TW546145B - Agent for treating visual cell function disorder with macrolide compound as active ingredient - Google Patents

Agent for treating visual cell function disorder with macrolide compound as active ingredient Download PDF

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TW546145B
TW546145B TW088122634A TW88122634A TW546145B TW 546145 B TW546145 B TW 546145B TW 088122634 A TW088122634 A TW 088122634A TW 88122634 A TW88122634 A TW 88122634A TW 546145 B TW546145 B TW 546145B
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active ingredient
agent
eye
macrolide compound
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Ryuji Ueno
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R Tech Ueno Ltd
Fujisawa Pharmaceutical Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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Abstract

The present invention provides an agent for treating visual cell function disorder containing an interleukin inhibitor such as macrolide compound, particularly FK506. An agent for treating ischemic retinopathy comprising a macrolide compound FK506 as active ingredient in the form of a preparation for local administration to the eye.

Description

經濟部智慧財產局員工消費合作社印製 546145 A7 B7 五、發明說明（6) R 13 、R14 、R 15 、R 16 、R 丄？、R 18 、R 19 、R22 和 R 23 分別 獨立表示氫原子或烷基； R 24為内含一個或K上雜原子之任意經取代環；且 η 為1或2 。 除了上述之定義以外，Υ 、R 1(5和R 23可與其結合之碳 原子共同表示内含氮原子、硫原子和/或氧原子之飽和 或不飽和五或六員雜環基，此雜環基可任意經一個或Μ 上之基團選自烷基、羥基、烷氧基、苄基、式 -CH 2 Se (C 6 Η ς )、和經一個或以上羥基所取代之烷基 所取代。 R 24較佳例如為任意具有適當取代基之環（C 5 - C 7 )烷 環，如下所列。 U) 3, 4 -二氧基環己基； (b) S-Rm-Ui21 環己基， 其中R20為羥基、烷氧基或-OCH2 OCH2 CH2 〇CH3 , 而 R21為羥基、-0CN、烷氧基、具有適當取代基之 雜芳氧基、-0CH2 OCH2 CH2 0CH3 、被保護羥基 、氯基、溴基、碘基、胺基鸣唑氧基、疊氮基、 對-甲苯氧硫羰氧基、或R25R2eCHC00-(其中R25 為任意經保護之羥基或被保護胺基，且R 26為氫 原子或甲基， 或R 2(3和R 21结合形成環氧基之氧原子）；或 (c) 環戊基其中環戊基為視需要，經甲氧甲基、任意被 -8 一 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------—--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 546145 經濟部智慧財產局員工消費合作社印製 A7 B7__ 五、發明說明（7 ) 保護羥甲基、醯氧甲基（其中醯基部分為任意季胺 化之二甲胺基或任意酯化羧基）、一個或Μ上任意 被保護胺基和/或羥基、或胺鸣唑氧甲基所取代。 式（I )所使用之各符號定義，其特殊例及其較佳具體 例為詳述於下。 「低」意指具有1至6個碳原子之基，除非另外指明。 「烷基」和「烷氧基」之烷基部分的較佳例包括直或 分支脂族羥類殘基，如低烷基（如甲基、乙基、丙基、 異丙基、丁基、異丁基、戊基、新戊基、己基等）。 「烯基」之較佳例包括具有一個雙鍵之直或分支脂族 烴類殘基，如低烯基（如乙烯基、丙烯基（如烯丙基等） 、丁烯基、甲基丙烯基、戊烯基、己烯基等。 「芳基」之較佳例包括苯基、甲苯基、二甲苯基、祜 基、采基、萘基等。 「被保護羥基」和「被保護胺基」之保護基的較佳例 包括1-(低烷硫基）低烷基，如低烷硫甲基（如甲硫甲基 、乙硫甲基、丙硫甲基、異丙硫甲基、丁硫甲基、異丁 硫甲基、己硫甲基等），更佳為Ci-C4烷硫甲基且最 佳為甲硫甲基； 三取代甲矽烷基如三（低）烷基甲矽烷基（如三甲基甲 矽烷基、三乙基甲矽烷基、三丁基甲矽烷基、第三丁基 二甲基甲矽烷基、三-第四丁基甲矽烷基等）、和低烷 基二芳基甲矽烷基（如甲基聯苯基甲矽烷基、乙基聯笨 基甲矽烷基、丙基聯苯基甲矽烷基、第三丁基聯苯基甲 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---.---„---·1-----------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 546145 A7 B7 五、發明說明（9) 芳醯基，如苄醯基、甲苯醯基、二甲苯醯基、萃醯基、 硝基苄醯基、二硝基苄醯基、硝基萘_基等；和 任意具有一個或以上適當取代基（如鹵素）芳磺醯基， 如苯磺醯基、甲苯磺醯基、二甲苯磺醯基、莆磺醯基、 氟苯磺醯基、氯苯磺釀基、溴苯磺醯基、碘苯磺醯基等。 經芳香族基所取代之脂族醢基例如可為任意具有一個 或Μ上適當取代（如低烷氧基或三鹵（低）烷基等）之芳 低烷醯基，其中特殊例為苯乙醯基、苯丙醯基、苯丁醜 基、2 -三氟甲基-2 -甲氧基-2-苯乙醯基、2 -乙基-2-三 氟甲基_2_苯乙醯基、2-三氟甲基-2 -丙氧基-2 -苯乙醯 基等。 於所述之醯基中，更佳之醯基包括任意具有狻基之 C 4烷醯基、於環烷基部分中具有兩個（C pC 4 )烷基 之環（C ς - C 6 )烷氧基（C i-C 4 )烷醯基、樟腦磺醯基、 狻（C t-C 4 >烷基胺甲醯基、三（C 4 )烷基甲矽烷基 (C ^C4 >烷氧羰基（C&C4 )烷基胺甲醯基、任意具有一 或二個硝基之苄醯基、和具有鹵素之苯磺醯基、具有 烷氧基之苯基（C1-C4 )烷醯基和三鹵（C^Ca )烷 基。其中，最佳為乙醯基、羧丙醯基、S氧乙醯基、樟 腦磺醯基、苄醯基、硝基苄醯基、二硝基苄醯基、碘基 笨磺醯基、2-三氟甲基-2-甲氧基- 2-苯乙醯基等。 「具有氮原子、硫原子和/或氧原子之飽和或不飽和 五或六員環所組成之雜環基」之較佳例為吡咯基、四氫 呋喃基等。 一1 1 一 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） .——-—--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 546145 經濟部智慧財產局員工消費合作社印製 A7 B7__ 五、發明說明（U) ]2日，寄存編號：FERM BP_928(EP-A-0184162)所產生， 且下列化合物FK506 ( —般名：Tacrolimus)為其代表 性化合物。Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 546145 A7 B7 V. Description of the invention (6) R 13, R 14, R 15, R 16, R 丄? , R 18, R 19, R 22 and R 23 each independently represent a hydrogen atom or an alkyl group; R 24 is an optionally substituted ring containing one or a heteroatom on K; and η is 1 or 2. In addition to the above definitions, Υ, R 1 (5 and R 23 may together represent a saturated or unsaturated five- or six-membered heterocyclic group containing nitrogen, sulfur, and / or oxygen atoms with the carbon atom to which they are bonded. The cyclic group may be optionally substituted by one or more groups selected from alkyl, hydroxyl, alkoxy, benzyl, formula -CH 2 Se (C 6 ς), and alkyl substituted with one or more hydroxyl groups Substituted. R 24 is preferably, for example, any ring (C 5 -C 7) alkane ring having an appropriate substituent, as listed below. U) 3, 4 -dioxycyclohexyl; (b) S-Rm-Ui21 ring Hexyl, where R20 is hydroxy, alkoxy or -OCH2 OCH2 CH2 〇CH3, and R21 is hydroxy, -0CN, alkoxy, heteroaryloxy with appropriate substituents, -0CH2 OCH2 CH2 0CH3, protected hydroxy, Chloro, bromo, iodo, aminooxazolyl, azide, p-tolyloxycarbonyloxy, or R25R2eCHC00- (where R25 is any protected hydroxyl or protected amine group, and R 26 Is a hydrogen atom or a methyl group, or R 2 (an oxygen atom where 3 and R 21 combine to form an epoxy group); or (c) a cyclopentyl group in which cyclopentyl is optionally, via methoxymethyl, Yiwei-8 A paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) --------------------- Order --- ------ line (Please read the precautions on the back before filling this page) 546145 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7__ V. Description of the invention (7) Protecting methylol, methyloxymethyl ( Wherein the fluorenyl moiety is any quaternized dimethylamino group or any esterified carboxyl group), one or M is optionally substituted with a protected amine group and / or a hydroxyl group, or an amine oxazolyl methyl group. Formula (I) The definitions of the symbols used, their special examples and their preferred specific examples are detailed below. "Low" means a group having 1 to 6 carbon atoms, unless otherwise specified. "Alkyl" and "alkoxy" Preferred examples of the alkyl moiety include straight or branched aliphatic hydroxy residues such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl Groups, hexyl, etc.). Preferred examples of "alkenyl" include straight or branched aliphatic hydrocarbon residues having a double bond, such as lower alkenyl (such as vinyl, propenyl (such as allyl, etc.), butadiene Groups, methacryl, pentenyl, hexenyl, etc. Preferred examples of "aryl" include phenyl, tolyl, xylyl, fluorenyl, phenyl, naphthyl, etc. "Protected hydroxyl" Preferred examples of the protecting group of "protected amine group" include 1- (lower alkylthio) lower alkyl, such as lower alkylthiomethyl (such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, Isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), more preferably Ci-C4 alkylthiomethyl and most preferably methylthiomethyl; tri-substituted silyl groups such as trimethyl (Low) alkyl silyl (such as trimethylsilyl, triethylsilyl, tributylsilyl, third butyldimethylsilyl, tri-fourth butylsilyl, etc.), And lower alkyl diaryl silyl (such as methyl biphenyl silyl, ethyl bibenyl silyl, propyl biphenyl silyl, third butyl biphenyl silyl) Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ---.--- „--- 1 --------- Order --------- (Please read the notes on the back before filling this page) Ministry of Economic Affairs Printed by the Intellectual Property Cooperative's Consumer Cooperatives 546145 A7 B7 V. Description of the invention (9) Aryl fluorenyl, such as benzyl fluorenyl, tolyl fluorenyl, xyl fluorenyl, sulfonyl, nitrobenzyl, nitrobenzyl Fluorenyl, nitronaphthyl, and the like; and any arylsulfonyl group having one or more appropriate substituents (such as halogen), such as benzenesulfonyl, tosylsulfonyl, xylsulfonyl, sulfonyl, Fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl and the like. The aliphatic fluorenyl group substituted with an aromatic group may be, for example, any arylene alkynyl group having one or more appropriate substitutions (such as a lower alkoxy group or a trihalo (low) alkyl group, etc.), among which a special example is benzene Ethyl fluorenyl, phenylpropyl fluorenyl, phenbutyl sulfonyl, 2-trifluoromethyl-2 -methoxy-2-phenethylfluorenyl, 2-ethyl-2-trifluoromethyl-2-phenylethylfluorenyl , 2-trifluoromethyl-2 -propoxy-2 -phenethylfluorenyl and the like. Among the above-mentioned fluorenyl groups, more preferable fluorenyl groups include any C 4 alkyl fluorenyl group having a fluorenyl group, and a cyclic (C ς-C 6) alkane having two (C pC 4) alkyl groups in a cycloalkyl moiety. (C iC 4) alkylfluorenyl, camphorsulfonyl, fluorene (C tC 4 > alkylaminomethyl, tri (C 4) alkylsilyl (C ^ C4 > alkoxycarbonyl) C & C4) alkylaminomethylamido, any benzamidine with one or two nitro groups, and benzenesulfonyl with halogen, phenyl (C1-C4) alkyl with alkoxy, and tris Halo (C ^ Ca) alkyl. Among them, ethenyl, carboxypropionyl, S-oxyethylsulfonyl, camphor sulfonyl, benzyl, nitrobenzyl, and dinitrobenzyl , Iodobenzylsulfonyl, 2-trifluoromethyl-2-methoxy-2-phenethylfluorenyl, etc. "Saturated or unsaturated five or six members with nitrogen, sulfur and / or oxygen atoms The preferred examples of the "heterocyclic group formed by a ring" are pyrrolyl, tetrahydrofuranyl, etc. 1 1 1 1 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). ------ Order --------- line (Please read the precautions on the back first (Fill in this page) 546145 Printed by A7 B7__ of the Consumer Cooperatives of Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (U)] 2 days, deposit number: FERM BP_928 (EP-A-0184162), and the following compound FK506 (- Name: Tacrolimus) as its representative compound.

化學名：17-烯丙基-1,14-二羥基-（2-[2-(4-羥基-3-甲氧基）-1 -甲基乙烯基]-23,25-二甲氧基-13, 19， 21,27 -四甲基-11，28- 二鸣-4-吖三環[22,3.1.0 1 二十八碳-18 -烯-2,3, 10, 16 -四酮 三環化合物（I )中，更佳為其中鄰接之R 3和R 4 、及 R 5和R 6配對分別獨立於結合該配對成員之碳原子間任 意形成另一鐽之化合物； R 8和R 23分別獨立表示氫原子； R 9為羥基；Chemical name: 17-allyl-1,14-dihydroxy- (2- [2- (4-hydroxy-3-methoxy) -1 -methylvinyl] -23,25-dimethoxy -13, 19, 21, 27 -tetramethyl-11,28- diming-4-azine tricyclic [22,3.1.0 1 octacosyl-18-ene-2,3, 10, 16 -tetra In the ketotricyclic compound (I), it is more preferably a compound in which adjacent R 3 and R 4, and R 5 and R 6 are paired independently from each other to form another amidine between carbon atoms of the paired member; R 8 and R 23 each independently represents a hydrogen atom; R 9 is a hydroxyl group;

RiQ為甲基、乙基、丙基或烯丙基； X 為（氫原子、氬原子）或氧基； Y 為氧基； R M 、R 15、R 16 、R 17 、R 18 、R 13 和 R 22 分別獨立表示甲 基； -13- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----------I.----------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 546145 A7 B7 14 五、發明說明（） B 、C 、D 、E 、F和G及其衍生物。特佳為環孢菌素 A 。其於此併入說明書中參考。 三環化合物（I )、其製藥容許鹽、環孢菌素及其衍生 物之製劑，且可經由口服投予、靜脈投予（包含灌注） 、皮下投予、直腸或陰道投予、對眼睛局部部位投予 (包括眼藥膏）進行全身性或局部性投藥。於考慮全身 性影響、功效之顯著表現上，其特佳為使用對眼睛局部 投藥之型式。 間白素2抑制劑之劑量，視投藥個體如人類及動物之 種類、年齡、體重、欲治療之狀況、所欲之治療功效、 投藥途徑、治療方法、治療期間等而異。一般，當全身 性投藥時，此劑量為約0.0001-1000毫克、較佳為0.001 -500毫克，其可為單一劑量或一天2至4劑或Μ持纊方 式投予。當對眼睛局部投予時，將內含0 . 0 0 1 - 1 0 . 0 w / ν % 、較佳0 . 0 0 5 - 5 . 0 w / ν %活性成份之製劑，對每一個眼睛 一天投藥數次，較佳為滴注或一天投藥1至6次。 根據本發明，活性成份之間白素2抑制劑可單獨或與 其他藥理活性成分組合投予。當配方成製劑後投予時， 其可依據傳統方法製造成製劑進行投予。劑量型式例如 為點眼劑、眼藥膏、粉末、顆粒、錠劑、膠囊、注射劑 、藥膏等，且特佳為點眼劑和眼藥膏。此類製劑可根據 傳統方法製備。此類口服製劑較佳為如EP-A-0 2 4 0 7 7 3製 法之相同方式，製造成固體溶液製劑。當需要點眼劑時 ,其較佳為述於E P _ A - 0 4 0 6 7 9 1之點眼劑。視需要，可加 一 16 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------J---------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 546145 經濟部智慧財產局員工消費合作社印製 A7 B7__ 五、發明說明（15) 入點眼劑所常用被歸類為「I L _2生產抑制劑」，其為抑 制IL-2之生產。雷帕黴素及其衍生物可被歸類為「IL-2 訊號轉導抑制劑」，其為抑制I L -2訊號之傳遞。 於本發明中，視细胞功能病意指視網膜之視綑胞為基 於某些理由而使得功能上出現紊亂，其可由ERG中，與 正常狀態比較之a -波的波峰潛伏狀態或振幅之變化而予 Μ確認。視綑胞功能病為由各種視網膜病如退化性視網 顏病、視網膜和脈絡膜病等所引起，本發明之視細胞功 能病治療劑可用於治療視網膜病。特別地，本發明之視 细胞功能病治療劑，由後述之缺血性視網膜病模型之實 驗證實，具有改善視綑胞功能病之優異作用，且可用於 治療缺血性視網膜病。缺血性視網膜病為由各種理由所 造成。例如，視網膜血管病為由全身性疾病，如糖尿病 、高血壓和動脈硬化所引起，且其可列舉糖尿病性視網 膜病、眼底高血壓，Κ及視網膜中的局部血管病，如中 央視網膜動脈閉合、中央視網膜靜脈栓塞、視網膜周邊 血管閉合、早熟性之視網膜病等。 本發明說明書中之治療為包含任何處理，如預防、治 療、減輕症狀、回復症狀、預防疾病進行等。 本發明中所使用之間白素2抑制劑可作為人類及動物 之添加劑，如等張化劑（如氯化鈉）、緩衝液（如硼酸 、磷酸納、磷酸二氫納等）、保存劑（如潔爾滅、氯化 苄乙氧銨、氯丁醇等）、黏合劑〔如糖類（乳糖、甘露 糖醇、麥芽糖等）、波尿酸（波尿酸納、波尿酸鉀等） -17 一 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------.-----------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 546145 A7 B7 五、發明說明（16) 、其鹽、黏多糖（硫酸軟骨素等）、聚丙烯酸納、乙稀 基羧基聚合物、交聯聚丙烯酸酯等〕。其於此併人說明 書中參考。 Μ下根據實施例更詳细說明本發明，但其並非用Μ侷 限本發明。 •實施例 實驗例1對於具有視網膜缺血鼠之E R G變化上之功效 對鼠將視網膜血管結紮誘發出缺血狀態並且再灌注， 作成鼠之缺血性視網膜病模型，並對其試驗對於視網膜 電位變化之功效。 ⑴試驗動物 對於L ο n g Ε ν a η有色鼠（公鼠，取得時為7或8週齡 :體重200-250克）預先飼養8天，並且將無一般狀況 如體重不正常之動物使用於試驗。 ⑵試驗物質及投予方法 使用F Κ 5 0 6作為本發明之活性成份，並且使用下列之 0 . 1 %點眼劑（懸浮液）作為試驗藥物。 試驗藥物 具有下列組成之懸浮液為同EP_A-0406791(實施例6) 之方式製備。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） —·— ^-----—訂—-----線 (請先閱讀背面之注意事項再填寫本頁) 546145 經濟部智慧財產局員工消費合作社印製 五、發明說明（17) FK5 0 6 1 . 0 毫克 聚乙烯醇 7，0毫克 磷酸氫二納1 2水合物 0 . 0 5毫克 磷酸二氫鈉2水合物 0.76毫克 鱗酸 適量 氫氧化納 適量 氯化納 8 . 5 6毫克 潔爾滅 0 . 1毫克 注射水 適量 A7 B7 總量 1 毫升 至於對照組，使用無活性成份之點眼劑之基劑。於試 驗第1天至第7天，使用微吸量管將試驗藥物Μ 10微升 /眼睛、一天3 (8:00、13:00、18:00)滴注至眼睛。 亦Μ相同方式將對照藥劑滴注。 W製備缺血性視網膜病模型 於試驗第8天，將鼠Μ地西洋（K i a z e ρ a m，0 . 6 2 5毫 克/公斤）、戊巴必妥（2 0毫克/公斤）腹腔内投藥麻 醉，並且由側面移出部分的眶骨膜。將視神經、眼動脈 和眼靜脈所組成之蒂（P e d i c 1 e )移出並且整個蒂结紮造 成其缺血。令缺血持續4 5分鐘並且放鬆结紮帶使其再灌 注。 ⑵E R G測定 其裝置和參數Μ下列予Μ標準化。「S t a n d a r d f 〇 r 一 1 9 一 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） —w—.—.—--------1---------^ (請先閱讀背面之注意事項再填寫本頁) 546145 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（18)RiQ is methyl, ethyl, propyl or allyl; X is (hydrogen atom, argon atom) or oxygen; Y is oxygen; RM, R 15, R 16, R 17, R 18, R 13 and R 22 represents methyl independently; -13- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ---------- I .-------- --Order --------- line (please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 546145 A7 B7 14 V. Description of the invention () B, C, D, E, F and G and their derivatives. Particularly preferred is cyclosporin A. It is incorporated herein by reference. Tricyclic compounds (I), pharmaceutically acceptable salts, cyclosporin and derivatives thereof, and can be administered orally, intravenously (including perfusion), subcutaneously, rectally or vaginally, to the eyes Local administration (including ophthalmic ointment) for systemic or local administration. Considering the systemic effects and the remarkable performance of the effect, it is particularly preferred to use a local administration to the eye. The dosage of the melatonin 2 inhibitor varies depending on the species, age, weight, condition to be treated, desired therapeutic effect, route of administration, treatment method, treatment period, etc. of the individual to be administered, such as humans and animals. Generally, when administered systemically, this dose will be about 0.0001-1000 mg, preferably 0.001-500 mg, which may be administered in a single dose or in 2 to 4 doses per day or in a M-dose manner. When administered topically to the eyes, a formulation containing 0. 0 1-1 0. 0 w / ν%, preferably 0. 0 5-5. 0 w / ν% active ingredient will be applied to each eye It is administered several times a day, preferably instillation or 1 to 6 times a day. According to the present invention, the interleukin-2 inhibitor may be administered alone or in combination with other pharmacologically active ingredients. When the formulation is administered after being formulated into a preparation, it can be manufactured into a preparation and administered according to a conventional method. Dosage forms are, for example, eye drops, eye ointments, powders, granules, tablets, capsules, injections, ointments, and the like, and particularly preferred are eye drops and eye ointments. Such formulations can be prepared according to conventional methods. Such oral preparations are preferably manufactured as solid solution preparations in the same manner as in the EP-A-0 2 4 0 7 7 3 method. When eyedrops are required, they are preferably the eyedrops described in EP_A-0 4 0 6 7 9 1. If necessary, you can add one 16-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ------- J --------------- Order --------- line (please read the precautions on the back before filling this page) 546145 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7__ 5. Description of the invention (15) Commonly used eyedrops It is classified as an "IL_2 production inhibitor", which inhibits the production of IL-2. Rapamycin and its derivatives can be classified as "IL-2 signal transduction inhibitors", which inhibit the transmission of the IL-2 signal. In the present invention, visual cell function disease means that the visual retinal cells of the retina are functionally disordered for some reason, which can be changed by the latent state or amplitude change of the a-wave peak in the ERG compared with the normal state. Confirmed by M. Apoptosis is caused by various retinopathy such as degenerative retinopathy, retina, and choroid disease, and the like, and the therapeutic agent for optocytosis of the present invention can be used to treat retinopathy. In particular, the therapeutic agent for visual cell dysfunction of the present invention is verified by a model of ischemic retinopathy to be described later, has an excellent effect of improving optic dysfunction, and can be used to treat ischemic retinopathy. Ischemic retinopathy is caused by a variety of reasons. For example, retinal vascular disease is caused by systemic diseases such as diabetes, hypertension, and arteriosclerosis, and it may include diabetic retinopathy, fundus hypertension, and local vascular disease in the retina, such as central retinal artery closure, Central retinal vein embolism, retinal vascular closure, precocious retinopathy, etc. The treatment in the specification of the present invention includes any treatment such as prevention, treatment, reduction of symptoms, recovery of symptoms, prevention of disease, and the like. The interleukin-2 inhibitor used in the present invention can be used as an additive for humans and animals, such as isotonicity agents (such as sodium chloride), buffers (such as boric acid, sodium phosphate, sodium dihydrogen phosphate, etc.), and preservatives. (Such as Jie Erfen, benzyl ethoxylammonium chloride, chlorobutanol, etc.), binders [such as sugars (lactose, mannitol, maltose, etc.), uric acid (sodium urate, potassium urate, etc.) -17 a This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -----------.----------- Order ------- --Line (Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 546145 A7 B7 V. Description of the invention (16), its salt, mucopolysaccharide (chondroitin sulfate, etc.) Sodium acrylate, ethylene carboxyl polymer, crosslinked polyacrylate, etc.]. It is incorporated herein by reference. The present invention will be described in more detail based on examples below, but it does not limit the present invention by M. • Example Experimental Example 1 Effect on ERG changes in rats with retinal ischemia In rats, retinal blood vessels were ligated to induce ischemic state and reperfused to make a rat model of ischemic retinopathy, and its test for retinal potential The effect of change. ⑴ The test animals were pre-bred for 8 days with L ο ng Ε ν a η colored mice (male rats, 7 or 8 weeks of age at the time of acquisition: 200-250 g in weight), and animals with no general conditions such as abnormal weight were used in test. ⑵Test substance and method of administration F K 5 06 was used as the active ingredient of the present invention, and the following 0.1% eye drop (suspension) was used as the test drug. Test drug A suspension having the following composition was prepared in the same manner as EP_A-0406791 (Example 6). This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) — · — ^ -----— Order —----- Line (Please read the precautions on the back before filling this page) 546145 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Description of the invention (17) FK5 0 6 1. 0 mg polyvinyl alcohol 7, 0 mg dinahydrogen phosphate 1 2 hydrate 0.5 mg sodium dihydrogen phosphate 2 0.76 mg of hydrate, appropriate amount of sodium chlorate, appropriate amount of sodium hydroxide, 8.56 mg of kelol, 0.1 mg of water for injection, appropriate amount of A7, B7, 1 ml in total, for the control group, the base of ophthalmic solution with no active ingredients is used. . From day 1 to day 7 of the test, the test drug M 10 µl / eye was instilled into the eye 3 (8:00, 13:00, 18:00) a day using a micropipette. Control agents were instilled in the same manner. W To prepare an ischemic retinopathy model. On the 8th day of the experiment, the rats were administered anesthesia by intraperitoneal administration of M Diazepam (K iaze ρ am, 0.625 mg / kg) and pentobarbital (20 mg / kg). And remove part of the orbital periosteum from the side. The pedicle composed of the optic nerve, ophthalmic artery, and ophthalmic vein (P e d i c 1 e) was removed and the entire pedicle was ligated to cause ischemia. Let the ischemia last for 4 to 5 minutes and relax the ligature for reperfusion. ⑵ERG measurement The device and parameters were standardized as follows. "S tandardf 〇r-1 9-This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) —w —.—.—-------- 1 ------ --- ^ (Please read the notes on the back before filling out this page) 546145 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (18)

Clinical Elactorretinography」（國際標準化委員會) 裝置： 電生理性個人化界面電腦-2000(LKC Technologies Incorporated) E R G測定參數： 放大器 高通行濾紙：5 0 0 Η z 低通行濾紙：0 . 3 Η z 凹槽濾紙：關閉 振幅：5 0 /i V /區隔（最大1 5 0 0 /i V ) 時間：20rns/區隔（最大2500ms) 角膜電極 電阻：10至20kQ 光剌激 單一閃光：1 5 m s 強度：2,289c.d.s.m2 g a n z f e 1 d 濾紙：無 於上述條件下，測定缺血前後經時之E R G。 (3)結果 將缺血前之E R G視為1 0 0 % ,並且測定再灌注後之a -波 的波峰潛伏狀態比例。此於再灌注後立即消失。结果示 於表1 。 一 20- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） .—^--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 546145 A7 五、發明說明（19) 表1 投予群 (η) a波之波峰潛伏狀態（¾平均土 SD) 再灌注後60分鐘 再灌注後90分鐘 再灌注後120分鐘 對照藥物 ⑻ 195.6±53,5 195.6±53.5 195.6±53.5 試驗藥物 ⑻ 137.1±47·1* 137·1±47·1* 137·1±47·1* ρ<〇·〇5 (MANOVM貞測比較對照藥物） a -波之波峰潛伏狀態於再灌注後立即消失，但於其後 之波峰潛伏狀態為經時延長。如表1所闡明，試驗藥物 投藥群比對照藥物群顯著抑制a -波之波峰潛伏狀態之延 長。 ---1--·---,-----------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）"Clinical Elactorretinography" (International Standardization Committee) device: Electrophysiology Personalized Interface Computer-2000 (LKC Technologies Incorporated) ERG measurement parameters: amplifier high pass filter paper: 5 0 0 Η z low pass filter paper: 0.3 Η z groove filter paper : Off amplitude: 50 / iV / segment (maximum 150,000 / iV) Time: 20rns / segment (maximum 2500ms) Corneal electrode resistance: 10 to 20kQ Light stimulation single flash: 15ms Intensity: 2,289cdsm2 ganzfe 1 d filter paper: Under the above conditions, ERG was measured before and after ischemia. (3) Results The E R G before ischemia was regarded as 100%, and the ratio of peak latency of a-wave after reperfusion was determined. This disappeared immediately after reperfusion. The results are shown in Table 1. 20- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm). — ^ -------- Order --------- line (please read the first Note: Please fill in this page again) 546145 A7 V. Description of the invention (19) Table 1 Administration group (η) A wave peak latency state (¾ average soil SD) 60 minutes after reperfusion 90 minutes after reperfusion 120 Minute control drug: 195.6 ± 53, 5 195.6 ± 53.5 195.6 ± 53.5 test drug: 137.1 ± 47 · 1 * 137 · 1 ± 47 · 1 * 137 · 1 ± 47 · 1 * ρ < 〇 · 〇5 (MANOVM test (Comparative control drug) a-The peak latency of the wave disappears immediately after reperfusion, but the peak latency after that is prolonged over time. As illustrated in Table 1, the test drug administration group significantly inhibited the extension of the latent state of the a-wave peak compared to the control drug group. --- 1-- · ---, ----------- Order --------- line (Please read the notes on the back before filling this page) Intellectual Property of the Ministry of Economic Affairs The paper size printed by the Bureau ’s Consumer Cooperatives applies the Chinese National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

546145 六、申請專利範圍 第88 1 22634號「以大環內..酯化合物爲活性成份之視細胞 ( —... ,Λ 〆 功能病治療劑」專利案 气彳彳心1¾充〜、 〔二11〜---------------—年2月18日修正） τ\申請專利範圍： 1 · 一種缺血性視網膜病治療劑，其包括大環內酯化合 物FK506爲活性成份以眼睛局部投予製劑之型式。 2 ·如申請專利範圍第1項之治療劑，其中缺血性視 網膜病爲糖尿病性視網膜病。 3 .如申請專利範圍第丨項之治療劑，其中眼睛局部投 予製劑之型式爲點眼劑。 4 .如申請專利範圍第1項之治療劑，係用於異常視網 月大電流圖（e 1 e c t r 〇 r e t i η 〇 g r a ιώ，稱爲E R G )情形之治 療0546145 VI. Application Patent No. 88 1 22634 "Paeocytes with macrocyclic: ester compounds as active ingredients (-..., Λ 〆 functional disease treatment agent) patent case Qi Zhixin 1¾ charge ~, [ II 11 ~ ---------------— Amended on February 18, 2010) τ \ Application patent scope: 1 · A therapeutic agent for ischemic retinopathy, which includes a macrolide compound FK506 is a form of topical administration of the active ingredient to the eye. 2. The therapeutic agent according to item 1 of the patent application scope, wherein the ischemic retinopathy is diabetic retinopathy. 3. The therapeutic agent according to item 丨 of the patent application, wherein the type of preparation for topical administration to the eye is an eye drop. 4. The therapeutic agent according to item 1 of the scope of patent application, which is used for the treatment of abnormal visual network monthly high current diagram (e 1 e c t r 〇 r e t i η 〇 g r a ιrent, called E R G).
TW088122634A 1998-12-24 1999-12-22 Agent for treating visual cell function disorder with macrolide compound as active ingredient TW546145B (en)

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WO2003061519A2 (en) 2002-01-18 2003-07-31 Massachusetts Eye And Ear Infirmary Methods and compositions for preserving the viability of photoreceptor cells
US8163726B2 (en) * 2002-09-18 2012-04-24 University Of Pennsylvania Method of inhibiting choroidal neovascularization
US20050118344A1 (en) 2003-12-01 2005-06-02 Pacetti Stephen D. Temperature controlled crimping
CA2539324A1 (en) 2003-09-18 2005-03-31 Macusight, Inc. Transscleral delivery
JP4974903B2 (en) 2005-02-09 2012-07-11 参天製薬株式会社 Liquid formulations for treating diseases or conditions
WO2007019427A2 (en) * 2005-08-08 2007-02-15 Massachusetts Eye & Ear Infirmary Methods and compositions for preserving the viability of photoreceptor cells
WO2007092620A2 (en) 2006-02-09 2007-08-16 Macusight, Inc. Stable formulations, and methods of their preparation and use
PL2001466T3 (en) 2006-03-23 2016-06-30 Santen Pharmaceutical Co Ltd Low-dose rapamycin for the treatment of vascular permeability-related diseases
JP7431451B2 (en) * 2018-10-15 2024-02-15 国立大学法人大阪大学 Pharmaceuticals for improving or preventing symptoms related to the retina and/or photoreception, and methods for screening for substances that improve or preventing symptoms related to the retina and/or photoreception

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