stereoisomer such as a non-image isomer, or a mixture of any stereoisomer or racemate may also be used. As the compound (B), (±)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridin dicarbonate 3 is preferably used. -(1-Diphenylmethyl azathiazide (azethizine-3-yl) ester 5-isopropyl vinegar. As the calcium ion channel blocker including the 1,4-dihydropyridine derivative, amlodipine is more preferably used. It can be easily prepared according to the method described in Japanese Patent No. 1401088 (U.S. Patent No. 4,5,72,909). Amlodipine may be a pharmacologically acceptable salt thereof, and these salts are included in the present invention. The pharmaceutically acceptable salt may be an acid addition salt or a base addition salt. This salt may, for example, be -16- 201000097 is a besylate, a hydrochloride, a hydrobromide, a fumarate, a citrate, a succinate, a maleate, a dextran A sulfonate, a lactate, a methanesulfonate, a nicotinate, a gluconate or the like, but the present invention is not limited to these salts, and benzenesulfonic acid is preferably used. The use of the diuretic as the compound (C) is a conventional compound, and is disclosed in, for example, U.S. Patent No. 2,554,816, U.S. Patent No. 2,980,679, U.S. Patent No. 2,783,241, British Patent No. 795,174, J. Chem. Soc. 1 25 (1 928), U.S. Patent No. 2,835,702, British Patent No. 851,287, U.S. Patent No. 3,356,692, U.S. Patent No. 3,055,904, U.S. Patent No. 2,976,289, U.S. Patent No. 3,058,882, Helv. Chim. Acta, 45, 23 1 6 (1 962) 'Applied Pharmacology, 21, 607 (1982), U.S. Patent No. 3,183,243, U.S. Patent No. 3,3,60,5,8, U.S. Patent No. 3,567,777, U.S. Patent No. 3,634,583 U.S. Patent No. 3,025,292, J. Am. Chem. Soc., 82, 1132 (1960), U.S. Patent No. 3,108,097, Experientia, 16, 1 1 3 (1 960), J. Org. Chem., 26,2814 (1961), U.S. Patent No. 3,009,9,1, U.S. Patent No. 3,265,573, U.S. Patent No. 3,254,076, U.S. Patent No. 3,255,241, U.S. Patent No. 3,75,506, and Belgian Patent No. 639,386 and the United States The first 3,1 No. 63,645. The diuretic can be a sulfonamide compound such as aceta ζ ο 1 amide, methaz 〇1 amide, ethoxzolamide 'clofenacamine (cl〇) Fenamide), dichlorphenamide, disulfamide 'mefruside', chlorthalidone, quinethazone, fur〇sernide ,lpiperamide-17- 201000097 (clopamide), tripamide, indapamide, cloxarone (c 1 ore χ ο 1 ο ne ), metopula knee (met ο 1 a ζ ο ne ), xipamide, bumetanide, H pitatanide or X-54; a tweezers compound such as hydrochlorothiazide, methyl chloride, benzene Methyl hydrochlorothiazide, triclosan, cyclopentanyl, polythiolin, ethidium, cyclosalt, benzyl fluorothiazide, and hydrofluorothiazepine; phenoxyacetic acid compounds, such as itani Ethacrynic acid, tienilic acid, indacrinone or quincarbate; Am (triamterene); amiloride; spironolactone; Potassium canrenoate; and torasemide; MK-447; or traxanox sodium ). It is preferably a sulfur trap compound, and more preferably hydrochlorothiazide. The chemical name of hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiazepine-7-sulfonamide 1,1-dioxide, and the present invention Hydrochlorothiazide includes its pharmacologically acceptable salts. The salt may, for example, be a hydrohalide salt such as a hydrofluoric acid salt, a hydrochloride, a hydrobromide salt, a hydroiodide salt; a nitrate; a perchlorate; a sulfate; a phosphate iCi-C4 alkane a sulfonate, which may be optionally substituted by a halogen atom, such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; C6-C10 allylsulfonate, which may be optionally subjected to C^-C4 alkane Substituted, for example, besylate or p-toluenesulfonate; Ci-C6 fatty acid salt such as acetate, malate, butyl succinate, citrate, citrate, tartrate, grass An acid salt or a maleate; or an amino acid salt such as a glycinate, a beet salt, a arginine, an alanate, a glutamate or an aspartate. It is preferably a hydrochloride, a nitrate, a sulfate or a phosphate, and particularly preferably a chlorate. Further, if the above compound has one or more pairs of palmitic carbons, the urinary -18-201000097 urine of the present invention also includes optical isomers and mixtures thereof. Further, hydrates of the above compounds are also included. In the present invention, 'simultaneous" administration means that the compound (A), the compound (B) and the compound (C) are substantially simultaneously administered. There is no restriction on the dosage form to be administered, but it is preferred to administer it in a single dosage form. In the present invention, "separate at a certain time interval" means that the compound (A), the compound (B) and the compound (C) are administered alone at different times. There is no limitation on the dosage form to be administered, for example, First administered with angiotensin 11 receptor blocker, 0 and then at a certain time interval, can simultaneously be administered with calcium channel blockers and diuretics (or they can be administered sequentially after a certain time interval) Alternatively, the calcium channel blocker or diuretic may be administered first, and after a certain time interval, the remaining two drugs may be administered in the same manner as described above. As clearly shown in the examples of the present specification, the drug of the present invention is The action of the combined compound (A), the compound (B) and the compound (C) can lower the blood pressure more effectively. According to the above effects, the medicament of the present invention is used as a prophylactic or therapeutic (especially treatment) hypertension, heart disease [such as angina pectoris) , myocardial infarction, heart rate irregularity (including sudden death), heart failure, heart hypertrophy], kidney disease (such as diabetic nephropathy, glomerulonephritis, nephrosclerosis), cerebrovascular disease (such as cerebral infarction, brain Blood), and/or vascular disease (eg, arteriosclerosis, restenosis after PTCA, vascular circulatory disease). Angiotensin II receptor blockers, calcium channel blockers, and diuretics The drug of the present invention can exhibit excellent effects as compared with the individual drug alone. The drug of the present invention comprising an angiotensin II receptor blocker, a calcium channel blocker and a diuretic can be separately formulated. Do not use drugs, make a few separate dosage forms, or make a single physical dosage form by mixing all the drugs. -19- 201000097 The body agent is in the form of a soluble agent. Urine makes the things and medicines of the spleen and the dysfunction of the dysentery and the dysfunction of the dysentery and the dysfunction of the disease. Equilibrium sugar injection or non-injection of eczema ' 接 齐 可 可 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上 上Fang Anzhi, a habit According to the chemical, the root emulsion IMI' powder agent, etc., the granules, the granules, and the granules Ba, are prepared by the additives. Because the compounds (A), (B) and (C) in the medicament of the invention are generally administered orally. The drug, therefore, the drug of the present invention is more profitable by oral administration. As "excipient", for example, organic excipients including sugar derivatives such as lactose, sucrose, glucose, and nectar can be listed. Sugar alcohol or sorbitol; starch derivatives such as corn starch, potato starch, alpha-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; or pullulan; And inorganic excipients, including phthalate derivatives such as light anhydrous citric acid, synthetic aluminum citrate, calcium citrate or magnesium aluminum silicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; Salt, such as calcium sulfate. 〇 as "lubricants" may, for example, be stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; cerium oxide; waxes such as beeswax and cetyl wax Oil; boric acid; adipic acid; sulfate, such as sodium sulfate; ethylene glycol; fumaric acid; sodium benzoate; DL-leucine; lauryl sulfate, such as sodium lauryl sulfate or magnesium lauryl sulfate; a citrate such as phthalic anhydride and citric acid hydrate; or the above starch derivative. As "bonding agent", for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol or the like can be listed. -20- 201000097 As "disintegrating agent", for example, cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internal cross-linking carboxy can be listed. Sodium methylcellulose; and chemically modified starch/cellulose derivatives such as carboxymethyl starch or sodium carboxymethyl starch. Examples of "emulsifiers" can be listed, such as clay gums, such as bentonite or gelatinous veegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants, for example Sodium lauryl sulfate or calcium stearate; cationic surfactants such as ammonium benzyl chloride; or nonionic cerium surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters Or sucrose esters of fatty acids. As "stabilizer", for example, P-hydroxybenzoic acid esters such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; alcohols, for example, Chlorobutanol, benzyl alcohol or phenylethyl alcohol; ammonium benzyl chloride; phenols such as phenol or cresol; thimerosal; dehydrated acetic acid; or sorbic acid. For example, a sweetener such as sodium saccharin or aspartame; an acidulant such as citric acid, malic acid or tartaric acid; or a perfume, such as menthol, lemon or orange. As "diluent", for example, diluents conventionally used, such as lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, may be listed. Water, ethanol 'polyethylene glycol, propylene glycol, glycerin, starch, polyvinylpyrrolidone, magnesium aluminum silicate or a mixture of these compounds. The dosage of the active ingredient of the medicament of the present invention, angiotensin II receptor blocker, calcium channel blocker and diuretic, can be selected according to various factors, such as the activity of the drug and the symptoms, age, and body weight of the patient. . Although the dose of-21-201000097 varies depending on symptoms, age, etc., for oral administration, the minimum limit for adults is 0.1 mg (preferably 0.5 mg) and the maximum limit is 1 000 mg (compared to Preferably, it is 500 mg), and it can be administered one to six times at the same time or at intervals depending on the symptoms of the patient. For parenteral administration, the minimum limit for adults is 0.01 mg (preferably 0.05 mg) and the maximum limit is 100 mg (preferably 50 mg) and can be daily depending on the patient's symptoms. At the same time or at intervals of one to six times. In addition, the dose ratio of angiotensin II receptor blocker, calcium channel blocker and diuretic of the active ingredient of the medicament of the present invention may also vary widely, but angiotensin II receptor blocker and calcium ion channel The dose ratio of the blocker and the diuretic can be, for example, in the range of weight ratio 1: 1 0, 0 0 0: 1 - 1 〇, 0 0 0 to 10,000: 1: 1-10,000, and preferably 1:1. 000: 1-1, 〇〇〇 to 1,000: 1: 1-1,000, and more preferably 1: 100: 1-100 to 100: 1: 1-100 ° Further, for the active ingredient of the medicament of the present invention, If the angiotensin II receptor blocker is olmesartan medoxomil, the calcium channel blocker is amlodipine and the loop diuretic is hydrochlorothiazide, the dosage may vary depending on various factors, such as the activity of the drug and the patient. Symptoms, age, and weight. Although the dosage varies depending on the symptoms, age, etc., if administered orally, the dose of olmesartan medoxomil is 5 mg to 80 mg (preferably 10 mg to 40 mg) per hour for adults, and clopidogrel ( The dose equivalent to the free radical is 2.5 mg to 20 mg (preferably 5 mg to 1 mg), and the dose of hydrochlorothiazide (equivalent to the free radical) is 5 mg to 50 mg (preferably 12.5 mg) Up to 25 mg), and one to six times per day (preferably once daily) depending on the symptoms of the patient, and may be administered simultaneously or at intervals. In addition, the dose ratio can also vary widely, but the dose ratio of olmesartan medoxomil, amlodipine-22-201000097 and hydrochlorothiazide can be, for example, in a weight ratio of 1: 5 0 : 1 - 5 0 to 50: 1: 1-50, and preferably 1:10: 1-10 to 10: 1: 1-10. The optimal dose ratio of olmesartan medoxomil / amlodipine / hydrochlorothiazide can be 40 mg / 10 mg / 12.5 mg, 40 mg / 5 mg / 12.5 mg, 40 mg / 5 mg / 25 mg, 40 Mg/10 mg/25 mg, 20 mg/10 mg/12.5 mg or 20 mg/5 mg/12.5 mg. In the present invention, in the case of using an angiotensin II receptor blocker or prevention or treatment of hypertension, since the calcium ion channel is used to block the excellent effects of the agent and the diuretic, the ratio can be used. A second dose of angiotensin II receptor blocker at a lower dose. EXAMPLES The present invention will hereinafter be described in more detail in the following Experimental Examples and Preparation Examples, but the scope of the present invention should not be construed as limited to the Examples. Test Example 1: Blood pressure lowering effect of olmesartan medoxomil, amlodipine and hydrochlorothiazide in combination with 20 male SHRs (spontaneously hypertensive rats; SPF grade; source: O Hoshino Laboratory Animals Co., Ltd.) surgically implanted a telemetry transmitter to measure blood pressure (ΤΑ 1 1 PA-C40, Data Sciences, Inc.). After the surgery was resumed, blood pressure monitoring began. Animals were divided into five groups (four in each group) after two days of measurement, so that each group showed a similar mean blood pressure (the composition of the group is shown in Table 1). At the age of 36 weeks, a 0.5% CMC-Na aqueous solution (2 mL/kg; control group) or a solution of the substance to be tested suspended in 0.5% CMC-Na aqueous solution (2 mL/kg) was orally administered. Day (once a day), and blood pressure is measured, and the blood pressure drop range within 24 hours is shown in Figure 1. Table 1 Composition of the group and the substance to be tested -23- 201000097 Ο
組 別 1 對 照 組 (0.5% CMC-Na 7jc 溶液） 組 別 2 奧 美 沙 坦酯（0· 1 mg/kg) 組 別 3 氨 氯 地 平（1 mg/kg)(投與爲苯磺酸氨氯地平） 組 別 4 氫 氯 噻 哄（1 0 mg/kg) 組 別 5 奧 美 沙 坦醋（0.1 mg/kg) +氣氣地平 （1 mg/kg) (投與爲苯磺酸氨氯地平） +氫氯噻明：(10 mg/kg) 於 共 同 投 與 奧 美 沙坦酯+氨氯地平+ 氫氯噻畊之組別中，可在 動 物 中 觀 察 到 優 異的降血壓效果。 製 備 實 施例 1 錠 劑 (組合藥物） RSn 奥 美 沙 坦 酯 4 0.0 mg 氨 氯 地 平 13.89 mg 氫 氯 噻 阱 12.50 mg α- .澱 粉 1 0 5.00 mg 結 晶 纖 維 素 112.41 mg 羧 甲 基 纖 維 素 鈉 15.00 mg 硬 脂 酸 鎂 1.20 mg 混合上述配方之粉末，使用製錠機壓製成錠劑，製成每 錠3 00 mg之錠劑。如果需要，可以糖衣塗布錠劑。 產業可利用性 根據本發明，可獲得用於預防或治療高血壓或由高血壓 引起之疾病之藥物。更具麗而言，可獲得用於預防及/或治 療高血壓、心臟病[例如心絞痛、心肌梗塞、心率不整（包括 猝死）、心臟衰竭及心肥大]、腎臟病（例如糖尿病腎病、腎小 -24- 201000097 球性腎炎及腎硬化症）、腦血管疾病（例如大腦梗塞及大腦出 血）、及/或血管疾病（例如動脈硬化症、PTCA後再狹窄、及 末梢血管循環疾病）之藥物。 【圖式簡單說明】 第1圖顯示24小時內之降血壓範圍値變化。 【主要元件符號說明】 無。Group 1 Control group (0.5% CMC-Na 7jc solution) Group 2 Olmesartan medoxomil (0·1 mg/kg) Group 3 Amlodipine (1 mg/kg) (administered as ammonia benzenesulfonate) Level 4 Group 4 Hydrochlorothiazepine (10 mg/kg) Group 5 Olmesartan vinegar (0.1 mg/kg) + gas-level level (1 mg/kg) (administered as amlodipine besylate) +Hydroxychlorothiazide: (10 mg/kg) Excellent antihypertensive effect was observed in animals in the group co-administered with olmesartan medoxomil + amlodipine + hydrochlorothiazide. Preparation Example 1 Lozenges (combination drugs) RSn Olmesartan 40.0 mg Amlodipine 13.89 mg Hydrochlorothiazide 12.50 mg α-. Starch 1 0 5.00 mg Crystalline cellulose 112.41 mg Carboxymethylcellulose sodium 15.00 mg Magnesium stearate 1.20 mg The powder of the above formula was mixed and compressed into a tablet using a tablet machine to prepare a tablet of 300 mg per tablet. If desired, the tablet can be coated with a sugar coating. Industrial Applicability According to the present invention, a medicament for preventing or treating hypertension or a disease caused by hypertension can be obtained. More beautifully, it can be used to prevent and/or treat high blood pressure, heart disease [eg angina pectoris, myocardial infarction, arrhythmia (including sudden death), heart failure and heart hypertrophy], kidney disease (eg diabetic nephropathy, small kidney) -24- 201000097 globular glomerulonephritis and nephrosclerosis), cerebrovascular diseases (such as cerebral infarction and cerebral hemorrhage), and/or vascular diseases (such as atherosclerosis, restenosis after PTCA, and peripheral vascular circulatory diseases). [Simple description of the diagram] Figure 1 shows the change in blood pressure range within 24 hours. [Main component symbol description] None.
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