CN108864079A - 一种三嗪化合物及其药学上可接受的盐 - Google Patents
一种三嗪化合物及其药学上可接受的盐 Download PDFInfo
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- CN108864079A CN108864079A CN201710339199.4A CN201710339199A CN108864079A CN 108864079 A CN108864079 A CN 108864079A CN 201710339199 A CN201710339199 A CN 201710339199A CN 108864079 A CN108864079 A CN 108864079A
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种三嗪类衍生物及其药学上可接受的盐、药物组合物和用途。具体地,本发明公开了式(I)化合物或其药学上可接受的盐,其中,R1、R2、R3和R4的定义如说明书和权利要求书中所述。本发明所述化合物或其盐可通过调节某些突变形式的表皮生长因子受体而用于治疗或预防疾病或病症。本发明还公开了包含所述化合物或其盐的药物组合物,以及使用所述化合物及其盐治疗由各种不同形式的EGFR所介导的多种疾病的方法,包括非小细胞肺癌。
Description
技术领域
本发明涉及一种治疗癌症的三嗪化合物及其药学上可接受的盐,尤其涉及一种治疗小细胞肺癌的化合物及其药学上可接受的盐。
背景技术
在抗癌药物领域中,对于新的具有更好的活性/选择性的抗癌化合物一直存在需求。已知EGFR是erbB受体家族的跨膜蛋白酪氨酸激酶成员。erbB受体的同源二聚化和/或异源二聚化导致胞内结构域中某些酪氨酸残基的磷酸化,并且激活参与细胞增殖和生存的多种细胞内信号传导通路。erbB家族信号传导的失调可导致细胞增殖、侵入、转移和血管生成,并且已在肺癌、头颈部癌和乳腺癌等癌症中有报道。因此,作为抗癌药物开发的靶点,靶向于EGFR或erbB2的许多药物目前在临床上已得到应用。例如,在新英格兰医学杂志(NewEngland Journal of medicine),2008年第358期,1160-1174页以及生物化学和生物物理研究通讯(Biochemical and Biophysical Research Communications),2004年第319卷,1-11页中给出了对erbB受体信号传导及其参与肿瘤发生的综述。
但是,在实际的癌症治疗中存在EGFR激活突变(例如L858R和delE746_A750),例如,参见科学(Science),2004年第304期,1497-500页和新英格兰医学杂志,2004年第350期,2129-39页。这些最普遍的EGFR激活突变(L858R和delE746_A750)相对于野生型(WT)EGFR而言,对小分子酪氨酸激酶抑制剂(例如吉非替尼和厄洛替尼)的亲和力增加、同时对三磷酸腺苷(ATP)的亲和力下降。最后,产生对吉非替尼或厄洛替尼治疗的获得性抗性,例如由于看门残基T790M的突变。由于这种突变导致对靶向于EGFR的现有药物的抗性,本领域中仍然需要能抑制包括看门基因突变的EGFR的新化合物。所述的新化合物应当相对于激活突变体形式的EGFR(例如L858R EGFR突变体、或者delE746_A750突变体或Exon19缺失EGFR突变体)和/或抗性突变体形式的EGFR(例如T790M EGFR突变体)而言,具有对野生型EGFR的有利活性和/或选择性。换言之,本领域需要对某些激活或抗性突变体形式的EGFR显示较高的抑制、同时对野生型EGFR显示相对较低的抑制的化合物,从而不仅能够发挥抗癌效力,而且能够降低与抑制野生型EGFR相关的不良反应和毒理学(例如皮疹和/或腹泻)。
为了解决这一问题,发明人经过研究后,令人惊讶地发现了一类苯胺基-三嗪化合物,其对于EGFR的突变体形式具有较高的抑制效力,同时又具有对野生型EGFR相对较低的抑制。此外,这些化合物具有较好的药理学效果、可接受的毒理学作用以及有利的药代动力学性质。
发明内容
本发明提供了式(I)的化合物或其药学上可接受的盐:
其中R1为-NR5R6,其中R5和R6各自独立地选自C1-C6烷基,其中所述烷基为未取代或被-NR7R8所取代;
其中R2选自C2-C6烯基,所述烯基为未取代或被-NR7R8所取代;
其中R7和R8在每次出现时各自独立地选自H或C1-C6烷基;
其中R3选自取代或未取代的稠合二环基团,所述稠合二环为五元环和六元环稠合;
其中R4选自C1-C6烷基。
根据本发明的一个实施方式,其中所述化合物为如下式(II)所示:
其中A1、A4、A9各自独立地选自N或C;A2、A3、A5、A6、A7、A8各自独立地选自N、NRa、CRa、CRaRb,其中Ra和Rb各自独立地选自H、C1-C6烷基和卤素,或者Ra、Rb和与它们所连接的同一个碳原子一起形成C3-C6环烷基,所述C1-C6烷基和C3-C6环烷基任选取代有一个或多个卤素原子,所述卤素原子为氟、氯或溴,条件是环A和环B至少一个为不饱和环。
根据本发明的一个实施方式,A2选自N、CH、CH2;A3选自N、CRa、NRa、CH、CRaRb;A5选自N或CH、CH2;A6选自N或CH、CH2、CF;A7选自N或CH、CH2、CF;A8选自N或CH、CH2、CF、CF2。
根据本发明的一个实施方式,其中A1为N。
根据本发明的一个实施方式,其中A1、A2、A3、A4、A5、A6、A7、A8、A9中有一个、两个或三个包含N原子。
根据本发明的一个实施方式,其中所述R1选自:
根据本发明的一个实施方式,其中所述R2选自:
根据本发明的一个实施方式,其中所述R3选自:
根据本发明的一个实施方式,其中所述化合物选自:
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(吡唑[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物1)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(吡唑[1,5-a]嘧啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物2)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(4,5,6,7-四氢吡唑[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物3)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吲哚-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物4)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-甲基-1H-吡咯[2,3-c]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物5)
N-(5-((4-(1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物6)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(咪唑并[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物7)
N-(5-((4-(1H-苯并[d]咪唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物8)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(吡唑并[1,5-c]嘧啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物9)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(咪唑并[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物10)
N-(5-((4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物11)
N-(5-((4-(1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物12)
N-(5-((4-(1H-吡咯并[3,2-c]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物13)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物14)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(5-氟代-3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物15)
(E)-4-(二甲基氨基)-N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丁-2-烯酰胺(化合物16)
N-(5-((4-(4,4-二氟-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物17)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吡咯并[3,2-c]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物18)
N-(5-((4-(1H-苯并[d][1,2,3]三唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物19)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(6-氟代-3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物20)
N-(5-((4-(3,3-二氟-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物21)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(螺[环丙烷-1,3'-吡咯[3,2-b]吡啶]-1'(2'H)-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物22)
N-(5-((4-(3,3-二甲基-5-氟-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物23)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(5'-氟代螺[环丙烷-1,3'-吡咯[3,2-b]吡啶]-1'(2'H)-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物24)
N-(5-((4-(3,3-二甲基-7-氟-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物25)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(8-甲基咪唑[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物26)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(8-氟代咪唑[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物27)
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(8-(三氟代甲基)咪唑并[1,2-a]吡啶-3-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物28)
本发明还提供了一种药物组合物,其包含根据本发明所述的化合物或其药学上可接受的盐。
本发明还提供了将本发明所述的化合物或其药学上可接受的盐在制备用于治疗小细胞肺癌的药物中的用途。
定义
在本发明中,下列术语具有以下所述的含义:
本发明的“烷基”是指直链、支链或环状的饱和烃基,优选12个碳原子以下的烷基,更优选6个碳原子以下的烷基。烷基的实施例包括甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、正己基、异己基、2,2,-甲基丁基和2,3-二甲基丁基。本发明的“C1-6烷基”是指含有1-6个碳原子的直链、支链或环状的饱和烃基。本发明的“C1-3烷基”是指含有1-3个碳原子的直链、支链或环状的饱和烃基。
本发明的“烯基”是指含有一个或多个碳碳双键(C=C)的直链或支链不饱和烃基。本发明的“C2-6烯基”是指含有1个或2个碳碳双键且含有2至6个碳原子的不饱和烃基。本发明的“C2-4烯基”是指含有1个或2个碳碳双键且含有2至4个碳原子的不饱和烃基。例如,乙烯基、丙烯基、正丁烯基、丁二烯基、戊烯基、己烯基。
本发明的“卤素”是指氟、氯、溴、碘。
在本说明书的上下文中,除非有相反的指示,术语“治疗”也包含“预防”。本文中使用的术语“治疗”意在具有其如下的普通含义:处理疾病以完全地或部分地缓解其症状中的一种、部分或全部,或者纠正或补偿潜在的病理。本文中使用的术语“预防”意在具有其正常日常含义,并且包括防止疾病发展的初级预防和防止已发生疾病的二级预防,暂时或持续地防止患者疾病的加剧或恶化或者与疾病相关的新症状的发生。
药学上可接受的盐
本领域技术人员应当理解,可以制备式(I)化合物的盐,包括药学上可接受的盐。这些盐类可以在所述化合物最终分离和纯化过程中原位制备,或者通过独立地分别将以其游离酸或游离碱形式的纯化的化合物与适合的碱或酸反应制备。
可以与无机酸和有机酸形成药学上可接受的酸加成盐,例如,乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘化物/碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、硬脂酸盐、油酸盐、草酸盐、软脂酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以生成盐的无机酸包括,例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以生成盐的有机酸包括,例如,乙酸、丙酸、羟乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。药学上可接受的碱加成盐可以与无机或有机碱形成。
可以生成盐的无机碱包括,例如铵盐和元素周期表的I至XII族的金属。在某些实施方案中,所述盐是衍生自钠、钾、铵、钙、镁、铁、银、锌和铜;特别适合的盐包括铵盐、钾盐、钠盐、钙盐和镁盐。
可以生成盐的有机碱包括,例如,伯胺、仲胺和叔胺,取代的胺包括天然产生的取代胺类,环胺、碱离子交换树脂等。某些有机胺类包括异丙胺、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪及氨基丁三醇。
本发明的药学上可接受的盐能够通过常规的化学方法由碱性或酸性部分合成而来。通常,这些盐能够通过将这些化合物的游离酸形式与化学量的合适的碱(Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应、或者通过将这些化合物的游离碱形式与化学量的合适的酸反应而进行制备。这些反应通常在水中或在有机溶剂中、或在两者的混合物中进行。通常,在适宜时,需要使用非水介质,例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。其它合适的盐的列表可在“Remington's Pharmaceutical Sciences”,第20版,Mack PublishingCompany,Easton,Pa.,(1985);以及Stahl和Wermuth的“Handbook of PharmaceuticalSalts:Properties,Selection,and Use”(Wiley-VCH,Weinheim,德国,2002)中找到。
还可以制备式(I)化合物的溶剂化物,包括药学上可接受的溶剂化物。“溶剂化物”是指由溶质和溶剂形成的可变化学量的复合物。为了本发明目的的此类溶剂不影响所述溶质的生物活性。适合溶剂的实例包括但不限于水、MeOH、EtOH和AcOH。其中水是溶剂分子的溶剂化物通常是指水合物。水合物包括包含化学计量的量的水的组分,以及包含可变量的水的组分。
如本文所用,术语“药学上可接受的”的含义是适用于药物用途的化合物。适用于药物的本发明化合物的盐和溶剂化物(例如水合物和盐的水合物)是其中平衡离子或结合溶剂是药学上可接受的那些。但是,具有非药学上可接受的平衡离子或结合溶剂的盐和溶剂化物也包含在本发明范围内,例如,用作制备其它本发明化合物和其药学上可接受的盐和溶剂化物的中间体。
式(I)化合物(包括其盐和溶剂化物)可以以结晶形式、非结晶形式或其混合物存在。所述化合物或其盐或溶剂化物还可以表现出多晶现象,即以不同结晶形式出现的能力。这些不同的结晶形式通常已知为“多晶型”。多晶型具有相同的化学组成,但是结晶固体状态的堆积、几何排列和其它描述特性不同。因此,多晶型可以具有不同的物理性质,例如形状、密度、硬度、变形性、稳定性和溶解度性质。多晶型通常表现出不同的熔点、IR光谱和X-射线粉末衍射图谱,其全部都可以用于鉴别。本领域技术人员能够了解,例如,通过改变或调整在式(I)化合物的结晶/重结晶中所使用的条件而可能产生不同的多晶型。
本发明还包含式(I)化合物的不同异构体。“异构体”是指具有相同构成和分子量,但是物理和/或化学性质不同的化合物。结构的区别可以是在结构中(几何异构体)或者在旋转平面偏振光的能力上(立体异构体)。关于立体异构体,式(I)化合物可以具有一个或多个不对称碳原子,并可以以外消旋体、外消旋混合物以及以单个对映异构体或非对映异构体出现。全部此类异构体形式都包含在本发明范围内,包括其混合物。如果所述化合物含有双键,取代基可以是E或Z构型。如果所述化合物包含二取代的环烷基,该环烷基的取代基可以具有顺式-或反式-构型。也期望包含全部的互变异构体形式。
式(I)化合物的任意不对称原子(例如碳等)都能够以外消旋或对映异构体富集存在,例如(R)-、(S)-或(R,S)-构型。在某些实施方案中,每一个不对称原子在(R)-或(S)-构型中有至少50%对映异构体过量、至少60%对映异构体过量、至少70%对映异构体过量、至少80%对映异构体过量、至少90%对映异构体过量、至少95%对映异构体过量、或至少99%对映异构体过量。如有可能,在具有不饱和双键的原子上的取代基以顺式-(Z)-或反式-(E)-形式存在。
因此,如本文所用,式(I)化合物能够是可能的异构体、旋转异构体、阻转异构体、互变异构体或其混合物之一的形式,例如作为基本上纯的几何异构体(顺式或反式)、非对映异构体、旋光异构体(对映异构体)、外消旋体或其混合物。
任何所得的异构体的混合物都能够基于组分的物理化学差异被分离成纯的或基本上纯的几何或旋光异构体、非对映异构体、外消旋体,例如通过色谱法和/或分步结晶。
任何所得的终产物或中间体的外消旋体能够通过已知的方法(例如通过其非对映体盐的分离)被拆分成旋光对映异构体,其用有光学活性的酸或碱获得,并且释放出有光学活性的酸性或碱性化合物。特别地,碱性部分因此可以用于将本发明的化合物拆分成其旋光对映异构体,例如通过与有光学活性的酸(例如酒石酸、二苯甲酰酒石酸、二乙酰酒石酸、二-O,O'-对甲苯酰酒石酸、扁桃酸、苹果酸或樟脑-10-磺酸)形成的盐的分步结晶。外消旋产物也能够通过手性色谱法进行拆分,例如使用手性吸附剂的高压液相色谱法(HPLC)。
本发明包括式(I)化合物的未标记的形式以及同位素标记的形式。同位素标记的化合物具有由本文所给出的化学式描述的结构,除了一个或多个原子被具有所选择的原子量或质量数的原子替换。能够被掺入本发明化合物的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别例如2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、125I。本发明包括如本文所定义的各种同位素标记的化合物,例如其中出现放射性同位素(例如3H和14C)的那些或其中出现非放射性同位素(例如2H和13C)的那些。这些同位素标记的化合物可用于代谢研究(例如使用14C)、反应动力学研究(例如用2H或3H)、检测或成像技术,例如正电子发射断层扫描术(PET)或单光子发射计算体层摄影术(SPECT),包括药物底物组织分布分析,或者用于患者的放射治疗。特别地,对于PET或SPECT研究可能特别需要18F或标记的化合物。同位素标记的式(I)化合物通常能够通过本领域的技术人员已知的常规技术或者通过与所附实施例和制备例中所述方法类似的方法、使用合适的同位素标记的试剂代替以前所用的未标记的试剂进行制备。
此外,用较重的同位素、特别是氘(即2H或D)的取代可能带来由更强的代谢稳定性导致的某些治疗优势,例如增加的体内半衰期或减少的剂量需求或治疗指数的改善。可以理解,在本文中氘被视为式(I)的化合物的取代基。该较重同位素、特别是氘的浓度可能由同位素富集因子决定。如本文所用的术语“同位素富集因子”是指特定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物中的取代基被标为氘,那么对于每一个标出的氘原子,该化合物具有至少3500(在每一个标出的氘原子处52.5%氘掺入)、至少4000(60%氘掺入)、至少4500(67.5%氘掺入)、至少5000(75%氘掺入)、至少5500(82.5%氘掺入)、至少6000(90%氘掺入)、至少6333.3(95%氘掺入)、至少6466.7(97%氘掺入)、至少6600(99%氘掺入)、或至少6633.3(99.5%氘掺入)的同位素富集因子。
药物组合物
本发明提供了药物组合物,其包含如上所述的式(I)的化合物或其药学上可接受的盐以及药学上可接受的稀释剂或载体。
药物组合物能够针对特定的给药途径进行配制,例如口服给药、肠胃外给药和直肠给药等。此外,本发明的药物组合物能够以固体形式(非限制性地包括胶囊、片剂、丸剂、颗粒剂、粉末剂或栓剂)或以液体形式(非限制性地包括溶液剂、混悬剂或乳剂)制成。药物组合物能够经历常规的制药操作(例如灭菌)和/或能够含有常规的惰性稀释剂、润滑剂或缓冲剂以及辅料,例如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂等。
通常,药物组合物是片剂或明胶胶囊,其包含活性成分以及
a)稀释剂,例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸;
b)润滑剂,例如二氧化硅、滑石粉、硬脂酸、其镁或钙盐和/或聚乙二醇;对于片剂也包含
c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如果需要,还有
d)崩解剂,例如淀粉、琼脂、海藻酸或其钠盐、或泡腾混合物;和/或
e)吸收剂、着色剂、调味剂和增甜剂。
根据本领域中已知的方法,片剂可以是薄膜包衣或肠溶包衣的。
用于口服给药的合适的组合物包括有效量的式(I)化合物或其药学上可接受的盐,其为片剂、锭剂、水或油混悬液、可分散的粉末或颗粒、乳剂、硬或软胶囊、或糖浆或酏剂的形式。根据本领域中已知的用于制备药物组合物的任意方法制备用于口服使用的组合物,并且为了提供精制和适口的制剂该组合物能够含有1种或多种选自增甜剂、调味剂、着色剂和防腐剂的试剂。片剂可以含有与适合于制备片剂的无毒的药学上可接受的赋形剂混合在一起的活性成分。这些赋形剂是例如惰性的稀释剂(例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠);成粒剂和崩解剂(例如玉米淀粉、或海藻酸);粘合剂(例如淀粉、明胶或阿拉伯胶);和润滑剂(例如硬脂酸镁、硬脂酸或滑石粉)。片剂是未经包衣的或者通过已知的技术进行包衣从而延缓在胃肠道的崩解和吸收,从而在较长的时期内提供持久的作用。例如,能够使用延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。用于口服的制剂能够以硬明胶胶囊呈递,其中活性成分与惰性的固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合,或者以软明胶胶囊呈递,其中活性成分与水或油介质(例如花生油、液体石蜡或橄榄油)混合。
某些可注射的组合物是等渗水溶液或混悬液,栓剂有利地由脂肪乳或混悬液制得。所述的组合物可以进行灭菌和/或含有辅料,例如防腐、稳定、润湿或乳化剂、溶解促进剂、用于调节渗透压的盐和/或缓冲剂。此外,其也可以含有其他的治疗上有价值的物质。所述的组合物分别根据常规的混合、制粒或包衣法进行制备,并且含有大约0.1-75%或含有大约1-50%的活性成分。
由于水可能促进某些化合物的降解,本发明还提供无水的药物组合物和剂型,其包含作为活性成分的本发明化合物。
使用无水或低水含量的成分和低水含量或低湿度的条件能够制备本发明的无水的药物组合物和剂型。可以制备和贮存无水的药物组合物以便保持其无水的性质。因此,使用已知防止与水接触的材料包装无水的组合物以便其能够包含于合适的配方药盒中。合适的包装的实例非限制性地包括气密的箔、塑料、单位剂量容器(例如管形瓶)、泡罩包装和条带包装。
本发明进一步提供药物组合物和剂型,其包含1种或多种降低作为活性成分的本发明化合物的分解速率的试剂。该试剂(其在本文中称作“稳定剂”)非限制性地包括抗氧化剂(例如抗坏血酸)、pH缓冲剂或盐缓冲剂等。
对于大约50-70kg的个体,本发明的药物组合物或组合产品能够是大约1-1000mg活性成分的单位剂量,或者大约1-500mg或大约1-250mg或大约1-150mg或大约0.5-100mg、或大约1-50mg活性成分。化合物、药物组合物或其组合产品的治疗有效剂量取决于个体的物种、体重、年龄和个体情况、其正在接受治疗的病症或疾病或其严重程度。普通技术的内科医生、临床医师或兽医能够容易地确定为了预防、治疗或抑制病症或疾病的发展所需的每一种活性成分的有效量。
治疗用途
另一方面,本发明提供了式(I)的化合物或其药学上可接受的盐,其用作药物。在另一方面,本发明还提供了式(I)的化合物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途。
另一方面,本发明还提供了在需要这种治疗的温血动物例如人中产生抗癌作用的方法,其包括:向所述动物给药有效量得如式(I)的化合物或其药学上可接受的盐。
另一方面,本发明还提供了式(I)的化合物或其药学上可接受的盐和另外的抗肿瘤物质的用途,用于癌症的同时、独立或序贯治疗。
在上文提及的任一方面或实施方案中,所述癌症可以选自卵巢癌、宫颈癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤,黑色素瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤(GIST)、甲状腺癌、胆管癌、子宫内膜癌、肾癌、间变性大细胞淋巴瘤、急性髓细胞白血病(AML)、多发性骨髓瘤、黑色素瘤、间皮瘤。
在一个优选实施方案中,所述癌症为非小细胞肺癌。
上述的式(I)的化合物或其药学上可接受的盐可作为单独治疗应用,或者除了本发明化合物以外还涉及到常规的手术或放射疗法或化学疗法或免疫疗法。这种化学疗法与本发明化合物可以并列地、同时地、序贯地、或分别地给药,并且可包含以下类型的抗肿瘤剂的一种或多种:
(i)医学肿瘤学中所使用的抗增殖/抗肿瘤药物及其组合,例如烷化剂(例如顺铂、奥沙利铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安、替莫唑胺、亚硝基脲类);抗代谢药(例如吉西他滨和抗叶酸剂,例如氟嘧啶(如5-氟尿嘧啶和替加氟)、雷替曲塞、甲氨喋呤、阿糖胞苷、羟基脲);抗肿瘤抗生素(例如蒽环类,如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素C、放线菌素、光神霉素);抗有丝分裂药剂(例如长春花生物碱,如长春新碱、长春碱、长春地辛、长春瑞滨;以及紫杉烷类,如紫杉醇、泰索帝);拓扑异构酶抑制剂(例如表鬼臼毒素(如依托泊苷、替尼泊苷),安吖啶、托泊替康、喜树碱);
(ii)细胞生长抑制剂,例如抗雌激素药(例如他莫昔芬、氟维司群、托瑞米芬、雷洛昔芬、屈洛昔芬、抗雄激素药(例如比卡鲁胺、氟他胺、尼鲁米特、醋酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林、和布舍瑞林)、孕激素类(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿那曲唑、来曲唑、伊西美坦)、5α-还原酶抑制剂(例如非那雄胺);
(iii)抗侵袭剂,例如c-Src激酶家族抑制剂,例如达沙替尼和波舒替尼(SKI-606),以及金属蛋白酶抑制剂(如马立马司他)、尿激酶纤溶酶原激活物受体功能的抑制剂或者类肝素酶的抗体;
(iv)生长因子功能的抑制剂:例如这种抑制剂包括生长因子抗体和生长因子受体抗体(例如抗erbB2抗体曲妥珠单抗、抗EGFR抗体帕尼单抗、抗erbB1抗体西妥昔单抗以及任何生长因子或生长因子受体抗体);这种抑制剂还包括:酪氨酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉基丙氧基)-喹唑啉-4-胺(吉非替尼,ZD1839)、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼,OSI-774)、6-丙烯酰胺基-N-(3-氯-4-氟苯基)-7-(3-吗啉基丙氧基)-喹唑啉-4-胺(CI 1033)、erbB2酪氨酸激酶抑制剂(例如拉帕替尼);肝细胞生长因子家族的抑制剂;胰岛素生长因子家族的抑制剂;血小板衍生的生长因子家族的抑制剂,例如伊马替尼和/或尼洛替尼(AMN107);丝氨酸/苏氨酸激酶的抑制剂(例如Ras/Raf信号传导抑制剂,例如法呢基转移酶抑制剂,例如索拉非尼(BAY43-9006)、替匹法尼(R115777)、氯那法尼(SCH66336))、通过mEK和/或AKT激酶的细胞信号传导抑制剂、c-kit抑制剂、abl激酶抑制剂、PI3激酶抑制剂、Plt3激酶抑制剂、CSF-1R激酶抑制剂、IGF受体(胰岛素样生长因子)激酶抑制剂;极光激酶(aurora kinase)抑制剂(例如AZD1152、PH739358、VX-680、MLN8054、R763、MP235、MP529、VX-528、AX39459),细胞周期蛋白依赖性激酶抑制剂,例如CDK2和/或CDK4抑制剂;
(v)抗血管生成剂,例如抑制血管内皮生长因子作用的药剂,例如抗人血管内皮细胞生长因子抗体贝伐珠单抗以及例如VEGF受体酪氨酸激酶抑制剂,例如凡德他尼(ZD6474)、伐他拉尼(PTK787)、舒尼替尼(SU11248)、阿西替尼(AG-013736)、帕唑帕尼(GW786034)、4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉(AZD2171;WO 00/47212中的实施例240),例如WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公开的那些;
(vi)血管损伤剂,例如康普瑞汀A4以及WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合物;
(vii)内皮素受体拮抗剂,例如齐泊腾坦(ZD4054)或者阿曲生坦;
(viii)基因治疗方法,包括例如替换异常基因(例如异常p53或者异常BRCA1或BRCA2)的方法;GDEPT(基因定向的酶前药治疗)法,例如使用胞嘧啶脱氨酶、胸苷激酶或者细菌硝基还原酶的那些;提高患者对化学治疗或放射治疗的耐受性的方法,例如多重耐药基因治疗;和
(ix)免疫治疗方法,包括例如提高患者肿瘤细胞的免疫原性的体外和体内方法,例如用细胞因子(例如白细胞介素2、白细胞介素4或者粒细胞巨噬细胞集落刺激因子)进行转染;降低T细胞无效能的方法;使用转染的免疫细胞(例如细胞因子转染的树突状细胞)的方法;使用细胞因子转染的肿瘤细胞系的方法;使用抗独特型抗体的方法;降低免疫抑制性细胞(例如调节性T细胞、髓源性抑制细胞、或表达IDO(吲哚胺2,3-脱氧酶)的树突状细胞)的功能的方法;以及使用衍生自肿瘤相关抗原(例如NY-ESO-1,mAGE-3、WT1或Her2/neu)的蛋白质类或肽类组成的癌症疫苗的方法。
本文中,如果术语“联合治疗”是用来描述组合治疗,则应理解这可以表示同时给药、独立给药或序贯给药。关于“联合给药”应类似地理解。在本发明的一个方面,“联合治疗”是指同时给药。在本发明的另一方面,“联合治疗”是指独立给药。在本发明的另一方面,“联合治疗”是指序贯给药。当序贯给药或独立给药时,给药第二组分的延迟不应例如失去使用组合产生的效果的利益。
本发明化合物的合成方法
本发明的式(I)化合物一般地可以按照以下流程的方法进行合成:
在所述流程中,由起始原料2,4-二氯-1,3,5-三嗪与适宜的稠环化合物R3H偶联得到中间体其与中间体在催化剂的存在下反应得到式(I)化合物。其中,R3如上文所定义。
具体地,例如的合成路径如下:
其中,环A、环B、A2、A3、A4、A5、A6、A7、A8、A9如上文所定义。
另外,中间体的制备合成路线如下:
具体实施方式
通过以下实施例对本发明的方法进行进一步的说明。应当理解,提供以下实施例的目的仅仅是为了能够更好的理解本发明,而不是以任何方式限定本发明的范围。
中间体III的合成:
在0℃下,向化合物a(50.0g,354mmol)的H2SO4(260mL)溶液在搅拌下缓慢加入KNO3(35.8g,354mmol),然后搅拌2小时。TLC(石油醚:乙酸乙酯=5:1,Rf=0.57)表明反应物转化完全。将反应混合物倒入冰水(3kg)中,用NaOH水溶液调节pH至7,然后用乙酸乙酯(1.5Lx 2)萃取。萃取有机相用Na2SO4干燥,浓缩得到粗产物。粗产物经硅胶柱纯化(洗脱剂:石油醚:乙酸乙酯=20:1~5:1)得到黄色固体化合物b(91.0g,产率:69%)。1H NMR:(ES6131-2-P1A,CDCl3,400MHz)δ7.45-7.43(d,J=9.2Hz,1H),6.82-6.79(d,J=12.0Hz,1H),3.89(s,3H),3.69(br s,2H).
将化合物b(79.0g,424mmol),N,N',N'-三甲基乙烷-1,2-二胺(65.1g,637mmol,82mL)和碳酸钾(88.0g,637mmol)的DMF(150mL)混合物在90℃下搅拌25小时。TLC(石油醚:乙酸乙酯=3:1)表明反应物已经消耗完全。向反应液中加入水(1.5L),二氯甲烷萃取(800mL x 3),饱和食盐水(1L)洗涤,Na2SO4干燥,浓缩得到粗产物。粗产物经硅胶柱纯化(洗脱剂:二氯甲烷:甲醇=100:1~20:1)得到黄色油状物化合物c(66.0g,产率:58%)。
1H NMR:(ES6131-2-P1A,CDCl3,400MHz)δ=7.31(s,1H),6.63(s,1H),3.90(s,3H),3.06-3.03(t,J=6.0Hz,2H),2.79(s,3H),2.51-2.48(t,J=6.0Hz,2H),2.31(s,6H).LCMS:269.1[M+H]+,Rt=1.240。
在0℃下向化合物c(18.0g,67.1mmol)的二氯甲烷(200mL)溶液中加入三乙胺(18.0g,178mmol,25mL),然后滴加烯丙酰氯(8.0g,88.6mmol,7.2mL)。反应混合物在0℃下搅拌16小时。TLC(二氯甲烷:甲醇=20:1)表明反应物基本反应完全。反应混合物用水(400mL)淬灭,二氯甲烷(200mL x 3)萃取。有机相用Na2SO4干燥,过滤,浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:甲醇=100:1~20:1)纯化得到棕色油状物化合物d(8.10g,产率:39%)。
1H NMR:(ES6131-4-p1a,CDCl3,400MHz)δ=10.12(s,1H),9.19(s,1H),6.79(s,1H),6.49-6.44(d,J=17.2Hz,1H),6.32-6.25(dd,J1=10.0Hz,J2=16.8Hz,2H),5.75–5.72(d,J=10.0Hz),3.93(s,3H),2.92-2.90(t,J=5.2Hz,2H),2.79(s,3H),2.49-2.46(m,2H),2.33(s,6H).LCMS:323.2[M+H]+。
向化合物d(9.0g,27.9mmol),Fe(7.8g,139mmol)and NH4Cl(7.5g,140mmol)的混合物中加入乙醇(100mL)和水(50mL),然后在50℃下搅拌16小时。TLC(二氯甲烷:甲醇=10:1)表明反应物反应完全。反应液过滤后浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:甲醇=20:1)纯化,洗脱液浓缩得到灰白色固体中间体III(7.6g,产率:93%)。1H NMR:(ES6131-12-p1a,CDCl3,400MHz)δ7.08(br s,1H),6.85(s,1H),6.65-6.58(dd,J1=10.0Hz,J=16.8Hz,1H),6.45-6.41(m,1H),5.86-5.83(dd,J1=10.0Hz,J=16.8Hz,1H),3.93(s,3H),3.37-3.31(m,2H),3.08(s,2H),2.75(s,6H),2.68(s,3H)。
实施例1
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吲哚-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物4)
合成路线
在0℃下向化合物B1_1(500mg,3.75mmol)和二异丙基乙胺(533mg,4.13mmol)的二氯甲烷(3mL)溶液中加入2,4-二氯-1,3,5-三嗪(562mg,3.75mmol),然后搅拌1小时。TLC(石油醚:乙酸乙酯=10:1,Rf=0.48)表明反应物反应完全。反应混合物浓缩得到粗产物。粗产物经硅胶柱层析(石油醚:乙酸乙酯=100:1~25:1)纯化得到灰白色固体化合物B1_2(720mg,产率:70%)。
1H NMR:(ES6208-30-P1A,CDCl3,400MHz)δ8.51(s,0.5H),8.47(s,0.5H),8.3(d,J=8.0Hz,0.5H),8.27(d,J=8.0Hz,0.5H),7.26-7.15(m,2H),7.06(t,J=7.6Hz,1H),4.39(t,J=12.0Hz,1H),3.74-3.70(m,1H),3.50-3.42(m,1H),1.33(d,J=6.8Hz,3H)。
向B1_2(600mg,2.4mmol)的二氯甲烷(15mL)溶液中加入DDQ(1.1g,4.9mmol)。反应液在氮气保护下于25℃搅拌5小时。TLC(石油醚:乙酸乙酯=10:1)表明反应物反应完全.反应液经硅胶柱层析(石油醚:乙酸乙酯=25:1)纯化得到白色固体化合物B1_3(560mg,产率:94%)。
1H NMR:(ES6176-26-P1A,CDCl3,400MHz)δ8.81(br s,1H),8.69-8.67(d,J=9.2Hz,1H),7.91(s,1H),7.56-7.54(d,J=8.0Hz,1H),7.43-7.39(t,J=7.6Hz,1H),7.36-7.33(t,J=7.6Hz,1H),2.34(s,3H)。
向中间体III(239mg,0.82mmol)的四氢呋喃(10mL)溶液中加入化合物B1_3(200mg,0.82mmol),然后加入吡啶(129mg,1.6mmol)。反应混合物在氮气保护下于25℃搅拌6小时。TLC(石油醚:乙酸乙酯=5:1)表明反应物反应完全。反应混合物浓缩得到粗产品。粗产品经prep-HPLC(column:Waters Xbridge 150*25 5u;mobile phase:[water(10mMNH4HCO3)-ACN];B%:48%-78%,8min)纯化得到黄色固体化合物4(79mg,产率:19%)。
1H NMR:(ES6176-27-P1A,CDCl3,400MHz)δ10.13(s,1H),9.81-9.76(br s,1H),8.79-8.77(d,J=8.4Hz,1H),8.63(s,1H),7.92-7.88(br s,1H),7.54-7.52(d,J=7.6Hz,1H),7.35-7.24(m,3H),6.82(s,1H),6.55-6.51(m,1H),6.41-6.36(m,1H),5.75-5.72(d,J=10.4Hz,1H),3.90(s,3H),2.91(s,2H),2.73(s,3H),2.49(s,3H),2.31(s,8H).LCMS:501.4[M+H]+,Rt=0.771.HPLC:96.41%purity(220nm),Rt=5.06。
实施例2
N-(5-((4-(1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物6)
合成路线
在0℃下向2,4-二氯-1,3,5-三嗪(257mg,1.70mmol)的DMF(12mL)溶液中加入化合物B2(202mg,1.70mmol)和二异丙基乙胺(234mg,1.80mmol),然后搅拌0.5小时。在0℃下中间体III(500mg,1.70mmol)和二异丙基乙胺(234mg,1.80mmol)依次加入反应液。该反应混合物在25℃下搅拌20小时。TLC(石油醚:乙酸乙酯=1:2,Rf=0.35)表明反应物反应完全。反应混合物经prep-HPLC(column:Waters Xbridge 150*25 5u;mobile phase:[water(10mM NH4HCO3)-ACN];B%:18%-48%,10min)纯化得到亮黄色固体化合物6(37.5mg,产率:4.5%)。
1H NMR:(ES6045-14-P1A,CDCl3,400MHz)δ10.21(br s,1H),9.01(d,J=8.0Hz,1H),8.65(s,1H),8.52(d,J=2.8Hz,1H),7.87(s,1H),7.20-7.28(m,1H),6.95(s,1H),6.84(s,1H),6.50(d,J=16.0Hz,1H),6.37-6.33(m,1H),5.75(d,J=10.0Hz,1H),3.92(s,3H),2.91(s,2H),2.75(s,3H),2.33(d,J=4.0Hz,2H),2.18(s.6H)。
LCMS:488.1[M+H]+,Rt=3.615.HPLC:98.31%purity(220nm),Rt=3.52。
实施例3
N-(5-((4-(1H-苯并[d]咪唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物8)
合成路线
在0℃下向2,4-二氯-1,3,5-三嗪(257mg,1.70mmol)的DMF(8mL)溶液中加入化合物B3(202mg,1.70mmol)和二异丙基乙胺(234mg,1.80mmol),然后搅拌1小时。在0℃下二异丙基乙胺(234mg,1.80mmol)和中间体III(500mg,1.70mmol)依次加入反应液。该反应混合物在25℃下搅拌16小时。LCMS(es6131-8-p1a)表明反应物反应完全。反应混合物经prep-HPLC(column:Waters X bridge 150*25 5u;mobile phase:[water(10mM NH4HCO3)-ACN];B%:25%-55%,10min),洗脱液冻干得到粗产物。粗产物经prep-TLC(二氯甲烷:甲醇=15:1)纯化得到白色固体化合物8(59mg,产率:7%)。
1H NMR:(ES6131-28-P1A1,CDCl3,400MHz)δ10.20(s,1H),9.72(s,2H),8.72(s,1H),8.60-8.58(m,1H),7.95(s,1H),7.93-7.84(m,1H),7.42(s,2H),6.84(s,1H),6.59-6.53(m,1H),7.42(s,2H),6.84(s,1H),6.59-6.53(m,1H),6.37-6.32(m,1H),5.76-5.73(d,J=10.8Hz,1H),3.92(s,3H),2.91(s,2H),2.75(s,3H),2.31(s,8H)。
LCMS:488.3[M+H]+,Rt=0.687.HPLC:97.53%purity(220nm),Rt=3.70。
实施例4
N-(5-((4-(3,3-二甲基-2,3-二氢-1H-吡咯并[3,2-b]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物11)
合成路线
氮气保护下于0℃向化合物B9_1(500mg,3.08mmol)的四氢呋喃(10mL)溶液中加入硼氢化钠(583mg,15.4mmol),然后滴加BF3.Et2O(6.82g,21.6mmol,5.93mL,45%纯度)。然后反应混合物在20℃搅拌6小时。TLC(石油醚:乙酸乙酯=1:1,Rf=0.45)表明反应物反应完全。反应混合物用饱和氯化铵淬灭(5mL),乙酸乙酯(10mL)萃取。水相用乙酸乙酯(5mL x 3)萃取。合并的有机相用饱和食盐水(5mL)洗涤,硫酸钠干燥,浓缩得到黄色固体化合物B9(400mg,产率:88%)。
1H NMR:(ES6174-5-P1A 400MHz CDCl3)δ7.86(dd,J=1.2Hz,4.8Hz,1H),6.98(dd,J=4.8Hz,8.0Hz,1H),6.93(dd,J=5.2Hz,8.0Hz,1H),3.42(s,2H),1.39(s,6H)。
向2,4-二氯-1,3,5-三嗪(202mg,1.40mmol)的四氢呋喃(10mL)溶液中加入化合物B9(200mg,1.40mmol)和吡啶(213mg,2.70mmol),然后在氮气保护下于25℃搅拌5小时。TLC(石油醚:乙酸乙酯=2:1)表明反应物反应完全。反应混合物减压浓缩得到粗产物。粗产物经硅胶柱层析(石油醚:乙酸乙酯=30:1~25:1)纯化得到白色固体化合物B9_2(35mg,产率:10%)。
向中间体III(39mg,0.13mmol)的四氢呋喃3mL溶液中加入化合物B9_2(35mg,0.13mmol)和吡啶(21mg,0.27mmol),然后在氮气保护下于25℃搅拌5小时。TLC(石油醚:乙酸乙酯=2:1)表明反应物反应完全。反应混合物减压浓缩得到粗产物。粗产物经prep-HPLC(column:Waters Xbridge 150*25 5u;mobile phase:[water(10mM NH4HCO3)-ACN];B%:31%-51%,8min)纯化得到黄色固体化合物11(9.5mg,产率:14%)。
1H NMR:(ES6176-31-P1B,CDCl3,400MHz)δ10.11-10.06(br s,1H),9.72(s,1H),8.60-8.58(d,J=8.4Hz,1H),8.54(s,1H),8.44(s,1H),7.79-7.76(br s,1H),7.13(s,1H),6.80(s,1H),6.48-6.44(m,1H),6.37-6.31(m,1H),5.73-5.69(d,J=11.6Hz,1H),4.44-4.40(br s,1H),3.88(s,3H),2.90(s,2H),2.72(s,3H),2.25(s,8H),1.50(s,6H),1.43(s,2H).LCMS:518.4[M+H]+,Rt=0.655.HPLC:89.62%purity(220nm),Rt=3.76。
实施例5
N-(5-((4-(1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物12)
合成路线
在0℃下向2,4-二氯-1,3,5-三嗪(206mg,1.40mmol)的乙腈(12mL)溶液中加入化合物B4(162mg,1.40mmol)和碳酸氢钠(127mg,1.50mmol),然后在0℃下搅拌6小时。中间体III(400mg,1.40mmol)加入,然后反应混合物在25℃下搅拌20小时。TLC(二氯甲烷:甲醇=20:1,Rf=0.40)表明反应物反应完全。反应混合物用水(12mL),二氯甲烷(12mL x 3)萃取。有机相用饱和食盐水洗涤,硫酸钠干燥,过滤浓缩得到粗产物。粗产物经prep-HPLC纯化,洗脱液冻干得到黄色固体化合物12(110mg,产率:16%)。
1H NMR:(ES6131-28-P1A1,CDCl3,400MHz)δ10.28-10.23(m,2H),9.96(s,1H),8.80(s,1H),8.24-8.21(m,1H),7.79-7.77(m,1H),7.34-7.30(m,1H),7.11-7.07(m,1H),6.84(s,1H),6.66-6.62(d,J=16.8Hz,1H),6.45-6.41(m,1H),5.83-5.80(d,J=9.6Hz,1H),3.93(s,3H),2.90-2.89(m,2H),2.74(s,3H),2.34-2.31(m,8H)。
LCMS:488.3[M+H]+,Rt=0.688。
HPLC:98.33%purity(220nm),Rt=4.52。
实施例6
N-(5-((4-(1H-吡咯并[3,2-c]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物13)
合成路线
在0℃下向2,4-二氯-1,3,5-三嗪(257mg,1.70mmol)的DMF(10mL)溶液中加入中间体III(500mg,1.71mmol)和二异丙基乙胺(234mg,1.80mmol),然后在0℃下搅拌1小时。二异丙基乙胺(234mg,1.80mmol)和化合物B5(202mg,1.71mmol)依次加入.然后反应混合物在25℃下搅拌15小时。LCMS表明反应物反应完全。反应混合物经prep-HPLC(column:Waters Xbridge 150*25 5u;mobile phase:[water(10mM NH4HCO3)-ACN];B%:23%-53%,10min)纯化,洗脱液冻干,然后再经prep-TLC(二氯甲烷:甲醇=15:1)纯化得到灰白色固体化合物13(60mg,产率:7%)。
1H NMR:(ES6131-13-P2A,CDCl3,400MHz)δ10.23(s,1H),9.66-9.60(m,1H),8.93-8.88(m,1H),8.67-8.60(m,2H),8.43-8.42(m,1H),7.92-7.89(m,1H),6.84(s,2H),6.51-6.46(d,J=17.6Hz,1H),6.38-6.31(dd,J1=10.0Hz,J2=16.8Hz,1H),5.75-5.73(d,J=13.0Hz,1H),3.90(s,3H),2.92-2.89(t,J=6.0Hz,2H),2.75(s,3H),2.35-2.33(t,J=5.6Hz,2H),2.30(s,6H).LCMS:488.4[M+H]+,Rt=0.660。
HPLC:97.75%purity(220nm),Rt=3.47。
实施例7
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物14)
合成路线
在25℃下向化合物B6(300mg,2.30mmol)的乙腈(5mL)溶液中加入2,4-二氯-1,3,5-三嗪(340mg,2.30mmol),然后在50℃下搅拌3小时。LCMS检测到产物。反应混合物过滤,浓缩得到黄色固体粗产物B6_1(410mg),该粗产物没有经过纯化直接用于下一步反应。
在25℃下向化合物B6_1(300mg,1.20mmol)的DMF(10mL)溶液中加入中间体III(357mg,1.20mmol),然后在25℃下搅拌3小时。LCMS检测到产物。反应混合物经prep-HPLC(column:Waters X bridge 150*25 5u;mobile phase:[water(10mM NH4HCO3)-ACN];B%:25%-55%,10min),洗脱液冻干得到粗产物。粗产物在乙酸乙酯(3mL)中重结晶,过滤得到黄色固体化合物14(127mg,产率:21%)。
1H NMR:(ES6131-31-p1b,CDCl3,400MHz)δ9.63(s,1H),9.09(s,1H),8.95(s,1H),8.17(s,1H),7.74-7.72(d,J=8.8Hz,1H),7.60-7.58(d,J=8.0Hz,1H),7.33-7.30(m,1H),7.06-7.03(m,1H),6.94-6.90(m,1H),6.72(s,1H),6.51-6.47(d,J=16.8Hz,1H),5.77-5.74(d,J=11.2Hz,1H),3.89(s,3H),3.29-3.27(t,J=5.2Hz,2H),3.19(s,2H),3.08(s,3H),2.84(s,6H),2.64(s,3H).LCMS:502.4[M+H]+,Rt=0.692。
HPLC:99.48%purity(220nm),Rt=3.38。
实施例8
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(5-氟代-3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物15)
合成路线
在0℃搅拌下向化合物B8_1(4.0g,26.1mmol)的浓盐酸(20mL)溶液中滴加亚硝酸钠(1.9g,27.9mmol)水(9.6mL)溶液,然后继续搅拌1小时。SnCl2.2H2O(13.2g,58.5mmol)的浓盐酸(9.6mL)溶液在0℃下滴加到反应液中,然后继续搅拌2小时。TLC(石油醚:乙酸乙酯=8:1)表明反应物反应完全。向反应液中加入饱和碳酸钾溶液至pH=8。用乙酸乙酯(200mLx 4)萃取。有机相用饱和食盐水(150mL)洗涤,硫酸钠干燥,过滤,减压浓缩得到黄色化合物B8(3.9g,产率:51%)。
1H NMR:(ES6176-15-P1A,CDCl3,400MHz)δ10.01(br s,1H),7.39-7.36(m,1H),7.32-7.29(dd,J1=2.0Hz,J2=8.8Hz,1H),7.19-7.14(td,J1=2.4Hz,J2=8.8Hz,1H),2.57(s,3H)。
在0℃下向化合物2,4-二氯-1,3,5-三嗪(500mg,3.33mmol)的乙腈(10mL)溶液中加入化合物B8(501mg,3.33mmol)和碳酸氢钠(308mg,3.66mmol)。然后反应混合物在氮气保护下于25℃搅拌16小时。TLC(二氯甲烷:石油醚=5:1)表明反应物反应完全。反应混合物过滤,滤液减压浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:石油醚=1:1~4:1)纯化得到黄色化合物B8_2(400mg,产率:46%)。
1H NMR:(ES6176-21-P1A2,CDCl3,400MHz)δ9.12(s,1H),7.72-7.69(m,1H),7.18-7.10(m,2H),3.02(s,3H)。
在25℃下向中间体III(222mg,0.76mmol)的四氢呋喃(10mL)溶液中加入化合物B8_2(200mg,0.76mmol),然后吡啶(120mg,1.50mmol)加入到反应液.该反应混合物在氮气的保护下于25℃搅拌6小时。TLC(石油醚:乙酸乙酯=4:1)表明反应物反应完全。反应混合物减压浓缩得到粗产物。粗产物经prep-HPLC(column:Gemini 150*25 5u;mobile phase:[water(10mM NH4HCO3)-ACN];B%:35%-60%,12.5min)纯化得到白色固体化合物15(46mg,产率:12%)。
1H NMR:(ES6176-23-P1A,CDCl3,400MHz)δ10.19(s,1H),9.60(s,1H),8.14(s,1H),7.72(br s,1H),7.15-7.11(m,2H),6.82(s,1H),6.49-6.45(m,1H),6.35-6.29(m,1H),5.73-5.70(d,J=9.6Hz,1H),3.88(s,3H),3.02(s,2H),2.84(s,2H),2.73(s,3H),2.66(s,1H),2.33(s,3H),2.29(s,6H)。
LCMS:520.4[M+H]+,Rt=0.695.HPLC:98.4%purity(220nm),Rt=3.75。
实施例9
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3-甲基-1H-吡咯并[3,2-c]吡啶-1-基)-1,3,5-三嗪-2-基)氨基)苯基)丙烯酰胺(化合物18)
合成路线
向化合物B10_1(1.0g,4.50mmol)的DMF(15mL)溶液中加入trimethyl(prop-1-ynyl)silane(1.5g,13.6mmol),氯化锂(192.9mg,4.50mmol),碳酸钠(964.5mg,9.10mmol)和Pd(dppf)Cl2.CH2Cl2(186mg,0.23mmol),然后反应混合物在氮气的保护下于25℃搅拌16小时。TLC(石油醚:乙酸乙酯=1:1)表明反应物反应完全。向反应液中加入水(80mL),用乙酸乙酯(100mL x 3)萃取。有机相用饱和食盐水洗涤,硫酸钠干燥,过滤,减压浓缩得到粗产物。粗产物经硅胶柱层析(石油醚:乙酸乙酯=20:1~1:1)纯化得到棕色固体B10_2(780mg,产率:84%)。
1H NMR:(ES6176-36-P1A,CDCl3,400MHz)δ8.89(s,1H),8.70(br s,1H),8.27-8.26(d,J=5.6Hz,1H),7.24-7.22(d,J=6.0Hz,1H),2.47(s,3H),0.40(s,9H)。
向化合物B10_2(780mg,3.80mmol)的乙醇(35mL)溶液中加入氢氧化钠(4.7g,117mmol),然后反应混合物在80℃下搅拌16小时。TLC(二氯甲烷:甲醇=20:1)表明反应物反应完全。反应液冷却到25℃,倒入水(50mL)中,用乙酸乙酯(60mL x 3)萃取。有机相用饱和食盐水溶液(50mL)洗涤,硫酸钠干燥,过滤,减压浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:甲醇=100:1~20:1)纯化得到棕色固体B10(400mg,产率:79%)。
1H NMR:(ES6176-39-P1A,CDCl3,400MHz)δ9.49(br s,1H),8.70(s,1H),8.09-8.07(d,J=5.6Hz,1H),7.07-7.06(d,J=6.0Hz,1H),6.83(s,1H),2.19(s,3H)。
在0℃下向中间体III(664mg,2.3mmol)的DMF(10mL)溶液中加入化合物2,4-二氯-1,3,5-三嗪(340mg,2.30mmol),然后反应混合物在氮气保护下于0℃搅拌1小时。化合物B10(300mg,2.30mmol)加入到反应液中,然后反应混合物在氮气保护下于0℃搅拌2小时.LCMS检测到目标产物。反应混合物减压浓缩得到粗产物。粗产物经prep-HPLC(column:WatersXbridge 150*25 5u;mobile phase:[water(10mM NH4HCO3)-ACN];B%:18%-48%,8min)and then was purified by prep-HPLC(column:Waters Xbridge 150*25 5u;mobilephase:[water(10mM NH4HCO3)-ACN];B%:32%-62%,10min)纯化得到白色固体化合物18(58mg,产率:5%)。
1H NMR:(ES6176-42-P1A,CDCl3,400MHz)δ10.19(s,1H),9.76-9.74(br s,1H),8.85(s,2H),8.65-8.59(m,2H),8.47(s,1H),7.97-7.96(br,1H),6.83(s,1H),6.54-6.39(m,2H),5.76-5.74(d,J=10.4Hz,1H),3.91(s,3H),2.94-2.91(m,2H),2.74(s,3H),2.49(s,3H),2.38(s,2H),2.33(s,6H).LCMS:502.3[M+H]+,Rt=0.632。
HPLC:100.0%purity(220nm),Rt=3.85。
实施例10
N-(5-((4-(1H-苯并[d][1,2,3]三唑-1-基)-1,3,5-三嗪-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物19)
合成路线
在0℃下向化合物2,4-二氯-1,3,5-三嗪(257mg,1.70mmol)的DMF(10mL)溶液中加入中间体III(204mg,1.70mmol)和二异丙基乙胺(234mg,1.80mmol),然后反应混合物在0℃下搅拌1小时。二异丙基乙胺(234mg,1.80mmol)和化合物B11(204mg,1.70mmol)依次加入到反应液中。然后反应混合物在25℃下搅拌15小时。LCMS表明反应物反应完全。该反应液直接经prep-HPLC(column:Waters X bridge 150*25 5u;mobile phase:[water(10mMNH4HCO3)-ACN];B%:25%-55%,10min)纯化,冻干后得到处产物(190mg)。粗产物再经prep-TLC(二氯甲烷:甲醇=20:1)纯化得到黄色固体化合物19(79mg,产率:13%)。
1H NMR:(ES6131-11-P1A,CDCl3,400MHz)δ10.22(s,1H),9.03(s,1H),9.02(s,1H),8.66-8.64(d,J=7.6Hz,1H),8.19-8.17(d,J=8.8Hz,2H),7.69(s,1H),7.51(s,1H),6.84(s,1H),6.55-6.33(m,2H),5.73-7.70(m,1H),3.91(s,3H),6.79(s,1H),2.89(s,2H),2.74(s,3H),2.29(s,8H)。
LCMS:489.2[M+H]+,Rt=0.673.HPLC:95.63%purity(220nm),Rt=3.27。
实施例11
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-5-((4-(6-氟代-3-甲基-1H-吲唑-1-基)-1,3,5-三嗪-2-基)氨基)-4-甲氧基苯基)丙烯酰胺(化合物20)
合成路线
在25℃下向水合肼(6.4g,128mmol)的DMF(50mL)溶液中加入化合物B7_1(10.0g,64.1mmol)。然后反应混合物在氮气保护下于120℃搅拌18小时。TLC(石油醚:乙酸乙酯=5:1)表明反应物反应完全。反应液冷却到室温,用水(200mL)稀释,乙酸乙酯(150mL x 3)萃取。有机相用饱和食盐水(200mL)洗涤,硫酸钠干燥,过滤,减压浓缩得到粗产物。粗产物经硅胶柱层析(石油醚:乙酸乙酯=5:1to 1:1)纯化得到白色固体化合物B7(3.0g,产率:31%)。
1H NMR:(ES6176-3-P1A1,CDCl3,400MHz)δ10.35(br s,3H),7.64-7.60(m,1H),7.09-7.06(dd,J1=2.0Hz,J2=9.2Hz,1H),6.95-6.92(td,J1=8.8Hz,J2=11.2Hz,1H),2.59(s,3H)。
在0℃下向化合物2,4-二氯-1,3,5-三嗪(500mg,3.33mmol)的乙腈(10mL)溶液中加入化合物B7(501mg,3.33mmol)和碳酸氢钠(308mg,3.66mmol),然后反应混合物在氮气保护下于25℃搅拌16小时。TLC(二氯甲烷:石油醚=4:1)表明反应物反应完全。反应液过滤,滤液减压浓缩得到粗产物。粗产物经硅胶柱层析(二氯甲烷:石油醚=1:1to 3:1)纯化得到黄色固体化合物B7_2(410mg,产率:47%)。
1H NMR:(ES6176-3-P1A1,CDCl3,400MHz)δ8.97(s,1H),8.42-8.39(dd,J1=1.6Hz,J2=9.6Hz,1H),7.70-7.67(m,1H),7.21-7.17(td,J1=2.0Hz,J2=4.4Hz,1H),2.68(s,3H)。
在25℃下向中间体III(222mg,0.76mmol)的四氢呋喃(10mL)溶液中加入B7_2(200mg,0.76mmol)和吡啶(120mg,1.5mmol)。然后反应混合物在氮气保护下于25℃搅拌6小时。TLC(石油醚:乙酸乙酯=4:1)表明反应物反应完全。反应液减压浓缩得到粗产物。粗产物经prep-HPLC(column:Gemini 150*25 5u;mobile phase:[water(10mM NH4HCO3)-ACN];B%:35%-60%,12.5min)纯化得到白色固体化合物20(76mg,产率:19%)。
1H NMR:(ES6176-24-P1A1,CDCl3,400MHz)δ10.20-10.13(m,1H),9.59(s,1H),8.90(s,1H),8.15(s,1H),7.63-7.58(br s,1H),7.31(s,1H),6.88-6.82(m,2H),6.48-6.44(m,1H),6.35-6.29(m,1H),5.73-5.70(d,J=10.8Hz,1H),3.88(s,3H),3.06(s,2H),2.90(s,2H),2.73(s,3H),2.66(s,1H),2.34(s,2H),2.29(s,6H)。
LCMS:520.4[M+H]+,Rt=0.689.HPLC:97.8%purity(220nm),Rt=3.67。
下表1是各实施例LC/MS数据
表1
实施例编号 | 化合物编号 | [M+H]+ |
1 | 化合物4 | 501.4 |
2 | 化合物6 | 488.1 |
3 | 化合物8 | 488.3 |
4 | 化合物11 | 518.4 |
5 | 化合物12 | 488.3 |
6 | 化合物13 | 488.4 |
7 | 化合物14 | 502.4 |
8 | 化合物15 | 520.4 |
9 | 化合物18 | 502.3 |
10 | 化合物19 | 489.2 |
11 | 化合物20 | 520.4 |
测试1:L858R/T790M EGFR(双突变体)细胞磷酸化测试
人肺细胞系NCI-H1975(L858R/T790M双突变EGFR)是从美国典型培养物保藏中心获得。将NCI-H1975细胞培养在含有10%胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5%CO2的加湿培养箱中于37℃生长。
依照R&D Systems公司的DuoSet IC Human Phospho-EGFR ELISA(R&D Systems目录号#DYC1095)中所描述的方案,来进行细胞裂解液中内源性细胞磷酸化p-EGFR的检测。将90μl细胞(8000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中,并于37℃下在5%CO2加湿培养箱中培养过夜后,将细胞培养液换成含有1%胎牛血清和2mM谷氨酰胺的RPMI1640培养基继续培养。使用移液器将100%DMSO中连续稀释的化合物加至细胞,轻柔混合培养基之后,并将细胞再培养2小时。将100μl1X裂解缓冲液添加到各孔中。将Greiner高结合力96孔板用捕获抗体覆盖,然后用3%BSA进行封闭。去除封闭液之后,将100μl裂解液转移到Greiner高结合力96孔板中,孵育2小时。轻柔混合并用PBS清洗培养板之后,添加100μl检测抗体,并孵育2小时。轻柔混合并用PBS清洗培养板之后,添加100μl TMB底物(CellSignaling Technology目录号7004),孵育1小时。将100μl终止溶液添加到培养板中,并检测各孔对450nm波长的吸光度。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50%抑制效果所需的化合物浓度来确定IC50值。
下表2显示了本发明的代表性化合物,即实施例2的化合物6与实施例4的化合物11,在上述的生物学实验中的IC50值(μM),其中用作对照的化合物Osimertinib(AZD9291)是按照以下文献所述的方法合成:
Discovery of a Potent and Selective EGFR Inhibitor(AZD9291)of BothSensitizing and T790M Resistance Mutations That Spares the Wild Type Form ofthe Receptor,J.Med.Chem.,2014,57(20),pp 8249–8267。
表2
如上表2所示,本发明的化合物6和化合物11在L858R/T790M EGFR(双突变体)细胞磷酸化测试中IC50值分别是0.0151和0.0111,与之相比,Osimertinib(AZD9291)在L858R/T790M EGFR(双突变体)细胞磷酸化测试中IC50值为0.0459,相当于采用本发明化合物6和化合物11情况下IC50值的三倍以上。
测试2:野生型EGFR细胞增殖测试
人肺细胞系A431(野生型EGFR)是从美国典型培养物保藏中心获得。将NCI-H838细胞培养在含有10%胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5%CO2的加湿培养箱中于37℃生长。
依照Promega公司的Cell Titer-Glo Luminescent cell Viability Assay(Promega目录号#G7570)中所描述的方案,来进行检测培养物中活细胞的数目。将90μl细胞(8000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中,并于37℃下在5%CO2加湿培养箱中培养过夜。使用移液器将100%DMSO中连续稀释的化合物加至细胞,并将细胞再培养72小时。将100μl混合好的Cell Titer-Glo试剂加入到96孔培养板中的细胞中裂解细胞,并轻柔混合。随后,在Envision微孔板检测仪上进行自发荧光的检测,得到化合物的数据。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50%抑制效果所需的化合物浓度来确定IC50值。
测试3:L858R/T790M EGFR(双突变体)细胞增殖测试
人肺细胞系NCI-H1975(L858R/T790M双突变EGFR)是从美国典型培养物保藏中心获得。将NCI-H1975细胞培养在含有10%胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5%CO2的加湿培养箱中于37℃生长。
依照Promega公司的Cell Titer-Glo Luminescent cell Viability Assay(Promega目录号#G7570)中所描述的方案,来进行检测培养物中活细胞的数目。将90μl细胞(8000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中,并于37℃下在5%CO2加湿培养箱中培养过夜。使用移液器将100%DMSO中连续稀释的化合物加至细胞,并将细胞再培养72小时。将100μl混合好的Cell Titer-Glo试剂加入到96孔培养板中的细胞中裂解细胞,并轻柔混合。随后,在Envision微孔板检测仪上进行自发荧光的检测,得到化合物的数据。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50%抑制效果所需的化合物浓度来确定IC50值。
下表3显示了本发明的代表性化合物,即实施例2的化合物6,在上述的生物学实验中的IC50值(μM),其中用作对照的化合物Osimertinib(AZD9291)是按照以下文献所述的方法合成:
Discovery of a Potent and Selective EGFR Inhibitor(AZD9291)of BothSensitizing and T790M Resistance Mutations That Spares the Wild Type Form ofthe Receptor,J.Med.Chem.,2014,57(20),pp 8249–8267。
表3
参见表3所示,本发明的化合物相对于Osimertinib(AZD9291),在L858R/T790MEGFR(双突变体)细胞增殖测试中,IC50值相对较小。采用Osimertinib(AZD9291)所获得的IC50值约为采用本发明化合物所获得IC50值的七倍以上。这表明本发明的化合物相对于Osimertinib(AZD9291)能够更好地抑制L858R/T790M EGFR(双突变体)细胞增殖。另外,如表3所示,表最右栏表示的是测试2的IC50值与测试3的IC50值的比值,其表征了化合物对于L858R/T790M EGFR(双突变体)细胞增殖抑制作用和对于野生型EGFR细胞增殖抑制作用的选择性,该值越大表明化合物在野生型EGFR细胞中对L858R/T790M EGFR(双突变体)细胞增殖作用抑制的选择性更好。如表3所示本发明化合物对L858R/T790M EGFR(双突变体)细胞增殖作用抑制的选择性远远好于Osimertinib(AZD9291)。
测试4:Ba/F3-CAT-EGFR细胞增殖测试
Ba/F3-CAT-EGFR细胞活力检测是基于CellTiter-开发的检测技术。通过过表达野生态EGFR的胞内激酶区域转化Ba/F3细胞,构建CAT-EGFR工具细胞株。这株细胞依赖EGFR的激酶活性才能生长,如果通过小分子化合物抑制野生态的EGFR,细胞就会凋亡。从而可以通过观察EGFR小分子对细胞活力的影响,评估其对野生态EGFR的特异性和活性。
Ba/F3-CAT-EGFR(野生型EGFR)细胞培养在含有10%胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5%CO2的加湿培养箱中于37℃生长。
依照Promega公司的Cell Titer-Glo Luminescent cell Viability Assay(Promega目录号#G7570)中所描述的方案,来进行检测培养物中活细胞的数目。将100μl细胞(3000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中,并于37℃下在5%CO2加湿培养箱中培养过夜。使用移液器将100%DMSO中连续稀释的化合物加至细胞,并将细胞再培养72小时。将100μl混合好的Cell Titer-Glo试剂加入到96孔培养板中的细胞中裂解细胞,并轻柔混合。随后,在Envision微孔板检测仪上进行自发荧光的检测,得到化合物的数据。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50%抑制效果所需的化合物浓度来确定IC50值。
测试5:Ba/F3-DTM-EGFR细胞增殖测试
Ba/F3-DTM-EGFR细胞活力检测是基于CellTiter-开发的检测技术。通过过表达野生态T790M突变和Exon19缺失的EGFR转化Ba/F3细胞,构建DTM-EGFR工具细胞株。这株细胞依赖EGFR的激酶活性才能生长,如果通过小分子化合物抑制突变态的EGFR,细胞就会凋亡。从而可以通过观察EGFR小分子对细胞活力的影响,评估其对突变EGFR的特异性和活性。
Ba/F3-DTM-EGFR(突变型EGFR)细胞培养在含有10%胎牛血清和2mM谷氨酰胺的RPMI1640培养基中。使细胞在有5%CO2的加湿培养箱中于37℃生长。
依照Promega公司的Cell Titer-Glo Luminescent cell Viability Assay(Promega目录号#G7570)中所描述的方案,来进行检测培养物中活细胞的数目。将100μl细胞(3000细胞/孔)培养在Corning黑色透明底96孔板里的生长培养基中,并于37℃下在5%CO2加湿培养箱中培养过夜。使用移液器将100%DMSO中连续稀释的化合物加至细胞,并将细胞再培养72小时。将100μl混合好的Cell Titer-Glo试剂加入到96孔培养板中的细胞中裂解细胞,并轻柔混合。随后,在Envision微孔板检测仪上进行自发荧光的检测,得到化合物的数据。最后将数据输入合适的软件包(例如Prism)以进行曲线拟合分析。基于此数据并通过计算获得50%抑制效果所需的化合物浓度来确定IC50值。
表4显示了本发明的代表性化合物,即实施例4、9和11的化合物在上述的生物学实验中的IC50值(μM),其中用作对照的化合物Osimertinib(AZD9291)是按照以下文献所述的方法合成:
Discovery of a Potent and Selective EGFR Inhibitor(AZD9291)of BothSensitizing and T790M Resistance Mutations That Spares the Wild Type Form ofthe Receptor,J.Med.Chem.,2014,57(20),pp 8249–8267。
表4
参见表4所示,本发明的化合物相对于Osimertinib(AZD9291)来说,针对Ba/F3-DTM-EGFR细胞增殖测试,其IC50值相对较小,表明本发明的化合物相对于Osimertinib(AZD9291)能够更好地抑制Ba/F3-DTM-EGFR细胞增殖。另外,如表4所示,表4最右栏表示的是测试4的IC50值与测试5的IC50值的比值,其表征了化合物对于Ba/F3-CAT-EGFR细胞增殖抑制作用和Ba/F3-DTM-EGFR细胞增殖作用的选择性,该值越大表明化合物在Ba/F3细胞中对Ba/F3-DTM-EGFR细胞增殖作用抑制的选择性更好。如表4所示本发明化合物对Ba/F3-DTM-EGFR细胞增殖作用抑制的选择性远远好于Osimertinib(AZD9291)。
测试6:血浆蛋白结合率(Plasma Protein Binding rate)测试
血浆蛋白结合率测试采用HTDialysis公司的96孔平衡透析装置,将浓度为2μM供试品和对照化合物的人血浆样品或小鼠血浆样品在37℃平衡透析4小时,来进行蛋白结合的研究。将150μL供试化合物血浆样品加入到每个透析孔的给药端,在透析孔对应的接收端中加入150μL空白透析缓冲液。然后将透析板置于湿润的、5%CO2的培养箱中,在37℃下孵育4小时。透析结束后,移取50μL透析后的缓冲液样品和透析后的血浆样品到新的96孔板中(样品接收板)。在样品中加入相应体积的对应空白血浆或缓冲液。所有样品经过蛋白沉淀后进行LC/MS/MS分析。样品的浓度用化合物与内标的峰面积比值表示(半定量)。最后根据公式计算出化合物的%未结合率(%Unbound)、%结合率(%Bound)和回收率(%Recovery)。
表5
在正常情况下,各种药物以一定的比率与血浆蛋白结合,在血浆中常同时存在结合型与未结合型(游离型),而只有未结合型药物才具有药物活性。参见表5所示,针对血浆蛋白结合率测试,本发明的化合物相对于Osimertinib(AZD9291)来说,其在人和小鼠血浆中的未结合药物比率相对较大,表明本发明的化合物相对于Osimertinib(AZD9291)能够增大其血浆未结合药物比率,即活性药物比率。
本文所公开的量纲和值不旨在被理解为严格地限于所述的精确值。相反,除非另外指明,每个这样的量纲是指所引用的数值和围绕该数值的功能上等同的范围。
除非明确排除或换句话讲有所限制,本文中引用的每一个文献,包括任何交叉引用或相关专利或专利申请,均据此以引用方式全文并入本文。对任何文献的引用均不是承认其为本文公开的或受权利要求书保护的任何发明的现有技术、或承认其独立地或以与任何其它一个或多个参考文献的任何组合的方式提出、建议或公开任何此类发明。进一步讲,如果此文献中术语的任何含义或定义与以引用方式并入本文的文献中相同术语的任何含义或定义相冲突,将以此文献中赋予那个术语的含义或定义为准。
尽管已用具体实施方案来说明和描述了本发明,但对于本领域的技术人员显而易见的是,在不背离本发明的精神和保护范围的情况下可作出许多其它的改变和变型。因此,随附权利要求书中旨在涵盖本发明范围内的所有这些改变和变型。
Claims (10)
1.式(I)的化合物或其药学上可接受的盐:
其中R1为-NR5R6,其中R5和R6各自独立地选自C1-C6烷基,其中所述烷基为未取代或被-NR7R8所取代;
其中R2选自C2-C6烯基,所述烯基为未取代或被-NR7R8所取代;
其中R7和R8在每次出现时各自独立地选自H或C1-C6烷基;
其中R3选自取代或未取代的稠合二环基团,所述稠合二环为五元环和六元环稠合;
其中R4选自C1-C6烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中所述化合物为如下式(II)所示:
其中,
A1、A4、A9各自独立地选自N或C;
A2、A3、A5、A6、A7、A8各自独立地选自N、NRa、CRa、CRaRb,
其中Ra和Rb各自独立地选自H、C1-C6烷基和卤素,或者Ra、Rb和与它们所连接的同一个碳原子一起形成C3-C6环烷基,所述C1-C6烷基和C3-C6环烷基任选取代有一个或多个卤素原子,
条件是环A和环B至少一个为不饱和环。
3.根据权利要求1至2任一项所述的化合物或其药学上可接受的盐,其中A1为N。
4.根据权利要求1至3任一项所述的化合物或其药学上可接受的盐,其中A1、A2、A3、A4、A5、A6、A7、A8、A9中有一个、两个或三个包含N原子。
5.根据权利要求1至4任一项所述的化合物或其药学上可接受的盐,其中所述R1选自:
6.根据权利要求1至5任一项所述的化合物或其药学上可接受的盐,其中所述R2选自:
7.根据权利要求1至6任一项所述的化合物或其药学上可接受的盐,其中所述R3选自:
8.根据权利要求1所述的化合物或其药学上可接受的盐,其中所述化合物选自:
9.一种药物组合物,其包含根据权利要求1至8任一项所述的化合物或其药学上可接受的盐。
10.权利要求1至8任一项所述的化合物或其药学上可接受的盐在制备用于治疗小细胞肺癌的药物中的用途。
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WO2020200158A1 (zh) * | 2019-03-29 | 2020-10-08 | 深圳福沃药业有限公司 | 用于治疗癌症的氮杂芳环酰胺衍生物 |
US20220177473A1 (en) * | 2019-03-29 | 2022-06-09 | Shenzhen Forward Pharmaceuticals Co., Ltd. | Azaaromatic amide derivatives for the treatment of cancer |
JP2022529616A (ja) * | 2019-03-29 | 2022-06-23 | 深▲せん▼福沃薬業有限公司 | 癌を治療するための窒素含有芳香族ヘテロ環アミド誘導体 |
JP7337951B2 (ja) | 2019-03-29 | 2023-09-04 | 深▲せん▼福沃薬業有限公司 | 癌を治療するための窒素含有芳香族ヘテロ環アミド誘導体 |
WO2021259315A1 (zh) * | 2020-06-23 | 2021-12-30 | 深圳福沃药业有限公司 | 化合物的盐以及包含盐的药物组合物 |
CN115836064A (zh) * | 2020-08-13 | 2023-03-21 | 上海和誉生物医药科技有限公司 | 具有egfr抑制活性的三嗪衍生物及其制备方法和应用 |
WO2022116995A1 (zh) * | 2020-12-02 | 2022-06-09 | 上海和誉生物医药科技有限公司 | 2,3-二氢-1H-吡咯并[3,2-b]吡啶衍生物、其制备方法和应用 |
CN115867539A (zh) * | 2020-12-02 | 2023-03-28 | 上海和誉生物医药科技有限公司 | 2,3-二氢-1H-吡咯并[3,2-b]吡啶衍生物、其制备方法和应用 |
WO2022237825A1 (zh) * | 2021-05-13 | 2022-11-17 | 上海和誉生物医药科技有限公司 | 具有egfr抑制活性的氮杂芳基衍生物、其制备方法和应用 |
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EP3705478B1 (en) | 2023-10-04 |
EP3705478A1 (en) | 2020-09-09 |
CN108864079B (zh) | 2021-04-09 |
CN110891950A (zh) | 2020-03-17 |
EP3705478A4 (en) | 2020-10-28 |
MA50506A (fr) | 2020-09-09 |
CN110891950B (zh) | 2023-04-07 |
WO2018210246A1 (zh) | 2018-11-22 |
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