CN104788430B - 吡唑衍生物钙释放激活钙通道调节剂及非小细胞肺癌的治疗方法 - Google Patents
吡唑衍生物钙释放激活钙通道调节剂及非小细胞肺癌的治疗方法 Download PDFInfo
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Abstract
公开了新型钙释放激活钙(CRAC)通道抑制剂、其制备方法、含有其的药物组合物和使用其的治疗方法。本公开还涉及用CRAC抑制剂治疗非小细胞肺癌(NSCLC)的方法,并且涉及鉴定用于治疗和诊断癌症的治疗剂的方法。
Description
本申请是申请号为201080055388.5、发明名称为“吡唑衍生物钙释放激活钙通道调节剂及非小细胞肺癌的治疗方法”的申请的分案申请,该母案申请是2010年10月7日提交的PCT申请PCT/IB2010/002539进入中国国家阶段的申请。
本申请要求2009年10月8日提交的印度临时专利申请案No.2440/CHE/2009;2009年10月30日提交的印度临时专利申请案No.2636/CHE/2009;2010年1月25日提交的印度临时专利申请案No.158/CHE/2010;2010年6月2日提交的印度临时专利申请案No.1513/CHE/2010;2010年6月2日提交的印度临时专利申请案No.1514/CHE/2010;以及2010年8月19日提交的印度临时专利申请案No.2385/CHE/2010和2009年12月1日提交的美国临时专利申请案No.61/265,540的利益,每个申请案通过引用特此并入。
技术领域
本发明涉及式I的钙释放激活钙(CRAC)通道抑制剂及其药学上可接受的盐、其制备方法、含有其的药物组合物和使用其的治疗方法。
本发明还涉及用CRAC抑制剂治疗非小细胞肺癌(NSCLC)的方法和鉴定用于治疗和诊断癌症的治疗剂的方法。
背景技术
细胞内钙的调控是进入细胞和细胞内信号转导的关键要素。通过钙依赖过程引发对生长因子、神经递质、激素和多种其它信号分子的细胞反应。钙离子作为第二信使的重要性通过许多一起工作以维持钙稳态的不同机制来强调。细胞内游离钙离子浓度的变化表示调控众多细胞反应最广泛和最重要的信号转导事件。钙离子进入细胞内的广泛路线是通过钙池操纵通道(SOC),即许多细胞类型采用钙池操纵型钙离子入口作为钙离子流入的主要途径。在钙离子从钙池释放后使用这种机制,其中钙池排空导致钙释放激活钙(CRAC)通道的激活。
通过从细胞内钙池,尤其从内质网(ER)释放钙激活钙池操纵通道的亚科CRAC通道。这些通道是调控广泛细胞功能的关键因子,包括肌肉收缩、蛋白质和液体分泌和对细胞生长和增殖的控制,因此在各种疾病(例如免疫性病症)和变态反应中起基本作用。在若干生物物理学上不同的钙池操纵电流中,最有特点且最具钙离子选择性之一是CRAC电流。因此,CRAC通道介导从分泌到基因表达和细胞生长的基本功能并形成免疫细胞激活所必需的网络,以建立适应性免疫反应。最近,已鉴定两种蛋白质,基质相互作用分子(STIM1)和CRAC调节剂1(CRACM1或Orai1)为具有相似生物物理指纹图谱的异源表达系统中完全重构和增强CRAC电流的基本组分。哺乳动物中,存在这些蛋白质的若干同系物:内质网中的STIM1和STIM2和质膜中的CRACM1、CRACM2和CRACM3。
最初在淋巴细胞和肥大细胞中发现CRAC电流,并且同时在各种细胞系,例如S2果蝇、DT40B细胞、肝细胞、树突细胞、巨核细胞和犬肾上皮细胞中已表征CRAC电流。在淋巴细胞和肥大细胞中,通过抗原或Fc受体的激活引发由第二信使(1,4,5)-三磷酸肌醇(Ins(1,4,5)P3)引起的从细胞内钙池释放钙离子,这依次导致通过质膜中的CRAC通道钙离子流入。来自各种组织的平滑肌、A431表皮细胞、内皮细胞和前列腺癌细胞系中表征的钙池操纵Ca2+电流表现出生物物理特征改变,表明分子来源不同。
例如,流过细胞膜的钙离子在淋巴细胞激活和适应性免疫反应中很重要。已证明通过TCR(T细胞抗原受体)刺激引起的[Ca2+]振荡显著并且似乎仅涉及单条钙离子流动途径,钙池操纵型CRAC通道。见,例如,Lewis″Calcium signalling mechanisms in Tlymphocytes,″Annu.Rev.Immunol.19,(2001),497-521;Feske等″Ca++calcineurinsignalling in cells of the immune system,″Biochem.Biophys.Res.Commun.311,(2003),1117-1132;Hogan等″Transcriptional regulation by calcium,calcineurin,and NFAT,″Genes Dev.17,(2003)2205-2232。
目前已确证,细胞内钙在各种细胞功能中起重要作用,并且其浓度经由流过细胞膜上的钙通道的钙离子调控。位于神经、内分泌、心血管和骨骼系统中并且受膜电位调节的钙离子通道称为电压操纵型Ca2+(VOC)通道。这些通道分为L、N、P、Q、R和T亚型。流过VOC通道的过量Ca2+引起高血压和脑部功能障碍。相反,不管膜电位如何,可激活炎症细胞(包括淋巴细胞、肥大细胞和嗜中性粒细胞)上的钙离子通道。已经证明这种类型的钙离子通道在炎症和自身免疫性疾病的危象和恶化中起作用。在T细胞中,已报道早期激活阶段由预Ca2+和后Ca2+事件组成。T细胞受体的刺激诱导预Ca2+事件,包括生成IP3,然后Ca2+从内质网(ER)释放。在后Ca2+事件中,ER中Ca2+排空诱导CRAC通道激活,并且通过CRAC通道的容量性Ca2+流维持细胞内高Ca2+浓度([Ca2+]i)。这样延长的高[Ca2+]i激活细胞溶质信号转导以生成脂质介体(例如,LTD4)、细胞因子[例如,白细胞介素-2(IL-2)]和基质金属蛋白酶,其参与炎症和自身免疫性疾病的发病机制。
这些事实表明CRAC通道调节剂可用于治疗炎症细胞激活引起的疾病,而没有在甾族化合物中观察到的副作用。因为VOC通道调节剂将引起神经和心血管系统的不良事件,因此对于CRAC通道调节剂而言,如果用作抗炎药物,可能必须表现出对VOC通道的足够选择性。
因此,据信CRAC通道调节剂用于钙释放激活钙通道相关疾病或病症的治疗、预防和/或改善,所述疾病或病症包括但不限于炎症、肾小球性肾炎、葡萄膜炎、肝脏疾病或病症、肾脏疾病或病症、慢性阻塞性肺病、类风湿性关节炎、炎症性肠病、脉管炎、皮炎、骨关节炎、炎症性肌肉疾病、过敏性鼻炎、阴道炎、间质性膀胱炎、硬皮病、骨质疏松症、湿疹、同种或异种移植、移植排斥、移植物抗宿主病、红斑狼疮、I型糖尿病、肺纤维化、皮肌炎、甲状腺炎、重症肌无力、自身免疫性溶血性贫血、囊性纤维化、慢性复发性肝炎、原发性胆汁性肝硬变、变应性结膜炎、肝炎和特应性皮炎、哮喘、干燥综合征、癌症和增生性疾病以及自身免疫性疾病或病症。见,例如,国际公布No.WO 2005/009954、WO 2005/009539、WO 2005/009954、WO 2006/034402、WO 2006/081389、WO 2006/081391、WO 2007/087429、WO 2007/087427、WO2007087441、WO 200/7087442、WO 2007/087443、WO 2007/089904、WO 2007109362、WO2007/112093、WO 2008/039520、WO 2008/063504、WO 2008/103310、WO 2009/017818、WO2009/017819、WO 2009/017831、WO 2010/039238、WO 2010/039237、WO 2010/039236、WO2009/089305和WO 2009/038775和美国公布No.:US 2006/0173006和US 2007/0249051。
已经鉴定的CRAC通道抑制剂包括SK&F 96365(1)、益康唑(2)和L-651582(3)。
然而,这些分子缺乏足够效力和对VOC通道的选择性,因此不适于治疗使用。
Taiji等(European Journal of Pharmacology,560,225-233,2007)和YasurioYonetoky等(Bio.&Med.Chem.,16,9457-9466,2008)的最近公布描述了能够抑制T细胞功能并且提出在包括支气管哮喘在内的炎症性疾病的治疗中有一些益处,代码为YM-58483的选择性CRAC通道抑制剂。
Yasurio Yonetoky等公开了在电压操纵型通道(VOC)中对CRAC通道有选择性的YM-58483,选择性指数为31。
公开的其它CRAC通道调节剂包括各种联芳基和/或杂环甲酰苯胺化合物,包括(例如)转让给Synta Pharmaceuticals的PCT或US专利申请案,即WO 2005/009954、WO 2005/009539、WO 2005/009954、WO 2006/034402、WO 2006/081389、WO 2006/081391、WO 2007/087429、WO 2007/087427、WO 2007087441、WO 200/7087442、WO 2007/087443、WO 2007/089904、WO 2007109362、WO 2007/112093、WO 2008/039520、WO 2008/063504、WO 2008/103310、WO 2009/017818、WO 2009/017819、WO 2009/017831、WO 2010/039238、WO 2010/039237、WO 2010/039236、WO 2009/089305和WO 2009/038775、US 2006/0173006和US2007/0249051。
涉及CRAC通道调节剂的其它专利公布包括Astellas、Queens Medical Centre、Calcimedica和其它的申请案,即WO 2007/121186、WO 2006/050214、WO 2007/139926、WO2008/148108、US 7,452,675、US 2009/023177、WO 2007/139926、US 6,696,267、US 6,348,480、WO 2008/106731、US 2008/0293092、WO 2010/048559、WO 2010/027875、WO 2010/025295、WO 2010/034011、WO 2010/034003、WO 2009/076454、WO 2009/035818、US 2010/0152241、US 2010/0087415、US 2009/0311720和WO 2004/078995。
CRAC通道领域的更多评论和文献公开包括Isabella Derler等,Expert Opinionin Drug Discovery,3(7),787-800,2008;Yousang G等,Cell Calcium,42,145-156,2007;Yasurio Yonetoky等,Bio.&Med.Chem.,14,4750-4760,2006;和Yasurio Yonetoky等,Bio.&Med.Chem.,14,5370-5383,2006。为了所有目的,将所有这些专利和/或专利申请案和文献公开通过引用并入本文。
癌症是印度、美国和世界许多其它地区的主要公共健康问题。现在,在印度1/4的死亡归因于癌症。由于肺癌的发病率和死亡率高,所以肺癌是全世界癌症死亡的主要原因,对于非小细胞肺癌(NSCLC)而言,5年幸存率估计为~10%。已报道为提高存活率需要对肺癌的肿瘤发生和化学抗性机制作进一步研究(Jemal A等,Cancer Statistics,CA Cancer.J.Clin.,56,106-130,2006)。有4种主要的NSCLC类型,即,腺癌、鳞状细胞癌、支气管肺泡癌和大细胞癌。基于细胞形态,腺癌和鳞状细胞癌是最常见的NSCLC类型(Travis等,LungCancer Principles and Practice,Lippincott-Raven,New York,361-395,1996)。腺癌特征在于在肺部中更外周的位置并且常常具有K-ras致癌基因突变(Gazdar等,AnticancerRes.,14,261-267,1994)。鳞状细胞癌通常位于更中心并且通常携带p53基因突变(Niklinska等,Folia Histochem.Cytobiol.,39,147-148,2001)。
大多数NSCLC特征在于存在ras突变,从而致使患者对通过已知激酶抑制剂的治疗相对不敏感。因此,目前的肺癌治疗通常受细胞毒性药物、手术和放射疗法的限制。需要有较少副作用并且更特异性靶向癌细胞,较少侵入且改善患者预后的治疗。
肺部肿瘤始发细胞和相关标记的鉴定可用于优化治疗方法和肺癌患者的预测和预后信息。因此,仍需要预测、评估和治疗受肺癌折磨的患者的新方法。
仍保持对对Stim1和/或Orai1有特异性的小分子调节剂的未满足且迫切的需要以调控和/或调节CRAC通道的活性,尤其是对于CRAC相关疾病和病症的治疗。
发明内容
本发明涉及式(I)的化合物及其制备方法,包含所述化合物的药物组合物和用所述化合物的治疗方法。
尤其,涉及式(I)的化合物及其药学上可接受的盐为用于治疗、预防、抑制和/或改善钙释放激活钙通道相关疾病或病症的钙释放激活钙通道调节剂。
一方面,本发明涉及式(I)的化合物:
或其互变异构体、前药、N-氧化物、药学上可接受的酯或药学上可接受的盐,其中
环Hy表示
任选地被R”’取代;
R1和R2相同或不同且独立地选自CH3、CH2F、CHF2、CF3、经取代或未经取代的C(3-5)环烷基、CH2-ORa、CH2-NRaRb、CN和COOH,条件是:
a)R1和R2不同时表示CF3;
b)R1和R2不同时表示CH3;
c)当R1为CF3时,则R2不为CH3;和
d)当R1为CH3时,则R2不为CF3;
环Ar表示:
T、U、V和W相同或不同且独立地选自CRa和N;
Z1、Z2和Z3相同或不同且独立地选自CRa、CRaRb、O、S和-NRa,条件是Z1、Z2和Z3的至少一个表示O、S或-NRa;
L1与L2一起表示-NH-C(=X)-、-NH-S(=O)q-、-C(=X)NH-或-S(=O)qNH-或-NH-CR’R”-;
A不存在或选自-(CR’R”)-、O、S(=O)q、C(=X)和-NRa;
R’和R”相同或不同且独立地选自氢、羟基、氰基、卤素、-ORa、-COORa、-S(=O)q-Ra、-NRaRb、-C(=X)-Ra、经取代或未经取代的C(1-6)烷基基团、经取代或未经取代的C(1-6)烯基、经取代或未经取代的C(1-6)炔基和经取代或未经取代的C(3-5)环烷基,或R’和R”可连接形成经取代或未经取代的饱和或不饱和3-6元环,所述环可任选地包括一个或多个可相同或不同且选自O、NRa和S的杂原子;
R”’选自氢、羟基、氰基、卤素、-ORa、-COORa、-S(=O)q-Ra、-NRaRb、-C(=X)-Ra、经取代或未经取代的C(1-6)烷基基团、经取代或未经取代的C(1-6)烯基、经取代或未经取代的C(1-6)炔基和经取代或未经取代的C(3-5)环烷基。
每次出现的X独立地选自O、S和-NRa;
Cy为选自经取代或未经取代的环烷基基团、经取代或未经取代的杂环基、经取代或未经取代的芳基和经取代或未经取代的杂芳基的双环;每次出现的Ra和Rb相同或不同且独立地选自氢、硝基、羟基、氰基、卤素、-ORc、-S(=O)q-Rc、-NRcRd、-C(=Y)-Rc、-CRcRd-C(=Y)-Rc、-CRcRd-Y-CRcRd-、-C(=Y)-NRcRd-、-NRRd-C(=Y)-NRcRd-、-S(=O)q-NRcRd-、-NRcRd-S(=O)q-NRcRd-、-NRcRd-NRcRd-、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基、经取代或未经取代的杂环基、经取代或未经取代的杂环基烷基、经取代或未经取代的芳基、经取代或未经取代的芳基烷基、经取代或未经取代的杂芳基和经取代或未经取代的杂芳基烷基,或当Ra和Rb与同一原子直接结合时,它们可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括一个或多个可相同或不同且选自O、NRc和S的杂原子;
每次出现的Rc和Rd相同或不同且独立地选自氢、硝基、羟基、氰基、卤素、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基、经取代或未经取代的杂环基团、经取代或未经取代的杂环基烷基,或当两个Rc和/或Rd取代基与同一原子直接结合时,它们可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括一个或多个可相同或不同且选自O、NH和S的杂原子;
每次出现的Y选自O、S和-NRa;并且
每次出现的q独立表示0、1或2;
条件(e)是式(I)的化合物不为:
N-[4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基]-1-甲基-3-(三氟甲基)-1H-噻吩并[2,3-c]吡唑-5-甲酰胺或N-[4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基]-吡唑并[1,5-a]嘧啶-2-甲酰胺。
在一个优选的实施方案中,R1为环丙基。
在一个优选的实施方案中,R2为环丙基。
根据一个优选的实施方案,Hy为
更优选的是式(I)的化合物,其中Hy为
更优选的是式(I)的化合物,其中Hy为
根据一个优选的实施方案,Ar为
更优选的是式(I)的化合物,其中Ar为
更优选的是式(I)的化合物,其中Ar为
根据一个优选的实施方案,L1与L2一起表示-NH-C(=O)-、-NH-S(=O)q-、-C(=O)NH-或-NH-CH2-。
根据一个优选的实施方案,A不存在或选自-(CR’R”)-、O、S(=O)q、C(=X)和-NRa。更优选地,A为-CH2-、-CHMe-或-(CR’R”)-,其中R’和R”连接形成经取代或未经取代的饱和或不饱和3-6元环,所述环可任选地包括一个或多个可相同或不同且选自O、NRa(例如NH)和S的杂原子。
更优选的是式(I)的化合物,其中A为
更优选的是式(I)的化合物,其中A为
更优选的是式(I)的化合物,其中A不存在。
更优选的是式(I)的化合物,其中A为-CH2-。
根据一个优选的实施方案,Cy为
更优选的是式(I)的化合物,其中Cy为
更优选的是式(I)的化合物,其中Cy为
又一实施方案为一种具有式(IA)的化合物:
或其互变异构体、前药、N-氧化物、药学上可接受的酯或药学上可接受的盐,其中变量(例如,R”’、R1、R2、T、U、V、W、L1、L2、A和Cy)如以上所述关于式(I)所定义,条件是式(IA)的化合物不为以上定义的条件(a-e)中的任何化合物。
又一实施方案为一种具有式(IA-I)的化合物:
或其互变异构体、前药、N-氧化物、药学上可接受的酯或药学上可接受的盐,其中变量(例如,R”’、R1、R2、T、U、V、W、A和Cy)如以上所述关于式(I)所定义,条件是式(IA)的化合物不为以上定义的条件(a-e)中的任何化合物。
更优选的是式(IA-I)的化合物
或其互变异构体、前药、N-氧化物、药学上可接受的酯或药学上可接受的盐,其中
R1和R2相同或不同且独立地选自CH2F、CHF2、CF3和环丙基,条件是R1和R2不同时表示CF3;
R”’为氢或卤素;
T、U、V、W独立地为CRa或N;
Ra为氢或卤素;
A不存在或选自
并且
Cy选自经取代或未经取代的双环芳基或经取代或未经取代的双环杂芳基,
条件是式(IA)的化合物不为以上定义的条件(e)中的任何化合物。
更优选的是式(IA-I)的化合物,其中R1和R2均表示环丙基。
更优选的是式(IA-I)的化合物,其中R1和R2中的一个为CF3而另一个为环丙基。
更优选的是式(IA-I)的化合物,其中R1为环丙基而R2为CF3。
更优选的是式(IA-I)的化合物,其中T、U、V、W为CH、CF或N。
更优选的是式(IA-I)的化合物,其中T为CF或N,并且U、V和W的每一个均为CH。
更优选的是式(IA-I)的化合物,其中T和V的每一个独立地为CF或N并且U和W的每一个为CH。
更优选的是式(IA-I)的化合物,其中A不存在或选自
更优选的是式(IA-I)的化合物,其中Cy选自
又一实施方案为具有式(IA-II)的化合物
或其互变异构体、前药、N-氧化物、药学上可接受的酯或药学上可接受的盐,其中
R1和R2相同或不同且独立地选自CH2F、CHF2、CF3和环丙基,条件是R1和R2不同时表示CF3;
R”’为氢或卤素;
T、U、V、W独立地为CRa或N;
Ra为氢或卤素;
A不存在或选自
并且
Cy选自经取代或未经取代的C(8-13)双环杂芳基,
条件是式(IA)的化合物不为以上定义的条件(e)中的任何化合物。
更优选的是式(IA-II)的化合物,其中R1和R2均表示环丙基。
更优选的是式(IA-II)的化合物,其中R1和R2中的一个为CF3而另一个为环丙基。
更优选的是式(IA-II)的化合物,其中R1为环丙基而R2为CF3。
更优选的是式(IA-II)的化合物,其中T、U、V、W为CH、CF或N。
更优选的是式(IA-II)的化合物,其中T为CF或N,并且U、V和W的每一个均为CH。
更优选的是式(IA-II)的化合物,其中T和V的每一个独立地为CF或N并且U和W的每一个为CH。
更优选的是式(IA-II)的化合物,其中A不存在或为-CH2-。
在一个实施方案中,A为-CH2-。
更优选的是式(IA-II)的化合物,其中Cy选自
又一实施方案为具有式(IA-III)的化合物
或其互变异构体、前药、N-氧化物、药学上可接受的酯或药学上可接受的盐,
其中
R1和R2相同或不同且独立地选自CH2F、CHF2、CF3、环丙基,条件是R1和R2不同时表示CF3;
T和V相同或不同且独立地选自CF和N;
U和V的每一个为CRa;
L1与L2一起表示-NH-C(=X)-、-NH-S(=O)q-、-C(=X)NH-或-S(=O)qNH-或-NH-CR’R”-;
A不存在或选自-(CR’R”)-和-NRa;
每次出现的R’和R”相同或不同且独立地选自氢或经取代或未经取代的C(1-6)烷基基团,或R’和R”可连接形成经取代或未经取代的饱和或不饱和3-6元环,所述环可任选地包括一个或多个可相同或不同且选自O、NRa和S的杂原子;
R”’选自氢或卤素;
每次出现的X独立地选自O、S和-NRa;
Cy为选自经取代或未经取代的杂环基、经取代或未经取代的芳基和经取代或未经取代的杂芳基的双环;
每次出现的Ra和Rb相同或不同且独立地选自氢、硝基、羟基、氰基、卤素、-ORc、-S(=O)q-Rc、-NRcRd、-C(=Y)-Rc、-CRcRd-C(=Y)-Rc、-CRcRd-Y-CRcRd-、-C(=Y)-NRcRd-、-NRRd-C(=Y)-NRcRd-、-S(=O)q-NRcRd-、-NRcRd-S(=O)q-NRcRd-、-NRcRd-NRcRd-、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基、经取代或未经取代的杂环基、经取代或未经取代的杂环基烷基、经取代或未经取代的芳基、经取代或未经取代的芳基烷基、经取代或未经取代的杂芳基和经取代或未经取代的杂芳基烷基,或当Ra和Rb取代基与同一原子直接结合时,它们可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括一个或多个可相同或不同且选自O、NRc和S的杂原子;
每次出现的Rc和Rd相同或不同且独立地选自氢、硝基、羟基、氰基、卤素、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基、经取代或未经取代的杂环基团、经取代或未经取代的杂环基烷基,或当两个Rc和/或Rd取代基与同一原子直接结合时,它们可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括一个或多个可相同或不同且选自O、NH和S的杂原子;
每次出现的Y选自O、S和-NRa;并且
每次出现的q独立表示0、1或2。
更优选的是式(IA-III)的化合物,其中R1和R2均表示环丙基。
更优选的是式(IA-III)的化合物,其中R1和R2中的一个为CF3且另一个为环丙基。
更优选的是式(IA-III)的化合物,其中R1和R2中的一个为CF3且另一个为CH2F、CHF2。
更优选的是式(IA-III)的化合物,其中R1为环丙基而R2为CF3。
更优选的是式(IA-III)的化合物,其中T为CF或N。
更优选的是式(IA-III)的化合物,其中U、V、W为CH、CF或N。
更优选的是式(IA-III)的化合物,其中L1和L2一起表示-NH-C(=O)-、C(=O)NH-或-NH-CH2-。
更优选的是式(IA-III)的化合物,其中A不存在或为-NH-或-CH2-。
更优选的是式(IA-III)的化合物,其中Cy选自
又一实施方案为具有式(IA-IV)的化合物
或其互变异构体、前药、N-氧化物、药学上可接受的酯或药学上可接受的盐,
其中
R1和R2相同或不同且独立地选自CH2F、CHF2、CF3、环丙基,条件是R1和R2不同时表示CF3;
T和V相同或不同且独立地选自CH、CF和N;
U和V的每一个为CRa;
L1与L2一起表示-NH-C(=X)-、-NH-S(=O)q-、-C(=X)NH-或-S(=O)qNH-或-NH-CR’R”-;
A选自-(CR’R”)-和-NRa;
每次出现的R’和R”相同或不同且独立地选自氢或经取代或未经取代的C(1-6)烷基基团,或R’和R”可连接形成经取代或未经取代的饱和或不饱和3-6元环,所述环可任选地包括一个或多个可相同或不同且选自O、NRa和S的杂原子;
R”’选自氢或卤素;
每次出现的X独立地选自O、S和-NRa;
Cy为经取代或未经取代的双环杂环基;
每次出现的Ra和Rb相同或不同且独立地选自氢、硝基、羟基、氰基、卤素、-ORc、-S(=O)q-Rc、-NRcRd、-C(=Y)-Rc、-CRcRd-C(=Y)-Rc、-CRcRd-Y-CRcRd-、-C(=Y)-NRcRd-、-NRRd-C(=Y)-NRcRd-、-S(=O)q-NRcRd-、-NRcRd-S(=O)q-NRcRd-、-NRcRd-NRcRd-、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基、经取代或未经取代的杂环基、经取代或未经取代的杂环基烷基、经取代或未经取代的芳基、经取代或未经取代的芳基烷基、经取代或未经取代的杂芳基和经取代或未经取代的杂芳基烷基,或当两个Ra和Rb取代基与同一原子直接结合时,它们可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括一个或多个可相同或不同且选自O、NRc和S的杂原子;
每次出现的Rc和Rd相同或不同且独立地选自氢、硝基、羟基、氰基、卤素、经取代或未经取代的烷基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的环烷基、经取代或未经取代的环烷基烷基、经取代或未经取代的环烯基、经取代或未经取代的杂环基团、经取代或未经取代的杂环基烷基,或当两个Rc和/或Rd取代基与同一原子直接结合时,它们可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括一个或多个可相同或不同且选自O、NH和S的杂原子;
每次出现的Y选自O、S和-NRa;并且
每次出现的q独立表示0、1或2。
更优选的是式(IA-IV)的化合物,其中R1和R2均表示环丙基。
更优选的是式(IA-IV)的化合物,其中R1和R2中的一个为CF3且另一个为环丙基。
更优选的是式(IA-IV)的化合物,其中R1和R2中的一个为CF3且另一个为CH2F、CHF2。
更优选的是式(IA-IV)的化合物,其中R1为环丙基而R2为CF3。
更优选的是式(IA-IV)的化合物,其中T为CH、CF或N。
更优选的是式(IA-IV)的化合物,其中U、V、W为CH、CF或N。
更优选的是式(IA-IV)的化合物,其中L1和L2一起表示-NH-C(=O)-、C(=O)NH-或-NH-CH2-。
更优选的是式(IA-IV)的化合物,其中A不存在或为-NH-或-CH2-。
更优选的是式(IA-IV)的化合物,其中Cy选自
在又一实施方案中本发明涉及用钙释放激活钙(CRAC)抑制剂治疗非小细胞肺癌(NSCLC)的方法和鉴定用于治疗和诊断癌症的治疗剂的方法。在某些实施方案中,CRAC抑制剂为如本文所述的任何实施方案中的式I、IA、IA-II、IA-III或IA-IV的化合物。
本发明人已经发现表达ORAI(例如ORAI1、ORAI2或ORAI3)或STIM(例如STIM1或STIM2)的癌细胞对用钙释放激活钙(CRAC)抑制剂治疗敏感。这些类型的癌细胞在患有非小细胞肺癌(NSCLC)的许多患者中表达。
本发明的一个实施方案为通过向患者施用有效量的CRAC抑制剂治疗患有NSCLC的患者的方法。在一个优选的实施方案中,至少一些癌细胞表达ORAI1、STIM1或STIM2。CRAC抑制剂可用作单一疗法或一种或多种治疗肺癌(或NSCLC)的其它方法的辅助疗法。在某些实施方案中,CRAC抑制剂为如本文所述的任何实施方案中的式I、IA、IA-II、IA-III或IA-IV的化合物。
另一实施方案是通过改变进入至少一些癌细胞的钙流,优选通过增强至少一些癌细胞的质膜中钙释放激活钙(CRAC)通道和/或STIM蛋白的表达水平治疗患有NSCLC的患者的方法。
又一实施方案是鉴定用于治疗NSCLC的候选试剂的方法。所述方法包括(a)确定(i)候选试剂是否调节钙释放激活钙(CRAC)通道,和/或(ii)候选试剂是否调节CRAC通道的Stim蛋白的表达,或二者;和(b)根据其调节CRAC通道或CRAC通道的Stim蛋白的能力选择所述候选试剂。
在一个优选的实施方案中,候选试剂可改变进入癌细胞的钙流量。例如,候选试剂可选择性调节CRAC通道或STIM蛋白。优选地,候选试剂选择性抑制CRAC通道或STIM蛋白。例如抑制的CRAC通道可选自CRACM1/Orai1、CRACM2/Orai2和CRACM3/Orai3。在另一实施方案中,候选试剂抑制位于细胞内质网膜上的STIM蛋白。在特定实施方案中,STIM蛋白选自跨膜蛋白家族,例如STIM1或STIM2。根据一个优选的实施方案,STIM蛋白为STIM1。在某些实施方案中,候选试剂为如本文所述的任何实施方案中的式I、IA、IA-II、IA-III或IA-IV的化合物。
又一实施方案为用于治疗NSCLC的药物组合物,所述药物组合物包含(a)根据以上方法鉴定的治疗NSCLC有效的候选试剂,和(b)药学上可接受的载体、稀释剂或赋形剂。在某些实施方案中,候选试剂为如本文所述的任何实施方案中的式I、IA、IA-II、IA-III或IA-IV的化合物。
又一实施方案为通过向患者施用(a)有效量的根据以上方法鉴定的候选试剂或(b)一种或多种包含(i)根据以上方法鉴定的治疗NSCLC有效的候选试剂和(b)药学上可接受的载体、稀释剂或赋形剂的药物组合物治疗患有NSCLC的患者的方法,其中药物组合物提供的候选试剂总量提供治疗有效量的候选试剂。在某些实施方案中,候选试剂为如本文所述的任何实施方案中的式I、IA、IA-II、IA-III或IA-IV的化合物。
又一实施方案为通过检测肺细胞(例如癌细胞)中钙释放激活钙(CRAC)通道和/或STIM蛋白的水平来确定人是易患肺癌还是患有肺癌的方法。在一个实施方案中,所述方法包括检测Orai和/或STIM蛋白的升高的水平。例如,所述方法包括检测癌细胞中STIM蛋白的升高的水平。例如,待检测的STIM蛋白是跨膜蛋白STIM家族的成员,例如STIM1或STIM2。在一个实施方案中,待检测的STIM蛋白为STIM1。
本发明的代表性化合物包括下文和表1中指定的化合物及其药学上可接受的盐。不得将本发明解释为限于所述化合物。
1.N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-1H-苯并[d]咪唑-6-甲酰胺
2.N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-1H-苯并[d][1,2,3]三唑-6-甲酰胺
3.N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]喹啉-6-甲酰胺盐酸盐
4.N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]喹喔啉-6-甲酰胺
5.2-(1H-苯并[d]咪唑-1-基)-N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]乙酰胺
6.2-(1H-苯并[d][1,2,3]三唑-1-基)-N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]乙酰胺
7.N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-2-(1H-吲哚-3-基)乙酰胺
8.N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-2-(咪唑并[1,2-a]吡啶-2-基)乙酰胺盐酸盐
9.N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-2-(喹啉-6-基)乙酰胺:
10.N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-2-(喹啉-6-基)乙酰胺盐酸盐
11.2-(1H-苯并[d][1,2,3]三唑-1-基)-N-(4-(3,5-二环丙基-1H-吡唑-1-基)-3-氟苯基)乙酰胺
12.N-[4-(3,5-二环丙基-1H-吡唑-1-基)-3-氟苯基]-2-(喹啉-6-基)乙酰胺盐酸盐
13.N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]喹啉-6-甲酰胺二盐酸盐
14.N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]喹喔啉-6-甲酰胺
15.2-(1H-苯并[d][1,2,3]三唑-1-基)-N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]乙酰胺
16.N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]-2-(喹啉-6-基)乙酰胺二盐酸盐
17.N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}喹啉-6-甲酰胺盐酸盐
18.N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}喹喔啉-6-甲酰胺
19.2-(1H-苯并[d]咪唑-1-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺
20.2-(1H-苯并[d][1,2,3]三唑-1-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺
21.2-(2H-苯并[d][1,2,3]三唑-2-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺
22.2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺
23.(S)-2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}丙酰胺
24.2-(6-氨基-9H-嘌呤-9-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺
25.N-(4-(5-环丙基-3-(三氟甲基)-1H-吡唑-1-基)苯基)-2-(1,3-二甲基-2,6-二氧代-2,3-二氢-1H-嘌呤-7(6H)-基)乙酰胺
26.N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基)苯基)-2-(咪唑并[1,2-a]吡啶-2-基)乙酰胺盐酸盐
27.N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}-2-(喹啉-6-基)乙酰胺盐酸盐
28.N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}-2-(喹啉-6-基)丙酰胺盐酸盐
29.N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-3-氟苯基}-1H-苯并[d][1,2,3]三唑-6-甲酰胺
30.2-(1H-苯并[d][1,2,3]三唑-1-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-3-氟苯基}乙酰胺
31.N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}-1H-苯并[d][1,2,3]三唑-5-甲酰胺
32.2-(1H-苯并[d][1,2,3]三唑-1-基)-N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}乙酰胺
33.2-(2H-苯并[d][1,2,3]三唑-2-基)-N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}乙酰胺
34.N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}-2-(喹啉-6-基)乙酰胺盐酸盐
35.2-(1H-苯并[d][1,2,3]三唑-1-基)-N-{6-[4-氯-5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}乙酰胺
36.4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-3-氟-N-(喹啉-6-基甲基)苯甲酰胺盐酸盐
37.1-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-3-(喹啉-6-基)脲
表1
本发明的化合物(例如,式I、IA、IA-I、IA-II、IA-III和/或IA-IV的化合物,包括其药学上可接受的酯和盐)用于钙释放激活钙(CRAC)通道相关疾病和病症的治疗、预防、抑制和/或改善。
本发明的另一实施方案为通过向需要这种治疗的患者施用有效量的本发明化合物(例如,以上定义的式I、IA、IA-I、IA-II、IA-III和/或IA-IV的化合物)调节CRAC通道而治疗疾病或病症的方法。
本发明的又一实施方案为通过与至少一种其它抗炎剂结合(同时或相继)向需要这种治疗的患者施用有效量的本发明化合物(例如,以上定义的式I、IA、IA-I、IA-II、IA-III和/或IA-IV的化合物)调节CRAC通道而治疗疾病或病症的方法。
本发明的又一实施方案为通过与至少一种其它抗癌剂结合(同时或相继)向需要这种治疗的患者施用有效量的本发明化合物(例如,以上定义的式I、IA、IA-I、IA-II、IA-III和/或IA-IV的化合物)调节CRAC通道而治疗疾病或病症的方法。
本发明的化合物可抑制钙池操纵型钙进入,阻断SOCE单元的装配,改变形成钙池操纵型钙通道复合物的蛋白质的功能性相互作用并改变STIM1与Orai1的功能性相互作用。这些化合物是SOC通道孔隙阻滞剂,并且是CRAC通道孔隙阻滞剂。
本文所述化合物的调节细胞内钙并用于细胞内钙的调节具有有益效果的疾病、病症或病状的治疗。在一个实施方案中,本文所述化合物抑制钙池操纵型钙进入。在一个实施方案中,能够调节细胞内钙水平的本发明化合物阻断SOCE单元的装配。在另一实施方案中,能够调节细胞内钙水平的本发明化合物改变形成钙池操纵型钙通道复合物的蛋白质的功能性相互作用。在一个实施方案中,能够调节细胞内钙水平的本发明化合物改变STIM1与Orai1的功能性相互作用。在其它实施方案中,能够调节细胞内钙水平的本发明化合物是SOC通道孔隙阻滞剂。在其它实施方案中,能够调节细胞内钙水平的本发明化合物是CRAC通道孔隙阻滞剂。
一方面,能够调节细胞内钙水平的本发明化合物抑制与激活SOC通道直接相关的电生理学电流(ISOC)。另一方面,能够调节细胞内钙水平的化合物抑制与激活CRAC通道直接相关的电生理学电流(ICRAC)。
本发明的化合物用于治疗受益于细胞内钙的调节的疾病、病状或病症,包括但不限于免疫系统相关疾病(例如,自身免疫性疾病)、涉及炎症的疾病或病症(例如,哮喘、慢性阻塞性肺病、类风湿性关节炎、炎症性肠病、肾小球性肾炎、神经炎症疾病、多发性硬化、葡萄膜炎和免疫系统病症)、癌症或其它增生性疾病、肝脏疾病或病症和肾脏疾病或病症。在一个实施方案中,本文所述化合物用作免疫抑制剂以预防(或抑制)移植排斥、同种或异种移植排斥(器官、骨髓、干细胞、其它细胞和组织)和/或移植物抗宿主病。例如,本发明的化合物可用于由组织或器官移植引起的预防(或抑制)移植排斥。本发明的化合物也可用于预防(或抑制)由骨髓或干细胞移植引起的移植物抗宿主病。
更特别地,式I、IA、IA-I、IA-II、IA-III和/或IA-IV的化合物用于治疗各种炎症疾病,包括但不限于炎症、肾小球性肾炎、葡萄膜炎、肝脏疾病或病症、肾脏疾病或病症、慢性阻塞性肺病、类风湿性关节炎、炎症性肠病、脉管炎、皮炎、骨关节炎、炎症性肌肉疾病、过敏性鼻炎、阴道炎、间质性膀胱炎、硬皮病、骨质疏松症、湿疹、同种或异种移植、移植排斥、移植物抗宿主病、红斑狼疮、I型糖尿病、肺纤维化、皮肌炎、甲状腺炎、重症肌无力、自身免疫性溶血性贫血、囊性纤维化、慢性复发性肝炎、原发性胆汁性肝硬变、变应性结膜炎、肝炎和特应性皮炎、哮喘和干燥综合征。
本文所述的化合物调节钙池操纵型钙通道复合物中至少一部分蛋白质的活性,调节其相互作用或与之结合或相互作用。在一个实施方案中,本文所述的化合物调节钙释放激活钙通道复合物中至少一部分蛋白质的活性,调节其相互作用或与之结合或相互作用。在一个实施方案中,本文所述的化合物降低功能性钙池操纵型钙通道复合物的水平。在另一实施方案中,本文所述的化合物降低激活钙池操纵型钙通道复合物的水平。在又一实施方案中,钙池操纵型钙通道复合物为钙释放激活钙通道复合物。
用于治疗疾病或病症的能够调节细胞内钙水平的本发明化合物,当向患有疾病或病症的受治疗者施用时,有效减轻、改善或消除疾病、病状或病症的症状或表现。在其它实施方案中,向尚未表现疾病、病状或病症的症状的易患疾病、病状或病症的受治疗者施用本文所述的化合物,预防或延迟所述疾病、病状或病症症状的发展。在更多实施方案中,本发明的化合物单独或与其它试剂结合具有这种效果,或作用以增强另一试剂的治疗效果。
本发明的另一实施方案是通过向需要这种治疗的患者施用有效量的如以上定义的式I、IA、IA-I、IA-II、IA-III和/或IA-IV的至少一种化合物经由调节钙来治疗增生性疾病的方法。
本发明的又一实施方案是通过与至少一种其它抗癌剂结合(同时或相继),向需要这种治疗的患者施用有效量的如以上定义的式I、IA、IA-I、IA-II、IA-III和/或IA-IV的至少一种化合物经由调节钙来治疗增生性疾病的方法。在一个实施方案中,增生性疾病为癌症。
更特别地,可施用式I、IA、IA-I、IA-II、IA-III和/或IA-IV的化合物及其药学上可接受的酯或盐以治疗、预防和/或改善牵涉钙的疾病或病症,包括但不限于癌症和其它增生性疾病或病症。
式I、IA、IA-I、IA-II、IA-III和/或IA-IV的化合物用于治疗多种癌症,包括但不限于以下:
· 淋巴系造血肿瘤:白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特氏淋巴瘤;
· 骨髓系造血肿瘤:急慢性骨髓性白血病、骨髓增生异常综合征和前髓细胞性白血病;
· 癌症,包括膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌、小细胞肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌、前列腺癌和皮肤癌(包括鳞状细胞癌);
· 间充质来源的肿瘤:纤维肉瘤和横纹肌肉瘤;
· 中枢和外周神经系统肿瘤,包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;
· 其它肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤、滤泡性甲状腺癌和卡波西氏肉瘤。
由于钙通常在调控细胞增殖中的关键作用,所以钙通道抑制剂可作为可逆性细胞抑制剂,可用于治疗特征为细胞增殖异常的任何疾病过程,例如,良性前列腺增生、家族性腺瘤息肉病、神经纤维瘤病、动脉粥样硬化、肺纤维化、关节炎、银屑病、肾小球性肾炎、血管成形术或血管手术后再狭窄、肥厚性疤痕形成、炎症性肠病、移植排斥、内毒素性休克和真菌感染。
本发明的化合物,作为细胞凋亡调节剂,用于治疗癌症(包括但不限于本文以上提及的那些类型)、病毒感染(包括但不限于肝炎病毒、痘病毒、爱波斯坦-巴尔病毒、辛德华斯病毒和腺病毒),预防HIV感染个体的AIDS发展、自身免疫性疾病(包括但不限于全身性狼疮、红斑狼疮、自身免疫介导的肾小球性肾炎、类风湿性关节炎、银屑病、炎症性肠病和自身免疫性糖尿病)、神经退化性疾病(包括但不限于阿耳茨海默氏病、AIDS相关痴呆、帕金森氏症、肌萎缩性侧索硬化、色素性视网膜炎、脊髓性肌萎缩和小脑退化)、骨髓增生异常综合征、再生障碍性贫血、心肌梗塞相关的缺血性损伤、中风和再灌注损伤、心律不齐、动脉粥样硬化、毒素诱导或酒精相关的肝病、血液病(包括但不限于慢性贫血和再生障碍性贫血)、肌肉骨骼系统的退化性疾病(包括但不限于骨质疏松症和关节炎)、阿司匹林敏感性鼻窦炎、囊性纤维化、多发性硬化、肾病和癌痛。
本发明的化合物可调节细胞RNA和DNA合成的水平。因此这些试剂用于治疗病毒感染(包括但不限于HIV、人乳头状瘤病毒、痘病毒、爱波斯坦-巴尔病毒、辛德华斯病毒和腺病毒)。
本发明的化合物用于化学预防癌症。化学预防定义为通过阻断引发诱变事件或阻断已经受损的癌前细胞的进展而抑制侵入性癌症或抑制肿瘤复发。化合物还用于抑制肿瘤血管生成和转移。
本发明的化合物还用于与已知抗癌治疗(例如放射治疗)或与细胞抑制剂或细胞毒素剂或抗癌剂结合(一起或相继施用),例如但不限于DNA交互作用剂,例如顺铂或阿霉素;拓扑异构酶II抑制剂,例如依托泊苷;自然存在或合成的拓扑异构酶I抑制剂,例如CPT-11或拓扑替康;微管蛋白交互作用剂,例如紫杉醇、多烯紫杉醇或埃博霉素(例如,伊沙匹隆);激素剂,例如他莫昔芬;胸苷酸合成酶抑制剂,例如5-氟尿嘧啶;和抗代谢物(例如甲氨蝶呤)、其它酪氨酸激酶抑制剂(例如易瑞莎和OSI-774);血管生成抑制剂;EGF抑制剂;VEGF抑制剂;CDK抑制剂;SRC抑制剂,c-Kit抑制剂;Her1/2抑制剂和针对生长因子受体的单克隆抗体,例如爱必妥(EGF)和赫塞汀(Her2)和其它蛋白质激酶调节剂。
本发明进一步提供了包含式I、IA、IA-I、IA-II、IA-III和/或IA-IV的一种或多种化合物和药学上可接受的载体的药物组合物。
本发明的又一实施方案为包含一种或多种本发明化合物,任选与药学上可接受的载体的剂型。剂型可为(例如)固体口服剂型,例如片剂或胶囊。
附图说明
为易于理解本发明并投入实际效果,现参考附图以举例的方式描述优选实施方案,其中相同参考编号指相同部分并且其中:
图1为显示A549和NCI-H460细胞系中Orai1和STIM1的mRNA表达的凝胶的照片。用Jurkat mRNA作对照。
图2为毒胡萝卜素诱导的钙流的抑制百分比与化合物A浓度对数的图。
图3为NCI-H460细胞增殖的抑制百分比与化合物A浓度对数的图。
图4为显示化合物B对NCI-H460细胞系中Orai和STIM表达的影响的凝胶的照片。
图5为用媒介物、紫杉醇或化合物A治疗的具有NCI-H460非小细胞肺癌异种移植物的雌性Balb/c裸鼠的肿瘤体积的图。
具体实施方式
除非另有定义,本文使用的所有技术和科学术语具有与要求的主题所属领域中通常理解的相同含义。本文术语存在多种定义的情况下,采用本部分中的定义。
应了解,先前的一般性描述和以下的详细描述仅为示例说明,并非对要求保护的任何主题的限制。在本申请案中,除非另有特别说明,单数的使用包括复数。必须注意,如同用于说明书和所附权利要求中,除非上下文另外明确指出,单数形式包括复数的所指事物。在本申请案中,除非另外指出,“或”的使用指“和/或”。而且,术语“包括”以及其它形式的使用并非限制性。
参考书中可找到标准化学和分子生物学术语的定义,包括但不限于Carey和Sundberg″ADVANCED ORGANIC CHEMISTRY第4版″第A(2000)和B(2001)卷,Plenum Press,New York和″MOLECULAR BIOLOGY OF THE CELL第5版″(2007),Garland Science,NewYork。除非另外指出,质谱分析、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学常规方法涵盖在本文公开的实施方案的范围之内。
除非提供了特殊定义,连同本文所述分析化学和医药化学采用的命名法及其实验步骤和技术是通常所使用的。在一些实施方案中,标准技术用于化学分析、药物制备、配制和递送以及患者的治疗。在其它实施方案中,标准技术用于重组DNA、寡核苷酸合成和组织培养和转化(例如,电穿孔、脂质转染)。在优选的实施方案中,例如使用生产商说明书或如本文所述的试剂盒进行反应和纯化技术。通常通过常规方法并且如本说明书全篇引用和讨论的各种一般性和更具体的参考中所述进行前述技术和步骤。
除非另有指明,如本文所使用的以下定义应适用。进一步地,本文定义的许多基团可任选地被取代。定义中的取代基清单为示例性并不视为限制说明书中其它地方定义的取代基。
术语“烷基”指只由碳和氢原子组成,不含不饱和,具有1至8个碳原子并且与分子的其余部分通过单键连接的直链或支链烃链基,例如甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基和1,1-二甲基乙基(叔丁基)。
术语经取代或未经取代的(C1-6)烷基指具有多达6个碳原子的如以上定义的烷基基团。
术语“烯基”指含有碳-碳双键并且可为直链或支链或具有约2至约10个碳原子的支链的脂肪族烃基团,例如乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基和2-丁烯基。
术语经取代或未经取代的(C1-6)烯基指具有多达6个碳原子的如以上定义的烯基基团。
术语“炔基”指具有至少一个碳-碳三键并且具有约2至12个碳原子(目前优选具有约2至10个碳原子的基团)的直链或支链烃基,例如乙炔基、丙炔基和丁炔基。
术语经取代或未经取代的(C1-6)炔基指具有多达6个碳原子的如以上定义的炔基基团。
术语“烷氧基”表示通过氧联接与分子的其余部分连接的如以上定义的烷基基团。那些基团的典型实例为-OCH3和-OC2H5。
术语“环烷基”表示约3至12个碳原子的非芳香族单环或多环系统,例如环丙基、环丁基、环戊基和环己基。多环环烷基基团的非限制性实例包括全氢萘基、金刚烷基、降冰片烷基基团(桥环基团)或螺环基团,例如螺(4,4)壬-2-基。
术语“环烷基烷基”指含有约3至8个与烷基基团直接连接的碳原子,然后在烷基基团中引起稳定结构产生的任何碳处与主要结构连接的含有环状环的基团,例如环丙基甲基、环丁基乙基和环戊基乙基。
术语“环烯基”指含有约3至8个碳原子和至少一个碳-碳双键的含有环状环的基团,例如环丙烯基、环丁烯基和环戊烯基。
术语“芳基”指具有6至20个碳原子的芳族基,例如苯基、萘基、四氢萘基、茚满基和联苯基。
术语“芳基烷基”指与以上定义的烷基基团直接键合的如以上定义的芳基基团,例如-CH2C6H5和-C2H5C6H5。
术语“杂环”指由碳原子和至少一个选自氮、磷、氧和硫的杂原子组成的非芳香族3-15元环。为了本发明的目的,杂环基可为单环、双环、三环或四环系统,其可包括稠环、桥环或螺环系统,并且杂环基中的氮、磷、碳、氧或硫原子可任选氧化为各种氧化态。另外,氮原子可任选地被季铵化。杂环基可在引起稳定结构产生的任何杂原子或碳原子处与主要结构连接。
术语“杂芳基”指具有作为环原子的一个或多个选自N、O和S的杂原子的任选取代的5-14元芳环。杂芳基可为单环、双环或三环系统。这种杂芳环基的实例包括但不限于噁唑基、噻唑基、咪唑基、吡咯基、呋喃基、吡啶基、嘧啶基、吡嗪基、苯并呋喃基、吲哚基、苯并噻唑基、苯并噁唑基、咔唑基、喹啉基和异喹啉基。杂芳环基可在引起稳定结构产生的任何杂原子或碳原子处与主要结构连接。
这种“杂环”或“杂芳基”基团的实例包括但不限于吖丁啶基、吖啶基、苯并间二氧杂环戊烯基、苯并二噁烷基、苯并呋喃基、咔唑基、噌啉基、二氧杂环戊烷基、吲嗪基、萘啶基、全氢氮杂环庚烷基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、吡啶基、蝶啶基、嘌呤基、喹唑啉基、喹喔啉基、喹啉基、异喹啉基、四唑基、咪唑基、四氢异喹啉基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、氮杂基、吡咯基、4-哌啶酮基、吡咯烷基、吡嗪基、嘧啶基、哒嗪基、噁唑基、噁唑啉基、噁唑啶基、三唑基、茚满基、异噁唑基、异噁唑烷基、吗啉基、噻唑基、噻唑啉基、噻唑烷基、异噻唑基、奎宁环基、异噻唑烷基、吲哚基、异吲哚基、二氢吲哚基、异二氢吲哚基、八氢吲哚基、八氢异吲哚基、喹啉基、异喹啉基、十氢异喹啉基、苯并咪唑基、噻二唑基、苯并吡喃基、苯并噻唑基、苯并噁唑基、呋喃基、四氢呋喃基、四氢吡喃基、噻吩基、苯并噻吩基、硫吗啉基、硫吗啉基亚砜、硫吗啉砜、二氧磷杂环戊烷基、噁二唑基、色满基、异色满基等。
术语“杂芳基烷基”指与烷基基团直接键合的如以上定义的杂芳环基。杂芳基烷基可在来自烷基基团的引起稳定结构产生的任何碳原子处与主要结构连接。
术语“杂环基烷基”指与烷基基团直接键合的如以上定义的杂环基。杂环基烷基可在烷基基团中引起稳定结构产生的任何碳原子处与主要结构连接。
除非另有说明,术语“经取代”指用以下取代基的任一个或任何组合取代:氢、羟基、卤素、羧基、氰基、硝基、氧代(=O)、硫代(=S)、经取代或未经取代的烷基、经取代或未经取代的烷氧基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的芳基、经取代或未经取代的芳基烷基、经取代或未经取代的环烷基、经取代或未经取代的环烯基、经取代或未经取代的芳基、经取代或未经取代的杂芳基、经取代的杂环基烷基环、经取代或未经取代的杂芳基烷基、经取代或未经取代的杂环、经取代或未经取代的胍、-COORx、-C(O)Rx、-C(S)Rx、-C(O)NRxRy、-C(O)ONRxRy、-NRyRz、-NRxCONRyRz、-N(Rx)SORy、-N(Rx)SO2Ry、-(=N-N(Rx)Ry)、-NRx C(O)ORy、-NRxRy、-NRxC(O)Ry-、-NRxC(S)Ry-NRxC(S)NRyRz、-SONRxRy-、-SO2NRxRy-、-ORx、-ORxC(O)NRyRz、-ORxC(O)ORy-、-OC(O)Rx、-OC(O)NRxRy、-RxNRyC(O)Rz、-RxORy、-RxC(O)ORy、-RxC(O)NRyRz、-RxC(O)Rx、-RxOC(O)Ry、-SRx、-SORx、-SO2Rx和-ONO2,其中以上每个基团中的Rx、Ry和Rz可为氢原子、经取代或未经取代的烷基、经取代或未经取代的烷氧基、经取代或未经取代的烯基、经取代或未经取代的炔基、经取代或未经取代的芳基、经取代或未经取代的芳基烷基、经取代或未经取代的环烷基、经取代或未经取代的环烯基、经取代或未经取代的氨基、经取代或未经取代的芳基、经取代或未经取代的杂芳基、经取代的杂环基烷基环、经取代或未经取代的杂芳基烷基、经取代或未经取代的杂环,或Rx、Ry和Rz的任何两个可连接形成经取代或未经取代的饱和或不饱和3-10元环,所述环可任选地包括相同或不同且选自O、NRX或S的杂原子。上述“经取代的”基团中的取代基不可进一步被取代。例如,当“经取代的烷基”上的取代基为“经取代的芳基”时,“经取代的芳基”上的取代基不可为“经取代的烯基”。本发明预想的取代基或取代基组合优选为引起稳定化合物形成的取代基或取代基组合。
术语“卤素”或“卤代”指氟、氯、溴和碘。
术语“保护基”或“PG”指用于阻断或保护特殊官能性的取代基。化合物上的其它官能团可保持反应性。例如,“氨基保护基”是与氨基连接,阻断或保护化合物中的氨基官能性的取代基。适合的氨基保护基包括但不限于乙酰基、三氟乙酰基、叔丁氧羰基(BOC)、苄氧羰基(CBz)和9-芴基亚甲氧基羰基(Fmoc)。类似地,“羟基保护基”指阻断或保护羟基官能性的羟基取代基。适合的羟基保护基包括但不限于乙酰基和甲硅烷基。“羧基保护基”指阻断或保护羧基官能性的羧基取代基。适合的羧基保护基包括但不限于-CH2CH2SO2Ph、氰基乙基、2-(三甲基甲硅烷基)乙基、2-(三甲基甲硅烷基)乙氧基甲基、2-甲苯磺酰基)乙基、2-(对硝基苯基亚磺酰基)乙基、2-二苯基-l-膦基)-乙基和硝基乙基。保护基及其用途的一般性描述,见T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,NewYork,1991。
术语“立体异构体”指具有相同化学组成,但关于原子和基团在空间上的排列不同的化合物。这些包括对映异构体、非对映异构体、几何异构体、阻转异构体或构象异构体。
本文所述化合物的所有立体异构体均在本发明范围之内。外消旋混合物也涵盖在本发明范围内。因此,本发明化合物的单一立体化学异构体和对映异构体、非对映异构体和几何(或构象)异构体混合物术语本发明的范围。
术语“互变异构体”指特征在于在平衡状态下异构形式相对易于相互转化的化合物。这些异构体旨在包括在本发明内。
术语“前药”指化合物的非活性前体,在体内通过正常代谢过程转化为其活性形式的化合物。
术语“酯”指通过酸和醇之间的反应,去除水形成的化合物。可用式RCOOR′表示酯,其中R为碱化合物而R’为酯部分(例如,乙基)。
另外,本发明还包括仅在一个或多个同位素富集原子的存在方面不同,例如用氘代替氢等的化合物。
形成本发明的一部分的药学上可接受的盐包括源自无机碱的盐,例如Li、Na、K、Ca、Mg、Fe、Cu、Zn和Mn;有机碱的盐,例如N,N′-二乙酰基乙二胺、葡糖胺、三乙胺、胆碱、氢氧化物、二环己基胺、二甲双胍、苄胺、三烷基胺和硫胺;手性碱,例如烷基苯胺、甘氨醇和苯甘氨醇;天然氨基酸的盐,例如甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、正亮氨酸、酪氨酸、胱氨酸、半胱氨酸、甲硫氨酸、脯氨酸、羟脯氨酸、组氨酸、鸟氨酸、赖氨酸、精氨酸和丝氨酸;本发明化合物与烷基卤化物或烷基硫酸盐的季铵盐,例如MeI和(Me)2SO4;非天然氨基酸,例如D异构体或经取代的氨基酸;胍或经取代的胍,其中取代基选自硝基、氨基、烷基、烯基、炔基、铵或经取代的铵盐和铝盐。适当时,盐可能包括酸加成盐,硫酸盐、硝酸盐、磷酸盐、高氯酸盐、硼酸盐、氢卤化物、醋酸盐、酒石酸盐、马来酸盐、柠檬酸盐、延胡索酸盐、琥珀酸盐、巴莫酸盐、甲磺酸盐、苯甲酸盐、水杨酸盐、苯磺酸盐、抗坏血酸盐、甘油磷酸盐和酮戊二酸盐。
术语“受治疗者”或“患者”涵盖哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物类的任何成员:人、非人灵长类(例如黑猩猩)和其它猿和猴种;农畜,例如牛、马、绵羊、山羊和猪;家畜,例如兔、狗和猫;和实验动物,包括啮齿动物,例如大鼠、小鼠和豚鼠。非哺乳动物的实例包括但不限于鸟和鱼。在本文提供的方法和组合物的一个实施方案中,哺乳动物为人。
如本文所使用的术语“治疗”包括缓和、减轻、改善或预防症状的潜在原因,抑制疾病、病症或病状,例如阻止疾病、病症或病状的发展,缓解疾病、病症或病状,引起疾病、病症或病状的消退,缓解疾病、病症或病状引起的情况或经预防和/或治疗终止疾病、病症或病状的症状。
如本文所使用的术语“靶蛋白”指能够与本文所述化合物,例如能够调节STIM蛋白和/或Orai蛋白的化合物结合或相互作用的蛋白质或蛋白质的一部分。在某些实施方案中,靶蛋白为STIM蛋白。在其它实施方案中,靶蛋白为Orai蛋白,并且在更多其它实施方案中,化合物靶向STIM和Orai蛋白。
术语“STIM蛋白”指位于内质网或质膜内刺激通过CRAC通道流入细胞的钙流量升高的任何蛋白质。(STIM指间质相互作用分子。)如本文所使用的术语“STIM蛋白”包括但不限于哺乳动物STIM-1例如人和啮齿动物(例如,小鼠)STIM-1、黑腹果蝇D-STIM、线虫C-STIM、冈比亚按蚊STIM,和哺乳动物STIM-2例如人和啮齿动物(例如,小鼠)STIM-2。如本文所述,已经鉴定这种蛋白质涉及、参与和/或提供钙池操纵型钙进入或其调节、细胞质钙缓冲和/或细胞内钙池(例如,内质网)中的钙水平、进入细胞内钙池、细胞内钙池内或外的钙移动。
将了解,用“激活”指STIM蛋白上调、刺激、增强或促进通过CRAC通道进入细胞的钙流。预计STIM蛋白和CRAC通道之间的干扰可通过直接或间接的分子相互作用进行。适合地,STIM蛋白为与CRAC通道相关或靠近的跨膜蛋白。
本领域已知STIM1是CRAC通道激活的必需组分。本发明人已观察到STIM1和STIM2在某些NSCLC细胞系中表达。而且,CRACM1/Orai1和CRACM3/Orai3在某些NSCLC细胞系中过度表达。虽然不希望受任何特殊理论限制,但是CRAC和STIM蛋白可能以下列方式引起NSCLC细胞的增殖途径的激活:(i)NSCLC细胞中STIM的过度失调引起STIM的质膜不适当积聚和(ii)在质膜上,STIM(通过直接或间接相互作用)激活CRAC,从而引起过量钙流入细胞和启动NSCLC细胞中的转录、增殖和侵入。因此,抑制CRAC通道或STIM途径是NSCLC的有效治疗。
如本文所使用,“Orai蛋白”包括Orai1(如WO 07/081,804中所述的SEQ ID NO:1)、Orai2(如WO 07/081,804中所述的SEQ ID NO:2)或Orai3(如WO 07/081,804中所述的SEQID NO:3)。Orai1核酸序列与GenBank登记号NM-032790相对应,Orai2核酸序列与GenBank登记号BC069270相对应且Orai3核酸序列与GenBank登记号NM-152288相对应。如本文所使用,Orai指任一Orai基因,例如Orai1、Orai2和Orai3(见WO 07/081,804的表I)。如本文所述,已鉴定这种蛋白质牵涉、参与和/或提供钙池操纵型钙进入或其调节,细胞质钙缓冲和/或调节细胞内钙池(例如,内质网)中的钙水平或向细胞内钙池内、外或在其中的钙的运动。在替代性实施方案中,可用标签分子标记Orai蛋白,仅举例而言,酶片段、蛋白质(例如,c-myc或其它标签蛋白或其片段)、酶标签、荧光标签、荧光团标签、发色团标签、Rama活化标签、化学发光标签、量子点标志、抗体、放射性标签或其组合。
当提及蛋白质(例如,STIM、Orai)时,术语“片段”或“衍生物”指在至少一项检测中基本上保持与天然蛋白质相同的生物功能或活性的蛋白质或多肽。例如,如通过钙流检测确定,提及蛋白质的片段或衍生物优选保持天然蛋白质的至少约50%的活性,天然蛋白质的至少75%或至少约95%活性。
如本文所使用的“改善”指疾病或病状的改善或疾病或病状相关症状的至少部分缓解。如本文所使用,通过施用特殊化合物或药物组合物改善特殊疾病、病症或病状的症状指归因于或与化合物或组合物的施用相关的永久或暂时、持久或瞬时的任何严重程度的减轻、发作延迟、进展减缓或持续时间缩短。
如本文所使用的术语“调节”指与靶蛋白直接或间接相互作用以改变靶蛋白的活性,包括(仅举例而言)抑制靶标的活性或限制或降低靶标的活性。
如本文所使用的术语“调节剂”指改变靶标(例如,靶蛋白)的活性。例如,在一些实施方案中,与在调节剂缺乏时的活性大小相比,调节剂引起靶标的某种活性大小升高或降低。在某些实施方案中,调节剂为降低靶标的一种或多种活性大小的抑制剂。在某些实施方案中,抑制剂完全防止靶标的一种或多种活性。
如本文所使用的关于细胞内钙的“调节”指细胞内钙的任何改变或调控,包括但不限于细胞质和/或细胞内钙储存细胞器(例如,内质网)中钙浓度的改变,或流入、流出细胞和细胞内钙流的动力学改变。一方面,调节指降低。
如本文所使用的术语SOC通道活性或CRAC通道活性的“抑制”或“抑制剂”指钙池操纵型钙通道活性或钙释放激活钙通道活性的抑制。
如本文所使用的关于制剂、组合物或成分的术语“可接受的”指对正治疗的受治疗者的身体状况无持久性有害作用。
术语“药学上可接受的”分子实体和组合物,当施用给人时,在生理上耐受并且不产生过敏或相似不良反应,例如胃部不适和眩晕。优选地,如本文所使用的术语“药学上可接受的”指经联邦管理机构或国家政府批准或列入用于动物,尤其用于人的美国药典或其它普遍公认药典中。
术语“药物组合物”指本发明的化合物与其它化学组分的混合物,例如载体、稳定剂、稀释剂、分散剂、助悬剂、增稠剂和/或赋形剂。
可通过各种施用途径,包括但不限于静脉内、口服、气溶胶、胃肠外、经眼、肺部和局部施用,施用本发明的化合物和药物组合物。
如本文所使用的术语“有效量”或“治疗有效量”指施用的将正治疗的疾病或病状的一种或多种症状缓解至某种程度的试剂或化合物的足够量。结果是疾病的病征、症状或病因减轻和/或缓和,或生物系统的任何其它所需改变。例如,治疗用的“有效量”为提供疾病症状在临床上显著减少所需的本发明化合物的量。在一些实施方案中,使用例如剂量增加研究等技术确定任何单独情况下的适当“有效”量。
如本文所使用的术语“增强”指增加或延长预期效果的效力或持续时间。因此,关于增强治疗剂的作用,术语“增强”指增加或延长其它治疗剂对系统的作用的效力或持续时间。如本文所使用的术语“增强有效量”指足以增强预期系统中另一治疗剂的作用的量。
如本文所使用的术语“载体”指促进化合物并入细胞或组织的相对无毒的化学化合物或试剂。
术语“稀释剂”指在递送之前用于稀释目标化合物的化学化合物。在一些实施方案中,稀释剂用于稳定化合物,因为它们提供更稳定的环境。利用溶于缓冲液(也提供pH控制或维持)的盐作为稀释剂,包括但不限于磷酸盐缓冲液。
用“癌细胞”指来自肺部的细胞,包括恶性肿瘤前细胞、瘤细胞、恶性肿瘤前细胞、致瘤细胞、非致瘤细胞和肺癌干细胞。
如本文所使用的“细胞内钙”指位于细胞内,未指定特殊细胞位置的钙。相反,关于钙的“细胞溶质”或“细胞质”指位于细胞细胞质内的钙。
如本文所使用,对细胞内钙的影响为细胞内钙任何方面的任何改变,包括但不限于细胞内钙水平和位置的改变和钙向细胞或细胞内钙池或细胞器内、外或在其中的运动。例如,在一些实施方案中,对细胞内钙的影响为钙流性质的改变,例如,动力学、敏感性、速率、幅度和电生理学特征,或细胞或其一部分中发生的运动。在一些实施方案中,对细胞内钙的影响为任何细胞内钙调节过程的改变,包括钙池操纵型钙进入、细胞溶质钙缓冲和细胞内钙池中的钙水平或向细胞内钙池内、外或在其中的运动。以各种方式检测任何这些方面,包括但不限于评估钙或其它离子(尤其是阳离子)水平、钙或其它离子(尤其是阳离子)的运动、钙或其它离子(尤其是阳离子)水平的波动、钙或其它离子(尤其是阳离子)流的动力学和/或钙或其它离子(尤其是阳离子)通过膜的转运。改变是任何这种在统计上显著的变化。因此,例如,在一些实施方案中,如果据称测试细胞和对照细胞内的细胞内钙不同,这种差异为统计上显著的差异。
细胞内钙的调节为细胞内钙的任何改变或调控,包括但不限于细胞质和/或细胞内钙储存细胞器(例如,内质网)中钙浓度或水平的改变,钙向细胞或细胞内钙池或细胞器内、外和在其中的运动的改变,细胞内钙位置的改变和流向细胞内、外和在其中的钙流的动力学或其它性质的改变。在一些实施方案中,细胞内钙调节涉及改变或调控(例如,减少或抑制)细胞内钙池或细胞器中钙池操纵型钙进入、细胞溶质钙缓冲、钙水平或向细胞内钙池或细胞器内、外或在其中的钙的运动和/或基底或静止细胞溶质钙水平。细胞内钙的调节涉及改变或调控受体介导的离子(例如,钙)运动、第二信使操纵的离子(例如,钙)运动、流入或流出细胞的钙和/或细胞内室(包括,例如核内体和溶酶体)的离子(例如,钙)摄取或释放。
如本文所使用的关于蛋白质和细胞内钙或细胞内钙调控的一方面之间的关系的“牵涉”指当细胞内蛋白质的表达或活性降低、改变或消除时,细胞内钙或细胞内钙调控的一个或多个方面存在伴随或相关的降低、改变或消除。表达或活性的这种改变或降低由于编码蛋白质的基因的表达改变或通过改变蛋白质水平而发生。因此,牵涉细胞内钙的一方面(例如钙池操纵型钙进入)的蛋白质为提供或参与细胞内钙或细胞内钙调控的一方面的蛋白质。例如,提供钙池操纵型钙进入的蛋白质为STIM蛋白质和/或Orai蛋白质。
如本文所使用,为钙通道组分的蛋白质为参与形成通道的多蛋白复合物的蛋白质。
如本文所使用,向细胞内的“阳离子进入”或“钙进入”指向细胞内位置(例如细胞质)或向细胞内细胞器或储存位点的内腔的阳离子(例如钙)的进入。因此,在一些实施方案中,阳离子进入为(例如)阳离子从细胞外介质或从细胞内细胞器或储存位点向细胞质的运动,或阳离子从细胞质或细胞外介质向细胞内细胞器或储存位点的运动。钙从细胞内细胞器或储存位点向细胞质的运动也称为从细胞器或储存位点的“钙释放”。
如本文所使用,“细胞反应”指由向细胞内或外或在细胞中的离子运动引起的任何细胞反应。在一些实施方案中,细胞反应与至少部分依赖于离子(例如,钙)的任何细胞活性相关。这种活性任选地包括(例如)细胞激活、基因表达、胞吞作用、胞吐作用、细胞运输和非凋亡性细胞死亡。
如本文所使用,“免疫细胞”包括免疫系统的细胞和在免疫反应中执行功能或活性的细胞,例如但不限于T细胞、B细胞、淋巴细胞、巨噬细胞、树突细胞、嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、肥大细胞、浆细胞、白细胞、抗原呈递细胞和自然杀手细胞。
如本文所使用,“细胞因子”指由细胞分泌的,在一些实施方案中改变分泌细胞或另一种细胞的行为或性质的可溶性小分子蛋白。细胞因子与细胞因子受体结合并触发在细胞内的行为或性质,例如,细胞增殖、死亡或分化。示例性细胞因子包括但不限于白细胞介素(例如,IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-15、IL-16、IL-17、IL-18、IL-1.α.、IL-1.β.和IL-1RA)、粒细胞集落刺激因子(G-CSF)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、制瘤素M、红细胞生成素、白血病抑制因子(LIF)、干扰素、B7.1(也称为CD80)、B7.2(也称为B70、CD86)、TNF家族成员(TNF-.α.、TNF-.β.、LT-.β.、CD40配体、Fas配体、CD27配体、CD30配体、4-1BBL、Trail)和MIF。
“钙池操纵型钙进入”或“SOCE”指协调钙离子从细胞内钙池的释放与流过质膜的离子流的机制。
细胞钙稳态是牵涉控制细胞内钙水平和运动的调控系统总和的结果。至少部分通过钙结合或钙跨过质膜向细胞内和细胞外和在细胞中的运动,通过钙跨过细胞内细胞器(包括例如内质网、肌质网、线粒体和内吞细胞器(包括核内体和溶酶体))的膜的运动达到细胞钙稳态。
钙通过细胞膜的运动由特化蛋白进行。例如,来自细胞外空间的钙通过各种钙通道和钠/钙交换器进入细胞并且由钙泵和钠/钙交换器主动挤出细胞。钙还通过肌醇三磷酸或兰尼碱受体从内部钙池释放并且很可能被这些细胞器借助于钙泵摄取。
钙通过若干一般类别的通道的任何一种进入细胞,包括但不限于电压操纵型钙(VOC)通道、钙池操纵型钙(SOC)通道和以逆向模式操纵的钠/钙交换器。通过膜去极化激活VOC通道并且在如同神经和肌肉的可兴奋细胞中发现,在多数情况下在不可兴奋细胞中未发现。在一些条件下,Ca2+还通过以逆向模式操纵的Na+--Ca2+交换器进入细胞。
胞吞作用提供细胞通过核内体从细胞外介质摄取钙的另一种方法。另外,一些细胞,例如外分泌细胞,通过胞吐作用释放钙。
哺乳动物细胞中,细胞溶质钙浓度受通常估计为0.1μM的静止水平紧密调控,而细胞外钙浓度通常为约2mM。这种紧密调控促进通过流过质膜和细胞内细胞器膜的瞬时钙流向细胞内和细胞中的信号转导。细胞中存在大量细胞内钙转运和缓冲系统,用于定形细胞内钙信号和维持较低静止细胞质钙浓度。在静止细胞中,维持基底钙水平中牵涉的主要组分为钙泵和内质网和质膜中的漏出物。干扰静止细胞溶质钙水平实现这种信号的传输并引起许多细胞过程的缺陷。例如,细胞增殖牵涉钙信号序列延长。其它细胞过程包括但不限于分泌、信号转导和受精,牵涉钙信号。
激活磷脂酶C(PLC)的细胞表面受体由细胞内和细胞外来源产生细胞溶质Ca2+信号。[Ca2+]i(细胞内钙浓度)的起始瞬时升高由Ca2+从内质网(ER)释放引起,这是由ER中的PLC产物、肌醇-1,4,5-三磷酸(P3)、开放IP3受体触发(Streb等Nature,306,67-69,1983)。后续阶段跨过质膜的持续Ca2+进入通过质膜中的特化钙池操纵型钙(SOC)通道随之发生(在为免疫细胞的情况下,SOC通道为钙释放激活钙(CRAC)通道)。钙池操纵型Ca2+进入(SOCE)是排空Ca2+池自身激活质膜中的Ca2+通道以助于再装满钙池的过程(Putney,Cell Calcium,7,1-12,1986;Parekh等,Physiol.Rev.757-810;2005)。SOCE不仅为再装满钙池提供Ca2+,而且自身产生控制如基因表达、细胞代谢和胞吐作用的基本功能的持续Ca2+信号(Parekh和Putney,Physiol.Rev.85,757-810(2005)。
淋巴细胞和肥大细胞中,抗原或Fc受体的激活引起Ca2+从细胞内钙池释放,这依次导致Ca2+流过质膜内的CRAC通道。细胞内Ca2+的后续升高激活钙神经蛋白,一种调控转录因子NFAT的磷酸酶。在静止细胞中,NFAT被磷酸化并留在细胞质内,但是当由钙神经蛋白去磷酸化时,NFAT移动至细胞核并根据刺激条件和细胞类型的不同激活不同遗传程序。响应于感染反应和移植排斥期间,NFAT与“效应子”T细胞的细胞核中的转录因子AP-1(Fos-Jun)配对,从而反式激活细胞因子基因、调控T细胞增殖的基因和配合活性免疫反应的其它基因(Rao等,Annu Rev Immunol,1997;15:707-47)。相反,在识别自身抗原的T细胞中,在AP-1缺乏时激活NFAT并激活也称为“无变应性”的抑制自身免疫反应的转录程序(Macian等,Transcriptional mechanisms underlying lymphocyte tolerance.Cell.2002年6月14日;109(6):719-31)。在一种亚类的T细胞中,称为抑制自身反应性效应子T细胞介导的自身免疫性的调控T细胞,NFAT与转录因子FOXP3配对以激活负责抑制子功能的基因(Wu等,Cell,2006年7月28日;126(2):375-87;Rudensky A Y,Gavin M,Zheng Y.Cell.2006年7月28日;126(2):253-256)。
内质网(ER)进行各种过程。ER具有作为激动剂敏感性Ca2+池和槽的作用,蛋白质折叠/加工在其内腔中发生。此时,大量Ca2+依赖型伴侣蛋白确保新合成的蛋白质正确折叠并送至恰当目的地。ER也牵涉于囊泡运输、应力信号释放、胆固醇代谢调控和细胞凋亡。许多这些过程需要管腔内Ca2+,并且蛋白质折叠、ER应力反应和细胞凋亡很可能均通过排空Ca2+的ER达更长时间来诱导。由于作为Ca2+源,显然ER Ca2+含量必须在刺激后下降。然而,为保护ER的功能完整性,至关重要的是Ca2+含量不要降得太低或维持在低水平。因此为ER补充Ca2+是所有真核细胞的中心过程。因为ER Ca2+含量下降激活质膜中钙池操纵型Ca2+通道,所以这种Ca2+进入途径的主要功能被认为是维持正确蛋白质合成和折叠所必需的ER Ca2+水平。然而,钙池操纵型Ca2+通道具有其它重要作用。
通过电生理学研究提供了对钙池操纵型钙进入的理解,其确认排空钙池的过程激活了肥大细胞中称为Ca2+释放激活的Ca2+电流或ICRAC的电流。ICRAC非电压激活,向内整流并且对Ca2+有显著选择性。在若干细胞类型中发现主要为造血来源。ICRAC不仅是钙池操纵型电流,并且现在显而易见的是钙池操纵流涵盖不同细胞类型中具有不同性质的Ca2+渗透性通道家族。ICRAC是预期的第一钙池操纵型Ca2+电流并且仍然是研究钙池操纵流的普遍模式。
可使用提供直接或间接评估或测量细胞(包括细胞溶质和细胞内细胞器或隔室)钙和/或离子向细胞、细胞器、钙池或其部分(例如,膜)内、在其中或向其外的运动的各种筛选/鉴定方法监控化合物或试剂对细胞内钙的影响。可使用各种方法评估钙水平和离子运动或流量。所用特殊方法和采用的条件应取决于是否监控或检测细胞内钙的特殊方面。例如,在一些方面,试剂和条件可用于特定评估钙池操纵型钙进入,静止细胞溶质钙水平、钙缓冲和钙水平以及细胞内细胞器和钙池的钙摄取或释放。可选地,可使用(例如)细胞、细胞内细胞器或钙储存室、膜(包括,例如分离膜片或脂双层)或无细胞系统(例如,外面向外膜泡)监控或检测化合物或试剂对细胞内钙的影响。通常,在测试试剂存在下监控或检测细胞内钙的某一方面并且与对照比较,例如在测试试剂缺乏时的细胞内钙。
疾病、病症或病状
临床研究证明T细胞对抗原的反应下基因的激活绝对需要CRAC通道。淋巴细胞激活和适应性免疫反应需要持续钙进入。钙进入淋巴细胞主要通过CRAC通道进行。钙增多导致NFAT激活和免疫反应所需的细胞因子的表达。抑制钙池操纵型钙进入是防止T细胞激活的有效方式。
用调节细胞内钙水平的化合物抑制CRAC通道活性提供了经过在重症联合免疫缺陷(SCID)患者中注意到钙池操纵型钙进入消除证明的免疫抑制疗法。来自T细胞激活有主要缺陷的T细胞免疫缺陷或SCID患者的T细胞、成纤维细胞和在一些情况下的B细胞显示钙池操纵型钙进入的强缺陷。SCID患者缺乏适应性免疫反应,但在主要器官中无任何损伤或毒性。SCID患者表现型显示抑制CRAC通道是免疫抑制的有效策略。
牵涉炎症的疾病/病症和与免疫系统有关的疾病/病症
在一些实施方案中,使用本文公开的能够调节细胞内钙水平的化合物或其组合物和本文提供的鉴定能够调节细胞内钙水平的化合物的方法治疗或预防的疾病、病症或病状包括牵涉炎症和/或与免疫系统有关的疾病、病状或病症。这些疾病包括但不限于哮喘、慢性阻塞性肺病、类风湿性关节炎、炎症性肠病、肾小球性肾炎、神经炎症疾病(例如多发性硬化)和免疫系统病症。
部分通过增加细胞溶质钙浓度实现炎症介质对嗜中性粒细胞(PMN)的激活。认为尤其钙池操纵型钙流在PMN激活中起重要作用。已证实外伤增加PMN钙池操纵型钙流并且由于钙池操纵型钙流增强引起的细胞溶质钙浓度长时期升高很可能改变与刺激反应趋化因子的偶联并归因于损伤后的PMN功能障碍。因此,调节通过钙池操纵型钙通道的PMN细胞溶质钙浓度可在损伤、中风或脓毒症后用于调控PMN介导的炎症和备用心血管功能。
钙在淋巴细胞激活中起关键作用。例如,通过抗原刺激激活淋巴细胞引起细胞内游离钙浓度快速增加和转录因子激活,包括激活T细胞的核因子(NFAT)、NF-κB、JNK1、MEF2和CREB。NFAT是IL-2(和其它细胞因子)基因的主要转录调控子。将NFAT保持在转录活性状态需要细胞内钙水平持续升高,并取决于钙池操纵型钙进入。减少或阻断淋巴细胞中钙池操纵型钙进入阻断钙依赖性淋巴细胞激活。因此,在一些实施方案中,调节淋巴细胞中的STIM蛋白和/或Orai蛋白,并且尤其是钙池操纵型钙进入(例如,减少或消除钙池操纵型钙进入)是治疗免疫和免疫相关病症的方法,包括(例如)慢性免疫疾病/病症、急性免疫疾病/病症、自身免疫性和免疫缺陷疾病/病症、牵涉炎症的疾病/病症、器官移植排斥和移植物抗宿主病和免疫反应改变(例如,亢进)。例如,在一些实施方案中,自身免疫病症/病症的治疗牵涉减少、阻断或消除淋巴细胞中钙池操纵型钙进入。
免疫病症的实例包括(例如)银屑病、类风湿性关节炎、脉管炎、炎症性肠病、皮炎、骨关节炎、哮喘、炎症性肌肉疾病、过敏性鼻炎、阴道炎、间质性膀胱炎、硬皮病、骨质疏松症、湿疹、同种或异种移植(器官、骨髓、干细胞和其它细胞和组织)移植排斥、移植物抗宿主病、红斑狼疮、炎症性疾病、I型糖尿病、肺纤维化、皮肌炎、干燥综合征、甲状腺炎(例如,桥本氏和自身免疫性甲状腺炎)、重症肌无力、自身免疫性溶血性贫血、多发性硬化、囊性纤维化、慢性复发性肝炎、原发性胆汁性肝硬变、变应性结膜炎和特应性皮炎。
在其它实施方案中,本文公开的能够调节细胞内钙水平的化合物、其组合物和本文提供的鉴定能够调节细胞内钙水平的化合物的方法连同恶性肿瘤治疗使用,包括但不限于淋巴网状内皮细胞源恶性肿瘤、膀胱癌、乳腺癌、结肠癌、子宫内膜癌、头颈癌、肺癌、黑素瘤、卵巢癌、前列腺癌和直肠癌。认为钙池操纵型钙进入在癌细胞增殖中起重要作用。
抑制SOCE足以防止肿瘤细胞增殖。吡唑衍生物BTP-2,一种直接ICRAC阻滞剂,抑制Jurkat细胞和结肠癌细胞中SOCE和增殖。而且,持续SOCE需要线粒体Ca2+摄取并且防止线粒体Ca2+摄取导致SOCE抑制。刺激Jurkat细胞诱导持续SOCE并激活去磷酸化NFAT的Ca2+依赖性磷酸酶钙神经蛋白,促进白细胞介素-2表达和增殖。在其它实施方案中,能够调节细胞内钙水平的化合物抑制SOCE并用于治疗癌症或其它增生性疾病或病状。
在一些实施方案中,使用本文公开的能够调节细胞内钙水平的化合物、其组合物和本文提供的鉴定能够调节细胞内钙水平的化合物的方法治疗或预防的疾病、病症或病状包括(例如)肝或肝脏疾病和病症。这些疾病、病症或病状包括但不限于(例如)由于移植引起的肝损伤、肝炎和肝硬变。
钙池操纵型钙进入已牵连于慢性肝脏疾病以及冷藏-热脱氧后的移植损伤。
在一些实施方案中,使用本文公开的能够调节细胞内钙水平的化合物、其组合物和本文提供的鉴定能够调节细胞内钙水平的化合物的方法治疗或预防的疾病、病症或病状包括肾脏或肾疾病和病症。肾小球膜细胞增生常常是这种疾病和病症的主要特征。在其它实施方案中,这种疾病和病症由免疫学或其它损伤机制引起,包括IgAN、膜性增生性肾小球肾炎或狼疮性肾炎。肾小球膜细胞复制控制的不均衡似乎也在进展性肾衰竭的发病机制中起关键作用。正常成人肾脏中肾小球膜细胞的更新极低,更新率低于1%。肾小球/肾病的显著特征是由于肾小球膜细胞增殖速率升高或细胞丢失减少引起肾小球膜增生。当在无细胞丢失下,例如由于促有丝分裂刺激诱导肾小球膜细胞增殖时,不产生系膜增生性肾小球肾炎。数据显示肾小球膜细胞生长调控剂,尤其是生长因子被认为通过调控钙池操纵型钙通道起作用。还有其它实施方案中,钙池操纵型钙流调节剂通过抑制肾小球膜细胞增殖帮助治疗肾小球疾病。
一方面,本文所述化合物调节细胞内钙,例如但不限于在免疫系统细胞(例如,淋巴细胞、白细胞、T细胞、B细胞)、成纤维细胞(或源自成纤维细胞的细胞)或表皮、真皮或皮肤细胞(例如,角化细胞)中调节(例如,减少或抑制)SOC通道活性,例如抑制CRAC通道活性(例如,抑制ICRAC、抑制SOCE)。在一些实施方案中,调节一种或多种牵涉调节细胞内钙的蛋白质(例如,STIM蛋白和/或Orai蛋白)的步骤牵涉(例如)降低蛋白质的水平、表达、活性、功能和/或分子相互作用。例如,如果细胞表现出钙水平升高或缺乏对细胞内钙调节的一方面的调控,例如钙池操纵型钙进入,则在其它实施方案中,调节牵涉降低蛋白质(例如,STIM蛋白和/或Orai蛋白)的水平、表达、活性或功能或分子相互作用。
鉴定NSCLC治疗剂的方法
一方面,本发明提供一种鉴定用于治疗NSCLC的治疗剂的方法,其中所述试剂抑制一个或多个质膜钙转运途径。所述方法包括确定候选试剂是否可调节NSCLC细胞中的全部或部分CRAC/STIM途径,从而改变上皮细胞的一个或多个癌症相关性质。
用“癌症相关性质”指由细胞癌症引起的细胞的任何生理和/或病理学表现。启动细胞转录、增殖、细胞死亡(例如凋亡和坏死)和侵入在范围之内,其中侵入包括转移、移行和失去粘性。
应了解在一般形式下,候选试剂可直接调节CRAC通道。在替代性形式下,候选试剂可调节STIM蛋白,从而改变进入癌细胞的钙流量。
在本发明上下文中,“改变”包括在其范围内减少、降低或下调通过质膜的钙流。设想改变进入癌细胞的钙流量包括选择性改变钙流量。
易于了解,“调节”、“调节剂”或“调节”机制包括在其范围之内干扰、抑制、阻断或阻碍或激活或增加CRAC通道和/或STIM蛋白的钙流相关活性的任何相互作用。在某些实施方案中,调节剂为抑制剂。在其它实施方案中,调节剂为拮抗剂。还有其它实施方案中,调节剂为激动剂。在更多实施方案中,调节剂为激活剂。
在本发明的一个实施方案中,候选试剂选择性调节CRAC通道和/或STIM蛋白。在另一实施方案中,候选试剂选择性抑制CRAC通道和/或STIM蛋白。在又一实施方案中,候选试剂通过抑制CRAC通道和/或STIM蛋白改变钙流量。
因此,调节剂可为具有所需生物活性和半衰期的肽、蛋白质(例如抗体)或其它有机分子(例如有机小分子)。设想针对整个蛋白质或其生物活性片段的多克隆和单克隆抗体均为适合调节剂。
用“生物活性片段”指展现出整个或全长蛋白质的至少10%,优选至少25%,更优选至少50%且更优选至少70%、80%或90%生物活性的蛋白质片段、部分、区域或区段。
对于CRAC通道,生物活性为钙转运活性。至于STIM蛋白,生物活性为通过与CRAC通道直接或间接相互作用来激活钙向细胞内的转运的能力。
本领域的普通技术人员应了解,用于人治疗应用的抗体必须具有使这些抗体适合用于人的特殊性质。通常,治疗性抗体“人源化”,其中所述抗体通常包含90%的人序列和鼠抗体的互补决定区。由于引起异物免疫反应的可能性降低,人源化抗体尤其利于医疗应用。
设想人源化抗体可针对任何STIM,例如但不限于STIM1和STIM2。在一个实施方案中,人源化抗体针对STIM1。
在其它特定实施方案中,调节剂为针对CRAC通道的抗体。在替代性实施方案中,针对CRAC通道的抗体针对CRACM1。
易于考虑到有效调节剂包括根据本发明所述可能有用的其它潜在CRAC通道抑制剂。适合实例包括但不限于SKF-96365、T182、YM-58483、BTP-2、镧系元素(例如钆)和以下公开的其它CRAC通道调节剂化合物,例如转让给Synta Pharmaceuticals的PCT或美国专利申请案即WO 2005/009954、WO 2005/009539、WO 2005/009954、WO 200/6034402、A1、WO 2006/081389、WO 2006/081391、WO 2007/087429、WO 2007/087427、WO 2007/087441、WO 2007/087442、WO 2007/087443、WO 2007/089904、WO 2007/109362、WO 2007/112093、WO 2008/039520、WO 2008/063504、WO 2008/103310、WO 2009/017818、WO 2009/017819、WO 2009/017831、US 2006/0173006 US 2007/0249051 A1、WO 2010/039238、WO 2010/039237、WO2010/039236、WO 2009/089305和WO 2009/038775;Astellas、Queens Medical Center、Calcimedica和其它的专利和/或专利申请案,包括,即WO 2007/121186、WO 2006/050214、WO 2007/139926、WO 2008/148108、US 7,452,675、US 2009/023177、WO 2007/139926、US6,696,267、US 6,348,480、WO 2008/106731、US 2008/0293092、WO 2010/048559、WO 2010/027875、WO 2010/025295、WO 2010/034011、WO 2010/034003、WO 2009/076454、WO 2009/035818、US 2010/0152241、US 2010/0087415、US 2009/0311720和WO 2004/078995。
更多适合的CRAC通道调节剂包括Isabella Derler等Expert opinion in DrugDiscovery 3(7)(2008),第787-800页;Yousang G等,Cell Calcium 42(2007)145-156;Yasurio Yonetoky等,Bio.&Med Chem.14(2006)4750-4760和Yasurio Yonetoky等,Bio.&Med Chem.14(2006)5370-5383中公开的调节剂。为了所有目的,所有这些专利和/或专利申请案和文献公开作为引用整体并入本文。
进一步考虑到可采用调节CRAC/STIM途径的分子生物学方法。RNA干扰,例如siRNA,提供了一种引人注目的通过序列特异性裂解同源mRNA使潜在治疗基因靶标沉默的方法。Takeshita和Ochiya(Cancer Sci,2006,97:689-696)提供了抗癌RNA干扰治疗潜力的大量实例并通过引用并入。
术语“基因”在本文中用于描述了基因组内可能包含一个或多个内含子、外显子、剪接位点、开发阅读框和5′和/或3′非编码调控序列(例如启动子和/或多聚腺苷酸化序列)的离散核酸基因座、单元和区域。
因此,本领域的技术人员将易于了解本发明考虑了包含一个或多个能够指导合成RNA分子的核苷酸序列的基因构建体,其中核苷酸序列选自:
(i)可转录为包含大体上与目标核苷酸序列编码的RNA序列同源的RNA序列的RNA分子的核苷酸序列;
(ii)(i)中核苷酸序列的反向互补序列;
(iii)(i)和(ii)中核苷酸序列的组合;
(iv)任选由间隔序列分开的(i)、(ii)或(iii)中核苷酸序列的多个拷贝;
(v)(i)和(ii)中核苷酸序列的组合,其中(ii)的核苷酸序列表示由间隔序列分开的(i)中核苷酸序列的反向重复序列;和
(vi)如(v)中所述的组合,其中间隔序列包含可从所述组合剪接的内含子序列。
若核苷酸序列包含非内含子间隔序列分开的反向重复序列,一旦转录,非内含子间隔序列的存在促进由于反向重复序列相互结合形成茎环结构。非内含子间隔序列的存在产生形成以大体上维持完整,本文可称为“发夹”的形式的转录RNA序列(本文也称为“转录本”)。可选地,若核苷酸序列包含其中间隔序列包含内含子序列的反向重复序列,一旦转录,内含子序列任一侧的内含子/外显子间接序列促进去除将形成环结构的序列。所得的转录本包含任选在一端或两端具有突出3’序列的双链RNA(dsRNA)分子。本文将这种dsRNA转录本称为“完美发夹”。RNA分子可包含包括在双链DNA序列中出现的单链DNA“凸出”的单个发夹或多个发夹。
依据应用的不同,RNA分子可针对单个靶标或可选地,针对若干靶标。
在某些实施方案中,RNA分子编码CRACM1/Orai1、CRACM2/Orai1或CRACM3/Orai1和/或STIM1或STIM2。
本领域的技术人员将意识到可通过许多方法鉴定的用于癌症治疗的本发明治疗剂。因此,鉴定治疗剂的方法包括确定候选试剂是否可直接调节CRAC通道和/或调节STIM蛋白。在一个实施方案中,所述方法包括确定候选试剂是否可通过调节CRAC通道和/或STIM蛋白改变进入细胞的钙流量。
在一个实施方案中,可通过如Nestler&Liu,1998,Comb.Chem.High ThroughputScreen,1,113和Kirkpatrick等,1999,Comb.Chem.High Throughput Screen,2,211中所述的方法等,筛选分子文库,例如合成化学品文库(包括组合文库)的方式鉴定用于NSCLC治疗的本发明治疗剂。
还考虑到可通过已知方法,例如Kolb,1998,Prog.Drug.Res.51,185中所述的方法筛选自然存在的分子文库。类似地,可由分子文库程序(MLP),例如美国国家健康研究所(NIH)提供的程序鉴定分子。
设计用于NSCLC治疗的治疗剂的更多合理方法可采用如本领域中已知的X线晶体照相术、NMR分光术、计算机辅助筛选结构数据库、计算机辅助建模或检测分子结合相互作用的更多传统生物物理学技术。
结构生物信息学也可用于鉴定用于治疗NSCLC的候选试剂。均通过引用并入的Fauman等,2003,Meth.Biochem.Anal.44:477和Nature Reviews Drug Discovery 7,783(2008年9月)中提出了对药物发现的结构生物学方法的评论。
计算机辅助的结构数据库筛选和生物信息学方法成为越来越多利用的用于鉴定和/或工程化激动剂和拮抗剂分子的方法。美国专利No.5,752,019和国际公布No.WO 97/41526(针对鉴定EPO模拟物)和针对蛋白质建模和蛋白质活性的结构模拟的更多一般性计算机方法的美国专利No.7,158,891和5,680,331中可找到数据库筛选方法的实例。
通常,其它适用方法包括任何各种鉴定分子相互作用的生物物理学技术。这种方法包括但不限于竞争放射性配体结合分析法、电气生理学、分析超离心、微热量测量法、表面等离子共振和基于光生物传感器的方法,例如通过引用并入本文的Coligan等编的CURRENT PROTOCOLS IN PROTEIN SCIENCE(John Wiley&Sons,1997),第20章中提供的方法。
本领域的技术人员将了解调节剂可呈结合伴侣形式并且同样地通过例如酵母双杂交法等相互作用检测法鉴定。通过引用并入本文的Coligan等编的CURRENT PROTOCOLSIN PROTEIN SCIENCE(John Wiley&Sons,1997),第20章中提供了双杂交筛选方法。
药物组合物和NSCLC的治疗方法
还考虑到,一方面,本发明提供了包括对治疗通过以上方法鉴定的癌症有效的治疗剂和药学上可接受的载体、稀释剂或赋形剂的药物组合物。
另一方面,本发明提供了通过向人施用对治疗通过以上方法鉴定的癌症有效的治疗剂治疗人癌症的方法。治疗剂,例如CRAC抑制剂,可用作单一疗法或与一种或多种其它NSCLC治疗方法的辅助疗法。
在一个实施方案中,对治疗癌症有效的治疗剂呈适于口服施用的药学上可接受的载体、稀释剂或赋形剂配制的有机小分子或肽形式,如透皮贴剂或其它非侵入性施用途径。
在又一方面,本发明包括通过向患者施用有效量的CRAC抑制剂治疗患有NSCLC的患者的方法。CRAC抑制剂可用作单一疗法或一种或多种其它治疗肺癌(或NSCLC)的方法的辅助疗法,包括用于治疗肺癌的化疗剂,例如,顺铂依托泊苷(VP-16;)、卡铂紫杉醇多西他赛酒石酸长春瑞滨阿霉素硫酸长春新碱异环磷酰胺和吉西他滨盐酸盐
作为辅助疗法,CRAC抑制剂可与肺癌标准化学疗法一起使用,标准化学疗法通常由(例如)顺铂依托泊苷(VP-16;)、卡铂紫杉醇多西他赛酒石酸长春瑞滨阿霉素硫酸长春新碱异环磷酰胺和吉西他滨盐酸盐的两种或更多种的组合组成。已经证实这种标准化学疗法组合疗法增强对治疗的整体反应。标准化学疗法组合疗法中众所周知的药物配对包括紫杉醇+卡铂、顺铂+酒石酸长春瑞滨、顺铂+依托泊苷和卡铂+依托泊苷。目前的放射性疗法经常与顺铂+依托泊苷或卡铂+依托泊苷的标准化学疗法组合一起使用。
可用于治疗肺癌的其它化疗剂包括(例如)环磷酰胺甲氨蝶呤、洛莫司汀(CCNU)和拓扑替康盐酸盐
对于非小细胞肺癌,作为辅助疗法,CRAC抑制剂可与吉西他滨盐酸盐一种对许多实体肿瘤(包括非小细胞肺癌(NSCLC))有独特活性的化疗剂组合使用。已发现与吉西他滨、顺铂和酒石酸长春瑞滨的组合疗法安全并且在有晚期NSCLC的人体内活性非常高。对有晚期疾病的NSCLC患者的另一种治疗选择是交替化学-放射疗法(例如顺铂和依托泊苷,然后进行放射疗法)。
术语“药学上可接受的载体、稀释剂或赋形剂”包括可安全用于全身性施用的固体或液体填料、稀释剂或封装物质。依据特殊施用途径,可使用本领域中已知的各种载体。这些载体选自糖、淀粉、纤维素及其衍生物、麦芽、明胶、滑石、硫酸钙、植物油、合成油、多元醇、藻酸、磷酸盐缓冲液、乳化剂、等渗盐水和盐,例如无机酸盐(包括盐酸盐、溴酸盐和硫酸盐)和有机酸(例如醋酸盐、丙酸盐和丙二酸盐)和无热原水。
描述了药学上可接受的载体、稀释剂和赋形剂的有用参考为通过引用并入本文的Remington′s Pharmaceutical Sciences(Mack Publishing Co.N.J.USA,1991)。
任何安全施用途径均可用于为患者提供本发明的治疗剂或药物组合物。例如,可采用口服、直肠、胃肠外、舌下、经颊、静脉内、关节内、肌肉内、皮内、皮下、吸入、眼内、腹膜内、脑室内和经皮施用。
适合剂型包括但不限于片剂、分散剂、悬浮剂、注射剂、溶液、糖浆剂、锭剂、胶囊、栓剂、气雾剂和透皮贴剂。这些剂型也可能包括为了该目的特别设计的注射或植入控释装置或改性为另外以此形式作用的其它形式的植入物。可通过为治疗剂涂覆(例如)疏水性聚合物,包括丙烯酸树脂、蜡、高级脂肪醇、聚乳酸和聚乙醇酸和某些纤维素衍生物,例如羟丙基甲基纤维素实现治疗剂的控释。另外,可使用其它聚合物基质、脂质体和/或微球实现控释。
适于口服或胃肠外施用的本发明药物组合物可以离散单元呈现,例如胶囊、小袋或片剂,各自含有预定量的一种或多种本发明治疗剂,作为粉剂或颗粒呈现或作为水性液体、非水性液体中的溶液或悬浮剂、水包油乳液或油包水液体乳液呈现。可通过任何药学方法,例如通过使以上所述一种或多种试剂与构成一种或多种成分的载体缔合来制备这种组合物。可通过均一且密切混合本发明的试剂和液体载体或精细固体载体或其二者,然后任选将产物定形为预期外观来制备组合物。
可按照与剂型相容的方式和药学上有效的量来施用以上组合物。在本发明上下文中,对患者施用的剂量应足以在适当时间段后在患者体内实现有利反应。施用试剂的量可取决于治疗的受治疗者(包括年龄、性别、体重及其一般健康状况)将取决于医师判断的因素。
诊断方法
在又一实施方案中,本发明针对利用CRAC通道和STIM蛋白作为诊断标志的NSCLC诊断方法。在一个特殊方面,本发明提供了通过测量癌细胞内质膜相关STIM的水平来确定患者是否对用通过CRAC和/或STIM途径改变钙流入量的治疗剂的治疗有反应的诊断方法。
在一个特定实施方案中,本发明提供了通过检测癌细胞,例如来自肺部的细胞中STIM蛋白的过量水平确定人是否易患或患有NSCLC的诊断方法。
在另一个特殊方面,本发明的诊断方法包括测量一种特殊形式的STIM相对于另一特殊形式的STIM的比值。
在另一实施方案中,本发明提供了检测肺细胞中CRAC通道表达的激活的诊断方法。预想可通过基于蛋白质或基于核酸的技术分析CRAC通道表达。
“易患的”和“易患”用于个体可能表现出NSCLC的临床症状或任何现有明显的NSCLC临床症状为根本的生化原因结果的可能情况下。
本领域的技术人员易于了解,可利用多种方法测量癌细胞质膜上STIM的表达水平。仅举例而言,使用标记抗体进行的荧光激活细胞分选术(FACS)分析便于定量测量蛋白质的细胞表面表达。例如,免疫荧光和其它荧光显微镜方法也可用于为组织染色以检测STIM水平。也可使用其它常规免疫组织化学技术。
可选地,可通过其它基于蛋白质的方法,包括免疫检测(例如,ELISA和免疫印迹)确定相对蛋白质表达水平以检测一种或多种蛋白质的相对表达水平。
蛋白质组学模式分析提供了尤其用于蛋白质的整体表达模式分析的替代性诊断方法。Conrads等,Expert Rev Mol Diagn.2003July;3(4):411-20中提供了使用蛋白质组学模式的癌症诊断方法并通过引用并入本文。
在特定实施方案中,若干蛋白质可用于以多种方式展示的蛋白质文库,例如噬菌体展示或细胞展示系统或通过双向凝胶电泳,或更特别地,差异双向维凝胶电泳(2D-DIGE)。这些特定实施方案通常可称为例如Coligan等编的CURRENT PROTOCOLS IN PROTEINSCIENC,EJohn Wiley&Sons NY USA(1996-2002)第3.9.1和22章中所述的“蛋白质组学”或“蛋白质图谱”方法。
在关于蛋白质阵列的某些实施方案中,本发明的癌症相关蛋白质(例如NSCLC相关蛋白质)位于阵列上的可鉴定处。
在示例性实施方案中,蛋白质阵列包括固定、注入、结合或偶联在癌症相关蛋白质(例如NSCLC相关蛋白质)或其片段上的基质。
基质可为化学衍生的铝芯片、合成膜,例如PVDF或硝化纤维、载玻片或微量滴定板。
可使用质谱法、ELISA、免疫组织化学、荧光显微法或通过比色检测进行基质结合蛋白的检测。
本发明的诊断方法可包括测量编码STIM蛋白和/或CRAC通道的核酸的表达水平。在这一点上,启动子中的核苷酸序列变异(例如)可影响染病或易患病的个体的一种或多种细胞中CRAC通道基因转录本的稳定状态水平。
还考虑到,可在本发明的诊断方法中测量和/或比较核酸的相对水平。举例而言,可测量CRAC和/或STIM mRNA水平。
使用核酸阵列可便于进行测量核酸水平相比于参考核酸的表达水平的相对水平。
核酸阵列技术已在本领域中变得众所周知并且(例如)在Ausubel等编的CURRENTPROTOCOLS IN MOLECULAR BIOLOGY第22章(John Wiley&Sons NY USA 1995-2001)中提供了可适用于阵列技术的方法的实例。
可通过各种方法,例如通过照相平版印刷术(见,例如,美国专利No.5,143,854、5,510,270和5,527,681)、机械法(例如,如美国专利No.5,384,261中所述的定向流动法)、基于销的方法(例如,如美国专利No.5,288,514中所述)和磁珠技术(例如,如国际公布No.PCT/US93/04145中所述)生成阵列。
还参考了Affymetrix核酸阵列系统,例如美国专利No.5,858,659和6,300,063中所述,其提供了与疾病相关多态现象的基于核酸阵列的检测的特殊学说。
在该实施方案的另一特殊形式下,使用与CRAC通道编码核酸或STIM编码核酸相对应的引物进行的定量或半定量PCR可用于定量CRAC通道核酸或STIM核酸的相对表达水平,从而确定个体是否易患或患有NSCLC。
PCR扩增是非线性的,因此终点分析并非总是允许精确测定核酸表达水平。
实时PCR分析提供了测量基因表达水平的高通量方式。其使用特定引物和荧光检测以测量每个周期后产物的量。杂交探针利用猝灭式染料或荧光以直接产生信号。这种方法用于证实和定量与从非患者获得的细胞或组织相比,从癌患者获得的细胞或组织的核酸表达差异。
本文所述的以下一般方法提供了制备和使用本发明化合物的方式和工艺并且为说明性,而非限制性。还可设计所提供方法的更多修改和另外的新方法以实现和服务于本发明目的。因此,应了解可能存在属于有关说明书定义的本发明精神和范围内的其它实施方案。
制备式(I)化合物的一般方法
本发明的化合物可通过以下工艺制备。除非另外指出,当用于以下公式时,所有变量将被理解为呈现以上关于式(IA)所述的那些基团。这些方法可类似应用于式(I)(例如,(IA-I)、(IA-II)、(IA-III)和(IA-IV))的其它化合物。
方案1提供了合成式(IA)的化合物的一般工艺,其中L1&L2一起为-NH-CO-,R”’为氢或卤素,并且所有其它变量R、R1、R2、T、U、V、W、A和Cy如以上关于式(IA)所述。
式1的化合物可与式2的化合物(例如,苯肼)反应形成式3的化合物。然后可(例如)使用浓H2SO4和浓HNO3硝化式3的化合物以形成式4的化合物。在活性炭存在下(例如)用FeCl3和肼还原式4的化合物产生其中R”’为氢的式5a的相应胺化合物。交替地,在还原式4的化合物后卤化产生其中R”’为卤素的式5b的相应胺化合物。在适合偶联剂存在下,式5a或5b的化合物可与各种其它中间产物偶联以提供式(IA)的化合物。可使用一种或多种酰胺偶联剂,例如(苯并三唑-1-基氧基)三(二甲氨基)膦六氟磷酸盐(BOP试剂)或N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐(EDC)使式5a或5b的化合物与i.Cy-A-COOH;与ii.式Cy-A-COCl的酰基氯;或与iii.其中A为NH的式Cy-NCO的异氰酸盐偶联。
方案2提供了合成式(IA)的化合物的一般工艺,其中L1&L2一起为-NH-CO-,R”’为氢或卤素,并且所有其它变量R、R1、R2、T、U、V、W、A和Cy如以上关于式(IA)所述。
步骤1
步骤2
步骤1:可在碱,例如金属醇盐(例如乙醇钠)存在下使式a的酮与式b的酯缩合以产生式1的二酮。
步骤2:可通过使式1的化合物与肼反应将式1的化合物转化为式2a的吡唑化合物。在适合碱,例如碱性金属碳酸盐(例如,Cs2CO3)存在下式2a的化合物可与其中Lg为离去基团(例如卤素)的式2b的化合物反应以产生式4的化合物,式4的化合物可进行如上所述相似顺序的转化以获得式IA的化合物。
方案2A提供了合成式(IA)的化合物的一般工艺,其中L1&L2一起为-CO-NH-,R”’为氢或卤素,并且所有其它变量R、R1、R2、T、U、V、W、A和Cy如以上关于式(IA)所述。
在适合碱,例如碱性金属碳酸盐(例如,Cs2CO3)存在下式2a的化合物可与其中Lg为离去基团(例如卤素)的式2c的化合物反应以产生式4a的化合物,然后可使式4a的化合物水解以产生式5c的化合物。可使用一种或多种酰胺偶联剂,例如(苯并三唑-1-基氧基)三(二甲氨基)膦六氟磷酸盐(BOP试剂)或N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐(EDC)使式5c的化合物与Cy-A-NH2偶联。
如本领域的技术人员已知具有某些修改的类似方法可用于使用适合中间产物和试剂合成式(I)、(IA-I)或(IA-II)的化合物,其中变量应理解为呈现以上关于式(I)、(IA-I)、(IA-II)、(IA-III)或(IA-IV)所述的那些基团。实验
以下缩写在整个公开中使用:EDC.Hcl[N-(3-二甲氨基丙基)-N’-乙基碳二亚胺盐酸盐]、HOBt[羟基苯并三唑]、TEA(三乙胺)、DMF(二甲基甲酰胺)、AcOEt(乙酸乙酯)、DCM(二氯甲烷)、DMSO(二甲亚砜)、THF(四氢呋喃)。除非另外提及,处理(work-up)指分配括号内指出的水相和有机相之间的反应混合物,分离和在Na2SO4上干燥有机层和蒸发溶剂以获得残留物。除非另外说明,纯化指使用作为固定相的硅胶和作为流动相的石油醚(沸点为60-80℃)和乙酸乙酯或二氯甲烷和适当极性的甲醇的混合物的柱色谱法。RT(或rt)指环境温度(~25-28℃)。
中间产物1:1,3-二环丙基丙烷-1,3-二酮:将乙醇钠(8g,117.64mmol)加入于DMSO(30mL)中的环丙基甲基酮(5g,59.4mmol)和环丙烷羧酸甲酯(12ml,118.9mmol)的溶液中。在60℃下加热所生成的混合物过夜,然后冷却至0℃。用6N HCl终止反应后,处理(H2O/AcOEt)产生呈褐色液体的标题化合物,所述化合物无需任何纯化即可使用。1H-NMR(δppm,CDCl3,400MHz):16.05(bs,0.6H),5.72(s,0.6H)3.78(s,0.8H),2.08-2.0(m,0.8H),1.62-1.53(m,1.2H),1.12-1.05(m,4H),0.97-0.83(m,4H).MS(m/z):153.2[M+H]+。
中间产物2:1-环丙基-4,4,4-三氟丁烷-1,3-二酮:按照相似于对中间产物1所述的过程。由环丙基甲基酮(10g,119mmol)、2,2,2-三氟乙酸乙酯(29ml,237mmol)、DMSO(60mL)和乙醇钠(16.1g,237mmol),获得呈褐色液体的标题化合物(15g),其无需纯化即可用于下一步骤。1H-NMR(δppm,CDCl3,400MHz):5.65(s,2H),2.16-2.04(m,1H),1.18-1.12(m,2H),0.98-0.94(m,2H)。
中间产物3:3,5-二环丙基-1H-吡唑:使于乙醇(20mL)中的中间产物1(5.3g,35mmol)和水合肼(1.8mL,38.3mmol)回流过夜。冷却至环境温度后处理(H2O/AcOEt)产生呈褐色固体的标题化合物。M.P.:161-164℃.1H-NMR(δppm,CDCl3,400MHz):15.2(bs,1H),5.65(s,1H),2.16-2.09(m,2H),1.18-1.14(m,4H),0.98-0.94(m,4H).MS(m/z):149.04[M+H]+。
中间产物4:5-环丙基-3-(三氟甲基)-1H-吡唑:将中间产物2(0.120g,0.66mmol)和水合肼(0.04mL,0.72mmol)溶于乙醇(6mL)中并回流过夜。将混合物冷却至RT后,处理(H2O/AcOEt)产生呈褐色固体的标题化合物(0.114g)。
中间产物5:3,5-二环丙基-1-(4-硝基苯基)-1H-吡唑:在160℃下于氮气中将中间产物3(2.0g,13.5mmol)和Cs2CO3(5.51g,40.5mmol)在DMSO(15mL)中的溶液加热0.5h。向混合物中加入4-氯-1-硝基苯(6.38g,40.5mmol)并且在相同温度下搅拌4h。处理(H2O/AcOEt)和纯化获得标题化合物(0.8g)。1H-NMR(δppm,CDCl3,400MHz):8.32(d,J 9.0,2H),7.92(d,J9.0,2H),5.76(s,1H),1.97-1.91(m,1H),1.86-1.80(m,1H),1.09-1.04(m,2H),0.98-0.94(m,2H),0.83-0.75(m,4H)。
中间产物6:3,5-二环丙基-1-(2-氟-4-硝基苯基)-1H-吡唑:在120℃下于氮气中将中间产物3(2.0g,13.5mmol)和K2CO3(5.5g,40.6mmol)在DMSO(20mL)中的溶液加热0.5h。向该混合物中加入3,4-二氟-1-硝基苯(2.15g,13.5mmol)并在相同温度下搅拌2h。处理(H2O/AcOEt)和纯化获得呈黄色固体的标题化合物(3.16g)。1H-NMR(δppm,CDCl3,400MHz):8.19-8.12(m,2H),7.78(t,J 7.9,1H),5.70(s,1H),2.10-2.00(m,1H),1.68-1.58(m,1H),1.08-0.92(m,4H),0.82-0.74(m,2H),0.72-0.65(m,2H)。
中间产物7:2-(3,5-二环丙基-1H-吡唑-1-基)-5-硝基吡啶:在110℃下于氮气中将中间产物3(8.0g,54.05mmol)和K2CO3(27.96g,202.6mmol)在DMSO(60mL)中的溶液加热0.5h。向该混合物中加入2-氯-5-硝基吡啶(12.8g,80.75mmol)并在相同温度下搅拌2h。处理(H2O/AcOEt)和纯化获得标题化合物(3.03g)。1H-NMR(δppm,CDCl3,400MHz):9.24(d,J2.6,1H),8.51(dd,J 2.6,9.9,1H),8.10(d,J 9.2,1H),5.72(s,1H),2.90-2.75(m,1H),1.99-1.90(m,1H),1.06-0.93(m,4H),0.82-0.64(m,4H)。
中间产物8:5-环丙基-1-(4-硝基苯基)-3-(三氟甲基)-1H-吡唑:采用与对中间产物5所遵循的过程相似的过程。由中间产物4(1.0g,5.67mmol)、Cs2CO3(5.5g,16.9mmol)、DMSO(4mL)和4-氯-1-硝基苯(1.93g,14.1mmol)获得标题化合物(0.7g)。1H-NMR(δppm,CDCl3,400MHz):8.38(d,J 7.08,2H),7.92(d,J 7.08,2H),6.32(s,1H),1.89-1.82(m,1H),1.19-1.11(m,2H),0.89-0.85(m,2H),MS(m/s):298.15[M+H]+。
中间产物9:5-环丙基-1-(2-氟-4-硝基苯基)-3-(三氟甲基)-1H-吡唑:在120℃下于氮气中将中间产物4(6.3g,35mmol)和K2CO3(14.6g,105mmol)在DMSO(20mL)中的溶液加热30min。向该混合物中加入2-二氟硝基苯(5.68g,35mmol)并在相同温度下搅拌2h。处理(H2O/AcOEt)和纯化获得标题化合物(7.52g)。1H-NMR(δppm,DMSO-d6,400MHz):8.49(dd,J2.4,9.9,1H),8.47-8.27(m,1H),8.04-8.02(m,1H),6.73(s,1H),1.76-1.68(m,1H),0.99-0.90(m,2H),0.84-0.74(m,2H)。
中间产物10:2-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-5-硝基吡啶:在90℃下于氮气中将中间产物4(1.0g,5.67mmol)和K2CO3(2.35g,17.03mmol)在DMSO(10mL)中的溶液加热30min。向该混合物中加入2-氯-5-硝基吡啶(1.35g,8.5mmol)并在相同温度下搅拌2h。处理(H2O/AcOEt)和纯化获得标题化合物(0.30g)。1H-NMR(δppm,CDCl3,400MHz):9.33(d,J2.5,1H),8.62(dd,J 2.8,9.0,1H),8.19(d,J 9.0,1H),6.29(s,1H),2.92-2.83(m,1H),1.60-1.50(m,2H),0.79-0.70(m,2H)。
中间产物11:2-[4-氯-5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-5-硝基吡啶:将中间产物10(1.5g,5.0mm0l)溶于DMF中并且在0℃下向其中加入N-氯琥珀酰亚胺(0.8g,6mmol)。然后使反应在rt下搅拌2h。反应完成后,处理(EtOAc)并纯化,获得标题化合物(0.802g)。1H-NMR(δppm,DMSO-d6,400MHz):9.34(d,J 2.5,1H),8.65(dd,J 2.5,9,1H),8.09(d,J 9,1H),2.48-2.38(m,1H),1.13-1.03(m,2H),0.90-0.82(m,2H)。
中间产物12:4-(3,5-二环丙基-1H-吡唑-1-基)苯胺:向于EtOH/H2O(2∶1,15mL)中的中间产物5(0.85g,3.15mmol)溶液加入铁粉(0.88g,15.8mmol)和氯化铵(17mg,0.3mmol)并且使混合物回流0.5h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。浓缩合并层后处理(H2O/AcOEt)获得呈黄色固体的标题化合物(0.68g)。1H-NMR(δppm,DMSO-d6,400MHz):7.11(d,J 8.6,2H),6.61(d,J 8.6,2H),5.65(s,1H),5.24(s,2H),1.81-1.74(m,1H),1.67-1.60(m,1H),0.86-0.77(m,4H),0.61-0.56(m,4H).MS(m/z):240.3[M+H]+。
中间产物13:4-(3,5-二环丙基-1H-吡唑-1-基)-3-氟苯胺:将中间产物6(2g,7.0mmol)在EtOH/H2O(2∶1,30mL)中的溶液加至铁粉(1.86g,34.8mmol)和氯化铵(30mg,0.7mmol)并且使混合物回流1h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。处理(H2O/AcOEt)并浓缩合并层,获得呈黄色固体的标题化合物(1.34g)。
中间产物14:6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-胺:将中间产物7(0.77g,2.86mmol)在EtOH/H2O(2∶1,15mL)中的溶液加至铁粉(0.79g,14.17mmol)和氯化铵(15mg,0.28mmol)并且使混合物回流1h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。浓缩合并层后处理(H2O/AcOEt),获得呈黄色固体的中间产物14(0.570g)。1H-NMR(δppm,DMSO-d6,400MHz):7.75(d,J 2.5,1H),7.27(d,J 8.6,1H),7.06(dd,J 2.7,8.6,1H),5.67(s,1H),5.43(s,2H),2.39-2.27(m,1H),1.88-1.74(m,1H),0.90-0.72(m,4H),0.69-0.50(m,4H)。
中间产物15:4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯胺:按照相似于对中间产物12采用的过程。由中间产物8(0.69g,2.32mmol)、EtOH-H2O(2∶1,12mL)、Fe(0.64g,15.8mmol)和NH4Cl(0.012mg,0.22mmol),获得呈黄色固体的标题化合物(0.49g)。1H-NMR(δppm,DMSO-d6,400MHz):7.19(d,J 8.64,2H),6.65(d,J 8.64,2H),6.47(s,1H),5.46(s,2H),1.75-1.69(m,1H),0.94-0.89(m,2H),0.77-0.73(m,2H).MS(m/z):268.1[M+H]+。
中间产物16:4-[3-环丙基-5-(三氟甲基)-1H-吡唑-1-基]-3-氟苯胺:向中间产物9(5g,17.00mmol)在EtOH/H2O(2∶1,45mL)中的溶液加入铁粉(4.75g,85.1mmol)和氯化铵(90mg,1.7mmol)并且使混合物回流1h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。浓缩合并层后处理(H2O/AcOEt),获得呈黄色固体的标题化合物(4.3g)。1H-NMR(δppm,DMSO-d6,400MHz):7.16(t,J 8.5,1H),6.50-6.45(m,3H),5.86(s,2H),1.60-1.51(m,1H),0.91-0.82(m,2H),0.76-0.69(m,2H)。
中间产物17:6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-胺:向中间产物10(0.77g,2.86mmol)在EtOH/H2O(2∶1,9mL)中的溶液加入铁粉(0.279g,5.00mmol)和氯化铵(5mg,0.09mmol)并且使混合物回流1h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。浓缩合并层后处理(H2O/AcOEt),获得呈黄色固体的中间产物17(0.239g)。1H-NMR(δppm,DMSO-d6,400MHz):7.84(d,J 2.6,1H),7.33(d,J 8.6,1H),7.12(dd,J 2.6,8.6,1H),6.49(s,1H),5.69(s,2H),2.45-2.36(m,1H),0.90-0.81(m,2H),0.74-0.65(m,2H).MS(m/z):269.2[M+H]+。
中间产物18:6-[4-氯-5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-胺:向于EtOH/H2O(2∶1,15mL)中的中间产物11(1.7g,5.60mmol)溶液加入铁粉(1.56g,28.0mmol)和氯化铵(600mg,11.2mmol)并且使混合物回流1h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。处理(H2O/AcOEt)并浓缩合并层获得呈黄色固体的中间产物18(1.1g)。1H-NMR(δppm,DMSO-d6,400MHz):8.04(s,1H),7.39(d,J 8.2,1H),7.20(d,J 8,1H),4.26(s,2H),2.10-1.99(m,1H),1.96-1.85(m,2H),1.84-1.70(m,2H)。
中间产物19:2-氯-N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]乙酰胺:在0℃下向中间产物12(600mg,2.24mmol)在二氯甲烷(DCM)中的溶液加入氯乙酰氯(0.2mL,2.39mmol)。搅拌混合物15min。处理(H2O/DCM)产生中间产物19,其无需进一步纯化即可用于下一步骤。
中间产物20:2-氯-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺:在0℃下向于二氯甲烷(DCM)中中间产物15(150mg,0.561mmol)的溶液加入氯乙酰氯(0.05mL,0.62mmol)。搅拌混合物15min。处理(H2O/DCM)产生标题化合物,其无需进一步纯化即可用于下一步骤。
中间产物21:2-氯-N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}乙酰胺:在0℃下向中间产物17(500mg,1.86mmol)在二氯甲烷(DCM)中的溶液加入氯乙酰氯(0.16mL,2.00mmol)。搅拌混合物15min。处理(H2O/DCM)产生中间产物21,其无需进一步纯化即可用于下一步骤。
中间产物22:5-环丙基-1-(2-氟-4-碘代苯基)-3-(三氟甲基)-1H-吡唑:向于5ml水中的中间产物16(1.9g,7.20mmol)加入浓HCl(5ml)并冷却至0℃。向该溶液中缓慢加入亚硝酸盐溶液(1g,15mmol)并在0℃下搅拌15min。在相同温度下向该混合物中加入碘化钾溶液(2.5g,15mmol)并在rt下搅拌反应混合物。处理(H2O/AcOEt)并纯化产生呈黄色液体的所需产物。1H-NMR(δppm,DMSO-d6,400MHz):8.01(dd,J 1.7,9.5,1H),7.79(dd,J 1.7,8.4,1H),7.45(t,J 8.1,1H),6.63(s,1H),1.64-1.56(m,1H),0.92-0.84(m,2H),0.79-0.71(m,2H)。
中间产物23:4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-3-氟苯甲酸:在惰性气体下将镁(143mg,6mmol)和少许碘悬浮于乙醚中。向其中加入少量碘甲烷并且使反应混合物回流以开始格氏形成。在该阶段加入中间产物22(790mg,2mmol)并且在回流条件下继续反应。原材料完全消耗后,冷却反应混合物至rt并向其中加入干冰片,然后加入2N HCl。过滤和在高真空下干燥所形成的固体以获得呈灰白色固体的标题化合物(160mg)。1H-NMR(δppm,DMSO-d6,400MHz):13-6(bs,1H),7.97-7.92(m,2H),7.84-7.78(m,1H),6.68(s,1H),1.69-1.61(m,1H),0.94-0.87(m,2H),0.80-0.74(m,2H)。
中间产物24:1H-苯并[d]咪唑-6-羧酸:混合3,4-二氨基苯甲酸(5g,32mmol)和甲酸(20ml)并回流过夜。用旋转蒸发仪去除甲酸并向残留物中加入水以获得固体。过滤固体并干燥以定量获得标题化合物。
中间产物25:1H-苯并[d][1,2,3]三唑-6-羧酸:将3,4-二氨基苯甲酸(5g,32.8mmol)溶于AcOH(30ml)中并冷却该混合物至5℃。向该混合物加入NaNO2溶液(2.7g于8ml水中),然后加入2ml硫酸。使反应混合物搅拌90min。之后,用冰终止反应混合物,过滤获得的固体并用水洗涤以获得呈褐色固体的标题化合物(4.5g)。
中间产物26:6-羧酸喹啉:在rt下向4-氨基苯乙酸(45g,297mmol)、甘油(61.7g,67mmol)和碘(1.14g,4mmol)中滴加硫酸(67.5ml)。加热混合物至140℃,持续5h。之后,用冰终止反应混合物并过滤形成的固体。将固体溶于MeOH中并向其中加入炭并回流1h。通过硅藻土过滤该混合物并去除甲醇以获得呈褐色固体的标题化合物(7g)。
中间产物27:6-羧酸喹喔啉:向碳酸钾水溶液(7ml,1.82g K2CO3)中缓慢加入3,4-二氨基苯甲酸(500mg,3.29mmol)。然后,缓慢加入乙二醛二(亚硫酸钠)水合加成物(963mg,3.62mmol)。加热该混合物至80℃达5h以获得澄清溶液。反应完成后,将反应混合物缓慢加入稀HCl中,过滤并干燥形成的固体以获得呈褐色固体的标题化合物(300mg)。
中间产物28:2-(咪唑并[1,2-a]吡啶-2-基)乙酸乙酯:将2-氨基吡啶(500mg,5.31mmol)和氯乙酰乙酸乙酯(870mg,5.31mmol)溶于DMSO中并在惰性气体中加热至100℃,持续1h。1h后,向反应混合物中加水,然后处理(H2O/AcOEt)并使用AcOEt和石油醚(30∶70)在60-120目硅胶上纯化,产生呈褐色液体的标题化合物(110mg)。1H-NMR(δppm,CDCl3,400MHz):8.06(d,J 6.7,1H),7.59(s,1H),7.55(d,J 9.4,1H),7.14(t,J 7.9,1H),6.75(t,J 6.7,1H),4.12(q,J 7.1,2H),3.87(s,2H),1.3(t,J 7.1,3H)。
中间产物29:2-(咪唑并[1,2-a]吡啶-2-基)乙酸:将中间产物28(7.5g,39.22mmol)溶于水(30ml)中并加入NaOH(2.35g,58.8mmol)。加热该混合物至90℃达1h。之后,通过蒸馏去除水并且用稀HCl酸化反应混合物至pH 7以获得固体。真空过滤并干燥固体以定量获得呈褐色固体的标题化合物。1H-NMR(δppm,CDCl3,400MHz):8.50(d,J 6.7,1H),7.82(s,1H),7.46(d,J 9,1H),7.20(t,J 7.5,1H),6.85(t,J 6.7,1H),3.69(s,2H)。
中间产物30:2-(喹啉-6-基)乙酸:向4-氨基苯乙酸(45g,297mmol)、甘油(61.7g,67mmol)和碘(1.14g,4mmol)中滴加硫酸(67.5ml)。加热混合物至140℃,持续24h。之后,冷却反应混合物至rt并用10%氢氧化钠溶液将pH调至5。向其中加入甲醇(350ml)和硫酸(3ml)并加热至100℃,持续24h。通过硅藻土过滤反应混合物并用旋转蒸发仪蒸发滤液以获得残留物。使用4%NaOH溶液将残留物的pH调至5并且用EtOAc萃取。用无水Na2SO4干燥EtOAc层并用旋转蒸发仪去除EtOAc以获得粗产物。使用EtOAc和石油醚作为洗脱剂通过柱纯化粗产物以获得2-(喹啉-6-基)乙酸甲酯(11.2g)。将2-(喹啉-6-基)乙酸甲酯(11.2g)溶于甲醇(8ml)和水(8ml)中并加入氢氧化钠(3.3g,82mmol)。搅拌该混合物30min并用旋转蒸发仪去除甲醇以获得残留物。使用0.8N HCl酸化残留物至pH 5以获得固体。过滤并干燥固体以获得标题化合物(8.2g)。
中间产物31:2-(3-硝基吡啶-2-基氨基)乙酸:将2-氯-3-硝基吡啶(5g,31.5mmol)溶于EtOH(125ml)中,加入碳酸钾(4.35g,31.5mmol),并且向该混合物中加入于25ml水中的甘氨酸(4.73g,6.3mmol)并回流过夜。冷却反应混合物至0℃以获得固体。然后用旋转蒸发仪去除EtOH并且用2NHCl酸化,用柱过滤和干燥固体以定量获得呈黄色固体的标题化合物。
中间产物32:2-(3-氨基吡啶-2-基氨基)乙酸:向中间产物31(10g,50.74mmol)在EtOH/H2O(2∶1,225mL)中的溶液加入铁粉(14.15g,0.25mol)和氯化铵(5.41g,101.47mmol),并且回流混合物1h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。处理(H2O/AcOEt)并浓缩合并层,获得呈褐色固体的标题化合物(10g)。
中间产物33:2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)乙酸:将中间产物32(10.92g,65.35mmol)溶于30ml水中并加入13ml AcOH。在rt下向该混合物中加入亚硝酸钠(4.96g,71.88mmol)溶液并且将混合物冷却至0℃。搅拌反应混合物30min并过滤反应混合物。在真空下干燥获得的固体以获得呈红色固体的标题化合物(7.5g)。
中间产物34:(R)-2-(3-硝基吡啶-2-基氨基)丙酸:将2-氯-3-硝基吡啶(500mg,3.15mmol)溶于EtOH(12.5ml)中,加入碳酸钾(435mg,3.15mmol)并向该混合物中加入于2.5ml水中的(S)-2-氨基丙酸(561mg,6.3mmol)并回流过夜。将反应混合物冷却至0℃以获得固体。然后用旋转蒸发仪去除EtOH并且用2N HCl酸化,过滤和真空干燥固体,以获得呈黄色固体的标题化合物(460mg)。
中间产物35:(R)-2-(3-氨基吡啶-2-基氨基)丙酸:将铁粉(657mg,11.78mmol)和氯化铵(25lmg,53.4mmol)加入于EtOH/H2O(2∶1,12mL)中的中间产物34(500mg,2.35mmol)溶液中并回流混合物1h。通过硅藻土过滤混合物并用乙醇洗涤硅藻土。处理(H2O/AcOEt)并浓缩合并层,获得呈黑色固体的标题化合物(600mg)。
中间产物36:(R)-2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)丙酸:将中间产物35(600mg,3.3mmol)溶于1.5ml水中并加入0.5ml AcOH。在rt下向该混合物中加入亚硝酸钠((190mg,2.76mmol)溶液并将混合物冷却至0℃。搅拌反应混合物30min,然后过滤。真空干燥所生成的固体以获得呈红色固体的标题化合物(160mg)。1H-NMR(δppm,DMSO-d6,400MHz):11.04(s,1H),8.18-8.17(m,1H),7.51-7.40(m,2H),5.30(q,J 7.12,1H),1.18(d,J7.12,3H)。
中间产物37:2-(喹啉-6-基)丙酸甲酯:将THF(5ml)置于RBF中,加入二异丙胺(0.19ml,1.29mmol)并在氮气中冷却至-78℃。然后加入正丁基锂(0.8ml,1.29mmol)并在相同温度下搅拌30min。在该阶段加入2-(喹啉-6-基)乙酸甲酯(0.2g,0.99mmol)并在-78℃下搅拌30min。然后加入碘甲烷(0.17g,1.2mmol)并在-78℃下搅拌30min,然后缓慢升至rt。在rt下使反应混合物搅拌过夜。用水终止反应混合物并用EtOAc萃取。经无水Na2SO4干燥有机层并使用旋转蒸发仪去除EtOAc以获得粗产物,在60-120目硅胶上用EA和石油醚(25∶75)作为洗脱剂进行柱色谱法纯化粗产物。1H-NMR(δppm,CDCl3,400MHz):8.89-8.86(m,1H),8.13(d,J 7.8,1H),8.07(d,J 8.7,1H),7.76-7.64(m,2H),7.42-7.37(m,1H),3.92(q,J 7.2,1H),3.68(s,3H),1.60(d,J 7.2,3H)。
中间产物38:2-(喹啉-6-基)丙酸:将中间产物37(440mg,2.04mmol)溶于MeOH(5ml)中,加入水(2ml)和氢氧化锂(427mg,10.2mmol)。使该混合物回流2h并冷却反应混合物。用旋转蒸发仪去除甲醇并且向残留物中加入6N HCl以将pH调至7。过滤并干燥获得的固体以获得呈固体的标题化合物。
中间产物39:喹啉-6-基甲胺:混合6-氰基喹啉(14g)[按照Srivastava,Rajiv等,Synthetic Communications 37(3),431-438,2007合成]、氨化甲醇(250ml)、兰尼镍(20g)并在40-45℃下保持于氢气(50-60Psi)中4h。反应完成后,通过硅藻土过滤反应混合物,并用MeOH洗涤硅藻土床。浓缩滤液以产生呈黑色糖浆状液体的标题化合物(13.5g)。
酰胺形成的一般过程
过程1:在RT下搅拌适当苯胺(1当量)、必需酸(1.1当量)、EDC.HCl(1.2当量)、HOBt(0.5当量)和TEA(3当量)在DMF中的溶液。处理(H2O/AcOEt)并纯化产生所需产物。
过程2:将酸(1当量)溶于DCM中,冷却至0℃,加入乙二酰氯(3当量)和3滴DMF。在室温下搅拌反应混合物30min并且用旋转蒸发仪去除DCM以获得酰基氯。在N2气体下将胺溶于DCM中并加入吡啶(1.3当量)。向该混合物中加入于DMC中的酰基氯并使其在室温下搅拌直至胺完全消耗。处理(H2O/AcOEt)并纯化产生所需产物。
使用这些过程制备以下化合物:
实施例1
N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-1H-苯并[d]咪唑-6-甲酰胺:
按照一般过程1,由中间产物24(97mg,0.60mmol)和中间产物12(120mg,0.50mmol)制备呈灰白色固体的标题化合物(160mg)。M.P.:170-176℃.1H-NMR(δppm,DMSO-d6,400MHz):12.74(bs,1H),10.37(s,1H),8.37(s,1H),8.30(s,1H),7.93(d,J 8.84,2H),7.87-7.84(m,1H),7.69(d,J 8.48,1H),7.55(d,J 8.84,2H),5.79(s,1H),1.86-1.76(m,2H),0.94-0.90(m,2H),0.89-0.82(m,2H),0.69-0.62(m,4H).MS(m/z):382.17.[M-H]-。
实施例2
N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-1H-苯并[d][1,2,3]三唑-6-甲酰胺:
按照一般过程1,由中间产物25(97mg,0.59mmol)和中间产物12(120mg,0.50mmol)制备呈白色固体的标题化合物(30mg)。M.P.:240-246℃.1H-NMR(δppm,DMSO-d6,400MHz):16.02(bs,1H),10.55(s,1H),8.6(bs,1H),8.06-7.98(m,2H),7.92(d,J 8.8,2H),7.57(d,J8.8,2H),5.80(s,1H),1.84-1.78(m,2H),0.93-0.82(m,4H),0.69-0.62(m,4H).MS(m/z):383.21[M-H]-。
实施例3
N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]喹啉-6-甲酰胺盐酸盐:
按照一般过程1,由中间产物26(95mg,0.55mmol)和中间产物12(120mg,0.5mmol)制备呈浅黄色固体的N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]喹啉-6-甲酰胺(60mg)并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈白色固体的标题化合物(46mg)。M.P.114-119℃.1H-NMR(δppm,DMSO-d6,400MHz):11.00(s,1H),9.34(d,J 3.8,1H),9.18(d,J 8.2,1H),9.00(s,1H),8.59(d,J8.8,1H),8.48(d,J 8.8,1H),8.15-8.05(m,1H),7.61(d,J 8.9,2H),7.61(d,J 8.9,2H),5.84(s,1H),1.89-1.77(m,2H),0.95-0.84(m,4H),0.70-0.64(m,4H).MS(m/z):393.05[M-H-HCl]-。
实施例4
N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]喹喔啉-6-甲酰胺
按照一般过程1,由中间产物27(104mg,0.574mmol)和中间产物12(120mg,0.50mmol)制备呈白色固体的标题化合物(48mg)。M.P.:162-167℃.1H-NMR(δppm,DMSO-d6,400MHz):10.77(s,1H),9.08-9.06(br.d,J 4.7,2H),8.77(d,J 1.7,1H),8.36(d,J 1.9,1H),8.24(d,J 8.76,1H),7.96(d,J 8.84,2H),7.59(d,J 8.84,2H),5.81(s,1H),1.88-1.77(m,2H),0.95-0.90(m,2H),0.87-0.82(m,2H),0.69-0.62(m,4H).MS(m/z):394.[M-H]-。
实施例5
2-(1H-苯并[d]咪唑-1-基)-N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]乙酰胺
在0℃下将中间产物19(130mg,0.41mmol)和苯并咪唑(53mg,0.45mmol)溶于DMF(5mL)中并向反应混合物中加入氢化钠(28.35mg,1.23mmol)。然后使反应在环境温度下搅拌过夜。处理(H2O∶AcOEt),然后在柱上纯化,获得呈白色固体的标题化合物(40mg)。M.P.230-235℃.1H-NMR(δppm,DMSO-d6,400MHz):10.61(s,1H),8.23(s,1H),7.70-7.65(m,3H),7.54-7.51(m,3H),7.26-7.18(m,2H),5.78(s,1H),5.19(s,2H),1.86-1.71(m,2H),0.92-0.80(m,4H),0.68-0.59(m,4H).MS(m/z):396.07[M-H]-。
实施例6
2-(1H-苯并[d][1,2,3]三唑-1-基)-N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]乙酰胺:
按照一般过程1,由2-(1H-苯并[d][1,2,3]三唑-1-基)乙酸(177mg,0.60mmol)和中间产物12(120mg,0.50mmol)制备呈灰白色固体的标题化合物(100mg)。M.P.:216-220℃.1H-NMR(δppm,DMSO-d6,400MHz):10.75(s,1H),8.07(d,J 8.4,1H),7.85(d,J 8.4,1H),7.69(d,J 8.84,2H),7.58-7.52(m,3H),7.44-7.40(m,1H),5.78(s,1H),5.71(s,2H),1.85-1.80(m,2H),0.90-0.80(m,4H),0.66-0.60(m,4H).MS(m/z):396.93[M-H]-。
实施例7
N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-2-(1H-吲哚-3-基)乙酰胺:
由2-(1H-吲哚-3-基)乙酸(104mg,0.6mmol)和中间产物12(120mg,0.500mmol)制备呈白色固体的标题化合物(160mg)。M.P.158-164℃.1H-NMR(δppm,DMSO-d6,400MHz):10.90(s,1H),10.23(s,1H),7.70(d,J 8.8,2H),7.60(d,J 7.8,1H),7.47(d,J 8.8,2H),7.34(d,J 8.0,1H),7.26-7.25(d,J 1.9,1H),7.06(t,J 7.4,1H),6.97(t,J 7.3,1H),5.76(s,1H),3.74(s,2H),1.84-1.80(m,1H),1.79-1.71(m,1H),0.89-0.79(m,4H),0.65-0.59(m,4H).MS(m/z):395.25[M-H]-。
实施例8
N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-2-(咪唑并[1,2-a]吡啶-2-基)乙酰胺盐酸盐:
按照一般过程1,由中间产物29(79mg,0.45mmol)和中间产物12(90mg,0.38mmol)制备呈褐色固体的N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-2-(咪唑并[1,2-a]吡啶-2-基)乙酰胺(56mg)并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈浅褐色固体的标题化合物(54mg)。M.P.92-97℃.1H-NMR(δppm,DMSO-d6,400MHz):10.82(s,1H),8.92(d,J 6.7,1H),8.32(s,1H),7.97-7.92(m,2H),7.75(d,J 8.7,2H),7.53(d,J 8.7,2H),7.52-7.47(m,1H),5.79(s,1H),3.80(s,2H),1.87-1.71(m,2H),0.93-0.79(m,4H),0.69-0.58(m,4H).MS(m/z):398.24[M+H-HCl]+。
实施例9
N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-2-(喹啉-6-基)乙酰胺:
按照一般过程1,由中间产物30(93mg,0.49mmol)和中间产物12(100mg,0.42mmol)获得呈褐色固体的标题化合物(45mg)。M.P.:171-177℃.1H-NMR(δppm,DMSO-d6,400MHz):10.41(s,1H),8.86-8.85(m,1H),8.34(d,J 8.26,1H),7.98(d,J 8.64,1H),7.89(s,1H),7.76-7.70(m,3H),7.52-7.48(m,3H),5.77(s,1H),3.88(s,2H),1.84-1.78(m,1H),1.77-1.70(m,1H),0.90-0.80(m,4H),0.65-0.59(m,4H).MS(m/z):409.38[M+H]+.。
实施例10
N-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-2-(喹啉-6-基)乙酰胺盐酸盐:
在0℃下将实施例9(200mg,0.48mmol)溶于于乙醚中的饱和HCl中并搅拌15min。过滤并干燥分离出的固体以产生呈褐色固体的标题化合物(140mg,产量65%)。M.P.:152-158℃.1H-NMR(δppm,DMSO-d6,400MHz):10.78(s,1H),9.26(m,1H),9.16(d,J 8.3,1H),8.36(d,J 8.8,1H),8.29(s,1H),8.17-8.15(m,1H),8.08-8.04(m,1H),7.75(d,J 8.9,2H),7.50(d,J 8.9,2H),5.79(s,1H),4.04(s,2H),1.85-1.70(m,2H),0.89-0.81(m,4H),0.66-0.60(m,4H).MS(m/z):443.01[M-H]-。
实施例11
2-(1H-苯并[d][1,2,3]三唑-1-基)-N-(4-(3,5-二环丙基-1H-吡唑-1-基)-3-氟苯基)乙酰胺:
按照一般过程1,由2-(1H-苯并[d][1,2,3]三唑-1-基)乙酸(133mg,0.75mmol)和中间产物13(120mg,0.47mmol)制备呈浅黄色固体的标题化合物(29mg)。M.P.:201-203℃.1H-NMR(δppm,DMSO-d6,400MHz):11.0(s,1H),8.07(d,J 8.4,1H),7.85(d,J 8.4,1H),7.74(dd,J 2,12.5,1H),7.56(t,J 7.4,1H),7.47(t,J 8.4,1H),7.43-7.40(m,2H),5.74(s,2H),1.86-1.80(m,1H),1.55-1.44(m,2H),0.90-0.74(m,4H),0.62-0.54(m,4H).MS(m/z):417.28[M+H]+。
实施例12
N-[4-(3,5-二环丙基-1H-吡唑-1-基)-3-氟苯基]-2-(喹啉-6-基)乙酰胺盐酸盐:
按照一般过程1,由中间产物13(200mg,0.78mmol)和中间产物30(232mg,1.2mmol)制备呈黄色固体的N-[4-(3,5-二环丙基-1H-吡唑-1-基)-3-氟苯基]-2-(喹啉-6-基)乙酰胺(95mg)并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈黄色固体的标题化合物(50mg)。M.P.:106.8-108.2℃.1H-NMR(δppm,DMSO-d6,400MHz):10.99(s,1H),9.24(d,J 4.5,1H),9.09(d,J 8.0,1H),8.32-8.25(m,2H),8.12(d,J 8.6,1H),8.05-8.01(m,1H),7.83(d,J 11.3,1H),7.50-7.41(m,2H),5.73(s,1H),4.07(s,2H),1.84-1.76(m,1H),1.52-1.42(m,1H),0.82-0.74(m,4H),0.62-0.52(m,4H).MS(m/z):427.10[M+H]+。
实施例13
N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]喹啉-6-甲酰胺二盐酸盐:
按照一般过程1,由中间产物26(103mg,0.59mmol)和中间产物14(120mg,0.49mmol)制备呈橙色固体的N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]喹啉-6-甲酰胺(71mg)并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈黄色固体的标题化合物(62mg)。M.P.232-238℃.1H-NMR(δppm,DMSO-d6,400MHz):11.09(s,1H),9.25(d,J 4.0,1H),9.02(d,J 7.3,1H),8.93(d,J 8.4,2H),8.53(d,J 9.0,1H),8.43-8.36(m,2H),8.02-7.95(m,1H),7.78(d,J 8.8,1H),5.83(s,1H),2.74-2.65(m,1H),1.93-1.84(m,1H),1.00-0.80(m,4H),0.74-0.58(m,4H).MS(m/z):393.94[M-H-2HCl]-。
实施例14
N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]喹喔啉-6-甲酰胺:
按照一般过程1,由中间产物27(104mg,0.59mmol)和中间产物14(120mg,0.49mmol)制备呈褐色固体的标题化合物(117mg)。M.P.193-198℃.1H-NMR(δppm,DMSO-d6,400MHz):10.98(s,1H),9.08(dd,J 1.6,5.8,2H),8.91(d,J 2.4,1H),8.81(d,J 1.6,1H),8.40-8.36(m,2H),8.25(d,J 8.7,1H),7.77(d,J 8.7,1H),5.83(s,1H),2.75-2.61(m,1H),1.94-1.81(m,1H),0.98-0.82(m,4H),0.70-0.55(m,4H).MS(m/z):397.22[M+H-HCl]+。
实施例15
2-(1H-苯并[d][1,2,3]三唑-1-基)-N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]乙酰胺:
按照一般过程1,由中间产物14(200mg,0.84mmol)和2-(1H-苯并[d][1,2,3]三唑-1-基)乙酸(237mg,1.34mmol)制备呈橙色固体的标题化合物(250mg)。M.P.:130.1-132.8℃.1H-NMR(δppm,DMSO-d6,400MHz):10.92(s,1H),8.64(d,J 2.6,1H),8.13(dd,J 2.6,8.9,1H),8.07(d,J 8.4,1H),7.86(d,J 8.4,1H),7.70(d,J 8.9,1H),7.56(t,J 7.6,1H),7.44(t,J 7.6,1H),5.81(s,1H),5.74(s,2H),2.70-2.60(m,1H),1.90-1.80(m,1H),0.93-0.83(m,4H),0.70-0.58(m,4H).MS(m/z):400.28[M+H-HCl]+。
实施例16
N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]-2-(喹啉-6-基)乙酰胺二盐酸盐:
按照一般过程1,由中间产物30(112mg,0.59mmol)和中间产物14(120mg,0.49mmol)制备呈浅黄色固体的N-[6-(3,5-二环丙基-1H-吡唑-1-基)吡啶-3-基]-2-(喹啉-6-基)乙酰胺(138mg)并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈灰白色固体的标题化合物(34mg)。M.P.62-67℃.1H-NMR(δppm,DMSO-d6,400MHz):10.86(s,1H),9.21(d,J 4.4,1H),9.04(d,J 8.1,1H),8.69(s,1H),8.30-8.22(m,2H),8.18(d,J 8.1,1H),8.09(d,J 8.4,1H),8.00-7.97(m,1H),7.68(d,J 8.8,1H),5.80(s,1H),4.05(s,2H),2.69-2.55(m,1H),1.89-1.75(m,1H),0.97-0.78(m,4H),0.70-0.50(m,4H).MS(m/z):410.26[M+H-2HCl]+。
实施例17
N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}喹啉-6-甲酰胺盐酸盐:
按照一般过程1,由中间产物26(85mg,0.49mmol)和中间产物15(120mg,0.45mmol)制备呈褐色固体(35mg)的N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}喹啉-6-甲酰胺(35mg)并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈黄色固体的标题化合物(30mg)。M.P.188-192℃.1H-NMR(δppm,DMSO-d6,400MHz):10.86(s,1H),9.15(d,J 4,1H),8.80-8.78(m,2H),8.39(d,J 8.8,1H),8.26(d,J 8.8,1H),8.04(d,J 8.8,2H),7.83-7.80(m,1H),7.67(d,J 8.8,2H),6.62(s,1H),1.89-1.84(m,1H),1.00-0.96(m,2H),0.84-0.80(m,2H).MS(m/z):457.16[M-H]-。
实施例18
N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}喹喔啉-6-甲酰胺:
按照一般过程1,由中间产物27(78mg,0.44mmol)和中间产物15(110mg,0.411mmol)制备呈浅黄色固体的标题化合物(60mg)。M.P.205-209℃.1H-NMR(δppm,DMSO-d6,400MHz):10.87(s,1H),9.08-9.05(m,2H),8.79(d,J 1.6,1H),8.36(dd,J 1.8,8.7,1H),8.25(d,J 8.72,1H),8.05(d,J 8.84,2H),7.67(d,J 8.8,2H),6.62(s,1H),1.88-1.84(m,1H),0.99-0.96(m,2H),0.84-0.81(m,2H).MS(m/z):422.03[M-H]-。
实施例19
2-(1H-苯并[d]咪唑-1-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺:
在0℃下将中间产物20(180mg,0.523mmol)和苯并咪唑溶于DMF(3mL)中并向反应混合物加入氢化钠(37.7mg,1.57mmol)。然后使反应在环境温度下搅拌过夜。处理(H2O∶AcOEt),然后在柱上纯化,获得呈白色固体的标题化合物。M.P.178-184℃.1H-NMR(δppm,DMSO-d6,400MHz):10.72(s,1H),8.23(s,1H),7.77(d,J 8.8,2H),7.66(d,J 7.72,1H),7.59(d,J 8.8,2H),7.54(d,J 7.72,1H),7.26-7.18(m,2H),6.59(s,1H),5.21(s,2H),1.82-1.78(m,1H),0.96-0.92(m,2H),0.81-0.77(m,2H).MS(m/z):424.04[M-H]-。
实施例20
2-(1H-苯并[d][1,2,3]三唑-1-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺:
在0℃下将中间产物20(150mg,0.44mmol)和苯并三唑(52mg,0.44mmol)溶于DMF(3mL)中并向反应混合物加入氢化钠(31.5mg,1.30mmol)。然后使反应在环境温度下搅拌过夜。处理(H2O∶AcOEt),然后在柱上纯化,获得呈白色固体的标题化合物(60mg)。M.P.200-204℃.1H-NMR(δppm,DMSO-d6,400MHz):10.86(s,1H),8.07(d,J 8.4,2H),7.86(d,J 8.4,2H),7.77(d,J 8.8,1H),7.60(d,J 8.8,1H),7.59-7.54(m,1H),7.44-7.40(m,1H),6.60(s,1H),5.73(s,2H),1.83-1.77(m,1H),0.97-0.92(m,2H),0.79-0.75(m,2H).MS(m/z):425.02[M-H]-。
实施例21
2-(2H-苯并[d][1,2,3]三唑-2-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺:
在0℃下将中间产物20(500mg,1.45mmol)和苯并三唑(173mg,1.45mmol)溶于DMF(10mL)中并向反应混合物加入氢化钠(31.5mg,1.30mmol)。然后使反应在环境温度下搅拌过夜。处理(H2O:AcOEt),然后在柱上纯化,获得呈白色固体的标题化合物(60mg)。M.P.188-192℃.1H-NMR(δppm,DMSO-d6,400MHz):10.85(s,1H),7.95(dd,J 2.8,6.4,2H),7.77(d,J8.7,2H),7.61(d,J 8.7,2H),7.45(dd,J 2.8,6.4,2H),6.60(s,1H),5.74(s,2H),1.86-1.78(m,1H),0.99-0.91(m,2H),0.83-0.76(m,2H).MS(m/z):425.14.[M-H]-。
实施例22
2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺:
按照一般过程2,由中间产物15(500mg,1.9mmol)和中间产物33(442mg,2.2mmol)制备呈白色固体的标题化合物(20mg)。M.P.:206-209℃.1H-NMR(δppm,DMSO-d6,400MHz):10.98(s,1H),7.83(dd,J 1.4,4.8,1H),7.71(d,J 8.9,2H),7.60(d,J 8.9,2H),7.35(dd,J1.4,8,1H),7.20-7.15(m,1H),6.61(s,1H),4.50(s,2H),1.85-1.76(m,1H),1.00-0.92(m,2H),0.82-0.76(m,2H).MS(m/z):468.71[M+CH3CN]+。
实施例23
(S)-2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}丙酰胺:
按照一般过程2,由中间产物15(180mg,0.67mmol)和中间产物36(170mg,0.81mmol)制备呈浅黄色固体的标题化合物(20mg)。M.P.:186-191℃.1H-NMR(δppm,DMSO-d6,400MHz):11.02(s,1H),7.86(dd,J 1.3,4.8,1H),7.72(d,J 8.8,2H),7.60(d,J 8.8,2H),7.38(dd,J 1.3,8,1H),7.22-7.14(m,1H),6.60(s,1H),4.94(q,J 7.2,1H),1.89-1.79(m,1H),1.29(d,J 7.2,3H),1.00-0.92(m,2H),0.82-0.74(m,2H).MS(m/z):482.78[M+CH3CN]+。
实施例24
2-(6-氨基-9H-嘌呤-9-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}乙酰胺:
将腺嘌呤(233mg,1.76mmol)溶于DMF(10ml)中并加入碳酸钾(298mg,2.2mmol),在rt下搅拌30min。向该反应混合物中加入中间产物15(233mg,1.8mmol)并在rt下搅拌2h。反应完成后,向反应混合物加水并用AcOEt萃取。在无水硫酸钠上干燥AcOEt层并用旋转蒸发仪去除AcOEt以获得粗产物。使用DCM∶MeOH(98∶2)作为洗脱剂通过柱纯化粗产物以获得呈白色固体的标题化合物。M.P.:249.3-251.7℃.1H-NMR(δppm,DMSO-d6,400MHz):10.73(s,1H),8.12(d,J 8.12,2H),7.76(d,J 8.8,2H),7.59(d,J 8.8,2H),7.23(s,2H),6.60(s,1H),5.10(s,2H),1.85-1.76(m,1H),1.00-0.90(m,2H),0.82-0.74(m,2H).MS(m/z):440.71[M-H]-。
实施例25
N-(4-(5-环丙基-3-(三氟甲基)-1H-吡唑-1-基)苯基)-2-(1,3-二甲基-2,6-二氧代-2,3-二氢-1H-嘌呤-7(6H)-基)乙酰胺:
按照一般过程1,由7-乙酸茶碱(117mg,0.49mmol)和中间产物15(120mg,0.45mmol)制备呈浅黄色固体的标题化合物(77mg)。M.P.178-184℃.1H-NMR(δppm,DMSO-d6,400MHz):10.66(s,1H),8.07(s,1H),7.75(d,J 8.9,2H),7.59(d,J 8.9,2H),6.59(s,1H),5.23(s,2H),3.45(s,3H),3.19(s,3H),1.83-1.77(m,1H),0.98-0.91(m,2H),0.85-0.76(m,2H).MS(m/z):486.20[M-H]-。
实施例26
N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基)苯基)-2-(咪唑并[1,2-a]吡啶-2-基)乙酰胺盐酸盐:
按照一般过程1,由中间产物29(71mg,0.40mmol)和中间产物15(90mg,0.34mmol)制备呈褐色固体的N-{4-[5(3)-环丙基-3(5)-(三氟甲基)-1H-吡唑-1-基)苯基)-2-(咪唑并[1,2-a]吡啶-2-基)乙酰胺并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈白色固体的标题化合物(79mg)。M.P.294-299℃.1H-NMR(δppm,DMSO-d6,400MHz):10.85(s,1H),8.90(d,J 6.5,1H),8.30(s,1H),7.97-7.88(m,2H),7.82(d,J 8.7,2H),7.61(d,J 8.7,2H),7.47(t,J 5.6,1H),6.61(s,1H),4.16(s,2H),1.84-1.79(m,1H),0.98-0.90(m,2H),0.64-0.49(m,2H).MS(m/z):426.27[M+H-HCl]+。
实施例27
N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}-2-(喹啉-6-基)乙酰胺盐酸盐:
按照一般过程1,由中间产物30(92mg,0.49mmol)和中间产物15(120mg,0.45mmol)制备呈灰白色固体的N-{4-[3-环丙基-5-(三氟甲基)-1H-吡唑-1-基]苯基}-2-(喹啉-6-基)乙酰胺(95mg)。在0℃下将该酰胺溶于于乙醚中的饱和HCl中并搅拌15min。过滤并干燥分离出的固体以产生呈灰白色固体的标题化合物(80mg)。M.P.248-254℃.1H-NMR(δppm,DMSO-d6,400MHz):10.75(s,1H),9.17(d,J 4.4,1H),8.95(d,J 8.2,1H),8.24-8.19(m,2H),8.05(d,J 8.6,1H),7.94-7.91(m,1H),7.82(d,J 8.7,2H),7.57(d,J 8.7,2H),6.59(s,1H),4.03(s,2H),1.79-1.75(m,1H),0.96-0.91(m,2H),0.80-0.77(m,2H).MS(m/z):435[M-H-HCl]-。
实施例28
N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}-2-(喹啉-6-基)丙酰胺盐酸盐:
按照一般过程1,由中间产物15(150mg,0.56mmol)和中间产物38(180mg,0.89mmol)制备呈褐色固体的N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]苯基}-2-(喹啉-6-基)丙酰胺(74mg)并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈褐色固体的标题化合物(45mg)。M.P.:168-170℃.1H-NMR(δppm,DMSO-d6,400MHz):10.61(s,1H),9.11(d,J 3.7,1H),8.87(d,J 8,1H),8.18(d,J 9,2H),8.07(dd,J 1.6,8.8,1H),7.85(dd,J 4.9,8.3,1H),7.79(d,J 8.9,2H),7.55(d,J 8.9,2H),6.59(s,1H),4.20(q,J 6.8,1H),1.80-1.70(m,1H),1.57(d,J 6.8,3H),1.00-0.90(m,2H),0.80-0.70(m,2H).MS(m/z):451.11[M+H-HCl]-。
实施例29
N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-3-氟苯基}-1H-苯并[d][1,2,3]三唑-6-甲酰胺:
按照一般过程1,由中间产物16(150mg,0.53mmol)和中间产物25(114mg,0.63mmol)制备呈白色固体的标题化合物(30mg)。M.P.:235-237℃.1H-NMR(δppm,DMSO-d6,400MHz):10.84(s,1H),8.66(s,1H),8.07(dd,J 2.2,12.7,1H),8.02(s,2H),7.79(dd,J1.8,8.7,1H),7.66(t,J 8.6,1H),6.62(s,1H),1.68-1.60(m,1H),0.96-0.88(m,2H),0.81-0.75(m,2H).MS(m/z):428.84[M-H]-。
实施例30
2-(1H-苯并[d][1,2,3]三唑-1-基)-N-{4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-3-氟苯基}乙酰胺:
按照一般过程1,由2-(1H-苯并[d][1,2,3]三唑-1-基)乙酸(112mg,0.80mmol)和中间产物16(300mg,1.14mmol)制备呈白色固体的标题化合物(145mg)。M.P.:197-202℃.1H-NMR(δppm,DMSO-d6,400MHz):11.09(s,1H),8.07(d,J 8.4,1H),7.86(d,J 8.4,1H),7.81(dd,J 2,12.4,1H),7.63(t,J 8.6,1H),7.57(t,J 7.7,1H),7.50-7.48(m,1H),7.42(t,J 7.8,1H),6.60(s,1H),5.75(s,2H),1.64-1.52(m,1H),0.92-0.84(m,2H),0.78-0.69(m,2H).MS(m/z):442.69[M-H]-。
实施例31
N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}-1H-苯并[d][1,2,3]三唑-5-甲酰胺:
按照一般过程1,由中间产物17(200mg,0.75mmol)和中间产物25(194mg,1.2mmol)制备呈白色固体的标题化合物(43mg)。M.P.:235.6-238.4℃.1H-NMR(δppm,DMSO-d6,400MHz):10.86(s,1H),8.99(d,J 2.5,1H),8.68(bs,1H),8.48(dd,J 2.6,8.8,1H),8.08-8.01(m,2H),7.82(d,J 8.8,1H),6.65(s,1H),2.58-2.50(m,1H),1.04-0.98(m,2H),0.82-0.74(m,2H).MS(m/z):413.89[M+H]+。
实施例32
2-(1H-苯并[d][1,2,3]三唑-1-基)-N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}乙酰胺:
在0℃下将中间产物21(200mg,0.58mmol)和苯并三唑(69mg,0.58mmol)溶于DMF(10mL)中并向反应混合物加入氢化钠(41.0mg,1.74mmol)。然后使反应在环境温度下搅拌过夜。处理(H2O:AcOEt),然后在柱上纯化,获得呈白色固体的标题化合物(60mg)。M.P.189-192℃.1H-NMR(δppm,DMSO-d6,400MHz):11.07(s,1H),8.76(d,J 2.1,1H),8.25(dd,J 2.3,8.81H),8.07(d,J 8.3,1H),7.87(d,J 8.3,1H),7.78(d,J 8.8,1H),7.57(t,J 7.6,1H),7.42(t,J 7.6,1H),6.62(s,1H),5.77(s,2H),2.40-2.30(m,1H),1.00-0.90(m,2H),0.80-0.70(m,2H).MS(m/z):426.13[M-H]-。
实施例33
2-(2H-苯并[d][1,2,3]三唑-2-基)-N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}乙酰胺
在0℃下将中间产物21(200mg,0.58mmol)和苯并三唑(69mg,0.58mmol)溶于DMF(10mL)中并向反应混合物加入氢化钠(41.0mg,1.74mmol)。然后使反应在环境温度下搅拌过夜。处理(H2O∶AcOEt),然后在柱上纯化,获得呈白色固体的标题化合物(60mg)。M.P.193-198℃.1H-NMR(δppm,DMSO-d6,400MHz):11.06(s,1H),8.75(d,J 2.4,1H),8.25(dd,J 2.5,8.8,1H),7.98-7.92(m,2H),7.78(d,J 8.8,1H),7.50-7.44(m,2H),6.62(s,1H),5.78(s,2H),2.58-2.40(m,1H),1.00-0.90(m,2H),0.80-0.71(m,2H).MS(m/z):425.99[M-H]-。
实施例34
N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}-2-(喹啉-6-基)乙酰胺盐酸盐
按照一般过程1,由中间产物30(133mg,0.71mmol)和中间产物17(120mg,0.45mmol)制备呈浅黄色固体的N-{6-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}-2-(喹啉-6-基)乙酰胺(67mg)并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈白色固体的标题化合物(63mg)。M.P.225-230℃.1H-NMR(δppm,DMSO-d6,400MHz):10.96(s,1H),9.15(d,J 4.4,1H),8.90(d,J 8.0,1H),8.80(d,J 2.3,1H),8.30(dd,J 2.4,8.8,1H),8.21(d,J 8.7,1H),8.18(s,1H),8.03(d,J 8.3,1H),7.90(dd,J 5,8.2,1H),7.75(d,J 8.8,1H),6.61(s,1H),4.06(s,2H),2.51-2.40(m,1H),1.01-0.90(m,2H),0.81-0.70(m,2H).MS(m/z):436.02[M-H-2HCl]-。
实施例35
2-(1H-苯并[d][1,2,3]三唑-1-基)-N-{6-[4-氯-5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]吡啶-3-基}乙酰胺:
按照一般过程1,由2-(1H-苯并[d][1,2,3]三唑-1-基)乙酸(123mg,0.68mmol)和中间产物18(120mg,0.43mmol)制备呈褐色固体的标题化合物(97mg)。M.P.:182.5-189.3℃.1H-NMR(δppm,DMSO-d6,400MHz):11.13(s,1H),8.78(d,J 2.4,1H),8.27(dd,J 2.6,8,1H),8.07(d,J 8.4,1H),7.87(d,J 8.4,1H),7.75(d,J 8.7,1H),7.6(t,J 7.3,1H),7.4(t,J 7.5,1H),5.78(s,2H),2.20-2.08(m,1H),0.92-0.84(m,2H),0.70-0.59(m,2H).MS(m/z):459.8[M-H]-。
实施例36
4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-3-氟-N-(喹啉-6-基甲基)苯甲酰胺盐酸盐:
按照一般过程2,由中间产物23(200mg,0.67mmol)和中间产物39(188mg,0.60mmol)制备呈白色固体的4-[5-环丙基-3-(三氟甲基)-1H-吡唑-1-基]-3-氟-N-(喹啉-6-基甲基)苯甲酰胺(83mg)并溶于THF中。在0℃下向该溶液加入于乙醚中的饱和HCl并搅拌15min。过滤并干燥分离出的固体以产生呈灰白色固体的标题化合物(70mg)。M.P.:156-159℃.1H-NMR(δppm,DMSO-d6,400MHz):9.61(t,J 5.7,1H),9.15(d,J 4.2,1H),8.95(d,J 8.4,1H),8.25(d,J 8.8,1H),8.17(s,1H),8.07-8.03(m,2H),7.98(d,J 8.3,1H),7.93-7.90(m,1H),7.84(t,J 7.8,1H),6.68(s,1H),4.75(d,J 5.7,2H),1.72-1.61(m,1H),0.97-0.88(m,2H),0.81-0.74(m,2H).MS(m/z):455.03[M+H-HCl]+。
实施例37
1-[4-(3,5-二环丙基-1H-吡唑-1-基)苯基]-3-(喹啉-6-基)脲:
将6-氨基喹啉(200mg,0.88mmol)、三光气(156mg,0.53mmol)和三乙胺(0.4ml,3.5mmol)溶于DCM中并在rt下于氮气中搅拌30min。之后,加入中间产物12(200mg,0.88mmol)并将混合物加热至40℃,持续40h。之后,向反应混合物中加入CHCl3(10ml)和0.2M柠檬酸(2.5mL)并去除水相。用盐水洗涤有机层并在无水Na2SO4上干燥。用旋转蒸发仪去除有机层以获得粗产物。使用60-120目硅胶,利用DMC和MeOH(98:2)作为洗脱剂通过柱色谱法纯化粗产物以获得呈褐色固体的标题化合物(25mg)。M.P.:102-104℃.1H-NMR(δppm,DMSO-d6,400MHz):9.07(s,1H),8.96(s,1H),8.73(dd,J 1.6,4.2,1H),8.23(d,J 7.9,1H),8.17(d,J 2.2,1H),7.94(d,J 9.01H),7.71(dd,J 2.4,9.1,1H),7.59(d,J 8.9,2H),7.48(d,J 8.9,2H),7.47-7.43(m,1H),5.77(s,1H),1.88-1.71(m,2H),0.90-0.82(m,4H),0.70-0.58(m,4H).MS(m/z):410.44[M+H]+。
生物检测
可通过许多生物学/药理学检测确认本发明化合物的性质。以下例证了可用根据本发明所述的化合物进行的生物学/药理学检测。类似地,也可使用其它检测,例如Jurkat以及人PBMC中的细胞因子(IL-2、IL-4、IL-5、IL-10、IL-12、TNFα、干扰素γ等)评估测试本发明的化合物。也可用各种动物模型测试本发明的化合物以确定本发明化合物的各种治疗潜能。
1.体外CRAC通道抑制检测
lA.对Jurkat细胞进行体外CRAC通道抑制检测
毒胡萝卜素(Sigma,Cat#T9033)诱导Jurkat细胞内质网钙释放后确定CRAC通道的抑制。(见Yasurio Yonetoky等Bio.&Med Chem.14(2006)4750-4760)。离心细胞并按2x105细胞/100μl/孔再次悬浮于96孔板中等体积的无Ca2+和Mg2+的Hank缓冲液和Fluo-8NW染料(ABD Bioquest,Inc.,Sunnyvale,CA)负载溶液中。在37℃/5%CO2下培育板30min,然后再在室温下培育15min。向孔内加入所需浓度的测试化合物(稀释于无Ca2+和Mg2+的Hank缓冲液中的DMSO原液)并培育15min。向孔内加入毒胡萝卜素(最终浓度1μM)并培育15min以抑制肌浆内质网Ca2+ATP酶泵,从而排空内质网钙并提高细胞溶质钙浓度。通过加入细胞外Ca2+至最终浓度为1.8mM而引发钙池操纵型钙进入。用酶标仪(BMG Labtech.,Germany)监控荧光5min,在485nm下激发且发射波长为520nm。使用GraphPad Prism分析数据。基于流入细胞内的毒胡萝卜素诱导的钙流的抑制百分比确定每种化合物的IC50。结果示于表1A。
表1A
化合物 | %抑制(1μM) | IC50(nM) | 化合物 | %抑制(1μM) | IC50(nM) |
实施例1 | 57.6 | - | 实施例20 | 100 | 39.17 |
实施例2 | 78 | 182.5 | 实施例21 | 83.03 | 139.0 |
实施例3 | 100 | - | 实施例22 | 30.86 | - |
实施例4 | 85 | - | 实施例23 | 69.87 | - |
实施例5 | 88.51 | 383.1 | 实施例24 | 14.77 | - |
实施例6 | 94.6 | 51.31 | 实施例25 | 39.07 | - |
实施例7 | 36.83 | - | 实施例26 | 30.86 | - |
实施例8 | 17.90 | - | 实施例27 | 100 | - |
实施例9 | 100 | - | 实施例28 | 0 | - |
实施例10 | 100 | 146.7 | 实施例29 | 81.1 | - |
实施例11 | 78.56 | - | 实施例30 | 100 | 160.5 |
实施例12 | 100 | 263.2 | 实施例31 | 50.62 | - |
实施例13 | 22.37 | - | 实施例32 | 41.23 | - |
实施例14 | 17.80 | - | 实施例33 | 49.54 | - |
实施例15 | 3.93 | - | 实施例34 | 51.21 | - |
实施例16 | 30.81 | - | 实施例35 | 15 | - |
实施例17 | 94.03 | 86.12 | 实施例36 | 51.04 | - |
实施例18 | 96.64 | 53.36 | 实施例37 | 57.28 | - |
实施例19 | 69.53 | - |
1B.对NCI-H460癌细胞系的体外CRAC通道抑制检测
在毒胡萝卜素(Sigma,Cat#T9033)诱导NCI-H460细胞(国家细胞科学中心(NCCS),Pune)内质网钙释放后确定CRAC通道的抑制。
将细胞(30,000个/孔)接种于完全RPMI培养基中过夜。用96孔板中的无Ca2+和Mg2+的Hank缓冲液和Fluo-8NW染料(ABD Bioquest,Inc.,Sunnyvale,CA)负载溶液代替培养基。在37℃/5%CO2下培育板30min,然后再在室温下培育15min。向孔内加入所需浓度的测试化合物(稀释于无Ca2+和Mg2+的Hank缓冲液中的DMSO原液)并培育15min。向孔内加入毒胡萝卜素(最终浓度1μM)并培育15min以抑制肌浆内质网Ca2+ATP酶泵,从而排空内质网钙并提高细胞溶质钙浓度。通过加入细胞外Ca2+至最终浓度为2.5mM引发钙池操纵型钙进入。用酶标仪(BMG Labtech.,Germany)监控荧光30min,在485nm下激发且发射波长为520nm。使用GraphPad Prism分析数据。基于流入细胞内的毒胡萝卜素诱导的钙流的抑制百分比确定每种化合物的IC50。结果示于表2。
1C.对NCI-H460癌细胞系(抗癌活性)的体外细胞增殖检测
使用补以10%FBS的培养基进行生长抑制检测。按5000个细胞/孔的浓度将细胞接种于96孔板上。24h后加入浓度范围为0.01至10000nM的测试化合物。在加入测试化合物后0h(加入测试化合物之前)和48h时使用3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑溴化物(MTT)染料还原测试评估生长。用Fluostar Optima(BMG Labtech,Germany),在450nm波长下读取吸光度。使用GraphPad Prism分析数据。基于与对照相比由测试化合物引起的抑制百分比确定每种化合物的IC-50。结果示于表2。
对于细胞增殖检测的方法,见,例如,Mosmann.T.,Journal of ImmunologicalMethods,65(1-2),55-63,(1983)。
表2
2.Jurkat细胞、人全血细胞和外周血单核细胞(PBMC)中细胞因子释放的体外抑制
如以下所述确定细胞因子IL-2、IL-4、IL-5和TNFα的抑制。
a.对Jurkat细胞中IL-2的抑制:用所需浓度的抑制剂培育细胞15min。对于IL-2&TNFα而言通过添加伴刀豆球蛋白A(25μg/ml)+十四酰佛波乙酸酯(50ng/ml)或对于IL-4&IL-5而言通过添加植物血球凝集素(5μg/ml)诱导细胞因子释放并且在37℃下于含有95%CO2的大气中培育。20h(IL-2&TNFα)或48h(IL-4&IL-5)后收集上清液以通过ELISA对细胞因子进行测定。使用GraphPad Prism分析数据。基于与对照相比由测试化合物引起的抑制百分比确定每种化合物的IC50值。
b.对人全血(HWB)中细胞因子释放的抑制:用RPMI培养基(1∶4.5)稀释新采集的HWB并加入96孔板中。用所需浓度的抑制剂培育孔15min。对于IL-2&TNFα而言通过添加伴刀豆球蛋白A(25μg/ml)+十四酰佛波乙酸酯(50ng/ml)或对于IL-4&IL-5而言通过添加植物血球凝集素(5μg/ml)诱导细胞因子释放并且在37℃下于含有95%CO2的大气中培育。20h(IL-2&TNFα)或48h(IL-4&IL-5)后收集上清液以通过ELISA对细胞因子进行评估。使用GraphPadPrism分析数据。基于与对照相比由测试化合物引起的抑制百分比确定每种化合物的IC50值。
c.对PBMC中细胞因子释放的抑制:使用Histopaque通过密度梯度从新采集的HWB中分离PBMC并接种于96孔板中。用所需浓度的抑制剂培育细胞15min。对于IL-2&TNFα而言通过添加伴刀豆球蛋白A(25μg/ml)+十四酰佛波乙酸酯(50ng/ml)或对于IL-4&IL-5而言通过添加植物血球凝集素(5μg/ml)诱导细胞因子释放并且在37℃下于含有95%CO2的大气中培育。20h(IL-2&TNFα)或48h(IL-4&IL-5)后收集上清液以通过ELISA对细胞因子进行评估。使用GraphPad Prism分析数据。基于与对照相比由测试化合物引起的抑制百分比确定每种化合物的IC50值。结果示于表3。
表3
抗癌活性
可通过许多生物学/药理学检测确认CRAC和STIM蛋白的相关性及其对本发明的用途。以下例证了可根据本发明进行的生物学/药理学检测。
化合物A,2-(1H-苯并[d]咪唑-1-基)-N-(4-(5-环丙基-3-(三氟甲基)-1H-吡唑-1-基)苯基)乙酰胺和化合物B,N-(4-(3,5-二环丙基-1H-吡唑-1-基)苯基)-2-(喹啉-6-基)乙酰胺用作生物学检测的CRAC通道抑制剂。
实施例I:A549和NCI-H460细胞中Orail&Stim1的表达
通过PCR(聚合酶链式反应)确认非小细胞肺癌细胞系中的Orai1和Stim1表达。简言之,收获5x106个用所需浓度的测试物品处理的细胞,离心沉淀并重新悬浮于1ml TRI中。按照生产商说明提取试剂(Sigma,St.Louis,MO)和总RNA。使用第一链cDNA合成制备cDNA并使用以下引物对扩增:
Orai1:正向5’CATGGTGGCAATGGTGGAGGTG 3’
反向5’AGGCACTGAAGGCGATGAGCA 3’
Orai2:正向5’ATGGTGCCATGGTGGAGGT 3’
反向5’TGCAGGCGCTGAAGGCAAT 3’
Orai3:正向5’AAGCTCAAAGCTTCCAGCCGC 3’
反向5’GGTGGGTACTCGTGGTCACTCT3’
Stim1:正向5’AAGGCTCTGGATACAGTGCTCTTT 3’
反向5’AGCATGAAGTCCTTGAGGTGATTAT 3’
Stim2:正向5’ACGACACTTCCCAGGATAGCA 3’
反向5’GACTCCGGTCACTGATTTTCAAC 3’
见,例如,Peel等,Respiratory Research,7,119,2006;Gwack等,J.Biol.Chem.,282,16232-16243,2006。
通过凝胶电泳解析泳道并使用SYBR安全DNA凝胶染色显影。结果示于图1中。
实施例II:对NCI-H460癌细胞系的体外CRAC通道抑制检测
在毒胡萝卜素(Sigma,Cat#T9033)诱导NCI-H460细胞(国家细胞科学中心(NCCS),Pune)内质网钙释放后确定CRAC通道的抑制。
对于方法:参考1B。
化合物A在1μM下显示100%抑制,IC50值小于200nM。见图2。
实施例III:对NCI-H460癌细胞系(抗癌活性)的体外细胞增殖检测按以下确定CRAC和/或STIM蛋白对肺癌细胞的增殖和成活力的影响。
化合物A在1μM下显示100%抑制,IC50值小于200nM。(见图3)。
实施例IV:化合物B对NCI-H460细胞中Orai和Stim表达的影响使用以上实施例1中所述的方法,但用1μM和10μM的化合物B测量NCI-H460细胞中Orai和Stim表达。
数据显示NCI-H460细胞表达Orai1、Orai3、Stim1和Stim2。如通过定性PCR证实一旦用化合物B处理细胞,Orai1、Stim1和Stim2的mRNA表达显著降低。见图4。
实施例V:确定NCI-H460细胞中的细胞毒性
按照进行一些较小修改的生产商说明,使用乳酸脱氢酶检测试剂盒(CaymanChemicals,MI)确定测试化合物(化合物B)的细胞毒性。简言之,在96孔组织培养板上接种于完全RPMI-1640培养基中的20,000个细胞/孔并在37℃和5%CO2下培育过夜。按所需浓度向孔内加入测试化合物,一式三份。阿霉素和/或1%Triton-X用作阳性对照。48h后,去除培养基并且在比色测定中检测乳酸脱氢酶。在490nM下,用酶标仪(BMG Labtech.,Germany)测量光密度。使用GraphPad Prism(Graphpad软件;San Diego CA)分析数据。数据显示,如培养基中不可检测的乳酸脱氢酶水平证明,化合物B在NCI-H460细胞系中无毒。
实施例VI:评估载有NCI-H460人非小细胞肺癌异种移植物的雌性Balb/c裸鼠体内的抗肿瘤功效
皮下异种移植物肺癌模型用于评估测试化合物的抗肿瘤功效。紫杉醇用作阳性对照。通过在每只动物的右侧(0.1mL/只小鼠)经皮下移植NCI-H460细胞(5x106个)来构建模型。当平均肿瘤体积达到约170mm3时,基于肿瘤体积选择30只裸鼠并随机分成每个治疗组6只动物。使动物口服30mg/kg测试化合物(化合物A)BID,施用15天。治疗期间,用游标卡尺以盲法形式测量移植肿瘤,每周3次。测量肿瘤的最大宽度(X)和长度(Y)并使用公式V=(X2Y)/2计算肿瘤体积(V)。同时还测量动物体重。使用Graphpad Prism(Graphpadsoftware;San Diego CA)分析数据。
施用测试化合物引起肿瘤生长减缓32%,体重无任何显著变化。在经静脉内施用紫杉醇处理的动物中观察到肿瘤生长减缓36%,体重显著减轻。见图5。
实施例VII:使用体内动物模型评估CRAC通道调节剂对各种抗炎和自身免疫向疾病的有效性
i.伴刀豆球蛋白(Con)A诱导的雌性Balb/C小鼠的肝炎:Con A常用于使实验动物具有高水平的细胞毒素T-淋巴细胞,因为这些细胞牵涉到人病毒感染的发展。在这种模型中,静脉内施用Con A前1h,经口服给动物施用测试化合物。24h后采集血样以确定血清内的血清谷草转氨酶(SGOT)和血清谷丙转氨酶(SGPT)。
可研究施用测试化合物后血清SGOT&SGPT的减少%。
ii.雌性Balb/c小鼠中TNCB诱导的接触性超敏反应:接触性超敏反应是对细胞介导的免疫功能的简单体外检测。在这个过程中,表皮细胞暴露于外源性半抗原引起可测量和定量的迟发型致敏反应。简言之,将7%TNCB溶液涂覆到8周龄Balb/c小鼠的腹部区域。TNCB致敏7天后测量耳厚。口服施用化合物,然后将1%TNCB涂覆至耳廓内侧和外侧。TNCB激发24h后测量耳厚。
可研究施用测试化合物后耳炎症的减轻%。
iii.雄性Balb/c小鼠的脚爪迟发型超敏反应:DTH肿胀反应可用于观察体内免疫抑制分子和/或T细胞抑制剂的活性。在第0天和第7天给小鼠(在尾根部)进行皮内抗原(甲基化BSA)注射。从第0天至第10天每日施用化合物一次并且在第10天向动物右后肢脚底注射甲基化BSA。通过在注射甲基化BSA(第11天)24h后,给右后爪和左后爪称重确定抗原诱导的重量差异。
可研究抗原诱导的小鼠爪炎症减轻%。
iv.OVA诱导的豚鼠哮喘:哮喘中,肺部嗜酸性细胞增多和气道重构,连同气道音调的神经控制改变和气道上皮脱落造成气道过度反应(AHR)。为确定嗜酸性细胞减少,在第0、7和14天用OVA使动致敏物,然后在第19天和第20天通过吸入进行另一轮(0.1%w/v)。OVA激发(0.3%)前1h,经口服施用化合物。在第22天采集BAL液体进行分类计数和细胞因子评估。为确定呼吸参数的变化,ova激发后立即对动物进行全身体积描记术。可研究施用测试化合物后血液嗜酸性细胞减少%,伴有呼吸同时改善。
v.雄性DBA/1Ola HSD小鼠中胶原诱导的关节炎:在啮齿动物模型中胶原诱导的关节炎已广泛用于说明和理解疾病的发展,此外用作用于确认人的类风湿性关节炎的治疗靶标的代用品。用异氟烷麻醉小鼠并以福氏完全佐剂注射(第0天和第21天)给予150μl牛II型胶原蛋白。在研究第0天开始治疗并每天持续进行,每日一次(po,qd)。在第18天开始,每天为每个爪子(右前、左前、右后、左后)给出临床评分并持续至处死之日(第34天)。可研究每天施用测试化合物(与对照动物相比)缓和关节炎症状、疾病进展以及发病率降低%。
其中可测试各种抗炎病症和自身免疫病症中CRAC通道调节剂的效果的其它体内模型包括C57/Bl6J的慢性实验性自身免疫性脑脊髓炎:实验性自身免疫性脑脊髓炎是一种中枢神经系统的炎症性疾病并且广泛用作多发性硬化的动物模型。在第0天给动物经静脉内施用百日咳毒素并且经皮下施用髓鞘少突胶质细胞糖蛋白(MOG)。在第0天开始治疗并持续至处死。在第9至42天观察到EAE的发展。治疗期结束时,处死动物进行组织病理学分析以及血浆的细胞因子测定。
虽然已参考特定实施方案描述了本文的发明,但是应了解这些实施方案仅为说明本发明的原理和应用。因此,应了解可对说明性实施方案进行大量修改并且在不背离说明书和权利要求中所述本发明精神和范围的前提下可设计其它排列。
本申请案中引用的所有公布和专利和/或专利申请案通过引用并入本文,其引用程度如同明确且单独指出将每个单独的公布或专利申请案通过引用。
Claims (10)
1.一种式(IA)的化合物
或其药学上可接受的盐,其中
R1或R2均为环丙基,或者R1和R2中的一个为CF3,且另一个为环丙基;
T、U、V和W相同或不同且独立地选自CRa和N,其中Ra是氢或卤素;
L1与L2一起表示-NH-C(=X)-;
A是-CH2-;
R”’是氢;
X是O;
Cy选自经取代或未经取代的双环芳基或者经取代或未经取代的双环杂芳基;
其中,
术语“烷基”指只由碳和氢原子组成,不含不饱和,具有1至8个碳原子的直链或支链烃链基;
术语“芳基”指具有6至20个碳原子的芳族基;
术语“杂芳基”指具有作为环原子的一个或多个选自N、O和S的杂原子的5-14元芳环;
术语“经取代”指用以下取代基的任一个取代:未经取代的烷基和胺。
2.根据权利要求1所述的化合物,其中
Cy为经取代或未经取代的双环杂芳基。
3.根据权利要求2的化合物,其中Cy为经取代或未经取代的C(8-13)双环杂芳基。
4.根据权利要求1-3中任一项所述的化合物,其中R1和R2均表示环丙基。
5.根据权利要求1-3中任一项所述的化合物,其中T、U、V和W独立地为CH、CF或N。
6.根据权利要求1所述的化合物,其中Cy选自
7.根据权利要求1所述的化合物,其中为
8.根据权利要求1-7中任一项所述的化合物在生产用于调节钙池操纵型钙(SOC)通道的药物中的用途。
9.根据权利要求1-7中任一项所述的化合物在生产用于治疗将受益于钙释放激活钙(CRAC)通道的调节的疾病、病症或病状的药物中的用途。
10.一种用于治疗非小细胞肺癌的药物组合物,包含权利要求1-7中任一项所述的化合物和药学上可接受的载体。
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2017
- 2017-12-20 JP JP2017243778A patent/JP2018080176A/ja active Pending
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2018
- 2018-07-02 HR HRP20181014TT patent/HRP20181014T1/hr unknown
- 2018-10-23 US US16/168,499 patent/US20190248791A1/en not_active Abandoned
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CN1930129A (zh) * | 2004-03-12 | 2007-03-14 | 拜尔农作物科学股份公司 | N1-((吡唑-1-基甲基)-2-甲基苯基)-邻苯二酰胺衍生物及相关的复合杀虫剂 |
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US10174034B2 (en) | 2019-01-08 |
RS57441B1 (sr) | 2018-09-28 |
PL2509974T3 (pl) | 2018-11-30 |
JP2018080176A (ja) | 2018-05-24 |
CN104788430A (zh) | 2015-07-22 |
JP2016028037A (ja) | 2016-02-25 |
TR201809711T4 (tr) | 2018-07-23 |
SI2509974T1 (en) | 2018-08-31 |
US8993612B2 (en) | 2015-03-31 |
JP6266568B2 (ja) | 2018-01-24 |
JP2013507351A (ja) | 2013-03-04 |
CN102958925B (zh) | 2015-04-15 |
EA025302B1 (ru) | 2016-12-30 |
US20190248791A1 (en) | 2019-08-15 |
DK2509974T3 (en) | 2018-07-30 |
WO2011042798A1 (en) | 2011-04-14 |
EP2509974B1 (en) | 2018-04-11 |
HUE039261T2 (hu) | 2018-12-28 |
US20110112058A1 (en) | 2011-05-12 |
CN110627724A (zh) | 2019-12-31 |
EA201290139A1 (ru) | 2012-11-30 |
LT2509974T (lt) | 2018-07-10 |
HRP20181014T1 (hr) | 2018-08-24 |
CA2784277C (en) | 2019-09-24 |
CA2784277A1 (en) | 2011-04-14 |
EA025302B8 (ru) | 2017-07-31 |
EP2509974A1 (en) | 2012-10-17 |
ES2676317T3 (es) | 2018-07-18 |
CN102958925A (zh) | 2013-03-06 |
US20150291588A1 (en) | 2015-10-15 |
JP5909312B2 (ja) | 2016-04-26 |
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