CN117561264A - 作为TRPA1抑制剂的3H,4H,5H,6H,7H‐嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮衍生物 - Google Patents
作为TRPA1抑制剂的3H,4H,5H,6H,7H‐嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮衍生物 Download PDFInfo
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Abstract
本公开内容提供某些3H,4H,5H,6H,7H‑嘧啶并[4,5‑b][1,4]噁嗪‑4,6‑二酮衍生物,其为瞬态受体电位锚蛋白1(transient receptor potential ankyrin 1;TRPA1)抑制剂且因此可用于治疗可通过抑制TRPA1治疗的疾病。本公开内容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
本公开内容提供某些3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮衍生物,其为瞬态受体电位锚蛋白1(TRPA1)抑制剂且因此可用于治疗可通过抑制TRPA1治疗的疾病。本公开内容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
瞬时受体电位信道(TRP信道)为主要位于许多哺乳动物细胞类型的质膜上的一组电压闸控离子信道。存在大约30种结构相关的TRP信道,其分为以下群组:TRPA、TRPC、TRPM、TRPML、TRPN、TRPP及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)为TRPA基因亚家族的唯一成员。在结构上,TRPA信道的特征在于多个N-末端锚蛋白重复(在人类TRPA1的N-末端中约14个),其产生锚蛋白名称的“A”(Montell,2005)。
TRPA1高度表达于服务于皮肤及肺二者的背根及结节神经节中的感觉神经元的质膜中、以及小肠、结肠、胰脏、骨骼肌、心脏、脑、膀胱及淋巴球中(https://www.proteinatlas.org/)以及人类肺纤维母细胞中。
TRPA1是最著名的环境刺激物的传感器,引起诸如疼痛、寒冷及瘙痒等体感觉样式。TRPA1由许多反应性、亲电刺激物(例如,异硫氰酸烯丙酯、活性含氧物)以及非反应性化合物(例如冰素(icilin))激活,其涉及与气喘、慢性肺阻塞性疾病(COPD)、特发性肺纤维化(IPF)或病毒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)。TRPA1抑制剂可用于治疗IPF,其中基于显示咳嗽引起TGF-β升高的研究,由于咳嗽与肺损伤之间的联系,咳嗽在IPF中非常普遍(Xie等人,2009;Froese等人,2016;Tschumperlin等人,2003;Yamamoto等人,2002;Ahamed等人,2008)。SARS-Cov-2感染导致的急性肺损伤至少部分地经由活性含氧物(ROS)介导。ROS为TRPA1的直接活化剂。此外,经由食用辛辣食物使TRPA1去敏被认为调节Nrf2路径并减少氧化压力(Bousquet等人,2020;Bousquet等人,2021)。因此,TRPA1抑制剂在治疗新冠病毒(Covid-19)/SARS-Cov-2引起的肺损伤方面具有潜力。TRPA1拮抗剂抑制由咳嗽触发因素(例如香烟烟雾提取物(CSE)氧化应激、发炎介质释放及抗氧化基因表达下调)触发的钙信号传导(Lin等人,2015;Wang等人,2019)。TRPA1拮抗剂在异位性皮肤炎(Oh等人,2013;Wilson等人,2013)、接触性皮肤炎(Liu等人,2013)、牛皮癣相关的瘙痒(Wilson等人,2013)及IL-31依赖性瘙痒(Cevikbas等人,2014)的研究中是有效的。人类TRPA1功能获得与家族性阵发性疼痛综合征相关联(Kremeyer等人,2010)。TRPA1拮抗剂在偏头痛相关的触摸痛的行为模型中是有效的(Edelmayer等人,2012)。与TRPA1在支配健康牙齿的三叉神经节中的表达相比,TRPA1在支配受损牙齿的三叉神经节中的表达选择性地增加(Haas等人,2011)。已知几种麻醉剂为TRPA1激动剂,包括异氟醚(Matta等人,2008),这是TRPA1抑制剂缓解术后疼痛提供理论基础。TRPA1剔除的小鼠及利用TRPA1拮抗剂治疗的野生型小鼠显示抗焦虑及抗抑郁样表型(de Moura等人,2014)。基于显示AMPK与TRPA1之间反向调节的机制联系的研究,TRPA1抑制剂预期在治疗糖尿病神经病变中具有益处(Hiyama等人,2018;Koivisto及Pertovaara,2013;Wang等人,2018)。TRPA1剔除小鼠与野生型小鼠相比展现较小的心肌梗塞大小(Conklin等人,2019)。TRPA1剔除及药理学介入抑制小鼠中TNBS引发的结肠炎(Engel等人,2011)。在小鼠脑缺血模型中,TRPA1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,尿酸盐晶体及关节发炎在TRPA1剔除小鼠中减少(Moilanen等人,2015)。大鼠中的TRPA1缺失在急性痛风发作的大鼠模型中改善关节发炎及痛觉过敏(Trevisan等人,2014)。TRPA1的激活引发在骨关节炎软骨细胞中引发发炎反应(Nummenmaa等人,2016)。TRPA1抑制及基因缺失减少骨关节炎小鼠软骨细胞及鼠类软骨中的发炎介质(Nummenmaa等人,2016)。最后,TRPA1剔除小鼠在MIA诱发的膝肿胀模型中展现骨关节炎肢体的负重改良(Horvath等人,2016)。TRPA1差异表达于膀胱出口阻塞的大鼠的膀胱上皮(Du等人,2007)及患者的膀胱上皮(Du等人,2008)中。TRPA1受体调节减弱脊髓损伤的大鼠模型中的膀胱过度活动(Andrade等人,2011)且鞘内施用TRPA1拮抗剂减弱患有反射过度排尿的大鼠中环磷酰胺引发的膀胱炎(Chen等人,2016)。
因此期望提供强效TRPA1抑制剂。
各种结构类型的TRPA1抑制剂综述于S.Skerratt,Progress in MedicinalChemistry,2017,第56卷,81-115及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公开为TRPA1拮抗剂的化合物,其具有以下结构通式
其中在钙通量分析中公开实施例53、72、73、86及90的TRPA1活性具有小于100nM的IC50。
L.Schenkel等人,J.Med.Chem.2016,59,2794-2809公开基于喹唑啉酮的TRPA1拮抗剂,其包括以下结构通式的化合物
其中化合物31(其中R为OH)在FLIPR分析中公开具有IC50 58nM的拮抗TRPA1活性且在人类肝微粒体中具有<14μL/min/kg的固有清除率。
具体实施方式
本发明公开新颖3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮衍生物,其为瞬态受体电位锚蛋白1(TRPA1)的抑制剂,具有适当药理学及药物动力学性质,使其能够作为药剂用于治疗可通过抑制TRPA1治疗的病况和/或疾病。
本发明化合物可提供若干优点,例如增强的功效、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、期望的血浆蛋白结合、增强的生物利用度、适宜药物动力学曲线及形成稳定盐的可能性。
本发明的化合物
本发明提供3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮衍生物,其为TRPA1的令人惊讶的强效抑制剂(分析A),其特征进一步在于
-在人类肝微粒体中经改良的稳定性(分析B)
-在人类肝细胞中经改良的稳定性(分析C)。
本发明化合物在结构上不同于WO2017/060488中的实施例53、72、73、86及90以及L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的实施例31,这是因为其含有经取代3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮核心以及毗邻第二脂肪族醇的取代基。所述结构差异意外地导致以下的有利组合:(i)TRPA1的抑制,(ii)在人类肝微粒体中的稳定性,及(iii)在人类肝细胞中的稳定性。
在人类肝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性质的药物作为第一筛选步骤的情景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。人类肝微粒体含有细胞色素P450(CYP),且因此代表用于研究体外I期药物代谢的模型系统。在人类肝微粒体中的增强稳定性与若干优点相关联,包括增加的生物利用度及足够半衰期,此可使能够降低及减少患者的频繁给药。因此,在人类肝微粒体中的增强稳定性为欲用于药物的化合物的有利特征。因此,除能够抑制TRPA1以外,本发明化合物预期具有有利的体内清除率且因此在人类中的期望作用持续时间。
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性质的药物的情景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,且因此代表用于研究体外药物代谢的模型系统。(重要的是,与肝微粒体分析相比,肝细胞分析亦涵盖II期生物转化以及肝特异性运输蛋白介导的过程,且因此代表用于药物代谢研究的更完整系统)。在人类肝细胞中的增强稳定性与若干优点相关联,包括增加的生物利用度及足够半衰期,此可使能够降低及减少患者的频繁给药。因此,在人类肝细胞中的增强稳定性为欲用于药物的化合物的有利特征。
本发明提供式(I)的新颖化合物
其中
A选自由以下组成的组:苯基、噻吩基、苯并呋喃基及苯并噻吩基,且其中A未经取代或经由卤素及C1-4-烷基组成的基团R1的一或两个成员取代。
本发明的另一实施方案涉及式(I)化合物,其中A选自由以下组成的组:苯基、噻吩基、苯并呋喃基及苯并噻吩基,且其中A未经取代或经由F、Cl、I及CH3组成的基团R1的一或两个成员取代。
本发明的另一实施方案涉及式(I)化合物,其中A选自由以下组成的组:苯基、苯并呋喃基及苯并噻吩基,且其中A未经取代或经由F、Cl、I及CH3组成的基团R1的一或两个成员取代。
本发明的另一实施方案涉及式(I)化合物,其中A选自由以下组成的组:
且其中A未经取代或经该基团R1的一或两个成员取代,
且R1为如前述实施方案中的任一者中所定义。
优选者为选自由以下组成的组的式(I)化合物
所用术语及定义
本文中未明确定义的术语应给予本领域技术人员根据公开内容及上下文会给予的含义。然而,除非指定相反含义,否则如说明书中所用的以下术语具有所指示含义且遵守以下惯例。
在下文所定义的基团(group)、基团(radical)或部分中,碳原子数通常在基团之前指明,例如C1-6烷基意指具有1至6个碳原子的烷基。通常在诸如HO、H2N、(O)S、(O)2S、NC(氰基)、HOOC、F3C或诸如此类的基团中,本领域技术人员可自基团本身的自由价看出至分子的基团附着点。对于包含两个或以上子基团的组合基团,最后命名的子基团为基团附接点,例如取代基“芳基-C1-3-烷基-”意指键合至C1-3-烷基-基团的芳基,该C1-3-烷基-基团键合至核心或该取代基所附接的基团。
在本发明化合物为以化学名称形式描述或描述为化学式的情形中,在出现任何不一致时,以化学式为准。可在子式中使用星号来指示如所定义连接至核心分子的键。
取代基的原子编号始于距离核心或取代基所附接的基团最近的原子。
举例而言,术语“3-羧基丙基-基团”代表以下取代基:
其中羧基附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-”基团代表以下基团:
可在子式中使用星号来指示如所定义连接至核心分子的键。
单独或与另一基团组合的术语“C1-n-烷基”(其中n为选自2、3、4或5的整数)表示具有1至n个C原子的非环状、饱和、具支链或直链烃基团。举例而言,术语C1-5-烷基包括基团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)-。
添加至“烷基”、“亚烷基”或“环烷基”(饱和或不饱和)的术语“氟”是指其中一个或多个氢原子经氟原子取代的烷基或环烷基。实例包括(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
术语苯并呋喃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3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮是指以下核心的基团
如本文所用,术语“经取代”意指所指定原子上的任一个或多个氢经来自所指示基团的选择置换,前提为不超过所指示原子的正常化合价,且该取代产生稳定化合物。
除非明确指示,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互变异构体及所有立体、光学及几何异构体(例如镜像异构体、非镜像异构体、E/Z异构体等)及其外消旋体,以及不同比例的单独镜像异构体的混合物、非镜像异构体的混合物或前述任一形式的混合物(倘若存在所述异构体及镜像异构体),以及其盐(包括药学上可接受的盐)及其溶剂合物,例如水合物,包括游离化合物的溶剂合物或该化合物的盐的溶剂合物。
一般而言,实质上纯的立体异构体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的起始材料和/或通过立体选择性合成。本领域已知如何制备光学活性形式,例如通过拆分外消旋形式或通过例如自光学活性起始材料开始来合成和/或通过使用手性试剂。
本发明的镜像异构纯化合物或中间体可经由不对称合成来制备,例如通过制备及随后分离可通过已知方法(例如通过色谱分离或晶体)分离的适当非镜像异构化合物或中间体和/或通过手性试剂,例如手性起始材料、手性触媒或手性助剂。
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纯化合物,例如通过相应外消旋混合物在手性固定相上的色谱分离;或通过外消旋混合物使用适当拆分剂的拆分,例如借助外消旋化合物与光学活性酸或碱的非镜像异构盐形成、盐的随后拆分及自盐释放期望化合物;或通过利用光学活性手性辅助试剂衍生相应外消旋化合物、随后非镜像异构体分离及去除手性辅助基团;或通过外消旋体的动力学拆分(例如通过酶拆分);通过在适宜条件下自镜像异构晶体的聚集体进行镜像选择性晶体;或通过在光学活性手性辅助剂的存在下自适宜溶剂(部分)晶体。
本文采用词组“药学上可接受”以指在合理的医学判断范围内适于使用而没有过度毒性、刺激、过敏反应或其他问题或并发症并与合理的收益/风险比相称的那些化合物、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,其中母体化合物与酸或碱形成盐或络合物。
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实施例包括无机或有机酸,例如苯磺酸、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、苦杏仁酸、甲磺酸、4-甲基-苯磺酸、磷酸、水杨酸、琥珀酸、硫酸及酒石酸。
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及碱的例子包括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-葡萄糖胺或三(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体化合物合成。通常,所述盐可通过使所述化合物的游离酸或碱形式与足量的适当碱或酸于水或有机稀释剂(例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈(或其混合物))中进行反应来制得。
除上述的那些以外可例如用于纯化或分离本发明化合物的其他酸的盐(例如三氟乙酸盐)亦构成本发明的一部分。
生物学分析
TRPA1活性的评估
分析A:TRPA1分析
本发明化合物的活性可使用以下体外TRPA1细胞分析来证实:
方法:
使用过表达人类TRPA1离子通道的人类HEK293细胞系(Perkin Elmer,产品号AX-004-PCL)作为化合物效能及功效的测试系统。化合物活性通过在FLIPRtetra系统(Molecular Devices)中测量化合物对AITC(异硫氰酸烯丙酯)促效作用诱导的细胞内钙浓度的效应来确定。
细胞培养:
细胞系在冷冻小瓶中呈冷冻细胞获得并在-150℃下储存直至使用。
使细胞在培养基(具有10% FCS及0.4mg/ML建那霉素(Geneticin)的MEM/EBSS培养基)中生长。重要的是密度不超过90%铺满。为进行传代培养,通过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,并将20000个细胞以20μl/孔接种于来自Corning的聚D-赖氨酸生物涂布的384孔板(黑色,透明底,Cat.356697)。在用于分析之前,将板在37℃/5% CO2下培育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,且在第一步骤中于DMSO中稀释至5mM的浓度,随后在100% DMSO中进行连续稀释步骤。稀释因子及稀释步骤的数量可根据需要而变。通常以1:5稀释度制备8个不同浓度,使用HBSS/HEPES缓冲液(来自Gibco的1xHEPES,Cat.14065,来自SIGMA的20mM HEPES,Cat.83264,来自Invitrogen的0.1% BSACat.11926,pH 7.4)实施物质的其他中间稀释度(1:20)。
FLIPR分析:
在分析日,细胞用分析缓冲液洗涤3次,洗涤后20μL缓冲液留在孔中。将于HBSS/HEPES中的10μL Ca6试剂盒(Cat.R8191 MolecularDevices)加载缓冲液添加至细胞中,并将板在37℃/5% CO2下加盖培育120分钟。将来自中间稀释板的于HBSS/HEPES缓冲液/5%DMSO中的10μL化合物或对照小心地添加至孔中。在FLIPRtetra装置上读取发光(指示钙流入或释放)达10分钟,以监测化合物诱导的效应(例如促效作用)。最后,将溶于HBSS/HEPES缓冲液/0.05% DMSO中的10μL激动剂AITC 50μM(最终浓度为10μM)添加至孔,随后在FLIPRtetra装置上额外读取10分钟。使用AITC添加后的信号曲线下面积(AUC)用于IC50/%抑制计算。
数据评估及计算:
每一分析微量滴定板均含有具有媒剂(1% DMSO)对照代替化合物的孔作为用于AITC诱导发光的对照(100%CTL;高对照)以及具有媒剂对照而无AITC的孔作为用于非特异性发光变化的对照(0%CTL;低对照)。
数据分析为通过计算个别孔的信号曲线下面积来实施。基于此值,使用MegaLab软件(内部开发)计算针对每一物质浓度测量的%值(AUC(试样)-AUC(低))*100/(AUC(高)-AUC(低))。IC50值为使用MegaLab软件自%对照值计算。计算:[y=(a-d)/(1+(x/c)^b)+d],a=低值,d=高值;x=浓度M;c=IC50 M;b=希尔(hill)斜率;y=%ctrl
表1:分析A中所获得本发明化合物的生物数据
实施例 | hTRPA1 IC50[nM] |
1 | 57 |
2 | 12 |
3 | 27 |
4 | 39 |
5 | 39 |
6 | 51 |
7 | 120 |
表2:分析A中所获得背景技术化合物(WO2017/060488中的实施例53、72、73、86、90)的生物数据.
WO2017/060488中的实施例 | hTRPA1 IC50[nM] |
53 | 36 |
72 | 14 |
73 | 28 |
86 | 67 |
90 | 41 |
表3:分析A中所获得背景技术化合物(L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的实施例31)的生物数据.
评估微粒体清除率
分析B:微粒体清除率:
测试化合物的代谢降解为在37℃下利用汇集的肝微粒体进行分析。每时间点的100μl最终培育体积含有在RT下pH 7.6的TRIS缓冲液(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℃下的短预培育时期后,反应通过添加经还原形式的β-烟碱酰胺腺嘌呤二核苷酸磷酸(NADPH,1mM)起始,并在不同时间点(0、5、15、30、60min)后通过将等份试样转移至溶剂中来终止。另外,在没有NADPH的培育中监测NADPH非依赖性降解,在最后一个时间点终止。NADPH独立培育后的[%]剩余测试化合物为由参数c(对照)(代谢稳定性)反映。将骤冷的培育物通过离心(10000g,5min)制成丸粒。
通过LC-MS/MS分析上清液等份试样的母体化合物的量。半衰期(t1/2INVITRO)为通过浓度-时间曲线的半对数曲线图的斜率确定。
固有清除率(CL_INTRINSIC)为通过考虑培育中蛋白质的量来计算:
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]x肝因子[g/kg体重])/1000
Qh[%]=(CL[ml/min/kg]/肝血流量[ml/min/kg])
肝细胞性,人类:120x10e6个细胞/g肝
肝因子,人类:25.7g/kg体重
血流量,人类:21ml/(min x kg)
表4:分析B中所获得本发明化合物的生物数据
实施例 | 人类LM[%Qh] |
1 | <23 |
2 | <23 |
3 | <23 |
4 | <23 |
5 | 29 |
6 | 56 |
7 | <23 |
表5:分析B中所获得背景技术化合物(WO2017/060488中的实施例53、72、73、86、90)的生物数据.
WO2017/060488中的实施例 | 人类LM[%Qh] |
53 | <23 |
72 | 30 |
73 | 38 |
86 | <23 |
90 | 39 |
表6:分析B中所获得背景技术化合物(L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的实施例31)的生物数据.
评估肝细胞清除率
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(冷冻保存)在含有5%物种血清的达尔伯克改良伊格尔培养基(Dulbecco′s modified eagle medium)(补充有3.5μg升糖素/500mL、2.5mg胰岛素/500mL及3.75mg氢化可的松/500mL)。
在培育器(37℃,10% CO2)中30min预培育之后,将5μl测试化合物溶液(80μM;自2mM于DMSO中的原液利用培养基1:25稀释)添加至395μl肝细胞悬浮液(取决于物种,细胞密度在0.25-5百万个细胞/mL的范围内,通常1百万个细胞/mL;测试化合物的最终浓度为1μM,最终DMSO浓度为0.05%)。
将细胞培育六小时(培育器、定轨振荡器)并在0、0.5、1、2、4及6小时时采集试样(25μl)。将试样转移至乙腈中并通过离心(5min)制成丸粒。将上清液转移至新的96深孔板,在氮下蒸发并重新悬浮。
通过HPLC-MS/MS分析母体化合物的减少。
CLint为如下计算:CL_INTRINSIC=剂量/AUC=(C0/CD)/(AUD+clast/k)×1000/60。C0:培育中的初始浓度[μM],CD:活细胞的细胞密度[10e6个细胞/mL],AUD:数据下面积[μM x h],clast:最后一个数据点的浓度[μM],k:母体减少的回归线斜率[h-1]。
所计算的体外肝固有清除率可放大至固有体内肝清除率并通过使用肝脏模型(充分搅拌模型)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肝细胞性[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])
肝细胞性,人类:120x10e6个细胞/g肝
肝因子,人类:25.7g/kg体重
血流量,人类:21ml/(min x kg)
表7:分析C中所获得本发明化合物的生物数据
实施例 | 人类肝细胞[%Qh] |
1 | 9 |
2 | 34 |
3 | 31 |
4 | 22 |
5 | 22 |
6 | 37 |
7 | 9 |
表8:分析C中所获得背景技术化合物(WO2017/060488中的实施例53、72、73、86、90)的生物数据.
WO2017/060488中的实施例 | 人类肝细胞[%Qh] |
53 | 25 |
72 | 50 |
73 | 36 |
86 | 12 |
90 | 61 |
表9:分析C中所获得背景技术化合物(L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的实施例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)接种于过滤器插入物(Costartranswell聚碳酸酯或PET过滤器,0.4μm孔径)并培养(DMEM)10至25天。
将化合物溶解于适当溶剂(如DMSO,1-20mM原液)中。原液用HTP-4缓冲液(128.13mM NaCl、5.36mM KCl、1mM MgSO4、1.8mM CaCl2、4.17mM NaHCO3、1.19mM Na2HPO4 x7H2O、0.41mM NaH2PO4xH2O、15mM HEPES、20mM葡萄糖、0.25% BSA,pH 7.2)稀释,以制备输送溶液(0.1-300μM化合物,最终DMSO<=0.5%)。输送溶液(TL)分别施加至顶端或底侧供给侧用于测量A-B或B-A渗透性(3个过滤器重复)。试样为在实验开始及结束时自供给处收集且亦自接收侧以不同时间间隔收集长达2小时,用于通过HPLC-MS/MS或闪烁计数进行浓度测量。所采样的接收体积由新鲜接收溶液取代。
评估血浆蛋白结合
使用此平衡透析(ED)技术测定测试化合物与血浆蛋白的体外分数结合的近似值。使用Dianorm铁氟龙(Teflon)透析细胞(micro 0.2)。每一单元由供体及受体腔室组成,所述腔室由具有5kDa分子量截止值的超薄半渗透膜隔开。每一测试化合物的原液为在DMSO中以1mM制备并稀释至1.0μM的最终浓度。随后的透析溶液为于来自雄性及雌性供体的汇集人类或大鼠血浆(具有NaEDTA)中制备。将200μL透析缓冲液(100mM磷酸钾,pH 7.4)的等份试样分配于缓冲液腔室中。将200μL测试化合物透析溶液的等份试样分配于血浆腔室中。培育在旋转下在37℃下实施2小时。
在透析时期结束时,将透析液转移至反应管中。缓冲液馏分的管中含有0.2mLACN/水(80/20)。将25μL血浆透析液的等份试样转移至深孔板中并与25μL ACN/水(80/20)、25μL缓冲液、25μL校正溶液及25μL内标准品溶液混合。通过添加200μL ACN实施蛋白质沉淀。将50μL缓冲液透析液的等份试样转移至深孔板中并与25μL空白血浆、25μL内标准品溶液及200μL ACN混合。试样在HPLC-MS/MS系统上进行测量并利用Analyst软件进行评估。结合百分比为利用以下方程式计算:结合%=(血浆浓度-缓冲液浓度/血浆浓度)×100。
评估溶解性
饱和溶液为在孔板(格式取决于机器人)中通过将适当体积的所选水性介质(通常在0.25-1.5ml范围内)添加至每一孔来制备,每一孔中含有已知数量的固体原料药(通常在0.5-5.0mg范围内)。将孔振荡或搅拌预定时间段(通常在2-24h的范围内)且然后使用适当过滤膜(通常具有0.45μm孔径的PTFE过滤器)过滤。通过丢弃最初几滴滤液来避免过滤器吸收。所溶解原料药的量为通过UV光谱测定。此外,使用玻璃电极pH计测量饱和水溶液的pH。
评估药物动力学特征
将测试化合物经静脉内或经口施用给各别测试物种。在施加测试化合物后的几个时间点采集血液试样,抗凝并离心。
对血浆试样中分析物(即,所施用化合物和/或代谢物)的浓度进行定量。PK参数为使用非房室法计算。AUC及Cmax正规化至1μmol/kg的剂量。
体外评估在人类肝细胞中的代谢
使用悬浮液中的原代人类肝细胞研究测试化合物的代谢途径。自冷冻保存恢复后,将人类肝细胞在含有5%人类血清且补充有3.5μg升糖素/500ml、2.5mg胰岛素/500ml及3.75mg氢化可的松/500ml的达尔伯克改良伊格尔培养基中培育。
在细胞培养培育器(37℃,10% CO2)中30min预培育之后,将测试化合物溶液掺加于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(取决于利用原代人类肝细胞观察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。
将细胞在细胞培养培育器中在水平振荡器上培育六小时,并在0、0.5、1、2、4或6小时后自培育取试样,此取决于代谢转换速率。试样用乙腈骤冷并通过离心制成丸粒。将上清液转移至96深孔板,在氮下蒸发并重新悬浮,然后通过液相色谱-高分辨率质谱进行生物分析以鉴别推定代谢物。
结构为基于傅里叶变换(Fourier-Transform)-MSn数据临时指派。代谢物报告为人类肝细胞培育中母体的百分比,其中临限值≥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活性相关或通过TRPA1活性调节的疾病和/或病况,包括(但不限于)治疗和/或预防纤维变性疾病、发炎及免疫调节病症、呼吸道或胃肠疾病或不适、眼科疾病、关节的炎性疾病及鼻咽、眼睛及皮肤的炎性疾病及疼痛及神经病症。所述病症、疾病及病苦包括咳嗽、特发性肺纤维化、其他肺间质性疾病及其他纤维变性、气喘或过敏性疾病、嗜酸性球疾病、慢性阻塞性肺病、以及发炎及免疫调节病症(例如类风湿性关节炎及动脉粥样硬化)、以及疼痛及神经病症(例如急性疼痛、手术疼痛、慢性疼痛及抑郁症)及膀胱病症。
通式1的化合物可用于预防和/或治疗以下各项:
(1)咳嗽,例如慢性特发性咳嗽或慢性难治性咳嗽、与气喘、COPD、肺癌、病毒感染后及特发性肺纤维化及其他肺间质性疾病相关的咳嗽。
(2)肺纤维变性疾病,例如肺炎或与胶原变性相关之间质性肺炎,例如红斑狼疮、全身性硬皮症、类风湿性关节炎、多发性肌炎及皮肌炎、特发性间质性肺炎,例如特发性肺纤维化(IPF)、非特异性间质性肺炎、呼吸性细支气管炎伴间质性肺病、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球性间质性肺炎、淋巴管平滑肌瘤病、肺泡蛋白质沉着症、兰格罕细胞组织球增生症(Langerhan’s cell histiocytosis)、胸膜实质弹性纤维增生、已知病因之间质性肺病,例如由于职业暴露导致之间质性肺炎,例如石棉肺、硅肺病、矿工肺(煤尘)、农夫肺(干草及霉菌)、鸽友肺(鸟类)或其他职业性空中浮游触发因素(例如金属粉尘或分枝杆菌),或由治疗(例如辐射、甲胺喋呤(methotrexate)、胺碘酮(amiodarone)、呋喃妥因(nitrofurantoin)或化学治疗剂)导致之间质性肺炎,或肉芽肿疾病,例如肉芽肿性多发性血管炎、查-施二氏综合征(Churg-Strauss syndrome)、类肉瘤病、过敏性肺炎或由不同病因造成之间质性肺炎(例如误吸、吸入有毒气体、蒸气,支气管炎或肺炎或由心脏衰竭、X-射线、辐射、化学疗法、M.boeck症或类肉瘤病、肉芽肿病、囊性纤维化或胶稠性黏液病、α-1-抗胰蛋白酶缺乏引起之间质性肺炎)、由新冠病毒/SARS-Cov-2感染导致的急性肺损伤或继发于新冠病毒/SARS-Cov-2感染的肺纤维化。
(3)其他纤维变性疾病,例如肝桥接纤维化、肝硬化、非酒精性脂肪性肝炎(NASH)、心房纤维化、心肌内膜纤维化、陈旧性心肌梗塞、胶质瘢痕、动脉僵硬、关节纤维化、Dupuytren氏挛缩、瘢瘤、硬皮症/全身性硬化、纵膈纤维化、骨髓纤维化、Peyronie氏病、肾原性全身性纤维化、腹膜后纤维化、黏连性滑膜囊炎。
(4)发炎、自体免疫或过敏性疾病及病况,例如过敏性或非过敏性鼻炎或窦炎、慢性窦炎或鼻炎、鼻瘜肉、慢性鼻窦炎、急性鼻窦炎、气喘、小儿气喘、过敏性支气管炎、肺泡炎、气道高反应性、过敏性结膜炎、支气管扩张症、成人呼吸窘迫综合征、支气管及肺水肿、支气管炎或肺炎、嗜酸性球性蜂窝组织炎(例如Well氏综合征)、嗜酸性球性肺炎(例如吕佛勒氏综合征(Loeffler's syndrome)、慢性嗜酸性球性肺炎)、嗜酸性球性筋膜炎(例如,Shulman氏综合征)、迟发型过敏、非过敏性气喘;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;全身性过敏反应或过敏性反应、药物过敏(例如对青霉素、头孢菌素)、由于摄入受污染色氨酸所致的嗜酸性球增多-肌痛综合征、昆虫刺伤过敏;自体免疫疾病,例如类风湿性关节炎、格雷氏病(Graves'disease)、薛格连氏综合征(Sjogren's syndrome)、牛皮癣关节炎、多发性硬化、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、儿童ITP)、免疫学溶血性贫血(自体免疫及药物诱发)、Evans氏综合征(血小板及红血球免疫性血球减少症)、新生儿Rh病、古巴士德氏综合征(Goodpasture's syndrome)(抗GBM病)、乳糜泻、自体免疫性心肌病、幼发型糖尿病;肾小球性肾炎、自体免疫性甲状腺炎、贝赛特氏病(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,例如克隆氏病(Crohn's disease)及溃疡性结肠炎;脊椎关节疾病;硬皮症;牛皮癣(包括T细胞介导的牛皮癣)及炎性皮肤病,例如皮肤炎、湿疹、异位性皮肤炎、过敏性接触性皮肤炎、荨麻疹;血管炎(例如,坏死性、皮肤及过敏性血管炎);结节性红斑;嗜酸性球性肌炎、嗜酸性球性筋膜炎、癌症伴皮肤或器官的白血球浸润;眼科疾病,例如年龄相关性黄斑退化、糖尿病视网膜病变及糖尿病黄斑水肿、角膜炎、嗜酸性球性角膜炎、角膜结膜炎、春季角膜结膜炎、结瘢、眼前段结瘢、眼睑炎、睑结膜炎、大疱性病症、疤痕性类天疱疮、结膜黑色素瘤、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、格雷氏眼病(Graves'ophthalmopathy)、眼内黑色素瘤、睑裂斑、增殖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,例如慢性特发性疼痛综合征、神经病性疼痛、感觉迟钝、触摸痛、偏头痛、牙齿痛及术后疼痛。
(6)抑郁症、焦虑、糖尿病性神经病变及膀胱病症,例如膀胱出口阻塞、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,本发明涉及作为药剂的通式1化合物。
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TRPA1活性调节的疾病和/或病况的用途。
此外,本发明涉及通式1的化合物用于治疗和/或预防纤维变性疾病、发炎及免疫调节病症、呼吸道或胃肠疾病或不适、眼科疾病、关节的炎性疾病及鼻咽、眼睛及皮肤的炎性疾病、疼痛及神经病症的用途。所述病症、疾病及病苦包括咳嗽、特发性肺纤维化、其他肺间质性疾病及其他纤维变性、气喘或过敏性疾病、嗜酸性球疾病、慢性阻塞性肺病、以及发炎及免疫调节病症(例如类风湿性关节炎及动脉粥样硬化)、以及疼痛及神经病症(例如急性疼痛、手术疼痛、慢性疼痛及抑郁症)及膀胱病症。
此外,本发明涉及通式1的化合物用于治疗和/或预防以下各项的用途:
(1)咳嗽,例如慢性特发性咳嗽或慢性难治性咳嗽、与气喘、COPD、肺癌、病毒后感染及特发性肺纤维化及其他肺间质性疾病相关的咳嗽。
(2)肺纤维变性疾病,例如肺炎或与胶原变性相关之间质性肺炎,例如红斑狼疮、全身性硬皮症、类风湿性关节炎、多发性肌炎及皮肌炎、特发性间质性肺炎,例如特发性肺纤维化(IPF)、非特异性间质性肺炎、呼吸性细支气管炎伴间质性肺病、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球性间质性肺炎、淋巴管平滑肌瘤病、肺泡蛋白质沉着症、兰格罕细胞组织球增生症、胸膜实质弹性纤维增生、已知病因之间质性肺病,例如由于职业暴露导致之间质性肺炎,例如石棉肺、硅肺病、矿工肺(煤尘)、农夫肺(干草及霉菌)、鸽友肺(鸟类)或其他职业性空中浮游触发因素(例如金属粉尘或分枝杆菌),或由治疗(例如辐射、甲胺喋呤、胺碘酮、呋喃妥因或化学治疗剂)导致的间质性肺炎,或肉芽肿疾病,例如肉芽肿性多发性血管炎、查-施二氏综合征、类肉瘤病、过敏性肺炎或由不同病因造成之间质性肺炎(例如误吸、吸入有毒气体、蒸气,支气管炎或肺炎或由心脏衰竭、X-射线、辐射、化学疗法、M.boeck症或类肉瘤病、肉芽肿病、囊性纤维化或胶稠性黏液病、α-1-抗胰蛋白酶缺乏引起之间质性肺炎)、由新冠病毒/SARS-Cov-2感染导致的急性肺损伤或继发于新冠病毒/SARS-Cov-2感染的肺纤维化。
(3)其他纤维变性疾病,例如肝桥接纤维化、肝硬化、非酒精性脂肪性肝炎(NASH)、心房纤维化、心肌内膜纤维化、陈旧性心肌梗塞、胶质瘢痕、动脉僵硬、关节纤维化、Dupuytren氏挛缩、瘢瘤、硬皮症/全身性硬化、纵膈纤维化、骨髓纤维化、Peyronie氏病、肾原性全身性纤维化、腹膜后纤维化、黏连性滑膜囊炎。
(4)发炎、自体免疫或过敏性疾病及病况,例如过敏性或非过敏性鼻炎或窦炎、慢性窦炎或鼻炎、鼻瘜肉、慢性鼻窦炎、急性鼻窦炎、气喘、小儿气喘、过敏性支气管炎、肺泡炎、气道高反应性、过敏性结膜炎、支气管扩张症、成人呼吸窘迫综合征、支气管及肺水肿、支气管炎或肺炎、嗜酸性球性蜂窝组织炎(例如Well氏综合征)、嗜酸性球性肺炎(例如吕佛勒氏综合征、慢性嗜酸性球性肺炎)、嗜酸性球性筋膜炎(例如,Shulman氏综合征)、迟发型过敏、非过敏性气喘;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;全身性过敏反应或过敏性反应、药物过敏(例如对青霉素、头孢菌素)、由于摄入受污染色氨酸所致的嗜酸性球增多-肌痛综合征、昆虫刺伤过敏;自体免疫疾病,例如类风湿性关节炎、格雷氏病、薛格连氏综合征、牛皮癣关节炎、多发性硬化、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、儿童ITP)、免疫学溶血性贫血(自体免疫及药物诱发)、Evans氏综合征(血小板及红血球免疫性血球减少症)、新生儿Rh病、古巴士德氏综合征(抗GBM病)、乳糜泻、自体免疫性心肌病、幼发型糖尿病;肾小球性肾炎、自体免疫性甲状腺炎、贝赛特氏病;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,例如克隆氏病及溃疡性结肠炎;脊椎关节疾病;硬皮症;牛皮癣(包括T细胞介导的牛皮癣)及炎性皮肤病,例如皮肤炎、湿疹、异位性皮肤炎、过敏性接触性皮肤炎、荨麻疹;血管炎(例如,坏死性、皮肤及过敏性血管炎);结节性红斑;嗜酸性球性肌炎、嗜酸性球性筋膜炎、癌症伴皮肤或器官的白血球浸润;眼科疾病,例如年龄相关性黄斑退化、糖尿病视网膜病变及糖尿病黄斑水肿、角膜炎、嗜酸性球性角膜炎、角膜结膜炎、春季角膜结膜炎、结瘢、眼前段结瘢、眼睑炎、睑结膜炎、大疱性病症、疤痕性类天疱疮、结膜黑色素瘤、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、格雷氏眼病、眼内黑色素瘤、睑裂斑、增殖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,例如慢性特发性疼痛综合征、神经病性疼痛、感觉迟钝、触摸痛、偏头痛、牙齿痛及术后疼痛。
(6)抑郁症、焦虑、糖尿病性神经病变及膀胱病症,例如膀胱出口阻塞、膀胱过度活动症、膀胱炎;心肌再灌注损伤或脑缺血损伤。
在其他方面中,本发明涉及通式1的化合物,其用于治疗和/或预防以上提及的疾病及病况。
在其他方面中,本发明涉及通式1的化合物用于制备药剂的用途,该药剂用于治疗和/或预防以上提及的疾病及病况。
在本发明的其他方面中,本发明涉及用于治疗或预防以上提及的疾病及病况的方法,该方法包含将有效量的通式1化合物施用给人类。
组合疗法
本发明化合物可进一步与一种或多种、优选一种其他治疗剂组合。根据一个实施方案,额外治疗剂选自以下的群:可用于治疗上文所述疾病或病况、特定地与纤维变性疾病、发炎及免疫调节病症、呼吸道或胃肠疾病或不适、关节的炎性疾病或鼻咽、眼睛及皮肤的炎性疾病或病况(例如咳嗽、特发性肺纤维化、其他肺间质性疾病、气喘或过敏性疾病、嗜酸性球疾病、慢性阻塞性肺病、异位性皮肤炎)以及自体免疫性病变(例如类风湿性关节炎及动脉粥样硬化)相关的疾病或病况的治疗剂或可用于治疗眼科疾病、疼痛及抑郁症的治疗剂。
适于所述组合的其他治疗剂特定包括那些(例如)加强一种或多种活性物质关于所提及适应症中之一者的治疗效应者和/或允许减少一种或多种活性物质的剂量者。
因此,本发明化合物可与一种或多种选自由以下组成的组的其他治疗剂组合:抗纤维化剂、止咳剂、消炎剂、抗异位性皮肤炎药剂、止痛药、抗发厥剂、抗焦虑剂、镇静剂、骨骼肌松弛剂或抗抑郁剂。
抗纤维化剂例如为尼达尼布(nintedanib)、吡非尼酮(pirfenidone)、磷酸二酯酶-IV(PDE4)抑制剂(例如罗氟司特(roflumilast))、自分泌运动因子抑制剂(autotaxininhibitor)(例如GLPG-1690或BBT-877);结缔组织生长因子(CTGF)阻断抗体,例如潘瑞鲁单抗(Pamrevlumab);B细胞活化因子受体(BAFF-R)阻断抗体,例如拉那鲁单抗(Lanalumab);α-V/β-6阻断抑制剂,例如BG-00011/STX-100、重组正五聚蛋白-2(recombinant pentraxin-2,PTX-2),例如PRM-151;c-Jun N-末端激酶(JNK)抑制剂,例如CC-90001;半乳糖凝集素-3抑制剂,例如TD-139;G蛋白偶联受体84(GPR84)抑制剂,例如GLPG-1205;G蛋白偶联受体84/G蛋白偶联受体40双重抑制剂,例如PBI-4050;含Rho相关卷曲螺旋蛋白激酶2(ROCK2)抑制剂,例如KD-025;热休克蛋白47(HSP47)小干扰RNA,例如BMS-986263/ND-L02-s0201;Wnt路径抑制剂,例如SM-04646;LD4/PDE3/4抑制剂,例如Tipelukast;组氨酰基tRNA合成酶(HARS)的重组免疫调节结构域,例如ATYR-1923;前列腺素合酶抑制剂,例如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,如2(LOXL2)抑制剂,例如PAT-1251、PXS-5382/PXS-5338;磷酸肌醇3-激酶(PI3K)/哺乳动物雷帕霉素靶蛋白(mTOR)双重抑制剂,例如HEC-68498;钙蛋白酶抑制剂,例如BLD-2660;促分裂原活化蛋白激酶激酶激酶(MAP3K19)抑制剂,例如MG-S-2525;壳质酶抑制剂,例如OATD-01;促分裂原活化蛋白激酶活化蛋白激酶2(MAPKAPK2)抑制剂,例如MMI-0100;转变生长因子β1(TGF-beta1)小干扰RNA,例如TRK250/BNC-1021;或溶血磷脂酸受体拮抗剂,例如BMS-986278。
止咳剂例如为嘌呤受体3(P2X3)受体拮抗剂,例如吉法匹生(gefapixant)、S-600918、BAY-1817080或BLU-5937;神经激肽1(NK-1)受体拮抗剂,例如奥维匹坦、阿瑞匹坦;烟碱型乙酰胆碱受体α7亚单位刺激物,例如ATA-101/布拉他尼林(bradanicline);可待因(codeine)、加巴喷丁(gabapentin)、普瑞巴林(pregablin)或阿奇霉素(azithromycin)。
消炎剂例如为皮质类固醇,例如普赖苏浓(prednisolone)或地塞米松(dexamethasone);环氧化酶-2(COX2)抑制剂,例如塞来昔布(celecoxib)、罗非昔布(rofecoxib)、帕瑞昔布(parecoxib)、伐地昔布(valdecoxib)、德拉昔布(deracoxib)、依托昔布(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,例如孟鲁司特(montelukast);5-脂肪加氧酶抑制剂;或其他非类固醇消炎剂(NSAID),例如阿斯匹林(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)。
抗异位性皮肤炎剂例如为环孢素(cyclosporin)、甲胺喋呤(methotrexate)、吗替麦考酚酯(mycophenolate mofetil)、硫唑嘌呤(azathioprine)、磷酸二酯酶抑制剂(例如阿普斯特(apremilast)、克立硼罗(crisaborole))、Janus相关激酶(JAK)抑制剂(例如托法替尼(tofacitinib))、针对IL-4/IL-13的中和抗体(例如度普利尤单抗(dupilumab))、IL-13(例如来瑞珠单抗(lebrikizumab)、曲罗芦单抗(tralokinumab))及IL-31(奈莫利珠单抗(nemolizumab))。
止痛药例如为类鸦片型,例如吗啡(morphine)、氧化吗啡(oxymorphine)、左啡诺(levorphanol)、羟考酮(oxycodone)、丙氧芬(propoxyphene)、纳美芬(nalmefene)、芬太尼(fentanyl)、氢可酮(hydrocodone)、氢吗啡酮(hydromorphone)、美利皮定(meripidine)、美沙酮(methadone)、纳洛芬(nalorphine)、那若松(naloxone)、那曲酮(naltrexone)、丁基原啡因(buprenorphine)、布托啡诺(butorphanol)、纳布啡(nalbuphine)、戊唑辛(pentazocine);或非类鸦片型,例如乙酰胺酚(acetaminophen)。
抗抑郁剂例如为三环抗抑郁剂,例如阿米替林(amitriptyline)、氯米帕明(clomipramine)、地昔帕明(desipramine)、多虑平(doxepin)、地昔帕明、伊米帕明(imipramine)、去甲替林(nortriptyline);选择性血清素再摄取抑制剂抗抑郁剂(SSRI),例如氟西汀(fluoxetine)、帕罗西汀(paroxetine)、舍曲林(sertraline)、西酞普兰(citalopram)、依地普仑(escitalopram);去甲肾上腺素再摄取抑制剂抗抑郁剂(SNRI),例如麦普替林(maprotiline)、洛非帕明(lofepramine)、米氮平(mirtazapine)、羟丙替林(oxaprotiline)、非唑拉明(fezolamine)、托莫西汀(tomoxetine)、米安舍林(mianserin)、安非他酮(buproprion)、羟基安非他酮(hydroxybuproprion)、诺米芬辛(nomifensine)、维洛沙嗪(viloxazine);双重血清素-去甲肾上腺素再摄取抑制剂抗抑郁剂(SNRI),例如度洛西汀(duloxetine)、万拉法辛(venlafaxine)、地万拉法辛(desvenlafaxine)、左米那普仑(levomilnacipran);非典型抗抑郁药,例如曲唑酮(trazodone)、米氮平、沃替西汀(vortioxetine)、维拉佐酮(vilazodone)、安非他酮;或单胺氧化酶抑制剂抗抑郁剂(MAOI),例如强内心百乐明(tranylcypromine)、苯乙肼(phenelzine)或异唑肼(isocarboxazid)。
抗焦虑剂例如为苯并二氮杂卓,例如阿普唑仑(alprazolam)、溴西泮(bromazepam)、氯二氮平(chlordiazepoxide)、可那氮平(clonazepam)、氯拉卓酸(clorazepate)、二氮平(diazepam)、氟西泮(flurazepam)、氯羟去甲安定(lorazepam)、去甲羟基安定(oxazepam)、替马西泮(temazepam)、三唑仑(triazolam)或托非索泮(tofisopam);或其为非苯并二氮杂卓类安眠药,例如右旋佐匹克隆(eszopiclone)、扎来普隆(zaleplon)、唑吡坦(zolpidem)或佐匹克隆(zopiclone);或其为氨基甲酸酯,例如甲丙胺酯(meprobamate)、肌安宁(carisoprodol)、泰巴氨酯(tybamate)或劳氨酯(lorbamate);或其为抗组织胺,例如羟嗪(hydroxyzine)、氯苯那敏(chlorpheniramine)或苯海拉明(diphenhydramine)。
镇静剂例如为巴比妥酸盐镇静剂,例如异戊巴比妥(amobarbital)、阿普比妥(aprobarbital)、仲丁巴比妥(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)、硫阿米妥(thiamylal)或硫喷妥(thiopental);或其为非巴比妥酸盐类镇静剂,例如格鲁米特(glutethimide)、甲丙胺酯(meprobamate)、甲喹酮(methaqualone)或氯醛比林(dichloralphenazone)。
骨骼肌松弛剂例如为巴氯芬(baclofen)、甲丙胺酯、肌安宁、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)或邻甲苯海拉明(orphenadrine)。
其他适宜组合配对物为乙酰胆碱酯酶抑制剂,例如多奈派齐(donepezil);5-HT-3拮抗剂,例如昂丹司琼(ondansetron);代谢型谷氨酸受体拮抗剂;抗心律不整剂,例如墨西律定(mexiletine)或苯妥英(phenytoin);或NMDA受体拮抗剂。
进一步适宜组合配对物为失禁药物,例如抗胆碱剂,例如羟布托尼(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,例如米拉贝隆(mirabegron);或其为α阻断剂,例如坦洛新(tamsulosin)、阿夫唑嗪(alfuzosin)、西洛多辛(silodosin)、多沙唑嗪(doxazosin)或特拉唑嗪(terazosin)。
上文所提及组合配对物的剂量通常为正常推荐最低剂量的1/5至最高正常推荐剂量的1/1。
因此,在另一方面中,本发明涉及本发明化合物与上文及下文所述一种或多种其他治疗剂组合的用途,其用于治疗可受TRPA1影响或由TRPA1介导的疾病或病况,特别地如上文及下文所述的疾病或病况。
在其他方面中,本发明涉及用于治疗患者的可受TRPA1抑制影响的疾病或病况的方法,其包括向需要该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与治疗有效量的一种或多种其他治疗剂的组合的步骤。
在其他方面中,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其他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况。
在另一方面中,本发明涉及用于治疗患者的由TRPA1活性介导的疾病或病况的方法,其包括向需要该治疗的患者、优选人类施用治疗有效量的本发明化合物与治疗有效量的上文及下文中所述一种或多种其他治疗剂的步骤。
本发明化合物与其他治疗剂组合的使用可同时或在交错时间进行。
本发明化合物及一种或多种其他治疗剂二者可一起存在于一种调配物(例如片剂或胶囊)中或分开存在于两种相同或不同调配物(例如所谓的部分试剂盒(kit-of-parts)形式)中。
因此,在另一方面中,本发明涉及药物组合物,其包含本发明的化合物及上文及下文所述的一种或多种其他治疗剂以及任选一种或多种惰性载剂和/或稀释剂。
在再另一方面中,本发明涉及本发明化合物在咳嗽测量装置中的用途。
根据以下更详细的例子可了解本发明的其他特征及优点,所述实施例以实施例方式说明本发明的原理。
制备
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阐述于有机合成文献中的合成方法来获得。优选地,化合物为以类似于下文更全面解释、特定地如实验部分中所述的制备方法来获得。在一些情形中,可改变实施反应步骤的顺序。亦可使用本领域技术人员已知但本文未详细阐述的反应方法的变化形式。
本领域技术人员在研究下文方案后将了解制备本发明化合物的一般制程。起始材料或中间体中的任何官能基可使用常规保护基团进行保护。所述保护基团可在反应顺序内的适宜阶段使用本领域技术人员熟知的方法再次裂解。
本发明化合物通过下文所述合成方法来制备,其中通式的取代基具有上文所给含义。所述方法意欲作为本发明的说明,而非限制其目标物及所述实施例所主张化合物的范围。在未阐述起始化合物的制备的情形中,其为市面可获得或可以与本文中所述已知化合物或方法类似的方式制备。文献中所阐述的物质为根据公开的合成方法制备。缩写定义于实施例部分中。
方案1:
在方案1中,式I化合物可经由在碱(例如碳酸钾)的存在下利用氯亚甲基-噁二唑(B)使中间体(A)进行N-烷基化来合成。
方案2:
在方案2中,5-氨基嘧啶-4,6-二醇利用在α位携带离去基团的经活化乙酸(例如,氯-乙酰氯)酰胺化且随后在碱(例如,DIPEA)的存在下环化获得(C)。具有保护基团(例如,对-甲氧基苄基)的嘧啶酮(C)的N-烷基化可通过在碱(例如,K2CO3)的存在下利用携带离去基团的适当试剂(例如,对-甲氧基苄基氯,PMB-Cl)处理(C)来达成。此允许在碱(例如,K2CO3)的存在下(D)的随后N-甲基化(例如,利用MeI),以获得(E)。最后,(E)的保护基团在适宜条件(例如,对于PMB:三氟乙酸,100℃)下的裂解获得中间体(A)。
方案3:
在方案3中,将自羧酸酯(D)合成的α-氰基酮(E)以对映选择性方式通过使用适当催化系统还原以提供醇(F),该催化系统使用过渡金属络合物(例如Ru或Ir)与手性配体(例如[(1S,2S)-(-)-2-氨基-1,2-二苯基乙基](4-甲苯磺酰基)酰胺基)的组合及氢源(例如甲酸三乙胺络合物)。将羟基胺添加至所述醇(F)以提供二羟基丙脒(G)。氯亚甲基-噁二唑(B)的死循环可通过将反应混合物与氯乙酰氯一起在碱(例如DIPEA)的存在下搅拌来达成。
实施例
制备
本发明化合物及其中间体可使用本领域技术人员已知且有机合成文献中阐述的合成方法(例如使用“Comprehensive Organic Transformations”,第2版,RichardC.Larock,John Wiley&Sons,2010及“March’s Advanced Organic Chemistry”,第7版,Michael B.Smith,John Wiley&Sons,2013中所述的方法)获得。优选地,化合物为类似于下文更全面地解释、特别地如实验部分中所述的制备方法获得。在一些情形中,可改变实施反应方案所采用的顺序。亦可使用本领域技术人员已知但本文未详细阐述的所述反应的变化形式。本领域技术人员在研究下文方案后将了解用于制备本发明化合物的一般方法。起始化合物可自市场购得或可通过文献或本文中阐述的方法来制备,或可以类似或相似的方式来制备。在实施反应之前,可使用常规保护基团来保护起始化合物中的任何相应官能基。所述保护基团可在反应序列内的适宜阶段使用本领域技术人员熟知且文献(例如“Protecting Groups”,第3版,Philip J.Kocienski,Thieme,2005及“Protective Groupsin Organic Synthesis”,第4版,Peter G.M.Wuts,Theodora W.Greene,John Wiley&Sons,2006)中所阐述的方法再次裂解。术语“环境温度”及“室温”可互换使用且指定约20℃的温度,例如介于19℃与24℃之间。
缩写:
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中间体的制备
中间体I
中间体I.1(一般途径)
(3S)-3-(4-氯苯基)-3-羟基丙腈
在惰性气氛下将10.0g(55.7mmol)4-氯苯甲酰基乙腈添加至100mL ACN。添加142mg(0.23mmol)氯([(1S,2S)-2-氨基-1,2-二苯基乙基](4-甲苯磺酰基)酰胺基)(均三甲苯基)钌(II)(CAS174813-81-1),随后逐滴添加8.30mL(19.8mmol)甲酸三乙胺络合物(5:2)。在RT下搅拌3h后,在真空中去除溶剂。向剩余粗制混合物中添加水且此混合物利用EtOAc萃取两次。将有机层合并,经MgSO4干燥,过滤,并在真空中去除溶剂,以提供中间体I.1。
C9H8ClNO (M=181.6g/mol)
ESI-MS: 226[M+HCOO]-
Rt(HPLC): 0.81min(方法B)
以下化合物为使用类似于针对中间体I.1所述那些的程序使用适当起始材料制备。如本领域技术人员所了解,所述类似实施例可涉及一般反应条件中的变化。
中间体II
中间体II.1(一般途径)
(3S)-3-(4-氯苯基)-N,3-二羟基丙脒
向于100mL MeOH中的9.82g(54.1mmol)(3S)-3-(4-氯苯基)-3-羟基丙腈(中间体I.1)添加8.00mL(136mmol)羟基胺(50%于水中)并将混合物在75℃下搅拌1.5h。冷却至RT后,在真空中去除所有挥发物以获得粗制产物,其不经进一步纯化即使用。
C9H11ClN2O2 (M=214.6g/mol)
ESI-MS: 215[M+H]+
Rt(HPLC): 0.60min(方法B)
以下化合物为使用类似于针对中间体II.1所述那些的程序使用适当起始材料制备。如本领域技术人员所了解,所述类似实施例可涉及一般反应条件中的变化。
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中间体III
中间体III.1(一般途径)
(1S)-2-[5-(氯甲基)-1,2,4-噁二唑-3-基]-1-(4-氯苯基)乙-1-醇
向于55mL NMP中的11.2g(52.4mmol)中间体II.1中添加10.0mL(57.8mmol)DIPEA。将混合物冷却至0℃,然后缓慢添加溶于5mL NMP中的4.60mL(57.7mmol)氯乙酰氯并将混合物于0℃下搅拌45min.。然后将混合物加热至高达95℃并继续搅拌4h。冷却至RT后,添加200mL水并将所得混合物利用EtOAc萃取三次。将有机层合并,经MgSO4干燥,过滤并在真空中去除溶剂。残余物通过柱色谱(硅胶;PE/EtOAc,7/3)纯化。
C11H10Cl2N2O2 (M=273.1g/mol)
ESI-MS: 271[M-H]-
Rt(HPLC): 0.93min(方法B)
以下化合物为使用类似于针对中间体III.1所述那些的程序使用适当起始材料制备。如本领域技术人员所了解,所述类似实施例可涉及一般反应条件中的变化。
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中间体IV
中间体IV.1(一般途径)
3-(6-氟-1-苯并噻吩-2-基)-3-氧代丙腈
在惰性气氛下在RT下向于9.0mL无水甲苯及0.78mL无水ACN中的0.63g(3.00mmol)6-氟-1-苯并噻吩-2-甲酸甲酯中添加0.36g(9.00mmol)的NaH(60%于油中)。将混合物加热至回流并搅拌16h,冷却至室温,倾倒于冰/水(30mL)上,用2M HCl处理以达到pH=1。添加EtOAc(20mL)且相分离。将水相再次用EtOAc(20mL)萃取,合并的有机相用盐水(20mL)洗涤,且在减压下去除溶剂。通过硅胶柱色谱使用EtOAc/己烷的梯度(30%至40%)纯化粗产物。
C11H6FNOS (M=219.23g/mol)
ESI-MS: 218[M-H]-
Rt(HPLC): 3.31min(E)
以下化合物为使用类似于针对中间体IV.1所述那些的程序使用适当起始材料制备。如本领域技术人员所了解,所述类似实施例可涉及一般反应条件中的变化。
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中间体V
3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮
在搅拌下在65℃下向于300mL DMF中的10.0g(127.10mmol)5-氨基嘧啶-4,6-二醇中缓慢添加7.5mL(94.41mmol)氯乙酰氯。在65℃下搅拌1.5h之后,将36.1mL(129.94mmol)DIPEA缓慢添加至反应混合物中并在65℃下继续搅拌45min。将反应混合物在减压下浓缩,用水处理,并将沉淀产物过滤,用少量EtOH洗涤并干燥。
C6H5N3O3 (M=167.1g/mol)
ESI-MS: 168[M+H]+
Rt(HPLC): 0.20min(方法G)
中间体VI
3-[(4-甲氧基苯基)甲基]-5-甲基-3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮
将于15mL DMF中的680mg(4.07mmol)3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮(中间体V)利用843mg(6.10mmol)碳酸钾处理并在RT下搅拌15min。添加0.58mL(4.27mmol)1-(甲基)-4-甲氧基苯并将反应混合物搅拌20h。添加843mg(6.10mmol)碳酸钾及0.30ml(4.88mmol)碘甲烷并将反应混合物在RT下搅拌20h。添加0.26ml(4.07mmol)碘甲烷并将反应混合物在RT下搅拌20h,过滤,在减压下浓缩并通过反相HPLC(ACN/H2O梯度,0.1% TFA)纯化。
C15H15N3O4 (M=301.3g/mol)
ESI-MS: 302[M+H]+
Rt(HPLC): 0.95min(方法B)
中间体VII
5-甲基-3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮
将5.30g(14.07mmol)3-[(4-甲氧基苯基)甲基]-5-甲基-3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮(中间体VI)用16ml TFA处理并在100℃下搅拌1.5h。此后,将反应混合物在微波中在120℃下搅拌15min,倾倒于冰水上并过滤。将滤液冻干并不经进一步纯化即直接使用。
C7H7N3O3 (M=181.2g/mol)
ESI-MS: 182[M+H]+
Rt(HPLC): 0.37min(方法B)
最终化合物的制备
实施例1(一般程序)
3-({3-[(2S)-2-(4-氯苯基)-2-羟乙基]-1,2,4-噁二唑-5-基}甲基)-5-甲基-3H,4H,5H,6H,7H-嘧啶并[4,5-b][1,4]噁嗪-4,6-二酮
将30mg(0.11mmol)中间体VII、20mg(0.11mmol)中间体III.1及30mg(0.22mmol)K2CO3于1.0mL DMF中的混合物在RT下搅拌1h。将反应混合物过滤且滤液通过反相HPLC(ACN/H2O梯度,0.1%TFA)纯化,获得期望产物。
C18H16ClN5O4 (M=417.80g/mol)
ESI-MS: 418[M+H]+
Rt(HPLC): 0.44min(方法A)
1H NMR(400MHz,DMSO-d6)δppm:2.90-3.10(m,2H),3.33(s,3H),4.82(s,2H),4.96(dd,J=7.9,5.7Hz,1H),5.48(s,2H),7.32-7.39(m,4H),8.44(s,1H)
以下化合物为使用类似于针对实施例1一般程序所述那些的程序使用适当起始材料制备。如本领域技术人员所了解,所述类似实施例可涉及一般反应条件中的变化。
以上表中所述化合物的分析数据:
分析型HPLC方法
方法A
分析型柱:XBridge BEH C18_2.1x30mm,1.7μm;柱温度:60℃
方法B
分析型柱:Stable Bond(Agilent)1.8μm;3.0x30mm;柱温度:60℃
方法C
分析型柱:Sunfire(Waters)2.5μm;3.0x30mm;柱温度:60℃
方法D
制备型柱:Sunfire(Waters)C18_3.0x30mm_2.5μm;柱温度:60℃
方法E
分析型柱:AQUITY UPLC C18_2.1x50mm_1.8μm.柱温度:25℃
方法F
分析型柱:AQUITY UPLC C18_2.1x50mm_1.8μm.柱温度:25℃
方法G
分析型柱:Zorbax StableBond(Agilent)C18_3.0x30mm_1.8μm;柱温度:60℃
方法H
分析型柱:XBridge Phenyl_2.1x30mm,1.7μm;柱温度:60℃
Claims (9)
1.一种式(I)化合物,
其中
A选自由以下组成的组:苯基、噻吩基、苯并呋喃基及苯并噻吩基,且其中A未经取代或经由卤素及C1-4-烷基组成的基团R1的一或两个成员取代。
2.根据权利要求1的式(I)化合物,其中R1选自F、Cl、I及CH3。
3.根据权利要求1或2中任一项的式(I)化合物,其中A选自由以下组成的组:
及/>
且其中A未经取代或经该基团R1的一或两个成员取代。
4.根据权利要求1的式(I)化合物,其选自由以下组成的组:
及
5.一种根据权利要求1至4中任一项的化合物的盐,特别是药学上可接受的盐。
6.一种药物组合物,其包含至少一种根据权利要求1至4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。
7.根据权利要求1至4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。
8.根据权利要求1至4中任一项的式(I)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。
9.根据权利要求1至4中任一项的式(I)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疾病(IPF)或咳嗽。
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