TWI781161B - (s)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)-甲醇之固體型式 - Google Patents
(s)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)-甲醇之固體型式 Download PDFInfo
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- TWI781161B TWI781161B TW107111176A TW107111176A TWI781161B TW I781161 B TWI781161 B TW I781161B TW 107111176 A TW107111176 A TW 107111176A TW 107111176 A TW107111176 A TW 107111176A TW I781161 B TWI781161 B TW I781161B
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- Prior art keywords
- methanol
- fluoro
- chloro
- morpholin
- methoxy
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- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 title abstract description 3
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
本發明係關於無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇,以及製造其之方法,及其醫藥組合物及醫學用途。
Description
本發明係關於無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇,以及製造其之方法,及其醫藥組合物及醫學用途。
(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇(下文所描述之化合物)在WO 2014/183850中揭示為實例136,作為芳基喹唑啉家族之一成員,已發現其具有有價值的藥理學特性。(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇為DNA依賴性蛋白激酶(DNA-PK)活性之強效及選擇性抑制劑,從而轉譯成對癌細胞株中之DNA-PK自體磷酸化的強效抑制,已藉由活體外以及活體內資料兩者證明。因此,其尤其可用於癌細胞對抗癌劑之敏化及/或電離輻射。 呈DNA形式之人類遺傳物質不斷地經受反應性氧物種(ROS)侵襲,該反應性氧物種主要形成為氧化代謝之副產物。ROS能夠導致DNA呈單股斷裂形式之損壞。若先前的單股斷裂發生在鄰近處,則可引起雙股斷裂。此外,若DNA複製叉遇到損壞的基礎模式,則可導致單股及雙股斷裂。另外,諸如電離輻射(例如γ或粒子輻射)之外源性影響及一定地抗癌藥劑(例如博萊黴素(bleomycin))能夠導致DNA雙股斷裂。DSB可另外作為體細胞重組(一種對所有脊椎動物之功能性免疫系統之形成而言至關重要的方法)之中間物出現。 若DNA雙股斷裂未修補或經不正確地修補,則可發生突變及/或染色體畸變,從而可引起細胞死亡。為對抗由DNA雙股斷裂造成之嚴重危險,真核細胞已產生多個機制以修復該等斷裂。高等真核生物主要使用所謂的非同源末端連接,其中DNA依賴性蛋白激酶(DNA-PK)採用關鍵作用。DNA依賴性蛋白激酶(DNA-PK)為結合DNA活化之絲胺酸/蘇胺酸蛋白激酶。生物化學研究已展示DNA-PK係藉由DNA-DSB之發生來最有效地活化。已經證實細胞株之已突變且非功能性的DNA-PK組分為輻射敏感的(Smith及Jackson,1999)。若保持未修復,則認為DSB為最致死性類型之DNA損壞。 WO 2014/183850揭示化合物136 (S)-[2-氯-4-氟-5-(7-嗎啉-4-基-喹唑啉-4-基)-苯基]-(6-甲氧基-嗒𠯤-3-基)-甲醇游離鹼之製備類似於先前實例進行且指示對掌性分離藉由超臨界流體層析(Supercritical Fluid Chromatography;SFC )使用一定的對掌性設置來進行。然而,未揭示對映異構體之固體型式。 本發明之目標為研發將適用於醫藥調配物中之(S)-[2-氯-4-氟-5-(7-嗎啉-4-基-喹唑啉-4-基)-苯基]-(6-甲氧基-嗒𠯤-3-基)-甲醇之固體型式。
如上文所解釋,(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇本身之合成描述於WO 2014/183850中,其全部內容以引用的方式揭示於本文中。對映異構體之固態型式未揭示於本申請案中。 本發明提供具有非常有利特性之無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇。 本文中對(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇之任何參考係指如上文所描繪之分子之游離型式,而非鹽型式。 該無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇之粉末X射線繞射圖案描繪在圖1中。如自圖1顯而易見,PXRD圖案之峰與規律有序之結晶型相比顯著加寬。此假定為由於缺乏嚴格的長程結晶週期性。 因此,無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇可表徵為具有實質上與圖1一致之粉末X射線繞射圖案。 由於晶體結構無序,所以峰位置及形狀改變大於有序結晶型式之情況。此藉由圖2中說明之PXRD來說明。 如自圖1及2中顯而易見,加寬峰出現在以下中之一或多處:表 1 : 無水無序結晶型之 X 射線峰之列表
換言之,本發明提供無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇,其特徵在於粉末X射線繞射圖案在選自以下之度2θ處具有至少兩個峰:3.9、5.1、6.1、8.4、10.7、12.7、14.6及22.8,各自±0.3度2θ (較佳地各自± 0.2度2θ),其中至少兩個峰中之每一者的特徵在於具有等於或大於0.2度2θ之半高全寬(FWHM)。粉末X射線繞射圖案亦可在選自以下之度2θ處具有三個、四個、五個或六個峰:3.9、5.1、6.1、8.4、10.7、12.7、14.6及22.8,各自±0.3度2θ (較佳地各自±0.2度2θ)。無水無序結晶型之特徵可進一步在於粉末X射線繞射圖案在選自以下之度2θ處具有至少又一個峰,例如又兩個、三個、四個、五個或超過五個峰:3.1、9.9、13.5、16.0、16.5、18.0、19.0、20.9、21.9、22.8、24.0、24.9及25.4,各自± 0.3,較佳± 0.2度2θ。 上文提及之粉末X射線繞射圖案係使用Cu-Kα 1
輻射(λ = 1.54Å)來記錄。一般而言,粉末X射線繞射圖案可藉由此項技術中已知,諸如European Pharmacopeia 第6版第2.9.33章中所描述之標準技術獲得。關於在記錄形成上述值之基礎的粉末X射線繞射圖案峰中已採用之粉末X射線繞射方法的其他細節將進一步描述於下文中。 術語「峰」根據其在此項技術中已確立之意義在本文中使用且與術語「最大值」同義。如熟習此項技術者將理解,此類繞射圖案中之相對強度(強度I)可變化至相對較大的程度,例如至多20%。若峰在指定繞射角之約± 0.3,較佳± 0.2 °2θ的實驗性誤差內,則繞射圖案將與圖1或2中之繞射圖案「實質上一致」。 無水無序結晶型為很大程度上無序的結晶型I種類,其描述於同在申請中之專利申請案中且其以具有晶格參數a
= 4.8 Å、b
= 27.5 Å、c
= 33.3及α=ß
=γ=90°之斜方晶空間群P
21
21
21
結晶。該結晶型I之特徵可進一步在於每單位晶胞具有8個分子式單位且單位晶胞體積為4436 Å3
,且計算密度為1.44 g/cm3
。此等資料係使用配備有CCD偵測器之Rigaku SuperNova繞射儀,在200 K下使用Cu-Kα輻射基於單晶體X射線結構資料來產生的。 因此,XRPD繞射圖由對表徵除等於或大於0.2度2θ之半高全寬(FWHM)之外的有序結晶型之光譜的峰進行峰加寬而產生,該繞射圖在以下處具有尖銳的峰:4.1、5.2、6.1、8.3、8.5、10.1、10.9、12.7、13.0、13.8、14.7、15.0、18.6、19.2、20.0、20.5、20.8、21.3、22.0、22.4、22.8、23.4、24.4,各自±0.2 °2θ,將呈現尤其適合於自其他結晶型中區分該結晶型之峰可在以下處之峰的一或多者中可見:4.1、5.2、8.3、8.5、10.1、10.9、12.7、13.0及21.3 °2θ,各自±0.2 °2θ。 在熱行為方面,除至多100℃下<0.5% m/m的較小重量耗損以外,根據本發明之無水無序結晶型展示在高於150℃下熔融/分解之前無熱事件,如自圖3及4中所描繪之DSC掃描及TGA特徵曲線中顯而易見。無水無序結晶型呈現在至多40℃/75%相對濕度下之長期DS(原料藥)穩定性研究時的高化學及物理穩定性。 根據本發明之無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇亦具有溶解度特徵,該特徵呈現其適用於生物相關之腸道介質。其特徵可在於以下中之一或多者:
溶解度量測根據下文進一步描述之方法來進行。 應注意無水無序型式之溶解度比之前提及之無水有序結晶狀化合物之溶解度顯著較好。舉例而言,在pH 1.2下,其具有超過結晶型之雙倍溶解度。 根據本發明之無水無序型式之另一優勢為其具有良好且不變的大規模可製造性。此自非晶態中區分根據本發明之型式,例如,其可經由如WO 2014/183850中所描述之由乙腈及水獲得之對映異構體之凍乾獲得。 本發明進一步係關於用於製備無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇之方法,該方法包含對(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇之反溶劑沈澱。 較佳地,用於製備該無水無序結晶型之方法包含 a) 視情況在加熱之情況下製備(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇於溶劑或溶劑混合物中之澄清溶液, b)將澄清溶液與反溶劑組合以便產生(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇於溶劑/反溶劑混合物中之懸浮液, c)自溶劑/反溶劑混合物中分離所得到的無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇,及 d)乾燥該無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇。 合適之溶劑或溶劑混合物包括例如DMSO (二甲基甲醯胺)、二氯甲烷、甲醇、1,4-二噁烷、四氫呋喃及其兩者或更多者之混合物,諸如二氯甲烷/甲醇,僅舉幾個實例。 合適之反溶劑包括例如丙酮、正庚烷及水。 對水之任何參考應理解為係指去離子蒸餾水。 用於根據本發明之方法中之合適溶劑/反溶劑系統包括:二氯甲烷及正庚烷;甲醇及水;1,4-二噁烷及水;四氫呋喃及正庚烷。 製備澄清溶液可包括過濾含有(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇之溶劑或溶劑混合物。替代地或另外,其可包含例如藉助於蒸發來濃縮溶液。 分離步驟c)可藉由例如過濾或離心來實現。 根據方法步驟d)之結晶化合物的乾燥可例如在真空或減壓下,或在惰性氣體,諸如氮氣,尤其乾燥氮氣下進行。另外,乾燥可在室溫下或在高溫下,例如在至少40℃或更高,例如50℃或更高,例如60℃或更高,或70℃或更高下進行。乾燥條件係依據在製備結晶狀材料中所使用之溶劑/溶劑混合物來選擇,如將參考下文詳細描述之例示性實施例來進一步例示。 因此,本發明進一步係關於無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇,其可藉由反溶劑製備,尤其使用如上文所提及之溶劑/反溶劑系統獲得。 在另一態樣中,本發明提供一種醫藥調配物,其包含視情況且較佳與一或多種醫藥學上可接受之賦形劑組合的該無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇。 較佳地,醫藥劑型係用於經口投與。醫藥劑型可包含將材料以其無水無序結晶型包含之任何劑型,尤其包括固體劑型,諸如膠囊、錠劑、口含錠、丸劑、粉末、顆粒劑或軟膏或噴霧劑。典型地,醫藥劑型包含一或多種賦形劑。 在一個態樣中,醫藥劑型為錠劑且包含無水無序結晶化合物,以及選自例如以下之一或多種賦形劑:a)填充劑、b)黏合劑、c)保濕劑、d)崩解劑、e)毛細作用劑、f)基質形成劑及g)潤滑劑。 本發明進一步係關於無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇,或包含其之醫藥劑型用於治療癌症的用途。 在一些實施例中,癌症治療進一步包含放射線療法及化學療法中之至少一者。舉例而言,無水無序結晶化合物可適宜地與放射線療法組合使用。證明(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇與放射線療法組合所提供之治療效果的實例陳述於實例5中。在其他實施例中,癌症治療進一步包含化學療法,亦即投與至少一種其他抗癌劑。舉例而言,其他抗癌劑可選自依託泊苷(etoposide)。在又一實施例中,癌症治療包含放射線療法及化學療法兩者,例如投與依託泊苷及放射線療法。 因此,本發明提供一種治療有需要之患者的方法,該方法包含向患者投與無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇,對應地根據本發明之包含其之醫藥組合物。類似於上文已揭示,治療患者可進一步包含藉由放射線療法及化學療法治療中之至少一者。 分析方法:粉末 X 射線繞射圖案
(XRPD)藉由如European Pharmacopeia 第7版第2.9.33章所描述之標準技術來獲得(Cu-Kα 1
輻射,λ = 1.5406 Å,Stoe StadiP 611 KL透繞射儀,環境溫度);且特定言之: 量測在配備有Mythen1K Si帶偵測器(PSD)之Stoe StadiP 611繞射儀上用Cu-Kα 1
輻射以透射幾何結構執行。在非晶形膜之間製備大約10-100 mg樣本。藉由設定以下參數來進行量測: 角程: 1 ° - 41 °2q 角度解析: 0.015 °2q PSD階躍為: 0.49 °2q 量測時間: 15 s / PSD-階躍 生成器設置: 40 mA,40 kVDSC:
在Mettler-Toledo熱流差示掃描熱量計系統DSC 1上採集DSC量測。將大約1-5 mg樣本量精確地稱量在具有鑽孔蓋之40 µl鋁盤中。掃描以5 K/min之線形加熱速率自及50 mL/min之氮氣沖洗氣體自25℃進行至350℃。TGA:
在具有自動取樣器之Mettler-Toledo熱解重量分析器TGA 851上使用氮氣惰性氣體氛圍(流速50 mL/min)研究樣本。將大約5-20 mg樣本量精確地稱量在100 µl鋁盤中且藉由鋁蓋氣密性封閉。剛好在插入至烘箱中之前,封蓋藉由自動取樣器系統之針刺穿。掃描以5 K/min自25℃進行至350℃。使用相同的溫度分佈,藉由同一類型之空100 µl鋁盤進行空白操作來對結果進行基線校正。溶解度量測 :
測試介質:SGF
(無胃蛋白酶之模擬胃液) pH 1.2: 將2.0 g氯化鈉置放於1 L量瓶中並且溶解於大約500 mL水。添加80 mL 1 M鹽酸溶液並且容積定為1 L。所得SGF溶液含有:34.2 mM氯化鈉。FaSSIF
(模擬空腹狀態之腸道液體) pH 6.5: 將0.224 g SIF粉末(獲自biorelevant.com)溶解於含FaSSIF緩衝液之100 mL量瓶中並且定容。使FaSSIF介質在環境室溫下平衡2 h並且在製備之48 h內使用。FaSSIF緩衝液可藉由將0.42 g NaOH丸粒、3.44 g無水磷酸二氫鈉及6.19 g氯化鈉溶解於約0.9 L純化水中,用1 N NaOH或1 N HCl將pH調節至6.5並且將容積定為1 L來配製。所得FaSSIF含有:3 mM牛磺膽酸鈉;0.75 mM卵磷脂;105.9 mM氯化鈉;28.4 mM磷酸二氫鈉及8.7 mM氫氧化鈉。FeSSIF
(模擬進食狀態之腸道液體) pH 5.0: 將1.12 g SIF粉末(biorelevant.com)溶解於含FeSSIF緩衝液之100 mL量瓶中並且定容。其在製備之48 h內使用。FeSSIF緩衝液可藉由將4.04 g NaOH丸粒、8.65 g冰乙酸及11.87 g氯化鈉溶解於約0.9 L純化水中,用1 N NaOH或1 N HCl將pH調節至6.5並且將容積定為1 L來配製。 所得FeSSIF含有:15 mM牛磺膽酸鈉;3.75 mM卵磷脂;203.2 mM氯化鈉;101.0 mM氫氧化鈉及144.1 mM乙酸。溶解度量測
:將過量物質稱量至Uniprep® Whatman小瓶中,向該瓶中添加1 mL測試介質。懸浮液在37℃下以450 rpm (轉/分鐘)振盪24 h。在1 h、6 h及24 h時量測pH並且檢測小瓶之未溶解化合物。必要時調節介質之pH。在24 h之後,溶液經由0.2 µmPTFE膜過濾器過濾且在適當稀釋之後使用HPLC分析濾液。HPLC:
設備: Agilent 1100 管柱: Chromolith®
Performance RP-18e100-3mm, Art. 1.52001 (h) 波長: 282 nm 注射體積: 5 µL 管柱烘箱: 37 ℃ 自動取樣器: 37 ℃ 用於HPLC之溶離劑A: 甲酸:超純水(1:999;v/v) 用於HPLC之溶離劑B: 甲酸+乙腈(1:999;v/v)HPLC - 梯度 :
現將相對於本發明之例示性實施例(其不應視為限制)描述本發明。如本文中所使用,「物質」、「API」或「化合物」係指(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇。實例 1 :
將49.6 g API溶解於305 g二氯甲烷/甲醇中,將9:1.186 g正庚烷填充至250 mL反應器中。在大約6 min內將108 g API溶液直接添加至經攪拌正庚烷渦流中。固體/液體分離藉由過濾進行且乾燥固體材料。實例 2 :
在室溫下使1.2 g API幾乎溶解於55 mL二氯甲烷中並且經由0.2 µm針筒過濾器過濾輕微混濁液。在室溫下將得到的澄清溶液快速添加至120 mL正庚烷中且觀測即時沈澱。固體/液體分離藉由過濾進行且在50℃下用乾燥氮氣流乾燥固體材料隔夜。實例 3 :
在室溫下使大約20-30 mg API幾乎溶解於幾種溶劑(參見下表)中且經由0.2 µm針筒過濾器過濾輕微渾濁液。在室溫下將得到的澄清溶液快速添加至幾種反溶劑(參見下表)中且觀測即時沈澱。固體/液體分離藉由離心進行且在室溫下用乾燥氮氣流乾燥固體材料隔夜。溶劑-反溶劑組合編輯於下表中。 實例 4
15.5公升經攪拌DMSO藉由氮氣流後接真空排氣之3次循環來相應地脫氣。在室溫下將1.7 kg API添加至經攪拌DMSO溶液中直至獲得澄清溶液(在大約15 min攪拌之後)。在真空下經由過濾器筒(精煉過濾)過濾溶液。將172.3公升水填充至純淨反應器中。之後,將含API溶液之DMSO在30 min內逐滴直接添加至經攪拌水渦流中。在室溫下攪拌所得懸浮液30 min,過濾且用水洗滌濾餅。隨後,將濕潤API裝回反應器中,填充17.5公升水且在室溫下攪拌1小時。藉由過濾再分離API。三種不同的潤濕小批料藉由含研磨漿之60.7公升水來組合。最終的固體/液體分離藉由過濾進行且在70℃在真空下乾燥固體材料隔夜。實例 5 : 治療效果
體內結合電離輻射(IR) (一種臨床上建立之DSB誘導治療)來研究原料藥本身對DNA-PK抑制之治療相關性。在具有人類癌症之六個異種移植小鼠模型中測試原料藥之活性。該等模型選自不同的癌症病症(結腸、肺、頭頸部、胰臟)及組織學亞型(腺細胞、鱗狀細胞、大細胞)。電離輻射使用連續五天每天施予2 Gy之分次時間表來施予(總輻射劑量= 10 Gy)。在每一分次輻射(ONC397-1-2AZ、ONC397-1-3AZ、ONC397-1-4AZ、ONC397-1-5AZ、ONC397-1-8AZ)之前10 min經口給藥。 在所有模型中,經口投與原料藥導致輻射效果極大提高。利用150 mg/kg研究組到達400%初始體積的時間,在整個測試模型中量化增強效果之放射線療法。所得Kaplan-Meier曲線藉由對數等級檢定來比較。發現此治療設置中之增強比率在1.5 (A549,HCT116)與2.6 (NCI-H460)之間。
圖1 展示無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇之粉末X射線繞射圖(PXRD)。 圖2 展示無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇之另一粉末X射線繞射圖(PXRD)。 圖3 展示無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇之DSC掃描。 圖4 展示無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒𠯤-3-基)甲醇之TGA特徵曲線。
Claims (11)
- 如請求項5之方法,其中該反溶劑沈澱包含:a)視情況在加熱下製備(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒-3-基)甲醇於溶劑或溶劑混合物中之澄清溶液,b)將該澄清溶液與反溶劑組合以便產生(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒-3-基)甲醇於溶劑/反溶劑混合物中之懸浮液,c)自該溶劑/反溶劑混合物中分離由此獲得之無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒-3-基)甲醇,及d)乾燥該無水無序結晶狀(S)-[2-氯-4-氟-5-(7-嗎啉-4-基喹唑啉-4-基)苯基]-(6-甲氧基-嗒-3-基)甲醇。
- 如請求項6之方法,其中該溶劑或溶劑混合物係選自DMSO、二氯甲烷、甲醇、1,4-二噁烷、四氫呋喃及其混合物。
- 如請求項6或7之方法,其中該反溶劑係選自丙酮、正庚烷及水。
- 如請求項6或7之方法,其中該溶劑係選自二氯甲烷、甲醇及1,4-二噁烷且該反溶劑為水;或該溶劑為四氫呋喃且該反溶劑為正庚烷。
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