CN116249535A - 作为trpa1抑制剂的四唑衍生物 - Google Patents
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Abstract
本发明提供某些四唑衍生物,其为瞬态受体电位锚蛋白1(TRPA1)的抑制剂,且因此可用于治疗可通过抑制TRPA1治疗的疾病。亦提供含有其的药物组合物及制备所述化合物的方法。
Description
技术领域
本发明提供某些四唑衍生物,其为瞬态受体电位锚蛋白1(TRPA1)的抑制剂,且因此可用于治疗可通过抑制TRPA1治疗的疾病。亦提供含有其的药物组合物及制备所述化合物的方法。
背景技术
瞬态受体电位信道(TRP信道)为一组主要位于众多哺乳动物细胞类型的质膜上的电压闸控离子信道。存在约30个结构相关的TRP信道,分成以下各组:TRPA、TRPC、TRPM、TRPML、TRPN、TRPP及TRPV。瞬态受体电位阳离子通道亚家族A成员1(TRPA1),也称为瞬态受体电位锚蛋白1,为TRPA基因亚家族的唯一成员。在结构上,TRPA信道的特征为多个N末端锚蛋白重复序列(约14个在人类TRPA1的N末端),由此产生锚蛋白名称中的“A”(Montell,2005)。
TRPA1在皮肤及肺的背根神经节及结状神经节中的感觉神经元的质膜中以及小肠、结肠、胰脏、骨胳肌、心脏、脑、膀胱及淋巴细胞(https://www.proteinatlas.org/)以及人类肺纤维母细胞中大量表达。
TRPA1为已知的最佳环境刺激物传感器,产生躯体感觉模态,诸如疼痛、发冷及搔痒。TRPA1通过多种反应性亲电子刺激物(例如异硫氰酸烯丙酯、活性含氧物)以及非反应性化合物(例如伊西林(icilin))活化,涉及与哮喘、慢性肺阻塞性疾病(COPD)、特发性肺纤维化(IPF)或病毒感染后咳嗽相关的咳嗽或慢性特发性咳嗽以及敏感患者的咳嗽。(Song及Chang,2015;Grace及Belvisi,2011)。基于展示咳嗽诱导的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关系,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拮抗剂抑制由诸如香烟烟雾提取物(cigarette smoke extract,CSE)氧化压力、炎性介体释放及抗氧化剂基因表达下调的类咳嗽触发因素触发的钙信号传导(Lin等人,2015;Wang等人,2019)。TRPA1拮抗剂在有关异位性皮肤炎(Oh等人,2013;Wilson等人,2013)、接触性皮肤炎(Liu等人,2013)、牛皮癣相关的搔痒(Wilson等人,2013)及IL-31依赖性搔痒(Cevikbas等人,2014)的研究中是有效的。人类TRPA1功能获得已与家族性间歇性疼痛综合征相关(Kremeyer等人,2010)。TRPA1拮抗剂在偏头痛相关异常疼痛的行为模型中是有效的(Edelmayer等人,2012)。当与神经支配健康牙齿的三叉神经节中的TRPA1表达相比时,TRPA1在神经支配损伤牙齿的三叉神经节中选择性增加(Haas等人,2011)。已知若干麻醉剂为TRPA1激动剂,包括异氟醚(isoflurane)(Matta等人,2008),为TRPA1抑制剂缓解手术后疼痛提供理论基础。用TRPA1拮抗剂治疗的TRPA1基因剔除小鼠及野生型小鼠显示出抗焦虑及抗抑郁样表型(de Moura等人,2014)。基于显示AMPK及TRPA1之间反向调节的机制联系的研究,预期TRPA1抑制剂在治疗糖尿病性神经病变中具有益处(Hiyama等人,2018;Koivisto及Pertovaara,2013;Wang等人,2018)。与野生型小鼠相比,TRPA1基因剔除小鼠展现较小的心肌梗塞尺寸(Conklin等人,2019)。TRPA1基因剔除及药理干预抑制小鼠的TNBS诱发的结肠炎(Engel等人,2011)。在小鼠脑缺血模型中,TRPA1基因剔除及TRPA1拮抗剂减少髓鞘损伤(Hamilton等人,2016)。在痛风的尿酸单钠小鼠模型中,TRPA1基因剔除小鼠的尿酸盐晶体及关节发炎减少(Moilanen等人,2015)。在大鼠急性痛风发作模型中,大鼠中的TRPA1缺失改善关节发炎及痛觉过敏(Trevisan等人,2014)。TRPA1活化会在骨关节炎软骨细胞中引起发炎反应(Nummenmaa等人,2016)。TRPA1抑制及基因缺失减少小鼠骨关节炎软骨细胞及鼠类软骨中的发炎介体(Nummenmaa等人,2016)。最后,TRPA1基因剔除小鼠在MIA诱发膝部肿胀模型中展现患骨关节炎肢体上负重的改善(Horvath等人,2016)。TRPA1在大鼠膀胱上皮(Du等人,2007)及患有膀胱出口阻塞的患者(Du等人,2008)中有差异性表达。TRPA1受体调节使大鼠脊髓损伤模型中的膀胱过度活动减弱(Andrade等人,2011),且鞘内施用TRPA1拮抗剂减轻排尿反射亢进的大鼠的环磷酰胺诱发的膀胱炎(Chen等人,2016)。
因此,需要提供强效的TRPA1抑制剂。
各种结构类别的TRPA1抑制剂评述于S.Skerratt,Progress in MedicinalChemistry,2017,第56卷,81-115;D.Preti,G.Saponaro,A.Szallasi,Pharm.Pat.Anal.(2015)4(2),75-94;及H.Chen,Transient receptor potential ankyrin 1(TRPA1)antagonists:a patent review(2015-2019),Expert Opin Ther Pat.,2020中。
WO2017/060488公开作为TRPA1拮抗剂的化合物,其具有以下通用结构式:
未公开其中带有四唑基环的例子28及29的TRPA1活性。
L.Schenkel等人,J.Med.Chem.2016,59,2794-2809公开基于喹唑啉酮的TRPA1拮抗剂,其包括以下通用结构式的化合物:
其中公开R为OH的化合物31在FLIPR分析中具有IC50为58nM的TRPA1拮抗活性,且在人类肝脏微粒体中具有<14μL/min/kg的固有清除率。
具体实施方式
本发明公开新颖四唑衍生物,其为瞬态受体电位锚蛋白1(TRPA1)的抑制剂,具有适当的药理学及药物动力学特性,使得其能够用作治疗可通过抑制TRPA1治疗的病状和/或疾病的药剂。
本发明的化合物可提供若干优点,诸如增强的效力、高代谢和/或化学稳定性、高选择性、安全性及耐受性、增强的溶解性、增强的渗透性、希望的血浆蛋白质结合、增强的生物可用性、适合的药物动力学型态及形成稳定盐的可能性。
本发明的化合物
本发明提供新颖四唑衍生物,其出人意料地作为TRPA1的强效抑制剂(分析A),且其他特征在于:
-人类肝脏微粒体中改良的稳定性(分析B)
-人类肝细胞中改良的稳定性(分析C)
本发明的化合物在结构上与WO2017/060488中的例子28及29的不同在于:其呋喃并[2,3-d]哒嗪酰基核心以及邻近于二级脂族醇的取代基。另外,本发明的化合物在结构上与L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的例子31的不同在于,本发明的化合物具有四唑基环。这些结构差异意外地引起以下的有利组合:(i)TRPA1的抑制、(ii)在人类肝脏微粒体中的稳定性及(iii)在人类肝细胞中的稳定性。
因此,本发明的化合物在以下参数的组合方面优于背景技术中公开的化合物:
-作为TRPA1抑制剂的效力
-在人类肝脏微粒体中的稳定性
-在人类肝细胞中的稳定性。
在人类肝脏微粒体中的稳定性是指在选择和/或设计具有有利药物动力学特性的药物作为第一筛选步骤的情形中化合物对生物转化的敏感性。许多药物的主要代谢部位为肝脏。人类肝脏微粒体含有细胞色素P450(CYP),且因此表示用于在体外研究I期药物代谢的模型系统。在人类肝脏微粒体中的稳定性增强与包括生物可用性增加及适当半衰期在内的若干优点相关,由此可使患者能够较少且不太频繁的给药。因此,在人类肝脏微粒体中的稳定性增强为打算用于药物的化合物的有利特征。因此,除能够抑制TRPA1以外,预期本发明的化合物在人体中还具有有利的体内清除率且因此具有所需的作用持续时间。
在人类肝细胞中的稳定性是指在选择和/或设计具有有利药物动力学特性的药物的情形中化合物对生物转化的敏感性。许多药物的主要代谢部位为肝脏。人类肝细胞含有细胞色素P450(CYP)及其他药物代谢酶,且因此表示用于在体外研究药物代谢的模型系统。(重要地是,与肝脏微粒体分析相比,肝细胞分析亦涵盖II期生物转化以及肝脏特异性转运体介导的过程,且因此表示用于药物代谢研究的更完整系统。)在人类肝细胞中的稳定性增强与包括生物可用性增加及适当半衰期在内的若干优点相关,由此能够使患者较少且不太频繁的给药。因此,在人类肝细胞中的稳定性增强为打算用于药物的化合物的有利特征。
本发明提供根据式(I)的新颖化合物
其中
A选自由以下组成的组:苯基、噻吩基、苯并噻吩基及苯并呋喃基,其未经取代或经群组R3的一个或两个成员取代,该群组由以下组成:-CN、卤素、C1-4烷基、O-C1-4烷基、C1-4氟烷基、O-C1-4氟烷基、C3-4环烷基、O-C3-4环烷基、C3-4环氟烷基及O-C3-4环氟烷基;
R1为H、H3C或H2N(O)C;
且
R2为H3C或H2N(O)C;
其限制条件为:
当R1为H2N(O)C时,R2为H3C;
当R2为H2N(O)C时,R1为H或H3C。
本发明的另一实施方案涉及一种式(I)化合物,其中
A选自由以下组成的组:
其未经取代或经该群组R3的一个或两个成员取代;
且取代基R1及R2如前述实施方案中的任一者中所定义。
本发明的另一实施方案涉及一种式(I)化合物,其中R3选自由以下组成的组:Br、Cl、F及H3C,且取代基A、R1及R2如前述实施方案中的任一者中所定义。
本发明的另一实施方案涉及一种式(I)化合物,其中
A选自由以下组成的组:
及
且取代基R1及R2如前述实施方案中的任一者中所定义。
本发明的另一实施方案涉及一种式(I)化合物,其中
R1为H3C且R2为H2N(O)C;
且取代基A及R3如前述实施方案中的任一者中所定义。
本发明的另一实施方案涉及一种式(I)化合物,其中
R1为H2N(O)C且R2为H3C;
且取代基A及R3如前述实施方案中的任一者中所定义。
优选选自由以下组成的组的式(I)化合物:
及
且取代基A如前述实施方案中的任一者中所定义。
尤其优选选自由以下组成的组的根据式(I)的化合物:
及
所用术语及定义
本文未具体定义的术语应具有本领域技术人员根据公开内容及上下文而提供的所述术语的含义。然而,除非有相反说明,否则如本说明书中所使用,以下术语具有所指定的含义且将遵守以下惯例。
在下文所定义的基团(group)、基团(radical)或部分中,碳原子数目通常在该基团之前指定,例如C1-6烷基意谓具有1至6个碳原子的烷基(alkyl group/alkyl radical)。一般而言,在基团如HO、H2N、(O)S、(O)2S、NC(氰基)、HOOC、F3C或类似基团中,本领域技术人员可看到自基团自身的自由价至分子的基团连接点。对于包含两个或多于两个子基团的组合基团,最后命名的子基团为基团连接点,例如取代基“芳基-C1-3烷基”意谓与C1-3烷基-结合的芳基,该C1-3烷基-与核心或与该取代基所连接的基团结合。
倘若以化学名称及化学式形式描绘本发明的化合物,在有任何分歧的情况下,将以化学式为凖。可在子化学式中使用星号来指示连接至如所定义的核心分子的键。
取代基各原子的编号始于最接近核心或最接近取代基所连接的基团的原子。
举例而言,术语“3-羧基丙基-基团”表示以下取代基:
其中羧基连接至丙基的第三个碳原子。术语“1-甲基丙基-”、“2,2-二甲基丙基-”或“环丙基甲基-”表示以下基团:
可在子化学式中使用星号来指示连接至如所定义的核心分子的键。
单独或与另一基团组合的术语“C1-n烷基”表示具有1至n个C原子的非环状、饱和、分支链或直链烃基,其中n为选自2、3、4或5的整数。举例而言,术语C1-5烷基涵盖基团H3C-、H3C-CH2-、H3C-CH2-CH2-、H3C-CH(CH3)-、H3C-CH2-CH2-CH2-、H3C-CH2-CH(CH3)-、H3C-CH(CH3)-CH2-、H3C-C(CH3)2-、H3C-CH2-CH2-CH2-CH2-、H3C-CH2-CH2-CH(CH3)-、H3C-CH2-CH(CH3)-CH2-、H3C-CH(CH3)-CH2-CH2-、H3C-CH2-C(CH3)2-、H3C-C(CH3)2-CH2-、H3C-CH(CH3)-CH(CH3)-及H3C-CH2-CH(CH2CH3)-。
术语“氟”添加至“烷基”、“亚烷基”或“环烷基”(饱和或不饱和)中意谓一个或多个氢原子经氟原子置换的此类烷基或环烷基。实施例包括但不限于:H2FC-、HF2C-及F3C-。
术语苯基是指以下环的基团:
术语噻吩基是指以下环的基团:
术语苯并噻吩基是指以下环的基团:
术语苯并呋喃基是指以下环的基团:
术语呋喃并[2,3-d]哒嗪酰基是指以下环的基团:
术语四唑是指以下环的基团:
如本文所用,术语“经取代”意谓指定原子上的任一个或多个氢经来自指定群组的选择置换,其限制条件为不超过指定原子的正常价态,且取代产生稳定化合物。
除非特别指示,否则在整个说明书及随附权利要求书中,给定化学式或名称应涵盖其互变异构物及所有立体异构物、光学异构物及几何异构物(例如镜像异构物、非镜像异构物、E/Z异构物等)及外消旋物,以及呈不同比例的各别镜像异构物的混合物、非镜像异构物的混合物或存在此类异构物及镜像异构物之前述形式中的任一者的混合物,以及盐,包括其药学上可接受的盐,及其溶剂合物,诸如水合物,包括游离化合物的溶剂合物或化合物的盐的溶剂合物。
一般而言,实质上纯的立体异构物可根据本领域技术人员已知的合成原理获得,例如通过分离相应混合物、通过使用立体化学纯起始物质和/或通过立体选择性合成来获得。本领域已知如何制备光学活性形式,诸如通过解析外消旋形式,或通过例如自光学活性起始物质起始来合成,和/或通过使用手性试剂。
本发明的镜像异构性纯化合物或中间体可经由不对称合成来制备,例如通过制备且随后分离适当非镜像异构化合物或中间体,其可通过已知方法(例如通过色谱分离或结晶)分离;和/或通过使用手性试剂,诸如手性起始物质、手性催化剂或手性助剂。
此外,本领域技术人员已知如何自相应外消旋混合物制备镜像异构性纯化合物,诸如通过在手性固定相上色谱分离相应外消旋混合物;或通过使用适当解析剂解析外消旋混合物,例如借助于外消旋化合物与光学活性酸或碱形成非镜像异构盐,随后解析所述盐且自该盐释放所需化合物;或通过用光学活性手性辅助试剂使相应外消旋化合物衍生化,随后分离非镜像异构物并移除手性辅助基团;或通过对外消旋体进行动力学解析(例如通过酶解析);通过在适合条件下自镜像晶体的聚结物进行镜像选择性结晶;或通过在光学活性手性助剂存在下自适合溶剂(分步)结晶。
词组“药学上可接受”在本文中用于指在合理医学判断的范围内,适于使用而无过度毒性、刺激、过敏性反应或其他问题或并发症且与合理的效益/风险比相称的化合物、材料、组合物和/或剂型。
如本文所用,“药学上可接受的盐”是指所公开化合物的衍生物,其中母化合物与酸或碱形成盐或络合物。与含有碱性部分的母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,诸如苯磺酸、苯甲酸、柠檬酸、乙烷磺酸、反丁烯二酸、龙胆酸、氢溴酸、氢氯酸、顺丁烯二酸、苹果酸、丙二酸、杏仁酸、甲烷磺酸、4-甲基-苯磺酸、磷酸、水杨酸、丁二酸、硫酸及酒石酸。
与含有酸性部分的母化合物形成药学上可接受的盐的阳离子及碱的例子包括Na+、K+、Ca2+、Mg2+、NH4 +、L-精氨酸、2,2'-亚胺双乙醇、L-赖氨酸、N-甲基-D-葡糖胺或三(羟基甲基)-氨基甲烷。本发明的药学上可接受的盐可通过常规化学方法自含有碱性或酸性部分的母化合物合成。一般而言,此类盐可通过使这些化合物的游离酸或游离碱形式与足量适当碱或酸于水或于有机稀释剂如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物中反应来制备。
可用于例如纯化或分离本发明的化合物的除上文所提及的酸外的其他酸的盐(例如三氟乙酸盐)亦构成本发明的一部分。
生物分析
TRPA1活性的评估
分析A:TRPA1分析
可使用以下体外TRPA1细胞分析来证实本发明的化合物的活性:
方法:
使用过度表达人类TRPA1离子通道的人类HEK293细胞株(Perkin Elmer,产品编号AX-004-PCL)作为化合物功效及效力的测试系统。通过在FLIPRtetra系统(MolecularDevices)中测量化合物对由异硫氰酸烯丙酯(Allylisothiocyanat,AITC)促效作用诱导的细胞内钙浓度的影响来测定化合物活性。
细胞培养:
细胞在冷冻小瓶中以冷冻细胞形式获得且在-150℃储存待用。
使细胞在培养基(具有10% FCS及0.4mg/ML遗传霉素(Geneticin)的MEM/EBSS培养基)中生长。重要的是,密度不超过90%汇合。对于继代培养,利用Versene将细胞自烧瓶分离。在分析前一天,将细胞分离,用培养基(具有10% FCS的MEM/EBSS培养基)洗涤两次,且将20000个细胞以每孔20μl接种至来自Corning的聚D-赖氨酸生物涂布的384孔盘(黑色,透明底部,目录号356697)中。将各盘在37℃/5% CO2下培育24小时,随后用于分析中。
化合物制备
将测试化合物以10mM的浓度溶解于100% DMSO中,且在第一步骤中在DMSO中稀释至5mM的浓度,之后在100% DMSO中进行连续稀释步骤。稀释因子及稀释步骤的数目可根据需要而变化。通常按1:5稀释度制备8种不同浓度,使用HBSS/HEPES缓冲液(来自Gibco的1×HEPES,目录号14065;来自SIGMA的20mM HEPES,目录号83264;来自Invitrogen的pH 7.4的0.1% BSA,目录号11926)对物质进行进一步中间稀释(1:20)。
FLIPR分析:
在分析日,用分析缓冲液洗涤细胞3次,在洗涤之后,有20μL缓冲液残留在孔中。将10μL于HBSS/HEPES中的Ca6试剂盒(目录号R8191 MolecularDevices)上样缓冲液添加至细胞中且将所述盘在盖存在下在37℃/5% CO2下培育120分钟。将10μL来自中间稀释盘的于HBSS/HEPES缓冲液/5% DMSO中的化合物或对照物小心地添加至孔中。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(例如促效作用)。最后,将10μL溶解于HBSS/HEPES缓冲液/0.05% DMSO(最终浓度为10μM)中的50μM激动剂AITC添加至孔中,随后在FLIPRtetra装置上再读取10分钟。使用在添加AITC之后的信号曲线下面积(AUC)计算IC50/抑制%。
数据评估及计算:
每个分析微量滴定盘含有具有媒剂(1% DMSO)对照而非化合物的孔作为AITC诱导的发光的对照(100% CTL;高对照),且含有具有媒剂对照且无AITC的孔作为发光的非特异性变化的对照(0% CTL;低对照)。
通过计算个别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(内部研发)计算用于测量各物质浓度的%值(AUC(样品)-AUC(低))×100/(AUC(高)-AUC(低))。使用MegaLab软件自对照值%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=峰;y=对照%
表1:分析A中获得的本发明的化合物的生物资料
表2:在分析A中获得的背景技术化合物(WO2017/060488中的例子28及29)的生物资料。
表3:在分析A中获得的背景技术化合物(L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的例子31)的生物数据。
微粒体清除率的评估
分析B:微粒体清除率:
在37℃下使用汇集的肝脏微粒体来分析测试化合物的代谢降解。每个时间点100μl的最终培育体积在室温下含有TRIS缓冲液pH 7.6(0.1M)、氯化镁(5mM)、微粒体蛋白质(1mg/ml)及最终浓度为1μM的测试化合物。
在37℃下预培育较短时段之后,通过添加呈还原形式的β-烟酰胺腺嘌呤二核苷酸磷酸(NADPH,1mM)起始且通过在不同时间点(0、5、15、30、60分钟)之后将等分试样转移至溶剂中终止反应。另外,监测在不含NADPH的培育物中的NADPH非依赖性降解,在最后时间点终止。在NADPH非依赖性培育之后的残留测试化合物[%]为由参数c(对照)反映(代谢稳定性)。通过离心(10000g,5分钟)使经淬灭的培育物沉淀。
通过LC-MS/MS分析上清液的等分试样中的母化合物的量。通过浓度-时间曲线的半对数标绘图的斜率来测定半衰期(t1/2体外)。
通过考虑培育物中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]×MPPGL[mg蛋白质/g肝脏]×肝脏因子[g/kg体重])/1000
Qh[%]=CL[ml/min/kg]/肝血流量[ml/min/kg])
人类肝细胞数:120×10e6个细胞/g肝脏
人类肝脏因子:25.7g/kg体重
人类血流量:21ml/(min×kg)
表4:分析B中获得的本发明的化合物的生物资料
表5:分析B中获得的背景技术化合物(WO2017/060488中的例子28及29)的生物资料。
表6:分析B中获得的背景技术化合物(L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的例子31)的生物数据。
肝细胞清除率的评估
分析C:肝细胞清除率
在肝细胞悬浮液中分析测试化合物的代谢降解。将肝细胞(经冷冻保存)在含有5%物种血清的Dulbecco改良型eagle培养基(补充有3.5μg升糖素/500mL、2.5mg胰岛素/500mL及3.75mg/500mL氢皮质酮)中培育。
在培育箱(37℃,10% CO2)中预培育30分钟后,将5μl测试化合物溶液(80μM;自2mM于DMSO储备溶液中的溶液用培养基按1:25稀释)添加至395μl肝细胞悬浮液(取决于物种,细胞密度在0.25至5百万个细胞/毫升范围内,通常为1百万个细胞/毫升;测试化合物的最终浓度为1μM,最终DMSO浓度为0.05%)中。
将细胞培育六小时(培育箱,回转式震荡器)且在0、0.5、1、2、4及6小时获取样品(25μl)。将样品转移至乙腈中,且通过离心(5分钟)使其沉淀。将上清液转移至新的96深孔盘中,在氮气下蒸发且再悬浮。
通过HPLC-MS/MS分析母化合物的减少。
CLint如下计算:CL_INTRINSIC=剂量/AUC=(C0/CD)/(AUD+clast/k)×1000/60。C0:培育物中的初始浓度[μM],CD:活细胞的细胞密度[10e6个细胞/毫升],AUD:资料下的面积[μM×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]。
所计算的体外肝固有清除率可按比例扩大而得到体内固有肝清除率,且使用该肝清除率,通过使用肝脏模型(良好搅拌模型)来预测体内肝血液清除率(CL)。
CL_INTRINSIC_INVIVO[ml/min/kg]=(CL_INTRINSIC[μL/min/10e6个细胞]×肝细胞数[10e6个细胞/g肝脏]×肝脏因子[g/kg体重])/1000
CL[ml/min/kg]=CL_INTRINSIC_INVIVO[ml/min/kg]×肝血流量[ml/min/kg]/(CL_INTRINSIC_INVIVO[ml/min/kg]+肝血流量[ml/min/kg])
Qh[%]=CL[ml/min/kg]/肝血流量[ml/min/kg])
人类肝细胞数:120×10e6个细胞/g肝脏
人类肝脏因子:25.7g/kg体重
人类血流量:21ml/(min×kg)
表7:分析C中获得的本发明的化合物的生物资料
实施例 | 人类肝细胞[%Qh] |
1 | 4 |
2 | 23 |
3 | 5 |
4 | 30 |
5 | 23 |
6 | 24 |
7 | 15 |
8 | 14 |
9 | 16 |
10 | <4 |
11 | 8 |
12 | 16 |
13 | 22 |
14 | 42 |
15 | 21 |
表8:分析C中获得的背景技术化合物(WO2017/060488中的例子28及29)的生物资料。
表9:分析C中获得的背景技术化合物(L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的例子31)的生物数据。
评估渗透性
将Caco-2细胞(1-2×105个细胞/1cm2面积)接种于过滤器插入件(Costartranswell聚碳酸酯或PET过滤器,0.4μm孔径)上并培养(DMEM)达10至25天。
将化合物溶解于适当溶剂(如DMSO,1-20mM储备溶液)中。用HTP-4缓冲液(128.13mM NaCl、5.36mM KCl、1mM MgSO4、1.8mM CaCl2、4.17mM NaHCO3、1.19mM Na2HPO4×7H2O、0.41mM NaH2PO4×H2O、15mM HEPES、20mM葡萄糖、0.25% BSA,pH 7.2)稀释储备溶液以制备转运溶液(0.1-300μM化合物,最终DMSO<=0.5%)。将转运溶液(TL)施加至顶部或底外侧供体侧以分别测量A-B或B-A渗透性(重复过滤3次)。在实验开始及最后自供体收集样品,且亦在至多2小时内的各个时间间隔自接收器侧收集样品,通过HPLC-MS/MS或闪烁计数进行浓度测量。用新鲜接收器溶液更换取样后的接收器体积。
评估血浆蛋白质结合
此平衡透析(ED)技术为用于测定测试化合物与血浆蛋白质的近似体外部分结合。使用Dianorm铁氟龙透析槽(0.2微米)。每个槽由经具有5kDa分子量截止值的超薄半透膜隔开的供体及受体室组成。在DMSO中制备1mM的各测试化合物的储备溶液且将其稀释至1.0μM的最终浓度。后续透析溶液以自雄性及雌性供体汇集的人类或大鼠血浆(具有NaEDTA)制备。将200μL透析缓冲液(100mM磷酸钾,pH 7.4)的等分试样分配至缓冲液室中。将200μL测试化合物透析溶液的等分试样分配至血浆室中。在37℃下,在旋转下培育2小时。
在透析期结束时,将透析液转移至反应管中。用于缓冲液部分的管含有0.2mLACN/水(80/20)。将25μL血浆透析液的等分试样转移至深孔盘中且与25μl ACN/水(80/20)、25μL缓冲液、25μL校准溶液及25μL内标溶液混合。通过添加200μL ACN进行蛋白质沉淀。将50μL缓冲液透析液的等分试样转移至深孔盘中且与25μL空白血浆、25μL内标溶液及200μLACN混合。在HPLC-MS/MS系统上测量样品且借助于Analyst软件加以评估。通过下式计算结合百分比:结合%=(血浆浓度-缓冲液浓度/血浆30浓度)×100。
评估溶解性
在孔盘(格式取决于机器人)中,通过将适当体积的所选水性培养基(通常在0.25-1.5ml范围内)添加至含有已知量的固体原料药(通常在0.5至5.0mg范围内)的各孔中来制备饱和溶液。将孔震荡或搅拌预定时间段(通常在2-24小时范围内)且随后使用适当的滤膜(通常为具有0.45μm孔径的PTFE过滤器)过滤。通过丢弃前几滴滤液来避免过滤器吸收。通过UV光谱分析来确定经溶解的原料药的量。另外,使用玻璃电极pH计测量饱和水溶液的pH值。
评估药物动力学特征
将测试化合物经静脉内或经口施用各别测试物种。在施用测试化合物后若干时间点采集血液样品,进行抗凝且离心。
对血浆样品中的分析物,即所施用的化合物和/或代谢物的浓度进行定量。使用非室体模型方法计算PK参数。将AUC及Cmax针对1μmol/kg剂量标准化。
评估体外在人类肝细胞中的代谢
使用呈悬浮液形式的初代人类肝细胞来研究测试化合物的代谢路径。在自冷冻保存恢复之后,将人类肝细胞在含有5%人类血清并补充有3.5μg升糖素/500ml、2.5mg胰岛素/500ml及3.75mg/500ml氢皮质酮的Dulbecco改良型eagle培养基中培育。
在细胞培养培育箱(37℃,10% CO2)中预培育30分钟之后,将测试化合物溶液掺入肝细胞悬浮液中以获得1.0×106至4.0×106个细胞/毫升的最终细胞密度(取决于利用初代人类肝细胞观察到的化合物的代谢转换速率)、10μM的最终测试化合物浓度及0.05%的最终DMSO浓度。
将细胞在水平震荡器上的细胞培养培育箱中培育六小时,且根据代谢转换速率,在0、0.5、1、2、4或6小时之后自培育物取出样品。将样品用乙腈淬灭且通过离心使其沉淀。将上清液转移至96孔深孔盘中,在氮气下蒸发且使其再悬浮,随后通过液相色谱-高分辨率质谱进行生物分析以鉴别推定的代谢物。
基于Fourier-Transform-MSn数据临时地指定结构。代谢物以人类肝细胞培育物中母体的百分比报导,且临限值为≥4%。
治疗方法
本发明涉及通式1的化合物,其可用于预防和/或治疗与TRPA1活性相关或由TRPA1活性调节的疾病和/或病状,包括但不限于治疗和/或预防纤维变性疾病、炎性及免疫调节病症、呼吸道或胃肠道疾病或不适、眼科疾病、关节的炎性疾病以及鼻咽、眼睛及皮肤的炎性疾病、以及疼痛及神经病症。所述病症、疾病及不适包括咳嗽、特发性肺纤维化、其他肺间质性疾病及其他纤维变性、哮喘或过敏性疾病、嗜伊红血球性疾病、慢性阻塞性肺病,以及炎性及免疫调节病症,诸如类风湿性关节炎及动脉粥样硬化,以及疼痛及神经病症,诸如急性疼痛、手术疼痛、慢性疼痛以及抑郁症及膀胱病症。
通式1的化合物可用于预防和/或治疗:
(1)咳嗽,诸如慢性特发性咳嗽或慢性难治性咳嗽、与哮喘、COPD、肺癌、病毒感染后及特发性肺纤维化以及其他肺间质性疾病相关的咳嗽。
(2)肺纤维变性疾病,诸如与胶原变性,例如红斑狼疮、全身性硬皮病、类风湿性关节炎、多发性肌炎及皮肌炎相关的肺炎或间质性肺炎;特发性间质性肺炎,诸如肺部肺纤维化(IPF)、非特异性间质性肺炎、呼吸性细支气管炎相关性间质性肺病、脱屑性间质性肺炎、隐源性机化性肺炎、急性间质性肺炎及淋巴细胞性间质性肺炎;淋巴管平滑肌瘤病;肺泡蛋白沉积症;朗格汉氏细胞(Langerhan's cell)组织细胞增生症;肋膜肺实质弹性纤维增生;已知病因的间质性肺病,诸如由职业暴露引起的间质性肺炎,诸如石棉沉着病、硅肺病、矿工肺(煤尘)、农夫肺(干草及霉菌)、饲鸽者肺(鸟类)或其他职业性空气传播的触发因素诸如金属粉尘或分枝杆菌,或由诸如放射、甲胺喋呤(methotrexate)、胺碘酮(amiodarone)、呋喃妥因(nitrofurantoin)或化学治疗剂的类治疗引起的间质性肺炎;或肉芽肿性疾病,诸如肉芽肿性多血管炎、查格-施特劳斯氏综合征(Churg-Strauss syndrome)、类肉瘤病、过敏性肺炎或由不同来源(例如抽吸、吸入有毒气体、蒸气、支气管炎或肺炎)引起的间质性肺炎;或由心脏衰竭、X射线、放射、化学疗法、M.boeck或类肉瘤病、肉芽肿病、囊性纤维化或黏液黏稠病或α-1抗胰蛋白酶缺乏症引起的间质性肺炎。
(3)其他纤维变性疾病,诸如肝桥纤维化、肝硬化、非酒精性脂肪变性肝炎(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、动脉硬化、关节纤维化、迪皮特朗氏挛缩(Dupuytren's contracture)、瘢痕瘤、硬皮病/全身性硬化症、纵隔纤维化、骨髓纤维化、佩洛尼氏病(Peyronie's disease)、肾源性全身性纤维化、腹膜后纤维化、黏黏性关节囊炎。
(4)炎性、自体免疫性或过敏性疾病及病状,诸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-鼻窦炎、急性鼻-鼻窦炎、哮喘、小儿哮喘、过敏性支气管炎、肺泡炎、气道高反应性、过敏性结膜炎、支气管扩张、成人呼吸窘迫综合征、支气管及肺水肿、支气管炎或肺炎、嗜伊红血球性蜂窝组织炎(例如威尔氏综合征(Well'ssyndrome))、嗜伊红血球性肺炎(例如勒夫勒氏综合征(Loeffler's syndrome)、慢性嗜伊红血球性肺炎)、嗜伊红血球性筋膜炎(例如舒尔曼氏综合征(Shulman's syndrome))、迟发型过敏、非过敏性哮喘;运动诱发的支气管收缩;慢性阻塞性肺病(COPD)、急性支气管炎、慢性支气管炎、咳嗽、肺气肿;全身性重度过敏或过敏性反应、药物过敏(例如对青霉素、头孢菌素过敏)、由摄入受污染的色氨酸引起的嗜伊红血球增多-肌痛综合征、昆虫蜇伤过敏;自体免疫性疾病,诸如类风湿性关节炎、格雷夫氏病(Graves'disease)、休格连氏综合征(Sjogren's syndrome)、牛皮癣性关节炎、多发性硬化症、全身性红斑狼疮、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)、免疫性溶血性贫血(自体免疫性及药物诱发)、伊凡氏综合征(Evans syndrome)(血小板及红血球免疫性血细胞减少症)、新生儿Rh病、古巴斯德氏综合征(Goodpasture's syndrome)(抗GBM疾病)、乳糜泻、自体免疫性心肌病、青少年发病型糖尿病;丝球体肾炎、自体免疫性甲状腺炎、白塞氏病(Behcet's disease);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疾病;炎性肠病,诸如克罗恩氏病(Crohn's disease)及溃疡性结肠炎;脊椎关节病;硬皮病;牛皮癣(包括T细胞介导型牛皮癣)及炎性皮肤病,诸如皮肤炎、湿疹、异位性皮肤炎、过敏性接触性皮肤炎、风疹;血管炎(例如坏死性、皮肤性及过敏性血管炎);结节性红斑;嗜伊红血球性肌炎、嗜伊红血球性筋膜炎、伴随皮肤或器官的白血球浸润的癌症;眼科疾病,诸如年龄相关的黄斑变性、糖尿病性视网膜病变及糖尿病性黄斑水肿、角膜炎、嗜伊红血球性角膜炎、角膜结膜炎、春季角膜结膜炎、瘢痕形成、前段瘢痕形成、睑缘炎、睑结膜炎、大疱性疾病、瘢痕性类天疱疮、结膜黑素瘤、乳头状结膜炎、干眼症、上巩膜炎、青光眼、神经胶瘤病、环状肉芽肿、格雷夫氏眼病(Graves'ophthalmopathy)、眼内黑素瘤、睑裂斑、增生性玻璃体视网膜病变、翼状胬肉、巩膜炎、眼色素层炎、急性痛风发作、痛风或骨关节炎。
(5)疼痛,诸如慢性特发性疼痛综合征、神经性病变疼痛、感觉迟钝、触摸痛、偏头痛、牙痛及术后疼痛。
(6)抑郁症、焦虑症、糖尿病性神经病及膀胱病症,诸如膀胱出口阻塞、膀胱过动症、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的化合物的用途,其用于治疗和/或预防与TRPA1活性相关或由TRPA1活性调节的疾病和/或病状。
此外,本发明涉及通式1的化合物的用途,其用于治疗和/或预防纤维变性疾病、炎性及免疫调节病症、呼吸道或胃肠道疾病或不适、眼科疾病、关节的炎性疾病以及鼻咽、眼睛及皮肤的炎性疾病、疼痛及神经病症。所述病症、疾病及不适包括咳嗽、特发性肺纤维化、其他肺间质性疾病及其他纤维变性、哮喘或过敏性疾病、嗜伊红血球性疾病、慢性阻塞性肺病,以及炎性及免疫调节病症,诸如类风湿性关节炎及动脉粥样硬化,以及疼痛及神经病症,诸如急性疼痛、手术疼痛、慢性疼痛以及抑郁症及膀胱病症。
此外,本发明涉及通式1的化合物的用途,其用于治疗和/或预防:
(1)咳嗽,诸如慢性特发性咳嗽或慢性难治性咳嗽、与哮喘、COPD、肺癌、病毒感染后及特发性肺纤维化以及其他肺间质性疾病相关的咳嗽。
(2)肺纤维变性疾病,诸如与胶原变性,例如红斑狼疮、全身性硬皮病、类风湿性关节炎、多发性肌炎及皮肌炎相关的肺炎或间质性肺炎;特发性间质性肺炎,诸如肺部肺纤维化(IPF)、非特异性间质性肺炎、呼吸性细支气管炎相关性间质性肺病、脱屑性间质性肺炎、隐源性机化性肺炎、急性间质性肺炎及淋巴细胞性间质性肺炎;淋巴管平滑肌瘤病;肺泡蛋白沉积症;朗格汉氏细胞组织细胞增生症;肋膜肺实质弹性纤维增生;已知病因的间质性肺病,诸如由职业暴露引起的间质性肺炎,诸如石棉沉着病、硅肺病、矿工肺(煤尘)、农夫肺(干草及霉菌)、饲鸽者肺(鸟类)或其他职业性空气传播的触发因素诸如金属粉尘或分枝杆菌,或由诸如放射、甲胺喋呤、胺碘酮、呋喃妥因或化学治疗剂的类治疗引起的间质性肺炎;或肉芽肿性疾病,诸如肉芽肿性多血管炎、查格-施特劳斯氏综合征(Churg-Strausssyndrome)、类肉瘤病、过敏性肺炎或由不同来源(例如抽吸、吸入有毒气体、蒸气、支气管炎或肺炎)引起的间质性肺炎;或由心脏衰竭、X射线、放射、化学疗法、M.boeck或类肉瘤病、肉芽肿病、囊性纤维化或黏液黏稠病或α-1抗胰蛋白酶缺乏症引起的间质性肺炎。
(3)其他纤维变性疾病,诸如肝桥纤维化、肝硬化、非酒精性脂肪变性肝炎(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、动脉硬化、关节纤维化、迪皮特朗氏挛缩、瘢痕瘤、硬皮病/全身性硬化症、纵隔纤维化、骨髓纤维化、佩洛尼氏病、肾源性全身性纤维化、腹膜后纤维化、黏黏性关节囊炎。
(4)炎性、自体免疫性或过敏性疾病及病状,诸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-鼻窦炎、急性鼻-鼻窦炎、哮喘、小儿哮喘、过敏性支气管炎、肺泡炎、气道高反应性、过敏性结膜炎、支气管扩张、成人呼吸窘迫综合征、支气管及肺水肿、支气管炎或肺炎、嗜伊红血球性蜂窝组织炎(例如威尔氏综合征)、嗜伊红血球性肺炎(例如勒夫勒氏综合征、慢性嗜伊红血球性肺炎)、嗜伊红血球性筋膜炎(例如舒尔曼氏综合征)、迟发型过敏、非过敏性哮喘;运动诱发的支气管收缩;慢性阻塞性肺病(COPD)、急性支气管炎、慢性支气管炎、咳嗽、肺气肿;全身性重度过敏或过敏性反应、药物过敏(例如对青霉素、头孢菌素过敏)、由摄入受污染的色氨酸引起的嗜伊红血球增多-肌痛综合征、昆虫蜇伤过敏;自体免疫性疾病,诸如类风湿性关节炎、格雷夫氏病、休格连氏综合征、牛皮癣性关节炎、多发性硬化症、全身性红斑狼疮、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)、免疫性溶血性贫血(自体免疫性及药物诱发)、伊凡氏综合征(血小板及红血球免疫性血细胞减少症)、新生儿Rh病、古巴斯德氏综合征(抗GBM疾病)、乳糜泻、自体免疫性心肌病、青少年发病型糖尿病;丝球体肾炎、自体免疫性甲状腺炎、白塞氏病;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疾病;炎性肠病,诸如克罗恩氏病及溃疡性结肠炎;脊椎关节病;硬皮病;牛皮癣(包括T细胞介导型牛皮癣)及炎性皮肤病,诸如皮肤炎、湿疹、异位性皮肤炎、过敏性接触性皮肤炎、风疹;血管炎(例如坏死性、皮肤性及过敏性血管炎);结节性红斑;嗜伊红血球性肌炎、嗜伊红血球性筋膜炎、伴随皮肤或器官的白血球浸润的癌症;眼科疾病,诸如年龄相关的黄斑变性、糖尿病性视网膜病变及糖尿病性黄斑水肿、角膜炎、嗜伊红血球性角膜炎、角膜结膜炎、春季角膜结膜炎、瘢痕形成、前段瘢痕形成、睑缘炎、睑结膜炎、大疱性疾病、瘢痕性类天疱疮、结膜黑素瘤、乳头状结膜炎、干眼症、上巩膜炎、青光眼、神经胶瘤病、环状肉芽肿、格雷夫氏眼病、眼内黑素瘤、睑裂斑、增生性玻璃体视网膜病变、翼状胬肉、巩膜炎、眼色素层炎、急性痛风发作、痛风或骨关节炎。
(5)疼痛,诸如慢性特发性疼痛综合征、神经性病变疼痛、感觉迟钝、触摸痛、偏头痛、牙痛及术后疼痛。
(6)抑郁症、焦虑症、糖尿病性神经病及膀胱病症,诸如膀胱出口阻塞、膀胱过动症、膀胱炎;心肌再灌注损伤或脑缺血损伤。
在另一方面中,本发明涉及一种通式1的化合物,其用于治疗和/或预防上文所提及的疾病及病状。
在另一方面中,本发明涉及通式1的化合物的用途,其用于制备供治疗和/或预防上文所提及的疾病及病状用的药剂。
在本发明的另一方面中,本发明涉及用于治疗或预防上文所提及的疾病及病状的方法,该方法包含向人类施用有效量的通式1的化合物。
组合疗法
本发明化合物可进一步与一种或多种、优选一种额外治疗剂组合。根据一个实施方案,该额外治疗剂选自以下的组:可用于治疗上文所描述的疾病或病状,特别是与纤维变性疾病、炎性及免疫调节病症、呼吸道或胃肠道疾病或不适、关节或鼻咽、眼睛及皮肤的炎性疾病或病状,诸如咳嗽、特发性肺纤维化、其他肺间质性疾病、哮喘或过敏性疾病、嗜伊红血球性疾病、慢性阻塞性肺病、异位性皮肤炎以及自体免疫性病变(诸如类风湿性关节炎及动脉粥样硬化)相关的疾病或病状的治疗剂;或可用于治疗眼科疾病、疼痛及抑郁症的治疗剂。
适用于此类组合的额外治疗剂特定地包括例如加强一种或多种活性物质对所提及的适应症中之一者的治疗作用和/或使一种或多种活性物质的剂量减少的治疗剂。
因此,本发明的化合物可与一种或多种选自由以下组成的组的额外治疗剂组合:抗纤维变性剂、止咳剂、抗炎剂、抗异位性皮肤炎剂、镇痛剂、抗惊厥剂、抗焦虑剂、镇静剂、骨骼肌松弛剂或抗抑郁剂。
抗纤维变性剂为例如尼达尼布(nintedanib);吡非尼酮(pirfenidone);磷酸二酯酶-IV(PDE4)抑制剂,诸如罗氟司特(roflumilast);自分泌运动因子抑制剂,诸如GLPG-1690或BBT-877;结缔组织生长因子(CTGF)阻断抗体,诸如潘瑞鲁单抗(Pamrevlumab);B细胞活化因子受体(BAFF-R)阻断抗体,诸如拉那鲁单抗(Lanalumab);α-V/β-6阻断抑制剂,诸如BG-00011/STX-100;重组穿透素-2(PTX-2),诸如PRM-151;c-Jun N末端激酶(JNK)抑制剂,诸如CC-90001;半乳糖凝集素-3抑制剂,诸如TD-139;G-蛋白偶联受体84(GPR84)抑制剂,诸如GLPG-1205;G蛋白偶联受体84/G蛋白偶联受体40双重抑制剂,诸如PBI-4050;Rho相关含卷曲螺旋蛋白激酶2(ROCK2)抑制剂,诸如KD-025;热休克蛋白47(HSP47)小干扰RNA,诸如BMS-986263/ND-L02-s0201;Wnt路径抑制剂,诸如SM-04646;LD4/PDE3/4抑制剂,诸如泰必鲁斯特(Tipelukast);组氨酰tRNA合成酶(HARS)的重组免疫调节域,诸如ATYR-1923;前列腺素合酶抑制剂,诸如ZL-2102/SAR-191801;15-羟基-二十碳五烯酸(15-HEPE,例如DS-102);赖氨酰氧化酶样蛋白2(LOXL2)抑制剂,诸如PAT-1251、PXS-5382/PXS-5338;磷酸肌醇3-激酶(PI3K)/哺乳动物雷帕霉素目标蛋白(mTOR)双重抑制剂,诸如HEC-68498;钙蛋白酶(calpain)抑制剂,诸如BLD-2660;促分裂原活化蛋白激酶激酶激酶(MAP3K19)抑制剂,诸如MG-S-2525;壳质酶抑制剂,诸如OATD-01;促分裂原活化蛋白激酶活化蛋白激酶2(MAPKAPK2)抑制剂,诸如MMI-0100;转型生长因子β1(TGF-β1)小干扰RNA,诸如TRK250/BNC-1021;或溶血磷脂酸受体拮抗剂,诸如BMS-986278。
止咳剂为例如嘌呤受体3(P2X3)受体拮抗剂,诸如吉法匹生(gefapixant)、S-600918、BAY-1817080或BLU-5937;神经激肽1(NK-1)受体拮抗剂,诸如奥维匹坦(Orvepitant)、阿瑞匹坦(Aprepitant);烟碱型乙酰胆碱受体α7次单元刺激剂,诸如ATA-101/布拉丹尼克(bradanicline);可待因(codeine)、加巴喷丁(gabapentin)、普瑞巴林(pregablin)或阿奇霉素(azithromycin)。
抗炎剂为例如皮质类固醇,诸如普赖苏秾(prednisolone)或地塞米松(dexamethasone);环加氧酶2(COX2)抑制剂,诸如塞内昔布(celecoxib)、罗非昔布(rofecoxib)、帕瑞昔布(parecoxib)、伐地昔布(valdecoxib)、德拉昔布(deracoxib)、依他昔布(etoricoxib)或罗美昔布(lumiracoxib);前列腺素E2拮抗剂;白三烯B4拮抗剂;白三烯D4拮抗剂,诸如孟鲁司特(monteleukast);5-脂肪加氧酶抑制剂;或其他非类固醇抗炎剂(NSAIDs),诸如阿司匹林(aspirin)、双氯芬酸(diclofenac)、二氟尼柳(diflunisal)、依托度酸(etodolac)、布洛芬(ibuprofen)或吲哚美辛(indomethacin)。
抗异位性皮肤炎剂为例如环孢素、甲胺喋呤、霉酚酸吗啉乙酯(mycophenolatemofetil)、硫唑嘌呤、磷酸二酯酶抑制剂(例如阿普斯特(apremilast)、克里硼罗(crisaborole))、詹纳斯(Janus)相关激酶(Janus Associated Kinase,JAK)抑制剂(例如托法替尼(tofacitinib))、针对IL-4/IL-13的中和抗体(例如度匹鲁单抗(dupilamab))、针对IL-13的中和抗体(例如来瑞组单抗(lebrikizumab)、曲罗芦单抗(tralokinumab))及针对IL-31的中和抗体(尼立珠单抗(nemolizumab))。
镇痛剂为例如类鸦片型,诸如吗啡碱、氧化吗啡碱(oxymorphine)、乐沃帕诺(levopanol)、羟考酮(oxycodon)、丙氧芬(propoxyphene)、纳美芬(nalmefene)、芬太尼(fentanyl)、氢可酮(hydrocondon)、氢吗啡酮(hydromorphone)、美利皮定(meripidine)、美沙酮(methadone)、纳洛芬(nalorphine)、纳洛酮(naloxone)、纳曲酮(naltrexone)、丁基原啡因(buprenorphine)、布托啡诺(butorphanol)、纳布啡(nalbuphine)、戊唑星(pentazocine);或非类鸦片型,诸如苯乙胺(acetophenamine)。
抗抑郁剂为例如三环类抗抑郁剂,诸如阿米替林(amitriptyline)、氯米帕明(clomipramine)、地斯帕明(despramine)、多虑平(doxepin)、地昔帕明(desipramine)、丙咪嗪(imipramine)、去甲替林(nortriptyline);选择性血清素再吸收抑制剂类抗抑郁剂(SSRI),诸如氟西汀(fluoxetine)、帕罗西汀(paroxetine)、舍曲林(sertraline)、西酞普兰(citalopram)、依地普兰(escitalopram);去甲肾上腺素再吸收抑制剂类抗抑郁剂(SNRI),诸如麦普替林(maprotiline)、洛夫帕明(lofepramine)、米氮平(mirtazapine)、羟丙替林(oxaprotiline)、非佐拉明(fezolamine)、托莫西汀(tomoxetine)、米安色林(mianserin)、丁胺苯丙酮(buproprion)、羟基安非他酮(hydroxybuproprion)、诺米芬辛(nomifensine)、维洛沙嗪(viloxazine);血清素-去甲肾上腺素双重再吸收抑制剂类抗抑郁剂(SNRI),诸如度洛西汀(duloxetine)、文拉法辛(venlafaxine)、去甲文拉法辛(desvenlafaxine)、左旋米那普仑(levomilnacipran);非典型抗抑郁剂,诸如曲唑酮(trazodone)、米氮平(mirtazapine)、沃替西汀(vortioxetine)、维拉唑酮(vilazodone)、安非他酮;或单胺氧化酶抑制剂类抗抑郁剂(MAOI),诸如反苯环丙胺(tranylcypromine)、苯乙肼(phenelzine)或异卡波肼(isocarboxazid)。
抗焦虑剂为例如苯并二氮杂卓类,诸如阿普唑仑(alprazolam)、溴西泮(bromazepam)、氯氮卓(chlordiazepoxide)、氯硝西泮(clonazepam)、氯拉西泮(clorazepate)、地西泮(diazepam)、弗拉西泮(flurazepam)、劳拉西泮(lorazepam)、奥沙西泮(oxazepam)、替马西泮(temazepam)、三唑仑(triazolam)或托非索泮(tofisopam);或其为非苯二氮卓类催眠药,诸如右佐匹克隆(eszopiclone)、扎来普隆(zaleplon)、唑吡坦(zolpidem)或佐匹克隆(zopiclone);或其为氨基甲酸酯类,例如美普巴(meprobamate)、卡利索普杜(carisoprodol)、泰巴胺酯(tybamate)或劳胺酯(lorbamate);或其为抗组胺药,诸如羟嗪(hydroxyzine)、氯芬尼拉明(chlorpheniramine)或苯海拉明(diphenhydramine)。
镇静剂为例如巴比妥酸盐类镇静剂,诸如阿莫巴比妥(amobarbital)、阿普巴比妥(aprobarbital)、丁巴比妥(butabarbital)、布他比妥(butabital)、甲苯巴比妥(mephobarbital)、美沙比妥(metharbital)、美索比妥(methohexital)、戊巴比妥(pentobarbital)、司可巴比妥(secobarbital)、他布比妥(talbutal)、塞麦妥(theamylal)或硫喷妥(thiopental);或其为非巴比妥酸盐类镇静剂,诸如格鲁米特(glutethimide)、美普巴、甲喹酮(methaqualone)或二氯苯甲酮(dichloalphenazone)。
骨骼肌松弛剂为例如贝可芬(baclofen)、美普巴、卡利索普杜、环苯扎林(cyclobenzaprine)、美他沙酮(metaxalone)、美索巴莫(methocarbamol)、替扎尼定(tizanidine)、氯唑沙宗(chlorzoxazone)或奥芬那君(orphenadrine)。
其他适合的组合搭配物为以下的抑制剂:乙酰胆碱酯酶抑制剂,诸如多奈哌齐(donepezil);5-HT-3拮抗剂,诸如昂丹司琼(ondansetron);代谢型谷氨酸受体拮抗剂;抗心律不整药,诸如美西律(mexiletine)或苯妥英(phenytoin);或NMDA受体拮抗剂。
其他适合的组合搭配物为失禁药物,例如抗胆碱激导性剂,诸如奥昔布宁(oxybutynin)、托特罗定(tolterodine)、达非那新(darifenacin)、非索罗定(fesoterodine)、索利那新(solifenacin)或曲司铵(trospium);或其为膀胱肌肉松弛剂,诸如米拉贝隆(mirabegron);或其为α阻断剂,诸如坦索罗辛(tamsulosin)、阿夫唑嗪(alfuzosin)、西洛多辛(silodosin)、多沙唑嗪(doxazosin)或特拉唑嗪(terazosin)。
上述组合搭配物的剂量通常为通常建议的最低剂量的1/5至通常建议的剂量的1/1。
因此,在另一方面中,本发明涉及根据本发明的化合物与一种或多种上下文中所述的额外治疗剂的组合的用途,其用于治疗可能受TRPA1影响或由TRPA1介导的疾病或病状,特别是如上下文中所述的疾病或病状。
在另一方面中,本发明涉及一种用于治疗患者的可受TRPA1抑制影响的疾病或病状的方法,其包括以下步骤:向需要此类治疗的患者施用治疗有效量的式(I)化合物或其药学上可接受的盐以及治疗有效量的一种或多种额外治疗剂。
在另一方面中,本发明涉及式(I)化合物或其药学上可接受的盐与一种或多种额外治疗剂的组合的用途,其用于治疗有需要的患者的可受TRPA1抑制影响的疾病或病状。
在又一方面中,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状的方法,其包括以下步骤:向需要此类治疗的患者(优选人类)施用治疗有效量的本发明的化合物以及治疗有效量的一种或多种上下文中所述的额外治疗剂。
与该额外治疗剂组合的根据本发明的化合物的使用可同时进行或在错开的时间进行。
根据本发明的化合物及一种或多种额外治疗剂可二者共同存在于一种调配物,例如片剂或胶囊中,或分别存在于两种相同或不同的调配物中,例如呈所谓的分装部分的试剂盒形式。
因此,在另一方面中,本发明涉及一种药物组合物,其包含根据本发明的化合物及一种或多种上下文中所述的额外治疗剂,任选连同一种或多种惰性载剂和/或稀释剂。
在又一方面中,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。
本发明的其他特征及优点将自以下更详细的例子而变得显而易知,所述实施例以举例方式说明本发明的原理。
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来获得。优选地,所述化合物是以与下文更完整解释且特别是如实验部分中所描述的制备方法类似的方式获得的。在一些情况下,进行反应步骤的次序可变化。亦可使用本领域技术人员已知但在此处未详细描述的反应方法的变型。
用于制备根据本发明的化合物的一般方法对研究以下流程的本领域技术人员将变得显而易知。可使用常规保护基来保护起始物质或中间体中的任何官能基。这些保护基可再在反应顺序内的适合阶段使用本领域技术人员熟悉的方法裂解。
根据本发明的化合物为通过下文所述的合成方法制备,其中各通式的取代基具有上文所给出的含义。这些方法意欲作为本发明的说明,而不限制其主题及这些实施例所主张的化合物的范围。当未描述起始化合物的制备时,其为可商购的或可按与本文中所述的已知化合物或方法类似地制备。文献中所述的物质为根据公开的合成方法制备。缩写如实施例部分中所定义。
流程1:
在流程1中,氯甲基四唑在碱(例如K2CO3)存在下用在羰基α位携带离去基“LG”(例如Cl或Br)的适当乙酮衍生物进行N-烷基化,得到两种区位异构物的混合物。非所需区位异构物(未绘示)可通过使用适当梯度进行的色谱移除。所得酮(A)可通过使用适当催化系统,使用过渡金属络合物(例如Ru或Ir)与手性配位体(例如[(1S,2S)-2-氨基-1,2-二苯基乙基](4-甲苯磺酰基)酰胺基)及氢源(诸如甲酸三乙胺络合物)的组合以镜像选择性方式还原以得到醇(B)。最终化合物(F)可通过以下方式合成:在碱(诸如K2CO3)存在下,用中间体(B)使6-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酸(C)烷基化,且随后在碱存在下,用偶合试剂(诸如HATU)及氨源(诸如碳酸铵)使羧酸(D)酰胺化。替代地,最终化合物(F)可经由用偶合试剂(诸如CDI)及氨使(C)酰胺化且随后用中间体(B)使酰胺(E)烷基化来合成。
流程2:
在流程2中,描述最终化合物(K)的合成。1-(4,6-二氯嘧啶-5-基)乙-1-酮在碱(诸如叔丁醇钾)存在下用乙醇酸乙酯进行亲核芳族取代得到中间体(G),其随后可用乙醇钠及碱(诸如叔丁醇钾)处理以得到中间体(H)。用例如碘化钠及氯化三甲基硅烷在乙腈中脱除(H)的嘧啶酮的保护基,得到酯(I),其可在刘易斯酸(Lewis acid)(诸如氯化钙)存在下与氨反应,得到酰胺(J)。最后,酰胺(J)在碱(诸如碳酸钾)存在下用中间体(B)烷基化,得到最终化合物(K)。
实施例
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,例如使用“Comprehensive Organic Transformations”,第2版,Richard C.Larock,John Wiley&Sons,2010及“March's Advanced Organic Chemistry”,第7版,Michael B.Smith,John Wiley&Sons,2013中描述的方法获得。优选地,所述化合物以与下文更完整解释且特别是如实验部分中所描述的制备方法类似的方式获得。在一些情况下,进行反应流程所采用的顺序可变化。亦可使用本领域技术人员已知但在本文中未详细描述的这些反应的变型。本领域技术人员研究以下流程将对用于制备根据本发明的化合物的一般方法变得显而易知。起始化合物为可商购的或可通过文献或本文中所述的方法制备,或可以类似或相似方式制备。在进行反应之前,起始化合物中的任何相应官能基均可使用常规保护基保护。这些保护基可再在反应顺序内的适合阶段使用本领域技术人员熟悉且文献中,例如“Protecting Groups”,第3版,Philip J.Kocienski,Thieme,2005及“Protective Groups in Organic Synthesis”,第4版,Peter G.M.Wuts,TheodoraW.Greene,John Wiley&Sons,2006中所述的方法裂解。术语“环境温度”及“室温”可互换使用且表示约20℃,例如介于19至24℃之间的温度。
缩写:
中间体的制备
中间体I
中间体I.1(一般程序)
2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-氯苯基)乙-1-酮
在室温下,在搅拌下,向于15mL DMA中的1.00g(8.44mmol)5-(氯甲基)-2H-1,2,3,4-四唑及2.17g(9.28mmol)4-氯苯甲酰甲基溴中添加1.63g(11.8mmol)K2CO3。在室温下搅拌反应混合物30分钟且随后过滤。将滤液用水及饱和NaCl水溶液稀释且用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,且在减压下移除溶剂。通过柱色谱(硅胶;CH/EtOAc,80/20至50/50梯度)纯化残余物以得到产物。
C10H8Cl2N4O (M=271.1g/mol)
ESI-MS: 271[M+H]+
Rt(HPLC): 1.01分钟(方法B)
以下化合物使用与针对中间体I.1所述程序类似的程序,使用适当起始物质制备。本领域技术人员应了解,这些类似实施例可涉及一般反应条件的变化。
中间体II
中间体II.1(一般程序)(1R)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-氯苯基)乙-1-醇
在惰性氛围下,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)溶解于20mL ACN中。添加12mg(0.02mmol)氯([(1S,2S)-2-氨基-1,2-二苯基乙基](4-甲苯磺酰基)酰胺基)(均三甲苯)钌(II)(CAS 174813-81-1),接着逐滴添加0.72mL(1.73mmol)甲酸三乙胺络合物(5:2)。在室温下搅拌3小时之后,在减压下移除溶剂。向剩余粗混合物中添加水且用EtOAc萃取此混合物。将有机层合并,经Na2SO4干燥,过滤,用活性炭处理,过滤且在减压下移除溶剂,得到中间体II.1。
C10H10Cl2N4O (M=273.1g/mol)
ESI-MS: 273[M+H]+
Rt(HPLC): 0.96分钟(方法B)
以下化合物使用与针对中间体II.1所述程序类似的程序,使用适当起始物质制备。本领域技术人员应了解,这些类似实施例可涉及一般反应条件的变化。
中间体III
中间体III.1
1-(7-氟-1-苯并呋喃-2-基)乙-1-酮
将6.00g(42.8mmol)3-氟-2-羟基苯甲醛于60mL丙酮中的经搅拌溶液冷却至0℃且随后用9.47g(68.5mmol)碳酸钾处理。在0℃下搅拌10分钟之后,逐滴添加5.12mL(64.2mmol)氯丙酮且在90℃下搅拌反应混合物1小时。将反应混合物冷却至室温且在减压下浓缩。将粗残余物用EtOAc/水萃取且将有机相在减压下浓缩以得到中间体III.1。
C10H7FO2 (M=178.2g/mol)
ESI-MS: 179[M+H]+
Rt(HPLC): 0.50分钟(方法A)
以下化合物以类似于中间体III.1的方式制备。本领域技术人员应了解,此类似实施例可涉及一般反应条件的变化。
中间体IV
中间体IV.1
2-溴基-1-(7-氟-1-苯并呋喃-2-基)乙-1-酮
在室温下,在搅拌下,向于66mL THF中的5.47g(30.7mmol)1-(7-氟-1-苯并呋喃-2-基)乙-1-酮(中间体III.1)中逐滴添加14.81g(30.7mmol)三溴化四丁基铵于3.3mL MeOH及32mL THF中的溶液。在室温下搅拌反应混合物2小时,在减压下浓缩且用EtOAc/水萃取残余物。在减压下浓缩有机层且将粗物质通过柱色谱(硅胶;己烷/EtOAc,梯度)纯化。
C10H6BrFO2 (M=257.1g/mol)
ESI-MS: 257/259[M+H]+
Rt(HPLC): 0.58分钟(方法A)
以下化合物为以类似于中间体IV.1的方式制备。本领域技术人员应了解,此类似实施例可涉及一般反应条件的变化。
中间体V
6-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酰胺
在室温下,将2.90g(14.94mmol)6-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酸(CAS:852399-94-1,European Journal of Medicinal Chemistry,2018,第144卷,第330-348页)及2.66g(16.43mmol)CDI在60mL THF中搅拌18小时。随后,添加90mL于THF中的NH3(0.5mol/L)且在室温下持续搅拌3小时。将反应混合物减压浓缩,倒入NaHCO3水溶液(100mL水+40mL饱和NaHCO3水溶液)中,且滤出所得沉淀物且干燥,得到中间体V。
C8H7N3O3 (M=193.2g/mol)
ESI-MS: 194[M+H]+
Rt(HPLC): 0.61分钟(方法B)
中间体VI
2-[(5-乙酰基-6-氯嘧啶-4-基)氧基]乙酸乙酯
在0℃下,向111μL(1.15mmol)乙醇酸乙酯于5.0mL THF中的经搅拌溶液中缓慢添加叔丁醇钾溶液(1.26mL,1.0mol/L)。在0℃下搅拌35分钟之后,添加200mg(1.05mmol)1-(4,6-二氯嘧啶-5-基)乙-1-酮,且在0℃下继续搅拌2小时且在室温下搅拌3小时。减压浓缩反应混合物且通过柱色谱(硅胶;己烷/EtOAc,梯度)纯化。
C10H11ClN2O4 (M=258.66g/mol)
ESI-MS: 259[M+H]+
Rt(HPLC): 1.05分钟(方法B)
中间体VII
4-乙氧基-5-甲基呋喃并[2,3-d]嘧啶-6-甲酸乙酯
在-12℃下,向2.23g(8.62mmol)中间体VI于THF中的经搅拌溶液中缓慢添加乙醇钠于乙醇中的溶液(2.95mL,21%)。在0℃下搅拌反应混合物90分钟,添加叔丁醇钾于THF中的溶液(4.31mL,1.0mol/L)且在室温下继续搅拌隔夜。再添加THF中的叔丁醇钾(1.0mL,1.0mol/L)且在室温下继续搅拌3小时。将反应混合物用乙酸进行酸化且在减压下浓缩。用水/EtOAc萃取反应混合物,将有机萃取物经MgSO4干燥,过滤且在减压下浓缩。经由反相HPLC(ACN/H2O梯度,0.1% TFA)纯化,得到中间体VII。
C12H14N2O4 (M=250.25g/mol)
ESI-MS: 251[M+H]+
Rt(HPLC): 0.63分钟(方法A)
中间体VIII
5-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-6-甲酸乙酯
向50mg(0.20mmol)中间体VII于2mL ACN中的经搅拌溶液中添加90mg(0.60mmol)碘化钠且在室温下搅拌混合物3分钟。随后,添加76μL(0.60mmol)氯化三甲基硅烷,且密封反应容器且在室温下继续搅拌2小时。将反应物用10mL水淬灭且在室温下搅拌5分钟。滤出沉淀物,用水洗涤且在50℃下减压干燥,得到中间体VIII。
C10H10N2O4 (M=222.20g/mol)
ESI-MS: 223[M+H]+
Rt(HPLC): 0.78分钟(方法B)
中间体IX
5-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-6-甲酰胺
在密封容器中,将800mg(3.60mmol)中间体VIII及400mg(3.60mmol)CaCl2于128mL氨/MeOH(7mol/L)中的混合物在50℃下搅拌36小时。在减压下浓缩反应混合物,在50mL水中搅拌且滤出所得沉淀物,用水洗涤且在60℃下减压干燥,得到中间体IX。
C8H7N3O3 (M=193.16g/mol)
ESI-MS: 194[M+H]+
Rt(HPLC): 0.50分钟(方法H)
中间体X
中间体X.1
将120mg(0.47mmol)6-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酸(CAS:852399-94-1)、92mg(0.47mmol)(1R)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-甲基苯基)乙-1-醇(中间体II.9)及98mg(0.71mmol)K2CO3于2mL DMA中的混合物在室温下搅拌隔夜。随后,添加98mg(0.71mmol)K2CO3且将混合物在60℃下搅拌2小时,且在80℃下搅拌5小时。将反应混合物冷却至室温且通过反相HPLC(ACN/H2O梯度,0.1% TFA)纯化,得到所需产物。
C19H18N6O5 (M=410.38g/mol)
ESI-MS: 411[M+H]+
Rt(HPLC): 0.90分钟(方法H)
以下化合物使用与针对中间体X.1所述程序类似的程序,使用适当起始物质制备。本领域技术人员应了解,这些类似实施例可涉及一般反应条件的变化。
最终化合物的制备
实施例1(一般程序A)
3-({2-[(2R)-2-羟基-2-(4-甲基苯基)乙基]-2H-1,2,3,4-四唑-5-基}甲基)-6-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酰胺
在室温下,将1.50g(7.77mmol)6-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酰胺(中间体V)、3.22g(23.30mmol)K2CO3及1.96g(7.77mmol)(1R)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-甲基苯基)乙-1-醇(中间体II.9)于25mL DMA中的混合物搅拌隔夜。将反应混合物倒于冰水上且用EtOAc萃取三次。将合并的有机层用MgSO4搅拌,过滤,在减压下浓缩,且通过反相HPLC(ACN/H2O梯度,0.3% TFA)纯化,得到所需产物。
C19H19N7O4 (M=409.4g/mol)
ESI-MS: 410[M+H]+
Rt(HPLC): 0.73分钟(方法B)
1H NMR(400MHz,DMSO-d6)δppm:2.25(s,3H),2.72(s,3H),4.74(d,J=6.6Hz,2H),5.02-5.08(m,1H),5.58(s,2H),5.74(s,1H),7.10(d,J=8.0Hz,2H),7.21(d,J=8.0Hz,2H),7.55(br d,J=1.3Hz,1H),8.74(s,1H),9.16-9.22(m,1H)
以下化合物使用与针对实施例1一般程序A所述程序类似的程序,使用适当起始物质制备。本领域技术人员应了解,这些类似实施例可涉及一般反应条件的变化。
化合物的分析数据描述于上表中:
最终化合物的制备
实施例1(一般程序B)
3-({2-[(2R)-2-羟基-2-(4-甲基苯基)乙基]-2H-1,2,3,4-四唑-5-基}甲基)-6-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酰胺
向于2.0mL DMF中的35mg(0.09mmol)3-({2-[(2R)-2-羟基-2-(4-甲基苯基)乙基]-2H-1,2,3,4-四唑-5-基}甲基)-6-甲基-4-氧代-3H,4H-呋喃并[2,3-d]嘧啶-5-甲酸(中间体X.1)中添加32mg(0.09mmol)HATU及73μL(0.43mmol)DIPEA,同时在室温下搅拌。在5分钟之后,添加82mg(0.85mmol)碳酸铵且在室温下搅拌混合物隔夜。通过反相HPLC(ACN/H2O梯度,0.1% NH3)纯化混合物,得到所需产物。
以下化合物使用与针对实施例1一般程序B所述程序类似的程序,使用适当起始物质制备。本领域技术人员应了解,这些类似实施例可涉及一般反应条件的变化。
化合物的分析数据描述于上表中:
分析型HPLC方法
方法A
分析柱:XBridge BEH(Waters)C18_2.1×30mm_1.7μm;柱温度:60℃
方法B
分析柱:Stable Bond(Agilent)C18_3.0×30mm_1.8μm;柱温度:60℃
方法C
分析柱:Xbridge(Waters)C18_3.0×30mm_2.5μm;柱温度:60℃
方法D
分析柱:XBridge C18_3.0×30mm_2.5μm(Waters);柱温度:60℃
方法E
分析柱:Sunfire(Waters);C18_3.0×30mm_2.5μm,柱温度:60℃
方法F
分析柱:XBridge BEH(Waters)C18_2.1×30mm_2.5μm;柱温度:60℃
方法G
分析柱:Zorbax StableBond C18(Agilent)1.8μm;2.1×30mm;柱温度:60℃
方法H
分析柱:Sunfire(Waters)2.5μm;3.0×30mm;柱温度:60℃
方法I
分析柱:Sunfire C18(Waters)2.5μm;3.0×30mm;柱温度:60℃
方法J
分析柱:Acquity UPLC BEH;C8_2.1×150mm_1.7μm;柱温度:55℃
方法K
分析柱:XBridge BEH Phenyl(Waters)2.1×30mm_1.7μm;柱温度:60℃
Claims (13)
3.根据权利要求1或2中任一项的式(I)化合物,其中R3选自由以下组成的组:Br、Cl、F及H3C。
5.根据权利要求1至4中任一项的式(I)化合物,其中R1为H3C且R2为H2N(O)C。
6.根据权利要求1至4中任一项的式(I)化合物,其中R1为H2N(O)C且R2为H3C。
9.一种根据权利要求1至8中任一项的化合物的盐,尤其是药学上可接受的盐。
10.一种药物组合物,其包含至少一种根据权利要求1至8中任一项的式I化合物或其药学上可接受的盐及一种或多种药学上可接受的赋形剂。
11.根据权利要求1至8中任一项的式(I)化合物或其药学上可接受的盐,其用作药物。
12.根据权利要求1至8中任一项的化合物或其药学上可接受的盐,其用于治疗或预防炎性气道疾病或纤维变性疾病或咳嗽。
13.根据权利要求1至8中任一项的化合物或其药学上可接受的盐,其用于治疗或预防特发性肺病(IPF)或咳嗽。
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EP20201708.3 | 2020-10-14 | ||
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PCT/EP2021/078295 WO2022079092A1 (en) | 2020-10-14 | 2021-10-13 | Tetrazole derivatives as trpa1 inhibitors |
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EP (1) | EP4228756B1 (zh) |
JP (1) | JP2023545159A (zh) |
KR (1) | KR20230087531A (zh) |
CN (1) | CN116249535A (zh) |
AU (1) | AU2021363101A1 (zh) |
CA (1) | CA3193606A1 (zh) |
CL (1) | CL2023000837A1 (zh) |
IL (1) | IL301706A (zh) |
MX (1) | MX2023004008A (zh) |
TW (1) | TW202229292A (zh) |
WO (1) | WO2022079092A1 (zh) |
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WO2017060488A1 (en) | 2015-10-09 | 2017-04-13 | Almirall, S.A. | New trpa1 antagonists |
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TW202229292A (zh) | 2022-08-01 |
WO2022079092A1 (en) | 2022-04-21 |
EP4228756A1 (en) | 2023-08-23 |
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CL2023000837A1 (es) | 2023-11-24 |
US11661427B2 (en) | 2023-05-30 |
US20220112202A1 (en) | 2022-04-14 |
EP4228756B1 (en) | 2024-06-12 |
AU2021363101A1 (en) | 2023-03-23 |
KR20230087531A (ko) | 2023-06-16 |
JP2023545159A (ja) | 2023-10-26 |
MX2023004008A (es) | 2023-04-26 |
IL301706A (en) | 2023-05-01 |
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