TWI443088B - Xa因子抑制劑之新穎醫藥鹽及多晶型 - Google Patents
Xa因子抑制劑之新穎醫藥鹽及多晶型 Download PDFInfo
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- TWI443088B TWI443088B TW095141382A TW95141382A TWI443088B TW I443088 B TWI443088 B TW I443088B TW 095141382 A TW095141382 A TW 095141382A TW 95141382 A TW95141382 A TW 95141382A TW I443088 B TWI443088 B TW I443088B
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Description
本發明係關於Xa因子抑制劑之新穎醫藥鹽及多晶型。
藉由外科方法或藉由血管收縮及凝血作用之生理特性而發生止血、出血控制。特定言之,本發明係關於血液凝聚作用及在損傷、發炎、疾病、先天性缺陷、功能異常或其他破裂後其參與維持哺乳動物循環完整性之方式。儘管在恢復止血及血栓性疾病中均包含血小板及血液凝聚,但凝血級聯反應之某些組份係在血小板凝集及血纖維蛋白沈積所包含之過程中造成放大及加速的主要原因,該血小板凝集及血纖維蛋白沈積係血栓形成及止血中之主要事件。
凝塊形成包含血纖維蛋白原轉化為血纖維蛋白,該血纖維蛋白聚合為網狀物以在損傷後恢復止血。類似過程在血栓性疾病中導致血管閉合。血纖維蛋白原轉化為血纖維蛋白係藉由凝血酶(血液凝聚級聯反應中之一系列反應之最終產物)來催化。凝血酶亦為活化血小板中之關鍵參與者,藉此在動脈及靜脈血流之兩種條件下有助於血栓形成。出於該等原因,假設凝血酶之有效調節可導致對於血栓形成之有效調節。多種當前使用之抗凝劑直接或間接影響凝血酶(亦即未分級肝素、低分子量肝素、類肝素化合物、五醣及殺鼠靈(warfarin))。對凝血酶活性之直接或間接抑制在臨床發展中已成為多種抗凝劑之焦點(由Eriksson及Quinlan所評論,Drugs 11:1411-1429,2006)。
凝血酶原(凝血酶之前驅物)藉由Xa因子轉化為活性酶。局部活化組織因子/VIIa因子介導之Xa因子之產生係由IXa因子/VIIIa因子複合物而放大,且其導致凝血酶原酶在經活化之血小板上組合。作為凝血酶原酶複合物之部分之Xa因子係引起維管結構中持續形成凝血酶之唯一酶。Xa因子為絲胺酸蛋白酶(其前驅物X因子之活化形式),且為鈣離子結合、含γ羧基麩胺酸(GLA)、維生素K依賴性及凝血因子之一員。與作用於包括血纖維蛋白原及PAR受體(經蛋白酶活化之受體,Coughlin,J Thrombosis Haemostasis
3:1800-1814,2005)之多種蛋白質基質的凝血酶不同,Xa因子似乎具有單一生理性基質(即凝血酶原)。由於Xa因子之一個分子可產生大於1000個分子之凝血酶(Mann等人,J.Thrombosis.Haemostasis
1:1504-1514,2003),因此作為間接抑制凝血酶形成之方法之Xa因子的直接抑制作用可為有效之抗凝策略。此論斷係基於凝血酶原酶在凝血酶合成中之關鍵作用,且係基於凝血酶原酶之抑制作用對所有血小板凝集及凝血路徑將具有顯著效應。
諸如VIIa因子、IXa因子或Xa因子之活化蛋白酶獨立具有較弱之蛋白水解活性。然而,其與輔因子依賴性膜結合複合物之組合顯著增強其催化效率。此效應對於因子Xa而言最為劇烈,其中效率增加105
倍(Mann等人,Blood
76(1):1-16,1990)。由於血液中存在較高濃度之酶原(1.4 μM凝血酶原比150 nM Xa因子)及活化動力學,因此需要抑制小於凝血酶量之Xa因子以達到抗凝效應。與凝血酶相比,作為治療靶之Xa因子之假設優勢的間接證據亦可在用於預防深靜脈血栓症之臨床試驗中發現。磺達肝素(Fondaparinux)(一種抗凝血酶III依賴性Xa因子抑制劑)在四次矯形外科手術之試驗中經證明係優於伊諾肝素(enoxaparin)(一種抑制凝血酶及Xa因子兩者之低分子量肝素)(Turpie,等人,Archives Internal Medicine
162(16):1833-1840,2002)。因此,建議選擇性抑制Xa因子之化合物可用作活體外診斷劑或用於某些血栓性失調症中之治療投藥(參見例如WO 94/13693)。
已報導多種Xa因子抑制劑作為來源於吸血性有機體之多肽,以及非大多肽型抑制劑之化合物。其他Xa因子抑制劑包括小分子有機化合物,諸如具有甲脒基取代基之含氮雜環化合物,其中化合物之兩個官能基可在兩個活性位點處結合至Xa因子。舉例而言,WO 98/28269描述具有末端甲脒基(-C(=NH)-NH2
)之吡唑化合物;WO 97/21437描述經鹼性基團取代之苯幷咪唑化合物,該等化合物經由直鏈或支鏈伸烷基、-C(=O)-或-S(=O)2
-橋基連接至萘基;WO 99/10316描述具有4-苯基-N-烷基甲脒基-哌啶及4-苯氧基-N-烷基甲脒基-哌啶基之化合物,該等化合物經由羧醯胺伸烷基胺基橋連接至3-甲脒基苯基;且EP 798295描述具有4-苯氧基-N-烷基甲脒基哌啶基之化合物,該等化合物經由經取代或未經取代之磺醯胺或羧醯胺橋基連接至甲脒基萘基。
其他所報導之Xa因子抑制劑包括具有包含經由醯胺鍵連接之苯基-甲脒基、苯基及鹵基-苯基之結構的彼等Xa因子抑制劑(美國專利第6,844,367 B1號)。其他Xa因子抑制劑之鹵基-苯基已由鹵基-吡啶基置換(參見美國專利第6,376,515 B2號及第6,835,739 B2號)。美國專利第6,376,515 B2號揭示在實例206中識別之特定Xa因子抑制劑化合物,其亦於美國專利第6,835,739 B2號中揭示為實例206且在本文中識別為式I化合物。式I化合物由以下結構表示:
研發Xa因子之選擇性抑制劑的進一步工作已導致驚人發現,此化合物之某些鹽展現出比游離鹼化合物本身或其他鹽更好之熱穩定性及水解穩定性,其中順丁烯二酸鹽具有所觀測之最佳穩定性。
在一實施例中,本發明係關於一種鹽,其包含式I化合物:
及酸,其中該酸係選自由鹽酸、乳酸、順丁烯二酸、苯氧乙酸、丙酸、丁二酸、己二酸、抗壞血酸、樟腦酸、葡萄糖酸、磷酸、酒石酸、檸檬酸、甲磺酸、反丁烯二酸、乙醇酸、萘-1,5-二磺酸、龍膽酸及苯磺酸組成之群。
在一較佳實施例中,該酸係選自由鹽酸、乳酸、順丁烯二酸、苯氧乙酸、丙酸、丁二酸、己二酸、抗壞血酸、樟腦酸、葡萄糖酸、磷酸、酒石酸、檸檬酸及甲磺酸組成之群。
在另一較佳實施例中,該酸係選自由鹽酸、乳酸、順丁烯二酸、苯氧乙酸、丙酸及丁二酸組成之群。在一實施例中,該鹽為順丁烯二酸鹽或丙酸鹽。預期式I化合物之順丁烯二酸鹽可藉由將式I化合物之一或多個氮原子質子化而形成。在一實施例中,式I之甲脒基氮(=NH)經質子化(=NH2 +
)以形成鹽。
在一較佳實施例中,式I化合物之順丁烯二酸鹽由式II來表示:
在另一實施例中,本發明提供一種具有結晶多晶型形態之式II之鹽。在較佳實施例中,結晶多晶型形態展現粉末X光繞射圖案,該粉末X光繞射圖案具有至少四個且更佳八個以下近似特徵峰位:4.9、9.7、13.8、14.1、15.2、17.6、18.5、20.8、21.6、22.7、24.1、26.3、26.8度2θ。在又一實施例中,粉末X光繞射圖案具有4.9、9.7、11.8、13.8、14.1,15.2、17.6、18.5、19.9、20.8、21.6、22.7、24.1、25.0、26.3、26.8度2θ之近似特徵峰位。本發明預期該等近似特徵峰將具有高達約±0.2度2θ之偏差。在又一實施例中,粉末X光繞射圖案近似於圖1所示之粉末X光繞射圖案。在其他實施例中,本發明提供一種具有結晶多晶型形態之式II之鹽,其具有近似於圖2所示之差示掃描熱量測定圖案之差示掃描熱量測定圖案。式II之鹽的此結晶多晶型提供用於適合於臨床研究之可再生形態之此化合物。
在另一實施例中,本發明提供一種用於預防或治療哺乳動物中特徵在於不良血栓形成之病症的醫藥組合物,其包含醫藥學上可接受之載劑及治療有效量之鹽,該鹽包含式I化合物、式I化合物之順丁烯二酸鹽、式II之鹽或具有結晶多晶型形態之式II之鹽。在另一實施例中,醫藥組合物為錠劑形式。在又一實施例中,醫藥組合物為膠囊形式。在又一實施例中,醫藥組合物為***劑形式。在其他實施例中,醫藥組合物為適於輸注、注射或經皮傳遞之形式。
在某些實施例中,本發明提供一種用於預防或治療哺乳動物中特徵在於不良血栓形成之病症的方法,其包含向哺乳動物投與治療有效量之鹽,該鹽包含式I化合物、式I化合物之順丁烯二酸鹽、式II之鹽或具有結晶多晶型形態之式II之鹽。在另一實施例中,該病症係選自由急性冠脈症候群、心肌梗塞、不穩定性心絞痛、頑固性心絞痛、溶血栓療法後或冠脈血管成形術後出現之閉塞性冠脈血栓、血栓介導性腦血管症候群、栓塞性中風、血栓性中風、短暫性缺血性發作、靜脈血栓症、深靜脈血栓症、肺栓塞、凝血症、散播性血管內凝血、血栓性血小板缺乏紫斑症、阻塞性血栓脈管炎、與肝素誘導性血小板減少症相關聯之血栓性疾病、與體外循環相關聯之血栓性併發症、與使用儀器相關聯之血栓性併發症及與假體裝置之裝配相關聯之血栓性併發症組成之群。在另一實施例中,本發明提供一種抑制血液樣品凝聚之方法,其包含使樣本與鹽接觸之步驟,該鹽包含式I化合物、式I化合物之順丁烯二酸鹽、式II之鹽或具有結晶多晶型形態之式II之鹽。
在又一實施例中,本發明提供一種製備式I化合物之方法,其包含使LiN(CH3
)2
與式III化合物:
或其鹽在親核性加成條件下接觸以形成式I化合物。
在某些實施例中,親核性加成條件包含使用非極性、非質子性溶劑。在某些其他實施例中,溶劑為選自由四氫呋喃、二***、二甲氧基甲烷、二噁烷己烷、甲基第三丁基醚、庚烷及環己烷組成之群之一員。在某些實施例中,式III化合物之鹽為鹽酸鹽。
在某些實施例中,本發明提供一種製備式I化合物之方法,其中該方法在小於10℃之溫度下進行。
在另一實施例中,本發明提供一種製備式I化合物之方法,其中以至少50%之產率提供具有式I之化合物。在另一實施例中,以至少65%之產率提供具有式I之化合物。在又一實施例中,以至少75%之產率提供具有式I之化合物。
在另一實施例中,本發明提供一種製備公克級或公斤級之式I化合物的方法。
如美國專利第6,376,515 B2號中所論述,式I化合物為有效Xa因子抑制劑。然而,式I化合物並未展現最佳溶解性或結晶性。發現式I化合物之乙酸鹽的製備具有良好結晶性,但並不具有良好熱穩定性及水解穩定性。驚人且出乎意料的是,發現某些鹽顯示良好結晶性及熱穩定性及水解穩定性,其包括(例如):鹽酸鹽、乳酸鹽、順丁烯二酸鹽、苯氧基乙酸鹽、丙酸鹽、丁二酸鹽、己二酸鹽、抗壞血酸鹽、樟腦酸鹽、葡萄糖酸鹽、磷酸鹽、酒石酸鹽、檸檬酸鹽、甲磺酸鹽、反丁烯二酸鹽、乙醇酸鹽、萘-1,5-二磺酸鹽、龍膽酸鹽及苯磺酸鹽。
詳言之,式II之順丁烯二酸鹽展現優良結晶性、熱穩定性及水解穩定性及純度。本發明之式II之順丁烯二酸鹽適用於治療哺乳動物中之不良血栓塞症。
如本文所用之術語"多晶型"係指不同於另一結晶形態但共用相同化學式之物質的結晶形態。
術語"治療"意謂對諸如哺乳動物之受檢者中之疾病或失調症的任何治療,其包括:.預防或防止疾病或失調症,亦即致使臨床症狀不發展;.抑制疾病或失調症,亦即阻止或抑制臨床症狀之發展;及/或.緩解疾病或失調症,亦即致使臨床症狀消退。
如本文所用之術語"預防"係指對有此需要之患者的預防性治療。預防性治療可藉由對具有罹患疾病風險之受檢者提供適當劑量之治療劑來完成,藉此大體上避免疾病發作。
熟習此項技術者應瞭解在人類醫學中,由於最終感應事件可為未知、潛伏的或直至事件發生患者仍未確認,因此並非總是可能區分"預防"與"抑制"。因此,如本文所用之術語"預防"意欲作為"治療"之要素以涵蓋如本文所定義之"預防"及"抑制"之兩者。如本文所用之術語"保護"意謂包括"預防"。
術語"治療有效量"係指當向需此治療之受檢者投藥時,足以實現治療(如上文所定義)之本發明之鹽的量。治療有效量將視受檢者及經治療之疾病病症、受檢者之體重及年齡、疾病病症之嚴重性、選擇之特定化合物、遵循之給藥方案、投藥時序、投藥方式及其類似物而變化,所有該等均易於由一般熟習此項技術者來確定。
如本文所用之術語"病症"係指使用本發明之化合物、鹽、組合物及方法抵抗之疾病狀態。
如本文所用之術語"血液樣品"係指自受檢者所獲取之全血或包括血漿或血清之血液的任何部分。
本發明之一實施例為包含式I化合物之鹽。熟習此項技術者應瞭解,式I之游離鹼之其他鹽亦用於本發明中。該等其他鹽可使用無機及有機酸來製備,該等酸提供必需之熱穩定性及水解穩定性,諸如(但不限於)鹽酸、乳酸、順丁烯二酸、苯氧乙酸、丙酸、丁二酸、己二酸、抗壞血酸、樟腦酸、葡萄糖酸、磷酸、酒石酸、檸檬酸、甲磺酸、反丁烯二酸、乙醇酸、萘-1,5-二磺酸、龍膽酸及苯磺酸。在一實施例中,式II之順丁烯二酸鹽表示為:
本發明之鹽(諸如式II之鹽)可採用多種不同結晶形態。單一化合物採用多種結晶形態之一之能力稱為多晶型。給定化合物之結晶多晶型與該化合物之任何其他結晶多晶型在含有以相同方式彼此結合之相同原子方面在化學性質上是一致的,但其晶體形態不同。相同化合物之不同結晶形態可對一或多種物理特性具有影響,諸如穩定性、溶解性、熔點、容積密度、流動特性、生物可用性等。
多晶型之特徵在於其結晶結構(X-光繞射圖案)、其熱特性(如由DSC及TGA所測定)、穩定性、溶解性等。X-光繞射圖案以特徵峰±0.2度2θ呈現。式II之鹽之一種多晶型的特徵在於圖1A及1B中所示之X-光繞射圖案、圖2A及2B中所示之DSC/TGA資料及圖3中所示之吸水性資料或該等特徵之兩者或所有該等之組合。熟習此項技術者應瞭解式II之鹽之其他多晶型亦適用於本發明。
本發明之醫藥組合物可用於預防或治療罹患病症之受檢者,其中該病症之特徵在於不良血栓塞。本發明之醫藥組合物包含醫藥學上可接受之載劑及治療學上可接受量之鹽,該鹽包含式I化合物、式I化合物之順丁烯二酸鹽、式II之鹽或具有結晶多晶型形態之式II之鹽。
A.醫藥學上可接受之載劑
本發明之鹽(一般為水溶液或懸浮液)之診斷學應用一般可利用諸如溶液或懸浮液之調配物。
在血栓性失調症之管理中,本發明之鹽可以諸如錠劑、膠囊、用於口服之***劑或酒劑、栓劑、無菌溶液或懸浮液或可注射投藥及其類似物之組合物形式利用,或併入定型物品中。可對需要治療之受檢者(一般為哺乳動物受檢者)投與適當劑量之可提供最佳功效之本發明化合物。投藥之劑量及方法因受檢者不同而變化,且取決於以下因素:諸如經治療之哺乳動物之類型、其性別、體重、飲食、並用藥物、全部臨床症狀、所採用之特定鹽、採用該等鹽之特定用途,及熟習醫藥技術者可識別之其他因素。
適用於本發明之膠囊可使用習知及已知封裝技術(諸如Stroud等人之美國專利第5,735,105號中所述)來製備。膠囊一般為通常之圓柱形的中空殼,其具有足夠之直徑及長度以使得將含有適當劑量活性劑之醫藥溶液組合物裝配至膠囊中。膠囊之外部可包括增塑劑、水、明膠、經改質澱粉、膠、角叉菜膠及其混合物。熟習此項技術者應瞭解何種組合物合適。
用於本發明之錠劑除活性劑以外可包含填充劑、黏合劑、壓縮劑、潤滑劑、崩解劑、著色劑、水、滑石粉及其他熟習此項技術者可識別之元素。錠劑可為均質的,其核心處具有單一層或具有多層以實現較佳釋放曲線。在某些情況下,本發明之錠劑可經諸如腸溶衣來塗覆。熟習此項技術者應瞭解其他適用於本發明之錠劑中之賦形劑。
適用於本發明之***劑包括適當量之活性劑,以及任何填充劑、黏合劑、崩解劑、溶劑、增溶劑、甜味劑、著色劑及熟習此項技術者應瞭解為必需之任何其他成份。設計本發明之***劑以使得一經與患者口腔接觸即溶解並釋放活性劑。熟習此項技術者應瞭解其他適用於本發明之傳遞方法。
本發明之鹽的調配物係藉由將具有所要純度之鹽與生理學上可接受之載劑、賦形劑、穩定劑等混合來製備以供儲存或投藥,且其可以持續釋放型或定時釋放型調配物來提供。用於治療用途之可接受之載劑或稀釋劑在醫藥領域中已熟知,且例如描述於Remington's Pharmaceutical Sciences、Mack Publishing Co.(A.R.Gennaro編,1985)中。該等材料在所採用之劑量及濃度下對受者而言係無毒的,且包括諸如磷酸鹽、檸檬酸鹽、乙酸鹽及其他有機酸鹽之緩衝劑、諸如抗壞血酸之抗氧化劑、諸如聚精胺酸之低分子量(小於約10個殘基)肽、諸如血清白蛋白、明膠或免疫球蛋白之蛋白質、諸如聚乙烯吡咯啶酮之親水性聚合物、諸如甘胺酸、麩胺酸、天冬胺酸或精胺酸之胺基酸、單醣、雙醣及包括纖維素或其衍生物、葡萄糖、甘露糖或糊精之其他碳水化合物、諸如EDTA之螯合劑、諸如甘露糖醇或山梨糖醇之糖醇、諸如鈉之平衡離子及/或諸如Tween、Pluronics或聚乙二醇之非離子性界面活性劑。
欲用於治療性投藥之本發明之鹽的劑量調配物須係無菌的。無菌性易於藉由經諸如0.2微米膜之無菌膜過濾或藉由其他習知方法來完成。調配物一般可以凍乾形式或水溶液形式儲存。本發明之製劑的pH一般介於3與11之間、更佳為5至9且最佳為7至8。應瞭解使用某些前述賦形劑、載劑或穩定劑可導致形成環狀多肽鹽。雖然投藥之較佳路線係藉由注射,但亦預期其他之投藥方法,諸如靜脈內(快速注射及/或輸注)、皮下、肌肉內、結腸、直腸、經鼻或腹膜內,採用多種劑型,諸如栓劑、植入式丸粒或小圓柱體、氣溶膠、口服劑型調配物(諸如錠劑、膠囊及***劑)及諸如軟膏、滴劑及真皮貼片之局部調配物。理想的是將本發明之滅菌劑併入諸如植入物之定型物品中,該等植入物可採用惰性材料,諸如生物可降解聚合物或例如矽橡膠、聚矽氧橡膠之合成聚矽氧或其他市售聚合物。
本發明之鹽亦可以諸如單層小微脂粒、單層大微脂粒或多層微脂粒之脂質體傳遞系統之形式投藥。脂質體可由多種脂質形成,諸如膽固醇、硬脂醯胺或磷脂醯膽鹼。
本發明之鹽亦可藉由使用鹽分子偶合之抗體、抗體片段、生長因子、激素或其他靶部分來傳遞。本發明之鹽亦可與作為可靶向藥物載劑之合適聚合物偶合。該等聚合物可包括經軟脂醯基殘基取代之聚乙烯吡咯啶酮、哌喃共聚物、聚羥基丙基甲基丙烯醯胺酚、聚羥基乙基天冬醯胺酚或聚氧化乙烯-聚離胺酸。此外,本發明之鹽可偶合至一類用於達成藥物之控制型釋放的生物可降解聚合物,例如聚乳酸、聚乙醇酸、聚乳酸及聚乙醇酸之共聚物、聚ε己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二氫哌喃、聚氰基丙烯酸酯及水凝膠之交聯或兩性嵌段共聚物。聚合物及半滲透性聚合物基質可形成定型物品,諸如瓣膜、血管支架、管道、假體及其類似物。
B.治療有效量
如可接受之醫藥實踐所要求,一般將約0.5至500 mg之本發明之鹽或鹽混合物與生理學上可接受之媒劑、載劑、賦形劑、黏合劑、防腐劑、穩定劑、染料、香料等混合。該等組合物中之活性成份之量係如此以便獲得在指示範圍內合適之劑量。
預期典型劑量介於約0.001 mg/kg至約1000 mg/kg之範圍內,較佳為約0.01 mg/kg至約100 mg/kg,且更佳為約0.10 mg/kg至約20 mg/kg。本發明之化合物可每日投與一或多次,且其他給藥方案亦可適用。
A.預防及治療特徵在於不良血栓塞之疾病病症
本發明之鹽可用於預防或治療哺乳動物中特徵在於不良血栓塞之病症,其係藉由向哺乳動物投與治療有效量之式I化合物之鹽、式I化合物之順丁烯二酸鹽、式II之鹽或具有結晶多晶型形態之式II之鹽。該等鹽可單獨使用,或與醫藥學上可接受之賦形劑結合使用以防止特徵為不良血栓塞之病症發作。經由減少醫藥治療及其相關之精神及物理成本,以及由避免對患者之長期治療而直接節約貨幣,預防性治療可大體上有益於具有疾病風險之患者。對於其中病症未足夠早偵測以防止發作之患者而言,本發明之鹽可單獨使用或與醫藥學上可接受之賦形劑結合使用以治療病症。
本發明之較佳鹽之特徵在於其抑制血栓形成之能力,該等鹽對凝聚參數、血小板及血小板功能之傳統量測及與其用途相關聯之可接受水平之出血併發症具有可接受之效應,同時展現合適穩定性。特徵在於不良血栓塞之病症可包括涉及動脈及靜脈維管結構之彼等病症。
關於冠狀動脈維管結構,異常血栓形成之特徵在於已確認之動脈粥樣硬化斑的破裂,其為急性心肌梗塞及不穩定性心絞痛之主要原因,且其特徵亦在於因溶血栓療法或經皮經管腔冠脈血管成形術(PTCA)造成之閉塞性冠脈血栓形成。
關於靜脈維管結構,異常血栓形成之特徵在於在下肢或腹部區域經受大手術之患者中觀測之病症,該等患者常遭受在靜脈維管結構中導致流向受影響肢體之血液減少且作為肺栓塞誘因之血栓形成。異常血栓形成之另一特徵在於散播性血管內凝血症,其通常出現於敗血性休克(某些病毒感染)及癌症(一種其中快速消耗凝血因子及全身性凝血之病症,該全身性凝血導致在整個微維管結構中出現形成危及生命之血栓,從而導致廣泛之器官衰竭)期間之兩種血管系統中。
咸信本發明之鹽(如本文所揭示進行選擇及使用)適用於預防或治療特徵在於不良血栓塞之病症,諸如(a)治療任何血栓介導性急性冠脈症候群,包括心肌梗塞、不穩定性心絞痛、頑固性心絞痛、溶血栓療法後或冠脈血管成形術後出現之閉塞性冠脈血栓,(b)治療任何血栓介導性腦血管症候群,包括栓塞性中風、血栓性中風或短暫性缺血性發作,(c)治療任何在靜脈系統中發生之血栓性症候群,包括深靜脈血栓症或自發出現或在惡性腫瘤、手術或外傷之情況下出現之肺栓塞,(d)治療任何凝血症,包括散播性血管內凝血(包括敗血性休克或其他感染、手術、妊娠、外傷或惡性腫瘤之情況及不管其與多器官衰竭是否相關)、血栓性血小板缺乏紫斑症、阻塞性血栓脈管炎或與肝素誘導性血小板減少症相關聯之血栓性疾病,(e)治療與體外循環(例如腎透析、心肺旁路或其他氧處理程序、血漿去除法)相關聯之血栓性併發症,(f)治療與使用儀器(例如心臟或其他血管內之導管***術、主動脈內球囊泵、冠脈血管支架或心瓣)相關聯之血栓性併發症,及(g)與假體裝置之裝配相關聯之彼等病症。
因此,一種用於治療哺乳動物中特徵在於不良血栓塞之病症的方法包含向哺乳動物投與治療有效量之本發明之鹽。預期使用本發明之鹽可治療之疾病狀態包括(但不限於)急性冠脈症候群、心肌梗塞、不穩定性心絞痛、頑固性心絞痛、溶血栓療法後或冠脈血管成形術後出現之閉塞性冠脈血栓、血栓介導性腦血管症候群、栓塞性中風、血栓性中風、短暫性缺血性發作、靜脈血栓症、深靜脈血栓症、肺栓塞、凝血症、散播性血管內凝血、血栓性血小板缺乏紫斑症、阻塞性血栓脈管炎、與肝素誘導性血小板減少症相關聯之血栓性疾病、與體外循環相關聯之血栓性併發症、與使用儀器相關聯之血栓性併發症、與假體裝置之裝配相關聯之血栓性併發症、由溶血栓療法或經皮經管腔冠脈血管成形術造成之閉塞性冠脈血栓形成、在靜脈維管結構中之血栓形成、散播性血管內凝血症、一種其中快速消耗凝血因子及全身性凝血之病症(該全身性凝血導致在整個微維管結構中出現形成危及生命之血栓,從而導致廣泛之器官衰竭)、出血性中風、腎透析、血液氧處理及心臟導管***術。
無論何時需要抑制血液凝聚以防止所儲存全血凝聚且防止其他用於測試或儲存之生物學樣本凝聚,亦可使用式I化合物之順丁烯二酸鹽或式II之鹽。因此,本發明之凝聚抑制劑可添加至所儲存之全血及任何含有或懷疑含有血漿凝聚因子之介質中或與其接觸,且其中需要抑制血液凝聚,例如當哺乳動物之血液與選自由人造血管、血管支架、矯形外科假器、心臟假器及體外循環系統組成之群之材料接觸時。
除用於人類治療以外,亦預期該等化合物用於伴侶動物、外來動物及農場動物(包括哺乳動物、齧齒動物及其類似動物)之獸醫治療。更佳動物包括馬、狗及貓。
B.投藥
通常將治療性液體調配物置於具有無菌接口之容器中,例如具有藉由皮下注射針可刺穿之塞子的靜脈內溶液袋或小瓶。
治療有效劑量可由活體外或活體內方法來確定。對於本發明之每一特定鹽而言,可進行個別測定以確定所需之最佳劑量。治療有效劑量之範圍受投藥途徑、治療目的及患者病症之影響。對於藉由皮下注射針之注射而言,可假定將劑量傳遞至體液中。對於其他投藥途徑而言,每一化合物之吸收效率必須由藥理學中熟知之方法來個別確定。因此,當需要獲得最佳治療效應時,治療師必需滴定劑量且改變投藥途徑。有效劑量水平之測定(亦即達到所要結果必需之劑量水平)可易於由熟習此項技術者確定。鹽之應用一般由較低濃度水平開始,增加劑量水平直至達到所要效應。
可併入錠劑、膠囊、***劑及其類似物之典型佐劑為諸如***膠、玉米澱粉或明膠之黏合劑及諸如微晶纖維素之賦形劑、諸如玉米澱粉或褐藻酸之崩解劑、諸如硬脂酸鎂之潤滑劑、諸如蔗糖或乳糖之甜味劑或調味劑。當劑型為膠囊時,其除以上材料之外亦可含有諸如水、鹽水或脂肪油之液體載劑。可使用多種類型之其他材料作為塗覆劑或劑量單位之物理形態的改質劑。用於注射之無菌組合物可根據習知醫藥實踐來調配。舉例而言,可能需要將活性化合物溶解或懸浮於諸如油或諸如油酸乙酯之合成脂肪媒劑之媒劑中,或溶解或懸浮於脂質體中。可根據可接受之醫藥實踐併入緩衝劑、防腐劑、抗氧化劑及其類似物。
C.組合療法
本發明之鹽亦可與其他治療劑或診斷劑組合使用。在某些較佳實施例中,本發明之鹽可與其他化合物一起共投與,該等其他化合物一般指定用於該等根據通常接受之醫療實踐之病症,通常接受之醫療實踐諸如抗凝劑、溶血栓劑或其他抗血栓形成劑,該等其他化合物包括血小板凝集抑制劑、組織血纖維蛋白溶酶原活化劑、尿激酶、前尿激酶、鏈球菌激酶、肝素、阿司匹靈(aspirin)或殺鼠靈。本發明之鹽可以協同方式起作用以防止成功溶血栓療法後之再阻塞及/或減少再灌注之時間。該等鹽亦使得可使用減少劑量之溶血栓劑,且因此最小化潛在之出血性副作用。本發明之鹽亦可在活體內(通常在哺乳動物中,諸如靈長類、人類、羊、馬、牛、豬、狗、貓、大鼠及小鼠)或活體外使用。
D.化合物製備1.式I化合物之順丁烯二酸鹽
式I化合物可轉化為各種無機及有機酸之鹽,其包括(但不限於)鹽酸鹽、乳酸鹽、順丁烯二酸鹽、苯氧基乙酸鹽、丙酸鹽、丁二酸鹽、己二酸鹽、抗壞血酸鹽、樟腦酸鹽、葡萄糖酸鹽、磷酸鹽、酒石酸鹽、檸檬酸鹽、甲磺酸鹽、反丁烯二酸鹽、乙醇酸鹽、萘-1,5-二磺酸鹽、龍膽酸鹽及苯磺酸鹽。熟習此項技術者可意識到其他可用於製備鹽之酸,該等鹽包含用於本發明之式I化合物。
為評估該等鹽之熱穩定性及水解穩定性,進行熟習此項技術者已知之測試。該等測試於下文實例4中更全面論述。
多種方法係用於製備上述鹽,且為熟習此項技術者已知。舉例而言,式I化合物與一或多莫耳當量之所要酸在鹽不溶於其中之溶劑或溶劑混合物中、或在例如水之溶劑中反應,之後藉由蒸發、蒸餾或冷凍乾燥移除溶劑。或者,可使式I化合物通過離子交換樹脂以形成所要之鹽或可使用相同之通用方法將產品之一種鹽形態轉化為另一種鹽形態。
根據下文所列程序製備式I化合物。為其優良結晶性、熱穩定性及水解穩定性及高純度選擇式I化合物之順丁烯二酸鹽。
2.式I
可根據多種不同方法之任一者製備公克級(<1 kg)或公斤級(>1 kg)之式I化合物。公克級方法於下文實例2中列出。另一種公克級方法於美國專利第6,844,367B1號(參見實例266)中列出,其以引用的方式併入本文中。
或者,可使用實例2中所列之程序製備公斤級之式I化合物。式I之二甲基脒之形成包括藉由去質子化胺對氰基進行親核性攻擊,其中該去質子化胺由二級胺及烷基鋰形成。熟習此項技術者可意識到,該去質子化胺可經由其他方法形成,且式I之脒官能基之形成可藉由多種其他方法來製備。
如上所述用於本發明方法之有用溶劑為非極性、非質子性溶劑,諸如四氫呋喃(THF)、***、二甲氧基甲烷、二噁烷己烷、甲基第三丁基醚、庚烷及環己烷。此外,去質子化胺之形成可在10℃以下之溫度下進行。形成式I化合物之胺的親核性加成反應亦可在10℃以下之溫度下進行。熟習此項技術者可意識到,可使用多種其他溶劑、試劑及反應溫度實踐本發明之方法。
使用本發明之方法可以大於50%之產率製備式I化合物。在某些情況下,可以大於65%之產率製備式I化合物。在其他情況下,可以大於75%之產率製備式I化合物。
此外,當用於製備公克級式I化合物之本發明方法類似於用於公斤級之程序時,反應量級增加超過3400%。此外,在若干步驟中,使用減少量之過量試劑獲得增加之產量。熟習此項技術者可意識到,經由其他化學方法可製備公克級及公斤級之式I化合物。
除非另外規定,否則整個本說明書所用之縮寫具有以下含義:=埃A%=總百分比面積aq.=水溶液cm=公分d=雙重峰DSC=差示掃描熱量測定EDTA=乙二胺四乙酸eq.=當量EtOH=乙醇g=公克HPLC=高效液相層析法hr=小時Hz=赫茲IR=紅外線J=偶合常數kg=公斤kV=千伏特L=公升LOD=偵測極限M=莫耳m=多重峰mA=毫安Me=甲基MeO=甲氧基MeOH=甲醇mg=毫克min.=分鐘mL=毫升mm=毫米MTBE=甲基第三丁基醚N=正常nM=奈莫耳NMR=核磁共振s=單重峰TDS=總溶解固體TGA=熱解重量分析THF=四氫呋喃μM=微莫耳
公克級製備
在裝配有冷凝器之三頸1500 mL圓底燒瓶中饋入式I之游離鹼化合物(25 g;1當量),且伴隨攪拌添加9:1之EtOH/水(500 mL)。將所得漿料加熱至70℃。逐滴添加順丁烯二酸(12.77 g;2當量)作為溶液(100 mL之9:1之EtOH/水)且在已添加50 mL後,溶液顯著變得更澄清。在順丁烯二酸溶液完全添加時,使溫度在80℃下保持5分鐘。使容器緩慢冷卻至45℃,且接著添加400 mL之MTBE。將溶液攪拌12小時。將所得沉澱物過濾,且於真空下乾燥。式II之鹽以45%之產率(14.2 g)回收。
公斤級製備
將式I化合物(24.6 Kg)饋入760 L GLMS反應器(反應器A)中。添加順丁烯二酸(12.7 Kg,2.0當量)、乙醇(445 Kg,18.1份)及高純水(140 Kg,5.7份)。將反應混合物調節至22℃(19-25℃)且在該溫度下攪拌約1小時,接著經精細過濾器傳輸至經調整之780 L哈斯特合金(Hastelloy)反應器(反應器B)中。將反應器A之泵及管線經由精細過濾器以額外乙醇(約45 Kg)正向沖洗至反應器B中。將濾液於真空下濃縮直至殘留約140 L(5.7體積份)。自反應器B之內容物取樣用於製程NMR中,其顯示乙醇:式II之莫耳比為26。將高純水(49 Kg,2.0份)饋入反應器B且在真空下恢復濃縮直至達到約140 L(5.7體積份)之罐體積。製程NMR指示乙醇:式II之鹽的莫耳比為14。再次饋入高純水(49 Kg,2.0份)且在真空下恢復濃縮以獲得約140 L之罐體積。製程NMR顯示乙醇:式II之鹽的莫耳比為5。將反應器B內容物之溫度調節至22℃(19-25℃),且視覺確認漿料之形成。將反應混合物在22℃(19-25℃)下攪拌約2小時,且接著在安裝有F-53濾布之30"離心機上過濾。將反應器B之泵及管線以兩份高純水(每份約30 Kg)經由精細過濾器正向沖洗至30"離心機中。自濾餅取樣用於製程HPLC,其顯示產物純度為99.1 A%,最大雜質為0.26 A%,且因此無需再結晶。在真空下乾燥濾餅(33.1 Kg)。在約30.5小時之後,製程LOD分析指示0%之溶劑含量。排出乾燥產物(26.4 Kg),且儲存於2-8℃下。最終產物之產率為85%,稍微高於預期值(預期為50-80%)。
使用實例4中所述之技術來表徵式II之鹽。式II之鹽之X光繞射圖案顯示於圖1A中,且其特徵在於以下近似峰位:4.9、9.7、11.8、13.8、14.1、15.2、17.6、18.5、19.9、20.8、21.6、22.7、24.1、25.0、26.3、26.8度2θ。使用差示掃描熱量測定(DSC,參見圖2A中之圖案)量測197與201℃之間之熔點。此外,經由熱解重量分析(TGA,參見圖2B中之圖案)量測式II之鹽在100℃下之重量損失為0.62%。式II之鹽之吸水作用可逆且顯示0.1與3%之間之吸水率(圖3)。藉由如HPLC所量測之水解脒含量之存在量測式II之鹽的純度,且發現其純度大於99%。
1
H NMR(DMSO-d6
):δ 3.0(s,3H)、3.2(s,3H)、3.82(s,3H)、7.2(d,1H,J=9.0 Hz)、7.42(s,1H)、7.68(d,1H,J=8.0 Hz)、7.95-8.15(m,2H)、8.12(m)、8.18(m,1H)、8.42(s,1H)、9.0(s,1H)、11.0(s,1H)、11.2(s,1H);IR(KBr,cm- 1
):3300,1685,1600,1515,1380,1270,1200,1100,1050,880,800,710。
公克級製備
在THF(4.67 kg,10.3份)中製備式F化合物之漿料(455 g,1.0當量),且調節至小於10℃。如下製備二甲基醯胺鋰:將己基鋰(2.3 N/己烷,2.45 L,5.5當量)添加至維持在小於10℃之二甲基胺溶液(2 N/THF,2.8 L,5.5當量)中。將二甲基醯胺鋰溶液饋入含有式F化合物之漿料中,維持小於10℃之罐溫度。藉由製程HPLC監控反應進程,該HPLC確認式F之量小於1.0 A%。在去離子水(6.6 kg,14.51份)中製備NaHCO3
(490 g,1.1份,5.7當量)及Na2
CO3
(490 g,1.1份,4.5當量)之緩衝溶液,且將上述反應混合物傳輸至該水溶液,維持小於5℃。將所沉澱出之產物及所得漿料調節至20℃歷經12小時之時期。過濾固體,且將所得濕濾餅以3.5 kg(7.7份)去離子水洗滌。使用粗燒結玻璃臺式過濾器濾出固體,且以冷(0-5℃)無水乙醇(628 g,1.4份)正向沖洗。將產物在30-35℃下乾燥。獲得乾燥產物458 g(73%產率)。
公斤級製備
在780 L哈斯特合金反應器(反應器A)中製備式F化合物(31.5 Kg,1.0當量)於THF(251 Kg,8.0份)中之漿料,且調節至0℃(-3至3℃)。將THF中之2 M二甲胺(161.0 Kg,5.0當量)及THF(63 Kg,2份)饋入1900 L GLMS反應器(反應器B)中,且伴隨最大攪拌調節至0℃(-3至3℃)。將己基鋰(2.3 M,97.2 Kg,4.5當量)緩慢饋入反應器B,同時維持10℃之最高溫度。將泵及管線以THF(3.2 Kg)正向沖洗至反應器B。將反應器B之內容物調節至0℃(-3至3℃),接著傳輸至反應器A,同時保持反應器A之溫度10℃。將反應器B之泵及管線以THF(31.4 Kg,,1.0份)正向沖洗。將反應器A之內容物調節至0℃(-3至3℃),且在此溫度下攪拌直至如HPLC所證實反應完全(1-2小時)。在攪拌約1小時後,製程HPLC分析指示殘留0 A%之起始物質(進程準則:最大1 A%)。將反應器A之內容物調節至-5℃(-8至-3℃)。以水進行對反應器B之製程清潔。將兩種先前製備之水溶液[水(236 Kg,7.5份)中之NaHCO3
(35.0 Kg,1.1份)及水(236 Kg,7.5份)中之Na2
CO3
(35.0 Kg,1.1份)]饋入反應器B,且調節至-3℃(0至6℃)。將反應器A之內容物經隔熱管線傳輸至反應器B,維持反應器B之溫度在-8℃至最大5℃。將反應器A之泵及管線以冷[-5℃(-8至-3℃)]THF(31.4 Kg,1.0份)正向沖洗。將反應器B之內容物調節至22℃(19-25℃),且攪拌約3小時。視覺確認漿料之形成,且將反應器B之內容物經安裝有F-16濾布之30"離心機過濾。將反應器B之泵及管線以飲用水(63 Kg,2份)正向沖洗至安裝有F-16濾布之30"離心機上。將濕濾餅(66.5 Kg)傳輸回反應器B且使其在22℃(19-25℃)下經受飲用水(1005 Kg,32份)之漿料洗滌歷時約1小時。將產物在30"離心機上過濾(在製程清潔且安裝F-53濾布之後),且將反應器B之管線及泵以飲用水(63 Kg,2份)正向沖洗。自沖洗之水取樣以供TDS測試,發現水沖洗為0.46%。將反應器B之泵、管線及濕濾餅以冷[0℃(-3至3℃)]乙醇(44 Kg,1.39份)進一步沖洗。在真空下乾燥濕濾餅。在乾燥約24小時之後製程LOD為0%,且將76.7%之產率排出產物(24.8 Kg)。HPLC顯示98%之純度,而脫氯雜質為1.14%。
步驟1. 2-硝基-N-(5-氯-吡啶-2-基)-5-甲氧基-苯甲醯胺(C)之合成
將5-甲氧基-2-硝基苯甲酸(A)(25.0 Kg,1.0當量)、2-胺基-5-氯吡啶(B)(16.3 Kg,1.0當量)及乙腈(87.5 Kg,3.5份)饋入380 L GLMS反應器中。將反應混合物調節至22℃(19-25℃)且添加吡啶(30.0 Kg,3.0當量)。將泵及管線以乙腈(22.5 Kg,0.9份)正向沖洗,且將反應器內容物調節至19-22℃之溫度。將磷醯氯(23.3 Kg,1.20當量)經由計量泵饋入反應器之內容物中,同時維持25℃(22-28℃)之溫度。將計量泵及管線以乙腈(12.5 Kg,0.5份)正向沖洗,同時保持25℃(22-28℃)之溫度。在添加約1/3之POCl3
之後,反應混合物通常自漿料轉變為透明溶液。在添加結束時,其變得渾濁。在完全添加之後,將反應混合物於25℃(22-28℃)下攪拌約1小時,此時HPLC分析證實反應完成。將溶液冷卻至15℃(12-18℃),且緩慢饋入飲用水(156.3 Kg,6.25份),同時保持反應溫度在12與30℃之間。接著將反應混合物調節至22℃(19-25℃),且攪拌約5小時直至放熱終止。視覺確認漿料之形成,且將反應器之內容物經安裝有F-19濾布之壓力吸濾器過濾。將反應器、泵及管線以兩份飲用水(每次62.5 Kg,2.5份)正向沖洗至壓力吸濾器上。濾液具有7之pH值。在真空下乾燥產物(41.8 Kg)。在約12小時之後,製程LOD分析指示溶劑濃度為0.72%。以88.2%之產率及由HPLC所測定之99.1%之純度排出乾燥產物(C)(34.4 Kg)。
步驟2. 2-胺基-N-(5-氯-吡啶-2-基)-5-甲氧基-苯甲醯胺(D)之合成
向780L哈斯特合金反應器中饋入化合物C(33 Kg,1.0當量)、5%鉑碳(經硫化,0.33 Kg,0.010份)及二氯甲烷(578 Kg,17.5份)。開始攪拌且將反應器內容物調節至22℃(19-25℃)。將反應器以約30 psi氫加壓且將反應混合物逐漸加熱至28℃(25-31℃)。在約30 psi下於28℃(25至31℃,最高31℃)下進行反應器內容物之氫化作用直至由HPLC測定反應完成。在16.5小時之後,確認起始物質(0.472 A%)消失後認為反應完成。使反應器之內容物經由在8"斯巴克(sparkler)過濾器中製備之經調節矽藻土襯墊(經20-55 Kg二氯甲烷調節之0.2-0.5 Kg矽藻土)循環以移除鉑催化劑。將反應器及矽藻土床以兩份二氯甲烷(每次83 Kg,2.5份)正向沖洗。將濾液傳輸至570L GLMS反應器中,且在大氣壓下濃縮至約132 L(4體積份)。饋入乙醇(69 Kg,2.1份)且在大氣壓力下繼續濃縮至約99 L(3體積份)。製程NMR指示二氯甲烷含量為39%。再次饋入乙醇(69 Kg,2.1份)且再次繼續濃縮至約99 L(3體積份)。製程NMR指示二氯甲烷含量為5%。接著將反應混合物調節至3℃(0至6℃),攪拌約1小時,且使所得漿料在安裝有F-19濾布之夾套壓力吸濾器上過濾。將反應器、泵及管線以冷[3℃(0至6℃)]乙醇(26 Kg,0.8份)正向沖洗。在真空下於40-50℃下乾燥濕濾餅(36.6 Kg)。12.5小時之後LOD分析指示溶劑含量為0.1%。以89.5%之產率排出乾燥產物(D)(26.4 Kg)。HPLC顯示98.4 A%之純度,而脫氯雜質為0.083%。
步驟3. N-(5-氯-吡啶-2-基)-2-(4-氰基-苯甲醯基-胺基)-5-甲氧基-苯甲醯胺鹽酸鹽(F)之合成
向780 L哈斯特合金反應器中饋入4-氰基氯化苯甲醯(E)(17.2 Kg,1.1當量)及THF(92 Kg,3.5份)。在22℃(19-25℃)下攪拌反應器內容物直至所有固體溶解。將所得溶液傳輸至下方接收器且將反應器以THF(26 Kg,1份)正向沖洗。將化合物D(26.4 Kg,1當量)、THF(396 Kg,15份)及吡啶(2.90 Kg,0.4當量)饋入清潔反應器中。將泵及管線以THF(34 Kg,1.3份)正向沖洗。經由計量泵將4-氰基氯化苯甲醯/THF溶液饋入反應器中,保持溫度為30℃且以THF(約10 Kg)正向沖洗。將所得黃色漿料在22℃(19-25℃)下攪拌約2小時。2小時後所進行之製程HPLC顯示式D化合物之含量為0%,指示反應完成。將漿料在安裝有F-19濾布之壓力吸濾器上過濾。將反應器、泵、管線及濕濾餅以三份乙醇(每份約15 Kg)沖洗。排出濕濾餅(65.4 Kg),且在22℃(19-25℃)下歷時約1小時傳輸回用於以乙醇(317 Kg,12份)洗滌漿料之反應器中。將漿料在壓力吸濾器上過濾,且將反應器、泵、管線及濕濾餅以兩份乙醇(每份約15 Kg)及兩份THF(每份約15 Kg)沖洗。在真空下乾燥濕濾餅。在乾燥14.5小時之後,LOD為0.75%。將經乾燥物質研磨(篩網0.125")以給出31.8 Kg產物,將該產物於真空下再乾燥10.5小時。乾燥之後之LOD為1.8%,且以74.8%之產率(預期60-90%)排出產物(31.5 Kg)。HPLC顯示100%之純度。
初始篩檢
向3 mL 10%(含水)THF混合物中之20 mg游離鹼中添加1 mL乙醇中之1.1當量酸。將混合物震盪2小時,繼而添加2 mL第三丁基甲基醚以引起沉澱且再震盪2小時。接著將樣本過濾、乾燥且接著分析以判定其純度、結晶性及穩定性。結果於下表1中呈現,且列舉所測試之酸。
二級篩檢
使用下述方法對多種鹽形態進行二級評估,結果概述於表5及圖1A、1B、2A、2B及3中。
差示掃描熱量測定(DSC)
在裝配有50個位置自動取樣器之TA儀器Q1000上收集DSC資料。能量及溫度校正標準為銦。在25與350℃之間以10℃/min之速率加熱樣本。在樣本上維持30 mL/min之氮氣淨化。除非另外規定,否則使用1及3 mg之間之樣本,且將所有樣本均在與外界隔絕型密封鋁盤中捲曲。
熱解重量分析(TGA)
在以鎳/鋁合金校正且以10℃/分鐘之掃描速率執行之TA儀器Q500 TGA上收集TGA資料。在樣本上維持60 mL/min之氮氣淨化。一般將10-20 mg之樣本負載於經預稱皮重之鉑坩堝上。
XRPD(X光粉末繞射)
在使用CuKα輻射(40 kV,40 mA)、θ-θ測角器、自動發散及接受狹縫、石墨二次單色器及閃爍計數器之Siemens D5000繞射儀上收集X光粉末繞射圖案。使用經鑒證之剛玉標準(NIST 1976)檢查儀器之效能。
將在周圍條件下執行之樣本使用粉末製備為平板樣品。將近似35 mg之樣本輕緩封裝於切割為經拋光之零背景(510)矽晶圓的空腔中。分析期間樣本在其自身平面內旋轉。對下表2中之方法給出詳細之資料收集:
使用Cu Kα1
(λ=1.5406)報導繞射資料,在使用EVA(評估軟體)除去Kα2
組份之後,藉由使用WIN-INDEX之ITO方法及使用WIN-METRIC改進之原始晶格常數檢索粉末圖案。
單一晶體XRD(X光繞射)
在裝配有Oxford Cryosystems Cryostream冷卻裝置之Bruker AXS 1K SMART CCD繞射器上收集資料。使用SHELXS或SHELXD程式解釋結構,且以SHELXL程式改進為Bruker AXS SHELXTL套組之部分。除非另外規定,否則使連接至碳之氫原子經幾何學放置且使其以沿曲線運動之各向同性位移參數進行改進。將連接至雜原子之氫原子安置於差異傅立葉合成中,且使其以各向同性位移參數進行自由改進。
重量分析蒸氣吸附(GVS)研究
在執行CFRSorp軟體之Hiden IGASorp吸濕分析器上執行所有樣本。樣本大小一般為10 mg。如下文概述(2次給定1個完全循環之掃描)進行吸濕解吸等溫線。所有樣本在典型室內濕度及溫度(40% RH,25℃)下負載/卸載。所有樣本均藉由XRPD後GVS分析來分析。在25℃下以10%RH之間隔在0-90%RH範圍內進行標準等溫線。式II之鹽顯示優良濕氣穩定性。
溶解度
此係藉由在0.25 mL溶劑(水)中懸浮足夠之鹽來量測,以給出鹽之親本自由形態的10 mg/mL之最大最終濃度。將懸浮液在25℃下平衡24小時,繼而檢查pH且經由玻璃纖維C 96孔板過濾。接著將濾液稀釋101倍。參考以近似0.1 mg/mL溶解於DMSO中之標準,藉由HPLC進行定量。注入不同體積之標準測試物、經稀釋測試物及未經稀釋測試物。藉由對在與標準注射中峰最大值相同之滯留時間時發現之峰面積進行積分來計算溶解度。若在濾板中有足夠之固體,則通常檢查XRPD以供相變化、水合物形成、無定形化、結晶等。
乙酸鹽提供10 mg/mL之溶解度,而順丁烯二酸鹽提供約2.05 mg/mL至約2.27 mg/mL之溶解度。
pKa測定
此係在具有D-PAS附著構件之Sirius GlpKa儀器上進行。藉由水溶液中之UV且藉由在25℃下甲醇及水混合物中之電位計來進行量測。滴定介質為經0.15 M KCl調節之離子強度。經由Yasuda-Shedlovsky外推法將甲醇及水混合物中發現之值修正為0%共溶劑。使用Refinement Pro軟體版本1.0改進該資料。使用ACD pKa預測軟體版本8.08進行pKa值之預測。式II之鹽之資料呈現於下表3中。
LogP測定
此係藉由Sirius GlpKa儀器上之電位滴定使用辛醇:ISA水之三種比率以產生Log P、Log P離 子
及Log D值。使用Refinement Pro軟體版本1.0改進該資料。使用ACD版本8.08及Syracuse KNOWWIN版本1.67軟體進行LogP之預測。順丁烯二酸鹽之資料顯示於下表4中。
卡爾-費休(Karl Fisher)水測定
使用Hydranal Coulomat AG試劑及氬氣淨化在Mettler Toledo DL39電量計上量測水含量。樣本作為在鉑TGA盤上稱出之固體引入容器中,該鉑TGA盤連接至subaseal以避免水進入。對於每次滴定均使用近似10 mg之樣本且每次分析均進行兩次。
穩定性
作為穩定性之量測,在使樣本經受75%室內濕度之57℃溫度之後藉由HPLC(Agilent HP1100)(滯留時間為34分鐘)量測水解脒之含量。樣本溶劑為甲醇,且採用0.1%三氟乙酸之移動相改質劑。除丙酸鹽之資料在第0、3及8天時收集以外,均在第3、6及10天之後收集資料。結果在表5中呈現為酸水解產物之百分比,表現為主峰之百分比。在計算中所有其他雜質峰均忽略不計。
式II之鹽之晶體資料
所有實驗均在裝配有Oxford Cryosystems Cryostream冷卻裝置之Bruker-Nonius Kappa CCD繞射器上進行。通常由SIR-97或SHELXS-97來解釋結構,且由SHELXL-97來改進結構。除非另外規定,否則將氫原子經幾何學放置,且使其以各向同性位移參數進行改進。下表(表6及表7)提供式II之鹽之晶體資料及結構改進。
儘管為達成清楚理解之目的,已藉由說明及實例相當詳細地描述上述發明,但熟習此項技術者應瞭解在隨附之申請專利範圍之範疇內可實踐某些改變及修改。此外,本文所提供之每一參考案均以全文引用的方式併入,其引用程度如同每一參考案個別以引用的方式併入一般。
圖1A及1B提供式II形式(順丁烯二酸鹽)之X光粉末繞射(XRPD)。圖1A顯示觀測之繞射圖案而圖1B顯示計算之繞射圖案。
圖2A及2B分別提供式II之順丁烯二酸鹽之差示掃描熱量測定(DSC)及熱解重量分析(TGA)資料。
圖3提供式II之順丁烯二酸鹽之重量分析吸水率(GVS)資料。
圖4提供式II之順丁烯二酸鹽分子來自顯示所用編號流程之晶體結構資料的兩張視圖。在50%概率水平下,顯示非氫原子之各向異性原子位移橢球體。用任意小之半徑顯示氫原子。
Claims (27)
- 一種式II之鹽,
- 如請求項1之鹽,其具有結晶多晶型形態。
- 如請求項2之鹽,其具有粉末X光繞射圖案,該粉末X光繞射圖案具有至少四個選自4.9、9.7、13.8、14.1、15.2、17.6、18.5、20.8、21.6、22.7、24.1、26.3、26.8度2θ之近似特徵峰位。
- 如請求項2之鹽,其具有粉末X光繞射圖案,該粉末X光繞射圖案具有至少八個選自4.9、9.7、11.8、13.8、14.1、15.2、17.6、18.5、19.9、20.8、21.6、22.7、24.1、25.0、26.3、26.8度2θ之近似特徵峰位。
- 如請求項2之鹽,其具有近似於圖1A或1B所示之粉末X光繞射圖案之粉末X光繞射圖案。
- 如請求項2之鹽,其具有近似於圖2A所示之差示掃描熱量測定圖案之差示掃描熱量測定圖案。
- 一種用於預防或治療哺乳動物中特徵在於不良血栓塞之病症的醫藥組合物,其包含醫藥學上可接受之載劑及治療有效量之如請求項1至6中任一項之鹽。
- 如請求項7之醫藥組合物,其係錠劑形式。
- 如請求項7之醫藥組合物,其係膠囊形式。
- 如請求項7之醫藥組合物,其係***劑形式。
- 如請求項7之醫藥組合物,其係適合於輸注、注射或經皮轉遞之形式。
- 如請求項7至11中任一項之醫藥組合物,其進一步包含第二藥劑,其係選自由抗凝劑、溶血栓劑及抗血栓形成劑所組成之群。
- 如請求項7至11中任一項之醫藥組合物,其進一步包含第二藥劑,其係選自由血小板凝集抑制劑、組織血纖維蛋白溶酶原活化劑、尿激酶、前尿激酶、鏈球菌激酶、肝素、阿司匹靈及殺鼠靈所組成之群。
- 一種如請求項1至6中任一項之鹽之用途,其用於製造供預防或治療哺乳動物中特徵在於不良血栓塞之病症的藥劑。
- 如請求項14之用途,其中該病症係選自由以下病症組成之群之一員:急性冠脈症候群、心肌梗塞、不穩定性心絞痛、頑固性心絞痛、溶血栓療法後或冠脈血管成形術後出現之閉塞性冠脈血栓、血栓介導性腦血管症候群、栓塞性中風、血栓性中風、短暫性缺血性發作、靜脈血栓症、深靜脈血栓症、肺栓塞、凝血症、散播性血管內凝血、血栓性血小板缺乏紫斑症、阻塞性血栓脈管炎、與肝素誘導性血小板減少症相關聯之血栓性疾病、與體外循環相關聯之血栓性併發症、與使用儀器相關聯之血栓性併發症及與假體裝置之裝配相關聯之血栓性併發 症。
- 如請求項14或15之用途,其中該藥劑係與第二藥劑一併使用,該第二藥劑係選自由抗凝劑、溶血栓劑及抗血栓形成劑所組成之群。
- 如請求項14或15之用途,其中該藥劑係與第二藥劑一併使用,該第二藥劑係選自由血小板凝集抑制劑、組織血纖維蛋白溶酶原活化劑、尿激酶、前尿激酶、鏈球菌激酶、肝素、阿司匹靈及殺鼠靈所組成之群。
- 一種如請求項1至6中任一項之鹽之用途,其用於製造供抑制血液樣品凝聚之藥劑。
- 一種製備式I化合物之方法,
- 如請求項19之方法,其中該式III化合物之鹽為鹽酸鹽。
- 如請求項19之方法,其中該等親核性加成條件包含使用非極性、非質子性溶劑。
- 如請求項21之方法,其中該溶劑係選自由四氫呋喃、二***、二甲氧基甲烷、二噁烷己烷、甲基第三丁基醚、庚烷及環己烷組成之群之一員。
- 如請求項19之方法,其中該等親核性加成條件包含在低於10℃之溫度下進行該方法。
- 如請求項19之方法,其中以至少50%之產率提供該式I化合物。
- 如請求項19之方法,其中以至少65%之產率提供該式I化合物。
- 如請求項19之方法,其中以至少75%之產率提供該式I化合物。
- 如請求項19之方法,其中在該式I化合物係以公克或公斤之規模製備。
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