CN106554318A - 氘代二苯基氨基嘧啶化合物 - Google Patents
氘代二苯基氨基嘧啶化合物 Download PDFInfo
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- CN106554318A CN106554318A CN201510621239.5A CN201510621239A CN106554318A CN 106554318 A CN106554318 A CN 106554318A CN 201510621239 A CN201510621239 A CN 201510621239A CN 106554318 A CN106554318 A CN 106554318A
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- 150000003839 salts Chemical class 0.000 claims abstract description 40
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Abstract
本发明属于医药领域,涉及氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,具体涉及式(Ⅰ)所示化合物或其药学上可接受的盐、其制备方法、其药物组合物及其在治疗细胞增殖性疾病中的用途。
Description
技术领域
本发明属于医药领域,涉及氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,具体涉及式(Ⅰ)所示化合物或其药学上可接受的盐、其制备方法、其药物组合物及其在治疗细胞增殖性疾病中的用途。
背景技术
肺癌是严重威胁人类健康的重大疾病,是世界上最常见的恶性肿瘤之一,已成为我国城市人口恶性肿瘤死亡原因的第1位。非小细胞肺癌(NSCLC)占所有类型肺癌的85%以上。EGFR(Epidermal Growth Factor Receptor)是上皮生长因子(EGF)细胞增殖和信号传导的受体,也被称作HER1、ErbB1。EGFR属于ErbB受体家族的一种,该家族包括EGFR(ErbB-1),HER2/c-neu(ErbB-2),HER3(ErbB-3)和HER4(ErbB-4)。EGFR是一种糖蛋白,属于酪氨酸激酶型受体,细胞膜贯通,分子量170KDa。
EGFR抑制剂易瑞沙(Gefinitib)和特罗凯(Erlotinib)等已在临床治疗非小细胞肺癌病人中获得巨大成功,但其耐药问题也日益突出,耐药的主要原因是EGFR-T790M突变,约占耐药病人总数的50%。目前虽有第二代EGFR非可逆抑制剂(Canertinib、Afatinib、Neratinib、Pelitinib等)进入临床试验,但这些分子对EGFR-T790M突变体的选择性差,造成药物临床耐受剂量较低,在其最大耐受剂量下,药物无法在体内达到其有效浓度而使得对多数耐药病人无效。多数临床试验也已被迫终止。此外,皮疹和腹泻是wt-EGFR抑制剂导致的最显著毒副作用。因此开发具有高特异性EGFR-T790M突变体抑制剂已成为解决目前耐药性问题的重要策略。
2014年5月20日,克洛维斯肿瘤公司(Clovis Oncology)宣布,美国FDA授予其试验药物Rociletinib(CO-1686,AVL-301)突破性治疗药物资格,其作为单一药物二线用于治疗T790M突变患者EGFR突变非小细胞肺癌(NSCLC)。
CO-1686可用于治疗EGFR突变型NSCLC,它能够选择性抑制T790M突变型EGFR的同时使野生型EGFR信号闲置。该药开发用于携带初始激活突变EGFR及T790M突变EGFR的NSCLC患者的治疗,所有不同剂量水平均能显示出良好反应和长久益处。
氘代修饰是改进药物代谢性质的一种非常有潜力的新药开发技术。在该方法中,设法通过将一个或多个氢原子用氘原子取代从而减慢CYP介导的药物代谢或减少不期望的代谢物的生成。氘是安全、稳定、不具有放射性的同位素,与氢相比,氘与碳可以形成更强的键。在某些情况下,由氘形成的增加的键强度可以积极影响药物的ADME性质,结果可能会明显地延长其药物代谢循环、减少有毒代谢物的产生和药物间的相互作用、提高安全性以及获得更佳的疗效。
即使氘原子掺入了已知的代谢位置,氘修饰对于药物的代谢性质的影响仍然是不可预测的。因此必须经过氘代分子的实际制备和测试,才能确定氘代药物与非氘代药物在代谢方面的差别。
虽然CO-1686能够有效地抵抗T790M抗性突变,并且同时几乎不抑制wt-EGFR并且无相关的剂量限制性毒性,但是发现具有治疗细胞增值性疾病(如非小细胞肺癌)且具有很好的口服生物利用度且有成药性的新型化合物还是具有挑战性的工作。
因此,本领域仍需要开发对适用作治疗剂的突变型EGFR激酶具有选择性抑制活性或更好的药效学/药代动力学的化合物。
发明内容
本发明的目的是提供一类新型的对突变型EGFR激酶具有选择性抑制活性和具有更好药效学/药代动力学性能的化合物及其用途。
本发明一方面提供一种式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐:
其中:
R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25和R26各自独立地为氢或氘;
R8为三氟甲基;
R9为氢;
附加条件是R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25和R26中至少一个是氘,并且排除如下所示的化合物Ⅰ-2和Ⅰ-16:
在本发明的部分实施方式中,式(Ⅰ)化合物优选至少含有2个氘原子,更优选至少含有4个氘原子,进一步优选至少含有6个氘原子。
在本发明的部分实施方式中,式(Ⅰ)化合物的R16、R17、R22和R23选自氘。
在本发明的部分实施方式中,式(Ⅰ)化合物的R18、R19、R20和R21选自氘。
在本发明的部分实施方式中,式(Ⅰ)化合物的R16、R17、R22和R23或者R18、R19、R20和R21选自氘。
在本发明的部分实施方式中,式(Ⅰ)化合物的R4、R5、R6和R7选自氘。
在本发明的部分实施方式中,式(Ⅰ)化合物的R1、R2和R3选自氘。
在本发明的部分实施方式中,式(Ⅰ)化合物的R10、R11和R12选自氘。
在本发明的部分实施方式中,式(Ⅰ)化合物的R13、R14和R15选自氘。
在本发明的部分实施方式中,式(Ⅰ)化合物的R24、R25和R26选自氘。
在本发明的部分优选实施方案中,式(Ⅰ)所示化合物的实例如下:
化合物 | R1~3 | R4~7 | R10~12 | R13~15 | R16 | R17 | R18 | R19 | R20 | R21 | R22 | R23 | R24~26 |
I-1 | H | H | H | H | D | D | D | D | D | D | D | D | H |
I-3 | H | H | H | H | D | D | H | H | H | H | D | D | H |
I-4 | H | H | H | D | D | D | D | D | D | D | D | D | D |
I-5 | H | H | H | D | H | H | H | H | H | H | H | H | D |
I-6 | H | H | H | D | D | D | H | H | H | H | D | D | D |
I-7 | H | H | H | D | D | D | D | D | D | D | D | D | H |
I-8 | H | H | D | H | H | H | H | H | H | H | H | H | D |
I-9 | H | H | H | D | D | D | H | H | H | H | D | D | H |
I-10 | H | H | H | H | D | D | D | D | D | D | D | D | D |
I-11 | H | H | H | H | H | H | D | D | D | D | H | H | D |
I-12 | H | H | D | H | D | D | H | H | H | H | D | D | H |
I-13 | H | H | D | H | D | D | D | D | D | D | D | D | H |
I-14 | H | H | H | H | D | D | H | H | H | H | D | D | D |
I-15 | H | H | H | D | H | H | D | D | D | D | H | H | D |
I-17 | H | H | D | H | H | H | H | H | H | H | H | H | H |
I-18 | H | H | H | H | H | H | D | D | D | D | H | H | H |
I-19 | H | D | H | H | H | H | H | H | H | H | H | H | H |
I-20 | H | H | H | D | H | H | D | D | D | D | H | H | H |
I-21 | H | H | D | H | H | H | D | D | D | D | H | H | H |
I-22 | D | D | H | H | H | H | H | H | H | H | H | H | H |
I-23 | D | H | H | H | H | H | H | H | H | H | H | H | H |
I-24 | D | D | H | D | H | H | H | H | H | H | H | H | H |
I-25 | H | D | H | H | D | D | D | D | D | D | D | D | H |
I-26 | H | D | H | H | H | H | D | D | D | D | H | H | H |
I-27 | H | D | H | H | D | D | H | H | H | H | D | D | H |
I-28 | D | H | H | H | H | H | D | D | D | D | H | H | H |
在本发明的一些优选实施方案中,式(Ⅰ)所示化合物的实例如下:
在本发明的一些优选实施方案中,所述药学上可接受的盐对应的酸选自盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸、脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸,优选自氢溴酸。
本发明的另一方面提供了一种治疗EGFR介导的疾病的方法,所述方法包括给予治疗有效量的式(Ⅰ)化合物或者其药学上可接受的盐。
本发明的另一个方面提供了式(Ⅰ)化合物或者其药学上可接受的盐在制备治疗EGFR介导的疾病的药物中的用途。
在本发明的部分实施方式中,所述EGFR介导的疾病选自EGFR-T790M激活突变介导的疾病。
在本发明的部分实施方式中,所述EGFR介导的疾病是癌症;所述癌症选自卵巢癌、***、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤、黑色素瘤、***癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病、多发性骨髓瘤、黑色素瘤、间皮瘤;所述肺癌可以选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌。
本发明的另一方面提供了一种药物组合物,其包含治疗有效量的式(Ⅰ)化合物或其药学上可接受的盐和一种或多种药学上可接受的载体或赋形剂。
本发明的药物组合物可通过将本发明的化合物或其盐与适宜的药学上可接受的载体组合而制备,例如可配制成固态、半固态、液态或气态制剂,如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本发明的化合物或其药物可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药,或者局部、经皮、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本发明的药物组合物可以采用本领域众所周知的方法制造,如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
对于口服给药,可以通过将活性化合物与本领域熟知的药学上可接受的载体混合来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等,用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如,可通过下述方法获得:将所述的活性化合物与固体赋形剂混合,任选地碾磨所得的混合物,如果需要则加入其它合适的辅剂,然后将该混合物加工成颗粒,得到了片剂或糖衣剂的核心。适合的辅料包括但不限于:粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、***胶浆、明胶溶液、蔗糖和淀粉糊;滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸;乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙;二氧化硅;交联羧甲基纤维素钠、预交化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣,尤其使用肠溶包衣。
药物组合物还可适用于肠胃外给药,如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本发明所述的式(Ⅰ)化合物或其药学上可接受的盐可以通过任何适用的途径和方法给药,例如通过口服或肠胃外(例如,静脉内)给药。式(Ⅰ)化合物的治疗有效量为从约0.0001到20mg/Kg体重/天,例如从0.001到10mg/Kg体重/天。
式(Ⅰ)化合物的剂量频率由患者个体的需求决定,例如,每天1次或2次,或每天更多次。给药可以是间歇性的,例如,其中在若干天的期间内,患者接受式(Ⅰ)化合物的每日剂量,接着在若干天的期间,患者不接受式(Ⅰ)化合物的每日剂量。
本发明的式(Ⅰ)化合物或者其药学上可接受的盐也可用于制备治疗心血管疾病、炎症、感染、免疫性疾病、细胞增值性疾病、病毒性疾病、代谢性疾病或器官移植的药物中的用途。
本发明的式(Ⅰ)化合物或者其药学上可接受的盐亦可与其他治疗药物联用治疗上述疾病或者延缓所述疾病的进展或发病,所述的其他治疗药物包括但并不限于:5-氟尿嘧啶、FOLFOX、阿瓦斯丁(avastin,bevacizumab)、贝沙罗汀(bexarotene)、硼替佐米(bortezomib)、骨化三醇(calcitriol)、卡奈替尼(canertinib)、卡培他滨(capecitabine)、吉西他滨(gemcitabine)、碳铂(carboplatin)、塞来考昔(celecoxib)、西妥昔单抗(cetuximab)、顺铂(cisplatin)、达沙替尼(dasatinib)、地高辛(digoxin)、埃罗替尼(Erlotinib)、依托泊甙(etoposide)、依维莫司(everolimus)、氟维司群(fulvestrant)、吉非替尼(gefitinib)金雀异黄素(genistein)、伊马替尼(imatinib)、依立替康(irinotecan)、拉帕替尼(lapatinib)、来那度胺(lenalidomide)、来曲唑(letrozole)、亚叶酸(leucovorin)、马妥珠单抗(matuzumab)奥沙利铂(oxaliplatin)、紫杉醇(paclitaxel)、多西他赛(doxetaxel)、帕尼单抗(panitumumab)、PEG化的粒细胞集落剌激因子(pegfilgrastin)、PEG化的α-干扰素(peglated alfa-interferon)、培美曲塞(pemetrexed)、沙柏(satraplatin)、西罗莫司(sirolimus)、舒尼替尼(sunitinib)、舒林酸(sulindac)、泰索帝(taxotere)、替莫唑胺(temozomolomide)、驮瑞塞尔(Torisel)、替西罗莫司(temsirolimus)、替吡法尼(tipifarnib)、曲妥单抗(trastuzumab)、丙戊酸(valproic acid)、长春氟宁(vinflunine)、索拉非尼(Sorafenib)、克唑替尼(Crizotinib)、埃克替尼(Lcotinib)、拉帕替尼(Lapatinib)、托法替尼(Tofacitinib)、PD-0332991(Palbociclib)、安贝生坦(ambrisentan)、CD40和/或CD154特异性抗体、融合蛋白、NF-kB抑制剂、非甾体抗炎药、凝血因子FXa抑制剂(如利伐沙班等)、抗-TNF抗体、抗生素药物如剌孢霉素(calicheamicin)、放线菌素(actinomycin)、阿霉素(doxorubicin)等。
有关定义:
术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
作为药学上可接受的盐,例如,与无机酸形成的盐、与有机酸形成的盐、与酸性氨基酸形成的盐等。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离碱形式的这些化合物与化学计量的适当酸反应来制备。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在,包括水合物形式。一般而言,溶剂化形式与非溶剂化的形式相当,都包含在本发明的范围之内。本发明的某些化合物可以以多晶或无定形形式存在。
本发明中所标记合成的化合物的任何原子若没有特别指定,可代表该原子的任何一种稳定的同位素。除非特别说明,当结构中某一位置被定义为H即氢(H-1)时,该位置仅含天然存在的同位素量。同样,除非特别说明,当结构中某一位置被定义为D即氘(H-2)时,该位置含同位素量至少比天然存在的同位素量(0.015%)大3340倍(即至少会50.1%氘同位素)。
本发明中所标记合成的化合物的氘代率是指标记合成的同位素含量与天然存在的同位素量的比值。本发明中所标记合成的化合物的每个指定氘原子的氘代率可至少为3500倍(52.5%)、至少为4000倍(60%)、至少为4500倍(67.5%)、至少为5000倍(75%)、至少为5500倍(82.5%)、至少为6000倍(90%)、至少为6333.3倍(95%)、至少为6466.7倍(97%)、至少为6566.7倍(98.5%)、至少为6600倍(99%)、至少为6633.3倍(99.5%)。
本发明中的同位素体(isotopologues)是指在化学结构方面仅有同位素组成上不同的化合物。本发明中所标记合成的化合物具有相同的化学结构、仅在其分子的原子组成中同位素的变化。因此,本发明中所标记合成的在特定位置含氘化合物也同样会含非常少的该位置的氢同位素体,本发明中所标记合成的化合物中的某位置的氢同位素体的量取决许多因素,其中包括氘代试剂(D2O、D2、NaBD4、LiAlD4等)的氘同位素纯度以及引入氘同位素合成方法的有效性。然而,如前所述这种某位置的氢同位素体的量总数将少于49.9%。本发明中所标记合成的化合物中的某位置的氢同位素体的量总数将少于47.5%、40%、32.5%、25%、17.5%、10%、5%、3%、1%或0.5%。
本发明中,任何未指定为氘的各原子以其天然同位素丰度存在。
术语“药学上可接受的载体”是指对有机体无明显刺激作用,而且不会损害该活性化合物的生物活性及性能的那些载体。“药学上可接受的载体”是指与活性成份一同给药的、有利于活性成份给药的惰性物质,包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等。关于载体的其他信息,可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005),该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效地治疗目标紊乱、疾病或病症。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
下面描述本发明式(Ⅰ)化合物的制备方法,但这些具体方法不对本发明构成任何限制。
本发明化合物可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
本发明制备方法描述中,化合物基团R1~R26的定义如前文所述。
下面的通用制备路线可以用于合成本发明式(Ⅰ)结构的化合物。
路线1:式Ⅰ化合物的合成
如路线1所示,式Ⅵ化合物和式XIV化合物在酸的作用下发生缩合反应得式Ⅰ化合物。所述酸包括无机酸和有机酸,可列举的实例包括盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸,在本发明的一个实施方案中,使用的酸为三氟乙酸。
路线2:式Ⅵ化合物的合成
如路线2所示,式Ⅱ化合物在低温下、碱性条件下与氘代或未氘代的丙烯酰氯(或其类似物如相应的酸及酸酐)反应得式Ⅲ化合物;式Ⅲ化合物经还原硝基得式Ⅳ化合物;式Ⅳ化合物在低温下、碱性条件下与式Ⅴ化合物反应得式Ⅵ化合物。
路线3:式XIV化合物的合成一
如路线3所示,式Ⅶ化合物为原料,先经亚硝基化反应制备得式Ⅷ化合物,在碱性条件下,重水、氘代甲醇或氘代乙醇等为氘源,经氢-氘交换可进一步制备得式Ⅸ化合物,在铝镍合金条件下脱亚硝基可制备得式Ⅹ化合物,然后与氘代或未氘代的乙酸酐、乙酰氯或乙酸进行乙酰化反应制备得式Ⅺ化合物,式Ⅺ化合物与式Ⅻ发生缩合反应得式XIII化合物,式XIII化合物经还原硝基得式XIV化合物。
路线4:式XIV化合物的合成二
如路线4所示,式XV为原料,经亚硝基化反应制备得式XVI,在碱性条件下,重水、氘代甲醇或氘代乙醇等为氘源,经氢-氘交换可进一步制备得式XVII化合物,式XVII化合物在铝镍合金条件下脱亚硝基得式XVIII化合物,式XVIII化合物与式Ⅻ发生缩合反应得式XIX化合物,式XIX化合物脱苄基得式XX化合物,然后与氘代或未氘代的乙酸酐、乙酰氯或乙酸进行乙酰化反应制备得式XIII化合物,式XIII化合物经还原硝基得式XIV化合物。
路线5:式XIV化合物的合成三
如路线5所示,式XVIII化合物与氘代或未氘代的乙酸酐、乙酰氯或乙酸进行乙酰化反应制备得式XXI化合物,式XXI化合物脱苄基得式Ⅺ化合物,式Ⅺ化合物与式Ⅻ化合物经缩合反应得式XIII化合物,式XIII化合物经还原硝基得式XIV化合物。
路线6:式Ⅻ化合物的合成方法
如路线6所示,式XXII化合物与氘代甲基化试剂反应得式Ⅻ化合物。
其中,下述氘代原料以及氘代乙酰化试剂(例如氘代乙酸酐、乙酰氯或乙酸)、氘代丙烯酰基化试剂(例如氘代丙烯酰氯)或氘代甲基化试剂(例如氘代碘甲烷)可以通过市售获得,例如从Sigma-Aldrich购买;或者通过已知的氘化方法进行制备,例如在酸性催化下,非氘代化合物在重水中进行交换得到。
上述路线表示了构成本发明的合成方法,是用于通过特定实施例描述可应用的化学方法,而不是表示本发明的范围或意在限制。不管是不是通过相同的变量名(即,R1、R2、R3等)进行标识,本文图解中的化学结构描绘了用本文化合物式中相应位置的化学基团定义在此进行适当限定的变量。在用于合成另一种化合物的化学结构式中化学基团的适当性在本领域普通技术人员的知识范围之内。
本发明所使用的所有溶剂是市售的,无需进一步纯化即可使用。涉及对水和/或氧气敏感的实验的所有操作都在预干燥玻璃仪器中于氮气氛下进行。除非另有说明,所有原料均为商业原料,并且在使用前未作进一步纯化。本发明所用柱层析采用的是青岛海洋化工所生产的硅胶(200-300目)。薄层色谱采用默克公司(E.Merck)预涂色谱板(硅胶60PF254,0.25毫米)。核磁共振光谱分析使用的仪器为瓦里安VNMRS-400共振光谱仪,化学位移以四甲基硅烷(TMS=δ0.00)为内标,核磁共振氢谱数据的记录格式为:质子数,峰型(s,单峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰),耦合常数(以赫兹Hz为单位)。
本发明采用下述缩略词:DCM代表二氯甲烷;DIPEA代表二异丙基乙基胺;PE代表石油醚;EA代表乙酸乙酯;DMSO代表二甲亚砜;DMA代表N,N-二甲基乙酰胺;TFA代表三氟乙酸。
化合物经手工或者软件命名,市售化合物采用供应商目录名称。
在本发明中,式Ⅰ所示化合物具对突变型EGFR激酶具有优异的选择性抑制活性,同时展现出优异的药代动力学性质。所述药代动力学性质可以通过本领域已知的实验方法得到,例如但不仅限于体外肝脏微粒体实验、大鼠体内药代动力学实验等等。
具体实施方式:
下面的实施例可以更详细地说明本发明,但不以任何形式限制本发明。
实施例1化合物Ⅰ-1的制备
步骤(1):N-(3-硝基苯基)丙烯酰胺(Ⅲ-1)
向反应瓶中加入式Ⅱ-1化合物(10.0g,72.4mmol)和无水四氢呋喃,加入Et3N(11.0g,108.6mmol),0℃滴加丙烯酰氯(10.29g,144.8mmol),滴完室温反应1.5~2hrs,TLC监测反应完全,反应液旋蒸干,加饱和Na2CO3水溶液调至pH=10,EA萃取干燥,旋蒸得粗品,过硅胶柱,PE-EA洗脱,合并浓缩得式Ⅲ-1化合物(6.50g)。
1H-NMR(300M,CD3OD):8.68(s,1H),7.96-7.92(t,2H),7.58-7.52(t,1H),6.44-6.42(t,2H),5.84-5.81(m,1H);
HRMS m/z:193.0604(ESI,M+H+)。
步骤(2):N-(3-氨基苯基)丙烯酰胺(Ⅳ-1)
向反应瓶中加入式Ⅲ-1化合物(6.0g,31.22mmol),乙醇和四氢呋喃作溶剂,加入SnCl2·2H2O(35.2g,156.1mmol),加热回流3~4hrs,TLC监测反应完全,反应液旋蒸干,加NaOH水溶液调至pH=12,EA萃取干燥,旋蒸得粗品,过硅胶柱,PE-EA洗脱(4:1到3:2),合并浓缩得式Ⅳ-1化合物(3.20g)。
1H-NMR(300M,DMSO-d6):6.98(s,1H),6.89-6.94(t,1H),6.74-6.77(d,1H),6.37-6.46(m,1H),6.17-6.28(m,2H),5.67-5.70(d,1H);
HRMS m/z:163.0867(ESI,M+H+)。
步骤(3):N-(3-((2-氯-5-(三氟甲基)嘧啶-4-基-氨基)苯基)丙烯酰胺(Ⅵ-1)
氮气下,向反应瓶中加入式Ⅳ-1化合物(3.2g,19.73mmol)和正丁醇,0℃滴加2,4-二氯-5-三氟甲基嘧啶(4.28g,19.73mmol)和DIPEA(3.06g,23.68mmol),室温反应2~3hrs,TLC检测原料点消失,反应液旋蒸近干,加饱和Na2CO3水溶液调至pH=10,EA萃取干燥,过硅胶柱,PE-EA洗脱(5:1到2:1),合并浓缩得目标产物6.35g,通过HPLC制备得目标物Ⅵ-1(4.08g)。
1H-NMR(300M,DMSO-d6):10.22(s,1H),9.57(s,1H),8.58(s,1H),7.79(s,1H),7.49-7.52(d,1H),7.33-7.38(t,1H),7.13-7.16(d,1H),6.40-6.49(m,1H),6.23-6.29(d,1H),5.75-5.78(d,1H);
13C-NMR(300M,DMSO-d6):163.14,162.30,157.59,156.71-156.49(m,2C),139.27,137.19,131.71,128.71,126.93,123.17(t),120.91,117.01,116.61;
HRMS m/z:343.0566(ESI,M+H+).。
步骤(4):1,4-二亚硝基哌嗪(Ⅷ-1)
向反应瓶中加入化合物Ⅶ-1(80g,930mmol),滴加2M盐酸溶液(1040mL,2080mmol),得到的反应液搅拌10分钟,然后向反应中滴加NaNO2的水溶液(152g,2196mmol),30分钟滴完。反应室温搅拌,将反应加2小时,再将反应瓶放置析出固体,最后通过抽滤分离出固体产物,水洗。通过减压烘箱干燥后得到Ⅷ-1化合物(123.21g),为淡黄色固体(产率92.02%)。
1H-NMR(400MHz,CDCl3):δ4.60(s,1.7H),4.46(t,J=5.4Hz,2.3H),4.21(t,2.3H),3.88(s,1.7H);
13C-NMR(400MHz,CDCl3):δ49.58,47.09,40.50,37.75;
HRMS m/z:144.0643(ESI,M+H+)。
步骤(5):[D8]1,4-二亚硝基哌嗪(Ⅸ-1)
向反应瓶中加入化合物Ⅷ-1(10.0g,69.4mmol),甲醇钠(15.0g,277.7mmol),氮气下,向反应瓶中加入重水(100mL,15.0mol)。然后加热到80℃,反应溶清。10小时后停止加热,待冷却到室温后,再将反应瓶放置析出固体。通过抽滤分离出固体产物。最后通过减压烘箱干燥得到化合物Ⅸ-1(8.569g),为淡黄色固体(产率81.61%)。
1H-NMR(300MHz,CDCl3)(对硝基苯甲醚做内标):δ8.20(2H,d,J=9.21Hz,Ph),6.96(2H,d,J=9.21Hz,Ph),3.91(3H,s,CH3)(除内标分子氢峰外,无其它氢峰,哌嗪上氢全部被氘取代);
HRMS m/z:153.1212(ESI,M+H+)。
步骤(6):[D8]哌嗪盐酸盐(Ⅹ-1)
向反应瓶中加入化合物Ⅸ-1(3.0g,19.74mmol),甲醇钠(5.99g,0.110mol),氮气下,缓慢向反应中加入重水(75mL)。分多次向反应中加入Al-Ni合金(24.0g),约2小时加完,通过抽滤除去固体金属,收集含有产物的滤液。进行蒸馏。待液体全部蒸出后,缓慢向其中滴加浓盐酸(4mL)。最后通过旋蒸,除去溶剂,得到白色固体。通过减压烘箱干燥后得到化合物Ⅹ-1(2.865g),为白色固体(产率82.45%)。
1H-NMR(300MHz,CDCl3)(对硝基苯甲醚做内标):δ8.20(2H,d,J=9.27Hz,Ph),7.07(2H,d,J=9.27Hz,Ph),3.91(3H,s,CH3)(除内标分子氢峰外,无其它氢峰,哌嗪上氢全部被氘取代);
HRMS m/z:95.1417(ESI,M+H+)。
步骤(7):1-([2,2,3,3,5,5,6,6-D8]哌嗪-1-基)乙酮(Ⅺ-1)
反应瓶中加入化合物Ⅹ-1(1.85g,11.05mmol),水(40mL),冰水浴下边搅拌边加入固体碳酸钠,调至pH=8,缓慢升温至室温,滴加乙酸酐(1.35g,13.26mmol)。TLC监测反应完全后,用DCM萃取,除去N,N-二乙酰基哌嗪。水相用固体碳酸钠调至碱性后,旋蒸出去溶剂,加入DCM,无水硫酸钠搅拌过夜。通过抽滤出去无机盐和干燥剂,旋蒸除去溶剂。将得到的固体通过减压烘箱50℃真空干燥,最终得到式Ⅺ-1-1化合物(0.76g),产率(50.67%)。
1H-NMR(300MHz,CDCl3):2.098(s,3H);
HRMS m/z:137.1522(ESI,M+H+)。
步骤(8):1-(4-(3-甲氧基-4-硝基苯基)[2,2,3,3,5,5,6,6-D8]哌嗪-1-基)乙酮(ⅩⅢ-1)
氮气下,将化合物Ⅺ-1(D8,0.75g,5.51mmol)和DIPEA(0.72g,5.51mmol)加入4-氟-2-甲氧基-1-硝基苯(0.785g,4.59mmol)的DMA(3mL)溶液中。反应溶液加热到90℃,搅拌反应过夜。TLC监测反应完全后,反应放冷至室温,加入水(30mL)淬灭反应。再用DCM萃取,有机相再用水洗两次,饱和食盐水洗一次,有机相合并加入无水硫酸镁干燥。抽滤除去干燥剂,通过旋蒸除去溶剂得到黄色固体。将得到的固体通过减压烘箱50℃干燥,最终得到式ⅩⅢ-1化合物(0.93g),为黄色固体(70.45%)。
1H-NMR(300MHz,CDCl3):7.95~7.99(d,J=9.3Hz,1H),6.38~6.42(dd,J=9.3Hz,1H),6.30~6.31(d,J=2.43Hz,1H),3.95(s,3H),2.15(s,3H);
HRMS m/z:288.1799(ESI,M+H+)。
步骤(9):1-(4-(4-氨基-3-甲氧基苯基)[2,2,3,3,5,5,6,6-D8]哌嗪-1-基)乙酮(ⅩⅣ-1)
向加氢反应釜中加入化合物Ⅺ-1(0.81g,2.82mmol),10%Pd/C(0.08g),乙醇(15mL)。然后排气,氮气置换排气三次后,再用氢气置换排气三次。最后通过氢气阀加压反应,反应放热,室温反应小时后,打开反应釜。TLC检测反应完全。后通过减压抽滤出去催化剂,滤液再通过减压蒸除溶剂,残留物加入正己烷打浆,一小时后通过抽滤,正己烷洗滤饼得到固体产物,最后减压烘箱50℃干燥后得到式ⅩⅣ-1化合物(0.76g),为淡紫色固体(产率100%)。
1H-NMR(300MHz,CD3OD):6.68~6.70(d,J=7.92Hz,1H),6.59~6.60(d,J=1.92Hz,1H),6.43(br,1H),3.82(s,3H),2.11(s,3H);
13C-NMR(300MHz,CD3OD):171.63,149.94,146.14,131.82,117.27,111.24,103.88,56.05,21.11;
HRMS m/z:258.2051(ESI,M+H+)。
步骤(10)N-(3-((2-((4-(4-乙酰基[2,2,3,3,5,5,6,6-D8]哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯酰胺(Ⅰ-1)
氮气下向反应瓶中加入化合物Ⅵ-1(0.45g,1.752mmol),化合物ⅩⅣ-1(0.50g,1.46mmol),TFA(cat.16.65mg,0.146mmol)及1,4-二氧六环(12mL)。反应加热到50℃搅拌过夜。TLC监测反应完成后,旋蒸除去溶剂,再向残留物中加入DCM(20mL)。冰水浴下滴加三乙胺至pH=8~9,逐渐溶清。有机相用饱和食盐水洗两次,水相再用DCM萃取,最后合并有机相,加入无水硫酸镁干燥。通过抽滤除去干燥剂,旋蒸除去溶剂,得到的固体再通过减压55℃干燥。最后通过重结晶得到式Ⅰ-1化合物。
1H-NMR(300MHz,DMSO-d6):10.1(s,1H),8.63(br,1H),8.28(s,1H),8.07(s,1H),7.75(br,1H),7.49~7.55(t,J=9.69Hz,2H),7.24~7.29(t,J=8.01Hz,1H),7.15~7.17(be,1H),6.59~6.60(d,J=2.07Hz,1H),6.40~6.49(dd,1H),6.28~6,29(d,J=1.98Hz,1H),6.22~6.23(d,J=1.74Hz,1H),5.74~5.78(dd,1H),3.77(s,3H),2.04(s,3H);
13C-NMR(300MHz,DMSO-d6):168.17,163.04,160.85,157.21,155.81,155.74,155.67,155.59,148.09,138.95,138.42,131.87,128.46,126.85,126.58,123.01,120.36,119.99,116.38,115.83,106.86,100.45,55.59,49.16-48.78(m,N-C-D),45.25(m,N-C-D),40.42(m,N-C-D),21.13;
HRMS m/z:564.2779(ESI,M+H+)。
实施例2化合物Ⅰ-3的制备
步骤(1):1-苄基-4-亚硝基哌嗪(ⅩⅥ-1)
向反应瓶中加入化合物ⅩⅤ-1(50.0g,0.284mol),0℃左右滴加2M盐酸溶液(160mL,0.318mol),得到的反应液在0℃下搅拌10分钟,然后向反应中滴加NaNO2的水溶液(NaNO2(24.50g,0.335mol)加入水(58mL)配成溶液),维持温度在0~10℃,40分钟滴完。反应室温搅拌过夜。次日,将反应加热到35℃约1小时(大量不溶固体生成),再将反应瓶放入低温槽中,0℃下冷却析出,最后通过抽滤分离出固体产物,水洗,水层再用DCM萃取,有机相合并,无水硫酸镁干燥,通过抽滤除去干燥剂,旋转蒸发除去溶剂得到固体产物。最后通过减压烘箱50℃干燥后得到式ⅩⅥ-1化合物(56.71g),为淡黄色固体(产率97.30%)。
1H-NMR(300MHz,CDCl3):7.26~7.34(m,5H),4.23~4.27(t,J=10.4Hz,2H),3.81~3.85(t,J=10.7Hz,2H),3.60(s,2H),2.66~2.70(t,J=10.3Hz,2H),2.43~2.46(t,J=10.7Hz,2H);
步骤(2):1-苄基-[3,3,5,5-D4]哌嗪(ⅩⅦ-1)
向反应瓶中加入化合物ⅩⅥ-1(20.0g,97.43mmol),甲醇钠(15.79g,292.29mmol),氮气下,缓慢向反应瓶中加入重水(150mL),氘代乙醇(d1,100mL)。然后加热到80℃,反应溶清。24小时后停止加热,待冷却到室温后,放入低温槽中,0℃下冷却析出。3小时后,通过抽滤分离出固体产物。最后通过减压烘箱50℃干燥得到式ⅩⅦ-1化合物(17.735g),为淡黄色固体(产率86.98%)。
1H-NMR(300MHz,CDCl3):7.25~7.33(m,5H),3.56(s,2H),2.64(s,2H),2.41(s,2H);
MS m/z:232.2(ESI,M+Na)。
步骤(3):1-苄基-[3,3,5,5-D4]哌嗪(ⅩⅧ-1)
向反应瓶中加入化合物ⅩⅦ-1(10.0g,47.78mmol),甲醇钠(7.74g,143.34mmol),氮气下,缓慢向反应中加入重水(75mL)及氘代乙醇(d1,75mL)。然后加热到70℃。反应3小时后停止加热,待冷却至室温后,分多次向反应中加入Al-Ni合金(30.0g),约2小时加完,反应混合物在室温下搅拌过夜。次日,通过抽滤除去固体金属,收集含有产物的滤液。再用DCM萃取,有机相合并,无水硫酸镁干燥,通过抽滤除去干燥剂,旋转蒸发除去溶剂得到固体产物。通过减压干燥后得到式ⅩⅧ-1化合物(7.13g),为淡黄色油状体(产率82.81%)。
1H-NMR(300MHz,CD3OD):7.20~7.31(m,5H),3.47(s,2H),2.39(s,4H);
MS m/z:181.2(ESI,M+H+)。
步骤(4):1-苄基-4-(3-甲氧基-4-硝基苯基)[3,3,5,5-D4]哌嗪(ⅩⅨ-1)
氮气下,分别将化合物ⅩⅧ-1(D4,6.0g,33.28mmol)和DIPEA(4.69g,36.312mmol)加入4-氟-2-甲氧基-1-硝基苯(5.18g,30.26mmol)的DMA(18mL)溶液中。反应溶液加热到90℃,搅拌反应过夜。TLC监测反应完全后,反应放冷至室温,加入水(200mL)淬灭反应。再用DCM萃取,有机相再用水洗两次,饱和食盐水洗一次,有机相合并加入无水硫酸镁干燥。抽滤除去干燥剂,通过旋蒸除去溶剂得到黄色固体。将得到的固体通过减压烘箱50℃干燥,最终得到式ⅩⅨ-1化合物(9.94g),产率(99.10%)。
1H-NMR(300MHz,CDCl3):7.90~7.93(d,J=9.36Hz,1H),7.24~7.32(m,5H),6.34~6.37(dd,J=9.33Hz,1H),6.28~6.29(d,J=2.28Hz,1H),3.89(s,3H),3.54(s,2H),2.55(s,4H);
HRMS m/z:322.1908(ESI,M+H+)。
步骤(5):1-(3-甲氧基-4-硝基苯基)[3,3,5,5-D4]哌嗪(ⅩⅩ-1)
向反应瓶中加入化合物ⅩⅨ-1(7.55g,22.78mmol),1,2-二氯乙烷(120mL),0℃下搅拌30分钟后,向其中滴加氯甲酸-1-氯乙酯(4.89g,34.17mmol)。搅拌30分钟后,取出低温槽,加热到回流反应过夜,TLC监测反应完成,旋蒸除去溶剂,加入甲醇(120mL),加热至回流。1小时后放冷至室温,旋蒸除去甲醇。加入0.5M盐酸溶液(500mL),用DCM萃取除去部分杂质,水相再用碳酸钾和至碱性,DCM萃取,产物合并用无水硫酸镁干燥。抽滤除去干燥剂,旋蒸除去溶剂得到黄色固体。最后通过减压烘箱50℃干燥后得到式ⅩⅩ-1化合物(4.11g),为黄色固体(产率74.73%)。
1H-NMR(300MHz,CD3OD):7.90~7.93(d,J=9.3Hz,1H),6.01~6.54(dd,J=9.24Hz,1H),6.48~6.49(d,J=2.4Hz,1H),3.92(s,3H),2.96(s,4H);
HRMS m/z:242.1444(ESI,M+H+)。
步骤(6):1-(4-(3-甲氧基-4-硝基苯基)[3,3,5,5-D4]哌嗪-1-基)乙酮(ⅩⅢ-2)
氮气下,分别向反应瓶中加入化合物ⅩⅩ-1(5.09g,21.10mmol),三乙胺(4.27g,42.20mmol),DCM(400mL),将反应混合物放入低温槽中(0℃)搅拌。然后向反应中滴加乙酰氯(1.82g,23.21mmol),约三十分钟滴加完。1小时后,TLC监测反应完成后,向反应中滴加0.5N NaOH的水溶液(约120mL)。分液,水相再用DCM萃取,有机相合并再用饱和食盐水水(150mL)洗,无水硫酸镁干燥。抽滤除去干燥剂,旋蒸除去溶剂。最后通过减压烘箱50℃干燥得到式ⅩⅢ-2化合物(4.55g),为黄色固体(产率76.09%)
1H-NMR(300MHz,CD3OD):7.88~7.91(d,J=9.27Hz,1H),6.48~6.52(dd,J=9.27Hz,1H),6.45~6.46(d,J=2.37Hz,1H),3.93(s,3H),3.69~3.72(d,J=7.17Hz,4H)2.15(s,3H);
HRMS m/z:284.1541(ESI,M+H+)。
步骤(7):1-(4-(4-氨基-3-甲氧基苯基))[3,3,5,5-D4]哌嗪-1-基)乙酮(ⅩⅣ-2)
通过实施例1步骤(9)类似的方法可以得到式ⅩⅣ-2化合物。
1H-NMR(300MHz,CD3OD):6.68~6.70(d,J=8.34Hz,1H),6.58~6.59(d,J=2.28Hz,1H),6.41~6.43(d,J=7.02Hz,1H),3.82(s,3H),3.68(s,2H),3.62(s,2H),2.11(s,3H);
13C-NMR(300MHz,CD3OD):171.63,149.93,146.10,131.83,117.27,111.23,103.89,56.06,47.42,42.66,21.13;
HRMS m/z:254.1952(ESI,M+H+)。
步骤(8):N-(3-((2-((4-(4-乙酰基[3,3,5,5-D4]哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯酰胺(Ⅰ-3)
通过实施例1中步骤(10)类似的方法可以得到式Ⅰ-3化合物.
1H-NMR(300MHz,DMSO-d6):10.1(s,1H),8.61(br,1H),8.28(s,1H),8.06(s,1H),7.75(br,1H),7.49~7.55(t,J=8.49Hz,1H),7.24~7.29(t,J=8.01Hz,1H),7.15~7.18(be,1H),6.59~6.60(d,J=2.01Hz,1H),6.40~6.49(dd,J=16.86Hz,1H),6.28~6,29(d,J=1.38Hz,1H),6.22~6.23(d,J=1.89Hz,1H),5.73~5.77(dd,J=9.99Hz,1H),3.77(s,3H),3.57(s,4H),2.04(s,3H);
13C-NMR(300MHz,DMSO-d6):168.16,163.02,160.84,157.19,155.71,155.64,148.02,138.93,138.40,131.85,128.42,126.78,126.55,122.98,120.31,119.99,116.35,115.82,106.86,100.43,55.58,49.16-48.78(m,N-C-D),45.25,40.44,21.09;
HRMS m/z:560.2524(ESI,M+H+)。
实施例3化合物Ⅰ-18的制备
步骤(1):1-(4-苄基[2,2,6,6-D4]哌嗪-1-基)乙酮(XXI-1)
室温搅拌下,将乙酸酐(4.98g,48.82mmol)滴加进化合物ⅩⅧ-1(D4,8.0g,44.38mmol)的水(160mL)中。十分钟后TLC监测反应完全后,加入固体碳酸钠中和至pH=8~9后,DCM萃取(100mL*5),有机相合并加入无水硫酸镁干燥。通过抽滤出去干燥剂,旋蒸除去溶剂。通过减压干燥,最终得到式XXI-1化合物(10.40g),产率(100%)。
1H-NMR(300MHz,CDCl3):7.22~7.31(m,5H),3.50(s,2H),2.38~2.39(d,J=3.84Hz,4H),2.04(s,3H);
HRMS m/z:233.1742(ESI,M+H+)。
步骤(2):1-([2,2,6,6-D4]哌嗪-1-基)乙酮(Ⅺ-2)
向加氢反应釜中加入化合物XXI-1(9.8g,44.08mmol),10%Pd/C(0.98g),乙醇(150mL)。然后排气,氮气置换排气三次后,再用氢气置换排气三次。最后通过氢气阀加压反应,50℃反应过夜,打开反应釜。TLC检测反应完全。后通过减压抽滤出去催化剂,滤液再通过减压蒸除溶剂,最后减压干燥后得到式Ⅺ-2化合物(5.78g),产率(99.14%)。
1H-NMR(300MHz,CD3OD):2.76~2.82(d,J=18.24Hz,4H),2.08(s,3H);
HRMS m/z:133.1275(ESI,M+H+)。
步骤(3):1-(4-(3-甲氧基-4-硝基苯基)[2,2,6,6-D4]哌嗪-1-基)乙酮(ⅩⅢ-3)
通过实施例1中步骤(8)类似的方法可以得到式ⅩⅢ-3化合物.
1H-NMR(300MHz,CDCl3):7.92~7.95(d,J=9.3Hz,1H),6.40~6.44(dd,J=9.3Hz,1H),6.34~6.35(d,J=2.1Hz,1H),3.95(s,3H),3.50(s,2H),3.43(s,2H),2.15(s,3H);
HRMS m/z:284.1543(ESI,M+H+)。
步骤(4):1-(4-(4-氨基-3-甲氧基苯基))[2,2,6,6-D4]哌嗪-1-基)乙酮(ⅩⅣ-3)
通过实施例1中步骤(9)类似的方法可以得到式ⅩⅣ-3化合物.
1H-NMR(300MHz,CD3OD):6.70(br,1H),6.60(br,1H),6.44(br,1H),3.83(s,3H),2.99~3.06(m,4H),2.12~2.13(d,J=4.62Hz,3H);
13C-NMR(300MHz,CD3OD):171.62,149.99,146.27,131.66,117.33,111.28,103.98,56.07,52.58,52.26,21.13;
HRMS m/z:254.1788(ESI,M+H+)。
步骤(5):N-(3-((2-((4-(4-乙酰基[2,2,6,6-D4]哌嗪-1-基)-2-甲氧基苯基)氨基)-5-(三氟甲基)嘧啶-4-基)氨基)苯基)丙烯酰胺(Ⅰ-18)
通过实施例1中步骤(10)类似的方法可以得到式Ⅰ-18化合物。
1H-NMR(300MHz,CD3OD):10.13(s,1H),8.61(br S,1H),8.21(s,1H),8.06(s,1H),7.76(s,1H),7.55-7.49(m,2H),7.29-7.24(m,1H),7.18-7.15(m,1H),6.60(d,1H),6.49-6.40(m,1H),6.28-6.23(m,2H),5.78-5.74(m,1H),3.77(s,3H),3.05-2.99(d,4H),2.04(s,3H);
13C-NMR(300MHz,DMSO-d6):168.12,163.03,160.83,157.19,155.71,155.64,148.01,138.94,138.40,131.85,128.43,126.79,126.55,122.98,120.32,120.09,116.37,115.83,106.97,100.54,55.58,49.16,48.78,45.25(m,N-C-D),40.33,21.07;
HRMS m/z:560.2528(ESI,M+H+)。
实验例1:表皮生长因子受体(epidermal growth factor receptor,EGFR)及致癌驱动基因ALK抑制活性。
配制方法:以上样品均用DMSO配成10mM的原液。使用时用培养液配成所需浓度。
细胞株:NCI-H292细胞均购自中国科学院上海生命科学院细胞库;NCI-H3122来自美国NCI。用含10%胎牛血清(FBS)的RPMI 1640培养基培养。
试剂及仪器:RPMI-1640购自Gibco BRL公司;胎牛血清购自Gibco公司;多功能酶标仪购自BioTek公司;SRB购自Sigma公司。
试验方法(SRB法):应用磺酰罗丹明B蛋白染色法(Sulforhodamine B,SRB)检测药物对肿瘤细胞增殖生长的抑制作用。主要步骤如下:接种对数生长期细胞于96孔培养板,加入不同浓度的药物,每个浓度设3个复孔,同时设相应浓度的溶媒对照。肿瘤细胞在37℃、5%CO2条件下培养72小时。细胞用SRB室温中染色,最后加入Tris溶液溶解,酶标仪(BioTek)510nm波长下测定OD值,以下列公式计算细胞生长抑制率:
抑制率=(OD值对照孔-OD值给药孔)/OD值对照孔×100%。
根据各浓度抑制率,根据非线性回归方法计算半数抑制浓度IC50。
试验结果:化合物对NCI-H292和NCI-H3122细胞增殖的作用见表1。
表1.化合物对体外培养肿瘤细胞NCI-H292和NCI-H3122的IC50(nM)总结
非氘代CO-1686和本发明的式Ⅰ化合物在ALK(NCI-H3122)和野生型EGFR(NCIH292)靶点上均表现出相似的抑制活性。
实验例2:对体外培养人肺腺癌H1975(T790M)细胞增殖的影响。
细胞株:H1975细胞购自中国科学院上海生命科学院细胞库,用含10%胎牛血清(FBS)的PRIM 1640培养基培养。
试剂及仪器:PRIM 1640购自Gibco BRL公司;胎牛血清购自Hyclone公司;多功能酶标仪购自BioTek公司;SRB购自Sigma公司。
试验方法(SRB法):应用磺酰罗丹明B(Sulforhodamine B,SRB)蛋白染色法检测药物对肿瘤细胞增殖生长的抑制作用。主要步骤如下:
接种对数生长期细胞于96孔培养板,加入不同浓度(1-10000nM)的药物,每个浓度设3个复孔,同时设相应浓度的溶媒对照。肿瘤细胞在37℃、5%CO2条件下培养72小时。细胞用SRB室温中染色,最后加入Tris溶液溶解,酶标仪(BioTek)510nm波长下测定OD值,以下列公式计算细胞生长抑制率:
抑制率=(OD值对照孔-OD值给药孔)/OD值对照孔×100%。
根据各浓度抑制率,根据非线性回归方法计算半数抑制浓度IC50。
试验结果:化合物对H1975细胞增殖的作用见表2。
表2.化合物对体外培养人肺腺癌H1975细胞增值抑制的IC50(nM)总结
本发明的式Ⅰ化合物对EGFR(NCIH1975)展现出明显的细胞增值抑制活性,对突变型EGFR具有选择性抑制活性。
Claims (14)
1.式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐:
其中:
R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25和R26各自独立地为氢或氘;
R8为三氟甲基;
R9为氢;
附加条件是R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25和R26中至少一个是氘,并且排除如下所示的化合物Ⅰ-2和Ⅰ-16:
2.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,式(Ⅰ)化合物优选至少含有2个氘原子,更优选至少含有4个氘原子,进一步优选至少含有6个氘原子。
3.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,式(Ⅰ)化合物的R16、R17、R22和R23选自氘。
4.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,式(Ⅰ)化合物的R18、R19、R20和R21选自氘。
5.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,式(Ⅰ)化合物的R16、R17、R22和R23或者R18、R19、R20和R21选自氘。
6.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,R4、R5、R6和R7选自氘。
7.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,式(Ⅰ)化合物的R1、R2和R3选自氘。
8.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,式(Ⅰ)化合物的R10、R11和R12选自氘。
9.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,式(Ⅰ)化合物的R13、R14和R15选自氘。
10.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,式(Ⅰ)化合物的R24、R25和R26选自氘。
11.如权利要求1所述的式(Ⅰ)所示的氘代二苯基氨基嘧啶化合物或其药学上可接受的盐,其特征在于,式(Ⅰ)所示的化合物如下:
12.权利要求1~11任一项所述的化合物或其药学上可接受的盐在制备治疗EGFR介导的疾病的药物中的用途。
13.根据权利要求12所述的用途,所述EGFR介导的疾病选自癌症。
14.药物组合物,其包含治疗有效量的式(Ⅰ)化合物或其药学上可接受的盐和一种或多种药学上可接受的载体或赋形剂。
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