CN106188045A - 作为wnt信号传导抑制剂的化合物、组合物及其应用 - Google Patents
作为wnt信号传导抑制剂的化合物、组合物及其应用 Download PDFInfo
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- CN106188045A CN106188045A CN201610534447.6A CN201610534447A CN106188045A CN 106188045 A CN106188045 A CN 106188045A CN 201610534447 A CN201610534447 A CN 201610534447A CN 106188045 A CN106188045 A CN 106188045A
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Abstract
本发明涉及一种作为WNT信号传导通路的抑制剂的具有通式(I)的结构的化合物以及包含所述化合物的组合物。进一步而言,本发明涉及所述化合物在抑制WNT信号传导通路方面的应用以及抑制WNT信号传导通路的方法。
Description
本申请为2014年12月10日进入中国国家阶段、申请号为201280073873.4、申请日为2012年6月15日、发明名称为“作为WNT信号传导抑制剂的化合物、组合物及其应用”的发明专利申请的分案申请。
技术领域
本发明涉及一种作为WNT信号传导通路的抑制剂的化合物以及包含该化合物的组合物。进一步而言,本发明涉及所述化合物在抑制WNT信号传导通路中的应用以及抑制WNT信号传导通路的方法。
背景技术
WNT信号传导对成体动物的胚胎发育和成体稳态具有至关重要的作用。WNT通路总体上由调节下列三个过程的蛋白质网络构成:1、WNT蛋白的产生和分泌;2、WNT蛋白与细胞受体的结合;3、细胞内传导由相互作用触发的生物化学反应(Mikels和Nusse,2006;MacDonald,2009;Moon,2005)。
通过WNT蛋白与细胞表面共受体卷曲蛋白(Frizzled)LRP5/6的结合而触发的经典WNT通路导致到达细胞核的β-链蛋白的量发生改变,在细胞核中,β-链蛋白和TCF/LEF家族转录因子发生相互作用,从而促进特定基因的转录。
由一系列不同的细胞内蛋白传导的非经典WNT通路控制昆虫体内平面细胞极性以及诸如脊椎动物体内原肠胚形成之类的若干种过程。
本领域已知WNT信号传导在控制胚胎干细胞和成体干细胞的多能性和分化方面发挥作用(Nusse,2008)。举例来说,在原肠胚形成的过程中,原条的形成与类胚体内局部WNT活化有关(ten Berge,2008)。从胚胎干细胞或iPS细胞中衍生诸如心脏细胞、胰腺β细胞,多巴胺神经元和肝细胞之类的多种类型的细胞都受到WNT调控的影响(Yang,2008;D’Amour,2006;Inestrosa和Arenas,2010;Sullivan,2010)。WNT通路在诸如骨形成和软骨形成之类的骨骼组织的发育中发挥非常重要的作用(Hoeppner,2009;Chun,2008)。WNT信号传导还与成体中枢神经系统的神经元再生有关(Lie,2005)。
WNT通路活性的改变可引发许多疾病。例如,经典WNT通路的超活化可导致异常细胞生长(Reya和Clevers,2005)。最值得关注的是,90%的结肠直肠癌是由腺瘤性结肠息肉(APC)基因的缺失引起的,所述腺瘤性结肠息肉(APC)是WNT/β-链蛋白通路的抑制因子(Kinzler和Vogelstein,1996)。WNT蛋白的高表达和通常抑制WNT蛋白功能的细胞外抑制因子的缺失可引发WNT-依赖性肿瘤(Polakis,2007)。另一方面,非经典WNT通路也表现出在一些癌症的发展过程中发挥作用(Camilli和Weeraratna,2010)。最新的研究成果也显示WNT信号传导还涉及癌症干细胞(Takahashi-Yanaga和Kahn,2010)。
有证据显示靶向Wnt-介导的信号传导通路在对很多种疾病的治疗中是有用的(Barker和Clevers,2006)。导致经典Wnt通路发生组成性活化的APC、β-链蛋白或者轴蛋白-1的突变是多种人类癌症中的至关重要的事件,所述人类癌症包括结肠直肠癌、黑色素瘤、肝细胞癌、胃癌、卵巢癌和其他癌症(Polakis,2007)。使用遗传学方法或化学方法阻断多种癌症中的Wnt通路已表现出限制异常细胞生长(Herbst和Kolligs,2007)。更进一步,抑制这条通路可直接影响如下细胞:所述细胞维持癌细胞生长且使癌细胞转移,并且所述细胞被认为对传统化疗剂具有耐受性。
除了受体下游的基因产物的突变而引起的Wnt通路的活化之外,由其它机制引起的异常Wnt通路活性也与许多癌症有关。这些癌症包括但不限于:肺(小细胞和非小细胞)癌、乳腺癌、前列腺癌、类癌、膀胱癌、上皮恶性肿瘤、食道癌、卵巢癌、子宫颈癌、子宫内膜癌、间皮瘤、黑色素瘤、肉瘤、骨肉瘤、脂肪肉瘤、甲状腺癌、硬纤维瘤、急性粒细胞白血病(AML)、慢性粒细胞白血病(CML)。本领域已有多种依赖于上调的自分泌或者旁分泌的Wnt信号传导的癌细胞实例,并且来自骨肉瘤、乳腺癌、头颈癌和卵巢癌的细胞系已表现出通过自分泌或者旁分泌的Wnt信号传导防止上述细胞系受细胞凋亡的影响(Kansara,2009;Bafico,2004;Akiri,2009;DeAlmeida,2007;Chan,2007;Chen,2009;和Rhee,2002)。
更进一步,异常Wnt通路涉及纤维化的发生,所述纤维化包括但不限于:肺纤维化(例如,特发性肺纤维化和放射诱导的纤维化)、肾脏纤维化和肝纤维化(Morrisey,2003;Hwang,2009;Cheng,2008)。
与异常WNT信号传导相关的其它疾病包括但不限于:骨和软骨疾病(例如,骨质疏松症和骨关节炎);与二型糖尿病相关的肥胖症;神经退行性疾病(例如阿尔兹海默症)(Hoeppner,2009;Ouchi,2010;Blom,2010和Boonen,2009)。WNT信号传导还有助于HSC的自我更新和维持,并且WNT信号传导的功能障碍会导致由HSC引发的各种疾病(如白血病)和多种其它血液相关癌症(Reya,2005)。
因此,调控WNT-依赖性细胞反应的方法和化合物的发现提供了一条用于调节与通路的异常活性相关的生理功能的途径并且为与通路的异常活性相关的疾病提供了治疗方法。
发明内容
总体而言,本发明提供一种用作WNT信号传导抑制剂的化合物及其药物组合物,以及所述化合物在抑制WNT信号传导通路方面的应用。
释义
本文使用的“WNT信号传导通路”或者“WNT通路”是指WNT蛋白和细胞受体的结合导致细胞行为改变的通路。WNT通路涉及多种蛋白,包括卷曲蛋白、蓬乱蛋白(Disheveled)、轴蛋白(Axin)、APC、GSK3β、β-链蛋白、LEF/TCF转录因子,以及与WNT蛋白的合成和分泌相关的分子。功能性WNT的分泌所涉及的蛋白质的实例包括但不限于:wntless/evennessinterrupted(Wls/Evi)、porcupine(Porcn)、Vps35p。Wls/Evi是一种具有七次跨膜结构的蛋白,其主要集中在高尔基体中并且是Wg(果蝇)、MOM-2(线虫)和Wnt3A分泌所必需的。它包含保守结构基序,该基序的结构和功能目前还处于未知的状态。Porcupine(Porcn)是棕榈酰转移酶的膜结合O-酰基转移酶(MBOAT)家族的一员。Wnt的脂肪酸修饰对于Wnt的功能非常重要。Wnt在一个或者两个高度保守位点上进行棕榈酰化。因此,Porcn的抑制剂可以阻断所有功能性Wnt信号传导。Vps35p是被称作retromer复合物的多蛋白复合物的亚基,这个蛋白复合物涉及细胞内蛋白的运输。Vps35p在结合像WNT这样的目标蛋白以将其招募进入囊泡方面发挥作用。
“WNT通路抑制剂”或者“WNT信号传导抑制剂”是一种有机小分子,分子量一般为约800g/mol或小于约800g/mol,其抑制WNT信号传导的活性。
术语“抑制WNT通路的方法”是指抑制与功能性WNT蛋白的产生有关的或与WNT蛋白的细胞反应有关的已知的生物化学事件的方法。正如本文中所提到的,根据该定义,有机小分子可抑制WNT反应。
“WNT蛋白”是一种与卷曲蛋白和LRP5/6共受体结合以活化经典或者非经典WNT信号传导的蛋白。WNT蛋白的具体实例包括:WNT-1(NM005430)、WNT-2(NM003391)、WNT-2B/WNT-13(NM004185)、WNT-3(NM030753)、WNT3a(NM033131)、WNT-4(NM030761)、WNT-5A(NM003392)、WNT-5B(NM032642)、WNT-6(NM006522)、WNT-7A(NM004625)、WNT-7B(NM058238)、WNT-8A(NM058244)、WNT-8B(NM003393)、WNT-9A/WNT-14(NM003395)、WNT-9B/WNT-15(NM003396)、WNT-10A(NM025216)、WNT-10B(NM003394)、WNT-11(NM004626)、WNT-16(NM016087)。
“WNT通路疾病”是指产生异常WNT信号传导的病症或者疾病状态。一方面,异常WNT信号传导是指在怀疑患有疾病的细胞或者组织中超出正常细胞或组织中的WNT信号传导水平的WNT信号传导水平。在一特定方面,WNT介导的疾病包含癌症或纤维化。
术语“癌症”是指特征为不受控制的细胞增殖的人体内病理状态。实例包括但不限于:癌、淋巴瘤、母细胞瘤和白血病。癌症更具体的实例包括但不限于:肺(小细胞和非小细胞)癌、乳腺癌、前列腺癌、类癌、膀胱癌、胃癌、胰腺癌、肝(肝细胞)癌、肝母细胞瘤、结直肠癌、头颈鳞状上皮细胞癌、食道癌、卵巢癌、子宫颈癌、子宫内膜癌、间皮瘤、黑色素瘤、肉瘤、骨肉瘤、脂肪肉瘤、甲状腺癌、硬纤维瘤、急性粒细胞白血病(AML)和慢性粒细胞白血病(CML)。
术语“纤维化”指通常特征为成纤维细胞的不受控增殖和组织硬化的人体内病理状态。特定实例包括但不限于:肺纤维化(特发性肺纤维化和放射诱导的纤维化)、肾脏纤维化、肝纤维化(包括肝硬化)。
“抑制”,“治疗”或者“治疗方法”是指缓解方法、治疗方法和预防或防治方法,其中,所述缓解方法、治疗方法和预防或防治方法的目的是缓解或者预防目标病理疾病或状况。在一个实例中,在给药WNT信号传导抑制剂之后,癌症患者可表现出肿瘤尺寸减小。“治疗”或者“治疗方法”包括:(1)抑制患有或表现出疾病的病理学或症状的受治者体内的疾病;(2)缓解患有或表现出疾病的病理学或症状的受治者体内的疾病;和/或(3)使患有或表现出疾病的病理学或症状的受治者或患者体内的疾病产生任何可测量的降低。WNT通路抑制剂可在一定程度上防止癌细胞生长和/或者杀死癌细胞,所述WNT通路抑制剂可以是抑制细胞生长的和/或细胞毒性的。
术语“治疗有效量”是指有效“治疗”受治者或哺乳动物体内的WNT通路疾病的WNT通路抑制剂的量。在癌症治疗中,治疗有效量的药物可以降低癌细胞的数量,减小肿瘤尺寸,抑制癌细胞渗透进入周围器官,抑制肿瘤转移,抑制肿瘤生长至一定程度,和/或在一定程度上缓解与癌症有关的症状中的一种或多于一种症状。
与一种其他治疗剂或多于一种其他治疗剂“联合”给药包括同步(同时)给药和以任何顺序连续给药。如本文使用的术语“药物组合”是指混合或者组合活性成分而获得的产品,并且“药物组合”包括活性成分的固定组合和非固定组合。术语“固定组合”是指以单一实体的形式或单一剂型的形式将活性成分(例如通式(1)的化合物)和联合药剂同时给药于患者。术语“非固定组合”是指以作为分开的实体将活性成分(如通式(1)的化合物)和联合药剂同步、同时或顺序给药于患者而无特定时间限制,其中这种给药方式可以在患者体内提供治疗有效水平的活性成分。第二种给药方式也被应用于鸡尾酒式治疗,例如给药三种或者多于三种活性成分。
“化疗剂”是在治疗癌症中有用的化学化合物。实例包括但不限于:吉西他滨、伊立替康、阿霉素、5-氟尿嘧啶、阿糖胞苷("Ara-C")、环磷酰胺(Cyclophosphamide)、三胺硫磷、白消安、细胞毒素(Cytoxin)、紫杉醇、氨甲喋呤、顺铂、美法仑、长春碱和卡铂。
具体实施方式
一方面,本发明提供一种作为WNT信号传导抑制剂的具有下述通式(I)的结构的化合物或其生理学上可接受的盐:
其中,
X1、X2、X3、X4、X5、X6、X7和X8独立地为CR4或N;
Y1为氢或—C(R4)3,每个R4相同或不同;
Y2和Y3独立地为氢、卤素或—C(R3)3,每个R3相同或不同;
R1和R2独立地选自:氢、卤素、C1-6烷基、喹啉基、C6-30芳基、含有1-2个选自N、O和S的杂原子的3-6元杂环烷基,以及含有1-4个选自N、O和S的杂原子的5或6元杂芳基;其中,喹啉基、C6-30芳基、3-6元杂环烷基以及5或6元杂芳基中的每一个可被1或2个相同或不同的R4任选地取代;
R3分别独立地选自:氢、卤素、氰基、C1-6烷基和C1-6烷氧基,其中,C1-6烷基和C1-6烷氧基中的每一个可被卤素、氨基、羟基、C1-6烷氧基或氰基任选地取代;
R4分别独立地选自:氢、卤素、氰基、C1-6烷氧基、-S(O)2R5、-C(O)OR5、-C(O)R5、-C(O)NR6R7、C1-6烷基、C2-6烯基和C2-6炔基,其中,C1-6烷氧基、-S(O)2R5、-C(O)OR5、-C(O)R5、-C(O)NR6R7、C1-6烷基、C2-6烯基和C2-6炔基中的每一个可被卤素、氨基、羟基、C1-6烷氧基或氰基任选地取代;
R5、R6和R7独立地选自:氢、C1-6烷基、C2-6烯基和C2-6炔基,其中,C1-6烷基、C2-6烯基和C2-6炔基中的每一个可被卤素、氨基、羟基、C1-6烷氧基或氰基任选地取代。
具体而言,通式(I)具有下述核心结构,但不限于此:
在通式(I)中,X1、X2、X3和X4所定义的环可以是下列基团中的任何一个,但不限于此:
优选地,通式I中的R1和R2可独立地选自:氢、氟、氯、甲基、苯基、吗啉基、哌嗪基和5或6元杂芳基,所述5或6元杂芳基选自下列基团:
优选地,R4可以相同或不同,并且分别独立地选自:氢、氟、氯、氰基、-CH3、-CHF2、-CF3、-OCH3、-COOCH3。
在一种实施方式中,通式I中的至少一个原子是选自2H、3H、11C、13C、14C、15N、17O、18O、35S、18F、36Cl和123I中的对应同位素中的至少一种。
如本文使用的,例如,任何取代基(例如,CH2)中的H原子包括所有合适的同位素变换形式,例如H、2H和3H。
如本文所使用的,例如,任何取代基中的其他原子包括所有合适的同位素变换形式,包括但不限于:11C、13C、14C、15N、17O、18O、35S、18F、36Cl和/或123I。
在优选的实施方式中,本发明的化合物的实例包括但不限于下列化合物或其生理学上可接受的盐:
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-苯基喹唑啉-4-胺;
N-((5-(2-甲基吡啶-4-基)吡啶-2-基)甲基)-7-苯基喹唑啉-4-胺;
N-(4-吗啉基苯甲基)-7-苯基喹唑啉-4-胺;
N-((6-吗啉基吡啶-3-基)甲基)-7-苯基喹唑啉-4-胺;
N-((6-(2-甲基吗啉基)吡啶-3-基)甲基)-7-苯基喹唑啉-4-胺;
N-((6-(4-甲基哌嗪-1-基)-吡啶-3-基)甲基)-7-苯基喹唑啉-4-胺;
4-(5-(((7-苯基喹唑啉-4-基)氨基)甲基)吡啶-2-基)硫代吗啉1,1-二氧化物;
N-((6-(6-甲基吡啶-3-基)吡啶-3-基)甲基)-7-苯基喹唑啉-4-胺;
N-((6-(5-甲基吡啶-3-基)吡啶-3-基)甲基)-7-苯基喹唑啉-4-胺;
7-苯基-N-((6-(吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-苯基-N-((6-(吡啶-3-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-苯基-N-((6-(吡啶-2-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-苯基-N-((6-(哒嗪-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-苯基-N-((6-(吡嗪-2-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-苯基-N-((6-(嘧啶-5-基)吡啶-3-基)甲基)喹唑啉-4-胺;
N-((6-(2-氟代吡啶-4-基)吡啶-3-基)甲基)-7-苯基喹唑啉-4-胺;
N-((6-(4-甲基-1H-咪唑-1-基)吡啶-3-基)甲基)-7-苯基喹唑啉-4-胺;
N-((6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)甲基)-7-苯基喹唑啉-4-胺;
N-((5-(6-甲基吡啶-3-基)吡啶-2-基)甲基)-7-苯基喹唑啉-4-胺;
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-苯基喹唑啉-4-胺;
N-(4-(2-氟代吡啶-4-基)苯甲基)-7-苯基喹唑啉-4-胺;
N-苯甲基-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(4-甲基苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(4-甲氧基苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(4-氟代苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(4-氯代苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(4-溴代苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(4-(三氟代甲基)苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
4-((7-(2-甲基吡啶-4-基)喹唑啉-4-基氨基)甲基)苯甲腈;
N-(4-吗啉基苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(4-苯基苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(3-氟代-4-苯基苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(4-(3-氟代苯基)苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
7-(3-氟代苯基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-(3-氯代苯基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-m-甲苯基喹唑啉-4-胺;
3-(4-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基氨基)喹唑啉-7-基)苯甲腈;
4-(4-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基氨基)喹唑啉-7-基)苯甲腈;
7-(2-甲基吡啶-4-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-(6-甲基吡啶-3-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-(5-甲基吡啶-3-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-(吡啶-2-基)喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-(吡啶-3-基)喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-(吡啶-4-基)喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-(哒嗪-4-基)喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-(吡嗪-2-基)喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-(嘧啶-5-基)喹唑啉-4-胺;
7-(2-氟代吡啶-4-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-(2-(三氟代甲基)吡啶-4-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-(2-甲氧基吡啶-4-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-(3-甲基吡啶-4-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-吗啉基喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-(哌啶-1-基)喹唑啉-4-胺;
7-(4-甲基哌嗪-1-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
1-(4-(4-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基氨基)喹唑啉-7-基)哌嗪-1-基)乙酮;
4-(4-(((2’-甲基-[2,4’-联吡啶]-5-基)甲基)氨基)喹唑啉-7-基)硫代吗啉1,1-二氧化物;
7-(1,2,3,6-四氢吡啶-4-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-(1,2,3,6-四氢吡啶-4-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
1-(4-(4-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基氨基)喹唑啉-7-基)哌啶-1-基)乙酮;
N-((2’-甲基-[2,4’-联吡啶]-5-基)甲基)-7-(4-(甲基磺酰基)哌嗪-1-基)喹唑啉-4-胺;
7-(1-甲基-1H-吡唑-4-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
7-(异恶唑-4-基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)喹唑啉-4-胺;
N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)-7-(噻唑-2-基)喹唑啉-4-胺;
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(3-氟代-4-(2-甲基吡啶-4-基)苯甲基)-7-(2-甲基吡啶-4-基)喹唑啉-4-胺;
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-(吡嗪-2-基)喹唑啉-4-胺;
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-(2-氟代吡啶-4-基)喹唑啉-4-胺;
N-(4-(2-甲基吡啶-4-基)苯甲基)-7-吗啉基喹唑啉-4-胺;
2-(3-氟代苯基)-N-(4-(2-甲基吡啶-4-基)苯甲基)吡啶并[3,4-b]吡嗪-5-胺;
2-(3-氟代苯基)-N-((2’-甲基-[2,4’-联吡啶]-5-基)甲基)吡啶并[3,4-b]吡嗪-5-胺;
2-(3-氟代苯基)-N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)吡啶并[3,4-b]吡嗪-5-胺;
N-(3-氟代-4-(2-甲基吡啶-4-基)苯甲基)-2-(3-氟代苯基)吡啶并[3,4-b]吡嗪-5-胺;
2-(2-甲基吡啶-4-基)-N-(4-(2-甲基吡啶-4-基)苯甲基)吡啶并[3,4-b]吡嗪-5-胺;
N-((2’-甲基-[2,4’-联吡啶]-5-基)甲基)-2-(2-甲基吡啶-4-基)吡啶并[3,4-b]吡嗪-5-胺;
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-2-(2-甲基吡啶-4-基)吡啶并[3,4-b]吡嗪-5-胺;
N-(3-氟代-4-(2-甲基吡啶-4-基)苯甲基)-2-(2-甲基吡啶-4-基)吡啶并[3,4-b]吡嗪-5-胺;
N-((2’,3-二甲基-[2,4’-联吡啶]-5-基)甲基)-6-(吡嗪-2-基)-2,7-萘啶-1-胺;
6-(2-甲基吗啉基)-N-(4-(2-甲基吡啶-4-基)苯甲基)-2,7-萘啶-1-胺;
(S)-6-(2-甲基吗啉基)-N-(4-(2-甲基吡啶-4-基)苯甲基)-2,7-萘啶-1-胺;
(R)-6-(2-甲基吗啉基)-N-(4-(2-甲基吡啶-4-基)苯甲基)-2,7-萘啶-1-胺;
1-(4-(8-((4-(2-甲基吡啶-4-基)苯甲基)氨基)-2,7-萘啶-3-基)哌嗪-1-基)乙酮;
6-(1H-咪唑-1-基)-N-(4-(2-甲基吡啶-4-基)苯甲基)-2,7-萘啶-1-胺;
6-(4-甲基-1H-咪唑-1-基)-N-(4-(2-甲基吡啶-4-基)苯甲基)-2,7-萘啶-1-胺;
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-(1H-四唑-5-基)-2,7-萘啶-1-胺;
6-(5-甲基-1,3,4-恶二唑-2-基)-N-(4-(2-甲基吡啶-4-基)苯甲基)-2,7-萘啶-1-胺;
6-(1-甲基-1H-吡唑-3-基)-N-(4-(2-甲基吡啶-4-基)苯甲基)-2,7-萘啶-1-胺;
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-(噻唑-5-基)-2,7-萘啶-1-胺;
N-(4-(2-甲基吡啶-4-基)苯甲基)-6-(恶唑-5-基)-2,7-萘啶-1-胺;
N-((2’,3-二甲基-[2,4’-联吡啶]-5-基)甲基)-6-(5-甲基吡啶-3-基)-2,7-萘啶-1-胺;
N-((2’,3-二甲基-[2,4’-联吡啶]-5-基)甲基)-6-(2-甲基吡啶-4-基)-2,7-萘啶-1-胺;
N-((3-氟代-2’-甲基-[2,4’-联吡啶]-5-基)甲基)-6-(2-甲基吡啶-4-基)-2,7-萘啶-1-胺;
N-((2’,3-二甲基-[2,4’-联吡啶]-5-基)甲基)-6-(5-氟代吡啶-3-基)-2,7-萘啶-1-胺;
N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-(吡嗪-2-基)-2,7-萘啶-1-胺;
N-(3-氟代-4-(2-甲基吡啶-4-基)苯甲基)-6-(吡嗪-2-基)-2,7-萘啶-1-胺;
4-(8-((4-(2-甲基吡啶-4-基)苯甲基)氨基)-2,7-萘啶-3-基)哌嗪-1-羧酸甲酯;
4-(8-((4-(2-甲基吡啶-4-基)苯甲基)氨基)-2,7-萘啶-3-基)哌嗪-2-酮;
2-(4-(8-((4-(2-甲基吡啶-4-基)苯甲基)氨基)-2,7-萘啶-3-基)哌嗪-1-基)乙腈;
2-甲基-4-(4-(((6-(2-甲基吡啶-4-基)-2,7-萘啶-1-基)氨基)甲基)苯基)吡啶-1-氧化物;
6-(2-氯代吡啶-4-基)-N-((2’,3-二甲基-[2,4’-联吡啶]-5-基)甲基)-2,7-萘啶-1-胺;
6-(2-氯代吡啶-4-基)-N-(4-(2-甲基吡啶-4-基)苯甲基)-2,7-萘啶-1-胺;
2’-甲基-4-(((6-(2-甲基吡啶-4-基)-2,7-萘啶-1-基)氨基)甲基)-2H-[1,4’-联吡啶]-2-酮;
2-(2-甲基吡啶-4-基)-5-(((6-(2-甲基吡啶-4-基)-2,7-萘啶-1-基)氨基)甲基)苯甲腈;
N-(3-甲氧基-4-(2-甲基吡啶-4-基)苯甲基)-6-(2-甲基吡啶-4-基)-2,7-萘啶-1-胺;
N-((3-氯代-2’-甲基-[2,4’-联吡啶]-5-基)甲基)-6-(2-甲基吡啶-4-基)-2,7-萘啶-1-胺;
N-(4-(2-(二氟代甲基)吡啶-4-基)苯甲基)-6-(2-甲基吡啶-4-基)-2,7-萘啶-1-胺。
另一方面,本发明提供一种药物组合物,所述药物组合物包括本发明的化合物并且所述药物组合物通常包括至少一种药学上可接受的载体或稀释剂,其中,所述化合物是游离形式或药学上可接受的盐的形式。这样的组合物可以是口服组合物、可注射组合物或栓剂。并且,所述组合物可以常规方式通过混合、造粒或包被方法制造。
在本发明的实施方式中,所述组合物是口服组合物,其可以是片剂或明胶胶囊。优选地,所述口服组合物含有本发明的化合物以及a)稀释剂,例如,乳糖、葡萄糖、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、硬脂酸、硬脂酸的镁盐或钙盐和/或聚乙二醇;对于片剂来说,所述口服组合物包括c)粘合剂,例如,硅酸镁铝盐、淀粉糊、明胶、tragamayth、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;并且需要时,还可以包括d)崩解剂,例如,淀粉、琼脂、褐藻酸或其钠盐,或泡腾混合物;和/或e)添加剂,例如,吸收剂、着色剂、调味剂和增甜剂。
在本发明的另一实施方式中,所述组合物是可注射组合物,其可以为水性等渗溶液或悬浮液。
在本发明的再一实施方式中,所述组合物是栓剂,可由脂肪乳液或悬浮液制备而成。
优选地,所述组合物是无菌的和/或包含辅料。所述辅料可以是防腐剂、稳定剂、润湿剂或乳化剂、溶液促进剂、用于调节渗透压的盐、缓冲剂和/或它们的任意组合。
可选地或另外地,所述组合物还可以包含其它治疗上有价值的物质以用于不同的应用中,例如,增溶剂、稳定剂、吸收增强剂、缓冲剂和/或防腐剂。
在本发明的实施方式中,所述组合物可以是适用于经皮施用的制剂。这种制剂包括有效量的本发明的化合物和载体。优选地,所述载体可以包括帮助通过宿主皮肤的可吸收的药学上可接受的溶剂。还可以使用包含所述制剂的经皮设备。所述经皮设备可以是绷带形式,所述绷带形式包含支撑件、含有所述化合物的储库、任选地以可控且预定的速率在一段较长的时间段内将所述化合物递送至宿主皮肤的控速屏障以及将所述设备固定至皮肤的工具,所述储库任选地包含载体。此外,还可以使用骨架经皮制剂。
在本发明的另一实施方式中,所述组合物可以是适于局部施用(例如,施用于皮肤和眼睛)的制剂,并且,所述组合物可以是本领域众所周知的水性溶液、软膏剂、霜剂或凝胶。
另一方面,本发明提供一种通过使细胞接触有效量的上述化合物或其生理学上可接受的盐或者上述药物组合物抑制WNT从细胞中分泌的方法。
再一方面,本发明提供一种通过有效量的上述化合物或其生理学上可接受的盐或者上述药物组合物抑制细胞中WNT信号传导的方法。在一种实施方式中,所述细胞包含在哺乳动物体内,并且给药的量是治疗有效量。在另一实施方式中,WNT信号传导的抑制会进一步导致细胞生长的抑制。在进一步的实施方式中,所述细胞是癌细胞。在又一实施方式中,所述细胞为纤维化细胞。
细胞增殖的检测使用在本领域技术人员熟知的方法。例如,检测细胞增殖的一个方便的方法是CellTiter-GloTM检测,由Promega(Madison,WI)公司销售提供。该检测的步骤包括:将试剂加入到多孔板培养的细胞中。由光度计或成像设备测量的发光信号与存在的ATP数量成比例,而存在的ATP数量与培养物中的活细胞数量正好成比例。另外,细胞增殖还可使用本领域已知的集落形成试验来检测。
本发明还提供一种用有效量的本发明的化合物治疗与WNT信号传导通路相关的癌症或纤维化症的方法。本领域技术人员可易于通过使用本领域已知的多种技术中的一种分析癌细胞来确定癌症是否与Wnt通路相关。例如,本领域技术人员可以使用免疫和核酸检测方法检测癌细胞中与Wnt信号传导相关的蛋白或mRNA水平的异常。
与Wnt通路相关的癌症或纤维化症包括:其中Wnt信号传导通路中一个或者多于一个组分的活性相对于基本水平被上调的癌症或纤维化症。在一种实施方式中,抑制Wnt通路可包括抑制Wnt分泌。另一种实施方式中,抑制Wnt通路可包括抑制细胞表面受体的下游组分。另一种实施方式中,抑制Wnt分泌可包括抑制功能性WNT的分泌所涉及的任何蛋白的活性。
而且,本发明提供了通过将治疗有效量的WNT抑制剂给药于受治者来治疗受治者的WNT通路疾病的方法。在一种实施方式中,所述疾病是与WNT信号传导的异常活性(例如活性提高)有关的细胞增殖性疾病。在另一实施方式中,所述疾病是由WNT蛋白的量增加引起的。在又一实施方式中,细胞增殖性疾病是癌症,包括但不限于:肺(小细胞和非小细胞)癌、乳腺癌、前列腺癌、类癌、膀胱癌、胃癌、胰腺癌、肝(肝细胞)癌、肝母细胞瘤、结直肠癌、头颈鳞状上皮细胞癌、食道癌、卵巢癌、子宫颈癌、子宫内膜癌、间皮瘤、黑色素瘤、肉瘤、骨肉瘤、脂肪肉瘤、甲状腺癌、硬纤维瘤、急性粒细胞白血病(AML)和慢性粒细胞白血病(CML)。在另一实施方式中,细胞增殖性疾病是纤维化,包括但不限于:肺纤维化(例如,特发性肺纤维化和放射引起的纤维化)、肾脏纤维化和肝纤维化(包括肝硬化)。在又一实施方式中,所述疾病是骨关节炎、帕金森病、视网膜病、黄斑变性。
对于治疗用途而言,本发明的化合物可以通过本领域公知的任何可接受的方法以治疗有效量单独给药。在本文中,治疗有效量可根据疾病的严重程度、受治者的年龄和相对健康状态、所使用的化合物的药效和其他因素而发生很大改变。通常,在每日剂量为约0.03mg/kg受治者体重至2.5mg/kg受治者体重的条件下全身给药所获得的结果显示为令人满意的结果。在一种实施方式中,诸如人类的较大的哺乳动物所需的每日剂量是约0.5mg至约100mg。优选地,所述化合物以一天多达4次的分开剂量给药或以缓释形式给药。在另一实施方式中,用于口服给药的合适的单位剂型包括约1mg至100mg活性成分。
可选地,本发明的化合物可以作为活性成分以治疗有效量与一种或多于一种治疗剂联合给药,如药物组合。当本发明的化合物与本领域已知的化疗剂联合使用时可以产生协同效应。联合给药的化合物的剂量可根据所使用的联合药物的类型、所使用的特定药物、正在被治疗的疾病等等而有所不同。
本发明的化合物或其组合物可以通过任意常规的途径给药。在一种实施方式中,本发明的化合物或其组合物肠内给药,例如口服给药,以及以片剂或胶囊的形式给药。在另一种实施方式中,本发明的化合物或其组合物肠胃外给药,以及以可注射的溶液或悬浮液的形式给药。在另一种实施方式中,本发明的化合物或其组合物局部给药以及以乳液、凝胶、软膏剂或霜剂的形式给药,或以鼻用形式或栓剂形式给药。
另一方面,本发明还提供了药物组合,优选试剂盒,其包括a)第一药剂,所述第一药剂是本文公开的游离形式的本发明的化合物或本发明的化合物的药学上可接受的盐的形式,以及b)至少一种联合药剂。此外,所述试剂盒可以包括其给药的说明书。
本发明的组合可以体外使用或体内使用。优选地,理想的给药治疗效果可通过使细胞、组织或生物体接触单独的组合物或包含本发明的化合物和一种或多于一种药剂的药物制剂来实现,或者通过使细胞接触两种或多于两种不同的组合物或制剂来实现,其中,一种组合物包括一种药剂,另一组合物包括另一药剂。组合的药剂可同时给药或在一段时间段内分开给药。优选地,分开给药可产生理想的治疗效果。本发明的化合物可以通过数分钟至数周的间隔在另一药剂之前、与所述另一种试剂同时和/或在所述另一种试剂之后给药。本领域技术人员通常可确保每次递送的时间间隔,其中,分开给药的药剂仍然能够对所述细胞、组织或生物体产生有利的结合效果。在一种实施方式中,本领域技术人员会考虑到可使细胞、组织或生物体基本同时(即少于约一分钟)接触作为备选物质的两种、三种、四种或更多种形态。在另一种实施方式中,一种或多于一种药剂可以在约1分钟至14天内给药。
另一方面,本发明提供本发明的化合物或其生理学上可接受的盐或者本发明的药物组合物在制备用于治疗上述WNT通路介导的疾病的药物中的应用。
另一方面,本发明提供一种制备本发明的化合物或其盐或衍生物的方法。
在一种实施方式中,通式(I)的化合物可根据下述实施例中描述的合成方法中的任何一种制备。在所描述的反应中,当期望反应性官能团(例如,羟基、氨基、亚氨基、硫代基或羧基)存在于最终产物中时,这些基团可被保护以避免它们不必要地参加反应。常规的保护基团可根据标准实践方法使用(参见例如T.W.Greene和P.G.M.Wuts,《有机化学中的保护基团》(Protecting Groups in Organic Chemistry),John Wiley和Sons,1991)。在所描述的合成方法中使用的合适的离去基团包括卤素离去基团以及其他本领域已知的常规离去基团。优选地,所述离去基团是氯或溴。
在另一实施方式中,本发明的化合物或其盐也可以水合物的形式获得,或者它们的晶体可以包括例如用于结晶的溶剂(以溶剂化物存在)。通常,盐可以通过用合适的碱性试剂处理,优选地用碱金属碳酸盐、碱金属碳酸氢盐或碱金属氢氧化物处理,更加优选地用碳酸钾或氢氧化钠处理而转化成游离形式的化合物。碱加成盐形式的本发明化合物可通过用诸如盐酸之类的合适的酸处理而转化成相应的游离酸。鉴于游离形式的新化合物及其盐(包括可用作中间体的那些盐)形式之间的紧密关系,例如在新化合物的纯化和鉴定过程中,任何提及游离化合物的内容可被适当地理解为也提及了其对应的盐。
带有成盐基团的本发明的化合物的盐可以采用本领域公知的方式制备。因此,通式(I)的化合物的酸加成盐可通过用酸或合适的阴离子交换剂处理获得。本发明的化合物的药学上可接受的盐可以通过使用有机酸或无机酸由带有碱性氮原子的通式(I)的化合物形成为酸加成盐。
优选地,合适的无机酸包括但不限于:氢卤酸(例如盐酸),硫酸或磷酸。
优选地,合适的有机酸包括但不限于:羧酸,磷酸,磺酸或氨基磺酸,例如乙酸,丙酸,辛酸,癸酸,十二烷酸,乙醇酸,乳酸,富马酸,琥珀酸,己二酸,庚二酸,辛二酸,壬二酸,苹果酸,酒石酸,柠檬酸,氨基酸,例如谷氨酸或天冬氨酸,马来酸,羟基马来酸,甲基马来酸,环己烷羧酸,金刚烷羧酸,苯甲酸,水杨酸,4-氨基水杨酸,酞酸,苯基乙酸,扁桃酸,肉桂酸,甲烷-或乙烷-磺酸,2-羟基乙烷磺酸,乙烷-1,2-二磺酸,苯磺酸,2-萘磺酸,1,5-萘-二磺酸,2-、3-或4-甲基苯磺酸,甲基硫酸,乙基硫酸,十二烷基硫酸,N-环己基氨基磺酸,N-甲基-、N-乙基-或N-丙基-氨基磺酸,或其他有机质子酸,例如抗坏血酸。
可选地,为了分离和纯化的目的,也可以使用药学上不可接受的盐,例如苦味酸盐或高氯酸盐。但是,为了治疗使用的目的,在应用于药物制剂形式中时,仅采用药学上可接受的盐或游离化合物。
在另一实施方式中,非氧化形式的本发明的化合物可通过在合适的惰性有机溶剂中、在0-80℃下,使用还原剂处理,由本发明的化合物的N-氧化物来制备。优选地,所述还原剂是硫、二氧化硫、三苯基膦、硼氢化锂、硼氢化钠、三氯化磷、三溴化磷或类似物。优选地,所述惰性有机溶剂是乙腈、乙醇、水性二氧六环或类似物。
在另一实施方式中,本发明的化合物的前药衍生物可通过本领域公知的方法来制备(详细描述请参见Saulnier等人(1994),生物有机和药物化学快报(Bioorganic andMedicinal Chemistry Letters),第4卷,第1985页)。在优选的实施方式中,合适的前药可通过非衍生的本发明化合物与合适的氨基甲酰化剂(例如1,1-酰氧基烷基氯碳酸酯(1,1-acyloxyalkylcarbanochloridate),对硝基苯基碳酸酯,或类似物)的反应来制备。
在又一实施方式中,被保护的本发明的化合物的衍生物可通过本领域已知的方式制备。对适用于生成保护基团以及除去保护基团的技术的详细描述可在T.W.Greene的《有机化学中的保护基团》中(第三版,John Wiley和Sons有限公司,1999)中找到。
在另一实施方式中,本发明的化合物可以被制备成其独立的立体异构体。制备过程包括:使化合物的外消旋混合物与光学活性拆分剂反应以生成一对非对映异构体化合物,分离所述非对映异构体并回收光学纯对映异构体。对映异构体的拆分可使用本发明的化合物的共价非对映异构体的衍生物进行,或者通过使用可分离的复合物(例如结晶的非对映的盐)来进行。非对映异构体具有不同的物理性能,表现在熔点、沸点、溶解度、反应活性等方面,并且非对映异构体可易于通过利用这些不同点来分离。非对映异构体可以通过分馏结晶、色谱法或者通过基于溶解度不同的分离/拆分技术来分离。然后光学纯的对映异构体与拆分试剂一起通过不会导致外消旋的任何实践方法回收。应用于从外消旋混合物中拆分化合物的立体异构体的技术的更加详细的描述披露于Jean Jacques,Andre Collet,Samuel H.Wilen,《对映体、外消旋物和离析》(“Enantiomers,Racemates andResolutions”)John Wiley和Sons有限公司,1981。
综上所述,本发明的化合物可以通过实施例中所描述的方法制备;并且
任选地,本发明的化合物可转化为药学上可接受的盐;
任选地,本发明的化合物的非氧化形式可转化为药学上可接受的N-氧化物;
任选地,异构体混合物可拆分出本发明的化合物的独立的异构体;以及
任选地,非衍生的本发明化合物可转化为药学上可接受的前药衍生物。
在没有特别描述起始原料的制备过程的情况下,化合物是已知的或者可以采用与本领域的公知方法类似的方法制备或者采用如下文的实施例中所披露的方法制备。本领域技术人员可以理解上述转变实例仅仅是制备本发明化合物的方法的代表,并且同样可以使用其它众所周知的方法。
实施例
通过下文以及详细描述本发明化合物的制备的实施例进一步举例说明本发明,但本发明并不受限于此。
缩写 定义或释义
DCM 二氯甲烷
DIEA N,N’-二异丙基乙胺
DMF N,N-二甲基甲酰胺
eq. 当量
TEA 三乙胺
THF 四氢呋喃
RT 室温
EA 乙酸乙酯
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
s-Phos 2-二环己基膦基-2',6'-二甲氧基联苯
Pd(PPh3)4 四(三苯基膦)钯
实施例1:N-(4-(2-甲基吡啶-4-基)苯甲基)-6-(2-甲基吡啶-4-基)-2,7-萘啶-1-胺(化合物1)
步骤1:
将2-氰基乙酰胺(50g,601.8mmol)和乙酰乙酸乙酯(75mL,601.8mmol)溶解于MeOH中。将KOH(37.0g,1.1eq)溶解于MeOH中,并且逐滴地添加至混合物中,出现一些白色固体。在油浴中将所述混合物加热回流8h,然后冷却至室温。过滤固体并且随后重新溶解在热水中,然后再次过滤。在滤液中加入6N HCl中和直至pH<7。白色固体再次出现并将其过滤。进一步用MeOH、水和MeOH洗涤所述固体,然后通过真空干燥,得到最终产物3-乙炔基-4-甲基吡啶-2,6-二醇(产率~41%)
步骤2:
将3-乙炔基-4-甲基吡啶-2,6-二醇(28.0g,195.2mmol)溶解于POCl3(60.0mL)中。将反应混合物密封在压力管中并且加热至180℃持续6h。在反应冷却至室温后,在真空下除去过量的POCl3。缓慢地将碎冰添加至混合物中,然后出现固体。将固体过滤并在真空下干燥,得到最终产物2,6-二氯-4-甲基吡啶-3-甲腈(产率~92%),无需进一步纯化。
步骤3
在200mL的2,6-二氯-4-甲基吡啶-3-甲腈(20.0g,107.5mmol)的异丙醇溶液中添加N,N-二甲基甲酰胺二甲基缩醛(12.82g,107.5mmol),并且在65℃搅拌反应持续18h。在反应冷却至RT后,通过过滤收集沉淀物并用50mL异丙醇洗涤,风干,获得产物2,6-二氯-4-((E)-2-(二甲基氨基)乙烯基)吡啶-3-甲腈(产率~26%),无需进一步纯化。
步骤4:
将2,6-二氯-4-((E)-2-(二甲基氨基)乙烯基)吡啶-3-甲腈(4.0g,16.6mmol)以及20mL浓HCl添加至密封管中。在45℃搅拌反应持续18h。在反应冷却至RT后,将冰水添加至溶液中,形成深黄色的浆状物。通过过滤收集沉淀物并用冷水、乙醚和乙酸乙酯洗涤,然后在真空下干燥,获得淡黄色的固体6,8-二氯-2,7-萘啶-1(2H)-酮(产率~80%)。MS m/z215.0(M+1)。1HNMR(300MHz,DMSO-d6):δ11.75(s,1H),7.76(s,1H),7.50(t,J=6.6Hz,1H),6.52(d,J=6.6Hz,1H)。
步骤5:
将6,8-二氯-2,7-萘啶-1(2H)-酮(3.0g,13.96mmol)溶解于iPrOH(120mL)中形成一种悬浮液。在冰浴中将溶液冷却至0℃,然后逐滴地添加联氨溶液(5.6g,80%,10eq)。在RT下搅拌混合物15分钟,然后在55℃的油浴中加热过夜。在反应混合物冷却至RT后,过滤,直接得到固体,然后用70mL MeOH洗涤所述固体并在真空下干燥。产物6-氯-8-肼基-2,7-萘啶-1(2H)-酮(产率~98%)直接用于下一步骤反应中,无需进一步纯化。
步骤6:
将6-氯-8-肼基-2,7-萘啶-1(2H)-酮(1.50g,7.12mmol)溶解于MeCN(90mL)中以生成一种悬浮液。添加1N NaOH(17.80mL,2.5eq),然后将等量的水(107.80mL)添加至混合物中。在50℃下加热并搅拌反应混合物直至所述混合物变为澄清的溶液。将所述溶液再次冷却至0℃,并且逐滴地添加NaOCl(11.05g,12%溶液,2.5eq),然后在室温下搅拌反应过夜。在反应完成后,将所述溶液冷却至0℃,然后加入1N HCl中和(pH~6)。收集沉淀物并且用100mL x 2EA萃取滤液。将有机层合并并且通过Na2SO4干燥,蒸发,获得额外的粗产物。合并的固体物质6-氯-2,7-萘啶-1(2H)-酮(产率~93%)用于下一反应中,无需进一步纯化。MSm/z 181.1(M+1)。
步骤7:
在压力管中将6-氯-2,7-萘啶-1(2H)-酮(400mg,2.2mmol)添加至POCl3(20.0mL)中。将反应混合物加热至160℃持续4h,得到澄清的溶液。将所述溶液冷却至室温并倒入DCM中,然后缓慢地添加碎冰。将饱和的NaHCO3添加至混合物中以中和反应中产生的HCl。在真空下除去DCM并且用100mL x 2EA萃取剩下的水溶液。用盐水洗涤一次合并的有机层,然后用Na2SO4干燥,然后在真空下蒸发,获得固体1,6-二氯-2,7-萘啶(产率~73%)用于下一步骤反应,无需进一步纯化。MS m/z 199.0(M+1)。
步骤8:
将(4-溴苯基)甲胺(1.00g,5.37mmol)和2-甲基吡啶-4-基-4-硼酸(883.30mg,6.45mmol)溶解于BuOH(10.0mL)和水(2.0mL)中。在N2下添加K3PO4(2.28g,10.75mmol),Pd2(dba)3(120.20mg,0.27mmol)和S-phos(220.70mg,0.54mmol)。将反应混合物密封在压力管中并且加热至125℃持续1h。在反应冷却至RT后,将所述混合物倒入水中并且用100mL x3EA萃取。用盐水洗涤合并的有机层,Na2SO4干燥并在真空下浓缩,获得粗产物。通过硅胶柱用含10%MeOH(包含~2N NH3)的DCM纯化固体,获得纯(4-(2-甲基吡啶-4-基)苯基)甲胺(产率~89%)。MS m/z 199.1(M+1)。
步骤9:
将1,6-二氯-2,7-萘啶(160mg,0.80mmol)和(4-(2-甲基吡啶-4-基)苯基)甲胺(239.10mg,1.21mmol)溶解于BuOH(5.0mL)中,然后加热至115℃过夜。在反应冷却至RT后,在真空下除去有机溶剂。通过硅胶快速色谱法用EA/己烷(1:1)纯化粗产物,获得固体N-(4-(2-甲基吡啶-4-基)苯甲基)-6-氯-2,7-萘啶-1-胺(产率~90%)。MS m/z 361.1(M+1)。
步骤10:
将N-(4-(2-甲基吡啶-4-基)苯甲基)-6-氯-2,7-萘啶-1-胺(50.00mg,0.14mmol)和2-甲基吡啶-4-基-4-硼酸(56.90mg,0.42mmol)溶解于BuOH(3.0mL)和水(0.6mL)中。在N2下将K3PO4(88.20mg,0.028mmol)、Pd2(dba)3(6.20mg,0.014mmol)和S-phos(11.40mg,0.011mmol)添加至混合物中。将反应混合物密封在压力管中,然后加热至105℃过夜。在反应冷却至RT后,将所述混合物倒入水中并用EA萃取三次。用盐水洗涤合并的有机层,用Na2SO4干燥并且在真空下浓缩。通过预-TLC法用含5%MeOH的DCM进一步纯化粗产物,从而获得最终产物N-(4-(2-甲基吡啶-4-基)苯甲基)-6-(2-甲基吡啶-4-基)-2,7-萘啶-1-胺(产率~70%)。MS m/z 418.2(M+1)。1HNMR(300MHz,CDCl3):δ2.46(s,3H),2.63(s,3H),4.94(d,J=5.10Hz,2H),5.94(br,1H),6.97(d,J=5.70Hz,1H),7.31(d,J=4.20Hz,1H),7.36(s,1H),7.54(d,J=8.10Hz,2H),7.63(d,J=8.40Hz,2H),7.90(s,1H),8.19(d,J=6.00Hz,1H),8.22(s,1H),8.51(m,2H),9.08(s,1H),9.30(s,1H)。
实施例2:N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-(2-甲基吡啶-4-基)-2,7-萘啶-1-胺(化合物2)
步骤1:
将6-氯-2,7-萘啶-1(2H)-酮(200mg,1.10mmol)和2-甲基吡啶-4-基-4-硼酸(227.60mg,1.66mmol)溶解于BuOH(5.0mL)和水(1.0mL)中。在N2下加入K3PO4(705.20g,3.32mmol)、Pd2(dba)3(49.60mg,0.22mmol)和S-phos(91.00mg,0.11mmol)。将压力管中的反应混合物加热至130℃持续1h。在反应冷却至RT后,将混合物倒入水中,用EA萃取三次。用盐水洗涤合并的有机层,通过Na2SO4干燥,在真空下浓缩,获得粗产物。通过柱层析用含5%MeOH的DCM纯化所述粗产物以获得最终化合物6-(2-甲基吡啶-4-基)-2,7-萘啶-1(2H)-酮(产率~61%)。MS m/z 238.1(M+1)。
步骤2:
将6-(2-甲基吡啶-4-基)-2,7-萘啶-1(2H)-酮(150mg,0.63mmol)溶解于POCl3(15.0mL)中,密封压力管并且加热至160℃持续4h。在反应冷却至RT后,在真空下除去过量的POCl3。将碎冰缓慢地加至混合物中,然后添加NaHCO3中和直至pH~7.5。用EA萃取溶液三次,用盐水洗涤合并的有机层,Na2SO4干燥,在真空下浓缩。通过柱层析用EA/己烷(1:1)纯化粗产物,获得化合物1-氯-6-(2-甲基吡啶-4-基)-2,7-萘啶(产率~55%)。MS m/z 256.1(M+1)。
步骤3:
将1-氯-6-(2-甲基吡啶-4-基)-2,7-萘啶(10.00mg,0.039mmol)和(3-甲基-4-(2-甲基吡啶-4-基)苯基)甲胺(10.00mg,0.047mmol)溶解于甲苯(1.0mL)中。在N2下将KOtBu(8.80mg,0.078mmol)、Pd(OAc)2(0.90mg,0.0039mmol)和BINAP(4.90mg,0.0078mmol)添加至混合物中。将反应加热至100℃过夜。在所述反应冷却至RT后,将混合物倒入水中,用EA萃取三次。用盐水洗涤合并的有机层,Na2SO4干燥,然后在真空下浓缩。通过预-TLC用EA/己烷(4:1)纯化粗产物以获得N-(3-甲基-4-(2-甲基吡啶-4-基)苯甲基)-6-(2-甲基吡啶-4-基)-2,7-萘啶-1-胺(8.8mg,产率~52%)。1H NMR(300MHz,CDCl3):δ2.31(s,3H),2.63(s,3H),2.70(s,3H),4.91(d,J=5.10Hz,2H),5.88(br,1H),7.00(d,J=5.40Hz,1H),7.08(d,J=5.10Hz,1H),7.12(s,1H),7.22(d,J=7.50Hz,1H),7.36(m,2H),7.77(d,J=4.50Hz,1H),7.88(s,1H),7.98(s,1H),8.24(d,J=6.00Hz,1H),8.53(d,J=4.80Hz,1H),8.64(d,J=5.40Hz,1H),9.31(s,1H)。MS m/z432.2(M+1)。
实施例3:6-(3-氟苯基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)异喹啉-1-胺(化合物3)
步骤1:
将6-溴异喹啉(1.80g,8.66mmol)溶解于DCM(40mL)中,在反应冷却至0℃后,少量、缓慢地添加m-CPBA(2.30g,1.3eq,最多77%)。将反应升温至RT以生成一种白色悬浮液。在4个小时内,将100mLDCM添加至溶液中,然后用饱和Na2CO3溶液、水和盐水洗涤。用Na2SO4干燥分离的有机层并在真空下除去溶剂,获得不需进一步纯化的黄色固体N-氧化物6-溴异喹啉(1.82g,产率~93%)。
步骤2:
将N-氧化物6-溴异喹啉(1.82g,8.12mmol)溶解于干燥的DCM(80mL)中,在RT下逐滴添加POCl3(1.12ml,1.5eq)。将反应加热至45℃持续2小时。在反应冷却至RT后,在真空下除去DCM和过量的POCl3。将粗产物重新溶解在100mL DCM中,并用饱和Na2CO3、水和盐水洗涤。Na2SO4干燥分离的有机层,然后浓缩得到棕色固体。通过快速柱层析用含2%MeOH的DCM纯化粗产物以获得淡黄色固体6-溴-1-氯异喹啉(1.27g,产率~65%)。MS m/z 242.0(M+1)。
步骤3:
在压力管中,将(6-氯吡啶-3-基)甲胺(300mg,2.1mmol)和2-甲基吡啶-4-基硼酸(345mg,2.52mmol)溶解于正丁醇(10mL)和水(2mL)中。在氮气保护下添加K3PO4(893mg,4.2mmol)、Pd2(dba)3(96.3mg,0.105mmol)和S-phos(86.4mg,0.21mmol)。将反应加热至125℃持续30分钟,然后冷却至室温。将溶液倒入水中并用EA萃取三次。用盐水洗涤合并的有机层,并且用Na2SO4干燥,然后在真空下浓缩。通过快速色谱用含10%MeOH(含有~2N NH3)的DCM进一步纯化粗产物以获得纯的(6-(2-甲基吡啶-4-基)吡啶-3-基)甲胺(0.19g,产率~45%)。MS m/z 200.1(M+1)。
步骤4:
在密封管中将6-溴-1-氯异喹啉(100mg,0.41mmol)和(6-(2-甲基吡啶-4-基)吡啶-3-基)甲胺(165mg,0.82mmol)溶解于0.5mL正丁醇中。将反应加热至160℃持续6h,然后冷却至RT。通过快速色谱用含8%MeOH(含有~2N NH3)的DCM纯化粗产物以获得纯的6-溴-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)异喹啉-1-胺(116mg,~70%)。MS m/z 405.2(M+1)。
步骤5:
将6-溴-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)异喹啉-1-胺(20mg,0.05mmol)、3-氟苯基硼酸(10.5mg,0.075mmol)、Na2CO3(21mg,0.2mmol)和四(三苯基膦)钯(5.8mg,0.005mmol)添加至压力管中。将二氧六环/水(3:1,2mL)添加至管中,并加热至125℃持续10分钟。在反应冷却至RT后,用50mL水稀释溶液并用EA萃取3次。用Na2SO4干燥合并的有机层,并且在真空下浓缩。通过快速色谱用含10%MeOH(含有~2N NH3)的DCM进一步纯化粗产物以获得纯的6-(3-氟苯基)-N-((6-(2-甲基吡啶-4-基)吡啶-3-基)甲基)异喹啉-1-胺(15.8mg,~75%)。1H NMR(400MHz,CDCl3):δ2.71(s,3H),5.00(d,J=5.6Hz,2H),7.32-7.38(m,2H),7.59-7.65(m,1H),7.75-7.83(m,3H),8.10(d,J=8.4Hz,1H),8.21(d,J=8.8Hz,1H),8.27-8.31(m,2H),8.39(s,2H),8.72(d,J=8.8Hz,1H),8.79(d,J=6.0Hz,1H),8.91(d,J=1.6Hz,1H),10.02(s,1H)。MSm/z 421.2(M+1)。
实施例4:N-(4-(2-甲基吡啶-4-基)苯甲基)-2-(2-甲基吡啶-4-基)-1,6-萘啶-5-胺(化合物4)
步骤1:
将1,6-萘啶-5(6H)-酮(2.9g,19.84mmol)溶解于POCl3(40mL)中,然后加热至100℃持续24h。在反应冷却至室温后,在真空下除去过量的POCl3。缓慢地加入带有少量碎冰的饱和Na2CO3溶液,并且产生大量气泡和固体。过滤固体,然后将用EA萃取溶液3次。用Na2SO4干燥合并的有机层,并在真空下浓缩。在真空下进一步干燥合并的固体以获得不需进一步纯化的5-氯-1,6-萘啶(2.6g,产率~80%)。MS m/z 165.1(M+1)。
步骤2:
将5-氯-1,6-萘啶(1.5g,9.11mmol)溶解于DCM(45mL)中,然后通过冰浴冷却,少量、缓慢地添加m-CPBA(3.7g,2eq,最多77%)。将反应升温至RT并保持3小时。再将100mL的DCM添加至溶液中,然后用饱和Na2CO3溶液、水和盐水洗涤。Na2SO4干燥有机层,并且在真空下浓缩以获得不需进一步纯化的黄色固体N-氧化物5-氯-1,6-萘啶(1.25g,产率~76%)。
步骤3:
将N-氧化物5-氯-1,6-萘啶(1.2g,6.64mmol)溶解于干燥的DCM(30mL)中,加入Et3N(1.85mL,13.29mmol),然后逐滴地添加溶于5mL干燥的DCM中的POCl3(0.93mL,9.97mmol)。将反应加热至48℃持续2h。再向溶液中加入100mL的DCM,并且用饱和Na2CO3溶液、水和盐水洗涤。Na2SO4干燥有机层,并且在真空下浓缩以获得黄色固体。通过硅柱层析用EA/己烷(1:4)进一步纯化粗产物以获得白色固体2,5-二氯-1,6-萘啶(0.6g,产率~45%)。MS m/z199.0(M+1)。
步骤4:
将2,5-二氯-1,6-萘啶(200mg,1.0mmol),2-甲基吡啶-4-基-4-硼酸(137mg,1.0mmol),Na2CO3(424mg,4.0mmol)和四(三苯基膦)钯(116mg,0.1mmol)加入烧瓶中,再加入16mL二氧六环和4mL水。将反应充分搅拌并加热至90℃持续4h。在反应冷却至RT后,用100mL水稀释溶液并用EA萃取3次。Na2SO4干燥合并的有机层,并且在真空下浓缩。通过快速色谱法用EA/己烷(1:1)进一步纯化粗产物以获得固体5-氯-2-(2-甲基吡啶-4-基)-1,6-萘啶(143mg,产率~56%)。MS m/z 256.1(M+1)。
步骤5:
将5-氯-2-(2-甲基吡啶-4-基)-1,6-萘啶(20.00mg,0.078mmol)和(4-(2-甲基吡啶-4-基)苯基)甲胺(25mg,0.118mmol)溶解于甲苯(2.0mL)中。在N2下将KOtBu(13.2mg,0.118mmol)、Pd(OAc)2(2.7mg,0.012mmol)和BINAP(15.0mg,0.024mmol)添加至混合物中。将反应加热至100℃过夜。在反应冷却至RT后,将所述混合物倒入水中,用EA萃取三次。用盐水洗涤合并的有机层,Na2SO4干燥,然后在真空下浓缩。通过预-TLC用含8%甲醇的DCM纯化粗产物以获得N-(4-(2-甲基吡啶-4-基)苯甲基)-2-(2-甲基吡啶-4-基)-1,6-萘啶-5-胺(31mg,产率~61%)。1H NMR(400MHz,DMSO-d6):δ9.12(d,J=8.8Hz,1H),8.77-8.83(m,2H),8.49(d,J=8.4Hz,1H),8.40(s,1H),8.31(d,J=6.4Hz,1H),8.21(s,1H),8.11(d,J=5.6Hz,1H),8.06(d,J=6.4Hz,1H),7.99(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.23(d,J=6.4Hz,1H),5.76(s,1H),4.93(d,J=5.6Hz,2H),2.72(s,6H)。MS m/z 432.2(M+1)。
实施例5:N-(4-(2-甲基吡啶-4-基)苯甲基)-2-苯基吡啶并[4,3-b]吡嗪-5-胺(化合物5)
步骤1:
将苯基乙二醛一水合物(940mg,6.99mmol)和2-氯-3,4-二氨基吡啶(1000mg,6.99mmol)加至20mL乙醇中。使混合物回流过夜。在反应冷却后,将粗沉淀产物过滤并用15mL乙醇洗涤,然后在真空下干燥,获得不需进一步纯化的5-氯-2-苯基吡啶并[3,4-b]吡嗪(1.28g,产率~76%),MS m/z 241.0(M+1);1H NMR(300MHz,DMSO-d6):δ9.82(s,1H),8.64(d,J=6.0Hz,1H),8.38-8.43(m,2H),8.07(d,J=6.0Hz,1H),7.64-7.68(m,3H)。
步骤2:
将N-(4-(2-甲基吡啶-4-基)苯甲基)-2-苯基吡啶并[3,4-b]吡嗪-5-胺(50mg,0.21mmol)和(4-(2-甲基吡啶-4-基)苯基)甲胺(42mg,0.21mmol)溶解于甲苯(4.0mL)中。在N2下将KOtBu(24mg,0.21mmol)、Pd(OAc)2(4.5mg,0.021mmol)和BINAP(26.4mg,0.042mmol)添加至混合物中。将反应加热至100℃过夜。在反应冷却至室温后,将混合物倒入水中,用EA萃取3次。用盐水洗涤合并的有机层,Na2SO4干燥,然后在真空下浓缩。通过快速色谱法用含7%MeOH的DCM纯化粗产物,获得N-(4-(2-甲基吡啶-4-基)苯甲基)-2-苯基吡啶并[4,3-b]吡嗪-5-胺(61mg,产率~72%)。MS m/z=404.2(M+1);1H NMR(400MHz,DMSO-d6)δ9.53(s,1H),8.77(d,J=6.4Hz,1H),8.35-8.39(m,2H),8.21(s,1H),8.11(d,J=6.0Hz,1H),8.07(d,J=6.4Hz,1H),7.96(d,J=8.4Hz,2H),7.60-7.65(m,5H),7.14(d,J=6.0Hz,1H),5.76(s,1H),4.90(d,J=6.4Hz,2H),2.71(s,3H)。
本领域技术人员可清楚地理解和知晓其他化合物可通过与实施例1-5相同的方案制备。
化合物列表:
实验例6:WNT通路报告基因分析
材料和方法:
用包含由5拷贝TCF元件驱动的荧光素酶基因的质粒转染小鼠成纤维细胞NIH3T3(美国典型培养物保藏中心,马纳萨斯,弗吉尼亚州)。由1μg/mL博来霉素(Gibco/Invitrogen,Carlsbad,加拿大)筛选得到的稳定细胞在37℃、气体氛围中含有5%CO2的条件下,在补充有10%FBS(Invitrogen),50单位/mL青霉素,50μg/mL链霉素(Invitrogen)的Dulbecco's改良的Eagle's培养基(DMEM,Invitrogen,Carlsbad,加拿大)中培养。用含有由CMV启动子驱动的人的全长WNT-3a cDNA序列的质粒转染悬浮的HEK293细胞(ATCC)。在补充有100ug/mL G418的FreeStyle 293培养基(Invitrogen)中筛选稳定细胞。
NIH3T3TCF-Luc细胞和293WNT3a细胞在带有补充了0.5%FBS的DMEM培养基的96孔板中共同培养。16小时后,在Steady-GloTM荧光素酶检测系统(Promega)中检测萤火虫荧光素酶的活性。在共同培养过程中,用不同浓度的本发明的化合物处理细胞。IC50被定义为使发光强度降低50%的化合物浓度。为了标准化细胞的数量和活性,随后重复两次CellTiterGlo检测。
在WNT信号通路报告基因分析中,本发明中的所有化合物的IC50值都小于5微摩尔(IC50<5μM)。所选择的化合物实例列于下表:
实验例7:WNT通路抑制剂的机理研究
对在初步分析中,抑制由共同培养的Wnt-3a细胞诱导的TCF报告基因活性的化合物随后进行了机理研究以确定化合物的作用点。评价了两个不同的活化剂,一个通过纯化的Wnt-3a重组蛋白(StemRD Inc.,Burlingame,CA)进行评价,另一个通过GSK-3b的抑制剂6-溴靛红-3'-肟(StemRD Inc.,Burlingame,CA)进行评价。
该机理研究的结果显示本发明的一些活性化合物在WNT-3a与受体发生相互作用之前的点抑制WNT通路的活化,而不会抑制重组WNT-3a蛋白活化TCF报告基因。这种作用的候选物包括但不限于:wntless/evenness interrupted(Wls/Evi)、porcupine(Porcn)、Vps35p。
实验例5:WNT通路抑制剂对癌细胞的作用
抑制Wnt分泌和细胞内信号传导的化合物预计会抑制依赖于自分泌Wnt信号传导的癌细胞的增殖。Wnt通路抑制剂对在2-D培养基中的细胞增殖的作用锚定已知的需要Wnt自分泌信号传导的细胞系中的独立生长和抗凋亡性。通过对目前已发表的著作中提到的Wnt依赖性细胞系的标准分析来评价化合物,这些Wnt依赖性细胞系包括:PA-1(卵巢畸胎癌)、MDA-MB-157(乳腺癌)、Saos-2(骨肉瘤)、SNU1076(头颈鳞状上皮癌)。在这些细胞系中观察到的抑制剂的作用进一步确认所预期的这些化合物的活性。
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Claims (15)
1.一种作为WNT信号传导抑制剂的化合物或其生理学上可接受的盐,所述化合物具有下述通式I的结构:
其中,
由X5,X6,X7和X8定义的通式I的核心结构选自:
Y1、Y2和Y3独立地为氢;
由X1、X2、X3和X4定义的通式I中的环选自:
R1独立地选自:氢、卤素、C1-6烷基、喹啉基、C6-30芳基、含有1-2个选自N、O和S的杂原子的3-6元杂环烷基和含有1-4个选自N、O和S的杂原子的5或6元杂芳基;其中,喹啉基、C6-30芳基、3-6元杂环烷基、5或6元杂芳基中的每一个可被1或2个相同或不同的R4任选地取代;所述5或6元杂芳基选自:
R2独立地选自:氢、卤素、C1-6烷基、喹啉基、C6-30芳基、含有1-4个选自N、O和S的杂原子的5或6元杂芳基;其中,喹啉基、C6-30芳基、5或6元杂芳基中的每一个可被1或2个相同或不同的R4任选地取代;所述5或6元杂芳基选自:
R4分别独立地选自:氢、卤素、氰基、C1-6烷氧基、-C(O)OR5、-C(O)R5、C1-6烷基,其中,C1-6烷氧基、-C(O)OR5、-C(O)R5、C1-6烷基中的每一个可以被卤素、氨基、羟基、C1-6烷氧基或氰基任选地取代;
R5独立地选自:氢和C1-6烷基。
2.如权利要求1所述的化合物,其中,R1独立地选自:氢、氟、氯、甲基、苯基、吗啉基、哌嗪基和含有1-4个选自N和S的杂原子的5或6元杂芳基;并且所述5或6元杂芳基选自:
R2独立地选自:氢、氟、氯、甲基、苯基、吗啉基和哌嗪基和含有1-4个N和O的杂原子的6元杂芳基,并且所述6元杂芳基选自:
R4分别独立地选自:氢、氟、氯、氰基、-CH3、-CHF2、-CF3、-OCH3、-COOCH3。
3.一种药物组合物,其包含上述权利要求1或2所述的化合物或其生理学上可接受的盐。
4.如权利要求3所述的药物组合物,其是口服组合物、可注射组合物或栓剂。
5.如权利要求4所述的药物组合物,其中,所述口服组合物是片剂或明胶胶囊;所述可注射组合物是水性等渗溶液或悬浮液;所述栓剂由脂肪乳液或悬浮液制备而成。
6.如权利要求3所述的药物组合物,其还包含稀释剂、润滑剂、粘合剂、崩解剂和添加剂中的至少一种,
所述稀释剂选自:乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素和甘氨酸;
所述润滑剂选自:二氧化硅、滑石、硬脂酸、硬脂酸的镁盐和钙盐和聚乙二醇;
所述粘合剂选自:硅酸镁铝盐、淀粉糊、明胶、tragamayth、甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮;
所述崩解剂选自:淀粉、琼脂、褐藻酸及其钠盐以及泡腾混合物;
所述添加剂选自:吸收剂、着色剂、调味剂和增甜剂。
7.如权利要求3所述的药物组合物,其进一步含有至少一种辅料,所述辅料选自:防腐剂、稳定剂、润湿剂、乳化剂、溶液促进剂、用于调节渗透压的盐和缓冲剂。
8.如权利要求7所述的药物组合物,其进一步包含增溶剂、稳定剂、张力增强剂、缓冲剂和防腐剂。
9.如权利要求8所述的药物组合物,其中,所述药物组合物局部施用并且是水性溶液、软膏剂、霜剂或凝胶的形式。
10.权利要求1或2所述的化合物或其生理学上可接受的盐以及权利要求3至9中任一项所述的药物组合物在制备用于抑制从细胞中分泌WNT的药物中的应用。
11.权利要求1或2所述的化合物或其生理学上可接受的盐以及权利要求3至9中任一项所述的药物组合物在制备用于抑制细胞中WNT信号传导的药物中的应用。
12.权利要求1或2所述的化合物或其生理学上可接受的盐以及权利要求3至9中任一项所述的药物组合物在制备用于治疗WNT通路介导的疾病的药物中的应用。
13.如权利要求12所述的应用,其中,所述疾病是癌症、纤维化、骨关节炎、帕金森病、视网膜病、黄斑变性。
14.如权利要求13所述的应用,其中,所述癌症选自:包括小细胞肺癌和非小细胞肺癌的肺癌、乳腺癌、前列腺癌、类癌、膀胱癌、胃癌、胰腺癌、肝癌或肝细胞癌、肝母细胞瘤、结直肠癌、肾癌和头颈鳞状上皮细胞癌、食道癌、卵巢癌、子宫颈癌、子宫内膜癌、间皮瘤、黑色素瘤、肉瘤、骨肉瘤、脂肪肉瘤、甲状腺癌、硬纤维瘤、急性粒细胞白血病(AML)、慢性粒细胞白血病(CML)。
15.如权利要求13所述的应用,其中,所述纤维化选自:系统性硬化症、皮肤纤维化、特发性肺纤维化、肾脏纤维化、肝纤维化、药物诱导的纤维化和放射引起的纤维化。
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