CN111247148A - Wnt通路调节剂 - Google Patents
Wnt通路调节剂 Download PDFInfo
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- CN111247148A CN111247148A CN201880068576.8A CN201880068576A CN111247148A CN 111247148 A CN111247148 A CN 111247148A CN 201880068576 A CN201880068576 A CN 201880068576A CN 111247148 A CN111247148 A CN 111247148A
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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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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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本申请涉及2,6‑二氧‑嘌呤衍生物,2‑(1,3‑二甲基‑2,6‑二氧‑1,2,3,6‑四氢‑7H‑嘌呤‑7‑基)‑N‑(6‑(2‑羟基苯基)哒嗪‑3‑基)乙酰胺,以及该化合物在调节Wnt通路中的用途,和该化合物在治疗与Wnt通路活性相关的疾病或病症(例如癌症、纤维化疾病、退行性疾病或代谢疾病)中的用途。
Description
技术领域
本发明涉及Wnt通路调节剂、其制备方法及其使用方法。
背景技术
Wnt蛋白是充当生长因子的分泌糖蛋白,其通过激活多种细胞内信号传导级联(包括β-连环蛋白依赖性和非依赖性通路)来调节多种细胞功能,包括增殖、分化、死亡、迁移和极性。在人和小鼠中发现了19个Wnt成员,它们在发育过程中表现出独特的表达模式和不同的功能。在人和小鼠中,卷曲蛋白(Frizzled,Fz)家族的10个成员包括一系列被鉴定为Wnt受体的七程跨膜受体。除Fz蛋白外,单程跨膜蛋白例如低密度脂蛋白受体相关蛋白5(LRP5)、LRP6、受体酪氨酸激酶(RTK)样孤儿受体1(Rorl)、Ror2和受体样酪氨酸激酶(Ryk)已显示出充当Wnt信号传导的共受体。因此,传统上一直假设,不同的Wnt与其特异性受体的结合通过不同的细胞内通路选择性触发不同的结果。
在没有Wnt信号传导的情况下,β-连环蛋白被包含结肠腺瘤样息肉基因(APC)和轴蛋白(Axin)蛋白以及糖原合酶激酶3(GSK3)和酪蛋白激酶I(CKI)的“破坏复合物”结合和磷酸化。磷酸化的β-连环蛋白被F盒蛋白Slimb/β-TrCP结合并多泛素化,导致蛋白体降解。另外,该复合物起到防止β-连环蛋白的核定位的作用。在Wnt与卷曲蛋白(Fz)和低密度脂蛋白相关蛋白5和6(LRP5/6)结合后,GSK3、轴蛋白和其它破坏复合物的成分被募集到受体复合物中。破坏复合物的功能受到抑制,并且未磷酸化的β-连环蛋白在细胞质中积聚并最终转位到核中。在那里,其与TCF蛋白结合,将TCF从Wnt响应性基因转录的阻遏物转化为激活物。
Wnt/β-连环蛋白信号传导的成分的失调涉及广泛多种疾病,包括退行性疾病、代谢疾病和许多癌症,例如宫颈癌、结肠癌、乳腺癌、膀胱癌、头颈癌、胃癌、肺癌、卵巢癌、前列腺癌、甲状腺癌、非小细胞肺癌以及慢性淋巴细胞性白血病、间皮瘤、黑色素瘤、胰腺腺癌、基底细胞癌、骨肉瘤、肝细胞癌、威尔姆肿瘤和髓母细胞瘤。Wnt信号传导在发育过程中以及在成人干细胞生态位中均发挥作用。这在皮肤、造血干细胞、乳腺和肠道增殖中是最良好确定的。例如,DKK1(Wnt信号传导的抑制剂)的高水平表达阻止了小鼠肠道中正常干细胞的增殖,这表明Wnt信号传导在维持消化道中的干细胞方面发挥着至关重要的作用。Wnt在干细胞自我更新和扩增中的作用也已被胚胎和神经干细胞证实,这表明Wnt信号传导可能是干细胞维持的普遍要求。
Wnt信号传导的抑制(例如通过轴蛋白(axin)或细胞外Wnt结合蛋白sFRP的过表达)降低了体外造血干细胞(HSC)的生长以及体内重组HSC的能力。值得注意的是,虽然活化的β-连环蛋白的过表达可以在延长的时间扩增培养中的HSC群体,但已有两个小组报告了HSC存活和连续移植不需要β-连环蛋白,这支持了在干细胞存活中Wnt信号传导比β-连环蛋白的稳定更为重要的提议。不同的Wnt可以调节干细胞增殖:Wnt 1、5a和10b能够刺激HSC群体的扩增,而Wnt5a与干细胞因子(SCF)协同作用以扩增和促进HSC的自我更新。Wnt5a在HSC自我更新中的作用及其与干细胞因子协同作用的能力的证明是特别有趣,因为Wnt5a通常以独立于β-连环蛋白的方式起作用。虽然Wnt信号传导对于维持干细胞至关重要,但其因此可能是通过与β-连环蛋白通路不同或平行的信号传导通路。
Wnt/β-连环蛋白信号传导通路对于总体胚胎发育和器官形态发生中是必不可少的,因此毫不奇怪,在成人中该通路的失调已与成纤维细胞生物学和纤维化有关。已经证实,Wnt/β-连环蛋白信号传导在严重的纤维化疾病如肺纤维化、肝纤维化、皮肤纤维化和肾纤维化中起作用。
Wnt/β-连环蛋白信号传导的失调还通过诱导视网膜炎症、血管渗漏和新血管形成而促进了糖尿病性视网膜病的发展。Wnt蛋白与间充质细胞上的质膜受体的结合诱导这些细胞分化为成骨细胞谱系并从而支持骨形成。Wnt也是关节重塑过程中的关键信号传导蛋白。活跃的Wnt信号传导促进了骨赘的形成,并且可能在强直性脊柱炎和骨关节炎中观察到的关节重塑的合成代谢模式中起重要作用。相比之下,Wnt信号传导的阻滞促进骨侵蚀并促进分解代谢的关节重塑,这是在类风湿性关节炎中观察到的过程。
因此,需要开发调节或抑制Wnt活性的化合物中的改进,以便更有效地治疗与Wnt活性相关的疾病。
发明内容
在一方面,提供下式的化合物或其药学上可接受的盐、溶剂合物或前药:
本发明的化合物出乎意料地具有良好的口服生物利用度和药代动力学性质。
在一方面,提供了如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药,用于作为药物使用。
在一方面,提供了调节Wnt分泌和/或porcupine活性的方法,该方法包括将细胞暴露于如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药。
细胞可以是过表达Wnt蛋白的细胞。所述方法可以是体外方法,也可以是体内方法。不希望被理论所束缚,发明人假设如本文所限定的化合物抑制Wnt蛋白的分泌。本发明的化合物能够抑制porcupine,porcupine对于分泌前Wnt蛋白的棕榈酰化是必要和特异性的。
在另一方面,提供了治疗与Wnt通路活性相关的疾病或病症的方法,该方法包括向有此需要的受试者施用治疗有效量的如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药。
在另一方面,提供了如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药,用于在治疗与Wnt通路活性相关的疾病或病症中使用。
在另一方面,提供了如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药在制备用于治疗与Wnt通路活性相关的疾病或病症的药物中的用途。
在另一方面,提供了药物组合物,该药物组合物包含如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药。
附图说明
图1显示了STF3A细胞中化合物1的抑制-剂量滴定法。抑制-剂量滴定法使得可确定化合物1的IC50值,其汇总在表1中。
图2显示了雄性BALB/c小鼠中单次静脉内(剂量:1mg/kg)和口服(剂量:5mg/kg)施用后,血浆中化合物1的平均血浆浓度-时间曲线。
具体实施方式
本发明涉及调节Wnt活性的新化合物的制备和用途,涉及使用所述化合物作为单一药剂或组合以用于治疗或预防与Wnt通路活性相关的疾病和病症的方法,所述疾病和病症特别是具有与Wnt信号传导通路相关的功能障碍的疾病和病症,即癌症、纤维化、干细胞和糖尿病性视网膜病。因此,本发明涉及充当Wnt通路的调节剂的化合物以及包含所述化合物的药物组合物,并且涉及其在制备药物中的用途,所述药物用于治疗具有与Wnt信号传导通路相关的功能障碍的疾病,其中Wnt通过多种机制在癌症增殖中起作用,包括在干细胞维持中的关键作用。Wnt通路的功能障碍与疾病相关,包括但不限于癌症,例如宫颈癌、结肠癌、乳腺癌、膀胱癌、头颈癌、胃癌、肺癌、卵巢癌、前列腺癌、甲状腺癌、非小细胞肺癌以及慢性淋巴细胞性白血病、间皮瘤、黑色素瘤、胰腺腺癌、基底细胞癌、骨肉瘤、肝细胞癌、威尔姆肿瘤和髓母细胞瘤以及具有高Wnt表达的其它疾病,例如纤维化(包括皮肤、特发性肺、肝、肾间质、心肌、梗死和肝)和糖尿病性视网膜病变。在某些实施例中,呼吸道疾病或呼吸道肿瘤可能不是本发明治疗的疾病。
本文提供下式的化合物或其药学上可接受的盐、溶剂合物或前药:
本发明的化合物出乎意料地具有良好的口服生物利用度和药代动力学性质。这与由于其酚部分而预期所述化合物的药代动力学性质较差相反。此外,发现当羟基部分处于邻位时,本发明的化合物在口服施用后能够充分地到达全身循环,而不会在胃肠道中被代谢、在血液中被代谢并且不会被肝门系统(即肝脏)清除。不受理论的束缚,邻位的酚基可被螯合(体内),因此不可用于缀合(2相代谢)。
本发明的化合物的特征在于对STF3A的IC50小于约10微摩尔。在一实施例中,IC50小于0.01微摩尔。测试IC50的合适方法如下:将75μl培养基中的约5000个细胞接种在黑色96孔板的每个孔中,并在37℃下孵育过夜。然后将25μl系列稀释的化合物添加到细胞中,使其达到最终浓度。处理1天后,将100μl的发光细胞生存力测定试剂添加到每个孔中,并在室温下孵育10分钟。然后测量发光以确定IC50。
所述化合物可以不调节或不抑制TRPA1。其可能不会以约10微摩尔或约5微摩尔或约2微摩尔或约1微摩尔的IC50抑制TRPA1。其可能是TRPA1的非抑制剂。在本文中,术语“不抑制”可以指在指定浓度下小于约10%、或小于约5%、2%或1%的抑制。
本发明的化合物可以以约2微摩尔的浓度在4小时后抑制PA-1畸形癌细胞和/或HPAF-II胰腺腺癌细胞中的共受体LRP6的磷酸化大于约40%。在本文中,抑制40%表明4小时后磷酸化的LRP6的浓度比未添加抑制化合物的对照低40%。在指定条件下的抑制可以大于约40%,或大于约45%、50%或55%,并且可以是例如约40%、45%、50%、55%或60%。可以利用以下浓度实现抑制:小于约3微摩尔或小于约2、1、0.5、0.2、0.1或0.05微摩尔的浓度,或者约0.003至2微摩尔或约0.003至1.5微摩尔、0.003至1微摩尔、0.003至0.5微摩尔、0.003至0.2微摩尔、0.003至0.1微摩尔、0.003至0.05、0.003至0.01、0.01至2、0.1至2、1至2、0.01至0.1、0.01至1、0.01至0.1以及0.05或0.005至0.5微摩尔的浓度,例如约0.003、0.005、0.01、0.002、0.05、0.1、0.2、0.5、1、1.5或2微摩尔的浓度。
本发明的化合物包括化合物的所有互变异构体。
药学上可接受的盐是指在合理的医学判断范围内适合用于在与人和低等动物的组织接触中使用而没有过度的毒性、刺激性、过敏反应等并且与合理的收益/风险比相称的盐。药学上可接受的盐是本领域众所周知的。
例如,可以通过将药学上可接受的酸如盐酸、硫酸、甲磺酸、琥珀酸、富马酸、马来酸、苯甲酸、磷酸、乙酸、草酸、碳酸、酒石酸或柠檬酸与本发明的化合物混合来制备根据本发明的化合物的合适的药学上可接受的盐。因此,本发明化合物的合适的药学上可接受的盐包括酸加成盐。
S.M.Berge等人在J.Pharmaceutical Sciences,1977,66:1-19中详细描述了药学上可接受的盐。盐可以在本发明化合物的最终分离和纯化过程中原位制备,或者通过使游离碱官能团与合适的有机酸反应而分开制备。代表性的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡萄糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐(hemisulfate)、庚酸盐、己酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐(pamoate)、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸酯、磷酸盐、苦味酸盐、新戊酸盐(pivalate)、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一烷酸盐、戊酸盐等。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁等,以及无毒铵、季铵和胺阳离子,包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺、三乙醇胺等。
术语“前药”以其最广含义使用,并且涵盖了在体内转化为本发明化合物的那些衍生物。这样的衍生物对于本领域技术人员而言是容易想到的,并且包括例如其中游离羟基可以被转化成酯(例如乙酸酯或磷酸酯)的化合物。用于使本发明化合物酯化(例如酰化)的程序在本领域中是周知的,并且可以包括在合适的催化剂或碱的存在下用合适的羧酸、酸酐或氯化物处理该化合物。特别优选的前药是磷酸二钠酯。
本发明的化合物可以是游离化合物或溶剂合物(例如水合物)的结晶形式,并且这两种形式均在本发明的范围内。溶剂化方法是本领域公知的。
在一个实施例中,提供了如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药,用于作为药物使用。
在一个实施例中,提供了调节Wnt分泌和/或porcupine活性的方法,该方法包括将细胞暴露于如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药。
在一个实施例中,调节可以是抑制。
在一个实施例中,提供了治疗与Wnt通路活性相关的疾病或病症的方法,该方法包括向有此需要的受试者施用治疗有效量的如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药。所述受试者可以是人或可以是非人,例如,非人哺乳动物或其它非人动物。
在一个实施例中,提供了如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药,用于在治疗与Wnt通路活性相关的疾病或病症中使用。
在一个实施例中,提供了如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药在制备用于治疗与Wnt通路活性相关的疾病或病症的药物中的用途。
疾病或病症可以是癌症,例如宫颈癌、结肠癌、乳腺癌、膀胱癌、头颈癌、胃癌、肺癌、卵巢癌、前列腺癌、甲状腺癌、非小细胞肺癌以及慢性淋巴细胞性白血病、间皮瘤、黑色素瘤、胰腺腺癌、基底细胞癌、骨肉瘤、肝细胞癌、威尔姆肿瘤或髓母细胞瘤。疾病或病症可以是纤维化疾病,例如肺纤维化、肝纤维化、皮肤纤维化或肾纤维化。其可以是退行性疾病。其可以是代谢疾病,例如糖尿病性视网膜病。疾病或病症也可以是增生性疾病。疾病或病症还可以是干细胞视网膜病、类风湿性关节炎、银屑病或心肌梗死。
在一个实施例中,疾病或病症是以异常的Wnt活性为特征的癌症。在一个实施例中,疾病或病症是以高Wnt活性为特征的癌症。
本发明的化合物可以如本文提供的实例中所举例说明的那样制备。
在适合于规模化生产和cGMP生产并最终用于临床和商业使用的固态形式药物的开发中,针对目标靶标的可接受的药物活性水平只是必须考虑的重要变量之一。例如,在药物组合物的制剂中,必须使药物活性物质处于可以在商业生产过程中可靠地复制的形式,并且其足够稳定以抵挡药物活性物质所暴露的条件。
在制造意义上,重要的是,在商业制造期间,药物活性物质的制造过程应使得当使用相同的制造条件时可再生相同的材料。另外,期望药物活性物质以固体形式存在,其中制造条件的微小变化不会导致所产生的药物活性物质的固体形式发生重大变化。例如,重要的是制造过程在可靠的基础上生产具有相同结晶特性的材料,并且还生产具有相同水合水平的材料。
此外,重要的是,药物活性物质对于降解、吸湿性以及随后对其固体形式的改变均是稳定的。这对于促进将药物活性成分引入药物制剂中很重要。如果药物活性物质在吸水(缓慢或随时间)的意义上具有吸湿性(“粘性”),则几乎不可能将药物活性物质可靠地配制成药物,因为待添加以提供相同剂量物质的量将根据水合程度而有很大差异。此外,水合或固体形式的变化(“多晶型”)可导致理化性质(例如溶解度或溶解速率)的变化,这继而可能导致患者口服吸收的不一致。
因此,药物活性剂的化学稳定性、固态稳定性和“保存期限”是非常重要的因素。在理想情况下,药物活性剂和包含它的任何组合物应能够在相当长的时间内有效地储存,而不会表现出活性成分的理化特性(例如活性、水分含量、溶解度特性、固体形式等)的显著变化。
本文还公开了用于调节Wnt活性,任选地用于治疗与Wnt通路活性相关的疾病或病症的组合物。这些包含了如上所限定的化合物以及一种或多种药学上可接受的佐剂、稀释剂和/或载体。
在一个实施例中,提供了药物组合物,该药物组合物包含如本文所限定的化合物或其药学上可接受的盐、溶剂合物或前药。药物组合物可进一步包含一种或多种药学上可接受的载体、稀释剂或佐剂。
本发明的化合物可以作为组合物治疗性或预防性施用。在治疗应用中,将组合物以足以治愈或至少部分阻止疾病及其并发症的量施用于已经患有疾病的患者。该组合物应提供足以有效治疗患者的量的化合物或药剂。
对于任何特定患者的治疗有效剂量水平将取决于多种因素,包括:正在治疗的疾病和疾病的严重性;所用化合物或药剂的活性;使用组合物;患者的年龄、体重、总体健康状况、性别和饮食;施用时间;施用途径;药剂或化合物的封存速率(rate ofsequestration);治疗的持续时间;与治疗组合或同时使用的药物,以及医学上周知的其它相关因素。
本领域技术人员将能够通过常规实验确定治疗适用疾病所需的药剂或化合物的有效、无毒的量。
通常,预期有效剂量为每24小时每千克体重约0.000l mg至约1000mg;通常,每24小时每千克体重约0.001mg至约750mg;每24小时每千克体重约0.01mg至约500mg;每24小时每千克体重约0.1mg至约500mg;每24小时每千克体重约0.1mg至约250mg;每24小时每千克体重约1.0mg至约250mg。更通常地,预期有效剂量范围为每24小时每千克体重约1.0mg至约200mg;每24小时每千克体重约1.0mg至约100mg;每24小时每千克体重约1.0mg至约50mg;每24小时每千克体重约1.0mg至约25mg;每24小时每千克体重约5.0mg至约50mg;每24小时每千克体重约5.0mg至约20mg;每24小时每千克体重约5.0mg至约15mg。
或者,有效剂量可以高至约500mg/m2。通常,预期有效剂量为约25至约500mg/m2,优选约25至约350mg/m2,更优选约25至约300mg/m2,再更优选约25至约250mg/m2,甚至更优选约50至约250mg/m2,甚至更优选约75至约150mg/m2。
通常,在治疗应用中,治疗通常在疾病状态的持续时间内进行。
此外,对于本领域普通技术人员来说显而易见的是,各个剂量的最佳量和间隔将由所治疗的疾病状态的性质和程度,施用的形式、途径和部位,以及所治疗的特定个体的性质决定。另外,可以通过常规技术确定这种最佳条件。
对于本领域普通技术人员来说显而易见的是,本领域技术人员可以使用常规的治疗过程确定测试方案来确定最佳治疗方案,例如在限定天数中每天给予的组合物的剂量数。
通常,合适的组合物可以根据本领域普通技术人员已知的方法制备,并且因此可以包含药学上可接受的载体、稀释剂和/或佐剂。
这些组合物可以通过标准途径施用。通常,组合物可以通过肠胃外(例如,静脉内、脊柱内、皮下或肌内)、口服或局部途径施用。更优选通过肠胃外途径施用。
就与组合物的其它成分相容而言,载体、稀释剂和佐剂必须是“可接受的”,并且对其接受者无害。
药学上可接受的载体或稀释剂的实例是软化水或蒸馏水;生理盐水;植物油,例如花生油、红花油、橄榄油、棉籽油、玉米油、芝麻油、落花生油或椰子油;硅油,包括聚硅氧烷,例如甲基聚硅氧烷、苯基聚硅氧烷和甲基苯基聚硅氧烷(methylphenyl polysolpoxane);挥发性硅酮;矿物油,例如液体石蜡、软石蜡或角鲨烷;纤维素衍生物,例如甲基纤维素、乙基纤维素、羧甲基纤维素、羧甲基纤维素钠或羟丙基甲基纤维素;低级链烷醇,例如乙醇或异丙醇;低级芳烷醇;低级聚亚烷基二醇或低级亚烷基二醇,例如聚乙二醇、聚丙二醇、乙二醇、丙二醇、1,3-丁二醇或甘油;脂肪酸酯,例如棕榈酸异丙酯、肉豆蔻酸异丙酯或油酸乙酯;聚乙烯基吡咯烷酮(polyvinylpyrridone);琼脂;角叉菜胶;黄蓍胶或阿拉伯树胶和凡士林。通常,一种或多种载体将占组合物的按重量计10%至99.9%。
本发明的组合物可以以适合于通过注射施用的形式,以适合于经口摄入的制剂形式(例如,胶囊剂、片剂、囊片、酏剂),以适于通过吸入(例如通过鼻内吸入或经口吸入)施用的气溶胶形式,以适合于肠胃外施用(即皮下、肌内或静脉内注射)的形式进行施用。
对于作为可注射溶液剂或混悬剂的施用,无毒的肠胃外可接受的稀释剂或载体可包括林格氏溶液、等渗盐水、磷酸盐缓冲盐水、乙醇和1,2-丙二醇。
用于口服使用的合适的载体、稀释剂、赋形剂和佐剂的一些实例包括花生油、液体石蜡、羧甲基纤维素钠、甲基纤维素、藻酸钠、阿拉伯胶、黄蓍胶、右旋糖、蔗糖、山梨糖醇、甘露醇、明胶和卵磷脂。另外,这些口服制剂可包含合适的矫味剂和着色剂。当以胶囊形式使用时,胶囊可以用延迟崩解的化合物(例如单硬脂酸甘油酯或二硬脂酸甘油酯)包衣。
佐剂通常包括润肤剂、乳化剂、增稠剂、防腐剂、杀菌剂和缓冲剂。
用于口服施用的固体形式可以包含人和兽药实践中可接受的粘合剂、甜味剂、崩解剂、稀释剂、矫味剂、包衣剂、防腐剂、润滑剂和/或延时剂。合适的粘合剂包括阿拉伯胶、明胶、玉米淀粉、黄蓍胶、藻酸钠、羧甲基纤维素或聚乙二醇。合适的甜味剂包括蔗糖、乳糖、葡萄糖、阿斯巴甜或糖精。合适的崩解剂包括玉米淀粉、甲基纤维素、聚乙烯吡咯烷酮、瓜尔胶、黄原胶、膨润土、藻酸或琼脂。合适的稀释剂包括乳糖、山梨糖醇、甘露糖醇、右旋糖、高岭土、纤维素、碳酸钙、硅酸钙或磷酸二钙。合适的矫味剂包括薄荷油、冬青油、樱桃、橙或覆盆子矫味剂。合适的包衣剂包括丙烯酸和/或甲基丙烯酸和/或它们的酯的聚合物或共聚物、蜡、脂肪醇、玉米蛋白、虫胶或麸质。合适的防腐剂包括苯甲酸钠、维生素E、α-生育酚、抗坏血酸、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯或亚硫酸氢钠。合适的润滑剂包括硬脂酸镁、硬脂酸、油酸钠、氯化钠或滑石。合适的延时剂包括单硬脂酸甘油酯或二硬脂酸甘油酯。
用于口服施用的液体形式除了上述试剂外,还可包含液体载体。合适的液体载体包括水、油(例如橄榄油、花生油、芝麻油、向日葵油、红花油、落花生油、椰子油)、液体石蜡、乙二醇、丙二醇、聚乙二醇、乙醇、丙醇、异丙醇、甘油、脂肪醇、甘油三酯或其混合物。
用于口服施用的混悬剂可以进一步包含分散剂和/或助悬剂。合适的助悬剂包括羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、聚乙烯基吡咯烷酮、藻酸钠或乙酰醇。合适的分散剂包括卵磷脂,脂肪酸(例如硬脂酸)的聚氧乙烯酯,聚氧乙烯山梨糖醇单或二油酸酯、硬脂酸酯或月桂酸酯,聚氧乙烯脱水山梨糖醇单或二油酸酯、硬脂酸酯或月桂酸酯等。
用于口服施用的乳剂可以进一步包含一种或多种乳化剂。合适的乳化剂包括上面举例说明的分散剂或天然树胶,例如瓜尔胶、阿拉伯树胶或黄蓍胶。
用于制备肠胃外施用的组合物的方法对本领域技术人员是显而易见的,并且在例如Remington's Pharmaceutical Science,第15版,Mack Publishing Company,Easton,Pa.中更详细地描述,其通过引用并入本文。
组合物可以引入任何合适的表面活性剂,例如阴离子、阳离子或非离子表面活性剂,例如脱水山梨醇酯或其聚氧乙烯衍生物。也可以包含助悬剂,例如天然树胶、纤维素衍生物或无机材料,例如硅质二氧化硅(silicaceous silicas),以及其它成分,例如羊毛脂。
组合物也可以以脂质体的形式施用。脂质体通常衍生自磷脂或其它脂质物质,并由分散在水性介质中的单层或多层水合液晶形成。可以使用能够形成脂质体的任何无毒的生理上可接受的和可代谢的脂质。脂质体形式的组合物可以包含稳定剂、防腐剂、赋形剂等。优选的脂质是天然和合成的磷脂和磷脂酰胆碱(卵磷脂)。形成脂质体的方法在本领域中是已知的,并且涉及以下具体参考文献:Prescott编,Methods in Cell Biology,第XIV卷,Academic Press,New York,N.Y.(1976),第33页及以后,其内容通过引用并入本文。
口服制剂可以与一种或多种药理学上可接受的成分一起配制以制成具有肠溶衣的片剂或胶囊剂等。这样的制剂的方法是本领域技术人员众所周知的(参见,例如,Remington:TheScience and Practice of Pharmacy,第19版.(1995)Mack PublishingCompany,Easton,Pa.;通过引用并入本文)。肠溶衣可以是增强组合物或活性药物向胃肠道特定区域的递送以提高生物利用度的肠溶衣,例如Sands等人的2004年8月19日公开的题为"Pharmaceutical formulations targeting specific regions of thegastrointestinal tract"的美国专利申请公开号20040162263中所述。
实例
以下实例提供了根据本发明的化合物以及用于制备该化合物的一般合成方案。为了制备其它相关化合物,本领域技术人员将容易理解合成方案中所示实例所需的变化。
实例1
化合物1的合成
步骤-1:1-溴-2-((4-甲氧基苄基)氧基)苯:
向2-溴苯酚(3g,0.0173mol)在乙腈(30mL)中的搅拌溶液中加入K2CO3(4.07g,0.0294mol),然后逐滴加入PMB-Cl(2.6mL,0.0193mol)。将反应混合物回流19小时。TLC分析证实起始原料完成,将反应物料过滤,用乙酸乙酯洗涤并在减压下浓缩。将获得的残余物溶解在乙酸乙酯(150mL)中,用水(2x 30mL)和盐水溶液(20mL)洗涤,用硫酸钠干燥并在减压下浓缩,得到作为浅棕色固体的标题化合物。
产率:4g(80%)。
步骤2:2-(2-((4-甲氧基苄基)氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷:
向1-溴-2((4-甲氧基苄基)氧基)苯(1g,0.00341mol)的混合物中加入双(频哪醇)二硼(0.953g,0.00375mol)、KOAc(1g,0.01023mol)和二氧六环(20mL),用氩气吹扫15分钟,然后加入PdCl2.dppf(0.125g,0.00017mol)。将混合物回流18小时。TLC分析证实SM完成,将反应物料通过硅藻土床过滤,用乙酸乙酯洗涤并在减压下浓缩。将获得的残余物溶解在乙酸乙酯中,用水(2x 20mL)、盐水溶液(20mL)洗涤,用硫酸钠干燥并在减压下浓缩以得到粗产物。将由此得到的粗产物通过硅胶柱色谱法(0-20%乙酸乙酯的石油醚(pet.ether)溶液)纯化为浅棕色固体。
产率:0.7g(60%)。
步骤3:6-(2-((4-甲氧基苄基)氧基)苯基)哒嗪-3-胺:
向2-(2-((4-甲氧基苄基)氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(0.7g,0.0020mol)和Cl哒嗪(0.265g,0.0020mol)在二氧六环:水(2.5:1)中的混合物中加入K3PO4(1.27g,0.006mol),用N2脱气15分钟,然后加入PdCl2.dppf(73mg,0.0001mol)。将反应混合物在102℃加热并搅拌18小时。使反应混合物冷却至室温,并加入DCM(200mL)。分离有机层,用水(3x 10mL)、盐水(10mL)洗涤,用无水Na2SO4干燥并在真空下蒸发。将粗产物通过硅胶色谱法(230-400目)纯化,用石油醚中的乙酸乙酯(0-50%)洗脱,得到作为棕色固体的标题产物,纯度为61%,其无需进一步纯化即可用于下一步骤。
产率:350mg(55%)。
LCMS:308.2(M+H)+
步骤4:2-(1,3-二甲基-2,6-二氧-1,2,3,6-四氢-7H-嘌呤-7-基)-N-(6-(2-((4-甲氧基苄基)氧基)苯基)哒嗪-3-基)乙酰胺:
在0℃下向6-(2-((4-甲氧基苄基)氧基)苯基)哒嗪-3-胺(0.3g,0.00097mol)和2-(1,3-二甲基-2,6-二氧-1,2,3,6-四氢-7H-嘌呤-7-基)乙酸(0.232g,0.00097mol)在无水二氯甲烷中的搅拌溶液中加入HATU(0.737g,0.00194mol),然后加入DIPEA(0.375g,0.00291mol),使其在搅拌下升温至室温过夜。通过TLC监测反应。将混合物在减压下浓缩,向残余物中加入水(10mL),过滤出沉淀的固体,并通过硅胶柱色谱法(0-4%的MeOH的DCM溶液)纯化,得到作为灰白色固体的标题化合物。
产率:325mg(63%)。
1H NMR(400MHz,DMSO-d6):δ3.20(s,3H),3.47(s,3H),3.73(s,3H),5.12(s,2H),5.36(s,2H),6.91(d,J=8.80Hz,2H),7.13(t,J=15.20Hz,1H),7.30(d,J=8.40Hz,1H),7.35(d,J=8.40Hz,2H),7.46-7.50(m,1H),7.75-7.77(m,1H),8.07-8.10(m,2H),8.17(s,1H),11.70(s,1H)。
LCMS:528.0(M+H)+。
步骤5:2-(1,3-二甲基-2,6-二氧-1,2,3,6-四氢-7H-嘌呤-7-基)-N-(6-(2-羟基苯基)哒嗪-3-基)乙酰胺:
在0℃下向2-(1,3-二甲基-2,6-二氧-1,2,3,6-四氢-7H-嘌呤-7-基)-N-(6-(2-((4-甲氧基苄基)氧基)苯基)哒嗪-3-基)乙酰胺(0.3g,0.00057mol)在二氯甲烷中的搅拌溶液中加入TFA(0.22ml,0.00285mol),使反应混合物升温至室温并且搅拌18小时。通过LCMS监测反应。将混合物在减压下浓缩并将残余物用水稀释。过滤由此获得的固体,用10%NaHCO3溶液洗涤,并通过制备型HPLC进一步纯化,得到作为灰白色固体的标题化合物。
产率:30mg(13%)。
1H NMR(400MHz,DMSO-d6):δ3.21(s,3H),3.47(s,3H),5.38(s,2H),6.97-7.02(m,2H),7.34-7.38(m,1H),7.93(d,J=9.36Hz,1H),8.10(s,1H),8.36-8.38(m,1H),8.46(d,J=9.60Hz,1H),11.78(s,1H),12.25(s,1H).
LCMS:408.0(M+H)+
材料和方法:
细胞系和培养条件:
HEK293-STF细胞系修饰自用STF报道基因转染的人胚胎肾细胞系HEK293。HEK293-STF3 A细胞系进一步修饰自HEK293-STF细胞系以表达Wnt3A。该细胞系用于鉴定调节Wnt通路的早期或晚期信号传导成分的化合物。L-Wnt3 A(ATCC,#CRL-2647)细胞系用于提供Wnt3A条件培养基。三种细胞系在含有10%FBS(胎牛血清)的DMEM(Dulbecco改良的Eagle培养基)中生长,并在37℃和5%CO2中孵育。
细胞活力测定:
将75μl培养基中的5000个细胞接种在黑色96孔板(Greiner#655090)的每个孔中,并在37℃下孵育过夜。将25μl系列稀释的化合物添加至细胞,得到50μM至1.5nM的终浓度。处理1天后,将100μl CellTiter-发光细胞活力测定试剂(#G7571,Promega)添加到每个孔中,并在室温下孵育10分钟。使用Tecan 酶标仪测量发光。
STF3A测定:
将75μl培养基中的2×l04个HEK293-STF3A细胞接种在白色96孔板(Greiner#655098)的每个孔中,并在37℃下孵育过夜。将25μl系列稀释的化合物添加至细胞,得到50μM至1.5nM的终浓度。处理1天后,将100μl Steady-发光测定试剂(#E2520,Promega)添加到每个孔中,并在室温下孵育10分钟。使用Tecan 酶标仪测量发光。
表1:结构和在STF3A细胞上的IC
50
活性
实例2
该研究的目的是研究在单次静脉内和口服剂量施用后,雄性BALB/c小鼠中化合物1的血浆药代动力学。将一组十八只雄性小鼠分为组1和组2两个组,每组九只小鼠。
组1中的动物以1mg/kg的剂量静脉内施用在7.5%NMP、5%Solutol HS-15和87.5%生理盐水中的化合物1溶液制剂。
组2中的动物以5mg/kg的剂量口服施用在7.5%NMP、5%Solutol HS-15和87.5%生理盐水中的化合物1溶液制剂。
在给药前、0.08、0.25、0.5、1、2、4、8和24小时(IV)以及给药前、0.25、0.5、1、2、4、6、8和24小时(PO)在轻度异氟烷麻醉下从眼眶后静脉丛收集血液样品(约60μL)。在每个采样点期间,将血液样品收集在标记的预冷管中,所述管中含有K2EDTA(20%K2EDTA溶液)作为抗凝剂和蛋白酶抑制剂(10μL 10×溶液/100μL血液)。维持低温直到血浆储存在-70℃。通过全血的离心来分离血浆样品,并在低于-70℃储存直至进行生物分析。所有样品均经过处理,以使用乙腈(ACN)通过蛋白质沉淀进行分析,并以适合用途的LC/MS/MS方法(定量下限(LLOQ:1.02ng/mL))进行分析。使用Phoenix (版本6.3)的非隔室分析工具计算药代动力学参数。总体药代动力学参数总结如下:
*-对于PO组,T1/2表示为T1/2Z,CL表示为CLf,并且Vss表示为Vza–对于i.v.组反向推断的浓度;b–考虑使用AUClast来计算口服生物利用度
在将化合物1向雄性BALB/c小鼠单次静脉内剂量施用后,化合物显示出低血浆清除率(11.20mL/min/kg;小鼠中正常肝血流量为90mL/min/kg),终末消除半衰期为4.24小时。Vss是正常体内总水量(0.7L/kg)的约2倍。在以5mg/kg的剂量对雄性BALB/c小鼠单次口服施用化合物1之后,血浆浓度可定量多至24小时(3只动物中有2只),Tmax为0.25小时。口服溶液的生物利用度为42%。
实例3
该研究的目的是确定在蛋白酶抑制剂存在下单次静脉内(1mg/kg)和口服(5mg/kg)施用后,雄性BALB/c小鼠中化合物1的血浆药代动力学。
测试化合物:化合物1(分子量:407.39;纯度:97.00%;批次/批号:批号1)。
测试系统
体重为25至30g的健康雄性BALB/c小鼠(8-12周龄)购自印度Global。每个笼子中饲养三只小鼠。温度和湿度分别保持在22±3℃和30-70%,并且控制照明以给出12小时亮和12小时暗周期的顺序。温度和湿度由自动控制的数据记录仪系统记录。向所有动物提供实验室啮齿动物饮食(Envigo Research private Ltd,Hyderabad)。以随意采食的方式提供用紫外线处理的反渗透水。
研究设计
将一组十八只雄性小鼠分为组1和组2两个组,每组九只小鼠。组1中的动物以1mg/kg的剂量静脉内施用在7.5%NMP、5%Solutol HS-15和87.5%生理盐水中的化合物1溶液制剂。组2中的动物以5mg/kg的剂量口服施用在7.5%NMP、5%Solutol HS-15和87.5%生理盐水中的化合物1溶液制剂。
施用的剂量体积为静脉内为5mL/kg,口服为10mL/kg。下表显示了动物的分配:
制剂制备
静脉内和口服溶液制剂的强度分别为0.2和0.5mg/mL。
IV制剂:将准确称量的0.72mg的化合物1转移至标记的瓶中。向该瓶中添加0.262mL的NMP、0.175mL的Solutol HS-15,并且在每次添加之后涡旋。添加体积为3.055mL的生理盐水并涡旋。将最终制剂涡旋2分钟以获得澄清溶液。
PO制剂:将准确称量的2.37mg的化合物1转移至标记的瓶中。向该瓶中添加0.345mL的NMP、0.230mL的Solutol HS-15,并且在每次添加之后涡旋。添加体积为4.023mL的生理盐水并涡旋。将最终制剂涡旋2分钟以获得澄清溶液。
配制结果
制备制剂后,将200μL的体积等分用于分析。分析了符合验收标准的制剂(内部验收标准为标称值的±20%)。在给药前新鲜配制制剂。
观察
在静脉内和口服施用后,发现所有动物都是正常的,没有任何临床体征。
样品收集
在每个时间点[给药前、0.08、0.25、0.5、1、2、4、8和24小时(IV)以及给药前、0.25、0.5、1、2、4、6、8和24小时(PO)]从三只小鼠的眼眶后静脉丛收集血液样品(约60μL)。在每个采样点期间,将血液样品收集在标记的预冷管中,所述管中含有K2EDTA(20%K2EDTA溶液)作为抗凝剂和蛋白酶抑制剂(10μL 10×溶液/100μL血液)。维持低温直到血浆储存在-70℃。通过在4±2℃下以4000rpm离心10分钟从血液中立即收集血浆,并在-70℃以下储存直至进行生物分析。蛋白酶抑制剂溶液的制备:将一片sigmaFAST(产品代码:S8820)重构到10mLMilli-Q水中以制备10×溶液。
生物分析
通过适合用途的LC-MS/MS方法测定小鼠血浆样品中化合物1的浓度。以下提供了样品处理和提取程序、色谱和质谱条件:
液相色谱条件:
流动相A:乙腈中的0.1%甲酸
B:水中0.1%的甲酸
柱:Phenomenex Kinetex,EVO,C18,100X 4.6mm,5μ
进样量(μL):5
柱箱温度(℃):45
保留时间(分钟):分析物:化合物1:1.89
IS:格列吡嗪:2.04
使用的LC梯度
质谱条件:
MRM转换
源参数:
提取程序:
血浆样品的提取程序和加标血浆校准标准品是相同的:
将25μL的研究样品(仅对少量样品应用DF)或加标血浆校准标准品添加到各个预先标记的微量离心管中,然后添加在乙腈中制备的100μL内标(格列吡嗪,500ng/mL),只有空白是添加100μL的乙腈。将样品涡旋5分钟。将样品在4℃下以4000rpm的速度离心10分钟。离心后,将100μL透明上清液转移至96孔板中,并使用LC-MS/MS进行分析。
数据分析
使用Phoenix (第6.3版)的非隔室分析工具评估药代动力学参数。峰值血浆浓度(Cmax)和峰值血浆浓度的时间(Tmax)是观察值。通过线性梯形法则计算浓度时间曲线下的面积(AUClast和AUCinf)。通过对数血浆浓度-时间曲线的线性末端部分的回归分析来确定终末消除速率常数ke。终末半衰期(T1/2)估计为0.693/ke;CLf.=剂量/AUCinf;Vz=MRT X CLF。
结果
在将化合物1向雄性BALB/c小鼠单次静脉内剂量施用后,化合物显示出低血浆清除率(11.20mL/min/kg;小鼠中正常肝血流量为90mL/min/kg),终末消除半衰期为4.24小时。Vss是正常体内总水量(0.7L/kg)的约2倍。在以5mg/kg的剂量对雄性BALB/c小鼠单次口服施用化合物1之后,血浆浓度可定量多至24小时(3只动物中有2只),Tmax为0.25小时。口服溶液的生物利用度为42%。
表2:在雄性BALB/c小鼠中单次静脉内(剂量:1mg/kg)和口服(剂量:5mg/kg)施用后,血浆中化合物1的药代动力学参数
*-对于PO组,T1/2表示为T1/2Z,CL表示为CLf,并且Vss表示为Vza–对于i.v.组反向推断的浓度;b–考虑使用AUClast来计算口服生物利用度
表3:雄性BALB/c小鼠中单次静脉内施用后化合物1的单独血浆浓度-时间数据(剂量:1mg/kg)
LLOQ=1.02ng/mL;NA-不适用;d–数据分析中考虑的两个值的平均值。
低于LLOQ的值或无峰值被视为零。
表4:雄性BALB/c小鼠单次口服施用后化合物1的单独血浆浓度-时间数据(剂量:5mg/kg)
LLOQ=1.02ng/mL;NA-不适用;d–数据分析中考虑的两个值的平均值。
低于LLOQ的值或无峰值被视为零。
本研究中使用的缩写是
ACN:乙腈
LLOQ:定量下限
CV:变异系数
IS:内标
IV:静脉内
LC-MS/MS:液相色谱质谱
NA:不适用
PO:口服
SD:标准偏差
SOP:标准操作程序
Cmax:最大浓度
Tmax:达到最大浓度的时间
AUC:血浆浓度时间曲线下的面积
CL:清除率
Vss:分布容积
T1/2:半衰期
%F:生物利用度。
Claims (17)
2.根据权利要求1所述的化合物或其药学上可接受的盐、溶剂合物或前药,用于作为药物使用。
3.一种调节Wnt分泌和/或porcupine活性的方法,包括将细胞暴露于根据权利要求1所述的化合物或其药学上可接受的盐、溶剂合物或前药。
4.一种治疗与Wnt通路活性相关的疾病或病症的方法,包括向有此需要的受试者施用治疗有效量的根据权利要求1所述的化合物或其药学上可接受的盐、溶剂合物或前药。
5.根据权利要求4所述的方法,其中所述疾病或病症选自由癌症、或纤维化疾病、或退行性疾病或代谢疾病组成的组。
6.根据权利要求5所述的方法,其中所述癌症选自宫颈癌、结肠癌、乳腺癌、膀胱癌、头颈癌、胃癌、肺癌、卵巢癌、前列腺癌、甲状腺癌、非小细胞肺癌、慢性淋巴细胞性白血病、间皮瘤、黑色素瘤、胰腺腺癌、基底细胞癌、骨肉瘤、肝细胞癌、威尔姆肿瘤或髓母细胞瘤,其中所述纤维化疾病选自肺纤维化、肝纤维化、皮肤纤维化或肾纤维化,并且其中所述代谢疾病是糖尿病性视网膜病。
7.根据权利要求4所述的方法,其中所述疾病或病症是以高Wnt活性为特征的癌症。
8.根据权利要求1所述的化合物或其药学上可接受的盐、溶剂合物或前药,用于在治疗与Wnt通路活性相关的疾病或病症中使用。
9.根据权利要求8所述的化合物,其中所述疾病或病症选自由癌症、或纤维化疾病、或退行性疾病或代谢疾病组成的组。
10.根据权利要求9所述的化合物,其中所述癌症选自宫颈癌、结肠癌、乳腺癌、膀胱癌、头颈癌、胃癌、肺癌、卵巢癌、前列腺癌、甲状腺癌、非小细胞肺癌、慢性淋巴细胞性白血病、间皮瘤、黑色素瘤、胰腺腺癌、基底细胞癌、骨肉瘤、肝细胞癌、威尔姆肿瘤或髓母细胞瘤,其中所述纤维化疾病选自肺纤维化、肝纤维化、皮肤纤维化或肾纤维化,并且其中所述代谢疾病是糖尿病性视网膜病。
11.根据权利要求8所述的化合物,其中所述疾病或病症是以高Wnt活性为特征的癌症。
12.根据权利要求1所述的化合物或其药学上可接受的盐、溶剂合物或前药在制备用于治疗与Wnt通路活性相关的疾病或病症的药物中的用途。
13.根据权利要求12所述的用途,其中所述疾病或病症选自由癌症、或纤维化疾病、或退行性疾病或代谢疾病组成的组。
14.根据权利要求13所述的用途,其中所述癌症选自宫颈癌、结肠癌、乳腺癌、膀胱癌、头颈癌、胃癌、肺癌、卵巢癌、前列腺癌、甲状腺癌、非小细胞肺癌、慢性淋巴细胞性白血病、间皮瘤、黑色素瘤、胰腺腺癌、基底细胞癌、骨肉瘤、肝细胞癌、威尔姆肿瘤或髓母细胞瘤,其中所述纤维化疾病选自肺纤维化、肝纤维化、皮肤纤维化或肾纤维化,并且其中所述代谢疾病是糖尿病性视网膜病。
15.根据权利要求13所述的用途,其中所述疾病或病症是以高Wnt活性为特征的癌症。
16.药物组合物,包含根据权利要求1所述的化合物或其药学上可接受的盐、溶剂合物或前药。
17.根据权利要求16所述的药物组合物,其中所述药物组合物还包含一种或多种药学上可接受的载体、稀释剂或佐剂。
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