TWI725488B - Bcl-2抑制劑與化療藥的組合產品及其在預防及/或治療疾病中的用途 - Google Patents
Bcl-2抑制劑與化療藥的組合產品及其在預防及/或治療疾病中的用途 Download PDFInfo
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- TWI725488B TWI725488B TW108125818A TW108125818A TWI725488B TW I725488 B TWI725488 B TW I725488B TW 108125818 A TW108125818 A TW 108125818A TW 108125818 A TW108125818 A TW 108125818A TW I725488 B TWI725488 B TW I725488B
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Abstract
本發明涉及一種包含Bcl-2抑制劑和化療藥的組合產品,該組合產品提供了在預防及/或治療疾病(例如,癌症)的用途。
Description
本發明屬於醫藥技術領域,具體涉及一種含有Bcl-2抑制劑和化療藥的組合產品及其在預防及/或治療疾病(例如,癌症)中的用途。
細胞凋亡(程式性細胞死亡)是機體清除異常或不需要的細胞的自然途徑,若其受到影響則可能導致各種疾病如癌症的發生。
抗細胞凋亡的Bcl-2蛋白與許多疾病相關。Bcl-2家族蛋白是線粒體介導細胞凋亡途徑中的關鍵調控因數。逃避細胞凋亡是人類癌症的特徵之一,並且是臨床上耐藥的常見原因。
隨著分子生物學的研究進展,分子靶向治療已成為醫藥研究(特別是腫瘤研究)的熱點,大部分腫瘤的生物學行為並非由單一信號傳導通路所支配,而是多個信號傳導通路共同起作用。因此,先前技術中存在針對不同靶蛋白及/或不同信號轉導通路的聯合用藥的方案和產品存在需求,該聯合用藥的方案和產品能夠減少單藥劑量、降低單藥毒副作用及/或以協同作用的方式起作用,實現預防及/或治療疾病的目的。
為了滿足先前技術中的需求,本發明提供了一種含有Bcl-2抑制劑和化療藥的組合產品及其在治療及/或預防疾病(例如,癌症)中的用途。
具體地,在本發明的第一方面涉及一種組合產品,該組合產品包含Bcl-2抑制劑和化療藥。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A的化合物或其藥學上可接受的鹽或其溶劑化物:
其中:A是
E是C原子以及是一個雙鍵;或者E是-C(H)-以及是一個單鍵;或者E是N原子以及是單鍵;X1、X2和X3獨立地是-CR8=和-N=;R1a和R1b與其連接的C原子一起形成3-、4-,或5-元任意取代的脂肪環;
R1a和R1b與其連接的C原子一起形成4-或5-元任意取代的雜環;R2是-NO2、-SO2CH3、-SO2CF3;R2a是H或X;R3是H、-CN、-C≡CH、-N(R4a)(R4b);R4a是任意取代的C1-6烷基、任意取代的C3-6環烷基、雜環、雜烷基、環烷基烷基和雜環烷基;R4b是H和C1-4烷基;R5是任意取代的C1-6烷基、雜環、環烷基烷基和雜環烷基;R6a、R6c、R6e、R6f和R6g獨立地是H、任意取代的C1-6烷基、任意取代的C3-6環烷基、任意取代的芳基、任意取代的雜環芳基、雜環、雜烷基、環烷基烷基和雜環烷基;R6b和R6d獨立地是H、C1-4烷基和鹵素;R7是任意取代的C1-6烷基、雜環、雜烷基、環烷基烷基和雜環烷基;R8是H和鹵素。
在一些實施方式中,該化療藥選自放線菌素、全反式維甲酸、阿紮胞苷、硫唑嘌呤、博萊黴素、硼替佐米、卡鉑、卡培他濱、順鉑、苯丁酸氮芥、環磷醯胺、阿糖胞苷、柔紅黴素、多西他賽、去氧氟尿苷、多柔比星、表柔比星、阿黴素、埃博黴素、依託泊苷、氟尿嘧啶、吉西他濱、羥基脲、伊達比星、伊馬替尼、伊立替康、氮芥、巰嘌呤、甲氨蝶呤、米托蒽醌、奧沙利鉑、紫杉醇、培美曲塞、替尼泊苷、硫鳥嘌呤、拓撲替康、戊柔比星、威羅菲尼、長春鹼、長春新鹼、長春地辛、長春瑞濱、喜樹鹼或羥基喜樹鹼。
在一些實施方式中,該化療藥是拓撲替康。
在一些實施方式中,該組合產品呈藥物組合物的形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥各自呈單獨的製劑形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥同時或先後施用。
在一些實施方式中,該組合產品還包含藥學上可接受的載體、稀釋劑或賦形劑。
在一些實施方式中,該組合產品呈片劑、膠囊劑、顆粒劑、糖漿劑、粉劑、錠劑、藥囊、扁囊劑、酏劑、混懸劑、乳劑、溶液、糖漿劑、氣霧劑、軟膏劑、乳膏劑和注射劑的形式。
在本發明的第二方面涉及Bcl-2抑制劑和化療藥在製備用於預防及/或治療疾病的藥物中的用途,該疾病是癌症。
在本發明的第三方面涉及一種用於預防及/或治療疾病的組合產品,該組合產品包含Bcl-2抑制劑和化療藥,且該疾病是癌症。
在本發明的第四方面涉及一種預防及/或治療疾病的方法,包括對有此需要的受試者施用Bcl-2抑制劑和化療藥,該疾病是癌症。
在一些實施方式中,該癌症選自膀胱癌、乳腺癌、子宮頸癌、結腸癌(包括結直腸癌)、食管癌、頭頸癌、肝癌、肺癌(小細胞肺癌和非小細胞肺癌)、黑色素瘤、骨髓瘤、成神經細胞瘤、卵巢癌、胰腺癌、前列腺癌、腎癌、肉瘤(包括骨肉瘤)、皮膚癌(包括鱗狀細胞癌)、胃癌、睪丸癌、甲狀腺癌、子宮癌、間皮瘤、膽管癌、平滑肌肉瘤、脂肪肉瘤、黑色素瘤、鼻咽癌、神經內分泌癌、卵巢癌、腎癌、唾液腺癌、梭形細胞癌引起的轉移瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓細胞性白血病(AML)、急性淋巴細胞白血病(ALL)、瀰漫性大B細胞淋巴瘤(DLBCL)、濾泡性淋巴瘤(FL)、慢性淋巴細胞性白血病(CLL)、慢性骨髓性白血病(CML)、套細胞淋巴瘤(MCL)。
在一些實施方式中,該癌症為小細胞肺癌(SCLC)。
在一些實施方式中,將該Bcl-2抑制劑或其藥學上可接受的鹽或溶劑化物以約0.0025-1500mg/日的量給藥。
在一些實施方式中,將該化療藥或其藥學上可接受的鹽或溶劑化物以約0.005mg/日至約1000mg/日的量。
p.o.:口服
qd:一天一次
TPT:拓撲替康
WST:水溶性四唑鹽
第1圖顯示了在NCI-H146小細胞肺癌(SCLC)中,化合物6與化療藥拓撲替康聯合用藥,對腫瘤細胞的影響。
第2圖顯示了化合物6單藥或與拓撲替康聯合用藥在人NCI-H146(SCLC)小鼠異種移植瘤模型中的抗腫瘤作用(A)和體重變化。
在本文中使用的術語“藥學上可接受的鹽”是指游離酸或游離鹼的鹽,通常藉由將游離鹼與合適的有機或無機酸反應或者藉由將酸與合適的有機或無機鹼反應而進行製備。該術語可以用於本發明中的任何化合物。代表性的鹽包括:乙酸鹽、苯磺酸鹽、苯甲酸鹽、碳酸氫鹽、硫酸氫鹽、酒石酸氫鹽、硼酸鹽、溴化物、依地酸鈣鹽、樟腦磺酸鹽、碳酸鹽、氯化物、克拉維酸鹽、檸檬酸鹽、二鹽酸鹽、依地酸鹽、乙二磺酸鹽、丙酸酯月桂硫酸鹽(estolate)、乙磺酸鹽(esylate)、富馬酸鹽、葡庚糖酸鹽、葡萄糖酸鹽、谷氨酸鹽、甘苯砷酸鹽(glycol lylarsanilate)、己基間苯二酚酸鹽(hexylresorcinate)、哈胺鹽(hydrabamine)、氫溴酸鹽、鹽酸鹽、羥萘酸鹽、碘化物、羥乙基磺酸鹽、乳酸鹽、乳糖酸鹽、月桂酸鹽、蘋果酸鹽、馬來酸鹽、扁桃酸鹽、甲磺酸鹽、甲溴酸鹽、甲硝酸鹽、甲硫酸鹽、馬來酸單鉀鹽、黏酸鹽(Mucate)、萘磺酸鹽、硝酸鹽、N-甲葡萄糖胺鹽、草酸鹽、巴莫酸鹽(雙羥萘酸鹽)、棕櫚酸鹽、泛酸鹽、磷酸鹽/二磷酸鹽、聚半乳糖醛酸鹽、鉀鹽、水楊酸鹽、鈉鹽、硬脂酸鹽、次乙酸鹽、琥珀酸鹽、丹寧酸鹽、酒石酸鹽、茶氯酸鹽、對甲苯磺酸鹽、三乙基碘鹽(triethiodide)、三甲胺鹽和戊酸鹽。當酸性取代基存在時,例如-COOH,可以形成銨鹽、嗎啉鹽、鈉鹽、鉀鹽、鋇鹽、鈣鹽等以供劑型使用。當鹼性基團存在時(例如在檸檬苦素類化合物或1,1-二甲基雙胍中),例如胺基或鹼性雜芳基如吡啶基,可形成酸性鹽,如鹽酸鹽、氫溴酸鹽、磷酸鹽、硫酸鹽、三氟乙酸鹽、三氯乙酸鹽、乙酸鹽、草酸鹽、馬來酸鹽、丙酮酸鹽、丙二酸鹽、琥珀酸鹽、檸檬酸鹽、酒石酸
鹽、富馬酸鹽、扁桃酸鹽、苯甲酸鹽、肉桂酸鹽、甲磺酸鹽、乙磺酸鹽、苦味酸鹽等。
在本文使用的術語“預防”是指當用於疾病或病症(例如癌症)時,與未施用化合物或藥物(例如,本申請要求保護的組合產品)的受試者相比,該化合物或藥物能降低受試者體內的醫學病症症狀的頻率或推遲其發病。
在本文中使用的術語“治療”是指減輕、緩解或改善疾病或病症的症狀,改善潛在的代謝引起的的症狀,抑制疾病或症狀,例如阻止疾病或病症的發展、緩解疾病或病症、引起疾病或病症的消退、緩解疾病或病症引起的病況、或阻止疾病或病症的症狀。
在本文中使用的術語“癌症”是指由異常的不受控制的細胞生長引起的新生物或腫瘤。非限制性的例子包括那些在發明詳述中所描述的示例性癌症。術語“癌症”包括同時涉及惡化前癌細胞和惡性癌細胞的疾病。
在本文中使用的術語“溶劑化物”是本發明所涉及的化合物與溶劑分子的組合、物理結合,及/或溶劑合,例如二溶劑化物、單溶劑化物、半溶劑化物。本發明涉及的化合物可以以與例如水、甲醇、乙醇等藥學上可接受溶劑形成溶劑化形式,其不顯著影響化合物的藥理學活性或毒性且這樣可以作為藥理學等價物起作用。
在本文中使用的術語“受試者”是指包括人類(例如,患者)和動物(例如,小鼠、大鼠、犬、貓、兔、雞或猴等)。當受試者是人類患者(通常體重按60kg來計算)時,除非另有說明,本發明所述的劑量可採用與實驗動物的轉換因數(例如,人用劑量=小鼠劑量/12.3)進行換算得到(請參考Kin Tam.“Estimating the“First in human”dose-a revisit with particular emphasis on oncology drugs,ADMET & DMPK 1(4)(2013)63-75)。本領域的普通技術人員能夠根據一般常識,根據受試者的具體體重、疾病的種類和嚴重程度以及其它因素對該劑
量進行合理調整,這些調整的技術方案均落入本發明要求保護的技術方案的範圍之內。
在本文中使用的術語“有效量”或“預防及/或治療有效量”是指施用的藥物或化合物的足夠量(例如,劑量),其將在一定程度上減輕被治療的疾病或病症的一種或多種症狀。結果可以是縮小及/或減輕病症或疾病原因或任意其它期望的生物系統的改變。例如,用於治療用途的“有效量”是提供以使疾病或病症的臨床症狀顯著減輕、而不產生過度的毒副作用的化合物或藥物(例如,本申請要求保護的組合產品)的量。
如本文中使用的術語“劑量”是指每千克(kg)受試者體重的活性物質的重量(例如,毫克(mg))。
如本文中使用的術語“IC50”是指在測量這樣的效應的試驗中獲得最大效應的50%抑制。
如本文使用的術語“室溫”是指25℃±1℃。同時,若沒有具體指明實驗溫度,均為室溫。
如本文使用的術語“約”是指該術語所修飾的數值的±10%,更佳為±5%,最佳為±2%,因此本領域的普通技術人員能夠清楚地根據所修飾的數值確定術語“約”的範圍。
在本文中使用的術語“脂肪環”、“雜環”、“雜環烷基”、“雜烷基”、“環烷基烷基”和“鹵素”等具有本領域通常的含義,且本領域的普通技術人員藉由一般知識或參考先前技術(例如,WO2018/027097,藉由全文引入本發明作為參考)能夠知曉其含義。
在本發明的第一方面涉及一種組合產品,該組合產品包含Bcl-2抑制劑和化療藥,或由它們組成。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A的化合物或其藥學上可接受的鹽或溶劑化物:
其中:A是
E是C原子以及是一個雙鍵;或者E是-C(H)-以及是一個單鍵;或者E是N原子以及是單鍵;X1、X2和X3獨立地是-CR8=和-N=;R1a和R1b與其連接的C原子一起形成3-、4-,或5-元任意取代的脂肪環;R1a和R1b與其連接的C原子一起形成4-或5-元任意取代的雜環;R2是-NO2、-SO2CH3、-SO2CF3;R2a是H或X;
R3是H、-CN、-C≡CH、-N(R4a)(R4b);R4a是任意取代的C1-6烷基、任意取代的C3-6環烷基、雜環、雜烷基、環烷基烷基和雜環烷基;R4b是H和C1-4烷基;R5是任意取代的C1-6烷基、雜環、環烷基烷基和雜環烷基;R6a、R6c、R6e、R6f和R6g獨立地是H、任意取代的C1-6烷基、任意取代的C3-6環烷基、任意取代的芳基、任意取代的雜環芳基、雜環、雜烷基、環烷基烷基和雜環烷基;R6b和R6d獨立地是H、C1-4烷基和鹵素;R7是任意取代的C1-6烷基、雜環、雜烷基、環烷基烷基和雜環烷基;R8是H和鹵素。
在上述式I-A的化合物中,變數R2a的定義中的“X”指鹵素。進一步地,上述鹵素是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
在一些實施方式中,該Bcl-2抑制劑是具有該式I-A的化合物,其中:A是A-1、A-2、A-3、A-4、A-5、A-6、A-7、A-8和A-9;R4a是任意取代的C1-6烷基,雜環,雜烷基,環烷基烷基和雜環烷基;R6a、R6c、R6e、R6f和R6g獨立地是H、任意取代的C1-6烷基,雜環,雜烷基,環烷基烷基和雜環烷基。
在一些實施方式中,該Bcl-2抑制劑是具有式I的化合物,或其藥學上可接受的鹽或溶劑化物,
其中:E是C原子以及是一個雙鍵;或者E是-C(H)-以及是一個單鍵;或者E是N原子以及是單鍵;R1a和R1b與其連接的C原子一起形成3-、4-,或5-元任意取代的脂肪環;R1a和R1b與其連接的C原子一起形成4-或5-元任意取代的雜環;R2是-NO2、-SO2CH3、-SO2CF3;R3是H、-CN、-C≡CH、-N(R4a)(R4b);R4a是任意取代的C1-6烷基、雜環、環烷基烷基和雜環烷基;R4b是H和C1-4烷基。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-1。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-2。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-3。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-4。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-5。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-6。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-7。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-8。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-9。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VI的化合物,或其藥學上可接受的鹽或溶劑化物,其中A是A-10。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VII的化合物,或其藥學上可接受的鹽或溶劑化物,其中X1、X2和X3都是-CH=。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VII的化合物,或其藥學上可接受的鹽或溶劑化物,其中X1是-CF=、X2和X3都是-CH=。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VII的化合物,或其藥學上可接受的鹽或溶劑化物,其中X1和X3都是-CH=,X2是-CF=。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VII的化合物,或其藥學上可接受的鹽或溶劑化物,其中X1和X2都是-CH=,X3是-CF=。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VII的化合物,或其藥學上可接受的鹽或溶劑化物,其中X1是-N=、X2和X3都是-CH=。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VII的化合物,或其藥學上可接受的鹽或溶劑化物,其中X1和X3都是-CH=,X2是-N=。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A、V,或VII的化合物,或其藥學上可接受的鹽或溶劑化物,其中X1和X2都是-CH=,X3是-N=。
在一些實施方式中,該Bcl-2抑制劑是具有式II-VII中的任何一個化合物,或其藥學上可接受的鹽或溶劑化物,其中Y是-O-。
在一些實施方式中,該Bcl-2抑制劑是具有式II-VII中的任何一個化合物,或其藥學上可接受的鹽或溶劑化物,其中Y是-CH2-。
在一些實施方式中,該Bcl-2抑制劑是具有式I-A或I-VII中的任何一個化合物,或其藥學上可接受的鹽或溶劑化物,其中R2是-NO2。
在一些實施方式中,該Bcl-2抑制劑是具有式VIII的化合物,或其藥學上可接受的鹽或溶劑化物,其中R2a是H或F,R4a如式I-A定義。
在一些實施方式中,該Bcl-2抑制劑是下表中的一個或多個化合物,或其藥學上可接受的鹽或溶劑化物。
在一些實施方式中,該Bcl-2抑制劑是表1-A中的一或多個化合物,或其藥學上可接受的鹽或溶劑化物。
在一些實施方式中,該Bcl-2抑制劑是表1-B中的化合物,或其藥學上可接受的鹽或溶劑化物。
在一些實施方式中,該組合產品呈藥物組合物的形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥各自呈單獨的製劑形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥同時或先後施用。
在一些實施方式中,該Bcl-2抑制劑和化療藥先後施用的時間間隔可為約1分鐘、約5分鐘、約10分鐘、約15分鐘、約30分鐘、約45分鐘、約1小時、約2小時、約4小時、約6小時、約12小時、約24小時、約48小時、約72小時、約96小時、約1週、約2週、約3週、約4週、約5週、約6週、約8週,或約12週。
在一些實施方式中,可以根據需要,將該呈藥物組合物的形式(較佳地,各自呈單獨的劑量單元形式)的含有該Bcl-2抑制劑和化療藥的本發明的組合產品,每天施用包括但不限於:1次、2次、3次、4次、5次或6次。
在一些實施方式中,可以根據需要,將該呈藥物組合物的形式(較佳地,劑量單元形式)的含有該Bcl-2抑制劑和化療藥的本發明的組合產品,每天施用包括但不限於:1次、2次、3次、4次、5次或6次。
在一些實施方式中,該組合產品可以藉由下述方式施用:口服、口腔、吸入噴霧、舌下、直腸、透皮、陰道黏膜、透黏膜、局部給藥,鼻或腸道給藥;注射給藥,如肌肉注射、皮下注射、髓內注射,以及鞘內、腦部直接給藥、原位給藥、皮下、腹腔內、靜脈注射、關節內滑膜、胸骨內、肝內、病灶內,顱內、腹腔、鼻腔、或眼內注射或其他藥物遞送方式。
在一些實施方式中,該Bcl-2抑制劑或其藥學上可接受的鹽或溶劑化物以約0.0025-1500mg/日的量給藥。該Bcl-2抑制劑的量是1mg、5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、460mg、470mg、480mg、487mg、490mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg,以及該各量之間的範圍,例如,1mg-1000mg、30mg-900mg、30mg-800mg、30mg-900mg、30mg-800mg、30mg-700mg、30mg-600mg、30mg-500mg、30mg-490mg、30mg-487mg等,且該化療藥或其藥學上可接受的鹽或溶劑化物以約0.005mg/日至約5000mg/日的量給藥。該化療藥的量,如拓撲替康的量,是0.1mg、0.2mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.8mg、0.9mg、1mg、2mg、3mg、4mg、4.1mg、4.2mg、4.3mg、4.4mg、4.5mg、4.6mg、4.7mg、4.8mg、4.88mg、4.9mg、5mg、6mg、7mg、8mg、9mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、
850mg、900mg、950mg、1000mg,以及該各量之間的範圍,例如,0.1mg-1000mg、0.5mg-1000mg、1mg-1000mg、4.88mg-1000mg、4.88mg-900mg、4.88mg-800mg、4.88mg-700mg、4.88mg-600mg、4.88mg-500mg、4.88mg-400mg、4.88mg-300mg、4.88mg-200mg、4.88mg-100mg、4.88mg-50mg、4.88mg-10mg等。
在一些實施方式中,該組合產品還包含藥學上可接受的載體、稀釋劑或賦形劑。
在一些實施方式中,該組合產品呈片劑、膠囊劑、顆粒劑、糖漿劑、粉劑、錠劑、藥囊、扁囊劑、酏劑、混懸劑、乳劑、溶液、糖漿劑、氣霧劑、軟膏劑、乳膏劑和注射劑的形式。
在本發明的第二方面涉及Bcl-2抑制劑和化療藥在製備用於預防及/或治療疾病的藥物中的用途,該疾病選自癌症。
在一些實施方式中,該Bcl-2抑制劑是如在本發明的第一方面中所具體描述的那些化合物(例如,化合物I-A)或其藥學上可接受的鹽或溶劑化物。
在一些實施方式中,該藥物呈藥物組合物的形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥各自呈單獨的製劑形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥同時或先後施用。
在一些實施方式中,該Bcl-2抑制劑和化療藥先後施用的時間間隔可為約1分鐘、約5分鐘、約10分鐘、約15分鐘、約30分鐘、約45分鐘、約1小時、約2小時、約4小時、約6小時、約12小時、約24小時、約48小時、約72小時、約96小時、約1週、約2週、約3週、約4週、約5週、約6週、約8週,或約12週。
在一些實施方式中,可以根據需要,將該呈藥物組合物的形式(較佳地,各自呈單獨的劑量單元形式)的含有該Bcl-2抑制劑和化療藥的本發明的藥物,每天施用包括但不限於:1次、2次、3次、4次、5次或6次。
在一些實施方式中,可以根據需要,將該呈藥物組合物的形式(較佳地,劑量單元形式)的含有該Bcl-2抑制劑和化療藥的本發明的藥物,每天施用包括但不限於:1次、2次、3次、4次、5次或6次。
在一些實施方式中,該藥物可以藉由下述方式施用:口服、口腔、吸入噴霧、舌下、直腸、透皮、陰道黏膜、透黏膜、局部給藥,鼻或腸道給藥;注射給藥,如肌肉注射、皮下注射、髓內注射,以及鞘內、腦部直接給藥、原位給藥、皮下、腹腔內、靜脈注射、關節內滑膜、胸骨內、肝內、病灶內,顱內、腹腔、鼻腔,或眼內注射或其他藥物遞送方式。
在一些實施方式中,該Bcl-2抑制劑或其藥學上可接受的鹽或溶劑化物以及該MDM2抑制劑或其藥學上可接受的鹽或溶劑化物的每日給藥量如在上述發明詳述中的本發明第一方面所述。
進一步地,在本發明中所述的癌症包括但不限於選自下述的癌症:腎上腺癌、淋巴上皮瘤、腺樣細胞癌、淋巴瘤、聽神經瘤、急性淋巴細胞白血病、肢端黑色素瘤、急性髓系白血病、肢端汗腺瘤、慢性淋巴細胞白血病、急性嗜酸粒細胞白血病、肝癌、急性紅細胞白血病、小細胞肺癌、急性淋巴細胞白血病、非小細胞肺癌、急性巨核細胞白血病、MALT淋巴瘤、急性單核細胞白血病、惡性纖維組織細胞瘤、急性早幼粒細胞白血病、惡性外周神經鞘瘤、腺癌、惡性海馬腫瘤、腺樣囊性癌、套細胞淋巴瘤、腺瘤、邊緣區B細胞淋巴瘤、腺瘤樣牙源性腫瘤、肥大細胞白血病、腺鱗癌、縱隔生殖細胞腫瘤、脂肪組織腫瘤、乳腺髓樣癌、腎上腺皮質癌、甲狀腺髓樣癌、成人T細胞白血病/淋巴瘤、成神經管細胞瘤、侵襲性NK細胞白血病、黑色素瘤、愛滋病相關淋巴瘤、
腦膜瘤、肺泡橫紋肌肉瘤、默克爾細胞癌、肺泡軟組織肉瘤、間皮瘤、成釉細胞瘤、轉移性尿路上皮癌、間變性大細胞淋巴瘤、混合苗勒氏腫瘤、甲狀腺未分化癌、黏液性腫瘤、血管免疫母細胞性T細胞淋巴瘤、多發性骨髓瘤、血管平滑肌脂肪瘤、肌肉組織腫瘤、血管肉瘤、蕈樣真菌病、星形細胞瘤、黏液樣脂肪肉瘤、非典型畸形性橫紋肌樣瘤、黏液瘤、B細胞慢性淋巴細胞白血病、黏液肉瘤、B細胞幼淋巴細胞白血病、鼻咽癌、B細胞淋巴瘤、神經鞘瘤、基底細胞癌、神經母細胞瘤、膽道癌、神經纖維瘤、膀胱癌、神經瘤、胚細胞瘤、結節性黑色素瘤、骨癌、眼癌、布倫納瘤、少突細胞瘤、褐色腫瘤、少突神經膠質瘤、伯基特氏淋巴瘤、嗜酸細胞瘤乳腺癌、鞘膜腦膜瘤、腦癌、視神經腫瘤癌、口腔癌原位癌、骨肉瘤、癌肉瘤、卵巢癌、軟骨腫瘤、肺上溝瘤、水泥瘤、乳頭狀甲狀腺癌、骨髓瘤、副神經節瘤、軟骨瘤、松果體母細胞瘤、脊索瘤、松果細胞瘤、絨毛膜癌、垂體瘤、脈絡叢乳頭狀瘤、垂體腺瘤、腎透明細胞肉瘤、垂體瘤、顱咽管瘤、漿細胞瘤、皮膚T細胞淋巴瘤、多胚胎瘤、宮頸癌、前驅體T淋巴母細胞淋巴瘤、結直腸癌、原發性中樞神經系統淋巴瘤、德戈斯病、原發性積液淋巴瘤、增生性小圓細胞瘤、原發性腹膜癌、瀰漫性大B細胞淋巴瘤、前列腺癌、胚胎發育不良的神經上皮腫瘤、胰腺癌、無性細胞瘤、咽癌、胚胎癌、腹膜假黏液瘤、內分泌腺腫瘤、腎細胞癌、內胚竇瘤、腎髓樣癌、腸病相關的T細胞淋巴瘤、視網膜母細胞瘤、食道癌、橫紋肌瘤、胎中胎、橫紋肌肉瘤、纖維瘤、Richter’s徵轉化、纖維肉瘤、直腸癌、濾泡性淋巴瘤、肉瘤、濾泡性甲狀腺癌、神經鞘瘤病、神經節細胞瘤、精原細胞瘤、胃腸癌、支援細胞瘤、生殖細胞腫瘤、性索-性腺間質瘤、妊娠絨毛膜癌、印戒細胞癌、巨細胞成纖維細胞瘤、皮膚癌、骨巨細胞瘤、小藍圓細胞瘤、膠質瘤、小細胞癌、多形性膠質母細胞瘤、軟組織肉瘤、膠質瘤、生長抑素瘤、膠質瘤病、煤煙疣、胰高血糖素瘤、脊柱腫瘤、性腺母細胞瘤、脾邊緣區淋巴瘤、顆粒細胞瘤、鱗
狀細胞癌、雌激素瘤、滑膜肉瘤、膽囊癌、Sezary疾病、胃癌、小腸癌、毛細胞白血病、鱗狀細胞癌、血管母細胞瘤、胃癌、頭頸癌、T細胞淋巴瘤、血管外皮細胞瘤、睪丸癌、血液系統惡性腫瘤、肉瘤肝母細胞瘤、甲狀腺癌、肝脾T細胞淋巴瘤、移行細胞癌、霍奇金淋巴瘤、喉癌、非霍奇金淋巴瘤、臍尿管癌、浸潤性小葉癌、泌尿生殖系統癌、腸癌、尿路上皮癌、腎癌、葡萄膜黑色素瘤、喉癌、子宮癌、惡性雀斑樣痣、疣狀癌、致死性中線癌、視覺通路膠質瘤、白血病、外陰癌、睪丸間質細胞瘤、陰道癌、脂肪肉瘤、瓦爾登斯特倫的巨球蛋白血症、肺癌、腺淋巴瘤、淋巴管瘤、腎母細胞瘤和淋巴管肉瘤。
較佳地,該癌症選自膀胱癌、乳腺癌、子宮頸癌、結腸癌(包括結直腸癌)、食管癌、頭頸癌、肝癌、肺癌(小細胞肺癌和非小細胞肺癌)、黑色素瘤、骨髓瘤、成神經細胞瘤、卵巢癌、胰腺癌、前列腺癌、腎癌、肉瘤(包括骨肉瘤)、皮膚癌(包括鱗狀細胞癌)、胃癌、睪丸癌、甲狀腺癌、子宮癌、間皮瘤、膽管癌、平滑肌肉瘤、脂肪肉瘤、黑色素瘤、鼻咽癌、神經內分泌癌、卵巢癌、腎癌、唾液腺癌、梭形細胞癌引起的轉移瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤,以及惡性血液病,例如急性髓細胞性白血病(AML)、急性淋巴細胞白血病(ALL)、瀰漫性大B細胞淋巴瘤(DLBCL)、濾泡性淋巴瘤(FL)、慢性淋巴細胞性白血病(CLL)、慢性骨髓性白血病(CML)、套細胞淋巴瘤(MCL)。
最佳地,該癌症是小細胞肺癌(SCLC)。
在本發明的第三方面涉及一種用於預防及/或治療疾病的組合產品,該組合產品包含Bcl-2抑制劑和化療藥,該疾病選自癌症。進一步地,該癌症包括但不限於如在上述發明詳述中本發明的第二方面所述的那些癌症。
在一些實施方式中,該Bcl-2抑制劑是如在本發明的第一方面中所具體描述的那些化合物(例如,化合物I-A)或其藥學上可接受的鹽或溶劑化物。
在一些實施方式中,該組合產品呈藥物組合物的形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥各自呈單獨的製劑形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥同時或先後施用。
在一些實施方式中,該Bcl-2抑制劑和化療藥先後施用的時間間隔可為約1分鐘、約5分鐘、約10分鐘、約15分鐘、約30分鐘、約45分鐘、約1小時、約2小時、約4小時、約6小時、約12小時、約24小時、約48小時、約72小時、約96小時、約1週、約2週、約3週、約4週、約5週、約6週、約8週,或約12週。
在一些實施方式中,可以根據需要,將該呈藥物組合物的形式(較佳地,各自呈單獨的劑量單元形式)的含有該Bcl-2抑制劑和化療藥的本發明的組合產品,每天施用包括但不限於:1次、2次、3次、4次、5次或6次。
在一些實施方式中,可以根據需要,將該呈藥物組合物的形式(較佳地,劑量單元形式)的含有該Bcl-2抑制劑和化療藥的本發明的組合產品,每天施用包括但不限於:1次、2次、3次、4次、5次或6次。
在一些實施方式中,該組合產品可以藉由下述方式施用:口服、口腔、吸入噴霧、舌下、直腸、透皮、陰道黏膜、透黏膜、局部給藥,鼻或腸道給藥;注射給藥,如肌肉注射、皮下注射、髓內注射,以及鞘內、腦部直接給藥、原位給藥、皮下、腹腔內、靜脈注射、關節內滑膜、胸骨內、肝內、病灶內,顱內、腹腔、鼻腔、或眼內注射或其他藥物遞送方式。
在一些實施方式中,該Bcl-2抑制劑或其藥學上可接受的鹽或溶劑化物以及該化療藥或其藥學上可接受的鹽或溶劑化物的每日給藥量如在上述發明詳述中的本發明第一方面所述。
在本發明的第四方面涉及一種預防及/或治療疾病的方法,包括對有此需要的受試者施用預防及/或治療有效量的Bcl-2抑制劑和化療藥,該疾病
是癌症。進一步地,該癌症包括但不限於如在上述發明詳述中本發明的第二方面所述的那些癌症。
在一些實施方式中,該Bcl-2抑制劑是如在本發明的第一方面中所具體描述的那些化合物(例如,化合物I-A)或其藥學上可接受的鹽或溶劑化物。
在一些實施方式中,該Bcl-2抑制劑和化療藥呈藥物組合物的形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥各自呈單獨的製劑形式。
在一些實施方式中,該Bcl-2抑制劑和化療藥同時或先後施用。
在一些實施方式中,該Bcl-2抑制劑和化療藥先後施用的時間間隔可為約1分鐘、約5分鐘、約10分鐘、約15分鐘、約30分鐘、約45分鐘、約1小時、約2小時、約4小時、約6小時、約12小時、約24小時、約48小時、約72小時、約96小時、約1週、約2週、約3週、約4週、約5週、約6週、約8週,或約12週。
在一些實施方式中,可以根據需要,將該呈藥物組合物的形式(較佳地,各自呈單獨的劑量單元形式)的該Bcl-2抑制劑和化療藥,每天施用包括但不限於:1次、2次、3次、4次、5次或6次。
在一些實施方式中,可以根據需要,將該呈藥物組合物的形式(較佳地,劑量單元形式)的該Bcl-2抑制劑和化療藥,每天施用包括但不限於:1次、2次、3次、4次、5次或6次。
在一些實施方式中,該Bcl-2抑制劑和化療藥可以藉由下述方式施用:口服、口腔、吸入噴霧、舌下、直腸、透皮、陰道黏膜、透黏膜、局部給藥,鼻或腸道給藥;注射給藥,如肌肉注射、皮下注射、髓內注射,以及鞘內、腦部直接給藥、原位給藥、皮下、腹腔內、靜脈注射、關節內滑膜、胸骨內、肝內、病灶內,顱內、腹腔、鼻腔、或眼內注射或其他藥物遞送方式。
在一些實施方式中,該Bcl-2抑制劑每天的施用量是0.017mg/kg、0.083mg/kg、0.17mg/kg、0.33mg/kg、0.5mg/kg(60kg受試者每天30mg)、0.67mg/kg、0.83mg/kg、1mg/kg、1.16mg/kg、1.33mg/kg、1.5mg/kg、1.67mg/kg、2.5mg/kg、3.33mg/kg、4.17mg/kg、5mg/kg、5.83mg/kg、6.67mg/kg、7.5mg/kg、7.67mg/kg、7.83mg/kg、8mg/kg、8.12mg/kg(60kg受試者每天487mg)、8.16mg/kg、8.33mg/kg、9.17mg/kg、10mg/kg、10.83mg/kg、11.66mg/kg、12.5mg/kg、13.33mg/kg、14.17mg/kg、15mg/kg、15.83mg/kg、16.67mg/kg,以及該各施用量之間的範圍,例如,0.017mg-16.67mg/kg、0.083mg-16.67mg/kg、0.17mg-16.67mg/kg、0.33mg-16.67mg/kg、0.5mg-15mg/kg、0.5mg-13.33mg/kg、0.5mg-11.67mg/kg、0.5mg-10mg/kg、0.5mg-8.33mg/kg、0.5mg-8.16mg/kg、0.5mg-8.12mg/kg等,且該化療藥,如拓撲替康每天的施用量是0.001mg/kg、0.005mg/kg、0.01mg/kg、0.02mg/kg、0.03mg/kg、0.04mg/kg、0.05mg/kg、0.06mg/kg、0.07mg/kg、0.08mg/kg(實施例拓撲替康小鼠1mg/kg/12.3)、0.09mg/kg、0.1mg/kg、0.5mg/kg、1mg/kg、5mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg、55mg/kg、60mg/kg、65mg/kg、70mg/kg、75mg/kg、80mg/kg、85mg/kg、90mg/kg、95mg/kg、100mg/kg、150mg/kg、200mg/kg、250mg/kg、300mg/kg、350mg/kg、400mg/kg、450mg/kg、500mg,以及該各量之間的範圍,例如,0.001mg-500mg/kg、0.005mg-500mg/kg、0.01mg-500mg/kg、0.05mg-500mg/kg、0.08mg-500mg/kg、0.08mg-400mg/kg、0.08mg-300mg/kg、0.08mg-200mg/kg、0.08mg-100mg/kg、0.08mg-50mg/kg、0.08mg-10mg/kg、0.08mg-1mg/kg、0.08mg-0.5mg/kg、0.08mg-0.1mg/kg等。
最後,WO 2018/027097以其整體並為了所有目的藉由引用併入本文。
下面藉由具體的實施例、對照例進一步說明本發明,但是,應當理解為,這些實施例、對照例僅僅是用於更詳細具體地說明之用,而不應理解為用於以任何形式限制本發明。
實施例1. 本發明所使用的一般實驗方法
(1)WST實驗
藉由基於水溶性四唑鹽(WST)的CCK-8(Cell Counting Kit-8)實驗檢測抗增殖作用(Ishiyama M,Tominaga H,Shiga M et al.,A combined assay of cell viability and in vitro cytotoxicity with a highly water-soluble tetrazolium salt,neutral red and crystal violet.Biol.Pharm.Bull 19(11)1518-1520(1996),Vol.19,No.11.和Tominaga H,Ishiyama M,Ohseto F et al.,A water-soluble tetrazolium salt useful for colorimetric cell viability assay.Anal.Commun.,1999,36,47-50.)。細胞接種於96孔板中,並以不同濃度受試物處理72小時。藉由使用9個不同濃度不同濃度(拓撲替康,其中在10-2至102中間按3倍梯度選取9個濃度)與3個不同濃度的化合物6作用72小時,測試化合物6與該藥物的聯合作用。每個測試劑量做3複孔。
通常,選擇受試物9個系列劑量,100μl/孔加到96孔板。對於聯合實驗,2個受試物的終體積為100μl/孔。每個測試劑量做3複孔。在同一培養板上選3-6孔加入100μl稀釋液作為對照組,另設3-6孔作為空白對照。除空白對照孔外,每孔加入100μl細胞懸液(含有合適細胞數,以確保需要檢測時細胞對照組的細胞剛好鋪滿孔底面)到相同96孔板。培養板於37℃,CO2培養箱中培養72小時。培養結束時,對於貼壁細胞,除去待測孔內舊液,加入100μl/孔CCK-8檢測液(含10% CCK-8,5% FBS的相應培養基)。對於懸浮細胞,直接加入20μl/孔CCK-8原液。培養板繼續37℃,CO2培養箱中孵育2-4小時。
酶標儀(SpectraMax Plus 384,Molecular Devices,LLC.,US)A450nm檢測OD值。使用3複孔平均OD值,藉由下列公式計算細胞存活率百分比:(O.D.測試孔-O.D.空白對照孔)/(O.D.細胞對照孔-O.D.空白對照孔)×100。
使用Graphpad Prism 6.0軟體的非線性回歸資料分析方法計算IC50。
對於聯合實驗,藉由單藥對照的3複孔平均OD值歸一化處理後計算細胞存活率。藉由聯合曲線與單藥曲線的IC50進行比較以藉由觀察聯合用藥組曲線左移是否左移來確定2個化合物的協同作用。
(2)體內藥效學實驗評估方法
細胞接種法建立人腫瘤免疫缺陷小鼠皮下異種移植瘤模型:收集對數生長期的腫瘤細胞,計數後重懸於1×PBS,調整細胞懸液濃度至2.5-5×107/mL。用1mL注射器(4號針頭)在免疫缺陷小鼠右側背部皮下接種腫瘤細胞,5-10×106/0.2mL/鼠(實驗動物購自北京維通利華實驗動物技術有限公司SCXK(京)2012-0001)。所有動物實驗操作嚴格遵守吉瑪基因股份有限公司和蘇州亞盛藥業有限公司實驗動物使用和管理規範。相關參數的計算參考中國CFDA《細胞毒類抗腫瘤藥物非臨床研究技術指導原則》。本研究所用NCI-H146細胞由美國密西根大學王少萌教授惠贈。
實驗期間每週測定兩次動物體重和腫瘤大小。每天觀察動物的狀態以及有無死亡等情況發生。常規監測包括了腫瘤生長及治療對動物正常行為的影響,具體內容有實驗動物的活動性、攝食和飲水情況、體重增加或降低情況、眼睛、被毛及其它異常情況。實驗過程中觀察到的死亡和臨床症狀均記錄在原始資料中。整個給藥、小鼠體重及腫瘤體積的測量操作均在超淨工作臺中
進行。根據實驗方案要求,末次給藥結束後,收集血漿和腫瘤組織,稱重並拍照記錄。血漿和腫瘤樣本-80℃凍存備用。
腫瘤體積(Tumor volume,TV)的計算公式為:TV=a×b2/2。其中a、b分別代表腫瘤測量長和寬。相對腫瘤體積(relative tumor volume,RTV)計算公式為:RTV=Vt/Vl。其中Vl為分組給藥時的腫瘤體積,Vt為給藥後某天測量時的腫瘤體積。抗腫瘤活性的評價指標為相對腫瘤增殖率T/C(%),計算公式分別為:相對腫瘤增殖率T/C(%)=(TRTV/CRTV)×100%,TRTV為治療組RTV,CRTV為媒介物對照組RTV;腫瘤緩解率(%)為治療後荷瘤小鼠出現SD(疾病穩定)、PR(腫瘤部分消退)及CR(腫瘤完全消退)的數目除以本組小鼠總數×100%。
動物體重變化(Change of body weight%)=(測量體重-分組時體重)/分組時體重×100%。
療效評價標準:根據中國CFDA《細胞毒類抗腫瘤藥物非臨床研究技術指導原則》(2006年11月),T/C(%)值40%並經統計學分析p<0.05為有效。若小鼠的體重下降超過20%或藥物相關的死亡數超過20%,則認為該藥物劑量具有嚴重毒性。
協同性分析採用以下公式6:協同因數=((A/C)×(B/C))/(AB/C);A=A藥單藥組的RTV值;B=B藥單藥組的RTV值;C=媒介物對照組的RTV值,AB=AB聯合用藥組的RTV值(Clarke R.Issues in experimental design and endpoint analysis in the study of experimental cytotoxic agents in vivo in breast cancer and other models[J].Breast Cancer Research & Treatment,1997,46(2-3):255-278)。若協同因數>1,則具有協同作用;若協同因數=1,則具有相加作用;若協同因數<1,則具有拮抗作用。
實施例2. Bcl-2抑制劑的示例性化合物(化合物3、6和13)的製備
(1)2-((1H-吡咯並[2,3-b]吡啶-5-基)氧基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯)苯甲醯胺的合成(化合物3)
2-((1H-吡咯並[2,3-b]吡啶-5-基)氧基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-的混合物7-基)甲基)哌嗪-1-基)苯甲酸(1.75g,3mmol),3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯磺醯胺(1.43g,4.5)在室溫下使EDCI(1.15g,6mmol)和4-(N,N-二甲基胺基)吡啶(550mg,4.5mmol)和二氯甲烷(40ml)反應過夜,然後加入水。用二氯甲烷萃取水層。將合併的有機層用鹽水洗滌,濃縮並藉由矽膠柱純化,得到2-((1H-吡咯並[2,3-b]吡啶-5-基)氧基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯)苯甲醯胺(1.7g,64.4%),為黃色固體。
1H NMR(400MHz,甲醇-d4)δ 8.70(d,J=2.3Hz,1H),8.01(d,J=2.7Hz,1H),7.87(d,J=9.2,2.3Hz,1H),7.66(d,J=8.9Hz,1H),7.55(d,J=2.7Hz,1H),7.47(d,J=3.4Hz,1H),7.38(d,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),6.97(d,J=9.2Hz,1H),6.77(dd,J=8.9,2.4Hz,1H),6.44(d,J=3.4Hz,1H),6.34(d,J=2.4Hz,1H),4.02-3.94(m,3H),3.66(s,3H),3.49-3.38(m,2H),3.41-3.25(m,7H),2.42(s,3H),2.26(s,3H),2.00-1.67(m,4H),1.45-1.38(m,2H)。
(2)(R)-N-((4-(((1,4-二噁烷-2-基)甲基)胺基)-3-硝基苯基)磺醯)-2-((1H-吡咯並[2,3-b]吡啶-5-基)氧基)-4-(4-((6-(4-氯苯基)螺[3.5]壬-6-烯-7-基)甲基)哌嗪-1-基)苯甲醯胺的合成(化合物13)
採用類似於合成化合物3所述的方法製備標題化合物。
1H NMR(400MHz,甲醇-d4)δ 8.66(d,J=2.4Hz,1H),7.99(d,J=2.4Hz,1H),7.84(dd,J=9.2,2.4Hz,1H),7.64(d,J=8.9Hz,1H),7.51(d,J=2.4Hz,2H),7.45(d,J=3.3Hz,1H),7.37(d,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),6.94(d,J=9.2Hz,1H),6.76(dd,J=8.9,2.3Hz,1H),6.40(d,J=3.3Hz,1H),6.36(d,J=2.3Hz,1H),3.87(dd,J=11.8,4.2Hz,3H),3.83-3.70(m,3H),3.67(s,2H),3.62(dd,J=11.7,2.9Hz,1H),3.51-3.41(m,2H),3.40-3.35(m,1H),3.29(dq,J=3.2,1.6Hz,1H),2.41(s,2H),2.26(s,2H),2.00-1.77(m,6H)。
實施例3. 拓撲替康單藥以及拓撲替康和化合物6聯合用藥對不同惡性腫瘤細胞的影響體外資料
(1)實驗方法如實施例1第(1)部分所述。在WST實驗中測定拓撲替康單藥以及拓撲替康和化合物6聯合用藥在下述惡性腫瘤細胞中的細胞存活率(%):NCI-H146(小細胞肺癌(SCLC))。
如第1圖所示,在NCI-H146小細胞肺癌(SCLC)中,化合物6與化療藥拓撲替康聯合用藥,對腫瘤細胞的增殖抑制作用增強。
具體地,在NCI-H146(SCLC)中,拓撲替康單藥的抑制增殖的IC50為0.127,而拓撲替康與化合物6(0.04μM、0.08μM、0.12μM)的抑制增殖的IC50分別為0.026、0.022和0.023;在另一個NCI-H146(SCLC)中,拓撲替康單藥的抑制增殖的IC50為0.068,而拓撲替康與化合物6(0.1μM、0.2μM、0.4μM)的抑制增殖的IC50分別為0.009、0.013和0.008。
(3)小結
由此可見,體外實驗中,當拓撲替康和化合物6時,在血液學惡性腫瘤的體外抗增殖活性得到進一步增強,且藉由聯合給藥曲線與單藥曲線的IC50進行比較,觀察到聯合用藥組曲線左移。因此,拓撲替康與化合物6聯用具有協同作用。
實施例4. 拓撲替康單藥以及拓撲替康和化合物6聯合用藥對人NCI-H146(SCLC)小鼠異種移植瘤模型的影響
(1)實驗方法如實施例1第(2)部分該。本實驗建立了NCI-H146人腫瘤細胞來源的SCLC小鼠異種移植瘤模型(Gould SE et al.Translational value of mouse models in oncology drug development.Nature medicine.2015 21,431-439)。在腫瘤體積長至100-200mm3時,根據腫瘤體積和小鼠體重進行隨機分組,並
在該模型上開展了兩個獨立的體內實驗,以評價化合物6與化療劑TPT(拓撲替康)聯合用藥的抗腫瘤作用。
在本實驗中,化合物6按100mg/kg劑量,p.o.,qd方案給藥;TPT按1mg/kg,p.o.,d1-5/w(即給藥5天後間隔2天)方案給藥。治療一週後,TPT組動物體重減輕約5%,為防止體重進一步減輕,TPT的給藥方案調整為d1-3/w(即給藥3天後間隔4天),再持續治療一週(研究編號APS-EF-51-2017-NCI-H146)。
(2)實驗結果
如第2圖A和表1所示,在給藥結束時(即給藥後第21天),化合物6單藥組顯示出中等的抗腫瘤活性,T/C值為49%(P<0.05),沒有出現CR、PR或SD(緩解率為0%)。TPT表現出有效的抗腫瘤活性,T/C值為5%(P<0.01)。在5隻接受TPT治療的小鼠中,2隻出現CR,3隻出現PR(緩解率為100%)。化合物6與TPT聯合用藥組的T/C值達到0%(P<0.01)。在給藥結束時,所有5隻接受聯合用藥治療的小鼠均出現CR(緩解率為100%)。雖然聯合用藥組的RTV值與TPT單藥組比較沒有統計學顯著性差異,但是聯合用藥對腫瘤生長的抑制作用明顯增強,表現為所有5隻接受聯合用藥治療的小鼠均出現CR。在停藥後的觀察中發現(給藥後第46天),化合物6單藥組,TPT單藥組和聯合治療組的緩解率分別轉為0%、40%(2/5 CR)和100%(3/5 CR、1/5 PR和1/5 SD),進一步證實了聯合治療的持續藥效。
(3)結論:
化合物6與TPT聯合用藥無明顯副作用(第2圖B),可顯著增加TPT單藥在人NCI-H146(SCLC)小鼠異種移植瘤模型中的抗腫瘤效果。因此,化合物6與TPT聯合用藥可能在臨床為小細胞肺癌(SCLC)患者帶來獲益。
p.o.:口服
qd:一天一次
Claims (11)
- 如申請專利範圍第1項所述的組合產品,其中該組合產品呈藥物組合物的形式。
- 如申請專利範圍第1項所述的組合產品,其中該Bcl-2抑制劑和化療藥各自呈單獨的製劑形式。
- 如申請專利範圍第1項所述的組合產品,其中該Bcl-2抑制劑和化療藥同時或先後施用。
- 如申請專利範圍第1項所述的組合產品,該組合產品還包含藥學上可接受的載體、稀釋劑或賦形劑。
- 如申請專利範圍第1項至第5項中任一項所述的組合產品,其中該組合產品呈片劑、膠囊劑、顆粒劑、糖漿劑、粉劑、錠劑、藥囊、扁囊劑、酏劑、混懸劑、乳劑、溶液、糖漿劑、氣霧劑、軟膏劑、乳膏劑和注射劑的形式。
- 一種如申請專利範圍第1項至第6項中任一項所述的組合產品在製備用於預防及/或治療疾病的藥物中的用途,該組合產品包含Bcl-2抑制劑和化療藥,該疾病是癌症。
- 如申請專利範圍第7項所述的用途,其中該癌症選自膀胱癌、乳腺癌、子宮頸癌、結腸癌(包括結直腸癌)、食管癌、頭頸癌、肝癌、肺癌(小細胞肺癌和非小細胞肺癌)、黑色素瘤、骨髓瘤、成神經細胞瘤、卵巢癌、胰腺癌、前列腺癌、腎癌、肉瘤(包括骨肉瘤)、皮膚癌(包括鱗狀細胞癌)、胃癌、睪丸癌、甲狀腺癌、子宮癌、間皮瘤、膽管癌、平滑肌肉瘤、脂肪肉瘤、黑色素瘤、鼻咽癌、神經內分泌癌、卵巢癌、腎癌、唾液腺癌、梭形細胞癌引起的轉移瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、急性髓細胞性白血病(AML)、急性淋巴細胞白血病(ALL)、瀰漫性大B細胞淋巴瘤(DLBCL)、濾泡性淋巴瘤(FL)、慢性淋巴細胞性白血病(CLL)、慢性骨髓性白血病(CML)、套細胞淋巴瘤(MCL)。
- 如申請專利範圍第7項或第8項所述的用途,其中該癌症是小細胞肺癌(SCLC)。
- 如申請專利範圍第7項或第8項所述的用途,其中該Bcl-2抑制劑或其藥學上可接受的鹽以約0.0025-1500mg/日的量給藥。
- 如申請專利範圍第7項或第8項所述的用途,其中該化療藥或其藥學上可接受的鹽以約0.005mg/日至約1000mg/日的量給藥。
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CN110776507B (zh) | 2020-12-18 |
US11491167B2 (en) | 2022-11-08 |
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TW202012404A (zh) | 2020-04-01 |
EP3672595B1 (en) | 2021-07-21 |
AU2019314819A1 (en) | 2020-10-22 |
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