CN113747920A - 使用喹啉甲酰胺衍生物的免疫检查点抑制剂并用疗法 - Google Patents
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Abstract
本发明提供一种发挥优异的抗肿瘤效果的STAT3抑制剂的使用方法。本发明的抗肿瘤剂是以下述式(I)所示的喹啉甲酰胺衍生物或其盐作为有效成分,且与免疫检查点抑制剂并用给药的抗肿瘤剂,在给药免疫检查点抑制剂之前给药。
Description
技术领域
本发明涉及一种使用喹啉甲酰胺衍生物的癌症并用疗法。
背景技术
作为转录调节因子的STAT(Signal Transducers and Activators ofTranscription)是DNA结合性蛋白质,其活性通过多种多样的细胞因子(IL-6、干扰素等)或生长因子(EGF、PDGF等)的刺激而进行调节。形成二聚物并经活化的STAT向核内转移,对处于基因启动子区域的特定的DNA序列特异性地进行识别并结合,诱发许多基因的转录。即,STAT是从细胞表面向核传递信号的路径中必需的媒介因子,深入参与细胞增殖或分化等。
关于STAT,已知有7个不同的成元,其中STAT3在大部分的细胞种中表达,且在肺癌、皮肤癌、胰腺癌、卵巢癌、骨髓瘤、乳腺癌、前列腺癌、脑肿瘤、头部和颈部癌、黑色素瘤、白血病淋巴瘤和多发性骨髓瘤等的癌细胞中确认到STAT3的持续活化和过度表达,认为这些癌细胞的增殖或浸润依赖于STAT3。
因此,认为STAT3作为针对这些癌种的靶分子有用,期待其抑制剂作为抗癌剂。例如,报告有特定的喹啉甲酰胺衍生物具有优异的STAT3抑制活性,对于各种癌症具有抗肿瘤活性(专利文献1)。
另一方面,癌细胞中存在妨碍针对癌的免疫应答的各种免疫检查点分子。免疫检查点抑制是消除免疫抑制机制,使针对癌的免疫反应活化的新的治疗法,作为免疫检查点抑制剂,在国内外已经使用了抗CTLA-4(cyt otoxic T lymphocyte-associated antigen-4)抗体的伊匹单抗(ipilimumab)或抗PD-1(programmed cell death-1)抗体的纳武单抗(nivolumab)和帕博利珠单抗(pembrolizumab)等。
现有技术文献
专利文献
专利文献1:日本专利第5650529号公报
发明内容
本发明涉及提供一种发挥优异的抗肿瘤效果的喹啉甲酰胺衍生物的使用方法。
本发明人等为了进一步提高下述式(I)所示的喹啉甲酰胺衍生物的有用性而反复进行了研究,结果发现通过以口服方式先给药该喹啉甲酰胺衍生物,其后给药免疫检查点抑制剂的并用给药,可得到优异的抗肿瘤效果。
即,本发明涉及以下的1)~19)的发明。
1)一种抗肿瘤剂,是以下述式(I)所示的喹啉甲酰胺衍生物或其盐作为有效成分,且与免疫检查点抑制剂并用给药的抗肿瘤剂,在给药免疫检查点抑制剂之前给药。
2)一种抗肿瘤剂,是并用给药下述式(I)所示的喹啉甲酰胺衍生物或其盐与免疫检查点抑制剂的抗肿瘤剂,上述喹啉甲酰胺衍生物或其盐在给药免疫检查点抑制剂之前给药。
3)根据1)或2)的抗肿瘤剂,其中,在给药免疫检查点抑制剂1天以上之前开始上述喹啉甲酰胺衍生物或其盐的给药。
4)根据1)~3)中任一项的抗肿瘤剂,其中,在给药免疫检查点抑制剂7~2天之前开始上述喹啉甲酰胺衍生物或其盐的给药。
5)根据1)~4)中任一项的抗肿瘤剂,其中,喹啉甲酰胺衍生物或其盐的给药途径为口服给药。
6)根据1)~5)中任一项的抗肿瘤剂,其中,式(I)中的R1和R2相同或不同,为取代或未取代芳基或者取代或未取代芳香族杂环基。
7)根据6)的抗肿瘤剂,其中,式(I)中的R3、R4、R5和R6的至少一个基团为氢原子以外的基团。
8)根据1)~7)中任一项的抗肿瘤剂,其中,式(I)中的R1和R2中的芳基为苯基,芳香族杂环基为呋喃基。
9)根据1)~7)中任一项的抗肿瘤剂,其中,式(I)中的R1为呋喃基,R2为取代或未取代苯基。
10)根据1)~9)中任一项的抗肿瘤剂,其中,R3、R4、R5和R6中的至少一个基团为三氟甲氧基。
11)根据1)~10)中任一项的抗肿瘤剂,其中,R4为三氟甲氧基。
13)根据1)~12)中任一项的抗肿瘤剂,其中,免疫检查点抑制剂为作用于选自CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM3、BTLA、B7H3、B7H4、2B4、CD160、A2aR、KIR、VISTA和TIGIT中的免疫检查点分子而抑制检查点功能的物质。
14)根据1)~12)中任一项的抗肿瘤剂,其中,免疫检查点抑制剂为PD-1通路抑制剂。
15)根据14)的抗肿瘤剂,其中,PD-1通路抑制剂为抗PD-1抗体或抗PD-L1抗体。
16)根据1)~15)中任一项的抗肿瘤剂,其中,癌症为选自非小细胞肺癌、肾细胞癌、霍奇金淋巴瘤、头颈部癌、胃癌、恶性胸膜间皮瘤、食道癌、食管胃结合部癌、小细胞癌、胶质母细胞瘤、尿路上皮癌、肌层浸润性尿路上皮癌、膀胱癌、肌层非浸润性膀胱癌、大肠癌、胰腺癌、前列腺癌、默克尔细胞癌、甲状腺癌、肝细胞癌、乳腺癌、卵巢癌、子宫体癌、子宫颈癌、软组织肉瘤、病毒阳性/阴性实体癌、中枢神经原发淋巴瘤/睾丸原发淋巴瘤、MSI-High实体癌、黑色素瘤和白血病中的1种以上。
17)一种下述式(I)所示的喹啉甲酰胺衍生物或其盐的用途,用于制造抗肿瘤剂,该抗肿瘤剂是与免疫检查点抑制剂并用给药的抗肿瘤剂,在给药免疫检查点抑制剂之前给药。
18)一种下述式(I)所示的喹啉甲酰胺衍生物或其盐,为了癌症治疗而与免疫检查点抑制剂组合使用,在给药免疫检查点抑制剂之前给药。
19)一种癌症的治疗方法,包括对患者给药有效量的下述式(I)所示的喹啉甲酰胺衍生物或其盐与免疫检查点抑制剂,上述喹啉甲酰胺衍生物或其盐在给药免疫检查点抑制剂之前给药。
[式中,R1、R2、R3、R4、R5和R6相同或不同,表示氢原子、取代或未取代芳基、取代或未取代芳香族杂环基、COOR7(式中,R7表示取代或未取代烷基)或OR8(式中,R8表示取代或未取代烷基)]
根据本发明的抗肿瘤剂,能够进行发挥较高的抗肿瘤效果的癌症治疗,因此带来患者的长期生存。另外,本发明的喹啉甲酰胺衍生物由于能够口服给药且对广泛的癌种有效,因此至少对免疫检查点抑制剂有效的任一种癌症均能够发挥并用效果。
附图说明
图1是STX-1159与抗PD-1抗体的并用时的抗肿瘤效果。
图2是STX-1159与抗PD-1抗体的并用时的抗肿瘤效果。
图3是STX-1159与抗PD-1抗体的并用时的抗肿瘤效果。
具体实施方式
通式(I)所示的喹啉甲酰胺衍生物(以下,也称为“喹啉甲酰胺衍生物”)中,R1、R2、R3、R4、R5和R6相同或不同,表示氢原子、取代或未取代芳基、取代或未取代芳香族杂环基、COOR7(式中,R7表示取代或未取代烷基)或OR8(式中,R8表示取代或未取代烷基)。
这里,作为烷基中的取代基,可举出卤素原子、羟基等。另外,作为芳基、芳香族杂环基中的取代基,可从碳原子数1~6的烷基、烯基、炔基、环烷基、芳烷基、ORa、NRbRc、S(O)qRd(式中,q表示0、1或2)、CORe、COORf、OCORg、CONRhRi、NRjCORk、NRlCOORm、NRnSO2Ro、C(=NRp)NRqRr、NRsSO2NRtRu、SO2NRvRw、硝基、氰基和卤素原子等中适当选择。这里,Ra~Rw相同或不同,可表示氢原子、烷基、烯基、炔基、环烷基等。
作为这些取代基的取代数,相同或不同,能够至多为最大各基团中存在的氢原子的数量,优选为1~10,更优选为1~5。
以下示出上述通式(I)中规定的各基团的详情。另外,各基团中存在位置异构体的基团表示所有可能的位置异构体。
作为烷基和烷氧基的烷基部分,例如可举出直链或支链状的碳原子数1~12的烷基,具体地可举出甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基等。
作为环烷基,可举出可以存在饱和或部分不饱和键的3~12元的环烷基,可以为单环性或者该单环性的环烷基多个缩合或与芳基或芳香族杂环基缩合而成的多环性的缩合环烷基。作为单环性的环烷基,例如可举出碳原子数3~8的单环性环烷基,具体地可举出环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环十二烷基、1-环己烯基等,作为多环性的环烷基,例如可举出碳原子数5~12的多环性环烷基,具体地可举出蒎烷基、金刚烷基、双环[3.3.1]辛基、双环[3.1.1]庚基等。
作为烯基,例如可举出直链或支链状的碳原子数2~12的烯基,具体地可举出乙烯基、烯丙基、1-丙烯基、异丙烯基、甲基丙烯基、丁烯基、1,3-丁二烯基、巴豆基、戊烯基、己烯基、庚烯基、癸烯基、十二烯基等。
作为炔基,例如可举出直链或支链状的碳原子数2~12的炔基,具体地可举出乙炔基、炔丙基、1-丙炔基、异丙炔基、2-丁炔基、戊炔基、2-戊烯-4-炔基、己炔基、庚炔基、癸炔基、十二炔基等。
作为芳基,例如可举出碳原子数6~14的芳基,具体地可举出苯基、萘基、蒽基、菲基等。
作为芳香族杂环基,相同或不同,由包含至少1个以上杂原子、例如氮、氧、硫等的5元或6元的芳香族杂环基构成,该杂环基可以为单环性或者该单环性杂环基多个缩合或与芳基缩合而成的多环性的缩合芳香族杂环基,例如二环性或三环性杂环基。作为单环性的芳香族杂环基的具体例,可举出呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、唑基、异唑基、二唑基、噻唑基、噻二唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基等,作为多环性的缩合芳香族杂环基,可举出苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、苯并三唑基、苯并唑基、苯并噻唑基、咔唑基、嘌呤基、喹啉基、异喹啉基、喹唑啉基、酞嗪基、喹喔啉基、噌啉基、萘啶基、吡啶并嘧啶基、嘧啶并嘧啶基、喋啶基、吖啶基、噻蒽基、吩噻基、吩噻嗪基、啡噻嗪基、吩嗪基等。
作为卤素原子,可举出氟、氯、溴、碘各原子。
本发明的喹啉甲酰胺衍生物中,优选R1和R2相同或不同,为取代或未取代芳基、取代或未取代芳香族杂环基的化合物,作为芳基的具体例,可优选例示苯基或萘基等,作为芳香族杂环基,可优选例示呋喃基或噻吩基等。另外,进一步优选R1为呋喃基且R2为取代或未取代苯基、取代或未取代呋喃基或者取代或未取代噻吩基的化合物,作为取代苯基的基团的取代基,可优选例示甲基等烷基、甲氧基、二氟甲氧基等取代或未取代烷氧基、氟原子、氯原子等卤素原子、羟基、叔丁氧基羰基等烷氧羰基、氨基、硝基、氰基等,作为取代呋喃基和取代噻吩基的取代基,可优选例示甲基等烷基、氯原子等卤素原子等。
另外,进一步更优选R3、R5和R6为氢原子且R4为OR8(优选为甲氧基或三氟甲氧基)的化合物。
作为本发明的喹啉甲酰胺衍生物的具体例,例如优选N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-苯基-4-喹啉甲酰胺、N-[5-(3-呋喃基)-1,3,4-二唑-2-基]-2-苯基-4-喹啉甲酰胺、2-苯基-N-(5-苯基-1,3,4-二唑-2-基)-4-喹啉甲酰胺、N-[5-(4-氯苯基)-1,3,4-二唑-2-基]-2-苯基-4-喹啉甲酰胺、N-[5-(4-硝基苯基)-1,3,4-二唑-2-基]-2-苯基-4-喹啉甲酰胺、2-苯基-N-[5-(3-吡啶基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(3-硝基苯基)-4-喹啉甲酰胺、2-(4-氰基苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、2-(2-呋喃基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、2-(5-氯-2-噻吩基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-6-甲氧基-2-苯基-4-喹啉甲酰胺、2-(1-丁氧基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、2-(2-氯苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(2-羟基苯基)-4-喹啉甲酰胺、2-(2-氨基苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、2-(3-氯苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(3-甲氧基苯基)-4-喹啉甲酰胺、2-(3-氰基苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、2-(3-叔丁氧基羰基苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、2-(4-氟苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、2-(4-氯苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(4-甲基苯基)-4-喹啉甲酰胺、2-(4-二氟甲氧基苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(4-羟基苯基)-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(4-甲氧基苯基)-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(4-硝基苯基)-4-喹啉甲酰胺、2-(4-叔丁氧基羰基苯基)-N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(2,4-二甲基苯基)-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(3,4-二甲氧基苯基)-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(3,4-亚甲基二氧基苯基)-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(1-萘基)-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(6-甲氧基-2-萘基)-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-(5-甲基-2-呋喃基)-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-苯基-6-三氟甲氧基-4-喹啉甲酰胺、N-[5-(5-硝基-2-呋喃基)-1,3,4-二唑-2-基]-2-苯基-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-6-(4-羟基苯基)-2-苯基-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-6-(3-噻吩基)-2-苯基-4-喹啉甲酰胺、N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-6-(3-吡啶基)-2-苯基-4-喹啉甲酰胺、N-(5-苯基-1,3,4-二唑-2-基)-2-苯基-6-三氟甲氧基-4-喹啉甲酰胺、N-[5-(2-氯苯基)-1,3,4-二唑-2-基]-2-苯基-6-三氟甲氧基-4-喹啉甲酰胺、N-[5-(4-甲氧基苯基)-1,3,4-二唑-2-基]-2-苯基-6-三氟甲氧基-4-喹啉甲酰胺、N-[5-(5-氯-2-噻吩基)-1,3,4-二唑-2-基]-2-苯基-4-喹啉甲酰胺、N-[5-(4-甲氧基苯基)-1,3,4-二唑-2-基]-2-苯基-4-喹啉甲酰胺和N-(5-苯基-1,3,4-二唑-2-基)-2-(2-噻吩基)-4-喹啉甲酰胺等,更优选N-[5-(2-呋喃基)-1,3,4-二唑-2-基]-2-苯基-6-三氟甲氧基-4-喹啉甲酰胺。
作为本发明的喹啉甲酰胺衍生物的盐,可举出药理学上可允许的酸加成盐、金属盐、铵盐、有机胺加成盐、氨基酸加成盐等。作为药理学上可允许的酸加成盐,可举出盐酸、氢溴酸、硫酸、硝酸、磷酸、硼酸等各无机酸盐和作为有机酸的甲酸、乙酸、丙酸、富马酸、丙二酸、琥珀酸、马来酸、酒石酸、柠檬酸、苯甲酸等羧酸类、甲磺酸、对甲苯磺酸等磺酸类、谷氨酸、天冬氨酸等氨基酸类。作为药理学上可允许的金属盐,可举出锂、钠、钾等的各碱金属盐、镁、钙等的各碱土金属盐、铝、锌等各金属盐,作为药理学上可允许的铵盐,可举出铵、四甲基铵等的各种盐,作为药理学上可允许的有机胺盐,可举出三乙胺、哌啶、吗啉、甲苯胺等的各种盐,作为药理学上可允许的氨基酸加成盐,可举出赖氨酸、甘氨酸、苯丙氨酸等的加成盐。
本发明的喹啉甲酰胺衍生物或其盐作为STAT3抑制剂记载于日本专利第5650529号公报(上述专利文献1)中,且可通过该公报中记载的方法进行制造。已知该喹啉甲酰胺衍生物或其盐抑制STAT3的二聚物形成而发挥抗肿瘤效果。
本发明中使用的免疫检查点抑制剂是指能够通过传递抑制性共信号而作用于作为发挥免疫抑制功能的分子的免疫检查点分子来抑制检查点的功能的物质。作为免疫检查点分子,例如可举出PD-1、CTLA-4、OX-40、TIM3(T cell immunoglobulin and mucin-3,T细胞免疫球蛋白和粘蛋白-3)、LAG-3(Lymphocyte activation gene 3,淋巴细胞活化基因3)、VISTA(V-domain Ig-containing suppressor of T cell activation,T细胞活化V结构域Ig抑制剂)、GITR(Glucocorticoid-induced TNFR-related protein,糖皮质激素诱导肿瘤坏死因子受体相关蛋白)、4-1BB、CD40、ICOS、CD28、TIGIT(T cell immunoglobulinand ITIM domain,T细胞免疫球蛋白和免疫受体络氨酸抑制基序结构域)、BTLA(B and Tlympho-cyte attenuator,B、T淋巴细胞衰减因子)、CD160、PD-L1(programmed celldeath-ligand 1,程序性细胞死亡配体1)、PD-L2(programmed cell death-ligand 2,程序性细胞死亡配体2)、CD86、OX40L、半乳凝素-9/HMGB1(highmobility group box-1protein,高迁移率族蛋白B1)、GITRL、4-1BBL、CD40L、ICOSL(inducible costimulator ligand,可诱导共刺激分子配体)、CD80、CD112/CD155、HVEM、B7H3、B7H4、2B4、A2aR(adenosine A2areceptor,腺苷A2a受体)、KIR(killer inhibitory receptor,杀伤抑制受体)等。
作为该免疫检查点抑制剂,优选为人类免疫检查点分子的抑制剂,进一步优选为针对人类免疫检查点分子的中和抗体。
作为免疫检查点抑制剂,例如为抗CTLA-4抗体(例如,伊匹单抗(Ipilimumab)(YERVOY(注册商标))、曲美单抗(Tremelimumab)、AGEN-1884);抗PD-1抗体(例如,纳武单抗(OPDIVO(注册商标))、REGN-2810、帕博利珠单抗(Pembrolizumab)(KEYTRUDA(注册商标))、PDR-001、BGB-A317、AMP-514(MEDI0680)、BCD-100、IBI-308、JS-001、PF-06801591、TSR-042);抗PD-L1抗体(例如,阿替利珠单抗(Atezolizumab)(TECENTRIQ(注册商标)、RG7446、MPDL3280A)、阿维鲁单抗(Avelumab)(BAVENCIO(注册商标)、PF-06834635、MSB0010718C)、度伐利尤单抗(Durvalumab)(MEDI4736)、BMS-936559、CA-170、LY-3300054、FAZ053);抗PD-L2抗体(例如,rHIgM12B7);PD-1抑制剂(例如,AUNP-12);PD-L1融合蛋白;PD-L2融合蛋白(例如,AMP-224);抗Tim-3抗体(例如,MBG453);抗LAG-3抗体(例如,BMS-986016、LAG525);抗KIR抗体(例如,利丽单抗(Lirilumab));抗OX-40抗体(例如,GSK3174998、PF-04518600)、抗VISTA抗体(例如,IGN-381)、抗GITR抗体(BMS-986156)、抗4-1BB抗体(例如,乌托鲁单抗(Utomilumab))等。
另外,包含上述已知的抗体的重链和轻链互补决定区(CDRs)或可变区(VR)的抗体也包含于本发明的免疫检查点抑制剂。另外,抗体也可以为功能性的抗体片段,作为这样的抗体片段,可举出Fab、Fab'、F(ab')2、Fv、scFv、dsFv等。
作为本发明的免疫检查点抑制剂,优选可举出抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体、PD-1抑制剂、PD-L1融合蛋白、PD-L2融合蛋白等抑制PD-1/PD-1配体通路的PD-1通路抑制剂和抗CTLA-4抗体,更优选为PD-1通路抑制剂,更优选为抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体,特别优选为抗PD-1抗体。
如后述的实施例所示,在并用给药本发明的喹啉甲酰胺衍生物或其盐与免疫检查点抑制剂的情况下,通过在给药免疫检查点抑制剂之前给药喹啉甲酰胺衍生物或其盐,从而发挥显著优异的抗肿瘤效果。
认为这是因为通过先给药喹啉甲酰胺衍生物或其盐,能够将肿瘤的免疫环境调整为在免疫检查点抑制剂发挥效果的方面优选的状态、即肿瘤免疫细胞被活化的状态、肿瘤免疫抑制环境被消除的状态等。因此,对于即使给药免疫检查点抑制剂也无法充分地得到通过免疫反应产生的抗肿瘤效果的肿瘤,也能够通过先给药喹啉甲酰胺衍生物,将肿瘤免疫环境调整为优选的状态而期待通过免疫检查点抑制剂产生的抗肿瘤效果。
因此,将本发明的喹啉甲酰胺衍生物或其盐与免疫检查点抑制剂组合使用,且在给药免疫检查点抑制剂之前给药喹啉甲酰胺衍生物或其盐成为有效的癌症的治疗方法,本发明的喹啉甲酰胺衍生物或其盐可成为一种抗肿瘤剂,是用于与免疫检查点抑制剂并用给药的抗肿瘤剂,在给药免疫检查点抑制剂之前给药。另外,本发明的喹啉甲酰胺衍生物或其盐是用于与免疫检查点抑制剂并用给药的抗肿瘤剂,在给药免疫检查点抑制剂之前给药,可用于制造抗肿瘤剂。
“并用给药”是指将本发明的喹啉甲酰胺衍生物或其盐与免疫检查点抑制剂在一定期间内组合给药,本发明中,关于其给药顺序,需要在给药免疫检查点抑制剂之前进行喹啉甲酰胺衍生物或其盐的给药,优选喹啉甲酰胺衍生物或其盐的给药开始在给药免疫检查点抑制剂1天以上之前。
本发明的喹啉甲酰胺衍生物或其盐的给药开始时期更优选为给药免疫检查点抑制剂2天以上之前,更优选为给药的28~2天之前,更优选为给药的21~2天之前,更优选为给药的14~2天之前,更优选为给药的7~2天之前。
另外,本发明的喹啉甲酰胺衍生物或其盐的给药只要在给药免疫检查点抑制剂之前开始即可,可以在免疫检查点抑制剂的给药开始后也继续,另外,也可以在免疫检查点抑制剂的给药开始前结束该给药或者停药。
作为可通过本发明的抗肿瘤剂进行治疗的癌症,没有特别限制,例如可举出恶性赘生物、癌、未分化癌、巨细胞和梭形细胞癌、小细胞癌、乳头癌、鳞状细胞癌、淋巴上皮癌、基底细胞癌、钙化上皮癌、移形上皮癌、乳头状移形上皮癌、腺癌、恶性胃泌素瘤、胆管癌、肝细胞癌、肝细胞癌与胆管癌的混合型、梁状腺瘤、腺样囊性癌、腺瘤性息肉中的腺癌、家族性大肠腺瘤性息肉病、实体癌、恶性类肿瘤、细支气管肺泡癌(branchiolo-alveolaradenocarcinoma)、乳头腺癌、嫌色细胞癌、嗜酸性粒细胞癌、嗜酸性腺癌、嗜碱性粒细胞癌、透明细胞腺癌、颗粒细胞癌、滤泡状腺癌、乳头和滤泡状腺癌、无包膜硬化性癌、肾上腺皮质癌、子宫内膜癌(endometroid carcinoma)、皮肤附属器癌、顶泌腺癌、皮脂腺癌、耵聍腺癌、粘液表皮样癌、囊腺癌、乳头状囊腺癌、乳头状浆液性囊腺癌、粘蛋白性囊腺瘤、粘液腺癌、印戒细胞癌、浸润性导管癌、髓样癌、小叶癌、炎症性癌、乳房佩吉特病、腺泡细胞癌、腺样鳞状细胞癌、伴随鳞状细胞化生的腺癌、恶性胸腺瘤、恶性卵巢间质瘤、恶性卵泡膜细胞瘤、恶性颗粒细胞瘤、恶性神经胚细胞瘤(roblastoma)、塞特利氏细胞瘤、恶性莱迪希氏细胞瘤、恶性脂质细胞瘤、恶性副神经节瘤、恶性乳房外副神经节瘤、褐色细胞瘤、血管球肉瘤、恶性黑色素瘤、黑色素缺乏性黑色素瘤、浅表扩散型黑色素瘤、巨大色素性母斑中的恶性黑色素瘤、类上皮细胞黑色素瘤、恶性青色母斑、肉瘤、纤维肉瘤、恶性纤维组织细胞瘤、粘液肉瘤、脂肪肉瘤、平滑肌肉瘤、横纹肌肉瘤、胚胎型横纹肌肉瘤、卵巢腺泡状横纹肌肉瘤、间质肉瘤、恶性混合肿瘤、苗勒管混合瘤、肾胚细胞瘤、肝胚细胞瘤、癌肉瘤、恶性间叶肿瘤、恶性布伦纳氏瘤、恶性叶状肿瘤、滑膜肉瘤、恶性间皮瘤、未分化胚细胞瘤、胚胎性癌、恶性畸胎瘤、恶性卵巢甲状腺瘤、绒毛膜癌、恶性中肾瘤、血管肉瘤、恶性血管内皮瘤、卡波西肉瘤、恶性血管外皮瘤、淋巴管肉瘤、骨肉瘤、骨旁骨肉瘤、软骨肉瘤、恶性软骨母细胞瘤、间叶性软骨肉瘤、骨巨细胞瘤、尤因肉瘤、恶性牙源性肿瘤、成釉细胞肉瘤、恶性成釉细胞瘤、成釉细胞纤维肉瘤、恶性松果体瘤、脊索瘤、恶性神经胶质瘤、室管膜瘤、星状细胞瘤、原浆性星状细胞瘤、纤维性星状细胞瘤、星状细胞瘤、胶质母细胞瘤、寡树突神经胶细胞瘤、寡树突胶质母细胞瘤、原始神经外胚层肿瘤(primitive neuroectodermal)、小脑肉瘤、成神经节细胞瘤、神经胚细胞瘤、视网膜母细胞瘤、嗅神经源性肿瘤、恶性脊膜瘤、神经纤维肉瘤、恶性神经鞘瘤、恶性颗粒细胞瘤、恶性淋巴瘤、霍奇金病、霍奇金淋巴瘤、单侧肉芽肿、恶性小淋巴细胞淋巴瘤、恶性弥漫性大细胞淋巴瘤、恶性滤泡性淋巴瘤、蕈样霉菌病、其它特定的非霍奇金淋巴瘤、恶性组织细胞增生症、多发性骨髓瘤、肥大细胞肉瘤、免疫增殖性小肠病、白血病、淋巴性白血病、浆细胞性白血病、红白血病、淋巴肉瘤细胞性白血病、骨髓性白血病、嗜碱性粒细胞白血病、嗜酸性粒细胞白血病、单核细胞白血病、肥大细胞性白血病、急性巨核细胞白血病、骨髓性肉瘤和毛细胞白血病等,优选为非小细胞肺癌、肾细胞癌、霍奇金淋巴瘤、头颈部癌、胃癌、恶性胸膜间皮瘤、食道癌、食管胃结合部癌、小细胞癌、胶质母细胞瘤、尿路上皮癌、肌层浸润尿路上皮癌、膀胱癌、肌层非浸润性膀胱癌、大肠癌、胰腺癌、前列腺癌、默克尔细胞癌、甲状腺癌、肝细胞癌、乳腺癌、卵巢癌、子宫体癌、子宫颈癌、软组织肉瘤、病毒阳性/阴性实体癌、中枢神经原发淋巴瘤/睾丸原发淋巴瘤、MSI-High实体癌、黑色素瘤和白血病。
由于本发明的喹啉甲酰胺衍生物或其盐为非肽性、非核酸性,因此能够口服给药,且通过口服给药能够有效地表现出如上述所述的并用效果。另外,作为口服给药的优点,没有侵入性或能够进行门诊治疗,因此对患者而言的方便性高。例如,如果是寡核苷酸的情况,则口服给药时不被吸收,因此不会发挥效果,通过口服给药的方法非常困难。即,作为本发明的喹啉甲酰胺衍生物或其盐的给药形态,没有特别限制,包括口服性或非口服性地给药。作为口服给药制剂,可举出口服固体剂(片剂、被覆片剂、颗粒剂、散剂、胶囊剂等)、口服液剂(内服液剂、糖浆剂、酏剂等)。作为非口服给药,除注射以外,可举出鼻腔内、经支气管、肌肉内、经皮性的给药;作为非口服给药制剂,可举出注射剂(点滴等静脉注射、皮下注射剂、肌肉注射剂、腹腔内注射剂)、软膏剂、贴附剂、凝胶剂、乳霜剂、外用散剂、喷雾剂、吸入散布剂等。
含有本发明的喹啉甲酰胺衍生物或其盐的制剂能够使用药理学上可允许的载体,通过通常公知的方法进行制备。作为该载体,可例示通常的药剂中通用的各种载体,例如赋形剂、粘合剂、崩解剂、润滑剂、稀释剂、增溶剂、悬浮剂、等渗剂、pH调节剂、缓冲剂、稳定剂、着色剂、矫味剂、矫臭剂等。
作为赋形剂,例如可举出乳糖、蔗糖、氯化钠、葡萄糖、麦芽糖、甘露醇、赤藻糖醇、木糖醇、麦芽糖醇、肌醇、葡聚糖、山梨糖醇、白蛋白、脲、淀粉、碳酸钙、高岭土、结晶纤维素、硅酸、甲基纤维素、甘油、海藻酸钠、阿拉伯胶和它们的混合物等。作为润滑剂,例如可举出精制滑石、硬脂酸盐、硼砂、聚乙二醇和该等的混合物等。作为粘合剂,例如可举出单糖浆、葡萄糖液、淀粉液、明胶溶液、聚乙烯醇、聚乙烯醚、聚乙烯基吡咯烷酮、羧甲基纤维素、虫胶、甲基纤维素、乙基纤维素、水、乙醇、磷酸钾和它们的混合物等。作为崩解剂,例如可举出干燥淀粉、海藻酸钠、琼脂末、昆布多糖末、碳酸氢钠、碳酸钙、聚氧乙烯山梨醇酐脂肪酸酯类、月桂基硫酸钠、硬脂酸单甘油酯、淀粉、乳糖和它们的混合物等。作为稀释剂,例如可举出水、乙醇、聚乙二醇、丙二醇、乙氧化基异硬脂醇、聚氧化异硬脂醇、聚氧乙烯山梨醇酐脂肪酸酯类和它们的混合物等。作为稳定剂,例如可举出焦亚硫酸钠、乙二胺四乙酸、硫代乙醇酸、硫代乳酸和它们的混合物等。作为等渗剂,例如可举出氯化钠、硼酸、葡萄糖、甘油和它们的混合物等。作为pH调节剂和缓冲剂,例如可举出柠檬酸钠、柠檬酸、乙酸钠、磷酸钠和它们的混合物等。作为无痛剂,例如可举出盐酸普鲁卡因、盐酸利多卡因和它们的混合物等。
应予说明,上述制剂中的本发明的喹啉甲酰胺衍生物或其盐的配合量可以适当地设定,一般而言,制剂中,本发明的喹啉甲酰胺衍生物或其盐为0.001~5000mg,优选为0.1~1000mg,更优选为1~500mg。
本发明的喹啉甲酰胺衍生物或其盐的给药量只要为能够发挥抗肿瘤效果而有效地治疗癌症的量就没有特别限制,根据患者的年龄、癌种类、病期、转移的有无、疗程、其它抗肿瘤剂的有无等适当地设定,以式(I)所示的喹啉甲酰胺衍生物换算量计为0.001~5000mg/天,优选为0.1~1000mg/天,更优选为1~500mg。
本发明中,免疫检查点抑制剂的给药形态是任意的,优选可举出静脉内给药。免疫检查点抑制剂的每1次的给药量没有特别限定,可根据癌或副作用等而适当地设定。该每1次的给药量优选为0.001~5000mg,更优选为0.1~2000mg,特别优选为1~1200mg。
免疫检查点抑制剂可以将上述用量以1次或分成几次(例如2~4次)持续地进行给药。给药间隔没有限定,可连续几天、或者每隔几天、1周、几周、1个月或几个月进行给药。例如可例示1周给药1次、每隔2周给药1次、每隔3周给药1次、每隔4周给药1次、1个月给药1次、每隔3个月给药1次或每隔3~6个月给药1次等。
本发明的抗肿瘤剂的给药日程表可根据各免疫检查点抑制剂的给药日程表而适当地设定,例如可举出从第1天连续几天给药喹啉甲酰胺衍生物或其盐,在第3天给药各免疫检查点抑制剂,其后适当地依照各免疫检查点抑制剂的使用法,从第1天连续几天给药喹啉甲酰胺衍生物或其盐,在第8天给药免疫检查点抑制剂,其后适当地依照各免疫检查点抑制剂的使用法,从第1天连续几天给药喹啉甲酰胺衍生物或其盐,在第15天给药免疫检查点抑制剂,其后适当地依照各免疫检查点抑制剂的使用法,从第1天连续几天给药喹啉甲酰胺衍生物或其盐,在第21天给药免疫检查点抑制剂,其后适当地依照各免疫检查点抑制剂的使用法,从第1天连续几天给药喹啉甲酰胺衍生物或其盐,在第28天给药免疫检查点抑制剂,其后适当地依照各免疫检查点抑制剂的使用法。
本发明的抗肿瘤剂是向患者并用给药喹啉甲酰胺衍生物或其盐与免疫检查点抑制剂,两药剂的提供方法没有特别限定。即,可以为与记载有并用时的用法、用量等的附件等一起分别个别地提供含有各药剂的制剂,或者将各制剂以适于每1次的并用给药的形态进行封装化而提供等中的任一种。
实施例
<使用药剂>
(1)喹啉甲酰胺衍生物
(2)免疫检查点抑制剂
从Biolegend购入抗PD-1抗体(抗小鼠PD-1抗体)。
实施例1通过喹啉甲酰胺衍生物与免疫检查点抑制剂的并用给药产生的抗肿瘤效果(1)
1.方法(1)向小鼠的肿瘤移植
从日本SLC购入6周龄的雌性BALB/c小鼠(72只),在静冈县立大学动物实验中心进行5天驯化饲养后,用于实验。
对BALB/c小鼠的背部和腹侧部进行剃毛,向左右的腹侧部分别皮下移植1×106cells的小鼠大肠癌细胞株CT26细胞(ATCC)(第0天)。从移植起5天后,使用数显卡尺(A&D)测定肿瘤的长径(mm)和短径(mm),算出肿瘤体积。肿瘤体积的算出式为肿瘤体积(mm3)=0.5×(长径mm)×(短径mm)2。
算出各个体、左右的肿瘤体积的平均,基于该值,以各组中的个体间的肿瘤体积的偏差变得均等的方式分组为8组(组内只数9只)。
(2)药剂给药
STX-1159以40mg/kg连续5天口服给药。具体而言,以成为4mg/mL的方式使用0.5%甲基纤维素溶液(Wako),制备悬浮液,利用金属探头(夏目制作所),以BALB/c小鼠的体重每1g口服给药0.01mL。给药日程表为给药抗小鼠PD-1抗体前的期间(5天至9天)、与给药抗小鼠PD-1抗体相同的期间(12天至16天)或给药抗小鼠PD-1抗体后的期间(19天至23天)中的任一期间。对于未给药STX-1159的组的个体,口服给药0.5%甲基纤维素溶液。
抗小鼠PD-1抗体以50μg/小鼠每隔1天3次腹腔内给药。具体而言,将抗小鼠CD279(PD-1)(Biolegend)利用PBS(Wako)进行稀释,制备为250μg/mL,利用29G带针注射器(BD)以BALB/c小鼠每1只200μL进行腹腔内给药。给药日程表为12天、14天和16天。对于未给药抗小鼠PD-1抗体的组的个体,腹腔内给药200μL的PBS。具体的组构成记载于以下。
1)对照
2)PD-1Ab(50μg/小鼠i.p.12天、14天、16天)
3)STX-1159×5次(40mg/kg p.o.5天~9天)
4)STX-1159×5次(40mg/kg p.o.12天~16天)
5)STX-1159×5次(40mg/kg p.o.19天~23天)
6)STX-1159×5次(40mg/kg p.o.5天~9天)+PD-1Ab(50μg/小鼠i.p.12天、14天、16天)
7)STX-1159×5次(40mg/kg p.o.12天~16天)+PD-1Ab(50μg/小鼠i.p.12天、14天、16天)
8)STX-1159×5次(40mg/kg p.o.19天~23天)+PD-1Ab(50μg/小鼠i.p.12天、14天、16天)
(3)评价项目
评价项目为各个体中的左右的肿瘤体积的平均。从第5天,以1天或2天间隔使用数显卡尺测定肿瘤的长径(mm)和短径(mm),算出肿瘤体积。肿瘤体积的算出式为肿瘤体积(mm3)=0.5×(长径mm)×(短径mm)2。算出各个体、左右的肿瘤体积的平均。
(4)评价指标
为了评价通过药剂给药对肿瘤体积产生的影响,对相对于对照组的评价项目的药剂给药组的评价项目实施t检验。在P<0.05或P<0.01的情形时,视为存在显著性差异,判定为存在通过药剂给药对肿瘤体积产生的影响。
2.结果
将结果示于图1。
先给药喹啉甲酰胺衍生物的组(STX-1159(5天~9天)+PD-1Ab(12天、14天、16天))中,确认到远高于同时给药组(STX-1159(12天~16天)+PD-1Ab(12天、14天、16天))、后给药组(STX-1159(19天~23天)+PD-1Ab(12天、14天、16天))的抗肿瘤效果。应予说明,对于同时给药组(STX-1159(12天~16天)+PD-1Ab(12天、14天、16天),可见低于作为单剂给药组的PD-1Ab单剂组(12天、14天、16天)、STX-1159单剂组(5天~9天)、STX-1159单剂组(12天~16天)和STX-1159单剂组(19天~23天)的抗肿瘤效果。
实施例2通过喹啉甲酰胺衍生物与免疫检查点抑制剂的并用给药产生的抗肿瘤效果(2)
1.方法
(1)向小鼠的肿瘤移植
从日本SLC购入6周龄的雌性BALB/c小鼠,在静冈县立大学动物实验中心进行1周左右驯化饲养后,用于实验。
对BALB/c小鼠的背部和腹侧部进行剃毛,向左右的腹侧部分别皮下移植1×106cells的小鼠大肠癌细胞株CT26细胞(ATCC)(第0天)。移植后6天后,使用数显卡尺(A&D)测定肿瘤的长径(mm)和短径(mm),算出肿瘤体积。肿瘤体积的算出式为肿瘤体积(mm3)=0.5×(长径mm)×(短径mm)2。算出各个体、左右的肿瘤体积的平均,基于该值,以各组中的个体间的肿瘤体积的偏差变得均等的方式进行分组。
(2)药剂给药
STX-1159以40mg/kg每隔1天3次口服给药。具体而言,以成为4mg/mL的方式使用0.5%甲基纤维素溶液(Wako),制备悬浮液,利用金属探头(夏目制作所),以BALB/c小鼠的体重每1g口服给药0.01mL。给药日程表为6天、8天和10天。对于未给药STX-1159的组的个体,口服给药0.5%甲基纤维素溶液。
抗小鼠PD-1抗体以50μg/小鼠每隔1天或2天3次腹腔内给药。具体而言,将抗小鼠CD279(PD-1)(Biolegend)利用PBS(Wako)进行稀释,制备为250μg/mL,利用29G带针注射器(BD)以BALB/c小鼠每1只200μL进行腹腔内给药。给药日程表为8天、10天和13天。对于未给药抗小鼠PD-1抗体的组的个体,腹腔内给药200μL的PBS。具体的组构成记载于以下。
1)对照
2)STX-1159×3次(40mg/kg p.o.6天、8天、10天)
3)PD-1Ab(50μg/小鼠i.p.8天、10天、13天)
4)STX-1159×3次(40mg/kg p.o.6天、8天、10天)+PD-1Ab(50μg/小鼠i.p.8天、10天、13天)
(3)评价项目
评价项目为各肿瘤体积。从第6天,以1天至4天间隔使用数显卡尺测定肿瘤的长径(mm)和短径(mm),算出肿瘤体积。肿瘤体积的算出式为肿瘤体积(mm3)=0.5×(长径mm)×(短径mm)2。
(4)评价指标
为了评价通过药剂给药对肿瘤体积产生的影响,对相对于对照组的评价项目的药剂给药组的评价项目实施t检验。在P<0.05的情况下,视为存在显著性差异,判定为存在通过药剂给药对肿瘤体积产生的影响。
2.结果
将结果示于图2。
先给药喹啉甲酰胺衍生物的喹啉甲酰胺衍生物与免疫检查点抑制剂的并用给药组(STX-1159(6天、8天、10天)+PD-1Ab(8天、10天、13天)中,确认到远高于喹啉甲酰胺衍生物或免疫检查点抑制剂的单独给药组的抗肿瘤效果。
实施例3通过喹啉甲酰胺衍生物与免疫检查点抑制剂的并用给药产生的抗肿瘤效果(3)
1.方法
(1)向小鼠的肿瘤移植
从日本SLC购入6周龄的雌性BALB/c小鼠,在静冈县立大学动物实验中心进行1周左右驯化饲养后,用于实验。
对BALB/c小鼠的背部和腹侧部进行剃毛,向左右的腹侧部分别皮下移植1×106cells的小鼠纤维肉瘤CMS5a(第0天)。从移植起5天后,使用数显卡尺(A&D)测定肿瘤的长径(mm)和短径(mm),算出肿瘤体积。肿瘤体积的算出式为肿瘤体积(mm3)=0.5×(长径mm)×(短径mm)2。算出各个体、左右的肿瘤体积的平均,基于该值,以各组中的个体间的肿瘤体积的偏差变得均等的方式进行分组。
(2)药剂给药
STX-1159以40mg/kg连续5天口服给药。具体而言,以成为4mg/mL的方式使用0.5%甲基纤维素溶液(Wako),制备悬浮液,利用金属探头(夏目制作所),以BALB/c小鼠的体重每1g口服给药0.01mL。给药日程表为给药抗小鼠PD-1抗体前的期间(5天至9天)。对于未给药STX-1159的组的个体,口服给药0.5%甲基纤维素溶液。
抗小鼠PD-1抗体以200μg/小鼠每隔1天3次腹腔内给药。具体而言,将抗小鼠CD279(PD-1)(Biolegend)利用PBS(Wako)进行稀释,制备为1mg/mL,利用29G带针注射器(BD)以BALB/c小鼠每1只200μL进行腹腔内给药。给药日程表为12天、14天和16天。对于未给药抗小鼠PD-1抗体的组的个体,腹腔内给药200μL的PBS。具体的组构成记载于以下。
1)对照
2)PD-1Ab(200μg/小鼠i.p.12天、14天、16天)
3)STX-1159×5次(40mg/kg p.o.5天~9天)
4)STX-1159×5次(40mg/kg p.o.5天~9天)+PD-1Ab(200μg/小鼠i.p.12天、14天、16天)
(3)评价项目
评价项目为各肿瘤体积。从第5天,以1天或2天间隔使用数显卡尺测定肿瘤的长径(mm)和短径(mm),算出肿瘤体积。肿瘤体积的算出式为肿瘤体积(mm3)=0.5×(长径mm)×(短径mm)2。
(4)评价指标
为了评价通过药剂给药对肿瘤体积产生的影响,对相对于对照组的评价项目的药剂给药组的评价项目实施t检验。在P<0.05或P<0.01的情况下,视为存在显著性差异,判定为存在通过药剂给药对肿瘤体积产生的影响。
2.结果
将结果示于图3。
先给药喹啉甲酰胺衍生物的喹啉甲酰胺衍生物与免疫检查点抑制剂的并用给药组(STX-1159(5天~9天)+PD-1Ab(12天、14天、16天)中,相对于对照组在并用组确认到显著的肿瘤缩小。PD-1Ab单独给药组中,相对于对照未确认到显著的肿瘤缩小,确认到即使对于被认为免疫检查点抑制剂不易奏效的CMS5a,通过在免疫检查点抑制剂并用喹啉甲酰胺衍生物进行给药,也能够得到抗肿瘤效果。
Claims (19)
3.根据权利要求1或2所述的抗肿瘤剂,其中,在给药免疫检查点抑制剂1天以上之前开始所述喹啉甲酰胺衍生物或其盐的给药。
4.根据权利要求1~3中任一项所述的抗肿瘤剂,其中,在给药免疫检查点抑制剂7~2天之前开始所述喹啉甲酰胺衍生物或其盐的给药。
5.根据权利要求1~4中任一项所述的抗肿瘤剂,其中,喹啉甲酰胺衍生物或其盐的给药途径为口服给药。
6.根据权利要求1~5中任一项所述的抗肿瘤剂,其中,式(I)中的R1和R2相同或不同,为取代或未取代芳基或者取代或未取代芳香族杂环基。
7.根据权利要求6所述的抗肿瘤剂,其中,式(I)中的R3、R4、R5和R6中的至少一个基团为氢原子以外的基团。
8.根据权利要求1~7中任一项所述的抗肿瘤剂,其中,式(I)中的R1和R2中的芳基为苯基,芳香族杂环基为呋喃基。
9.根据权利要求1~7中任一项所述的抗肿瘤剂,其中,式(I)中的R1为呋喃基,R2为取代或未取代苯基。
10.根据权利要求1~9中任一项所述的抗肿瘤剂,其中,R3、R4、R5和R6中的至少一个基团为三氟甲氧基。
11.根据权利要求1~10中任一项所述的抗肿瘤剂,其中,R4为三氟甲氧基。
13.根据权利要求1~12中任一项所述的抗肿瘤剂,其中,免疫检查点抑制剂为作用于选自CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM3、BTLA、B7H3、B7H4、2B4、CD160、A2aR、KIR、VISTA和TIGIT中的免疫检查点分子而抑制检查点功能的物质。
14.根据权利要求1~12中任一项所述的抗肿瘤剂,其中,免疫检查点抑制剂为PD-1通路抑制剂。
15.根据权利要求14所述的抗肿瘤剂,其中,PD-1通路抑制剂为抗PD-1抗体或抗PD-L1抗体。
16.根据权利要求1~15中任一项所述的抗肿瘤剂,其中,癌症为选自非小细胞肺癌、肾细胞癌、霍奇金淋巴瘤、头颈部癌、胃癌、恶性胸膜间皮瘤、食道癌、食管胃结合部癌、小细胞癌、胶质母细胞瘤、尿路上皮癌、肌层浸润尿路上皮癌、膀胱癌、肌层非浸润性膀胱癌、大肠癌、胰腺癌、前列腺癌、默克尔细胞癌、甲状腺癌、肝细胞癌、乳腺癌、卵巢癌、子宫体癌、子宫颈癌、软组织肉瘤、病毒阳性/阴性实体癌、中枢神经原发淋巴瘤/睾丸原发淋巴瘤、MSI-High实体癌、黑色素瘤和白血病中的1种以上。
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