CN1311678A - 具有蛋白激酶活性的取代的三环吡唑衍生物 - Google Patents
具有蛋白激酶活性的取代的三环吡唑衍生物 Download PDFInfo
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Abstract
是2H[1]-苯并硫杂并[5,4-c]吡唑衍生物、2H[1]-苯并氧杂并[5,4-c]吡唑、1-苯并噻喃[4,3-c]吡唑、1-苯并吡喃[4,3-c]吡唑、4,5-二氢-2H-呋喃并[2,3-g]吲唑、和4,5-二氢-2H-噻吩并[2,3-g]吲唑衍生物、2H[1]-苯并硫杂并[5,4-c]吡唑、1-苯并噻喃[4,3-c]吡唑、4,5-二氢-2H-呋喃并[2,3-g]吲唑、和4,5-二氢-2H-噻吩并[2,3-g]吲唑衍生物的化合物是蛋白激酶活性抑制剂。几种其活性被这些化合物抑制的蛋白激酶参与血管生成和/或水肿过程。因此,这些化合物可改善其中血管生成、水肿或内皮细胞增殖过多或渗透性过高是致病因素的病症。所述疾病有例如癌症、关节炎、动脉粥样硬化、牛皮癣、血管瘤、心肌血管生成、冠状动脉和脑动脉旁路、局部缺血性四肢血管生成、角膜疾病、潮红、新血管性青光眼、黄斑变性、伤口愈合、消化性溃疡螺杆菌相关疾病、骨折、糖尿病性视网膜病、和猫抓热。
Description
发明背景
至少有400种酶被确定为蛋白激酶。这些酶催化靶蛋白底物的磷酸化。磷酸化通常是其中磷酸基从ATP转移到蛋白底物上的转移反应。磷酸基转移到其上的靶底物的特定结构是酪氨酸、丝氨酸或苏氨酸残基。由于这些氨基酸残基是磷酰基转移的靶结构,因此这些蛋白激酶通常被称为酪氨酸激酶或丝氨酸/苏氨酸激酶。
在酪氨酸、丝氨酸和苏氨酸残基上的磷酸化反应和对抗性磷酸酶反应参与无数的细胞过程,这些细胞过程成为对不同的细胞内信号(一般是通过细胞受体介导的)起反应、调节细胞功能、以及将细胞过程活化或失活的基础。蛋白激酶级联经常参与细胞内信号转导,并且是实现这些细胞过程所必需的。由于它们在这些过程中普遍存在,因此可发现蛋白激酶是质膜的整合部分,或者是胞质酶,或者位于核中,并且经常是酶复合物的组分。在许多情况下,这些蛋白激酶是决定细胞内的细胞过程在哪里和何时发生的酶和结构蛋白复合物的必需元素。蛋白酪氨酸激酶
蛋白酪氨酸激酶(PTKs)是催化细胞蛋白中特定酪氨酸残基磷酸化的酶。这些底物蛋白、通常是酶自身的这种翻译后修饰起调节细胞增殖、活化或分化的分子开关的作用(参见Schlessinger和Ulrich,1992,Neuron 9:383-391)。已经在多种病症中观察到了异常或过度的PTK活性,这些病症包括良性和恶性增生性疾病,以及免疫系统的不适当活化所致的疾病(例如自身免疫性疾病),同种移植物排斥,和移植物对宿主疾病。此外,内皮细胞特异性受体PTKs如KDR和Tie-2介导血管生成过程,因此参与支持癌症和其它涉及不适当血管生成的疾病(例如糖尿病性视网膜病、由于老年黄斑变性所致的脉络膜新血管生成、牛皮癣、关节炎、婴儿血管瘤)的进程。
酪氨酸激酶可以是受体型(具有细胞外、跨膜和细胞内结构域)或非受体型(全部在细胞内)。受体酪氨酸激酶(RTKs)
RTKs包括一大家族具有不同生物活性的跨膜受体。目前,已经鉴定了至少19个不同的RTK亚家族。受体酪氨酸激酶(RTK)家族包括对于多种类型细胞的生长和分化起决定性作用的受体(Yarden和Ullrich,Ann.Rev.Biochem.57:433-478,1988;Ullrich和Schlessinger,Cell 61:243-254,1990)。RTKs的固有功能通过配体结合来激活,配体结合导致受体和多种细胞底物磷酸化,从而引发多种细胞反应(Ullrich&Schlessinger,1990,Cell 61:203-212)。因此,受体酪氨酸激酶介导的信号转导是通过下述方式启始的:与特定生长因子(配体)的细胞外相互作用,随后通常是受体的二聚作用,激活固有的蛋白酪氨酸激酶活性,以及受体反式磷酸化。因此,产生了结合位点以适合于细胞内信号转导分子,并导致形成了与辅助适当细胞反应(例如细胞分裂、分化、代谢作用、细胞外微环境变化)的一系列胞质信号分子的复合物(参见Schlessinger和Ullrich,1992,Neuron 9:1-20)。
具有SH2(src同源性-2)或磷酸酪氨酸结合(PTB)结构域的蛋白以高亲和力结合激活的酪氨酸激酶受体及它们的底物,以把信号传播到细胞内。这两个结构域都识别磷酸酪氨酸(Fantl等人,1992,Cell 69:413-423;Songyang等人,1994,Mol.Cell.Biol.14:2777-2785;Songyang等人,1993,Cell 72:767-778;Koch等人,1991,Science 252:668-678;Shoelson,Curr.Opin.Chem.Biol.(1997),1(2),227-234;和Cowburn,Curr.Opin.Struct.Biol.(1997),7(6),835-838)。已经鉴定出了几种与受体酪氨酸激酶(RTKs)结合的细胞内底物蛋白。它们可分为主要的两类:(1)具有催化结构域的底物;和(2)缺乏催化结构域、但是起衔接子作用并与催化活性分子结合的底物(Songyang等人,1993,Cell 72:767-778)。受体或蛋白与它们的底物上的SH2或PTB结构域之间的相互作用的特异性是由直接环绕在磷酸化酪氨酸残基周围的氨基酸残基决定的。例如,SH2结构域与环绕在特定受体上的磷酸酪氨酸残基周围的氨基酸序列之间的结合亲和力的差别与在它们的底物磷酸化分布图中所观察到的差别相关(Songyang等人,1993,Cell 72:767-778)。观察结果表明每种受体酪氨酸激酶的功能不仅决定于其表达模式和配体可利用性,而且决定于由特定受体激活的下游信号转导途径的排列以及那些刺激的时机选择和持续时间。因此,磷酸化提供了重要的调节步骤,该调节步骤决定了由特定生长因子受体和分化因子受体所补充的信号途径的选择性。
人们已经提出几种受体酪氨酸激酶和与其结合的生长因子在血管生成中起作用,虽然它们中有些可能是间接促进血管生成(Mustonen和Alitalo,J.Cell Biol.129:895-898,1995)。称为“胎肝激酶1”(FLK-1)的一种这样的受体酪氨酸激酶是第Ⅲ亚类RTKs中的一员。人FLK-1的另一名称是“含有激酶插入结构域的受体”(KDR)(Terman等人,Oncogene 6:1677-83,1991)。FLK-1/KDR的另一名称是“血管内皮细胞生长因子受体2”(VEGFR-2),这是由于其以高亲和力结合VEGF的缘故。FLK-1/VEGFR-2的鼠变型也已被称为NYK(Oelrich等人,Oncogene 8(1):11-15,1993)。已经分离出了编码小鼠、大鼠和人FLK-1的DNA,并已报道了核苷酸和编码的氨基酸序列(Matthews等人,Proc.Natl.Acad.Sci.USA,88:9026-30,1991;Terman等人,1991,见上文;Terman等人,Biochem.Biophys.Res.Comm.187:1579-86,1992;Sarzani等人,见上文;和Millauer等人,Cell 72:835-846,1993)。有很多研究如在上文中Millauer等人的文献中所报道的研究表明,VEGF和FLK-1/KDR/VEGFR-2是配体-受体对,其在血管内皮细胞的增殖、以及血管的形成和萌发(分别称为血管形成和血管生成)中起重要作用。
称为“类fms酪氨酸激酶-1”(Flt-1)的另一第Ⅲ亚类RTKs与FLK-1/KDR有关(DeVries等人,Science 255;989-991,1992;Shibuya等人,Oncogene 5:519-524,1990)。Flt-1的另一名称是“血管内皮细胞生长因子受体1”(VEGFR-1)。迄今为止,人们已经发现FLK-1/KDR/VEGFR-2和Flt-1/VEGFR-1亚家族的成员主要在内皮细胞上表达。这些亚类成员被配体的血管内皮细胞生长因子(VEGF)家族的成员特异性地激活(Klagsburn和D’Amore,Cytokine&GrowthFactor Reviews 7:259-270,1996)。血管内皮细胞生长因子(VEGF)以比结合FLK-1/KDR更高的亲和力与Flt-1结合,并导致血管内皮细胞有丝分裂(Terman等人,1992,见上文;Mustonen等人,见上文;DeVries等人,见上文)。据信,Flt-1对于血管发育期间的内皮机化是必不可少的。Flt-1的表达与小鼠胚胎中早期的血管发育有关,并且在伤口愈合期间与新血管形成有关(Mustonen和Alitalo,见上文)。Flt-1在成熟器官如肾小球中的表达表明与细胞生长无关的该受体的附加功能(Mustonen和Alitalo,见上文)。
如上所述,最近的证据表明VEGF在正常和病理性血管生成的刺激中起作用(Jakeman等人,Endocrinology 133:848-859,1993;Kolch等人,Breast Cancer Research and Treatment 36:139-155,1995;Ferrara等人,Endocrine Reviews 18(1);4-25,1997;Ferrara等人,Regulation of Angiogenesis(L.D.Goldberg和E.M.Rosen编辑),209-232,1997)。此外,VEGF参与控制和增强血管渗透性(Connolly等人,J.Biol.Chem.264:20017-20024,1989;Brown等人,Regulation of Angiogenesis(L.D.Goldberg和E.M.Rosen编辑),233-269,1997)。
人们已经报道了由mRNA可变剪接所产生的不同形式的VEGF,包括Ferrara等人描述的4种VEGF(J.Cell.Biochem,47:211-218,1991)。Ferrara等人(参见上文)已经鉴定了分泌的和主要与细胞相关的VEGF,并且已知这种蛋白以二硫键连接的二聚体形式存在。
最近已经鉴定出了几种相关的VEGF同系物。然而,迄今为止人们还没有阐明它们在正常生理和疾病过程中的作用。此外,VEGF家族的成员在多种组织中经常与VEGF共表达,并且通常能与VEGF形成杂二聚体。这种特性可能改变了该杂二聚体的受体特异性和生物效应,并进一步使得阐明它们如下所述的特异功能变得复杂(Korpelainen和A1italo,Curr.Opin.Cell Biol.,159-164,1998及其中所引用的参考文献)。
胎盘生长因子(PlGF)具有表现出与VEGF序列有显著同源性的氨基酸序列(Park等人,J.Biol.Chem.269:25646-54,1994;Maglione等人,Oncogene 8:925-31,1993)。像VEGF一样,不同的PlGF源自mRNA的可变剪接,并且该蛋白以二聚体形式存在(Park等人,见上文)。PlGF-1和PlGF-2以高亲和力与Flt-1结合,并且PlGF-2还强有力地与神经纤维网素-1结合(Migdal等人,J.Biol.Chem.273(35):22272-22278),但是二者都不与FLK-1/KDR结合(Park等人,见上文)。据报道,当VEGF以低浓度存在时(似乎是由于形成了杂二聚体),PlGF既增强血管渗透性,又增强VEGF对内皮细胞的致有丝分裂作用(Park等人,见上文)。
VEGF-B以两个同种型(167和185个残基)产生,并且可能地结合Flt-1/VEGFR-1。其通过调制尿激酶型纤溶酶原激活物和纤溶酶原激活物抑制剂1的表达和活性而在细胞外基质降解、细胞粘着、和迁移的调节中起作用(Pepper等人,Proc.Natl.Acad.Sci.U.S.A.(1998),95(20):11709-11714)。
VEGF-C最初是作为主要由淋巴内皮细胞表达的VEGFR-3/Flt-4的配体克隆的。以其全加工形式,VEGF-C也能够结合KDR/VEGFR-2并刺激内皮细胞的增殖和迁移(在体外)以及血管生成(在体内模型中)(Lymboussaki等人,Am.J.Pathol.(1998),153(2):395-403;Witzenbichler等人,Am.J.Pathol.(1998),153(2),381-394)。VEGF-C的转基因过度表达仅引起淋巴管的增殖和增大,并不影响血管。与VEGF不同,VEGF-C的表达不是由氧不足诱导的(Ristimaki等人,J.Biol.Chem.(1998),273(14),8413-8418)。
最近发现的VEGF-D在结构上与VEGF-C非常相似。据报道,VEGF-D结合并活化至少两种VEGFRs、VEGFR-3/Flt-4和KDR/VEGFR-2。VEGF-D最初是作为成纤维细胞的c-fos诱导促分裂原克隆的,并且最主要在肺和皮肤的间质细胞中表达(Achen等人,Proc.Natl.Acad.Sci.U.S.A.(1998),95(2),548-553及其中引用的参考文献)。
已经有人在专利中要求保护通过注射到皮肤组织中用VEGF-C和VEGF-D来在Miles测定中体内诱导血管渗透性的增加(PCT/US97/14696;WO98/07832,Witzenbichler等人,见上文)。这些配体在调节血管渗透性过高中的生理作用和意义以及在表达它们的组织中的内皮反应仍是不确定的。
根据其它VEGF和VEGFRs同系物的发现和配体和受体异二聚作用的先例,这些VEGF同系物的作用可能涉及VEGF配体杂二聚体的形成、和/或受体的异二聚作用,或结合尚未发现的VEGFR(Witzenbichler等人,见上文)。最近的报道还表明,神经纤维网素-1(Migdal等人,见上文)或VEGFR-3/Flt-4(Witzenbichler等人,见上文)或除KDR/VEGFR-2的受体可能诱导血管渗透性(Stacker,S.A.,Vitali,A.,Domagala,T.,Nice,E.,和Wilks,A.F.,“血管生成和癌症”会议,Amer.Assoc.Cancer Res.,Jan.1998,Orlando,FL;Williams,Diabetelogia 40:S118-120(1997))。迄今为止,对于KDR在VEGF-介导的血管渗透性过高中所起的关键作用,没有公开任何直接证据。非-受体酪氨酸激酶
非-受体酪氨酸激酶代表着没有细胞外和跨膜序列的细胞酶。目前,已经鉴定了24种以上独立的非-受体酪氨酸激酶,包括11个亚家族(Src、Frk、Btk、Csk、Abl、Zap70、Fes/Fps、Fak、Jak、Ack和LIMK)。目前,非-受体酪氨酸激酶的Src亚家族由最大量的PTKs构成,并包括Src、Yes、Fyn、Lyn、Lek、Blk、Hck、Fgr和Yrk。Src亚家族酶与肿瘤发生有关。Bolen,1993,Oncogene 8:2015-2031中提供了对非-受体酪氨酸激酶的更详细论述,该文献引入本发明以作参考。
人们已经发现,有许多酪氨酸激酶,不论它们是RTK还是非-受体酪氨酸激酶,都参与包括癌症、牛皮癣、和其它超增殖性疾病或超免疫反应在内的多种病症状态下的细胞信号途径。开发调节PTKs的化合物
鉴于PTK对于控制、调节、和调制细胞增殖、与异常细胞增殖有关的疾病和障碍的所推测的重要性,人们已经作了很多尝试,采用了多种途径来鉴定受体和非-受体酪氨酸激酶“抑制剂”,包括使用突变配体(US 4966849)、可溶性受体和抗体(WO 94/10202;Kendall&Thomas,1994,Proc.Natl.Acad.Sci 90:10705-09;Kim等人,1993,Nature 362:841-844)、RNA配体(Jellinek等人,Biochemistry 33:10450-56;Takano等人,1993,Mol.Bio.Cell4:358A;Kinsella等人,1992,Exp.Cell Res.199:56-62;Wright等人,1992,J.Cellular Phys.152:448-57)和酪氨酸激酶抑制剂(WO 94/03427;WO 92/21660;WO 91/15495;WO 94/14808;US5330992;Mariani等人,1994,Proc.Am.Assoc.Cancer Res.35:2268)。
最近,人们已经尝试着鉴定起酪氨酸激酶抑制剂作用的小分子。例如,双单环、二环或杂环芳基化合物(PCT WO 92/20642)和亚乙烯基吖吲哚衍生物(PCT WO 94/14808)已被描述为酪氨酸激酶抑制剂。苯乙烯基化合物(US 5217999)、苯乙烯基取代的吡啶化合物(US5302606)、一些喹唑啉衍生物(EP申请0566266A1;Expert Opin.Ther.Pat.(1998),8(4):475-478)、硒基吲哚和硒化物(PCT WO94/03427)、三环多羟基化合物(PCT WO 92/21660)以及苄基膦酸化合物(PCT WO 91/15495)已被描述为可用于治疗癌症的酪氨酸激酶抑制剂。苯胺基噌啉(PCT WO 97/34876)和喹唑啉衍生物化合物(PCT WO 97/22596;PCT WO 97/42187)已被描述为血管生成和血管渗透性的抑制剂。
此外,人们已经尝试着鉴定出起丝氨酸/苏氨酸激酶抑制剂作用的小分子。尤其是,据描述二(吲哚基马来酰亚胺)化合物可抑制其机能障碍与VEGF-相关性疾病中改变的血管渗透性有关的特别的PKC丝氨酸/苏氨酸激酶同种型(PCT WO 97/40830;PCT WO 97/40831)。
因此,鉴定出通过调制受体和非-受体酪氨酸和丝氨酸/苏氨酸激酶的活性来特异性抑制信号转导以调节和调制异常或不适当细胞增殖、分化、或代谢的有效小化合物是理想的。尤其是,鉴定出特异性地抑制酪氨酸激酶的功能(对于血管生成过程或导致水肿、腹水、积液、渗出物、大分子外渗和基质沉积及相关疾病的血管渗透性过高形成起关键作用的酪氨酸激酶是必需的)的方法以及化合物将是有益的。
发明简述
本发明涉及下式所示化合物:其中:X是氧或硫;环A代表下述结构:n是1或2;Ar是且R1是氢、甲基、COR3、或SO2R3;R2代表原子量为19-36的卤素;且R3是-CH3或其中Y是氢、氯或-CH3。
上述化合物的立体异构体和立体异构体混合物也包括在本发明范围内。上述化合物的互变异构体也包括在本发明范围内。上述化合物的可药用盐也包括在本发明范围内。
本发明化合物可用作蛋白激酶活性抑制剂。尤其是,本发明化合物可用作在血管生成和/或血管渗透性过程中起重要作用的蛋白激酶的抑制剂。因为本发明化合物具有抗血管生成和/或抗水肿作用,所以它们是用于抑制表现出血管生成和/或水肿的病症的进程的重要物质。
本发明化合物可用作丝氨酸/苏氨酸和酪氨酸激酶抑制剂。尤其是,本发明化合物可用作在超增殖性疾病、特别是在血管生成过程中起重要作用的酪氨酸激酶的抑制剂。因为本发明化合物具有抗血管生成作用,因此它们是用于抑制其中血管生成是重要致病因素的病症的进程的重要物质。
本发明还包括本发明化合物在含有药物有效量本发明化合物和可药用载体或赋形剂的药物组合物中的应用。这些药物组合物可对个体给药以减缓或中止血管生成受益性疾病中的血管生成过程或治疗水肿积液、渗出物、腹水以及与血管渗透性过高有关的其它病症。
发明详述
本发明化合物具有抗血管生成特性。这些抗血管生成特性是至少部分由于抑制了在血管生成过程中起关键作用的蛋白酪氨酸激酶所致。出于该原因,本发明化合物可用作活性剂以治疗诸如关节炎、动脉粥样硬化、牛皮癣、血管瘤、心肌血管生成、冠状动脉和脑动脉旁路、局部缺血性四肢血管生成、伤口愈合、消化性溃疡螺杆菌相关疾病、骨折、猫抓热、潮红、新血管性青光眼、和视网膜病如糖尿病性视网膜病或老年黄斑变性等疾病。此外,某些本发明化合物可用作活性剂以治疗实体瘤、恶性腹水、造血性癌和超增殖性疾病如甲状腺增生(尤其是格雷夫斯病)和囊肿(如特征为多囊卵巢综合征(斯坦因-利文撒尔综合征)的卵巢基质血管过多),这是因为这些疾病需要血管细胞增殖以生长和/或转移。
此外,某些本发明化合物可用作活性剂以治疗烧伤、慢性肺病、中风、息肉、过敏症、慢性和过敏性炎症、卵巢刺激过度综合征、与脑肿瘤相关的脑水肿、高海拔反应、创伤或低氧引起的脑或肺水肿、眼和斑点水肿、腹水、以及血管渗透性过高、积液、渗出物、蛋白外渗或水肿是疾病表征的其它疾病。本发明化合物还可用于治疗其中蛋白外渗导致纤维蛋白和细胞外基质沉积、促进基质增殖的疾病(例如纤维变性、硬变和腕管综合征)。
VEGF是独特的,因为它们是已知促使血管渗透性过高和形成水肿的唯一血管生成性生长因子。实际上,与表达或给予许多其它生长因子有关的血管渗透性过高和水肿可能是通过VEGF生成介导的。炎症细胞因子刺激VEGF生成。在很多组织中,低氧导致VEGF的明显上调,因此涉及梗塞、闭塞、局部缺血、贫血、或循环损伤的情境通常会引起VEGF/VPF介导的反应。血管渗透性过高、相关水肿、改变的跨内皮交换以及通常伴有血细胞渗出的大分子外渗可导致过度基质沉积、基质增殖异常、纤维变性等。因此,VEGF介导的渗透性过高可显著地引起具有这些病因学特征的疾病。
我们认为上述疾病在很大程度上是由涉及KDR/VEGFR-2和/或Flt-1/VEGFR-1酪氨酸激酶的蛋白酪氨酸激酶活性介导的。通过抑制这些酪氨酸激酶的活性,上述疾病的进展被抑制了,这是因为显著地减轻了这些疾病状态的血管生成或血管渗透性过高致病因素所致。由于本发明化合物选择性地作用于特异性酪氨酸激酶,因此使副作用(如果使用具有较小选择性的酪氨酸激酶抑制剂将会发生的副作用)减至最小。
本发明化合物具有抗蛋白激酶的抑制活性。也就是说,本发明化合物调节通过蛋白激酶介导的信号转导。本发明化合物抑制丝氨酸/苏氨酸和酪氨酸激酶类的蛋白激酶。尤其是,本发明化合物选择性抑制KDR/FLK-1/VEGFR-2酪氨酸激酶的活性。一些本发明化合物还抑制其它酪氨酸激酶如Flt-1/VEGFR-1、Src亚家族激酶如Lck、Src、fyn、yes等的活性。此外,一些本发明化合物显著地抑制丝氨酸/苏氨酸激酶如在细胞周期进程中起关键作用的CDKs。通常可改变本发明通式化合物对特定蛋白激酶的效力和特异性,并且可通过改变这些化合物上取代基(即R1、R2和R3)的性质、数目和排列以及构象限制来使其最佳化。此外,一些本发明化合物的代谢物也可能具有显著的蛋白激酶抑制活性。
当对需要用本发明化合物治疗的个体给药时,本发明化合物会在这些个体中抑制血管渗透性过高以及水肿的形成。据信,本发明化合物通过抑制参与血管渗透性过高和水肿形成过程的KDR酪氨酸激酶的活性而起作用。KDR酪氨酸激酶也被称为FLK-1酪氨酸激酶、NYK酪氨酸激酶或VEGFR-2酪氨酸激酶。当血管内皮细胞生长因子(VEGF)或另一活化配体(如VEGF-C、VEGF-D或HIV Tat蛋白)结合到位于血管内皮细胞表面上的KDR酪氨酸激酶上时,KDR酪氨酸激酶被活化。在这种KDR酪氨酸激酶活化之后,会发生血管渗透性过高,流体从血流中穿过血管壁进入组织间隙,由此形成水肿区域。该反应还经常伴有血细胞渗出。同样,在关键组织和器官(例如肺和肾脏)中,过度的血管渗透性过高可破坏正常的跨内皮分子交换,从而引起大分子外渗和沉积。在这种对KDR刺激(据信促进随后的血管生成过程)的急性反应之后,长时间的KDR酪氨酸激酶刺激导致血管内皮细胞增殖和趋化性以及形成新血管。通过抑制KDR酪氨酸激酶活性,即通过阻断活化配体的产生、通过阻断活化配体与KDR酪氨酸激酶受体结合、通过阻止受体二聚作用和反式磷酸化、通过抑制KDR酪氨酸激酶的酶活性(抑制该酶的磷酸化功能),或通过中断其下游信号的一些其它机制(D.Mukhopedhyay等人,Cancer Res.58:1278-1284(1998)及其中引用的参考文献),可抑制和减轻渗透性过高、相关的外渗、随后的水肿形成和基质沉积、以及血管生成反应。
一组优选的本发明化合物具有抑制KDR酪氨酸激酶活性、同时不显著地抑制Flt-1酪氨酸激酶活性(Flt-1酪氨酸激酶也被称为VEGFR-1酪氨酸激酶)的特性。KDR酪氨酸激酶和Flt-1酪氨酸激酶都是由于VEGF分别与KDR酪氨酸激酶受体和Flt-1酪氨酸激酶受体结合而被活化的。因为在内皮维持和血管功能中Flt-1酪氨酸激酶活性可介导重要事件,因此抑制该酶活性可能会产生毒性或不利作用。最起码对于阻断血管生成反应、血管渗透性过高的诱导以及水肿的形成,这种抑制作用不是必需的,因此对于受治疗个体来说,这种抑制作用是浪费和没有任何价值的。一些优选的本发明化合物是独特的,这是因为它们抑制由活化配体活化的一种VEGF受体酪氨酸激酶(KDR)的活性,但是不抑制也是由一些活化配体活化的其它受体酪氨酸激酶如Flt-1。因此,优选的本发明化合物在其酪氨酸激酶抑制活性方面具有选择性。
本发明化合物还可用于治疗溃疡-细菌性、真菌性、莫伦氏溃疡和溃疡性结膜炎。
本发明化合物还可用于治疗其中不需要的血管生成、水肿或基质沉积是在病毒感染如单纯性疱疹、带状疱疹、AIDS、卡波济氏肉瘤、原生动物感染和弓形体病中发生的,在创伤、辐射、中风、子宫内膜异位、卵巢刺激过度综合征、系统性狼疮、肉样瘤病、滑膜炎、克罗恩氏病、镰状细胞性贫血、莱姆病、类天疱疮、佩吉特氏病、粘滞性过高综合征、遗传性出血性毛细血管扩张、慢性炎症、慢性闭塞性肺病、哮喘、类风湿性关节炎和骨关节炎后发生的病症。
本发明化合物还可用于治疗眼科疾病例如眼和斑点水肿、眼睛新血管性疾病、巩膜炎、放射状角膜切开术、眼色素层炎、玻璃体炎、近视、眼球下凹、慢性视网膜脱落、激光后并发症、结膜炎、施塔加特病、伊耳斯氏病、以及视网膜病和黄斑变性。
本发明化合物还可用于治疗心血管病症如动脉粥样硬化、再狭窄、血管闭塞和颈动脉阻塞性疾病。
本发明化合物还可用于治疗与癌症有关的适应征,例如实体瘤,肉瘤(尤其是尤因氏肉瘤和骨肉瘤),成视网膜细胞瘤,横纹肌肉瘤,成神经细胞瘤,造血性恶性肿瘤、包括白血病和淋巴瘤,肿瘤诱导的胸膜或心包积液,和恶性腹水。
本发明化合物还可用于治疗糖尿病性病症如青光眼、糖尿病性视网膜病和微血管病。
我们认为上述疾病在很大程度上是由涉及VEGF受体(例如KDR和Flt-1)的蛋白酪氨酸激酶活性介导的。通过抑制这些受体酪氨酸激酶的活性,上述疾病的进程被抑制了,这是因为显著地减轻了这些病症的血管生成致病因素所致。由于本发明化合物选择性地作用于特异性酪氨酸激酶,因此使副作用(如果使用具有较小选择性的酪氨酸激酶抑制剂将会发生的副作用)减至最小。
另一方面,本发明提供了用作药物、尤其是蛋白激酶活性例如酪氨酸激酶活性、丝氨酸激酶活性和苏氨酸激酶活性抑制剂的其定义如上所述(包括限制条件)的式Ⅰ化合物。另一方面,本发明提供了其定义如上所述(包括限制条件)的式Ⅰ化合物在制备用于抑制蛋白激酶活性的药物中的应用。
在本发明中,下述定义是适用的:
“可药用盐”是指能保持本发明游离碱的生物有效性和特性的盐,所述盐是通过与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸或有机酸如磺酸、羧酸、有机磷酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸、乳酸、酒石酸等反应而获得的。
“烷基”是指饱和脂族烃,包括具有1-4个碳原子的直链或支链基团。
“烷氧基”是指“O-烷基”,其中“烷基”定义同上。药物制剂
本发明化合物可以以自身形式或在它们与适当载体或赋形剂混合的药物组合物中以治疗或改善多种疾病的剂量对病人给药。这些化合物的混合物也可作为单纯合剂或在适当配制的药物组合物中对患者给药。治疗有效的剂量是指足以阻止疾病进展的化合物的量。配制和给药本发明化合物的技术可参见“Remington's PharmaceuticalSciences”,Mack Publishing Co.,Easton,PA,最新版。给药途径
合适的给药途径可包括例如口服给药、滴眼给药、直肠给药、透粘膜给药、局部给药、或肠内给药;非胃肠道给药,包括肌内注射、皮下注射、髓内注射、以及鞘内注射、直接的心室内注射、静脉内注射、腹膜内注射、鼻内注射、或眼内注射。
或者,可将化合物以非系统方式的局部方式给药,例如,通过将化合物直接注射到实体瘤内来给药(通常以储存式制剂或缓释制剂给药)。
此外,可将药物在靶向药物递送系统中给药,例如在包裹有肿瘤特异性抗体的脂质体中给药。脂质体将靶向肿瘤并选择性地被肿瘤摄取。组合物/制剂
本发明药物组合物可通过其自身已知的方式制备,例如,通过常规的混合、溶解、制粒、制糖锭剂、研磨、乳化、装胶囊、包埋或冷冻干燥方法来制备。
可用一种或多种包括赋形剂和促进活性化合物加工成可药用的制剂的辅料在内的可药用载体、以常规方法配制依据本发明使用的药物组合物。适当制剂取决于所选的给药途径。
为了注射,可将本发明活性剂在水溶液、优选在生理相容性缓冲液如Hank's溶液、林格溶液或生理盐水缓冲液中配制。为了透粘膜给药,在制剂中使用有助于渗透过屏障的适当渗透剂。这类渗透剂通常是本领域已知的。
为了口服给药,可通过将活性化合物与本领域众所周知的可药用载体混合来容易地配制本发明化合物。所述载体能使本发明化合物配制成片剂、丸剂、糖锭剂、胶囊剂、液体制剂、凝胶剂、糖浆剂、浆状制剂、悬浮液制剂等,以使待治疗的患者口服摄入。口服用药物制剂可如下所述制得:将活性化合物与固体赋形剂混合,任选将所得混合物研磨,加入适当辅料后(如果需要的话)加工颗粒混合物,以获得片剂或糖锭剂芯。合适的赋形剂尤其是填充剂如糖,包括乳糖、蔗糖、甘露糖醇、或山梨糖醇;纤维素制备物如玉米淀粉、小麦淀粉、大米淀粉、土豆淀粉、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、和/或聚乙烯吡咯烷酮(PVP)。如果需要的话,可加入崩解剂如交联聚乙烯吡咯烷酮、琼脂、或藻酸或其盐如藻酸钠。
给糖锭剂芯提供适当包衣。为了进行包衣,可使用任选含有阿拉伯树胶、滑石、聚乙烯吡咯烷酮、卡波姆凝胶、聚乙二醇、和/或二氧化钛的浓缩糖溶液,涂敷溶液,和合适的有机溶剂或溶剂混合物。可将染料或色素加到片剂或糖浆剂包衣中,以鉴别或表征活性化合物剂量的不同组合。
可口服使用的药物制剂包括由明胶制成的推入配合型胶囊、以及由明胶和增塑剂如甘油或山梨糖醇制成的软的密封胶囊。推入配合型胶囊可含有活性组分与填充剂如乳糖、粘合剂如淀粉、和/或润滑剂如滑石或硬脂酸镁、和任选加入的稳定剂的混合物。在软胶囊中,可将活性化合物溶于或悬浮在适当液体如脂肪油、液体石蜡、或液体聚乙二醇中。此外,可加入稳定剂。所有口服给药制剂都应当呈适于口服给药的剂型。
对于颊给药,组合物可呈以常规方式配制的片剂或锭剂形式。
为了通过吸入给药,使用合适的推进剂,例如,二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳和其它合适气体将按照本发明使用的化合物配制成便于给药的、从加压包装或喷雾器中递送的气雾剂形式。对于加压气雾剂,可通过提供递送计量剂量的阀来决定单位剂量。可配制含有本发明化合物和适当粉末基质如乳糖或淀粉的粉末混合物的、在吸入器或吹入器中使用的、由例如明胶制成的胶囊和药筒。
可将本发明化合物配制成通过注射,例如快速浓注注射或连续输注来进行非胃肠道给药的制剂。注射剂可呈单位剂型,例如在加入防腐剂的安瓿或多剂量容器中。这种组合物可以是在油或水载体中的悬浮剂、溶液剂或乳液,并且可含有配制剂如悬浮剂、稳定剂和/或分散剂。
非胃肠道给药的药物制剂包括水溶形式的活性化合物的水溶液。此外,可制备活性化合物的悬浮液如适当的含油注射悬浮液。合适的亲脂性溶剂或载体包括脂肪油如芝麻油,或合成脂肪酸酯如油酸乙酯或甘油三酯,或脂质体。含水注射悬浮液可含有提高悬浮液粘度的物质,例如羧甲基纤维素钠、山梨糖醇、或葡聚糖。悬浮液也可任选含有合适的稳定剂或提高化合物溶解度以制备高浓度溶液的物质。
或者,活性组分可以呈用于在使用前用合适载体,例如无菌不含热原的水再配制的粉剂形式。
还可以将本发明化合物配制成直肠给药组合物如栓剂或保留灌肠剂,例如含有常规栓剂基质如椰子油或其它甘油酯的栓剂或保留灌肠剂。
除了上述制剂以外,还可将本发明化合物配制成储存式制剂。这种长效制剂可通过植入(例如皮下或肌内植入或肌内注射)来给药。因此,例如可用合适的聚合或疏水性材料(例如配制成在可接受油中的乳液)或离子交换树脂来配制化合物,或者将化合物转化成难溶性衍生物,例如难溶性盐。
用于本发明疏水性化合物的药物载体是包含苯甲醇、非极性表面活性剂、水可混溶有机聚合物、和水相的共溶剂系统。该共溶剂系统可以是VPD共溶剂系统。VPD是由3%w/v苯甲醇、8%w/v非极性表面活性剂吐温80、和65%w/v聚乙二醇300在无水乙醇中配制的溶液。该VPD共溶剂系统(VPD:5W)是由用5%葡萄糖水溶液进行1∶1稀释的VPD构成的。该共溶剂系统能很好地溶解疏水性化合物,并且其自身对系统给药产生很小的毒性。通常,共溶剂系统的比例可变化很大,同时并不破坏其溶解性和毒性特征。此外,该共溶剂系统的组成成分可改变:例如,可使用其它低毒性非极性表面活性剂来代替吐温80;聚乙二醇的份额大小可改变;可用其它生物相容性聚合物例如聚乙烯吡咯烷酮代替聚乙二醇;可用其它糖或多糖代替葡萄糖。
或者,对于疏水性药物化合物可使用其它递送系统。脂质体和乳液是疏水性药物众所周知的递送赋形剂或载体的实例。也可使用一些有机溶剂如二甲亚砜,虽然它们通常以更大的毒为代价性。此外,可用缓释系统如含有治疗剂的固体疏水性聚合物的半渗透基质来递送化合物。现在已经确立了各种缓释材料,并且它们是本领域技术人员所众所周知的。根据其化学性质的不同,缓释胶囊可在从几周到高达100天以上的期间内释放化合物。根据治疗剂的化学性质和生物稳定性,可使用其它用于稳定蛋白的措施。
本发明组合物还可含有合适的固相或凝胶相载体或赋形剂。这类载体或赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖、淀粉、纤维素衍生物、明胶、和聚合物如聚乙二醇。
本发明的许多蛋白激酶调节化合物可以以与药物相容性抗衡离子形成的盐的形式提供。可以与多种酸形成药物相容性盐,所述酸包括但不限于盐酸、硫酸、乙酸、乳酸、酒石酸、苹果酸、琥珀酸等。盐在水或其它质子溶剂中的溶解度比其相应的游离碱形式大。有效剂量
适用于本发明的药物组合物包括其中含有有效量活性组分以实现其治疗目的的组合物。更具体说,治疗有效量是指能有效地阻止被治疗者现有症状的发展或减轻该症状的量。有效量的确定是本领域技术人员众所周知的,尤其是依据本说明书所详细公开的内容更是如此。
对于本发明方法中使用的任一化合物,最初都可用细胞测定法来估计治疗有效剂量。例如,可在动物模型中制订剂量以获得包括在细胞测定中确定的IC50(即达到最大抑制PTK活性一半的测试化合物的浓度)在内的循环浓度范围。这样的信息可用于更精确地确定在人中的适用剂量。
治疗有效剂量是指能改善症状或延长患者存活的化合物的量。可通过标准药理方法在细胞培养物或实验动物中确定这类化合物的毒性和疗效,以确定例如最大耐受剂量(MTD)和ED50(在50%测试群体中治疗有效的剂量)。毒性和治疗效果之间的剂量比是治疗指数,并且可以以MTD和ED50之间的比例来表示。优选表现出高治疗指数的化合物。从这些细胞培养测定和动物研究中获得的数据可用于制定适用于人的剂量范围。这类化合物的剂量优选位于包括ED50在内的引起很小毒性或不引起任何毒性的循环浓度范围内。根据所用剂型和所用给药途径,实际剂量可在该范围内变化。医师可根据患者状况选择适用的制剂、给药途径和剂量(参见例如Fingl等人,1975,“治疗的药理学基础”,Ch.1 p1)。
可独立地调整剂量和给药间隔以提供足以维持激酶调节作用的活性部分的血浆水平或最小有效浓度(MEC)。对于每一化合物,MEC将有所不同,但是可从体外数据估计;例如使用本文所述的测定方法,确定达到激酶的50-90%抑制所需的浓度。达到MEC所需的剂量将取决于个体的特点和给药途径。然而,可使用HPLC测定或生物测定来确定血浆浓度。
还可用MEC值来确定给药间隔。应当采用能在10-90%时间、优选30-90%时间、最优选50-90%时间保持MEC之上的血浆水平的治疗方案来将化合物给药。对于局部给药或选择性摄取,药物的有效局部浓度也许与血浆浓度无关。
当然,组合物的给药量将取决于所治疗的个体、个体体重、患病的严重程度、给药方式以及处方医师的判断。包装
如果需要的话,可在可以包含一个或多个含有活性组分的单位剂型的包装或药物分配装置中提供本发明组合物。包装可以包括例如金属或塑料箔,例如压泡包装。包装或药物分配装置可附有服药指令说明。也可制备包含在相容性药物载体中配制的本发明化合物的组合物,将其置于适当容器中,并贴上说明所治疗的适应征的标签。在标签上指出的适当病症可包括治疗细胞超增殖性疾病、抑制血管生成、治疗纤维变性、糖尿病等。
在某些制剂中,以非常小的颗粒形式(例如通过水力研磨获得的)使用本发明化合物可能是有益的。
在本发明组合物中,如果需要的话,可将活性化合物与其它相容性药理活性组分联合使用。例如,可将本发明化合物与具有下述作用的一种或多种另外的药剂联合给药:抑制或阻止VEGF生成、减轻细胞内对VEGF的反应、阻断细胞内信号转导、抑制血管渗透性过高、减轻炎症、或抑制或预防水肿形成或新血管生成。本发明化合物可在所述另外的药剂给药前给药,或在另外的药剂给药后给药,或者与其同时给药,只要给药过程是合适的即可。所述另外的药剂包括但不限于抗水肿甾类化合物、NSAIDS、ras抑制剂、抗-TNF剂、抗-IL1剂、抗组胺剂、PAF拮抗剂、COX-1抑制剂、COX-2抑制剂、NO合酶抑制剂、PKC抑制剂和PI3激酶抑制剂。本发明化合物与所述另外的药剂以加合或协同方式起作用。因此,与仅施用其中一种物质相比,给予能抑制血管渗透性过高和/或抑制水肿形成的物质的这种组合可更好地减轻高增殖性疾病、血管生成、血管渗透性过高或水肿的有害作用。在恶性疾病的治疗中,优先采用与抗增殖或细胞毒性化疗或放疗的组合。
本发明还包括式Ⅰ化合物作为药物的使用。
Src和Syk家族的激酶都在免疫功能的调控中起关键作用。Src家族通常包括Fyn、Lck、Fgr、Fes、Lyn、Src、Yes、Hck、和Blk。Syk家族通常仅包括Zap和Syk。Janus家族的激酶参与生长因子和促炎细胞因子通过多种受体的信号转导。虽然BTK和ITK、Tec家族激酶的成员在免疫生物学中起着较不为人所知的作用,但是可证明通过抑制剂对它们进行调节在治疗上是有益的。激酶RIP、IRAK-1、IRAK-2、NIK、IKK-1和IKK-2参与关键的促炎细胞因子TNF和IL-1的信号转导途径。由于式Ⅰ化合物能抑制一种或多种这些激酶,因此它们可起免疫调节剂的作用,以用于维持同种移植物和治疗自身免疫性疾病。因为本发明化合物能调节T细胞活化或炎症过程的加强,因此它们可用于治疗这种自身免疫性疾病。目前可利用的免疫抑制剂的毒性限制了骨髓移植(因为宿主对实体器官移植物或移植物对宿主的排斥现象),因此具有改善的治疗指数的有效药物将有助于这种移植。基因寻靶实验已经证实了Src在破骨细胞生物学中的关键作用。因为式Ⅰ化合物能调节Src,所以它们也可用于治疗骨质疏松、骨硬化病、佩吉特氏病、肿瘤诱导的血钙过多、以及可用于治疗骨转移。
已经证实了多种蛋白激酶是原癌基因。染色体断裂(在染色体5上的ltk激酶断裂点)、BCR(费城染色体)的Abl基因所发生的转座、在诸如c-Kit或EGFR情形下发生的截短、或突变(例如Met)导致生成把它们从原癌基因转化成癌基因产物的异常调节蛋白。在其它肿瘤中,自分泌或旁分泌配体/生长因子受体相互作用驱使癌发生。src家族激酶的成员通常参与下游信号转导,从而加强了癌发生,并且它们自身可通过过度表达或突变而变得致癌。通过抑制这些蛋白的蛋白激酶活性,可阻断疾病过程。血管再狭窄可涉及FGF和/或PDGF-促进的平滑肌和内皮细胞增殖的过程。抑制FGFr或PDGFr激酶活性可能是抑制该现象的有效手段。因此,抑制正常或异常c-kit、c-met、c-fms、src家族成员、EGFr、erbB2、erbB4、BCR-Abl、PDGFr、FGFr和其它受体或胞质酪氨酸激酶的激酶活性的式Ⅰ化合物可能在治疗良性和肿瘤性增殖性疾病方面具有价值。
在许多病症(例如实体原发瘤和转移瘤、卡波济氏肉瘤、类风湿性关节炎、由于眼睛不适当新血管生成所致的失明、牛皮癣和动脉粥样硬化)中,疾病进程是由于持续血管生成所附带造成的。疾病组织或相关炎症细胞经常产生多肽生长因子,并且它们相应的内皮细胞特异性受体酪氨酸激酶(例如KDR/VEGFR-2、Flt-1/VEGFR-1、Tie-2/Tek和Tie)对于刺激内皮细胞生长、迁移、机化、分化以及建立必需的新功能血管系统是必不可少的。
作为VEGF在介导血管渗透性过高中的“血管渗透性因子”活性的结果,据信VEGFR激酶的VEGF-刺激还在下述病症的形成中起重要作用:肿瘤腹水,脑和肺水肿,胸膜和心包积液,延迟型过敏反应,创伤、烧伤、局部缺血后的组织水肿和器官机能障碍,糖尿病并发症,子宫内膜异位,成人呼吸窘迫综合征(ARDS),与心肺后旁路有关的低血压和渗透性过高,导致青光眼的眼睛水肿,或由于不适当的新血管生成而导致的失明。除了VEGF以外,最近鉴定的VEGF-C和VEGF-D以及HIV-Tat蛋白也可引起通过刺激VEGFR激酶所致的血管渗透性过高反应。
Tie-2还在一群选择的造血干细胞中表达,在所述造血干细胞中,Tie-2可能在它们的汇集、粘着、调节和分化中起作用(Blood 89,4317-4326(1997));该Tie-2表达群体可起循环血管生成内皮祖体的作用。一些式Ⅰ活性剂能阻断内皮细胞特异性激酶的激酶活性,因此可抑制涉及这些状况的疾病进程。
式Ⅰ化合物或其盐或含有治疗有效量的式Ⅰ化合物或其盐的药物组合物可用于治疗良性和肿瘤性增殖性疾病和免疫系统障碍。这类疾病包括自身免疫性疾病,例如类风湿性关节炎、甲状腺炎、Ⅰ型糖尿病、多发性硬化、肉样瘤病、炎性肠病、重症肌无力和系统性红斑狼疮;牛皮癣、器官移植排斥(例如肾脏排斥、移植物对宿主排斥性疾病)、良性和肿瘤性增殖性疾病,人癌症,例如肺癌、乳腺癌、胃癌、膀胱癌、结肠癌、胰腺癌、卵巢癌、前列腺癌和直肠癌以及造血细胞癌(白血病和淋巴瘤),以及涉及不适当血管生成的疾病,例如人的糖尿病性视网膜病、由于老年黄斑变性所致的脉络膜新血管生成、和婴儿血管瘤。此外,本发明抑制剂还可用于治疗涉及VEGF介导的水肿、腹水、积液和渗出物的疾病,包括例如斑点水肿、脑水肿、和成人呼吸窘迫综合征(ARDS)。
本发明化合物还可用于预防上述疾病。
另一方面,本发明提供了式Ⅰ化合物或其盐在制备用于在哺乳动物、尤其是人中治疗血管渗透性过高、血管生成依赖性疾病、增殖性疾病和/或免疫系统障碍的药物中的应用。
本发明还提供了治疗血管渗透性过高、不适当新血管生成、增殖性疾病和/或免疫系统障碍的方法,包括将治疗有效量的式Ⅰ化合物对需要这种治疗的哺乳动物、尤其是人给药。
可通过下文中详述的方法确定本发明化合物在抑制这些蛋白激酶中的体外效力。
可通过测试化合物相对于对照抑制外源性底物(例如合成肽(Z.Songyang等人,Nature.373:536-539))磷酸化的量来确定化合物的效力。
实施例Ⅰ.合成
式Ⅰ化合物可通过在US 3816438中描述的方法合成。式Ⅱ化合物可通过在US 3816437中描述的方法合成。
通过将式Ⅳ化合物与肼在惰性溶剂中加热来形成吡唑环。该反应优选在35℃-150℃、优选在该系统的回流温度下进行8小时-5天。然后在空气或氧气存在下通过与二氧化硅或氧化铝接触使化合物Ⅴ脱氢以生成化合物Ⅰ。或者,可使用脱氢剂如硫或钯或氧化剂如二氧化锰。当使用脱氢剂或氧化剂时,优选使用惰性溶剂,反应时间为5-50小时,且反应温度为20-250℃。下述反应方案代表该转化。
形成吡唑环的第二种方法是在惰性溶剂中用肼处理式Ⅶ化合物。该反应在30-150℃、优选在该反应混合物的回流温度下进行。下述反应方案代表该转化。
同样,以类似方式,化合物Ⅱ可通过在惰性溶剂中用肼处理化合物Ⅷ而形成。
形成吡唑环的第三种方法是,在催化量的无机酸、强的有机酸或路易斯酸存在下,在惰性溶剂中用肼处理式Ⅸ环氧化物。优选的酸是对甲苯磺酸和三氟化硼。该反应在35℃-200℃、优选在该反应混合物的回流温度下进行。反应时间为8小时-5天。下述反应方案代表该转化。
式Ⅳ化合物是通过在惰性溶剂中、在催化量的酸或碱存在下、用适当的芳基醛Ⅻ处理式Ⅺ化合物而合成的。合适的碱包括氢氧化钠、氢氧化钾、三乙胺、或二乙胺。合适的酸包括盐酸、硫酸、磷酸、乙酸、甲苯磺酸和甲磺酸。该反应的温度为15-100℃,反应时间为2-24小时。下述反应方案代表该转化。
同样,式Ⅵ化合物可通过在惰性溶剂中、在催化量的酸或碱存在下、使式ⅩⅢ化合物与适当的芳基醛反应而合成。
式Ⅸ化合物是通过在惰性气氛下、在惰性溶剂中、在碱性条件下、用芳基醛处理式ⅩⅣ化合物而合成的。合适的碱包括碱金属或碱土金属的氢氧化物、碱金属低级醇盐、脂族叔胺或芳香胺、和环状叔胺如吡啶。该反应在0℃-30℃进行1-5小时。下述反应方案代表该转化。其中Z是离去基团,例如卤素、甲苯磺酸根、甲磺酸根等。
同样,式Ⅹ化合物可通过在碱性条件下、在惰性溶剂中使式ⅩⅤ化合物与适当的芳基醛反应而合成。
式ⅩⅣ和ⅩⅤ化合物是通过标准方法分别由式Ⅺ和ⅩⅢ化合物合成的。例如,可在惰性溶剂中、在室温-50℃、用氯或溴将式Ⅺ化合物处理1-12小时,以生成式ⅩⅣ化合物。
式Ⅶ、Ⅷ、Ⅺ和ⅩⅢ化合物是已知的,并且可通过文献中公开的方法制得。
上述转化的具体实例可参见US 3816438或US 3816437。Ⅱ.体外蛋白激酶测定
下述体外测定可用于测定不同的本发明化合物对一种或多种蛋白激酶的活性和作用的水平。可依据相同思路用本领域众所周知的技术设计用于其它蛋白激酶的类似测定。
A.用杆状病毒系统制备KDR蛋白:
用从HUVEC细胞中分离的cDNA通过PCR产生KDR细胞内结构域(aa789-1354)的编码序列。也在该蛋白的N-末端引入多聚-His6序列。在Xba1和Not1位点将该片段克隆到转染载体pVL1393中。用BaculoGold转染试剂(PharMingen)通过共转染产生重组杆状病毒(BV)。将重组BV进行噬斑纯化,并通过Western分析检验。为了产生蛋白,将SF-9细胞以2×106/ml的量在SF-900-Ⅱ培养基中培养,并以0.5噬斑形成单位/细胞(MOI)感染。在感染后48小时收获细胞。
B.纯化KDR
通过将50 ml Triton X-100溶胞缓冲液(20 mM Tris,pH 8.0,137 mM NaCl,10%甘油,1%Triton X-100,1 mM PMSF,10μg/ml抑肽酶,1μg/ml亮抑蛋白酶肽)加到由1 L细胞培养物获得的细胞沉淀中,使表达(His)6KDR(aa789-1354)的SF-9细胞溶解。在SorvalSS-34旋转器中,在4℃,以19,000 rpm将溶胞产物离心30分钟。将该溶胞产物加到用50 mM HEPES,pH 7.5,0.3 M NaCl平衡过的5ml NiCl2螯合琼脂糖柱上。用含有0.25 M咪唑的相同缓冲液洗脱KDR。采用SDS-PAGE和测定激酶活性的ELISA测定(下文)分析该柱洗脱部分。将纯化的KDR交换到25mM HEPES,pH 7.5,25mM NaCl,5mM DTT缓冲液中,并于-80℃贮存。制备和纯化人Tie-2激酶
用从人胎盘中分离的cDNA作为模板通过PCR产生人Tie-2细胞内结构域(aa775-1124)的编码序列。在N-末端引入多聚-His6序列,并在Xba1和Not1位点将该构建物克隆到转染载体pVL1393中。用BaculoGold转染试剂(PharMingen)通过共转染产生重组BV。将重组BV进行噬斑纯化,并通过Western分析检验。为了产生蛋白,将SF-9昆虫细胞以2×106/ml的量在SF-900-Ⅱ培养基中培养,并以0.5的MOI感染。使用与筛选KDR所用的方法相似的方法纯化该His-标记的激酶。制备和纯化人Flt-1酪氨酸激酶
使用杆状病毒表达载体pVL1393(Phar Mingen,Los Angeles,CA)。将编码多聚-His6的核苷酸序列的5’端置于编码整个人Flt-1细胞内激酶结构域(氨基酸786-1338)的核苷酸区域内。编码该激酶结构域的核苷酸序列是用从HUVEC细胞中分离的cDNA文库通过PCR产生的。该组氨酸残基使得能够按照与KDR和ZAP70类似的方式亲和纯化该蛋白。以0.5的感染复数感染SF-9昆虫细胞,并在感染后48小时收获细胞。EGFR酪氨酸激酶来源
EGFR购自Sigma(Cat#E-3641;500单位/50μl),EGF配体得自Oncogene Research Products/Calbiochem(Cat#PF011-100)。表达ZAP70
所用杆状病毒表达载体是pVL1393(Phar Mingen,Los Angeles,CA)。将编码氨基酸M(H)6LVPR9S的核苷酸序列的5’端置于编码整个ZAP70(氨基酸1-619)的区域内。编码该ZAP70编码区的核苷酸序列是用从Jurkat无限增殖T-细胞中分离的cDNA文库通过PCR产生的。该组氨酸残基使得能够亲和纯化该蛋白。以0.5的感染复数感染SF-9昆虫细胞,并在感染后48小时收获细胞。提取和纯化ZAP70
将SF-9细胞在由20 mM Tris,pH 8.0,137 mM NaCl,10%甘油,1%Triton X-100,1 mM PMSF,10μg/ml抑肽酶,1μg/ml亮抑蛋白酶肽和1 mM正钒酸钠组成的缓冲液中溶解。将该可溶性溶胞产物加到用50 mM HEPES,pH 7.5,0.3 M NaCl平衡过的螯合琼脂糖HiTrap柱(Pharmacia)上。用250 mM咪唑洗脱融合蛋白。将该酶贮存在含有50 mM HEPES,pH 7.5,50 mM NaCl和5 mM DTT的缓冲液中。Lck来源
Lck或Lck的截短形式可商购获得(例如购自UpstateBiotechnology Inc.(Saranac Lake,N.Y)和Santa CruzBiotechnology Inc.(Santa Cruz,Ca.)),或者用常规方法由已知的天然或重组来源纯化得到。Cdc2来源
该人重组酶和测定缓冲液可商购获得(New England Biolabs,Beverly,MA.USA),或者用常规方法由已知的天然或重组来源纯化得到。Cdc2测定
所用方案是将购买的试剂所附的说明进行较小改变而形成的方案。简言之,在由50mM Tris pH 7.5,100 mM NaCl,1mM EGTA,2mMDTT,0.01%Brij,5%DMSO和10mM MgCl2组成的(市售缓冲液)、补充有新鲜的300μM ATP(31μCi/ml)和30μg/ml Ⅲ SS型组蛋白(终浓度)的缓冲液中进行反应。在或不在抑制剂存在下,将含有酶单位的80μl反应混合物在25℃进行20分钟。通过加入120μl 10%乙酸来终止反应。通过将该混合物点在磷酸纤维素纸上、然后用75mM磷酸洗涤3次(每次5分钟)来从未掺入的标记物中分离出底物。在液体闪烁剂存在下用β计数器测得计数。
一些本发明化合物以50μM以下的浓度显著地抑制cdc2。PKC激酶来源
催化亚单位PKC可商购获得(Calbiochem)。PKC激酶测定
按照出版的方法(Yasuda,I.,Kirshimoto,A.,Tanaka,S.,Tominaga,M.,Sakurai,A.,Nishizuka,Y.Biochemical andBiophysical Research Communication 3:166,1220-1227(1990))进行放射性激酶测定。简言之,所有反应都是在由50 mM Tris-HClpH7.5,10mM MgCl2,2mM DTT,1mM EGTA,100μM ATP,8μM肽,5%DMSO和33P ATP(8Ci/mM)组成的激酶缓冲液中进行的。将化合物和酶在反应容器中混合,通过加入ATP和底物混合物使反应开始。加入10μl终止缓冲液(在75mM磷酸中的5 mM ATP)终止反应后,将一部分该混合物点到磷酸纤维素滤纸上。将该点滴样品在室温下用75 mM磷酸洗涤3次(每次5-15分钟)。通过液体闪烁计数法定量测定所掺入的放射标记物。Erk2酶来源
该重组小鼠酶和测定缓冲液可商购获得(New England Biolabs,Beverly MA.USA),或者可通过常规方法由天然或重组来源纯化得到。Erk2酶测定
简言之,在由50mM Tris pH 7.5,1mM EGTA,2mM DTT,0.01%Brij,5%DMSO和10mM MgCl2组成的(市售缓冲液)、补充有新鲜的100μMATP(31μCi/ml)和30μM髓磷脂碱性蛋白的缓冲液中、在供应商推荐的条件下进行反应。反应混合物以及测定所掺入的放射活性的方法如PKC测定(上文)所述。
C.酶联免疫吸附测定(ELISA)
酶联免疫吸附测定(ELISA)可用于检测和测量存在的酪氨酸激酶活性。可依据在例如Voller等人,1980,“酶联免疫吸附测定”,见:Manual of Clinical Immunology,2d ed.,Rose和Friedman编辑,pp 359-371 Am.Soc.of Microbiology,Washington,D.C.中描述的已知方案进行ELISA。
可将上述公开的方案改动以适于测定特异性RTK的活性。例如,下文中提供了进行用于KDR的ELISA实验的优选方案。改动这些方案以适于测定化合物对于RTK家族其它成员以及非受体酪氨酸激酶的活性,这对于本领域技术人员来说是无需付出创造性劳动的。KDR体外ELISA
使用下述方法以测定本发明化合物对KDR酪氨酸激酶活性的抑制作用:缓冲液和溶液:PGT∶Poly(Glu,Tyr)4∶1
在-20℃贮存粉末。将粉末溶于磷酸盐缓冲盐水(PBS)中以制备50 mg/ml溶液。在-20℃贮存1 ml等分试样。当制备培养板时在GibcoPBS中稀释至250μg/ml。反应缓冲液:
100mM Hepes,20mM MgCl2,4mM MnCl2,5mM DTT,0.02%BSA,200μM NaVO4,pH 7.10ATP:在-20℃贮存100 mM的等分试样。在水中稀释至20μM。洗涤缓冲液:
含有0.1%吐温20的PBS抗体稀释缓冲液:
在使用前立即将TMB底物和过氧化物溶液以9∶1比例混合,或者使用购自Neogen的K-Blue底物终止溶液:
1M磷酸方法1.制备培养板:
将PGT贮备液(50 mg/ml,冷冻)在PBS中稀释至250μg/ml。向Corning改良平底高亲和性ELISA板(corning#25805-96)的每个孔中加入125μl。向空白孔中加入125μl PBS。用密封带覆盖,并在37℃培养过夜。用250μl洗涤缓冲液洗涤1次,并在37℃干燥恒温箱中干燥约2小时。
将包被的培养板在密封袋中于4℃贮存直至使用。2.酪氨酸激酶反应:-在20%DMSO水溶液中以4×浓度制备抑制剂溶液。-制备反应缓冲液-制备酶溶液,以使预期单位是在50μl溶液中,例如,对于KDR,制成1 ng/μl的溶液,在反应中,每孔中共加入50 ng酶。贮存在冰上。-用100 mM贮存在水中的ATP溶液制备20μM的4×ATP溶液。贮存在冰上-每孔加入50μl酶溶液-加入25μl 4×抑制剂-加入用于抑制剂测定的25μl 4×ATP-在室温培养10分钟-通过每孔中加入50μl 0.05N Hcl来停止反应-洗涤培养板**反应的终浓度:ATP:5μM5%DMSO3.抗体结合-通过2步稀释(100X,然后200×),在0.1%BSA的PBS溶液中,将1 mg/ml等分试样的PY20-HRP(Pierce)抗体稀释至50 ng/ml。-每孔中加入100μl Ab。在4℃培养1小时。-将培养板洗涤4次4.颜色反应-制备TMB底物,每孔中加入100μl-在650 nm监视OD直至达到0.6-用1M磷酸停止。在平板读数器上摇动。-在450 nm立即读取OD
对于酶制备物,最佳培养次数和酶反应条件变化很小,并且每批都可凭经验确定。
对于Lck,所用反应缓冲液是100mM MOPSO,pH 6.5,4mM MnCl2,20mM MgCl2,5mM DTT,0.2%BSA,200mM NaVO4,采用类似测定条件。
式Ⅰ化合物可具有治疗疾病的治疗应用,所述疾病涉及可通过式Ⅰ化合物抑制的、已经鉴定(包括本说明书未提及的)和尚未鉴定的蛋白酪氨酸激酶。所有本说明书中例举的化合物都以50微摩尔或50微摩尔以下的浓度显著地抑制KDR激酶。一些本发明化合物还以50微摩尔或50微摩尔以下的浓度显著地抑制其它PTKs如lck。结果
获得了代表性化合物的下列抑制浓度:
ELISA测定 | 化合物Ⅲ的IC50 |
KDR | 13.4μM |
Lck | >30.0μM |
TIE2 | >30.0μM |
zapfl | 30.3μM |
这些结果证实了本发明化合物对于KDR酪氨酸激酶以及其它激酶具有显著的抑制活性。T-细胞活化的体外模型
通过促细胞分裂剂或抗原的活化来诱导T-细胞分泌IL-2-支持T-细胞后续增殖期的生长因子。因此,可测定由于原代T-细胞的细胞增殖所产生的IL-2或适当的T-细胞系来作为T-细胞活化的代替物。这些测定都在文献中充分地描述过,并且很好地记载了其参数(见Current Protocols in Immunology,Vol 2,7.10.1-7.11.2)。
简言之,T-细胞可通过与同种异型刺激器细胞共培养-称为单向混合淋巴细胞反应的方法-来活化。通过Ficoll-Hypaque梯度装置(Pharmacia)、按照生产商的指导说明纯化响应器和刺激器外周血单核细胞。通过用丝裂霉素C(Sigma)处理或γ辐射来将刺激器细胞进行有丝分裂的失活。在或不在测试化合物存在下,将响应器和刺激器细胞以2∶1的比例共培养。通常将105个响应器与5×104个刺激器混合并铺在(200μl体积)U形底微量滴定板(Costar Scientific)上。将细胞在补充有热灭活胎牛血清(Hyclone Laboratories)或混合人AB血清(来自男性供体)、5×10-5M 2-巯基乙醇和0.5%DMSO的RPMI1640中培养,在收获前一天(一般是第三天)向该培养物中用脉冲输送0.5μCi3H胸腺嘧啶核苷(Amersham)。收获(用Betaplate收获器,Wallac)该培养物,通过液体闪烁法(Betaplate,Wallac)测定同位素摄取。
该同一培养系统可用于通过测定IL-2生成来评估T-细胞活化。培养开始18-24小时后,除去上清液,按照生产商的指导说明通过ELISA(R和D系统)测定IL-2的浓度。T-细胞活化的体内模型
可在已知用于直接测定T-细胞活化或据证实T-细胞是其效应器的动物模型中测定化合物的体内效力。可通过将T-细胞受体的恒定部分与单克隆抗-CD3抗体(Ab)连接来体内激活T-细胞。在该模型中,在取血前2小时对BALB/c小鼠腹膜内给予10μg抗-CD3 Ab。在给予抗-CD3 Ab前1小时,用单剂量的化合物对欲接受测试药物的动物进行预处理。通过ELISA测定促炎细胞因子干扰素-γ(IFN-γ)和肿瘤坏死因子-α(TNF-α)(T-细胞活化的指示剂)的血清水平。类似模型在体内使用用特异性抗原如匙孔血蓝蛋白(KLH)引发的T-细胞,然后用相同抗原在体外第二次攻击排出的淋巴结细胞。如上所述,通过测定细胞因子产生来评估培养细胞的活化状态。简言之,在第0天通过皮下给予在完全弗氏佐剂中乳化的100μg KLH来对C57BL/6小鼠进行免疫接种。在免疫接种前一天,然后在免疫接种后第1、2和3天用化合物用化合物预处理动物。在第4天收获排出的淋巴结,将它们的细胞以6×106/ml的量在组织培养基(补充有热灭活胎牛血清(Hyclone Laboratories)、5×10-5M 2-巯基乙醇和0.5%DMSO的RPMI1640)中培养24和48小时。然后通过ELISA估测培养物上清液中自分泌T-细胞生长因子白细胞介素-2(IL-2)和/或IFN-γ的水平。
还可在人疾病动物模型中测试先导化合物。这可通过实验自身免疫性脑脊髓炎(EAE)和胶原诱导的关节炎(CIA)来举例说明。已经有人描述过在大鼠和小鼠中建立的模拟人多发性硬化的EAE模型(FASEB J.5:2560-2566,1991;小鼠模型:Lab.Invest.4(3):278,1981;啮齿动物模型:J.Immunol 146(4):1163-8,1991)。简言之,用髓磷脂碱性蛋白(MBP)或其神经原肽衍生物和CFA的乳液将小鼠或大鼠免疫接种。通过加入细菌毒素如百日咳博代氏杆菌(bordetellapertussis)来诱导急性疾病。通过T-细胞从用MBP/肽免疫接种的动物中的继承性转移来诱导疾病的恢复/缓解。
CIA可在DBA/1小鼠中通过用Ⅱ型胶原免疫接种来诱导(J.Immunol:142(7):2237-2243)。用胶原攻击后,小鼠将在早至10天表现出关节炎症状,并且可在免疫接种后长至90天的时间打分。在EAE和CIA模型中,可将化合物进行预防性给药,或者在疾病发作时给药。有效力的药物应当能减轻严重程度和/或发病率。
在这些模型中,抑制一种或多种血管生成性受体PTK、和/或蛋白激酶如参与介导炎性反应的lck的一些本发明化合物可减轻关节炎的严重程度和发病率。
可以还在小鼠皮肤(Ann.Rev.Immunol.,10:333-58,1992;Transplantation:57(12):1701-17D6,1994)或心脏(Am.J.Anat.:113:273,1963)同种移植物模型中测试化合物。简言之,将全厚皮肤移植物从C57BL/6小鼠移植到BALB/c小鼠中。从第6天开始,每天都检查移植物,以观察排斥的迹象。在小鼠新生儿心脏移植模型中,把新生儿心脏从C57BL/6小鼠中异位移植到成年CBA/J小鼠的耳廓中。移植后4-7天,心脏开始跳动,通过用解剖显微镜观察心跳的停止来目测评定排斥反应。细胞受体PTK测定
使用下述细胞测定来确定不同本发明化合物对KDR/VEGFR2的活性和作用的水平。可用本领域众所周知的技术、按照相同思路来设计用于其它酪氨酸激酶的采用特异性配体刺激的类似受体PTK测定。
通过蛋白质印迹法测定人脐静脉内皮细胞(HUVEC)中VEGF-诱导的KDR磷酸化。
1.HUVEC细胞(来自混合供体)购自Clonetics(San Diego,CA),并依据生产商的指导说明培养。在该测定中仅使用早期传代(3-8)细胞。在100mm培养皿(用于组织培养的Falcon;BectonDickinson;Plymouth,England)中用完全EBM培养基(Clonetics)培养细胞。
2.为了评价化合物的抑制活性,将细胞进行胰蛋白酶作用,并以0.5-1.0×105细胞/孔的量接种到6-孔簇式培养板(Costar;Cambridge,MA)的各孔中。
3.接种3-4天后,培养板达到了90-100%融合。将培养基从所有孔中取出,将细胞用5-10 ml PBS洗涤,并用不加入任何补充物(即血清饥饿)的5 ml EBM基础培养基培养18-24小时。
4.将系列稀释的抑制剂加到1 ml EBM培养基中(终浓度为25μM、5μM、或1μM),将该培养基加到细胞中并在37℃培养1小时。然后将终浓度为50 ng/ml、在2 ml EBM培养基中的人重组VEGF165(R&D Systems)加到所有孔中,并在37℃培养10分钟。使用未用VEGF处理或仅用VEGF处理的对照细胞来评价通过VEGF诱导的背景磷酸化和磷酸化。
然后将所有孔用5-10 ml含有1 mM正钒酸钠(Sigma)的冷的PBS洗涤,将细胞溶解并刮擦到含有蛋白酶抑制剂(PMSF 1mM,抑肽酶1μg/ml,胃蛋白酶抑制剂1μg/ml,亮抑蛋白酶肽1μg/ml,钒酸钠1mM,氟化钠1mM)和1μg/ml DNA酶(所有化学药品都购自Sigma ChemicalCompany,St Louis,MO)的200μl RIPA缓冲液(50 mM Tris-HCl,pH7,150mM NaCl,1%NP-40,0.25%脱氧胆酸钠,1mM EDTA)中。将该溶胞产物以14000 rpm的转速离心30分钟,以除去细胞核。
然后通过加入冷(-20℃)的乙醇(2体积)用最少1小时或最多过夜的时间沉淀出等量蛋白。将该蛋白沉淀物重悬在含有5%β-巯基乙醇的Laemli样品缓冲液(BioRad;Hercules,CA)中,并煮沸5分钟。通过聚丙烯酰胺凝胶电泳(6%,1.5mm Novex,San Deigo,CA)解析该蛋白,并用Novex系统将蛋白转移到硝基纤维素膜上。用牛血清白蛋白(3%)阻断后,在4℃用抗-KDR多克隆抗体(C20,Santa CruzBiotechnology;Santa Cruz,CA)或用抗-磷酸酪氨酸单克隆抗体(4G10,Upstate Biotechnology,Lake Placid,NY)将蛋白探测过夜。洗涤并与HRP缀合的山羊抗-兔或山羊抗-鼠IgG的F(ab)2培养1小时后,用发射化学发光(ECL)系统(Amersham Life Sciences,Arlington Height,IL)将谱带显形。
一些本发明实例化合物以低于50μM的浓度显著地抑制了细胞VEGF-诱导的KDR酪氨酸激酶磷酸化。子宫水肿体内模型
这一测定用来测量化合物抑制用雌激素刺激后头几个小时中出现的小鼠子宫重量急性增加的能力。已知早期发生的子宫重量增加是由于子宫血管渗透性增加而导致的水肿所致。Cullinan-Bove和Koss(Endocrinology(1993),133:829-837)证实了雌激素刺激的子宫水肿与子宫中VEGF mRNA的表达增加之间密切的时间关系。通过使用显著地减轻了雌激素刺激后的子宫重量急性增加的VEGF的中和单克隆抗体(WO 97/42187)已经证实了上述结果。因此,该系统可作为体内抑制VEGF信号以及相关的渗透性过高和水肿的模型。材料:所有激素都购自Sigma(St.Louis,MO)或Cai Biochem(LaJolla,CA),是冻干粉末,并且依据供应商的教导进行制备。载体组分(DMSO,Cremaphor EL)购自Sigma(St.Louis,MO)。小鼠(Balb/c,8-12周龄)购自Taconic(Germantown,NY),并依据institutional Animal Care and Use Committee Guidelines在不含病原体的动物设施中饲养。方法:
第1天:对Balb/c小鼠腹膜内(i.p.)注射12.5单位妊娠母马血清促性腺素(PMSG)。
第3天:对小鼠腹膜内注射15单位人绒毛膜促性腺激素(hCG)。
第4天:将小鼠随机分成5-10组。根据溶解度和载体,通过腹膜内、静脉内或口服途径以1-100 mg/kg的剂量给予测试化合物。载体对照组仅接受载体,有两组未处理。
30分钟后,给实验组、载体组和1个未治疗组腹膜内注射17 β-雌二醇(500 μg/kg)。2-3小时后,通过吸入CO2将动物处死。从中线切开后,通过刚好在子宫颈下面、且在子宫和输卵管接合处的位置切割来分离并取出各子宫。在称重前,小心除去脂肪和结缔组织,注意不要破坏子宫的完整性。比较处理组与未处理组或载体处理组的平均重量。通过Student’s t检验确定显著性。使用未刺激对照组来监测雌二醇反应。
结果证实,当通过不同途径系统给药时,一些本发明化合物抑制了水肿的形成。
是血管生成性受体酪氨酸激酶抑制剂的一些本发明化合物还可在新血管生成的Matrigel移植物模型中表现出活性。该Matrigel新血管生成模型包括在皮下移植的、由产生肿瘤细胞的促血管生成因子的存在而诱导的清楚的细胞外基质“大理石”内形成新血管(例如参见:Passaniti,A.,等人,Lab.Investig.(1992),67(4),519-528;Anat.Rec.(1997),249(1),63-73;Int.J.Cancer(1995),63(5),694-701;Vasc.Biol.(1995),15(11),1857-6)。该模型优选运行3-4天,并且终点包括,取出移植物后,目视检查新血管生成/给新血管生成进行成像打分、目视测定微血管密度、和定量测定血红蛋白(Drabkin方法),将这些结果与从未用抑制剂处理的动物中取出的对照移植物的结果比较。或者该模型可采用bFGF或HGF作为刺激物。
抑制一种或多种致癌、原致癌、或增殖依赖性蛋白激酶、或血管生成性受体PTK的一些本发明化合物还在小鼠中抑制原发小鼠、大鼠或人异种移植肿瘤的生长,或在小鼠模型中抑制肿瘤转移。等同方案
虽然已经用优选的实施方案具体地表明和描述了本发明,但是本领域技术人员应当理解,可在不背离如所附权利要求书所限定的本发明实质和范围的前提下对本发明在形式和细节上作各种改变。使用至多常规实验,本领域技术人员应当认识到或者能够确定本说明书中具体描述的本发明具体实施方案的许多等同方案。这些等同方案也包括在本申请权利要求书所限定的范围内。
Claims (14)
2.权利要求1的应用,其中所述化合物是以其立体异构形式或其立体异构体混合物的形式存在。
3.权利要求1的应用,其中所述化合物是在与一种或多种其它所述化合物的混合物中。
4.权利要求1的应用,其中所述蛋白激酶是受体酪氨酸激酶或非受体酪氨酸激酶。
5.权利要求4的应用,其中所述酪氨酸激酶选自KDR、flt-1、TIE-2、Lck、Src、Fyn和yes。
6.权利要求1的应用,其中所述蛋白激酶的活性影响血管生成。
7.权利要求6的应用,其中所述蛋白激酶抑制是抗血管生成的。
8.权利要求7的应用,其中所述蛋白激酶抑制是抑制疾病进程,所述疾病选自:癌症、关节炎、动脉粥样硬化、牛皮癣、血管瘤、心肌血管生成、冠状动脉和脑动脉旁路、局部缺血性四肢血管生成、角膜疾病、潮红、新血管性青光眼、黄斑变性、伤口愈合、消化性溃疡螺杆菌相关疾病、骨折、糖尿病性视网膜病、和猫抓热。
9.权利要求1的应用,其中所述蛋白激酶的活性影响血管渗透性过高或产生水肿。
10.权利要求9的应用,其中所述蛋白激酶抑制是抗水肿作用。
11.权利要求10的应用,其中所述蛋白激酶抑制是抑制疾病进程,所述疾病选自:烧伤、慢性肺病、中风、息肉、牛皮癣、变应性炎症、黄斑变性、糖尿病性视网膜病、卵巢刺激过度综合征、以及与脑肿瘤相关的脑水肿。
12.权利要求1的应用,其中所述蛋白激酶是丝氨酸激酶。
13.权利要求1的应用,其中所述蛋白激酶是苏氨酸激酶。
14.权利要求1的应用,其中所述化合物是
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CN101434595A (zh) * | 2008-12-19 | 2009-05-20 | 沈阳药科大学 | 抗真菌剂-硫色满酮缩氨基(硫)脲系列物 |
CN102086212B (zh) * | 2009-12-03 | 2013-06-12 | 沈阳药科大学 | 抗真菌剂-2,3,4,5-四氢-4H-苯并[b]噻喃并[4,3-c]吡唑-2-甲酰胺衍生物 |
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JP4959049B2 (ja) | 1997-08-22 | 2012-06-20 | アストラゼネカ・ユーケイ・リミテッド | 血管新生阻害剤としてのオキシインドリルキナゾリン誘導体 |
CA2347916A1 (en) * | 1998-11-06 | 2000-05-18 | Basf Aktiengesellschaft | Inhibition of the formation of vascular hyperpermeability |
EP1229925A2 (en) * | 1999-11-19 | 2002-08-14 | Axxima Pharmaceuticals Aktiengesellschaft | Inhibitors of helicobacter pylori induced gastrointestinal diseases |
US6849409B2 (en) | 2000-10-16 | 2005-02-01 | Axxima Pharmaceuticals Ag | Cellular kinases involved in Cytomegalovirus infection and their inhibition |
DE10134196B4 (de) * | 2001-07-13 | 2005-08-18 | Forschungszentrum Karlsruhe Gmbh Technik Und Umwelt | Pharmazeutische Zusammensetzung zur Hemmung der unkontrollierten Vermehrung und/oder Induzierung der Apoptose von Zellen |
EP1427706B1 (en) | 2001-09-19 | 2007-05-30 | Pharmacia Corporation | Substituted pyrazolo compounds for the treatment of inflammation |
EP1432416B1 (en) * | 2001-09-26 | 2011-01-19 | Pfizer Italia S.r.l. | Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them |
ATE353013T1 (de) * | 2002-02-19 | 2007-02-15 | Pfizer Italia Srl | Trizyklische pyrazolderivate, verfahren zu ihrer herstellung und ihre verwendung als antitumor mittel |
US7166293B2 (en) * | 2002-03-29 | 2007-01-23 | Carlsbad Technology, Inc. | Angiogenesis inhibitors |
AR045037A1 (es) | 2003-07-10 | 2005-10-12 | Aventis Pharma Sa | Tetrahidro-1h-pirazolo [3,4-c] piridinas sustituidas, composiciones que las contienen y su utilizacion. |
EP2260849A1 (en) | 2004-01-21 | 2010-12-15 | Emory University | Compositions and methods of use for tyrosine kinase inhibitors to treat pathogenic infection |
EP2021338A1 (en) | 2006-05-09 | 2009-02-11 | Pfizer Products Inc. | Cycloalkylamino acid derivatives and pharmaceutical compositions thereof |
GEP20115239B (en) | 2006-10-31 | 2011-06-10 | Pfizer Prod Inc | Pyrazoline compounds as mineralocorticoid receptor antagonists |
CN102448459A (zh) * | 2009-04-15 | 2012-05-09 | 意大利癌症研究国立研究所基金会 | 多激酶抑制剂在治疗血管渗透性过高中的用途 |
US8853207B2 (en) | 2012-04-12 | 2014-10-07 | Development Center For Biotechnology | Heterocyclic pyrazole compounds, method for preparing the same and use thereof |
RU2674447C1 (ru) * | 2017-12-19 | 2018-12-10 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Дальневосточный государственный медицинский университет" Министерства здравоохранения Российской Федерации (ФГБОУ ВО ДВГМУ Минздрава России) | Способ лечения синдрома избыточного бактериального роста в тонком кишечнике у больных сахарным диабетом 2 типа в сочетании с гастродуоденальным хеликобактериозом |
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CN101434595A (zh) * | 2008-12-19 | 2009-05-20 | 沈阳药科大学 | 抗真菌剂-硫色满酮缩氨基(硫)脲系列物 |
CN101434595B (zh) * | 2008-12-19 | 2014-06-25 | 沈阳药科大学 | 抗真菌剂-硫色满酮缩氨基(硫)脲系列物 |
CN102086212B (zh) * | 2009-12-03 | 2013-06-12 | 沈阳药科大学 | 抗真菌剂-2,3,4,5-四氢-4H-苯并[b]噻喃并[4,3-c]吡唑-2-甲酰胺衍生物 |
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PT1073435E (pt) | 2004-10-29 |
JP2002512962A (ja) | 2002-05-08 |
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EP1073435A1 (en) | 2001-02-07 |
ES2224650T3 (es) | 2005-03-01 |
ATE270549T1 (de) | 2004-07-15 |
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DE69918542T2 (de) | 2005-08-18 |
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