CN104093722A - 作为TBK1和IKK抑制剂的呋喃并[3,2-b]-和噻吩并[3,2-b]吡啶衍生物 - Google Patents
作为TBK1和IKK抑制剂的呋喃并[3,2-b]-和噻吩并[3,2-b]吡啶衍生物 Download PDFInfo
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- CN104093722A CN104093722A CN201380008648.7A CN201380008648A CN104093722A CN 104093722 A CN104093722 A CN 104093722A CN 201380008648 A CN201380008648 A CN 201380008648A CN 104093722 A CN104093722 A CN 104093722A
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Abstract
式(I)化合物为TBK1和IKKε的抑制剂,并可尤其用于治疗癌症和炎性疾病,其中R1、R2和X具有在权利要求1中指定的意义。
Description
发明背景
本发明的目的是发现具有有价值的特性的新化合物,特别是可用于制备药物的那些化合物。
本发明涉及能够抑制一种或多种激酶的吡啶化合物。所述化合物在治疗多种病症中得到应用,所述病症包括癌症、脓毒性休克、原发性开角型青光眼(POAG)、增生、类风湿性关节炎、银屑病、动脉粥样硬化、视网膜病、骨关节炎、子宫内膜异位、慢性炎症,和/或神经退行性疾病例如阿尔茨海默氏病。
本发明涉及化合物和涉及化合物在抑制、控制和/或调节激酶(特别是受体酪氨酸激酶)的信号转导中的用途,本发明进一步涉及包含这些化合物的药用组合物,并且涉及所述化合物用于治疗激酶-诱导疾病的用途。
由于蛋白激酶调节几乎每一种细胞过程,包括代谢、细胞增殖、细胞分化和细胞存活,它们是对各种疾病状态的治疗性干预的受关注的靶标。例如、细胞周期调控和血管生成,其中蛋白激酶在与许多疾病状况有关的细胞过程中起着关键作用,所述疾病为例如但不限于癌症、炎性疾病、异常的血管生成及与其相关的疾病、动脉粥样硬化、黄斑变性、糖尿病、肥胖症和疼痛。
特别是,本发明涉及化合物和涉及在抑制、控制和/或调节通过TBK1和IKKε的信号转导中起作用的化合物的用途。
实现细胞调节的主要机理之一是通过细胞外信号跨膜转导,其进而调节细胞内的生物化学途径。蛋白磷酸化代表细胞内信号借以从分子向分子传播,最终导致细胞应答的一种过程。这些信号转导级联受到高度调节并经常重叠,如从许多蛋白激酶以及磷酸酶的存在所证实的。蛋白的磷酸化主要地发生在丝氨酸、苏氨酸或酪氨酸残基,因此蛋白激酶已根据它们的磷酸化位点的特异性进行分类,即丝氨酸/苏氨酸激酶和酪氨酸激酶。因为磷酸化是这样一种细胞内的遍在过程并且因为细胞表型在很大程度上受这些途径的活性的影响,目前已认为许多疾病状态和/或疾病可归因于激酶级联的分子成分的异常激活或者功能突变。因此,相当多的关注已投入到表征能够调节它们的活性的这些蛋白和化合物(对于综述,参见:Weinstein-Oppenheimer等人,Pharma. &. Therap., 2000, 88, 229-279)。
IKKε和TBK1是彼此高度同源的并与其它IkB激酶高度同源的丝氨酸/苏氨酸激酶。两种激酶在先天免疫系统中起着整体作用。双链RNA病毒通过Toll-样受体3和4以及RNA解旋酶RIG-I和MDA-5识别并导致TRIF-TBK1/IKKe-IRF3信号传导级联的激活,这导致I型干扰素应答。
在2007年,Boehm等描述了作为一种新的乳腺癌致癌基因的IKKε [J.S. Boehm等人, Cell 129, 1065-1079, 2007]。对354激酶与激活形式的MAPK激酶Mek一起,就其重演Ras-转化表型的能力进行了研究。IKKε在本文被鉴定为一种协作性致癌基因。另外,作者们能够表明IKKε在许多乳腺癌细胞系和肿瘤样本中扩增和过度表达。借助于乳腺癌细胞中的RNA干涉减少基因表达诱导了细胞凋亡并减弱其增殖。Eddy等在2005年获得了类似的结果,其强调了IKKε在乳腺癌疾病中的重要性[S.F.Eddy等人, Cancer Res. 2005; 65
(24), 11375-11383]。
在2006年首次报道了TBK1的原致癌性(protumorigenic)效应。在包含251,000个cDNA的基因库的筛选中,Korherr等精确地识别了三个基因:TRIF、TBK1和IRF3,这三个基因作为原血管新生因子(proangiogenic factors)一般与先天性免疫防御有关[C.Korherr等, PNAS, 103, 4240-4245,
2006]。在2006年,Chien等[Y.Chien等, Cell 127, 157-170, 2006]发表了TBK1-/-细胞只能有限程度地用致癌Ras转化,这提示在Ras-介导的转化中TBK1的参与。另外,他们能够表明TBK1的由RNAi-介导的敲除在MCF-7和Panc-1细胞中触发凋亡。Barbie等最近发表了TBKl在众多带有突变型K-Ras的癌症细胞系中具有不可或缺的重要性,其提示TBK1介入在相应的肿瘤中可能具有治疗性重要意义[D.A.Barbie等, Nature Letters 1-5, 2009]。
由蛋白激酶引起的疾病的特征在于这样的蛋白激酶的异常活性或活动过度。异常活性涉及以下的任一方面:(1) 在通常不表达这些蛋白激酶的细胞中表达;(2) 增加的激酶表达,导致不期望的细胞增殖如癌症;(3) 增加的激酶活性,导致不期望的细胞增殖如癌症,和/或导致相应蛋白激酶活动过度。活动过度涉及编码某种蛋白激酶的基因的扩增,或者涉及可能与细胞增殖性疾病相关的活性水平的产生(即,细胞增殖性疾病的一种或多种症状的严重性随激酶水平的增加而增加)。蛋白激酶的生物利用度还可能受到是否存在这种激酶的结合蛋白组的影响。
IKKε和TBK1是通过诱导1型干扰素和其它细胞因子,关键地参与先天免疫应答的高度同源的Ser/Thr激酶。这些激酶在响应于病毒/细菌感染中受到刺激。对病毒和细菌感染的免疫应答涉及抗原例如细菌脂多糖(LPS)、病毒双链RNS (dsRNA)与Toll样受体的结合,随后激活TBK1途径。激活的TBK1和IKKε使IRF3和IRF7磷酸化,其触发那些干扰素调节转录因子的二聚化和核易位,最后诱导导致IFN产生的信号传导级联。
最近,IKKε和TBK1也已牵涉到癌症。已表明IKKε与激活的MEK协作以转化人细胞。另外,IKKε在乳腺癌细胞系和患者-来源的肿瘤中频繁地扩增/过度表达。TBK1在缺氧条件下被诱导并以显著水平在许多实体瘤中表达。
此外,需要TBK1以支持致癌基因Ras转换,而TBK1激酶活性在转化的细胞中升高并且对于它们在培养物中的存活是必要的。类似地,已发现TBK1和NF-kB信号传导在KRAS突变肿瘤中是必要的。他们已鉴定TBK1为一种致癌基因KRAS的合成致死配偶体。
文献:
Y.-H.Ou等, Molecular Cell 41, 458-470, 2011;
D.A.
Barbie等, nature, 1-5, 2009。
因此,给予依据本发明的化合物或其药学上可接受的盐以治疗癌症,包括实体癌,例如,诸如癌(例如肺癌、胰腺癌、甲状腺癌、膀胱癌或结肠癌)、骨髓疾病(例如髓性白血病)或腺瘤(例如绒毛状结肠腺瘤)。
肿瘤还包括单核细胞白血病、脑癌、泌尿生殖系统癌、淋巴系统癌、胃癌、喉癌和肺癌(包括肺腺癌和小细胞肺癌)、胰腺癌和/或乳腺癌。
所述化合物还适合用于治疗HIV-1 (1型人免疫缺陷病毒)引起的免疫缺陷。
癌症样的过度增殖性疾病被认为有脑癌、肺癌、鳞状上皮癌、膀胱癌、胃癌、胰腺癌、肝癌、肾癌、结肠直肠癌、乳腺癌、头癌、颈癌、食道癌、妇科癌、甲状腺癌、淋巴瘤、慢性白血病和急性白血病。特别是,癌症样的细胞生长是代表本发明的靶标的疾病。因此,本发明涉及在治疗和/或预防所述疾病中用作药物和/或药物活性成分的依据本发明的化合物,和涉及依据本发明的化合物在制备用于治疗和/或预防所述疾病的药物中的用途,以及涉及治疗所述疾病的方法,该方法包括给予需要这样的给药的患者一种或多种依据本发明的化合物。
可以显示,依据本发明的化合物具有抗增殖作用。给予罹患过度增殖疾病的患者依据本发明的化合物,例如以抑制肿瘤生长、减轻与淋巴增殖疾病有关的炎症、抑制由于组织修复引起的移植排斥或神经性损伤等。本发明的化合物适用于预防或治疗目的。如本文所用的术语“治疗”既用于指预防疾病,又用于指治疗已经存在的病症。预防增殖/活力通过在发生明显疾病之前给予依据本发明的化合物(例如用于阻止肿瘤生长)而达到。或者,所述化合物通过稳定或改善患者的临床症状而用于治疗正在发生的疾病。
宿主或患者可属于任何哺乳动物物种,例如灵长类、特别是人;啮齿动物,包括小鼠、大鼠和仓鼠;兔;马、牛、犬、猫等。动物模型是实验研究所关注的,其提供用于治疗人类疾病的模型。
特定细胞对用依据本发明的化合物治疗的易感性可以通过体外测试来确定。通常,将细胞培养物与各种浓度的依据本发明的化合物一起温育,经过足以允许活性剂诱导细胞死亡或抑制细胞增殖、细胞活力或迁移的时间段,通常在约I小时至I周之间。体外测试可以采用来自活组织检测样品的培养细胞来进行。然后确定在治疗后剩余的细胞量。剂量根据所用的具体化合物、具体疾病、患者状态等而改变。治疗剂量通常足以显著地降低靶组织中不期望的细胞种群,而同时维持患者的生存力。通常继续治疗直到产生显著的降低,例如细胞负荷降低至少约50%,并且可以继续治疗直到在身体中基本上不再检测到不期望的细胞。
有很多与细胞增殖和细胞死亡(细胞凋亡)的失调相关的疾病。关注的病症包括但不限于如下那些。依据本发明的化合物适于治疗其中平滑肌细胞和/或炎性细胞增殖和/或迁移入血管内层、导致经过该血管的血流受限(例如在新生内膜闭塞性损伤的情况下)的各种病症。所关注的闭塞性移植物血管疾病包括动脉粥样硬化、移植后冠状血管疾病、静脉移植狭窄、周环吻合修复再狭窄(perianastomatic prosthetic restenosis)、血管成形术或支架置入后的再狭窄等。
另外,依据本发明的化合物可用于某些现有癌症化学疗法和放射疗法中以获得增效作用或协同作用,和/或恢复某些现有癌症化学疗法和放射疗法的功效。
术语"方法"指用于完成给定任务的方式、手段、技术和程序,包括但不限于化学、药学、生物学、生物化学和医学领域的从业者已知的,或者从这些从业者已知的方式、手段、技术和程序容易地开发出的那些方式、手段、技术和程序。
如本文所用的术语"给药"指使本发明的化合物和靶激酶以这样一定方式结合在一起,使得化合物可直接(即通过与激酶本身相互作用)或者间接地(即通过与激酶的催化活性所依赖的另一分子相互作用)影响激酶的酶活性的方法。如本文所用的,给药可在体外(即在试验试管中)或在体内(即在活生物体的细胞或组织中)实现。
本文中,术语"治疗"包括消除、基本抑制、减慢或逆转疾病或病症的进展,基本缓解疾病或病症的临床症状或基本预防疾病或病症的临床症状的出现。
本文中,术语"预防"指从一开始就使生物体避免获得病症或疾病的方法。
对于用于本发明的任何化合物,治疗有效量,在本文也称为治疗有效剂量,可从细胞培养测定初始估算。例如,可在动物模型中配制剂量以获得包括如在细胞培养中测定的IC50或IC100的循环浓度范围。这样的信息可用于更精确地确定人的有用剂量。初始剂量也可从体内数据估测。使用这些最初的指导方针,本领域普通技术人员可确定用于人的有效剂量。
而且,本文描述的化合物的毒性和治疗效果可通过标准的制药程序,在细胞培养或实验动物中,例如通过测定LD50和ED50来确定。毒性和治疗效果之间的剂量比是治疗指数并可表示为LD50和ED50之间的比率。显示出高治疗指数的化合物是优选的。从这些细胞培养测定和动物研究获得的数据可用于配制对用于人无毒性的剂量范围。这样的化合物的剂量优选地位于包括具有很少毒性甚或没有毒性的ED50的循环浓度范围内。根据所用的剂型和所用的给药途径,剂量可以在该范围内变化。精确的配方、给药途径和剂量可由个体医师在考虑到患者的状况后进行选择(参见,例如Fingl等, 1975, 在The Pharmacological Basis of Therapeutics (治疗的药理学基础)中, 第1章,第1页)。
可个别调整给药的剂量和间隔以提供活性化合物足以维持治疗效果的血浆水平。供口服给药的通常患者剂量范围是约50-2000 mg/kg/天,通常约100-1000 mg/kg/天,优选地约150-700 mg/kg/天和最优选约250-500 mg/kg/天。
优选地,治疗有效血清水平将通过每天给予多个剂量来获得。在局部给药或选择性摄取的情况下,药物的有效局部浓度可能与血浆浓度无关。本领域技术人员将能够优化治疗有效局部剂量而无需过度的实验。
本文描述的化合物可用于预防、治疗和/或研究的优选的疾病或病症是细胞增殖性病症,尤其是癌症,例如但不限于,乳头状瘤、胚神经胶质瘤(blastoglioma)、卡波济氏肉瘤、黑素瘤、肺癌、卵巢癌、前列腺癌、鳞状上皮细胞癌、星形细胞瘤、头癌、颈癌、皮肤癌、肝癌、膀胱癌、乳腺癌、肺癌、子宫癌、前列腺癌、睾丸癌、结肠直肠癌、甲状腺癌、胰腺癌、胃癌、肝细胞癌、白血病、淋巴瘤、何杰金氏病和伯基特氏病(Burkitt's disease)。
现有技术
其它杂环衍生物及它们作为抗肿瘤剂的用途已描述于WO 2011/046970 A1和WO
2007/129044中。
其它吡啶和吡嗪衍生物在治疗癌症中的用途已描述于WO 2009/053737中,而治疗其它疾病的用途已描述于WO 2004/055005中。
其它杂环衍生物作为IKKε抑制剂已公开于WO 2009/122180中。
吡咯并嘧啶作为IKKε和TBK1抑制剂已公开于WO 2010/100431中。
嘧啶衍生物作为IKKε和TBK1抑制剂已公开于WO 2009/030890中。
发明概述
本发明涉及式I化合物
其中
X表示O或S,
R1表示O(CYY)nHet1、NY(CYY)nHet1、O(CYY)nCyc或NY(CYY)nCyc,
R2表示H、Hal、A、OY、NYY、O(CYY)mNYY、O(CYY)nHet2、NY(CYY)mNYY、NY(CYY)nHet2、Ar或Het2,
Het1表示二氢吡咯基、吡咯烷基、四氢咪唑基、二氢吡唑基、四氢吡唑基、四氢吡喃基、二氢吡啶基、四氢吡啶基、哌啶基、吗啉基、六氢哒嗪基、六氢嘧啶基、[1,3]二氧杂环戊烷基、2-氧杂-6-氮杂-螺[3.3]庚烷基、氮杂环庚烷基、二氮杂环庚烷基、四氢呋喃基、呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、苯并二氢吡喃基或哌嗪基,其中的每一个为未取代的或被以下基团单取代或二取代:Hal、CN、A、COOA、OY、S(O)nA、S(O)nAr和/或=O (羰基氧),
Het2表示具有1-4个N、O和/或S原子的单环、二环或三环的饱和、不饱和或芳族杂环,其可为未取代的或被以下基团单取代、二取代、三取代、四取代或五取代:Hal、A、(CYY)p-OY、-(CYY)p-NYY、(CYY)p-Het1、NO2、CN、(CYY)p-COOY、CO-NYY、NY-COA、NY-SO2A、SO2-NYY、S(O)nA、-CO-Het1、O(CYY)p-NYY、-O(CYY)p-Het1、NH-COOA、NH-CO-NYY、NH-COO-(CYY)p-NYY、NH-COO-(CYY)p-Het1、NH-CO-NH-(CYY)p-NYY、NH-CO-NH(CYY)p-Het1、OCO-NH-(CYY)p-NYY、OCO-NH-(CYY)p-Het1、CHO、COA、=S、=NY和/或=O,
Ar表示苯基、萘基或联苯基,其中的每一个为未取代的或被以下基团单取代、二取代或三取代:Hal、A、(CYY)p-OY、(CYY)p-NYY、(CYY)p-Het1、NO2、CN、(CYY)p-COOY、CO(CYY)pNH2、CO-NYA、CONY(CYY)mNYCOOA、NY-COA、NY-SO2A、SO2-NYY、S(O)nA、CO-Het1、O(CYY)p-NYY、O(CYY)p-Het1、NH-COOA、NH-CO-NYY、NH-COO-(CYY)p-NYY、NH-COO-(CYY)p-Het1、
NH-CO-NH-(CYY)p-NYY、NH-CO-NH(CYY)p-Het1、OCO-NH-(CYY)p-NYY、OCO-NH-(CYY)p-Het1、CHO、CONY(CYY)pHet1、CONH(CYY)pNHCOA和/或COA,
Y表示H或具有1、2、3或4个C原子的烷基,
A表示具有1-10个C原子的未分支或分支的烷基,其中1-7个H原子可以被F和/或Cl替代和/或其中一个或两个非相邻的CH和/或CH2基团可以被O和/或N替代,
Cyc表示具有3-7个C原子的环烷基,其为未取代的或被Hal、CN或A单取代,
Hal表示F、Cl、Br或I,
n表示0、1或2,
m表示1、2或3,
p表示0、1、2、3或4,
及其可药用盐、互变异构体和立体异构体,包括其所有比例的混合物。
本发明也涉及这些化合物的光学活性形式(立体异构体)、盐、对映体,外消旋体,非对映异构体和水合物和溶剂合物。采用术语化合物的溶剂合物意指由于惰性溶剂分子和化合物的相互吸引力而形成的惰性溶剂分子加合到化合物上。溶剂合物是,例如,一水合物或二水合物或醇盐。
当然,本发明也涉及盐的溶剂合物。
采用术语可药用的衍生物意指例如依据本发明的化合物的盐,并且也称为前药化合物。
采用术语前药衍生物意指已通过例如烷基或酰基、糖或寡肽修饰、并在生物体内迅速裂解以形成有效的依据本发明的化合物的式I化合物。
这些也包括依据本发明的化合物的生物可降解的聚合物衍生物,如在例如Int. J. Pharm. 115, 61-67 (1995)中所描述的。
表述“有效量”表示药物或药用活性成分在组织、系统、动物或人中引起生物学或医学反应的量,这样的反应是例如研究者或医师所寻求或期望的。
此外,表述"治疗有效量”表示与没有接受该量的对应的受试者比较,具有以下结果的量:
改善治疗、治愈、预防或消除疾病、综合征、病症、痛苦、紊乱或副作用,或者也减慢疾病、病症或紊乱的发展。
表述"治疗有效量”也涵盖有效提高正常生理学功能的量。
本发明也涉及式I化合物的混合物的用途,例如两种非对映异构体的混合物,例如采用比例1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100或1:1000。
这些是特别优选的立体异构化合物的混合物。
本发明涉及式I化合物及其盐和涉及制备依据权利要求1-12的式I化合物及其可药用盐、互变异构体和立体异构体的方法,其特征在于
a) 使式II化合物
其中Q表示 Cl、Br或I,
X和R2具有在权利要求1中指定的意义,
与式III化合物反应
R1-L III
其中R1具有在权利要求1中指定的意义和
L表示硼酸或硼酸酯基团,
或
b) 通过将COOH基团转化为酰胺基团而将基团R2转化为另一个基团R2,
和/或将式I的碱或酸转化为其盐中的一种。
在上下文中,基团R1、R2和X具有对式I指定的意义,除非另有明确说明。
A表示烷基,其为未分支的(线性)或分支的,并具有1、2、3、4、5、6、7、8、9或10个C原子。A优选地表示甲基、此外表示乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外也表示戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,此外优选地表示例如三氟甲基。
A更特别优选地表示具有1、2、3、4、5或6个C原子的烷基,优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基、三氟甲基、五氟乙基或1,1,1-三氟乙基。
A中的一个或两个CH和/或CH2基团也可被N、O或S原子替代。A因此也表示,例如2-甲氧基乙基。
更优选地,A表示具有1-10个C原子的未分支或分支的烷基,其中1-7个H原子可以被F替代和/或其中一个或两个非相邻的CH和/或CH2基团可以被O和/或N替代。
Ar表示例如苯基、邻、间或对甲苯基、邻、间或对乙基苯基、邻、间或对丙基苯基、邻、间或对异丙基苯基、邻、间或对叔丁基苯基、邻、间或对三氟甲基苯基、邻、间或对氟代苯基、邻、间或对溴代苯基、邻、间或对氯代苯基、邻、间或对羟基苯基、邻、间或对甲氧基苯基、邻、间或对甲基磺酰基苯基、邻、间或对硝基苯基、邻、间或对氨基苯基、邻、间或对甲基氨基苯基、邻、间或对二甲基氨基苯基、邻、间或对氨基磺酰基苯基、邻、间或对甲基氨基磺酰基苯基、邻、间或对氨基羰基苯基、邻、间或对羧基苯基、邻、间或对甲氧基羰基苯基、邻、间或对乙氧基羰基苯基、邻、间或对乙酰基苯基、邻、间或对甲酰基苯基、邻、间或对氰基苯基、进一步优选2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二溴苯基、2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基、对碘代苯基、4-氟-3-氯代苯基、2-氟-4-溴代苯基、2,5-二氟-4-溴代苯基或2,5-二甲基-4-氯代苯基。
Ar特别优选地表示苯基,其被以下基团单取代、二取代或三取代:(CYY)p-OY、(CYY)p-NYY、(CYY)p-Het1、(CYY)p-COOY、CO(CYY)pNH2、CO-NYA、CONY(CYY)mNYCOOA、CONY(CYY)pHet1、CONH(CYY)pNHCOA和/或CO-Het1。
Het1优选地表示二氢吡咯基、吡咯烷基、四氢咪唑基、二氢吡唑基、四氢吡唑基、四氢吡喃基、二氢吡啶基、四氢吡啶基、哌啶基、吗啉基、六氢哒嗪基、六氢嘧啶基、[1,3]二氧杂环戊烷基、2-氧杂-6-氮杂-螺[3.3]庚烷基、氮杂环庚烷基、二氮杂环庚烷基、四氢呋喃基、吡啶基、苯并二氢吡喃基或哌嗪基,其中的每一个为未取代的或被以下基团单取代或二取代:Hal、CN、A、COOA、OY、S(O)nA、S(O)nAr和/或=O (羰基氧)。
不论另外的取代基,Het2优选地表示,例如,2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-噁唑基、3-、4-或5-异噁唑基、2-、4-或5-噻唑基、3-、4-或5-异噻唑基、2-、3-或4-吡啶基、2-、4-、5-或6-嘧啶基,更优选地1,2,3-三唑-1-、-4-或-5-基、1,2,4-三唑-1-、-3-或5-基、1-或5-四唑基、1,2,3-噁二唑-4-或-5-基、1,2,4-噁二唑-3-或-5-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、3-或4-哒嗪基、吡嗪基、1-、2-、3-、4-、5-、6-或7-吲哚基、4-或5-异吲哚基、吲唑基、1-、2-、4-或5-苯并咪唑基、1-、3-、4-、5-、6-或7-苯并吡唑基、2-、4-、5-、6-或7-苯并噁唑基、3-、4-、5-、6-或7-苯并异噁唑基、2-、4-、5-、6-或7-苯并噻唑基、2-、4-、5-、6-或7-苯并异噻唑基、4-、5-、6-或7-苯并-2,1,3-噁二唑基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、3-、4-、5-、6-、7-或8-噌啉基、2-、4-、5-、6-、7-或8-喹唑啉基、5-或6-喹喔啉基、2-、3-、5-、6-、7-或8-2H-苯并-1,4-噁嗪基,更优选地1,3-苯并二氧杂环戊烯-5-基、1,4-苯并二氧杂环己烷-6-基、2,1,3-苯并噻二唑-4-、-5-基或2,1,3-苯并噁二唑-5-基、氮杂双环[3.2.1]辛基或二苯并呋喃基。
杂环基也可以被部分或完全氢化。
不论另外的取代基,Het2因此也可表示,例如,2,3-二氢-2-、-3-、-4-或-5-呋喃基、2,5-二氢-2-、-3-、-4-或5-呋喃基、四氢-2-或-3-呋喃基、1,3-二氧杂环戊烷-4-基、四氢-2-或-3-噻吩基、2,3-二氢-1-、-2-、-3-、-4-或-5-吡咯基、2,5-二氢-1-、-2-、-3-、-4-或-5-吡咯基、1-、2-或3-吡咯烷基、四氢-1-、-2-或-4-咪唑基、2,3-二氢-1-、-2-、-3-、-4-或-5-吡唑基、四氢-1-、-3-或-4-吡唑基、1,4-二氢-1-、-2-、-3-或-4-吡啶基、1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-或-6-吡啶基、1-、2-、3-或4-哌啶基、2-、3-或4-吗啉基、四氢-2-、-3-或-4-吡喃基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷-2-、-4-或-5-基、六氢-1-、-3-或-4-哒嗪基、六氢-1-、-2-、-4-或-5-嘧啶基、1-、2-或3-哌嗪基、1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基、1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-异喹啉基、2-、3-、5-、6-、7-或8-3,4-二氢-2H-苯并-1,4-噁嗪基,更优选2,3-亚甲二氧基苯基、3,4-亚甲二氧基苯基、2,3-亚乙二氧基苯基、3,4-亚乙二氧基苯基、3,4-(二氟亚甲二氧基)苯基、2,3-二氢苯并呋喃-5-或6-基、2,3-(2-氧代亚甲二氧基)苯基或者还有3,4-二氢-2H-1,5-苯并二氧杂环庚烯-6-或-7-基,更优选2,3-二氢苯并呋喃基、2,3-二氢-2-氧代呋喃基、3,4-二氢-2-氧代-1H-喹唑啉基、2,3-二氢苯并噁唑基、2-氧代-2,3-二氢苯并噁唑基、2,3-二氢苯并咪唑基、1,3-二氢吲哚、2-氧代-1,3-二氢吲哚或2-氧代-2,3-二氢苯并咪唑基。
Het2优选地表示呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、三唑基、四唑基、噻二唑基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、2,3-二氢-1H-苯并咪唑基、吲唑基、喹啉基、1,3-苯并二氧杂环戊烯基、苯并噻吩基、苯并呋喃基或咪唑并吡啶基,其中的每一个为未取代的或被以下基团单取代或二取代:A、S(O)nA、(CYY)p-Het1和/或=O。
R1特别优选表示O(CYY)nHet1。
Hal优选地表示F、Cl或Br,但是也表示I,特别优选F或Cl。
在整个本发明中,出现一次以上的所有基团可以是相同的或不同的,即彼此独立。
式I化合物可以具有一个或多个手性中心并因此可以多种立体异构形式出现。式I涵盖所有这些形式。
因此,本发明特别涉及式I化合物,其中至少一个所述基团具有以上指定的优选意义之一。化合物的一些优选基团可以通过以下的子式Ia-Ic表示,其符合式I,且其中未更详细地指定的基团具有对式I指出的意义,但是其中
在Ia中,Het2表示呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、三唑基、四唑基、噻二唑基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、2,3-二氢-1H-苯并咪唑基、吲唑基、喹啉基、1,3-苯并二氧杂环戊烯基、苯并噻吩基、苯并呋喃基或咪唑并吡啶基、其中的每一个为未取代的或被A、S(O)nA、(CYY)p-Het1和/或=O单取代或二取代;
在Ib中,Ar表示苯基,其为未取代的或被以下基团单取代、二取代或三取代:(CYY)p-OY、(CYY)p-NYY、(CYY)p-Het1、(CYY)p-COOY、CO(CYY)pNH2、CO-NYA、CONY(CYY)mNYCOOA、CONY(CYY)pHet1、CONH(CYY)pNHCOA和/或CO-Het1;
在Ic中,X表示O或S,
R1表示O(CYY)nHet1、NY(CYY)nHet1、O(CYY)nCyc或NY(CYY)nCyc,
R2表示Ar或Het2,
Het1表示二氢吡咯基、吡咯烷基、四氢咪唑基、二氢吡唑基、四氢吡唑基、四氢吡喃基、二氢吡啶基、四氢吡啶基、哌啶基、吗啉基、六氢哒嗪基、六氢嘧啶基、[1,3]二氧杂环戊烷基、2-氧杂-6-氮杂-螺[3.3]庚烷基、氮杂环庚烷基、二氮杂环庚烷基、四氢呋喃基、吡啶基、苯并二氢吡喃基或哌嗪基,其中的每一个为未取代的或被以下基团单取代或二取代:Hal、CN、A、COOA、OY、S(O)nA、S(O)nAr和/或=O (羰基氧),
Het2表示呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、三唑基、四唑基、噻二唑基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、2,3-二氢-1H-苯并咪唑基、吲唑基、喹啉基、1,3-苯并二氧杂环戊烯基、苯并噻吩基、苯并呋喃基或咪唑并吡啶基,其中的每一个为未取代的或被以下基团单取代或二取代:A、S(O)nA、(CYY)p-Het1和/或=O,
Ar表示苯基,其为未取代的或被以下基团单取代、二取代或三取代:(CYY)p-OY、(CYY)p-NYY、(CYY)p-Het1、(CYY)p-COOY、CO(CYY)pNH2、CO-NYA、CONY(CYY)mNYCOOA、CONY(CYY)pHet1、CONH(CYY)pNHCOA和/或CO-Het1,
Y表示H或具有1、2、3或4个C原子的烷基,
A表示具有1-10个C原子的未分支或分支的烷基,其中1-7个H原子可以被F和/或Cl替代,和/或其中一个或两个非相邻的CH和/或CH2基团可以被O和/或N替代,
Cyc表示具有3-7个C原子的环烷基,其为未取代的或被Hal、CN或A单取代,
Hal表示F、Cl、Br或I,
n表示0、1或2,
m表示1、2或3,
p表示0、1、2、3或4;
及其可药用盐、互变异构体和立体异构体,包括其所有比例的混合物。
此外,式I化合物以及还有用于制备它们的起始原料通过本身已知的方法制备,如在文献中描述的(例如在标准教科书中,例如Houben-Weyl, Methoden der organischen Chemie [有机化学的方法],Georg-Thieme-Verlag,
Stuttgart),以在已知的和适用于所述反应的反应条件下精确进行。也可按本文未更详细地提及的本身已知的变体在此进行使用。
式I化合物可优选地通过使式II化合物与式III化合物反应而获得。
式II化合物和式III化合物是公知的。然而,如果它们是新的,则可通过本身已知的方法制备它们。
所述反应在技术人员称为Suzuki反应的标准条件下进行。
在式III化合物中,L优选地表示
或。
取决于所用的条件,反应时间在数分钟和14天之间,反应温度在约-30°和140°之间,通常在0°和110°之间,特别是在约60°和约110°之间。
合适的惰性溶剂的实例是烃,例如己烷、石油醚、苯、甲苯或二甲苯;氯代烃,例如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇,例如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,例如二乙醚、二异丙醚、四氢呋喃(THF)或二氧杂环己烷;二醇醚,例如乙二醇单甲基或单乙基醚、乙二醇二甲基醚(二甘醇二甲醚);酮,例如丙酮或丁酮;酰胺,例如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,例如乙腈;亚砜,例如二甲亚砜(DMSO);二硫化碳;羧酸,例如甲酸或乙酸;硝基化合物,例如硝基甲烷或硝基苯;酯,例如乙酸乙酯,或所述溶剂的混合物。
特别优选乙醇、甲苯、甲氧基乙烷(imethoxyethane)、乙腈、二氯甲烷、DMF、二氧杂环己烷和/或水。
此外,式I化合物可优选如下获得:在技术人员已知的标准条件下,通过将COOH基团转化为酰胺基团,而将基团R2转化为另一个基团R2。
醚的断裂通过本领域技术人员已知的方法进行。
醚(例如甲基醚)断裂的标准方法是使用三溴化硼。
可氢解除去的基团,例如苄基醚的断裂,可例如通过在催化剂(例如贵金属催化剂,例如钯,有利地在载体例如碳上)的存在下,用氢处理来断裂。在此合适的溶剂为以上指明的那些,特别是,例如醇,如甲醇或乙醇,或酰胺,例如DMF。氢解通常在约0和100°之间的温度下和约1和200巴之间的压力下进行,优选20-30°和1-10巴。
酯可例如使用乙酸或使用NaOH或KOH在水、水/THF或水/二氧杂环己烷中,在0和100°之间的温度下进行皂化。
如本领域技术人员已知的,在氮上的烷基化在标准条件下进行。
此外,式I化合物可通过溶剂分解,特别是水解或氢解,将它们从其官能衍生物中释出而获得。
供溶剂分解或氢解的优选起始原料为含有相应的受保护氨基和/或羟基而不是一个或多个游离氨基和/或羟基的那些,优选地为携带氨基-保护基团而不是键结于N原子的H原子的那些,例如符合式I、但含有NHR’基团(其中R’表示氨基-保护基团,例如BOC或CBZ)而不是NH2基团的那些。
此外,优选携带羟基-保护基团而不是羟基的H原子的起始原料,例如符合式I、但含有RO-苯基(其中R”表示羟基-保护基团)而不是羟基苯基的那些。
多个相同或不同的受保护氨基和/或羟基存在于起始原料的分子中也是可能的。如果存在的保护基团是彼此不同的,则它们可在许多情况下选择性地解离。
表述"氨基-保护基团"在通用术语中为已知的并涉及适用于保护(封闭)氨基以免受化学反应,但在所需的化学反应在分子中别处进行后可容易地将其除去的基团。典型的此类基团特别是,未取代的或取代的酰基、芳基、芳烷氧基甲基或芳烷基。因为氨基-保护基团在所需的反应(或反应序列)后被除去,它们的类型和大小不是特别关键的;然而,优选具有1-20个,特别是1-8个碳原子的那些保护基团。表述"酰基"应按在最广意义上与本方法关联来理解。其包括衍生自脂族、芳脂族、芳族或杂环羧酸或磺酸的酰基,且特别是烷氧基羰基、芳基氧基羰基和尤其是芳烷氧基羰基。此类酰基的实例是烷酰基,例如乙酰基、丙酰基和丁酰基;芳烷酰基,例如苯基乙酰基;芳酰基,例如苯甲酰基、甲苯基;芳基氧基烷酰基,例如POA;烷氧基羰基,例如甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC、2-碘代乙氧基羰基;芳烷氧基羰基,例如CBZ ("苄氧甲酰基(carbobenzoxy)")、4-甲氧基苄基氧基羰基、FMOC;芳基磺酰基、例如Mtr、Pbf、Pmc。优选的氨基-保护基团是BOC和Mtr,此外还有CBZ、Fmoc、苄基和乙酰基。
表述"羟基-保护基团"同样在通用术语中是已知的并涉及适用于保护羟基以免受化学反应,但在所需的化学反应在分子中别处完成后可容易地将其除去的基团。典型的此类基团为上述未取代的或取代的芳基、芳烷基或酰基,此外还为烷基。羟基-保护基团的性质和大小不是关键的,因为它们在所需化学反应或反应序列后再次被除去;优选具有1-20个,特别是1-10个碳原子的基团。羟基-保护基团的实例尤其是叔丁氧基羰基、苄基、对-硝基苯甲酰基、对-甲苯磺酰基、叔丁基和乙酰基,其中苄基和叔丁基是特别优选的。天冬氨酸和谷氨酸中的COOH基团优选以其叔丁基酯的形式(例如Asp(OBut))被保护。
取决于所用的保护基团,将式(I)化合物从它们的官能衍生物中释出,例如采用强酸,有利地采用TFA或高氯酸,但也采用其它强无机酸例如盐酸或硫酸,强有机羧酸例如三氯乙酸或磺酸,例如苯磺酸或对甲苯磺酸。存在另外的惰性溶剂是可能的,但不总是必要的。合适的惰性溶剂优选地为有机的,例如羧酸,例如乙酸;醚,例如四氢呋喃或二氧杂环己烷;酰胺,例如DMF;卤代烃,例如二氯甲烷;此外也包括醇,例如甲醇、乙醇或异丙醇,和水。此外,上述溶剂的混合物也是合适的。TFA优选地以过量所用,而不加入另外的溶剂,高氯酸优选地以乙酸和70%高氯酸以比例9:1的混合物的形式使用。用于分解的反应温度有利地在约0和约50℃之间,优选地在15和30℃之间(室温)。
BOC、OBut、Pbf、Pmc和Mtr基团可例如优选地采用在二氯甲烷中的TFA或采用在二氧杂环己烷中的大约3-5N HCl在15-30℃下分离,FMOC基团可采用二甲胺、二乙胺或哌啶在DMF中的大约5-50%溶液在15-30℃下解离。
可氢解除去的保护基团(例如CBZ或苄基)可例如通过在催化剂(例如贵金属催化剂,例如钯,有利地在载体例如碳上)的存在下,用氢处理而分离。此处的合适溶剂为上文指出的那些溶剂,特别是,例如醇,例如甲醇或乙醇,或酰胺,例如DMF。氢解通常在约0和100℃之间的温度下和在约1和200巴之间的压力下进行,优选地在20-30℃和1-10巴下进行。CBZ基团的氢解,例如,在5-10% Pd/C上在甲醇中,或采用甲酸铵(而不是氢)在Pd/C上在甲醇/DMF中,在20-30℃下很好地进行。
药用盐和其它形式
依据本发明的所述化合物可以其最终的非盐形式使用。另一方面,本发明也包括这些化合物以其药学上可接受的盐形式的用途,所述盐可通过本领域已知的程序衍生自各种有机和无机酸和碱。式I化合物的药学上可接受的盐形式大部分通过常规的方法制备。如果式I化合物含有羧基,其合适的盐之一可通过化合物与合适的碱反应以得到相应的碱-加成盐来形成。这样的碱为例如碱金属氢氧化物,包括氢氧化钾、氧化钠和氢氧化锂;碱土金属氢氧化物,例如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;和各种有机碱,例如哌啶、二乙醇胺和N-甲基葡糖胺。同样包括式I化合物的铝盐。在某些式I化合物的情况下,酸加成盐可通过用以下物质处理这些化合物而形成:药学上可接受的有机和无机酸,例如氢卤酸,例如盐酸、氢溴酸或氢碘酸;其它矿物酸及其对应的盐,例如硫酸盐、硝酸盐或磷酸盐等;和烷基磺酸盐和单芳基磺酸盐,例如乙烷磺酸盐、甲苯磺酸盐和苯磺酸盐;和其它有机酸及其对应的盐,例如乙酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此,式I化合物的药学上可接受的酸加成盐包括以下:乙酸盐、己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate)、亚硫酸盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯代苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、半乳糖酸盐(galacterate) (得自粘酸)、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙烷磺酸盐、碘化物、羟乙基磺酸盐(isethionate)、异丁酸盐、乳酸盐、乳糖醛酸盐(lactobionate)、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲烷磺酸盐、甲基苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、棕榈酸盐(palmoate)、果胶酸盐(pectinate)、过硫酸盐、苯乙酸盐、3-苯丙酸盐、磷酸盐、膦酸盐、酞酸盐,但这不表示限制。
此外,依据本发明的化合物的碱盐包括铝、铵、钙、铜、铁(III)、铁(II)、锂、镁、锰(III)、锰(II)、钾、钠和锌盐,但这并不意图表示限制。在上述盐中,优选铵;碱金属钠盐和钾盐,和碱土金属钙盐和镁盐。由药学上可接受的有机无毒碱衍生的式I化合物的盐包括以下物质的盐:伯胺、仲胺和叔胺、取代胺,也包括天然存在的取代胺、环胺,和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、N,N'-二苄基乙二胺(苄星)、二环己胺、二乙醇胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡糖、组胺酸、海巴明、异丙基胺、利多卡因、赖氨酸、甲葡胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟甲基)-甲基胺(氨丁三醇),但这并不意图表示限制。
含有碱性含氮基团的本发明化合物可使用以下试剂季铵化:例如(C1-C4)烷基卤化物,例如甲基、乙基、异丙基和叔丁基的氯化物、溴化物和碘化物;二(C1-C4)烷基硫酸盐,例如二甲基、二乙基和二戊基硫酸盐;(C10-C18)烷基卤化物,例如癸基、十二烷基、月桂基、肉豆蔻基和十六烷基的氯化物、溴化物和碘化物;和芳基(C1-C4)烷基卤化物,例如苄基氯和苯乙基溴。依据本发明的水溶性和油溶性化合物两者可使用这样的盐制备。
优选的以上提及的药用盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙基磺酸盐、扁桃酸盐、甲葡胺、硝酸盐、油酸盐、膦酸盐、三甲基乙酸盐、磷酸钠、硬脂酸盐、硫酸盐、碱式水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这并不意图表示限制。
碱性式I化合物的酸加成盐通过使游离碱形式与足够量的所需酸接触,以常规方式导致盐形成来制备。游离碱可通过使盐形式与碱接触并以常规方式分离游离碱来再生。游离碱形式在某些方面(关于某些物理特性,例如在极性溶剂中的溶解度)不同于对应的其盐形式;然而,为了本发明的目的,所述盐另外地对应于其相应的游离碱形式。
如已提及的,式I化合物的药学上可接受的碱加成盐用金属或胺形成,例如碱金属和碱土金属或有机胺。优选的金属是钠、钾、镁和钙。优选的有机胺是N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
依据本发明的酸性化合物的碱加成盐通过使游离酸形式与足够量的所需碱接触,以常规方式导致盐的形成来制备。游离酸可通过使盐形式与酸接触并以常规方式分离游离酸来再生。游离酸形式在某些方面(关于某些物理特性,例如在极性溶剂中的溶解度)不同于对应的其盐形式;然而,为了本发明的目的,所述盐另外地对应于其相应的游离酸形式。
如果依据本发明的化合物含有一个以上的能够形成这种类型的药学上可接受的盐的基团,则本发明也涵盖多盐。典型的多盐形式包括,例如,酒石酸二盐(bitartrate)、二乙酸盐、富马酸二盐(difumarate)、二甲葡胺、二磷酸盐、二钠和三盐酸盐,但这并不意图表示限制。
关于以上所述,可以见到,在本文中采用表述"药学上可接受的盐”意指活性成分,其包括形式为其盐中的一种的式I化合物,特别是如果与游离形式的活性成分或较早使用的活性成分的任何其它盐形式比较,这种盐形式赋予所述活性成分改进的药代动力学特性。活性成分的药学上可接受的盐形式也可首次提供具有所需药代动力学特性的这种活性成分,所述药代动力学特性是其早先没有的并可甚至对这种活性成分关于其在体内的治疗效果的药效学具有正面的影响。
同位素
此外,预期使式I化合物包括其同位素-标记的形式。同位素-标记形式的式I化合物与这种化合物是相同的,但除了以下事实:化合物的一个或多个原子已被具有不同于通常天然存在的原子的原子质量或质量数的原子质量或质量数的一个或多个原子替代。可容易经市售获得的和可通过熟知的方法结合到式I化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别为例如2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36CI。预期含有一个或多个上述同位素和/或其它原子的其它同位素的式I化合物、其前药,或药学上可接受的盐为本发明的一部分。同位素-标记的式I化合物可以许多有益的方式使用。已掺入例如放射性同位素(例如3H或14C)的同位素-标记的式I化合物适用于药物和/或底物组织分布测定。这些放射性同位素,即氚(3H)和碳-14 (14C),由于制备简单和优良的可检测性而为特别优选的。较重的同位素,例如氘(2H),结合到式I化合物中,由于这种同位素-标记的化合物的较高代谢稳定性而具有治疗优势。较高的代谢稳定性直接转化为增加的体内半衰期或较低的剂量,其在大多数情况下将代表本发明的优选实施方案。同位素-标记的式I化合物通常可通过进行在合成方案和相关描述中、在本文的实施例部分和在制备部分中公开的程序,用可容易获得的同位素-标记的反应物替代非同位素-标记的反应物来制备。
氘(2H)也可掺入式I化合物中,目的是为了通过初级动力学同位素作用而操控化合物的氧化代谢。初级动力学同位素作用是改变由同位素核的交换引起的化学反应的速率,同位素核的交换转而通过在这种同位素交换后共价键形成所必需的基态能量变化而引起。较重同位素的交换通常导致化学键的基态能量的降低并因此引起速率限制性断键(rate-limiting bond breakage)的速率下降。如果键结断裂发生在沿着多产物反应坐标的鞍点区或鞍点区附近,则产物分配率可基本改变。为了解释:如果氘在非可交换的位置结合于碳原子,则kM/kD
= 2-7的比率差分(rate
differences)是典型的。如果这种比率差分成功应用于易受氧化作用影响的式I化合物,则这种化合物体内的分布可被极大的改变并导致改进的药代动力学特性。
当发现和开发治疗剂时,本领域技术人员试图使药代动力学参数最优化,同时保留所需的体外特性。合理的是假定许多具有不良药代动力学特性的化合物易受氧化代谢的影响。目前可获得的体外肝微粒体测定提供关于这种类型氧化代谢的过程的有价值的信息,其进而允许合理的设计具有通过抵抗这样的氧化代谢而具有改进稳定性的氘化式I化合物。由此获得式I化合物的药代动力学特性中的重大改进,并可根据体内半衰期(t/2)的增加、在最大疗效的浓度(Cmax)、剂量应答曲线(AUC)下的面积和F,并根据减少的清除率、剂量和材料成本进行定量表示。
以下旨在说明上文:具有受氧化代谢攻击的多个潜在位点(例如苯甲型氢原子和键结于氮原子的氢原子)的式I化合物经制备为一系列类似物,其中氢原子的多种组合被氘原子替代,以使这些氢原子中的一些、大多数或全部已被氘原子替代。半衰期测定能够有利和精确地测定抵抗氧化代谢改进的改进程度。这样,由于这种类型的氘-氢交换,确定母化合物的半衰期可延长最多至100%。
式I化合物中的氘-氢交换也可用于实现起始化合物的代谢谱的有利改善,以减少或消除不期望的毒性代谢物。例如,如果毒性代谢物通过氧化性碳-氢(C-H)键断裂而产生,则可合理地假定氘化类似物将极大地减少或消除不需要的代谢物的产生,即使特殊的氧化不是速控步骤。更多的关于涉及氘-氢交换的技术发展现状的信息可见于例如Hanzlik等, J. Org. Chem. 55, 3992-3997, 1990, Reider等, J. Org. Chem. 52,
3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette等, Biochemistry 33(10)
2927-2937, 1994,和Jarman等. Carcinogenesis 16(4), 683-688, 1993。
本发明还涉及药物,该药物包含至少一种式I化合物和/或其药用盐、互变异构体和立体异构体,包括其所有比例的混合物,和任选的赋形剂和/或辅助剂。
药物制剂可以每剂量单位包含预定量的活性成分的剂量单位形式给药。这样的单位可包含,例如0.5 mg-1 g,优选1 mg-700 mg,特别优选5 mg-100 mg的依据本发明的化合物,这取决于所治疗的病症、给药方法和患者的年龄、体重和身体状况,或者药物制剂可以剂量单位形式给药,该计量单位包含预定量的活性成分/剂量单位。优选的剂量单位制剂为包含日剂量或如上指明的部分剂量,或其活性成分对应部分的那些制剂。此外,这种类型的药物制剂可使用制药领域通常已知的方法制备。
药物制剂可适合于经由任何期望的合适方法,例如通过口服(包括颊下或舌下)、直肠、鼻、局部(包括颊下、舌下或透皮)、阴道或胃肠外(包括皮下、肌内、静脉内或皮内)方法给药。这样的制剂可使用制药领域已知的所有方法,通过例如使活性成分与赋形剂或辅助剂组合来制备。
适合于口服给药的药物制剂可作为分开的单位,例如胶囊或片剂;散剂或颗粒剂;在水性或非-水性液体中的溶液剂或混悬剂;可食用泡沫剂或发泡食物;或水包油液体乳剂或油包水液体乳剂给予。
因此,例如,在以片剂或胶囊的形式口服给药的情况下,活性成分组分可与口服的、非毒性的和药学上可接受的惰性赋形剂,例如像乙醇、甘油、水等结合。散剂通过将化合物粉碎为合适的细尺寸并使其与以类似的方法粉碎的药用赋形剂(例如可食用碳水化合物,例如像淀粉或甘露醇)混合来制备。同样可存在矫味剂、防腐剂、分散剂和染料。
胶囊通过制备如上所述的粉末混合物并用其填充成形的明胶壳来制备。助流剂和润滑剂,例如,诸如高分散性硅酸、滑石粉、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇,可加入到粉末混合物中,然后进行填充操作。同样可加入崩解剂或增溶剂,例如,像琼脂、碳酸钙或碳酸钠,以改进胶囊被摄取后药物的可利用度。
此外,如果需要或必要,可同样将合适的粘合剂、润滑剂和崩解剂以及染料掺入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖(例如葡萄糖或β-乳糖)、由玉米制得的甜味剂、天然和合成橡胶(例如像阿拉伯胶、黄蓍胶或藻酸钠)、羧甲基纤维素、聚乙二醇、蜡等。用于这些剂型的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括,但不限于,淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。片剂通过以下配制:例如制备粉末混合物,将该混合物制粒或干压,加入润滑剂和崩解剂并压制整个混合物以得到片剂。粉末混合物通过将以合适的方式粉碎的化合物与如上所述的稀释剂或基质,和任选与粘合剂(例如像羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮)、溶解阻滞剂例如像石蜡,吸收促进剂例如像季胺盐,和/或吸收剂(例如像膨润土、高岭土或磷酸二钙)混合来制备。粉末混合物可通过将其用粘合剂例如糖浆、淀粉糊、阿拉伯胶或纤维素或聚合物材料的溶液湿润并将其压过筛来制粒。作为对制粒的备选方案,可使粉末混合物通过压片机,得到不均匀形状的块状物,将其破碎以形成颗粒。颗粒可通过加入硬脂酸、硬脂酸盐、滑石粉或矿物油进行润滑,以防止粘附在片剂铸模上。然后压制经润滑的混合物,得到片剂。依据本发明的化合物也可与自由流动的惰性赋形剂组合,然后无需进行制粒或干压步骤而直接压制,得到片剂。可存在由虫胶密封层、糖或聚合物材料层和蜡的光泽层组成的透明或不透明的保护层。可将染料加入到这些包衣料中,以便能够在不同的剂量单位之间进行区分。
口服液体,例如,诸如溶液、糖浆和酏剂,可以剂量单位的形式制备,以使给定的量包含预定量的化合物。糖浆剂可通过将化合物溶于含合适的矫味剂的水性溶液中制备,而酏剂使用无毒的醇性媒介物制备。混悬剂可通过将化合物分散于无毒的媒介物中来配制。同样可加入增溶剂和乳化剂,例如,诸如乙氧基化异硬脂醇和聚氧乙烯山梨醇醚、防腐剂、香料添加剂,例如薄荷油或天然甜味剂或糖精,或其它人工甜味剂等。
如果需要,可将供口服给药的剂量单位制剂封装到微囊中。也可以一定方式来制备所述制剂,例如,诸如通过将颗粒原料包衣或包埋在聚合物、蜡等中,使得延长或延迟释放。
式I化合物及其药用盐、互变异构体和立体异构体也可以脂质体传递系统的形式给予,例如像小单层囊泡、大单层囊泡和多层囊泡。脂质体可由多种磷脂,例如像胆固醇、硬脂胺或卵磷脂形成。
式I化合物及其药用盐、互变异构体和立体异构体也可使用作为化合物分子偶联的单个载体的单克隆抗体来传递。化合物也可偶联于作为靶向药物载体的可溶性聚合物。这样的聚合物可以包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰氨基苯酚、聚羟乙基天门冬氨酰基苯酚或聚氧化乙烯聚赖氨酸(被棕榈酰基取代)。化合物可以进一步偶合于一类可生物降解的聚合物,其适合于实现药物的控制释放,所述聚合物有例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯和水凝胶的交联或芳脂族嵌段共聚物。
适于经皮给药的药物制剂可以作为与接受者的表皮长期、紧密接触的独立糊剂来给药。因此,例如,活性成分可以通过离子电渗疗法(如Pharmaceutical Research,3(6),318 (1986)的通用术语中所述),由该糊剂来传递。
适于局部给药的药用化合物可以被配制成软膏、乳膏、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶、喷雾剂、气雾剂或油。
对于眼睛或其它外部组织例如口腔和皮肤的治疗而言,所述制剂优选作为局部软膏或乳膏施用。在给予软膏制剂的情况中,活性成分可以与石蜡或者水可混溶的乳膏基质一起使用。或者,可以将活性成分用水包油乳膏基质或油包水基质配制而得到乳膏。
适于局部施用于眼睛的药物制剂包括滴眼剂,其中活性成分被溶解或混悬于适宜的载体,特别是水性溶剂中。
适于局部施用于口腔的药物制剂包括锭剂、软锭剂和漱口剂。
适于直肠给药的药物制剂可以以栓剂或灌肠剂的形式给药。
其中所述载体物质为固体的适于鼻给药的药物制剂包含粒径为例如范围在20-500微米的粗粉末,其以用鼻吸入的方式给药,即通过经由鼻道从举到鼻子附近的包含所述粉末的容器中快速吸入来给药。用于以具有作为载体物质的液体的鼻喷雾或滴鼻剂给药的适宜制剂包含在水或油中的活性成分溶液。
适于通过吸入进行给药的药物制剂包含细颗粒粉尘或雾,其可以通过各种类型的具有气雾剂的加压分配器、喷雾器或吸入器来产生。
适于阴道给药的药物制剂可以作为阴道栓、棉塞、乳膏、凝胶、糊剂、泡沫剂或喷雾制剂给药。
适于胃肠外给药的药物制剂包括水性或非水性无菌注射溶液,其包含抗氧化剂、缓冲剂、抑菌剂和使制剂与待治疗的接受者的血液等渗的溶质;和可包含混悬介质和增稠剂的水性和非水性无菌混悬液。该制剂可以以单剂量或多剂量容器(例如密封安瓿和小瓶)给予,并且以冷冻干燥(冻干)状态储存,从而使得必需在临用前即刻仅加入无菌的液体载体,例如注射用水。根据处方制备的注射溶液和混悬液可以由无菌的粉末、颗粒和片剂来制备。
不言而喻,除上面特别提及的组分外,对特定类型的制剂而言,所述制剂还可包含本领域中常用的其它剂;因此,例如适于口服给药的制剂可包含矫味剂。
式I化合物的治疗有效量取决于许多因素,包括例如动物的年龄和体重、需要治疗的准确病情及其严重性、制剂的性质和给药方法,并且最终由进行治疗的医生或兽医确定。然而,用于治疗瘤生长例如结肠癌或乳腺癌的依据本发明的化合物的有效量通常在每天0.1至100mg/kg接受者(哺乳动物)体重的范围内,并且特别典型地在每天1至10mg/kg体重的范围内。因此,对体重为70kg的成年哺乳动物而言,每天的实际数量通常为70至700mg,其中该量每天可以作为单剂量给予或者通常按每天一系列部分剂量(例如像两份、三份、四份、五份或六份)给予,从而使得总的日剂量相同。盐或溶剂合物或其生理学上的官能衍生物的有效量可以作为依据本发明的化合物本身有效量的分数来确定。可以推定相似的剂量也适用于治疗上述的其它病症。
本发明还涉及药物,该药物包含至少一种式I化合物和/或其药用盐、互变异构体和立体异构体,包括其所有比例的混合物,和至少一种另外的药物活性成分。
本发明也涉及药物套装(试剂盒),其由以下分开的包组成:
(a) 有效量的式I化合物和/或其药用盐、互变异构体和立体异构体,包括其所有比例的混合物,
和
(b) 有效量的另外的药物活性成分。
药物套装包含合适的容器,例如盒、单个瓶、袋或安瓿。药物套装可例如包含分开的安瓿,每个安瓿含有有效量的式I化合物和/或其药用盐、互变异构体和立体异构体,包括其所有比例的混合物,
和溶解或冻干形式的有效量的另外的药物活性成分。
用途
本发明涉及式I化合物,其用于治疗癌症、脓毒性休克、原发性开角型青光眼(POAG)、增生、类风湿性关节炎、银屑病、动脉粥样硬化、视网膜病、骨关节炎、子宫内膜异位、慢性炎症,和/或神经退行性疾病例如阿尔茨海默氏病。
本发明涉及式I化合物用于制备供治疗癌症、脓毒性休克、原发性开角型青光眼(POAG)、增生、类风湿性关节炎、银屑病、动脉粥样硬化、视网膜病、骨关节炎、子宫内膜异位、慢性炎症,和/或神经退行性疾病例如阿尔茨海默氏病的药物的用途。
本发明涉及治疗患有选自以下疾病的哺乳动物的方法:癌症、脓毒性休克、原发性开角型青光眼(POAG)、增生、类风湿性关节炎、银屑病、动脉粥样硬化、视网膜病、骨关节炎、子宫内膜异位、慢性炎症,和/或神经退行性疾病例如阿尔茨海默氏病,其中该方法包括给予哺乳动物治疗有效量的式I化合物。
本发明化合物适合作用于哺乳动物,尤其是用于人的治疗和控制癌症疾病和炎性疾病的药物活性成分。
宿主或患者可属于任何哺乳动物物种,例如灵长类种类,特别是人;啮齿类动物,包括小鼠、大鼠和仓鼠;兔;马、牛、狗、猫等。动物模型为实验研究所关注,提供治疗人类疾病的模型。
特殊细胞对用依据本发明的化合物治疗的易感性可通过体外试验确定。典型地,将细胞培养与各种浓度的依据本发明的化合物结合一定的时间段(通常在约1小时和1周之间),其足以使得活性剂例如抗IgM诱导细胞应答例如表面标记物的表达。体外试验可采用来自血或来自活组织检查样本的培养细胞进行。所表达的表面标记物的量通过流式细胞计数仪,使用识别标记物的特异性抗体来评测。
所述剂量根据所用的特定化合物、特定疾病、患者状态等而变化。治疗剂量典型地足以显著减少靶组织中的不期望的细胞种群,同时维持患者的生存能力。治疗一般持续至出现显著减少,例如细胞负荷减少至少约50%,和可持续至在体内基本不再检测出不期望的细胞。
为了鉴定信号转导途径和为了检测各种信号转导途径之间的相互作用,许多科学家已开发合适的模型或模型系统,例如细胞培养模型(例如Khwaja等, EMBO, 1997, 16, 2783-93)和转基因动物模型(例如White等, Oncogene,
2001, 20, 7064-7072)。为了确定信号转导级联中的某些阶段,可利用相互作用的化合物以调节信号(例如Stephens等, Biochemical
J., 2000, 351, 95-105)。依据本发明的化合物也可用作在本申请提及的动物和/或细胞培养模型或在临床疾病中测试激酶依赖性信号转导途径的试剂。
激酶活性的测量是本领域技术人员熟知的技术。用于确定激酶活性使用底物,例如组蛋白(例如Alessi等, FEBS Lett. 1996, 399, 3, 第333-338页)或碱性髓磷脂蛋白的通用测试系统,描述于文献(例如Campos-González,
R. 和Glenney, Jr., J.R. 1992, J. Biol. Chem. 267, 14535页)。
为鉴定激酶抑制剂,各种测定系统是可以利用的。在闪烁迫近试验(Sorg等,J. of. Biomolecular Screening, 2002, 7,11-19)和快速板试验(flashplate assay)中检测使用γATP的作为底物的蛋白或肽的放射性磷酸化。在存在抑制性化合物时,可检测到减弱的放射性信号或根本检测不到。此外,均匀时间分辨荧光共振能量转移(HTR-FRET)和荧光偏振(FP)技术适合用作试验方法(Sills 等,J. of Biomolecular Screening,
2002,191-214)。
其它的非放射性ELISA试验方法采用特异性磷酸-抗体(磷酸-AB)。此种磷酸-AB只结合磷酸化的底物。可使用过氧化物酶-缀合的抗绵羊二次抗体通过化学发光法检测这种结合(Ross等, 2002, Biochem. J.)。
本发明涵盖式I化合物和/或其生理学上可接受的盐、互变异构体和溶剂合物用于制备供治疗或预防癌症的药物中的用途。优选的待治疗的癌症源自脑癌、泌尿生殖道癌、淋巴系统癌、胃癌、喉癌、肺癌、肠癌。另一组优选形式的癌症是单核细胞性白血病、肺腺癌、小细胞肺癌、胰腺癌、胶质母细胞瘤和乳腺癌。
也涵盖在内的是式I化合物和/或其生理学上可接受的盐、互变异构体和溶剂合物用于制备供治疗和/或控制哺乳动物的肿瘤-诱导疾病的药物中的用途,其中对于这种方法是将治疗有效量的依据本发明的化合物给予需要这样的治疗的患病哺乳动物。治疗量根据具体疾病而变化并可由本领域技术人员确定而无需过度的努力。
特别优选用于治疗疾病,其中癌症疾病是实体瘤。
实体瘤优选地选自以下的肿瘤:鳞状上皮、膀胱、胃、肾、头和颈、食道、子宫颈、甲状腺、肠、肝、脑、前列腺、泌尿生殖道、淋巴系统、胃、喉和/或肺。
实体瘤更优选地选自肺腺癌、小细胞肺癌、胰腺癌、胶质母细胞瘤、结肠癌和乳腺癌。
进一步优选用于治疗血液和免疫系统肿瘤,优选地用于治疗选自急性髓性白血病、慢性髓性白血病、急性淋巴性白血病和/或慢性淋巴性白血病的肿瘤。
本发明进一步涉及依据本发明的化合物用于治疗骨病变的用途,其中骨病变源自骨肉瘤、骨关节炎和软骨病。
式I化合物也可与其它熟知的治疗剂同时给药, 所述治疗剂根据其针对待治疗的病症的特定有用性进行选择。
本化合物也适合与已知的抗癌剂组合。这些已知的抗癌剂包括以下:雌激素受体调节剂、雄激素受体调节剂、类视黄醇受体调节剂、细胞毒性剂、抗增殖剂、异戊二烯基蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂和另外的血管生成抑制剂。本化合物特别适合与放射疗法同时给予。
"雌激素受体调节剂"指不论以何种机理干扰或抑制雌激素与受体结合的化合物。雌激素受体调节剂的实例包括,但不限于,他莫昔芬、雷洛昔芬、艾多昔芬(iodoxyfene)、LY353381、LY 117081、托瑞米芬、氟维司群、4-[7-(2,2-二甲基-1-氧代丙氧基-4-甲基-2-[4-[2-(1-哌啶基)乙氧基]苯基]-2H-1-苯并吡喃-3-基]苯基2,2-二甲基丙酸盐、4,4'-二羟基苯甲酮-2,4-二硝基苯基腙和SH646。
"雄激素受体调节剂"指不论以何种机理干扰或抑制雄激素结合于受体的化合物。雄激素受体调节剂的实例包括非那雄胺和其它5α-还原酶抑制剂、尼鲁米特、氟他胺、比卡鲁胺、利阿唑和醋酸环丙孕酮。
"类视黄醇受体调节剂"指不论以何种机理干扰或抑制类视黄醇与受体的结合的化合物。这样的类视黄醇受体调节剂的实例包括贝沙罗汀、维A酸、13-顺式-视黄酸、9-顺式-视黄酸、α-二氟甲基鸟氨酸、ILX23-7553、反式-N-(4'-羟基苯基)-视黄酰胺(retinamide)和N-4-羧基苯基视黄酰胺。
"细胞毒性剂"指主要通过直接作用于细胞功能或抑制或干扰细胞有丝分裂(myosis)导致细胞死亡的化合物,包括烷基化剂、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。
细胞毒性剂的实例包括,但不限于,普拉扎明(tirapazimine)、sertenef、恶病质素、异环磷酰胺、他索纳明、氯尼达明、卡铂、六甲密胺、泊尼莫司汀、二溴卫矛醇、雷莫司汀、福莫司汀、奈达铂、奥沙利铂、替莫唑胺、庚铂(heptaplatin)、雌莫司汀、英丙舒凡甲苯磺酸盐、曲磷胺、尼莫司汀、二溴螺氯铵、嘌嘧替派、洛铂、沙铂、甲基丝裂霉素、顺铂、伊罗夫文、右异环磷酰胺(dexifosfamide)、顺式-胺二氯(2-甲基吡啶)铂、苄基鸟嘌呤、葡磷酰胺、GPX100、(反式,反式,反式)-二-μ-(己烷-1,6-二胺)-μ-[二胺-铂(II)]双[二胺(氯)铂(II)]四氯化物、diarizidinylspermine、三氧化二砷、1-(11-十二烷基氨基-10-羟基十一烷基)-3,7-二甲基黄嘌呤、佐柔比星、伊达比星、柔红霉素、比生群、米托蒽醌、吡柔比星、吡萘非特、戊柔比星、氨柔比星、抗瘤酮(antineoplaston)、3'-脱氨基-3'-吗啉代-13-脱氧代-10-羟基洋红霉素、安那霉素、加柔比星、依利奈法德、MEN10755和4-脱甲氧基-3-脱氨基-3-环乙亚胺基-4-甲基磺酰基柔红霉素(参见WO
00/50032)。
微管蛋白抑制剂的实例包括紫杉醇、硫酸长春地辛、3',4'-二脱氢-4'-脱氧-8'-去长春花碱、多西他赛、根霉素、多拉司他汀、米伏布林羟乙基磺酸盐、奥里斯他汀、西马多丁、RPR109881、BMS184476、长春氟宁、隐藻素、2,3,4,5,6-五氟-N-(3-氟-4-甲氧基苯基)苯磺酰胺、无水长春碱(anhydrovinblastine)、N,N -二甲基-L-缬氨酰基-L-缬氨酰基-N-甲基-L-缬氨酰基-L-脯氨酰基-L-脯氨酸-叔丁酰胺、TDX258和BMS188797。
拓扑异构酶抑制剂是例如托泊替康、hycaptamine、伊立替康、卢比替康、6-乙氧基丙酰基-3',4'-O-外亚苄基-教酒菌素、9-甲氧基-N,N-二甲基-5-硝基吡唑并[3,4,5-kl]吖啶-2-(6H)丙胺、1-氨基-9-乙基-5-氟-2,3-二氢-9-羟基-4-甲基-1H,12H-苯并[de]吡喃并[3',4':b,7]吲嗪并[1,2b]喹啉-10,13(9H,15H)二酮、勒托替康、7-[2-(N-异丙基氨基)乙基]-(20S)喜树碱、BNP1350、BNPI1100、BN80915、BN80942、磷酸依托泊苷、替尼泊苷、索布佐生、2'-二甲基氨基-2'-脱氧-依托泊苷、GL331、N-[2-(二甲基氨基)乙基]-9-羟基-5,6-二甲基-6H-吡啶并[4,3-b]咔唑-1-甲酰胺、asulacrine、(5a,5aB,8aa,9b)-9-[2-[N-[2-(二甲基氨基)乙基]-N-甲基氨基]乙基]-5-[4-羟基-3,5-二甲氧基苯基]-5,5a,6,8,8a,9-六氢呋喃并(3',4':6,7)萘并(2,3-d)-1,3-二氧杂环戊烯-6-酮、2,3-(亚甲二氧基)-5-甲基-7-羟基-8-甲氧基苯并[c]菲啶鎓(phenanthridinium)、6,9-双(2-氨基乙基)氨基]苯并[g]异喹啉-5,10-二酮、5-(3-氨基丙基氨基)-7,10-二羟基-2-(2-羟基乙基氨基甲基)-6H-吡唑并[4,5,1-de]吖啶-6-酮、N-[1-[2(二乙基氨基)乙基氨基]-7-甲氧基-9-氧代-9H-噻吨-4-基甲基]甲酰胺、N-(2-(二甲基氨基)乙基)吖啶-4-甲酰胺、6-[[2-(二甲基氨基)乙基]氨基]-3-羟基-7H-茚并[2,1-c]喹啉-7-酮和地美司钠。
"抗增殖剂"包括反义RNA和DNA寡核苷酸如G3139、ODN698、RVASKRAS、GEM231和INX3001,以及抗代谢物如依诺他滨、卡莫氟、替加氟、喷司他丁、去氧氟尿苷、曲美沙特、氟达拉滨、卡培他滨、加洛他滨、阿糖胞苷十八烷基磷酸盐(cytarabine ocfosfate)、水合氨磷汀钠(fosteabine sodium
hydrate)、雷替曲塞、帕替曲塞(paltitrexid)、乙嘧替氟、噻唑呋林、地西他滨、诺拉曲塞、培美曲塞、萘拉滨(nelzarabine)、2'-脱氧-2'-亚甲基胞苷、2'-氟亚甲基-2'-脱氧胞苷、N-[5-(2,3-二氢苯并呋喃基)磺酰基]-N'-(3,4-二氯苯基)脲、N6-[4-脱氧-4-[N2-[2(E),4(E)-十四碳二烯酰基]甘氨酰基氨基]-L-甘油-B-L-甘露糖-吡喃庚糖基(manno-heptopyranosyl)]腺嘌呤、脱氢膜海鞘素(aplidine)、海鞘素、曲沙他滨、4-[2-氨基-4-氧代-4,6,7,8-四氢-3H-嘧啶并[5,4-b]-1,4-噻嗪-6-基-(S)-乙基]-2,5-噻吩甲酰基-L-谷氨酸、氨基蝶呤、5-氟尿嘧啶、阿拉诺新、11-乙酰基-8-(氨基甲酰氧基甲基)-4-甲酰基-6-甲氧基-14-氧杂-1,11-二氮杂四环(7.4.1.0.0)-十四碳-2,4,6-三烯-9-基醋酸酯、苦马豆碱、洛美曲索、右雷佐生、蛋氨酸酶、2'-氰基-2'-脱氧-N4-棕榈酰基-1-B-D-阿糖呋喃糖基(arabino furanosyl)胞嘧啶和3-氨基吡啶-2-甲醛硫代半卡巴腙(carboxaldehyde
thiosemicarbazone)。"抗增殖剂"也包括不同于在"血管生成抑制剂"下列出的那些生长因子的单克隆抗体,例如曲妥珠单抗,和肿瘤抑制基因,例如p53,其可经由重组病毒-介导的基因转移传递(参见例如美国专利号6,069,134)。
优选地,本发明涉及其中疾病是癌症的方法。
特别优选的,本发明涉及一种方法,其中疾病是癌症,其中给药是与至少一种其它活性药剂同时、顺序或交替给予。
公开的式I化合物可与其它已知的治疗剂,包括抗癌剂组合给予。如在本文所用的,术语"抗癌剂"涉及为治疗癌症的目的而给予患有癌症的患者的任何剂。
本文定义的抗癌治疗可以作为单一的疗法应用或者除了本发明的化合物外,还可包括常规手术或放射性疗法或化学疗法。这样的化学疗法可以包括以下种类的抗肿瘤剂中的一个或多个:
(i) 如用于医学肿瘤学的抗增殖/抗肿瘤/DNA-破坏剂及其组合,例如烷基化剂(例如顺铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安和亚硝基脲);抗代谢药(例如抗叶酸剂例如氟代嘧啶像5-氟尿嘧啶和替加氟、雷替曲塞、氨甲喋呤、阿糖胞苷、羟基脲和吉西他滨);抗肿瘤抗生素(例如蒽环霉素,像阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素-C、放线菌素D和普卡霉素);抗有丝分裂剂(例如长春花生物碱,像长春新碱、长春碱、长春地辛和长春瑞滨,和紫杉烷类,像紫杉醇和泰素帝);拓扑异构酶抑制剂(例如表鬼臼毒素,像依托泊苷和替尼泊苷、安吖啶、托泊替康、伊立替康和喜树碱)和细胞分化剂(例如所有反式-视黄酸、13-顺式--视黄酸和芬维A胺);
(ii) 细胞生长抑制剂,例如抗雌激素剂(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬和艾多昔芬(iodoxyfene))、雌激素受体下调剂(例如氟维司群)、抗雄激素剂(例如比卡鲁胺、氟他胺、尼鲁米特和醋酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕酮(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿那曲唑、来曲唑、伏氯唑和尹西美坦)和5a-还原酶抑制剂例如非那雄胺;
(iii) 抑制癌细胞侵袭的剂(例如金属蛋白酶抑制剂,像马立马司他和尿激酶纤溶酶激活剂受体功能的抑制剂);
(iv) 生长因子功能的抑制剂,例如此类抑制剂包括生长因子抗体、生长因子受体抗体(例如抗-erbb2抗体曲妥珠单抗[HerceptinTM]和抗-erbbl抗体西妥昔单抗[C225])、法呢基转移酶抑制剂、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,例如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(吉非替尼,AZD1839)、N-(3-乙炔基苯基)-6,7-二(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼,OSI-774)和6-丙烯酰氨基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)喹唑啉-4-胺(CI 1033)),例如血小板衍生的生长因子家族的抑制剂;和例如肝细胞生长因子家族的抑制剂;
(v) 抗血管生成剂,例如抑制血管内皮生长因子的作用的那些剂(例如抗血管内皮细胞生长因子抗体贝伐单抗[AvastinTM],化合物例如在国际专利申请WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354)中公开的那些,和通过其它机理起作用的化合物(例如利诺胺、整联蛋白αvβ3功能抑制剂和血管他丁);
(vi) 血管破坏剂,例如考布他汀A4和在国际专利申请WO 99/02166、WO 00/40529、WO00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合物;
(vii) 反义疗法,例如导向上列靶标的那些,例如ISIS 2503、抗-Ras反义药物;
(viii) 基因治疗方法,包括例如替换异常基因例如异常p53或异常BRCA1或BRCA2的方法;GDEPT (基因引导的酶前药治疗)方法,例如用胞嘧啶脱酰胺酶、胸腺苷激酶或细菌硝基还原酶的那些方法,和增加患者对化疗或放疗的耐受性的方法,例如多重耐药性基因疗法;和
(ix) 免疫疗法,包括例如增加患者肿瘤细胞的免疫原性的离体和体内方法,例如用细胞因子例如白介素2、白介素4或粒细胞巨嗜细胞集落刺激因子转染;减少T细胞无反应性的方法;用转染的免疫细胞例如细胞因子-转染的树突细胞的方法;用细胞因子-转染的肿瘤细胞系的方法,和用抗独特型抗体的方法。
下表1的药物优选(但不排他地)与式I化合物组合。
公开的式I化合物及其药学上可接受的溶剂合物、盐、互变异构体和立体异构体,包括其所有比例的混合物,可优选地与免疫调节剂,优选地与抗-PDL-1-或IL-12联合给药。
抑制 IKKε的试验
IKKε–激酶测定(IKKε)
概述
激酶测定以384孔快速板试验的形式进行(用于例如Topcount测量)。
将1 nM IKKε、800 nM生物素化IκBα(19-42)肽(生物素-C6-C6-GLKKERLLDDRHDSGLDSMKDEE)和10 µM ATP (掺加0.3 µCi 33P-ATP/孔)以总体积50µl (10 mM MOPS、10 mM Mg-acetat、0.1 mM EGTA、1 mM二硫苏糖醇、0.02 % Brij35、0.1 % BSA、0.1 % BioStab, pH 7.5),在含有或不含试验化合物下,于30℃温育2小时。用25µl 200 mM EDTA终止反应。于室温下30 Min后,除去液体并用100
µl 0.9%氯化钠溶液洗涤各孔3次。在3 µM MSC2119074 (BX-795)的存在下测定非特异性反应。放射性用Topcount (PerkinElmer)测量。用由IT-部门提供的程序工具(如AssayExplorer,
Symyx)计算结果(如IC50-值)。
抑制
TBK1
的试验
酶试验
概述
激酶测定以384孔快速板试验试验进行(用于例如Topcount测量)。
将0.6
nM TANK结合激酶(TBK1)、800 nM生物素化MELK-衍生的肽(生物素-Ah-Ah-AKPKGNKDYHLQTCCGSLAYRRR)和10
µM ATP (掺加0.25 µCi 33P-ATP/孔)以总体积50µl
(10 mM MOPS、10 mM Mg-acetat, 0.1 mM EGTA、1 mM
DTT、0.02 % Brij35、0.1 % BSA, pH 7.5),在含有或不含试验化合物下,于30℃温育120
Min。用25µl 200 mM EDTA终止反应。于室温下30 Min后,除去液体并用100
µl 0.9%氯化钠溶液洗涤各孔3次。在100 nM星形孢菌素的存在下测定非特异性反应。放射性以Topcount (PerkinElmer)测量。用由IT-部门提供的程序工具(如AssayExplorer,
Symyx)计算结果(如IC50-值)。
细胞试验
Phospho-IRF3 @ Ser 386细胞/MDAMB468/INH/PHOS/IMAG/pIRF3的剂量应答抑制
1. 范围
虽然TBK1和IKKε在先天免疫应答中的关键作用最被熟知,但最近的结果已指向在Ras-诱导的致癌基因转换中TBK1和IKKε的作用。TBK1被鉴定为一种在Ras(如(Ral))-鸟氨酸核苷酸交换因子(GEF)途径中的RalB效应子,其对于Ras-诱导的转换是必需的。TBK1直接地激活IRF3,其经磷酸化后,被均二聚化和转位到细胞核,在那里它激活包括炎症、免疫调节、细胞存活和增殖症的过程。
已经制定这种测定以评价基于核局部化磷酸-IRF3 (一种TBK1下游的靶标)的免疫细胞化学探测的TBK1/IKKε抑制剂化合物的功效/效力。
用聚肌苷酸-聚胞嘧啶核苷酸(poly(I:C)(一种双链RNA
(dsRNA)的合成类似物)进行处理,将通过Toll-样受体3 (TLR3)识别的与病毒感染有关的分子模式用于诱导TBK1/IKKe活性和在Ser386的IRF3磷酸化。
2. 测定概述
第1天:用HyQ-Tase使MDA-MB-468细胞分离,计数,并以10,000个细胞每孔的密度,在总体积35ul的完全培养基中,接种于384-孔透明底TC-表面板。或者将细胞从冷冻瓶直接接种。
第2天:将细胞用抑制剂化合物预处理1h,然后是Poly(I:C)刺激。用Poly(I:C)培养2小时后,使细胞固定于(低聚)甲醛(PFA)并用甲醇(MeOH)渗透。然后封闭细胞并连同抗-pIRF3抗体于4℃培养过夜。
第3天:洗去初次抗体,加入AlexaFluor488-缀合的二次抗体,细胞用碘化丙啶复染,接着在IMX Ultra高容量读出仪进行图像采集。
3. 试剂, 材料
细胞:ATCC HTB 132,
Burger lab (MP-CB 2010-327或MDA-MB-468 / 10)
平板培养基 = 培养基:
RPMI
1640, Invitrogen # 31870
10%
FCS, Invitrogen # 10270-106
2mM Glutamax, Invitrogen
#35050-038
1mM Natrium-Pyruvat,
Invitrogen # 11360
1% Pen / Strep
37℃, 5% CO2
板:黑色/透明底384孔底细胞培养板,Falcon #35 3962或Greiner #781090
转种:HyQ-Tase, Thermo Scientific (HyClone) # SV30030.01
其它试剂:
Poly(I:C) (LMW), Invivogen
# tlrl-picw (制备20mg/ml在无菌PBS中的储备液,于55℃水浴中变性30min,缓慢冷却至RT,以等分液于-20℃贮存)
参考抑制剂:MSC2119074A-4 = BX-795 ( IC50 : 200-800nM)
抑制对照:10µM MSC2119074A-4 = BX-795
中性对照:0.5% DMSO
采用MSC2119074A-4 = BX-795的10点剂量-响应曲线包括在每个实验中。
Hepes,
Merck #1.10110
PBS 1x
DPBS , Invitrogen # 14190
甲醛(无甲醇, 16%, 超纯EM Grade), Polysciences # 18814 (RT下贮存), 最终浓度:4%
甲醇, Merck #
1.06009.1011 (-20℃预冷却)
山羊血清, PAA # B15-035
(4℃下贮存, 长时间于-20℃), 最终浓度:10%
BSA (无IgG和蛋白酶, 30%),
US-Biological # A1317(4℃下贮存, 长时间于-20℃), 最终浓度:2%
Tween 20清洁剂, Calbiochem #
655204 (RT下贮存), (制备10%在水中的储备液; 最终浓度:0.1%)
抗-pIRF-3兔mAb,
Epitomics # 2526-B (-20℃下贮存), 最终浓度:1:2000在PBS / 2% BSA中
Alexa
Fluor山羊-抗-兔-488,
Invitrogen # A11034或# A11008 (4℃下暗处贮存), 最终浓度:1:2000在PBS / 2%
BSA / 0.1% Tween中
碘化丙啶(PI), Fluka #
81845, 1mg/ml 在H2O中 (4℃下暗处贮存), 最终浓度:0.2µg/ml
4.
程序
HPLC/MS条件:
柱:Chromolith SpeedROD RP-18e, 50-4.6
梯度:A:B = 96:4-0:100
4% B → 100% B: 0 min-2.8 min
100% B: 2.8
min-3.3 min
100%B → 4%B: 3.3 min-4 min
流速:2.4 ml/min
洗脱液A:水+ 0.05 %甲酸
洗脱液B: 乙腈+ 0.04 %甲酸
波长:220 nm
质谱:正模式
1H NMR:偶合常数 J [Hz]。
实施例
合成7-氯-2-碘-呋喃并[3,2-b]吡啶
步骤1:2-三甲基硅烷基-呋喃并[3,2-b]吡啶
使2-溴吡啶-3-醇 (400 g, 2.3 mol)溶于1,4-二氧杂环己烷(4 l, 46.76 mol)。加入乙炔基-三甲基-硅烷(248.37 g, 2.53 mol)、碘化铜(I) (43.78 g, 0.23 mol)和双(三苯膦)氯化钯(II) (80.68 g, 0,11 mol)。于20℃将该混合物搅拌15分钟。经20 min向反应溶液中加入三乙胺(697.90 g, 6.9 mol)。于50℃将该混合物搅拌4h,冷却至室温14 h并蒸发。使残留物溶于6 l乙酸乙酯,过滤,然后有机层用水提取,用盐水洗涤,然后分离并经Na2SO4干燥。过滤干燥剂并真空除去溶剂。通过使用甲基叔丁基醚的层析分离产物;得到268 g 2-三甲基硅烷基-呋喃并[3,2-b]吡啶;HPLC/MS: 2.60 min, [M+H] = 192;
1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.71 (d, J = 5.2 Hz, 1H), 8.58 (d, J = 8.4 Hz,
1H), 7.69 (dt, J = 18.8, 9.4 Hz, 1H), 7.46 (s, 1H), 0.25 (s, 9H)。
步骤2:2-三甲基硅烷基-呋喃并[3,2-b]吡啶4-氧化物
使2-三甲基硅烷基-呋喃并[3,2-b]吡啶(268 g, 0.14 mol)溶于二氯甲烷(3 l)并于0-5℃搅拌。经30 min向该溶液中加入3-氯代过苯甲酸,搅拌1 h并升温至室温。14 h后,用NaHCO3溶液和水提取反应混合物。分离有机层并经Na2SO4干燥。过滤干燥剂并真空除去溶剂;得到296 g 2-三甲基硅烷基-呋喃并[3,2-b]吡啶4-氧化物;HPLC/MS: 2.0 min,
[M+H] = 208;
1H NMR (400 MHz,
CDCl3) δ [ppm] 7.97 (d, J = 6.3 Hz, 1H), 7.22 (d, J =
8.4 Hz, 1H), 7.18 (s, 1H), 6.92 (dt, J = 8.4, 6.3 Hz, 1H), 0.15 (s, 9H)。
步骤3:7-氯-2-三甲基硅烷基-呋喃并[3,2-b]吡啶
于室温下,使2-三甲基硅烷基-呋喃并[3,2-b]吡啶4-氧化物(296 g, 0.14 mol)溶于甲苯(100 ml, 9.44
mol)并滴加入POCl3。于95℃将反应混合物搅拌4h,然后蒸发溶剂。使残留物溶于甲基叔丁基醚,用NaHCO3溶液和水提取。分离有机层并经Na2SO4干燥。过滤并真空除去溶剂后,分离7-氯-2-三甲基硅烷基-呋喃并[3,2-b]吡啶;得到230 g 7-氯-2-三甲基硅烷基-呋喃并[3,2-b]吡啶;HPLC/MS: 2.65
min, [M+H] = 226;
1H NMR (400 MHz,
DMSO-d6) δ [ppm] 8.46 (d, J = 5.2 Hz, 1H), 7.48 (d, J
= 5.2 Hz, 1H), 7.46 (s, 1H), 0.37 (s, 9H)。
步骤4:7-氯-2-碘-呋喃并[3,2-b]吡啶
在氮气氛下,使7-氯-2-三甲基硅烷基-呋喃并[3,2-b]吡啶(185 g, 0.23 mol)溶于ACN。然后加入KF (47.6 g, 0.82 mol)和碘代琥珀酰亚胺(553.1 g, 0.25
mol)。于60℃将反应混合物搅拌14 h,然后冷却至室温。向反应混合物中加入乙酸乙酯(5 l)和水(5 l)。分离有机层,用硫代硫酸钠(5 l)溶液洗涤,然后用NaHCO3溶液提取和用盐水洗涤。有机层经Na2SO4干燥。过滤干燥剂并真空除去溶剂;得到133 g 7-氯-2-碘-呋喃并[3,2-b]吡啶;HPLC/MS: 2.34
min, [M+H] = 280;
1H NMR (400 MHz,
DMSO-d6) δ [ppm] 8.44 (d, J = 5.3 Hz, 1H), 7.55 (s, 1H), 7.44
(dd, J = 5.4, 3.1 Hz, 1H)。
合成2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈
步骤1:5-溴-2-(四氢-吡喃-4-基氧基)-苯甲腈
于0℃,向四氢-吡喃-4-醇(3.3 g, 33.0
mmol)的DMF (60 ml)溶液中加入氢化钠(1.4 g, 33.0 mmol)。于0℃滴加入在DMF (30 ml)中的5-溴-2-氟-苯甲腈(5.5 g, 27.5
mmol)。于45℃将反应物搅拌16 h。使反应物冷却至室温并通过将所述反应物倾入水(500 ml)中猝灭。过滤沉淀物并在真空下干燥;得到6.8 g 5-溴-2-(四氢-吡喃-4-基氧基)-苯甲腈;
HPLC/MS: 2.27
min, [M+H] = 283。
步骤2:2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈
向5-溴-2-(四氢-吡喃-4-基氧基)-苯甲腈(6.7 g, 19 mmol)的1,4-二氧杂环己烷(70 ml)溶液中加入二(频哪醇合)二硼(7.3 g, 28.6 mmol)、乙酸钾(5.6 g, 57.2 mmol)和Pd(dppf)Cl2 (778.4 mg, 0.95 mmol)。将该混合物加热至90℃经4 h,然后用水(50 ml)猝灭,接着用乙酸乙酯提取。分离有机层,用盐水洗涤并经硫酸钠干燥。过滤干燥剂并真空除去溶剂。产物经层析(石油醚/乙酸乙酯)纯化;得到5.6 g 2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 2.553 min, [M+H] = 330。
5-[2-(4-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶-7-基]-2-(四氢-吡喃-4-基氧基)-苯甲腈("A1")
步骤1:7-氯-2-(4-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶
使7-氯-2-碘-呋喃并[3,2-b]吡啶(100 mg, 0.36 mmol)和4-吗啉代苯基硼酸(77.8 mg, 0.38 mmol)溶于1,4二氧杂环己烷(2 ml)。在氮气下加入碳酸钾(0.15 g)和水(0.25 ml)。加入二环己基-(2',6'-二甲氧基-联苯-2-基)-正磷烷和乙酸钯(II)并于100℃将该混合物搅拌3 h。使反应混合物冷却至室温并通过蒸发除去溶剂。产物经层析分离;得到92 mg 7-氯-2-(4-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶;HPLC/MS: 2.411
min, [M+H] = 315。
类似地,获得以下化合物:
7-氯-2-(3-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和4-[3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]吗啉;HPLC/MS: 2.45
min, [M+H] = 315;
4-(7-氯-呋喃并[3,2-b]吡啶-2-基)-N-乙基-N-(2-甲氧基-乙基)-苯甲酰胺
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和N-乙基-N-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲酰胺;HPLC/MS: 2.18
min, [M+H] = 359;
7-氯-2-(4-甲氧基-苯基)-呋喃并[3,2-b]吡啶
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和4-甲氧基苯基硼酸;HPLC/MS: 2.55
min, [M+H] = 260;
7-氯-2-(2-甲氧基-苯基)-呋喃并[3,2-b]吡啶
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和2-甲氧基苯硼酸;HPLC/MS: 2.65
min, [M+H] = 262;
7-氯-2-(3-甲氧基-苯基)-呋喃并[3,2-b]吡啶
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和3-甲氧基苯基硼酸;HPLC/MS: 2.70
min, [M+H] = 262;
3-(7-氯-呋喃并[3,2-b]吡啶-2-基)-N-乙基-N-(2-甲氧基-乙基)-苯甲酰胺
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和N-乙基-N-(2-甲氧基-乙基)-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲酰胺;HPLC/MS: 2.19
min, [M+H] = 359;
4-(7-氯-呋喃并[3,2-b]吡啶-2-基)-苯甲酸乙酯
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和4-乙氧基羰基苯基硼酸;
HPLC/MS: 2.89
min, [M+H] = 302;
7-氯-2-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-呋喃并[3,2-b]吡啶
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑;HPLC/MS: 2.90 min, [M+H] = 278;
7-氯-2-[3-(4-甲基-哌嗪-1-基)-苯基]-呋喃并[3,2-b]吡啶
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基]-哌嗪;HPLC/MS: 1.57 min, [M+H] = 328;
7-氯-2-[4-(4-甲基-哌嗪-1-基)-苯基]-呋喃并[3,2-b]吡啶
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和1-甲基-4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基]-哌嗪;HPLC/MS: 1.51 min, [M+H] = 328;
1H NMR (400 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.72 (1 H, d, J =6.4
Hz), 8.08 (2 H, d, J= 9.0Hz), 7.87 (1 H, d, J =6.4Hz), 7.73 (1 H, s), 7.23 (2
H, d, J =9.1Hz), 4.16 (2 H, d, J =11.0 Hz), 3.62 (2 H, d, J =9.1 Hz), 3.26 (4
H, m);
4-[4-(7-氯-呋喃并[3,2-b]吡啶-2-基)-吡唑-1-基]-哌啶-1-甲酸叔丁基酯
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-吡唑-1-基]-哌啶-1-甲酸叔丁基酯;HPLC/MS: 2.507
min, [M+H] = 403;
4-[4-(7-氯-呋喃并[3,2-b]吡啶-2-基)-2-甲氧基-苯甲酰基]-哌嗪-1-甲酸叔丁基酯
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和4-[2-甲氧基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲酰基]-哌嗪-1-甲酸叔丁基酯;HPLC/MS: 2.40
min, [M+H] = 472;
4-(7-氯-呋喃并[3,2-b]吡啶-2-基)-2-甲氧基-苯甲酸甲酯
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和3-甲氧基-4-甲氧基羰基苯基硼酸, 频哪醇酯;HPLC/MS: 2.425
min, [M+H] = 318;
2-(1H-苯并咪唑-4-基)-7-氯-呋喃并[3,2-b]吡啶
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和1H-苯并咪唑-4-基硼酸;
HPLC/MS: 1.843
min, [M+H] = 270;
1H NMR (400 MHz,
DMSO-d6/TFA-d1)δ[ppm] 9.82 (1 H, s), 8.72 (1
H, d, J 5.6), 8.26 (1 H, d, J 7.0), 8.15 (1 H, s), 8.08 (1 H, dd, J 8.3, 0.8),
7.79 (2 H, m);
5-(7-氯-呋喃并[3,2-b]吡啶-2-基)-1,3-二氢-苯并咪唑-2-酮
得自7-氯-2-碘-呋喃并[3,2-b]吡啶和2,3-二氢-2-氧代-1H-苯并咪唑-5-硼酸, 频哪醇酯;HPLC/MS: 1.755
min, [M+H] = 286;
1H NMR (400 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.73 (1 H, d, J 6.3),
7.90 (1 H, d, J 6.3), 7.84 (2 H, m), 7.72 (1 H, d, J 1.6), 7.18 (1 H, d, J 7.7,
4.0)。
步骤2:5-[2-(4-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶-7-基]-2-(四氢-吡喃-4-基氧基)-苯甲腈("A1")
使用在步骤1对7-氯-2-(4-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶描述的相同方法,从7-氯-2-(4-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈获得标题化合物;得到67 mg 5-[2-(4-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶-7-基]-2-(四氢-吡喃-4-基氧基)-苯甲腈;HPLC/MS: 2.26
min, [M+H] = 482;
1H NMR (400 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.74 (d, J= 6.4
Hz, 1H), 8.64 (d, J= 2.4 Hz, 1H), 8.58 (dd, J= 9.0, 2.4 Hz, 1H),
8.09 (t, J =5.9 Hz, 1H), 8.06 (d, J= 9.0 Hz, 2H), 7.68 (d, J=
10.6 Hz, 2H), 7.17 (d, J= 9.1 Hz, 2H), 5.08 – 4.98 (m, 1H), 3.99 – 3.92
(m, 2H), 3.83 – 3.78 (m, 4 H), 3.67 – 3.58 (m, 2 H), 3.43 – 3.35 (m, 4 H), 2.18
– 2.09 (m, 2 H), 1.86 – 1.77 (m, 2 H)。
类似地获得以下化合物:
5-[2-(3-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶-7-基]-2-(四氢-吡喃-4-基氧基)-苯甲腈("A2")
得自7-氯-2-(3-吗啉-4-基-苯基)-呋喃并[3,2-b]吡啶和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;
HPLC/MS: 2.45
min, [M+H] = 482;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.88 (d, J =6.4
Hz, 1H), 8.76 (d, J =2.4 Hz, 1H), 8.59 (dd, J =9.0, 2.4 Hz, 1H),
8.25 (d, J =6.4 Hz, 1H), 8.01 (s, 1H), 7.88 (d, J =8.0 Hz, 1H),
7.75 (d, J =7.8 Hz, 1H), 7.68 (d, J =9.2 Hz, 1H), 7.58 – 7.52 (m,
1H), 7.37 – 7.31 (m, 1H), 5.10 – 4.97 (m, 1H), 4.01 – 3.93 (m, 2H), 3.92 – 3.87
(m, 4H), 3.67 – 3.59 (m, 2H), 3.42 – 3.35 (m, 4H), 2.16 – 2.09 (m, 2H), 1.87 –
1.77 (m, 2H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-乙基-N-(2-甲氧基-乙基)-苯甲酰胺("A3")
得自4-(7-氯-呋喃并[3,2-b]吡啶-2-基)-N-乙基-N-(2-甲氧基-乙基)-苯甲酰胺和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 2.20
min, [M+H] = 526;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.91 (d, J= 6.3
Hz, 1H), 8.68 (d, J= 2.4 Hz, 1H), 8.64 (dd, J= 9.0, 2.4 Hz, 1H),
8.29 – 8.23 (m, 3H), 8.04 (s, 1H), 7.69 (t, J= 8.5 Hz, 1H), 7.64 (d, J=
7.6 Hz, 2H), 5.10 – 4.98 (m, 1 H), 4.00 – 3.91 (m, 2 H), 3.70 – 3.59 (m, 4H),
3.58 – 3.17 (m, 7H), 2.20 – 2.07 (m, 2H), 1.86 – 1.75 (m, 2H), 1.16 (d, J
=57.6Hz, 3H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸乙酯("A4")
得自4-(7-氯-呋喃并[3,2-b]吡啶-2-基)-苯甲酸乙酯和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 2.64 min, [M+H] = 369;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.94 (d, J =
6.3 Hz, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.64 (dd, J = 9.0, 2.4 Hz,
1H), 8.34 (d, 2H), 8.28 (d, 1H), 8.21 (d, J = 1.7 Hz, 2H), 8.13 (s, 1H),
7.71 (d, J = 9.2 Hz, 1H), 5.09 – 5.00 (m, 1H), 4.40 (q, J = 7.1
Hz, 2H), 3.99 – 3.92 (m, 2H), 3.66 – 3.58 (m, 2H), 2.17 – 2.09 (m, 2H), 1.85 –
1.77 (m, 2H), 1.43 – 1.35 (m, 3H);
5-[2-(2-甲氧基-苯基)-呋喃并[3,2-b]吡啶-7-基]-2-(四氢-吡喃-4-基氧基)-苯甲腈("A5")
得自7-氯-2-(2-甲氧基-苯基)-呋喃并[3,2-b]吡啶和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 2.33 min, [M+H] = 427;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.89 (d, J =
6.3 Hz, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.64 (dd, J = 9.0, 2.4 Hz,
1H), 8.24 (d, J = 6.4 Hz, 1H), 8.13 (dd, J = 7.8, 1.5 Hz, 1H),
7.75 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.67 – 7.62 (m, 1H), 7.36 (t, J
= 8.4 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 5.09 – 5.01 (m, 1H), 4.10 (s,
3H), 3.95 – 3.89 (m, 2H), 3.65 – 3.57 (m, 2H), 2.15 – 2.09 (m, 2H), 1.82 – 1.73
(m, 2H);
5-[2-(3-甲氧基-苯基)-呋喃并[3,2-b]吡啶-7-基]-2-(四氢-吡喃-4-基氧基)-苯甲腈("A6")
得自7-氯-2-(3-甲氧基-苯基)-呋喃并[3,2-b]吡啶和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 2.48 min, [M+H] = 427;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.90 (d, J =
6.3 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.62 (dd, J = 9.0, 2.4 Hz,
1H), 8.25 (d, J = 6.3 Hz, 1H), 8.04 (s, 1H), 7.79 (d, J = 7.8 Hz,
1H), 7.78 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.23
(dd, J = 8.2, 2.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.10 – 4.99
(m, 1H), 3.96 – 3.94 (m, 1H), 3.93 (s, 3H), 3.65 (s, 1H), 3.64 – 3.58 (m, 2H),
2.15 – 2.08 (m, 2H), 1.82 – 1.75 (m, 2H);
5-[2-(4-甲氧基-苯基)-呋喃并[3,2-b]吡啶-7-基]-2-(四氢-吡喃-4-基氧基)-苯甲腈("A7")
得自7-氯-2-(4-甲氧基-苯基)-呋喃并[3,2-b]吡啶和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 2.23 min, [M+H] = 427;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.83 (d, J =
6.3 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.61 (dd, J = 9.0, 2.4 Hz,
1H), 8.19 – 8.12 (m, 3H), 7.83 (s, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.21
(d, 2H), 5.09 – 4.98 (m, 1H), 3.96 – 3.92 (m, 1H), 3.91 (s, 3H), 3.64 (s, 2H),
3.62 – 3.58 (m, 1H), 2.15 – 2.08 (m, 2H), 1.81 – 1.75 (m, 2H);
5-{2-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-呋喃并[3,2-b]吡啶-7-基}-2-(四氢-吡喃-4-基氧基)-苯甲腈("A8")
得自7-氯-2-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-呋喃并[3,2-b]吡啶和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 1.89 min, [M+H] = 445;
1H NMR (400 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.78 (d, J =
6.4 Hz, 1H), 8.67 – 8.63 (m, 2H), 8.59 (dd, 1H), 8.31 (s, 1H), 8.14 (d, J
= 6.5 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.57 (s, 1H), 5.08 – 4.98 (m,
1H), 4.44 (t, J = 5.1 Hz, 2H), 4.01 – 3.89 (m, 2H), 3.80 (t, J =
5.1 Hz, 2H), 3.67 – 3.59 (m, 2H), 3.29 (s, 3H), 2.19 – 2.07 (m, 2H), 1.87 –
1.74 (m, 2H)。
5-{2-[3-(4-甲基-哌嗪-1-基)-苯基]-呋喃并[3,2-b]吡啶-7-基}-2-(四氢-吡喃-4-基氧基)-苯甲腈("A9")
得自7-氯-2-[3-(4-甲基-哌嗪-1-基)-苯基]-呋喃并[3,2-b]吡啶和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 1.65 min, [M+H] = 495;
1H NMR (400 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.81 (d, J =
6.4 Hz, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.50 (dd, J = 9.1, 2.4 Hz,
1H), 8.17 (d, J = 6.4 Hz, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.63 (d, J
= 8.0 Hz, 1H), 7.60 (d, J = 9.3 Hz, 1H), 7.46 (t, J = 8.0 Hz,
1H), 7.22 (dd, J = 8.3, 2.1 Hz, 1H), 5.03 – 4.89 (m, 1H), 4.01 (d, J
= 13.0 Hz, 2H), 3.93 – 3.80 (m, 2H), 3.64 – 3.48 (m, 4H), 3.29 – 3.06 (m, 4H),
2.88 (s, 3H), 2.12 – 1.99 (m, 2H), 1.80 – 1.67 (m, 2H);
5-{2-[4-(4-甲基-哌嗪-1-基)-苯基]-呋喃并[3,2-b]吡啶-7-基}-2-(四氢-吡喃-4-基氧基)-苯甲腈("A10")
得自7-氯-2-[4-(4-甲基-哌嗪-1-基)-苯基]-呋喃并[3,2-b]吡啶和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 1.59 min, [M+H] = 495;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.77 (1 H, d, J 6.3), 8.65 (1 H, d, J 2.4), 8.57 (1 H, dd,
J 9.0, 2.4), 8.09 (3 H, dd, J 19.1, 7.7), 7.73 (2 H, m), 7.24 (2 H, d, J 9.1),
5.04 (1 H, tt, J 7.8, 3.8), 4.14 (2 H, t, J 23.6), 3.93 (2 H, m), 3.61 (4 H,
ddd, J 11.3, 8.5, 2.9), 3.21 (4 H, d, J 9.2), 2.92 (3 H, s), 2.11 (2 H, m),
1.77 (2 H, dtd, J 12.4, 8.2, 3.9);
4-(4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-2-甲氧基-苯甲酰基)-哌嗪-1-甲酸叔丁基酯("A11")
得自4-[4-(7-氯-呋喃并[3,2-b]吡啶-2-基)-2-甲氧基-苯甲酰基]-哌嗪-1-甲酸叔丁基酯和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 2.44
min, [M+H] = 639;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.59 (1 H, d, J 5.1),
8.55 (1 H, d, J 2.4), 8.44 (1 H, dd, J 9.0, 2.4), 7.87 (1 H, s), 7.66 (4 H, m),
7.39 (1 H, d, J 7.8), 4.97 (1 H, m), 3.96 (3 H, s), 3.89 (2 H, m), 3.58 (4 H,
m), 3.43 (4 H, s), 3.17 (2 H, m), 2.07 (2 H, m), 1.72 (2 H, m), 1.41 (9 H, s);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-2-甲氧基-苯甲酸甲酯("A12")
得自4-(7-氯-呋喃并[3,2-b]吡啶-2-基)-2-甲氧基-苯甲酸甲酯和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 2.413
min, [M+H] = 485;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.93 (1 H, d, J 6.3),
8.73 (1 H, d, J 2.4), 8.59 (1 H, dd), 8.28 (1 H, d, J 6.4), 8.17 (1 H, s), 7.88
(2 H, m), 7.82 (1 H, dd, J 8.0, 1.4), 7.65 (1 H, d, J 9.2), 5.03 (1 H, m), 4.04
(3 H, s), 3.96 (2 H, m), 3.87 (3 H, s), 3.63 (2 H, m), 2.13 (2 H, m), 1.82 (2
H, m);
5-[2-(1H-苯并咪唑-4-基)-呋喃并[3,2-b]吡啶-7-基]-2-(四氢-吡喃-4-基氧基)-苯甲腈("A13")
得自2-(1H-苯并咪唑-4-基)-7-氯-呋喃并[3,2-b]吡啶和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;
HPLC/MS: 1.975
min, [M+H] = 437;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 9.73 (1 H, s), 8.91 (1
H, d, J 6.2), 8.65 (1 H, d, J 2.4), 8.56 (1 H, dd, J 9.0, 2.4), 8.24 (2 H, dd,
J 7.0, 3.2), 8.20 (1 H, s), 8.06 (1 H, d, J 8.2), 7.74 (1 H, dd, J 13.6, 5.6),
7.59 (1 H, d, J 9.2), 4.95 (1 H, tt, J 7.7, 3.8), 3.88 (2 H, m), 3.55 (2 H, m),
2.05 (2 H, m), 1.74 (2 H, m);
5-[2-(2-氧代-2,3-二氢-1H-苯并咪唑-5-基)-呋喃并[3,2-b]吡啶-7-基]-2-(四氢-吡喃-4-基氧基)-苯甲腈("A14")
得自5-(7-氯-呋喃并[3,2-b]吡啶-2-基)-1,3-二氢-苯并咪唑-2-酮和2-(四氢-吡喃-4-基氧基)-5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲腈;HPLC/MS: 1.811 min, [M+H] = 453;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.79 (1 H, d, J 6.4),
8.64 (1 H, d, J 2.3), 8.58 (1 H, dd, J 9.0, 2.4), 8.13 (1 H, d, J 6.4), 7.86 (1
H, dd, J 8.2, 1.6), 7.83 (1 H, s), 7.76 (1 H, d, J 1.5), 7.69 (1 H, dd, J 5.4,
3.9), 7.21 (1 H, t, J 6.6), 5.04 (1 H, tt, J 7.8, 3.8), 3.96 (2 H, m), 3.64 (2
H, m), 2.14 (2 H, m), 1.82 (2 H, m)。
合成4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-甲基氨基-乙基)-苯甲酰胺("A15")
步骤1:4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸("A16a")
将4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸乙酯(1.6 g, 3.42 mmol)在50 ml 乙醇中的溶液和1M NaOH (20 mL, 40.0 mmol)于室温下搅拌14 h。真空除去乙醇并用1M盐酸酸化该混合物。过滤除去生成的沉淀物,用水洗涤并干燥16 h;得到1.4 g 4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸;
HPLC/MS: 2.12 min, [M+H] = 441;
1H NMR (400 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.84 (d, J = 6.3 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H),
8.55 (dd, J = 9.0, 2.4 Hz, 1H), 8.22 (d, J = 8.6 Hz, 2H), 8.19
(d, J = 6.4 Hz, 1H), 8.13 (d, J = 8.6 Hz, 2H), 8.01 (s, 1H), 7.61
(d, J = 9.2 Hz, 1H), 5.01 – 4.91 (m, 1H), 3.94 – 3.84 (m, 2H), 3.61 –
3.50 (m, 2H), 2.13 – 2.00 (m, 2H), 1.80 – 1.66 (m, 2H)。
类似地获得以下化合物
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-2-甲氧基-苯甲酸
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-2-甲氧基-苯甲酸甲酯;HPLC/MS: 2.136 min, [M+H] = 471。
步骤2:[2-(4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]呋喃并[3,2b]吡啶-2-基}-苯甲酰基氨基)-乙基]-甲基-氨基甲酸叔丁基酯("A16")
使4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸(100 mg, 0.23 mmol)和N-(2-氨基乙基)-N-甲基-氨基甲酸叔丁基酯(47.5 mg, 0.27 mmol)溶于DMSO (2 ml)。将N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐(DAPECI) (87.0 mg, 0.45 mmol)、1-羟基苯并三唑水合物(HOBt) (34.8 mg, 0.15 mmol)和N-甲基吗啉(49.9 µl, 0.45 mmol)加入到该溶液中。将该混合物于室温下搅拌16 h。蒸发DMSO和使产物经层析分离;得到61 mg [2-(4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酰基氨基)-乙基]-甲基-氨基甲酸叔丁基酯;HPLC/MS: 2.37 min, [M+H] = 597;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.84 (d, J = 6.5 Hz, 1H), 8.62 (d, J = 2.3 Hz, 1H),
8.55 (dd, J = 9.0, 2.3 Hz, 1H), 8.25 – 8.17 (m, 3H), 8.11 – 7.97 (m,
3H), 7.62 (d, J = 9.2 Hz, 1H), 5.02 – 4.87 (m, 1H), 3.96 – 3.81 (m, 2H),
3.65 – 3.49 (m, 3H), 3.47 – 3.29 (m, 4H), 2.80 (s, 3H), 2.10 – 2.02 (m, 2H),
1.79 – 1.70 (m, 2H), 1.28 (s, 9H)。
类似地获得以下化合物:
5-{2-[4-(4-甲基-哌嗪-1-羰基)-苯基]-呋喃并[3,2-b]吡啶-7-基}-2-(四氢-吡喃-4-基氧基)-苯甲腈("A17")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和1-甲基-哌嗪;HPLC/MS: 1.60
min, [M+H] = 523;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.91 (dd, J =
6.3, 2.9 Hz, 1H), 8.67 (t, J = 2.5 Hz, 1H), 8.61 (dd, 1H), 8.30 (dd, J
= 8.4, 2.0 Hz, 2H), 8.26 (dd, J = 6.3, 2.6 Hz, 1H), 8.05 (d, J =
3.5 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.66 (dd, J = 9.1, 3.8 Hz, 1H), 5.09 –
4.96 (m, 1H), 4.55 (d, J = 119.7 Hz, 1H), 4.03 – 3.77 (m, 3H), 3.70 –
3.33 (m, 6H), 3.21 (t, J = 11.2 Hz, 2H), 2.91 (s, 3H), 2.17 – 2.07 (m,
2H), 1.88 – 1.76 (m, 2H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酰胺("A18")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和氨;HPLC/MS: 1.96
min, [M+H] = 440;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.92 – 8.88 (m, 1H),
8.68 (d, 1H), 8.62 (dd, 1H), 8.32 – 8.23 (m, 3H), 8.18 (d, 2H), 8.06 (dd, 1H),
7.68 (dd, J = 7.3 Hz, 1H), 5.07 – 4.97 (m, 1H), 4.02 – 3.91 (m, 2H),
3.69 – 3.57 (m, 2H), 2.19 – 2.09 (m, 2H), 1.89 – 1.77 (m, 2H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-甲基-苯甲酰胺("A19")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和甲胺;HPLC/MS: 2.04 min,
[M+H] = 454;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.89 (dd, J =
6.3, 1.6 Hz, 1H), 8.68 (t, 1H), 8.62 (dd, 1H), 8.28 (d, 2H), 8.24 (dd, 1H),
8.13 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 1.9 Hz, 1H), 7.67 (dd, J
= 9.2, 1.8 Hz, 1H), 5.07 – 4.99 (m, 1H), 4.01 – 3.90 (m, 2H), 3.68 – 3.59 (m,
2H), 2.90 (s, 3H), 2.18 – 2.08 (m, 2H), 1.89 – 1.74 (m, 2H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-乙基-苯甲酰胺("A20")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和乙胺;HPLC/MS: 2.13
min, [M+H] = 468;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.87 (dd, J =
6.3, 2.0 Hz, 1H), 8.66 (t, J = 1.9 Hz, 1H), 8.60 (dd, 1H), 8.27 (d, 2H),
8.23 (dd, J = 6.4, 2.0 Hz, 1H), 8.14 (d, J = 8.5 Hz, 2H), 8.01
(d, J = 2.5 Hz, 1H), 7.64 (dd, J = 9.2, 2.2 Hz, 1H), 5.07 – 4.97
(m, 1H), 4.03 – 3.93 (m, 2H), 3.67 – 3.58 (m, 2H), 3.41 (q, J = 7.2 Hz,
2H), 2.17 – 2.09 (m, 2H), 1.90 – 1.76 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H);
N-(2-叔丁氧基-乙基)-4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酰胺("A21")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和2-叔丁氧基乙胺;HPLC/MS: 2.34 min, [M+H] = 540;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.90 (dd, J =
6.3, 1.9 Hz, 1H), 8.68 (t, J = 2.0 Hz, 1H), 8.62 (dd, 1H), 8.29 (d, J
= 8.5, 1.4 Hz, 2H), 8.25 (dd, J = 6.4, 1.8 Hz, 1H), 8.14 (d, J =
8.5 Hz, 2H), 8.05 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 9.2, 2.3 Hz,
1H), 5.07 – 5.00 (m, 1H), 4.00 – 3.92 (m, 2H), 3.70 – 3.59 (m, 3H), 3.56 – 3.49
(m, 2H), 3.49 – 3.41 (m, 2H), 2.17 – 2.07 (m, 2H), 1.88 – 1.77 (m, 2H), 1.18
(s, 9H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-甲氧基-乙基)-苯甲酰胺("A22")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和2-甲氧基-乙胺;HPLC/MS: 2.08
min, [M+H] = 498;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.88 (dd, J =
6.3, 1.3 Hz, 1H), 8.67 (s, 1H), 8.61 (dd, J = 9.0 Hz, 1H), 8.28 (d, J
= 8.0 Hz, 2H), 8.24 (dd, J = 6.4, 1.2 Hz, 1H), 8.16 (d, J = 8.4
Hz, 2H), 8.03 (d, J = 1.6 Hz, 1H), 7.66 (dd, 1H), 5.02 (d, J =
3.7 Hz, 1H), 4.05 – 3.91 (m, 2H), 3.69 – 3.61 (m, 2H), 3.56 (s, 4H), 3.34 (s,
3H), 2.20 – 2.08 (m, 2H), 1.88 – 1.79 (m, 2H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N,N-二甲基-苯甲酰胺("A23")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和二甲基-胺;HPLC/MS: 2.08 min, [M+H] = 468;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.89 (dd, J =
6.3, 1.4 Hz, 1H), 8.66 (s, 1H), 8.63 (dd, 1H), 8.30 – 8.21 (m, 3H), 8.01 (d, J
= 1.5 Hz, 1H), 7.71 – 7.64 (m, 3H), 5.07 – 4.98 (m, 1H), 4.03 – 3.93 (m, 2H),
3.68 – 3.60 (m, 2H), 3.08 (s, 3H), 2.99 (s, 3H), 2.19 – 2.08 (m, 2H), 1.88 –
1.77 (m, 2H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-乙基-N-甲基-苯甲酰胺("A24")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和乙基-甲基-胺;HPLC/MS: 2.17
min, [M+H] = 482;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.90 (dd, J =
6.3, 1.6 Hz, 1H), 8.67 (s, 1H), 8.64 (d, J = 9.1 Hz, 1H), 8.31 – 8.23
(m, 3H), 8.03 (d, 1H), 7.72 – 7.61 (m, 3H), 5.12 – 4.98 (m, 1H), 4.00 – 3.92
(m, 2H), 3.67 – 3.58 (m, 2H), 3.42 (d, J = 130.1 Hz, 2H), 3.04 (s, 3H),
2.19 – 2.09 (m, 2H), 1.88 – 1.75 (m, 2H), 1.17 (t, J = 40.6 Hz, 3H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-羟基-乙基)-N-甲基-苯甲酰胺("A25")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和2-甲基氨基-乙醇;HPLC/MS: 1.89
min, [M+H] = 498;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.80 (dd, J =
6.2, 3.1 Hz, 1H), 8.62 – 8.51 (m, 2H), 8.22 – 8.12 (m, 3H), 7.92 (s, 1H), 7.65
– 7.52 (m, 3H), 5.00 – 4.89 (m, 1H), 3.94 – 3.82 (m, 2H), 3.65 (s, 1H), 3.59 –
3.46 (m, 4H), 3.28 (s, 1H), 2.97 (d, J = 26.3 Hz, 3H), 2.10 – 1.99 (m,
2H), 1.79 – 1.68 (m, 2H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-甲氧基-乙基)-N-甲基-苯甲酰胺("A26")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和(2-甲氧基-乙基)-甲基-胺;HPLC/MS: 2.11
min, [M+H] = 512;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.90 (dd, J =
6.3, 2.7 Hz, 1H), 8.67 (dd, J = 2.2 Hz, 1H), 8.63 (dd, J = 9.0,
2.2 Hz, 1H), 8.32 – 8.22 (m, 3H), 8.02 (s, 1H), 7.71 – 7.63 (m, 3H), 4.04 –
3.88 (m, 2H), 3.77 – 3.59 (m, 5H), 3.56 – 3.42 (m, 2H), 3.31 (s, 3H), 3.05 (s,
3H), 2.21 – 2.06 (m, 2H), 1.92 – 1.75 (m, 2H);
3-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-乙基-N-(2-甲氧基-乙基)-苯甲酰胺("A26a")
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.92 (d, J = 6.3 Hz, 1H), 8.70 (d, J =
2.4 Hz, 1H), 8.61 (dd, J = 9.0, 2.4 Hz, 1H), 8.26 (d, J = 6.3 Hz,
2H), 8.22 (s, 1H), 8.12 (s, 1H), 7.71 (d, J = 8.9 Hz, 2H), 7.62 (d, J
= 6.9 Hz, 1H), 5.09 – 5.00 (m, 1H), 3.99 – 3.91 (m, 2H), 3.66 – 3.13 (m, 11H),
2.16 – 2.08 (m, 2H), 1.85 – 1.73 (m, 2H), 1.25 – 1.07 (m, 3H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-二甲基氨基-乙基)-苯甲酰胺("A27")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和N1,N1-二甲基-乙烷-1,2-二胺;HPLC/MS: 1.66 min, [M+H] = 511;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.91 (dd, J =
6.3, 2.9 Hz, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.61 (dd, 1H), 8.33 (dd, J
= 8.5, 1.9 Hz, 2H), 8.26 (dd, J = 6.3, 2.6 Hz, 1H), 8.18 (d, J =
8.5 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 3.5 Hz, 1H),
7.66 (dd, J = 9.1, 3.5 Hz, 1H), 5.07 – 4.99 (m, 1H), 4.02 – 3.93 (m,
2H), 3.74 (t, J = 5.8 Hz, 2H), 3.69 – 3.60 (m, 2H), 3.39 (t, J =
5.8 Hz, 2H), 2.94 (d, J = 7.8 Hz, 6H), 2.20 – 2.07 (m, 2H), 1.88 – 1.77
(m, 2H);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-二甲基氨基-乙基)-N-甲基-苯甲酰胺("A28")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和N,N,N'-三甲基-乙烷-1,2-二胺;HPLC/MS: 1.62 min, [M+H] = 525;
1H NMR (500 MHz,
DMSO-d6)δ[ppm] 8.91 (1 H, d, J 6.3), 8.68 (1 H, d, J 2.0), 8.61 (1 H,
dd, J 9.0, 2.3), 8.28 (3 H, dd, J 17.0, 7.4), 8.10 (1 H, s), 8.04 (1 H, d, J
7.4), 7.77 (2 H, d, J 7.9), 7.67 (1 H, d, J 9.1), 5.03 (1 H, m), 3.95 (4 H, m),
3.64 (2 H, m), 3.47 (2 H, s), 3.02 (8 H, d, J 27.5), 2.14 (2 H, m), 1.84 (2 H,
m);
4-(4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酰基)-哌嗪-1-甲酸叔丁基酯("A29")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酸和哌嗪-1-甲酸叔丁基酯;HPLC/MS: 2.41 min, [M+H] = 609;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.88 (d, J =
6.3 Hz, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.61 (dd, J = 9.0, 2.3 Hz,
1H), 8.27 (d, J = 8.3 Hz, 2H), 8.23 (d, J = 6.4 Hz, 1H), 8.00 (s,
1H), 7.69 (d, J = 8.3 Hz, 2H), 7.63 (d, 1H), 5.07 – 4.97 (m, 1H), 4.02 –
3.89 (m, 2H), 3.73 – 3.59 (m, 4H), 3.58 – 3.33 (m, 6H), 2.19 – 2.08 (m, 2H),
1.89 – 1.81 (m, 2H), 1.45 (s, 9H);
5-{2-[3-甲氧基-4-(2-氧杂-6-氮杂-螺[3.3]庚烷-6-羰基)-苯基]-呋喃并[3,2-b]吡啶-7-基}-2-(四氢-吡喃-4-基氧基)-苯甲腈("A30")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-2-甲氧基-苯甲酸和2-氧杂-6-氮杂螺[3.3]庚烷草酸酯;HPLC/MS: 2.041
min, [M+H] = 552;
1H NMR (500 MHz,
DMSO-d6)δ[ppm] 8.58 (1 H, d, J 5.5), 8.56 (1 H, d, J 2.4), 8.44 (1 H,
dd, J 9.0, 2.4), 7.89 (1 H, s), 7.70 (2 H, dd, J 5.8, 3.2), 7.63 (2 H, d, J
9.2), 7.46 (1 H, d, J 7.8), 4.98 (1 H, tt, J 7.8, 3.8), 4.69 (4 H, dd, J 24.5,
6.9), 4.20 (2 H, s), 4.11 (2 H, d, J 8.0), 3.98 (3 H, s), 3.89 (2 H, m), 3.58
(2 H, ddd, J 11.5, 8.4, 3.1), 2.08 (2 H, m), 1.72 (2 H, dtd, J 12.4, 8.2, 3.8);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-二甲基氨基-乙基)-N-乙基-2-甲氧基-苯甲酰胺("A31")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-2-甲氧基-苯甲酸和N,N-二甲基-N'-乙基乙二胺;HPLC/MS: 1,728 min, [M+H] = 569;
1H NMR (400 MHz,
DMSO-d6)δ[ppm] 8.58 (1 H, d, J 5.1), 8.55 (1 H, d, J 2.4), 8.44 (1 H,
dd, J 8.9, 2.4), 7.85 (1 H, d, J 3.3), 7.69 (2 H, d, J 5.1), 7.64 (2 H, ddd, J
8.7, 5.0, 3.7), 7.33 (1 H, dd, J 7.8, 4.8), 4.97 (1 H, m), 3.91 (5 H, m), 3.56
(6 H, m), 3.16 (2 H, dd, J 16.0, 9.0), 2.30 (4 H, m), 2.07 (2 H, m), 1.97 (2 H,
s), 1.72 (2 H, dtd, J 12.3, 8.2, 3.8), 1.07 (3 H, dt, J 63.3, 7.1);
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-二甲基氨基-乙基)-2-甲氧基-苯甲酰胺("A32")
得自4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-2-甲氧基-苯甲酸和N,N-二甲基乙二胺;HPLC/MS: 1,713
min, [M+H] = 541;
1H NMR (400 MHz,
DMSO-d6)δ[ppm] 8.59 (1 H, d, J 5.1), 8.55 (1 H, d, J 2.4), 8.43 (1 H,
dd, J 9.0, 2.4), 8.36 (1 H, t, J 5.3), 7.96 (1 H, d, J 8.1), 7.90 (1 H, s),
7.70 (3 H, ddd, J 11.5, 8.5, 1.4), 7.62 (1 H, d, J 9.1), 4.97 (1 H, tt, J 7.8,
3.8), 4.05 (3 H, s), 3.90 (2 H, m), 3.58 (2 H, m), 3.42 (2 H, m), 2.52 (2 H,
m), 2.28 (6 H, s), 2.08 (2 H, m), 1.73 (2 H, m)。
步骤3:4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N (2-甲基氨基-乙基)-苯甲酰胺("A15")
使[2-(4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}苯甲酰基-氨基)-乙基]-甲基-氨基甲酸叔丁基酯(59.0 mg, 0.1 mmol)溶于二氯甲烷(1 ml)。将三氟-乙酸(1 ml, 12.98 mmol)加入该溶液中。将该混合物于室温下搅拌16 h。真空除去溶剂;得到20 mg 4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-甲基-氨基-乙基)-苯甲酰胺三氟乙酸盐;HPLC/MS: 1.61 min, [M+H] = 497;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.91 (dd, 1H), 8.69 (d, 1H), 8.60 (dd, J = 10.7, 5.6 Hz, 1H),
8.32 (d, J = 6.5 Hz, 2H), 8.26 (dd, 1H), 8.18 (dd, J = 8.4, 1.8
Hz, 2H), 8.06 (dd, 1H), 7.67 (dd, J = 8.6, 3.0 Hz, 1H), 5.12 – 4.97 (m,
1H), 4.01 – 3.92 (m, 2H), 3.73 – 3.60 (m, 4H), 3.21 (t, J = 5.3 Hz, 2H),
2.68 (s, 3H), 2.18 – 2.10 (m, 2H), 1.88 – 1.76 (m, 2H)。
类似地获得以下化合物:
4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-N-(2-羟基-乙基)-苯甲酰胺("A33")
得自N-(2-叔丁氧基-乙基)-4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酰胺;HPLC/MS: 1.90 min, [M+H] = 484;
1H NMR (500 MHz,
DMSO-d6)δ[ppm] 8.57 (1 H, m), 8.47 (1 H, m),
8.11 (1 H, d, J 8.5), 8.03 (1 H, d, J 8.5), 7.85 (1 H, s), 7.69 (1 H, d, J
5.1), 7.65 (1 H, d, J 9.0), 4.98 (1 H, tt, J 7.9, 3.8), 4.73 (1 H, t, J 5.6),
3.90 (1 H, m), 3.57 (2 H, m), 3.37 (1 H, q, J 6.0), 2.08 (1 H, m), 1.73 (1 H,
m);
5-{2-[4-(哌嗪-1-羰基)-苯基]-呋喃并[3,2-b]吡啶-7-基}-2-(四氢-吡喃-4-基氧基)-苯甲腈x TFA ("A34")
得自4-(4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-苯甲酰基)-哌嗪-1-甲酸叔丁基酯;HPLC/MS: 1.60 min, [M+H] = 509;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.89 (dd, J = 6.1, 4.1 Hz, 1H), 8.66 (d, 1H), 8.61 (dd, 1H),
8.28 (dd, J = 8.3, 2.6 Hz, 2H), 8.24 (dd, J = 6.1, 3.7 Hz, 1H),
8.03 (d, 1H), 7.75 (dd, J = 8.3, 2.0 Hz, 2H), 7.65 (dd, J = 8.1,
5.8 Hz, 1H), 5.08 – 4.93 (m, 1H), 4.02 – 3.56 (m, 8H), 3.27 (s, 4H), 2.21 –
2.05 (m, 2H), 1.87 – 1.77 (m, 2H);
5-{2-[3-甲氧基-4-(哌嗪-1-羰基)-苯基]-呋喃并[3,2-b]吡啶-7-基}-2-(四氢-吡喃-4-基氧基)-苯甲腈x TFA ("A35")
得自4-(4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-2-甲氧基-苯甲酰基)-哌嗪-1-甲酸叔丁基酯和三氟乙酸;HPLC/MS: 1.63 min, [M+H] = 539;
1H NMR (500 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.89 (1 H, d, J 6.3), 8.72 (1 H, d, J 2.4), 8.58 (1 H, dd, J 9.0,
2.4), 8.25 (1 H, d, J 6.4), 8.10 (1 H, s), 7.87 (2 H, d, J 5.1), 7.62 (1 H, d,
J 9.2), 7.55 (1 H, d), 5.02 (1 H, m), 4.06 (3 H, s), 3.97 (4 H, m), 3.64 (2 H,
m), 3.50 (2 H, m), 3.24 (4 H, m), 2.13 (2 H, m), 1.84 (2 H, m);
4-(4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-吡唑-1-基)-哌啶x TFA ("A36")
得自4-(4-{7-[3-氰基-4-(四氢-吡喃-4-基氧基)-苯基]-呋喃并[3,2-b]吡啶-2-基}-吡唑-1-基)-哌啶-1-甲酸叔丁基酯;HPLC/MS: 1.50 min, [M+H] = 470;
1H NMR (400 MHz,
DMSO-d6/TFA-d1)δ[ppm] 8.77 (1 H, d, J 6.4), 8.70 (1 H, s), 8.61 (1 H, d, J 2.4), 8.57 (1
H, dd, J 9.0, 2.4), 8.34 (1 H, s), 8.12 (1 H, d, J 6.5), 7.62 (1 H, d, J 9.2),
7.56 (1 H, s), 5.01 (1 H, tt, J 7.6, 3.7), 4.73 (1 H, m), 3.97 (2 H, m), 3.63
(2 H, ddd, J 11.6, 7.4, 3.3), 3.53 (2 H, d, J 13.0), 3.20 (2 H, td, J 13.0,
8.4), 2.33 (4 H, m), 2.13 (2 H, m), 1.83 (2 H, dtd, J 12.1, 8.1, 3.8)。
合成N-乙基-N-(2-甲氧基-乙基)-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)苯甲酰胺
步骤1:N-乙基-N-(2-甲氧基-乙基)-3-硼酸-2-基)-苯甲酰胺
使3-羧基苯基硼酸(500 mg, 3.01 mmol)和乙基-(2-甲氧基-乙基)-胺(373 mg, 3.62 mmol)溶于5 ml DMSO。将2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基尿鎓六氟磷酸盐甲铵(HATU) (1718
mg, 4.52 mmol)和N-甲基吗啉(457 mg, 4.52 mmol)加入到溶液中。将该混合物室温下搅拌2 h。真空浓缩后,产物经层析分离;得到700 mg N-乙基-N-(2-甲氧基-乙基)-3-硼酸-2-基)-苯甲酰胺;HPLC/MS: 1.394 min, [M+H] = 252。
类似地获得以下化合物:
3-甲氧基-4-(4-(叔丁氧基羰基)哌嗪-1-基)苯基硼酸
得自3-甲氧基-4-羧基苯基硼酸和1-哌嗪甲酸叔丁酯;HPLC/MS: 1.765
min, [M+H] = 365。
步骤2:N-乙基-N-(2-甲氧基-乙基)-3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)苯甲酰胺
使在200 ml无水甲苯中的3-[乙基-(2-甲氧基-乙基)-氨基甲酰基]-硼酸(700 mg, 2.79
mmol)、2,3-二甲基-丁烷-2,3-二醇(329 mg, 2.79
mmol)和48 mg甲苯-4-磺酸在迪安-斯塔克装置(Dean-Stark apparatus)中回流3。冷却至室温后,用碳酸氢盐水溶液洗涤该混合物。用Na2SO4干燥有机层后,过滤并真空除去溶剂,分离产物;得到880 mg N-乙基-N-(2-甲氧基-乙基)-3-(4,4,5,5-四甲基-[1,3,2]二氧杂-硼杂环戊烷-2-基)苯甲酰胺;HPLC/MS: 2.23 min, [M+H] = 334。
类似地获得以下化合物:
4-[2-甲氧基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯甲酰基]-哌嗪-1-甲酸叔丁基酯
得自3-甲氧基-4-(4-(叔丁氧基羰基)哌嗪-1-基)苯基硼酸和频哪醇;HPLC/MS: 2.46 min, [M+H] = 447;
1H NMR (400 MHz,
DMSO-d6)δ[ppm] 7.31 (1 H, dd, J 7.3, 0.8),
7.24 (1 H, s), 7.20 (1 H, d, J 7.3), 3.81 (3 H, s), 3.58 (2 H, m), 3.37 (2 H,
m), 3.25 (2 H, m), 3.07 (2 H, m), 1.40 (9 H, s), 1.31 (12 H, s)。
合成1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑
使4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑(19.4 g, 0.10 mol)、1-溴-2-甲氧基-乙烷(14.18 ml, 0.15 mol)和碳酸铯(32.58 g, 0.1 mol)溶于DMF (200 ml)。于80℃将悬浮液搅拌16 h,过滤并真空除去溶剂。残留物用叔丁基甲基醚(200 ml)处理,经硅藻土(Celite)过滤,然后真空除去溶剂;得到25.4 g 1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-1H-吡唑;HPLC/MS: 1.82
min, [M+H] = 253。
合成1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基]-哌嗪
步骤1:1-(3-溴-苯基)-4-甲基-哌嗪
将1-甲基-哌嗪(1 ml, 8.99 mmol)和1,3-二溴-苯(3 ml, 24.82
mmol)在密封管中,在微波照射下加热至200℃,经300 min (150 W, 9巴)。残留物用叔丁基甲基醚(50 ml)稀释并用1M HCl提取。用碳酸氢钠中和含水层,并用乙酸乙酯(150 ml)提取。分离有机层并经MgSO4干燥。过滤干燥剂并真空除去溶剂;得到700 mg 1-(3-溴-苯基)-4-甲基-哌嗪;HPLC/MS:
1.24 min, [M+H] = 255。
步骤2:1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼杂环戊烷-2-基)-苯基]-哌嗪
向在1,4二氧杂环己烷(100 ml)中的1-(3-溴-苯基)-4-甲基-哌嗪(0.7 g,
2.73 mmol)加入二(频哪醇酯合)二硼(1.04 g, 4.09 mmol)、KOAc (0.80 g, 8.19 mmol)和Pd(dppf)Cl2
(111 mg, 0.14 mmol)。将该混合物加热至90℃,经3 h,用水(100 ml)猝灭,接着用EtOAc提取。分离有机层, 用盐水洗涤并经Na2SO4干燥。过滤干燥剂并真空除去溶剂。经层析(DCM/EtOH)分离产物;得到198 mg 1-甲基-4-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂-硼杂环戊烷-2-基)-苯基]-哌嗪;HPLC/MS: 1.48 min, [M+H] =
303。
类似地获得以下化合物
依据本发明的化合物抑制TBK1和IKKε的IC50值
IC50:< 0.3 M = A 0.3- 3 M = B 3-50 M = C
以下实施例涉及药物:
实施例
A:
注射小瓶
用2 N盐酸将100 g的式I的活性成分和5g磷酸氢二钠在3l重蒸馏水中的溶液调节至pH 6.5,无菌过滤,转移至注射小瓶中,在无菌条件下冻干并在无菌条件下密封。每个注射小瓶含有5mg活性成分。
实施例
B:
栓剂
将20 g的式I的活性成分与100g大豆卵磷脂和1400g可可酯的混合物熔化,倾入模具中并使之冷却。每个栓剂含有20mg活性成分。
实施例
C
:溶液
由1 g式I的活性成分、9.38 g NaH2PO4∙2 H2O、28.48g Na2HPO4∙12
H2O和0.1 g苯扎氯铵在940ml重蒸馏水制备溶液。将pH调节至6.8,并使溶液补充至1 l并经辐照灭菌。这种溶液可用于滴眼剂形式。
实施例
D
:软膏剂
将500mg式I的活性成分与99.5g凡士林在无菌条件下混合。
实施例
E
:片剂
将1 kg式I的活性成分、4 kg乳糖、1.2 kg马铃薯淀粉、0.2 kg滑石粉和0.1 kg硬脂酸镁的混合物以常规方式压制,得到片剂,以这样一种方式得到的每一片剂含有10mg活性成分。
实施例
F
:糖衣丸
类似于实施例E压制片剂,随后用蔗糖、马铃薯淀粉、滑石粉、黄蓍胶和染料的包衣料以常规方式包衣。
实施例
G:
胶囊
将2 kg式I的活性成分以常规方式引入硬明胶胶囊,以这样一种方式获得的每粒胶囊含有20mg活性成分。
实施例
H
:安瓿
将1 kg式I的活性成分在60 l重蒸馏水中的溶液无菌过滤,转移至安瓿中,在无菌条件下冻干并在无菌条件下密封。每个安瓿含有10mg活性成分。
Claims (9)
1. 式I化合物
其中
X表示O或S,
R1表示O(CYY)nHet1、NY(CYY)nHet1、O(CYY)nCyc或NY(CYY)nCyc,
R2表示H、Hal、A、OY、NYY、O(CYY)mNYY、OiCYY^Het2、NY(CYY)mNYY、NY(CYY)nHet2、Ar或Het2,
Het1表示二氢吡咯基、吡咯烷基、四氢咪唑基、二氢吡唑基、四氢吡唑基、四氢吡喃基、二氢吡啶基、四氢吡啶基、哌啶基、吗啉基、六氢哒嗪基、六氢嘧啶基、[1,3]二氧杂环戊烷基、2-氧杂-6-氮杂-螺[3.3]庚烷基、氮杂环庚烷基、二氮杂环庚烷基、四氢呋喃基、呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、苯并二氢吡喃基或哌嗪基,其中的每一个为未取代的或被以下基团单取代或二取代:Hal、CN、A、COOA、OY、S(O)nA、S(O)nAr和/或=O (羰基氧),
Het2表示具有1-4个N、O和/或S原子的单环、二环或三环的饱和、不饱和或芳族杂环,其可为未取代的或被以下基团单取代、二取代、三取代、四取代或五取代:Hal、A、(CYY)p-OY、-(CYY)p-NYY、(CYY)p-Het1、NO2、CN、(CYY)p-COOY、CO-NYY、NY-COA、NY-SO2A、SO2-NYY、S(O)nA、-CO-Het1、O(CYY)p-NYY、-O(CYY)p-Het1、NH-COOA、NH-CO-NYY、NH-COO-(CYY)p-NYY、NH-COO-(CYY)p-Het1、NH-CO-NH-(CYY)p-NYY、NH-CO-NH(CYY)p-Het1、OCO-NH-(CYY)p-NYY、OCO-NH-(CYY)p-Het1、CHO、COA、=S、=NY和/或=O,Ar表示苯基、萘基或联苯基,其中的每一个为未取代的或被以下基团单取代、二取代或三取代:Hal、A、(CYY)p-OY、(CYY)p-NYY、(CYY)p-Het1、NO2、CN、(CYY)p-COOY、CO(CYY)pNH2、CO-NYA、CONY(CYY)mNYCOOA、NY-COA、NY-SO2A、SO2-NYY、S(O)nA、CO-Het1、O(CYY)p-NYY、O(CYY)p-Het1、NH-COOA、NH-CO-NYY、NH-COO-(CYY)p-NYY、NH-COO-(CYY)p-Het1、
NH-CO-NH-(CYY)p-NYY、NH-CO-NH(CYY)p-Het1、OCO-NH-(CYY)p-NYY、OCO-NH-(CYY)p-Het1、CHO、CONY(CYY)pHet1、CONH(CYY)pNHCOA和/或COA,
Y表示H或具有1、2、3或4个C原子的烷基,
A表示具有1-10个C原子的未分支或分支的烷基,其中1-7个H原子可以被F和/或Cl替代和/或其中一个或两个非相邻的CH和/或CH2基团可以被O和/或N替代,
Cyc表示具有3-7个C原子的环烷基,其为未取代的或被Hal、CN或A单取代,
Hal表示F、Cl、Br或I,
n表示0、1或2,
m表示1、2或3,
p表示0、1、2、3或4,
及其可药用盐、互变异构体和立体异构体,包括其所有比例的混合物。
2. 依据权利要求1的化合物,其中
Het2表示呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、三唑基、四唑基、噻二唑基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、2,3-二氢-1H-苯并咪唑基、吲唑基、喹啉基、1,3-苯并二氧杂环戊烯基、苯并噻吩基、苯并呋喃基或咪唑并吡啶基,其中的每一个为未取代的或被以下基团单取代或二取代:A、S(O)nA、(CYY)p-Het1和/或=O,
及其可药用盐、互变异构体和立体异构体,包括其所有比例的混合物。
3. 依据权利要求1或2的化合物,其中
Ar表示苯基,其为未取代的被以下基团单取代、二取代或三取代:(CYY)p-OY、(CYY)p-NYY、(CYY)p-Het1、(CYY)p-COOY、CO(CYY)pNH2、CO-NYA、CONY(CYY)mNYCOOA、CONY(CYY)pHet1、CONH(CYY)pNHCOA和/或CO-Het1,
及其可药用盐、互变异构体和立体异构体,包括其所有比例的混合物。
4. 依据权利要求1-3的任何一项或多项的化合物,其中
X表示O或S,
R1表示O(CYY)nHet1、NY(CYY)nHet1、O(CYY)nCyc或NY(CYY)nCyc,
R2表示Ar或Het2,
Het1表示二氢吡咯基、吡咯烷基、四氢咪唑基、二氢吡唑基、四氢吡唑基、四氢吡喃基、二氢吡啶基、四氢吡啶基、哌啶基、吗啉基、六氢哒嗪基、六氢嘧啶基、[1,3]二氧杂环戊烷基、2-氧杂-6-氮杂-螺[3.3]庚烷基、氮杂环庚烷基、二氮杂环庚烷基、四氢呋喃基、吡啶基、苯并二氢吡喃基或哌嗪基,其中的每一个为未取代的或被以下基团单取代或二取代:Hal、CN、A、COOA、OY、S(O)nA、S(O)nAr和/或=O (羰基氧),
Het2表示呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、吡啶基、嘧啶基、三唑基、四唑基、噻二唑基、哒嗪基、吡嗪基、吲哚基、异吲哚基、苯并咪唑基、2,3-二氢-1H-苯并咪唑基、吲唑基、喹啉基、1,3-苯并二氧杂环戊烯基、苯并噻吩基、苯并呋喃基或咪唑并吡啶基,其中的每一个为未取代的或被以下基团单取代或二取代:A、S(O)nA、(CYY)p-Het1和/或=O,
Ar表示苯基,其为未取代的被以下基团单取代、二取代或三取代:(CYY)p-OY、(CYY)p-NYY、(CYY)p-Het1、(CYY)p-COOY、CO(CYY)pNH2、CO-NYA、CONY(CYY)mNYCOOA、CONY(CYY)pHet1、CONH(CYY)pNHCOA和/或CO-Het1,
Y表示H或具有1、2、3或4个C原子的烷基,
A表示具有1-10个C原子的未分支或分支的烷基,其中1-7个H原子可以被F和/或Cl替代和/或其中一个或两个非相邻的CH和/或CH2基团可以被O和/或N替代,
Cyc表示具有3-7个C原子的环烷基,其为未取代的或被Hal、CN或A单取代,
Hal表示F、Cl、Br或I,
n表示0、1或2,
m表示1、2或3,
p表示0、1、2、3或4,
及其可药用盐、互变异构体和立体异构体,包括其所有比例的混合物。
5. 依据权利要求1的化合物,其选自
及其可药用盐、互变异构体和立体异构体,包括其所有比例的混合物。
6. 制备依据权利要求1-5的式I化合物及其可药用盐、互变异构体和立体异构体的方法,其特征在于
a) 使式II化合物
其中Q表示Cl、Br或I,
X和R2具有在权利要求1中指定的意义,
与式III化合物反应
R1-L III
其中R1具有在权利要求1中指定的意义,和
L表示硼酸或硼酸酯基团,
或
b) 通过将COOH基团转化为酰胺基团,使基团R2转化为另一个基团R2
和/或
将式I的碱或酸转化为其盐中的一种。
7. 药物,所述药物包含至少一种依据权利要求1-5的式I化合物和/或其可药用盐、互变异构体和立体异构体,包括其所有比例的混合物,和任选的赋形剂和/或辅助剂。
8. 依据权利要求1-5的化合物及其可药用盐、互变异构体和立体异构体,包括其所有比例的混合物,其用于治疗癌症、脓毒性休克、原发性开角型青光眼(POAG)、增生、类风湿性关节炎、银屑病、动脉粥样硬化、视网膜病、骨关节炎、子宫内膜异位、慢性炎症,和/或神经退行性疾病。
9. 依据权利要求1-5的式I化合物和/或其生理学上可接受的盐、互变异构体和立体异构体,其用于治疗肿瘤,其中将治疗有效量的式I化合物与选自以下的化合物联合给药:1) 雌激素受体调节剂, 2) 雄激素受体调节剂, 3) 类视黄醇受体调节剂, 4) 细胞毒性剂, 5) 抗增殖剂, 6) 异戊二烯基蛋白转移酶抑制剂, 7) HMG-CoA还原酶抑制剂,
8) HIV蛋白酶抑制剂, 9) 逆转录酶抑制剂和10) 其它的血管生成抑制剂。
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RS55388B1 (sr) | 2017-03-31 |
DK2812337T3 (en) | 2016-11-07 |
JP6138831B2 (ja) | 2017-05-31 |
CA2863985A1 (en) | 2013-08-15 |
KR20140120371A (ko) | 2014-10-13 |
EP2812337B1 (en) | 2016-09-07 |
SI2812337T1 (sl) | 2017-01-31 |
RU2622034C2 (ru) | 2017-06-09 |
MX2014009173A (es) | 2014-08-27 |
MX350112B (es) | 2017-08-28 |
LT2812337T (lt) | 2016-11-25 |
ES2606637T3 (es) | 2017-03-24 |
BR112014017762A8 (pt) | 2017-07-11 |
EP2812337A1 (en) | 2014-12-17 |
HRP20161578T1 (hr) | 2016-12-30 |
SG11201404630UA (en) | 2014-09-26 |
BR112014017762A2 (zh) | 2017-06-20 |
PL2812337T3 (pl) | 2017-01-31 |
RU2014136366A (ru) | 2016-03-27 |
ZA201406581B (en) | 2015-12-23 |
HUE032203T2 (en) | 2017-08-28 |
CN104093722B (zh) | 2016-07-27 |
CA2863985C (en) | 2020-08-11 |
AU2013218354B2 (en) | 2017-01-19 |
PT2812337T (pt) | 2016-12-14 |
JP2015510511A (ja) | 2015-04-09 |
US20150005284A1 (en) | 2015-01-01 |
US9045493B2 (en) | 2015-06-02 |
WO2013117285A1 (en) | 2013-08-15 |
AR089945A1 (es) | 2014-10-01 |
IL233981A (en) | 2016-09-29 |
HK1202550A1 (zh) | 2015-10-02 |
AU2013218354A1 (en) | 2014-09-25 |
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