200934484 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種伴隨眼內血管透過性亢進疾病之預 防或治療用醫藥，其含有血管緊張素II受體拮抗劑作爲有 效成分。 【先前技術】 血管緊張素II受體拮抗劑除用於作爲高血壓症治療劑 之外，作爲心肥大、心衰竭、或心肌梗塞等之心臓病、或 0 腦中風或腎炎等之循環器系疾病治療劑，其作用機序係被 認爲抑制具有強血管收縮作用的血管緊張素Π對血管緊張 素II受體之結合。 ' 奧美沙坦（oimesartan)對眼內血管性疾病的作用， ' 已知會改善糖尿病動物模式之網膜電圖之變化（例如，參 照非專利文獻1)、於增殖網膜症之動物模式中抑制網膜血 管新生（例如，參照專利文獻1)。然而，向來並未知奧美 沙坦具有對於糖尿病網膜症初期等之網膜中血管透過性亢 G 進的疾病之預防或治療效果。 非專手IJ 文獻 1 Nakamura 等人，Eur. J. Pharmacol. 2005; 5 1 2:23 9-246 專利文獻1 國際公開第2004/09 1 659號小冊 【發明内容】 發明揭示 發明欲解決之課題 本發明之課題係提供網膜缺血性疾病之預防或治療上 200934484 有用的醫藥。 解決課題之手段 本發明者們爲解決上述課題不斷進行硏究的結果，發 現奧美沙坦具有糖尿病黃斑浮腫等之眼內血管透過性冗進 病患之預防或治療上的高有效性。本發明係基於上述見解 而完成者。 即，本發明爲 (1) 一種網膜缺血性疾病之預防或治療用醫藥，其爲 Φ 含有血管緊張素Π受體拮抗劑作爲有效成分之醫藥； (2) —種伴隨眼內血管透過性亢進之網膜缺血性疾病 之預防或治療用醫藥，其爲含有血管緊張素II受體拮抗劑 ' 作爲有效成分之醫藥； • (3)如（2)記載之醫藥，其中伴隨眼內血管透過性 亢進之網膜缺血性疾病爲糖尿病網膜症（單純網膜症、前 增殖網膜症、增殖網膜症）、網膜靜脈閉塞症、網膜動脈閉 塞症、老年黃斑病變、中心性漿液性網脈絡膜症、糖尿病 〇 黃斑浮腫、嚢胞樣黃斑浮腫、葡萄膜炎、或貝西氏病 (Beh9et's disease); (4) 如（1)至（3)中任一項記載之醫藥，其中血管 緊張素Π受體拮抗劑爲選自4-(1-羥基-1-甲基乙基）-2-丙基-1-[2，- (1H-四唑-5·基）聯苯基-4-基甲基]咪唑-5-羧 酸及其藥理學上可接受的酯，以及其藥理學上可接受的鹽 組成之群； (5) 如（1)至（3)中任一項記載之醫藥，其中血管 緊張素Π受體拮抗劑爲（5-甲基-2-酮基-1,3-二氧戊環-4- 200934484 基）甲基 4- ( 1-羥基-1-甲基乙基）-2_丙基-〖-[2，- ( 1H-四哩-5-基）聯苯基-4-基甲基]咪哩·5_竣酸醋。 依本發明之更佳態樣，提供之血管緊張素II受體拮抗 劑爲選自4- ( 1-羥基-1-甲基乙基）-2-丙基·1-[2，- ( 1H-四 唑-5·基）聯苯基-4-基甲基]咪唑-5-羧酸及其藥理學上可接 受的酯’以及藥理學上可接受的此等鹽類組成之群的上述 醫藥，依特佳態樣，提供血管緊張素II受體拮抗劑爲（5-甲基-2-酮基-1，3-二氧戊環-4-基）甲基 4-(1·羥基-1-甲基 0 乙基）-2-丙基( 1Η-四唑-5-基）聯苯基-4-基甲基] 咪唑-5-羧酸酯之上述醫藥。 由其他觀點，依本發明，提供之上述醫藥之製造用之 血管緊張素II受體拮抗劑較佳爲選自4-(1-羥基-1-甲基乙 ' 基）-2-丙基-1-[2’-(1Η-四唑-5-基）聯苯基-4-基甲基]咪 唑-5-羧酸及其藥理學上可接受的酯，以及藥理學上可接受 的鹽組成之群的血管緊張素II受體拮抗劑，更佳爲提供（5-甲基-2-酮基-1，3-二氧戊環-4-基）甲基 4-(1-羥基-卜甲基 ❹ 乙基）-2-丙基-1-[2’-(1Η-四唑-5-基）聯苯基-4-基甲基] 咪唑-5-羧酸酯之使用。 又由其他觀點，提供伴隨眼內血管透過性亢進疾病， 較佳爲糖尿病網膜症（單純網膜症、前增殖網膜症、增殖 網膜症）、網膜靜脈閉塞症、網膜動脈閉塞症、老年黃斑病 變、中心性漿液性網脈絡膜症、糖尿病黃斑浮腫、囊胞樣 黃斑浮腫、葡萄膜炎、或貝西氏病之預防或治療方法，血 管緊張素II受體拮抗劑較佳爲選自4-(1-羥基-1-甲基乙 基）-2-丙基-1-[2’-(1Η-四唑-5-基）聯苯基-4·基甲基]咪BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preventive or therapeutic medicine for vascular hyperpermeability in the eye, which comprises an angiotensin II receptor antagonist as an effective ingredient. [Prior Art] An angiotensin II receptor antagonist is used as a therapeutic device for hypertension, as a circulatory system for heart disease, heart failure, or myocardial infarction, or a circulatory system such as 0 stroke or nephritis. A therapeutic agent for disease, whose mechanism of action is thought to inhibit the binding of angiotensin Π to an angiotensin II receptor having a strong vasoconstrictor action. 'Omesartan's effect on intraocular vascular diseases, 'is known to improve changes in omental electrograms in diabetic animal models (see, for example, Non-Patent Document 1), to inhibit retinal vessels in an animal model of proliferative retinopathy Freshman (for example, refer to Patent Document 1). However, it has not been known that olmesartan has a preventive or therapeutic effect on a disease in which vascular permeability is increased in the omentum at the early stage of diabetic retinopathy. Non-hands-on IJ document 1 Nakamura et al., Eur. J. Pharmacol. 2005; 5 1 2:23 9-246 Patent Document 1 International Publication No. 2004/09 1 659 booklet [Summary of the Invention] Problem The subject of the present invention is a medicine useful for the prevention or treatment of retinal ischemic diseases 200934484. MEANS TO SOLVE THE PROBLEM As a result of the inventors of the present invention, the present inventors have found that olmesartan has high effectiveness in prevention or treatment of intraocular vascular permeation patients such as diabetic macular edema. The present invention has been completed based on the above findings. That is, the present invention is (1) a medicine for preventing or treating an ischemic disease of the omentum, which is a medicine containing Φ an angiotensin receptor antagonist as an active ingredient; (2) a vascular permeability accompanying the eye Medicine for the prevention or treatment of retinal ischemic diseases, which is an medicine containing an angiotensin II receptor antagonist as an active ingredient; (3) The medicine according to (2), which is accompanied by intraocular blood permeation Osmotic ischemic disease is diabetic retinopathy (reticulolateral disease, preproliferative retinopathy, proliferative retinopathy), retinal vein occlusion, retinal artery occlusion, age-related macular degeneration, central serous choroidal diarrhea, diabetes 〇 〇 〇 嚢 嚢 嚢 嚢 嚢 嚢 嚢 嚢 嚢 嚢 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 血管 血管 血管The agent is selected from 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2,-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl] Imidazole-5-carboxylic acid and its pharmacologically acceptable ester, and its pharmacologically acceptable (5) The medicine according to any one of (1) to (3) wherein the angiotensin receptor antagonist is (5-methyl-2-keto-1,3-di) Oxolane-4-200934484 yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-[-[2,-(1H-tetradec-5-yl)biphenyl -4-ylmethyl]imidine·5_ citrate. According to a more preferred aspect of the invention, the angiotensin II receptor antagonist is selected from the group consisting of 4-(1-hydroxy-1-methylethyl)-2-propyl·1-[2,- ( 1H a tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylic acid and a pharmacologically acceptable ester thereof, and a pharmacologically acceptable group of such salts Medicine, according to the special aspect, provides angiotensin II receptor antagonist (5-methyl-2-keto-1,3-dioxolan-4-yl)methyl 4-(1·hydroxyl The above-mentioned medicine of -1-methyl 0 ethyl)-2-propyl ( 1 Η-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate. According to another aspect of the invention, the angiotensin II receptor antagonist for the manufacture of the above-mentioned medicament is preferably selected from the group consisting of 4-(1-hydroxy-1-methylethyl)-2-propyl- 1-[2'-(1Η-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylic acid, and pharmacologically acceptable ester thereof, and pharmacologically acceptable salt thereof An angiotensin II receptor antagonist composed of a group, more preferably (5-methyl-2-keto-1,3-dioxolan-4-yl)methyl 4-(1-hydroxy- Use of methyl hydrazine ethyl)-2-propyl-1-[2'-(1Η-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate. Further, from other viewpoints, it is provided with an intraocular vascular hyperreactive disease, preferably diabetic retinopathy (reticulosus, preproliferative retinopathy, proliferative retinopathy), retinal venous occlusion, retinal occlusion, age-related macular degeneration, Central serous choroidal choroidosis, diabetic macular edema, cystatinous macular edema, uveitis, or prevention or treatment of Besi's disease, angiotensin II receptor antagonist is preferably selected from 4-(1) -hydroxy-1-methylethyl)-2-propyl-1-[2'-(1Η-tetrazol-5-yl)biphenyl-4-ylmethyl]imi
〇 200934484 唑-5-羧酸及其藥理學上可接受的酯、以及藥理 的此等鹽組成之群的血管緊張素Π受體拮抗齊 甲基-2-酮基-1，3-二氧戊環-4·基）甲基 4-(1-乙基）-2-丙基-1-[2’-(1Η-四唑·5·基）聯苯3 咪唑-5-羧酸酯，經由本發明提供包含將預防或 之上述有效成分投與至包含人類之哺乳類動物 法。 本發明者們指出爲血管緊張素π受體拮Ιϋ (5-甲基-2-酮基-1，3-二氧戊環-4-基）甲基 4 甲基乙基）-2-丙基-1-[2’·（1Η-四唑-5-基）聯 基]咪唑-5·羧酸酯（以下，稱爲「奧美沙坦酯） medoxomil))顯示具有改善伴隨眼內血管透遇 的可能性。於現時點上在所知範圍內並沒有勇 善伴隨眼內血管透過性亢進疾病的報告，關护 新穎性。又此藥劑臨床上已使用於作爲降血塵 隨眼內血管透過性亢進疾病患者於內服時的5 乎無問題的大特徴。 發明效果 含有以血管緊張素II受體拮抗劑爲有效 醫藥，有用於糖尿病網膜症（單純網膜症、前 增殖網膜症）、網膜靜脈閉塞症、網膜動脈閉 斑病變、中心性漿液性網脈絡膜症、糖尿病 胞樣黃斑浮腫、葡萄膜炎、或貝西氏病等之 性亢進病患之預防或治療》 【實施方式】 學上可接受 丨，更佳爲（5-羥基-1-甲基 I -4-基甲基] 治療有效量 的步驟的方 藥之一種之 .(1-羥基-1-苯基-4-基甲 〔Ο lme s artan 性亢進疾病 美沙坦酯改 此點則具有 藥，具有伴 全性方面幾 分之本發明 殖網膜症、 症、老年黃 斑浮腫、囊 內血管透過 200934484 實施發明之最佳態樣 本發明中，血管緊張素II受體拮抗劑係指可競爭性或 非競爭性抑制血管緊張素II對血管緊張素II受體之結合的 物質。血管緊張素II受體拮抗劑爲低分子有機化合物、胜 肽化合物、糖類化合物之外，亦可爲蛋白質、糖蛋白質、 多糖類化合物等之高分子化合物。某物質是否具有血管緊 張素II受體拮抗作用，本項技術領域者可依例如美國專利 第5,616,599號說明書記載之方法而容易地確認。本說明書 0 中所使用的「血管緊張素II受體拮抗劑」之用語，無論爲 何意義亦不作限定解釋，必須最廣義地解釋。 作爲可適合本發明之醫藥使用之血管緊張素η受體拮 • 抗劑之一例，例如，可列舉4 - ( 1 ·羥基-1 -甲基乙基）-2 - • 丙基-1-[2，-( 1Η-四唑-5-基）聯苯基-4-基甲基]咪唑-5-羧 酸、其藥理學上可接受的酯、或藥理學上可接受的此等鹽。 4- ( 1-羥基-1-甲基乙基）-2-丙基( 1Η-四唑-5-基） 聯苯基-4-基甲基]咪唑-5-羧酸爲公知，例如，依特開平 φ 5-78328號公報（美國專利第5，616,599號說明書）等記載 之方法可容易地取得。 4- ( 1-羥基-1-甲基乙基）-2-丙基-1-[2，- ( 1Η-四唑- 5- 基）聯苯基-4-基甲基]咪唑-5-羧酸之藥理學上可接受的鹽 之種類並未特別限定，本項技術領域者可適宜選擇’例如’ 可列舉鈉鹽、鉀鹽、鋰鹽等鹼金屬鹽、鈣鹽、鎂鹽等鹼土 類金屬鹽、鋁鹽、鐵鹽、鋅鹽、銅鹽、鎳鹽 '鈷鹽等金屬 鹽；或銨鹽、t ·辛基胺鹽、二苄基胺鹽、嗎福琳鹽、葡糖 胺鹽' 苯基甘胺酸烷基酯鹽、乙二胺鹽、N -甲基葡萄糖胺 200934484 鹽、胍鹽、二乙基胺鹽、三乙基胺鹽、二環己基胺鹽、N， Ν’-二苄基乙二胺鹽、氯普魯卡因鹽、普魯卡因鹽、二乙 醇胺鹽、Ν-苄基-苯乙基胺鹽、哌畊鹽、四甲基銨鹽、參 (羥基甲基）胺基甲烷鹽等胺鹽等，但未限於此等。較佳 可使用鹼金屬鹽，特佳可使用鈉鹽。 4- ( 1-經基-1-甲基乙基）·2·丙基( 1Η-四唑- 5-基）聯苯基-4-基甲基]咪哩-5-竣酸之藥理學上可接受的醋 意指該化合物分子內之羧酸部分爲經酯化的化合物。藥理 0 學上可接受的酯之種類未特別限定，本項技術領域者可適 宜選擇。該酯於活體內經由水解等生物學方法可裂開獲得 者爲較佳。作爲構成該酯之基（該酯以- COOR表示的場合 中R所表示的基），例如，可列舉甲氧基甲基、丨_乙氧基乙 • 基、甲基-1-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-ΐ_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 氧基甲基等之C1-C4院氧基C1-C4院基；2 -甲氧基乙氧基 〇 甲基等之C1-C4烷氧基化C1-C4烷氧基C1-C4烷基；苯氧 基甲基等之C6-C10芳氧基C1-C4院基；2,2,2-三氯乙氧基 甲基或雙（2-氯乙氧基）甲基等之鹵素化C1_C4烷氧基 C1-C4烷基；甲氧基羰基甲基等之C1-C4烷氧基羰基C1-C4 烷基；氰基甲基或2-氰基乙基等之氰基C1-C4烷基；甲基 硫甲基或乙基硫甲基等之C1-C4烷基硫甲基；苯基硫甲基 或萘基硫甲基等之C6-C10芳基硫甲基；2-甲烷磺醯基乙基 或2 -三氟甲烷磺醯基乙基等之可經鹵素取代之C1-C4烷基 磺醯基C1-C4低級烷基；2-苯磺醯基乙基或2-甲苯磺醯基 200934484 乙基等之C6-C10芳基磺醯基C1-C4烷基；甲醯氧基甲基、 乙醯氧基甲基、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 φ 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、卜異戊醯氧基丙基、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 氧基己基等之C1-C7脂肪族醯氧基C1-C4烷基；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 〇 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 羰基氧基丁基等之C5-C6環烷基羰基氧基C1-C4烷基；苄 醯氧基甲基等之C6-C10芳基羰基氧基C1-C4烷基、甲氧 基羰基氧基甲基、1-(甲氧基羰基氧基）乙基、1-(甲氧 甲氧氧乙 { 乙乙 { I 1 ' ( 1 ' 基1-、 基己、基 丁 /-s 基丁 } 基乙 } 基氧}基 氧基基氧 基羰氧基 羰基基羰 基氧羰基 氧甲基氧 甲 C 氧乙 C1-乙 C I I 1 ' ( 1 、基1-、 基戊、基 丙} 基丙 } 基甲 } 基氧基基 氧基氧氧 基羰基基 羯基羰羰 基氧基基 -10- 200934484 氧基羰基氧基）戊基' ι-(乙氧基羰基氧基）己基、丙氧 基羰基氧基甲基、ι-(丙氧基羰基氧基）乙基、丨_(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-(異丙氧基羰基氧基）乙基、1-(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、Ια (異丁氧基羰基氧基）丁基、t-丁氧基羰基氧基甲基、1-(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）丙基等之C1-C6烷氧基羰基氧基C1-C4烷 基；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 ❹ 基）乙基、1·(環己氧基羰基氧基）丙基或1-(環己氧基 羰基氧基）丁基等之C5-C6環烷氧基羰基氧基C1-C4烷 基；（5-甲基-2-酮基-1，3-二氧戊環-4-基）甲基、（5-乙基-2-酮基-1，3-二氧戊環-4-基）甲基、（5-丙基-2-酮基-1,3-二氧 戊環-4-基）甲基、（5-異丙基-2-酮基-1，3·二氧戊環-4-基） 甲基或（5-丁基-2-酮基-1，3-二氧戊環-4-基）甲基等之[5-(C1-C4烷基）-2-酮基-1，3-二氧戊環-4-基]甲基；（5-苯基 -2-酮基-1，3-二氧戊環-4-基）甲基、[5- (4-甲基苯基）-2-酮基-1，3-二氧戊環-4-基]甲基、[5- (4-甲氧基苯基）-2-酮 -11- 200934484 基-1，3-二氧戊環-4-基]甲基、[5-( 4-氟苯基）-2·酮 二氧戊環-4-基]甲基或[5- (4-氯苯基）-2-酮基-1，3. 環-4-基]甲基等之[5-( C1-C4烷基、C1-C4烷氧基或 素取代之苯基）-2-酮基-1，3-二氧戊環-4-基]甲基、每 二甲基酞基或二甲氧基酞基等之可經C1-C4烷基或 烷氧基取代之酞基等。較佳可使用三甲基乙醯氧基 酞基、或（5-甲基-2-酮基-1,3-二氧戊環-4-基）甲基 可使用（5-甲基-2-酮基-1，3-二氧戊環-4·基）甲基c H 4- ( 1-羥基-1-甲基乙基）-2-丙基-l-[2’- ( 1H- 基）聯苯基-4-基甲基]咪唑-5-羧酸之酯爲形成藥理 接受的鹽的場合，藥理學上可接受的鹽之種類可由 ' 術領域者適宜選擇，未特別限定。例如，氟化氫酸 - 酸鹽、溴化氫酸鹽或碘化氫酸鹽等之鹵素化氫酸鹽 鹽；過氯酸鹽：硫酸鹽；磷酸鹽；甲烷磺酸鹽、三 磺酸鹽或乙烷磺酸鹽等之可經鹵素取代之 C1-C4 鹽；苯磺酸鹽、P-甲苯磺酸鹽等之可經C1-C4烷基 〇 C6-C10芳基磺酸鹽；乙酸、蘋果酸、反丁烯二酸鹽 酸鹽、檸檬酸鹽、酒石酸鹽、草酸鹽或順丁烯二酸 C1-C6脂肪酸鹽；或甘胺酸鹽、離胺酸鹽、精胺酸 胺酸鹽、麩胺酸鹽或天冬胺酸鹽等之胺基酸鹽等。 使用鹽酸鹽、硝酸鹽、硫酸鹽、或磷酸鹽，特佳爲 鹽酸鹽。 JUT. pqPs .γΤΠ. 作爲血管緊張素II受體拮抗劑，較佳可使用4 基-1-甲基乙基）-2 -丙基-1-[2’-( 1Η -四哩-5-基）聯 基甲基]咪唑-5-羧酸或其藥理學上可接受的酯，更佳 基-1，3 -•二氧戊 可經鹵 艺酞基、 C1-C4 甲基、 ，更佳 四唑-5-學上可 本項技 鹽、鹽 :硝酸 氟甲烷 烷磺酸 取代之 、丁二 鹽等之 鹽、鸟 CEil· 較佳可 可使用 -(1-羥 苯基-4- :可使用 -12- 200934484 4- ( 1-經基-1-甲基乙基）-2 -丙基- ( iH -四哩-5-基） 聯苯基-4-基甲基]咪唑-5-羧酸之其藥理學上可接受的酯， 再更佳爲4- ( 1-羥基-1·甲基乙基）2_丙基( 1只_四 嗤-5-基）聯苯基-4-基甲基]咪唑-5_羧酸之三甲基乙醯氧基 甲基酯、酞基酯、或（5-甲基-2-酮基-丨，3_二氧戊環-4-基） 甲基酯。最佳可使用（5-甲基-2·酮基- i，3_二氧戊環-4-基） 甲基4_( 羥基-1-甲基乙基）-2-丙基- l-[2，-( 1H-四唑- 5-基）聯苯基-4-基甲基]咪嗖-5-竣酸醋。 φ 作爲選自“（丨-羥基-1-甲基乙基）-2 -丙基-1-[2，-(1Η- 四嗤-5-基）聯苯基-4-基甲基]咪哩·5_竣酸及其藥理學上可 接受的酯、以及此等藥理學上可接受的鹽組成之群的物 質，亦可使用水合物或溶劑化物。 ' 使用4-(丨-羥基-1-甲基乙基）-2 -丙基-1-[2，-(1Η -四 哩-5-基）聯苯基-4-基甲基]咪哩-5-竣酸之其藥理學上可接 受的酯的場合’該酯化合物具有1或2以上之不對稱碳， 基於該不對稱碳亦可使用純粹形態之光學異構物或非對映 〇 異構物等之立體異構物、或立體異構物之任意混合物或外 消旋體等。 又，作爲本發明中可利用的血管緊張素II受體拮抗 劑，例如，可列舉咪唑衍生物（特開昭5 6 - 7 1 0 7 3號公報、 特開昭56-71074號公報、特開昭57-98270號公報、特開 昭 58-157768 號公報、USP4,355,040、USP4,340,598 等、 EP-25 3 3 1 0 、 EP-29 1 969 、 EP-3243 77 、 EP-403 1 58 、 WO-9 1 00277、特開昭63-23 868號公報、及特開平1-117876 號公報等）、吡咯、吡唑、及三唑衍生物（USP5,183,899、 -13- 200934484 EP-323841、 EP-409332、及特開平 1-287071 號公報等）、 苯并咪唑衍生物（USP4,880,804 、 EP-03923 1 7、 EP-0399732 ' EP-0400835 、 EP-425921 、 EP-459136 、特開 2001-10975號公報、及特開平3-632 64號公報等）、氮雜茚 (a z a i n d e n e )衍生物（E P · 3 9 9 7 3 1 等）、喃陡萌衍生物 (EP-407342等）、喹唑啉衍生物（EP-411766等）、黃嘌呤 衍生物（EP-430300等）、縮合咪唑衍生物（EP-434038等）、 嘧啶二酮衍生物（EP-442473等）、噻吩并吡啶酮衍生物 ❿ （EP-443568 等）、雜環化合物(EP-445 8 1 1 > EP-483683、 EP-518033 ' EP-520423 、 EP-588299、 EP-603712 等）等， 較佳可列舉洛沙坦（Losartan)、依普羅沙坦（Eprosartan)、 坎地沙坦醋（Candesartan cilexetil)、纈沙坦（Valsartan)、 - 替米沙坦（Telmisartan)、厄貝沙坦（Irbesartan)、他索沙 坦（Tasosartan)、阿齊沙坦（Azilsartan)、或此等之代謝活 性物質等。又，亦可此等化合物之生理學上可容許之鹽或 遊離形態或鹽形態之化合物之水合物或溶劑化物、或前藥 ^ 等衍生物。再者，阿齊沙坦酯（azilsartan medoxomil )、2-環丙基-l-{ [2’ -(5-酮基·4,5-二氫-1，2,4-噚二唑-3-基）聯苯 基-4-基]甲基} -1H-苯并咪嗖-7-羧酸（5-甲基-2-酮基-1,3-二氧雜環戊烯4-基）甲基或其鹽及2-環丙基-l-{[2’-(5-酮 基-2,5-二氫-1,2,4-噚二唑-3-基）聯苯基-4-基]甲基} -1H-苯 并咪唑-7-羧酸（5-甲基-2-酮基-1，3-二氧雜環戊烯4-基）甲 基或其鹽，作爲高血壓症等之治療藥被認爲是有希望的， 經由國際公開第 2005/080384號小冊或國際公開第 2006/107062號小冊等揭示之方法或依據此等之方法等可 -14- 200934484 製造。 本發明之醫藥可用於伴隨眼內血管透過性亢進疾病之 預防或治療。本說明書中「預防或治療」之用語除了疾病 之改善或治癒外，亦包含疾病進行之抑制、發病之阻止、 及再發之預防等》「預防或治療」之用語無論爲何意義亦不 作限定解釋，此用語必須最廣義地解釋。 作爲眼內中血管透過性亢進的疾病，例如，包含糖尿 病網膜症（單純網膜症、前增殖網膜症、增殖網膜症）、網 0 膜靜脈閉塞症、網膜動脈閉塞症、老年黃斑病變、中心性 漿液性網脈絡膜症、糖尿病黃斑浮腫、囊胞樣黃斑浮腫、 葡萄膜炎、或貝西氏病等。 ' 可用於糖尿病網膜症（單純網膜症、前增殖網膜症、 - 增殖網膜症）、網膜靜脈閉塞症、網膜動脈閉塞症、老年黃 斑病變、中心性漿液性網脈絡膜症、糖尿病黃斑浮腫、囊 胞樣黃斑浮腫、葡萄膜炎、或貝西氏病等之眼內中血管透 過性亢進的疾病之預防或治療。 φ 上述血管緊張素II受體拮抗劑因一般爲經口投與的藥 劑，故本發明之醫藥期望爲經口投與者。然而，本發明醫 藥之投與形態未限於經口投與，例如亦可靜脈內投與、直 腸內投與、經皮投與、經黏膜投與、點眼投與等非經口投 與。作爲適於經口投與的單位投與形態，例如，可列舉散 劑、顆粒劑、錠劑、膠囊劑等，但未限定於此。於單位投 與形態之調製時，可使用適宜之I或2種以上藥理學上可 接受的賦形劑、潤滑劑、結合劑、崩壞劑、乳化劑、安定 劑、矯味矯臭劑、稀釋劑等製劑用添加物。 -15- 200934484 作爲製劑用添加物，例如，可列舉賦形劑（例如，可 列舉乳糖、白糖、葡萄糖、甘露糖醇或山梨糖醇等之糖衍 生物；玉米澱粉、馬鈴薯澱粉、α澱粉或糊精等之澱粉衍 生物；結晶纖維素等之纖維素衍生物；阿拉伯樹膠；葡聚 糖；或普魯蘭多糖（Pullulan)等之有機系賦形劑；或，輕 質無水矽酸、合成矽酸鋁、矽酸鈣、或偏矽酸鋁酸鎂等之 酸鹽衍生物；磷酸氫鈣等之磷酸鹽；碳酸鈣等之碳酸鹽； 硫酸鈣等之硫酸鹽等之無機系賦形劑）、潤滑劑（例如，可 φ 列舉硬脂酸、硬脂酸鈣或硬脂酸鎂等之硬脂酸金屬鹽；滑 石；蜂蠟或鯨蠟等之蠟類；硼酸；己二酸；硫酸鈉等之硫 酸鹽：二醇；反丁烯二酸；苯甲酸鈉；DL白胺酸；月桂基 ' 硫酸鈉或月桂基硫酸鎂等之月桂基硫酸鹽；或無水矽酸或 - 矽酸水合物等之矽酸類；或，上述澱粉衍生物）、結合劑（例 如，可列舉羥基丙基纖維素、羥基丙基甲基纖維素、聚乙 烯吡咯啶酮、聚乙二醇（macrogol )、或相同於前述賦形劑 之化合物）、崩壞劑（例如，可列舉低取代度羥基丙基纖維 0 素、羧基甲基纖維素、羧基甲基纖維素鈣或內部交聯羧基 甲基纖維素鈉等之纖維素衍生物；羧基甲基澱粉、羧基甲 基澱粉鈉或交聯聚乙烯吡咯啶酮等之經化學修飾的澱粉· 纖維素類；或上述澱粉衍生物）、乳化劑（例如，可列舉膨 潤土或VEEGUM®等之膠性黏土；氫氧化鎂或氫氧化鋁等之 金屬氫氧化物；月桂基硫酸鈉或硬脂酸鈣等之陰離子界面 活性劑；氯化苄烷銨等之陽離子界面活性劑；或，聚氧乙 烯烷基醚、聚氧乙烯山梨聚糖脂肪酸酯或蔗糖脂肪酸酯等 之非離子界面活性劑）、安定劑（例如，可列舉對羥苯甲酸 -16- 200934484 甲酯或對羥苯甲酸丙酯等之對羥苯甲酸酯類；氯丁醇、节 醇或苯乙醇等之醇類；氯化苄烷銨；苯酚或甲酚等之酚類； 硫柳隶；去氫乙酸；或山梨酸等）、矯味橋臭劑（例如，可 列舉通常使用之甘味料、酸味料或香料等）、或稀釋劑等， 但未限於此等。 本發明之醫藥之投與量視投與路徑、有效成分種類、 患者年齡、體重、或症状、預防或治療目的等各種要因可 適宜選擇，但一般而言，可投與成人每一日之血管緊張素 0 II受體拮抗劑之重量爲約0.001〜1,000 mg，較佳爲0.1〜 500 mg，更佳爲5〜80 mg左右之範圍內。 實施例 ' 以下，由實施例及製劑例更具體地説明本發明，但本 - 發明之範圍未受限於下列實施例。 試驗例 將出生後 7 日齡之 Brown-Norway 大鼠（日本 Charlesriver)與母大鼠一起於70-75%氧氣下飼育至出生後 φ 12日齡。之後，回到大氣下飼育至出生後16日齡。大氣 下飼育中，將奧美沙坦酯之懸濁液（溶劑：0.5 %羧基甲基 纖維素）或溶劑（0.5 %羧基甲基纖維素）以1日1次經口 投與。投與終了後，網膜血管透過性經由FITC -葡聚糖法 (Ishida 等人 ’ Invest · Οphtha 1 mο 1· Vis . Sci. 2003; 44: 2155-2162)之修改法測定。即，經由戊巴比妥 (pentobarbitone)(50mg/kg)腹腔內投與麻醉下，對動物 大腿靜脈投與FITC-葡聚糖（分子量4.4kDa) 100mg/kg。 1 〇分鐘後開胸，自心臓採取血液樣品。接著’於經由右心 -17- 200934484 房切開確保排出路徑上，自插到左心室的插管以80mmHg 壓力灌流PBS2分鐘，摘出網膜。測定網膜濕重量，於0.3 ml 蒸餾水中進行均質化，經由離心過濾器（Millipore Ultrafree-MC;分子量3 0,000 )進行過濾。另一方面，經 由血液樣品之離心分離，獲得血漿。網膜之濾液及血漿中 之色素量以微量平盤讀數器（激發波長485nm，螢光波長 535nm)測定’扣除作爲空白組之未進行色素投與的動物之〇200934484 oxazol-5-carboxylic acid and its pharmacologically acceptable esters, and a pharmacological group of such an angiotensin receptor antagonizing benzyl-2-keto-1,3-dioxolane -4·yl)methyl 4-(1-ethyl)-2-propyl-1-[2'-(1Η-tetrazole·5·yl)biphenyl 3 imidazole-5-carboxylate via this The invention provides a mammalian method comprising administering a prophylactic or an active ingredient as described above to a human. The present inventors have pointed out that angiotensin π receptor antagonist (5-methyl-2-keto-1,3-dioxolan-4-yl)methyl 4-methylethyl)-2-propene Alkyl-1-[2'·(1Η-tetrazol-5-yl)alkyl]imidazole-5·carboxylate (hereinafter referred to as "olmesartan melon") has been shown to have improved vascular permeability in the eye. The possibility of encountering. At the present point, there is no report on the vascular permeabilization of the eye in the range of the known range, and the novelty is taken care of. This drug has been clinically used as a blood-reducing blood vessel with intraocular blood vessels. The problem is that there are five problems without problems in patients with inflammatory disease. The effect of the invention contains an angiotensin II receptor antagonist as an effective medicine, and it is used for diabetic retinopathy (reovascular disease, pre-proliferative retinopathy), omentum. Prevention or treatment of venous occlusive disease, retinal artery plaque lesions, central serous choroidosis, diabetic cystoid edema, uveitis, or Beth's disease. [Embodiment] Acceptable oxime, more preferably (5-hydroxy-1-methyl I -4-ylmethyl) therapeutically effective amount One of the steps of the prescription. (1-hydroxy-1-phenyl-4-yl-methyl [Ο lme s artan hyperthyroidism disease valsartan ester changed this point has a drug, with a full range of aspects of the invention Retinal disease, disease, age-related macular edema, intracapsular vascular permeability 200934484 Inventive Best Practice Sample Invented, angiotensin II receptor antagonist refers to competitive or non-competitive inhibition of angiotensin II on angiotensin A substance which binds to a receptor II. An angiotensin II receptor antagonist is a low molecular organic compound, a peptide compound, or a saccharide compound, and may be a polymer compound such as a protein, a glycoprotein, or a polysaccharide compound. Whether or not angiotensin II receptor antagonism is effective can be easily confirmed by those skilled in the art, for example, in the method described in the specification of U.S. Patent No. 5,616,599. "Angiotensin II receptor antagonist" used in the present specification 0 The terminology, no matter what the meaning is, is not to be construed as limiting, and must be interpreted in the broadest sense. As an angiotensin η receptor antagonist suitable for use in the medicine of the present invention • An example of an anti-agent, for example, 4-(1·hydroxy-1-methylethyl)-2 - •propyl-1-[2,-(1Η-tetrazol-5-yl)biphenyl 4-ylmethyl]imidazol-5-carboxylic acid, a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt. 4-(1-hydroxy-1-methylethyl)-2 -propyl (1Η-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylic acid is known, for example, from JP-A-5-78328 (U.S. Patent No. 5,616,599) The method described in the specification can be easily obtained. 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[2,-(1Η-tetrazole-5-yl)biphenyl The kind of the pharmacologically acceptable salt of the benzyl-4-ylmethyl]imidazol-5-carboxylic acid is not particularly limited, and those skilled in the art may suitably select 'for example', and may, for example, be a sodium salt, a potassium salt or a lithium salt. Alkaline metal salts, calcium salts, magnesium salts and other alkaline earth metal salts, aluminum salts, iron salts, zinc salts, copper salts, nickel salts 'cobalt salts and the like metal salts; or ammonium salts, t · octylamine salts, dibenzyl Base amine salt, ifolin salt, glucosamine salt 'phenyl phenylglycine alkyl ester salt, ethylene diamine salt, N-methyl glucosamine 20093 4484 salt, strontium salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, Ν'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, An amine salt such as a diethanolamine salt, a hydrazine-benzyl-phenethylamine salt, a piperazine salt, a tetramethylammonium salt or a hydroxymethylaminomethane salt is not limited thereto. It is preferred to use an alkali metal salt, and particularly preferably a sodium salt. Pharmacology of 4-(1-carbyl-1-methylethyl)·2·propyl ( 1Η-tetrazole-5-yl)biphenyl-4-ylmethyl]imidon-5-decanoic acid By acceptable vinegar is meant a carboxylic acid moiety within the molecule of the compound that is an esterified compound. Pharmacology 0 The types of the acceptable esters are not particularly limited, and those skilled in the art can suitably select them. It is preferred that the ester is cleaved by a biological method such as hydrolysis in vivo. Examples of the group constituting the ester (the group represented by R in the case where the ester is represented by -COOR) include, for example, methoxymethyl group, oxime ethoxymethyl group, and methyl-1-methoxy group. Ethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-oxime-methoxymethyl, ethoxymethyl C1-C4-laboxy-C1-C4-terminated group such as propyl, propoxymethyl, isopropoxymethyl or t-butoxymethyl; 2-methoxyethoxy C1-C4 alkoxylated C1-C4 alkoxy C1-C4 alkyl group of 〇methyl etc; C6-C10 aryloxy C1-C4 courtyard group of phenoxymethyl group; 2,2,2-three Halogenated C1_C4 alkoxy C1-C4 alkyl group such as chloroethoxymethyl or bis(2-chloroethoxy)methyl; C1-C4 alkoxycarbonyl C1-C4 such as methoxycarbonylmethyl Alkyl; cyano C1-C4 alkyl such as cyanomethyl or 2-cyanoethyl; C1-C4 alkylthiomethyl such as methylthiomethyl or ethylthiomethyl; phenylthio a C6-C10 aryl thiomethyl group such as a naphthylthiomethyl group; a C1-C4 alkyl sulfonyl group which may be halogen-substituted, such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl醯基C1 -C4 lower alkyl; 2-phenylsulfonylethyl or 2-toluenesulfonyl 200934484 C6-C10 arylsulfonyl C1-C4 alkyl such as ethyl; methyloxymethyl, ethoxylated Methyl, propenoxymethyl, butyloxymethyl, trimethylacetoxymethyl, pentyloxymethyl, isoamyloxymethyl, hexyloxymethyl, 1-Methoxyoxyethyl, 1-ethyloxyethyl, 1-propoxyethyl, 1-butenoxyethyl, 1-trimethylethyloxyethyl, 1- Pentamethoxyethyl, 1-isopentyloxyethyl, 1-hexyloxyethyl, 2-methyloxyethyl, 2-ethyloxyethyl, 2-propoxy Ethyl, 2-butoxycarbonylethyl, 2-trimethylacetoxyethyl, 2-pentyloxyethyl, 2-isopentyloxyethyl, 2-hexyloxy Ethyl, 1-methyloxypropyl, 1-ethoxymethoxypropyl, 1-propoxypropyl, 1-butoxypropyl, 1-trimethylethoxypropyl , 1-pentyloxypropyl, puisoamyloxypropyl, 1-hexyloxypropyl, '1-acetoxybutyl, 1-propoxybutyl, 1-butyl Oxyloxybutyl, 1- • trimethylacetoxy , 1-ethenyloxypentyl, 1-propenyloxypentyl, 1-butenoxypentyl, 1-trimethylethenyloxypentyl or 1-trimethylethenyloxy C1-C7 aliphatic decyloxy C1-C4 alkyl group of hexyl group, etc.; cyclopentylcarbonyloxymethyl group, cyclohexylcarbonyloxymethyl group, 1-cyclopentylcarbonyloxyethoxymethyl group, 1-cyclohexyl group C5 such as carbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl -C6 cycloalkylcarbonyloxy C1-C4 alkyl; benzyloxymethyl and the like C6-C10 arylcarbonyloxy C1-C4 alkyl, methoxycarbonyloxymethyl, 1-(methoxy Alkylcarbonyloxy)ethyl, 1-(methoxymethoxyethoxy){ethyl b{I 1 '( 1 'yl 1-, hexyl, butyl/-s butyl butyl} yl} oxy}yloxy Base oxycarbonyloxycarbonylcarbonylcarbonylcarbonyloxymethyloxymethyl C oxyethyl C1-ethyl CII 1 '(1,yl-1,ylpentyl,ylpropano)yl}yl}yloxyoxyl Oxyoxycarbonylcarbonyl fluorenylcarbonylcarbonyloxy-10-104 2009484 oxycarbonyloxy)pentyl ' ι-(ethoxycarbonyloxyl Hexyl, propoxycarbonyloxymethyl, i-(propoxycarbonyloxy)ethyl, 丨-(propoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)butyl , isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)butyl, butoxycarbonyloxymethyl, 1- (butoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)butyl, isobutoxycarbonyloxymethyl, 1-( Isobutoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)propyl, Ια (isobutoxycarbonyloxy)butyl, t-butoxycarbonyloxymethyl, 1 -(t-butoxycarbonyloxy)ethyl, pentyloxycarbonyloxymethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)propyl, hexyl C1-C6 alkoxycarbonyloxy C1-C4 alkane such as oxy-carbonylcarbonylmethyl, 1-(hexyloxycarbonyloxy)ethyl or 1-(hexyloxycarbonyloxy)propyl Cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propane , 1-(cyclopentyloxycarbonyloxy)butyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1·(cyclohexyloxycarbonyloxy) a C5-C6 cycloalkoxycarbonyloxy C1-C4 alkyl group such as propyl or 1-(cyclohexyloxycarbonyloxy)butyl; (5-methyl-2-keto-1,3-) Dioxol-4-yl)methyl, (5-ethyl-2-keto-1,3-dioxolan-4-yl)methyl, (5-propyl-2-keto- 1,3-dioxolan-4-yl)methyl, (5-isopropyl-2-keto-1,3.dioxolan-4-yl)methyl or (5-butyl- [5-(C1-C4 alkyl)-2-keto-1,3-dioxolan-4-yl, 2-keto-1,3-dioxolan-4-yl)methyl Methyl; (5-phenyl-2-keto-1,3-dioxolan-4-yl)methyl, [5-(4-methylphenyl)-2-keto-1, 3-Diethoxypentan-4-yl]methyl, [5-(4-methoxyphenyl)-2-one-11- 200934484-1,3-1,3-dioxolan-4-yl]- , [5-(4-fluorophenyl)-2. ketodioxolan-4-yl]methyl or [5-(4-chlorophenyl)-2-keto-1,3. 4-yl]methyl or the like [5-(C1-C4 alkyl, C1-C4 alkoxy or phenyl substituted phenyl)-2-keto-1,3- Dioxolan-4-yl] methyl, dimethyl phthalate per dimethoxy phthalidyl group or the like may be substituted with the C1-C4 alkyl group or alkoxy phthalocyanine and the like. Preferably, trimethylacetoxyfluorenyl or (5-methyl-2-keto-1,3-dioxolan-4-yl)methyl can be used (5-methyl-2). -keto-1,3-dioxolan-4.yl)methyl c H 4-(1-hydroxy-1-methylethyl)-2-propyl-l-[2'- ( 1H- When the ester of the bisphenyl-4-ylmethyl]imidazol-5-carboxylic acid is a pharmaceutically acceptable salt, the type of the pharmacologically acceptable salt can be appropriately selected from the art, and is not particularly limited. For example, a hydrogen halide salt of a hydrogen fluoride acid salt, a hydrogen bromide or a hydrogen iodide; a perchlorate: a sulfate; a phosphate; a methanesulfonate, a trisulfonate or a a C1-C4 salt which may be halogen-substituted with an alkanesulfonate or the like; a C1-C4 alkyl sulfonium C6-C10 aryl sulfonate such as a benzenesulfonate or a P-toluenesulfonate; acetic acid, malic acid , a fumarate, a citrate, a tartrate, an oxalate or a C1-C6 fatty acid salt of maleic acid; or a glycinate, an aminate, an arginine, An amino acid salt such as glutamate or aspartate or the like. A hydrochloride, a nitrate, a sulfate, or a phosphate is used, and a hydrochloride is particularly preferred. JUT. pqPs .γΤΠ. As an angiotensin II receptor antagonist, 4-yl-1-methylethyl)-2-propyl-1-[2'-(1Η-tetraindole-5- is preferably used. Alkylmethyl]imidazole-5-carboxylic acid or a pharmacologically acceptable ester thereof, more preferably 1,3 -•dioxol can be halogenated fluorenyl, C1-C4 methyl, and Jiatetrazol-5-study can be used in this formula salt, salt: fluoromethanesulfonic acid substituted with butyl chloride, salt, bird CEil, preferably cocoa-(1-hydroxyphenyl-4-: -12- 200934484 4-(1-Phenyl-1-methylethyl)-2-propyl-(iH-tetradec-5-yl)biphenyl-4-ylmethyl]imidazole-5 can be used. a pharmacologically acceptable ester of a carboxylic acid, more preferably 4-(1-hydroxy-1.methylethyl)2-propyl (1 _tetraind-5-yl)biphenyl- Trimethyl ethoxymethyl methyl ester of 4-methylmethyl]imidazole-5-carboxylic acid, decyl ester, or (5-methyl-2-keto-anthracene, 3-dioxolane-4 -yl)methyl ester. The best use is (5-methyl-2.keto-i,3-dioxolan-4-yl)methyl 4_(hydroxy-1-methylethyl)-2 -propyl- l-[2,-( 1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidate-5- Acidic vinegar. φ is selected from "(丨-hydroxy-1-methylethyl)-2-propyl-1-[2,-(1Η-tetradec-5-yl)biphenyl-4-yl A substance or a pharmacologically acceptable ester, and a group of such pharmacologically acceptable salts can also be used as a hydrate or a solvate. 'Using 4-(丨-hydroxy-1-methylethyl)-2-propyl-1-[2,-(1Η-tetradec-5-yl)biphenyl-4-ylmethyl]imidine-5-decanoic acid In the case of a pharmacologically acceptable ester, the ester compound has an asymmetric carbon of 1 or more, and based on the asymmetric carbon, a stereoscopic optical isomer or a diastereomeric isomer can also be used. An isomer or a mixture of any of the stereoisomers, a racemate, etc. Further, as an angiotensin II receptor antagonist which can be used in the present invention, for example, an imidazole derivative can be cited. - 7 1 0 7 3rd, JP-A-56-71074, JP-A-57-98270, JP-A-58-157768, USP 4,355,040, USP 4,340,598, etc., EP-25 3 3 1 0 , EP-29 1 969 , EP-3243 77 , EP-403 1 58 WO-9 1 00277, JP-A-63-23 868, and JP-A-1-117876, etc., pyrrole, pyrazole, and triazole derivatives (USP 5,183,899, -13-200934484 EP-323841, EP-409332, and JP-A-1-287071, etc., benzimidazole derivatives (USP 4,880,804, EP-03923 1 7 , EP-0399732 'EP-0400835, EP-425921, EP-459136, special open 2001 -10975, and JP-A-3-632 64, etc., azaindene derivatives (EP · 3 9 9 7 3 1 , etc.), stagnation derivatives (EP-407342, etc.), quinine Oxazoline derivatives (EP-411766, etc.), xanthine derivatives (EP-430300, etc.), condensed imidazole derivatives (EP-434038, etc.), pyrimidinedione derivatives (EP-442473, etc.), thienopyridone derivatives A substance (EP-443568, etc.), a heterocyclic compound (EP-445 8 1 1 > EP-483683, EP-518033 'EP-520423, EP-588299, EP-603712, etc.), etc., preferably exemplified by Loxa Losartan, Eprosartan, Candesartan cilexetil, Valsartan, - Telmisartan Artan), Irbesartan, Tasosartan, Azilsartan, or such metabolically active substances. Further, a physiologically acceptable salt of the compound or a hydrate or solvate of a compound in a free form or a salt form, or a derivative such as a prodrug may be used. Furthermore, azilsartan medoxomil, 2-cyclopropyl-l-{[2'-(5-keto-4,5-dihydro-1,2,4-oxadiazole-3) -yl)biphenyl-4-yl]methyl}-1H-benzopyrene-7-carboxylic acid (5-methyl-2-keto-1,3-dioxol-4-yl) Methyl or its salt and 2-cyclopropyl-l-{[2'-(5-keto-2,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl 4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5-methyl-2-keto-1,3-dioxol-4-yl)methyl or a salt thereof, It is considered to be promising as a therapeutic drug for hypertension, etc., and may be disclosed by the method disclosed in International Publication No. 2005/080384 or International Publication No. 2006/107062, or the like. - 200934484 Manufactured. The medicament of the present invention can be used for the prevention or treatment of vascular hyperreactive diseases in the eye. The term "prevention or treatment" in this manual includes, in addition to the improvement or cure of the disease, the suppression of the disease, the prevention of the disease, and the prevention of recurrence. The term "prevention or treatment" is not intended to be construed as a limitation. This term must be interpreted in the broadest sense. As a disease of hypervascular hyperpermeability in the eye, for example, including diabetic retinopathy (reticulolateral disease, preproliferative retinopathy, proliferative retinopathy), venous venous occlusion, retinal artery occlusion, age-related macular degeneration, centrality Serous choroidal diarrhea, diabetic macular edema, cystic macular edema, uveitis, or Beth's disease. 'Can be used for diabetic retinopathy (reticulolateral disease, preproliferative retinopathy, - proliferative retinopathy), omental venous occlusion, retinal artery occlusion, age-related macular degeneration, central serous choroidosis, diabetic macular edema, cystic Prevention or treatment of diseases such as macular edema, uveitis, or Besie's disease, which are vascular hyperpermeability in the eye. φ The above angiotensin II receptor antagonist is generally an orally administered drug, and therefore the pharmaceutical of the present invention is expected to be orally administered. However, the administration form of the medicament of the present invention is not limited to oral administration, and may be administered, for example, by intravenous administration, intrarectal administration, transdermal administration, transmucosal administration, or ophthalmic administration. Examples of the unit administration form suitable for oral administration include a powder, a granule, a tablet, a capsule, and the like, but are not limited thereto. When the unit dosage form is prepared, one or two or more kinds of pharmacologically acceptable excipients, lubricants, binders, disintegrating agents, emulsifiers, stabilizers, flavoring agents, and diluents may be used. Additives for preparations. -15- 200934484 As an additive for preparation, for example, an excipient (for example, a sugar derivative such as lactose, white sugar, glucose, mannitol or sorbitol; corn starch, potato starch, alpha starch or a starch derivative such as dextrin; a cellulose derivative such as crystalline cellulose; an arabic gum; a glucan; or an organic excipient such as pullulan; or a light anhydrous citric acid, synthetic An acid salt such as aluminum citrate, calcium citrate or magnesium metasilicate aluminate; a phosphate such as calcium hydrogen phosphate; a carbonate such as calcium carbonate; an inorganic excipient such as a sulfate such as calcium sulfate; And a lubricant (for example, φ can be listed as stearic acid, calcium stearate or magnesium stearate, etc.; talc; beeswax or cetyl wax; boric acid; adipic acid; Sulfate: diol; fumaric acid; sodium benzoate; DL leucine; lauryl sulfate such as lauryl 'sodium sulfate or lauryl magnesium sulfate; or anhydrous citric acid or - citric acid hydrate Anthracene acid; or, the above starch derivative), combined (For example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or a compound similar to the aforementioned excipients), a breaker (for example, Examples thereof include cellulose derivatives of low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, or internally crosslinked carboxymethylcellulose sodium; carboxymethyl starch, carboxymethyl starch a chemically modified starch or a cellulose such as sodium or a cross-linked polyvinylpyrrolidone; or a starch derivative; or an emulsifier (for example, a colloidal clay such as bentonite or VEEGUM®; magnesium hydroxide or hydrogen; a metal hydroxide such as alumina; an anionic surfactant such as sodium lauryl sulfate or calcium stearate; a cationic surfactant such as benzalkonium chloride; or a polyoxyethylene alkyl ether or a polyoxyethylene sorbent a nonionic surfactant such as a glyco fatty acid ester or a sucrose fatty acid ester) or a stabilizer (for example, a paraben of p-hydroxybenzoic acid-16-200934484 methyl ester or propyl paraben may be mentioned. class; Alcohols such as butanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thiosulfate; dehydroacetic acid; or sorbic acid, etc., flavoring bridge odor (for example, The sweetener, sour or flavor, etc. which are usually used, or a diluent, etc. are mentioned, but it is not limited to these. The dosage of the medicine of the present invention can be appropriately selected depending on the route of administration, the type of active ingredient, the age, weight, or symptom of the patient, the purpose of prevention or treatment, but generally, the blood vessel of the adult can be administered every day. The weight of the angiotensin 0 II receptor antagonist is from about 0.001 to 1,000 mg, preferably from 0.1 to 500 mg, more preferably from about 5 to 80 mg. EXAMPLES Hereinafter, the present invention will be specifically described by examples and formulation examples, but the scope of the invention is not limited to the following examples. Test Example Brown-Norway rats (Japan Charlesriver) 7 days old after birth were bred together with mother rats under 70-75% oxygen to φ 12 days of age after birth. After that, return to the atmosphere and feed to 16 days after birth. In the intragastric feeding, a suspension of olmesartan medoxomil (solvent: 0.5% carboxymethylcellulose) or a solvent (0.5% carboxymethylcellulose) was orally administered once a day. After the administration, the retinal vascular permeability was measured by the modification method of the FITC-dextran method (Ishida et al. 'Invest · Οphtha 1 mο 1 · Vis. Sci. 2003; 44: 2155-2162). Namely, FITC-dextran (molecular weight 4.4 kDa) 100 mg/kg was administered to the thigh vein of the animal under anesthesia under pentobarbitone (50 mg/kg). 1 Open the chest after a few minutes and take a blood sample from your heart. Then, the incision was made through the right heart -17-200934484 to ensure that the cannula inserted into the left ventricle was perfused with PBS for 2 minutes at a pressure of 80 mmHg, and the omentum was removed. The wet weight of the reticulum was measured, homogenized in 0.3 ml of distilled water, and filtered through a centrifugal filter (Millipore Ultrafree-MC; molecular weight 3,000). On the other hand, plasma is obtained by centrifugation of a blood sample. The amount of the pigment in the filtrate and plasma of the omentum was measured by a microplate reader (excitation wavelength 485 nm, fluorescence wavelength 535 nm) minus the animals that were not subjected to pigment administration as a blank group.
❹ 網膜濾液之螢光。 網膜血管透過性爲網膜中色素濃度除以 血漿中色素濃度， 再除以網膜濕重量而求得。 製劑例1 :膠囊劑 奧美沙坦酯 20.0 mg 乳糖 15 8.7 mg 玉米澱粉 7 0.0 mg 硬脂酸鎂 1.3 mg 合計 2 5 0 mg 混合上述處方之粉末，通過60網孔篩後，將此粉末放 入25 Omg之3號明膠膠囊，作成膠囊劑。 製劑例2 :錠劑 奧美沙坦酯 2 0.0 mg 乳糖 15 4.0 mg 玉米澱粉 2 5.0 mg 硬脂酸鎂 1.0 mg 合計 2 0 0 mg 混合上述處方之粉末，經由打錠機打錠，作成1錠200 mg之錠劑》此錠劑視需要可施加糖衣。 -18- 200934484 産業上之利用可能性 依據本發明，提供伴隨眼內血管透過性充進疾病之預 防或治療上有用的醫藥成爲可能。 【圖式簡單說明】 第1圖 新生仔大鼠氧氣誘發網膜血管透過性亢進模式中奧美 沙坦酯之作用。N爲大氣下飼育/溶劑投與群，v爲氧氣負 荷/溶劑投與群，CS0.3爲氧氣負荷/奧美沙坦酯0.3 mg/kg 〇 投與群，CS1爲奧美沙坦酯1 mg/kg投與群，及CS3爲奧 美沙坦酯3 mg/kg投與群。資料以平均値±標準誤差表示。 ##表示相對於大氣下飼育/溶劑投與群爲 P<0.01(Student’s-t test)、*表示相對於氧氣負荷/溶劑投與 ’ 群爲P<0.0 5 ( Dunnett’s test)、**表示相對於氧氣負荷/溶 劑投與群爲 Ρ<〇·〇1 ( Dun nett’s test)。 【主要元件符號說明】萤 Fluorescence of the omentum filtrate. The vascular permeability of the omentum is obtained by dividing the pigment concentration in the omentum by the pigment concentration in the plasma and dividing it by the wet weight of the omentum. Formulation Example 1: Capsule olmesartan medoxomil 20.0 mg Lactose 15 8.7 mg Corn starch 7 0.0 mg Magnesium stearate 1.3 mg Total 2 5 0 mg The powder of the above formulation was mixed, and after passing through a 60 mesh sieve, the powder was placed. 25 Omg No. 3 gelatin capsules, made into capsules. Formulation Example 2: Lozenge olmesartan medoxomil 2 0.0 mg Lactose 15 4.0 mg Corn starch 2 5.0 mg Magnesium stearate 1.0 mg Total 2 0 0 mg The powder of the above prescription is mixed, and the ingot is ingot by a tableting machine to make 1 ingot 200 The tablet of mg" This tablet can be coated with sugar if necessary. -18- 200934484 Industrial Applicability According to the present invention, it is possible to provide a preventive or therapeutically useful medicine accompanying an intraocular vascular perfusion disease. [Simplified illustration] Figure 1 The effect of olmesartan medoxomil on oxygen-induced revascularization in neonatal rats. N is the under-breeding/solvent-administered group, v is the oxygen load/solvent-administered group, CS0.3 is the oxygen load/olmesartan medoside 0.3 mg/kg 〇, and CS1 is olmesartan medoxomil 1 mg/ The kg was administered to the group, and CS3 was the olmesartan medoxomil 3 mg/kg donor group. Data are expressed as mean ± standard error. ## indicates that the diet/solvent group is P<0.01 (Student's-t test), * indicates that it is relative to the oxygen load/solvent, and the group is P<0.0 5 ( Dunnett's test), ** indicates relative The oxygen load/solvent administration group is Dun Dun 〇 ( 1 ( Dun nett's test). [Main component symbol description]
Arrt. 無。 -19-Arrt. None. -19-