TWI534147B - 多晶型 - Google Patents

多晶型 Download PDF

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TWI534147B
TWI534147B TW102106563A TW102106563A TWI534147B TW I534147 B TWI534147 B TW I534147B TW 102106563 A TW102106563 A TW 102106563A TW 102106563 A TW102106563 A TW 102106563A TW I534147 B TWI534147 B TW I534147B
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methyl
medicament
quinazolin
piperidin
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席格 彼德
德克 坎默
彼德 柯伯
湯瑪斯 尼寇拉
馬丁 蘭茲
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百靈佳殷格翰國際股份有限公司
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Description

多晶型
本發明係關於DPP-IV抑制劑之多晶型晶體變體、其製備及其於製備藥物中之用途。
酶DPP-IV(已知亦稱為CD26)係絲胺酸蛋白酶，其促進在N-終端具有脯胺酸或丙胺酸基之胺基酸中的二鈦分解。DPP-IV抑制劑藉此影響生物活性肽(包括肽GLP-1)之血漿含量。此類化合物適用於預防或治療與DPP-IV活性提高相關或可藉由降低DPP-IV活性來預防或緩解之疾病或病狀，尤其I型或II型糖尿病、前驅糖尿病或低葡萄糖耐受性。
WO 2004/018468描述具有有價值醫藥性質之DPP-IV抑制劑。其中所揭示抑制劑之一實例為1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤。
在本發明之範疇內，已發現1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤可具有各種多晶型晶體變體，且在WO 2004/018468中所製備之該化合物在環境溫度下係以兩種互變多晶型物之混合物存在。該兩種多晶型物彼此轉換之溫度為25±15℃(參看圖1及圖2)。
可藉由加熱該混合物至大於40℃之溫度獲得之純高溫形態(多晶型物A)於206±3℃熔化。在X射線粉末圖(參看圖3)中，此形態展示以下d值之特性反射：11.49 Å、7.60 Å、7.15 Å、3.86 Å、3.54 Å與3.47 Å(亦參看表1及表2)。
可藉由以下步驟製備無水多晶型物A：(a)在無水乙醇中回流1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤，且視情況過濾該混合物，(b)將該熱溶液或該熱濾液冷卻，直至開始結晶，(c)使用諸如第三丁基甲基醚之溶劑將其稀釋，(d)對該溶劑混合物進行吸濾，及(e)在真空中於45℃下乾燥該多晶型物A。
低溫形態(多晶型物B)係藉由冷卻至小於10℃之溫度而獲得。在X射線粉末圖(參看圖4)中，此形態展示以下d值之特性反射：11.25 Å、9.32 Å、7.46 Å、6.98 Å及3.77 Å(亦參看表3及表4)。
可藉由以下步驟製備無水多晶型物B：(a)在無水乙醇中溶解1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤且使其回流，且視情況過濾該混合物，(b)將該熱溶液或熱濾液冷卻至低於10℃之溫度以進行結晶，(c)使用諸如第三丁基甲基醚之溶劑將其稀釋，(d)對該溶劑混合物進行吸濾，及(e)在真空中於低於10℃之溫度下乾燥該多晶型物。
在X射線粉末圖(參看圖5)中，另一多晶型物(多晶型物C)展示以下d值之特性反射：12.90 Å、11.10 Å、6.44 Å、3.93 Å及3.74 Å(亦 參看表5)。
如下獲得多晶型物C：(a)在甲醇中溶解1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤且使其回流，且視情況在活性炭之存在下過濾之，(b)將該甲醇溶液冷卻至40-60℃之溫度，(c)添加諸如第三丁基甲基醚或二異丙醚之溶劑，(d)首先將所得懸浮液緩慢冷卻至15-25℃，且然後冷卻至0-5℃，(e)對所形成之晶體進行吸濾，且使用第三丁基甲基醚或二異丙醚再次洗滌之，及(f)在真空乾燥器中於70℃之溫度下乾燥如此獲得之晶體。
另一多晶型物(多晶型物D)於150±3℃熔化。若將多晶型物C加熱至30-100℃之溫度或在此溫度下乾燥，則獲得此多晶型物D。
最後，亦存在多晶型物E，其於175±3℃熔化。若將多晶型物D熔化，則形成無水多晶型物E。進一步加熱後，多晶型物E自熔融物結晶出。
如此獲得之多晶型物可以與WO 2004/018468中所述之兩種多晶型物A及B之混合物相同之方式用於製備醫藥組合物，其適於治療患有I型及II型糖尿病、前驅糖尿病或葡萄糖耐受性降低、患有類風濕性關節炎、肥胖或降鈣素引發之骨質疏鬆症之患者，以及實施同種異體移植之患者。除一或多種惰性載劑外，此等藥物含有至少0.1%至0.5%，較佳至少0.5%至1.5%且尤其較佳至少1%至3%的該等多晶型物A、B或C中之一者。
圖1：無水形態A/B之熱分析
圖2：互變相轉變之循環DSC圖
圖3：無水形態A之X射線粉末圖
圖4：無水形態B之X射線粉末圖
圖5：多晶型物C之X射線粉末圖
圖6：形態C之熱分析
以下實例意欲更詳細說明本發明。
實例1 多晶型物A之結晶
使用5倍之無水乙醇回流粗製1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤，且經由活性炭將熱溶液過濾乾淨。在濾液冷卻至20℃且開始結晶之後，以第三丁基甲基醚將該溶液稀釋為兩倍體積。然後該懸浮液經冷卻至2℃、攪拌2小時、對其進行吸濾且將其在真空乾燥器中於45℃下乾燥。
多晶型物A於206±3℃熔化。在DSC圖中，在約25℃處可看到另一輕微吸熱信號。此為在兩個吸熱晶體變體A與B之間完全可逆之固相轉變。在此轉換溫度以上該形態A為熱力學穩定變體，而形態B在此轉換溫度以下為熱力學穩定變體。
圖2展示一循環DSC圖，其中進行總共三次自-40℃至120℃之相轉變及相反之轉變。加熱期間，相轉變係作為吸熱信號而被觀測到，且相應地，冷卻期間其係作為放熱信號而被觀測到。在第一加熱週期期間，該相轉變亦可作為吸熱雙信號或作為極寬之信號而被觀測到，而在所有其他週期中，該信號作為極尖之吸熱或放熱信號而發生，此係視發生加熱抑或冷卻而定。
實例2 多晶型物B之結晶
多晶型物B係藉由將來自實例1之形態A冷卻至小於10℃之溫度而獲得。
實例3 多晶型物C之結晶
使用157 l甲醇(與1.3 kg活性炭組合)回流粗製1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤(26 kg)，且在攪拌30分鐘之後，過濾該混合物且使用26 l甲醇漂洗之。自濾液蒸餾出122 l甲醇，然後將殘餘物冷卻至45-55℃。經30分鐘添加52 l第三丁基甲基醚至該殘餘物中。然後在45-55℃下攪拌該混合物另外60分鐘。結晶發生於此時間內。經30分鐘添加另外78 l第三丁基甲基醚至該懸浮液中，且然後在45-55℃下將其再次攪拌另外60分鐘。將其稀釋為四倍體積。緩慢冷卻該懸浮液至15-25℃，且在此溫度下將其攪拌隔夜。在該懸浮液冷卻至0-5℃之後，對該等晶體進行吸濾，使用2批第三丁基甲基醚洗滌，且在真空乾燥器中於70℃下乾燥之。
實例4 多晶型物D之結晶
若將來自實例3之多晶型物C加熱至30-100℃之溫度或在此溫度下乾燥，則獲得多晶型物D。
實例5 多晶型物E之結晶
若將多晶型物D熔化，則獲得無水多晶型物E。進一步加熱後，多晶型物E自熔融物結晶出。
在形態C之DSC圖中，可觀測到完整範圍之信號。最強信號係在約206℃處無水形態A之熔點，該形態係於DSC實驗中產生。在該熔點之前，可觀測到多個其他吸熱及放熱信號。因此，舉例而言，在30℃與100℃之間可看到極寬且弱之吸熱信號，其與熱重量法(TR)中之主要失重相關。TG/IR偶合實驗提供在此溫度範圍內僅水分自樣本逸出之資訊。
對於維持於100℃之溫度下的樣本所測得之X射線粉末圖展示來自起始物質之不同X射線反射，說明形態C為具有半水合物或單水合物之區域中某處之化學計量的水合物相。該溫度受控之樣本為另一無水變體D，其僅在無水條件下穩定。D形態於約150℃熔化。另一無水晶體變體E自該熔融物結晶而得，且當加熱時於約175℃進一步熔化。最後，形態A自形態E之熔融物結晶而得。形態E亦為亞穩晶體變體，其僅存在於高溫下。

Claims (20)

  1. 一種藥物，其含有化合物1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤之無水多晶型物A，其特徵在於其於206±3℃熔化，且其進一步特徵在於在X射線粉末圖中，其在以下d值處尤其具有特性反射：11.59Å、7.60Å、7.15Å、3.86Å、3.54Å及3.47Å，其中除一或多種惰性載劑外，該藥物尚含有0.1%至0.5%，或0.5%至1.5%，或1%至3%的無水多晶型物A。
  2. 一種藥物，其含有化合物1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤之無水多晶型物B，其特徵在於，在10-40℃之溫度下，其可逆地轉換為如請求項1之多晶型物A，且其進一步特徵在於，在X射線粉末圖中，其在以下d值處尤其具有特性反射：11.25Å、9.32Å、7.46Å、6.98Å及3.77Å，其中除一或多種惰性載劑外，該藥物尚含有0.1%至0.5%，或0.5%至1.5%，或1%至3%的無水多晶型物B。
  3. 一種藥物，其含有化合物1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤之多晶型物C，其特徵在於，其在30-100℃之溫度下失水，且在DSC圖中，其在約150℃及175℃處展現進一步之熱效應，且其進一步特徵在於，在X射線粉末圖中，其在以下d值處尤其具有特性反射：12.90Å、11.10Å、6.44Å、3.93Å及3.74Å，其中除一或多種惰性載劑外，該藥物尚含有0.1%至0.5%，或0.5%至1.5%，或1%至3%的無水多晶型物C。
  4. 如請求項3之藥物，其中該多晶型物C係由以下步驟所製得：(a)在甲醇中回流1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁 炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤，(b)將該甲醇溶液冷卻至40-60℃之溫度，(c)添加諸如第三丁基甲基醚之溶劑，(d)首先將所得懸浮液冷卻至15-25℃，且然後冷卻至0-5℃，(e)對該等晶體進行吸濾，及(f)在70℃之溫度下於真空中乾燥。
  5. 如請求項4之藥物，其特徵在於，在步驟(a)之後過濾該熱溶液。
  6. 如請求項1之藥物，其中無水多晶型物A係由以下步驟所製得：(a)在無水乙醇中回流1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤，且視情況過濾該混合物，(b)將該熱溶液或該熱濾液冷卻，直至開始結晶，(c)使用諸如第三丁基甲基醚之溶劑將其稀釋，(d)對該溶劑混合物進行吸濾，及(e)在真空中於45℃下乾燥該多晶型物A；或藉由加熱如請求項2所定義之多晶型物B或一種多晶型物A及B之混合物至大於40℃之溫度。
  7. 如請求項2之藥物，其中無水多晶型物B係由以下步驟所製得：(a)在無水乙醇中溶解1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤且使其回流，且視情況過濾該混合物，(b)將該熱溶液或熱濾液冷卻至低於10℃之溫度以進行結晶，(c)使用諸如第三丁基甲基醚之溶劑將其稀釋，(d)對該溶劑混合物進行吸濾，及(e)在真空中於低於10℃之溫度下乾燥該多晶型物；或藉由冷卻如請求項1所定義之多晶型物A或一種多晶型物 A及B之混合物至小於10℃之溫度。
  8. 一種如請求項1至7中任一項所定義之化合物1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤之多晶型物A、B或C中之一者於製備如請求項1至7中任一項之藥物的用途，該藥物係用於治療患有II型糖尿病、前驅糖尿病或葡萄糖耐受性降低、類風濕性關節炎或肥胖之患者，或實施同種異體移植之患者。
  9. 一種藥物，其含有化合物1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤，其特徵在於，除一或多種惰性載劑及/或稀釋劑外，該藥物尚含有1%至3%之如請求項1至7中任一項多晶型物A、B或C中之一者。
  10. 如請求項1或6之藥物，其中該多晶型物A具有大體上如圖3所示之X射線粉末圖。
  11. 如請求項2或7之藥物，其中該多晶型物B具有大體上如圖4所示之X射線粉末圖。
  12. 如請求項1或6之藥物，其中該多晶型物A之X射線粉末圖大體上沒有如請求項2之多晶型物B之特性反射。
  13. 如請求項2或7之藥物，其中該多晶型物B之X射線粉末圖大體上沒有如請求項1之多晶型物A之特性反射。
  14. 如請求項1或6之藥物，其中多晶型物A之特徵在於其晶格量度：
  15. 如請求項2或7之藥物，其中多晶型物B之特徵在於其晶格量度：
  16. 如請求項1或2之藥物，其中除一或多種惰性載劑外，該藥物尚含有0.1%至0.5%多晶型物A或B。
  17. 如請求項1或2之藥物，其中除一或多種惰性載劑外，該藥物尚含有0.5%至1.5%多晶型物A或B。
  18. 如請求項1或2之藥物，其中除一或多種惰性載劑外，該藥物尚含有1%至3%多晶型物A或B。
  19. 一種製備藥物之方法，其特徵在於使用如請求項1、6、10、12或14所定義之多晶型物A。
  20. 一種製備藥物之方法，其特徵在於使用如請求項2、7、11、13或15所定義之多晶型物B。
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