TWI418553B - 3-〔(2-{〔4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基〕-甲基}-1-甲基-1h-苯并咪唑-5-羰基)-吡啶-2-基-胺基〕-丙酸乙酯-甲磺酸鹽及其作為藥物之用途 - Google Patents
3-〔(2-{〔4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基〕-甲基}-1-甲基-1h-苯并咪唑-5-羰基)-吡啶-2-基-胺基〕-丙酸乙酯-甲磺酸鹽及其作為藥物之用途 Download PDFInfo
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Description
本發明係關於式A化合物之3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽及其作為醫藥組合物之用途,
式A為:
從WO 98/37075中已知悉式A化合物之鹼,其中WO 98/37075係揭示具有抑制凝血酶之效應及延長凝血酶時間之活性之化合物,其名稱為1-甲基-2-[N-[4-(N-n-己氧基羰基-脒基)苯基]-胺基-甲基]-苯幷咪唑-5-基-羧酸-N-(2-吡啶基)-N-(2-乙氧基羰基乙基)-醯胺。式A化合物係式(B)化合物之雙重前藥,
意即,式A化合物(BIBR 1048 MS)僅於體內轉化為實際有效之化合物(此即式B之化合物)。化學式A化合物之主要應用領域係術後預防深靜脈血栓形成及防止中風。
先前技術中所揭示之雙基取代雙環雜環之上述藥理學有益特性係該等化合物作為醫藥組合物之有效用途之主要先決條件。然而,活性物質亦必須滿足其他要求以使其能夠作為醫藥組合物使用。該等參數於較大程度上係與該活性物質之物理化學特性相關聯。
不受此處所列實例之限制,該等參數之實例係不同周圍條件下起始物質效應之穩定性、該醫藥調配物製備過程中之穩定性及該醫藥製劑之最終組成之穩定性。因此,用於製備醫藥組合物之醫藥活性物質應該具有高穩定性,高穩定性即使在不同環境條件下亦應該得到保障。此情形對於防止使用其中除自身活性物質外含有其(例如)分解產物之醫藥組合物而言係絕對必需。在該等狀況中,醫藥調配物中所發現之活性物質含量可能少於所指定之含量。
由於吸取水份導致重量增加,因此濕氣之吸收減少醫藥活性物質之含量。具有吸收濕氣之趨勢之醫藥組合物在儲存時必須受保護以避免濕氣,例如,藉由添加合適之乾燥劑或藉由在藥物受保護以避免濕氣之環境中將其儲存。此外,若醫藥物質曝露於環境中而未以任何方式受保護以避免濕氣,則在製造期間濕氣之吸取可減少醫藥活性物質之含量。因此,醫藥活性物質較佳應僅具有輕微吸濕性。
由於活性物質之結晶變體形態對於製劑之可再生活性物質含量較重要,因此需要盡可能闡明以結晶形態而存在之活性物質之任何多晶型。若存在活性物質之不同多晶型變體形態,則必須注意以確保該物質之結晶變體形態在隨後自其所產製之醫藥製劑中不會改變。否則,此情形對於藥物的可再生效能具有有害效應。對照此背景情況,僅具有輕微多晶型之活性物質為較佳。
在視調配物之選擇或製造方法之選擇而定之某些環境下可能尤其重要之另一標準係活性物質之可溶性。例如,若製備醫藥溶劑(例如用於輸注),則活性物質應充分可溶於生理上可接受之溶劑中係必需的。對於經口服用之藥物而言,活性物質充分可溶亦非常重要。
本發明之問題係提供一種醫藥活性物質,其不僅具有高藥理學效能之特徵且亦盡可能滿足上述之物理化學要求。
式A之3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽可解決上述問題。
事實上,吾人已驚奇地發現:該鹽之結晶變體形態I可藉由實例1中描述之方法製備之,且該鹽之結晶變體形態II可藉由實例2至4描述之方法製備,其中在各自狀況下製備過程均具有選擇性及均一性。
此外,於如(例如)實例5中所描述之某些合成條件下,可獲得一種水合物形態,其水含量揭示其為一種半水合物。
對於醫藥組合物之用途而言,其中所含有之活性物質必需為均一的結晶變體形態以確保可靠之生物利用度。
根據本發明之甲磺酸鹽於所有三種結晶變體形態中之特徵為:在研磨及壓縮期間均具有良好結晶度及低度非晶化。此外,其在所有三種結晶變體形態中均具有非吸濕性且極易溶解於生理上可接受之酸性水介質中。
根據本發明之化合物3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯的甲磺酸鹽之結晶形態特徵為:其熔點Tm.p..
=180±3℃(形態I)、Tm.p..
=190±3℃(形態II)或Tm.p..
=120±5℃(半水合物)(以DSC=差示掃描熱量測定法來測定;以最大峰值評估;加熱速率:10℃/分鐘)。所示之數值係使用Messrs Mettler Toledo所製造之DSC 821e
測定。
因此,在第一態樣中,本發明係關於較佳呈結晶形態的3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽之三種上述多晶型形態,其特徵為:熔點Tm.p..
=180±3℃、Tm.p..
=190±3℃或Tm.p..
=120±5℃(由DSC測定;由最大峰值核定;加熱速率:10℃/分鐘)。具有熔點Tm.p..
=180±3℃之多晶型I較佳。
本發明亦係關於選擇性產製三種多晶型形態之方法,以及關於藉由該等方法可獲得之變體形態。
a)於大約30℃至36℃之溫度下,將溶於丙酮之稍不足量(例如0.98當量)之甲磺酸溶液緩慢加至溶於丙酮中之BIBR 1048鹼溶液,
b)於約26℃至33℃之溫度下,攪拌該混合物約1小時,
c)將其冷卻至大約17℃至23℃間,且於該溫度下進一步攪拌40至80分鐘,
d)抽氣過濾BIBR 1048 MS形態I之沈澱晶體,及
e)據此所得之產物於最高為50℃之溫度下真空乾燥至少4小時。
a)於大約40℃至46℃之溫度下,將溶於丙酮中之稍不足量(例如0.98當量)之甲磺酸溶液緩慢加至溶於丙酮中之BIBR 1048鹼溶液,
b)視情況接種BIBR 1048多晶型II晶體,
c)於大約40℃至46℃之溫度下,攪拌該混合物約1小時,
d)將其冷卻至大約17℃至23℃間,且於此溫度下進一步攪拌40至80分鐘,
e)抽氣過濾BIBR 1048 MS形態II之沈澱晶體,及
f)據此所得之產物於最高為50℃之溫度下真空乾燥至少4小時。
a)加熱攪拌溶於丙酮中之BIBR 1048 MS多晶型I懸浮液至45℃至50℃間約4小時,
b)視情況 i)接種BIBR 1048多晶型II晶體,或ii)接種BIBR 1048多晶型II晶體,且額外添加少量BIBR 1048鹼,
c)隨後冷卻至大約15℃,
d)抽氣過濾BIBR 1048 MS形態II之沈澱晶體,及
e)據此所得之產物於最高為50℃之溫度下真空乾燥至少4小時。
a)將BIBR 1048 MS多晶型I溶於丙酮中,及
b)視情況 i)接種少量BIBR 1048 MS多晶型II,或ii)接種BIBR 1048多晶型II晶體,且額外添加少量BIBR 1048鹼,
c)加熱攪拌據此所得之混合物至40℃至46℃間至少1小時,
d)隨後冷卻至大約17℃至23℃間,且於此溫度下進一步攪拌40至80分鐘,
e)分離出BIBR 1048 MS形態II之沈澱晶體,及
f)據此所得之產物於最高為50℃之溫度下真空乾燥至少4小時。
a)於大約35℃至40℃之溫度下,緩慢加入一當量甲磺酸於乙酸乙酯中之溶液至BIBR 1048鹼於體積比率大約為2:5之90%水性乙醇與乙酸乙酯之混合物中之溶液,
b)視情況加入更多乙酸乙酯以作為產物結晶化起始時之稀釋劑,
c)於大約35℃至40℃之溫度下再攪拌大約30分鐘,
d)隨後於周圍溫度下進一步攪拌30分鐘,
e)吸濾BIBR 1048 Ms半水合物之沈澱物,及
f)在40℃下於循環空氣乾燥櫃中乾燥。
根據本發明之3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽之結晶形態由X射線粉末繞射來進行更詳細研究。所獲得之繞射圖如圖1中所示。
下列表1至3列出該分析中所獲得之資料:
表1:3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽(形態I)之X射線粉末反射及強度(經標準化)
表2:3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽(形態II)之X射線粉末反射及強度(經標準化)
表3:3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽(半水合物)之X射線粉末反射及強度(經標準化)
在上述表1至3中,數值"2Θ[°]"以度數表示繞射角,且數值"dhk1
[]"以表示晶格平面間之特定距離。
在本發明之範疇中,X射線粉末繞射圖係使用配備有位置敏感偵測儀(OED)及作為X射線源之Cu陽極(CuKα1
輻射,λ=1.5406,40 kV,40 mA)之Bruker D8進階繞射儀記錄之。
根據本發明化合物3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽之水合物於標準條件下以半水合物形態出現,在約120℃下水會從該半水合物中逸出,與此形態之熔融具有對應關係。
圖2展示三種形態之熱分析。
52.6公斤3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯鹼(其較佳已預先藉由自乙酸乙酯重結晶而純化)置放於已使之具有惰性之攪拌裝置中,且隨後加入293公斤丙酮。加熱該裝置之內含物至40至46℃間並同時攪拌。形成澄清溶液之後,經透鏡過濾器(lens filter)過濾該裝置之內含物至第二攪拌裝置中且隨後冷卻至30至36℃間。33公斤預先冷卻至0至5℃間之丙酮、7.9公斤99.5%之甲磺酸及另外9公斤用於漂洗之丙酮置放於該第二裝置之懸掛容器中。於26至36℃之溫度下在15至40分鐘內,將懸掛容器之內含物以經量測之量加入至3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯鹼之溶液中。隨後,該混合物於26至33℃之溫度下攪拌40至60分鐘。隨後將其冷卻至17至23℃間且進一步攪拌40至80分鐘。
晶體懸浮物經過濾乾燥器過濾且以總量為270 L之丙酮洗滌。於50℃之最大溫度下在真空下乾燥該產物至少4小時。
產量:54.5-59.4公斤;以3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯鹼計算之理論產量為90-98%。
將4克BIBR 1048 MS多晶型I及35毫升丙酮置放於具有攪拌器及回流冷凝器之玻璃燒瓶中。加熱該懸浮液至45至50℃間並同時攪拌且保持該懸浮液於此溫度下歷經4小時。隨後將其冷卻至15℃且經Bchner漏斗吸濾出晶體,以20 ml丙酮洗滌且於45℃下在真空中乾燥。
注意:該合成亦可藉由以BIBR 1048 MS多晶型II接種來進行。若轉化速度較慢,則除以BIBR 1048 MS多晶型II來接種外,可藉由加入少量BIBR 1048鹼(例如按照工業規模,約50克BIBR 1048鹼對應於約90公斤BIBR 1048 MS多晶型I)而使其加速。
52.6公斤3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯鹼(其較佳已預先藉由自乙酸乙酯重結晶而純化)置放於已使之具有惰性之攪拌裝置中且隨後加入293公斤丙酮。加熱該裝置之內含物至40至46℃間並同時攪拌。形成澄清溶液之後,經透鏡過濾器過濾該裝置之內含物至第二攪拌裝置中。33公斤預先冷卻至0至5℃間之丙酮、7.9公斤99.5%之甲磺酸及另外9公斤用於漂洗之丙酮置放於該第二裝置之懸掛容器中。於40至46℃之溫度下在15至40分鐘內,將懸掛容器之內含物以經量測之量加入至3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯鹼之溶液中且以10克BIBR 1048 MS多晶型II(例如,其根據實例2製備)來接種。隨後,該混合物於40至46℃之溫度下攪拌40至60分鐘。隨後將其冷卻至17至23℃間且進一步攪拌40至80分鐘。晶體懸浮物經過濾乾燥器過濾且以總量為270 L之丙酮洗滌。於50℃之最大溫度下在真空下乾燥該產物至少4小時。
產量:54.5-59.4公斤;以3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯鹼計算之理論產量之90-98%。
注意:該合成亦可不以BIBR 1048 MS多晶型II接種來進行。然而,使用接種之方法較佳。
將30.7公斤BIBR 1048 MS多晶型I置放於已使之具有惰性之攪拌裝置中且隨後加入199公斤丙酮。將裝置之內含物以10克BIBR 1048 MS多晶型II(例如其根據實例2製備)來接種,加熱至40至46℃間並同時攪拌,且將其保持於此溫度下至少1小時。隨後冷卻該混合物至17至23℃間且進一步攪拌40至80分鐘。
晶體懸浮物藉由使用臥式離心機(horizontal centrifuge)分離出且以總量為45公斤之丙酮洗滌。於50℃之最大溫度下,在真空乾燥櫃中乾燥該產物至少4小時。
產量:27.7-30.1公斤;理論產量之90-98%。
注意:該合成亦可不以BIBR 1048 MS多晶型II接種來進行。然而,使用接種之方法較佳。若轉化速度較慢,則除以BIBR 1048 MS多晶型II來接種外,可加入少量BIBR 1048鹼(例如,約50克BIBR 1048鹼對應於約90公斤BIBR 1048 MS多晶型I)。
在35至40℃下,將1.53克(15.93毫莫耳)甲磺酸於15毫升乙酸乙酯中之溶液逐滴加入至10.0克(15.93毫莫耳)3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯鹼(如WO 98/37075中所描述來製備)(於16.5毫升之90%水性乙醇及40毫升乙酸乙酯中之溶液並同時攪拌。數分鐘後,該產物開始出現結晶且以30毫升乙酸乙酯稀釋。在35至40℃下將其另外攪拌30分鐘且於周圍溫度下進一步攪拌30分鐘,隨後吸濾出沈澱物,以大約20毫升乙酸乙酯洗滌且於40℃下在循環空氣乾燥櫃中乾燥。
產量:理論產量之99%。
圖1展示3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯甲磺酸鹽之三種結晶形態之X射線粉末繞射圖。
圖2展示3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯甲磺酸鹽之三種結晶形態之熱分析及熔點量測(DSC)。
(無元件符號說明)
Claims (5)
- 一種呈結晶形態之3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽,其特徵為:熔點Tm.p.. =120±5℃(半水合物),其中該熔點係以DSC測定;以最大峰值評估;加熱速率:10℃/分鐘。
- 一種醫藥組合物,其含有如請求項1之結晶形態3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽半水合物,並視情況併與一或多種惰性載劑及/或稀釋劑。
- 一種如請求項1之結晶形態3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽半水合物之用途,其係用於製備適用於預防術後深靜脈血栓形成及防止中風之醫藥組合物。
- 一種用於製備如請求項2之醫藥組合物之方法,其特徵為:以一非化學方法將如請求項1之結晶形態3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽半水合物併入一或多種惰性載劑及/或稀釋劑中。
- 一種用於製備如請求項1之結晶形態3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪 唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽半水合物之方法,其特徵為:a)於約35℃至40℃之溫度下,將溶於乙酸乙酯中之一個當量甲磺酸溶液緩慢加至溶於90%乙醇水溶液與乙酸乙酯之混合物(體積比約為2:5)中之3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯溶液中,b)於該產物開始出現結晶時,視情況進一步加入乙酸乙酯進行稀釋,c)於約35℃至40℃之溫度下,另外攪拌該混合物約30分鐘,d)隨後於周圍溫度下進一步攪拌30分鐘,e)抽氣過濾3-[(2-{[4-(己氧基羰基胺基-亞胺基-甲基)-苯胺基]-甲基}-1-甲基-1H-苯幷咪唑-5-羰基)-吡啶-2-基-胺基]-丙酸乙酯-甲磺酸鹽半水合物之沈澱物,及f)在約40℃下於循環空氣乾燥櫃中乾燥。
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