CN102448968A - C-met蛋白激酶的取代的吡唑抑制剂 - Google Patents
C-met蛋白激酶的取代的吡唑抑制剂 Download PDFInfo
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- CN102448968A CN102448968A CN2010800231025A CN201080023102A CN102448968A CN 102448968 A CN102448968 A CN 102448968A CN 2010800231025 A CN2010800231025 A CN 2010800231025A CN 201080023102 A CN201080023102 A CN 201080023102A CN 102448968 A CN102448968 A CN 102448968A
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Abstract
本发明涉及用于抑制c-Met蛋白激酶的式(I)的化合物。本发明还提供了包含式(I)的化合物的药学上可接受的组合物和使用该组合物治疗增殖性疾病的方法。
Description
本发明的技术领域
本发明涉及c-Met选择性抑制剂。本发明还提供了包含c-Met抑制剂的药学上可接受的组合物和使用这些组合物治疗各种增殖性疾病的方法。
发明背景
肝细胞生长因子(HGF),也称作离散因子,是通过诱导有丝分裂发生和细胞运动性促进转化和肿瘤发育的多功能生长因子。此外,HGF通过刺激细胞运动性和通过各种信号传导途径侵入促进转移。为了产生细胞效应,HGF必须结合其受体c-Met,即受体酪氨酸激酶。由50千道尔顿(kDa)α-亚单位和145kDaα-亚单位组成的广泛表达的异型二聚体蛋白质c-Met(Maggiora等人,J.Cell Physiol.,173:183-186,1997)在大量百分比的人癌症中超表达并且在原发性肿瘤与转移灶之间的过渡过程中扩增。涉及c-Met超表达的各种癌包括但不限于胃腺癌、肾癌、小细胞肺癌、结肠直肠癌、前列腺癌、脑癌、肝癌、胰腺癌和乳腺癌。c-Met还涉及动脉粥样硬化和肺纤维化。
因此,对研发用作c-Met蛋白激酶受体抑制剂的化合物存在巨大需求。特别地,优选的化合物硬具有对c-Met受体的高度亲和力且显示作为拮抗剂功能活性,同时显示对其他激酶受体或已知涉及不良反应的靶标几乎无亲和力。
发明概述
已经发现在吡唑3-位上取代且任选地在连接三唑并噻二唑和喹啉环的亚甲基上取代的1-甲基-1H-吡唑-4-基-[1,2,4]三唑并[3,4-b][1,3,4]噻二唑-3-基)甲基)喹啉类有效地抑制c-Met。因此,本发明的特征在于具有下式的化合物:
或其药学上可接受的盐,其中R1、R2、R3和R4各自如本文另外部分所定义。
本发明还提供了包括式I的化合物和药学上可接受的载体、佐剂或媒介物的药物组合物。此外,本发明提供了治疗患者增殖性疾病、病症或障碍或减轻其严重性的方法,所述方法包括对所述患者给予治疗有效剂量的式I的化合物或其药物组合物。
发明详述
定义和一般术语
除非另作陈述,否则应使用本文所用的下列定义。就本发明的目的而言,按照元素周期表,CAS版和Handbook of Chemistry andPhysics,第75版,1994鉴定化学元素。另外,有机化学的一般原理描述在“Organic Chemistry”,Thomas Sorrell,University ScienceBooks,Sausalito:1999和“March′s Advanced Organic Chemistry”,第5版,Smith,M.B.和March,J.,eds.John Wiley & Sons,New York:2001中,将这些文献的全部内容引入本文参考。
本发明化合物的描述
在第一个方面中,本发明的特征在于下列式I的化合物:
或其药学上可接受的盐,其中R1是环丙基或C1-3脂族基团,其任选地被1-3个氟原子取代;R2是氢、氟或甲基;R3是氢、氟或甲基;且R4各种独立地是氢或氟。
在一个实施方案中,R1是甲基、乙基、三氟甲基、异丙基或环丙基;R2是氢或甲基;R3是氢或甲基;且R4是氢或氟。在另一个实施方案中,R1是甲基、乙基、三氟甲基、异丙基或环丙基;R2和R3各自是氟;且R4是氢。
在一个实施方案中,R1是甲基。
在另一个实施方案中,R1是乙基、三氟甲基、异丙基或环丙基。
在一个实施方案中,R2是氢且R3是甲基。
在另一个实施方案中,R2是甲基且R3是氢。
在另一个实施方案中,R2和R3各自是氟。
在另一个实施方案中,R2和R3各自是氢。
在一个实施方案中,R4各自是氢。
在另一个实施方案中,R4各自是氟。
式I的化合物包括下列化合物:
在另一个方面中,本发明的特征在于包含式I的化合物或其药学上可接受的盐和药学上可接受的载体、佐剂或媒介物的药物组合物。在一个实施方案中,该组合物包括另外的化疗剂或抗增殖剂、抗炎药、治疗动脉粥样硬化的药剂或治疗肺纤维化的药剂。
在另一个方面中,本发明的特征在于治疗患者增殖性疾病或减轻其严重性的方法,所述方法包括给予所述患者足以治疗所述增殖性疾病或减轻其严重性用量的式I的化合物。在一个实施方案中,所述增殖性疾病是转移癌。在另一个实施方案中,所述增殖性疾病是胶质母细胞瘤;胃癌;或选自结肠癌、乳腺癌、前列腺癌、脑癌、肝癌、胰腺癌或肺癌的癌症。
本发明化合物的组合物、制剂和给药
在另一个方面中,本发明提供了包含式I的化合物或其药学上可接受的衍生物和药学上可接受的载体、佐剂或媒介物的组合物。在一个实施方案中,本发明组合物中化合物的量使得能够有效地可测定地抑制生物样品或患者中的c-Met。优选根据患者对这种组合物的给药需求配制本发明的组合物。最优选为对患者口服给药配制本发明的组合物。
本文所用的术语“患者”意指动物,优选哺乳动物且最优选人。
还可以理解式I的化合物可以作为游离形式存在以便治疗,或如果适合,可以作为其药学上可接受的衍生物存在。本发明的药学上可接受的衍生物包括但不限于药学上可接受的前体药物、盐、酯、这类酯的盐或者任意其他加合物或衍生物,其一旦对需要的患者给药即能够直接或间接提供本文其他部分所述式I的化合物或其代谢物或残留物。
本文所用的术语“药学上可接受的盐”意指在合理医学判断范围内适用于接触人和低等动物组织但没有不适当的毒性、刺激、过敏反应等的那些盐。
药学上可接受的盐是本领域众所周知的。例如,S.M.Berge等人在J.Pharmaceutical Sciences,66:1-19,1977中详细描述了药学上可接受的盐,将该文献引入本文参考。式I的化合物的药学上可接受的盐包括那些衍生自适合的无机和有机酸和碱的盐。药学上可接受的无毒性酸加成的盐为与无机酸或有机酸形成的氨基的盐,所述无机酸例如盐酸,氢溴酸,磷酸,硫酸和高氯酸,所述有机酸例如乙酸,草酸,马来酸,酒石酸,柠檬酸,琥珀酸或丙二酸;或通过使用本领域中所使用的其他方法例如离子交换形成的氨基的盐。其他药学上可接受的盐包括己二酸盐,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,环戊烷丙酸盐,二葡糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,富马酸盐,葡庚糖酸盐,甘油磷酸盐,葡糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖酸盐,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,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,磷酸盐,苦味酸盐,新戊酸盐,丙酸盐,硬脂酸盐,琥珀酸盐,硫酸盐,酒石酸盐,硫氰酸盐,对-甲苯磺酸盐,十一烷酸盐,戊酸盐等。衍生自适合的碱的盐包括碱金属盐,碱土金属盐,铵盐和N+(C1-4烷基)4盐。
如上所述,本发明药学上可接受的组合物还包括药学上可接受的载体、佐剂或媒介物,正如本文所用的,它们包括任意和所有的溶剂,稀释剂或其他液体媒介物,分散或混悬助剂,表面活性剂,等渗剂,增稠剂或乳化剂,防腐剂,固体粘合剂,润滑剂等,它们为适合于所需的特定剂型。在Remington:The Science and Practice ofPharmacy,第21版,2005,ed.D.B.Troy,Lippincott Williams &Wilkins,Philadelphia和Encyclopedia of PharmaceuticalTechnology,eds.J.Swarbrick和J.C.Boylan,1988-1999,MarcelDekker,New York中,披露了用于配制药学上可接受的组合物及其制备的公知技术,将这些文献各自的内容引入本文参考。除了任何常规载体介质与本发明化合物不相容以外,例如产生任何不可取的生物学效应或者以有害方式相互作用于药学上可接受的组合物的任何其他成分,它的使用涵盖在本发明的范围内。
可以用作药学上可接受的载体的材料的某些实例包括但不限于离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白质,例如人血清清蛋白;缓冲物质,例如磷酸盐,甘油,山梨酸或山梨酸钾,饱和植物脂肪酸的偏甘油酯混合物,水,盐;或电解质,例如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态二氧化硅,三硅酸镁,聚乙烯吡咯烷酮,聚丙烯酸酯,蜡,聚乙烯-聚氧丙烯-嵌段聚合物,羊毛脂;糖,例如乳糖,葡萄糖和蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,例如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;西黄蓍胶粉;麦芽;明胶;滑石粉;赋形剂,例如可可脂和栓剂蜡;油,例如花生油,棉籽油;红花油;芝麻油;橄榄油;玉米油和大豆油;二醇类;例如丙二醇或聚乙二醇;酯类,例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;藻酸;无热原水;等渗盐水;林格液;乙醇和磷酸盐缓冲溶液,以及其他无毒性相容性润滑剂,例如十二烷基硫酸钠和硬脂酸镁;且根据配制者的判断,着色剂,释放剂,包衣衣料,甜味剂,矫味剂和香味剂,防腐剂和抗氧化剂也可以存在于组合物中。
可以通过口服,非肠道,通过吸入喷雾,局部,直肠,鼻部,口含,阴道或通过植入储器给予本发明的组合物。本文所用的术语“非肠道”包括皮下,静脉内,肌内,关节内,滑膜内,胸骨内,鞘内,眼内,肝内,内部损害和颅内注射或输注技术。优选通过口服,腹膜内或静脉内给予所述组合物。本发明的无菌可注射形式可以为水或油混悬液。可以按照本领域公知的技术,使用适合的分散剂或湿润剂和混悬剂配制这些混悬液。无菌可注射制剂还可以为在无毒性非肠道可接受稀释剂或溶剂中的无菌可注射溶液或混悬液,例如在1,3-丁二醇中的溶液。在可以使用的可接受媒介物和溶剂中有水,林格液和等渗氯化钠溶液。此外,无菌固定油常用作溶剂或混悬介质。
为了这一目的,可以使用任意温和的固定油,包括合成的单酸甘油酯或甘油二酯。脂肪酸,例如油酸及其甘油酯衍生物用于制备可注射制剂,因为它们为天然药学上可接受的油,例如橄榄油或蓖麻油,尤其是其聚乙氧基化形式。这些油溶液或混悬液还可以包含长链醇稀释剂或分散剂,例如羧甲基纤维素或类似分散剂,它们通常用于药学上可接受剂型的配制,包括乳剂和混悬液。其他常用表面活性剂,例如Tweens,Spans和其他常用于制备药学上可接受的固体、液体或其他剂型的乳化剂或生物利用度促进剂也可以用于配制目的。
可以通过口服以任何口服可接受的剂型给予本发明的药学上可接受的组合物,包括但不限于胶囊、片剂、含水混悬液或溶液。就口服应用的片剂而言,常用载体包括乳糖和玉米淀粉。一般也使用润滑剂,例如硬脂酸镁。就胶囊形式的口服给药而言,有用的稀释剂包括乳糖和干燥的玉米淀粉。当口服应用需要含水混悬液时,将活性组分与乳化剂和混悬剂合并。如果需要,还可以加入某些甜味剂,矫味剂或着色剂。
可选择地,可以以直肠给药用栓剂的形式给予本发明药学上可接受的组合物。可以通过将药剂与适合的无刺激性赋形剂混合制备它们,所述赋形剂在室温下为固体,而在直肠温度下为液体且由此在直肠中熔化以便释放药物。这种物质包括可可脂、蜂蜡和聚乙二醇类。
本发明药学上可接受的组合物还可以通过局部给药,尤其是在治疗靶标包括易于通过局部施用达到的区域或器官,包括眼、皮肤或小肠道疾病。易于制备用于这些区域或器官各自的适合的局部用制剂。
可以以直肠栓剂(参见上文)或适合的灌肠剂形式进行小肠道的局部施用。还可以使用局部用透皮贴剂。
就局部施用而言,可以将药学上可接受的组合物配制成包含混悬于或溶于一种或多种载体的活性成分的软膏剂。用于局部给予式I的化合物的载体包括但不限于矿物油,液体石蜡,白凡士林,丙二醇,聚氧乙烯,聚氧丙烯化合物,乳化蜡和水。可选择地,可以将药学上可接受的组合物配制成含混悬于或溶于一种或多种药学上可接受的载体中的活性成分的适合的洗剂或霜剂。适合的载体包括但不限于矿物油,硬脂山梨坦,聚山梨醇酯60,鲸蜡酯类,蜡,十六醇十八醇混合物(cetearyl alcohol),2-辛基十二醇,苄醇和水。
就眼部应用而言,可以将药学上可接受的组合物配制成例如在等渗的pH调节的无菌盐水中的微粉化混悬液或其他水溶液,其中使用或不使用防腐剂,例如苯扎氯铵。可选择地,就眼部应用而言,可以将药学上可接受的组合物配制成软膏剂,例如凡士林。还可以通过鼻用气溶胶或吸入给予本发明药学上可接受的组合物。按照药物制剂领域众所周知的技术制备这种组合物并且可以使用苄醇或其他将它们制备成在适合的防腐剂,提高生物利用度的其他吸收促进剂,氟碳化合物和/或其他常用增溶剂或分散剂的盐水中的溶液。
最优选为配制本发明药学上可接受的组合物用于口服给药。
口服给药用的液体剂型包括但不限于药学上可接受的乳剂,微乳,溶液,混悬液,糖浆剂和酏剂。除活性化合物外,液体剂型还可以包含本领域中常用的惰性稀释剂,例如,水或其他溶剂,增溶剂和乳化剂,例如乙醇,异丙醇,碳酸乙酯,乙酸乙酯,苄醇,苯甲酸苄酯,丙二醇,1,3-丁二醇,二甲基甲酰胺,油(特别是棉籽油,花生油,玉米油,胚油,橄榄油,蓖麻油和芝麻油),甘油,四氢糠醇,聚乙二醇类和脱水山梨糖醇的脂肪酸酯类及其混合物。除惰性稀释剂外,口服组合物还可以包括佐剂,例如湿润剂,润滑剂和助悬剂,甜味剂,矫味剂和香味剂。
可以按照本领域公知的方式使用适合的分散剂或湿润剂和混悬剂配制可注射制剂,例如,无菌可注射水或油混悬液。无菌可注射制剂还可以为在无毒性非肠道可接受稀释剂或溶剂中的无菌可注射制剂,例如为在1,3-丁二醇中的溶液。在可以使用的可接受的媒介物和溶剂中有水,林格液,U.S.P.和等渗氯化钠溶液。此外,无菌固定油常用作溶剂或混悬介质。为了这一目的,可以使用任意温和的固定油,包括合成的单酸甘油酯或甘油二酯。脂肪酸,例如油酸及其甘油酯衍生物用于制备可注射制剂。
例如,可以通过经截留细菌的滤膜过滤或通过掺入无菌固体组合物形式的灭菌剂对可注射制剂进行灭菌,所述无菌固体组合物可以在使用前溶于或分散于无菌水或其他无菌可注射介质中。
为了延长式I的化合物的效果,通常期望延缓化合物从皮下或肌内注射中吸收。可以通过使用具有极低水溶性的晶体或非晶形物质的液体混悬液进行该步骤。然后式I的化合物的吸收速率取决于其溶出速率,由此取决于晶体粒度和晶型。可选择地,式I的化合物溶于或悬浮于油介质实现了非肠道给药的化合物形式的延缓吸收。通过在生物可降解聚合物,例如聚丙交酯-聚乙交酯中形成式I的化合物微囊基质制备可注射长效剂型。根据化合物与聚合物之比和所用具体聚合物的不同,化合物的释放速率可以受到控制。其他生物可降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。还通过将式I的化合物截留在与身体组织相容的脂质体或微乳内制备贮库型可注射制剂。
用于直肠或阴道给药的组合物优选为栓剂,可以通过混合式I的化合物与适合的无刺激性赋形剂或载体,例如可可脂,聚乙二醇或栓剂蜡制备它们,这些赋形剂或载体在环境温度下为固体,而在体温下为液体且由此在直肠或阴道腔内熔化并且释放活性化合物。
口服给药用的固体剂型包括胶囊,片剂,丸剂,粉末和颗粒。在这种固体剂型中,将活性化合物与至少一种惰性的药学上可接受的赋形剂或载体混合,例如柠檬酸钠或磷酸二钙和/或:a)填充剂或增量剂,例如淀粉,乳糖,蔗糖,葡萄糖,甘露糖醇和硅酸;b)粘合剂,例如,例如羧甲基纤维素,藻酸盐,明胶,聚乙烯吡咯烷酮,蔗糖和阿拉伯胶;c)保湿剂,例如甘油;d)崩解剂,例如琼脂,碳酸钙,马铃薯或木薯淀粉,藻酸,某些硅酸盐和碳酸钠;e)溶解阻滞剂,例如石蜡;f)吸收促进剂,例如季铵化合物;g)湿润剂,例如,例如鲸蜡醇和单硬脂酸甘油酯;h)吸收剂,例如高岭土和膨润粘土;和i)润滑剂,例如滑石粉,硬脂酸钙,硬脂酸镁,固体聚乙二醇类,十二烷基硫酸钠及其混合物。就胶囊,片剂和丸剂而言,剂型还可以包括缓冲剂。
相似类型的固体组合物也可以用作使用例如乳糖(lactose)或乳糖(milk sugar)以及高分子量聚乙二醇等这种赋形剂的软和硬胶囊中的填充剂。可以使用包衣衣料和壳,例如肠溶衣和其他制药领域众所周知的包衣衣料制备片剂,锭剂,胶囊和颗粒的剂型。它们可以任选包含遮光剂并且还可以具有仅或优先在肠道某些部位任选以延缓方式释放活性组分的组成。可以使用包埋组合物的实例包括聚合物和蜡。相似类型的固体组合物也可以用作使用例如乳糖(lactose)或乳糖(milk sugar)以及高分子量聚乙二醇等这种赋形剂的软和硬胶囊中的填充剂。
活性化合物还可以为具有一种或多种如上所述赋形剂的微囊形式。可以使用包衣衣料和壳,例如肠溶衣,控释包衣衣料和其他制药领域众所周知的包衣衣料制备片剂,锭剂,胶囊和颗粒的固体剂型。在这类固体剂型中,可以将活性化合物与至少一种惰性稀释剂,例如蔗糖,乳糖或淀粉混合。这类剂型还可以包括作为一般实施中使用的非惰性稀释剂的另外的物质,例如压片润滑剂和其他压片助剂,例如硬脂酸镁和微晶纤维素。就胶囊,片剂和丸剂而言,剂型还可以包括缓冲剂。它们可以任选包含遮光剂并且还可以具有仅或优先在肠道某些部位任选以延缓方式释放活性组分的组成。可以使用包埋组合物的实例包括聚合物和蜡。
用于式I的化合物局部或透皮给药的剂型包括软膏剂,糊剂,霜剂,洗剂,凝胶,粉末,溶液,喷雾剂,吸入剂或贴剂。在无菌条件下将活性成分与药学上可接受的载体混合并且可能需要任意所需的防腐剂或缓冲剂。还将眼科用制剂,滴耳剂和滴眼液视为在本发明范围内。另外,本发明关注透皮贴剂的应用,它们具有附加的提供式I的化合物对身体控释的优点。可以通过将式I的化合物溶于或分散于适当介质中制备这类剂型。吸收促进剂也可以用于增加式I的化合物通过皮肤的流量。可以通过提供速率控制膜或通过将式I的化合物分散于聚合物基质或凝胶中控制速率。
优选将式I的化合物配制成易于给药和剂量均匀的单位剂型。本文所用的表达方式“单位剂型”意指适合于所治疗患者的药剂的物理分散单位。然而,可以理解式I的化合物和包含式I的化合物的组合物的总每日剂量由主治医师在合理医学判断范围内决定。用于任何特定患者或生物体的具体有效剂量水平取决于各种因素,包括所治疗的病症和该病症的严重性;所用具体化合物的活性;患者的年龄,体重,一般健康状况,性别和膳食;给药时间,给药途径和所用具体化合物的排泄速率;治疗期限;与所用具体化合物组合或同时使用的药物和医学领域众所周知的类似因素。
可以与载体物质合并产生单一剂型的组合物的式I的化合物的量根据所治疗宿主,特定给药方式的不同而改变。优选应将组合物配制成可以对接受这些组合物的患者给予0.01-100mg/kg体重/天抑制剂的剂量。在一个实例中,将组合物配制成式I的化合物的剂量在5-30mg/kg体重/天。
根据所治疗或预防的具体疾患或疾病的不同,一般给药治疗或预防该疾病的另外的治疗剂也可以存在于本发明的组合物中。本文所用的一般给药治疗或预防的特定疾病或疾患的另外的治疗剂称作“适合于所治疗的疾病或病症”。下文提供了另外的治疗剂的实例。
存在于本发明组合物中的另外的治疗剂的量不超过一般包括该治疗剂作为唯一药剂的组合物中给予的量。优选目前披露的组合物中另外的治疗剂的量占一般存在于包括该药剂作为唯一治疗药剂的组合物中存在的量的约50%-100%。
式I的化合物和包含式I的化合物的组合物的应用
本发明的一个实施方案涉及抑制生物样品中c-Met蛋白激酶活性的方法,所述方法包括使所述生物样品接触式I的化合物或包含所述化合物的组合物的步骤。本文所用的术语“生物样品”意指活生物体外的样品且包括但不限于细胞培养物或其提取物;获自哺乳动物的活检材料或其提取物;和血液,唾液,尿,粪便,精液,泪液或其他体液或其提取物。抑制生物样品中的激酶活性用于本领域技术人员公知的各种目的。这类目的的实例包括但不限于生物样本储存和生物试验。在一个实施方案中,抑制生物样品中激酶活性的方法限于非治疗方法。
术语“c-Met”与“c-MET”、“cMet”、“MET”、“Met”或本领域技术人员公知的其他名称为同义词。
本发明的另一个实施方案涉及抑制患者c-Met激酶活性的方法,所述方法包括对所述患者给予式I的化合物或包含所述化合物的组合物的步骤。
本文所用的术语“c-Met-介导的疾病”或“c-Met-介导的疾患”意指已知c-Met起作用的任何疾病状态或其他有害疾患。术语“c-Met-介导的疾病”或“c-Met-介导的疾患”还意指通过使用c-Met抑制剂治疗缓解的那些疾病或疾患。这种疾患包括但不限于肾癌,胃癌,结肠癌,脑癌,乳腺癌,前列腺癌,肝癌,胰腺癌或肺癌,胶质母细胞瘤,动脉粥样硬化或肺纤维化。
在一个方面中,本发明的特征在于治疗患者增殖性疾病的方法,所述方法包括对所述患者给予治疗有效量的式I的化合物或包含式I的化合物的组合物的步骤。
根据一个实施方案,所述增殖性疾病为癌症,例如肾癌,胃癌,结肠癌,脑癌,乳腺癌,肝癌,前列腺癌和肺癌或胶质母细胞瘤。
本发明在另一个实施方案中涉及在有需要的患者中治疗肝细胞癌或减轻其严重性的方法,所述方法包括对所述患者给予式I的化合物或其组合物。
在另一个实施方案中,所述增殖性疾病是真性红细胞增多症,原发性血小板增多症,慢性特发性黄瘤病,伴有骨髓纤维变性的髓样化生,慢性髓样白血病(CML),慢性粒-单核细胞白血病,慢性嗜酸性白血病,高嗜酸粒细胞综合征,全身肥大细胞病,非典型CML或青少年粒单核细胞白血病。
在另一个实施方案中,所述增殖性疾病是动脉粥样硬化或肺纤维化。
本发明的另一个方面涉及在有需要的患者中抑制肿瘤转移的方法,所述方法包括对所述患者给予式I的化合物或其组合物。
根据所治疗特定疾患或疾病情况的不同,一般给药治疗或预防该疾患的另外的治疗剂也可以存在于本发明的组合物中。本文所用的一般给药治疗或预防的特定疾病或疾患的另外的治疗剂称作“适合于所治疗的疾病或病症”。
在一个实施方案中,可以将化疗剂或其他抗增殖药与式I的化合物联合治疗增殖性疾病和癌症。已知化疗剂的实例包括但不限于烷化剂,例如环磷酰胺,洛莫司汀,白消安,丙卡巴肼,异环磷酰胺,六甲蜜胺,美法仑,磷酸雌莫司汀,六甲基三聚氰胺,氮芥,塞替派,链佐星,苯丁酸氮芥,替莫唑胺,达卡巴嗪,司莫司汀或卡莫司汀;铂药,例如顺铂,卡铂,奥沙利铂,ZD-0473(AnorMED),顺螺铂,洛铂(Aeterna),carboxyphthalatoplatinum,沙铂(Johnson Matthey),四铂BBR-3464,(Hoffmann-La Roche),ormiplatin,SM-11355(Sumitomo),异丙铂或AP-5280(Access);抗代谢药,例如氮胞苷,拓优得,吉西他滨,三甲曲沙,卡培他滨,脱氧考福霉素,5-氟尿嘧啶,氟达拉滨,氟尿苷,喷司他丁,2-氯脱氧腺苷,雷替曲塞,6-巯嘌呤,羟基脲,6-硫鸟嘌呤,地西他滨(SuperGen),阿糖胞苷,氯法拉滨(Bioenvision),2-氟脱氧胞苷,伊罗夫文(MGI Pharma),甲氨蝶呤,DMDC(Hoffmann-La Roche),依达曲沙(idatrexate)或乙炔基胞啶(Taiho);拓扑异构酶抑制剂,例如安吖啶,卢比替康(SuperGen),表柔比星,甲磺酸依沙替康(Daiichi),依托泊苷,quinamed(ChemGenex),替尼泊苷,米托蒽醌,吉马替康(Sigma-Tau),伊立替康(CPT-11),二氟替康(Beaufour-Ipsen),7-乙基-10-羟基-喜树碱,TAS-103(Taiho),托泊替康,依沙芦星(Spectrum),右雷佐生(dexrazoxanet)(TopoTarget),J-107088(Merck & Co),匹蒽醌(Novuspharma),BNP-1350(BioNumerik),若贝霉素类似物(Exelixis),CKD-602(Chong Kun Dang),BBR-3576(Novuspharma)或KW-2170(KyowaHakko);抗肿瘤抗生素,例如更生霉素(放线菌素D),氨萘非特(amonafide),多柔比星(阿霉素),氨萘非特(azonafide),deoxyrubicin,蒽吡唑,戊柔比星,吡罗蒽醌(oxantrazole),柔红霉素(道诺霉素),洛索蒽醌,表柔比星,博来霉素硫酸盐(硫酸博来霉素),吡柔比星,博来霉素酸(bleomycinic acid),伊达比星,博来霉素A,柔红霉素苯腙,博来霉素B,普卡霉素,丝裂霉素C,泊非霉素,MEN-10755(Menarini),氰基吗啉代多柔比星,GPX-100(Gem Pharmaceuticals)或米托蒽醌(诺肖林),抗有丝分裂药,例如紫杉醇,SB 408075(GlaxoSmithKline),多西他赛,E7010(Abbott),秋水仙碱,PG-TXL(Cell Therapeutics),长春碱,IDN 5109(Bayer),长春新碱A,105972(Abbott),长春瑞滨,A 204197(Abbott),长春地辛,LU 223651(BASF),多拉司他汀10(NCI),D 24851(ASTAMedica),根霉素(Fujisawa),ER-86526(Eisai),米伏布林(Warner-Lambert),考布他汀A4(BMS),西马多丁(BASF),异高软海绵素B(PharmaMar),RPR 109881A(Aventis),ZD 6126(AstraZeneca),TXD 258(Aventis),PEG-紫杉醇(Enzon),埃坡霉素B(Novartis),AZ10992(Asahi),T 900607(Tularik),IDN-5109(Indena),T138067(Tularik),AVLB(PrescientNeuroPharma),念珠藻环肽52(Eli Lilly),氮杂埃坡霉素B(BMS),长春氟宁(Fabre),BNP-7787(BioNumerik),auristatin PE(TeikokuHormone),CA-4前体药物(OXiGENE),BMS 247550(BMS),多拉司他汀-10(NIH),BMS 184476(BMS),CA-4(OXiGENE),BMS 188797(BMS)或二十二碳六烯酸和紫杉醇轭合物(taxoprexin)(Protarga);芳香酶抑制剂,例如,氨鲁米特,依西美坦,来曲唑,阿他美坦(BioMedicines),阿那曲唑(anastrazole),YM-511(Yamanouchi)或福美坦;胸苷酸合酶抑制剂,例如培美曲塞(Eli Lilly),诺拉曲塞(Eximias),ZD-9331(BTG)或CoFactorTM(BioKeys);DNA拮抗剂,例如曲贝替定(PharmaMar),马磷酰胺(Baxter International),葡磷酰胺(BaxterInternational),阿帕齐醌(Spectrum Pharmaceuticals),白蛋白+32P(同位素溶液),O6苄基鸟嘌呤(Paligent),thymectacin(NewBiotics)或依度曲肽(Novartis);法尼基转移酶抑制剂,例如,arglabin(NuOncology Labs),非拟肽法尼基转移酶抑制剂(Johnson &Johnson),法尼醇蛋白转移酶抑制剂(Schering-Plough),紫苏子醇(DOR BioPharma)或BAY-43-9006(Bayer);泵抑制剂,例如CBT-1(CBAPharma),佐舒喹达三盐酸盐(Eli Lilly),他立喹达(Xenova),二柠檬酸比立考达(Vertex)或MS-209(ScheringAG);组蛋白乙酰转移酶抑制剂,例如他地那兰(Pfizer),丁酸新戊酰氧基甲酯(Titan),SAHA(Aton Pharma),缩酚酸肽(Fujisawa)或MS-275(ScheringAG);金属蛋白酶抑制剂,例如新伐司他(Aeterna Laboratories),CMT-3(CollaGenex),马立马司他(British Biotech)或BMS-275291(Celltech);核苷还原酶抑制剂,例如,gallium maltolate(Titan),替扎他滨(tezacitabine)(Aventis),triapine(Vion)或didox(Molecules for Health);TNFα激动剂/拮抗剂,例如维鲁利秦(virulizin)(Lorus Therapeutics),来那度胺(revimid)(Celgene),CDC-394(Celgene),依那西普(Immunex Corp.),英夫利昔单抗(Centocor,Inc.)或阿达木单抗(Abbott Laboratories);内皮缩血管肽A受体拮抗剂,例如阿曲生坦(Abbott)YM-598(Yamanouchi)或ZD-4054(Astra Zeneca);视黄酸受体激动剂,例如芬维A胺(Johnson& Johnson),阿利维A酸(Ligand)或LGD-1550(Ligand);免疫调节剂,例如干扰素dexosome疗法(Anosys),个体化癌症疫苗(Antigenics),pentrix(Australian Cancer Technology),GMK(Progenics),ISF-154(Tragen),腺癌疫苗(Biomira),癌症疫苗(Intercell),CTP-37(AVI BioPharma),norelin(Biostar),IRX-2(Immuno-Rx),BLP-25(Biomira),PEP-005(Peplin Biotech),MGV(Progenics),synchrovax疫苗(CTL Immuno),β-alethine(Dovetail),黑瘤疫苗(CTL Immuno),CLL疗法(Vasogen)或p21RAS疫苗(GemVax);激素和抗激素药,例如雌激素,泼尼松,共轭雌激素类,甲泼尼龙,炔雌醇,泼尼松龙,chlortrianisen,氨鲁米特,idenestrol,亮丙瑞林,己酸羟孕酮,戈舍瑞林,甲羟孕酮,leuporelin,睾酮,比卡鲁胺,丙酸睾酮,氟甲睾酮,氟他胺,甲睾酮,奥曲肽,己烯雌酚,尼鲁米特,甲地孕酮,米托坦,他莫昔芬,P 04(Novogen),toremofine,2-甲氧基雌二醇(EntreMed),地塞米松或阿佐昔芬(EliLilly);光动力药,例如,他拉泊芬(Light Sciences),Pd-bacteriopheophorbide(Yeda),Theralux(Theratechnologies),lutetium texaphyrin(Pharmacyclics),莫特沙芬钆(Pharmacyclics)或金丝桃素;和酪氨酸激酶抑制剂,例如伊马替尼(Novartis),kahalide F(PharmaMar),来氟米特(Sugen/Pharmacia),CEP-701(Cephalon),ZD1839(AstraZeneca),CEP-751(Cephalon),厄洛替尼(Oncogene Science),MLN518(Millenium),卡纳替尼(Pfizer),PKC412(Novartis),角鲨胺(Genaera),phenoxodiol,SU5416(Pharmacia),曲妥珠单抗(Genentech),SU6668(Pharmacia),C225(ImClone),ZD4190(AstraZeneca),rhu-Mab(Genentech),ZD6474(AstraZeneca),MDX-H210(Medarex),伐他拉尼(Novartis),2C4(Genentech),PKI166(Novartis),MDX-447(Medarex),GW2016(GlaxoSmithKline),ABX-EGF(Abgenix),EKB-509(Wyeth),IMC-1C11(ImClone)或EKB-569(Wyeth)。
那些另外的药剂可以与包含式I的化合物的组合物分开给予,作为多剂量方案的组成部分。可选择地,那些药剂可以为单一剂型的组成部分,与式I的化合物混合成单一组合物。如果作为多剂量方案的组成部分给予,那么可以彼此同时,依次或在彼此相隔一定期限、通常5小时内给予两种活性剂。
可以与载体物质合并产生单一剂型的式I的化合物和另外的治疗剂(在那些包括如上所述另外的治疗剂的组合物中))的量根据所治疗宿主和特定给药方式的不同而改变。优选应将本发明的组合物配制成可以给予0.01-100mg/kg体重/天的式I的化合物的剂量。在一个实例中,将组合物配制成式I的化合物的剂量在3-30mg/kg体重/天。
在那些包括另外的治疗剂的组合物中,该另外的治疗剂和式I的化合物可以协同起作用。因此,另外的治疗剂在这类组合物中的量低于仅使用该治疗剂的单一疗法中所需的量。在这种组合物中,可以给予0.01-100mg/kg体重/天的另外的治疗剂的剂量。
存在于本发明组合物中的另外的治疗剂的量不超过一般包括该治疗剂作为唯一药剂的组合物中给予的量。优选目前披露的组合物中另外的治疗剂的量占一般存在于包括该药剂作为唯一治疗药剂的组合物中存在的量的约50%-100%。
还可以将式I的化合物或其药物组合物掺入用于涂敷可植入医疗装置,例如假体,人造瓣膜,血管移植物,支架和导管的组合物。例如,血管支架已经用于克服再狭窄(损伤后血管壁再狭窄)。然而,使用支架或其他可植入装置的患者存在血块形成或血小板活化的风险。可以通过使用包含激酶抑制剂的药学上可接受的组合物预涂敷装置预防或缓解这些不需要的作用。合适的涂敷可植入装置的涂层和一般制备描述在美国专利US 6,099,562;US 5,886,026;和US 5,304,121中。涂层一般为生物相容性聚合物材料,例如水凝胶聚合物,聚甲基二硅氧烷,聚己内酯,聚乙二醇,聚乳酸,乙烯乙酸乙烯酯及其混合物。可以任选用氟硅氧烷,多糖类,聚乙二醇,磷脂类或其组合的合适的外涂层覆盖涂层,以赋予组合物控释特性。使用式I的化合物涂敷的可植入装置为本发明的另一个实施方案。
为了更完整地理解本文所述的发明,列出了下列实施例。应理解这些实施例仅用于示例目的,而不应被视为以任何方式限定本发明。
式1化合物的制备
下列定义描述本文所用的术语和缩写:
本文所用的其他缩写、符号和规定与当代科学文献中所使用的那些一致。例如,参见Janet S.Dodd,ed.,The ACS Style Guide:AManual for Authors and Editors,第2版,Washington,D.C.:AmericanChemical Society,1997,将该文献完整地引入本文参考。
本文所用的术语“Rt(min)”意指按照分钟计的与化合物相关的HPLC保留时间。除非另有指示,否则用于得到所报道的保留时间的HPLC方法如下:柱:Zorbax SB C18柱,3.0x 150mm;梯度:10-90%乙腈/水(0.1%TFA),5分钟;流速:1.0mL/分钟;和检测:254 & 214nm。
本发明化合物的制备
实施例1.式II的化合物
化合物1001和1002购自Okeanos Tech,Beijing,China(目录号分别为OK-J-05024和OK-J-05025)。化合物1003由化合物1002通过下列步骤制备:(i)制备甲酯;(ii)用二异丙基氨基锂处理该甲酯,然后用碘甲烷处理;和(iii)水解α,α-二甲基甲酯,得到羧酸。
如反应路线1中所示制备化合物1004。因此,如步骤1-i中所示,在0℃向NaH(60%,在矿物油中,8.47g,212mmol)在DMSO(260mL)中的混悬液中缓慢加入2-甲基丙二酸二乙酯(化合物1005,29.5g,169.4mmol)。将该混合物在0℃搅拌2小时,加入3,4,5-三氟硝基苯(25g,141.2mmol)。将得到的混合物温至RT,搅拌12小时。将该反应混合物倾入饱和NH4Cl水溶液,通过过滤收集沉淀。在用水洗涤3次后,减压干燥得到的2-(2,6-二氟-4-硝基苯基)-2-甲基丙二酸二乙酯(化合物1006[R=CH3],44.5g,95%收率),用于下一步反应。
如步骤1-ii中所示,在氮气气氛中向2-(2,6-二氟-4-硝基-苯基)-2-甲基丙二酸二乙酯(44.5g,135mmol)在MeOH中的溶液中加入Pd/C(10%,4.0g)。用H2替代氮气气氛,将该混合物在50psi氢化3天。用氮气替代H2气氛,将该混合物通过硅藻土过滤,减压除去挥发性物质。减压干燥得到的2-(4-氨基-2,6-二氟苯基)-2-甲基丙二酸二乙酯(化合物1007[R=CH3],40.5g,99%收率),用于下一步反应。
如步骤1-iii中所示,向2-(4-氨基-2,6-二氟苯基)-2-甲基丙二酸二乙酯(40.0g,132.8mmol)在甲醇(200mL)中的溶液中加入6M NaOH(110.7mL,664.0mmol)。将该混合物在100℃加热4小时,冷却至0℃,用浓HCl酸化至得到pH为3。将该混合物温至RT,搅拌3小时。通过过滤收集得到的沉淀,用水洗涤,在50℃、高真空下干燥20小时,得到2-(4-氨基-2,6-二氟苯基)丙酸(化合物1008[R=CH3],22g,84%收率):1H NMR(300.0MHz,DMSO)δ12.25(brs,1H),6.16(d,J=10.8Hz,2H),5.58(s,2H),3.74(q,J=7.2Hz,1H)和1.28(d,J=7.2Hz,3H)ppm。
如步骤1-iv中所示,温和加热2-(4-氨基-2,6-二氟苯基)丙酸(19.0g,94.45mmol)、甘油(35.83g,28.41mL,389.1mmol)、硝基苯(7.209g,6.028mL,58.56mmol)和浓硫酸(30.57g,16.61mL,311.7mmol)的混合物。在最初的剧烈反应停止后,将该混合物加热至170℃ 16小时。冷却后,减压除去挥发性物质,将残余物溶于MeOH(150mL),加入150mL 6N NaOH,将该混合物在110℃加热3小时。冷却至RT后,用浓HCl将该混合物酸化至pH为3。通过过滤收集得到的深色沉淀,用水洗涤。将沉淀溶于乙醇,小心地滴加亚硫酰氯(11.24g,6.891mL,94.45mmol)。在添加完成后,将该混合物在50℃加热20小时。冷却至RT后,减压除去挥发性物质,将残余物溶于饱和NaHCO3和DCM的混合物。分离各层,用DCM萃取水层。用MgSO4干燥合并的有机层,减压减小体积,进行中-压硅胶色谱(0%EtOAc/己烷-30%,36分钟内),得到2-(5,7-二氟喹啉-6-基)丙酸甲酯(14.0g,两步56%收率)。通过将其溶于甲醇(30mL)、用NaOH(16.58mL,6M,99.50mmol)处理得到的溶液、在RT搅拌20小时皂化所述甲酯(5.0g)。用浓HCl小心酸化至pH为2后,通过过滤收集得到的沉淀,在高真空下干燥,得到2-(5,7-二氟喹啉-6-基)丙酸,其用于随后的反应。可以通过与制备化合物1004中所用相同的方法,通过用丙二酸二乙酯替代2-甲基丙二酸二乙酯制备化合物1003。
实施例2.式III化合物的制备
可以如反应路线2中所示制备式III的化合物,其中R2和R3是氢或甲基。因此,如反应路线2的步骤2-i中所示,将式II的适当取代的喹啉乙酸(248.5mmol,1.0当量)和1,3-二氨基硫脲(273.4mmol,1.1当量)混悬于四亚甲基砜(环丁砜,38mL)和水(57mL)的混合物。向该混合物中加入甲磺酸(546.7mmol,2.2当量),此时全部固体溶解。将该反应混合物缓慢温至90℃,将该反应体系在90℃加热40小时。用冰浴冷却该反应混合物,加入水(75mL),然后小心地添加饱和碳酸氢钠(500mL),直到达到pH 8。通过真空过滤收集得到的沉淀,分别用水、饱和碳酸氢钠、水和甲基叔丁基醚洗涤。在55℃真空烘箱内干燥产物,得到式III的化合物。
实施例3.5-(二氟(喹啉-6-基)甲基)-4-氨基-4H-1,2,4-三唑-3-硫醇(化合物1010)的制备
可以如反应路线3中所示制备式III的化合物,其中R2和R3各自是氟且R4是氢。因此,如步骤3-i中所示,向6-碘喹啉(10.0g,39.21mmol,购自Hangzhou Trylead Chemical Technology Co.,Ltd.,China)和铜(纳米粉)(9.964g,156.8mmol)在DMSO(150mL)中的混合物中加入2-溴-2,2-二氟-乙酸乙酯(10.35g,50.97mmol)。将该混合物在60℃加热6h,在此过程中该混合物从红色铜混悬液变成深红近-均匀溶液。冷却至室温后,用乙酸乙酯(300mL)和饱和NH4Cl水溶液(450mL)稀释该混合物。搅拌30分钟后,分离有机层,用水洗涤,用盐水洗涤,用硫酸镁(magnisium sulfate)干燥。减压除去挥发性物质,得到粗产物,为红色液体。通过中压硅胶色谱法纯化(DCM/乙酸乙酯:100%-30%,25min),得到2,2-二氟-2-(喹啉-6-基)乙酸乙酯(化合物1009,51%收率):1H NMR(300.0MHz,CDCl3)d 9.04-9.03(m,1H),8.29-8.21(m,2H),8.15(s,1H),7.93(dd,J=2.1,8.9Hz,1H),7.52(q,J=4.2Hz,1H),4.35(q,J=7.1Hz,2H)和1.34(t,J=7.1Hz,3H)ppm。
如反应路线3步骤3-ii中所示,将化合物1009(10.0g,39.80mmol)溶于乙醇(100mL),加入肼(7.65g,7.50mL,239mmol),将该反应混合物在室温搅拌10分钟。将该混合物倾入2N HCl溶液后,用DCM洗涤该水性混合物两次,将pH调整至8,同时使氮气通过该溶液鼓泡。用DCM(10x)彻底萃取得到的水溶液,用MgSO4干燥合并的有机层,过滤,减压除去挥发性物质,得到2,2-二氟-2-(喹啉-6-基)乙酰肼,为黄色固体(化合物1010,91%收率)。将该化合物未经进一步纯化直接使用。
如反应路线3的步骤3-iii所示,用氢氧化钾(924mg,16.5mmol)处理在EtOH(71mL)中的化合物1010(3.55g,14.97mmol),将该反应混合物温和地温热以达到均匀。加入二硫化碳(1.38g,1.09mL,18.2mmol),将该混合物在90℃搅拌4小时,此时形成中间体化合物5-(二氟(喹啉-6-基)甲基)-1,3,4-噁二唑-2-硫醇钠盐。向回流的溶液加入肼(4.80g,4.70mL,150mmol),然后添加3A分子筛(3g)。回流2小时后,通过过滤除去分子筛,用EtOH洗涤。用冰浴将合并的有机层冷却至0℃,用浓HCl在氮气气氛中处理至得到pH为6.5。通过过滤除去沉淀,将滤液回流4小时,使用迪安-斯达克榻分水器收集任何过量的水。减压除去挥发性物质,将残余物溶于水,将pH调整至6.5。通过过滤收集得到的固体,用水洗涤,干燥,得到5-(二氟(喹啉-6-基)甲基)-4-氨基-4H-1,2,4-三唑-3-硫醇(化合物1011,61%收率):1H NMR(300.0MHz,DMSO)δ14.28(s,1H),9.03-9.02(m,1H),8.56(d,J=8.0Hz,1H),8.31(s,1H),8.16(d,J=8.8Hz,1H),7.90(dd,J=1.9,8.8Hz,1H),7.65(q,J=4.2Hz,1H)和5.69(s,2H)ppm。
实施例4.式IV的化合物
化合物1012和1016购自Ryan Scientific Co.(目录号分别为B021891和11M-321S)。化合物1013和1014购自PrincetonBiomolecular Research(目录号分别为PBMR 006134和PBMR 019329)。化合物1015购自UkrOrgSynthesis(目录号BBV-2081906)。
实施例5.式I的化合物的制备
如反应路线5的步骤5-i所示,将式III的化合物(453.3mmol,1.00当量)和式IV的化合物(476.0mmol,1.05当量)溶于POCl3(1.23升)和环丁砜(246mL)。将得到的混合物在83℃搅拌18小时。减压蒸发挥发性物质,另外将残余物与甲苯一起再减压共沸2次。将得到的油状物缓慢倾入搅拌的冰-水,用二氯甲烷萃取该水溶液,以除去任何残留的环丁砜。用饱和碳酸氢钠(3.2升)处理该水溶液,直到达到pH为7。倾析出得到的油状物,溶于少量甲醇,用二氯甲烷萃取剩余的水层(4次)。将合并的有机萃取物和油状物的甲醇溶液合并,分别用饱和碳酸氢钠、水和盐水洗涤。用无水MgSO4干燥有机层,过滤,减压蒸发,得到粗产物,为浓稠棕色油状物。通过硅胶色谱法纯化产物,用二氯甲烷-5%甲醇的二氯甲烷溶液梯度洗脱。减压蒸发包含产物的级分,得到式I的化合物,其可以进一步通过从二氯甲烷和甲基叔丁基醚中结晶纯化。通过超临界流体色谱法、使用ChiralPakAD-H柱(20mm x 250mm,5微米柱)或ChiralCelOJ-H柱(20mm x 250mm,5微米柱)、用适合的MeOH(0.1%DEA)/CO2之比以适合的流速洗脱,可以将化合物的外消旋混合物分离成其相应的对映异构体。本发明化合物的分析数据如表1中所示。
表1.式I的化合物的物理表征
式I的化合物的生物学测定
实施例2.c-Met激酶抑制测定
使用标准放射性测定试验筛选本发明化合物抑制c-Met激酶活性的能力。简言之,在该激酶测定中,查验33P-ATP中末端33P-磷酸盐至底物polyE4Y的转移。该测定在96孔平板中进行至最终体积100μL/孔,每孔含0.5nM c-Met、100mM HEPES(pH 7.5)、10mM MgCl2、25mMNaCl、0.01%BSA、1mM DTT、0.5mg/mL polyE4Y和35μM ATP。因此,将本发明的化合物溶于DMSO制成10mM起始储备溶液。然后在DMSO中进行顺序稀释而获得用于测定的最终溶液。将1.5μL DMSO或在DMSO中的抑制剂的等分部分加入到各孔中,然后添加33P-ATP,最终添加c-Met和polyE4Y(获自Sigma)。20min后,使用含4mM ATP的50μL 30%三氯乙酸(TCA)使反应停止。将该反应混合物转至0.66mm GF滤板(Corning),用5%TCA洗涤三次。在添加50μL Ultimate GoldTM高效闪烁剂(Packard Bioscience)后,在Packard TopCount NXT MicroplateScintillation and Luminescence Counter(Packard BioScience)中对样品计数。使用Microsoft Excel Solver宏指令计算表2中所示的Ki值以便使数据与竞争性紧密结合抑制的动力学模型拟合。
实施例3.Snu5胃癌细胞中c-Met活性的抑制
还筛选了式I的化合物在改造的Snu5细胞系中抑制荧光素酶-诱导的信号的能力。Snu5[获自美国模式培养物保藏中心(American TypeCulture Collection)(目录号CRL-5973)]是已知超表达为组成型活性的c-Met的人胃癌。用逆转录病毒pCLPCX转导该细胞系,所述逆转录病毒包含由6xAP1启动子反应元件和具有C-末端PEST序列的荧光素酶(来自减少荧光素酶半衰期的小鼠鸟氨酸脱羧酶的蛋白水解信号)组成的遗传构建体。组成型活性的c-Met活化细胞途径(主要是MAP激酶),导致AP-1-诱导的荧光素酶-PEST转录和翻译成终产物,其活性在添加荧光素(来自Promega的Steady-Glo)时被定量为化学发光读出值。残留的发光与c-Met抑制显著关联。通过用嘌呤霉素选择新的细胞系(Snu5-AP1-Luc-Pest)得到稳定的细胞系。使细胞生长在完全培养基中[包含10%胎牛血清(FBS,Hyclone)和青霉素/庆大霉素(Invitrogen)的Iscove′s培养基(Invitrogen)]。将本发明的化合物溶于DMSO制成10mM起始储备溶液。然后用DMSO进行连续稀释并且转至完全培养基制成10x溶液。计数Snu5-AP1-Luc-Pest细胞并且稀释至200,000细胞/mL溶液。将细胞(90μL)加入到具有澄清底板(Costar)的96-黑色孔的各孔中。然后一式三份向细胞中加入10μL 10x化合物溶液。将培养板在37℃/5%CO2孵育箱中孵育。6小时后,向各孔中加入50μL Steady-Glo试剂(Promega)并且将其放置在培养板振荡器上5分钟以确保细胞完全裂解。用1450Microbeta液体闪烁和发光计数器(Perkin-Elmer)读取培养板。使用4-参数拟合,应用绘图软件Prism(GraphPad)计算表2中所示的IC50值。
表2.式I的化合物的对比c-Met受体结合和SNU5活性值
将本说明书中引述的全部公开文献和专利引入参考,就如同将每一篇公开文献或专利各自特别和分别引入参考的含义相同。尽管通过示例和目的在于清楚理解的实施例在一定程度上详细描述了上述发明,但是本领域技术人员显而易见根据本发明的教导可以在不脱离待批权利要求精神或范围的情况下对其进行一些改变和变型。
Claims (18)
2.权利要求1的化合物,其中R1是甲基、乙基、三氟甲基、异丙基或环丙基;R2是氢或甲基;R3是氢或甲基;且R4是氢或氟。
3.权利要求1的化合物,其中R1是甲基、乙基、三氟甲基、异丙基或环丙基;R2和R3各自是氟;且R4是氢。
4.权利要求1的化合物,其中R1是甲基。
5.权利要求1的化合物,其中R1是乙基、三氟甲基、异丙基或环丙基。
6.权利要求1的化合物,其中R2是氢且R3是甲基。
7.权利要求1的化合物,其中R2是甲基且R3是氢。
8.权利要求1的化合物,其中R2和R3各自是氢。
9.权利要求1的化合物,其中R2和R3各自是氟。
10.权利要求4-8任一项的化合物,其中R4各自是氟。
11.权利要求4-9任一项的化合物,其中R4各自是氢。
13.药物组合物,包含权利要求1-9或12任一项的化合物或其药学上可接受的盐和药学上可接受的载体、佐剂或媒介物。
14.权利要求13的组合物,另外包含化疗剂或抗增殖剂、抗炎药、治疗动脉粥样硬化的药剂或治疗肺纤维化的药剂。
15.治疗患者增殖性疾病或减轻其严重性的方法,所述方法包括给予所述患者足以治疗所述增殖性疾病或减轻其严重性用量的权利要求1的化合物或包含所述化合物的药物组合物。
16.权利要求15的方法,其中所述疾病是转移癌。
17.权利要求15的方法,其中所述疾病是胶质母细胞瘤;胃癌;或选自结肠癌、乳腺癌、前列腺癌、脑癌、肝癌、胰腺癌或肺癌的癌症。
18.权利要求15的方法,其中所述疾病是肝细胞癌。
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WO2017114249A1 (zh) * | 2015-12-31 | 2017-07-06 | 北京浦润奥生物科技有限责任公司 | 化合物在制备用于治疗脑胶质瘤的药物中的用途 |
CN109897054A (zh) * | 2017-12-08 | 2019-06-18 | 中国药科大学 | 三唑并噻二唑类c-Met激酶抑制剂的制备方法及其用途 |
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