CN113543851A - 2’3’-环二核苷酸及其前药 - Google Patents
2’3’-环二核苷酸及其前药 Download PDFInfo
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- CN113543851A CN113543851A CN202080019433.5A CN202080019433A CN113543851A CN 113543851 A CN113543851 A CN 113543851A CN 202080019433 A CN202080019433 A CN 202080019433A CN 113543851 A CN113543851 A CN 113543851A
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Abstract
本发明是关于式(I)的2'3'环膦酸二核苷酸、其医药学上可接受的盐、其医药组合物及所述物质与其他药剂或医药的组合。本发明还关于所述化合物用于治疗或预防可通过调节STING蛋白来改善的疾病或病状的用途,该疾病或病状诸如癌症或病毒性、过敏性及发炎性疾病。另外,这些物质可用作疫苗中的佐剂。
Description
相关申请的交叉引用
本申请要求2019年3月7日申请的美国临时申请案第62/815,170号及2019年6月17日申请的美国临时申请案第62/862,460号的优先权,所述申请均出于所有目的全文并入本文中。
技术领域
本发明是关于2'3'环二核苷酸及其衍生物,其适用于治疗可因调节STING衔接蛋白(干扰素基因的刺激子)而受益的疾病,例如炎症、过敏性及自体免疫性疾病、癌症及病毒感染,诸如慢性B型肝炎及人类免疫缺乏病毒,及用于制备免疫原性组合物或疫苗佐剂。
背景技术
先天性免疫系统通过一连串模式识别受体(PRR)识别病原体的存在或宿主的体内平衡破坏,所述受体侦测与病原体或损坏相关联的小型配位体集合。所述配位体一般被称作病原体相关分子模式(PAMP)或损害相关分子模式(DAMP)(Takeuchi O等人,Cell,2010:140,805-820)。在过去的二十年,已鉴别多种PRR,包括Toll样受体、视黄酸诱导性基因(RIG-I)样受体、核苷酸结合寡聚域样(NOD)受体、C型凝集素受体及胞溶质DNA感测子(Brubaker SW等人,Annu Rev Immunol,2015:33,257-290)。通过PRR识别PAMP及DAMP最终引起细胞因子及趋化因子(包括干扰素)的上调,及免疫细胞募集至感染位点。所有这些过程减缓病原体复制且促进适应性免疫性的产生。
细胞DNA通常限于健康细胞的细胞核及粒线体。因此,存在于胞溶质中的DNA代表指示存在病原体或宿主体内平衡破坏的信号。外源性DNA的感测由若干DNA传感器起始,诸如IRF的DNA依赖性活化因子(DAI)或DEAD匣多肽41(DDX41)。这些DNA传感器通过募集触发转录因子NF-κB(核因子κB)及IRF-3(干扰素调节因子3)的活化的蛋白激酶TBK1,经由STING衔接蛋白(干扰素基因刺激子,亦被称作STING、STING蛋白、TMEM173、MITA或ERIS)(Unterholzner L,Immunology,2013:218,1312-1321)传信。据信,STING衔接蛋白的活化最终引起I型及III型干扰素以及多种细胞因子及趋化因子(诸如,介白素-6(IL-6)、肿瘤坏死因子-α(TNF-α)及干扰素-γ(INF-γ))的释放。
可替代地,STING衔接蛋白可通过第二信使环二核苷酸(CDN)活化(Burdette等人Nature 2011:478,515-518)。具有针对STING的亲和力的CDN含有与两个3'-5'(3'3'-CDN)、两个2'-5'(2'2'-CDN)或2'-5'及3'-5'磷酸二酯键(2'3'-CDN)连接的两个嘌呤核苷酸单磷酸。原型2'3'-cGAMP(c[G(2',5')pA(3',5')p])为在病原体或自身dsDNA的存在下活化宿主cGAS蛋白的产物(Zhang等人,Molecular Cell 2013:51,226-235)。
I型干扰素(IFN)为免疫调节细胞因子,其在病毒免疫中起关键作用。其可诱导树突状细胞(DC)及巨噬细胞成熟及活化(Galluci等人,Nat Med,1999:5,1249-1255)且可促进T细胞及B细胞存活、活化及分化。此外,干扰素能够活化抑制病毒复制的许多胞内路径。I型干扰素的临床效用已由其在治疗慢性B型及C型肝炎中的有效性证明(Lin及Young,Cytokine Growth Factor Rev,2014:25,369-376)。
另外,干扰素在治疗人类癌症中展示效用(Cohen等人,N Engl J Med,2005:353,2477-2490,Tsao等人,N Engl J Med,2004:351,998-1012)。其可抑制肿瘤细胞增殖且可与许多经批准的抗癌剂发挥协同作用。此外,I型IFN可对免疫细胞起作用以诱导抗肿瘤反应(Musella等人,Oncoimmunology 2017:6:e1314424)。I型IFN信号传导经展示为在小鼠中的肿瘤起始T细胞预致敏(priming)中至关重要。缺乏树突状细胞中IFN-α/β受体的动物无法抑制免疫原性肿瘤,且在向CD8+T细胞的抗原交叉呈递中有缺陷(Fuertes等人,J Exp Med,2011:208,2005-2016,Diamond等人,J Exp Med,2011:208:1989-2003)。与这些观测结果一致,已展示STING蛋白促效剂的瘤内注射会诱导小鼠中的已形成肿瘤的消退,且产生能够抑制远程癌转移及提供长期存活的免疫记忆的实质性全身免疫反应(Corrales等人,CellRep,2015:11,1018-1030)。
据信CDN可促进细胞及体液免疫的预致敏。举例而言,在动物模型中展示CDN为有效佐剂(Dubensky等人,Ther Adv Vaccines,2013:1,131-143)。
专利公开案WO 2014/093936、WO 2014/189805、WO 2013/185052、US 2014/03441976、WO 2015/077354、WO 2015/185565、WO 2016/145102、WO 2017/093933、WO 2017/027646、WO 2017/027645、WO 2017/175156、WO 2017/175147、WO 2017/123657、WO 2018/013908、WO 2018/013887、WO2018/009652、WO 2018/009648及WO 2018/009466公开某些CDN及其在诱导免疫反应中的用途。
仍需要可活化STING的新颖CDN。
发明内容
在一个实施例中,本发明提供一种式(I)化合物:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐,
其中
X1及X3各自独立地为OH、OR1、SH或SR1,其限制条件为X1及X3中的至少一者为OR1、SH或SR1;
X2及X4各自独立地为O或S;
R4及R10各自独立地为H、OH或卤素;
各R1独立地为C1-C6烷基或-L-R2;
各R2独立地为-O(C=O)-N(R2a)2、-O(C=O)-NHR2a、-O(C=O)-R2a或-O(C=O)-O-R2a;
各R2a独立地为C1-C20烷基、C2-C20烯基、C2-C20炔基、-(C1-C6亚烷基)-(C3-C14环烷基)或C3-C20环烷基,其中各R2a独立地视情况经1、2或3个R2b取代;
各R2b独立地为-OH、-SH、-NH2、=O、=NH、=S、卤素、-N3、-CN、C1-C6烷氧基、C1-C6烷硫基、C1-C6烷胺基或C1-C6二烷胺基;
L为L1、L1-O(C=O)-L2、L1-(C=O)O-L2、L1-O-L2、L1-S(O)n-L2、L1-O(C=O)O-L2、L1-O(C=O)NR6-L2、L1-NR6(C=O)O-L2或L1-O(C=O)-L2-O-L3;
L1为C1-C6亚烷基、C2-C6亚烯基、C2-C6亚炔基或C7-C13烷基亚芳基;
L2为C1-C6亚烷基、C2-C6亚烯基、C2-C6亚炔基、C6-C10亚芳基或5元至10元亚杂芳基;
L3为C1-C6亚烷基、C2-C6亚烯基或C2-C6亚炔基;
R6为H或C1-C6烷基;
n为0、1或2;
碱基1及碱基2各自独立地为
其中
A、A1、A2、A3及A4各自独立地为H、OH、SH、F、Cl、Br、I、NH2、OR15、SR15、NHR15、N(R15)2或R16;
各Z独立地为O、S或NR15;
各R15独立地为H、-C(=Z1)R16、-C(=Z1)OR16、-C(=Z1)SR16、-C(=Z1)N(R16)2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C2-C10杂环烷基、C6-C10芳基或C2-C10杂芳基;
各Z1独立地为O或S;且
各R16独立地为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C2-C10杂环烷基、C6-C10芳基或C2-C10杂芳基。
在一些实施例中,医药组合物包含式(I)的环二核苷酸或其对映异构体、水合物、溶剂合物或医药学上可接受的盐,及医药学上可接受的载剂、赋形剂及/或稀释剂。
在一些实施例中,治疗疾病或病症的方法,例如治疗或预防病毒感染、B型肝炎病毒感染、HIV感染、过度增殖性疾病或癌症的方法包含向有需要的人类或动物施用治疗有效量的式(I)的环二核苷酸,或其对映异构体、水合物、溶剂合物或医药学上可接受的盐,或前述任一者的医药组合物。
在一些实施例中,增强疫苗的功效的方法包含施用治疗有效量的式(I)的环二核苷酸,或其对映异构体、水合物、溶剂合物或医药学上可接受的盐,或前述任一者的医药组合物。
在一些实施例中,调节人类或动物中的STING衔接蛋白诱导I型干扰素、细胞因子及/或趋化因子(依赖于STING衔接蛋白)产生(例如诱导STING衔接蛋白依赖性I型干扰素、细胞因子或趋化因子)的活性的方法,包含施用治疗有效量的式(I)的环二核苷酸或其对映异构体、水合物、溶剂合物或医药学上可接受的盐,或前述任一者的医药组合物。
具体实施方式
I.综述
本文提供包含至少一个膦酰基甲氧基的新颖2'3'-环二核苷酸,其结合至STING蛋白且调节STING蛋白活性,例如活化STING蛋白。
II.定义
除非另外定义,否则本文中所用的所有技术及科学术语均具有如一般熟习此项技术者通常所理解的相同含义。在化学基团之前或末端的破折号为方便起见指示与母基团的连接点;化学基团可在具有或不具有一或多个破折号的情况下描绘而不失去其一般含义。前缀,诸如“Cu-v”或“Cu-Cv”指示后继基团具有u至v个碳原子,其中u及v为整数。举例而言,“C1-6烷基”或“C1-C6烷基”指示烷基具有1至6个碳原子。
“烷基”为直链或支链饱和单价烃。举例而言,烷基可具有1至10个碳原子(亦即,C1-10烷基)或1至8个碳原子(亦即,C1-8烷基)或1至6个碳原子(亦即,C1-6烷基)或1至4个碳原子(亦即,C1-4烷基)。烷基的实例包括但不限于甲基(Me,-CH3)、乙基(Et,-CH2CH3)、1-丙基(n-Pr,正丙基,-CH2CH2CH3)、2-丙基(i-Pr,异丙基,-CH(CH3)2)、1-丁基(n-Bu,正丁基,-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu,异丁基,-CH2CH(CH3)2)、2-丁基(s-Bu,第二丁基,-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu,第三丁基,-C(CH3)3)、1-戊基(正戊基,-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3),3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3及辛基(-(CH2)7CH3)。烷基可未经取代或经取代。
如本文所用的“亚烷基”指二价直链或支链饱和单价烃基,其通过自不同碳原子移除两个氢原子而衍生自烷烃。
“烷氧基”指基团-O-烷基,其中烷基如上文所定义。举例而言,C1-4烷氧基指具有1至4个碳的-O-烷基。
“烯基”为具有至少一个碳-碳双键的直链或支链单价烃基。举例而言,烯基可具有2至8个碳原子(亦即,C2-8烯基)或2至6个碳原子(亦即,C2-6烯基)或2至4个碳原子(亦即,C2-4烯基)。烯基的实例包括但不限于乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)及-CH2-CH=CH-CH3。烯基可未经取代或经取代。
如本文所用的“亚烯基”指具有至少一个碳-碳双键的二价直链或支链单价烃基,其通过自不同碳原子移除两个氢原子而衍生自烯烃。
“炔基”为具有至少一个碳-碳三键的直链或支链单价烃基。举例而言,炔基可具有2至8个碳原子(亦即,C2-8炔基)或2至6个碳原子(亦即,C2-6炔基)或2至4个碳原子(亦即,C2-4炔基)。炔基的实例包括但不限于乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)及-CH2-C≡C-CH3。炔基可未经取代或经取代。
如本文所用的“亚炔基”指具有至少一个碳-碳三键的二价直链或支链单价烃基,其通过自不同碳原子移除两个氢原子而衍生自炔烃。
烷胺基为-HNRb基团,其中Rb为烷基。
烷硫基为-SRb基团,其中Rb为烷基。
如本文所用的“卤基”或“卤素”指氟(-F)、氯(-Cl)、溴(-Br)及碘(-I)。
如本文所用的“芳基”指单全碳芳环或多稠合全碳环系统,其中至少一个环为芳族。举例而言,在某些实施例中,芳基具有6至20个碳原子、6至14个碳原子、6至12个碳原子或6至10个碳原子。芳基包括苯基。芳基亦包括具有约9至20个碳原子的多稠环系统(例如,包含2、3或4个环的环系统),其中至少一个环为芳族且其中其他环可为芳族或可不为芳族(亦即,碳环)。此类多稠环系统视情况在多稠环系统的任何碳环部分上经一或多个(例如,1、2或3个)侧氧基取代。多稠环系统的环在价数要求允许时可经由稠合、螺环及桥键彼此连接。亦应理解,当参考某一原子范围成员芳基(例如,6元至10元芳基)时,原子范围是针对芳基的总环原子。举例而言,6元芳基将包括苯基且10元芳基将包括萘基及1,2,3,4-四氢萘基。芳基的非限制性实例包括但不限于苯基、茚基、萘基、1,2,3,4-四氢萘基、蒽基及其类似基团。芳基可未经取代或经取代。
如本文所用的“亚芳基”指单芳环或多稠合全碳环系统(其中至少一个环为芳族)上的二价基团,其通过自环或环系统上的不同碳原子移除两个氢原子而形成。
如本文所用的“烷芳基”指如本文所定义的烷基,其中烷基的一或多个氢原子独立地经可相同或不同的芳基取代基置换。烷基及芳基可为上文所描述的烷基及芳基中的任一者。在某些实施例中,烷芳基具有7至24个碳原子、7至16个碳原子、7至13个碳原子或7至11个碳原子。由碳原子数界定的烷芳基指组成性烷基及芳基的组合中存在的碳原子总数。举例而言,C7烷芳基指苯甲基,而C11烷芳基包括1-甲基萘基及正戊基苯基。烷芳基的非限制性实例包括但不限于苯甲基、2,2-二甲基苯基、正戊基苯基、1-甲基萘基、2-乙基萘基及其类似基团。烷芳基可未经取代或经取代。
如本文所用的“烷基亚芳基”指由烷烃与芳环连接形成的基团上的二价基团,其中该基团通过自烷烃及芳环中的各者移除两个氢原子而形成。
如本文所用的术语“杂芳基”指环中具有至少一个除碳以外的原子的单芳环,其中该原子选自由氧、氮及硫组成的群;“杂芳基”亦包括具有至少一个此类芳环的多稠环系统,这些多稠环系统进一步描述于下文中。因此,“杂芳基”包括具有约1至6个碳原子及约1至4个选自由氧、氮及硫组成的群的杂原子的单芳环。硫及氮原子亦可以氧化形式存在,其限制条件为环为芳族。例示性杂芳基环系统包括但不限于吡啶基、嘧啶基、噁唑基或呋喃基。“杂芳基”亦包括多稠环系统(例如,包含2、3或4个环的环系统),其中如上文所定义的杂芳基与选自以下的一或多个环缩合以形成多稠环系统:杂芳基(以形成例如1,8-萘啶基)、杂环(以形成例如1,2,3,4-四氢-1,8-萘啶基)、碳环(以形成例如5,6,7,8-四氢喹啉基)及芳基(以形成例如吲唑基)。因此,杂芳基(单芳环或多稠环系统)在杂芳基环内具有约1至20个碳原子及约1至6个杂原子。此类多稠环系统可视情况在稠环的碳环或杂环部分上经一或多个(例如,1、2、3或4个)侧氧基取代。多稠环系统的环在价数要求允许时可经由稠合、螺环及桥键彼此连接。应理解,多稠环系统的个别环可相对于彼此以任何顺序连接。应理解,杂芳基或杂芳基多稠环系统的连接点可在杂芳基或杂芳基多稠环系统的任何适合原子处,包括碳原子及杂原子(例如,氮)。亦应理解,当参考某一原子范围成员杂芳基(例如,5元至10元杂芳基)时,原子范围是针对杂芳基的总环原子且包括碳原子及杂原子。举例而言,5元杂芳基将包括噻唑基且10元杂芳基将包括喹啉基。例示性杂芳基包括但不限于吡啶基、吡咯基、吡嗪基、嘧啶基、哒嗪基、吡唑基、噻吩基、吲哚基、咪唑基、噁唑基、异噁唑基、噻唑基、呋喃基、噁二唑基、噻二唑基、喹啉基、异喹啉基、苯并噻唑基、苯并噁唑基、吲唑基、喹喔啉基、喹唑啉基、5,6,7,8-四氢异喹啉基、苯并呋喃基、苯并咪唑基、硫茚基、吡咯并[2,3-b]吡啶基、喹唑啉基-4(3H)-酮及三唑基。杂芳基可未经取代或经取代。
如本文所用的“亚杂芳基”指杂芳环或环系统上的二价基团,其中该基团通过自不同碳移除两个氢原子而形成。
“环烷基”指具有3至20个环碳原子(亦即,C3-20环烷基),例如3至12个环原子,例如3至10个环原子,或3至8个环原子,或3至6个环原子,或3至5个环原子,或3至4个环原子的单饱和或部分不饱和全碳环。术语“环烷基”亦包括多稠合的饱和及部分不饱和全碳环系统(例如包含2、3或4个碳环的环系统)。因此,环烷基包括多环碳环,诸如双环碳环(例如,具有约6至12个环碳原子的双环碳环,诸如双环[3.1.0]己烷及双环[2.1.1]己烷),及多环碳环(例如具有至多约20个环碳原子的三环及四环碳环)。多稠环系统的环在价数要求允许时可经由稠合、螺环及桥键彼此连接。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基及1-环己-3-烯基。环烷基可未经取代或经取代。
如本文所用的“杂环基”或“杂环”或“杂环烷基”指环中具有至少一个杂原子(亦即,至少一个选自氧、氮及硫的环杂原子)的单饱和或部分不饱和非芳环或非芳族多环系统。除非另外说明,否则杂环基具有3至约20个环原子,例如3至12个环原子,例如3至10个环原子,或3至8个环原子,或3至6个环原子,或3至5个环原子,或4至6个环原子,或4至5个环原子。因此,术语包括环中具有约1至6个环碳原子及约1至3个选自由氧、氮及硫组成的群的环杂原子的单饱和或部分不饱和环(例如,3、4、5、6或7元环)。多稠环(例如双环杂环基)系统的环在价数要求允许时可经由稠合、螺环及桥键彼此连接。杂环包括但不限于氮杂环丁烷、氮杂环丙烷、咪唑啶、吗啉、环氧乙烷(环氧化物)、氧杂环丁烷、硫杂环丁烷、哌嗪、哌啶、吡唑啶、哌啶、吡咯啶、吡咯啶酮、四氢呋喃、四氢噻吩、二氢吡啶、四氢吡啶、奎宁环、2-氧杂-6-氮杂螺[3.3]庚-6-基、6-噁-1-氮杂螺[3.3]庚-1-基、2-硫杂-6-氮杂螺[3.3]庚-6-基、2,6-二氮杂螺[3.3]庚-2-基、2-氮杂双环[3.1.0]己-2-基、3-氮杂双环[3.1.0]己基、2-氮杂双环[2.1.1]己基、2-氮杂双环[2.2.1]庚-2-基、4-氮杂螺[2.4]庚基、5-氮杂螺[2.4]庚基及其类似物。杂环基可未经取代或经取代。
如本文所用是“侧氧基”指=O。
如本文所用是“经取代”指其中基团是一或多个氢原子独立地经如所指示是一或多个取代基(例如,1、2、3或4个或更多)置换。
“本发明化合物”包括本文所公开的化合物,例如本发明化合物包括式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)、(IIId)及/或(IIIe)的化合物,包括实例的化合物。
如本文所用的“治疗(treatment/treat/treating)”指用于获得有益或所要结果的方法。出于本发明的目的,有益或所要结果包括但不限于症状缓解及/或症状程度减轻及/或预防与疾病或病状相关的症状的恶化。在一个实施例中,“治疗”包括以下中的一或多者:a)抑制疾病或病状(例如,减少由疾病或病状引起的一或多种症状,及/或减轻疾病或病状的程度);b)减缓或遏制与疾病或病状相关的一或多种症状的发展(例如,使疾病或病状稳定、推迟疾病或病状的恶化或进展);及c)缓解疾病或病状,例如使临床症状消退、改善疾病病况、推迟疾病进展、提高生活质量及/或延长存活期。
如本文所用的“推迟”意谓推迟、阻碍、减缓、扼止、稳定及/或延迟疾病或病状的发展。此推迟可具有不同时间长度,视所治疗的疾病及/或个体的病史而定。如熟习此项技术者显而易见,足够或显着推迟可实际上涵盖预防,从而使个体不罹患疾病或病状。
如本文所用的“预防(prevent/prevention/preventing)”指防止疾病或病症发作以使得疾病的临床症状不发展的疗法。因此,“预防”是关于在个体中可侦测到疾病病征之前向个体施用疗法(例如,施用治疗物质)(例如,在个体中不存在可侦测癌症(例如,肝细胞癌)的情况下向个体施用治疗物质)。个体可为具有罹患疾病或病症的风险的个体,诸如具有已知与疾病或病症的罹患或发作相关的一或多个风险因素的个体。因此,在某些实施例中,术语“预防癌症”指向不具有可侦测的癌症的个体施用抗癌治疗物质。应理解,抗癌预防性疗法的个体可为具有罹患癌症的风险的个体。亦应理解,预防不需要100%成功率。在一些实例中,预防可理解为降低癌症风险,而非完全消除癌症发生。
在某些实施例中,术语“预防HBV感染”指向不具有可侦测的HBV感染的个体施用抗HBV治疗物质。应理解,抗HBV预防性疗法的个体可为具有感染HBV病毒的风险的个体。亦应理解,预防不需要100%成功率。在一些情况下,预防可理解为降低感染风险,而非完全消除感染发生。
如本文所用,“调节(modulation/modulating)”蛋白质(例如,STING衔接蛋白)的活性指改变活性以使得活性提高或降低。在一些实施例中,调节提高活性。
如本文所用,“病毒感染”描述一种患病病况,其中病毒侵入健康细胞,使用细胞的繁殖机制以倍增或复制且最终溶解细胞,从而导致细胞死亡,释放病毒颗粒且通过新产生的后代病毒感染其他细胞。某些病毒的潜伏感染亦为病毒感染的可能结果。
如本文所用,术语“增强”指由于向动物或人类施用治疗有效剂量的本发明化合物,有效剂量的疫苗的免疫原性活性的任何形式提高,其中该化合物在向同一动物或人类施用有效剂量的疫苗之前、同时或紧接之后的任何时间施用。
如本文所用的“动物”指哺乳动物,例如家畜,诸如猪、牛、马、狗、猫、大鼠或小鼠,或非人类灵长类动物,诸如食蟹猕猴或黑猩猩。
如本文所使用的“具有风险的个体”指具有罹患待治疗病状的风险的个体。“具有风险”的个体可患有或可不患有可侦测的疾病或病状,且在本文所描述的方法治疗之前可显示或可不显示可侦测的疾病。“具有风险”指示个体具有一或多种所谓的风险因素,其为与罹患疾病或病状相关的可量测参数且为此项技术中已知的。具有此等风险因素中的一或多者的个体比不具有此等风险因素的个体具有更高的罹患疾病或病状的机率。
如本文所用的“治疗有效量”或“有效量”指可有效地引发所需生物学或医学反应的量,包括在向个体施用以用于治疗疾病时足以实现此类疾病治疗的化合物的量。有效量将视化合物、待治疗的个体的疾病及其严重程度及年龄、体重等而变化。有效量可包括一系列量。如此项技术中所理解,有效量可呈一或多次剂量形式,亦即,单次剂量或多次剂量可为达成所需治疗终点所需的。在施用一或多种治疗剂的情形下可考虑有效量,且若与一或多种其他药剂结合可达成或已达成所要或有益的结果,则单一药剂可视为以有效量给予。任何共施用化合物的适合剂量可视情况因化合物的组合作用(例如,累加或协同效应)而减少。
在一些实施例中,治疗有效量的本文所提供的化合物或其医药学上可接受的盐可(i)减少病变细胞数目;(ii)减小肿瘤尺寸;(iii)抑制、扼止、在一定程度上减缓且优选地停止病变细胞向周边器官中的浸润;(iv)抑制(例如,在一定程度上减缓且优选地停止)肿瘤转移;(v)抑制肿瘤生长;(vi)预防或推迟肿瘤发生及/或复发;及/或(vii)在一定程度上缓解与癌症或过度增殖性疾病相关的一或多种症状。在一些实施例中,治疗有效量足以改善、缓和、减轻及/或推迟癌症或过度增殖性疾病的一或多种症状。
“医药学上可接受的赋形剂”包括但不限于任何佐剂、载剂、赋形剂、助滑剂、甜味剂、稀释剂、防腐剂、染料/着色剂、风味增强剂、界面活性剂、湿润剂、分散剂、悬浮剂、稳定剂、等张剂、溶剂或乳化剂,其已经美国食品与药物管理局(United States Food and DrugAdministration)批准为可接受用于人类或家畜。
如本文所用的“共施用”指在施用单位剂量的一或多种额外治疗剂之前或之后施用单位剂量的本文所公开的化合物,例如,在施用一或多种额外治疗剂的数秒、数分钟或数小时内施用本文所公开的化合物。举例而言,在一些实施例中,首先施用单位剂量的本发明化合物,接着在数秒或数分钟内施用单位剂量的一或多种额外治疗剂。可替代地,在其他实施例中,首先施用单位剂量的一或多种额外治疗剂,接着在数秒或数分钟内施用单位剂量的本发明化合物。在一些实施例中,首先施用单位剂量的本发明化合物,接着在数小时(例如,1至12小时)的时段后施用单位剂量的一或多种额外治疗剂。在其他实施例中,首先施用单位剂量的一或多种额外治疗剂,接着在数小时(例如,1至12小时)的时段后施用单位剂量的本发明化合物。共施用本文所公开的化合物与一或多种额外治疗剂一般指同时或依序施用本文所公开的化合物及一或多种额外治疗剂,使得治疗有效量的各药剂存在于个体体内。
亦提供本文所描述的化合物的医药学上可接受的盐、水合物、溶剂合物、互变异构形式、多晶型物及前药。“医药学上可接受”或“生理学上可接受”指化合物、盐、组合物、剂型及其他物质适用于制备适用于兽医学或人类医药用途的医药组合物。
本文所描述的化合物可制备及/或调配为医药学上可接受的盐或在适当时制备及/或调配为游离碱。医药学上可接受的盐为拥有所要的游离碱的药理学活性的化合物的游离碱形式的无毒盐。此等盐可衍生自无机或有机酸或碱。举例而言,含有碱性氮的化合物可通过使该化合物与无机或有机酸接触而制备为医药学上可接受的盐。医药学上可接受的盐的非限制性实例包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸单氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、乙二酸盐、丙二酸盐、丁二酸盐、辛二酸盐、癸二酸盐、反丁烯二酸盐、顺丁烯二酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、甲基磺酸盐、丙基磺酸盐、苯磺酸盐、二甲苯磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、γ-羟丁酸盐、乙醇酸盐、酒石酸盐及杏仁酸盐。其他适合的医药学上可接受的盐的清单见于Remington:The Science and Practice of Pharmacy,第21版,Lippincott Wiliams and Wilkins,Philadelphia,Pa.,2006中。
本文所公开的化合物的“医药学上可接受的盐”的实例亦包括衍生自适当碱的盐,该碱诸如碱金属(例如,钠、钾)、碱土金属(例如,镁)、铵及NX4 +(其中X为C1-C4烷基)。亦包括碱加成盐,诸如钠盐或钾盐。
亦提供本文中所描述的化合物或其医药学上可接受的盐、异构体或混合物,其中连接至碳原子的1至n个氢原子可经氘原子或D置换,其中n为分子中的氢原子的数目。如此项技术中已知,氘原子为氢原子的非放射性同位素。此类化合物可增加代谢抗性,且因此当向哺乳动物施用时,可适用于延长本文所描述的化合物或其医药学上可接受的盐、异构体或混合物的半衰期。参见例如Foster,“Deuterium Isotope Effects in Studies of DrugMetabolism”,Trends Pharmacol.Sci.,5(12):524-527(1984)。通过此项技术中熟知的手段,例如通过采用其中一或多个氢原子已经氘置换的起始物质合成此类化合物。
可并入所公开的化合物中的同位素的实例亦包括氢、碳、氮、氧、磷、氟、氯及碘的同位素,诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I及125I。经正电子发射同位素(诸如11C、18F、15O及13N)取代可适用于正电子发射断层摄影术(PET)研究,以检查受质受体占用率。经同位素标记的式(I)化合物一般可通过熟习此项技术者已知的常规技术或通过类似于如以下所陈述的实例中所描述的方法的方法,使用适当的经同位素标记的试剂替代先前所采用的未经标记的试剂来制备。
本文所公开的实施例的化合物或其医药学上可接受的盐可含有一或多个不对称中心,且可因此产生对映异构体、非对映异构体及其他立体异构形式,这些立体异构形式可在绝对立体化学方面针对氨基酸定义为(R)-或(S)-或(D)-或(L)-。本发明意欲包括所有此类可能的异构体,以及其外消旋及光学纯形式。具光学活性的(+)及(-)、(R)-及(S)-或(D)-及(L)-异构体可使用对手性合成子或对手性试剂来制备,或使用常规技术(例如层析及分步结晶)来解析。用于制备/分离个别对映异构体的常规技术包括自适合的光学纯前驱体进行对手性合成或使用例如对手性高压液相层析(HPLC)对外消旋体(或盐或衍生物的外消旋体)进行解析。当本文所描述的化合物含有烯系双键或其他几何不对称中心时,且除非另外规定,否则意欲化合物包括E及Z几何异构体。同样,亦意欲包括所有互变异构形式。在化合物以其对手性形式表示时,应理解,实施例涵盖但不限于特定非对映异构性或对映异构性增浓形式。在未指定但存在对手性时,应理解,实施例是针对特定非对映异构性或对映异构性增浓形式;或此类化合物的外消旋或非外消旋混合物。如本文所用,“非外消旋混合物”是比率不为1:1的立体异构体的混合物。
如本文所用的“立体异构体”指由相同键所键结的相同原子构成但具有不可互换的不同三维结构的化合物。本发明涵盖各种立体异构体及其混合物且包括“对映异构体”,对映异构体指分子彼此间为不可重迭的镜像的两种立体异构体。
如本文所用的“互变异构体”指质子自分子的一个原子转移至同一分子的另一原子。本发明包括任何这种化合物的互变异构体。
如本文所用的“溶剂合物”指溶剂与化合物的相互相用的产物。亦提供本文所描述的化合物的盐的溶剂合物。亦提供本文所描述的化合物的水合物。
如本文所用的“水合物”指与一或多个水分子以化学方式缔合的本发明化合物。
如本文所用的“前药”指药物的衍生物,其在向人体施用时根据一些化学或酶促路径转化成母体药物。在一些实施例中,前药为药物的生物学上非活性衍生物,其在向人体施用后,根据一些化学或酶促路径转化成生物学上活性母体药物。膦酸盐及磷酸盐的前药为此项技术中已知的。
III.化合物
在一方面中,本文提供一种式(I)化合物:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐,
其中
X1及X3各自独立地为OH、OR1、SH或SR1,其限制条件为X1及X3中的至少一者为OR1、SH或SR1;
X2及X4各自独立地为O或S;
R4及R10各自独立地为H、OH或卤素;
各R1独立地为C1-C6烷基或-L-R2;
各R2独立地为-O(C=O)-N(R2a)2、-O(C=O)-NHR2a、-O(C=O)-R2a或-O(C=O)-O-R2a;
各R2a独立地为C1-C20烷基、C2-C20烯基、C2-C20炔基、-(C1-C6亚烷基)-(C3-C14环烷基)或C3-C20环烷基,其中各R2a独立地视情况经1、2或3个R2b取代;
各R2b独立地为-OH、-SH、-NH2、=O、=NH、=S、卤素、-N3、-CN、C1-C6烷氧基、C1-C6烷硫基、C1-C6烷胺基或C1-C6二烷胺基;
L为L1、L1-O(C=O)-L2、L1-(C=O)O-L2、L1-O-L2、L1-S(O)n-L2、L1-O(C=O)O-L2、L1-O(C=O)NR6-L2、L1-NR6(C=O)O-L2或L1-O(C=O)-L2-O-L3;
L1为C1-C6亚烷基、C2-C6亚烯基、C2-C6亚炔基或C7-C13烷基亚芳基;
L2为C1-C6亚烷基、C2-C6亚烯基、C2-C6亚炔基、C6-C10亚芳基或5元至10元亚杂芳基;
L3为C1-C6亚烷基、C2-C6亚烯基或C2-C6亚炔基;
R6为H或C1-C6烷基;
n为0、1或2;
碱基1及碱基2各自独立地为
其中
A、A1、A2、A3及A4各自独立地为H、OH、SH、F、Cl、Br、I、NH2、OR15、SR15、NHR15、N(R15)2或R16;
各Z独立地为O、S或NR15;
各R15独立地为H、-C(=Z1)R16、-C(=Z1)OR16、-C(=Z1)SR16、-C(=Z1)N(R16)2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C2-C10杂环烷基、C6-C10芳基或C2-C10杂芳基;
各Z1独立地为O或S;且
各R16独立地为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C2-C10杂环烷基、C6-C10芳基或C2-C10杂芳基。
在一些实施例中,A、A1、A2、A3及A4各自独立地为H、OH或NH2。在一些实施例中,A为NH2。在一些实施例中,A1为NH2。在一些实施例中,A2为NH2。在一些实施例中,A3为NH2。在一些实施例中,A4为NH2。
在一些实施例中,各R15独立地为H、-C(=Z1)R16、、-C(=Z1)OR16、-C(=Z1)N(R16)2、C1-C6烷基、C3-C7环烷基、C2-C10杂环烷基、C6-C10芳基或C2-C10杂芳基。在一些实施例中,各R15独立地为H、C1-C6烷基或C6-C10芳基。
在一些实施例中,各R16独立地为C1-C6烷基。
在一些实施例中,Z为O。
在一些实施例中,Z1为O。
在一些实施例中,X2及X4各自为O。在一些实施例中,X2及X4各自为S。在一些实施例中,X2为O,且X4为S。在一些实施例中,X2为S,且X4为O。
在一些实施例中,式(I)化合物具有式(Ia)的结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。
在一些实施例中,式(I)化合物具有式(II)的结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。
在一些实施例中,式(I)、(Ia)及/或(II)化合物结构式(IIa)的结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。
在式(I)、(Ia)、(II)及/或(IIa)化合物的一些实施例中,碱基1及碱基2各自独立地为:
在一些实施例中,碱基1及碱基2各自独立地为:
在一些实施例中,碱基1及碱基2各自独立地为:
在一些实施例中,碱基1及碱基2各自独立地为
在一些实施例中,碱基1为
碱基2为
在一些实施例中,碱基1为
碱基2为
在一些实施例中,碱基1为
碱基2为
在一些实施例中,碱基1为
碱基2为
在一些实施例中,碱基1及碱基2各自为
在式(I)、(Ia)、(II)及/或(IIa)化合物的一些实施例中,A1、A2、A3及A4各自独立地为H、OH或NH2。在一些实施例中,A1为OH或NH2。在一些实施例中,A2为H或NH2。在一些实施例中,A3为H或NH2。在一些实施例中,A4为NH2。
在式(I)、(Ia)、(II)及/或(IIa)化合物的一些实施例中,A1、A2及A3各自独立地为H、OH或NH2。在一些实施例中,A1为OH或NH2。在一些实施例中,A2为H或NH2。在一些实施例中,A3为H或NH2。
在一些实施例中,式(I)、(Ia)、(II)及/或(IIa)化合物具有式(III)的结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐,其中
A1为OH或NH2;A2为H或NH2;且A3为H。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,X1为OH;且X3为OR1。在一些实施例中,X1为OR1;且X3为OH。在一些实施例中,X1及X3各自独立地为OR1。在一些实施例中,X1为SR1;且X3为OH。在一些实施例中,X1为OH;且X3为SR1。在一些实施例中,X1及X3各自独立地选自由OH及SH组成的群,其中X1及X3中的至少一者为SH。在一些实施例中,X1为SH;且X3为OH。在一些实施例中,X1为OH;且X3为SH。在一些实施例中,X1为SR1;且X3为SH。在一些实施例中,X1为SH;且X3为SR1。在一些实施例中,X1及X3各自为SH。在一些实施例中,X1及X3各自独立地为SR1。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,各R1独立地为-L-R2。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,L为L1、L1-O(C=O)-L2、L1-(C=O)O-L2、L1-O-L2、L1-O(C=O)O-L2、L1-O(C=O)NR6-L2或L1-NR6(C=O)O-L2。在一些实施例中,L为L1、L1-O(C=O)-L2、L1-(C=O)O-L2或L1-O-L2。在一些实施例中,L为L1、L1-O(C=O)-L2或L1-O-L2。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,L1为C1-C6亚烷基或C7-C13烷基亚芳基。在一些实施例中,L1为-CH2-或-CH2-Ph-。在一些实施例中,L1为-CH2-。在一些实施例中,L1为C7-C13烷基亚芳基,诸如-CH2-Ph-。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,L2为C1-C6亚烷基、C6-C10亚芳基或5元至10元亚杂芳基。在一些实施例中,L2为C1-C6亚烷基或C6-C10亚芳基。举例而言,L2可为-CH2-。在一些实施例中,L2为C6-C10亚芳基。举例而言,L2可为亚苯基。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,L3为C1-C6亚烷基,例如-CH2-。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,R2为-O(C=O)-R2a或-O(C=O)-O-R2a。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,R2a为C1-C20烷基、C2-C20烯基、C2-C20炔基或-(C1-C6亚烷基)-(C3-C14环烷基)。在一些实施例中,R2a为C3-C20环烷基,例如C3-C16环烷基、C3-C10环烷基、C3-C8环烷基、C3-C7环烷基、C5-C8环烷基或C4-C7环烷基。在一些实施例中,R2a为C1-C20烷基或-(C1-C6亚烷基)-(C3-C14环烷基)。在一些实施例中,R2a为C1-C20烷基或-CH2-(C3-C14环烷基)。在一些实施例中,R2a为-CH2-(C3-C14环烷基),例如-CH2-(C3-C10环烷基)、-CH2-(C3-C8环烷基)、-CH2-(C3-C7环烷基)或-CH2-(C5-C8环烷基)。在一些实施例中,R2a为C1-C20烷基,诸如C1-C16烷基、C3-C20烷基、C3-C18烷基、C3-C16烷基、C3-C14烷基、C3-C12烷基、C3-C10烷基、C3-C8烷基、C2-C8烷基、C1-C8烷基、C1-C6烷基、C2-C6烷基或C3-C6烷基。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,X1为
在一些实施例中,X1为
R2a为C3-C20烷基。
在一些实施例中,X1为
R2a为C3-C20烷基。
在一些实施例中,X1为
在一些实施例中,X1为
在一些实施例中,X1为
在一些实施例中,X1为
在一些实施例中,X1为
R2a为C3-C20烷基。
在一些实施例中,X1为
在一些实施例中,X1为
在一些实施例中,X1为
在一些实施例中,X1为
在一些实施例中,X1为
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,X3为
在一些实施例中,X3为
R2a为C3-C20烷基。
在一些实施例中,X3为
R2a为C3-C20烷基。
在一些实施例中,X3为
在一些实施例中,X3为
在一些实施例中,X3为
在一些实施例中,X3为
在一些实施例中,X3为
R2a为C3-C20烷基。
在一些实施例中,X3为
在一些实施例中,X1为
在一些实施例中,X3为
在一些实施例中,X3为
在一些实施例中,X3为
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,R2a经1或2个R2b取代。在一些实施例中,R2a经一个R2b取代。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,R2b为-OH、卤素、-CN、C1-C6烷氧基或C1-C6烷硫基。在一些实施例中,R2b为卤素,例如F或Cl。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,X1为OR1或SR1;R1为-L-R2;L为L1;L1为C1-C6亚烷基;R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且R2a为C1-C20烷基。在一些实施例中,X1为OR1或SR1;R1为-L-R2;L为-CH2-;R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且R2a为C3-C20烷基。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,X3为OR1或SR1;R1为-L-R2;L为L1;L1为C1-C6亚烷基;R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且R2a为C1-C20烷基。在一些实施例中,X3为OR1或SR1;R1为-L-R2;L为-CH2-;R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且R2a为C3-C20烷基。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,X1为OR1或SR1;R1为-L-R2;L为L1;L1为C7-C13烷基亚芳基;R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且R2a为C1-C20烷基。在一些实施例中,X1为OR1或SR1;;R1为-L-R2;L为L1;L1为-CH2-Ph-;R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且R2a为C3-C20烷基。
在式(I)、(Ia)、(II)、(IIa)及/或(III)化合物的一些实施例中,X3为OR1或SR1;R1为-L-R2;L为L1;L1为C7-C13烷基亚芳基;R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且R2a为C1-C20烷基。在一些实施例中,X3为OR1或SR1;;R1为-L-R2;L为L1;L1为-CH2-Ph-;R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且R2a为C3-C20烷基。
在一些实施例中,式(III)化合物具有式(IIIa)的结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。。
在一些实施例中,式(III)化合物具有式(IIIb)的结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。。
在一些实施例中,式(III)化合物具有式(IIIc)的结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。。
在一些实施例中,式(III)化合物具有式(IIId)的结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。。
在式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)及/或(IIId)化合物的一些实施例中,A2为H。在一些实施例中,A2为NH2。
在式(IIIa)、(IIIb)、(IIIc)及/或(IIId)化合物的一些实施例中,R3为C3-C20烷基或-O-(C3-C20烷基)。在一些实施例中,R3为C1-C16烷基或-O-(C1-C16烷基)。在一些实施例中,R3为C3-C16烷基或-O-(C3-C16烷基)。在一些实施例中,R3为C1-C6烷基或-O-(C1-C6烷基)。在一些实施例中,R3为C1-C6烷基。
在式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)及/或(IIId)化合物的一些实施例中,A1为OH。在一些实施例中,A1为NH2。
在式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)及/或(IIId)化合物的一些实施例中,A2为H且A1为NH2。在一些实施例中,A2为NH2且A1为OH。
在一些实施例中,化合物为式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)及/或(IIId)化合物,或其医药学上可接受的盐。
在式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)及/或(IIId)化合物的一些实施例中,R4及R10各自独立地为H或F。在一些实施例中,R4及R10各自为H。在一些实施例中,R4及R10各自为F。
在一些实施例中,式(III)化合物具有式(IIIe)的结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。。
在式(IIIe)化合物的一些实施例中,A2为H。在一些实施例中,A2为NH2。
在式(IIIe)化合物的一些实施例中,R3为C3-C20烷基或-O-(C3-C20烷基)。在一些实施例中,R3为C1-C16烷基或-O-(C1-C16烷基)。在一些实施例中,R3为C3-C16烷基或-O-(C3-C16烷基)。在一些实施例中,R3为C1-C6烷基或-O-(C1-C6烷基)。在一些实施例中,R3为C1-C6烷基。
在式(IIIe)化合物的一些实施例中,A1为OH。在一些实施例中,A1为NH2。
在式(IIIe)化合物的一些实施例中,A2为H且A1为NH2。在一些实施例中,A2为NH2且A1为OH。
在一些实施例中,化合物为式(IIIe)化合物,或其医药学上可接受的盐。
在式(IIIe)化合物的一些实施例中,R4及R10各自独立地为H或F。在一些实施例中,R4及R10各自为H。在一些实施例中,R4及R10各自为F。
在式(IIIa)、(IIIb)、(IIIc)、(IIId)及/或(IIIe)化合物的一些实施例中,R2a为C2-C20烷基,例如C2-C16烷基、C2-C14烷基、C2-C12烷基、C2-C8烷基、C2-C6烷基、C3-C16烷基、C3-C14烷基、C3-C12烷基、C3-C8烷基或C3-C6烷基。
在一些实施例中,本发明化合物具有以下结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。。
在一些实施例中,本发明化合物具有以下结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。。
在一些实施例中,本发明化合物具有以下结构:
或其对映异构体、水合物、溶剂合物或医药学上可接受的盐。。
在一些实施例中,式(I)、(Ia)、(II)、(IIa)、(III)、、(IIIa)、(IIIb)、(IIIc)、(IIId)及/或(IIIe)化合物具有如所描绘的结构,或为其互变异构体、对映异构体或医药学上可接受的盐。在一些实施例中,化合物为式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)、(IIId)及/或(IIIe)化合物,或其医药学上可接受的盐。
本发明化合物,例如式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)、(IIId)及/或(IIIe)化合物可在数个等效绘图中展示。举例而言,式(Ia)化合物通常如上文所示在本文中描绘,其中各核苷的2'-取代基或3'-取代基面向彼此:
上文式(Ia)化合物等效于如下文所描绘的式(Ia)化合物:
此外,先前绘图中的各者等效于以下对式(Ia)化合物的描绘:
先前绘图中的各者等效于以下对式(Ia)化合物的描绘:
手性中心的存在允许化合物以两种可能的光学异构体((R)-对映异构体或(S)-对映异构体)中的一者的形式存在或以该两者的外消旋混合物的形式存在。在可连接于分子中的不同位置处的取代基存在的情况下,所有区位异构体及所形成的区位异构体的混合物包括于本发明中所描述的式(I)的范围内。
IV.组合物
在某些实施例中,本发明提供一种医药组合物,其包含本发明化合物(例如式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)、(IIId)及/或(IIIe)化合物)或其医药学上可接受的盐,及医药学上可接受的赋形剂。
在某些实施例中,医药组合物包含一或多种额外治疗剂,如下文更充分阐述。
包含本文所公开的化合物或其医药学上可接受的盐的医药组合物可用可根据常规实践选择的一或多种医药学上可接受的赋形剂制备。片剂可含有包括助滑剂、填充剂、黏合剂及其类似物的赋形剂。水性组合物可以无菌形式制备,且在意欲用于通过除经口施用以外的途径进行递送时一般可为等张的。所有组合物均可视情况含有赋形剂,诸如Rowe等人,Handbook of Pharmaceutical Excipients,第6版,American PharmacistsAssociation,2009中所阐述的赋形剂。赋形剂可包括抗坏血酸及其他抗氧化剂、螯合剂(诸如EDTA)、碳水化合物(诸如糊精)、羟烷基纤维素、羟烷基甲基纤维素、硬脂酸及其类似物。在某些实施例中,组合物以固体剂型提供,包括固体口服剂型。
组合物包括适用于各种施用途径,包括经口施用的组合物。组合物可以单位剂型呈现,且可通过药剂学技术中熟知的任何方法制备。此类方法包括使活性成分(例如,本发明化合物或其医药盐)与一或多种医药学上可接受的赋形剂缔合的步骤。组合物可通过使活性成分与液体赋形剂或细粉状固体赋形剂或两者均匀且紧密地缔合,且随后视需要使产物成形来制备。技术及调配物一般见于Remington:The Science and Practice ofPharmacy,第21版,Lippincott Wiliams and Wilkins,Philadelphia,Pa.,2006中。
本文所描述的适用于经口施用的组合物可以离散单元(单位剂型)呈现,包括但不限于胶囊、药囊或片剂,各自含有预定量的活性成分。在一个实施例中,医药组合物为片剂。
本文所公开的医药组合物包含一或多种本文所公开的化合物,或其医药学上可接受的盐,以及医药学上可接受的赋形剂及视情况选用的其他治疗剂。含有活性成分的医药组合物可呈适用于预期施用方法的任何形式。当用于例如口服使用时,可制备片剂、糖衣锭、口含锭、水性或油性悬浮液、可分散散剂或颗粒、乳液、硬或软胶囊、糖浆或酏剂。可根据制造医药组合物的技术中已知的任何方法制备意欲用于口服使用的组合物,且这种组合物可含有一或多种赋形剂,包括甜味剂、调味剂、着色剂及防腐剂以便提供可口制剂。含有与医药学上可接受的无毒赋形剂掺合的活性成分的片剂为可接受的,这种赋形剂适用于制造片剂。这种赋形剂可为例如惰性稀释剂,诸如碳酸钙或碳酸钠、乳糖、单水合乳糖、交联羧甲纤维素钠、聚维酮、磷酸钙或磷酸钠;粒化剂及崩解剂,诸如玉米淀粉或褐藻酸;黏合剂,诸如纤维素、微晶纤维素、淀粉、明胶或阿拉伯胶;及润滑剂,诸如硬脂酸镁、硬脂酸或滑石。片剂可未经包覆或可利用已知技术(包括微囊封装)包覆以推迟在胃肠道中的崩解及吸附,且因此提供较长时段的持续作用。举例而言,可单独或与蜡一起使用诸如单硬脂酸甘油酯或二硬脂酸甘油酯的时间延迟材料。
可与非活性成分组合产生剂型的活性成分的量可视预期治疗个体及特定施用模式而变化。举例而言,在一些实施例中,向人类经口施用的剂型可含有约1至1000mg活性物质,该活性物质与适当且适宜量的医药学上可接受的赋形剂一起调配。在某些实施例中,医药学上可接受的赋形剂的范围为总组合物的约5至约95%(重量:重量)。
在某些实施例中,包含本发明化合物或其医药学上可接受的盐的组合物在一个变化形式中不含有影响活性成分代谢速率的试剂。因此,应理解,包含本发明化合物的组合物在一个方面中不包含将影响(例如减缓、阻碍或扼止)本发明化合物或与本发明化合物分开、依序或同时施用的任何其他活性成分的代谢的试剂。亦应理解,本文所详述的方法、套组、制品及其类似者中的任一者在一个方面中不包含将影响(例如减缓、阻碍或扼止)本发明化合物或与本发明化合物分开、依序或同时施用的任何其他活性成分的代谢的试剂。
本发明亦包括如上文所描述的医药组合物,其用于调节STING蛋白活性,以诱导I型干扰素、细胞因子或趋化因子的STING依赖性产生。
本发明亦包括如上文所描述的医药组合物,其用于治疗或预防病毒感染,由B型肝炎病毒、HIV引起的感染,过度增殖性疾病或癌症。
在一些实施例中,上文所描述的医药组合物为用于人类或动物。
本发明进一步包括以医药学上可接受的组合物的单一活性成分施用的本发明化合物,其可通过此项技术中已知的常规方法制备,例如通过使活性成分与医药学上可接受的治疗惰性有机及/或无机载剂或赋形剂结合,或通过与其混合。
在一个方面中,本文提供使用本发明化合物作为与已知药物中的其他活性成分具有协同效应的第二或其他活性成分,或与此类药物一起施用本发明化合物。
本发明化合物亦可以在活体内释放活性成分的前药形式或其他经适当改质的形式使用。
V.方法
在一个实施例中,本文提供一种治疗疾病或病症的方法,其包含向有需要的人类或动物施用治疗有效量的本发明化合物,包括式(I)、(Ia)、(II)、(IIa)、(III)、(IIIa)、(IIIb)、(IIIc)、(IIId)及/或(IIIe)化合物,或其对映异构体或医药学上可接受的盐。
亦提供一种调节STING蛋白的活性的方法,其包含施用治疗有效量的本发明化合物,或其对映异构体或医药学上可接受的盐。
干扰素基因衔接蛋白的刺激因子(STING),亦称为STING、STING蛋白、跨膜蛋白173(TMEM173)、MPYS、IRF3活化的介体(MITA)或内质网干扰素刺激子(ERIS),为人类中由TMEM173基因(UniProt码Q86WV6;NCBI参考序列:NP_938023.1(同功异型物1)及NP_001288667(同功异型物2))编码的蛋白质。据信STING衔接蛋白经由不同分子机制充当直接胞溶质DNA感测子(CDS)及I型干扰素信号传导的衔接蛋白。已证实STING衔接蛋白可经由TBK1活化下游转录因子STAT6及IRF3,且经由IKKβ活化NF-κB,其可实现针对胞内病原体的抗病毒反应或先天性免疫反应。当细胞经胞内病原体(诸如病毒、分枝杆菌及胞内寄生虫)感染时,STING衔接蛋白通过诱导I型干扰素产生而在先天性免疫中起作用。由STING衔接蛋白介导的I型干扰素通过自分泌及旁分泌信号传导保护经感染细胞及邻近细胞免受局部感染。
进一步提供一种预防或治疗对STING衔接蛋白的调节作用有反应的疾病或病状的方法,其包含向有需要的人类或动物施用治疗有效量的本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐。
进一步提供一种在人类或动物中诱导STING衔接蛋白依赖性I型干扰素、细胞因子或趋化因子的方法,其包含施用治疗有效量的本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐。
STING衔接蛋白的活化又活化蛋白激酶TBK1,其随后活化下游转录因子NF-κB及IRF-3。据信STING衔接蛋白的活化最终会引起释放I型及III型干扰素以及多种细胞因子及趋化因子,诸如IL-6、TNF-α及INF-γ。因此,在人类或动物中诱导STING衔接蛋白依赖性I型干扰素、细胞因子或趋化因子会引起该人类或动物中NF-κB、IRF-3、I型干扰素、III型干扰素、IL-6、TNF-α及INF-γ中的一或多者的活化。
进一步提供一种治疗或预防病毒感染,例如由B型肝炎或HIV感染的方法,其包含向有需要的人类或动物施用治疗有效量的本发明化合物,或其对映异构体或医药学上可接受的盐。
可通过本发明方法治疗或预防的病毒感染可为任何由病毒引起的感染,例如来自病毒的肝DNA病毒科(Hepadnaviridae family)的病毒,例如B型肝炎;或任何逆转录病毒,例如α逆转录病毒属,诸如劳斯肉瘤病毒(Rous sarcoma virus);β逆转录病毒属,诸如猴逆转录病毒;δ逆转录病毒属,诸如牛白血病病毒或人类T-淋巴病毒(HTLV),包括HTLV-1、HTLV-2及HTLV-3;γ逆转录病毒属,诸如鼠类白血病病毒或猫白血病病毒;或慢病毒,诸如人类免疫缺乏病毒(HIV)(包括HIV-1及HIV-2)、猿猴免疫缺乏病毒、马感染性贫血病毒、牛免疫缺乏病毒、K型兔内源性慢病毒(RELIK)或猫免疫缺乏病毒。
进一步提供一种治疗或预防过度增殖性疾病或癌症的方法,其包含向有需要的人类或动物施用治疗有效量的本发明化合物,或其对映异构体或医药学上可接受的盐。
过度增殖性疾病包括由非癌细胞的过度生长引起的疾病。此类病状包括但不限于牛皮癣、光化性角化症及皮脂溢性角化症、疣、瘢痕瘤及湿疹。
可通过本发明方法治疗或预防的癌症包括实体肿瘤及淋巴瘤,包括但不限于肾上腺癌、膀胱癌、骨癌、脑癌、乳癌、结肠癌、结肠直肠癌、眼癌、头颈癌、诸如肾细胞癌的肾脏癌、肝癌、诸如非小细胞肺癌的肺癌、卵巢癌、胰脏癌、前列腺癌、诸如鳞状细胞癌及黑素瘤的皮肤癌、甲状腺癌、子宫癌、阴道癌及诸如多发性骨髓瘤的骨髓瘤。癌症可为未经治疗的,或复发性及/或难治性的。
在一些实施例中,癌症为伯基特氏淋巴瘤(Burkitt's lymphoma)、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤(NHL)、惰性非霍奇金氏淋巴瘤(iNHL)、难治性iNHL、多发性骨髓瘤(MM)、慢性骨髓白血病(CML)、急性淋巴细胞性白血病(ALL)、B细胞ALL、急性骨髓白血病(AML)、慢性淋巴细胞性白血病(CLL)、小淋巴细胞性淋巴瘤(SLL)、骨髓发育不良症候群(MDS)、骨髓增殖性疾病(MPD)、套细胞淋巴瘤(MCL)、滤泡性淋巴瘤(FL)、瓦尔登斯特伦氏巨球蛋白血症(Waldestrom's macroglobulinemia;WM)、T细胞淋巴瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)或边缘区淋巴瘤(MZL)。在一个实施例中,癌症为微小残留病(MRD)。在一些实施例中,癌症选自霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤(NHL)、惰性非霍奇金氏淋巴瘤(iNHL)及难治性iNHL。在一些实施例中,癌症为惰性非霍奇金氏淋巴瘤(iNHL)。在一些实施例中,癌症为难治性iNHL。在一些实施例中,癌症为慢性淋巴细胞性白血病(CLL)。在一些实施例中,癌症为弥漫性大B细胞淋巴瘤(DLBCL)。
在一些实施例中,癌症为选自由以下组成的群的实体肿瘤:胰脏癌;膀胱癌;结肠直肠癌;乳癌,包括转移性乳癌;前列腺癌,包括雄激素依赖性及非雄激素依赖性前列腺癌;肾脏癌或肾癌,包括例如转移性肾细胞癌;肝细胞癌;肺癌,包括例如非小细胞肺癌(NSCLC)、细支气管肺泡癌(BAC)及肺腺癌;卵巢癌,包括例如进行性上皮或原发性腹膜癌;子宫颈癌;胃癌;食道癌;头颈癌,包括例如头颈部鳞状细胞癌;黑素瘤;神经内分泌癌症,包括转移性神经内分泌肿瘤;脑瘤,包括例如神经胶质瘤、多形性寡树突状神经胶质瘤、成年人多形性胶质母细胞瘤及成年人多形性星形细胞瘤;骨癌;及软组织肉瘤、肝癌瘤、直肠癌、阴茎癌、外阴癌、甲状腺癌、唾液腺癌、子宫内膜或子宫癌、肝细胞瘤、肝细胞癌、肝癌、胃部癌症或胃癌(包括胃肠癌)、腹膜癌症、肺部鳞状癌瘤、胃食道癌、胆道癌、胆囊癌、结肠直肠/阑尾癌、鳞状细胞癌(例如上皮鳞状细胞癌)。
本文所提供的治疗方法中的任一者可用于治疗各种阶段的癌症。举例而言,癌症阶段包括但不限于早期、晚期、局部晚期、缓解期、难治性、在缓解的后复发的及进行性癌症。
个体
本文所提供的治疗方法中的任一者可用于治疗已诊断患有或怀疑患有癌症的个体(例如,人类)。如本文所用,个体指哺乳动物,包括例如人类。
在一些实施例中,个体可为展现一或多种与癌症或过度增殖性疾病相关的症状的人类。在一些实施例中,个体可为展现一或多种与癌症相关的症状的人类。在一些实施例中,个体处于癌症早期。在其他实施例中,个体处于癌症晚期。
在一些实施例中,个体可为具有罹患癌症或过度增殖性疾病风险或基因上或以其他方式倾向于(例如,风险因素)罹患癌症或过度增殖性疾病且已经诊断或尚未经诊断的人类。如本文所用,“具有风险”的个体为具有罹患癌症的风险的个体。在进行本文所描述的治疗方法之前,个体可能患有或可能未患有可侦测疾病,且可能显示或可能未显示可侦测疾病。具有风险的个体可具有一或多种所谓的风险因素,该等风险因素为与本文所描述的癌症的发展相关的可量测的参数。具有一或多种这种风险因素的个体比不具有这种风险因素的个体具有更高的罹患癌症的概率。这种风险因素可包括例如年龄、性别、种族、饮食、先前疾病的病史、前驱疾病的存在、基因(例如,遗传)因素及环境曝露。在一些实施例中,具有癌症风险的个体包括例如亲戚已经历该疾病的个体及通过基因或生物化学标记物的分析确定具有风险的个体。
另外,个体可为经受一或多种标准疗法,诸如化学疗法、放射线疗法、免疫疗法、手术或其任何组合的人类。因此,一或多种本文所提供的化合物可在化学疗法、放射线疗法、免疫疗法、手术或其组合的施用之前、期间或之后施用。
在一些实施例中,个体可为满足以下条件的人类:(i)实质上难以用至少一种化学疗法治疗,或(ii)在化学疗法治疗后复发,或满足(i)及(ii)两者。在一些实施例中,个体难以用至少两种、至少三种或至少四种化学疗法治疗(包括标准或实验化学疗法)来治疗。
进一步提供一种增强疫苗的功效的方法,其包含向有需要的人类或动物施用治疗有效量的本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐。
本发明包括本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐,其用作人类或动物的药剂。
本发明包括本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐,其用于治疗人类或动物的疾病或病症。
本发明进一步包括本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐,其用于调节STING蛋白的活性。
本发明进一步包括本文所提供的环二核苷酸,包括本发明化合物或其对映异构体或医药学上可接受的盐,其用于预防或治疗对STING蛋白的调节作用有反应的人类或动物的疾病或病状。
本发明进一步包括本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐,其单独或与一或多种治疗活性物质组合用于人类或动物中的I型干扰素、细胞因子或趋化因子的STING依赖性诱导。
本发明进一步包括本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐,其单独或与一或多种治疗活性剂组合用于治疗或预防人类或动物的病毒感染。
本发明进一步包括本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐,其单独或与一或多种治疗活性物质组合用于治疗或预防人类或动物的由B型肝炎病毒或HIV引起的感染。
本发明进一步包括本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐,其单独或与一或多种治疗活性剂组合用于治疗或预防人类或动物的过度增殖性疾病或癌症。
本发明进一步包括本文所提供的环二核苷酸,包括本发明化合物,或其对映异构体或医药学上可接受的盐,其用于在人类或动物中增强疫苗功效。
本发明进一步包括一种医药组合物,其用于调节STING蛋白活性以在人类或动物中诱导I型干扰素、细胞因子或趋化因子的STING依赖性产生。
本发明进一步包括一种医药组合物,其用于治疗或预防人类或动物的病毒感染,由B型肝炎病毒、HIV引起的感染,过度增殖性疾病或癌症。
本发明进一步包括本文所提供的环二核苷酸(包括本发明化合物,或其对映异构体或医药学上可接受的盐)用于制造用于治疗或预防由B型肝炎病毒、HIV引起的感染、过度增殖性疾病或癌症的药剂的用途。
VI.施用
本发明化合物(在本文中亦称为活性成分)可通过适于待治疗病状的任何途径施用。适合途径包括经口、经直肠、经鼻、局部(包括颊内及舌下)、经皮、经阴道及非经肠(包括皮下、肌肉内、静脉内、瘤内、皮内、鞘内及硬膜外)及其类似途径。应了解,优选的途径可随例如接受者的病状而变化。本文所公开的某些化合物的优点为其为经口生物可用且可经口给药。
本发明化合物可根据有效给药方案向个体施用持续所要时间段或持续时间,诸如至少约一个月、至少约2个月、至少约3个月、至少约6个月或至少约12个月或更长时间。在一个变化形式中,化合物按每日或间歇性时程施用个体生命的持续时间。
本发明化合物的剂量或给药频率可在治疗疗程内基于施用医师的判断来调节。
化合物可以有效量向个体(例如,人类)施用。在某些实施例中,化合物每日施用一次。
化合物可通过任何适用途径及手段,诸如通过经口或非经肠(例如,静脉内)施用来施用。化合物的治疗有效量可包括每日每公斤体重约0.00001mg至每日每公斤体重约10mg,诸如每日每公斤体重约0.0001mg至每日每公斤体重约10mg,或诸如每日每公斤体重约0.001mg至每日每公斤体重约1mg,或诸如每日每公斤体重约0.01mg至每日每公斤体重约1mg,或诸如每日每公斤体重约0.05mg至每日每公斤体重约0.5mg,或诸如每日约0.3mg至约30mg,或诸如每日约30mg至约300mg。
本发明化合物可以任何剂量的本发明化合物(例如,1mg至1000mg的化合物)与一或多种额外治疗剂组合。治疗有效量可包括每剂量约1mg至每剂量约1000mg,诸如每剂量约50mg至每剂量约500mg,或诸如每剂量约100mg至每剂量约400mg,或诸如每剂量约150mg至每剂量约350mg,或诸如每剂量约200mg至每剂量约300mg。本发明化合物的其他治疗有效量为每剂量约100、125、150、175、200、225、250、275、300、325、350、375、400、425、450、475或约500mg。本发明化合物的其他治疗有效量为每剂量约100mg,或每剂量约125、150、175、200、225、250、275、300、350、400、450或约500mg。可每小时、每日或每周施用单次剂量。举例而言,单次剂量可每隔1小时、2小时、3小时、4小时、6小时、8小时、12小时、16小时施用一次或每隔24小时施用一次。单次剂量亦可每隔1天、2天、3天、4天、5天、6天施用一次或每隔7天施用一次。单次剂量亦可每隔1周、2周、3周施用一次,或每隔4周施用一次。在某些实施例中,单次剂量可每隔一周施用一次。单次剂量亦可每月施用一次。
本发明中亦包括套组,其包含本发明化合物或其对映异构体或医药学上可接受的盐,或含有以上中的任一者的医药组合物。
在一个实施例中,提供套组,其包含本文所公开的化合物或其医药学上可接受的盐与一或多种(例如,一种、两种、三种、四种、一或两种、一至三种或一至四种)额外治疗剂的组合。
VII.组合疗法
在某些实施例中,提供一种用于治疗或预防患有感染性疾病、病毒感染、B型肝炎感染、HIV感染、癌症或过度增殖性疾病或具有罹患该疾病的风险的人类的该疾病的方法,其包含向人类施用治疗有效量的本发明化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、四种、一或两种、一至三种或一至四种)额外治疗剂的组合。在一个实施例中,提供一种用于治疗患有感染性疾病、病毒感染、B型肝炎感染、HIV感染、癌症或过度增殖性疾病或具有罹患该疾病的风险的人类的该疾病的方法,其包含向人类施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、四种、一或两种、一至三种或一至四种)额外治疗剂的组合。
在某些实施例中,本发明提供一种用于治疗病毒感染的方法,其包含向有需要的个体施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、四种、一或两种、一至三种或一至四种)额外治疗剂的组合,这种额外治疗剂适用于治疗病毒感染。在一些实施例中,病毒感染为B型肝炎感染。在一些实施例中,病毒感染为HIV感染。
在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与一种、两种、三种、四种或更多种额外治疗剂组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与两种额外治疗剂组合。在其他实施例中,本文所公开的化合物或其医药学上可接受的盐与三种额外治疗剂组合。在其他实施例中,本文所公开的化合物或其医药学上可接受的盐与四种额外治疗剂组合。一种、两种、三种、四种或更多种额外治疗剂可为选自相同类别的治疗剂的不同治疗剂,及/或其可选自不同类别的治疗剂。
组合疗法的施用
在某些实施例中,本文所公开的化合物与一或多种额外治疗剂一起施用。本文所公开的化合物与一或多种额外治疗剂的共施用通常指同时或依序施用本文所公开的化合物及一或多种额外治疗剂,使得个体体内存在治疗有效量的本文所公开的化合物及一或多种额外治疗剂。当依序施用时,该组合可以两次或更多次施用形式施用。
共施用本文所公开的化合物与一或多种额外治疗剂一般指同时或依序施用本文所公开的化合物及一或多种额外治疗剂,使得治疗有效量的各药剂存在于患者体内。
在某些实施例中,如本文所公开的化合物(例如,任何式I化合物)可以任何剂量的式I化合物(例如,10mg至1000mg的化合物)与一或多种(例如,一种、两种、三种、四种、一或两种、一至三种或一至四种)额外治疗剂组合。
共施用包括在施用单位剂量的一或多种额外治疗剂之前或之后施用单位剂量的本文所公开的化合物。本文所公开的化合物可在施用一或多种额外治疗剂的数秒、数分钟或数小时内施用。举例而言,在一些实施例中,首先施用单位剂量的本文所公开的化合物,接着在数秒或数分钟内施用单位剂量的一或多种额外治疗剂。可替代地,在其他实施例中,首先施用单位剂量的一或多种额外治疗剂,接着在数秒或数分钟内施用单位剂量的本文所公开的化合物。在一些实施例中,首先施用单位剂量的本文所公开的化合物,接着在数小时(例如,1至12小时)的时段后施用单位剂量的一或多种额外治疗剂。在其他实施例中,首先施用单位剂量的一或多种额外治疗剂,接着在数小时(例如,1至12小时)的时段后施用单位剂量的本文所公开的化合物。
在某些实施例中,本文所公开的化合物以单一剂型形式与一或多种额外治疗剂组合,以用于例如以用于经口施用的固体剂型形式同时施用给个体。
在某些实施例中,将本发明的化合物调配为片剂,其可视情况含有一或多种适用于治疗所治疗的疾病的其他化合物。在某些实施例中,片剂可含有用于治疗病毒性疾病,例如B型肝炎病毒或HIV的另一活性成分。
在某些实施例中,这种片剂适用于每日一次给药。
在一个实施例中,提供医药组合物,其包含本文所公开的化合物或其医药学上可接受的盐与一或多种(例如,一种、两种、三种、一或两种或一至三种)额外治疗剂的组合,及医药学上可接受的载剂、稀释剂或赋形剂。
在一个实施例中,提供套组,其包含本发明化合物或其医药学上可接受的盐与一或多种(例如,一种、两种、三种、四种、一或两种、一至三种或一至四种)额外治疗剂的组合。
病毒组合疗法
本文中所描述的化合物可与一或多种抗病毒剂一起使用或组合,该等抗病毒剂包括阿巴卡韦(abacavir)、阿昔洛韦(aciclovir)、阿德福韦(adefovir)、金刚胺(amantadine)、安普那韦(amprenavir)、阿比朵尔(arbidol)、阿扎那韦(atazanavir)、立普妥(artipla)、溴夫定(brivudine)、西多福韦(cidofovir)、可比韦(combivir)、依度尿苷(edoxudine)、依法韦仑(efavirenz)、安卓西他宾(emtricitabine)、恩夫韦地(enfuvirtide)、因提弗(entecavir)、弗维森(fomvirsen)、夫萨那韦(fosamprenavir)、膦甲酸(foscarnet)、膦乙醇(fosfonet)、更昔洛韦(ganciclovir)、加德西(gardasil)、伊巴他滨(ibacitabine)、英木洛韦(immunovir)、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韦(indinavir)、肌苷、整合酶抑制剂、干扰素(包括III型干扰素、II型干扰素、I型干扰素)、拉米夫定(lamivudine)、洛匹那韦(lopinavir)、洛韦胺(loviride)、MK-0518、马拉维若(maraviroc)、吗啉脒胍(moroxydine)、奈非那韦(nelfinavir)、奈韦拉平(nevirapine)、多吉美(nexavir)、核苷类似物、奥司他韦(oseltamivir)、喷昔洛韦(penciclovir)、帕拉米韦(peramivir)、普可那利(pleconaril)、鬼臼毒素(podophyllotoxin)、蛋白酶抑制剂、逆转录酶抑制剂、利巴韦林(ribavirin)、金刚乙胺(rimantadine)、利托那韦(ritonavir)、沙奎那韦(saquinavir)、司他夫定(stavudine)、替诺福韦(tenofovir)、替诺福韦双索酯(tenofovir disoproxil)、替拉那韦(tipranavir)、曲氟尿苷(trifluridine)、曲利志韦(trizivir)、曲金刚胺(tromantadine)、特鲁瓦达(truvada)、缬更昔洛韦(valganciclovir)、维克维若(vicriviroc)、阿糖腺苷(vidarabine)、伟拉咪定(viramidine)、扎西他滨(zalcitabine)、扎那米韦(zanamivir)、齐多夫定(zidovudine)及其组合。
在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与5-30mg反丁烯二酸替诺福韦埃拉酚胺(tenofovir alafenamide fumarate)、半反丁烯二酸替诺福韦埃拉酚胺(tenofovir alafenamide hemifumarate)或替诺福韦埃拉酚胺(tenofoviralafenamide)组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与5-10;5-15;5-20;5-25;25-30;20-30;15-30;或10-30mg的反丁烯二酸替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺或替诺福韦埃拉酚胺组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与10mg反丁烯二酸替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺或替诺福韦埃拉酚胺组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与25mg反丁烯二酸替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺或替诺福韦埃拉酚胺组合。本发明化合物可以任何剂量的化合物(例如,50mg至500mg的化合物)与本文所提供的试剂组合,如同剂量的各组合具体且分别地列出一样。
在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与100-400mg反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯或替诺福韦双索酯组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与100-150、100-200、100-250、100-300、100-350、150-200、150-250、150-300、150-350、150-400、200-250、200-300、200-350、200-400、250-350、250-400、350-400或300-400mg反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯或替诺福韦双索酯组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与300mg反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯或替诺福韦双索酯组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与250mg反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯或替诺福韦双索酯组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与150mg反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯或替诺福韦双索酯组合。如本文所公开的化合物(例如,式(I)化合物)可以任何剂量的化合物(例如,50mg至500mg的化合物)与本文所提供的试剂组合,如同剂量的各组合具体且分别地列出一样。
HIV组合疗法
在某些实施例中,提供一种用于治疗或预防患有HIV感染或具有罹患HIV感染的风险的人类或动物的方法,其包含向人类或动物施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、一或两种或一至三种)额外治疗剂的组合。在一个实施例中,提供一种用于治疗患有HIV感染或具有罹患HIV感染的风险的人类或动物的方法,其包含向人类或动物施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、一或两种或一至三种)额外治疗剂的组合。
在某些实施例中,本发明提供一种用于治疗HIV感染的方法,其包含向有需要的个体施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种适用于治疗HIV感染的额外治疗剂的组合。
在某些实施例中,本文所公开的化合物调配为片剂,其可视情况含有一或多种适用于治疗HIV的其他化合物。在某些实施例中,片剂可含有用于治疗HIV的另一活性成分,诸如HIV蛋白酶抑制剂、HIV非核苷或非核苷酸逆转录酶抑制剂、HIV核苷或核苷酸逆转录酶抑制剂、HIV整合酶抑制剂、HIV非催化位点(或异位)整合酶抑制剂、药物动力学增强剂及其组合。
在某些实施例中,此类片剂适用于每日一次给药。
在上述实施例中,额外治疗剂可为抗HIV剂。在一些实施例中,额外治疗剂选自由以下组成的群:HIV组合药物、HIV蛋白酶抑制剂、HIV非核苷或非核苷酸逆转录酶抑制剂、HIV核苷或核苷酸逆转录酶抑制剂、HIV整合酶抑制剂、HIV非催化位点(或异位)整合酶抑制剂、HIV进入抑制剂、HIV成熟抑制剂、免疫调节剂、免疫治疗剂、抗体-药物接合物、基因修饰剂、基因编辑剂(诸如CRISPR/Cas9、锌指核酸酶、归巢核酸酶、合成核酸酶、TALEN)、细胞疗法(诸如嵌合抗原受体T细胞,CAR-T及经工程改造的T细胞受体,TCR-T)、潜时逆转剂、靶向HIV衣壳的化合物(包括衣壳抑制剂)、基于免疫的疗法、磷脂酰肌醇3-激酶(PI3K)抑制剂、α-4/β-7拮抗剂、HIV抗体、双特异性抗体及“抗体样”医疗性蛋白质、HIV p17基质蛋白抑制剂、IL-13拮抗剂、肽基-脯胺酰基顺式-反式异构酶A调节剂、二硫化蛋白质异构酶抑制剂、补体C5a受体拮抗剂、DNA甲基转移酶抑制剂、HIV vif基因调节剂、Vif二聚拮抗剂、HIV-1病毒感染性因子抑制剂、TAT蛋白抑制剂、HIV-1Nef调节剂、Hck酪胺酸激酶调节剂、混合谱系激酶-3(MLK-3)抑制剂、HIV-1剪接抑制剂、Rev蛋白抑制剂、整合素拮抗剂、核蛋白抑制剂、剪接因子调节剂、含有COMM域的蛋白1调节剂、HIV核糖核酸酶H抑制剂、逆细胞周期素调节剂、CDK-9抑制剂、树突状ICAM-3捕获非整合素1抑制剂、HIV GAG蛋白抑制剂、HIV POL蛋白抑制剂、补体因子H调节剂、泛素连接酶抑制剂、脱氧胞苷激酶抑制剂、细胞周期素依赖性激酶抑制剂、前蛋白转化酶PC9刺激剂、ATP依赖性RNA解螺旋酶DDX3X抑制剂、逆转录酶激活复合抑制剂、G6PD及NADH-氧化酶抑制剂、药物动力学增强剂、HIV基因疗法、HIV疫苗及其他HIV治疗剂及其组合。
在一些实施例中,额外治疗剂选自由以下组成的群:用于HIV的组合药物、用于治疗HIV的其他药物、HIV蛋白酶抑制剂、HIV逆转录酶抑制剂、HIV整合酶抑制剂、HIV非催化位点(或异位)整合酶抑制剂、HIV进入(融合)抑制剂、HIV成熟抑制剂、潜伏逆转剂、衣壳抑制剂、基于免疫的疗法、PI3K抑制剂、HIV抗体,及双特异性抗体,及“抗体样”医疗性蛋白质,及其组合。
HIV组合药物
组合药物的实例包括(依法韦仑、反丁烯二酸替诺福韦双索酯及安卓西他宾);(利匹韦林(rilpivirine)、反丁烯二酸替诺福韦双索酯及安卓西他宾);(埃替格韦(elvitegravir)、考比西他(cobicistat)、反丁烯二酸替诺福韦双索酯及安卓西他宾);(反丁烯二酸替诺福韦双索酯及安卓西他宾;TDF+FTC);(替诺福韦埃拉酚胺及安卓西他宾);(替诺福韦埃拉酚胺、安卓西他宾及利匹韦林)、(替诺福韦埃拉酚胺、安卓西他宾、考比西他及埃替格韦);(比替拉韦(bictegravir)、安卓西他宾、替诺福韦埃拉酚胺);地瑞那韦(darunavir)、半反丁烯二酸替诺福韦埃拉酚胺、安卓西他宾及考比西他;依法韦仑、拉米夫定(lamivudine)及反丁烯二酸替诺福韦双索酯;拉米夫定及反丁烯二酸替诺福韦双索酯;替诺福韦及拉米夫定;替诺福韦埃拉酚胺及安卓西他宾;半反丁烯二酸替诺福韦埃拉酚胺及安卓西他宾;半反丁烯二酸替诺福韦埃拉酚胺、安卓西他宾及利匹韦林;半反丁烯二酸替诺福韦埃拉酚胺、安卓西他宾、考比西他及埃替格韦;(齐多夫定及拉米夫定;AZT+3TC);(硫酸阿巴卡韦及拉米夫定;ABC+3TC);(洛匹那韦及利托那韦);(都鲁拉韦(dolutegravir)、阿巴卡韦及拉米夫定);(硫酸阿巴卡韦、齐多夫定及拉米夫定;ABC+AZT+3TC);阿扎那韦及考比西他;硫酸阿扎那韦及考比西他;硫酸阿扎那韦及利托那韦;地瑞那韦(darunavir)及考比西他;都鲁拉韦及利匹韦林;都鲁拉韦及盐酸利匹韦林;都鲁拉韦、硫酸阿巴卡韦及拉米夫定;拉米夫定、奈韦拉平及齐多夫定;雷特格韦(raltegravir)及拉米夫定;多拉韦林(doravirine)、拉米夫定及反丁烯二酸替诺福韦双索酯;多拉韦林、拉米夫定及替诺福韦双索酯;都鲁拉韦+拉米夫定、拉米夫定+阿巴卡韦+齐多夫定、拉米夫定+阿巴卡韦、拉米夫定+反丁烯二酸替诺福韦双索酯、拉米夫定+齐多夫定+奈韦拉平、洛匹那韦+利托那韦、洛匹那韦+利托那韦+阿巴卡韦+拉米夫定、洛匹那韦+利托那韦+齐多夫定+拉米夫定、替诺福韦+拉米夫定,及反丁烯二酸替诺福韦双索酯+安卓西他宾+盐酸利匹韦林、咯匹那韦、利托那韦、齐多夫定及拉米夫定;Vacc-4x及罗米地辛(romidepsin);及APH-0812。
HIV蛋白酶抑制剂
HIV蛋白酶抑制剂的实例包括安普那韦、阿扎那韦、贝卡那韦(brecanavir)、地瑞那韦、夫萨那韦、夫萨那韦钙、茚地那韦、硫酸茚地那韦、洛匹那韦、奈非那韦、甲磺酸奈非那韦、利托那韦、沙奎那韦、甲磺酸沙奎那韦、替拉那韦、DG-17、TMB-657(PPL-100)、T-169、BL-008及TMC-310911。
HIV逆转录酶抑制剂
HIV非核苷或非核苷酸逆转录酶抑制剂的实例包括达匹韦林(dapivirine)、地拉韦定(delavirdine)、甲磺酸地拉韦定、多拉韦林、依法韦仑、依曲韦林(etravirine)、香菇多醣(lentinan)、奈韦拉平、利匹韦林、ACC-007、AIC-292、KM-023、PC-1005及VM-1500。
HIV核苷或核苷酸逆转录酶抑制剂的实例包括阿德福韦、阿德福韦酯、阿兹夫定(azvudine)、安卓西他宾、替诺福韦、替诺福韦埃拉酚胺、反丁烯二酸替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺、替诺福韦双索酯、反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯、及VIDEX(地达诺新(didanosine),ddl)、阿巴卡韦、硫酸阿巴卡韦、阿洛夫定(alovudine)、阿普瑞西他滨(apricitabine)、森沙戊定(censavudine)、地达诺新、艾夫他滨(elvucitabine)、非替那韦(festinavir)、氟沙定替酯(fosalvudine tidoxil)、CMX-157、达匹韦林、多拉韦林、依曲韦林、OCR-5753、乳清酸替诺福韦双索酯、福齐夫定替酯(fozivudine tidoxil)、拉米夫定、福斯非兹(phosphazid)、司他夫定(stavudine)、扎西他滨(zalcitabine)、齐多夫定、GS-9131、GS-9148、MK-8504及KP-1461。
HIV整合酶抑制剂
HIV整合酶抑制剂的实例包括埃替格韦、姜黄素、姜黄素的衍生物、菊苣酸、菊苣酸的衍生物、3,5-二咖啡酰奎宁酸、3,5-二咖啡酰奎宁酸的衍生物、金黄三羧酸、金黄三羧酸的衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯的衍生物、酪胺酸磷酸化抑制剂、酪胺酸磷酸化抑制剂的衍生物、槲皮素、槲皮素的衍生物、雷特格韦、都鲁拉韦、JTK-351、比替拉韦(bictegravir)、AVX-15567、卡伯拉韦(cabotegravir)(长效可注射)、二酮喹啉-4-1衍生物、整合酶-LEDGF抑制剂、莱德金(ledgin)、M-522、M-532、NSC-310217、NSC-371056、NSC-48240、NSC-642710、NSC-699171、NSC-699172、NSC-699173、NSC-699174、芪二磺酸、T-169及卡伯拉韦。
HIV非催化位点或异位整合酶抑制剂(NCINI)的实例包括CX-05045、CX-05168及CX-14442。
HIV进入抑制剂
HIV进入(融合)抑制剂的实例包括森尼韦若(cenicriviroc)、CCR5抑制剂、gp41抑制剂、CD4连接抑制剂、gp120抑制剂及CXCR4抑制剂。
CCR5抑制剂的实例包括阿普纳维(aplaviroc)、维克维若、马拉维若、森尼韦若、PRO-140、埃达他韦(adaptavir)(RAP-101)、尼非韦罗(nifeviroc)(TD-0232)、抗GP120/CD4或CCR5双特异性抗体、B-07、MB-66、多肽C25P、TD-0680及vMIP(海米普(Haimipu))。
gp41抑制剂的实例包括艾博韦他(albuvirtide)、恩夫韦地、BMS-986197、恩夫韦地生物更佳药、恩夫韦地生物类似药、HIV-1融合抑制剂(P26-Bapc)、ITV-1、ITV-2、ITV-3、ITV-4、PIE-12三聚体及西夫韦他(sifuvirtide)。
CD4连接抑制剂的实例包括伊利祖单抗(ibalizumab)及CADA类似物。
gp120抑制剂的实例包括Radha-108(瑞西普托(receptol))3B3-PE38、BanLec、基于膨润土的纳米医药、福斯萨维缓血酸胺(fostemsavir tromethamine)、IQP-0831及BMS-663068。
CXCR4抑制剂的实例包括普乐沙福(plerixafor)、ALT-1188、N15肽及vMIP(海米普)。
HIV成熟抑制剂
HIV成熟抑制剂的实例包括BMS-955176及GSK-2838232。
潜伏逆转剂
潜伏逆转剂的实例包括组蛋白去乙酰基酶(HDAC)抑制剂、诸如万珂(velcade)的蛋白酶体抑制剂、蛋白激酶C(PKC)活化剂、Smyd2抑制剂、BET-溴域4(BRD4)抑制剂、离子霉素(ionomycin)、PMA、SAHA(辛二酰苯胺异羟肟酸或辛二酰基、苯胺及异羟肟酸)、AM-0015、ALT-803、NIZ-985、NKTR-255、IL-15调节抗体、JQ1、二硫龙、两性霉素B及诸如拉格唑拉(largazole)类似物的泛素抑制剂以及GSK-343。
HDAC抑制剂的实例包括罗米地辛、伏立诺他(vorinostat)及帕比诺他(panobinostat)。
PKC活化剂的实例包括吲哚拉坦(indolactam)、普罗斯坦(prostratin)、巨大戟醇B,及DAG-内酯。
衣壳抑制剂
衣壳抑制剂的实例包括衣壳聚合抑制剂或衣壳分裂化合物、诸如偶氮二甲酰胺的HIV核衣壳p7(NCp7)抑制剂、HIV p24衣壳蛋白质抑制剂、AVI-621、AVI-101、AVI-201、AVI-301及AVI-CAN1-15系列。
基于免疫的疗法
基于免疫的疗法的实例包括toll样受体调节剂,诸如TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12及TLR13;计划性细胞死亡蛋白1(Pd-1)调节剂;计划性死亡配位体1(Pd-L1)调节剂;IL-15调节剂;德玛韦(DermaVir);介白素-7;氯奎宁(plaquenil)(羟基氯奎);普留净(proleukin)(阿地介白素(aldesleukin),IL-2);干扰素α;干扰素α-2b;干扰素α-n3;聚乙二醇化干扰素α;干扰素γ;羟基脲;霉酚酸吗啉乙酯(MPA)及其酯衍生物霉酚酸吗啉乙酯(MMF);利巴韦林;瑞他立德(rintatolimod)、聚合物聚乙二亚胺(PEI);吉朋(gepon);瑞他立德;IL-12;WF-10;VGV-1;MOR-22;BMS-936559;CYT-107、介白素-15/Fc融合蛋白、诺姆福隆(normferon)、聚乙二醇化干扰素(peginterferon)α-2a、聚乙二醇化干扰素α-2b、重组型介白素-15、RPI-MN、GS-9620、STING调节剂、RIG-I调节剂、NOD2调节剂及IR-103。
TLR8调节剂的实例包括莫托莫特(motolimod)、雷西莫特(resiquimod)、3M-051、3M-052、MCT-465、IMO-4200、VTX-763、VTX-1463及以下文献中公开的调节剂:US20140045849(Janssen)、US20140073642(Janssen)、WO2014/056953(Janssen)、WO2014/076221(Janssen)、WO2014/128189(Janssen)、US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US20080306050(Array Biopharma)、US20100029585(Ventirx Pharma)、US20110092485(Ventirx Pharma)、US20110118235(Ventirx Pharma)、US20120082658(Ventirx Pharma)、US20120219615(Ventirx Pharma)、US20140066432(Ventirx Pharma)、US20140088085(VentirxPharma)、US20140275167(Novira therapeutics)、US20130251673(Novira therapeutics)、美国专利第9670205号(Gilead Sciences Inc.)、US20160289229(Gilead Sciences Inc.)、美国专利申请案第15/692161号(Gilead Sciences Inc.)及美国专利申请案第15/692093号(GileadSciences Inc.)。
磷脂酰肌醇3-激酶(PI3K)抑制剂
PI3K抑制剂的实例包括艾德斯布(idelalisib)、艾培昔布(alpelisib)、布帕昔布(buparlisib)、CAI乳清酸盐、考班昔布(copanlisib)、杜维力丝(duvelisib)、吉达力丝(gedatolisib)、来那替尼(neratinib)、帕努昔布(panulisib)、哌立福新(perifosine)、皮克立西(pictilisib)、皮拉力丝(pilaralisib)、甲磺酸普喹替尼(puquitinib mesylate)、瑞戈替布(rigosertib)、瑞戈替布钠、索诺昔布(sonolisib)、泰尼西布(taselisib)、AMG-319、AZD-8186、BAY-1082439、CLR-1401、CLR-457、CUDC-907、DS-7423、EN-3342、GSK-2126458、GSK-2269577、GSK-2636771、INCB-040093、LY-3023414、MLN-1117、PQR-309、RG-7666、RP-6530、RV-1729、SAR-245409、SAR-260301、SF-1126、TGR-1202、UCB-5857、VS-5584、XL-765及ZSTK-474。
α-4/β-7拮抗剂
整合素α-4/β-7拮抗剂的实例包括PTG-100、TRK-170、阿布里单抗(abrilumab)、艾托珠单抗(etrolizumab)、卡洛斯特甲基(carotegrast methyl)及维多珠单抗(vedolizumab)。
HIV抗体、双特异性抗体及“抗体样”医疗性蛋白质
HIV抗体、双特异性抗体及“抗体样”医疗性蛋白质的实例包括 Fab衍生物、bnAB(广谱中和HIV-1抗体)、BMS-936559、TMB-360及靶向HIV gp120或gp41的抗体、靶向HIV的抗体募集分子、抗CD63单株抗体、抗GB病毒C抗体、抗GP120/CD4、CCR5双特异性抗体、抗nef单域抗体、抗Rev抗体、骆驼衍生的抗CD18抗体、骆驼衍生的抗ICAM-1抗体、DCVax-001、靶向gp140的抗体、基于gp41的HIV治疗性抗体、人类重组型mAb(PGT-121)、伊利祖单抗、Immuglo及MB-66。
以此方式靶向HIV的抗体的实例包括巴维昔单抗(bavituximab)、UB-421、C2F5、2G12、C4E10、C2F5+C2G12+C4E10、8ANC195、3BNC117、3BNC60、10-1074、PGT145、PGT121、PGT-151、PGT-133、MDX010(伊派利单抗(ipilimumab))、DH511、N6、VRC01 PGDM1400、A32、7B2、10E8、10E8v4、CAP256-VRC26.25、DRVIA7、VRC-07-523、VRC-HIVMAB080-00-AB、VRC-HIVMAB060-00-AB、MGD-014及VRC07。HIV双特异性抗体的实例包括MGD014。
药物动力学增强剂
药物动力学增强剂的实例包括考比西他及利托那韦。
HIV疫苗
HIV疫苗的实例包括肽疫苗、重组型子单元蛋白疫苗、活载体疫苗、DNA疫苗、CD4衍生的肽疫苗、疫苗组合、rgp120(AIDSVAX)、ALVAC HIV(vCP1521)/AIDSVAX B/E(gp120)(RV144)、单体gp120 HIV-1次型C疫苗、Remune、ITV-1、Contre Vir、Ad5-ENVA-48、DCVax-001(CDX-2401)、Vacc-4x、Vacc-C5、VAC-3S、多进化枝DNA重组型腺病毒-5(rAd5)、Pennvax-G、Pennvax-GP、HIV-TriMix-mRNA疫苗、HIV-LAMP-vax、Ad35、Ad35-GRIN、NAcGM3/VSSP ISA-51、聚-ICLC辅佐疫苗、TatImmune、GTU-multiHIV(FIT-06)、gp140[δ]V2.TV1+MF-59、rVSVINHIV-1gag疫苗、SeV-Gag疫苗、AT-20、DNK-4、ad35-Grin/ENV、TBC-M4、HIVAX、HIVAX-2、NYVAC-HIV-PT1、NYVAC-HIV-PT4、DNA-HIV-PT123、rAAV1-PG9DP、GOVX-B11、GOVX-B21、TVI-HIV-1、Ad-4(Ad4-env进化枝C+Ad4-mGag)、EN41-UGR7C、EN41-FPA2、PreVaxTat、AE-H、MYM-V101、CombiHIVvac、ADVAX、MYM-V201、MVA-CMDR、DNA-Ad5 gag/pol/nef/nev(HVTN505)、MVATG-17401、ETV-01、CDX-1401、rcAD26.MOS1.HIV-Env、Ad26.Mod.HIV疫苗、AGS-004、AVX-101、AVX-201、PEP-6409、SAV-001、ThV-01、TL-01、TUTI-16、VGX-3300、IHV-001及病毒样颗粒疫苗(诸如假病毒颗粒疫苗)、CombiVICHvac、LFn-p24 B/C融合疫苗、基于GTU的DNA疫苗、HIV gag/pol/nef/env DNA疫苗、抗TAT HIV疫苗、缀合多肽疫苗、树突状细胞疫苗、基于gag的DNA疫苗、GI-2010、gp41 HIV-1疫苗、HIV疫苗(PIKA佐剂)、I i-key/MHC II类抗原决定基杂交肽疫苗、ITV-2、ITV-3、ITV-4、LIPO-5、多进化枝Env疫苗、MVA疫苗、Pennvax-GP、pp71缺失型HCMV载体HIV gag疫苗、重组型肽疫苗(HIV感染)、NCI、rgp160 HIV疫苗、RNActive HIV疫苗、SCB-703、Tat Oyi疫苗、TBC-M4、治疗性HIV疫苗、UBI HIV gp120、Vacc-4x+罗米地辛、变异型gp120多肽疫苗、rAd5 gag-pol env A/B/C疫苗、DNA.HTI及MVA.HTI。
额外HIV治疗剂
额外HIV治疗剂的实例包括公开于以下中的化合物:WO 2004/096286(GileadSciences)、WO 2006/015261(Gilead Sciences)、WO 2006/110157(Gilead Sciences)、WO2012/003497(Gilead Sciences)、WO 2012/003498(Gilead Sciences)、WO 2012/145728(Gilead Sciences)、WO 2013/006738(Gilead Sciences)、WO 2013/159064(GileadSciences)、WO 2014/100323(Gilead Sciences)、US 2013/0165489(University ofPennsylvania)、US 2014/0221378(Japan Tobacco)、US 2014/0221380(Japan Tobacco)、WO 2009/062285(Boehringer Ingelheim)、WO 2010/130034(Boehringer Ingelheim)、WO2013/006792(Pharma Resources)、US 20140221356(Gilead Sciences)、US 20100143301(Gilead Sciences)及WO 2013/091096(Boehringer Ingelheim)。
用于治疗HIV的其他药物的实例包括乙酰吗喃(acemannan)、阿拉泊韦(alisporivir)、BanLec、去铁酮、格玛木因(Gamimune)、米特法林(metenkefalin)、纳曲酮(naltrexone)、普拉斯汀(Prolastin)、REP 9、RPI-MN、VSSP、H1viral、SB-728-T、1,5-二咖啡酰奎宁酸、rHIV7-shl-TAR-CCR5RZ、AAV-eCD4-Ig基因疗法、MazF基因疗法、BlockAide、ABX-464、AG-1105、APH-0812、BIT-225、CYT-107、HGTV-43、HPH-116、HS-10234、IMO-3100、IND-02、MK-1376、MK-8507、MK-8591、NOV-205、PA-1050040(PA-040)、PGN-007、SCY-635、SB-9200、SCB-719、TR-452、TEV-90110、TEV-90112、TEV-90111、TEV-90113、RN-18、Immuglo,及VIR-576。
基因疗法及细胞疗法
基因疗法及细胞疗法包括用于使基因沉默的基因修饰;用于直接杀死经感染细胞的基因方法;经设计以将个体的大部分自身免疫系统替换以增强对经感染细胞的免疫反应或使个体的自身免疫系统活化以杀死经感染细胞或寻找且杀死经感染细胞的免疫细胞输注;用于修饰细胞活性以进一步改变针对感染的内源性免疫反应性的基因方法。
树突状细胞疗法的实例包括AGS-004。
基因编辑剂
基因编辑系统的实例包括CRISPR/Cas9系统、锌指核酸酶系统、TALEN系统、归巢核酸内切酶系统及大范围核酸酶系统。
靶向HIV的CRISPR/Cas9系统的实例包括EBT101。
CAR-T细胞疗法
CAR-T细胞疗法包括工程改造以表现嵌合抗原受体(CAR)的免疫效应细胞的群体,其中CAR包含HIV抗原结合域。HIV抗原包括HIV包膜蛋白或其部分、gp120或其部分、gp120上的CD4结合位点、gp120上的CD4诱导结合位点、gp120上的N聚醣、gp120的V2、gp41上的近膜区域。免疫效应细胞为T细胞或NK细胞。在一些实施例中,T细胞为CD4+T细胞、CD8+T细胞或其组合。
HIV CAR-T的实例包括VC-CAR-T。
TCR-T细胞疗法
TCR-T细胞疗法包括经工程改造以靶向经病毒感染的细胞表面上的HIV衍生的肽的T细胞。
熟习此项技术者应了解,上文所列的额外治疗剂可包括于上文所列的类别中的多于一者中。特定类别不欲限制那些类别中所列的那些化合物的功能。
在一具体实施例中,本文所公开的化合物或其医药学上可接受的盐与HIV核苷或核苷酸逆转录酶抑制剂及HIV非核苷逆转录酶抑制剂组合。在另一具体实施例中,本文所公开的化合物或其医药学上可接受的盐与HIV核苷或核苷酸逆转录酶抑制剂及HIV蛋白酶抑制化合物组合。在另一实施例中,本文所公开的化合物或其医药学上可接受的盐与HIV核苷或核苷酸逆转录酶抑制剂、HIV非核苷逆转录酶抑制剂及药物动力学增强剂组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与至少一种HIV核苷逆转录酶抑制剂、整合酶抑制剂及药物动力学增强剂组合。在另一实施例中,本文所公开的化合物或其医药学上可接受的盐与两种HIV核苷或核苷酸逆转录酶抑制剂组合。
在一特定实施例中,本文所公开的化合物或其医药学上可接受的盐与一种、两种、三种、四种或更多种选自以下的额外治疗剂组合:(依法韦仑、反丁烯二酸替诺福韦双索酯及安卓西他宾);(利匹韦林、反丁烯二酸替诺福韦双索酯及安卓西他宾);(埃替格韦、考比西他、反丁烯二酸替诺福韦双索酯及安卓西他宾);(反丁烯二酸替诺福韦双索酯及安卓西他宾;TDF+FTC);(替诺福韦埃拉酚胺及安卓西他宾);(替诺福韦埃拉酚胺、安卓西他宾及利匹韦林);(替诺福韦埃拉酚胺、安卓西他宾、考比西他及埃替格韦);(比替拉韦、安卓西他宾、替诺福韦埃拉酚胺);阿德福韦;阿德福韦酯;考比西他;安卓西他宾;替诺福韦;替诺福韦双索酯;反丁烯二酸替诺福韦双索酯;替诺福韦埃拉酚胺;半反丁烯二酸替诺福韦埃拉酚胺;(都鲁拉韦、阿巴卡韦及拉米夫定);都鲁拉韦、硫酸阿巴卡韦及拉米夫定;雷特格韦;雷特格韦及拉米夫定;马拉维若;恩夫韦地;(咯匹那韦及利托那韦);(齐多夫定及拉米夫定;AZT+3TC);(硫酸阿巴卡韦及拉米夫定;ABC+3TC);(硫酸阿巴卡韦、齐多夫定及拉米夫定;ABC+AZT+3TC);利匹韦林;盐酸利匹韦林;硫酸阿扎那韦及考比西他;阿扎那韦及考比西他;地瑞那韦及考比西他;阿扎那韦;硫酸阿扎那韦;都鲁拉韦;埃替格韦;利托那韦;硫酸阿扎那韦及利托那韦;地瑞那韦;拉米夫定;普拉斯汀;夫萨那韦;夫萨那韦钙依法韦仑;依曲韦林;奈非那韦;甲磺酸奈非那韦;干扰素;地达诺新;司他夫定;茚地那韦;硫酸茚地那韦;替诺福韦及拉米夫定;齐多夫定;奈韦拉平;沙奎那韦;甲磺酸沙喹那韦;阿地介白素;扎西他滨;替拉那韦;安普那韦;地拉韦定;甲磺酸地拉韦定;Radha-108(瑞西普托);拉米夫定及反丁烯二酸替诺福韦双索酯;依法韦仑;拉米夫定及反丁烯二酸替诺福韦双索酯;福斯非兹;拉米夫定;奈韦拉平及齐多夫定;阿巴卡韦;以及硫酸阿巴卡韦。
在一特定实施例中,本文所公开的化合物或其医药学上可接受的盐与以下组合:硫酸阿巴卡韦、替诺福韦、替诺福韦双索酯、反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯、替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺或比替拉韦。
在一特定实施例中,本文所公开的化合物或其医药学上可接受的盐与以下组合:替诺福韦、替诺福韦双索酯、反丁烯二酸替诺福韦双索酯、替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺或比替拉韦。
在一特定实施例中,本文所公开的化合物或其医药学上可接受的盐与以下组合:选自由以下组成的群的第一额外治疗剂:硫酸阿巴卡韦、替诺福韦、替诺福韦双索酯、反丁烯二酸替诺福韦双索酯、替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺及比替拉韦;及选自由安卓西他宾及拉米夫定组成的群的第二额外治疗剂。
在一特定实施例中,本文所公开的化合物或其医药学上可接受的盐与以下组合:选自由以下组成的群的第一额外治疗剂:替诺福韦、替诺福韦双索酯、反丁烯二酸替诺福韦双索酯、替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺及比替拉韦;及第二额外治疗剂,其中第二额外治疗剂为安卓西他宾。
在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与5-30mg反丁烯二酸替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺或替诺福韦埃拉酚胺及200mg安卓西他宾组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与5-10mg、5-15mg、5-20mg、5-25mg、25-30mg、20-30mg、15-30mg或10-30mg反丁烯二酸替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺或替诺福韦埃拉酚胺及200mg安卓西他宾组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与10mg反丁烯二酸替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺或替诺福韦埃拉酚胺及200mg安卓西他宾组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与25mg反丁烯二酸替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺或替诺福韦埃拉酚胺及200mg安卓西他宾组合。如本文所公开的化合物(例如,式(I)化合物)可以任何剂量的化合物(例如,1mg至500mg的化合物)与本文所提供的试剂组合,如同剂量的各组合具体且分别地列出一样。
在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与200-400mg反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯或替诺福韦双索酯及200mg安卓西他宾组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与200-250、200-300、200-350、250-350、250-400、350-400、300-400或250-400mg反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯或替诺福韦双索酯及200mg安卓西他宾组合。在某些实施例中,本文所公开的化合物或其医药学上可接受的盐与300mg反丁烯二酸替诺福韦双索酯、半反丁烯二酸替诺福韦双索酯或替诺福韦双索酯及200mg安卓西他宾组合。本发明化合物可以任何剂量的化合物(例如,1mg至500mg的化合物)与本文所提供的试剂组合,如同剂量的各组合具体且分别地列出一样。
HBV组合疗法
在某些实施例中,提供一种用于治疗或预防患有HBV感染或具有罹患HBV感染的风险的人类的HBV感染的方法,其包含向人类施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、四种、一或两种、一至三种或一至四种)额外治疗剂的组合。在一个实施例中,提供一种用于治疗患有HBV感染或具有罹患HBV感染的风险的人类的HBV感染的方法,其包含向人类施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、四种、一或两种、一至三种或一至四种)额外治疗剂的组合。
在某些实施例中,本发明提供一种用于治疗HBV感染的方法,其包含向有需要的患者施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、四种、一或两种、一至三种或一至四种)适用于治疗HBV感染的额外治疗剂的组合。
本文所描述的化合物可与以下中的一或多者一起使用或组合:化学治疗剂、免疫调节剂、免疫治疗剂、治疗性抗体、治疗性疫苗、双特异性抗体及“抗体样”医疗性蛋白质(诸如Fab衍生物)、抗体-药物接合物(ADC)、基因修饰剂或基因编辑剂(诸如CRISPR Cas9、锌指核酸酶、归巢核酸内切酶、合成核酸酶、TALEN)、细胞疗法(诸如CAR-T(嵌合抗原受体T细胞)及TCR-T(经工程改造的T细胞受体)药剂)或其任何组合。
在某些实施例中,本发明化合物调配为片剂,其可视情况含有一或多种适用于治疗HBV的其他化合物。在某些实施例中,片剂可含有用于治疗HBV的另一活性成分,诸如3-二加氧酶(IDO)抑制剂、载脂蛋白A1调节剂、精胺酸酶抑制剂、B淋巴细胞及T淋巴细胞衰减因子抑制剂、布鲁顿氏酪胺酸激酶(Bruton's tyrosine kinase;BTK)抑制剂、CCR2趋化因子拮抗剂、CD137抑制剂、CD160抑制剂、CD305抑制剂、CD4促效剂及调节剂、靶向HBcAg的化合物、靶向B型肝炎核心抗原(HBcAg)的化合物、核心蛋白异位调节剂、共价闭合环状DNA(cccDNA)抑制剂、亲环素抑制剂、细胞毒性T淋巴细胞相关蛋白质4(ipi4)抑制剂、DNA聚合酶抑制剂、核酸内切酶调节剂、表观遗传调节剂、法尼醇X受体(Farnesoid X receptor)促效剂、HBsAg抑制剂、HBsAg分泌或组装抑制剂、HBV DNA聚合酶抑制剂、HBV复制抑制剂、HBVRNAse抑制剂、HBV病毒进入抑制剂、HBx抑制剂、B型肝炎大型包膜蛋白调节剂、B型肝炎大型包膜蛋白刺激剂、B型肝炎结构蛋白调节剂、B型肝炎表面抗原(HBsAg)抑制剂、B型肝炎表面抗原(HBsAg)分泌或组装抑制剂、B型肝炎病毒E抗原抑制剂、B型肝炎病毒复制抑制剂、肝炎病毒结构蛋白抑制剂、HIV-1逆转录酶抑制剂、玻尿酸酶抑制剂、IAPs抑制剂、IL-2促效剂、IL-7促效剂、免疫调节剂、吲哚胺-2抑制剂、核糖核苷酸还原酶抑制剂、介白素-2配位体、ipi4抑制剂、离胺酸去甲基酶抑制剂、组蛋白去甲基酶抑制剂、KDM1抑制剂、KDM5抑制剂、杀手细胞凝集素样受体子族G成员1抑制剂、淋巴细胞活化基因3抑制剂、淋巴毒素β受体活化剂、Axl调节剂、B7-H3调节剂、B7-H4调节剂、CD160调节剂、CD161调节剂、CD27调节剂、CD47调节剂、CD70调节剂、GITR调节剂、HEVEM调节剂、ICOS调节剂、Mer调节剂、NKG2A调节剂、NKG2D调节剂、OX40调节剂、SIRPα调节剂、TIGIT调节剂、Tim-4调节剂、Tyro调节剂、Na+-牛胆酸酯共输送多肽(NTCP)抑制剂、自然杀手细胞受体2B4抑制剂、NOD2基因刺激剂、核蛋白抑制剂、核蛋白调节剂、PD-1抑制剂、PD-L1抑制剂、肽基脯胺酰异构酶抑制剂、磷脂酰肌醇-3激酶(PI3K)抑制剂、视黄酸诱导性基因1刺激剂、逆转录酶抑制剂、核糖核酸酶抑制剂、RNADNA聚合酶抑制剂、SLC10A1基因抑制剂、SMAC模拟物、Src酪胺酸激酶抑制剂、干扰素基因刺激因子(STING)促进剂、NOD1刺激剂、T细胞表面醣蛋白CD28抑制剂、T细胞表面醣蛋白CD8调节剂、胸腺素促效剂、胸腺素α1配位体、Tim-3抑制剂、TLR-3促效剂、TLR-7促效剂、TLR-9促效剂、TLR9基因刺激剂、toll样受体(TLR)调节剂、病毒性核糖核苷酸还原酶抑制剂及其组合。
HBV组合药物
用于治疗HBV的组合药物的实例包括(反丁烯二酸替诺福韦双索酯及安卓西他宾);ABX-203、拉米夫定及PEG-IFN-α;ABX-203阿德福韦及PEG-IFNα;以及INO-1800(INO-9112及RG7944)。
其他HBV药物
用于治疗HBV的其他药物的实例包括α-羟基环庚三烯酚酮、安多索韦(amdoxovir)、β-羟基胞嘧啶核苷、AL-034、CCC-0975、艾夫他滨(elvucitabine)、依泽替米贝(ezetimibe)、环孢素A、龙胆苦苷(gentiopicrin/gentiopicroside)、JNJ-56136379、硝唑尼特(nitazoxanide)、比林纳潘特(birinapant)、NJK14047、NOV-205(莫里克桑(molixan),BAM-205)、寡苷酸、米沃替酯(mivotilate)、菲隆(feron)、GST-HG-131、左旋咪唑(levamisole)、卡舒宁(Ka Shu Ning)、阿洛菲隆(alloferon)、WS-007、Y-101(替芬泰(TiFen Tai))、rSIFN-co、PEG-IIFNm、KW-3、BP-Inter-014、齐墩果酸(oleanolic acid)、HepB-nRNA、cTP-5(rTP-5)、HSK-II-2、HEISCO-106-1、HEISCO-106、赫普巴纳(Hepbarna)、IBPB-006IA、和普印芬(Hepuyinfen)、DasKloster 0014-01、ISA-204、将安泰(Jiangantai)(肝西康(Ganxikang))、MIV-210、OB-AI-004、PF-06、胡黄连苷(picroside)、DasKloster-0039、和普兰太(hepulantai)、IMB-2613、TCM-800B、还原麸胱甘肽、RO-6864018、RG-7834、UB-551及ZH-2N,及US20150210682(Roche)、US2016/0122344(Roche)、WO2015173164、WO2016023877、US2015252057A(Roche)、WO16128335A1(Roche)、WO16120186A1(Roche)、US2016237090A(Roche)、WO16107833A1(Roche)、WO16107832A1(Roche)、US2016176899A(Roche)、WO16102438A1(Roche)、WO16012470A1(Roche)、US2016220586A(Roche)及US2015031687A(Roche)中所公开的化合物。
HBV疫苗
HBV疫苗包括预防性及治疗性疫苗。HBV预防性疫苗的实例包括Vaxelis、Hexaxim、Heplisav、Mosquirix、DTwP-HBV疫苗、Bio-Hep-B、D/T/P/HBV/M(LBVP-0101;LBVW-0101)、DTwP-Hepb-Hib-IPV疫苗、Heberpenta L、DTwP-HepB-Hib、V-419、CVI-HBV-001、Tetrabhay、B型肝炎预防性疫苗(Advax Super D)、Hepatrol-07、GSK-223192A、ENGERIX重组型B型肝炎疫苗(肌肉内,Kangtai Biological Products)、重组型B型肝炎疫苗(汉逊多形酵母(Hansenual polymorpha yeast),肌肉内,Hualan Biological Engineering)、重组B型肝炎表面抗原疫苗、Bimmugen、Euforavac、Eutravac、anrix-DTaP-IPV-Hep B、HBAI-20、Infanrix-DTaP-IPV-Hep B-Hib、Pentabio Vaksin DTP-HB-Hib、Comvac 4、Twinrix、Euvax-B、Tritanrix HB、Infanrix Hep B、Comvax、DTP-Hib-HBV疫苗、DTP-HBV疫苗、YiTai、Heberbiovac HB、Trivac HB、GerVax、DTwP-Hep B-Hib疫苗、Bilive、Hepavax-Gene、SUPERVAX、Comvac5、Shanvac-B、Hebsulin、Recombivax HB、Revac B mcf、Revac B+、Fendrix、DTwP-HepB-Hib、DNA-001、Shan5、Shan6、rhHBsAG疫苗、HBI五价疫苗、LBVD、Infanrix HeXa及DTaP-rHB-Hib疫苗。
HBV治疗性疫苗的实例包括HBsAG-HBIG复合物、ARB-1598、Bio-Hep-B、NASVAC、abi-HB(静脉内)、ABX-203、Tetrabhay、GX-110E、GS-4774、肽疫苗(εPA-44)、Hepatrol-07、NASVAC(NASTERAP)、IMP-321、BEVAC、Revac B mcf、Revac B+、MGN-1333、KW-2、CVI-HBV-002、AltraHepB、VGX-6200、FP-02、FP-02.2、TG-1050、NU-500、HBVax、im/TriGrid/抗原疫苗、Mega-CD40L佐剂化疫苗、HepB-v、RG7944(INO-1800)、基于重组型VLP的治疗性疫苗(HBV感染,VLP Biotech)、AdTG-17909、AdTG-17910、AdTG-18202、ChronVac-B、TG-1050及LmHBV。
HBV DNA聚合酶抑制剂
HBV DNA聚合酶抑制剂的实例包括阿德福韦安卓西他宾反丁烯二酸替诺福韦双索酯替诺福韦埃拉酚胺、替诺福韦、替诺福韦双索酯、反丁烯二酸替诺福韦埃拉酚胺、半反丁烯二酸替诺福韦埃拉酚胺、替诺福韦迪皮夕(tenofovir dipivoxil)、反丁烯二酸替诺福韦迪皮夕、替诺福韦十八烷氧基乙酯、CMX-157、拜斯福韦(besifovir)、因提弗顺丁烯二酸因提弗、替比夫定(telbivudine)非洛西韦(filocilovir)、帕拉德福韦(pradefovir)、克来夫定(clevudine)、利巴韦林、拉米夫定迭氮膦(phosphazide)、泛昔洛韦(famciclovir)、弗索林(fusolin)、美他卡韦(metacavir)、SNC-019754、FMCA、AGX-1009、AR-II-04-26、HIP-1302、天冬胺酸替诺福韦双索酯、乳清酸替诺福韦双索酯及HS-10234。
免疫调节剂
免疫调节剂的实例包括瑞他立德、盐酸艾咪朵尔(imidol hydrochloride)、因加容(ingaron)、德玛韦、氯奎宁(羟基氯奎)、普留净、羟基脲、霉酚酸吗啉乙酯(MPA)及其酯衍生物霉酚酸吗啉乙酯(MMF)、JNJ-440、WF-10、AB-452、利巴韦林、IL-12、INO-9112、聚合物聚亚乙亚胺(PEI)、吉朋、VGV-1、MOR-22、CRV-431、JNJ-0535、TG-1050、ABI-H2158、BMS-936559、GS-9688、RO-7011785、RG-7854、AB-506、RO-6871765、AIC-649及IR-103。
Toll样受体(TLR)调节剂
TLR调节剂包括TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12及TLR13的调节剂。TLR3调节剂的实例包括瑞他立德、聚-ICLC、阿伯辛(Apoxxim)、IPH-33、MCT-465、MCT-475及ND-1.1。
TLR7调节剂的实例包括GS-9620、GSK-2245035、咪喹莫特、雷西莫特、DSR-6434、DSP-3025、IMO-4200、MCT-465、MEDI-9197、3M-051、SB-9922、3M-052、林托普(Limtop)、D、特拉莫德(telratolimod))、SP-0509、TMX-30X、TMX-202、RG-7863、RG-7795、LHC-165、RG-7854及US20100143301(Gilead Sciences)、US20110098248(Gilead Sciences)及US20090047249(Gilead Sciences)中所公开的化合物。
TLR8调节剂的实例包括莫托莫特、雷西莫特、3M-051、3M-052、MCT-465、IMO-4200、VTX-763、VTX-1463、GS-9688及以下中所公开的化合物:US20140045849(Janssen)、US20140073642(Janssen)、WO2014/056953(Janssen)、WO2014/076221(Janssen)、WO2014/128189(Janssen)、US20140350031(Janssen)、WO2014/023813(Janssen)、US20080234251(Array Biopharma)、US20080306050(Array Biopharma)、US20100029585(VentirxPharma)、US20110092485(Ventirx Pharma)、US20110118235(Ventirx Pharma)、US20120082658(Ventirx Pharma)、US20120219615(Ventirx Pharma)、US20140066432(Ventirx Pharma)、US20140088085(Ventirx Pharma)、US20140275167(NoviraTherapeutics)、US20130251673(Novira Therapeutics)、美国专利案第9670205号、US20160289229、美国专利申请案第15/692161号及美国专利申请案第15/692093号。
TLR9调节剂的实例包括BB-001、BB-006、CYT-003、IMO-2055、IMO-2125、IMO-3100、IMO-8400、IR-103、IMO-9200、阿托莫特(agatolimod)、DIMS-9054、DV-1079、DV-1179、AZD-1419、利福莫特(leftolimod)(MGN-1703)、利腾莫特(litenimod)及CYT-003-QbG10。
TLR7、TLR8及TLR9调节剂的实例包括以下中所公开的化合物:WO2017047769(Teika Seiyaku)、WO2015014815(Janssen)、WO2018045150(Gilead Sciences Inc)、WO2018045144(Gilead Sciences Inc)、WO2015162075(Roche)、WO2017034986(堪萨斯州大学)、WO2018095426(Jiangsu Hengrui Medicine Co Ltd)、WO2016091698(Roche)、WO2016075661(GlaxoSmithKline Biologicals)、WO2016180743(Roche)、WO2018089695(Dynavax Technologies)、WO2016055553(ROche)、WO2015168279(Novartis)、WO2016107536(Medshine Discovery)、WO2018086593(Livo(Shanghai)Pharmaceutical)、WO2017106607(Merck)、WO2017061532(Sumitomo Dainippon Pharma)、WO2016023511(ChiaTai Tianqing Pharmaceutical)、WO2017076346(Chia Tai Tianqing Pharmaceutical)、WO2017046112(ROche)、WO2018078149(Roche)、WO2017040233(3M Co)、WO2016141092(Gilead Sciences)、WO2018049089(BristolMyers Squibb)、WO2015057655(Eisai CoLtd)、WO2017001307(Roche)、WO2018005586(BristolMyers Squibb)、WO201704023(3MCo)、WO2017163264(科学与工业研究委员会(印度))、WO2018046460(GlaxoSmithKlineBiologicals)、WO2018047081(Novartis)、WO2016142250(Roche)、WO2015168269(Novartis)、WO201804163(Roche)、WO2018038877(3M Co)、WO2015057659(Eisai Co Ltd)、WO2017202704(Roche)、WO2018026620(BristolMyers Squibb)、WO2016029077(JanusBiotherapeutics)、WO201803143(Merck)、WO2016096778(Roche)、WO2017190669(ShanghaiDe Novo Pharmatech)、US09884866(明尼苏达州大学)、WO2017219931(SichuanKelunBiotech Biopharmaceutical)、WO2018002319(Janssen Sciences)、WO2017216054(Roche)、WO2017202703(Roche)、WO2017184735(IFM Therapeutics)、WO2017184746(IFMTherapeutics)、WO2015088045(Takeda Pharmaceutical)、WO2017038909(TakedaPharmaceutical)、WO2015095780(堪萨斯州大学)、WO2015023958(堪萨斯州大学)。
干扰素α受体配位体
干扰素α受体配位体的实例包括干扰素α-2b(INTRON)、聚乙二醇化干扰素α-2a聚乙二醇化干扰素α-1b、干扰素α1b维尔多纳(Veldona)、因氟拉度(Infradure)、罗飞龙-A(Roferon-A)、YPEG-干扰素α-2a(YPEG-rhIFNα-2a)、P-1101、艾尔吉隆(Algeron)、阿尔法隆(Alfarona)、因加容(干扰素γ)、rSIFN-co(重组型超级化合物干扰素)、Y聚乙二醇化干扰素α-2b(YPEG-rhIFNα-2b)、MOR-22、聚乙二醇化干扰素α-2b拜氟隆(Bioferon)、乐复能(Novaferon)、因木塔(Inmutag)(因氟隆(Inferon))、干扰素α-n1干扰素β-1a沙氟隆(Shaferon)、干扰素α-2b(Axxo)、阿法菲酮(Alfaferone)、干扰素α-2b(BioGenericPharma)、干扰素-α2(CJ)、拉氟隆(Laferonum)、VIPEG、BLAUFERON-A、BLAUFERON-B、因特玛斯(Intermax)α、瑞尔迪隆(Realdiron)、兰斯嗪(Lanstion)、匹伽氟隆(Pegaferon)、PDferon-B PDferon-B、干扰素α-2b(IFN,Laboratorios Bioprofarma)、α干扰素2b、卡尔氟隆(Kalferon)、匹格纳咯(Pegnano)、氟隆雪(Feronsure)、PegiHep、干扰素α2b(Zydus-Cadila)、干扰素α2a、Optipeg A、Realfa 2B、瑞力氟隆(Reliferon)、干扰素α-2b(Amega)、干扰素α-2b(Virchow)、ropeg干扰素α-2b、rHSA-IFNα-2a(重组型人类血清白蛋白干扰素α2a融合蛋白)、rHSA-IFNα2b、重组型人类干扰素α-(1b、2a、2b)、聚乙二醇化干扰素α-2b(Amega)、聚乙二醇化干扰素α-2a、里阿非隆-EC(Reaferon-EC)、普罗喹氟(Proquiferon)、优尼氟隆(Uniferon)、优瑞福(Urifron)、干扰素α-2b(Changchun Institute ofBiological Products)、安特氟隆(Anterferon)、山氟隆(Shanferon)、雷氟隆(Layfferon)、上生雷泰(Shang Sheng Lei Tai)、INTEFEN、SINOGEN、福康泰(Fukangtai)、匹格斯塔(Pegstat)、rHSA-IFNα-2b、SFR-9216及Interapo(Interapa)。
玻尿酸酶抑制剂
玻尿酸酶抑制剂的实例包括阿斯君默(astodrimer)。
B型肝炎表面抗原(HBsAg)抑制剂
HBsAg抑制剂的实例包括HBF-0259、PBHBV-001、PBHBV-2-15、PBHBV-2-1、REP-9AC、REP-9C、REP-9、REP-2139、REP-2139-Ca、REP-2165、REP-2055、REP-2163、REP-2165、REP-2053、REP-2031及REP-006及REP-9AC'。
HBsAg分泌抑制剂的实例包括BM601。
细胞毒性T淋巴细胞相关蛋白质4(ipi4)抑制剂
细胞毒性T淋巴细胞相关蛋白质4(ipi4)抑制剂的实例包括AGEN-2041、AGEN-1884、伊匹鲁密单抗(ipilumimab)、贝拉西普(belatacept)、PSI-001、PRS-010、ProbodymAb、曲美木单抗(tremelimumab)及JHL-1155。
亲环素抑制剂
亲环素抑制剂的实例包括CPI-431-32、EDP-494、OCB-030、SCY-635、NVP-015、NVP-018、NVP-019、STG-175,及US8513184(Gilead Sciences)、US20140030221(GileadSciences)、US20130344030(Gilead Sciences)及US20130344029(Gilead Sciences)中所公开的化合物。
HBV病毒进入抑制剂
HBV病毒进入抑制剂的实例包括米鲁德西B(Myrcludex B)。
靶向病毒mRNA的反义寡核苷酸
靶向病毒mRNA的反义寡核苷酸的实例包括ISIS-HBVRx、IONIS-HBVRx、IONIS-GSK6-LRx、GSK-3389404、RG-6004。
短干扰RNA(siRNA)及ddRNAi。
siRNA的实例包括TKM-HBV(TKM-HepB)、ALN-HBV、SR-008、HepB-nRNA,及ARC-520、ARC-521、ARB-1740、ARB-1467。
DNA引导RNA干扰(ddRNAi)的实例包括BB-HB-331。
核酸内切酶调节剂
核酸内切酶调节剂的实例包括PGN-514。
核糖核苷酸还原酶抑制剂
核糖核苷酸还原酶抑制剂的实例包括曲美多斯(Trimidox)。
HBV E抗原抑制剂
HBV E抗原抑制剂的实例包括汉黄芩素(wogonin)。
共价闭合环状DNA(cccDNA)抑制剂
cccDNA抑制剂的实例包括BSBI-25及CHR-101。
法尼醇X受体促效剂
法尼醇X受体促效剂的实例为诸如EYP-001、GS-9674、EDP-305、MET-409、曲匹氟索(Tropifexor)、AKN-083、RDX-023、BWD-100、LMB-763、INV-3、NTX-023-1、EP-024297及GS-8670。
HBV抗体
靶向B型肝炎病毒表面抗原的HBV抗体的实例包括GC-1102、XTL-17、XTL-19、KN-003、IV Hepabulin SN及完全人类单株抗体疗法(B型肝炎病毒感染,Humabs BioMed)。
包括单株抗体及多株抗体的HBV抗体的实例包括祖泰特(Zutectra)、上生甘迪(Shang Sheng Gan Di)、Uman Big(B型肝炎超免疫)、Omri-Hep-B、Nabi-HB、Hepatect CP、HepaGam B、易甘替(igantibe)、硫力瓦(Niuliva)、CT-P24、B型肝炎免疫球蛋白(静脉内,pH4,HBV感染,Shanghai RAAS Blood Products)及福韦普(Fovepta)(BT-088)。
完全人类单株抗体包括HBC-34。
CCR2趋化因子拮抗剂
CCR2趋化因子拮抗剂的实例包括丙帕锗(propagermanium)。
胸腺素促效剂
胸腺素促效剂的实例包括胸腺法新(Thymalfasin),重组型胸腺素α1(GeneScience)。
细胞因子
细胞因子的实例包括重组型IL-7、CYT-107、介白素-2(IL-2,Immunex)、重组型人类介白素-2(Shenzhen Neptunus)、IL-15、IL-21、IL-24及西莫介白素(celmoleukin)。
核蛋白调节剂
核蛋白调节剂可为HBV核心或衣壳蛋白抑制剂。核蛋白调节剂的实例包括GS-4882、AB-423、AT-130、GLS4、NVR-1221、NVR-3778、AL-3778、BAY41-4109、甲磺酸莫非赛定(morphothiadine mesilate)、ARB-168786、ARB-880、JNJ-379、RG-7907、HEC-72702、AB-506、ABI-H0731、JNJ-440、ABI-H2158及DVR-23。
衣壳抑制剂的实例包括以下中所公开的化合物:US20140275167(NoviraTherapeutics)、US20130251673(Novira Therapeutics)、US20140343032(Roche)、WO2014037480(Roche)、US20130267517(Roche)、WO2014131847(Janssen)、WO2014033176(Janssen)、WO2014033170(Janssen)、WO2014033167(Janssen)、WO2015/059212(Janssen)、WO2015118057(Janssen)、WO2015011281(Janssen)、WO2014184365(Janssen)、WO2014184350(Janssen)、WO2014161888(Janssen)、WO2013096744(Novira)、US20150225355(Novira)、US20140178337(Novira)、US20150315159(Novira)、US20150197533(Novira)、US20150274652(Novira)、US20150259324、(Novira)、US20150132258(Novira)、US9181288(Novira)、WO2014184350(Janssen)、WO2013144129(Roche)、WO2017198744(Roche)、US 20170334882(Novira)、US 20170334898(Roche)、WO2017202798(Roche)、WO2017214395(Enanta)、WO2018001944(Roche)、WO2018001952(Roche)、WO2018005881(Novira)、WO2018005883(Novira)、WO2018011100(Roche)、WO2018011160(Roche)、WO2018011162(Roche)、WO2018011163(Roche)、WO2018036941(Roche)、WO2018043747(Kyoto Univ)、US20180065929(Janssen)、WO2016168619(印第安纳大学)、WO2016195982(The Penn State Foundation)、WO2017001655(Janssen)、WO2017048950(Assembly Biosciences)、WO2017048954(Assembly Biosciences)、WO2017048962(Assembly Biosciences)、US20170121328(Novira)、US20170121329(Novira)。
转录抑制剂的实例包括以下中所公开的化合物:WO2017013046(Roche)、WO2017016960(Roche)、WO2017017042(Roche)、WO2017017043(Roche)、WO2017061466(Toyoma chemicals)、WO2016177655(Roche)、WO2016161268(Enanta)、WO2017001853(Redex Pharma)、WO2017211791(Roche)、WO2017216685(Novartis)、WO2017216686(Novartis)、WO2018019297(Ginkgo Pharma)、WO2018022282(Newave Pharma)、US20180030053(Novartis)、WO2018045911(Zhejiang Pharma)。
视黄酸诱导性基因1刺激剂
视黄酸诱导性基因1刺激剂的实例包括SB-9200、SB-40、SB-44、ORI-7246、ORI-9350、ORI-7537、ORI-9020、ORI-9198及ORI-7170、RGT-100。
NOD2刺激剂
NOD2刺激剂的实例包括SB-9200。
磷脂酰肌醇3-激酶(PI3K)抑制剂
PI3K抑制剂的实例包括艾德昔布、ACP-319、AZD-8186、AZD-8835、布帕昔布、CDZ-173、CLR-457、皮克立西、来那替尼、瑞戈替布、瑞戈替布钠、EN-3342、TGR-1202、艾培昔布、杜维昔布、IPI-549、UCB-5857、泰尼昔布、XL-765、吉达昔布、ME-401、VS-5584、考班昔布、乳清酸CAI、哌立福新、RG-7666、GSK-2636771、DS-7423、帕努昔布、GSK-2269557、GSK-2126458、CUDC-907、PQR-309、INCB-40093、皮拉昔布、BAY-1082439、甲磺酸普喹替尼、SAR-245409、AMG-319、RP-6530、ZSTK-474、MLN-1117、SF-1126、RV-1729、索诺昔布、LY-3023414、SAR-260301、TAK-117、HMPL-689、特纳昔布(tenalisib)、沃塔昔布(voxtalisib)及CLR-1401。
吲哚胺-2,3-二加氧酶(IDO)路径抑制剂
IDO抑制剂的实例包括艾帕斯塔(epacadostat)(INCB24360)、雷米诺他(resminostat)(4SC-201)、因多莫得(indoximod)、F-001287、SN-35837、NLG-919、GDC-0919、GBV-1028、GBV-1012、NKTR-218,及US20100015178(Incyte)、US2016137652(FlexusBiosciences、Inc.)、WO2014073738(Flexus Biosciences、Inc.)及WO2015188085(FlexusBiosciences、Inc.)中所公开的化合物。
PD-1抑制剂
PD-1抑制剂的实例包括赛咪单抗(cemiplimab)、纳武单抗(nivolumab)、派立珠单抗(pembrolizumab)、皮立珠单抗(pidilizumab)、BGB-108、STI-A1014、SHR-1210、PDR-001、PF-06801591、IBI-308、GB-226、STI-1110、JNJ-63723283、CA-170、德瓦鲁单抗(durvalumab)、阿特珠单抗(atezolizumab)及mDX-400、JS-001、坎立珠单抗(Camrelizumab)、斯迪利单抗(Sintilimab)、斯迪利单抗、缇勒珠单抗(tislelizumab)、BCD-100、BGB-A333、JNJ-63723283、GLS-010(WBP-3055)、CX-072、AGEN-2034、GNS-1480(表皮生长因子受体拮抗剂;计划性细胞死亡配位体1抑制剂)、CS-1001、M-7824(PD-L1/TGF-β双功能融合蛋白)、杰诺珠单抗(Genolimzumab)、BMS-936559。
PD-L1抑制剂
PD-L1抑制剂的实例包括阿特珠单抗、阿维鲁单抗(avelumab)、AMP-224、MEDI-0680、RG-7446、GX-P2、德瓦鲁单抗、KY-1003、KD-033、MSB-0010718C、TSR-042、ALN-PDL、STI-A1014、GS-4224、CX-072及BMS-936559。
PD-1抑制剂的实例包括以下中所公开的化合物:WO2017112730(Incyte Corp)、WO2017087777(Incyte Corp)、WO2017017624、WO2014151634(BristolMyers Squibb Co)、WO201317322(BristolMyers Squibb Co)、WO2018119286(Incyte Corp)、WO2018119266(Incyte Corp)、WO2018119263(Incyte Corp)、WO2018119236(Incyte Corp)、WO2018119221(Incyte Corp)、WO2018118848(BristolMyers Squibb Co)、WO20161266460(BristolMyers Squibb Co)、WO2017087678(BristolMyers Squibb Co)、WO2016149351(BristolMyers Squibb Co)、WO2015033299(Aurigene Discovery Technologies Ltd)、WO2015179615(Eisai Co Ltd;Eisai Research Institute)、WO2017066227(BristolMyersSquibb Co)、WO2016142886(Aurigene Discovery Technologies Ltd)、WO2016142852(Aurigene Discovery Technologies Ltd)、WO2016142835(Aurigene DiscoveryTechnologies Ltd;Individual)、WO2016142833(Aurigene Discovery TechnologiesLtd)、WO2018085750(BristolMyers Squibb Co)、WO2015033303(Aurigene DiscoveryTechnologies Ltd)、WO2017205464(Incyte Corp)、WO2016019232(3M Co;Individual;Texas A&M University System)、WO2015160641(BristolMyers Squibb Co)、WO2017079669(Incyte Corp)、WO2015033301(Aurigene Discovery Technologies Ltd)、WO2015034820(BristolMyers Squibb Co)、WO2018073754(Aurigene DiscoveryTechnologies Ltd)、WO2016077518(BristolMyers Squibb Co)、WO2016057624(BristolMyers Squibb Co)、WO2018044783(Incyte Corp)、WO2016100608(BristolMyersSquibb Co)、WO2016100285(BristolMyers Squibb Co)、WO2016039749(BristolMyersSquibb Co)、WO2015019284(Cambridge Enterprise Ltd)、WO2016142894(AurigeneDiscovery Technologies Ltd)、WO2015134605(BristolMyers Squibb Co)、WO2018051255(Aurigene Discovery Technologies Ltd)、WO2018051254(Aurigene DiscoveryTechnologies Ltd)、WO2017222976(Incyte Corp)、WO2017070089(Incyte Corp)、WO2018044963(BristolMyers Squibb Co)、WO2013144704(Aurigene DiscoveryTechnologies Ltd)、WO2018013789(Incyte Corp)、WO2017176608(BristolMyers SquibbCo)、WO2018009505(BristolMyers Squibb Co)、WO2011161699(Aurigene DiscoveryTechnologies Ltd)、WO2015119944(Incyte Corp;Merck Sharp & Dohme Corp)、WO2017192961(Incyte Corp)、WO2017106634(Incyte Corp)、WO2013132317(AurigeneDiscovery Technologies Ltd)、WO2012168944(Aurigene Discovery TechnologiesLtd)、WO2015036927(Aurigene Discovery Technologies Ltd)、WO2015044900(AurigeneDiscovery Technologies Ltd)、WO2018026971(Arising International)。
重组型胸腺素α-1
重组型胸腺素α-1的实例包括NL-004及聚乙二醇化胸腺素α-1。
布鲁顿氏酪胺酸激酶(BTK)抑制剂
BTK抑制剂的实例包括ABBV-105、阿卡拉布鲁替尼(acalabrutinib)(ACP-196)、ARQ-531、BMS-986142、达沙替尼(dasatinib)、依鲁替尼(ibrutinib)、GDC-0853、PRN-1008、SNS-062、ONO-4059、BGB-3111、ML-319、MSC-2364447、RDX-022、X-022、AC-058、RG-7845、司培替尼(spebrutinib)、TAS-5315、TP-0158、TP-4207、HM-71224、KBP-7536、M-2951、TAK-020、AC-0025及在US20140330015(Ono Pharmaceutical)、US20130079327(OnoPharmaceutical)及US20130217880(Ono Pharmaceutical)中所公开的化合物。
KDM抑制剂
KDM5抑制剂的实例包括以下中所公开的化合物:WO2016057924(Genentech/Constellation Pharmaceuticals)、US20140275092(Genentech/ConstellationPharmaceuticals)、US20140371195(Epitherapeutics)及US20140371214(Epitherapeutics)、US20160102096(Epitherapeutics)、US20140194469(Quanticel)、US20140171432、US20140213591(Quanticel)、US20160039808(Quanticel)、US20140275084(Quanticel)、WO2014164708(Quanticel)。
KDM1抑制剂的实例包括US9186337B2(Oryzon Genomics)中所公开的化合物、GSK-2879552及RG-6016。
STING促效剂
STING促效剂的实例包括SB-11285、AdVCA0848、STINGVAX及以下中所公开的化合物:WO 2018065360(Biolog Life Science Institute Forschungslabor undBiochemica-Vertrieb GmbH、Germany)、WO 2018009466(Aduro Biotech)、WO 2017186711(InvivoGen)、WO 2017161349(Immune Sensor)、WO 2017106740(Aduro Biotech)、US20170158724(Glaxo Smithkiline)、WO 2017075477(Aduro Biotech)、US 20170044206(Merck)、WO 2014179760(加利福尼亚大学)、WO2018098203(Janssn)、WO2018118665(Merck)、WO2018118664(Merck)、WO2018100558(Takeda)、WO2018067423(Merck)、WO2018060323(Boehringer)。
非核苷逆转录酶抑制剂(NNRTI)
NNRTI的实例包括以下中所公开的化合物:WO2018118826(Merck)、WO2018080903(Merck)、WO2018119013(Merck)、WO2017100108(Idenix)、WO2017027434(Merck)、WO2017007701(Merck)、WO2008005555(Gilead)。
HBV复制抑制剂
B型肝炎病毒复制抑制剂的实例包括异噻氟定(isothiafludine)、IQP-HBV、RM-5038及新甘帖(Xingantie)。
精胺酸酶抑制剂
精胺酸酶抑制剂的实例包括CB-1158、C-201及雷米诺他。
基因疗法及细胞疗法
基因疗法及细胞疗法包括用于使基因沉默的基因修饰;用于直接杀死经感染细胞的基因方法;经设计以将患者的大部分自身免疫系统替换以增强对经感染细胞的免疫反应或使患者的自身免疫系统活化以杀死经感染细胞或寻找且杀死经感染细胞的免疫细胞输注;用于修饰细胞活性以进一步改变针对感染的内源性免疫反应性的基因方法。
基因编辑剂
基因组编辑系统的实例包括CRISPR/Cas9系统、锌指核酸酶系统、TALEN系统、归巢核酸内切酶系统及大范围核酸酶系统;例如,经由靶向裂解进行的cccDNA消除,及改变B型肝炎病毒(HBV)病毒基因中的一或多者。改变(例如,基因剔除及/或阻断基因表现)PreC、C、X、PreSI、PreS2、S、P或SP基因指(1)降低或消除PreC、C、X、PreSI、PreS2、S、P或SP基因表现;(2)干扰前核心蛋白(Precore)、核心蛋白(Core)、X蛋白质、长表面蛋白质、中表面蛋白质、S蛋白质(亦称为HBs抗原及HBsAg)、聚合酶蛋白质及/或B型肝炎剪接蛋白质功能(HBe、HBc、HBx、PreS1、PreS2、S、Pol及/或HBSP);或(3)减少或消除HBe、HBc、HBx、LHBs、MHBs、SHBs、Pol及/或HBSP蛋白质的细胞内、血清及/或脑实质内含量。PreC、C、X、PreSI、PreS2、S、P及/或SP基因中的一或多个的基因表现阻断为通过靶向在HBV cccDNA及/或整合式HBV DNA内的基因来进行。
CAR-T细胞疗法
CAR T细胞疗法包括经工程改造以表现嵌合抗原受体(CAR)的免疫效应细胞的群体,其中CAR包含HBV抗原结合域。免疫效应细胞为T细胞或NK细胞。在一些实施例中,T细胞为CD4+T细胞、CD8+T细胞或其组合。细胞可为自体或同种异体的。
TCR-T细胞疗法
TCR T细胞疗法包括表现HBV特异性T细胞受体的T细胞。TCR-T细胞经工程改造以靶向经病毒感染细胞的表面上呈现的HBV衍生肽。在一些实施例中,T细胞表现HBV表面抗原(HBsAg)特异性TCR。针对HBV的治疗的TCR-T疗法的实例包括LTCR-H2-1。
在另一具体实施例中,本文所公开的化合物或其医药学上可接受的盐与以下组合:HBV DNA聚合酶抑制剂;一或两种选自由以下组成的群的额外治疗剂:免疫调节剂、TLR调节剂、HBsAg抑制剂、HBsAg分泌或组装抑制剂、HBV治疗性疫苗、HBV抗体(包括靶向B型肝炎病毒表面抗原的HBV抗体及双特异性抗体)及“抗体样”医疗性蛋白质(诸如Fab衍生物或TCR样抗体)、亲环蛋白抑制剂、视黄酸诱导性基因1刺激剂、RIG-I样受体刺激剂、PD-1抑制剂、PD-L1抑制剂、精胺酸酶抑制剂、PI3K抑制剂、IDO抑制剂及NOD2刺激剂;及一或两种选自由以下组成的群的额外治疗剂:HBV病毒进入抑制剂、NTCP抑制剂、HBx抑制剂、cccDNA抑制剂、靶向B型肝炎病毒表面抗原的HBV抗体、siRNA、miRNA基因治疗剂、sshRNA、KDM5抑制剂及核蛋白调节剂(HBV核心或衣壳蛋白调节剂)。
在另一具体实施例中,本文所公开的化合物或其医药学上可接受的盐与HBV DNA聚合酶抑制剂及至少一种选自由以下组成的群的第二额外治疗剂组合:免疫调节剂、TLR调节剂、HBsAg抑制剂、HBV治疗性疫苗、HBV抗体(包括靶向B型肝炎病毒表面抗原的HBV抗体)以及双特异性抗体及“抗体样”医疗性蛋白质(诸如Fab衍生物或TCR样抗体)、亲环蛋白抑制剂、视黄酸诱导性基因1刺激剂、RIG-I样受体刺激剂、PD-1抑制剂、PD-L1抑制剂、精胺酸酶抑制剂、PI3K抑制剂、IDO抑制剂及NOD2刺激剂。
在另一具体实施例中,本文所公开的化合物或其医药学上可接受的盐与HBV DNA聚合酶抑制剂及至少一种选自由以下组成的群的第二额外治疗剂组合:HBV病毒进入抑制剂、NTCP抑制剂、HBx抑制剂、cccDNA抑制剂、靶向B型肝炎病毒的表面抗原的HBV抗体、siRNA、miRNA基因治疗剂、sshRNA、KDM5抑制剂及核蛋白调节剂(HBV核心或衣壳蛋白抑制剂)。
在一特定实施例中,本文所公开的化合物或其医药学上可接受的盐与以下组合:化合物,诸如以下中所公开的化合物:美国公开案第2010/0143301号(Gilead Sciences)、美国公开案第2011/0098248号(Gilead Sciences)、美国公开案第2009/0047249号(GileadSciences)、美国专利第8722054号(Gilead Sciences)、美国公开案第2014/0045849号(Janssen)、美国公开案第2014/0073642号(Janssen)、WO2014/056953(Janssen)、WO2014/076221(Janssen)、WO2014/128189(Janssen)、美国公开案第2014/0350031号(Janssen)、WO2014/023813(Janssen)、美国公开案第2008/0234251号(Array Biopharma)、美国公开案第2008/0306050号(Array Biopharma)、美国公开案第2010/0029585号(Ventirx Pharma)、美国公开案第2011/0092485号(Ventirx Pharma)、US2011/0118235(Ventirx Pharma)、美国公开案第2012/0082658号(Ventirx Pharma)、美国公开案第2012/0219615号(VentirxPharma)、美国公开案第2014/0066432号(Ventirx Pharma)、美国公开案第2014/0088085号(Ventirx Pharma)、美国公开案第2014/0275167号(Novira Therapeutics)、美国公开案第2013/0251673号(Novira Therapeutics)、美国专利第8513184号(Gilead Sciences)、美国公开案第2014/0030221号(Gilead Sciences)、美国公开案第2013/0344030号(GileadSciences)、美国公开案第2013/0344029号(Gilead Sciences)、US20140275167(NoviraTherapeutics)、US20130251673(Novira Therapeutics),美国公开案第2014/0343032号(Roche)、WO2014037480(Roche)、美国公开案第2013/0267517号(Roche)、WO2014131847(Janssen)、WO2014033176(Janssen)、WO2014033170(Janssen)、WO2014033167(Janssen)、WO2015/059212(Janssen)、WO2015118057(Janssen)、WO2015011281(Janssen)、WO2014184365(Janssen)、WO2014184350(Janssen)、WO2014161888(Janssen)、WO2013096744(Novira)、US20150225355(Novira)、US20140178337(Novira)、US20150315159(Novira)、US20150197533(Novira)、US20150274652(Novira)、US20150259324、(Novira)、US20150132258(Novira)、US9181288(Novira)、WO2014184350(Janssen)、WO2013144129(Roche)、US20100015178(Incyte)、US2016137652(FlexusBiosciences、Inc.)、WO2014073738(Flexus Biosciences、Inc.)、WO2015188085(FlexusBiosciences、Inc.)、美国公开案第2014/0330015号(Ono Pharmaceutical)、美国公开案第2013/0079327号(Ono Pharmaceutical)、美国公开案第2013/0217880号(Onopharmaceutical)、WO2016057924(Genentech/Constellation Pharmaceuticals)、US20140275092(Genentech/Constellation Pharmaceuticals)、US20140371195(Epitherapeutics)及US20140371214(Epitherapeutics)、US20160102096(Epitherapeutics)、US20140194469(Quanticel)、US20140171432、US20140213591(Quanticel)、US20160039808(Quanticel)、US20140275084(Quanticel)、WO2014164708(Quanticel)、US9186337B2(Oryzon Genomics),及用于治疗HBV的其他药物及其组合。
癌症组合疗法
在一个实施例中,本发明化合物可与癌症治疗的其他治疗方法一起采用。优选地,涵盖具有化学治疗剂、激素、抗体、手术及/或辐射治疗的组合疗法。
在一些实施例中,其他抗癌疗法为手术及/或放射线疗法。
在一些实施例中,其他抗癌疗法为至少一种额外癌症药剂。
在一些实施例中,提供一种组合,其包含本发明化合物或其医药学上可接受的盐及至少一种其他癌症药剂。
在一些实施例中,提供一种用于疗法的组合,其包含本发明化合物或其医药学上可接受的盐及至少一种其他癌症药剂。
在一些实施例中,提供包含本发明化合物或其医药学上可接受的盐及至少一种癌症药剂的组合用于制造用于治疗癌症的药剂的用途。
其他癌症药物的实例包括:嵌入物质,诸如蒽环霉素(anthracycline)、小红莓(doxorubicin)、埃达霉素(idarubicin)、表柔比星(epirubicin)及道诺霉素(daunorubicin);拓朴异构酶抑制剂,诸如伊立替康(irinotecan)、拓朴替康(topotecan)、喜树碱(camptothecin)、片螺素D(lamellarin D)、依托泊苷(etoposide)、替尼泊苷(teniposide)、米托蒽醌(mitoxantrone)、安吖啶(amsacrine)、玫瑰树碱(ellipticines)及金黄三羧酸(aurintricarboxylic acid);亚硝基脲化合物,诸如卡莫司汀(carmustine)(BCNU)、洛莫司汀(lomustine)(CCNU)及链脲菌素(streptozocin);氮芥,诸如环磷酰胺、双氯乙基甲胺(mechlorethamine)、乌拉莫司汀(uramustine)、苯达莫司汀(bendamustine)、美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、马磷酰胺(mafosfamide)、曲洛磷胺(trofosfamid)及异环磷酰胺(ifosfamide);磺酸烷基酯,诸如白消安及曲奥舒凡(treosulfan);烷基化剂,诸如普卡巴嗪(procarbazin)、达喀尔巴嗪(dacarbazin)、替莫唑胺(temozolomid)及噻替派(thiotepa);铂类似物,诸如顺铂(cisplatin)、卡铂(carboplatin)、奈达铂(nedaplatin)、奥沙利铂(oxaliplatin)、赛特铂(satraplatin)及四硝酸三铂(triplatin tetranitrate);微管破坏药物,诸如长春碱(vinblastine)、秋水仙酰胺(colcemid)及诺考达唑(nocodazole);抗叶酸剂,诸如甲胺喋呤(methotrexate)、胺基喋呤(aminopterin)、二氯甲胺喋呤(dichloromethotrexat)、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)及普拉曲沙(pralatrexate):嘌呤类似物,诸如硫唑嘌呤(azathioprine)、巯基嘌呤(mercaptopurine)、硫鸟嘌呤(thioguanine)、氟达拉滨(fludarabine)、磷酸氟达拉宾、喷司他汀(pentostatin)及克拉屈滨(cladribine);嘧啶类似物,诸如5-氟尿嘧啶(fluorouracil)、氟尿苷(floxuridine)、阿糖胞苷(cytarabine)、6-氮尿嘧啶、吉西他滨(gemcitabine);类固醇,诸如吉西他津(gestagene)、安德罗津(androgene)、糖皮质激素(glucocorticoids)、地塞米松(dexamethasone)、泼尼龙(prednisolone)及泼尼松(prednisone);抗癌抗体,诸如单株抗体,例如阿仑单抗(alemtuzumab)、阿泊珠单抗(apolizumab)、西妥昔单抗(cetuximab)、依帕珠单抗(epratuzumab)、加利昔单抗(galiximab)、吉妥单抗(gemtuzumab)、伊派利单抗、拉贝珠单抗(labetuzumab)、帕尼单抗(panitumumab)、利妥昔单抗(rituximab)、曲妥珠单抗(trastuzumab)、尼妥珠单抗(nimotuzumab)、马帕木单抗(mapatumumab)、马妥珠单抗(matuzumab)、rhMab ICR62及帕妥珠单抗(pertuzumab)、放射性标记抗体及抗体-药物接合物;抗癌肽,诸如放射性标记肽及肽-药物接合物;及紫杉烷(taxane)及紫杉烷类似物,诸如太平洋紫杉醇(paclitaxel)及多西他赛(docetaxel)。
在某些实施例中,提供一种用于治疗或预防患有过度增殖性病症或癌症或具有罹患过度增殖性病症或癌症的风险的人类或动物的过度增殖性病症或癌症的方法,其包含向人类或动物施用治疗有效量的本发明化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、一或两种或一至三种)额外治疗剂的组合。在一个实施例中,提供一种用于治疗患有过度增殖性病症或癌症或具有罹患过度增殖性病症或癌症的风险的人类或动物的过度增殖性病症或癌症的方法,其包含向人类或动物施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、一或两种或一至三种)额外治疗剂的组合。
在某些实施例中,本发明提供一种治疗过度增殖性病症或癌症的方法,该方法包含向有需要的个体施用治疗有效量的本文所公开的化合物或其医药学上可接受的盐与治疗有效量的一或多种适用于治疗过度增殖性病症或癌症的额外治疗剂的组合。
本文所描述的化合物可与以下中的一或多者一起使用或组合:化学治疗剂、抗癌剂、抗血管生成剂、抗纤维化剂、免疫治疗剂、治疗性抗体、双特异性抗体及“抗体样”医疗性蛋白质(诸如 Fab衍生物)、抗体-药物接合物(ADC)、放射线治疗剂、抗肿瘤剂、抗增殖剂、溶瘤病毒、基因修饰剂或编辑剂(诸如CRISPR/Cas9、锌指核酸酶或合成核酸酶、TALEN)、CAR(嵌合抗原受体)T细胞免疫治疗剂、经工程改造的T细胞受体(TCR-T)或其任何组合。这种治疗剂可呈化合物、抗体、多肽或聚核苷酸的形式。在一个实施例中,本文提供一种产品,其包含用于同时、分开或依序用于疗法的呈组合制剂形式的本文所描述的化合物及额外治疗剂。
额外治疗剂的非限制性实例包括:阿贝尔森(Abelson)鼠类白血病病毒致癌基因同源物1基因(ABL,诸如ABL1)、乙酰基-CoA羧化酶(诸如ACC1/2)、活化CDC激酶(ACK,诸如ACK1)、腺苷脱胺酶、腺苷受体(诸如A2B、A2a、A3)、腺苷酸环化酶、ADP核糖基环化酶-1、促肾上腺皮质激素受体(ACTH)、气单胞菌溶素、AKT1基因、Alk-5蛋白激酶、碱性磷酸酶、α1肾上腺素受体、α2肾上腺素受体、α-酮戊二酸去氢酶(KGDH)、胺肽酶N、AMP活化蛋白激酶、多形性淋巴瘤激酶(ALK,诸如ALK1)、雄激素受体、血管生成素(诸如配位体-1、配位体-2)、血管收缩素原(AGT)基因、鼠类胸腺瘤病毒致癌基因同源物1(AKT)蛋白激酶(诸如AKT1、AKT2、AKT3)、载脂蛋白A-I(APOA1)基因、细胞凋亡诱导因子、细胞凋亡蛋白(诸如1、2)、细胞凋亡信号调节激酶(ASK,诸如ASK1)、精胺酸酶(I)、精胺酸脱亚胺酶、芳香酶、流星(Asteroid)同源物1(ASTE1)基因、共济失调毛细管扩张及Rad 3相关(ATR)丝胺酸/苏胺酸蛋白激酶、极光(Aurora)蛋白激酶(诸如1、2)、Axl酪胺酸激酶受体、含杆状病毒IAP重复序列5(BIRC5)基因、基础免疫球蛋白、B细胞淋巴瘤2(BCL2)基因、Bcl2结合组分3、Bcl2蛋白、BCL2L11基因、BCR(断点簇区)蛋白及基因、β肾上腺素受体、β-连环蛋白、B淋巴细胞抗原CD19、B淋巴细胞抗原CD20、B淋巴细胞细胞黏附分子、B淋巴细胞刺激剂配位体、骨形态生成蛋白-10配位体、骨形态生成蛋白-9配位体调节剂、短尾畸形蛋白、缓激肽受体、B-Raf原癌基因(BRAF)、Brc-Abl酪胺酸激酶、含溴域及外部域(BET)溴域蛋白(诸如BRD2、BRD3、BRD4)、布鲁顿氏酪胺酸激酶(BTK)、调钙蛋白、调钙蛋白依赖性蛋白激酶(CaMK,诸如CAMKII)、癌症睪丸抗原2、癌症睪丸抗原NY-ESO-1、癌症/睪丸抗原1B(CTAG1)基因、大麻受体(诸如CB1、CB2)、碳酸酐酶、酪蛋白激酶(CK,诸如CKI、CKII)、凋亡蛋白酶(诸如凋亡蛋白酶-3、凋亡蛋白酶-7、凋亡蛋白酶-9)、凋亡蛋白酶8细胞凋亡相关半胱胺酸肽酶CASP8-FADD样调节子、凋亡蛋白酶募集域蛋白-15、组织蛋白酶G、CCR5基因、CDK活化激酶(CAK)、检查点激酶(诸如CHK1、CHK2)、趋化因子(C-C基元)受体(诸如CCR2、CCR4、CCR5)、趋化因子((C-X-C基元)受体(诸如CXCR4、CXCR1及CXCR2)、趋化因子CC21配位体、胆囊收缩素CCK2受体、绒膜促性腺激素、c-套组(酪胺酸-蛋白激酶套组或CD117)、紧密连接蛋白(诸如6、18)、分化簇(CD),诸如CD4、CD27、CD29、CD30、CD33、CD37、CD40、CD40配位体受体、CD40配位体、CD40LG基因、CD44、CD45、CD47、CD49b、CD51、CD52、CD55、CD58、CD66e、CD70基因、CD74、CD79、CD79b、CD79B基因、CD80、CD95、CD99、CD117、CD122、CDw123、CD134、CDw137、CD158a、CD158b1、CD158b2、CD223、CD276抗原;群集素(CLU)基因、群集素、c-Met(肝细胞生长因子受体(HGFR))、补体C3、结缔组织生长因子、COP9信号体次单元5、CSF-1(群落刺激因子1受体)、CSF2基因、CTLA-4(细胞毒性T淋巴细胞蛋白4)受体、细胞周期素D1、细胞周期素G1、细胞周期素依赖性激酶(CDK,诸如CDK1、CDK1B、CDK2-9)、环加氧酶(诸如1、2)、CYP2B1基因、半胱胺酸棕榈酰基转移酶豪猪蛋白、细胞色素P450 11B2、细胞色素P450 17、细胞色素P450 17A1、细胞色素P450 2D6、细胞色素P450 3A4、细胞色素P450还原酶、细胞因子信号传导-1、细胞因子信号传导-3、细胞质异柠檬酸去氢酶、胞嘧啶脱胺酶、胞嘧啶DNA甲基转移酶、细胞毒性T淋巴细胞蛋白-4、DDR2基因、δ样蛋白配位体(诸如3、4)、脱氧核糖核酸酶、Dickkopf-1配位体、二氢叶酸还原酶(DHFR)、二氢嘧啶去氢酶、二肽基肽酶IV、盘状域受体(DDR,诸如DDR1)、DNA结合蛋白(诸如HU-β)、DNA依赖性蛋白激酶、DNA旋转酶、DNA甲基转移酶、DNA聚合酶(诸如α)、DNA引子酶、dUTP焦磷酸酶、L-多巴色素互变异构酶、棘皮动物微管样蛋白4、EGFR酪胺酸激酶受体、弹性蛋白酶、延长因子1α2、延长因子2、内皮因子、核酸内切酶、内质网素、内皮唾酸蛋白、内皮生长抑素、内皮素(诸如ET-A、ET-B)、zeste基因增强子同源物2(EZH2)、肝配蛋白(Ephrin)(EPH)酪胺酸激酶(诸如Epha3、Ephb4)、肝配蛋白B2配位体、表皮生长因子、表皮生长因子受体(EGFR)、表皮生长因子受体(EGFR)基因、后生因子、上皮细胞黏附分子(EpCAM)、Erb-b2(v-erb-b2禽类有核红血球白血病病毒致癌基因同源物2)酪胺酸激酶受体、Erb-b3酪胺酸激酶受体、Erb-b4酪胺酸激酶受体、E-选择蛋白、雌二醇17β去氢酶、雌激素受体(诸如α、β)、雌激素相关受体、真核转译始动因子5A(EIF5A)基因、输出蛋白1、胞外信号相关激酶(诸如1、2)、胞外信号调节激酶(ERK)、因子(诸如Xa、VIIa)、法尼醇X受体(FXR)、Fas配位体、脂肪酸合酶(FASN)、铁蛋白、FGF-2配位体、FGF-5配位体、纤维母细胞生长因子(FGF,诸如FGF1、FGF2、FGF4)、纤维结合蛋白、Fms相关酪胺酸激酶3(Flt3)、局部黏着斑激酶(FAK,诸如FAK2)、叶酸水解酶前列腺特异性膜抗原1(FOLH1)、叶酸受体(诸如α)、叶酸、叶酸转运体1、FYN酪胺酸激酶、成对碱性氨基酸切割酶(FURIN)、β-葡糖苷酸酶、半乳糖苷基转移酶、半乳糖凝集素-3、神经节苷脂GD2、糖皮质激素、糖皮质激素诱导的TNFR相关蛋白质GITR受体、麸胺酸羧肽酶II、麸酰胺酸酶、麸胱甘肽S-转移酶P、肝糖合成酶激酶(GSK,诸如3-β)、磷脂肌醇蛋白聚醣3(GPC3)、促性腺激素释放激素(GNRH)、颗粒球巨噬细胞群落刺激因子(GM-CSF)受体、颗粒球-群落刺激因子(GCSF)配位体、生长因子受体结合蛋白2(GRB2)、Grp78(78kDa葡萄糖调节蛋白)钙结合蛋白、分子伴随蛋白groEL2基因、热休克蛋白(诸如27、70、90α、β)、热休克蛋白基因、热稳定肠毒素受体、刺猬蛋白、肝素酶、肝细胞生长因子、HERV-HLTR相关蛋白质2、己醣激酶、组胺H2受体、组蛋白甲基转移酶(DOT1L)、组蛋白去乙酰基酶(HDAC,诸如1、2、3、6、10、11)、组蛋白H1、组蛋白H3、HLA第I类抗原(A-2α)、HLA第II类抗原、同源盒蛋白NANOG、HSPB1基因、人类白细胞抗原(HLA)、人类乳头状瘤病毒(诸如E6、E7)蛋白、玻尿酸、玻尿酸酶、低氧诱导性因子-1α(HIF1α)、压印母本表现转录物(H19)基因、促分裂原活化蛋白激酶激酶激酶激酶1(MAP4K1)、酪胺酸-蛋白激酶HCK、I-κ-B激酶(IKK,诸如IKKbe)、IL-1α、IL-1β、IL-12、IL-12基因、IL-15、IL-17、IL-2基因、IL-2受体α次单元、IL-2、IL-3受体、IL-4、IL-6、IL-7、IL-8、免疫球蛋白(诸如G、G1、G2、K、M)、免疫球蛋白Fc受体、免疫球蛋白γFc受体(诸如I、III、IIIA)、吲哚胺2,3-二加氧酶(IDO,诸如IDO1)、吲哚胺吡咯2,3-二加氧酶1抑制剂、胰岛素受体、胰岛素样生长因子(诸如1、2)、整合素α-4/β-1、整合素α-4/β-7、整合素α-5/β-1、整合素α-V/β-3、整合素α-V/β-5、整合素α-V/β-6、细胞间黏附分子1(ICAM-1)、干扰素(诸如α、α2、β、γ)、黑素瘤中不存在的干扰素诱导性蛋白2(AIM2)、I型干扰素受体、介白素1配位体、介白素13受体α2、介白素2配位体、介白素-1受体相关的激酶4(IRAK4)、介白素-2、介白素-29配位体、异柠檬酸去氢酶(诸如IDH1、IDH2)、杰纳斯激酶(JAK,诸如JAK1、JAK2)、Jun N端激酶、激肽释放酶相关肽酶3(KLK3)基因、杀手细胞Ig样受体、激酶插入域受体(KDR)、驱动蛋白样蛋白KIF11、基尔斯滕(Kirsten)大鼠肉瘤病毒致癌基因同源物(KRAS)基因、吻素(KiSS-1)受体、KIT基因、v-套组哈迪-朱克曼(Hardy-Zuckerman)4猫肉瘤病毒致癌基因同源物(KIT)酪胺酸激酶、乳铁传递蛋白、羊毛固醇-14去甲基酶、LDL受体相关蛋白质-1、白三烯A4水解酶、李斯特菌溶胞素、L-选择蛋白、促黄体生成激素受体、解离酶、淋巴细胞活化基因3蛋白(LAG-3)、淋巴细胞抗原75、淋巴细胞功能抗原-3受体、淋巴细胞特异性蛋白酪胺酸激酶(LCK)、淋巴细胞趋化因子、Lyn(Lck/Yes新颖型)酪胺酸激酶、离胺酸去甲基酶(诸如KDM1、KDM2、KDM4、KDM5、KDM6、A/B/C/D)、溶血磷脂酸-1受体、溶酶体相关膜蛋白家族(LAMP)基因、离胺酰氧化酶同源物2、离胺酰氧化酶蛋白(LOX)、离胺酰氧化酶样蛋白(LOXL,诸如LOXL2)、造血祖细胞激酶1(HPK1)、肝细胞生长因子受体(MET)基因、巨噬细胞群落刺激因子(MCSF)配位体、巨噬细胞迁移抑制性因子、MAGEC1基因、MAGEC2基因、主穹隆蛋白、MAPK活化蛋白激酶(诸如MK2)、Mas相关G蛋白偶合受体、基质金属蛋白酶(MMP,诸如MMP2、MMP9)、Mcl-1分化蛋白、Mdm2 p53结合蛋白、Mdm4蛋白、Melan-A(MART-1)黑素瘤抗原、黑素细胞蛋白Pmel 17、黑素细胞刺激性激素配位体、黑素瘤抗原家族A3(MAGEA3)基因、黑素瘤相关抗原(诸如1、2、3、6)、膜铜胺氧化酶、间皮素、MET酪胺酸激酶、代谢型麸胺酸受体1、金属还原酶STEAP1(前列腺六跨膜上皮抗原1)、转移抑素、甲硫胺酸胺肽酶-2、甲基转移酶、粒线体3酮脂酰CoA硫解酶、活化促分裂原蛋白激酶(MAPK)、促分裂原活化蛋白激酶(MEK,诸如MEK1、MEK2)、mTOR(雷帕霉素机制性目标(丝胺酸/苏胺酸激酶)、mTOR复合物(诸如1、2)、黏蛋白(诸如1、5A、16)、mut T同源物(MTH,诸如MTH1)、Myc原癌基因蛋白、骨髓细胞白血病1(MCL1)基因、富肉豆蔻酰基化丙胺酸蛋白激酶C受质(MARCKS)蛋白、NAD ADP核糖基转移酶、利钠肽受体C、神经细胞黏附分子1、神经激肽1(NK1)受体、神经激肽受体、神经纤毛蛋白2、NFκB活化蛋白、NIMA相关激酶9(NEK9)、氧化氮合酶、NK细胞受体、NK3受体、NKG2 A B活化NK受体、去甲肾上腺素转运体、Notch(诸如Notch-2受体、Notch-3受体、Notch-4受体)、核红细胞2相关因子2、核因子(NF)κB、核仁素、核仁磷酸蛋白、核仁磷酸蛋白多形性淋巴瘤激酶(NPM-ALK)、2侧氧基戊二酸酯去氢酶、2,5-寡腺苷酸合成酶、O-甲基鸟嘌呤DNA甲基转移酶、类鸦片受体(诸如δ)、鸟胺酸去羧酶、乳清酸磷酸核糖转移酶、孤儿核激素受体NR4A1、骨钙化素、破骨细胞分化因子、骨桥蛋白、OX-40(肿瘤坏死因子受体超家族成员4TNFRSF4,或CD134)受体、P3蛋白、p38激酶、p38 MAP激酶、p53肿瘤抑制蛋白、副甲状腺激素配位体、过氧化体增殖物活化受体(PPAR,诸如α、δ、γ)、P-醣蛋白(诸如1)、磷酸酶及张力蛋白同源物(PTEN)、磷脂酰肌醇3-激酶(PI3K)、磷酸肌醇-3激酶(PI3K,诸如α、δ、γ)、磷酸化酶激酶(PK)、PKN3基因、胎盘生长因子、血小板衍生生长因子(PDGF,诸如α、β)、血小板衍生生长因子(PDGF,诸如α、β)、多效性抗药性转运体、丛蛋白B1、PLK1基因、polo样激酶(PLK)、Polo样激酶1、聚ADP核糖聚合酶(PARP,诸如PARP1、2及3)、黑素瘤中优先表现的抗原(PRAME)基因、戊烯基结合蛋白(PrPB)、可能转录因子PML、孕酮受体、计划性细胞死亡1(PD-1)、计划性细胞死亡配位体1抑制剂(PD-L1)、saposin前体(PSAP)基因、前列腺素受体(EP4)、前列腺特异性抗原、前列腺酸磷酸酶、蛋白酶体、蛋白E7、蛋白法尼基转移酶、蛋白激酶(PK,诸如A、B、C)、蛋白酪胺酸激酶、蛋白酪胺酸磷酸酶β、原癌基因丝胺酸/苏胺酸-蛋白激酶(PIM,诸如PIM-1、PIM-2、PIM-3)、P-选择蛋白、嘌呤核苷磷酸化酶、嘌呤受体P2X配位体闸控离子通道7(P2X7)、丙酮酸去氢酶(PDH)、丙酮酸去氢酶激酶、丙酮酸激酶(PYK)、5-α-还原酶、Raf蛋白激酶(诸如1、B)、RAF1基因、Ras基因、Ras GTP酶、RET基因、Ret酪胺酸激酶受体、视网膜母细胞瘤相关蛋白质、视黄酸受体(诸如γ)、类视黄素X受体、Rheb(大脑中富集的Ras同源物)GTP酶、Rho(Ras同源物)相关蛋白激酶2、核糖核酸酶、核糖核苷酸还原酶(诸如M2次单元)、核糖体蛋白S6激酶、RNA聚合酶(诸如I、II)、Ron(来源于南特的受体(Recepteur d'OrigineNantais))酪胺酸激酶、ROS1(ROS原癌基因1,受体酪胺酸激酶)基因、Ros1酪胺酸激酶、Runt相关转录因子3、γ-分泌酶、S100钙结合蛋白A9、肌内质网钙ATP酶、第二粒线体衍生的凋亡蛋白酶活化子(SMAC)蛋白、分泌卷曲相关蛋白质-2、信号蛋白-4D、丝胺酸蛋白酶、丝胺酸/苏胺酸激酶(STK)、丝胺酸/苏胺酸-蛋白激酶(TBK,诸如TBK1)、信号转导及转录(STAT,诸如STAT-1、STAT-3、STAT-5)、信号传导淋巴细胞性活化分子(SLAM)家族成员7、前列腺六跨膜上皮抗原(STEAP)基因、SL细胞因子配位体、平滑(SMO)受体、碘化钠共转运体、磷酸钠共转运体2B、生长抑素受体(诸如1、2、3、4、5)、音猬因子蛋白、非七激酶子(Son of sevenless;SOS)、特异蛋白1(Sp1)转录因子、鞘磷脂合酶、神经鞘胺醇激酶(诸如1、2)、神经鞘胺醇-1-磷酸盐受体-1、脾酪胺酸激酶(SYK)、SRC基因、Src酪胺酸激酶、STAT3基因、类固醇硫酸酯酶、干扰素基因刺激因子(STING)受体、干扰素基因刺激蛋白、基质细胞衍生的因子1配位体、SUMO(小泛素样修饰因子)、超氧化物歧化酶、存活素蛋白、突触蛋白3、多配位体蛋白聚醣-1、共核蛋白α、T细胞表面醣蛋白CD28、tank结合激酶(TBK)、TATA盒结合蛋白相关因子RNA聚合酶I次单元B(TAF1B)基因、T细胞CD3醣蛋白ζ链、T细胞分化抗原CD6、含T细胞免疫球蛋白及黏蛋白域3(TIM-3)、T细胞表面醣蛋白CD8、Tec蛋白酪胺酸激酶、Tek酪胺酸激酶受体、端粒酶、端粒酶逆转录酶(TERT)基因、肌腱蛋白、TGFβ2配位体、血小板生成素受体、胸苷激酶、胸苷磷酸化酶、胸苷酸合酶、胸腺素(诸如α1)、甲状腺激素受体、促甲状腺激素受体、组织因子、TNF相关细胞凋亡诱导配位体、TNFR1相关死亡域蛋白、TNF相关细胞凋亡诱导性配位体(TRAIL)受体、TNFSF11基因、TNFSF9基因、toll样受体(TLR,诸如1-13)、拓朴异构酶(诸如I、II、III)、转录因子、转移酶、运铁蛋白、转型生长因子(TGF,诸如β)激酶、转型生长因子TGF-β受体激酶、转麸酰胺酸酶、移位相关蛋白质、跨膜醣蛋白NMB、Trop-2钙信号转导蛋白、滋胚层醣蛋白(TPBG)基因、滋胚层醣蛋白、肌旋蛋白受体激酶(Trk)受体(诸如TrkA、TrkB、TrkC)、色胺酸5-羟化酶、微管蛋白、肿瘤坏死因子(TNF,诸如α、β)、肿瘤坏死因子13C受体、肿瘤进展基因座2(TPL2)、肿瘤蛋白53(TP53)基因、肿瘤抑制因子候选物2(TUSC2)基因、酪胺酸酶、酪胺酸羟化酶、酪胺酸激酶(TK)、酪胺酸激酶受体、含免疫球蛋白样及EGF样域酪胺酸激酶(TIE)受体、酪胺酸蛋白激酶ABL1抑制剂、泛素、泛素羧基水解酶同工酶L5、泛素硫酯酶-14、泛素缀合酶E2I(UBE2I、UBC9)、尿素酶、尿激酶纤维蛋白溶酶原活化物、子宫球蛋白、香草精类VR1、血管细胞黏附蛋白1、血管内皮生长因子受体(VEGFR)、T细胞活化V域Ig抑制因子(VISTA)、VEGF-1受体、VEGF-2受体、VEGF-3受体、VEGF-A、VEGF-B、波形蛋白、维生素D3受体、原癌基因酪胺酸-蛋白激酶Yes、Wee-1蛋白激酶、威尔姆斯氏(Wilms')肿瘤抗原1、威尔姆斯氏肿瘤蛋白、X性联细胞凋亡抑制蛋白、锌指蛋白转录因子或其任何组合。
额外治疗剂的非限制性实例可由其作用机制分类成例如以下各组:
-抗代谢物/抗癌剂,诸如嘧啶类似物氟尿苷、卡培他滨(capecitabine)、阿糖胞苷、CPX-351(脂质体阿糖胞苷、道诺霉素)及TAS-118;
-嘌呤类似物、叶酸拮抗剂(诸如普拉曲沙)及相关抑制剂;
-抗增殖/抗有丝分裂剂,包括天然产物,诸如长春花生物碱(vinca alkaloid)(长春碱、长春新碱(vincristine))及微管瓦解剂,诸如紫杉烷(太平洋紫杉醇、多西他赛)、长春碱、诺考达唑、埃博霉素(epothilone)、长春瑞宾(vinorelbine)及表鬼臼毒素(epipodophyllotoxin)(依托泊苷、替尼泊苷);
-DNA损伤剂,诸如放射菌素、安吖啶、白消安、卡铂、苯丁酸氮芥、顺铂、环磷酰胺放线菌素D、道诺霉素、小红莓、表柔比星、异环磷酰胺、美法仑、二氯甲二乙胺、丝裂霉素C、米托蒽醌、亚硝基脲、丙卡巴肼、紫杉醇、克癌易(Taxotere)、替尼泊苷、依托泊苷及三亚乙基硫代磷酰胺;
-DNA低甲基化剂,诸如瓜达西汀(guadecitabine)(SGI-110)、ASTX727;
-抗生素,诸如放线菌素D、道诺霉素、小红莓、埃达霉素、蒽环霉素、米托蒽醌、博来霉素(bleomycin)、普卡霉素(plicamycin)(光神霉素(mithramycin));
-酶,诸如系统地代谢L-天冬酰胺且剥夺不具有合成其自身天冬酰胺的能力的细胞的L-天冬酰胺酶;
-抗血小板剂;
-靶向Bcl-2的DNAi寡核苷酸,诸如PNT2258;
-活化或再活化潜伏人类免疫缺乏病毒(HIV)的药剂,诸如帕比诺他及罗米地辛;
-泛Trk、ROS1及ALK抑制剂,诸如恩曲替尼(entrectinib)、TPX-0005;
-多形性淋巴瘤激酶(ALK)抑制剂,诸如艾乐替尼(alectinib)、色瑞替尼(ceritinib);
-抗增殖/抗有丝分裂烷基化剂,诸如氮芥环磷酰胺及类似物(美法仑、氯芥苯丁酸、六甲蜜胺(hexamethylmelamine)、噻替派)、烷基亚硝基脲(卡莫司汀)及类似物、链脲菌素及三氮烯(达喀尔巴嗪);
-抗增殖/抗有丝分裂抗代谢物,诸如叶酸类似物(甲胺喋呤);
-铂配位错合物(顺铂、奥沙利铂(oxiloplatinim)及卡铂)、丙卡巴肼、羟基脲、米托坦及胺麸精(aminoglutethimide);
-激素、激素类似物(雌激素、他莫昔芬(tamoxifen)、戈舍瑞林(goserelin)、比卡鲁胺(bicalutamide)及尼鲁胺(nilutamide))及芳香酶抑制剂(来曲唑(letrozole)及阿那曲唑(anastrozole));
-抗凝剂,诸如肝素、合成肝素盐及其他凝血酶的抑制剂;
-纤维蛋白溶解剂,诸如组织纤维蛋白溶酶原活化因子、链球菌激酶、尿激酶、阿司匹林(aspirin)、双嘧达莫(dipyridamole)、噻氯匹定(ticlopidine)及克罗匹多(clopidogrel);
-抗迁移剂;
-抗分泌剂(布瑞汀(breveldin));
-免疫抑制剂,诸如他克莫司(tacrolimus)、西罗莫司(sirolimus)、硫唑嘌呤及霉酚酸酯;
-生长因子抑制剂及血管内皮生长因子抑制剂;
-纤维母细胞生长因子抑制剂,诸如FPA14;
-抗VEGFR抗体,诸如IMC-3C5、GNR-011、塔尼比单抗(tanibirumab);
-抗VEGF/DDL4抗体,诸如ABT-165;
-抗钙黏素抗体,诸如HKT-288;
-抗CD70抗体,诸如AMG-172;含有抗富含白胺酸的重复物的15号(LRRC15)抗体,诸如ABBV-085.ARGX-110;
-血管收缩素受体阻断剂、氧化氮供体;
-反义寡核苷酸,诸如AEG35156、IONIS-KRAS-2.5Rx、EZN-3042、RX-0201、IONIS-AR-2.5Rx、BP-100(普瑞博森(prexigebersen))、IONIS-STAT3-2.5Rx;
-DNA干扰寡核苷酸,诸如PNT2258、AZD-9150;
-抗ANG-2抗体,诸如MEDI3617及LY3127804;
-抗ANG-1/ANG-2抗体,诸如AMG-780;
-抗MET/EGFR抗体,诸如LY3164530;
-抗EGFR抗体,诸如ABT-414、AMG-595、莱西单抗(necitumumab)、ABBV-221、马佛多坦德帕土西珠单抗(depatuxizumab mafodotin)(ABT-414)、托木妥昔单抗(tomuzotuximab)、ABT-806、维必施(vectibix)、莫多西单抗(modotuximab)、RM-1929;
-抗CSF1R抗体,诸如埃玛图单抗(emactuzumab)、LY3022855、AMG-820、FPA-008(卡比拉单抗(cabiralizumab));
-抗CD40抗体,诸如RG7876、SEA-CD40、APX-005M、ABBV-428;
-抗内皮因子抗体,诸如TRC105(卡妥昔单抗(carotuximab));
-抗CD45抗体,诸如131I-BC8(lomab-B);
-抗HER3抗体,诸如LJM716、GSK2849330;
-抗HER2抗体,诸如马妥昔单抗(margetuximab)、MEDI4276、BAT-8001;
-抗HLA-DR抗体,诸如IMMU-114;
-抗IL-3抗体,诸如JNJ-56022473;
-抗OX40抗体,诸如MEDI6469、MEDI6383、MEDI0562(塔沃西单抗(tavolixizumab))、MOXR0916、PF-04518600、RG-7888、GSK-3174998、INCAGN1949、BMS-986178、GBR-8383、ABBV-368;
-抗EphA3抗体,诸如KB-004;
-抗CD20抗体,诸如奥比珠单抗(obinutuzumab)、IGN-002;
-抗CD20/CD3抗体,诸如RG7828;
-抗CD37抗体,诸如AGS67E、奥特勒土珠单抗(otlertuzumab)(TRU-016);
-抗ENPP3抗体,诸如AGS-16C3F;
-抗FGFR-3抗体,诸如LY3076226、B-701;
-抗FGFR-2抗体,诸如GAL-F2;
-抗C5抗体,诸如ALXN-1210;
-抗CD27抗体,诸如瓦里木单抗(varlilumab)(CDX-1127);
-抗TROP-2抗体,诸如IMMU-132;
-抗NKG2a抗体,诸如莫纳珠单抗(monalizumab);
-抗VISTA抗体,诸如HMBD-002;
-抗PVRIG抗体,诸如COM-701;
-抗EpCAM抗体,诸如VB4-845;
-抗BCMA抗体,诸如GSK-2857916;
-抗CEA抗体,诸如RG-7813;
-抗分化簇3(CD3)抗体,诸如MGD015;
-抗叶酸受体α抗体,诸如IMGN853;
-MCL-1抑制剂,诸如AMG-176、S-64315及AZD-5991、483-LM、A-1210477、UMI-77、JKY-5-037;
-epha2抑制剂,诸如MM-310;
-抗LAG-3抗体,诸如瑞拉单抗(relatlimab)(ONO-4482)、LAG-525、MK-4280、REGN-3767;
-raf激酶/VEGFR抑制剂,诸如RAF-265;
-多蜂房蛋白(EED)抑制剂,诸如MAK683;
-抗纤维母细胞活化蛋白(FAP)/IL-2R抗体,诸如RG7461;
-抗纤维母细胞活化蛋白(FAP)/TRAIL-R2抗体,诸如RG7386;
-抗海藻糖基-GM1抗体,诸如BMS-986012;
-p38 MAP激酶抑制剂,诸如那力替尼(ralimetinib);
-PRMT1抑制剂,诸如MS203;
-神经鞘胺醇激酶2(SK2)抑制剂,诸如奥帕尼布(opaganib);
-FLT3-ITD抑制剂,诸如BCI-332;
-核红细胞2相关因子2刺激剂,诸如奥玛韦隆(omaveloxolone)(RTA-408);
-肌旋蛋白受体激酶(TRK)抑制剂,诸如LOXO-195、ONO-7579;
-抗ICOS抗体,诸如JTX-2011、GSK3359609;
-抗DR5(TRAIL2)抗体,诸如DS-8273;
-抗GD2抗体,诸如APN-301;
-抗介白素-17(IL-17)抗体,诸如CJM-112;
-抗碳酸酐酶IX抗体,诸如TX-250;
-抗CD38阿腾金(attenukine),诸如TAK573;
-抗黏蛋白1抗体,诸如加迪珠单抗(gatipotuzumab);
-黏蛋白1抑制剂,诸如GO-203-2C;
-MARCKS蛋白抑制剂,诸如BIO-11006;
-叶酸拮抗剂,诸如阿弗地林(arfolitixorin);
-半乳糖凝集素-3抑制剂,诸如GR-MD-02;
-磷酸化P68抑制剂,诸如RX-5902;
-CD95/TNF调节剂,诸如奥弗沃巴(ofranergene obadenovec);
-PI3K/Akt/mTOR抑制剂,诸如ABTL-0812;
-泛PIM激酶抑制剂,诸如INCB-053914;
-IL-12基因刺激剂,诸如EGEN-001、塔沃特德(tavokinogene telseplasmid);
-热休克蛋白HSP90抑制剂,诸如TAS-116、PEN-866;
-VEGF/HGF拮抗剂,诸如MP-0250;
-SYK酪胺酸激酶/FLT3酪胺酸激酶抑制剂,诸如TAK-659;
-SYK酪胺酸激酶/JAK酪胺酸激酶抑制剂,诸如ASN-002;
-FLT3酪胺酸激酶抑制剂,诸如FF-10101;
-FLT3酪胺酸激酶促效剂,诸如CDX-301;
-FLT3/MEK1抑制剂,诸如E-6201;
-IL-24拮抗剂,诸如AD-IL24;
-RIG-I促效剂,诸如RGT-100;
-气单胞菌溶素刺激剂,诸如托普欣(topsalysin);
-P-醣蛋白1抑制剂,诸如HM-30181A;
-CSF-1拮抗剂,诸如ARRY-382、BLZ-945;
-抗间皮素抗体,诸如SEL-403;
-胸苷激酶刺激剂,诸如阿格维克(aglatimagene besadenovec);
-Polo样激酶1抑制剂,诸如PCM-075;
-TLR-7促效剂,诸如TMX-101(咪喹莫特);
-NEDD8抑制剂,诸如佩沃塔特(pevonedistat)(MLN-4924)、TAS-4464;
-多效性路径调节剂,诸如阿多米德(avadomide)(CC-122);
-FoxM1抑制剂,诸如硫链丝菌;
-抗MUC1抗体,诸如Mab-AR-20.5;
-抗CD38抗体,诸如伊萨土西单抗(isatuximab)、MOR-202;
-UBA1抑制剂,诸如TAK-243;
-Src酪胺酸激酶抑制剂,诸如VAL-201;
-VDAC/HK抑制剂,诸如VDA-1102;
-BRAF/PI3K抑制剂,诸如ASN-003;
-Elf4a抑制剂,诸如罗西替布(rohinitib)、eFT226;
-TP53基因刺激剂,诸如ad-p53;
-PD-L1/EGFR抑制剂,诸如GNS-1480;
-视黄酸受体α(RARα)抑制剂,诸如SY-1425;
-SIRT3抑制剂,诸如YC8-02;
-基质细胞衍生的因子1配位体抑制剂,诸如聚乙二醇化奥拉希德(olaptesedpegol)(NOX-A12);
-IL-4受体调节剂,诸如MDNA-55;
-精胺酸酶-I刺激剂,诸如佩拉酶(pegzilarginase);
-拓朴异构酶I抑制剂/低氧诱导性因子-1α抑制剂,诸如PEG-SN38(聚乙二醇化非特坎(firtecan pegol));
-低氧诱导性因子-1α抑制剂,诸如PT-2977、PT-2385;
-CD122促效剂,诸如NKTR-214;
-p53肿瘤抑制蛋白刺激剂,诸如克维林(kevetrin);
-Mdm4/Mdm2 p53结合蛋白抑制剂,诸如ALRN-6924;
-纺锤体驱动蛋白(KSP)抑制剂,诸如非那西布(filanesib)(ARRY-520);
-CD80-fc融合蛋白抑制剂,诸如FPT-155;
-多发性内分泌腺瘤蛋白及混合系白血病(MLL)抑制剂,诸如KO-539;
-肝x受体促效剂,诸如RGX-104;
-IL-10促效剂,诸如AM-0010;
-EGFR/ErbB-2抑制剂,诸如瓦尼替尼(varlitinib);
-VEGFR/PDGFR抑制剂,诸如沃罗拉尼(vorolanib);
-IRAK4抑制剂,诸如CA-4948;
-抗TLR-2抗体,诸如OPN-305;
-调钙蛋白调节剂,诸如CBP-501;
-糖皮质激素受体拮抗剂,诸如瑞拉兰特(relacorilant)(CORT-125134);
-第二粒线体衍生的凋亡蛋白酶活化子(SMAC)蛋白抑制剂,诸如BI-891065;
-乳铁传递蛋白调节剂,诸如LTX-315;
-Kit酪胺酸激酶/PDGF受体α拮抗剂,诸如DCC-2618;
-KIT抑制剂,诸如PLX-9486;
-输出蛋白1抑制剂,诸如艾塔尼西(eltanexor);
-EGFR/ErbB2/Ephb4抑制剂,诸如特色瓦替尼(tesevatinib);
-抗CD33抗体,诸如IMGN-779;
-抗KMA抗体,诸如MDX-1097;
-抗TIM-3抗体,诸如TSR-022、LY-3321367、MBG-453;
-抗CD55抗体,诸如PAT-SC1;
-抗PSMA抗体,诸如ATL-101;
-抗CD100抗体,诸如VX-15;
-抗EPHA3抗体,诸如非巴珠单抗(fibatuzumab);
-抗Erbb抗体,诸如CDX-3379、HLX-02、塞里班土单抗(seribantumab);
-抗APRIL抗体,诸如BION-1301;
-抗Tigit抗体,诸如BMS-986207、RG-6058;
-CHST15基因抑制剂,诸如STNM-01;
-RAS抑制剂,诸如NEO-100;
-生长抑素受体拮抗剂,诸如OPS-201;
-CEBPA基因刺激剂,诸如MTL-501;
-DKK3基因调节剂,诸如MTG-201;
-p70s6k抑制剂,诸如MSC2363318A;
-甲硫胺酸胺基肽酶2(MetAP2)抑制剂,诸如M8891、APL-1202;
-精胺酸N-甲基转移酶5抑制剂,诸如GSK-3326595;
-抗计划性细胞死亡蛋白1(抗PD-1)抗体,诸如纳武单抗(BMS-936558、MDX-1106)、派立珠单抗(MK-3477、SCH-900475、拉立珠单抗(lambrolizumab),CAS登记号1374853-91-4)、皮立珠单抗、PF-06801591、BGB-A317、GLS-010(WBP-3055)、AK-103(HX-008)、MGA-012、BI-754091、REGN-2810(赛咪单抗(cemiplimab))、AGEN-2034、JS-001、JNJ-63723283、杰诺珠单抗(CBT-501)、LZM-009、BCD-100、LY-3300054、SHR-1201、BAT-1306,以及抗计划性死亡配位体1(抗PD-L1)抗体,诸如BMS-936559、阿特珠单抗(MPDL3280A)、德瓦鲁单抗(MEDI4736)、阿维鲁单抗、CK-301(MSB0010718C)、MEDI0680、CX-072、CBT-502、PDR-001(斯帕塔利单抗(spartalizumab))、TSR-042(多斯利单抗(dostarlimab))、JTX-4014、BGB-A333、SHR-1316、CS-1001(WBP-3155、KN-035、IBI-308、FAZ-053及MDX1105-01);
-PD-L1/VISTA拮抗剂,诸如CA-170;
-抗PD-L1/TGFβ抗体,诸如M7824;
-抗运铁蛋白抗体,诸如CX-2029;
-抗IL-8(介白素-8)抗体,诸如HuMax-Inflam;
-ATM(共济失调毛细管扩张)抑制剂,诸如AZD0156;
-CHK1抑制剂,诸如GDC-0575、LY2606368(普瑞替布(prexasertib))、SRA737、RG7741(CHK1/2);
-CXCR4拮抗剂,诸如BL-8040、LY2510924、布利沙福(burixafor)(TG-0054)、X4P-002、X4P-001-IO;
-EXH2抑制剂,诸如GSK2816126;
-HER2抑制剂,诸如来那替尼(neratinib)、图卡替尼(tucatinib)(ONT-380);
-KDM1抑制剂,诸如ORY-1001、IMG-7289、INCB-59872、GSK-2879552;
-CXCR2拮抗剂,诸如AZD-5069;
-GM-CSF抗体,诸如朗齐鲁单抗(lenzilumab);
-DNA依赖性蛋白激酶抑制剂,诸如MSC2490484A(尼瑟替布(nedisertib))、VX-984、AsiDNA(DT-01);
-蛋白激酶C(PKC)抑制剂,诸如LXS-196、索塔妥林(sotrastaurin);
-选择性雌激素受体共价拮抗剂(SERCA),诸如H3B-6545;
-选择性雄激素受体调节剂(SARM),诸如GTX-024、达诺米德(darolutamide);
-转型生长因子-β(TGF-β)激酶拮抗剂,诸如高伦替布(galunisertib);
-抗转型生长因子-β(TGF-β)抗体,诸如LY3022859、NIS793、XOMA 089;
-双特异性抗体,诸如MM-141(IGF-1/ErbB3)、MM-111(Erb2/Erb3)、JNJ-64052781(CD19/CD3)、PRS-343(CD-137/HER2)、AFM26(BCMA/CD16A)、JNJ-61186372(EGFR/cMET)、AMG-211(CEA/CD3)、RG7802(CEA/CD3)、ERY-974(CD3/GPC3)、范茨珠单抗(vancizumab)(血管生成素/VEGF)、PF-06671008(钙黏素/CD3)、AFM-13(CD16/CD30)、APVO436(CD123/CD3)、弗图珠单抗(flotetuzumab)(CD123/CD3)、REGN-1979(CD20/CD3)、MCLA-117(CD3/CLEC12A)、MCLA-128(HER2/HER3)、JNJ-0819、JNJ-7564(CD3/血红素)、AMG-757(DLL3-CD3)、MGD-013(PD-1/LAG-3)、AK-104(CTLA-4/PD-1)、AMG-330(CD33/CD3)、AMG-420(BCMA/CD3)、BI-836880(VEFG/ANG2)、JNJ-63709178(CD123/CD3)、MGD-007(CD3/gpA33)、MGD-009(CD3/B7H3);
-突变型选择性EGFR抑制剂,诸如PF-06747775、EGF816(纳扎替尼(nazartinib))、ASP8273、ACEA-0010、BI-1482694;
-抗GITR(糖皮质激素诱导的肿瘤坏死因子受体相关蛋白质)抗体,诸如MEDI1873、FPA-154、INCAGN-1876、TRX-518、BMS-986156、MK-1248、GWN-323;
-抗δ样蛋白配位体3(DDL3)抗体,诸如特西诺瓦单抗(rovalpituzumabtesirine);
-抗群集素抗体,诸如AB-16B5;
-抗肝配蛋白-A4(EFNA4)抗体,诸如PF-06647263;
-抗RANKL抗体,诸如德诺单抗(denosumab);
-抗间皮素抗体,诸如BMS-986148、抗MSLN-MMAE;
-抗磷酸钠共转运体2B(NaP2B)抗体,诸如立伐土珠单抗(lifastuzumab);
-抗c-Met抗体,诸如ABBV-399;
-腺苷A2A受体拮抗剂,诸如CPI-444、AZD-4635、普雷迪南(preladenant)、PBF-509;
-α-酮戊二酸去氢酶(KGDH)抑制剂,诸如CPI-613;
-XPO1抑制剂,诸如西林俄(selinexor)(KPT-330);
-异柠檬酸去氢酶2(IDH2)抑制剂,诸如艾那尼布(enasidenib)(AG-221);
-IDH1抑制剂,诸如AG-120及AG-881(IDH1及IDH2)、IDH-305、BAY-1436032;
-介白素-3受体(IL-3R)调节剂,诸如SL-401;
-精胺酸脱亚胺酶刺激剂,诸如聚乙二醇精胺酸酶(ADI-PEG-20);
-抗体-药物接合物,诸如MLN0264(抗GCC、鸟苷酸环化酶C)、T-DM1(曲妥珠单抗恩他新(trastuzumab emtansine),Kadcycla)、米拉珠单抗(milatuzumab)-小红莓(hCD74-DOX)、贝伦妥单抗维多汀(brentuximab vedotin)、DCDT2980S、保纳珠单抗维多汀(polatuzumab vedotin)、SGN-CD70A、SGN-CD19A、英妥珠单抗奥米欣(inotuzumabozogamicin)、洛瓦土珠单抗美登素(lorvotuzumab mertansine)、SAR3419、尹萨珠单抗戈维特坎(isactuzumab govitecan)、因福土单抗维多汀(enfortumab vedotin)(ASG-22ME)、ASG-15ME、DS-8201(曲妥珠单抗德鲁特坎(trastuzumab deruxtecan))、225Ac-林妥珠单抗(lintuzumab)、U3-1402、177Lu-特特拉克斯坦-特图玛(tetraxetan-tetuloma)、替索图单抗维多汀(tisotumab vedotin)、阿内图单抗拉夫坦辛(anetumab ravtansine)、CX-2009、SAR-566658、W-0101、保纳珠单抗维多汀、ABBV-085;
-紧密连接蛋白-18抑制剂,诸如克迪西单抗(claudiximab);
-β-连环蛋白抑制剂,诸如CWP-291;
-抗CD73抗体,诸如MEDI-9447(奥勒鲁单抗(oleclumab))、CPX-006、IPH-53、BMS-986179;
-CD73拮抗剂,诸如AB-680、PSB-12379、PSB-12441、PSB-12425;
-CD39/CD73拮抗剂,诸如PBF-1662;
-趋化因子受体2(CCR)抑制剂,诸如PF-04136309、CCX-872、BMS-813160(CCR2/CCR5);
-胸苷酸合酶抑制剂,诸如ONX-0801;
-ALK/ROS1抑制剂,诸如劳拉替尼(lorlatinib);
-端粒酶抑制剂,诸如G007-LK;
-Mdm2 p53-结合蛋白抑制剂,诸如CMG-097、HDM-201;
-c-PIM抑制剂,诸如PIM447;
-BRAF抑制剂,诸如达拉非尼(dabrafenib)、维罗非尼(vemurafenib)、恩拉菲尼(encorafenib)(LGX818)、PLX8394;
-细胞周期抑制剂,诸如司美替尼(selumetinib)(MEK1/2),及沙帕他滨(sapacitabine);
-AKT抑制剂,诸如MK-2206、伊巴替布(ipatasertib)、阿弗替布(afuresertib)、AZD5363及ARQ-092、卡瓦替布(capivasertib)、曲西立滨(triciribine);
-抗CTLA-4(细胞毒性T淋巴细胞蛋白-4)抑制剂,诸如曲美木单抗、AGEN-1884、BMS-986218;
-c-MET抑制剂,诸如AMG-337、萨沃替尼(savolitinib)、提瓦替尼(tivantinib)(ARQ-197)、卡普尼布(capmatinib)及特泼替尼(tepotinib)、ABT-700、AG213、AMG-208、JNJ-38877618(OMO-1)、默莱替尼(merestinib)、HQP-8361;
-c-Met/VEGFR抑制剂,诸如BMS-817378、TAS-115;
-c-Met/RON抑制剂,诸如BMS-777607;
-BRAF/EGFR抑制剂,诸如BGB-283;
-bcr/abl抑制剂,诸如瑞巴替尼(rebastinib)、阿西尼布(asciminib);
-MNK1/MNK2抑制剂,诸如eFT-508;
-mTOR抑制剂/细胞色素P450 3A4刺激剂,诸如TYME-88;
-离胺酸特异性去甲基酶-1(LSD1)抑制剂,诸如CC-90011;
-泛RAF抑制剂,诸如LY3009120、LXH254、TAK-580;
-Raf/MEK抑制剂,诸如RG7304;
-CSF1R/KIT及FLT3抑制剂,诸如派西尼布(pexidartinib)(PLX3397);
-激酶抑制剂,诸如凡德他尼(vandetanib);
-E选择蛋白拮抗剂,诸如GMI-1271;
-分化诱导剂,诸如维甲酸;
-表皮生长因子受体(EGFR)抑制剂,诸如奥希替尼(osimertinib)(AZD-9291);
-拓朴异构酶抑制剂,诸如小红莓、道诺霉素、放线菌素D、艾尼西德(eniposide)、表柔比星、依托泊苷、埃达霉素、伊立替康、米托蒽醌、匹蒽醌(pixantrone)、索布佐生(sobuzoxane)、拓朴替康、伊立替康、MM-398(脂质体伊立替康)、沃萨洛辛(vosaroxin)及GPX-150、阿多比欣(aldoxorubicin)、AR-67、玛韦替尼(mavelertinib)、AST-2818、阿维替尼(avitinib)(ACEA-0010)、伊洛福芬(irofulven)(MGI-114);
-皮质类固醇,诸如可的松(cortisone)、地塞米松、氢化可的松、甲基泼尼龙、泼尼松、泼尼龙;
-生长因子信号转导激酶抑制剂;
-核苷类似物,诸如DFP-10917;
-Axl抑制剂,诸如BGB-324(贝西替尼(bemcentinib))、SLC-0211;
-BET抑制剂,诸如INCB-054329、INCB057643、TEN-010、AZD-5153、ABT-767、BMS-986158、CC-90010、GSK525762(莫尼西布(molibresib))、NHWD-870、ODM-207、GSK-2820151、GSK-1210151A、ZBC246、ZBC260、ZEN3694、FT-1101、RG-6146、CC-90010、米韦西布(mivebresib)、BI-894999、PLX-2853、PLX-51107、CPI-0610、GS-5829;
-PARP抑制剂,诸如奥拉帕尼(olaparib)、芦卡帕尼(rucaparib)、维利帕尼(veliparib)、他拉柔帕尼(talazoparib)、ABT-767、BGB-290;
-麸酰胺酸酶抑制剂,诸如CB-839;
-疫苗,诸如肽疫苗TG-01(RAS)、GALE-301、GALE-302、莱尼哌吗-s(nelipepimut-s)、SurVaxM、DSP-7888、TPIV-200、PVX-410、VXL-100、DPX-E7、ISA-101、6MHP、OSE-2101、加利哌吗-S(galinpepimut-S)、SVN53-67/M57-KLH、IMU-131;细菌载体疫苗,诸如CRS-207/GVAX、阿利莫金非洛巴克(axalimogene filolisbac)(ADXS11-001);腺病毒载体疫苗,诸如那多拉金非拉维克(nadofaragene firadenovec);自体Gp96疫苗;树突状细胞疫苗,诸如CVactm、斯塔赛尔-T(stapuldencel-T)、艾他赛尔-T(eltrapuldencel-T)、SL-701、BSK01TM、洛卡赛尔-T(rocapuldencel-T)(AGS-003)、DCVAC、CVactm、斯塔赛尔-T、艾他赛尔-T、SL-701、BSK01TM、ADXS31-142;溶瘤疫苗,诸如塔里穆尼拉赫韦克(talimogenelaherparepvec)、派替莫金德瓦维克(pexastimogene devacirepvec)、GL-ONC1、MG1-MA3、小病毒H-1、ProstAtak、恩那希瑞(enadenotucirev)、MG1MA3、ASN-002(TG-1042);治疗性疫苗,诸如CVAC-301、CMP-001、PF-06753512、VBI-1901、TG-4010、ProscaVaxTM;肿瘤细胞疫苗,诸如(IND-14205)、Oncoquest-L疫苗;减毒活、重组型、血清型1脊髓灰白质炎病毒疫苗,诸如PVS-RIPO;阿达洛德西莫林(Adagloxad simolenin);MEDI-0457;DPV-001,一种肿瘤衍生的自噬小体增浓型癌症疫苗;RNA疫苗,诸如CV-9209、LV-305;DNA疫苗,诸如MEDI-0457、MVI-816、INO-5401;表现p53的经修饰的痘疮病毒安卡拉(vaccinia virus Ankara)疫苗,诸如MVA-p53;DPX-Survivac;BriaVaxTM;GI-6301;GI-6207;GI-4000;
-抗DLL4(δ样配位体4)抗体,诸如登西珠单抗(demcizumab);
-STAT-3抑制剂,诸如那帕布新(napabucasin)(BBI-608);
-ATP酶p97抑制剂,诸如CB-5083;
-平滑(SMO)受体抑制剂,诸如(索尼得吉(sonidegib),先前LDE-225)、LEQ506、维莫德吉(vismodegib)(GDC-0449)、BMS-833923、格拉吉伯(glasdegib)(PF-04449913)、LY2940680及伊曲康唑(itraconazole);
-干扰素α配位体调节剂,诸如干扰素α-2b、干扰素α-2a生物类似物(Biogenomics)、罗派干扰素(ropeginterferon)α-2b(AOP-2014、P-1101、PEG IFNα-2b)、穆提非隆(Multiferon)(阿法耐提(Alfanative),维拉金(Viragen))、干扰素α1b、罗飞龙-A(Roferon-A)(坎非隆(Canferon)、Ro-25-3036)、干扰素α-2a后续生物制剂(拜斯度(Biosidus))(因木塔,Inter 2A)、干扰素α-2b后继生物制剂(拜斯度-拜非隆、斯托非隆(Citopheron)、嘎纳帕(Ganapar),Beijing Kawin Technology-卡非隆(Kaferon))、阿法菲酮、聚乙二醇化干扰素α-1b、聚乙二醇化干扰素α-2b后续生物制剂(Amega)、重组型人类干扰素α-1b、重组型人类干扰素α-2a、重组型人类干扰素α-2b、维托珠单抗(veltuzumab)-IFNα2b结合物、Dynavax(SD-101)及干扰素α-n1(霍莫非隆(Humoferon)、SM-10500、苏米非隆(Sumiferon));
-干扰素γ配位体调节剂,诸如干扰素γ(OH-6000、奥格玛(Ogamma)100);
-IL-6受体调节剂,诸如托西利单抗(tocilizumab)、思图昔单抗(siltuximab)、AS-101(CB-06-02、IVX-Q-101);
-端粒酶调节剂,诸如特托莫肽(tertomotide)(GV-1001、HR-2802、Riavax)及伊美司他(imetelstat)(GRN-163、JNJ-63935937);
-DNA甲基转移酶抑制剂,诸如替莫唑胺(temozolomide)(CCRG-81045)、地西他滨(decitabine)、瓜达西汀(S-110、SGI-110)、KRX-0402、RX-3117、RRx-001及阿扎胞苷(azacitidine);
-DNA旋转酶抑制剂,诸如匹蒽醌及索布佐生;
-Bcl-2家族蛋白抑制剂,诸如ABT-263、维奈托克(venetoclax)(ABT-199)、ABT-737及AT-101;
-Notch抑制剂,诸如LY3039478(克尼斯塔(crenigacestat))、他瑞妥单抗(tarextumab)(抗Notch2/3)、BMS-906024;
-抗肌肉抑制素抑制剂,诸如兰多单抗(landogrozumab);
-玻尿酸酶刺激剂,诸如PEGPH-20;
-Wnt路径抑制剂,诸如SM-04755、PRI-724、WNT-974;
-γ-分泌酶抑制剂,诸如PF-03084014、MK-0752、RO-4929097;
-Grb-2(生长因子受体结合蛋白-2)抑制剂,诸如BP1001;
-TRAIL路径诱导性化合物,诸如ONC201、ABBV-621;
-局部黏着斑激酶抑制剂,诸如VS-4718、迪法替尼(defactinib)、GSK2256098;
-刺猬抑制剂,诸如萨瑞德吉(saridegib)、索尼得吉(LDE225)、格拉吉伯及维莫德吉;
-极光激酶抑制剂,诸如阿立塞替(alisertib)(MLN-8237)及AZD-2811、AMG-900、巴塞替尼(barasertib)、ENMD-2076;
-HSPB1调节剂(热休克蛋白27,HSP27),诸如溴夫定(brivudine)、阿帕托森(apatorsen);
-ATR抑制剂,诸如BAY-937、AZD6738、AZD6783、VX-803、VX-970(贝佐替布(berzosertib))及VX-970;
-mTOR抑制剂,诸如赛泮替布(sapanisertib)及维塞替布(vistusertib)(AZD2014)、ME-344;
-mTOR/PI3K抑制剂,诸如吉达力丝、GSK2141795、奥米力丝(omipalisib)、RG6114;
-Hsp90抑制剂,诸如AUY922、奥那勒斯(onalespib)(AT13387)、SNX-2112、SNX5422;
-鼠类双重微小(mdm2)致癌基因抑制剂,诸如DS-3032b、RG7775、AMG-232、HDM201及伊达努素(idasanutlin)(RG7388);
-CD137促效剂,诸如乌瑞鲁单抗(urelumab)、乌图木单抗(utomilumab)(PF-05082566);
-STING促效剂,诸如ADU-S100(MIW-815)、SB-11285、MK-1454、SR-8291、AdVCA0848、GSK-532、SYN-STING、MSA-1、SR-8291;
-FGFR抑制剂,诸如FGF-401、INCB-054828、BAY-1163877、AZD4547、JNJ-42756493、LY2874455、Debio-1347;
-脂肪酸合酶(FASN)抑制剂,诸如TVB-2640;
-抗KIR单株抗体,诸如利瑞路单抗(lirilumab)(IPH-2102)、IPH-4102;
-抗原CD19抑制剂,诸如MOR208、MEDI-551、AFM-11、因厄比利珠单抗(inebilizumab);
-CD44结合子,诸如A6;
-蛋白质磷酸酶2A(PP2A)抑制剂,诸如LB-100;
-CYP17抑制剂,诸如西维诺尼(seviteronel)(VT-464)、ASN-001、ODM-204、CFG920、乙酸阿比特龙(abiraterone acetate);
-RXR促效剂,诸如IRX4204;
-刺猬/平滑(hh/Smo)拮抗剂,诸如塔拉吉伯(taladegib)、帕替吉伯(patidegib);
-补体C3调节剂,诸如因普拉姆PGG(Imprime PGG);
-IL-15促效剂,诸如ALT-803、NKTR-255及hetIL-15;
-EZH2(zeste基因增强子同源物2)抑制剂,诸如塔泽斯塔(tazemetostat)、CPI-1205、GSK-2816126;
-溶瘤病毒,诸如派拉瑞普(pelareorep)、CG-0070、MV-NIS疗法、HSV-1716、DS-1647、VCN-01、ONCOS-102、TBI-1401、塔沙图瑞(tasadenoturev)(DNX-2401)、沃西金阿米维克(vocimagene amiretrorepvec)、RP-1、CVA21、Celyvir、LOAd-703、OBP-301;
-DOT1L(组蛋白甲基转移酶)抑制剂,诸如皮诺斯塔(pinometostat)(EPZ-5676);
-毒素,诸如霍乱毒素(Cholera toxin)、蓖麻毒素、假单胞菌外毒素(Pseudomonasexotoxin)、百日咳博特氏菌(Bordetella pertussis)腺苷酸环化酶毒素、白喉毒素及凋亡蛋白酶活化剂;
-DNA质体,诸如BC-819;
-PLK 1、2及3的PLK抑制剂,诸如伏拉塞替(volasertib)(PLK1);
-WEE1抑制剂,诸如AZD1775(阿达替布(adavosertib));
-Rho激酶(ROCK)抑制剂,诸如AT13148、KD025;
-ERK抑制剂,诸如GDC-0994、LY3214996、MK-8353;
-IAP抑制剂,诸如ASTX660、debio-1143、比林纳潘特、APG-1387、LCL-161;
-RNA聚合酶抑制剂,诸如鲁尼特丁(lurbinectedin)(PM-1183)、CX-5461;
-微管蛋白抑制剂,诸如PM-184、BAL-101553(利沙布尔(lisavanbulin))、OXI-4503、弗拉帕欣(fluorapacin)(AC-0001)及普拉布尔(plinabulin);
-Toll样受体4(TL4)促效剂,诸如G100、GSK1795091及PEPA-10;
-延长因子1α2抑制剂,诸如普替德新(plitidepsin);
-CD95抑制剂,诸如APG-101、APO-010、阿苏赛普(asunercept);
-WT1抑制剂,诸如DSP-7888;
-剪接因子3B次单元1(SF3B1)抑制剂,诸如H3B-8800;
-PDGFRα/KIT突变体特异性抑制剂,诸如BLU-285;
-SHP-2抑制剂,诸如TNO155(SHP-099)、RMC-4550;及
-类视黄素Z受体γ(RORγ)促效剂,诸如LYC-55716。
在一些实施例中,本文提供治疗或预防患有过度增殖性病症或癌症或具有罹患过度增殖性病症或癌症的风险的人类或动物的过度增殖性病症或癌症的方法,其包含向人类或动物施用治疗有效量的本发明化合物或其医药学上可接受的盐与治疗有效量的一或多种(例如,一种、两种、三种、一种或两种或一至三种)选自由以下组成的群的额外治疗剂的组合:细胞凋亡信号调节激酶(ASK)抑制剂;布鲁顿氏酪胺酸激酶(BTK)抑制剂;分化簇47(CD47)抑制剂;周期素依赖性激酶(CDK)抑制剂;盘状域受体(DDR)抑制剂;组蛋白去乙酰基酶(HDAC)抑制剂;吲哚胺-吡咯-2,3-二加氧酶(IDO1)抑制剂;杰纳斯激酶(JAK)抑制剂;离胺酰氧化酶样蛋白(LOXL)抑制剂;基质金属蛋白酶(MMP)抑制剂;促分裂原活化蛋白激酶(MEK)抑制剂;磷脂酰肌醇3-激酶(PI3K)抑制剂;脾酪胺酸激酶(SYK)抑制剂;toll样受体8(TLR8)抑制剂;toll样受体9(TLR9)抑制剂;酪胺酸激酶抑制剂(TKI)及其任何组合或其医药学上可接受的盐。非限制性实例包括:
-细胞凋亡信号调节激酶(ASK)抑制剂:ASK抑制剂包括ASK1抑制剂。ASK1抑制剂的实例包括但不限于WO 2011/008709(Gilead Sciences)及WO 2013/112741(GileadSciences)中所描述的抑制剂;
-布鲁顿氏酪胺酸激酶(BTK)抑制剂:BTK抑制剂的实例包括但不限于(S)-6-胺基-9-(1-(丁-2-炔酰基)吡咯啶-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮、阿卡拉布鲁替尼(ACP-196)、BGB-3111、CB988、HM71224、依鲁替尼、M-2951(伊沃替尼(evobrutinib))、M7583、替拉替尼(tirabrutinib)(ONO-4059)、PRN-1008、司培替尼(CC-292)、TAK-020、维卡替尼(vecabrutinib)、ARQ-531、SHR-1459、DTRMWXHS-12、TAS-5315;
-分化簇47(CD47)抑制剂:CD47抑制剂的实例包括但不限于抗CD47 mAb(Vx-1004)、抗人类CD47 mAb(CNTO-7108)、CC-90002、CC-90002-ST-001、人类化抗CD47抗体(Hu5F9-G4)、NI-1701、NI-1801、RCT-1938及TTI-621;
-细胞周期素依赖性激酶(CDK)抑制剂:CDK抑制剂包括CDK1、2、3、4、6、7及9的抑制剂,诸如阿贝力布(abemaciclib)、阿昔迪布(alvocidib)HMR-1275、夫拉平度(flavopiridol))、AT-7519、戴那西里(dinaciclib)、艾博兰斯(ibrance)、FLX-925、LEE001、帕泊昔布(palbociclib)、利伯西利(ribociclib)、瑞戈替布、西林俄、UCN-01、SY1365、CT-7001、SY-1365、G1T38、米西西尼(milciclib)、曲拉西利(trilaciclib)及TG-02;
-盘状域受体(DDR)抑制剂:DDR抑制剂包括DDR1及/或DDR2的抑制剂。DDR抑制剂的实例包括(但不限于)WO 2014/047624(Gilead Sciences)、US 2009-0142345(TakedaPharmaceutical)、US 2011-0287011(Oncomed Pharmaceuticals)、WO 2013/027802(Chugai Pharmaceutical)及WO 2013/034933(Imperial Innovations)中所公开的抑制剂;
-组蛋白去乙酰基酶(HDAC)抑制剂:HDAC抑制剂的实例包括但不限于阿贝司他(abexinostat)、ACY-241、AR-42、BEBT-908、贝林诺他(belinostat)、CKD-581、CS-055(HBI-8000)、CUDC-907(非米斯他(fimepinostat))、恩替诺特(entinostat)、吉韦诺他(givinostat)、莫塞诺他(mocetinostat)、帕比诺他、普拉诺他(pracinostat)、奎西诺他(quisinostat)(JNJ-26481585)、雷米诺他、瑞科诺他(ricolinostat)、SHP-141、丙戊酸(VAL-001)、伏立诺他、替诺斯汀(tinostamustine)、雷米斯特(remetinostat)、恩替诺特;
-吲哚胺-吡咯-2,3-二加氧酶(IDO1)抑制剂:IDO1抑制剂的实例包括但不限于BLV-0801、艾帕斯塔、F-001287、GBV-1012、GBV-1028、GDC-0919、因多莫得、NKTR-218、基于NLG-919的疫苗、PF-06840003、哌喃并萘醌衍生物(SN-35837)、雷米诺他、SBLK-200802、BMS-986205及shIDO-ST、EOS-200271、KHK-2455、LY-3381916;
-杰纳斯激酶(JAK)抑制剂:JAK抑制剂抑制JAK1、JAK2及/或JAK3。JAK抑制剂的实例包括(但不限于)AT9283、AZD1480、巴瑞替尼(baricitinib)、BMS-911543、非达替尼(fedratinib)、非戈替尼(filgotinib)(GLPG0634)、甘多替尼(gandotinib)(LY2784544)、INCB039110、来他替尼(lestaurtinib)、莫罗替尼(momelotinib)(CYT0387)、NS-018、帕瑞替尼(pacritinib)(SB1518)、皮非替尼(peficitinib)(ASP015K)、卢佐替尼(ruxolitinib)、托法替尼(tofacitinib)(先前塔索替尼(tasocitinib))、INCB052793及XL019;
-离胺酰氧化酶样蛋白(LOXL)抑制剂:LOXL抑制剂包括LOXL1、LOXL2、LOXL3、LOXL4及/或LOXL5的抑制剂。LOXL抑制剂的实例包括但不限于WO2009/017833(ArrestoBiosciences)中所描述的抗体。LOXL2抑制剂的实例包括但不限于WO 2009/017833(Arresto Biosciences)、WO 2009/035791(Arresto Biosciences)及WO 2011/097513(Gilead Biologics)中所描述的抗体;
-基质金属蛋白酶(MMP)抑制剂:MMP抑制剂包括MMP1至MMP10的抑制剂。MMP9抑制剂的实例包括但不限于马立马司他(marimastat)(BB-2516)、西马司他(cipemastat)(Ro32-3555)、GS-5745(安德西单抗(andecaliximab))及WO2012/027721(Gilead Biologics)中描述的抑制剂;
-促分裂原活化蛋白激酶(MEK)抑制剂:MEK抑制剂包括安奎诺尔(antroquinonol)、毕尼替尼(binimetinib)、考比替尼(cobimetinib)(GDC-0973、XL-518)、MT-144、司美替尼(AZD6244)、索拉非尼(sorafenib)、曲美替尼(trametinib)(GSK1120212)、阿瑟替布(uprosertib)+曲美替尼、PD-0325901、皮马瑟替(pimasertib)、LTT462、AS703988、CC-90003、瑞法美替尼(refametinib);
-磷脂酰肌醇3-激酶(PI3K)抑制剂:PI3K抑制剂包括PI3Kγ、PI3Kδ、PI3Kβ、PI3Kα及/或泛PI3K的抑制剂。PI3K抑制剂的实例包括但不限于ACP-319、AEZA-129、AMG-319、AS252424、AZD8186、BAY 10824391、BEZ235、布帕昔布(BKM120)、BYL719(艾培昔布)、CH5132799、考班昔布(BAY 80-6946)、杜维昔布、GDC-0032、GDC-0077、GDC-0941、GDC-0980、GSK2636771、GSK2269557、艾德斯布INCB50465、IPI-145、IPI-443、IPI-549、KAR4141、LY294002、LY3023414、MLN1117、OXY111A、PA799、PX-866、RG7604、瑞戈替布、RP5090、RP6530、SRX3177、泰尼西布、TG100115、TGR-1202(温布昔布(umbralisib))、TGX221、WX-037、X-339、X-414、XL147(SAR245408)、XL499、XL756、渥曼青霉素(wortmannin)、ZSTK474以及WO 2005/113556(ICOS)、WO 2013/052699(GileadCalistoga)、WO 2013/116562(Gilead Calistoga)、WO 2014/100765(Gilead Calistoga)、WO 2014/100767(Gilead Calistoga)及WO 2014/201409(Gilead Sciences)中所描述的化合物;
-脾酪胺酸激酶(SYK)抑制剂:SYK抑制剂的实例包括但不限于6-(1H-吲唑-6-基)-N-(4-N-吗啉基苯基)咪唑并[1,2-a]吡嗪-8-胺、BAY-61-3606、瑟杜替尼(cerdulatinib)(PRT-062607)、恩妥替尼(entospletinib)、福他替尼(fostamatinib)(R788)、HMPL-523、NVP-QAB 205 AA、R112,R343、塔马替尼(tamatinib)(R406)及US 8450321(GileadConnecticut)中所描述的SYK抑制剂及U.S.2015/0175616中所描述的SYK抑制剂;
-Toll样受体8(TLR8)抑制剂:TLR8抑制剂的实例包括但不限于E-6887、IMO-4200、IMO-8400、IMO-9200、MCT-465、MEDI-9197、莫托莫特、雷西莫特、VTX-1463及VTX-763;
-Toll样受体9(TLR9)抑制剂:TLR9抑制剂的实例包括但不限于AST-008、IMO-2055、IMO-2125、勒菲妥莫特(lefitolimod)、利腾莫特、MGN-1601及PUL-042;及
-酪胺酸激酶抑制剂(TKI):TKI可靶向表皮生长因子受体(EGFR)以及纤维母细胞生长因子(FGF)、血小板衍生生长因子(PDGF)及血管内皮生长因子(VEGF)的受体。TKI的实例包括但不限于阿法替尼(afatinib)、ARQ-087(德赞替尼(derazantinib))、asp5878、AZD3759、AZD4547、伯舒替尼(bosutinib)、布加替尼(brigatinib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、克诺拉尼(crenolanib)、达可替尼(dacomitinib)、达沙替尼、多韦替尼(dovitinib)、E-6201、厄达替尼(erdafitinib)、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、吉列替尼(gilteritinib)(ASP-2215)、FP-1039、HM61713、埃克替尼(icotinib)、伊马替尼(imatinib)、KX2-391(Src)、拉帕替尼(lapatinib)、来他替尼、乐伐替尼(lenvatinib)、米哚妥林(midostaurin)、尼达尼布(nintedanib)、ODM-203、奥希替尼(AZD-9291)、普纳替尼(ponatinib)、波齐奥替尼(poziotinib)、喹杂替尼(quizartinib)、拉多替尼(radotinib)、罗西替尼(rociletinib)、索凡替尼(sulfatinib)(HMPL-012)、舒尼替尼(sunitinib)、替沃尼布(tivoanib)及TH-4000、MEDI-575(抗PDGFR抗体)。
如本文所用,术语“化学治疗剂”或“化学治疗”(或在用化学治疗剂治疗的情况下的“化学疗法”)意欲涵盖适用于治疗癌症的任何非蛋白质(亦即,非肽)化合物。化学治疗剂的实例包括但不限于:烷基化剂,诸如噻替派及环磷酰胺磺酸烷基酯,诸如白消安、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,诸如苯佐替派(benzodepa)、卡波醌(carboquone)、美妥替派(meturedepa)及乌瑞替派(uredepa);亚乙亚胺及甲基三聚氰胺,包括六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺及三米蜜胺;多聚乙酰,尤其布拉他辛(bullatacin)及布拉他辛酮(bullatacinone);喜树碱,包括合成类似物拓朴替康;苔藓抑素(bryostatin)、海洋抑素(callystatin);CC-1065,包括其阿多来新(adozelesin)、卡折来新(carzelesin)及比折来新(bizelesin)合成类似物;念珠藻素(cryptophycin),尤其念珠藻素1及念珠藻素8;海兔毒素(dolastatin);多卡霉素(duocarmycin),包括合成类似物KW-2189及CBI-TMI;艾榴塞洛素(eleutherobin);5-氮杂胞苷;水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑素(spongistatin);氮芥,诸如苯丁酸氮芥、萘氮芥、环磷酰胺、葡磷酰胺(glufosfamide)、伊沃酰胺(evofosfamide)、苯达莫司汀、雌莫司汀(estramustine)、异环磷酰胺、甲基二(氯乙基)胺、甲基二(氯乙基)胺氧化物盐酸盐、美法仑、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)及尿嘧啶氮芥;亚硝基脲,诸如卡莫司汀、氯脲菌素(chlorozotocin)、福莫司汀(foremustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimustine);抗生素,诸如烯二炔抗生素(例如,卡奇霉素(calicheamicin),尤其卡奇霉素γII及卡奇霉素)、包括达内霉素(dynemicin)A的达内霉素,诸如氯屈膦酸盐(clodronate)的双膦酸盐、埃斯培拉霉素(esperamicin)、新制癌菌素(neocarzinostatin)发色团及相关色蛋白烯二炔抗生素色素体、阿克拉霉素(aclacinomycin)、放线菌素、安曲霉素(authramycin)、偶氮丝胺酸、博来霉素、放线菌素C、卡拉比辛(carabicin)、卡尼米辛(carrninomycin)、嗜癌菌素(carzinophilin)、色霉素(chromomycin)、放线菌素D、道诺霉素、地托比星(detorubicin)、6-重氮-5-侧氧基-L-正白胺酸、小红莓(包括N-吗啉基-小红莓、氰基-N-吗啉基-小红莓、2-吡咯啉基-小红莓及脱氧小红莓)、表柔比星、依索比星(esorubicin)、埃达霉素、麻西罗霉素(marcellomycin)、诸如丝裂霉素C的丝裂霉素、霉酚酸、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非罗霉素(porfiromycin)、嘌呤霉素(puromycin)、奎那霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲菌素、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)及左柔比星(zorubicin);抗代谢物,诸如甲胺喋呤及5-氟尿嘧啶(5-FU);叶酸类似物,诸如迪莫林(demopterin)、甲胺喋呤、蝶罗呤(pteropterin)及曲美沙特(trimetrexate);嘌呤类似物,诸如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、及硫鸟嘌呤;嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、二脱氧尿苷、脱氧氟尿苷、依诺他滨(enocitabine)及氟尿苷;雄激素,诸如卡鲁睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)及睪内酯(testolactone);抗肾上腺,诸如胺麸精、米托坦及曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸;放射性治疗剂,诸如镭-223;单端孢霉烯(trichothecene),尤其T-2毒素、黏液霉素(verracurin)A、杆孢菌素(roridin)A及胺癸叮(anguidine);类紫杉醇,诸如太平洋紫杉醇白蛋白结合型紫杉醇(abraxane)、多西他赛卡巴他赛(cabazitaxel)、BIND-014、替司他赛(tesetaxel);铂类似物,诸如顺铂及卡铂、NC-6004奈铂(nanoplatin);乙酰葡醛酯;醛磷酰胺醣苷;胺基乙酰丙酸;恩尿嘧啶;安吖啶;赫布西尔(hestrabucil);比山群(bisantrene);埃达曲克(edatraxate);得弗伐胺(defofamine);秋水仙碱;地吖醌(diaziquone);艾弗欣(elformthine);依利醋铵(elliptinium acetate);埃博霉素;依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多醣;甲酰四氢叶酸;氯尼达明(lonidamine);类美登素(maytansinoid),诸如美登素及安丝菌素(ansamitocin);丙脒腙(mitoguazone);米托蒽醌;莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷司他汀;苯来美特(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);氟嘧啶;醛叶酸;鬼臼酸;2-乙基酰肼;丙卡巴肼;多醣-K(PSK);雷佐生(razoxane);根瘤菌素(rhizoxin);西索菲兰(sizofiran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);曲贝替定(trabectedin)、三亚胺醌(triaziquone);2,2',2”-特洛米安(tricUorotriemylamine);胺基甲酸酯;长春地辛(vindesine);达喀尔巴嗪;甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;赛派塔(thiopeta);苯丁酸氮芥;吉西他滨6-硫鸟嘌呤;巯基嘌呤;甲胺喋呤;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱(vancristine);长春瑞宾诺凡特龙(novantrone);替尼泊苷;依达曲沙(edatrexate);道诺霉素;胺基喋呤;希罗达(xeoloda);伊班膦酸盐(ibandronate);CPT-11;拓朴异构酶抑制剂RFS 2000;二氟甲基鸟胺酸(DFMO);类视黄素,诸如视黄酸;卡培他滨;NUC-1031;FOLFIRI(氟尿嘧啶、甲酰四氢叶酸及伊立替康);及以上中的任一者的医药学上可接受的盐、酸或衍生物。
“化学治疗剂”的定义亦包括抗激素剂,诸如用于调节或抑制肿瘤上的激素作用的抗雌激素及选择性雌激素受体调节剂(SERM)、芳香酶抑制剂、抗雄激素及以上中的任一者的医药学上可接受的盐、酸或衍生物。
抗激素剂
抗雌激素及SERM的实例包括例如他莫昔芬(包括NOLVADEXTM)、雷诺昔芬(raloxifene)、曲洛昔芬(droloxifene)、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)及托瑞米芬(toremifene)
芳香酶抑制剂调节肾上腺中的雌激素产生。实例包括4(5)-咪唑、胺麸精、乙酸甲地孕酮依西美坦(exemestane)、福美司坦(formestane)、法屈唑(fadrozole)、伏罗唑(vorozole)来曲唑及阿那曲唑
抗雄激素的实例包括阿珀鲁胺(apalutamide)、阿比特龙、恩杂鲁胺(enzalutamide)、氟他胺(flutamide)、加利特隆(galeterone)、尼鲁胺、比卡鲁胺、亮丙立德(leuprolide)、戈舍瑞林、ODM-201、APC-100、ODM-204。
孕酮受体拮抗剂的实例包括奥那司酮。
抗血管生成剂
抗血管生成剂包括但不限于类视黄素酸及其衍生物、2-甲氧雌二醇、瑞戈非尼(regorafenib)、尼库拉布(necuparanib)、苏拉明(suramin)、角鲨胺(squalamine)、金属蛋白酶-1的组织抑制剂、金属蛋白酶-2的组织抑制剂、纤维蛋白溶酶原活化物抑制剂-1、纤维蛋白溶酶原活化物抑制剂-2、软骨衍生的抑制剂、太平洋紫杉醇(白蛋白结合型太平洋紫杉醇)、血小板因子4、硫酸鱼精蛋白(鲱精蛋白)、硫酸盐化几丁质衍生物(由雪蟹壳制备)、硫酸盐化多醣肽聚醣复合物(sp-pg)、星形孢菌素、基质代谢调节剂(包括脯胺酸类似物,诸如l-氮杂环丁烷-2-甲酸(LACA)、顺羟基脯胺酸、d,I-3,4-去氢脯胺酸、硫脯胺酸)、α,α'-二吡啶基、β-胺基丙腈反丁烯二酸盐、4-丙基-5-(4-吡啶基)-2(3h)-噁唑酮、甲胺喋呤、米托蒽醌、肝素、干扰素、2巨球蛋白-血清、金属蛋白酶-3的鸡抑制剂(ChIMP-3)、胰凝乳蛋白酶抑制剂(chymostatin)、十四硫酸β-环糊精、艾尼米欣(eponemycin)、烟霉素(fumagillin)、硫代苹果酸金钠、d-青霉胺、β-1-抗胶原酶-血清、α-2-抗纤维蛋白溶酶、比山群、氯苯扎利二钠(lobenzarit disodium)、n-2-羧基苯基-4-氯胺基苯甲酸二钠或“CCA”、沙力度胺(thalidomide)、血管生成抑制性类固醇、羧基胺基咪唑、金属蛋白酶抑制剂(诸如BB-94)、S100A9的抑制剂(诸如他喹莫德(tasquinimod))。其他抗血管生成剂包括抗体,优选针对以下此等血管生成生长因子的单株抗体:β-FGF、α-FGF、FGF-5、VEGF同功异型物、VEGF-C、HGF/SF及Ang-1/Ang-2。
抗纤维化剂
抗纤维化剂包括但不限于诸如β-胺基丙腈(BAPN)的化合物,以及关于离胺酰氧化酶抑制剂及其在治疗与胶原蛋白异常沈积相关的疾病及病状中的用途的US4965288及关于抑制LOX以治疗各种病理性纤维化状态的化合物的US 4997854中所公开的化合物,这些申请案以引用的方式并入本文中。其他例示性抑制剂描述于与诸如2-异丁基-3-氟-烯丙胺、2-异丁基-3-氯-烯丙胺或2-异丁基-3-溴-烯丙胺的化合物相关的US 4943593中;US5021456、US 5059714、US 5120764、US 5182297、与2-(1-萘基氧基甲基)-3-氟烯丙胺相关的US 5252608中;及US 2004-0248871中,该等申请案以引用的方式并入本文中。
例示性抗纤维化剂亦包括与离胺酰氧化酶的活性位点的羰基反应的一级胺,且更尤其在结合羰基之后生成共振稳定化产物的一级胺,诸如以下一级胺:乙二胺(emylenemamine)、肼、苯肼及其衍生物;胺脲及脲衍生物;胺基腈,诸如BAPN或2-硝基乙胺;不饱和或饱和卤胺,诸如2-溴基-乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙胺及对卤基苯甲基胺;及硒基高半胱胺酸内酯。
其他抗纤维化剂为渗透或不渗透细胞的铜螯合剂。例示性化合物包括阻断来源于通过离胺酰氧化酶使离胺酰残基及羟离胺酰残基氧化去胺的醛衍生物的间接抑制剂。实例包括硫醇胺(尤其D-青霉胺)及其类似物,诸如2-胺基-5-巯基-5-甲基己酸、D-2-胺基-3-甲基-3-((2-乙酰胺基乙基)二硫基)丁酸、对2-胺基-3-甲基-3-((2-胺基乙基)二硫基)丁酸、硫化钠-4-((对1-二甲基-2-胺基-2-羧基乙基)二硫基)丁烷、2-乙酰胺基乙基-2-乙酰胺基乙硫醇磺酸盐及三水合钠-4-巯基丁烷亚磺酸盐。
免疫治疗剂
免疫治疗剂包括且不限于适用于治疗个体的治疗性抗体。治疗性抗体的一些实例包括阿巴伏单抗(abagovomab)、ABP-980、阿达木单抗(adecatumumab)、阿夫妥珠单抗(afutuzumab)、阿仑单抗、阿妥莫单抗(altumomab)、阿玛西单抗(amatuximab)、麻安莫单抗(anatumomab)、阿西莫单抗(arcitumomab)、巴维昔单抗、贝妥莫单抗(bectumomab)、贝伐珠单抗(bevacizumab)、比伐珠单抗(bivatuzumab)、布尔莫单抗(blinatumomab)、贝伦妥单抗、坎妥珠单抗(cantuzumab)、卡托莫西单抗(catumaxomab)、CC49、西妥昔单抗、西他土珠单抗(citatuzumab)、西妥木单抗(cixutumumab)、昔瓦土单抗(clivatuzumab)、康纳木单抗(conatumumab)、达西珠单抗(dacetuzumab)、达洛图单抗(dalotuzumab)、达雷木单抗(daratumumab)、地莫单抗(detumomab)、迪奴图单抗(dinutuximab)、德珠单抗(drozitumab)、杜里土单抗(duligotumab)、杜西吉土单抗(dusigitumab)、依美昔单抗(ecromeximab)、埃罗妥珠单抗(elotuzumab)、艾米贝珠单抗(emibetuzumab)、恩斯土昔单抗(ensituximab)、鄂托默单抗(ertumaxomab)、埃达珠单抗(etaracizumab)、伐吐珠单抗(farletuzumab)、费拉妥珠单抗(ficlatuzumab)、非吉单抗(figitumumab)、法兰土单抗(flanvotumab)、浮土西单抗(futuximab)、加尼图单抗(ganitumab)、吉妥珠单抗、吉瑞昔单抗(girentuximab)、格雷巴土木单抗(glembatumumab)、异贝莫单抗(ibritumomab)、伊戈伏单抗(igovomab)、伊姆加土珠单抗(imgatuzumab)、因达西单抗(indatuximab)、英妥珠单抗(inotuzumab)、英妥木单抗(intetumumab)、伊派利单抗(MDX-010、BMS-734016及MDX-101)、伊妥木单抗(iratumumab)、拉贝珠单抗、来沙木单抗(lexatumumab)、林妥珠单抗、洛瓦土珠单抗、鲁卡木单抗(lucatumumab)、马帕木单抗、马妥珠单抗、米拉珠单抗、明瑞莫单抗(minretumomab)、米妥莫单抗(mitumomab)、莫格利珠单抗(mogamulizumab)、莫昔土莫单抗(moxetumomab)、那莫单抗(naptumomab)、纳纳土单抗(narnatumab)、莱西单抗、尼妥珠单抗、诺非单抗(nofetumomab)、OBI-833、奥比珠单抗、奥卡拉珠单抗(ocaratuzumab)、奥伐木单抗(ofatumumab)、奥拉单抗(olaratumab)、奥那组单抗(onartuzumab)、奥普珠单抗(oportuzumab)、奥戈伏单抗(oregovomab)、帕尼单抗、帕萨珠单抗(parsatuzumab)、帕苏多托克斯(pasudotox)、帕特里土单抗(patritumab)、潘妥莫单抗(pemtumomab)、帕妥珠单抗、平妥单抗(pintumomab)、普托木单抗(pritumumab)、拉克莫单抗(racotumomab)、拉德瑞单抗(radretumab)、雷莫芦单抗(ramucirumab)里乐木单抗(rilotumumab)、利妥昔单抗、罗妥木单抗(robatumumab)、萨马里珠单抗(samalizumab)、沙妥莫单抗(satumomab)、西罗珠单抗(sibrotuzumab)、思图昔单抗、索利托单抗(solitomab)、辛图珠单抗(simtuzumab)、他卡珠单抗(tacatuzumab)、他普莫单抗(taplitumomab)、泰纳莫单抗(tenatumomab)、泰普洛单抗(teprotumumab)、替加珠单抗(tigatuzumab)、托西莫单抗(tositumomab)、曲妥珠单抗、土库珠单抗(tucotuzumab)、乌妥昔单抗(ublituximab)、维托珠单抗、沃尔希珠单抗(vorsetuzumab)、伏妥莫单抗(votumumab)、扎鲁姆单抗(zalutumumab)及3F8。利妥昔单抗可用于治疗惰性B细胞癌症,其包括边缘区淋巴瘤、WM、CLL及小淋巴细胞性淋巴瘤。利妥昔单抗与化学疗法剂的组合尤其有效。
例示性治疗性抗体可进一步用放射性同位素粒子,诸如铟-111、钇-90(90Y-昔瓦土单抗)或碘-131标记或与其组合。
癌症基因疗法及细胞疗法
癌症基因疗法及细胞疗法包括将正常基因插入至癌细胞中以置换突变或改变基因;使突变基因沉默的基因修饰;直接杀死癌细胞的遗传学方法;包括经设计以置换个体自身免疫系统的大部分的免疫细胞输注,以增强对癌细胞的免疫反应,或活化个体自身免疫系统(T细胞或自然杀手细胞)以杀死癌细胞,或发现且杀死癌细胞;修改细胞活性以进一步改变针对癌症的内源性免疫反应性的遗传学方法。
基因编辑剂
基因组编辑系统的实例包括CRISPR/Cas9系统、锌指核酸酶系统、TALEN系统、归巢核酸内切酶系统及大范围核酸酶系统。
CAR-T细胞疗法及TCR-T细胞疗法
CAR-T细胞疗法包括经工程改造以表现嵌合抗原受体(CAR)的免疫效应细胞群体,其中CAR包含肿瘤抗原结合域。免疫效应细胞为T细胞或NK细胞。TCR-T细胞疗法包括经工程改造以靶向肿瘤细胞表面上的肿瘤衍生肽的TCR-T细胞。细胞可为自体或同种异体的。
在一些实施例中,CAR包含抗原结合域、跨膜域及胞内信号传导域。
在一些实施例中,胞内域包含初级信号传导域、共刺激域或初级信号传导域及共刺激域两者。
在一些实施例中,初级信号传导域包含一或多种选自由以下组成的群的蛋白质的功能信号传导域:CD3ζ、CD3γ、CD3δ、CD3ε、共同FcRγ(FCERIG)、FcRβ(FcεRlb)、CD79a、CD79b、FcγRIIa、DAP10及DAP12。
在一些实施例中,共刺激域包含一或多种选自由以下组成的群的蛋白质的功能域:CD27、CD28、4-1BB(CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴细胞功能相关抗原-1(LFA-I)、CD2、CD7、LIGHT、NKG2C、B7-H3、与CD83特异性结合的配位体、CDS、ICAM-1、GITR、BAFFR、HVEM(LIGHTR)、SLAMF7、NKp80(KLRFI)、CD160、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD 1 ld、ITGAE、CD103、ITGAL、CD 1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、NKp44、NKp30、NKp46及NKG2D。
在一些实施例中,跨膜域包含选自由以下组成的群的蛋白质的跨膜域:T细胞受体的α、β或ζ链、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、KIRDS2、OX40、CD2、CD27、LFA-1(CD1 la、CD18)、ICOS(CD278)、4-1BB(CD137)、GITR、CD40、BAFFR、HVEM(LIGHTR)、SLAMF7、NKp80(KLRF1)、CD160、CD19、IL2Rβ、IL2Rγ、IL7R u、ITGA1、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD1ld、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、PAG/Cbp、NKp44、NKp30、NKp46、NKG2D及NKG2C。
在一些实施例中,抗原结合域结合肿瘤抗原。
在一些实施例中,肿瘤抗原选自由以下组成的群:CD19;CD123;CD22;CD30;CD171;CS-1(亦称为CD2亚类1、CRACC、SLAMF7、CD319及19A24);C型凝集素样分子-1(CLL-1或CLECLI);CD33;表皮生长因子受体变异体III(EGFRvlll);神经节苷脂G2(GD2);神经节苷脂GD3(aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer);TNF受体家族成员B细胞成熟(BCMA);Tn抗原((Tn Ag)或(GaINAcu-Ser/Thr));前列腺特异性膜抗原(PSMA);受体酪胺酸激酶样孤儿受体1(RORI);Fms样酪胺酸激酶3(FLT3);肿瘤相关醣蛋白72(TAG72);CD38;CD44v6;癌胚抗原(CEA);上皮细胞黏附分子(EPCAM);B7H3(CD276);KIT(CD117);介白素-13受体次单元α-2(IL-13Ra2或CD213A2);间皮素;介白素11受体α(IL-11Ra);前列腺干细胞抗原(PSCA);蛋白酶丝胺酸21(睪蛋白或PRSS21);血管内皮生长因子受体2(VEGFR2);刘易斯(Lewis)(Y)抗原;CD24;血小板衍生生长因子受体β(PDGFR-β);阶段特异性胚胎抗原-4(SSEA-4);CD20;δ样3(DLL3);叶酸受体α;受体酪胺酸蛋白激酶,ERBB2(Her2/neu);黏蛋白1,细胞表面相关(MUC1);表皮生长因子受体(EGFR);神经细胞黏附分子(NCAM);前列腺酶;前列腺酸磷酸酶(PAP);突变型延长因子2(ELF2M);肝配蛋白B2;纤维母细胞活化蛋白α(FAP);胰岛素样生长因子1受体(IGF-I受体),碳酸酐酶IX(CAIX);蛋白酶体(前体,巨蛋白因子)次单元,β型,9(LMP2);醣蛋白100(gp100);由断点簇区(BCR)及阿贝尔森鼠类白血病病毒致癌基因同源物1(Abl)组成的致癌基因融合蛋白(bcr-abl);酪胺酸酶;肝配蛋白A型受体2(EphA2);海藻糖基GM1;唾液酸基刘易斯黏附分子(sLe);神经节苷脂GM3(aNeuSAc(2-3)bDGalp(1-4)bDGlcp(1-1)Cer);转麸酰胺酸酶5(TGS5);高分子量黑素瘤相关抗原(HMWMAA);o-乙酰基-GD2神经节苷脂(OAcGD2);叶酸受体β;肿瘤内皮细胞标记物1(TEM1/CD248);肿瘤内皮细胞标记物7相关(TEM7R);前列腺六跨膜上皮抗原I(STEAP1);紧密连接蛋白6(CLDN6);促甲状腺激素受体(TSHR);G蛋白偶合受体类别C第5组,成员D(GPRCSD);X染色体开读框61(CXORF61);CD97;CD179a;多形性淋巴瘤激酶(ALK);聚唾液酸;胎盘特异性1(PLAC1);globoH醣基神经酰胺六醣部分(GloboH);乳腺分化抗原(NY-BR-1);尿溶蛋白2(UPK2);A型肝炎病毒细胞受体1(HAVCR1);肾上腺素受体β3(ADRB3);泛连接蛋白3(PANX3);G蛋白偶合受体20(GPR20);淋巴细胞抗原6复合物,基因座K 9(LY6K);嗅觉受体51E2(ORSIE2);TCRγ替代读框蛋白(TARP);威尔姆斯氏肿瘤蛋白(WT1);癌症/睪丸抗原1(NY-ESO-1);癌症/睪丸抗原2(LAGE-la);黑素瘤相关抗原1(MAGE-A1);定位于染色体12p上的ETS移位变异体基因6(ETV6-AML);精子蛋白17(SPA17);X抗原家族成员1A(XAGE1);血管生成素结合细胞表面受体2(Tie 2);黑素瘤癌症睪丸抗原-1(MADCT-1);黑素瘤癌症睪丸抗原-2(MAD-CT-2);Fos相关抗原1;肿瘤蛋白p53(p53);p53突变体;前列腺蛋白;存活素;端粒酶;前列腺癌肿瘤抗原-1(PCTA-1或半乳糖凝集素8),由T细胞识别的黑素瘤抗原1(MelanA或MARTI);大鼠肉瘤(Ras)突变体;人类端粒酶逆转录酶(hTERT);肉瘤移位断点;黑素瘤细胞凋亡抑制剂(ML-IAP);ERG(跨膜蛋白酶,丝胺酸2(TMPRSS2)ETS融合基因);N-乙酰基葡糖胺基-转移酶V(NA17);成对盒蛋白Pax-3(PAX3);雄激素受体;细胞周期素B1;v-myc禽类髓细胞瘤病病毒致癌基因神经母细胞瘤衍生同源物(MYCN);Ras同源物家族成员C(RhoC);酪胺酸酶相关蛋白质2(TRP-2);细胞色素P450 1B1(CYP IBI);CCCTC结合因子(锌指蛋白)样(BORIS或压印位点调节子兄弟蛋白),由T细胞识别的鳞状细胞癌抗原3(SART3);成对盒蛋白Pax-5(PAX5);前顶体素结合蛋白sp32(OY-TES I);淋巴细胞特异性蛋白酪胺酸激酶(LCK);激酶锚蛋白4(AKAP-4);滑膜肉瘤,X断点2(SSX2);晚期醣化最终产物受体(RAGE-I);肾普遍存在蛋白1(RUI);肾普遍存在蛋白2(RU2);豆荚蛋白;人类乳头状瘤病毒E6(HPVE6);人类乳头状瘤病毒E7(HPV E7);肠羧基酯酶;突变型热休克蛋白70-2(mut hsp70-2);CD79a;CD79b;CD72;白细胞相关免疫球蛋白样受体1(LAIRI);IgA Fc片段受体(FCAR或CD89);白细胞免疫球蛋白样受体子族A成员2(LILRA2);CD300分子样家族成员f(CD300LF);C型凝集素域家族12成员A(CLEC12A);骨髓基质细胞抗原2(BST2);含EGF样模块黏蛋白样激素受体样2(EMR2);淋巴细胞抗原75(LY75);磷脂肌醇蛋白聚醣-3(GPC3);Fc受体样5(FCRL5);及免疫球蛋白λ样多肽1(IGLL1)。
在一些实施例中,肿瘤抗原选自CD150、5T4、ActRIIA、B7、BMCA、CA-125、CCNA1、CD123、CD126、CD138、CD14、CD148、CD15、CD19、CD20、CD200、CD21、CD22、CD23、CD24、CD25、CD26、CD261、CD262、CD30、CD33、CD362、CD37、CD38、CD4、CD40、CD40L、CD44、CD46、CD5、CD52、CD53、CD54、CD56、CD66a-d、CD74、CD8、CD80、CD92、CE7、CS-1、CSPG4、ED-B纤维结合蛋白、EGFR、EGFRvIII、EGP-2、EGP-4、EPHa2、ErbB2、ErbB3、ErbB4、FBP、GD2、GD3、HER1-HER2组合、HER2-HER3组合、HERV-K、HIV-1包膜醣蛋白gp120、HIV-1包膜醣蛋白gp41、HLA-DR、HM1.24、HMW-MAA、Her2、Her2/neu、IGF-1R、IL-11Rα、IL-13R-α2、IL-2、IL-22R-α、IL-6、IL-6R、Ia、Ii、L1-CAM、L1细胞黏附分子、刘易斯Y、Ll-CAM、MAGE A3、MAGE-A1、MART-1、MUC1、NKG2C配位体、NKG2D配位体、NYESO-1、OEPHa2、PIGF、PSCA、PSMA、ROR1、T101、TAC、TAG72、TIM-3、TRAIL-R1、TRAIL-Rl(DR4)、TRAIL-R2(DR5)、VEGF、VEGFR2、WT-I、G蛋白偶合受体、α胎蛋白(AFP)、血管生成因子、外源性同源结合分子(ExoCBM)、致癌基因产物、抗叶酸受体、c-Met、癌胚抗原(CEA)、细胞周期素(D1)、肝配蛋白B2、上皮肿瘤抗原、雌激素受体、胚胎乙酰胆碱e受体、叶酸结合蛋白、gp100、B型肝炎表面抗原、κ链、κ轻链、kdr、λ链、活素(livin)、黑素瘤相关抗原、间皮素、小鼠双微小2同源物(MDM2)、黏蛋白16(MUC16)、突变型p53、突变型ras、坏死抗原、癌胚抗原、ROR2、孕酮受体、前列腺特异性抗原、tEGFR、肌腱蛋白、P2-微球蛋白、Fc受体样5(FcRL5)。
细胞疗法的非限制性实例包括艾普塞尔-L(Algenpantucel-L)、西普亮塞-T(Sipuleucel-T)、(BPX-501)瑞沃赛尔(rivogenlecleucel)US9089520、WO2016100236、AU-105、ACTR-087、活化的同种异体自然杀手细胞CNDO-109-AANK、MG-4101、AU-101、BPX-601、FATE-NK100、LFU-835造血干细胞、艾米亮塞-T(Imilecleucel-T)、巴塔赛尔-T(baltaleucel-T)、PNK-007、UCARTCS1、ET-1504、ET-1501、ET-1502、ET-190、CD19-ARTEMIS、ProHema、经FT-1050处理的骨髓干细胞疗法、CD4CARNK-92细胞、CryoStim、AlloStim、慢病毒转导的huCART-meso细胞、CART-22细胞、EGFRt/19-28z/4-1BBL CAR T细胞、自体4H11-28z/fIL-12/EFGRt T细胞、CCR5-SBC-728-HSPC、CAR4-1BBZ、CH-296、dnTGFbRII-NY-ESOc259T、Ad-RTS-IL-12、IMA-101、IMA-201、CARMA-0508、TT-18、CMD-501、CMD-503、CMD-504、CMD-502、CMD-601、CMD-602、CSG-005。
在一些实施例中,肿瘤靶向抗原包括:α-胎蛋白,诸如ET-1402及AFP-TCR;炭疽毒素受体1,诸如抗TEM8 CAR T细胞疗法;B细胞成熟抗原(BCMA),诸如bb-2121、UCART-BCMA、ET-140、KITE-585、MCM-998、LCAR-B38M、CART-BCMA、SEA-BCMA、BB212、UCART-BCMA、ET-140、P-BCMA-101、AUTO-2(APRIL-CAR);抗CLL-1抗体,诸如KITE-796;B7同源物6,诸如CAR-NKp30及CAR-B7H6;B淋巴细胞抗原CD19,诸如TBI-1501、CTL-119 huCART-19T细胞、JCAR-015US7446190、JCAR-014、JCAR-017、WO2016196388、WO2016033570、WO2015157386)、西卡思罗(axicabtagene ciloleucel)(KTE-C19)、US7741465、US6319494、UCART-19、EBV-CTL、T替沙津鲁-T(Ttisagenlecleucel-T)(CTL019)、WO2012079000、WO2017049166、表现CD19CAR-CD28-CD3ζ-EGFRt的T细胞、CD19/4-1BBL铠装CAR T细胞疗法、C-CAR-011、CIK-CAR.CD19、CD19CAR-28-ζT细胞、PCAR-019、MatchCART、DSCAR-01、IM19 CAR-T;B淋巴细胞抗原CD20,诸如ATTCK-20;B淋巴细胞细胞黏附物,诸如UCART-22、JCAR-018 WO2016090190;NY-ESO-1,诸如GSK-3377794、TBI-1301;碳酸酐酶,诸如DC-Ad-GMCAIX;凋亡蛋白酶9自杀基因,诸如CaspaCIDe DLI、BPX-501;CCR5,诸如SB-728;CDw123,诸如MB-102、UCART-123;CD20m,诸如CBM-C20.1;CD4,诸如ICG-122;CD30,诸如CART30(CBM-C30.1;CD33,诸如CIK-CAR.CD33;CD38,诸如T-007、UCART-38;CD40配位体,诸如BPX-201;CEACAM蛋白4调节剂,诸如MG7-CART;紧密连接蛋白6,诸如CSG-002;靶向EBV,诸如CMD-003;EGFR,诸如自体4H11-28z/fIL-12/EFGRt T细胞;核酸内切酶,诸如PGN-514、PGN-201;埃-巴二氏病毒(Epstein-Barrvirus)特异性T淋巴细胞,诸如TT-10;Erbb2,诸如CST-102、CIDeCAR;神经节苷脂(GD2),诸如4SCAR-GD2;麸胺酸羧肽酶II,诸如CIK-CAR.PSMA、CART-PSMA-TGFβRDN、P-PSMA-101;磷脂酰肌醇蛋白聚醣-3(GPC3),诸如TT-16、GLYCAR;血红素,诸如PGN-236;肝细胞生长因子受体,诸如抗cMet RNA CAR T;人类乳头状瘤病毒E7蛋白,诸如KITE-439;免疫球蛋白γFc受体III,诸如ACTR087;IL-12,诸如DC-RTS-IL-12;IL-12促效剂/黏蛋白16,诸如JCAR-020;IL-13α2,诸如MB-101;IL-2,诸如CST-101;K-Ras GTPase,诸如抗KRAS G12V mTCR细胞疗法;神经细胞黏附分子L1 L1CAM(CD171),诸如JCAR-023;潜伏性膜蛋白1/潜伏性膜蛋白2,诸如Ad5f35-LMPd1-2转导的自体树突状细胞;黑素瘤相关抗原10,诸如MAGE-A10C796TMAGE-A10TCR;黑素瘤相关抗原3/黑素瘤相关抗原6(MAGE A3/A6),诸如KITE-718;间皮素,诸如CSG-MESO、TC-210;NKG2D,诸如NKR-2;Ntrkr1酪胺酸激酶受体,诸如JCAR-024;T细胞受体,诸如BPX-701、IMCgp100;T淋巴细胞,诸如TT-12;肿瘤浸润性淋巴细胞,诸如LN-144、LN-145;及威尔姆斯氏肿瘤蛋白,诸如JTCR-016、WT1-CTL。
淋巴瘤或白血病组合疗法
在一些实施例中,额外治疗剂适用于治疗淋巴瘤或白血病。这种药剂包括阿地介白素、阿昔迪布、三水合阿米福汀(amifostine trihydrate)、胺基喜树碱(aminocamptothecin)、抗新普拉通(antineoplaston)A10、抗新普拉通AS2-1、抗胸腺细胞球蛋白、三氧化二砷、Bcl-2家族蛋白抑制剂ABT-263、β阿立辛(beta alethine)、BMS-345541、硼替佐米(bortezomib)硼替佐米(PS-341)、苔藓抑素1、布舒凡(bulsulfan)、坎帕斯(campath)-1H、卡铂、卡非佐米卡莫司汀、乙酸卡泊芬净(caspofungin acetate)、CC-5103、苯丁酸氮芥、CHOP(环磷酰胺、小红莓、长春新碱及泼尼松)、顺铂、克拉屈滨、氯法拉滨、姜黄素、CVP(环磷酰胺、长春新碱及泼尼松)、环磷酰胺、环孢灵(cyclosporine)、阿糖胞苷、地尼介白素迪夫托斯(denileukindiftitox)、地塞米松、多西他赛、海兔毒素10、小红莓、盐酸小红莓、DT-PACE(地塞米松、沙力度胺、顺铂、小红莓、环磷酰胺及依托泊苷)、恩扎妥林(enzastaurin)、阿法依泊汀(epoetin alfa)、依托泊苷、依维莫司(everolimus)(RAD001)、FCM(氟达拉滨、环磷酰胺及米托蒽醌)、FCR(氟达拉滨、环磷酰胺及利妥昔单抗)、非瑞替尼(fenretinide)、非格司亭(filgrastim)、夫拉平度、氟达拉滨、FR(氟达拉滨及利妥昔单抗)、格尔德霉素(geldanamycin)(17-AAG)、hyperCVAD(超分割环磷酰胺、长春新碱、小红莓、地塞米松、甲胺喋呤及阿糖胞苷)、ICE(异环磷酰胺、卡铂及依托泊苷)、异环磷酰胺、盐酸伊立替康、干扰素α-2b、伊沙匹隆、来那度胺(CC-5013)、淋巴介质活化的杀手细胞、MCP(米托蒽醌、苯丁酸氮芥及泼尼龙)、美法仑、美司钠(mesna)、甲胺喋呤、盐酸米托蒽醌、莫特沙芬钆(motexafin gadolinium)、霉酚酸吗啉乙酯(mycophenolate mofetil)、奈拉滨(nelarabine)、奥巴克拉(obatoclax)(GX15-070)、奥利默森(oblimersen)、乙酸奥曲肽(octreotide acetate)、Ω-3脂肪酸、Omr-IgG-am(WNIG,Omrix)、奥沙利铂、太平洋紫杉醇、帕泊昔布(PD0332991)、派非格司亭(pegfilgrastim)、聚乙二醇化脂质体盐酸小红莓、派瑞弗辛(perifosin)、泼尼龙、泼尼松、重组型flt3配位体、重组型人类血小板生成素、重组型干扰素α、重组型介白素-11、重组型介白素-12、利妥昔单抗、R-CHOP(利妥昔单抗及CHOP)、R-CVP(利妥昔单抗及CVP)、R-FCM(利妥昔单抗及FCM)、R-ICE(利妥昔单抗及ICE)及R-MCP(利妥昔单抗及MCP)、R-罗斯维汀(R-roscovitine)(塞利希布(seliciclib)、CYC202)、沙格司亭(sargramostim)、柠檬酸西地那非(sildenafil citrate)、辛伐他汀(simvastatin)、西罗莫司、苯乙烯基砜、他克莫司、坦螺旋霉素(tanespimycin)、坦罗莫司(temsirolimus)(CCl-779)、沙力度胺、治疗性同种异体淋巴细胞、噻替派、替吡法尼(tipifarnib)、长春新碱、硫酸长春新碱、酒石酸氢长春瑞宾、SAHA(辛二酰苯胺异羟肟酸,或辛二酰基、苯胺及氧肟酸)、维罗非尼维奈托克(ABT-199)。
一种改良方法为放射免疫疗法,其中单株抗体与放射性同位素粒子,诸如铟-111、钇-90及碘-131组合。组合疗法的实例包括但不限于碘-131托西莫单抗钇-90替伊莫单抗(ibritumomab tiuxetan)以及及CHOP。
上文所提及的疗法可补充有干细胞移植或治疗或与其组合。治疗性程序包括周边血液干细胞移植、自体造血干细胞移植、自体骨髓移植、抗体疗法、生物疗法、酶抑制剂疗法、全身照射、干细胞输注、在干细胞支持下的骨髓消融、经活体外处理的周边血液干细胞移植、脐带血移植、免疫酶技术、低LET钴-60γ射线疗法、博莱霉素、常规手术、辐射疗法及非清髓性同种异体造血干细胞移植。
非霍奇金氏淋巴瘤组合疗法
在一些实施例中,额外治疗剂适用于治疗非霍奇金氏淋巴瘤(NHL),尤其B细胞起源的非霍奇金氏淋巴瘤,这种治疗剂包括单株抗体、标准化学疗法方法(例如CHOP、CVP、FCM、MCP及其类似物)、放射免疫疗法及其组合,尤其抗体疗法与化学疗法的整合。
用于治疗NHL/B细胞癌症的非缀合的单株抗体的实例包括利妥昔单抗、阿仑单抗、人类或人类化抗CD20抗体、卢米西单抗(lumiliximab)、抗TNF相关细胞凋亡诱导配位体(抗TRAIL)、贝伐珠单抗、加利昔单抗、依帕珠单抗、SGN-40及抗CD74。
用于NHL/B细胞癌症的治疗的实验抗体药剂的实例包括奥伐木单抗、ha20、PRO131921、阿仑单抗、加利昔单抗、SGN-40、CHIR-12.12、依帕珠单抗、卢米西单抗、阿泊珠单抗、米拉珠单抗及贝伐珠单抗。
用于NHL/B细胞癌症的化学疗法的标准方案的实例包括CHOP、FCM、CVP、MCP、R-CHOP、R-FCM、R-CVP及R-MCP。
套细胞淋巴瘤组合疗法
在一些实施例中,额外治疗剂适用于治疗套细胞淋巴瘤(MCL),其包括组合化学疗法,诸如CHOP、hyperCVAD及FCM。这种方案亦可补充有单株抗体利妥昔单抗以形成组合疗法R-CHOP、hyperCVAD-R及R-FCM。上文所提及的疗法中的任一者可与干细胞移植或ICE组合以治疗MCL。
适用于治疗MCL的治疗剂的其他实例包括:
-免疫疗法,诸如单株抗体(如利妥昔单抗)及癌症疫苗,诸如GTOP-99,其是基于个别个体的肿瘤的基因组成;
-引起Bcl-2蛋白分解且提高癌细胞对化学疗法的敏感性的药物,诸如奥利默森,与其他化学治疗剂组合;
-mTOR抑制剂,其可引起细胞生长的抑制及甚至细胞死亡。非限制性实例为西罗莫司、坦罗莫司(CCI-779)、CC-115、CC-223、SF-1126、PQR-309(必米昔布(bimiralisib))、沃塔昔布(voxtalisib)、GSK-2126458以及坦罗莫司与或其他化学治疗剂组合;
-其他药剂,诸如夫拉平度、帕泊昔布(PD0332991)、R-罗斯维汀(塞利希布,CYC202)、苯乙烯基砜、奥巴克拉(GX15-070)、TRAIL、抗TRAIL死亡受体DR4及DR5抗体、坦罗莫司(CCl-779)、依维莫司(RAD001)、BMS-345541、姜黄素、SAHA、沙力度胺、来那度胺(CC-5013)及格尔德霉素(17-AAG)。
瓦尔登斯特伦氏巨球蛋白血症组合疗法
在一些实施例中,额外治疗剂适用于治疗瓦尔登斯特伦氏巨球蛋白血症(WM),其包括阿地介白素、阿仑单抗、阿昔迪布、三水合阿米福汀、胺基喜树碱、抗新普拉通A10、抗新普拉通AS2-1、抗胸腺细胞球蛋白、三氧化二砷、自体人类肿瘤衍生的HSPPC-96、Bcl-2家族蛋白抑制剂ABT-263、β阿立辛、硼替佐米苔藓抑素1、白消安、坎帕斯-1H、卡铂、卡莫司汀、乙酸卡泊芬净、CC-5103、顺铂、氯法拉滨、环磷酰胺、环孢灵、阿糖胞苷、地尼介白素迪夫托斯、地塞米松、多西他赛、海兔毒素10、盐酸小红莓、DT-PACE、恩扎妥林、阿法依泊汀、依帕珠单抗(hLL2-抗CD22人类化抗体)、依托泊苷、依维莫司、非瑞替尼、非格司亭、氟达拉滨、异环磷酰胺、铟-111单株抗体MN-14、碘-131托西莫单抗、盐酸伊立替康、伊沙匹隆、淋巴激素活化的杀手细胞、美法仑、美司钠、甲胺喋呤、盐酸米托蒽醌、单株抗体CD19(诸如替沙津鲁-T、CART-19、CTL-019)、单株抗体CD20、莫特沙芬钆、霉酚酸吗啉乙酯、奈拉滨、奥利默森、乙酸奥曲肽、ω-3脂肪酸、奥沙利铂、太平洋紫杉醇、派非格司亭、聚乙二醇化脂质体盐酸小红莓、喷司他汀、哌立福新、泼尼松、重组型flt3配位体、重组型人类血小板生成素、重组型干扰素α、重组型介白素-11、重组型介白素-12、利妥昔单抗、沙格司亭、柠檬酸西地那非辛伐他汀、西罗莫司、他克莫司、坦螺旋霉素、沙力度胺、治疗性同种异体淋巴细胞、噻替派、替吡法尼、托西莫单抗、维托珠单抗、硫酸长春新碱、酒石酸氢长春瑞宾、伏立诺他、WT1 126-134肽疫苗、WT-1类似物肽疫苗、钇-90替伊莫单抗、钇-90人类化依帕珠单抗及其任何组合。
用于治疗WM的治疗性程序的其他实例包括周边血液干细胞移植、自体造血干细胞移植、自体骨髓移植、抗体疗法、生物疗法、酶抑制剂疗法、全身照射、干细胞输注、在干细胞支持下的骨髓消融、经活体外处理的周边血液干细胞移植、脐带血移植、免疫酶技术、低LET钴-60γ射线疗法、博莱霉素、常规手术、辐射疗法及非清髓性同种异体造血干细胞移植。
弥漫性大B细胞淋巴瘤组合疗法
在一些实施例中,额外治疗剂适用于治疗弥漫性大B细胞淋巴瘤(DLBCL),其包括环磷酰胺、小红莓、长春新碱、泼尼松、抗CD20单株抗体、依托泊苷、博莱霉素、关于WM所列出的许多药剂及其任何组合,诸如ICE及R-ICE。
慢性淋巴细胞性白血病组合疗法
在一些实施例中,额外治疗剂适用于治疗慢性淋巴细胞性白血病(CLL),其包括苯丁酸氮芥、环磷酰胺、氟达拉滨、喷司他汀、克拉屈滨、小红莓、长春新碱、泼尼松、泼尼龙、阿仑单抗、关于WM所列出的许多药剂以及组合化学疗法及化学免疫疗法,包括以下常用组合方案:CVP、R-CVP、ICE、R-ICE、FCR及FR。
骨髓纤维化组合疗法
在一些实施例中,额外治疗剂适合于治疗骨髓纤维化,其包括刺猬抑制剂、组蛋白去乙酰基酶(HDAC)抑制剂及酪胺酸激酶抑制剂。刺猬抑制剂的非限制性实例为萨瑞德吉及维莫德吉。
HDAC抑制剂的实例包括但不限于普拉诺他及帕比诺他。
酪胺酸激酶抑制剂的非限制性实例为来他替尼、伯舒替尼、伊马替尼、吉列替尼、拉多替尼及卡博替尼。
过度增殖性疾病组合疗法
在一些实施例中,额外治疗剂适用于治疗过度增殖性疾病,其包括吉西他滨、白蛋白结合型太平洋紫杉醇及吉西他滨/白蛋白结合型太平洋紫杉醇与JAK抑制剂及/或PI3Kδ抑制剂。
膀胱癌组合疗法
在一些实施例中,额外治疗剂适合于治疗膀胱癌,其包括阿特珠单抗、卡铂、顺铂、多西他赛、小红莓、氟尿嘧啶(5-FU)、吉西他滨、伊多米德(idosfamide)、干扰素α-2b、甲胺喋呤、丝裂霉素、白蛋白结合型太平洋紫杉醇、太平洋紫杉醇、培美曲塞、噻替派、长春碱及其任何组合。
乳癌组合疗法
在一些实施例中,额外治疗剂适合于治疗乳癌,其包括白蛋白结合型太平洋紫杉醇、阿那曲唑、卡培他滨、卡铂、顺铂、环磷酰胺、多西他赛、小红莓、表阿霉素、依维莫司、依西美坦、氟尿嘧啶、氟维司群、吉西他滨、伊沙匹隆、拉帕替尼、来曲唑、甲胺喋呤、米托蒽醌、太平洋紫杉醇、聚乙二醇化脂质体小红莓、帕妥珠单抗、他莫昔芬、托瑞米芬、曲妥珠单抗、长春瑞宾及其任何组合。
三阴性乳癌组合疗法
在一些实施例中,额外治疗剂适用于治疗三阴性乳癌,其包括环磷酰胺、多西他赛、小红莓、表柔比星、氟尿嘧啶、太平洋紫杉醇及其组合。
结肠直肠癌组合疗法
在一些实施例中,额外治疗剂适用于治疗结肠直肠癌,其包括贝伐珠单抗、卡培他滨、西妥昔单抗、氟尿嘧啶、伊立替康、甲酰四氢叶酸、奥沙利铂、帕尼单抗、ziv-阿柏西普及其任何组合。
去势抵抗性前列腺癌组合疗法
在一些实施例中,额外治疗剂适用于治疗去势抵抗性前列腺癌,其包括阿比特龙、卡巴他赛、多西他赛、恩杂鲁胺、泼尼松、西普亮塞-T及其任何组合。
食道及食道胃接合处癌症组合疗法
在一些实施例中,额外治疗剂适用于治疗食道及食道胃接合处癌症,其包括卡培他滨、卡铂、顺铂、多西他赛、表柔比星、氟嘧啶、氟尿嘧啶、伊立替康、甲酰四氢叶酸、奥沙利铂、太平洋紫杉醇、雷莫芦单抗、曲妥珠单抗及其任何组合。
胃癌组合疗法
在一些实施例中,额外治疗剂适用于治疗胃癌,其包括卡培他滨、卡铂、顺铂、多西他赛、表柔比星、氟嘧啶、氟尿嘧啶、伊立替康、甲酰四氢叶酸、丝裂霉素、奥沙利铂、太平洋紫杉醇、雷莫芦单抗、曲妥珠单抗及其任何组合。
头颈癌组合疗法
在一些实施例中,额外治疗剂适用于治疗头颈癌,其包括阿法替尼、博莱霉素、卡培他滨、卡铂、西妥昔单抗、顺铂、多西他赛、氟尿嘧啶、吉西他滨、羟基脲、甲胺喋呤、纳武单抗、太平洋紫杉醇、派立珠单抗、长春瑞宾及其任何组合。
肝胆癌组合疗法
在一些实施例中,额外治疗剂适用于治疗肝胆癌,其包括卡培他滨、顺铂、氟嘧啶、5-氟尿嘧啶、吉米他宾(gemecitabine)、奥沙利铂、索拉非尼及其任何组合。
肝细胞癌组合疗法
在一些实施例中,额外治疗剂适用于治疗肝细胞癌,其包括卡培他滨、小红莓、吉西他滨、索拉非尼及其任何组合。
非小细胞肺癌组合疗法
在一些实施例中,额外治疗剂适用于治疗非小细胞肺癌(NSCLC),其包括阿法替尼、白蛋白结合型太平洋紫杉醇、艾乐替尼、贝伐珠单抗、贝伐珠单抗、卡博替尼、卡铂、顺铂、克卓替尼、达拉非尼、多西他赛、埃罗替尼、依托泊苷、吉西他滨、纳武单抗、太平洋紫杉醇、派立珠单抗、培美曲塞、雷莫芦单抗、曲美替尼、曲妥珠单抗、凡德他尼、维罗非尼、长春碱、长春瑞宾及其任何组合。
小细胞肺癌组合疗法
在一些实施例中,额外治疗剂适用于治疗小细胞肺癌(SCLC),其包括本达斯米(bendamustime)、卡铂、顺铂、环磷酰胺、多西他赛、小红莓、依托泊苷、吉西他滨、伊皮利单抗(ipillimumab)、伊立替康、纳武单抗、太平洋紫杉醇、替莫唑胺、拓朴替康、长春新碱、长春瑞宾及其任何组合。
黑素瘤组合疗法
在一些实施例中,额外治疗剂适用于治疗黑素瘤,其包括白蛋白结合型太平洋紫杉醇、卡铂、顺铂、克比替尼(cobiemtinib)、达拉非尼、达拉巴嗪(dacrabazine)、IL-2、伊马替尼、干扰素α-2b、伊派利单抗、亚硝基脲、纳武单抗、太平洋紫杉醇、派立珠单抗、皮利木单抗(pilimumab)、替莫唑胺、曲美替尼、维罗非尼、长春碱及其任何组合。
卵巢癌组合疗法
在一些实施例中,额外治疗剂适用于治疗卵巢癌,其包括5-氟尿嘧啶、白蛋白结合型太平洋紫杉醇、六甲蜜胺、阿那曲唑、贝伐珠单抗、卡培他滨、卡铂、顺铂、环磷酰胺、多西他赛、小红莓、依托泊苷、依西美坦、吉西巴宾(gemcibabine)、异环磷酰胺、伊立替康、来曲唑、乙酸亮丙立德、脂质体小红莓、乙酸甲地孕酮、美法仑、奥拉帕尼、奥沙利铂、太平洋紫杉醇、帕佐泮尼、培美曲塞、他莫昔芬、拓朴替康、长春瑞宾及其任何组合。
胰脏癌组合疗法
在一些实施例中,额外治疗剂适用于治疗胰脏癌,其包括5-氟尿嘧啶、白蛋白结合型太平洋紫杉醇、卡培他滨、顺铂、多西他赛、埃罗替尼、氟嘧啶、吉西他滨、伊立替康、甲酰四氢叶酸、奥沙利铂、太平洋紫杉醇及其任何组合。
肾细胞癌组合疗法
在一些实施例中,额外治疗剂适用于治疗肾细胞癌,其包括阿西替尼、贝伐珠单抗、卡博替尼、埃罗替尼、依维莫司、乐瓦替尼(levantinib)、纳武单抗、帕佐泮尼、索拉非尼、舒尼替尼、坦罗莫司及其任何组合。
VIII.套组
本发明提供一种套组,其包含本发明化合物或其医药学上可接受的盐。该套组可进一步包含例如用于治疗病毒感染的使用说明书。使用说明书一般为书面说明书,但含有说明书的电子储存媒体(例如,磁盘或光盘)亦为可接受的。
本发明亦提供一种医药套组,其包含有包含本发明化合物或其医药学上可接受的盐的一或多个容器。与这种容器视情况相关联的可为由管理医药产物的制造、使用或销售的政府机构所规定形式的注意事项,该注意事项反映由用于人类施用的制造、使用或销售机构的批准。各种组分(若存在超过一种组分)可封装于独立容器中,或在交叉反应性及存放期允许的情况下,可以将一些组分合并于一个容器中。套组可呈单位剂型、散装封装(例如,多剂量封装)或次单位剂量。套组亦可包括多个单位剂量的化合物及使用说明书,且以足以供药房(例如,医院药房及混配药房)储存及使用的量封装。
亦提供制品,其包含单位剂量的本发明化合物或其医药学上可接受的盐,以适合封装用于本文所描述的方法。适合封装为此项技术中已知,且包括例如小瓶、容器、安瓿、瓶子、罐、可挠性封装及其类似物。制品可进一步经灭菌及/或密封。
IX.实例
实施例亦关于适用于制备目标化合物或其医药学上可接受的盐的方法及中间物。
提供适用于合成所公开的化合物的通常已知的化学合成流程及条件的许多一般参考文献为可用的(参见例如Smith,March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,第7版,Wiley-Interscience,2013)。
如本文所描述的化合物可通过此项技术中已知的任何方法纯化,包括层析法,诸如高效液相层析(HPLC)、制备型薄层层析、急骤管柱层析及离子交换层析。可使用任何适合的固定相,包括正相及逆相以及离子树脂。所公开的化合物最通常经由硅胶及/或氧化铝层析法来纯化。参见例如Introduction to Modern Liquid Chromatography,第2版,L.R.Snyder及J.J.Kirkland编,John Wiley and Sons,1979;及Thin LayerChromatography,E.Stahl(编),Springer-Verlag,纽约,1969。
化合物是使用标准仪器法表征。除非另外说明,否则1H、19F及31P NMR谱在BrukerAvanceTM III HD 400MHz NMR上获得。在Waters Q-Tof Micro上获得电洒离子化法(ESI)模式下的质谱。在Waters LC-MS仪器(Waters 600控制器、Waters 3100质量侦测器、Waters光电二极管数组侦测器)上经Luna C18管柱(Phenomenex,5μm,150×4.6mm)及Zic-Hilic管柱(SeQuant,5μm,100×4.6mm)获得HPLC。
在用于制备目标化合物的任何制程期间,可能必要及/或需要保护所涉及的任何分子上的敏感性或反应性基团。此可藉助于常规保护基达成,如描述于标准著作中,诸如T.W.Greene及P.G.M.Wuts,“Protective Groups in Organic Synthesis”,第4版,Wiley,纽约2006。可在适宜后续阶段使用此项技术已知的方法移除保护基。
适用于实施例的方法的例示性化学实体现将参考说明性合成流程关于本文中其通用制备及随后具体实例来描述。业内人士应认识到,为获得本文的各种化合物,起始物质可经适当选择,以使得按需要在存在或不存在保护措施下经由反应流程带有最终所要取代基,得到所要产物。可替代地,可能需要或希望在最终所要取代基的位置利用可经由反应流程携带且适当时经所要取代基置换的适合基团。此外,熟习此项技术者应认识到,以下流程中所展示的转化可按与特定侧基的官能性兼容的任何次序执行。一般流程中所描绘的各反应较佳在约0℃至所用有机溶剂的回流温度的温度下运作。
本文所提供的实例描述本文所公开的化合物的合成以及用于制备该等化合物的中间物。应理解,可组合本文所描述的个别步骤。亦应理解,独立批次的化合物可组合且随后继续用于下一合成步骤中。
在以下实例描述中,描述具体实施例。足够详细地描述这些实施例以使熟习此项技术者能够实践本发明的某些实施例。可利用其他实施例,且可在不脱离本发明的范围的情况下作出逻辑及其他改变。因此,以下描述并不意欲限制本发明的范围。
本发明的方法一般提供特定对映异构体或非对映异构体作为所要产物,但在所有情况下均未确定对映异构体或非对映异构体的立体化学。当未确定对映异构体或非对映异构体中特定立体中心的立体化学时,在不展示彼特定立体中心处的任何立体化学的情况下绘制化合物,尽管该化合物可为实质上对映异构性或非对映异构性纯。
本发明化合物的代表性合成描述于以下流程及随后特定实例中。
实例中详细描述的特定2'3'-环二核苷酸根据下文所描述的通用合成方法合成。除非另外指示,否则化合物使用ChemAxon(匈牙利布达佩斯)命名。
下文展示的实例中使用的缩写包括以下:
实例1.核苷酸单体的制备
流程1
H-次膦酸2:在4℃在氩气下向中间物1(5g,7.4mmol)于DMF(75mL)中的搅拌溶液中添加氢化钠(900mg,22.2mmol)(流程1)。将反应混合物在4℃下在氩气下再搅拌60分钟。在氩气下向反应混合物中添加H-次膦酸甲苯磺酰酯(3.05g,11.1mmol)。将反应混合物在室温下在氩气下再搅拌16小时。此后,在4℃下向反应混合物中逐滴添加于DMF(10mL)中的冰醋酸(1.27mL,22.2mmol),且将反应混合物蒸发。将残余物溶解于氯仿(0.5L)中且用碳酸氢钠(3×100ml)萃取。有机层经无水硫酸钠干燥,且蒸发。将粗H-次膦酸2在DCM(50mL)中装载于硅胶管柱上。将管柱用二氯乙酸(DCA,50mL,3%DCM溶液)洗涤,且在室温下静置15分钟。随后将管柱用DCA(100mL,3%DCM溶液)/10%EtOH的CHCl3溶液(100mL)洗涤,且此后用10%EtOH的CHCl3溶液(500mL)洗涤。将中间物2用50%MeOH的H2O溶液(500mL)洗涤出管柱,蒸发,通过制备型HPLC纯化(用0-50%甲醇的水溶液的梯度溶离)且自水中冷冻干燥,得到冻干物:HRMS(ESI)C18H19O6N5FNaP(M+Na)+的计算值474.09492,实验值474.09485;1H NMR(MeOD-d4)δ8.74(s,2H),8.09(m,2H),7.66(m,1H),7.56(m,2H),7.10(ddd,J=508.5,2.9,1.2Hz,1H),6.46(dd,J=16.0,2.6Hz,1H),5.69(ddd,J=52.2,4.2,2.6Hz,1H),4.60(ddd,J=17.4,6.9,4.2Hz,1H),4.27(dddd,J=6.9,3.0,2.4,1.1Hz,1H),3.96(dd,J=12.8,2.4Hz,1H),3.86(dd,J=12.8,3.0Hz,1H),3.80(ddd,J=13.3,5.7,1.2Hz,1H),3.64(ddd,J=13.3,9.3,2.9Hz,1H);31P NMR(MeOD-d4)δ18.79;19F NMR(MeOD-d4)δ-203.85。
膦酸酯3的制备:在4℃在氩气下向中间物1(4g,6mmol)于DMF(60mL)中的搅拌溶液中添加氢化钠(720mg,18mmol)。将反应混合物在4℃下在氩气下再搅拌60分钟。在氩气下向反应混合物中添加膦酸甲苯磺酰酯(3.144g,9mmol)。将反应混合物在r.t.下在氩气下再搅拌16小时。此后,在4℃下向反应混合物中逐滴添加于DMF(10mL)中的冰AcOH(1.03mL,18mmol)。蒸发反应混合物且通过硅胶层析(用0-10%乙醇/氯仿的梯度溶离))纯化膦酸酯3:HRMS(ESI)C45H49O9N5FNaP(M+Na)+的计算值876.31441,实验值876.31425;1H NMR(DMSO-d6)δ11.28(br s,1H),8.72(s,1H),8.59(s,1H),8.04(m,2H),7.65(m,1H),7.55(m,2H),7.31(m,2H),7.22(m,2H),7.18(m,5H),6.80(m,4H),6.48(dd,J=19.5,1.6Hz,1H),5.98(ddd,J=51.9,4.2,1.6Hz,1H),4.81(ddd,J=20.7,8.1,4.2Hz,1H),4.54(m,2H),4.25(ddd,J=8.1,5.6,2.5Hz,1H),3.96(dd,J=13.7,8.8Hz,1H),3.89(dd,J=13.7,9.2Hz,1H),3.74(dd,J=10.9,5.6Hz,1H),3.70(s,6H),3.24(dd,J=10.9,2.5Hz,1H),1.21(d,J=6.2Hz,3H),1.18(d,J=6.2Hz,3H),1.16(d,J=6.2Hz,3H),1.14(d,J=6.2Hz,3H);31P NMR(DMSO-d6)δ18.96;19F NMR(DMSO-d6)δ-199.06。
单体4的制备:将溴三甲基硅烷(2.164mL;16.4mmol)添加至膦酸二乙酯(3.5g;4.1mmol)及2,6-二甲基吡啶(3.82mL;32.8mmol)于ACN(45mL)中的溶液中。将反应混合物在r.t.下搅拌16小时且蒸发。将残余物溶解于氯仿(0.5L)中且用0.2M TEAB(3×100ml)萃取。有机层经无水硫酸钠干燥,蒸发,且与二噁烷及吡啶共同蒸发。粗核苷膦酸不经进一步纯化即使用。
将2-氯-5,5-二甲基-1,3,2-二氧磷杂环己烷2-氧化物(DMOCP)(3.772g;20.5mmol)添加至前述粗核苷膦酸、4-甲氧基-2-吡啶基甲醇(Pic-OH)(1.712g;12.3mmol)及4-甲氧基吡啶-N-氧化物(MPNO)(2.564g;20.5mmol)于吡啶(45mL)中的溶液中。将反应混合物在r.t.下搅拌16小时,通过添加2M TEAB(20mL)淬灭,且蒸发。将残余物溶解于氯仿(0.5L)中且用0.2M TEAB(3×100ml)萃取。有机层经无水硫酸钠干燥,蒸发,且与二噁烷共同蒸发。在r.t.下用于二噁烷(45mL)中的苯硫酚(6mL)及TEA(8.4mL)处理粗产物6小时。将后续反应混合物用乙酸乙酯稀释,且直接通过硅胶层析(用0-100%乙酸乙酯/乙醇/丙酮/水4:1:1:1于乙酸乙酯中的梯度溶离(SiO2经TEA缓冲))纯化,且自二噁烷中冻干,得到中间物4:HRMS(ESI)C46H43O10N6FP(M-H)-的计算值889.27678,实验值889.27583;1H NMR(DMSO-d6)δ11.25(br s,1H),8.74(s,1H),8.67(s,1H),8.26(d,J=5.7Hz,1H),8.04(m,2H),7.64(m,1H),7.54(m,2H),7.27(m,2H),7.19(m,2H),7.14(m,5H),7.04(d,J=2.6Hz,1H),6.81(dd,J=5.7,2.6Hz,1H),6.76(m,4H),6.43(dd,J=18.6,1.6Hz,1H),6.01(ddd,J=51.8,4.0,1.6Hz,1H),4.90(ddd,J=22.3,8.1,4.0Hz,1H),4.80(dd,J=14.3,7.5Hz,1H),4.78(dd,J=14.3,7.5Hz,1H),4.20(ddd,J=8.1,5.0,2.5Hz,1H),3.96(dd,J=13.7,8.8Hz,1H),3.89(dd,J=13.7,9.2Hz,1H),3.77(s,3H),3.67(s,6H),3.64(m,2H),3.31(dd,J=11.0,2.5Hz,1H),3.22(dd,J=11.0,5.0Hz,1H);31P NMR(DMSO-d6)δ12.48;19F NMR(DMSO-d6)δ-199.61。
单体5的制备:将膦酸酯4(1.3g,1.5mmol)在DCM(10mL)中装载于硅胶管柱上。将管柱用DCA(10mL,3%DCM溶液)洗涤,且在r.t.下静置15分钟。随后将管柱用DCA(25mL,3%DCM溶液)/10%EtOH的CHCl3溶液(25mL)洗涤,且此后用10%EtOH的CHCl3溶液(100mL)洗涤。将粗产物5用50%MeOH的H2O溶液(100mL)洗涤出管柱,蒸发,通过制备型HPLC(用0-50%甲醇的水溶液的梯度溶离)纯化,使用DOWEXTM Na+转化为钠盐,且自水中冷冻干燥,得到中间物5:HRMS(ESI)C25H25O8N6FP(M-H)-的计算值587.14610,实验值587.14561;1H NMR(DMSO-d6)δ11.23(br s,1H),8.82(s,1H),8.76(s,1H),8.26(d,J=5.6Hz,1H),8.05(m,2H),7.64(m,1H),7.55(m,2H),7.11(d,J=2.6Hz,1H),6.81(dd,J=5.6,2.6Hz,1H),6.36(br d,J=16.1Hz,1H),5.55(br dd,J=53.1,3.7Hz,1H),4.82(ddd,J=26.5,9.2,3.7Hz,1H),4.82(dd,J=14.5,7.7Hz,1H),4.80(dd,J=14.5,7.7Hz,1H),4.00(dt,J=9.2,2.1Hz,1H),3.82(s,3H),3.82(dd,J=13.2,2.1Hz,1H),3.78(dd,J=13.2,2.1Hz,1H),3.64(dd,J=14.2,8.0Hz,1H),3.60(dd,J=14.2,3.5Hz,1H);31P NMR(DMSO-d6)δ13.65;19F NMR(DMSO-d6)δ-198.08。
流程2
亚胺基磷酸酯使用标准方案根据以下制备:Páv,O;I.;I.;Pohl,R.;M.;Rosenberg,I.Synthesis of oligoribonucleotides withphosphonate-modified linkages.Org.Biomol.Chem.2011,,9,6120-6126及Páv,O.;Panova,N.;J.;E.;Rosenberg I.Activation of human RNase L by2'-and 5'-O-methylphosphonate-modified oligoadenylates.Bioorg.Med.Chem.Lett.2012,22,181-185(流程2)。
亚胺基磷酸酯单体6-C的例示性制备:在氩气下向中间物6-B(1.4g,2.2mmol)及N,N,N′,N′-四异丙基二胺基磷酸甲酯(1.8mL,6.5mmol)于DCM(20mL)中的搅拌溶液中添加于ACN中的0.45M四唑(14.4mL,6.5mmol)。将反应混合物在r.t.下在氩气下搅拌2小时,随即将混合物用DCM(300mL)稀释且用饱和碳酸氢钠溶液(3×100ml)洗涤。有机层经无水硫酸钠干燥,且蒸发。将残余物溶解于甲苯(5mL)中且逐滴添加至己烷(300mL)中,形成固体沈淀物。收集沈淀物且自苯中冷冻干燥,得到中间物6-C:31P NMR(C6D6)δ155.69(d,J=4.8Hz),155.27(d,J=5.8Hz)。
以与上文所描述的方案类似的方式,由中间物7-B制备中间物7-C。
中间物 | NMR资料 |
7-C | <sup>31</sup>P NMR(C<sub>6</sub>D<sub>6</sub>)δ155.13(d,J=4.0Hz),154.76(d,J=8.0Hz)。 |
实例2.硫代磷酸环二核苷酸的制备
流程3
将DMOCP(0.66g;3.6mmol)添加至膦酸酯单体4(0.8g;0.9mmol)及核苷8(0.7g;1.1mmol)于吡啶(20mL)中的溶液中(流程3)。将反应混合物在r.t.下搅拌2小时,通过添加甲醇(5mL)淬灭,蒸发,且与甲醇(3×10mL)共同蒸发。在r.t.下用80%乙酸的水溶液(10mL)处理残余物16小时。将溶液直接装载于C18管柱上,且使用乙腈的水溶液的线性梯度分离直链二聚体9:ESI-MS(中间物9)C39H41F2N11O12P(M-H)-的计算值924.3,实验值924.3。
将直链二聚体9与DCM-二噁烷1:1(3×10mL)共同蒸发,溶解于DCM(50mL)中,且添加TEA(0.25mL;1.8mmol)。将亚磷酸三(1,1,1,3,3,3-六氟-2-丙基)酯每15分钟逐份添加至混合物中(6×48μL;0.15mmol(0.29mL;0.9mmol;总量))。在r.t.下1.5小时后,添加0.1MTEAB水溶液(10mL),且将混合物在r.t.下严密搅拌30分钟。蒸发混合物,且直链H-膦酸酯二聚体10不经进一步纯化即使用:ESI-MS((中间物10)C39H42F2N11O14P2(M-H)-的计算值988.2,实验值988.3。
将DMOCP(0.22g;1.2mmol)添加至直链H-膦酸酯二聚体10(0.23g;0.23mmol)于吡啶(60mL)中的溶液中,且将反应混合物在r.t.下搅拌2.5小时。此后,添加硫(73mg;2.3mmol)。在r.t.下搅拌1小时后,添加水(40mL)且将混合物在65℃下搅拌4小时,蒸发,且与甲醇(3×10mL)共同蒸发。将混合物溶解于50%ACN的水溶液(10mL)中且添加33%甲胺的乙醇溶液(5mL)。将混合物搅拌7小时且蒸发。两种非对映异构体的混合物使用制备型C18HPLC以大致3:2比率分离为HPLC较快溶离异构体化合物11a及较慢溶离异构体化合物11b。用于纯化的制备型HPLC条件如下:Luna C18(5μm,250×21.2mm,Phenomenex);流量10毫升/分钟;流动相A:0.1M TEAB/H2O,流动相B:50%ACN/0.1M TEAB/H2O。HPLC方法:等度溶离A(10分钟),随后线性梯度A-40%B(60分钟)。滞留时间(min):35.4(化合物11a)及55.3(化合物11b)。
非对映异构体使用DOWEX Na+转化为钠盐,且自水中冷冻干燥,得到化合物11a及化合物11b。
化合物11a:ESI-MS C21H23F2N10O10P2S(M-H)-的计算值707.1,实验值707.1;1H NMR(D2O)δ8.32(s,1H),8.26(s,1H),8.08(s,1H),6.45(d,J=17.4Hz,1H),6.15(d,J=8.2Hz,1H),5.75(dd,J=51.8,4.0Hz,1H),5.45(dd,J=53.5,4.1Hz,1H),5.32(dddd,J=24.8,13.1,8.2,4.1Hz,1H),4.82(m,2H),4.49(ddd,J=8.2,5.0,2.7Hz,1H),4.29(m,2H),4.12(m,2H),4.01(dd,J=13.7,9.2Hz,1H),3.96(dd,J=13.7,9.0Hz,1H);19F NMR(D2O)δ-192.90,-199.21;32P NMR(D2O)δ59.07,17.67。
化合物11b:ESI-MS C21H23F2N10O10P2S(M-H)-的计算值707.1,实验值707.1;1H NMR(D2O)δ8.26(s,1H),8.21(s,1H),8.03(s,1H),6.44(d,J=17.9Hz,1H),6.15(d,J=8.3Hz,1H),5.70(dd,J=52.0,3.8Hz,1H),5.53(dd,J=53.3,4.0Hz,1H),5.26(dddd,J=24.8,11.3,8.3,4.0Hz,1H),4.75(ddd,J=9.0,2.4,2.1Hz,1H),4.69(ddd,J=25.2,9.1,3.8Hz,1H),4.55(m,1H),4.35(ddd,J=11.9,4.5,3.5Hz,1H),4.27(ddd,J=11.6,5.5,2.4Hz,1H),4.14(ddd,J=11.9,4.8,2.5Hz,1H),4.10(ddt,J=11.6,3.2,2.1Hz,1H),4.06(dd,J=14.0,8.5Hz,1H),3.91(dd,J=14.0,9.2Hz,1H);19F NMR(D2O)δ-193.23,-199.04;32P NMR(D2O)δ54.70,17.85。
流程4
将ETT(0.47g;3.7mmol)添加至5(0.39g;0.66mmol)及亚胺基磷酸酯7-C(0.54g;0.73mmol)于DCM(20mL)中的溶液中。将反应混合物在r.t.下在氩气下搅拌2.5小时。此后,添加DDTT(0.29g;1.4mmol)且将混合物在r.t.下搅拌1小时。蒸发反应混合物。在r.t.下用80%乙酸的水溶液(10mL)处理残余物2小时。将溶液直接装载于C18管柱上且使用乙腈/5mM碳酸氢铵的线性梯度分离直链膦酸酯二聚体12:ESI-MS(中间物12)C36H37F2N10O13P2S(M-H)-的计算值949.2,实验值949.4。
将5,5-二甲基-2-侧氧基-2-氯-1,3,2-二氧杂磷杂环己烷(DMOCP,0.48g;2.5mmol)添加至直链膦酸酯二聚体12(0.18g;0.2mmol)于吡啶(10mL)中的溶液中,且将反应混合物在r.t.下搅拌3.0小时。随后添加水(5mL)且将混合物在65℃下搅拌4小时,蒸发,且与甲醇(3×10mL)共同蒸发。将混合物溶解于50%ACN的水溶液(10mL)中且添加33%甲胺的乙醇溶液(5mL)。将混合物搅拌4小时且蒸发。两种非对映异构体的混合物使用制备型C18HPLC以大致1:2比率分离为HPLC较快溶离异构体化合物13a及较慢溶离异构体化合物13b。用于纯化的制备型HPLC条件如下:Luna C18(5μm,250×21.2mm,Phenomenex);流量10毫升/分钟;流动相A:0.1M TEAB/H2O,流动相B:50%ACN/0.1M TEAB/H2O。HPLC方法:等度溶离A(10分钟),随后线性梯度A-40%B(60分钟)。滞留时间(min):38.1(化合物13a)及58.3(化合物13b)。
非对映异构体使用DOWEX Na+转化为钠盐,且自水中冷冻干燥,得到化合物13a及化合物13b。
化合物13a:ESI-MS C21H22F2N9O10P2S(M-H)-的计算值692.1,实验值692.3;1H NMR(D2O)δ8.41(s,1H),8.31(s,1H),8.26(s,1H),8.12(s,1H),6.46(dd,J=17.1,0.8Hz,1H),6.35(d,J=8.1Hz,1H),5.74(ddd,J=52.0,3.8,0.8Hz,1H),5.48(dd,J=53.4,4.1Hz,1H),5.41(dddd,J=24.7,13.2,8.1,4.1Hz,1H),4.80-4.76(m,2H),4.51(ddd,J=8.5,4.6,2.6Hz,1H),4.31(ddd,J=11.4,5.7,4.6Hz,1H),4.30(ddd,J=11.5,5.2,2.7Hz,1H),4.17(dddd,J=11.5,3.9,2.6,1.6Hz,1H),4.12(ddd,J=11.4,4.1,2.6Hz,1H),4.01(dd,J=13.6,8.8Hz,1H),3.96(dd,J=13.6,10.1Hz,1H);19F NMR(D2O)δ-193.25,-199.71;32P NMR(D2O)δ58.60,17.95。
化合物13b:ESI-MS C21H22F2N9O10P2S(M-H)-的计算值692.1,实验值692.2;1H NMR(D2O)δ8.36(s,1H),8.26(s,1H),8.19(s,1H),8.11(s,1H),6.45(d,J=17.5Hz,1H),6.34(d,J=8.2Hz,1H),5.69(dd,J=51.9,3.7Hz,1H),5.55(dd,J=53.2,4.1Hz,1H),5.39(dddd,J=24.6,11.2,8.2,4.1Hz,1H),4.79(m,1H),4.65(ddd,J=25.2,9.2,3.7Hz,1H),4.56(ddd,J=9.2,3.0,2.4Hz,1H),4.36(ddd,J=11.9,4.3,3.0Hz,1H),4.28(ddd,J=11.5,5.5,2.6Hz,1H),4.13(dddd,J=11.5,3.5,2.3,1.9Hz,1H),4.12(ddd,J=11.9,4.8,2.4Hz,1H),4.05(dd,J=13.7,8.0Hz,1H),3.91(dd,J=13.7,10.6Hz,1H);19F NMR(D2O)δ-193.49,-199.51;32P NMR(D2O)δ54.67,18.09。
实例3.硫代膦酸环二核苷酸的制备
流程5
将ETT(0.56g;4.3mmol)添加至H-次膦酸酯2(0.4g;0.85mmol)及亚胺基磷酸酯6-C(0.7g;0.85mmol)于DCM(15mL)中的溶液中。将反应混合物在r.t.下在氩气下搅拌2小时。此后,添加(-)-(8,8-二氯樟脑基磺酰基)-噁吖丙啶(CSO)(0.7g;2.6mmol),且将混合物在r.t.下搅拌1小时。随后用甲醇(15mL)处理溶液,且将混合物在r.t.下搅拌1小时,引起DMTr基团裂解。蒸发溶液且使用乙腈/5mM碳酸氢铵的线性梯度在C18逆相上分离直链H-次膦酸酯二聚体14:ESI-MS(中间物14)C33H37F2N10O13P2(M-H)-的计算值881.2,实验值881.2。
将DMOCP(0.18g;1.0mmol)添加至直链H-次膦酸酯二聚体14(0.18g;0.2mmol)于吡啶(60mL)中的溶液中,且将反应混合物在r.t.下搅拌3.0小时。此后,添加硫(63mg;2.0mmol)。在r.t.下搅拌1小时后,添加水(40mL)且将混合物在65℃下搅拌4小时,蒸发,且与甲醇(3×10mL)共同蒸发。将混合物溶解于50%ACN的水溶液(10mL)中且添加33%甲胺的乙醇溶液(5mL)。将混合物搅拌7小时且蒸发。两种非对映异构体的混合物使用制备型C18HPLC以大致2:1比率分离为HPLC较快溶离异构体化合物15a及较慢溶离异构体化合物15b。用于纯化的制备型HPLC条件如下:Luna C18(5μm,250×21.2mm,Phenomenex);流量10毫升/分钟;流动相A:0.1M TEAB/H2O,流动相B:50%ACN/0.1M TEAB/H2O。HPLC方法:等度溶离A(10分钟),随后线性梯度A-40%B(60分钟)。滞留时间(min):42.0(化合物15a)及55.1(化合物15b)。
非对映异构体使用DOWEX Na+转化为钠盐,且自水中冷冻干燥,得到化合物15a及化合物15b。
化合物15a:ESI-MS C21H23F2N10O10P2S(M-H)-的计算值707.1,实验值707.1;1H NMR(D2O)δ8.24(s,1H),8.15(s,1H),8.07(s,1H),6.41(d,J=17.3Hz,1H),6.16(d,J=8.0Hz,1H),5.68(dd,J=51.9,3.7Hz,1H),5.50(dd,J=52.9,3.9Hz,1H),5.02(dtd,J=24.8,8.2,3.9Hz,1H),4.82(m,1H),4.61(ddd,J=25.1,9.2,3.7Hz,1H),4.51(dq,J=9.2,2.7Hz,1H),4.31(ddt,J=11.6,3.8,2.6Hz,1H),4.29(dt,J=11.8,3.0Hz,1H),4.22(dd,J=13.6,2.8Hz,1H),4.17(ddd,J=11.6,3.5,2.2Hz,1H),4.165(dt,J=11.8,2.3Hz,1H),3.96(dd,J=13.6,6.2Hz,1H);19F NMR(D2O)δ-193.20,-199.43;32P NMR(D2O)δ69.17,-1.06。
化合物15b:ESI-MS C21H23F2N10O10P2S(M-H)-的计算值707.1,实验值707.1;1H NMR(D2O)δ8.24(s,1H),8.18(s,1H),8.01(s,1H),6.42(d,J=17.8Hz,1H),6.15(d,J=8.1Hz,1H),5.69(dd,J=51.9,3.8Hz,1H),5.43(dd,J=53.3,4.1Hz,1H),5.02(dddd,J=24.5,8.8,8.1,4.1Hz,1H),4.78(m,1H),4.66(ddd,J=25.5,9.3,3.8Hz,1H),4.52(dq,J=9.3,2.6Hz,1H),4.48(ddd,J=11.8,7.8,2.1Hz,1H),4.29(dt,J=11.9,3.0Hz,1H),4.16(ddd,J=11.9,3.8,2.6Hz,1H),4.09(dd,J=13.2,1.5Hz,1H),4.06(dt,J=11.8,2.1Hz,1H),3.99(dd,J=13.2,10.7Hz,1H);19F NMR(D2O)δ-193.42,-198.95;32P NMR(D2O)δ72.25,-1.02。
实例4.硫代磷酸-硫代膦酸环二核苷酸的制备
流程6
将ETT(0.26g;2.0mmol)添加至H-次膦酸酯2(0.17g;0.36mmol)及亚胺基磷酸酯6-C(0.32g;0.4mmol)于DCM(10mL)中的溶液中。将反应混合物在r.t.下在氩气下搅拌2小时。此后,添加DDTT(81mg;0.4mmol),且将混合物在r.t.下搅拌1小时。随后用甲醇(10mL)处理溶液,且将混合物在r.t.下搅拌1小时,引起DMTr基团裂解。蒸发溶液且通过硅胶层析(用0-50%甲醇/氯仿的梯度溶离)纯化直链H-次膦酸酯二聚体16:ESI-MS(中间物16)C33H37F2N10O12P2S(M-H)-的计算值897.2,实验值897.2。
将DMOCP(0.17g;0.9mmol)添加至直链H-次膦酸酯二聚体16(0.17g;0.18mmol)于吡啶(60mL)中的溶液中,且将反应混合物在r.t.下搅拌3.0小时。此后,添加硫(59mg;1.8mmol)。在r.t.下搅拌1小时后,添加水(40mL)且将混合物在65℃下搅拌4小时,蒸发,且与甲醇(3×10mL)共同蒸发。将混合物溶解于50%ACN的水溶液(10mL)中且添加33%甲胺的乙醇溶液(5mL)。将混合物搅拌6小时且蒸发。四种非对映异构体的混合物使用制备型C18HPLC以大致3:1:9:4比率分别分离为HPLC最快至最慢溶离异构体17a-17d。(化合物17b未分离为纯非对映异构体。)用于纯化的制备型HPLC条件如下:Luna C18(5μm,250×21.2mm,Phenomenex);流量10毫升/分钟;流动相A:0.1M TEAB/H2O,流动相B:50%ACN/0.1MTEAB/H2O。HPLC方法:等度溶离A(10分钟),随后线性梯度A-40%B(60分钟),随后等度40%B(10分钟)。滞留时间(min):46.0(化合物17a)、57.1(化合物17c)及73.2(化合物17d)。
非对映异构体使用DOWEX Na+转化为钠盐,且自水中冷冻干燥,得到化合物17a、化合物17c及化合物17d。
化合物17a:ESI-MS C21H23F2N10O9P2S2(M-H)-的计算值723.1,实验值723.1;1H NMR(D2O)δ8.32(s,1H),8.26(s,1H),8.17(s,1H),6.44(dd,J=16.7,1.1Hz,1H),6.16(d,J=8.1Hz,1H),5.78(ddd,J=51.8,3.8,1.1Hz,1H),5.47(dd,J=53.0,4.0Hz,1H),5.28(dddd,J=25.3,12.8,8.1,4.0Hz,1H),4.94(ddd,J=23.4,8.4,3.8Hz,1H),4.82(m,1H),4.50(m,1H),4.29(ddd,J=11.4,6.3,5.3Hz,1H),4.29(m,1H),4.20(ddd,J=11.4,5.2,2.6Hz,1H),4.18(dd,J=13.6,4.5Hz,1H),4.11(ddd,J=11.3,4.0,2.8Hz,1H),4.05(dd,J=13.6,4.6Hz,1H);19F NMR(D2O)δ-192.92,-200.10;32P NMR(D2O)δ69.07,58.84。
化合物17c:ESI-MS C21H23F2N10O9P2S2(M-H)-的计算值723.1,实验值723.1;1H NMR(D2O)δ8.26(s,1H),8.17(s,1H),8.08(s,1H),6.42(d,J=17.4Hz,1H),6.16(d,J=8.1Hz,1H),5.70(dd,J=51.9,3.8Hz,1H),5.61(dd,J=53.0,3.9Hz,1H),5.16(dddd,J=25.0,10.7,8.1,3.9Hz,1H),4.82(m,1H),4.69(ddd,J=24.8,9.0,3.8Hz,1H),4.57(ddt,J=9.0,3.5,2.5Hz,1H),4.33(ddd,J=11.9,4.7,3.5Hz,1H),4.28(ddt,J=11.5,3.5,2.6Hz,1H),4.21(dd,J=13.7,3.4Hz,1H),4.18(ddd,J=11.5,5.4,2.2Hz,1H),4.16(ddd,J=11.9,4.8,2.5Hz,1H),4.00(dd,J=13.7,5.6Hz,1H);19F NMR(D2O)δ-192.79,-199.30;32P NMR(D2O)δ69.18,54.27。
化合物17d:ESI-MS C21H23F2N10O9P2S2(M-H)-的计算值723.1,实验值723.1;1H NMR(D2O)δ8.26(s,1H),8.19(s,1H),8.02(s,1H),6.44(d,J=17.9Hz,1H),6.14(d,J=8.2Hz,1H),5.69(dd,J=52.0,3.8Hz,1H),5.51(dd,J=53.3,4.0Hz,1H),5.15(dddd,J=24.6,10.9,8.2,4.0Hz,1H),4.78(m,1H),4.69(ddd,J=25.1,9.1,3.8Hz,1H),4.56(dq,J=9.0,2.6Hz,1H),4.48(ddd,J=11.9,8.0,2.2Hz,1H),4.34(ddd,J=11.9,4.7,2.8Hz,1H),4.15(ddd,J=11.9,4.7,2.5Hz,1H),4.09(dd,J=13.2,2.1Hz,1H),4.05(dq,J=11.9,2.2Hz,1H),4.02(dd,J=13.2,10.2Hz,1H);19F NMR(D2O)δ-192.86,-198.54;32P NMR(D2O)δ72.21,54.35。
实例5.甲基膦酸环二核苷酸的制备
流程7
将DIAD(0.7mL;3.4mmol)添加至中间物7-B(1.0g;1.7mmol)、苯甲醇(0.4mL;3.4mmol)及三苯基膦(0..9g;3.4mmol)于THF(20mL)中的溶液中(流程7)。将反应混合物在室温下搅拌16小时,随即将混合物用DCM(300mL)稀释,用水(3×100ml)洗涤,且浓缩有机层。通过硅胶层析(用0-10%乙醇/氯仿的梯度溶离)纯化残余物,得到中间物18:ESI-MSC38H36FN4O6(M+H)+的计算值663.3,实验值663.3;1H NMR(DMSO-d6)δ8.47(s,1H),8.25(s,1H),7.35-7.17(m,11H),6.85(m,4H),5.91(d,J=7.5Hz,1H),5..25(d,J=14.5Hz,1H),5.20(d,J=14.5Hz,1H),5.11(ddd,J=54.2,4.3,1.6Hz,1H),4.99(dddd,J=23.8,7.3,6.3,4.3Hz,1H),4.34(dddd,J=26.3,5.6,4.4,1.6Hz,1H),3.72(s,6H),3.33(dd,J=10.5,5.6Hz,1H),3.25(dd,J=10.5,4.5Hz,1H)。
在氩气下向中间物18(0.7g,1.1mmol)及N,N,N′,N′-四异丙基二胺基磷酸甲酯(0.9mL,3.3mmol)于DCM(10mL)中的搅拌溶液中添加于乙腈中的0.45M四唑(7.2mL,3.3mmol)。将反应混合物在室温下在氩气下搅拌2小时,随即将混合物用DCM(300mL)稀释,且用饱和碳酸氢钠溶液(3×100ml)洗涤。有机层经无水硫酸钠干燥,且蒸发。通过硅胶层析(用0-50%乙酸乙酯/甲苯的梯度溶离)纯化残余物。将产物蒸发且自苯中冷冻干燥,得到中间物19:31P NMR(C6D6)δ155.08(d,J=4.7Hz),154.73(d,J=6.1Hz)。
流程8
将ETT(52mg;0.4mmol)添加至中间物5(50mg;0.09mmol)及中间物19(83mg;0.1mmol)于DCM(20mL)中的溶液中(流程8)。将反应混合物在室温下在氩气下搅拌2小时。此后,添加CSO(75mg;0.25mmol)且将混合物在室温下搅拌1小时。蒸发反应混合物。在室温下用80%乙酸的水溶液(10mL)处理残余物2小时。将溶液直接装载于C18管柱上且使用乙腈/5mM碳酸氢铵的线性梯度分离直链膦酸酯二聚体20:ESI-MS C43H45F2N10O14P2(M+H)+的计算值1025.3,实验值1025.5。
将5,5-二甲基-2-侧氧基-2-氯-1,3,2-二氧杂磷杂环己烷(DMOCP,81mg;0.44mmol)添加至中间物20(90mg;0.09mmol)于吡啶(6mL)中的溶液中,且将反应混合物在室温下搅拌4小时。随后添加水(4mL)且将混合物在65℃下搅拌3小时,蒸发,且与甲醇(3×10mL)共同蒸发。使用制备型C18 HPLC分离核碱基保护的CDN。用于纯化的制备型HPLC条件如下:Luna C18(15μm,200×40mm,Phenomenex);流量20毫升/分钟;流动相A:5mM碳酸氢铵/H2O。流动相B:ACN。HPLC方法:用水等度溶离(10分钟),随后用A等度溶离(10分钟)且随后线性梯度A-75%B(60分钟)。将含有核碱基保护的CDN的溶离份蒸发,且在室温下用氨水的乙醇溶液3:1混合物处理16小时。蒸发混合物且使用制备型C18HPLC分离化合物21。用于纯化的制备型HPLC条件如下:Luna C18(5μm,,250×21.2mm,Phenomenex);流量10毫升/分钟;流动相A:0.1M TEAB/H2O,流动相B:50%ACN/0.1M TEAB/H2O。HPLC方法:等度溶离A(10分钟),随后线性梯度A-B(50分钟),滞留时间(min):51.4。
产物使用DOWEX Na+转化为钠盐,且自水中冷冻干燥,得到化合物21:ESI-MSC28H30F2N9O11P2(M+H)+的计算值768.1,实验值768.1;1H NMR(D2O)δ8.51(s,1H),8.24(s,1H),8.21(s,1H),8.08(s,1H),7.47(m,2H),7.42(m,2H),7.38(m,1H),6.39(d,J=16.7Hz,1H),6.39(d,J=8.0Hz,1H),5.67(dd,J=51.5,3.6Hz,1H),5.63(d,J=12.4Hz,1H),5.56(d,J=12.4Hz,1H),5.53(dd,J=52.3,4.0Hz,1H),5.49(dtd,J=25.3,8.0,4.0Hz,1H),4.80(m,1H),4.62(ddd,J=25.8,9.3,3.6Hz,1H),4.51(dq,J=9.3,2.5Hz,1H),4.26(ddd,J=11.5,5.1,2.6Hz,1H),4.23(dt,J=11.8,2.8Hz,1H),4.15(ddd,J=11.8,3.7,2.0Hz,1H),4.14(dddd,J=11.5,3.0,2.4,2.1Hz,1H),4.07(dd,J=13.6,6.8Hz,1H),3.95(dd,J=13.6,12.0Hz,1H);31P NMR(D2O)δ18.36,-1.23;19F NMR(D2O)δ-193.93,-199.77。
将化合物21(10mg,0.013mmol)溶解于50%乙醇-水(5mL)中,添加10%钯/活性木炭(5mg),且将反应混合物在室温下在氢气氛围(1.5atm)下搅拌3小时。经由耐纶针筒过滤器过滤反应混合物且蒸发滤液。产物使用制备型C18 HPLC纯化(用于纯化的制备型HPLC条件如下:Luna C18(5μm,250×10mm,Phenomenex);流量3毫升/分钟;流动相A:0.1M TEAB/H2O,流动相B:50%ACN/0.1M TEAB/H2O;等度溶离A(15分钟),随后线性梯度A-20%B(35分钟),滞留时间(min)=49.8)。所要化合物(1S,6R,8R,9R,10R,16R,18R,19R)-8-(6-胺基-9H-嘌呤-9-基)-9,19-二氟-3,13-二羟基-18-(6-侧氧基-6,9-二氢-1H-嘌呤-9-基)-2,4,7,11,14,17-六氧杂-3λ5,13λ5-二磷杂三环[14.2.1.06,10]十九烷-3,13-二酮(22)使用DOWEX Na+转化为钠盐,且自水中冷冻干燥:ESI-MS(M-H)-C21H22F2N9O11P2的计算值:676.1;实验值:676.1。在25℃下在D2O中的1H、19F及31P NMR资料:1HNMRδ8.35(s,1H),8.18(s,1H),8.08(s,1H),8.06(s,1H),6.45(d,J=17.3Hz,1H),6.35(d,J=8.2Hz,1H),5.68(dd,J=51.9,3.6Hz,1H),5.51(dd,J=53.2,4.0Hz,1H),5.29(dddd,J=24.5,9.3,8.2,4.0Hz,1H),4.80(m,1H),4.62(ddd,J=25.4,9.2,3.6Hz,1H),4.52(dq,J=9.2,2.6Hz,1H),4.30(dt,J=12.0,2.8Hz,1H),4.28(ddd,J=11.5,5.4,2.6Hz,1H),4.15(ddd,J=12.0,3.8,2.4Hz,1H),4.13(ddt,J=11.5,3.6,2.0Hz,1H),4.05(dd,J=13.7,7.7Hz,1H),3.90(dd,J=13.7,11.0Hz,1H);19F NMRδ-193.47,-193.81;31P NMRδ18.14,-0.88。
流程9
将膦酸酯4(2.2g;2.5mmol)溶解于甲醇(20mL)中,且在室温下用33%MeNH2的乙醇溶液(10mL)处理2小时(流程9)。将反应混合物浓缩且与吡啶(30mL)共同蒸发。将残余物溶解于吡啶中,且添加4-戊烯酸酐(1.8mL;10mmol)及DMAP(76mg;0.5mmol)。将反应混合物在50℃下搅拌24小时,随即添加水(10mL),且在60℃下继续加热3小时。浓缩反应混合物。将后续残余物溶解于氯仿(0.5L)中,且用10%柠檬酸(3×100ml)洗涤,且随后用0.2M TEAB(3×100ml)洗涤。有机层经无水硫酸钠干燥且浓缩。将残余物在室温下用80%乙酸的水溶液处理2小时,且将溶液直接装载于C18管柱上。将中间物23使用乙腈的水溶液的线性梯度分离,使用DOWEXTM Na+转化为钠盐,且自二噁烷-水中冷冻干燥:ESI-MS C23H27FN6O8P(M-H)-的计算值565.2,实验值565.2;1H NMR(DMSO-d6)δ10.76(s,1H),8.70(s,1H),8.66(s,1H),8.47(d,J=6.1Hz,1H),7.25(d,J=2.6Hz,1H),7.09(dd,J=6.1,2.6Hz,1H),6.34(dd,J=16.4,2.0Hz,1H),5.87(ddt,J=17.2,10.2,6.4Hz,1H),5.66(ddt,J=52.6,4.0,2.0Hz,1H),5.08(ddt,J=17.2,,2.0,1.6Hz,1H),5.04(d,J=9.2Hz,2H),4.99(ddt,J=10.2,2.0,1.3Hz,1H),4.60(ddd,J=20.8,7.6,4.0Hz,1H),4.07(dddd,J=7.6,3.1,2.5,0.7Hz,1H),3.91(s,3H),3.90(dd,J=13.9,8.6Hz,1H),3.86(dd,J=13.9,7.2Hz,1H),3.77(dd,J=12.7,2.5Hz,1H),3.66(dd,J=12.7,3.1Hz,1H),2.68(m,2H),2.36(m,2H);19F NMR(DMSO-d6)δ-200.01;31P NMR(DMSO-d6)δ17.65。
流程10
将TBDMS-Cl(0.7g;4.5mmol)添加至中间物24(2.0g;3.0mmol;Carbosynth,目录号NB63548)及咪唑(0.3g;4.5mmol)于DMF(30mL)中的溶液中(流程10)。将反应混合物在室温下搅拌16小时,且随后通过添加甲醇(5mL)淬灭。将混合物浓缩,随后用DCM(300mL)稀释,用饱和碳酸氢钠溶液(3×100ml)洗涤,且蒸发。将残余物溶解于甲醇(20mL)中,且在室温下用33%MeNH2的乙醇溶液(10mL)处理2小时。将反应混合物蒸发,且与吡啶共同蒸发。将残余物溶解于吡啶(30mL)中,且添加4-戊烯酸酐(2.3mL;12mmol)及DMAP(91mg;0.6mmol)。将反应混合物在50℃下搅拌24小时。此后,添加水(10mL),且在60℃下继续加热3小时。蒸发反应混合物,且将残余物溶解于氯仿(0.5L)中,且用10%柠檬酸(3×100ml)洗涤,且随后用0.2MTEAB(3×100ml)洗涤。有机层经无水硫酸钠干燥,蒸发,且与甲苯共同蒸发。将残余物溶解于THF(24mL)中,且在室温下用0.5M TBAF(12mL)处理16小时。将溶液用乙醚(200mL)稀释,用10%氯化铵溶液(3×100ml)洗涤,且蒸发。通过硅胶层析(用0-50%丙酮/甲苯的梯度溶离)纯化残余物,得到中间物25:ESI-MS C36H37FN5O6(M+H)+的计算值654.3,实验值654.3;1HNMR(DMSO-d6)δ10.76(s,1H),8.60(s,1H),8.52(s,1H),7.40-7.36(m,2H),7..30-7.17(m,7H),6.90-6.80(m,4H),6.05(d,J=6.4Hz,2H),5.88(ddt,J=16.8,10.3,6.4Hz,1H),5.29-5.16(m,1H),5.09(dq,J=17.2,1.7Hz,1H),5.04-4.95(m,1H),4.47-4.33(m,1H),3.734(s,3H),3.732(s,3H),3.41-3.25(m,2H),2.69(dd,J=8.0,6.9Hz,2H),2.37(ddt,J=7.7,6.4,1.4Hz,2H)。
在氩气下向中间物25(0.7g,1.1mmol)及N,N,N',N'-四异丙基二胺基磷酸甲酯(0.9mL,3.3mmol)于DCM(10mL)中的搅拌溶液中添加于ACN中的0.45M四唑(7.2mL,3.3mmol)。将反应混合物在室温下在氩气下搅拌2小时,随即将混合物用DCM(300mL)稀释且用饱和碳酸氢钠溶液(3×100ml)洗涤。有机层经无水硫酸钠干燥,且蒸发。通过硅胶层析(用0-50%乙酸乙酯/甲苯的梯度溶离)纯化残余物。将产物蒸发且自苯中冷冻干燥,得到中间物26:31P NMR(C6D6)δ155.18(d,J=4.4Hz),154.91(d,=6.7Hz)。
流程11
将ETT(0.66g;5.5mmol)添加至膦酸酯23(0.5g;0.88mmol)及亚胺基磷酸酯26(0.9g;1.1mmol)于DCM(35mL)中的溶液中。将反应混合物在室温下在氩气下搅拌1小时。此后,添加CSO(0.9g;3.3mmol)且将混合物在室温下搅拌1小时。随后将溶液用甲醇(5mL)处理且蒸发。将残余物在室温下用80%乙酸的水溶液(10mL)处理2小时,且此后将溶液直接装载于C18管柱上,且使用乙腈的水溶液的线性梯度分离直链二聚体。ESI-MS C39H46F2N11O14P2(M-H)-的计算值992.3,实验值992.3。
将DMOCP(0.66g;3.5mmol)添加至直链二聚体(0.7g;0.7mmol)于吡啶(70mL)中的溶液中,且将反应混合物在室温下搅拌2.5小时。此后,添加水(30mL)且将混合物在60℃下搅拌3小时,蒸发,且与乙腈(3×50mL)共同蒸发。使用制备型C18 HPLC分离化合物27。用于纯化的制备型HPLC条件如下:Luna C18(15μm,200×55mm,Phenomenex);流量30毫升/分钟;流动相A:H2O,流动相B:ACN。HPLC方法:等度溶离A(10分钟),随后线性梯度A-50%B(60分钟)。将产物使用DOWEX Na+转化为钠盐,且自二噁烷-水中冷冻干燥,得到化合物27:ESI-MSC31H35F2N10O12P2(M-H)-的计算值839.2,实验值839.3;滞留时间(min):38.4。1H NMR(D2O)δ8.33(s,1H),8.25(s,1H),8.10(s,1H),7.99(s,1H),6.40(d,J=15.6Hz,1H),6.30(d,J=8.2Hz,1H),5.88(ddt,J=17.3,10.2,6.4Hz,2H),5.69(dd,J=51.8,3.6Hz,1H),5.51(dd,J=53.3,4.0Hz,1H),5.37(dtd,J=24.8,8.2,4.0Hz,1H),5.07(m,2H),4.99(m,2H),4.77(m,1H),4.66(ddd,J=15.6,8.2,3.6Hz,1H),4.52(dq,J=8.2,2.2Hz,1H),4.33(dt,J=12.0,2.5Hz,1H),4.24(ddd,J=11.5,5.2,2.6Hz,1H),4.17(ddd,J=12.0,3.8,2.0Hz,1H),4.14(dtd,J=11.5,3.3,2.2Hz,1H),4.07(dd,J=13.6,6.8Hz,1H),3.97(dd,J=13.6,11.6Hz,1H),2.70(m,4H),2.47(m,4H);19F NMR(D2O)δ-199.46,-194.01;31P NMR(D2O)δ18.15,-0.79。
将化合物27(0.1g,0.12mmol)溶解于50%ACN的水溶液(10mL)中,且添加33%甲胺的乙醇溶液(5mL)。将混合物搅拌2小时且蒸发。产物使用制备型C18HPLC纯化(用于纯化的制备型HPLC条件如下:Luna C18(5μm,250×10mm,Phenomenex);流量10毫升/分钟;流动相A:0.1M TEAB/H2O,流动相B:50%ACN/0.1M TEAB/H2O;等度溶离A(15分钟),随后线性梯度A-20%B(35分钟))。滞留时间(min)=50.1。所要化合物(1S,6R,8R,9R,10R,16R,18R,19R)-8,18-双(6-胺基-9H-嘌呤-9-基)-9,19-二氟-3,13-二羟基-2,4,7,11,14,17-六氧杂-3λ5,13λ5-二磷杂三环[14.2.1.06,10]十九烷-3,13-二酮(28)使用DOWEX Na+转化为钠盐,且自水中冷冻干燥:ESI-MS(M-H)-C21H23F2N10O10P2的计算值:675.1;实验值:675.1。化合物28:在25℃下在D2O中的1H、19F及31P NMR资料:1H NMRδ8.34(s,1H),8.27(s,1H),8.12(s,1H),8.01(s,1H),6.42(d,J=16.4Hz,1H),6.31(d,J=8.2Hz,1H),5.70(dd,J=51.6,3.5Hz,1H),5.52(dd,J=53.1,4.0Hz,1H),5.39(dtd,J=24.7,8.3,4.0Hz,1H),4.78(m,1H),4.67(ddd,J=26.0,9.3,3.5Hz,1H),4.53(dq,J=9.3,2.5Hz,1H),4.34(dt,J=12.0,2.5Hz,1H),4.25(ddd,J=11.5,5.1,2.6Hz,1H),4.18(ddd,J=12.0,3.6,2.1Hz,1H),4.14(dddd,J=11.5,3.2,2.4,2.0Hz,1H),4.08(dd,J=13.8,11.6Hz,1H),3.98(dd,J=13.8,11.6Hz,1H);19FNMRδ-193.93,-199.93;31P NMRδ18.38,-1.14。
流程12
将ETT(0.26g;2.0mmol)添加至中间物2(0.17g;0.36mmol)及亚胺基磷酸酯29(0.35g;0.4mmol)于DCM(10mL)中的溶液中(流程12)。将反应混合物在室温下在氩气下搅拌2小时,随即添加DDTT(81mg;0.4mmol)且将混合物在室温下搅拌1小时。随后添加甲醇(5mL)且蒸发所得溶液。将残余物溶解于80%乙酸的水溶液(10mL)中且在室温下搅拌2小时。将溶液直接装载于C18管柱上且使用乙腈的水溶液的线性梯度分离直链二聚体:ESI-MSC36H35F2N10O11P2S(M-H)-的计算值915.7,实验值915.7。
将DMOCP(0.19g;1.0mmol)添加至直链二聚体(0.2g;0.2mmol)于吡啶(50mL)中的溶液中,且将反应混合物在室温下搅拌3.0小时。此后,添加硫(59mg;1.8mmol),且将混合物在室温下搅拌1小时。此后,,添加水(30mL)且将混合物在60℃下搅拌3小时,蒸发,且与乙腈(3×50mL)共同蒸发。将残余物溶解于50%ACN的水溶液(10mL)中且添加33%甲胺的乙醇溶液(5mL)。将混合物搅拌3小时且蒸发。混合物使用制备型C18 HPLC分离成三个峰:化合物30a-c。用于纯化的制备型HPLC条件如下:Luna C18(5μm,250×21.2mm,Phenomenex);流量10毫升/分钟;流动相A:0.1M TEAB/H2O,流动相B:50%ACN/0.1M TEAB/H2O。HPLC方法:等度溶离A(10分钟),随后线性梯度A-40%B(60分钟),随后等度40%B(10分钟)。分离峰使用DOWEX Na+转化为钠盐,且自水中冷冻干燥。1H、19F及31P NMR数据在25℃下在D2O中收集。
化合物30a:滞留时间(min):43.0;ESI-MS C21H23F2N10O8P2S2(M-H)-的计算值707.1,实验值707.1;1H NMRδ8.48(s,1H),8.28(s,1H),8.26(s,1H),8.04(s,1H),6.43(d,J=15.8Hz,1H),6.32(d,J=8.0Hz,1H),5.77(dd,J=51.6,3.8Hz,1H),5.51(dddd,J=23.8,11.5,8.0,4.0Hz,1H),5.49(dd,J=54.3,4.0Hz,1H),4.93(ddd,J=24.3,8.6,3.8Hz,1H),4.82(m,1H),4.51(ddd,J=8.6,4.4,2.3Hz,1H),4.33(ddd,J=14.4,5.2,4.4Hz,1H),4.22(dd,J=13.4,2.6Hz,1H),4.18(ddd,J=11.4,5.1,2.3Hz,1H),4.13(ddd,J=11.4,3.6,2.3Hz,1H);19F NMRδ-200.58,-192.58;31P NMRδ69.16,57.34。
化合物30b:滞留时间(min):50.0;ESI-MS C21H23F2N10O8P2S2(M-H)-的计算值707.1,实验值707.1。
化合物30c:滞留时间(min):56.1;ESI-MS C21H23F2N10O8P2S2(M-H)-的计算值707.1,实验值707.1。
1H NMRδ8.36(s,1H),8.26(s,1H),8.09(s,1H),8.02(s,1H),6.39(d,J=16.2Hz,1H),6.29(d,J=8.2Hz,1H),5.70(dd,J=51.7,3.6Hz,1H),5.66(dd,J=52.8,3.9Hz,1H),5.42(dddd,J=25.0,9.7,8.2,3.9Hz,1H),4.82(m,1H),4.72(ddd,J=25.5,9.2,3.6Hz,1H),4.57(dq,J=9.2,2.5Hz,1H),4.38(ddd,J=12.0,4.0,3.0Hz,1H),4.26(ddt,J=11.5,3.2,2.5Hz,1H),4.24(dd,J=13.3,1.6Hz,1H),4.19(ddd,J=12.0,4.5,2.1Hz,1H),4.16(ddd,J=11.5,5.3,2.2Hz,1H);19F NMRδ-200.08,-192.11;31P NMRδ69.28,53.69。
实例6.前药的制备
方法A
在室温下将于50%ACN水溶液(800μL)中的环二核苷酸(1μmol,Et3NH+或Na+盐)用适合烷基碘(10μmol稀释于10μL ACN中)处理隔夜,形成对应前药。(烷基碘根据文献方法制备:苯甲基型烷基碘根据Gollnest,T.等人Nat.Commun.2015,6:8716及Alvarez-Manzaneda,E.J.等人Tetrahedron Lett.2005,46,3755-3759制备;且POM样烷基碘根据Ellis,E.E.等人ChemBioChem.2013,14,1134-1144及Yang,Y.等人Helv.Chim.Acta 2006,89,404-415制备。POC样烷基碘根据US2011/166128及Yang,Y.等人Helv.Chim.Acta 2006,89,404-415制备。)将反应混合物用水(3mL)稀释,且直接施加至HPLC管柱,且使用HPLC方法1纯化。将含产物的溶离份冷冻干燥。
HPLC方法1
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 1 | 100 | - | - |
3 | 1 | 100 | - | - |
10 | 3 | 100 | - | - |
40 | 3 | - | 100 | - |
55 | 3 | - | - | 100 |
60 | 3 | - | - | 100 |
方法B
在室温下将于80%ACN水溶液(800μL)中的环二核苷酸(1μmol,Et3NH+或Na+盐)用适合烷基碘(10μmol稀释于10μL DMF中)处理隔夜,形成对应前药。将反应混合物用水(3mL)稀释,且直接施加至HPLC管柱,且使用HPLC方法2纯化。将含产物的溶离份冷冻干燥。
HPLC方法2
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 80 | 20 | - |
10 | 3 | 80 | 20 | - |
30 | 3 | - | 100 | - |
50 | 3 | - | 50 | 50 |
60 | 3 | - | - | 100 |
方法C
在室温下将于50%ACN水溶液(800μL)中的环二核苷酸(1μmol,Et3NH+或Na+盐)用烷基碘(10μmol稀释于10μL ACN中)处理隔夜。将反应混合物用水(2mL)稀释,且直接施加至HPLC管柱,且使用HPLC方法3纯化。将含产物的溶离份冷冻干燥。
HPLC方法3
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 95 | 5 | - |
10 | 3 | 95 | 5 | - |
50 | 3 | 0 | 100 | - |
60 | 3 | 0 | 0 | 100 |
制备型HPLC纯化使用Luna C18管柱(5μm,250×10mm,Phenomenex)在Ingos层析系统上进行。在所有方法中,使用线性梯度。
方法D
在室温下将于80%ACN水溶液(800μL)中的环二核苷酸(1μmol,Et3NH+或Na+盐)用烷基碘(10μmol稀释于10μL DMF中)处理隔夜。将反应混合物用水(1mL)稀释,且直接施加至HPLC管柱,且使用HPLC方法4纯化。将含产物的溶离份冷冻干燥。
HPLC方法4
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 80 | 20 | - |
10 | 3 | 80 | 20 | - |
30 | 3 | - | 100 | - |
50 | 3 | - | 50 | 50 |
60 | 3 | - | - | 100 |
制备型HPLC纯化使用Luna C18管柱(5μm,250×10mm,Phenomenex)在Ingos层析系统上进行。在所有方法中,使用线性梯度。
方法E
在室温下将于无水MeOH(1mL)中的环二核苷酸(1μmol,Et3NH+或Na+盐)用碘代甲烷(40μmol)处理40小时。将反应混合物用水(3mL)稀释,且直接施加至HPLC管柱,且使用HPLC方法5纯化。将含产物的溶离份冷冻干燥。
HPLC方法5
制备型HPLC纯化使用Luna C18管柱(5μm,250×10mm,Phenomenex)在Ingos层析系统上进行。在所有方法中,使用线性梯度。
方法F
在室温下将于H2O/THF/丙酮混合物(1:2:2,0.5mL)中的环二核苷酸(1μmol,Et3NH+或Na+盐)用适合烷基碘(10μmol)处理隔夜,形成对应前药。将反应混合物用水(3mL)稀释,且直接施加至HPLC管柱,且使用HPLC方法6、HPLC方法7、HPLC方法8或HPLC方法9纯化。将含产物的溶离份冷冻干燥。
HPLC方法6
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 80 | 20 | - |
10 | 3 | 80 | 20 | - |
30 | 3 | - | 100 | - |
50 | 3 | - | - | 100 |
60 | 3 | - | - | 100 |
HPLC方法7
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 80 | 20 | - |
10 | 3 | 80 | 20 | - |
30 | 3 | - | 100 | - |
55 | 3 | - | 100 | - |
60 | 3 | - | - | 100 |
HPLC方法8
HPLC方法9
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 50 | 50 | - |
10 | 3 | 50 | 50 | - |
20 | 3 | - | 100 | - |
30 | 3 | - | - | 100 |
60 | 3 | - | - | 100 |
方法G
将环二核苷酸(1μmol,Et3NH+)溶解于甲醇(200μL)中,且通过DOWEX50四丁铵盐(1mL)的管柱。用甲醇(3×1mL)洗涤树脂且蒸发溶液。将残余物与二噁烷(3×1mL)及乙腈(3×1mL)共同蒸发。将残余物溶解于ACN(0.5mL)中,添加适合烷基碘(10μmol稀释于10μL ACN中),且将反应混合物在室温下振荡2小时。将反应混合物用水(3mL)稀释,且直接施加至HPLC管柱,且使用HPLC方法10纯化。收集含产物的溶离份且冷冻干燥。
HPLC方法10
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 100 | - | - |
20 | 3 | - | 100 | - |
80 | 3 | - | - | 100 |
85 | 3 | - | - | 100 |
将残余物溶解于纯乙醇(2mL)中,添加10%钯/活性木炭,且将反应混合物在r.t.下在氢气氛围(1.5atm)下搅拌3小时。反应混合物经由耐纶针筒过滤器过滤且蒸发。将反应混合物溶解于50%ACN的水溶液(4mL)中,且直接施加至HPLC管柱。粗混合物使用HPLC方法11纯化。
HPLC方法11
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 100 | - | - |
60 | 3 | - | 100 | - |
65 | 3 | - | 100 | - |
制备型HPLC纯化使用Luna C18管柱(5μm,250×10mm,Phenomenex)在Ingos层析系统上进行。
以下化合物使用前述方法使用上文所描述的化合物合成。
方法H
在室温下将于H2O/THF/丙酮混合物(1:2:2,0.5mL)中的环二核苷酸(1μmol,Et3NH+或Na+盐)用适合烷基碘(2μmol)处理隔夜,形成对应前药。将反应混合物用DCM(3ml)稀释,且用硫代硫酸钠(10%水溶液,3mL)及水(3ml)萃取。蒸发有机溶离份,将残余物溶解于庚烷/EtOH混合物(4:6,4ml)中,且施加至HPLC制备型纯化(线性梯度,正庚烷-EtOH,40-100%EtOH,具有装填有二氧化硅(2) 100×10mm管柱的Waters Delta 600层析系统)。在减压下蒸发含产物的溶离份。
方法I
将受保护的环二核苷酸(4μmol,Et3NH+)溶解于甲醇(200μL)中,且通过DOWEX 50四丁铵盐(3mL)的管柱。用甲醇(3×3mL)洗涤树脂且蒸发溶液。将残余物与二噁烷(3×3mL)及乙腈(3×3mL)共同蒸发。在室温下将于无水ACN(1mL)中的残余物用适合烷基碘(6μl)处理2小时,形成对应前药。将混合物施加至HPLC制备型纯化(等度梯度,正庚烷-EtOH,7:3,具有装填有二氧化硅(2)100×10mm的Waters Delta 600层析系统)。在减压下蒸发含产物的溶离份,得到三种非对映异构体。将各非对映异构体溶解于EtOH(2ml)中,用Pd/C(10wt.%)处理,且将反应物在r.t.下在氢气氛围(1.0atm)下搅拌3小时。反应混合物经由耐纶针筒过滤器过滤且蒸发,得到前药。
方法J:将环二核苷酸(1μmol,Et3NH+)溶解于甲醇(200μL)中,且通过DOWEX 50四丁铵盐(1mL)的管柱。用甲醇(3×1mL)洗涤树脂且蒸发溶液。将残余物与二噁烷(3×1mL)及乙腈(3×1mL)共同蒸发。将残余物溶解于ACN(0.5mL)中,添加适合烷基碘(10μmol稀释于10μLACN中),且将反应混合物在室温下振荡2小时。将反应混合物通过添加饱和Na2S2O3×5H2O水溶液(200μL)淬灭,用50%ACN的水溶液(3mL)稀释,且直接通过HPLC使用HPLC方法12纯化。将含产物的溶离份收集,蒸发,且与ACN共同蒸发。
HPLC方法12
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 100 | - | - |
20 | 3 | - | 100 | - |
50 | 3 | - | - | 100 |
此后,添加NIS(5μmol)且将反应混合物在室温下振荡30分钟。随后,添加10%乙酸的水溶液(100μL),且将反应混合物在室温下再振荡30分钟。将反应混合物通过添加饱和Na2S2O3×5H2O水溶液(200μL)淬灭,用50%ACN的水溶液(3mL)稀释,且直接通过HPLC使用HPLC方法13纯化。
HPLC方法13
时间(分钟) | 流量(毫升/分钟) | H<sub>2</sub>O(%) | 1:1 H<sub>2</sub>O/ACN(%) | ACN(%) |
0 | 3 | 100 | - | - |
60 | 3 | - | 100 | - |
70 | 3 | - | 100 | - |
制备型HPLC纯化使用Luna C18管柱(5μm,250×10mm,Phenomenex)在Ingos层析系统(LCD5000侦测器及LCP5020泵;Ingos s.r.o,Prague,捷克)上进行。
表1:例示性化合物及表征资料
实例7.生物资料
环二核苷酸判定为STING促效剂:(A)若其在STING差示扫描荧光测定分析法(DSF)中证明其在热偏移>0.5℃的情况下结合于人类STING蛋白的AQ对偶基因形式,及(B)若其在EC50<100μmol..l-1的情况下在以下细胞检测中的任一者中证明STING活化。
ISRE报导子质体(pGL64.27-4xISRE)
通过Sigma Aldrich(捷克布拉格)合成含有四个干扰素敏感性反应组件(ISRE)的序列
AAAGATCTTGGAAAGTGAAACCTTGGAAAACGAAACTGGACAAAGGGAAACTGCAGAAACTGAAACAAAGCTTAA(SEQ ID NO:1)及
TTAAGCTTTGTTTCAGTTTCTGCAGTTTCCCTTTGTCCAGTTTCGTTTTCCAAGGTTTCACTTTCCAAGATCTTT(SEQ ID NO:2)的两个互补寡核苷酸。寡核苷酸以等莫耳量混合,杂交且通过限制性核酸内切酶HindIII(目录号R0104S,NEB,美国伊普斯维奇)及BglII(目录号R0144S,NEB,美国伊普斯维奇)裂解。最终,其接合至由相同酶线性化的质体pGL4.27(目录号E6651,Promega,美国麦迪逊)。因此,具有四个ISRE位点的序列置放于萤火虫荧光素酶报导基因的最小启动子的上游。
293T wtSTING-FL报导细胞
在转染的前一天,293T细胞(目录号CRL-3216,ATCC,美国马纳萨斯)在具有高葡萄糖(目录号D5796,Sigma Aldrich,捷克)的补充有10%热灭活FBS(目录号S1520,Biowest,美国河滨市)的不含抗生素的DMEM中,以125,000个细胞/公分2的密度接种至经聚-D-离胺酸(目录号P6407,Sigma Aldrich,捷克)涂布的六孔盘上。在转染之日,将编码人类野生型STING(WT STING)的2.5μg质体pUNO1-hSTING-WT(目录号puno1-hstingwt,InvivoGen,美国圣地亚哥),在125μL OptiMEM培养基(目录号31985062,ThermoFisher,美国沃尔瑟姆)中稀释且与相同的含有12.5μL脂染胺2000的125μL培养基(目录号11668019,ThermoFisher,美国沃尔瑟姆)混合。在室温(RT)下培育5分钟后,将250μL混合物逐滴添加至一个孔中的细胞。细胞在37℃,5%CO2下培育36小时,且随后用0.05%胰蛋白酶及0.22g/L的EDTA(目录号皆为L0941,Biowest,美国河滨市)剥离。
经转染的细胞在具有高葡萄糖的含有10%热灭活FBS、30μg/mL的杀稻瘟菌素(blasticidin)(目录号ant-bl-05,InvivoGen,美国圣地亚哥)、0.06mg/ml的青霉素G及0.1mg/ml的硫酸链霉素(目录号皆为L0018,Biowest,美国河滨市)的DMEM培养基中,以50,000个细胞/1公分2的密度接种至经聚-D-离胺酸涂布的六孔盘上。每3-4天补充培养基一次,直至形成对杀稻瘟菌素具有抗性的可见细胞群落。
根据如上文所描述的相同程序,稳定表现WT STING的杀稻瘟菌素抗性细胞用pGL64.27-4xISRE质体进一步转染。在具有高葡萄糖的含有10%热灭活FBS、30μg/mL的杀稻瘟菌素、0.06mg/ml的青霉素G及0.1mg/ml的硫酸链霉素的DMEM中,关于对300μg/mL的潮霉素(hygromycin)(目录号10687010,ThermoFisher,美国沃尔瑟姆)的抗性选择经转染的细胞。由细胞在96孔盘中经过限数稀释法来制备经稳定地双重转染的细胞的均质培养物,且选择具有来源于单一细胞的细胞的孔。扩增这种细胞,且使用单株小鼠抗STING抗体(目录号MAB7169,1:1000稀释;2°抗体目录号HAF007,1:2000稀释,皆来自R&D Systems,美国明尼阿波利斯)通过西方墨点法(western blot)及通过在50μM STING促效剂2'3'cGAMP(目录号tlrl-nacga23,InvivoGen,美国圣地亚哥)存在下诱导萤火虫荧光素酶表现来确认WTSTING的表现。用与pUNO1质体互补的引子pUNO1_Seq_F(TGCTTGCTCAACTCTACGTC)(SEQ IDNO:3)及pUNO1_Seq_R(GTGGTTTGTCCAAACTCATC)(SEQ ID NO:4)扩增来自经转染的细胞的基因组DNA,且通过DNA测序来确认经转染的细胞中存在WT STING基因。
使用293T wtSTING-FL报导细胞的毛地黄皂苷(Digitonin)检测法
293T wtSTING-FL细胞在具有高葡萄糖的补充有10%热灭活FBS的100μl DMEM中,以250,000个细胞/公分2的密度接种至经聚-D-离胺酸涂布的96孔盘上。次日,移除培养基且向细胞中添加含于毛地黄皂苷缓冲液中的化合物的三倍连续稀释液,该缓冲液包含:50mmol.l-1HEPES(目录号H3375,Sigma Aldrich,捷克)pH 7.0、100mmol.l-1KCl、3mmol.l- 1MgCl2、0.1mmol.l-1DTT(目录号D0632,Sigma Aldrich,捷克)、85mmol.l-1蔗糖(目录号S7903,Sigma Aldrich,捷克)、0.2%BSA(目录号A2153,Sigma Aldrich,捷克)、1mmol.l- 1ATP(目录号A1852,Sigma Aldrich,捷克)、0.1mmol.l-1GTP(目录号G8877,Sigma Aldrich,捷克)及10μg/mL的毛地黄皂苷A(目录号D141,Sigma Aldrich,捷克)。在37℃,5%CO2下培育30分钟后移除缓冲液,细胞用100μl培养基洗涤一次,且将100μl培养基添加至各孔中。具有细胞的盘在37℃,5%CO2下培育5小时,移除50μl培养基且向各孔中添加30μl ONE-GloTM荧光素酶检测系统试剂(目录号E6120,Promega,美国麦迪逊)。用Synergy H1(Biotek,美国威努斯基)读取发亮度。使用GraphPad Prism(美国加州圣地亚哥)由8点剂量-反应曲线计算50%有效浓度(EC50)。对照化合物3'3'-c-二-GMP(目录号tlrl-nacdg)、3'3'-c-二-AMP(目录号tlrl-nacda)、3'3'-cGAMP(目录号tlrl-nacga)、2'3'-cGAMP(目录号tlrl-nacga23)及2'2'-cGAMP(目录号tlrl-nacga22)购自Invivogen(美国圣地亚哥)。
WT STING及AQ STING蛋白质
使用PCR(High-Fidelity DNA Polymerase,目录号M0530S,NEB,美国伊普斯威奇),使用来自pUNO1-hSTING-WT(目录号puno1-hstingwt,InvivoGen,美国圣地亚哥)及pUNO1-hSTING-HAQ质体(puno1-hsting-haq,InvivoGen,美国圣地亚哥)的寡核苷酸hSTING140-BamH-For(GTGGGATCCGCCCCAGCTGAGATCTCTGCAG)(SEQ ID NO:5)及hSTING379-Not-Rev3(TATGCGGCCGCCTATTACACAGTAACCTCTTCCTTTTC)(SEQ ID NO:6)扩增WT及AQ人类STING(G230A-R293Q)cDNA。经纯化的PCR产物用限制酶BamHI(目录号R0136S,NEB,美国伊普斯威奇)及NotI(目录号R0189S,NEB,美国伊普斯威奇)裂解且选殖至经相同酶线性化的pSUMO载体中。通过在pHis-parallel2质体(Clontech,美国山景城)的NdeI与BamHI位点之间引入8-His-SUMO序列来产生质体pSUMO。因此,pSUMO-STING WT或pSUMO-STING AQ质体编码具有N端8×His及SUMO标签的经截短的人类WT STING或AQ STING(氨基酸残基140-343)。
重组型WT STING及AQ STING蛋白在Rosetta-gami B(DE3)胜任细胞(目录号71136-3,Merck Millipore,美国比勒利卡)中过表现。使用Dounce均质器,使细菌集结粒再悬浮于含有50mmol.l-1TrisCl(目录号T1503,Sigma Aldrich,捷克)pH 8.0、300mmol.l- 1NaCl、3mmol.l-1β-巯基乙醇(目录号M6250,Sigma Aldrich,捷克)、10%甘油(目录号G5516,Sigma Aldrich,捷克)及20mmol.l-1咪唑(目录号I5513,Sigma Aldrich,捷克)的冰冷的溶解缓冲液中。。向均质物中添加DNase I(目录号D5025,Sigma Aldrich,捷克)及RNase A(目录号R6513,Sigma Aldrich,捷克)(最终浓度50μg/ml)以及MgCl2(最终浓度5mmol.l-1)且使用French Press G-MTM High-Pressure Cell Press Homogenizer(1500psi,3个循环)使细菌溶解。溶解物在30,000g下旋转20分钟且上清液与Ni-NTA树脂(目录号745400.25,Macherey-Nagel,德国多伦)一起温和搅拌30分钟。将树脂倒入层析管柱中,用50ml缓冲液A(50mmol.l-1TrisCl(pH 8.0)、800mmol.l-1NaCl、3mmol.l-1β-巯基乙醇;10%甘油;20mmol.l-1咪唑)洗涤且用含有300mmol.l-1咪唑的15ml缓冲液A溶离经8-His-SUMO标记的STING蛋白。用重组型SUMO蛋白酶(80μg/ml的蛋白质溶液,目录号12588018,ThermoFisher,美国沃尔瑟姆)使经溶离的蛋白质裂解。在含有150mmol.l-1NaCl及10%甘油的50mmol.l-1Tris Cl缓冲液pH 7.4中,使用HiLoad 16/60 Superdex 75(目录号28989333,GE Healthcare Bio-Sciences,美国匹兹堡)通过尺寸排阻层析进一步纯化蛋白质。蛋白质用Ultra-15 10K装置(目录号UFC901008,Merck Millipore,美国比勒利卡)浓缩且在液态N2中急骤冷冻。
8-His-SUMO的DNA序列
8-His-SUMO的氨基酸序列
经截短的WT STING的氨基酸序列
经截短的AQ STING的氨基酸序列
用WT STING及AQ STING进行的差示扫描荧光测定
STING蛋白的WT及AQ对偶基因形式在含有150mmol.l-1NaCl、1:500Orange(目录号S6650,ThermoFisher,美国沃尔瑟姆)及150μM CDN或水的100mmol.l- 1TrisCl缓冲液pH 7.4中稀释至最终浓度0.1mg/mll。将反应混合物的20μL溶液一式三份地抽吸至96孔光学反应盘中且用实时PCR循环器(480Instrument II-Roche,瑞士巴塞尔)进行样品的热变性。进行热变性曲线的一阶导数以计算STING-CDN复合物及STING去辅基蛋白质的变性温度。通过自STING CDN复合物的平均变性温度减去STING去辅基蛋白的平均变性温度来计算各CDN的热偏移。
表2:STING结合及293T WT STING毛地黄皂苷细胞数据
293T WT STING标准报导子检测
293T wtSTING-FL细胞在具有高葡萄糖的补充有10%热灭活FBS的100μlDMEM培养基中,以250,000个细胞/公分2的密度接种至经聚-D-离胺酸涂布的白色96孔微盘上。次日,移除培养基且向细胞中添加化合物于100μl培养基中的三倍连续稀释物。将盘在37℃与5%CO2下培育7小时。接下来,自孔中移除50μl培养基,且将30μl ONE-GloTM荧光素酶检测系统试剂(目录号E6120,Promega,美国威斯康星州麦迪逊)添加至各孔中。用Synergy H1(Biotek,美国佛蒙特州威努斯基)读取发亮度。使用GraphPad Prism(La Jolla,美国加州)由8点剂量-反应曲线计算50%有效浓度(EC50)。对照化合物3'3'-cGAMP(目录号tlrl-nacga)、2'3'-cGAMP(目录号tlrl-nacga23)及2'2'-cGAMP(目录号tlrl-nacga22)购自Invivogen(美国加州圣地亚哥)。
表3:293T WT STING标准报导子检测数据
周边血液单核细胞检测
在活体外周边血液单核细胞(PBMC)检测中测试所选化合物。将新分离的PBMC以500,000个细胞/孔的密度在50μl补充有10%热灭活FBS的RPMI 1640培养基中接种于U形96孔盘中。连续稀释测试化合物在50μl培养基中添加至孔中,且细胞与化合物一起在37℃与5%CO2下培育1小时。随后含有细胞的盘在500g下旋转5分钟,且移除培养基。将细胞通过使用离心用细胞培养基洗涤两次,且温和地再悬浮于100μl不含化合物的培养基中。在37℃与5%CO2下培育15小时后,收集细胞培养基且用ProcartaPlex Assays(ThermoFisher,美国沃尔瑟姆)及MAGPIX System(Merck KGaA,德国达姆施塔特)测定干扰素-α(INF-α)、干扰素-γ(INF-γ)及肿瘤坏死因子-α(TNF-α)的含量。使用GraphPad Prism(美国加州圣地亚哥)由6点剂量-反应曲线计算50%有效浓度(EC50)。报告值为一至四个供体运作的平均值。
表4:周边血液单核细胞资料
尽管出于清楚理解的目的已通过说明及实例相当详细地描述了前述发明,但熟习此项技术者应了解,可在所附申请专利范围的范围内实践某些改变及修改。另外,本文中所提供的各参考文献以全文引用的方式并入本文中,其并入程度如同与各参考文献单独以引用的方式并入的程度相同。当本申请案与本文所提供的参考文献之间存在冲突时,应以本申请案为准。
序列表
<110> 加布里埃尔·比尔库斯
翁德雷·帕夫
翁德雷·科斯托夫
佩特拉·布雷霍瓦
马丁·麦克斯米利安·凯撒
<120> 2'3'-环二核苷酸及其前药
<130> 052838-549P01US
<140> 未指定
<141> 2019-03-07
<160> 10
<170> PatentIn 版本 3.5
<210> 1
<211> 75
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 1
aaagatcttg gaaagtgaaa ccttggaaaa cgaaactgga caaagggaaa ctgcagaaac 60
tgaaacaaag cttaa 75
<210> 2
<211> 75
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 2
ttaagctttg tttcagtttc tgcagtttcc ctttgtccag tttcgttttc caaggtttca 60
ctttccaaga tcttt 75
<210> 3
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 3
tgcttgctca actctacgtc 20
<210> 4
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 4
gtggtttgtc caaactcatc 20
<210> 5
<211> 31
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 5
gtgggatccg ccccagctga gatctctgca g 31
<210> 6
<211> 38
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 6
tatgcggccg cctattacac agtaacctct tccttttc 38
<210> 7
<211> 330
<212> DNA
<213> 人工序列
<220>
<223> 合成构建体
<400> 7
atgtcgcatc accatcatca tcaccaccat gggatgtcgg actcagaagt caatcaagaa 60
gctaagccag aggtcaagcc agaagtcaag cctgagactc acatcaattt aaaggtgtcc 120
gatggatctt cagagatctt cttcaagatc aaaaagacca ctcctttaag aaggctgatg 180
gaagcgttcg ctaaaagaca gggtaaggaa atggactcct taagattctt gtacgacggt 240
attagaattc aagctgatca gacccctgaa gatttggaca tggaggataa cgatattatt 300
gaggctcacc gcgaacagat tggtggatcc 330
<210> 8
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 8
Met Ser His His His His His His His His Gly Met Ser Asp Ser Glu
1 5 10 15
Val Asn Gln Glu Ala Lys Pro Glu Val Lys Pro Glu Val Lys Pro Glu
20 25 30
Thr His Ile Asn Leu Lys Val Ser Asp Gly Ser Ser Glu Ile Phe Phe
35 40 45
Lys Ile Lys Lys Thr Thr Pro Leu Arg Arg Leu Met Glu Ala Phe Ala
50 55 60
Lys Arg Gln Gly Lys Glu Met Asp Ser Leu Arg Phe Leu Tyr Asp Gly
65 70 75 80
Ile Arg Ile Gln Ala Asp Gln Thr Pro Glu Asp Leu Asp Met Glu Asp
85 90 95
Asn Asp Ile Ile Glu Ala His Arg Glu Gln Ile Gly Gly Ser
100 105 110
<210> 9
<211> 204
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 9
Ala Pro Ala Glu Ile Ser Ala Val Cys Glu Lys Gly Asn Phe Asn Val
1 5 10 15
Ala His Gly Leu Ala Trp Ser Tyr Tyr Ile Gly Tyr Leu Arg Leu Ile
20 25 30
Leu Pro Glu Leu Gln Ala Arg Ile Arg Thr Tyr Asn Gln His Tyr Asn
35 40 45
Asn Leu Leu Arg Gly Ala Val Ser Gln Arg Leu Tyr Ile Leu Leu Pro
50 55 60
Leu Asp Cys Gly Val Pro Asp Asn Leu Ser Met Ala Asp Pro Asn Ile
65 70 75 80
Arg Phe Leu Asp Lys Leu Pro Gln Gln Thr Gly Asp Arg Ala Gly Ile
85 90 95
Lys Asp Arg Val Tyr Ser Asn Ser Ile Tyr Glu Leu Leu Glu Asn Gly
100 105 110
Gln Arg Ala Gly Thr Cys Val Leu Glu Tyr Ala Thr Pro Leu Gln Thr
115 120 125
Leu Phe Ala Met Ser Gln Tyr Ser Gln Ala Gly Phe Ser Arg Glu Asp
130 135 140
Arg Leu Glu Gln Ala Lys Leu Phe Cys Arg Thr Leu Glu Asp Ile Leu
145 150 155 160
Ala Asp Ala Pro Glu Ser Gln Asn Asn Cys Arg Leu Ile Ala Tyr Gln
165 170 175
Glu Pro Ala Asp Asp Ser Ser Phe Ser Leu Ser Gln Glu Val Leu Arg
180 185 190
His Leu Arg Gln Glu Glu Lys Glu Glu Val Thr Val
195 200
<210> 10
<211> 204
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 10
Ala Pro Ala Glu Ile Ser Ala Val Cys Glu Lys Gly Asn Phe Asn Val
1 5 10 15
Ala His Gly Leu Ala Trp Ser Tyr Tyr Ile Gly Tyr Leu Arg Leu Ile
20 25 30
Leu Pro Glu Leu Gln Ala Arg Ile Arg Thr Tyr Asn Gln His Tyr Asn
35 40 45
Asn Leu Leu Arg Gly Ala Val Ser Gln Arg Leu Tyr Ile Leu Leu Pro
50 55 60
Leu Asp Cys Gly Val Pro Asp Asn Leu Ser Met Ala Asp Pro Asn Ile
65 70 75 80
Arg Phe Leu Asp Lys Leu Pro Gln Gln Thr Ala Asp Arg Ala Gly Ile
85 90 95
Lys Asp Arg Val Tyr Ser Asn Ser Ile Tyr Glu Leu Leu Glu Asn Gly
100 105 110
Gln Arg Ala Gly Thr Cys Val Leu Glu Tyr Ala Thr Pro Leu Gln Thr
115 120 125
Leu Phe Ala Met Ser Gln Tyr Ser Gln Ala Gly Phe Ser Arg Glu Asp
130 135 140
Arg Leu Glu Gln Ala Lys Leu Phe Cys Gln Thr Leu Glu Asp Ile Leu
145 150 155 160
Ala Asp Ala Pro Glu Ser Gln Asn Asn Cys Arg Leu Ile Ala Tyr Gln
165 170 175
Glu Pro Ala Asp Asp Ser Ser Phe Ser Leu Ser Gln Glu Val Leu Arg
180 185 190
His Leu Arg Gln Glu Glu Lys Glu Glu Val Thr Val
195 200
Claims (65)
1.一种式(I)化合物:
或其医药学上可接受的盐,
其中
X1及X3各自独立地为OH、OR1、SH或SR1,其限制条件为X1及X3中的至少一者是OR1、SH或SR1;
X2及X4各自独立地为O或S;
R4及R10各自独立地为H、OH或卤素;
各R1独立地为C1-C6烷基或-L-R2;
各R2独立地为-O(C=O)-N(R2a)2、-O(C=O)-NHR2a、-O(C=O)-R2a或-O(C=O)-O-R2a;
各R2a独立地为C1-C20烷基、C2-C20烯基、C2-C20炔基、-(C1-C6亚烷基)-(C3-C14环烷基)或C3-C20环烷基,其中各R2a独立地视情况经1、2或3个R2b取代;
各R2b独立地为-OH、-SH、-NH2、=O、=NH、=S、卤素、-N3、-CN、C1-C6烷氧基、C1-C6烷硫基、C1-C6烷胺基或C1-C6二烷胺基;
L为L1、L1-O(C=O)-L2、L1-(C=O)O-L2、L1-O-L2、L1-S(O)n-L2、L1-O(C=O)O-L2、L1-O(C=O)NR6-L2、L1-NR6(C=O)O-L2或L1-O(C=O)-L2-O-L3;
L1为C1-C6亚烷基、C2-C6亚烯基、C2-C6亚炔基或C7-C13烷基亚芳基;
L2为C1-C6亚烷基、C2-C6亚烯基、C2-C6亚炔基、C6-C10亚芳基或5元至10元亚杂芳基;
L3为C1-C6亚烷基、C2-C6亚烯基或C2-C6亚炔基;
R6为H或C1-C6烷基;
n为0、1或2;
碱基1及碱基2各自独立地为
其中
A、A1、A2、A3及A4各自独立地为H、OH、SH、F、Cl、Br、I、NH2、OR15、SR15、NHR15、N(R15)2或R16;
各Z独立地为O、S或NR15;
各R15独立地为H、-C(=Z1)R16、-C(=Z1)OR16、-C(=Z1)SR16、-C(=Z1)N(R16)2、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C2-C10杂环烷基、C6-C10芳基或C2-C10杂芳基;
各Z1独立地为O或S;且
各R16独立地为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C2-C10杂环烷基、C6-C10芳基或C2-C10杂芳基。
5.如权利要求4所述的化合物,其中
A1、A2、A3及A4各自独立地为H、OH或NH2。
6.如权利要求4所述的化合物,其中
A1、A2及A3各自独立地为H、OH或NH2。
10.如权利要求1至9中任一项所述的化合物,其中
X1为OH;且
X3为OR1。
11.如权利要求1至9中任一项所述的化合物,其中
X1为OR1;且
X3为OH。
12.如权利要求1至9中任一项所述的化合物,其中
X1及X3各自独立地为OR1。
13.如权利要求1至9中任一项所述的化合物,其中
X1为OH;且
X3为SR1。
14.如权利要求1至9中任一项所述的化合物,其中
X1为SR1;且
X3为OH。
15.如权利要求1至9中任一项所述的化合物,其中
X1为OR1;且
X3为SR1。
16.如权利要求1至9中任一项所述的化合物,其中
X1为SR1;且
X3为OR1。
17.如权利要求1至9中任一项所述的化合物,其中
X1及X3各自独立地为SR1。
18.如权利要求1至17中任一项所述的化合物,其中
各R1独立地为L-R2。
19.如权利要求1至18中任一项所述的化合物,其中
各R2独立地为-O(C=O)-R2a或-O(C=O)-O-R2a。
20.如权利要求1至19中任一项所述的化合物,其中
各R2a独立地为C1-C20烷基-(C1-C6亚烷基)-(C3-C14环烷基)。
21.如权利要求1至20中任一项所述的化合物,其中
L为L1、L1-O(C=O)-L2或L1-O-L2;
L1为C1-C6亚烷基或C7-C13烷基亚芳基;且
L2为C1-C6亚烷基或C6-C10亚芳基。
23.如权利要求1至9中任一项所述的化合物,其中
X1为OR1或SR1;
R1为-L-R2;
L为L1;
L1为C1-C6亚烷基;
R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且
R2a为C1-C20烷基。
25.如权利要求1至9中任一项所述的化合物,其中
X1为OR1或SR1;
R1为-L-R2;
L为L1;
L1为C7-C13烷基亚芳基;
R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且
R2a为C1-C20烷基。
28.如权利要求1至9中任一项所述的化合物,其中
X3为OR1或SR1;
R1为-L-R2;
L为L1;
L1为C1-C6亚烷基;
R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且
R2a为C1-C20烷基。
30.如权利要求1至9中任一项所述的化合物,其中
X3为OR1或SR1;
R1为-L-R2;
L为L1;
L1为C7-C13烷基亚芳基;
R2为-O(C=O)-R2a或-O(C=O)-O-R2a;且
R2a为C1-C20烷基。
32.如权利要求1至9中任一项所述的化合物,其中
X1及X3各自独立地选自由OH及SH组成的群,其中X1及X3中的至少一者为SH。
38.如权利要求33至37中任一项所述的化合物,其中
R2a为C3-C16烷基。
39.如权利要求1至38中任一项所述的化合物,其中
R4及R10各自独立地为H或F。
40.如权利要求1至39中任一项所述的化合物,其中
R4及R10各自为F。
43.一种医药组合物,其包含如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐,及医药学上可接受的载剂、赋形剂及/或稀释剂。
44.如权利要求43所述的医药组合物在调节STING衔接蛋白的活性以诱导STING衔接蛋白依赖性I型干扰素、细胞因子和/或趋化因子中的用途。
45.如权利要求43所述的医药组合物在治疗或预防人类或动物的病毒感染、过度增殖性疾病或癌症中的用途。
46.如权利要求45所述的医药组合物,其中该病毒感染为B型肝炎病毒感染或HIV感染。
47.一种在有需要的人类或动物中治疗或预防疾病或病症的方法,该方法包括对该人类或动物施用治疗有效量的如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐。
48.一种调节STING衔接蛋白的活性的方法,该方法包括施用治疗有效量的如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐。
49.一种在有需要的人类或动物中治疗或预防对STING衔接蛋白的调节有反应的疾病或病症的方法,该方法包括对该人类或动物施用治疗有效量的如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐。
50.一种在有需要的人类或动物中诱导STING衔接蛋白依赖性I型干扰素、细胞因子或趋化因子的方法,该方法包括对该人类或动物施用治疗有效量的如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐。
51.一种在有需要的人类或动物中治疗或预防病毒感染的方法,该方法包括对该人类或动物施用治疗有效量的如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐。
52.一种在有需要的人类或动物中治疗或预防B型肝炎病毒或HIV感染的方法,该方法包括对该人类或动物施用治疗有效量的如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐。
53.一种在有需要的人类或动物中治疗或预防过度增殖性疾病或癌症的方法,该方法包括对该人类或动物施用治疗有效量的如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐。
54.一种在有需要的人类或动物中增强疫苗功效的方法,该方法包括对该人类或动物施用治疗有效量的如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐。
55.如权利要求47至54中任一项所述的方法,其中该化合物与另一种治疗活性剂一起施用。
56.如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐在有需要的人类或动物中治疗或预防疾病或病症中的用途。
57.如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐在调节STING衔接蛋白的活性中的用途。
58.如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐单独或与一种或多种治疗活性剂组合用于治疗或预防人类或动物的对STING衔接蛋白的调节有反应的疾病或病症的用途。
59.如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐用于在人类或动物中诱导STING衔接蛋白依赖性I型干扰素、细胞因子或趋化因子的用途。
60.如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐单独或与一种或多种治疗活性剂组合用于治疗或预防人类或动物的病毒感染的用途。
61.如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐单独或与一种或多种治疗活性剂组合用于治疗或预防人类或动物的B型肝炎病毒或HIV感染的用途。
62.如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐单独或与一种或多种治疗活性剂组合用于治疗或预防人类或动物的过度增殖性疾病或癌症的用途。
63.如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐用于在人类或动物中增强疫苗功效的用途。
64.如权利要求1至42中任一项所述的化合物或其医药学上可接受的盐在制备用于治疗或预防人类或动物的病毒感染、过度增殖性疾病或癌症的药剂中的用途。
65.如权利要求64所述的用途,其中该病毒感染是B型肝炎或HIV感染。
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EP3934757A1 (en) | 2022-01-12 |
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KR20210137517A (ko) | 2021-11-17 |
TW202100163A (zh) | 2021-01-01 |
WO2020178769A1 (en) | 2020-09-10 |
CA3129022C (en) | 2023-08-01 |
AU2020231201A1 (en) | 2021-08-26 |
EP3934757B1 (en) | 2023-02-22 |
CA3129022A1 (en) | 2020-09-10 |
JP2022523423A (ja) | 2022-04-22 |
US20220152078A1 (en) | 2022-05-19 |
JP7350871B2 (ja) | 2023-09-26 |
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