TWI373335B - Pharmaceutical composition for therapeutic treatment of arteriosclerosi and hypertension - Google Patents
Pharmaceutical composition for therapeutic treatment of arteriosclerosi and hypertension Download PDFInfo
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- TWI373335B TWI373335B TW093102081A TW93102081A TWI373335B TW I373335 B TWI373335 B TW I373335B TW 093102081 A TW093102081 A TW 093102081A TW 93102081 A TW93102081 A TW 93102081A TW I373335 B TWI373335 B TW I373335B
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Classifications
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Landscapes
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- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
1373335 修正本 玖、發明說明 【發明所屬之技術領域】 本發明爲有關預防及/或治療動脈硬化之醫藥。 又本發明爲有關預防及/或治療高血壓症，心臓疾病[心絞 痛，心肌梗塞，心律不整（包括猝死），心臟衰竭或心肥大]， 腎臓疾病（糖尿病性腎症，腎小球腎炎或腎硬化症）或腦血管 性疾病（腦梗塞或腦出血）之醫藥。 【先前技術】 現在，鈣拮抗劑及腎酵素·血管緊縮素系之抑制藥在臨床 泛用於高血壓之治療及預防之醫藥。鈣拮抗劑有種種系列之 藥劑使用，尤其 1,4-二氫吡啶系化合物之氨氯地平 (amlodipine)， SU 尼地平（benidipine)，尼妥聯地平 (nitrendipine) > 嗎尼地平（manidipine)，尼卡地平 (nicardipine) > 尼費地平（nifedipine)，尼索地平 (nisoldipine)，西路尼地平（cilnidipine)，列卡尼地平 (lercanidipine)，尼克地平（nigludipine)，尼莫地平 (nimodipine)，阿拉尼地平（aranidipine)，也何尼地平 (efonidipine)，巴路尼地平（balnidipine)，飛洛地平 (felodipine)，尼巴地平（nilvadipine)，及阿折地平 (azelnidipine)等爲持續性之鈣拮抗劑，當作高血壓症之第一 選擇藥在臨床汎用。至於腎酵素血管緊縮素系之抑制藥，以 血管緊縮素Π受體拮抗劑無見諸從來之血管緊縮素變換酵 素（ACE)抑制劑之咳等副作用，且對心血管或腎臓之障害有 保護效果而使用擴大。但，這些既存之1種藥劑不能將患者 1373335 修正本 之血壓充分控制。 鈣拮抗劑不只有血管擴張作用，且有鈉利尿作用，故對體 液貯留性（腎酵素非依存性）高血壓也有效。又，血管緊縮素 II受體拮抗劑對腎酵素依存性高血壓特別有效，且有優異之 臓器保護效果效果。故藉鈣拮抗劑與血管緊縮素II受體拮 抗劑之併用，不拘高血壓之病因，可期待安定且充分之降壓 治療。
將鈣拮抗劑及血管緊縮素II受體拮抗劑組合之醫藥有種種 提案（例如，國際公開第01/15674號手冊，國際公開第 01/78699號手冊，國際公開第〇2M3 807號手冊，國際公開 第01/76632號手冊，國際公開第01/74390號手冊，特表 2002-5 244 08號公報，國際公開第92/10097號手冊，特公平 7-03 5 3 72號公報，英國專利申請公開2268743號說明書，特 開平6-56789號公報，特開平5-155867號公報，美國專利 申請公開第2001/0004640號說明書，美國專利第620428 1 號說明書，專利第305747 1號公報，專利第2930252號公報， 特表1002-5 07 213號公報，特表2001-513498號公報，特表 2000-508632號公報，特公平7-91299號公報，特公平7-14939 號公報，特開平6-65207號公報，特開平5-2 1 3 894號公報， 特表2002-5 18417號公報，特表2002-506010號公報，及特 表2001 -522872號公報），這些中若干刊行物揭示由兩者之 組合，達成更所望降壓作用。但從未知將本發明之特定之血 管緊縮素II受體拮抗劑與特定之鈣拮抗劑倂用之例。 一方面，動脈硬化之初期病變之特徵爲在中或大動脈之病 1373335 修正本 的内膜肥厚，内皮傷害，血管平滑肌細胞（VSMC)往内膜遊 走與增殖，及往細胞内之脂質蓄積（泡沫細胞）等。又在與動 脈硬化之進展相關之高血壓等之病態，已知與血管相關之種 種負荷反應而血管壁之細胞構築變化，起血管之再造。血管 再造乃指對血流量變化及血管壁張力之變化等血行動態變 化所致之血管構造上之變化。暗示在此過程，除成長因子及 細胞激動素等物質之外，血管激動物質也參與。例如，屬於 内皮由來之血管收縮因子之血管緊縮素II對血管平滑肌細 胞有增殖促進作用（臨床醫，Vol.21,1 924,1 995)，但已知係對 再造有促進作用之物質（醫學之進步，.V〇 1.1 93,36 1，2000)。 尤其，由動脈硬化之發生進展之機制仍未充分解明，血管 再造之機制也甚多不明。血管緊縮素II受體拮抗劑與血管 再造之關連雖有報告（Circulation，1 04,27 1 6,2001)，但有關鈣 拮抗劑予以動脈硬化性病變予血管傷害之影響及機制殆無 解明，對由鈣拮抗劑與血管緊縮素II受體拮抗劑之組合之 動脈硬化之預防及治療效果殆無報告。尤其，鈣拮抗劑之作 用與腎酵素一血管緊縮素系之相關及兩藥劑效果之相乘 性，則在治療面雖也爲重要問題，仍多未明。 又以經皮冠狀動脈形成術（PTC A)及支架術爲首之冠狀動 脈介入（PCI)因其低侵襲性，故現在之虛血性心疾病之治療 佔有中心地位，術後數個月個以30〜45 %之比例發生再狹窄 造成問題。PCI後之再狹窄之機序，除平滑肌細胞群之增殖 及由這些産生之細胞外基質蓄積所致之新生内膜之增生及 肥厚之外，遠隔期之全血管徑之縮小（即再造）受重視 1373335 修正本 (Coronary Intervention, Vo 1 .1,12; 臨 床 醫，Vol.2 1,1 924,1 995)。在此狀況下，殷望開發能有效預防 PCT後之血管再狹窄之醫藥，但仍未開發高效發揮之藥劑。 【發明內容】 本發明之課題爲提供預防及/或治療動脈硬化之醫藥。更具 體而言，提供能抑制血管平滑肌增殖及新生内膜形成之醫藥 爲本發明之課題。又，本發明之另一課題爲提供有效抑制血 管再造，預防動脈硬化之進展及PCI後之再狹窄之醫藥。 又，本發明之另一課題爲提供預防或治療高血壓症或高血 壓症由來之疾病之醫藥。更具體而言爲提供預防及/或治療 高血壓症，心臓疾病[心絞痛，心肌梗塞，心律不整（包括猝 死），心臟衰竭或心肥大]，腎臓疾病（糖尿病性腎症，腎小球 腎炎或腎硬化症）或腦血管性疾病（腦梗塞或腦出血）之醫藥 (尤其預防或治療高血壓症之醫藥）。 本發明者爲解決上述課題而致力硏究之結果，發現將特定 之鈣拮抗劑與特定之血管緊縮素II受體拮抗劑予以組合， 強力抑制可血管平滑肌增殖及新生内膜形成，及達成其抑制 作用兩者呈相乘作用’以少於兩者各別有效用量呈現優異之 抑制效果。本發明者更藉上述組合發現血管再造顯著抑制， 此醫藥對PCI後之再狹窄之抑制極爲有效。 本發明者更藉上述特定之血管緊縮素II受體拮抗劑與特定 之鈣拮抗劑之組合，發現達成優異之血壓下降作用。另，本 發明者發現此醫藥對高血壓症，心臓疾病[心絞痛，心肌梗 塞’心律不整（包括猝死）’心臟衰竭或心肥大]，腎臓疾病（糖 1373335 修正本 尿病性腎症，腎小球腎炎或腎硬化症）或腦血管性疾病（腦梗 塞或腦出血）之預防及/或治療極爲有效。本發明乃基於這些 知見完成。 即，本發明爲預防及/或治療動脈硬化之醫藥，內含有效成 分爲下述成分： (A)選自如下式（I):
化合物及其藥理容許酯’及藥理容許鹽之血管緊縮素Π受 體拮抗劑；及 (B)選自1,4-二氫吡啶系化合物及藥理容許鹽之鈣拮抗劑。 又從本發明之另一觀點而言，係提供以上述成分（A)及成分 (B)爲有效成分而用以抑制血管平滑肌細胞增殖之醫藥，以 上述成分（A)及成分（B>爲有效成分而抑制血管新生内膜形 成之醫藥’及以上述成分（A)及成分（B)爲有效成分而抑制血 管再造之醫藥。這些醫藥可用於預防例如，冠狀動脈介入後 之再狹窄之醫藥。從此觀點而言，本發明提供以成分（A)及 成分（B)爲有效成分之預防冠狀動脈介入後再狹窄之醫藥。 -11- 1373335 修正本 本發明更提供預防及/或治療高血壓症或高血壓症由來之 疾病之醫藥，係以下述成分： (A) 上述式（I)化合物及其藥理容許酯，及藥理容許鹽所選之 血管緊縮素II受體拮抗劑；及 (B) 1，4-二氫吡啶系化合物及藥理容許鹽所選之鈣拮抗劑 爲有效成分含有之醫藥；及 預防及/或治療心臓疾病[心絞痛，心肌梗塞，心律不整（包括 猝死）’心臟衰竭，或心肥大等]，腎臓疾病（糖尿病性腎症， 腎小球腎炎，或腎硬化症等），或腦血管性疾病（腦梗塞或腦 出血等）之醫藥，係以下述成分： (A) 上述式（I)化合物及其藥理容許酯，及藥理容許鹽所選之 血管緊縮素II受體拮抗劑；及 (B) l，4-二氫吡啶系化合物及藥理容許鹽所選之鈣拮抗劑 爲有效成分含有之醫藥。 依上述各發明之適宜態樣，提供上述醫藥以成分（A)及成分 (B)之兩者爲有效成分醫藥組成物。此醫藥組成物也可含i 種或2種以上製劑用添加物。依上述各發明之另一適宜態 樣’可提供將成分（A)及成分（B)同時，或將成分（A)及成分（B) 改變時間來投與之上述醫藥。 又依上述各發明之更適宜態樣，提供血管緊縮素II受體拮 抗劑爲（5-甲基-2·氧-1,3-二嗶茂烷-4-基）甲基4-(1-羥基-1-甲基乙基_)-2-丙基-1-[2’-(1Η-四唑-5-基）聯苯-4-基甲基]咪唑 -5-羧酸酯（以下在本說明書有時稱「噚美撒旦·美多奇索米 (olmesartan.medoxomil)」）之上述醫藥；鈣拮抗劑爲選自 -12- 1373335 修正本 胺基-1，4-二氫-6·甲基-4-(3-硝苯基）-3,5-吡啶二羧酸3(1-二 苯甲基吖丁啶-3-基）酯5-異丙酯（以下在本說明書有時稱「阿 折地平j)，氨氯地平，別尼地平，尼妥聯地平，嗎尼地平， 尼卡地平，尼費地平，尼索地平，西路尼地平，列卡尼地平， 尼克地平，尼莫地平，阿拉尼地平，也何尼地平，巴路尼地 平’飛洛地平，及尼巴地平之鈣拮抗劑之上述醫藥；及鈣拮 抗劑爲阿折地平之上述醫藥。
從本發明之另一觀點，提供上述爲製造醫藥使用選自上述 式（I)之化合物及其藥理容許酯，及藥理容許鹽之血管緊縮素 Π受體拮抗劑；爲製造上述醫藥使用選自I，4·二氫吡啶系化 合物及藥理容許鹽之鈣拮抗劑》
又依本發明，提供動脈硬化之預防及/或治療方法，包括將 上述成分（A)及成分（B)之預防及/或治療有效量投與包括人 等哺乳類動物之方法；在包括人等哺乳類動物之活體内抑制 血管平滑肌細胞增殖之方法，包括將上述成分（A)及成分（B) 之有效量投與人等哺乳類動物之方法；在人等哺乳類動物之 活體内抑制血管新生内膜形成之方法，包括將上述成分（A) 及成分（B)之有效量投與人等哺乳類動物之方法；在人等哺 乳類動物之活體内抑制血管再造之方法，包括將上述成分（A) 及成分（B)之有效量投與人等哺乳類動物之方法；及預防冠 狀動脈介入後再狹窄之方法，包括將上述成分（A)及成分（B) 之有效量投與人等哺乳類動物之方法。宜上述各發明中，成 分（A)及成分（B)之組合中各成分之有效量爲成分（A)及成分 (B)各單獨使用時有效用量之下限附近或比此更低量。 -13- 1373335 修正本 又本發明提供預防及/或治療高血壓症或高血壓症由來之 疾病之方法，包括將上述成分（A)及成分（B)之預防及/或治療 有效量投與人等哺乳類動物之方法；預防或治療高血壓症 之方法，包括將上述成分（A)及成分（B)之有效量投與人等哺 乳類動物之方法；預防或治療心臓疾病之方法，包括將上述 成分（A)及成分（B)之有效量投與人等哺乳類動物之方法；預 防或治療心絞痛之方法，包括將上述成分（A)及成分（B)之有 效量投與人等哺乳類動物之方法；預防或治療心肌梗塞之 方法，包括將上述成分（A)及成分（B)之有效量投與人等哺乳 類動物之方法；預防或治療心律不整之方法，包括將上述成 分（A)及成分（B)之有效量投與人等哺乳類動物之方法；預防 猝死之方法，包括將上述成分（A)及成分（B)之有效量投與人 等哺乳類動物之方法；預防或治療心臟衰竭之方法，包括將 上述成分（A)及成分（B)之有效量投與人等哺乳類動物之方 法；預防或治療心肥大之方法，包括將上述成分（A)及成分（B) 之有效量投與人等哺乳類動物之方法；預防或治療腎臓疾 病之方法，包括將上述成分（A)及成分（B)之有效量投與人等 哺乳類動物之方法；預防或治療糖尿病性腎症之方法，包括 將上述成分（M及成分（B)之有效量投與人等哺乳類動物之 方法；預防或治療腎小球腎炎之方法，包括將上述成分（A) 及成分（B)之有效量投與人等哺乳類動物之方法；預防或治 療腎硬化症之方法，包括將上述成分（A)及成分（B)之有效量 投與人等哺乳類動物之方法；預防或治療腦血管性疾病之 方法，包括將上述成分（A)及成分（B)之有效量投與人等哺乳 -14- 1373335 修正本 類動物之方法；預防或治療腦梗塞之方法，包括將上述成分 (A)及成分（B)之有效量投與人等哺乳類動物方法；及/或預防 或治療腦出血之方法，包括將上述成分（A)及成分（B)之有效 量投與人等哺乳類動物之方法。 【實施方式】 本發明之醫藥以（A)選自上述式（I)化合物及其藥理容許 酯，及藥理容許鹽之血管緊縮素Π受體拮抗劑；及（B)選自 1，4-二氫吡啶系化合物及藥理容許鹽之鈣拮抗劑爲有效成 分爲特徴。 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）聯苯-4-基甲基]咪唑-5-羧酸〕爲公 知，可依例如，特開平5-783 28號公報（美國專利第5,6 16.,599 號說明書）等記載之方法容易獲得。上述式（I)化合物之藥理 容許鹽之種類無特限，業者可適宜'選擇。上述式⑴化合物之 藥理容許鹽可爲例如，鈉鹽，鉀鹽，鋰鹽等鹼金屬鹽，鈣鹽， 鎂鹽等鹼土金屬鹽，鋁鹽，鐵鹽，鋅鹽，銅鹽，鎳鹽，鈷鹽 等金屬鹽；或銨鹽，第三辛胺鹽，二苄胺鹽’嗎啉鹽’葡萄 糖胺鹽，苯甘胺酸烷酯鹽，乙二胺鹽，N-甲基葡糖胺鹽，胍 鹽，二乙胺鹽，三乙胺鹽，二環辛胺鹽’ N，N'-二苄乙二胺 鹽，氯普羅卡因鹽，普羅卡因鹽’二乙醇胺鹽’ N-苄基苯乙 胺鹽，哌啶鹽，四甲基銨鹽，參（羥基甲基）胺基甲烷鹽等胺 鹽等，但不限於這些。宜用鹼金屬鹽，尤其宜用鈉鹽。 上述式⑴化合物之藥理容許酯乃指上述式⑴化合物之羧 酸部分被酯化之化合物》藥理容許酯之種類無特限，業者可 -15- 1373335 修正本 適宜运擇。該醋宜在活體内以加水分解等生物學方法開裂 者。構成該醋之基（該醋以- COOR表示時以r表示之基）可爲 例如’甲氧甲基’ 1-乙氧乙基’ 1·甲基-1_甲氧乙基，1_(異 丙氧基）乙基，2 -甲氧乙基，2 -乙氧乙基，ΐ，ι_二甲基-i_甲氧 甲基，乙氧甲基’丙氧甲基，異丙氧甲基，丁氧甲基，第三 丁氧甲基等C1-C4烷氧C1-C4烷基，2-甲氧乙氧甲基等 C1-C4烷氧基化C1-C4烷氧基C1-C4烷基，苯氧甲基等 〇6-(：10芳氧基（：1-(：4烷基，2,2,2-三氯乙氧基甲基，雙（2-氯乙氧基）甲基等鹵化C1-C4烷氧基C1-4烷基，甲氧羰甲基 等C1-C4烷氧羰基C1-CM烷基’氰甲基，2-氰乙基等氰基 C1-C4烷基，甲硫甲基，乙硫甲基等C1-C4烷基硫甲基，苯 硫甲基，萘硫甲基等C6-C10芳硫甲基，2-甲磺醯乙基，2-三氟甲磺醯乙基等可有鹵素取代之C1-C4烷磺醯基C1-C4 低烷基，2-苯磺醯乙基，2-甲苯磺醯乙基等C6-C 10芳磺醯 基C1-C4烷基，甲醯氧甲基，乙醯氧基基，丙醯氧甲基，丁 醯氧甲基，特戊醯氧甲基，戊醯氧甲基，異戊醯氧甲基，己 醯氧甲基，1-甲醯氧乙基，1-乙醯氧乙基，1-丙醯氧乙基， 1-丁醯氧乙基，1-特戊醯氧乙基，1-戊醯氧乙基，1-異戊醯 氧乙基，1己醯氧乙基，2-甲醯氧乙基，2-乙醯氧乙基，2-丙醯氧乙基，2-丁醯氧乙基，2-特戊醯氧乙基，2-戊醯氧乙 基，2-異戊醯氧乙基，2_己醯氧乙基，1-甲醯氧丙基，1·乙 醯氧丙基，1-丙醯氧丙基，1-丁醯氧丙基’ 1-特戊醯氧丙基’ 1-戊醯氧丙基，1-異戊醯氧丙基’ 1-己醯氧丙基’丨-乙醯氧 丁基，1丙醯氧基丁基，1-丁醯氧丁基，1-特戊醯氧丁基’ -16- 1373335 修正本 1-乙醯氧戊基，1-丙醯氧戊基，1-丁醯氧戊基，1-特戊醯氧 戊醯基，1-特戊醯氧己基等C1-C7脂族醯氧基C1-C4烷基， 環戊羰氧甲基，環己羰氧甲基，1-環戊醯羰氧乙基，1-環己 羰氧乙基，1-環戊羰氧丙基，1-環己羰氧丙基，1-環戊羰氧 丁基’ 1-環己羰氧丁基等C5-C6環烷羰氧基C1-C4烷基，苄 醯氧甲基等C6-C10芳羰氧基C1-C4烷基，甲氧羰氧甲基， 1-(甲氧羰氧基）乙基，1-(甲氧羰氧基）丙基，1-(甲氧羰氧基） 丁基，1-(甲氧羰氧基）戊基’ 1-(甲氧羰氧基）己基，乙氧羰 氧甲基’ 1-(乙氧羰氧基）乙基，1-(乙氧羰氧基）丙基，u(乙 氧羰氧基）丁基，1-(乙氧羰氧基）戊基，1-(乙氧羰氧基）己基， 丙氧羰氧甲基，1-(丙氧羰氧基）乙基，！-(丙氧羰氧基）丙基， 1-(丙氧羰氧基）丁基’異丙氧羰氧甲基，1-(異丙氧羰氧基） 乙基’ 1-(異丙氧羰氧基）丁基，丁氧羰氧甲基，1_(丁氧羰氧 基）乙基’ 1-( 丁氧羰氧基）丙基，1·(丁氧羰氧基）丁基，異丁 氧羰氧甲基’ 1-(異丁氧羰氧基）乙基，異丁氧羰氧基）丙 基’ 1-(異丁氧羰氧基）丁基，第三丁氧羰氧甲基，1-(第三丁 氧羯氧基）乙基，戊氧羰氧甲基’ 1-(戊氧羰氧基）乙基，1_ (戊 氧羰氧基）丙基，己氧羰氧甲基，1-(己氧羰氧基）乙基，1_(己 氧兔氧基）丙基等C1-C6院氧鑛氧基C1-C4院基，環戊氧羯 氧甲基，1-(環戊氧羰氧基）乙基，1_(環戊氧羰氧基）丙基， 1-(環戊氧羯氧基）丁基’環己氧羯氧基甲基，(環己氧羯氧 基）乙基，1-(環己氧羰氧基）丙基，丨_(環己氧羰氧基）丁基等 c 5 - C 6環烷氧羰氧基c 1 - C 4烷基，（5 -甲基_ 2-氧-1，3 -二噚茂 烷-4-基）甲基，（5-乙基-2-氧-1，3-二噚茂烷._4_基）甲基，（5- -17- 1373335 修正本 丙基-2-氧-1，3-二噚茂烷-4-基）甲基，（5-異丙基-2-氧-1,3-二 噚茂烷·4·基）甲基，（5-丁基-2-氧-1,3-二噚茂烷-4-基）甲基等 [5-(C1-C4烷基）-2-氧-1,3-二噚茂烷-4-基]甲基，（5-苯基-2·氧 ·1，3·二噚茂烷-4-基）甲基，[5(4-甲苯基）-2-氧-1,3-二曙茂烷 -4-基]甲基，[5-(4-甲氧苯基）-2-氧·1，3-二噚茂烷-4-基]甲 基，[5-(4-氟苯基）2-氧-1，3-二噚茂烷-4-基]甲基，[5-(4-氯苯 基）-2-氧-1，3-二噚茂烷-4-基]甲基等[5-(Cl-C4烷基’ C1-C4 烷氧基或可有鹵素取代之苯基）-2-氧-1，3-二噚茂烷-4-基]甲 基或酞基，二甲酞基，二甲氧酞基等可有C1-C4烷基或C1-C4 烷氧基取代之酞基等。宜特戊醯氧甲基，酞基，或（5·甲基-2-氧-1,3-二噚茂烷-4-基）甲基，尤宜（5-甲基-2-氧-1,3-二噚茂 烷-4-基）甲基。 上述式⑴化合物之酯形成藥理容許鹽時，藥理容許鹽之種 類可由業者適宜選擇，無特別限定。可爲例如，氫氟酸鹽， 鹽酸鹽，氫漠酸鹽，氫碘酸鹽等氫_酸鹽；硝酸鹽；過氯酸鹽； 硫酸鹽；磷酸鹽；甲磺酸鹽，三氟甲磺酸鹽，乙磺酸鹽等可有 鹵素取代之C1-C4烷磺酸鹽；苯磺酸鹽，對甲苯磺酸鹽等可 有C1-CM烷基取代之C6-C10芳磺酸鹽；乙酸，蘋果酸，富馬 酸鹽，丁二酸鹽，檸檬酸鹽，酒石酸鹽，草酸鹽，馬來酸鹽 等Cl -C6脂肪酸鹽；或甘胺酸鹽，離胺酸鹽，精胺酸鹽，鳥 胺酸鹽，麩胺酸鹽’天冬胺酸鹽等胺基酸鹽等。宜鹽酸鹽， 硝酸鹽’硫酸鹽，或磷酸鹽，尤宜鹽酸鹽。 當作成分（A)使用之血管緊縮素π受體拮抗劑宜用上述式 (I)化α物或其藥理容許醋’尤宜上述式⑴化合物之藥理容 -18- 1373335 修正本 許酯，更宜上述式（I)化合物之待戊醯氧甲酯，酞酯，或（5-甲基-2-氧-1，3·二噚茂烷-4-基）甲酯。最好（5-甲基-2-氧-1,3-二噚茂烷_4·基）甲基 4-(1-羥基-1-甲基乙基）-2 -丙基 -1-[2’-(1Η-四唑-5-基）聯苯-4-基甲基]咪唑-5-羧酸酯。選自 上述式（I)化合物及其藥理容許酯，及藥理容許鹽之物質也可 用水合物或溶劑合物。 使用上述式（I)化合物之其藥理容許酯時，該酯化合物可有 1或2以上不對稱碳之情形，也可將基於該不對稱碳之純形 態之光學異構物或非對映異構物等立體異構物，或立體異構 物之任意混合物或消旋體等當作成分（A)使用。 包括當作成分（B)使用之1，4-二氫吡啶系化合物之鈣拮抗 劑乃以分子内有1,4-二氫吡啶部分構造或與其化學上等價 之部分構造爲特徴之鈣拮抗劑。包括1，4 -二氫吡啶系化合物 之鈣拮抗劑有種種藥劑之提案，而實際在臨床使用，故業者 可將有本發明效果之適宜藥劑選擇。包括1,4-二氫吡啶系化 合物之鈣拮抗劑可用例如，阿折地平，氨氯地平，別尼地平， 尼妥聯地平’嗎尼地平，尼卡地平，尼費地平，尼索地平， 西路尼地平，列卡尼地平，尼克地平，尼莫地平，阿拉尼地 平，也何尼地平，巴路尼地平，飛洛地平，或尼巴地平等， 但不限於這些。阿折地平可依特開昭63 -253082號公報（美 國專利第4,77 2，5 96號說明書）等記載之方法容易製造。又， 氨氯地平可依美國專利第4,572,909號說明書或美國專利第 4,8 79,3 03號說明書記載之方法容易製造。 I，4-二氫吡啶系化合物之藥理容許鹽之種類無特限，業者 -19- 1373335 修正本 可適宜選擇。藥理容許鹽可爲酸加成鹽或鹼加成鹽。例如， 鈉鹽，鉀鹽，鋰鹽等鹼金屬鹽，鈣鹽，鎂鹽等鹼土金屬鹽， 鋁鹽，鐵鹽，鋅鹽，銅鹽，鎳鹽，鈷鹽等金屬鹽；或銨鹽， 第三辛胺鹽，二苄胺鹽，嗎啉鹽，葡萄糖胺鹽，苯甘胺酸烷 酯鹽，乙二胺鹽，N-甲基葡糖胺鹽，胍鹽，二乙胺鹽，三乙 胺鹽，二環辛胺鹽，Ν，Ν·-二苄乙二胺鹽，氯普羅卡因鹽， 普羅卡因鹽，二乙醇胺鹽，N-苄基苯乙胺鹽，哌啶鹽，四甲 基銨鹽，參（羥甲基）胺甲烷鹽等胺鹽等鹼加成鹽；或氫氟酸 鹽，鹽酸鹽，氫溴酸鹽，氫碘酸鹽等氫_酸鹽；硝酸鹽；過氯 酸鹽；硫酸鹽；隣酸鹽；甲磺酸鹽，三氟甲磺酸鹽，乙磺酸鹽等 可有鹵素取代之C1-C4烷磺酸鹽；苯磺酸鹽，對甲苯磺酸鹽 等可有C1-C4烷基取代之C6-C10芳磺酸鹽；乙酸，蘋果酸， 富馬酸鹽，丁二酸鹽，檸檬酸鹽，酒石酸鹽，草酸鹽，馬來 酸鹽等C1-C6脂肪酸鹽；或甘胺酸鹽，離胺酸鹽，精胺酸鹽， 鳥胺酸鹽，麩胺酸鹽，天冬胺酸鹽等胺基酸鹽等。但不限於 這些》 包括1，4二氫吡啶系化合物之鈣拮抗劑也可用上述化合物 或藥理容許鹽之水合物或溶劑合物。又包括1，4 -二氫吡啶系 化合物之鈣拮抗劑有時在分子内有1或2個以上不對稱碳， 基於該不對稱碳之純形態之光學異構物或非對映異構物等 之立體異構物’或立體異構物之任意混合物或消旋體等也可 當作成分（B)使用。成分（B)宜（±)_2-胺基-i，4-二氫-6-甲基 -4 - (3 -硝苯基）-3，5 -吡啶二羧酸3 i _二苯甲基吖丁啶-3 _基） 酯5-異丙酯’（R)-2-胺基-i，4-二氫-6-甲基-4-(3-硝苯基）-3,5- -20- 1373335 修正本 吡啶二羧酸3-(1-二苯甲基吖丁啶-3-基）酯5-異丙基酯，氨氯 地平·苯磺酸鹽，或氨氯地平·馬來酸鹽。 本發明之醫藥乃如本說明書之實施例具體例示，成分（A) 及成分（B)相乘作用來抑制血管新生内膜形成及血管平滑肌 細胞增殖，結果可抑制血管再造。基於上述作用，本發明之 醫藥可用於動脈硬化症之預防及/或治療，也可用於冠狀動 脈介入後之再狹窄之預防。 本發明之醫藥即使爲成分（A)及成分（B)各單獨使用時之有 效用量下限附近或其以下之用量組合，也可達成優異之血管 新生内膜形成抑制效果及血管平滑肌細胞增殖抑制效果之 特徵。尤其各成分之單獨投與則無效果之低用量之組合。 又如說明書之實施例具體所示，本發明之醫藥因成分（A) 及成分（B)相乘地作用而更有效使血壓下降。基於上述作 用，本發明之醫藥可用於高血壓症，心臓疾病[心絞痛，心 肌梗塞，心律不整（包括猝死），心臟衰竭，或心肥大等]，腎 臓疾病（糖尿病性腎症，腎小球腎炎，或腎硬化症等）或腦血 管性疾病（腦梗塞或腦出血等）之預防及/或治療，宜用於治 療。本發明之醫藥藉將血管緊縮素Π受體拮抗劑及鈣拮抗 劑組合使用，呈現出比各單獨投與時優異之效果。 本發明之醫藥也可將上述成分（A)及（B)之兩者當作有效成 分調製成醫藥組成物（「合劑」之形態）。例如，混合兩者有 效成分來調製成物理上1個單位投與形態。又也可將上述成 分（A)及（B)調製成分別之單位投與形態，將這些投與形態 之組合當作醫藥提供。後者之醫藥可將上述成分（A)及（B)同 -21 - 1373335 修正本 時或變化時間投與之醫藥來使用。 本說明書中’成分（A)及（B)「同時」投與乃指兩成分大致 同時投與，不可限定解釋爲嚴密地同時投與之態樣。爲同時 投與之投與形態無特限，例如，將一方之成分經口投與，將 他方之成分非經口投與之形態等也包含，尤宜將兩者之成分 調製成單一組成物來投與。 本發明中’將成分（A)及（B)「隔時分別」投與乃指將兩者 之成分於不同時間分別投與。隔時分別投與之投與形態無特 限’例如，最初將血管緊縮素II受體拮抗劑投與，次在所 定時間經過後將鈣拮抗劑投與之形態，或最初將鈣拮抗劑投 與，次在所定時間之經過後將血管緊縮素II受體拮抗劑投 與之形態等也包含，但不限於這些態樣。 本發明之醫藥除有效成分之上述成分（A)及（B)之外，必要 時用適宜之藥理容許之賦形劑，滑澤劑，結合劑，崩壞劑， 乳化劑，安定劑，矯味矯臭劑，稀釋劑等添加劑而依周知之 方法調製成錠劑，膠囊劑，顆粒劑，散劑，或糖漿劑等適合 經口投與之醫藥，或注射劑或坐劑等適合非經口投與之醫藥 來投與。本發明之醫藥所含之成分（A)及（B)—般爲經口投與 之藥劑，故本發明之醫藥宜經口投與。 「賦形劑」可爲例如，乳糖，白糖，葡萄糖，甘露糖醇或 山梨糖醇等糖衍生物；玉米澱粉，馬鈴薯澱粉，α-澱粉或糊 精等澱粉衍生物；結晶纖維素等纖維素衍生物；阿拉伯膠；葡 聚糖；或三聚葡糖等有機系賦形劑；或輕質矽酸酐，合成矽酸 鋁，矽酸鈣或偏矽酸鋁酸鎂等矽酸鹽衍生物；磷酸氫鈣等磷 -22- 1373335 修正本 酸鹽；碳酸鈣等碳酸鹽；或硫酸鈣等硫酸鹽等無機系賦形劑。 「滑澤劑」可爲例如，硬脂酸；硬脂酸鈣或硬脂酸鎂等硬脂 酸金屬鹽；滑石；膠狀矽石；蜂蠟或鯨蠟等蠟類；硼酸；己二酸； 硫酸鈉等硫酸鹽；乙二醇；富馬酸；苯甲酸鈉；D，L-白胺酸；十二 基硫酸鈉或十二基硫酸鎂等十二基硫酸鹽；矽酸酐或矽酸水 合物等矽酸類；或上述澱粉衍生物。 「結合劑」可爲例如，羥丙基纖維素，羥丙基甲基纖維素， 聚乙烯吡略啶酮，聚乙二醇，或與前述賦形劑同樣之化合物。 「崩壞劑」可爲例如，低取代度羥丙基纖維素，羧甲基纖 維素，羧甲基纖維素鈣或内部交聯羧甲基纖維素鈉等纖維素 衍生物；交聯聚乙烯吡咯啶酮；或羧甲基澱粉或羧甲基澱粉鈉 等化學修飾之澱粉·纖維素類。 「乳化劑」可爲例如，膨土或矽酸鎂鋁等膠體性粘土；氫氧 化鎂或氫氧化鋁等金屬氫氧化物；十二基硫酸鈉或硬脂酸鈣 等陰離子界面活性劑；苄烷氯化銨等陽離子界面活性劑；或聚 氧乙烯烷醚，聚氧乙烯山梨糖脂肪酸酯或蔗糖脂肪酸酯等非 離子界面活性劑。 「安定劑」可爲例如，對羥苯甲酸甲酯或對羥苯甲酸丙酯 等對羥苯甲酸酯類；氯丁醇，苄醇或苯乙醇等醇類；苄烷氯化 銨；酣或甲酚等酚類；硫柳汞；去氫乙酸；或山梨酸。 「矯味矯臭劑」可爲例如，糖精鈉或阿斯巴甜等甘味料； 檸檬酸，蘋果酸或酒石酸等酸味料；或薄荷腦，檸檬或桔子 等香料。 「稀釋劑」可爲例如，乳糖，甘露糖醇，葡萄糖，蔗糖， -23- 1373335 修正本 硫酸鈣，磷酸鈣，羥丙基纖維素’微結晶性纖維素，水，乙 醇，聚乙烯乙二醇，丙烯乙二醇，甘油，澱粉，聚乙烯吡咯 啶酮，偏矽酸鋁酸鎂或這些之混合物等通常當作稀釋劑者。 有效成分血管緊縮素π受體拮抗劑與鈣拮抗劑之投與量及 投與比率可依個別藥劑之活性，患者之症狀，年齡，體重等 種種條件而適宜選擇。其投與量依症狀，年齡等而異，經口 投與時，各每回下限O.lmg(宜0.5mg)，上限lOOOmg(宜 50 Omg)，非經口投與時每回下限0.01 mg(宜0.05mg)，上限 lOOmg(宜50mg)，對成人每日1〜6回之程度，依症狀而同 時或隔時分別投與。例如，成分（A)與成分（B)之投與量比率 依重量比爲1:1 0000〜1 0000:1之範圍内，宜1:1000〜1000:1 之範圍内，尤宜1:100〜100:1之範圍内。 本發明之醫藥當作動脈硬化之預防及/或治療使用時，一般 宜適宜調整成投與後之成分（A)及成分（B)之血中濃度分別 單獨有效血中濃度之下限附近或以下之濃度。 本發明之醫藥當作高血壓之預防及/或治療使用時，血管緊 縮素II受體拮抗劑之容量可設定爲低於本來用途降壓劑之 通常用量，可藉倂用鈣拮抗劑之優異效果而一般可將投與量 大幅下降。 實施例 以下舉本發明之實施例來具體説明，但本發明之範圍不限 於下述實施例。實施例中，將曙美撒旦.美多奇索米簡稱「曙 美撒旦」。 例1:動脈硬化抑制作用 -24- 1373335 修正本 (A)材料及方法 (1) 縮帶血管損傷模式 動物使用10週齡之C5 7BL/6小白鼠。在一部分實驗使用 ATla受體基因缺損（ATlaKO)小白鼠》在小白鼠之股動脈周 圍將聚乙烯管呈縮帶狀留置，來誘發炎症性血管傷害。在此 傷害血管，檢討下列項目。對血管再造解析有關此模式之有 用性已有報告（Physiol.Genomics.，2,pp.l3-30,2000;Circulation，104，pp.2716-2721， 2001 ;Circulation, 106,pp.847-853,2002) ° (2) 新生内膜形成與DNA合成 製備縮帶留置14日後之傷害血管之石蠟切片，而施行 Elastica vanGieson染色，將新生内膜及中膜之斷面積以畫 像解析軟骨計測。血管平滑肌細胞之DNA合成之定量化乃 在縮帶留置第7日之小白鼠投與BrdU，算出其往細胞核之 吸入指數。 (3) 在野生型小白鼠將屬於AT1受體遮斷劑之噚美撒旦以浸 透壓小泵浦腹腔内投與來施行上述（2)之測定，檢討噚美撒 旦之用量依存性^在野生型小白鼠從縮帶留置術時起經口投 與阿折地平後，施行上述（2)之測定，檢討阿折地平效果之 用量依存性。 (4) 在野生型小白鼠同時投與噚美撒旦及阿折地平之兩者來 施行上述（2)之測定，倂用投與之效果與單獨投與予以比較 檢討。爲使噚美撒旦與阿折地平分別單獨投與低有效用量之 檢討而更明確觀察相乘效果，觀察單獨投與無效之用量之倂 -25· 1373335 修正本 用效果。 (5)用老鼠培養血管平滑肌細胞，檢討由於血管緊縮素II刺 激所致之DNA合成亢進（以[3H]胸苷吸入來測定）之噚美撒 旦與阿折地平之倂用效果。 (B)結果 (1) 在野生型小白鼠惹起縮帶血管傷害時，認定血管平滑肌 細胞之DN A合成增加與增強新生内膜形成。此變化在〇.1 〜l.Omg/kg/日之範圍由於阿折地平投與不影響血壓而用 • 量依存地抑制（第1圖及第2圖）》又，曙美撒旦也以不影 響血壓之用量之0.5〜3 .Omg/kg/日之範圍呈用量依存性 之抑制作用（第3圖及第4圖）。在野生型小白鼠同時投與 阿折地平〇.lmg/kg/日及噚美撒旦0.5mg/kg/日（分別單獨 則無顯著效果之用量），則顯著抑制在縮帶傷害血管之血 管平滑肌細胞之DN A合成增強及新生内膜形成（第5圖及 第6圖）。由此結果顯示於活體內實驗，由於阿折地平及 噚美撒旦之倂用兩者相乘地作用，抑制血管平滑肌細胞 ® 之增殖且改善血管再造。 (2) 將上述相乘作用在活體外實驗檢討。如第7圖所示，在 老鼠培養血管平滑肌細胞由於血管緊縮素II刺激之DN A 合成亢進因阿折地平投與而用量依存地被抑制》將單獨 無效之低用量阿折地平，與單獨無效之低用量曙美撒旦 予以倂用，則在培養血管平滑肌細胞之DNA合成顯著地 被抑制（第8圖）》 例2:降壓作用 •26- 1373335 修正本 在56隻20週齡雄性ShR高血壓自然發症老鼠 [Spontaneously Hypertensive Rat，SPF 級，生産所：星野試驗 動物飼育所公司]實施血壓測定用遙測計送信機 (TA1 1PA-C40 > DATA SCIENCES. Inc.)之埋入手術。俟從手 術回復，從24週齡開始血壓監視，所有動物均將0.5%羧甲 基纖維素鈉（CMC-Na)水溶液（2ml/kg)以7日連續（1日1回） 用經口導管經口投與。以從〇.5%CMC-Na水溶液投與之第5 日及6日之測定値爲基準使血壓均勻地分爲7群（各群8隻） 動物（群構成如表1)，從25週齡起，將〇·5 % CMC-Na水溶液 (2ml/kg對照群）或被驗物質懸浮在0.5%CMC-Na水溶液之 液（2 ml/kg)連日經口投與14日（1日1回），觀察血壓之推移。 群6及群7之血壓變化如表2(表中之數値乃示平均値±標準 偏差）。噚美撒旦與阿折地平之倂用群確認優異之降壓作用。
-27- 1373335 修正本 表1 群1 對照群（0.5%CMC-Na水溶液） 群2曙美撒旦（〇.2mg/kg) 群3噚美撒旦（l.〇mg/kg) 群4阿折地平（2.0mg/kg) 群5阿折地平（5.0mg/kg) 群6噚美撒旦（〇.2mg/kg) +阿折地平（2.0mg/kg) 群7噚美撒旦（1.0mg/kg) +阿折地平（5.0mg/kg) 表2 被驗化合物 η 血壓（mmHg) 第1曰 第2日 第5日 第13曰 對照群 8 169.2±23.8 167.0±20.6 170.4±21.1 173.0±21.2 群6 8 150.3+11.7 144.5±9.8 147.2±10.1 145.9+8.8 群7 8 124.2+13.2 122.3+8.4 127.8±9.01 25.9+10.0 例3:降壓作用 將12週齡雄性脫輔基脂蛋白E(ApoE)擊昏小白鼠分爲對照 群（0.5 %羧甲基纖維素（CMC)水溶液投與），噚美撒旦（3 mg/kg) 投與群’阿折地平（3mg/kg)投與群，噚美撒旦（3mg/kg)/阿折 地平（3 mg/kg)倂用群之4群（各群1 5例），經口投與藥物24 週。又在所有群也從藥物投與開始時（1 2週齡）起給與高脂肪 飼料（含有0.1 5 %膽固醇，15%無鹽奶油）。藥物投與第23週 之投藥2 1 -24小時後’用老鼠·小白鼠用無加温型非觀血式 血壓計（MODEL MK-2 000，室町機械公司）測定收縮期血壓。 結果如表3(表中數値乃示平均値±標準誤差）。 -28- 1373335 修正本 表 投與群 收縮期血壓（mmHg) 對照群 1 29±3 噚美撒旦投與群 121+4 阿折地平投與群 1 27±4 噚美撒旦+阿折地平倂用群 1 12±3 如上述結果所示，噚美撒旦/阿折地平倂用群顯示未見諸單 獨投與群之顯著降壓作用（p = 0.0063;Dunnet’s多重比較檢 定），與單獨投與群相較，其效果爲相乘者（P = 〇. 0065 ;2元配 置分散分析）。 製劑例1 錠劑（合劑） 噚美撒旦·美多奇索米 1 0 . Omg 阿折地平 1 O.Omg 乳糖 278.Omg 玉米澱粉 5 0. Omg 硬脂酸鎂 2 . Omg 混合上述處方之粉末 ，以打錠機打錠，作成1錠350mg之 錠劑。此錠劑必要時，可予以糖衣。 産業上之利用可能性 本發明之醫藥可當作預防及/或治療動脈硬化及高血壓症 之醫藥。 【圖式簡單說明】 第1圖乃示因投與0.1〜l.〇mg/kg/曰之屬於鈣拮抗劑之阿 -29- 1373335 修正本 折地平（azelnidipine)之血管平滑肌細胞而DNA合成被抑制。 第2圖乃示因投與0.1〜l.Omg/kg/日之屬於鈣拮抗劑之阿 折地平而血管新生内膜形成被抑制之結果。 第3圖乃示因投與0.5〜3. Omg/kg/曰屬於血管緊縮素II受 體拮抗劑之噚美撒旦（olmesartan)而血管平滑肌細胞之DN A 合成被抑制之結果》 第4圖乃不因投與0.5〜3.0mg/kg /日屬於血管緊縮素II受 體拮抗劑之噚美撒旦而新生内膜形成被抑制之結果。 第5圖乃不因阿折地平0.1mg/kg /日及Of美撒旦〇.5mg/kg/ 曰（分別單獨則無顯著效果之用量）同時投與而血管平滑肌 細胞之DNA合成被抑制之結果。 第6圖乃示同時投與阿折地平〇.1 mg/kg/日及噚美撒旦 0.5mg/kg/日（分別單獨則無顯著效果之用量）而新生内膜形 成被抑制之結果。 第7圖乃示在老鼠培養血管平滑肌細胞因血管緊縮素II刺 激之DNA合成亢進因投與阿折地平而用量依存地被抑制。 第8圖乃示併用阿折地平及噚美撒旦分別單獨無效果之低 用量在培養血管平滑肌細胞之DNA合成顯著被抑制。 【主要元件符號說明】 無。 -30-
Claims (1)
1373335
修正本 第093102081號「治療動脈硬化及高血壓症之醫藥組成物」專利案 (2012年6月29日修正） 拾、申請專利範圍 1. 一種治療動脈硬化之醫藥組成物’內含有效成分爲下述 成分= (A)含有選自如下式（I)化合物、其藥理容許酯及藥理容許 鹽組成之群之物質的血管緊縮素Π受體拮抗劑：
:及（B)含有選自1，4-二氫吡啶系化合物阿折地平（ azelnidipine)或氨氯地平（amlodipine)及其藥理容許 鹽組成之群之物質的鈣拮抗劑。 2. —種用於血管平滑肌細胞之增殖抑制之醫藥組成物，含 有如申請專利範圍第1項之成分（A)及成分（B)爲有效成 分。 3. —種用於血管新生內膜形成之抑制之醫藥組成物，含有 如申請專利範圍第1項之成分（A)及成分（B)爲有效成分。 4. —種用於血管再造之抑制之醫藥組成物，含有如申請專 利範圍第1項之成分（A)及成分（B)爲有效成分。 1373335 修正本 5. —種用於治療高血壓症或高血壓症由來之疾病之醫藥組 成物，含有如申請專利範圍第1項之成分（A)及成分（B) 爲有效成分。 6. 如申請專利範圍第5項之醫藥組成物，其係用於治療高 血壓症之醫藥組成物。 7 ·如申請專利範圍第5項之醫藥組成物，其係用於治療心 臟疾病之醫藥組成物。 8 ·如申請專利範圍第5項之醫藥組成物，其係用於治療心 絞痛之醫藥組成物。 9 ·如申請專利範圍第5項之醫藥組成物，其係用於治療心 肌梗塞之醫藥組成物。 1 〇 ·如申請專利範圍第5項之醫藥組成物，其係用於治療心 律不整之醫藥組成物。 1 1 .如申請專利範圍第5項之醫藥組成物，其係用於治療心 臟衰竭之醫藥組成物》 1 2 .如申請專利範圍第5項之醫藥組成物，其係用於治療心 肥大之醫藥組成物。 1 3 .如申請專利範圍第5項之醫藥組成物，其係用於治療腎 臟疾病之醫藥組成物。 1 4 .如申請專利範圍第5項之醫藥姐成物，其係用於治療糖 尿病性腎症之醫藥組成物。 15.如申請專利範圍第5項之醫藥組成物，其係用於治療腎 小球腎炎之醫藥組成物。 1373335 修正本 16.如申請專利範圍第5項之醫藥組成物，其係用於治療腎 硬化症之醫藥組成物。 1 7 .如申請專利範圍第5項之醫藥組成物，其係用於治療腦 血管性疾病之醫藥組成物。 18.如申請專利範圍第5項之醫藥組成物，其係用於治療腦 梗塞之醫藥組成物。 1 9.如申請專利範圍第5項之醫藥組成物，其係用於治療腦 出血之醫藥組成物》 20.如申請專利範圍第1至1 9項中任一項之醫藥組成物， 其中血管緊縮素II受體拮抗劑爲（5-甲基-2-氧-1，3-二噚 茂烷·4·基）甲基 4-(1·羥基-1-甲基乙基）-2-丙基 -1·[2’-(1Η-四唑-5-基）聯苯-4-基甲基]咪唑-5·羧酸酯。 2 1 ·如申請專利範圍第1至1 9項中任一項之醫藥組成物， 其中鈣拮抗劑爲阿折地平。 2 2 ·如申請專利範圍第1至1 9項中任一項之醫藥組成物， 其中血管緊縮素II受體拮抗劑爲（5_甲基-2-氧-1，3-二嘮 茂烷-4-基）甲基 4-(1-羥基-1-甲基乙基）_2_丙基 -1-[2'-(1Η -四唑-5-基）聯苯-4-基甲基]咪唑-5-羧酸酯，鈣 拮抗劑爲阿折地平。 2 3.如申請專利範圍第1至19項中任一項之醫藥組成物， 其中鈣拮抗劑爲氨氯地平° 24·如申請專利範圍第1至19項中任—項之醫藥組成物， 其中血管緊縮素Π受體拮抗劑爲（5-甲基-2-氧-1，3·二嘮 1373335 修正本 茂烷-4-基）甲基 4-(1-羥基-1-甲基乙基）-2-丙基 -1-[2·-(1Η-四唑-5-基）聯苯-4-基甲基]咪唑-5-羧酸酯，鈣 拮抗劑爲氨氯地平。
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