CN107805240A - 一种新型的pdgfr激酶抑制剂及其用途 - Google Patents
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种新型的PDGFR激酶抑制剂,其包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物、或前药。本发明还提供式(I)的化合物用于预防或治疗与PDGFR激酶活性相关的病症的用途和方法,特别是与PDGFRα激酶活性相关的病症。
Description
技术领域
本申请涉及一种作为选择性的PDGFR激酶抑制剂的化合物、以及使用这样的化合物抑制PDGFR激酶活性的方法和用途。
背景技术
血小板衍生生长因子(PDGF)是针对几乎所有间充质源(mesenchyme-derived)细胞的有效促细胞分裂原的家族。有四种PDGF亚型(isoform)——A、B、C和D,它们形成五种不同的通过二硫化物连接的二体蛋白——PDGF-AA、BB、-AB、-CC和DD。这些生长因子通过两种结构相关的酪氨酸激酶受体——PDGF受体α(PDGFRα)和PDGF受体β(PDGFRβ)来发挥其细胞作用(Sandy,J.R.(1998)Br.J.Orthod.25:269-74;Betsholtz,C.等人(2001)BioEssays23:494-507)。
PDGFRα与PDGFRβ结构相似,并能形成异源二聚体和同源二聚体。PDGF-BB和PDGF-DD是ββ同源二聚体的主要激活子。PDGF-AA仅活化αα受体二聚体,而PDGF-AB、PDGF-BB和PDGF-CC活化αα和αβ受体二聚体。二聚体配体分子与两种受体蛋白同时结合,并且诱导受体二聚化、受体胞质结构域内的特定残基的自身磷酸化和细胞信号传达。
高嗜酸性粒细胞综合征(hypereosinophilic syndrome,HES)是一种少见的、原因不明的嗜酸性粒细胞持续增高并伴有多脏器损害的血液系统疾病,2001年Schaller等首次报道甲磺酸伊马替尼(商品名:格列卫,一种ABL、KIT及PDGFR酪氨酸激酶小分子抑制剂)治疗1例HES患者,疗效显著,故提出HES可能存在ABL、KIT、PDGFR或其他不明靶基因的固有激活。2003年,Cools等与Griffins等分别在HES患者及体外培养的EOL-1细胞(慢性嗜酸性粒细胞白血病细胞系)中检测到FIP1L1-PDGFRA融合基因(PDGFRA基因编码PDGFRα),不仅确定了格列卫治疗HES的分子靶,为HES的诊断及治疗提供了有力的分子标志,而且从分子水平揭示HES是一种造血系统恶性克隆性疾病的本质。Cools等的研究证明,转录活化因子5(STAT5)是FIP1L1-PDGFRA融合基因作用的下游靶标,STAT5的激活有助于嗜酸粒细胞增殖。
目前报道的针对PDGFRα和PDGFRβ二者的选择性抑制剂的例子包括CP-673451(CAS号343787-29-1;分子量:417.5)和伊马替尼(CAS号152459-95-5;分子量:493.60),但以较高的选择性抑制PDGFR、特别是选择性抑制PDGFRα的抑制剂还没有报道。因此,有必要提供一种选择性抑制PDGFR、特别是选择性抑制PDGFRα的抑制剂,以便为精准靶向治疗提供研究基础。
因此,本发明的发明人经过实验,发现了一种选择性PDGFR抑制剂,该抑制剂对表达FIP1L1-PDGFRA融合基因的EOL-1细胞(慢性嗜酸性粒细胞白血病细胞系)增殖有明显的抑制作用,并且在小鼠用EOL-1细胞肿瘤移植模型中也能够明显抑制肿瘤的生长。
发明内容
本发明提供了一种选择性PDGFR抑制剂,特别是选择性的PDGFRα抑制剂。
更具体地,本发明提供一种选择性的PDGFR激酶抑制剂,包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
R1选自氨基、C1-8烷基、C3-8环烷基、C2-8烯基、C1-8烷基氨基C1-8烷基、任选被1-3个R3基团取代的芳基、和任选被1-3个R3基团取代的杂芳基;
R2选自氢、氨基、C1-8烷基、C1-8烷基氨基、羟基、和任选被1-3个R3基团取代的杂环基;
R3独立地选自C1-8烷基、C1-8烷氧基、卤素、氨基、硝基、羟基、和氰基。
本发明还涉及包括以上化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药的药物组合物,以及该化合物或药物组合物抑制酪氨酸激酶(野生型或各种突变或其组合)活性的方法和用途,及其治疗、预防或改善由酪氨酸激酶(野生型或各种突变或其组合)活性调节的或者受其影响的或者其中涉及酪氨酸激酶(野生型或各种突变或其组合)活性的疾病、障碍或病症的方法和用途,其中酪氨酸激酶可以为PDGFR。
附图说明
图1a示出化合物4i和伊马替尼对人慢性嗜酸性粒细胞白血病细胞EOL-1中的信号通路的蛋白的影响;图1b示出化合物4i和伊马替尼对人肺癌细胞NCI-H1703中的信号通路的蛋白的影响。
图2a和图2b-2c分别示出化合物4i和伊马替尼对人慢性嗜酸性粒细胞白血病细胞EOL-1以及对人肺癌细胞NCI-H1703的细胞凋亡的影响,其中图2b显示未添加血小板衍生生长因子PDGF AA进行刺激的结果,图2c显示添加血小板衍生生长因子PDGF AA进行刺激的结果。
图3a和3b分别示出化合物4a、伊马替尼对人慢性嗜酸性粒细胞白血病细胞EOL-1以及对人肺癌细胞NCI-H1703的细胞周期的影响;图3c和3d分别示出化合物4i、伊马替尼对人慢性嗜酸性粒细胞白血病细胞EOL-1以及对人肺癌细胞NCI-H1703的细胞周期的影响,Ctrl:所采用的化合物浓度为0。
图4a和4b示出化合物4i对激酶的体外抑制活性的实验结果。
图5示出使用不同浓度的化合物4i和溶媒对照分别对人慢性嗜酸性粒细胞白血病细胞EOL-1的小鼠肿瘤模型进行处理得到的实验结果,其中图5a示出在人慢性嗜酸性粒细胞白血病细胞EOL-1的小鼠肿瘤模型中,不同处理组中的小鼠平均体重(以实验开始时的小鼠重量为基准计算的百分数)随时间的变化;图5b示出在人慢性嗜酸性粒细胞白血病细胞EOL-1的小鼠肿瘤模型中,不同处理组中的肿瘤的平均体积(以实验开始时的小鼠荷载的肿瘤体积为基准计算的百分数)随时间的变化;图5c示出在人慢性嗜酸性粒细胞白血病细胞EOL-1的小鼠肿瘤模型中,不同处理组中的小鼠的平均肿瘤体积随时间的变化;图5d示出在人慢性嗜酸性粒细胞白血病细胞EOL-1的小鼠肿瘤模型中,不同处理组中的小鼠在用药后第29天的平均肿瘤重量和计算出的抑瘤率。
具体实施方式
术语
除非另外定义,所有本文使用的科技术语都具有与要求保护的主题所属领域的技术人员一般理解相同的含义。
除非另有说明,本发明采用本领域技术范围内的质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学等常规方法。除非提供具体的定义,否则与本文描述的分析化学、合成有机化学、以及医学和药物化学等化学上相关的命名和实验室操作和技术,是本领域技术人员已知的。一般而言,前述技术和步骤可以通过本领域众所周知的和在各种一般文献和更具体文献中描述的常规方法来实施,这些文献在本说明书中被引用和讨论。
“烷基”是指脂肪族烃基团,可以是支链或直链的烷基。根据结构,烷基可以是单价基团或双价基团(即亚烷基)。在本发明中,烷基优选是具有1-8个碳原子的烷基,更优选具有1-6个碳原子的“低级烷基”,甚至更优选具有1-4个碳原子的烷基。。典型的烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等。应理解,本文提到的“烷基”包括可能存在的所有构型和构象的该烷基,例如本文提到的“丁基”包括正丁基、异丁基和叔丁基。
术语“环烷基”是指单环或多环基,其仅含有碳和氢。环烷基包括具有3-8个环原子的基团。根据结构,环烷基可以是单价基团或双价基团(例如亚环烷基)。在本发明中,环烷基优选是具有3-8个碳原子的环烷基,更优选具有3-6个碳原子的“低级环烷基”。
“烷氧基”是指-O-烷基,其中烷基如本文中定义。典型的烷氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、己氧基等。
术语“氨基”是指基团-NH2。术语“氨酰基”是指-CO-NH2。术语“酰胺基”或“酰氨基”是指-NR-CO-R’,其中R和R’各自独立地为氢或烷基。
术语“烷基氨基”是指进一步被一个或两个烷基取代的氨基取代基,具体是指基团-NRR’,其中R和R’各自独立地选自氢或低级烷基,条件是-NRR’不是-NH2。
“烷基氨基烷基”是指本文定义的烷基被本文定义的烷基氨基取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
本文使用的术语“氰基”是指式-CN基团。
术语“芳香基”是指平面环具有离域的π电子系统并且含有4n+2个π电子,其中n是整数。芳香基环可以由五、六、七、八、九或多于九个原子构成。芳香基可以是任选取代的。术语“芳香基”包括碳环芳基(例如苯基)和杂环芳基(或“杂芳基”或“杂芳香基”)基团(例如吡啶)。该术语包括单环或稠环多环(即共用相邻的碳原子对的环)基团。
本文使用的术语“芳基”是指芳香基环中每一个构成环的原子都是碳原子。芳基环可以由五、六、七、八、九或多于九个原子构成。芳基可以是任选取代的。芳基的实例包括但不限于苯基、萘基、菲基、蒽基、芴基和茚基。根据结构,芳基可以是单价基团或双价基团(即亚芳基)。
术语“杂芳基”是指芳基中包括一个或多个选自氮、氧和硫的环杂原子。含N“杂芳基”部分是指芳香基中环上至少有一个骨架原子是氮原子。根据结构,杂芳基可以是单价基团或双价基团(即亚杂芳基)。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、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、吲唑基、吲嗪基、酞嗪基、哒嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、噻二唑基、呋喃基、苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、萘啶基和呋喃并吡啶基等。
本文使用的术语“杂环烷基”或“杂环基”是指非芳香基环中一个或多个构成环的原子是选自氮、氧和硫的杂原子。杂环烷基环可以由三、四、五、六、七、八、九或多于九个原子构成。杂环烷基环可以是任选取代的。杂环烷基的实例包括但不限于内酰胺、内酯、环亚胶、环硫代亚胺、环氨基甲酸酯、四氢噻喃、4H-吡喃、四氢吡喃、哌啶、1,3-二噁英、1,3-二噁烷、1,4-二噁英、1,4-二噁烷、哌嗪、1,3-氧硫杂环己烷、1,4-氧硫杂环己二烯、1,4-氧硫杂环己烷、四氢-1,4-噻嗪、2H-1,2-噁嗪、马来酰亚胺、琥珀酰亚胺、巴比妥酸、硫代巴比妥酸、二氧代哌嗪、乙内酰脲、二氢尿嘧啶、吗啉、三噁烷、六氢-1,3,5-三嗪、四氢噻吩、四氢呋喃、吡咯啉、吡咯烷(四氢吡咯)、咪唑烷,吡咯烷酮、吡唑啉、吡唑烷、咪唑啉、咪唑烷、1,3-二氧杂环戊烯、1,3-二氧杂环戊烷、1,3-二硫杂环戊烯、1,3-二硫杂环戊烷、异噁唑啉、异噁唑烷、噁唑啉、噁唑烷、噁唑烷酮、噻唑啉、噻唑烷和1,3-氧硫杂环戊烷。根据结构,杂环烷基可以是单价基团或双价基团(即亚杂环烷基)。
术语“取代的”是指所提及的基团可以被一个或多个额外的基团取代,所述额外的基团各自并且独立地选自烷基、环烷基、芳基、杂芳基、羟基、烷氧基、氰基、卤素、酰胺基、硝基、卤代烷基、氨基、烷基羰基、烷氧基羰基、烷基(杂芳基)、烷基(杂环烷基)、烷基砜基、氨酰基等。
本文使用的术语“酪氨酸激酶(tyrosine protein kinase,TPK)”是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶,能催化多种底物蛋白质酪氨酸残基磷酸化,在细胞生长、增殖、分化中具有重要作用。
本文使用的术语激酶的“抑制”、“抑制的”或“抑制剂”,是指磷酸转移酶活性被抑制。
本文公开的化合物的“代谢物”是当该化合物被代谢时形成的化合物的衍生物。术语“活性代谢物”是指当该化合物被代谢时形成的化合物的生物活性衍生物。本文使用的术语“被代谢”,是指特定物质被生物体改变的过程总和(包括但不限于水解反应和由酶催化的反应,例如氧化反应)。因此,酶可以产生特定的结构转变为化合物。例如,细胞色素P450催化各种氧化和还原反应,同时二磷酸葡萄糖甘酸基转移酶催化活化的葡萄糖醛酸分子至芳香醇、脂肪族醇、羧酸、胺和游离的巯基的转化。新陈代谢的进一步的信息可以从《ThePharmacological Basis of Therapeutics》,第九版,McGraw-Hill(1996)获得。本文公开的化合物的代谢物可以通过将化合物给予宿主并分析来自该宿主的组织样品、或通过将化合物与肝细胞在体外孵育并且分析所得化合物来鉴别。这两种方法都是本领域已知的。在一些实施方式中,化合物的代谢物是通过氧化过程形成并与相应的含羟基化合物对应。在一些实施方式中,化合物被代谢为药物活性代谢物。本文使用的术语“调节”,是指直接或间接与靶标相互作用,以改变靶标的活性,仅仅举例来说,包括增强靶标的活性、抑制靶标的活性、限制靶标的活性或者延长靶标的活性。
本文使用的术语“靶蛋白”是指能被选择性结合化合物所结合的蛋白质分子或部分蛋白质。在某些实施方式中,靶蛋白是酪氨酸激酶PDGFR(包括其野生型或各种突变或其组合)。
本文使用的GI50是指使50%细胞生长被抑制所需的药物浓度,即药物使50%细胞(如癌细胞)的生长得到抑制或控制时的药物浓度。
本文使用的IC50是指在测量效应的分析中获得最大效应的50%抑制的特定测试化合物的量、浓度或剂量。
本文使用的EC50是指测定化合物的剂量、浓度或量,其引起特定测定化合物诱导、刺激或加强的特定反应的50%的最大表达的剂量依赖反应。
本发明新型的激酶抑制剂
本发明提供一种选择性的PDGFR激酶抑制剂,包括式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
R1选自氨基、C1-8烷基、C3-8环烷基、C2-8烯基、C1-8烷基氨基C1-8烷基、任选被1-3个R3基团取代的芳基、和任选被1-3个R3基团取代的杂芳基;
R2选自氢、氨基、C1-8烷基、C1-8烷基氨基、羟基、和任选被1-3个R3基团取代的杂环基;
R3独立地选自C1-8烷基、C1-8烷氧基、卤素、氨基、硝基、羟基、和氰基。
在优选的实施方式中,式(I)中的R1选自C1-6烷基、C3-6环烷基、C2-6烯基、C1-4烷基氨基C1-4烷基、任选被1-3个R3基团取代的苯基、和任选被1-3个R3基团取代的杂芳基。例如,R1优选为乙烯基、丙烯基、乙基、正丙基、异丙基、叔丁基、环丙基、N,N-二甲氨基甲基、苯基、对甲基苯基、吡啶基、异噁唑基、或噻吩基等。
在优选的实施方式中,R2选自C1-6烷基、C1-4烷基氨基、羟基、和杂环基。例如,R2优选为N,N-二甲基氨基、N,N-二乙基氨基、四氢吡咯基、羟基、或异丙基等。
在优选的实施方式中,R3独立地选自C1-6烷基,更优选甲基。
在本发明中,优选的PDGFR激酶抑制剂包括下表的化合物及其药学可接受的盐、溶剂化物、异构体、酯、酸、代谢物、或前药:
对于各个变量,上述基团的任意组合也在本文考虑之中。可以理解的是:本文所提供的化合物上的取代基和取代模式可以由本领域技术人员进行选择,以便提供化学上稳定的且可以使用本领域已知的技术以及本文阐述的技术合成的化合物。
本文描述的是新型的激酶抑制剂。本文也描述了此化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物和前药。
在另外的或进一步的实施方式中,将本文描述的化合物给予有需要的生物体后在其体内代谢产生代谢物,所产生的代谢物然后用于产生期望的效果,包括期望的治疗效果。
本文描述的化合物可以被制成和/或被用作药学可接受的盐。药学可接受的盐的类型包括但不限于:(1)酸加成盐、通过将化合物的游离碱形式与药学可接受的无机酸反应形成,所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸、偏磷酸等;或与有机酸反应形成,所述有机酸如乙酸、丙酸、己酸、环戊烷丙酸、羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、柠檬酸、琥珀酸、马来酸、酒石酸、反丁烯二酸、三氟乙酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、甲苯磺酸、4-甲基双环-[2.2.2]辛-2-烯-1-甲酸、2-萘磺酸、叔丁基乙酸、葡庚糖酸、4,4'-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、水杨酸、羟基萘酸、硬脂酸、粘康酸等;(2)碱加成盐,其在母体化合物中的酸性质子被金属离子置换时形成,例如碱金属离子(例如锂、钠、钾)、碱土金属离子(例如镁或钙)或铝离子;或与有机碱配位。可接受的有机碱包括乙醇胺、二乙醇胺、三乙醇胺、三甲胺、N-甲基葡萄糖胺,等等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠、氢氧化钠等。
药学可接受的盐的相应的平衡离子可以使用各种方法分析和鉴定,所述方法包括但不限于离子交换色谱、离子色谱、毛细管电泳、电感耦合等离子体、原子吸收光谱、质谱或它们的任何组合。
使用以下技术的至少一种回收所述盐:过滤、用非溶剂沉淀接着过滤、溶剂蒸发,或水溶液的情况下使用冻干法。
筛选和表征药学可接受的盐、多晶型和/或溶剂化物可以使用多种技术完成,所述技术包括但不限于热分析、X射线衍射、光谱、显微镜方法、元素分析。使用的各种光谱技术包括但不限于Raman、FTIR、UVIS和NMR(液体和固体状态)。各种显微镜技术包括但不限于IR显微镜检术和拉曼(Raman)显微镜检术。
本发明的药物组合物
本申请还提供药物组合物,其包含至少一种式(I)的化合物或所述化合物的药学可接受的盐、溶剂化物、酯、酸、药物活性代谢物或前药,以及药学可接受的载体或赋形剂,以及者任选的其它治疗剂。
在治疗过程中,可以根据情况单独或与一种或多种其它的治疗剂组合使用。可以通过注射、口服、吸入、直肠和经皮施用中的至少一种将包含本发明化合物的药物施用给患者。其它的治疗剂可以选自以下药物:免疫抑制剂(例如他克莫司、环孢菌素、雷帕霉素、甲氨蝶呤、环磷酰胺、硫唑嘌呤、巯嘌呤、麦考酚酯或FTY720)、糖皮质激素类药(例如泼尼松、醋酸可的松、泼尼松龙、甲泼尼龙、地塞米松、倍他米松、曲安西龙、氟羟强的松龙、倍氯米松、醋酸氟氢可的松、醋酸脱氧皮质酮、醛固酮)、非甾体抗炎药(例如水杨酸盐、芳基烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、考昔类或硫酰替苯胺)、变态反应疫苗、抗组胺药、抗白三烯药、β-激动剂、茶碱、抗胆碱药或其它选择性激酶抑制剂(例如mTOR抑制剂、c-Met抑制剂)或her2抗体-药物。另外,所提及的其它治疗剂还可以是雷帕霉素(Rapamycin)、克唑替尼(Crizotinib)、他莫昔芬、雷洛昔芬、阿那曲唑、依西美坦、来曲唑、赫赛汀TM(曲妥珠单抗)、格列卫TM(伊马替尼)、紫杉醇TM(紫杉醇)、环磷酰胺、洛伐他汀、美诺四环素(Minosine)、阿糖胞苷、5-氟尿嘧啶(5-FU)、甲氨蝶呤(MTX)、紫杉特尔TM(多西他赛)、诺雷德TM(戈舍瑞林)、长春新碱、长春碱、诺考达唑、替尼泊苷、依托泊苷、健择TM(吉西他滨)、埃博霉素(Epothilone)、诺唯本、喜树碱、柔红霉素(Daunonibicin)、更生霉素、米托蒽醌、安吖啶、多柔比星(亚德里亚霉素)、表柔比星或伊达比星。或者,其它治疗剂也可以是细胞因子例如G-CSF(粒细胞集落刺激因子)。或者,其它治疗剂也可以是,例如但不限于,CMF(环磷酰胺、甲氨蝶呤和5-氟尿嘧啶)、CAF(环磷酰胺、亚德里亚霉素和5-氟尿嘧啶)、AC(亚德里亚霉素和环磷酰胺)、FEC(5-氟尿嘧啶、表柔比星和环磷酰胺)、ACT或ATC(亚德里亚霉素、环磷酰胺和紫杉醇)或CMFP(环磷酰胺、甲氨蝶呤、5-氟尿嘧啶和泼尼松)。
在本发明的实施方式中,在根据本发明对患者进行治疗时,给定药物的量取决于诸多因素,如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重),但是,根据特定的周围情况,包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主,施用剂量可由本领域已知的方法常规决定。通常,就成人治疗使用的剂量而言,施用剂量典型地在0.02-5000mg/天,例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量,例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是,尽管给出了上述剂量范围,但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
本发明的药物的用途
式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或药物组合物能够选择性地抑制PDGFR酪氨酸激酶(野生型或各种突变或其组合)活性,特别是PDGFRα活性。式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或其药物组合物可用于治疗、预防或改善一种或多种由PDGFR(特别是PDGFRα)活性调节的或者受其影响的或者其中涉及PDGFR(特别是PDGFRα)活性的疾病、障碍或病症,例如选自下组的疾病:实体瘤(包括良性或者恶性类型)、肉瘤、胃肠道间质瘤(Gastrointestinal StromalTumors,GIST)、结直肠癌(colon cancer)、急性粒细胞白血病(Acute MyeloblasticLeukemia,AML)、慢性髓性白血病(Chronic Myelogenous Leukemia,CML)、瘤形成、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合症、慢性嗜酸性粒细胞白血病、纤维变性、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、睾丸上皮内瘤形成、黑色素瘤、乳腺癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、以及其他增生性或增殖性疾病或类似疾病、或其组合。特别优选治疗胃肠道间质瘤(Gastrointestinal Stromal Tumors,GIST)、结直肠癌(colorectal cancer)、乳腺癌、嗜酸性粒细胞增多综合症、慢性嗜酸性粒细胞白血病、急性粒细胞白血病(AcuteMyeloblastic Leukemia,AML)、慢性髓性白血病(Chronic Myelogenous Leukemia,CML)、甲状腺癌(thyroid carcinoma)或类似疾病、或其组合。
式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药、或其药物组合物还可用于治疗、预防或改善选自下组的自身免疫性疾病:关节炎、风湿性关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、骨关节炎、斯蒂尔病(Still's disease)、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎(Hashimoto's thyroiditis)、奥德甲状腺炎(Ord's hyroiditis)、格雷夫斯病(Graves'disease)、类风湿性关节炎综合征(syndrome)、多发性硬化症、传染性神经元炎(Guillain-Barrésyndrome)、急性播散性脑脊髓炎、阿狄森病(Addison's disease)、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻(coeliac disease)、古德帕斯彻综合征(Goodpasture's syndrome)、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征(Reiter's syndrome)、高安动脉炎(Takayasu'sarteritis)、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病(Wegener'sgranulomatosis)、银屑病、全身脱毛、贝赫切特病(Behcet's disease)、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病、外阴痛或其组合。
化合物的制备
使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本文描述的方法组合,可以合成式(I)的化合物。另外,本文给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。作为进一步的指导,也可以利用以下的合成方法。
所述反应可以按顺序使用,以提供本文描述的化合物;或它们可以用于合成片段,所述片段通过本文描述的方法和/或本领域已知的方法随后加入。
在某些实施方式中,本文提供的是本文描述的酪氨酸激酶抑制剂化合物的制备方法及其使用方法。在某些实施方式中,本文描述的化合物可以使用以下合成的方案合成。可以使用与下述类似的方法,通过使用适当的可选择的起始原料,合成化合物。
用于合成本文描述的化合物的起始原料可以被合成或可以从商业来源获得。本文描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本文公开的化合物的一般方法可以来自本领域已知的反应,并且该反应可以通过由本领域技术人员所认为适当的试剂和条件修改,以引入本文提供的分子中的各种部分。
如果需要,反应产物可以使用常规技术分离和纯化,包括但不限于过滤、蒸馏、结晶、色谱等方法。这些产物可以使用常规方法表征,包括物理常数和图谱数据。
制备式(I)的化合物的合成方案的非限制性实施例参见以下合成路线。
实施例1
4-(氯甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺化
合物2的合成
将5mmol的6-甲基-N-(4-(吡啶-3-基)嘧啶-2-基)苯-1,3-二胺1(购自上海皓元化学)和7mmol三乙胺于15mL N,N-二甲基甲酰胺中冷却到零摄氏度。在搅拌状态下,分批加入5.5mmol的4-(氯甲基)苯甲酰氯(购自Alfa-Aesar)并于零摄氏度下搅拌反应2小时。反应体系用乙酸乙酯萃取,合并有机相并用无水硫酸钠干燥。旋转蒸发仪除去溶剂,粗产品用硅胶色谱柱分离得产品4-(氯甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺2。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.29(s,1H),8.98(s,1H),8.69(s,1H),8.52(s,2H),8.12(s,1H),7.99(s,2H),7.70-7.33(m,5H),7.22(s,1H),4.85(s,2H),2.24(s,3H)。LC/MS(ESI,m/z)[M+H]+:430.1369。
4-((2-(二甲氨基)乙基氨基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)
氨基)苯基)苯甲酰胺化合物3a的合成
将4mmol的4-(氯甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺2和12mmol N,N-二甲基乙二胺(购自购自Alfa-Aesar)于12mL N,N-二甲基甲酰胺中,在室温下搅拌12小时。旋转蒸发仪除去N,N-二甲基甲酰胺溶剂,残余物用硅胶色谱柱分离得产品:4-((2-(二甲氨基)乙基氨基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺3a。LC/MS(ESI,m/z)[M+H]+:482.2576。
4-((异戊基氨基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)
苯甲酰胺化合物3b的合成
化合物3b的合成采用类似于化合物3a的合成方法。1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.29(s,1H),8.98(s,1H),8.69(s,1H),8.52(s,2H),8.22-7.83(m,4H),7.61-7.44(m,5H),7.22(d,J=6.3Hz,1H),4.01(s,2H),2.74(s,2H),2.24(s,3H),1.63(s,1H),1.47(s,2H),0.88(s,6H)。LC/MS(ESI,m/z)[M+H]+:481.2616。
4-((2-(二乙氨基)乙基氨基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)
氨基)苯基)苯甲酰胺化合物3c的合成
化合物3c的合成采用类似于化合物3a的合成方法。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.28(s,1H),8.98(s,1H),8.70(s,1H),8.51(s,2H),8.10(s,1H),7.98(s,2H),7.58-7.44(m,5H),7.23(s,1H),3.95(s,2H),2.78(s,8H),2.23(s,3H),1.07(s,6H)。LC/MS(ESI,m/z)[M+H]+:510.2916。
N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)4-(((2-(吡咯烷-1-基)乙
基)氨基)甲基)苯甲酰胺化合物3d的合成
化合物3d的合成采用类似于化合物3a的合成方法。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.29(s,1H),8.98(s,1H),8.69(s,1H),8.52(s,2H),8.11(s,1H),7.97(s,2H),7.72-7.31(m,5H),7.22(s,1H),3.93(s,2H),2.86(s,8H),2.24(s,3H),1.83(s,4H).LC/MS(ESI,m/z)[M+H]+:508.2716.
4-(((2-羟乙基)氨基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯
基)苯甲酰胺化合物3e的合成
化合物3e的合成采用类似于化合物3a的合成方法。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.29(s,1H),8.98(s,1H),8.69(s,1H),8.52(s,2H),8.11(s,1H),7.95(s,2H),7.52-7.43(m,5H),7.22(s,1H),4.69(s,1H),3.91(s,2H),3.54(s,2H),2.69(s,2H),2.24(s,3H)。LC/MS(ESI,m/z)[M+H]+:455.2126。
4-((N-(2-(二甲氨基)乙基)丙烯酰胺基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)
嘧啶-2-基)氨基)苯基)苯甲酰胺化合物4a的合成
将0.05mmol 4-((2-(二甲氨基)乙基氨基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺3a溶解于0.5mL N,N-二甲基甲酰胺中,用冰水浴冷却至零摄氏度。将0.06mmol丙烯酰氯(购自Alfa-Aesar)加入反应体系,然后0摄氏度搅拌2h。用乙酸乙酯萃取,无水硫酸钠干燥,旋转蒸发仪除去溶剂,粗产品用硅胶色谱柱分离(展开剂:甲醇:二氯甲烷=1:10)得产品4-((N-(2-(二甲氨基)乙基)丙烯酰胺基)甲基)-N-(4-甲基-3-((4-(吡啶-3-基)嘧啶-2-基)氨基)苯基)苯甲酰胺4a。1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.27(s,1H),9.00(s,1H),8.68(d,J=3.3Hz,1H),8.14-7.85(m,3H),7.54-7.29(m,5H),7.20(d,J=8.3Hz,1H),6.73(dd,J=16.5,10.3Hz,1H),6.23(dd,J=16.8,10.6Hz,1H),5.80-5.70(m,1H),4.83(s,1H),4.67(s,1H),3.67(s,2H),3.14(s,2H),2.69(s,6H),2.22(s,3H)。LC/MS(ESI,m/z)[M+H]+:536.2683。
化合物4b-4r的合成采用类似于化合物4a的合成方法。
表1.本发明的示例性化合物及其表征数据
实施例2
新型激酶抑制剂对癌细胞生长的影响
通过测试本发明的化合物4i作为抑制剂对癌细胞增殖的影响,我们对本发明的化合物在癌细胞增殖抑制试验中的活性和选择性进行了评估,并以伊马替尼(购自上海皓元化学科技有限公司)作为参照。
本实施例选用了慢性髓性白血病细胞K562(表达P210BCR/ABL1突变型基因)、人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)、人肺癌细胞NCI-H1703(表达PDGFRα)及小鼠原B细胞BaF3(均购自ATCC,美国)。
此外,本实施例还选用了小鼠Tel-cKit-BaF3(稳定表达野生型cKit激酶)、小鼠Tel-PDGFRα-BaF3(稳定表达PDGFRα激酶)、小鼠Tel-PDGFRβ-BaF3(稳定表达PDGFRβ激酶)、小鼠Tel-VEGFR2-BaF3(稳定表达VEGFR2激酶)。上述细胞株均由本实验室构建,构建方法为:经PCR分别扩增人类cKIT、PDGFRα、PDGFRβ、VEGFR2激酶区序列,并分别插入到带有N端TEL片段和/或者NPM片段和/或者TPR片段的MSCV-Puro载体(购自Clontech),通过逆转录病毒方法,稳定转入小鼠BaF3细胞,并且撤除IL-3生长因子,最终得到依赖cKIT、PDGFRα、PDGFRβ、VEGFR2转入蛋白的细胞系。
在实施例中将不同浓度(0.000508μM、0.00152μM、0.00457μM、0.0137μM、0.0411μM、0.123μM、0.370μM、1.11μM、3.33μM、10μM)的化合物4a-4r及对照化合物伊马替尼分别加入到上述细胞中,并孵育72小时,通过CCK-8细胞活力检测试剂盒(购自贝博生物公司,中国上海)(CCK-8可被活细胞中的脱氢酶还原为具有高度水溶性的黄色甲瓒产物,生成的甲瓒物数量与活细胞的数量成正比)对孵育后的细胞进行检测,通过酶标仪对活细胞的数目进行定量,并计算化合物和各个对照化合物的GI50(结果示于表2,表3)。
结果显示,在同样的实验中,对照化合物伊马替尼除了表现出对分别表达PDGFRα和PDGFRβ的小鼠Tel-PDGFRα-BaF3和小鼠Tel-PDGFRβ-BaF3细胞的抑制作用(GI50分别为0.034μM和0.019μM)外,还对表达KIT激酶的BaF3细胞的增殖具有显著的抑制作用(GI50为0.412μM),并且对表达P210BCR/ABL1突变型基因的K562细胞的增殖也具有显著的抑制作用(GI50为0.267μM),这表明在考察针对靶标KIT、ABL、PDGFRα和PDGFRβ的抑制作用时,作为对照的伊马替尼并未表现出期望的选择性。
相比之下,表2示出的本发明化合物对小鼠Tel-cKit-BaF3和慢性髓性白血病细胞K562并未表现出明显的抑制作用,例如4a和4i的GI50均大于10,几乎没有抑制作用,而表2的所有化合物对小鼠Tel-PDGFRα-BaF3和小鼠Tel-PDGFRβ-BaF3细胞均具有显著的抑制作用,这表明本发明的化合物对这四种细胞表现出差异性的抑制作用,具有期望的PDGFR选择性。
从表2还可以看出,化合物4a对小鼠Tel-PDGFRα-BaF3和小鼠Tel-PDGFRβ-BaF3这两种细胞表现出差异性的抑制作用,具体来说,其强烈抑制表达PDGFRα的BaF3细胞系(GI50为0.011μM),而对表达PDGFRβ的BaF3细胞系作用相对较弱(GI50为0.35μM)。其它化合物4b-4r也表现出了同样的趋势,例如化合物4i表现出更明显的选择性,其对表达PDGFRα的BaF3细胞系的作用很强,GI50为0.034μM,而对表达PDGFRβ的BaF3细胞系几乎没有任何作用,GI50为2.9μM。这样的比较说明,相较于对照化合物伊马替尼,在针对靶标PDGFRα和PDGFRβ的抑制作用方面,本发明的化合物进一步选择性地抑制PDGFRα激酶,而对PDGFRβ激酶的抑制作用相对较弱(在下表中,同一化合物针对两种细胞的GI50值至少相差2.4倍)。
此外,对于表达PDGFR基因的EOL-1和NCI-H1703细胞中,本发明的化合物4i都能够明显抑制EOL-1的增殖,与伊马替尼表现出的效果相当。在PDGF AA刺激之后,PDGFR的信号通路被激活,化合物4i对NCI-H1703的增殖有一定的抑制,而伊马替尼能够明显抑制NCI-H1703细胞增殖,这与伊马替尼是一个多靶点抑制剂相关。
表2.不同的抑制剂对癌细胞生长的影响(结果示为GI50值,单位为μM)
表3.伊马替尼和化合物4i对EOL-1、NCI-H1703细胞生长的影响(结果示为GI50值,
单位为μM)
化合物/细胞系 | EOL-1 | NCI-H1703 | NCI-H1703+PDGF AA |
伊马替尼 | <0.001 | >10 | 0.58 |
4i | <0.001 | >10 | 2.2 |
实施例3
化合物4i、对照伊马替尼对细胞信号通路的影响
在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)、人肺癌细胞NCI-H1703(表达PDGFRα)两株细胞上进行测试,对化合物4i和对照化合物伊马替尼(购自上海皓元化学科技有限公司)对于细胞中蛋白激酶、融合蛋白以及与这些蛋白密切相关的其他蛋白激酶PDGFRα、Stat3、Stat5、AKT、ErK等蛋白磷酸化的影响进行评估。
使用不同浓度0μM、1nM、3nM、10nM、30nM、100nM、300nM的化合物4i以及100nM的对照化合物伊马替尼,处理人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)细胞2小时;人肺癌细胞NCI-H1703细胞首先用血小板衍生生长因子PDGF-AA(购自R&D Systems ChinaCo.Ltd.)刺激人肺癌细胞NCI-H1703细胞10分钟,激活PDGFRα信号通路,然后使用不同浓度0μM、0.3μM、1μM、3μM、10μM的化合物4i、对照化合物伊马替尼1μM处理人肺癌细胞NCI-H1703细胞2小时;收集样品。测定化合物4i、以及对照化合物伊马替尼对细胞中的PDGFRα、Stat3、Stat5、AKT、ErK等蛋白磷酸化的影响。结果示于图1a-1b。
结果表明,在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)及人肺癌细胞NCI-H1703(表达PDGFRα)细胞中,化合物4i的浓度分别为10nM和1μM时就能够明显地抑制PDGFRα蛋白的磷酸化,而且对细胞中关键信号通路中的Stat3、Stat5、ErK等蛋白磷酸化也有非常明显的抑制作用。在该实验中,对照化合物伊马替尼也表现出相似的磷酸化抑制作用。
这样的结果说明,化合物4i与伊马替尼都对相关的信号通路发挥作用,并且它们可能都通过抑制致癌蛋白的磷酸化来影响携带致癌蛋白的人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)和人肺癌细胞NCI-H1703(表达PDGFRα)细胞增殖。
实施例4
化合物4i和伊马替尼各自对细胞凋亡的影响
为了研究用药以后细胞的死亡是通过凋亡还是坏死,在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)、人肺癌细胞NCI-H1703(表达PDGFRα)中,检测了化合物4i对与细胞凋亡密切相关的DNA修复酶聚腺苷二磷酸-核糖聚合酶PARP、含半胱氨酸的天冬氨酸蛋白水解酶Caspase 3蛋白剪切的影响。用不同浓度0nM、3nM、10nM、30nM、100nM的化合物4i和30nM的对照化合物伊马替尼处理人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)然后分别在24小时后收集细胞(结果见图2a)。
在人肺癌细胞NCI-H1703(表达PDGFRα)上检测凋亡时,用两组不同浓度0μM、0.3μM、1μM、3μM、10μM化合物4i和1μM的对照化合物伊马替尼给药,实验进行两组,其中一组饥饿处理并加血小板衍生生长因子PDGF AA刺激72小时,同时在72小时后收样(结果见图2c);另外一组未加血小板衍生生长因子PDGF AA进行刺激,也在72小时后收样(结果见图2b)。用Western Blot检测不同浓度的药对DNA修复酶聚腺苷二磷酸-核糖聚合酶PARP和含半胱氨酸的天冬氨酸蛋白水解酶Caspase 3的剪切蛋白的影响。
结果表明,对于人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)细胞,化合物4i在3nM用药24小时后就能够明显引起DNA修复酶聚腺苷二磷酸-核糖聚合酶PARP和含半胱氨酸的天冬氨酸蛋白水解酶Caspase 3的剪切。对于人肺癌细胞NCI-H1703(表达PDGFRα),在没有加血小板衍生生长因子PDGF AA刺激的情况下给药72小时没有观测到DNA修复酶聚腺苷二磷酸-核糖聚合酶PARP和含半胱氨酸的天冬氨酸蛋白水解酶Caspase 3的剪切,在加血小板衍生生长因子PDGF AA刺激的情况下给药72小时,3μM能够观测到DNA修复酶聚腺苷二磷酸-核糖聚合酶PARP和含半胱氨酸的天冬氨酸蛋白水解酶Caspase 3的剪切。这些结果表明,化合物4i对细胞的抑制是通过细胞凋亡作用而非是细胞坏死引起的。
实施例5
化合物4a、4i和伊马替尼各自对细胞周期的影响
为了研究用药后细胞被阻止在哪个生长周期,在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)、人肺癌细胞NCI-H1703(表达PDGFRα)中,对化合物4a、化合物4i、伊马替尼(购自上海皓元化学科技有限公司)对这些细胞株的细胞周期分布的影响进行测试。
考虑到相对于NCI-H1703细胞,EOL-1细胞对已知PDGFR抑制剂的作用比较敏感,用两组不同系列浓度的化合物4a、4i(具体浓度如图3a-3d所示)以及0.3或3μM的对照化合物伊马替尼分别处理人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)、人肺癌细胞NCI-H1703(表达PDGFRα),然后分别在12小时、24小时后收集细胞,用1×PBS缓冲液洗涤两次,将其用75%的乙醇于-20℃固定24小时,用1×PBS缓冲液再洗涤两次,加0.5mL 1×PBS缓冲液和0.5mL的PI染色液(购自美国BD Bioscience)到细胞中并将细胞放置于黑暗避光37℃染色15分钟,用流式细胞仪(BD FACS Calibur)检测细胞周期分布。结果参见图3a-3d。
结果显示,在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)细胞中作用12小时、及人肺癌细胞NCI-H1703(表达PDGFRα)细胞中作用24小时后,化合物4a和化合4i对这两株细胞的细胞周期有明显的影响,均使得这两种细胞的细胞周期均显著地被阻止在G0-G1期。
实施例6
化合物4i的体外抑制活性(酶活)检测
在体外酶活实验中测定化合物4i对蛋白激酶的IC50值。取购买的PDGFRα、PDGFRβ、cKIT、FLT3蛋白激酶各9μL,6ng/μL,(购自Promega,美国)分别与三倍梯度稀释的化合物4i各1μL室温反应4小时(药物终浓度为10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM);
加入2μL ATP和3μL底物Poly(4:1Glu,Tyr)Peptide(Promega,美国)(终浓度分别为10μM和0.2μg/μL),37℃反应1小时;
取5μL反应后的激酶溶液,加入5μL ADP-GloTM(Promega,美国)试剂于室温反应40min,以终止激酶反应并消耗完剩余的ATP;
加入10μL激酶检测试剂将ADP转化成ATP,使用偶联的萤光素酶/萤光素反应检测新合成的ATP,利用Envision读数后作图,计算IC50值。
实验结果如图4a和4b所示:本发明的化合物4i对PDGFRα蛋白激酶的磷酸化具有强烈抑制作用,其IC50值为147nM,对PDGFRβ的抑制作用相对较弱,而对cKIT和FLT3蛋白激酶的磷酸化几乎没有抑制作用。该结果说明本发明的化合物4i是PDGFR选择性抑制剂,并且特别是PDGFRα选择性激酶抑制剂。
实施例7
化合物4i在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)小鼠模型中的实
验结果
1.从上海斯莱克实验动物有限责任公司购买饲养4-6周龄的Balb/c雌性小鼠,饲养于SPF级实验室中,饮水及垫料均经高压消毒无菌处理,有关小鼠的所有操作均在无菌条件下进行;
2.第0天分别在所有小鼠左侧背部皮下注入约5×106个人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)(购自ATCC);
3.从第15天开始,每天向对应小鼠腹腔给药甲基纤维素溶媒(6只小鼠);剂量为25mg/kg鼠重的化合物4i(6只小鼠);剂量为50mg/kg鼠重的化合物4i(6只小鼠);剂量为100mg/kg鼠重的化合物4i(7只小鼠);
4.第15天开始,每天用游标卡尺测量皮下肿瘤的长/宽,并每天记录小鼠体重,确定化合物4i对小鼠体重的影响;
5.第29天,用二氧化碳处死小鼠,取出皮下肿瘤,将肿瘤称重比较;
6.将肿瘤样品组织制备出蛋白裂解液样品待用;
7.统计15-29天内皮下肿瘤生长趋势,肿瘤体积计算方法:长×宽×宽/2mm3。
实验结果如图5a-5d所示,在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)的小鼠肿瘤模型中,在用药后,用药剂量为25mg/kg的化合物4i已经表现出一定的抑制小鼠肿瘤的效果,且随着用药剂量及用药天数的增加,化合物4i对小鼠肿瘤的抑制作用愈发显著。对于化合物4i的用药剂量为25mg/kg的小组,在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)小鼠模型中用药后第29天(即图5b中横坐标“14”处)抑瘤率[tumor growthinhibition rate:TGI=(对照组肿瘤的重量-实验组肿瘤的重量)/对照组肿瘤的重量]达到71.5%(见图5d);这说明本发的化合物4i在人慢性嗜酸性粒细胞白血病细胞EOL-1(表达PDGFRα)动物模型中能够明显移植肿瘤的生长。
另外,结合图5a-5d的结果,说明化合物4i不仅有效地抑制小鼠肿瘤的生长,并且对小鼠的体重基本没有影响,表明化合物4i可适用于动物给药。
Claims (11)
1.一种式(I)的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药:
其中,
R1选自氨基、C1-8烷基、C3-8环烷基、C2-8烯基、C1-8烷基氨基C1-8烷基、任选被1-3个R3基团取代的芳基、和任选被1-3个R3基团取代的杂芳基;
R2选自氢、氨基、C1-8烷基、C1-8烷基氨基、羟基、和任选被1-3个R3基团取代的杂环基;
R3独立地选自C1-8烷基、C1-8烷氧基、卤素、氨基、硝基、羟基、和氰基。
2.如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中R1选自C1-6烷基、C3-6环烷基、C2-6烯基、C1-4烷基氨基C1-4烷基、任选被1-3个R3基团取代的苯基、和任选被1-3个R3基团取代的杂芳基,其中R3独立地选自C1-6烷基。
3.如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中R2选自C1-6烷基、C1-4烷基氨基、羟基、和杂环基。
4.如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中R1为乙烯基、丙烯基、乙基、正丙基、异丙基、叔丁基、环丙基、N,N-二甲氨基甲基、苯基、对甲基苯基、吡啶基、异噁唑基、或噻吩基。
5.如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其中R2为N,N-二甲基氨基、N,N-二乙基氨基、四氢吡咯基、羟基、或异丙基。
6.如权利要求1所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药,其选自以下化合物:
7.如权利要求1-6中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备用于抑制PDGFR活性的药物中的用途。
8.如权利要求1-6中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备用于抑制PDGFRα活性的药物中的用途。
9.如权利要求1-6中任一项所述的化合物或其药学可接受的盐、溶剂化物、酯、酸、代谢物或前药在制备用于治疗、预防或改善由PDGFR活性调节的或者受其影响的或者其中涉及PDGFR活性的疾病、障碍或病症的药物中的用途。
10.如权利要求9所述的用途,其中所述疾病、障碍或病症选自以下增殖性疾病:实体瘤、肉瘤、胃肠道间质瘤、结直肠癌、急性粒细胞白血病、慢性髓性白血病、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合症、慢性嗜酸性粒细胞白血病、纤维变性、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、睾丸上皮内瘤形成、黑色素瘤、乳腺癌、神经母细胞瘤、乳头状/滤泡型甲状腺癌、恶性淋巴瘤、非霍奇金淋巴瘤、2型多发性内分泌瘤形成、嗜铬细胞瘤、甲状腺癌、甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成或其组合。
11.如权利要求9所述的用途,其中所述疾病、障碍或病症选自以下自身免疫性疾病:关节炎、风湿性关节炎、骨关节炎、狼疮、类风湿性关节炎、炎性肠病、银屑病性关节炎、斯蒂尔病、青少年关节炎、糖尿病、重症肌无力症、桥本甲状腺炎、奥德甲状腺炎、格雷夫斯病、类风湿性关节炎综合征、多发性硬化症、传染性神经元炎、急性播散性脑脊髓炎、阿狄森病、视性眼阵孪-肌阵孪综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻、古德帕斯彻综合征、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、莱特尔综合征、高安动脉炎、颞动脉炎、温型自身免疫性溶血性贫血、韦格纳肉芽肿病、银屑病、全身脱毛、贝赫切特病、慢性疲劳、家族性自主神经功能异常、子宫内膜异位、间质性膀胱炎、神经肌强直、硬皮病、外阴痛或其组合。
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