TW201818934A - Mdm2抑制劑與dna甲基轉移酶抑制劑之倂用治療法 - Google Patents
Mdm2抑制劑與dna甲基轉移酶抑制劑之倂用治療法 Download PDFInfo
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- TW201818934A TW201818934A TW106135252A TW106135252A TW201818934A TW 201818934 A TW201818934 A TW 201818934A TW 106135252 A TW106135252 A TW 106135252A TW 106135252 A TW106135252 A TW 106135252A TW 201818934 A TW201818934 A TW 201818934A
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Abstract
提供一種組合具有MDM2抑制活性的化合物與DNA甲基轉移酶抑制劑而成之醫藥/癌症之治療方法。
提供一種組合(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑而成的醫藥或併用治療方法。
Description
本發明係關於組合具有鼠雙微基因2(Murine Double Minute 2,MDM2)抑制活性的化合物及DNA甲基轉移酶抑制劑而成的醫藥/癌症之治療方法。
已知p53為抑制細胞的癌化的重要因子之一。p53係一種轉錄因子,其對各式各樣的壓力反應而誘導參與細胞周期或細胞凋亡之基因的表現。p53被認為藉由其轉錄調節機能而抑制細胞的癌化,實際上,於人類的癌症的約半數觀察到p53基因的缺失或變異。
另一方面,已知E3泛蛋白連接酶(E3 ubiquitin ligase)之一種的MDM2(鼠雙微基因2)之過度表現為癌化的要因之一。MDM2係藉由p53而表現被誘導的蛋白質。MDM2係於與p53之轉錄活性域結合而使p53的轉錄活性降低的同時,將p53排出至核外,且進而作為對p53之泛蛋白化連接酶作用而媒介p53的分解,藉以負向控制p53。因此,於MDM2過度表現的細胞,被認為有p53機能的不活化及分解被促進,且引起癌化(非專利文獻1)。
著眼於此種MDM2之機能,至今已進行了許多將會阻礙因MDM 2之p53功能抑制的物質作為抗腫瘤劑的候選物的嚐試。就將MDM2與p53的結合部位作為標的的MDM2抑制劑而言,已有報告螺羥基吲哚(spiro-oxindole)衍生物(專利文獻1~15、非專利文獻1~3)、吲哚衍生物(專利文獻16)、吡咯啶-2-甲醯胺衍生物(專利文獻17)、吡咯啶酮衍生物(專利文獻18)、異吲哚啉酮(isoindolinone)衍生物等(專利文獻19、非專利文獻4)、二螺吡咯啶化合物(專利文獻20)等。
近年來,作為癌化的新機制而表觀基因組(epigenome)異常正受到注目。於癌症抑制基因的不活化、癌症基因的異常活性化上,已清楚得知除了DNA序列變異以外,過度的DNA甲基化或組織蛋白(histone)修飾等之表觀基因組異常亦深入參與,而著眼於表觀基因組異常的醫藥品(表觀基因組藥)的開發正在進行中(非專利文獻5~7)。
DNA甲基轉移酶係將DNA進行甲基化的酵素。已有報告各種腫瘤中的DNA甲基轉移酶的異常活性化,而DNA甲基轉移酶係表觀基因組藥之最被知悉的目標之一者。阿扎胞苷(azacytidine)、地西他濱(decitabine)等之核苷類似物,自古以來已知為核酸合成抑製劑,但後來已清楚得知,此等藥劑會抑制DNA甲基轉移酶而使高甲基化狀態恢復為原樣,因此美國FDA於2004年承認了阿扎胞苷,於2006年承認了地西他濱為表觀基因組試劑。
對於阿扎胞苷、地西他濱等之DNA甲基轉移酶抑制劑,亦有進行檢討許多有關與其他抗癌劑的併用(非專利文獻5)。
專利文獻1 WO2006/091646
專利文獻2 WO2006/136606
專利文獻3 WO2007/104664
專利文獻4 WO2007/104714
專利文獻5 WO2008/034736
專利文獻6 WO2008/036168
專利文獻7 WO2008/055812
專利文獻8 WO2008/141917
專利文獻9 WO2008/141975
專利文獻10 WO2009/077357
專利文獻11 WO2009/080488
專利文獻12 WO2010/084097
專利文獻13 WO2010/091979
專利文獻14 WO2010/094622
專利文獻15 WO2010/121995
專利文獻16 WO2008/119741
專利文獻17 WO2010/031713
專利文獻18 WO2010/028862
專利文獻19 WO2006/024837
專利文獻20 WO2012/121361
專利文獻21 WO2008/039218
專利文獻22 WO2013/059738
非專利文獻1 J.Am.Chem.Soc., 2005, 127, 10130-10131
非專利文獻2 J.Med.Chem., 2006, 49, 3432-3435
非專利文獻3 J.Med.Chem., 2009, 52, 7970-7973
非專利文獻4 J.Med.Chem., 2006, 49, 6209-6221
非專利文獻5 Trends Pharmacol. Sci., 2010, 31, 536-546
非專利文獻6 Drug Discov. Today, 2011, 16, 418-425
非專利文獻7 Cell. Signal., 2011, 23, 1082-1093
本發明係提供組合具有MDM2抑制活性的化合物及DNA甲基轉移酶抑制劑而成的醫藥/癌症之治療方法。本發明係提供有意義地抗腫瘤效果高的優異醫藥/癌症之治療方法。
本發明者等人深入檢討的結果,發現將為具有MDM2抑制活性的化合物的(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及為DNA甲基轉移酶抑制劑的阿扎胞苷或 地西他濱組合來使用,藉此可獲得特別優異的抗腫瘤效果,而完成了本發明。
即,本發明係關於下列之[1]~[22]。
[1]一種用以治療癌症之醫藥,其特徵為組合而投予(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑。
[2]記載於[1]之醫藥,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係各自作為不同製劑的有效成分被含有,而於同時或不同時間被投予。
[3]記載於[1]之醫藥,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係被含於單一製劑中。
[4]記載於[1]之醫藥,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上 可容許的鹽及DNA甲基轉移酶抑制劑為含有彼等的套組製劑。
[5]一種癌症之治療方法,其特徵為組合而投予(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑。
[6]記載於[5]之治療方法,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係各自作為不同製劑的有效成分被含有,而於同時或不同時間被投予。
[7]記載於[5]之治療方法,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係被含於單一製劑中。
[8]記載於[5]之治療方法,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑為含有彼等的套組製劑。
[9]記載於[1]~[4]中任一項之醫藥,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺之鹽為p-甲苯磺酸鹽。
[10]記載於[5]~[8]中任一項之治療方法,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺之鹽為p-甲苯磺酸鹽。
[11]記載於[1]~[4]及[9]中任一項之醫藥,其中DNA甲基轉移酶抑制劑為核酸衍生物。
[12]記載於[5]~[8]及[10]中任一項之治療方法,其中DNA甲基轉移酶抑制劑為核酸衍生物。
[13]記載於[1]~[4]及[9]中任一項之醫藥,其中DNA甲基轉移酶抑制劑為阿扎胞苷或地西他濱。
[14]記載於[5]~[8]及[10]中任一項之治療方法,其中DNA甲基轉移酶抑制劑為阿扎胞苷或地西他濱。
[15]記載於[1]~[4]、[9]、[11]及[13]中任一項之醫藥,其中癌症為血癌、腦腫瘤、頭頸部癌、食道癌、胃癌、闌尾癌、大腸癌、肛門癌、膽囊癌、膽管癌、胰臟癌、胃腸道基質瘤(gastrointestinal stromal tumor)、肺癌、肝癌、間皮瘤(mesothelioma)、甲狀腺癌、***癌、神經內分泌腫瘤、黑色素瘤、乳癌、子宮體癌、子宮頸癌、卵巢癌、骨肉瘤、軟組織肉瘤、卡波西氏肉瘤(Kaposi's sarcoma)、肌肉瘤、腎臟癌、膀胱癌或睪丸癌。
[16]記載於[5]~[8]、[10]、[12]及[14]中任一項之治療方法,其中癌症為血癌、腦腫瘤、頭頸部癌、食道癌、胃癌、闌尾癌、大腸癌、肛門癌、膽囊癌、膽管癌、胰臟癌、胃腸道基質瘤、肺癌、肝癌、間皮瘤、甲狀腺癌、***癌、神經內分泌腫瘤、黑色素瘤、乳癌、子宮體癌、子宮頸癌、卵巢癌、骨肉瘤、軟組織肉瘤、卡波西氏肉瘤、肌肉瘤、腎臟癌、膀胱癌或睪丸癌。
[17]記載於[1]~[4]、[9]、[11]及[13]中任一項之醫藥,其中癌症為血癌。
[18]記載於[5]~[8]、[10]、[12]及[14]中任一項之治療方法,其中癌症為血癌。
[19]記載於[17]之醫藥,其中血癌為慢性淋巴性白血病(CLL)、小淋巴球性淋巴瘤(SLL)、高風險之CLL、非CLL/SLL淋巴瘤、濾泡性淋巴瘤(FL)、瀰漫性大細胞型B細胞淋巴瘤(DLBCL)、被套細胞淋巴瘤(mantle cell lymphoma,MCL)、華氏巨球蛋白血症(Waldenstrom's macroglobulinemia)、多發性骨髓瘤(MM)、邊緣區淋巴瘤(marginal zone lymphoma)、伯奇氏淋巴瘤(Burkitt's lymphoma)、非伯奇氏淋巴瘤型高惡性度B細胞淋巴瘤、結外邊緣區B細胞淋巴瘤(Extranodal marginal zone B cell lymphoma)、急性或慢性之骨髓性(或骨髓球性)白血病、骨髓化生不良症候群(myelodysplastic syndrome)或急性淋巴細胞性白血病。
[20]記載於[18]之治療方法,其中血癌為慢性淋巴性白血病(CLL)、小淋巴球性淋巴瘤(SLL)、高風險之CLL、 非CLL/SLL淋巴瘤、濾泡性淋巴瘤(FL)、瀰漫性大細胞型B細胞淋巴瘤(DLBCL)、被套細胞淋巴瘤(MCL)、華氏巨球蛋白血症、多發性骨髓瘤(MM)、邊緣區淋巴瘤、伯奇氏淋巴瘤、非伯奇氏淋巴瘤型高惡性度B細胞淋巴瘤、結外邊緣區B細胞淋巴瘤、急性或慢性之骨髓性(或骨髓球性)白血病、骨髓化生不良症候群或急性淋巴細胞性白血病。
[21]記載於[17]或[19]之醫藥,其中血癌為具有野生型之TP53的癌症。
[22]記載於[18]或[20]之治療方法,其中血癌為具有野生型之TP53的癌症。
本發明係有用於作為癌症之治療方法、及/或抗癌劑。
圖1呈示(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺p-甲苯磺酸鹽(化合物A)及阿扎胞苷對為人類急性骨髓性白血病細胞株之MOLM-13細胞小鼠皮下移植腫瘤的在活體內之併用效果(圖1A)及併用投予時之體重變化(圖1B)的圖。符號×表示無處置對照組,符號白色圓圈表示阿扎胞苷2.5mg/kg,符號黑色圓圈表示阿扎胞苷4mg/kg,符號白色三角形表示化合物A 25mg/kg,符號白色四方形表示化合物A 25mg/kg+阿 扎胞苷2.5mg/kg,符號黑色四方形表示化合物A 25mg/kg+阿扎胞苷4mg/kg。橫軸表示腫瘤移植後的日數。圖1A縱軸表示由腫瘤徑算出的推定腫瘤體積,圖1B縱軸表示相對於投予初日之體重的體重變化率。橫軸上之符號白色三角形表示化合物A之投予日,黑色三角形表示阿扎胞苷之投予日。誤差槓係上段表示SE,下段表示SD。
圖2呈示化合物A及阿扎胞苷對為人類急性骨髓性白血病細胞株之MOLM-13細胞小鼠皮下移植腫瘤的在活體內之併用效果(圖2A)及併用投予時之體重變化(圖2B)的圖。符號×表示無處置對照組,符號白色圓圈表示阿扎胞苷2.5mg/kg,符號黑色圓圈表示阿扎胞苷4mg/kg,符號黑色三角形表示化合物A 50mg/kg,符號白色四方形表示化合物A 50mg/kg+阿扎胞苷2.5mg/kg,符號黑色四方形表示化合物A 50mg/kg+阿扎胞苷4mg/kg。橫軸表示腫瘤移植後之日數。圖2A縱軸表示由腫瘤徑算出的推定腫瘤體積,圖2B縱軸表示相對於投予初日之體重的體重變化率。橫軸上之符號白色三角形表示化合物A之投予日,黑色三角形表示阿扎胞苷之投予日。誤差槓係上段表示SE,下段表示SD。
圖3呈示化合物A及地西他濱對為人類急性骨髓性白血病細胞株之MOLM-13細胞小鼠皮下移植腫瘤的在活體內之併用效果(圖3A)及併用投予時之體重變化(圖3B)的圖。符號×表示無處置對照組,符號白色圓圈表示地西他濱50mg/kg,符號黑色圓圈表示地西他濱1mg/kg,符號白色三角形表示化合物A 25mg/kg,符號 白色四方形表示化合物A 25mg/kg+地西他濱50mg/kg,符號黑色四方形表示化合物A 25mg/kg+地西他濱1mg/kg。橫軸表示腫瘤移植後之日數。圖3A縱軸表示由腫瘤徑算出的推定腫瘤體積,圖3B縱軸表示相對於投予初日之體重的體重變化率。橫軸上之符號白色三角形表示化合物A之投予日,黑色三角形表示地西他濱1mg/kg之投予日,白色菱形表示地西他濱50mg/kg之投予日。誤差槓係上段表示SE,下段表示SD。
圖4呈示化合物A與地西他濱對為人類急性骨髓性白血病細胞株之MOLM-13細胞小鼠皮下移植腫瘤的在活體內之併用效果(圖4A)及併用投予時之體重變化(圖4B)的圖。符號×表示無處置對照組,符號白色圓圈表示地西他濱50mg/kg,符號黑色圓圈表示地西他濱1mg/kg,符號黑色三角形表示化合物A 50mg/kg,符號白色四方形表示化合物A 50mg/kg+地西他濱50mg/kg,符號黑色四方形表示化合物A 50mg/kg+地西他濱1mg/kg。橫軸表示腫瘤移植後之日數,圖4A縱軸表示由腫瘤徑算出的推定腫瘤體積,圖4B縱軸表示相對於投予初日之體重的體重變化率。橫軸上之符號白色三角形表示化合物A之投予日,黑色三角形表示地西他濱1mg/kg之投予日,白色菱形表示地西他濱50mg/kg之投予日。誤差槓係上段表示SE,下段表示SD。
於本發明,(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺(DS-3032)係WO2012/121361之實施例70的化合物。本化合物可藉由WO2012/121361記載之方法來製造(WO2012/121361係經由引用而全部被併入本說明書中)。
於哺乳類,在生殖細胞、胚發生的初期、以及使細胞產生的蛋白質變化的分化時期,基因組的甲基化樣式會變化。作為新近描繪DNA中甲基化樣式的酶DNMT3A及DNMT3B,以及於複製過程中將一旦描繪的DNA甲基化樣式傳入下一世代細胞的酵素DNMT 1,共計存有3種之DNA甲基轉移酶。於本發明,DNA甲基轉移酶抑制劑可為抑制上述之任一者之酵素活性者,亦可為抑制全部的酵素活性者,抑制形式亦未限定。DNA甲基轉移酶抑制劑係主要被分類為核酸衍生物及非核酸抑制劑。就核酸衍生物而言,可列舉阿扎胞苷、地西他濱、折布拉林(zebularine)、硫鳥嘌呤、5-氟-2’-去氧胞苷、4’-硫-2’-去氧胞苷等,就非核酸抑制劑而言,可列舉MG98、EGCG、Psammaplins、普魯卡因(procaine)、普魯卡因胺(procainamide)、聯胺肼(Hydralazine)、RG108、小白菊內酯(Parthenolide)、薑黃素、米拉黴素A(Mithramycin A)、七尾黴素A(Nanaomycin A)、MSC14778等,但並未限定於此等。此等之DNA甲基轉移酶抑制劑係作為市售品而可容易取得,或可參考公知文獻等而由本項技術領域中具通常知識者合成。
就於本發明所使用的DNA甲基轉移酶抑制劑而言,阿扎胞苷或地西他濱為特佳。
於本發明,阿扎胞苷係4-胺基-1-β-D-呋喃核糖基-1,3,5-三-2(1H)-酮,亦有時記載為5-阿扎胞苷,又亦有記載為委丹扎(註冊商標)或Vidaza(註冊商標)的情形。作為市售品而可容易取得。
於本發明,地西他濱係4-胺基-1-(2-去氧-β-D-赤型-戊呋喃糖基)-1,3,5-三-2(1H)-酮,亦有時記載為5-氮雜-2’-去氧胞苷,又亦有記載為DACOGEN(註冊商標)的情形。作為市售品而可容易取得。
於本發明,(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺及DNA甲基轉移酶抑制劑亦可為各種之藥學上可容許的鹽。
就鹽而言,可列舉例如鹽酸鹽、碘化氫酸鹽等之鹵化氫酸鹽;硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等之無機酸鹽;甲烷磺酸鹽、三氟甲烷磺酸鹽、乙烷磺酸鹽等之低級鏈烷磺酸鹽;苯磺酸鹽、p-甲苯磺酸鹽等之芳基磺酸鹽;甲酸鹽、乙酸鹽、蘋果酸鹽、反丁烯二酸鹽、琥珀酸鹽、檸檬酸鹽、酒石酸鹽、草酸鹽、順丁烯二酸鹽鹽等之有機酸鹽;及鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽等之胺基酸鹽、鈉鹽、鉀鹽、鋰鹽等之鹼金屬鹽;鈣鹽、鎂鹽等之鹼土類金屬鹽;銨鹽等之無機鹽;二苄胺鹽、啉鹽、苯基甘胺酸烷基酯鹽、乙二胺鹽、 N-甲基葡糖胺鹽、二乙基胺鹽、三乙基胺鹽、環己基胺鹽、二環己基胺鹽、N,N’-二苄乙二胺鹽、二乙醇胺鹽、N-芐基-N-(2-苯基乙氧基)胺鹽、哌鹽、四甲基銨鹽、參(羥基甲基)胺基甲烷鹽等之有機胺鹽等。
就(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺之鹽而言,較佳為p-甲苯磺酸鹽。
於本發明,(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑亦有呈游離體或溶媒合物存在的情形。亦有藉由吸收空氣中的水分而呈水合物存在的情形。就溶媒合物而言,只要為醫藥上可容許者即可,並未特別限定,但具體而言,較佳可為水合物、乙醇合物等,又可成為N-氧化物體,此等溶媒合物及N-氧化物體亦包含於本發明之範圍。
(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係依彼等之結構,可產生立體異構物。亦包含此等之立體異構物、及此等之立體異構物體之任意比率的混合物全部。立體異構物之定義係如1996 IUPC,Pure and Applied Chemistry 68,2193-2222所示。(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑呈互變異構物存在的情形,彼等之互變異構物為平衡狀態存在的情形,或某一形為支配性存在的情形之任一者皆包含於本發明之範圍內。互變異構物係指因分子之一個原子的質子位移至其他原子而產生的異構物。
又,(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑亦可為於活體內的生理條件下經由酵素、胃酸等所致的反應而引起酵素性氧化、還原、水解等,或利用胃酸等而引起水解等,會被變換成所冀望的化合物的「醫藥上可容許的前藥化合物」。
就上述前藥而言,可列舉被醯化、烷基化、磷酸化的化合物等。
化合物的前藥可藉由公知方法來製造。又,化合物的前藥亦包含如廣川書店1990年刊「醫藥品之開發」第7卷分子設計163頁~198頁記載的會在生理的條件下變換成所冀望的化合物者。
於本發明,用語「腫瘤」及「癌症」可交替地使用。又,於本發明,係有將腫瘤、惡性腫瘤、癌症、 惡性新生物、癌、肉瘤等總稱,而表現為「腫瘤」或「癌症」的情形。又,用語「腫瘤」及「癌症」亦包含骨髓增生不良症候群(myelodysplastic syndrome)等,會依情形而被區分為前癌症階段的病態。
本發明之一態樣係關於一種醫藥或治療方法,特徵為組合(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑而投予。尤其,因若依據本發明,則會獲得優異的抗腫瘤效果,故本發明之一態樣係關於一種用以治療癌症之醫藥或治療方法,特徵為組合(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑而投予。
於本發明,(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係「特徵為組合而投予」意指假設兩藥劑係組合而被投予。
於本發明,(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4- 基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑為「組合而投予」係指於某一定期間,被投予對象將兩藥劑攝取至其體內。可為於單一製劑中含有兩藥劑的製劑被投予,或可各自各別地被製劑化而各別地被投予。各別地被製劑化的情形,其投予時期並未特別限定,可於同時投予,亦可隔開時間於不同時間,或於不同日被投予。(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑各自於不同時間或不同日被投予的情形,其投予的順序並未特別限定。通常,各自的製劑因按照各自的投予方法而被投予,故彼等之投予有成為相同次數的情形,亦有成為不同次數的情形。又,各自被各別地製劑化的情形,各製劑之投予方法(投予路徑)可相同,亦可利用不同的投予方法(投予路徑)被投予。又,並無兩藥劑同時存在於體內的必要,於某一定期間(例如一個月,較佳為1週,更佳為數日,進一步較佳為1日)之間被攝入體內即可,於任一者投予時,另一者之有效成分亦可自體內消失。
若例示本發明之醫藥之投予形態,則可列舉例如,1)包含(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶 -3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽與DNA甲基轉移酶抑制劑的單一製劑之投予、2)將(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽與DNA甲基轉移酶抑制劑各別地製劑化而獲得的2種製劑之利用同一投予路徑的同時投予、3)將(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽與DNA甲基轉移酶抑制劑各別地製劑化而獲得的2種製劑之利用同一投予路徑的隔開時間差的投予、4)將(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽與DNA甲基轉移酶抑制劑各別地製劑化而獲得的2種製劑之利用不同投予路徑的同時投予、5)將(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽與DNA甲基轉移酶抑制劑各別地製劑化而獲得的2種製劑之利用不同投予路徑的隔開時間差的投予等。
於本發明,作成2種不同製劑的情形,亦可作成含有彼等的套組。
本發明之醫藥係包含(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及/或DNA甲基轉移酶抑制劑、與藥學上可容許的載劑,且可作為靜脈內注射、肌肉內注射、皮下注射等之各種注射劑,或者藉由經口投予或經皮投予等之各種方法來投予。藥學上可容許的載劑係意指參與將組成物自某器官或臓器輸送至其他器官或臓器之藥學上可容許的材料(例如,賦形劑、稀釋劑、添加劑、溶媒等)。
就製劑之調製方法而言,可因應投予法而選擇適當製劑(例如,經口劑或注射劑),以通常使用的各種製劑之調製法來調製。就經口劑而言,可例示例如,錠劑、散劑、顆粒劑、膠囊劑、丸劑、***錠(lozenge)劑、溶液劑、糖漿劑、酏劑、乳劑、或者油性或水性之懸浮液等。於經口投予的情形,可為游離體直接,亦可為鹽之型的任一者。水性製劑係可使藥學上可容許的酸與酸加成物形成,或可作成與鈉等之鹼金屬鹽而調製。注射劑的情形係亦可於製劑中使用安定劑、防腐劑或溶解輔助劑等。將可能含有此等輔助劑等的溶液收容於容器後,亦可藉由凍結乾燥等作成固形製劑而作為用時調製之製劑。又,亦可將一次投予量收容於一個容器,還亦可將複數次投予量收容於一個容器。
就固形製劑而言,可列舉例如,錠劑、散劑、顆粒劑、膠囊劑、丸劑、或***錠劑。此等之固形製劑係可同時含有本發明之化合物與藥學上可容許的添加物。就添加物而言,可列舉例如,填充劑類、增量劑類、結合劑類、崩解劑類、溶解促進劑類、濕潤劑類或潤滑劑類,且可因應必要選擇此等而混合,進行製劑化。
就液體製劑而言,可列舉例如,溶液劑、糖漿劑、酏劑、乳劑、或懸浮劑。就添加物而言,可列舉例如,懸浮化劑或乳化劑,可因應必要選擇此等而混合,進行製劑化。
作為製劑用之物質,可列舉以下,但並未限制於此等:甘胺酸、丙胺酸、麩醯胺酸、天冬醯胺酸、精胺酸或離胺酸等之胺基酸類、抗菌劑、抗壞血酸、硫酸鈉或亞硫酸氫鈉等之抗氧化劑、磷酸、檸檬酸、硼酸緩衝液、碳酸氫鈉、TRIS-鹽酸鹽(Tris-Hcl)溶液等之緩衝劑、甘露糖醇或甘胺酸等之填充劑、乙二胺四乙酸(EDTA)等之螯合劑、咖啡因、聚乙烯吡咯啶、β-環糊精或羥基丙基-β-環糊精等之錯化劑、葡萄糖、甘露糖或糊精等之增量劑、單糖類、二糖類等之其他碳水化物、著色劑、香味劑、稀釋劑、乳化劑或聚乙烯吡咯啶等之親水聚合物、低分子量多肽、鹽形成抗衡離子、氯化苄烷銨(benzalkonium chloride)、苯甲酸、水楊酸、硫柳汞、苯乙醇、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、氯己定(chlorlexidine)、山梨酸或過氧化氫等之防腐劑、甘油、丙二醇或聚乙二醇等之溶媒、甘露糖醇或山梨糖醇 之糖醇、懸浮劑、山梨糖醇酐酯、聚山梨糖醇酯20或聚山梨糖醇酯80等之聚山梨糖醇酯、曲拉通(triton)、胺基丁三醇(tromethamine)、卵磷脂或膽固醇等之界面活性劑、蔗糖或山梨糖醇等之安定化增強劑、氯化鈉、氯化鉀或甘露糖醇.山梨糖醇等之彈性增強劑、輸送劑、賦形劑、及/或藥學上之輔助劑。此等之製劑用物質之添加量,相對於藥劑之重量,較佳為添加0.01~100倍,特別是添加0.1~10倍。製劑中之較佳醫藥組成物之組成可依本項技術領域中具通常知識者,因應適用疾病、適用投予路徑等而適宜決定。
醫藥組成物中之賦形劑或載劑可為液體,亦可為固體。適當的賦形劑、載劑亦可為注射用之水或生理食鹽水、人工腦脊髓液或非經口投予所通常使用的其他物質。亦可於載劑使用中性之生理食鹽水或含血清白蛋白的生理食鹽水。於醫藥組成物可包含pH7.0-8.5之Tris緩衝液、pH4.0-5.5之乙酸緩衝液、pH3.0-6.2之檸檬酸緩衝液。又,此等之緩衝液中亦可含有山梨糖醇或其他化合物。
就阿扎胞苷之製劑之適合例而言,可列舉添加了D-甘露糖醇的注射用冷凍乾燥製劑,但並未限定於此。
就地西他濱之製劑之適合例而言,可列舉含有磷酸二氫鉀及氯化鈉作為添加劑的注射用凍結乾燥製劑,但未限定於此。
本發明可用於哺乳類,特別是人類之癌症治療。本發明之醫藥之投予量及投予間隔係可依疾病的部位、患者的身高、體重、性別或病歴,根據醫師的判斷加以適宜選擇。將本發明之醫藥對人類投予的情形,投予量之範圍,每一種類之有效成分,每1日為約0.01mg/kg體重~約500mg/kg體重,較佳為約0.1mg/kg體重~約100mg/kg體重。對人類投予的情形,較佳為每1日1次,或者分成2至4次投予,且以適當間隔重複為較佳。又,1日量係根據醫師的判斷而依需要亦可超過上述的量。
就阿扎胞苷而言,對於成人,係將75mg/m2(體表面積)以1日1次7日皮下投予或花費10分鐘點滴靜脈注射,停藥3週。可列舉將此作為1次週期,而重複投予的方法作為較佳例,但亦可依患者的狀態而適宜增減。
就地西他濱而言,對於成人,係將1次15mg/m2(體表面積)以每8小時花費3小時持續點滴靜脈注射,將其於3日間連日投予。可列舉將此投予週期每6週重複的方法、及以5日間連續進行1日1次將20mg/m2之地西他濱花費1小時以上持續點滴靜脈注射,停藥23日當成1週期而重複投予的方法,但亦可依患者的狀態而適宜增減。
成為治療對象的癌症之種類,係只要對本發明之併用治療被確認有感受性的癌症則未特別限定,但可列舉血癌、腦腫瘤、頭頸部癌、食道癌、胃癌、闌尾 癌、大腸癌、肛門癌、膽囊癌、膽管癌、胰臟癌、胃腸道基質瘤、肺癌、肝癌、間皮瘤、甲狀腺癌、腎臟癌、***癌、神經內分泌腫瘤、黑色素瘤、乳癌、子宮體癌、子宮頸癌、卵巢癌、骨肉瘤、軟組織肉瘤、卡波西氏肉瘤、肌肉瘤、膀胱癌或睪丸癌。
其中較佳為血癌,就血癌而言,可列舉慢性淋巴性白血病(CLL)、小淋巴球性淋巴瘤(SLL)、高風險之CLL、非CLL/SLL淋巴瘤、濾泡性淋巴瘤(FL)、瀰漫性大細胞型B細胞淋巴瘤(DLBCL)、被套細胞淋巴瘤(MCL)、華氏巨球蛋白血症、多發性骨髓瘤(MM)、邊緣區淋巴瘤、伯奇氏淋巴瘤、非伯奇氏淋巴瘤型高惡性度B細胞淋巴瘤、結外邊緣區B細胞淋巴瘤、急性或慢性之骨髓性(或骨髓球性)白血病、骨髓化生不良症候群或急性淋巴細胞性白血病作為例示。可列舉急性骨髓性白血病及骨髓異型性症候群作為特佳例。
就成為治療對象的癌症之種類而言,由其他觀點,則較佳為將對MDM2抑制劑有感受性的癌症作為對象者,更佳為具有野生型TP53的癌症。
就確認TP53為野生型的方法而言,可列舉使用對變異DNA序列為特異性的探針的微陣列法(AmpliChip p53,Roche Molecular Systems,Inc.等、http://www.ncbi.nlm.nih.gov/pubmed/21319261)、使用對變異DNA序列為特異性的探針的PCR法(qBiomarker Somatic Mutation PCR Arrays,QIAGEN等)、利用Sanger定序儀讀取p53基因序列的方法(http://p53.iarc.fr/Download /TP53_DirectSequencing_IARC.pdf)、利用次世代定序儀讀取p53基因序列的方法(TruSeq Amplicon-Cancer Panel,Illumina http://www.illuminakk.co.jp/products/truseq_amplicon_cancer_panel.ilmn、Oncomine(R)Cancer Research Panel,Lifetechnologies http://www.lifetechnologies.com/jp/ja/home/clinical/preclinical-companion-diagnostic-development/oncomine-cancer-research-panel-workflow.html等)。
本發明之醫藥亦可與其他抗腫瘤劑併用來使用。可列舉例如,抗腫瘤抗生素、抗腫瘤性植物成分、BRM(生物學的反應性控制物質)、荷爾蒙、維生素、抗腫瘤性抗體、分子標的藥、烷基化劑、代謝拮抗劑其他之抗腫瘤劑等。
更具體地,就烷基化劑而言,可列舉例如,氮芥(nitrogen mustard)、氮芥N-氧化物(nitrogen mustard N-oxide)、苯達莫司汀(bendamustine)或氯蒽醌(chlorambutyl)等之烷基化劑、卡巴酮(carboquone)或噻替派(thiotepa)等之氮丙啶(aziridine)系烷基化劑、二溴甘露糖醇(dibromomannitol)或二溴莨菪醇(dibromodicitol)等之環氧化物係烷基化劑、卡莫司汀(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、鹽酸尼莫司汀(nimustine hydrochloride)、鏈脲佐菌素(streptozocin)、氯聯酮(chlorozotocin)或雷莫司汀(ranimustine)等之亞硝基脲(Nitrosourea)系烷基化劑、白消安(busulfan)、甲磺英丙舒凡(improsulfan tosilate)、替莫唑胺(temozolomide)或達卡巴嗪(dacarbazine)等。
就各種代謝拮抗劑而言,可列舉例如,6-巰基嘌呤、6-硫鳥嘌呤或硫代肌苷(thioinosine)等之嘌呤代謝拮抗劑、氟尿嘧啶(fluorouracil)、替加氟(tegafur)、替加氟‧尿嘧啶(tegafur‧uracil)、卡莫氟(carmofur)、去氧氟尿嘧啶(doxifluridine)、溴尿苷(broxuridine)、阿糖胞苷(cytarabine)或依諾他濱(enocitabine)等之嘧啶代謝拮抗劑、甲胺蝶呤(methotrexate)或三甲曲沙(trimetrexate)等之葉酸代謝拮抗劑等。
就抗腫瘤性抗生素而言,可列舉例如,絲裂黴素C(Mitomycin C)、博萊黴素(bleomycin)、培洛黴素(peplomycin)、柔紅黴素(daunorubicin)、阿柔比星(aclarubicin)、多柔比星(doxorubicin)、伊達比星(idarubicin)、吡柔比星(pirarubicin)、THP-阿黴素(THP-adriamycin)、4’-表柔比星(4'-epidoxorubicin)或表柔比星(epirubicin)、色黴素A3(chromomycin A3)或放線菌黴素D(actinomycin D)等。
就抗腫瘤性植物成分及彼等之衍生物而言,可列舉例如,長春地辛(vindesine)、長春新鹼(vincristine)或長春花鹼(vinblastine)等之長春花生物鹼類(Vinca alkaloids)、紫杉醇(paclitaxel)、多西他賽(docetaxel)、卡巴他賽(cabazitaxel)等之紫杉烷類(taxanes)、或依托泊苷(etoposide)或替尼泊苷(teniposide)等之表鬼臼毒素類(epipodophyllotoxins)。
就BRM而言,可列舉例如,腫瘤壞死因子或吲哚美辛(indomethacin)等。
就荷爾蒙而言,可列舉例如,氫化可的松(hydrocortisone)、***(dexamethasone)、甲基潑尼松龍(methyl prednisolone)、潑尼松龍(prednisolone)、普拉睪酮(prasterone)、倍他米松(betamethasone)、氟羥潑尼松龍(triamcinolone)、羥甲烯龍(oxymetholone)、諾龍(nandrolone)、美替諾龍(methenolone)、福司他丁(fosfestrol)、炔雌醇(ethinyl estradiol)、氯地孕酮(chlormadinone)、美雄烷(mepitiostane)或甲羥孕酮(medroxyprogesterone)等。
就維生素而言,可列舉例如,維生素C或維生素A等。
就抗腫瘤性抗體、分子標的藥而言,可列舉曲妥珠單抗(trastuzumab)、利妥昔單抗(rituximab)、西妥昔單抗(cetuximab)、尼妥珠單抗(nimotuzumab)、地諾單抗(denosumab)、貝伐單抗(bevacizumab)、英夫利昔單抗(infliximab)、伊匹單抗(ipilimumab)、纳武單抗(nivolumab)、派姆單抗(pembrolizumab)、阿維魯單抗(avelumab)、皮地利珠單抗(pidilizumab)、阿特朱單抗(atezolizumab)、雷莫蘆單抗(ramucirumab)、伊馬替尼甲磺酸酯(imatinib mesylate)、達沙替尼(dasatinib)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、澳希替尼(osimertinib)、舒尼替尼(sunitinib)、拉帕替尼 (lapatinib)、達拉菲尼(dabrafenib)、曲美替尼(trametinib)、考比替尼(cobimetinib)、帕唑帕尼(pazopanib)、帕博西尼(palbociclib)、帕比司他(panobinostat)、索拉非尼(sorafenib)、克里唑蒂(crizotinib)、威罗菲尼(vemurafenib)、奎扎替尼(quizartinib)、硼替佐米(bortezomib)、卡非佐米(carfirzomib)、伊克昔佐米(ixazomib)、米哚妥林(midostaurin)、基特替尼(gilteritinib)等。
就其他之抗腫瘤劑而言,可列舉例如,順鉑(cisplatin)、卡鉑(carboplatin)、奧沙利鉑(oxaliplatin)、他莫昔芬(tamoxifen)、來曲唑(letrozole)、阿那曲唑(anastrozole)、依西美坦(exemestane)、托瑞米芬檸檬酸鹽(toremifene citrate)、氟維司群(fulvestrant)、比卡魯胺(bicalutamide)、氟他胺(flutamide)、米托坦(mitotane)、亮丙瑞林(leuprorelin)、戈舍瑞林乙酸鹽(goserelin acetate)、喜樹鹼(camptothecin)、異環磷醯胺(ifosfamide)、環磷醯胺(cyclophosphamide)、美法崙(melphalan)、L-天冬醯胺酸酶(L-asparaginase)、依拉酮(acclaton)、西索菲蘭(sizofiran)、畢西巴尼(picibanil)、甲苄肼(procarbazine)、哌泊溴烷(pipobroman)、新抑癌素(neocarzinostatin)、羥基脲(hydroxy Urea)、鳥苯美司(ubenimex)、沙利竇邁(thalidomide)、來那度胺(lenalidomide)、泊馬度胺(pomalidomide)、艾日布林(eribulin)、視網酸(tretinoin)或克速鎮(Krestin)等。
藉由以下所示的實施例具體地說明本發明,但本發明並未被限定於此等例,此等並未以任何方式被限定解釋。
(試驗例1 化合物A與阿扎胞苷之活體內併用效果的檢討)
使用磷酸緩衝生理食鹽水,使為人類急性骨髓性白血病細胞株的MOLM-13細胞懸浮成為5×107個細胞/mL,將所調製的細胞懸浮液0.1mL移植至NOD-SCID小鼠(雄性、6週齡)之皮下。於移植後第6日確認腫瘤體積之平均超過100mm3後,使用腫瘤體積值進行分組。化合物A係以25mg/kg或50mg/kg對小鼠強制經口投予,阿扎胞苷係以2.5mg/kg或4mg/k對小鼠進行了尾靜脈內投予。於併用組中,係依序投予了化合物A 25mg/kg或50mg/kg與阿扎胞苷2.5mg/kg或4mg/kg。化合物A之投予係自分組當日(移植後第6日)起1日1次,連續進行了5日(自移植後第6日至第10日)之後,間隔2日的停藥,以1日1次連續進行了4日(自移植後第13日至第16日),阿扎胞苷投予係自分組當日(移植後第6日)起1日1次,連續進行了5日(自移植後第6日至第10日)。經時地以電子數位游標尺(electronic digital nonius)測量腫瘤的長徑(mm)及短徑(mm),以利用以下所示計算式(4)算出的判定日(腫瘤移植後第17日)之腫瘤增殖抑制率(TGI%)進行了評價。又經時地使用小動物用自動天秤測量體重,利用以下所示的計算式(5)算出體重變化率 (Body weight change%)而檢討藥劑投予對體重的影響,同時將最新的體重測定結果用於投予量算出。
TGI(%)=(1-A/B)×100...(4)
A:化合物投予組之判定日的平均腫瘤體積(*)
B:無處置對照組之判定日之平均腫瘤體積(*)
*:腫瘤體積係以1/2×[腫瘤長徑]×[腫瘤短徑]×[腫瘤短徑]算出。
體重變化(%)=各個體之體重變化率的平均值...(5)
各個體之體重變化率=(1-BWn/BWs)×100
BWn:第n日之體重
BWs:投予開始日之體重
將結果示於圖1至2及表1至3。
推定腫瘤體積(mm3)
體重變化(%)
(試驗例2 化合物A與地西他濱之活體內併用效果之檢討)
使用磷酸緩衝生理食鹽水,使為人類急性骨髓性白血病細胞株的MOLM-13細胞懸浮成為5×107個細胞/mL,將調製的細胞懸浮液0.1mL移植至NOD-SCID小鼠(雄性、6週齡)之皮下。於移植後第6日確認腫瘤體積之平均超過100mm3後,使用腫瘤體積值進行分組。化合物A係以25mg/kg或50mg/kg對小鼠強制經口投予,地西他濱係以1mg/kg或50mg/kg對小鼠進行了尾靜脈內投予。於併用組中,係依序投予了化合物A 25mg/kg或50mg/kg與地西他濱1mg/kg或50mg/kg。化合物A之投予係自分組當日(移植後第6日)起1日1次,連續進行5日(自移植後第6日至第10日)之後,間隔2日的停藥,以1日1次連續進行了4日(自移植後第13日至第16日)。關於地西他濱,50mg/kg組的投予係於分組當日(移植後第6日)進行,1mg/kg組的投予係自分組當日(移植後第6日)起1日1次,連續進行了5日(自移植後第6日至第10日)。經時地以電子數位游標尺測量腫瘤的長徑(mm)及短徑(mm),以利用以下所示計算式(4)算出的判定日(腫瘤移植後第17日)之腫瘤增殖抑制率(TGI%)進行了評價。又經時地使用小動物用自動天秤測量體重,利用以下所示的計算式(5)算出體重變化率(Body weight change%)而檢討對藥劑投予之體重的影響,同時將最新的體重測定結果用於投予量算出。
TGI(%)=(1-A/B)×100...(4)
A:化合物投予組之判定日之平均腫瘤體積(*)
B:無處置對照組之判定日之平均腫瘤體積(*)
*:腫瘤體積係以1/2×[腫瘤長徑]×[腫瘤短徑]×[腫瘤短徑]算出。
體重變化(%)=各個體之體重變化率的平均值...(5)
各個體之體重變化率=(1-BWn/BWs)×100
BWn:第n日之體重
BWs:投予開始日之體重
將結果示於圖3至4及表4至6。
推定腫瘤體積(mm3)
體重變化(%)
Claims (22)
- 一種用以治療癌症之醫藥,其特徵為組合而投予(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑。
- 如請求項1之醫藥,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係各自作為不同製劑的有效成分被含有,而於同時或不同時間被投予。
- 如請求項1之醫藥,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係被含於單一製劑中。
- 如請求項1之醫藥,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑為含有彼等的套組製劑。
- 一種癌症之治療方法,其特徵為組合而投予(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑。
- 如請求項5之治療方法,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係各自作為不同製劑的有效成分被含有,而於同時或不同時間被投予。
- 如請求項5之治療方法,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑係被含於單一製劑中。
- 如請求項5之治療方法,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺或其藥學上可容許的鹽及DNA甲基轉移酶抑制劑為含有彼等的套組製劑。
- 如請求項1至4中任一項之醫藥,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺之鹽為p-甲苯磺酸鹽。
- 如請求項5至8中任一項之治療方法,其中(3’R,4’S,5’R)-N-[(3R,6S)-6-胺甲醯基四氫-2H-哌喃-3-基]-6”-氯-4’-(2-氯-3-氟吡啶-4-基)-4,4-二甲基-2”-側氧基-1”,2”-二氫二螺[環己烷-1,2’-吡咯啶-3’,3”-吲哚]-5’-甲醯胺之鹽為p-甲苯磺酸鹽。
- 如請求項1至4及9中任一項之醫藥,其中DNA甲基轉移酶抑制劑為核酸衍生物。
- 如請求項5至8及10中任一項之治療方法,其中DNA甲基轉移酶抑制劑為核酸衍生物。
- 如請求項1至4及9中任一項之醫藥,其中DNA甲基轉移酶抑制劑為阿扎胞苷(azacytidine)或地西他濱(decitabine)。
- 如請求項5至8及10中任一項之治療方法,其中DNA甲基轉移酶抑制劑為阿扎胞苷或地西他濱。
- 如請求項1至4、9、11及13中任一項之醫藥,其中癌症為血癌、腦腫瘤、頭頸部癌、食道癌、胃癌、闌尾癌、大腸癌、肛門癌、膽囊癌、膽管癌、胰臟癌、胃腸道基質瘤(gastrointestinal stromal tumor)、肺癌、肝癌、間皮瘤(mesothelioma)、甲狀腺癌、***癌、神經內分泌腫瘤、黑色素瘤、乳癌、子宮體癌、子宮 頸癌、卵巢癌、骨肉瘤、軟組織肉瘤、卡波西氏肉瘤(Kaposi's sarcoma)、肌肉瘤、腎臟癌、膀胱癌或睪丸癌。
- 如請求項5至8、10、12及14中任一項之治療方法,其中癌症為血癌、腦腫瘤、頭頸部癌、食道癌、胃癌、闌尾癌、大腸癌、肛門癌、膽囊癌、膽管癌、胰臟癌、胃腸道基質瘤、肺癌、肝癌、間皮瘤、甲狀腺癌、***癌、神經內分泌腫瘤、黑色素瘤、乳癌、子宮體癌、子宮頸癌、卵巢癌、骨肉瘤、軟組織肉瘤、卡波西氏肉瘤、肌肉瘤、腎臟癌、膀胱癌或睪丸癌。
- 如請求項1至4、9、11及13中任一項之醫藥,其中癌症為血癌。
- 如請求項5至8、10、12及14中任一項之治療方法,其中癌症為血癌。
- 如請求項17之醫藥,其中血癌為慢性淋巴性白血病(CLL)、小淋巴球性淋巴瘤(SLL)、高風險之CLL、非CLL/SLL淋巴瘤、濾泡性淋巴瘤(follicular lymphoma,FL)、瀰漫性大細胞型B細胞淋巴瘤(DLBCL)、被套細胞淋巴瘤(mantle cell lymphoma,MCL)、華氏巨球蛋白血症(Waldenstrom's macroglobulinemia)、多發性骨髓瘤(MM)、邊緣區淋巴瘤(marginal zone lymphoma)、伯奇氏淋巴瘤(Burkitt's lymphoma)、非伯奇氏淋巴瘤型高惡性度B細胞淋巴瘤、結外邊緣區B細胞淋巴瘤(Extranodal marginal zone B cell lymphoma)、急性或慢性之骨髓性(或骨髓球性)白血病、骨髓化生不良症候群(myelodysplastic syndrome)或急性淋巴細胞性白血病。
- 如請求項18之治療方法,其中血癌為慢性淋巴性白血病(CLL)、小淋巴球性淋巴瘤(SLL)、高風險之CLL、非CLL/SLL淋巴瘤、濾泡性淋巴瘤(FL)、瀰漫性大細胞型B細胞淋巴瘤(DLBCL)、被套細胞淋巴瘤(MCL)、華氏巨球蛋白血症、多發性骨髓瘤(MM)、邊緣區淋巴瘤、伯奇氏淋巴瘤、非伯奇氏淋巴瘤型高惡性度B細胞淋巴瘤、結外邊緣區B細胞淋巴瘤、急性或慢性之骨髓性(或骨髓球性)白血病、骨髓化生不良症候群或急性淋巴細胞性白血病。
- 如請求項17或19之醫藥,其中血癌為具有野生型之TP53的癌症。
- 如請求項18或20之治療方法,其中血癌為具有野生型之TP53的癌症。
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CN (1) | CN109843329A (zh) |
CA (1) | CA3040840A1 (zh) |
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AU2020323033A1 (en) * | 2019-07-26 | 2021-04-22 | Ascentage Pharma (Suzhou) Co., Ltd. | Pharmaceutical composition of MDM2 inhibitor and use thereof for preventing and/or treating disease |
KR20230004768A (ko) * | 2020-04-23 | 2023-01-06 | 써던 리서취 인스티튜트 | 4'-티오-5-아자-2'-데옥시시티딘을 이용한 혈액암 치료용 조성물 및 그의 용도 |
CN113801120B (zh) * | 2020-06-15 | 2024-03-22 | 苏州亚盛药业有限公司 | Mdm2抑制剂的微悬浮液以及治疗应用 |
BR112023001236A2 (pt) | 2020-07-23 | 2023-04-04 | Southern Res Inst | Polimorfos de 5-aza-4'-tio-2-desoxicitidina |
WO2023134707A1 (en) * | 2022-01-11 | 2023-07-20 | Ascentage Pharma (Suzhou) Co., Ltd. | Methods for treating aml-mrc and mds |
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JPWO2018074387A1 (ja) | 2019-08-08 |
WO2018074387A1 (ja) | 2018-04-26 |
CN109843329A (zh) | 2019-06-04 |
US20190240210A1 (en) | 2019-08-08 |
EP3527226A4 (en) | 2020-06-17 |
JP2021006576A (ja) | 2021-01-21 |
KR20190068544A (ko) | 2019-06-18 |
CA3040840A1 (en) | 2018-04-26 |
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