TWI290145B - Preventives/remedies for inflammatory airway diseases - Google Patents
Preventives/remedies for inflammatory airway diseases Download PDFInfo
- Publication number
- TWI290145B TWI290145B TW090131849A TW90131849A TWI290145B TW I290145 B TWI290145 B TW I290145B TW 090131849 A TW090131849 A TW 090131849A TW 90131849 A TW90131849 A TW 90131849A TW I290145 B TWI290145 B TW I290145B
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- Taiwan
- Prior art keywords
- respiratory tract
- patent application
- inflammatory diseases
- tract inflammatory
- group
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Otolaryngology (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
1290145
技術範疇 本發明係關於支氣管性氣喘及鼻過敏症等發炎性呼吸道 疾病之預防及/或治療劑。 背景技術 支氣管性氣喘及鼻過敏症（過敏性鼻炎及血管運動性鼻炎 等）等呼吸道疾病，從最近之研究被認定為係一種以與肥胖 細胞、嗜酸性球及淋巴球等多種炎症細胞有關之慢性呼吸 道黏膜炎症及基於該症之呼吸道黏膜過敏性亢進為特徵之 發炎性疾病。基於此，該疾病之治療藥正從支氣管擴張 藥、抗過敏藥或抗組織胺劑變換為使用具有減少呼吸道黏 、表層之嗜驗性細胞及唁酸性細胞數、減少淋巴球及抑制 淋巴因子從其中游離、抑制傳遞質從嗜鹼性細胞游離、抑 制腺分泌細胞之分泌及進一步抑制血管通透性等作用之抗 炎症藥。其中，治療效果大且副作用少之類固醇化合物局 部治療法受到注目，至目前為止，已開發數個適用於呼吸 道之吸入型類固醇劑。 但是，目前之實況為縱使一般被認定具局部抗炎症活性 之類固醇在詩呼吸道之場合亦不發揮局料擇性， 目前被使用之藥劑，局部選擇性亦不充分， 現嚴重副仙等，無法韻充㈣安純。⑴aib 因此’亟望開發一種具有優異的抗炎症作用，而且在藉 由鼻腔内投與吸人而直接用於呼吸道之場合，具有高局部 選擇性、生物利用率減無全身作用之類固 為發炎性呼料疾狀治㈣。 1290145 A7 __B7 五、發明説明（2 ) 發明之揭示： 本發明之目的為^供一種具有優異抗過敏及抗炎症作 用、對於呼吸道之局部選擇性高且全身副作用低之發炎性 呼吸道疾病之預防及/或治療劑。 本發明者，鑑於現狀，對於既存之類固醇系化合物加以 檢討，發現下述通式（1)表示之類固醇衍生物，具有優異之 抗過敏及抗炎症作用，同時在直接用於呼吸道之場合，局 部選擇性高且幾乎無全身作用，能夠預防及/或治療發炎性 呼吸道疾病，本發明於焉完成。 亦即’本發明提供一種發炎性呼吸道疾病之預防及/或治 療劑’其以下述通式（1 )表示之類固醇衍生物做為有效成 分：
[式中，R表示氫原子、鹵素原子、羥基或- 0(：〇R1基（其中 R表示有_素原子或環烧基取代之直鏈或分支鏈燒基、環 烧基或芳基）]。 又，本發明提供該類固醇衍生物在製造發炎性呼吸道疾 病之預防及/或治療劑上之用途。 再者，本發明提供一種發炎性呼吸道疾病之治療方法， • 6 - 紙張尺度適用巾@國家標準(CNS) A4規格(21GX 297公董） " ----- 1290145
I A7 B7 ___ 五、發明説明（3 ) 其特徵為經口吸入或經鼻腔内投與該類固醇衍生物。 圖式之簡單說明 圖1係表示化合物2投與後遲發相之呼吸道抵抗曲線下面 積之圖。 圖2係表示化合物2投與後遲發相之鼻腔抵抗曲線下面積 之圖。 圖3係表示化合物1投與後之抗酸性球數之圖。 圖4表示化合物2投與後之抗酸性球數之圖。 (A) 化合物2 (2%，4%及8%)於挑釁前24小時投與。 (B) 化合物2 (8%)於挑釁前12，24及48小時投與。 實施本發明之最佳形態 在本發明發炎性呼吸道疾病之預防及/或治療劑之通式（1) 中，R表示之鹵素原子為氟、氣、溴或碘，以氣或溴為特 佳。 以R1表示之直鏈或分支鏈烷基，碳數為1〜23，以1〜15 為特佳。取代在該烷基上之齒素原子為氟、氣、溴或碘， 以氣或溴為特佳，環烷基以碳數3〜6者為較佳。 又，以R1表示之直鏈烷基之較佳具體例為曱基、乙基、 正丙基、正丁基、正壬基、正--基、正十三基及正十五 基等；分支鏈烧基之較佳具體例為異丙基、異丁基、第二 丁基、第三丁基、異戊基、新戊基、第三戊基及異己基 等。 鹵代烧基之較佳具體例為3 -氣丙基、3 -漠丙基、3 -氟丙 基、4-氣丁基、4-溴丁基、4-氟丁基、5-氯戊基、5-溴戊 -7 - ^紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) " 1290145
質。 文為本發月/σ療劑之對象之發炎性呼吸道疾病，除上呼 吸道發炎性疾病及下呼吸道發炎性疾病之外，尚包含喉頭 過敏、慢性閉塞性肺疾病及間質性肺炎等。該上呼吸道發 炎f生疾病例如為過敏性鼻炎及血管運動性(本態性)鼻炎等 a敏纟m胃彳鼻腔炎等；該下啤吸道發炎性疾病例如 為支氣管炎、支氣管性氣喘及小兒氣喘等。 又，在本發明中，所謂過敏性鼻炎意指鼻腔黏膜之任意 過敏性反應，包含以噴嚏、流鼻涕、鼻塞、眼睛癢、充血 及流淚為特徵之花粉症（季節性過敏性鼻炎）及全年性過敏 性鼻炎。 再者，在支氣官性氣喘中，其之呼吸道反應之病態按時 間被區分為即時型氣喘反應、遲發型氣喘反應及後遲發型 氣喘反應（過敏性氣喘）。在本發明中，對於此等之任何階 段之氣喘反應均適用，尤其是對於以暴露於抗原數小時後 產生呼吸道炎症反應為主之遲發型氣喘反應特別有效。 本發明之發炎性呼吸道疾病之預防及/或治療劑，以直接 投與至呼吸道黏膜之形態，經由例如鼻腔内投與及經口吸 入投與等而被使用。 供鼻腔内投與之製劑，例如可以使用加壓式定量噴霧 器、乾粉噴霧器及滴入容器等，以液狀或粉末狀組合物投 與。 供經口吸入投與之製劑，例如可以使用加壓式定量吸入 器、乾粉吸入ρ、喷射霧化器及超音波霧化器等，以液狀 — -9 - ^紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) " " --
I 1290145 A7 ----- - B7 五、發明説明（6 ) 或粉末狀組合物投與α 為本發明之發炎性呼吸道疾病之預防及/或治療劑之液狀 或粉末狀組合物，在為有效成分之化合物（丨）中，於需要時 可含有溶劑、基劑、稀釋劑、充填劑及增量劑等賦與液狀 或粉末狀組合物之形態之賦形劑；溶解補助劑、可溶化 劑、緩衝劑、等張化劑、乳化劑、界面活性劑、安定劑、 懸浮劑、分散劑、增粘劑、潤滑劑、粘合劑、附著防止劑 及噴霧劑等具有能幫助保持液狀或粉末狀形態之機能之補 助劑；保存劑、殺菌劑、防腐劑、甘味劑、香味劑.、芳香 hJ著色劑及抗氧化劑等為改善使用上之性質而添加之添 加劑，以及藉由常用方法製造成經鼻投與製劑或經口吸入 投與製劑。 本發明之有效成分之預防及/或治療之有效量視投與路 徑、患者之年齡、性別及疾病之程度而異，通常為約5 0〜 2〇〇〇/zg/日，以100〜800 #g/a為較佳，投與次數通常為 1〜數次/日，較佳調製能滿足此等條件之製劑。 因此，被調製之本發明之發炎性呼吸道疾病之預防及/或 治療劑，如後述實施例所示，對於土撥鼠及大鼠之過敏性 氣喘（呼吸道收縮）模型藉由吸入投與，又，對於土撥鼠之 過敏性鼻炎模型，藉由吸入或點鼻，顯示對於呼吸道及鼻 腔抗性之增大具有意義之抑制效果，而且幾乎未顯示全身 作用，因此為副作用低且安全性高之發炎性呼吸道疾病之 預防及/或治療劑，在臨床上有用。 實施例 -10 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公复) 1290145 A7 B7 五、發明説明（7 ) — 製造例 依據特公平7-116215號公報記載之方法，合成9_友 - 1 1 冷，17,2 1-三羥基-16 α -甲基-1，4-孕二烯_3 2〇·- ’ ^* QpJ - 1 7 - 環丙烷羧酸酯（化合物1)及9-氟-1 1 /9，17 21_ r鉍盆，r ’一一—d里卷-1 6 α -甲基-1，4 -孕二烯-3,20 -二圃-2上屋―己就羧酸|旨一J 7 •環丙 烷羧酸酯（化合物2)。 亦即，使地塞米松（dexamethasone)與環丙烧三緩酸之一 烧s旨於酸存在下反應，生成分子内原酯（orth〇ester)，繼而 错由酸性水解得到化合物1，使其與環己燒緩酸之反廣性衍 生物反應，得到化合物2。 實施例1對於土撥鼠·過敏性氣喘模型之作用 使雄性土撥鼠（1群8隻）吸入1 %卵白白蛋白溶液，i曰i 〇 分鐘連續8日。最終致敏1星期後，使其吸入2%卵白白蛋白 溶液5分鐘（挑釁）。在挑釁24小時前及1小時前將麥提拉彭 (metiraP〇n)(10 mg/kg)投與至靜脈内，於3〇分鐘前將沘拉 明（pyrilamine)(10 mg/kg)投與至腹腔内。用綜合呼吸機能 解析系統（Pulmos-I，M.I.P.S·公司）測定呼吸道抗性 (sRaw)。求出挑釁4〜8小時後之sRaw之增加率曲線下面 積’當做遲發型反應。將本發明化合物2及i提卡宗 (fluticaz〇n)(FP)分別懸浮於0.2% HCO-60生理食鹽液中， 在挑釁2 4小時前及1小時前分別吸入3 〇分鐘。將結果示於 圖1中。 由此可知本發明之預防及/或治療劑比Fp更能強力抑制土 撥鼠之過敏性氣喘反應之遲發型反應（LAR)。 -11 - 本紙張尺度適财g 8家標準(CNS) Α4^(21〇Χ 297公釐) ~ ----- 1290145
實施例2對於土撥鼠.過敏性鼻炎模型之作用 將20/zg/ml之卵白白蛋白溶液與2〇 mg/ml之氫氧化鋁凝 踢溶液之等量混合液經由腹腔内投與至雄性土撥鼠（〖群9 隻），每隻1 ml。1星期後進行同樣之操作。從最終致敏後1 生期反覆進行鼻炎誘發’每週1次，並於第5次誘發之2 日’ 1日及1小時前共3次，將懸浮於〇 2%Hc〇-6〇生理食鹽 液之本發明化合物2分別投與至土撥鼠之二鼻孔，每鼻孔 2 0 // L，兩鼻共計投與40 # L。藉由將o j mg/mli卵白白 蛋白溶液投與至土撥鼠之二鼻孔（每鼻孔2〇 ，兩鼻共計 投與40 // L)以誘發鼻炎。用綜合呼吸機能解析系統 (Pulmos-I，M.I.P.S.公司）測定鼻腔抗性（sRaw)。求出挑釁 3〜7小時後之sRaw增加率曲線下面積，當作遲發型反應。 將結果示於圖2中。 由此可知本發明之預防及/或治療劑能抑制土撥鼠·過敏 性鼻炎反應之遲發型反應（LAR)。 實施例3對於大鼠·過敏性氣喘模型之作用 將2〇 # g/ml之卵白白蛋白溶液與5 mg/ml之氫氧化銘凝 膠溶液之1 : 1混合液經由腹腔内投與至大鼠〇群7隻），每 隻動物1 ml，以進行致敏。又，關於追加致敏，於其之第2 及第3日，用同樣之方法進行致敏。最終致敏之丨3日後， 使其吸入抗原（2%卵白白蛋白溶液）25分鐘（挑釁）。挑釁24 小時後用生理食鹽液洗淨呼吸道内部，然後測定洗淨液中 游離炎症細胞（嗜酸性球）之數目以做為氣喘反應之指標。 (1)將本發明化合物1用乳糖稀釋（8 而得之粉體製劑， _____- 12 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公董) 1290145 A7 B7 五、發明説明（9 ) 於挑釁前12小時及24小時投與至氧管内（10 mg/大鼠），然 後將結果示於圖3中。 (2)①將本發明化合物2用乳糖稀釋（2%，4%，8 %)而得 之粉體製劑，於挑釁前24小時投與至氣管内（1〇 mg/大 鼠），然後將結果示於圖4(A)中。 ②將含有8 %本發明化合物2之粉體製劑於挑釁前1 2， 2 4及4 8小時前投與至氣管内（1 〇 mg /大鼠），然後將結果示 於圖4(B)中。 結果’本發明之預防及/或治療劑，在投與粉體後顧示持 續24小時以上之抗氣喘作用。 實施例4單次投與毒性試驗 將本發明化合物1及2單次投與至大鼠，並求出致死量。 將結果示於表1中。藉此確認本發明化合物1及2為低毒 性。 動物種類（性別） 投與路徑 約略之致死量 大鼠（雄、雌） 經口投與 2000 mg/kg 以上 大鼠（雄、雌） 皮下投與 2000 mg/kg 以上 實施例5 製劑例 (1 ) 吸入劑 用下述處方，得到藉一般方法吸入用之粉末。 化合物1或2 0.8 mg 乳蓋___19.2 mg 合计 20.0 mg -13- 本紙張尺度適财國國家標準(CNS) A4規格(21GX 297公董) 1290145
(2)點鼻藥 用下述處方，得到藉一般方法點鼻用之噴霧矿 化合物1或2 0.01% w/w 叛甲基纖維素執 1.0% w/w 0.9% w/w 100%。 氯化納__ 用精製水調成全量 產業上之利用可能性 本發明之類固醇衍生物（丨）可以持續地抑制呼吸道炎症及 呼吸道反應亢進，而且在直接用於呼吸道之場合，由於局 部選擇性咼’幾乎未顯示全身作用，所以可做為長期投與 安全性高之發炎性呼吸道疾病之預防及/或治療劑，在臨床 上之有用性極高。 L__- 14 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
Claims (1)
- A8 B81290145)90131849 號專利申請案 b88 中文申請專利範圍替換本(％年8月）漂 六、申請專利範圍 1· 一種上呼吸道發炎性疾病及下呼吸道發炎性疾病之治療 劑’其以通式（1 )表示之類固醇衍生物做為有效成分：[式中，R表示羥基或環己烷羧酸酯基]。 2_如申請專利範圍第1項之上呼吸道發炎性疾病及下呼吸道 發炎性疾病之治療劑’其中類固醇衍生物為9 _氟-1 1 /5，17,2 1_三羥基_16 α -甲基孕二烯_3,2〇_二酮· 17_環丙烷羧酸酯、或9_氟_UiS，17,21_三羥基_16α_ 甲基-1，4_孕二烯_3,20_二酮21 •環己烷羧酸酯17•環丙 烧敌酸g旨。 3 ·如申請專利範圍第1或2項之上呼吸道發炎性疾病及下呼 吸道發炎性疾病之治療劑，其中上呼吸道發炎性疾病及 下呼吸道發炎性疾病為從支氣管性氣喘、鼻過敏症、喉 過敏及副鼻腔炎中選出者。 4·如申請專利範圍第！或2項之上呼吸道發炎性疾病及下呼 吸道發炎性疾病之治療劑，其為經口吸入或鼻腔内投與 製劑。 "V 5 ·如申請專利範圍第3項之上呼吸道發炎性疾 發炎性疾病之治療劑，其為經口吸入 病及下呼吸道 其為經口吸入或鼻腔内投與製8 8 8 8 A B c D 1290145 六、申請專利範圍 劑。 6 · —種以如申請專利範圍第1或2項之通式（1)表示之類固醇 衍生物用於製造一種上呼吸道發炎性疾病及下呼吸道發 炎性疾病之治療劑之用途。 75795-960803.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)
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| MX (1) | MXPA03005660A (zh) |
| PE (1) | PE20020793A1 (zh) |
| PT (1) | PT1344526E (zh) |
| TW (1) | TWI290145B (zh) |
| WO (1) | WO2002051422A1 (zh) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6777399B2 (en) * | 2000-08-05 | 2004-08-17 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative compositions |
| US6858596B2 (en) * | 2000-08-05 | 2005-02-22 | Smithkline Beecham Corporation | Formulation containing anti-inflammatory androstane derivative |
| GB0019172D0 (en) * | 2000-08-05 | 2000-09-27 | Glaxo Group Ltd | Novel compounds |
| US6759398B2 (en) * | 2000-08-05 | 2004-07-06 | Smithkline Beecham Corporation | Anti-inflammatory androstane derivative |
| WO2002012265A1 (en) * | 2000-08-05 | 2002-02-14 | Glaxo Group Limited | 6.ALPHA., 9.ALPHA.-DIFLUORO-17.ALPHA.-`(2-FURANYLCARBOXYL) OXY!-11.BETA.-HYDROXY-16.ALPHA.-METHYL-3-OXO-ANDROST-1,4,-DIENE-17-CARBOTHIOIC ACID S-FLUOROMETHYL ESTER AS AN ANTI-INFLAMMATORY AGENT |
| SI1383786T1 (sl) * | 2001-04-30 | 2009-02-28 | Glaxo Group Ltd | Protivnetni 17.beta-karbotioatestrski derivati androstana s ciklično estrsko skupino na položaju 17.alfa |
| ES2307751T3 (es) * | 2001-06-12 | 2008-12-01 | Glaxo Group Limited | Nuevos esteres heterociclicos centi-inflamatorios 17 alfa de derivados 17 beta de carbotioato de androstano. |
| US20050175545A1 (en) * | 2002-02-04 | 2005-08-11 | Keith Biggadike | Formulation for inhalation comprising a glucocorticoid and a beta 2-adrenoreceptor agonist |
| GB0202635D0 (en) * | 2002-02-05 | 2002-03-20 | Glaxo Wellcome Mfg Pte Ltd | Formulation containing novel anti-inflammatory androstane derivative |
| GB2389530B (en) * | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| JP3691459B2 (ja) * | 2002-06-14 | 2005-09-07 | 久光メディカル株式会社 | 粉末状吸入剤組成物 |
| EP1645266A1 (en) * | 2004-10-08 | 2006-04-12 | Hisamitsu Medical Co., Ltd. | Aqueous suspension for nasal drops |
| GB0507165D0 (en) * | 2005-04-08 | 2005-05-18 | Glaxo Group Ltd | Novel crystalline pharmaceutical product |
| GB0615108D0 (en) * | 2006-07-28 | 2006-09-06 | Glaxo Group Ltd | Novel formulations |
| EP2111861A1 (en) | 2008-04-21 | 2009-10-28 | Ranbaxy Laboratories Limited | Compositions of phosphodiesterase type IV inhibitors |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3639434A (en) | 1967-02-02 | 1972-02-01 | Boots Pure Drug Co Ltd | 17-acyloxysteroids and their manufacture |
| SE418294B (sv) * | 1974-03-27 | 1981-05-18 | Plurichemie Anstalt | Sett att framstella en 16alfa- eller 16beta-9alfa-klor eller -fluorsteroidester |
| US4933168A (en) * | 1975-05-27 | 1990-06-12 | Syntex Pharmaceuticals International Limited | Stable, crystalline flunisolide |
| IL66432A0 (en) * | 1981-08-04 | 1982-12-31 | Plurichemie Anstalt | Process for the preparation of steroidal esters |
| JPH07116215B2 (ja) * | 1989-04-19 | 1995-12-13 | エスエス製薬株式会社 | 新規なステロイド化合物 |
| PE44995A1 (es) | 1994-01-27 | 1995-12-18 | Schering Corp | Furoato de mometasona para el tratamiento de las enfermedades pulmonares y de las vias respiratorias |
-
2001
- 2001-12-21 AT AT01271858T patent/ATE396733T1/de active
- 2001-12-21 CN CNA2009100064252A patent/CN101518537A/zh active Pending
- 2001-12-21 EP EP01271858A patent/EP1344526B1/en not_active Expired - Lifetime
- 2001-12-21 KR KR1020037007282A patent/KR100833157B1/ko active Protection Beyond IP Right Term
- 2001-12-21 TW TW090131849A patent/TWI290145B/zh not_active IP Right Cessation
- 2001-12-21 DE DE60134267T patent/DE60134267D1/de not_active Expired - Lifetime
- 2001-12-21 PT PT01271858T patent/PT1344526E/pt unknown
- 2001-12-21 WO PCT/JP2001/011264 patent/WO2002051422A1/ja active IP Right Grant
- 2001-12-21 JP JP2002552566A patent/JP3691487B2/ja not_active Expired - Lifetime
- 2001-12-21 ES ES01271858T patent/ES2305029T3/es not_active Expired - Lifetime
- 2001-12-21 US US10/451,061 patent/US7214672B2/en not_active Expired - Lifetime
- 2001-12-21 MX MXPA03005660A patent/MXPA03005660A/es active IP Right Grant
- 2001-12-21 CN CNA018210422A patent/CN1481246A/zh active Pending
- 2001-12-21 DK DK01271858T patent/DK1344526T3/da active
- 2001-12-21 CA CA002438799A patent/CA2438799C/en not_active Expired - Lifetime
- 2001-12-26 PE PE2001001303A patent/PE20020793A1/es not_active Application Discontinuation
- 2001-12-26 AR ARP010106024A patent/AR031969A1/es not_active Application Discontinuation
-
2014
- 2014-09-23 AR ARP140103518A patent/AR097737A2/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR097737A2 (es) | 2016-04-13 |
| CA2438799C (en) | 2009-09-01 |
| WO2002051422A1 (fr) | 2002-07-04 |
| DE60134267D1 (de) | 2008-07-10 |
| ATE396733T1 (de) | 2008-06-15 |
| DK1344526T3 (da) | 2008-09-15 |
| CN101518537A (zh) | 2009-09-02 |
| CA2438799A1 (en) | 2002-07-04 |
| EP1344526B1 (en) | 2008-05-28 |
| JP3691487B2 (ja) | 2005-09-07 |
| ES2305029T3 (es) | 2008-11-01 |
| EP1344526A4 (en) | 2005-03-16 |
| MXPA03005660A (es) | 2004-12-03 |
| PT1344526E (pt) | 2008-06-18 |
| AR031969A1 (es) | 2003-10-08 |
| KR100833157B1 (ko) | 2008-05-28 |
| JPWO2002051422A1 (ja) | 2004-04-22 |
| KR20030064414A (ko) | 2003-07-31 |
| EP1344526A1 (en) | 2003-09-17 |
| US7214672B2 (en) | 2007-05-08 |
| PE20020793A1 (es) | 2002-09-06 |
| US20040053904A1 (en) | 2004-03-18 |
| CN1481246A (zh) | 2004-03-10 |
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