CN111971283B - 具有增强的抗肿瘤作用的新型化合物 - Google Patents
具有增强的抗肿瘤作用的新型化合物 Download PDFInfo
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Abstract
一种式(I)的化合物，其中，‑R基团可以表示＝O或‑H，是具有显著的体内抗肿瘤作用的新型抗增殖剂，特别显示出针对不同来源的淋巴瘤的广谱活性，
Description
背景技术
尽管在药物和医学研究中取得了进展，但肿瘤仍然对生活质量和预期寿命造成了巨大挑战。其中，包括慢性淋巴细胞白血病的淋巴瘤是一组起源于淋巴样细胞的肿瘤(Swerdlow,et al 2016)，是最常见的癌症之一，占成人中所有新病例的约5％，在儿童和青少年中最高达25％(Siegel,et al 2016,Stewart and Wild 2014)。淋巴瘤包括60多种根据组织学特征、免疫表型特征、遗传特征和临床特征的组合进行区分的不同实体或临时实体(Swerdlow,et al 2016)。最常见的淋巴瘤亚型是弥漫性大B细胞淋巴瘤(DLBCL)，占所有淋巴瘤的30％-40％(Sehn and Gascoyne 2015)，并且其包括至少两种主要的亚型，生发中心B细胞(GCB)型和活化B细胞样(ABC)型(Sehn and Gascoyne 2015,Swerdlow,et al2016,Testoni,et al 2015)。大多数DLBCL患者可以使用诸如R-CHOP(利妥昔单抗、环磷酰胺、阿霉素、长春新碱和强的松)的方案进行治疗，但他们中的30-40％患有难治性疾病或经历复发，表明需要进一步的治疗。依鲁替尼(Imbruvica)是具有以下结构的一种小分子药物：
其与B细胞中重要的蛋白质布鲁顿酪氨酸激酶(BTK)永久结合；该药物用于治疗B细胞癌。
目前，仍在继续努力寻找抗肿瘤药，以扩大可用产品的范围，减少不良副作用，在耐药性的情况下提供其他选择，鉴定对特定形式的肿瘤具有足够广谱的活性和/或优先活性的抗肿瘤药。特别地，由于在治疗中批准的有效产品的数量相对较少，像淋巴瘤和白血病这样的液体肿瘤仍然是重要的研究领域。
发明内容
本发明的申请人合成了具有以下结构(I)的新化合物：
其中，基团-R可以表示＝O或-H。生物学测试表明本发明化合物具有出乎意料的强效的抗增殖活性，并在体内具有显著的抗肿瘤作用；特别是对各种来源/症状的淋巴瘤和白血病(例如：B细胞淋巴瘤、霍奇金(Hodgkin)淋巴瘤、T细胞淋巴瘤、慢性淋巴细胞白血病、T细胞白血病等)具有广谱活性。本发明涉及式(I)的化合物本身，以及它们在治疗中的用途，在治疗肿瘤中的用途，特别是在治疗白血病和淋巴瘤中的用途；本发明还包括本发明化合物的生产方法，以及包含它们的药物组合物。
附图说明
图1.EG-011在15个DLBCL细胞系中的IC50值的分布。将细胞系处理72小时。X轴，ABC，活化B细胞样DLBCL；GCB，生发中心B细胞DLBCL。Y轴，IC50值，以nM为单位。
图2.EG-011在2个PLL、9个MCL和4个HL细胞系中的IC50值的分布。将细胞系处理72小时。X轴，PLL，慢性淋巴细胞白血病；MCL，套细胞淋巴瘤；HL，霍奇金淋巴瘤。Y轴，IC50值，以nM为单位。
图3.EG-011在2个PLL、9个MCL和4个HL细胞系中的IC50值的分布。将细胞系处理72小时。X轴，ALCL，间变性大T细胞淋巴瘤；CTCL，皮肤T细胞淋巴瘤；PTCL，外周T细胞淋巴瘤；ATCL，急性T细胞白血病。Y轴，IC50值，以nM为单位。
图4.细胞周期阶段分布。OCI-LY-19和REC1用两种不同浓度的EG-011(500nM和2000nM)处理72小时。
图5.细胞周期峰表示，参考图4中报告的实验。
图6.REC1模型在体内实验期间的肿瘤体积分布。当肿瘤可见(180mm3)时，开始使用EG-011进行治疗。Y轴，肿瘤体积，以mm3表示。在每个方框图中，方框中间的线表示每天的中位数体积，方框从第25个百分点延伸到第75个百分点(四分位数范围，IQ)；晶须(whisker)延伸到上下相邻的值(即±1.5IQ)。载剂(N＝8只小鼠)，EG-011(N＝9只小鼠)。
补充图1.实验期间的平均肿瘤体积：REC1模型。当肿瘤可见(180mm3)时，开始使用EG-011进行治疗。Y轴，肿瘤体积，以mm3表示。
补充图2.报告的平均肿瘤重量和标准偏差。P＜0.001。
具体实施方式
本发明的主要目的是如下的式(I)的化合物：
其中，基团-R可以表示＝O或-H。
其中-R为＝O的化合物的化学名称为：1-[(4-苯氧基苯基)甲基]-3-(1-丙-2-烯酰基-3-哌啶基)吡啶并[3,2-d]嘧啶-2,4-二酮(本文也简称为“EG-011”)。其中-R为-H的化合物的化学名称为：1-[(4-苯氧基苯基)甲基]-3-(1-丙-2-烯酰基-3-哌啶基)吡啶并[3,2-d]嘧啶-2-酮。
在本发明中，式(I)的化合物可以原样使用或以其药学上可接受的盐使用。如本文所用，术语“药学上可接受的”是指在制备通常安全、无毒的且在生物学方面或其他方面不是不期望的药物组合物时有用的，并且包括兽用和人用药物是可接受的那些。式(I)的化合物的药学上可接受的盐通常为(但不限于)由其一个或多个氮原子的质子化产生的那些(I)；在这些盐中，式(I)的化合物通常为阳离子形式，并与合适的抗衡阴离子偶联；抗衡阴离子的非限制性实例是氯离子、溴离子、硫酸根、磺酸根、氨基磺酸根、磷酸根、膦酸根、甲酸根、碳酸根、乙酸根、丙酸根、丁酸根、富马酸根、马来酸根、甲磺酸根、柠檬酸根、草酸根、新戊酸根等。式(I)的化合物也可以以前药形式使用，例如作为药学上可接受的酯，其在给药后可以水解，并因此释放出式(I)的化合物。所有这些形式均应包括以用于本发明。
如本文所用，术语“肿瘤”或“抗肿瘤”或“用作抗肿瘤剂”或“肿瘤疾病”是指以肿瘤细胞的形成和增殖为特征的任何疾病；上述术语包括癌、淋巴瘤、白血病、肉瘤、骨髓瘤和相应的混合型形式；上述术语包括实体瘤和液体瘤。优选的液体肿瘤是白血病和淋巴瘤。在白血病中，特别关注的是慢性淋巴细胞白血病、T细胞白血病，例如急性T细胞白血病。在淋巴瘤中，特别关注的是B细胞淋巴瘤，例如弥漫性大B细胞淋巴瘤(例如，活化B细胞样弥漫性大B细胞淋巴瘤或生发中心B细胞弥漫性大B细胞淋巴瘤)、套细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、T细胞淋巴瘤(例如，皮肤T细胞淋巴瘤、外周T细胞淋巴瘤、间变性大T细胞淋巴瘤)等。
通过一种或多种式(I)的化合物治疗或预防肿瘤疾病是本发明的另一个目的。因此，在一个实施方案中，本发明涉及上述式(I)的化合物或其药学上可接受的盐，其用作抗肿瘤剂，即用于治疗或预防肿瘤疾病；在另一个实施方案中，本发明涉及式(I)的化合物或其药学上可接受的盐在制备用于治疗或预防肿瘤疾病的药物中的用途。本发明涉及式(I)的化合物或其药学上可接受的盐，其用于医学。
如本文所用，“治疗”是指将本发明的化合物施用于已经显示出所述肿瘤的一种或多种症状的受试者(人或动物)。术语“治疗”还指旨在治愈、减轻、稳定或预防相关疾病、病理状况或病症的患者的医学管理。该术语包括积极治疗，即专门针对疾病、病理状况或病症的改善的治疗，还包括因果治疗，即针对消除相关疾病、病理状况或病症的起因的治疗。另外，该术语包括姑息治疗，即设计用于缓解症状而不是治愈疾病、病理状况或病症的治疗。
如本文所用，“预防”是指将本发明的化合物施用于显示出所述肿瘤疾病的症状不清楚或没有症状，但是处于具有肿瘤疾病的发展风险的受试者，例如与环境中的致瘤物质接触而具有肿瘤疾病的发展风险、遗传上易患肿瘤疾病等的受试者；预防性治疗通常旨在最小化、或部分抑制、或完全抑制相关肿瘤疾病的发展。
式(I)的化合物或其药学上可接受的盐可以根据肿瘤疾病的类型/严重程度、患者的状况/年龄以及选择的施用途径以各种剂量和方案施用。作为非限制性指示，式(I)的化合物以游离碱表示的剂量可以在10mg/Kg至500mg/Kg变化，优选在100mg/Kg至300mg/Kg变化；根据需要，方案可以涉及每周一天或多天(例如每周2、3、4、5、6或7天)施用上述剂量，持续一周、二周、三周或更多周。方便地，将式(I)的化合物或其药学上可接受的盐作为一个或多个剂量单位提供给患者，每个剂量单位包含上述剂量。
式(I)化合物或其药学上可接受的盐可以通过任何可能的施用途径来施用，例如口服、经口、经颊、经舌下、吸入、经肌内、经静脉内、经局部、经皮肤、经皮、经直肠等，出于方便和/或医疗原因。根据所选择的施用途径，将式(I)的化合物或其药学上可接受的盐配制为相应合适的施用形式。本文中可以非限制性地提及片剂、丸剂(pill)、胶囊剂、微胶囊剂、颗粒剂、微粒剂、小丸剂(pellet)、微丸剂、散剂、冻干粉剂、溶液剂、混悬剂或乳剂、膜剂、凝胶剂、乳膏、经皮或透皮递送系统如贴剂、石膏剂等。在任何可能的情况下，施用形式都将以上述定义的一个或多个剂量单位提供给患者。
本发明的另一目的是药物组合物，包含上述式(I)的化合物或其药学上可接受的盐。在这样的组合物中，式(I)的化合物或其药学上可接受的盐将在一种或多种药物赋形剂中存在。
赋形剂的选择将主要取决于对所选择的施用形式。片剂、丸剂、胶囊剂、锭剂等可以包含以下任何成分或类似性质的化合物：粘合剂，例如微晶纤维素、黄蓍胶或明胶；赋形剂，例如淀粉或乳糖；崩解剂，例如藻酸、原始凝胶(Primogel)或玉米淀粉；润滑剂，例如硬脂酸镁；顺滑剂(gliding)，例如胶态二氧化硅；甜味剂，例如蔗糖或糖精；或调味剂，例如薄荷、水杨酸甲酯或橙子调味剂。当单位剂型是胶囊时，除上述类型的材料外，它还可以包含液体载体，例如脂肪油。另外，单位剂型可以包含改变剂量单位的物理形式的各种其他材料，例如糖、虫胶或其他肠溶剂的包衣。所述化合物可以作为酏剂、混悬剂、糖浆、薄片、口腔崩解膜、口腔崩解片、口香糖的组分来施用。除活性化合物外，糖浆还可以包含作为甜味剂的蔗糖和某些防腐剂、染料、着色剂和调味剂。用于注射的溶液剂或混悬剂可以包括以下组分：无菌稀释液，例如注射用水、盐溶液、不挥发油、聚乙二醇、甘油、丙二醇或其他合成溶剂；抗菌剂，例如苯甲醇或对羟基苯甲酸甲酯；抗氧化剂，如抗坏血酸或亚硫酸氢钠；螯合剂，如乙二胺四乙酸；缓冲液，例如乙酸盐、柠檬酸盐或磷酸盐；以及张力调节剂，例如氯化钠、甘露醇和葡萄糖。可以将注射制剂装入玻璃或塑料制成的安瓿瓶、一次性注射器或多剂量小瓶中。
本发明的另一个目的是制备上述药物组合物的方法，该方法包括将式(I)的化合物或其药学上可接受的盐与一种或多种药物赋形剂配制(例如混合或接触)。
为了用于治疗，式(I)的化合物或其药学上可接受的盐可以单独施用或(替代地)与其他活性剂，特别是其他抗肿瘤剂一起施用。在后一种情况下，可以通过施用将两种活性剂共同配制在一起的剂型来进行相关的联合治疗，或(替代地)通过在合适的时间窗内施用含有一种或其他活性剂的单独剂型来进行相关的联合治疗。适合于所述联合治疗的其他抗肿瘤剂的实例是：甲氨蝶呤(Methotrexate)、紫杉酚(Paclitaxel)、本妥昔单抗(Brentuximab)、阿霉素(Adriamycin)、阿法替尼(Afatinib)、咪喹莫特(Imiquimod)、阿来替尼(Alectinib)、阿仑单抗(Alemtuzumab)、培美曲塞(Pemetrexed)、美法仑(Melphalan)、布加替尼(Brigatinib)、苯丁酸氮芥(Chlorambucil)、氨基乙酰丙酸(AminolevulinicAcid)、帕米膦酸二钠(Pamidronate)、奥法木单抗(Ofatumumab)、阿特朱单抗(Atezolizumab)、安维汀(Avastin)、阿维鲁单抗(Avelumab)、阿扎胞苷(Azacitidine)、阿维鲁单抗(Avelumab)、卡莫司汀(Carmustine)、贝利司他(Belinostat)、奥英妥珠单抗(Inotuzumab Ozogamicin)、贝伐珠单抗(Bevacizumab)、贝沙罗汀(Bexarotene)、比卡鲁胺(Bicalutamide)、博莱霉素(Bleomycin)、博纳吐单抗(Blinatumomab)、硼替佐米(Bortezomib)、博苏替尼(Bosutinib)、本妥昔单抗(Brentuximab)、布加替尼(Brigatinib)、卡巴他赛(Cabazitaxel)、阿卡替尼(Acalabrutinib)、阿伦单抗(Alemtuzumab)、伊立替康(Irinotecan)、卡培他滨(Capecitabine)、氟尿嘧啶(Fluorouracil)、卡铂(Carboplatin)、卡非佐米(Carfilzomib)、色瑞替尼(Ceritinib)、柔红霉素(Daunorubicin)、西妥昔单抗(Cetuximab)、苯丁酸氮芥(Chlorambucil)、顺铂(Cisplatin)、克拉屈滨(Cladribine)、环磷酰胺(Cyclophosphamide)、氯法拉滨(Clofarabine)、氯法拉滨(Clofarabine)、考比替尼(Cobimetinib)、卡博替尼(Cometriq)、库潘尼西(Copanlisib)、更生霉素(Dactinomycin)、考比替尼(Cobimetinib)、克唑替尼(Crizotinib)、环磷酰胺(Cyclophosphamide)、异环磷酰胺(Ifosfamide)、雷莫芦单抗(Ramucirumab)、阿糖孢苷(Cytarabine)、阿糖孢苷(Cytarabine)、达拉非尼(Dabrafenib)、氮烯咪胺(Dacarbazine)、达克金(Dacogen)、更生霉素(Dactinomycin)、达雷木单抗(Daratumumab)、达雷木单抗(Daratumumab)、达沙替尼(Dasatinib)、柔红霉素(Daunorubicin)、地西他滨(Decitabine)、去纤苷(Defibrotide)、地加瑞克(Degarelix)、地诺单抗(Denosumab)、地塞米松(Dexamethasone)、右雷佐生(Dexrazoxane)、地努图希单抗(Dinutuximab)、多西他赛(Docetaxel)、多柔比星(Doxorubicin)、氮烯咪胺(Dacarbazine)、氟尿嘧啶(Fluorouracil)、盐酸表柔比星(Epirubicin Hydrochloride)、埃罗妥珠单抗(Elotuzumab)、奥沙利铂(Oxaliplatin)、埃罗妥珠单抗(Elotuzumab)、恩西地平(Enasidenib)、恩杂鲁胺(Enzalutamide)、表柔比星(Epirubicin)、西妥昔单抗(Cetuximab)、艾日布林(Eribulin)、维莫德吉(Erivedge)、厄洛替尼(Erlotinib)、氨磷汀(Amifostine)、依托泊甙(Etoposide)、多柔比星(Doxorubicin)、雷洛昔芬(Raloxifene)、依西美坦(Exemestane)、托瑞米芬(Toremifene)、帕比司他(Panobinostat)、氟维司群(Fulvestrant)、氟达拉滨(Fludarabine)、氟尿嘧啶(Fluorouracil)、氟他胺(Flutamide)、奥滨尤妥珠单抗(Obinutuzumab)、吉非替尼(Gefitinib)、吉西他滨(Gemcitabine)、艾日布林(Eribulin)、曲妥珠单抗(Trastuzumab)、拓扑替康(Topotecan)、帕博西尼(Palbociclib)、替伊莫单抗(Ibritumomab)、依鲁替尼(Ibrutinib)、普纳替尼(Ponatinib)、伊达比星(Idarubicin)、艾代拉里斯(Idelalisib)、恩西地平(Enasidenib)、异环磷酰胺(Ifosfamide)、伊马替尼(Imatinib)、德瓦鲁单抗(Durvalumab)、咪喹莫特(Imiquimod)、奥英妥珠单抗(Inotuzumab Ozogamicin)、伊匹单抗(Ipilimumab)、吉非替尼(Gefitinib)、伊立替康(Irinotecan)、罗米地辛(Romidepsin)、伊沙匹隆(Ixabepilone)、伊沙佐米(Ixazomib)、伊沙匹隆(Ixabepilone)、鲁索替尼(Ruxolitinib)、卡巴他赛(Cabazitaxel)、派姆单抗(Pembrolizumab)、瑞博西尼(Ribociclib)、司利弗明(Tisagenlecleucel)、卡非佐米(Carfilzomib)、拉帕替尼(Lapatinib)、奥拉木单抗(Olaratumab)、来那度胺(Lenalidomide)、乐伐替尼(Lenvatinib)、来曲唑(Letrozole)、甲酰四氢叶酸(Leucovorin)、亮丙瑞林(Leuprolide)、洛莫司汀(Lomustine)、奥拉帕尼(Olaparib)、长春新碱(Vincristine)、甲基苄肼(Procarbazine)、氮芥(Mechlorethamine)、曲美替尼(Trametinib)、巯嘌呤(Mercaptopurine)、美司钠(Mesna)、替莫唑胺(Temozolomide)、甲氨蝶呤(Methotrexate)、甲基纳曲酮(Methylnaltrexone)、米哚妥林(Midostaurin)、丝裂霉素C(Mitomycin C)、米托蒽醌(Mitoxantrone)、长春瑞滨(Vinorelbine)、耐昔妥珠单抗(Necitumumab)、奈拉滨(Nelarabine)、来那替尼(Neratinib)、索拉非尼(Sorafenib)、尼鲁米特(Nilutamide)、尼罗替尼(Nilotinib)、伊沙佐米(Ixazomib)、尼拉帕利(Niraparib)、纳武单抗(Nivolumab)、他莫昔芬(Tamoxifen)、奥滨尤妥珠单抗(Obinutuzumab)、奥法木单抗(Ofatumumab)、奥拉帕尼(Olaparib)、奥拉木单抗(Olaratumab)、奥马西他辛(Omacetaxine)、纳武单抗(Nivolumab)、奥希替尼(Osimertinib)、奥沙利铂(Oxaliplatin)、紫杉醇(Paclitaxel)、帕博西尼(Palbociclib)、帕利夫明(Palifermin)、帕尼单抗(Panitumumab)、帕比司他(Panobinostat)、卡铂(Carboplatin)、派姆单抗(Pembrolizumab)、帕妥珠单抗(Pertuzumab)、普纳替尼(Ponatinib)、耐昔妥珠单抗(Necitumumab)、普拉曲沙(Pralatrexate)、甲基苄肼(Procarbazine)、地诺单抗(Denosumab)、雷莫芦单抗(Ramucirumab)、拉布立酶(Rasburicase)、瑞格非尼(Regorafenib)、甲基纳曲酮(Methylnaltrexone)、来那度胺(Lenalidomide)、瑞博西尼(Ribociclib)、利妥昔单抗(Rituximab)、罗米地辛(Romidepsin)、瑞卡帕布(Rucaparib)、司妥昔单抗(Siltuximab)、索尼德吉(Sonidegib)、索拉非尼(Sorafenib)、达沙替尼(Dasatinib)、瑞格非尼(Regorafenib)、舒尼替尼(Sunitinib)、司妥昔单抗(Siltuximab)、奥马西他辛(Omacetaxine)、硫鸟嘌呤(Thioguanine)、达拉非尼(Dabrafenib)、奥希替尼(Osimertinib)、厄洛替尼(Erlotinib)、贝沙罗汀(Targretin)、尼罗替尼(Nilotinib)、紫杉醇(Taxol)、紫杉特尔(Taxotere)、阿特朱单抗(Atezolizumab)、替莫唑胺(Temozolomide)、替莫唑胺(Temozolomide)、塞替派(Thiotepa)、拓扑替康(Topotecan)、托瑞米芬(Toremifene)、曲贝替定(Trabectedin)、曲美替尼(Trametinib)、苯达莫司汀(Bendamustine)、二甲苯磺酸拉帕替尼(LapatinibDitosylate)、地努图希单抗(Dinutuximab)、戊柔比星(Valrubicin)、凡德他尼(Vandetanib)、帕尼单抗(Panitumumab)、长春碱(Vinblastine)、硼替佐米(Bortezomib)、维罗非尼(Vemurafenib)、阿贝西利(Abemaciclib)、长春瑞滨(Vinorelbine)、维莫德吉(Vismodegib)、伏立诺他(Vorinostat)、帕唑帕尼(Pazopanib)、克唑替尼(Crizotinib)、伊匹单抗(Ipilimumab)、曲贝替定(Trabectedin)、替伊莫单抗(Ibritumomab)、戈舍瑞林(Goserelin)、唑来膦酸(Zoledronic Acid)、色瑞替尼(Ceritinib)、其药学上可接受的盐、酯或衍生物。
本发明的另一个目的是制备式(I)的化合物或其药学上可接受的盐的方法，其中所述化合物获自一种或多种合适的前体。典型的前体是在以下方案1中以式(1)至(7)表示的那些，参考其中-R为＝O的化合物。
方案1
在以下示例中详细描述和报告了可以使用的方法。然而，它们不应被视为限制可用于制备本发明的化合物的合成方法的范围。在没有描述原料的制备的情况下，它们是可商购的，文献中已知的，或通过本领域技术人员使用标准程序容易获得的。本文所示的任何外消旋的化合物和中间体也可以对映异构体存在并用作对映异构体。
式(3)的中间体可以根据以上报告的方案1通过使3-异氰酸酯基吡啶-2-羧酸甲酯1与3-氨基哌啶-1-羧酸叔丁酯2反应而制备。典型的反应条件包括在合适的极性非质子溶剂(例如DCM)中，在适当的温度(例如室温)，使3-异氰酸酯基吡啶-2-羧酸甲酯1与3-氨基哌啶-1-羧酸叔丁酯2反应。
式(4)的中间体化合物可以根据以上报告的方案1通过使3-[(1-叔丁氧羰基-3-哌啶基)氨基甲酰氨基]吡啶-2-羧酸甲酯3与乙醇钠反应来制备。典型的反应条件包括在合适的醇(例如MeOH或EtOH)中，在适当的温度(例如65至80℃)，使3-[(1-叔丁氧羰基-3-哌啶基)氨基甲酰氨基]吡啶-2-羧酸甲酯3与20％乙醇钠的乙醇溶液反应。
式(6)的中间体可以根据以上报告的方案1通过将3-(2,4-二氧代-1H-吡啶并[3,2-d]嘧啶-3-基)哌啶-1-羧酸叔丁酯4用1-(溴甲基)-4-苯氧基-苯5进行烷基化来制备。典型的反应条件包括在适当的碱(例如K2CO3)存在下，在合适的极性非质子溶剂(例如DMF)中，在适当的温度(例如室温)，使3-(2,4-二氧代-1H-吡啶并[3,2-d]嘧啶-3-基)哌啶-1-羧酸叔丁酯4与1-(溴甲基)-4-苯氧基-苯反应。
式(7)的中间体可以根据以上报告的方案1通过在酸性介质中将3-[2,4-二氧代-1-[(4-苯氧基苯基)甲基]吡啶并[3,2-d]嘧啶-3-基]哌啶-1-羧酸叔丁酯5去保护而制备。典型的反应条件包括在合适的极性非质子溶剂(例如DCM)中，在适当的温度(例如0℃至室温的范围)，使3-[2,4-二氧代-1-[(4-苯氧基苯基)甲基]吡啶并[3,2-d]嘧啶-3-基]哌啶-1-羧酸叔丁酯6与酸(例如4M的二氧六环中的HCl)反应[供一般参考，参见T.W.Green；Protective Groups in Organic Synthesis(Wiley,N.Y.1981)]。
其中-R为＝O的式(I)的化合物可以根据以上报告的方案1通过将1-[(4-苯氧基苯基)甲基]-3-(3-哌啶基)吡啶并[3,2-d]嘧啶-2,4-二酮7用丙烯酰氯8进行酰化反应来制备。典型的反应条件包括在适当的碱(例如TEA)存在下，在合适的极性非质子溶剂(例如DCM)中，在适当的温度(例如室温)，使1-[(4-苯氧基苯基)甲基]-3-(3-哌啶基)吡啶并[3,2-d]嘧啶-2,4-二酮7与丙烯酰氯8反应。为了合成其中-R为-H的式(I)的化合物，可以参考上述方案1反应，并进行适当的调整，以使相应的前体、中间体和最终产物具有同样调整的-R。
接下来参考以下非限制性实施例来描述本发明。
实施例
实施例1：化合物(I)EG-011的合成与化学表征
化合物的化学名称是使用BIOVIA Draw 2017R2工具生成的。后处理(workups)中常用的无机盐溶液是水溶液。
缩略语：
| DCM | 二氯甲烷 |
| DMF | N，N-二甲基甲酰胺 |
| EtOAc | 乙酸乙酯 |
| MeOH | 甲醇 |
| TEA | 三乙胺 |
| TFA | 三氟乙酸 |
| h | 小时 |
| eq | 等效物 |
| min | 分钟 |
| r.t. | 室温 |
| Rt | 保留时间 |
| sat. | 饱和的 |
NMR表征：
使用氘代溶剂(DMSO-d6)在25℃在Bruker Avance 300MHz上收集质子磁共振(1HNMR)光谱。化学位移以百万分率(ppm)表示，并使用残留溶剂信号作为参考进行测量。多重性表示如下：(s)单峰、(d)双重峰、(dd)双重峰、(t)三重峰、(q)四重峰、(m)多重峰、(br s)宽信号。
LC/UV/MS分析方法：
以下文本中报告的MS/ESI+[MH]+值可以通过质谱仪ZQ或等效物获得：
MS仪器：Waters ZQ(或等效物)
极性(Polarity)：ES+
毛细管电压(Capillary)(kV)：3.50
锥孔电压(Cone)(V)：20.00
提取锥孔电压(Extractor)(V)：2.00
RF透镜电压(Lens)(V)：0.2
源温(Source Temperature)(℃)：130
脱溶剂温度(Desolvation Temperature)(℃)：350
脱溶剂气流量(Desolvation Gas Flow)(L/hr)：600
质量范围(Mass range)(Da)：50to 900
扫描时间(Scan time)(秒)：0.6
扫描延迟时间(Inter-Scan delay)(秒)：0.2
LC仪器：Waters Alliance e2695
仪器：带有发电二极管检测器2998、柱温箱和质谱仪ZQ的HPLC Waters或等效物
柱：Phenomenex Gemini-NX C18,150×2.0，3μm或等效物
柱温(℃)：25
波长(nm)：215
流量(mL/min)：0.2
注入体积(μL)：5
流动相溶剂A：(H2O+0.1％甲酸)；流动相溶剂B(乙腈+0.1％甲酸。
梯度：
| T(min) | A％ | B％ |
| 0 | 80 | 20 |
| 15 | 30 | 70 |
| 35 | 30 | 70 |
使用Biotage Isolera自动纯化系统进行快速色谱纯化，并在预装的BiotageSNAP KP-Sil柱、Biotage SNAP Ultra或Biotage SNAP KP-NH柱上进行。
盐水是指NaCl的饱和水溶液。
结构(I)的化合物可以按照方案2所示的合成路线制备：
方案2
步骤1：合成3-[(1-叔丁氧羰基-3-哌啶基)氨甲酰氨基]吡啶-2-羧酸甲酯
向3-异氰酸酯基吡啶-2-羧酸甲酯(根据Synthetic Communications,2003,33(24),4259-4268的描述制备；1.20g，6.736mmol)的无水二氯甲烷溶液(8mL)中，逐滴添加外消旋的3-氨基哌啶-1-羧酸叔丁酯(1.349g，6.736mmol)的DCM溶液(4mL)，并将所得的混合物在室温搅拌过夜。减压蒸发溶剂后，残留物通过快速色谱法在Biotage KP-Sil SNAP柱(DCM：EtOAc＝80％：20％-100％EtOAc)上进行纯化。需要通过快速色谱法在Bitotage NHSNAP柱(己烷：EtOAc＝80：20至40：60)上进一步纯化，得到标题化合物(1.4g)。MS/ESI+379.1[MH]+，Rt＝13.6分钟。
步骤2：合成3-(2,4-二氧代-1H-吡啶并[3,2-d]嘧啶-3-基)哌啶-1-羧酸叔丁酯
向3-[(1-叔丁氧羰基-3-哌啶基)氨基甲酰氨基]吡啶-2-羧酸甲酯(1.3g)的MeOH溶液(15mL)中加入20％乙醇钠的EtOH溶液(1.48mL，3.8mmol)，并将所得混合物加热回流8小时，然后在室温搅拌过夜。将该混合物与较少量的批次(通过0.100g的3-[(1-叔丁氧羰基-3-哌啶基)氨基甲酰氨基]吡啶-2-羧酸甲酯在相同条件下的反应而获得)一起蒸发至干，并将残留物溶于水，并用乙酸(pH≈4-5)酸化。通过过滤收集沉淀物，并用大量水洗涤几次。将该固体在50℃的真空干燥，得到标题化合物，为米色固体(1.1g，3.175mmol，步骤2的产率47％)。MS/ESI+347.0[MH]+,Rt＝11.8分钟。
步骤3：合成3-[2,4-二氧代-1-[(4-苯氧基苯基)甲基]吡啶并[3,2-d]嘧啶-3-基]哌啶-1-羧酸叔丁酯：
向3-(2,4-二氧代-1H-吡啶并[3,2-d]嘧啶-3-基)哌啶-1-羧酸叔丁酯(1.00g，2.89mmol)的无水DMF悬浮液(8mL)中加入K2CO3(0.798g，5.78mmol)，接着加入1-(溴甲基)-4-苯氧基-苯(0.911g，3.46mmol)的DMF溶液(1mL)，并将所得混合物在室温搅拌46小时。用EtOAc(70mL)和水(60mL)分离混合物。有机相用盐水(3×70mL)洗涤，经硫酸钠干燥，过滤并浓缩。将残留物通过快速色谱法在Biotage KP-Sil SNAP柱(100％EtOAc)上纯化，得到标题化合物，为米色泡沫状物(1.380g，2.61mmol，90％产率)。MS/ESI+529.1[MH]+,Rt＝25.4分钟。
步骤4：合成1-[(4-苯氧基苯基)甲基]-3-(3-哌啶基)吡啶并[3,2-d]嘧啶-2,4-二酮：
向冷却至3℃的3-[2,4-二氧代-1-[(4-苯氧基苯基)甲基]吡啶并[3,2-d]嘧啶-3-基]哌啶-1-羧酸叔丁酯(1.375g，2.60mmol)的DCM溶液(20mL)中逐滴加入TFA(1.992mL，26.0mmol)，并将所得混合物放置至室温，并搅拌6小时。将混合物用DCM稀释并用饱和的NaHCO3洗涤。有机相经硫酸钠干燥，过滤并浓缩，得到标题化合物，为米色泡沫状物(1.086g，2.53mmol，97％产率)，其无需纯化即可使用。MS/ESI+429.0[MH]+,Rt＝8.9分钟。
步骤5：合成1-[(4-苯氧基苯基)甲基]-3-(1-丙-2-烯酰基-3-哌啶基)吡啶并[3,2-d]嘧啶-2,4-二酮
将1-[(4-苯氧基苯基)甲基]-3-(3-哌啶基)吡啶并[3,2-d]嘧啶-2,4-二酮(1.08g，2.52mmol)和TEA(1.054mL，7.56mmol)的DCM溶液(20mL)冷却至3℃，并加入丙烯酰氯(0.246mL，3.02mmol)。将混合物放置至室温，搅拌过夜。用DCM稀释混合物并用5％柠檬酸水溶液洗涤。用DCM萃取水相，用盐水冲洗合并的有机层，用硫酸钠干燥，过滤和浓缩。将残留物通过快速色谱法在Biotage KP-Sil SNAP柱(DCM至DCM：MeOH＝95：5)上纯化。需要通过快速色谱法在Biotage Ultra silica SNAP柱(EtOAc至EtOAc∶MeOH＝95：5)上进一步纯化，得到标题化合物，为白色泡沫状物(0.640g，1.326mmol，53％产率)。MS/ESI+483.1[MH]+,Rt＝17.4min；1H NMR(300MHz,DMSO-d6)δppm 8.54,(d,1H),7.60-7.85(m,2H),7.27-7.50(m,4H),7.13(t,1H),6.65-7.05(m,5H),6.14(d,1H),5.69(d,1H),5.20-5.48(m,2H),4.71-4.88(m,1H),4.40-4.65(m,1H),4.05-4.260(m,1H),3.50-4.05(m,1H),2.35-3.15(m,2H),1.77-1.95(m,2H),1.34-1.62(m,1H)。
实施例2：化合物(I)EG-011的生物学表征
细胞系
根据推荐条件培养来自活化B细胞样(ABC)(n＝3)和生发中心B细胞(GCB)(n＝12)弥漫性大B细胞淋巴瘤(DLBCL)、套细胞淋巴瘤(MCL)(n＝9)、慢性淋巴细胞白血病(CLL)(n＝2)、霍奇金淋巴瘤(HL)(n＝4)、皮肤T细胞淋巴瘤(CTCL)(n＝3)、周围T细胞淋巴瘤(PTCL)(n＝1)、间变性大T细胞淋巴瘤(ALCL)(n＝4)、急性T细胞白血病(ATCL)(n＝1)的39个细胞系。所有培养基均补充有胎牛血清(10％)、青霉素-链霉素-新霉素(
单位青霉素、5mg链霉素和10mg新霉素/mL，Sigma)和L-谷氨酰胺(1％)。
化合物
将EG-011溶解在二甲基亚砜(DMSO)中，以得到10mM的原液(stock)浓度以用于体外实验。将EG-011溶于25％的羟丙基β-环糊精(HP-β-CD)的水中，并使用NaOH(0.1N)和HCl(0.1N)将pH调节至6.0，以进行体内实验。施用体积为4.5mL/kg(在4.5mL中为100mg)，并且小鼠通过腹膜内i.p.接受200微升(相当于200mg/kg)的注射，每天一次，每周五天。
增殖MTT测定
对于所有细胞系，将细胞以10,000个细胞的密度接种在96孔板中(未经组织培养处理)。将每种化合物溶解在二甲基亚砜(DMSO)中。为了处理细胞，将化合物在适当的组织培养基中按照1：2的稀释倍数以20mcM至78nM的范围连续稀释，然后添加到细胞中(一式三份)。将细胞在37℃，5％CO2下孵育72小时。将DMSO单独添加到阴性对照(未处理)细胞中。每个平板上包括仅包括培养基的孔，其用作吸光度读数的空白。将MTT(Sigma-AldrichChemie GmbH，Buchs，Switzerland)制成5mg/ml PBS储备液，并进行过滤灭菌。将MTT溶液(22μL)加入每个孔中，并将组织培养板在37℃下孵育4小时。然后，用25％SDS裂解缓冲液裂解细胞，并使用AD340读板仪(Beckman Coulter International SA，Switzerland)在570nm处读取吸光度。与对照细胞(对照对应于100％)相比，吸光度值以增殖细胞的百分比表示。
碘化丙啶细胞周期染色方案
将淋巴瘤细胞(每种条件下106个)固定在70％的冷乙醇中(在4℃持续至少30分钟)，然后在涡旋的同时逐滴添加到细胞沉淀(pellet)中。将细胞在PBS中洗涤两次，并以2000rpm旋转；弃去上清液，将细胞悬浮于PBS(0.5mL)中，并用核糖核酸酶(50μl的100μg/mLRNase)处理。然后添加200μL碘化丙啶(50μg/ml)，并使用BD FACS-Canto II进行数据采集。
FITC Annexin V凋亡测定
将淋巴瘤细胞(每种条件下106个)暴露于单一药物72小时，并通过FITC AnnexinV细胞凋亡检测试剂盒(BD Biosciences)并按照官方方案进行测定。
异种移植实验
NOD-Scid(NOD.CB17-Prkdcscid/NCrHsd)小鼠购自Harlan实验室(五至六周龄，约20g体重)。小鼠的维护和动物实验是根据为动物设施制定的机构指南和当地州兽医局批准的研究方案进行的。小鼠皮下移植了15×106的人类Mantle细胞淋巴瘤REC1细胞，并分为两个实验组。从体积为180mm3的肿瘤开始，小鼠接受了单药治疗，而对照组仅接受了载剂。每周5天以200mg/kg(200微升)的剂量经腹膜内注射施用EG-011。
数据挖掘
计算中位数百分比的精确二项式95％置信区间(95％C.I.)。使用t-Student检验计算淋巴瘤亚型之间IC50值的差异。统计显著性由P值为0.05或更低来定义。
结果
EG-011在39个细胞系中表现出抗肿瘤活性，中位数IC50为2500nM(95％C.I.；100nM至20000nM)(表1)。特别是，ABC-DLBCL呈现的中位数IC50为10μM，GCB-DLBCL为550nM，MCL为1000nM，HL为13.5μM，PLL为7.5，T细胞淋巴瘤(CTCL、PTCL、ALCL)为2.5μM(图1-图3)。总体而言，39个细胞系中有12个显示出的IC50值低于1μM(95％C.I.；100nM至600nM)。TP53、BCL2和MYC与所有细胞系的灵敏度/抗性均不相关。在表示最大组的GCB-DLBCL中，6个GCB-DLBCL敏感的(IC50<600nM)细胞系中有5个以及4个GCB-DLBCL抵抗的(IC50>600nM)细胞系中有3个检测到TP53失活(P＝n.s.)。6个GCB-DLBCL敏感的(IC50<600nM)细胞系中有5个以及3个GCB-DLBCL抵抗的(IC50>600nM)细胞系中有1个检测到BCL2易位(P＝n.s.)。7个GCB-DLBCL敏感的(IC50<600nM)细胞系中有3个以及3个GCB-DLBCL抵抗的(IC50>600nM)细胞系中有1个中检测到MYC易位(P＝n.s.)。
将两种细胞系(OCI-LY-19和REC1)暴露于两种浓度的EG-011(500nM和2000nM)72小时，sub-G0期(指示死亡细胞)的细胞的剂量依赖性增加(图4-图5)。
EG-011作为单一制剂在体内的抗肿瘤活性已在已显示出体外敏感性的MCL模型REC1细胞系中得到证实。每天1次且每周5天以200mg/Kg的剂量施用EG-011(图6和补充图1)。还使用了一组对照小鼠。与对照(第6天、第7天、第9天，P<0.05)相比，EG-011 200mg/Kg延迟了肿瘤的生长(体积)和肿瘤重量(补充图2)。用EG-011治疗的动物的体重没有减少，证实了没有体内毒性。
表1.在淋巴瘤细胞系中用72小时暴露时间从MTT测定中获得的IC50值。
参考文献
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Siegel,R.L.,Miller,K.D.&Jemal,A.(2016)Cancer statistics,2016.CACancer J Clin,66,7-30.
Stewart,B.&Wild,C.P.(eds.)(2014)World Cancer Report 2014.IARCNonserial Publication.
Swerdlow,S.H.,Campo,E.,Pileri,S.A.,Harris,N.L.,Stein,H.,Siebert,R.,Advani,R.,Ghielmini,M.,Salles,G.A.,Zelenetz,A.D.&Jaffe,E.S.(2016)The2016revision of the World Health Organization classification of lymphoidneoplasms.Blood,127,2375-2390.
Testoni,M.,Zucca,E.,Young,K.H.&Bertoni,F.(2015)Genetic lesions indiffuse large B-cell lymphomas.Ann Oncol,26,1069-1080.
Claims (24)
1.式(I)的化合物或其药学上可接受的盐，
其中，-R表示＝O。
2.一种药物组合物，包含权利要求1所述的式(I)的化合物或其药学上可接受的盐，以及一种或多种药学上可接受的赋形剂。
3.根据权利要求2所述的药物组合物，其中，所述式(I)的化合物或其药学上可接受的盐以10mg/Kg至500mg/Kg的剂量存在或施用。
4.根据权利要求3所述的药物组合物，其中，所述式(I)的化合物或其药学上可接受的盐以100mg/Kg至300mg/Kg的剂量存在或施用。
5.根据权利要求2所述的药物组合物，其中，所述式(I)的化合物或其药学上可接受的盐与另外的抗肿瘤剂一起配制或共同施用。
6.根据权利要求2所述的药物组合物，其中，所述式(I)的化合物或其药学上可接受的盐被配制为用于通过选自以下的途径施用：经静脉内、经局部。
7.根据权利要求2所述的药物组合物，其中，所述式(I)的化合物或其药学上可接受的盐被配制为用于通过选自以下的途径施用：经口、经颊、经舌下、吸入、经肌内、经皮、经直肠。
8.根据权利要求2所述的药物组合物，其中，所述式(I)的化合物或其药学上可接受的盐被配制为用于通过口服施用。
9.权利要求1所述的式(I)的化合物或其药学上可接受的盐在配制抗肿瘤剂和/或抗增殖剂中的用途。
10.根据权利要求9所述的用途，其中，所述抗肿瘤剂和/或抗增殖剂用于治疗和/或预防癌。
11.根据权利要求9所述的用途，其中，所述抗肿瘤剂和/或抗增殖剂用于治疗和/或预防淋巴瘤、白血病、肉瘤、骨髓瘤和相应的混合型形式中的一种或多种。
12.根据权利要求11所述的用途，其中，所述抗肿瘤剂和/或抗增殖剂用于治疗和/或预防以下中的一种或多种：慢性淋巴细胞白血病；T细胞白血病；T细胞淋巴瘤；B细胞白血病；B细胞淋巴瘤；套细胞淋巴瘤；霍奇金淋巴瘤；非霍奇金淋巴瘤。
13.根据权利要求12所述的用途，其中所述T细胞白血病是急性T细胞白血病。
14.根据权利要求12所述的用途，其中所述T细胞淋巴瘤是皮肤T细胞淋巴瘤、外周T细胞淋巴瘤、或间变性大T细胞淋巴瘤。
15.根据权利要求12所述的用途，其中所述B细胞淋巴瘤是弥漫性大B细胞淋巴瘤。
16.根据权利要求15所述的用途，其中所述弥漫性大B细胞淋巴瘤是活化B细胞样弥漫性大B细胞淋巴瘤或生发中心B细胞弥漫性大B细胞淋巴瘤。
17.根据权利要求9-16中任一项所述的用途，其中所述式(I)的化合物或其药学上可接受的盐以10mg/Kg至500mg/Kg的剂量存在或施用。
18.根据权利要求17所述的用途，其中所述式(I)的化合物或其药学上可接受的盐以100mg/Kg至300mg/Kg的剂量存在或施用。
19.根据权利要求9-16中任一项所述的用途，其中所述式(I)的化合物或其药学上可接受的盐与另外的抗肿瘤剂一起配制或共同施用。
20.根据权利要求9-16中任一项所述的用途，其中所述式(I)的化合物或其药学上可接受的盐被配制为用于通过选自以下的途径施用：经静脉内、经局部。
21.根据权利要求9-16中任一项所述的用途，其中所述式(I)的化合物或其药学上可接受的盐被配制为用于通过选自以下的途径施用：经口、经颊、经舌下、吸入、经肌内、经皮、经直肠。
22.根据权利要求9-16中任一项所述的用途，其中所述式(I)的化合物或其药学上可接受的盐被配制为被配制为用于通过口服施用。
23.一种制备权利要求2所述的药物组合物的方法，包括使式(I)的化合物或其盐与一种或多种药物赋形剂接触。
24.一种获得权利要求1所定义的式(I)的化合物的方法，包括使其中-R为＝O的式(II)的化合物与丙烯酰氯反应：
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| CN111971283A (zh) | 2020-11-20 |
| US11471459B2 (en) | 2022-10-18 |
| WO2019185117A1 (en) | 2019-10-03 |
| US20210113565A1 (en) | 2021-04-22 |
| EP3774793A1 (en) | 2021-02-17 |
| EP3774793B1 (en) | 2022-02-23 |
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