TW201504236A - ３－［（３－｛［４－（４－嗎啉基甲基）－１ｈ－吡咯－２－基］亞甲基｝－２－側氧基－２，３－二氫－１ｈ－吲哚－５－基）甲基］－１，３－噻唑啶－２，４－二酮之新穎鹽，其製備方法，及包含其之調配物 - Google Patents
３－［（３－｛［４－（４－嗎啉基甲基）－１ｈ－吡咯－２－基］亞甲基｝－２－側氧基－２，３－二氫－１ｈ－吲哚－５－基）甲基］－１，３－噻唑啶－２，４－二酮之新穎鹽，其製備方法，及包含其之調配物 Download PDFInfo
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
一種新穎的式(II)3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽：
□
Description
本發明係關於一種下式(I)之3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮之新穎鹽：
其製備方法且亦關於包含其之醫藥組合物。
3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮在癌學領域具有極有價值的藥理性質。實際上，已顯示3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮具有抑制癌細胞遷移之能力，此使其尤其可用於治療癌症，及更尤其可用於治療實體轉移性腫瘤。在可治療的癌症中，可尤其提及(但不意味任何限制)結腸癌、乳癌、肝癌、腎癌、腦癌及食道癌、黑素
瘤、骨髓瘤、卵巢癌、非小細胞性肺癌、小細胞性肺癌、前列腺癌及胰臟癌及肉瘤。
3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮及其與醫藥上可接受之酸的加成鹽及更尤其係其鹽酸鹽之製備及治療用途已描述於(例如)歐洲專利說明書EP 2281822中。
鑒於該化合物的醫藥價值，重要的是能以極佳產率及高純度及極佳可再現性得到該活性化合物。已很快發現所使用的鹽酸鹽呈現純化及再結晶及極難以使產率最佳化之問題。此外，已觀察到所得之活性化合物之可再現性及一致性的問題。在許多研究試驗之後，可確定一種結合各種優勢(尤其係關於純化、獲得方法的可再現性及產率的優勢)的新穎鹽，其亦出乎意料地具有極顯著地提高該活性化合物的可溶性之優勢。從物理化學及藥代動力學之角度來看，該新穎鹽因此具有對其用作藥劑而言不可缺少的所有品質。
因此，本發明係關於一種3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮之新穎鹽，更尤其關於式(II)之3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽：
其中符號表示雙鍵具有組態Z或E。
本發明較佳係關於3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲
基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽之Z型異構體。
該新穎鹽具有以下優勢：以極佳產率得到其之簡單且可再現的方法；在水及有機溶劑中的溶解度增加，此使得可預期進行純化階段(例如澄清)，以提高其純度。
本發明亦係關於一種獲得3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽(更尤其指其Z型異構體)之方法，其特徵在於使用根據(例如)描述於專利說明書EP 2281822中之方法獲得之3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮作為起始材料。將該二酮溶解於溶劑/水的二元系統中，然後添加1至2莫耳當量的甲磺酸，且攪拌該混合物，直至甲磺酸鹽沉澱析出。
該溶劑宜為極性溶劑，諸如(例如)乙腈、丙酮、1,4-二噁烷、四氫呋喃、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、二甲亞碸、醇(例如甲醇、乙醇及異丙醇)、水及該等溶劑的水性/有機混合物。較佳地，溶劑/水之比例將係0/100至100/0。
本發明方法之一變型包括使用3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮鹽酸鹽作為起始材料；獲得該化合物之方法已描述於(例如)專利說明書EP 2281822中。將該鹽酸鹽溶解於溶劑/水的二元系統中，且藉由添加鹼將該混合物之pH調節至8。過濾排除所形成的鹽。加熱濾液，且然後添加甲磺酸。然後使溫度緩慢恢復至室溫，並濾出所得到的甲磺酸鹽。所使用之溶劑更尤其為極性溶劑，例如：乙腈、丙酮、1,4-二噁烷、四氫呋喃、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、二
甲亞碸或醇(例如甲醇、乙醇及異丙醇)。較佳地，溶劑/水之比將係70/30，及更尤其係90/10。使用過量(尤其係1至2當量)的甲磺酸。
根據本發明之式(II)化合物甚至在以下變性條件下經過一段時間後仍具有極佳安定性：在25℃/60%相對濕度下、在25℃/90%相對濕度下、在30℃/65%相對濕度下、在40℃/75%相對濕度下，或在50℃下，該式(II)化合物在6個月後仍然沒有變化。
本發明亦係關於包含本發明式(II)化合物(更尤其係其Z型異構體)作為活性成分及一種或多種適宜之惰性及無毒性赋形劑之醫藥組合物。在根據本發明之醫藥組合物中，可尤其提及彼等適合經口、非經腸(靜脈內或皮下)或經鼻投與者、錠劑或糖衣丸劑、粒劑、舌下錠劑、膠囊、糖錠、栓劑、乳劑、軟膏、皮膚用凝膠、注射製劑、可飲用懸浮液及咀嚼膠質。
根據本發明之包含式(II)化合物(更尤其係其Z型異構體)的醫藥形式將用於治療癌症，尤其係實體轉移性腫瘤。在可治療的癌症中，可尤其提及(但不意味任何限制)結腸癌、乳癌、肝癌、腎癌、腦癌及食道癌、黑素瘤、骨髓瘤、卵巢癌、非小細胞性肺癌、小細胞性肺癌、前列腺癌及胰臟癌及肉瘤。
有效劑量可根據疾病的性質及嚴重性、投與途徑及患者年齡及重量而變化。以鹼當量計，劑量係在1mg至1g/天之間變化(一或多次投藥)。
以下實例闡述本發明，但不以任何方式加以限制。
實例1：3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽，Z型異構體
將1.26g 3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮加入100mL燒瓶
中。在添加20ml之乙腈/水(90/10)的溶液後，在70℃下加熱該混合物。製備含有2ml甲磺酸及50ml的乙腈/水(90/10)混合物的溶液。將5ml所得溶液加入反應混合物中，該混合物隨後變澄清。冷卻該混合物至20℃(0.5℃/min，在200rpm下攪拌)。在室溫下隔夜攪拌後，藉由過濾單離該標題產物，並在真空及40℃下乾燥(10mbar)。
熔點：270-274℃(熔融/分解)
該標題產物係藉由其粉末繞射圖分析特徵，其進行方式係取50mg實例1化合物置於兩個Kapton®薄膜之間或置於載體上，並加載於呈具有3-55°的2θ角範圍(0.017°步進及35.5s/步進)的傳輸模式之Panalytical Xpert-Pro MPD繞射儀(銅陽極)中，此使得可判定以下結晶參數：晶胞參數：a=15.0958(5)Å，b=18.4586(6)Å，c=8.8269(2)Å，β=94.074(1)°，γ=90°
空間群：C 1 c 1(9)
晶胞體積：V晶胞=2453.37600Å3
該標題產物亦藉由實例1化合物之單晶X射線繞射分析特徵，其係藉助Rigaku XtaLAB裝置，使用石墨單色Mo-Ka輻射進行。觀察到以下結晶參數：晶胞參數：a=14.995(4)Å，b=18.302(4)Å，c=8.850(2)Å，β=93.528(7)°，γ=90°
空間群：C 1 c 1(9)
晶胞體積：V晶胞=2424.0(9)Å3
在使用粉末所得到的參數中所觀察到之微小差異歸因於用於得到單晶參數之溫度(-100℃)，其引起沿軸線a及b之收縮。
該標題產物亦藉由於其顯示於圖1中之X射線粉末繞射圖分析特徵，其係利用Panalytical Xpert-Pro MPD繞射儀(銅陽極)測定，並以平
面間距d、布拉格(Bragg's)角2θ(以°±0.2表示)及相對強度(以相對於最高強度直線的百分比表示)表示：
X射線粉末繞射圖之布拉格角2θ(以°±0.2表示)特徵：12.86、15.13、15.50、17.70、18.25、18.71、20.11、21.46、21.67、21.89、22.29、22.58、24.57、25.82、26.33。
實例1化合物之特徵亦在於其DSC圖，其中將5-10mg樣品加載於TA InstrumentsDSC Q1000裝置中並冷卻至0℃。然後以10℃/min之速率加熱該樣品至300℃。得到的圖係示於圖2中。
實例2：3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽(Z型異構體)在變性條件下之純度及安定性
實例3：3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽(Z型異構體)之溶解度
在室溫下攪拌含有溶於7ml水中之於實例1中得到的140mg化合物的溶液24小時。使用Acrodisc GHP 0.45μm過濾後，藉由HPLC分析該溶液。實例1化合物之溶解度係14.7mg/ml(或就鹼當量而言係12.1mg/ml)。
在相同條件下，3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮之鹽酸鹽(Z型異構體)之溶解度係4.3mg/ml(或就鹼當量而言係4mg/ml)。
實例4：3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽(Z型異構體)在pH2下(胃pH)之溶解動力學
在室溫及pH2(10mL的0.01N HCl)下，使用μDiss溶解裝置及0.075cm2丸劑(在90bar下壓縮製成)，在100rpm攪拌速率下測定實例1產物之恆定表面積溶解動力學(或固有溶解動力學)2分鐘。
實例1產物以23μg.s-1.cm-2 +/- 11%之動力學溶解。相比較而言，相應鹽酸鹽之溶解動力學係1.6μg.s-1.cm-2。
因此，該甲磺酸鹽的溶解速率比相應鹽酸鹽的溶解速率快約14倍。
實例5：醫藥組合物
1000個錠劑，每個錠劑含有5mg劑量之3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮。
圖1顯示本發明化合物之X射線粉末繞射圖。
圖2顯示實例1化合物之DSC圖。
Claims (14)
- 一種式(II)之3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽，
- 如請求項1之化合物，其係3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽之Z型異構體。
- 如請求項1或2之化合物，其中該化合物之X射線粉末繞射圖具有以下布拉格(Bragg's)角2θ(以°±0.2表示)：12.86、15.13、15.50、17.70、18.25、18.71、20.11、21.46、21.67、21.89、22.29、22.58、24.57、25.82、26.33。
- 如請求項1或2之化合物，其中該化合物具有自粉末繞射圖獲得之以下參數，該粉末繞射係在呈具有3-55°的2θ角範圍(0.017°步進及35.5s/步進)的傳輸模式之Panalytical Xpert-Pro MPD繞射儀(銅陽極)上進行，此使得可判定以下結晶參數：晶胞參數：a=15.0958(5)Å，b=18.4586(6)Å，c=8.8269(2)Å，β=94.074(1)°，γ=90°空間群：C 1 c 1(9)晶胞體積：V晶胞=2453.37600Å3。
- 一種獲得如請求項1之式(II)化合物之方法，其特徵在於：使用3- [(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮作為起始材料，將其溶解於溶劑/水的二元系統中，向其中添加1至2莫耳當量的甲磺酸，攪拌直至甲磺酸鹽沉澱析出並濾出該甲磺酸鹽。
- 一種獲得如請求項1之式(II)化合物之方法，其特徵在於：使用3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮鹽酸鹽作為起始材料，將其溶解於溶劑/水的二元系統中，藉由添加鹼將其pH調節至8，藉由過濾除去所形成的鹽，然後加熱濾液並添加甲磺酸，且攪拌及冷卻該介質，直至甲磺酸鹽沉澱析出並濾出該甲磺酸鹽。
- 一種醫藥組合物，其包含如請求項1至4中任一項之式(II)化合物及一種或多種醫藥上可接受之賦形劑。
- 如請求項7之醫藥組合物，其中該式(II)化合物係3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽之Z型異構體。
- 如請求項7或8之醫藥組合物，其係用於製造用以治療結腸癌、乳癌、肝癌、腎癌、腦癌及食道癌、黑素瘤、骨髓瘤、卵巢癌、非小細胞性肺癌、小細胞性肺癌、前列腺癌及胰臟癌或肉瘤之藥劑。
- 一種如請求項1至4中任一項之式(II)化合物與抗癌劑之締合物，該抗癌劑係選自遺傳毒性劑、有絲分裂毒劑、抗代謝物、蛋白酶體抑制劑及激酶抑制劑。
- 如請求項10之締合物，其中該式(II)化合物係3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽之Z型異構體。
- 一種如請求項10或11之締合物之用途，其係製造用於治療癌症之藥劑。
- 一種如請求項1至4中任一項之式(II)化合物之用途，其係與放射療法結合製造用於治療癌症之藥劑。
- 如請求項13之用途，其中該式(II)化合物係3-[(3-{[4-(4-嗎啉基甲基)-1H-吡咯-2-基]亞甲基}-2-側氧基-2,3-二氫-1H-吲哚-5-基)甲基]-1,3-噻唑啶-2,4-二酮甲磺酸鹽之Z型異構體。
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| TW105105577A TW201630906A (zh) | 2013-07-12 | 2014-07-11 | ３-［（３-｛［４-（４-嗎啉基甲基）-１ｈ-吡咯-２-基］亞甲基｝-２-側氧基-２，３-二氫-１ｈ-吲哚-５-基）甲基］-１，３-噻唑啶-２，４-二酮之新穎鹽，其製備方法，及包含其之調配物 |
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