CN104093719A - 作为酪氨酸激酶抑制剂的三唑并吡啶衍生物 - Google Patents
作为酪氨酸激酶抑制剂的三唑并吡啶衍生物 Download PDFInfo
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Abstract
本发明提供了具有不可逆的酪氨酸激酶抑制活性的新三唑并吡啶衍生物,以及包含所述新三唑并吡啶衍生物的药物组合物,所述药物组合物可用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
Description
技术领域
本发明涉及具有不可逆的酪氨酸激酶抑制活性的新三唑并吡啶衍生物,以及包含作为活性成分的所述新三唑并吡啶衍生物的药物组合物。
背景技术
蛋白激酶是通过借助磷酸化向其他蛋白质的特定残基上化学地添加磷酸基来修饰所述蛋白质的酶。人类基因组包含约500个蛋白激酶基因,其占全部人基因的约2%。一般来说,可根据其底物将蛋白激酶分成3类:使丝氨酸和/或苏氨酸残基磷酸化的丝氨酸/苏氨酸特异性蛋白激酶、使酪氨酸残基磷酸化的酪氨酸特异性蛋白激酶、以及使酪氨酸和丝氨酸/苏氨酸残基磷酸化的蛋白激酶。蛋白激酶在介导响应于多种细胞外刺激的由细胞表面到细胞核的信号转导中具有关键作用。它们调节多种生理和病理的细胞现象,包括细胞分裂、增殖、分化、凋亡、细胞迁移、致有丝分裂等,因此其与多种疾病密切相关。这样的激酶相关疾病的实例是:自身免疫病,例如特应性皮炎、哮喘、类风湿性关节炎、克隆病(Crohn’s disease)、银屑病、克鲁宗综合征(Crouzon syndrome)、软骨发育不全和致死性发育不良;癌症,例如前列腺癌、结直肠癌、乳腺癌、脑癌和喉癌、白血病和淋巴瘤;糖尿病;再狭窄(restenosis);动脉粥样硬化;肾和肝纤维化;骨髓增生性疾病和淋巴增生性疾病;以及眼病。已知这些疾病直接或间接地由激酶调节机制的中断造成,例如激酶的突变、过表达或异常活化,影响上游或下游信号传导的生长因子或细胞因子的过量产生或不足量产生。因此,预期可通过选择性地对激酶的机制进行抑制来预防或治疗这样的疾病,因此在药物和化学领域已经进行了多种尝试来发现有效的蛋白激酶抑制剂。
同时,炎症是诸如类风湿性关节炎等疾病的病因。尽管最近发现了生物学治疗,但仍已经进行了持续的尝试以开发治疗炎症的有效药物。已经发现支持T细胞(或T淋巴细胞)和B细胞(或B淋巴细胞)对炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病和/或免疫介导的疾病的发作具有重要作用的多个证据。
这样的T细胞通过经由位于细胞表面上的T细胞受体(TCR)接收来自抗原呈递细胞的信号来介导信号转导,这激活多种激酶,例如Janus激酶(JAK),从而将信号传导至效应器。就这一点而言,可通过造血细胞因子和干扰素激活作为酪氨酸激酶的JAK蛋白,并且该过程可调节转录调节因子STAT蛋白的活化。基于抑制(或促进)JAK/STAT途径的治疗可能性可在免疫调节领域提供潜在的药物治疗。
在4种JAK蛋白中,认为JAK3与炎症相关,因为其仅在T细胞中表达并且被IL-2激活。与参与造血活动和红血球内稳态的JAK2或可在不同种类的组织中表达的JAK1不同,JAK3主要在淋巴细胞中表达,并且通过使用多种细胞因子(包括IL-2、IL-4、IL-7、IL-9、IL-15等)在信号传导中发挥非常重要的作用,因此,JAK3在副作用方面受到越来越多的关注(Flanagan等,Journal of Medicinal Chemistry,53,8468,2010)。根据动物研究,JAK3不仅在B细胞和T细胞的成熟中具有重要作用,而且还在维持T细胞的功能中具有重要作用。因此,JAK抑制剂(特别是JAK3抑制剂)可用于治疗自身免疫病,例如类风湿性关节炎、银屑病、特应性皮炎、狼疮、多发性硬化、I型糖尿病及糖尿病并发症、癌症、哮喘、甲状腺自身免疫病、溃疡性结肠炎、克隆病、阿尔茨海默病(Alzheimer’s disease)、白血病等,以及需要免疫抑制的多种病症,例如同种异体移植排斥和异种移植(Pesu M,Laurence A,Kishore N,等,Immunol. Rev,223,132,2008.;Kawahara A,Minami Y,Miyazaki T,等,Proc.Natl.Acad.Sci.USA,92,8724,1995;Nosaka T,van Deursen JMA,Tripp RA等,Science,270,800,1995;以及Papageorgiou AC,WikmanLEK.,等,Trends Pharm.Sci.,25,558,2004)。
同时,酪氨酸蛋白激酶(Bruton’s tyrosine kinase,BTK)是TEC激酶家族中的一种,其在B细胞的活化和信号转导中具有重要作用。1993年,发现BTK的突变与主要B细胞免疫缺陷即X连锁无丙种球蛋白血症(XLA)和小鼠X连锁免疫缺陷(XID)有关。还发现BTK是非受体蛋白酪氨酸激酶(NRPTK),其参与控制信号转导途径、B淋巴细胞的生长和分化。
BTK是B细胞发育、活化、信号传导和生存的关键调节剂(Kurosaki,Curr.Op.Imm.,276-281,2000;以及Schaeffer和Schwartzberg,Curr.Op.Imm.,282-288,2000)。此外,BTK在许多其他造血细胞信号传导通路中发挥作用,例如巨噬细胞中由toll样受体(TLR)或细胞因子受体介导的TNF-α产生、肥大细胞中IgE受体(FcepsilonRi)信号传导、B淋巴细胞中Fas/APO-1凋亡信号传导的抑制以及胶原蛋白刺激的血小板聚集。
BTK参与由多种细胞外配体与其细胞表面受体的结合引发的多种信号转导途径。在B细胞抗原受体(BCR)与抗原结合后,需要通过蛋白质酪氨酸激酶Lyn和Syk的协同作用激活BTK以诱导磷脂酶C-γ2介导的钙动员(Kurosaki,T.,Curr.Opin.Immunol.,9,309-318,1997)。因此,抑制BTK可成为有用的治疗选择,因为其防止B细胞介导的疾病的发展。
例如,已经证实BTK缺陷小鼠抗胶原诱导之关节炎中的疾病临床表现,且已经知道BTK抑制剂剂量依赖地有效抗小鼠中的胶原诱导之关节炎(Jansson和Holmdahl,Clin.Exp.Immunol.,94,459,1993;和Pan等,Chem.Med Chem.,2,58,2007)。因此,有效的BTK抑制剂可用于治疗类风湿性关节炎。
此外,抑制BTK活化可用于治疗自身免疫病和/或炎性疾病和/或变应性疾病,例如系统性红斑狼疮(SLE)、类风湿性关节炎、银屑病关节炎、骨关节炎、幼年型关节炎、糖尿病、重症肌无力、桥本甲状腺炎(Hashimoto’s thyroiditis)、多发性硬化、强直性脊柱炎、血管炎、炎性肠病、银屑病、全身脱毛(alopecia universalis)、特发性血小板减少性紫癜(ITP)、重症肌无力、变态反应、变应性结膜炎、变应性鼻炎、特发性皮炎和哮喘,但不限于此。另外,已知BTK调节细胞的凋亡,因此,抑制BTK活化也可用于治疗B细胞淋巴瘤和白血病。
如上文解释的,Janus激酶(例如JAK3和TEC激酶(例如BTK))在激活T细胞和/或B细胞中具有重要作用,其与炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病以及免疫介导的疾病的发展密切相关。因此,开发这样的激酶的有效抑制剂可导致发现用于治疗多种炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病以及免疫介导的疾病的强效药物。
目前,辉瑞(Pfizer)正在开发作为口服药的Tofacitinib(CP-690550)(作为JAK3的抑制剂)并且正在进行III期试验。作为BTK抑制剂的PCI-32765(Pharmacyclics)处于I期临床试验阶段,但是,已报道该药物可激活不同的靶标,并伴随有不利的副作用,包括皮疹和痢疾。因此,强烈需要可以安全且有效的方式抑制Janus激酶和TEC激酶的新药。
发明内容
因此,本发明的一个目的是提供抑制主要在异常激活的淋巴细胞(T淋巴细胞和/或B淋巴细胞)中表达的激酶的新化合物,所述激酶包括Janus激酶(如JAK3)和TEC激酶(如BTK(酪氨酸蛋白激酶,Burton’styrosine kinase)、ITK(IL2诱导型T细胞激酶)、BMX(骨髓酪氨酸激酶)、RLK(静息淋巴细胞激酶,resting lymphocyte kinase)等。
本发明另一目的是提供包含本发明化合物的药物组合物,其用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
本发明又一目的是提供用于通过使用所述化合物来预防和治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的方法。
本发明再一目的是提供所述化合物在制备用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的药物中的用途。
根据本发明的一个方面,提供了式(I)化合物或其可药用盐:
其中,
X是O、NH、CH2、S、SO或SO2;
Y是苯基或吡啶基;
Z是
n是0至4的整数;
R1各自独立地为氢、C1-6烷氧基或二(C1-6烷基)氨甲基;并且
W是苯基、吡啶基或者被选自以下的一个或更多个取代基取代的苯基:氢、卤素、羟基、氨基、C1-6烷基氨基、C1-6烷基杂环氨基、二(C1-6烷基)氨基C1-6烷基、杂环、羟基杂环、C1-6烷基杂环、羟基C1-6烷基杂环、C1-6烷氧基C1-6烷基杂环、杂环基羰基和杂环基C1-6烷基羰基,其中所述杂环为独立地含有一个或更多个选自N、O和S的杂原子的饱和3至8元单环杂环。
根据本发明的另一个方面,提供了药物组合物,其用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤,所述药物组合物包含式(I)化合物或其可药用盐。
根据本发明的又一个方面,提供了用于预防或治疗动物中的炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的方法,其包括向所述动物施用有效量的式(I)化合物或其可药用盐的步骤。
根据本发明的再一个方面,提供了式(I)化合物或其可药用盐在制备用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的药物中的用途。
根据本发明的新三唑并吡啶衍生物可选择性地并有效地抑制主要在异常活化的淋巴细胞(T淋巴细胞和/或B淋巴细胞)中表达的激酶,包括Janus激酶(如JAK3)和TEC激酶(如BTK、ITK、BMX和RLK)等。因此,根据本发明作为酪氨酸激酶抑制剂的新三唑并吡啶衍生物可用于预防或治疗通过异常活化的T淋巴细胞、B淋巴细胞或它们二者介导的疾病,例如炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
发明详述
在式(I)中,取代基W的具体实例可选自W1至W18,优选W2、W4、W9、W12或W17,但不限于此。
根据本发明的化合物的实例如下:
N-(3-(2-(4-(4-甲基哌嗪-1-基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺;
N-(3-(2-(3-氟-4-(1-甲基哌啶-4-基氨基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺;
N-(3-(2-(4-((二甲基氨基)甲基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺;
N-(3-(2-(4-(4-甲基哌嗪-1-羰基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺;以及
N-(3-(2-(4-(4-异丙基哌嗪-1-基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺。
本发明的式(I)化合物可通过下文所示反应方案I中示出的方法制备:
<反应方案I>
其中
X、Y、Z和W与上文定义相同。
在以下的逐步反应中对该反应过程进行举例说明。
例如,使式(9)化合物在二氯甲烷条件下与式(8)化合物进行缩合反应以得到式(7)缩合化合物。然后,可将盐酸羟胺和二异丙基乙胺添加至溶剂(例如甲醇和乙醇的混合溶剂)中,接着添加上文制备的式(7)化合物以得到式(6)化合物。
接下来,使式(6)化合物于140℃至150℃下在无机碱(例如碳酸铯、碳酸钠或碳酸钾)的存在下在有机溶剂(例如N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或N-甲基吡咯烷)中在搅拌下与X-Y-NO2(例如,3-氟硝基苯)反应以得到含有硝基的式(5)化合物。向式(5)化合物添加溴化铜和溴酸,随后,在-10℃至0℃下逐滴添加亚硝酸钠水溶液以得到含有溴基的式(4)化合物。
使上文制备的式(4)化合物于100℃至110℃下在钯催化剂或三氟乙酸的存在下在有机溶剂(例如1,4-二氧六环)中在搅拌下与W-NH2反应8小时以获得含有W-NH2基团的式(3)化合物。
可通过使式(3)化合物经历铁介导的还原反应或使用钯/碳作为催化剂的加氢反应将式(3)化合物的硝基转化为氨基以得到式(2)的苯胺化合物。
接着,可使式(2)化合物于-10℃至10℃的低温下在无机碱(如碳酸氢钠)或有机碱(如三乙胺或二异丙基乙胺)的存在下在有机溶剂(如二氯甲烷或四氢呋喃)或混合溶剂(如50%四氢呋喃水溶液)中与R1取代的丙烯酰氯反应;或者通过使用接合剂(binder)(例如吡啶中的1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDCI)或2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐甲铵(methanaminium)(HATU)使其与R1取代的丙烯酸反应以获得期望的含有丙烯酰胺基团的本发明的式(1)化合物。
本发明的式(I)化合物也可形成可药用的无机或有机酸加成盐。这样的盐的实例是由例如以下的酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、羟基乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸、甲苯磺酸等。
具体地,本发明的可药用盐可通过将式(I)化合物溶解在水溶性有机溶剂中随后添加有机或无机酸并过滤沉淀的晶体来制备,所述水溶性有机溶剂例如丙酮、甲醇、乙醇或乙腈。此外,其可通过以下来制备:在减压下从添加有酸的反应混合物中除去溶剂或过量的酸,随后干燥残余物,或者使用不同的有机溶剂进行离析(eduction)接着过滤沉淀的盐。
本发明的式(I)化合物或其可药用盐可以是溶剂合物或水合物的形式,并且这些化合物也涵盖在本发明的范围内。
本发明的式(I)化合物或其可药用盐可选择性地并有效地抑制蛋白激酶。在一个实施方案中,这些化合物可选择性地并有效地抑制主要在异常活化的淋巴细胞(T淋巴细胞和/或B淋巴细胞)中表达的激酶,包括Janus激酶3(JAK3)、酪氨酸蛋白激酶(BTK)、IL2诱导型T细胞激酶(ITK)、静息淋巴细胞激酶(RLK)和骨髓酪氨酸激酶(BMX),因此,可用于预防或治疗通过异常活化的B淋巴细胞、T淋巴细胞或它们二者介导的疾病,例如炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤。
因此,本发明提供了药物组合物,其用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤,所述药物组合物包含作为活性成分的式(I)化合物或其可药用盐。
所述炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病或免疫介导的疾病的实例可选自:关节炎、类风湿性关节炎、脊柱关节病、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节病症、狼疮、系统性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、特应性皮炎、疼痛、肺疾病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗死、充血性心力衰竭、心肌缺血再灌注损伤(cardiac reperfusioninjury)、炎性肠病、克隆病、溃疡性结肠炎、肠易激惹综合征、哮喘、舍格伦综合征(Sjogren’s syndrome)、自身免疫性甲状腺疾病、荨麻疹、多发性硬化、硬皮病、同种异体移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔茨海默病、糖尿病相关疾病、炎症、盆腔炎性疾病、变应性鼻炎、变应性支气管炎、变应性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴细胞白血病(ALL)、慢性淋巴细胞白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、多毛细胞白血病、霍奇金病、非霍奇金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥散性大B细胞淋巴瘤和滤泡型淋巴瘤,但不限于此。
另外,所述癌症和肿瘤的实例可选自:肝癌、肝细胞癌、甲状腺癌、结直肠癌、睾丸癌、骨癌、口腔癌、基底细胞癌、卵巢癌、脑肿瘤、胆囊癌、胆道癌、头颈癌、膀胱癌、舌癌、食道癌、神经胶质癌、胶质母细胞瘤、肾癌、恶性黑素瘤、胃癌、乳腺癌、肉瘤、咽癌(pharynx carcinoma)、子宫癌、宫颈癌、前列腺癌、直肠癌、胰腺癌、肺癌、皮肤癌和其他实体瘤,但是不限于此。
本发明的式(I)化合物或其可药用盐可与其他药物组合使用以增强在治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病或者免疫介导的疾病中的效力。
可与本发明化合物或其可药用盐组合用于治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病或者免疫介导的疾病的药物的实例是选自以下的一种或更多种药物:类固醇(泼尼松(prednisone)、泼尼松龙(prednisolone)、甲泼尼龙(methylprednisolone)、可的松(cortisone)、羟基可的松(hydroxycortisone)、倍他米松(betamethasone)、地塞米松(dexamethasone)等)、甲氨喋呤(methotrexate)、来氟米特(lefiuonomide)、抗TNF-α剂(依那西普(etanercept)、因福利美(infiiximab)、阿达木单抗(adalimumab)等)、钙调磷酸酶抑制剂(他克莫司(tacrolimus)、吡美莫司(pimecrolimus)等)和抗组胺剂(苯海拉明(diphenhydramine)、羟嗪(hydroxyzine)、氯雷他定(loratadine)、依巴斯汀(ebastine)、酮替芬(ketotifen)、西替利嗪(cetirizine)、左旋西替利嗪(levocetirizine)、非索非那定(fexofenadine)等),但不限于此。
可与本发明化合物或其可药用盐组合用于治疗癌症或肿瘤之药物的实例包括选自以下的一种或更多种:细胞信号转导抑制剂(格列卫(glivec)、易瑞沙(iressa)、特罗凯(tarceva)等)、有丝分裂抑制剂(长春新碱(vincristine)、长春碱(vinblastine)等)、烷基化剂(环磷酰胺(cyclophosphamide)、塞替派(thiotepa)、白消安(busulfan)等)、抗代谢物(替加氟(tagafur)、甲氨喋呤、吉西他滨(gemcitabine)等)、拓扑异构酶抑制剂(伊立替康(irinotecan)、拓扑替康(topotecan)、安吖啶(amsacrine)、依托泊苷(etoposide)、替尼泊苷(teniposide)等)、免疫治疗剂(干扰素α、β、γ、白细胞介素(interleukin)等)以及抗激素剂(他莫昔芬(tamoxifen)、亮丙瑞林(leuprorelin)、阿那曲唑(anastrozole)等),但不限于此。
本发明的化合物或其可药用盐可作为活性成分以约0.1mg/天至2,000mg/天、优选1mg/天至1,000mg/天的有效量每天1至4次或者依照/脱离时间表经口或肠胃外向人(约70kg体重)以单剂量或分剂量施用。可根据多种相关因素调整活性成分的剂量,所述相关因素例如待治疗对象的病情、疾病的类型和严重程度、施用途径(administration rate)和医生的意见。在某些情况下,少于上述剂量的量可为合适的。可使用大于上述剂量的量,除非其引起有害的副作用,并且这样的量可以每天分剂量施用。
本发明的药物组合物通常可包含可药用添加剂、载体或赋形剂。本发明的药物组合物可根据常规方法配制,并且可制备成口服制剂或肠胃外制剂的形式,所述口服制剂例如片剂、丸剂、散剂、胶囊剂、糖浆剂、乳剂、微乳剂等,所述肠胃外制剂例如肌内、静脉内或皮下施用。
对于口服制剂,可使用例如以下的载体或添加剂:纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、葡萄糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石、表面活性剂、助悬剂、乳化剂、稀释剂等。对于可注射制剂,可使用例如以下的载体或添加剂:水、盐水、葡萄糖溶液、葡萄糖溶液类似物、醇、二醇、醚(例如,聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、助悬剂、乳化剂等。
另外,本发明提供了用于预防或治疗动物中的炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的方法,其包括向所述动物施用有效量的式(I)化合物或其可药用盐的步骤。
本发明提供了式(I)化合物或其可药用盐在制备用于预防和治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的药物中的用途。
本发明的式(I)化合物可用于研究激酶的生物学和病理学现象,研究由激酶介导的细胞内信号传导通路以及对新激酶抑制剂的比较评价。
实施例
提供了以下实施例以说明本发明的优选实施方案,但是它们不限制本发明的范围。
实施例1:N-(3-(2-(4-(4-甲基哌嗪-1-基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺的制备
步骤1)N-(3-羟基-2吡啶基)-N’-乙氧羰基硫脲的制备
将二氯甲烷(100mL)添加至2-氨基-3-羟基吡啶(10.0g,0.091mol)中。将反应溶液冷却至0℃,并且向其中逐滴添加乙氧羰基异硫氰酸酯(11.3mL,0.1mol)。将该混合物温度升至室温并将混合物搅拌12小时。将形成的固体冷却至0℃,用20mL二氯甲烷洗涤,并且在减压下过滤。将如此得到的固体在减压下干燥以得到标题化合物(8.4g,产率:38%)。
步骤2)2-氨基-[1,2,4]三唑并[1,5-a]吡啶-8-醇的制备
在室温下,将乙醇和甲醇(1∶1)的混合溶剂(30mL)添加至盐酸羟胺(4.6g,0.066mol)中。将二异丙基乙胺(11.6mL,0.066mol)添加至该混合物中,接着搅拌1小时。将步骤1中获得的化合物(8.4g,0.035mol)添加到反应溶液中,接着在80℃或更高温度下回流2小时。将反应溶液冷却至0℃,搅拌1小时,用20mL蒸馏水洗涤所形成的固体并在减压下过滤。将如此得到的固体在减压下干燥以得到标题化合物(3.2g,产率:54%)。
1H-NMR(300MHz,DMSO-d6)δ5.80(s,2H),6.68(m,2H),8.01(d,1H).
步骤3)8-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺的制备
将N,N-二甲基甲酰胺(30mL)添加至步骤2中获得的化合物(3.2g,0.021mol)中。将3-氟硝基苯(2.7mL,0.026mol)和碳酸铯(13.9g,0.043mol)添加至反应溶液中。将所得混合物在150℃下搅拌6小时,然后用二氯甲烷、蒸馏水和氯化铵水溶液洗涤。分离出有机层,经无水硫酸钠干燥,过滤并在减压下蒸馏。将所得残余物经过柱色谱(二氯甲烷∶甲醇=60∶1(v∶v))分离以得到标题化合物(1.7g,产率:30%)。
1H-NMR(300MHz,DMSO-d6)δ6.14(s,2H),6.94(t,1H),7.35(d,2H),7.47(m,1H),7.64(m2H),7.96(d,1H),8.52(d,1H).
步骤4)2-溴-8-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]吡啶的制备
将溴酸(17mL,47%至49%)添加至步骤3中获得的化合物(1.7g,0.006mol)与溴化铜(0.42g,0.002mol)的混合物中。将反应溶液冷却至0℃,并向其中缓慢地逐滴添加通过将亚硝酸钠(0.52g,0.008mol)溶解于蒸馏水(3.5mL)中所制备的溶液。将反应溶液在室温下搅拌15小时,然后用二氯甲烷、蒸馏水和氯化铵水溶液洗涤。分离出有机层,经无水硫酸钠干燥,过滤并在减压下蒸馏。将所得残余物经过柱色谱(二氯甲烷∶甲醇=40∶1(v∶v))分离以得到标题化合物(1.8g,产率:86%)。
1H-NMR(300MHz,DMSO-d6)δ7.10(m2H),7.48(m,1H),7.60(t,1H),7.90(m,1H),8.06(dd,1H),8.43(dd,1H).
步骤5)N-(4-(4-甲基哌嗪-1-基)苯基-8-(3-硝基苯氧基)-[1,2,4]三唑并[1,5-a]
吡啶-2-胺的制备
将1,4-二氧六环(30mL)添加至步骤4中获得的化合物(1.8g,0.005mol)与4-(4-甲基哌嗪-1-基)苯胺(1.03g,0.005mol)的混合物中。将三(二亚苄基丙酮)二钯(0)(0.49g,0.001mol)和2,2’-双(二苯基膦基)-1,1’-联萘(0.33g,0.001mol)添加至该混合物中,接着在室温下搅拌5分钟。将碳酸铯(3.5g,0.011mol)添加至该反应混合物中,接着在100℃下搅拌8小时。将反应混合物冷却至室温,经硅藻土过滤器(Cellite filter)过滤,用二氯甲烷稀释并用水洗涤滤液。分离出有机层,经无水硫酸钠干燥,过滤并在减压下蒸馏。将所得残余物经过柱色谱(二氯甲烷∶甲醇=20∶1(v∶v))分离以得到标题化合物(0.91g,产率:38%)。
1H-NMR(300MHz,DMSO-d6)δ2.31(s,3H),2.62(m,4H),3.10(m,4H),6.97(m,3H),7.23(d,1H),7.44(m,3H),7.58(t,1H),7.85(m,1H),8.00(m,1H),8.41(d,1H).
步骤6)8-(3-氨基苯氧基)-N-(4-(4-甲基哌嗪-1-基)苯基)-[1,2,4]三唑并[1,5-a]
吡啶-2-胺的制备
将铁(0.57g,0.010mol)和12N盐酸水溶液(68μL,0.001mol)在50%乙醇水溶液中稀释,接着在100℃下搅拌1小时。将步骤5中获得的化合物(0.91g,0.002mol)溶解在50%乙醇水溶液(10mL)中,添加至含有活化铁的反应瓶中,接着在100℃下搅拌1小时。经硅藻土过滤器过滤反应混合物以便除去铁,并在减压下蒸馏滤液。用二氯甲烷稀释残余物,并用饱和碳酸氢钠水溶液洗涤。分离出有机层,经无水硫酸钠干燥,过滤并在减压下蒸馏。将所得残余物经过柱色谱(二氯甲烷∶甲醇=10∶1(v∶v))分离以得到标题化合物(0.76g,产率:90%)。
1H-NMR(300MHz,DMSO-d6)δ2.21(s,3H),2.44(m,4H),3.02(m,4H),5.22(s,2H),6.18(m,2H),6.32(m,1H),6.99(m,4H),7.12(d,1H),7.52(d,2H),8.57(d,1H),9.38(s,1H).
步骤7)N-(3-((2-((4-(4-甲基哌嗪-1-基)苯基)氨基)-[1,2,4]三唑并[1,5-a]吡啶
-8-基)氧基)苯基)丙烯酰胺的制备
将四氢呋喃(10mL)和蒸馏水(2mL)添加至步骤6中获得的化合物(0.76g,0.002mol)和碳酸氢钠(0.46g,0.006mol)中。在0℃下,将丙烯酰氯(0.18mL,0.002mol)缓慢地逐滴添加至反应溶液中,接着在室温下搅拌2小时。用二氯甲烷稀释反应混合物,然后用饱和碳酸氢钠水溶液洗涤。分离出有机层,经无水硫酸钠干燥,过滤并在减压下蒸馏。将所得残余物经过柱色谱(二氯甲烷∶甲醇=10∶1(v∶v))分离以得到标题化合物(0.34g,产率:40%)。
1H-NMR(300MHz,DMSO-d6)δ2.22(s,3H),2.50(m,4H),3.03(m,4H),5.73(dd,1H),6.23(dd,1h),6-33(m,1H),6.89(m,4H),7.38(m,5H),8.65(d,1H),9.40(s,1H),10.19(s,1H).
实施例2:N-(3-(2-(3-氟-4-(1-甲基哌啶-4-基氨基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺的制备
依次重复实施例1的步骤5、6和7的过程,不同之处是使用步骤4中获得的化合物(0.21g,约0.001mol)和2-氟-N1-(1-甲基哌啶-4-基)苯-1,4-二胺(0.14g,0.001mol),得到标题化合物(0.1g,产率:32%)。
1H-NMR(300MHz,DMSO-d6)δ1.43(m,1H),1.82(m,2H),1.95(m,2H),2.15(s,3H),2.72(m,2H),3.13(m,1H),4.53(d,1H),5.73(dd,1H),6.24(dd,1H),6.35(dd,1H),6.79(m,2H),6.99(t,1H),7.12(dd,1H),7.40(m,5H),8.66(d,1H),9.45(s,1H),10.22(s,1H).
实施例3:N-(3-(2-(4-((二甲基氨基)甲基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺的制备
依次重复实施例1的步骤5、6和7的过程,不同之处是使用步骤4中获得的化合物(0.45g,0.001mol)和4-((二甲基氨基)甲基)苯胺(0.2g,0.001mol),得到标题化合物(0.11g,产率:23%)。
1H-NMR(300MHz,DMSO-d6)δ2.10(s,6H),3.28(s,2H),5.73(dd,1H),6.24(dd,1H),6.33(dd,1H),6.80(dd,1H),7.00(t,1H),7.15(m,2H),7.32(m,4H),7.56(d,2H),8.69(d,1H),9.70(s,1H),10.22(s,1H).
实施例4:N-(3-(2-(4-(4-甲基哌嗪-1-羰基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺的制备
依次重复实施例1的步骤5、6和7的过程,不同之处是使用步骤4中获得的化合物(0.35g,0.001mol)和(4-氨基苯基)(4-甲基哌嗪-1-基)甲酮(0.23g,0.001mol),得到标题化合物(0.13g,产率:25%)。
1H-NMR(300MHz,DMSO-d6)δ2.19(s,3H),2.30(m,4H),3.48(m,4H),5.74(dd,1H),6.22(dd,1H),6.37(dd,1H),6.80(d,1H),7.04(t,1H),7.32(m,4H),7.41(m,2H),7.66(d,2H),8.71(d,1H),10.21(s,1H),10.29(s,1H).
实施例5:N-(3-(2-(4-(4-异丙基哌嗪-1-基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺的制备
依次重复实施例1的步骤5、6和7的过程,不同之处是使用步骤4中获得的化合物(0.37g,0.001mol)和4-(4-异丙基哌嗪)(0.24g,0.001mol),得到标题化合物(0.15g,产率:27%)。
1H-NMR(300MHz,DMSO-d6)δ1.02(d,6H),2.50(s,3H),2.60(m,4H),3.02(m,4H),3.40(m,1H),5.73(dd,1H),6.23(dd,1H),6.33(m,1H),6.89(m,4H),7.38(m,5H),8.64(d,1H),9.41(s,1H),10.19(s,1H).
制剂实施例1:片剂的制备
根据常规方法,基于表1中示出的组成和量制备了包含实施例1至5中获得的每种式(I)化合物作为活性成分的用于经口施用的单片剂。
[表1]
组成 | 量/片剂 |
活性成分 | 100mg |
玉米淀粉 | 80mg |
乳糖 | 80mg |
硬脂酸镁 | 5mg |
制剂实施例2:胶囊剂的制备
根据常规方法,基于表2中示出的组成和量制备了包含实施例1至5中获得的每种式(I)化合物作为活性成分的用于经口施用的硬明胶胶囊剂。
[表2]
组成 | 量/胶囊剂 |
活性成分 | 100mg |
玉米淀粉 | 40mg |
乳糖 | 80mg |
结晶纤维素 | 80mg |
硬脂酸镁 | 5mg |
制剂实施例3:可注射制剂的制备
根据常规方法,基于表3中示出的组成和量制备了包含实施例1至5中获得的每种式(I)化合物作为活性成分的可注射制剂,其中,当使用式(I)化合物的盐时,未调节pH值。
[表3]
组成 | 量/可注射制剂 |
活性成分 | 20mg |
5%葡萄糖溶液 | 10mL |
HCl(1N) | 适量至pH4 |
制剂实施例4:可注射制剂的制备
根据常规方法,基于表4中示出的组成和量制备了包含实施例1至5中获得的每种式(I)化合物作为活性成分的可注射制剂。
[表4]
组成 | 量/可注射制剂 |
活性成分 | 20mg |
聚乙二醇400 | 2mL |
无菌水 | 8mL |
测试例1:JAK3和BTK抑制活性的评价
测试在实施例1至5中制备的化合物对于JAK3和BTK激酶的抑制活性。通过使用Z-Lyte激酶分析试剂盒(Invitrogen)测量激酶抑制活性,JAK3和BTK酶购自Invitrogen(PV3855,PV3190)。
具体地,用4%DMSO水溶液稀释实施例1至5的化合物,得到浓度为1μM至0.0001μM的溶液。将每一种激酶都稀释为1ng/测定至10ng/测定,并通过计算近似Kd值将ATP稀释以形成激酶缓冲液(50mMHEPES,pH7.4;10mM MgCl2;1mM EGTA;和0.01%BRIJ-35)。在384孔聚苯乙烯平底板上进行测定。将具有合适浓度的肽底物、10μL混合的激酶溶液和5μL浓度为5μM至300μM的ATP溶液添加至5μL稀释的化合物溶液中,并使之在室温下于混合器中反应60分钟。60分钟后,向每一种混合物中添加10μL荧光标记试剂以使得对肽底物进行荧光标记,然后添加完成溶液(finishing solution)以完成反应。使用MolecularDevice在400nm处(激发滤光片(excitation filter))和520nm处(发射滤光片(emission filter))测定荧光水平。根据试剂盒的参考方案,相对于对照组(星形孢菌素或每一种激酶抑制剂)以0%至100%的磷酸化率计算化合物的激酶抑制活性,测定抑制百分比并对浓度(x轴)作图以计算50%抑制浓度(IC50)。通过使用Microsoft Excel进行IC50的计算和分析。结果在表5中示出。
在表5中,A是指IC50≤100nM;B是指IC50=100nM至500nM;C是指IC50=500nM至1,000nM;并且D是指IC50≥1,000nM。
[表5]
Claims (11)
1.式(I)化合物或其可药用盐:
其中,
X是O、NH、CH2、S、SO或SO2;
Y是苯基或吡啶基;
Z是
n是0至4的整数;
R1各自独立地为氢、C1-6烷氧基或二(C1-6烷基)氨甲基;并且
W是苯基、吡啶基或者被选自以下的一个或更多个取代基取代的苯基:氢、卤素、羟基、氨基、C1-6烷基氨基、C1-6烷基杂环氨基、二(C1-6烷基)氨基C1-6烷基、杂环、羟基杂环、C1-6烷基杂环、羟基C1-6烷基杂环、C1-6烷氧基C1-6烷基杂环、杂环基羰基和杂环基C1-6烷基羰基,其中所述杂环为独立地含有一个或更多个选自N、O和S的杂原子的饱和3至8元单环杂环。
2.根据权利要求1所述的化合物,其中W选自:
3.根据权利要求1所述的化合物,其选自:
N-(3-(2-(4-(4-甲基哌嗪-1-基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺;
N-(3-(2-(3-氟-4-(1-甲基哌啶-4-基氨基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺;
N-(3-(2-(4-((二甲基氨基)甲基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺;
N-(3-(2-(4-(4-甲基哌嗪-1-羰基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺;以及
N-(3-(2-(4-(4-异丙基哌嗪-1-基)苯基氨基)-[1,2,4]三唑并[1,5-a]吡啶-8-基氧基)苯基)丙烯酰胺。
4.药物组合物,其用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤,所述药物组合物包含作为活性成分的根据权利要求1所述的式(I)化合物或其可药用盐。
5.根据权利要求4所述的药物组合物,其中所述炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤由选自以下的一种或更多种激酶介导:Janus激酶3(JAK3)、酪氨酸蛋白激酶(BTK)、IL-2诱导型T细胞激酶(ITK)、静息淋巴细胞激酶(RLK)和骨髓酪氨酸激酶(BMX)。
6.根据权利要求4所述的药物组合物,其中所述炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤由异常活化的T淋巴细胞、B淋巴细胞或它们二者介导。
7.根据权利要求4所述的药物组合物,其中所述炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病或免疫介导的疾病选自:关节炎、类风湿性关节炎、脊柱关节病、痛风性关节炎、骨关节炎、幼年型关节炎、其他关节病症、狼疮、系统性红斑狼疮(SLE)、皮肤相关疾病、银屑病、湿疹、皮炎、特应性皮炎、疼痛、肺疾病、肺部炎症、成人呼吸窘迫综合征(ARDS)、肺结节病、慢性肺部炎性疾病、慢性阻塞性肺病(COPD)、心血管疾病、动脉粥样硬化、心肌梗死、充血性心力衰竭、心肌缺血再灌注损伤、炎性肠病、克隆病、溃疡性结肠炎、肠易激惹综合征、哮喘、舍格伦综合征、自身免疫性甲状腺疾病、荨麻疹、多发性硬化、硬皮病、同种异体移植排斥、异种移植、特发性血小板减少性紫癜(ITP)、帕金森病、阿尔茨海默病、糖尿病相关疾病、炎症、盆腔炎性疾病、变应性鼻炎、变应性支气管炎、变应性鼻窦炎、白血病、淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、骨髓瘤、急性淋巴细胞白血病(ALL)、慢性淋巴细胞白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、多毛细胞白血病、霍奇金病、非霍奇金淋巴瘤、多发性骨髓瘤、骨髓增生异常综合征(MDS)、骨髓增生性肿瘤(MPN)、弥散性大B细胞淋巴瘤和滤泡型淋巴瘤。
8.根据权利要求4所述的药物组合物,其还包含作为活性成分的选自以下的另外的抗癌剂:细胞信号转导抑制剂、有丝分裂抑制剂、烷基化剂、抗代谢物、嵌入剂(intercalating agent)、拓扑异构酶抑制剂、免疫治疗剂、抗激素剂及其混合物。
9.根据权利要求4所述的药物组合物,其还包含作为活性成分的选自以下的另外的药物:类固醇、甲氨喋呤、来氟米特、抗TNF-α剂、钙调磷酸酶抑制剂、抗组胺剂及其混合物。
10.用于预防或治疗动物中的炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的方法,所述方法包括向所述动物施用有效量的根据权利要求1所述的式(I)化合物或其可药用盐的步骤。
11.根据权利要求1所述的式(I)化合物或其可药用盐在制备用于预防或治疗炎性疾病、自身免疫病、增殖性疾病或过度增殖性疾病、免疫介导的疾病、癌症或肿瘤的药物中的用途。
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KR10-2012-0012758 | 2012-02-08 | ||
PCT/KR2013/000539 WO2013118986A1 (en) | 2012-02-08 | 2013-01-23 | Triazolopyridine derivatives as a tyrosine kinase inhibitor |
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CN107021963A (zh) | 2016-01-29 | 2017-08-08 | 北京诺诚健华医药科技有限公司 | 吡唑稠环类衍生物、其制备方法及其在治疗癌症、炎症和免疫性疾病上的应用 |
JOP20170113B1 (ar) * | 2016-05-09 | 2023-03-28 | Bayer Pharma AG | مركبات 5، 6، 7، 8-رباعي هيدرو [1، 2، 4] تريازولو [4، 3-أ] بيريدين 3(2h)-ون مستبدلة ومركبات 2، 5، 6، 7-رباعي هيدرو-3h-بيرولو [2، 1-ج] [1، 2، 4] تريازول-3-ون واستخداماتها |
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BR112014017701A2 (zh) | 2017-06-20 |
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WO2013118986A1 (en) | 2013-08-15 |
HK1201824A1 (zh) | 2015-09-11 |
IN2014DN07266A (zh) | 2015-04-24 |
RU2014136170A (ru) | 2016-03-27 |
JP2015506974A (ja) | 2015-03-05 |
US20140364438A1 (en) | 2014-12-11 |
CA2862718A1 (en) | 2013-08-15 |
BR112014017701A8 (pt) | 2017-07-11 |
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MX2014009524A (es) | 2014-09-08 |
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