TWI579280B - N-[5-(3,5-二氟-苄基)-1h-吲唑-3-基]-4-(4-甲基-哌-1-基)-2-(四氫-哌喃-4-基胺基)-苯甲醯胺之製備方法 - Google Patents
N-[5-(3,5-二氟-苄基)-1h-吲唑-3-基]-4-(4-甲基-哌-1-基)-2-(四氫-哌喃-4-基胺基)-苯甲醯胺之製備方法 Download PDFInfo
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Description
本發明係有關於一種N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌-1-基)-2-(四氫-哌喃-4-基胺基)-苯甲醯胺之製備方法。此種化合物之新穎固體形式、其用於治療由蛋白質激酶活性失調所引發的疾病之用途,及含有該等化合物之醫藥組成物也屬本發明之目的。
蛋白質激酶(PK)的功能異常為多種疾病的特徵。有大量致癌基因及原致癌基因乃涉及編碼PK的人類癌症。PK的活性增強也與許多非惡性病有關連,諸如良性攝護腺肥大、家族性腺瘤病、息肉病、神經纖維瘤、乾癬、與動脈粥狀硬化相聯結的血管平滑肌細胞增殖、肺纖維化、關節炎、腎小球腎炎、及術後血管狹窄及血管再度狹窄。
PK也與發炎病況及病毒與寄生蟲的繁殖有關連。PK也在神經退化病症的病因及發展上扮演主要角色。
有關PK功能異常或失調的一般參考文獻請見Current Opinion in Chemical Biology 1999,3,459-465;Nature Rev.Drug Discov.2002;及Carcinogenesis 2008,29,1087-1091。
PK的一個子集乃具有內因性蛋白質-酪胺酸激酶活性(RPTK)的一組膜受體。當結合生長因子時,RPTK變成活化且磷酸化其本身及一串列的胞質內的酶基質。透過此項機轉,RPTK可轉導作為增殖、分化、或其他生物變化的胞內傳訊。於人體腫瘤經常觀察得RPTK的結構異常、過度表現及活化,提示信號轉導的組成性發動結果導致之細胞增殖,可造成惡性轉形。未分化淋巴瘤激酶(ALK)乃屬於胰島素受體RTK亞族的酪胺酸激酶受體;ALK基因係位在染色體2,主要係表現在神經元細胞,特別於發育期間。ALK基因係涉及於未分化大細胞淋巴瘤(ALCL)的一大子集中在染色體5上的核磷酸蛋白(NPM)基因的平衡染色體轉位。於ALK+ALCL中,由於轉位結果,NPM泛在啟動子驅動融合蛋白的異位表現,其中該NPM部分二聚合,及ALK激酶功能部位進行自行磷酸化且變成組成性活化態。
文獻中許多資料已經證實NPM-ALK融合蛋白具有強力致癌潛力,其異位表現造成細胞的轉形。此外,人類NPM-ALK於小鼠T細胞淋巴細胞的組成性表現係足夠以短的潛伏週期在基因轉殖動物發展成淋巴瘤。
ALCL係為以CD30抗原(Ki-1)的表面表現為特徵定義的疾病,且為成人非何杰金氏淋巴瘤的2%及兒童非何杰金氏淋巴瘤的13%,主要影響年輕男性病人。ALK-ALCL係為全部ALCL的70%,且屬具有系統性病徵的攻擊性疾病,且經常影響到節外(骨髓、皮膚、骨骼、軟組織)。
發現約15-20% ALK表現性ALCL具有不同的染色體轉位,涉及ALK的胞質部分,具有不同的N端部,全部皆導致ALK激酶功能部位的組成性活化。
此外,發現從外胚層來源的實體腫瘤,例如黑素瘤、乳癌,以及神經母細胞瘤、神經膠細胞瘤、尤英氏肉瘤、視網膜母細胞瘤所確立的細胞系會表現ALK受體。
總結而言,干擾ALK傳訊可能表示於ALCL及可能其他適應症阻斷腫瘤細胞增殖的特定有效方式。
國際專利申請案WO2009/013126(Nerviano Medical Sciences Srl.)係描述及主張一種具有式(I)的N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌-1-基)-2-(四氫-哌喃-4-基胺基)-苯甲醯胺的自由態鹼形式,
及報告該化合物具有作為激酶抑制劑,更特別為ALK抑制劑之活性,因而可用於多種癌症及細胞增殖病症之治療。
此種化合物之製備係說明於前述專利申請案之實施例2(步驟i’)及實施例7。
如前述專利申請案之實施例2(步驟i’)描述的式(I)化合物之已知製備,大致上包含,添加5-(3,5-二氟-苄基)-1H-吲唑-3-基胺之溶液至4-(4-甲基-哌-1-基)-2-[(四氫-哌喃-4-基)-(2,2,2-三氟-乙醯基)-胺基]-苯甲醯氯,及然後使用有機鹼於高溫將所得化合物脫去保護而於藉管柱層析術及結晶純化後,獲得期望的式(I)醯胺。
如前述專利申請案之實施例7描述的式(I)化合物之已知
製備,大致上包含,2-胺基-N-[5-(3,5-二氟-苄基]-1H-吲唑-3-基)-4-(4-甲基-哌-1-基)-苯甲醯胺與四氫-哌喃-4-酮於三氟乙酸及三乙醯氧基硼氫化四甲銨存在下反應而於藉管柱層析術純化後,獲得期望的式(I)醯胺。
就此方面而言,現意外地發現經由一種方法可優異地製備式(I)化合物,該方法許可以工業上優異的且高度可再現性之方式,以高純度,具有適合投予人體的特性且降低成本獲得期望的產物。此外,該新穎方法更適合應用於大規模製造。最後,該化合物係以所定義的固體形式獲得。
因此,本發明之第一目的為如前文定義之式(I)化合物之製備方法,該方法係包含:a)以化學計量方式添加式(II)之醯基氯化物:
至式(III)之吲唑-3-基胺:
當式(III)之吲唑-3-基胺已經完全反應時阻斷該添加;b)於溫和鹼性條件下將所得式(IV)化合物脫去保護:
以獲得期望的式(I)化合物,其係呈非晶型形式分離;然後如下獲得期望的結晶型:c1)於晶種存在下,使用乙醇與水之混合物處理所得式(I)非晶型化合物而獲得呈結晶型1的期望的式(I)化合物,或c2)使用乙醇與水之混合物處理所得式(I)非晶型化合物而獲得呈結晶型2的期望的式(I)化合物,及選擇性地d)將步驟b)、步驟c1)、或步驟c2)所得化合物轉換成醫藥上可接受之鹽。
該新穎程序許可未經層析純化而獲得具有高純度的式(I)化合物及控制該固體形式。
由於添加順序及式(II)醯基衍生物以化學計算量添加至式(III)之吲唑基胺衍生物,接著為使用適當溶劑混合物之分離後續處理,於步驟a)所得式(IV)經保護的中間產物之純度係比先前方法更純。實際上,本新穎程序顯著減少雜質的生成,諸如非期望的位置異構物及雙重加成產物的形成,如此避免需要使用不適用於大規模製造的層析術管柱純化如此所得的式(IV)產物,原因在於此種程序相聯結的的時間及成本。
又復,於步驟b)中,將式(IV)產物變換成式(I)終產物,
包含使用無機鹼的低溫水性水解的溫和脫去保護條件,可防止因使用有機鹼於甲醇的高溫處理所導致於先前程序觀察得副產物的生成。
最後,於步驟c1)或步驟c2)中,首先以非晶型形式獲得的式(I)化合物,然後藉播晶種或以適當溶劑處理而分別地轉換成結晶型1或結晶型2。先前方法中於此點,化合物的純度及藉不溶解化及/或藉層析純化之分離程序使得妨礙其轉換成結晶型1或結晶型2。
依據步驟a),式(II)化合物係懸浮於溶劑,諸如THF或DCM,較佳地係懸浮於無水DCM,及然後懸浮液徐緩地及漸進地添加至式(III)化合物於吡啶之溶液。
較佳地,該反應係於-20℃至-40℃間之溫度進行,較佳係於-30℃至-40℃間之溫度操作。
反應結束時,蒸發去除溶劑,殘餘物使用溶劑例如DCM、MTBE、MeOH以1/1/1至30/30/1間之預先界定的比例處理,較佳地該處理係以DCM/MTBE/MeOH之比8/8/1至30/30/1間進行而獲得純質式(IV)化合物之沈澱。
依據步驟b),式(IV)化合物之脫去保護可藉溫和鹼性條件進行,諸如水性或水性/甲醇性鹼性碳酸鹽或氫氧化物,較佳地使用碳酸鉀於水/甲醇之溶液。
較佳反應係於20℃至5℃之溫度進行,較佳於約10℃操作。然後期望的式(I)化合物藉於5℃至25℃,較佳5℃至10℃之溫度滴入水中呈非晶型分離。
根據步驟c1),非晶型式(I)化合物首先使用乙醇加熱至回流及蒸餾去除部分溶劑處理,然後使用水及結晶型I種晶於10℃至30℃之溫度,較佳於20℃至25℃之溫度處理。所得式(I)化合物為結晶型1。
根據步驟c2),根據步驟b)所得產物依序使用乙醇於10℃至30℃之溫度,較佳於20℃至25℃之溫度處理,及然後使用水於10℃至30℃之溫度,較佳於20℃至25℃之溫度處理。所得式(I)化合物為結晶型2。
於本發明方法中,採用的起始化合物及反應劑為已知化合物或可使用眾所周知之方法從已知化合物獲得。特別,如前文定義之式(II)及(III)化合物之製備係描述於前文引用之專利申請案。
非固體形式、非晶型或晶體係描述於前文引用之專利申請案的實施例2(步驟i’)及實施例7。發明人研究發現如實施例2(步驟i’)製備之式(I)化合物為晶體溶劑合物,於後文中為求方便稱作為結晶型3;如實施例7所述製備之式(I)化合物為非晶型,後文稱作為非晶型。
此外,發明人發現如本案實施例1步驟b)製備的式(I)化合物為非晶型;如本案實施例1步驟c1)製備之式(I)化合物為晶體,後文稱作為結晶型1;最後,如本案實施例1步驟c2)所述製備之式(I)化合物為晶體,後文稱作為結晶型2。
然後,於進一步態樣中,本發明係有關於藉前述方法製備之式(I)化合物的新穎安定結晶型,亦即結晶型1及結晶型2。
結晶型3為與乙酸乙酯及及正己烷形成的溶劑合物,由於無法接受量之溶劑存在而不適合投予人類;非晶型為吸濕性固體,較不適合發展成口服配方。
水分吸收乃醫藥散劑的顯著擔憂。水分例如對藥物、賦形劑、及配方的物理性質、化學性質及製造性質產生顯著影響。水分也是考慮有關包裝、儲存、處理及儲存壽命相關決定的關鍵性因素,成功的發展需要對吸濕性質有深度瞭解。
例如,當相對濕度超過關鍵性濃度及固體中的水分含量快速增高時,觀察得從非晶型轉成水合物形式。如此,不僅對藥物本身的物理性質及藥物性質產生影響,同時也對生物製藥方面產生影響。此外,眾所周知水合物形式通常比較同系列的無水形式較為不可溶性,也對活性藥物本身的溶解速率性質及其通過胃腸道的吸收數據產生潛在有害影響。同理,從非晶型轉換成結晶型可在濕度存在之下觀察得,就物理安定性而言有潛在缺點。非晶型活性藥物物質若潮解時,例如可能從大氣中吸收相當大量水分直到其溶解,同時其化學安定性可能受影響,原因在於非晶型結構為熱力學活性,較為容易進行化學降解及與其它化學物質產生化學交互作用。如此,配方及活性成分的性能及功效可能被顯著改變。
如此,需要有適合用於人類投藥的式(I)化合物之固體治療劑型,該劑型不含無法接受量的殘餘溶劑,具有低吸濕性,以及具有良好而可再現性的生物製藥性質用而容許更安全及有效的口服投藥。
發明人藉由提供適合人類投藥且具有改良物理化學性質的新穎式(I)化合物之結晶型而解決前述技術問題。實際上,新穎結晶型不會保有溶劑,比較非晶型更不具有吸濕性,此外,具有已知劑型所具有的全部其他優點,特別為治療優點。
將參考後文描述之附圖舉例說明本發明。
圖1顯示結晶型3之X光繞射圖。2-θ角(度)係報告於x軸,密度(CPS)係報告於y軸。
圖2顯示非晶型之X光繞射圖。2-θ角(度)係報告於x軸,密度(CPS)
係報告於y軸。
圖3顯示結晶型1之X光繞射圖。2-θ角(度)係報告於x軸,密度(CPS)係報告於y軸。
圖4顯示結晶型2之X光繞射圖。2-θ角(度)係報告於x軸,密度(CPS)係報告於y軸。
圖5顯示非晶型、結晶型1及結晶型2之DSC熱分析圖。熱分析圖報告溫度(℃)及時間(分鐘)於x軸,熱流(毫瓦)報告於y軸。
圖6顯示非晶型、結晶型1及結晶型2之DVS恆溫圖。相對濕度(RH,%)值報告於x軸,質量的改變(%)報告於y軸。曲線係與於25℃ 0% RH至90% RH間的吸附步驟有關。
圖7顯示結晶型1之1H NMR光譜。化學移位(ppm)係報告於x軸。
圖8顯示結晶型3之1H NMR光譜。化學移位(ppm)係報告於x軸。
結晶型3係以X光繞射圖特徵化,該圖實質上係與圖1報告圖相同,於表1描述的2-θ值(度)具有顯著峰強度。於不含任何額外物質(其他結晶型,賦形劑)之樣本中,可約與表2所述2-θ值(度)觀察得繞射峰。
非晶型係以X光繞射圖特徵化,該圖實質上與圖2報告圖相同。
結晶型1係以X光繞射圖特徵化,該圖實質上係與圖3報告圖相同,於表1描述的2-θ值(度)具有顯著峰強度。於不含任何額外物質(其他結晶型,賦形劑)之樣本中,可約與表3所述2-θ值(度)觀察得繞射峰。
結晶型2係以X光繞射圖特徵化,該圖實質上係與圖4報
告圖相同,於表1描述的2-θ值(度)具有顯著峰強度。於不含任何額外物質(其他結晶型,賦形劑)之樣本中,可約與表4所述2-θ值(度)觀察得繞射峰。
至於進一步態樣,發現非晶型3為式(I)化合物的高熔結晶型,顯示與乙酸乙酯及正己烷的溶劑合作用(PXRD數據:圖1;-其他有關PXRD之關係述於表1)。
至於又一態樣,發現非晶型顯示於25℃/90%RH水吸收量2.5%,於25℃恆溫藉降低相對濕度可逆轉(PXRD數據:圖2;DSC數據:圖5;DSC數據:圖6;其他有關PXRD、DSC及DVS數據之關係係描述於表1)。
至於又一態樣,發現結晶型1為式(I)化合物的高熔結晶型,顯示於25℃/90% RH的水吸收量為0.6%,此點低於非晶型且可藉於25℃恆溫降低RH逆轉。(PXRD數據:圖3;DSC數據:圖5;DSC數據:圖6;其他有關PXRD、DSC及DVS數據之關係係描述於表1)。
至於又一態樣,發現結晶型2為式(I)化合物的高熔結晶型,顯示於25℃/90% RH的水吸收量為0.2%,此點低於非晶型且可藉於25℃恆溫降低RH逆轉。(PXRD數據:圖4;DSC數據:圖5;DSC數據:圖6;其他有關PXRD、DSC及DVS數據之關係係描述於表1)。
表1-式(I)化合物之結晶型3、非晶型、結晶型1及結晶型2之固態性質描述及圖/表關係。
本發明之又一目的係提供一種醫藥組成物,包含治療上有效量之如前文定義之結晶型1或結晶型2或其醫藥上可接受之鹽作為活性成分及醫藥上可接受之賦形劑、載劑或稀釋劑。
如前文定義之結晶型1或結晶型2或其醫藥上可接受之鹽容易經口服吸收,因此較佳係經口服投藥。無庸殆言,本發明化合物可藉任何投藥途徑例如藉腸道外、局部、直腸及鼻途徑投予。
本發明組成物可呈適合經口服使用的劑型。此等劑型之實例為:錠劑、硬或軟膠囊劑、水性或油性懸浮液劑、乳液劑、可分散散劑或粒劑。本發明之組成物也可呈適合局部使用的劑型。此等劑型之實例有:乳膏劑、軟膏劑、凝膠劑、或水性或油性溶液劑或懸浮液劑。本發明之組成物也可呈適合藉吸入投藥的劑型,例如細分粉末或液體噴霧劑。本發明之組成物也可呈適合藉吹入投藥的劑型,例如細分粉末。本發明組成物也可呈適合腸道外投藥(例如供靜脈、皮下、或肌肉使用的無菌水性或油性溶液劑)或呈供直腸投藥之栓劑。
本發明之組成物可使用技藝界已知之習知醫藥賦形劑獲得。
如此口服投藥用之組成物可含有一或多種添加劑例如
著色劑、甜味劑、矯味劑及保藏劑。
舉例言之,固體口服劑型連同活性成分可含有稀釋劑例如乳糖、葡萄糖、蔗糖、果糖、甘露糖醇、纖維素、玉米澱粉或馬鈴薯澱粉;潤滑劑例如二氧化矽、滑石、硬脂酸、硬脂酸鎂或硬脂酸鈣、及/或聚乙二醇類;滑動劑例如膠體二氧化矽;黏結劑例如澱粉類、阿拉伯膠、明膠、甲基纖維素、羧基甲基纖維素或聚乙烯基吡咯啶酮;崩散劑例如澱粉、褐藻酸、褐藻酸酯類或澱粉乙醇酸鈉;發泡混合物;染料;甜味劑;濕潤劑;諸如卵磷脂、聚山梨酸酯、月桂基硫酸酯;及通常用於醫藥配方的無毒及藥理上無活性物質。此等醫藥製劑可呈已知方式例如利用混合、造粒、打錠、包糖衣或包膜衣過程製造。
口服投藥用之液體懸浮液劑例如可呈糖漿劑、乳液劑及懸浮液劑。
舉例言之,糖漿劑可含有蔗糖或蔗糖與甘油及/或甘露糖醇及山梨糖醇作為載劑。
懸浮液劑及乳液劑可含有天然樹膠、瓊脂、褐藻酸鈉、果膠、甲基纖維素、羧基甲基纖維素或聚乙烯醇作為載劑之實例。
肌肉注射用之懸浮液劑或溶液劑連同活性化合物可含有醫藥上可接受之載劑,例如無菌水、橄欖油、油酸乙酯、二醇類例如丙二醇及若有所需適量鹽酸利度卡因(lidocaine)。
靜脈注射或靜脈輸注用之溶液劑可含有無菌水作為載劑,或較佳可呈無菌水性等張食鹽水溶液或含有丙二醇作為載劑。
栓劑連同活性化合物可含有醫藥上可接受之載劑,例如可可脂、聚乙二醇、聚氧伸乙基聚山梨糖脂肪酸酯界面活性劑或卵磷脂。
本發明之又一目的係提供如前文定義之結晶型1或結晶型2或其醫藥上可接受之鹽用作為藥物。
本發明之又一目的係提供如前文定義之結晶型1或結晶型2或其醫藥上可接受之鹽,以單獨或聯合其他治療劑或放射性治療用於可藉ALK抑制治療的疾病狀態,諸如癌症及細胞增殖病症。
本發明之又一目的係提供一種治療由ALK抑制之需要的哺乳動物包括人類之方法,包含對該哺乳動物投予治療上有效量之如前文定義之結晶型1或結晶型2或其醫藥上可接受之鹽。
最後,本發明之另一目的係提供如前文定義之結晶型1或結晶型2或其醫藥上可接受之鹽,或單獨或聯合其他治療劑或放射性治療用於製造治療可藉ALK抑制治療的疾病狀態,諸如癌症及細胞增殖病症之藥物之用途。
「可治療的疾病狀態」一詞表示依據本發明之治療提供疾病狀態的緩解或至少接受治療的哺乳類之狀況及生活品質的改善。
此等疾病狀態特別為不同癌症之實例可包括特定型別的癌症包括癌瘤、鱗狀細胞癌、骨髓系或淋巴系之造血腫瘤、間葉來源之腫瘤、中樞神經系統及周邊神經系統之腫瘤、黑素瘤、精細胞瘤、睪丸癌、骨肉瘤、著色性乾皮病、角膜眥疣、甲狀腺濾泡癌、及卡波西氏肉瘤。
其他較佳疾病狀態為特定型別的癌症,諸如但非限於乳癌、肺癌、大腸直腸癌、攝護腺癌、卵巢癌、子宮內膜癌、胃癌、透明細胞腎細胞癌、葡萄膜黑素瘤、多發性骨髓瘤、橫紋肌肉瘤、歐文氏肉瘤、卡波西氏肉瘤、及水母細胞瘤。其他較佳疾病狀態為ALK+退行性大細胞淋巴瘤(ALCL)及可能其中ALK活性扮演某種角色的其他適
應症,例如神經母細胞瘤、橫紋肌肉瘤、神經膠母細胞瘤、發炎性肌纖維母細胞瘤、及其他種類的黑素瘤、乳癌、歐文氏肉瘤、視網膜母細胞瘤、及非小細胞肺癌(NSCLC)。
更佳疾病狀態為細胞增殖病症,諸如但非限於良性攝護腺肥大、家族性腺腫息肉、神經纖維瘤病、乾癬、血管平滑肌增殖相連結的動脈粥狀硬化、肺臟纖維化、關節炎、腎小球腎炎及手術後血管狹窄及再狹窄。
「其他治療劑」一詞包括但非僅限於抗激素劑,諸如抗雌激素劑、抗雄激素劑、及芳香酶抑制劑、拓樸異構酶I抑制劑、拓樸異構酶II抑制劑、靶定於微細管之藥劑、以鉑為主之藥劑、烷化劑、DNA損壞劑或嵌合劑、抗腫瘤抗代謝劑、其他激酶抑制劑、其他抗血管新生劑、驅動蛋白抑制劑、治療性單株抗體、mTOR抑制劑、組織蛋白腖去乙醯化酶抑制劑、法尼基轉移酶抑制劑、及低氧反應抑制劑。
式(I)化合物、如前文定義之結晶型1或結晶型2或其醫藥上可接受之鹽的有效劑量可隨疾病、病症嚴重程度及欲接受治療的病人狀況而改變。因此醫生須針對各個病人設定最佳劑量。總而言之,有效劑量為每劑約10毫克至約1克(以自由態鹼計算)每日1至3次。
下列實施例舉例說明本發明。
溫度係以攝氏度數(℃)測量。
除非另行指示,否則反應及實驗係於室溫進行。
RT:室溫
RH:相對濕度
PXRD:粉末X光繞射
DSC:差示掃描量熱術
DVS:動態氣相吸附
TGA:熱重分析
ACN(乙腈)
EtOAc(乙酸乙酯)
DCM(二氯甲烷)
DMA(N,N-二甲基乙醯胺)
DMF(N,N-二甲基甲醯胺)
DMSO(二甲亞碸)
MTBE(甲基第三丁基醚)
THF(四氫呋喃)
TFA(三氟乙酸)
如下反應圖1顯示式(I)化合物之結晶型1及結晶型2之製備。
反應式1
於4-(4-甲基哌-1-基)-2-[四氫-2H-哌喃-4-基(三氟乙醯基)-胺基]-苯甲酸三氟乙酸酯(3.7千克,7莫耳)於無水DCM(36升)及N,N-二甲基甲醯胺(14毫升)之懸浮液內添加草醯氯(1.78升,21莫耳)。混合物攪拌約1.5小時及氣化成油性殘餘物;然後添加無水DCM及蒸發兩次。
式(II)醯基氯懸浮於無水DCM,懸浮液於-40/-30℃緩慢及漸進地添加至5-(3,5-二氟-苄基)-1H-吲唑-3-基胺(1.6千克,6.1莫耳)於無水吡啶(16升)之溶液。當5-(3,5-二氟-苄基)-1H-吲唑-3-基胺完全反應時停止添加。約1小時後蒸發去除溶劑及循序添加DCM(55升)、甲醇(6.5升)、及MTBE(55升)。已純化且經保護之式(IV)化合物經過濾,以混合物10/10/1 DCM/MTBE/MeOH洗滌及於減壓下乾燥(3.8千克)。
如此所得粗產物N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌-1-基)-2-[(四氫-哌喃-4-基)-2,2,2-三氟-乙醯基)-胺基]-苯甲醯胺,具有HPLC純度大於95%,溶解於甲醇及然後於10℃添
加碳酸鉀於水/甲醇之溶液。溶液經過濾及滴入水中;沈澱物非晶型N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌-1-基)-2-(四氫-哌喃-4-基胺基)-苯甲醯胺經過濾,以水洗滌及於減壓下乾燥(2.88千克)。
5.5克乾燥無水N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌-1-基)-2-(四氫-哌喃-4-基胺基)-苯甲醯胺懸浮於130毫升乙醇及加熱至回流歷10分鐘;蒸餾去除約70毫升乙醇隨後冷卻至室溫。添加110毫升水,懸浮液以55毫克結晶型1播種晶。懸浮液攪拌約72小時取樣,藉DSC監視轉換成結晶型1。然後懸浮液經過濾及乾燥獲得4.3克期望的結晶型1。
乾燥非晶型N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌-1-基)-2-(四氫-哌喃-4-基胺基)-苯甲醯胺(2.88千克)於約10倍體積乙醇調成料漿,許可其轉換成期望的結晶型2;然後添加20倍體積水及懸浮液經過濾。產物最終於減壓下乾燥,獲得約2.6千克N-[5-(3,5-二氟-苄基)-1H-吲唑-3-基]-4-(4-甲基-哌-1-基)-2-(四氫-哌喃-4-基胺基)-苯甲醯胺(4.6莫耳)呈期望的結晶型2。
式(I)化合物之結晶型3、非晶型、結晶型1及結晶型2係藉粉末X光繞射(PXRD)決定特徵,使用Thermo/ARL XTRA裝置進行,於室溫使用2度至40度2-θ CuKα來源(45kV,40mA,1.8kW-Kα1射線,波長λ=1.54060埃)照射粉末樣本。
掃描速率為1.20度/分鐘(0.020度梯階,每階計數時間1秒)。
於X光繞射圖中,繞射角2-θ係於橫軸(x軸)作圖及線強度係於縱軸(y軸)作圖。
於針對式(I)化合物之結晶型定義X光粉末繞射峰之各段落中,「...於約表中報告之2-θ角...」中「於約」係指峰的精確位置(亦即所引述的2-θ角值)不應視為絕對值,原因在於如熟諳技藝人士瞭解,峰之精確位置依不同機器、不同樣本、或由於所用的測量條件的些微改變可能略有差異。
先前各段也陳述式(I)化合物之非晶型及結晶型提供X光粉末繞射圖案實質上係與圖1、2、3及4所示X光繞射圖案相同,具有實質上最顯著的峰於表1、2、3、及4所示之2-θ值。須瞭解於本上下文中使用「實質上」一詞意圖指示X光粉末繞射圖案的2-θ角值可依不同機器、不同樣本、或由於測量條件的些微改變而略有變化,因此圖中顯示的或表中引述的峰位置再度並非絕對值。
就此方面而言,技藝界已知取決於測量條件(例如設備及/或樣本製備),可能獲得具有一或多個測量誤差的X光粉末繞射圖案。特別,一般已知X光粉末繞射圖案的強度可取決於測量條件及樣本製備改變。
舉例言之,X光粉末繞射技藝界之熟諳技藝人士將瞭解峰的相對強度例如可能受大小約為30微米的晶粒及縱橫比非一致的影響,可能影響樣本的分析。
熟諳技藝人士亦瞭解反射位置受到樣本於繞射計位置的精確高度及樣本的繞射計歸零校準的影響。
樣本的表面平坦度也影響結果。
如此熟諳技藝人士須瞭解此處程式之繞射圖案資料不應視為絕對值(有關進一步資訊請參考「粉末繞射及結構特徵化的基礎(Fundamentals of Powder Diffraction and Structural Characterization)」,
Pecharsky及Zavalij,Kluwer Academic Publishers,2003年)。因此須瞭解本發明描述的式(I)化合物之非晶型及結晶型非僅限於提供圖1、2、3及4所示X光粉末繞射圖案相同的X光粉末繞射圖案之非晶型及結晶型,提供與圖1、2、3及4所示圖案實質上相同的X光粉末繞射圖案之式(I)化合物之非晶型或結晶型的任何樣本及批料皆係落入於本發明之範圍。X光粉末繞射之熟諳技藝人士能夠判定X光粉末繞射圖案的實質相同性。
一般而言,於X光粉末繞射中繞射角的測量誤差約為2-θ=0.5度或以下(或更適合約2-θ=0.2度或以下),此等測量誤差程度於考慮圖1、2、3及4中的X光粉末繞射圖案時及比較內文中及表1、2、3及4中的圖案或解譯峰位置時將列入考慮。
因此,當敘述例如式(I)結晶型具有X光粉末繞射圖案具有至少一個特定峰於約2-θ=20.1度(或其他所述角度中之任一者)時,則可解譯為2-θ=20.1度±0.5度,或2-θ=20.1度±0.2度。
結晶型3、非晶型、結晶型1及結晶型2之X光繞射圖案分別係報告於圖1、2、3及4。結晶型3、結晶型1及結晶型2之X光繞射峰位置分別係報告於表2、3及4。
DSC分析係使用Mettler Toledo Star系統裝置進行。鋁DSC盤內載荷2-4毫克樣本。分析範圍為25℃至300℃之最大值。樣本係於氮氣靜態條件下以10℃/分鐘之加熱速率分析。
圖5報告非晶型、結晶型1及結晶型2之DSC熱分析圖。
觀察得結晶型1之熔解吸熱係於約188-196℃(峰溫)之範圍,具有△H於54-64焦耳/克之範圍。觀察得結晶型2之熔解吸熱係於約197-198.5℃(峰溫)之範圍,具有△H於72-78.5焦耳/克之範圍。須瞭解DSC之起始溫度及峰溫可能依不同裝置、不同方法或不同樣本而異,因此引述值並非視為絕對值。實際上,觀察得之溫度將取決於溫度變化速率以及樣本製備技術及特別為所採用的儀器。須估計及考慮應用此等不同條件所得溫度值可有±約4℃之變化。
觀察水吸收係利用DVS 1000(SMS)將此等物質樣本接受吸收性測試進行研究。該裝置為「受控制的環境微平衡」,經測量的樣本係於恆定受控制的溫度暴露於相對濕度(RH)經程式規劃的變化。測得的參數(重量、時間及相對濕度)係以Excel試算表報告,允許於所測試的相對濕度範圍獲得吸濕性曲線。例如,可於25℃控制溫度進行0%至90%相對濕度之吸附/解吸附週期。相對濕度之進行性變化例如為10%及3%,藉軟體於樣本重量平衡操作。此種條件可以百分比重量變化例如0.005%/分鐘之恆定速率定義。
圖6報告式(I)化合物之非晶型、結晶型1及結晶型2之DVS數據。相對濕度(RH,%)值報告於x軸,質量變化(%)報告於y軸。曲線係與於25℃ 0% RH至90% RH間之吸附步驟有關。
實驗結果顯示化合物(I)之結晶型1及結晶型2分別以於25℃/90% RH 0.6%及0.2%之水吸收量特徵化。此種水吸收可藉於25℃恆定溫度降低相對濕度逆轉。化合物(I)之結晶型1及2被視為具有低吸濕性。
實驗結果也顯示化合物(I)之非晶型係以於25℃/90% RH具有2.5%水吸收特徵化,水吸收可藉於25℃之恆定溫度降低相對濕度逆轉。化合物(I)之非晶型顯示比結晶型1及2更高的吸濕性。化合物(I)之非晶型的水吸收係高於結晶型1及2。至於又一態樣,化合物(I)之非晶型的水吸收從1% RH增高,比30% RH減低,隨後於高相對濕度值區域中斜率增高。
TGA分析係使用Perkin-Elmer TGA-7裝置進行。鋁DSC盤載荷5-10毫克樣本。分析溫度範圍為30℃至約250℃之最大值。樣本係以2℃/分鐘之加熱速率於氮氣流下分析(已去除氧化及熱解效應)。
1H NMR實驗針對結晶型3樣本係於28℃恆定溫度於Varian Inova 500光譜儀上進行(參考圖8)及對結晶型1樣本係於28℃恆定溫度於Varian Inova 400光譜儀上進行(參考圖7)。小量各樣本溶解於0.75毫升DMSO-d6且轉移至5毫米NMR管接受隨後分析。
因相同1H NMR光譜係得自不同結晶型,亦即結晶型1及2具有相同相同1H NMR光譜,只報告結晶型1之光譜。報告結晶型3之
光譜只顯示殘餘溶劑的存在,殘餘溶劑之信號與產物信號明顯區別,於圖8中以箭頭強調。
Claims (9)
- 一種製備式(I)化合物之方法
- 一種式(I)化合物之結晶型2,
- 如申請專利範圍第2項之結晶型2,其中,DSC熱分析圖係包含與197℃至198.5℃範圍之熔解有關的吸熱峰。
- 一種醫藥組成物,其係包括治療上有效量之申請專利範圍第2項定義之結晶型2,或其醫藥上可接受之鹽作為活性成分,以及醫藥上可接受之賦形劑、載劑或稀釋劑。
- 如申請專利範圍第2項定義之結晶型2,或其醫藥上可接受之鹽,其係用作為藥物。
- 一種申請專利範圍第2項定義之結晶型2或其醫藥上可接受之鹽之用途,其係單獨使用或聯合其他治療劑或放射治療,用以製造治療可藉ALK抑制治療的疾病狀態的藥物。
- 如申請專利範圍第1項之方法,其中,該式(II)化合物係懸浮於二氯甲烷及該式(III)化合物係懸浮於吡啶。
- 如申請專利範圍第1項之方法,其中,該式(IV)化合物之脫去保護係於碳酸鉀於水/甲醇之溶液進行。
- 如申請專利範圍第1項之方法,其中,該非晶型式(I)化合物係以於20℃至25℃間之溫度的乙醇及然後以於20℃至25℃間之溫度的水循序地處理。
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