CN114555601A - 新颖的四唑类 - Google Patents
新颖的四唑类 Download PDFInfo
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- CN114555601A CN114555601A CN202080071658.5A CN202080071658A CN114555601A CN 114555601 A CN114555601 A CN 114555601A CN 202080071658 A CN202080071658 A CN 202080071658A CN 114555601 A CN114555601 A CN 114555601A
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Abstract
本发明涉及四唑类及其作为TRPA1活性的抑制剂的用途、含有四唑类的药物组合物、以及将四唑类用作用于治疗和/或预防纤维化疾病、炎型和自身免疫性疾病和CNS相关疾病的药剂的方法。
Description
技术领域
本发明涉及四唑类及其作为TRPA1活性的抑制剂的用途、含有四唑类的药物组合物、以及将四唑类用作用于治疗和/或预防纤维化疾病、炎型和自身免疫性疾病和CNS相关疾病的药剂的方法。
背景信息
瞬时受体电位通道(TRP通道)是一组电压门控离子通道,主要位于多种哺乳动物细胞类型的质膜上。存在被分类为以下几组的大约30个结构相关的TRP通道:TRPA、TRPC、TRPM、TRPML、TRPN、TRPP和TRPV。瞬时受体电位阳离子通道亚家族A成员1(TRPA1)(也称为瞬时受体电位锚蛋白1)是TRPA基因亚家族的唯一成员。在结构上,TRPA通道的特征在于多个N末端锚蛋白重复序列(在人TRPA1的N末端中约14个),产生了用于锚蛋白名称的“A”(Montell,2005)。
TRPA1在服务于皮肤和肺二者的背根和节状神经节中的感觉神经元以及小肠、结肠、胰腺、骨骼肌、心脏、大脑、膀胱和淋巴细胞(https://www.proteinatlas.org/)以及人肺成纤维细胞的质膜中高度表达。
TRPA1最为人所知的是作为引起躯体感觉模式,如疼痛、寒冷和瘙痒的环境刺激物的传感器。TRPA1被许多反应性、亲电子刺激物(例如异硫氰酸烯丙酯、活性氧物质)以及非反应性化合物(例如icilin)激活,其与以下有关:与哮喘、慢性肺阻塞性疾病(COPD)、特发性肺纤维化(IPF)相关的咳嗽或病毒感染后的咳嗽或慢性特发性咳嗽以及敏感患者的咳嗽。(Song和Chang,2015;Grace和Belvisi,2011)。基于显示出咳嗽诱导的TGF-β升高的研究,TRPA1抑制剂可用于治疗IPF,其中由于咳嗽与肺损伤之间的联系,因此咳嗽非常普遍(Xie等人,2009;Froese等人,2016;Tschumperlin等人,2003;Yamamoto等人,2002;Ahamed等人,2008)。TRPA1拮抗剂抑制由咳嗽引发因素(如香烟烟雾提取物(CSE)氧化应激、炎性介质释放和下调的抗氧化基因表达)引发的钙信号传导(Lin等人,2015;Wang等人,2019)。TRPA1拮抗剂在特应性皮炎(Oh等人,2013;Wilson等人,2013)、接触性皮炎(Liu等人,2013)、银屑病相关瘙痒(Wilson等人,2013)和IL-31依赖性瘙痒(Cevikbas等人,2014)的研究中有效。人TRPA1功能获得与家族性发作性疼痛综合征相关(Kremeyer等人,2010)。TRPA1拮抗剂在偏头痛相关的触诱发痛的行为模型中有效(Edelmayer等人,2012)。与支配健康牙齿的三叉神经节中的TRPA1表达相比,在支配受损牙齿的三叉神经节中TRPA1选择性增加(Haas等人,2011)。已知有若干种麻醉剂是TRPA1激动剂,包括异氟烷(Matta等人,2008),其为TRPA1抑制剂缓解术后疼痛提供了理论依据。用TRPA1拮抗剂治疗的TRPA1敲除小鼠和野生型小鼠显示出抗焦虑和抗抑郁样表型(de Moura等人,2014)。基于显示出AMPK与TRPA1之间存在反向调节的机制联系的研究,预计TRPA1抑制剂将在治疗糖尿病性神经病变中具有益处(Hiyama等人,2018;Koivisto和Pertovaara,2013;Wang等人,2018)。与野生型小鼠相比,TRPA1敲除小鼠展现出更小的心肌梗塞面积(Conklin等人,2019)。TRPA1敲除和药物干预抑制了小鼠的TNBS诱导的结肠炎(Engel等人,2011)。在小鼠脑缺血模型中,TRPA1敲除和TRPA1拮抗剂减少髓磷脂损伤(Hamilton等人,2016)。在尿酸单钠小鼠痛风模型中,TRPA1敲除小鼠的尿酸盐结晶和关节炎症减少(Moilanen等人,2015)。大鼠中的TRPA1缺失改善了大鼠急性痛风发作模型中的关节炎症和痛觉过敏(Trevisan等人,2014)。TRPA1的激活引发骨关节炎软骨细胞中的炎性应答(Nummenmaa等人,2016)。TRPA1抑制和基因缺失减少了骨关节炎小鼠软骨细胞和小鼠软骨组织中的炎性介质(Nummenmaa等人,2016)。最后,TRPA1敲除小鼠在MIA诱发的膝肿胀模型中展现出在骨关节炎肢体上的负重的改善(Horvath等人,2016)。TRPA1在膀胱上皮大鼠中(Du等人,2007)以及在患有膀胱出口梗阻的患者(Du等人,2008)中差异表达。TRPA1受体调节减轻了大鼠脊髓损伤模型中的膀胱过度活动(Andrade等人,2011),并且鞘内施用TRPA1拮抗剂减轻了具有反射亢进排尿的大鼠中的环磷酰胺诱导的膀胱炎(Chen等人,2016)。
因此希望提供有效的TRPA1抑制剂。
各种结构类别的TRPA1抑制剂综述于S.Skerratt,Progress in MedicinalChemistry,2017,第56卷,81-115中并且综述于D.Preti,G.Saponaro,A.Szallasi,Pharm.Pat.Anal.(2015)4(2),75-94中。
WO 2017/060488公开了作为TRPA1的拮抗剂的化合物,其具有通用结构式
没有公开其中带有四唑环的实施例28和29的TRPA1活性。
L.Schenkel,等人,J.Med.Chem.2016,59,2794-2809公开了基于喹唑啉酮的TRPA1拮抗剂,其包括以下通用结构式的化合物
其中化合物31(其中R是OH)被公开为在FLIPR测定中的拮抗TRPA1活性为IC50 58nM并且在人肝微粒体中的内在清除率<14μL/min/kg。
具体实施方式
本发明提供了新颖的噻吩并嘧啶酮类,所述噻吩并嘧啶酮类是出乎意料地有效的TRPA1抑制剂(测定A),其特征进一步在于
-在人肝微粒体中改善的稳定性(测定B)
-在人肝细胞中改善的稳定性(测定C)。
本发明的化合物与WO 2017/060488中的实施例28和29在结构上的不同之处在于它们含有附接至与对氯苯基相邻的苄基碳的羟基取代基;其中一些化合物另外具有经由亚甲基接头附接至四唑基环的不同的双环部分。另外,本发明的化合物与L.Schenkel,等人,J.Med.Chem.2016,59,2794-2809中的实施例31在结构上的不同之处在于它们具有四唑基环。这些结构差异出乎意料地导致以下的有利的组合:(i)TRPA1的抑制、(ii)在人肝微粒体中的稳定性、(iii)在人肝细胞中的稳定性和(iv)更少的不需要的人体代谢物。
因此,本发明的化合物在以下参数的组合方面优于现有技术中公开的那些:
-作为TRPA1抑制剂的效力
-在人肝微粒体中的稳定性
-在人肝细胞中的稳定性
-产生更少的不需要的人体代谢物
在人肝微粒体中的稳定性是指在选择和/或设计具有有利的药代动力学特性的药物作为第一筛选步骤的情况下,化合物对生物转化的敏感性。许多药物的主要代谢部位是肝脏。人肝微粒体含有细胞色素P450(CYP),并且因此代表用于在体外研究I期药物代谢的模型系统。在人肝微粒体中增强的稳定性与几种优点相关,包括增加的生物利用度和足够的半衰期,这可以使得能够对患者以较低剂量和频率给药。因此,在人肝微粒体中增强的稳定性是要用于药物的化合物的有利特征。因此,除能够抑制TRPA1外,预期本发明的化合物在人体中具有有利的体内清除,并且因此具有所需作用持续时间。
在人肝细胞中的稳定性是指在选择和/或设计具有有利的药代动力学特性的药物的情况下,化合物对生物转化的敏感性。许多药物的主要代谢部位是肝脏。人肝细胞含有细胞色素P450(CYP)和代谢酶的其他药物,并且因此代表用于在体外研究药物代谢的模型系统。(重要的是,与肝微粒体测定相比,肝细胞测定还涵盖II期生物转化以及肝脏特异性转运蛋白介导的过程,并且因此代表了更完整的药物代谢研究系统)。在人肝细胞中增强的稳定性与几种优点相关,包括增加的生物利用度和足够的半衰期,这可以使得能够对患者以较低剂量和频率给药。因此,在人肝细胞中增强的稳定性是要用于药物的化合物的有利特征。
所用的术语和定义
在本文中未明确定义的术语应当被理解为具有本领域技术人员根据本披露和上下文能得出的含义。然而,如在本说明书中所用,除非有相反说明,以下术语具有所指示的含义并且遵循以下惯例。
术语四唑基是指下列环的基团
除非明确指示,否则贯穿整个说明书和所附权利要求书,给定的化学式或名称应当包括互变异构体和所有立体异构体、光学异构体和几何异构体(例如对映异构体、非对映异构体、E/Z异构体等)及其外消旋体以及处于不同比例的单独的对映异构体的混合物、非对映异构体的混合物、或任何前述形式的混合物,其中存在此类异构体和对映异构体,以及盐,包括其药学上可接受的盐及其溶剂化物,例如像水合物,包括游离化合物的溶剂化物或化合物的盐的溶剂化物。
一般而言,可根据本领域技术人员已知的合成原理,例如通过分离相应的混合物、通过使用立体化学纯的起始材料和/或通过立体选择性合成获得基本上纯的立体异构体。本领域已知如何制备光学活性形式,如通过拆分外消旋形式或通过合成,例如从光学活性起始材料开始和/或通过使用手性试剂。
本发明的对映体纯化合物或中间体可通过不对称合成制备,例如通过制备并随后分离可通过已知方法(例如通过色谱分离或结晶)分离的适当的非对映异构化合物或中间体,和/或通过使用手性试剂,例如手性起始材料、手性催化剂或手性助剂来制备。
此外,本领域技术人员已知如何从相应的外消旋混合物制备对映异构体纯的化合物,例如通过在手性固定相上色谱分离相应的外消旋混合物;或通过使用适当的拆分剂拆分外消旋混合物,例如借助用光学活性的酸或碱进行外消旋化合物的非对映异构体盐形成、随后拆分所述盐并且从所述盐中释放所希望的化合物或通过用光学活性的手性助剂衍生化相应的外消旋化合物、随后进行非对映异构体分离并且除去手性辅助基团;或通过对外消旋体的动力学拆分(例如,通过酶促拆分);通过在合适的条件下从对映形态晶体的聚集物对映选择性结晶或通过在光学活性手性助剂的存在下从合适的溶剂中(分级)结晶。
本文采用的短语“药学上可接受的”是指这样的化合物、材料、组合物和/或剂型,其在健全的医疗判断范围内,适于在没有过度毒性、刺激、过敏反应或其他问题或并发症的情况下使用并且与合理的益处/风险比率相称。
如本文所用,“药学上可接受的盐”是指所公开的化合物的衍生物,其中所述母体化合物与酸或碱形成盐或复合物。与含有碱性部分的母体化合物形成药学上可接受的盐的酸的例子包括无机酸或有机酸,如苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、龙胆酸、氢溴酸、盐酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、4-甲基苯磺酸、磷酸、水杨酸、琥珀酸、硫酸和酒石酸。
与含有酸性部分的母体化合物形成药学上可接受的盐的阳离子和碱的例子包括Na+、K+、Ca2+、Mg2+、NH4 +、L-精氨酸、2,2'-亚氨基双乙醇、L-赖氨酸、N-甲基-D-谷氨酰胺或三(羟甲基)-氨基甲烷。本发明的药学上可接受的盐可以通过常规的化学方法由含有碱性或酸性部分的母体化合物合成。通常,此类盐可以通过使这些化合物的游离酸或碱形式与足量的适当的碱或酸在水中或在有机稀释剂(如醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物)中反应来制备。
例如可用于纯化或分离本发明的化合物的除上述提及的那些以外的其他酸的盐(例如三氟乙酸盐)也构成本发明的一部分。
生物测定
测定A:TRPA1测定
本发明的化合物的活性可以使用以下体外TRPA1细胞测定来证实:
方法:
将过表达人TRPA1离子通道的人HEK293细胞系(Perkin Elmer,产品编号AX-004-PCL)用作用于化合物功效和效力的测试系统。通过在FLIPRtetra系统(MolecularDevices)中测量化合物对由AITC(Allylisothiocyanat)激动作用诱导的细胞内钙浓度的影响来确定化合物活性。
细胞培养:
所述细胞是作为冷冻小瓶中的冷冻细胞而获得,并且储存在-150℃下直至使用。
使细胞在培养基(具有10%FCS和0.4mg/ML遗传霉素的MEM/EBSS培养基)中生长。重要的是,密度不超过90%汇合。对于传代培养,通过Versene使细胞脱离烧瓶。在测定前一天,使细胞脱离,用培养基(具有10%FCS的MEM/EBSS培养基)洗涤两次,并且将20000个细胞以20μl/孔接种到来自Corning的聚D-赖氨酸生物包被的384孔板(黑色,透明底,目录356697)中。在用于测定之前,将板在37℃/5%CO2下孵育24小时。
化合物制备
将测试化合物以10mM的浓度溶解于100%DMSO中,并在第一步骤中稀释于DMSO中至5mM浓度,之后在100%DMSO中进行连续稀释步骤。稀释因子和稀释步骤的数量可以根据需求而变化。通常,以1:5的稀释度制备8种不同浓度,用HBSS/HEPES缓冲液(来自Gibco的1xHEPES,目录14065;来自SIGMA的20mM HEPES,目录83264;来自Invitrogen的0.1%BSA,目录11926;pH 7,4)对物质进行进一步中间稀释(1:20)。
FLIPR测定:
在测定当天,将细胞用测定缓冲液洗涤3x,在洗涤后,孔中保留20μL缓冲液。将在HBSS/HEPES中的10μL Ca6试剂盒(目录R8191 MolecularDevices)加载缓冲液添加至细胞中并且将板在37°/5%CO2下加盖孵育120分钟。将来自中间稀释板的10μL在HBSS/HEPES缓冲液/5%DMSO中的化合物或对照小心添加至孔中。在FLIPRtetra装置上读取发光(指示钙流入或释放),持续10分钟以监测化合物诱导的作用(例如激动作用)。最后,将溶解在HBSS/HEPES缓冲液/0,05%DMSO(最终浓度10μM)中的10μL的激动剂AITC 50μM添加到孔中,然后在FLIPRtetra装置上再读取10分钟。使用添加AITC后的信号曲线下面积(AUC)进行IC50/%抑制计算
数据评价和计算:
每个测定微量滴定板含有具有媒介物(1%DMSO)对照而不是化合物作为AITC诱导发光的对照(100%CTL;高对照)的孔以及具有不含AITC的媒介物对照作为发光非特异性变化的对照的孔(0%CTL;低对照)。
通过计算各个孔的信号曲线下面积来进行数据分析。基于此值,使用MegaLab软件(内部开发)计算每种物质浓度的测量的%值(AUC(样品)-AUC(低))*100/(AUC(高)-AUC(低))。使用MegaLab软件从对照值%计算IC50值。计算:[y=(a-d)/(1+(x/c)^b)+d],a=低值,d=高值;x=浓度M;c=IC50 M;b=斜率;y=%对照
表1:如在测定A中获得的本发明的化合物的生物学数据
实施例 | hTRPA1 IC<sub>50</sub>[nM] |
1 | 35 |
2 | 288 |
3 | 75 |
4 | 197 |
5 | 27 |
6 | 120 |
7 | 275 |
8 | 27 |
9 | 72 |
表2:如在测定A中获得的现有技术化合物的生物学数据(WO 2017/060488中的实施例28和29)。
表3:如在测定A中获得的现有技术化合物的生物学数据(L.Schenkel,等人,J.Med.Chem.2016,59,2794-2809中的实施例31)。
测定B:微粒体清除率:
在37℃下用合并的肝微粒体测定测试化合物的代谢降解。100μl的最终孵育体积/时间点含有TRIS缓冲液pH 7.6(在RT下)(0.1M)、氯化镁(5mM)、微粒体蛋白(1mg/ml)和最终浓度为1μM的测试化合物。
在37℃下的短的预孵育期后,通过添加还原形式的β-烟酰胺腺嘌呤二核苷酸磷酸(NADPH,1mM)使反应开始,并且通过在不同时间点(0、5、15、30、60min)后将等分试样转移到溶剂中使反应终止。此外,在没有NADPH的孵育中监测NADPH非依赖性降解,并且在最后的时间点终止。NADPH独立孵育后剩余的测试化合物[%]由参数c(对照)(代谢稳定性)反映。通过离心(10000g,5min)将淬灭的孵育物沉淀。
通过LC-MS/MS测定上清液的等分试样的母体化合物量。通过浓度-时间特征曲线的半对数曲线图的斜率确定半衰期(t1/2INVITRO)。
通过考虑孵育中的蛋白质的量来计算固有清除率(CL_INTRINSIC):
CL_INTRINSIC[μl/min/mg蛋白质]=(Ln 2/(半衰期[min]*蛋白质含量[mg/ml]))*1000
CL_INTRINSIC_INVIVO[ml/min/kg]=(CL_INTRINSIC[μL/min/mg蛋白质]x MPPGL[mg蛋白质/g肝脏]x肝因子[g/kg体重])/1000
Qh[%]=CL[ml/min/kg]/肝血流[ml/min/kg])
肝细胞,人:120x10e6个细胞/g肝
肝因子,人:25.7g/kg体重
血流,人:21ml/(min x kg)
表4:如在测定B中获得的本发明的化合物的生物学数据
实施例 | 人LM[%Qh] |
1 | <23 |
3 | >89 |
4 | <23 |
5 | <23 |
6 | <23 |
7 | <23 |
8 | <23 |
9 | <23 |
表5:如在测定B中获得的现有技术化合物的生物学数据(WO 2017/060488中的实施例28和29)。
表6:如在测定B中获得的现有技术化合物的生物学数据(L.Schenkel,等人,J.Med.Chem.2016,59,2794-2809中的实施例31)。
测定C:肝细胞清除率
在肝细胞悬浮液中测定测试化合物的代谢降解。将肝细胞(冷冻保存)在含有5%或50%物质血清的杜氏改良伊格尔培养基(补充有3.5μg胰高血糖素/500mL、2.5mg胰岛素/500mL和3.75mg/500mL氢化可的松)中孵育。
在培养箱(37℃,10%CO2)中预孵育30min后,将5μl的测试化合物溶液(80μM;从在DMSO储备溶液中的2mM用培养基1:25稀释)添加到395μl肝细胞悬浮液中(细胞密度在0.25-5Mio细胞/mL范围内,取决于种类,典型地为1Mio细胞/mL;测试化合物的最终浓度为1μM,最终DMSO浓度为0.05%)。
将细胞孵育六小时(培养箱,定轨摇床),并且在0、0.5、1、2、4和6小时进行取样(25μl)。将样品转移到乙腈中并且通过离心沉淀(5min)。将上清液转移到新的96深孔板上,在氮气下蒸发并且重新悬浮。
通过HPLC-MS/MS分析母体化合物的下降。
CLint计算如下:CL_INTRINSIC=剂量/AUC=(C0/CD)/(AUD+clast/k)x1000/60。C0:孵育中的初始浓度[μM],CD:活细胞的细胞密度[10e6个细胞/mL],AUD:数据下面积[μMx h],clast:最后数据点的浓度[μM],k:母体下降的回归线的斜率[h-1]。
通过使用肝脏模型(良好的搅拌的模型),可以将计算的体外肝固有清除率按比例放大为固有体内肝清除率,并且用于预测肝体内血液清除率(CL)。
CL_INTRINSIC_INVIVO[ml/min/kg]=(CL_INTRINSIC[μL/min/10e6个细胞]x肝细胞[10e6个细胞/g肝]x肝因子[g/kg体重])/1000
CL[ml/min/kg]=CL_INTRINSIC_INVIVO[ml/min/kg]x肝血流[ml/min/kg]/(CL_INTRINSIC_INVIVO[ml/min/kg]+肝血流[ml/min/kg])
Qh[%]=CL[ml/min/kg]/肝血流[ml/min/kg])
肝细胞,人:120x 10e6个细胞/g肝
肝因子,人:25.7g/kg体重
血流,人:21ml/(min x kg)
表7:如在测定C中获得的本发明的化合物的生物学数据
实施例 | 人肝细胞[%Qh] |
1 | <4 |
5 | 31 |
8 | 22 |
9 | <4 |
表8:如在测定C中获得的现有技术化合物的生物学数据(WO2017/060488中的实施例28和29)。
表9:如在测定C中获得的现有技术化合物的生物学数据(L.Schenkel,等人,J.Med.Chem.2016,59,2794-2809中的实施例31)。
测定D:体外人肝细胞中的代谢
使用悬浮液中的原代人肝细胞研究测试化合物的代谢途径。从冷冻保存中恢复后,将人肝细胞在含有5%人血清并且补充有3.5μg胰高血糖素/500ml、2.5mg胰岛素/500ml和3.75mg/500ml氢化可的松的杜氏改良伊格尔培养基中孵育。
在细胞培养箱(37℃,10%CO2)中预孵育30min后,将测试化合物溶液添加到肝细胞悬浮液中以获得1.0*106至4.0*106个细胞/ml的最终细胞密度(取决于用原代人肝细胞观察到的化合物的代谢转换速率),最终测试化合物浓度为10μM,并且最终DMSO浓度为0.05%。
将细胞在水平摇床上的细胞培养箱中孵育六小时,并且根据代谢转换速率,在0、0.5、1、2、4或6小时后从孵育中取出样品。将样品用乙腈淬灭并且通过离心沉淀。将上清液转移至96深孔板中,在氮气下蒸发并且重新悬浮,然后通过液相色谱-高分辨率质谱法进行生物分析,以鉴定推定的代谢物。
表10:如通过测定D获得的对于本发明实施例5观察到的主要代谢物:
基于暂定的LC-MSn结构阐明,四唑环的完整性在任何主要描述的代谢物中都没有受到影响。
治疗方法
本发明涉及通式1的化合物,所述化合物可用于预防和/或治疗与TRPA1活性相关或由其调节的疾病和/或病症,包括但不限于治疗和/或预防纤维化疾病、炎性和免疫调节性障碍、呼吸系统或胃肠道疾病或不适、眼科疾病、关节炎性疾病以及鼻咽部、眼睛和皮肤的炎性疾病。所述障碍、疾病和不适包括咳嗽、特发性肺纤维化、其他肺间质疾病和其他纤维化、哮喘或过敏性疾病、嗜酸性粒细胞疾病、慢性阻塞性肺疾病以及自身免疫性病状如类风湿性关节炎和动脉粥样硬化、疼痛和神经障碍如抑郁症。
通式1的化合物可用于预防和/或治疗:
(1)咳嗽,如慢性特发性咳嗽或慢性难治性咳嗽、与哮喘、COPD和肺癌相关的咳嗽以及病毒感染后的咳嗽。
(2)肺纤维化疾病,如与胶原性疾病(例如红斑狼疮、系统性硬皮病、类风湿性关节炎、多肌炎和皮肌炎)相关的肺炎或间质性肺炎、特发性间质性肺炎(如肺纤维化(IPF))、非特异性间质性肺炎、呼吸性细支气管炎相关的间质性肺疾病、脱屑性间质性肺炎、隐源性机化性肺炎、急性间质性肺炎和淋巴细胞间质性肺炎、淋巴管平滑肌瘤病、肺泡蛋白沉积症、朗格汉斯细胞组织细胞增生症、胸膜实质弹力纤维增生症、已知原因的间质性肺疾病(如由于职业暴露,如石棉肺、矽肺、矿工肺(煤尘)、农民肺(干草和霉菌)、饲鸽者肺(Pidgeonfanciers lung)(鸟类)或其他职业性空气触发因素(如金属粉尘或分枝杆菌),或由于治疗(如放射、甲氨蝶呤、胺碘酮、呋喃妥因或化学治疗剂)引起的间质性肺炎)、或肉芽肿病(如伴有小血管炎的肉芽肿病)、许尔许斯特劳斯综合征(Churg-Strauss syndrome)、结节病、超敏性肺炎或由不同来源(例如误吸、吸入有毒气体、蒸气)引起的间质性肺炎、支气管炎或肺炎或由心力衰竭、X射线、放射、化学疗法、伯克病(M.boeck)或结节病、肉芽肿病、囊性纤维化或黏液黏稠病或α-1-抗胰蛋白酶缺乏引起的间质性肺炎。
(3)其他纤维化疾病,如肝桥接纤维化、肝硬化、非酒精性脂肪性肝炎(NASH)、心房纤维化、心内膜心肌纤维化、陈旧性心肌梗塞、胶质瘢痕、动脉僵硬、关节纤维化、杜普伊特伦挛缩、瘢痕疙瘩、硬皮病/系统性硬化症、纵隔纤维化、骨髓纤维化、佩罗尼氏病、肾源性全身性纤维化、腹膜后纤维化、粘连性关节囊炎。
(4)炎性、自身免疫性或过敏性疾病和病症,如过敏性或非过敏性鼻炎或鼻窦炎、慢性鼻窦炎或鼻炎、鼻息肉、慢性鼻窦炎、急性鼻窦炎、哮喘、小儿哮喘、过敏性支气管炎、肺泡炎、过度反应性气道、过敏性结膜炎、支气管扩张、成人呼吸窘迫综合征、支气管和肺水肿、支气管炎或肺炎、嗜酸性粒细胞性蜂窝织炎(例如韦尔斯综合征)、嗜酸性粒细胞性肺炎(例如莱夫勒综合征、慢性嗜酸性粒细胞性肺炎)、嗜酸性粒细胞性筋膜炎(例如舒尔曼综合征)、迟发型超敏反应、非过敏性哮喘;运动诱发的支气管收缩;慢性阻塞性肺疾病(COPD)、急性支气管炎、慢性支气管炎、咳嗽、肺气肿;全身性过敏反应或超敏反应、药物过敏(例如,对青霉素、头孢菌素过敏)、由于摄入受污染的色氨酸引起的嗜酸性粒细胞增多症肌痛综合征、昆虫叮咬过敏;自身免疫性疾病,如类风湿性关节炎、格雷夫斯病、干燥综合征、银屑病性关节炎、多发性硬化症、系统性红斑狼疮、重症肌无力、免疫性血小板减少症(成人ITP、新生儿血小板减少症、小儿ITP)、免疫溶血性贫血(自身免疫性和药物诱发的)、伊文氏综合征(血小板和红细胞免疫性血细胞减少症)、新生儿Rh病、古德帕斯丘综合征(抗GBM病)、乳糜泻、自身免疫性心肌病、青少年发作性糖尿病;肾小球肾炎、自身免疫性甲状腺炎、白塞病;移植物排斥(例如,在移植中),包括同种异体移植物排斥或移植物抗宿主病;炎性肠病,如克罗恩病和溃疡性结肠炎;脊柱关节病;硬皮病;银屑病(包括T细胞介导的银屑病)和炎性皮肤病如皮炎、湿疹、特应性皮炎、过敏性接触性皮炎、荨麻疹;血管炎(例如,坏死性、皮肤和超敏性血管炎);结节性红斑;嗜酸性粒细胞性肌炎、嗜酸性粒细胞性筋膜炎、白细胞浸润皮肤或器官的癌症;眼科疾病,如年龄相关性黄斑变性、糖尿病性视网膜病变和糖尿病性黄斑水肿、角膜炎、嗜酸性粒细胞性角膜炎、角膜结膜炎、春季角膜结膜炎、瘢痕、眼前段瘢痕、睑缘炎、睑结膜炎、大疱性障碍、瘢痕性类天疱疮、结膜黑色素瘤、乳头状结膜炎、干眼症、巩膜外层炎、青光眼、神经胶质增多症、环状肉芽肿、格雷夫斯眼病、眼内黑色素瘤、结膜黄斑、增生性玻璃体视网膜病变、翼状胬肉、巩膜炎、葡萄膜炎、急性痛风发作、痛风或骨关节炎。
(5)疼痛,如慢性特发性疼痛综合征、神经性疼痛、感觉迟钝、触诱发痛、偏头痛、牙痛和术后疼痛。
(6)抑郁症、焦虑、糖尿病性神经病变和膀胱障碍如膀胱出口梗阻、膀胱过度活动症、膀胱炎;心肌再灌注损伤或脑缺血损伤。
因此,本发明涉及一种通式1的化合物,其用作药物。
此外,本发明涉及通式1的化合物用于治疗和/或预防与TRPA1活性相关或由其调节的疾病和/或病症的用途。
此外,本发明涉及通式1的化合物用于治疗和/或预防纤维化疾病、炎性和免疫调节性障碍、呼吸系统或胃肠道疾病或不适、眼科疾病、关节炎性疾病以及鼻咽部、眼睛和皮肤炎性疾病的用途。所述障碍、疾病和不适包括咳嗽、特发性肺纤维化、其他肺间质性疾病和其他纤维化、哮喘或过敏性疾病、嗜酸性粒细胞疾病、慢性阻塞性肺疾病以及自身免疫性病状如类风湿性关节炎和动脉粥样硬化。
此外,本发明涉及通式1的化合物用于治疗和/或预防以下疾病的用途:
(1)咳嗽,如慢性特发性咳嗽或慢性难治性咳嗽、与哮喘、COPD和肺癌相关的咳嗽以及病毒感染后的咳嗽。
(2)肺纤维化疾病,如与胶原性疾病(例如红斑狼疮、系统性硬皮病、类风湿性关节炎、多肌炎和皮肌炎)相关的肺炎或间质性肺炎、特发性间质性肺炎(如肺纤维化(IPF))、非特异性间质性肺炎、呼吸性细支气管炎相关的间质性肺疾病、脱屑性间质性肺炎、隐源性机化性肺炎、急性间质性肺炎和淋巴细胞间质性肺炎、淋巴管平滑肌瘤病、肺泡蛋白沉积症、朗格汉斯细胞组织细胞增生症、胸膜实质弹力纤维增生症、已知原因的间质性肺疾病(如由于职业暴露,如石棉肺、矽肺、矿工肺(煤尘)、农民肺(干草和霉菌)、饲鸽者肺(Pidgeonfanciers lung)(鸟类)或其他职业性空气触发因素(如金属粉尘或分枝杆菌),或由于治疗(如放射、甲氨蝶呤、胺碘酮、呋喃妥因或化学治疗剂)引起的间质性肺炎)、或肉芽肿病(如伴有小血管炎的肉芽肿病)、许尔许斯特劳斯综合征(Churg-Strauss syndrome)、结节病、超敏性肺炎或由不同来源(例如误吸、吸入有毒气体、蒸气)引起的间质性肺炎、支气管炎或肺炎或由心力衰竭、X射线、放射、化学疗法、伯克病(M.boeck)或结节病、肉芽肿病、囊性纤维化或黏液黏稠病或α-1-抗胰蛋白酶缺乏引起的间质性肺炎。
(3)其他纤维化疾病如肝桥接纤维化、肝硬化、非酒精性脂肪性肝炎(NASH)、心房纤维化、心内膜心肌纤维化、陈旧性心肌梗塞、胶质瘢痕、动脉僵硬、关节纤维化、杜普伊特伦挛缩、瘢痕疙瘩、硬皮病/系统性硬化症、纵隔纤维化、骨髓纤维化、佩罗尼氏病、肾源性全身性纤维化、腹膜后纤维化、粘连性关节囊炎。
(4)炎性、自身免疫性或过敏性疾病和病症,如过敏性或非过敏性鼻炎或鼻窦炎、慢性鼻窦炎或鼻炎、鼻息肉、慢性鼻窦炎、急性鼻窦炎、哮喘、小儿哮喘、过敏性支气管炎、肺泡炎、过度反应性气道、过敏性结膜炎、支气管扩张、成人呼吸窘迫综合征、支气管和肺水肿、支气管炎或肺炎、嗜酸性粒细胞性蜂窝织炎(例如韦尔斯综合征)、嗜酸性粒细胞性肺炎(例如莱夫勒综合征、慢性嗜酸性粒细胞性肺炎)、嗜酸性粒细胞性筋膜炎(例如舒尔曼综合征)、迟发型超敏反应、非过敏性哮喘;运动诱发的支气管收缩;慢性阻塞性肺疾病(COPD)、急性支气管炎、慢性支气管炎、咳嗽、肺气肿;全身性过敏反应或超敏反应、药物过敏(例如,对青霉素、头孢菌素过敏)、由于摄入受污染的色氨酸引起的嗜酸性粒细胞增多症肌痛综合征、昆虫叮咬过敏;自身免疫性疾病,如类风湿性关节炎、格雷夫斯病、干燥综合征、银屑病性关节炎、多发性硬化症、系统性红斑狼疮、重症肌无力、免疫性血小板减少症(成人ITP、新生儿血小板减少症、小儿ITP)、免疫溶血性贫血(自身免疫性和药物诱发的)、伊文氏综合征(血小板和红细胞免疫性血细胞减少症)、新生儿Rh病、古德帕斯丘综合征(抗GBM病)、乳糜泻、自身免疫性心肌病、青少年发作性糖尿病;肾小球肾炎、自身免疫性甲状腺炎、白塞病;移植物排斥(例如,在移植中),包括同种异体移植物排斥或移植物抗宿主病;炎性肠病,如克罗恩病和溃疡性结肠炎;脊柱关节病;硬皮病;银屑病(包括T细胞介导的银屑病)和炎性皮肤病如皮炎、湿疹、特应性皮炎、过敏性接触性皮炎、荨麻疹;血管炎(例如,坏死性、皮肤和超敏性血管炎);结节性红斑;嗜酸性粒细胞性肌炎、嗜酸性粒细胞性筋膜炎、白细胞浸润皮肤或器官的癌症;眼科疾病,如年龄相关性黄斑变性、糖尿病性视网膜病变和糖尿病性黄斑水肿、角膜炎、嗜酸性粒细胞性角膜炎、角膜结膜炎、春季角膜结膜炎、瘢痕、眼前段瘢痕、睑缘炎、睑结膜炎、大疱性障碍、瘢痕性类天疱疮、结膜黑色素瘤、乳头状结膜炎、干眼症、巩膜外层炎、青光眼、神经胶质增多症、环状肉芽肿、格雷夫斯眼病、眼内黑色素瘤、结膜黄斑、增生性玻璃体视网膜病变、翼状胬肉、巩膜炎、葡萄膜炎、急性痛风发作、痛风或骨关节炎。
(5)疼痛,如慢性特发性疼痛综合征、神经性疼痛、感觉迟钝、触诱发痛、偏头痛、牙痛和术后疼痛。
(6)抑郁症、焦虑、糖尿病性神经病变和膀胱障碍如膀胱出口梗阻、膀胱过度活动症、膀胱炎;心肌再灌注损伤或脑缺血损伤。
在另一方面,本发明涉及通式1的化合物,其用于治疗和/或预防上述疾病和病症。
在另一方面,本发明涉及通式1的化合物用于制备治疗和/或预防上述疾病和病症的药物的用途。
在本发明的另一方面,本发明涉及用于治疗或预防上述疾病和病症的方法,所述方法包括向人类施用有效量的通式1的化合物。
组合疗法
本发明的化合物可以进一步与一种或多种、优选一种另外的治疗剂组合。根据一个实施方案,另外的治疗剂选自可用于治疗上文所述的疾病或病症(特别是与纤维化疾病、炎性和免疫调节性障碍、呼吸系统或胃肠道疾病或不适、关节炎性疾病或鼻咽部、眼睛和皮肤的炎性疾病或病症相关的疾病或病症,例如像咳嗽、特发性肺纤维化、其他肺间质性疾病、哮喘或过敏性疾病、嗜酸性粒细胞疾病、慢性阻塞性肺疾病、特应性皮炎以及自身免疫性疾病,如类风湿性关节炎和动脉粥样硬化)的治疗剂,或可用于治疗眼科疾病、疼痛和抑郁症的治疗剂。
适用于此类组合的另外的治疗剂特别包括例如关于所提及适应症之一增强一种或多种活性物质的治疗作用和/或允许一种或多种活性物质的剂量减少的那些。
因此,本发明的化合物可以与选自以下的一种或多种另外的治疗剂组合:抗纤维化剂、止咳剂、抗炎剂、抗特应性皮炎剂、镇痛剂、抗惊厥剂、抗焦虑药、镇静剂、骨骼肌松弛剂或抗抑郁药。
抗纤维化剂是例如尼达尼布、吡非尼酮、磷酸二酯酶-IV(PDE4)抑制剂(如罗氟司特)、自分泌运动因子抑制剂(如GLPG-1690或BBT-877);结缔组织生长因子(CTGF)阻断抗体,如潘瑞鲁单抗;B细胞激活因子受体(BAFF-R)阻断抗体,如伊利尤单抗(Lanalumab);α-V/β-6阻断抑制剂(如BG-00011/STX-100)、重组正五聚蛋白-2(PTX-2)(如PRM-151);c-JunN末端激酶(JNK)抑制剂(如CC-90001);半乳糖凝集素-3抑制剂,如TD-139;G-蛋白偶联受体84(GPR84)抑制剂(如GLPG-1205);G-蛋白偶联受体84/G-蛋白偶联受体40双重抑制剂(如PBI-4050);Rho相关含有卷曲螺旋的蛋白激酶2(ROCK2)抑制剂,如KD-025;热休克蛋白47(HSP47)小干扰RNA,如BMS-986263/ND-L02-s0201;Wnt途径抑制剂,如SM-04646;LD4/PDE3/4抑制剂,如Tipelukast;组氨酰tRNA合酶(HARS)的重组免疫调节结构域,如ATYR-1923;前列腺素合酶抑制剂,如ZL-2102/SAR-191801;15-羟基-二十碳五烯酸(15-HEPE,例如DS-102);赖氨酰氧化酶样2(LOXL2)抑制剂,如PAT-1251、PXS-5382/PXS-5338;磷酸肌醇3-激酶(PI3K)/哺乳动物雷帕霉素靶标(mTOR)双重抑制剂,如HEC-68498;钙蛋白酶抑制剂,如BLD-2660;丝裂原活化蛋白激酶激酶激酶(MAP3K19)抑制剂,如MG-S-2525;几丁质酶抑制剂,如OATD-01;丝裂原活化蛋白激酶活化蛋白激酶2(MAPKAPK2)抑制剂,如MMI-0100;转化生长因子β1(TGF-β1)小干扰RNA,如TRK250/BNC-1021;或溶血磷脂酸受体拮抗剂,如BMS-986278。
止咳剂是例如嘌呤受体3(P2X3)受体拮抗剂,如吉法匹坦(gefapixant)、S-600918、BAY-1817080或BLU-5937;神经激肽1(NK-1)受体拮抗剂,如奥维匹坦、阿瑞匹坦;烟碱型乙酰胆碱受体α7亚基刺激剂,如ATA-101/布瑞克兰(bradanicline);可待因、加巴喷丁、普瑞巴林或阿奇霉素。
抗炎剂是例如皮质类固醇,如泼尼松龙或地塞米松;环加氧酶-2(COX2)抑制剂,如塞来昔布、罗非昔布、帕瑞昔布、伐地昔布、德拉昔布、依托昔布或罗美昔布;前列腺素E2拮抗剂;白三烯B4拮抗剂;白三烯D4拮抗剂,如孟鲁司特;5-脂氧合酶抑制剂;或其他非甾体抗炎药(NSAID),如阿司匹林、双氯芬酸、二氟尼柳、依托度酸、布洛芬或吲哚美辛。
抗特应性皮炎剂是例如环孢菌素、甲氨蝶呤、吗替麦考酚酯、硫唑嘌呤、磷酸二酯酶抑制剂(例如阿普斯特、克利保洛)、Janus相关激酶(JAK)抑制剂(例如托西替尼)、针对IL-4/IL-13的中和抗体(例如度匹鲁单抗)、IL-13(例如乐瑞吉珠单抗、曲洛吉努单抗)和IL-31(奈莫利珠单抗)。
镇痛剂属于例如阿片类物质类型,如吗啡、氧化吗啡、左旋帕醇(levopanol)、羟考酮(oxycodon)、丙氧芬、纳美芬、芬太尼、氢可酮(hydrocondon)、氢化吗啡酮、美利皮定(meripidine)、美沙酮、纳洛芬、纳洛酮、纳曲酮、丁丙诺啡、布托啡诺、纳布啡、喷他佐辛;或非阿片类物质类型,如醋奋乃静(acetophenamine)。
抗抑郁药是例如三环类抗抑郁药,如阿米替林、氯米帕明、despramine、多塞平、地昔帕明、丙咪嗪、去甲替林;选择性血清素再摄取抑制剂抗抑郁药(SSRI),如氟西汀、帕罗西汀、舍曲林、西酞普兰、依他普仑;去甲肾上腺素再摄取抑制剂抗抑郁药(SNRI),如马普替林、洛非帕明、米氮平、羟丙替林、非唑拉明、托莫西汀、米安色林、安非他酮、羟基安非他酮、诺米芬辛、维洛沙嗪;双血清素-去甲肾上腺素再摄取抑制剂抗抑郁药(SNRI),如度洛西汀、文拉法辛、去甲文拉法辛、左米那普仑;非典型抗抑郁药,如曲唑酮、米氮平、沃替西汀、维拉佐酮、安非他酮;或单胺氧化酶抑制剂抗抑郁药(MAOI),如反苯环丙胺、苯乙肼或异卡波肼。
抗焦虑药是例如苯二氮卓类,如阿普唑仑、溴西泮、氯氮卓、氯硝西泮、氯氮卓酸钾、地西泮、氟西泮、劳拉西泮、奥沙西泮、替马西泮、三唑仑或托非索泮;或者它们是非苯二氮卓类安眠药,如右佐匹克隆、扎来普隆、唑吡坦或佐匹克隆;或者它们是氨基甲酸酯,例如氨甲丙二酯、卡立普多、羟戊丁氨酯或劳氨酯;或者它们是抗组胺药,如羟嗪、氯苯那敏或苯海拉明。
镇静剂是例如巴比妥类镇静剂,如异戊巴比妥、阿普比妥、丁巴比妥、布他比妥(butabital)、甲苯比妥、美沙比妥、美索比妥、戊巴比妥、司可巴比妥、他布比妥、theamylal或硫代巴比妥;或者它们是非巴比妥类镇静剂,如格鲁米特、氨甲丙二酯、甲喹酮或二氯安替比林(dichloalphenazone)。
骨骼肌松弛剂是例如巴氯芬、氨甲丙二酯、卡立普多、环苯扎林、美他沙酮、美索巴莫、替扎尼定、氯唑沙宗或奥芬那君。
其他合适的组合配偶体是乙酰胆碱酯酶抑制剂,如多奈哌齐;5-HT-3拮抗剂,如昂丹司琼;代谢型谷氨酸受体拮抗剂;抗心律失常药,如美西律或苯妥英;或NMDA受体拮抗剂。
其他合适的组合配偶体是尿失禁药物,例如抗胆碱能药,如奥昔布宁、托特罗定、达非那新、非索罗定、索利那新或曲司氯胺;或者它们是膀胱肌肉松弛剂,如米拉贝隆;或者它们是α阻断剂,如坦索罗辛、阿夫唑嗪、西洛多辛、多沙唑嗪或特拉唑嗪。
上述组合配偶体的剂量通常是正常推荐的最低剂量的1/5至多正常推荐剂量的1/1。
因此,在另一方面,本发明涉及根据本发明的化合物与上文和下文所述的一种或多种另外的治疗剂的组合用于治疗可能受TRPA1影响或由其介导的疾病或病症(特别是如上文和下文所述的疾病或病症)的用途。
在又一方面,本发明涉及一种用于治疗患者的可能受TRPA1抑制影响的疾病或病症的方法,所述方法包括向需要这种的治疗的所述患者施用治疗有效量的式(I)的化合物或其药学上可接受的盐与治疗有效量的一种或多种另外的治疗剂的组合的步骤。
在又一方面,本发明涉及式(I)的化合物或其药学上可接受的盐与一种或多种另外的治疗剂的组合用于治疗有需要的患者的可能受TRPA1抑制影响的疾病或病症的用途。
在又另一方面,本发明涉及一种用于治疗患者的由TRPA1活性介导的疾病或病症的方法,所述方法包括向需要这样的治疗的患者(优选地人)施用治疗有效量的本发明的化合物与治疗有效量的上文和下文所述的一种或多种另外的治疗剂的组合的步骤。
根据本发明的化合物与另外的治疗剂的组合的使用可以同时地或以交错的时间发生。
根据本发明的化合物及一种或多种另外的治疗剂可以一起存在于一种配制品中,例如片剂或胶囊,或分开地存在于两种相同或不同的配制品中,例如呈所谓的成套试剂盒的形式。
因此,在另一方面,本发明涉及药物组合物,其包含根据本发明的化合物和上文和下文所述的一种或多种另外的治疗剂、任选地连同一种或多种惰性载体和/或稀释剂。
在又另一方面,本发明涉及根据本发明的化合物在咳嗽测量装置中的用途。
根据以下更详细的实施例(其通过举例的方式阐明了本发明的原理),本发明的其他特征和优点将变得清楚。
制备
根据本发明的化合物及其中间体可使用本领域技术人员已知且描述于有机合成文献中的合成方法获得,例如使用“Comprehensive Organic Transformations”,第2版,Richard C.Larock,John Wiley&Sons,2010和“March’s Advanced Organic Chemistry”,第7版,Michael B.Smith,John Wiley&Sons,2013中描述的方法。优选地,化合物类似地通过在下文中更加全面解释(特别是如在实验部分中所述)的制备方法获得。在一些情况下,进行反应方案所采用的顺序可以变化。也可以使用熟练的技术人员已知但未在本文详细描述的这些反应的变体。用于制备根据本发明的化合物的通用方法对于正在研究以下方案的技术人员而言将变得清楚。起始化合物是可商购的,或可以通过文献或本文中描述的方法制备或可以以类似或相似方式制备。在进行反应之前,可以使用常规保护基团保护起始化合物中的任何相应官能团。这些保护基团可在反应顺序内的适合阶段使用本领域技术人员公知的方法再次裂解,并且在例如“Protecting Groups”,第3版,Philip J.Kocienski,Thieme,2005和“Protective Groups in Organic Synthesis”,第4版,Peter G.M.Wuts,Theodora W.Greene,John Wiley&Sons,2006等文献中描述。术语“环境温度”和“室温”可互换使用,并且指定约20℃(例如在19℃与24℃之间)的温度。
缩写:
起始化合物的制备
中间体I
中间体I.1
1-(4-溴苯基)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]乙-1-酮
向在15mL DMA中的1.00g(8.44mmol)的5-(氯甲基)-2H-1,2,3,4-四唑和2.17g(9.28mmol)4-氯苯甲酰甲基溴中添加1.63g(11.8mmol)K2CO3。将反应混合物在RT下搅拌30min并且然后将混合物过滤。将溶液用水和NaCl饱和水溶液稀释并且用EtOAc萃取三次。将合并的有机相用水洗涤,经Na2SO4干燥,经活性炭过滤并且在真空中去除溶剂。将残余物通过柱色谱法(硅胶;CH/EtOAc,8/2→1/1)纯化。
C10H8Cl2N4O (M=271.1g/mol)
ESI-MS: 271[M+H]+
Rt(HPLC): 1.01min(方法B)
中间体II
中间体II.1
(1R)-1-(4-氯苯基)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]乙-1-醇
在惰性气氛下将1.30g(4.80mmol)1-(4-氯苯基)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]乙-1-酮(中间体I.1)添加至20mL ACN中。添加11.9mg(0.02mmol)氯([(1S,2S)-(-)-2-氨基-1,2-二苯乙基](4-甲苯磺酰基)酰胺基)(均三甲基苯)钌(II)(CAS 174813-81-1),然后逐滴添加0.72mL(1.73mmol)甲酸三乙胺复合物(5:2)。在RT下搅拌3h后,在真空中去除溶剂。向剩余的粗混合物中添加水并且将此混合物用EtOAc萃取。将有机层合并,经Na2SO4和活性炭干燥,过滤并且在真空中去除溶剂。
C10H10Cl2N4O (M=273.1g/mol)
ESI-MS: 273[M+H]+
Rt(HPLC): 0.96min(方法B)
中间体III
中间体III.1
4-氨基-2-甲烷磺酰基-1,3-噻唑-5-甲酸乙酯
在搅拌的同时将20.0g(0.092mol)4-氨基-2-(甲基硫烷基)-1,3-噻唑-5-甲酸乙酯(CAS:39736-29-3)添加到500mL DCM中。将混合物冷却至0℃并且分批添加35.0g(0.142mol)3-氯过氧苯甲酸(70%),保持反应混合物的温度低于24℃。将混合物在环境温度下搅拌过夜并且用300mL DCM稀释,然后添加10.0g(0.041mol)3-氯过氧苯甲酸(70%)并且将混合物在环境温度下搅拌另外的2.5h。添加另外的10g(0.041mmol)并且将反应混合物搅拌2h。然后将混合物通过添加饱和Na2SO3溶液淬灭并且搅拌10min。将有机相分离并且用2M饱和Na2CO3溶液(2x)和盐水洗涤。然后将有机萃取物经MgSO4干燥,过滤并且浓缩以得到所需的产物。
C7H10N2O4S2 (M=250.3g/mol)
ESI-MS: 251[M+H]+
Rt(HPLC): 0.96min(方法E)
中间体III.2
4-氨基-1,3-噻唑-5-甲酸乙酯
向7.0g(28.0mmol)4-氨基-2-甲烷磺酰基-1,3-噻唑-5-甲酸乙酯中添加EtOH(100mL)并且将混合物冷却至0℃。分批添加3.14g(83.9mmol)硼氢化钠并且将反应混合物在环境温度下搅拌3h。将反应混合物浓缩并且将水和EtOAc添加至残余物中。将有机相分离,用饱和NaHCO3水溶液洗涤,经MgSO4干燥,过滤并且浓缩以得到所需的产物。
C6H8N2O2S (M=172.2g/mol)
ESI-MS: 173[M+H]+
Rt(HPLC): 0.77min(方法B)
中间体III.3
6H,7H-[1,3]噻唑并[4,5-d]嘧啶-7-酮
向在EtOH(5.0mL)中的250mg(1.45mmol)4-氨基-1,3-噻唑-5-甲酸乙酯中添加650mg(6.2mmol)乙酸甲脒。将反应混合物加热至80℃并且在此温度下搅拌16h。冷却至环境温度后,添加605mg(5.8mmol)乙酸甲脒并且将反应混合物加热至80℃并且在此温度下搅拌5h。将其进一步加热至110℃并且在此温度下搅拌另外的16h。冷却至环境温度后,将混合物通过制备型HPLC(X-Bridge C18,含有0.1%TFA的ACN/H2O梯度)纯化以得到所需的产物。
C5H3N3OS (M=153.2g/mol)
ESI-MS: 154[M+H]+
Rt(HPLC): 0.12min(方法A)
中间体IV
中间体IV.1
1-甲基-1H,6H,7H-咪唑并[4,5-d]哒嗪-7-酮氢溴酸盐
在高压釜反应器中向5.3g(23.1mmol)2-溴-1-甲基-1H,6H,7H-咪唑并[4,5-d]哒嗪-7-酮在75mL MeOH中的混合物中添加200mg Pd/C(10%)。将反应混合物上方的空间排空并且装入50psi的氢气压力。将反应混合物在环境温度和50psi的氢气压力下搅拌过夜。去除氢气并且用氮气回填后,将反应混合物用300mL温水稀释并且过滤。将滤液浓缩至干以得到所需的产物。
C6H6N4O (M=231.1g/mol)
ESI-MS: 11[M-HBr+H]+
Rt(HPLC):0.12min(方法C)
中间体V
中间体V.1
2-(7-甲基-6-氧代-6,7-二氢-1H-嘌呤-1-基)乙腈
向0.750g(4.99mmol)的7-甲基-6,7-二氢-1H-嘌呤-6-酮在15mL DMF中的溶液中添加2.07g(15.0mmol)K2CO3并且将混合物在环境温度下搅拌30min。然后添加0.418mL(5.99mmol)溴乙腈并且将反应混合物在环境温度下搅拌过夜。将混合物过滤并且将获得的滤液浓缩。将沉淀物悬浮在二异丙醚中并且将剩余的固体通过过滤收集。将其用冷的二异丙醚进一步洗涤并且在真空下在50℃下干燥以得到所需的产物。
C8H7N5O (M=189.7g/mol)
ESI-MS: 190[M+H]+
Rt(HPLC): 0.18min(方法B)
中间体V.2
7-甲基-1-[(2H-1,2,3,4-四唑-5-基)甲基]-6,7-二氢-1H-嘌呤-6-酮
向1.27g(6.71mmol)的2-(7-甲基-6-氧代-6,7-二氢-1H-嘌呤-1-基)乙腈在15mL的DMF的混合物中添加0.480g(7.39mmol)的叠氮化钠和0.395g(7.39mmol)的氯化铵。将反应混合物加热至95℃并且在此温度下搅拌过夜。冷却至环境温度后,将沉淀物通过过滤收集并且用MeOH洗涤。将获得的固体在50℃下在真空干燥下以得到所需的产物。
C8H8N8O (M=232.2g/mol)
ESI-MS: 233[M+H]+
Rt(HPLC): 0.17min(方法B)
中间体V.3
1-({2-[2-(4-氯苯基)-2-氧代乙基]-2H-1,2,3,4-四唑-5-基}甲基)-7-甲基-6,7-二氢-1H-嘌呤-6-酮
向111mg(0.474mmol)的4-氯苯甲酰甲基溴在5mL ACN的溶液中添加100mg(0.431mmol)的7-甲基-1-[(2H-1,2,3,4-四唑-5-基)甲基]-6,7-二氢-1H-嘌呤-6-酮和83.3mg(0.603mmol)K2CO3。将反应混合物在70℃下搅拌过夜。冷却后,添加2.5mL的DMA,并且允许混合物在70℃下搅拌另外的14h。冷却至环境温度后,将反应混合物过滤、浓缩并且通过制备型HPLC(ACN/H2O/TFA梯度)纯化两次以得到所需的产物。
C16H13ClN8O2 (M=384.8g/mol)
ESI-MS: 385[M+H]+
Rt(HPLC): 0.82min(方法B)
最终化合物的制备
实施例1(通用途径)
3-({2-[(2R)-2-(4-氯苯基)-2-羟基乙基]-2H-1,2,3,4-四唑-5-基}甲基)-5-甲基-4-氧代-3H,4H-噻吩并[2,3-d]嘧啶-6-甲酰胺
将50.0mg(0.331mmol)的1-甲基-1H,6H,7H-[1,2,3]三唑并[4,5-d]嘧啶-7-酮添加至1.0mL DMF中。然后,添加137mg(0.993mmol)K2CO3和108.4g(0.397mmol)的中间体II.1并且将混合物在50℃下搅拌4h。冷却至RT后,将混合物用乙腈和甲醇稀释,过滤并且通过制备型HPLC(ACN/H2O/TFA)纯化以得到所需的产物。
C15H14ClN9O2 (M=387.8g/mol)
ESI-MS: 388[M+H]+
Rt(HPLC): 0.43min(方法B)
1H NMR(400MHz,DMSO-d6)δppm 4.36(s,3H),4.73-4.83(m,2H),5.12(dd,J=7.4,5.4Hz,1H),5.55(s,2H),5.61-6.38(br s,1H),7.31-7.43(m,4H),8.61(s,1H)。
根据上述通用程序(实施例1)制备以下化合物:
上表所述化合物的分析数据:
实施例9
1-({2-[(2R)-2-(4-氯苯基)-2-羟基乙基]-2H-1,2,3,4-四唑-5-基}甲基)-7-甲基-6,7-二氢-1H-嘌呤-6-酮
在惰性气氛下向在MeCN(1.0mL)中的30mg(0.078mmol)中间体V.3中添加0.194mg(0.32μmol)氯([(1S,2S)-(-)-2-氨基-1,2-二苯乙基](4-甲苯磺酰基)酰胺基)(均三甲基苯)钌(II)(CAS 174813-81-1),然后逐滴添加12μL(0.028mmol)甲酸三甲胺复合物(5:2)。将反应混合物在环境温度下搅拌3h。将混合物浓缩并且将残余物用水稀释。将混合物用EtOAc(2x)萃取。将合并的有机萃取物经MgSO4干燥,过滤并且通过制备型HPLC纯化。
C16H15ClN8O2 (M=386.8g/mol)
ESI-MS: 387[M+H]+
Rt(HPLC): 0.55min(方法G)
1H NMR(400MHz,DMSO-d6)δppm 3.96(s,3H),4.75-4.82(m,2H),5.12(dd,J=7.4,5.4Hz,1H),5.52(s,2H),7.34-7.42(m,4H),8.25(d,J=0.4Hz,1H),8.47(s,1H)。
分析型HPLC方法
方法A
分析柱:XBridge BEH C18_2.1x30mm,1.7μm;柱温:60℃
方法B
分析柱:Stable Bond(Agilent)1.8μm;3.0x30mm;柱温:60℃
方法C
分析柱:Sunfire(Waters)2.5μm;3.0x30mm;柱温:60℃
方法D
分析柱:XBridge C18_3.0x30mm_2.5μm(Waters);柱温:60℃
方法E
分析柱:XBridge C18_3.0x30mm_2.5μm;柱温:60℃
方法F
分析柱:XSelect HSS PFP 2.1x30mm,1.8μm;柱温:60℃
方法G
分析柱:Sunfire C18,3.0x30mm,2.5μm;柱温:60℃。
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