CN111971291A - 用作sting激动剂的含有2-氮杂-次黄嘌呤或6h-吡唑并[1,5-d][1,2,4]三嗪-7-酮的环状二核苷酸化合物 - Google Patents
用作sting激动剂的含有2-氮杂-次黄嘌呤或6h-吡唑并[1,5-d][1,2,4]三嗪-7-酮的环状二核苷酸化合物 Download PDFInfo
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- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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Abstract
公开了式I的化合物,其中碱基、R1和R2如权利要求1所定义,所述化合物为STING的调节剂。
Description
技术领域
本发明涉及诱导细胞因子产生的新颖式I的环状二核苷酸化合物(“CDN”)及其药学上可接受的盐。此外,本发明涉及包含所述化合物的药物组合物及组合,且涉及其在用于治疗与STING(干扰素基因刺激物)相关或经STING调节的疾病的方法中的用途。特别是,本发明的药物组合物适用于治疗炎症、过敏性及自体免疫疾病、传染病、癌症且适用于作为疫苗佐剂。
背景技术
免疫系统的作用在于保护身体避免病原体及恶性细胞。然而,病毒及癌细胞会找到避开免疫系统的方式。因此,免疫疗法的目的为在免疫系统的特定细胞类型中引发抗原特异性免疫反应或再活化预先存在的反应来对抗病原侵入者或癌细胞。
免疫系统由若干专门谱系构成,可大致分成两个分支:先天性及后天性免疫系统。为得到成功的免疫反应,来自两个分支的谱系必须共同作用。先天性免疫系统的主要作用为对抗病原体或恶性细胞建立快速免疫反应,不同于后天性系统,其并非抗原特异性且持久的。除了直接杀灭病原体或转型细胞的外,先天性免疫系统亦活化且随后引导后天性免疫系统。抗原呈递细胞,例如树突状细胞,捕集抗原且以肽-主要组织兼容复合体(majorhistocompatibility complex;MHC)复合体的形式呈现抗原至淋巴组织中的T细胞。此抗原呈递与某些细胞因子的分泌一起引起抗原特异性效应子CD4及CD8 T细胞的活化及分化。通过抗原呈递细胞及其他细胞类型生成I型干扰素(IFN)视为T细胞活化中的关键事件,因为I型IFN的缺失会引起抗病毒感染或肿瘤细胞的T细胞依赖型免疫反应降低(Zitvogel等人,Nature Reviews Immunology 15,405-414,2015)。另一方面,癌症治疗期间I型IFN标记的存在与肿瘤浸润性T细胞的数目增加及潜在有利临床结果相关(Sistigu等人,NatureMedicine 20,1301-1309,2014)。
近期在小鼠中的研究显示,肿瘤微环境中的I型IFN的有效分泌及抗癌细胞的T细胞依赖型免疫反应的诱导依赖于接附蛋白干扰素基因刺激物(STING,亦称为Tmem173、MPYS、MITA、ERIS)的存在(Woo等人,Immunity41,5,830-842,2014;Corrales等人,CellReports 11,1018-1030,2015;Deng等人,Immunity 41,5,843-852,2014)。STING的缺失引起肿瘤微环境中的I型IFN含量降低及在若干肿瘤小鼠模型中的抗肿瘤作用降低的事实强调了I型IFN的存在的重要性。另一方面,STING的特异性活化引起提高的抗癌细胞的抗原特异性T细胞免疫反应。
STING属于核酸传感器家族且为用于胞溶质DNA信号传递的接附子(adaptor)。STING在其基本状态下为以其N端域锚定于ER中且C端域驻存在胞溶质中的二聚体的形式存在。环状二核苷酸(CDN),由蛋白环GMP-AMP合成酶(cGAS)生成,为STING的天然配位体(Ablasser等人,Nature 498,380-384,2013)。CDN与STING的结合诱导构形变化,使得实现TANK结合激酶(TANK binding kinase;TBK1)与干扰素调节因子3(interferon regulatoryfactor3;IRF3)的结合及活化以及自ER至核周内体的再配置(Liu等人,Science 347,第6227期,2630-1-2630-14,2015)。通过TBK1的转录因子IRF3与NF-kB的磷酸化引起多个细胞因子,包括I型IFN,的表达。
鉴于I型IFN在若干恶性疾病(包括病毒感染)及癌症疗法中的重要性,治疗关注点在于允许STING的特异性活化的策略。
WO 2014/093936描述环状二核苷酸化合物,其特征在于具有两个嘌呤核碱基及两个典型3',5'磷酸二酯或硫代磷酸酯部分且诱导STING依赖型细胞因子生成。
US 7,709,458描述环状二核苷酸化合物,其特征在于具有两个嘌呤核碱基及两个典型3',5'磷酸二酯部分且可用于抑制癌细胞增殖或增加癌细胞凋亡,特别是对称细菌CDNc-di-GMP。
US 7,592,326描述免疫刺激性环状二核苷酸化合物,其特征在于具有两个嘌呤核碱基及两个典型3',5'磷酸二酯部分,特别是对称细菌CDN c-di-GMP。
WO 2016/096174及WO 2016/145102描述环状二核苷酸化合物,其特征在于具有两个嘌呤核碱基及两个典型3',5'磷酸二酯或硫代磷酸酯部分且诱导STING依赖型细胞因子生成。
WO 2018/009466描述环状二核苷酸化合物,其特征在于锁核酸部分和两个硫代磷酸酯部分且诱导STING依赖型细胞因子生成。
Bioorg.Med.Chem.Lett.18(2008)5631-5634描述对称细菌CDN c-di-GMP的免疫刺激性单及双硫代磷酸酯类似物。
WO 2014/189805描述环状二核苷酸化合物,其特征在于具有两个嘌呤核碱基及至少一个非典型2',5'磷酸二酯或硫代磷酸酯部分且诱导STING依赖型细胞因子生成。
WO 2015/185565描述环状二核苷酸化合物,其特征在于具有两个嘌呤核碱基、代替核糖四氢呋喃环的一或两个环戊烷及一个非典型2',5'磷酸二酯部分且调节STING。
WO 2016/120305描述环状二核苷酸化合物,其特征在于具有两个嘌呤核碱基、一个其中2'-OH由2'-F替代的核糖部分及一个非典型2',5'磷酸二酯部分且调节STING。
US 2014/0329889、WO 2014/099824、WO 2015/017652、Cell 154,748-762(2013)及Molecular Cell 51,226-235(2013)描述环状二核苷酸2'3'-cGAMP(环[G(2',5')pA(3',5')p]),其特征在于具有两个嘌呤核碱基、一个典型3',5'及一个非典型2',5'磷酸二酯部分。非标准连接的2'3'-cGAMP以高于标准连接的3'3'-cGAMP或对称细菌c-di-GMP的亲和力结合于人类STING,且诱导I型干扰素生成。
具有2',5'-2',5'或2',5'-3',5'连接性的其他环状二核苷酸作为STING激动剂分别揭示于WO 2017/027645及WO 2017/027646中。
发明内容
在第一方面中,本发明涉及一种式I化合物
其中
R1选自H、F、和OH,和
R2是H,或者
R2是-CH2-且R1是-O-,它们共同形成-CH2-O-桥(“锁核酸”;“LNA”),和
R3为选自以下的嘌呤核碱基:嘌呤、腺嘌呤、鸟嘌呤、次黄嘌呤,其经由其N9氮原子连接,
R4选自R4a和R4b,其中
R4a表示2-氮杂-次黄嘌呤
R4b表示6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮
其同种型、互变异构体、立体异构体、代谢物、前药、溶剂合物、水合物及盐,特别是其与无机或有机碱的生理学上可接受的盐。
在第二方面中,本发明涉及一种药物组合物,其包含一或多种如上文或下文所定义的式I化合物或其药学上可接受的盐,任选连同一或多种惰性载剂及/或稀释剂。
在第三方面中,本发明涉及一种药物组合物,其包含一或多种如上文或下文所定义的式I化合物或其药学上可接受的盐,及一或多种其它治疗剂,任选连同一或多种惰性载剂及/或稀释剂。
在第四方面中,本发明涉及一种供用作药剂的式I化合物或其药学上可接受的盐。
在第五方面中,本发明涉及式I化合物或其药学上可接受的盐作为疫苗佐剂的用途。
在第六方面中,本发明涉及一种用于在有需要的患者中治疗与STING相关或经STING调节的疾病或病状,特别是用于治疗炎症、过敏性或自体免疫疾病、传染病或癌症的方法。
此外,本发明涉及所述抑制剂中的一或多种在制造用于在有需要的患者中治疗与STING相关或经STING调节的疾病或病状,特别是用于治疗炎症、过敏性或自体免疫疾病、传染病或癌症的药剂中的用途。
此外,本发明涉及如上文或下文所定义的式I化合物或其药学上可接受的盐,其用于在有需要的患者中治疗与STING相关或经STING调节的疾病或病状,特别是用于治疗炎症、过敏性或自体免疫疾病、传染病或癌症的方法中。
对于本领域技术人员,本发明的其他方面将直接自前述及以下描述及实施例而变得明显。
通用术语及定义
本文中未特定地定义的术语应赋予本领域技术人员依据本发明及上下文将对其赋予的含义。然而,如本说明书中所用,除非相反说明,否则以下术语具有指定的含义且将遵守以下惯例。
术语“一或多种根据本发明的化合物”、“一或多种式I化合物”、“一或多种本发明的化合物”等表示根据本发明的式I化合物,包括其互变异构体、立体异构体及其混合物及其盐(尤其是其药学上可接受的盐)及所述化合物的溶剂合物及水合物,包括所述互变异构体、立体异构体及其盐的溶剂合物及水合物。
除非特定说明,否则在整篇本说明书及随附申请专利范围中,指定化学式或名称应涵盖互变异构体及所有立体、光学及几何异构体(例如对映异构体、非对映异构体、E/Z异构体等)及其外消旋体,以及不同比例的各别对映异构体的混合物、非对映异构体的混合物、或存在此类异构体及对映异构体的任何上述形式的混合物、以及其盐(包括其药学上可接受的盐)及其溶剂合物(例如水合物),包括游离化合物的溶剂合物或化合物的盐的溶剂合物。
在本发明化合物以化学名称及化学式形式描述的情况下,若有任何不一致的情况,则应以化学式为准。
可在子式中使用星号来指示连接至如所定义的核心分子的键。
如本文所用,关于式I化合物的术语“实质上纯”是指相对于关于磷原子的其他可能非对映异构体,一种(Rp,Rp)、(Rp,Sp)、(Sp,Rp)或(Sp,Sp)非对映异构体的纯度为至少75%。在优选实施方案中,实质上纯的通式(I)的化合物的纯度为至少85%、至少90%、至少95%、至少97%或至少99%。
如本文所用,术语“保护基”,且除非另外定义,否则指连接于氧、氮或磷原子以防止该原子的进一步反应或用于其他目的的化学官能基。各种保护基为熟习有机合成技术者所已知且描述于例如T.W.Greene及P.G.M.Wuts的“Protective Groups in OrganicSynthesis”,第三版,1999中。
术语“药学上可接受”在本文中用于指那些化合物、物质、组合物及/或剂型,其在合理医学判断的范畴内,适用于与人类及动物的组织接触而无过度毒性、刺激、过敏反应或其他问题或并发症,且与合理益处/风险比率相匹配。
如本文所使用,“药学上可接受的盐”是指所揭示的化合物的衍生物,其中母体化合物通过制得其酸盐或碱盐而改性。药学上可接受的盐的实例包括(但不限于)碱性残基(例如胺)的无机或有机酸盐;酸性残基(例如磷酸二酯或硫代磷酸酯部分)的碱金属、铵或有机盐;及其类似物。
除非另外指明,否则如本文所用,术语“调节(modulated)”或“调节(modulating)”或“调节(modulate(s))”是指用一或多种本发明的化合物,在此情况下表示STING激动剂,来活化STING路径。
如本文所用,术语“治疗(treatment)”及“治疗(treating)”涵盖治疗性(亦即治愈性及/或缓解性)及预防性(亦即防治性)治疗两者。
治疗性治疗是指已罹患呈明显急性或慢性形式的所述病状中的一或多种的患者的治疗。治疗性治疗可为对症治疗,其为了减轻特定适应症的症状,或可为对因治疗,其为了逆转或部分逆转适应症的病状或阻止或减缓疾病的发展。此外,治疗性治疗涵盖历经一段时间的治疗以及长期疗法。
预防性治疗(“预防”、“防治性治疗”)是指在疾病临床发作之前,对处于罹患所述病状中的一或多种的风险下的患者的治疗以便减小该风险。
术语“治疗(treatment)”及“治疗(treating)”包括给予一或多种活性化合物以便预防或延迟症状或并发症的发病,且预防或延迟罹患疾病、病况或病症,及/或以便消除或控制疾病、病况或病症,以及缓解与疾病、病况或病症相关的症状或并发症。
术语“治疗有效量”是指(i)治疗或预防特定疾病或病状,(ii)减轻、改善或消除特定疾病或病状的一或多个症状,或(iii)预防或延迟本文所述的特定疾病或病状的一或多个症状的发病的本发明的化合物的量。
当本发明提及需要治疗的患者时,其主要地涉及哺乳动物(尤其人类)中的治疗。
具体实施方式
本发明的化合物
本发明的第一方面是在前文的发明内容中所定义的式I化合物,或更特别地,下文中的优选实施方式。式I的CDN表现出对人类STING的良好结合亲和力,在带有不同人类STING等位基因的细胞中也具有有利的活性,这可以实现低剂量时的药理功效。因此,预期本发明的化合物可用于治疗与STING有关或由STING调节的疾病或病况。
除非另有规定,否则R1、R2、R3和R4如上下文中所定义。在下文中将给出根据本发明的化合物的各个取代基的一些优选含义。这些定义中的任何一个都可以彼此组合。
R1和R2:
在第一实施方式中,R1和R2如上文中所定义。
在另一种实施方式中,R1合R2都是H。
再在另一种实施方式中,R1是F且R2是H。
再在另一种实施方式中,R1是-OH且R2是H。
再在另一种实施方式中,R1是-O-且R2是-CH2-,它们共同形成-O-CH2-桥。
R3:
在第一实施方式中,R3如上文中所定义。
在另一种实施方式中,R3是通过其N9氮原子连接的嘌呤。
在另一种实施方式中,R3是通过其N9氮原子连接的腺嘌呤。
再在另一种实施方式中,R3是通过其N9氮原子连接的鸟嘌呤。
再在另一种实施方式中,R3是通过其N9氮原子连接的次黄嘌呤。
R4:
在第一实施方式中,R4如上文中所定义。
在另一种实施方式中,R4是如上文中所定义的群组R4a。
在另一种实施方式中,R4是如上文中所定义的群组R4b。
进一步限定的实施方式I-1至I-13列于表1中,其中标为"a"的实施方式例如I-1a表示其中R4是R4a的实施方式,标为"b"的实施方式例如I-1b表示其中R4是R4b的实施方式。
表1:
根据本发明的化合物的优选子结构显示在式Ia中,
其中R1和R2以及其实施方式如上文中所定义,
包括其盐,特别是其与无机或有机碱的生理学上可接受的盐。
根据本发明的化合物的优选子结构显示在式Ib中,
其中R1和R2以及其实施方式如上文中所定义,
包括其盐,特别是其与无机或有机碱的生理学上可接受的盐。
本发明的化合物含有具有Rp或Sp构型的手性磷原子。本发明涵盖式I、Ia、Ib的化合物的所有立体异构体和实施方式I-1a至I-16a以及实施方式I-1b至I-16b,其或为基本上纯的形式或作为其混合物。优选的是作为基本上纯的(Rp,Rp)、(Rp,Sp)、(Sp,Rp)或(Sp,Sp)立体异构体的通式I、Ia、Ib的化合物和实施方式I-1a至I-16a以及实施方式I-1b至I-16b。
制备
根据本发明的化合物及其中间体可使用本领域技术人员已知的且描述于有机合成的文献中的合成方法获得。优选地,以与下文较充分解释的制备方法(尤其如实验部分中所述)类似地来获得化合物。在一些情况下,实施反应流程所采用的顺序可有所变化。亦可使用本领域技术人员已知的但未在此详细描述的这些反应的变化形式。基于研究以下方法,用于制备根据本发明的化合物的一般制程对于本领域技术人员将明显。起始化合物可商购或可通过描述于文献或本文中的方法制备,或可以类似或相似方式制备。在进行反应之前,起始化合物中的任何相应官能基可使用常规保护基加以保护。这些保护基可在反应顺序内适合阶段中使用本领域技术人员熟悉的方法来断裂。
本文所揭示的CDN可如下文中详细描述或通过本领域技术人员已知的其他方法来制备。一般本领域技术人员将理解,这些方案绝非限制性且可在不背离本发明的精神的情况下进行细节的变化。
CDN可通过描述于Chem.Rev.113,7354-7401(2013);Org.Lett.,12,3269-3271(2010);Tetrahedron 49,1115-1132(1993);WO 2017/0247645;WO 2017/027646;WO 2014/189805;WO 2016/096174;WO 2015/185565;WO 2016/145102;WO 2018/009466;或WO 2016/120305及其中所引用的参考文献中的方法获得。
根据本发明的另一方面,式I化合物及其盐可通过下文中所述的方法来制备。
本领域技术人员应认识到,式(I)中的两个硫代磷酸酯部分可各自存在于R构型(RP)或S构型(SP)中。下文中所述的方法可在合成的不同阶段产生至多四个关于磷原子的非对映异构体,其可通过本领域技术人员已知的方法,例如通过色谱和/或分级结晶,例如具有适合溶剂系统及柱的HPLC来分离。在一些情况中,例如当一个硫化步骤以非对映立体选择性方式进行时,下文中所述的方法在合成的不同阶段可优先产生仅两个非对映异构体,其可通过本领域技术人员已知的色谱或结晶方法来分离。
如上文所提及,式I化合物可通过本领域技术人员已知的方法转化成盐,特别是转化成药学上可接受的盐以用于医药用途。
根据本发明的化合物亦宜使用描述于以下实施例中的方法获得,所述方法亦可出于此目的与技术人员自文献中已知的方法组合。
未在以下制备方法中明确指定的取代基应理解为涵盖上文发明内容部分所提及的定义。
式I化合物可以通过将式II化合物脱保护来制备
其中R1至R4如上文中定义,
其中R2、R3和R4如上文中所定义,R5是携载适当保护基的氧,例如叔丁基二甲基甲硅烷基(TBS),且R1.1如上文针对R1所提及的来定义,条件是-OH由携载适当保护基的氧例如叔丁基二甲基甲硅烷基(TBS)替代。例如,将式II化合物溶解于适合溶剂例如吡啶或THF中,用三乙胺三氢氟酸盐或四丁基氟化铵的混合物处理,并在适合温度例如0-60℃搅拌适合时段例如1-6小时。
式II化合物可以通过将式III化合物脱保护来制备,
其中
R3.1表示携载适当保护基、例如苯甲酰基的NH,且R4表示H(“经保护的腺嘌呤”)或
R3.1表示OH且R3.2表示携载适当保护基、例如异丁酰基或N,N-二甲基甲脒基的NH(“经保护的鸟嘌呤”)或
R3.1表示OH且R3.2表示H(“次黄嘌呤”)或
R3.1和R3.2两者表示H(“嘌呤”)或,
以及其它取代基如上文所定义。
例如,将式(III)的化合物溶解于适合混合物例如甲醇或乙醇中的甲胺或氨水中,且在适合温度例如20℃至60℃搅拌适合时段例如1至24小时。
式III化合物可通过对下式IV化合物进行环化且随后进行硫化来制备,其中R1.1、R2、R3.1、R3.2、R4和R5如上文所定义:
例如,将式IV化合物溶解于适合溶剂例如吡啶中,且用适合偶联剂,例如2-氯-5,5-二甲基-1,3,2-二氧磷杂环己烷2-氧化物(DMOCP)、或特戊酰氯或金刚烷酰氯(adamantoyl chloride)处理,且在适合温度例如20℃下搅拌适合时段,例如0.1至2小时。通过用适合硫化试剂,例如3H-1,2-苯并二硫醇-3-酮或元素硫处理来淬灭环化反应,且在适合温度例如20℃下搅拌适合时段,例如0.1至2小时。
式IV化合物可通过使式V化合物与式VI化合物偶联来制备,其中R1.1、R2、R3.1、R3.2、R4和R5如上文中所定义:
例如,将式VI化合物溶解于适合溶剂例如乙腈中,且用溶解于适合溶剂例如乙腈中的商购式V化合物的溶液处理,任选在适合偶联剂例如四唑、Activator(活化剂溶液,含有于乙腈中的5-(3,5-双(三氟甲基)苯基)-1H-四唑)、二氯乙酸吡啶鎓或三氟乙酸吡啶鎓(或偶联试剂的混合物)存在下、且在适合温度例如20℃搅拌适合时段例如0.1至2小时。通过用适合硫化试剂,例如3-((N,N-二甲基氨基亚甲基)氨基)-3H-1,2,4-二噻唑-3-硫酮(DDTT)或苯乙酰基二硫化物(PADS)或3H-1,2-苯并二硫醇-3-酮1,1-二氧化物(布凯吉氏试剂(Beaucage's reagent))处理来淬灭偶联反应,且在适合温度例如20℃搅拌适合时段例如0.1至2小时。在蒸发溶剂之后,将残余物溶解于适合溶剂,例如二氯甲烷与水的混合物中,且用适合试剂,例如二氯乙酸处理,且在适合温度例如20℃搅拌适合时段例如0.1至2小时。包含产物IV的溶液如下获得:添加适合的溶剂例如吡啶,和通过蒸发浓缩。
式VI化合物可以通过VII化合物的反应制备,其中R1.1、R2、R3.1和R3.2如上文中所定义:
例如,将式VII化合物溶解于适合混合物例如含水乙腈中,且用三氟乙酸吡啶鎓处理,且在适合温度例如20℃搅拌适合时段例如1至30分钟。随后添加叔丁胺且将混合物在适合温度例如20℃搅拌适合时段例如0.1至1小时。通过蒸发溶剂分离产物,随后溶解于适合溶剂例如含水二氯甲烷中,且用二氯乙酸处理,且在适合温度例如20℃搅拌适合时段例如0.1至1小时。获得产物V在乙腈中的浓缩溶液,例如通过添加吡啶然后将该混合物与乙腈共沸来获得。
式VII化合物可以通过式VIII化合物的反应制备,其中R4和R5如上文中所定义:
例如,在于合适的溶剂例如乙腈共沸之后,将式VIII化合物溶解于合适溶剂例如二氯甲烷中,使其与亚磷酰化试剂例如2-氰基乙基-N,N,N',N'-四异丙基亚磷酰二胺在活化剂例如1H-四唑存在下反应,并在适合温度例如20℃搅拌适合时段例如1-48小时。
式VIII化合物可以通过式IX化合物的反应制备,其中R4如上文中所定义:
例如,将式IX化合物溶解于合适溶剂例如吡啶中,使其与适合的硅烷化试剂例如叔丁基二甲基硅烷氯化物在合适的碱例如咪唑存在下反应,并在适合温度例如20℃搅拌适合时段例如1-48小时。区域异构的2’-硅烷化产物和3’-硅烷化产物在水法后处理后被隔开,并且可以例如通过硅胶色谱法用合适的溶剂体系将其进行分离。
式IX化合物可以通过式X化合物的反应制备,其中R4如上文中所定义:
例如,将式X化合物溶解于合适溶剂例如吡啶中,使其与4,4'-二甲氧基三苯甲基氯反应,并在适合温度例如20℃搅拌适合时段例如1-48小时。
通式I化合物或其合成中间体可以如下所述拆分成其非对映异构体。通式I化合物的非对映异构体混合物可以通过利用其不同物理化学特性使用本身已知方法例如色谱和/或分级结晶而拆分成其非对映异构体。
如上所述,可以将式I化合物转化成盐,特别是针对药物用途而转化成药学上可接受的盐。
根据本发明的化合物亦宜使用描述于以下实施例中的方法获得,所述方法亦可出于此目的与技术人员自文献中已知的方法组合。
本发明的药学上可接受的盐可通过常规化学方法由含有碱性部分的母体化合物合成。一般而言,此类盐可通过使这些化合物的游离酸形式与足够量的于于水中或有机稀释剂,如醚、乙酸乙酯、乙醇、正丙醇、异丙醇、丙酮或乙腈或其混合物中的合适碱反应来制备。或者,采用“挥发性缓冲液”,例如三乙基乙酸铵、三乙基甲酸铵、乙酸铵或碳酸氢铵的水溶液的本发明的化合物(游离酸或盐形式)的反相色谱在冻干/冷冻干燥之后产生呈相应三乙基铵或铵盐形式的本发明化合物。或者,盐可通过离子交换,例如通过用阳离子交换剂处理本发明的化合物(游离酸或盐形式)的水溶液来制备。
药理学活性
根据本发明的化合物展现有利的与人类STING的结合亲和力。结合亲和力可例如通过基于闪烁近接分析(scintillation proximity assay;SPA)的竞争结合分析测定,如Nat.Chem.Biol.10,1043-1048(2014)中所述。或者,结合亲和力可例如通过等温滴定热测量定(isothermal titration calorimetry;ITC)测定,如Molecular Cell 51,226-235(2013)中所述。或者,结合亲和力可例如通过表面等离子共振(SPR)测定,如WO 2016/145102中所述。或者,结合亲和力可例如通过如下文所述的差示扫描荧光测定法(DSF)测定。
根据本发明的化合物展现有利的细胞活性。可在报导细胞株中,例如THP1细胞中测量活体外细胞因子诱导,如下文所述。人类STING存在于至少五种已知变异体(WT、HAQ、REF/232H、AQ、Q/293Q)中。为测试不同CDN在人类STING变异体上的活性,可使用编码不同STING变异体编码的载体稳定转导THP1-STING KO细胞。另外,可在人类原生PBMC或人类树突状细胞中测量活体外细胞因子诱导。
本发明的化合物与人类STING的结合可使用以下分析证实:
差示扫描荧光测定法(DSF)
材料:
于DMSO中的SYPRO橙色溶液(SIGMA目录号S5692-500UL),浓度“5000×”
仪器:读取器:CFX384实时系统(Bio-Rad)
自动移液机:HamiltonStarlet
分析缓冲液:20mM Tris,150mM NaCl pH7.5
靶蛋白:人类STING(hSTING,残基155-341,具有N-末端His8-标记的野生型序列及TEV-裂解位点,MW:23601.5Da)
蛋白储备溶液:在分析缓冲液中的c=309μM的储备溶液
测试化合物的最终分析浓度:100μM,3μM靶蛋白,“5×”SYPR Orange
分析程序:
1)在分析缓冲液中制备化合物储备溶液及其稀释液。
2)将5μl荧光染料储备溶液(5000×SYPRO Orange)与50μl靶蛋白(309μM)及945μl缓冲液混合。
3)将2μl此蛋白-染料混合物(25×SYPRO Orange及15μM蛋白)添加至8μl化合物溶液中。最终体积为10μL。
4)某些孔位置用作阴性对照。
5)制备盘用于重复测量且以1000g离心2min。
6)在测量中,使用160次0.5℃的循环(温度逐渐上升15秒/循环,15℃至95℃)。
数据分析:在Bio-Rad CFX Manager中处理解离曲线。峰类型设定成“负”。将至少两次测量结果平均化。Tm变化(“热位移”)展示于表1中。
表1:如通过差示扫描荧光测定法所测定的hSTING结合
实施例 | hSTING Tm位移[℃] |
1.1 | 23.9 |
2.1 | 17.9 |
本发明化合物的细胞活性可使用以下活体外THP1分析展示:
活体外细胞因子诱导
根据本发明的化合物的细胞因子诱导活性已通过使用THP1报导细胞株证明。
在THP1细胞中表达的STING蛋白质的活化导致干扰素产生的提高。通过干扰素调控因子(IRF)-诱导性SEAP(分泌性胚胎碱性磷酸酶)报导构建体的稳定整合可监测功能性干扰素信号传递路径。使用Invivogen`s QUANTI-BlueTM比色酶分析及适合光密度(OD)读取器,可检测到且定量SEAP的活性。此技术可用于表征STING蛋白质的药理学修饰。
在稳定表达人类STING蛋白质及IRF-诱导性SEAP报导构建体的THP1-Blue ISG细胞中进行SEAP活性的测量。在37度、湿度95%及5%CO2的培育箱中在RPMI1640培养基中使用10%胎牛血清、50μg/ml青霉素(Penicillin)-链霉素(Streptomycin)、100μg/ml吉欧霉素(Zeocin)及100μg/ml新霉素(Normocin)培养扩增细胞。将分析备用细胞以冷冻储备液形式储存。
在分析的准备中,在不含吉欧霉素/新霉素的培养基中将细胞解冻,且分配至具有15000个细胞/15微升每孔的密度的分析盘中。通过在50%水性DMSO中的8或16点连续稀释及在培养基中进行的为确保分析中最终DMSO浓度为0.5%的最终稀释步骤来制备化合物。将5μL经稀释的化合物加上5μL培养基添加至盘中,随后在37℃下培育24小时。
在分析当天,将每孔75微升的Quanti-Blue试剂添加至盘的全部孔中,且将盘在37℃下再培育30分钟。在EnVision读取器(PerkinElmer)上测量620nm处的OD。
EC50值及Hill斜度来自用Megalab软件(Boehringer Ingelheim)使用在620nM处的OD的8或16点四参数非线性曲线拟合。参见表2。
表2:THP1-Blue ISG细胞分析中的细胞活性
实施例 | EC<sub>50</sub>[μM] |
1.1 | 0.16 |
2.1 | 0.14 |
已在人类STING基因中鉴别出若干单核苷酸多态性现象,其可能影响对环状二核苷酸的反应。为测定本发明化合物的活性,已生成表达不同人类STING变异体的THP1-BlueISG报导细胞株。为此,首先使用CRISPR/CAS9系统将内源性人类STING删除:用靶向STING基因之一体式CRISPR质体(购自Sigma,编码gRNA且GFP作为成功转导的报导基因)电穿孔THP1-Blue ISG细胞。随后,在转染及扩增24h后分选出GFP阳性细胞。随后将细胞分散于半固体甲基纤维素培养基中来使单细胞纯系分离。随后使用Quanti-blue报导分析针对cGAMP反应筛检纯系。之后通过西方墨点法及STING基因座的定序针对STING损失分析无反应纯系。
对于人类STING变体的过度表达,用编码hSTING的等位基因变异体(WT、HAQ、R232H、AQ及R293Q)的个别反转录病毒质体(MSCV-ires-GFP-Blasti)分别转导经确认的THP1-Blue ISG hSTING KO纯系。针对不同程度的GFP荧光分选转导细胞,且通过西方墨点法分析STING等位基因表达。从亲本未经修饰THP1-Blue ISG细胞株中选拔表达程度相当于内源性STING的表达异位STING蛋白质(WT、HAQ、R232H、AQ及R293Q)的群体,且用于判别化合物特征。出人意料地发现,根据本发明的化合物在以上全部五个变异细胞株中均展现出极具强效的细胞活性,例如实施例1.1和实施例1.2在WT、HAQ、R232H、AQ及R293Q变异细胞株中展现出≤10μM EC50值。所观测到的细胞活性为STING依赖性的,因为未在缺失人类STING的THP1细胞株中观测到活性。
如下测定本发明化合物的细胞稳定性:将化合物溶解于细胞培养基(补充有10%FCS、1%非必需氨基酸及1%丙酮酸盐的MEM)中以得到最终浓度10μM,且与人类肺上皮细胞株Calu-3一起培育(在24孔盘中,60000个细胞/孔)直至24h。在1h、6h、24h时取得细胞培养上清液的样本且通过LC-MS/MS进行定量。
治疗方法
在本发明的另一方面中,发现式I化合物或其药学上可接受的盐可适用于治疗其中STING的调节具有治疗效益的疾病或病状。此外,本发明的化合物因为其活性而适用作疫苗佐剂。
与STING相关或经STING调节的疾病和病状涵盖(但不限于)炎症、过敏性或自体免疫疾病(例如过敏性鼻炎或哮喘)、传染病或癌症。
自体免疫疾病包括(但不限于):全身性红斑性狼疮、牛皮癣、胰岛素依赖型糖尿病(IDDM)、皮肌炎及休格连氏综合征(Sjogren's syndrome;SS)。
炎症代表对外伤的血管、细胞及神经反应的群。炎症可表征为炎性细胞,例如单核球、嗜中性白血球及颗粒球向组织内的移动。此通常与降低的内皮障壁功能及组织内的水肿相关。炎症可分为急性或慢性。急性炎症为身体对有害刺激的初始反应且通过增加血浆及白血球自血液至受伤组织的移动达成。一连串生化事件传播且促成炎症反应,涉及局部血管系统、免疫系统及受伤组织内的各种细胞。长期炎症,称为慢性炎症,引起存在于炎症部位的细胞的类型发生进展性变换且特征在于自炎症过程起同时进行的组织的破坏及愈合。
当炎症作为对感染的免疫反应的部分或作为对外伤的急性反应出现时可能有利且通常为自我限制的。然而,在各种条件下炎症可能有害。此包括对传染媒介物起反应的过度炎症的产生,其可导致显著器官损伤及死亡(例如在败血症的情况中)。而且,慢性炎症通常有害且为多种慢性疾病的根源,对组织造成严重且不可逆损伤。在此类情况中,免疫反应通常为针对自身组织(自体免疫),但对外来实体的慢性反应亦可能导致对自身组织的旁路损坏。因此抗炎疗法的目标为减弱此炎症、抑制自体免疫(若存在)及允许生理过程或愈合及组织修复进展。
本发明化合物可用于治疗身体的任何组织及器官的炎症,包括肌肉骨胳炎症、血管炎症、神经炎症、消化系统炎症、眼部炎症、生殖系统炎症及其他炎症,如下所例示。
肌肉骨胳炎症是指肌肉骨胳系统的任何炎性病状,特别是那些影响骨骼关节的病状,包括手、腕、肘、肩、颌、脊椎、颈、髋、膝、踝及足的关节,及影响连接肌肉与骨的组织(例如肌腱)的病状。可用本发明化合物治疗的肌肉骨胳炎症的实例包括:关节炎(包括例如骨关节炎、类风湿性关节炎、牛皮癣性关节炎、僵直性脊椎炎、急性及慢性感染性关节炎、与痛风及伪通风相关的关节炎及青少年特发性关节炎)、肌腱炎、关节膜炎、腱鞘炎、滑囊炎、纤维组织炎(肌肉纤维疼痛)、上髁炎、肌炎及骨炎(包括例如佩吉特氏病(Paget's disease)、耻骨炎及囊性纤维性骨炎)。眼部炎症是指眼睛的任何结构,包括眼睑的炎症。可用本发明化合物治疗的眼部炎症的实例包括:睑炎、眼睑松弛(blepharochalasis)、结膜炎、泪腺炎、角膜炎、干眼症(眼睛干燥)、巩膜炎、倒睫及葡萄膜炎。可用本发明化合物治疗的神经系统的炎症的实例包括:脑炎、格-巴二氏综合征(Guillain-Barre syndrome)、脑膜炎、神经肌强直、发作性睡病、多发性硬化、脊髓炎及精神分裂症。
可用本发明化合物治疗的血管结构或淋巴系统的炎症的实例包括:关节硬化、关节炎、静脉炎、脉管炎及淋巴管炎。
可用本发明化合物治疗的消化系统的炎症病状的实例包括:胆管炎、胆囊炎、肠炎、小肠结肠炎、胃炎、胃肠炎、炎性肠病(例如克罗恩氏病(Crohn's disease)及溃疡性结肠炎)、回肠炎及直肠炎。
可用本发明化合物治疗的生殖系统的炎症病状的实例包括:子宫颈炎、绒毛膜羊膜炎(chorioamnionitis)、子宫内膜炎、附睾炎、脐炎、卵巢炎、睾丸炎、输卵管炎、输卵管卵巢囊肿、尿道炎、阴道炎、外阴炎及外阴疼痛。
药剂可用于治疗具有炎性部分的自体免疫病状。此类病状包括急性播散性普遍斑秃(acute disseminated alopecia universalise)、贝切特氏病(Behcet's disease)、恰加斯氏病(Chagas'disease)、慢性疲劳综合征、自主神经障碍、脑脊髓炎、僵直性脊椎炎、再生障碍性贫血、化脓性汗腺炎、自体免疫肝炎、自体免疫卵巢炎、乳糜泻、克罗恩氏病、1型糖尿病、巨大细胞动脉炎、古德帕斯丘氏综合征(goodpasture's syndrome)、格雷氏病(Grave's disease)、格-巴二氏综合征、桥本氏病(Hashimoto's disease)、过敏性紫斑(Henoch-Schonlein purpura)、川崎氏病(Kawasaki's disease)、红斑狼疮、显微性结肠炎、显微性多动脉炎、混合性结缔组织病、多发性硬化、重症肌无力、眼阵挛肌阵挛综合征、视神经炎、奥德氏甲状腺炎(ord's thyroiditis)、天疱疮、结节性多动脉炎、多肌痛、类风湿性关节炎、莱特尔氏综合征(Reiter's syndrome)、休格连氏综合征、颞动脉炎、韦格纳氏肉芽肿病(Wegener's granulomatosis)、温型自体免疫溶血性贫血、间质性膀胱炎、莱姆病(lyme disease)、硬斑病、牛皮癣、类肉瘤病、硬皮病、溃疡性结肠炎及白斑病。
药剂可用于治疗具有炎性部分的T细胞介导的超敏性疾病。此类病状包括:接触超敏、接触性皮炎(包括因毒葛引起的接触性皮炎)、风疹、皮肤过敏、呼吸过敏(枯草热、过敏性鼻炎)及谷质敏感性肠病(gluten-sensitive enteropathy)(赛利亚病(Celliacdisease))。
其他可用药剂治疗的炎症病状包括例如阑尾炎、皮炎、皮肌炎、心内膜炎、纤维组织炎、齿龈炎、舌炎、肝炎、化脓性汗腺炎、虹膜炎、喉炎、乳房炎、心肌炎、肾炎、耳炎、胰脏炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、肺炎、前列腺炎、肾盂肾炎及口炎、移植排斥(涉及例如肾脏、肝、心脏、肺、胰脏(例如胰岛细胞)、骨髓、角膜、小肠的器官、皮肤同种异体移植物、皮肤同种移植物及心脏瓣膜异种移植物、血清病及移植物抗宿主疾病)、急性胰脏炎、慢性胰脏炎、急性呼吸窘迫综合征、塞扎里综合征(Sexary's syndrome)、先天性肾上腺增生、非化脓性甲状腺炎、与癌症相关的高钙血症、天疱疮、大疱性疱疹样皮炎、严重多形性红斑、剥脱性皮肤炎、脂溢性皮肤炎、季节性或常年性过敏性鼻炎、支气管哮喘、接触性皮炎、异位性皮炎、药物超敏性反应、过敏性结膜炎、角膜炎、眼带状疱疹、虹膜炎及虹膜睫体炎、脉络膜视网膜炎、视神经炎、症状性类肉瘤病、暴发性或多发性肺结核化学疗法、成年人的特发性血小板减少性紫癜、成年人的继发性血小板减少、获得性(自体免疫)溶血性贫血、成年人白血病及淋巴瘤、儿童急性白血病、局部肠炎、自体免疫脉管炎、多发性硬化、慢性阻塞性肺病、实体器官移植排斥、败血症。优选治疗包括移植排斥、类风湿性关节炎、牛皮癣性关节炎、多发性硬化、1型糖尿病、哮喘、炎性肠病、全身性红斑狼疮、牛皮癣、慢性肺病及伴随传染性病状的炎症(例如败血症)的治疗。
在一个方面中,待使用本发明化合物治疗的疾病或病状为癌症。其中式I化合物或其药学上可接受的盐或溶剂合物可具有潜在有益抗肿瘤作用的癌症疾病及病状的实例包括(但不限于):肺、骨、胰脏、皮肤、头、颈、子宫、卵巢、胃、结肠、乳房、卵巢、食道、小肠、肠、内分泌系统、甲状腺、副甲状腺、肾上腺、尿道、前列腺、阴茎、睾丸、输尿管、膀胱、肾脏或肝脏的癌症;尿道上皮癌;直肠癌;肛门区癌;输卵管、子宫内膜、子宫颈、阴道、外阴、肾盂、肾细胞的癌瘤;软组织肉瘤;粘液瘤;横纹肌瘤;纤维瘤;脂肪瘤;畸胎瘤;胆管癌;肝胚细胞瘤;血管肉瘤;血管瘤;肝细胞瘤;纤维肉瘤;软骨肉瘤;骨髓瘤;慢性或急性白血病;淋巴球性淋巴瘤;原发性CNS淋巴瘤;CNS的赘瘤;脊椎轴肿瘤;鳞状细胞癌;滑膜肉瘤;恶性胸膜间皮瘤;脑干神经胶质瘤;垂体腺瘤;支气管腺瘤;软骨瘤性错构瘤;间皮瘤(inesothelioma);霍奇金氏病(Hodgkin's Disease)或前述癌症中的一或多种的组合。
可用根据本发明化合物治疗的优选癌症为皮肤、肺、肝脏、结肠、脑、乳房、卵巢、前列腺癌、胰脏、肾脏、胃、头、颈、皮肤及尿道上皮癌以及淋巴瘤及白血病。
新型化合物可用于上文所提及疾病的预防、短期或长期治疗,任选亦与手术、放射线疗法或其他“本领域技术(state-of-the-art)”化合物(例如细胞生长抑制或细胞毒性物质、细胞增殖抑制剂、抗血管生成物质、类固醇或抗体)组合。
在其作为佐剂的作用中,在某些实施方案中,本发明化合物及组合物可在采用疫苗的治疗或防治性策略中用作佐剂。因此,本发明的实质上纯CDN或其前药或药学上可接受的盐可与一或多种经选择用于刺激对一或多种预定抗原的免疫反应的疫苗一起使用。本发明的实质上纯CDN或其前药或药学上可接受的盐可与此类疫苗一起提供或除了此类疫苗外额外提供。
疫苗可包含灭活或减毒细菌或病毒,其包含相关抗原、经纯化抗原、为表达及/或分泌抗原而以重组方式工程改造的活性病毒或细菌递送载体、包含负载有抗原或经包含编码抗原的核酸的组合物转染的细胞的抗原呈递细胞(APC)载体、脂质抗原递送媒剂或编码抗原的裸核酸载体。此清单并不意欲为限制性的。举例而言,此类疫苗亦可包含表达且分泌GM-CSF、CCL20、CCL3、IL-12p70、FLT-3配位体、细胞因子中的一或多种的灭活肿瘤细胞。
每天可用的通式I化合物的剂量范围通常为每千克体重0.00001至10mg,例如每千克患者体重0.00001至1mg。各剂量单位可宜含有0.001至1000mg,例如0.001至100mg。
当然,实际治疗有效量或治疗剂量将视本领域技术人员已知的因素,例如患者的年龄及体重、给药途径及疾病的严重程度而定。在任何情况下,化合物或组合物应根据患者的特有病状以能达成递送治疗有效量的剂量及方式给予。
根据本发明的化合物、组合物,包括与一或多种其它治疗剂的任何组合可通过粘膜(例如口服、舌下、阴道、经鼻、颈椎等)、瘤内、瘤周、经皮、吸入或非经肠(例如皮下、静脉内、肌肉内、动脉内、皮内、鞘内及硬膜外给药)途径给予。在可能的给药方法中,瘤内、瘤周、皮下或静脉内给药为优选的。
本发明化合物展现出若干优点,例如与人类STING的有利结合亲和力、有利细胞活性,亦即在携载不同人类STING等位基因的细胞中,细胞分析中展现有利稳定性。
因此,在另一方面中,本发明提供新型式I化合物,包括其药学上可接受的盐,其以STING依赖型方式活体外及/或活体内诱导细胞因子产生,且具有供用于疗法中,亦即供用作药剂的适合药理学及药物动力学特性。
在另一方面中,本发明提供新型式I化合物,包括其药学上可接受的盐,其供用于治疗与STING相关或经STING调节的疾病或病状的方法中。
在另一方面中,本发明提供新型式I化合物或其药学上可接受的盐,其用于治疗炎症、过敏性或自体免疫疾病,例如过敏性鼻炎或哮喘,用于治疗传染病或癌症,或用于用作疫苗佐剂。
在另一方面中,本发明提供式I化合物或其药学上可接受的盐在制造用于治疗STING的调节具有益处的疾病或病状的药剂中的用途。
在另一方面中,本发明提供式I化合物或其药学上可接受的盐在制造用于治疗炎症、过敏性或自体免疫疾病,例如过敏性鼻炎或哮喘,用于治疗传染病或癌症的药剂中的用途。
因此,本发明涉及作为药剂的式I化合物。
此外,本发明涉及式I化合物在用于在患者中,优选人类中治疗与STING相关或经STING调节的疾病或病状的方法中的用途。
此外,本发明涉及式I化合物在用于治疗炎症、过敏性或自体免疫疾病,例如过敏性鼻炎或哮喘,用于治疗传染病或癌症的方法中的用途。
在又一方面中,本发明涉及一种用于在哺乳动物中治疗与STING相关或经STING调节的疾病或病状的方法,其包括向需要此类治疗的患者,优选人类给予治疗有效量的本发明的化合物或药物组合物的步骤。
在另一方面中,本发明提供一种用于在个体中治疗与STING相关或经STING调节的疾病或病状的方法,其包括向个体给予治疗有效量的式I化合物或其药学上可接受的盐。
在另一方面中,本发明提供一种在有需要的患者中治疗炎症、过敏性或自体免疫疾病,例如过敏性鼻炎或哮喘,治疗传染病或癌症的方法,其包括向患者给予治疗有效量的式I化合物或其药学上可接受的盐。
在一相关方面中,本发明涉及在个体中诱导、刺激或辅助免疫反应的方法。这些方法包含向个体给予本发明的实质上纯CDN或其前药或药学上可接受的盐。
在另一方面中,本发明提供式I化合物或其药学上可接受的盐的用途,其为用于制造用于治疗或预防疾病的包含抗原或抗原组合物的免疫原性组合物。
在另一方面中,本发明提供一种治疗或预防疾病的方法,其包括向患有或易患疾病的人类个体给予包含抗原或抗原组合物及式I化合物或其药学上可接受的盐的免疫原性组合物。
在另一方面中,本发明提供用于治疗或预防疾病的包含抗原或抗原组合物及式I化合物或其药学上可接受的盐的疫苗组合物。
在另一方面中,本发明提供式I化合物或其药学上可接受的盐的用途,其为用于制造用于治疗或预防疾病的包含抗原或抗原组合物的疫苗组合物。
在另一方面中,本发明提供一种治疗或预防疾病的方法,其包括向患有或易患疾病的人类个体给予包含抗原或抗原组合物及式I化合物或其药学上可接受的盐的疫苗组合物。
药物组合物
在本发明的另一方面中,发现上述化合物的药物组合物可经调配而适用于给予治疗有效量的所述抑制剂以治疗与STING相关或经STING调节的疾病或病状。
出于本发明的目的,药物组合物可通过多种手段给予,包括以含有药学上可接受的载剂、佐剂及媒剂的调配物形式经肠、非经肠、通过吸入喷雾、局部或经直肠进行。本发明化合物的瘤内(直接进入肿瘤块)或瘤周(肿瘤块周围)给予可直接活化局部浸润性DC,直接促进肿瘤细胞的细胞凋亡或使肿瘤细胞对细胞毒素剂敏感。
本发明的药物组合物可呈无菌可注射制剂形式,例如无菌可注射水性或油性悬浮液。此悬浮液可根据已知技术使用上文或下文所提及的那些适合分散剂或湿润剂及悬浮剂调配。无菌可注射制剂亦可为在无毒非经肠可接受稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如于1,3-丁二醇中的溶液;或制备成冻干粉末。在可接受的媒剂及溶剂中,可采用的有水、林格氏溶液(Ringer's solution)及等张氯化钠溶液。此外,无菌不挥发性油可常规地用作溶剂或悬浮介质。出于此目的,可采用任何温和不挥发性油,包括合成单甘油酯或二甘油酯。此外,例如油酸的脂肪酸亦可用于制备可注射剂。
适用于在口腔中局部给予的调配物包括在调味基质(通常为蔗糖及阿拉伯胶或黄蓍)中包含活性成分的口含锭;在惰性基质(例如明胶及甘油或蔗糖及阿拉伯胶)中包含活性成分的片剂;及在适合液体载剂中包含活性成分的漱口剂。
适用于经阴道给予的调配物可呈现为子宫托、棉塞、乳膏、凝胶、糊状物、发泡体或喷雾剂调配物形式,除了含有活性成分以外,其亦含有例如此项技术中已知为合适的载剂。
适用于非经肠给予的调配物包括水性及非水性等张无菌注射溶液,其可含有抗氧化剂、缓冲剂、抑菌剂及溶质,其使得调配物与既定接受者的血液等张;及水性及非水性无菌悬浮液,其可包括悬浮剂及增稠剂。可使调配物存于单位剂量或多剂量密封容器(例如安瓿及小瓶)中,且可在经冷冻干燥(冻干)条件下储存,仅需要在即将使用之前添加无菌液体载剂,例如注射用水。可自上述种类的无菌粉末、颗粒及片剂制备注射溶液及悬浮液。
因此,根据本发明的另一方面,提供药物组合物,其包含一或多种式I化合物或其药学上可接受的盐,任选连同一或多种惰性载剂及/或稀释剂。
此外,本发明涉及根据本发明的药物组合物用于在患者中,优选人类中治疗与STING相关或经STING调节的疾病或病状的用途。
根据本发明的第二方面的一个实施方案,提供一种供用于治疗与STING相关或经STING调节的疾病或病状的方法中的药物组合物,其包含上述化合物中的一或多种或其药学上可接受的盐,任选连同一或多种惰性载剂及/或稀释剂。
根据另一实施方案,提供一种包含一或多种式I化合物或其药学上可接受的盐的疫苗。
在另一方面中,本发明提供一种包含式I化合物或其药学上可接受的盐的疫苗佐剂。
在另一方面中,本发明提供一种包含抗原或抗原组合物及式I化合物或其药学上可接受的盐的免疫原性组合物。
在另一方面中,本发明提供一种用于治疗或预防疾病的包含抗原或抗原组合物及式I化合物或其药学上可接受的盐的免疫原性组合物。
根据另一实施方案,提供一种药物组合物,其包含一或多种式I化合物或其药学上可接受的盐及一或多种其它治疗剂,任选连同一或多种惰性载剂及/或稀释剂。优选地,此组合物包含一种式I化合物或其药学上可接受的盐及一或多种其它治疗剂。
组合疗法
本发明化合物可以足以诱导、调节或刺激合适免疫反应的量独立使用或可与药学上可接受的赋形剂组合使用。免疫反应可包含(但不限于)特异性免疫反应、非特异性免疫反应、特异性及非特异性反应、先天性反应、原初免疫反应、继承免疫性、二次免疫反应、记忆免疫反应、免疫细胞活化、免疫细胞增殖、免疫细胞分化及细胞因子表达。在某些实施方案中,本文所述的化合物及其组合物与一或多种其他组合物结合给予,该一或多种其他组合物包括旨在刺激对一或多种预定抗原的免疫反应的疫苗;佐剂;CTLA-4及PD-1路径拮抗剂、脂质、脂质体、化学治疗剂、免疫调节细胞株等。
本文所述的化合物及其组合物可在其他治疗性或防治性组合物或模态之前、之后及/或同时给予。这些包括(但不限于):B7共刺激分子、白介素-2、干扰素-g、GM-CSF、CTLA-4拮抗剂、OX-40/OX-40配位体、CD40/CD40配位体、沙格司亭(sargramostim)、左旋咪唑(levamisol)、痘疮病毒、卡介苗(Bacille Calmette-Guerin;BCG)、脂质体、矾、弗氏完全或不完全佐剂(Freund's complete or incomplete adjuvant)、解毒内毒素、矿物油、表面活性物质(例如脂质卵磷脂(lipolecithin))、普洛尼克多元醇(pluronic polyol)、聚阴离子、肽及油或烃乳液。优选为诱导T细胞免疫反应的载剂,其相对于抗体反应优先刺激细胞溶解T细胞反应,但亦可使用刺激两种类型的反应的载剂。在试剂为多肽的情况下,可给予多肽本身或编码多肽的聚核苷酸。载剂可为细胞,例如抗原呈递细胞(APC)或树突状细胞。抗原呈递细胞包括此类如巨噬细胞、树状细胞及B细胞的细胞类型。其他专门的抗原呈递细胞包括单核细胞、边缘区库普弗细胞(marginal zone Kupffer cell)、微神经胶质细胞、兰格汉氏细胞(Langerhans'cell)、啮合树突状细胞、滤泡树突状细胞及T细胞。亦可使用兼性抗原呈递细胞。兼性抗原呈递细胞的实例包括星形胶质细胞、滤泡细胞、内皮细胞及纤维母细胞。载剂可为细菌细胞,其经转型以表达多肽或递送聚核苷酸,其之后在经疫苗接种的个体的细胞中表达。可添加佐剂(例如氢氧化铝或磷酸铝)以提高疫苗触发、增强或延长免疫反应的能力。其他材料,例如细胞因子、趋化激素及细菌核酸序列,例如CpG、Toll样受体(TLR)9激动剂以及TLR 2、TLR 4、TLR 5、TLR 7、TLR 8、TLR9的其他激动剂,包括脂蛋白、LPS、单磷酰基脂质A、脂磷壁酸、咪喹莫特(imiquimod)、雷西莫特(resiquimod)以及视黄酸诱导性基因I(RIG-I)激动剂,例如聚I:C亦为潜在佐剂,其单独或与所述组合物组合使用。佐剂的其他代表性实施例包括合成佐剂QS-21,其包含自皂皮树的树皮纯化的均质皂素及短小棒状杆菌(Corynebacterium parvum)(McCune等人,Cancer,1979;43:1619)。
用于与其他治疗剂共同给予的方法为此项技术中所熟知(Hardman等人(编)(2001)Goodman and Gilman's The Pharmacological Basis of Therapeutics,第10版,McGraw-Hill,New York,NY;Poole及Peterson(编)(2001)Pharmacotherapeutics forAdvanced Practice:A Practical Approach,Lippincott,Williams&Wilkins,Phila.,PA;Chabner及Longo(编)(2001)Cancer Chemotherapy and Biotherapy,Lippincott,Williams&Wilkins,Phila.,PA)。通常,共同给药或一起给药指示用两种或多于两种药剂治疗个体,其中所述药剂可同时或在不同时间给予。举例而言,此类药剂可以单独给予形式递送至单一个体,单独给予可在基本上相同时间或不同时间进行,且其可通过相同给予途径或不同给予途径进行。此类药剂可在同一给药(例如同一调配物)中递送至单一个体,以使得其通过同一给药途径得到同时给予。
由于本发明化合物的佐剂特性,其亦可与其他治疗模态(包括其他疫苗、佐剂、抗原、抗体及免疫调节剂)组合使用。实施例提供于下。
佐剂
除了本文所述的本发明化合物及其组合物的外,本发明的组合物或方法可进一步包含一或多种其他物质,由于其性质,其可用以刺激或以其他方式利用免疫系统对经靶向的肿瘤细胞上存在的癌症抗原作出反应。此类佐剂包括(但不限于)脂质、脂质体、诱导先天性免疫的灭活细菌(例如灭活或减毒单核球增多性李氏菌(Listeria monocytogenes))、经由Toll样受体(TLR)、(NOD)-样受体(NLR)介导先天性免疫活化的组合物、视黄酸诱导性基因类(RIG)-I样受体(RLR)、C型凝集素受体(CLR)及/或病原体相关分子模式(“PAMPS”)。PAMP的实例包括脂蛋白、脂多肽、肽聚糖、酵母聚糖、脂多糖、奈瑟氏球菌外膜蛋白(neisserial porin)、鞭毛蛋白、普洛非林(profillin)、半乳糖神经酰胺、胞壁酰二肽。肽聚糖、脂蛋白及脂磷壁酸为革兰氏阳性(Gram-positive)细胞壁组分。脂多糖由大部分细菌表达,MPL为其中一个实施例。鞭毛蛋白指由病原性及共生细菌分泌的细菌鞭毛的结构组分。半乳糖苷基神经酰胺为天然杀伤T(NKT)细胞的活化因子。胞壁酰二肽为所有细菌共有的生物活性肽聚糖主结构。
免疫检查点抑制剂
本发明的化合物可与免疫检查点抑制剂,例如选自由以下组成的群的免疫检查点抑制剂:CTLA-4路径拮抗剂、PD-1路径拮抗剂、Tim-3路径拮抗剂、Vista路径拮抗剂、BTLA路径拮抗剂、LAG-3路径拮抗剂或TIGIT路径拮抗剂组合使用。在一些实施方案中,免疫检查点抑制剂选自由以下组成的群:抗CTLA-4抗体、抗PD-1抗体、抗Tim-3抗体、抗Vista抗体、抗BTLA抗体、抗LAG-3抗体或抗TIGIT抗体。
本发明的化合物可与CTLA-4路径拮抗剂组合使用。在一些实施方案中,组合用于治疗实体肿瘤或血液科恶性疾病。认为CTLA-4为后天性免疫反应的重要负调控剂。经活化的T细胞上调CTLA-4,其与CD28相比以较高亲和力结合抗原呈递细胞上的CD80及CD86,由此抑制T细胞刺激、IL-2基因表达及T细胞增殖。已在结肠癌瘤、转移性前列腺癌及转移性黑素瘤的鼠类模型中观测到CTLA4阻断的抗肿瘤作用。在一些实施方案中,CTLA-4路径拮抗剂为选自由曲美单抗(tremelimumab)及伊派利单抗(ipilimumab)组成的群的抗CTLA-4抗体分子。
伊派利单抗(CTLA-4抗体,亦称为MDX-010,CAS编号477202-00-9)及曲美单抗(IgG2单克隆抗体,原名替西单抗(ticilimumab),CP-675,206)为结合于人类CTLA4且防止其与CD80及CD86相互作用的人类化单克隆抗体。可由类似策略靶向的其他负免疫调节剂包括计划性细胞死亡1(PD-1)、B及T淋巴细胞弱化子、转型生长因子β、白介素-10及血管内皮生长因子。
在一些实施方案中,本发明化合物可与抗CTLA-4抗体及抗PD-1抗体组合使用。在一个实施方案中,组合包括抗PD-1抗体分子,例如如本文中所述,及抗CTLA-4抗体,例如伊派利单抗。可使用的例示性剂量包括约1至10mg/kg,例如3mg/kg的抗-PD-1抗体分子的剂量及约3mg/kg的抗CTLA-4抗体,例如伊派利单抗。
本发明化合物可与PD-1路径拮抗剂组合使用。在一些实施方案中,组合用于治疗实体肿瘤或血液科恶性疾病。PD-1为在活化T细胞上表达之后天性免疫反应的另一负调控剂。PD-1结合于B7-H1及B7-DC,且PD-1的接合抑制T细胞活化。抗肿瘤作用已经PD-1路径阻断证明。已在文献中报导抗PD-1抗体分子(例如纳武单抗(Nivolumab)(OpdivoTM)、派立珠单抗(pembrolizumab)(KeytrudaTM)及皮立珠单抗(pidilizumab))及AMP-224为可用于本发明中的PD-1路径阻断剂的实施例。在一些实施方案中,PD-1路径拮抗剂为选自由纳武单抗、派立珠单抗或皮立珠单抗组成的群的抗PD-1抗体分子。
在一些实施方案中,PD-1路径拮抗剂为免疫粘附素(例如包含与恒定区(例如免疫球蛋白序列的Fc区)融合的PD-L1或PD-L2的细胞外或PD-1结合部分的免疫粘附素)。在一些实施方案中,PD-1抑制剂为AMP-224(B7-DCIg;Amplimmune;例如WO2010/027827及WO2011/066342中所揭示),其为阻断PD-1与B7-H1之间的相互相用的PD-L2 Fc融合可溶性受体。
在一些实施方案中,PD-1路径拮抗剂为PD-L1或PD-L2抑制剂。在一些实施方案中,PD-L1或PD-L2抑制剂为抗PD-L1抗体或抗PD-L2抗体。在一些实施方案中,抗PD-L1抑制剂选自YW243.55.S70、MPDL3280A、MEDI-4736、MSB-0010718C或MDX-1105。在一些实施方案中,PD-L1抑制剂为抗PD-L1抗体MSB0010718C。MSB0010718C(亦称为A09-246-2;Merck Serono)为单克隆抗体,其结合于PD-L1。
本发明化合物可与TIM-3路径拮抗剂组合使用。在一些实施方案中,组合用于治疗实体肿瘤或血液科恶性疾病。在一些实施方案中,TIM-3路径拮抗剂为抗TIM-3抗体。在一些实施方案中,抗TIM-3抗体分子揭示于2015年8月6日公开的题为“Antibody Molecules toTIM-3 and Uses Thereof”的US2015/0218274中。
本发明化合物可与LAG-3路径拮抗剂组合使用。在一些实施方案中,组合用于治疗实体肿瘤或血液科恶性疾病。在一些实施方案中,LAG-3路径拮抗剂为抗LAG-3抗体。在一些实施方案中,抗LAG-3抗体分子揭示于2015年3月13日申请的题为“Antibody Molecules toLAG-3 and Uses Thereof”的US2015/0259420中。
T细胞受体激动剂
本发明化合物可与T细胞受体激动剂组合使用,例如CD28激动剂、OX40激动剂、GITR激动剂、CD137激动剂、CD27激动剂或HVEM激动剂。
本发明化合物可与CD27激动剂组合使用。例示性CD27激动剂包括抗CD27激动性抗体,例如PCT公开案第WO 2012/004367号中所述。
本发明化合物可与GITR激动剂组合使用。在一些实施方案中,组合用于治疗实体肿瘤或血液科恶性疾病。例示性GITR激动剂包括例如GITR融合蛋白及抗GITR抗体(例如二价抗GITR抗体)。
TLR激动剂
本发明化合物可与Toll样受体激动剂组合使用。如本文所用,术语“Toll样受体”(或“TLR”)是指感测微生物产物及/或引发后天性免疫反应的蛋白质的Toll样受体家族的成员或其片段。在一个实施方案中,TLR活化树突状细胞(DC)。Toll样受体(TLR)为模式识别受体的家族,其最初鉴别为识别微生物病原体的先天性免疫系统的传感器。TLR包含含有富含白氨酸的重复的胞外域、跨膜域及胞内TIR(Toll/IL-1R)域的保守性跨膜分子的家族。TLR识别微生物中的不同结构,通常称为“PAMP”(病原体相关分子模式)。结合于TLR的配位体调用细胞内信号传递路径的级联,该级联诱导参与炎症及免疫的因子的产生。
此项技术中已知且在本发明中使用的TLR激动剂包括(但不限于)以下:
Pam3Cys,一种TLR-1/2激动剂;
CFA,一种TLR-2激动剂;
MALP2,一种TLR-2激动剂;
Pam2Cys,一种TLR-2激动剂;
FSL-1,一种TLR-2激动剂;
Hib-OMPC,TLR-2激动剂;
聚肌胞苷酸(聚I:C),一种TLR-3激动剂;
聚腺苷-聚尿苷酸(聚AU),一种TLR-3激动剂;
单磷酰基脂质A(MPL),一种TLR-4激动剂;
LPS,一种TLR-4激动剂;
细菌鞭毛蛋白,一种TLR-5激动剂;
唾液酸基-Tn(STn),一种与许多人类癌细胞上的MUC1粘蛋白相关的碳水化合物及一种TLR-4激动剂;
咪喹莫特,一种TLR-7激动剂;
雷西莫特,一种TLR-7/8激动剂;
洛索立宾(loxoribine),一种TLR-7/8激动剂;及
未甲基化CpG二核苷酸(CpG-ODN),一种TLR-9激动剂。
由于其佐剂质量,TLR激动剂优选与其他疫苗、佐剂及/或免疫调节剂组合使用,且可组合于多种组合中。由此在某些实施方案中,如本文所述,结合于STING且诱导STING依赖型TBK1活化的单或二FCDN化合物及表达且分泌一或多种刺激树突状细胞诱导、募集及/或成熟的细胞因子的灭活肿瘤细胞可与用于治疗目的的一或多种TLR激动剂一起给予。
抗体治疗
本发明化合物可与治疗性抗体组合使用。在一些实施方案中,治疗性抗体的作用机制为抗体依赖性细胞介导的细胞毒性(ADCC)。ADCC为细胞介导的免疫防御机制,藉此免疫系统的效应细胞主动溶解细胞膜表面抗原已由特异性抗体结合的靶细胞。其为抗体作为体液免疫反应之一部分可发挥作用来限制及制约感染的机制中之一者。经典ADCC由天然杀伤(NK)细胞介导;巨噬细胞、嗜中性白血球及嗜伊红血球亦可介导ADCC。ADCC为针对肿瘤的治疗性单克隆抗体(包括曲妥珠单抗(trastuzumab)及利妥昔单抗(rituximab))的重要作用机制。本发明化合物可用于增强ADCC。
以下为可与本发明化合物一起使用的抗体的例示性清单。
莫罗莫那-CD3(Muromonab-CD3)、英利昔单抗(Infliximab)、阿达木单抗(adalimumab)、奥马珠单抗(Omalizumab)、达利珠单抗(Daclizumab)、利妥昔单抗、布突默单抗(Ibritumomab)、托西莫单抗(Tositumomab)、西妥昔单抗(Cetuximab)、曲妥珠单抗、阿仑单抗(Alemtuzumab)、Lym-1伊派利单抗、维他欣(Vitaxin)、贝伐单抗(Bevacizumab)及阿昔单抗(Abciximab)。
可与本发明化合物组合使用的其他治疗性抗体包括催乳激素受体(PRLR)抑制剂、HER3抑制剂、EGFR2及/或EGFR4抑制剂、M-CSF抑制剂、抗APRIL抗体或抗SIRP或抗CD47抗体。
化学治疗剂
在本文所述的方法的其他实施方案中,本发明化合物与化学治疗剂(例如小分子医药化合物)组合使用。因此,方法进一步涉及给予个体有效量的一或多种化学治疗剂作为额外治疗或组合治疗。在某些实施方案中,该一或多种化学治疗剂选自由以下组成的群:乙酸阿比特龙(abiraterone acetate)、六甲蜜胺(altretamine)、脱水长春花碱(anhydrovinblastine)、奥瑞他汀(auristatin)、贝瑟罗汀(bexarotene)、比卡鲁胺(bicalutamide)、BMS 184476、2,3,4,5,6-五氟-N-(3-氟-4-甲氧苯基)苯磺酰胺、博莱霉素(bleomycin)、N,N-二甲基-L-缬胺酰基-N-甲基-L-缬胺酰基-L-脯胺酰基-1-L脯氨酸-叔丁基酰胺、恶病质素(cachectin)、西马多丁(cemadotin)、苯丁酸氮芥(chlorambucil)、环磷酰胺、3',4'-二去氢-4'-脱氧-8'-去甲长春碱(3',4'-didehydro-4'-deoxy-8'-norvin-caleukoblastine)、多烯紫杉醇(docetaxol)、多西他赛(doxetaxel)、环磷酰胺、卡铂(carboplatin)、卡莫司汀(carmustine)、顺铂(cisplatin)、克瑞托欣(cryptophycin)、环磷酰胺、阿糖胞苷(cytarabine)、达卡巴嗪(dacarbazine;DTIC)、放线菌素D、道诺霉素(daunorubicin)、地西他滨多拉司他汀(decitabine dolastatin)、多柔比星(doxorubicin)(阿德力霉素(adriamycin))、依托泊苷(etoposide)、5-氟尿嘧啶、非那雄安(finasteride)、氟他胺(flutamide)、羟基尿素(hydroxyurea)及羟基尿素紫杉烷(hydroxyureataxanes)、异环磷酰胺(ifosfamide)、利阿唑(liarozole)、氯尼达明(lonidamine)、洛莫司汀(lomustine;CCNU)、恩杂鲁胺(enzalutamide)、双氯乙基甲胺(氮芥)、美法仑(melphalan)、羟乙基磺酸米伏布尔(mivobulin isethionate)、根瘤菌素(rhizoxin)、塞尼氟(sertenef)、链脲菌素(streptozocin)、丝裂霉素(mitomycin)、甲胺喋呤(methotrexate)、紫杉烷(taxanes)、尼鲁胺(nilutamide)、奥那司酮(onapristone)、太平洋紫杉醇(paclitaxel)、泼尼氮芥(prednimustine)、丙卡巴肼(procarbazine)、RPR109881、磷酸斯穆斯汀(stramustine phosphate)、他莫昔芬(tamoxifen)、他索那明(tasonermin)、紫杉醇(taxol)、维甲酸(tretinoin)、长春碱(vinblastine)、长春新碱(vincristine)、硫酸长春地辛(vindesine sulfate)及长春氟宁(vinflunine)。
在本文所述的方法的其他实施方案中,本发明化合物与化学治疗剂及/或其他用于治疗如本文方法中所述的适应症的药剂组合使用。在一些实施方案中,本发明化合物与一或多种选自由以下组成的群的药剂组合使用:索塔妥林(sotrastaurin)、尼罗替尼(nilotinib)、5-(2,4-二羟基-5-异丙基苯基)-N-乙基-4-(4-((N-吗啉基)甲基)苯基)异噁唑-3-甲酰胺、达妥昔布(dactolisib)、8-(6-甲氧基-吡啶-3-基)-3-甲基-1-(4-哌嗪-1-基-3-三氟甲基-苯基)-1,3-二氢-咪唑并[4,5-c]喹啉-2-酮、3-(2,6-二氯-3,5-二甲氧基苯基)-1-(6-((4-(4-乙基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-1-甲基脲、布帕昔布(buparlisib)、8-(2,6-二氟-3,5-二甲氧基苯基)-N-(4-((二甲氨基)甲基)-1H-咪唑-2-基)喹喏啉-5-甲酰胺、(S)-N1-(4-甲基-5-(2-(1,1,1-三氟-2-甲基丙-2-基)吡啶-4-基)噻唑-2-基)吡咯烷-1,2-二甲酰胺、(S)-1-(4-氯苯基)-7-异丙氧基-6-甲氧基-2-(4-(甲基-(((1r,4S)-4-(4-甲基-3-氧代哌嗪-1-基)环己基)甲基)氨基)苯基)-1,2-二氢异喹啉-3(4H)-酮、地拉罗司(deferasirox)、来曲唑(letrozole)、(4S,5R)-3-(2'-氨基-2-(N-吗啉基)-4'-(三氟甲基)-[4,5'-二嘧啶]-6-基)-4-(羟甲基)-5-甲基噁唑烷-2-酮、(S)-5-(5-氯-1-甲基-2-氧代-1,2-二氢吡啶-3-基)-6-(4-氯苯基)-2-(2,4-二甲氧基嘧啶-5-基)-1-异丙基-5,6-二氢吡咯并[3,4-d]咪唑-4(1H)-酮、4-((2-(((1R,2R)-2-羟基环己基)氨基)苯并[d]噻唑-6-基)氧基)-N-甲基-2-吡啶甲酰胺、甲磺酸伊马替尼(imatinib mesylate)、2-氟-N-甲基-4-(7-(喹啉-6-基甲基)咪唑并[1,2-b][1,2,4]三嗪-2-基)苯甲酰胺、卢佐替尼(ruxolitinib)、帕比诺他(panobinostat)、奥卓司他(osilodrostat)、(S)-N-((S)-1-环己基-2-((S)-2-(4-(4-氟苯甲酰基)噻唑-2-基)吡咯烷-1-基)-2-氧代乙基)-2-(甲氨基)丙酰胺、(S)-N-((S)-1-环己基-2-((S)-2-(4-(4-氟苯甲酰基)噻唑-2-基)吡咯烷-1-基)-2-氧代乙基)-2-(甲氨基)丙酰胺、磷酸索尼蒂吉伯(sonidegib phosphate)、色瑞替尼(ceritinib)、7-环戊基-N,N-二甲基-2-((5-(哌嗪-1-基)吡啶-2-基)氨基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺、N-(4-((1R,3S,5S)-3-氨基-5-甲基环己基)吡啶-3-基)-6-(2,6-二氟苯基)-5-氟吡啶甲酰胺、2-(2',3-二甲基-[2,4'-二吡啶]-5-基)-N-(5-(吡嗪-2-基)吡啶-2-基)乙酰胺、恩拉菲尼(encorafenib)、7-环戊基-N,N-二甲基-2-((5-((1R,6S)-9-甲基-4-氧代-3,9-二氮双环[4.2.1]-壬-3-基)吡啶-2-基)氨基)-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺、毕尼替尼(binime-tinib)、米哚妥林(midostaurin)、依维莫司(everolimus)、1-甲基-5-((2-(5-(三氟甲基)-1H-咪唑-2-基)吡啶-4-基)氧基)-N-(4-(三氟甲基)苯基)-1H-苯并[d]咪唑2-胺、二天冬氨酸帕瑞肽(pasi-reotide diaspartate)、多韦替尼(dovitinib)、(R,E)-N-(7-氯-1-(1-(4-(二甲氨基)丁-2-烯酰基)氮杂环庚烷-3-基)-1H-苯并[d]咪唑-2-基)-2-甲基异烟碱酰胺、N6-(2-异丙氧基-5-甲基-4-(1-甲基哌啶-4-基)苯基)-N4-(2-(异丙基磺酰基)-苯基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺、3-(4-(4-((5-氯-4-((5-甲基-1H-吡唑-3-基)氨基)嘧啶-2-基)氨基)-5-氟-2-甲基苯基)哌啶-1-基)硫杂环丁烷1,1-二氧化物、5-氯-N2-(2-氟-5-甲基-4-(1-(四氢-2H-哌喃-4-基)哌啶-4-基)苯基)-N4-(5-甲基-1H-吡唑-3-基)嘧啶-2,4-二胺、5-氯-N2-(4-(1-乙基哌啶-4-基)-2-氟-5-甲基苯基)-N4-(5-甲基-1H-吡唑-3-基)嘧啶-2,4-二胺、伐司扑达(valspodar)及丁二酸瓦他拉尼(vatalanib succinate)。
在其他实施方案中,本发明化合物可与PKC抑制剂、BCR-ABL抑制剂、HSP90抑制剂、PI3K及/或mTOR的抑制剂、FGFR抑制剂、PI3K抑制剂、FGFR抑制剂、PI3K抑制剂、细胞色素P450的抑制剂(例如CYP17抑制剂)、HDM2抑制剂、芳香酶抑制剂、p53及/或p53/Mdm2相互作用的抑制剂或CSF-1R酪氨酸激酶抑制剂组合使用。
适合制剂包括例如片剂、胶囊、栓剂、溶液(尤其注射用溶液(皮下、静脉内、肌肉内)及输注用溶液)、酏剂、乳液或可分散性粉末。医药活性化合物的含量应占整体组合物的0.1至90重量%,优选0.5至50重量%范围内,亦即呈足以达成下文所指定的剂量范围的量。必要时,指定的剂量可一日给予若干次。
上述组合搭配物的剂量通常为一般建议最低剂量的1/5至一般建议剂量的1/1。
在又一方面中,本发明涉及一种用于在患者中治疗与STING相关或经STING调节的疾病或病状的方法,其包括向需要此类治疗的患者(优选为人类)组合给予治疗有效量的本发明化合物与治疗有效量的上文所述一或多种其它治疗剂的步骤。
根据本发明的化合物与其他治疗剂组合的用法可同时进行或以错开的时间进行。
根据本发明的化合物及一或多种其它治疗剂可一起存在于一种调配物中或独立地在两种相同或不同调配物中,例如作为所谓的分装部分的试剂盒。
因此,在另一方面中,本发明提供一种包含式I化合物或其药学上可接受的盐及至少一种其他治疗剂的组合。
本发明的另一目的在于提供一种药物组合物,其包含式I化合物或其药学上可接受的盐及至少一种其他治疗剂及药学上可接受的赋形剂中的一或多种。
在另一方面中,本发明提供一种供用于疗法中的包含式I化合物或其药学上可接受的盐及至少一种其他治疗剂的组合。
在另一方面中,本发明提供一种供用于治疗STING的调节具有益处的疾病或病状的组合,其包含式I化合物或其药学上可接受的盐及至少一种其他治疗剂。
在另一方面中,本发明提供一种供用于治疗炎症、过敏性及自体免疫疾病、传染病及癌症的组合,其包含式I化合物或其药学上可接受的盐及至少一种其他治疗剂。
在另一方面中,本发明提供一种在患者中治疗STING的调节具有益处的疾病或病状的方法,其包括给予治疗有效量的包含式I化合物或其药学上可接受的盐及至少一种其他治疗剂的组合。
在另一方面中,本发明提供一种在患者中治疗炎症、过敏性或自体免疫疾病、传染病或癌症的方法,其包括给予治疗有效量的包含式I化合物或其药学上可接受的盐及至少一种其他治疗剂的组合。
当然,实际药学上的有效量或治疗剂量将视本领域技术人员已知的因素,例如患者的年龄及体重、给药途径及疾病的严重性而定。在任何情况下,组合应根据患者的特有病状以能达成递送药学上的有效量的剂量及方式给予。
在另一方面中,本发明涉及一种药物组合物,其包含根据本发明的化合物及一或多种上下文所述的其它治疗剂,任选连同一或多种惰性载剂及/或稀释剂。
本发明的其他特征及优点将自以下较详细的实施例而变得明显,所述实施例以举例方式说明本发明的原理。
实施例及实验数据
以下实施例仅出于说明本发明的目的且并不意欲以任何方式限制本发明的范畴。
在上下文中使用以下缩写:
aq. 水溶液
Bz 苯甲酰基
CEP (2-氰基乙基)-(N,N-二异丙基)-氨基磷酸酯
DA 二极管阵列
DCM 二氯甲烷
DDTT 3-((N,N-二甲基-氨基亚甲基)氨基)-3H-1,2,4-二噻唑-3-硫酮
dmf N,N-二甲基甲脒基
DMOCP 2-氯-5,5-二甲基-2-氧代-1,3,2-二氧磷杂环己烷
DMSO 二甲亚砜
DMT 4,4'-二甲氧基三苯甲基
ESI 电喷雾电离
eq. 摩尔当量
h 小时
HPLC 高效液相色谱
LC 液相色谱
m/z 质荷比
MeOH 甲醇
min 分钟
MS 质谱
NH4OH NH3的水溶液
NMR 核磁共振
ppm 百万分率
s 单峰
Sol 溶剂
TBS 叔丁基二甲基甲硅烷基
TEA 三乙胺
TEAB 三乙基碳酸氢铵
TEAF 三乙基甲酸铵
TFA 三氟乙酸
tRet 以分钟为单位的保留时间
UV 紫外线
Vis 可见光
一般技术批注
术语“环境温度”及“室温”可互换使用且表示约20℃,例如15至25℃的温度。
一般而言,已获得根据本发明的化合物的1H NMR光谱及/或质谱。除非另外说明,否则所有色谱操作均在室温进行。在环状二核苷酸合成期间,典型地通过使用不超过35℃的水浴温度在减压下旋转蒸发来进行溶剂的蒸发。此外,在环状二核苷酸合成期间,反应典型地在氮气或氩气下进行。
A)分析方法
NMR光谱分析:
核磁共振(NMR)光谱:对于1H光谱,化学位移参考DMSO溶剂信号(2.50ppm),或者,对于在D2O中的测量值,参考DSS(4,4-二甲基-4-硅戊烷-1-磺酸)。31P NMR光谱通过对比1H/31P的绝对频率间接参考(Bruker BioSpin GmbH,软件:TopSpin,au程序:xsi)。所有31PNMR光谱均用质子去偶记录。
分析型HPLC构型:
方法名称:012_CA01:
方法名称:X012_S01:
方法名称:X011_S04:
装置描述:具有DA-检测器和MS-检测器的Waters Acquity
柱:XBridge BEH C18_2.1x 30mm_2.5μm
柱生产商:Waters
B)中间体的合成
中间体1.1
2-氮杂肌苷
将6M盐酸(125mL,750mmol,38.7当量)冷却至-30℃,添加5-氨基咪唑-4-甲酰胺1-β-D-呋喃糖苷(AICAR,5.00g,19.4mmol,1.00当量)。将其搅拌5min,然后通过滴液漏斗添加溶解在水(20mL)中的亚硝酸钠(4.01g,58.1mmol,3.00当量)。将温度保持在-28℃和-32℃之间。在完成添加之后,将其在-30℃搅拌2.5h。添加预先冷却的乙醇(125mL),将温度升至-20℃。通过添加浓氨溶液(32wt%在水中;45.0mL,746mmol,38.5当量)中和反应混合物,在该方法过程中使温度保持在低于-15℃。然后移走冷却浴,将反应混合物温热至室温,然后将其蒸发至干燥。
使粗产物与甲苯共沸4次,其无需进一步纯化在包含氯化铵的情况下即可用于下一步骤。
中间体1.2
5′-DMT-2-氮杂肌苷
首先将2-氮杂肌苷(中间体1.1,粗制,理论含量4.50g,16.7mmol,1.00当量)与无水吡啶(2x 50mL)共沸,然后溶解在无水吡啶(135mL)中。将二甲氧基三苯甲基氯溶解在吡啶(45mL)中,将其缓慢滴入反应混合物中。将其在室温搅拌过夜。滤除未溶解的盐,将滤饼用吡啶洗涤。将滤液蒸发至干燥。将该残余物溶解在乙酸乙酯中,并用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤,经硫酸钠干燥,并蒸发至干燥。将所得微黄色油状物通过中压柱色谱纯化(硅胶,20-100%乙酸乙酯在环己烷中的梯度)。
LC-MS(X012_S01):tRet=0.59min ESI-MS:572[M+H]+
中间体1.3-a和1.3-b
将5′-DMT-2-氮杂肌苷(中间体1.2,4.20g,7.35mmol,1,00当量)溶解在DMF(25mL)和2,6-二甲基吡啶(0.89mL,7.60mmol,1.00当量)中,添加三氟甲烷磺酸叔丁基二甲基甲硅烷基酯(1.72mL,7.50mmol,1.00当量)。将反应混合物在室温搅拌过夜。在添加饱和碳酸氢钠溶液之后,将反应混合物用乙酸乙酯萃取两次。将合并的有机层用饱和氯化钠溶液洗涤,经硫酸钠干燥,并蒸发至干燥。将所得残余物通过中压柱色谱纯化(硅胶,20-70%乙酸乙酯在环己烷中的梯度)。
中间体1.3-a:
LC-MS(X012_S01):tRet=0.80min ESI-MS:686[M+H]+
中间体1.3-b:
LC-MS(X012_S01):tRet=0.84min ESI-MS:686[M+H]+
中间体1.4
5′-DMT-3′-TBS-2′-CEP-2-氮杂肌苷
将5′-DMT-3′-TBS-2-氮杂肌苷(中间体1.3-b,1.90g,2.80mmol,1.00当量)与乙腈(2x 5mL)共沸,然后将其溶解在无水二氯甲烷中。然后添加2-氰基乙基-N,N,N,N′-四异丙基亚磷酰二胺(1.32mL,4.16mmol,1.00当量)和1H-四唑(0.45M在乙腈中的溶液,9.85mL,4.43mmol,1.00当量),将反应混合物在室温搅拌过夜。将反应混合物用饱和碳酸氢钠溶液萃取,经硫酸钠干燥,并蒸发至干燥。将所得残余物溶解在ACN中并通过反相色谱纯化(RP-18,5-90%乙腈在水中的梯度)。得到两种非对映异构体。
中间体1.4:
LC-MS(X012_S01):tRet=0.81min ESI-MS:887[M+H]+
31P NMR(162MHz,D2O,303K):δ150(s,1P)
中间体1.5
5′-OH-3′-TBS-2′-H-磷酸酯-2-氮杂肌苷
将5′-DMT-3′-TBS-2′-CEP-2-氮杂肌苷(中间体1.4,1.46g,1.65mmol,1.00当量)溶解无水乙腈中,添加水(60.0μL,3.33mmol,2.00当量),然后添加三氟乙酸吡啶鎓(0.38g,1.98mmol,1.20当量)。在搅拌5min之后,添加叔丁基胺(8.00mL,76.0mmol,46.0当量)。在搅拌另外20min之后,将反应混合物在减压下蒸发至干燥,得到白色固体。将其溶解在二氯甲烷(18mL)和水(300μL,16.7mmol,10当量)中,添加二氯乙酸(6体积%,在二氯甲烷中,18.0mL,11.5mmol,7.00当量)。10min之后,添加吡啶(2.23mL,27.7mmol,17当量),通过旋转蒸发移除溶剂。将残余物与乙腈(3x 15mL)共沸。在最后的蒸发过程期间,将溶液浓缩至4-5mL的体积。所得无水溶液用于下一反应步骤中。
中间体1.5:
LC-MS(X012_S01):tRet=0.43min ESI-MS:448[M+H]+
中间体1.6
线型二聚体5′-OH-2′-F-N6-Bz-2′-脱氧腺苷-(3′→5′)-氰基乙基-硫代磷酸酯-2′-H-磷酸酯-3′-TBS-2-氮杂肌苷
将5′-DMT-2′-F-3′-CEP-N6-Bz-2′-脱氧腺苷(购自Ark Pharm,2.00g,2.28mmol,1.40当量)与乙腈(3x 10mL)共沸,最后一次留下约4mL的体积。将该溶液添加到来自前一步骤的5′-OH-3′-TBS-2′-H-磷酸酯-2-氮杂肌苷(中间体1.5:0.74g,溶解在4-5mL乙腈中,1.65mmol,1.00当量)的溶液中。将反应混合物在室温搅拌20min。添加((N,N-二甲基氨基-亚甲基)氨基)-3H-1,2,4-二噻唑啉-3-硫酮(DDTT)(370mg,1.80mmol,1.10当量),将反应混合物在室温搅拌30min。将挥发物真空蒸发,使残余物吸收进二氯甲烷(37mL)和水(0.30mL,16.5mmol,10.0当量)中。添加在二氯甲烷(6体积%,37mL)中的二氯乙酸,将所得橙色溶液在室温搅拌10min。然后添加吡啶(15mL),将反应混合物真空蒸发。
中间体1.6:
LC-MS(X12_S01):tRet=0.55min ESI-MS:952[M+H]+
中间体1.7
环状二聚体3′-TBS-2-氮杂肌苷-(2′→5′)-硫代磷酸酯-2′-F-N6-Bz-2′-脱氧腺苷-(3′→5′)-氰基乙基-硫代磷酸酯
将粗制5′-OH-2′-F-N6-Bz-2′-脱氧腺苷-(3′→5′)-氰基乙基-硫代磷酸酯-2′-H-磷酸酯-3′-TBS-2-氮杂肌苷(中间体1.6,最大理论量:1.64mmol)溶解在吡啶(40mL)中,将溶液真空浓缩至约20mL。添加2-氯-5,5-二甲基-1,3,2-二氧磷杂环己烷2-氧化物(DMOCP)(900mg,4.88mmol,3.00当量),将所得混合物在室温搅拌15min。添加水(0.90mL,50.0mmol,30.5当量)和3H-1,2苯并二硫醇-3-酮(415mg,2.47mmol,1.5当量),继续在室温搅拌。在30min之后,将反应混合物倒入碳酸氢钠(6.00g,71.4mmol)在200mL水的溶液中,将其在室温搅拌5min。将反应混合物用乙酸乙酯/甲基叔丁基醚的混合物萃取三次。将有机相合并,经硫酸钠干燥,真空移除挥发物。将残余物通过反相(RP-18)中压色谱使用乙腈和水作为洗脱剂纯化(用5%乙腈/95%水的等度步骤起始历经5个柱体积(CV),5至90%乙腈在水中的梯度历经15个CV,90%乙腈/10%水的等度步骤历经5个CV)。
将级分通过HPLC-MS进行分析。将包含产物的级分合并,将其冻干,得到作为非对映异构体的粗制混合物的中间体1.7。
LC-MS(X12_S01):tRet=0.60-0.71min;ESI-MS:966[M+H]+
中间体1.8
环状二聚体3′-TBS-2-氮杂肌苷-(2′→5′)-硫代磷酸酯-2′-F-2′-脱氧腺苷-(3′→5′)-硫代磷酸酯
向3′-TBS-2-氮杂肌苷-(2′→5′)-硫代磷酸酯-2′-F-N6-Bz-2′-脱氧腺苷-(3′→5′)-氰基乙基-硫代磷酸酯(中间体1.8,530mg,最大理论量:0.55mmol)中添加33%甲胺在乙醇中的溶液(40mL),将混合物在室温搅拌2小时。将挥发物真空移除,将残余物与乙腈共沸两次。将残余物通过制备HPLC纯化(RP-18/Xbridge,乙腈,水,氨)。将各级分使用分析HPLC-MS按照方法X018_S01进行分析。实现全部四种非对映异构体的分离。将各异构体的级分合并、且冻干。
LC-MS(X018_S03):
中间体1.8-a:tRet=0.65min;ESI-MS:809[M+H]+
中间体1.8-b:tRet=0.76min;ESI-MS:809[M+H]+
中间体1.8-c:tRet=0.73min;ESI-MS:809[M+H]+
中间体1.8-d:tRet=0.87min;ESI-MS:809[M+H]+
中间体2.1
5′-DMT-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮
首先将3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮(合成描述于Carbohydrate Research,1983,vol.112,C1-C3;3.00g,11.2mmol,1.00当量)与无水吡啶(3x 30mL)共沸,然后将其溶解在无水吡啶(30mL)中。添加二甲氧基三苯甲基氯,将反应混合物在室温搅拌过夜。减压移除溶剂,使残余物吸收进乙酸乙酯和饱和碳酸氢钠溶液中。分离水相,将有机相再用饱和碳酸氢钠溶液洗涤一次。将有机相经硫酸钠干燥,真空移除挥发物。将残余物与甲苯共沸三次,然后溶解在乙酸丙酯中,其在添加二异丙基醚之后沉淀出来。在搅拌2小时之后,通过过滤收集沉淀物。
LC-MS(X011_S04):tRet=0.60min ESI-MS:571[M+H]+
中间体2.2-a和2.2-b
5′-DMT-2′-TBS-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮(中间体2.2-a)和5′-DMT-3′-TBS-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮(中间体2.2-b)
将5′-DMT-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮(中间体2.1,3.05g,5.35mmol,1.00当量)溶解在吡啶(30mL)和2,6-二甲基吡啶(1.86mL,16.0mmol,3.00当量)中,添加三氟甲烷磺酸叔丁基二甲基甲硅烷基酯(1.68mL,5.88mmol,1.10当量)。将反应混合物在室温搅拌过夜。添加饱和碳酸氢钠溶液,将混合物用乙酸乙酯萃取两次,将有机相合并,用盐水洗涤,净硫酸钠干燥,并蒸发至干燥。将所得残余物通过中压柱色谱纯化(硅胶,17-100%乙酸乙酯在环己烷中的梯度),得到两种区域异构体。
中间体2.2-a:
LC-MS(X012_S01):tRet=0.81min ESI-MS:685[M+H]+
中间体2.2-b:
LC-MS(X012_S01):tRet=0.86min ESI-MS:685[M+H]+
中间体2.3
5′-DMT-3′-TBS-2′-CEP-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮
将5′-DMT-3′-TBS-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮(中间体2.2-b,2.72g,3.97mmol,1.00当量)与乙腈(2x 5mL)共沸,然后溶解在无水二氯甲烷(80mL)中。添加2-氰基乙基-N,N,N′,N′-四异丙基亚磷酰二胺(1.90mL,5.99mmol,1.50当量)和1H-四唑(0.45M在乙腈中的溶液,14.0mL,6.30mmol,1.60当量),将反应混合物在室温搅拌过夜。在搅拌下,将饱和碳酸氢钠溶液添加到反应中,将各相分离。将有机相经硫酸钠干燥,并蒸发至干燥。将所得残余物溶解在ACN中并通过反相色谱纯化(RP-18,5-90%乙腈在水中的梯度)。得到两种非对映异构体。
中间体2.3-a:
LC-MS(X012_S01):tRet=0.82min ESI-MS:886[M+H]+
中间体2.3-b:
LC-MS(X012_S01):tRet=0.83min ESI-MS:886[M+H]+
中间体2.4
5′-OH-3′-TBS-2′-H-磷酸酯-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮
将5′-DMT-3′-TBS-2′-CEP-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮(中间体2.3-b,1.50g,1.70mmol,1.00当量)溶解在无水乙腈中,添加水(61μL,3.39mmol,2.00当量),然后添加三氟乙酸吡啶鎓(0.390g,2.03mmol,1.20当量)。在搅拌15min之后,添加叔丁基胺(8.19mL,78.0mmol,46.0当量)。再过30min后,将反应混合物减压蒸发至干燥,得到白色固体,将其与乙腈(2x 10mL)共蒸发。将残余物重新溶解在二氯甲烷(18mL)中,添加水(305μL,16.9mmol,10当量)和二氯乙酸(6体积%在二氯甲烷中,18.6mL,11.9mmol,7.0当量)。10min后,添加吡啶(2.3mL,28.5mmol,17当量)和甲醇(2,00mL),减压移除溶剂。将残余物与乙腈(3x 15mL)共沸。在最后的蒸发过程期间,将溶液浓缩至4-5mL。所得无水溶液用于下一步骤。
中间体2.4:
LC-MS(X012_S01):tRet=0.44min ESI-MS:447[M+H]+
中间体2.5
线型二聚体5′-OH-2′-F-N6-Bz-2′-脱氧腺苷-(3′→5′)-氰基乙基-硫代磷酸酯-2′-H-磷酸酯-3′-TBS-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮
将5′-DMT-2′-F-3′-CEP-N6-Bz-2′-脱氧腺苷(购自Ark Pharm,2.20g,2.51mmol,1.40当量)与乙腈(3x 10mL)共沸,最后留下约5mL的体积。将该溶液添加到来自前一步骤的5′-OH-3′-TBS-2′-H-磷酸酯-8-β-D-呋喃核糖基-吡唑并[1,5-d]-1,2,4-三嗪-4(3H)-酮(中间体2.4:0.8g溶解在4-5mL乙腈中,1.79mmol,1.00当量)的溶液中。将反应混合物在室温搅拌20min。添加((N,N-二甲基氨基-亚甲基)氨基)-3H-1,2,4-二噻唑啉-3-硫酮(DDTT)(405mg,1.97mmol,1.10当量),将反应混合物在室温搅拌30min。将挥发物真空蒸发,将残余物溶解在二氯甲烷(37mL)和水(0.32mL,17.9mmol,10.0当量)中。添加在二氯甲烷中的二氯乙酸(6体积%,37mL),将所得橙色溶液在室温搅拌10min。之后,添加吡啶(15mL),将反应混合物真空蒸发。
中间体2.5:
LC-MS(X12_S01):tRet=0.56min ESI-MS:951[M+H]+
中间体2.6
环状二聚体3′-TBS-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮-(2′→5′)-硫代磷酸酯-2′-F-N6-Bz-2′-脱氧腺苷-(3′→5′)-氰基乙基-硫代磷酸酯
将粗制5′-OH-2′-F-N6-Bz-2′-脱氧腺苷-(3′→5′)-氰基乙基-硫代磷酸酯-2′-H-磷酸酯-3′-TBS-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮(中间体2.5:最大理论量:1.79mmol)溶解在吡啶(40mL)中,将溶液真空浓缩至约20mL。添加2-氯-5,5-二甲基-1,3,2-二氧磷杂环己烷2-氧化物(DMOCP)(990mg,5.36mmol,3.00当量),将所得混合物在室温搅拌15min。添加水(0.97mL,53.9mmol,30.1当量)和3H-1,2-苯并二硫醇-3-酮(450mg,2.68mmol,1.50当量),将其继续在室温搅拌。在30分钟之后,将反应混合物倒入碳酸氢钠(6.00g,71.4mmol)在200mL水中的溶液内,并将其在室温搅拌5min。将该混合物用乙酸乙酯/甲基叔丁基醚(1:1)的混合物萃取三次。将有机相合并,经硫酸钠干燥,真空移除挥发物。将残余物通过反相(RP-18)中压色谱使用乙腈和水作为洗脱液纯化(用5%乙腈/95%水的等度步骤起始历经5个柱体积(CV),5至90%乙腈在水中的梯度历经15个CV,90%乙腈/10%水的等度步骤历经5个CV)。
将级分通过HPLC-MS进行分析。将包含产物的级分合并,并冻干,得到中间体2.6作为非对映异构体的粗制混合物。
LC-MS(X12_S01):tRet=0.61-0.72min;ESI-MS:965[M+H]+
中间体2.7
环状二聚体3′-TBS-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮-(2′→5′)-硫代磷酸酯-2′-F-2′-脱氧腺苷-(3′→5′)-硫代磷酸酯
向3′-TBS-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮-(2′→5′)-硫代磷酸酯-2′-F-N6-Bz-2′-脱氧腺苷-(3′→5′)-氰基乙基-硫代磷酸酯(中间体2.6,460mg,最大理论量:0.477mmol)中添加33%甲胺在乙醇中的溶液(35mL),将混合物在室温搅拌2小时。真空移除挥发物,将残余物与乙腈共沸两次。将残余物通过制备HPLC纯化(RP-18/Xbridge,乙腈,水,氨)。将各级分使用分析HPLC-MS按照方法X018_S01进行分析。实现对所有四种非对映异构体的分离。将各异构体的级分合并,将其冻干。
LC-MS(X018_S01):
中间体2.7-a:tRet=0.60min;ESI-MS:808[M+H]+
中间体2.7-b:tRet=0.69min;ESI-MS:808[M+H]+
中间体2.7-c:tRet=0.68min;ESI-MS:808[M+H]+
中间体2.7-d:tRet=0.79min;ESI-MS:808[M+H]+
实施例1
环状2-氮杂肌苷-(2′→5′)-硫代磷酸酯-2′-F-2′-脱氧腺苷-(3′→5′)-硫代磷酸酯
环状2-氮杂肌苷-(2′→5′)-硫代磷酸酯-2′-F-2′-脱氧腺苷-(3′→5′)-硫代磷酸酯钠盐
使环状二聚体3′-TBS-2-氮杂肌苷-(2′→5′)-硫代磷酸酯-2′-F-2′-脱氧腺苷-(3′→5′)-硫代磷酸酯(中间体1.8-d,37mg,0.046mmol,1.0当量)悬浮在吡啶(2mL)和三乙胺(1mL)中。将体积真空减少至约0.5-1mL。添加另外0.41mL的三甲胺,然后添加三乙胺三氢氟酸盐(135μl,0.828mmol,18.1当量)。将反应混合物加热至50℃并保持2小时。添加甲氧基三甲基硅烷(400μL,2.92mmol,63.8当量),将混合物搅拌另外30min,然后减压移除挥发物。将残余物与甲苯共沸一次。将残余物通过HPLC使用缓冲体系纯化(柱:Waters Atlantis T330 mm x 100mm;缓冲液:三乙基乙酸铵20mM在水中;2-20%乙腈在缓冲液中的梯度历时28min)。使收集的各级分经受分析HPLC-MS,将包含产物的级分合并,将其冻干。通过使用离子交换剂50W-X2(得自Bio-Rad Laboratories,250mg)将冻干物转化为钠盐。将冻干物溶解在2mL水中,将其在离子交换剂床上洗脱,该离子交换剂之前通过用氢氧化钠溶液洗脱/用水洗涤来转化成钠形式。将包含产物的级分合并,并将其冻干。
实施例1.1:
LC-MS(X018_S03):tRet=0.3min ESI-MS:695[M+H]+
HPLC(012_CA01):tRet=9.41min
31P NMR(162MHz,D2O,303K):δ52.2(s,1P),54.5(s,1P)ppm
实施例1.2:
从中间体1.8-c按照类似于以上针对实施例1.1所述的过程制备。
LC-MS(X018_S03):tRet=0.24min ESI-MS:695[M+H]+
HPLC(012_CA01):tRet=6.810min
31P NMR(162MHz,D2O,303K):δ54.7(s,1P),55.1(s,1P)ppm
实施例1.3:
从中间体1.8-b按照类似于以上针对实施例1.1所述的过程制备。
LC-MS(X018_S03):tRet=0.24min ESI-MS:695[M+H]+
HPLC(012_CA01):tRet=7.726min
31P NMR(162MHz,D2O,303K):δ52.1(s,1P),53.7(s,1P)ppm
实施例1.4:
从中间体1.8-a按照类似于以上针对实施例1.1所述的过程制备。
LC-MS(X018_S03):tRet=0.17min ESI-MS:695[M+H]+
HPLC(012_CA01):tRet=4.564min
31P NMR(162MHz,D2O,303K):δ54.2(s,1P),55.4(s,1P)ppm
实施例2
环状8-β-D-呋喃核糖基-吡唑并[1,5-d]-1,2,4-三嗪-4(3H)-酮-(2′→5′)-硫代磷酸酯-2′-F-2′-脱氧腺苷-(3′→5′)-硫代磷酸酯
环状8-β-D-呋喃核糖基-吡唑并[1,5-d]-1,2,4-三嗪-4(3H)-酮-(2′→5′)-硫代磷酸酯-2′-F-2′-脱氧腺苷-(3′→5′)-硫代磷酸酯钠盐
将环状二聚体3′-TBS-3-β-D-呋喃核糖基-6H-吡唑并[1,5-d][1,2,4]三嗪-7-酮-(2′→5′)-硫代磷酸酯-2′-F-2′-脱氧腺苷-(3′→5′)-硫代磷酸酯(中间体2.7-d,25mg,0.031mmol,1.00当量)溶解在吡啶(2.0mL)和三乙胺(1.0mL)中。将体积真空减少至约0.5-1mL。添加另外0.26mL三乙胺,然后添加三乙胺三氢氟酸盐(90.0μL,0.552mmol,17.8当量)。将反应混合物加热至50℃并保持6h。添加甲氧基三甲基硅烷(260μL,1.90mmol,61.3当量),将混合物搅拌另外30min,然后减压移除挥发物,将残余物与甲苯共沸一次。将残余物通过HPLC使用缓冲体系纯化(柱:Waters Atlantis T3 30mm x 100mm;缓冲液:三乙基乙酸铵20mM在水中;2-20%乙腈在缓冲液中的梯度历时28min)。将各级分使用分析HPLC-MS进行分析,将包含产物的级分合并,将其冻干。如针对实施例1.1所述将冻干物转化成钠盐。
实施例2.1:
收率:6mg(20%)
LC-MS(X018_S01):tRet=0.28min ESI-MS:694[M+H]+
HPLC(012_CA01):tRet=11.99min
31P NMR(162MHz,D2O,303K):δ51.8(s,1P),55.1(s,1P)ppm
实施例2.2:
从中间体2.7-c按照类似于以上针对实施例2.1所述的过程制备。
ESI-MS:694[M+H]+
HPLC(012_CA01):tRet=7.14min
31P NMR(162MHz,D2O,303K):δ55.1(s,1P)
实施例2.3:
从中间体2.7-b按照类似于以上针对实施例2.1所述的过程制备。
ESI-MS:694[M+H]+
HPLC(012_CA01):tRet=6.88min
31P NMR(162MHz,D2O,303K):δ51.4(s,1P),53.9(s,1P)ppm
实施例2.4:
从中间体2.7-a按照类似于以上针对实施例2.1所述的过程制备。
ESI-MS:694[M+H]+
HPLC(012_CA01):tRet=6.51min
31P NMR(162MHz,D2O,303K):δ54.3(s,1P),54.7(s,1P)ppm
Claims (16)
2.根据权利要求1所述的化合物,其中R3是嘌呤。
3.根据权利要求1所述的化合物,其中R3是腺嘌呤。
4.根据权利要求1所述的化合物,其中R3是鸟嘌呤。
5.根据权利要求1所述的化合物,其中R3是次黄嘌呤。
6.根据权利要求2至5中任一项所述的化合物,其中R1表示F,且R2表示H。
7.一种根据权利要求1至6中任一项或多项所述的化合物的实质上纯(Sp,Sp)、(Rp,Rp)、(Sp,Rp)或(Rp,Sp)立体异构体或其盐。
8.一种根据权利要求1至7中任一项或多项所述的化合物的药学上可接受的盐。
9.一种药物组合物,其包含一种或多种根据权利要求1至8中任一项或多项所述的化合物或其药学上可接受的盐,任选连同一种或多种惰性载剂及/或稀释剂。
10.一种疫苗,其包含根据权利要求1至8中任一项或多项所述的化合物。
11.一种药物组合物,其包含一种或多种根据权利要求1至8中任一项或多项所述的化合物或其药学上可接受的盐,及一种或多种其它治疗剂,任选连同一种或多种惰性载剂及/或稀释剂。
12.根据权利要求11所述的药物组合物,其包含一种根据权利要求1至8中任一项或多项所述的化合物及一种或多种其它治疗剂。
13.根据权利要求1至8中任一项或多项所述的化合物,其用作药剂。
14.根据权利要求1至8中任一项或多项所述的化合物作为疫苗佐剂的用途。
15.一种在有需要的患者中治疗与STING相关或经STING调节的疾病或病状的方法,特别是用于治疗炎症、过敏性或自体免疫疾病、传染病或癌症的方法,该方法的特征在于向所述患者给予一种或多种根据权利要求1至8中任一项或多项所述的化合物。
16.根据权利要求1至8中任一项或多项所述的化合物,其用于治疗与STING相关或经STING调节的疾病或病状的方法中,特别是用于治疗炎症、过敏性或自体免疫疾病、传染病或癌症的方法中,其中该方法的特征在于向所述患者给予一种或多种根据权利要求1至8中任一项或多项的化合物。
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