CN114008058A - 用于治疗癌症的cdk抑制剂的前药 - Google Patents
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Abstract
Description
相关申请的交叉引用
本发明要求于2019年4月26日递交的中国申请No 201910343182.5的优先权权益,该申请通过引用来整体并入。
技术领域
本发明涉及抑制或调节细胞周期蛋白依赖性激酶(CDK)和/或糖原合成酶激酶-3(GSK-3)活性并且治疗由细胞周期蛋白依赖性激酶和/或糖原合成酶激酶-3介导的疾病症状或病症,诸如癌症的4-(2,6-二氯苯甲酰氨基)-N-(4-哌啶基)-1H-吡唑-3-甲酰胺的衍生物和前药,以及其组合物。
背景技术
早在2006年,Berdini及其合作者就报道了4-(2,6-二氯苯甲酰氨基)-N-(4-哌啶基)-1H-吡唑-3-甲酰胺(吡唑衍生物,也被称为4-[(2,6-二氯苯甲酰基)氨基]-N-4-哌啶基-1H-吡唑-3-甲酰胺,4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-羧酸N-(哌啶-4-基)酰胺,AT7519、AT-7519或AT7519M)(例如参见WO 2005012256),其具有以下化学结构:
AT7519是具有潜在抗肿瘤活性的口服生物可利用的小分子。它选择性地结合并抑制周期蛋白依赖性激酶(CDK),从而可引起细胞周期停滞,诱导细胞凋亡并抑制肿瘤细胞增殖。CDK是参与细胞周期调节的丝氨酸/苏氨酸激酶,并且可能在某些类型的癌细胞中过表达。迄至今日,已经在包括专利/专利申请以及科学期刊论文和通讯在内的100多种出版物中报道了上述化合物。这些专利和早期专利申请的实例包括WO2006077425、WO2006077416、WO2006077419、US7385059和US2010021420。科学文献的实例包括:“Identification of N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide(AT7519),a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-RayCrystallography and Structure Based Drug Design”(Wyatt,et al.,J.Med.Chem.,2008,51(16),4986-4999);“Biological characterization of AT7519,a small-molecule inhibitor of cyclin-dependent kinases,in human tumor cell lines”(Squires,et al.,Mol.Cancer Ther.,2009,8(2),324-332.);“AT7519,a Cyclin-Dependent Kinase Inhibitor,Exerts Its Effects by Transcriptional Inhibitionin Leukemia Cell Lines and Patient Samples”(Squires,et al.,Mol.Cancer Ther.,2010,9(4),920-928.);和“AT7519,A novel small molecule multi-cyclin-dependentkinase inhibitor,induces apoptosis in multiple myeloma via GSK-3βactivationand RNApolymerase II inhibition”(Santo,et al.,Oncogene,2010,29(16),2325-2336.)。
许多研究已经证实了AT7519在治疗癌症中的潜在治疗用途。AT7519是ATP竞争性CDK抑制剂,对于CDK1,Ki值为38nM。除GSK3β(IC50=89nM)外,AT7519对所有非CDK激酶均无活性。AT7519在多种人肿瘤细胞系中均显示出有效的抗增殖活性,IC50值的范围为40nM(对于MCF-7)至940nM(对于SW620),该活性与其对CDK1和CDK2的抑制相一致(Squires MS,etal.Mol.Cancer Ther,2009,8(2),324-332.)。AT7519在多发性骨髓瘤(MM)细胞系中诱导剂量依赖性细胞毒性,其中在48小时时,IC50值为0.5~2μΜ,其中最敏感的细胞系为MM.1S(0.5μM)和U266(0.5μM),并且最耐受的细胞系为MM.1R(>2μM)。AT7519在外周单核细胞(PBMNC)中不会诱导细胞毒性。AT7519部分克服了IL6和IGF-1赋予的增殖优势,以及骨髓基质细胞(BMSC)的保护作用。AT7519诱导RNA pol II CTD的2位丝氨酸和5位丝氨酸的快速去磷酸化,并且导致转录抑制,部分地引起了MM细胞中AT7519诱导的细胞毒性。AT7519通过下调GSK-3β磷酸化来诱导GSK-3β的活化,从而可有助于使AT7519诱导的细胞凋亡独立于转录抑制的影响(Santo L,et al.Oncogene,2010,29(16),2325-2336.)。
已经表明,在HCT116和HT29结肠癌异种移植模型中,每天两次给药AT7519(9.1mg/kg)导致早期和晚期s.c.肿瘤消退(Squires MS,et al.Mol.Cancer Ther,2009,8(2),324-332)。在人MM异种移植小鼠模型中,AT7519治疗(15mg/kg)可抑制肿瘤生长并且延长小鼠的中位总生存期,同时增加了胱天蛋白酶3的活性(Santo L,et al.Oncogene,2010,29(16),2325-2336)。
AT7519被认为是多种适应性,包括多发性骨髓瘤、套细胞淋巴瘤、慢性淋巴细胞白血病、实体瘤、非霍奇金淋巴瘤和血液瘤的潜在治疗剂。人们进行了若干项临床试验,以测试AT7519在多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)以及包括套细胞淋巴瘤(MCL)在内的实体瘤中的治疗效果(例如,参见“A Phase I study of cyclin-dependent kinaseinhibitor,AT7519,in patients with advanced cancer:NCIC Clinical Trials GroupIND 177”,(Chen,E.X.,et al.,Br.J.of Cancer,2014,111(12),2262-2267))。然而,由于AT7519参与转录和增殖所必需的多种途径,不良事件的可能性很高。实际上,AT7519已经在动物和人体测试中均显示出显著水平的毒性。用AT7519治疗的大多数患者具有至少有一种与治疗相关的AE(82.1%)。根据“不良事件通用术语标准”,大多数AE的严重程度为1级或2级(分别为46.7%和37.8%)。最常见的治疗引发的AE为恶心(50.0%),疲劳(42.9%),呕吐和厌食(各39.3%),便秘(32.1%)以及外周性水肿、发热、和低血压(各25.0%)(Mahadevan,D;et al.,Ann.Oncol.,2011,22:2137-2143)。在I期临床试验中,AT7519M剂量递增至32.4mg/m2。在最初入组的三名患者中,一名患者经历了DLT(3级疲劳)。另外两名患者使用了该剂量水平,且两人均出现DLT(发热性中性粒细胞减少症和3级低钾血症和粘膜炎)(Chen,E.X.;et al.,Br.J.Cancer,2014,111:2262-2267)。
这就需要增强AT7519治疗用途的潜力和/或降低毒性。
发明内容
本发明的目的是改善现有技术中存在的至少一些缺陷。本技术的实施方式至少部分地基于发明人的理解而开发,即需要降低4-(2,6-二氯苯甲酰氨基)-N-(4-哌啶基)-1H-吡唑-3-甲酰胺(AT7519)的毒性,以使其适用于治疗应用。这些或其他需求可通过本文所限定的AT7519衍生物和/或前药,药物组合物,以及它们抑制或调节周期蛋白依赖性激酶(CDK)和/或糖原合成酶激酶-3(GSK-3)的活性、治疗由细胞周期蛋白依赖性激酶和/或糖原合成酶激酶-3介导的疾病症或病症(诸如癌症)的用途来得以满足。
在第一方面,提供了式I的化合物,或其药学上可接受的盐或酯:
其中,R1和R2独立地为氢(H)或保护基(P),并且所述保护基可相同或不同,条件是R1和R2中的至少一个不为氢。
在一个实施方式中,R1和R2各自独立选自以下项的保护基:酰基、羰基、硫代羰基、和氨基甲酰基;取代或未取代的乙酰基、氨基烷酰基和α-氨基烷酰基;衍生自天然氨基酸或非天然氨基酸的取代或未取代的酰基;肽残基的取代或未取代的酰基;取代或未取代的环烷基羰基、杂环烷基-羰基、烷氧羰基、芳氧羰基、杂烷氧基羰基或杂芳氧基羰基;以及O-取代的羟甲基。在一实施方式中,R1和R2独立地为氢,或者结构为R3W(R4R5C)m-的保护基;其中,m为选自1至6的整数,W为氧(-O-)、硫(-S-)、氮(-NH-)或不存在,R4和R5独立地为氢或低级烷基,并且R3为 其中,
X为氧(-O-)、硫(-S-)、氮(-NH-)或亚甲基(-CH2-);
R6和R7独立地为氢;取代或未取代的烷基或环烷基;具有取代基或不具有取代基的芳基或杂芳基;结构为R8-(OCH2CH2)n-的PEG残基,其中,n=1至10,R8为氢或低级烷基;成酯基团,诸如低级烷基或芳基;或者,当X为氧或硫时,为成盐部分,诸如钠、钾、四乙铵或四丁铵;或者,R6和X的组合一起形成具有额外取代基或不具有额外取代基的烷基或芳基;其中,条件是R1和R2中的至少一个不为氢。
在又一实施方式中,R2为氢,R1选自以下项的保护基:酰基、羰基、硫代羰基和氨基烷酰基;取代的或未取代的乙酰基、氨基烷酰基和α-氨基烷酰;衍生自天然氨基酸或非天然氨基酸的具有取代基或不具有取代基的酰基;肽残基的酰基;取代或未取代的环烷基-羰基、杂环烷基-羰基;烷氧羰基、芳氧羰基、杂烷氧基羰基或杂芳氧基羰基;具有取代基或不具有取代基的O-取代的羟甲基;以及R3W(R4R5C)m-,其中,m为0至6,W、X、R3、R4和R5如上所限定。
在另一实施方式中,R1为氢,并且R2为R3W(R4R5C)m-,其中m为选自1至6的整数,W、R3、R4和R5如上所限定。
在又一实施方式中,R1和R2独立地选自氢、 其中,X、R6和R7如上所限定,其中条件是R1和R2之一不为氢。在一些实施方式中,R9是选自低级烷基、羟基、卤素(-F、-Cl、-Br或-I)、硝基、氨基、低级烷基氨基和低级烷氧基的取代基。
在一些实施方式中,式I的化合物为表1中示出的化合物或其药学上可接受的盐、酯、螯合物、水合物、溶剂化合物、立体异构体或多晶型形式。
在一些实施方式中,式I的化合物为AT7519的衍生物或前药。
表1.式I化合物的实例
在一些实施方式中,本文提供的化合物是周期蛋白依赖性激酶的抑制剂,尤其是选自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7和CDK9。在一些实施方式中,化合物可抑制选自CDK1、CDK2、CDK4、CDK5、CDK6和CDK9中的一种或多种CDK。在一实施方式中,化合物抑制CDK1、CDK2,或者抑制CDK1和CDK2。在实施方式中,化合物抑制CDK4、CDK6,或者抑制CDK4和CDK6。额外地或可替代地,在实施方式中,本文提供的化合物是糖原合成酶激酶-3(GSK-3)的抑制剂。
在一些实施方式中,本文提供的化合物是AT7519的前药。
在第二概括性方面,本发明提供了一种包括本文所述化合物或其药学上可接受的盐或酯,以及药学上可接受的载体的药物组合物。在一些实施方式中,提供了包括式I化合物或其药物学上可接受的盐或酯,以及药学上可接受的载体的药物组合物。
在第三概括性方面,本发明提供了抑制或调节受试者中周期蛋白依赖性激酶(CDK)和/或糖原合成酶激酶-3(GSK-3)活性的方法。在一些实施方式中,提供了在有需要的受试者中治疗由周期蛋白依赖性激酶和/或糖原合成酶激酶-3介导的疾病症状或病症的方法,包括将有效量的上文所述的化合物和/或药物组合物施用至受试者。通过本文所提供的方法可治疗的由周期蛋白依赖性激酶和/或糖原合成酶激酶-3介导的疾病病症或病症的非限制性实例包括、中风、癫痫、神经变性疾病(如阿尔茨海默病)、运动神经元疾病、进行性核上性麻痹、皮质基底变性和皮克氏病,以及增殖、凋亡或分化障碍,诸如各种肿瘤和癌症。在其他实施方式中,化合物对于治疗肿瘤和癌症是有用的。根据本文提供的方法可治疗的肿瘤和癌症的实例包括但不限于:多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性髓系白血病(AML)、套细胞淋巴瘤(MCL)、实体瘤、难治性实体瘤、非霍奇金淋巴瘤、结肠的瘤,血液瘤和骨髓增生异常综合征(MDS)。其它肿瘤和癌症包括但不限于:神经母细胞瘤、结直肠癌、宫颈癌、肺癌、白血病、乳腺癌、胰腺癌、B细胞恶性肿瘤、瘤和转移性肿瘤。
在一些实施方式中,与施用AT7519相比,施用本发明提供的化合物和/或其药物组合物的优点在于:降低与治疗有关的毒性和/或副作用,和/或增加AT7519耐受性,和/或改善药物治疗效果。
在其它实施方式中,与施用AT7519自身相比,施用本文提供的化合物和/或药物组合物具有改善AT7519的生物分布,降低AT7519的毒副作用,和/或拓宽在受试者中应用范围(例如剂量方案,包括施用途径、给药频率和最大耐受剂量等)。
在另一概括性方面中,本发明提供了包括本文所述的一种或多种化合物或药物组合物的试剂盒。该试剂盒可进一步包括一种或多种额外的治疗剂和/或说明,例如使用该试剂盒以治疗患有由周期蛋白依赖性激酶和/或糖原合成酶激酶-3介导的疾病症状或病症的说明。
附图说明
为了更好地理解本发明以及更清楚了示出如何实施本发明,现将通过实例的方式并参考附图来进一步阐述本发明,其中附图示出了根据本发明的实施例的方面和特征,其中:
图1示出了静脉注射AT7519、化合物11和化合物12至小鼠后,血浆AT7519浓度-时间曲线;
图2示出了静脉注射AT7519、化合物11和化合物12至小鼠后,体重随时间的变化;
图3示出了静脉注射等摩尔剂量的AT7519、化合物11和化合物12至大鼠后,血浆AT7519浓度-时间曲线。
具体实施方式
定义
为了对本发明的说明书中所使用的术语提供清楚且一致的理解,在下文中提供一些定义。此外,除了特殊说明,本发明所用的全部技术和科学术语具有同本发明所属领域中普通技术人员通常所理解的相同含义。
当在权利要求和/或说明书中与术语“包括”结合使用时,词语“一(a或an)”的使用可以表示“一个/种”,但它也与“一个/种或多个/种”,“至少一个/种”和“一个/种或多于一个/种”的含义一致。类似地,词语“另一个/种”可以表示至少第二个/种或者很多个/种。
如在本说明书和权利要求中所使用的词语“包括(comprising)”(以及包括(comprising)的任何形式,诸如“包括(comprise)”和“包括(comprises)”),“具有(having)”(以及具有(having)的任何形式,诸如“具有(have)”、“具有(has)”),“含有(including)”(以及“含有(including)”的任何形式,诸如“含有(include)”和“含有(includes)”)或者“包含(containing)”(以及包含(containing)的任何形式,诸如“包含(contain)”和“包含(contains)”)是包括性的或开放式的,并且不排除另外的未列出的要素或处理步骤。
术语“约”用于表示该值包括在确定该值中所用的仪器和方法带来的误差的固有变化。
本发明所用的术语“衍生物”应理解为是结构上类似,在一些细微结构上有所不同的物质。
本说明书涉及了本领域技术人员所使用的许多化学术语和缩写。然而,为了清楚和一致性,提供了所选术语的定义。
如本文所使用的,术语“取代”或“具有取代基”是指母体化合物或部分具有至少一个(1)取代基团。术语“未取代的”或“不具有取代基”是指母体化合物或部分除了未确定的化合价被氢原子化学饱和外,不具有其他取代基。
如本文所述,“取代基”或“取代基团”是指选自卤素(F、Cl、Br或I)、羟基、巯基、氨基、硝基、羰基、羧基、烷基、烷氧基、烷基氨基、芳基、芳基氧基、芳基氨基、酰基、亚硫酰基、磺酰基、膦酰基或在有机化学中常规使用和接受的其它有机部分。
本发明所用术语“烷基”是指具有1至12个碳原子的饱和烃,包括直链,支链和环状烷基。烷基的实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、异丙基、叔丁基、仲丁基、异丁基、环丙基、环戊基、环己基、环庚基、环辛基等。术语烷基包括未取代的烷基和取代的烷基。术语“C1-Cn烷基”(其中n是2至12的整数)表示具有1至所示“n”个碳原子的烷基。烷基残基可以是取代的或未取代的。在一些实施方式中,例如,烷基可以被羟基、氨基、羧基、羧酸酯、酰胺、氨基甲酸酯或氨基烷基等基团取代。
除非对碳数有限定,否则本文中所使用的“低级脂肪族”、“低级烷基”、“低级烯基”和“低级炔基”中的“低级”表示该部分具有至少一个(对于烯基和炔基为至少两个)且等于或小于6个碳原子。
术语“环烷基”,“脂环族”,“碳环”和等同表述是指在单环、螺环(共享一个原子)或稠合(共享至少一个键)碳环体系中包含饱和或部分不饱和碳环的基团,其中碳环体系具有3至15个碳原子。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯-1-基、环戊烯-2-基、环戊烯-3-基、环己基、环己烯-1-基、环己烯-2-基、环己烯-3-基、环庚基、双环[4,3,0]壬基、降冰片基等。术语环烷基包括未取代的环烷基和取代的环烷基。术语“C3-Cn环烷基”其中n是4至15的整数,表示在环结构中具有3至所示“n”个碳原子的环烷基。除非另有说明,否则本发明使用的“低级环烷基”基团指在其环结构中具有至少3个且等于或小于8个碳原子。
环烷基残基可以是饱和的或在环体系中含有一个或多个双键。特别地,它们可以是饱和的或在环体系内含有一个双键。在不饱和环烷基残基中,双键可存在于任何合适的位置。单环烷基残基包括例如环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基或环十四烷基,其也可例如取代有C1-4烷基。取代的环烷基残基的实例是4-甲基环己基和2,3-二甲基环戊基。双环体系的母体结构的实例是降冰片烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷和双环[3.2.1]辛烷。
术语“杂环烷基”和等同表述是指在单环、螺环(共享一个原子)或稠合(共享至少一个键)碳环体系中包含饱和或部分不饱和碳环的基团,其中该碳环体系具有3个至15个碳原子的基团,包括1至6个杂原子(例如N、O、S、P)或者含杂原子(例如NH、NRx(Rx是烷基、酰基、芳基、杂芳基或环烷基),PO2、SO、SO2等)的基团。在可能的情况下,杂环烷基可以与C连接或与杂原子连接的(例如通过氮原子)。杂环烷基的实例包括但不限于吡咯烷基、四氢呋喃基、四氢二噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、高哌啶基、氧杂环戊烷基、硫杂环戊烷基、氧氮杂卓基、二氮杂卓基、硫氮杂基、1,2,3,6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、2H-吡喃基、4H-吡喃基、二氧六环基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫杂环戊烷基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基、咪唑啉基、咪唑烷基、3-氮杂双环[3,1,0]己基、3-氮杂双环[4,1,0]庚基、3H-吲哚基、喹嗪基和糖等。术语杂环烷基包括未取代的杂环烷基和取代的杂环烷基。术语“C3-Cn杂环烷基”,其中n是4至15的整数,表示在环结构中具有3至所示“n”个原子的杂环烷基,包括至少一个如上所定义的杂基团或原子。除非另有说明,否则本发明使用的“低级杂环烷基”在其环状结构中具有至少3个且等于或小于8个碳原子。
术语“芳基”和“芳基环”是指在共轭单环或多环体系(稠和或非稠和的)中具有“4n+2”个(π)电子,并具有6至14个环原子的芳族基团,其中n是1至3的整数。多环体系包括至少一个芳环。芳基可以直接连接或通过C1-C3烷基(也称为芳基烷基或芳烷基)连接。芳基的实例包括但不限于苯基、苄基、苯乙基、1-苯基乙基、甲苯基、萘基、联苯基、三联苯基、茚基、苯并环辛烯基、苯并环庚烯基、薁基、苊基、芴基、菲基、蒽基等。术语芳基包括未取代的芳基和取代的芳基。术语“C6-Cn芳基”(其中n是6至15的整数)表示在环结构中具有6至所示“n”个碳原子的芳基,包括至少一个如上所定义的杂环基团或原子。
术语“杂芳基”和“杂芳基环”是指在共轭单环或多环体系(稠和或非稠和的)中具有“4n+2”个(π)电子,并且具有5至14个环原子的芳族基团,其中n是1至3的整数,并包括一个至六个杂原子(例如N、O、S)或者包括杂原子(例如NH、NRx(Rx是烷基、酰基、芳基、杂芳基或环烷基)、SO等)的基团。多环体系包括至少一个杂芳环。杂芳基可以直接连接或通过C1-C3烷基(也称为杂芳基烷基或杂芳烷基)连接。在可能的情况下,杂芳基可以与碳连接的或者与杂原子连接的(例如,通过氮原子)。杂芳基的实例包括但不限于吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、四唑基、呋喃基、噻吩基;异恶唑基、噻唑基、恶唑基、异噻唑基、吡咯烷基、喹啉基、异喹啉基、吲哚基、异吲哚基、色烯基、异色烯基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、吡嗪基、三嗪基、异吲哚基、喋啶基、嘌呤基、噁二唑基、噻二唑基、呋喃基、苯并呋喃基、苯并苯硫基(benzothiophenyl)、苯并噻吩基、苯并噻唑基、苯并恶唑基、喹唑啉基、喹啉基、喹啉酮基、异喹啉酮基、喹喔啉基、萘啶基、呋喃并吡啶基、咔唑基、菲啶基、吖啶基、苝基、菲咯啉基、吩嗪基、吩噻嗪基、吩恶嗪基、二苯并呋喃基等。术语杂芳基包括未取代的杂芳基和取代的杂芳基。术语“C5-Cn杂芳基”,其中n是6至15的整数,表示在环结构中具有从5至所示“n”个原子的杂芳基,包括至少一个如上所定义的杂环基团或原子。
术语“杂环”或“杂环的”包括杂环烷基和杂芳基。杂环的实例包括但不限于吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫呋喃基、苯并苯硫基、苯并恶唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4αH-咔唑基、咔啉基、苯并吡喃基(chromanyol)、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃、呋喃基、呋吖基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基(indolenyl)、二氢吲哚基、哚啉嗪基(indolizinyl)、吲哚基、3H-吲哚基、异苯并呋喃基、异苯并吡喃基、异吲哚基、异吲哚啉基、异吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基、八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、恶唑烷基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、氮苯基(pyridyl)、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并恶唑基、噻吩并咪唑基、苯硫基(thiophenyl)、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、呫吨基等。术语杂环包括未取代的杂环基和取代的杂环基。
本发明所用术语“胺”或“氨基”是指未取代或取代的通式-NRaRb的片段,其中Ra和Rb各自独立地为氢、烷基、芳基或杂环基,或Ra和Rb一起与它们所连接的氮原子形成杂环。术语氨基包括其中氮原子与至少一个碳或杂原子共价键合的化合物或片段。因此,本发明所用术语“烷基氨基”和“二烷基氨基”分别是指具有与之附接的一个和至少两个C1-C6烷基的胺基。术语“芳基氨基”和“二芳基氨基”分别包括其中氮原子与至少一个或两个芳基结合的基团。术语“酰胺”或“氨基羰基”包括含有与羰基或硫代羰基的碳连接的氮原子结构的化合物或片段。术语“酰基氨基”是指直接与本文所限定的酰基连接的氨基。
术语“烷巯基”是指具有巯基连接其上的烷基。合适的烷巯基包括具有1至约12个碳原子,优选1至约6个碳原子的基团。本文所用的术语“烷基羧基”是指具有羧基连接其上的烷基。
本发明所用术语“烷氧基”或“低级烷氧基”是指具有氧原子连接其上的烷基。代表性的烷氧基包括具有1至约6个碳原子的基团,例如甲氧基、乙氧基、丙氧基、叔丁氧基等。烷氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基、丙氧基、丁氧基、戊氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、氯甲氧基、二氯甲氧基、三氯甲氧基等。术语“烷氧基”包括未取代或取代的烷氧基,以及全卤代烷氧基等。
术语“羰基”或“羧基”是指含有通过双键与氧原子连接的碳的化合物和部分。含有羰基的部分的实例包括醛、酮、羧酸、酰胺、酯、酸酐等。
术语“酰基”是羰基的碳原子连接到氢(即甲酰基)、脂族基团(C1-C6烷基,C1-C6烯基,C1-C6炔基,例如乙酰基)、环烷基(C3-C8环烷基)、杂环基(C3-C8杂环烷基和C5-C6杂芳基)、芳基(C6芳基,例如苯甲酰基)相连的结构。酰基可以是未取代的或取代的酰基(例如水杨酰基)。
术语“溶剂化物”是指化合物与一种或多种溶剂分子(无论是有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情况下,溶剂化物能够被分离,例如当一个或多个溶剂分子并入晶体的晶格中时。“溶剂化物”包括溶液相和可被分离的溶剂化物。“溶剂化物”的实例包括但不限于水合物、乙醇化物、甲醇化物、半乙醇化物等。术语“水合物”是指化合物与水分子的物理缔合。
术语“螯合物”是指化合物与中心金属原子的物理缔合,通常在两个或更多个点键合,且通常在环状或环结构中。
应当理解的是,本发明所述的化合物可含有一个或多个手性中心和/或双键,并且因此,可存在立体异构体,诸如双键异构体(即,几何异构体),对映异构体或非对映异构体。本发明公开的化学结构用于涵盖所示化合物的所有可能的对映异构体和立体异构体,包括单一立体异构形式(例如,纯的几何异构体形式、纯的对映异构体形式,或纯的非对映异构体)以及对映异构体和立体异构体的混合物。使用本领域技术人员熟知的分离技术或手性合成技术,例如手性色谱(例如手性HPLC)、免疫测定技术来将对映异构体和立体异构混合物拆分成它们的组成异构体或立体异构体,或者利用共价键手性试剂(例如Mosher's酯)和非共价键手性试剂(诸如手性盐)来相应形成可通过常规方法如色谱法、蒸馏、结晶或升华进行分离的非对映体混合物,然后通过手性盐或酯交换或裂解的方法,回收所需的异构体。化合物还可存在数种互变异构体形式,包括烯醇形式、酮形式以及其混合物。本文所描述的化学结构还旨在涵盖所示化合物的所有可能的互变异构形式。
某些化合物可存在多种结晶或无定形形态。总体上,所有的物理形式都涵盖在本文中。术语“多晶型”是指化合物可显示的各种物理形式。
化合物的“药学上可接受的盐”是指药学上可接受的化合物的盐。可取的是,化合物的盐可以保留或改善如本发明所定义的母体化合物的游离酸和碱的生物有效性和性质,并且有利于该分子的固有的碱性、酸性或带电功能性,否则则是生物学上不需要的或不可取的。药学上可接受的盐可以是Berge等人在"Pharmaceutical Salts",J.Pharm.Sci.66,1-19(1977)所提到的。这些盐的非限制性实例包括:
(1)通过加入无机酸或有机酸而在碱性或带正电荷的官能团上形成酸加成盐,其中可加入的无机酸诸如为盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、硝酸、磷酸、碳酸盐形成剂等;有机酸诸如为乙酸、丙酸、乳酸、草酸、乙醇酸、新戊酸、叔丁基乙酸、β-羟基丁酸、戊酸、己酸、环戊烷丙酸、丙酮酸、丙二酸、琥珀酸、苹果酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、环己基氨基磺酸、苯磺酸、磺胺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、3-苯基丙酸、月桂基磺酸、月桂基硫酸、油酸、棕榈酸、硬脂酸、月桂酸、帕莫酸(扑酸)、扑酸、泛酸、乳糖酸、藻酸、半乳糖二酸、半乳糖醛酸、葡萄糖酸、葡庚糖酸、谷氨酸、萘甲酸、羟基萘甲酸、水杨酸、抗坏血酸、硬脂酸、粘康酸等。
(2)当母体化合物中存在的酸性质子被金属离子取代或者与有机碱配位形成的碱加成盐,其中所述金属离子包括碱性金属离子(例如锂、钠、钾),碱土金属离子(镁、钙、钡)或其它金属离子如铝、锌、铁等;有机碱诸如为氨、乙胺、二乙胺、乙二胺、N,N’-二苄基乙二胺、乙醇胺、二乙醇胺、三乙醇胺、氨基丁三醇、N-甲基葡萄糖胺、哌嗪、氯普鲁卡因、普鲁卡因、胆碱、赖氨酸等。
药学上可接受的盐可以由含有碱性或酸性部分的母体化合物通过常规化学方法合成。通常,这种盐通过使游离酸或碱形式的化合物与等化学计量的合适的碱或酸在水中或有机溶剂中或在两者的混合物中反应来制备。盐可以在化合物的最终分离或纯化过程中原位制备,或者使处于其游离酸或碱形式的化合物与所需的相应碱或酸反应,然后分离由此形成的盐而制备。术语“药学上可接受的盐”还包括含有共价键合至阴离子基团的阳离子基团的两性离子化合物,它们被称作“内盐”。应当理解的是,本发明化合物的所有酸,盐,碱和其它离子和非离子形式均涵盖在本发明的范围内。例如,如果本发明中化合物为酸,该化合物盐的形式也涵盖在本发明的范围内。同样,如果本发明中化合物为盐,该化合物的酸和/或碱的形式也涵盖在本发明的范围内。
如本文所使用的,术语“有效量”是指以单剂量或多剂量施用至受试者后,在受试者中提供所需的治疗、诊断或预后效应的治疗剂(例如化合物)的量或剂量。主治医生或诊断医生通过已知技术并通过观察在类似情况下获得的结果可容易地确定有效量。在确定施用的化合物的有效量或剂量时,考虑许多因素,包括但不限于:受试者的体重、年龄和一般健康状况;涉及的具体疾病;待治疗的疾病或病症的涉及程度或严重程度;受试者个体的回应;施用的特定化合物;施用模式;所施用制剂的生物利用度特征;所选的剂量方案;使用伴随药物;和其他相关考虑。
“药学上可接受的”是指该术语描述的药剂、药品、惰性成分等适合用于与人和动物的细胞或组织相接触,而没有异常毒性、不相容性、不稳定性、刺激性、过敏反应等,与合理的利益/风险比率相称。通常是指由联邦或州政府的管理机构批准或可批准,或者在美国药典或其它公认的药典中列出的用于动物,更尤其是用于人的化合物或组合物。
“药学上可接受上的载体”是指与化合物一起施用的稀释剂、佐剂、赋形剂、载体或载剂。术语“药学上可接受的载剂”和“药学上可接受的载体”在本文中可互换使用。
“药物组合物”是指包括如本文所述的化合物以及至少一种组分的组合物,其中该至少一种组分,取决于给药方式和剂型的要求,包括药学上可接受的载体、稀释剂、佐剂、赋形剂或载剂,诸如防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、调味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂等。
“预防(preventing)”或“预防(prevention)”用于表示至少降低罹患疾病或病症的风险(或易感性)的可能性(即,使疾病的至少一种临床症状不发展为可能暴露于或易患疾病但尚未经历或显示疾病症状的患者)。
在一些实施方式中,“治疗(treating)”或“治疗(treatment)”任何疾病或病症是指缓解了至少一种疾病或病症。在某些实施方式中,治疗”或“治疗”是指缓解至少一种身体参数,其可以是患者可以分辨的或不可分辨的。在某些实施方式中,“治疗”或“治疗”是指身体上(例如,可辨别的症状的稳定)或生理学上(例如,身体参数的稳定)或这两者上来抑制疾病或病症。在某些实施方式中,“治疗”或“治疗”是指在有需要的受试者中改善生活品质,减少症状或疾病的副作用。“治疗有效量”是指施用至受试者用于治疗或预防疾病的化合物的量足以达到治疗或预防该疾病的效果。“治疗有效量”将依据化合物;疾病及其严重程度;待治疗或预防患有疾病的受试者的年龄、体重等而变化。如本文中所使用的,术语“治疗有效量”是指化合物或组合物的量足以预防、治疗、抑制、降低、缓解或消除疾病(诸如癌症)的一种或多种病因、症状或并发症。
术语“受试者”是指包括哺乳动物和人在内的动物,尤其是指人。
术语“前药”或其等同表述是指在体外或体内直接或间接转化成活性形式的试剂(例如参见R.B.Silverman,1992,"The Organic Chemistry of Drug Design and DrugAction,"Academic Press,Chap.8;Bundgaard,Hans;Editor.Neth.(1985),"Design ofProdrugs".360pp.Elsevier,Amsterdam;Stella,V.;Borchardt,R.;Hageman,M.;Oliyai,R.;Maag,H.;Tilley,J.(Eds.)(2007),"Prodrugs:Challenges and Rewards,XVIII,1470p.Springer)。前药可用于改变具体药物的生物分布(例如,使药剂通常不会进入蛋白酶反应位点)或药代动力学。已经使用多种基团来修饰化合物以形成前药,例如酯、醚、磷酸酯/盐等。当将前药施用至受试者时,该基团通过酶促或非酶促、还原、氧化或水解地裂解掉,或者以其它方式释放出活性化合物。如本文中所使用的,“前药”包括药学上可接受的盐或酯,或药学上可接受的溶剂化物或螯合物,以及上文的任何结晶形式。
前药通常(尽管不一定)是药学上无活性的,直至其转化为活性形成。“无活性的”前药是药学上无活性的药物,其可在体内代谢成活性形式。例如,代替直接给药,可使用相应的前药来改善药物的吸收、分配、代谢和排泄方式(ADME)(例如,参见Malhotra,B.,etal.,"The design and development of fesoterodine as a prodrug of 5-hydroxymethyl tolterodine(5-HMT),the active metabolite of tolterodine",Curr.Med.Chem.,2009,16(33):4481–9;and Stella,V.J.,et al,"Prodrugs.Do theyhave advantages in clinical practice?".Drugs,1985.29(5):455–73)。前药可用于改善药物与细胞或与其预期靶标不同的过程相互作用的选择性。这可以减少药物的不良或非预期效果,这在可能会产生严重的意外和不良副作用的化疗等治疗中尤为重要。例如,替诺福韦艾拉酚胺(TAF)是替诺福韦的一种新型前药,其开发用于提供增强的抗病毒效力且降低全身毒性(Byrne,R.,et al,Therap.Adv.Gastroenterol.,2018,11:1-12)。
术语“酯”是指可由式RCOOR(羧酸酯)或式RSO3R’(磺酸酯)表示的化合物,通常可分别由羧酸或磺酸与醇之间反应(消除一分子水)来形成。
术语“氨基酸”通常是指同时包含羧酸基团和氨基基团的有机化合物。术语“氨基酸”包括“天然”和“非天然”或“不是天然”的氨基酸。另外,术语氨基酸包括O-烷基化的氨基酸和N-烷基化的氨基酸,以及具有含氮或含氧侧链的氨基酸(例如Lys,Cys或Ser),其中氮或氧原子已被酰基化或烷基化。氨基酸可以是纯的L-异构体或D-异构体,或者是L-异构体和D-异构体的混合物,包括(但不限于)外消旋混合物。
术语“天然氨基酸”和等同表达是指通常在天然存在的蛋白质中发现的L-氨基酸。天然氨基酸的实例包括但不限于丙氨酸(Ala),半胱氨酸(Cys),天冬氨酸(Asp),谷氨酸(Glu),苯丙氨酸(Phe),甘氨酸(Gly),组氨酸(His),异亮氨酸(Ile),赖氨酸(Lys),亮氨酸(Leu),甲硫氨酸(Met),天冬酰胺(Asn),脯氨酸(Pro),谷氨酰胺(Gln),精氨酸(Arg),丝氨酸(Ser),苏氨酸(Thr),缬氨酸(Val)、色氨酸(Trp),酪氨酸(Tyr),β-丙氨酸(β-Ala)和γ-氨基丁酸(GABA)。
术语“非天然氨基酸”是指天然氨基酸的任何衍生物,包括D-型氨基酸,以及α-和β-氨基酸衍生物。术语“非天然氨基酸”和“不是天然氨基酸”在本文中可互换使用。应注意的是,在本发明中可归类为非天然氨基酸的某些氨基酸(例如羟脯氨酸)也可存在于自然界中的某些生物组织或特定蛋白质中。具有许多不同保护基团、适于固相肽合成中直接应用的氨基酸是可以通过购买得到的。除了二十种最常见的天然氨基酸,根据本发明可使用如下示例性非天然氨基酸和氨基酸衍生物(括号中为常见的缩写):2-氨基己二酸(Aad),3-氨基己二酸(β-Aad),2-氨基丁酸(2-Abu),α,β-脱氢-2-氨基丁酸(8-AU),1-氨基环丙烷-1-羧酸(ACPC),氨基异丁酸(Aib),3-氨基异丁酸(β-Aib),2-氨基-噻唑啉-4-羧酸,5-氨基戊酸(5-Ava),6-氨基己酸(6-Ahx),2-氨基庚酸(Ahe),8-氨基辛酸(8-Aoc),11-氨基十一烷酸(11-Aun),12-氨基十二烷酸(12-Ado),2-氨基苯甲酸(2-Abz),3-氨基苯甲酸(3-Abz),4-氨基苯甲酸(4-Abz),4-氨基-3-羟基-6-甲基庚酸(抑胃酶氨酸,Sta),氨基氧基乙酸(Aoa),2-氨基四氢化萘-2-羧酸(ATC),4-氨基-5-环己基-3-羟基戊酸(ACHPA),对氨基苯丙氨酸(4-NH2-Phe),2-氨基庚二酸(Apm),联苯基丙氨酸(Bip),对溴苯丙氨酸(4-Br-Phe),邻氯苯丙氨酸(2-Cl-Phe),间氯苯丙氨酸(3-Cl-Phe),对氯苯丙氨酸(4-Cl-Phe),间-氯酪氨酸(3-Cl-Tyr),对苯甲酰基苯丙氨酸(Bpa),叔丁基甘氨酸(TLG),环己基丙氨酸(Cha),环己基甘氨酸(Chg),锁链素(Des),2,2-二氨基庚二酸(Dpm),2,3-二氨基丙酸(Dpr),2,4-二氨基丁酸(Dbu),3,4-二氯苯丙氨酸(3,4-Cl2-Phe),3,4-二氟苯丙氨酸(3,4-F2-Phe),3,5-二碘酪氨酸(3,5-I2-Tyr),N-乙基甘氨酸(EtGly),N-乙基天冬酰胺(EtAsn),邻氟苯丙氨酸(2-F-Phe),间氟苯丙氨酸(3-F-Phe),对氟苯丙氨酸(4-F-Phe),间-氟酪氨酸(3-F-Tyr),高丝氨酸(Hse),高苯丙氨酸(Hfe),高酪氨酸(Htyr),羟基赖氨酸(Hyl),异羟基赖氨酸(aHyl),5-羟色氨酸(5-OH-Trp),3-或4-羟基脯氨酸(3-或4-Hyp),对碘苯丙氨酸(4-I-Phe),3-碘酪氨酸(3-I-Tyr),二氢吲哚-2-羧酸(Idc),异艾杜霉素(Ide),异亮氨酸(α-Ile),异哌啶酸(Inp),N-甲基异亮氨酸(Melle),N-甲基赖氨酸(MeLys),间甲基酪氨酸(3-Me-Tyr),N-甲基缬氨酸(MeVal),1-萘基丙氨酸(1-Nal),2-萘基丙氨酸(2-Nal),对硝基苯丙氨酸(4-NO2-Phe),3-硝基酪氨酸(3-NO2-Tyr),正亮氨酸(Nle),正缬氨酸(Nva),鸟氨酸(Orn),邻磷酸酪氨酸(H2PO3-Tyr),八氢吲哚-2-羧酸(Oic),青霉胺(Pen),五氟苯丙氨酸(F5-Phe),苯基甘氨酸(Phg),哌啶酸(Pip),炔丙基甘氨酸(Pra),焦谷氨酸(PGLU),肌氨酸(Sar),四氢异喹啉-3-羧酸(Tic),噻吩基丙氨酸和噻唑烷-4-羧酸(硫代脯氨酸,Th)。
对于本文所提供的化合物,在一些实施方式中,还涵盖其盐,包括药学上可接受的盐。本领域技术人员将知晓多种可能的盐形式(例如,TFA盐、四唑盐、钠盐、钾盐等),也可基于本领域已知的考虑选择合适的盐。术语“药学上可接受的盐”是指由药学上可接受的没有毒性的酸或碱(包括无机酸和碱以及有机酸和碱)制备的盐。例如,对于含有碱性氮的化合物,其盐可以通过药学上可接受的没有毒性的酸(包括无机酸和有机酸)来制备。适用于本发明化合物的药学上可接受的酸加成盐包括但不限于乙酸、苯磺酸(苯磺酸盐)、苯甲酸、樟脑磺酸、柠檬酸、乙烯磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。当化合物含有酸性侧链时,适用于本发明化合物的药学上可接受的碱加成盐包括但不限于由铝、钙、锂、镁、钾、钠和锌制成的金属盐或由赖氨酸、N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡萄糖胺)和普鲁卡因制成的有机盐。
组合物
化合物可通过以药物组合物(例如,制剂)的形式来施用,其中该药物组合物包括至少一种本技术的活性化合物以及一种或多种药学上可接受的载体、佐剂、赋形剂、稀释剂、填充剂、缓冲剂、稳定剂、防腐剂、润滑剂或本领域技术人员熟知的其他材料,以及可选的其他治疗剂或预防剂。因此,进一步提供了药物组合物以及制备药物组合物的方法,包括将如上所限定的至少一种活性化合物与在此所述的一种或多种药学上可接受的载体、佐剂、赋形剂、稀释剂、填充剂、缓冲剂、稳定剂或其他材料混合。
药物组合物可为适用于口服、肠胃外、局部、鼻内、眼、耳、直肠、阴道内或经皮施用的任何形式。当组合物用于肠胃外给药时,它们可以配制用于静脉内、肌肉内、腹膜内、皮下施用或通过注射、输注或其他递送方式直接递送到靶向器官或组织中。在一个具体实施方式中,药物组合物为适合静脉内(i.v.)施用的形式,例如通过注射或输注施用。在另一具体实施方式中,药物组合物为适合皮下(s.c.)施用的形式。
适用于口服施用的药物剂型例如包括但不限于片剂、胶囊、丸剂、锭剂、糖浆、溶剂、粉末、颗粒、酏剂和悬浮液、舌下片剂、糯米纸囊剂(wafer),或者贴剂和口腔贴剂。
包含本文提供的化合物的药物组合物可以根据已知技术配制,参见例如,Remington’s Pharmaceutical Sciences,Mack Publishing Company,Easton,PA,USA。
在一些实施方式中,组合物可包含单位剂量的活性化合物以及惰性稀释剂或载体,例如糖或糖醇,例如乳糖、蔗糖、山梨糖醇或甘露糖醇;和/或非糖衍生的稀释剂,诸如碳酸钠、磷酸钙、碳酸钙;或者纤维素或其衍生物,诸如甲基纤维素、乙基纤维素、羟丙基甲基纤维素和淀粉(诸如玉米淀粉)。片剂还可能含有那些标准成分:粘合剂和造粒剂,诸如聚乙烯吡咯烷酮,崩解剂(例如可溶胀的交联聚合物,例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液),以及泡腾剂,例如柠檬酸盐/碳酸氢盐混合物。这些赋形剂是众所周知的。
胶囊制剂可以是硬质明胶或软质明胶类型,并且可以包含固体、半固体或液体形式的活性成分。明胶胶囊可由动物明胶或合成的或植物衍生的等价物来形成。
固体剂型(片剂、胶囊等)可以被包衣或未被包衣,但通常具有包衣,例如保护性膜包衣(例如,蜡或清漆)或控释包衣。包衣(例如EudragitTM型聚合物)可设计成在胃肠道内的所需位置释放活性成分。因此,可对包衣进行选择以在胃肠道内的某些pH条件下降解,从而在胃中或在回肠或十二指肠中选择性地释放化合物。
代替包衣或除包衣外,化合物可存在于包含控释剂的固体基质中,例如释放延迟剂,其可适于在胃肠道内于不同酸度或不同酸性的条件下选择性释放化合物。或者,基质材料或缓释包衣可以采用可侵蚀聚合物(例如马来酸酐聚合物)的形式,该聚合物随着剂型通过胃肠道而基本上连续被侵蚀。作为进一步的替代,活性化合物可以配制在提供化合物释放的渗透控制的递送系统中。渗透释放和其他延迟释放或持续释放制剂可以根据本领域技术人员公知的方法制备。
用于局部使用的组合物包括软膏剂、乳膏剂、喷雾剂、贴剂、凝胶剂、液滴和插入物(例如,眼内插入物)。此类组合物可根据已知方法配制。
用于肠胃外施用的组合物通常以无菌水性溶液或油性溶液或细悬浮液形式提供,或者可以以微细的无菌粉末形式提供,用于即时无菌水配制来用于注射。
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,它们可以例如由含有活性化合物的成型的可模压或蜡状材料形成。
用于吸入给药的组合物可以采用可吸入粉末组合物或液体或粉末喷雾剂的形式,并且可以使用粉末吸入器装置或气雾剂分配装置来以标准形式施用。这种装置是众所周知的。对于吸入给药,粉状制剂通常包含活性化合物和惰性固体粉状稀释剂,例如乳糖。
化合物也可以单位剂型存在,并且因此通常含有足够的化合物以提供所需水平的生物活性。短语“单位剂型”是指物理上离散的单位,每个单位含有预定量的活性化合物,其单独或与一种或多种附加药剂组合,足以产生所需的效果。应当理解的是,单位剂型的参数将取决于具体药剂和要达到的效果。
在一些实施方式中,药物组合物在一次性容器(例如,一次性小瓶、安瓿、注射器或自动注射器)中提供,在其他实施方式中也可提供在多次使用容器(例如,多次使用小瓶)中。
在一些实施方式中,化合物可以以每kg受试者体重约0.01mg至每kg受试者体重约50mg,或每kg受试者体重约1mg至每kg受试者体重约25mg的剂量水平每天一次或多次施用(例如,口服),以获得所需的治疗效果。对于口服药剂的施用,组合物可以以片剂、胶囊等形式提供,其含有1.0毫克至1000毫克的活性成分,特别是1、3、5、10、15、20、25、50、75、100、150、200、250、300、400、500、600、750、800、900或1000毫克的活性成分。例如,用于口服施用的制剂可含有0.1毫克至2克的活性成分,更通常为10毫克至1克,例如50毫克至500毫克的活性成分。
在一些实施方案中,提供了一种组合物,其包含如本文所述的化合物和至少一种组分,该至少一种组分包含药学上可接受的载体、稀释剂、佐剂、赋形剂或载剂,例如防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、调味剂、加香剂、抗细菌剂、抗真菌剂、润滑剂或分散剂。
在一实施方式中,提供了药物组合物,该药物组合物包括本发明的化合物,例如式I的化合物或其药学上可接受的盐、酯或溶剂化物,以及药学上可接受的载体。在一实施方式中,提供了一种药物组合物,包括表1的化合物或其药物上可接受的盐或酯,以及其药学上可接受的载体。在又一实施方式中,提供了包括式I化合物或表1的化合物或其药学上可接受的盐或酯,以及药学上可接受的载体的药物组合物。
在另一实施方式中,本发明的化合物和/或组合物通过各种途径施用于受试者,包括例如但不限于静脉内(i.v.)施用、口服(p.o.)施用、胃内(i.g.)施用、腹膜内(i.p.)施用、肌肉内(i.m.)施用、皮下(s.c.)施用、肠胃外施用等来有效地递送化合物。
使用方法
本发明提供的化合物抑制细胞周期蛋白依赖性激酶,例如选自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7和CDK9的一种或多种细胞周期蛋白依赖性激酶,和/或糖原合酶激酶-3(GSK3)。通过它们在调节或抑制CDK激酶和糖原合酶激酶方面的活性,预期的是,化合物可用于提供阻止或恢复控制异常分裂细胞的细胞周期的手段。因此,设想的是,这些化合物将证明可用于治疗或预防增殖性疾病,诸如癌症。还设想的是,本发明的化合物可用于治疗病症,例如但不限于病毒感染、II型或非胰岛素依赖型糖尿病、自身免疫疾病、头部创伤、中风、癫痫、神经变性疾病(诸如阿尔茨海默病)、运动神经元病、进行性核上性麻痹、皮质基底节变性和皮克病。在具体实施方式中,化合物可用于治疗病毒感染、自身免疫疾病和/或神经变性疾病。
CDK在细胞周期、细胞凋亡、转录、分化和CNS功能的调节中发挥作用。因此,CDK抑制剂可用于治疗存在增殖、凋亡或分化障碍的疾病,例如癌症和肿瘤。根据本技术可抑制或治疗的癌症的实例包括但不限于癌,例如膀胱癌、乳腺癌、结肠癌(例如结肠直肠癌,例如结肠腺癌和结肠腺瘤)、肾癌、表皮癌、肝癌、肺癌(例如腺癌、小细胞肺癌和非小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌(例如外分泌胰腺癌)、胃癌、子宫颈癌、甲状腺癌、前列腺癌或皮肤癌(例如鳞状细胞癌);淋巴系造血肿瘤,例如白血病、急性淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤或伯克特淋巴瘤;骨髓系造血肿瘤,例如急性骨髓性白血病和慢性骨髓性白血病、骨髓增生异常综合征或早幼粒细胞白血病;甲状腺滤泡癌;间充质源性肿瘤,例如纤维肉瘤或横纹肌肉瘤,中枢或外周神经系统的肿瘤,例如星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经鞘瘤;黑色素瘤;精原细胞瘤;畸胎瘤;骨肉瘤;着色性干皮病;角化棘皮瘤(keratoctanthoma);甲状腺滤泡癌;或卡波西肉瘤。
待治疗或抑制的癌症可以是对抑制选自CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7和CDK9的任何一种或多种细胞周期蛋白依赖性激酶敏感的癌症,例如选自CDK1、CDK2、CDK4、CDK5、CDK6和CDK9的一种或多种CDK激酶敏感的癌症,例如CDK1和/或CDK2、CDK4和/或CDK6等敏感的癌症。
还已知CDK在细胞凋亡、增殖、分化和转录中发挥作用,并且因此CDK抑制剂还可用于治疗除癌症之外的以下疾病:病毒感染,例如疱疹病毒、痘病毒、Epstein-Barr病毒、Sindbis病毒、腺病毒、HIV、HPV、HCV和HCMV;预防HIV感染个体中AIDS的发展;慢性炎症性疾病,例如系统性红斑狼疮、自身免疫介导的肾小球肾炎、类风湿性关节炎、牛皮癣、炎症性肠病和自身免疫性糖尿病;心血管疾病,例如心脏肥大、血管再狭窄、动脉粥样硬化;神经变性疾病,例如阿尔茨海默病、艾滋病相关性痴呆、帕金森病、肌萎缩侧索硬化、色素性视网膜炎、脊髓性肌萎缩症和小脑萎缩症;肾小球肾炎;骨髓增生异常综合征,缺血性损伤相关的心肌梗塞,中风和再灌注损伤,心律失常,动脉粥样硬化,毒素诱导或酒精相关的肝病,血液病例如慢性贫血和再生障碍性贫血;肌肉骨骼系统的退行性疾病,例如骨质疏松症和关节炎、阿司匹林敏感性鼻窦炎,囊性纤维化,多发性硬化症,肾脏疾病和癌症疼痛。
因此,在本发明的用于治疗包含异常细胞生长的疾病或病症的药物组合物、用途或方法中,包含异常细胞生长的疾病或病症的一个实施方式是癌症。一组癌症包括人类乳腺癌(例如原发性乳腺癌、淋巴结阴性乳腺癌、乳腺浸润性导管腺癌、非子宫内膜样乳腺癌);和套细胞淋巴瘤。此外,其他癌症是结直肠癌和子宫内膜癌。癌症的另一个亚组包括乳腺癌、卵巢癌、结肠癌、前列腺癌、食道癌、鳞状细胞癌和非小细胞肺癌。
预期的是,本文提供的化合物和组合物可用于预防或治疗由细胞周期蛋白依赖性激酶(CDK)和/或糖原合酶激酶-3(GSK-3)介导的任何疾病状态或病症。如本文所用,表述“由细胞周期蛋白依赖性激酶(CDK)和/或糖原合酶激酶-3(GSK-3)介导的疾病状态或病症”是预期抑制或调节CDK和/或GSK-3将在有需要的受试者中提供治疗或预防益处的本文提及的任何疾病或病症。
在一些实施方案中,将活性化合物或组合物以足以实现所需治疗效果的量给药至有需要的受试者(例如,人类或动物患者)。化合物和组合物通常以治疗或预防有用且通常无毒的量给药。然而,在某些情况下(例如在危及生命的疾病的情况下),施用化合物或组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,以与一定程度的毒性有关的量来施用化合物可能被任何是合乎需要的。
化合物的典型日剂量可以在每公斤体重100皮克至100毫克的范围内,更通常为每公斤体重5纳克至25毫克的范围内,更通常为每公斤体重10纳克至15毫克(例如,每公斤体重10纳克至10毫克),但在需要时可给予更高或更低的剂量。最终,施用的化合物的量和使用的组合物的类型将与所治疗的疾病或生理状况的特征相称,并且将由医生自行决定。
本文提供的化合物和组合物可以作为唯一的治疗剂给药,或者它们可以与用于治疗具体疾病状态(例如肿瘤疾病,如癌症)的一种或多种其它化合物以联合疗法的方式给药。可以与本文提供的化合物和组合物一起(无论是同时或以不同时间间隔)给药的其他治疗剂的实例包括但不限于:拓扑异构酶抑制剂、烷化剂、抗代谢物、DNA结合剂和微管抑制剂(微管蛋白靶向剂),例如顺铂、环磷酰胺、多柔比星、伊立替康、氟达拉滨、夫拉平度(flavopiridol)、5FU、紫杉烷类、丝裂霉素C或其他化疗药物、免疫检查点抑制剂或放疗。或者,本文提供的化合物和组合物可以与单克隆抗体或信号转导抑制剂以联合疗法的方式来施用。化合物和组合物也可以与骨髓移植、外周血干细胞移植或其他类型的移植疗法联合施用。
在一些实施方案中,化合物和组合物可以与免疫检查点抑制剂组合施用。免疫检查点的阻断会导致抗原特异性T细胞反应的放大,这已被证明是人类癌症治疗中一种很有前途的方法。免疫检查点(配体和受体)的非限制性实例中,一些实例在各种类型的肿瘤细胞中被选择性上调,是阻断的候选者,包括PD1(程序性细胞死亡蛋白1);PDL1(PD1配体);BTLA(B和T淋巴细胞衰减因子);CTLA4(细胞毒性T淋巴细胞相关抗原4);TIM3(T细胞膜蛋白3);LAG3(淋巴细胞活化基因3);A2aR(腺苷A2a受体A2aR);和杀手抑制受体(KillerInhibitory Receptors)。免疫检查点抑制剂的非限制性实例包括伊普木单抗、纳武单抗和兰博利珠单抗。
在其他实施方式中,提供了治疗受试者癌症的方法,包括向受试者施用治疗有效量的至少本公开的化合物或组合物,以及至少一种化疗剂,此类药剂包括但不限于烷化剂(例如,氮芥,如苯丁酸氮芥、环磷酰胺、异环磷酰胺、甲氯乙胺、美法仑和尿嘧啶芥;氮丙啶,如噻替哌;甲磺酸酯,如白消安;核苷类似物(如吉西他滨);亚硝基脲,如甲氧苄啶,洛莫司汀和链脲佐菌素;拓扑异构酶I抑制剂(例如,伊立替康);铂络合物,例如顺铂和卡铂;生物还原性烷化剂,例如丝裂霉素、丙卡巴肼、达卡巴嗪和阿曲胺);DNA链断裂剂(如博来霉素);拓扑异构酶II抑制剂(如安吖啶、更生霉素、柔红霉素、伊达比星、米托蒽醌、多柔比星、依托泊苷和替尼泊苷);DNA小沟结合剂(例如,普卡霉素plicamydin);抗代谢物(如叶酸拮抗剂,诸如甲氨蝶呤和三甲曲沙;嘧啶拮抗剂,如氟尿嘧啶、氟脱氧尿苷、CB3717、阿扎胞苷、阿糖胞苷和氟尿苷;嘌呤拮抗剂,如巯嘌呤、6-硫鸟嘌呤、氟达拉滨,喷司他丁,利血生;以及核糖核苷酸还原酶抑制剂,诸如羟基脲);微管蛋白相互作用剂(例如,长春新碱、雌莫司汀、长春碱、多西紫杉醇、埃坡霉素衍生物和紫杉醇);激素剂(例如,雌激素;结合雌激素;乙炔雌二醇;己烯雌酚;氯三苯甲醚;艾奈雌酚;孕激素,例如己酸羟孕酮、甲羟孕酮和甲地孕酮;以及雄激素,例如睾酮、丙酸睾酮和甲睾酮);甲睾酮肾上腺皮质类固醇(如泼尼松、地塞米松、甲泼尼龙和泼尼松龙);促黄体激素释放剂或促性腺激素释放激素拮抗剂(如醋酸亮丙瑞林和醋酸戈舍瑞林);和抗激素抗原(如他莫昔芬、抗雄激素药物如氟他胺;以及抗肾上腺药物如米托坦和氨基鲁米特)。还提供了化合物和组合物与本领域已知的其他药剂(例如,三氧化二砷)和未来可能开发的其他化学治疗剂组合的用途。
在涉及治疗癌症的方法的一些实施方式中,施用治疗有效量的化合物或组合物与至少一种化学治疗剂的组合使得癌症存活率高于通过单独施用任一药剂所观察到的癌症存活率。在涉及治疗癌症的方法的进一步实施方式中,施用治疗有效量的化合物或组合物与至少一种化合物治疗剂的组合使得肿瘤尺寸的减小或肿瘤生长的减慢大于通过单独施用任一药剂所观察到的肿瘤尺寸的减小或肿瘤生长减慢。
在进一步的实施方式中,提供了治疗或预防受试者癌症的方法,包括向受试者施用治疗有效量的至少一种CDK和/或GSK3抑制剂化合物或组合物,以及至少一种信号转导抑制剂(STI)。在一具体实施方式中,至少一种STI选自由bcr/abl激酶抑制剂、表皮生长因子(EGF)受体抑制剂、her-2/neu受体抑制剂和法呢基转移酶抑制剂(FTI)组成的组。
在其他实施方式中,提供了在受试者中增强肿瘤细胞排斥的方法,包括联合施用化合物或组合物与至少一种化疗剂和/或放射疗法,其中所产生的肿瘤细胞排斥大于单独施用化合物、化学治疗剂或放射疗法获得的排斥。
在进一步的实施方式中,提供了在受试者中治疗癌症的方法,包括向受试者施用治疗有效量的至少一种CDK和/或GSK3抑制剂和至少一种除CDK抑制剂之外的免疫调节剂。应当理解的是,如本文所用,“CDK和/或GSK3抑制剂”是指本文提供的化合物,例如式I的化合物、表1的化合物或其药学上可接受的盐或酯,以及其药物组合物。
在一些实施方式中,提供了在有需要的受试者中治疗或预防由细胞周期蛋白依赖性激酶(CDK)和/或糖原合酶激酶-3(GSK-3)介导的疾病状态或病症的方法,包括向受试者施用治疗有效量的至少一种CDK和/或GSK3抑制剂或其药物组合物,从而在受试者中治疗或预防CDK和/或GSK-3相关疾病、障碍或病症。
对于CDK抑制剂与其他疗法组合的情况,两种或多种治疗可以分别以不同的剂量方案并通过不同的途径来施用。
在一些实施方式中,提供了抑制或调节受试者中的细胞周期蛋白依赖性激酶(CDK)和/或糖原合酶激酶-3(GSK-3)的方法,包括将有效量的至少一种CDK和/或GSK3抑制剂或其药物组合物施用至受试者,使得CDK和/或GSK-3在受试者中被抑制或调节。
当本文提供的化合物或组合物与一种、两种、三种、四种或更多种其他治疗剂(优选一种或两种,更优选一种)在联合疗法中施用时,所述化合物可以同时或依次给药。当依次给药时,它们可以以相近间隔(例如,在5-10分钟的时间段内)或以更长的时间间隔(例如,相隔1、2、3、4或更多小时,或者甚至在需要时以更长的时间间隔给药),精确的剂量方案与治疗剂的性质相称。
本文提供的化合物和组合物也可以与非化疗治疗联合施用,例如但不限于放疗、光动力治疗、基因治疗、手术、移植、免疫检查点抑制剂治疗和控制饮食。
试剂盒
本文还提供了包含本技术的化合物或组合物的试剂盒。试剂盒通常采用容纳各种组分的物理结构的形式,并且可以用于例如实施本文提供的方法。例如,试剂盒可以包括一种或多种本文公开的化合物(提供在例如无菌容器中),其可以是适合施用于受试者的药物组合物的形式。化合物可以以即用形式(例如,片剂或胶囊)提供或以需要例如在给药前重构或稀释(例如,粉末)的形式提供。当化合物处于需要由使用者重构或稀释的形式时,试剂盒还可以包括与化合物一起包装或与化合物分开包装的稀释剂(例如无菌水)、缓冲剂、药学上可接受的赋形剂等。当考虑联合疗法时,试剂盒可包含几种独立的治疗剂,或者它们可能已经组合在试剂盒中。试剂盒的每个组件可以封装在单独的容器中,并且所有不同的容器可以在单个包装中。本发明的试剂盒可以针对恰当保持容纳在其中的组分所必需的条件(例如冷藏或冷冻)而设计。
试剂盒还可以包含标签或包装插页,包括其中组分的鉴定信息和它们的使用说明(例如,剂量参数、活性成分的临床药理学,包括作用机制、药代动力学和药效学,不良反应、禁忌症等)。标签或插页可以包括制造商信息,例如批号和有效期。标签或包装插页可以例如整合到容纳组分的物理结构中,单独包含在物理结构内,或固定到试剂盒的组件(例如,安瓿、管或小瓶)上。
实施例
通过参考以下实施例将更容易理解本发明,所述实施例用于说明本发明,而不应被解释为以任何方式限制本发明的范围。
除非另有定义或上下文另有明确规定,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。应当理解,与本文所述类似或等同的任何方法和材料可用于本发明的实践或测试。
实施例1:4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰氨基)哌啶-1-羧酸叔丁酯(化合物A)的制备
将4-(4-氨基-1H-吡唑-3-甲酰氨基)哌啶-1-羧酸叔丁酯(0.6g,1.98mmol,1.0eq.)溶解在DMF(10mL)中,加入Et3N(404mg,4.0mmol,2.0eq.),然后滴加2,6-二氯苯甲酰氯(490mg,2.3mmol,1.2eq.)。在氮气气氛下,于室温下搅拌混合物12h。然后在减压下对混合物进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA=1/2~1/1)进行纯化,得到化合物A(720mg,75%)。
1H NMR(CD3OD,500MHz):δppm 1.44-1.53(m,11H),1.90(d,J=10Hz,2H),2.91(s,2H),3.99-4.09(m,3H),4.6(s,1H),7.41-7.53(m,3H),8.33(s,1H)。
13C NMR(CD3OD,125MHz):δppm 37.57,40.50,55.32,88.13,130.18,130.99,137.92,140.74,141.38,142.37,144.85,163.36,169.77,172.07。
m/z(ESI-):480.0(M-H)。
实施例2:4-(2,6-二氯苯甲酰氨基)-N-(1-(4-((2-氧代-1,2,3,4-四氢喹啉-7-基)氧基)丁基)哌啶-4-基)-1H-吡唑-3-甲酰胺(化合物2)的制备
将4-(2,6-二氯苯甲酰氨基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺甲磺酸盐(240mg,0.5mmol,1.0eq.)溶解在DMF(10mL)中,然后加入Et3N(101mg,1.0mmol,2.0eq.),随后滴加7-(4-溴丁氧基)-3,4-二氢-2(1H)-喹啉酮(163mg,0.55mmol,1.1eq.)。在N2气氛下,于室温下搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,MeOH:DCM=1/30~1/20)进行纯化,得到化合物2(120mg,40%)。
1H NMR(DMSO-d6,500MHz):δppm 1.51-1.54(m,2H),1.60-1.70(m,6H),1.88(t,J=10Hz,2H),2.28(t,J=5Hz,2H),2.40(t,J=5Hz,2H),2.77(t,J=5Hz,2H),2.83(d,J=10Hz,2H),3.70(s,1H),3.89(t,J=5Hz,2H),6.42(s,1H),6.47(dd,J=10Hz,5Hz,1H),7.03(d,J=10Hz,1H),7.51-7.54(m,1H),7.58(d,J=5Hz,2H),8.27(s,1H),8.34(s,1H),9.95(s,1H),10.17(s,1H),13.39(s,1H)。
13C NMR(DMSO-d6,125MHz):δppm 23.09,24.00,26.67,30.76,31.29,46.32,52.38,57.42,67.31,101.70,107.55,115.43,121.48,128.36,128.41,131.25,131.86,132.71,135.37,139.17,157.87,160.31,162.47,170.26。
m/z(ESI+):599.1(M+H)。
实施例3:4-(2,6-二氯苯甲酰氨基)-N-(1-(L-缬酰基)哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(化合物3)的制备
将4-(2,6-二氯苯甲酰胺基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺甲磺酸盐(480mg,1.0mmol,1.0eq.)溶解在DMF(7mL)和Et3N(220mg,2.0mmol,2.0eq.)的混合物中。然后加入2,5-二氧代吡咯烷-1-基N-(叔丁氧羰基)-L-缬氨酸(320mg,1.0mmol,1.0eq.)。在N2气氛下,于室温下搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA=1:1)进行纯化,得到4-(2,6-二氯苯甲酰氨基)-N-(1-(L-(N-叔丁氧基缬酰基)哌啶-4-基)-1H-吡唑-3-甲酰胺(516mg,89%)。
将前一步骤所得4-(2,6-二氯苯甲酰氨基)-N-(1-(L-(N-叔丁氧基缬酰基)哌啶-4-基)-1H-吡唑-3-甲酰胺(516mg,0.9mmol,1.0eq.)溶解在二氧六环(5mL)中,然后滴入在二氧六环中的4M HCl(2mL)。于室温下搅拌混合物5小时,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,DCM和MeOH,20:1)进行纯化,得到化合物3(120mg,45%)。
1H NMR(D2O,500MHz):δppm 0.98(t,J=4Hz,3H),1.08(dd,J=8Hz,4Hz,3H),1.55-1.61(m,2H),2.03-2.07(m,2H),2.22(s,1H),3.01(t,J=8Hz,1H),3.35(s,1H),3.94(s,1H),4.09(s,1H),4.36(dd,J=12Hz,4Hz,2H),7.47(s,3H),8.30(d,J=8Hz,1H)。
13C NMR(D2O,125MHz):δppm 15.75,18.10,29.37,30.49,31.17,41.50,44.67,45.94,55.41,119.80,123.28,128.18,131.46,131.87,133.82,134.26,163.02,164.29,167.88。
m/z(ESI+):480.8(M+H)。
实施例4:4-(2,6-二氯苯甲酰氨基)-N-(哌啶-4-基)-1H-1-(十二烷氧基甲基)吡唑-3-甲酰胺盐酸盐(化合物4)的制备
将十二碳酸(2.0g,10.0mmol,1.0eq.)溶解在DCM-H2O(1:1,40mL)中,然后依次加入氯甲基磺酰氯(1.2mL,11.5mmol,1.15eq.),Na2CO3(4.1g,40mmol,4.0eq.)和TBAB(320mg,1.0mmol,0.1eq.)。于室温下搅拌混合物12h,然后加入H2O(100mL)和DCM(100mL)进行稀释。分出有机层,用饱和食盐水(50mL)洗涤,并在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,石油醚),得到氯甲基十二碳酸酯(2.0g,80%)。
将化合物A(530mg,1.1mmol,1.0eq.)溶解在CH3CN(10mL)中,然后依次加入氯甲基十二碳酸酯(273mg,1.1mmol,1.0eq.)和NaHCO3(185mg,2.2mmol,2.0eq.)。在氮气下,搅拌混合物48h并加热至60℃,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA=2:1)进行纯化,得到4-(4-(2,6-二氯苯甲酰氨基)-1-((十二烷酰氧基)甲基)-1H-吡唑-3-甲酰氨基)哌啶-1-羧酸叔丁酯(190mg,25%)。
1H NMR(CDCl3,500MHz):δppm 0.81(t,J=10Hz,3H),1.18-1.21(m,18H),1.39(s,9H),1.51-1.60(m,2H),1.89(d,J=5Hz,2H),2.30(t,J=10Hz,2H),2.80(t,J=10Hz,2H),3.95-4.03(m,3H),5.94(s,2H),6.76(d,J=5Hz,1H),7.20-7.28(m,3H),8.50(s,1H),9.77(s,1H)。
将前一步骤所得化合物(190mg,0.3mmol,1.0eq.)溶于二氧六环(10mL)中,然后加入在二氧六环中的4M HCl(4mL)。于室温下搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,DCM:MeOH=20:1),得到化合物4(120mg,40%)。
1H NMR(CD3OD,500MHz):δppm 0.87(t,J=8Hz,3H),1.25(s,16H),1.60(s,2H),1.91(dd,J=12Hz、4Hz,2H),2.13(d,J=8Hz,2H),2.38(t,J=8Hz,2H),3.10(t,J=8Hz,2H),3.43(d,J=8Hz,2H),4.12(t,J=8Hz,1H),6.13(s,2H),7.47(s,3H),8.55(s,1H)。
13C NMR(CD3OD,125MHz):δppm 14.47,23.69,25.74,29.42,29.94,30.31,30.41,30.56,30.68,33.02,34.63,44.27,45.30,73.93,124.01,125.27,129.48,132.89,133.34,135.61,136.38,163.16,164.12,174.30。
m/z(ESI+):594.1(M+H)。
实施例5:4-(2,6-二氯苯甲酰氨基)-N-(1-(N-甘氨酰基-L-缬氨酰基)哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(化合物5)的制备
将N-(叔丁氧基羰基)甘氨酰基-L-缬氨酸(274mg,1.0mmol,1.0eq.)和Et3N(202mg,2.0mmol,2.0eq.)加入至4-(2,6-二氯苯甲酰胺基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(417mg,1.0mmol,1.0eq.)在DMF(10mL)的溶液中,然后加入HATU(418mg,1.1mmol,1.1eq.)。混合物于室温搅拌12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,乙酸乙酯),得到4-(2,6-二氯苯甲酰氨基)-N-(1-(N-(N-叔丁氧基羰基甘氨酰基)-L-缬氨酰基)哌啶-4-基)-1H-吡唑-3-甲酰胺(500mg,78%)。将由此得到的材料(500mg,1.27mmol,1.0eq.)溶于二氧六环(10mL)中,然后加入在二氧六环的4M HCL(5mL)。于室温下搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,DCM:MeOH=20:1),得到化合物5(100mg,14%)。
1H NMR(D2O,500MHz):δppm 0.92-0.97(m,6H),1.50(s,1H),1.66(d,J=8Hz,1H),2.05-2.09(m,3H),2.96(s,1H),3.35(s,1H),3.84-3.94(m,2H),4.10(t,J=12Hz,2H),4.35(d,J=12Hz,1H),4.79(s,1H),7.46(s,3H),8.30(d,J=8Hz,1H)。
13C NMR(CD3OD,125MHz):δppm 18.15,19.84,31.75,32.30,33.09,41.47,42.32,45.95,47.39,55.66,122.70,122.83,129.38,132.76,133.21,134.15,136.41,163.13,164.43,167.15,171.41。
m/z(ESI+):537.9(M+H)。
实施例6:4-(2,6-二氯苯甲酰氨基)-N-(1-(3-甲基丁酰基)哌啶-4-基)-1H-吡唑-3-甲酰胺(化合物6)的制备
将Et3N(202mg,2.0mmol,2.0eq.)和3-甲基丁酸(102mg,1.0mmol,1.0eq.)加入至4-(2,6-二氯苯甲酰氨基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(417mg,1.0mmol,1.0eq.)在DMF(10mL)的溶液中,然后加入HATU(418mg,1.1mmol,1.1eq.)。于室温下搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,2:1)以得到化合物6(380mg,82%)。
1H NMR(CD3OD,500MHz):δppm 0.97(dd,J=10Hz,5Hz,6H),1.52-1.56(m,2H),1.93-2.07(m,3H),2.29(d,J=10Hz,2H),2.80(t,J=15Hz,1H),3.21(t,J=15Hz,1H),3.99(d,J=15Hz,1H),4.08-4.12(m,1H),4.52(d,J=15Hz,1H),7.46-7.52(m,3H),8.35(s,1H)。
13C NMR(CD3OD,125MHz):δppm 23.02,23.12,27.30,32.60,33.47,42.02,43.09,46.24,47.78,122.49,123.16,129.64,132.94,133.62,134.70,136.85,163.42,164.99,173.56。
m/z(ESI+):466.0(M+H)。
实施例7:4-(2,6-二氯苯甲酰氨基)-N-(1-(L-缬氨酰基)甘氨酰基)哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(化合物7)的制备
将4-(2,6-二氯苯甲酰氨基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(417mg,1.0mmol,1.0eq.)和N-(叔丁氧基羰基)-L-甘氨酰基-缬氨酸(274mg,1.0mmol,1.0eq.)溶解在DMF(10mL)中。向混合物中加入Et3N((202mg,2.0mmol,2.0eq.)和HATU(418mg,1.1mmol,1.1eq.)。混合物于室温下搅拌12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA=1:1)得到4-(2,6-二氯苯甲酰氨基)-N-(1-(N-Boc-L-甘氨酰基-缬氨酰基)哌啶-4-基)-1H-吡唑-3-甲酰胺(560mg,88%)。将由此得到的化合物(560mg,0.88mmol,1.0eq.)溶于二氧六环(5mL)中,然后加入在二氧六环中的4M HCl(5mL)。于室温下搅拌混合物12h,并在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,DCM:MeOH=20:1),得到化合物7(230mg,50%)。
1H NMR(CD3OD,500MHz):δppm 1.08(d,J=10Hz,6H),1.50-1.69(m,2H),1.95-2.05(m,2H),2.17-2.25(m,1H),2.88(t,J=15Hz,1H),3.23(t,J=15Hz,1H),3.71(d,J=10Hz,1H),3.90(d,J=15Hz,1H),4.08-4.26(m,3H),4.46(d,J=15Hz,1H),7.44-7.52(m,3H),8.34(s,1H)。
13C NMR(D2O,125MHz):δppm 17.09,17.67,29.99,30.63,31.17,40.93,41.45,43.65,46.09,58.79,120.51,122.98,128.30,131.62,131.86,133.89,134.11,162.99,163.64,167.70,169.62。
m/z(ESI+):538.0(M+H)。
实施例8:4-(2,6-二氯苯甲酰氨基)-N-(1-Boc-哌啶-4-基)1-月桂酰基-1H-吡唑-3-甲酰胺(化合物8)的制备
将化合物A(481mg,1.0mmol,1.0eq.)和Et3N(202mg,2.0mmol,2.0eq.)溶解在DMF(10mL)中,然后加入月桂酰氯(219mg,1.0mmol,1.0eq。在氮气保护下,搅拌反应物12h。在减压下,对混合物进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,3:1)进行纯化,得到化合物8(300mg,45%)。
1H NMR(DMSO-d6,500MHz):δppm 0.9(t,J=10Hz,3H),1.29-1.40(m,25H),1.55-1,59(m,2H),1.75-1.81(m,2H),1.87-1.91(m,2H),2.85(s,2H),3.23(t,J=10Hz,2H),4.06-4.12(m,3H),7.45-7.52(m,3H),8.91(s,1H)。
13C NMR(DMSO-d6,125MHz):δppm 14.49,23.72,25.20,28.73,30.10,30.45,30.60,30.71,32.46,33.04,34.12,48.07,81.13,120.44,125.23,129.50,132.93,133.31,136.23,138.76,156.33,163.33,163.49,173.21。
m/z(ESI-):662.2(M-H)。
实施例9:4-(2,6-二氯苯甲酰氨基)-N-(哌啶-4-基)-1-(L-缬氨酰氧基甲基)-1H-吡唑-3-甲酰胺二盐酸盐(化合物10)的制备
将(叔丁氧基羰基)-L-缬氨酸(434mg,2.0mmol,1.0eq.)溶解在DCM-H2O(v/v,1:1;10mL)中,然后依次加入氯甲基氯磺酸酯(0.24mL,2.3mmol,1.15eq.),Na2CO3(850mg,8.0mmol,4.0eq.)和TBAB(65mg,0.2mmol,0.1eq.)。于室温下搅拌混合物12h,然后用DCM(50mL)和H2O(50mL)稀释。分离有机相,随后用食盐水(3×20mL)洗涤,并在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,石油醚)进行纯化,得到氯甲基N-(叔丁氧基羰基)-L-缬氨酸酯(480g,90.5%)。
将化合物A(481mg,1.0mmol,1.0eq.)溶于CH3CN(10mL)中,然后依次加入氯甲基N-(叔丁氧基羰基)-L-缬氨酸酯(265mg,1.0mmol,1.0eq.)和NaHCO3(168mg,2.0mmol,2.0eq.)。在氮气保护下,于60℃下搅拌混合物48h。在减压下,对混合物进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA=2:1),得到4-(2,6-二氯苯甲酰氨基)-N-(哌啶-4-基)-1-(N-Boc-L缬氨酰氧基甲基)-1H-吡唑-1-3-甲酰胺(450mg,63%)。
将Boc-保护的化合物(240mg,0.5mmol,1.0eq.)溶于二氧六环(10mL)中,然后加入在二氧六环中的4M HCl(0.5mL)。于室温下搅拌混合物12h,并在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,DCM:MeOH=20:1),得到化合物10(120mg,47%)。
1H NMR(D2O,500MHz):δppm 0.93(t,J=10Hz,6H),1.82-1.91(m,2H),2.22(d,J=10Hz,2H),2.30-2.36(m,1H),3.18(t,J=10Hz,2H),3.52(d,J=10Hz,2H),4.12-4.15(m,2H),6.24(d,J=10Hz,1H),6.47(d,J=10Hz,1H),7.47-7.54(m,3H),8.58(s,1H)。
13C NMR(D2O,125MHz):δppm 16.91,27.79,29.35,42.91,44.21,57.94,73.75,120.78,126.71,128.30,128.48,131.51,132.17,133.72,162.66,165.30,168.91。
m/z(ESI+):511.1(M+H)。
实施例10:4-(2,6-二氯苯甲酰氨基)-3-(哌啶-4-基氨基羰基)-1H-吡唑-1-甲基磷酸酯二钠盐(化合物11)的合成
将化合物A(481mg,1.0mmol,1.0eq.)和二叔丁基(氯甲基)磷酸酯(258.7mg,1.0mmol,1.0eq.)溶于AcNMe2(10mL)中,然后加入Cs2CO3(652mg,2.0mmol,2.0eq.)。在氮气保护下,于40℃至45℃下搅拌混合物12h。混合物用用DCM(50mL)和H2O(50mL)稀释。分离有机相,随后用食盐水(3×20mL)洗涤,并在减压下进行浓缩残留材料用快速柱层析(硅胶;洗脱剂,PE:丙酮;3:1)进行纯化,得到4-(2,6-二氯苯甲酰胺)-3-(哌啶-4-基氨基羰基)-1H-吡唑-1-甲基磷酸二叔丁基酯(240mg,34.1%)。
将由此得到的磷酸酯化合物(150mg,0.2mmol,1.0eq.)溶解在DCM(2mL)中,随后加入CF3COOH(1mL)。搅拌混合物1分钟,然后在减压下浓缩,并用t-BuOMe(5mL)处理。通过过滤收集固体材料,干燥,得到4-(2,6-二氯苯甲酰胺)-3-(哌啶-4-基氨基羰基)-1H-吡唑-1-基)甲基二氢磷酸酯(75mg,76.2%)。
将该4-(2,6-二氯苯甲酰胺)-3-(哌啶-4-基氨基羰基)-1H-吡唑-1-基)甲基二氢磷酸酯(49.1mg,0.1mmol,1.0eq.)溶于水(2mL)中,然后用NaOH(8mg,0.2mmol,2.0eq.)处理。搅拌混合物0.5h,并进行冷冻干燥,得到化合物11(47mg,87.9%)。
1H NMR(500MHz,D2O):δppm 1.53(d,J=10.5Hz,2H),1.94(d,J=12.8Hz,2H),2.72(t,J=12.2Hz,2H),3.07(d,J=12.2Hz,2H),3.90(s,1H),5.66(d,J=7.5Hz,2H),7.37(d,J=8.4Hz,1H),7.43(d,J=8.0Hz,2H),8.32(s,1H)。
13C NMR(125MHz,D2O):δppm 30.30,43.26,45.70,75.70,123.45,125.10,128.18,131.30,131.44,135.57,136.54,163.00,165.66。
m/z(ESI+):491.8(M+H)。
实施例11:N-((4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰氨基)-1-哌啶基)(苯氧基)次膦酰基)-L-丙氨酸甲酯(化合物12)的制备
将苯基二氯磷酸酯(4.0g,18.96mmol,1.0eq.)和L-丙氨酸甲酯盐酸盐(2.64g,18.96mmol,1.0eq.)溶于DCM(40mL)中。在-78℃至-70℃下,向混合物中滴加Et3N(3.83g,37.92mmol,2.0eq.)。在氮气保护下,搅拌混合物1h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,3:1)进行纯化,得到N-(氯(苯氧基)磷酰基)-L-丙氨酸甲酯(2.0g,38.1%)。
1H NMR(CDCl3,500MHz):δppm 1.52-1.57(m,3H),3.78-3.85(m,3H),4.16-4.26(m,2H),7.30(d,J=10Hz,3H),7.36-7.44(m,2H)。
将4-(2,6-二氯苯甲酰胺基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(208mg,0.5mmol,1.0eq.)和(氯(苯氧基)磷酰基)-L-丙氨酸甲酯(140mg,0.5mmol,1.0eq.)溶于DCM(5mL)中,然后加入Et3N(101mg,1.0mmol,2.0eq)。在氮气保护下,搅拌混合物12h,并在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,2:1)进行纯化,得到化合物12(120mg,38.5%)。
1H NMR(CD3OD,500MHz):δppm 1.39(dd,J=15Hz,10Hz,3H),1.52-1.57(m,2H),1.86-1.90(m,2H),2.82-2.89(m,2H),3.72(d,J=10Hz,6H),3.93-3.96(m,2H),4.64(s,1H),7.15-7.22(m,3H),7.34-7.37(m,2H),7.45-7.51(m,3H),8.35(s,1H)。
m/z(ESI+):622.9(M+H)。
实施例12:4-(2,6-二氯苯甲酰氨基)-N-(1-(2-氧化-4H-1,3,2-苯并二氧杂磷-2-基)哌啶-4-基)-1H-吡唑-3-甲酰胺(化合物13)的制备
将2-(羟甲基)苯酚(2.0g,16.1mmol,1.0eq.)和POCl3(2.7g,17.7mmol,1.1eq.)溶于THF(40mL)中,然后滴加Et3N(3.4g,35.8mmol,2.1eq.),同时将该体系冷却至-78℃至-70℃。在氮气保护下,搅拌反应物1h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,3:1),得到2-氯-2-氧化-4H-1,3,2-苯并二氧杂磷(2.3g,70.0%)。
1H NMR(CDCl3,500MHz):δppm 5.51-5.57(m,2H),7.13-3.16(m,2H),7.25-7.29(m,1H),7.39-7.43(m,1H)。
将4-(2,6-二氯苯甲酰胺基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(417mg,1.0mmol,1.0eq.)和2-氯-2-氧化-4H-1,3,2-苯并二氧杂磷(204mg,1.0mmol,1.0eq.)溶解于DCM(10mL)中,然后加入Et3N(202mg,2.0mmol,2.0eq.)。在氮气的保护下,搅拌混合物12h。在减压下,对混合物进行浓缩,并且。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,1:1),得到化合物13(300mg,54.5%)。
1H NMR(CD3OD,500MHz):δppm 1.59-1.64(m,2H),1.92(d,J=10Hz,2H),2.98(t,J=15Hz,2H),3.58(s,2H),4.0-4.03(m,1H),5.28-5.35(m,1H),5.51-5.53(m,1H),7.11-7.12(m,1H),7.19(d,J=10Hz,1H),7.26(d,J=10Hz,1H),7.38(s,1H),7.47-7.52(m,3H),8.36(s,1H)。
13C NMR(CD3OD,125MHz):δppm 32.96,44.83,47.44,68.53,119.20,122.59,123.01,123.26,125.30,126.97,129.48,130.96,132.78,133.45,134.42,136.68,152.47,163.29,164.66。
m/z(ESI+):549.8(M+H)。
实施例13:N-((4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰氨基)哌啶-1-基)(萘-1-基氧基)磷酰基)-L-丙氨酸甲酯(化合物16)的合成
将1-萘酚(0.72g,4.99mmol,1.0eq.)和三氯氧磷(767mg,4.99mmol,1.0eq.)溶于无水乙醚(20mL)中,并且温度冷却至-78℃。向混合物中滴加三乙胺(505mg,4.99mmol,1.0eq.),并且在-78℃下,搅拌反应混合物0.5h。将反应混合物升温至室温,并于室温条件下搅拌。过滤混合物,并对滤液进行浓缩,得到为黄色油状物的粗品1-萘基磷酸二氯酯(1.1g,85.0%),其无需纯化便可使用。
在氮气保护下,于-78℃下,将无水TEA(848mg,8.4mmol,2.0eq.)滴加至1-萘基磷酸二氯酯(1.1g,4.2mmol,1.0eq.)和L-氨基丙酸甲酯盐酸盐(586mg,4.2mmol,1.0eq.)在无水DCM(30mL)的搅拌溶液中。反应混合物在-78℃下搅拌1h,然后在室温下搅拌1h。在减压下,移除溶剂,残留物材料用快速柱层析(硅胶;洗脱剂,PE:EA,1:1)进行纯化,得到N-(氯(1-萘氧基)磷酰基)-L-丙氨酸甲酯(790mg,57.4%)。
在氮气保护下,于0℃下,将N-(氯(1-萘氧基)磷酰基)-L-丙氨酸甲酯(289mg,0.88mmol,1.0eq.)滴加至4-(2,6-二氯苯甲酰胺基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(410mg,0.98mmol,1.1eq.)和TEA(198mg,1.96mmol,2.2eq.)在无水DCM(10mL)的搅拌的溶液中。于室温下搅拌反应混合物5h。在减压下除去溶剂,残留物用快速柱层析(硅胶;洗脱剂,DCM:MeOH,20:1)进行纯化,得到化合物16(226mg,38.1%)。
1H NMR(500MHz,CD3OD):δppm 1.59-1.32(m,5H),1.81(s,2H),2.81(d,J=23.5Hz,2H),3.81-3.64(m,5H),3.87(s,1H),4.00(s,1H),7.59-7.32(m,7H),7.66(s,1H),7.86(d,J=6.8Hz,1H),8.17(dd,J=15.0,7.9Hz,1H),8.31(s,1H)。
13C NMR(125MHz,CD3OD):δppm 20.68,33.01,45.18,47.65,51.02,52.71,115.90,122.32,122.63,122.72,122.96,125.39,125.49,126.56,127.31,127.68,128.87,129.43,132.73,133.40,134.49,136.27,136.62,148.32,163.20,164.62,175.83。
m/z(ESI-):670.7(M-H)。
实施例14:N-((4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰氨基)哌啶-1-基)(萘-1-基氧基)磷酰基)-L-丙氨酸异丙酯(化合物17)的制备
将4-(2,6-二氯苯甲酰氨基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(417mg,1.0mmol,1.0eq.)和N(氯(1-萘基氧基)磷酰基)-L-丙氨酸异丙酯(356mg,1.0mmol,1.0eq.)溶于DCM(15mL)中。然后加入Et3N(303mg,3.0mmol,2.0eq.)。在氮气保护下,搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,DCM:MeOH,30:1)得到化合物17(200mg,29%)。
1H NMR(CD3OD,500MHz):δppm 1.21-1.37(m,6H),1.40-1.44(m,4H),1.53(t,J=10Hz,1H),1.85(s,2H),2.86(s,2H),3.78(s,2H),3.88-4.0(m,2H),4.99-5.03(m,1H),7.43-7.57(m,7H),7.70(s,1H),7.88(s,1H),8.18-8.33(m,1H),8.33(s,1H)。
31P NMR(CD3OD,203MHz):δppm 10.83,11.40。
m/z(ESI+):701.1(M+H)。
实施例15:((4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰氨基)哌啶-1-基)(苯氧基)磷酰基)-L-丙氨酸异丙酯(化合物18)的制备
将苯氧基二氯化磷(2.0g,9.5mmol,1.0eq.)和L-丙氨酸异丙酯盐酸盐(1.6g,9.5mmol,1.0eq.)溶于DCM(20mL)中。于-78℃至-70℃下,向混合物中滴入Et3N(1.9g,19mmol,2.0eq.)。在氮气保护下,搅拌混合物1h,并在减压下进行浓缩。材料用快速柱层析(硅胶;洗脱剂,PE:EA,3:1)进行纯化,得到N-(氯(苯氧基)磷酰基)-L-丙氨酸异丙酯(1.9g,65.4%)。
将4-(2,6-二氯苯甲酰胺)-N-(哌啶-4-基)-1H-吡唑-3-羧酰胺盐酸盐(417mg,1.0mmol,1.0eq.)和N-(氯(苯氧基)磷酰基)-L-丙氨酸异丙酯(305mg,1.0mmol,1.0eq.)溶于DCM(10mL)中,然后加入Et3N(202mg,2.0mmol,2.0eq.)。在氮气保护下,搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,2:1)进行纯化,得到化合物18(200mg,30.7%)。
1H NMR(CD3OD,500MHz):δppm 1.27-1.31(m,6H),1.38-1.44(m,3H),1.56(d,J=15Hz,2H),1.93(s,2H),2.87(s,2H),3.77(s,2H),3.94-3.97(m,2H),5.03-5.06(m,1H),7.25-7.26(m,3H),7.38-7.40(m,2H),7.50-7.56(m,3H),8.39(s,1H)。
13C NMR(CD3OD,125MHz):δppm 20.52,21.82,32.88,44.84,47.67,51.06,69.90,121.31,121.47,122.41,122.82,125.53,129.32,130.52,132.62,133.30,134.24,136.52,152.38,163.12,164.48,174.72。
m/z(ESI+):651.0(M+H)。
实施例16:4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰氨基)哌啶-1-甲烷膦酸二钠盐(化合物20)的制备
将4-(2,6-二氯苯甲酰氨基)-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺盐酸盐(1.04g,2.5mmol,1.0eq.)和(二乙氧基磷酰基)甲基4-甲基苯磺酸酯(0.81g,2.5mmol,1.0eq.)溶于DMF(10mL)中,然后加入Et3N(732mg,7.15mmol,3.0eq.)。搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,DCM:MeOH,10:1)得到4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰胺基)哌啶-1-甲烷膦酸二乙酯(320mg,24%)。
将4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰氨基)哌啶-1-甲烷膦酸二乙酯(300mg,0.56mmol,1.0eq.)溶于CH3CN(5mL)中,加入TMSBr(260mg,1.7mmol,3.0eq.)。在氮气保护下搅拌混合物36h,用MeOH(10mL)稀释。通过过滤收到固体材料,并且用MeOH(10mL)洗涤滤饼,干燥得到4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰胺基)哌啶-1-甲烷膦酸(100mg,38%)。
将该4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰胺基)哌啶-1-甲烷膦酸(100mg,0.21mmol,1.0eq.)溶于H2O(5mL)中,并用NaOH(16.8mg,0.42mmol,2.0eq.)处理。搅拌混合物0.5h,并冷冻干燥,得到化合物20(100mg,92%)。
1H NMR(CD3OD,500MHz):δppm 1.31(d,J=15Hz,1H),1.67-1.75(m,2H),1.90-1.93(m,2H),2.39(t,J=10Hz,2H),2.58(d,J=10Hz,2H),3.27(s,1H),3.84(s,1H),7.41-7.49(m,3H),8.26(s,1H)。
13C NMR(CD3OD,125MHz):δppm 32.29,47.10,55.32,58.60,59.72,123.31,124.30,129.44,132.59,133.51,134.16,137.02,163.30,164.94。
31P NMR(CD3OD,203MHz):δppm 13.86。
m/z(ESI+):477.6(M+H)。
实施例17:(4-(2,6-二氯苯甲酰胺)-3-(哌啶-4-基氨基甲酰基)-1H-吡唑-1-基)甲基异丙基碳酸酯盐酸盐(化合物25)的制备
将化合物A(481mg,1.0mmol,1.0eq.)和氯甲基异丙基碳酸酯(304mg,2.0mmol,2.0eq.)溶解在CH3CN(10mL)中,然后加入NaHCO3(168mg,2.0mmol,2.0eq.)。在氮气保护下,于25℃下搅拌混合物12h,并在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,1:1),得到叔丁基4-(4-(2,6-二氯苯甲酰胺)-1-((异丙氧羰基氧基)甲基)-1H-吡唑-3-甲酰胺基)哌啶-1-羧酸酯(240mg,40.1%)。
将所得产物(240mg,0.4mmol,1.0eq.)溶解在1,4-二氧六环(4mL)中,然后加入在1,4-二氧六环中的4M HCl(2mL)。搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,DCM和MeOH,20:1),得到化合物25(100mg,46.7%)。
1H NMR(D2O,500MHz):δppm 1.26-1.28(m,6H),1.79-1.87(m,2H),2.17(d,J=15Hz,2H),3.14(t,J=10Hz,2H),3.50(d,J=10Hz,2H),4.03(s,1H),4.89-4.94(m,1H),6.13(s,2H),7.41(s,3H),8.53(s,1H)。
13C NMR(D2O,125MHz):δppm 20.72,20.81,27.72,42.87,44.02,75.07,120.84,125.87,128.25,131.44,132.08,133.65,136.14,153.91,162.50,164.59。
m/z(ESI+):497.8(M+H)。
实施例18:4-(2,6-二氯苯甲酰胺)-1-月桂酰基-N-(哌啶-4-基)-1H-吡唑-3-甲酰胺(化合物27)的制备
将4-(2,6-二氯苯甲酰胺)-N-(哌啶-4-基)-1H-吡唑-3-羧酰胺盐酸盐(1.6g,3.8mmol,1.0eq.)和(9H-芴-9-基)甲基氯甲酸酯(1.0g,3.8mmol,1.0eq.)溶于-二氧六环-H2O(20mL,1:1)中,然后加入NaHCO3(640mg,7.6mmol,2.0eq.)。搅拌混合物12h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,1:1),得到(9H-芴-9-基)甲基4-(4-(2,6-二氯苯甲酰胺)-1H-吡唑-3-甲酰胺基)哌啶-1-羧酸酯(1.0g,43.6%)。
将(9H-芴-9-基)甲基4-(4-(2,6-二氯苯甲酰胺)-1H-吡唑-3-甲酰胺基)哌啶-1-羧酸酯(900mg,1.5mmol,1.0eq.)和月桂酰氯(358mg,1.64mmol,1.1eq.)溶于DCM(10mL)中,然后加入Et3N(303mg,3.0mmol,2.0eq.)。在氮气气氛下,于室温下搅拌混合物12h。然后在减压下对混合物进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA=5:1)得到(9H-芴-9-基)甲基4-(4-(2,6-二氯苯甲酰氨基)-1-月桂酰基-1H-吡唑-3-甲酰胺基)哌啶-1-羧酸甲酯(800mg,68%)。
将(9H-芴-9-基)甲基4-(4-(2,6-二氯苯甲酰氨基)-1-月桂酰基-1H-吡唑-3-甲酰胺基)哌啶-1-羧酸甲酯(560mg,0.71mmol,1.0eq.)溶于DMF(5mL)中,然后用DIPEA(5mL)处理。搅拌混合物48h,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,2:1),得到化合物27(150mg,68%)。
1H NMR(CD3OD,500MHz):δppm 0.89-1.01(m,3H),1.30(s,17H),1.50-1.61(m,3H),1.96(d,J=10Hz,2H),2.40(s,2H),2.80(t,J=15Hz,1H),3.21(t,J=15Hz,1H),3.98(t,J=15Hz,1H),4.10(s,1H),4.50(d,J=10Hz,1H),7.46-7.51(m,3H),8.36(s,1H)。
13C NMR(CD3OD,125MHz):δppm 14.38,23.67,26.64,30.40,30.44,30.48,30.58,30.68,32.39,33.02,33.28,34.12,41.87,45.87,47.63,122.35,123.02,129.48,132.76,133.47,134.53,136.69,163.26,164.81,174.11。
m/z(ESI+):564.0(M+H)。
实施例19:((4-(4-(2,6-二氯苯甲酰氨基)-1-月桂酰基-1H-吡唑-3-甲酰氨基)哌啶-1-基)(苯氧基)次膦酰基)-L-丙氨酸甲酯(化合物38)的制备
将化合物12(310mg,0.5mmol,1.0eq.)和十二烷酰氯(130mg,0.6mmol,1.2eq.)溶于DCM(5mL)中,然后加入Et3N(101mg,1.0mmol,2.0eq.)。在氮气气氛下,于室温下搅拌混合物,然后在减压下进行浓缩。残留材料用快速柱层析(硅胶;洗脱剂,PE:EA,3:1),得到化合物38(120mg,30%)。
1H NMR(CD3OD,500MHz):δppm 0.92(s,3H),1.32-1.45(m,21H),1.61(s,2H),1.78-1.90(m,4H),2.84(s,2H),3.23(s,2H),3.73(s,4H),3.96(s,1H),7.18-7.24(m,3H),7.37(s,2H),7.50(s,3H),8.93(s,1H)。
13C NMR(CD3OD,125MHz):δppm 14.46,20.68,23.68,25.19,30.08,30.41,30.56,30.67,32.85,33.00,34.12,45.00,45.21,48.22,50.98,52.72,120.46,121.41,121.57,125.23,125.67,129.49,130.64,132.91,133.30,136.21,138.79,152.46,163.30,163.46。
31P NMR(CD3OD,203MHz):δppm 10.54,11.09。
m/z(ESI+):805.2(M+H)。
实施例20:4-(4-(2,6-二氯苯甲酰氨基)-1H-吡唑-3-甲酰氨基)哌啶-1-乙酸氢溴酸盐(化合物54)的合成
在氮气保护下,将2-溴乙酸叔丁酯(419mg,2.1mmol,1.0eq.)滴加至4-(2,6-二氯苯甲酰胺)-N-(哌啶-4-基)-1H-吡唑-3-羧酰胺盐酸盐(900mg,2.1mmol,1.0eq.)和三乙胺(530mg,5.3mmol,2.5eq.)在DCM(25mL)的搅拌的溶液中。室温下搅拌反应混合物过夜。在减压下,除去溶剂,残留物用快速柱层析(硅胶;洗脱剂,DCM:MeOH,20:1),得到4-(4-(2,6-二氯苯甲酰胺)-1H-吡唑-3-甲酰胺基)哌啶-1-乙酸叔丁酯(620mg,59.5%)。
1H NMR(500MHz,CD3OD):δppm 1.46(s,9H),1.70(d,J=10.9Hz,2H),1.89(d,J=11.7Hz,2H),2.30(t,J=11.5Hz,2H),2.94(d,J=10.4Hz,2H),3.13(s,2H),3.84(s,1H),7.47(dd,J=16.4,6.6Hz,3H),8.33(s,1H)。
将TFA(8mL)加入至该乙酯衍生物(620mg,1.2mmol,1.0eq.)在无水DCM(16mL)的搅拌的溶液中。室温下搅拌反应混合物过夜。在减压下,除去溶剂,残留物溶于40%HBr(5mL)处理,冷冻干燥,得到化合物54(533mg,85.2%)。
1H NMR(500MHz,D2O):δppm 2.04(d,J=13.2Hz,2H),2.32(d,J=13.4Hz,2H),3.30(t,J=12.3Hz,2H),3.82(d,J=11.9Hz,2H),4.13(d,J=28.8Hz,3H),7.54(d,J=6.5Hz,1H),7.56(s,2H),8.40(s,1H)。
13C NMR(125MHz,DMSO-d6):δppm 28.42,43.94,51.85,55.33,121.65,128.55,131.35,132.06,132.39,135.42,160.59,162.85,167.21。
m/z(ESI+):439.8(M+H)。
实施例21:小鼠中毒性研究
将20~22g的雄性小鼠(BABL/c)于标准条件下饲养,随机分组。在第1天,三组动物分别静脉给与AT7519(甲磺酸盐形式),化合物11和化合物12。对剂量进行计算并以毫摩尔/公斤体重单位(mmol/kg)来表示,并且对对药物耐受性、药代动力学和对体重的影响进行评价。
(a)耐受性:将60只动物分为3组(每组20只),并且分别以以下剂量给与化合物:AT7519,0.031mmol/kg(相当于12mg/kg AT7519自由碱形式);化合物11,0.062mmol/kg;化合物12,0.124mmol/kg。另一组(该组有5只动物),以0.039mmol/kg(15mg/kg)的剂量给与AT7519,作为参照。结果总结在2中。
表2.静脉给予不同化合物后的动物死亡
如表2中的数据所示,AT7519在0.031mmol/kg的低剂量导致20%的动物死亡率;而高剂量(0.039mmol/kg)的AT7519,导致全部动物死亡,即便该剂量仅增加了25%(从低剂量),这表明了0.031mmol/kg是AT7519的临界死亡剂量。相比之下,当在分别给与的化合物相当于AT7519阈值水平的两倍及四倍摩尔当量的剂量时,化合物11和化合物12没有导致一例死亡。总之,化合物11和化合物12的毒性大大低于AT7519的毒性。
(b)毒代动力学:为了证实上述毒性研究的有效性,确定施用各种化合物后,血浆AT7519浓度。AT7519、化合物11和化合物12的静脉注射剂量与上文相同,即分别为:AT7519,0.031mmol/kg;化合物11,0.062mmol/kg;化合物12,0.124mmol/kg。在2min、10min、1h和4h采集血浆样品。利用LC-MS/MS方法分析各样品中AT7519的AT7519浓度。结果总结在表3中,并且浓度-时间曲线示出在图1中。
表3.毒代研究中小鼠血浆中的AT7519浓度*
化合物 | AT7519 | 化合物11 | 化合物12 |
剂量(mmol/kg) | 0.031 | 0.062 | 0.124 |
给药途径 | I.V. | I.V. | I.V. |
给药浓度(mM) | 0.0031 | 0.0062 | 0.0124 |
给药体积(mL/kg) | 10 | 10 | 10 |
2min | 10230 | 45000 | 99067 |
10min | 1837 | 12627 | 17867 |
1h | 489 | 970 | 1657 |
4h | 47 | 170 | 197 |
*浓度单位为ng/mL.
表3中的数据表明,化合物11和化合物12在静脉注射后于短时间内(<2min)转化为AT7519。在各个时间点,无论所施用的化合物是AT7519本身或其前药(化合物11或化合物12),血浆浓度和剂量之间都存在粗略的相关性。在化合物11和化合物12的情况下,血浆AT7519暴露量要高的多。
(c)静脉注射单剂后药物对动物体重的影响:将60只动物分为三组(每组20只),并且第0天(研究的起始日)通过静脉分别给与各种测试化合物:AT7519,0.031mmol/kg(等同于12mg/kg的AT7519游离形式);化合物11,0.062mmol/kg;化合物12,0.124mmol/kg。按照以下方案进行临床观察:给药后连续观察第一个4小时,然后每天观察两次,一周时间,以及第14天。观察的参数包括动物的身心行为、自主活动、毛发、腺体分泌、粪便和死亡。给药前,给药后第3、5、7、10天测量身体的体温。
在该研究中,AT751组中,有4只动物死亡,而给与化合物11和12的组中,未观察到动物死亡。
动物的体重总结在表4中,并且各组中动物体重变化的趋势线示出图2中。其中,体重值为单次测量中各组所有动物体重的平均值。
表4.给药后动物体重的变化
结果表明:在最初几天,与接受AT7519的动物相比,接受化合物(化合物11和12)的动物,其体重有下降的趋势,但在狭窄范围,即3~5%范围内变动。在第7天以及之后,所有组的动物体重相同或非常相似。据推断,最初的体重下降归因于动物对非常高剂量化合物的正常反应。
实施例22:大鼠中的毒代研究
将体重220~240g的雄性SD(Sprague Dawley)大鼠于标准条件下饲养,随机分三组。第0天(起始日),所有动物都静脉注射三种化合物之一。剂量换算成以mmol/kg来表示。
(a)剂量探索
每组各取1只动物给予拟定的最高剂量的化合物。观察结果示出在表5中。
表5.测试化合物的毒性
表5的数据表明,仅化合物12不会引起动物死亡,而AT7519和化合物11已经处于它们的致死剂量(剂量如该表中所示)。
(b)TK研究:将剩余的动物随机分三组,每组6只。在时间0,向动物给与AT7519(剂量,0.039mmol/kg)或者化合物11(0.050mmol/kg)或者化合物12(0.124mmol/kg)。TK(毒代)分析如下进行:在2min、10min、1h、2h和6h的时间点将血液样品采集到样品管(肝素化)。在转化为血浆样品后,对AT7519浓度进行分析(LC-MS/MS)。结果总结在表6中,浓度-时间曲线示出在图3中。
表6.大鼠TK研究中血浆AT7519浓度
实施例23:大鼠中的毒性研究
雄性SD(Sprague Dawley)大鼠静脉给药0.031mmol-当量/kg的各测试化合物,其中注射时间控制为30秒至45秒。采用四级评分系统来描述测试化合物的毒性:A,注射过程中动物死亡;B,动物静脉给药后5min内出现休克,恢复后伏地,运动减少;C,无动物死亡,但0-30min内出现伏地,运动减少;D,无动物死亡,未出现明显行为学反应,体重未明显减轻,参见表7。
表7:大鼠中的毒性评分
尽管参照本发明的实施例详细描述了本发明,但提供这些实施例是为了说明而不是限制本发明。根据本发明原理能够得到的其它实施例均属于本发明权利要求所界定的范畴。
本文所列出的所有文件和文献的内容通过引用而整体并入本文中。
Claims (28)
1.一种式I所示的化合物,或其药学上可接受的盐或酯:
其中:
(a)R1和R2各自选自以下项的保护基:
酰基、羰基、硫代羰基、氨基甲酰基、取代或未取代的乙酰基、取代或未取代的氨基烷酰基、取代或未取代的α-氨基烷酰基、衍生自天然氨基酸或非天然氨基酸的具有取代基或不具有取代基的酰基、肽残基的酰基、取代或未取代的环烷基羰基、取代或未取代的杂环烷基-羰基、取代或未取代的烷氧羰基、取代或未取代的芳氧羰基、取代或未取代的杂烷氧基羰基、取代或未取代的杂芳氧基羰基,和具有或不具有取代基的O-取代的羟甲基;或者,
(b)R1和R2独立地为H或者结构为R3W(R4R5C)m-的保护基,
其中,m为选自1至6的整数,
W为氧(-O-)、硫(-S-)、氮(-NH-)或不存在,
R4和R5独立地为氢或低级烷基,并且
其中X为氧(-O-)、硫(-S-)、氮(-NH)或亚甲基(-CH2-),
R6和R7独立地为氢;取代或未取代的烷基;环烷基;芳基或杂芳基;或者结构为R8-(OCH2CH2)n-的PEG残基,其中n=1至10并且R8为氢或低级烷基;成酯基团,诸如低级烷基或芳基;或者当X为氧或硫时,为成盐部分,诸如钠、钾、四乙铵或四丁铵;或者,R6和X的组合一起形成具有额外取代基或不具有额外取代基的烷基或芳基;或者
(c)R2为氢,并且R1为选自以下项的保护基:酰基、羰基、硫代羰基、氨基甲酰基、取代的或未取代的乙酰基、取代或未取代的氨基烷酰基、取代或未取代的α-氨基烷酰基、衍生自天然氨基酸或非天然氨基酸的具有取代基或不具有取代基的酰基、肽残基的酰基、取代或未取代的环烷基-羰基、取代或未取代的杂环烷基-羰基、取代或未取代的烷氧羰基、取代或未取代的芳氧羰基、取代或未取代的杂烷氧基羰基、取代或未取代的杂芳氧基羰基、具有取代基或不具有取代基的O-取代的羟甲基和R3W(R4R5C)m-,其中,m为0至6,W、X、R3、R4和R5如(b)中所限定;条件是R1和R2中的至少一个不为氢;或者
(d)R1为氢,并且R2为R3W(R4R5C)m-,其中m为选自1至6的整数,W、R3、R4和R5如(b)中所限定;或者
2.根据权利要求1所述的化合物,其中式I的化合物为表1中示出的化合物,或其药学上可接受的盐、酯、螯合物、水合物、溶剂化物、立体异构体或多晶型形式。
3.根据权利要求1或2所述的化合物,其中,所述化合物抑制或调节一种或多种周期蛋白依赖性激酶(CDK)或GSK-3。
4.根据权利要求3所述的化合物,其中,所述化合物抑制或调节CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7和CDK9中的一种或多种。
5.根据权利要求4所述的化合物,其中,所述化合物抑制或调节CDK1、CDK2,或者CDK1和CDK2。
6.根据权利要求3至5中任一项所述的化合物,其中,所述化合物抑制或调节一种或多种CDK和GSK-3。
7.根据权利要求1至6中任一项所述的化合物,其中,所述化合物为4-(2,6-二氯苯甲酰氨基)-N-(4-哌啶基)-1H-吡唑-3-甲酰胺(AT7519)的前药。
9.一种药物组合物,包括根据权利要求1至8中任一项所述的化合物,以及药学上可接受的载体。
10.根据权利要求9所述的药物组合物,其中,所述组合物适用于口服施用。
11.根据权利要求23所述的药物组合物,其中,所述组合物为硬壳明胶胶囊、软壳明胶胶囊、扁囊剂、丸剂、片剂、锭剂、粉剂、颗粒剂、弹丸剂、溶液、锭剂、糖衣丸、乳剂、酏剂或糖浆的形式。
12.根据权利要求9所述的药物组合物,其中,所述组合物适用于注射施用。
13.根据权利要求9或12所述的药物组合物,其中,所述组合物适用于静脉内、肌肉内、腹腔内和皮下给药。
14.一种用于抑制或调节受试者中周期蛋白依赖性激酶(CDK)和/或糖原合成酶激酶-3(GSK-3)的方法,包括将有效量的根据权利要求1至8中任一项所述的化合物,或者根据权利要求9至13中任一项所述的药物组合物施用至受试者,从而抑制或调节所述受试者中的CDK和/或GSK-3。
15.根据权利要求14所述的方法,其中,所述受试者患有由CDK和/或GSK-3介导的疾病症状或病症。
16.根据权利要求15所述的方法,其中,所述疾病症状或病症是肿瘤或癌症。
17.一种用于治疗受试者中由周期蛋白依赖性激酶(CDK)和/或糖原合成酶激酶-3(GSK-3)介导的疾病症状或病症的方法,包括:将有效量的根据权利要求1至8中任一项所述的化合物或其药学上可接受的盐或酯,或者根据权利要求9至13中任一项所述的药物组合物施用至受试者,以治疗所述受试者中的疾病症状或病症。
18.根据权利要求17所述的方法,其中,所述受试者中的CDK和/或GSK-3被抑制或被调节。
19.根据权利要求17或18所述的方法,其中,所述疾病症状或病症是肿瘤或癌症。
20.一种用于治疗受试者中肿瘤或癌症的方法,包括:将有效量的根据权利要求1至8中任一项所述的化合物或其药学上可接受的盐或酯,或者根据权利要求9至13中任一项所述的药物组合物施用至所述受试者,从而治疗所述受试者中的肿瘤或癌症。
21.根据权利要求20所述的方法,其中,所述受试者中的CDK和/或GSK-3被抑制或被调节。
22.根据权利要求16以及19至21中任一项所述的方法,其中,所述肿瘤或癌症选自多发性骨髓瘤(MM)、慢性淋巴细胞白血病(CLL)、急性髓系白血病(AML)、套细胞淋巴瘤(MCL)、实体瘤、难治性实体瘤、非霍奇金淋巴瘤、血液瘤、神经母细胞瘤、结直肠癌、宫颈癌、肺癌、白血病、乳腺癌、胰腺癌、B-细胞恶性肿瘤、肿瘤、转移性肿瘤、结肠癌和骨髓增生异常综合征。
23.根据权利要求16以及19至22中任一项所述的方法,其中,所述有效量为有效抑制异常细胞生长的量。
24.根据权利要求14至23中任一项所述的方法,其中,所述受试者是哺乳动物。
25.根据权利要求24所述的方法,其中所述哺乳动物是人。
26.根据权利要求14至25中任一项所述的方法,其中所述施用包括静脉内、肌肉内、腹腔内和皮下给药。
27.根据权利要求14至25中任一项所述的方法,其中所述施用包括口服施用。
28.一种试剂盒,包括:权利要求1至8中任一项所述的化合物或其药学上可接受的盐或酯,或者根据权利要求9至13中任一项所述的药物组合物;以及其使用说明。
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CN112979567B (zh) * | 2021-03-05 | 2023-07-18 | 中国医科大学 | Cdk12小分子抑制剂的化合物及其应用 |
CN114569616B (zh) * | 2022-04-08 | 2023-05-02 | 武汉科技大学 | 一种小分子组合物和在制备治疗神经母细胞瘤的药物中的应用 |
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US20090318430A1 (en) * | 2006-07-21 | 2009-12-24 | Astex Therapeutics Limited | Medical use of cyclin dependent kinases inhibitors |
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AR052660A1 (es) | 2005-01-21 | 2007-03-28 | Astex Therapeutics Ltd | Derivados de pirazol para inhibir la cdk's y gsk's |
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CN101146794A (zh) * | 2005-01-21 | 2008-03-19 | 阿斯泰克斯治疗有限公司 | 用于抑制cdk和gsk的吡唑衍生物 |
CN101146806A (zh) * | 2005-01-21 | 2008-03-19 | 阿斯泰克斯治疗有限公司 | 用于抑制cdk和gsk的吡唑衍生物 |
CN101146795A (zh) * | 2005-01-21 | 2008-03-19 | 阿斯泰克斯治疗有限公司 | 用于抑制cdk和gsk的吡唑衍生物 |
US20090318430A1 (en) * | 2006-07-21 | 2009-12-24 | Astex Therapeutics Limited | Medical use of cyclin dependent kinases inhibitors |
CN111848579A (zh) * | 2019-04-26 | 2020-10-30 | 润佳(苏州)医药科技有限公司 | 4-(2,6-二氯苯甲酰氨基)-n-(4-哌啶基)-1h-吡唑-3-甲酰胺的前药 |
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