[go: up one dir, main page]

TWI337881B - Treating agent for glaucoma comprising rho kinase inhibitor and prostaglandin - Google Patents

Treating agent for glaucoma comprising rho kinase inhibitor and prostaglandin Download PDF

Info

Publication number
TWI337881B
TWI337881B TW092123857A TW92123857A TWI337881B TW I337881 B TWI337881 B TW I337881B TW 092123857 A TW092123857 A TW 092123857A TW 92123857 A TW92123857 A TW 92123857A TW I337881 B TWI337881 B TW I337881B
Authority
TW
Taiwan
Prior art keywords
kinase inhibitor
rho kinase
prostaglandin
glaucoma
intraocular pressure
Prior art date
Application number
TW092123857A
Other languages
English (en)
Other versions
TW200409654A (en
Inventor
Nakajima Tadashi
Matsugi Takeshi
Hara Hideaki
Original Assignee
Santen Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co Ltd filed Critical Santen Pharmaceutical Co Ltd
Publication of TW200409654A publication Critical patent/TW200409654A/zh
Application granted granted Critical
Publication of TWI337881B publication Critical patent/TWI337881B/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

玖、發明說明： 【發明所屬之技術領域】 本發明爲有關由Rho激酶抑制劑及前列腺素類而成之 青光眼治療劑。 【先前技術】 青光眼爲由種種病因而眼壓上昇、眼球内部組織（網 膜、視神經等）受障害所致失明之有危險性之難治性眼疾 病。青光眼之治療方法一般爲降眼壓療法，其代表有薬物 療法，雷射治療法，手術療法等。 藥物療法可用交感神經刺激藥（腎上腺素等非選擇性刺 激藥、阿布拉苦羅尼定等<2 2刺激藥）、交感神經遮斷藥（記 莫羅、別府諾羅等遮斷藥、鹽酸部那坐新等遮斷 藥）、副交感神經激動藥（毛果藝香鹼等）、碳酸酐酶抑制 劑（鹽酸杜坐醯胺等）、前列腺素類（異丙基吳諾普羅史 酮、拉他諾普羅史脫、多拉波普羅史脫、必馬多普羅史脫 等）等藥物。 最近，作爲基於新作用機制之青光眼治療藥，發現Rho 激酶抑制劑（國際公開WOOO/09 1 62號號。Rho激酶抑制劑 可促進從纖維柱帶流出經路之房水流出而使降眼壓已在 非專利文獻1揭示，且其作用機制爲在纖維柱帶細胞之細 胞骨架之再構築乃在I0VS，42(1)，137-144(2001)及 I0VS,42( 5)，1029-1037(2001)提示，故以青光眼治療目 的，將具有降眼壓作用之藥劑組合使用，乃以前就已硏 究，已有若干報告。例如在日本專利第2 7 2 6 6 7 2號公報， 1337881 有交感神經遮斷藥與前列腺素類之組合投與之報告。又在 國際公開W002 / 38】58號，揭示將若干具有降眼壓作用之 藥劑組合在眼投與之青光眼治療方法。 但在任何報告從無有關Rho激酶抑制劑之記載，當然也 無其與前列腺素類之倂用效果之記載。 如上所述，至今從無有關將R h 〇激酶抑制劑與前列腺素 類組合時之青光眼之治療效果之硏究及報告。 【發明內容】
將Rho激酶抑制劑與前列腺素類組合之青光眼治療劑 之有用性找出爲非常有趣之課題。 本發明者將Rho激酶抑制劑與前列腺素類之組合之效 果致力硏究之結果，發現將這些藥劑組合，則與各藥劑單 獨使用時比較，可使降眼壓作用増強及/或改善其作用之 持續性，完成本發明。詳細試驗方法及其結果容後述藥理 試驗説明，Rho激酶抑制劑與前列腺素類組合，則發現降 眼壓作用之顯著増強及/或其作用之持續性顯著改善。
本發明爲Rho激酶抑制劑與前列腺素類之組合而成之 青光眼治療劑，互相使其作用補全及/或増強。 投與形態可爲將Rho激酶抑制劑與前列腺素類分別以 製劑之形投與，即可倂用投與，又可將這些以1製劑化之 形，也即以合劑之形投與。 _ 本發明所謂之Rho激酶抑制劑及前列腺素類也包括鹽 之形態。若這些化合物含有胺基等鹼性基時，可成鹽酸、 硝酸等無機酸之鹽或草酸、丁二酸、乙酸等有機酸之鹽， 若含有羧基等酸性基時可成鈉、鉀等鹼金屬鹽、鈣等鹼土 1337881 至於前列腺素類只要具有降眼壓作用而對青光眼治療 有用即可。具有降眼壓作用之前列腺素類之具體例可爲特 開昭5 9 - 1 4 1 8揭示之前列腺素類（尤其是如前列腺素F2 α 等天然前列腺素特表平3-501 02 5揭示之拉他諾普羅史 脫等前列腺素類，特開平2-108揭示之異丙基吳諾普羅史 酮等前列腺素類，特表平8-501310揭示之必馬多普羅史 脫等前列腺素類，特開平10-182465揭示之多拉波普羅史 脫等前列腺素類等例示，尤其宜用當作青光眼治療藥銷售 之拉他諾普羅史脫、異丙基吳諾普羅史酮、必馬多普羅史 脫或多拉波普羅史脫。 本發明中青光眼可爲原發性開放隅角青光眼，正常眼壓 青光眼，房水産生過多青光眼，高眼壓症，急性閉塞隅角 靑光眼’慢性閉塞隅角青光眼，混合型青光眼，類固醇青 光眼’類澱青光眼，血管新生青光眼，悪性青光眼水晶體 之囊性青光眼，平坦彩虹症候組等之例示。 實施本發明之製劑可爲將Rho激酶抑制劑與前列腺素 類分別處方之2製劑，也可爲將各成分配合各1製劑。這 些製劑化無需特別技術，可用汎用技術來製劑化。投與方 法宜眼局部投與，其劑型宜點眼劑或眼軟膏。 將Rho激酶抑制劑與前列腺素與分別製劑化時，可依各 公知方法調製製劑。例如，Rh〇激酶抑制劑之製劑可參照 上述國際公開專利公報（W000/O9162，WO97/23222)記載之 製劑例來調製。前列腺素類之製劑可參照上述日本公開專 利公報或日本公表專利公報（特開昭5 9 - 1 4 I 8，特表平 1337881 3-501025，特開平2-108，特表平8-501310，特開平 10- 1 82465 )記載之製劑例來調製，尤其是已當作青光眼治 療藥銷售之拉他諾普羅史脫、異丙基吳諾普羅史酮、必馬 多普羅史脫 '多拉波普羅史脫等可用市售之製劑。 欲調製將R h 〇激_抑制劑與前列腺素類配合之製劑時， 也可依公知之方法調製。例如點眼劑可將氯化鈉、濃甘油 等之等張化劑’磷酸鈉、乙酸鈉等緩衝劑、聚氧乙烯單油 酸山梨糖酯、硬脂酸聚乙二醇40、聚氧乙烯硬化蓖麻油 等界面活性劑，檸檬酸鈉、乙二胺四乙酸鈉等安定化劑， 苄烷氯化銨、對羥苄酸酯等防腐劑等視必要而使用調製。 pH只要爲眼科製劑容爲之範圍内即可，宜爲pH4〜8之範 圍內。將其製劑例之一部分在後述實施例記載，但此製劑 例乃供參考，非限定本發明之範圍。
Rho激酶抑制劑及前列腺素類之投與量可依患者之症 狀、年齡、劑型、投與經路等來決定。以點眼投與爲例， 以下簡單説明之》Rho激酶抑制劑之投與量依藥物種類而 異’通常1日之投與量爲0.025〜10000" g之範圍內，可 1曰分1回或數回投與’這些用量可依患者之年齡、症狀 等適宜増減。 前列腺素類之投與量依藥物種類而異，通常1日之投與 量爲0.1〜l〇〇〇#g之範圍內，可1日分1回或數回投與。 更具體而言’拉他諾普羅史脫時1日量1〜5vg、異丙基 吳諾普羅史酮時1日量30〜300//g爲通常使用，這些用 量可依患者之年齡、症狀等適宜増減。又其他前列腺素類 1337881 也可依同様基準，將其用量決定。 這些投與量爲將Rh0激酶抑制劑與前列腺素類倂用投 與時適用，但在將Rh〇激酶抑制劑與前列腺素類配合之製 劑投與時，調製使1日之投與量呈上述各成分之量或其以 下地將配合比率適宜選擇之製劑，將此配合製劑分】曰] 回或數回投與。 【實施方式】 以下作爲實施例列示製劑例及藥理試驗，但這些爲使本 發明更能理解者，非限定本發明之範圍》 [製劑例] 本發明中R h 〇激酶抑制劑（（R )-( + )- N - ( 1 Η -吡略并 [2，3 - b ]吡啶-4 -基）-4 -(卜胺乙基）苄醯胺二鹽酸鹽）與前 列腺素類類（異丙基吳諾普羅史酮）配合之點眼劑之一般 製劑例如下。 點眼劑（1 OOmL中） (R)-( + )- N-(lH-吡咯并[2,3-b]吡啶-4-基）-4-(1-肢乙基 苄醯胺二鹽酸鹽 〇 , 3 g 異丙基吳諾普羅史酮 〇.〇6g 硼酸 0 . 2g 濃甘油 0 . 2 5 g 苄烷氯化鞍 〇.0〇5g 稀鹽酸 適量 氫氧化鈉 適量 精製水 適量 -10- 1337881 上述處方中，將Rho激酶抑制劑及前列腺素類之種類及 量改變，又將添加劑之量適宜變化，則可調製所望組合及 所望濃度之點眼液。 [藥理試驗] 爲調查Rho激酶抑制劑與前列腺素類之組合之有用 性，於日本白兔（系統：]W ,性別：雄性）或食蟹猴（性別：雄 性）將Rho激酶抑制劑與前列腺素類倂用投與時之降眼壓
效果予以檢討。Rho激酶抑制劑乃用（R ) · ( + ) _ N - ( 1 Η -吡咯 并[2, 3-b]吡啶-4-基）-4-(1-胺乙基）苄醯胺二鹽酸鹽[化 合物A]或1-(5-異喹啉磺醯基）高哌啶二鹽酸鹽[化合物 B]，前列腺素類乃用異丙基吳諾普羅史酮或拉他諾普羅史 脫。 (被驗化合物溶液之調製） 1 . Rho激酶抑制劑溶液之調製 將Rho激酶抑制劑溶在生理食鹽水後，以氫氧化鈉中和 (pH6 · 0〜7 . 0)來調製所望濃度之Rho激酶抑制劑溶液。
2 .前列腺素類溶液之調製 將市售之異丙基吳諾普羅史酮點眼液（商品名：列斯久 拉點眼液）或拉他諾普羅史脫點眼液（商品名：奇砂拉坦點 眼液）就此，或以生理食鹽水稀釋，來調製所望濃度之前 列腺素類溶液。 (試驗方法） 檢討將Rho激酶抑制劑與前列腺素類倂用投與時之降眼壓 效果。作爲比較對照，也檢討Rho激酶抑制劑單獨投與或 -11 - 1337881 前列腺素類單獨投與時之降眼壓效果。對照只投與基劑（生 理食鹽水）》又實驗動物使用日本白兔（系統：JW，性別：雄性） 或食蟹猴（性別：雄性）。 (投與方法及測定方法） 1 . Rho激酶抑制劑與前列腺素類之併用投與 1)將0.4%鹽酸氧普羅卡因點眼液在實驗動物之兩眼點眼 一滴來局部麻酔。 2 )被驗化合物溶液投與即前測定眼壓，當作初期眼壓。
3 ) Rho激酶抑制劑溶液在實驗動物之一眼點眼（對側眼無 處置）。不可能同時將前列腺素類溶液點眼，故稍隔時間 (約5分）而將前列腺素類溶液在同一眼點眼。 4 ) R h 〇激酶抑制劑溶液點眼之2小時、4小時、6小時及8 小時後，將0 · 4%鹽酸氧普羅卡因點眼液在兩眼點眼一滴， 局部麻酔後，測定眼壓。眼壓測定3回，其平均値列示於 結果。
至於以下試驗例所示之試驗2，當作2小時、4小時及 6小時後之眼壓之測定。 2. Rho激酶抑制劑單獨投與 以前列腺素類溶液代替生理食鹽水，其他仿上述併用投 與試驗之相同方法試驗。 3.前列腺素類單獨投與 以Rho激酶抑制劑溶液代替生理食鹽水，其他仿上述倂 用投與試驗之相同方法試驗。 4.對照 -12- 1337881 以Rho激酶抑制劑溶液及前列腺素類溶液代替生理食 鹽水，其他仿上述倂用投與試驗相同方法試驗。 (試驗1〜4 ) 各試驗所用之Rho激酶抑制劑溶液 '前列腺素類溶液及 實驗動物如表1所示。 依上述（試驗方法）及（投與方法及測定方法），實施試驗 1 4 〇 -13- 1337881 表】
Rho激酶抑制劑溶液 前列腺素類溶液 實驗動物 試驗1 0.3%化合物A溶液 (50“1) 0.06%異丙基吳諾普羅史酮溶 m(5〇ui) 兔(一組4隻） 試驗2 1%化合物B溶液 (50 β 1) 0.06%異丙基吳諾普羅史酮溶 液(50//1) __ 兔(一組5隻） 試驗3 0.1%化合物Α溶液 (20//1) 0.005%拉他諾普羅史脫溶液 (20α 1) 食蟹猴(一組3隻） 試驗4 匕合物B溶液 (20β\) 0.005%拉他諾普羅史脫溶液 (20//1)__ 食蟹猴(一組3隻） (結果及考察） 試驗1之結果如第1圖’試驗2之結果如第2圖’試驗 3之結果如第3圖，試驗4之結果如第4圖。眼壓乃示從 初期眼壓之變化値。 如第1圖、第2圖、第3圖及第4圖所示’ Rho激酶抑 制劑與前列腺素類之倂用組比藥劑單獨投與組’也即Rho 激酶抑制劑投與組或前列腺素類投與組均優之降眼壓作 用，且改善其作用之持續性。由上述確認將Rho激酶抑制 劑與前列腺素類組合，則可得更強降眼壓效果及/或持續 性之改善。 産業上利用可能件 將Rho激酶抑制劑與前列腺素類組合投與在眼，則可得 增強降眼壓效果及/或持續性之改善。故此組合可當作青 光眼治療劑。 【圖式簡單說明】 第1圖乃示各投與組之眼壓之經時變化。眼壓以從初期 眼壓之變化値表示。口爲化合物A與異丙基吳諾普羅史酮 -14- 1337881 之倂用投與組，爲化合物A單獨投與組，△爲異丙基吳 諾普羅史酮單獨投與組，〇爲對照組。 第2圖乃示各投與組之眼壓之經時變化。眼壓以從初期 眼壓之變化値表示。口爲化合物B與異丙基吳諾普羅史酮 之倂用投與組，爲化合物B單獨投與組，△爲異丙基吳 諾普羅史酮單獨投與組，〇爲對照組。 第3圖乃示各投與組之眼壓之經時變化》眼壓以從初期 眼壓之變化値表示。口爲化合物A與拉他諾普羅史脫之倂 用投與組，爲化合物A單獨投與組，△爲拉他諾普羅史 f 脫單獨投與組，〇爲對照組。 第4圖乃示各投與組之眼壓之經時變化。眼壓以從初期眼 壓之變化値表示。口爲化合物B與拉他諾普羅史脫之倂用 < 投與組，爲化合物B單獨投舆組，△爲拉他諾普羅史脫 . 單獨投與組，〇爲對照組。
-15-

Claims (1)

1337881 第9 2 1 2 3 8 5 7「由Rh 〇激酶抑制劑及前列腺素類而成之青光 眼治療劑」專利案 拾、申請專利範圍 (2Θ40年1月22 ρ修正） 本年Λ曰 補充 1 . 一種青光眼治療劑，其係由Rho激酶抑制劑： (R)( + )- N- (lH -吡咯并[2,3-b]吡啶·4 -基）-4-(1-胺乙 基）苄醯胺與拉他諾普羅史脫（latanoprost)之組合而 成。 2 . —種青光眼治療劑，其特徴爲由Rho激酶抑制劑： (R)( + )-N-(lH-吡咯并[2,3-b]吡啶-4-基）-4-(1-胺乙 基）苄醯胺與拉他諾普羅史脫（latanoprost)之組合而 成，而互相輔助及/或增強其作用。
TW092123857A 2002-08-29 2003-08-29 Treating agent for glaucoma comprising rho kinase inhibitor and prostaglandin TWI337881B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2002250223 2002-08-29

Publications (2)

Publication Number Publication Date
TW200409654A TW200409654A (en) 2004-06-16
TWI337881B true TWI337881B (en) 2011-03-01

Family

ID=31972618

Family Applications (2)

Application Number Title Priority Date Filing Date
TW092123857A TWI337881B (en) 2002-08-29 2003-08-29 Treating agent for glaucoma comprising rho kinase inhibitor and prostaglandin
TW099103157A TWI350170B (en) 2002-08-29 2003-08-29 Treating agent for glaucoma comprising rho kinase inhibitor and prostaglandin

Family Applications After (1)

Application Number Title Priority Date Filing Date
TW099103157A TWI350170B (en) 2002-08-29 2003-08-29 Treating agent for glaucoma comprising rho kinase inhibitor and prostaglandin

Country Status (11)

Country Link
US (4) US20050245509A1 (zh)
EP (2) EP2314299A1 (zh)
JP (1) JP5174777B2 (zh)
KR (2) KR101092048B1 (zh)
CN (1) CN100425241C (zh)
AT (1) ATE546143T1 (zh)
AU (1) AU2003257588A1 (zh)
CA (1) CA2496797C (zh)
ES (1) ES2382733T3 (zh)
TW (2) TWI337881B (zh)
WO (1) WO2004019951A1 (zh)

Families Citing this family (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100425241C (zh) * 2002-08-29 2008-10-15 参天制药株式会社 由Rho激酶抑制剂和前列腺素类物质构成的青光眼治疗剂
WO2004045644A1 (ja) * 2002-11-18 2004-06-03 Santen Pharmaceutical Co., Ltd. Rhoキナーゼ阻害剤とβ遮断薬からなる緑内障治療剤
US7799336B2 (en) 2004-04-30 2010-09-21 Allergan, Inc. Hypotensive lipid-containing biodegradable intraocular implants and related methods
US8722097B2 (en) 2004-04-30 2014-05-13 Allergan, Inc. Oil-in-water method for making polymeric implants containing a hypotensive lipid
US7993634B2 (en) 2004-04-30 2011-08-09 Allergan, Inc. Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and related methods
US8673341B2 (en) 2004-04-30 2014-03-18 Allergan, Inc. Intraocular pressure reduction with intracameral bimatoprost implants
US9498457B2 (en) 2004-04-30 2016-11-22 Allergan, Inc. Hypotensive prostamide-containing biodegradable intraocular implants and related implants
KR101333970B1 (ko) * 2005-05-19 2013-11-27 코와 가부시키가이샤 녹내장 예방 또는 치료제
CN101198354B (zh) * 2005-06-21 2012-01-11 兴和株式会社 青光眼的预防或治疗剂
ES2416334T3 (es) * 2005-07-12 2013-07-31 Kowa Company. Ltd. Agente para la prevención o el tratamiento del glaucoma
KR101149954B1 (ko) * 2005-08-30 2012-06-01 아사히 가세이 파마 가부시키가이샤 술폰아미드 화합물
EP2111863B1 (en) 2005-10-26 2012-03-28 Asahi Kasei Pharma Corporation Fasudil in combination with bosentan for the treament of pulmonary arterial hypertension
JP5235887B2 (ja) 2006-09-20 2013-07-10 アエリー ファーマシューティカルズ インコーポレイテッド Ｒｈｏキナーゼ阻害剤
US8071779B2 (en) 2006-12-18 2011-12-06 Inspire Pharmaceuticals, Inc. Cytoskeletal active rho kinase inhibitor compounds, composition and use
US8455513B2 (en) 2007-01-10 2013-06-04 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
US8415372B2 (en) 2007-02-27 2013-04-09 Asahi Kasei Pharma Corporation Sulfonamide compound
WO2008105442A1 (ja) 2007-02-28 2008-09-04 Asahi Kasei Pharma Corporation スルホンアミド誘導体
CN101313926B (zh) * 2007-05-30 2012-12-26 中央研究院 转录调控物组合物
WO2009004792A1 (ja) 2007-07-02 2009-01-08 Asahi Kasei Pharma Corporation スルホンアミド化合物及びその結晶
US8207195B2 (en) 2008-06-26 2012-06-26 Inspire Pharmaceuticals, Inc. Method for treating neurological and neuropathic diseases using rho kinase inhibitor compounds
US8410147B2 (en) 2008-06-26 2013-04-02 Inspire Pharmaceuticals, Inc. Method for treating diseases associated with alterations in cellular integrity using Rho kinase inhibitor compounds
US8450344B2 (en) 2008-07-25 2013-05-28 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
CA2929545C (en) 2009-05-01 2019-04-09 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
CN103052406A (zh) * 2010-07-19 2013-04-17 印斯拜尔药品股份有限公司 双官能rho激酶抑制剂化合物、组合物及应用
JP5822840B2 (ja) 2010-09-30 2015-11-24 ダイトーケミックス株式会社 眼疾患処置薬
ES2684351T3 (es) * 2011-02-04 2018-10-02 Kowa Co., Ltd. Terapia farmacológica para prevenir o tratar glaucoma
WO2014010654A2 (ja) * 2012-07-13 2014-01-16 参天製薬株式会社 スルホンアミド化合物の組み合わせ
US9339496B2 (en) 2012-07-13 2016-05-17 Santen Pharmaceutical Co., Ltd. Composition for treating or preventing glaucoma comprising a sulfonamide compound, and a beta-receptor antagonist
CA2905089C (en) * 2013-03-15 2023-06-13 Aerie Pharmaceuticals, Inc. Isoquinoline compounds for the treatment of ocular diseases
CN105682645B (zh) 2013-10-31 2019-09-06 阿勒根公司 含前列腺酰胺的眼内植入物及其使用方法
KR20150090445A (ko) 2014-01-29 2015-08-06 주식회사 이노칩테크놀로지 적층칩 소자
KR20170093836A (ko) * 2014-12-12 2017-08-16 코와 가부시키가이샤 조성물
CN107921036A (zh) * 2015-05-29 2018-04-17 优势医疗公司 用于减少视力丧失的组合物和方法
US9643927B1 (en) 2015-11-17 2017-05-09 Aerie Pharmaceuticals, Inc. Process for the preparation of kinase inhibitors and intermediates thereof
CA3005707C (en) 2015-11-17 2023-11-21 Aerie Pharmaceuticals, Inc. Process for the preparation of kinase inhibitors and intermediates thereof
WO2018045091A1 (en) 2016-08-31 2018-03-08 Aerie Pharmaceuticals, Inc. Ophthalmic compositions
KR20190135027A (ko) 2017-03-31 2019-12-05 에어리 파마슈티컬즈, 인코포레이티드 아릴 시클로프로필-아미노-이소퀴놀리닐 아미드 화합물
EP3730143A4 (en) 2017-12-21 2021-08-18 Santen Pharmaceutical Co., Ltd. OMIDENEPAG COMBINATION
EP4338751B1 (en) * 2017-12-21 2025-09-03 Santen Pharmaceutical Co., Ltd. Combination of sepetaprost and netarsudil for use in the prophylaxis or treatment of glaucoma or ocular hypertension
US10696638B2 (en) 2017-12-26 2020-06-30 Industrial Technology Research Institute Compounds for inhibiting AGC kinase and pharmaceutical compositions comprising the same
CN108815169A (zh) * 2018-05-23 2018-11-16 中南大学湘雅医院 一种前列腺素类物质组合得到有效的青光眼治疗剂
CA3112391A1 (en) 2018-09-14 2020-03-19 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds
JP7747618B2 (ja) * 2020-03-13 2025-10-01 興和株式会社 上眼瞼溝深化改善剤

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2945008C2 (de) * 1979-11-08 1981-08-20 Lück, Werner, 4290 Bocholt Stützelement für medizinische Lagerungszwecke
US4599353A (en) 1982-05-03 1986-07-08 The Trustees Of Columbia University In The City Of New York Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma
US4952581A (en) * 1987-04-03 1990-08-28 The Trustees Of Columbia University In The City Of New York Use of a prostaglandin in combination with an adrenergic blocking agent for reduction of intraocular pressure
DE3871596T3 (de) * 1987-04-03 2000-09-07 Pharmacia & Upjohn Ab, Stockholm Anwendung eines Prostaglandins in Mischung mit einem adrenergischen Blocker zur Verminderung des Augen-Innendruckes.
CA1324129C (en) * 1987-04-30 1993-11-09 Ryuzo Ueno Prostaglandins of the f series
GB2209939B (en) 1987-09-18 1992-01-02 R Tech Ueno Ltd The use of 13,14-dihydro-15-keto-prostaglandins as ocular hypotensive agents
CA1334168C (en) * 1988-04-26 1995-01-31 Louis M. De Santis Antiglaucoma compositions containing combinations of .alpha.-2 agonists and .beta. blockers
JPH02108U (zh) 1988-06-14 1990-01-05
ATE101342T1 (de) * 1988-09-06 1994-02-15 Kabi Pharmacia Ab Prostaglandinderivate zur behandlung des gruenen stars oder einer okularen hypertension.
US5352708A (en) * 1992-09-21 1994-10-04 Allergan, Inc. Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
US5510383A (en) * 1993-08-03 1996-04-23 Alcon Laboratories, Inc. Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension
ATE289815T1 (de) * 1995-12-21 2005-03-15 Alcon Lab Inc Verwendung von substituierten isochinolinsulfonyl-verbindungen zur herstellung eines medikaments für die behandlung von glaukom und okularer ischämie
IL128456A0 (en) * 1996-08-12 2000-01-31 Yoshitomi Pharmaceutical Compositions containing a Rho kinase inhibitor
US6187304B1 (en) * 1998-04-02 2001-02-13 Genentech, Inc. Effects of IFN-γ on cardiac hypertrophy
JP4212149B2 (ja) 1998-06-11 2009-01-21 株式会社デ・ウエスタン・セラピテクス研究所 医薬
EP1034793B1 (en) * 1998-08-17 2005-10-26 Senju Pharmaceutical Co., Ltd. Preventives/remedies for glaucoma
SE9803761D0 (sv) * 1998-11-04 1998-11-04 Synphora Ab Method to avoid increased iridial pigmentation during prostaglandin treatment
WO2000057914A1 (en) * 1999-03-25 2000-10-05 Santen Pharmaceutical Co., Ltd. Ocular tension-lowering agents
US7217722B2 (en) 2000-02-01 2007-05-15 Kirin Beer Kabushiki Kaisha Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same
AR035541A1 (es) 2000-11-13 2004-06-16 Pharmacia Ab Un metodo de tratamiento para pacientes que sufren de glaucoma severo o necesitan una reduccion de la presion intraocular (pio) y el uso de una combinacion de agentes reductores de la pio
US20030125344A1 (en) 2001-03-23 2003-07-03 Bayer Corporation Rho-kinase inhibitors
DE60218138T2 (de) 2001-03-23 2007-09-20 Bayer Pharmaceuticals Corp., West Haven Rho-kinase inhibitoren
JPWO2002100833A1 (ja) 2001-06-12 2004-09-24 住友製薬株式会社 Ｒｈｏキナーゼ阻害剤
JP2005516914A (ja) * 2001-12-12 2005-06-09 ファルマシア・コーポレーション エポキシ−ステロイド系アルドステロン受容体アンタゴニストで眼病を治療する方法
CN100425241C (zh) * 2002-08-29 2008-10-15 参天制药株式会社 由Rho激酶抑制剂和前列腺素类物质构成的青光眼治疗剂
WO2004045644A1 (ja) * 2002-11-18 2004-06-03 Santen Pharmaceutical Co., Ltd. Rhoキナーゼ阻害剤とβ遮断薬からなる緑内障治療剤
WO2004106325A1 (en) * 2003-05-29 2004-12-09 Schering Aktiengesellschaft Prodrugs of 1-(1-hydroxy-5-isoquinolinesulfonyl)homopiperazine

Also Published As

Publication number Publication date
CA2496797C (en) 2012-01-10
US20050245509A1 (en) 2005-11-03
EP1541151A1 (en) 2005-06-15
ES2382733T3 (es) 2012-06-13
EP2314299A1 (en) 2011-04-27
TW201032807A (en) 2010-09-16
KR101160780B1 (ko) 2012-06-27
WO2004019951A1 (ja) 2004-03-11
KR20050057014A (ko) 2005-06-16
CA2496797A1 (en) 2004-03-11
ATE546143T1 (de) 2012-03-15
TWI350170B (en) 2011-10-11
KR101092048B1 (ko) 2011-12-12
US20100063060A1 (en) 2010-03-11
JP5174777B2 (ja) 2013-04-03
CN100425241C (zh) 2008-10-15
TW200409654A (en) 2004-06-16
AU2003257588A1 (en) 2004-03-19
KR20110004920A (ko) 2011-01-14
US20120040994A1 (en) 2012-02-16
JP2009298808A (ja) 2009-12-24
CN1684689A (zh) 2005-10-19
US20100041671A1 (en) 2010-02-18
EP1541151B1 (en) 2012-02-22
EP1541151A4 (en) 2007-07-18

Similar Documents

Publication Publication Date Title
TWI337881B (en) Treating agent for glaucoma comprising rho kinase inhibitor and prostaglandin
JP4934653B2 (ja) Ｒｈｏキナーゼ阻害剤とβ遮断薬からなる緑内障治療剤
TWI643619B (zh) 一種用於預防或治療青光眼或高眼壓症、或降低眼壓之醫藥組合物及其用途
JP4482726B2 (ja) Ｒｈｏキナーゼ阻害剤とプロスタグランジン類からなる緑内障治療剤
US20140018350A1 (en) Combination of sulfonamide compound and tafluprost
TWI842692B (zh) 含有吡啶基胺乙酸化合物之醫藥製劑
JP4300347B2 (ja) ブナゾシンとプロスタグランジン類からなる緑内障治療剤
CN100496500C (zh) 含布那唑嗪和前列腺素的青光眼治疗剂
EP3730137B1 (en) Therapeutic agent for glaucoma comprising an fp agonist and timolol
JP2001504100A (ja) 緑内障を治療するための炭酸脱水素酵素阻害剤とプロスタグランジンとの組合せの使用
JP5460996B2 (ja) 眼科用剤
JP2012250949A (ja) アデノシン誘導体と炭酸脱水酵素阻害剤とβ受容体遮断薬の組合せ剤
EP0607697A2 (en) DILAZEP for reduction of elevated intraocular pressure
CN111491636A (zh) 奥米帕格的组合
JP2012250952A (ja) アデノシン誘導体とＲｈｏキナーゼ阻害剤の組合せ剤
JP2012250948A (ja) アデノシン誘導体と炭酸脱水酵素阻害剤の組合せ剤

Legal Events

Date Code Title Description
MM4A Annulment or lapse of patent due to non-payment of fees