TWI424841B - 5-乙醯胺基-4-胍基-9-o-辛醯基-2,3,4,5-四去氧-7-o-甲基-d-甘油基-d-半乳糖基-壬-2-烯吡喃糖酸用於製造h5n1型流行性感冒治療劑或預防劑之使用 - Google Patents
5-乙醯胺基-4-胍基-9-o-辛醯基-2,3,4,5-四去氧-7-o-甲基-d-甘油基-d-半乳糖基-壬-2-烯吡喃糖酸用於製造h5n1型流行性感冒治療劑或預防劑之使用 Download PDFInfo
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- TWI424841B TWI424841B TW097107984A TW97107984A TWI424841B TW I424841 B TWI424841 B TW I424841B TW 097107984 A TW097107984 A TW 097107984A TW 97107984 A TW97107984 A TW 97107984A TW I424841 B TWI424841 B TW I424841B
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- influenza
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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Description
本發明為有關以式(I)化合物為有效成分含有之H5N1型流行性感冒之治療劑或預防劑。
家禽類之H5N1型禽流感病毒之感染為2003年以來,於包括亞洲、歐洲、非洲等之廣泛地域擴大,對人之感染,不只亞洲,於中東、非洲之地域也有認定。新型之H5N1型流行性感冒病毒出現而其感染開始時,幾全部人對其病毒無免疫,又因流行性感冒病毒為由飛沫感染而傳播,故感染急速擴大,引起世界性流行,也即「流行性感冒大流行」。感染H5N1型流行性感冒病毒之人患者之半數以上致死,致死率高。周知20世紀中引起西班牙流感、亞洲流感、及香港流感之3度流行性感冒大流行,於患者數最多之西班牙流感,推計世界中有約2000~4000萬人,日本也有約50萬人死亡。
依2005年11月厚生勞動省(日本)之報告,新型流行性感冒病毒流行時,於日本該新型流行性感冒之罹患而受診之患者數推計為約1800萬人~2500萬人。更於新型流行性感冒病毒之病原性為重度時,入院患者數推定為約20萬人,死亡者數為64萬人,與健康被害同時對社會活動有莫大影響而甚危險。
由以上而殷望早期開發對新型流行性感冒病毒嚴重性高之疾病有效之治療劑。
具有神經胺酸酶(Neuraminidase)抑制活性之流行性感冒治療劑札那米偉(Zanamivir)(尤其札那米偉水合物)、及奧司他偉(Oseltamivir)(尤其奧司他偉磷酸鹽、或奧司他偉羧酸酯)對H5N1型流行性感冒病毒有抑制活性之報告,但殷望具有更優活性之化合物(非專利文獻1或2)。又有奧司他偉不呈示抑制活性(也即奧司他偉耐性)之H5N1型流行性感冒病毒株之報告,殷望對這些奧司他偉耐性之H5N1型流行性感冒病毒具有抑制活性之化合物(非專利文獻1或2)。
已知式(I)化合物作為具有神經胺酸酶抑制活性之流行性感冒治療劑有用(專利文獻1至3)。但這些化合物對H5N1型流行性感冒病毒具有抑制活性並無報告。又式(I)化合物之構造雖與札那米偉類似,但與奧司他偉完全不同。
【非專利文獻1】Nature,2005年,第437卷,p.1108【非專利文獻2】N.Engl.J.Med.,2005年,第353卷,(25):2667-72
【專利文獻1】美國專利6340702號說明書(專利第3209946號公報)【專利文獻2】美國專利6451766號說明書(特開平10-109981號公報)【專利文獻3】美國專利6844363號說明書(特開2002-012590號公報)
發明者等就流行性感冒之治療劑或預防劑致力檢討,發現式(I)化合物作為H5N1型流行性感冒之治療劑或預防劑極有用。本發明為基於上述知見而完成。
本發明提供如下述H5N1型流行性感冒之治療劑或預防劑。
(1)一種H5N1型流行性感冒之治療劑或預防劑,內含有效成分為如下式(I)化合物
[式中R1
及R2
可相同或不同為氫原子或碳數2至20個之烷醯基,X為鹵原子、羥基、碳數1至4個之烷氧基或碳數2至20個之烷醯氧基,R3
為氫原子或碳數1至20個之烷基,但R1
及R2
為氫原子,X為羥基,且R3
為氫原子之化合物除外]。
(2)如(1)之H5N1型流行性感冒之治療劑或預防劑,其中以X為碳數1至4個之烷氧基之化合物為有效成分。
(3)如(1)之H5N1型流行性感冒之治療劑或預防劑,其中以X為甲氧基之化合物為有效成分。
(4)如(1)至(3)中(1)中任一項之H5N1型流行性感冒之治療劑或預防劑,其中以R1
為碳數6至20個之烷醯基,R2
為氫原子,R3
為氫原子之化合物為有效成分。
(5)如(1)至(3)中(1)中任一項之H5N1型流行性感冒之治療
劑或預防劑,其中以R1
為碳數6至18個之烷醯基,R2
為氫原子,R3
為氫原子之化合物為有效成分,(6)如(1)至(3)中(1)中任一項之H5N1型流行性感冒之治療劑或預防劑,其中以R1
為己醯基、辛醯基、癸醯基、十二醯基、十四醯基、十六醯基或十八醯基,R2
為氫原子,R3
為氫原子之化合物為有效成分。
(7)如(1)至(3)中(1)中任一項之H5N1型流行性感冒之治療劑或預防劑,其中以R1
及R2
為氫原子,R3
為碳數8至20個之烷基之化合物為有效成分。
(8)如(1)至(3)中(1)中任一項之H5N1型流行性感冒之治療劑或預防劑,其中以R1
及R2
為氫原子,R3
為癸基、十二基、十四基、十六基或十八基之化合物為有效成分,或(9)如(1)之H5N1型流行性感冒之治療劑或預防劑,其中以由下述群選擇之化合物為有效成分:5-乙醯胺基-4-胍基-9-O-己醯基-2,3,4,5-四去氧-7-O-甲基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸(enopyranosoic acid)、5-乙醯胺基-4-胍基-9-O-辛醯基-2,3,4,5-四去氧-7-O-甲基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸、5-乙醯胺基-4-胍基-9-O-癸醯基-2,3,4,5-四去氧-7-O-甲基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸、5-乙醯胺基-4-胍基-9-O-十二醯基-2,3,4,5-四去氧-7-O-甲基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸、及5-乙醯胺基-4-胍基-9-O-十四醯基-2,3,4,5-四去氧-7-O-甲
基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸。
(10)一種治療或預防H5N1型流行性感冒之方法,其係於脊椎動物投與藥理有效量如下式(I)化合物
[式中R1
及R2
可相同或不同為氫原子或碳數2至20個之烷醯基,X為鹵原子、羥基、碳數1至4個之烷氧基或碳數2至20個之烷醯氧基,R3
為氫原子或碳數1至20個之烷基,但R1
及R2
為氫原子,X為羥基,且R3
為氫原子之化合物除外]。
(11)一種如下式(I)化合物之使用,用以製造H5N1型流行性感冒之治療劑或預防劑
[式中R1
及R2
可相同或不同為氫原子或碳數2至20個之烷醯基,X為鹵原子、羥基、碳數1至4個之烷氧基或碳數2至20個之烷醯氧基,R3
為氫原子或碳數1至20個之烷基,但R1
及R2
為氫原子,X為羥基,且R3
為氫原子之化合物除外]。
上述中,式(I)化合物為例如US6340702(專利第3209946號公報)、US6451766(特開平10-109981號公報)
、US6844363(特開2002-012590號公報)等記載之2-去氧-2,3-二去氫-N-乙醯神經胺酸衍生物。
式(1)化合物中,X中「鹵原子」為例如氟、氯、溴或碘原子,宜為氟或氯原子,最宜為氟原子。X中「碳數1至4個之烷氧基」為例如甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、第二丁氧基或第三丁氧基等碳數1至4個之直鏈或分枝狀烷氧基,宜為甲氧基或乙氧基,最宜為甲氧基。
X宜為碳數1至4個之烷氧基,最宜為甲氧基。R1
及R2
中「碳數2至20個之烷醯基」,及X中「碳數2至20個之烷醯氧基」之烷醯基部分為碳數2至20個之直鏈或分枝鏈烷醯基,宜為碳數6至20個之烷醯基,更宜為碳數6至18個之烷醯基,更宜為己醯基、辛醯基、癸醯基、十二醯基、十四醯基、十六醯基或十八醯基。R3
中「碳數1至20個之烷基」為碳數1至20個之直鏈或分枝狀烷基。上述R3
中「碳數1至20個之烷基」為R1
及R2
為氫原子,X為鹵原子、羥基或碳數1至4個之烷氧基時,宜為碳數8至20個之烷基,更宜為碳數10至20個之烷基,更宜為癸基、十二基、十四基、十六基或十八基。
R1
或R2
為碳數6至20個之烷醯基時,R3
為宜為氫原子或碳數1至4個之烷基,更宜為氫原子。
式(1)化合物為宜為下述化合物:(I-1)X為碳數1至4個之烷氧基之化合物、(I-2)X為甲氧基之化合物、
(I-3)R1
為碳數6至20個之烷醯基,R2
為氫原子,X為碳數1至4個之烷氧基,R3
為氫原子之化合物、(I-4)R1
為碳數6至20個之烷醯基,R2
為氫原子,X為甲氧基,R3
為氫原子之化合物、(I-5)R1
為碳數6至18個之烷醯基,R2
為氫原子,X為甲氧基,R3
為氫原子之化合物、(I-6)R1
為己醯基、辛醯基、癸醯基、十二醯基、十四醯基、十六醯基或十八醯基,R2
為氫原子,X為甲氧基,R3
為氫原子之化合物、(I-7)R1
及R2
為氫原子,X為甲氧基,R3
為碳數8至20個之烷基之化合物、或(I-8)R1
及R2
為氫原子,X為甲氧基,R3
為癸基、十二基、十四基、十六基或十八基之化合物。
式(I)化合物中,R1
或R2
為烷醯基時、X為烷醯氧基時、或R3
為烷基時,R1
O-、R2
O-、X、或R3
OCO-各形成酯基。式(I)化合物有這些酯基時,該化合物可為前藥(「醫藥品之開發」,廣川書店,1990年刊,第7卷,分子設計,p.163-198)。式(I)化合物中上述酯基為投與後,於活體內之代謝過程(例如水解)轉換為羥基或羧基,其轉換而生成之化合物呈示藥理活性(例如US6451766之試驗例1’至4’、特開平10-109981號公報之試驗例1至4)。
式(1)化合物因於分子內有胍基或羧基,故可與藥理學上無毒性之酸或鹼一起形成藥理容許鹽。
「藥理容許鹽」可為例如氫氟酸鹽、鹽酸鹽、氫溴酸鹽
、氫碘酸鹽等氫鹵酸鹽;硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等無機酸鹽;甲磺酸鹽、乙磺酸鹽、三氟甲磺酸鹽等烷磺酸鹽;苯磺酸鹽、對甲苯磺酸鹽等芳磺酸鹽;乙酸鹽、三氟乙酸鹽、檸檬酸鹽、酒石酸鹽、草酸鹽、馬來酸鹽等有機酸鹽;甘胺酸鹽、離胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽等胺基酸鹽;鋰鹽、鈉鹽、鉀鹽等鹼金屬鹽;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、第三辛胺鹽、二苄胺鹽、嗎啉鹽、葡萄糖胺鹽、乙二胺鹽、胍鹽、二乙胺鹽、三乙胺鹽、二環己胺鹽、普羅卡因鹽、乙醇胺鹽、二乙醇胺鹽、哌鹽、四甲基銨鹽等有機胺鹽或有機銨鹽,宜為鹼金屬鹽、有機酸鹽或無機酸鹽。
式(I)化合物於大氣中放置,或與水或有機溶劑混和等,則有時形成水合物或溶劑合物。
上述式(I)化合物之藥理容許鹽、水合物及溶劑合物包括於本發明之治療劑或預防劑之有效成分。
式(I)化合物作為H5N1型流行性感冒之治療劑或預防劑極為有用。上述H5N1型流行性感冒為由於奧司他偉感受性或耐性之H5N1型流行性感冒病毒之流行性感冒,宜為由於奧司他偉耐性之H5N1型流行性感冒病毒之流行性感冒。上述奧司他偉感受性之H5N1型流行性感冒病毒為例如A/Hanoi/30408/2005(clone 7)、上述奧司他偉耐性之H5N1型流行性感冒病毒可為例如A/Hanoi/30408/2005(clone 9)。又由別之觀點,式(I)化合物作為由於奧司他偉
耐性之流行性感冒病毒(不限於H5N1型)之流行性感冒之治療劑或預防劑有用。
式(I)化合物作為H5N1型流行性感冒之治療劑或預防劑也極有用,又作為由於奧司他偉耐性之H5N1型流行性感冒病毒之流行性感冒之治療劑或預防劑也有用。
本說明書包括記載於本案優先権之基礎日本國專利申請特願2007-56872之說明書及/或圖面之內容。
本發明治療劑或預防劑之有效成分式(I)化合物可依記載於US6340702(專利第3209946號公報)、US6451766(特開平10-109981號公報)、US6844363(特開2002-012590號公報)等之方法或仿這些之方法製造。
式(I)化合物作為流行性感冒之治療劑或預防劑使用時,可(i)以其本身;或(ii)與適宜之藥理容許之賦形劑、稀釋劑等混合製造之製劑(例如錠劑、膠囊劑、顆粒劑、散劑、糖漿劑、軟膏劑、液劑、懸浮劑、噴霧劑、舌片劑等)來投與。
這些製劑可用賦形劑、結合劑、崩壞劑、滑澤劑、安定劑、矯味矯溴劑、懸浮化劑、稀釋劑、製劑用溶劑等添加物依周知之方法製造。
賦形劑可為例如乳糖、白糖、葡萄糖、甘露醇或山梨糖醇等糖衍生物;玉米澱粉、馬鈴薯澱粉、α-澱粉或糊精等
澱粉衍生物;羧甲基澱粉等澱粉衍生物;結晶纖維素、低置換度羥丙基纖維素、羥丙基甲基纖維素、羧甲基纖維素、羧甲基纖維素鈣、內部交聯羧甲基纖維素鈉等纖維素衍生物;阿拉伯膠;葡聚糖;三聚葡糖;輕質矽酐、合成矽酸鋁、偏矽酸鋁酸鎂等矽酸鹽類;磷酸鈣等磷酸鹽類;碳酸鈣等碳酸鹽類;或硫酸鈣等硫酸鹽類。
結合劑可為例如上述賦形劑例示之化合物;明膠;聚乙烯吡咯啶酮;或聚乙二醇。
崩壞劑可為例如上述賦形劑例示之化合物;或交聯羧甲醚纖維素鈉、羧甲基澱粉鈉、交聯聚乙烯吡咯啶酮等化學修飾之澱粉或纖維素衍生物。
滑澤劑可為例如滑石;硬脂酸;硬脂酸鈣、硬脂酸鎂等硬脂酸金屬鹽;膠狀矽石;矽酸鎂鋁;蜂蠟、鯨蠟等蠟類;硼酸;乙二醇;富馬酸、己二酸等羧酸類;苯甲酸鈉等羧酸鈉鹽;硫酸鈉等硫酸類鹽;白胺酸;十二基硫酸鈉、十二基硫酸鎂等十二基硫酸鹽;矽酐、矽酸水合物等矽酸類;或上述賦形劑中澱粉衍生物。
安定劑」可為例如對羥苯甲酸甲酯、對羥苯甲酸丙酯等對羥苯甲酸酯類;氯丁醇、苄醇或苯乙醇等醇類;苄烷氯化銨;苯酚或甲酚等酚類;硫柳汞;乙酐;或山梨酸等。
矯味矯溴劑可為例如通常使用之甘味料、酸味料或香料。
懸浮化劑可為例如聚山梨酸酯80或羧甲基纖維素鈉。
製劑用溶劑可為例如水、乙醇或甘油。
本發明之治療劑或預防劑可經口或非經口投與,唯以有效成分可送達流行性感冒病毒之主要感染經路之受容者之呼吸器組織(口腔、鼻腔、氣道或肺之組織)之投與方法(例如點鼻、經鼻、經肺、口腔內投與等)來投與較佳。一般,有效成分可以溶液、懸浮液或乾燥粉末之形態投與。溶液劑及懸浮劑為水性,例如可由只水(例如無菌水或無含有發熱物質之水)、或水及藥理上容許之助溶劑(例如乙醇、聚丙二醇、聚乙二醇或PEG 400)一般地製造。此等溶液劑或懸浮劑可更含有其他賦形劑、防腐劑(例如苄烷氯化銨)、聚山梨酸酯等可溶化劑/表面活性劑(例如Tween 80、Span 80或苄烷氯化銨)、緩衝劑、等張性調節劑(例如氯化鈉)、吸收促進劑或增粘劑。懸浮液可更含有懸浮化劑(例如微結晶質纖維素或羧甲基纖維素鈉)。溶液劑或懸浮劑可以一般手段(例如吸管、滴管或噴霧器)於鼻腔或口腔直接投與。溶液劑或懸浮劑可以只一回之投與量或多數回投與量之形態提供。後者時,以設定投與量之計量手段較佳。使用吸管或滴管時,患者自行以適切之所定容量之溶液劑或懸浮劑投與。使用噴霧器時,可例如以計量噴霧泵浦之手段投與。氣道或肺之投與可令有效成分與適當噴射劑[例如氯氟化碳(CFC)、二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二酸化碳等氣]一起作成加壓包之形態之噴霧配合物。噴霧配合物以含有卵磷脂等表面活性劑較佳。有效成分之投與量可以於投與機器具備計量閥來控制。又有效成分可以其本身之乾燥粉末、或於乳糖、澱粉、澱粉衍
生物(例如羥丙基甲基纖維素)或聚乙烯吡咯啶(PVP)等適當粉末基劑混合有效成分之粉末混合物之形態提供。以上述乾燥粉末或粉末混合物於鼻腔內形成凝膠較佳。上述乾燥粉末或粉末混合物可以例如由明膠而成之膠囊或卡匣、或由泡包成單位投與量之形態提供、由這些膠囊、卡匣或泡包以吸入器投與。於含有鼻腔內配合物之氣道或肺投與之配合物,有效成分之粒子大小一般較小。此等粒子大小之有效成分可依超微粉化等製劑學之領域周知之方法獲得。也可用令有效成分持續放出而製造之配合物。
本發明之治療劑或預防劑以粉末混合物由鼻或口吸入投與特佳。
本發明之治療劑或預防劑可與其他治療劑組合使用,組合使用之治療劑宜為奧司他偉(尤其奧司他偉磷酸鹽,或奧司他偉羧酸酯)、札那米偉(尤其札那米偉水合物)、金剛胺(amantadine)(尤其金剛胺鹽酸鹽)、金剛乙胺(Rimantadine)、三唑核苷(Ribavirin)等流行性感冒治療劑。此等組合之各有效成分可以分別或一起之醫藥配合物之形順次或同時投與。本發明之治療劑或預防劑與對相同病毒活性之其他治療劑一起使用時,各有效成分之投與量可與各有效成分單獨使用時之投與量相同也可相異。
本發明之治療劑或預防劑之投與為於起大流行時、或於到流行家禽類之流行性感冒之地域時,可依必要而開始每週1至7回,依必要而邊增減回數邊施行。起大流行時、接近流行時、施行集團生活時、於不特定多數之人集合之
場所(例如保育園、幼稚園、學校、公司、病院、養老院、電影院、圖書館、音樂會會場、比賽觀戰會場等)過生活或工作時、或到這些場所時,可增加投與回數、或可事前投與。於流行家禽類之流行性感冒之地域施行調查或旅行等時,也可增加投與回數、或可事前投與。增加投與回數可例如每日投與1回,事前投與可於流行性感冒感染之可能性之行動前,或該行動之後流行性感冒發症之前投與。
本發明之治療劑或預防劑之投與量可依使用有效成分之種類、流行性感冒之流行程度、投與患者之體重或年齡等狀態而不同,對人吸入投與時,體重每kg以每回10μg至5mg之用量,每週1~7回至每日1~3回程度投與較佳。
本發明之治療劑或預防劑之有效成分可抑制H5N1型流行性感冒病毒之增殖必須之神經胺酸酶、抑制病毒之增殖。此神經胺酸酶抑制活性可例如以下等方法評價,其評價方法不限於以下之方法。
例如混合具有神經胺酸酶酵素活性之H5N1型流行性感冒病毒及神經胺酸酶基質,於檢出酵素活性之反應系,添加本發明之治療劑或預防劑之有效成分,則可定量評價酵素抑制活性。
又例如於培養細胞感染H5N1型流行性感冒病毒、於形成基於病毒增殖之噬菌斑之實驗系,添加本發明治療劑或預防劑之有效成分後,測定噬菌斑之數或大小之減少、或培養液中之病毒量,可定量評價H5N1型流行性感冒病毒
之增殖抑制活性。
由本發明治療劑或預防劑對流行性感冒病毒感染之治療效果或預防效果可依以下等方法評價,但其評價方法不限於以下之方法。
例如本發明治療劑或預防劑之有效成分之適量以溶液、懸浮液或粉末之形態,於人、小鼠、大鼠、雪貂(ferrets)、猪、鳥等脊椎動物之呼吸器點鼻、經鼻、經肺、吸入等投與方法投與。投與即後~1個月後之間之適當時期每回令流行性感冒病毒吸入、或滴下鼻來感染。其後,觀察或測定流行性感冒之症狀(例如發熱;頭痛;全身倦怠感;關節痛;肌肉痛;咳嗽或痰等呼吸器症狀;含於咽喉嗽口液、鼻汁或肺洗淨液等中病毒量;生死等),可評價治療效果或預防效果。
又於流行性感冒流行地域,經口、直腸、鼻、局所(包括口內及舌下)、陰道、非經口(包括肌肉內、皮下及靜脈內)或吸入來投與,作成本發明治療劑或預防劑之有效成分之適量投與氣道(包括通過鼻)之人群。他方面,作成無投與本發明治療劑或預防劑之有效成分之人群。一定期間後,感染流行性感冒病毒而統計檢証兩群發症流行性感冒症狀之人之比例,則可評價治療效果或預防效果。
使用小鼠來評價預防效果時,令溶解於生理食鹽水或適切緩衝液之本發明治療劑或預防劑之有效成分於鼻腔內適量滴下來經鼻投與,其即後~1個月後之適當時期,以同樣方法經鼻感染流行性感冒病毒。感染後,取出小鼠之肺來
測定肺中之病毒量,則可評價預防效果。使用流行性感冒病毒對小鼠引起致死感染時,觀察小鼠之生死,則可評價預防效果。
以下列示製造例、實施例及製劑例來更詳細說明本發明,但本發明之範圍不受這些限定。
5-乙醯胺基-4-胍基-9-O-辛醯基-2,3,4,5-四去氧-7-O-甲基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸
紅外線吸收譜(KBr)νmax cm-1
:3412,2929,2856,1676,1401,1320,1285,1205,1137,722.
1
H核磁共振譜(400MHz,CD3
OD)δppm:5.88(1H,d,J=2.5Hz),4.45(3H,m),4.27(1H,dd,J=10.0Hz,10.0Hz),4.15(1H,m),3.47(2H,m),3.42(3H,s),2.37(2H,t,J=7.4Hz),2.10(3H,s),1.31(2H,m),1.20-1.40(8H,m),0.85-0.95(3H,m).
13
C核磁共振譜(100MHz,CD3
OD)δppm:176.5,173.7,164.7,158.9,146.7,108.7,80.1,78.0,69.3,66.8,61.4,52.4,35.1,32.8,30.2,30.1,26.0,23.7,22.8,14.4.
(2)標題化合物也可依如下方法製得。
將US6340702(專利第3209946號公報)之實施例35(ii)記載之5-乙醯胺基-4-胍基-9-O-辛醯基-2,3,4,5-四去氧-7-O-甲基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸三氟乙酸鹽(3.0g,5.1mmol)通入逆相柱層析[Cosmosil75C18PREP(半井生技公司),100g],以甲醇/水(0/1-1/1-2/1)溶出。將含有目的物之分劃減壓濃縮,以吸引過濾濾集析出結晶而減壓乾燥。於空氣中放置1日,得標題化合物之水合物結晶(1.2g,產率49%)。所得化合物之物性數據與上述(1)所得化合物一致。
5-乙醯胺基-4-胍基-2,3,4,5-四去氧-7-O-甲基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸
1
H核磁共振譜(400MHz,CD3
OD)δppm:5.64(1H,d,J=2.0Hz),4.43(2H,m),4.22(1H,dd,J=10.0Hz,10.0Hz),4.00(1H,m),3.85(1H,dd,J=10.0Hz,2.4Hz),3.68(1H,dd,J=10.0Hz,5.5Hz),3.58(1H,m),3.43(3H,s).製造例2之化合物為製造例1之化合物於體內代謝生成之化合物。也即製造例1之化合物為製造例2之化合物之前藥,製造例2之化合物為活性本體。
以下之試驗為仿Nature,2005年,第437卷,p.1108記載之方法施行。
將稀釋成神經胺酸酶活性為800至1200螢光單位之H5N1型病毒液,及調整為0.01至100000nM之試驗化合物混合,於37℃反應30分後,加基質0.1mM之2'-(4-甲
繖醯基)-α-D-N-乙醯神經胺酸,更於37℃反應1小時。其後,測定360nm之激勵波長及465nm之螢光波長。由所得螢光強度算出以試驗化合物無添加時為100時之於各濃度之試驗化合物之抑制率(%),而算出予以50%酵素抑制活性之試驗化合物之濃度(IC50
)。結果如表1。
本發明之治療劑或預防劑之有效成分對奧司他偉感受性及耐性之H5N1型流行性感冒病毒株具有強力神經胺酸酶抑制活性,對奧司他偉耐性之H5N1型流行性感冒病毒株也呈示優異抑制活性。
奧司他偉感受性株:A/Hanoi/30408/2005(clone 7)奧司他偉耐性株:A/Hanoi/30408/2005(clone 9)
於MDCK細胞接種H5N1型流行性感冒病毒,使每穴形成50至100個噬菌斑(plaque),於37℃吸附1小時後,將含有0.1至1000nM濃度之試驗化合物之洋菜培養基疊層,培養MDCK細胞2日後,以溶解於19%甲醇之0.1%結晶紫來固定染色,而測定噬菌斑數及噬菌斑之直徑。為基於面積算出抑制率,計算全噬菌斑之直徑之自乘之和,算
出以試驗化合物無添加時為100%時之於各濃度之試驗化合物之抑制率(%),而算出予以50%病毒增殖抑制活性之試驗化合物之濃度(IC50
)。結果如表2。
本發明之治療劑或預防劑之有效成分對奧司他偉感受性及耐性之H5N1型流行性感冒病毒株具有強力病毒增殖抑制活性,與札那米偉比較,呈極優異病毒增殖抑制活性。
奧司他偉感受性株:A/Hanoi/30408/2005(clone 7)奧司他偉耐性株:A/Hanoi/30408/2005(clone 9)
於Balb/c小鼠經鼻投與只生理食鹽水或溶解於生理食鹽水之種種濃度之試驗化合物,投與7日後,將H5N1型流行性感冒病毒經鼻接種來感染。感染之1日、2日及3日後,採集小鼠之肺,而定量肺中含有之H5N1型流行性感冒病毒,調查H5N1型流行性感冒病毒之增殖抑制效果。將本發明之治療劑或預防劑之有效成分投與小鼠,與只投與生理食鹽水之小鼠比較,肺中之病毒量顯著減少。
與實施例3同樣投與試驗化合物,接種H5N1型流行性
感冒病毒之小鼠之生存觀察至感染之20日後。
只投與生理食鹽水之小鼠於感染20日後幾乎全例死亡,但投與本發明治療劑或預防劑之有效成分之小鼠至感染20日後仍有生存例。
具體而言,將由H5N1禽流感病毒感染患者分離之A/Hanoi/UT30408(clone7)/2005(H5N1)含有80pfu(噬菌斑形成單位)之溶液50μl於小鼠(BALB/C,雌,6週齡)經鼻滴下感染。將製造例1之化合物溶解於生理食鹽水,或3%克流感(Tamiflu)乾糖漿(註冊商標)(磷酸奧司他偉)溶解於蒸餾水。為使製造例1之化合物成70或700μg/kg/50μl之投與量,將磷酸奧司他偉調製成0.5、5或50mg/kg/200μl,製造例1之化合物於感染之2小時後經鼻投與1回,磷酸奧司他偉於感染之2小時後,經口投與1回,以後每日2回5日,計10回。結果,以感染後6日、8日、10日、15日、20日之生存小鼠數列示。試驗以各群10隻施行。
本說明書引用之全部刊物、專利及專利申請案就此作為參考列入本說明書。
式(I)化合物作為H5N1型流行性感冒之治療劑或預防劑極有用,又可作為仿奧司他偉耐性之H5N1型流行性感冒病毒之流行性感冒之治療劑或預防劑也有用。
Claims (2)
- 一種以下式所示之5-乙醯胺基-4-胍基-9-O-辛醯基-2,3,4,5-四去氧-7-O-甲基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸(enopyranosoic acid)之使用,係用於製造H5N1型流行性感冒之治療劑或預防劑,
- 如請求項1之5-乙醯胺基-4-胍基-9-O-辛醯基-2,3,4,5-四去氧-7-O-甲基-D-甘油基-D-半乳糖基-壬-2-烯吡喃糖酸之使用,其中係將該治療劑或預防劑作為粉末混合物,由鼻或口吸入投與。
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SI2123271T1 (sl) | 2012-05-31 |
WO2008108323A1 (ja) | 2008-09-12 |
ATE526960T1 (de) | 2011-10-15 |
JP6012076B2 (ja) | 2016-10-25 |
JP5286251B2 (ja) | 2013-09-11 |
US20100204314A1 (en) | 2010-08-12 |
ES2372996T3 (es) | 2012-01-30 |
HRP20110861T1 (hr) | 2011-12-31 |
US20140018418A1 (en) | 2014-01-16 |
DK2123271T3 (da) | 2012-01-23 |
KR20090129414A (ko) | 2009-12-16 |
CN101715343B (zh) | 2012-09-26 |
HK1137142A1 (en) | 2010-07-23 |
JP2013139483A (ja) | 2013-07-18 |
KR101473028B1 (ko) | 2014-12-15 |
PT2123271E (pt) | 2011-12-20 |
EP2123271A1 (en) | 2009-11-25 |
TW200848018A (en) | 2008-12-16 |
CN101715343A (zh) | 2010-05-26 |
CA2680415A1 (en) | 2008-09-12 |
EP2123271A4 (en) | 2010-03-17 |
CY1112201T1 (el) | 2015-12-09 |
EP2123271B1 (en) | 2011-10-05 |
JPWO2008108323A1 (ja) | 2010-06-17 |
PL2123271T3 (pl) | 2012-03-30 |
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