CN107148416B - 作为新抗癌药的被取代的2,4二氨基-喹啉 - Google Patents
作为新抗癌药的被取代的2,4二氨基-喹啉 Download PDFInfo
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- CN107148416B CN107148416B CN201580058830.2A CN201580058830A CN107148416B CN 107148416 B CN107148416 B CN 107148416B CN 201580058830 A CN201580058830 A CN 201580058830A CN 107148416 B CN107148416 B CN 107148416B
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Abstract
本发明涉及新的2‑伯氨基‑4‑仲氨基‑喹啉衍生物、它们的制备、包含它们的药物组合物以及它们作为药剂的用途。本发明的活性化合物可用于治疗和预防增殖性肿瘤和非肿瘤性疾病。
Description
发明领域
本发明涉及新的2-伯氨基-4-仲氨基-喹啉衍生物、它们的制备、包含它们的药物组合物以及它们作为药剂的用途。本发明的活性化合物用于治疗和预防增殖性肿瘤和非肿瘤性疾病。
发明背景
新抗癌药的药物发现近来已从基于细胞的测定法发展到更集于药物靶标蛋白的充分表征的、分离的和转染辅助表达的蛋白的体外方法。本领域中充分描述了这种蛋白靶向药物发现范例,在人类激酶抑制剂的合理设计的药物发现领域中进行了巨大努力,使得能够探索人类激酶组。实际上,人类激酶可以突变,且激酶失调通常发生在人类癌症的恶性转化、生长和最终转移进化中。在例如白血病、淋巴瘤、非小细胞肺癌、黑素瘤、结肠癌、乳腺癌、肾癌、肝癌中充分确立了这种激酶牵涉癌症的发生和增殖。目前,尽管在一些癌症中靶向人类激酶功能障碍进行了这种巨大努力,但是在抗癌疗法中使用激酶抑制剂的临床突破显然并不伴随治愈或缓解,并且几种癌症对激酶抑制剂的临床应用似乎仍然是天然抵抗(例如肝细胞癌)。此外,激酶抑制剂可以选择体内一些突变和抗性株或转化的细胞可以同样找到补偿的途径。在这种情况下,我们决定考虑整个细胞小室和细胞培养环境,开发无偏表型细胞筛选试验。此外,细胞转化、癌症生长和转移进化的分子理解和分子描述仍然在不断发展,例如最近描述癌干细胞(CSCs)概念或肿瘤起始细胞(TIC)。细胞筛选中的预料不到的效果可能暗示用于发现新的可成药靶标的其它靶标或特异性相互作用。因此,新抗癌药的开发仍然是具有不可预期的结果的独特挑战和用于发现新颖和创新化合物的地方。
本发明人已制备了一系列新的多样性定向的2-氨基-2-仲氨基-芳基喹啉化合物库,针对一组人类癌细胞系(MOLM14、KG-1、MV4-11、A375、HCT116、HepG2、huh-7、MDA-MB-231、CAKI-1、786-O)和从患者中得到的癌症初级细胞筛选了该库,使得能够发现新的抗癌药。此外,这类化合物对人类癌干细胞(CSCs)同样表现出额外的活性,所述癌干细胞被广泛认为是抗癌疗法后癌症复发和再发的原因。在本领域中充分描述的ALDH测定法用作描述针对CSCs的活性的癌干细胞功能标记(Greve,B.等人Cytometry A 2012(81)284-293,Liu,S.等人PLoS One 2013(25)e81050,Ran,D.等人Exp.Hematol.2009(37)1423-1434,Cheung,A.M.等人Leukemia 2007(21)1423-1430,Pearce,D.J.等人Stem Cells 2005(23)752-760)。
因此,本发明的目的在于提供用于预防或抑制多种多样生物体中细胞增殖的活性剂,并提供它们的合成的方法。本发明的另一个目的在于提供药物组合物,其包含治疗有效量的本发明的活性剂(单独或与其它活性剂组合)以及药学上可接受的助剂、稀释剂或载体。
本发明的另一个目的在于提供用于疗法中的活性剂。
本发明的另一个目的在于提供用于治疗和/或预防增殖性和/或肿瘤生成性疾病的方法。
本发明的另一个目的在于提供抑制癌干细胞(CSC)、肿瘤起始细胞、与癌症相关的间充质样细胞、间充质癌细胞或间充质细胞的生长或分化的方法。
发明概述
本发明提供式(I)的化合物,及其任意药学上可接受的盐、溶剂合物、异构体、立体异构体或立体异构体混合物、溶剂合物或前药,
其中
·R1可以选自被R9取代或未被取代的C6-C10芳基;被R9取代或未被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;被R9取代或未被取代的如所定义的包含8-13个原子(包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子)的稠合杂芳基;
·Lw可以选自任选被取代的(C1-C10)烷基;被R4取代的直链或支链(C1-C10)烷基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;C=O;SO;SO2;(C=O)-NR8;(C=O)-O;(C=O)-O-(C1-C4)烷基;SO2-NR8;NR8;其中R4可以选自H;任选被取代的(C1-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;任选被取代的(C6-C10)芳基;被一个或多个取代基取代或未被取代的如所定义的包含8-13个原子(包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子)的稠合杂芳基或5-8元杂芳基环,所述取代基独立地选自氢、卤素原子、被一个或多个卤素原子取代的(C1-C10)烷基、(C1-C10)烷氧基、羟基、氰基、硝基、羧基、NR8R8’、包含1、2或直至3个独立地选自O、N和S的杂原子的4-9元饱和或不饱和环;
·R2选自NR5R6;
·R3可以选自氢原子;卤素原子;被一个或多个卤素原子、羟基、烷氧基、-NR5R6取代或未被取代的直链或支链(C1-C10)烷基;(C2-C10)烯基;(C2-C10)炔基;(C3-C10)环烷基;(C5-C10)环烯基;(C8-C10)环炔基;(C1-C10)烷氧基;羟基;硝基;氰基;NR5R6;O-(R7);(CO)-R7;(CO)-O-R7;(CO)-NR5R6;O-(CO)-R7;O-(CO)-NR5R6;NR5-(CO)-R7;NR5-(CO)-OR7;NR5-(CO)-NR5R6;-(O-CH2CH2-)m-OR11;-(O-CH2CH2-)m-NR11R11’;SO2-R7;NR5-SO2-R7;SO2-NR5R6;NR5-(C2-C6)-烷基-NR5R6;任选被取代的芳基;任选被取代的苄基;任选被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;任选被取代的如所定义的包含8-13个原子(包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子)的稠合杂芳基;任选被取代的包含1、2或直至3个独立地选自O、N和S的杂原子的4-9元杂环基环;
·R5和R6可以独立地选自氢;任选被取代的(C1-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;(CO)-R7;(CO)-O-R7;(CO)-NR8R8’;SO2-R7;SO2-NR8R8’;被NR8R8’取代的(C1-C10)烷基;被NR8R8’取代的(C3-C10)环烷基;任选被取代的芳基;任选被取代的苄基;任选被取代的包含1、2或直至3个选自O、N和S的杂原子的5-8元杂芳基环;任选被取代的包含1、2或3个独立地选自O、N和S的杂原子的饱和或不饱和4-9元杂环基环;或R5和R6可以与它们所共价连接的氮原子一起形成杂环基,其构成可以包含另外1、2或3个选自O、N和S的杂原子的4-9元环;
·R7和R7’可以独立地选自氢;任选被取代的(C1-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;被NR8R8’取代的直链或支链C1-C10烷基;任选被取代的(C6-C10)芳基、任选被取代的苄基、任选被取代的包含1、2或3个独立地选自O、N和S的杂原子的5-8元杂芳族环;
·R8和R8’可以独立地选自氢;任选被取代的(C1-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;或R8和R8’可以与它们所共价连接的氮原子一起形成杂环基,其构成可以包含另外1、2或3个选自O、N和S的杂原子的4-9元环;
·R9可以独立地选自氢;卤素原子;任选被取代的(C1-C10)烷基;被一个或多个卤素原子、羟基、烷氧基取代的直链或支链(C1-C10)烷基;任选被取代的(C2-C10)烯基;任选被取代的(C2-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;任选被取代的(C1-C10)烷氧基;羟基;硝基;氰基;NR5R6;(CO)-R7;(CO)-O-R7;(CO)-NR5R6;O-(CO)-R7;O-(CO)-NR5R6;NR5-(CO)-R7;NR5-(CO)-OR7;NR5-(CO)-NR5R6;SO2-R7;NR5-SO2-R7;SO2-NR5R6;被NR5R6取代的(C1-C10)烷基;NR5-(C2-C10)-烷基-NR5R6;-(O-CH2CH2-)m-OR11;-(O-CH2CH2-)m-NR11R11’;任选被取代的(C6-C10)芳基;任选被取代的苄基;任选被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;任选被取代的杂环基,其构成可以包含1、2或3个选自O、N和S的杂原子的4-9元环;-NR5R10;-O-R10;
·R10可以独立地选自氢;被R12取代或未被取代的(C6-C12)-芳基;被R12取代或未被取代的苄基;被R12取代或未被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;被R12取代或未被取代的如所定义的包含8-13个原子(包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子)的稠合杂芳基;被R12取代或未被取代的杂环基,其构成可以包含0、1、2或3个选自O、N和S的杂原子的4-9元环;
·R11和R11’可以独立地选自氢原子;任选被取代的(C2-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;被一个或多个卤素原子取代或未被取代的直链或支链(C2-C10)烷基;或R11和R11’可以与它们所共价连接的氮原子一起形成杂环基,其构成可以包含另外1、2或3个选自O、N和S的杂原子的饱和或不饱和4-9元环;
·R12可以选自氢原子;卤素原子;被一个或多个卤素原子、羟基、烷氧基、NR11R11’取代或未被取代的直链或支链(C1-C10)烷基;(C2-C10)烯基;(C2-C10)炔基;(C3-C10)环烷基;(C5-C10)环烯基;(C8-C10)环炔基;(Cl-C10)烷氧基;羟基;硝基;氰基;NR11R11’;O-(R7);(CO)-R7;(CO)-O-R7;(CO)-NR11R11’;O-(CO)-R7;O-(CO)-NR11R11’;NR11-(CO)-R7;NR11-(CO)-OR11’;NR11-(CO)-NR11R11’;-(O-CH2CH2-)m-OR11;-(O-CH2CH2-)m-NR11R11’;SO2-R7;NR5-SO2-R7;SO2-NR11R11’;NR11-(C2-C6)-烷基-NR11R11’;任选被取代的芳基;任选被取代的苄基;任选被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;任选被取代的如所定义的包含8-13个原子(包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子)的稠合杂芳基;任选被取代的包含1、2或直至3个独立地选自O、N和S的杂原子的饱和或不饱和4-9元杂环基环;
·n可以表示相等的整数,其可以具有数值0、1、2、3或4的任意一个;
·m可以表示相等的整数,其可以具有数值1、2或3的任意一个;
·w可以表示相等的整数,其可以具有数值0或1的任意一个;
其中术语“任选被取代的”意指任选地被一个或多个取代基取代,所述取代基独立地选自卤素原子、被一个或多个卤素原子取代或未被取代的直链或支链(C1-C10)烷基、被一个或多个卤素原子取代或未被取代的直链或支链(C2-C10)烯基、被一个或多个卤素原子取代或未被取代的直链或支链(C2-C10)炔基、被一个或多个卤素原子取代或未被取代的(C3-C10)环烷基、被一个或多个卤素原子取代或未被取代的(C5-C10)环烯基、被一个或多个卤素原子取代或未被取代的(C8-C10)环炔基、(C1-C10)烷氧基、羟基、氰基、硝基、NR8R8’(其中R8和R8’如上文所定义)。
在一些具体实施方案中,本发明提供选自如下的化合物:
式(Ia)的2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉(1-5)
式(Ib)的2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉(2-2)
式(Ic)的2-[3-甲基-4-(嘧啶-2-基氨基)苯基氨基]-4-(4-叔丁基氨基哌啶-1-基)-喹啉(3-4)
式(Id)的2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-(4-叔丁基氨基哌啶-1-基)-喹啉(4-2)
或其药学上可接受的盐、溶剂合物或前药。
在其它一些具体实施方案中,本发明提供选自2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐(1-6)、2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐(2-3)、2-[3-甲基-4-(嘧啶-2-基氨基)苯基氨基]-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐(3-5)、2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐(4-3)的化合物。
在另一方面,本发明提供药物组合物,其可以包含治疗有效量的上述化合物或其药学上可接受的盐、溶剂合物或前药,以及药学上可接受的助剂、稀释剂或载体。
在一些特定实施方案中,本发明的药物组合物还可以包含一种或多种抗肿瘤药。
在一些特定实施方案中,上述药物组合物可以包含治疗有效量的本发明的化合物,其可以被配制或共同配制在纳米粒中。
在本发明药物组合物的一些具体实施方案中,所述纳米粒可以包含脂质体(lisosomal)可被生物降解的组合物。
在本发明药物组合物的一些具体实施方案中,所述纳米粒可以包含生物相容聚合物或共聚物。
在本发明药物组合物的一些具体实施方案中,所述纳米粒可以与聚乙二醇(PEG)共价或非共价结合。
在本发明药物组合物的一些具体实施方案中,所述纳米粒可以具有约80-约600纳米的平均粒径。
在本发明药物组合物的一些具体实施方案中,所述纳米粒可以是含有信号模体的靶向纳米粒。
在一些具体实施方案中,所述纳米粒可以包含聚合物可被生物降解的组合物。
在一些特别具体的实施方案中,所述聚合物可以基于聚(DL-乳酸-共-乙醇酸),其可以具有7-240kDa的分子量;或聚乳酸(PLA)和聚乙醇酸(PGA)的共聚物,其中分子比可以在95:5-50:50之间。
在本发明药物组合物的一些具体实施方案中,所述纳米粒可以包含选自PLGA纳米粒、PLGA-PEG纳米粒(嵌段类型AB、BA、ABA或BAB,其中A=PLGA和B=PEG)和靶向纳米粒的项目。
在本发明药物组合物的一些具体实施方案中,所述纳米粒可以包含选自脂质体的项目。
在一些实施方案中,本发明的药物组合物可以适合于缓慢释放或持续释放。
在一些具体实施方案中,本发明的药物组合物可以适合于经口给药、肠胃外给药、眼给药、透皮给药、鼻给药或用于吸入。
在本发明药物组合物的一些具体实施方案中,本发明的活性化合物可以与至少一种治疗活性抗癌药结合。
在一些具体实施方案中,本发明的药物组合物可以包含治疗有效量的本发明的化合物与治疗有效量的一种或多种抗肿瘤药的组合,其中构成该组合的成分可以同时、单独或依次用于癌症疗法中。
在本发明药物组合物的一些具体实施方案中,所述抗肿瘤药可以选自由以下药物组成的组:依维莫司、氯喹、羟氯喹、曲贝替定、abraxane、TLK 286、AV-299、DN-101、帕唑帕尼、GSK690693、RTA 744、ON0910.Na、AZD 6244(ARRY-142886)、AMN-107、TKI-258、GSK461364、AZD 1152、恩扎啕林、凡德他尼、ARQ-197、MK-0457、MLN8054、PHA-739358、R-763、AT-9263、培美曲塞、厄洛替尼、达沙替尼(dasatanib)、尼洛替尼、decatanib、帕木单抗、氨柔比星、奥戈伏单抗、Lep-etu、诺拉曲塞、azd2171、巴他布林、奥法木单抗、扎木单抗、艾特咔林、粉防己碱(tetrandrme)、芦比替康、替米利芬、奥利美生、替西木单抗(ticilimumab)、伊匹木单抗、棉酚、Bio 111、131-I-TM-601、ALT-110、BIO 140、CC 8490、西仑吉肽、吉马替康、IL13-PE38QQR、TNO 1001、IPdRl KRX-0402、硫蒽酮、LY 317615、碘[131I]抗肌腱蛋白单抗、维特斯朋(vitespan)、Rta 744、Sdx 102、他仑帕奈、阿曲生坦、Xr 311、罗米地新、ADS-100380、舒尼替尼、5-氟尿嘧啶、伏林司他、依托泊苷、吉西他滨、多柔比星、伊立替康、多柔比星脂质体、5'-脱氧-5-氟尿苷、长春新碱、替莫唑胺、ZK-304709、塞利西利、PD0325901、AZD-6244、卡培他滨、L-谷氨酸、N-[4-[2-(2-氨基-4,7-二氢-4-氧代-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-二钠盐七水合物、喜树碱、PEG-标记的伊立替康、他莫昔芬、枸橼酸托瑞米芬、阿那曲唑(anastrazole)、依西美坦、来曲唑、DES(己烯雌酚)、雌二醇、雌激素、缀合雌激素、贝伐珠单抗、IMC-1C11、CHIR-258、3-[5-(甲基磺酰基哌啶甲基)-吲哚基]-喹诺酮、伐拉尼布、AG-013736、AVE-0005、[D-Ser(But)6,Azgly10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2的乙酸盐、醋酸戈舍瑞林、醋酸亮丙瑞林、双羟萘酸曲普瑞林、醋酸甲羟孕酮、己酸羟孕酮、醋酸甲地孕酮、雷洛昔芬、比卡鲁胺、氟他胺、尼鲁米特、醋酸甲地孕酮、CP-724714;TAK-165、HKI-272、厄洛替尼、拉帕替尼(lapatanib)、卡纽替尼、ABX-EGF抗体、爱必妥、EKB-569、PKI-166、GW-572016、洛那法尼(lonafamib)、BMS-214662、替匹法尼;氨磷汀、NVP-LAQ824、辛二酰苯胺异羟肟酸(suberoylanalide hydroxamic acid)、丙戊酸、制滴菌素A、FK-228、SU11248、索拉非尼、KRN951、氨鲁米特、arnsacrine、阿那格雷、L-天冬酰胺酶、卡介苗(BCG)疫苗、博来霉素、布舍瑞林、白消安、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、克拉屈滨、氯屈膦酸盐、环丙孕酮、阿糖胞苷、达卡巴嗪、更生霉素、柔红霉素、己烯雌酚、表柔比星、氟达拉滨、氟氢可的松、氟甲睾酮、氟他胺、吉西他滨、格列卫、羟基脲、伊达比星、异环磷酰胺、伊马替尼、亮丙瑞林、左旋咪唑、洛莫司汀、氮芥、美法仑、6-巯嘌呤、美司钠、甲氨蝶呤、丝裂霉素、米托坦、米托蒽醌、尼鲁米特、奥曲肽、奥沙利铂、帕米膦酸盐、喷司他丁、普卡霉素、卟菲尔钠、丙卡巴肼、雷替曲塞、利妥昔单抗、链脲霉素、替尼泊苷、睾酮、沙利度胺、硫鸟嘌呤、噻替派、维甲酸、长春地辛、13-顺式-视黄酸、苯丙氨酸氮芥、尿嘧啶氮芥、雌莫司汀、六甲蜜胺、氟尿苷、5-脱氧尿苷、阿糖胞苷、6-巯嘌呤、脱氧考福霉素、骨化三醇、戊柔比星、光辉霉素、长春碱、长春瑞滨、托泊替康、雷佐生、马立马司他、COL-3、新伐司他、BMS-275291、角鲨胺、内皮抑素、SU5416、SU6668、EMD121974、白细胞介素-12、1M862、血管抑素、αVβ3人源化抗单抗、屈昔洛芬、艾多昔芬、螺内酯、非那雄胺、西咪替丁、曲妥珠单抗、地尼白介素2、吉非替尼、bortezimib、紫杉醇、伊立替康、托泊替康、多柔比星、多西他赛、长春瑞滨、贝伐单抗(单克隆抗体)和爱必妥、无乳浮紫杉醇、epithilone B、BMS-247550、BMS-310705、屈洛昔芬、4-羟基他莫昔芬、哌喷昔芬、ERA-923、阿佐昔芬、氟维司群、阿考比芬、拉索昔芬、艾多昔芬、TSE-424、HMR-3339、ZK186619、PTK787/ZK 222584、VX-745、PD 184352、雷帕霉素、40-O-(2-羟乙基)-雷帕霉素、坦罗莫司、AP-23573、RAD001、ABT-578、BC-210、LY294002、LY292223、LY292696、LY293684、LY293646、渥曼青霉素、ZM336372、L-779,450、PEG-非格司亭、达贝泊汀、红细胞生成素、粒细胞集落刺激因子、唑来膦酸盐(zolendronate)、泼尼松、西妥昔单抗、粒细胞巨噬细胞集落刺激因子、组氨瑞林、聚乙二醇化干扰素α-2a、干扰素α-2a、聚乙二醇化干扰素α-2b、干扰素α-2b、阿扎胞苷、PEG L-天冬酰胺酶、来那度胺、吉妥珠单抗、氢化可的松、白细胞介素-11、右丙亚胺、阿仑珠单抗、全反式维甲酸、酮康唑、白细胞介素-2、甲地孕酮、氮芥、甲泼尼龙、替伊莫单抗(ibritgumomab tiuxetan)、雄激素、地西他滨、六甲蜜胺、贝沙罗汀、托西莫单抗、三氧化二砷、可的松、羟乙膦酸钠(editronate)、米托坦、环孢菌素、脂质体柔红霉素、Edwina天冬酰胺酶、锶89、卡索匹坦、奈妥匹坦、NK-1受体拮抗剂、帕洛诺司琼、阿瑞匹坦、苯海拉明、羟嗪、甲氧氯普胺、劳拉西泮、阿普唑仑、氟哌啶醇、氟哌利多、屈大麻酚、地塞米松、甲泼尼龙、丙氯拉嗪、格拉司琼、昂丹司琼、多拉司琼、托烷司琼、培非司亭、依伯汀α和达贝泊汀α、伊匹木单抗(ipilumumab)、威罗菲尼(vemurafenib)、FLT-3抑制剂、VEGFR抑制剂、EGFR TK抑制剂、aurora激酶抑制剂、PIK-1调节剂、Bcl-2抑制剂、HDAC抑制剂、c-MET抑制剂、PARP抑制剂、Cdk抑制剂、EGFR TK抑制剂、IGFR-TK抑制剂、抗HGF抗体、PI3激酶抑制剂、mTOR抑制剂、AKT抑制剂、JAK/STAT抑制剂、限制点1或限制点2抑制剂、黏着斑激酶抑制剂、Map激酶激酶(MEK)抑制剂、VEGF俘获抗体以及它们的混合物。
在另一方面,本发明提供用于治疗和/或预防增殖性疾病和/或肿瘤性疾病的方法,它包括对有此需要的人或动物施用治疗有效量的本发明的化合物或包含它们的药物组合物的步骤。
在另一方面,本发明提供用于抑制癌干细胞(CSC)、肿瘤起始细胞、与癌症相关的间充质样细胞、间充质癌细胞或间充质细胞的生长或分化的方法,它包括对有此需要的人或动物施用治疗有效量的本发明的化合物或包含它们项的药物组合物的步骤。
在另一方面,本发明提供用于治疗和/或预防增殖性疾病和/或肿瘤性疾病的化合物。
在另一方面,本发明提供用于抑制癌干细胞(CSC)、肿瘤起始细胞、与癌症相关的间充质样细胞、间充质癌细胞或间充质细胞的生长或分化的化合物。
附图简述
通过下列实施例并且参考附图,本发明的上述和其它特征和优势将更容易地明显,其中:
图1显示当被用化合物2-3处理时CRC患者来源的细胞(CPP19、CPP30和CPP45)中ALDH+群体细胞的减少(AldefluorTM测定法);
图2显示化合物2-3对肝转移性结肠直肠癌(CRC)患者来源的细胞的肿瘤球体(tumorosphere)形成的抑制;
图3显示化合物1-6在DMSO-d6中的1H NMR光谱;
图4显示化合物2-3在DMSO-d6中的1H NMR光谱;
图5显示化合物3-5在DMSO-d6中的1H NMR光谱;
图6显示化合物4-3在DMSO-d6中的1H NMR光谱。
详细描述
在本说明书中,术语“烷基”,单独地或与其它基团组合,是指1至20个碳原子,优选1至16个碳原子,更优选1至10个碳原子的支链或直链一价饱和脂族烃基团。术语“低级烷基”,单独或组合,表示1至6个碳原子的直链或支链烷基(“C1-C6-烷基”),优选1至5个碳原子的直链或支链烷基(“C1-C5-烷基”),特别优选的是1至3个碳原子的直链或支链烷基(“C1-C3-烷基”)。直链和支链低级烷基的实例是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、异构戊基、异构己基,优选甲基和乙基和丙基和异丙基,最优选甲基。
术语“低级烷氧基”是指基团R'-O-,其中R'是低级烷基,且术语“低级烷基”具有上文给出的含义。低级烷氧基的实例是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基,优选甲氧基和乙氧基和异丙氧基和叔丁氧基,最优选甲氧基和乙氧基。
术语“低级烯基”表示包含烯键和2至6个碳原子的直链或支链烃残基(“C2-C6-烯基”),优选2至5个碳原子(“C2-C5-烯基”),特别优选2至4个碳原子(“C2-C4-烯基”)。低级烯基的实例是乙烯基、1-丙烯基、2-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、异丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、异戊烯基。优选的实例是2-丙烯基、2-丁烯基和异戊烯基。
术语“低级炔基”表示包含炔键和2至6个碳原子的直链或支链烃残基(“C2-C6-炔基”),优选2至5个碳原子(“C2-C5-炔基”),特别优选2至4个碳原子(“C2-C4-炔基”)。炔基的实例是乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、3-丁炔基、4-丁炔基、1-丁-2-炔、1-戊炔基、戊-2-炔-1-基、戊-3-炔-1-基、戊-4-炔-1-基、戊-2-炔-3-基。优选的实例是丙炔-1-基、丙炔-3-基、丁炔-1-基、丁炔-3-基、丁炔-4-基、丁炔-2-炔-1-基。
术语“卤素”是指氟、氯、溴和碘,优选氟、氯和溴。
术语“环烷基”表示包含3至7个碳原子的饱和碳环基团(“C3-C7-环烷基”),例如环丙基、环丁基、环戊基、环己基或环庚基。优选的环烷基是环丙基、环戊基和环己基。
术语“杂环基团”表示完全饱和或不饱和但不是完全不饱和的例如3至7元单环基团或7至11元稠合双环环系,其具有至少一个选自氧原子、氮原子或硫原子的杂原子。杂环基团的每个环可以具有至少一个选自氮原子、氧原子和/或硫原子的杂原子。优选的杂环基团是吡咯烷、哌啶、哌嗪、四氢呋喃、双-四氢呋喃和吗啉。
术语“羧基”意指基团-COOH。
术语“杂芳基”通常是指芳族5元或11元环,其包含至少一个杂原子并且可以另外包含1、2、3或4个选自氮、氧和/或硫的原子,例如吡啶基、吡嗪基、嘧啶基、哒嗪基、2-氧代-1,2-二氢吡啶基、二唑基、异唑基、噻二唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、呋喃基、唑基、异噻唑基和噻唑基。术语“杂芳基”还指包含两个5元或6元环的双环芳族或部分不饱和基团,其中一个或两个环可以包含1、2、3或4个选自氮、氧或硫的原子,例如喹啉基、异喹啉基、噌啉基、吡唑基、咪唑基、噻唑基、噻吩基、呋喃基、唑基、异噻唑基、吡唑并[1,5-a]吡啶基、咪唑并[1,2-a]吡啶基、喹喔林基、喹唑啉基、苯并噻唑基、苯并三唑基、1H-苯并[d]咪唑、苯并[d]异唑基、苯并[d]异噻唑基、苯并[c]异唑基、苯并[c]异噻唑基、吲哚基、异二氢吲哚基、6,7-二氢-5H-吡咯并[3,4-b]吡啶基、2,3-二氢-lH-吡咯并[3,4-c]吡啶基、6,7-二氢-5H-吡咯并[3,4-d]嘧啶基、嘌呤基、吲唑基、吲嗪基、咪唑并[1,2-a]吡啶基、咪唑并[1,5-a]吡啶基、咪唑并[1,5-a]吡嗪基、咪唑并[1,2-a]吡嗪基、1H-咪唑并[4,5-b]吡嗪基、吡唑并[1,5-a]吡啶基、吡咯并[l,2-a]嘧啶基、吡咯并[1,2-a]吡嗪基、吡咯并[1,2-c]嘧啶基、唑并[4,5-b]吡啶基、唑并[4,5-c]吡啶基、唑并[5,4-c]吡啶基、唑并[5,4-b]吡啶基、噻唑并[4,5-b]吡啶基、噻唑并[4,5-c]吡啶基、噻唑并[5,4-c]吡啶基、噻唑并[5,4-b]吡啶基、唑并[5,4-d]嘧啶基、唑并[4,5-d]嘧啶基、噻唑并[5,4-d]嘧啶基、噻唑并[4,5-d]嘧啶基、唑并[4,5-b]吡嗪基、噻唑并[4,5-b]吡嗪基、异唑并[4,5-b]吡嗪基、异噻唑并[4,5-b]吡嗪基、异唑并[4,5-d]嘧啶基、异噻唑并[4,5-d]嘧啶基、异唑并[5,4-d]嘧啶基、异噻唑并[5,4-d]嘧啶基、异唑并[5,4-b]吡啶基、异噻唑并[5,4-c]嘧啶基、异唑并[5,4-c]吡啶基、异噻唑并[4,5-c]吡啶基、异唑并[4,5-c]吡啶基、异唑并[4,5-b]吡啶基、异唑并[4,3-d]嘧啶基、异噻唑并[4,3-d]嘧啶基、异唑并[3,4-d]嘧啶基、异噻唑并[3,4-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[4,3-d]啶基、吡啶并[3,2-d]嘧啶基、吡啶并[2,3-b]吡嗪基、吡啶并[3,4-b]吡嗪基、[1,2,3]三唑并[4,5-b]吡啶基、[1,2,3]三唑并[4,5-c]吡啶基、3H-[1,2,3]三唑并[4,5-d]嘧啶基。优选的杂芳基是吡啶基、噻唑基、异噻唑基、唑基、异唑基、喹唑啉基(quinozolinyl)和吡嗪基。
术语“药学上可接受的盐”是指保留游离碱或游离酸的生物有效性和特性的那些盐,它们不是在生物学或其它方面不合乎需要的。所述盐是与无机酸和有机酸形成的,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等,优选盐酸;所述无机酸例如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、水杨酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、戊二酸、肉桂酸、扁桃酸、苹果酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、N-乙酰半胱氨酸等。此外,可以通过向游离酸中添加无机碱或有机碱制备这些盐。衍生自无机碱的盐包括,但不限于钠、钾、锂、铵、钙、镁盐等。衍生自有机碱的盐包括,但不限于伯胺、仲胺和叔胺类的盐、取代的胺类(包括天然存在的取代的胺类)的盐、环胺类的盐和碱性离子交换树脂的盐,例如异丙基胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N-乙基哌啶、哌啶、聚胺树脂等。式I的化合物还可以以两性离子的形式存在。
式I的化合物的特别优选的药学上可接受的盐是盐酸盐。
式I的化合物还可以被溶剂化,例如水化。溶剂化可以在制备过程中进行或可以作为式I或II的最初无水化合物的吸湿特性的结果发生(水合)。术语“药学上可接受的盐”还包括生理学上可接受的溶剂合物。
“异构体”是具有相同分子式但性质或它们的原子键合顺序或它们的原子空间排列不同的化合物。它们的原子空间排列不同的异构体称作“立体异构体”。彼此不是镜像的立体异构体称作“非对映异构体”,是不能重叠的镜像的立体异构体称作“对映体”,或有时称作光学异构体。
如本申请中所使用的,术语“受试者”或“患者”互换使用。如本申请中所使用的,术语“受试者”是指动物(例如禽类、爬行动物和哺乳动物),优选哺乳动物,包括非灵长类(例如骆驼、驴、斑马、牛、猪、马、山羊、绵羊、猫、狗、大鼠和小鼠)和灵长类(例如猴子、黑猩猩和人类),最优选人类。
如本申请中所使用的,术语“疗法”可以指可以用于预防、治疗、管理或改善疾病的任意方案、方法、组合物、制剂和/或物质,所述疾病包括病毒感染或细菌感染或与之相关的症状、癌症等。在一些实施方案中,术语“疗法”是指生物疗法、支持疗法和/或其它疗法,它们可用于治疗、管理、预防或改善本领域技术人员已知的不同疾病。
术语化合物的“治疗有效量”意指有效预防、缓解或改善疾病症状或延长被治疗的受试者的存活的化合物的量。治疗有效量的确定在本领域的技能范围内。本发明化合物的治疗有效量或剂量可在宽的界限内改变,并且可以按照本领域中已知的方式确定。在每种特定情况中这类剂量可以根据个体需求进行调整,包括被施用的具体化合物、施用途径、被治疗的病症以及被治疗的患者。通常,在对体重约为70千克的成年人进行口服或胃肠外施用的情况中,0.1毫克至5克,优选约0.1毫克至1克,更优选0.5毫克至500毫克,最优选约1毫克至300毫克的日剂量应当是适合的,不过,如果有需要,则可以超出上限。可以将日剂量作为单剂量或分剂量施用,或为了进行胃肠外施用,可以将其作为连续输注给予。
术语“药学上可接受的载体”意欲包括任意和所有与药物施用相容的物质,包括溶剂、分散介质、包衣剂、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂以及其它与药物施用相容的物质和化合物。任意常用介质或物质除了与活性化合物不相容的以外,它们在本发明的组合物中的应用被考虑。还可以将补充的活性化合物掺入组合物。可以通过应用本领域中的已知技术制备这些组合物,所述已知技术如以下文献中所述的技术:Ansel’sPharmaceutical Dosage Forms and Drug Delivery Systems(第10版)2014,Loyd Allen编辑,Howard C.Ansel,Wolters Kluwer Health出版和Remington:The Science andPratice of Pharmacy(第22版)2012,Loyd V.Allen编辑,Pharmaceutical Press出版,通过参考将上述文献各自并入本申请。
如本申请中所使用的,术语“治疗”在对受试者施用疗法以治疗病毒感染的上下文中是指因施用疗法或疗法的组合导致的如下作用的一、二、三、四、五或更多种:(i)疾病和/或与之相关的症状的严重性减轻或改善;(ii)疾病和/或与之相关的症状的持续时间缩短;(iii)疾病和/或与之相关的症状消退;(iv)病原体滴度降低;(v)与疾病相关的器官衰竭减轻;(vi)受试者住院减少;(vii)住院时间减少;(viii)受试者的存活提高;(ix)感染消除;(x)感染和/或与之相关的症状的进展的抑制;(xi)病毒从一种细胞、组织或受试者扩散至另一种细胞、组织或受试者的预防;和/或(xii)另一种疗法的治疗作用增强或改善。
“前药”意指在生物系统内转化成本发明化合物的化合物。前药是无活性或活性低于药物自身的化学衍生物。在施用和在体内扩散后,前药衍生物经历释放活性药物的一个或多个代谢过程。前药转化成药物通常在酶促过程的控制下(通常通过代谢方式,例如水解、还原或氧化)进行,较不常通过其在体内扩散过程中的传统化学反应进行。载体与药物之间的键可以是,但不限于酯、酰胺、碳酸酯、氨基甲酸酯、亚胺、缩醛、醚(例如糖缀合)、可氧化的官能和分子系统、可还原的官能和可还原的分子系统、光敏化官能和光敏化分子系统。例如,包含羟基的化合物的酯前药可以通过体内水解转化成母体分子。本发明包含羟基的化合物的适合的酯类是,例如乙酸酯类、柠檬酸酯、乳酸酯类、酒石酸酯类、丙二酸酯类、草酸酯类、水杨酸酯类、丙酸酯类、琥珀酸酯类、富马酸酯类、马来酸酯类、亚甲基-双-β-羟基萘甲酸酯类、龙胆酸酯类(gestisates)、羟乙基磺酸酯类、二-对甲苯酰酒石酸酯类、甲磺酸酯类、乙磺酸酯类、苯磺酸酯类、对甲苯磺酸酯类、环己基氨基磺酸酯类和奎尼酸酯类(quinates)。作为另一个实例,本发明包含羧基的化合物的酯前药可以通过在体内水解转化成母体分子(酯前药的实例由F.J.Leinweber,Drug Metab.Res.1987,(18)pp379描述,通过参考将其并入本申请)。类似地,本发明包含氨基的化合物的酰基前药可以通过在体内水解转化成母体分子(这些和其它官能团(包括胺、醇)的前药的实例描述在Prodrugs:Challenges and Rewards(第1和2部分);Ed V.Stella,R.Borchardt等人,Springer,2007,以及Prodrugs and Targeted Delivery:Towards Better ADME PropertiesEd.J.Rautio,Seies Ed.R.Mannhold,H.Kubinyl,G.Folkers.Wiley-VCH 2011中,通过参考将上述文献各自并入本申请)。
通常使用前药载体系统以便增加水溶性或脂溶性、降低毒性、增加敏感性化合物的化学和生物学稳定性、增加体内的循环时间(T1/2)、增加总药物暴露(AUC)和器官分布(PK-PD分布)和位置特异性靶向。
涉及实施例1、2、3和4的材料和方法
试剂和溶剂从商品供应商获得并且是在没有进一步纯化的情况下使用的。将二氯甲烷干燥并且在CaCl2上蒸馏,在氩气气氛中分子筛上储存。四氢呋喃在氩气气氛中用钠/二苯酮ketyl进行干燥并且在使用前蒸馏。用Merck硅胶(40-63μΜ或15-40μΜ)作为固定相进行急骤色谱法纯化。
在Bruker Avance 300MHz上记录NMR光谱。分析型超高液相色谱法-质量分析(UHPLC-MS):UPLC Waters Acquity,UV DAD,与质谱仪串联四极Waters Quattro PremierXE偶联。
柱Acquity UPLC BEH C18(2.1x 50mm)1.7μm,流动相:A H2O+0.1%TFA,B:MeCN+0.1%TFA。洗脱条件包含线性梯度(分钟/%B):0/5%B,4/98%B,流速0.4ml/min。
1.实施例1:2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐(1-6) 的制备
中间体4-叔丁基氨基哌啶(1-2)的制备:
1.1.1-苄基-4-叔丁基氨基哌啶(1-1)的合成
在T<15℃向N-苄基-4-哌啶酮(60.0g,314mmol)在500ml无水甲苯和叔丁基胺(135ml,1280mmol)中的溶液中滴加四氯化钛(23.0ml,210mmol)在250ml无水甲苯中的溶液。将得到的混合物在室温搅拌20小时期间,然后通过垫过滤。将甲苯溶液转入高压氢化反应器,加入催化剂二氧化铂(160mg,0.70mmol)。在5巴压力下将氢气导入反应器,使反应在RT进行2天。然后用2M NaOH水溶液(400ml)稀释得到的混合物,通过垫过滤。分离各层,用甲苯萃取水层。用Na2SO4干燥合并的有机层,减压浓缩,得到68.05g(收率88%)橙色油状物,对应于1-苄基-4-叔丁基氨基哌啶。
质量:(ES+)C16H26N2理论值246;测定值247[M+H]
1H NMR(300MHz,CDCl3)
1.2.4-叔丁基氨基哌啶(1-2)的合成
在氢气化学反应器中,在氮气气氛中向氮气脱气的1-苄基-4-叔丁基氨基哌啶(68.05g,276mmol)在700ml甲醇中的溶液中加入披钯碳粉末10wt%,50%湿(29.40g,13.81mmol,5mol%)。在3巴的压力下将氢气导入反应器,使反应在RT进行2天。然后通过垫过滤得到的混合物,减压浓缩滤液,得到38.86g(收率90%)的黄色固体,对应于4-叔丁基氨基哌啶。
质量:(ES+)C9H20N2理论值156;测定值157[M+H]
1H NMR(300MHz,CDCl3)
1.3.2,4-二氯喹啉(1-3)的合成
在0℃向喹啉-2,4-二醇(50.0g,310mmol)中滴加磷酰氯(250ml,2682mmol)。搅拌得到的混合物,回流加热过夜。然后冷却该混合物,减压浓缩,与500ml甲苯共蒸发2次。然后用DCM(500ml)溶解残余物,用冷水洗涤。用DCM萃取水层,合并合并的有机层,用MgSO4干燥,过滤,减压浓缩,得到棕色固体(57.0g,收率93%),对应于2,4-二氯喹啉。
质量:(ES+)C9H5Cl2N理论值197;测定值198[M+H]
1H NMR(300MHz,CDCl3)
1.4.2-(4-氯苯基氨基)-4-氯喹啉(1-4)的合成
在氮气气氛中,向2,4-二氯喹啉(2.00g,10.1mmol)在无水THF(20ml)中的溶液中加入4-氯苯胺(1.45g,11.1mmol)和K2CO3(3.91g,28.3mmol)。用氮气给得到的混合物脱气5分钟,然后加入Xantphos(590mg,1.01mmol)和Pd(OAc)2(120mg,0.5mmol),将该反应混合物回流加热2小时。然后将该反应混合物冷却至室温,减压浓缩。使残余物分配在水与AcOEt之间,用AcOEt萃取水层。用Na2SO4干燥合并的有机层,过滤,减压浓缩,得到黄色油状物。通过急骤色谱法纯化粗产物(梯度为7/3至0/10的环己烷/AcOEt),得到2.13g(收率73%)的黄色固体,对应于2-(4-氯苯基氨基)-4-氯喹啉。
质量:(ES+)C15H10Cl2N2理论值288;测定值289[M+H]
1H NMR(300MHz,CDCl3)
1.5.2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉(1-5)的合成
向2-(4-氯苯基氨基)-4-氯喹啉(1.00g,3.46mmol)和4-(叔丁基氨基)-哌啶(684mg,4.38mmol)在5ml NMP中的溶液中加入N,N-二异丙基乙胺(0.947ml,5.47mmol),将该混合物在140℃加热24小时。然后冷却该反应混合物,用1N NaOH水溶液稀释,用AcOEt萃取得到的混合物。用Na2SO4干燥合并的有机层,过滤,减压浓缩,得到棕色液体。通过急骤色谱法纯化粗产物(梯度为8/2至2/8的环己烷/AcOEt),得到淡黄色固体。使该固体从MeCN中重结晶,得到1.19g(收率84%)的白色固体,对应于2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉。
HPLC-MS:tr=1.24分钟,(ES+)C24H29ClN4理论值408;测定值409[M+H],353[M-tBu+H]
1H NMR(300MHz,CDCl3)
1.6.2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐(1-6)的合成
向2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉(440mg,1.1mmol)在4mlEtOH中的混悬液中滴加371μl 7.25M HCl的EtOH溶液。固体溶解,将该混合物在室温搅拌20分钟。然后将得到的溶液减压浓缩至一半体积,加入6ml乙醚。将得到的混合物在室温搅拌1小时,得到白色固体,将其滤出,用乙醚冲洗,在45℃真空干燥,得到401mg(收率85%)的白色固体,对应于2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐。
HPLC-MS:tr=1.21分钟,(ES+)C24H29ClN4理论值408;测定值409[M+H]353[M-tBu+H]
1H NMR(300MHz,CD3OD)
13C NMR(75MHz,CD3OD)
2.实施例2:2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐(2-3)
的制备
2.1.2-(4-氯苄基氨基)-4-氯喹啉(2-1)的合成
在氮气气氛中向2,4-二氯喹啉(1.00g,5.05mmol)在无水THF(10ml)中的溶液中加入4-氯苄基胺(1.46g,10.1mmol)和t-BuONa(1.36g,14.1mmol)。用氮气给得到的混合物脱气5分钟,然后加入Xantphos(295mg,0.51mmol)和Pd(OAc)2(58mg,0.25mmol),将该反应混合物回流加热2小时。然后将该反应混合物冷却至室温,减压浓缩。使残余物分配在盐水与AcOEt之间,用AcOEt萃取水层。用Na2SO4干燥合并的有机层,过滤,减压浓缩,得到棕色油状物。通过急骤色谱法纯化粗产物(梯度为5/5至0/10的环己烷/DCM),得到897mg(收率59%)棕色固体,对应于2-(4-氯苄基氨基)-4-氯喹啉。
质量:(ES+)C16H12Cl2N2理论值302;测定值303[M+H]
1H NMR(300MHz,CDCl3)
2.2.2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉(2-2)的合成
向2-(4-氯苄基氨基)-4-氯喹啉(1.05g,3.46mmol)和4-(叔丁基氨基)-哌啶(0.684g,4.38mmol)在5ml NMP中的溶液中加入N,N-二异丙基乙胺(0.947ml,5.47mmol),将该混合物在140℃加热22小时。然后冷却该反应混合物,用1N NaOH水溶液稀释,用AcOEt萃取得到的混合物。用Na2SO4干燥合并的有机层,过滤,减压浓缩,得到黄色油状物。通过急骤色谱法纯化粗产物(梯度为8/2至0/10的环己烷/AcOEt),得到黄色固体。使该固体从MeCN中重结晶,得到904mg(收率62%)的白色固体,对应于2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉。
HPLC-MS:tr=1.30分钟,(ES+)C25H31ClN4理论值422;测定值423[M+H],368[M-tBu+H]
1H NMR(300MHz,CDCl3)
2.3.2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐(2-3)的合成
向2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉(450mg,1.06mmol)在2.5ml EtOH中的混悬液中滴加400μl 7M HCl的EtOH溶液。固体溶解,将该混合物在室温搅拌3小时。然后将得到的溶液减压浓缩,添加乙醚。搅拌得到的混合物,在室温下研磨,得到淡黄色固体,将其滤出,用乙醚冲洗,真空干燥。将淡黄色固体溶于纯水,然后冷冻干燥,得到401mg(收率94%)的白色固体,对应于2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐。
HPLC-MS:tr=1.31分钟,(ES+)C25H31ClN4理论值422;测定值423[M+H],369[M-tBu+H]
1H NMR(300MHz,DMSO-d6)
3.实施例3:2-[3-甲基-4-(嘧啶-2-基氨基)苯基氨基]-4-(4-叔丁基氨基哌啶-1-
基)-喹啉盐酸盐(3-5)的制备
3.1.2-甲基-N1-(嘧啶-2-基)-N4-(叔丁基氧基羰基)-苯-1,4-二胺(3-1)的合成
用氮气给2-甲基-N4-(叔丁基氧基羰基)-苯-1,4-二胺(2.40g,10.8mmol)、2-氯嘧啶(0.78g,6.5mmol)和K2CO3(2.24g,16.2mmol)在无水THF(48ml)中的溶液脱气,历时15分钟。然后加入Pd(OAc)2(58mg,0.26mmol)和BINAP配体(320mg,0.52mmol),第二次给该反应混合物脱气,历时20分钟。最终将该反应混合物回流加热1小时。然后将该反应混合物冷却至室温,减压浓缩。使残余物分配在水与AcOEt之间,用AcOEt萃取水层。用Na2SO4干燥合并的有机层,过滤,减压浓缩。通过急骤色谱法纯化粗产物(梯度为10/0至7/3的环己烷/AcOEt),得到650mg(收率33%)的棕色固体,对应于2-甲基-N1-(嘧啶-2-基)-N4-(叔丁基氧基羰基)-苯-1,4-二胺。
HPLC-MS:tr=2.06分钟,(ES+)C16H20N4O2理论值300;测定值301[M+H]
1H NMR(300MHz,CD3OD)
3.2.2-甲基-N1-(嘧啶-2-基)-苯-1,4-二胺(3-2)的合成
在室温向2-甲基-N1-(嘧啶-2-基)-N4-(叔丁基氧基羰基)-苯-1,4-二胺(1.18g,3.93mmol)中滴加3M HCl的甲醇溶液(15ml)。然后将该反应混合物在室温搅拌,历时1小时。然后减压浓缩该反应体系,使残余物分配在DCM与1M NaOH水溶液之间,用DCM萃取水层。用Na2SO4干燥合并的有机层,过滤,减压浓缩,得到787mg(收率98%)的黄色油状物,对应于2-甲基-N1-(嘧啶-2-基)-苯-1,4-二胺。
质量:(ES+)C11H12N4理论值200;测定值201[M+H]
1H NMR(300MHz,CD3OD)
3.3.2-[4-(2-嘧啶基氨基)-3-甲基-苯基氨基]-4-氯喹啉(3-3)的合成
用氮气给2-甲基-N1-(嘧啶-2-基)-苯-1,4-二胺(771mg,3.85mmol)、2,4-二氯喹啉(693mg,3.5mmol)和K2CO3(1.35g,9.80mmol)在无水THF(7ml)中的溶液脱气,历时20分钟。然后加入Pd(OAc)2(47mg,0.21mmol)和XantPhos配体(61mg,0.10mmol),第二次给该反应混合物脱气,历时20分钟。最终将该反应混合物回流加热4小时。然后将该反应混合物冷却至室温,减压浓缩。使残余物分配在水与AcOEt之间,用AcOEt萃取水层。用Na2SO4干燥合并的有机层,过滤,减压浓缩。通过急骤色谱法纯化粗产物(梯度为10/0至5/5的环己烷/AcOEt),得到520mg(收率41%)的黄色固体,对应于2-[4-(2-嘧啶基氨基)-3-甲基-苯基氨基]-4-氯喹啉。
质量:(ES+)C20H16ClN5理论值361;测定值362[M+H]
3.4.2-[4-(2-嘧啶基氨基)-3-甲基-苯基氨基]-4-(4-叔丁基氨基哌啶-1-基)-喹 啉(3-4)的合成
向2-[4-(2-嘧啶基氨基)-3-甲基-苯基氨基]-4-氯喹啉(350mg,0.97mmol)在NMP(1.5ml)中的溶液中加入4-叔丁基氨基哌啶(760mg,4.80mmol)。将得到的溶液在200℃在实验室微波炉中加热30分钟。然后冷却得到的混合物,使其分配在水与AcOEt之间,用AcOEt萃取水层。用Na2SO4干燥合并的有机层,过滤,减压浓缩。通过急骤色谱法纯化粗产物(梯度为10/0至5/5的环己烷/AcOEt),得到75mg(收率16%)的棕色固体,对应于2-[4-(2-嘧啶基氨基)-3-甲基-苯基氨基]-4-(4-叔丁基氨基哌啶-1-基)-喹啉。
HPLC-MS:tr=1.15分钟,(ES+)C29H35N7理论值481;测定值482[M+H],426[M-tBu+H]
3.5.2-[4-(2-嘧啶基氨基)-3-甲基-苯基氨基]-4-(4-叔丁基氨基哌啶-1-基)-喹 啉盐酸盐(3-5)的合成
将3.0M HCl的EtOH溶液(290μL)滴加到2-[4-(2-嘧啶基氨基)-3-甲基-苯基氨基]-4-(4-叔丁基氨基哌啶-1-基)-喹啉(75mg,0.16mmol)中。过滤得到的混合物,减压蒸发,得到80mg(收率93%)的淡黄色固体,对应于2-[4-(2-嘧啶基氨基)-3-甲基-苯基氨基]-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐。
HPLC-MS:tr=1.15分钟,(ES+)C29H35N7理论值481;测定值482[M+H],426[M-tBu+H]
1H NMR(300MHz,CD3OD+几滴DMSO-d6)
4.实施例4:2-[3-甲基-4-(嘧啶-2-基氨基)苯基氨基]-4-(4-叔丁基氨基哌啶-1- 基)-喹啉盐酸盐(4-3)的制备
4.1.2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-氯喹啉(4-1)的 合成
向2-甲基-N1-[4-(吡啶-3-基)-嘧啶-2-基]苯-1,4-二胺(1.18g,4.26mmol)、2,4-二氯喹啉(767mg,3.87mmol)在无水THF(11.9ml)中的溶液中加入K2CO3(2.7g,19.0mmol),用氮气给该反应混合物脱气,历时15分钟。然后加入XantPhos配体(226mg,0.387mmol)和Pd(OAc)2(44mg,0.19mmol),第二次给该反应混合物脱气,历时15分钟。最终将该反应混合物回流加热过夜。然后将该反应混合物冷却至室温,减压浓缩。使残余物分配在水与AcOEt之间,用AcOEt萃取水层。用Na2SO4干燥合并的有机层,过滤,减压浓缩。通过急骤色谱法纯化粗产物(梯度为10/0至0/10的环己烷/AcOEt),得到1.08g(收率64%)的棕色固体,对应于2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-氯喹啉。
质量:(ES+)C25H19ClN6理论值438;测定值439[M+H]
1H NMR(300MHz,CD3OD)
4.2.2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-(4-叔丁基氨基 哌啶-1-基)-喹啉(4-2)的合成
向2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-氯喹啉(1.0g,2.28mmol)在NMP(10ml)中的溶液中加入4-叔丁基氨基哌啶(1.8g,11.0mmol)。将得到的溶液在200℃在实验室微波炉中加热90分钟。将得到的混合物分配在水与AcOEt之间,用AcOEt萃取水层。用Na2SO4干燥合并的有机层,过滤,减压浓缩。通过急骤色谱法纯化粗产物(AcOEt/DCM 3/2,然后DCM/MeOH 9/1),得到1.01g黄色固体,使其从EtOH中重结晶,得到550mg(收率43%)的白色固体,对应于2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-(4-叔丁基氨基哌啶-1-基)-喹啉。
HPLC-MS:tr=1.20分钟,(ES+)C34H38N8理论值558;测定值559[M+H],503[M-tBu+H]
1H NMR(300MHz,DMSO-d6)
4.3.2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-(4-叔丁基氨基 哌啶-1-基)-喹啉盐酸盐(4-3)的合成
向2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-(4-叔丁基氨基哌啶-1-基)-喹啉在EtOH(5.5ml)中的混悬液中滴加3.0M HCl的EtOH溶液(4ml)。过滤出形成的黄色固体,然后与环己烷一起研磨。过滤出混悬液,得到505mg(收率77%)的白色固体,对应于2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐。
HPLC-MS:tr=1.22分钟,(ES+)C34H38N8理论值558;测定值559[M+H],503[M-tBu+H]
1H NMR(300MHz,CD3OD+几滴DMSO-d6)13C NMR(125MHz,CD3OD)
5.实施例5:化合物1-6、2-3、3-5和4-3在MOLM-14、KG-1、MV4-11、A375、HCT-116、 HepG2、Huh-7、MRC-5、MDA-MB-231、ARPE-19细胞系和PBMC细胞中的活性谱
细胞培养:将所有细胞系维持在包含1%青霉素-链霉素(Dutscher,P06-07100)和10%胎牛血清(Gibco,W3387L)(但是20%用于KG-1细胞系和PBMC)的培养基中,并在37℃与5%CO2下培养。
将HepG2、Huh7、HCT-116、MDA-MB-231和A375细胞系在Dulbecco改良的Eagle培养基(Dutscher,L0103)中培养。
将KG-1和MV4-11细胞系维持在Iscove改良的Dulbecco培养基中(Dutscher,L0190)中。
将MOLM-14细胞系维持在MEMα培养基(Gibco,22561-021)中。
将PBMC维持在RPMI 1640培养基(Dutscher,L0498)中。
将MRC-5细胞系维持在MEM(Dutscher,L0416)中。
将ARPE-19细胞系维持在DMEM:F12培养基(Dutscher,L0093)中培养。
细胞生存力测定:使用Infinite F200Pro发光计(Tecan),使用发光细胞生存力测定法,按照制造商(Promega,Ref G7571)所述,测定细胞生存力。简言之,对于贴壁细胞,将细胞在96孔板(白色,底部透明)中铺板,每孔90μl的培养基中,并在测定前使其生长过夜。对于在悬浮液中生长的细胞,在测定前立即将细胞在96孔板上铺板。每孔接种的细胞数量如下表1中所示:
表1:用于细胞生存力测定的每孔接种的细胞数量
项目 | 细胞系 | 每孔细胞数量 |
1 | HCT-116 | 2,000 |
2 | A375 | 800 |
3 | Huh7 | 10,000 |
4 | HepG2 | 7,500 |
5 | MOLM-14 | 10,000 |
6 | KG-1 | 20,000 |
7 | MV4-11 | 20,000 |
8 | PBMC | 10,000 |
9 | MRC-5 | 5,000 |
10 | ARPE-19 | 5,000 |
11 | MDA-MB-231 | 10,000 |
将化合物以不同浓度加到每个孔中,并将细胞培养物温育72小时。使用介质(H2O)作为对照,并且以恒定百分比的H2O测试所有化合物。加入100μl后,使用Infinite F200Pro(Tecan)测量发光。EC50值被确定为将发光值降低至对于未处理的细胞培养物所获得的信号的50%所需的化合物的剂量。使用计算机程序Graphpad Prism v5(GraphPad Software,Inc.La Jolla,CA)分析实验数据。
所有实验至少按照一式两份进行并且独立地重复两次。
表2:在化合物1-6、2-3、3-5、4-3的存在下MOLM-14细胞系的生长抑制测定
表3:在化合物2-3的存在下MOLM-14、KG-1、MV4-11细胞系和PBMC的生长抑制测定
表4:在化合物2-3的存在下A375、HCT-116、HepG2和Huh-7细胞系的生长抑制测定
细胞系 | A375 | HCT-116 | HepG2 | Huh-7 |
描述 | 恶性黑素瘤 | 结肠直肠癌 | 肝细胞癌 | 肝细胞癌 |
EC<sub>50</sub>(μM) | 1.0 | 1.6 | 0.9 | 1.7 |
表5:在化合物2-3的存在下MRC-5、MDA-MB-231和ARPE-19细胞系的生长抑制测定
细胞系 | MRC-5 | MDA-MB-231 | ARPE-19 |
描述 | 人胎儿肺成纤维细胞 | 乳腺腺癌 | 人视网膜色素化上皮 |
EC<sub>50</sub>(μM) | ≈3.4 | 2.0 | ≈6.9 |
表6:在化合物4-3的存在下MOLM-14、A375、HCT-116和HepG2细胞系的生长抑制测定
细胞系 | MOLM-14 | A375 | HCT-116 | HepG2 |
描述 | 急性髓性白血病 | 恶性黑素瘤 | 结肠直肠癌 | 肝细胞癌 |
EC<sub>50</sub>(μM) | 2.3 | 1.4 | 1.8 | 6.3 |
6.实施例6:MOLM-14细胞系中的ALDH+房室分析
在补充有10%v/v胎儿牛血清、1%青霉素-链霉素的MEMα培养基中培养MOLM-14细胞系,并维持在37℃与5%CO2下。在测定之前,即刻将10,000个细胞在96孔板上铺板。
将每个化合物以不同浓度(6个浓度的组合)加入每个孔中,并将细胞培养物温育72小时。将介质(H2O)用作对照,所有化合物以恒定百分比的介质进行测试。使用Centro(Berthold,法国)平板读数器,应用发光细胞生存力测定法,按照制造商(Promega,Ref G7571Madison,WI,USA)所述,测定细胞生长晕。
在每个实验中,每个点代表细胞培养物中一式三份的平均值。
使用计算机程序Graphpad Prism v5(GraphPad Software,Inc.La Jolla,CA)分析实验数据,并且将EC50值确定为将吸光度值降低至对于介质处理的细胞培养物所获得的信号的50%所需的化合物的剂量。
醛脱氢酶(ALDH)隔室和醛脱氢酶活性的高活性水平(ALDH+)的分析用于检测肿瘤起始细胞(癌干细胞,CSC)群体。如在MOLM-14急性髓性白血病细胞系群体中那样,AldefluorTM试剂盒测定法(StemCell Technologies,01700)允许评价药物对CSC细胞的活性(参考文献:Storms,R.W.,Trujillo,A.P.,Springer,J.B.,Shah,L.,Colvin,O.M.,Ludeman,S.M.,&Smith,C.(1999).Isolation of primitive human hematopoieticprogenitors on the base of aldehyde dehydeogenase activity.Proceedings of theNational Academy of Sciences,96(16),9118-9123)。根据制造商描述的方法,使用AldefluorTM试剂盒测定法。简言之,将MOLM-14细胞系在补充有10%v/v胎牛血清、1%青霉素-链霉素的MEMα培养基中培养,并维持在37℃与5%CO2下。在该测定中使用5.105个细胞。每种化合物以不同的浓度加入(见表8),并将细胞培养物温育72小时。将介质(H2O)用作对照,所有化合物以恒定百分比的介质进行测试。将从细胞培养物获得的细胞在包含BodipyTM-氨基乙醛(荧光ALDH醛底物)的AldefluorTM缓冲液测定法中在37℃下温育45分钟。ALDH将荧光底物BAAA转化成保留在细胞中的BodipyTM-氨基乙酸(BAA)。在AldefluorTM测定缓冲液中存在主动外流抑制剂,以避免来自底物产物ALDH依赖性转化的BAA从细胞中主动流出。荧光信号与细胞中的ALDH活性成正比,并通过流式细胞术测量。阴性对照用于测量背景荧光水平。为此目的,使用4-(N,N-二乙基氨基)-苯甲醛(DEAB)作为选择性ALDH抑制剂。使用可固定远红死细胞染色试剂盒(Invitrogen)进行生存力细胞计数。使用计算机程序Graphpad Prism v5(GraphPad Software,Inc.La Jolla,CA)分析实验数据,并且将EC50值确定为将吸光度值降低至对于介质处理的细胞培养物所获得的信号的50%所需的化合物的剂量。
表7:在阿糖胞苷和化合物2-3的存在下MOLM-14细胞系的生长抑制测定
化合物 | 阿糖胞苷 | 2-3<sup>a</sup> |
EC<sub>50</sub>(μM) | 0.290 | 2.2 |
a:EC50得自实施例5中所述的方法,参见表3
表8:使用AldefluorTM试剂盒测定法化合物2-3导致的MOLM-14细胞系中ALDH群体减少
7.实施例7:在化合物2-3的存在下Hep3B-Luc细胞系的生长抑制测定法(EC50,μM)
在化合物处理之前,将化合物溶于H2O中以制成10mM储备溶液。然后用包含10%胎牛血清(Gibco,10099141)的MEM培养基(Gibco,1128319)制备工作溶液(5倍最终浓度)。
当进行测定法时,多柔比星对BEL-7402细胞系(人原发性肝细胞癌)的剂量反应试验将用作每个测定板中的内部对照用于测定法。补充有5%H2O(5x)的MEM培养基将作为阴性对照添加到细胞中。每个孔中最终的H2O浓度为1%。
将Hep3B-Luc细胞系(用于原位肿瘤模型的萤光素酶转染的人肝癌细胞系)在补充有10%v/v胎牛血清(FBS)、1%青霉素-链霉素的MEM培养基中培养,并维持在37℃与5%CO2下。将800个细胞在384孔平底透明白色板(Corning,3707)上铺板。
测定方法:收集对数期中的细胞并计数。将细胞悬浮液以800个细胞/孔(总体积40μl)加入到384孔板的每个孔中。边缘孔填充PBS缓冲液。加入不同浓度的测试化合物,一式两份(向板中加入10μl 5x化合物溶液)。将测定板在37℃/5%CO2培养箱中培养72小时。使用发光细胞生存力测定法,按照制造商(Promega,Ref G7571)所述,测量细胞生存力。在加入100μl的反应(reactifs)溶液后,使用PHERAstarPlus发光计测量发光。数据由PHERAstar Plus记录,使用Microsoft Excel程序和GraphPadPrism v.6软件进行数据采集和分析。
表9:在化合物2-3的存在下Hep3B-Luc细胞系的生长抑制测定
化合物 | 多柔比星 | 2-3 |
细胞系 | BEL-7402 | Hep3B-Luc |
EC<sub>50</sub>(μM) | 0.15 | 1.1 |
8.实施例8:在化合物2-3的存在下CAKI-1和786-O细胞系的生长抑制测定(EC50,μ M)
细胞培养:将CAKI-1和786-O细胞系维持在包含1%青霉素-链霉素(Dutscher,P06-07100)和10%胎牛血清(Gibco,W3387L)的RPMI1640培养基(Dutscher,L0498)中,并在37℃与5%CO2培养。
细胞生存力测定:使用Infinite F200Pro发光计(Tecan),使用发光细胞生存力测定法,按照制造商(Promega,Ref G7571)所述,测定细胞生存力。简言之,将细胞在96孔板(白色,底部透明)中铺板,每孔90μl的培养基,并在测定前使其生长过夜。每孔接种的细胞数量如下表中所示:
表10:用于CAKI-1和786-O细胞生存力测定的每孔接种的细胞数量
每孔细胞数量 | |
CAKI-1 | 2250 |
786-O | 1250 |
将化合物2-3和两种参考化合物(索拉非尼和舒尼替尼)以不同浓度加到每个孔中,并将细胞培养物温育72小时。对于化合物2-3分析,使用H2O作为阴性对照(=未处理),并以恒定百分比的H2O测试所有浓度。对于索拉非尼和舒尼替尼分析,使用DMSO作为阴性对照(=未处理),并以恒定百分比的DMSO测试所有浓度。温育化合物后72小时,向每个孔中加入100μl的并使用Infinite F200Pro(Tecan)测量发光。EC50值被确定为将发光值降低至对于未处理的细胞培养物所获得的信号的50%所需的化合物的剂量。使用计算机程序Graphpad Prism v5(GraphPad Software,Inc.La Jolla,CA)分析实验数据。所有实验至少一式三份进行,并且重复至少独立的三次。
表11:在化合物2-3和作为对照的索拉非尼、舒尼替尼的存在下CAKI-1细胞系的生长抑制测定
化合物 | EC<sub>50</sub>(μM) | SD |
2-3 | 1.4 | 0.1 |
索拉非尼 | 4.5 | 1.5 |
舒尼替尼 | 1.7 | 0.7 |
表12:在化合物2-3和作为对照的索拉非尼、舒尼替尼的存在下786-O细胞系的生长抑制测定
化合物 | EC<sub>50</sub>(μM) | SD |
2-3 | 2.1 | 0.2 |
索拉非尼 | 6.8 | 1.7 |
舒尼替尼 | 6.0 | 1.1 |
9.实施例9:化合物2-3对肝转移性结肠癌细胞和结肠癌干细胞亚群的体外作用
本研究的目的在于评价化合物2-3对从患者中新鲜分离的肝转移性结肠癌患者来源的细胞的体外细胞毒活性,更具体地对CSCs亚群的体外细胞毒活性。目前很少方法可用于体外追踪CSCs。例如,醛脱氢酶(ALDH)活性可用作鉴定结肠癌中的癌性人干细胞的标志物。此外,通过在补充有生长因子的无血清培养基中悬浮培养细胞,可以富集CSC。在这类条件下,仅CSCs生长为被称作“肿瘤球体”的多细胞三维克隆。通过利用肿瘤球体形成能力,然后我们可以估计样品中CSCs的量,因此评价给定分子对CSCs自我更新能力的影响。
患者来源的肿瘤细胞培养
将患者来源的肝转移细胞(CPP19、30、36和CPP45-临床描述参见表1)维持在具有10%FBS的完全DMEM(Gibco)中。在批准方案内,从CHU-Carémeau(法国)提供的活组织检材中获得细胞。根据所有伦理道德和法律方面,在采样前从患者获得签名的知情同意书。将肿瘤清洗,切碎成碎片(<2mm3),并用重悬于Accumax(Sigma-Aldrich)中的释放酶(liberase)H(0.26U/mL,Roche)消化。在37℃下2小时后,将细胞悬浮液通过40μm筛目过滤,得到单细胞悬浮液并在补充有FBS、谷氨酰胺、抗生素和非必需氨基酸的DMEM培养基中铺板。当形成患者来源的肿瘤细胞的单层时,使用胰蛋白酶/EDTA将细胞分离并重新悬浮于含有10%FBS的DMEM(用于贴壁细胞)或定义的M11培养基(用于球体形成)中。将细胞在37℃和5%CO2的加湿气氛中培养。
体外毒性测定
将细胞以每孔104个细胞接种在具有10%FBS的DMEM中的P96孔板中。24小时后,用化合物2-3处理细胞,处理后72小时通过发光细胞生存力测定法(Promega)评价细胞生存力。使用GraphPad Prism Software v6(Graphpad Software,IncLa Jolla,CA)计算EC50。
AldefluorTM测定法和荧光激活的细胞分选(FACS)
根据制造商的说明(Stem Cell Technologies)进行AldefluorTM测定法(StemCell Technologies,01700)。通过比较含有和不含ALDH抑制剂二乙基氨基苯甲醛(DEAB)的相同样品来鉴定ALDH阳性细胞。在DEAB存在下,将ALDH活性的FACS闸门设置为0.1%。使用MacsQuant分析细胞并且使用Cyflogic软件分析数据。CPP36细胞由于它们的高细胞自体荧光特征而未被用于这些分析中。
球体形成测定法
在超低附着平板(Corning)中,在P96孔中的M11培养基中,在500个细胞/200μl孔铺板后,确定细胞形成球体的评价。M11是DMEM/F12(1:1)培养基(Gibco),其中补充有N2、谷氨酰胺3mM、葡萄糖0.6%、胰岛素4μg/ml(Sigma-Aldrich)、hBasic-FGF 10ng/ml(R&DSystems)和hEGF 20ng/ml(R&D Systems)。在10天后计数尺寸超过50μm的球体,并以每个图像视野中的球体数量表示。CPP45细胞未用于这些分析中,因为它们不能形成肿瘤球体。
统计分析
对于每个实验,数据显示为三次独立实验的平均值S.E.M。GraphPad PrismSoftware v6(Graphpad Software,Inc La Jolla,CA)用于数据分析,即斯氏(student)t检验。
表13:结肠癌患者的临床特征
·化合物2-3对肝转移性结肠直肠癌(CRC)患者来源的细胞的细胞毒性的体外评价
使用发光细胞生存力测定法,如制造商(Promega,Ref G7571)所述,测定化合物2-3在肝脏转移CRC患者来源的细胞中的细胞毒性。将来自未处理的对照细胞的细胞生存力设定为100%。首先在P96平板中以10.000个细胞/100μL/孔的密度接种细胞,并在37℃的5%CO2的加湿气氛中温育24小时。然后将细胞与溶剂(0.1%DMSO,未处理的对照细胞)或增加浓度的化合物2-3一起温育。在0.1至30μM的浓度下温育72小时后,化合物2-3对建立自新鲜肝转移活组织检材的4种不同CRC患者来源的细胞表现出剂量响应细胞毒活性(表14)。
表14:在化合物2-3的存在下对肝转移CRC患者来源的细胞的生长抑制测定
CRC ID | CPP19 | CPP30 | CPP36 | CPP45 |
EC<sub>50</sub>(μM) | 1.88 | 1.22 | 1.45 | 1.12 |
·化合物2-3对来自肝转移CRC患者来源的细胞的AldefluorTM阳性细胞的体外评价
首先将细胞在P96平板中以250.000个细胞/1000μL/孔的密度铺板,并在37℃与5%CO2的加湿气氛中温育24小时。然后将细胞与溶剂(0.1%DMSO)或增加浓度的化合物2-3一起温育72小时。将细胞进行胰蛋白酶消化,收集和洗涤。使用MACSQuant流式细胞仪(Miltenyi biotec),基于低光散射和Sytox Blue死细胞染色阳性(Life Technologies)排除无细胞颗粒和死细胞。然后使用AldefluorTM测定法(Stemcell Technologies,01700)对ALDH光亮细胞的百分比进行定量。加入ALDH抑制剂二乙基氨基苯甲醛(DEAB),以确保ALDH阳性细胞的准确鉴定。当应用ALDH抑制剂DEAB时,荧光减少(向左移动),并绘制一个闸门以描绘这些细胞的上限。该闸门用于选择ALDH高染色亚群。如所示,在1至3μM的浓度下温育72小时后,在建立自新鲜肝转移活组织检材的3种不同的CRC患者来源的细胞中化合物2-3证实对AldefluorTM阳性细胞亚群具有显著(p<0.001)和剂量响应细胞毒活性(图1)。
·化合物2-3阻断肝转移CRC患者来源的细胞的肿瘤球体形成。
体外肿瘤球体形成被广泛用于鉴定实体瘤或异种细胞群体中癌干细胞(CSCs)的存在,因为只有这些细胞具有自我更新的能力。我们使用该测定法作为CSC频率和生存力的功能量度,并且检查了用化合物2-3处理后肝转移患者来源的细胞形成肿瘤球体的能力。为此目的,首先使细胞作为单层生长在具有胎牛血清(FBS)的DMEM完全培养基的组织培养瓶中,直到它们达到接近汇合。将细胞进行胰蛋白酶消化,收集,洗涤以除去FBS并通过40μm网目细胞过滤器。然后将单细胞悬浮液与补充有20ng/ml EGF、20ng/ml bFGF和N2补充剂的由DMEM-F12组成的CSC培养基(即,M11培养基)(Invitrogen,Carlsbad,CA,USA)一起在P96孔超低附着板(Corning Life Sciences,Tewksbury,MA)中培养。将细胞以500个细胞/100μL/孔的密度铺板,并在37℃的5%CO2的加湿气氛中温育。为了确定化合物2-3对肿瘤球体形成效率和球体尺寸的影响,在以200μl最终体积的M11中铺板后24小时,以两种浓度(0.3μM或3μM)加入化合物2-3。10天后,用倒置显微镜检查平板的肿瘤球体形成(>50μm)。取得相对比图片,并且手动测量球体尺寸和数量,且使用ImageJ从图像中计数。如图2中所示,化合物2-3诱导了从肝转移瘤中分离的3种测试的CRC患者来源的细胞(CPP19、CPP30和CPP36)中肿瘤球体形成的显著和剂量依赖性降低。实际上,3μM的化合物2-3显著抑制了肿瘤球体形成效率。与此形成对比的是,除了在3μM对CPP19细胞(p=0.02)以外,所述处理没有统计学上减小肿瘤球体的尺寸。
实施例10:在化合物2-3的存在下肝细胞癌(HCC)患者来源的细胞的生长抑制测定
(EC50,μM)
在CrownBio机构审查委员会批准下,在严格遵照关于涉及人类受试者的医学研究的赫尔辛基宣言下,在书面知情同意后,获得了患者来源的肝细胞癌(HCC)细胞。
将患者来源的肝细胞癌(HCC)细胞维持在包含1%青霉素-链霉素(LifeTechnologies,15070-063)的表15中分别描述的培养基中,其中含有用于原代细胞培养(PCS)的补充剂,该补充剂包含氢化可的松(50nM)、表皮生长因子(20ng/ml)、β-成纤维细胞生长因子(10ng/ml)、肝素(2μg/ml)ITS液体培养基补充剂(1X)和非必需氨基酸(NEAA,0.01mM,1X)。将初级细胞在37℃与含有5%CO2的加湿气氛(95%相对湿度)中培养。
表15:用于患者来源的肝细胞癌(HCC)细胞的培养基和培养条件
项目 | 初级细胞 | 培养基 | 培养条件 |
1 | LI0050 | DMEM/F12+10%FBS+PCS | 37℃,5%CO<sub>2</sub>,95%相对湿度 |
2 | LI0574 | DMEM/F12+10%FBS+PCS | 37℃,5%CO<sub>2</sub>,95%相对湿度 |
3 | LI0612 | DMEM/F12+10%FBS+PCS | 37℃,5%CO<sub>2</sub>,95%相对湿度 |
4 | LI0752 | DMEM/F12+10%FBS+PCS | 37℃,5%CO<sub>2</sub>,95%相对湿度 |
5 | LI0801 | DMEM/F12+10%FBS+PCS | 37℃,5%CO<sub>2</sub>,95%相对湿度 |
6 | LI1005 | DMEM/F12+10%FBS+PCS | 37℃,5%CO<sub>2</sub>,95%相对湿度 |
7 | LI1098 | DMEM/F12+10%FBS+PCS | 37℃,5%CO<sub>2</sub>,95%相对湿度 |
8 | LI1646 | DMEM/F12+10%FBS+PCS | 37℃,5%CO<sub>2</sub>,95%相对湿度 |
使用发光细胞生存力测定法,按照制造商(Promega,Ref G7571)所述,如上述实施例5中所述,进行细胞生长抑制测定。表16中描述了每孔接种的细胞数(在96孔平底透明黑色聚苯乙烯TC处理的微量培养板中,Cat#3340,)。在记录发光之前,将背面密封的黑色贴纸(Cat#6005189,Perkin Elmer)放置到每个板的底部。
表16:用于HCC患者来源的细胞生存力测定的每孔接种的细胞数量
项目 | HCC患者来源的细胞 | 每孔细胞数量 |
1 | LI0050 | 2,500 |
2 | LI0574 | 3,000 |
3 | LI0612 | 4,000 |
4 | LI0752 | 3,500 |
5 | LI0801 | 2,500 |
6 | LI1005 | 2,500 |
7 | LI1098 | 2000 |
8 | LI1646 | 2000 |
使用计算机程序Graphpad Prism V 5.0(GraphPad Software,Inc.La Jolla,CA)分析实验数据,EC50值被确定为将吸光度值降低至介质处理的细胞培养物获得的信号的50%所需的化合物的剂量,并且是至少三次独立实验的平均值。
培养72小时后,化合物2-3对八种不同HCC患者来源的细胞显示了剂量-响应细胞毒活性(参见表17)。
表17:在化合物2-3、索拉非尼和顺铂的存在下肝细胞癌(HCC)患者来源的细胞的生长抑制测定
Claims (10)
1.式(I)的化合物,及其任意药学上可接受的盐,
其中
·R1选自被R9取代或未被取代的C6-C10芳基;被R9取代或未被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;被R9取代或未被取代的包含8-13个原子包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子的稠合杂芳基;
·Lw选自任选被取代的(C1-C10)烷基;被R4取代的直链或支链(C1-C10)烷基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;C=O;SO;SO2;(C=O)-NR8;(C=O)-O;(C=O)-O-(C1-C4)烷基;SO2-NR8;NR8;其中R4选自H;任选被取代的(C1-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;任选被取代的(C6-C10)芳基;被一个或多个取代基取代或未被取代的包含8-13个原子包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子的稠合杂芳基或5-8元杂芳基环,所述的取代基独立地选自氢、卤素原子、被一个或多个卤素原子取代的(C1-C10)烷基、(C1-C10)烷氧基、羟基、氰基、硝基、羧基、NR8R8’、包含1、2或直至3个独立地选自O、N和S的杂原子的4-9元饱和或不饱和环;
·R2选自NR5R6;
·R3选自氢原子;卤素原子;被一个或多个卤素原子、羟基、(C1-C10)烷氧基、-NR5R6取代或未被取代的直连或支链(C1-C10)烷基;(C2-C10)烯基;(C2-C10)炔基;(C3-C10)环烷基;(C5-C10)环烯基;(C8-C10)环炔基;(C1-C10)烷氧基;羟基;硝基;氰基;NR5R6;O-(R7);(CO)-R7;(CO)-O-R7;(CO)-NR5R6;O-(CO)-R7;O-(CO)-NR5R6;NR5-(CO)-R7;NR5-(CO)-OR7;NR5-(CO)-NR5R6;-(O-CH2CH2-)m-OR11;-(O-CH2CH2-)m-NR11R11’;SO2-R7;NR5-SO2-R7;SO2-NR5R6;NR5-(C2-C6)-烷基-NR5R6;任选被取代的苄基;任选被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;任选被取代的包含8-13个原子包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子的稠合杂芳基;任选被取代的包含1、2或直至3个独立地选自O、N和S的杂原子的饱和或不饱和4-9元杂环基环;
·R5和R6独立地选自氢;任选被取代的(C1-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;(CO)-R7;(CO)-O-R7;(CO)-NR8R8’;SO2-R7;SO2-NR8R8’;被NR8R8’取代的(C1-C10)烷基;被NR8R8’取代的(C3-C10)环烷基;任选被取代的苄基;任选被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;任选被取代的包含1、2或直至3个独立地选自O、N和S的杂原子的饱和或不饱和4-9元杂环基环;或R5和R6与它们所共价连接的氮原子连在一起形成杂环基,其构成可以包含另外1、2或3个选自O、N和S的杂原子的4-9元环;
·R7和R7’独立地选自氢;任选被取代的(C1-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;被NR8R8’取代的直链或支链C1-C10烷基;任选被取代的(C6-C10)芳基、任选被取代的苄基、任选被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳族环;
·R8和R8’独立地选自氢;任选被取代的(C1-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;或R8和R8’与它们所共价连接的氮原子连在一起形成杂环基,其构成可以包含另外1、2或3个选自O、N和S的杂原子的4-9元环;
·R9独立地选自氢;卤素原子;任选被取代的(C1-C10)烷基;被一个或多个卤素原子、羟基、(C1-C10)烷氧基取代的直链或支链(C1-C10)烷基;任选被取代的(C2-C10)烯基;任选被取代的(C2-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;任选被取代的(C1-C10)烷氧基;羟基;硝基;氰基;NR5R6;(CO)-R7;(CO)-O-R7;(CO)-NR5R6;O-(CO)-R7;O-(CO)-NR5R6;NR5-(CO)-R7;NR5-(CO)-OR7;NR5-(CO)-NR5R6;SO2-R7;NR5-SO2-R7;SO2-NR5R6;被NR5R6取代的(C1-C10)烷基;NR5-(C2-C10)-烷基-NR5R6;-(O-CH2CH2-)m-OR11;-(O-CH2CH2-)m-NR11R11’;任选被取代的(C6-C10)芳基;任选被取代的苄基;任选被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;任选被取代的杂环基,其构成可以包含1、2或3个选自O、N和S的杂原子的4-9元环;-NR5R10;-O-R10;
·R10独立地选自氢;被R12取代或未被取代的(C6-C12)-芳基;被R12取代或未被取代的苄基;被R12取代或未被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;被R12取代或未被取代的包含8-13个原子包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子的稠合杂芳基;被R12取代或未被取代的杂环基,其构成可以包含0、1、2或3个选自O、N和S的杂原子的4-9元环;
·R11和R11’独立地选自氢原子;任选被取代的(C2-C10)烷基;任选被取代的(C3-C10)烯基;任选被取代的(C3-C10)炔基;任选被取代的(C3-C10)环烷基;任选被取代的(C5-C10)环烯基;任选被取代的(C8-C10)环炔基;被一个或多个卤素原子取代或未被取代的直链或支链(C2-C10)烷基;或R11和R11’与它们所共价连接的氮原子连一起形成杂环基,其构成可以包含另外1、2或3个选自O、N和S的杂原子的饱和或不饱和4-9元环;
·R12选自氢原子;卤素原子;被一个或多个卤素原子、羟基、(C1-C10)烷氧基、NR11R11’取代或未被取代的直链或支链(C1-C10)烷基;(C2-C10)烯基;(C2-C10)炔基;(C3-C10)环烷基;(C5-C10)环烯基;(C8-C10)环炔基;(Cl-C10)烷氧基;羟基;硝基;氰基;NR11R11’;O-(R7);(CO)-R7;(CO)-O-R7;(CO)-NR11R11’;O-(CO)-R7;O-(CO)-NR11R11’;NR11-(CO)-R7;NR11-(CO)-OR11’;NR11-(CO)-NR11R11’;-(O-CH2CH2-)m-OR11;-(O-CH2CH2-)m-NR11R11’;SO2-R7;NR5-SO2-R7;SO2-NR11R11’;NR11-(C2-C6)-烷基-NR11R11’;任选被取代的苄基;任选被取代的包含1、2或3个选自O、N和S的杂原子的5-8元杂芳基环;任选被取代的包含8-13个原子包括1、2、3、4个选自O、N和S的杂原子且包含至少2个碳原子的稠合杂芳基;任选被取代的包含1、2或直至3个独立地选自O、N和S的杂原子的饱和或不饱和4-9元杂环基环;
·n可以表示相等的整数,其可以具有数值0、1、2、3或4的任意一个;
·m可以表示相等的整数,其可以具有数值1、2或3的任意一个;
·w可以表示相等的整数,其可以具有数值0或1的任意一个;
其中术语“任选被取代的”意指任选地被一个或多个取代基取代,所述取代基独立地选自卤素原子、被一个或多个卤素原子取代或未被取代的直链或支链(C1-C10)烷基、被一个或多个卤素原子取代或未被取代的直链或支链(C2-C10)烯基、被一个或多个卤素原子取代或未被取代的直链或支链(C2-C10)炔基、被一个或多个卤素原子取代或未被取代的(C3-C10)环烷基、被一个或多个卤素原子取代或未被取代的(C5-C10)环烯基、被一个或多个卤素原子取代或未被取代的(C8-C10)环炔基、(C1-C10)烷氧基、羟基、氰基和硝基。
2.根据权利要求1的化合物,其选自2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉;2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉;2-[3-甲基-4-(嘧啶-2-基氨基)苯基氨基]-4-(4-叔丁基氨基哌啶-1-基)-喹啉;2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-(4-叔丁基氨基哌啶-1-基)-喹啉或它们的药学上可接受的盐。
3.根据权利要求1的化合物,其选自2-(4-氯苯基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐;2-(4-氯苄基氨基)-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐;2-[3-甲基-4-(嘧啶-2-基氨基)苯基氨基]-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐;2-{4-[4-(吡啶-3-基)-2-嘧啶氨基]-3-甲基-苯基氨基}-4-(4-叔丁基氨基哌啶-1-基)-喹啉盐酸盐。
4.药物组合物,其包含治疗有效量的根据权利要求1-3任一项的化合物或其药学上可接受的盐,以及药学上可接受的助剂、稀释剂或载体。
5.根据权利要求4的药物组合物,其适合于口服、肠胃外给药、眼给药、透皮给药、鼻给药或吸入。
6.根据权利要求4或5的药物组合物,其适合于缓慢或持续释放。
7.根据权利要求1-3任一项的化合物或根据权利要求4-6任一项的药物组合物在制备用于治疗和/或预防增殖性疾病和/或肿瘤性疾病的药物中的用途。
8.根据权利要求7的用途,其中所述的增殖性疾病和/或肿瘤性疾病选自由以下各项组成的组:癌;头癌、肾癌、肝癌、肺癌、鼻咽癌、颈癌、卵巢癌、乳腺癌、宫颈癌、胰腺癌、前列腺癌或胃癌;白血病;恶性淋巴瘤、恶性黑素瘤;骨髓增生性疾病;肉瘤;中枢神经系统的肿瘤;种系肿瘤;睾丸癌;甲状腺癌;星形细胞瘤;食管癌;结肠癌;以及混合型的瘤形成。
9.根据权利要求8的用途,其中所述的白血病是急性髓细胞性白血病、急性淋巴细胞性白血病、急性早幼粒细胞性白血病、急性T细胞成淋巴细胞性白血病、成人T细胞白血病、嗜碱细胞性白血病、嗜酸细胞性白血病、粒细胞性白血病、毛细胞性白血病、白细胞减少性白血病、淋巴细胞性白血病、成淋巴细胞性白血病、淋巴细胞性白血病、巨核细胞型白血病、小原粒型白血病、单核细胞性白血病、嗜中性白细胞性白血病和干细胞白血病。
10.根据权利要求1-3任一项的化合物或根据权利要求4-6任一项的药物组合物在制备用于抑制癌干细胞、肿瘤起始细胞、与癌症相关的间充质样细胞、间充质癌细胞或间充质细胞的生长或分化的药物中的用途。
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