CN114846003A - 用于治疗癌症的氘代化合物 - Google Patents
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- CN114846003A CN114846003A CN202080070533.0A CN202080070533A CN114846003A CN 114846003 A CN114846003 A CN 114846003A CN 202080070533 A CN202080070533 A CN 202080070533A CN 114846003 A CN114846003 A CN 114846003A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
本申请涉及式(I)的氘代酰胺衍生物及其在治疗和预防癌症中的用途,并且涉及包含所述衍生物的组合物及其制备方法。
Description
发明领域
本发明涉及杂环酰胺衍生物及其在治疗和预防癌症中的用途,并且涉及包含所述衍生物的组合物及其制备方法。
发明背景
DNA双链断裂(DSB)的稳定修复对于维持基因组稳定性和细胞活力而言至关重要。DSB可以通过以下三种主要途径之一进行修复:同源重组(HR)、非同源末端连接(NHEJ)和替代NHEJ(alt-NHEJ)。微同源性介导的末端连接(MMEJ)是最充分表征的alt-NHEJ机制。HR介导的修复是一种高保真机制,其对于准确无误修复至关重要,从而防止癌症易感基因组稳定性。相反,NHEJ和MMEJ是容易错的途径,其可以在修复部位留下突变疤痕。MMEJ可以与HR和NHEJ通路同时发挥作用(Truong等人PNAS 2013,110(19),7720-7725)。
与正常细胞不同,癌细胞的存活通常依赖于DNA损伤反应(DDR)通路的错误调节。例如,对一种途径(通常是诱变)的依赖性增加以应对另一种途径的失活,或因增殖增加而导致的复制压力增强。异常的DDR还可以使癌细胞对特定类型的DNA损伤敏感,因此可以利用有缺陷的DDR来开发靶向癌症疗法。至关重要的是,具有HR和NHEJ受损或失活的癌细胞变得超高度依赖于MMEJ-介导的DNA修复。遗传、细胞生物学和生化数据已将Polθ(UniProtKB-O75417(DPOLQ_HUMAN)鉴定为MMEJ中的关键蛋白(Kent等人,Nature Structural&Molecular Biology(2015),22(3),230-237,Mateos-Gomez等人Nature(2015),518(7538),254-257)。Polθ为多官能酶,其包含N-末端解旋酶结构域(SF2 HEL308-型)和C-末端低保真度DNA聚合酶结构域(A-型)(Wood&DoubliéDNA Repair(2016),44,22-32)。已证明这两个结构域在MMEJ中具有一致的机械功能。解旋酶结构域介导RPA蛋白从ssDNA末端的去除并刺激退火。聚合酶结构域延伸ssDNA末端并填补剩余的空位。
因此,Polθ的治疗性失活将使细胞执行MMEJ的能力失能,并在一系列确定的肿瘤环境中提供新的靶向策略。首先,Polθ已被证明对HR缺陷(HRD)细胞的存活至关重要(例如具有FA/BRCA缺陷的合成致死性)并且在HRD肿瘤细胞系中上调(Ceccaldi等人Nature(2015),518(7538),258-262)。体内研究还表明,Polθ在与相关预后不良的HRD卵巢癌、子宫癌和乳腺癌亚群中显著过表达(Higgins等人Oncotarget(2010),1,175-184,Lemée等人PNAS(2010),107(30),13390-13395,Ceccaldi等人(2015),上文)。重要的是,Polθ在正常组织中很大程度上受到抑制,但已显示在匹配的癌症样本中上调,因此将升高的表达与疾病相关联(Kawamura等人International Journal of Cancer(2004),109(1),9-16)。其次,它的抑制或阻滞赋予肿瘤细胞放射敏感性。最后,可以想象抑制Polθ可以阻止BRCA2突变的MMEJ依赖性功能逆转,这是肿瘤中出现顺铂和PARPi耐药性的基础。
因此,需要提供治疗癌症的有效的Polθ抑制剂。
发明概述
本发明的第一个方面提供了式(I)化合物的氘代衍生物:
或其互变异构体或立体化学异构体形式,或其药学上可接受的溶剂化物。
附图描述
图1:实施例1的1H NMR光谱(300MHz,CD3OD,300.6K)。
发明详述
本文涉及的“氘代衍生物”是指式(I)的任一化合物,其中任意一个或多个(例如1、2或3个)氢原子被较重的稳定同位素氘取代,即2H(D)。
因此,在一个实施方案中,所述氘代衍生物包含1、2或3个氢原子的氘代物。在另一个实施方案中,所述氘代衍生物包含所述式(I)化合物的N-甲基的1、2或3个氢原子的氘代物。在另一个实施方案中,所述氘代衍生物包含所述式(I)化合物的N-甲基的所有3个氢原子的氘代物。
因此,在另一个实施方案中,所述氘代衍生物为式(II)的化合物:
或其互变异构体或立体化学异构体形式,或其药学上可接受的溶剂化物。
仍然在另一个实施方案中,式(II)化合物为式(II)化合物的游离碱,并且为(2S,3S,4S)-N-(5-氯-2,4-二氟苯基)-3,4-二羟基-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-氧代吡咯烷-2-甲酰胺(E1)。
对式(I)化合物及其亚组的称谓还包括其溶剂化物、异构体(包括几何和立体化学异构体)、互变异构体、N-氧化物、酯、前药、同位素和被保护的形式,例如,如下所述;优选地,其互变异构体或异构体或N-氧化物或溶剂化物;更优选其互变异构体或N-氧化物或溶剂化物,甚至更优选其互变异构体或溶剂化物。在下文中,如本发明任何方面所定义的化合物及其溶剂化物、异构体(包括几何和立体化学异构体)、互变异构体、N-氧化物、酯、前药、同位素(例如其氘代衍生物)和被保护的形式(化学方法中的中间体化合物除外)称作“本发明的化合物”。
溶剂化物
有机化学领域的技术人员将理解,许多有机化合物可以与溶剂形成配合物,其中它们发生反应或从其中沉淀或结晶。这些配合物称作“溶剂化物”。例如,与水的配合物称作“水合物”。本发明化合物的药学上可接受的溶剂化物在本发明的范围内。在一个实施方案中,本发明化合物的药学上可接受的溶剂化物包括其水合物。
在一个实施方案中,式(I)化合物的所述结晶形式为共晶体或共形成物(coformer)。这种共晶体或共形成物可以使用水溶性分子例如糖精、咖啡因、烟酰胺或羧酸来制备。共形成物可如Emami S等人(2018)BioImpacts 8(4),305-320中所述制备,其技术通过引用并入本文。
应当理解,本发明包括式(I)化合物的药学上可接受的衍生物并且这些包括在本发明的范围内。
如本文所用,“药学上可接受的衍生物”包括式(I)化合物的任意药学上可接受的酯,在施用于接受者时,其能够提供(直接或间接)式(I)化合物或其活性代谢物或残留物。
N-氧化物
包含含氮官能团/部分的式(I)化合物也可以形成N-氧化物。本文涉及的包含含氮官能团/部分的式(I)化合物也包括N-氧化物。
如果化合物包含几个含氮官能团/部分,则一个或一个以上的氮原子可以被氧化成N-氧化物。N-氧化物的具体实例为叔胺或含氮杂环的氮原子的N-氧化物。
N-氧化物可以通过用氧化剂如过氧化氢或过酸(例如过氧羧酸)处理相应的含氮官能团/部分而形成,参见例如Advanced Organic Chemistry,Jerry March,第4版,WileyInterscience。更具体地,N-氧化物可以通过L.W.Deady(Syn.Commun.1977,7,509-514)的方法制备,其中包含含氮官能团/部分的化合物与间-氯过氧苯甲酸(mCPBA)例如在惰性溶剂例如二氯甲烷中反应。
前药
本领域技术人员将理解,可以在最终脱保护阶段之前制备的、式(I)化合物的某些被保护衍生物本身可能不具有药理学活性,但在某些情况下可以通过口服或肠胃外施用,然后在体内代谢形成具有药理活性的本发明化合物。因此,此类衍生物可被描述为“前药”。本发明化合物的所有这些前药都包括在本发明的范围内。适合于本发明化合物的前药官能团的实例描述在Drugs of Today,19,9,1983,499-538和Topics in Chemistry,第31章,pp.306-316和“Design of Prodrugs”,H.Bundgaard,Elsevier,1985,第1章中(这些文件中的公开内容通过引用并入本文)。本领域技术人员进一步理解,本领域技术人员称作“前-部分”的某些部分,例如H.Bundgaard在“Design of Prodrugs”中所述的那些(这些文件中的公开内容通过引用并入本文),当存在于本发明的化合物中时,可以位于适当的官能团上。
本发明化合物的范围内还包括其多晶型物。
对映体
如果式(I)化合物中存在手性中心,则本发明在其范围内包括所有可能的对映异构体和非对映异构体,包括它们的混合物。不同的异构体形式可以通过常规方法彼此分离或拆分,或者任何给定的异构体可以通过常规合成方法或立体特异性或不对称合成获得。本发明还扩展到任何互变异构形式或其混合物。
同位素
本发明还包括所有药学上可接受的同位素标记的化合物,这些化合物与式(I)中列举的那些相同,但一个或多个原子被原子量或质量数不同于自然界中最常见的原子量或质量数的原子替代。
适于包括在本发明的化合物中的同位素的实例包括氢的同位素,如2H(D)和3H(T);碳的同位素,如11C、13C以及14C;氯的同位素,如36Cl;氟的同位素,如18F;碘的同位素,如123I、125I以及131I;氮的同位素,如13N和15N;氧的同位素,如15O、17O以及18O;磷的同位素,如32P;以及硫的同位素,如35S。
某些同位素标记的式(I)的化合物,例如包含放射性同位素的那些可用于药物和/或底物组织分布研究中。式(I)的化合物还可以具有有价值的诊断特性,这是因为它们可以用于检测或鉴定标记的化合物与其它分子、肽、蛋白质、酶或受体之间的复合物的形成。所述检测或鉴定方法可以使用用标记剂标记的化合物,所述标记剂诸如放射性同位素、酶、荧光物质、发光物质(例如鲁米诺、鲁米诺衍生物、荧光素、水母发光蛋白以及荧光素酶)等。放射性同位素氚,即3H(T),以及碳-14,即14C鉴于它们易于掺入和现成的检测手段而特别可用于实现该目的。
用更重的同位素如氘即2H(D)取代可以提供由更大的代谢稳定性所带来的某些治疗优势,例如体内半衰期延长或剂量要求降低,并且因此在一些情况下可能是优选的。
用正电子发射同位素(例如11C、18F、15O和13N)进行取代可以用于正电子发射拓扑(PET)研究以检查靶点占有率。
同位素标记的式(I)化合物通常可以通过本领域技术人员已知的常规技术或通过与所附实施例和制备例中描述的那些类似的方法、使用适合的同位素标记的试剂替代在先使用的未标记的试剂来制备。
纯度
由于预期式(I)化合物用于药物组合物,因此,易于理解它们各自优选以基本上纯的形式提供,例如至少60%纯,更适合地至少75%纯,且优选至少85%,尤其是至少98%的纯度(基于重量以重量%给出)。化合物的不纯制品可以用于制备药物组合物中使用的更纯的形式。
方法
本发明的另一个方面提供了制备式(I)化合物及其衍生物的方法。以下方案是可以用于合成本发明化合物的合成方案的实例。在以下方案中,可以用保护基团保护反应基团并根据充分确立的技术脱保护。
本发明的另一个方面提供了用于制备如本文所定义的式(I)化合物的氘代衍生物的方法,该方法包括:
(a)使式(III)化合物的氘代衍生物:
与式(IV)化合物反应:
(b)使式(I)化合物的被保护的衍生物脱保护;和
(c)使式(I)化合物或其被保护的衍生物相互转化成式(I)的另一种化合物或其被保护的衍生物。
方法(a)典型地包括使式(III)化合物与式(IV)化合物在适合的催化剂和配体例如Pd2(dba)3和XantPhos存在下、并且在适合的碱例如K2CO3存在下、在适当的条件下如在适合的溶剂如1,4-二噁烷中加热至适合的温度(例如90-95℃)来反应。
式(III)化合物可以按照本文所述的方法制备。例如,式(III)化合物可以按照实施例1中所示的实验方法制备。
在一个实施方案中,式(III)化合物为式(III)a的化合物:
式(IV)的化合物为已知的或可以按照公知方法制备。
方法(c)的各种众所周知的官能团互换为本领域技术人员已知用于将前体转化成式(I)的化合物,并且描述在Advanced Organic Chemistry by Jerry March,第4版,JohnWiley&Sons,1992中所述。例如,可能的金属催化的官能化,例如使用有机-锡试剂(Stille反应)、格利雅试剂和与氮亲核体的反应描述在‘Palladium Reagents and Catalysts’[Jiro Tsuji,Wiley,ISBN 0-470-85032-9]和Handbook of OrganoPalladium Chemistryfor Organic Synthesis[第1卷,Ei-ichi Negishi编辑,Wiley,ISBN 0-471-31506-0]。
如果适合,本文所述的反应之后或之前是本领域技术人员已知的一种或多种反应,并且以适当的顺序进行,以实现对式(I)化合物上的必不可少的取代,得到式(I)的其他的化合物。其条件可在文献中找到的此类反应的非限制性实例包括:
反应性官能团的保护;
反应性官能团的脱保护;
卤化;
脱卤;
脱烷基化;
胺、苯胺、醇以及酚的烷基化或芳基化;
羟基上的光延反应(Mitsunobu reaction);
适当的基团上的环加成反应;
硝基、酯、氰基、醛的还原;
过渡金属催化的偶联反应;
酰化;
磺酰化/引入磺酰基;
酯基的皂化/水解;
酯基的酰胺化或酯交换;
羧基的酯化或酰胺化;
卤素交换;
用胺、硫醇或醇进行亲核取代;
还原胺化;
羰基和羟基胺基上的肟形成;
S-氧化;
N-氧化;
盐化。
认识到,涉及芳基偶联和还原的反应顺序可变。还认识到,广泛的基于钯的催化剂适合于进行芳基偶联反应。
还可以认识到,异构体分离可以发生在合成顺序的任何适合的阶段。应当强调,这种手性分离构成本发明的一个关键方面,并且这种分离可以根据本文所述的方法进行或可以根据已知的方法进行。还认识到,在合成中暂时形成中间体的被保护的衍生物可能是有益的,例如,Boc保护的胺或SEM保护的酰胺,以促进色谱分离、手性拆分或得到特定步骤中改善的溶解度或收率。
在上述许多反应中,可能需要保护一个或多个基团以防止反应发生在分子上不期望的位置。保护基的实例以及保护和脱保护官能团的方法可以在Protective Groups inOrganic Synthesis(T.Green和P.Wuts;第4版;John Wiley和Sons,2007)中找到。
例如,羟基可以被保护为醚(-OR)或酯(-OC(=O)R),例如为:叔丁基醚;四氢吡喃基(THP)醚;苄基、二苯甲基(二苯基甲基)或三苯甲基(三苯基甲基)醚;三甲基甲硅烷基或叔丁基二甲基甲硅烷基醚;或乙酰基酯(-OC(=O)CH3)。
胺基可以被保护成例如酰胺(-NRCO-R)或氨基甲酸酯(-NRCO-OR),例如:甲基酰胺(-NHCO-CH3);氨基甲酸苯甲酯(-NHCO-OCH2C6H5、-NH-Cbz或NH-Z);氨基甲酸叔丁酯(-NHCO-OC(CH3)3、-NH-Boc);氨基甲酸2-联苯-2-丙基酯(-NHCO-OC(CH3)2C6H4C6H5、-NH-Boc)、氨基甲酸9-芴基甲酯(-NH-Fmoc)、氨基甲酸6-硝基藜芦基酯(-NH-Nvoc)、氨基甲酸2-三甲基甲硅烷基乙酯(-NH-Teoc)、氨基甲酸2,2,2-三氯乙酯(-NH-Troc)、氨基甲酸烯丙酯(-NH-Alloc)、或氨基甲酸2-(苯基磺酰基)乙酯(-NH-Psec)。
用于胺的其它保护基,如环胺和杂环N-H基团包括甲苯磺酰基(toluenesulfonyl/tosyl)和甲烷磺酰基(甲磺酰基)、苯甲基如对甲氧基苯甲基(PMB)以及四氢吡喃基(THP)。
羧酸基团可以被保护为酯例如:C1-7烷基酯(例如甲基酯;叔丁基酯);C1-7卤代烷基酯(例如C1-7三卤代烷基酯);三C1-7烷基甲硅烷基-C1-7烷基酯;或C5-20芳基-C1-7烷基酯(例如苄基酯;硝基苄基酯;对-甲氧基苄基酯。
本领域技术人员将理解,本发明的某些化合物可以根据标准化学方法转化为本发明的其他化合物。
治疗用途
本发明、其亚组及其实施例的化合物为Polθ聚合酶活性的抑制剂,并且其可以用于预防或治疗本文所述的疾病状态或病症。此外,本发明的化合物及其亚组将用于预防或治疗由Polθ介导的疾病或病症。对疾病状态或病症例如癌症的预防或防止或治疗在其范围内包括减轻或降低癌症的发病率。
因此,例如,预期本发明的化合物可用于缓解或降低癌症的发病率。
本发明的化合物可以用于治疗成年人群。本发明的化合物可以用于治疗儿科人群。
由于它们对Polθ的抑制作用,这些化合物可以用于提供一种使细胞无法执行MMEJ的能力的方法。因此,预计这些化合物可以证明用于治疗或预防增殖性疾病,例如癌症。此外,本发明的化合物可以用于治疗存在与细胞累积相关障碍的疾病。
不受理论束缚,预期本发明的Polθ抑制剂显示某些特性,使它们在某些癌症的治疗治疗中特别有用。例如,在一个实施方案中,本发明的Polθ抑制剂在BRCA1和BRCA2缺陷型原发性和继发性实体瘤中为适当致死性的,包括乳腺、卵巢、前列腺和胰腺。
在另一个实施方案中,本发明的Polθ抑制剂在多种原发性和继发性实体瘤中具有适当的致死性,这些实体瘤通过除BRCA缺陷之外的机制为HRD,例如具有启动子超甲基化的那些。在这些没有DSB修复途径可能被完全下调的肿瘤中,Polθi可以与另一种DDR调节剂如PARP抑制剂、DNA-PK抑制剂、ATR抑制剂、ATM抑制剂、wee1抑制剂或CHK1抑制剂一起给予。
在另一个实施方案中,本发明的Polθ抑制剂在原发性和继发性乳腺、卵巢、前列腺和胰腺肿瘤中具有适当的致死性,所述肿瘤保留BRCA1缺陷,但在暴露于或未暴露于PARPi药物之后,对PARPi治疗具有抗性。
在另一个实施方案中,本发明的Polθ抑制剂适当地增加包括CRR在内的ORR,将延迟PARPi抗性的发作,将增加复发时间和DFS,并且与PARPi治疗方案一起给予时将增加HRD(BRCA1/2缺陷和其他HRD机制)原发性和继发性肿瘤(乳腺、卵巢、前列腺和胰腺)的OS。
在另一个实施方案中,本发明的Polθ抑制剂在具有ATM活性(ATM-/-)丧失的多种肿瘤中,特别是在WT p53的情况下,合适地显示合成疾病(synthetic sickness)和/或合成致死性(synthetic lethality)。肿瘤类型包括约10%的所有实体肿瘤,包括胃、肺、乳腺和CRC,以及CLL。与另一种DDR调节剂联合用药,例如DNA-PK抑制剂、PARP抑制剂或ATR抑制剂,可以进一步增强这种活性。Polθ抑制剂使CLL对出现耐药性的典型化疗和化学免疫疗法再敏感。因此,根据另一个实施方案,本发明的药物组合物还包含DNA-PK抑制剂、PARP抑制剂或ATR抑制剂。
在另一个实施方案中,本发明的Polθ抑制剂在非同源末端连接(NHEJ-D)的DNA双链断裂修复过程缺陷的多种肿瘤中适当地显示合成疾病和/或合成致死性。肿瘤类型包括所有实体瘤的约2-10%,包括前列腺、胰腺、宫颈、乳腺、肺、膀胱和食道。与另一种DDR调节剂联合用药,例如PARP抑制剂、ATM抑制剂、wee1抑制剂、CHK抑制剂或ATR抑制剂,可以进一步增强这种活性。Polθ抑制剂进一步使NHEJD癌细胞对DNA DSB诱导化学疗法和基于电离辐射的疗法敏感。因此,根据另一个实施方案,本发明的药物组合物还包含PARP抑制剂、ATM抑制剂、wee1抑制剂、CHK抑制剂或ATR抑制剂。
在另一个实施方案中,本发明的Polθ抑制剂适当地降低HR有效(HR proficient)肿瘤例如过表达Polθ的乳腺、卵巢、NSCL肿瘤化疗期间的DNA复制应激反应。这将增加对治疗的ORR并增加OS。这种效果尤其可能与用于广泛白血病包括CML和处置鳞状细胞癌的阿糖胞苷(Ara-C)和羟基脲有关。
在另一个实施方案中,本发明的Polθ抑制剂适当地选择性地使实体瘤对放疗、包括EBRT和近距离放射疗法(brachytherapy)和基于放射性配体的疗法敏感,而对正常组织几乎没有或不敏感。在分级治愈目的(fractionated curative-intent)情况下,这将增加局部区域控制,驱动生存率增加。这在NSCLC、SCCH&N、直肠癌、前列腺癌和胰腺癌的处置中尤为明显。
在另一个实施方案中,本发明的Polθ抑制剂在PTEN缺失肿瘤例如CaP中适当地显示合成疾病和/或合成致死性,与或不与PARPi联合给药均如此。此外,通过PTEN缺失以及Polθ抑制剂诱导的放射敏感性,此类肿瘤将对放疗表现出极高的敏感性。
在另一个实施方案中,本发明的Polθ抑制剂适当地抑制TLS聚合酶活性,使原发性和继发性实体瘤(例如乳腺、肺、卵巢、CRC)对药物(例如顺铂、丝裂霉素和环磷酰胺)敏感以及减少药物诱导突变的获取,所述药物诱导的突变牵涉于肿瘤抗性,导致缓解期延长和TTR增加。
在另一个实施方案中,本发明的Polθ抑制剂适当地使已经发生伊马替尼抗性的BCR-ABL-阳性CML以及具有升高的连接酶IIIα水平、降低的连接酶IV水平和增加的altEJDSB修复依赖性的其他实体瘤再敏感。
在另一个实施方案中,本发明的Polθ抑制剂在以下中适当地显示合成疾病和/或合成致死性,芳香酶抑制剂抗性ER-原发性和继发性乳腺癌,同样显示升高的连接酶IIIα水平、降低的连接酶IV水平和增加的altEJ DSB修复依赖性。
本发明的另一个方面提供了如本文所定义的式(I)化合物,其用于治疗以同源重组(HRD)缺陷为特征的肿瘤。
应当理解,本文涉及的“同源重组缺陷(HRD)”是指导致所得同源重组基因功能缺陷或丧失的任何遗传变异。所述遗传变异的实例包括突变(例如点突变)、取代、缺失、单核苷酸多态性(SNP)、单体型、染色体异常、拷贝数变异(CNV)、表观遗传学、DNA倒位、表达减少和错位分布。
在一个实施方案中,所述同源重组基因选自如下的任一种:ATM、ATR、BRCA1、BRCA2,BARD1、RAD51C、RAD50、CHEK1、CHEK2、FANCA、FANCB、FANCC、FANCD2、FANCE、FANCF、FANCG、FANCI、FANCL、FANCM、PALB2(FANCN)、FANCP(BTBD12)、ERCC4(FANCQ)、PTEN、CDK12、MRE11、NBS1、NBN、CLASPIN、BLM、WRN、SMARCA2、SMARCA4、LIG1、RPA1、RPA2、BRIP1和PTEN。
应当理解,本文涉及的“非同源末端连接缺陷(NHEJD)”是指导致所得同源重组基因的缺陷或功能丧失的任何遗传变异。所述遗传变异的实例包括突变(例如点突变)、取代、缺失、单核苷酸多态性(SNP)、单体型、染色体异常、拷贝数变异(CNV)、表观遗传学、DNA倒位、表达减少和错位分布。
在一个实施方案中,所述非同源末端连接基因选自如下的任意一种或多种:LIG4、NHEJ1、POLL、POLM、PRKDC、XRCC4、XRCC5、XRCC6和DCLRE1C。
本发明的另一个方面提供了如本文所定义的式(I)化合物,其用于治疗过表达Polθ的肿瘤。
本发明的另一个方面提供了如本文所定义的式(I)化合物,其用于治疗具有升高的连接酶IIIα水平、降低的连接酶IV水平和增加的altEJ DSB修复依赖性的肿瘤。
可以治疗(或抑制)的癌症(和它们的良性对应物)的实例包括但不限于上皮来源的肿瘤(各种类型的腺瘤和癌瘤,包括腺癌、鳞状癌、移行细胞癌以及其它癌瘤),如膀胱癌和泌尿道癌、乳腺癌、胃肠道癌(包括食管癌、胃(stomach/gastric)癌、小肠癌、结肠癌、直肠癌以及肛门癌)、肝癌(肝细胞癌)、胆囊癌和胆道系统癌、外分泌胰腺癌、肾癌、肺癌(例如腺癌、小细胞肺癌、非小细胞肺癌、细支气管肺泡癌(bronchioloalveolar carcinoma)以及间皮瘤)、头颈部癌(例如舌癌、颊腔癌、喉癌、咽癌、鼻咽癌、扁桃体癌、唾液腺癌、鼻腔癌以及副鼻窦癌)、卵巢癌、输卵管癌、腹膜癌、阴道癌、外阴癌、阴茎癌、宫颈癌、子宫肌层癌、子宫内膜癌、甲状腺癌(例如甲状腺滤泡癌)、肾上腺癌、前列腺癌、皮肤癌以及附件癌(例如黑色素瘤、基底细胞癌、鳞状细胞癌、角化棘皮瘤、发育不良痣(dysplastic naevus));血液系统恶性肿瘤(即白血病、淋巴瘤)和恶化前血液系统病症(premalignant haematologicaldisorders)以及交界性恶性病症(disorders of borderline malignancy),包括血液系统恶性肿瘤和淋巴系的相关病况(例如急性淋巴细胞性白血病[ALL]、慢性淋巴细胞性白血病[CLL]、B细胞淋巴瘤如弥漫性大B细胞淋巴瘤[DLBCL]、滤泡性淋巴瘤、伯基特氏淋巴瘤(Burkitt's lymphoma)、套细胞淋巴瘤、MALT淋巴瘤、T细胞淋巴瘤和白血病、自然杀伤[NK]细胞淋巴瘤、霍奇金氏淋巴瘤、毛细胞白血病、意义未明的单克隆丙种球蛋白病(monoclonal gammopathy of uncertain significance)、浆细胞瘤、多发性骨髓瘤、以及移植后淋巴增生性病症)、以及血液系统恶性肿瘤和髓系相关病况(例如急性髓性白血病[AML]、慢性髓性白血病[CML]、慢性粒单核细胞白血病[CMML/chronic myelomonocyticleukemia]、嗜酸性粒细胞增多综合征、骨髓增生性病症如真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化、骨髓增生性综合征、骨髓增生异常综合征、以及早幼粒细胞性白血病);间充质来源的肿瘤,例如软组织、骨或软骨的肉瘤,如骨肉瘤、纤维肉瘤、软骨肉瘤、横纹肌肉瘤、平滑肌肉瘤、脂肪肉瘤、血管肉瘤、卡波西肉瘤、尤文氏肉瘤、滑膜肉瘤、上皮样肉瘤、胃肠道间质瘤、良性和恶性组织细胞瘤、以及隆突性皮肤纤维肉瘤(dermatofibrosarcoma protuberans);中枢或外周神经系统的肿瘤(例如星形细胞瘤,神经胶质瘤和成胶质细胞瘤、脑膜瘤、室管膜瘤、松果体瘤以及神经鞘瘤);内分泌肿瘤(例如垂体肿瘤、肾上腺肿瘤、胰岛细胞肿瘤、甲状旁腺肿瘤、类癌肿瘤以及甲状腺髓样癌);眼和附件肿瘤(例如成视网膜细胞瘤);生殖细胞和滋养细胞(trophoblastic)肿瘤(例如畸胎瘤、精原细胞瘤、无性细胞瘤、葡萄胎以及绒毛膜癌);以及儿科和胚胎肿瘤(例如成神经管细胞瘤(medulloblastoma)、成神经细胞瘤、肾母细胞瘤(Wilms tumour)、以及原始神经外胚层肿瘤);或使患者易患恶性肿瘤的先天性或其它综合征(例如着色性干皮病(XerodermaPigmentosum))。
许多疾病的特征在于持续的和失调的血管生成。慢性增殖性疾病常常伴有显著的血管生成,这可以导致或维持炎症和/或增殖状态,或这会经由血管的侵入性增殖而造成组织破坏。已经发现肿瘤生长和转移具有血管生成依赖性。本发明的化合物因此可用于预防和破坏肿瘤血管生成的引发。特别地,本发明的化合物可用于治疗转移灶和转移性癌症。
转移灶或转移性疾病是疾病从一个器官或部分传播到另一个不相邻的器官或部分。可用本发明化合物治疗的癌症包括原发性肿瘤(即起源部位的癌细胞)、局部侵袭性(癌细胞在局部区域穿透和浸润周围正常组织)和转移性(或继发性)肿瘤,即由恶性细胞形成的肿瘤,这些细胞通过血液循环(血源性扩散)或通过淋巴管或通过体腔(跨体腔)循环到身体的其他部位和组织。
特定的癌症包括肝细胞癌、黑素瘤、食道癌、肾癌、结肠癌、结肠直肠癌、肺例如间皮瘤或肺腺癌、乳腺癌、膀胱癌、胃肠癌、卵巢癌和前列腺癌。
另一方面提供了化合物在制备用于治疗如本文所述的疾病或病症、特别是癌症的药物中的用途。
该化合物还可以用于通过使细胞对化疗敏感和作为抗转移剂来治疗肿瘤生长、发病机制、对化疗和放疗的抗性。
本发明的化合物作为Polθ抑制剂的功效可以使用本文实施例中举出的生物学和生物物理学测定法来测量,并且给定化合物表现出的亲和力水平可以根据IC50值来定义。本发明的具体化合物是具有IC50值小于1μM、更特别是小于0.1μM的化合物。
WO 2017/062754中描述了Polθ的丧失增强CRISPR介导的基因编辑的功效的作用。因此,Polθ抑制性化合物可能有助于增强基于CRISPR的编辑方法和/或基于CRISPR的编辑治疗的效率。此外,化合物介导的Polθ抑制可能会降低随机整合事件的频率,且由此提供改善CRISPR介导技术的任何安全问题的途径。因此,本发明的另一个方面提供了本文定义的式(I)化合物在基于CRISPR的编辑方法和/或基于CRISPR的编辑治疗中的用途,例如增强基于CRISPR的编辑方法和/或基于CRISPR的编辑治疗的效率。
药物组合物
虽然有可能单独施用活性化合物,但是它优选作为药物组合物(例如制剂)存在。在一个实施方案中,其是无菌药物组合物。
因此,本发明还提供了如上文所定义的药物组合物、以及制备药物组合物的方法,所述药物组合物包含(例如混合)至少一种式(I)化合物(以及如本文所定义的其亚组)、以及一种或多种药学上可接受的赋形剂和任选的如本文所述的其它治疗剂或预防剂。
一种或多种药学上可接受的赋形剂可以选自例如载体(例如固体、液体或半固体载体)、佐剂、稀释剂、填充剂或增量剂、造粒剂、包衣剂、释放控制剂、粘合剂、崩解剂、润滑剂、防腐剂、抗氧化剂、缓冲剂、助悬剂、增稠剂、调味剂、甜味剂、掩味剂、稳定剂或常规用于药物组合物中的任何其它赋形剂。用于各种类型的药物组合物的赋形剂的实例更详细地阐述于下文中。
如本文所用的术语“药学上可接受的”涉及在合理的医学判断范围内,适用于与受试者(例如人类)的组织接触而不会有过度的毒性、刺激性、过敏反应、或其它问题或并发症的、与合理的利益/风险比相称的化合物、材料、组合物和/或剂型。每一种载体、赋形剂等在与制剂的其它成分相容的意义上也必须是“可接受的”。
含有式(I)化合物的药物组合物可以根据已知的技术来配制,参见例如Remington's Pharmaceutical Science,Mack Publishing Company,Easton,PA,USA。
药物组合物可以呈适用于口服、肠胃外、局部、鼻内、支气管内、舌下、眼科、耳部、经直肠、阴道内、或透皮施用的任何形式。在所述组合物意图用于肠胃外施用的情况下,它们可以被配制用于通过注射、输注或其它递送手段静脉内、肌内、腹膜内、皮下施用或用于直接递送到靶器官或靶组织中。所述递送可以通过推注、短期输注或更长期的输注并且可以经由被动递送或经由利用合适的输注泵或注射器驱动器。
适合于肠胃外施用的药物制剂包括水性和非水性无菌注射溶液,它们可以含有抗氧化剂、缓冲剂、抑菌剂、共溶剂、表面活性剂、有机溶剂混合物、环糊精络合剂、乳化剂(用于形成和稳定乳液制剂)、用于形成脂质体的脂质体组分、用于形成聚合物凝胶的可胶凝的聚合物、冻干保护剂以及特别是用于使可溶形式的活性成分稳定并且使制剂与预期接受者的血液等渗的试剂的组合。用于肠胃外施用的药物制剂也可以采用水性和非水性无菌悬浮液的形式,它们可以包括助悬剂和增稠剂(R.G.Strickly,Solubilizing Excipients inoral and injectable formulations,Pharmaceutical Research,第21(2)卷2004,第201-230页)。
制剂可以存在于单剂量或多剂量容器例如密封安瓿、小瓶和预装注射器中,并且可以在冷冻干燥(冻干)条件下储存,只需要在使用前即刻添加无菌液体载体,例如注射用水。在一个实施方案中,该制剂作为活性药物成分提供在瓶中,用于随后使用适当的稀释剂进行重构。
药物制剂可以通过冻干式(I)化合物或其亚组来制备。冻干是指冷冻干燥组合物的过程。因此,冷冻干燥和冻干在本文中用作同义词。
临时注射溶液和混悬液可以由无菌粉剂、颗粒和片剂制备。
用于肠胃外注射的本发明药物组合物还可以包含药学上可接受的无菌水性或非水性溶液、分散液、混悬液或乳剂以及用于在使用前重构为无菌可注射溶液或分散液的无菌粉末。
适合的水性和非水性载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等)、羧甲基纤维素及其适合的混合物、植物油(例如向日葵油、红花油、玉米油或橄榄油)和可注射有机酯,例如油酸乙酯。例如,可以通过使用增稠或包衣材料例如卵磷脂、通过在分散液的情况下维持所需的粒径、和通过使用表面活性剂来维持适当的流动性。
本发明的组合物还可以含有佐剂,如防腐剂、润湿剂、乳化剂、以及分散剂。可以通过包括各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、三氯叔丁醇、酚、山梨酸等来确保防止微生物的作用。还可能期望包括调节张力剂,如糖、氯化钠等。可以通过包括如单硬脂酸铝和明胶的延迟吸收剂来使可注射的药物形式的吸收延长。
在本发明的一个具体的实施方案中,药物组合物为适合于i.v.施用的形式,例如通过注射或输注。对于静脉内施用,溶液可以按原样施用,也可以在施用前注入输液袋中(包含药学上可接受的赋形剂,例如0.9%盐水或5%葡萄糖)。
在另一个具体的实施方案中,药物组合物为适合于皮下(s.c.)施用的形式。
适合口服施用的药物剂型包括片剂(包衣或未包衣)、胶囊(硬壳或软壳)、胶囊形片剂、丸剂、锭剂、糖浆剂、溶液、粉剂、颗粒剂、酏剂和混悬剂、舌下片剂、糯米纸囊剂或贴剂如口腔贴片剂。
因此,片剂组合物可以包含单位剂量的活性化合物与惰性稀释剂或载体,例如糖或糖醇,例如:乳糖、蔗糖、山梨醇或甘露糖醇;和/或非糖衍生的稀释剂,例如碳酸钙、磷酸钙、碳酸钙,或纤维素或衍生物如微晶纤维素(MCC)、甲基纤维素或乙基纤维素、羟丙基甲基纤维素,和淀粉如玉米淀粉。片剂还可以包含标准成分作为粘合和造粒剂如聚乙烯吡咯烷酮、崩解剂(例如可膨胀的交联聚合物如交联羧甲基纤维素)、润滑剂(例如硬脂酸盐)、防腐剂(例如对羟基苯甲酸酯)、抗氧化剂(例如BHT)、缓冲剂(例如磷酸盐或柠檬酸盐缓冲剂)和泡腾剂如柠檬酸盐/碳酸氢盐混合物。这样的赋形剂是众所周知的,并且无需在本文中详细讨论。
片剂可以被设计成在与胃液接触时释放药物(立即释放片剂)或以受控方式在一段较长的时间内或在胃肠道的特定区域中释放(受控释放片剂)。
胶囊制剂可以是硬明胶品种或软明胶品种并且可以含有呈固体、半固体、或液体形式的活性组分。明胶胶囊可以由动物明胶或其合成或植物源性等同物形成。
固体剂型(例如片剂、胶囊等)可以有包衣或无包衣。包衣可以用作保护膜(例如聚合物、蜡或清漆)或用作用于控制药物释放或用于美观或识别目的的机构。包衣(例如EudragitTM类型聚合物)可以被设计成在胃肠道内所期望的位置处释放活性组分。因此,包衣可以选择成在胃肠道内的某些pH值条件下降解,从而选择性地在胃中或在回肠、十二指肠、空肠或结肠中释放化合物。
代替包衣或除了包衣之外,药物可以存在于固体基质中,所述固体基质包含释放控制剂,例如释放延迟剂,所述释放控剂可以适用于在胃肠道中以受控方式释放化合物。或者,药物可以存在于聚合物包衣中,例如聚甲基丙烯酸酯聚合物包衣,它可以适用于在胃肠道中变化的酸度或碱度的条件下选择性地释放化合物。或者,所述基质材料或释放延缓包衣可以采用易蚀聚合物的形式(例如马来酸酐聚合物),所述聚合物在剂型通过胃肠道时基本上连续地被溶蚀。在另一个替代方案中,包衣可以被设计成在肠道中的微生物作用下崩解。作为另一个替代方案,可以将活性化合物配制在提供所述化合物释放的渗透控制的递送系统中。渗透释放和其它延迟释放或持续释放制剂(例如基于离子交换树脂的制剂)可以根据本领域技术人员公知的方法来制备。
式(I)化合物可以与载体一起配制并且以纳米颗粒的形式施用,纳米颗粒的增加的表面积有助于它们的吸收。此外,纳米颗粒提供直接穿透到细胞中的可能性。纳米颗粒药物递送系统描述于“Nanoparticle Technology for Drug Delivery”,Ram B Gupta和UdayB.Kompella编著,Informa Healthcare,ISBN 9781574448573,2006年3月13日出版。用于药物递送的纳米颗粒还描述于J.Control.Release,2003,91(1-2),167-172;以及Sinha等,Mol.Cancer Ther.8月1日,(2006)5,1909中。
药物组合物通常包含约1%(w/w)至约95%的活性成分以及99%(w/w)至5%(w/w)的药学上可接受的赋形剂或赋形剂的组合。具体地,组合物包含约20%(w/w)至约90%(w/w)的活性成分以及80%(w/w)至10%的药学上可接受的赋形剂或赋形剂的组合。药物组合物包含约1%至约95%、具体地约20%至约90%的活性成分。根据本发明的药物组合物可以例如呈单位剂型如呈安瓿、小瓶、栓剂、预填充注射器、糖衣丸、片剂或胶囊的形式。
一种或多种药学上可接受的赋形剂可以根据制剂的期望物理形式来选择并且可以例如选自稀释剂(例如固体稀释剂如填充剂或增量剂;以及液体稀释剂如溶剂和共溶剂)、崩解剂、缓冲剂、润滑剂、助流剂、释放控制剂(例如释放延缓或延迟聚合物或蜡)、粘合剂、造粒剂、颜料、增塑剂、抗氧化剂、防腐剂、调味剂、掩味剂、张力调节剂以及包衣剂。
本领域技术人员将具有选择用于制剂中成分的适当量的专业知识。举例来说,片剂和胶囊通常含有0%-20%的崩解剂、0%-5%的润滑剂、0%-5%的助流剂和/或0%-99%(w/w)的填充剂/或增量剂(这取决于药物剂量)。它们还可以含有0%-10%(w/w)的聚合物粘合剂、0%-5%(w/w)的抗氧化剂、0%-5%(w/w)的颜料。缓慢释放片剂另外将含有0%-99%(w/w)的释放控制(例如延迟)聚合物(这取决于剂量)。片剂或胶囊的膜包衣通常含有0%-10%(w/w)的聚合物、0%-3%(w/w)的颜料、和/或0%-2%(w/w)的增塑剂。
肠胃外制剂通常含有0%-20%(w/w)的缓冲剂、0%-50%(w/w)的共溶剂、和/或0%-99%(w/w)的注射用水(WFI)(这取决于剂量以及是否冷冻干燥)。用于肌内贮库的制剂还可以含有0%-99%(w/w)的油。
用于口服施用的药物组合物可以通过将活性成分与固体载体合并获得,如果需要,将所得混合物制粒,并且如果需要或必要,在添加适合的赋形剂之后将混合物加工成片剂、糖锭芯或胶囊。还能够将它们掺入聚合物或蜡基质中,使活性成分以可测量的量扩散或释放。
也可以将本发明的化合物配制成固体分散体。固体分散体是两种或多种固体的均匀极细分散相。固溶体(分子分散系统)是固体分散体的一种类型,众所周知其用于制药技术(参见(Chiou和Riegelman,J.Pharm.Sci.,60,1281-1300(1971)),并且可用于增加溶出速率和增加水溶性差的药物的生物利用度。
本发明还提供了包含上述固溶体的固体剂型。固体剂型包括片剂、胶囊、咀嚼片和分散片或泡腾片。已知的赋形剂可以与固溶体共混,得到期望的剂型。例如,胶囊可以包含与(a)崩解剂和润滑剂,或(b)崩解剂、润滑剂和表面活性剂共混的固溶体。此外,胶囊可以包含填充剂,例如乳糖或微晶纤维素。片剂可以包含与至少一种崩解剂、润滑剂、表面活性剂、填充剂和助流剂共混的固溶体。咀嚼片可以包含与填充剂、润滑剂和如果期望另外的甜味剂(例如人造甜味剂)和适合的香料共混的固溶体。固溶体也可以通过将药物和适合的聚合物溶液喷洒到惰性载体如糖珠(“不均匀的(non-pareils)”)的表面上来形成。随后可以将这些珠填充到胶囊中或压制成片剂。
药物制剂可以以“患者包”的形式提供给患者,该“患者包”包含单个包装中的整个治疗过程,通常是泡罩包装。患者包优于传统处方(药剂师将患者的药品供应从批量供应中分离),因为患者始终可以得到患者包中包含的包装插页,而患者处方中通常缺少该包装插页。已显示包含包装插页可提高患者对医生指示的依从性。
用于局部使用和经鼻递送的组合物包括软膏、霜剂、喷雾剂、贴剂、凝胶、滴液剂和插入物(例如眼内插入物)。可以根据已知方法配制此类组合物。
用于直肠或阴道内施用的制剂的实例包括阴道栓剂和栓剂,它们可以例如由包含活性化合物的成型可模塑或蜡状材料形成。活性化合物的溶液也可用于直肠施用。
通过吸入施用的组合物可以采取可吸入粉末组合物或液体或粉末喷雾剂的形式,并且可以使用干粉吸入装置或气雾剂分配装置以标准形式施用。这种装置是众所周知的。例如,对于吸入施用,粉状制剂典型地包含活性化合物与惰性固体粉状稀释剂如乳糖。
式(I)化合物通常以单位剂型存在,并且就此通常包含足量的化合物,以提供期望水平的生物活性。例如,制剂可以包含1纳克至2克的活性成分,例如1纳克至2毫克的活性成分。在这些范围内,化合物的特定子范围为0.1毫克至2克活性成分(更通常为10毫克至1克,例如50毫克至500毫克),或1微克至20毫克(例如1微克至10毫克,例如0.1毫克至2毫克的活性成分)。
对于口服组合物,单位剂型可以包含1毫克至2克,更通常为10毫克至1克,例如50毫克至1克,例如100毫克至1克的活性化合物。
活性化合物将以足以实现期望治疗效果的量施用于有此需要的患者(例如人或动物患者)。
治疗方法
本文定义的式(I)化合物和亚组可用于预防或治疗由Polθ介导的一系列疾病状态或病症。因此,本发明的另一方面提供了治疗由Polθ介导的疾病状态或病症(例如癌症)的方法,该方法包括向有此需要的受试者施用本文所述的式(I)化合物。此类疾病状态和病状的实例如上文所述,且尤其包括癌症。
化合物通常施用于需要这种施用的受试者,例如人或动物患者,特别是人。
化合物通常以治疗或预防有用的量施用并且通常是无毒的。然而,在某些情况下(例如在危及生命的疾病的情况下),施用式(I)化合物的益处可能超过任何毒性作用或副作用的缺点,在这种情况下可能认为施用与一定毒性相关的化合物的量是期望的。
化合物可以长期施用以维持有益的治疗效果,或者可以仅短期施用。或者,它们可以以连续方式或以提供间歇给药的方式(例如脉冲方式)施用。
式(I)化合物的典型每日剂量可以在100皮克至100毫克/千克体重,更典型地为5纳克至25毫克/千克体重,且更通常地为10纳克至15毫克/千克(例如10纳克至10毫克,且更典型地为1毫克/千克至20毫克/千克,例如1毫克至10毫克/千克)/千克体重,不过,如果需要,可以施用更高或更低的剂量。可以基于每日或基于重复、例如每2或3或4或5或6或7或10或14或21或28天施用式(I)化合物。
可以通过口服以一定剂量范围施用本发明的化合物,例如1-1500mg、2-800mg或5-500mg,例如2-200mg或10-1000mg,特定的剂量实例包括10、20、50和80mg。该化合物可以每天施用一次或一次以上,例如,一次适合的剂量方案可能需要1000mg-1500mg,每天2或3次。该化合物可以连续施用(即在治疗方案期间每天不间断地服用)。或者,该化合物可以间歇施用(即在整个治疗方案的期限内连续服用指定期限,例如一周,然后停药一段时间期限,例如一周,且然后连续服用另一段时间如一周等)。涉及间歇性施用的治疗方案的实例包括以下方案:其中施用为一周使用、一周停用的周期;或两周使用、一周停用的周期;或三周使用、一周停用的周期;或两周使用、两周停用的周期;或四周施用、两周停用的周期;或一周使用、三周停用的周期,持续一个或多个周期,例如2、3、4、5、6、7、8、9或10个或更多个周期。
在一个具体的给药方案中,给予患者输注式(I)化合物,持续时间期限为每天一小时,持续最多十天,特别是最多五天,持续一周,并且以期望的时间间隔重复治疗,例如两到四周,特别是每三周。
更具体地,可以给予患者输注式(I)化合物,时间期限为每日1小时,持续5天,并且每三周重复治疗。
在另一个具体的给药方案中,给予患者输注30分钟至1小时,然后维持时间期限可变的输注,例如1-5小时,例如3小时。
在另一个具体的给药方案中,给予患者12小时至5天的连续输注,特别是24小时至72小时的连续输注。
在另一个具体的给药方案中,给予患者每周一次口服化合物。
在另一个具体的给药方案中,给予患者口服化合物,每日1次,持续7-28天,例如7、14或28天。
在另一个具体的给药方案中,给予患者每天口服一次化合物,持续1天、2天、3天、5天或1周,随后休息所需要的天数,以完成一周或两周的周期。
在另一个具体的给药方案中,给予患者每天口服一次该化合物,持续2周,然后休息2周。
在另一个具体的给药方案中,给予患者每天口服一次该化合物,持续2周,然后休息1周。
在另一个具体的给药方案中,给予患者每天口服一次该化合物,持续1周,然后休息1周。
然而,最终化合物的施用量和所用组合物的类型将与所治疗的疾病或生理状况的性质相称,并且由临床医师决定。
应当理解,Polθ抑制剂可以用作单一药剂或与其他抗癌剂组合使用。可以进行组合实验,例如如Chou TC,Talalay P.Quantitative analysis of dose-effectrelationships:the combined effects of multiple drugs or enzyme inhibitors.AdvEnzyme Regulat 1984;22:27–55中所述。
本文定义的化合物可以作为单独的治疗剂施用,或者它们可以与一种或多种其他化合物(或疗法)在联合疗法中施用以治疗特定疾病状态,例如肿瘤疾病,例如上文定义的癌症。对于上述病症的治疗,本发明的化合物可以有利地与一种或多种其他药剂组合使用,更具体地,与癌症疗法中的其他抗癌剂或佐剂(疗法中的支持剂)组合使用。可以与式(I)化合物一起(无论是同时还是在不同时间间隔)施用的其他治疗剂或治疗手段的实例包括但不限于:
·拓扑异构酶I抑制剂
·抗代谢物
·微管蛋白靶向剂
·DNA结合剂和拓扑异构酶II抑制剂
·烷基化剂
·单克隆抗体
·抗激素剂
·信号转导抑制剂
·蛋白酶体抑制剂
·DNA甲基转移酶抑制剂
·细胞因子和类视色素
·染色质靶向治疗
·放射治疗,以及
·其它治疗剂或预防剂。
抗癌剂或佐剂(或其盐)的具体实例包括但不限于选自以下组(i)-(xlvi)和任选组(xlvii)的任何药剂:
(i)铂化合物,例如顺铂(任选地与氨磷汀(amifostine)组合)、卡铂或奥沙利铂;
(ii)紫杉烷化合物,例如紫杉醇(paclitaxel)、紫杉醇蛋白质结合颗粒(AbraxaneTM)、多烯紫杉醇(docetaxel)、卡巴他赛(cabazitaxel)或拉洛他赛(larotaxel);
(iii)拓扑异构酶I抑制剂,例如喜树碱化合物,例如喜树碱、伊立替康(CPT11)、SN-38、或拓扑替康;
(iv)拓扑异构酶II抑制剂,例如抗肿瘤表鬼臼毒素或鬼臼毒素衍生物,例如依托泊苷、或替尼泊苷;
(v)长春花生物碱,例如长春花碱(vinblastine)、长春新碱(vincristine)、脂质体长春新碱(Onco-TCS)、长春瑞滨(vinorelbine)、长春地辛(vindesine)、长春氟宁(vinflunine)或长春韦塞(vinvesir);
(vi)核苷衍生物,例如5-氟尿嘧啶(5-FU,任选地与甲酰四氢叶酸(leucovorin)组合)、吉西他滨、卡培他滨、替加氟、UFT、S1、克拉屈滨、阿糖胞苷(Ara-C、胞嘧啶阿拉伯糖苷)、氟达拉滨、氯法拉滨(clofarabine)、或奈拉滨(nelarabine);
(vii)抗代谢物,例如氯法拉滨、氨基蝶呤(aminopterin)、或甲氨蝶呤(methotrexate)、阿扎胞苷(azacitidine)、阿糖胞苷、氟尿苷(floxuridine)、喷司他丁、硫鸟嘌呤、硫嘌呤、6-巯基嘌呤、或羟基脲(羟基碳酰二胺(hydroxycarbamide));
(viii)烷化剂,如氮芥或亚硝基脲,例如环磷酰胺、苯丁酸氮芥(chlorambucil)、卡莫司汀(BCNU)、苯达莫司汀(bendamustine)、噻替哌(thiotepa)、美法仑(melphalan)、苏消安(treosulfan)、洛莫司汀(lomustine)(CCNU)、六甲蜜胺(altretamine)、白消安(busulfan)、达卡巴嗪(dacarbazine)、雌莫司汀(estramustine)、福莫司汀(fotemustine)、异环磷酰胺(任选地与美司钠(mesna)组合)、哌泊溴烷(pipobroman)、丙卡巴肼(procarbazine)、链脲霉素(streptozocin)、替莫唑胺(temozolomide)、尿嘧啶、二氯甲基二乙胺(mechlorethamine)、甲基环己基氯乙基亚硝基脲、或尼莫司汀(nimustine)(ACNU);
(ix)蒽环霉素(anthracycline)、蒽二酮类以及相关药物,例如柔红霉素(daunorubicin)、多柔比星(doxorubicin)(任选地与右雷佐生(dexrazoxane)组合)、多柔比星的脂质体制剂(例如CaelyxTM、MyocetTM、DoxilTM)、伊达比星(idarubicin)、米托蒽醌(mitoxantrone)、表柔比星(epirubicin)、安吖啶(amsacrine)、或戊柔比星(valrubicin);
(x)埃坡霉素(epothilone),例如伊沙匹隆(ixabepilone)、帕妥匹隆(patupilone)、BMS-310705、KOS-862和ZK-EPO、埃坡霉素A、埃坡霉素B、脱氧埃坡霉素B(也被称为埃坡霉素D或KOS-862)、氮杂埃坡霉素B(也被称为BMS-247550)、奥利马徳(aulimalide)、异洛利马徳(isolaulimalide)、或洛塞罗宾(luetherobin);
(xi)DNA甲基转移酶抑制剂,例如替莫唑胺、氮杂胞苷(azacytidine)或地西他滨(decitabine),或SGI-110;
(xii)抗叶酸剂,例如甲氨蝶呤、培美曲塞二钠(pemetrexed disodium)、或雷替曲塞(raltitrexed);
(xiii)细胞毒性抗生素,例如放线菌素D(antinomycin D)、博莱霉素(bleomycin)、丝裂霉素C(mitomycin C)、更生霉素(dactinomycin)、洋红霉素(carminomycin)、道诺霉素(daunomycin)、左旋咪唑(levamisole)、普卡霉素(plicamycin)、或光辉霉素(mithramycin);
(xiv)微管蛋白结合剂,例如考布他汀(combrestatin)、秋水仙碱(colchicine)或诺考达唑(nocodazole);
(xv)信号转导抑制剂,如激酶抑制剂(例如EGFR(上皮生长因子受体)抑制剂、VEGFR(血管内皮生长因子受体)抑制剂、PDGFR(血小板衍生生长因子受体)抑制剂、MTKI(多靶点激酶抑制剂)、Raf抑制剂、mTOR抑制剂例如甲磺酸伊马替尼、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、达沙替尼(dasatinib)、拉帕替尼(lapatinib)、多韦替尼(dovotinib)、阿西替尼(axitinib)、尼罗替尼(nilotinib)、凡德他尼(vandetanib)、瓦他拉尼(vatalinib)、帕唑帕尼(pazopanib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、替西罗莫司(temsirolimus)、依维莫司(everolimus)(RAD 001)、威罗菲尼(vemurafenib)(PLX4032或RG7204)、达拉菲尼(dabrafenib)、安拉菲尼(encorafenib),或IκB激酶抑制剂如SAR-113945、巴多索隆(bardoxolone)、BMS-066、BMS-345541、IMD-0354、IMD-2560或IMD-1041,或MEK抑制剂如司美替尼(AZD6244)和曲美替尼(Selumetinib)(GSK121120212);
(xvi)极光(Aurora)激酶抑制剂,例如AT9283、巴拉塞替(barasertib)(AZD1152)、TAK-901、MK0457(VX680)、塞尼塞替(cenisertib)(R-763)、达努塞替(danusertib)(PHA-739358)、阿立塞替(alisertib)(MLN-8237)、或MP-470;
(xvii)CDK抑制剂,例如AT7519、罗可嘌呤(roscovitine)、塞利西尼(seliciclib)、阿伏西地(alvocidib)(夫拉平度(flavopiridol))、地那西尼(dinaciclib)(SCH-727965)、7-羟基-星形孢菌素(UCN-01)、JNJ-7706621、BMS-387032(也被称为SNS-032)、PHA533533、PD332991、ZK-304709、或AZD-5438;
(xviii)PKA/B抑制剂和PKB(akt)途径抑制剂,例如AKT抑制剂如KRX-0401(哌立福辛/NSC 639966)、依帕他塞(ipatasertib)(GDC-0068;RG-7440)、埃瑞塞替(afuresertib)(GSK-2110183;2110183)、MK-2206、MK-8156、AT13148、AZD-5363、磷酸曲西立滨(triciribine phosphate)(VQD-002;磷酸曲西立滨一水合物(API-2;TCN-P;TCN-PM;VD-0002)、RX-0201、NL-71-101、SR-13668、PX-316、AT13148、AZ-5363、塞马氟瑞(Semaphore)、SF1126或盐酸恩扎妥林(enzastaurin HCl)(LY317615),或MTOR抑制剂如雷帕霉素类似物,如RAD 001(依维莫司)、CCI 779(替西罗莫司)、AP23573和地磷莫司(ridaforolimus)、西罗莫司(最初称作雷帕霉素)、AP23841和AP23573,钙调蛋白抑制剂如CBP-501(叉头易位抑制剂)、盐酸恩扎妥林(enzastaurin HCl)(LY317615),或PI3K抑制剂如达托利司(dactolisib)(BEZ235)、布帕利司(buparlisib)(BKM-120;NVP-BKM-120)、BYL719、考泮利司(copanlisib)(BAY-80-6946)、ZSTK-474、CUDC-907、阿帕利司(apitolisib)(GDC-0980;RG-7422)、皮克利司(pictilisib)(皮瑞利司(pictrelisib)、GDC-0941、RG-7321)、GDC-0032、GDC-0068、GSK-2636771、艾代拉利司(idelalisib)(在先的CAL-101、GS 1101、GS-1101)、MLN1117(INK1117)、MLN0128(INK128)、IPI-145(INK1197)、LY-3023414、依帕他塞、埃瑞塞替、MK-2206、MK-8156、LY-3023414、LY294002、SF1126或PI-103或索诺利司(sonolisib)(PX-866);
(xix)Hsp90抑制剂,例如AT13387、除莠霉素(herbimycin)、格尔德霉素(geldanamycin)(GA)、17-烯丙基氨基-17-脱甲氧基格尔德霉素(17-AAG),例如NSC-330507、Kos-953以及CNF-1010、17-二甲基氨基乙基氨基-17-脱甲氧基格尔德霉素盐酸盐(17-DMAG),例如NSC-707545和Kos-1022,NVP-AUY922(VER-52296)、NVP-BEP800、CNF-2024(BIIB-021,一种口服嘌呤)、詹特斯匹(ganetespib)(STA-9090)、SNX-5422(SC-102112)或IPI-504;
(xx)单克隆抗体(未缀合或与放射性同位素、毒素或其它药剂缀合)、抗体衍生物以及相关药剂,如抗CD抗体、抗VEGFR抗体、抗HER2抗体、抗-CTLA4抗体、抗-PD-1或抗EGFR抗体,例如利妥昔单抗(rituximab)(CD20)、奥法木单抗(ofatumumab)(CD20)、替坦异贝莫单抗(ibritumomab tiuxetan)(CD20)、GA101(CD20)、托西莫单抗(tositumomab)(CD20)、依帕珠单抗(epratuzumab)(CD22)、林妥珠单抗(lintuzumab)(CD33)、吉妥珠单抗奥唑米星(gemtuzumab ozogamicin)(CD33)、阿仑珠单抗(alemtuzumab)(CD52)、加利昔单抗(galiximab)(CD80)、曲妥珠单抗(trastuzumab)(HER2抗体)、帕妥珠单抗(pertuzumab)(HER2)、曲妥珠单抗-DM1(HER2)、厄马索单抗(ertumaxomab)(HER2和CD3)、西妥昔单抗(cetuximab)(EGFR)、帕尼单抗(panitumumab)(EGFR)、奈昔木单抗(necitumumab)(EGFR)、尼妥珠单抗(nimotuzumab)(EGFR)、贝伐单抗(bevacizumab)(VEGF)、卡妥索单抗(catumaxumab)(EpCAM和CD3)、阿巴伏单抗(abagovomab)(CA125)、法利珠单抗(farletuzumab)(叶酸受体)、依洛珠单抗(elotuzumab)(CS1)、地诺单抗(denosumab)(RANK配体)、芬妥木单抗(figitumumab)(IGF1R)、CP751,871(IGF1R)、马帕木单抗(mapatumumab)(TRAIL受体)、metMAB(met)、米妥莫单抗(mitumomab)(GD3神经节苷脂)、那妥莫单抗酯(naptumomab estafenatox)(5T4)、或司妥昔单抗(siltuximab)(IL6)或免疫调节剂,如CTLA-4阻断抗体和/或针对PD-1和PD-L1和/或PD-L2的抗体,例如伊匹木单抗(ipilimumab)(CTLA4)、MK-3475(帕博利珠单抗(pembrolizumab),原称为莱博珠单抗(lambrolizumab),抗PD-1)、纳武单抗(nivolumab)(抗PD-1)、BMS-936559(抗PD-L1)、MPDL320A、AMP-514或MEDI4736(抗PD-L1)、或曲美木单抗(tremelimumab)(原称为替立木单抗(ticilimumab)、CP-675,206,抗CTLA-4);
(xxi)雌激素受体拮抗剂或选择性雌激素受体调节剂(SERM)或雌激素合成抑制剂,例如他莫昔芬、氟维司群、托瑞米芬、屈洛昔芬(droloxifene)、法斯罗德(faslodex)、或雷洛昔芬(raloxifene);
(xxii)芳香酶抑制剂和相关药物,如依西美坦、阿那曲唑、来曲唑、睾内酯、氨鲁米特、米托坦(mitotane)或伏氯唑(vorozole);
(xxiii)抗雄激素剂(即雄激素受体拮抗剂)和相关药剂,例如比卡鲁胺、尼鲁米特、氟他米特(flutamide)、环丙孕酮(cyproterone)、或酮康唑;
(xxiv)激素和其类似物,如甲羟孕酮、己烯雌酚(diethylstilbestrol)(也被称为二乙基己烯雌酚)或奥曲肽(octreotide);
(xxv)类固醇,例如丙酸屈他雄酮(dromostanolone propionate)、醋酸甲地孕酮(megestrol acetate)、诺龙(nandrolone)(癸酸酯、苯丙酸酯)、氟甲睾酮(fluoxymestrone)或棉子酚(gossypol);
(xxvi)类固醇细胞色素P450 17α-羟化酶-17,20-裂解酶抑制剂(CYP17),例如阿比特龙(abiraterone);
(xxvii)促性腺激素释放激素激动剂或拮抗剂(GnRA),例如阿巴瑞克(abarelix)、醋酸戈舍瑞林(goserelin acetate)、醋酸组胺瑞林(histrelin acetate)、醋酸亮丙瑞林(leuprolide acetate)、曲普瑞林(triptorelin)、布舍瑞林(buserelin)、或地洛瑞林(deslorelin);
(xxviii)糖皮质激素,例如泼尼松(prednisone)、泼尼松龙(prednisolone)、地塞米松;
(xxix)分化剂,如类视色素、维甲酸类(Rexinoids)、维生素D或视黄酸和视黄酸代谢阻断剂(RAMBA),例如异维甲酸(accutane)、阿利维甲酸(alitretinoin)、贝沙罗汀(bexarotene)、或维甲酸(tretinoin);
(xxx)法呢基转移酶抑制剂,例如替吡法尼(tipifarnib);
(xxxi)染色质靶向治疗,例如组蛋白脱乙酰基酶(HDAC)抑制剂,例如帕比司他(panobinostat)、Resminostat、abexinostat、伏力诺他(vorinostat)、罗米地新(romidepsin)、贝林司他(belinostat)、恩替司他(entinostat)、quisinostat、pracinostat、替菲诺司他(tefinostat)、莫西司他(mocetinostat)、吉维司他(givinostat)、CUDC-907、CUDC-101、ACY-1215、MGCD-290、EVP-0334、RG-2833、4SC-202、罗米地新、AR-42(Ohio State University)、CG-200745、丙戊酸(valproic acid)、CKD-581、丁酸钠、辛二酰苯胺异羟肟酸(SAHA)、缩肽(FR 901228)、达西司特(dacinostat)(NVP-LAQ824)、R306465/JNJ-16241199、JNJ-26481585、曲古抑菌素A(trichostatin A)、克米多肽(chlamydocin)、A-173、JNJ-MGCD-0103、PXD-101、或阿佩西丁(apicidin);
(xxxii)蛋白酶体抑制剂,例如硼替佐米、卡非佐米(carfilzomib)、地兰佐米(delanzomib)(CEP-18770)、艾沙佐米(ixazomib)(MLN-9708)、前佐米(oprozomib)(ONX-0912)或马里佐米(marizomib);
(xxxiii)光动力药物,例如卟吩姆钠(porfimer sodium)或替莫泊芬(temoporfin);
(xxxiv)海洋生物体源性抗癌剂,如曲贝替定(trabectidin);
(xxxv)用于放射免疫治疗的放射性标记药物,例如用发射β粒子的同位素(例如碘-131、钇-90)或发射α粒子的同位素(例如铋-213或锕-225),例如替伊莫单抗(ibritumomab)或碘托西莫单抗;
(xxxvi)端粒酶抑制剂,例如端粒抑素(telomestatin);
(xxxvii)基质金属蛋白酶抑制剂,例如巴马司他(batimastat)、马立马司他(marimastat)、普利诺司他(prinostat)或美他司他(metastat);
(xxxviii)重组干扰素(如干扰素-γ和干扰素α)和白细胞介素(例如白细胞介素2),例如阿地白介素(aldesleukin)、地尼白介素2(denileukin diftitox)、干扰素α2a、干扰素α2b、或聚乙二醇化干扰素α2b;
(xxxix)选择性免疫应答调节剂,例如沙利度胺(thalidomide)或来那度胺(lenalidomide);
(xl)治疗性疫苗,如司普吕塞-T(sipuleucel-T)(Provenge)或OncoVex;
(xli)细胞因子激活剂,包括溶链菌(Picibanil)、罗莫肽(Romurtide)、西佐喃(Sizofiran)、维如利金(Virulizin)、或胸腺素(Thymosin);
(xlii)三氧化二砷;
(xliii)G蛋白偶联受体(GPCR)抑制剂,例如阿曲生坦(atrasentan);
(xliv)酶,如L-天冬酰胺酶、培加帕酶(pegaspargase)、拉布立酶(rasburicase)、或培加酶(pegademase);
(xlv)DNA修复抑制剂,如PARP抑制剂,例如奥拉帕尼(olaparib)、维拉帕尼(velaparib)、印尼帕尼(iniparib)、乌卡帕利(rucaparib)(AG-014699或PF-01367338)、他拉佐帕利(talazoparib)或AG-014699;
(xlvi)DNA损伤响应抑制剂,例如ATM抑制剂AZD0156 MS3541、ATR抑制剂AZD6738、M4344、M6620 wee1抑制剂AZD1775;
(xlvii)死亡受体(例如TNF相关细胞凋亡诱导配体(TRAIL)受体)激动剂,如马帕木单抗(原称为HGS-ETR1)、可那木单抗(conatumumab)(原称为AMG 655)、PRO95780、来沙木单抗(lexatumumab)、度拉纳明(dulanermin)、CS-1008、阿泊单抗(apomab)或重组TRAIL配体,如重组人类TRAIL/Apo2配体;
(xlvii)预防剂(助剂);即减少或缓解与化学治疗剂相关的副作用中的一些的药剂,例如
-止吐剂;
-预防化学治疗相关的中性粒细胞减少症或缩短化学治疗相关的中性粒细胞减少症的持续时间以及预防由血小板、血红细胞或白细胞的水平降低所引起的并发症的药剂,例如白细胞介素-11(例如奥普瑞白介素(oprelvekin))、促红细胞生成素(EPO)和其类似物(例如达依泊汀α(darbepoetin alfa))、集落刺激因子类似物如粒细胞巨噬细胞集落刺激因子(GM-CSF)(例如沙格司亭(sargramostim)),以及粒细胞集落刺激因子(G-CSF)和其类似物(例如非格司亭(filgrastim)、聚乙二醇化非格司亭(pegfilgrastim));
-抑制骨再吸收的药剂,如地诺单抗(denosumab)或双膦酸盐,例如唑来膦酸盐(zoledronate)、唑来膦酸(zoledronic acid)、帕米膦酸盐(pamidronate)以及伊班膦酸盐(ibandronate);
-抑制炎症反应的药剂,如地塞米松、泼尼松、以及泼尼松龙;
-用于降低患有肢端肥大症或其它罕见的产生激素的肿瘤的患者的生长激素和IGF-I(以及其它激素)的血液水平的药剂,如激素生长抑素的合成形式,例如醋酸奥曲肽;
-降低叶酸水平的药物的解毒剂,如甲酰四氢叶酸、或亚叶酸;
-用于疼痛的药剂,例如阿片制剂,如吗啡、二乙酰吗啡(diamorphine)以及芬太尼(fentanyl);
-非类固醇抗炎药(NSAID),如COX-2抑制剂,例如塞内昔布(celecoxib)、艾托考昔(etoricoxib)以及鲁米考昔(lumiracoxib);
-用于粘膜炎的药剂,例如帕利夫明(palifermin);
-用于治疗包括厌食、恶病质、水肿或血栓栓塞事件的副作用的药剂,如醋酸甲地孕酮。
在一个实施方案中,抗癌剂选自重组干扰素(例如干扰素-γ和干扰素α)和白介素(例如白介素2),例如阿地白介素、地尼白介素、干扰素α2a、干扰素α2b或聚乙二醇干扰素α2b;干扰素-α2(500μ/ml),特别是干扰素-β;和信号转导抑制剂,例如激酶抑制剂(例如EGFR(上皮生长因子受体)抑制剂,VEGFR(血管内皮生长因子受体)抑制剂,PDGFR(血小板衍生生长因子受体)抑制剂,MTKI(多靶标激酶抑制剂),Raf抑制剂,mTOR抑制剂,例如甲磺酸伊马替尼、埃罗替尼、吉非替尼、达沙替尼、拉帕替尼、多韦替尼、阿西替尼、尼罗替尼、凡德他尼、瓦他拉尼、帕唑帕尼、索拉非尼、舒尼替尼、替西罗莫司、依维莫司(RAD 001)、威罗菲尼(PLX4032/RG7204)、达拉菲尼、安拉菲尼或IκB激酶抑制剂如SAR-113945、巴多索隆、BMS-066、BMS-345541、IMD-0354、IMD-2560或IMD-1041,或MEK抑制剂如司美替尼(AZD6244)和曲美替尼(GSK121120212),尤其是Raf抑制剂(例如威罗菲尼)或MEK抑制剂(例如曲美替尼)。
本发明的组合中存在的化合物中的每一种可以按照单独变化的剂量方案并且经由不同的途径给予。因而,所述两种或更多种药剂中的每一种的剂量学可能不同:每一种可以同时或在不同的时间被施用。本领域技术人员将经由他的或她的普通常识知道待使用的给药方案和联合治疗。例如,本发明的化合物可以与一种或多种其它药剂组合使用,所述一种或多种其它药剂是根据它们已经存在的组合方案施用的。标准组合方案的实例提供于下文中。
紫杉烷化合物有利地以每疗程每平方米体表面积50mg至400mg(mg/m2)的剂量施用,例如每疗程75mg/m2至250mg/m2,特别是对于紫杉醇,以每疗程约175mg/m2至250mg/m2的剂量,并且对于多烯紫杉醇,以每疗程约75mg/m2至150mg/m2的剂量。
喜树碱化合物有利地以每疗程每平方米体表面积0.1mg至400mg(mg/m2)的剂量施用,例如每疗程1mg/m2至300mg/m2,特别是对于伊立替康,以每疗程约100mg/m2至350mg/m2的剂量,并且对于拓扑替康,以每疗程约1mg/m2至2mg/m2的剂量。
抗肿瘤鬼臼毒素衍生物有利地以每疗程每平方米体表面积30mg至300mg(mg/m2)的剂量施用,例如每疗程50mg/m2至250mg/m2,特别是对于依托泊苷,以每疗程约35mg/m2至100mg/m2的剂量,并且对于替尼泊苷,以每疗程约50mg/m2至250mg/m2的剂量。
抗肿瘤长春花生物碱有利地以每疗程每平方米体表面积2mg至30mg(mg/m2)的剂量施用,特别是对于长春花碱,以每疗程约3mg/m2至12mg/m2的剂量,对于长春新碱,以每疗程约1mg/m2至2mg/m2的剂量,并且对于长春瑞滨,以每疗程约10mg/m2至30mg/m2的剂量。
抗肿瘤核苷衍生物有利地以每疗程每平方米体表面积200mg至2500mg(mg/m2)的剂量施用,例如每疗程700mg/m2至1500mg/m2,特别是对于5-FU,以每疗程200mg/m2至500mg/m2的剂量,对于吉西他滨,以每疗程约800mg/m2至1200mg/m2的剂量,并且对于卡培他滨,以每疗程约1000mg/m2至2500mg/m2的剂量。
烷化剂如氮芥或亚硝基脲有利地以每疗程每平方米体表面积100mg至500mg(mg/m2)的剂量施用,例如每疗程120mg/m2至200mg/m2,特别是对于环磷酰胺,以每疗程约100mg/m2至500mg/m2的剂量,对于苯丁酸氮芥,以每疗程约0.1mg/kg至0.2mg/kg的剂量,对于卡莫司汀,以每疗程约150mg/m2至200mg/m2的剂量,并且对于洛莫司汀,以每疗程约100mg/m2至150mg/m2的剂量。
抗肿瘤蒽环霉素衍生物有利地以每疗程每平方米体表面积10mg至75mg(mg/m2)的剂量施用,例如每疗程15mg/m2至60mg/m2,特别是对于多柔比星,以每疗程约40mg/m2至75mg/m2的剂量,对于柔红霉素,以每疗程约25mg/m2至45mg/m2的剂量,并且对于伊达比星,以每疗程约10mg/m2至15mg/m2的剂量。
抗雌激素剂有利地以每天约1mg至100mg的剂量施用,这取决于具体的药剂和所治疗的病况。他莫昔芬有利地以5mg至50mg(具体是10mg至20mg)的剂量每天两次口服施用,持续治疗足够的时间以实现和维持治疗作用。托瑞米芬有利地以约60mg的剂量每天一次口服施用,持续治疗足够的时间以实现和维持治疗作用。阿那曲唑有利地以约1mg的剂量每天一次口服施用。屈洛昔芬有利地以约20mg-100mg的剂量每天一次口服施用。雷洛昔芬有利地以约60mg的剂量每天一次口服施用。依西美坦有利地以约25mg的剂量每天一次口服施用。
抗体有利地以每平方米体表面积约1mg至5mg(mg/m2)的剂量施用,或如本领域已知的那样(如果不同的话)。曲妥珠单抗有利地以每疗程每平方米体表面积1mg至5mg(mg/m2)、特别是2mg/m2至4mg/m2的剂量施用。
在式(I)化合物在联合治疗中与一种、两种、三种、四种或更多种其它治疗剂(具体是一种或两种,更具体是一种)一起施用的情况下,所述化合物可以同时或依次施用。在后一种情况下,所述两种或更多种化合物将在一段时间内并且以一定的量和方式施用,所述时间以及量和方式足以确保实现有利效应或协同效应。当依次施用时,它们可以以紧密隔开的时间间隔(例如在5分钟-10分钟的时间内)或以更长的时间间隔(例如相隔1小时、2小时、3小时、4小时或更长时间、或甚至在必要的情况下相隔更长的时间)施用,精确的给药方案与一种或多种治疗剂的特性相称。这些剂量可以每疗程施用例如一次、两次或更多次,这可以例如每7天、14天、21天或28天重复一次。
在一个实施方案中,提供了用于制备用于疗法的药物的式(I)化合物,其中所述化合物与一种、两种、三种或四种其他治疗剂组合使用。在另一个实施方案中,提供了用于治疗癌症的药物,其包含式(I)化合物,其中所述药物与一种、两种、三种或四种其他治疗剂组合使用。本发明进一步提供了式(I)化合物在制备用于增强或强化患有癌症的患者的反应率的药物中的用途,其中该患者正在用一种、两种、三种或四种其他治疗剂治疗。
应当理解,具体的施用方法和顺序以及组合的每种成分的相应剂量和方案取决于所施用的具体的其他药剂和本发明的化合物、它们的施用途径、所治疗的具体肿瘤和所治疗的具体宿主。本领域技术人员可以使用常规方法并鉴于本文中列出的信息容易地确定最佳施用方法和顺序以及剂量和方案。
本发明化合物与一种或多种其他抗癌剂在作为组合给予时的重量比可由本领域技术人员确定。所述比例和施用的准确剂量和频率取决于本发明的具体化合物和所用的其他抗癌剂、所治疗的具体病症、所治疗病症的严重程度、特定患者的年龄、体重、性别、膳食、施用时间和一般身体状况、施用方式以及个体可能正在服用的其他药物,正如本领域技术人员众所周知。此外,显而易见,根据治疗受试者的反应和/或根据开出本发明化合物处方的临床医师的评价的不同,可以降低或增加每日有效量。本发明的式(I)化合物与另一种抗癌剂的具体重量比可以为1/10至10/1,更具体地为1/5至5/1,甚至更具体地为1/3至3/1。
本发明的化合物也可以与非化疗治疗方法联合施用,例如放疗、光动力疗法、基因疗法;手术和控制饮食。
本发明的化合物在使肿瘤细胞对放疗和化疗敏感方面也具有治疗应用。因此,本发明的化合物可以用作“放射增敏剂”和/或“化学增敏剂”,或者可以与另一种“放射增敏剂”和/或“化学增敏剂”组合使用。在一个实施方案中,本发明的化合物用作化学增敏剂。
将术语“放射增敏剂”定义为以治疗有效量施用于患者以增加细胞对电离辐射的敏感性和/或促进电离辐射可治疗的疾病的治疗的分子。
将术语“化学增敏剂”定义为以治疗有效量施用于患者以增加细胞对化疗的敏感性和/或促进可用化疗剂治疗的疾病的治疗的分子。
在一个实施方案中,本发明的化合物与“放射增敏剂”和/或“化学增敏剂”一起施用。在一个实施方案中,本发明的化合物与“免疫敏化剂”一起施用。
将术语“免疫敏化剂”定义为以治疗有效量施用于患者以增加细胞对Polθ抑制剂的敏感性的分子。
许多癌症治疗方案目前使用放射增敏剂与X射线的放射联合。X射线活化的放射增敏剂的实例包括但不限于以下:甲硝唑(metronidazole)、迷索硝唑(misonidazole)、脱甲基迷索硝唑、哌莫硝唑(pimonidazole)、依他硝唑(etanidazole)、尼莫拉唑(nimorazole)、丝裂霉素C、RSU 1069、SR 4233、EO9、RB 6145、烟酰胺、5-溴脱氧尿苷(BUdR)、5-碘脱氧尿苷(IUdR)、溴脱氧胞苷、氟脱氧尿苷(FudR)、羟基脲、顺铂、以及其治疗有效的类似物和衍生物。
癌症的光动力治疗(PDT)使用可见光作为增敏剂的放射活化剂。光动力放射增敏剂的实例包括但不限于以下各项:血卟啉衍生物、光卟啉(Photofrin)、苯并卟啉衍生物、锡初卟啉(tin etioporphyrin)、脱镁叶绿酸-a(pheoborbide-a)、细菌叶绿素-a(bacteriochlorophyll-a)、萘酞菁()naphthalocyanines、酞菁(phthalocyanines)、锌酞菁(zinc phthalocyanine)、以及其治疗有效的类似物和衍生物。
放射增敏剂可以与治疗有效量的一种或多种其他化合物联合施用,包括但不限于:本发明的化合物;促进放射增敏剂掺入靶细胞的化合物;控制治疗剂、营养物和/或氧气流向靶细胞的化合物;在有或没有额外辐射的情况下作用于肿瘤的化学治疗剂;或用于治疗癌症或其他疾病的其他治疗有效的化合物。
化学敏化剂可以与治疗有效量的一种或多种其他化合物联合施用,包括但不限于:本发明的化合物;促进化学敏化剂掺入靶细胞的化合物;控制治疗剂、营养物和/或氧气流向靶细胞的化合物;作用于肿瘤的化学治疗剂或用于治疗癌症或其他疾病的其他治疗有效的化合物。发现钙拮抗剂如维拉帕米可与抗肿瘤剂联合使用,以在对公认的化疗剂有抗性的肿瘤细胞中建立化学敏感性,并增强此类化合物在药物敏感性恶性肿瘤中的功效。
免疫敏化剂的实例包括但不限于:免疫调节剂、例如单克隆抗体、例如免疫检查点抗体[例如CTLA-4阻断抗体和/或针对PD-1和PD-L1和/或PD-L2的抗体,例如伊匹木单抗(CTLA4)、MK-3475(帕博利珠单抗,原称为莱博珠单抗,抗PD-1)、纳武单抗(抗PD-1)、BMS-936559(抗PD-L1)、MPDL320A、AMP-514或MEDI4736(抗PD-L1)、或曲美木单抗(原称为替立木单抗、CP-675,206,抗CTLA-4);或信号转导抑制剂;或细胞因子(例如重组干扰素);或溶瘤病毒;或免疫佐剂(例如BCG)。
免疫敏化剂可以与治疗有效量的一种或多种其他化合物联合施用,包括但不限于:本发明的化合物;促进免疫敏化剂结合到靶细胞的化合物;控制治疗剂、营养物和/或氧气流向靶细胞的化合物;作用于肿瘤的治疗剂或用于治疗癌症或其他疾病的其他治疗有效的化合物。
对于与另一种化疗剂的联合疗法,式(I)化合物和一种、两种、三种、四种或更多种其他治疗剂可以例如一起配制在包含两种、三种、四种或更多种治疗剂的剂型中,即在包含所有药剂的单一药物组合物中。在一个可替代选择的实施方案中,可以单独配制单独的治疗剂并以药盒的形式一起呈现,任选地附有它们的使用说明书。
在一个实施方案中,提供了式(I)化合物与一种或多种(例如1或2种)另外的治疗剂(例如如上所述的抗癌剂)的组合。在另一个实施方案中,提供了如本文所述的Polθ抑制剂与PI3K/AKT途径抑制剂的组合,所述PI3K/AKT途径抑制剂选自:阿帕利司、布帕利司、考泮利司、皮克利司、ZSTK-474、CUDC-907、GSK-2636771、LY-3023414、依帕他塞、埃瑞塞替、MK-2206、MK-8156、艾代拉利司、BEZ235(达托利司)、BYL719、GDC-0980、GDC-0941、GDC-0032和GDC-0068。
在另一个实施方案中,提供了式(I)化合物与一种或多种(例如1或2种)另外的治疗剂(例如抗癌剂)的组合,其用于疗法,例如用于预防或治疗癌症。
在一个实施方案中,所述药物组合物包含式(I)化合物以及药学上可接受的载体和任选的一种或多种治疗剂。
在另一个实施方案中,本发明涉及根据本发明的组合用于制造用于抑制肿瘤细胞生长的药物组合物的用途。
在另一个实施方案中,本发明涉及一种产品,所述产品含有式(I)化合物和一种或多种抗癌剂,作为组合制品用于同时、分开或相继用于治疗患有癌症的患者。
实施例
现在参照下列实施例中所述的具体实施方案示例本发明,但不限于此。
缩写
DCM 二氯甲烷
DMSO 二甲亚砜
EtOAc 乙酸乙酯
h 小时
HPLC 高效液相色谱法
KHMDS 双(三甲基甲硅烷基)氨基钾
LCMS 液相色谱法–质谱法
MeCN 乙腈
MeOH 甲醇
min 小时
NMR 核磁共振
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
PE 石油醚
rt 室温或环境温度
T3P 1-丙膦酸酐溶液
THF 四氢呋喃
Xantphos 4,5-双(二苯基膦基)-9,9-二甲基呫吨
实施例1
(2S,3S,4S)-N-(5-氯-2,4-二氟苯基)-3,4-二羟基-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-氧代吡咯烷-2-甲酰胺(E1)
步骤a:向5-氯-2,4-二氟苯胺(2.00g,12.2mmol)在1,4-二噁烷(10mL)和水(10mL)中的溶液中加入二碳酸二-叔丁酯(5.34g,24.5mmol)和NaHCO3(4.11g,48.9mmol)。将该混合物在40℃搅拌12h。完成时,真空浓缩该反应混合物,用水(20mL)稀释,用EtOAc(20mL x3)萃取。合并的有机层用盐水(60mL x 2)洗涤,用Na2SO4干燥,蒸发。通过柱色谱法纯化残余物(含3-5%EtOAc的PE),得到(5-氯-2,4-二氟苯基)氨基甲酸叔丁酯(1.00g,31%收率),为白色固体。1H NMR(400MHz,DMSO-d6)δppm 9.21(s,1H),7.82(t,J=8.0Hz,1H),7.55(dd,J=9.6,10.8Hz,1H),1.45(s,9H).
步骤b:在0℃、在N2气氛中向(5-氯-2,4-二氟苯基)氨基甲酸叔丁酯(900mg,3.41mmol)在二甲基甲酰胺(9mL)中的溶液中分批加入NaH(205mg,5.12mmol,60%的矿物油分散液),将该混合物在20℃搅拌0.5h。滴加碘甲烷-d3(594mg,4.10mmol),将该混合物在0℃搅拌1h。完成时,用水稀释该反应混合物(10mL),用EtOAc(10mL x 3)萃取。用盐水洗涤合并的有机层(30mL x 3),干燥,蒸发,得到(5-氯-2,4-二氟苯基)(甲基-d3)氨基甲酸叔丁酯(990mg,粗品),为无色油状物。m/z ES+[M-55]+225.0。
步骤c:将(5-氯-2,4-二氟苯基)(甲基-d3)氨基甲酸叔丁酯(990mg,粗品)和三氟乙酸(3.08g,27.0mmol)在DCM(10mL)中的溶液在rt搅拌0.5h。完成时,用水(15mL)稀释该反应混合物,用DCM(15mL x 3)萃取。用盐水(40mL x 2)洗涤合并的有机层,干燥,蒸发。通过柱色谱法纯化残余物(含3-5%EtOAc的PE),得到5-氯-2,4-二氟-N-(甲基-d3)苯胺(490mg,77%收率,2步),为无色油状物。m/z ES+[M+H]+181.1。
步骤d:在氮气惰性气氛中向20L 4-颈圆底烧瓶中加入(2R)-3-(苄氧基)-2-[(叔丁氧基羰基)氨基]丙酸(CAS编号47173-80-8;800g,2.68mol)、N-甲基吗啉(298g,2.95mol)和THF(8L)。将该混合物冷却至-20℃,滴加氯甲酸甲酯(266g,2.82mol)。将得到的混合物在-10℃在水/冰浴中搅拌0.5h。通过过滤采集固体,得到(2R)-3-(苄氧基)-2-[(叔丁氧基羰基)氨基]-1-[(甲氧基羰基)氧基]丙-1-酮,将其不经进一步纯化用于下一步。
步骤e:在氮气惰性气氛中向20L 4-颈圆底烧瓶加入水(8L),将其冷却至0℃,然后添加NaBH4(254g,6.70mol)。在0℃滴加(2R)-3-(苄氧基)-2-[(叔丁氧基羰基)氨基]-1-[(甲氧基羰基)氧基]-丙-1-酮(957g,2.68mol)在THF(8L)中的溶液。将得到的溶液在rt搅拌过夜。通过过滤除去固体。用DCM(3 x 3L)萃取滤液,浓缩有机相。通过硅胶色谱法纯化粗产物(含30%EtOAc的PE),得到N-[(2S)-1-(苄氧基)-3-羟基丙-2-基]氨基甲酸叔丁酯(670g,88%收率),为白色固体。
m/z ES+[M+H]+282.2。
步骤f:在氮气惰性气氛中向50L 4-颈圆底烧瓶中加入(COCl)2(545g,4.29mol)在DCM(15L)中的溶液。随后在-78℃、在搅拌的同时滴加DMSO(670g,8.59mol)。0.5h后,在-78℃、在搅拌的同时通过滴加N-[(2S)-1-(苄氧基)-3-羟基丙-2-基]氨基甲酸叔丁酯(610g,2.17mol)在DCM(3L)中的溶液处理该混合物,再搅拌0.5h。在-78℃、在搅拌的同时向该混合物中滴加N,N-二异丙基乙胺(1664g,12.88mol)。在-78℃将得到的混合物搅拌2h,然后在-40℃再搅拌2h。将该反应混合物冷却至-70℃,通过添加5%KHSO4水溶液(18L)淬灭。用DCM(5L)萃取得到的溶液。用盐水洗涤有机相,用Na2SO4干燥,浓缩。将粗产物不经进一步纯化用于下一步。
注意,产物在LCMS中不稳定,通过薄层色谱法检测粗产物,用1HNMR证实。
步骤g:在氮气惰性气氛中向20L 4-颈圆底烧瓶中加入2-[双(2,2,2-三氟乙氧基)磷酰基]乙酸甲酯(682g,2.14mol)在THF(6L)中的溶液,向其中加入18-冠-6(567g,2.14mol)。随后在-78℃、在搅拌的同时滴加KHMDS(1M的THF溶液,2.14L,2.14mol)。在-78℃向其中加入N-[(2R)-1-(苄氧基)-3-氧代丙-2-基]氨基甲酸叔丁酯(605g,2.14mol)在THF(1.8L)中的溶液。将得到的反应混合物在-78℃搅拌2h。通过添加1M HCl(12L)使反应淬灭。用EtOAc(2x 5L)萃取得到的溶液,用水洗涤,用Na2SO4干燥,浓缩。通过硅胶色谱法纯化粗产物(30%EtOAc的PE溶液),得到(2Z,4S)-5-(苄氧基)-4-[(叔丁氧基羰基)氨基]戊-2-烯酸甲酯(655g,90%收率),为白色固体。
m/z ES+[M+H]+336.1;1H NMR(300MHz,DMSO-d6)δppm 7.36–7.26(m,5H),6.18–6.12(m,1H),5.90–5.86(m,1H),5.39–5.32(m,1H),4.55–4.43(m,2H),3.64(s,3H),3.50–3.39(m,2H),1.47(s,9H).
步骤h:在氮气惰性气氛中向5L 3-颈圆底烧瓶中加入(2Z,4S)-5-(苄氧基)-4-[(叔丁氧基羰基)氨基]戊-2-烯酸甲酯(655g,1.93mol)和MeOH(3275mL),随后在0℃在搅拌的同时滴加乙酰氯(455g,5.80mol)。将得到的混合物在rt搅拌12h。浓缩得到的混合物,将残余物再溶于THF,再浓缩。用正己烷处理粗产物,通过过滤采集固体,得到(2Z,4S)-4-氨基-5-(苄氧基)戊-2-烯酸甲酯盐酸盐(480g,90%收率),为浅棕色固体。
m/z ES+[M+H]+236.1;1H NMR(300MHz,DMSO-d6)δppm 8.58(bs,3H),7.38–7.29(m,5H),6.38–6.32(m,1H),6.16–6.12(m,1H),5.39–5.32(m,1H),4.61–4.49(m,2H),3.68(s,3H),3.44(bs,2H).
步骤i:在氮气惰性气氛中向5L 3-颈圆底烧瓶加入DCM(2.40L)、(2Z,4S)-4-氨基-5-(苄氧基)戊-2-烯酸甲酯盐酸盐(480g,1.75mol),随后滴加二苯基甲胺(diphenylmethanimine)(317g,1.75mol)。将得到的混合物在rt搅拌12h。浓缩该反应混合物,得到(2Z,4S)-5-(苄氧基)-4-[(二苯基亚甲基)氨基]戊-2-烯酸甲酯(780g,粗品),为浅棕色油状物。m/z ES+[M+H]+400.2。
步骤j:在氮气惰性气氛中向20L 3-颈圆底烧瓶加入(2Z,4S)-5-(苄氧基)-4-[(二苯基亚甲基)氨基]戊-2-烯酸甲酯(95.0g,1.85mol)、THF(7.80L)、水(7.80L)、N-甲基吗啉-N-氧化物(543g,4.64mol),随后分4部分添加OsO4(23.6g,92.7mmol)。将得到的混合物在35℃搅拌48h。将该反应混合物冷却至rt。用EtOAc(2 x 5L)萃取得到的溶液。用水(2 x 3L)洗涤有机相。用Na2SO4干燥该混合物,浓缩。在己烷中搅拌固体产物,通过过滤采集固体,得到粗的(2S,3S,4R)-5-(苄氧基)-4-[(二苯基亚甲基)氨基]-2,3-二羟基戊酸甲酯和(2R,3R,4R)-5-(苄氧基)-4-((二苯基亚甲基)氨基)-2,3-二羟基戊酸甲酯的混合物(650g),为浅棕色固体。m/z ES+[M+H]+434.1。
步骤k:在氮气惰性气氛中向10L 4-颈圆底烧瓶中加入(2S,3S,4R)-5-(苄氧基)-4-[(二苯基亚甲基)氨基]-2,3-二羟基戊酸甲酯和(2R,3R,4R)-5-(苄氧基)-4-((二苯基亚甲基)氨基)-2,3-二羟基戊酸甲酯(650g,1.42mol)、甲苯(6.5L)、对甲苯磺酸吡啶鎓(89.5g,356mmol)和2,2-二甲氧基丙烷(742g,7.12mol)的混合物。将得到的混合物在100℃搅拌12h。浓缩该反应混合物。通过硅胶柱色谱法纯化粗产物(3%EtOAc的PE溶液),得到(4S,5S)-5-[(1R)-2-(苄氧基)-1-[(二苯基亚甲基)氨基]乙基]-2,2-二甲基-1,3-二氧戊环-4-甲酸甲酯445g(65%收率,3步),为淡黄色油状物。
m/z ES+[M+H]+474.2;1H NMR(300MHz,DMSO-d6)δppm 7.75–7.16(m,15H),4.65–4.63(m,1H),4.55–4.50(m,1H),4.31(s,2H),3.74–3.68(m,1H),3.59–3.57(m,2H),3.26(s,3H),1.54(s,3H),1.33(s,3H)。
步骤l:向10L氢气压力槽型反应器中加入(4S,5S)-5-[(1R)-2-(苄氧基)-1-[(二苯基亚甲基)氨基]乙基]-2,2-二甲基-1,3-二氧戊环-4-甲酸甲酯(445g,930mmol)、MeOH(4.45L)、20%Pd(OH)2/C(65g,93mmol)和10%Pd/C(99g,93mmol)。将得到的混合物在氢气气氛中(20atm)在40℃搅拌4天。然后过滤该反应混合物,浓缩。在己烷中搅拌粗产物,然后通过过滤采集,得到(3aS,6R,6aS)-6-(羟甲基)-2,2-二甲基-四氢-[1,3]二氧戊环并[4,5-c]吡咯-4-酮(153g,87%收率),为白色固体。
m/z ES+[M+H]+188.0;1H NMR(300MHz,DMSO-d6)δppm 7.89(bs,1H),4.77–4.75(m,1H),4.68–4.65(m,1H),4.57–4.55(m,1H),3.65–3.55(m,2H),3.47–3.39(m,1H),1.30(s,6H)。
步骤m:在氮气惰性气氛中向10L 3-颈圆底烧瓶加入(3aS,6R,6aS)-6-(羟甲基)-2,2-二甲基-四氢-[1,3]二氧戊环并[4,5-c]吡咯-4-酮(153g,809mmol)、MeCN(1.38L)、四氯化碳(1.38L)、水(2.00L)、高碘酸钠(519g,2.43mol)和RuCl3(16.8g,80.9mmol)。将该反应混合物在20-35℃搅拌3h。然后过滤该反应混合物,浓缩。将粗产物溶于MeOH,过滤,浓缩,得到(3aS,4S,6aS)-2,2-二甲基-6-氧代-四氢-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酸(170g,72%),为浅棕色固体。m/z ES+[M+H]+202.2;1H NMR(300MHz,DMSO-d6)δppm 12.86(s,1H),8.19(s,1H),4.88(t,J=5.6Hz,1H),4.56(d,J=5.9Hz,1H),4.31(d,J=5.3Hz,1H),1.27(d,J=5.4Hz,6H);[a]D=13.2度(C=0.22g/100mL in MeOH,T=21.2)。
步骤n:用吡啶(1.57g,19.8mmol)处理5-氯-2,4-二氟-N-(甲基-d3)苯胺(2.15g,11.9mmol)在N,N-二甲基乙酰胺(20mL)中的溶液,搅拌15min,然后添加(3aS,4S,6aS)-2,2-二甲基-6-氧代-四氢-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酸(2.3g,11.4mmol)。将该反应混合物冷却至0℃,通过在0℃搅拌的同时滴加T3P(19g,30mmol,50%wt.%的EtOAc溶液)处理。将得到的溶液在0℃搅拌0.5h,然后在rt搅拌24h。将该反应混合物加热至50℃,再搅拌24h。通过添加冰水(80mL)使反应淬灭,用EtOAc(3 x 60mL)萃取,浓缩。通过制备型-HPLC纯化残余物(柱:C18;流动相:A=水(5%NH4HCO3),B=MeCN;B%:15-45%,40min),得到(3aS,4S,6aS)-N-(5-氯-2,4-二氟苯基)-2,2-二甲基-N-(甲基-d3)-6-氧代四氢-4H-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酰胺。
使用(3aS,4S,6aS)-2,2-二甲基-6-氧代-四氢-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酸(3.0g,14.9mmol)重复该反应,合并两次反应产物,得到(3aS,4S,6aS)-N-(5-氯-2,4-二氟苯基)-2,2-二甲基-N-(甲基-d3)-6-氧代四氢-4H-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酰胺(6.2g,65%收率)。
m/z ES+[M+H]+364.0;1H NMR(400MHz,DMSO-d6)δppm 8.28–7.50(m,3H),5.26–3.80(m,3H),1.40–1.09(m,6H)。
步骤o:用2-氯-6-甲基-4-(三氟甲基)吡啶(CAS编号22123-14-4;1.5g,7.7mmol)、XantPhos(0.95g,1.6mmol)、Pd2(dba)3(0.5g,0.55mmol)和K2CO3(1.52mg,11mmol)处理(3aS,4S,6aS)-N-(5-氯-2,4-二氟苯基)-2,2-二甲基-N-(甲基-d3)-6-氧代四氢-4H-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酰胺(2.0g,5.5mmol)在1,4-二噁烷中的溶液,在90-95℃搅拌24h。通过过滤除去固体。浓缩滤液,通过柱色谱法纯化残余物(10%EtOAc的PE溶液),得到(3aS,4S,6aS)-N-(5-氯-2,4-二氟苯基)-2,2-二甲基-N-(甲基-d3)-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧代四氢-4H-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酰胺。
使用(3aS,4S,6aS)-N-(5-氯-2,4-二氟苯基)-2,2-二甲基-N-(甲基-d3)-6-氧代四氢-4H-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酰胺(5.0g,13.7mmol)重复该反应,合并两次反应产物,得到(3aS,4S,6aS)-N-(5-氯-2,4-二氟苯基)-2,2-二甲基-N-(甲基-d3)-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧代四氢-4H-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酰胺(6.5g,64%收率)。
m/z ES+[M+H]+523.0;1H NMR(300MHz,CD3OD)δppm 8.48–8.44(m,1H),8.03–7.79(m,1H),7.56–7.41(m,1H),7.36–7.27(m,1H),5.96–5.10(m,1H),5.03–4.53(m,2H),2.69–2.54(m,3H),1.49–1.36(m,6H)。
步骤p:将(3aS,4S,6aS)-N-(5-氯-2,4-二氟苯基)-2,2-二甲基-N-(甲基-d3)-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧代四氢-4H-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酰胺(5.8g,11.1mmol)在DCM(58mL)中的溶液冷却至-20℃,然后通过在-20℃滴加BCl3(22.2mL,22.2mmol,1M DCM溶液)处理。将该反应混合物温热至rt,搅拌2h。通过添加饱和NaHCO3的冰水溶液(58mL)使反应淬灭,用DCM(3 x 29mL)萃取,浓缩。通过制备型-HPLC(柱:C18;流动相:A=水,B=MeCN;B%:20-50%,30min)纯化残余物,得到标题化合物。
使用(3aS,4S,6aS)-N-(5-氯-2,4-二氟苯基)-2,2-二甲基-N-(甲基-d3)-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧代四氢-4H-[1,3]二氧戊环并[4,5-c]吡咯-4-甲酰胺(0.5g,0.96mmol)重复该反应,合并两次反应产物,得到标题化合物(4.0g,69%收率)。
m/z ES+[M+H]+483.1;1H NMR(300MHz,CD3OD)δppm 8.40–8.37(m,1H),8.06–8.01和7.91–7.86(m x2,1H),7.53–7.43(m,1H),7.30–7.24(m,1H),5.82,5.19和5.03(d x3,J=5.4Hz,1H),4.45和4.28(dd,J=6.8Hz,1H),4.25–4.08(m,1H),2.67–2.53(m,3H)。实施例1的NMR光谱如图1中所示。
生物学数据
Polθ全长酶功效测定
PicoGreen测定法用于测定化合物体外抑制Polθ活性的能力。纯化杆状病毒中表达的N-His、C-term FLAG标记的Polθ蛋白质(氨基酸2-2590),等分储存在-80℃下。使用包含25mM Tris HCl pH 7.5、12.5mM NaCl、0.5mM MgCl2、5%甘油、0.01%Triton X-100、0.01%BGG和1mM DTT的1X缓冲液进行试验测定。通过用100%DMSO稀释制备测试化合物,得到12点浓度响应的正确剂量范围,将适当体积(60nL)使用Labcyte Echo 550声分配器分配入384孔微量测定板(Perkin Elmer小体积黑色ProxiPlates产品代码6008269)。通过用DMSO溶液反填充将DMSO浓度维持在1%。3μL纯化的重组Polθ和引物(5’-GCG GCT GTC ATAAG–3’(SEQ ID NO:1)):模板(5’–GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGTCTT ATG ACA GCC GCG–3’(SEQ ID NO:2))双链体(1:1.1)用测定缓冲液稀释至2X工作浓度(4nMPolθ和100nM PTD)。使用VIAFLO 16通道手动移液管(Integra)将其分配入化合物板的每个孔,在rt预温育30min。然后加入用测定缓冲液稀释的dNTPs的3μL 2X工作溶液(40μM)(dATP,dCTP,dGTP,dTTP;Sigma D6500,D4635,D4010,T0251),将该反应体系在rt温育60min。通过添加10mM EDTA、25mM Tris pH7.5和1:200 PicoGreen染料稀释液(InvitrogenP7581)终止反应。在rt在黑暗中90分钟后,用BMG Pherastar FS平板读出器、使用485/520nm模块读取荧光,使用IDBS Activity Base分析原始数据,生成IC50值。
在上述举出的酶功效测定法中测试实施例1的化合物,结果如下表中所示:
实施例编号 | PolθIC<sub>50</sub>(nM) | PolθpIC<sub>50</sub> | n | PolθpIC<sub>50</sub>(SD) |
1 | 12.2 | 7.92 | 15 | 0.157 |
Claims (10)
2.权利要求1的化合物,其中所述氘代衍生物包含N-甲基的一个或多个(例如全部3个)氢原子的氘代。
4.权利要求3的化合物,其为式(II)化合物的游离碱,并且为(2S,3S,4S)-N-(5-氯-2,4-二氟苯基)-3,4-二羟基-N-(甲基-d3)-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-氧代吡咯烷-2-甲酰胺(E1)。
5.药物组合物,包含权利要求1-4任一项的式(I)化合物。
6.药物组合物,包含权利要求1-4任一项的式(I)化合物与一种或多种治疗剂。
7.权利要求1-4任一项的式(I)化合物,用于疗法。
8.权利要求1-4任一项的式(I)化合物,用于预防或治疗癌症。
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CA3209604A1 (en) * | 2021-02-07 | 2022-08-11 | Artios Pharma Limited | Novel process |
WO2023125841A1 (zh) * | 2021-12-29 | 2023-07-06 | 武汉人福创新药物研发中心有限公司 | 作为Polθ抑制剂的杂环化合物及其制备方法和用途 |
WO2023125918A1 (zh) * | 2021-12-30 | 2023-07-06 | 上海湃隆生物科技有限公司 | 一种DNA聚合酶theta抑制剂及其应用 |
WO2023169547A1 (zh) * | 2022-03-10 | 2023-09-14 | 四川海思科制药有限公司 | DNA聚合酶θ抑制剂及其用途 |
CN116730979A (zh) * | 2022-03-11 | 2023-09-12 | 武汉人福创新药物研发中心有限公司 | 一种Polθ抑制剂 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013107291A1 (en) * | 2012-01-19 | 2013-07-25 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
WO2013107405A1 (en) * | 2012-01-19 | 2013-07-25 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
WO2015010626A1 (en) * | 2013-07-25 | 2015-01-29 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and use thereof |
CN105829310A (zh) * | 2013-12-20 | 2016-08-03 | 阿斯特克斯治疗有限公司 | 双环杂环化合物及其治疗用途 |
WO2017190637A1 (zh) * | 2016-05-06 | 2017-11-09 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制蛋白酪氨酸激酶活性的稠合嘧啶类化合物 |
CN108137544A (zh) * | 2015-12-10 | 2018-06-08 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制蛋白酪氨酸激酶活性的氨基嘧啶类化合物 |
US20190218251A1 (en) * | 2018-01-12 | 2019-07-18 | Enb Therapeutics, Inc. | Deuterated compounds, compositions, and methods for treating cancers associated with etbr activation |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017062754A1 (en) | 2015-10-07 | 2017-04-13 | New York University | Compositions and methods for enhancing crispr activity by polq inhibition |
CN107556366A (zh) * | 2016-06-30 | 2018-01-09 | 上海海和药物研究开发有限公司 | 具有突变型异柠檬酸脱氢酶抑制活性的化合物、其制备方法及用途 |
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013107291A1 (en) * | 2012-01-19 | 2013-07-25 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
WO2013107405A1 (en) * | 2012-01-19 | 2013-07-25 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and their methods of use |
WO2015010626A1 (en) * | 2013-07-25 | 2015-01-29 | Agios Pharmaceuticals, Inc. | Therapeutically active compounds and use thereof |
CN105829310A (zh) * | 2013-12-20 | 2016-08-03 | 阿斯特克斯治疗有限公司 | 双环杂环化合物及其治疗用途 |
CN108137544A (zh) * | 2015-12-10 | 2018-06-08 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制蛋白酪氨酸激酶活性的氨基嘧啶类化合物 |
WO2017190637A1 (zh) * | 2016-05-06 | 2017-11-09 | 深圳市塔吉瑞生物医药有限公司 | 用于抑制蛋白酪氨酸激酶活性的稠合嘧啶类化合物 |
US20190218251A1 (en) * | 2018-01-12 | 2019-07-18 | Enb Therapeutics, Inc. | Deuterated compounds, compositions, and methods for treating cancers associated with etbr activation |
Non-Patent Citations (2)
Title |
---|
HAO SUN,等: "Deuterium isotope effects in drug pharmacokinetics II: substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs", 《PLOS ONE》, 14 November 2018 (2018-11-14), pages 0206279 * |
李苏,等: "氘代药物及其在抗肿瘤新药研发中的应用前景", 《临床肿瘤学杂志》, 31 December 2020 (2020-12-31), pages 1138 - 1143 * |
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US20220259174A1 (en) | 2022-08-18 |
HRP20231037T1 (hr) | 2023-12-08 |
PT4010329T (pt) | 2023-08-18 |
WO2021028670A1 (en) | 2021-02-18 |
RS64486B1 (sr) | 2023-09-29 |
ES2952281T3 (es) | 2023-10-30 |
DK4010329T3 (da) | 2023-09-04 |
KR20220050148A (ko) | 2022-04-22 |
IL290415A (en) | 2022-04-01 |
CA3149119A1 (en) | 2021-02-18 |
EP4010329B1 (en) | 2023-06-07 |
FI4010329T3 (fi) | 2023-08-30 |
TW202120486A (zh) | 2021-06-01 |
AU2020327661A1 (en) | 2022-02-24 |
MX2022001690A (es) | 2022-05-10 |
PL4010329T3 (pl) | 2023-10-16 |
ZA202201364B (en) | 2023-11-29 |
JP2022544211A (ja) | 2022-10-17 |
LT4010329T (lt) | 2023-09-11 |
BR112022002496A2 (pt) | 2022-04-26 |
HUE063145T2 (hu) | 2023-12-28 |
EP4010329A1 (en) | 2022-06-15 |
SI4010329T1 (sl) | 2023-10-30 |
EP4010329B9 (en) | 2023-10-04 |
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