CN113121502A - 一种杂芳烃类化合物、中间体、组合物及应用 - Google Patents
一种杂芳烃类化合物、中间体、组合物及应用 Download PDFInfo
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- CN113121502A CN113121502A CN202010679194.8A CN202010679194A CN113121502A CN 113121502 A CN113121502 A CN 113121502A CN 202010679194 A CN202010679194 A CN 202010679194A CN 113121502 A CN113121502 A CN 113121502A
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- compound
- butyl
- alkyl
- substituted
- membered heteroaryl
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Abstract
本发明公开了一种杂芳烃类化合物、中间体、组合物及应用。该化合物的结构如式I所示，其对A2aR受体均显示了一定的抑制活性，而且绝对生物利用度高。
Description
技术领域
本发明涉及一种杂芳烃类化合物、中间体、组合物及应用。
背景技术
近年来，多种针对免疫检查点程序性死亡蛋白配体1/程序性死亡蛋白1(programmed death ligand 1/programmed death 1,PDL1/PD1)和细胞毒T淋巴细胞相关抗原4(cytotoxic T lymphocyteassociated antigen-4,CTLA-4)的药物陆续上市，免疫检查点疗法已成为肿瘤免疫疗法中最有希望的策略之一。以PD-1/PD-L1、CTLA-4单抗为代表的第一代免疫检查点抑制剂已逐渐成为肿瘤免疫治疗的基石，尽管疗效明显，可是还有相当一部分人群对此类疗法产生耐受，这也从侧面表明在肿瘤微环境中同时存在其他的免疫耐受的机制，其中一个重要免疫耐受机制与腺苷通路相关，细胞外的腺苷(adenosine,ADO)可通过激活并结合与G蛋白偶联的四种腺苷受体(adenosine receptor,AR)调控机体免疫系统。
2a型腺苷受体(type 2a adenosine receptor,A2aR)在T细胞、B细胞、单核巨噬细胞、中性粒细胞等多种免疫细胞上表达水平较高，其在人体内的天然配体是腺嘌呤核苷即腺苷(ADO)，ADO-A2aR是维持肿瘤微环境中免疫抑制状态的重要因素之一。肿瘤细胞在缺氧和炎症等因素作用下可产生大量单磷酸腺苷AMP，AMP被外核苷酸酶CD73催化为腺苷并积聚于肿瘤微环境中。腺苷与T细胞和NK细胞表面的A2aR结合，导致NK细胞和CD8+T细胞的细胞毒活性减弱，最终削弱抗肿瘤免疫反应。临床前研究显示，A2aR抑制剂单药或联合其他免疫治疗具有良好的抗瘤活性。通过基因或药物干预，同时阻断外核苷酸酶CD73和腺苷受体A2aR可抑制肿瘤的发生、生长和转移。肿瘤细胞系中的CD73过表达会削弱PD-1单抗的体内抑瘤作用，而同时应用A2aR抑制剂后上述情况的得到缓解。另有研究证实抑制或下调A2aR表达可显著增强CAR-T细胞的抗肿瘤活性。Corvus制药公司开展的A2aR抑制剂CPI-444单药或联合PD-L1抗体Atezolizumab治疗晚期肿瘤的I/Ib期临床试验显示，无论是单药还是联合Atezolizumab，CPI-444对RCC和NSCLC患者，均显示出了良好疗效和安全性。此外，Novartis公司开发了另一个A2aR抑制剂PBF-509，其单药或联合PD-1单抗治疗NSCLC的I期研究也在进行之中，但上述处于临床研究阶段的CPI-444和PBF-509均只作用于A2aR单一靶点。在腺苷通路中，2b型腺苷受体(type 2b adenosine receptor,A2bR)在树突状细胞，肿瘤相关巨噬细胞及骨髓来源的抑制性细胞中高表达，在调控机体免疫耐受方面也发挥重要作用，因此同时作用于A2aR和A2bR两个受体的化合物可能会发挥更好的抗肿瘤作用，但现有报道显示同时作用于A2aR和A2bR两个受体的化合物研究较少，结构也不明确，在本研究中，我们设计了同时靶向A2aR和A2bR受体的系列化合物，期望可以获得有更好成药价值的先导化合物。
发明内容
本发明所要解决的技术问题是针对现有技术同时靶向A2aR受体的化合物存在不足等缺陷，为此，本发明提供了一种杂芳烃类化合物、中间体、组合物及应用。该类化合物对A2aR受体均显示了一定的抑制活性，而且绝对生物利用度高。
本发明提供了一种如式I所示的化合物或其药学上可接受的盐：
其中，R1为氢、C1～C4烷基或被一个或多个卤素取代的C1～C4烷基；当取代基为多个时，相同或不同；
R2为氰基、-C(＝O)-O-R、-C(＝O)-N(RaRb)、5-6元杂芳基或被一个或多个Rc取代的5-6元杂芳基；所述的5-6元杂芳基或被一个或多个Rc取代的5-6元杂芳基里的5-6元杂芳基中杂原子选自N、O和S中的一种或多种，杂原子数为1-3个；当取代基为多个时，相同或不同；
R、Ra、Rb和Rc独立地为H、C1～C4烷基或被一个或多个卤素取代的C1～C4烷基；当取代基为多个时，相同或不同；
或，R1与R2及其相连的吡啶基一起形成
或被一个或多个Rd取代的
当取代基为多个时，相同或不同；
Rd独立地为C1～C4烷基或被一个或多个卤素取代的C1～C4烷基或-N(ReRf)；当取代基为多个时，相同或不同；
Re和Rf独立地为H、C1～C4烷基或被一个或多个卤素取代的C1～C4烷基；当取代基为多个时，相同或不同。
本发明中，所述的如式I所示的化合物或其药学上可接受的盐中某些取代基的定义可如下所述，未提及的取代基的定义均如本发明任一方案所述。
在本发明的某一优选方案中，所述的R1为氢；所述的R2为氰基、-C(＝O)-O-R、-C(＝O)-N(RaRb)、5-6元杂芳基或被一个或多个Rc取代的5-6元杂芳基；或，R1与R2及其相连的吡啶基一起形成
或被一个或多个Rd取代的
较佳地，所述的R为氢；所述的R2为氰基、-C(＝O)-O-R或-C(＝O)-N(RaRb)、5-6元杂芳基，或，R1与R2及其相连的吡啶基一起形成
或被一个或多个Rd取代的
在本发明的某一优选方案中，所述的R1为氢；所述的R2为氰基或-C(＝O)-O-R；较佳地，R为氢或C1～C4烷基；更佳地，R为氢。
在本发明的某一优选方案中，所述的R1为氢；所述的R2为-C(＝O)-N(RaRb)或5-6元杂芳基；或，R1与R2及其相连的吡啶基一起形成
或被一个或多个Rd取代的
在本发明的某一优选方案中，所述的R1为氢；所述的R2为氰基、-C(＝O)-O-R或-C(＝O)-N(RaRb)、5-6元杂芳基；较佳地，R2为氰基、-C(＝O)-O-R或-C(＝O)-N(RaRb)。
在本发明的某一优选方案中，所述的5-6元杂芳基和被一个或多个Rc取代的5-6元杂芳基里的5-6元杂芳基为杂原子选自N、O或S，杂原子数为两个的5元杂芳基，优选杂原子为N。
在本发明的某一优选方案中，所述的5-6元杂芳基和被一个或多个Rc取代的5-6元杂芳基里的5-6元杂芳基为咪唑(例如
)。
在本发明的某一优选方案中，R1中，所述的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基。
在本发明的某一优选方案中，R1中，所述的卤素取代的C1～C4烷基中的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基。
在本发明的某一优选方案中，R1中，所述的卤素取代的C1～C4烷基中的卤素为氟、氯、溴或碘。
在本发明的某一优选方案中，R、Ra、Rb和Rc中，所述的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基。
在本发明的某一优选方案中，R、Ra、Rb和Rc中，所述的卤素取代的C1～C4烷基中的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基。
在本发明的某一优选方案中，R、Ra、Rb和Rc中，所述的卤素取代的C1～C4烷基中的卤素为氟、氯、溴或碘。
在本发明的某一优选方案中，Rd中，所述的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基。
在本发明的某一优选方案中，Rd中，所述的卤素取代的C1～C4烷基中的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基。
在本发明的某一优选方案中，Rd中，所述的卤素取代的C1～C4烷基中的卤素为氟、氯、溴或碘。
在本发明的某一优选方案中，Re和Rf中，所述的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基。
在本发明的某一优选方案中，Re和Rf中，所述的卤素取代的C1～C4烷基中的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基。
在本发明的某一优选方案中，Re和Rf中，所述的卤素取代的C1～C4烷基中的卤素为氟、氯、溴或碘。
在本发明的某一优选方案中，所述的R1为氢。
在某一优选技术方案中，所述的R为氢或C1～C4烷基；较佳地，为氢。
在本发明的某一优选方案中，Re和Rf为氢。
在本发明的某一优选方案中，Ra和Rb独立地为氢；例如-C(＝O)-N(RaRb)为
在本发明的某一优选方案中，Rc为氢。
在某一优选技术方案中，所述的Rd为-N(ReRf)；较佳地为-NH2。
在本发明的某一优选方案中，所述的R2为氰基、-C(＝O)-O-R或-C(＝O)-N(RaRb)；所述的R为氢或C1～C4烷基；较佳地，所述的R为氢；所述的R2为氰基或
在本发明的某一优选方案中，所述的R2为5-6元杂芳基或被一个或多个Rc取代的5-6元杂芳基；较佳地为5-6元杂芳基；更佳地，所述的R2为
在本发明的某一优选方案中，R1与R2及其相连的吡啶基一起形成
或被一个或多个Rd取代的
较佳地，所述的被一个或多个Rd取代的
为
(例如
)。
在某一具体技术方案中，所述的如式I所示的化合物或其药学上可接受的盐里，所述的如式I所示的化合物可为下述任一化合物：
优选为如下化合物：
所述的如式I所示的化合物药学上可接受的盐优选为：
本发明还提供一种如式I所示的化合物的制备方法，其包括如下步骤：在溶剂中，在一价铜催化剂的作用，将化合物II和化合物8进行如下所示的叠氮-炔基Husigen环加成反应(Copper-Catalyzed Azide–Alkyne Cycloaddition)，得到化合物I即可；
其中，R1和R2的定义如前所述。
所述的溶剂可为本领域进行此类反应的常规溶剂，优选酰胺类溶剂和/或醇类溶剂。所述的酰胺类溶剂优选N,N-二甲基甲酰胺。所述的醇类溶剂优选甲醇、乙醇、异丙醇和叔丁醇中的一种或多种。当所用的溶剂为酰胺类溶剂和醇类溶剂的混合溶剂时，所述的酰胺类溶剂与所述的醇类溶剂的体积比值优选为0.1～1.0，例如，0.2。
所述的溶剂的用量可为本领域常规，优选其与化合物8的体积摩尔比为6L/mol～20L/mol，例如，12L/mol。
所述的一价铜催化剂可为本领域进行此类反应的常规一价铜催化剂，优选为卤代亚酮或者二价铜盐经过还原剂进行还原所得。所述的卤代亚铜可为碘化亚铜、溴化亚铜和氯化亚铜中的一种或多种。所述的二价铜盐优选为硫酸铜。所述的还原剂可为抗坏血酸钠。
当所述的一价铜盐为二价铜盐经过还原剂进行还原所得时，所述的二价铜盐与化合物8的摩尔比值优选为0.1～1.0，例如，0.5。所述的还原剂与化合物8的摩尔比值优选为0.5～1.5，例如，1.0。
所述的一价铜盐的用量可为本领域进行此类反应的常规用量，优选其与化合物8的摩尔比值为0.1～1.0，例如，0.5。
所述的叠氮-炔基Husigen环加成反应的温度可为本领域进行此类反应的常规温度，优选为室温～100℃，例如，60℃。
在所述的反应中，所述的叠氮-炔基Husigen环加成反应的进程可采用本领域中的常规监测方法(例如TLC、HPLC或NMR)进行检测，一般以化合物8消失时作为反应终点。所述的反应时间优选12～48小时，例如，12小时。
在所述的反应中，所述的反应后处理方法可为此类反应的常规后处理，优选包含以下步骤：反应完成后，减压浓缩除去溶剂，硅胶柱层析纯化得到化合物I。
本发明还提供了一种化合物，其结构如下：
本发明还提供了一种药物组合物，其包含如式I所示的化合物或其药学上可接受的盐和药用辅料。
本发明还提供了一种如式I所示的化合物或其药学上可接受的盐在制备A2aR抑制剂中的应用。
本发明提供了所述如式I所示的化合物或其药学上可接受的盐在制备用于治疗与A2aR受体有关的疾病的药物中的应用；所述的与A2aR受体有关的疾病可为肿瘤、精神障碍类疾病、心血管疾病和糖尿病中的一种或多种。
本发明还提供了一种如式I所示的化合物或其药学上可接受的盐在制备药物中的应用。所述的药物可为用于治疗肿瘤的药物。
所述的肿瘤可为黑色素瘤、肺癌、肝癌、乳腺癌、胃癌、肠癌、胰腺癌、头颈部癌、肾细胞癌、泌尿道上皮癌和非霍奇金淋巴瘤中的一种或多种。
本发明还提供了一种治疗与A2aR受体有关的疾病的方法，其包括向患者施用治疗有效量的如式I所示的化合物或其药学上可接受的盐。
如无特别说明，本发明所用术语具有如下含义：
术语“多个”是指2个、3个、4个或5个。
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全，并且适合于患者使用。所述的“患者”优选哺乳动物，更优选为人类。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of PharmaceuticalSalts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“化合物”和“药学上可接受的盐”可以以晶型或无定型的形式存在。术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列，并具有间隔一定距离周期重复出现规律；因上述周期性排列的不同，可存在多种晶型，也即多晶型现象。术语“无定型”是指其中的离子或分子呈现杂乱无章的分布状态，即离子、分子间不具有周期性排列规律。
术语“化合物”和“药学上可接受的盐”如存在互变异构体，则可以以单一的互变异构体或它们的混合物的形式存在，较佳地以较稳定的互变异构体为主的形式存在。
术语“化合物”和“药学上可接受的盐”中的原子可以以其天然丰度或非天然丰度的形式存在。以氢原子为例，其天然丰度的形式是指其中约99.985％为氕、约0.015％为氘；其非天然丰度的形式是指其中约95％为氘。也即，术语“化合物”、“药学上可接受的盐”、“溶剂合物”和“药学上可接受的盐的溶剂合物”中的一个或多个原子可为以非天然丰度的形式存在的原子。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有一个到十二个碳原子的饱和的直链或支链的一价烃基(例如C1-C6烷基，又例如C1-C4烷基)。烷基的实例包括但不仅限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丁基、2-丁基、2-甲基-2-丙基、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基和1-辛基。
术语“杂芳基”是指各环中可高达7个原子的稳定单环或者二环，其中至少一个环是芳香环并且含有1-4个选自硼、硅、氧、硫、硒、氮和磷的杂原子。在此定义范围内的杂芳基包括但不限于：吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009Sixth Edition)。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时，足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。
术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的化合物对A2aR受体均显示了一定的抑制活性，相比现有技术，绝对生物利用度高。
附图说明
图1为化合物BS005在小鼠血浆中随时间的代谢曲线(左：灌胃；右：静注)。
图2为化合物AB928在小鼠血浆中随时间的代谢曲线(左：灌胃；右：静注)。
图3为化合物BS007在小鼠血浆中随时间的代谢曲线(左：灌胃；右：静注)。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1.中间体化合物3-(2-氨基-6-乙炔基嘧啶-4-基)-2-甲基苯甲腈(8)
步骤1.1.合成2-甲基-3-氰基苯硼酸频哪醇酯(3)
将取化合物1(10.00g，51mmol)加入500mL三口瓶中，加入100mL 1,4-二氧六环，搅拌溶解。氮气保护下依次加入化合物2(15.54g，61mmol)、乙酸钾(10.01g，102mmol)和Pd(dppf)Cl2(1.12g，1.53mmol)。回流下搅拌反应5h，降温至25℃。抽滤，滤饼用50mL乙酸乙酯洗涤。向滤液中加H2O和乙酸乙酯各50mL，搅拌5min，分液，水相用乙酸乙酯(30mL×3)萃取，合并乙酸乙酯相，然后用饱和食盐水30mL洗涤，无水Na2SO4干燥5min，抽滤，减压浓缩得黄绿色液体。硅胶柱层析(正己烷：乙酸乙酯＝20：1至10:1)得11.15g白色固体(化合物3，收率90％)。1H NMR(400MHz,CDCl3):δ7.95(dd,J＝7.5,1.4Hz,1H),7.64(dd,J＝7.7,1.5Hz,1H),7.24(td,J＝7.6,0.5Hz,1H),2.74(s,3H),1.34(s,12H).
步骤1.2：3-(2-氨基-6-氯嘧啶-4-基)-2-甲基苯甲腈(5)的合成
氮气保护下，将50mL N,N-二甲基甲酰胺和5mL水加入250mL三口圆底烧瓶中，依次加入化合物4(4.55g，27.77mmol)、碳酸钾(7.68g，55.53mmol)，搅拌5min。将反应体系升温至45℃，逐滴加入化合物3(4.50g，18.51mmol)的N,N-二甲基甲酰胺溶液。115℃下搅动反应5h，停止加热并冷却至25℃。加入H2O和乙酸乙酯各50mL搅拌5min，静置分液，水相用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥5min，抽滤，滤液减压浓缩得橙黄色油状液体。硅胶柱层析(正己烷：乙酸乙酯＝10：1至5:1)，得1.68g白色固体(化合物5，收率37％)。1H NMR(400MHz,CDCl3):δ7.69(dd,J＝7.7,1.3Hz,1H),7.56(dd,J＝7.8,1.3Hz,1H),7.40–7.34(m,1H),6.72(s,1H),5.40(s,2H),2.58(s,3H).
步骤1.3：3-(2-氨基-6-((三甲基硅基)乙炔基)嘧啶-4-基)-2-甲基苯甲腈(7)的合成
氮气保护下，将化合物5(1.00g，4.08mmol)加入至100mL三口圆底烧瓶中，加入40mL无水THF，搅拌溶解，然后依次加入三乙胺(1.24g，12.24mmol)、三甲基硅乙炔(0.601g，6.12mmol)，搅拌5min，再依次加入Pd(PPh3)2Cl2(72mg，0.102mmol)、CuI(39mg，0.204mmol)，回流条件下搅拌反应16h，停止加热，冷至25℃。减压浓缩除去溶剂得黑色浆状粗产物。加入30mL乙酸乙酯，搅拌5min，抽滤除去不溶物。滤液以此用NH4Cl：NH3.H2O＝1:1(10mL×2)、饱和食盐水(30mL)洗涤，用无水Na2SO4干燥5min，抽滤，减压浓缩得1.12g黑色固体(化合物7)，MS(ESI)m/z:307.40[M+H]+，1H NMR(400MHz,DMSO-d6)δ7.84(dd,J＝7.5,1.2Hz,1H),7.65(dd,J＝7.7,1.3Hz,1H),7.46–7.42(m,1H),7.25(s,1H),6.94(s,2H),2.46(s,3H),0.20(s,9H)，直接加入下一步反应。
步骤1.4：3-(2-氨基-6-乙炔基嘧啶-4-基)-2-甲基苯甲腈(8)的合成
氮气保护下，将上一步化合物7(1.12g)溶于15mL无水四氢呋喃中，降温至0℃，搅拌下逐滴加浓度为1M的四丁基氟化铵(TBAF)四氢呋喃溶液(6mL)，滴加完毕后0℃继续搅拌30min，然后室温反应20h。将反应温度降至0℃，加如饱和的NH4Cl溶液(15mL)淬灭，用乙酸乙酯(30mL×3)萃取，合并有机相用无水Na2SO4干燥5min，抽滤，减压浓缩得黑色固体，硅胶柱层析(正己烷：乙酸乙酯＝3:1)，得0.575g棕色固体(化合物8，收率60％)。MS(ESI)m/z:235.41[M+H]+，1H NMR(400MHz,DMSO-d6):δ7.84(dd,J＝7.8,1.2Hz,1H),7.65(dd,J＝7.8,1.1Hz,1H),7.48–7.43(m,1H),6.96(s,2H),6.81(s,1H),4.50(s,1H),2.46(s,3H)。
实施例2化合物3-(2-氨基-6-(1-(喹啉-2-基甲基)-1H-1,2,3-三唑-4-基)嘧啶-4-基)-2-甲基苯甲腈(11)(BS001)的制备
合成路线如下：
步骤2.1：2-(叠氮甲基)喹啉(10)的合成
25℃，氮气保护下，将化合物9(1.00g，4.50mmol)加入50mL三口圆底烧瓶中。加入10mL无水四氢呋喃，搅拌溶解。将体系降温至-10℃，依次滴加TMSN3(1.04g，9.02mmol)和DIPEA(1.16g，8.98mmol)。滴加完毕后，将体系温度升至25℃，搅拌反应24h。抽滤除去不溶物，减压浓缩除去溶剂，硅胶柱层析(正己烷：乙酸乙酯＝10:1)，得0.515g淡黄色液体(化合物10，收率62％)。MS(ESI)m/z:185.1[M+H]+,1H NMR(400MHz,CDCl3):δ8.21(d,J＝8.4Hz,1H),8.10(d,J＝8.6Hz,1H),7.83(dd,J＝8.2,1.3Hz,1H),7.74(ddd,J＝8.4,6.9,1.5Hz,1H),7.56(ddd,J＝8.1,6.9,1.2Hz,1H),7.48(d,J＝8.5Hz,1H),4.69(s,2H).
步骤2.2：3-(2-氨基-6-(1-(喹啉-2-基甲基)-1H-1,2,3-三唑-4-基)嘧啶-4-基)-2-甲基苯甲腈(11)的合成
25℃下，将化合物8(350mg，1.50mmol)加入50mL三口圆底烧瓶中。加入3mL N,N-二甲基甲酰胺和15mL叔丁醇，搅拌溶解，再加入9mL水。然后，依次加入化合物10(304mg，1.65mmol)、五水硫酸铜(187mg，0.75mmol)和L-抗坏血酸钠(297mmol，1.50mmol)，搅拌10min，然后60℃搅拌12h。减压浓缩除去溶剂，硅胶柱层析(二氯甲烷：甲醇＝50:1)得490mg黄褐色固体(化合物11，收率78％)。1H NMR(400MHz,DMSO-d6):δ8.73(s,1H),8.39(d,J＝8.4Hz,1H),7.96(dd,J＝8.2,1.1Hz,1H),7.92(d,J＝8.6Hz,1H),7.85(dd,J＝7.7,1.2Hz,1H),7.77–7.69(m,2H),7.59(ddd,J＝8.1,6.9,1.1Hz,1H),7.50–7.39(m,2H),7.25(s,1H),6.84(s,2H),6.01(s,2H),2.51(s,3H).
实施例3 3-(2-氨基-6-(1-((8-氨基喹啉-2-基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-4-基)-2-甲基苯甲腈盐酸盐(16)(BS002)的制备
合成路线如下：
步骤3.1：2-(溴甲基)-8-硝基喹啉(13)的合成
将化合物12(1.42g，10mmol)加入100mL三口瓶中，然后加入30mL四氯化碳。25℃搅拌下依次加入N-溴代琥珀酰亚胺(2.67g，15mmol)和0.2g过氧化苯甲酰。加热至回流，并在回流状态下反应14个小时。将反应液抽滤，除去不溶物，减压浓缩得2.1g黄色固体，硅胶柱层析(正己烷：乙酸乙酯＝3:1)，得1.69g白色固体(化合物13，收率63.5％)。MS(ESI)m/z:222.0,224.0[M+H]+，1H NMR(400MHz,CDCl3):δ8.17(d,J＝8.5Hz,1H),8.08(d,J＝8.5Hz,1H),7.81(dd,J＝8.1,1.3Hz,1H),7.73(ddd,J＝8.4,6.9,1.5Hz,1H),7.59–7.51(m,2H),4.72(s,2H).
步骤3.2：2-(叠氮甲基)-8-硝基喹啉(14)的合成
25℃，氮气保护下，将化合物13(600mg，2.25mmol)加入50mL三口圆底烧瓶中。加入6mL无水四氢呋喃，搅拌溶解。将体系降温至-15℃，依次滴加TMSN3(648mg，5.63mmol)和DIPEA(728mg，5.63mmol)。滴加完毕后，将体系温度升至25℃，搅拌反应27h。依次加入10mL水和10mL乙酸乙酯，搅拌5min，分液，水相用乙酸乙酯(30mL×3)萃取，合并有机相用无水Na2SO4干燥5min，抽滤，滤液减压浓缩得505mg黑色固体(化合物14，收率98％)。MS(ESI)m/z:252.33[M+Na]+。
步骤3.3：3-(2-氨基-6-(1-((8-硝基喹啉-2-基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-4-基)-2-甲基苯甲腈(15)的合成
25℃下，将化合物8(270mg，1.15mmol)加入50mL三口圆底烧瓶中。加入3mL N,N-二甲基甲酰胺和17mL叔丁醇，搅拌溶解，再加入10mL水。然后，依次加入化合物14(240mg，1.05mmol)、五水硫酸铜(125mg，0.50mmol)和L-抗坏血酸钠(199mmol，1.00mmol)，搅拌10min，然后60℃搅拌15h。减压浓缩除去溶剂，硅胶柱层析(二氯甲烷：甲醇＝50:1至25：1)得210mg黄色固体(化合物15，收率43％)。MS(ESI)m/z:464.43[M+H]+。
步骤3.4：3-(2-氨基-6-(1-((8-氨基喹啉-2-基)甲基)-1H-1,2,3-三唑-4-基)嘧啶-4-基)-2-甲基苯甲腈盐酸盐(16)的合成
在搅拌下，将化合物15(100mg，0.216mmol)、15mL乙醇、氯化亚锡(205mg，1.08mmol)加入至50mL三口圆底烧瓶中，70℃反应2h。将反应降温至25℃，倒入50mL水中，减压浓缩除去溶剂，反向硅胶柱层析(甲醇：水＝0％，20％，50％)得灰色固体，甲醇打浆得10mg灰色固体(化合物16，收率9.8％)。MS(ESI)m/z:434.52[M+H]+,1H NMR(400MHz,DMSO-d6):δ8.75(s,1H),8.19(d,J＝8.5Hz,1H),7.85(d,J＝7.7Hz,1H),7.72(d,J＝7.7Hz,1H),7.47(t,J＝7.8Hz,1H),7.38(d,J＝8.5Hz,1H),7.30–7.22(m,2H),7.03(d,J＝8.1Hz,1H),6.84(m,,4H),5.95(s,2H),5.77(s,2H),2.52(s,3H).
实施例4 6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-三唑-1-基)甲基)吡啶酸(20)(BS003)的制备
合成路线如下
将化合物19(128mg，0.300mmol)加入50mL单口圆底烧瓶中，加入10叔丁醇：水＝2：1的混合溶液，搅拌5min，加入氢氧化锂(18.5mg，0.441mmol)，继续搅拌8h。用1M的盐酸调节体系pH为5-6。加入10mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥5min，抽滤，滤液减压浓缩除去溶剂，硅胶柱层析(二氯甲烷：甲醇＝20:1)得81mg白色固体(化合物20，收率65％)。MS(ESI)m/z:413.42[M+H]+，1H NMR(400MHz,DMSO-d6):δ13.25(s,1H),8.68(s,1H),7.98(d,J＝5.4Hz,2H),7.88–7.82(m,1H),7.72(d,J＝8.0Hz,1H),7.54–7.41(m,2H),7.23(s,1H),6.84(s,2H),5.87(s,2H),2.51(s,3H).
实施例5 6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-三唑-1-基)甲基)吡啶甲酸甲酯(19)(BS004)的制备
合成路线如下：
步骤4.1：6-(叠氮甲基)吡啶甲酸甲酯(18)的合成
氮气保护下，将化合物17(2.30g，10mmol)加入100mL三口圆底烧瓶中。加30mL N,N-二甲基甲酰胺，搅拌溶解。将体系降温至-10℃，依次滴加TMSN3(2.88g，25mmol)和DIPEA(3.23g，25mmol)。滴加完毕后，将体系温度升至25℃，搅拌反应12h。依次加入50mL水和30mL乙酸乙酯，搅拌5min，分液，水相用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥5min，抽滤，滤液减压浓缩得1.85g淡黄色液体(化合物18，收率96％)。1H NMR(400MHz,CDCl3):δ8.04(d,J＝8.1Hz,1H),7.86(t,J＝7.8Hz,1H),7.55(d,J＝7.8Hz,1H),4.59(s,2H),3.96(s,3H).
步骤4.2：6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-三唑-1-基)甲基)吡啶甲酸甲酯(19)的合成
25℃下，将化合物8(200mg，0.854mmol)加入50mL三口圆底烧瓶中。加入2mL N,N-二甲基甲酰胺和9mL叔丁醇，搅拌溶解，再加入5mL水。然后，依次加入化合物18(180mg，0.936mmol)、五水硫酸铜(106mg，0.425mmol)和L-抗坏血酸钠(168mmol，0.854mmol)，搅拌10min，然后60℃搅拌12h。减压浓缩除去溶剂，硅胶柱层析(二氯甲烷：甲醇＝50:1)得210mg黄褐色固体(化合物19，收率58％)。MS(ESI)m/z:427.42[M+H]+，1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.03–7.96(m),7.84(dd,J＝7.7,1.3Hz),7.71(dd,J＝7.8,1.3Hz),7.52–7.43(m),7.24(s,1H),6.85(s,2H),5.89(s,2H),3.84(s,3H),2.51(s,3H).
实施例6 6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-三唑-1-基)甲基)吡啶腈(23)(BS005)的制备
合成路线如下：
步骤6.1：6-(叠氮甲基)吡啶腈(22)的合成
氮气保护下，将化合物21(1.00g，7.45mmol)加入100三口圆底烧瓶中，加入15mL无水四氢呋喃，搅拌溶解。降温至-5℃，依次滴加叠氮磷酸二苯酯(2.46g，8.95mmol)和1,8-二氮杂二环十一碳-7-烯(1.36g，8.95mmol)。自然升至25℃，并在25℃搅拌反应10h。加入30mL水，搅拌5min，静置分液，水相用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥5min，抽滤，滤液减压浓缩除去溶剂，硅胶柱层析(正己烷：乙酸乙酯＝10:1)得1.10g淡黄色液体(化合物22，收率93％)。MS(ESI)m/z:160.32[M+H]+。
步骤6.2：6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-三唑-1-基)甲基)吡啶腈(23)的合成
25℃下，将化合物8(290mg，1.239mmol)加入50mL三口圆底烧瓶中。加入3mL N,N-二甲基甲酰胺和14mL叔丁醇，搅拌溶解，再加入5mL水。然后，依次加入化合物22(215mg，1.363mmol)、五水硫酸铜(155mg，0.621mmol)和L-抗坏血酸钠(246mmol，1.242mmol)，搅拌10min，然后60℃搅拌13h。减压浓缩除去溶剂，硅胶柱层析(二氯甲烷：甲醇＝50:1)得200mg类白色固体(化合物23，收率41％)。MS(ESI)m/z:394.51[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.70(s,1H),8.08(t,J＝7.8Hz,1H),7.99(d,J＝7.7Hz,1H),7.85(d,J＝7.4Hz,1H),7.72(dd,J＝7.8,1.3Hz,1H),7.66(dd,J＝7.9,0.8Hz,1H),7.47(t,J＝7.7Hz,1H),7.24(s,1H),6.85(s,2H),5.90(s,2H),2.51(s,3H).
实施例7 6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-三唑-1-基)甲基)吡啶甲酸异丙酯(26)(BS006)的制备
合成路线如下：
步骤7.1：6-(叠氮甲基)吡啶酸异丙酯(25)的合成
氮气保护下，将化合物24(1.30g，6.66mmol)加入100三口圆底烧瓶中，加入20mL无水四氢呋喃，搅拌溶解。降温至-5℃，依次滴加叠氮磷酸二苯酯(2.60g，9.45mmol)和1,8-二氮杂二环十一碳-7-烯(1.44g，9.45mmol)。自然升至25℃，并在25℃搅拌反应16h。加入30mL水，搅拌5min，静置分液，水相用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥5min，抽滤，滤液减压浓缩除去溶剂，硅胶柱层析(正己烷：乙酸乙酯＝10:1)得1.20g淡黄色液体(化合物25，收率82％)。MS(ESI)m/z:243.31[M+Na]+。
步骤7.2：6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-三唑-1-基)甲基)吡啶甲酸异丙酯(26)的合成
25℃下，将化合物8(200mg，0.854mmol)加入50mL三口圆底烧瓶中。加入2mL N,N-二甲基甲酰胺和14mL叔丁醇，搅拌溶解，再加入8mL水。然后，依次加入化合物25(226mg，1.025mmol)、五水硫酸铜(107mg，0.427mmol)和L-抗坏血酸钠(169mmol，0.854mmol)，搅拌10min，然后60℃搅拌15h。减压浓缩除去溶剂，硅胶柱层析(二氯甲烷：甲醇＝50:1)得310mg白色固体(化合物26，收率80％)。MS(ESI)m/z:455.53[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.69(s,1H),8.01–7.94(m,2H),7.85(dd,J＝7.7,1.4Hz,1H),7.71(dd,J＝7.8,1.4Hz,1H),7.47(td,J＝7.8,0.6Hz,1H),7.44(dd,J＝7.2,1.7Hz,1H),7.23(s,1H),6.84(s,1H),5.89(s,2H),5.11(p,J＝6.3Hz,1H),2.51(s,3H),1.28(d,J＝6.3Hz,6H).
实施例8 6-((4-(2-氨基-6-(3-氰基-2-甲基苯基)嘧啶-4-基)-1H-1,2,3-三唑-1-基)甲基)吡啶酰胺(27)(BS007)的制备
合成路线如下：
氮气保护下，将化合物19(50mg，0.117mmol)加入25mL三口圆底烧瓶中。加入10mL甲醇搅拌5min。降温至-10℃，滴加3mL氨水。滴加完毕后，25℃反应14h。减压除去溶剂，加水(8mL)打浆30min，抽滤的30.5mg黄色固体，硅胶柱层析(二氯甲烷：甲醇＝25:1)得21mg白色固体(化合物27，收率44％)。MS(ESI)m/z:412.52[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.79(s,1H),8.02–7.93(m,2H),7.91(s,1H),7.85(dd,J＝7.8,1.2Hz,1H),7.71(dd,J＝7.9,1.2Hz,2H),7.51–7.44(m,2H),7.24(s,1H),6.82(s,2H),5.85(s,2H),2.51(s,3H).
实施例9 3-(6-(1-((6-(1H-咪唑-2-基)吡啶-2-基)甲基)-1H-1,2,3-三唑-4-基)-2-氨基嘧啶-4-基)-2-甲基苯甲腈(31)(BS008)的制备
合成路线如下：
步骤9.1：(6-(1H-咪唑-2-基)吡啶-2-基)甲醇(29)的合成
氮气保护下，将化合物21(600mg，4.51mmol)加入150mL三口圆底烧瓶中，依次加入20mL甲醇和甲醇钠(51mg，0.947mmol)，搅拌溶解。40℃下搅拌1h，然后依次加入化合物28(395mg，3.76mmol)和醋酸(542mg，9.02mmol)，加热至回流，回流条件下继续反应2h。降温至25℃，补加20mL甲醇，然后加入6M盐酸(3.13mL)。反应体系继续回流反应5h。减压浓缩除去溶剂，加入10mL水，用饱和碳酸钠溶液调节pH为8-10。体系用二氯甲烷(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥5min，抽滤，滤液减压浓缩除去溶剂，甲叔醚(6mL)打浆，抽滤得220mg淡棕色固体(化合物29，收率33％)。1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),7.88–7.79(m,2H),7.36(dd,J＝6.6,2.2Hz,1H),7.19(s,1H),7.02(s,1H),5.36(t,J＝5.8Hz,1H),4.60(d,J＝5.8Hz,2H).
步骤9.2：2-(叠氮甲基)-6-(1H-咪唑-2-基)吡啶(30)的合成
氮气保护下，将化合物29(220mg，1.26mmol)加入50三口圆底烧瓶中，加入10mL无水四氢呋喃，搅拌溶解。降温至-5℃，依次滴加叠氮磷酸二苯酯(416mg，1.51mmol)和1,8-二氮杂二环十一碳-7-烯(229mg，1.51mmol)。自然升至25℃，并在25℃搅拌反应18h。加入20mL水，搅拌5min，静置分液，水相用乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水Na2SO4干燥5min，抽滤，滤液减压浓缩除去溶剂得400mg淡黄色固体。将固体溶于1M盐酸(10mL)中，加入5mL甲叔醚萃取，甲叔醚相再用水(20mL×3)萃取，合并水相，并用2N氢氧化钠水溶液调pH为8-10。然后体系用乙酸乙酯(30mL×3)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水Na2SO4干燥5min，抽滤，滤液减压浓缩除去溶剂得232mg类白色固体(化合物30，收率92％)。MS(ESI)m/z:201.41[M+H]+.1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),7.95(dd,J＝7.9,0.9Hz,1H),7.88(t,J＝7.7Hz,1H),7.37(dd,J＝7.5,0.9Hz,1H),7.20(s,1H),7.04(s,1H),4.56(s,2H)。
步骤9.3：3-(6-(1-((6-(1H-咪唑-2-基)吡啶-2-基)甲基)-1H-1,2,3-三唑-4-基)-2-氨基嘧啶-4-基)-2-甲基苯甲腈(31)的合成
25℃下，将化合物8(195mg，0.832mmol)加入50mL三口圆底烧瓶中。加入2mL N,N-二甲基甲酰胺和14mL叔丁醇，搅拌溶解，再加入8mL水。然后，依次加入化合物30(200mg，0.999mmol)、五水硫酸铜(104mg，0.416mmol)和L-抗坏血酸钠(165mmol，0.832mmol)，搅拌10min，然后60℃搅拌15h。减压浓缩除去溶剂，反向硅胶柱层析(甲醇：水＝0％，50％，80％)得25mg灰白色固体(化合物31，收率6.9％)。MS(ESI)m/z:435.42[M+H]+，1H NMR(400MHz,DMSO-d6):δ12.63(s,1H),8.7(s,1H)5,7.96(dd,J＝7.9,0.9Hz,1H),7.90–7.82(m,2H),7.75–7.68(m,1H),7.47(td,J＝7.8,0.6Hz,1H),7.24(s,2H),7.16(dd,J＝7.6,0.8Hz,1H),7.05(s,1H),6.82(s,2H),5.81(s,2H),2.51(s,3H).
一、抑制活性数据
效果实施例1
采用cAMP法评价合成的系列化合物(BS001-BS008)对A2aR受体的抑制活性。
本发明中使用的CHO-K1/ADORA2A/Gα15稳定转染细胞系(编号：M00246)，由南京金斯瑞公司构建。细胞于含10％胎牛血清的F12K完全培养基(Gibco,21127-022)，在37℃、5％CO2+95％无菌空气条件下培养。
激动活性测试：将ADORA2A/CHO-K1细胞重悬于F12K完全培养基中，按3000/孔(5μL)铺于384孔板中。将阳性激动剂NECA(MedChemExpress,HY-103173)用Hank's平衡盐溶液(Gibco,14175-095)配置成2x工作液，按5μL/孔加入细胞中，室温避光孵育30min。再加入10μL/孔检测试剂(Cisbio,62AM4PEC)后室温避光孵育1h，经PheraStar检测FRET信号并采集，计算EC80。
抑制活性测试：将ADORA2A/CHO-K1细胞重悬于F12K完全培养基中，按3000/孔(5μL)铺于384孔板中。用Hank's平衡盐溶液配置4x样品工作液(BS001-BS006)，工作浓度(10nM,100nM,1000nM)和4x EC80剂量的阳性激动剂NECA工作液，将不同浓度样品工作液与NECA工作液按照1:1的体积比混合均匀，向细胞中加入5μL混合溶液，室温避光孵育30min。加入10μL/孔检测试剂后室温避光孵育1h，经PheraStar检测FRET信号，不同波长的信号比值由以下计算方式得到：Ration665/620＝Raw Data(337,665)/Raw Data(337,620)×10000，计算各化合物的抑制率。
表1
如表1所示，合成的8个化合物对A2aR受体均显示了一定的抑制活性。化合物BS007、BS008、BS003、BS004和BS005的抑制活性较强，在化合物终浓度为1000nM时，BS007、BS008、BS003、BS004和BS005的抑制活性分别为102.58±0.90、107.33±0.30、92.62％±1.90％，91.27％±4.29％和92.42％±0.40％。其中，化合物BS007对A2aR受体的拮抗活性最强，在化合物终浓度为100nM时，仍能完全拮抗EC80剂量的激动剂NECA对A2aR受体的激动作用。其中化合物BS005对A2aR受体的抑制活性最强，在化合物终浓度为100nM时，仍显示了84.22％±2.95％的抑制活性。
效果实施例2
采用ELISA法评价系列化合物对NECA导致的T淋巴细胞功能抑制的修复作用。
本发明中使用的人外周血淋巴细胞(PBMC)购买自美国Allcells公司(货号：PB006F)。
(1)冻存状态下的PBMC在37℃水浴条件下快速融化复苏，将复苏的PBMC细胞用含10％胎牛血清的1640完全培养液在37℃，5％CO2+95％无菌空气条件下过夜培养。
(2)系列化合物(BS001-BS006)用DMSO稀释至100X样品工作液(工作浓度：10nM，100nM，1000nM)，NECA的工作浓度为1000nM。
(3)将100μL PBMC接种至U型96孔板(2.5x105细胞/孔)，将2μL不同浓度的化合物和NECA加入到96孔板中，并与细胞充分混匀。对照孔加入4μL DMSO，细胞在37℃条件下孵育1h。
(4)每孔中加入100μL含2ug/mL anti-CD3和anti-CD28抗体的细胞培养液后继续培养48h。
(5)培养48h后，收集细胞培养液上清，用ELISA方法测定上清中的IL-2含量。
表2
如表2所示，与DMSO空白组比较，1000nM NECA组IL-2含量有显著下降，这说明NECA可以抑制T淋巴细胞的活性。当不同浓度的化合物加入后，IL-2的含量均得到了一定程度的恢复，这说明NECA对淋巴细胞激活的抑制作用可以被我们合成的化合物所拮抗。在这些化合物中，BS006、BS005和BS004都显示了较强的A2aR拮抗活性，BS001、BS002和BS003拮抗活性相对较弱，拮抗活性的排序为BS006＝BS005＝BS004>BS001＝BS002＝BS003。
二、药物代谢数据
药代实施例1
采用UPLC-MS/MS法研究合成的化合物(BS005、AB928)小鼠绝对生物利用度。
本实验所用动物为Balb/c小鼠，雌性，24只，每组6只，交叉时间点采集，每点3只小鼠。口服剂量30mg/kg，浓度3mg/ml，给药体积0.1ml/10g。静脉注射10mg/kg，浓度1mg/ml，给药体积0.1ml/10g。静脉注射采血点：5min，15min，30min，1h，2h，4h，6h，8h，12h，24h。口服采血点：15min，30min，1h，2h，3h，4h，6h，8h，12h，24h。
血浆样品处理方法：血浆置于涂有肝素的EP管中，12000pm离心4min，后吸取上清液(血清)，-20℃保存备用。取血清样品25μL加入100μL的沉淀剂乙腈涡旋8min，在10000rpm，4℃条件下离心10min，取50μL上清液进液质测定。
标准工作曲线：取空白血清样品20μL加入5μL的BS005的混合标准溶液配制成2.5-10000ng/mL的基质血浆样品，然后加入100μL的沉淀剂乙腈涡旋8min，在10000rpm，4℃条件下离心10min，取50μL上清液进液质测定。
液相色谱质谱联用分析方法：(1)色谱条件：色谱柱为ACQUITY UPLC色谱柱(150×2.1mm，3.5μm)；流动相：0.1％甲酸-乙腈(v/v 20:80)；流速：0.6mL/min；柱温：40℃；进样量：10μL；分析时间：6min。(2)质谱条件：离子源为电喷雾离子源(electrosprayionization，ESI)；扫描模式为正离子模式。扫描方式：多反应监测模式(MRM)定量；BS005定量离子：m/z 394.100→366.100；DP：101volts，EP：6volts，CE：25volts，CXP：12volts；AB928定量离子：m/z 427.200→381.3；DP：70volts，EP：9volts，CE：28volts，CXP：12volts。
表3小鼠体内灌胃和注射BS005和AB928的药动学参数
小鼠灌胃给药BS005和注射给药测得其血浆中BS005的浓度变化，得平均血药浓度-时间曲线(见图1)。口服给药BS005达峰浓度Cmax为7162.80μg/L，达峰时间Tmax为2.0h。注射给药的达峰浓度Cmax为5010.30μg/L，达峰时间Tmax为0.25h。BS005口服和注射的曲线下面积分别为45490.39μg·h/L和17286.84μg·h/L，其绝对生物利用度为87.7％。
小鼠灌胃给药AB928和注射给药测得其血浆中AB928的浓度变化，得平均血药浓度-时间曲线(见图2)。口服给药AB928达峰浓度Cmax为7451.48μg/L，达峰时间Tmax为0.50h。注射给药的达峰浓度Cmax为5983.05μg/L，达峰时间Tmax为0.25h。AB928口服和注射的曲线下面积分别为42762.50μg·h/L和27980.60μg·h/L，其绝对生物利用度为50.9％。
药代实施例2
采用UPLC-MS/MS法研究合成的化合物(BS007)小鼠绝对生物利用度。
本实验所用动物为Balb/c小鼠，雌性，24只，每组6只，交叉时间点采集，每点3只小鼠。口服剂量30mg/kg，浓度3mg/mL，给药体积0.1mL/10g。静脉注射10mg/kg，浓度1mg/mL，给药体积0.1mL/10g。静脉注射采血点：5min，15min，30min，1h，2h，4h，6h，8h，12h，24h。口服采血点：15min，30min，1h，2h，3h，4h，6h，8h，12h，24h。
血浆样品处理方法：血浆置于涂有肝素的EP管中，12000pm离心4min，后吸取上清液(血清)，-20℃保存备用。取血清样品25μL加入100μL的沉淀剂乙腈涡旋8min，在10000rpm，4℃条件下离心10min，取50μL上清液进液质测定。
标准工作曲线：取空白血清样品20μL加入5μL的BS007的混合标准溶液配制成2.5-10000ng/mL的基质血浆样品，然后加入100μL的沉淀剂乙腈涡旋8min，在10000rpm，4℃条件下离心10min，取50μL上清液进液质测定。
液相色谱质谱联用分析方法：(1)色谱条件：色谱柱为Waters XBridge色谱柱(150×2.1mm，3.5μm)；流动相：0.1％甲酸-乙腈(v/v 20:80)；流速：0.6mL/min；柱温：40℃；进样量：10μL；分析时间：6min。(2)质谱条件：离子源为电喷雾离子源(electrosprayionization，ESI)；扫描模式为正离子模式。扫描方式：多反应监测模式(MRM)定量；定量离子：m/z 412.100→339.000；DP：75volts，EP：11volts，CE：29volts，CXP：26volts。
表4小鼠体内灌胃和注射BS007的药动学参数
小鼠灌胃给药BS007和注射给药测得其血浆中BS007的浓度变化，得平均血药浓度-时间曲线(见图3)。口服给药BS007达峰浓度Cmax为1007.40μg/L，达峰时间Tmax为1.0h。注射给药的达峰浓度Cmax为7266.60μg/L，达峰时间Tmax为0.08h。BS007口服和注射的曲线下面积分别为7904.90μg·h/L和4484.58，其绝对生物利用度为58.8％。
药代实施例3
采用UPLC-MS/MS法研究合成的化合物(BS005、BS007和AB928)在肝微粒的代谢稳定性。
本实验所用人肝微粒体为瑞德肝脏疾病研究(上海)有限公司提供男性(混合)人肝微粒体(20mg/mL)和雄性SD大鼠(混合)肝微粒体(20mg/mL)。样品处理方法：(1)烟酰胺腺嘌呤二核苷酸磷酸(NADPH)再生系统：1mL2％NaHCO3中包含葡萄糖-6-磷酸钠盐7.8mg，葡萄糖-6-磷酸脱氢酶(100U/mL)60μL，β-烟酰胺腺嘌呤二核苷酸磷酸(β-NADP)1.7mg，尿苷二磷酸葡萄糖醛酸(UDPGA)6.45mg和MgCl2.6H2O 5.1mg。(2)肝微粒体稀释液：280μL磷酸盐缓冲溶液加入3948μL水和140μL 20mg/mL肝微粒体。(3)肝微粒体孵育：取640μL肝微粒体稀释液然后加入16μL 25μM工作液(BS005、BS007和阳性化合物7-Ethoxycoumarin(7-乙氧基香豆素))，37℃孵育5min，取出80μL孵化液加入200μL乙腈和20μL NADPH生成溶液，记作0min样品；剩余的孵化液加入加140μL NADPH生成溶液，分别孵育10min、20min、30min、40min、50min、60min后取出100μL孵化液加入200μL乙腈终止反应。(4)样品处理：将上述0～60min取出的样品涡旋3min后在在10000rpm，4℃条件下离心10min，取50μL上清液待测。
液相色谱质谱联用分析方法：(1)色谱条件：色谱柱为Waters BEH C18柱(2.1×100mm，1.7μm)；流动相：0.1％(甲酸+乙酸铵)-乙腈(v/v 20:80)；流速：0.4mL/min；柱温：40℃；进样量：5μL；分析时间：6min。(2)质谱条件：离子源为电喷雾离子源(electrosprayionization，ESI)；扫描模式为正离子模式。扫描方式：多反应监测模式(MRM)定量；BS005定量离子：007m/z 394.100→366.100，DP：101volts，CE：25volts；BS007定量离子：m/z412.100→339.000；DP：75volts，CE：29volts；7-Ethoxycoumarin定量离子191.100→107.100；DP：85volts，CE：36volts；AB928定量离子：m/z 427.200→381.3；DP：70volts，EP：9volts，CE：28volts，CXP：12volts。
表5 7-乙氧基香豆素在肝微粒上的代谢稳定性
由表5可知，7-Ethoxycoumarin为阳性对照，该化合物清除率在9～13mL/min/gliver为可接受的范围，本实验7-Ethoxycoumarin在大鼠与人体内的清除率分别为10.0以及9.0，在可接受范围内，说明实验测试体系可靠。
表6 BS005、BS007及AB928在肝微粒上的代谢稳定性
由表6可知，BS005、BS007和AB928该化合物在人肝微粒体上几乎不代谢，而在鼠微粒体上呈现缓慢代谢状态，清除率分别为0.78、1.08和2.15mL/min/g liver。
Claims (10)
1.一种如式I所示的化合物或其药学上可接受的盐：
其中，R1为氢、C1～C4烷基或被一个或多个卤素取代的C1～C4烷基；当取代基为多个时，相同或不同；
R2为氰基、-C(＝O)-O-R、-C(＝O)-N(RaRb)、5-6元杂芳基或被一个或多个Rc取代的5-6元杂芳基；所述的5-6元杂芳基和被一个或多个Rc取代的5-6元杂芳基里的5-6元杂芳基中杂原子选自N、O和S中的一种或多种，杂原子数为1-3个；当取代基为多个时，相同或不同；
R、Ra、Rb和Rc独立地为H、C1～C4烷基或被一个或多个卤素取代的C1～C4烷基；当取代基为多个时，相同或不同；
或，R1与R2及其相连的吡啶基一起形成
或被一个或多个Rd取代的
当取代基为多个时，相同或不同；
Rd独立地为C1～C4烷基或被一个或多个卤素取代的C1～C4烷基或-N(ReRf)；当取代基为多个时，相同或不同；
Re和Rf独立地为H、C1～C4烷基或被一个或多个卤素取代的C1～C4烷基；当取代基为多个时，相同或不同。
2.如权利要求1所述的如式I所示的化合物或其药学上可接受的盐，其特征在于，所述的5-6元杂芳基和被一个或多个Rc取代的5-6元杂芳基里的5-6元杂芳基为杂原子选自N、O或S，杂原子数为两个的5元杂芳基，优选杂原子为N；
和/或，R1中，所述的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基；
和/或，R1中，所述的卤素取代的C1～C4烷基中的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基；
和/或，R1中，所述的卤素取代的C1～C4烷基中的卤素为氟、氯、溴或碘；
和/或，R、Ra、Rb和Rc中，所述的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基；
和/或，R、Ra、Rb和Rc中，所述的卤素取代的C1～C4烷基中的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基；
和/或，R、Ra、Rb和Rc中，所述的卤素取代的C1～C4烷基中的卤素为氟、氯、溴或碘；
和/或，Rd中，所述的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基；
和/或，Rd中，所述的卤素取代的C1～C4烷基中的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基；
和/或，Rd中，所述的卤素取代的C1～C4烷基中的卤素为氟、氯、溴或碘；
和/或，Re和Rf中，所述的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基；
和/或，Re和Rf中，所述的卤素取代的C1～C4烷基中的C1～C4烷基为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基或异丁基；
和/或，Re和Rf中，所述的卤素取代的C1～C4烷基中的卤素为氟、氯、溴或碘。
3.如权利要求1所述的如式I所示的化合物或其药学上可接受的盐，其特征在于，所述的R1为氢；
和/或，当所述的Rd为-N(ReRf)时，所述的Re和Rf独立地为氢；
和/或，当所述的R2为被一个或多个Rc取代的5-6元杂芳基时，所述的Rc为氢；
和/或，当所述的R2为被一个或多个Rd取代的
时，所述的Rd为-N(ReRf)；
和/或，所述的R2为氰基、-C(＝O)-O-R、-C(＝O)-N(RaRb)或5-6元杂芳基；或，R1与R2及其相连的吡啶基一起形成
或被一个或多个Rd取代的
和/或，当所述的R2为-C(＝O)-O-R时，所述的R为氢或C1～C4烷基；较佳地，所述的R为氢；
和/或，当所述的R2为-C(＝O)-N(RaRb)时，所述的Ra和Rb独立地为氢；
和/或，当所述的R2为5-6元杂芳基或被一个或多个Rc取代的5-6元杂芳基时，所述的5-6元杂芳基和被一个或多个Rc取代的5-6元杂芳基里的5-6元杂芳基为
和/或，当R1与R2及其相连的吡啶基一起形成
或被一个或多个Rd取代的
时，所述的被一个或多个Rd取代的
为
较佳地为
4.如权利要求3所述的如式I所示的化合物或其药学上可接受的盐，其特征在于，所述的如式I所示的化合物可为下述任一化合物：
和/或，所述的如式I所示的化合物药学上可接受的盐为：
5.一种如权利要求1～4任一项所述的式I所示的化合物的制备方法，其特征在于，其包括如下步骤：在溶剂中，在一价铜催化剂的作用，将化合物II和化合物8进行如下所示的叠氮-炔基Husigen环加成反应，得到化合物I即可；
其中，R1和R2的定义如权利要求1～4任一项所述。
6.如权利要求5所述的制备方法，其特征在于，其包括如下步骤：所述的溶剂为酰胺类溶剂和/或醇类溶剂；所述的酰胺类溶剂优选N,N-二甲基甲酰胺；所述的醇类溶剂优选甲醇、乙醇、异丙醇和叔丁醇中的一种或多种；当所用的溶剂为酰胺类溶剂和醇类溶剂的混合溶剂时，所述的酰胺类溶剂与所述的醇类溶剂的体积比值优选为0.1～1.0；
和/或，所述的溶剂与化合物8的体积摩尔比为6L/mol～20L/mol；
和/或，所述的一价铜催化剂为卤代亚酮或者二价铜盐经过还原剂进行还原所得；所述的卤代亚铜可为碘化亚铜、溴化亚铜和氯化亚铜中的一种或多种；所述的二价铜盐优选为硫酸铜；所述的还原剂可为抗坏血酸钠；当所述的一价铜盐为二价铜盐经过还原剂进行还原所得时，所述的二价铜盐与化合物8的摩尔比值优选为0.1～1.0；所述的还原剂与化合物8的摩尔比值优选为0.5～1.5；
和/或，所述的一价铜盐与化合物8的摩尔比值为0.1～1.0；
和/或，所述的叠氮-炔基Husigen环加成反应的温度为室温～100℃。
7.一种化合物，其结构如下：
8.一种药物组合物，其特征在于，其包含如权利要求1～4任一项所述的如式I所示的化合物或其药学上可接受的盐和药用辅料。
9.一种如权利要求1～4任一项所述的如式I所示的化合物或其药学上可接受的盐或如权利要求8所述的药物组合物在制备A2aR抑制剂或者在制备用于治疗与A2aR受体有关的疾病的药物中的应用。
10.如权利要求9所述的应用，其特征在于，所述的与A2aR受体有关的疾病为肿瘤、精神障碍类疾病、心血管疾病和糖尿病中的一种或多种；所述的肿瘤可为黑色素瘤、肺癌、肝癌、乳腺癌、胃癌、肠癌、胰腺癌、头颈部癌、肾细胞癌、泌尿道上皮癌和非霍奇金淋巴瘤中的一种或多种。
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Citations (2)
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|---|---|---|---|---|
| WO2018136700A1 (en) * | 2017-01-20 | 2018-07-26 | Arcus Biosciences, Inc. | Azolopyrimidine for the treatment of cancer-related disorders |
| WO2019161054A1 (en) * | 2018-02-16 | 2019-08-22 | Arcus Biosciences, Inc. | Dosing with an azolopyrimidine compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018136700A1 (en) * | 2017-01-20 | 2018-07-26 | Arcus Biosciences, Inc. | Azolopyrimidine for the treatment of cancer-related disorders |
| WO2019161054A1 (en) * | 2018-02-16 | 2019-08-22 | Arcus Biosciences, Inc. | Dosing with an azolopyrimidine compound |
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| ZHI LI, ET AL.: "Design, synthesis, and biological evaluation of triazole-pyrimidine-methylbenzonitrile derivatives as dual A 2A /A 2B adenosine receptor antagonists", 《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》, vol. 37, no. 1, pages 1514 - 1526 * |
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