CN103748086B - 吡啶和吡嗪衍生物 - Google Patents
吡啶和吡嗪衍生物 Download PDFInfo
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- CN103748086B CN103748086B CN201280025133.3A CN201280025133A CN103748086B CN 103748086 B CN103748086 B CN 103748086B CN 201280025133 A CN201280025133 A CN 201280025133A CN 103748086 B CN103748086 B CN 103748086B
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- Prior art keywords
- amino
- pyridin
- nicotinamide
- compound
- hplc
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Classifications
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Abstract
通式I所示的化合物,式中,R、R1和X具有权利要求1中所给的意义,所述化合物是TBK1和IKK的抑制剂,能够用于治疗癌症和炎症疾病。
Description
技术领域
本发明的目的是发现具有有价值的特性的新型化合物,尤其是可用于制备药物的化合物。
本发明涉及能够抑制一种或多种激酶的吡啶化合物。这些化合物可用于治疗多种疾病,包括癌症、败血性休克、原发性开角型青光眼(POAG)、增生、类风湿性关节炎、牛皮癣、动脉粥样硬化、视网膜病变、骨关节炎、子宫内膜异位、慢性炎症、和/或诸如阿尔兹海默症的神经退行性疾病。
本发明涉及化合物及其在激酶、尤其是受体酪氨酸激酶的信号传导的抑制、控制和/或调节中的用途,还涉及包括这些化合物的药物组合物,以及所述化合物在治疗激酶诱导的疾病中的用途。
发明背景
由于蛋白质激酶调节几乎每一种细胞过程,包括新陈代谢、细胞增殖、细胞分化、以及细胞存活,因此它们是对各种疾病状态进行治疗性介入的理想标靶。例如,蛋白质激酶在细胞循环控制和血管生成中起着关键作用,这两种细胞过程与很多疾病有关,例如但不限于癌症、炎性疾病、异常血管生成及其相关疾病、动脉粥样硬化、黄斑部退化、糖尿病、肥胖、以及疼痛。
本发明尤其涉及化合物及其用途,其中TBK1和IKKε的信号传导的抑制、控制和/或调节是有作用的。
实施细胞调节的基本机制之一是细胞外信号传导通过跨膜,该信号继而在细胞内调节生化过程。蛋白质磷酸化代表了细胞内信号在分子间传导的一种过程,其最终导致产生细胞反应。这些信号传导级联反应是高度调节的并经常重叠,这由许多蛋白质激酶以及磷酸酶的存在而得以证明。蛋白质的磷酸化主要发生在丝氨酸、苏氨酸或络氨酸残基上,因此蛋白质激酶按其磷酸化位点的特异性来分类,即丝氨酸/苏氨酸激酶和络氨酸激酶。由于磷酸化是细胞中普遍存在的过程,且细胞表型受通道活性的高度影响,因此目前相信许多疾病状态和/或疾病可归因于激酶级联反应的分子成份的异常活化或功能性变异。因此,这些能够调节其活性的蛋白质和化合物的表征获得了大量的关注(参见综述:Weinstein-Oppenheimer等Pharma.&.Therap.,2000,88,229-279)。
IKKε和TBK1是彼此以及与其他IkB激酶高度同源的丝氨酸/苏氨酸激酶。这两种激酶在先天免疫系统中具有重要作用。Toll样受体3和4以及RNA解旋酶RIG-I和MDA-5识别双链RNA病毒,导致TRIG-TBK1/IKKε-IRF3信号级联反应被激活,并导致I型干扰素反应。
2007年,Boehm等人将IKKε描述为一种新型乳腺癌致癌基因[J.S.Boehm等,Cell129,1065-1079,2007]。研究了354种激酶在与MAPK激酶Mek的活化形式联用时重现Ras转化表型的能力。其中,IKKε被确定为协同致癌基因。此外,作者还证明了IKKε在大量的乳腺癌细胞系和肿瘤样本中被扩增及过表达。通过乳腺癌细胞中的RNA干扰降低基因表达而诱导了细胞凋亡并阻碍其增殖。2005年Eddy等人获得了类似的研究结果,这凸显了IKKε在乳腺癌疾病中的重要性[S.F.Eddy等,CancerRes.2005;65(24),11375-11383]。
2006年首次报道了TBK1的促癌作用。在对包含251,000个cDNA的基因库的筛选中,Korherr等人准确地确定了作为促血管生成因子参与先天免疫防御的三种基因:TRIF、TBK1和IRF3[C.Korherr等,PNAS,103,4240-4245,2006]。2006年,Chien等人[Y.Chien等,Cell127,157-170,2006]报道了使用致癌性Ras仅能在有限的程度上转化TBK-/-细胞,这表明TBK1参与Ras介导的转化。此外,他们还证明了RNAi介导的TBK1的低水平触发MCF-7和Panc-1细胞的凋亡。Barbie等人最近报道了TBK1在许多具有变异K-Ras的癌细胞系中具有巨大重要性,这表明TBK1干预在相关肿瘤的治疗中具有重要性[D.A.Barbie等,NatureLetters1-5,2009]。
蛋白质激酶引起的疾病的特征是所述蛋白质激酶的异常活性或过度活性。异常活性涉及:(1)在通常不表达这些蛋白质激酶的细胞中的表达;(2)增强的激酶表达,其导致不良细胞增殖,例如癌症;或(3)增强的激酶活性,其导致诸如癌症的不良细胞增殖和/或相应蛋白质激酶的过度活性。过度活性涉及编码某种蛋白质激酶的基因的扩增,或者与细胞增殖疾病相关的活性水平的产生(即,所述细胞增殖疾病的一个或多个症状的严重程度随着激酶水平的升高而升高)。蛋白质激酶的生物利用率也可受到该激酶的一组结合蛋白质的存在与否影响。
IKKε和TBK1是高度同源的丝氨酸/苏氨酸激酶,其关键性地参与通过1型干扰素和其他细胞因子诱导的先天免疫反应。这些激酶响应病毒/细菌感染而被刺激。病毒及细菌感染的免疫响应涉及诸如细菌脂多糖(LPS)的抗原、病毒双链RNA(dsRNA)与Toll样受体的结合,以及随后TBK1途径的激活。被激活的TBK1和IKKε使IRF3和IRF7磷酸化,这触发这些干扰素调节转录因子发生二聚化和核转位,并最终诱导信号级联反应导致IFN产生。
最近,IKKε和TBK1也被证实与癌症有关。已证明IKKε与激活的MEK合作以转化人类细胞。此外,在乳腺癌细胞系和来自病人的肿瘤中IKKε经常被扩增/过表达。TBK1在缺氧条件下被诱导,在许多实体肿瘤中被以显著水平表达。
此外,需要TBK1以支持致癌性Ras转化,而被转化细胞中TBK1激酶活性升高,且其在培养物中的存活需要TBK1激酶活性。类似地,还发现了TBK1和NF-kB信号传导在KRAS变异肿瘤中极为重要。已将TBK1确定为致癌性KRAS的合成致死伴侣。
文献:
Y.-H.Ou等,MolecularCell41,458-470,2011;
D.A.Barbie等,Nature,1-5,2009.
因此,根据本发明的化合物或其药学上可接受的盐用于治疗包括实体肿瘤的癌症,例如,肿瘤(例如肺癌、胰腺癌、甲状腺癌、膀胱癌或结肠癌)、骨髓疾病(例如骨髓性白血病)或腺瘤(例如绒毛状结肠腺瘤)。
所述肿瘤还包括单核细胞性白血病、脑瘤、泌尿生殖系统肿瘤、淋巴系统肿瘤、胃癌、喉部及肺部肿瘤(包括肺腺癌和小细胞肺癌)、胰腺癌和/或乳腺癌。
所述化合物还可用于治疗HIV-1(1型人类免疫缺陷病毒)诱导的免疫缺陷。
癌样过度增殖疾病应理解为脑癌、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、头部肿瘤、颈部肿瘤、食道癌、妇科癌症、甲状腺癌、淋巴瘤、慢性白血病和急性白血病。具体是,癌样细胞生长是一种代表本发明的目标的疾病。因此,本发明涉及用作治疗和/或预防所述疾病的药物和/或药物活性成分的根据本发明的化合物、根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、以及用于治疗所述疾病的方法,所述方法包括向需要施用的病人施用根据本发明的一种或多种化合物。
可以显示本发明化合物在异种移植肿瘤模型中具有体内抗增殖作用。可将本发明化合物给予过度增殖疾病的患者,例如,抑制肿瘤生长,减轻与淋巴增殖疾病相关的炎症,抑制移植物被排斥或由于组织修复而致的神经损伤。本发明化合物适合预防或治疗目的。本文所用术语“治疗”指预防疾病和治疗已有疾病二者。在疾病明显发生之前给予本发明化合物可防止增殖/生长,例如防止肿瘤生长,防止转移瘤生长,减少心血管手术相关的再狭窄等。或者,用所述化合物治疗现有疾病,可稳定或改善患者的临床症状。
所述宿主或患者可属于哺乳动物,如灵长类动物,具体是人;啮齿动物,包括小鼠、大鼠和仓鼠;兔,马,牛,狗,猫等。供实验研究的感兴趣动物模型可提供治疗人类疾病的模型。
可用体外试验测定对用本发明化合物治疗具体细胞的敏感性。通常混合培育细胞培养物与各种浓度的本发明化合物足够时间,其时间使活性药物得以诱导细胞死亡或抑制其迁移,培养时间常介于1小时与1周之间。可用活检样品的培养细胞进行体外试验。然后计数治疗后存留的活细胞。
根据所用的具体化合物,具体的疾病,患者的状态等给药剂量有所不同。治疗剂量通常应足以降低靶组织中的不良细胞群同时维持患者生存。这种治疗一般持续进行直到相当程度减少了癌细胞负荷,例如至少减少50%,可持续治疗直到机体中基本上不再检测到不良细胞。
许多疾病与细胞增殖失调和细胞死亡(凋亡)相关。感兴趣的疾病包括但不限于以下所述。本发明的化合物适合治疗各种疾病,此类疾病中平滑肌细胞和/或炎症细胞增殖和/或迁移到血管内膜层中,导致通过血管例如阻塞病灶新生内膜血管的血流受限。感兴趣的移植物血管阻塞疾病包括:动脉粥样硬化、冠状血管移植后疾病、移植静脉狭窄、血管修复术吻合口周围再狭窄、血管成形术或支架安置术后再狭窄等等。
此外,使用根据本发明的化合物可在某些现有的癌症化学疗法和放射疗法中取得附加或增效作用,以及/或者恢复某些现有的癌症化学疗法和放射疗法的疗效。
“方法”一词指完成指定任务的方式、手段、技术和过程,包括但不限于化学、药学、生物学、生物化学和医学领域技术人员所知的方式、手段、技术和过程,以及所述领域技术人员由已知的方式、手段、技术和过程经过简单的修改而得到的方式、手段、技术和过程。
本说明书所用的“给药”一词指使本发明的化合物与标靶激酶接触的方法,所述接触的方式使得所述化合物能够直接(即,与所述激酶本身相互作用)或间接(即,与所述激酶的催化活性依赖的另一个分子相互作用)影响所述激酶的酶活性。本说明书中所述的给药可在体外(即,在试管中)进行,也可在体内(即,在细胞或活的生物体的组织中)进行。
在本说明书中,“治疗”一词包括消除、大致上抑制、减缓或逆转疾病或病症的发展,大致上减轻疾病或病症的临床症状,或者大致上预防疾病或病症的临床症状的出现。
在本说明书中,“预防”一词指从一开始就防止生物体得到疾病或病症的方法。
对本发明中使用的任何化合物,可首先从细胞培养试验估计治疗有效量,其在本说明书中也称为治疗有效剂量。例如,可在动物模型中制定剂量以获得包括在细胞培养物中确定的IC50或IC100的循环浓度范围。该信息可用于更准确地确定人体中的有效剂量。也可由体内数据估计起始剂量。采用这些起始指引,本领域技术人员就能够确定人体中的有效剂量。
此外,可通过细胞培养物或实验动物中的标准药学程序(例如,通过确定LD50和ED50)确定所述化合物的毒性和疗效。毒性和治疗有效性之间的剂量比为治疗指数,其可表示为LD50和ED50之间的比率。优选具有高治疗指数的化合物。由这些细胞培养试验和动物研究获得的数据可用于制定在人体中使用无毒性的剂量范围。优选地,所述化合物的剂量在包括毒性很小或没有毒性的ED50的循环浓度的范围内。根据采用的剂型和给药途径,所述剂量可在所述范围内变化。准确的配方、给药途径和剂量可由各医生根据患者的情况选择(例如,参见Fingl等人,1975,ThePharmacologicalBasisofTherapeutics第一章第一页)。
剂量和间隔可个别调整,以使活性化合物在血浆中的浓度足以维持疗效。一般患者口服给药的剂量范围为约50-2000毫克/千克/日,通常为约100-1000毫克/千克/日,优选为约150-700毫克/千克/日,最优选为250-500毫克/千克/日。
优选地,通过每日多次给药获得治疗上有效的血清浓度。在局部给药或选择性摄入的情况下,药物的有效局部浓度可与血浆浓度无关。本领域技术人员无需大量的实验就能够优化局部治疗有效剂量。
本说明书所描述的化合物优选用于预防、治疗和/或研究细胞增殖性疾病,尤其是癌症,例如但不限于:乳头状瘤,神经胶质瘤,卡波济氏肉瘤,黑色素瘤,肺癌,卵巢癌,前列腺癌,鳞状细胞癌,星形细胞瘤,头部肿瘤,颈部肿瘤,皮肤癌,肝癌,膀胱癌,乳腺癌,肺癌,子宫癌,前列腺癌,睾丸癌,结直肠癌,甲状腺癌,胰腺癌,胃癌,肝细胞癌,白血病,淋巴瘤,霍奇金病和伯基特氏病。
现有技术
WO2007/129044中描述了其他杂环衍生物及其作为抗肿瘤剂的用途。
WO2009/053737中描述了其他吡啶和吡嗪衍生物在治疗癌症中的用途,WO2004/055005描述了这些化合物在治疗其他疾病中的用途。
WO2009/122180中公开了作为IKKε抑制剂的其他杂环衍生物。
WO2010/100431中描述了作为IKKε和TBK1抑制剂的吡咯并嘧啶。
WO2009/030890中描述了作为IKKε和TBK1抑制剂的嘧啶衍生物。
发明内容
本发明涉及通式I所示的化合物,
式中,
X表示CH或N,
R表示Ar或Het,
R1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、哒嗪基、吲哚基、异吲哚基,苯并咪唑基、吲唑基、喹啉基、1,3-苯并二氧杂环戊二烯基、苯并噻吩基、苯并呋喃基,咪唑并吡啶基或呋喃并[3,2-b]吡啶基,上述每个基团是未取代的或者被Hal、A、OR5、CN、COOA、COOH、CON(R5)2和/或NR5COA'单取代或二取代,
Ar表示苯基、二苯基或萘基,上述每个基团是未取代的或者被Hal、A、Het1、(CH2)nOR5、(CH2)nN(R5)2、NO2、CN、(CH2)nCOOR5、CON(R5)2、CONH(CH2)qNHCOOA'、CON[R5(CH2)nHet1]、NR5COA、NHCOOA、NR5SO2A、COR5、SO2Het2、SO2N(R5)2和/或S(O)pA单取代、二取代或三取代,
Het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、哒嗪基、吡嗪基、吲哚基、异吲哚基,苯并咪唑基、吲唑基、喹啉基、1,3-苯并二氧杂环戊二烯基、苯并噻吩基、苯并呋喃基或咪唑并吡啶基,上述每个基团是未取代的或者被A、COA、(CH2)pHet2、OH、OA、Hal、(CH2)pN(R5)2、NO2、CN、(CH2)pCOOR5、(CH2)pCON(R5)2、NR5COA、(CH2)pCOHet2和/或(CH2)p苯基单取代、二取代或三取代,
Het1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、哒嗪基、吡嗪基,上述每个基团是未取代的或者被A、OH、OA、Hal、CN和/或(CH2)pCOOR5单取代、二取代或三取代,
Het2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、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、哌嗪基,上述每个基团是未取代的或者被OH和/或A单取代,
A'表示含有1-6个碳原子的直链或支链烷基,其中1-7个氢原子可被F取代,
A表示含有1-10个碳原子的直链或支链的烷基,其中一个或两个非相邻CH和/或CH2基团可被氮、氧、硫原子和/或被–CH=CH基团所取代,和/或其中1-7个氢原子可被F取代,
R5表示H或含有1-6个碳原子的直链或支链烷基,其中1-7个氢原子可被F取代,
Hal表示F、Cl、Br或I,
n表示0、1、2、3或4,
p表示0、1或2,
q表示1、2、3或4,
及其药学上可用的盐、互变异构体和立体异构体,包括其所有比例的混合物。
本发明还涉及这些化合物的光学活性形通式(立体异构体)、盐、对映异构体、外消旋体、非对映异构体以及水合物和溶剂化物。术语“化合物的溶剂化物”用来表示这些化合物与惰性溶剂分子由于彼此引力作用而形成的加合物。溶剂化物是,例如,单水合物或双水合物或醇化物。当然,本发明还涉及盐的溶剂化物。
术语“药学上可用的衍生物”用来表示,例如,本发明的化合物的盐类和所谓的前体药物化合物。
术语“前体药物衍生物”用来表示用例如烷基或酰基、糖或寡肽修饰的通式I化合物,它们在机体内迅速裂解形成活性形式通式的化合物。
其中也包括可生物降解的本发明化合物的聚合衍生物,例如见Int.J.Pharm.115,61-67(1995)中所述。
用语“有效量”表示可引起组织、系统、动物或人体产生一种例如研究人员或医生所寻求或期望的生物学或医学反应的药物或药物活性成分的量。
此外,用语“治疗有效量”表示与未接受此量的相应患者相比,该量产生如下结果:
治疗改善,治愈,预防或消除疾病、综合征、疾病状况、患者主诉、病变或副作用或也减缓疾病、主诉或病变的进程。
用语“治疗有效量”也涵盖了对增进正常生理功能有效的量。
本发明也涉及式I化合物的混合物的用途,例如两种非对映体的混合物,例如混合比例为1:1,1:2,1:3,1:4,1:5,1:10,1:100或1:1000。
这些混合物特别优选立体异构体化合物的混合物。
本发明还涉及通式I所示的化合物及其盐,以及一种制备方法,用于制备如权利要求1-12所述的通式I所示的化合物及其药学上可用的盐、互变异构体和立体异构体,包括其所有比例的混合物,所述方法的特征在于,
a)通式II所示的化合物,
式中,Y表示Br或I,X和R1具有权利要求1中所给的意义,
与通式III所示的化合物反应,
R-LIII
式中,R具有权利要求1中所给的意义,L表示硼酸或硼酸酯基团,
或者,
b)通式IV所示的化合物,
式中,R和X具有权利要求1中所给的意义,L1表示Cl、Br、I或者游离OH基团或具有反应活性的功能修饰OH基团,
与通式V所示的化合物反应,
R1-NH2V
式中,R1具有权利要求1中所给的意义,
或者,
c)通过用溶剂分解剂或氢解剂处理其官能团衍生物中之一,从而释放出所述化合物,
和/或将通式I所示的碱或酸转化成它的一种盐。
在上下文中,基团或参数R1、R和X具有与通式I下标明的意义相同的定义,除非另有明确规定。
A表示烷基,是非支链(直链)或支链的,且含有1、2、3、4、5、6、7、8、9或10个碳原子。A较佳为表示甲基,还可以是乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,也可以是戊基、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,更优选地为例如三氟甲基。
特别优选的是,A表示含有1、2、3、4、5或6个碳原子的烷基,优选自甲基、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中的一或两个CH和/或CH2基团还可以被氮、氧或硫原子和/或被-CH=CH-基团取代。因此A也表示例如2-甲氧基乙基。
更特别优选的是,A表示含有1-8个碳原子的烷基,其中一个或两个非相邻CH和/或CH2可被氮和/或氧原子所取代,和/或其中1-7个氢原子可被F取代。
A'表示烷基,是非支链(直链)或支链的,且含有1、2、3、4、5或6个碳原子。A'较佳为表示甲基,还可以是乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,也可以是戊基、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,更优选地为例如三氟甲基。
优选的是,A'表示含有1、2、3或4个碳原子的烷基,优选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基或1,1,1-三氟甲基。
Ar表示例如苯基,邻、间、对位-甲苯基,邻、间、对位-乙苯基,邻、间、对位-丙苯基,邻、间、对位-异丙苯基,邻、间、对位-叔丁苯基,邻、间、对位-三氟甲苯基,邻、间、对位-氟代苯基,邻、间、对位-溴代苯基,邻、间、对位-氯代苯基,邻、间、对位-羟基苯基,邻、间、对位-甲氧基苯基,邻、间、对位-甲基磺酰基苯基,邻、间、对位-硝基苯基,邻、间、对位-氨基苯基,邻、间、对位-甲基氨基苯基,邻、间、对位-二甲基氨基苯基,邻、间、对位-氨基磺酰基苯基,邻、间、对位-甲基氨基磺酰基苯基,邻、间、对位-氨基羰基苯基,邻、间、对位-羧苯基,邻、间、对位-甲氧基羰基苯基,邻、间、对位-乙氧基羰基苯基,邻、间、对位-乙酰基苯基,邻、间、对位-甲酰基苯基,邻、间、对位-氰基苯基,还优选2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二氟代苯基,2,3-,2,4-,2,5-,2,6-,3,4-或3,5-二氯代苯基,2,4-,2,5-,2,6-,3,4-或3,5-二溴代苯基,2,3,4-,2,3,5-,2,3,6-,2,4,6-或3,4,5-三氯苯基,对位碘代苯基,4-氟-3-氯代苯基,2-氟-4-溴苯基,2,5-二氟-4-溴苯基或2,5-二甲基-4-氯代苯基。
特别优选的是,Ar表示苯基、二苯基或萘基,上述每个基团是未取代的或者被A、Hal、Het1、COR5、CON(R5)2、CONH(CH2)qNHCOOA'、CON[R5(CH2)nHet1]、NHCOOA、(CH2)nN(R5)2、(CH2)nOR5、(CH2)nCOOR5、SO2Het2和/或SO2N(R5)2单取代、二取代或三取代。
Het优选地表示噻吩基、吡唑基、吡啶基,上述每个基团是未取代的或者被A、(CH2)pHet2、(CH2)pCON(R5)2和/或(CH2)p苯基单取代或二取代。
Het1优选地表示吡唑基或咪唑基,上述每个基团是未取代的或者被A单取代。
Het2优选地表示吡咯烷基、哌啶基、吗啉基、[1,3]二氧杂环戊烷基、哌嗪基,上述每个基团是未取代的或者被OH和/或A单取代。
R1优选地表示吡啶基,嘧啶基,哒嗪基或呋喃并[3,2-b]吡啶基,上述每个基团是未取代的或者被Hal,A,OR5,COOA,COOH,CON(R5)2和/或NR5COA'单取代。
R5优选地表示H、含有1、2、3或4个碳原子的烷基,更优选的是H、甲基、乙基、丙基,异丙基、丁基、异丁基、仲丁基、叔丁基或三氟甲基。
Hal优选地表示F、Cl或Br,但也可以是I,特别优选是F或Cl。
在整个本发明中,对于所有不止出现一次的基团和标志符,可以是同样的或不同的,即它们是相互独立的。
通式I所示的化合物可以有一个或多个手性中心,因此可以不同的立体异构体形式出现。通式I涵盖了所有这些形式。
因此,本发明特别涉及的是通式I的化合物,其中至少一个上述基团具有如上所示的优选意义。化合物的某些优选基团可用以下子结构式Ia到Ig表示,它们符合通式I,并且在没有指定更详细的含义时这些基团具有如通式I下所指定的意义,但是在
Ia中R1表示吡啶基、嘧啶基、哒嗪基或呋喃并[3,2-b]吡啶基,上述每个基团是未取代的或者被Hal、A、OR5、COOA、COOH、CON(R5)2和/或NR5COA'单取代;
Ib中Ar表示苯基、二苯基或萘基,上述每个基团是未取代的或者被A、Hal、Het1、COR5、CON(R5)2、CONH(CH2)qNHCOOA'、CON[R5(CH2)nHet1]、NHCOOA、(CH2)nN(R5)2、(CH2)nOR5、(CH2)nCOOR5、SO2Het2和/或SO2N(R5)2单取代、二取代或三取代;
Ic中Het表示噻吩基、吡唑基、吡啶基,上述每个基团是未取代的或者被A、(CH2)pHet2、(CH2)pCON(R5)2和/或(CH2)p苯基单取代或二取代;
Id中Het1表示吡唑基或咪唑基,上述每个基团是未取代的或者被A单取代;
Ie中Het2表示吡咯烷基、哌啶基、吗啉基、[1,3]二氧杂环戊烷基、哌嗪基,上述每个基团是未取代的或者被OH和/或A单取代;
If中A表示含有1-6个碳原子的直链或支链的烷基,其中一个或两个非相邻CH和/或CH2可被氮和/或氧原子所取代,和/或其中1-7个氢原子可被F取代;
Ig中X表示CH或N,
R表示Ar或Het,
R1表示吡啶基、嘧啶基、哒嗪基或呋喃并[3,2-b]吡啶基,上述每个基团是未取代的或者被Hal、A、OR5、COOA、COOH、CON(R5)2和/或NR5COA'单取代,
Ar表示苯基、二苯基或萘基,上述每个基团是未取代的或者被A、Hal、Het1、COR5、CON(R5)2、CONH(CH2)qNHCOOA'、CON[R5(CH2)nHet1]、NHCOOA、(CH2)nN(R5)2、(CH2)nOR5、(CH2)nCOOR5、SO2Het2和/或SO2N(R5)2单取代、二取代或三取代,
Het表示噻吩基、吡唑基、吡啶基,上述每个基团是未取代的或者被A、(CH2)pHet2、(CH2)pCON(R5)2和/或(CH2)p苯基单取代或二取代,
Het1表示吡唑基或咪唑基,上述每个基团是未取代的或者被A单取代,
Het2表示吡咯烷基、哌啶基、吗啉基、[1,3]二氧杂环戊烷基、哌嗪基,上述每个基团是未取代的或者被OH和/或A单取代,
A'表示含有1-6个碳原子的直链或支链烷基,其中1-7个氢原子可被F取代,
A表示含有1-6个碳原子的直链或支链的烷基,其中一个或两个非相邻CH和/或CH2可被氮和/或氧原子所取代,和/或其中1-7个氢原子可被F取代,
R5表示H或含有1-6个碳原子的直链或支链烷基,其中1-7个氢原子可被F取代,
Hal表示F、Cl、Br或I,
n表示0、1、2、3或4,
p表示0、1或2,
q表示1、2、3或4,
及其药学上可用的盐、互变异构体和立体异构体,包括其所有比例的混合物。
通式I化合物及其合成用的起始原料,按照文献所述,由已知的方法(例如标准的著作,如Houben-Weyl,MethodenderorganischenChemie[有机化学方法],Georg-Thieme-Verlag,斯图加特),在已知的并适合上述反应的反应条件下进行制备。
也可以使用本身已知但在本说明书中没有更详细提及的变体。
也可以将通式II化合物与通式III化合物反应来制备通式I所示的化合物。
通式II与通式III所示的化合物通常是已知的。如果是新颖的,那么也可以由本身已知的方法制备。
在本领域技述人员所公知的Suzuki反应的标准条件下进行反应。
通式III的化合物中,L优选地表示
根据采取的反应条件,反应时间一般为几分钟至14天之间,反应温度在-30℃和140℃之间,通常为0℃和110℃之间,优选约60℃和约110℃之间。
合适的惰性溶剂的例子有:烃类,如正己烷、石油醚、苯、甲苯或二甲苯;氯代烃,如三氯乙烯、1,2-二氯乙烷、四氯甲烷、氯仿或二氯甲烷;醇类,如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚类,如乙醚、异丙醚、四氢呋喃(THF)或二氧六环;乙二醇醚,如乙二醇单甲醚或单乙醚或乙二醇二甲醚(diglyme);酮,如丙酮或丁酮;酰胺,如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈,如乙腈;亚砜,如二甲基亚砜(DMSO);二硫化碳;羧酸,如甲酸或乙酸;硝基化合物,如硝基甲烷或硝基苯;酯类,如乙酸乙酯,或上述溶剂的混合物。
特别优选的是乙醇、甲苯、乙氧基乙烷、乙腈、二氯甲烷、DMF和/或水。
也可以将通式IV化合物与通式V化合物反应来制备通式I所示的化合物。
通式IV与通式V所示的化合物通常是已知的。如果是新颖的,那么也可以由本身已知的方法制备。
在通式IV的化合物中,L1优选地表示Cl、Br、I或者游离的OH基团或具有反应活性的修饰OH基团,例如活化酯、咪唑(imidazolide)或含有1-6个碳原子的烷基磺酰基氧基(优选为甲基-磺酰基氧基或三氟甲基磺酰基氧基)或含有6-10个碳原子的芳基磺酰基氧基(优选为苯基-或对甲苯基磺酰基氧基)。
通常,在酸结合剂存在下进行反应,酸结合剂优选是有机碱例如DIPEA、三乙胺、二甲基苯胺、吡啶或喹啉。
有利的是碱金属或碱土金属氢氧化物、碳酸盐或碳酸氢盐或者碱金属或碱土金属的弱酸的另一种盐,优选是钾、钠、钙或铯。
根据采取的反应条件,反应时间一般为几分钟至14天之间,反应温度在-30℃和140℃之间,通常为-10℃和90℃之间,优选约0℃和约70℃之间。
合适的惰性溶剂的例子有烃类,如正己烷、石油醚、苯、甲苯或二甲苯;氯代烃,如三氯乙烯、1,2-二氯乙烷、四氯甲烷、三氟甲苯、氯仿或DCM;醇类,如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚,如乙醚、异丙醚、四氢呋喃(THF)或二氧六环;乙二醇醚,如乙二醇单甲醚、乙二醇单乙醚或乙二醇二甲醚(diglyme);酮,如丙酮或丁酮;酰胺,如乙酰胺、二甲基乙酰胺、N-甲基吡咯烷酮(NMP)或二甲基甲酰胺(DMF);腈,如乙腈;亚砜,如二甲基亚砜(DMSO);二硫化碳;羧酸,如甲酸和乙酸;硝基化合物,如硝基甲烷或硝基苯;酯类,如乙酸乙酯,或上述溶剂的混合溶剂。
特别优选的是乙腈、二氯甲烷和/或DMF。
可以采用本领域技术人员已知的方法进行酯的裂解。
酯(例如甲酯)裂解的标准方法是使用三溴化硼。
能用氢解去除的基团(如苄酯的裂解)可以在催化剂(例如贵金属催化剂,如钯,最好固定在如碳一类的载体上)存在下通过与氢气作用被裂解。此处合适的溶剂如上所示,特别是例如醇,如甲醇或乙醇,或酰胺,如DMF。氢解一般在约0到100℃之间的温度下和约1至200巴之间的压力下进行,优选的是20-30℃和1-10巴。
酯可以皂化,例如,使用乙酸或使用NaOH或KOH在水、水/THF或水/二氧六环中,在0到100℃之间的温度下反应。
在如本领域技术人员所知的标准条件下对氮进行烷基化。
通式I化合物还可以通过从它们的一种官能团衍生物与溶媒分解剂或氢解剂作用释放通式I化合物而得到。
优选的溶剂解或氢解的起始原料是含有相应的保护氨基和/或羟基,而不是含一个或多个游离氨基和/或羟基的化合物。优选那些带有氨基保护基而不是H原子连接在N原子上的化合物,例如符合通式I,但带有NHR’基团(其中R’是指氨基保护基,如BOC或CBZ),而不是NH2基团。
优选的起始原料含有羟基保护基团,而不是羟基的氢原子,例如符合通式I,但带有R”O-苯基基团(其中R”是指羟基保护基),而不是羟基苯基。
也有可能起始原料分子中存在大量的-相同或不同的-保护氨基和/或羟基。如果存在的保护基团是彼此不同的,在多数情况下它们可以被选择性裂解去除。
术语“氨基保护基”是通用术语,指的是适用于保护(阻止)氨基发生化学反应的基团,但它在分子其他部位需要进行的化学反应结束后容易被脱除。这些基团的典型代表有未取代的或取代的酰基、芳基、芳烷氧基甲基或芳烷基。由于氨基保护基在所需反应(或反应序列)之后会被移除,它们的类型和大小都不是太重要的,但是,优先考虑的还是那些有1-20个,尤其是1-8个碳原子的基团。术语“酰基”是与本方法有关的最广义的理解。它包括来自脂肪族的、芳基脂肪族的、芳香族的或杂环的羧酸或磺酸的酰基,并且特别是烷氧羰基、芳氧羰基和芳烷氧羰基。这样的酰基的例子有烷酰基,如乙酰基、丙酰基和丁酰基;芳烷酰基,如苯乙酰基;芳酰基,如苯甲酰基和甲苯基;芳氧烷酰基,如POA;烷氧羰基,如甲氧羰基、乙氧羰基、2,2,2-三氯乙氧羰基、BOC(叔丁氧羰基)和2-碘乙氧羰基;芳烷氧羰基,如CBZ(“苄氧羰基”)、4-甲氧基苄氧基羰基和FMOC;和芳磺酰基,如Mtr。优选的氨基保护基是BOC和Mtr,还可以是CBZ、Fmoc、苄基和乙酰基。
术语“羟基保护基”也同样是通用术语,指的是适用于保护羟基不发生化学反应的基团,它在分子其他部位需要进行的化学反应结束后容易被脱除。这些基团的典型代表有上面提到的未取代的或取代的芳基、芳烷基或酰基,还可以是烷基。羟基保护基的类型和大小并不是太重要,因为它们在所需的化学反应或反应序列之后会被移除,优先考虑的是有1-20个,尤其是1-10个碳原子的基团。羟基保护基的例子有,特别是叔丁氧基羰基、苄基、对硝基苯甲酰基、对甲苯磺酰基、叔丁基和乙酰基,其中苄基和叔丁基特别优选。天冬氨酸和谷氨酸中的COOH基团优选地以它们的叔丁酯形式受到保护(例如Asp(OBut))。
通式I化合物由它们的官能团衍生物释放得到-根据所使用的保护基-例如使用强酸,最好是用TFA或高氯酸,也可使用强无机酸,如盐酸或硫酸,强有机羧酸,如三氯乙酸或磺酸如苯磺酸或对甲苯磺酸。额外的惰性溶剂的存在是可能的,但并非总是必要的。合适的惰性溶剂较佳为有机溶剂,例如羧酸如醋酸,醚类如THF或二氧六环,酰胺如DMF,卤代烃如DCM,也可以是醇,如甲醇、乙醇或异丙醇,以及水。此外上述溶剂的混合物也是适用的。TFA以过量使用为佳,不需要进一步加入溶剂,而高氯酸最好是以乙酸与70%高氯酸按9:1的比例混合的形通式使用。裂解反应的温度最好控制在月0至约50℃之间,优选15至30℃之间(室温)。
例如,BOC、OBut、Pbf、Pmc和Mtr基团,最好使用TFA在DCM溶液中或使用大约3-5NHCl在二噁烷中于15-30℃裂解,而FMOC基团可以使用大约5-50%二甲胺、二乙胺或哌啶在DMF中的溶液于15-30℃裂解。
能用氢解去除的保护基(如CBZ或苄基)可以在催化剂(例如贵金属催化剂,如钯,最好固定在如碳一类的载体上)存在下通过与氢气作用被裂解。此处合适的溶剂如上所示,特别是例如醇,如甲醇或乙醇,或酰胺,如DMF。氢解一般在约0到100℃之间的温度下和约1至200巴之间的压力下进行,优选的是20-30℃和1-10巴。CBZ基团的氢解很容易成功,例如,用5至10%Pd/C在甲醇中,或用甲酸铵(而不是氢气)在Pd/C上、甲醇/DMF中、于20-30℃反应。
药用盐类和其他形式
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,本发明还涉及这些化合物以其药学上可接受的盐的形式使用,可以采用本技术领域的专业人员已知的程序,从各种有机和无机的酸和碱衍生而来。通式I化合物的药学上可接受的盐形式,绝大部分是用传统方法合成的。如果通式I化合物含有羧基,其合适的盐之一可以通过此化合物与合适的碱反应而生成相应的碱加成盐。这样的碱包括,如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钠或乙醇钾和丙醇钠或丙醇钾;以及各种有机碱,如哌啶、二乙醇胺和N–甲基谷氨酰胺。通式I所示化合物的铝盐也同样包括在内。对于通式I中包含碱性中心的某些化合物的情况,可以将这些化合物与药学上可接受的有机酸和无机酸作用形成它们的酸加成盐,例如卤化氢,如氯化氢、溴化氢或碘化氢;其他矿物酸及其相应的盐,如硫酸盐、硝酸盐和磷酸盐等;和烷基-和单芳基-磺酸,如乙基磺酸、对甲苯磺酸和苯磺酸,以及其他有机酸及其相应的盐,如醋酸盐、三氟醋酸盐、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,通式I化合物药学上可接受的酸加成盐包括以下盐:醋酸盐、己二酸盐、藻酸盐、精氨酸盐、天门冬氨酸盐、苯甲酸盐、苯磺酸盐(besylate)、硫酸氢盐、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、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、葡萄糖酸盐、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、粘液酸盐(从粘液酸制得)、半乳糖醛酸盐、葡庚糖酸盐、葡萄糖酸盐、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–羟基乙磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖酸钠、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、palmoate、果胶酸盐、过硫酸盐、苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但这并不代表仅限于此。
此外,本发明的化合物的碱式盐包括铝盐、铵盐、钙盐、铜盐、铁(III)盐、亚铁(Ⅱ)盐、锂盐、镁盐、锰(III)盐、亚锰(II)盐、钾盐、钠盐和锌盐,但这并不代表仅限于此。在上述盐中,优先考虑铵盐,碱金属盐钠盐和钾盐,和碱土金属盐钙盐和镁盐。通式I所示化合物与药学上可接受的无毒有机碱形成的盐包括下列胺的盐,即伯、仲和叔胺、取代胺,也包括自然存在的取代胺、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、二乙基胺、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、葡萄糖胺、组氨酸、哈胺、异丙胺、利多卡因、赖氨酸、葡甲胺、N-甲基-D-葡萄糖胺、吗啉、哌嗪、哌啶、聚酰胺树脂、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)甲胺(氨丁三醇),但这并不代表仅限于此。
含有碱性氮基团的本发明化合物,可以使用诸如(C1-C4)卤代烃的试剂进行季铵化,例如甲基、乙基、异丙基和叔丁基氯化物、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)卤代烃,例如癸烷基、十二烷基、月桂基、十四烷基和十八烷基氯化物、溴化物和碘化物;以及芳基-(C1-C4)烷基卤化物,例如氯化苄和苯乙基溴。这些盐类化合物可以用来制备水溶性和油溶性的本发明化合物。
上述较优选的药用盐类包括醋酸盐、三氟醋酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、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、葡甲胺盐、硝酸盐、油酸盐、膦酸盐、特戊酸盐、磷酸钠盐、硬脂酸盐、硫酸盐、磺酰基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨丁三醇,但这并不代表仅限于此。
通式I所示碱性化合物的酸加成盐,通过将游离碱的形式与足够量的所需酸混合接触的方法制备,使按照常规方式生成相应的盐类。这种游离碱是可以再生的,通过使盐类形式与碱接触,用常规方式分离游离碱。这种游离碱的形式在某种意义上与其相应的盐形式在某些物理特性上是不同的,如在极性溶剂中的溶解性;但是,出于本发明的目的,这些盐类在另一方面也对应于其各自的游离碱形式。
如上所述,通式I化合物的药学上可接受的碱加成盐,通过与金属或胺的反应生成,如碱金属和碱土金属或有机胺。优选的金属是钠、钾、镁和钙。优选的有机胺为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-葡萄糖胺和普鲁卡因。
本发明的酸性化合物的碱加成盐,通过将游离酸的形式与足够量的所需碱混合接触的方法制备,使按照常规方式生成相应的盐类。这种游离酸是可以再生的,通过使盐类形式与酸接触,用常规方式分离游离酸。这种游离酸的形式在某种意义上与其相应的盐形式在某些物理特性上是不同的,如在极性溶剂中的溶解性;但是,出于本发明的目的,这些盐类在另一方面也对应于其各自的游离酸形式。
如果某个本发明化合物上含有不止一个可以形成这种类型药学上可接受盐的基团,本发明也包括复盐。典型的复盐的形式包括,例如,二酒石酸盐、二醋酸盐、二富马酸盐,二葡甲胺盐、二磷酸盐、二钠盐和三盐酸盐,但这并不代表仅限于此。
根据上面所述可以看出,术语“药学上可接受的盐”一词在本说明书前后关联中是指一种活性成分,包括以盐形式之一存在的通式I化合物,特别是如果这种盐的形式赋予了活性成分较其游离形式或任何前面使用的活性成分的其他盐形式更为改善的药代动力学特性。该活性成分的药学上可接受的盐的形式也可以是首次给活性成分提供这种理想的药代动力学性质,这种性质是它以前所没有的,并对于其体内疗效来说,它甚至可以对该活性成分的药效学产生积极的影响。
同位素
具有通式I的化合物还应包括其同位素标记形式。具有通式I的化合物的同位素标记形式与所述化合物的区别仅在于所述化合物的一个或多个原子被原子量或质量数与通常是天然存在的原子的原子量或质量数不同的一个或多个原子取代。市场上容易买到且可通过已知方法被结合到具有通式I的化合物中的同位素的例子包括氢、碳、氮、氧、磷、氟和氯,例如分别为2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F和36CI。含有一或多个上述同位素和/或其他原子的同位素的通式I化合物、其前药或它们中任一个的药学上可接受的盐都应理解为本发明的一部分。可以多种有利的方式使用同位素标记的通式I化合物。例如,结合了诸如3H或14C的放射性同位素的同位素标记的通式1化合物可用于药物和/或底物组织分布试验。由于其制备简单及可检测性良好而尤其优选这两种放射性同位素,即氚(3H)和碳-14(14C)。由于诸如氘(2H)的较重的同位素具有较高的代谢稳定性,将这种同位素标记化合物结合到通式I化合物中在治疗上是有好处的。较高的代谢稳定性直接导致体内半衰期延长或剂量减少,这在多数情况下代表了本发明的优选实施例。通常可通过进行本文本的实施例部分和制备部分中的合成方案和相关描述中公开的步骤来制备同位素标记的通式I化合物,用容易得到的同位素标记反应物代替非同位素标记反应物。
为了通过一级动力学同位素效应控制化合物的氧化代谢,可将氘(2H)结合到所述化合物中。一级动力学同位素效应是由于同位素核的替换而导致化学反应速率发生变化,这是由于所述同位素替换之后形成共价键所需的基态能量的变化而引起的。较重的同位素的替换通常导致化学键的基态能量降低,从而引起速率限制的键断裂反应的速率降低。如果键断裂发生在沿着多产物反应的坐标的鞍点区中或其附近,产物分布比率可被显著改变。解释如下:如果氘被键合到碳原子的非可替换位置上,通常速率差异km/kd=2-7。如果该速率差异被成功地应用于易于氧化的通式I化合物,则该化合物在体内的性质可被显著地改变,从而改善药物动力学特性。
在发现和开发治疗剂时,本领域技术人员尝试在保持有利的体外特性的同时优化药物动力学参数。可以合理地认为,许多药物动力学性质差的化合物易于被氧化代谢。现有的体外肝微粒体试验提供了关于这种类型的氧化代谢过程的有价值的信息,这些信息使得可以合理地设计具有通式I的含氘化合物,使其由于抗氧化代谢而提高稳定性。因此,通式I化合物的药物动力学性质显著地改善了,这种改善可用体内半衰期(t/2)的延长、疗效最好的浓度(Cmax)、剂量响应曲线下的面积(AUC)以及F来定量地表示,也可用降低的清除率、剂量和材料成本来定量地表示。
以下阐述用于说明上述内容:把通式I化合物制备成一系列类似物,其中所述通式I化合物具有多个氧化代谢可能攻击的位点,例如苯甲基氢原子和与氮原子键合的氢原子,在所述类似物中各种组合的氢原子被氘原子取代,因此所述氢原子中的一部分、大多数或全部被氘原子取代。半衰期的确定使得可以有利地及准确地确定对氧化代谢的抵抗能力提高的程度。通过这种方式确定了,由于这种类型的氘-氢替换,母化合物的半衰期可被提高高达100%。
通式I化合物中的氘-氢替换也可被用来有利地改变起始化合物的代谢物谱,以减少或消除不良有毒代谢物。例如,如果通过氧化性碳-氢(C-H)键断裂产生了有毒代谢物,可以合理地认为,含氘类似物将会显著地减少或消除不良代谢物的产生,即使该具体的氧化反应并不是速率决定步骤。更多现有技术中关于氘-氢替换的信息可参见例如Hanzlik等,J.Org.Chem.55,3992-3997,1990,Reider等,J.Org.Chem.52,3326-3334,1987,Foster,Adv.DrugRes.14,1-40,1985,Gilletteetal,Biochemistry33(10)2927-2937,1994,andJarman等Carcinogenesis16(4),683-688,1993。
本发明还涉及药物,所述药物包含至少一种通式I化合物和/或其药学上可使用的盐、互变异构体和立体异构体,包括它们的各种比例的混合物,并任选地包含赋形剂和/或佐剂。
药物制剂可以剂量单位的形式给药,剂量单位由每单位剂量的活性成分的预设量组成。根据所治疗的病情、给药方式和病人年龄、体重和身体状况的差别,这样一个单位包括的本发明化合物的量可以是,例如,0.5mg到1g,优选是1mg至700mg,尤其是优选5mg至100mg,或者药物制剂可以以剂量单位的形式给药,其中包括每单位剂量的活性成分的预设量。优选的剂量单位制剂包括如上所述活性成分的每日剂量或部分剂量,或相应的其中一部分。
此外,这种类型的药物制剂可以用药学领域的专业人员普遍熟知的方法加以制备。
药物制剂可适应于经所需的适当方法给药,例如通过口服(包括口腔或舌下)、直肠、鼻腔、局部(包括口腔、舌下或透皮)、阴道或非肠道(包括皮下、肌肉注射、静脉注射或皮内)方法。这种制剂可以用药学领域的专业人员已知的各种方法制备,例如,将有效成分与辅料或佐剂混合。
适合于口服给药的药物制剂可作为独立的单元给药,例如,胶囊或片剂;粉剂或颗粒剂;在水和非水液体中的溶液或悬浮液;食用泡沫或泡沫食品;或水包油型液体乳剂与油包水型液体乳剂。
因此,举例来说,在口服片剂或胶囊的情况下,活性组成成分可以与口服、无毒、药学上可接受的惰性辅料混合,例如,乙醇、甘油、水等。粉剂则通过将化合物粉碎到合适的粒度尺寸,并将它与以类似方式粉碎的药物赋形剂(例如食用碳水化合物,如淀粉或甘露醇)混合的方法来制备。香味剂、防腐剂、分散剂和染料同样也可存在。
胶囊剂的制备是先按照上面所述制备粉末混合物,然后充填到成型的明胶壳中。可在充填操作前将助流剂和润滑剂(例如,高度分散硅酸、滑石粉、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇)添加到粉末混合物中。崩解剂或增溶剂,例如,琼脂、碳酸钙或碳酸钠,同样可以添加进去,以提高服用胶囊后药物的生物利用度。
此外,如果有需要或有必要,适当的粘合剂、润滑剂和崩解剂以及染料同样可以被添加入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖类(如葡萄糖或β-乳糖、玉米甜味剂)、天然和合成橡胶(如阿拉伯树胶、黄芪胶)或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡,等等。这些剂量形式中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠、氯化钠等。崩解剂包括(但不是仅限于)淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。片剂的制剂过程如下,例如,制备粉末混合物、混合物制粒或干压、添加润滑剂和崩解剂、全部混合物压片制成药片。粉末混合物的制备,按照上面所述,将以适当方式粉碎的化合物与稀释剂或基质混合,也可任意选择地与粘合剂(如羧甲基纤维素、海藻酸盐、明胶或聚乙烯吡咯烷酮)、溶出阻缓剂(如石蜡)、促吸收剂(如季铵盐)和/或吸收剂(如膨润土、高岭土或磷酸氢钙)混合。粉末混合物先经粘合剂加湿再经过筛处理可以形成颗粒,粘合剂为例如糖浆、淀粉糊、阿卡迪亚粘胶或纤维素或高分子材料溶液。制备颗粒的另一种可选方法是,粉末混合物可运行通过制片机,获得形状不均匀的小块,再碎裂形成颗粒。为防止片剂粘附在压片模具上,可以在颗粒中加入润滑剂,硬脂酸、硬脂酸盐、滑石粉或矿物油。然后将该润滑混合物压片制得药片。活性成分还可以与自由流动的惰性辅料混合,然后不经过制粒或干压的步骤,直接压片得到片剂。也可存在由虫胶密封层组成的透明或不透明的保护层,糖或高分子材料层,以及蜡光层。染料可以被添加到这些包衣材料中,以便能够区分不同剂量单位。
口服液,例如,溶液剂、糖浆剂和酏剂,可以以剂量单位的形式制备,以便使某一特定量的制剂包含预定数量的化合物。糖浆剂可以通过将化合物溶解在水溶液中并加入合适的香味剂来制备,而酏剂的制备则用的是无毒醇类溶媒。配制悬浮剂,可以将化合物分散在一种无毒溶媒中。同样可以添加增溶剂和乳化剂(如,乙氧基异硬脂醇和聚氧乙烯山梨醇醚),防腐剂,芳香添加剂,例如,薄荷油或天然甜味剂或糖精,或其他人工甜味剂等
如果需要的话,口服给药的剂量单位制剂可以封装在微胶囊中。这种制剂也可以制备成药物释放被延长或减缓的形式,例如,将颗粒材料覆盖或包埋于聚合物、蜡等材料中。
通式I化合物及其药学上可使用的盐、互变异构体和立体异构体也可以以脂质体递送系统的形式给药,例如,小单层脂质体、大单层脂质体和多层脂质体。脂质体可由各种磷脂形成,例如,胆固醇、硬脂胺或磷脂酰胆碱。
通式I化合物及其药学上可使用的盐、互变异构体和立体异构体,也可以用单克隆抗体作为与该化合物分子相偶联的单个载体进行递药。该化合物也可以偶联到作为靶向药物载体的可溶性聚合物上。这种聚合物可包括棕榈酰基取代的聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰氨基苯酚、聚羟乙基天冬酰氨基苯酚或聚乙烯氧化聚赖氨酸。此外,该化合物还可以偶联到一类适合于实现药物控制释放的可生物降解的聚合物上,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、聚氰基丙烯酸酯和交联或两亲的嵌段共聚物水凝胶。
适合于透皮给药的药物制剂可作为独立的贴膏剂给药,并与受治疗者的表皮长时间紧密接触。因此,举例来说,活性成分可以用离子电渗疗法从贴膏剂中递送进入体内,如在PharmaceuticalResearch,3(6),318(1986)中描述的一般条件。
适合于局部给药的化合物可以制成软膏剂、乳膏剂、悬浮剂、乳剂、散剂、溶液剂、贴膏剂、凝胶剂、喷雾剂、气雾剂或油剂。
对于眼部或其他外部组织的治疗,例如口腔和皮肤,应用的最好制剂是局部软膏剂或乳膏剂。在制备软膏剂的制剂过程中,活性成分可以与石蜡基质或可与水混溶的霜类基质一起使用。另外,活性成分与水包油性霜类基质或油包水性基质一起可以制成乳膏剂。
适合于眼部局部应用的药物制剂,包括眼药水,其活性成分是溶解或悬浮在合适的载体中的,尤其是水性溶剂。
适合于口腔局部应用的药物制剂包括锭剂、含片和漱口液。
适合于直肠给药的药物制剂可以以栓剂或灌肠剂的形式给药。
适合于鼻腔给药其载体物质是固体的药物制剂,由具有一定粒度的粗粉组成,例如,粒度范围在20-500微米,采取鼻吸的方式给药,即迅速从置于鼻子附近的装有粉末的容器中,经由鼻腔吸入。作为鼻腔喷雾剂或滴鼻液给药的合适制剂以液体作为载体物质,它包含活性成分的水或油溶液。
适合于吸入给药的药物制剂包含颗粒细粉尘或烟雾,可用各种类型的加压分配器、雾化器、喷雾器或吹药器产生。
适合于阴道给药的药物制剂可以作为阴道栓剂、棉塞、乳膏剂、凝胶剂、贴膏、泡沫或喷雾制剂给药。
适合于非肠道给药的药物制剂,包括水和非水无菌注射液,由抗氧化剂、缓冲液、抑菌剂和溶质组成,通过这一手段使制剂与受治疗者的血液呈现等渗;还包括水和非水无菌悬浮液,其中可包括悬浮介质和增稠剂。该制剂可以装在单剂量或多剂量容器中给药,例如密封安瓿和小瓶,并以冷冻干燥(冻干)状态储存,这样只需要在临用前立即加入无菌载体液体,例如注射用水。注射液和悬浮液按照处方可以从无菌粉、颗粒剂和片剂制备。
不用说,除上述特别提到的成分以外,这些制剂也可包括关于特定制剂类型的本技术领域人员通用的其他物质,因此,例如,适合口服给药的制剂可以包含芳香剂。
通式I所示化合物的治疗有效量取决于多种因素,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程度、制剂的性质和给药方法,并最终由主治医生或兽医确定剂量。然而,化合物的有效剂量一般在每日0.1至100mg/kg受治疗者(哺乳动物)体重的范围内,特别是通常在每日1到10mg/kg体重的范围内。因此,体重70kg的成年哺乳动物每日的实际剂量通常在70至700mg之间,这个剂量可以作为单一剂量每天服用,通常也可以系列部分剂量每天多次服用(例如,二、三、四、五、六次),使每日总剂量保持相同。盐类或溶剂化物或其生理功能衍生物的有效剂量可确定为化合物本身有效剂量的分数。可以设想,类似的剂量适用于治疗上文提及的其中症状。
本发明此外还涉及药物,所述药物包含至少一种通式I化合物和/或其药学上可用的盐、互变异构体和立体异构体,包括它们的各种比例的混合物,和至少一种其他药物活性成分。
本发明同时还涉及由下列独立包装所组成的组件(药盒):
(a)有效量的至少一种通式I所示化合物和/或其药学上可用的盐、互变异构体和立体异构体,包括其任何比例的混合物,以及
(b)有效量的另一种药物活性成分。
该组件包括合适的容器,例如药盒,独立的药瓶、药包或安瓿瓶。例如,该组件可包括独立的安瓿瓶,每瓶含有有效量的一种通式I化合物和/或其药学上可用的盐、互变异构体和立体异构体,其中包括其任何比例的混合物,以及有效量的一种溶解或冻干形式的其他药物活性成份。
用途
本发明涉及具有通式I的化合物,所述化合物用于治疗癌症、败血性休克、原发性开角型青光眼(POAG)、增生、类风湿性关节炎、牛皮癣、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/或诸如阿尔兹海默症的神经退行性疾病。
本发明涉及具有通式I的化合物在制备药物中的用途,所述药物用于治疗癌症、败血性休克、原发性开角型青光眼(POAG)、增生、类风湿性关节炎、牛皮癣、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/或诸如阿尔兹海默症的神经退行性疾病。
本发明涉及治疗患有如下疾病的哺乳动物的方法,所述疾病选自癌症、败血性休克、原发性开角型青光眼(POAG)、增生、类风湿性关节炎、牛皮癣、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/或诸如阿尔兹海默症的神经退行性疾病,其中,所述方法包括对哺乳动物施用治疗有效量的通式I化合物。
本发明化合物适用于作为哺乳类动物尤其是人类药用活性成分治疗和控制癌症疾病和炎症疾病。
所述宿主或患者可属于哺乳动物,如灵长类动物,具体是人;啮齿动物,包括小鼠、大鼠和仓鼠;兔,马,牛,狗,猫等。供实验研究的感兴趣动物模型可提供治疗人类疾病的模型。
可用体外试验测定对用本发明化合物治疗敏感的具体细胞。通常混合培养的细胞与各种浓度的本发明化合物足够时间,使活性药物如IgM得以诱导细胞反应,例如表面标记物的表达,培养时间常界于1小时与1周之间。可用血液或活检样品的培养细胞进行体外试验。然后使用识别该标记物的特异性抗体通过流式细胞仪评估表达的表面标记物的数量。
根据所用的具体化合物,具体的疾病,患者的状态等给药剂量有所不同。治疗剂量通常应足以降低靶组织中的不良细胞群同时维持患者生存。这种治疗一般持续进行直到相当程度减少了癌细胞负荷,例如至少减少50%,可持续治疗直到机体中基本上不再检测到不良细胞。
为了鉴定信号转导通路和检测各种信号转导通路之间的相互作用,许多科学家开发了适当的模型或模型系统,例如细胞培养模型(如Khwaja等,EMBO,(1997),16:2783-93)和转基因动物模型(如White等,Oncogene,(2001),20:7064-7072)。为了检测信号转导级联反应所处的某些阶段,可采用相互作用的化合物来调节信号(如Stephens等,BiochemicalJ.,(2000),351:95-105)。可将本发明化合物用作试剂来检测动物模型和/或细胞培养模型或本申请书中所提及临床疾病中的激酶依赖信号转导通路状况。
检测激酶的活性是本领域技术人员熟知的技术。文献中描述了检测激酶活性的通用检测系统,所用底物例如有组蛋白(如Alessi等,FEBSLett.(1996),399(3):333-338),或碱性髓磷脂蛋白(如Campos-González,R.和Glenney,Jr.,J.R.,J.Biol.Chem.(1992),267:14535)。
现已有鉴定激酶抑制剂的各种试验系统。闪烁迫近试验(Sorg等J.of.BiomolecularScreening,(2002),7:11-19)和闪光板试验(flashplateassay)中用γATP检测磷酸化底物蛋白或肽的放射活性。存在抑制化合物时,检测到的放射活性信号减弱或根本检测不到。此外,均质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.ofBiomolecularScreening,(2002)191-214)。
其它的非放射性ELISA试验方法采用特异性磷酸-抗体(磷酸化-AB)。此种磷酸-AB只结合磷酸化的底物。可用偶联过氧化物酶的抗绵羊第二抗体化学发光法检测这种结合(Ross等,2002,Biochem.J.)。
本发明涵盖了通式I化合物和/或其生理上可接受的盐、互变异构体和溶剂化物在制备预防或治疗癌症的药物中的用途。优选治疗的癌症疾病组选自脑癌、泌尿生殖系统癌症、淋巴系统癌症、胃癌、咽喉癌、肺癌和肠癌。另一组优选的癌症疾病为单核细胞性白血病、肺腺癌、小细胞性肺癌、胰腺癌、胶质母细胞瘤和乳腺癌。
同样涵盖在本发明范围内的还有通式I化合物和/或其生理上可接受的盐、互变异构体和溶剂化物在制备预防或治疗哺乳类动物中肿瘤诱发疾病的药物中的用途,在该方法中给予需要此种治疗的患病哺乳动物有效量的本发明化合物。治疗量可应具体疾病而异,本领域技术人员无需作出努力即可确定。
特别优选治疗实体肿瘤疾病的用途。
实体肿瘤优先选自鳞状上皮细胞、膀胱、胃部、肾脏、头颈部、食管、子宫颈、甲状腺、肠道、肝脏、大脑、前列腺、泌尿生殖道、淋巴系统、胃部、喉部和/或肺部的肿瘤。
实体肿瘤进一步优先选自肺腺癌、小细胞性肺癌、胰腺癌、成胶质细胞瘤、结肠癌和乳腺癌。
更优选的是,本发明化合物在血液和免疫系统肿瘤的治疗上用途,优选治疗选自急性骨髓性白血病、慢性骨髓性白血病、急性淋巴细胞性白血病和/或慢性淋巴细胞性白血病的肿瘤。
本发明还涉及根据本发明的化合物在治疗骨科疾病中的用途,其中所述骨科疾病源自骨肉瘤、骨关节炎或软骨病。
通式I化合物也可与其他已知治疗剂同时施用,所述其他已知治疗剂由于其针对待治疗的疾病具有特定有效性而被选用。
本发明的化合物也可与已知抗癌剂结合使用。所述已知抗癌剂包括:雌激素受体调节剂,雄激素受体调节剂,类视色素受体调节剂,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,逆转录酶抑制剂和血管生成抑制剂。本发明的化合物尤其适于与放射疗法同时施用。
“雌激素受体调节剂”指以任何机制干扰或抑制雌激素与受体的结合的化合物。雌激素受体调节剂的例子包括但不限于他莫昔芬,雷洛昔芬,碘昔芬,LY353381,LY117081,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2-1,2-二甲基丙酸酯,4,4'-二羟基二苯甲酮-2,4-二硝基苯肼和SH646。
“雄激素受体调节剂”指以任何机制干扰或抑制雄激素与受体结合的化合物。雄激素受体调节剂的例子包括非那雄胺和其他5α-还原酶抑制剂、尼鲁米特、氟他胺、比卡鲁胺、利阿唑和醋酸阿比特龙。
“类视色素受体调节剂”指以任何机制干扰或抑制类视色素与受体结合的化合物。所述类视色素受体调节剂的例子包括贝沙罗汀,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)维胺酸和N-4-羧基苯基维胺酸。
“细胞毒性剂”指主要通过直接作用于细胞功能而导致细胞死亡、或者抑制或干扰细胞减数分裂的化合物,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。
细胞毒性剂的例子包括但不限于:替拉扎明,sertenef、恶病质素,异环磷酰胺,他索纳明,氯尼达明,卡铂,六甲蜜胺,松龙苯芥、二溴卫矛醇、雷莫司汀,福莫司汀,奈达铂,奥沙利铂,替莫唑胺,heptaplatin,雌莫司汀、英丙舒凡、甲苯磺酸盐,氯乙环磷酰胺,尼莫司汀,氯化二溴螺氯铵,嘌嘧替派,洛铂,赛特铂,甲基丝裂霉素,顺铂,依洛福芬、右异环磷酰胺,顺胺二氯(2-甲基吡啶)合铂,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)二[二胺(氯)铂(II)]四氯化碳,diarisidinylspermine、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、3′-脱氨基-3′-吗啉代基-13-脱氧-10-羟基洋红霉素、annamycin、加柔比星、依利奈法德、MEN10755和4-脱甲氧基-3-脱氨基-3-氮丙啶基-4-甲磺酰基柔红霉素(参见WO00/50032)。
微管蛋白抑制剂的例子包括紫杉醇、硫酸长春地辛、3′,4′-二脱氢-4′-脱氧-8′-norvincaleukoblastine、多西他赛、根霉素、多拉司他汀、羟乙磺酸米伏布林、auristatin、西马多丁、RPR109881、BMS184476、长春氟宁、cryptophycin、2,3,4,5,6-五氟-N-(3-氟-4-甲氧基苯基)苯磺酰胺、脱水长春碱、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-叔丁基酰胺、TDX258和BMS188797。
拓扑异构酶抑制剂的例子有托泊替康、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(chartreusin)、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、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,和抗代谢物,如依诺他滨、卡莫氟、替加氟、喷司他丁、去氧氟尿苷、三甲曲沙、氟达拉滨、卡培他滨、加洛他滨、阿糖胞苷十八烷基磷酸盐、fosteabine钠水合物、雷替曲塞、paltitrexid、乙嘧替氟、噻唑呋林、地西他滨、诺拉曲塞、培美曲塞、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]甘氨酰氨基]-L-甘油-B-L-甘露庚-吡喃糖基]腺嘌呤、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)十四-2,4,6-三烯-9-基乙酸酯、八氢吲嗪三醇、洛美曲索、右雷佐生、蛋氨酸酶、2′-氰基-2′-脱氧-N4-棕榈酰-1-B-D-阿拉伯呋喃糖基胞嘧啶和3-氨基吡啶-2-甲醛胺苯硫脲。“抗增殖剂”还包括除了在“血管生成抑制剂”下列举的那些之外的生长因子单克隆抗体如曲妥单抗和肿瘤抑制基因如p53,它可以经由重组病毒介导基因转移来递送(例如参见US专利第6,069,134号)。
具体实施方式
IKKε的抑制测试
IKKε-激酶分析试验(IKKepsilon)
概述
以384孔Flashplate试验(例如,Topcount测量)进行激酶试验。
将含或不含测试化合物的总体积为50μl(10mMMOPS,10mM醋酸镁,0.1mMEGTA,1mM二硫苏糖醇,0.02%Brij35,0.1%BSA,0.1%BioStab,pH7.5)的1nMIKKε、800nM生物素化I B (19-42)肽(生物素-C6-C6-GLKKERLLDDRHDSGLDSMKDEE)及10μMATP(加入0.3μCi33P-ATP/孔)在30℃培育2小时。用25μl200mMEDTA终止反应。在室温下放置30分钟后,移除液体,并以100μl0.9%氯化钠溶液清洗每孔三次。以3μMMSC2119074(BX-795)确定非特异性反应。用Topcount(PerkinElmer)测量放射性。用IT部门提供的程序工具(例如,AssayExplorer、Symyx)计算结果(例如,IC50-值)。
TBK1的抑制测试
酶测试
概述
以384孔闪光板试验(例如,Topcount测量)进行激酶分析试验。
将含或不含测试化合物的总体积为50μl(10mMMOPS,10mM醋酸镁,0.1mMEGTA,1mMDTT,0.02%Brij35,0.1%BSA,pH7.5)的0.6nMTANK结合激酶(TBK1)、800nM生物素化MELK衍生肽(生物素-Ah-Ah-AKPKGNKDYHLQTCCGSLAYRRR)及10μMATP(加入0.25μCi33P-ATP/孔)在30℃培育120分钟。用25μl200mMEDTA终止反应。在室温下放置30分钟后,移除液体,并以100μl0.9%氯化钠溶液清洗每孔三次。用Topcount(PerkinElmer)测量放射性。用IT部门提供的程序工具(例如,AssayExplorer、Symyx)计算结果(例如,IC50-值)。
细胞测试
剂量反应磷-IRF3抑制Ser386
细胞/MDAMB468/INH/PHOS/IMAG/pIRF3
1.范围
虽然TBK1和IKKε已知是先天免疫反应的关键参与者,但最近的研究结果显示TBK1和IKKε在Ras诱导的致癌转化中也有作用。TBK1被确定为Ras诱导的转化所需的Ras样(RAL)-鸟嘌呤核苷酸交换因子(GEF)途径中的RalB效应器。TBK1直接激活IRF3,后者在磷酸化后同二聚化并转位至细胞核,并在细胞核中激活涉及发炎、免疫调节、细胞存活和增殖的过程。
本试验的目的是基于对核定位磷-IRF3的免疫细胞化学检测来评估TBK1/IKKε抑制剂化合物的效果/效力,所述核定位磷-IRF3是TBK1直接下游的标靶。
用聚肌苷-聚胞嘧啶核苷酸(poly(I:C))处理以诱导TBK1/IKKε活性及在Ser386处使IRF3磷酸化,所述聚肌苷-聚胞嘧啶核苷酸是双链RNA(dsRNA)的合成类似物,所述双链RNA是与病毒感染相关的分子模式,其可被Toll样受体3(TLR3)识别。
2.试验概览
第一天:用HyQ-Tase洗脱MDA-MB-468细胞,计数,并将总体积为35μl的完整培养基以每孔10,000个细胞的密度种植到透明底TC-表面384孔板中。或者,也可直接种植冷冻管中细胞。
第二天:在用Poly(I:C)刺激之前,用抑制剂化合物预处理细胞1小时。用Poly(I:C)培育2小时后,将细胞固定在多聚甲醛(PFA)中并用甲醇(MeOH)透化。然后封闭细胞,并用抗pIRF3抗体在4℃培育过夜。
第三天:洗掉第一抗体,加入结合AlexaFluor88的第二抗体,用碘化丙啶复染细胞,然后在IMXUltra高含量读出器中获取图像。
3.试剂,材料
细胞:ATCCHTB132,Burger实验室(MP-CB2010-327或MDA-MB-468/10)
平板培养基=培养基:
RPMI1640,Invitrogen#31870
10%FCS,Invitrogen#10270-106
2mMGlutamax,Invitrogen#35050-038
1mM丙酮酸钠,Invitrogen#11360
1%Pen/Strep
37℃,5%CO2
平板:黑底/透明底384孔细胞培养板,Falcon#353962或Greiner#781090
转种:HyQ-Tase,ThermoScientific(HyClone)#SV30030.01
其他试剂:
Poly(I:C)(LMW),Invivogen#tlrl-picw(用消毒PBS制备20mg/ml储液,在55℃水浴中变性30分钟,缓慢冷却至室温,分装储存于-20℃。
参照抑制剂:MSC2119074A-4=BX-795(IC50:200-800nM)
抑制对照:10μMMSC2119074A-4=BX-795
中性对照:0.5%DMSO
每个实验包括一个10点剂量反应曲线,其中MSC2119074A-4=BX-795。
Hepes,Merck#1.10110
PBS1xDPBS,Invitrogen#14190
甲醛(无甲醇,16%,超纯EM级),Polysciences#18814(室温储存),最终浓度:4%
甲醇,Merck#1.06009.1011(-20℃预冷却)
山羊血清,PAA#B15-035(储存于4℃,长期储存于20℃),最终浓度:10%
BSA(无IgG及蛋白酶,30%),US-Biological#A1317(储存于4℃,长期储存于20℃),最终浓度:2%
吐温20洗涤剂,Calbiochem#655204(室温储存),(用水制备10%储液;最终浓度:0.1%)
抗-pIRF-3兔mAb,Epitomics#2526-B(储存于-20℃),最终浓度:1:2000溶于PBS/2%BSA
AlexaFluor山羊-抗-兔-488,Invitrogen#A11034or#A11008(储存于4℃,避光),最终浓度:1:2000溶于PBS/2%BSA/0.1%吐温
碘化丙啶(PI),Fluka#81845,1mg/ml溶于水(储存于4℃,避光),最终浓度:0.2μg/ml
4.步骤
将35ul完整RPMI+10%FCS以10,000细胞/孔种植到
黑底/透明底384孔细胞培养板中
室温下在实验台上培育2小时,
然后在37℃,5%CO2及90%rH下培育22小时
化合物处理:加入5μl预稀释化合物、标准或对照试剂
(8倍浓度)
用20mMHepespH7,2从DMSO储液稀释化合物;最终DMSO浓度:0.5%
从10mM储液(Remp)用DMSO以每级3.16倍连续10级稀释化合物
30μM9.49μM3μM0.95μM0.3μM0.095μM0.03μM0.0095μM
0.003μM0.00095μM
在37℃,5%CO2及90%rH下培育60分钟。
刺激处理:除了未刺激的对照之外向所有孔加入10μlPoly(I:C),以获得100ug/ml
最终浓度。
(储液20mg/ml→1:40溶于PBS)(5倍浓度)
在37℃,5%CO2及90%rH下培育120分钟。
完全抽出上清液
固定细胞:加入100μl4%溶于PBS的多聚甲醛
在室温下培育15分钟
用80μlPBS(Tecanpowerwasher)冲洗3次,完全抽出上清液
置平板于冰上
透化细胞:快速加入100μl-20℃冷甲醇(预冷却容器)
在室温或4℃下培育10分钟
用80μlPBS(Tecanpowerwasher)冲洗一次,完全抽出上清液
阻断非特异性结合:加入30μl10%溶于PBS/2%BSA的山羊血清
在MultidropCombi上振动(17秒)
在37℃下培育60分钟
完全抽出上清液
初染:加入25μl以1:2000稀释于PBS/2%BSA中的第一抗体
在MultidropCombi上振动(17秒)
在4℃培育过夜
用80μlPBS(Tecanpowerwasher)冲洗3次,完全抽出上清液
复染及核染色:加入25μl第二抗体(1:2000)
及
0.2μg/ml溶于PBS/2%BSA/0.1%吐温中的碘化丙啶
在MultidropCombi上振动(17秒)
在37℃培育75分钟
用80μlPBS(Tecanpowerwasher)冲洗3次,完全抽出上清液
将80μlPBS分配至所有孔中
用透明胶带密封平板
在IMXUltra(Metaexpress3.1.扫描设置TBK_10x_pin8)上获取图像
图像分析(Metaexpress3.1.<细胞计分>,TBK1-Cellscoring)
用Assayexplorer进行数据分析及报告
HPLC/MS条件:
色谱柱:ChromolithSpeedRODRP-18e,50x4.6mm2
梯度:A:B=96:4至0:100
流速:2.4ml/min
洗脱液A:水+0.05%甲酸
洗脱液B:乙腈+0.04%甲酸
波长:220nm
质谱分析:正离子模式
1HNMR:耦合常数J[Hz]。
制备通式I化合物的优选的通用流程如下:
实验程序:
边搅拌边向5-溴代-2-氨基-烟酸(500mg,2.3mol,1当量)和4-氨基吡啶(260mg,2.7mol,1.2当量)在干DMF(5ml)中的溶液加入HATU(1.31g,3.4mol,1.5当量)和N-甲基吗啉(690mg,6.9mol,3当量),搅拌3小时。待反应完成后,浓缩反应混合物;加入水,沉淀和滤出固体,用NaHCO3和水洗涤,得到产物。
1HNMR(400MHz,DMSO-d6)δ10.51(s,1H),8.47-8.46(d,J=5.4Hz,2H),8.25-8.22(dd,J=2.4,7.4Hz,2H),7.69-7.67(d,J=6.2Hz,2H)。
边搅拌边向2-氨基-5-溴代-N-吡啶-4-基-烟酰胺(1当量)在甲苯:乙醇(4:1)中的溶液加入取代的硼酸(1.2当量)、2MNa2CO3(1.5当量),在氮气气氛下脱气15分钟。向该反应混合物加入Pd(PPh3)4(0.012当量),加热至100℃,保持18小时。待反应完成后,使混合物经过硅藻土床,以除去无机杂质。滤液在真空下浓缩。经柱色谱处理得到纯的化合物。
实施例1
参照以下流程制备2-氨基-5-(5-哌啶-1-基甲基-噻吩-2-基)-N-吡啶-4-基-烟酰胺("A1")
1.12-氨基-5-溴代-N-吡啶-4-基-烟酰胺:
将2.0g2-氨基-5-溴烟酸和1.06g4-氨基-吡啶溶解在20mLDMF中。向该溶液加入5.26gHATU((2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸酯)和3.04mLN-甲基吗啉。
混合物室温搅拌5小时。蒸发DMF,残留物在水中研磨。滤出固体,用NaHCO3溶液和水洗涤。得到2.5g浅褐色固体。
HPLC/MS:1.13min,[M+H]=293;
1HNMR(400MHz,DMSO-d6)δ[ppm]10.51(s,1H,NH),8.48(d,J=6.0,2H),8.25(dd,J=10.8,2.3,2H),7.69(d,J=6.3,2H),7.18(s,2H,NH2)。
1.22-氨基-5-(5-哌啶-1-基甲基-噻吩-2-基)-N-吡啶-4-基-烟酰胺("A1"):
将200mg2-氨基-5-溴代-N-吡啶-4-基-烟酰胺和218mg5-(1-哌啶基甲基)-噻吩-2-硼酸频那醇酯溶解在8mlDMF中。在氮气存在下加入0.84ml2摩尔Na2CO3溶液。加入7.81mg四(三苯基膦)钯(0)。混合物在100℃搅拌6小时。
反应混合物冷却至室温,蒸发DMF。加入水,滤出所得到的沉淀物,用水洗涤,干燥。固体在乙酸乙酯中研磨,过滤。得到47mg所希望的产物"A1",为浅褐色固体。
HPLC/MS:1.08min,[M+H]=394;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.58(s,1H,NH),8.48(d,J=6.2,2H),8.44(d,J=2.3,1H),8.22(d,J=2.3,1H),7.71(dd,J=4.8,1.5,2H),7.25(d,J=3.5,1H),7.13(s,2H,NH2),6.93(d,J=3.5,1H),3.61(s,2H),2.37(br,4H),1.51(m,4H),1.39(m,2H)。
类似地,获得以下化合物:
2-氨基-N-吡啶-4-基-5-(5-吡咯烷-1-基甲基-噻吩-2-基)-烟酰胺("A2")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与5-(1-吡咯烷基-甲基)-噻吩-2-硼酸频那醇酯反应,得到化合物"A2";
HPLC/MS:1.16min,[M+H]=380;
1HNMR(400MHz,DMSO-d6)δ[ppm]10.51(s,1H,NH),8.51–8.46(m,3H),8.27(d,J=2.4,1H),8.24(d,J=2.4,1H),7.69(m,3H),7.18(s,2H),4.70(s,2H),3.54(m,2H),3.23(m,2H),2.12(m,2H),1.98(m,2H);
2-氨基-5-(5-甲基-噻吩-2-基)-N-吡啶-4-基-烟酰胺("A3")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与5-甲基噻吩-2-硼酸频那醇酯反应,得到化合物"A3";
HPLC/MS:1.45min,[M+H]=311;
1HNMR(400MHz,DMSO-d6)δ[ppm]10.74(s,1H,NH),8.53(d,J=4.9,2H),8.40(d,J=2.3,1H),8.22(d,J=2.1,1H),7.79(d,J=11.8,2H),7.22(d,J=3.5,1H),7.12(s,2H,NH2),6.86–6.74(m,1H),2.47(s,3H);
2-氨基-5-(3-吡唑-1-基-苯基)-N-吡啶-4-基-烟酰胺("A4")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与1-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-苯基]-1H-吡唑反应,得到化合物"A4";
HPLC/MS:1.44min,[M+H]=357;
1HNMR(400MHz,DMSO-d6)δ[ppm]11.40(s,1H,NH),8.74(t,J=7.2,2H),8.72(s,1H),8.62(d,J=2.3,1H),8.53(d,J=2.4,1H),8.19(d,J=7.2,2H),8.16(t,J=1.8,1H),7.83(ddd,J=7.9,2.1,1.0,1H),7.78(d,J=1.6,1H),7.67(dd,J=6.6,1.4,1H),7.60(t,J=7.9,1H),7.38(s,2H),6.58(dd,J=2.4,1.8,1H);
2-氨基-5-(4-吡唑-1-基-苯基)-N-吡啶-4-基-烟酰胺("A5")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与[4-(1H-吡唑-1-基)-苯基]-硼酸反应,得到化合物"A5";
HPLC/MS:1.38min,[M+H]=357;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.60(s,1H,NH),8.59(d,J=2.4,1H),8.54(d,J=2.4,1H),8.52–8.45(m,2H),8.40(d,J=2.4,1H),7.98–7.92(m,2H),7.88–7.84(m,2H),7.78–7.72(m,3H),7.16(d,J=15.2,2H),6.60–6.56(m,1H);
2-氨基-5-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-N-吡啶-4-基-烟酰胺("A6")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-1H-吡唑反应,得到化合物"A6";
HPLC/MS:1.05min,[M+H]=339;
1HNMR(400MHz,DMSO-d6)δ[ppm]11.37(s,1H,NH),8.75(d,J=7.2,2H),8.51(d,J=2.2,1H),8.34(d,J=2.3,1H),8.18(d,J=7.2,2H),8.12(s,1H),7.89(s,1H),4.29(t,J=5.3,3H),3.72(t,J=5.3,3H),3.23(s,3H);
2-氨基-N-吡啶-4-基-5-(4-氨磺酰基-苯基)-烟酰胺("A7")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与苯磺酰胺-4-硼酸频那醇酯反应,得到化合物"A7";
HPLC/MS:1.12min,[M+H]=370;
1HNMR(400MHz,DMSO-d6)δ[ppm]10.57(s,1H,NH),8.61(d,J=2.3,1H),8.55–8.46(m,2H),8.42(d,J=2.4,1H),7.92(m,4H),7.80–7.65(m,2H),7.35(s,2H),7.24(s,2H);
2-氨基-N-(2-甲基-吡啶-4-基)-5-(5-吗啉-4-基甲基-噻吩-2-基)-烟酰胺("A8")
2-氨基-5-溴代-N-(2-甲基-吡啶-4-基)-烟酰胺与5-(4-吗啉基-甲基)噻吩-2-硼酸频那醇酯反应,得到化合物"A8";
HPLC/MS:1.02min,[M+H]=410;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.49(s,1H,NH),8.44(d,J=2.3,1H),8.35(d,J=5.6,1H),8.23(d,J=2.4,1H),7.59(d,J=1.7,1H),7.53(dd,J=5.6,1.9,1H),7.32–7.27(d,J=3.5,1H),7.12(s,2H),6.96(d,J=3.5,1H),3.71(s,2H),3.61–3.53(m,4H),2.45(s,3H),2.43(m,4H);
2-氨基-N-(2-乙氧基-吡啶-4-基)-5-(5-吗啉-4-基甲基-噻吩-2-基)-烟酰胺("A9")
2-氨基-5-溴代-N-(2-乙氧基-吡啶-4-基)-烟酰胺与5-(4-吗啉基-甲基)噻吩-2-硼酸频那醇酯反应,得到化合物"A9";
HPLC/MS:1.37min,[M+H]=440;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.51(s,1H,NH),8.44(d,J=2.3,1H),8.19(d,J=2.3,1H),8.06(d,J=5.7,1H),7.26(m,2H),7.22(d,J=1.6,1H),7.12(s,2H),6.96(d,J=3.5,1H),4.30(q,J=7.0,2H),3.66(s,2H),3.58(m,4H),2.42(br,4H),1.31(t,J=7.0,3H)。
实施例2
3-氨基-6-(5-吗啉-4-基甲基-噻吩-2-基)-吡嗪-2-羧酸吡啶-4-基酰胺("A10")
2.13-氨基-6-溴代-吡嗪-2-羧酸吡啶-4-基酰胺
按照"A1"的制备方法的步骤1中描述的程序由3-氨基-6-溴代-吡嗪-2-羧酸和4-氨基吡啶制成标题化合物;
HPLC/MS:1.18min,[M+H]=294。
2.23-氨基-6-(5-吗啉-4-基甲基-噻吩-2-基)-吡嗪-2-羧酸吡啶-4-基酰胺("A10")
按照"A1"的制备方法的步骤2中描述的程序制成标题化合物;HPLC/MS:1.08min,[M+H]=397。
实施例3
6-氨基-6'-哌嗪-1-基-[3,3']二吡啶基-5-羧酸吡啶-4-基酰胺("A11")
3.14-[6'-氨基-5'-(吡啶-4-基氨甲酰基)-[3,3']二吡啶基-6-基]-哌嗪-1-羧酸叔丁酯
按照"A1"的制备方法的步骤2中描述的程序由2-氨基-5-溴代-N-(2-乙氧基-吡啶-4-基)-烟酰胺和2-(4-叔丁氧基-羰基哌嗪-1-基)吡啶-5-硼酸频那醇酯制成标题化合物;HPLC/MS:1.43min,[M+H]=476。
3.2将1.1g4-[6'-氨基-5'-(吡啶-4-基氨甲酰基)-[3,3']二吡啶基-6-基]-哌嗪-1-羧酸叔丁酯溶解在25ml二噁烷中。加入11mlHCl在二噁烷(4摩尔)中的溶液。混合物室温搅拌3小时。混合物过滤,用二噁烷洗涤。产物经色谱法纯化;
HPLC/MS:1.02min,[M+H]=376;
1HNMR(400MHz,DMSO-d6)δ[ppm]9.08(d,J=2.2,1H),8.84(d,J=7.3,2H),8.77(d,J=2.1,1H),8.67(d,J=2.3,1H),8.48(dd,J=9.5,2.4,1H),8.38(d,J=7.3,2H),7.54(d,J=9.5,1H),4.09–3.96(m,4H),3.47–3.35(m,4H)。
实施例4
参照实施例2的方法获得以下化合物:
3-氨基-6-(1-[1,3]二氧戊环-2-基甲基-1H-吡唑-4-基)-吡嗪-2-羧酸吡啶-4-基酰胺("A12")
3-氨基-6-溴代-吡嗪-2-羧酸吡啶-4-基酰胺(按照"A10"的合成方法)与1-[1,3]二氧戊环-2-基甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-1H-吡唑反应,得到化合物"A12";
HPLC/MS:1.02min,[M+H]=376;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.55(s,1H,NH),8.71(s,1H),8.55–8.41(m,3H),8.27(s,1H),7.91–7.86(m,2H),7.51(s,2H),5.22(t,J=4.3,1H),4.30(d,J=4.3,2H),3.96–3.70(m,4H);
3-氨基-6-(5-哌啶-1-基甲基-噻吩-2-基)-吡嗪-2-羧酸吡啶-4-基酰胺("A13")
3-氨基-6-溴代-吡嗪-2-羧酸吡啶-4-基酰胺(按照"A10"的合成方法)与1-[5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-噻吩-2-基甲基]-哌啶反应,得到化合物"A13";
HPLC/MS:1.13min,[M+H]=395;
1HNMR(400MHz,DMSO-d6)δ[ppm]10.41(s,1H,NH),8.80(s,1H),8.51(dd,J=4.8,1.6,2H),7.82(dd,J=4.8,1.6,2H),7.67(d,J=3.6,1H),7.63(s,2H),6.98(d,J=3.6,1H),3.64(s,2H),2.40(s,4H),1.59–1.32(m,6H);
3-氨基-6-(5-吡咯烷-1-基甲基-噻吩-2-基)-吡嗪-2-羧酸吡啶-4-基酰胺("A14")
3-氨基-6-溴代-吡嗪-2-羧酸吡啶-4-基酰胺(按照"A10"的合成方法)与1-[5-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-噻吩-2-基甲基]-吡咯烷反应,得到化合物"A14";
HPLC/MS:1.08min,[M+H]=381;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.40(s,1H,NH),8.83(s,1H),8.51(dd,J=4.8,1.5,2H),7.88–7.75(m,2H),7.67(d,J=3.6,1H),7.63(s,2H),6.96(d,J=3.6,1H),3.78(s,2H),2.51(m,4H),1.78–1.62(m,4H);
2-氨基-N-(2-甲基-吡啶-4-基)-5-(5-吗啉-4-基甲基-噻吩-3-基)-烟酰胺("A15")
2-氨基-5-溴代-N-(2-甲基-吡啶-4-基)-烟酰胺与4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-噻吩-2-基甲基]-吗啉反应,得到化合物"A15";
HPLC/MS:0.99min,[M+H]=410;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.45(s,1H,NH),8.53(d,J=2.3,1H),8.35(d,J=5.6,1H),8.30(d,J=2.3,1H),7.69(d,J=1.4,1H),7.60(d,J=1.7,1H),7.56–7.50(m,1H),7.44(s,1H),7.04(s,2H),3.71(s,2H),3.61–3.58(m,4H),2.45(m,7H)。
实施例5
2-氨基-5-(5-吗啉-4-基甲基-噻吩-2-基)-N-哒嗪-4-基-烟酰胺("A16")
5.12-氨基-5-溴代-N-哒嗪-4-基-烟酰胺
按照"A1"的制备方法的步骤1中描述的程序由2-氨基-5-溴烟酸和4-氨基哒嗪制成标题化合物;
HPLC/MS:1.40min,[M+H]=294。
5.2按照"A1"的制备方法的步骤2中描述的程序由2-氨基-5-溴代-N-哒嗪-4-基-烟酰胺和5-(4-吗啉基甲基)噻吩-2-硼酸频那醇酯制成2-氨基-5-(5-吗啉-4-基甲基-噻吩-2-基)-N-哒嗪-4-基-烟酰胺;
HPLC/MS:1.15min,[M+H]=397;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.78(s,1H,NH),9.47(d,J=1.9,1H),9.08(d,J=5.9,1H),8.48(d,J=2.3,1H),8.27(d,J=2.3,1H),8.03(dd,J=5.9,2.7,1H),7.27(d,J=3.1,1H),7.20(s,2H),6.98(s,1H),3.68(s,2H),3.59(s,4H),2.48–2.35(m,4H)。
类似地,获得以下化合物:
2-氨基-5-(1-苄基-1H-吡唑-4-基)-N-(2-甲基-吡啶-4-基)-烟酰胺("A17")
2-氨基-5-溴代-N-(2-甲基-吡啶-4-基)-烟酰胺与4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-噻吩-2-基甲基]-吗啉反应,得到化合物"A17";
HPLC/MS:1.41min,[M+H]=385;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.45(s,1H,NH),8.53(d,J=2.3,1H),8.35(d,J=5.6,1H),8.30(d,J=2.3,1H),7.69(d,J=1.4,1H),7.60(d,J=1.7,1H),7.55(dd,J=5.6,1.9,1H),7.44(s,1H),7.04(s,2H),3.71(s,2H),3.63–3.57(m,4H),2.45(s+m,7H);
2-氨基-5-(3-吡唑-1-基-苯基)-N-哒嗪-4-基-烟酰胺("A18")
2-氨基-5-溴代-N-哒嗪-4-基-烟酰胺(参见"A16"的合成方法的步骤1)和1-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-苯基]-1H-吡唑反应,得到化合物"A18";
HPLC/MS:1.15min,[M+H]=397;
1HNMR(400MHz,DMSO-d6)δ[ppm]11.06(s,1H,NH),9.54(d,J=2.1,1H),9.14(d,J=5.9,1H),8.67(dd,J=4.1,2.4,2H),8.58(d,J=2.3,1H),8.19(t,J=1.8,1H),8.14(dd,J=6.0,2.7,1H),7.89–7.80(m,1H),7.77(d,J=1.7,1H),7.68(d,J=7.9,1H),7.59(t,J=7.9,1H),7.37(s,2H),6.60–6.56(m,1H);
2-氨基-N-(3-甲基-吡啶-4-基)-5-(4-吡唑-1-基-苯基)-烟酰胺("A19")
2-氨基-5-溴代-N-(3-甲基-吡啶-4-基)-烟酰胺与[4-(1H-吡唑-1-基)-苯基]-硼酸反应,得到化合物"A19";
HPLC/MS:1.41min,[M+H]=371;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.07(s,1H,NH),8.59(d,J=2.3,1H),8.55(d,J=2.4,1H),8.45(s,1H),8.44(d,J=2.3,1H),8.40(d,J=5.3,1H),7.96–7.91(m,2H),7.90–7.83(m,2H),7.76(d,J=1.6,1H),7.53(d,J=5.3,1H),7.17(s,2H),6.60–6.54(m,1H),2.28(s,3H);
2-氨基-5-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-N-(2-甲基-吡啶-4-基)-烟酰胺("A20")
2-氨基-5-溴代-N-(2-甲基-吡啶-4-基)-烟酰胺与1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-1H-吡唑反应,得到化合物"A20";
HPLC/MS:1.11min,[M+H]=353;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.44(s,1H,NH),8.43(d,J=2.2,1H),8.36(d,J=5.6,1H),8.20(d,J=2.2,1H),8.09(s,1H),7.86(d,J=0.5,1H),7.62(s,1H),7.55(d,J=5.6,1H),6.94(s,2H),4.33–4.22(m,2H),3.76–3.66(m,2H),3.25(s,3H),2.46(s,3H);
2-氨基-N-(3-甲基-吡啶-4-基)-5-(5-吗啉-4-基甲基-噻吩-2-基)-烟酰胺("A21")
2-氨基-5-溴代-N-(3-甲基-吡啶-4-基)-烟酰胺与5-(4-吗啉基-甲基)-噻吩-2-硼酸频那醇酯反应,得到化合物"A21";
HPLC/MS:0.97min,[M+H]=410;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.8(br,1H,NH),8.72(d,J=2.2,1H),8.70(s,1H),8.67(d,J=6.7,1H),8.52–8.47(m,2H),7.54(d,J=3.7,1H),7.34(d,J=3.7,1H),4.61(s,2H),4.01–3.87(m,2H),3.67(m,2H),3.33(m,2H),3.14(m,2H);
2-氨基-5-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-N-(3-甲基-吡啶-4-基)-烟酰胺("A22")
2-氨基-5-溴代-N-(3-甲基-吡啶-4-基)-烟酰胺与1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-1H-吡唑反应,得到化合物"A22";
HPLC/MS:1.07min,[M+H]=353;
2-氨基-5-(4'-甲基-二苯基-3-基)-N-吡啶-4-基-烟酰胺("A23")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与[3-(对甲苯基)苯基]-硼酸反应,得到化合物"A23";
HPLC/MS:1.90min,[M+H]=381;
1HNMR(500MHz,DMSO-d6)δ[ppm]11.4(s,1H,NH),9.03(d,J=2.2,1H),8.75(d,J=6.6,2H),8.71(d,J=2.1,1H),8.25(d,J=7.3,2H),8.00(s,1H),7.69(dd,J=10.1,8.7,2H),7.62(d,J=8.1,2H),7.56(t,J=7.7,1H),7.37(br,2H,NH2),7.25(d,J=8.1,2H),2.31(s,3H);
2-氨基-5-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-N-哒嗪-4-基-烟酰胺("A24")
2-氨基-5-溴代-N-哒嗪-4-基-烟酰胺(参见"A16"的合成方法的步骤1)与1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-1H-吡唑反应,得到化合物"A24";
HPLC/MS:1.21min,[M+H]=340;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.98(br,1H,NH),9.51–9.48(m,1H),9.17(d,J=6.1,1H),8.48(d,J=2.2,1H),8.42(d,J=1.6,1H),8.14(m,2H),7.91(s,1H),7,36(br,2H),4.29(t,J=5.3,2H),3.72(t,J=5.3,3H),3.25(s,3H);
2-氨基-5-(1-氨甲酰基甲基-1H-吡唑-4-基)-N-吡啶-4-基-烟酰胺("A25")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与2-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-吡唑-1-基]-乙酰胺反应,得到化合物"A25";
HPLC/MS:0.94min,[M+H]=338;
1HNMR(400MHz,DMSO-d6)δ[ppm]10.51(s,1H,NH),8.48(dd,J=4.8,1.5,2H),8.44(d,J=2.3,1H),8.22(d,J=2.3,1H),8.08(d,J=0.5,1H),7.88(d,J=0.6,1H),7.72(dd,J=4.8,1.6,2H),7.49(s,1H),7.24(s,1H),6.94(s,2H),4.78(s,2H);
2-氨基-N-(2,6-二甲基-吡啶-4-基)-5-(5-吗啉-4-基甲基-噻吩-2-基)-烟酰胺("A26")
2-氨基-5-溴代-N-(2,6-二甲基-吡啶-4-基)-烟酰胺与5-(4-吗啉基-甲基)-噻吩-2-硼酸频那醇酯反应,得到化合物"A26";
HPLC/MS:1.09min,[M+H]=424;
1HNMR(400MHz,DMSO-d6)δ[ppm]10.43(s,1H,NH),8.43(d,J=2.3,1H),8.21(d,J=2.3,1H),7.43(s,2H),7.26(d,J=3.5,1H),7.14(s,2H),6.96(d,J=3.5,1H),3.68(s,2H),3.64–3.54(m,4H),2.53–2.47(m,4H),2.43(s,6H)。
实施例6
2-氨基-5-(5-吗啉-4-基甲基-噻吩-2-基)-N-嘧啶-4-基-烟酰胺("A27")
6.1按照"A1"的制备方法的步骤1中描述的合成程序由2-氨基-5-溴代-吡啶-3-羧酸与嘧啶-4-胺制成2-氨基-5-溴代-N-嘧啶-4-基-吡啶-3-羧酰胺。
6.2按照"A1"的制备方法的步骤2中描述的合成程序由2-氨基-5-溴代-N-嘧啶-4-基-吡啶-3-羧酰胺和5-(4-吗啉基-甲基)-噻吩-2-硼酸频那醇酯制成"A27";
HPLC/MS:1.27min,[M+H]=397;
1HNMR(400MHz,DMSO-d6)δ[ppm]11.34(s,1H,NH),8.97(d,J=0.9,1H),8.72(d,J=5.8,1H),8.46(d,J=2.3,1H),8.40(d,J=2.3,1H),8.14(dd,J=5.8,1.2,1H),7.33(d,J=3.5,1H),7.25(s,2H),6.97(d,J=3.4,1H),3.69(s,2H),3.65–3.56(m,4H),2.45(s,4H)。
实施例7
2-氨基-N-呋喃并[3,2-b]吡啶-7-基-5-[1-(2-甲氧基-乙基)-1H-吡唑-4-基]-烟酰胺("A28")
7.1按照"A1"的制备方法的步骤1中描述的合成程序由2-氨基-5-溴代-吡啶-3-羧酸与呋喃并[3,2-b]吡啶-7-胺制成2-氨基-5-溴代-N-呋喃并[3,2-b]吡啶-7-基-吡啶-3-羧酰胺。
7.2按照"A1"的制备方法的步骤2中描述的程序由2-氨基-5-溴代-N-呋喃并[3,2-b]吡啶-7-基-吡啶-3-羧酰胺和1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-1H-吡唑制成化合物"A28";
HPLC/MS:1.22min,[M+H]=379;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.70(s,1H,NH),8.48–8.44(m,2H),8.34(d,J=2.0,1H),8.32(d,J=2.2,1H),8.10(s,1H),7.88(s,1H),7.60(d,J=5.3,1H),7.15(d,J=2.2,1H),7.02(s,2H),4.28(t,J=5.3,2H),3.71(t,J=5.3,2H),3.25(s,3H)。
类似地,获得以下化合物:
2-氨基-N-呋喃并[3,2-b]吡啶-7-基-5-(5-吗啉-4-基甲基-噻吩-2-基)-烟酰胺("A29")
2-氨基-5-溴代-N-呋喃并[3,2-b]吡啶-7-基-吡啶-3-羧酰胺(参见上述合成方法)与5-(4-吗啉基-甲基)-噻吩-2-硼酸频那醇酯反应,得到化合物"A29";
HPLC/MS:1.17min,[M+H]=436;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.85(s,1H,NH),8.48(t,J=3.5,2H),8.36(d,J=2.3,1H),8.33(d,J=2.2,1H),7.62(d,J=5.3,1H),7.30(d,J=3.5,1H),7.23(s,2H),7.16(d,J=2.2,1H),6.98(d,J=3.5,1H),3.68(s,2H),3.62–3.56(m,4H),2.44(m,4H);
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸甲酯("A30")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与4-(甲氧基-羰基)-苯甲酸反应,得到化合物"A30";
HPLC/MS:1.48min,[M+H]=349;
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸("A31")
将190mg4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸甲酯溶解在20ml甲醇中,加入175mgNa2CO3在6ml水中的溶液。反应混合物在50℃搅拌过夜。
经色谱法纯化所希望的物质"A31";
HPLC/MS:1.28min,[M+H]=335;
1HNMR(400MHz,DMSO-d6)δ[ppm]13.24–12.61(m,1H,OH),11.36(s,1H,NH),8.74(d,J=6.7,2H),8.69(d,J=2.4,1H),8.51(d,J=2.4,1H),8.18(d,J=7.2,2H),8.06–7.98(m,2H),7.90–7.81(m,2H),7.40(s,2H);
3-{4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯基}-丙酸("A32")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与3-(4-二羟硼基-苯基)-丙酸反应,得到化合物"A32";
HPLC/MS:1.28min,[M+H]=363;
1HNMR(500MHz,DMSO-d6)δ[ppm]12.09(s,1H,OH),10.52(s,1H,NH),8.48(dd,J=6.7,4.2,3H),8.31(d,J=2.2,1H),7.72(d,J=6.1,2H),7.62(d,J=8.1,2H),7.32(d,J=8.1,2H),7.09(s,2H),2.86(t,J=7.5,2H),2.56(t,J=7.5,2H);
2-氨基-N-(3-氯-吡啶-4-基)-5-(5-吗啉-4-基甲基-噻吩-2-基)-烟酰胺("A33")
2-氨基-5-溴代-N-(3-氯-4-吡啶基)吡啶-3-羧酰胺与5-(4-吗啉基-甲基)-噻吩-2-硼酸频那醇酯反应,得到化合物"A33";
HPLC/MS:1.25min,[M+H]=343;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.30(s,1H,NH),8.70(s,1H),8.53(d,J=5.3,1H),8.49(d,J=2.3,1H),8.30(d,J=2.4,1H),7.79(d,J=5.3,1H),7.28(d,J=3.5,1H),7.21(s,2H),6.97(d,J=3.5,1H),3.68(s,2H),3.62–3.55(m,4H),2.44(s,4H);
2-氨基-5-(1H-吡唑-4-基)-N-吡啶-4-基-烟酰胺("A34")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑反应,得到化合物"A34";
HPLC/MS:0.89min,[M+H]=281;
1HNMR(500MHz,DMSO-d6)δ[ppm]12.89(s,1H,NH),10.48(s,1H,NH),8.47(dd,J=10.1,4.2,3H),8.23(d,J=2.2,1H),8.11(s,1H),7.91(s,1H),7.71(dd,J=10.9,9.6,2H),6.91(s,2H);
4-{[2-氨基-5-(5-吗啉-4-基甲基-噻吩-2-基)-吡啶-3-羰基]-氨基}-烟酸甲酯("A35")
4-[(2-氨基-5-溴代-吡啶-3-羰基)氨基]吡啶-3-羧酸甲酯与5-(4-吗啉基-甲基)-噻吩-2-硼酸频那醇酯反应,得到化合物"A35";
HPLC/MS:1.36min,[M+H]=454;
1HNMR(500MHz,DMSO-d6)δ[ppm](s,1H,NH),9.04(s,1H),8.70(d,J=5.8,1H),8.52(d,J=2.3,1H),8.34(d,J=5.8,1H),8.20(d,J=2.3,1H),7.31(s,2H),7.26(d,J=3.5,1H),6.98(d,J=3.5,1H),3.92(s,3H),3.69(s,2H),3.62–3.53(m,4H),2.44(s,4H);
N-(2-乙酰基氨基-吡啶-4-基)-2-氨基-5-(5-吗啉-4-基甲基-噻吩-2-基)-烟酰胺("A36")
N-(2-乙酰氨基-4-吡啶基)-2-氨基-5-溴代-吡啶-3-羧酰胺与5-(4-吗啉基-甲基)-噻吩-2-硼酸频那醇酯反应,得到化合物"A36";
HPLC/MS:1.14min,[M+H]=453;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.63(s,1H,NH),10.37(s,1H,NH),8.43(d,J=2.3,1H),8.38(d,J=1.2,1H),8.23(d,J=2.3,1H),8.20(d,J=5.6,1H),7.60(dd,J=5.6,1.9,1H),7.26(d,J=3.5,1H),7.13(s,2H),6.96(d,J=3.5,1H),3.67(s,2H),3.61–3.57(m,4H),2.43(s,4H),2.09(s,3H);
3-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-2-基]-苯甲酸("A37")
1.按照"A1"的制备方法的步骤2中描述的程序由(3-甲氧基羰基苯基)硼酸和2-氨基-5-溴代-N-吡啶-4-基-烟酰胺反应,制成3-[6-氨基-5-(4-吡啶基氨甲酰基)-3-吡啶基]苯甲酸甲酯。
2.按照"A31"的制备方法中描述的程序由3-[6-氨基-5-(4-吡啶基氨甲酰基)-3-吡啶基]苯甲酸甲酯制成化合物"A37";
HPLC/MS:1.19min,[M+H]=335;
1HNMR(400MHz,DMSO-d6)δ[ppm]13.07(br,1H,OH),11.41(s,1H,NH),8.74(d,J=7.2,2H),8.64(d,J=2.4,1H),8.48(d,J=2.4,1H),8.26(t,J=1.6,1H),8.19(d,J=7.2,2H),8.01–7.88(m,2H),7.62(t,J=7.8,1H),7.38(s,2H);
2-氨基-N-(3-氯-吡啶-4-基)-5-[1-(2-甲氧基-乙基-)-1H-吡唑-4-基]烟酰胺("A38")
2-氨基-5-溴代-N-(3-氯-4-吡啶基)吡啶-3-羧酰胺与1-(2-甲氧基-乙基)-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-1H-吡唑反应,得到化合物"A38";
HPLC/MS:1.39min,[M+H]=373;
1HNMR(500MHz,DMSO-d6)δ[ppm]10.16(s,1H,NH),8.69(s,1H),8.51(d,J=5.3,1H),8.46(d,J=2.2,1H),8.28(d,J=2.3,1H),8.09(s,1H),7.86(s,1H),7.79(d,J=5.3,1H),7.00(s,2H),4.28(t,J=5.3,2H),3.71(t,J=5.3,2H),3.24(s,4H);
2-氨基-N-(4-甲氧基-苯基)-5-(5-吗啉-4-基甲基-噻吩-2-基)-烟酰胺("A39")
2-氨基-5-溴代-N-(4-甲氧基苯基)吡啶-3-羧酰胺与5-(4-吗啉基-甲基)-噻吩-2-硼酸频那醇酯反应,得到化合物"A39";
HPLC/MS:1.46min,[M+H]=425;
2-氨基-N-(6-甲氧基-吡啶-3-基)-5-(5-吗啉-4-基甲基-噻吩-2-基)-烟酰胺("A40")
2-氨基-5-溴代-N-(6-甲氧基-3-吡啶基)吡啶-3-羧酰胺与5-(4-吗啉基-甲基)-噻吩-2-硼酸频那醇酯反应,得到化合物"A40";
HPLC/MS:1.29min,[M+H]=426。
实施例8
2-氨基-N-(3-甲基氨甲酰基-吡啶-4-基)-5-(5-吗啉-4-基-甲基-噻吩-2-基)-烟酰胺("A41")
将100mg4-[[2-氨基-5-[5-(吗啉代甲基)-2-噻吩基]吡啶-3-羰基]-氨基]吡啶-3-羧酸甲酯(MSC2392368)溶解在4mlTHF中,加入4ml甲胺(40%的水溶液)。混合物室温搅拌2小时。蒸发混合物,并用石油醚和乙酸乙酯处理该混合物。过滤后,得到79mg黄色固体;
HPLC/MS:1.17min,[M+H]=453;
1HNMR(500MHz,DMSO-d6)δ[ppm]12.76(s,1H),9.05(d,J=4.3,1H),8.94(s,1H),8.61(d,J=5.7,1H),8.51(d,J=2.3,1H),8.45(d,J=5.7,1H),8.16(d,J=2.3,1H),7.35(s,2H),7.25(d,J=3.5,1H),6.98(d,J=3.5,1H),3.68(s,2H),3.60–3.57(m,4H),2.86(d,J=4.5,3H),2.44(m,4H)。
实施例9
2-氨基-5-[1-(2-羟基-乙基)-1H-吡唑-4-基]-N-吡啶-4-基-烟酰胺("A42")
9.12-氨基-5-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-烟酸:
将1.5g1-[2-(四氫吡喃-2-基氧基)-乙基]-4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-1H-吡唑和808mg2-氨基-5-溴烟酸溶解在10mlDMF。向该溶液加入3.3g碳酸钾。混合物加热至80℃。加入395mg1,1′-双(二苯基膦基)二茂铁二氯化钯(II)、二氯甲烷加成物,混合物加热2小时。
蒸发该溶液,粗产物经硅胶色谱法纯化(采用乙酸乙酯/甲醇9:1);得到496mg2-氨基-5-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-烟酸,为褐色油;HPLC/MS:1.27min,[M+H]=333。
9.22-氨基-N-吡啶-4-基-5-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-烟酰胺:
将303mg2-氨基-5-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-烟酸、84mg4-氨基吡啶和284mgO-(1H-苯并三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸盐(TBTU)溶解在10mlDMF中。加入0.15mlN-乙基二异丙胺和21mg4-(二甲基氨基)-吡啶。混合物室温搅拌过夜。
反应混合物蒸发,经硅胶色谱法纯化(采用二氯甲烷/甲醇9:1);得到160mg2-氨基-N-吡啶-4-基-5-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-烟酰胺,为黄色固体;
HPLC/MS:1.27min,[M+H]=409.
9.32-氨基-5-[1-(2-羟基-乙基)-1H-吡唑-4-基]-N-吡啶-4-基-烟酰胺:
将160mg2-氨基-N-吡啶-4-基-5-{1-[2-(四氢-吡喃-2-基氧基)-乙基]-1H-吡唑-4-基}-烟酰胺溶解在4ml二氯甲烷中。加入0.4mlHCl在二噁烷(约4mol/l)中的溶液。1小时后,滤出沉淀物,用二氯甲烷洗涤。
得到99mg2-氨基-5-[1-(2-羟基-乙基)-1H-吡唑-4-基]-N-吡啶-4-基-烟酰胺,为黄色固体;
HPLC/MS:0.98min,[M+H]=325;
1HNMR(400MHz,DMSO-d6)δ[ppm]10.56(s,1H,NH),8.50(d,J=6.2,2H),8.43(d,J=2.2,1H),8.21(d,J=2.3,1H),8.09(s,1H),7.86(s,1H),7.76(d,J=6.3,2H),6.94(s,2H),4.90(s,1H,OH),4.16(t,J=5.6,2H),3.76(d,J=4.8,2H)。
实施例10
参照实施例1的方法获得以下化合物:
HPLC方法:A-0.1%TFA的水溶液,B-0.1%TFA的ACN溶液:流速–2.0ml/min。
柱:XBridgeC8(50x4.6mm.3.5μ)。
2-氨基-5-(5-吗啉-4-基甲基-噻吩-3-基)-N-吡啶-4-基-烟酰胺("A43")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.53(s,1H),8.53(d,J=2.08Hz,1H),8.48(d,J=5.00Hz,2H),8.30(d,J=2.12Hz,1H),7.69-7.71(m,3H),7.44(s,1H),7.07-7.12(m,2H),3.69(s,2H),3.57-3.59(m,4H),2.49-2.49(m,4H);
LCMS:实测值(M+1,396);
HPLC>97%,Rt(min):1.362。
5-(4-乙酰基-1H-吡咯-2-基)-2-氨基-N-吡啶-4-基-烟酰胺("A44")
1HNMR(400MHz,DMSO-d6)δ[ppm]11.96(s,1H),10.61(s,1H),8.48-8.53(m,1H),8.47(d,J=1.40Hz,2H),8.40(d,J=2.04Hz,1H),7.74(dd,J=1.48,4.90Hz,2H),7.68(dd,J=1.64,2.88Hz,1H),7.07(s,2H),6.85(t,J=2.24Hz,1H),2.34(s,3H);
LCMS:实测值(M+1,322);
HPLC>93%,RTL(min):1.62。
2-氨基-5-呋喃-3-基-N-吡啶-4-基-烟酰胺("A45")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.54(s,1H),8.44-8.44(m,3H),8.23(d,J=2.32Hz,1H),8.12(d,J=2.36Hz,1H),7.74(t,J=3.36Hz,1H),7.68(d,J=4.64Hz,2H),6.97-7.02(m,2H);
LCMS:实测值(M+1,281);
HPLC>96%,Rt(min):1.64。
2-氨基-5-(1-苄基-1H-吡唑-4-基)-N-吡啶-4-基-烟酰胺("A46")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.49(s,1H),8.43-8.48(m,3H),8.20(dd,J=2.28,6.54Hz,2H),7.90-7.91(m,2H),7.69(dd,J=1.52,4.82Hz,2H),7.25-7.37(m,5H),6.94(s,1H),5.34(s,1H);
LCMS:实测值(M+1,371);
HPLC>98%,Rt(min):2.34。
2-氨基-5-(1-甲基-1H-吡唑-3-基)-N-吡啶-4-基-烟酰胺("A47")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.65(s,1H),8.59(d,J=2.20Hz,1H),8.48(d,J=6.20Hz,2H),8.36(d,J=2.20Hz,1H),7.73(dd,J=2.12,4.42Hz,3H),7.07(s,1H),6.66(d,J=2.24Hz,1H),3.87(s,3H);
LCMS:实测值(M+1,295);
HPLC>99%,Rt(min):1.46。
2-氨基-5-(3,5-二甲基-1H-吡唑-4-基)-N-吡啶-4-基-烟酰胺("A48")
1HNMR(400MHz,DMSO-d6)δ[ppm]12.29(s,1H),10.36(s,1H),8.45(d,J=5.24Hz,2H),8.09(d,J=2.00Hz,1H),8.00(d,J=2.00Hz,1H),7.70(d,J=6.24Hz,2H),7.01(s,1H),2.16(s,6H);
LCMS:实测值(M+1,309);
HPLC>99%,Rt(min):3.71。
2-氨基-N-吡啶-4-基-5-噻吩-3-基-烟酰胺("A49")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.53(s,1H),8.57(d,J=2.28Hz,1H),8.47(d,J=6.24Hz,2H),8.35(d,J=2.28Hz,1H),7.80-7.81(m,1H),7.71(dd,J=1.48,4.86Hz,2H),7.66(dd,J=2.92,5.00Hz,1H),7.59(dd,J=1.20,5.00Hz,1H),7.09(s,2H);
LCMS:实测值(M+1,297);
HPLC>95%,Rt(min):1.88。
2-氨基-5-(1-甲基-1H-吡咯-2-基)-N-吡啶-4-基-烟酰胺("A50")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.45(s,1H),8.46(d,J=6.12Hz,2H),8.24(d,J=2.16Hz,1H),8.14(d,J=2.12Hz,1H),7.71(d,J=6.32Hz,2H),7.13(s,2H),6.83(t,J=2.00Hz,1H),6.16(dd,J=1.84,3.52Hz,1H),6.05-6.07(m,1H),3.60(s,3H);
LCMS:实测值(M+1,294);
HPLC>95%,Rt(min):1.84。
2-氨基-5-[1-(2-吗啉-4-基-乙基)-1H-吡唑-4-基]-N-吡啶-4-基-烟酰胺("A51")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.51(s,1H),8.47(dd,J=1.48,4.82Hz,2H),8.42(dd,J=2.24,Hz,1H),8.18(dd,J=2.24,Hz,1H),8.12(s,1H),7.84-7.85(m,1H),7.70(dd,J=1.52,4.80Hz,2H),6.92(s,2H),4.23(t,J=6.64Hz,2H),3.54(t,J=4.68Hz,4H),2.73(t,J=6.64Hz,2H),2.41(t,J=4.40Hz,4H);
LCMS:实测值(M+1,394);
HPLC>99%,Rt(min):3.84。
2-氨基-5-苯并[b]噻吩-2-基-N-吡啶-4-基-烟酰胺("A52")
1HNMR(400MHz,DMSO-d6)δ[ppm]11.41(s,1H),8.73(d,J=6.52Hz,2H),8.65(d,J=2.32Hz,1H),8.15(s,1H),8.15(d,J=6.88Hz,2H),7.97(d,J=7.52Hz,1H),7.79-7.82(m,2H),7.32-7.43(m,4H);
LCMS:实测值(M+1,347);
HPLC>94%,Rt(min):2.87。
5-(5-乙酰基-噻吩-2-基)-2-氨基-N-吡啶-4-基-烟酰胺("A53")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.62(s,1H),8.60(d,J=2.40Hz,1H),8.49(dd,J=1.40,4.86Hz,2H),8.37(d,J=2.40Hz,1H),7.95(d,J=4.00Hz,1H),7.71(dd,J=1.56,4.82Hz,2H),7.59(d,J=3.96Hz,1H),7.39(s,2H),2.48(s,3H);
LCMS:实测值(M+1,339);
HPLC>96%,Rt(min):2.01。
2-氨基-5-(5-吗啉-4-基甲基-噻吩-2-基)-N-吡啶-4-基-烟酰胺("A54")
1HNMR(400MHz,DMSO-d6)δ[ppm]8.27-8.34(m,3H),7.60(s,2H),7.06(d,J=3.64Hz,1H),6.93(d,J=3.36Hz,1H),3.65(s,2H),3.58(t,J=4.48Hz,4H),2.41-2.49(m,4H),1.50(s,3H);
LCMS:实测值(M+1,396);
HPLC>98%,Rt(min):1.39。
2-氨基-5-(1H-吲哚-2-基)-N-吡啶-4-基-烟酰胺("A55")
1HNMR(400MHz,DMSO-d6)δ[ppm]11.43(s,1H),10.63(s,1H),8.69(d,J=2.04Hz,1H),8.47-8.49(m,3H),7.73(d,J=5.12Hz,2H),7.50(d,J=7.64Hz,1H),7.37(d,J=7.96Hz,1H),7.13(s,2H),6.83-7.08(m,3H);
LCMS:实测值(M+1,330);
HPLC>99%,Rt(min):2.60。
2-氨基-5-(1H-吲哚-3-基)-N-吡啶-4-基-烟酰胺("A56")
1HNMR(400MHz,DMSO-d6)δ[ppm]11.33(s,1H),10.55(s,1H),8.46-8.51(m,3H),8.30(d,J=2.28Hz,2H),7.83(d,J=7.92Hz,1H),7.67-7.82(m,2H),7.44(d,J=8.00Hz,1H),7.05-7.16(m,2H),6.93(s,2H);
LCMS:实测值(M+1,330);
HPLC>93%,Rt(min):2.23。
2-氨基-N-吡啶-4-基-5-(1H-吡咯-2-基)-烟酰胺("A57")
1HNMR(400MHz,DMSO-d6)δ[ppm]11.15(s,1H),10.54(s,1H),8.46-8.48(m,3H),8.22(d,J=2.28Hz,1H),7.71(dd,J=1.52,4.86Hz,2H),6.89(s,2H),6.82(dd,J=2.56,4.02Hz,1H),6.42(t,J=3.60Hz,1H),6.10(dd,J=2.52,5.66Hz,1H);
LCMS:实测值(M+1,280);
HPLC>94%,Rt(min):1.71。
2-氨基-5-(1H-咪唑并[1,2-a]吡啶-2-基)-N-吡啶-4-基-烟酰胺("A58")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.46(s,1H),8.55(d,J=6.88Hz,1H),8.47(d,J=6.04Hz,2H),8.41(d,J=2.12Hz,1H),8.35(d,J=2.00Hz,1H),7.79(s,1H),7.74-7.77(m,2H),7.63-7.65(m,1H),7.26-7.30(m,3H),6.92-6.94(m,1H),.
LCMS:实测值(M+1,331);
HPLC>91%,Rt(min):3.68。
2-氨基-N-吡啶-4-基-5-(1H-吡咯-3-基)-烟酰胺("A59")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.90(s,1H),10.50(s,1H),8.47(dd,J=1.52,4.80Hz,2H),8.40(dd,J=2.24,Hz,1H),8.15(dd,J=2.28,Hz,1H),7.72(dd,J=1.52,4.78Hz,2H),7.18(dd,J=1.88,4.20Hz,1H),6.79-6.82(m,3H),6.43-6.45(m,1H);
LCMS:实测值(M+1,280);
HPLC>98%,Rt(min):1.43。
2-氨基-5-苯并呋喃-3-基-N-吡啶-4-基-烟酰胺("A60")
1HNMR(400MHz,DMSO-d6)δ[ppm]10.58(s,1H),8.54-8.55(m,3H),8.33-8.36(m,2H),7.95-7.97(m,1H),7.72(d,J=3.44Hz,2H),7.65-7.65(m,1H),7.32-7.41(m,2H),7.13(s,2H);
LCMS:实测值(M+1,331);
HPLC>93%,Rt(min):2.50。
2-氨基-5-(1-甲基-1H-吡唑-4-基)-N-吡啶-4-基-烟酰胺("A61")
实施例11
LC-MS条件
惠普HP1200系列系统,具有以下特征:离子源:电喷雾(正离子模式);扫描:100-1000m/e;碎裂电压:100V;气体温度:350℃,UV:220nm.
方法1
HPLC/MS条件:
柱:ChromolithSpeedRODRP-18e,50-4.6
梯度:A:B=96:4至0:100
4%B→100%B:0min,重复一次2.8min
100%B:2.8min,重复一次3.3min
100%B→4%B:3.3min,重复一次4min
流速:2.4ml/min
洗脱液A:水+0.05%甲酸
洗脱液B:乙腈+0.04%甲酸
波长:220nm
质谱:正向离子模式
方法2
HPLC/MS条件:
柱:ChromolithSpeedRODRP-18e,50-4.6
梯度:A:B=100:0至0:100
0%B→0%B:0min,重复一次0.5min
0%B→100%B0.5min,重复一次2.6min
100%B:2.6min,重复一次3.0min
100%B→0%B:3.0min,重复一次3.1min
流速:2.4ml/min
洗脱液A:water+0.05%甲酸
洗脱液B:乙腈+0.04%甲酸
波长:220nm
质谱:正向离子模式
2-氨基-5-(3-羟基甲基-苯基)-N-吡啶-4-基-烟酰胺("A62")
将100mg2-氨基-5-溴代-N-吡啶-4-基-烟酰胺和62.2mg3-羟基-甲基-苯硼酸溶解在4mlDMF。在氩气气氛下加入90.4mgNa2CO3和1ml水。加入13.9mg[1,1-双(二苯基膦基)二茂铁二氯化钯(II)。混合物在100℃搅拌14小时。
将反应混合物冷却至室温,蒸发DMF,色谱法纯化产物,得到45mg"A62";
方法1:HPLC/MS:1.11min,[M+H]=321;
1HNMR(400MHz,DMSO-d6)δ[ppm]9.01(1H,d,J2.2),8.88–8.83(2H,m),8.67(1H,d,J2.3),8.34–8.29(2H,m),7.79(1H,s),7.69(1H,d,J7.6),7.52(1H,t,J7.6),7.46(1H,d,J7.8),4.65(2H,s)。
类似地,获得以下化合物:
2-氨基-5-(2-羟基甲基-苯基)-N-吡啶-4-基-烟酰胺("A63")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与2-(羟基甲基)-苯硼酸反应,得到化合物"A63";
方法1:HPLC/MS:1.07min,[M+H]=321;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]8.88(1H,d,J2.1),8.81(2H,d,J7.2),8.52(1H,d,J2.1),8.31(2H,d,J7.3),7.63(1H,d,J7.3),7.53–7.44(3H,m),4.52(2H,s);
2-氨基-5-(2-叔丁基氨磺酰基-苯基)-N-吡啶-4-基-烟酰胺("A64")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与2-叔丁基-氨磺酰基-苯硼酸反应,得到化合物"A64";
方法1:HPLC/MS:1.41min,[M+H]=426;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]8.86–8.80(3H,m),8.39(1H,d,J2.1),8.28(2H,d,J7.3),8.15(1H,dd,J7.9,1.2),7.73(2H,dtd,J31.4,7.6,1.4),7.57(1H,dd,J7.6,1.2),1.09(9H,s);
2-氨基-5-(4-氨基-苯基)-N-吡啶-4-基-烟酰胺("A65")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与4-氨基苯基-硼酸盐酸盐反应,得到化合物"A65";
方法2:HPLC/MS:1.53min,[M+H]=306;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]9.05(1H,d,J2.2),8.87(2H,d,J7.5),8.72(1H,d,J2.2),8.36(2H,d,J7.3),7.99(2H,d,J8.5),7.60–7.55(2H,m);
2-氨基-5-(2-甲酰基-苯基)-N-吡啶-4-基-烟酰胺("A66")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与2-甲酰基苯基-硼酸反应,得到化合物"A66";
方法1:HPLC/MS:1.23min,[M+H]=319;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]10.08(1H,s),8.88(1H,d,J2.2),8.81(2H,d,J7.3),8.51(1H,d,J2.2),8.32–8.28(2H,m),8.11–8.07(1H,m),7.83(1H,td,J7.6,1.5),7.72(1H,t,J7.2),7.64(1H,dd,J7.6,0.9);
3-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸乙酯("A67")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与3-乙氧基羰基-苯基-硼酸反应,得到化合物"A67";
方法1:HPLC/MS:1.48min,[M+H]=363;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]9.06(1H,d,J2.2),8.85(2H,d,J7.3),8.76(1H,d,J2.2),8.41(1H,t,J1.7),8.33(2H,d,J7.3),8.13–8.03(2H,m),7.70(1H,t,J7.8),4.41(2H,q,J7.1),1.39(3H,t,J7.1);
2-氨基-5-(4-羟基甲基-苯基)-N-吡啶-4-基-烟酰胺("A68")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与4-(羟基甲基)-苯基硼酸反应,得到化合物"A68";
方法1:HPLC/MS:1.12min,[M+H]=321;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]9.02(1H,d,J2.2),8.83(2H,d,J7.3),8.65(1H,d,J2.2),8.33(2H,d,J7.3),7.79(2H,d,J8.2),7.54(2H,d,J8.4),4.63(2H,s);
2-氨基-5-(3-羟基-苯基)-N-吡啶-4-基-烟酰胺("A69")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与3-羟基苯基-硼酸频那醇酯反应,得到化合物"A70";
方法1:HPLC/MS:1.12min,[M+H]=307;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]9.02(1H,d,J2.2),8.82(2H,d,J5.1),8.62(1H,s),8.34(2H,d,J7.3),7.36(1H,t,J7.8),7.22(2H,d,J8.1),6.96(1H,dd,J7.5,1.8);
2-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸乙酯("A70")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸以酯反应,得到化合物"A70";
方法1:HPLC/MS:1.37min,[M+H]=363;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]8.86(1H,d,J2.1),8.79(2H,d,J7.1),8.40(1H,d,J2.0),8.32(2H,d,J7.3),8.12(1H,dd,J7.8,0.9),7.75(1H,td,J7.6,1.1),7.64(1H,td,J7.7,0.9),7.57(1H,d,J7.5),4.23(2H,q,J7.1),1.22(3H,t);
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸乙酯("A71")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与4-乙氧基羰基-苯基硼酸反应,得到化合物"A71";方法1:HPLC/MS:1.46min,[M+H]=363;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.08(1H,d,J2.2),8.84(2H,d,J7.2),8.77(1H,d,J2.1),8.33(2H,d,J7.2),8.17(2H,d,J8.5),7.97(2H,d,J8.4),4.38(2H,q,J7.1),1.38(3H,t,J7.1);
2-氨基-5-(4-羟基-苯基)-N-吡啶-4-基-烟酰胺("A72")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与4-羟基苯-硼酸反应,得到化合物"A72";
方法1:HPLC/MS:1.07min,[M+H]=307;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]8.99(1H,d,J2.1),8.78(2H,dd,J7.2,2.4),8.51(1H,t,J2.1),8.35(2H,d,J7.2),7.61(2H,dd,J8.5,1.8),7.01(2H,d,J8.6);
2-氨基-5-(2-羟基-苯基)-N-吡啶-4-基-烟酰胺("A73")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯酚反应,得到化合物"A73";
方法1:HPLC/MS:1.16min,[M+H]=307;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]8.95(1H,d,J2.1),8.83(2H,d,J7.2),8.62(1H,d,J2.1),8.30(2H,d,J7.2),7.53(1H,dd,J7.7,1.5),7.32–7.27(1H,m),7.11–7.07(1H,m),7.03–6.98(1H,m);
2-氨基-5-(3-甲酰基-苯基)-N-吡啶-4-基-烟酰胺("A74")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与3-甲酰基苯-硼酸反应,得到化合物"A74";
方法1:HPLC/MS:1.29min,[M+H]=319;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]10.13(1H,s),9.13(1H,d,J2.2),8.83–8.75(3H,m),8.36(3H,d,J7.2),8.14–8.02(2H,m),7.78(1H,t,J7.7);
2-氨基-5-(4-甲酰基-苯基)-N-吡啶-4-基-烟酰胺("A75")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与4-甲酰基苯-硼酸反应,得到化合物"A75";
方法1:HPLC/MS:1.29min,[M+H]=319;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]10.10(1H,s),9.08(1H,d,J2.2),8.86(2H,d,J7.2),8.82(1H,d,J2.2),8.32(2H,d,J7.3),8.12–8.05(4H,m);
2-氨基-5-(3-氨基甲基-苯基)-N-吡啶-4-基-烟酰胺("A76")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与3-氨基甲基-苯基-硼酸盐酸盐反应,得到化合物"A76";
方法1:HPLC/MS:0.94min,[M+H]=320;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]8.99(1H,d,J2.3),8.86(2H,d,J7.3),8.65(1H,d,J2.2),8.31(2H,d,J7.3),7.93(1H,s),7.87(1H,d,J7.6),7.61(2H,dt,J15.7,7.7),4.17(2H,s);
2-氨基-5-(4-氨基甲基-苯基)-N-吡啶-4-基-烟酰胺("A77")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与4-氨基甲基-苯基-硼酸盐酸盐反应,得到化合物"A77";
方法1:HPLC/MS:1.07min,[M+H]=320;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.02(1H,d,J2.2),8.86(2H,d,J7.3),8.73(1H,d,J2.3),8.31(2H,d,J7.3),7.91(2H,d,J8.4),7.67(2H,d,J8.4),4.15(2H,s);
2-氨基-N-吡啶-4-基-5-(3-氨磺酰基-苯基)-烟酰胺("A78")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与苯磺酰胺-3-硼酸频那醇酯反应,得到化合物"A78";
方法1:HPLC/MS:1.13min,[M+H]=370;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.01(1H,d,J2.2),8.86(2H,d,J7.3),8.74(1H,d,J2.3),8.33–8.28(3H,m),8.05(1H,d,J7.8),7.98(1H,d,J7.9),7.77(1H,t,J7.9);
2-氨基-5-[3-(4-羟基-哌啶-1-磺酰基)-苯基]-N-吡啶-4-基-烟酰胺("A79")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与1-[3-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-苯磺酰基]-哌啶-4-醇反应,得到化合物"A79";
方法1:HPLC/MS:1.29min,[M+H]=454;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]9.01(1H,d,J2.3),8.86(2H,d,J7.3),8.80(1H,d,J2.2),8.30(2H,d,J7.3),8.19–8.13(2H,m),7.87–7.80(2H,m),3.64–3.57(1H,m),3.25–3.17(2H,m),2.93–2.89(2H,m),1.83–1.75(2H,m),1.58–1.44(2H,m);
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-2-氟-苯甲酸甲酯("A80")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与3-氟-4-甲氧基羰基-苯基硼酸反应,得到化合物"A80";
方法1:HPLC/MS:1.48min,[M+H]=367;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]9.10(1H,d,J2.2),8.84(3H,t,J4.8,2.5),8.34(2H,d,J7.3),8.09(1H,t,J8.0),7.87(1H,dd,J12.2,1.6),7.80(1H,dd,J8.2,1.7),3.92(3H,s);
{2-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯基}-氨基甲酸叔丁酯("A81")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与[2-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-苯基]-氨基甲酸叔丁酯反应,得到化合物"A81";
方法1:HPLC/MS:1.38min,[M+H]=406;
{3-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯基}-氨基甲酸叔丁酯("A82")
2-氨基-5-溴代-N-吡啶-4-基-烟酰胺与3-(N-Boc-氨基)苯基硼酸反应,得到化合物"A82";
方法1:HPLC/MS:1.56min,[M+H]=406。
实施例12
2-氨基-5-{4-[(2-甲氧基-乙基)-甲基-氨甲酰基]-苯基}-N-吡啶-4-基-烟酰胺("A83")
12.14-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸("A31")
将4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸乙酯(290mg,0.08mmol)、THF(5mL)和1NNaOH(4mL,25.0)的溶液室温搅拌14小时。真空除去THF,混合物用1NHCl酸化。
滤出得到的沉淀物,用水洗涤,干燥。获得260mg所希望的产物,为白色固体;
方法1:HPLC/MS:1.21min,[M+H]=335;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]9.13(1H,s),8.93–8.70(4H,m),8.38(2H,d,J6.6),7.97(2H,d,J8.4),7.83(1H,d,J8.5)。
类似地,采用上文描述的程序获得以下化合物:
3-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸("A84")
使3-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸乙酯反应,得到化合物"A84";
方法1:HPLC/MS:1.21min,[M+H]=335;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.12(1H,d,J2.2),8.85(2H,d,J7.2),8.78(1H,d,J2.2),8.44(1H,s),8.37(2H,d,J7.2),8.10(2H,d,J7.9),7.68(1H,t,J7.8);
2-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸("A85")
使2-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸乙酯反应,得到化合物"A85";
方法1:HPLC/MS:1.15min,[M+H]=335;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]8.86(1H,d,J2.1),8.79(2H,d,J7.1),8.40(1H,d,J2.0),8.32(2H,d,J7.3),8.12(1H,dd,J7.8,0.9),7.75(1H,td,J7.6,1.1),7.64(1H,td,J7.7,0.9),7.57(1H,d,J7.5);
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-2-氟-苯甲酸("A86")
使4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-2-氟-苯甲酸甲酯反应,得到化合物"A86";
方法1:HPLC/MS:1.22min,[M+H]=353;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]9.13(1H,d,J2.2),8.83(3H,t,J4.7),8.37(2H,d,J7.4),8.10(1H,t,J8.0),7.85(1H,dd,J12.1,1.7),7.78(1H,dd,J8.2,1.7)。
12.22-氨基-5-{4-[(2-甲氧基-乙基)-甲基-氨甲酰基]-苯基}-N-吡啶-4-基-烟酰胺("A83")
将60mg(0.18mmol)4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸和23.13μl(0.22mmol)N-(甲氧基乙基)甲胺溶解在2mLDMF中。向该溶液加入102.36mgHATU((2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基-脲六氟磷酸酯)和59.19μLN-甲基吗啉。混合物室温搅拌3小时。蒸发DMF,产物经色谱法纯化。
得到16mg化合物"A83";
方法1:HPLC/MS:1.22min,[M+H]=406;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.05(1H,d,J2.2),8.86(2H,d,J7.3),8.74(1H,d,J2.2),8.31(2H,d,J7.3),7.89(2H,d,J8.0),7.60(2H,d,J8.3),3.75–3.57(2H,m),3.53–3.41(3H,m),3.38–3.19(2H,m),3.04(3H,s)。
类似地,采用上文描述的程序获得以下化合物:
2-氨基-5-(4-二乙基氨甲酰基-苯基)-N-吡啶-4-基-烟酰胺("A87")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与二乙胺反应,得到化合物"A87";
方法1:HPLC/MS:1.36min,[M+H]=390;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.05(1H,d,J2.3),8.86(2H,d,J7.3),8.74(1H,d,J2.2),8.31(2H,d,J7.3),7.90(2H,d,J8.4),7.55(2H,d,J8.3),3.60–3.17(4H,m),1.29–1.00(6H,m);
2-氨基-5-(4-氨甲酰基-苯基)-N-吡啶-4-基-烟酰胺("A88")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与氨反应,得到化合物"A88";
方法1:HPLC/MS:1.10min,[M+H]=334;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.06(1H,d,J2.2),8.86(2H,d,J7.2),8.77(1H,d,J2.2),8.31(2H,d,J7.2),8.11(2H,d,J8.4),7.94(2H,d,J8.4);
2-氨基-5-{4-[二-(2-甲氧基-乙基)-氨甲酰基]-苯基}-N-吡啶-4-基-烟酰胺("A89")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与二-(2-甲氧基-乙基)-胺反应,得到化合物"A89";
方法1:HPLC/MS:1.30min,[M+H]=450;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.08(1H,d,J2.2),8.83(2H,d,J7.2),8.72(1H,d,J2.1),8.34(2H,d,J7.3),7.88(2H,d,J8.2),7.59(2H,d,J8.3),3.73–3.26(14H,m);
2-氨基-5-{4-[(2-二甲基氨基-乙基)-甲基-氨甲酰基]-苯基}-N-吡啶-4-基-烟酰胺("A90")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与N,N,N'-三甲基乙二胺反应,得到化合物"A90";
方法2:HPLC/MS:1.55min,[M+H]=419;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.08(1H,d,J2.1),8.80(2H,dd,J7.3,1.1),8.71(1H,d,J2.0),8.35(2H,d,J7.3),7.91(2H,d,J8.1),7.69(2H,d,J8.1),3.90(2H,t),3.46(2H,t),3.05(3H,s),2.95(6H,s);
2-氨基-5-{4-[(2-二甲基氨基-乙基)-乙基-氨甲酰基]-苯基}-N-吡啶-4-基-烟酰胺("A91")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与N'-乙基-N,N-二甲基-乙烷-1,2-二胺反应,得到化合物"A91";
方法1:HPLC/MS:1.08min,[M+H]=433;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.09(1H,d,J2.2),8.80(2H,d,J7.3),8.71(1H,d,J2.2),8.36(2H,d,J7.4),7.91(2H,d,J8.3),7.64(2H,d,J8.3),3.86(2H,t),3.44(2H,t,J6.4),3.41–3.27(2H,m),2.98(6H,s),1.14(3H,t,J6.6);
2-氨基-5-[4-(2-甲氧基-乙基氨甲酰基)-苯基]-N-吡啶-4-基-烟酰胺("A92")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与2-甲氧基-乙基胺反应,得到化合物"A92";
方法1:HPLC/MS:1.25min,[M+H]=392;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.10(1H,d,J2.2),8.81(2H,d,J7.3),8.74(1H,d,J2.2),8.35(2H,d,J7.4),8.11(2H,d,J8.5),7.91(2H,d,J8.5),3.55(4H,s),3.34(3H,s);
2-氨基-5-{4-[二-(2-羟基-乙基)-氨甲酰基]-苯基}-N-吡啶-4-基-烟酰胺("A93")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与2-(2-羟基-乙基氨基)-乙醇反应,得到化合物"A93";
方法2:HPLC/MS:1.62min,[M+H]=422;
1HNMR(500MHz,DMSO-d6)δ[ppm]8.57(1H,d,J2.3),8.49(2H,dd,J4.8,1.5),8.39(1H,d,J2.3),7.77(2H,d,J8.3),7.73(2H,dd,J4.8,1.5),7.49(2H,d,J8.3),3.64–3.46(8H,m);
2-氨基-5-[4-(3-甲氧基-丙基氨甲酰基)-苯基]-N-吡啶-4-基-烟酰胺("A94")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与3-甲氧基-丙基胺反应,得到化合物"A94";
方法1:HPLC/MS:1.30min,[M+H]=406;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.11(1H,d,J2.2),8.76(2H,d),8.69(1H,d,J2.1),8.37(2H,d,J7.3),8.07(2H,d,J3.3),7.88(2H,d,J8.4),3.48–3.45(4H,m),3.31(3H,s),1.88(2H,p,J6.5);
2-氨基-5-{4-[甲基-(3-甲基-3H-咪唑并l-4-基甲基)-氨甲酰基]-苯基}-N-吡啶-4-基-烟酰胺("A95")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与甲基-(3-甲基-3H-咪唑并l-4-基甲基)-胺反应,得到化合物"A95";
方法1:HPLC/MS:1.07min,[M+H]=442;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.09(1H,s),9.08(1H,d,J2.1),8.79(2H,d,J7.3),8.70(1H,d,J2.0),8.35(2H,d,J7.3),7.89(2H,d,J8.3),7.71(1H,s),7.68(2H,d,J8.3),3.97(2H,s),3.00(3H,s),2.79(3H,s);
2-{4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯并yl氨基}-乙基氨基甲酸叔丁酯("A96")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与(2-氨基-乙基)-氨基甲酸叔丁酯反应,得到化合物"A96";
方法1:HPLC/MS:1.47min,[M+H]=477;
2-氨基-5-{3-[(2-甲氧基-乙基)-甲基-氨甲酰基]-苯基}-N-吡啶-4-基-烟酰胺("A97")
3-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与N-(甲氧基-乙基)-甲基-胺反应,得到化合物"A97";
方法1:HPLC/MS:1.23min,[M+H]=406;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.03(1H,s),8.86(2H,d,J7.3),8.74(1H,s),8.31(2H,d,J7.4),7.88(2H,d,J1.6),7.62(1H,t,J7.9),7.49(1H,d,J7.7),3.73–2.96(10H,m);
2-氨基-5-(3-二乙基氨甲酰基-苯基)-N-吡啶-4-基-烟-酰胺("A98")
3-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与二乙胺反应,得到化合物"A98";
方法1:HPLC/MS:1.37min,[M+H]=390;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.04(1H,d,J2.1),8.85(2H,d,J7.2),8.74(1H,d,J2.1),8.31(2H,d,J7.2),7.89(1H,d,J8.1),7.84(1H,s),7.62(1H,t,J7.7),7.45(1H,d,J7.5),3.57–3.23(4H,m),1.28–1.01(6H,m);
2-氨基-5-(3-氨甲酰基-苯基)-N-吡啶-4-基-烟酰胺("A99")
3-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与氨反应,得到化合物"A99";
方法2:HPLC/MS:1.64min,[M+H]=334.
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.07(1H,d,J2.2),8.85(2H,d,J7.3),8.76(1H,d,J2.2),8.36(1H,t,J1.7),8.32(2H,d,J7.3),8.00(2H,td,J8.3,1.6),7.65(1H,t,J7.8);
2-氨基-5-(2-二乙基氨甲酰基-苯基)-N-吡啶-4-基-烟-酰胺("A100")
2-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与二乙胺反应,得到化合物"A100";
方法2:HPLC/MS:1.35min,[M+H]=390;
1HNMR(500MHz,DMSO-d6)δ[ppm]8.83(2H,d,J7.3),8.81(1H,d,J2.2),8.35(1H,d,J2.1),8.31(2H,d,J7.3),7.70–7.67(1H,m),7.62(1H,td,J7.6,1.3),7.56(1H,ddd,J6.0,5.5,1.4),7.45(1H,dd,J7.5,1.1),3.47–3.30(2H,m),3.03(2H,q,J7.0),1.02–0.91(3H,m);
2-氨基-5-(2-氨甲酰基-苯基)-N-吡啶-4-基-烟酰胺("A101")
2-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯甲酸与氨反应,得到化合物"A101";
方法1:HPLC/MS:1.05min,[M+H]=334;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]8.86(1H,d,J2.1),8.79(2H,d,J7.1),8.40(1H,d,J2.0),8.32(2H,d,J7.3),8.12(1H,dd,J7.8,0.9),7.75(1H,td,J7.6,1.1),7.64(1H,td,J7.7,0.9),7.57(1H,d,J7.5);
2-氨基-5-{3-氟-4-[(2-甲氧基-乙基)-甲基-氨甲酰基]-苯基}-N-吡啶-4-基-烟酰胺("A102")
4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-2-氟-苯甲酸与N-(甲氧基乙基)-甲胺反应,得到化合物"A102";
方法1:HPLC/MS:1.34min,[M+H]=424;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.09(1H,d,J2.0),8.81(2H,d,J7.2),8.76(1H,d,J2.2),8.35(2H,d,J7.3),8.08(1H,s),7.82–7.69(1H,m),7.57(1H,td,J7.6,2.9),3.72(1H,t,J5.5),3.63(1H,t,J5.5),3.43(2H,dd,J10.0,4.1),3.36(2H,s),3.23(1H,s),3.10(2H,s),2.97(1H,s)。
实施例13
2-氨基-5-(2-氨基-苯基)-N-吡啶-4-基-烟酰胺("A103")
13.12-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯基-氨基甲酸叔丁酯
参照"A62"的制备方法由2-氨基-5-溴代-N-(2-乙氧基-吡啶-4-基)-烟酰胺和[2-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-苯基]-氨基甲酸叔丁酯获得标题化合物;
方法1:HPLC/MS:1.34min,[M+H]=406.
13.22-氨基-5-(2-氨基-苯基)-N-吡啶-4-基-烟酰胺
将100mg{2-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯基}-氨基甲酸叔丁酯溶解在2ml二氯甲烷中。加入0.5mlHCl在二噁烷(4摩尔)中的溶液。混合物室温搅拌2小时。混合物过滤,用二氯甲烷洗涤固体。得到80mg化合物"A103"盐酸盐;
方法1:HPLC/MS:1.17min,[M+H]=306;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]8.99(1H,d,J2.2),8.85(2H,d,J7.3),8.49(1H,d,J2.1),8.43(2H,d,J7.5),7.68–7.55(4H,m)。
类似地,采用上文描述的程序获得以下化合物:
2-氨基-5-(3-氨基-苯基)-N-吡啶-4-基-烟酰胺("A104")
溶剂分解{3-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯基}-氨基甲酸叔丁酯,得到化合物"A104";
方法1:HPLC/MS:0.99min,[M+H]=306;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.02(1H,d,J2.2),8.86(2H,d,J7.3),8.69(1H,d,J2.2),8.37(2H,d,J7.3),7.94(1H,d,J8.1),7.86(1H,t,J1.8),7.70(1H,t,J7.9),7.54(1H,dd,J8.0,1.2);
2-氨基-5-[4-(2-氨基-乙基氨甲酰基)-苯基]-N-吡啶-4-基-烟酰胺("A105")
溶剂分解(2-{4-[6-氨基-5-(吡啶-4-基氨甲酰基)-吡啶-3-基]-苯并基氨基}-乙基)-氨基甲酸叔丁酯,得到化合物"A105";
方法2:HPLC/MS:1.57min,[M+H]=377;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]9.18(1H,d,J2.2),8.77(2H,d,J7.3),8.72(1H,d,J2.2),8.42(2H,d,J7.3),8.13(2H,d,J8.4),7.96(2H,d,J8.5),3.67(2H,t,J10.6,4.6),3.14(2H,t,J5.8)。
实施例14
2-氨基-N-吡啶-4-基-5-(2-氨磺酰基-苯基)-烟酰胺("A106")
14.12-氨基-5-(2-叔丁基氨磺酰基-苯基)-N-吡啶-4-基-烟-酰胺
按照"A62"的制备方法的步骤1中描述的程序由2-氨基-5-溴代-N-(2-乙氧基-吡啶-4-基)-烟酰胺与2-叔丁基氨磺酰基-苯硼酸反应,制成标题化合物;
方法1:HPLC/MS:1.41min,[M+H]=426;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]8.86–8.80(3H,m),8.39(1H,d,J2.1),8.28(2H,d,J7.3),8.15(1H,dd,J7.9,1.2),7.73(2H,dtd,J31.4,7.6,1.4),7.57(1H,dd,J7.6,1.2),1.09(9H,s)。
14.22-氨基-N-吡啶-4-基-5-(2-氨磺酰基-苯基)-烟酰胺("A106")
将20mg2-氨基-5-(2-叔丁基氨磺酰基-苯基)-N-吡啶-4-基-烟酰胺溶解在0.5ml三氟乙酸中。混合物在80℃搅拌14小时。反应混合物冷却至室温,加入2ml庚烷,真空蒸发溶剂,残留物溶解在二氯甲烷中,滤出得到的沉淀物,获得17mg化合物"A106",为三氟乙酯盐;
方法1:HPLC/MS:1.07min,[M+H]=370;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]8.86(1H,d,J2.2),8.82(2H,d,J7.3),8.42(1H,d,J2.2),8.33(2H,d,J7.5),8.18(1H,dd,J7.8,1.4),7.73(2H,dtd,J22.4,7.6,1.4),7.58(1H,dd,J7.4,1.4)。
实施例15
2-氨基-5-[4-(叔丁基氨基-甲基)-苯基]-N-吡啶-4-基-烟酰胺("A107")
15.12-氨基-5-(4-甲酰基-苯基)-N-吡啶-4-基-烟酰胺
按照"A62"的制备方法的步骤1中描述的程序由2-氨基-5-溴代-N-(2-乙氧基-吡啶-4-基)-烟酰胺和4-甲酰基苯硼酸反应,制成标题化合物;
方法1:HPLC/MS:1.29min,[M+H]=319;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]10.10(1H,s),9.08(1H,d,J2.2),8.86(2H,d,J7.2),8.82(1H,d,J2.2),8.32(2H,d,J7.3),8.12–8.05(4H,m)。
15.22-氨基-5-[4-(叔丁基氨基-甲基)-苯基]-N-吡啶-4-基-烟酰胺("A107")
将70mgNaB(OAc)3H加入至50mg2-氨基-5-(4-甲酰基-苯基)-N-吡啶-4-基-烟酰胺、20.6μl叔丁胺和9μl乙酸在0.5ml1,2-二氯乙烷和0.5ml四氢呋喃的混合物中。得到的悬液在50℃搅拌14小时。反应混合物用2NNaOH溶液碱化,用二氯甲烷萃取。有机层用盐水洗涤,然后分离,经Na2SO4干燥。滤掉干燥剂,真空除去溶剂。产物经色谱法纯化,得到10mg化合物"A107",为白色固体;
方法1:HPLC/MS:1.10min,[M+H]=376;
1HNMR(400MHz,DMSO-d6/TFA-d1)δ[ppm]9.05(1H,d,J2.2),8.84(2H,d,J7.3),8.75(1H,d,J2.2),8.34(2H,d,J7.3),7.94(2H,d,J8.4),7.73(2H,d,J8.4),4.20(2H,s),1.44(9H,s)。
实施例16
2-氨基-5-(2-乙基氨磺酰基-苯基)-N-吡啶-4-基-烟酰胺("A108")
在氩气气氛下,向反应容器加入100mg2-氨基-5-溴代-N-吡啶-4-基-烟酰胺、86mg联硼酸频那醇酯、5ml脱气N,N-二甲基-甲酰胺和134mg醋酸钾,室温搅拌。再向反应容器加入27mg(1,1'-双(二苯基膦基)二茂铁二氯化钯(II),80℃搅拌14小时。向该溶液加入108mg2-溴代-N-乙基-苯磺酰胺、27mg(1,1'-双(二苯基膦基)二茂铁二氯化钯(II)和200μl水。反应混合物在100℃搅拌14小时,冷却至室温,蒸发。产物经色谱法纯化,得到8mg化合物"A108";
方法1:HPLC/MS:1.32min,[M+H]=398;
1HNMR(500MHz,DMSO-d6/TFA-d1)δ[ppm]8.95(1H,d,J2.0),8.73(2H,d,J7.3),8.38(1H,d,J2.1),8.36(2H,d,J7.3),8.14(1H,d,J7.9),7.76(1H,t,J7.5),7.70(1H,t,J7.7),7.57(1H,d,J7.5),2.85(2H,q,J7.2),1.01(3H,t,J7.2)。
根据本发明的化合物抑制TBK1和IKKε的IC50值
以下实施例涉及药物:
实施例A:注射液瓶
将100g通式I化合物作为活性成分与5g磷酸二氢钠在3L再蒸馏水中的溶液用2N盐酸调它的pH至6.5,无菌过滤,转移到注射瓶中,无菌条件下冻干,并在无菌条件下密封。每个注射液瓶含有5mg活性成分。
实施例B:栓剂
将20g通式I化合物作为活性成分与100g大豆卵磷脂和1400g可可油混合,倒入模中,冷却。每片栓剂含20mg活性成分。
实施例C:溶液制剂
由1g作为活性成分的通式I化合物、9.38gNaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g苯扎氯铵在940mL再蒸馏水中制成一种溶液。将该溶液的pH调至6.8,再将该溶液配至1L,放射灭菌。该溶液以眼药水形式使用。
实施例D:软膏
在无菌条件下将500mg通式I化合物作为活性成分与99.5g凡士林混合。
实施例E:片剂
将1kg通式I化合物作为活性成分、4kg乳糖、1.2kg马铃薯粉、0.2kg滑石和0.1kg硬脂酸镁按照常规方法压成片剂,以致于每片含10mg活性成分。
实施例F:包衣片剂
类似实施例E压成片剂,然后按照常规方法用蔗糖包衣、马铃薯粉、滑石、黄芪胶和染料来包衣片剂。
实施例G:胶囊剂
将2kg通式I化合物作为活性成分按照常规方法导入硬胶囊中,以致于每个胶囊含20mg活性成分。
实施例H:安瓿剂
将1kg通式I化合物作为活性成分在60L再蒸馏水中的溶液无菌过滤,转移到安瓿中,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 (2)
1.一种化合物,选自以下组内,
及其药学上可用的盐、互变异构体和立体异构体,包括其所有比例的混合物。
2.一种药物,包含权利要求1所述的至少一种通式I化合物和/或其药学上可使用的盐、互变异构体和立体异构体,包括它们的各种比例的混合物,并任选地包含赋形剂和/或佐剂。
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