TWI516499B - 泰諾福韋(tenofovir)亞拉芬醯胺(alafenamide)之半反式丁烯二酸鹽 - Google Patents
泰諾福韋(tenofovir)亞拉芬醯胺(alafenamide)之半反式丁烯二酸鹽 Download PDFInfo
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- TWI516499B TWI516499B TW101129542A TW101129542A TWI516499B TW I516499 B TWI516499 B TW I516499B TW 101129542 A TW101129542 A TW 101129542A TW 101129542 A TW101129542 A TW 101129542A TW I516499 B TWI516499 B TW I516499B
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Description
本申請案主張在2011年8月16日申請之美國臨時專利申請案號61/524,224之優先權利益,將其完整內容特此併入本文以供參考。
本發明關於9-[(R)-2-[[(S)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基(phosphinyl)]甲氧基]丙基]腺嘌呤之半反式丁烯二酸鹽形式(泰諾福韋(tenofovir)拉芬亞醯胺(alafenamide)),及使用泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之抗病毒療法(例如,抗-HIV和抗-HBV療法)。
美國專利案號7,390,791和7,803,788(將各者的完整內容特此併入本文以供參考)說明在治療法中有用的膦酸鹽核苷酸類似物之特定前藥。一種此前藥為9-[(R)-2-[[(S)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤。此化合物亦由化學摘要名稱已知為L-丙胺酸,N-[(S)-[[(1R)-2-(6-胺基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基亞膦醯基]-1-甲基乙酯。美國專利案號7,390,791和7,803,788亦揭示此化合
物的單反式丁烯二酸鹽形式及其製備方法(參見例如實例4)。
本發明說明9-[(R)-2-[[(S)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤之半反式丁烯二酸鹽形式。9-[(R)-2-[[(S)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤的名稱為泰諾福韋拉芬亞醯胺。泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式在本文亦稱為泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。
在本發明的一個具體例中,其係提供泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。
在另一具體例中,其係提供泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽,其中反式丁烯二酸對泰諾福韋拉芬亞醯胺之比為0.5±0.1,或0.5±0.05,或0.5±0.01,或約0.5。
在一個具體例中,其係提供固體形式的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。
在一個具體例中,其係提供具有6.9±0.2°及8.6±0.2°之2θ值的X-射線粉末繞射(XRPD)圖案之泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。在另一具體例中,其係提供其中XRPD圖案包含6.9±0.2°、8.6±0.2°、11.0±0.2°、15.9±0.2°及20.2±0.2°之2θ值的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。
在一個具體例中,其係提供具有131±2℃或131±1℃之微差掃瞄熱量法(DSC)起始吸熱的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。
在一個具體例中,其係提供一種包含泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽及醫藥上可接受之賦形劑的醫藥組成物。在另一具體例中,其係提供另外包含額外的治療劑之醫藥組成物。在進一步的具體例中,額外的治療劑係選自人類免疫缺乏病毒(HIV)蛋白酶抑制化合物、反轉錄酶之HIV非核苷抑制劑、反轉錄酶之HIV核苷抑制劑、反轉錄酶之HIV核苷酸抑制劑、HIV整合酶抑制劑及CCR5抑制劑。
在一個具體例中,其係提供一種治療人類免疫缺乏病毒(HIV)感染之方法,其包含將治療有效量之泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽投予需要其之對象。在另一具體例中,其係提供一種治療HIV感染之方法,其包含將治療有效量之醫藥組成物投予需要其之對象,該醫藥組成物包含泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。在進一步的具體例中,該方法包含將一或多種額外的治療劑投予對象,該額外的治療劑係選自HIV蛋白酶抑制化合物、反轉錄酶之HIV非核苷抑制劑、反轉錄酶之HIV核苷抑制劑、反轉錄酶之HIV核苷酸抑制劑、HIV整合酶抑制劑及CCR5抑制劑。
在一個具體例中,其係提供一種治療B型肝炎病毒(HBV)感染之方法,其包含將治療有效量之泰諾福韋拉
芬亞醯胺半反式丁烯二酸鹽投予需要其之對象。在另一具體例中,其係提供一種治療HBV感染之方法,其包含將治療有效量之醫藥組成物投予需要其之對象,該醫藥組成物包含泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。
在一個具體例中,其係提供一種製備醫藥組成物之方法,其包含將泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽與醫藥上可接受之賦形劑組合,以提供醫藥組成物。
在一個具體例中,其係提供一種製備泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之方法,其包含使包含適合的溶劑、反式丁烯二酸、泰諾福韋拉芬亞醯胺及隨意地泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之一或多種晶種的溶液接受供給反式丁烯二酸及泰諾福韋拉芬亞醯胺結晶之條件。在一個具體例中,溶劑包含乙腈。在另一具體例中,使溶液接受在從約0℃至約75℃之範圍內的溫度。
在一個具體例中,其係提供用於醫學療法中的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。
在一個具體例中,其係提供泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽用於預防性或治療性治療HIV感染之用途。在另一具體例中,其係提供泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽用於治療HIV感染之用途。在進一步的具體例中,其係提供泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽用於製備或製造供治療HIV感染之藥劑的用途。在另一進一步的具體例中,其係提供泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽用於治療HIV感染之用途。
在一個具體例中,其係提供泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽用於預防性或治療性治療HBV感染之用途。在另一具體例中,其係提供泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽用於治療HBV感染之用途。在進一步的具體例中,其係提供泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽用於製備或製造供治療HBV感染之藥劑的用途。在另一進一步的具體例中,其係提供泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽用於治療HBV感染之用途。
在本發明的一些具體例中,治療及類似之方法包含以每日多次劑量投予。在其他的具體例中,治療及類似之方法包含以每日單次劑量投予。
在本發明的一個具體例中,其係提供基本上由泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽所組成之組成物。
在本發明的說明範圍內所列示之基團、取代基及範圍的具體數值僅為例證而已;該等不排除其他經定義之數值或在經定義之範圍內的其他數值用於基團及取代基。
在一個具體例中,其係提供泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式(亦即泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽)。此形式可具有0.5±0.1,0.5±0.05,0.5±0.01,或約0.5,或類似之反式丁烯二酸對泰諾福韋拉芬亞醯胺之比(亦即化學計量比或莫耳比)。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二
酸鹽係由0.5±0.1之比的反式丁烯二酸及泰諾福韋拉芬亞醯胺所組成。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽基本上係由0.5±0.1之比的反式丁烯二酸及泰諾福韋拉芬亞醯胺所組成。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽具有包含6.9±0.2°、8.6±0.2°、10.0±0.2°、11.0±0.2°、12.2±0.2°、15.9±0.2°、16.3±0.2°、20.2±0.2°及20.8±0.2°之2θ值的XRPD圖案。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽具有包含至少四個選自6.9±0.2°、8.6±0.2°、10.0±0.2°、11.0±0.2°、12.2±0.2°、15.9±0.2°、16.3±0.2°、20.2±0.2°及20.8±0.2°之2θ值的XRPD圖案。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽具有131±2℃或131±1℃之DSC之起始吸熱。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽組成物包含少於約5重量%之泰諾福韋拉芬亞醯胺單反式丁烯二酸鹽。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽組成物包含少於約1重量%之泰諾福韋拉芬亞醯胺單反式丁烯二酸鹽。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽組成物包含少於約0.5重量%之泰諾福韋拉芬亞醯胺單反式丁烯二酸鹽。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽組成物包含不可偵測之泰諾福韋拉芬亞醯胺單反式丁烯二酸鹽。
泰諾福韋拉芬亞醯胺(亦即化合物9-[(R)-2-[[(S)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤)可如美國專利案號7,390,791中所述而製備。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽可使用選擇性結晶來製備。此製備方法的流程實例係如下。
該方法可藉由使包含a)適合的溶劑;b)反式丁烯二酸;c)泰諾福韋拉芬亞醯胺;及隨意地d)包含泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之一或多種晶種的溶液接受供給反式丁烯二酸及泰諾福韋拉芬亞醯胺結晶之條件來進行。起始溶液可含有泰諾福韋拉芬亞醯胺之單一非鏡像異構物或泰諾福韋拉芬亞醯胺與其其他的非鏡像異構物(例如,GS-7339,如在美國專利案號7,390,791中所述)中之一或多者的混合物。
選擇性結晶可在任何適合的溶劑中進行。例如,其可
在質子性溶劑或非質子性有機溶劑或其混合物中進行。在一個具體例中,溶劑包含質子性溶劑(例如,水或異丙醇)。在另一具體例中,溶劑包含非質子性有機溶劑(例如,丙酮、乙腈(ACN)、甲苯、乙酸乙酯、乙酸異丙酯、庚烷、四氫呋喃(THF)、2-甲基THF、甲基乙酮或甲基異丁酮或其混合物)。在一個具體例中,溶劑包含ACN或ACN與至多約50%之二氯甲烷(以體積計)的混合物。選擇性結晶亦可在任何適合的溫度下進行,例如在從約0℃至約70℃之範圍內的溫度。在一個特定的具體例中,分解係在約0℃之溫度下進行。
泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式超越單反式丁烯二酸鹽形式的一個主要優勢為其清除GS-7339(亦即9-[(R)-2-[[(R)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤;在例如美國專利案號7,390,791中所述,其為活性醫藥成分中主要的非鏡像異構物雜質)的特殊能力。因此,泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式可比單反式丁烯二酸鹽形式更輕易且容易與雜質分離。泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽超越單反式丁烯二酸鹽形式的其他主要優勢包括改進之熱動力學和化學穩定性(包括長期貯存穩定性)、卓越的處理再現性、卓越的藥物產品含量均一性及較高的熔點。
泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽有用於治療及/或預防人類或動物中的一或多種病毒感染,包括由DNA
病毒、RNA病毒、疱疹病毒(例如,CMV、HSV 1、HSV 2、VZV)、反轉錄病毒、嗜肝DNA病毒(例如,HBV)、乳頭狀瘤病毒、漢他病毒(hantavirus)、腺病毒和HIV所引起的感染。美國專利案號6,043,230(以其完整內容併入本文以供參考)及其他發表案說明核苷酸類似物的抗病毒特異性,諸如泰諾福韋雙異丙醯氧基甲酯(disoproxil)。與泰諾福韋雙異丙醯氧基甲酯一樣,泰諾福韋拉芬亞醯胺為泰諾福韋的另一前藥形式,且可用於治療及/或預防相同的病況。
泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽可以任何適合於欲治療之病況的途徑投予。適合的途徑包括口服、直腸、鼻、局部(包括眼睛、頰內和舌下)、陰道和非經腸(包括皮下、肌肉內、靜脈內、穿透皮膚、椎管內和硬膜外)。泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽通常經口服投予,但是其可以本文所註釋之其他途徑中任一者投予。
據此,醫藥組成物包括那些適合於局部或全身投予者,包括口服、直腸、鼻、頰內、舌下、陰道或非經腸(包括皮下、肌肉內、靜脈內、穿透皮膚、椎管內和硬膜外)投予。調配物係呈單位劑型且可以藥學技藝中熟知的方法中任一者製備。
用於口服治療投予之泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽可與一或多種賦形劑組合且可以可攝食的錠劑、頰內錠劑、片劑、膠囊、酏劑、懸浮液、糖漿、粉片及類似者的形式使用。此等醫藥組成物和製劑典型地含有至少
0.1%之泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。此活性化合物在組成物和製劑中的百分比當然可變動且可適宜地介於約2%至約60%或更多的既定之單位劑型重量。活性化合物在此等治療有效的醫藥組成物中的量較佳地使得有效劑量水平在投予單次單位劑量(例如,錠劑)時獲得。其他的劑量調配物可在重複投予其亞臨床有效量時提供治療有效量之泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。較佳的單位劑量調配物包括那些含有每日劑量(例如,每日單次劑量),以及那些含有每日單位亞臨床劑量或其適當分服量(例如,每日多次劑量)之泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽的調配物。
適合於口服投予之醫藥組成物可以下述方式呈現:離散單元,諸如膠囊、扁囊劑或錠劑,各含有預定量之泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽;粉劑或顆粒;在水性液體或非水性液體中的溶液或懸浮液;或水包油型液體乳液或油包水型液體乳液。泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽亦可以大丸藥、藥糖劑或糊劑呈現。
泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽較佳地以醫藥組成物或調配物的一部分投予。此等醫藥組成物或調配物包含泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽與一或多種醫藥上可接受之載劑/賦形劑及隨意的其他治療成分。賦形劑(類)/載劑(類)必須為與調配物的其他成分可相容且對病患無害之意義的〝可接受的〞。賦形劑包括但不限於可充當泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之媒劑或
介質之物質(例如,稀釋劑載劑)。可將賦形劑封入硬或軟殼明膠膠囊中,可壓製成錠劑,或可直接併入病患飲用的食物中。
據此,錠劑、片劑、丸劑、膠囊及類似者亦可含有下列者(非限制):黏結劑(類),諸如羥丙基纖維素、聚維酮(povidone)或羥丙基甲基纖維素;填充劑(類),諸如微結晶纖維素、預膠凝化澱粉、澱粉、甘露醇或單水合乳糖;崩解劑(類),諸如羧甲基纖維素鈉(croscarmellose sodium)、交聯之聚維酮或澱粉乙醇酸鈉;潤滑劑(類),諸如硬脂酸鎂、硬脂酸或其他金屬硬脂酸鹽;甜味劑(類),諸如蔗糖、果糖、乳糖或阿斯巴甜;及/或調味劑(類),諸如薄荷、冬青油或櫻桃調味。當單位劑型為膠囊時,則除了上述類型的材料以外,其可含有液體載劑,諸如植物油或聚乙二醇。各種其他材料可以包膜或以另外方式修改固體單位劑型的物理形式而存在。例如,錠劑、丸劑或膠囊可以明膠、聚合物、蠟、蟲膠或糖及類似者包膜。當然,在製備單位劑型所使用之任何材料通常為醫藥上可接受且所使用之量實質上無毒性。另外,可將泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽併入持續釋放型製劑和裝置中。
用於眼睛或其他外部組織(例如嘴和皮膚)的醫藥組成物較佳地以局部用軟膏或乳霜施予,其含有例如介於0.01至10%w/w(包括在介於0.1%與5%之範圍內以0.1%w/w增量(諸如0.6%w/w、0.7%w/w等)的活性成
分),較佳為0.2至3%w/w及最佳為0.5至2%w/w之量的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。當以軟膏調配時,活性成分可與石蠟或與水混溶之軟膏基底使用。另一選擇地,活性成分可與水包油型乳霜基底調配成乳霜。
適合於局部投予嘴中的醫藥組成物包括菱形錠,其包含在調味基底中(例如,蔗糖、阿拉伯膠或黃蓍膠)的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽;錠片,其包含在惰性基底中(諸如明膠和甘油,或蔗糖和阿拉伯膠)的活性成分;及漱口水,其包含在適合液體載劑中的活性成分。
用於直腸投予之調配物可以具有適合的基底之栓劑呈現,該基底包含例如可可脂或柳酸酯。
適合於非經腸投予之醫藥調配物為無菌的且包括水性和非水性注射溶液,其可含有抗氧化劑、緩衝劑、制菌劑和使得調配物與意欲之接受者的血液具有等滲透壓之溶質,及水性和非水性無菌懸浮液,其可包括懸浮劑和增稠劑。調配物可以單位劑量或多次劑量容器呈現,例如具有彈性體瓶塞的密封式安瓶和小瓶,且可貯存在冷凍乾燥(凍乾)條件中,只需要在使用前立即添加無菌液體載劑(例如,注射用水)。注射溶液和懸浮液可從先前所述種類的無菌粉劑、顆粒和錠劑製備。
除了上文特別述及的成分以外,醫藥組成物/調配物可包括在關於討論中的調配物類型之技藝中習知的其他成分。
在另一具體例中,其係提供包含泰諾福韋拉芬亞醯胺
半反式丁烯二酸鹽與為此之獸醫用載劑的獸醫用組成物。獸醫用載劑為以投予組成物至貓、狗、馬、兔和其他動物為目的而有用的材料,且可為固體、液體或氣體材料,其在獸醫學技藝中另為惰性或可接受的且與活性成分可相容。該等獸醫用組成物可經口服、非經腸或任何其他所欲途徑投予。
泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽可用於提供受控釋出型醫藥調配物,其含有基質或吸收劑材料及本發明的活性成分,其中可控制且調節活性成分的釋出而容許較不頻繁的給藥或改進化合物的藥物動力學或毒性輪廓。適合於口服投予之受控釋出型調配物(其中離散單位包含本發明化合物)可根據習知的方法製備。
泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽的有用劑量可藉由比較試管內活性及動物模式中的活體內活性來決定。在大鼠和其他動物中的有效量/劑量之外推至人類中的治療有效量/劑量之方法為本技藝中所知。
用於治療所必要的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽量將隨許多因素而變動,包括但不限於投予途徑、欲治療之病況本質及病患的年齡和病況;最終所投予之量將由主治醫師或臨床醫師謹慎判斷。泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽的治療有效量/劑量至少係取決於欲治療之病況本質、任何毒性或藥物交互作用爭議、化合物是否以預防(例如,有時需要較低的劑量)或抵抗活動性疾病或病況而於使用中、輸送方法和醫藥調配物而定,且由臨
床醫師使用習知的劑量遞增研究來決定。
在一個具體例中,泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之口服劑量可在每天從約0.0001至約100毫克/公斤體重之範圍內,例如每天從約0.01至約10毫克/公斤體重,每天從約0.01至約5毫克/公斤體重,每天從約0.5至約50毫克/公斤體重,每天從約1至約30毫克/公斤體重,每天從約1.5至約10毫克/公斤體重,或每天從約0.05至約0.5毫克/公斤體重。作為非限制性實例:約70公斤體重的成人之每日候選劑量係以從約0.1毫克至約1000毫克,或從約1毫克至約1000毫克,或從約5毫克至約500毫克,或從約1毫克至約150毫克,或從約5毫克至約150毫克,或從約5毫克至約100毫克為範圍,且可能採取單次或多次劑量的形式。
除了泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽以外,本文所述之醫藥組成物可進一步包括一或多種治療劑。在本發明的一個特定具體例中,額外的治療劑可選自HIV蛋白酶抑制化合物、反轉錄酶之HIV非核苷抑制劑、反轉錄酶之HIV核苷抑制劑、反轉錄酶之HIV核苷酸抑制劑、HIV整合酶抑制劑及CCR5抑制劑。
治療方法包括將泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽投予需要其作為治療或預防性治療之對象/病患。因此,可將泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽投予患有醫學病症之對象/病患或可能獲得病症之對象。一般熟諳本技藝者應理解此治療的給與是為了使病症(包括復發性
病症)的症狀或一組症狀得到改善、預防、延遲、治癒及/或減輕嚴重性。治療的給與亦可延長病患的存活,例如超過沒有此治療所預期的存活時間。可以泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽治療的醫學病症包括那些本文所討論者,包括(非限制)HIV感染和HBV感染。
以下為非限制性例證實例。
將泰諾福韋拉芬亞醯胺單反式丁烯二酸鹽固體(5.0公克)及9-[(R)-2-[[(R)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤(GS-7339)單反式丁烯二酸鹽固體(0.75公克)在22℃下裝入35公克MTBE中且將混合物攪拌1小時。形成漿液且將其在旋轉蒸發器中乾燥。將58公克乙腈(ACN)裝入固體中且將混合物加熱至回流,使固體溶解。容許所得溶液自然冷卻,同時攪動。形成漿液且將漿液以冰-水-浴進一步冷卻。將固體以過濾分離且以5公克ACN清洗。將固體在40℃之真空烘箱中經隔夜乾燥。獲得5.52公克灰白色固體。將固體以XRPD分析且發現含有泰諾福韋拉芬亞醯胺單反式丁烯二酸鹽、GS-7339單反式丁烯二酸鹽及泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。
將在ACN中成為漿液的9-[(R)-2-[[[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤(9.7公斤漿液,13.8重量%,1.0公斤(2.10莫耳,1莫耳當量)9-[(R)-2-[[(S)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤與0.35公斤9-[(R)-2-[[(R)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤之非鏡像異構物混合物)裝入反應器中且提前以二氯甲烷(5公斤)沖洗。將混合物在真空下以低於40℃之夾套溫度濃縮至約3公升。接著將濃縮物與ACN(6公斤)在真空下以低於40℃之夾套溫度共蒸發至約3公升。將濃縮物以ACN(8.5公斤)稀釋且溫熱至40-46℃。將溫的混合物過濾至第二反應器中且將濾液冷卻至19-25℃。
將反式丁烯二酸(0.13公斤,1.12莫耳,0.542莫耳當量)裝入上述溶液中,接著裝入ACN(1公斤)且將混合物加熱至67-73℃。將熱的混合物經由增澤過濾器(polishing filter)轉移至反應器中,且接著調整至54-60℃。將泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式的晶種(5公克)(例如,可將混合物以實例1中所形成之泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽接種或於後續製造),且將所得混合物在54-60℃下攪動約30分鐘。將混合物經最少4小時冷卻至0-6℃,且接著在0-6℃下攪動最少1小時。將所得漿液過濾且以驟冷(0-6℃)之ACN(2
公斤)沖洗。將產物在真空下以低45℃乾燥,直到符合乾燥減重(LOD)及有機揮發性雜質(OVI)限度為止(LOD1.0%,二氯甲烷含量0.19%,乙腈含量0.19%),以供應成為白色至灰白色粉末的泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式的最終化合物(典型的產量為約0.95公斤)。1H NMR(400 MHz,d6 DMSO):δ 1.06(d,J=5.6 Hz,3H),1.12-1.16(m,9H),3.77(dd,J=10.4,11.6 Hz,1H),3.84-3.90(m,2H),3.94(m,1H),4.14(dd,J=6.8,14.8 Hz,1H),4.27(m,1H),4.85(七重,J=6.0 Hz,1H),5.65(t,J=11.2 Hz,1H),6.63(s,1H),7.05(d.J=7.6 Hz,2H),7.13(t,J=7.2 Hz,1H),7.24(s,2H),7.29(t,J=7.6 Hz,2H),8.13(t,J=13.6 Hz,2H),31P NMR(162 MHz,d6 DMSO):δ 23.3。
將9-[(R)-2-[[(S)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤(10公克)、反式丁烯二酸(1.22公克)及ACN(100毫升)裝入配備有高架攪動器之夾套式反應器中。將混合物加熱至70-75℃,使固體溶解。將任何未溶解之微粒通過過濾筒過濾而移除。將過濾之溶液冷卻至60-65℃且以1%(重量計)之泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽接種。將漿液經30分鐘老化且經2小時冷卻至0-5℃。將溫度維持1-18小時,且所得漿液過濾及以2毫升冷ACN(0-5℃)清
洗。將固體在真空下以50℃乾燥,提供泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式,將其以下述方式特徵化。
來自實例3的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽係由9-[(R)-2-[[(S)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤及1/2當量之反式丁烯二酸所組成。泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽為無水的不吸濕性且具有約131℃之DSC起始吸熱。
泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之XRPD圖案係由下列的實驗設定而獲得:45 KV,45 mA,Kα1=1.5406Å,掃描範為2.-40°,階距0.0084°,計數時間:8.25s。泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之XRPD圖案顯示於圖1中。特徵性波峰包括:6.9±0.2°、8.6±0.2°、10.0±0.2°、11.0±0.2°、12.2±0.2°、15.9±0.2°、16.3±0.2°、20.2±0.2°和20.8±0.2°。
晶體大小為0.32 x 0.30 x 0.20立方毫米。將樣品固定在123 K且使用具有0.71073Å之波長的輻射源收集在
1.59至25.39°之θ範圍內的數據。將單晶體X-射線繞射的條件及從其所收集之數據顯示於表1中。
DSC分析係使用2.517毫克泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽進行。將其以10℃/分鐘在40-200℃之範圍內加熱。起始吸熱溫度實測為約131℃(圖2)。
TGA數據係使用4.161毫克泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽獲得。將其以10℃/分鐘在25-200℃之範圍內加熱。樣品在熔融前損失0.3重量%(圖3)。經測定
其為無水形式。
DVS分析係使用4.951毫克泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽進行。將材料保持在25℃之氮氣中及從10%至90%之相對濕度的濕度範圍內;將各步驟平衡120分鐘。將吸附等溫線顯示在圖4上。發現材料不具吸濕性,且在90%之相對濕度下吸收0.65%水。
在先前的泰諾福韋拉芬亞醯胺合成中,主要的雜質之一典型為非鏡像異構物9-[(R)-2-[[(R)-[[(S)-1-(異丙氧基羰基)乙基]胺基]苯氧基亞膦醯基]甲氧基]丙基]腺嘌呤。來自實例3的泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式與單反式丁烯二酸鹽形式(在美國專利案號7,390,791中所述)之能力比較下具有清除此非鏡像異構物雜質之特殊能力。在(以下)表2中的數據證明泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽(批組2)清除非鏡像異構物雜質至少於起始濃度的十分之一,而泰諾福韋拉芬亞醯胺之單反式丁烯二酸鹽形式(批組1)卻僅略微地清除非鏡像異構物雜質。
比較泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式與單反式丁烯二酸鹽形式的化學穩定性。如(以下)表3中所示,在相同的條件下,泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式比單反式丁烯二酸鹽形式更具化學穩定性且展現更好的長期貯存穩定性,具有顯著較低的降解(產物總降解%)。評估的條件包括溫度、相對濕度(RH)及容器蓋打開或密閉狀態。
泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之穩定形式篩選顯示其在大部分的溶劑中具有熱動力學穩定性,諸如ACN、甲苯、乙酸乙酯、甲基第三丁醚(MTBE)、丙酮、THF和2-甲基THF。單反式丁烯二酸鹽形式之類似的穩定形式篩選顯示此形式在上文列示之溶劑中不具有熱動力學穩定性。當懸浮在該等溶劑中時,泰諾福韋拉芬亞醯胺之單反式丁烯二酸鹽形式在THF和2-甲基THF中完全轉化成半反式丁烯二酸鹽形式,而在ACN、乙酸乙酯、MTBE和丙酮中以及在周圍溫度下部分轉化半反式丁烯二
酸鹽形式。
如以DSC數據顯示,泰諾福韋拉芬亞醯胺之半反式丁烯二酸鹽形式具有比單反式丁烯二酸鹽形式高約10℃之熔點,表明半反式丁烯二酸鹽形式與單反式丁烯二酸鹽形式比較下具有改進的熱穩定性。
將所有的公開案、專利及專利文件併入以供參考,雖然以逐個併入以供參考。本發明已參考各種特定且較佳的具體例及技術予以說明。然而,應瞭解可進行許多但仍維持在本發明的精神和範疇內的變化及修改。
圖1顯示泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之X-射線粉末繞射(XRPD)圖案。
圖2顯示泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之DSC分析圖。
圖3顯示泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之熱重量分析(TGA)數據圖。
圖4顯示泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之動態蒸氣吸附(DVS)分析圖。
Claims (35)
- 一種泰諾福韋(tenofovir)拉芬亞醯胺(alafenamide)半反式丁烯二酸鹽。
- 一種泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽,其具有之X-射線粉末繞射圖案包含6.9±0.2°及8.6±0.2°之2θ值。
- 根據申請專利範圍第2項之半反式丁烯二酸鹽,其中X-射線粉末繞射圖案包含6.9±0.2°、8.6±0.2°、11.0±0.2°、15.9±0.2°及20.2±0.2°之2θ值。
- 根據申請專利範圍第1項之半反式丁烯二酸鹽,其具有131±2℃之微差掃瞄熱量法(DSC)起始吸熱溫度。
- 根據申請專利範圍第4項之半反式丁烯二酸鹽,其具有131±1℃之DSC起始吸熱溫度。
- 一種醫藥組成物,其包含申請專利範圍第1項之半反式丁烯二酸鹽及醫藥上可接受之賦形劑。
- 根據申請專利範圍第6項之醫藥組成物,其進一步包含額外的治療劑。
- 根據申請專利範圍第7項之醫藥組成物,其中該額外的治療劑係選自人類免疫缺乏病毒(HIV)蛋白酶抑制化合物、反轉錄酶之HIV非核苷抑制劑、反轉錄酶之HIV核苷抑制劑、反轉錄酶之HIV核苷酸抑制劑、HIV整合酶抑制劑及CCR5抑制劑。
- 根據申請專利範圍第6項之醫藥組成物,其用於治療人類免疫缺乏病毒(HIV)感染。
- 根據申請專利範圍第9項之醫藥組成物,其進一步包含一或多種額外的治療劑,該額外的治療劑係選自HIV蛋白酶抑制化合物、反轉錄酶之HIV非核苷抑制劑、反轉錄酶之HIV核苷抑制劑、反轉錄酶之HIV核苷酸抑制劑、HIV整合酶抑制劑及CCR5抑制劑。
- 根據申請專利範圍第6項之醫藥組成物,其用於治療B型肝炎病毒(HBV)感染。
- 一種製備醫藥組成物之方法,其包含將申請專利範圍第1項之半反式丁烯二酸鹽與醫藥上可接受之賦形劑組合,以提供醫藥組成物。
- 一種製備泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之方法,其包含混合a)非質子性有機溶劑;b)反式丁烯二酸;c)泰諾福韋拉芬亞醯胺;及d)泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之一或多種晶種;以及結晶額外的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽。
- 根據申請專利範圍第13項之方法,其中該溶劑包含乙腈。
- 根據申請專利範圍第13項之方法,其中使溶液接受在從0℃至75℃之範圍內的溫度。
- 一種申請專利範圍第1項之半反式丁烯二酸鹽之用途,其係用於製備或製造供治療HIV感染之藥劑。
- 根據申請專利範圍第16項之用途,其中該半反式丁烯二酸鹽以及額外的治療劑係投予至對象,以及其中該額外的治療劑係選自人類免疫缺乏病毒(HIV)蛋白酶抑 制化合物、反轉錄酶之HIV非核苷抑制劑、反轉錄酶之HIV核苷抑制劑、反轉錄酶之HIV核苷酸抑制劑、HIV整合酶抑制劑及CCR5抑制劑。
- 根據申請專利範圍第16項之用途,其中該半反式丁烯二酸鹽係以每日多次劑量投予。
- 根據申請專利範圍第16項之用途,其中該半反式丁烯二酸鹽係以每日單次劑量投予。
- 一種申請專利範圍第1項之半反式丁烯二酸鹽之用途,其係用於製備或製造供治療人類中的HBV感染之藥劑。
- 根據申請專利範圍第20項之用途,其中該半反式丁烯二酸鹽係以每日多次劑量投予。
- 根據申請專利範圍第20項之用途,其中該半反式丁烯二酸鹽係以每日單次劑量投予。
- 一種包含泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之組成物,其中該反式丁烯二酸對泰諾福韋拉芬亞醯胺之比為0.5±0.1。
- 根據申請專利範圍第23項之組成物,其中該反式丁烯二酸對泰諾福韋拉芬亞醯胺之比為0.5±0.05。
- 根據申請專利範圍第23項之組成物,其中該反式丁烯二酸對泰諾福韋拉芬亞醯胺之比為0.5±0.01。
- 根據申請專利範圍第23項之組成物,其中該反式丁烯二酸對泰諾福韋拉芬亞醯胺之比為0.5。
- 根據申請專利範圍第23-26項中之任一項之組成 物,其為固體。
- 一種申請專利範圍第6項之醫藥組成物的用途,其係用於製備或製造供治療HIV感染之藥劑。
- 根據申請專利範圍第28項之用途,其中該醫藥組成物係以每日多次劑量投予。
- 根據申請專利範圍第28項之用途,其中該醫藥組成物係以每日單次劑量投予。
- 一種申請專利範圍第6項之醫藥組成物的用途,其係用於製備或製造供治療人類中的HBV感染之藥劑。
- 根據申請專利範圍第31項之用途,其中該醫藥組成物係以每日多次劑量投予。
- 根據申請專利範圍第31項之用途,其中該醫藥組成物係以每日單次劑量投予。
- 一種製備泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之方法,其包含下列步驟:混合a)溶劑,其選自水、異丙醇、丙酮、乙腈、甲苯、乙酸乙酯、乙酸異丙酯、庚烷、四氫呋喃、2-甲基四氫呋喃、甲基乙酮、甲基異丁酮或其混合物;b)反式丁烯二酸;c)泰諾福韋拉芬亞醯胺;及d)泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽之一或多種晶種;以及結晶額外的泰諾福韋拉芬亞醯胺半反式丁烯二酸鹽,於0℃至70℃之溫度。
- 根據申請專利範圍第34項之方法,其中該溶劑包含乙腈以及至多50體積%之二氯甲烷。
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MX347512B (es) | 2010-11-19 | 2017-04-28 | Gilead Sciences Inc | Composiciones terapeuticas que comprenden hcl de rilpivirina y fumarato de disoproxilo de tenofovir. |
BR112014003420B1 (pt) | 2011-08-16 | 2021-07-20 | Gilead Sciences, Inc | Hemifumarato de tenofovir alafenamida. composição, seus métodos de preparação e uso |
ES2661705T3 (es) | 2011-10-07 | 2018-04-03 | Gilead Sciences, Inc. | Métodos para la preparación de análogos de nucleótidos antivirales |
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