CN116917273A - 作为dnmt1抑制剂的经取代的吡啶 - Google Patents
作为dnmt1抑制剂的经取代的吡啶 Download PDFInfo
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- CN116917273A CN116917273A CN202280018744.9A CN202280018744A CN116917273A CN 116917273 A CN116917273 A CN 116917273A CN 202280018744 A CN202280018744 A CN 202280018744A CN 116917273 A CN116917273 A CN 116917273A
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Abstract
本发明涉及经取代的吡啶衍生物,其是DNA甲基转移酶1(DNMT1)活性的抑制剂。本发明还涉及包含此类化合物的药物组合物以及使用此类化合物治疗癌症、癌前综合征、β血红蛋白病障碍和其他与不适当的DNMT1活性相关的疾病的方法。
Description
技术领域
本发明涉及经取代的吡啶衍生物,其是DNA甲基转移酶1(DNMT1)活性的抑制剂。本发明还涉及包含此类化合物的药物组合物以及使用此类化合物治疗癌症、癌前综合征、β血红蛋白病障碍和其他与不适当的DNMT1活性相关的疾病的方法。
背景技术
表观遗传学是一种独立于基础DNA序列开启和关闭基因的方法。基因启动子中发生的DNA甲基化是导致染色质压缩和基因沉默的抑制性表观遗传标志物的实例。DNA甲基化由DNA甲基转移酶(DNMT)家族介导,该家族由五个家族成员组成。该家族的三个成员DNMT1、DNMT3A和DNMT3B含有DNA甲基转移酶活性。这三个成员负责建立从头DNA甲基化模式,而DNMT1还负责在DNA复制后维持子链的甲基化模式。
在癌症中,DNA甲基化模式变得异常,导致启动子区域内的整体低甲基化和局部高甲基化。这可以导致肿瘤抑制基因的下游沉默(Ting等人Genes Dev.2006;20:3215-3231)。此外,DNMT1的沉默会导致DNA去甲基化和肿瘤抑制基因的重新表达,从而抑制肿瘤生长(Zhou等人Oncol.Lett.2014;5:2130-2134)。
DNA甲基化抑制剂(称为DNA低甲基化剂)是经过临床验证的抗癌疗法,用于治疗MDS、AML和CMML。虽然这些药物是可用的,但在毒性、实体瘤中的效用和口服生物利用度方面仍然有很大的改进机会。因此,新颖DNMT抑制剂对于癌症和/或由DNA甲基化介导的任何疾病或病症的治疗是引人关注的。本发明特别关注的是特异性靶向DNMT1,以防止复制期间异常甲基化模式(如癌症中出现的那些)传递到子链。
血红蛋白疾病,例如镰状细胞性贫血和β-地中海贫血,是世界上最常见的遗传性血液疾病。镰状细胞性贫血和β-地中海贫血的特征是血红蛋白紊乱,血红蛋白是红细胞中携带氧的蛋白质复合物。在结构上,血红蛋白通常由两对蛋白质加四个血红素分子组成。成人和四个月以上的儿童表达一种被称为成人血红蛋白的血红蛋白,它主要由两个α珠蛋白与两个β珠蛋白配对加四个血红素分子组成。然而,胎儿和婴儿通常主要表达胎儿血红蛋白,它由两个α珠蛋白与两个γ珠蛋白配对加四个血红素分子组成。注意,有两种形式的γ-珠蛋白,称为G-γ和A-γ,它们由两种不同的基因(HBG1和HBG2)编码,但在很大程度上功能相当;胎儿血红蛋白是指一对G-γ和/或A-γ加上一对α-珠蛋白加上四个血红素分子的任意组合。
在镰状细胞性贫血中,编码β-珠蛋白的基因包含突变,导致血红蛋白结构异常,并导致红细胞在某些条件下呈现特征性的镰状形状。这种镰状形状会导致红细胞可塑性降低、毛细血管传递时间延长以及频繁的血管闭塞过程,从而损害组织并导致患者发病。相比之下,β-地中海贫血的特征是β-珠蛋白生成不足,无法与正常生成的α-珠蛋白组合。由此产生的α珠蛋白的积累对红细胞前体具有毒性,并导致无效的红细胞生成和广泛的红细胞溶血。
目前尚无批准的药物治疗可治愈镰状细胞性贫血或β-地中海贫血。然而,增加产生胎儿血红蛋白的红细胞的数量,连同总体上增加每个红细胞的胎儿血红蛋白水平,已被证明通过降低急性血管闭塞危象的频率,为镰状细胞性贫血和镰状细胞病患者提供了临床益处。此外,尽管未经临床证实,β-地中海贫血的疾病生物学表明,将胎儿血红蛋白的产生提高到高水平可能也是治疗这种疾病的可行策略。
这种治疗方法的目的是通过干预红细胞生成的表观遗传过程可以实现沉默的HBG1和HBG2基因的去阻遏。DNA甲基化的变化是造血过程中的关键决定事件,标志着分化里程碑,导致向各种细胞谱系的分化。在红细胞生成过程中,整体DNA甲基化的快速降低标志着向红系特异性调节因子GATA1和KLF1表达,以及造血祖细胞调节因子GATA2和PU.1(1,2)的抑制的转折点。对于成人骨髓中的红系祖细胞,β-珠蛋白HBB基因启动子区域的DNA变为非甲基化,对应于β-珠蛋白的高水平表达。相比之下,HBG1和HBG2基因座的启动子高度甲基化,导致γ-球蛋白(3)的表达大大减少。虽然DNA甲基转移酶DNMT1、DNMT3A和DNMT3B均在红系祖细胞中表达,但DNMT1的相对较高表达,特别是在红系分化的最后阶段,表明它在珠蛋白基因调控中发挥主导作用(2)。5-氮杂胞苷和5-氮杂-2'-脱氧胞苷(地西他滨)是泛DNMT抑制剂,其是红系祖细胞中胎儿血红蛋白的已知诱导剂。在红系细胞培养物和胎儿血红蛋白诱导(4,5)的体内模型中,用这些药剂治疗会导致HBG启动子中CpG位点的甲基化减少,同时相应γ珠蛋白表达增加。此外,在一组有限的临床研究中,这两种药剂都会导致镰状细胞贫血、镰状细胞病和β-地中海贫血患者的胎儿血红蛋白增加(6-9)。虽然在诱导胎儿血红蛋白方面有效,但由于对长期安全性、剂量限制性毒性和不合适的给药途径的担忧,这些药剂尚未广泛用于治疗镰状细胞贫血、镰状细胞病或β-地中海贫血。
参考文献
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(4)Chin J,Singh M,Banzon V,Vaitkus K,Ibanez V,Kouznetsova T,etal.Transcriptional activation of theglobin gene in baboons treated withdecitabine and in cultured erythroid progenitor cells involves differentmechanisms.2009;37:1131-42.
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本发明的目的是提供作为DNMT1抑制剂的新颖化合物。
发明内容
本发明涉及新颖化合物。
具体地,本发明涉及式(I)的化合物
及其前药及其盐。
本发明进一步涉及药物组合物,其包含式(I)的化合物或其前药或其药学上可接受的盐,以及一种或多种药学上可接受的赋形剂。
本发明进一步涉及治疗与不适当的DNMT1活性相关的疾病的方法,这些方法包括向有需要的患者施用安全有效量的式(I)的化合物或其前药或其药学上可接受的盐。
本发明进一步涉及式(I)的化合物或其前药或其药学上可接受的盐,用于医学疗法中。
本发明进一步涉及式(I)的化合物或其前药或其药学上可接受的盐,用于治疗与不适当的DNMT1活性相关的疾病。
本发明进一步涉及式(I)的化合物或其前药或其药学上可接受的盐在制备用于治疗与不适当的DNMT1活性相关的疾病的药物中的用途。
本发明进一步涉及包含式(I)的化合物或其前药或其药学上可接受的盐和一种或多种其他治疗剂的组合。
附图说明
图1是实施例1的化合物的甘氨酸盐的X射线粉末衍射图。
图2是实施例1的化合物的甘氨酸盐的差示扫描量热图。
图3是实施例1的化合物的甘氨酸盐的差示扫描量热图。
图4是实施例1的化合物的甘氨酸盐一水合物的X射线粉末衍射图。
图5是实施例1的化合物的甘氨酸盐一水合物的差示扫描量热图。
图6是实施例1的化合物的甘氨酸盐一水合物的热重分析图。
图7是实施例1的化合物的X射线粉末衍射图。
图8是实施例1的化合物的差示扫描量热图。
图9.实施例1的化合物的热重分析图。
具体实施方式
在一个实施方案中,本发明涉及式(I)的化合物
及其前药及其盐(下文中“本发明的化合物”)。
本发明的化合物含有至少一个不对称中心(也称为手性中心),因此可以作为单独的对映体、非对映体或其他立体异构形式、或作为它们的混合物存在。手性中心,例如手性碳原子,也可以存在于取代基例如烷基中。当本发明化合物中存在的手性中心的立体化学或本文所示的任何化学结构中存在的手性中心的立体化学未指定时,该结构旨在涵盖任何立体异构体及其所有混合物。因此,本发明的化合物可以作为外消旋混合物、对映体富集的混合物或作为对映体纯的单独立体异构体使用。
因此,在一个实施方案中,本发明的化合物是式(II)的化合物
或其前药,或其盐。
在另一个实施方案中,本发明的化合物是式(II)的化合物
或其前药。
在进一步的实施方案中,本发明的化合物是式(III)的化合物
或其前药,或其盐。
本发明化合物的各个立体异构体可以通过本领域技术人员已知的方法来拆分。例如,这样的拆分可以通过以下来进行:(1)通过形成非对映异构盐、复合物或其他衍生物;(2)通过与立体异构体特异性试剂选择性反应,例如通过酶促氧化或还原;或(3)在手性环境中,例如在手性载体如具有结合的手性配体的二氧化硅上或在手性溶剂存在下,通过气液或液相色谱法。技术人员将理解,当通过上述分离程序之一将所需立体异构体转化为另一种化学实体时,需要进一步的步骤来释放所需形式。可替代地,可以通过使用光学活性试剂、底物、催化剂或溶剂的不对称合成,或通过不对称转化将一种对映体转化为另一种对映体来合成特定的立体异构体。
本发明的化合物还可以含有几何不对称中心。当本发明的化合物或本文所示的任何化学结构中存在的几何不对称中心的立体化学未指定时,该结构旨在涵盖反式几何异构体、顺式几何异构体及其所有混合物。同样,也包括所有互变异构体形式,无论这些互变异构体是平衡存在还是主要以一种形式存在。
本发明的化合物可以作为前药施用。如本文所用,式(I)的化合物的“前药”是该化合物的功能衍生物,其在施用给患者后最终在体内释放式(I)的化合物。式(I)的化合物作为前药的施用可以使得本领域技术人员能够进行以下一项或多项:(a)改变化合物在体内的溶解度,(b)改变化合物在体内活性的起始;(c)改变化合物在体内的作用持续时间;(d)改变化合物在体内的运输或分布;以及(e)克服该化合物的副作用或遇到的其他困难。用于制备前药的典型功能衍生物包括在体内可化学或酶促切割的化合物的修饰。此类修饰,包括磷酸酯、酰胺、酯、硫酯、碳酸酯和氨基甲酸酯的制备,是本领域技术人员众所周知的。在一个实施方案中,前药部分是-P(O)(OH)2。
因此,在一个实施方案中,本发明的化合物是式(IV)的前药
或其盐。
在另一个实施方案中,本发明的化合物是式(V)的前药
或其盐。
在另一个实施方案中,本发明的化合物是式(V)的前药
在进一步的实施方案中,本发明的化合物是式(VI)的前药
或其盐。
应当理解,本文提及的式(I)的化合物及其前药和其盐包括游离酸或游离碱形式的式(I)的化合物及其前药,或其盐,例如其药学上可接受的盐。因此,在一个实施方案中,本发明涉及游离酸或游离碱形式的式(I)的化合物或其前药。在另一个实施方案中,本发明涉及式(I)的化合物或其前药或其盐。在另一个实施方案中,本发明涉及式(I)的化合物或其前药或其药学上可接受的盐。
技术人员将理解,可以制备式(I)的化合物或其前药的药学上可接受的盐。事实上,在本发明的某些实施方案中,式(I)的化合物或其前药的药学上可接受的盐可能优于各自的游离碱或游离酸,因为这样的盐可以赋予分子更大的稳定性或溶解度,从而促进配制成剂型。
本文所用的术语“药学上可接受的盐”是指保留主题化合物的期望的生物活性并表现出最小的不期望的毒理学作用的盐。这些药学上可接受的盐可以在化合物的最终分离和纯化过程中原位制备,或者通过将游离酸或游离碱形式的纯化化合物或非药学上可接受的盐分别与合适的碱或酸反应来制备。
具有非药学上可接受的抗衡离子或相关溶剂的盐和溶剂化物在本发明的范围内,例如,用作制备式(I)的化合物或其前药及其药学上可接受的盐的中间体。因此,本发明的一个实施方案包括式(I)的化合物及其前药、及其盐。
药学上可接受的盐尤其包括以下中描述的那些:Berge,J.Pharm.Sci.,1977,66,1-19,或以下中列出的那些:P H Stahl和C G Wermuth,editors,Handbook ofPharmaceutical Salts;Properties,Selection and Use,第二版Stahl/Wermuth:Wiley-VCH/VHCA,2011(参见http://www.wiley.com/WileyCDA/WileyTitle/productCd- 3906390519.html)。
在某些实施方案中,根据式(I)的化合物或其前药可以含有酸性官能团。合适的药学上可接受的盐包括此类酸性官能团的盐。代表性的盐包括但不限于铝、2-氨基-2-(羟基甲基)-1,3-丙二醇(TRIS,氨丁三醇)、精氨酸、苯乙胺(N-苄基苯乙胺)、苄星青霉素(N,N’-二苄基乙二胺)、双-(2-羟基乙基)胺、铋、钙、氯普鲁卡因、胆碱、克立咪唑(1-对氯苄基-2-吡咯烷-1'-基甲基苯并咪唑)、环己胺、二苄基乙二胺、二乙胺、二乙基三胺、二甲胺、二甲基乙醇胺、多巴胺、乙醇胺、乙二胺、L-组氨酸、铁、异喹啉、勒皮啶(lepidine)、锂、L-赖氨酸、镁、葡甲胺(N-甲基葡糖胺)、哌嗪、哌啶、钾、普鲁卡因(procaine)、奎宁、喹啉、钠、锶、叔丁胺、甜菜碱(三甲基甘氨酸)、L-脯氨酸、L-苯丙氨酸、L-丙氨酸、L-酪氨酸、L-亮氨酸、咪唑、甘氨酸、L-缬氨酸、L-丝氨酸、吗啉、三胆碱、二乙烯三胺、1-(2-羟基乙基)-2-吡咯烷、和锌。
这种碱加成盐可以通过式(I)的化合物或其前药(例如,含有羧酸或其他酸性官能团)与合适的碱反应形成,任选在合适的溶剂如有机溶剂中反应,得到盐,该盐可以通过多种方法分离,包括结晶和过滤。
应当理解,如果式(I)的化合物或其前药包含两个或更多个碱性部分,则盐形成的化学计量可包括1、2或更多个当量的酸。此类盐将含有1、2或更多个酸性抗衡离子,例如二盐酸盐。
式(I)的化合物或其前药的药学上可接受的盐的化学计量和非化学计量形式包括在本发明的范围内,包括亚化学计量的盐,例如其中抗衡离子含有多于一个酸性质子。
在某些实施方案中,根据式(I)的化合物或其前药可以含有碱性官能团并且因此能够通过用合适的酸处理形成药学上可接受的酸加成盐。合适的酸包括药学上可接受的无机酸和药学上可接受的有机酸。代表性的药学上可接受的酸加成盐包括但不限于4-乙酰氨基苯甲酸盐、醋酸盐、己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐(benzenesulfonate)(苯磺酸盐(besylate))、苯甲酸盐、硫酸氢盐、酒石酸氢盐、丁酸盐、依地酸钙、樟脑酸盐、樟脑磺酸盐(camphorsulfonate)(樟脑磺酸盐(camsylate))、癸酸盐(caprate)(癸酸盐(decanoate))、己酸盐(caproate)(己酸盐(hexanoate))、辛酸盐(caprylate)(辛酸盐(octanoate))、肉桂酸盐、柠檬酸盐、环磺酸盐、二葡糖酸盐、2,5-二羟基苯甲酸盐、二琥珀酸盐、十二烷基硫酸盐(埃托盐(estolate))、乙二胺四乙酸盐(edetate)(乙二胺四乙酸盐(ethylenediaminetetraacetate))、埃托盐(estolate)(月桂基硫酸盐)、乙烷-1,2-二磺酸盐(乙二磺酸盐)、乙磺酸盐(ethanesulfonate)(乙磺酸盐(esylate))、甲酸盐、富马酸盐、半乳糖酸盐(galactarate)(粘酸盐)、龙胆酸盐(2,5-二羟基苯甲酸盐)、葡庚糖酸盐(glucoheptonate)(葡庚糖酸盐(gluceptate))、葡萄糖酸盐、葡萄糖醛酸盐、谷氨酸盐、戊二酸盐、甘油磷酸盐、乙醇酸盐、己基间苯二酚酸盐(hexylresorcinate)、马尿酸盐、哈胺盐(hydrabamine,N,N'-二(脱氢枞基)-乙二胺)、氢溴酸盐、盐酸盐、氢碘酸盐、羟基萘甲酸盐、异丁酸盐、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐(methanesulfonate)(甲磺酸盐(mesylate))、甲基硫酸盐、粘液酸盐、萘-1,5-二磺酸盐(萘二磺酸盐)、萘-2-磺酸盐(萘磺酸盐)、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、对氨基苯磺酸盐、对氨基水杨酸盐、双羟萘酸盐(恩波酸盐)、泛酸盐、果胶酸盐、过硫酸盐、苯乙酸盐、苯乙基巴比妥酸盐、磷酸盐、聚半乳糖醛酸盐、丙酸盐、对甲苯磺酸盐(甲苯磺酸盐)、焦谷氨酸盐、丙酮酸盐、水杨酸盐、癸二酸盐、硬脂酸盐、碱式醋酸盐、琥珀酸盐、氨基磺酸盐、硫酸盐、丹宁酸盐、酒石酸盐、茶氯酸盐(8-氯茶碱酸盐)、硫氰酸盐、三乙基碘、十一酸盐、十一烯酸盐、和戊酸盐。
这种酸加成盐可以通过式(I)化合物或其前药(例如含有碱性胺或其他碱性官能团)与合适的酸反应形成,任选在合适的溶剂如有机溶剂中反应,得到盐,该盐可以通过多种方法分离,包括结晶和过滤。
盐可以在式(I)的化合物或其前药的最终分离和纯化过程中原位制备。如果式(I)的碱性化合物或其前药作为盐分离,则该化合物的相应游离碱形式可以通过本领域已知的任何合适的方法来制备,包括用无机碱或有机碱处理该盐。类似地,如果含有羧酸或其他酸性官能团的式(I)的化合物或其前药以盐的形式分离,则该化合物的相应游离酸形式可以通过本领域已知的任何合适方法制备,包括用无机酸或有机酸处理该盐。
“本发明的化合物”的范围内包括式(I)的化合物及其前药及其盐的所有光学异构体、立体异构体、多晶型物和放射性标记衍生物。
本发明的化合物可以以固体或液体形式存在。在固态下,本发明的化合物可以以结晶或非结晶形式、或作为其混合物存在。对于结晶形式的本发明化合物,技术人员将理解,可以形成药学上可接受的溶剂化物,其中溶剂分子在结晶过程中掺入晶格中。本发明的化合物可以以溶剂化和非溶剂化形式存在。溶剂化物可涉及非水溶剂,例如乙醇、异丙醇、DMSO、乙酸、乙醇胺和EtOAc,或者它们可涉及水作为掺入晶格的溶剂。其中水是掺入晶格中的溶剂的溶剂化物通常称为“水合物”。水合物包括化学计量的水合物以及含有可变量水的组合物。
本领域技术人员还应当理解,以结晶形式存在的某些本发明化合物,包括其各种溶剂化物,可以表现出多晶型现象(即以不同结晶结构出现的能力)。这些不同的结晶形式通常被称为“多晶型物”。本发明包括所有此类多晶型物。多晶型物具有相同的化学组成,但在堆积、几何排列和结晶固态的其他描述性质方面有所不同。因此,多晶型物可能具有不同的物理性质,例如形状、密度、硬度、可变形性、稳定性和溶解性质。多晶型物通常表现出不同的熔点、IR光谱和X射线粉末衍射图,这些可用于鉴定。技术人员将理解,可以例如通过改变或调整用于制备化合物的反应条件或试剂来产生不同的多晶型物。例如,温度、压力或溶剂的变化可能导致多晶型物的产生。此外,在某些条件下,一种多晶型物可以自发地转化为另一种多晶型物。
本发明还包括同位素标记的化合物,其与本发明的化合物相同,但是一个或多个原子被原子质量或质量数不同于自然界中最常见的原子质量或质量数的原子替代。可掺入本发明化合物中的同位素的实例包括氢、碳、氮、氧和氟的同位素,例如2H、3H、11C、14C和18F。
“对映体富集”是指对映体过量大于零的产物。例如,对映体富集是指对映体过量大于50%ee、大于75%ee和大于90%ee的产物。
“对映体过量”或“ee”是一种对映体相对于另一种的过量,以百分比表示。结果,由于两种对映体以等量存在于外消旋混合物中,因此对映体过量为零(0%ee)。然而,如果一种对映体被富集,使其占产物的95%,则对映体过量将为90%ee(富集的对映体的量95%,减去另一种对映体的量5%)。在一些实施方案中,本发明的化合物相对于R或S对映体可具有至少50%ee、至少60%ee、至少65%ee、至少70%ee、至少75%ee、至少80%ee、至少85,至少90%ee、至少95%ee、至少96%ee、至少97%ee、至少98%ee、或至少99%ee。
“对映体纯”是指对映体过量为99%ee或更高的产物。
“药学上可接受的”是指在合理医学判断范围内的那些化合物、盐、材料、组合物和剂型,其适合用于与人类和动物的组织接触而没有过度毒性、刺激或其他问题或并发症,与合理的益处/风险比相称。
本发明的化合物可用作需要其的哺乳动物、特别是人类的选择性DNMT1抑制剂。作为DNMT1抑制剂的化合物可用于治疗其中潜在病理学(至少部分地)可归因于不适当的DNMT1活性的疾病,例如癌症。“不适当的DNMT1活性”是指特定患者中偏离预期的正常DNMT1活性的任何DNMT1活性。不适当的DNMT1可能表现为,例如,活性异常增加,或DNMT1活性的时间和/或控制异常。因此,在另一方面,本发明涉及治疗此类疾病的方法。
在本发明的一些方面,式(I)的化合物及其前药和其盐是DNMT1的有效抑制剂并且对DNMT1的选择性高于DNMT3A和DNMT3B。
此类疾病包括癌症、癌前综合征(有时称为癌前期病症)或β血红蛋白病障碍。癌前期病症是涉及异常细胞的病症或病变,其与发展成癌症的风险增加相关。临床上,癌前期病症包括多种发展为癌症的风险增加的病症或病变。
可以治疗的癌症包括:腺癌、基底细胞癌、鳞状细胞癌、腺鳞癌、癌肉瘤、黑色素瘤、肾上腺癌、肾上腺皮质癌、嗜铬细胞瘤、乳腺癌、导管原位癌、小叶癌、炎症性乳腺癌、浸润性导管癌、乳头佩吉特病、乳头状乳腺癌、髓样癌(medullary carcinoma)、乳腺癌、肛门癌、泄殖腔癌、肛门直肠黑色素瘤、阑尾癌、阑尾神经内分泌肿瘤、阑尾粘液性囊腺癌、结肠型腺癌、印戒细胞腺癌、杯状细胞癌/腺神经内分泌癌、胆管癌、肝内胆管癌、肝外胆管癌、肝门周围胆管癌、远端肝外胆管癌、结直肠癌(CRC)、粘液腺癌、胃肠道类癌种类、胃肠道间质瘤、原发性结直肠淋巴瘤、平滑肌肉瘤、食道癌、小细胞癌、平滑肌瘤、胆囊癌、非乳头状腺癌、乳头状腺癌、胃癌、胃腺癌、肝癌、肝细胞癌、纤维板层癌、血管肉瘤、淋巴管肉瘤、血管内皮瘤、肝母细胞瘤、胰腺癌、导管腺癌、腺泡腺癌、腺泡细胞癌、胶样癌、巨细胞瘤、肝样癌、粘液性囊性肿瘤、胰母细胞瘤、浆液性囊腺瘤、导管内乳头状粘液性肿瘤、胰腺神经内分泌肿瘤、胃泌素瘤、胰岛瘤、胰高血糖素瘤、血管活性肠肽瘤(VIPoma)、生长抑素瘤、胰多肽瘤(PPoma)、小肠癌、眼癌、眼内黑色素瘤、眼内淋巴瘤、眼内视网膜母细胞瘤、结膜黑色素瘤、眼睑癌、皮脂腺癌、泪腺肿瘤、恶性混合上皮瘤、腺样囊性癌、膀胱癌、尿路上皮癌、肾癌、肾细胞癌(RCC)、透明细胞RCC、乳头状RCC、嫌色细胞RCC、集合管RCC、多房性囊性RCC、肾粘液管状细胞癌和梭形细胞癌、管状囊性RCC、甲状腺样滤泡性RCC、获得性囊性肾病相关的RCC、具有t(6;11)易位(TFEB)的RCC、混合型嗜酸细胞瘤/嫌色细胞RCC、肾母细胞瘤、阴茎癌、前列腺癌、去势抵抗性前列腺癌、移行细胞癌、睾丸癌、精原细胞瘤、典型精原细胞瘤、精细胞精原细胞瘤、非精原细胞瘤、胚胎性癌、卵黄囊癌、绒毛膜癌、畸胎瘤、间质细胞肿瘤、支持细胞肿瘤、睾丸网癌、尿道癌、颅外生殖细胞肿瘤、生殖细胞瘤、性腺母细胞瘤、混合生殖细胞肿瘤、性腺外生殖细胞肿瘤、内胚窦肿瘤、宫颈癌、子宫内膜癌、卵巢癌、输卵管癌、上皮细胞癌、无性细胞瘤、性索间质肿瘤、妊娠滋养细胞肿瘤、原发性腹膜癌、子宫肉瘤、子宫乳头状浆液性癌、阴道癌、透明细胞腺癌、外阴癌、疣状癌、头颈癌、头颈鳞状细胞癌、咽癌、下咽癌、鼻咽癌、口咽癌、非角化性鳞状细胞癌、未分化癌、喉癌、口腔癌、口腔癌、粘液表皮样癌、鼻窦癌和鼻腔癌、感觉神经母细胞瘤、唾液腺癌、上皮肌上皮癌、甲状旁腺癌、甲状腺癌、乳头状甲状腺癌、滤泡性甲状腺癌、许特耳氏细胞癌(Hurthle cell carcinoma)、甲状腺髓质瘤、无结构性甲状腺癌、副神经节瘤、颈动脉副神经节瘤、颈鼓室副神经节瘤、迷走神经副神经节瘤、白血病、急性淋巴细胞性白血病T淋巴细胞白血病、前体B细胞淋巴细胞白血病、急性髓性白血病(AML)、急性髓细胞性白血病、急性早幼粒细胞性白血病、急性粒单核细胞白血病、急性单核细胞性白血病、急性巨核细胞白血病、红白血病、慢性淋巴细胞性白血病、B细胞慢性淋巴细胞白血病、B细胞幼淋巴细胞白血病、T细胞幼淋巴细胞白血病、大颗粒淋巴细胞白血病、T细胞大颗粒淋巴细胞白血病、NK细胞颗粒淋巴细胞白血病、毛细胞白血病、慢性髓细胞性白血病、慢性粒单核细胞白血病、慢性中性粒细胞白血病、慢性嗜酸性粒细胞白血病、浆细胞白血病、淋巴瘤、霍奇金淋巴瘤、经典霍奇金淋巴瘤、结节性硬化性经典霍奇金淋巴瘤、混合细胞性经典霍奇金淋巴瘤、富含淋巴细胞的经典霍奇金淋巴瘤、淋巴细胞耗尽的经典霍奇金淋巴瘤、结节性淋巴细胞为主的霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、弥漫性大B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤、原发性渗出性淋巴瘤、富含T细胞/组织细胞的大B细胞淋巴瘤、淋巴浆细胞淋巴瘤、淋巴母细胞淋巴瘤、小淋巴细胞淋巴瘤、双联性/三联性淋巴瘤、伯基特淋巴瘤、伯基特样淋巴瘤、小非裂解细胞淋巴瘤、滤泡性淋巴瘤、滤泡性大细胞淋巴瘤、免疫母细胞淋巴瘤、血管内大细胞淋巴瘤、原发性脾淋巴瘤、间变性大细胞淋巴瘤、套细胞淋巴瘤、边缘区淋巴瘤(MZL)、结外MZL、节点MZL、脾MZL、脾MZL与绒毛淋巴细胞、外周T细胞淋巴瘤、血管免疫母细胞T细胞淋巴瘤、成人T细胞淋巴瘤/白血病、结外NK/T细胞淋巴瘤、肠病相关T细胞淋巴瘤、肝脾T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤、未另有说明的T细胞非霍奇金淋巴瘤、γ/δT细胞淋巴瘤、粘膜相关淋巴组织淋巴瘤、移植后淋巴增殖性疾病、HIV相关淋巴瘤、朗格汉斯细胞组织细胞增多症、多发性骨髓瘤、闷性多发性骨髓瘤、活动性多发性骨髓瘤、浆细胞瘤、骨孤立性浆细胞瘤、髓外浆细胞瘤、原发性淀粉样变性、骨髓增生异常综合征(MDS)、难治性贫血、难治性贫血伴环状铁粒幼细胞、难治性贫血伴原始细胞过多、难治性贫血伴转化中原始细胞过多、骨髓增生性肿瘤、真性红细胞增多症、原发性血小板增多症、骨髓纤维化、系统性肥大细胞增多症、骨癌、尤文肉瘤、骨肉瘤、髓内骨肉瘤、皮质旁骨肉瘤、骨外骨肉瘤、骨恶性纤维组织细胞瘤、脊索瘤、经典脊索瘤、软骨样脊索瘤、去分化脊索瘤、软骨肉瘤、传统软骨肉瘤、透明细胞软骨肉瘤、粘液样软骨肉瘤、间充质软骨肉瘤、去分化软骨肉瘤、横纹肌肉瘤、胚胎性横纹肌肉瘤、肺泡状横纹肌肉瘤、葡萄状横纹肌肉瘤、多形性横纹肌肉瘤、软组织肉瘤、骨外肉瘤、隆突性皮纤维肉瘤、上皮样肉瘤、卡波西氏肉瘤、脂肪肉瘤、恶性周围神经鞘瘤、纤维肉瘤、黏肉瘤、滑膜瘤、脑癌、间变性星形细胞瘤、胶质母细胞瘤、多形性胶质母细胞瘤、脑膜瘤、垂体癌、神经鞘瘤、少突胶质细胞瘤、室管膜瘤、髓母细胞瘤、星形细胞瘤、脑干胶质瘤、非典型畸胎瘤/横纹肌样瘤、松果体瘤、成神经细胞瘤、原发性CNS淋巴瘤、原始神经外胚层肿瘤、弥漫性内在脑桥胶质瘤、肺癌、非小细胞肺癌(NSCLC)、未分化NSCLC、小细胞肺癌、胸膜肺母细胞瘤、支气管源性癌、恶性间皮瘤、恶性胸膜间皮瘤、恶性腹膜间皮瘤、胸腺瘤、胸腺癌、皮肤癌、角化棘皮瘤、皮脂腺癌、汗腺腺癌、顶浆腺癌,小汗腺癌,透明细胞小汗腺癌、默克尔细胞癌、皮肤T细胞淋巴瘤、蕈样真菌病、塞萨里综合征(Sézary syndrome)、软骨样汗管瘤、HPV相关癌症、含有转化细胞的肿瘤、含有癌前状态细胞的肿瘤、癌前增生、癌前化生、癌前不典型增生、原位癌、混合瘤、恶性混合瘤、和复杂癌。
可以治疗的癌症还包括具有以下的癌症:高肿瘤突变负荷(TMB)、有缺陷的DNA错配修复系统(dMMR)、高微卫星不稳定状态(MSI-H)、低微卫星不稳定状态(MSI-L)、选定的四核苷酸重复处微卫星改变增加(EMAST)、微卫星稳定(MSS)癌症、包含聚合酶δ(POLD)突变的癌症、包含聚合酶ε(POLE)突变的癌症或具有同源重组修复缺陷(HRD)的癌症。
可以治疗的癌症进一步包括通过表达谱定义的乳腺癌(三阴性乳腺癌、HER2阳性乳腺癌、管腔A乳腺癌、管腔B乳腺癌、正常样乳腺癌)或具有BRCA1或BRCA2突变的乳腺癌。
在本发明的一个实施方案中,所治疗的癌症是骨髓增生异常综合征(MDS)、急性髓性白血病(AML)、结直肠癌(CRC)、非霍奇金淋巴瘤(NHL)、黑色素瘤或乳腺癌。在本发明的另一个实施方案中,癌症是急性髓性白血病(AML)。在本发明的另一个实施方案中,癌症是结直肠癌(CRC)。
本发明的治疗方法包括向有需要的患者施用安全有效量的式(I)的化合物或其前药或其药学上可接受的盐。本发明的各个实施方案包括通过向有需要的患者施用安全有效量的式(I)的化合物或其前药或其药学上可接受的盐来治疗任何一种上述障碍的方法。
如本文所用,关于障碍的“治疗”是指:(1)改善或预防障碍或障碍的一种或多种生物学表现,(2)干扰(a)导致或造成障碍的生物级联中的一个或多个点,或(b)障碍的一种或多种生物学表现,(3)减轻一种或多种与障碍相关的症状或影响,或(4)减缓障碍或障碍的一种或多种生物学表现的进展。
如本文所用,涉及式(I)的化合物或其前药、或其药学上可接受的盐、或其他药学活性剂时,“安全有效量”是指在合理的医学判断范围内,该化合物的量足以治疗患者的病症但又足够低以避免严重副作用(合理的效益/风险比)。化合物的安全有效量将根据以下而变化:所选择的特定化合物(例如考虑化合物的效力、功效和半衰期);选择的施用途径;正在治疗的障碍;正在治疗的障碍的严重程度;接受治疗的患者的年龄、体型、体重和身体状况;接受治疗的患者的病史;治疗的持续时间;同步治疗的性质;期望的治疗效果;以及类似的但是仍然可以由技术人员常规地确定的因素。
如本文所用,“患者”是指人类(包括成人和儿童)或其他动物。在一个实施方案中,“患者”是指人类。
因此,本发明涉及治疗与不适当的DNMT1活性相关的疾病的方法,这些方法包括向有需要的患者施用安全且有效量的式(I)的化合物或其前药或其药学上可接受的盐。
在一个实施方案中,本发明提供了一种治疗癌症、癌前综合征或β血红蛋白病障碍的方法,该方法包括向有需要的患者施用安全有效量的式(I)的化合物或其前药或其药学上可接受的盐。
在另一个实施方案中,本发明提供了治疗癌症、癌前综合征或β血红蛋白病障碍的方法,该方法包括向有需要的患者施用安全有效量的式(I)的化合物或其前药或其药学上可接受的盐。
在另一个实施方案中,本发明提供了治疗骨髓增生异常综合征(MDS)、急性髓性白血病(AML)、结直肠癌(CRC)、非霍奇金淋巴瘤(NHL)、黑素瘤或乳腺癌的方法,该方法包括向有需要的患者施用安全有效量的式(I)的化合物或其前药或其药学上可接受的盐。
在另一个实施方案中,本发明提供了治疗急性髓性白血病(AML)的方法,该方法包括向有需要的患者施用安全有效量的式(I)的化合物或其前药或其药学上可接受的盐。
在另一个实施方案中,本发明提供了治疗结直肠癌(CRC)的方法,该方法包括向有需要的患者施用安全有效量的式(I)的化合物或其前药或其药学上可接受的盐。
在另一个实施方案中,本发明提供了治疗镰状细胞病(sickle cell disease)、镰状细胞贫血(sickle cell anemia)或β地中海贫血(beta thalassemia)的方法,该方法包括向有需要的患者施用安全有效量的式(I)的化合物或其前药或其药学上可接受的盐。镰状细胞性贫血是一种单一的特定疾病,其特征是两个β珠蛋白基因等位基因均出现纯合E6V突变。相比之下,镰状细胞病是几种相关疾病的集合,所有疾病都表现出不同严重程度的相似症状。镰状细胞病患者的一个β珠蛋白基因等位基因带有E6V突变(像镰状细胞贫血那样),第二个β珠蛋白基因等位基因携带任意数量的突变,尤其是导致β地中海贫血的突变。最常见的镰状细胞病表现称为“镰状细胞β零”和“镰状细胞β+”,但也有其他表现。请注意,镰状细胞病患者的第二个β珠蛋白等位基因并非没有突变(一个E6Vβ珠蛋白等位基因加上一个正常的β珠蛋白等位基因被称为镰状细胞性状,这不是完全良性的,但通常不进行治疗),但只是第二个等位基因的突变不是E6V突变。请注意,镰状细胞性状不被视为镰状细胞病。
本发明进一步涉及式(I)的化合物或其前药或其药学上可接受的盐,用于医学疗法中。
本发明进一步涉及式(I)的化合物或其前药或其药学上可接受的盐,用于治疗与不适当的DNMT1活性相关的疾病。
本发明还进一步涉及式(I)的化合物或其前药或其药学上可接受的盐在制备用于治疗与不适当的DNMT1活性相关的疾病的药物中的用途。
式(I)的化合物及其前药及其药学上可接受的盐通常但不必然在施用于患者之前配制成药物组合物。
因此,一方面,本发明涉及药物组合物,其包含式(I)的化合物或其前药或其药学上可接受的盐,以及一种或多种药学上可接受的赋形剂。
另一方面,本发明涉及药物组合物,其包含0.5mg至3500mg的式(I)的化合物或其前药或其药学上可接受的盐,和0.1g至2g的一种或多种药学上可接受的赋形剂。
另一方面,本发明涉及用于治疗由不适当的DNMT1活性介导的疾病的药物组合物,其包含式(I)的化合物或其前药或其药学上可接受的盐。
式(I)的化合物或其前药或其药学上可接受的盐可以通过任何合适的施用途径施用,包括全身施用和局部施用。全身施用包括口服施用、肠胃外施用、透皮施用和直肠施用。肠胃外施用是指肠内或透皮以外的施用途径,并且通常通过注射或输注施用。肠胃外施用包括静脉内、肌肉内和皮下注射或输注。局部施用包括施用于皮肤以及眼内、耳内、阴道内、吸入和鼻内施用。吸入是指通过口腔或鼻腔吸入患者的肺部。在一个实施方案中,式(I)的化合物或其前药或其药学上可接受的盐可以口服施用。
在一些实施方案中,式(I)的化合物的某些前药可能特别适合口服施用,因为溶解度改善导致口服生物利用度增加。
式(I)的化合物或其前药或其药学上可接受的盐可以一次施用或根据给药方案施用,其中在给定的时间段内以不同的时间间隔施用多个剂量。例如,剂量可以每天施用一次、两次、三次、四次、五次或六次。可以施用剂量直至实现所期望的治疗效果或无限期地维持所期望的治疗效果。式(I)的化合物或其前药或其药学上可接受的盐的合适给药方案取决于该化合物的药代动力学性质,例如吸收、分布和半衰期,其可以由技术人员确定。此外,式(I)的化合物或其前药或其药学上可接受的盐的合适的给药方案,包括施用该方案的持续时间,取决于所治疗的障碍、所治疗的疾病的严重程度、待治疗患者的年龄和健康状况、待治疗患者的病史、伴随疗法的性质、期望的治疗效果以及本领域技术人员的知识和专业知识内的类似因素。本领域技术人员还应当理解,考虑到个体患者对给药方案的应答或者个体患者需求随时间的变化,合适的给药方案可能需要调整。
如上所述的药物剂量单位中的本发明的药物活性化合物的剂量将是有效的、无毒的量,优选选自0.001-500mg/kg活性化合物、优选0.01-100mg/kg的范围。当治疗需要DNMT1抑制剂的人类患者时,所选择的剂量优选每天口服或肠胃外施用1-6次。肠胃外施用的优选形式包括局部、直肠、经皮、通过注射和连续输注。用于人类施用的口服剂量单位优选含有0.5mg至3500mg的活性化合物。用于人类施用的合适的口服剂量单位优选含有0.5mg至1,000mg的活性化合物。优选口服施用,其剂量较低。然而,在对患者安全且方便的情况下,也可以使用高剂量的肠胃外施用。
式(I)的化合物及其药学上可接受的盐通常但不必然在施用于患者之前配制成药物组合物。
因此,一方面,本发明涉及药物组合物,其包含式(I)的化合物或其药学上可接受的盐,以及一种或多种药学上可接受的赋形剂。
另一方面,本发明涉及药物组合物,其包含0.05mg至1000mg的式(I)的化合物或其药学上可接受的盐,和0.1g至2g的一种或多种药学上可接受的赋形剂。
另一方面,本发明涉及用于治疗或预防由不适当的DNMT1活性介导的障碍的药物组合物,其包含式(I)的化合物或其药学上可接受的盐。
本发明的药物组合物可以以散装形式制备和包装,其中可以提取安全有效量的式(I)的化合物或其药学上可接受的盐,然后例如以粉末或糖浆的形式给予患者。可替代地,本发明的药物组合物可以以单位剂型制备和包装,其中每个物理离散的单位含有式(I)的化合物或其药学上可接受的盐。当以单位剂量形式制备时,本发明的药物组合物通常可含有例如0.5mg至1,000mg、或1mg至700mg、或5mg至100mg的式(I)的化合物或其前药或其药学上可接受的盐。
本发明的药物组合物通常含有一种式(I)的化合物或其前药或其药学上可接受的盐。
本文所用的“药学上可接受的赋形剂”是指参与赋予药物组合物形式或稠度的药学上可接受的材料、组合物或媒介物。当混合时,每种赋形剂必须与药物组合物的其他成分相容,以避免当施用给患者时会显著降低式(I)的化合物或其前药或其药学上可接受的盐的功效的相互作用,以及会导致药物组合物不可药用的相互作用。此外,每种赋形剂当然必须是药学上可接受的,例如具有足够高的纯度。
式(I)的化合物或其前药或其药学上可接受的盐和药学上可接受的一种或多种赋形剂通常被配制成适合于通过期望的施用途径向患者施用的剂型。例如,剂型包括(1)适合于口服施用的剂型,例如片剂、胶囊剂、囊片剂、丸剂、锭剂、粉剂、糖浆剂、酏剂、混悬剂、溶液、乳剂、袋剂和扁囊剂;(2)肠胃外施用,如无菌溶液、混悬剂、复溶粉剂等;(3)透皮施用,例如透皮贴剂;(4)直肠施用,如栓剂;(5)吸入,例如气雾剂、溶液、干粉剂;以及(6)局部施用,例如霜剂、软膏剂、洗剂、溶液、糊剂、喷雾剂、泡沫剂和凝胶剂。
合适的药学上可接受的赋形剂将根据所选择的具体剂型而变化。此外,可以针对它们可以在组合物中发挥的特定功能来选择合适的药学上可接受的赋形剂。例如,可以根据某些药学上可接受的赋形剂促进均匀剂型生产的能力来选择它们。可以根据某些药学上可接受的赋形剂促进稳定剂型生产的能力来选择它们。可以选择某些药学上可接受的赋形剂,因为一旦从一个器官或身体的一部分施用于患者,它们有利于携带或运输式(I)的化合物或其前药或其药学上可接受的盐到另一个器官或身体的一部分。可以根据某些药学上可接受的赋形剂增强患者依从性的能力来选择它们。
合适的药学上可接受的赋形剂包括以下类型的赋形剂:稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、造粒剂、包衣剂、湿润剂、溶剂、助溶剂、悬浮剂、乳化剂、甜味剂、矫味剂、掩味剂、着色剂、抗结剂、半透明剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。技术人员将理解,某些药学上可接受的赋形剂可以起到多于一种的功能,并且可以起到替代性的功能,这取决于配制品中存在多少赋形剂以及配制品中存在哪些其他赋形剂。
技术人员拥有本领域的知识和技能,使得他们能够以适当的量选择合适的药学上可接受的赋形剂用于本发明。此外,有许多技术人员可获得的资源描述了药学上可接受的赋形剂并且可用于选择合适的药学上可接受的赋形剂。示例包括Remington's Pharmaceutical Sciences(Mack Publishing Company)、The Handbook of Pharmaceutical Additives(Gower Publishing Limited)和The Handbook of Pharmaceutical Excipients(American Pharmaceutical Association and thePharmaceutical Press)。
本发明的药物组合物使用本领域技术人员已知的技术和方法制备。Remington's Pharmaceutical Sciences(Mack Publishing Company)中描述了本领域常用的一些方法。
因此,在另一方面,本发明涉及制备包含式(I)的化合物或其前药或其药学上可接受的盐和一种或多种药学上可接受的赋形剂的药物组合物的方法,该方法包括将各成分混合。包含式(I)的化合物或其前药或其药学上可接受的盐的药物组合物可以通过例如在环境温度和大气压下混合来制备。
在一个实施方案中,式(I)的化合物或其前药或其药学上可接受的盐将配制用于口服施用。在另一个实施方案中,式(I)的化合物或其前药或其药学上可接受的盐将被配制用于肠胃外施用。
一方面,本发明涉及固体口服剂型,例如片剂或胶囊,其包含安全有效量的式(I)的化合物或其前药或其药学上可接受的盐,以及稀释剂或填充剂。合适的稀释剂和填充剂包括乳糖、蔗糖、右旋糖、甘露醇、山梨醇、淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、纤维素及其衍生物(例如微晶纤维素)、硫酸钙和磷酸氢钙。口服固体剂型还可包含粘合剂。合适的粘合剂包括淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、明胶、阿拉伯胶、海藻酸钠、海藻酸、黄蓍胶、瓜尔胶、聚维酮和纤维素及其衍生物(例如微晶纤维素)。口服固体剂型还可包含崩解剂。合适的崩解剂包括交聚维酮、羟基乙酸淀粉钠、交联羧甲基纤维素、海藻酸和羧甲基纤维素钠。口服固体剂型还可包含润滑剂。合适的润滑剂包括硬脂酸、硬脂酸镁、硬脂酸钙和滑石粉。
在适当的情况下,用于口服施用的剂量单位配制品可以被微囊化。还可以制备组合物以延长或持续释放,例如通过将颗粒材料涂覆或嵌入聚合物、蜡等中。
式(I)的化合物或其前药或其药学上可接受的盐还可以与作为可靶向药物载剂的可溶性聚合物偶联。此类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天冬酰胺苯酚或被棕榈酰残基取代的聚环氧乙烷聚赖氨酸。此外,式(I)的化合物或其前药或其药学上可接受的盐可以与用于实现药物控释的一类生物可降解聚合物偶联,例如聚乳酸、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。
另一方面,本发明涉及液体口服剂型。口服液体例如溶液、糖浆剂和酏剂可以以剂量单位形式制备,使得给定量含有预定量的式(I)的化合物或其前药或其药学上可接受的盐。糖浆剂可以通过将式(I)的化合物或其前药或其药学上可接受的盐溶解在适当调味的水溶液中来制备,而酏剂可以通过使用无毒的醇载剂来制备。悬浮液可以通过将式(I)的化合物或其前药或其药学上可接受的盐分散在无毒载剂中来配制。还可以添加增溶剂和乳化剂例如乙氧基化异硬脂醇和聚氧乙烯山梨醇醚、防腐剂、风味添加剂例如薄荷油或天然甜味剂或糖精或其他人造甜味剂等。
适合肠胃外施用的药物组合物包括水性和非水性无菌注射溶液,其可含有抗氧化剂、缓冲剂、抑菌剂和使配制品与预期接受者的血液等渗的溶质;以及可包含悬浮剂和增稠剂的水性和非水性无菌悬浮液。组合物可以存在于单位剂量或多剂量容器中,例如密封的安瓿和小瓶中,并且可以储存在冷冻干燥(冻干)条件下,仅需要添加无菌液体载剂,例如注射用水,在使用前立即添加。临时注射溶液和悬浮液可以由无菌粉末、颗粒和片剂制备。
式(I)的化合物或其前药或其药学上可接受的盐可以与一种或多种其他活性剂共同施用。因此,在一个实施方案中,本发明提供了包含式(I)的化合物或其前药或其药学上可接受的盐和一种或多种其他活性剂的组合。在进一步的实施方案中,已知其他活性剂可用于治疗癌症或癌前综合征。
本文所用术语“共同施用”是指同时施用或以任何方式分别顺序施用本文所述的DMNT1活性抑制剂和已知可用于癌症治疗(包括化疗和放疗)的另一种活性剂。如本文所用,术语“活性成分”、“多个活性成分”、“活性剂”或“多个活性剂”还包括已知的或在施用于患者时表现出有利特性的任何化合物或治疗剂。优选地,如果施用不同时,则化合物在彼此接近的时间施用。此外,化合物是否以相同的剂型施用并不重要,例如一种化合物可以通过注射施用,而另一种化合物可以通过口服施用。
通常,对所治疗的易感肿瘤具有活性的任何抗肿瘤剂可以在本发明的癌症治疗中共同施用。此类药剂的实例可以在以下中找到:Cancer Principles and Practice ofOncology,V.T.Devita,T.S.Lawrence,和S.A.Rosenberg(editors),第10版(2014年12月5日),Lippincott Williams&Wilkins Publishers。本领域普通技术人员将能够基于药物和所涉及的癌症的具体特征来辨别哪些药剂的组合是有用的。可用于本发明的典型抗肿瘤剂包括但不限于抗微管剂或抗有丝分裂剂;铂配位络合物;烷化剂;抗生素剂;I型拓扑异构酶抑制剂;拓扑异构酶II抑制剂;抗代谢药;激素和激素类似物;信号转导途径抑制剂;非受体酪氨酸激酶血管生成抑制剂;免疫治疗剂;促凋亡剂;细胞周期信号抑制剂;蛋白酶体抑制剂;热休克蛋白抑制剂;癌症代谢抑制剂;和癌症基因治疗剂。
与式(I)的化合物或其前药或其药学上可接受的盐组合使用或共同施用的另外一种或多种活性成分的实例是抗肿瘤剂。抗肿瘤剂的实例包括但不限于化疗剂;免疫调节药剂;免疫调节剂;和免疫刺激佐剂。
抗微管剂或抗有丝分裂剂是在细胞周期的M期或有丝分裂期期间对肿瘤细胞的微管有活性的周期特异性(phase specific)药剂。抗微管剂的实例包括但不限于二萜类化合物和长春花生物碱。
铂配位络合物是非周期特异性抗癌剂,可与DNA相互作用。铂络合物进入肿瘤细胞,发生水化,并与DNA形成链内和链间交联,对肿瘤产生不利的生物效应。铂配位络合物的实例包括但不限于顺铂和卡铂。
烷基化剂是非相抗癌特异性剂和强亲电子剂。通常,烷基化剂通过烷基化,通过DNA分子的亲核部分,如磷酸、氨基、巯基、羟基、羧基和咪唑基团,与DNA形成共价键。这种烷基化破坏核酸功能,导致细胞死亡。烷基化剂的实例包括但不限于氮芥类如环磷酰胺、美法仑和苯丁酸氮芥;烷基磺酸盐,例如白消安;亚硝基脲类,例如卡莫司汀;和三氮烯如达卡巴嗪。
抗生素抗肿瘤药物是非周期特异性药剂,可与DNA结合或嵌入。这种作用破坏了核酸的正常功能,导致细胞死亡。抗生素抗肿瘤剂的实例包括但不限于放线菌素,例如更生霉素;蒽环霉素,例如柔红霉素和多柔比星;和博莱霉素。
拓扑异构酶I抑制剂包括但不限于喜树碱。喜树碱的细胞毒活性被认为与其拓扑异构酶I抑制活性有关。
拓扑异构酶II抑制剂包括但不限于表鬼臼毒素。表鬼臼毒素是源自曼德拉草的周期特异性抗肿瘤剂。表鬼臼毒素通常通过与拓扑异构酶II和DNA形成三元复合物导致DNA链断裂,影响细胞周期的S期和G2期的细胞。链断裂累积,随后细胞死亡。表鬼臼毒素的实例包括但不限于依托泊苷和替尼泊苷。
抗代谢肿瘤剂是周期特异性抗肿瘤剂,其通过抑制DNA合成或通过抑制嘌呤或嘧啶碱基合成从而抑制DNA合成而在细胞周期的S期(DNA合成)起作用。因此,S期不会进行,随后细胞死亡。抗代谢抗肿瘤剂的实例包括但不限于氟尿嘧啶、甲氨蝶呤、阿糖胞苷、巯基嘌呤、硫鸟嘌呤和吉西他滨。
激素和激素类似物是用于治疗癌症的有用化合物,其中一种或多种激素与癌症的生长和/或缺乏生长之间存在关系。可用于癌症治疗的激素和激素类似物的实例包括但不限于肾上腺皮质类固醇,例如泼尼松和泼尼松龙;氨鲁米特和其他芳香酶抑制剂,例如阿那曲唑、来曲唑、沃唑和依西美坦;孕激素,例如醋酸甲地孕酮;雌激素、雄激素和抗雄激素,例如氟他胺、尼鲁米特、比卡鲁胺、醋酸环丙孕酮和5α-还原酶,例如非那雄胺和度他雄胺;抗雌激素,例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬、碘氧芬,以及选择性雌激素受体调节剂(SERMS);和促性腺激素释放激素(GnRH)及其类似物,其刺激促黄体生成素(LH)和/或卵泡刺激素(FSH)、LHRH激动剂和拮抗剂如醋酸戈舍瑞林和亮丙瑞林的释放。
信号转导途径抑制剂是那些阻断或抑制引起细胞内变化的化学过程的抑制剂。如本文所用,这种变化是细胞增殖或分化。可用于本发明的信号转导抑制剂包括但不限于受体酪氨酸激酶、非受体酪氨酸激酶、SH2/SH3结构域阻断剂、丝氨酸/苏氨酸激酶、磷脂酰肌醇-3激酶、肌醇信号传导和Ras癌基因的抑制剂。
几种蛋白质酪氨酸激酶催化参与细胞生长调节的各种蛋白质中特定酪氨酰残基的磷酸化。此类蛋白酪氨酸激酶可大致分为受体或非受体激酶。
受体酪氨酸激酶是具有胞外配体结合结构域、跨膜结构域和酪氨酸激酶结构域的跨膜蛋白。受体酪氨酸激酶参与细胞生长的调节,通常称为生长因子受体。许多这些激酶的不适当或不受控制的激活,即异常的激酶生长因子受体活性,例如通过过度表达或突变,已被证明会导致不受控制的细胞生长。因此,此类激酶的异常活性与恶性组织生长有关。因此,此类激酶的抑制剂可以提供癌症治疗方法。生长因子受体包括例如表皮生长因子受体(EGFr)、血小板衍生的生长因子受体(PDGFr)、erbB2、erbB4、血管内皮生长因子受体(VEGFR)、具有免疫球蛋白样和表皮生长因子同源结构域的酪氨酸激酶(TIE-2)、胰岛素生长因子–I(IGFI)受体、巨噬细胞集落刺激因子Cfms、BTK、ckit、cmet、成纤维细胞生长因子(FGF)受体、Trk受体(TrkA、TrkB和TrkC)、肝配蛋白(eph)受体和RET原癌基因。几种生长受体抑制剂正在开发中,包括配体拮抗剂、抗体、酪氨酸激酶抑制剂和反义寡核苷酸。生长因子受体和抑制生长因子受体功能的药剂描述于例如Kath J.C.,Exp.Opin.Ther.Patents,10(6):803-818(2000);Shawver L.K.,等人,Drug Discov.Today,2(2):50-63(1997);和Lofts,F.J.和Gullick W.J.,“Growth factor receptors as targets.”New MolecularTargets for Cancer Chemotherapy,Kerr D.J.和Workman P.(编辑),(1994年6月27日),CRC Press。生长因子受体抑制剂的非限制性实例包括帕唑帕尼和索拉非尼。
酪氨酸激酶不是生长因子受体激酶,被称为非受体酪氨酸激酶。用于本发明的非受体酪氨酸激酶(其是抗癌药物的靶标或潜在靶标)包括cSrc、Lck、Fyn、Yes、Jak、cAbl、FAK(粘着斑激酶)、Brutons酪氨酸激酶和Bcr-Abl。此类非受体激酶和抑制非受体酪氨酸激酶功能的药剂描述于Sinha S.和Corey S.J.,J.Hematother.Stem Cell Res.,8(5):465-480(2004)和Bolen,J.B.,Brugge,J.S.,Annu.Rev.Immunol.,15:371-404(1997)。
SH2/SH3结构域阻断剂是破坏多种酶或衔接蛋白(包括PI3-K p85亚基、Src家族激酶、衔接分子(Shc、Crk、Nck、Grb2)和Ras-GAP)中SH2或SH3结构域结合的试剂。SH2/SH3结构域作为抗癌药物的靶标讨论于Smithgall T.E.,J.Pharmacol.Toxicol.Methods,34(3):125-32(1995)。
丝氨酸/苏氨酸激酶抑制剂包括但不限于MAP激酶级联阻断剂,其包括Raf激酶(rafk)、丝裂原或胞外调节激酶(MEK)和胞外调节激酶(ERK)的阻断剂;蛋白激酶C家族成员阻断剂,包括PKC阻断剂(α、β、γ、ε、μ、λ、ι、ζ);IkB激酶(IKKa、IKKb);PKB家族激酶;AKT激酶家族成员;TGFβ受体激酶;和哺乳动物雷帕霉素靶点(mTOR)抑制剂,包括但不限于雷帕霉素(FK506)和雷帕霉素类似物、RAD001或依维莫司CCI-779或替西罗莫司、AP23573、AZD8055、WYE-354、WYE-600、WYE-687和Pp121。丝氨酸/苏氨酸激酶抑制剂的实例包括但不限于曲美替尼、达拉非尼和Akt抑制剂阿芙罗替尼(afuresertib)和N-{(1S)-2-氨基-1-[(3,4-二氟苯基)甲基]乙基}-5-氯-4-(4-氯-1-甲基-1H-吡唑-5-基)-2-呋喃甲酰胺。
磷脂酰肌醇3-激酶家族成员的抑制剂(包括PI3-激酶阻断剂、ATM、DNA-PK和Ku)也可用于本发明。此类激酶讨论于Abraham R.T.,Curr.Opin.Immunol.,8(3):412-418(1996);Canman C.E.,and Lim D.S.,Oncogene,17(25):3301-3308(1998);Jackson S.P.,Int.J.Biochem.Cell Biol.,29(7):935-938(1997);和Zhong H.,等人,Cancer Res.,60(6):1541-1545(2000)。
肌醇信号传导抑制剂例如磷脂酶C阻断剂和肌醇类似物也可用于本发明。此类信号抑制剂在以下中描述:Powis G.,和Kozikowski A.,“Inhibitors of Myo-InositolSignaling.”New Molecular Targets for Cancer Chemotherapy,Kerr D.J.and WorkmanP.(编辑),(1994年6月27日),CRC Press。
另一组信号转导途径抑制剂是Ras癌基因的抑制剂。此类抑制剂包括法呢基转移酶、香叶基-香叶基转移酶和CAAX蛋白酶以及反义寡核苷酸、核酶和其他免疫疗法的抑制剂。此类抑制剂已被证明可以阻断含有野生型突变体ras的细胞中的ras激活,从而起到抗增殖剂的作用。Ras癌基因抑制讨论于:Scharovsky O.G.,等人,J.Biomed.Sci.,7(4):292-298(2000);Ashby M.N.,Curr.Opin.Lipidol.,9(2):99-102(1998);和Bennett C.F.和Cowsert L.M.,Biochim.Biophys.Acta.,1489(1):19-30(1999)。
受体激酶配体结合的拮抗剂也可用作信号转导抑制剂。这组信号转导途径抑制剂包括使用人源化抗体或受体酪氨酸激酶的胞外配体结合结构域的其他拮抗剂。受体激酶配体结合的抗体或其他拮抗剂的实例包括但不限于西妥昔单抗曲妥珠单抗曲妥珠单抗-厄塔毒素偶联物/>帕妥珠单抗ErbB抑制剂包括拉帕替尼、厄洛替尼和吉非替尼;和2C3 VEGFR2特异性抗体(参见Brekken R.A.,等人,Cancer Res.,60(18):5117-5124(2000))。
非受体激酶血管生成抑制剂也可用于本发明。血管生成相关的VEGFR和TIE2的抑制剂在上面关于信号转导抑制剂(两种受体都是受体酪氨酸激酶)中讨论。血管生成通常与erbB2/EGFR信号传导相关,因为erbB2和EGFR抑制剂已被证明可以抑制血管生成,主要是抑制VEGF表达。因此,非受体酪氨酸激酶抑制剂可以与本发明的EGFR/erbB2抑制剂组合使用。例如,抗VEGF抗体,它不识别VEGFR(受体酪氨酸激酶),但与配体结合;整合素(αvβ3)的小分子抑制剂会抑制血管生成;内皮抑素和血管抑素(非RTK)也可证明与所公开的化合物组合是有用的。(参见Bruns C.J.,等人,Cancer Res.,60(11):2926-2935(2000);SchreiberA.B.,等人,Science,232(4755):1250-1253(1986);Yen L.,等人,Oncogene,19(31):3460-3469(2000))。
免疫治疗方案中使用的药剂也可与本发明组合使用。有多种免疫策略可产生针对erbB2或EGFR的免疫应答。这些策略通常属于肿瘤疫苗接种领域。通过使用小分子抑制剂联合抑制erbB2/EGFR信号传导通路,可以大大增强免疫学方法的功效。针对erbB2/EGFR的免疫学/肿瘤疫苗方法的讨论可见于Reilly R.T.,等人,Cancer Res.,60(13):3569-3576(2000);和Chen Y.,等人,Cancer Res.,58(9):1965-1971(1998)。
用于促凋亡方案的药剂(例如,Bcl-2反义寡核苷酸)也可以用于本发明的组合中。Bcl-2蛋白家族的成员可阻止细胞凋亡。因此,Bcl-2的上调与化疗耐药有关。研究表明,表皮生长因子(EGF)可刺激Bcl-2家族的抗凋亡成员(即Mcl-1)。因此,旨在下调肿瘤中Bcl-2表达的策略已证明具有临床益处。这种使用Bcl-2反义寡核苷酸策略的促凋亡策略讨论于Waters J.S.,等人,J.Clin.Oncol.,18(9):1812-1823(2000);和Kitada S.,等人,Antisense Res.Dev.,4(2):71-79(1994)。
细胞周期信号传导抑制剂抑制参与细胞周期控制的分子。称为细胞周期蛋白依赖性激酶(CDK)的蛋白激酶家族及其与称为细胞周期蛋白的蛋白质家族的相互作用控制着真核细胞周期的进展。不同细胞周期蛋白/CDK复合物的协调激活和失活对于细胞周期的正常进展是必要的。几种细胞周期信号传导抑制剂正在开发中。例如,细胞周期蛋白依赖性激酶(包括CDK2、CDK4和CDK6)及其抑制剂的实例描述于例如Rosania G.R.,和Chang Y.T.,Exp.Opin.Ther.Patents,10(2):215-230(2000)。此外,p21WAF1/CIP1已被描述为细胞周期蛋白依赖性激酶(Cdks)的有效且通用的抑制剂(Ball K.L.,Prog.Cell Cycle Res.,3:125-134(1997))。已知诱导p21WAF1/CIP1表达的化合物涉及细胞增殖的抑制并具有肿瘤抑制活性(Richon V.M.,等人,Proc.Natl.Acad.Sci.USA,97(18):10014-10019(2000)),并被列为细胞周期信号传导抑制剂。组蛋白脱乙酰酶(HDAC)抑制剂涉及p21WAF1/CIP1的转录激活(Vigushin D.M.,和Coombes R.C.,Anticancer Drugs,13(1):1-13(2002)),并且是在本文中组合使用的合适的细胞周期信号传导抑制剂。此类HDAC抑制剂的实例包括但不限于伏立诺他、罗米地辛、帕比司他、丙戊酸和莫西司他。
蛋白酶体抑制剂是阻断蛋白酶体作用的药物,蛋白酶体是分解蛋白质(如p53蛋白质)的细胞复合物。几种蛋白酶体抑制剂已上市或正在研究用于治疗癌症。在本文中组合使用的合适的蛋白酶体抑制剂包括但不限于硼替佐米、双硫仑、表没食子儿茶素没食子酸酯、盐孢酰胺A和卡非佐米。
70千道尔顿热休克蛋白(Hsp70s)和90千道尔顿热休克蛋白(Hsp90s)是普遍表达的热休克蛋白家族。Hsp70和Hsp90在某些癌症类型中过度表达。几种Hsp70和Hsp90抑制剂正在研究用于治疗癌症。在本文中组合使用的Hsp70和Hsp90抑制剂的实例包括但不限于坦斯匹霉素(tanespimycin)和根赤壳菌素。
许多肿瘤细胞表现出与正常组织明显不同的代谢。例如,糖酵解(将葡萄糖转化为丙酮酸的代谢过程)的速率增加,并且生成的丙酮酸被还原为乳酸,而不是通过三羧酸(TCA)循环在线粒体中进一步氧化。即使在有氧条件下,这种效应也经常出现,被称为瓦伯格效应。
乳酸脱氢酶A(LDH-A)是肌肉细胞中表达的乳酸脱氢酶的同种型,通过将丙酮酸还原为乳酸,然后将其输出到细胞外,在肿瘤细胞代谢中发挥着关键作用。该酶已被证明在许多肿瘤类型中表达上调。瓦伯格效应中描述的葡萄糖代谢的改变对于癌细胞的生长和增殖至关重要,并且使用RNA-i敲低LDH-A已被证明可导致异种移植模型中细胞增殖和肿瘤生长的减少(Tennant D.A.,等人,Nat.Rev.Cancer,10(4):267-277(2010);Fantin V.R.,等人,Cancer Cell,9(6):425-434(2006))。
在癌症前期病变中发现了高水平的脂肪酸合酶(FAS)。FAS的药理抑制会影响与癌症发展和维持相关的关键癌基因的表达。Alli P.M.,等人,Oncogene,24(1):39-46(2005)。
癌症代谢抑制剂,包括LDH-A抑制剂和脂肪酸生物合成抑制剂(或FAS抑制剂),适合在本文中组合使用。
癌症基因疗法涉及使用病毒或非病毒基因递送载体选择性转移重组DNA/RNA,以修饰癌症调用以达到治疗目的。癌症基因疗法的实例包括但不限于自杀和溶瘤基因疗法,以及过继性T细胞疗法。
如本文所用,“免疫调节剂”是指影响免疫系统的任何物质,包括单克隆抗体。本发明的式(I)的化合物或其前药或其药学上可接受的盐可以被认为是免疫调节剂。免疫调节剂可用作治疗癌症的抗肿瘤剂。例如,免疫调节剂包括但不限于CTLA-4的抗体或其他拮抗剂,例如伊匹单抗和曲美木单抗;PD-1,例如多斯塔利单抗(dostarlimab)、纳武单抗/>派姆单抗/>和西米普利单抗/>和TIM-3,例如考伯利单抗(cobolimab)。其他免疫调节剂包括但不限于PD-L1、OX-40、LAG3、TIM-3、41BB和GITR的抗体或其他拮抗剂。
如本文所用,“PD-1拮抗剂”是指任何化合物或生物分子,所述化合物或生物分子阻断癌细胞上表达的PD-L1与免疫细胞(T细胞、B细胞或NKT细胞)上表达的PD-1的结合,优选地还阻断在癌细胞上表达的PD-L2与免疫细胞表达的PD-1的结合。PD-1及其配体的可替代名称或同义词包括:PD-1的PDCD1、PD1、CD279和SLEB2;PD-L1的PDCD1L1、PDL1、B7H1、B7-4、CD274和B7-H;和PD-L2的PDCD1L2、PDL2、B7-DC、Btdc和CD273。人PD-1氨基酸序列可在NCBI基因座号:NP_005009中找到。人PD-L1和PD-L2氨基酸序列可分别在NCBI基因座号:NP_054862和NP_079515中找到。
可用于本发明的任何方面的PD-1拮抗剂包括单克隆抗体(mAb)或其抗原结合片段,其特异性结合PD-1或PD-L1,并优选特异性结合人PD-1或人PD-L1。mAb可以是人抗体、人源化抗体或嵌合抗体,并且可以包括人恒定区。在一些实施方案中,人恒定区选自由IgG1、IgG2、IgG3和IgG4恒定区组成的组,并且在优选的实施方案中,人恒定区是IgG1或IgG4恒定区。在一些实施方案中,抗原结合片段选自由Fab、Fab'-SH、F(ab')2、scFv和Fv片段组成的组。
与人PD-1结合并可用于本发明的各个方面和实施方案的mAb的实例描述于美国专利号8,552,154;美国专利号8,354,509;美国专利号8,168,757;美国专利号8,008,449;美国专利号7,521,051;美国专利号7,488,802;WO2004072286;WO2004056875;和WO2004004771中。
在本发明的任何方面和实施方案中有用的其他PD-1拮抗剂包括特异性结合PD-1的免疫粘附素,优选特异性结合人PD-1的免疫粘附素,例如含有与免疫球蛋白分子的恒定区如Fc区融合的PD-L1或PD-L2的胞外或PD-1结合部分的融合蛋白。特异性结合PD-1的免疫粘附素分子的实例描述于WO2010027827和WO2011066342中。在本发明的治疗方法、药物和用途中可用作PD-1拮抗剂的具体融合蛋白包括AMP-224(也称为B7-DCIg),其是PD-L2-FC融合蛋白并结合人PD-1。
纳武单抗是一种人源化单克隆抗PD-1抗体,商品名为纳武单抗适用于治疗一些不可切除或转移性黑色素瘤。纳武单抗通过其配体PD-L1和PD-L2结合并阻断PD-1(一种Ig超家族跨膜蛋白)的激活,从而激活T细胞和针对肿瘤细胞或病原体的细胞介导的免疫应答。激活的PD-1通过抑制P13k/Akt通路激活来负调节T细胞激活和效应子功能。纳武单抗的其他名称包括:BMS-936558、MDX-1106和ONO-4538。纳武单抗的氨基酸序列以及使用和制备方法公开于美国专利号US 8,008,449中。
派姆单抗是一种人源化单克隆抗PD-1抗体,商品名为派姆单抗适用于治疗一些不可切除或转移性黑色素瘤。派姆单抗的氨基酸序列和使用方法公开于美国专利号8,168,757中。
抗PD-L1抗体及其制备方法是本领域已知的。此类PD-L1抗体可以是多克隆的或单克隆的,和/或重组的,和/或人源化的。PD-L1抗体正在开发作为治疗癌症的免疫调节剂。
示例性的PD-L1抗体公开于美国专利号9,212,224;美国专利号8,779,108;美国专利号8,552,154;美国专利号8,383,796;美国专利号8,217,149;美国专利公开号20110280877;WO2013079174;和WO2013019906中。其他示例性PD-L1抗体(也称为CD274或B7-H1)及其使用方法公开于美国专利号8,168,179;美国专利号7,943,743;美国专利号7,595,048;WO2014055897;WO2013019906;和WO2010077634中。在本发明的治疗方法、药物和用途中可用作PD-1拮抗剂的具体抗人PD-L1单克隆抗体包括MPDL3280A、BMS-936559、MEDI4736、MSB0010718C。
阿特珠单抗是一种完全人源化的单克隆抗PD-L1抗体,商品名为阿特珠单抗适用于治疗某些局部晚期或转移性尿路上皮癌。阿特珠单抗阻断PD-L1与PD-1和CD80的相互作用。其他示例性PD-L1抗体包括阿维鲁单抗/>和度伐鲁单抗/>
靶向PD-1或PD-L1以及另一靶标的双功能融合蛋白也可用于本发明。Bintrafuspalfa是一种双功能融合蛋白,设计用于同时阻断PD-L1和TGF-β途径,在美国专利号9,676,863中公开。
CD134,也称为OX40,是TNFR受体超家族的成员,与CD28不同,它不在静息幼稚T细胞上组成型表达。OX40是一种次级共刺激分子,在激活后24至72小时后表达;它的配体OX40L也不在静息抗原呈递细胞上表达,但随着它们的激活而表达。OX40的表达取决于T细胞的完全激活;如果没有CD28,OX40的表达就会延迟,并且水平会降低四倍。OX-40抗体、OX-40融合蛋白及其使用方法公开于美国专利号:US 7,504,101;US 7,758,852;US 7,858,765;US 7,550,140;US 7,960,515;WO2012027328;WO2013028231中。
与所公开的化合物组合使用或共同施用的另外一种或多种活性成分(抗肿瘤剂)的另外实例是CD20、类视黄醇A或其他激酶抑制剂的抗体或其他拮抗剂。此类抗体或拮抗剂的实例包括但不限于利妥昔单抗(和/>)、奥法木单抗/>和贝沙罗汀/>
与所公开的化合物组合使用或共同施用的另外一种或多种活性成分(抗肿瘤剂)的另外实例是Toll样受体4(TLR4)拮抗剂,包括但不限于氨烷基氨基葡萄糖苷磷酸酯(AGP)。
已知AGP可用作疫苗佐剂和免疫刺激剂,用于刺激细胞因子产生、激活巨噬细胞、促进先天免疫应答以及增强免疫动物中的抗体产生。AGP是TLR4的合成配体。AGP及其通过TLR4的免疫调节作用公开于专利公布例如WO 2006016997、WO 2001090129和/或美国专利号6,113,918中并且已在文献中报道。另外的AGP衍生物公开于美国专利号7,129,219、美国专利号6,911,434和美国专利号6,525,028中。某些AGP充当TLR4激动剂,而其他AGP则被认为是TLR4拮抗剂。
与所公开的化合物组合使用或共同施用的另外一种或多种活性成分(抗肿瘤剂)的另外的非限制性实例是ICOS的抗体。
具有激动剂活性的针对人ICOS的鼠抗体的CDR显示于PCT/EP2012/055735(WO2012131004)中。针对ICOS的抗体还公开于WO 2008137915、WO 2010056804、EP 1374902、EP1374901和EP1125585中。
与所公开的化合物组合使用或共同施用的另外一种或多种活性成分(抗肿瘤剂)的另外实例是聚ADP核糖聚合酶(PARP)抑制剂。此类抑制剂的非限制性实例包括尼拉帕尼、奥拉帕尼、卢卡帕尼和他拉佐帕尼(talazoparib)。
B细胞成熟抗原(BCMA)的正常功能是通过转导来自两种已知配体(TNF家族的B细胞激活因子(BAFF/BLyS)和增殖诱导配体(APRIL))的信号来促进细胞存活。BCMA表达仅限于分化后期的B细胞,在扁桃体、血浆母细胞和长寿命浆细胞的生发中心B细胞上表达。BCMA在多种B细胞恶性肿瘤中以不同的频率表达,包括多发性骨髓瘤(MM)、弥漫性大B细胞淋巴瘤(DLBCL)、大B细胞淋巴瘤(LBCL)、慢性淋巴细胞白血病(CLL)和华氏巨球蛋白血症(WM)。BCMA受限的正常组织表达谱,及其在MM和其他癌症中的上调和生存功能,使其成为具有直接细胞杀伤活性的治疗性抗体的有吸引力的靶标。BCMA抑制剂和其他靶向剂,例如抗体药物缀合物,可以与本发明一起使用。贝兰他单抗马福多汀(belantamab mafodotin)是一种抗BCMA抗体药物缀合物,公开于美国专利号9,273,141中。
与所公开的化合物组合使用或共同施用的另外的一种或多种活性成分(抗肿瘤剂)的另外的非限制性实例是STING调节化合物、CD39抑制剂以及A2a和A2a腺苷拮抗剂。
选择的可与式(I)的化合物或其前药或其药学上可接受的盐组合使用的抗肿瘤剂包括但不限于:阿巴瑞克(abarelix)、阿贝西利、阿比特龙、阿法替尼、阿柏西普(aflibercept)、aldoxorubicin、阿列克替尼(alectinib),阿仑单抗、三氧化二砷、天冬酰胺酶(asparaginase)、阿昔替尼、AZD-9291、贝诺司他、苯达莫司汀(bendamustine)、贝伐珠单抗、布利妥莫单抗(blinatumomab)、博舒替尼、布仑妥昔单抗-维多汀(brentuximabvedotin)、卡巴紫杉醇、卡赞替尼、卡培他滨、色瑞替尼、氯法拉滨、考比替尼、克唑替尼、达雷妥木单抗、达沙替尼、地加瑞克、地诺单抗、地努妥昔单抗、多西他赛、依洛妥珠单抗、恩诺司他、恩杂鲁胺、表柔比星(epirubicin)、艾瑞布林、非格司亭、氟马替尼、氟维司群、呋喹替尼、吉妥珠单抗-奥加米星(gemtuzumab ozogamicin)、替伊莫单抗(ibritumomab)、依鲁替尼、idelalisib、伊马替尼、伊立替康、伊沙匹隆、伊沙佐米、来那度胺(lenalidomide)、乐伐替尼、亚叶酸、二氯甲基二乙胺、奈西妥木单抗、奈拉滨、奈妥吡坦、尼洛替尼、奥比妥珠单抗、奥拉帕尼、奥马西汀、奥希替尼、奥沙利铂、紫杉醇、帕柏西利、帕洛诺司琼、帕尼妥木单抗、聚乙二醇非格司亭(pegfilgrastim)、聚乙二醇干扰素α-2b、培美曲塞、普乐沙福、泊马度胺、帕纳替尼、普拉曲沙、奎扎替尼、镭223、雷姆赛卢单抗、瑞拉非尼、罗拉吡坦、卢卡帕利、西普鲁塞-T(sipuleucel-T)、索尼地吉、舒尼替尼、拉-他利莫近(talimogenelaherparepvec)、地匹福林(tipiracil)、拓扑替康、曲贝替定、曲氟尿苷、曲普瑞林、尿苷、万迪他尼、维拉帕尼(velaparib)、维拉非尼、维尼妥拉、长春新碱、维莫德吉、和唑来膦酸。优选的抗肿瘤剂包括维奈托克。
优选的药剂包括BCL2靶向剂,例如维奈托克(venetoclax),酪氨酸激酶抑制剂,例如针对FLT3突变的抑制剂(吉瑞替尼和米多司他林),声猬抑制剂格拉吉布,IDH1或IHD2突变靶向剂,例如艾伏尼布(ivosidenib)或恩西地平(enasidenib),NEDD8靶向药物,例如pevonedistat,HDAC抑制剂,例如伏立诺他或帕比司他,靶向PRC2复合物的药物,例如他泽美司他(EZH2i)或MAK683(EEDi),铂类抗肿瘤药,例如顺铂,IO靶向剂例如抗CD47(magrolimab),TIM-3(沙巴托利单抗),CTLA-4(伊匹单抗),和抗PD-1/PD-L1(派姆单抗),以及P53靶向药物。
在一个实施方案中,本发明的癌症治疗方法包括共同施用式(I)的化合物和/或其前药和/或其药学上可接受的盐和至少一种抗肿瘤剂,例如选自由以下组成的组的一种:抗微管剂、铂配位络合物、烷基化剂、抗生素、拓扑异构酶II抑制剂、抗代谢物、拓扑异构酶I抑制剂、激素和激素类似物、信号转导途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、免疫治疗剂、促凋亡剂、细胞周期信号传导抑制剂;蛋白酶体抑制剂;和癌症代谢抑制剂。
式(I)的化合物或其前药及其药学上可接受的盐可以与至少一种已知用于治疗β血红蛋白病如镰状细胞病、镰状细胞贫血和β地中海贫血的其他活性剂共同施用。
与本发明组合进行组合使用或共同施用的另外一种或多种活性成分的实例是羟基脲。
本发明的化合物是使用常规有机合成方法制备的。合适的合成路线在下面的一般反应方案中描述。所有起始材料均可商购或由本领域技术人员容易地由商购起始材料制备。
如本文所使用的,这些过程、方案和实例中使用的符号和约定与当代科学文献中使用的符号和约定一致,例如,Journal of the American Chemical Society or theJournal of Biological Chemistry。标准的单字母或三字母缩写通常用于指定氨基酸残基,除非另有说明,否则假定其处于L-构型。除非另有说明,否则所有起始材料均从市场供应商获得,并且不经进一步纯化即可使用。具体地,在实施例和整个说明书中可以使用以下缩写:Ac(乙酰基);
Ac2O(乙酸酐);
CH3CN(乙腈);
Boc(叔丁氧羰基);
Boc2O(二碳酸二叔丁基酯);
Cbz(苄基氧基羰基);
DCE(1,2-二氯乙烷);
DCM(二氯甲烷);
ATP(三磷酸腺苷);
双-频哪醇二硼(4,4,4',4',5,5,5',5'-八甲基-2,2'-双-1,3,2-二氧杂环戊硼烷);
BSA(牛血清白蛋白);
C18(指HPLC固定相中硅上的18碳烷基)
Cy(环己基);
DCM(二氯甲烷);
DIEA(二异丙基乙胺);
DIPEA(Hünig碱,N-乙基-N-(1-甲基乙基)-2-丙胺);
二噁烷(1,4-二噁烷);
DMAP(4-二甲基氨基吡啶);
DME(1,2-二甲氧基乙烷);
DMEDA(N,N'-二甲基乙二胺);
DMF(N,N-二甲基甲酰胺);
DMSO(二甲基亚砜);
DPPA(二苯基磷酰叠氮化物);
EDC(N-(3-二甲基氨基丙基)-N’乙基碳二亚胺)盐酸盐;
EDTA(乙二胺四乙酸);
EtOAc(乙酸乙酯);
EtOH(乙醇);
Et2O(乙醚);
HEPES(4-(2-羟乙基)-1-哌嗪基乙磺酸);
HATU(O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐);
HOAt(1-羟基-7-氮杂苯并三唑);
HOBt(1-羟基苯并三唑);
HOAc(乙酸);
HPLC(高压液相色谱);
HMDS(六甲基二硅氮烷);
Hunig碱(N,N-二异丙基乙胺);
IPA(异丙醇);
二氢吲哚(2,3-二氢-1H-吲哚);
KHMDS(六甲基二硅氮烷钾);
LAH(氢化铝锂);
LDA(二异丙基氨基锂);
LHMDS(六甲基二硅氮烷锂);
MeOH(甲醇);
MTBE(甲基叔丁基醚);
mcM(微摩尔);
mCPBA(间氯过苯甲酸);
NaHMDS(六甲基二硅氮烷钠);
NCS(N-氯代琥珀酰亚胺);
NBS(N-溴代琥珀酰亚胺);
PE(石油醚);
Pd2(dba)3(三(二亚苄基丙酮)二钯(0));
Pd(dppf)Cl2.DCM络合物([1,1'-双(二苯基膦)二茂铁]二氯化钯(II).二氯甲烷络合物);
PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基鏻);
PyBrOP(溴三吡咯烷鏻六氟磷酸盐);
RPHPLC(反相高压液相色谱);
RT(室温);
Sat.(饱和);
SFC(超临界流体色谱);
SGC(硅胶色谱);
SM(起始材料);
TLC(薄层色谱);
TEA(三乙胺);
TEMPO(2,2,6,6-四甲基哌啶基1-氧基,自由基);
TFA(三氟乙酸);
THF(四氢呋喃);和
Ts-Cl(对甲苯磺酰氯)。
所有提及乙醚时均指二乙醚,盐水均指饱和NaCl水溶液。
合成方案
本领域技术人员将理解,如果本文描述的取代基与本文描述的合成方法不相容,则可以用对反应条件稳定的合适的保护基保护取代基。可以在反应顺序中的合适点除去保护基以提供所需的中间体或目标化合物。合适的保护基以及使用此类合适的保护基保护和去保护不同取代基的方法是本领域技术人员众所周知的;其实例可参见T.Greene和P.Wuts,Protecting Groups in Organic Synthesis(第4版),John Wiley&Sons,NY(2006)。在一些情况下,可以具体选择取代基以在所使用的反应条件下具有反应性。在这些情况下,反应条件将所选取代基转化为另一取代基,后者取代基可用作中间体化合物,或者是目标化合物中的所需取代基。
方案1中的式16的前药可以是单一对映体或外消旋体,取决于是否进行手性拆分。二氰基吡啶核心中间体6可以容易地由2-氰基乙酰胺1制备。含有中间体的前药可以通过用取代的扁桃酸例如市售的4-羟基扁桃酸7开始来制备。可以设想各种保护基方案以及离去基团,它们将允许7转化为SN2亲电子伴侣13。
方案1
没有前药官能团的化合物,例如17,可以由中间体11制备,如方案2所示。在此阶段,如果需要,可以拆分17以获得单一对映体18。
方案2
可以利用不对称途径代替手性拆分来提供手性酰胺22或其前药对应物16,如方案3中详述。可以通过文献中描述的各种方法通过酮酰胺中间体19的不对称还原来建立单独的立体中心。
方案3
方案4
甘氨酸盐的不对称合成
方案5
甘氨酸盐一水合物的不对称合成
本发明的具体化合物在实施例部分中制备。
实施例
实施例1
方法A
(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基
磺酰基)氧基)苯基)乙酰基)磷酰胺酸
步骤1:5-(4-羟基苯基)-2,2-二甲基-1,3-二氧戊环-4-酮
向16L JLR(容器A)中加入2-羟基-2-(4-羟基苯基)乙酸(1000g,5.947mol)以及二氯甲烷(DCM)(5000mL)并开始搅拌。然后将2,2-二甲氧基丙烷(2925mL,23.8mol)添加到反应混合物中。将反应混合物冷却至0℃。当反应温度达到0-5℃时,通过移液管在2分钟内添加BF3·OEt2络合物(45.2mL,0.357mol)。使用DCM完成添加。然后将反应混合物在0℃搅拌4小时。
向单独的反应容器(容器B)中添加5L饱和NaHCO3水溶液,并将容器的内部温度设定为0℃。通过真空转移将来自容器A的反应混合物添加至容器B中的饱和碳酸氢钠溶液中。添加完成后,将悬浮液搅拌10分钟,然后温热至20℃。将有机层分离到20L细颈大瓶(carboy)中。用另外的DCM(1.2L)萃取水层并将该有机层与20L细颈大瓶中的有机层合并。将合并的有机层返回至JLR并用盐水(3L)洗涤。再次分离有机层。第二天,将DCM蒸馏至最小搅拌体积。将剩余的反应混合物在旋转蒸发器上浓缩至干。然后将剩余的灰白色固体在真空下干燥以提供5-(4-羟基苯基)-2,2-二甲基-1,3-二氧戊环-4-酮(720g,58.1%产率),为灰白色固体。1HNMR(400MHz,CDCl3)δppm 7.28-7.24(m,2H),6.83-6.78(m,2H),5.37(s,1H),1.75(s,3H),1.70-1.67(m,3H).
步骤2:4-(2,2-二甲基-5-氧代-1,3-二氧戊环-4-基)苯基甲磺酸酯
将5-(4-羟基苯基)-2,2-二甲基-1,3-二氧戊环-4-酮(720.0g,3458mmol)溶解在二氯甲烷(DCM)(4390mL)中的溶液装入16L JLR(容器A)中并将反应混合物冷却至0℃。然后在约5分钟内通过加料漏斗将甲磺酰氯(323mL,4150mmol)添加至反应混合物中;通过用100mL DCM冲洗加料漏斗至反应器中来完成转移。使用加料漏斗在约43分钟内缓慢添加三乙胺(723mL,5187mmol);通过用100mL DCM冲洗加料漏斗至反应器中来完成转移。将反应混合物在0℃搅拌2小时。
向单独的反应容器(容器B)中添加4390mL饱和NaHCO3水溶液,并将容器的内部温度设定为0℃。将容器B置于减压下以促进反应混合物从容器A缓慢真空转移至容器B中。用300mL DCM冲洗容器A并将该洗涤溶液也转移至容器B中。停止搅拌,通过喷雾球向容器B中加入500mL DI水以冲洗反应器壁。重新开始搅拌并将内部温度设定为20℃。30分钟后暂停搅拌,并将双相混合物在20℃下静置过夜。将内部温度设置为10℃并将容器置于真空下。30分钟后,内部温度升至25℃。在接下来的1.5小时内,体积减少至1.5L至2L之间,并释放真空。将容器B中的有机层排出并用DCM冲洗反应器以完成转移。将剩余的有机层在旋转蒸发器上浓缩至干燥并在高真空下进一步干燥以提供4-(2,2-二甲基-5-氧代-1,3-二氧戊环-4-基)苯基甲磺酸酯(689.67g,69.7%产率),为灰白色固体。LCMS m/z=304.2[M+H2O]+.1HNMR(400MHz,CDCl3)δppm 7.61-7.56(m,2H),7.39-7.35(m,2H),5.44(s,1H),3.18(s,3H),1.76(s,3H),1.72(s,3H).
步骤3:4-(2-氨基-1-羟基-2-氧代乙基)苯基甲硫酸酯
向16L JLR中加入4-(2,2-二甲基-5-氧代-1,3-二氧戊环-4-基)苯基甲磺酸酯(689.67g,2409mmol)以及甲醇(2400mL),并搅拌溶液。夹套温度设置为0℃。经47分钟向反应混合物中添加氨的MeOH溶液(7M)(1377mL,9636mmol)。将反应混合物在相同温度下搅拌7.5小时后,将夹套温度升温至10℃。添加另外250mL(1750mmol)的7M氨的甲醇溶液并将反应混合物在相同温度下搅拌16.5小时。然后将反应混合物通过盘式过滤器过滤。将收集的固体用另外的甲醇洗涤并干燥,得到4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯(544.86g,92%产率),为白色固体。LCMS m/z=268.1[M+Na]+.1HNMR(400MHz,DMSO-d6)δppm7.64-7.54(m,3H),7.40-7.32(m,3H),6.29(d,J=4.4Hz,1H),5.03(d,J=4.4Hz,1H),3.38(s,3H).
步骤4:4-(2-氨基-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯
将4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯(545g,2222mmol)和二氯甲烷(DCM)(4331mL)装入16L JLR(容器A)中。开始搅拌并将夹套温度设置为0℃。25分钟后,将甲磺酰氯(216mL,2778mmol)添加至反应混合物中。然后经35分钟通过加料漏斗缓慢添加三乙胺(465mL,3333mmol)。添加完成后,经40分钟将夹套温度升至20℃。将反应混合物在相同温度下搅拌19小时,但起始材料有剩余。将夹套温度重置为0℃。将另外的甲磺酰氯(30mL,385.8mmol)与70mL的DCM一起添加至反应混合物中以完成添加。然后添加另外量的三乙胺(70mL,501.7mmol)。添加完成后,将夹套温度设定至22℃并将反应混合物搅拌1小时。
将饱和碳酸氢钠水溶液(2166mL)装入单独的反应容器(容器B)中并将夹套温度设定至0℃。将来自容器A的反应混合物以控制放热和气体逸出的速率真空转移到容器B中。转移完成后,经30分钟将夹套温度升至20℃,并将反应混合物在此温度下再搅拌30分钟。然后将反应混合物通过盘式过滤器过滤。用水(550mL)洗涤收集的固体物质并在盘式过滤器中真空干燥过夜。然后将固体在真空烘箱中在45℃下进一步干燥过夜以提供4-(2-氨基-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(530.36g,73.8%产率),为白色固体。LCMS m/z=346.1[M+Na]+.1HNMR(400MHz,DMSO-d6)δppm 7.88(s,1H),7.63-7.58(m,2H),7.45-7.41(m,2H),5.92(s,1H),3.42(s,3H),3.27(s,3H).
步骤5:4-(2-((双(苄基氧基)磷酰基)氨基)-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯
向内部温度设定为-5℃的16L JLR(容器A)中加入8L四氢呋喃(THF)并开始搅拌。然后通过粉末加料漏斗向反应容器中加入氢化钠(60重量%)(203.45g,5.087mol)。用1LTHF冲洗容器和漏斗到反应器中以完成转移。通过粉末加料漏斗向反应混合物中添加焦磷酸四苄酯(1471g,2.732mol)。用0.5L THF冲洗容器和漏斗到反应器中以完成转移。将反应温度设置为-3℃并向反应混合物中添加额外的2.5L THF。经30分钟向反应混合物中分7份添加4-(2-氨基-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(736g,2276mol),同时在添加之间对反应混合物进行排气。通过用另外的THF(3L)冲洗二甲磺酸酯容器以使反应器中的总THF达到15L来完成添加。将搅拌增加至300rpm并且经30分钟将反应夹套温热至25℃。然后将反应混合物在相同温度下搅拌2小时。
分2份淬灭反应。向内部温度设定为0℃的单独反应容器(容器B)中添加6L饱和柠檬酸溶液。经30分钟向容器B中的该溶液中添加8.5L来自容器A的反应混合物。在添加过程中,将容器B的夹套温度调节至-15℃。添加完成后,将容器B的夹套温度升至10℃。在10℃下搅拌1小时后,将混合物通过盘式过滤器过滤(使用两张鲨鱼皮滤纸)。将容器B完全排空后,第二次加入6L饱和柠檬酸溶液,并将温度调节至-15℃。通过经35分钟将剩余的反应混合物从容器A添加到容器B来重复淬灭程序。将容器B的温度再次调节至10℃。用500mL THF冲洗容器A,并将该冲洗液加入到容器B中。将容器B的夹套温度调节至25°℃,并将混合物在相同温度下保持25分钟。将反应混合物通过先前使用的相同盘式过滤器过滤。将叔-丁基甲基醚(TBME)添加到盘式过滤器中以帮助过滤,但提供即使有也很少的改善。50分钟后,通过真空转移将盘式过滤器中的材料转移回反应器容器中。将TBME(8L)添加到反应器中并且再次通过盘式过滤器过滤混合物。随着过滤的进行,固体混合物变成糊状,需要刮擦以促进该过程。1.5小时后,将容器中的所有内容物添加到盘式过滤器中,并用另外1.5L TBME冲洗反应器容器。将该漂洗液添加到盘式过滤器中并过滤过夜。过夜真空过滤后,将分离的固体转移至玻璃干燥托盘中。将托盘放入25℃的真空烘箱中过夜。
在真空烘箱中干燥过夜后,将固体材料转移至12L三颈烧瓶中并悬浮在8L水中。使用顶置机械搅拌器将混合物剧烈混合1小时,然后通过配备有3层鲨鱼皮滤纸的不锈钢盘式过滤器过滤。另外使用2L水来完成转移。将滤饼用2L水洗涤两次,然后用4L TBME洗涤。然后将固体在盘式过滤器中真空干燥过夜。将固体从盘式过滤器转移到两个烤盘中,并在不加热的情况下在真空烘箱中用氮气吹扫进一步干燥约48小时。合并固体,得到呈白色固体的4-(2-((双(苄基氧基)磷酰基)氨基)-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(1060g,80%)。LCMS m/z=584.3[M+H]+.1HNMR(400MHz,DMSO-d6)δppm 10.51(d,J=9.4Hz,1H),7.67-7.61(m,2H),7.48-7.43(m,2H),7.41-7.31(m,8H),7.28-7.23(m,2H),6.11(s,1H),5.10-4.85(m,4H),3.41(s,3H),3.29(s,3H).
步骤6:3,5-二氰基-4-乙基-6-羟基吡啶-2-醇铵
向冷却至0℃的2-氰基乙酰胺(300g,3.571mol)和氨(在水中25重量%,618mL,7.142mol)在水(750mL)中的搅拌溶液中滴加丙醛(128mL,1.785mol)。将反应混合物在室温下搅拌3小时。通过过滤收集沉淀的固体,用冰冷水(2×500mL)洗涤,然后用冷甲醇(300mL)洗涤,并干燥,得到3,5-二氰基-4-乙基-6-羟基吡啶-2-醇铵(150g,39%),为灰白色固体。LCMS m/z=188.0[M-H]–.1H NMR(400MHz,DMSO-d6)δppm 10.35(s,1H),7.1(br s,4H),2.48(q,J=7.6Hz,2H),1.17(t,J=7.6Hz,3H).
步骤7:2,6-二氯-4-乙基吡碇-3,5-二甲腈
将3,5-二氰基-4-乙基-6-羟基吡啶-2-醇铵(150g,697mmol)在POCl3(750mL,8046mmol)中的搅拌悬浮液冷却至0℃,滴加N,N-二甲基苯胺(150mL,1601mmol)。将反应混合物在120℃加热6小时。通过TLC监测反应进程(TLC系统10%EtOAc/己烷,Rf:0.6,检测:UV)。将反应混合物减压浓缩以获得粗物质。将粗物质用冰冷的水稀释并搅拌10分钟。通过过滤收集沉淀的固体并干燥。将固体溶解在二氯甲烷(2L)中,用饱和碳酸氢钠溶液(1L)、水(1.5L)和盐水溶液(1L)洗涤。将有机层经无水Na2SO4干燥、过滤并减压浓缩,得到黄色固体。将固体物质用乙醚(500mL)研磨,过滤并干燥,得到2,6-二氯-4-乙基吡啶-3,5-二甲腈(130g,571mmol,82%产率),为黄色固体。LCMS m/z=224.1[M-H]–.1H NMR(400MHz,CDCl3)δppm 3.13(q,J=7.6Hz,2H),1.42(t,J=7.6Hz,3H).
步骤8:2-(二甲基氨基)-4-乙基-6-巯基吡啶-3,5-二甲腈
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向具有顶置搅拌装置和温度探针的3L 3颈烧瓶中加入2,6-二氯-4-乙基吡啶-3,5-二甲腈(130.0g,575mmol)和DMF(1300mL),并搅拌以形成微红色溶液。将反应烧瓶置于冰浴中并搅拌溶液直至内部温度达到约3℃。通过加料漏斗添加二甲胺的THF溶液(288mL,575mmol),添加速率为使得内部温度保持<5℃。滴加三乙胺(80mL,575mmol),保持内部温度<7℃。在三乙胺添加接近结束时,混合物变成深紫色。添加硫代乙酸钾(164g,1438mmol)并移除冷却浴。将混合物在室温下搅拌2小时并倒入冷的1N HCl溶液(1150mL,1150mmol)和水(2600mL)的混合物中。将混合物搅拌约30分钟并通过过滤收集沉淀的固体。将滤饼用几份水(总共1L)洗涤并在布氏漏斗上干燥过夜。在顶置搅拌下将橙色固体转移至3L三颈烧瓶中。加入乙酸乙酯(1200mL)并将浆液搅拌约30分钟。通过过滤收集固体。将滤饼用200mLEtOAc打浆并在布氏漏斗上抽干。浆化/干燥再重复两次,得到2-(二甲基氨基)-4-乙基-6-巯基吡啶-3,5-二甲腈(115.57g,87%产率),为亮黄色固体。LCMS m/z=233.0[M+H]+.1HNMR:(400MHz,DMSO-d6)δppm 14.05–9.86(m,1H),3.29(s,6H),2.68(q,J=7.3Hz,2H),1.21(t,J=7.6Hz,3H).
步骤9:4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯
向16L JLR中添加二氯甲烷(8L)、4-(2-((双(苄基氧基)磷酰基)氨基)-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(966g,1.655mol)、2-(二甲基氨基)-4-乙基-6-巯基吡啶-3,5-二甲腈(381g,1.640mol)和二氯甲烷(8L)。将反应混合物冷却至5℃。经21分钟通过加料漏斗将三乙胺(174g,1.722mol)添加至反应混合物中,同时保持反应温度在3.3-4.9℃之间。将反应混合物在5℃下保持5分钟,然后升温至室温。室温下30分钟后,反应完成。经6分钟将水(6L)添加至反应混合物中。然后添加另外的1L水并将反应混合物搅拌13分钟。使各层分离并使用在线过滤器将有机层转移至20L细颈大瓶中。用500mL二氯甲烷洗涤水层并分离各层。该有机层与20L细颈大瓶中的原先有机层合并。使用旋转蒸发仪在20L圆底烧瓶中减压浓缩合并的有机层。将所得泡沫状/胶状半固体用6L甲醇处理并在50℃的旋转蒸发浴中在非真空下旋转20分钟。在旋转蒸发仪上烧瓶旋转期间,开始出现淡黄色固体。将烧瓶从旋转蒸发仪中取出并将混合物冷却至室温过夜。第二天早上,使用配备有3x鲨鱼皮滤纸的不锈钢盘式过滤器过滤混合物。使用甲醇(1L)来促进转移。将滤饼用甲醇(2L)冲洗两次。通过在固体上抽吸空气然后抽吸氮气将固体在盘式过滤器中真空干燥过夜。第二天早上,将固体用3L的2:1二乙醚/乙酸乙酯溶剂混合物洗涤并干燥,得到4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯(963g,82%),为棕褐色固体。LCMS m/z=720.3[M+H]+.1HNMR:(400MHz,DMSO-d6)δppm 10.62-10.52(m,1H),7.63-7.57(m,2H),7.43-7.38(m,2H),7.36-7.27(m,8H),7.26-7.20(m,2H),5.82(s,1H),5.11-4.84(m,4H),3.40(s,3H),3.27(s,6H),2.77(q,J=7.6Hz,2H),1.22(t,J=7.6Hz,3H).
步骤10:(R)-4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯
将4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯(1kg)溶解在乙腈:甲醇90:10混合物中(120g分部份溶解在2L 90:10乙腈:甲醇中)。该材料通过玻璃纤维纸过滤,并在VarianPrep HPLC、Chiralpak AS20u 77x250mm柱上使用等度95:5-CH3CN:CH3OH(50mM NH4OAc)方法纯化(拆分)以获得所期望的E2(R)-对映体。标准注射液为150mL流动相中的9g 4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯。使用此方法处理1000g外消旋体后,获得所期望的E2(R)-对映体,为浅棕褐色固体,化学纯度为99.73%(0.17%E1对映体;0.1%杂质)。在20LBuchii烧瓶中分离出含有深棕色/黑色条纹(带有残留溶剂)的固体物质。将二乙醚(1.5L)添加到该材料中并用大抹刀将固体从烧瓶壁上移出。旋转烧瓶以产生悬浮于黑色醚层中的灰白色固体。使用不锈钢盘式过滤器过滤来收集固体。用滤液冲洗Buchii烧瓶3次,以便从烧瓶中转移尽可能多的所期望对映体。将所得滤液浓缩至干并将剩余残余物悬浮于乙醚(500mL)中以产生第二批所期望对映体。通过在已含有第一批产物的同一盘式过滤器中过滤来收集该固体。将合并的固体用另外的乙醚(1L)洗涤,然后在真空下干燥过夜,得到(R)-4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯(296.4g,67.6%产率),为浅灰色固体。LCMS m/z=720.3[M+H]+.1HNMR(400MHz,DMSO-d6)δppm 10.57(d,J=10.8Hz,1H),7.62-7.58(m,2H),7.43-7.38(m,2H),7.34-7.27(m,8H),7.25-7.20(m,2H),5.82(s,1H),5.10-4.84(m,4H),3.39(s,3H),3.26(s,6H),2.76(q,J=7.6Hz,2H),1.21(t,J=7.6Hz,3H).手性HPLC:99.6%(R)-对映体。
步骤11:(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸
向配备有机械顶置搅拌器的12L 3颈圆底烧瓶中加入(R)-4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯(200.0g,278mmol)和二氯甲烷(2000mL)以提供均匀的橙色溶液。在室温下,经50分钟通过加料漏斗向该溶液滴加三甲基碘硅烷(122g,611mmol)的二氯甲烷(200mL)溶液。添加三甲基碘硅烷后搅拌25分钟后,对淬灭到MeOH/MeCN中的等分试样进行LCMS分析,结果表明期望的产物加上4%单苄基磷酸酯。添加另外的三甲基碘硅烷(1.660mL,12.19mmol)并将浅橙色悬浮液搅拌20分钟。总共搅拌2小时后,经28分钟通过加料漏斗滴加甲醇(200mL,4946mmol)。再加入200mL二氯甲烷,并继续搅拌。需要用200mL二氯甲烷进一步稀释以帮助搅拌。继续搅拌15分钟,然后添加另外200mL二氯甲烷(总二氯甲烷为2800mL)。甲醇添加完成后,将混合物机械搅拌2小时45分钟。将悬浮液分开并通过6个配有聚乙烯烧结盘的一次性聚丙烯过滤漏斗进行过滤。用二氯甲烷反复冲洗固体,直至滤液中不再出现红色/粉色。将收集的白色固体在真空下在漏斗中干燥,转移到单一研钵中,并缓慢研磨成精细的自由流动的白色粉末。将固体置于真空烘箱中14小时,不加热,得到(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸(123.4g,82%),为白色固体。LCMS m/z=540.0[M+H]+.1H NMR(500MHz,DMSO-d6)δppm 11.55(br s,2H),9.74(br d,J=9.3Hz,1H),7.61(d,J=8.7Hz,2H),7.39(d,J=8.7Hz,2H),5.79(br s,1H),3.41(s,3H),3.36(s,6H),2.75(q,J=7.6Hz,2H),1.20(t,J=7.6Hz,3H).手性HPLC:98.9%(R)-对映体。
实施例1的游离酸母体的X射线粉末衍射(XRPD)图显示在图7中,并且在下表III中给出了衍射角和d-间距的总结。
表III实施例1XRPD衍射角和d-间距的游离酸母体总结
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该游离酸母体材料的差示扫描量热法(DSC)温谱图与之前的DSC设备相同,显示在图8中。实验是在轻微卷边的铝盘中以10℃/min的加热速率加热至300℃的最终温度进行。该化合物在DSC中具有简单的单次熔融事件,起始温度为166.6℃,峰值温度为173.8℃,熔融焓为68J/g,随后在超过200℃时热分解。该化合物在分解事件之前基于TGA损失表现出可忽略不计的重量损失。本领域技术人员将认识到吸热的起始温度、峰值温度和吸热焓可以根据实验条件而变化。
该游离酸母体材料的热重分析(TGA)温谱图与之前的TGA设备相同,显示在图9中。实验在N2吹扫下在敞口铝盘中进行,加热速率为10℃/min,最终温度为200℃。该化合物在分解事件之前在190℃下重量损失1.3%。
方法B(通过对映选择性途径)
(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基
磺酰基)氧基)苯基)乙酰基)磷酰胺酸
步骤1:(S)-4-(2-((双(苄基氧基)磷酰基)氨基)-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯)苯基甲磺酸酯
用热风枪将500mL圆底烧瓶加热约5分钟,同时用氮气吹扫。冷却至室温后,向烧瓶中加入NaH(60%分散在矿物油中,1.089g,27.2mmol)和THF(120mL)。将混合物冷却至0℃并添加二磷酸四苄酯(7.99g,14.85mmol),随后经约3分钟分批添加(S)-4-(2-氨基-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(4.0g,12.37mmol)。将反应混合物在氮气气球下于0℃搅拌。0℃ 2小时后,LCMS分析显示没有剩余起始材料。将反应混合物小心地倒入10%柠檬酸水溶液(200mL)中并剧烈搅拌。通过过滤收集所得沉淀,用水(3x50mL)冲洗,然后用Et2O(3x50mL)冲洗,并在高真空下干燥至恒重以提供(S)-4-(2-((双(苄基氧基)磷酰基)氨基)-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(6.57g,11.26mmol,91%产率),呈白色固体。LCMS m/z=584.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.48(br s,1H),7.69–7.57(m,2H),7.48–7.41(m,2H),7.41–7.22(m,10H),6.11(s,1H),5.13–4.96(m,3H),4.96–4.88(m,1H),3.40(s,3H),3.28(s,3H).手性SFC:100%ee。
步骤2:(R)-4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯
在0℃下,向2-(二甲基氨基)-4-乙基-6-巯基吡啶-3,5-二甲腈(480mg,2.066mmol)在THF(20mL)中的溶液中添加NaH(83mg,2.066mmol)。将所得混合物在0℃下搅拌30分钟,然后在0℃滴加至(S)-4-(2-((双(苄基氧基)磷酰基)氨基)-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(1266mg,2.170mmol)在DCM(1mL)中的溶液。将混合物温热至室温,搅拌1小时并用氯化铵淬灭。将水层用DCM萃取并经硫酸钠干燥。将残余物用MeOH研磨,得到(R)-4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯(908mg,1.198mmol,58%产率),为灰白色固体。LCMS m/z=720.2[M+H]+.1H NMR(400MHz,DMSO-d6)δ10.56(d,J=10.8Hz,1H),7.67–7.56(m,2H),7.48–7.39(m,2H),7.37–7.29(m,8H),7.29–7.23(m,2H),5.81(s,1H),5.09–4.86(m,4H),3.39(s,3H),3.27(s,6H),2.76(q,J=7.6Hz,2H),1.21(t,J=7.6Hz,3H),含有约25%起始甲磺酸盐污染物。手性HPLC:99.3%ee。
方法C(甘氨酸盐的对映选择性合成)
(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基
磺酰基)氧基)苯基)乙酰基)磷酰胺酸甘氨酸盐
步骤1:(S)-4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯
向配有顶置搅拌装置的1L JLR中加入H2O(400mL),然后加入2,2-双(羟乙基)-(亚氨基三)-(羟基甲基)-甲烷(10.8g,51.4mmol)并搅拌3分钟,夹套温度设置为20℃。然后将由β-烟酰胺腺嘌呤二核苷酸磷酸二钠盐(NADP+,二钠)(500mg)、酮还原酶(1.50g)和H2O(15mL)制成的溶液加入到JLR中,将所得溶液搅拌5分钟。添加4-(2-氨基-2-氧代乙酰基)苯基甲磺酸酯(50.0g,206mmol)、H2O(100mL),然后添加异丙醇(63.4mL,822mmol)并将反应物加热至30℃。搅拌24小时后,将反应冷却至0℃并添加1N NaOH水溶液(25.0mL)。将所得浆料在0℃下保持23小时,然后通过真空过滤滤出沉淀的固体。将分离的固体用H2O(每次洗涤250mL)洗涤两次,然后用叔-丁基甲基醚(250mL)洗涤。真空干燥后,分离出所期望产物(S)-4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯,为白色至灰白色固体(45.0g,184mmol,产率89%)。
LCMS m/z=246.0[M+H]+.1H NMR:(400MHz,DMSO-d6)δppm 7.54–7.49(m,2H),7.42(br s,1H),7.33–7.28(m,2H),7.21(br s,1H),6.13(d,J=4.9Hz,1H),4.89(d,J=4.9Hz,1H),3.37(s,3H).手性HPLC:>99%ee。
步骤2:(S)-4-(2-氨基-1-((甲基磺酰基)氨基)-2-氧代乙基)苯基甲硫酸酯
将(S)-4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯(2.57g,10.5mmol)和N,N-二甲基乙酰胺(10.3mL)装入配备有顶置搅拌装置的100mL JLR中并搅拌,夹套温度设置为20℃。然后添加1-甲基咪唑(1.51g,18.4mmol)并将反应冷却至0℃。向黄色溶液中缓慢添加甲磺酸酐(2.56g,14.7mmol)的N,N-二甲基乙酰胺(5.12mL)溶液,同时保持反应温度<5℃。然后将反应升温至20℃并在该温度搅拌21小时。完成后,将反应冷却至0℃,通过经1小时添加H2O(26mL)随后经2小时添加5%硫酸钠水溶液(51.5mL)淬灭。将所得浆液搅拌20小时,然后通过真空过滤收集固体。将分离的固体用H2O洗涤两次(每次洗涤25mL),然后用叔-丁基甲基醚洗涤两次(每次洗涤15mL)。真空干燥后,分离出所期望产物(S)-4-(2-氨基-1-((甲磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯,为白色固体(3.14g,9.71mmol,产率93%)。
LCMS m/z=324.0[M+H]+.1H NMR(400MHz,DMSO-d6)δppm 7.86(s,1H),7.63–7.54(m,3H),7.41(d,J=7.8Hz,2H),5.91(s,1H),3.41(s,3H),3.26(s,3H).
步骤3:(S)-4-(2-((二甲基氧基磷酰基)氨基)-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯
将四氢呋喃(200mL)装入经氮气吹扫的1L JLR(配有顶置搅拌装置)中,然后装入(S)-4-(2-氨基-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(40g,124mmol),然后搅拌约5分钟,夹套温度设置为20℃。然后将浆液冷却至0℃并将氯代磷酸二甲酯(20mL,186mmol)加入到容器中。搅拌1小时后,缓慢添加1M叔丁醇锂的四氢呋喃溶液(272mL,272mmol),同时保持反应温度<5℃。将反应搅拌约1小时并通过HPLC分析确定反应不完全。将另外的氯代磷酸二甲酯(6.3mL,58mmol)加入到反应中,然后缓慢添加1M叔丁醇锂的四氢呋喃溶液(37.1mL,37.1mmol)。将反应搅拌30分钟,然后通过缓慢添加10%柠檬酸水溶液(w/w,40mL)淬灭,同时保持反应温度<5℃。将反应搅拌约15分钟,然后加入另外的10%柠檬酸水溶液(w/w,80mL),同时保持反应温度<5℃。将温度升至20℃并在该温度下保持约30分钟。然后将反应混合物冷却至0℃并保持约14小时。通过真空蒸馏将反应浓缩至约300mL总体积。将异丙醇(380mL)加入到反应中并将反应在20℃下搅拌2小时。通过真空蒸馏将反应物浓缩至约520mL总体积,然后添加H2O(80mL)和异丙醇(80mL)并将反应物冷却至0℃。搅拌19小时后,将产物浆液转移至过滤干燥器。使用氮气压力过滤母液。将反应器用H2O(400mL)冲洗,然后转移至过滤干燥器以洗涤分离的固体。使用氮气压力推动洗涤液通过产物滤饼。将反应器用异丙醇(400mL)冲洗,然后转移至过滤干燥器以洗涤分离的固体。使用氮气压力推动洗涤液通过产物滤饼。然后用叔-丁基甲基醚(200mL)洗涤产物固体。将分离的固体在氮气下干燥23小时,然后在20℃下真空干燥21小时,得到所期望产物(S)-4-(2-((二甲基氧基磷酰基)氨基)-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯,为白色固体(35.1g,81mmol,66%产率)。
LCMS m/z=454.1[M+Na]+.1H NMR(400MHz,DMSO-d6)δppm 10.28(br s,1H),7.60-7.68(m,2H),7.44-7.51(m,2H),6.07(s,1H),3.67(d,J=12Hz,3H),3.57(d,J=12Hz,3H),3.43(s,3H),3.30(s,3H).手性HPLC:>99%ee。
步骤4:(R)-4-(1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-((二甲氧基磷酰基)氨基)-2-氧代乙基)苯基甲磺酸酯
向配有顶置搅拌装置的经氮气吹扫的1L JLR中加入H2O(338mL)和碳酸钠(5.18g,48.9mmol),然后在20℃搅拌。用另外的H2O(42.0mL)冲洗反应容器壁,然后将混合物搅拌10分钟。加入丙酮(170mL),然后加入2-(二甲基氨基)-4-乙基-6-巯基吡啶-3,5-二甲腈(22.7g,98.0mmol)和另外的丙酮(42.0mL)。将混合物搅拌约1小时,然后一次性添加(S)-4-(2-((二甲氧基磷酰基)氨基)-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(42.2g,98.0mmol)。将反应搅拌2小时,然后通过真空过滤收集沉淀的固体。将分离的固体用H2O洗涤两次(每次洗涤126mL),然后用异丙醇洗涤两次(每次洗涤210mL),然后用叔-丁基甲基醚(420mL)洗涤并用氮气流吹干15小时。然后将产物滤饼用叔-丁基甲基醚(336mL)重新浆化。混合约10分钟后,将固体过滤至干燥并用另外的叔-丁基甲基醚(126mL)冲洗。真空干燥后,收集所期望产物(R)-4-(1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-((二甲氧基磷酰基)氨基)-2-氧代乙基)苯基甲磺酸酯,得到灰白色固体(50.6g,88.0mmol,90%产率)。
LCMS m/z=568.1[M+H]+.1H NMR(400MHz,DMSO-d6)δppm 10.33-10.43(m,1H),7.55-7.66(m,2H),7.36-7.48(m,2H),5.81(br s,1H),3.64(d,J=12Hz,3H),3.52(d,J=12Hz,3H),3.42(s,3H),3.37(s,6H),2.77(q,J=8Hz,2H),1.21(t,J=8Hz,3H).手性HPLC:>99%ee。
步骤5:(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸DMF半溶剂化物
向经氮气吹扫的2L JLR中加入二氯甲烷(250mL)和(R)-4-(1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-((二甲氧基磷酰基)氨基)-2-氧代乙基)苯基甲磺酸酯(65.0g,115mmol),然后用另外的二氯甲烷(100mL)洗涤容器壁以产生均匀的棕褐色溶液。将该溶液冷却至0℃后,加入三甲基碘硅烷(42.1mL,309mmol),同时保持内部温度<5℃。将所得棕色反应混合物在0℃搅拌1小时。反应混合物的HPLC分析表明反应不完全,因此加入另外的三甲基碘硅烷(3.12mL,22.9mmol)。搅拌13分钟后,通过添加约50%的DMF淬灭溶液(91mL)淬灭反应,同时保持内部温度<5℃(注:通过将H2O(3.30mL,183mmol)添加至无水DMF(179mL)来制备DMF淬灭溶液)。将反应混合物在0℃下保持3分钟,然后用在二氯甲烷(6.50mL)中浆化的(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸DMF半溶剂化物(165mg)接种结晶,并在0℃保持约30分钟。然后通过分批添加二氯甲烷(650mL)进一步稀释稀浆料,然后在0℃搅拌约30分钟。缓慢加入剩余约50%的DMF淬灭溶液(91mL),同时保持内部温度<5℃。添加完成后,将夹套温度以2℃/分钟的速率升至20℃,并在20℃下保持约45分钟。将反应浆液进一步用二氯甲烷(650mL)稀释并搅拌12小时。通过真空过滤收集沉淀的固体,然后用二氯甲烷洗涤两次(每次洗涤325mL)。将固体在20℃下用乙酸乙酯(325mL)重新浆化约2.5小时,通过真空过滤分离,然后真空干燥,得到(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸DMF半溶剂化物(58.4g,101mmol,产率89%),为白色至灰白色产物。1H NMR显示产物:DMF比率为1:0.8。
LCMS m/z=540.0[M+H]+.1H NMR(400MHz,DMSO-d6)δppm 10.77-12.19(br s,1H),9.75(br d,J=9.5Hz,1H),7.96(s,0.8H,DMF),7.58-7.65(m,2H),7.31-7.46(m,2H),5.80(br s,1H),3.42(s,3H),3.37(m,6H),2.90(s,2.8H,DMF),2.74(m,4.8H,包括DMF),1.21(t,J=7.5Hz,3H).手性HPLC:>99%ee。
步骤6:(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸甘氨酸盐
该过程在一对16L JLR中进行,分别称为容器A和容器B,每个容器均配备有顶置搅拌装置。将微粉化的甘氨酸(71.5g,0.952mol)、二氯甲烷(9L)和甲醇(896.5mL)加入到容器A中,并将相同的装料重复加入到容器B中。将混合物在25℃下搅拌。然后,(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸DMF半溶剂化物(137.5g,0.238mol)在乙酸乙酯(1.1L)中的浆料经至少15分钟加入到容器A中。用乙酸乙酯(550mL)冲洗浆料容器,然后将该冲洗液转移至反应器。在容器B中重复进行浆料装料和乙酸乙酯冲洗。用(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸甘氨酸盐(5.5g)接种容器A和容器B中的结晶。缓慢添加在乙酸乙酯(1.1L)中的(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸DMF半溶剂化物(137.5g,0.238mol)、用乙酸乙酯(550mL)冲洗容器,及接种后向容器A和容器B转移冲洗液的过程对每个反应器重复三次。将浆料在25℃下搅拌过夜并且反应完成。将容器A和B的浆料混合物倒入配有滤纸的不锈钢盘式过滤器中。使用真空压力过滤母液。容器A和容器B各自用乙酸乙酯(3.3L)冲洗,然后转移至盘式过滤器以洗涤分离的固体并过滤。用乙酸乙酯重复第二次对容器A和容器B的冲洗。使用真空压力推动洗涤液通过产物滤饼。将分离的固体在50℃下真空干燥,直到LOD分析给出<1%,得到(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸甘氨酸盐(1101g,1.791mol,92.5%产率),为白色固体。1H NMR显示产物:甘氨酸的比为1:1。
LCMS m/z=540.2[M+H]+.1H NMR(400MHz,DMSO-d6)δppm 9.41(br d,J=7.50Hz,1H),7.66(br d,J=8.0Hz,2H),7.36(br d,J=8.0Hz,2H),5.80(s,1H),3.48(s,2H),3.41(s,3H),3.34(s,7H),2.74(q,J=7.5Hz,3H),1.19(t,J=7.5Hz,3H).手性HPLC:>99%ee。
实施例1的结晶化合物,甘氨酸化合物与(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸(1:1)。
这种材料的X-射线粉末衍射(XRPD)图如图1所示,衍射角和d-间距的总结见下表I。XRPD分析是在PANanalytical X’Pert Pro衍射仪上使用X’celeratorTM RTMS(实时多带)检测器在Si零背景晶圆上进行的。采集条件包括:Cu Kα辐射,波长(λ):发电机压:45kV,发电机电流:40mA,步长:0.0167°2θ。入射光束侧的配置:10mm可编程发散狭缝、0.02rad Soller狭缝、防散射狭缝(0.5°)和10mm光束掩模。衍射光束侧的配置:10mm可编程防散射狭缝组件(X'celerator模块)和0.02rad Soller狭缝。
表I衍射角和d间距的XRPD总结
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该材料的差示扫描量热法(DSC)温谱图是在配有自动进样器和冷冻冷却系统的TAInstruments Discovery差示扫描量热仪上在40mL/min的N2吹扫下记录的,并显示在图2中。实验是在轻微卷边的铝盘中以10℃/min的加热速率加热至200℃的最终温度进行。该化合物在DSC中具有简单的单次熔融事件,起始温度为183.6℃,峰值温度为188.8℃,熔融焓为64J/g。由于熔融后立即热分解,熔融焓的测定并不可靠。该化合物在分解事件之前基于TGA损失表现出可忽略不计的重量损失。本领域技术人员将认识到吸热的起始温度、峰值温度和吸热焓可以根据实验条件而变化。
在TA Instruments Discovery热重分析仪上记录该材料的热重分析(TGA)温谱图,并显示在图3中。实验在N2吹扫下在敞口铝盘中进行,加热速率为10℃/min,最终温度为200℃。该化合物在分解事件之前在160℃下重量损失0.3%。
上述段落中与XRPD、DSC和TGA有关的一般要点各自均适用于本申请中进行的每个XRPD、DSC和TGA分析。此外,在本申请中报告的所有XRPD数据中,数据具有±0.2的精度。
步骤7:(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰胺)氧基)苯基)乙酰基)磷酰胺酸甘氨酸盐一水合物
向配有顶置搅拌装置的50mL JLR中加入(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸DMF半溶剂化物(1.5g,2.54mmol)和乙酸乙酯(37.5mL)。在搅拌的同时,将反应器的夹套以1℃/分钟的速度加热至50℃,并在50℃下维持95分钟。将2M甘氨酸水溶液(2.67mmol甘氨酸)装入连接的10mL计量单元中。经90分钟将2M甘氨酸的水溶液(1.33mL)加入到反应混合物中。加入后,将混合物保持60分钟,然后以0.25℃/分钟冷却至5℃。将反应混合物在5℃下保持60分钟。然后将反应混合物程控过夜以完成两个温度循环:以1℃/分钟加热至50℃,保持在50℃,以0.25℃/分钟冷却至5℃,并在5℃保持60分钟。将反应混合物在5℃下保持4.5天,然后通过一次性过滤漏斗过滤。将反应固体的湿滤饼用乙酸乙酯(2x 9mL)冲洗两次并过滤。将固体在25℃的真空烘箱中放置过夜并干燥以产生(R)-(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸水合物甘氨酸盐(1.55g,2.45mmol),为白色固体。
1H NMR(400MHz,DMSO-d6)δppm 9.34(s,1H),7.65(br d,J=7.5Hz,2H),7.36(brd,J=7.5Hz,2H),5.79(br s,1H),3.40(s,6H),3.35(br s,9H),2.74(q,J=7.0Hz,2H),1.19(t,J=7.0Hz,3H).手性HPLC:>99%ee。
实施例1的一水合甘氨酸盐的X射线粉末衍射(XRPD)图显示在图4中,并且在下表II中给出了衍射角和d-间距的总结。
表II实施例1一水合甘氨酸盐的XRPD衍射角和d-间距的总结
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该水合甘氨酸盐材料的差示扫描量热法(DSC)温谱图与之前的DSC设备相同,显示在图5中。实验是在轻微卷边的铝盘中以10℃/min的加热速率加热至250℃的最终温度进行。该化合物在40-140℃范围内发生广泛的吸热脱水事件,随后出现急剧的熔化吸热,起始温度为175.5℃,峰值温度为179.3℃,熔融焓为52J/g。由于熔融后立即热分解,熔融焓的测定并不可靠。本领域技术人员将认识到吸热的起始温度、峰值温度和吸热焓可以根据实验条件而变化。
该水合甘氨酸盐材料的热重分析(TGA)温谱图与之前的TGA设备相同,显示在图6中。实验在N2吹扫下在敞口铝盘中进行,加热速率为10℃/min,最终温度250℃。该化合物在40至140℃范围内重量损失3.0%,表明在分解事件之前为一水合物形态。
实施例2
(R)-4-(2-氨基-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-
氧代乙基)苯基甲磺酸酯
步骤1:4-(2-氨基-2-氧代乙酰基)苯基甲磺酸酯
在氮气下,在室温下,一次性经1分钟向4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯(50g,204mmol)在乙腈(3000mL)中的搅拌悬浮液中添加二氧化锰(248g,2854mmol)。将反应混合物在70℃下加热16小时,然后在80℃下加热48小时。将反应混合物冷却至室温,通过硅藻土过滤,并用乙腈(2000mL)洗涤硅藻土床。将滤液减压浓缩,得到44g所期望的粗产物,为灰白色固体。通过UPLC MS对材料的分析表明,46.67%的曲线下面积对应于产物质量,48.26%的曲线下面积对应于起始材料质量。如下所述,使用PCC对粗产物/起始材料混合物进行氧化反应。
向含有4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯和4-(2-氨基-2-氧代乙酰基)苯基甲磺酸酯(42.0g,86mmol)在四氢呋喃(THF)(2.4L)中的混合物的搅拌溶液中在氮气下在室温下通过与硅藻土一次性混合来添加PCC(18.53g,86mmol)。将反应混合物在室温下搅拌2小时。将反应混合物通过硅藻土过滤并用(2000mL)THF洗涤硅藻土床。真空浓缩滤液,得到粗产物,为深棕色固体。将粗产物溶解在100mL甲醇和150mL DCM的混合物中并吸收到400g二氧化硅(60-120目)上。将所得材料通过4kg二氧化硅(230-400目)过滤,并用(3000mL)乙酸乙酯洗涤二氧化硅床。将滤液真空浓缩,得到4-(2-氨基-2-氧代乙酰基)苯基甲磺酸酯(26g,52%),为灰白色固体。LCMS m/z=244.0[M+H]+.1HNMR(400MHz,DMSO-d6)δppm 8.37(br s,1H),8.13-8.09(m,2H),8.06(br s,1H),7.58-7.54(m,2H),3.49(s,3H).
步骤2:(S)-4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯
向配备有超大搅拌棒的500mL圆底烧瓶中加入4-(2-氨基-2-氧代乙酰基)苯基甲磺酸酯(5.0g,20.56mmol)和异丙醇(10mL)。向所得混合物中添加80mL的1.25mg/mLβ-烟酰胺腺嘌呤二核苷酸磷酸二钠盐(NADP+,二钠)(100mg,20.56mmol)在0.1M KPi pH 7.0缓冲液中的溶液,然后添加SynBio Ketoreductase Enzyme Seq ID S00000617(300mg,20.56mmol)。将所得浆料在室温下剧烈搅拌。总共46小时后,水层用固体KCl饱和并用EtOAc(200mL)稀释混合物。由此,形成乳液,将混合物通过垫过滤并用大量的EtOAc(3x75mL)冲洗,得到清晰的不同层。用盐水洗涤有机层,并用EtOAc(2x75mL)反萃取合并的水层。将合并的有机物经Na2SO4干燥,过滤,并且在减压下浓缩。将残余物在高真空下干燥至恒重,得到(S)-4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯(4.40g,87%产率),为白色固体。LCMS m/z=246.0[M+H]+.1HNMR:(400MHz,DMSO-d6)δppm 7.54–7.49(m,2H),7.42(brs,1H),7.33–7.28(m,2H),7.21(br s,1H),6.13(d,J=4.9Hz,1H),4.89(d,J=4.9Hz,1H),3.37(s,3H).手性HPLC:>99%ee。
步骤3:(S)-4-(2-氨基-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯
向(S)-4-(2-氨基-1-羟基-2-氧代乙基)苯基甲磺酸酯(4.3g,17.53mmol)在二氯甲烷(DCM)(40mL)中的冷(0℃)悬浮液中经约1分钟添加Ms-Cl(1.639mL,21.04mmol),然后经约3分钟添加TEA(3.67mL,26.3mmol)。2小时后,LCMS显示约15%起始物质(3小时后没有额外进展),因此将反应混合物重新冷却至0℃并添加额外部分的Ms-Cl(0.410mL,5.26mmol)和TEA(1.222mL,8.77mmol)。除去冰浴并使反应温热至室温。另外30分钟后,将反应混合物用饱和NaHCO3水溶液(50mL)淬灭并剧烈搅拌。过滤所得悬浮液/乳液,并依次用水(3x30mL)和乙醚(3x30mL)冲洗固体,并在高真空下干燥至恒重,得到(S)-4-(2-氨基-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(4.44g,78%产率),为浅灰白色固体。LCMS m/z=324.0[M+H]+.1HNMR(400MHz,DMSO-d6)δppm 7.86(s,1H),7.63–7.54(m,3H),7.41(d,J=7.8Hz,2H),5.91(s,1H),3.41(s,3H),3.26(s,3H).
步骤4:(R)-4-(2-氨基-1-((3,5-二氧基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯
向2-(二甲基氨基)-4-乙基-6-巯基吡啶-3,5-二甲腈(1.437g,6.19mmol)在乙酸乙酯(50mL)中的悬浮液中添加iPr2EtN(1.350mL,7.73mmol)。将橙色悬浮液在室温下搅拌。30分钟后,添加(S)-4-(2-氨基-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(2.0g,6.19mmol)在乙酸乙酯(30mL)中的悬浮液,并将所得橙色悬浮液在室温下搅拌。4小时后,用抹刀刮擦烧瓶内部,引发产物沉淀。将所得悬浮液再搅拌30分钟,然后冷却至0℃。使用过滤漏斗通过过滤收集沉淀物,依次用冷(0℃)EtOAc(2x20mL)、水(2x10mL)、冷(0℃)EtOAc(2x20mL)冲洗,然后用乙醚(2x10mL)冲洗。将固体在高真空下干燥48小时,得到(R)-4-(2-氨基-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯(1.37g,48.2%产率),为灰白色固体。LCMS m/z=460.2[M+H]+.1H NMR(400MHz,DMSO-d6)δppm 7.96(s,1H),7.62(d,J=8.8Hz,2H),7.42–7.31(m,3H),5.66(s,1H),3.39(s,3H),3.33(s,6H),2.75(q,J=7.8Hz,2H),1.20(t,J=7.8Hz,3H).
实施例3
(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫代)-2-(4-((甲基磺酰
基)氧基)苯基)乙酰基)磷酰胺酸
在0℃下向4-(2-((双(苄基氧基)磷酰基)氨基)-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯(77.34g,107mmol)在乙腈(1L)中的溶液中添加三甲基碘硅烷(34mL,247mmol),并将混合物温热至室温。将反应混合物在室温下搅拌30分钟。用1.2L 10%焦亚硫酸钠淬灭反应。形成沉淀并搅拌粘稠混合物。过滤混合物并用1L水洗涤收集的固体。在过滤漏斗中真空干燥过夜。将所得固体悬浮于2L乙醚中并搅拌30分钟。过滤混合物,干燥收集的固体,得到(2-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-(4-((甲基磺酰基)氧基)苯基)乙酰基)磷酰胺酸(32g,59.3mmol,55.2%产率),为灰白色固体。LCMS m/z=540.0[M+H]+.1H NMR(400MHz,DMSO-d6)δppm 9.48(s,1H),7.66(d,J=8.5Hz,2H),7.35(d,J=8.5Hz,2H),5.81(s,1H),3.40(s,3H),3.34(s,6H),2.74(q,J=7.6Hz,2H),1.20(t,J=7.6Hz,3H)(2个磷酸质子未观察到)。
实施例4
4-(2-氨基-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代
乙基)苯基甲磺酸酯
向2-(二甲基氨基)-4-乙基-6-巯基吡啶-3,5-二甲腈(2.0g,8.61mmol)在乙酸乙酯(50mL)中的黄色悬浮液中一次性顺序添加DIEA(1.880mL,10.76mmol)和4-(2-氨基-1-((甲基磺酰基)氧基)-2-氧代乙基)苯基甲磺酸酯(2.78g,8.61mmol)。将混合物在室温下搅拌24小时。通过过滤收集固体,用乙酸乙酯、水和更多的乙酸乙酯冲洗。将固体干燥,得到3.50g浅黄色固体。将固体物质悬浮在30mL水中并搅拌1小时。过滤收集固体,用水冲洗,干燥,得到4-(2-氨基-1-((3,5-二氰基-6-(二甲基氨基)-4-乙基吡啶-2-基)硫基)-2-氧代乙基)苯基甲磺酸酯(3.09g,76%),为淡黄色固体。LCMS m/z=460.0[M+H]+.1H NMR(400MHz,DMSO-d6)δppm 7.97(s,1H),7.65–7.59(m,2H),7.41–7.34(m,3H),5.65(s,1H),3.40(s,3H),3.33(s,6H),2.75(q,J=7.6Hz,2H),1.20(t,J=7.6Hz,3H).
生物学数据
DNMT1邻近闪烁测定(SPA)–测定A(全长人DNMT1)
该测定使用信号增强形式的邻近闪烁技术来评估化合物的效力。利用全长人类DNMT1、半甲基化DNA双链体*和氚化SAM来监测活性。测定板的创建包含以下参数:将500nL的11pt、3倍连续稀释的化合物压印到96孔Costar板(#3884)中。在测定当天制备测定缓冲液混合物,其组成为:20mM Tris pH 7.5、1mM DTT、1mM EDTA和5%甘油。然后在测定缓冲液中制备由30nM DNMT1蛋白(全长人DNMT,内部制造)组成的2X酶混合物。最后制备2X底物混合物,其由测定缓冲液中的160nM 40mer半甲基化DNA*、0.48μM 3H-SAM和2.92μM冷SAM组成(3H-SAM最后添加)。淬灭剂(1mM SAH)批量制备并冷冻在-20°直至使用。使用多通道电子移液器将10uL 2X底物混合物添加到整个板中。添加之间将板振荡至少10秒以确保混合。接下来,使用多通道移液管(振荡板)将20uL的2x淬灭混合物添加到第12列中。使用多通道电子移液器,将10uL的2x酶混合物添加到全板中,从第11列开始,移至第10列(最后是第12列,以避免预淬灭携流(carryover))。将板在盖上的情况下在摇床上孵育30分钟。孵育期结束时,将20uL淬灭混合物添加到除第12列(振荡板)之外的所有孔中,然后添加在不含DNAse的水稀释的20uL 3mg/mL PerkinElmer PEIPVT SPA珠(Cat.#RPNQ0097)并振荡至少30分钟。将板用透明密封件密封并以500rpm离心1分钟。在MicroBeta(PerkinElmer,读取3H)上读取板(1分钟/孔)。
Microsoft Excel用于分析Vi/Vo数据,GraFit用于拟合数据。将应答针对每个板内的未抑制(DMSO)和预淬灭对照进行归一化。使用三参数逻辑拟合分析剂量-应答曲线,其中Ymin约束为0,结果表示为IC50值。
最终测定条件:20mM Tris(Hampton Research-HR-937-06),pH 7.5,1mM DTT(Invitrogen–P2325),1mM EDTA(Invitrogen–AM9260G),5%甘油(Teknova–G1796),0.02%Pluronic F127(Life Technologies–P6866),15nM DNMT1(全长人DNMT1–GSK内部制造),240nM 3H-SAM(PerkinElmer–NET155H001MC),1460nM冷SAM(New England Biolabs-B9003S)和80nM40-mer半甲基化DNA寡核苷酸(Integrated DNA Technologies–定制),1mMSAH(Sigma A9384)和1mg/mL PEIPVT SPA珠(PerkinElmer RPNQ0097),重悬于水中。
*40mer me-DNA寡聚体双链体:
5'-CCTCTTCTAACTGCCAT(Me-dC)GATCCTGATAGCAGGTGCATGC-3'
5'-GCATGCACCTGCTATCAGGATCGATGGCAGTTAGAAGAGG-3'
DNMT1邻近闪烁测定(SPA)–测定B(人截短的DNMT1(601-1600))
该测定使用信号增强形式的邻近闪烁技术来评估化合物的效力。利用人截短的DNMT1(601-1600)、单个半甲基化CpG位点寡核苷酸和氚化SAM来监测活性。测定板的创建包含以下参数:将10mM化合物(11点、3倍连续稀释)以每孔100nL(100X,在100%DMSO中)压印到Griener白色LV 384孔板(#784075)中。在测定当天制备测定缓冲液混合物,其组成为:碱性缓冲液:(500mM Hepes,ph 8,预先制备的1M MgCl2,作为储备液在室温下保存)、10%NP40-Surfact AMPS、10%超纯BSA 50mg/ml和2M DTT(DL-二硫苏糖醇)。然后制备2X酶混合物,其组成为:DNMT1蛋白(截短的人DNMT1-601-1600,内部制备,储备液浓度为16.876uM),添加到测定缓冲液混合物中。2X底物混合物是最后制备的,其组成为:1mM 40-mer半甲基化DNA寡核苷酸、12.5uM 3H-SAM(腺苷-L-蛋氨酸-S-[甲基-3H]比活性55-85Ci/mmol)和32mMS-腺苷-L-甲硫氨酸溶液(在添加到底物混合物之前,将其在无核酸酶-H2O中稀释至1mM),添加到测定缓冲液混合物中(最后添加3H-SAM)。仅使用Thermo Multidrop Combi将5uL测定缓冲液混合物分配至第18列。接下来,使用Thermo Multidrop Combi将5uL 2X酶混合物分配至第1-17、19-24列。然后使用Thermo Multidrop Combi将5uL 2X底物混合物分配到整个板中。将板堆叠并在顶板上盖上盖板,孵育40分钟。淬灭混合物在孵育步骤25分钟左右制备,其组成为:S-腺苷-L-甲硫氨酸和PerkinElmer PEIPS Imaging Beads(Cat.#RPNQ0098)(10mg/ml)在无核酸酶-H2O中的32mM溶液。在使用之前将淬灭混合物涡旋以使珠进入溶液中。孵育40分钟后,使用Thermo Multidrop Combi将10uL淬灭混合物分配到整个板中。将板用透明密封件密封并以1000rpm/1min离心并暗适应30分钟。在Viewlux上读取板(PerkinElmer,613nm发射滤光片,300秒双重曝光,(10分钟,总读取时间))。
使用Abase数据库对数据进行分析。将应答针对每个板内的未抑制(DMSO)和低对照进行归一化。使用四参数逻辑拟合分析剂量-应答曲线,结果表示为pIC50值。
最终测定条件:50mM HEPES(Teknova–H1035)pH 8.0,2mM MgCl2(Sigma–M1028),1mM DTT(Sigma–D5545),0.01%NP40表面活性剂Amps(Themo Scientific–28324),0.01%BSA(Ambion–AM2618),40nM DNMT1(截短的人DNMT1(601-1600–GSK内部制造)),100nM 3H-SAM(American Radiolabeled Chemicals Inc–ART 0288),900nM冷SAM(New EnglandBiolabs-B9003S)和200nM 40-mer半甲基化DNA寡核苷酸(Integrated DNA Technologies–43334514)。
固体化合物在禁食状态模拟肠液中的溶解度
在室温下平衡4小时后,在pH 6.5下测定固体化合物在禁食状态模拟肠液(FaSSIF)中的溶解度(使用以下中描述的程序:Sou,T.;C.A.S.Automatedassays for thermodynamic(equilibrium)solubility determination.Drug DiscoveryToday:Technologies 2018,27,11-19)。将1ml FaSSIF缓冲液(3mM牛磺胆酸钠,0.75mM卵磷脂,在磷酸钠缓冲液中,pH 6.5)添加至手动称重的在4ml小瓶中的1mg固体化合物。将所得悬浮液在室温下以900rpm振荡4小时,然后转移至Multiscreen HTS、96孔溶解度过滤板以分离残余固体和滤液。使用DMSO中已知浓度的化合物的单点校准,通过HPLC-UV对滤液中的化合物浓度进行定量。与化合物一起测试了一组3个已知溶解度的内标(阿托伐醌、尼美舒利和华法林,分别为2、20和140μg/ml),以评估该过程的适用性。测定的动态范围为1-1000μg/ml。
结果
a DNMT1全长
b DNMT1截短
药代动力学研究:所有研究均根据GSK关于实验动物照护、福利和处理的政策进行,并由GSK的机构动物照护和使用委员会或研究开展地的机构的伦理审查程序进行审查。以非交叉设计,对于实施例2使用非禁食状态的雄性Wistar Han大鼠(n=3/剂量途径)及对于参照化合物4使用非禁食状态的雄性Sprague-Dawley大鼠(n=2/剂量途径)进行药代动力学研究。将化合物制备为5%DMA/15%Solutol中的溶液并以60分钟IV输注和PO强饲法施用。从给药前到给药后24小时在多个时间点连续收集血样,并通过LC/MS/MS对分析物进行定量。通过将PO给药获得的剂量归一化曲线下面积(DNAUC)与IV途径的DNAUC进行比较来计算百分比生物利用度[(PO DNAUC/IV DNAUC)*100]。
小鼠体内研究-方法:
将悬浮在50%Matrigel(BD Biosciences)/50%Dulbecco磷酸盐缓冲盐水(DPBS)中的SKM-1细胞(3.8x106)植入8-11周龄雌性NOD.CB17-Prkdc<scid>1NCrCrl小鼠。使用数字卡尺测量肿瘤,并根据肿瘤大小(P值>0.9085)将其分层区组随机化到平均肿瘤体积为219或1076mm3的治疗组中,分别用于功效或PK/PD研究。GSK4172239A每周在无菌水中配制。每周两次测量小鼠的体重和肿瘤大小。随机分组后的第二天开始给药。通过口服强饲法(PO)对动物每日两次(BID)以22、67或200mg/kg施用实施例1。研究期间,没有连续两次测量的最大肿瘤负荷≥2,500mm3。对于PK/PD研究,在第20次剂量(10天)后两小时收集肿瘤、血液和骨髓。对于PK,将血液与水按50:50混合,同时将肿瘤以1:4稀释度在无菌水中匀浆(Omni手持式匀浆器)。两个样品均用乙腈沉淀,并通过HPLC-MS/MS(Waters Acquity uPLC,Sciex API5000)测定实施例4的浓度。使用整体DNA甲基化(5-甲基胞嘧啶)LC-MS/MS测定评估SKM-1肿瘤和小鼠骨髓样品。根据制造商的说明,使用Quick-DNA Miniprep Kit(ZymoResearch)分离DNA。对于每个样品,根据制造商的说明将DNA Degradase Plus(ZymoResearch)添加到1,250ng DNA中,以从基因组DNA中释放各核苷。将降解酶处理的DNA(10μl)与190μl乙腈/水/氢氧化铵(90:10:0.1)溶液混合,所述溶液中含有100ng/ml 2′-脱氧胞苷-13C,15N2(Toronto Research Chemicals)和10ng/ml 5-甲基-2′-脱氧胞苷-13C,15N2(Toronto Research Chemicals)标记的标准品。优化了HPLC-MS/MS方法来定量2'-脱氧胞苷和5-甲基-2'-脱氧胞苷。使用Waters Acquity UPLC上的Acquity BEH Amide,1.7μm,2.1×50mm2柱通过HILIC(亲水相互作用液相色谱)分离分析物和经标记的标准品,随后在Sciex API5000上使用正离子涡轮喷雾电离进行MS/MS分析。使用纯2'-脱氧胞苷(Sigma-Aldrich)和5-甲基-2'-脱氧胞苷(Santa Cruz Biotechnology)生成的标准曲线测定2'-脱氧胞苷和5-甲基-2'-脱氧胞苷的浓度。将5-甲基胞嘧啶的浓度针对总胞嘧啶浓度进行归一化以确定5-甲基胞嘧啶的百分比。将处理过的样品的值针对媒介物对照进行归一化。
小鼠体内研究-结果:
实施例1显示了体内活性。在带有皮下SKM-1人AML(急性髓性白血病)异种移植物的免疫受损小鼠中评估实施例1。通过口服强饲法(PO)对动物每日两次(BID)以22、67或200mg/kg施用实施例1。为了检查药代动力学(PK)和药效(PD)变化,在第20次剂量(10天;n=5只动物/组)后两小时收集肿瘤、血液和骨髓。药代动力学评估显示药物暴露(以外消旋活性部分实施例4测量)与剂量成比例,并且在血液和肿瘤中大致相等。此外,使用基于LC-MS/MS的5-甲基胞嘧啶测定对抑制DNMT1的机制后果(DNA甲基化减少)进行了全面评估。与媒介物相比,实施例1的所有剂量的整体DNA甲基化均降低,在200mg/kg组中观察到肿瘤中的最大变化为49%,骨髓中的最大变化为47%。在随后的研究中,为了检查抗肿瘤功效,在治疗期间每周两次测量肿瘤体积(每组10只动物),持续≥4周。实施例1诱导了肿瘤体积的剂量依赖性减少,其中当与第22天的媒介物比较时,肿瘤生长抑制的范围为从22mg/kg组的平均35%到200mg/kg组的显著消退,最后一天媒介物组包含9只动物。
Claims (21)
1.一种式(I)的化合物
或其前药,或其药学上可接受的盐。
2.一种式(II)的化合物
或其前药,或其药学上可接受的盐。
3.一种化合物,其是式(IV)的前药
或其药学上可接受的盐。
4.一种化合物,其是式(V)的前药
或其药学上可接受的盐。
5.如权利要求4所述的前药,其中所述盐是甘氨酸盐。
6.如权利要求5所述的甘氨酸盐,其中所述盐是无水的。
7.如权利要求6所述的甘氨酸盐,其中所述盐是无水结晶甘氨酸盐。
8.如权利要求7所述的无水结晶甘氨酸盐,其特征在于它提供了基本上如表I中所列的XRPD图谱
表I衍射角和d间距的XRPD总结
其中所述表中的数据是±0.2。
9.如权利要求7所述的无水结晶甘氨酸盐,其特征在于它提供了基本上与图1一致的XRPD图谱。
10.如权利要求7所述的无水结晶甘氨酸盐,其特征在于它提供了具有代表性衍射峰的XRPD图谱。
11.一种药物组合物,其包含如权利要求1至10中任一项所定义的化合物或前药、或其药学上可接受的盐,以及一种或多种药学上可接受的赋形剂。
12.如权利要求1至10中任一项所定义的化合物或前药、或其药学上可接受的盐,用于医学疗法中。
13.如权利要求1至10中任一项所定义的化合物或前药、或其药学上可接受的盐,用于治疗与不适当的DNMT1活性相关的疾病。
14.如权利要求1至10中任一项所定义的化合物或前药、或其药学上可接受的盐在制备用于治疗与不适当的DNMT1活性相关的疾病的药物中的用途。
15.一种治疗与不适当的DNMT1活性相关的疾病的方法,所述方法包括向有需要的人患者施用如权利要求1至5中任一项所定义的化合物或前药、或其药学上可接受的盐。
16.如权利要求15所述的方法,其中所述与不适当的DNMT1活性相关的疾病是癌症、癌前综合征或β血红蛋白病障碍。
17.如权利要求16所述的方法,其中所述癌症是骨髓增生异常综合征(MDS)、急性髓性白血病(AML)、结直肠癌(CRC)、淋巴瘤例如非霍奇金淋巴瘤、黑色素瘤、肾癌、胃癌、非小细胞肺癌(NSCLC)或乳腺癌。
18.如权利要求16所述的方法,其中所述β血红蛋白病障碍是镰状细胞病、镰状细胞性贫血或β地中海贫血。
19.一种组合,其包含如权利要求1至10中任一项所定义的化合物或前药、或其药学上可接受的盐,以及一种或多种其他活性剂。
20.一种治疗镰状细胞病、镰状细胞性贫血或β地中海贫血的方法,所述方法包括向有需要的人患者施用如权利要求4-10中任一项所述的前药或其药学上可接受的盐。
21.一种治疗骨髓增生异常综合征(MDS)、急性髓性白血病(AML)、结直肠癌(CRC)、非霍奇金淋巴瘤(NHL)、黑色素瘤或乳腺癌的方法,所述方法包括向有需要的人患者施用如权利要求4-10中任一项所述的前药或其药学上可接受的盐。
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PCT/IB2022/051637 WO2022185160A1 (en) | 2021-03-02 | 2022-02-24 | Substituted pyridines as dnmt1 inhibitors |
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