CN102573480A - 三嗪衍生物及其治疗应用 - Google Patents
三嗪衍生物及其治疗应用 Download PDFInfo
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- CN102573480A CN102573480A CN2010800328482A CN201080032848A CN102573480A CN 102573480 A CN102573480 A CN 102573480A CN 2010800328482 A CN2010800328482 A CN 2010800328482A CN 201080032848 A CN201080032848 A CN 201080032848A CN 102573480 A CN102573480 A CN 102573480A
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Abstract
本发明提供三嗪衍生物,还提供用这些化合物来调节蛋白激酶的方法和用于治疗由蛋白激酶介导的疾病和病症的方法。
Description
发明领域
本发明一般地涉及化合物用来治疗各种障碍、疾病和病理病症的用途,更特别地涉及三嗪化合物用来调节蛋白激酶类和用于治疗蛋白激酶介导的疾病的用途。
发明背景
蛋白激酶类构成一个大家族的结构相关的负责控制细胞内的各种信号转导过程的酶。含有相似250-300个氨基酸催化域的蛋白激酶类催化靶标蛋白质底物的磷酸化。
激酶可以通过磷酸化的底物分为多个家族(例如,蛋白质-酪氨酸,蛋白质-丝氨酸/苏氨酸,脂质,等)。酪氨酸磷酸化是调节各种生物学过程比如细胞增殖、移行、分化和生存的中心事件。数个家族的受体和非受体酪氨酸激酶类控制这些事件:催化磷酸从ATP转移至特定细胞蛋白质靶标的酪氨酸残余物。已确认一般相应于各个上述激酶家族的基序[Hanks et al.,FASEB J.,(1995),9,576-596;Knighton et al.,Science,(1991),253,407-414;Garcia-Bustos et al.,EMBO J.,(1994),13:2352-2361)。蛋白激酶家族中的激酶的实例包括,不加限制地,abl,Akt,bcr-abl,Blk,Brk,Btk,c-试剂盒,c-Met,c-src,c-fms,CDK1,CDK2,CDK3,CDK4,CDK5,CDK6,CDK7,CDK8,CDK9,CDK10,cRaf1,CSF1R,CSK,EGFR,ErbB2,ErbB3,ErbB4,Erk,Fak,fes,FGFR1,FGFR2,FGFR3,FGFR4,FGFR5,Fgr,flt-1,Fps,Frk,Fyn,Hck,IGF-1R,INS-R,Jak,KDR,Lck,Lyn,MEK,p38,PDGFR,PIK,PKC,PYK2,ros,Tie,Tie-2,TRK,Yes,和Zap70。
研究指出蛋白激酶类在调节和维护各式各样的细胞过程和细胞功能中发挥中心作用。例如,激酶活性充当调节细胞增殖、活化和/或分化的分子开关。不受控的或过度的激酶活性已在许多疾病状态中观察到,包括良性的和恶性的增殖障碍以及免疫系统不适当激活导致的疾病(自身免疫障碍),同种异体移植排斥,和移植物抗宿主疾病。
据报告许多疾病与蛋白激酶介导的事件引发的异常细胞应答有关。这些疾病包括自身免疫性疾病,炎性疾病,骨疾病,代谢病,神经疾病和神经变性疾病,癌症,心血管疾病,变态反应和哮喘,阿尔茨海默病和激素相关疾病。此外,内皮细胞特异性受体PTKs,比如VEGF-2和Tie-2,介导血管生成过程并在支持癌和牵涉不受控血管形成的其它疾病进展中有所牵涉。相应地,医药化学领域已进行大量努力以寻找作为治疗剂有效的蛋白激酶抑制剂。
特别有兴趣的一个激酶家族是Src家族的激酶。Src激酶牵涉于许多细胞类型的增殖和移行应答,细胞活化,粘着,运动性,和存活,生长因子受体信号转导,和破骨细胞活化中(Biscardi et al.,Adv.CancerRes.(1999),76,61-119;Yeatman et al.,Nat.Rev.Cancer(2004),4,470-480;Owens,D.W.;McLean et al.,Mol.Biol.Cell(2000),11,51-64)。Src家族的成员包括下述哺乳动物中的八类激酶:Src,Fyn,Yes,Fgr,Lyn,Hck,Lck,和Blk(Bolen et al.,Annu.Rev.Immunol,(1997),15,371)。这些非受体蛋白激酶的分子量为52至62 kD。全体的特征是包括六个不同功能域的共同结构组织:Src同源性域4(SH4)、独特域,SH3域,SH2域,催化域(SH1),和C-末端调节性域(Brown et al.,BiochimBiophys Acta(1996),1287,121-149;Tatosyan et al.Biochemistry(Moscow)2000,65,49-58)。SH4域含有十四烷基化信号,其将Src分子引导至细胞膜。Src蛋白的该独特域负责它们与特别受体和蛋白质靶标的特异相互作用(Thomas et al.,Annu Rev Cell Dev Biol(1997),13,513-609)。调节域,SH3和SH2,控制与蛋白质底物的分子内以及分子间相互作用,其影响Src催化活性,局域化和与蛋白质靶标的联系(Pawson T.,Nature(1995),373,573-580)。Src家族全部蛋白中存在的激酶域SH1负责酪氨酸激酶活性且在底物结合中具有中心作用。Src激酶的N-末端一半含有用于酪氨酸磷酸化和调节Src催化活性的位点(Thomas et al.,Annu Rev Cell Dev Biol(1997),13:513-609)。v-Src与细胞Src(c-Src)的区别基于负责调节激酶活性的C-末端域的结构差异。
Src家族蛋白质酪氨酸激酶类的原型成员最初确认为致癌反转录病毒,Rous肉瘤病毒,RSV的转化蛋白质(v-Src)(Brugge et al.,Nature(1977),269,346-348);Hamaguchi et al.(1995),Oncogene 10:1037-1043)。病毒的v-Src是具有内在酪氨酸激酶活性的普通细胞蛋白质(c-Src)的突变且活化形式(Collett等人,Proc Natl Acad Sci U S A(1978),75,2021-2024)。该激酶仅在酪氨酰残余部分上磷酸化其蛋白质底物(Hunter et al.,Proc Natl Acad Sci U S A(1980),77,1311-1315)。
研究指出Src是细胞质型蛋白质酪氨酸激酶,其活化和向膜周信号转导复合物的募集与细胞命运有重大牵连。据充分记载Src蛋白质水平和Src激酶活性在下述中显著升高:人类乳腺癌(Muthuswamy et al.,Oncogene,(1995),11,1801-1810);Wang et al.,Oncogene(1999),18,1227-1237;Warmuth et al.,Curr.Pharm.Des.(2003),9,2043-2059],结肠癌(Irby et al.,Nat Genet(1999),21,187-190),胰腺癌(Lutz et al.,Biochem Biophys Res Commun(1998),243,503-508],某些B-细胞白血病和淋巴瘤(Talamonti et al.,J.Clin.Invest.(1993),91,53;Lutz et al.,Biochem.Biophys.Res.(1998),243,503;Biscardi et al.,Adv.CancerRes.(1999),76,61;Lynch et al.,Leukemia(1993),7,1416;Boschelli et al.,Drugs of the Future(2000),25(7),717),胃肠道癌(Cartwright et al.,Proc.Natl.Acad.Sci.USA,(1990),87,558-562 and Mao et al.,Oncogene,(1997),15,3083-3090),非小细胞肺癌(NSCLCs)(Mazurenko et al.,European Journal of Cancer,(1992),28,372-7),膀胱癌(Fanning et al.,Cancer Research,(1992),52,1457-62),食道癌(Jankowski et al.,Gut,(1992),33,1033-8),前列腺和卵巢癌(Wiener et al.,Clin.Cancer Research,(1999),5,2164-70),黑色素瘤和肉瘤(Bohlen et al.,Oncogene,(1993),8,2025-2031;tatosyan et al.,Biochemistry(Moscow)(2000),65,49-58)。另外,Src激酶通过多种致癌途径,包括EGFR,Her2/neu,PDGFR,FGFR,和VEGFR,调节信号转导(Frame et al.,Biochim.Biophys.Acta(2002),1602,114-130;Sakamoto et al.,Jpn J Cancer Res,(2001),92:941-946)。
从而,据预计通过抑制Src的激酶活性阻断信号转导是调节驱动细胞肿瘤学转化的异常途径的有效手段。Src激酶抑制剂可以是有用的抗癌药(Abram et al.,Exp.Cell Res.,(2000),254,1)。据报告src激酶的抑制剂对癌细胞系具有显著抗增殖活性(M.M.Moasser et al.,Cancer Res.,(1999),59,6145;Tatosyan et al.,Biochemistry(Moscow)(2000),65,49-58).)并且抑制细胞转化为致癌表型(R.Karni et al.,Oncogene(1999),18,4654)。另外,卵巢和结肠肿瘤细胞中的反义Src表达已显示抑制肿瘤生长(Wiener et al.,Clin.Cancer Res.,(1999),5,2164;Staley et al.,CellGrowth Diff.(1997),8,269)。也已报告Src激酶抑制剂在大脑缺血的动物模型是有效的(Paul et al.Nature Medicine,(2001),7,222),这表明Src激酶抑制剂可以对在卒中之后限制脑损害是有效的。抑制关节炎性骨骼破坏已通过在风湿样滑膜细胞和破骨细胞中过表达CSK得以实现(Takayanagi et al.,J.Clin.Invest.(1999),104,137)。CSK,或C-末端Src激酶,进行磷酸化并由此抑制Src催化活性。这暗指Src抑制可以预防罹患类风湿性关节炎患者特有的关节破坏(Boschelli et al.,Drugs of theFuture(2000),25(7),717)。
据充分记载Src-家族激酶类对其它免疫细胞受体下游的信号转导也是重要的。Fyn,类似Lck,牵涉于T细胞的TCR信号转导中(Applebyet al.,Cell,(1992),70,751)。Hck和Fgr牵涉于导致中性白细胞活化的Fcγ受体信号转导中(Vicentini et al.,J.Immunol.(2002),168,6446)。Lyn和Src也参与导致释放组胺和其它变应性的介导物的Fcγ受体信号转导(Turner,H.and Kinet,J-P Nature(1999),402,B24)。这些发现表明Src家族激酶抑制剂可以用于治疗变应性疾病和哮喘。
其它Src家族激酶类也是潜在的治疗靶标。Lck在T-细胞信号转导中起作用。缺少Lck基因的小鼠具有发展胸腺细胞的低劣能力。Lck的功能是T-细胞信号转导的阳性活化剂,这表明Lck抑制剂可以用于治疗自身免疫性疾病比如类风湿性关节炎(Molina et al.,Nature,(1992),357,161)。
Hck是Src蛋白质-酪氨酸激酶家族的成员并且在巨噬细胞即重要HIV靶标细胞中强烈地表达并且其在HIV-感染的巨噬细胞中的抑制可能减缓疾病进展(Ye et al.,Biochemistry,(2004),43(50),15775-15784)。
Hck,Fgr和Lyn已确认为髓性白细胞中整联蛋白信号转导的重要介导物(Lowell et al.,J.Leukoc.Biol.,(1999),65,313)。因此,抑制这些激酶介导物可以用于治疗炎症(Boschelli et al.,Drugs of the Future(2000),25(7),717)。
据报告Syk是酪氨酸激酶,其在细胞去粒和嗜酸性粒细胞活化中发挥关键作用,并且Syk激酶牵涉于各种过敏性疾患尤其是哮喘中(Taylor et al.,Mol.Cell.Biol.(1995),15,4149)。
BCR-ABL编码BCR-AEL蛋白质,其是在慢性髓性白血病(CML)全部患者的90%中和急性成淋巴细胞白血病(ALL)成人患者的15-30%中存在的组成型活性的细胞质的酪氨酸激酶。许多研究已展示BCR-ABL的激活是该嵌合型蛋白质致癌能力所需要。
Src激酶类在乙肝病毒复制中发挥作用。病毒编码的转录因素HBx在传播病毒所需的步骤中活化Src(Klein et al.,EMBO J.(1999),18,5019;Klein et al.,Mol.Cell.Biol.(1997),17,6427)。某些基因和生物化学数据清楚地展示Src-家族酪氨酸激酶类经由磷酸化c-Cbl为脂肪蓄积充当关键的信号中继,并提供用于治疗肥胖的潜在新策略(Sun et al.,Biochemistry,(2005),44(44),14455-14462)。由于Src在额外信号转导途径中发挥作用,Src抑制剂也为治疗包括骨质疏松症和卒中的其它疾病所寻求(Susva et al.,Trends Pharmacol.Sci.(2000),21,489-495;Paulet al.,Nat.Med.(2001),7,222-227)。
还可能的是Src激酶活性的抑制剂用于治疗骨质疏松症(Soriano etal.,Cell(1991),64,693;Boyce et al.J Clin.Invest(1992),90,1622;Owenset al.,Mol.Biol.Cell(2000),11,51-64),T细胞介导的炎症(Anderson etal.,Adv.Immunol.(1994),56,151;Goldman,F D et al.J.Clin.Invest.(1998),102,421),和大脑缺血(Paul et al.Nature Medicine(2001),7,222)。
此外,src家族激酶类参与数种细胞类型的信号转导。例如,fyn,类似lck,牵涉于T-细胞活化中。Hck和fgr牵涉于Feγ受体介导的中性白细胞氧化进发中。Src和lyn据信在Fcε诱导的肥大细胞去粒中是重要,并因此可以在哮喘和其它变应性疾病中发挥作用。激酶lyn已知牵涉于对紫外光(Hiwasa et al.,FEBS Lett.(1999),444,173)或离子化辐射(Kumar et al.,J Biol Chein,(1998),273,25654)诱导的DNA损害的细胞应答中。从而,lyn激酶的抑制剂可以用作放疗中的增效剂。
T细胞在调节免疫应答中发挥中枢作用,并且对于建立对病原体的免疫是重要。此外,T细胞常常在炎性自身免疫性疾病期间被激活,比如类风湿性关节炎,炎性肠病,类型I糖尿病,多发性硬化,斯耶格伦氏疾病,重症肌无力,牛皮癣,和狼疮。T细胞激活也是移植排斥、变应性反应和哮喘的重要组成部分。
T细胞通过在细胞表面表达的T细胞受体被特异抗原所活化。该活化引发由细胞内表达的酶介导的一系列的细胞内信号转导级联(Kane etal.Current Opinion in Immunol.(2000),12,242)。这些级联导致引起制备细胞因子比如白细胞介素-2(IL-2)的基因调节事件。IL-2是T细胞活化中必需的细胞因子,其导致特异免疫应答的增殖和放大。
因此,Src激酶和其它激酶已成为药物发现的有吸引力的靶标(Parang et al.,Expert Opin.Ther.Pat.(2005),15,1183-1207;Parang etal.,Curr.Opin.Drug Discovery Dev.(2004),7,630-638)。已公开许多类别的化合物,其调节或更特别地抑制激酶活性,用来治疗激酶相关的病症或其它障碍。例如,U.S.专利号US专利号6,596,746和PCT WO05/096784A2公开作为激酶抑制剂的苯并三嗪;PCT WO 01/81311公开取代的苯甲酸酰胺用于抑制血管生成;U.S.专利号6,440,965,公开取代的嘧啶衍生物用于治疗神经变性或神经障碍中;PCT WO 02/08205报告嘧啶衍生物具有神经营养活性;PCT WO 03/014111公开芳基哌嗪和芳基哌啶和它们作为金属蛋白酶抑制剂的用途;PCT WO 03/024448描述化合物作为组蛋白脱乙酰基酶酶促活性的抑制剂;PCT WO 04/058776公开具有抗血管生成活性的化合物。PCT WO 01/94341和WO 02/16352公开喹唑啉衍生物类Src激酶抑制剂。PCT WO03/026666A1和WO03/018021A1公开作为激酶抑制剂的嘧啶基衍生物。U.S.Pat.No6498165报告嘧啶化合物类的Src激酶抑制剂化合物。作为Src酪氨酸激酶抑制剂的肽最近有所报告(Kumar et al.,J.Med.Chem.,(2006),49(11),3395-3401)。据报告喹啉腈衍生物是有效的Src和Abl激酶的双重抑制剂(Diane et al.,J.Med.Chem.,(2004),47(7),1599-1601)。
特别有兴趣的又一激酶家族是极光(aurora)激酶。极光激酶家族是一类高度有关的丝氨酸/苏氨酸激酶,其是有丝分裂的关键调节剂,对于自母细胞至子细胞的基因组物质的精确且相等分隔(segtion)是必需的。极光激酶家族的成员包括三类有关的激酶类,称为极光-A、极光-B和极光-C。尽管显著程序同源性,这些激酶的局域化和功能彼此大有不同(Richard D.Carvajal,et al.Clin Cancer Res 2006;12(23):6869-6875;Daruka Mahadevan,et al.Expert Opin.Drug Discov.20072(7):1011-1026).
极光-A普遍地表达并调节从晚期S期经M期发生的细胞周期事件,包括中心体成熟(Berdnik D,et al.Curr Biol 2002;12:640-7),有丝分裂进入(Hirota T,et al.Cell 2003;114:585-98;Dutertre S,et al.J Cell Sci2004;117:2523-31),中心体分离(Marumoto T,等人J Biol Chem 2003;278:51786-95),两极纺锤体组装物(Kufer TA,et al.J Cell Biol2002;158:617-23;Eyers PA,et al.Curr Biol 2003;13:691-7.),赤道板上的染色体排列(Marumoto T,et al.J Biol Chem 2003;278:51786-95;Kunitoku N,et al.Dev Cell 2003;5:853-64.),胞质分裂(Marumoto T,et al.J Biol Chem 2003;278:51786-95),和有丝分裂结束。从G2经M期极光-A蛋白质水平和激酶活性都增加,其峰值活性在前中期。一旦活化,极光-A通过与各种底物包括中心体蛋白(centrosomin)相互作用介导其多种功能,转化酸性卷曲的-卷曲蛋白质、cdc25b、Eg5和着丝粒蛋白质A。
极光-B是对精确的染色体隔离,胞质分裂(Hauf S,et al.J Cell Biol2003;161:281-94;Ditchfield C,et al.J Cell Biol 2003;161:267-80;Giet R,et al.J Cell Biol 2001;152:669-82;Goto H,et al.J Biol Chem2003;278:8526-30),蛋白质局域化至着丝点和着丝粒,正确的微管-着丝粒附着(Murata-Hori M,et al.Curr Biol 2002;12:894-9),和调节有丝分裂关卡关键的染色体乘客蛋白。极光-B首先在前期期间局域化于染色体,然后在前中期和中期期间局域化于姊妹染色单体之间的内着丝点区(Zeitlin SG,et al.J Cell Biol 2001;155:1147-57)。极光-B参与确立染色体的生物取向,其中姊妹着丝粒经由双取向附着连接至两极纺锤的相反极。该过程的错误,表现为部分取向连接状态(一个着丝粒连接至来自双极的微管)或共取向连接状态(两个姊妹着丝粒连接至来自相同级的微管),如果在后期开始之前不加校正这将导致染色体的不稳定性和非整倍性。在有丝分裂点的极光-B的主要作用是修补不正确的微管-着丝粒附着(HaufS,et al.J Cell Biol 2003;161:281-94;Ditchfield C,et al.J Cell Biol2003;161:267-80;Lan W,et al.Curr Biol 2004;14:273-86.)。无极光-B活性的情况下,有丝分裂关卡受到损坏,引起增加数量的非整倍体细胞,基因不稳定性,和肿瘤发生(Weaver BA,et al.Cancer Cell 2005;8:7-12)。
极光-A过表达是极光-A-诱导的肿瘤发生的必需特征。在具极光-A过表达的细胞中,有丝分裂的特征是存在多个中心体和多极纺锤体(Meraldi P et al.EMBO J 2002;21:483-92.)。尽管得到异常微管-着丝粒附着,细胞仍废除有丝分裂关卡并从中期进展至后期,引起许多染色体分离缺陷。这些细胞不会发生胞质分裂,并且发展出额外的细胞周期,多倍性和进行性染色体不稳定性(Anand S,et al.Cancer Cell2003;3:51-62)。
连接极光过表达和恶性的证据刺激开发用于癌症治疗的极光抑制剂的兴趣。在正常细胞中,极光-A抑制引起延缓的但并非阻断的有丝分裂进入,引起单极有丝分裂纺锤体的中心体分离缺陷,和胞质分裂失败(Marumoto T,et al.J Biol Chem 2003;278:51786-95)。用极光-A抑制激励抗肿瘤效果示于三种人类胰腺癌细胞系(Panc-1,MIA PaCa-2,和SU.86.86)中,其中在细胞培养物中具有生长抑制以及小鼠异种移植物中的致肿瘤性的近乎全部废除(Hata T,et al.Cancer Res2005;65:2899-905.)。
极光-B抑制引起异常着丝粒-微管附着,无法实现染色体的生物取向,和胞质分裂失败(Goto H,et al.J Biol Chem 2003;278:8526-30;Severson AF,et al.Curr Biol 2000;10:1162-71)。不包括胞质分裂的异常有丝分裂的重复循环引起巨大的多倍性并最终导致细胞凋亡(Hauf S,etal.J Cell Biol 2003;161:281-94;Ditchfield C,et al.J Cell Biol2003;161:267-80;Giet R,et al.J Cell Biol 2001;152:669-82;Murata-HoriM,Curr Biol 2002;12:894-9;Kallio MJ,et al.Curr Biol 2002;12:900-5)。
在肿瘤细胞中抑制极光-A或极光-B活性引起损伤的染色体排列,有丝分裂关卡的废除,多倍性,和随后的细胞死亡。这些体外效果在转化的细胞中比在非转化的或非分化的细胞中更高(Ditchfield C,et al.JCell Biol 2003;161:267-80)。从而,靶标极光可以实现对癌症的体内选择性。尽管期望对造血系统和胃肠道系统的快速分化细胞的毒性,示于异种移植物模型的活性和临床耐受性指出存在合理的治疗指数。
在临床前抗肿瘤活性和肿瘤选择性潜力的前提下,已开发了数种极光激酶抑制剂。首次描述的3种小分子极光抑制剂包括ZM447439(Ditchfield C,et al.J Cell Biol 2003;161:267-80),Hesperadin(Hauf S,etal.J Cell Biol 2003;161:281-94),和MK0457(VX680)(Harrington EA,etal.Nat Med 2004;10:262-7)。下述试剂是无特异性的抑制剂:ZM447439抑制极光-A和极光-B;Herperadin主要地抑制极光-B;MK0457抑制全部三种极光激酶类。各自在基于细胞的测定中诱导相似表型,特征是抑制Ser10上组蛋白H3的磷酸化,抑制胞质分裂,和发展多倍性。选择性的极光抑制剂也已开发。选择性的极光-A抑制剂是MLN8054(HoarHM,et al.[abstract C40]。Proc AACR-NCI-EORTC InternationalConference:Molecular Targets and Cancer Therapeutics 2005)。选择性的极光-B抑制剂的实例是AZD1152(Schellens J,et al.[abstract 3008]。Proc Am Soc Clin Oncol 2006;24:122s)。目前正在开发下一代极光抑制剂,包括下述试剂:Nerviano Medical Sciences(PHA-680632和PHA-739358),Rigel(R763),Sunesis(SNS-314),NCE Discovery Ltd.(NCED#17),Astex Therapeutics(AT9283),和MontigenPharmaceuticals(MP-235和MP-529)。这些试剂中数种正在经历临床试验评价。
许多癌症的特征是细胞信号转导途径的破裂,其导致不受控的癌性细胞生长和增殖。受体酪氨酸激酶类(RTKs)在这些信号转导途径中发挥关键作用,将细胞外分子信号传播至细胞质和/或细胞核。RTKs是一般包括细胞外配体-结合域、跨膜域和催化性细胞质酪氨酸激酶域的跨膜蛋白。据信配体与细胞外部分的结合会促进二聚体化,引起反式-磷酸化和活化细胞内酪氨酸激酶域(Schlessinger et al.Neuron 1992;9:383-391)。
特别有兴趣的又一激酶家族是FLT3。FMS-相关的酪氨酸激酶3(FLT3),也称为FLK-2(胎儿肝激酶2)和STK-1(人类干细胞激酶1),属于包括KIT、PDGFR、FMS和FLT1的类别III受体酪氨酸激酶(RTKIII)家族的成员(Stirewalt DL,et al.Nat.Rev.Cancer2003;3:650-665;Rosnet O,et al.Genomics 1991;9:380-385;Yarden Y,etal.Nature 1986;323:226-232;Stanley E R,et.al.J.Cell.Biochem.198321:151-159;Yarden Y,et al.EMBO J 1987;6:3341-3351)。FLT3是跨膜蛋白质并由四个域组成;由五个免疫球蛋白类结构组成的细胞外配体-结合域,跨膜(TM)域,近膜(JM)域和细胞质C-末端酪氨酸激酶(TK)域。(Agnes F,et al.Gene 1994;145:283-288;Scheijen B,et al.Oncogene2002;21:3314-3333)。
FLT3(FLT3或FL)的配体在1993年得以克隆并据显示是造血骨髓微环境细胞包括骨髓成纤维细胞和其它细胞中表达的Type I跨膜蛋白质(Lyman SD,et al.Cell 1993;75:1157-1167)。膜结合和可溶形式均能活化受体的酪氨酸激酶活性并刺激骨髓和血液中的祖细胞生长。配体至受体的结合诱导受体二聚体化并活化激酶域;然后其自磷酸化并催化各种信号转导途径的底物蛋白磷酸化,比如转录5的信号转导物和活化剂(STAT5),RAS/丝裂原活化的蛋白激酶(RAS/MAPK),磷酸肌醇3-激酶(PI3K),src同种的和胶原基因(SHC),含有SH2的肌醇-5-磷酸酶(SHIP),和具有2个Src-同源性2(SH2)域(SHP2)的细胞质酪氨酸磷酸酶,其在细胞增殖、分化和生存中发挥重要作用(Dosil M,et al.Mol Cell Biol1993;13:6572-6585.Zhang S,Biochem Biophys Res Commun1999;254:440-445)。除了造血细胞之外,FLT3基因也在胎盘、性腺和脑中表达(Maroc N,et al.Oncogene 1993;8:909-918)并且在免疫应答中发挥重要作用(deLapeyriere O,et al.Leukemia 1995;9:1212-1218)。
FLT3在急性髓性白血病(AML)的70-100%的情况中,和在高百分比的T-急性淋巴细胞的白血病(ALL)情况中以各水平过表达(Griffin JD,et al.Haematol J.2004;5:188-190)。在原始细胞危象中,其也在慢性髓性白血病(CML)的较小亚型中过表达。研究已显示B谱系白血病ALL和AML的细胞频繁地共表达FL,设立引起FLT3组成型活化的自分泌或旁分泌信号转导循环(Zheng R,et.al.Blood.2004;103:267-274)。
证据日益快速聚集的是许多类型的白血病和骨髓增生综合征具有酪氨酸激酶的突变。FLT3突变是AML中最频繁的体变更之一,发生在大约1/3的患者中。白血病患者中描述了两种类型的FLT3活化突变。这些包括一系列在自抑制性近膜域中发生的内部串联复制(ITD)(NakaoM,et al.Leukemia 1996;10:1911-1918;Thiede C,et al.Blood2002;99:4326-4335),和活化循环突变,其包括Asp835Tyr(D835Y),Asp835Val(D835V),Asp835His(D835H),Asp835Glu(D835E),Asp835Ala(D835A),Asp835Asn(D835N),Asp835缺失和Ile836缺失(Yamamoto Y,et al.,Blood 2001:97:2434-2439;Abu-Duhier FM,et al.Br.J.Haematol.2001;113:983-988)。JM域内的内部串联复制(ITD)突变有助于AML中约17-34%的FLT3活化突变。FLT3-ITD也以低频率在骨髓增生异常综合征得以检测(MDS)(Yokota S,et al.Leukemia1997;11:1605-1609;Horiike S,et al.Leukemia 1997;11:1442-1446)。ITDs总是框内的,并局限于JM域。然而,不同患者的长度和位置有变化。这些重复程序可以用来破坏JM域的自抑制活性,引起FLT3组成型活化。FLT3-ITD和FLT3-Asp835突变均与FLT3自磷酸化和下游靶标的磷酸化有关(Mizuki M,et al.Blood 2000;96:3907-3914;Mizuki M,et al.Blood 2003;101:3164-3173;Hayakawa F,et al.Oncogene 2000;19:624-631)。
目前,正在研究FLT3抑制剂并且作为其中某些或全部具有FLT3突变的复发或顽固AML患者的单一疗法已达到临床试验。FLT3抑制剂,比如PKC412(N-苯甲酰基星孢素)(Fabbro D,et al.Anticancer DrugDes 2000;15:17-28;Weisberg E,et al.Cancer Cell 2002;1:433-443),CT53518(也称为MLN518)(Kelly LM,et al.Cancer Cell2002;1:421-432),SU11248(O′Farrell AM,et al.Blood2003;101:3597-3605),SU5614(Spiekermann K,et al.Blood2003;101:1494-1504),和SU5416(Giles FJ,et al.Blood2003;102:795-801),已显示具有抗肿瘤活性。总体地,这些数据表明FLT3是用来开发用于AML和其它有关疾病的激酶抑制剂的有吸引力的治疗靶标。
考虑到对于与蛋白激酶有关的病症中大多数缺少目前可获得的治疗选择,仍非常需要抑制这些蛋白质靶标的新治疗剂。特别,极光激酶抑制剂在治疗某些障碍包括癌症中特别有意义。
发明内容
相应地,本发明目标是,提供包含描述于式(I)的三嗪衍生物的抗肿瘤药,其药学上可接受的配制剂,制备新化合物和使用该化合物的组合物的方法。化合物和包含式(I)化合物的组合物在治疗各种疾病中具有效用。
本文描述的组合疗法可以这样提供:制备式(I)三嗪衍生物和作为单独药物配制剂的其它治疗剂,随后同时地、半同时地、分开地或在定期间隔内将其给药至患者。
本发明提供使用某些化合物比如激酶抑制剂来治疗各种疾病、障碍和病理学状况,例如癌症和血管的障碍比如心肌梗死(MI)、卒中或缺血的方法。描述于本发明的三嗪化合物可以阻断极光激酶家族成员中某些或许多的酶活性,另外还阻断其它受体和非受体激酶活性。所述化合物可以有益于治疗其中障碍影响细胞运动性、粘着和细胞周期进展的疾病,以及具有有关的含氧量低的条件的疾病,骨质疏松症以及导致或涉及血管渗透性增加的病症,炎症或呼吸性窘迫,肿瘤生长,侵入,血管生成,转移和细胞凋亡。
发明详述
本发明涉及如式(I)所示的化合物
或其药学上可接受的盐,其中:
W和Y独立地选自S,O,NR3或CR3;
R3独立地选自氢或任选经取代的C1-4脂族基团,卤素,羟基,氨基,酰胺,氰基,-COON,-SO2NH2,氧代,硝基和烷氧羰基。
Ar代表杂芳基或芳基,其各自用0至4个独立选自下述的取代基取代:
1.卤素,羟基,氨基,酰胺,氰基,-COON,-SO2NH2,氧代,硝基和烷氧羰基;和
2.C1-C6烷基,C1-C6烷氧基,C3-C10环烷基,C2-C6烯基,C2-C6炔基,C2-C6烷酰基,C1-C6卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基和一-和二-(C1-C6烷基)氨基羰基;苯基C0-C4烷基和(4-至7-元杂环)C0-C4烷基,其各自用独立选自下述的0至4个第二取代基取代:卤素,羟基,氰基,氧代,亚氨基,C1-C4烷基,C1-C4烷氧基和C1-C4卤代烷基。
R1选自:
(i)氨基,烷基氨基,芳基氨基,杂芳基氨基;
(ii)式(Ia)基团:
其中:
R4代表氢,C1-C4烷基,氧代;在R5是氢的情况下,X是CH;或X-R5是O;或X是N,R5代表下述基团:氢,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C10芳基或杂芳基,(C3-C7环烷基)C1-C4烷基,C1-C6卤代烷基,C1-C6烷氧基,C1-C6烷硫基,C2-C6烷酰基,C1-C6烷氧羰基,C2-C6烷酰基氧基,一-和二-(C3-C8环烷基)氨基C0-C4烷基,(4-至7-元杂环)C0-C4烷基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基,和一-和二-(C1-C6烷基)氨基羰基,其各自用独立选自下述的0至4个取代基取代:卤素,羟基,氰基,氨基,-COOH和氧代;
R2是独立地选自下述的0至5个取代基:
(i)卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2,氧代,硝基和烷氧羰基;和
(ii)C1-C6烷基,C1-C6烷氧基,C3-C10环烷基,C2-C6烯基,C2-C6炔基,C2-C6烷酰基,C1-C6卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基和一-和二-(C1-C6烷基)氨基羰基;苯基C0-C4烷基和(4-至7-元杂环)C0-C4烷基,其各自用独立选自下述的0至4个第二取代基取代:卤素,羟基,氰基,氧代,亚氨基,C1-C4烷基,C1-C4烷氧基和C1-C4卤代烷基。
K选自
(i)O,S,
(ii)NR6
R6代表氢,烷基,环烷基,烯基,炔基,烷硫基,芳基,芳基烷基。
下述定义适用上文和本文通篇中所用的各术语。
本文一般用标准命名描述化合物。对于具有不对称中心的化合物,应理解(除非另有指定)涵盖全部旋光异构体及其混合物。此外,具有碳-碳双键的化合物可以以Z-和E-形式存在,其中除非另有指定本发明包括化合物的全部异构形式。在化合物以各种互变异构体形式存在的情况下,所述化合物并不局限于任一特定的互变异构体,但是相当期望涵盖全部互变异构体形式。本文用通式包括变量(例如X、Ar.)描述某些化合物。除非另有指定,上式中各变量独立于任意其它变量进行定义,且对在式中出现多于一次的任意变量独立地定义其各次出现。
术语″卤代″或″卤素″是指氟,氯,溴或碘。
术语″烷基″在本文中单独或作为又一基团的一部分除非另有定义是指含有1至12个碳原子的一价烷烃(烃)衍生的残基。烷基可以在任意可能连接点进行取代。用又一烷基取代的烷基也称为″支化的烷基″。示范性烷基包括甲基,乙基,丙基,异丙基,正-丁基,叔丁基,异丁基,戊基,己基,异己基,庚基,二甲基戊基,辛基,2,2,4-三甲基戊基,壬基,癸基,十一烷基,十二烷基,等。示范性取代基包括但不限于下述基团中的一个或多个:烷基,芳基,卤代(比如F,Cl,Br,I),卤代烷基(比如CCl3或CF3),烷氧基,烷硫基,羟基,羧基(-COOH),烷氧基羰基(-C(O)R),烷基羰氧基(-OCOR),氨基(-NH2),氨基甲酰基(-NHCOOR-或-OCONHR-),脲(-NHCONHR-)或巯基(-SH)。在本发明的某些优选实施方式中,烷基用例如氨基,杂环烷基比如吗啉、哌嗪、哌啶、氮杂环丁烷,羟基,甲氧基,或杂芳基比如吡咯烷取代。
术语″环烷基″在本文中单独或作为又一基团的一部分是指完全饱和的和部分不饱和的3至9个,优选3至7个碳原子的烃环。实例包括环丙基,环丁基,环戊基和环己基等。此外,环烷基可以是取代的。取代的环烷基是指具有一、二或三个取代基的环,所述取代基选自卤代,烷基,取代的烷基,烯基,炔基,硝基,氰基,氧代(=O),羟基,烷氧基,硫烷基,-CO2H,-C(=O)H,CO2-烷基,-C(=O)烷基,酮基,=N-OH,=N-O-烷基,芳基,杂芳基,杂环,-NR′R″,-C(=O)NR′R″,-CO2NR′R″,-C(=O)NR′R″,-NR′CO2R″,-NR′C(=O)R″,-SO2NR′R″,和-NR′SO2R″,其中R′和R″各独立地选自氢,烷基,取代的烷基,和环烷基,或者R′和R″一起形成杂环或杂芳基环。
术语″烯基″在本文中单独或作为又一基团的一部分是指直链、支化或环状的含有2至12个碳原子和至少一个碳-碳双键的烃残基。所述基团的实例包括乙烯基,烯丙基,1-丙烯基,异丙烯基,2-甲基-1-丙烯基,1-丁烯基,2-丁烯基,3-丁烯基,1-戊烯基,2-戊烯基,3-戊烯基,4-戊烯基,1-己烯基,2-己烯基,3-己烯基,4-己烯基,5-己烯基,1-庚烯基,等。烯基还可以在任意可能连接点进行取代。烯基的示范性取代基包括上述为烷基所列的那些,且特别包括C3-C7环烷基比如环丙基,环戊基和环己基,其可以进一步用例如氨基、氧代、羟基等取代。
术语″炔基″是指直链或支化的链炔基团,其具有一个或多个不饱和的碳-碳键,其中至少一个是三键。炔基包括分别具有2至8,2至6或2至4个碳原子的C2-C8炔基,C2-C6炔基和C2-C4炔基。示例性的炔基包括乙烯基,丙烯基,异丙烯基,丁烯基,异丁烯基,戊烯基,和己烯基。炔基还可以在任意可能连接点进行取代。炔基的示范性取代基包括上文为烷基所列的那些,比如氨基,烷基氨基,等。在符号″C″之后的下标数字定义特定基团能够含有的碳原子数。
术语″烷氧基″单独或作为又一基团的一部分表示通过氧桥(-O-)键合的如上所述的烷基。优选的烷氧基具有1至8个碳原子。所述基团的实例包括甲氧基,乙氧基,正-丙氧基,异丙氧基,正-丁氧基,异丁氧基,仲-丁氧基,叔-丁氧基,正-戊基氧基,异戊基氧基,正-己基氧基,环己基氧基,正-庚基氧基,正-辛基氧基和2-乙基己基氧基。
术语″烷硫基″是指通过硫桥连接的上述烷基。优选的烷氧基和烷硫基是其中烷基通过杂原子桥连接的那些。优选的烷硫基具有1至8个碳原子。所述基团的实例包括甲硫基,乙硫基,正丙硫基,正丁硫基等。
术语″氧代″如本文所用是指酮基(C=O)基团。非芳族碳原子的取代基的氧代基团使得-CH2-转化为-C(=O)-。
术语″烷氧羰基″在本文中单独或作为又一基团的一部分表示通过羰基键合的烷氧基。烷氧羰基残基由式-C(O)OR代表,其中R基团是直链或支化的C1-C6烷基,环烷基,芳基,或杂芳基。
术语″烷基羰基″在本文中单独或作为又一基团的一部分是指经过羰基或-C(O)R键合的烷基。
术语″芳基烷基″在本文中单独或作为又一基团的一部分表示经过如上所述的烷基(比如苄基)键合的芳族环。
术语″芳基″在本文中单独或作为又一基团的一部分是指单环或双环芳族环,例如苯基,取代的苯基等,以及稠合基团例如萘基、菲基等。从而,芳基含有至少一个具有至少6个原子的环,其中最多存在五个所述环,含有多至20个原子,在相邻碳原子或适宜杂原子间具有交替(共振)双键。芳基可以任选地用一个或多个下述基团取代:包括,但不限于卤素比如I、Br、F或Cl;烷基比如甲基、乙基、丙基,烷氧基比如甲氧基或乙氧基,羟基,羧基,氨基甲酰基,烷氧基羰基,硝基,烯氧基,三氟甲基,氨基,环烷基,芳基,杂芳基,氰基,烷基S(O)m(其中m=0,1,2),或巯基。
术语″芳族″是指环形共轭的分子个体,其稳定性由于离域作用具有显著大于假设定域结构比如Kekule结构。
术语″氨基″在本文中单独或作为又一基团的一部分是指-NH2。″氨基″可以任选地用一个或两个取代基取代,其可以是相同或不同的,比如烷基,芳基,芳基烷基,烯基,炔基,杂芳基,杂芳基烷基,环杂烷基,环杂烷基烷基,环烷基,环烷基烷基,卤代烷基,羟基烷基,烷氧基烷基,硫代烷基,羰基或羧基。这些取代基可以进一步用羧酸,本文所述的烷基或芳基取代基中任意取代。在某些实施方式中,氨基用羧基或羰基取代以形成N-酰基或N-氨基甲酰基衍生物。
术语″烷基磺酰基″是指式(SO2)-烷基,其中硫原子是连接点。优选,烷基磺酰基包括C1-C6烷基磺酰基,其具有1至6个碳原子。甲磺酰基是一种代表性的烷基磺酰基。
术语″杂原子″是指不是碳的任意原子例如N、O或S。
术语″杂芳基″在本文中单独或作为又一基团的一部分是指取代的和未经取代的芳族5或6元单环基团,9或10元双环基团,和11至14元三环基团,其在各环的至少一个中具有至少一个杂原子(O、S或N)。含有杂原子的杂芳基的各环能够含有一个或两个氧或硫原子和/或一个至四个氮原子,条件是各环杂原子的总数是四或更少且各环具有至少一个碳原子。
完成双环和三环基团的稠环可以仅含有碳原子且可以是饱和的、部分饱和的或不饱和的。氮和硫原子可以任选被氧化而氮原子可以任选被季铵化。是双环或三环的杂芳基必须包括至少一个完全芳族环,但是其它稠环或环可以是芳族或非芳族。杂芳基可以在任意环的任意可能氮或碳原子处连接。杂芳基环系可以含有零、一、二或三个选自下述的取代基:卤代,烷基,取代的烷基,烯基,炔基,芳基,硝基,氰基,羟基,烷氧基,硫烷基,-CO2H,-C(=O)H,-CO2-烷基,-C(=O)烷基,苯基,苄基,苯基乙基,苯基氧基,苯硫基,环烷基,取代的环烷基,杂环,杂芳基,-NR′R″,-C(=O)NR′R″,-CO2NR′R″,-C(=O)NR′R″,-NR′CO2R″,-NR′C(=O)R″,-SO2NR′R″,和-NR′SO2R″,其中R′和R″各独立地选自氢,烷基,取代的烷基,和环烷基,或R′和R″一起形成杂环或杂芳基环。
优选单环杂芳基包括吡咯基,吡唑基,吡唑啉基,咪唑基,噁唑基,二唑基,异噁唑基,噻唑基,噻二唑基,S异噻唑基,呋喃基,噻吩基,噁二唑基,吡啶基,吡嗪基,嘧啶基,哒嗪基,三嗪基等。
优选双环杂芳基包括吲哚基,苯并噻唑基,苯并二氧杂环戊烯基,苯并噁唑基,苯并噻吩基,喹啉基,四氢异喹啉基,异喹啉基,苯并咪唑基,苯并吡喃基,吲嗪基,苯并呋喃基,色酮基,香豆素基,苯并吡喃基,噌啉基,喹喔啉基,吲唑基,吡咯并吡啶基,二氢异吲哚基,四氢喹啉基等。
优选三环杂芳基包括咔唑基,苯并吲哚基(benzidolyl),菲咯啉基,吖啶基,菲啶基,呫吨基等。
术语″杂环″或″杂环烷基″在本文中单独或作为又一基团的一部分是指其中环上碳原子之一用选自O、S或N的杂原子替换的环烷基(非芳族)。
″杂环″具有1至3稠合环、侧挂环或螺环,其中至少一个是杂环(也即,一个或多个环原子是杂原子,其中剩余的环原子是碳)。杂环可以是任选经取代的,其指杂环可以在一个或多个可取代的环位置被一个或多个独立选自下述的基团取代:烷基(优选低级烷基),杂环烷基,杂芳基,烷氧基(优选低级烷氧基),硝基,一烷基氨基(优选低级烷基氨基),二烷基氨基(优选烷基氨基),氰基,卤代,卤代烷基(优选三氟甲基),烷酰基,氨基羰基,一烷基氨基羰基,二烷基氨基羰基,烷基酰胺基(优选低级烷基酰胺基),烷氧基烷基(优选低级烷氧基;低级烷基),烷氧羰基(优选低级烷氧羰基),烷基羰氧基(优选低级烷基羰氧基)和芳基(优选苯基),所述芳基任选由卤代、低级烷基和低级烷氧基取代。杂环基团可以一般地经由任意环或取代基原子连接,条件是稳定的化合物结果。N-连接的杂环基团经由组成式氮原子连接。
一般地,杂环包含1-4个杂原子;在某些实施方式中,各杂环具有1或2个杂原子/环。各杂环一般地含有3至8环成员(具有至7环成员的环在某些实施方式中有所描述),而包含稠合环、侧挂环或螺环的杂环一般含有9至14环成员,其包括碳原子且含有一、二或三个选自氮、氧和/或硫的杂原子。
″杂环″或″杂环烷基″的实例包括哌嗪,哌啶,吗啉,硫吗啉,吡咯烷,咪唑烷和噻唑烷(thiazolide)。
术语″取代基″,如本文所用,是指共价键合至有关分子中的原子的分子部分。例如,″环取代基″可以是这样的部分:比如卤素、烷基、卤烷基或本文所述的共价键合至环成员原子(优选碳或氮原子)的其它基团。
术语″任选经取代的″是指芳基或杂环基或其它基团可以在一个或多个可取代位置被独立选自下述的一个或多个基团取代:烷基(优选低级烷基),烷氧基(优选低级烷氧基),硝基,一烷基氨基(优选具有一至六个碳),二烷基氨基(优选具有一至六个碳),氰基,卤代,卤代烷基(优选三氟甲基),烷酰基,氨基羰基,一烷基氨基羰基,二烷基氨基羰基,烷基酰胺基(优选低级烷基酰胺基),烷氧基烷基(优选低级烷氧基和低级烷基),烷氧羰基(优选低级烷氧羰基),烷基羰氧基(优选低级烷基羰氧基)和芳基(优选苯基),所述芳基任选由卤代、低级烷基和低级烷氧基取代。短语″用0至X个取代基取代″也指任选的取代,其中X是可能取代基的最大数目。某些任选经取代的基团用0至2、3或4个独立选择的取代基取代。
不在两个字母或符号之间的破折号(″-″)用来指出取代基的连接点。例如,-CONH2通过碳原子连接。
位于杂环环内的虚线环用来指出共轭系统。两个原子间的键可以是单键或双键。
术语″抗癌的″试剂包括用于治疗癌症的任意已知试剂包括但不限于:阿西维辛;阿柔比星;阿考达唑盐酸盐;AcrQnine;阿多来新;阿地白介素;六甲蜜胺;安波霉素;阿美蒽醌乙酸盐;氨鲁米特;安吖啶;阿那曲唑;安曲霉素;天冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;比生群盐酸盐;甲磺酸双奈法德;比泽来新;博来霉素硫酸盐;布喹那钠;溴匹立明;白消安;放线菌素C;卡普睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;卡柔比星盐酸盐;卡泽来新;西地芬戈;苯丁酸氮芥;西罗霉素;顺铂;克拉屈滨;克立那托甲磺酸盐;环磷酰胺;阿糖胞苷;达卡巴嗪;放线菌素D;柔红霉素盐酸盐;地西他滨;右奥马铂;地扎呱宁;地扎呱宁甲磺酸盐;地吖醌;多西他赛;多柔比星;多柔比星盐酸盐;屈洛昔芬;屈洛昔芬柠檬酸盐;屈他雄酮丙酸盐;达佐霉素;依达曲沙;依氟鸟氨酸(Eflomithine)盐酸盐;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;表柔比星盐酸盐;厄布洛唑;依索比星盐酸盐;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;乙碘油I 131;依托泊苷;依托泊苷磷酸盐;氯苯乙嘧胺;法倔唑盐酸盐;法扎拉滨;芬维A胺;氟尿苷;氟达拉滨磷酸盐;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;吉西他滨盐酸盐;金Au 198;羟基脲;伊达比星盐酸盐;异环磷酰胺;伊莫福新;干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-Ia;干扰素γ-Ib;异丙铂;伊立替康盐酸盐;兰瑞肽乙酸盐;来曲唑;亮丙立德乙酸盐;利阿唑盐酸盐;洛美曲索钠;洛莫司汀;洛索蒽醌盐酸盐;马索罗酚;美坦生;氮芥盐酸盐;甲地孕酮乙酸盐;美仑孕酮乙酸盐;美法仑;美诺立尔;巯嘌呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托卡星;丝裂红素;米托洁林;米托马星;丝裂霉素;米托司培;米托坦;米托蒽醌盐酸盐;麦考酚酸;诺考达唑;诺拉霉素;奥马铂;奥昔舒仑;紫杉醇;培门冬酶;培利霉素;奈莫司汀;培洛霉素硫酸盐;培磷酰胺;哌泊溴烷;哌泊舒凡;吡罗蒽醌盐酸盐;普卡霉素;普洛美坦;卟吩姆钠;泊非霉素;泼尼莫司汀;丙卡巴肼盐酸盐;嘌罗霉素;嘌罗霉素盐酸盐;吡唑呋喃菌素;利波腺苷;罗谷亚胺;Safmgol;沙芬戈盐酸盐;司莫司汀;辛曲秦;磷乙酰天冬氨酸钠;司帕霉素;锗螺胺盐酸盐;螺莫司汀;螺铂;链黑霉素;链佐星;氯化锶Sr 89;磺氯苯脲;他利霉素;Taxane;Taxoid;替可加兰钠;替加氟;替洛蒽醌盐酸盐;替莫泊芬;替尼泊苷;替罗昔隆;睾内酯;硫咪嘌呤;硫鸟嘌呤;塞替派;噻唑羧胺核苷;替拉扎明;托泊替康盐酸盐;托瑞米芬柠檬酸盐;曲托龙乙酸盐;曲西立滨磷酸盐;三甲曲沙;三甲曲沙葡糖醛酸盐;曲普瑞林;妥布氯唑盐酸盐;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬;长春碱硫酸盐;长春新碱硫酸盐;长春地辛;长春地辛硫酸盐;长春匹定硫酸盐;长春甘酯硫酸盐;长春罗新硫酸盐;长春瑞滨酒石酸盐;长春罗定硫酸盐;长春利定硫酸盐;伏氯唑;泽尼铂;净司他丁;和佐柔比星盐酸盐。
术语″激酶″是指催化磷酸基团加至蛋白质残余部分的任意酶;例如,丝氨酸和苏氨酸激酶催化磷酸基团加入丝氨酸和苏氨酸残余部分。
术语″Src激酶″″Src激酶家族″和″Src家族″是指属于哺乳动物Src激酶家族的有关同源染色体或类似物,包括例如c-Src,Fyn,Yes和Lyn激酶和造血-受限的激酶Hck,Fgr,Lck和Blk。
术语″治疗有效量″是指研究者、兽医、医生或其它临床医师所寻求的引起组织、系统、动物或人类的生物学或医学应答的化合物或药物组合物的量,所述应答是例如恢复或维持血管停滞(vasculostasis)或者防止损伤或损失或血管停滞;降低肿瘤负担;降低发病率和/或死亡率。
术语″药学上可接受的″是指载体、稀释剂或赋形剂必须与配制剂其它成分相容并且对接受者无害。
术语″给药化合物″或″给予化合物″是指本发明化合物或药物组合物提供至需要治疗的受试者的行为。
术语″保护的″是指基团为修饰形式以防止在保护位点的不希望的副反应。本发明化合物的适宜保护基团在虑及本领域技术水平并参照标准教材比如Greene,T.W.et al.,Protective Groups in Organic Synthesis,John Wiley & Sons,New York(1999)的情况下将从本申请中有所了解。
本文所述的术语化合物的″药学上可接受的盐″是酸式盐或碱式盐,其适于用于与人类或动物组织接触而不具过度毒性或致癌性,优选不具刺激、变态反应或其它问题或者并发症。所述盐包括碱性残基比如胺的无机和有机酸盐,以及酸性残基比如羧酸的碱金属或有机盐。特定的药物盐包括,但不限于,下述酸的盐:比如盐酸,磷酸,氢溴酸,苹果酸,羟基乙酸,富马酸,硫酸,氨基磺酸,对氨基苯磺酸,甲酸,甲苯磺酸,甲磺酸,苯磺酸,乙烷二磺酸,2-羟基乙基磺酸,硝酸,苯甲酸,2-乙酰氧基苯甲酸,柠檬酸,酒石酸,乳酸,硬脂酸,水杨酸,谷氨酸,抗坏血酸,双羟萘酸,琥珀酸,富马酸,马来酸,丙酸,羟基马来酸,氢碘酸,苯基乙酸,烷酸比如乙酸、其中n是0-4的HOOC-(CH2)n-COOH,等。类似地,药学上可接受的阳离子包括,但不限于钠,钾,钙,铝,锂和铵。本领域普通技术人员会认识到本文提供的化合物的其它药学上可接受的盐。通常,药学上可接受的酸式盐或碱式盐能够通过任意常规的化学方法合成自含碱性或酸性部分的母体化合物。简言之,所述盐能够这样制备:在水或有机溶剂或者两者的混合物中,将这些化合物的游离酸或碱形式与化学计量的量的适当碱或酸反应;一般地,优选使用非水介质,比如醚,乙酸乙酯,乙醇,异丙醇或乙腈。明显的是,各式I化合物可以但是不是必须配制为水合物,溶剂化物或非共价复合物。此外,各种晶型和多晶型也属于本发明的范围。本文也提供式I化合物的前药。
术语″前药″是指可以不完全满足本文提供的化合物的结构要求的化合物,但是在给药至患者之后在体内被修饰以产生本文提供的式I或其它式的化合物。例如,前药可以是本文提供的化合物的酰化衍生物。前药包括这样的化合物,其中羟基、胺或硫醇基团键合至在给予哺乳动物受试者的情况下分别裂解形成游离羟基、氨基或硫醇基团的任意基团。前药的实例包括,但不限于,本文提供的化合物中的醇和胺官能团的乙酸酯、甲酸酯和苯甲酸酯衍生物。本文提供的化合物的前药可以这样制备:化合物中存在的官能团的修饰形式使得该修饰物在体内裂解产生母体化合物。
″任选经取代的″基团是未经取代的或在一个或多个可能位置被不是氢的取代基取代。所述可选取代基包括,例如,羟基,卤素,氰基,硝基,C1-C6烷基,C2-C6烯基,C2-C6炔基,C1-C6烷氧基,C2-C6烷基醚,C3-C6烷酮,C2-C6烷硫基,氨基,一-或二-(C1-C6烷基)氨基,C1-C6卤代烷基,-COOH,-CONH2,一-或二-(C1-C6烷基)-氨基羰基,-SO2NH2,和/或一或二(C1-C6烷基)磺酰氨基,以及碳环和杂环基团。
短语″用0至X个取代基取代″也指任选的取代,其中X是可能取代基的最大数目。某些任选经取代的基团用0至2、3或4个独立选择的取代基取代。
式(I)的优选Ar基团列于如下:
式(I)的优选R1基团列举如下:
式(I)的优选R2基团列举如下,
优选,本发明化合物可以是式(I)化合物,其中
W和Y独立地选自S,O,NR3,或CR3;
R3独立地选自氢或任选经取代的C1-C4脂族基团,卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2,氧代,硝基和烷氧羰基。
Ar代表杂芳基或芳基,其各自用0至4个独立选自下述的取代基取代:
1.卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2,氧代,硝基和烷氧羰基;和
2.C1-C6烷基,C1-C6烷氧基,C3-C10环烷基,C2-C6烯基,C2-C6炔基,C2-C5烷酰基,C1-C6卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基和一-和二-(C1-C6烷基)氨基羰基;苯基C0-C4烷基和(4-至7-元杂环)C0-C4烷基,其各自用独立选自下述的0至4个第二取代基取代:卤素,羟基,氰基,氧代,亚氨基,C1-C4烷基,C1-C4烷氧基和C1-C4卤代烷基。
R1选自:
(i)氨基,烷基氨基,芳基氨基,杂芳基氨基;
(ii)式(Ia)基团:
其中:
R4代表氢,C1-C4烷基,氧代;
在R5是氢的情况下,X是CH;或X-R5是O;或X是N,R5代表下述基团:氢,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C10芳基或杂芳基,(C3-C7环烷基)C1-C4烷基,C1-C6卤代烷基,C1-C6烷氧基,C1-C6烷硫基,C2-C6烷酰基,C1-C6烷氧羰基,C2-C6烷酰基氧基,一-和二-(C3-C8环烷基)氨基C0-C4烷基,(4-至7-元杂环)C0-C4烷基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基,和一-和二-(C1-C6烷基)氨基羰基,其各自用独立选自下述的0至4个取代基取代:卤素,羟基,氰基,氨基,-COON和氧代;
R2是独立地选自下述的0至4个取代基:
(i)卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2,氧代,硝基和烷氧羰基;和
(ii)C1-C6烷基,C1-C6烷氧基,C3-C10环烷基,C2-C6烯基,C2-C6炔基,C2-C6烷酰基,C1-C8卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基和一-和二-(C1-C6烷基)氨基羰基;苯基C0-C4烷基和(4-至7-元杂环)C0-C4烷基,其各自用独立选自下述的0至4个第二取代基取代:卤素,羟基,氰基,氧代,亚氨基,C1-C4烷基,C1-C4烷氧基和C1-C4卤代烷基。
K选自
i)O,S,
ii)NR6
R6代表氢,烷基,环烷基,烯基,炔基,烷硫基,芳基,芳基烷基。
更优选,本发明化合物可以是式(I)化合物,其中
W和Y独立地选自S,O,NR3,或CR3;
R3独立地选自氢或任选经取代的C1-C4脂族基团,卤素,羟基,氨基,酰胺,氰基。
Ar代表杂芳基或芳基,其各自用0至4个独立选自下述的取代基取代:
1.卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2;和
2.C1-C6烷基,C1-C6烷氧基,C3-C10环烷基,C2-C6烯基,C2-C6烷酰基,C1-C6卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基和一-和二-(C1-C6烷基)氨基羰基;苯基C0-C4烷基和(4-至7-元杂环)C0-C4烷基,其各自用独立选自下述的0至4个第二取代基取代:卤素,羟基,氰基,氧代,亚氨基,C1-C4烷基,C1-C4烷氧基和C1-C4卤代烷基。
R1选自:
(i)氨基,烷基氨基,芳基氨基,杂芳基氨基;
(ii)式(Ia)基团:
其中:
Ra代表氢,C1-C4烷基,氧代;
在R5是氢的情况下,X是CH;或X-R5是O;或X是N,R5代表下述基团:氢,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C10芳基或杂芳基,(C3-C7环烷基)C1-C4烷基,C1-C6卤代烷基,C1-C6烷氧基,C1-C6烷硫基,C2-C6烷酰基,C1-C6烷氧羰基,C2-C6烷酰基氧基,一-和二-(C3-C8环烷基)氨基C0-C4烷基,(4-至7-元杂环)C0-C4烷基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基,和一-和二-(C1-C6烷基)氨基羰基,其各自用独立选自下述的0至4个取代基取代:卤素,羟基,氰基,氨基,-COOH和氧代;
R2是独立地选自下述的0至4个取代基:
(i)卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2,氧代,硝基和烷氧羰基;和
(ii)C1-C6烷基,C1-C6烷氧基,C3-C10环烷基,C2-C6烯基,C2-C6炔基,C2-C6烷酰基,C1-C6卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基和一-和二-(C1-C6烷基)氨基羰基;苯基C0-C4烷基和(4-至7-元杂环)C0-C4烷基,其各自用独立选自下述的0至4个第二取代基取代:卤素,羟基,氰基,氧代,亚氨基,C1-C4烷基,C1-C4烷氧基和C1-C4卤代烷基。
K选自
(i)O,S,
(ii)NR6
R6代表氢,烷基,环烷基,烯基,炔基,烷硫基,芳基,芳基烷基。
最优选,本发明化合物可以是式(I)化合物,其中
W和Y独立地选自S,NR3,或CR3;
R3独立地选自氢或任选经取代的C1-C4脂族基团,卤素,羟基,氨基,酰胺,氰基。
Ar代表杂芳基或芳基,其各自用0至4个独立选自下述的取代基取代:
1.卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2;和
2.C1-C6烷基,C1-C6烷氧基,C3-C10环烷基,C2-C6烯基,C2-C6烷酰基,C1-C6卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,
R1选自:
(i)氨基,烷基氨基,芳基氨基,杂芳基氨基;
(ii)式(Ia)基团:
其中:
R4代表氢,在R5是氢的情况下,X是CH;或X-R5是O;或X是N,R5代表下述基团:氢,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C10芳基或杂芳基,(C3-C7环烷基)C1-C4烷基,C1-C6卤代烷基,C1-C6烷氧基,C1-C6烷硫基,C2-C6烷酰基,C1-C6烷氧羰基,C2-C6烷酰基氧基。
R2是独立地选自下述的0至4个取代基:
(i)卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2,氧代,硝基和烷氧羰基;和
(ii)C1-C6烷基,C1-C6烷氧基,环烷基,C2-C6烯基,C2-C6炔基,C2-C6烷酰基,C1-C6卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基和一-和二-(C1-C6烷基)氨基羰基;苯基C0-C4烷基和(4-至7-元杂环)C0-C4烷基,其各自用独立选自下述的0至4个第二取代基取代:卤素,羟基,氰基,氧代,亚氨基,C1-C4烷基,C1-C4烷氧基和C1-C4卤代烷基。
K选自
(i)O,S,
(ii)NR6
R6代表氢,烷基,环烷基,烯基,炔基,烷硫基,芳基,芳基烷基。
根据又一实施方式,本发明涉及式(I)化合物,其中R1是氢。
根据又一实施方式,本发明涉及式(I)化合物,其中R1是氯。
根据又一实施方式,本发明涉及式(I)化合物,其中R1是甲基。
根据又一实施方式,本发明涉及式I化合物,其中R1是乙基。
根据又一实施方式,本发明涉及式I化合物,其中R1是丙基。
根据又一实施方式,本发明涉及式I化合物,其中R1是异丙基。
根据又一实施方式,本发明涉及式I化合物,其中R1是异丁基。
根据又一实施方式,本发明涉及式I化合物,其中R1是叔丁基。
根据又一实施方式,本发明涉及式I化合物,其中R1是环丙基。
根据又一实施方式,本发明涉及式I化合物,其中R1是环丁基。
根据又一实施方式,本发明涉及式I化合物,其中R2是甲基-哌嗪基。
根据又一实施方式,本发明涉及式I化合物,其中R2是(2-羟基乙基)-哌嗪基。
根据又一实施方式,本发明涉及式I化合物,其中R2是(4-吡啶基)-哌嗪基。
根据又一实施方式,本发明涉及式I化合物,其中R2是甲基。
根据又一实施方式,本发明涉及式I化合物,其中R2是乙基。
根据又一实施方式,本发明涉及式I化合物,其中R2是环丙基。
特定的本发明化合物的实例是下面定义的那些化合物:
在又一实施方式中,提供制备本发明化合物的方法。本发明化合物能够一般用氰尿酰氯作原料来制备。化合物(I)可以含有各种立体异构体,几何异构体,互变异构体等。全部可能异构体及其混合物包括在本发明中,而混合比例并无特别限制。
本发明中的式(I)的三嗪衍生物化合物能够通过现有技术的已知程序制备。实例可参见US专利No.2005250945A1;US专利No.20050227983A1;PCT WO 05/007646A1;PCT WO 05/007648A2;PCTWO 05/003103A2;PCT WO 05/011703 A1;和J.of Med.Chem.(2004),47(19),4649-4652.原料可商购自供应商比如Sigma-Aldrich Corp.(St.Louis,MO),或者可以用已确立的方案合成自可商购的前体。比方说,可以使用类似示于任意下述方案的合成路线,以及合成有机化学领域已知的合成方法,或本领域技术人员所了解的其变型。下述方案中的各变量是指与本文提供的化合物的描述相符的任意基团。
在后续方案中,术语″还原″是指将硝基官能度(functionality)还原为氨基官能度的方法,或者将酯官能度转化为醇的方法。能够以许多有机合成领域技术人员熟知的许多方法还原硝基,包括但不限于,催化氢化,用SnCl2还原和用二氯化钛还原。还原酯基团一般地用金属氢化物试剂进行,包括,但不限于,氢化二异丁基铝(DIBAL),氢化铝锂(LAH),和硼氢化钠。对于还原方法的概览可参见:Hudlicky,M.Reductions in Organic Chemistry,ACS Monograph 188,1996。在后续方案中,术语″水解″是指底物或反应物与水的反应。更特别地,″水解″是指将酯或亚硝酸酯官能度转化为羧酸。该过程能够通过有机合成领域技术人员熟知的各种酸或碱进行催化。
式(I)化合物可以通过使用已知化学反应和程序来制备。提供下述一般制备方法来帮助本领域技术人员合成抑制剂,而在描述实施例的实验部分提供更详述的实施例。
杂环胺如式(II)中所定义。杂环胺中的某些是可商购的,其它可以通过现有技术的已知程序(Katritzky,et al.Comprehensive HeterocyclicChemistry;Permagon Press:Oxford,UK,1984,March.AdvancedOrganic Chemistry,3″Ed.;John Wiley:New York,1985),或通过使用一般有机化学知识进行制备。
例如,取代的杂环胺能够用标准方法(March,J.Advanced OrganicChemistry,4th Ed.;John Wiley,New York(1992);Larock,R.C.Comprehensive Organic Transformations,2nd Ed.,John Wiley,NewYork(1999);世界专利No.WO 99/32106)产生。如方案1中所示,杂环胺能够通过还原硝基杂环(nitroheteros)一般地合成:使用金属催化剂,比如Ni,Pd,或Pt,和H2或氢化物转移试剂,比如甲酸酯,环己二烯,或硼氢化物(Rylander.Hydrogenation Methods;Academic Press:London,UK(1985))。硝基杂环还可以这样直接还原:用强氢化物源比如LAH,(Seyden-Penne.Reductions by the Alumino-and Borohydrides inOrganic Synthesis;VCH Publishers:New York(1991)),或用0价金属(常常在酸性介质中)比如Fe,Sn或Ca。存在合成硝基芳基的许多方法(March,J.Advanced Organic Chemistry,4th Ed.;John Wiley,NewYork(1992);Larock,R.C.Comprehensive Organic Transformations,2ndEd.,John Wiley,New York(1999)))。
方案1
如方案2中所示,具取代基的噻唑胺(IIb)能够制备自如方案2中所示的商业化合物。通过途径1,取代的醛(可以是可商购的或通过氧化醇来制备)能够通过溴或NBS(N-溴代琥珀酰亚胺)溴化;在溴化之后,能通过与硫脲反应将醛转化为相应噻唑胺(IIb)。对于氧化步骤,可使用各种氧化剂,比如吡啶鎓氯铬酸盐(PCC)活化的二甲亚砜(DMSO),超化合价碘化物化合物,高钌酸四丙基铵(TPAP)或2,2,6,6-四甲基哌啶-1-氧基(oxyl)(TEMPO)。许多噻唑胺能够通过该方式制备。
方案2
许多取代的吡唑胺是可商购的并能直接使用。在某些特殊情况下,具取代基的吡唑胺(IIc)能够通过现有技术的已知程序比如US专利6407238;F.Gabrera Escribano,et al.Tetrahedron Letters,Vol.29,No.46,pp.6001-6004,1988;Org.Biomol.Chem.,2006,4,4158-4164;WO/2003/026666来制备。
前体R1H能够购自供应商比如Alderich。
前体R2PhKH能够购买自例如上述供应商,或用已确定的方案合成自可商购的前体。例如,如方案3中所示,取代的N-(巯基苯基)甲酰胺(IIIa)容易地得自将氨基苯硫酚(thiophenol)与羧酸或其衍生物比如酰氯、酸酐或酯反应。
方案3
另选地,如方案4中所示,取代的巯基-N-苯甲酰胺(IIIb)能够这样制备:将被适当基团保护的巯基苯甲酸制备与相应胺反应。
方案4
本发明式(I)化合物的制备能够通过本领域已知方法进行(例如,J.Med.Chem.1996,39,4354-4357;J.Med.Chem.2004,47,600-611;J.Med.Chem.2004,47,6283-6291;J.Med.Chem.2005,48,1717-1720;J.Med.Chem.2005,48,5570-5579;US专利号6340683 B1;JOC,2004,29,7809-7815)。
如方案5中所示,三嗪衍生物能够这样合成:将氰尿酰氯与一系列杂环胺反应,得到化合物b的二氯噻嗪中间体,能够将其与R2PhKH反应产生,进一步的化合物c的一氯中间体。用R1H替代最后的氯能够通过升高温度实现,提供三取代的-1,3,5-三嗪(I)。反应能够是分步的或一锅进行。如方案5中所示,备择程序也能用来制备三嗪衍生物。
方案5
反应优选在惰性溶剂存在下进行。对将使用的溶剂的性质没有特别限制,条件是其对反应或对有关试剂不存在不良作用并且其能够溶解(至少以一定程度)所述试剂。适宜的溶剂的实例包括:脂族烃,比如己烷,庚烷,石脑油和石油醚;芳族烃,比如苯,甲苯和二甲苯;卤化烃,特别是芳族和脂族烃,比如二氯甲烷,氯仿,四氯化碳,二氯乙烷,氯苯和二氯苯;酯,比如甲酸乙酯,乙酸乙酯,乙酸丙酯,乙酸丁酯和碳酸二乙酯;醚,比如二乙醚,二异丙基醚,四氢呋喃,二噁烷。二甲氧基乙烷和二乙二醇二甲基醚;酮,比如丙酮,甲基乙基酮,甲基异丁基酮,异佛尔酮和环己酮;硝基化合物,其可以是硝基烷烃或硝基芳烃,比如硝基乙烷和硝基苯;腈,比如乙腈和异丁腈;酰胺,其可以是脂肪酸酰胺,比如甲酰胺,二甲基甲酰胺,二甲基乙酰胺和六甲基磷酸三酰胺;和亚砜,比如二甲亚砜和环丁砜。
反应能够在宽温度范围发生,且精确的反应温度并不是本发明的关键。通常,我们发现在-50℃至100℃的温度进行反应是方便的。
本发明提供物质的组合物,其是一种或多种活性药物和药学上可接受的载体的配制剂。有鉴于此,本发明提供用于给药至哺乳动物受试者的组合物,其可以包括式I化合物,或其药学上可接受的盐。
本发明化合物的药学上可接受的盐包括衍生自药学上可接受的无机和有机的酸和碱的那些。适宜的酸式盐的实例包括乙酸盐,己二酸盐,藻酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,柠檬酸盐,樟脑酸盐,樟脑磺酸盐,环戊烷丙酸盐,二葡糖酸盐,十二烷基硫酸盐,乙烷磺酸盐,甲酸盐,富马酸盐,葡庚酸盐,甘油磷酸盐,羟乙酸盐,半硫酸盐,庚酸盐,己酸盐,盐酸盐,氢溴酸盐,氢碘酸盐,2-羟基乙烷磺酸盐,乳酸盐,马来酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,草酸盐,棕榈酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,磷酸盐,苦味酸盐,特戊酸盐,丙酸盐,水杨酸,琥珀酸盐,硫酸盐,酒石酸盐,硫氰酸盐,甲苯磺酸盐和十一碳酸盐。其它酸比如草酸,虽然本身不是药学上可接受的,但在获得本发明化合物及其药学上可接受的酸加成盐的过程中,可以用于制备用作中间体的盐。
衍生自适当碱的盐包括碱金属(例如,钠和钾),碱土金属(例如,镁),铵和N(C1-C4烷基)4 +盐。本发明也预想本文公开化合物的任意碱性含氮基团的季铵化。可溶于或者可分散于水或油的产品可以通过所述季铵化而获得。本发明组合物可以这样给予:口服,经肠胃外,吸入喷雾,局部,直肠,鼻部,颊部,阴道或经由植入式储库。术语″肠胃外″如本文所用包括皮下,静脉内,肌内,关节内,滑膜内,胸骨内,鞘内,肝内,病灶内和颅内注射或输注技术。优选,组合物是口服、经腹膜内或经静脉内给予的。
本发明的药学上可接受的组合物可以以任意口服可接受的剂型口服给予,所述剂型包括,但不限于,胶囊,片剂,含锭,酏剂,悬浮液,糖浆剂,糯米纸囊剂(wafers),口香糖,悬浮液或水溶液。
口服组合物可以含有额外的成分比如:粘合剂比如微晶纤维素,黄蓍胶或明胶;赋形剂比如淀粉或乳糖,崩解剂比如藻酸,玉米淀粉等;润滑剂比如硬脂酸镁;助流剂比如胶体二氧化硅;和甜味剂比如蔗糖或糖精或者矫味试剂比如胡椒薄荷,水杨酸甲酯,或橙味剂。在剂量单元形式是胶囊的情况下,其可以额外地含有液体载体比如脂肪油。其它剂量单元形式可以含有修饰剂量单元的物理形式的其它各种物质,例如包衣。因此,片剂或丸剂可以包覆有糖、虫胶、或其它肠包衣剂。糖浆除了活性成分之外,还可以含有作为甜味剂的蔗糖和某些防腐剂,染料和着色剂和香料。在制备这些各种组合物中所用的物质在所用量下应是药学或兽医上纯的和非毒性的。
出于肠胃外治疗给药的意图,可以将活性成分掺入溶液或悬浮液。溶液或悬浮液还可以包括下述组分:注射用的无菌稀释剂比如水,盐水溶液,非挥发油,聚乙二醇,甘油,丙二醇或其它合成的溶剂;抗菌剂比如苯甲醇或甲基羟苯酯类;抗氧化剂比如抗坏血酸或亚硫酸氢钠;螯合试剂比如乙二胺四乙酸;缓冲液比如乙酸盐,柠檬酸盐或磷酸盐和调整张力的试剂如氯化钠或葡萄糖。肠胃外制剂能够封闭在玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。
适于可注射用途的药物形式包括无菌溶液,分散液,乳液,和无菌粉末。最终形式应在制备和贮藏条件下是稳定的。另外,最终的药物形式应防范污染,因此应能够抑制微生物比如细菌或真菌的生长。可以给予单次静脉内或腹腔内剂量。另选地,可以使用缓慢长期输注或多次短期每日输注,一般持续1至8天。还可以运用隔天给药或数天给药一次。
无菌可注射溶液可以这样制备:以所需量将化合物掺入一种或多种适当的溶剂,并可以根据需要向其加入上述的或本领域技术人员已知的其它成分。无菌可注射的溶液可以这样制备:以所需量将化合物掺入含所需要的各种其它成分的适当溶剂。然后,可以进行灭菌程序,比如过滤。一般地,这样制备分散液:将化合物掺入还含有分散液介质和上述的所需要的其它成分的无菌媒介物。在无菌粉末的情况下,优选的方法包括真空干燥或冻干,并向其加入任意所需成分。
适宜的药物载体包括无菌水;盐水,葡萄糖;葡萄糖的水或盐水溶液;蓖麻油与环氧乙烷的缩合产品,其成分为约30至约35摩尔环氧乙烷/摩尔蓖麻油;液态酸;低级链烷醇;油比如玉米油;花生油,芝麻油等,其含乳化剂比如脂肪酸一或二甘油酯,或磷脂,例如卵磷脂,等;二醇;聚亚烷基二醇;在助悬剂例如羧甲纤维素钠存在下的含水介质;藻酸钠;聚(乙烯基吡咯烷酮);等,单独或者与适宜的分配剂比如卵磷脂;聚氧乙烯硬脂酸酯;等一起。载体还可以含有佐剂比如防腐剂、稳定剂、润湿剂、乳化剂等以及穿透增强剂。在全部情况中,应指出,最终形式必须是无菌的并且也应能够容易地经过注射装置比如中空针头。通过合适选择溶剂或赋形剂可以实现并保持合适的粘度。此外,可以使用分子或颗粒包衣比如卵磷脂,合适选择的分散液颗粒尺寸,或具表面活性剂特性的物质。
按照本发明,提供含有三嗪衍生物的组合物和用于体内递送纳米粒子形式的三嗪衍生物的方法,其适于前述给药途径中任意途径。
美国专利号5,916,596,6,506,405和6,537,579教导自生物可相容的聚合物比如白蛋白制备纳米粒子。从而,按照本发明,提供通过溶剂蒸发技术自在高剪切力(例如超声、高压匀化等)条件下制备的水包油乳液形成本发明的纳米粒子的方法。
另选地本发明的药学上可接受的组合物可以以用于直肠给药的栓剂形式给予。它们能够这样制备:将试剂与在室温下是固体但是在直肠温度是液体并因此在直肠中融化释放药物的适宜无刺激性赋形剂混合。所述物质包括可可油,蜂蜡和聚乙二醇。
本发明的药学上可接受的组合物还可以局部给予,特别是在治疗靶标包括可通过局部应用容易地接触的区域或器官的情况下,包括眼部、皮肤或下部肠道(lower intestinal tract)疾病的情况。可容易地制备用于各自这些区域或器官的适宜局部用配制剂。
下部肠道的局部应用能够用直肠栓剂配制剂(参见上文)或适宜的灌肠配制剂进行。还可以使用局部-透皮贴剂。
对于局部应用,药学上可接受的组合物可以配制为含有悬浮或溶于一种或多种载体的活性组分的适宜软膏剂。局部给药本发明化合物的载体包括,但不限于,矿物油,液态凡士林,白凡士林,丙二醇,聚氧乙烯,聚氧丙烯化合物,乳化型蜡和水。另选地,药学上可接受的组合物能够配制为适宜的洗液或霜剂,其含有悬浮或溶于一种或多种药学上可接受的载体的活性组分。适宜的载体包括,但不限于,矿物油,去水山梨糖醇单硬脂酸酯,聚山梨醇60,鲸蜡基酯蜡,鲸蜡硬脂醇,2-辛基十二碳醇,苯甲醇和水。
对于眼用,药学上可接受的组合物可以配制为等渗、经pH调节的无菌盐水中的微粒化悬浮液,或者优选,配置为等渗、经pH调节的无菌盐水中的溶液,其中含或不含防腐剂比如苯扎氯铵。另选地,对于眼用,药学上可接受的组合物可以配制为软膏剂比如凡士林。
本发明药学上可接受的组合物还可以通过鼻用气雾剂或吸入来给予。根据药物配制领域熟知的技术制备所述组合物,并且可以用苯甲醇或其它适宜防腐剂,增强生物利用度的吸收促进剂,碳氟化合物,和/或其它常规溶剂化试剂或分散剂制备为盐水中的溶液。
最优选,本发明药学上可接受的组合物配制用于口服给药。
按照本发明,本发明化合物可以用来治疗与细胞增殖或过度增殖有关的疾病,比如癌症,其包括但不限于鼻腔、鼻旁窦、鼻咽、口腔、口咽、喉、下咽、唾腺的肿瘤和副神经节瘤。本发明化合物还可以用来治疗肝癌和胆道系统癌(特别肝细胞癌),肠癌,特别是结直肠癌,卵巢癌,小细胞和非小细胞肺癌,乳腺癌,肉瘤(包括纤维肉瘤,恶性纤维组织细胞瘤,胚胎型横纹肌肉瘤,平滑肌结缔组织瘤,神经纤维肉瘤,骨肉瘤,滑膜肉瘤,脂肪肉瘤,和牙槽软部肉瘤),中枢神经系统瘤(特别脑癌),和淋巴瘤(包括霍奇金淋巴瘤,淋巴类浆细胞淋巴瘤,滤泡淋巴瘤,粘膜有关的淋巴样组织淋巴瘤,外套细胞淋巴瘤,B-谱系大细胞淋巴瘤,Burkitt淋巴瘤,和T-细胞还原成形术型大细胞淋巴瘤)。
本发明的化合物和方法,无论在单独或与其它试剂(例如,描述如下的化疗药或蛋白质治疗剂)组合给予的情况下也用于治疗各种障碍,包括但不限于,例如:卒中,心血管疾病,心肌梗死,充血性心力衰竭,心肌病,心肌炎,缺血性心脏病,冠状动脉疾病,心源性休克,血管性休克,肺动脉高压,肺水肿(包括心原性肺水肿),胸膜积液,类风湿性关节炎,糖尿病性视网膜病,视网膜色素变性,和视网膜病,包括糖尿病性视网膜病和早产儿视网膜病,炎性疾病,再狭窄,哮喘,急性或成人呼吸性窘迫综合征(ARDS),狼疮,血管渗漏,保护免受缺血或再灌注损伤比如在器官移植期间招致的缺血或再灌注损伤,移植耐受诱导(transplantation tolerance induction);血管成形术后的缺血或再灌注损伤;关节炎(比如类风湿性关节炎,牛皮癣型关节炎或骨关节炎);多发性硬化;炎性肠病,包括溃疡性结肠炎和克罗恩病;狼疮(全身性红斑狼疮);移植物抗宿主疾病;T-细胞介导的超敏感性疾病,包括接触性超敏感性,延缓型超敏感性,和麸质敏感性肠病变(乳糜泻);类型1糖尿病;牛皮癣;接触性皮炎(包括由于毒物藤引起的那些);桥本氏甲状腺炎;斯耶格伦氏综合征;自身免疫甲状腺功能亢进,比如格雷夫斯病;艾迪生病(肾上腺的自身免疫性疾病);自身免疫多腺病(也称为自身免疫多腺性综合征);自身免疫脱发;恶性贫血;白斑;自身免疫垂体机能减退;格-巴二氏综合征;其它自身免疫性疾病;癌症,包括其中激酶比如Src-家族激酶活化的或过表达的那些,比如结肠癌和胸腺瘤,或者其中激酶活性促进肿瘤生长或生存的癌症;肾小球肾炎,血清病;荨麻疹;变应性疾病比如呼吸性变态反应(哮喘,花粉症,变应性鼻炎)或皮肤变态反应;蕈样肉芽肿病;急性炎性反应(比如急性或成人呼吸性窘迫综合征和缺血再灌注损伤);皮肤肌炎;斑秃;慢性光化性皮炎;湿疹;Behcet疾病;掌跖脓疱病;脓皮病坏疽;赛杂瑞综合征;特应性皮炎;全身性硬化;硬斑病;外周四肢缺血和缺血性四肢疾病;骨骼疾病比如骨质疏松症,骨软化,甲状旁腺功能亢进,佩吉特病,和肾性骨营养不良;血管渗漏综合征,包括化疗或免疫调节剂比如IL-2诱导的血管渗漏综合征;脊髓和脑伤害或创伤;青光眼;视网膜疾病,包括黄斑变性;玻璃体视网膜疾病;胰腺炎;脉管炎(vasculatides),包括脉管炎,川崎病,闭塞性血栓性脉管炎,Wegener肉芽肿病,和Behcet疾病;硬皮病;先兆子痫;地中海贫血;卡波西肉瘤;希-林病;等。
按照本发明,本发明化合物可以用来治疗与不希望的细胞增殖或过度增殖有关的疾病,包括鉴别患所述疾病或病症的哺乳动物并且向所述患病哺乳动物给予包含式1化合物的组合物,其中所述疾病或病症与激酶有关。
按照本发明,本发明化合物可以用来治疗与不希望的细胞增殖或过度增殖有关的疾病,包括鉴别患所述疾病或病症的哺乳动物并且向所述患病哺乳动物给予包含式1化合物组合物,其中所述疾病或病症与酪氨酸激酶有关。
按照本发明,本发明化合物可以用来治疗与不希望的细胞增殖或过度增殖有关的疾病,包括鉴别患所述疾病或病症的哺乳动物并且向所述患病哺乳动物给予包含式1化合物的组合物,其中所述疾病或病症与是丝氨酸激酶或苏氨酸激酶的激酶有关。
按照本发明,本发明化合物可以用来治疗与不希望的细胞增殖或过度增殖有关的疾病,包括鉴别患所述疾病或病症的哺乳动物并且向所述患病哺乳动物给予包含式1化合物的组合物,其中所述疾病或病症与是Src家族激酶的激酶有关。
本发明也提供治疗患上述疾病和病症的哺乳动物的方法。可以与载体物质相组合以获得单剂形式的组合物的本发明化合物的量取决于治疗的宿主、特定给药模式而变化。优选,应这样配制组合物,使得能够将0.01-100mg/kg体重/天的剂量的抑制剂给予至接受这些组合物的患者。
在一方面,本发明化合物与化疗药、抗炎剂,抗组胺药,化疗药,免疫调节剂,治疗抗体或蛋白激酶抑制剂例如酪氨酸激酶抑制剂组合给予需要该治疗的受试者。
该方法包括将一种或多种本发明化合物给予患病的哺乳动物。该方法可以还包括给药第二活性剂,比如细胞毒素剂,包括烷基化试剂,肿瘤坏死因子,嵌入剂,微管蛋白抑制剂,和拓扑异构酶抑制剂。所述第二活性剂可以在相同组合物中或在第二组合物中共同给予。适宜的第二活性剂的实例包括,但不限于,细胞毒素药比如阿西维辛;阿柔比星;阿考达唑盐酸盐;AcrQnine;阿多来新;阿地白介素;六甲蜜胺;安波霉素;阿美蒽醌乙酸盐;氨鲁米特;安吖啶;阿那曲唑;安曲霉素;天冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;比生群盐酸盐;甲磺酸双奈法德;比泽来新;博来霉素硫酸盐;布喹那钠;溴匹立明;白消安;放线菌素C;卡普睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;卡柔比星盐酸盐;卡泽来新;西地芬戈;苯丁酸氮芥;西罗霉素;顺铂;克拉屈滨;克立那托甲磺酸盐;环磷酰胺;阿糖胞苷;达卡巴嗪;放线菌素D;柔红霉素盐酸盐;地西他滨;右奥马铂;地扎呱宁;地扎呱宁甲磺酸盐;地吖醌;多西他赛;多柔比星;多柔比星盐酸盐;屈洛昔芬;屈洛昔芬柠檬酸盐;屈他雄酮丙酸盐;达佐霉素;依达曲沙;依氟鸟氨酸盐酸盐;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;表柔比星盐酸盐;厄布洛唑;依索比星盐酸盐;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;乙碘油131;依托泊苷;依托泊苷磷酸盐;氯苯乙嘧胺;法倔唑盐酸盐;法扎拉滨;芬维A胺;氟尿苷;氟达拉滨磷酸盐;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;吉西他滨盐酸盐;金Au 198;羟基脲;伊达比星盐酸盐;异环磷酰胺;伊莫福新;干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-La;干扰素γ-Ib;异丙铂;伊立替康盐酸盐;兰瑞肽乙酸盐;来曲唑;亮丙立德乙酸盐;利阿唑盐酸盐;洛美曲索钠;洛莫司汀;洛索蒽醌盐酸盐;马索罗酚;美坦生;氮芥盐酸盐;甲地孕酮乙酸盐;美仑孕酮乙酸盐;美法仑;美诺立尔;巯嘌呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托卡星;丝裂红素;米托洁林;米托马星;丝裂霉素;米托司培;米托坦;米托蒽醌盐酸盐;麦考酚酸;诺考达唑;诺拉霉素;奥马铂;奥昔舒仑;紫杉醇;培门冬酶;培利霉素;奈莫司汀;培洛霉素硫酸盐;培磷酰胺;哌泊溴烷;哌泊舒凡;吡罗蒽醌盐酸盐;普卡霉素;普洛美坦;卟吩姆钠;泊非霉素;泼尼莫司汀;丙卡巴肼盐酸盐;嘌罗霉素;嘌罗霉素盐酸盐;吡唑呋喃菌素;利波腺苷;罗谷亚胺;Safmgol;沙芬戈盐酸盐;司莫司汀;辛曲秦;磷乙酰天冬氨酸钠;司帕霉素;锗螺胺盐酸盐;螺莫司汀;螺铂;链黑霉素;链佐星;氯化锶Sr 89;磺氯苯脲;他利霉素;Taxane;Taxoid;替可加兰钠;替加氟;替洛蒽醌盐酸盐;替莫泊芬;替尼泊苷;替罗昔隆;睾内酯;硫咪嘌呤;硫鸟嘌呤;塞替派;噻唑羧胺核苷;替拉扎明;托泊替康盐酸盐;托瑞米芬柠檬酸盐;曲托龙乙酸盐;曲西立滨磷酸盐;三甲曲沙;三甲曲沙葡糖醛酸盐;曲普瑞林;妥布氯唑盐酸盐;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬;长春碱硫酸盐;长春新碱硫酸盐;长春地辛;长春地辛硫酸盐;长春匹定硫酸盐;长春甘酯硫酸盐;长春罗新硫酸盐;长春瑞滨酒石酸盐;长春罗定硫酸盐;长春利定硫酸盐;伏氯唑;泽尼铂;净司他丁;和佐柔比星盐酸盐。
本发明也涉及如式(A)所示的化合物:
或其药学上可接受的盐,其中:
Y选自C1-C6烷基,C2-C6烯基,C2-C6炔基,-NR4R5,和-Q-R3;
Q选自芳基,杂芳基,环烷基,和杂环烷基,其各自任选用下述取代:C1-C6烷基或氧代;
R3选自H,C1-C6烷基,C2-C6烯基,C2-C6炔基,C1-C6烷基-R6,芳基,和杂芳基;
R4和R5各自独立地选自H,C1-C6烷基,(C1-C6)卤代烷基,和C1-C6烷基-R6;
R6选自羟基,-NH2,一(C1-C6烷基)氨基,二(C1-C6烷基)氨基,环烷基,和杂环烷基;
X是-K-Ar1-R1;
K选自-NR4,O和S;Ar1是苯基;
R1是一个或多个独立地选自下述的取代基:H,-NHC(O)W,卤代,(C1-C6)卤代烷基,-OR4,和-NH2;
W是C-C6烷基;
Z是-NH-Ar2-R2;
Ar2是包括至少一个氮的杂芳基,该杂芳基任选用下述取代:C1-C6烷基,卤素,羟基,氨基,氰基,-COOH,或氧代;
R2选自芳基和杂芳基,其各自任选用下述取代:C1-C6烷基,卤素,羟基,氨基,氰基,-COOH,或氧代。
本发明也涉及如式(A)所示的化合物:
或其药学上可接受的盐,其中:
Y选自C1-C6烷基和-Q-R3;
Q是哌嗪基;
R3是C1-C6烷基;
X是-K-Ar1-R1;
K选自-NR4,O和S;
Ar1是苯基;
R1是一个或多个独立地选自下述的取代基:H,-NHC(O)W,卤代,(C1-C6)卤代烷基,-OR4,和-NH2;
R4选自H,C1-C6烷基,和(C1-C6)卤代烷基;
W是C1-C6烷基;
Z是-NH-Ar2-R2;
Ar2选自吡唑基和噻唑基;
R2选自呋喃基,噻吩基,和苯基。
按照本发明,化合物和组合物可以以亚细胞毒素水平与其它试剂组合使用以便在治疗非肿瘤性障碍比如心脏病、卒中和神经变性疾病中实现高度选择性的活性(Whitesell等人,Curr Cancer Drug Targets(2003),3(5),349-58)。
可以与本发明化合物组合给予的示范性治疗剂包括EGFR抑制剂,比如吉非替尼,厄洛替尼,和西妥昔单抗。Her2抑制剂包括卡奈替尼,EKB-569,和GW-572016。还包括Src抑制剂,达沙替尼,以及Casodex(比卡鲁胺),他莫昔芬,MEK-1激酶抑制剂,MARK激酶抑制剂,PI3抑制剂,和PDGF抑制剂,比如伊马替尼,Hsp90抑制剂,比如17-AAG和17-DMAG。还包括抗血管生成剂和抗血管剂,其通过打断向固体肿瘤的血液流动,剥夺它们的营养,使得癌细胞静息。还可以运用阉割,其也使得雄激素依赖性癌变得不增殖。还包括IGF1R抑制剂,非受体和受体酪氨酸激酶的抑制剂,和整联蛋白的抑制剂。
本发明的药物组合物和方法还可以含有其它蛋白质治疗剂比如细胞因子,免疫调节药和抗体。如本文所用术语″细胞因子″涵盖趋化因子,白细胞介素,淋巴因子,单核因子,集落刺激因子,和受体相关的蛋白,及其功能片段。如本文所用,术语″功能片段″是指具有通过确定的功能测试确认的生物学功能或活性的多肽或肽。细胞因子包括内皮单核细胞激活多肽II(EMAP-II),粒性白细胞,粒细胞-巨噬细胞-CSF(GM-CSF),粒性白细胞,粒细胞-CSF(G-CSF),巨噬细胞-CSF(M-CSF),IL-1,IL-2,IL-3,IL4,IL-5,IL-6,IL-12,和IL-13,干扰素类等,而且其与细胞或细胞机制中的特定生物学、形态学或表型变化有关。
用于组合疗法的其它治疗剂包括环孢菌素类(例如,环孢素A),CTLA4-Ig,抗体比如ICAM-3,抗-IL-2受体(抗-Tac),抗-CD45RB,抗-CD2,抗-CD3(OKT-3),抗-CD4,抗-CD80,抗-CD86,阻断CD40和gp39之间相互作用的试剂,比如特异于CD40和gpn39的抗体(也即,CD154),构建自CD40和gp39的融合蛋白(CD40Ig和CD8gp39),抑制剂,比如核转位抑制剂,NF-kappa B功能的抑制剂,比如脱氧精胍菌素(DSG),胆固醇生物合成抑制剂比如HMG CoA还原酶抑制剂(洛伐他汀和辛伐他汀),非甾族抗炎药(NSAIDs)比如布洛芬和环加氧酶抑制剂比如罗非考昔,类固醇比如泼尼松或地塞米松,金化合物,抗增殖剂比如甲氨蝶呤,FK506(他克莫司,Prograf),麦考酚酸莫酯,细胞毒素药比如硫唑嘌呤和环磷酰胺,TNF-a抑制剂比如替尼达普,抗-TNF抗体或可溶的TNF受体,和雷帕霉素(西罗莫司或雷帕鸣)或其衍生物。
在其它治疗剂与本发明化合物组合使用的情况下,它们可以例如以Physician Desk Reference(PDR)中注明的或以本领域普通技术人员确定的量使用。
具体实施方式
提供下述实施例来进一步说明本发明,但是,当然不应解释为以任何方式限制其范围。
全部实验都这样进行:在无水条件(也即无水溶剂)下,在氩气氛中,除另有说明,用经炉干燥的设备并采用处理空气敏感物质的标准技术。碳酸氢钠(NaHCO3)和氯化钠(盐水)的水溶液是饱和的。
在Merck Kiesel凝胶60 F254板上进行分析薄层色谱法(TLC),用紫外光和/或茴香醛、高锰酸钾或磷钼酸浸染进行可视化。
NMR谱图:于400MHz记录1H核磁共振谱图。数据表示如下:化学位移,多重度(s=单峰,d=二重峰,t=三重峰,q=四重峰,qn=五重峰,dd=双二重峰,m=多重峰,bs=宽单峰),偶合常数(J/Hz)和积分。偶合常数直接自谱图读取并计算,并且不加校正。
低分辨率质谱:使用电喷雾(ES+)离子化。引用质子化的母体离子(M+H)或母体钠离子(M+Na)或最高质量片段。除非另有说明,分析梯度为在5分钟内从10%ACN/水直至100%ACN。
用高效液相色谱(HPLC)来分析三嗪衍生物的纯度。HPLC这样进行:在Phenomenex Synergi Polar-RP,4u,80A,150x4.6mm柱上,用vShimadzu系统,配有SPD-M10A Phospho二极管阵列检测器。流动相A是水而流动相B是乙腈,梯度在60分钟内从20%到80%B,在A/B(80∶20)再次平衡10分钟。在220和54nm检测UV。
实施例1
在-5℃,向4-氨基苯硫酚(6.00g,47.93mmol)和吡啶(5.3mL,65.53mmol)的THF(100mL)溶液逐滴加入环丙烷碳酰氯(3.00mL,32.77mmol)的THF(100mL)溶液。在0℃至室温搅拌反应过夜,用EtOAc(100mL)稀释,用1 N HCl(100mLx5)洗涤,在Na2SO4上干燥,浓缩,在真空下干燥,产生化合物1,是灰白固体(6.01g,95%)。Rf 0.50(50%EtOAc/己烷);1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),7.45(d,J=8.8Hz,2H),7.18(d,J=8.8Hz,2H),5.18(s,1H),1.72(m,1H),0.78(m,4H);ESI-MS:计算(C10H11NOS)193,测得194[M+H]+。
实施例2
于0℃,将化合物1(1.85g,9.57mmol)和DIPEA(1.70mL,9.76mmol)的THF(75ml)溶液滴加至搅拌中的氰尿酰氯(1.90g,10.30mmol)的THF(50mL)溶液。在加入完成之后,于10至20℃再搅拌反应混合物30分钟。将饱和的氯化铵水溶液加至反应混合物,混合物用乙酸乙酯(1x)萃取。有机层用盐水洗涤,干燥(Na2SO4),浓缩,提供化合物2,是白色固体(3.22g,99%收率)。1H NMR(400MHz,DMSO-d6):δ11.12(s,1H),7.69(d,t=8.4Hz,2H),7.45(d,t=8.4Hz,2H),1.80(m,1H),0.81(m,4H)。ESI-MS:计算(C13H10Cl2N4OS)340,测得341[M+H]+。
实施例3
在-5℃,将3-氨基苯硫酚(5.00g,39.93mmol)和吡啶(4.5mL,55.00mmol)的THF(100mL)溶液逐滴加入将环丙烷碳酰氯(2.50mL,27.31mmol)的THF(80mL)溶液。在0℃至室温搅拌反应过夜,用EtOAc(100mL)稀释,用1N HCl(100mL x 5)洗涤,在Na2SO4上干燥,浓缩,在真空下干燥,产生化合物3,是白色固体(4.51g,85%)。Rf 0.50(50%EtOAc/己烷);1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),7.60(s,1H),7.24(d,J=8.4Hz,1H),7.13(t,J=8.4Hz,1H),6.92(d,J=8.8Hz,1H),5.38(s,1H),1.72(m,1H),0.77(m,4H)。
实施例4
于0℃,将化合物3(2.12g,10.97mmol)和DIPEA(1.90mL,10.90mmol)的THF(75ml)溶液滴加至搅拌中的氰尿酰氯(2.20g,11.93mmol)的THF(50mL)溶液。在加入完成之后,于10至20℃再搅拌反应混合物30分钟。饱和的氯化铵水溶液加至反应混合物,混合物用乙酸乙酯(1x)萃取。有机层用盐水洗涤,干燥(Na2SO4),浓缩,提供化合物4,是浅紫色的固体(3.50g,93%收率)。该化合物不加纯化地用于后续反应。
实施例5
向化合物2(300mg,0.88mmol)的THF(5mL)溶液加入3-氨基-5-92-呋喃基)吡唑(105mg,0.70mmol)和DIPEA(0.16mL,0.88mmol)在10-20mL微波瓶中的溶液。用盖密封小瓶,在150℃于微波综合器中搅拌混合物5分钟。然后,将化合物1-甲基哌嗪(0.15mL,1.32mmol)和DIPEA(0.23mL,1.32mmol)加入上述混合物,在60℃在微波综合器中搅拌10分钟。蒸发溶剂,残余物在硅胶柱上进行色谱法,用0-5%MeOH/DCM洗脱,提供化合物5,是米白色固体(120mg,26%)。1H NMR(400MHz,DMSO-d6)δ12.66(bs,1H,NH),10.37(s,1H,NH),9.79(s,1H,NH),7.71(bs,3H,Ar-H),7.51(d,J=8.4Hz,1H,Ar-H),6.07-6.01(bs,1H,Ar-H),3.70(bs,4H,2CH2),2.33(m,4H,2CH2),2.20(s,3H,CH3),1.85-1.78(m,1H,CH),1.84-1.82(m,4H,Ar-H);ESI-MS:计算(C25H27N9OS2)517,测得518[M+H]+。HPLC:保留时间:17.10分钟。纯度:100%。
实施例6
用与实施例5相同的程序,自化合物2(300mg,0.88mmol),5-氨基-3(2-噻吩基)吡唑(116mg,0.70mmol)和1-甲基哌嗪,获得化合物6,是淡黄色固体(230mg,49%)。1H NMR(400MHz,DMSO-d6)δ12.66(bs,1H,NH),10.44(s,1H,NH),9.81(bs,1H,NH),8.98(bs,1H,Ar-H),7.74-7.42(m,5H,Ar-H),7.07(bs,1H,Ar-H),5.98(bs,1H,Ar-H),3.71(bs,2H,CH2),3.59(bs,2H,CH2),2.37(bs,4H,2CH2),1.84(s,3H,CH3),1.86-1.83(m,1H,CH),0.84-0.82(m,4H,Ar-H);ESI-MS:计算(C25H27N9OS2)533,测得534[M+H]+。HPLC:保留时间:18.13分钟。纯度:99%。
实施例7
在-10℃,将溴化乙基镁的醚(3M,15ml,45mmol)溶液滴加至搅拌中的氰尿酰氯(5.64g,30.58mmol)的无水二氯甲烷溶液。在加入完成之后,在-5℃搅拌反应混合物1小时,在该时间之后,逐滴加水,其速率将反应温度保持低于10℃。
在温热至室温之后,反应混合物用额外的水和二氯甲烷稀释,通过C盐垫,用饱和氯化铵洗涤,干燥,浓缩,提供2,4-二氯-6-乙基-1,3,5-三嗪(7),是黄色液体,其在储存于冰箱中之后固化(5.20g,96%)。1H NMR(CDCl3)δ2.95(q,J=7.5Hz.2H),1.38(t,J=7.5Hz.3H)。
实施例8
用制备化合物5所描述的相同程序,将化合物7(200mg,1.12mmol)的THF(16mL)溶液依次与3-氨基-5-(2-呋喃基)吡唑(167mg,1.12mmol)和化合物1(435mg,2.25mmol)反应。获得化合物8,是浅黄色固体(70mg,14%)。1H NMR(400MHz,DMSO-d6)δ12.76(bs,1H,NH),10.47(bs,1H,NH),10.39(s,1H,NH),7.78-7.54(m,5H,Ar-H),6.52(bs,1H,Ar-H),6.46(bs,1H,Ar-H),5.96(bs,1H,Ar-H),2.60-2.54(m,2H,CH2),1.83-1.80(m,1H,CH),1.19(t,J=7.6Hz,3H,CH3),0.85-0.83(m,4H,Ar-H);ESI-MS:计算(C22H21N7O2S)447,测得448[M+H]+。HPLC:保留时间:27.10分钟。纯度:98%。
实施例9
在0℃,向氰尿酰氯(300mg,1.63mmol)的THF(16mL)溶液加入苯硫酚(0.17mL,1.63mmol)和DIPEA(0.28mL,1.63mmol)。在0℃至室温搅拌反应混合物2h。在原料消耗之后,在0℃加入3-氨基-3(2-呋喃基)吡唑(243mg,1.63mmol)和DIPEA(0.28mL,1.63mmol)。在室温下搅拌混合物额外的3小时。将1-甲基哌嗪(0.27mL,2.45mmol)和DIPEA(0.43mL,2.45mmol)加入上述混合物,在室温下搅拌过夜。加入饱和的NaHCO3水溶液,混合物用乙酸乙酯萃取。经合并的有机相用盐水洗涤,在硫酸钠上干燥,浓缩。残余物在硅胶柱上进行色谱法,用0-5% MeOH/DCM洗脱,提供化合物9,是浅黄色固体(100mg,14%)。1H NMR(400MHz,DMSO-d6)δ12.69(bs,1H,NH),9.79(s,1H,NH),7.79(bs,1H,NH),7.61(bs,2H,Ar-H),7.45(s,3H,Ar-H),6.60(s,1H,Ar-H),5.98(bs,1H,Ar-H),3.70(bs,4H,2CH2),2.31(bs,4H,2CH2),2.18(s,3H,CH3);ESI-MS:计算(C21H22N8OS)434,测得435[M+H]+。HPLC:保留时间:18.68分钟。纯度:99%。
实施例10
用制备化合物9所描述的相同程序,在氢化钠(60%,52mg,2.18mmol)存在下,将氰尿酰氯(200mg,1.09mmol)依次与3-氨基-5-(2-呋喃基)吡唑(162mg,1.09mmol)、1-甲基哌嗪和4-氨基苯硫酚(272mg,2.18mmol)反应。获得化合物10,是黄色固体(35mg,14%)。1H NMR(400MHz,DMSO-d6)δ12.67(bs,1H,NH),9.72(bs,1H,NH),7.77(bs,1H,NH),7.19(d,J=8.0Hz,2H,Ar-H),6.62-6.60(m,5H,Ar-H),5.48(s,1H,Ar-H),3.68(bs,4H,2CH2),2.31(bs,4H,2CH2),2.19(s,3H,CH3);ESI-MS:计算(C21H23N9OS)449,测得450[M+H]+。HPLC:保留时间:13.10分钟。纯度:96%。
实施例11
在0℃,向氰尿酰氯(200mg,1.09mmol)的THF(16.0mL)溶液逐滴加入3-氨基-5-(2-呋喃基)吡唑(162mg,1.09mmol)和DIPEA(0.19mL,1.09mmol)的THF(5mL)溶液。在0℃至室温搅拌反应混合物2h。然后,将1-甲基哌嗪(0.12mL,1.09mmol)和DIPEA(0.19mL,1.30mmol)加入混合物。在室温下搅拌混合物3h。滤出固体,提供化合物11,是白色固体(110mg,14%)。%)。1H NMR(400MHz,DMSO-d6)δ12.92(s,1H,NH),10.38(s,1H,NH),7.76(s,1H,Ar-H),6.81-6.61(m,3H,Ar-H),3.77-3.72(m,4H,2CH2),2.38-2.35(m,4H,2CH2),2.21(2,3H,CH3);ESI-MS:计算(C15H17ClN8O)360,测得361[M+H]+。
实施例12
将溴(0.92mL,18.00mmol)滴加至苯基乙醛(2.0mL,17.12mmol)的1,4-二噁烷/Et2O(30mL,1∶1)溶液。在室温下搅拌反应混合物1h。将反应混合物倾至CH2Cl2(45mL)中,加入碳酸氢钠(3.0g,36mmol),搅拌16小时。滤出固体,浓缩滤液,提供12(3.0g)。粗制褐色油状物不加纯化地用于后续步骤。
实施例13
将化合物12(3.0g,15.05mmol)加入硫脲(1.4g,18.10mmol)的乙醇悬浮液。回流反应混合物8h。冷却之后,浓缩溶剂,残余物用DCM/MeOH纯化,提供13,是黄色固体(2.3g,80%)。1H NMR(400MHz,DMSO-d6)δ9.37(bs,2H,NH2),7.82(s,1H,Ar-H),7.58-7.34(m,6H,Ar-H);ESI-MS:计算(C9H8N2S)176,测得177[M+H]+。
实施例14
按照与化合物9相同的程序,化合物14制备自氰尿酰氯(200mg,1.09mmol),苯硫酚,化合物13和1-甲基哌嗪,是黄色固体(120mg,24%)。1H NMR(400MHz,DMSO-d6)δ11.66(bs,1H,NH),7.76-7.27(d,11H,Ar-H),3.84(bs,2H,CH2),3.57(bs,2H,CH2),2.41(bs,2H,CH2),2.30(bs,2H,CH2),2.21(s,3H,CH3);ESI-MS:计算(C23H23N7S2)461,测得462[M+H]+。HPLC:保留时间:25.60分钟。纯度:95%。
实施例15
按照与化合物9相同的程序,化合物15制备自氰尿酰氯(230mg,1.25mmol),4-巯基苯酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是白色固体(80mg,14%)。1H NMR(400MHz,DMSO-d6)δ12.68(bs,1H,NH),9.84-9.74(m,2H),7.74-6.16(m,8H,Ar H),3.68(bs,4H,2CH2),2.31(bs,4H,2CH2),2.19(s,3H,CH3);ESI-MS:计算(C21H22N8O2S)450,测得451[M+H]+。HPLC:保留时间:32.56分钟。纯度:98%。
实施例16
按照与化合物9相同的程序,化合物16制备自氰尿酰氯(230mg,1.25mmol),4-氯苯硫酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是白色固体(160mg,28%)。1H NMR(400MHz,DMSO-d6)δ12.71(bs,1H,NH),9.84(bs,1H,NH),7.76-6.10(m,8H,Ar-H),3.70(bs,4H,2CH2),2.31(bs,4H,2CH2),2.19(s,3H,CH3);ESI-MS:计算(C21H21ClN8OS)468,测得469[M+H]+。HPLC:保留时间:42.27分钟。纯度:99%。
实施例17
按照与化合物9相同的程序,化合物17制备自氰尿酰氯(230mg,1.25mmol),3-氯苯硫酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是白色固体(230mg,39%)。1H NMR(400MHz,DMSO-d6)δ12.71(bs,1H,NH),9.85(bs,1H,NH),7.80-6.00(m,8H,Ar-H),3.70(bs,4H,2CH2),2.31(bs,4H,2CH2),2.19(s,3H,CH3);ESI-MS:计算(C21H21ClN8OS)468,测得469[M+H]+。HPLC:保留时间:41.74分钟。纯度:98%。
实施例18
按照与化合物9相同的程序,化合物18制备自氰尿酰氯(230mg,1.25mmol),2-氯苯硫酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是白色固体(240mg,41%)。1H NMR(400MHz,DMSO-d6)δ12.66(bs,1H,NH),9.81(bs,1H,NH),7.92-5.91(m,8H,Ar-H),3.69(bs,4H,2CH2),2.30(bs,4H,2CH2),2.20(s,3H,CH3);ESI-MS:计算(C21H21ClN8OS)468,测得469[M+H]+。HPLC:保留时间:40.69分钟。纯度:96%。
实施例19
按照与化合物9相同的程序,化合物19制备自氰尿酰氯(230mg,1.25mmol),4-(三氟甲基)苯硫酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是白色固体(150mg,24%)。1H NMR(400MHz,DMSO-d6)δ12.78(bs,1H,NH),9.86(bs,1H,NH),7.87-6.23(m,8H,Ar-H),3.72-3.55(m,4H,2CH2),2.33-2.27(m,4H,2CH2),2.19(s,3H,CH3);ESI-MS:计算(C22H21F3N8OS)502,测得503[M+H]+。HPLC:保留时间:44.60分钟。纯度:100%。
实施例20
按照与化合物9相同的程序,化合物20制备自氰尿酰氯(230mg,1.25mmol),苯胺,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是浅黄色固体(250mg,48%)。1H NMR(400MHz,DMSO-d6)δ12.74(bs,1H,NH),10.14-9.14(m,2H,NH),7.77-6.04(m,9H,Ar-H),3.77(s,4H,2CH2),2.37(s,4H,2CH2),2.22(s,3H,CH3);ESI-MS:计算(C21H23N9O)417,测得418[M+H]+。HPLC:保留时间:48.93分钟。纯度:97%。
实施例21
按照与化合物9相同的程序,化合物21制备自氰尿酰氯(300mg,1.63mmol),苯硫酚,5-噻吩(thine)-2-基-1,3-噻唑-2-胺和1-甲基哌嗪,是米白色固体(500mg,66%)。1H NMR(400MHz,DMSO-d6)δ11.83(bs,1H,NH),7.64-7.07(m,9H,Ar-H),3.84-3.48(m,4H,2CH2),2.39-2.25(m,4H,2CH2),2.19(s,3H,CH3);ESI-MS:计算(C21H21N7S3)467,测得468[M+H]+。HPLC:保留时间:29.60分钟。纯度:97%。
实施例22
按照与化合物9相同的程序,化合物22制备自氰尿酰氯(230mg,1.25mmol),3,5-二氯苯硫酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是白色固体(400mg,64%)。1H NMR(400MHz,DMSO-d6)δ12.73(bs,1H,NH),9.91(bs,1H,NH),7.81-5.98(m,7H,Ar-H),3.72-3.59(m,4H,2CH2),2.33(s,4H,2CH2),2.20(s,3H,CH3);ESI-MS:计算(C21H20Cl2N8OS)503,测得503[M]+。HPLC:保留时间:26.43分钟。纯度:97%。
实施例23
按照与化合物9相同的程序,化合物23制备自氰尿酰氯(230mg,1.25mmol),3,4-二氯苯硫酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是白色固体(300mg,48%)。1H NMR(400MHz,DMSO-d6)δ12.73(bs,1H,NH),9.89(bs,1H,NH),7.91-6.09(m,7H,Ar-H),3.72-3.59(m,4H,2CH2),2.33(s,4H,2CH2),2.20(s,3H,CH3);ESI-MS:计算(C21H20Cl2N8OS)503,测得503[M]+。HPLC:保留时间:26.90分钟。纯度:98%。
实施例24
按照与化合物9相同的程序,化合物24制备自氰尿酰氯(230mg,1.25mmol),4-甲氧基苯硫酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是米白色固体(420mg,72%)。1H NMR(400MHz,DMSO-d6)δ12.68(bs,1H,NH),9.77(bs,1H,NH),7.73-6.06(m,8H,Ar-H),3.74-3.69(m,4H,2CH2),2.32-2.30(m,4H,2CH2),2.19(s,3H,CH3);ESI-MS:计算(C22H24N8O2S)464,测得465[M+H]+。HPLC:保留时间:12.75分钟。纯度:100%。
实施例25
按照与化合物9相同的程序,化合物25制备自氰尿酰氯(230mg,1.25mmol),4-(三氟甲氧基)苯硫酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是米白色固体(400mg,62%)。1H NMR(400MHz,DMSO-d6)δ12.73(bs,1H,NH),9.85(bs,1H,NH),7.75-6.12(m,8H,Ar-H),3.78-3.48(m,4H,2CH2),2.35-2.32(m,4H,2CH2),2.209(s,3H,CH3);ESI-MS:计算(C22H21F3N8O2S)518,测得519[M+H]+。HPLC:保留时间:16.49分钟。纯度:98%。
实施例26
按照与化合物9相同的程序,化合物26制备自氰尿酰氯(230mg,1.25mmol),苯酚,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是米白色固体(450mg,86%)。1H NMR(400MHz,DMSO-d6)δ12.66(bs,1H,NH),9.89(bs,1H,NH),7.75-6.12(m,9H,Ar-H),3.78-3.65(m,4H,2CH2),2.34-2.33(m,4H,2CH2),2.20(s,3H,CH3);ESI-MS:计算(C21H22N8O2)418,测得419[M+H]+。HPLC:保留时间:9.27分钟。纯度:100%。
实施例27
按照与化合物9相同的程序,化合物27制备自氰尿酰氯(230mg,1.25mmol),N-甲基苯胺,3-氨基-5-(2-呋喃基)吡唑和1-甲基哌嗪,是米白色固体(260mg,48%)。1H NMR(400MHz,DMSO-d6)δ12.56(bs,1H,NH),9.20(bs,1H,NH),7.75-5.96(m,9H,Ar-H),3.71(bs,4H,2CH2),2.33(s,4H,2CH2),2.21(s,3H,CH3);ESI-MS:计算(C21H25N9O)431,测得432[M+H]+。HPLC:保留时间:9.19分钟。纯度:97%。
实施例28
向化合物2(300mg,0.88mMol)的4mL THF溶液加入3-氨基-5-苯基吡唑(140mg,0.88mMol)和DIPEA(169pL,125mg,0.97mMol)的1mL THF溶液。在150℃微波下反应10分钟。将1-甲基哌嗪(98pL,88mg,0.88mMol)和DIPEA(169pL,125mg,0.97mMol)加入,在60℃微波下反应10分钟。减压除去溶剂。快速柱色谱法(二氧化硅,CH2Cl2/MeOH 95/5至90/10)产生330mg(71%)的希望产品。1H NMR(400MHz,DMSO)δ12.64(bs,1H),10.42(s,1H),9.79(s,1H),8.00-7.20(m,9H),6.14(bs,1H),3.73(m,4H),2.38(m,4H),2.23(s,3H),1.81(m,1H),0.82(m,4H)。MS(ESI)m/z 528[M+H]+。
实施例29
向化合物4(0.2g,0.588mmol)的THF(12mL)悬浮液加入DIPEA(0.13mL,0.65mmol)和5-苯基-1H-吡唑-3-胺(93.3mg,0.586mmol)。用微波引发器在150℃加热混合物10分钟。在室温下,将N-甲基哌嗪(70.4mg,0.703mmol)和DIPEA((0.13mL,0.65mmol)的THF(5mL)溶液加入上述小瓶。在60℃加热混合物0.2h。在冷却至室温后,饱和的NaHCO3水溶液加至烧瓶,混合物用二氯甲烷(3x25ml)萃取,通过盐水洗涤,在硫酸钠上干燥,浓缩。所得粗制产品通过Teledyne-Isco快速系统纯化,使用DCM/MeOH、0至5%的甲醇/二氯甲烷,提供化合物29,是白色固体(152mg,51%)。1H NMR(400MHz,DMSO-d6)δ11.95(brs,1H),10.45(br,1H),9.65(brs,1H),7.06-7.85(m,9H),6.23(br s,1H),3.67(m,4H),2.41(m,4H),2.20(s,3H),1.12(m,1H),0.84(m,4H,);ESI-MS:计算(C27H29N9OS)527,测得528(MH+)。HPLC:保留时间:12.2分钟。纯度:99%。
实施例30
向化合物4(0.2g,0.588mmol)的THF(12mL)悬浮液加入DIPEA(0.13mL,0.65mmol)和5-(呋喃-2-基)-1H-吡唑-3-胺(87.4mg,0.586mmol)。用微波引发器在150℃加热混合物10分钟。在室温下,将N-甲基哌嗪(70.4mg,0.703mmol)和DIPEA((0.13mL,0.65mmol)的THF(5mL)溶液加入上述小瓶。在60℃加热混合物0.2h。在冷却至室温后,饱和的NaHCO3水溶液加至烧瓶,混合物用二氯甲烷(3x25ml)萃取,用盐水洗涤,在硫酸钠上干燥,浓缩。所得粗制产品通过Teledyne-Isco快速系统纯化,使用DCM/MeOH、0至15%的甲醇/二氯甲烷,提供化合物30,是浅黄色固体(155mg,32%)。1H NMR(400MHz,DMSO-d6)δ12.66(bs,1H),10.37(s,1H),9.79(s,1H),7.79-7.06(m,7H,),6.07(bs,1H),3.70(m,4H),2.33(m,4H),2.20(s,3H),1.42(m,1H),0.85(m,4H);ESI-MS:计算(C25H27N9O2S)517,测得518(MH+)。HPLC:保留时间:10.92分钟。纯度:96%。
实施例31
向化合物4(0.2g,0.588mmol)的THF(12mL)悬浮液加入DIPEA(0.13mL,0.65mmol)和5-(噻吩-2-基)噻唑-2-胺(107mg,0.586mmol)。用微波引发器在150℃加热混合物10分钟。在室温下,将N-甲基哌嗪(70.4mg,0.703mmol)和DIPEA((0.13mL,0.65mmol)的THF(5mL)溶液加入上述小瓶。在60℃加热混合物0.2h。在冷却至室温后,饱和的NaHCO3水溶液加至烧瓶,混合物用二氯甲烷(3x25ml)萃取,用盐水洗涤,在硫酸钠上干燥,浓缩。所得粗制产品通过Teledyne-Isco快速系统纯化,使用DCM/MeOH、0至15%的甲醇/二氯甲烷,提供化合物31,是灰白固体(55mg,18%)。1H NMR(400MHz,DMSO-d6)δ11.55brs,1H),10.27(s,1H),7.95(s,1H,),7.65(brs,1H),7.49-7.20(m,5H),7.07(m,1H),3.80(m,2H),3.50(m,2H),2.35(m,2H),2.25(m,2H),2.15(s,3H),1.75(m,1H),0.85(m,4H);ESI-MS:计算(C25H26N8OS3)550,测得551(MH+)。HPLC:保留时间:27.83分钟。纯度:97%。
实施例32
向化合物4(0.2g,0.588mmol)的THF(12mL)悬浮液加入DIPEA(0.13mL,0.65mmol)和5-(苯基)噻唑-2-胺(103mg,0.586mmol)。用微波引发器在150℃加热混合物10分钟。在室温下,将N-甲基哌嗪(70.4mg,0.703mmol)和DIPEA((0.13mL,0.65mmol)的THF(5mL)溶液加入上述小瓶。在60℃加热混合物0.2h。在冷却至室温后,饱和的NaHCO3水溶液加至烧瓶,混合物用二氯甲烷(3x25ml)萃取,用盐水洗涤,在硫酸钠上干燥,浓缩。所得粗制产品通过Teledyne-Isco快速系统纯化,使用DCM/MeOH、0至15%的甲醇/二氯甲烷,提供化合物32,是白色固体(31mg,11%)。1H NMR(400MHz,DMSO-d6)δ11.55(brs,1H),10.25(brs,1H),7.95(s,1H,),7.49-7.05(m,9H),3.45(m,4H),2.39(m,4H),2.20(s,3H),1.45(m,1H),0.85(m,4H);ESI-MS:计算(C27H28N8OS2)544,测得545(MH+)。HPLC:保留时间:16分钟。纯度:98%。
实施例33
在0℃,向氰尿酰氯(300mg,1.63mmol)的THF(16mL)溶液加入化合物1(320mg,1.63mmol)和DIPEA(0.28mL,1.63mmol)。在0℃至室温搅拌反应混合物2h。将3-氨基-5-(4-甲氧基苯基)吡唑(308mg,1.63mmol)和DIPEA(0.28mL,1.63mmol)加入上述混合物,所得混合物用微波引发器在150℃加热10分钟。将1-甲基哌嗪(0.36mL,3.26mmol)和DIPEA(0.57mL,3.26mmol)加入混合物,混合物用微波引发器在60℃加热10分钟。加入饱和的NaHCO3水溶液,混合物通过乙酸乙酯(3x50mL)萃取。经合并的有机相用盐水洗涤,在硫酸钠上干燥,浓缩。残余物在硅胶柱上进行色谱法,用0-5%MeOH/DCM洗脱,提供33,是浅黄色固体(450mg,65%)。1H NMR(400MHz,DMSO-d6)δ12.46(bs,1H,NH),10.41(s,1H,NH),9.71(bs,1H,NH),7.75-6.05(m,9H,Ar-H),3.80(s,3H,OCH3),3.72(bs,4H,2CH2),2.35(bs,4H,2CH2),2.21(s,3H,CH3),1.82-1.80(m,1H,CH),0.81(bs,4H,Ar-H);ESI-MS:计算(C28H31N9O2S)557,测得558[M+H]+。HPLC:保留时间:19.89分钟。纯度:99%。
实施例34
在0℃,向氰尿酰氯(300mg,1.63mmol)的THF(16mL)溶液加入化合物1(320mg,1.63mmol)和DIPEA(0.28mL,1.63mmol)。在0℃至室温搅拌反应混合物2h。将3-氨基-5-(4-氟苯基)吡唑(289mg,1.63mmol)和DIPEA(0.28mL,1.63mmol)加入上述混合物,所得混合物用微波引发器在150℃加热10分钟。将1-甲基哌嗪(0.36mL,3.26mmol)和DIPEA(0.57mL,3.26mmol)加入混合物,混合物用微波引发器在60℃加热10分钟。加入饱和的NaHCO3水溶液,混合物通过乙酸乙酯(3x50mL)萃取。经合并的有机相用盐水洗涤,在硫酸钠上干燥,浓缩。残余物在硅胶柱上进行色谱法,用0-5%MeOH/DCM洗脱,提供34,是浅黄色固体(620mg,91%)。1H NMR(400MHz,DMSO-d6)δ12.63(bs,1H,NB),10.42(s,1H,NH),9.78(bs,1H,NH),7.74-6.07(m,9H,Ar-H),3.73(bs,4H,2CH2),2.39(bs,4H,2CH2),2.24(s,3H,CH3),1.82-1.80(m,1H,CH),0.82(d,4H,Ar-H);ESI-MS:计算(C27H28FN9OS)545,测得546[M+H]+。HPLC:保留时间:20.60分钟。纯度:99%。
实施例35
在0℃,向氰尿酰氯(300mg,1.63mmol)的THF(16mL)溶液加入化合物1(320mg,1.63mmol)和DIPEA(0.28mL,1.63mmol)。在0℃至室温搅拌反应混合物2h。将5-吡啶-2-基-吡唑-3-基胺(321mg,1.63mmol)和DIPEA(0.28mL,1.63mmol)加入上述混合物,所得混合物用微波引发器在150℃加热10分钟。将1-甲基哌嗪(0.36mL,3.26mmol)和DIPEA(0.57mL,3.26mmol)加入混合物,混合物用微波引发器在60℃加热10分钟。加入饱和的NaHCO3水溶液,混合物用乙酸乙酯(3x50mL)萃取。经合并的有机相用盐水洗涤,在硫酸钠上干燥,浓缩。残余物在硅胶柱上进行色谱法,用0-5%MeOH/DCM洗脱,提供35,是浅黄色固体(350mg,53%)。1H NMR(400MHz,DMSO-d6)δ12.85(bs,1H,NH),10.36(s,1H,NH),9.81(bs,1H,NH),8.58-6.29(m,9H,Ar-H),3.72(bs,4H,2CH2),2.34(bs,4H,2CH2),2.21(s,3H,CH3),1.79-1.72(m,1H,CH),0.82(d,4H,Ar-H);ESI-MS:计算(C26H28N10OS)528,测得529[M+H]+。HPLC:保留时间:
实施例36
在0℃,向氰尿酰氯(230mg,1.25mmol)的THF(16mL)溶液加入3-乙炔基苯胺(146mg,1.25mmol)和DIPEA(0.22mL,1.25mmol)。在0℃至室温搅拌反应混合物2h。将3-氨基-5-(2-呋喃基)吡唑(187mg,1.25mmol)和DIPEA(0.22mL,1.25mmol)加入上述混合物,所得混合物用微波引发器在150℃加热10分钟。将1-甲基哌嗪(0.28mL,2.50mmol)和DIPEA(0.44mL,2.50mmol)加入混合物,混合物用微波引发器在60℃加热10分钟。加入饱和的NaHCO3水溶液,混合物通过乙酸乙酯(3x50mL)萃取。经合并的有机相用盐水洗涤,在硫酸钠上干燥,浓缩。残余物在硅胶柱上进行色谱法,用0-5%MeOH/DCM洗脱,提供36,是浅褐色固体(130mg,24%)。1H NMR(400MHz,DMSO-d6)δ12.75(bs,1H,NH),10.19-9.44(m,2H,NH),7.83-6.06(m,8H,Ar-H),4.14-4.04(m,1H,CH),3.77(s,4H,2CH2),2.37(s,4H,2CH2),2.22(s,3H,CH3);ESI-MS:计算(C23H23N9O)441,测得442[M+H]+。HPLC:保留时间:15.31分钟。纯度:95%。
实施例37
在0℃,向氰尿酰氯(230mg,1.25mmol)的THF(16mL)溶液加入6-氨基-苯并噻唑(188mg,1.25mmol)和DIPEA(0.22mL,1.25mmol)。在0℃至室温搅拌反应混合物2h。将3-氨基-5-(2-呋喃基)吡唑(187mg,1.25mmol)和DIPEA(0.22mL,1.25mmol)加入上述混合物,所得混合物用微波引发器在150℃加热10分钟。将1-甲基哌嗪(0.28mL,2.50mmol)和DIPEA(0.44mL,2.50mmol)加入混合物,混合物用微波引发器在60℃加热10分钟。加入饱和的NaHCO3水溶液,混合物通过乙酸乙酯(3x50mL)萃取。经合并的有机相用盐水洗涤,在硫酸钠上干燥,浓缩。残余物在硅胶柱上进行色谱法,用0-5%MeOH/DCM洗脱,提供37,是白色固体(200mg,34%)。1H NMR(400MHz,DMSO-d6)δ12.86(bs,1H,NH),10.99(bs,1H,NH),9.61(bs,1H,NH),9.21-6.59(m,8H,Ar-H),4.68(bs,2H,CH2),3.43(bs,2H,CH2),3.09(bs,4H,2CH2),2.76(s,3H,CH3);ESI-MS:计算(C22H22N10OS)474,测得475[M+H]+。HPLC:保留时间:14.52分钟。纯度:97%。
实施例38
该实施例说明选自本发明的化合物的c-Src激酶、极光-A激酶、Flt3激酶、Ret激酶和TrkA激酶测定(参见Daniele Fancelli等人,J.Med.Chem.,2006,49(24),pp 7247-7251)。用KinaseProfilerTM服务测定方案(Millipore)来试验本发明新化合物的激酶抑制活性。为了进行该试验,缓冲剂组成是:20mM MOPS,1mM EDTA,0.01% Brij-35,5%甘油,0.1%p-巯基乙醇,1mg/mL BSA。最初,将试验化合物以所希望浓度溶于DMSO,然后系列地稀释于激酶测试缓冲剂。在25pL的最终反应体积中,用8mM MOPS pH 7.0、0.2mM EDTA、200pM LRRASLG(Kemptide)、10mM乙酸镁和[y33P-ATP]温育极光-A(h)(5-10mU)。加入MgATP混合物来引发反应。在室温下温育40分钟之后,加入5pL的3%磷酸溶液来停止反应。然后,将10pL的反应液点至P30滤层,在50mM磷酸中洗涤5分钟共三次,在甲醇中洗涤一次,随后干燥并闪烁计数。用含有底物但无激酶的孔和含有磷酸肽对照的孔来分别设定0%和100%磷酸化值。
也用激酶Hotspot SM激酶测定来测试化合物的IC50或%抑制(Reaction Biology Corp.)。通过滴定最佳激酶浓度(激酶EC50)的化合物来确定抑制剂IC50值。
表1显示浓度1pM的本发明化合物抑制c-Src激酶,极光-A激酶,Flt3激酶,Ret激酶和TrkA激酶的代表性数据。
表1
Claims (28)
1.下式化合物
或其药学上可接受的盐,其中:
W和Y独立地选自S,O,NR3或CR3;
R3独立地选自氢或任选经取代的C1-C4脂族基团,卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2,氧代,硝基和烷氧羰基;
Ar代表杂芳基或芳基,其各自用0至4个独立选自下述的取代基取代:
(1)卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2,氧代,硝基和烷氧羰基;和
(2)C1-C6烷基,C1-C6烷氧基,C3-C10环烷基,C2-C6烯基,C2-C6炔基,C2-C6烷酰基,C1-C6卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基和一-和二-(C1-C6烷基)氨基羰基;苯基C0-C4烷基和(4-至7-元杂环)C0-C4烷基,其各自用独立选自下述的0至4个第二取代基取代:卤素,羟基,氰基,氧代,亚氨基,C1-C4烷基,C1-C4烷氧基和C1-C4卤代烷基;
R1选自:
(i)氨基,烷基氨基,芳基氨基,杂芳基氨基;
(ii)式(Ia)基团:
其中:
R4代表氢,C1-C4烷基,氧代;
在R5是氢的情况下,X是CH;或X-R5是O;或X是N,R5代表下述基团:氢,C1-C6烷基,C2-C6烯基,C2-C6炔基,C3-C10芳基或杂芳基,(C3-C7环烷基)C1-C4烷基,C1-C6卤代烷基,C1-C6烷氧基,C1-C6烷硫基,C2-C6烷酰基,C1-C6烷氧羰基,C2-C6烷酰基氧基,一-和二-(C3-C8环烷基)氨基C0-C4烷基,(4-至7-元杂环)C0-C4烷基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基,和一-和二-(C1-C6烷基)氨基羰基,其各自用独立选自下述的0至4个取代基取代:卤素,羟基,氰基,氨基,-COOH和氧代;
R2是独立地选自下述的0至5个取代基:
(i)卤素,羟基,氨基,酰胺,氰基,-COOH,-SO2NH2,氧代,硝基和烷氧羰基;和
(ii)C1-C6烷基,C1-C6烷氧基,C3-C10环烷基,C2-C6烯基,C2-C6炔基,C2-C6烷酰基,C1-C6卤代烷基,C1-C6卤代烷氧基,一-和二-(C1-C6烷基)氨基,C1-C6烷基磺酰基,一-和二-(C1-C6烷基)磺酰氨基和一-和二-(C1-C6烷基)氨基羰基;苯基C0-C4烷基和(4-至7-元杂环)C0-C4烷基,其各自用独立选自下述的0至4个第二取代基取代:卤素,羟基,氰基,氧代,亚氨基,C1-C4烷基,C1-C4烷氧基和C1-C4卤代烷基;
K选自
(i)O,S,
(ii)NR6
R6代表氢,烷基,环烷基,烯基,炔基,烷硫基,芳基,或芳基烷基。
2.制备权利要求1的化合物或它的药学上可接受的盐,水合物,溶剂化物,晶型盐及其单独非对映体的方法。
3.药物组合物,包含权利要求1化合物中至少一种或它的药学上可接受的盐,水合物,溶剂化物,晶型盐及其单独非对映体,和药学上可接受的载体。
5.根据权利要求3的组合物,还包含额外的治疗剂。
6.用于在哺乳动物中治疗特征是不希望的细胞增殖或过度增殖的疾病或病症的方法,包括鉴别患所述疾病或病症的哺乳动物并且向所述患病哺乳动物给予包含权利要求1的化合物的组合物。
7.权利要求6的方法,其中所述疾病或病症是癌症,卒中,充血性心力衰竭,缺血或再灌注损伤,关节炎或其它关节病,视网膜病或玻璃体视网膜疾病,黄斑变性,自身免疫性疾病,血管渗漏综合征,炎性疾病,水肿,移植排斥,烧伤,或者急性或成人呼吸性窘迫综合征。
8.权利要求7的方法,其中所述疾病或病症是癌症。
9.权利要求7的方法,其中所述疾病或病症是自身免疫性疾病。
10.权利要求7的方法,其中所述疾病或病症是卒中。
11.权利要求7的方法,其中所述疾病或病症是关节炎。
12.权利要求7的方法,其中所述疾病或病症是炎性疾病。
13.权利要求7的方法,其中所述疾病或病症与激酶有关。
14.根据权利要求7的方法,其中所述方法还包括给予额外的治疗剂。
15.根据权利要求7的方法,其中所述额外的治疗剂是化疗药。
16.权利要求13的方法,其中所述激酶是酪氨酸激酶。
17.权利要求13的方法,其中所述激酶是丝氨酸激酶或苏氨酸激酶。
18.权利要求16的方法,其中所述激酶是Src家族激酶。
19.权利要求16的方法,其中所述激酶是Abl家族激酶。
20.权利要求8的方法,其中所述癌症选自肝癌和胆道系统癌,肠癌,结直肠癌,卵巢癌,小细胞和非小细胞肺癌,乳腺癌,肉瘤,纤维肉瘤,恶性纤维组织细胞瘤,胚胎型横纹肌肉瘤,平滑肌结缔组织瘤,神经纤维肉瘤,骨肉瘤,滑膜肉瘤,脂肪肉瘤,牙槽软部肉瘤,中枢神经系统瘤,脑癌,和淋巴瘤,包括霍奇金淋巴瘤、淋巴类浆细胞淋巴瘤、滤泡淋巴瘤、粘膜有关的淋巴样组织淋巴瘤、外套细胞淋巴瘤、B-谱系大细胞淋巴瘤、Burkitt淋巴瘤和T-细胞还原成形术型大细胞淋巴瘤及其各组合。
21.如式(A)所示的化合物:
或其药学上可接受的盐,其中:
Y选自C1-C6烷基,C2-C6烯基,C2-C6炔基,-NR4R5,和-Q-R3;
Q选自芳基,杂芳基,环烷基,和杂环烷基,其各自任选用下述取代:C1-C6烷基或氧代;
R3选自H,C1-C6烷基,C2-C6烯基,C2-C6炔基,C1-C6烷基-R6,芳基,和杂芳基;
R4和R5各自独立地选自H,C1-C6烷基,(C1-C6)卤代烷基,和C1-C6烷基-R6;
R6选自羟基,-NH2,一(C1-C6烷基)氨基,二(C1-C6烷基)氨基,环烷基,和杂环烷基;
X是-K-Ar1-R1;
K选自-NR4,O和S;
Ar1是苯基;
R1是一个或多个独立地选自下述的取代基:H,-NHC(O)W,卤代,(C1-C6)卤代烷基,-OR4,和-NH2;
W是C1-C6烷基;
Z是-NH-Ar2-R2;
Ar2是包括至少一个氮的杂芳基,该杂芳基任选用下述取代:C1-C6烷基,卤素,羟基,氨基,氰基,-COOH,或氧代;和
R2选自芳基和杂芳基,其各自任选用下述取代:C1-C6烷基,卤素,羟基,氨基,氰基,-COOH,或氧代。
23.制备权利要求21的化合物或它的药学上可接受的盐,水合物,溶剂化物,晶型盐及其单独非对映体的方法。
24.药物组合物,包含权利要求21的化合物中至少一种或它的药学上可接受的盐,水合物,溶剂化物,晶型盐及其单独非对映体,和药学上可接受的载体。
25.用于在哺乳动物中治疗特征是不希望的细胞增殖或过度增殖的疾病或病症的方法,包括鉴别患所述疾病或病症的哺乳动物并且向所述患病哺乳动物给予包含权利要求21的化合物的组合物。
26.制备权利要求22的化合物或它的药学上可接受的盐,水合物,溶剂化物,晶型盐及其单独非对映体的方法。
27.药物组合物,包含权利要求22的化合物中至少一种或它的药学上可接受的盐,水合物,溶剂化物,晶型盐及其单独非对映体,和药学上可接受的载体。
28.用于在哺乳动物中治疗特征是不希望的细胞增殖或过度增殖的疾病或病症的方法,包括鉴别患所述疾病或病症的哺乳动物并且向所述患病哺乳动物给予包含权利要求22的化合物的组合物。
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- 2010-06-09 KR KR1020127000666A patent/KR101457027B1/ko active IP Right Grant
- 2010-06-09 CN CN201080032848.2A patent/CN102573480B/zh active Active
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CN113292509A (zh) * | 2021-06-11 | 2021-08-24 | 浙江工业大学 | 一种芳硫醚类化合物及其制备方法和应用 |
CN113292509B (zh) * | 2021-06-11 | 2022-09-27 | 浙江工业大学 | 一种芳硫醚类化合物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
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KR101457027B1 (ko) | 2014-10-31 |
JP5785940B2 (ja) | 2015-09-30 |
IL216831A0 (en) | 2012-02-29 |
US9078902B2 (en) | 2015-07-14 |
CA2765030C (en) | 2015-10-27 |
JP2012529528A (ja) | 2012-11-22 |
AU2010258853B2 (en) | 2014-07-31 |
CN102573480B (zh) | 2015-06-10 |
US20120196860A1 (en) | 2012-08-02 |
AU2010258853A1 (en) | 2012-01-12 |
EP2440057A1 (en) | 2012-04-18 |
BRPI1011318A2 (pt) | 2019-09-24 |
WO2010144550A1 (en) | 2010-12-16 |
IL216831A (en) | 2017-03-30 |
EP2440057A4 (en) | 2012-12-05 |
KR20120026615A (ko) | 2012-03-19 |
CA2765030A1 (en) | 2010-12-16 |
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