TWI343256B - Cornea-conjunctiva disorder treating agent - Google Patents

Cornea-conjunctiva disorder treating agent Download PDF

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TWI343256B
TWI343256B TW093132101A TW93132101A TWI343256B TW I343256 B TWI343256 B TW I343256B TW 093132101 A TW093132101 A TW 093132101A TW 93132101 A TW93132101 A TW 93132101A TW I343256 B TWI343256 B TW I343256B
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salt
corneal
ylmethoxy
methoxy
benzyl
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TW200518750A (en
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Masatsugu Nakamura
Shin-Ichiro Hirai
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Santen Pharmaceutical Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/427Thiazoles not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • A61P27/04Artificial tears; Irrigation solutions
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

1343256 九、發明說明: 【發明所屬之技術領域】 本發明係相關於以5-[4-( 6 -甲氧基-1-甲基-1H -苯并咪唑 -2-基甲氧基)苄基]四氫噻唑_2,4-二酮或其鹽作爲有效成分 之角結膜障害之治療劑。 【先前技術】 角膜係一直徑約1 cm、厚約1 mm的透明無血管之組織, 又’結膜係覆蓋角膜邊緣稍後方的眼球的表面和眼瞼內面 之黏膜’角膜和結膜對視覺機能有重要的影響。角膜潰瘍、 角膜炎、結膜炎、乾眼症等各種疾病引起的角結膜障害, 若因某些因素導致延遲修復或無法修復而轉移,因角膜和 結膜爲相連組織,對上皮的正常組織產生不良影響,且可 能傷及實質和內皮的結構和機能。近年,隨著細胞生物學 的發展’已了解細胞的分裂•移動•黏著•伸展•分化等 相關因素,而這些因素在角膜障害的修復過程中扮演重要 的角色(非特許文獻1、非特許文獻2 )。 另一方面,特許文獻1揭示5-[4-(6-甲氧基-1-甲基-1H-苯并咪唑-2-基甲氧基)苄基]四氫噻唑-2,4-二酮係糖尿 病、高血糖症等胰島素抵抗性引起的疾病或骨關節炎、類 風濕性關節炎等炎症性疾病的有效治療藥,又,特許文獻 2及特許文獻3揭示上述化合物的鹽酸鹽的溶解性較其自 由體(不形成鹽之化合物)的溶解性明顯地更佳,發揮優 越的經口吸收性。 惟,無探討上述化合物對角結膜障害等眼疾病的藥理作 用之報告。 1343256 【特許文獻1】特許第2976885號公報 【特許文獻2】特開200 1 -3 997 6號公報 【特許文獻3】特開2002-220336號公報 【非特許文獻1】臨眼,46,7 3 8_743 ( 1 992 ) 【非特許文獻2】眼_手術,5,7 1 9 - 7 2 7 ( 1 9 9 2 ) 【發明內容】 【發明之目的】 本發明的目的係探索雜環化合物5_ [4-(6-甲氧基-1-甲基 -1H-苯并咪唑-2-基甲氧基)苄基]四氫噻唑-2,4-二酮或其 鹽之新穎醫藥用途。 本案發明者們爲要探索上述化合物之新穎醫藥用途,經 精心硏究而在角膜障害的治癒效力試驗中,發現上述化合 物對角膜障害可發揮優越的改善效果,而完成本發明。 亦即,本發明係以5-[4-(6 -甲氧基-1-甲基-1H -苯并咪哩 -2 -基甲氧基)苄基]四氫噻唑_2,4 -二酮或其鹽作爲有效成 分的乾眼症、角膜潰瘍、角膜炎、結膜炎' 點狀表層角膜 症' 角膜上皮缺損、結膜上皮缺損、乾性角結膜炎、上輪 部角結膜炎、絲狀角膜炎等角結膜障害之治療劑。 本發明之5-[4-(6-甲氧基·1-甲基-1H-苯并咪唑-2-基甲氧 基)苄基]四氫噻唑-2,4-二酮(以下簡稱爲(本化合物)) 係如下面化學結構式(1)所表不之縮合雜環化合物,又, 其鹽類無特別的限制,爲醫藥許可的鹽即可,例如和鹽酸、 硝酸、硫酸等無機酸形成的鹽,或和鈉、鉀、鈣等鹼金屬 或鹼土類金屬形成的鹽等。以鹽酸鹽較佳。又,本發明之 鹽亦包含本化合物的第四級銨鹽。且,本化合物存有幾何 1343256 異又
圍 範 明 發 本 損點 膜' 結炎 或膜 膜結 角、 致炎 導膜 素角 因、 種瘍 各潰 因膜 指角 係 、 害症 障眼 膜乾 結如 角例 中, 明態 發狀 本的 傷 狀表層角膜症、角膜上皮缺損、結膜上皮缺損、乾性角結 膜炎、上輪部角結膜炎、絲狀角膜炎等。 本發明的角結膜障害治療劑可由經口或非經口方式投 與。投與劑型例如點眼劑、眼軟膏、注射劑、錠劑、膠囊 劑、顆粒劑、散劑等。尤以點眼劑較理想。可採用泛用的 技術進行製劑化。例如,可依需求使用氯化鈉、濃甘油等 等張劑、磷酸鈉、醋酸鈉等緩衝劑、聚環氧乙烷山梨糖醇 酐一油酸酯、聚氧硬脂酸40、聚環氧乙烷硬化蓖麻油等界 面活性劑、檸檬'酸鈉、EDTA-鈉安定化劑、氯化苄烷銨、 對胺基苯甲酸等防腐劑等,調製成點眼劑。其pH爲眼科製 劑可容許的範圍爲佳,在4-8的範圍較佳。 眼軟膏係使用白色凡士林、液態蠟等泛用的基劑而調 製。又’錠劑、膠囊、顆粒劑、散劑等經口劑可依需求添 加乳糖、結晶纖維素 '澱粉、植物油等增量劑、硬脂酸鎂、 滑石等潤滑劑、羥丙基纖維素、聚乙烯吡略烷酮等黏合劑、 羧甲基纖維素鈣、低取代羥丙基甲基纖維素等崩解劑、羥 丙基甲基纖維素、聚乙二醇(Macrogol)、矽樹脂等包覆劑、 1343256 明膠皮膜等皮膜劑等進行調製。 可依症狀、年齡、劑型適當地選擇給藥量,惟點眼劑通 常爲0.0001-1% (w/v),較理想爲0.001〜1% (w/v)的量 1曰中分成1〜數次投與。又,若爲經口劑通常丨日量爲 0.1〜5000mg,較理想爲i~i〇〇〇mg分成1-•數次投與。 【發明的效果】 如後述般’實施角膜障害的治癒效力試驗時,因本化合 物在乾眼模式中發揮優越的促進治療效果,有助於作爲乾 眼症、角膜潰瘍、角膜炎' 結膜炎、點狀表層角膜症.、角 膜上皮缺損、結膜上皮缺損、乾性角結膜炎、上輪部角結 膜炎、絲狀角膜炎等角結膜障害的治療劑。 【實施方式】 【實施發明之最佳型態】 以下所示爲製劑例及藥理試驗的結果,爲要更清楚了解 本發明而進行這些舉例,惟本發明的範圍不受限於這些舉 例。 〔製劑例〕 以下所示爲使用5-[4-(6-甲氧基-1-甲基-1H-苯并咪唑-2-基甲氧基)苄基]四氫噻唑-2,4-二酮(本化合物)的代表 製劑例》 製劑例1 1 Omg 900mg 適量 100ml 中 本化合物 氯化鈉 滅菌純化水 1343256 經由改變本化合物之添加量’可調製濃度〇. Ο 〇丨% (w/v)、0.01% (w/v)、0.03% (w/v)、0.1¾ (w/v) 0.3% ( w/v ) ' 1.0% (w/v) ' 3.0% (w/v)的點眼劑。 製劑例2 100ml 中 本化合物 lOOmg 氯化納 8 0 〇 m g 磷酸氫二鈉 lOOmg 憐酸二氫鈉 適量 滅菌純化水 適量 經由改變本化合物之添加量’可調製濃度0.1% ( w/v )、 0.3¾ (w/v) > 0.5% ( w/v) 、1.5% ( w/v) '3.0% ( w/v ) 的點眼劑。 製劑例3 100g 中 本化合物 0.3 g 液態石蠟 1 0.0 g 白色凡士林 適量 經由改變本化合物之添加量’可調製濃度1 % ( W/V )' 3 % ( w/v )的眼軟膏。 〔藥理試驗〕 角膜障害的治癒效力試驗 使用雄性SD老鼠,以藤原等的方法(In vest. Ophthalmol. Vis. Sci42(I) : 96-100( 2001))爲基準,製作乾眼模式。 作成乾眼模式後,以宮田等的方法(眼科臨床醫報48( 2 ): 1343256 183-188 ( 1994))爲基準,評定角膜障害的治癒率。 (試驗方法) 在雄性SD老鼠的腹腔內,以35mg/kg的比例投與戊巴比 妥鈉進行全身麻醉。其次,取出眼窩外淚腺,經時2個月 使發生角膜障害》 之後,分別在單眼滴入本化合物的0.01%生理食鹽水溶 解液,另一眼滴入生理食鹽水(對照組),1日6次共進 行7日。 開始點眼的7日後,以螢光素染色角膜的障害部分。根 據下述的基準,評估有關角膜的上部 '中間部及下部中螢 光素染色的程度,從上述各部總計得分的平均値算出角膜 障害的改善率。 至於正常眼亦進行和上述相同的試驗,求出上述各部的 總計得分的平均値》 (評定基準) . 0 :無染色 1:稀疏染色,各點狀的染色部分分離 2 :中程度染色,部分的點狀染色部分相鄰接 3:密集染色,各點狀的染色部分相鄰接 (結果) 在生理食鹽水點藥組(對照組)中,以上述各部的總計 得分的平均値爲基準(改善率:〇% ),並根據下述計算式 算出’表1所示係本化合物的0.01%點藥組的改善率。又, 得分的平均値係各8例的平均。 改善率(% ) = {(對照組)一(本化合物.)} /障害度χ 1 〇〇 -10- 1343256 障害度={(對照組)一(正常眼)} (表1 ) 組 總計得分平均値 改善率(% ) 正常眼 2.9 4πχ 無 對照組 6.1 0 本化合物 4.4 5.3 (考察) 從上述使用老鼠的藥理試驗之結果可知,5-[4- ( 6-甲氧 基-1-甲基-1H -苯并咪唑-2-基甲氧基)苄基]四氫噻唑-2,4
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Claims (1)

1343256 .公告本; 修正頁 第93132101「角結膜障害之治療劑」專^利案 (2 0 1 0年1 2月1曰修正) 十、申請專利範圍: _ ^ 1.一種乾性角結膜炎之治療劑,其含有5-[4-(6-甲氧基-1-甲基-1H-苯并咪唑-2-基甲氧基)苄基]四氫噻唑-2,4-二 酮或其鹽作爲有效成分。 2 .如申請專利範圍第1項之治療劑,其中劑型係點眼劑或 眼軟膏。
TW093132101A 2003-10-24 2004-10-22 Cornea-conjunctiva disorder treating agent TWI343256B (en)

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US7358255B2 (en) 2008-04-15
CA2543452A1 (en) 2005-05-06
US20070060628A1 (en) 2007-03-15
DE602004030470D1 (de) 2011-01-20
DK1679074T3 (da) 2011-03-21
WO2005039574A8 (ja) 2005-06-23
CN1870997A (zh) 2006-11-29
JP2005145961A (ja) 2005-06-09
CY1111191T1 (el) 2015-06-11
KR101154175B1 (ko) 2012-06-14
TW200518750A (en) 2005-06-16
EP1679074A4 (en) 2009-03-25
CA2543452C (en) 2012-03-13
KR20060100440A (ko) 2006-09-20
PL1679074T3 (pl) 2011-05-31
EP1679074A1 (en) 2006-07-12
PT1679074E (pt) 2011-03-03
ATE490771T1 (de) 2010-12-15
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EP1679074B1 (en) 2010-12-08
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