CN115803029A - 作为trpa1抑制剂的四唑衍生物 - Google Patents
作为trpa1抑制剂的四唑衍生物 Download PDFInfo
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- CN115803029A CN115803029A CN202180045969.9A CN202180045969A CN115803029A CN 115803029 A CN115803029 A CN 115803029A CN 202180045969 A CN202180045969 A CN 202180045969A CN 115803029 A CN115803029 A CN 115803029A
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Abstract
本发明提供为短暂性受体电位锚蛋白1(transient receptor potential ankyrin 1;TRPA1)的抑制剂的某些四唑衍生物,且因此适用于治疗可通过抑制TRPA1来治疗的疾病。本发明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
本发明提供为短暂性受体电位锚蛋白1(TRPA1)的抑制剂的某些四唑衍生物,且因此适用于治疗可通过抑制TRPA1来治疗的疾病。本发明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
短暂性受体电位信道(TRP信道)是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。存在大约30个结构相关的TRP信道,其被分成以下类别:TRPA、TRPC、TRPM、TRPML、TRPN、TRPP及TRPV。短暂性受体电位阳离子通道子族A成员1(TRPA1),也称为短暂性受体电位锚蛋白1,为TRPA基因子族的唯一成员。在结构上,TRPA信道的特征是有多个N端锚蛋白重复序列(人类TRPA1的N端处有约14个),其产生针对锚蛋白的“A”的命名(Montell,2005)。
TRPA1高度表达于为皮肤及肺服务的背根神经节及结节神经节的感觉神经元的质膜中,以及小肠、结肠、胰脏、骨胳肌、心脏、脑部、膀胱及淋巴细胞中(https://www.proteinatlas.org/),以及人类肺纤维母细胞中。
TRPA1最广为人知的为作为产生诸如疼痛、寒冷及瘙痒的体觉模态的环境刺激物的传感器。TRPA1为由多个反应性、亲电性刺激(例如异硫氰酸烯丙酯、反应性含氧物),以及非反应性化合物(例如伊西林(icilin))激活,其涉及与哮喘、慢性阻塞性肺病(COPD)、特发性肺纤维化(IPF)相关的咳嗽或病毒感染后咳嗽(post-viral cough),或者慢性特发性咳嗽以及敏感患者的咳嗽(Song及Chang,2015;Grace及Belvisi,2011)。基于显示咳嗽诱发TGF-β升高的研究(Xie等人,2009;Froese等人,2016;Tschumperlin等人,2003;Yamamoto等人,2002;Ahamed等人,2008),TRPA1抑制剂适用于治疗由于咳嗽与肺脏损伤之间有联系而咳嗽非常普遍的IPF。TRPA1拮抗剂抑制由咳嗽诱因(诸如香烟烟雾提取物(CSE)氧化应激、炎症介质释放及抗氧化基因表达下调)触发的钙信号(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)、接触性皮炎(Liu等人,2013)、牛皮癣相关的瘙痒(Wilson等人,2013)及IL-31相关的瘙痒(Cevikbas等人,2014)的研究中有效。人类TRPA1的功能获得与家族性阵发性疼痛综合征相关(Kremeyer等人,2010)。TRPA1拮抗剂在偏头痛相关的异常疼痛的行为模型中亦有效(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在神经支配受损牙齿的三叉神经节中选择性增加(Haas等人,2011)。已知若干麻醉剂是TRPA1激动剂,包括异氟醚(Matta等人,2008),其为TRPA1抑制剂提供了缓解术后疼痛的基本原理。TRPA1基因剔除小鼠及野生型小鼠经TRPA1拮抗剂治疗后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之间存在反向调节的机理联系的研究,预期TRPA1抑制剂将有益于治疗糖尿病神经病变(Hiyama等人,2018;Koivisto及Pertovaara,2013;Wang等人,2018)。与野生型小鼠相比,所展现的TRPA1基因剔除小鼠的心肌梗塞面积较小(Conklin等人,2019)。TRPA1基因剔除及药理学干预抑制小鼠中TNBS诱发的结肠炎(Engel等人,2011)。在小鼠脑局部缺血模型中,TRPA1基因剔除及TRPA1拮抗剂减少髓鞘损伤(Hamilton等人,2016)。在痛风的单钠尿酸盐小鼠模型中,TRPA1基因剔除小鼠中的尿酸盐晶体及关节炎症减少(Moilanen等人,2015)。大鼠中TRPA1缺失改善大鼠急性痛风发作模型中的关节炎症及痛觉过敏(Trevisan等人,2014)。TRPA1的激活引起骨关节炎软骨细胞的发炎反应(Nummenmaaet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炎症介质(Nummenmaa等人,2016)。最后,TRPA1基因剔除小鼠在MIA诱发的膝关节肿胀模型中显现出对骨关节炎肢体负重的改善(Horvath等人,2016)。TRPA1在大鼠(Du等人,2007)及膀胱出口阻塞患者(Du等人,2008)的膀胱上皮中表达不同。TRPA1受体调节减轻脊髓损伤大鼠模型中的膀胱过动症(Andrade等人,2011)且鞘内施用TRPA1拮抗剂减轻排尿反射过度大鼠中的环磷酰胺诱发的膀胱炎(Chen等人,2016)。
因此,需要提供有效的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及D.Preti,G.Saponaro,A.Szallasi,Pharm.Pat.Anal.(2015)4(2),75-94中。
WO2017/060488公开了作为TRPA1拮抗剂的化合物,其具有以下结构通式
但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公开了基于喹唑啉酮的TRPA1拮抗剂,其包括以下结构通式的化合物
其中R为OH的化合物31被公开为在FLIPR分析中具有IC50为58nM的拮抗TRPA1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,其为短暂性受体电位锚蛋白1(TRPA1)的抑制剂,具有适当药理学及药物动力学特性,使得其能够用作治疗可通过抑制TRPA1来治疗的病状和/或疾病的药剂。
本发明化合物可提供若干优点,诸如增强的效能;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;所需的血浆蛋白结合;增强的生物可用性;适合的药物动力学概况;及形成稳定盐的可能性。
本发明化合物
本发明提供新颖四唑衍生物,其为TRPA1(分析A)的出人意料的强效抑制剂,其特征进一步在于
人类肝脏微粒体(分析B)中的稳定性得到改良
人类肝细胞(分析C)中的稳定性得到改良。
本发明化合物与WO2017/060488中的例子28及29在结构上的不同之处在于本发明化合物含有具有N-取代基、酰胺基取代基以及邻近于二级脂族醇的取代基的单环二氧代二氢嘧啶核。本发明化合物与L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的例子31在结构上的不同之处在于本发明化合物带有四唑基环。这些结构差异意想不到地引起以下的有利组合:(i)TRPA1的抑制、(ii)人类肝脏微粒体中的稳定性及(iii)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现有技术中所公开的那些化合物:
-作为TRPA1抑制剂的效能
-人类肝脏微粒体中的稳定性
-人类肝细胞中的稳定性。
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易感性。肝脏是许多药物的主要代谢部位。人类肝脏微粒体含有细胞色素P450(CYP),且因此代表了用于研究体外I期药物代谢的模型系统。人类肝脏微粒体中的增强的稳定性与若干优势(包括增加的生物可用性及适当的半衰期)相关,其可实现患者的给药量减少且频率较低。因此,人类肝脏微粒体中的增强的稳定性是待用于药物的化合物的有利特征。因此,除能够抑制TRPA1以外,本发明的化合物亦预期具有有利的体内清除率且因此在人类中具有所需的作用持续时间。
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易感性。肝脏为许多药物的主要代谢部位。人类肝细胞含有细胞色素P450(CYP)及其他药物代谢酶,且因此代表了用于研究体外药物代谢的模型系统。(重要地,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,且因此代表了用于药物代谢研究的更完整系统)。人类肝细胞中的增强的稳定性与若干优势(包括增加的生物可用性及适当的半衰期)相关,其可实现患者的给药量减少且频率较低。因此,人类肝细胞中的增强的稳定性是待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选自由苯基、噻吩基、苯并噻吩基或苯并呋喃基组成的组,其未经取代或经由卤素、C1-4烷基、C1-4氟烷基、C3-4环烷基、C3-4环氟烷基、-O-C1-4烷基、-O-环丙基及NC-组成的基团R3的一个、两个或三个成员取代;
或
A选自由以下组成的组:
R1选自由C1-4烷基、C1-4氟烷基、C3-6环烷基、R4-(H2C)m-及R5-(H2C)n-组成的组;
其中
m为1或2;
n为2;
R4为C3-6环烷基;
R5为-O-C1-4烷基或-O-C1-4氟烷基;
R2选自由H、C1-4烷基、C3-6环烷基、C3-6环氟烷基、HO-C1-4烷基-、C1-4氟烷基、R6-(H2C)p-、R7-(H2C)q-、R6-(H(R8)C)p-及R7-(H(R9)C)q-组成的组;
其中
p为1或2;
q为2;
R6选自由HO-C1-2烷基-、C3-6环烷基、C-吗啉基、C-咪唑基及C-吡唑基组成的组;
其中该C-吡唑基、C-咪唑基及C-吗啉基为未经取代或经C1-4烷基或C1-4氟烷基取代;
R7选自由-O-C1-4烷基、-O-C1-4氟烷基、C1-4烷基-S(O)2-、N-吗啉基、N-咪唑基及N-吡唑基组成的组;
其中该N-吡唑基、N-咪唑基、N-吗啉基为未经取代或经C1-4烷基或C1-4氟烷基取代;
R8及R9为独立地选自H或C1-4烷基。
本发明的另一实施方案涉及一种式(I)化合物,其中
A选自由苯基、噻吩基、苯并噻吩基或苯并呋喃基组成的组,其未经取代或经由卤素、C1-4烷基、-O-C1-4烷基及NC-组成的基团R3之一或两个成员取代;
或
A为
R1选自由C1-4烷基、C3-6环烷基、R4-(H2C)m-及R5-(H2C)n-组成的组;
其中
m为1或2;
n为2;
R4为C3-6环烷基;
R5为-O-C1-4烷基;
R2选自由H、C1-4烷基、C3-6环烷基、HO-C1-4烷基-、C1-4氟烷基、R6-(H2C)p-及R7-(H2C)q-组成的组;
其中
p为1或2;
q为2;
R6选自由C3-6环烷基、C-吗啉基、C-咪唑基及C-吡唑基组成的组;
其中该C-吡唑基、C-咪唑基及C-吗啉基为未经取代或经C1-4烷基取代;
R7选自由-O-C1-4烷基、-O-C1-4氟烷基、C1-4烷基-S(O)2-、N-吗啉基、N-咪唑基及N-吡唑基组成的组;
其中该N-吡唑基、N-咪唑基、N-吗啉基为未经取代或经C1-4烷基取代。
本发明的另一实施方案涉及一种式(I)化合物
其中
A选自由苯基、噻吩基、苯并噻吩基或苯并呋喃基组成的组,其未经取代或经由Cl、F、Br、H3C、H3C-O-及NC-组成的基团R3之一或两个成员取代;
或
A为
且取代基R1及R2如前述实施方案中所定义。
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:
其未经取代或经由Cl、F、Br、H3C、H3C-O-及NC-组成的基团R3之一或两个成员取代,
或
A为
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
A选自由以下组成的组:
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选自由C1-4烷基、C3-6环烷基、R4-(H2C)m-及R5-(H2C)n-组成的组;
其中
m为1;
n为2;
R4为C3-6环烷基;
R5为-O-C1-4烷基;
且取代基A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选自由C1-4烷基、C3-4环烷基、R4-(H2C)m-及R5-(H2C)n-组成的组;
其中
m为1;
n为2;
R4为C3-4环烷基;
R5为-O-C1-4烷基;
且取代基A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选自由C1-4烷基、C3-4环烷基、R4-(H2C)m-及R5-(H2C)n-组成的组;
其中
m为1;
n为2;
R4为C3-4环烷基;
R5为H3C-O-;
且取代基A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选自由以下组成的组:H3C、H3CH2C、H3COH2CH2C、
且取代基A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;
且取代基A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
R2选自由H、C1-4烷基、C3-6环烷基、HO-C1-4烷基-、C1-4氟烷基、R6-(H2C)p-及R7-(H2C)q-组成的组;
其中
p为1;
q为2;
R6选自由C3-6环烷基、C-吗啉基、C-咪唑基及C-吡唑基组成的组;
其中该C-吡唑基、C-咪唑基及C-吗啉基为未经取代或经C1-4烷基取代;
R7选自由-O-C1-4烷基、-O-C1-4氟烷基、C1-4烷基-S(O)2-、N-吗啉基、N-咪唑基及N-吡唑基组成的组;
其中该N-吡唑基、N-咪唑基、N-吗啉基为未经取代或经C1-4烷基取代;
且取代基A及R1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
R2选自由H、C1-4烷基、C3-6环烷基、HO-C1-4烷基-、C1-2氟烷基、R6-(H2C)p-及R7-(H2C)q-组成的组;
其中
p为1;
q为2;
R6选自由C3-6环烷基、C-吗啉基、C-咪唑基及C-吡唑基组成的组;
其中该C-吡唑基、C-咪唑基及C-吗啉基为未经取代或经H3C取代;
R7选自由H3C-O-、-O-氟甲基、H3C-S(O)2-、N-吗啉基、N-咪唑基及N-吡唑基组成的组;
其中该N-吡唑基、N-咪唑基、N-吗啉基为未经取代或经H3C取代;
且取代基A及R1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
R2选自由H、C1-4烷基、C3-6环烷基、HO-C1-4烷基-、C1-2氟烷基、R6-(H2C)p-及R7-(H2C)q-组成的组;
其中
p为1;
q为2;
R6选自由以下组成的组:C3-6环烷基、
R7选自由以下组成的组:H3C-O、-O-氟甲基、H3C-S(O)2-、
且取代基A及R1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
R2选自由以下组成的组:H、H3C、H3CH2C、H3COH2CH2C、F2HCH2C、F3CH2C、FH2CH2C、H3C(O)2SH2CH2C、F3COH2CH2C、
且取代基A及R1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
R2为H;
且取代基A及R1如前述实施方案中的任一者中所定义。
优选为式(I)化合物,其选自由以下组成的组:
且取代基A如前述实施方案中的任一者中所定义。
优选为根据式(I)的化合物,其选自
且取代基A如前述实施方案中的任一者中所定义。
尤其优选为根据式(I)的化合物,其选自由以下组成的组:
所用术语及定义
未在本文中具体定义的术语应赋予本领域技术人员鉴于公开内容及上下文所赋予其的含义。然而,除非相反规定,否则如本说明书中所使用,以下术语具有指定的含义且将遵守以下约定。
在下文定义的基团(group)、基(radical)或部分中,通常在基团之前指定碳原子数目,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,在如HO、H2N、(O)S、(O)2S、NC(氰基)、HOOC、F3C或其类似者的基团中,本领域技术人员可看到自基团自身的游离价至分子的基团连接点。对于包含两个或更多个亚基的组合基团,最后命名的亚基为基团连接点,例如取代基“芳基-C1-3烷基”意谓与C1-3烷基键合的芳基,该C1-3烷基与核或与取代基所连接的基团键合。
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,将以化学式为准。可在子式中使用星号来指示如所定义的连接至核分子的键。
取代基原子的记数始于最接近核或最接近取代基所连接的基团的原子。
例如,术语“3-羧丙基”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:
星号可用于子式中以指示如所定义的连接至核分子的键。
术语“C1-n烷基”(其中n选自2、3、4或5的整数)单独或与另一基团组合表示具有1至n个C原子的非环状饱和分支链或直链烃基。例如,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)-。
添加至“烷基”、“亚烷基”或“环烷基”(饱和或不饱和)的术语“氟”意谓其中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“C3-n环烷基”(其中n为4至n的整数)单独或与另一基团组合表示具有3至n个C原子的环状饱和非分支链烃基。例如,术语“C3-6环烷基”包括环丙基、环丁基、环戊基及环己基。
术语卤素一般表示氟、氯、溴及碘。
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“四唑基”是指以下环的基团:
术语“二氧代二氢嘧啶羧酰胺”是指以下环的基团:
术语“C-吗啉基”是指以下环的基团:
术语“C-咪唑基”是指以下环的基团:
术语“C-吡唑基”是指以下环的基团:
术语“N-吗啉基”是指以下环的基团:
术语“N-咪唑基”是指以下环的基团:
术语“N-吡唑基”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何一个或多个氢为经自指定基团的选择置换,其限制条件为不超过指定原子正常价,且该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互变异构体及所有立体异构体、光学异构体及几何异构体(例如镜像异构体、非镜像异构体、E/Z异构体等)及其外消旋体以及呈不同比例的独立镜像异构体的混合物、非镜像异构体的混合物或存在此类异构体及镜像异构体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(诸如包括游离化合物的溶剂合物或化合物的盐的溶剂合物的水合物)。
一般而言,实质上纯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起始物质和/或通过立体选择性合成。本领域已知如何制备光活性形式,诸如通过外消旋形式的拆分或通过合成,例如以光活性起始物质开始和/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,例如通过制备及后续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由相应之外消旋混合物制备镜像异构纯化合物,诸如通过在手性固定相上色谱分离相应之外消旋混合物;或通过使用适当拆分剂拆分外消旋混合物,例如借助外消旋化合物与光活性酸或碱形成非镜像异构盐,之后拆分盐且自盐中释放所需化合物;或通过使用光活性手性辅助试剂衍生相应外消旋化合物,之后分离非镜像异构体且移除手性辅助基团;或通过动力学拆分外消旋体(例如通过酶促拆分);通过在适当条件下由同形异向晶体的聚结物进行镜像选择性晶体;或通过在光活性手性助剂的存在下由适合溶剂进行(分级)晶体。
词组“药学上可接受”在本文中用于指在合理医学判断范畴内适合使用而无过度毒性、刺激、过敏反应或其他问题或并发症且与合理效益/风险比相称的那些化合物、物质、组合物和/或剂型。
如本文所用,“药学上可接受的盐”是指其中母体化合物与酸或碱形成盐或复合物的所公开的化合物的衍生物。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酸或有机酸,诸如苯磺酸、苯甲酸、柠檬酸、乙磺酸、反丁烯二酸、龙胆酸(gentisic acid)、氢溴酸、氢氯酸、顺丁烯二酸、苹果酸、丙二酸、杏仁酸、甲磺酸、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-还原葡糖胺或参(羟甲基)-氨基甲烷。本发明的药学上可接受的盐可由含碱性或酸性部分的母体化合物通过常规化学方法合成。一般而言,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的水溶液或有机稀释剂溶液(如醚、乙酸乙酯、乙醇、异丙醇或乙腈)或其混合物反应来制备此类盐。
除上文所提及的那些盐外,例如适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细胞分析来证明本发明化合物的活性:
方法:
将过度表达人类TRPA1离子通道的人类HEK293细胞株(Perkin Elmer,产品编号AX-004-PCL)用作化合物功效及效能的测试系统。通过在FLIPRtetra系统(MolecularDevices)中测量化合物对由异硫氰酸烯丙酯(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:
在冷冻小瓶中以冷冻细胞形式获得细胞且在使用前储存在-150℃下。
使细胞在培养基(具有10% FCS及0.4mg/ML Geneticin的MEM/EBSS培养基)中生长。重要的是密度不超过90%汇合度。对于继代培养,通过Versene将细胞自烧瓶中分离出来。在分析前一天,将细胞分离出来,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20μl/孔接种至来自Corning的聚-D-赖氨酸(Poly D-Lysin)生物涂布的384孔盘(黑色透明底,Cat.356697)。将培养盘在37℃/5% CO2下培育24小时,随后用于分析中。
化合物制备
将测试化合物以浓度为10mM溶解于100% DMSO中且第一步于DMSO中稀释至浓度为5mM,接着于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。通常通过1:5稀释来制备8种不同浓度,用HBSS/HEPES缓冲液(1×HEPES,Cat.14065,来自Gibco;20mM HEPES,Cat.83264,来自自SIGMA;0.1% BSACat.11926,来自Invitrogen,pH 7.4)对物质进行进一步中间稀释(1:20)。
FLIPR分析:
在分析当日,将细胞用分析缓冲液洗涤3次,在洗涤后孔中剩余20μL缓冲液。将于HBSS/HEPES中的10μL Ca6试剂盒(Cat.R8191,MolecularDevices)上样缓冲液添加至细胞中且将各盘在37℃/5% CO2下加盖培育120分钟。将于HBSS/HEPES缓冲液/5% DMSO中的10μL化合物或对照自中间稀释盘中谨慎地添加至各孔中。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中的激动剂AITC 50μM(最终浓度10μM)添加至各孔中,随后在FLIPRtetra装置上再读取10分钟。添加AITC后的信号曲线下面积(AUC)用于IC50/抑制%计算。
数据评估及计算:
各分析微量滴定盘含有具有媒剂(1% DMSO)对照代替化合物的孔,作为AITC诱导的发光的对照(100% CTL;高对照),及具有无AITC的媒剂对照的孔,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)计算各物质浓度的测量值的%(AUC(样本)-AUC(低))*100/(AUC(高)-AUC(低))。使用MegaLab软件由对照值%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=IC50M;b=希尔斜率(hill);y=对照%
表1:如在分析A中获得的本发明化合物的生物资料
表2:如在分析A中获得的现有技术化合物(WO2017/060488中的例子28及29)的生物资料.
表3:如在分析A中获得的现有技术化合物(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℃下使用所合并的肝脏微粒体来分析测试化合物的代谢降解。每个时间点的100μl的最终培育体积含有在RT下pH 7.6(0.1M)的TRIS缓冲液、氯化镁(5mM)、微粒体蛋白(1mg/ml)及最终浓度为1μM的测试化合物。
在37℃下的短暂预培育期之后,通过添加呈还原形式(NADPH,1mM)的β-烟碱酰胺腺嘌呤二核苷酸磷酸启动反应且通过在不同时间点(0、5、15、30、60min)之后将等分试样转移至溶剂中来终止反应。另外,在不含NADPH的培育物中监测NADPH非依赖性降解,在最后一个时间点终止。NADPH非依赖性培育之后的剩余测试化合物[%]为由参数c(对照)(代谢稳定性)反映。通过离心(10000g,5min)使经淬灭的培育物集结。
通过LC-MS/MS分析上清液的等分试样中的母体化合物量。通过浓度-时间特征曲线的半对数图的斜率来测定半衰期(t1/2INVITRO)。
通过考虑培育物中蛋白质的量来计算内在清除率(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]×肝因子[g/kg体重])/1000
Qh[%]=CL[ml/min/kg]/肝血流量[ml/min/kg])
肝细胞数,人类:120×10e6个细胞/公克肝脏
肝因子,人类:25.7g/kg体重
血流量,人类:21ml/(min×kg)
表4:如分析B中获得的本发明化合物的生物资料
表5:如在分析B中获得的现有技术化合物(WO2017/060488中的例子28及29)的生物资料.
表6:如在分析B中获得的现有技术化合物(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。在含有5%或50%物种血清的杜氏改良伊格尔培养基(Dulbecco's modified eagle medium)(补充有3.5μg升糖素/500mL、2.5mg胰岛素/500mL及3.75mg/500mL氢皮质酮)中培育肝细胞(冷冻保存)。
在培育箱(37℃,10% CO2)中预培育30min之后,将5μl的测试化合物溶液(80μM;由2mM DMSO储备溶液用培养基按1:25稀释而成)添加至395μl肝细胞悬浮液中(细胞密度在0.25-5百万个细胞/mL范围内,其视物种而定,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(培育箱,回转式震荡器)且在0、0.5、1、2、4及6小时获取样本(25μl)。将样本转移至乙腈中且通过离心(5min)集结。将上清液转移至新的96深孔盘,在氮气下蒸发且再悬浮。
通过HPLC-MS/MS来分析母体化合物的减少
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/mL]、AUD:资料下面积[μM×h]、clast:最后一个数据点的浓度[μM]、k:母体减少的回归线的斜率[h-1]。
所计算的体外肝内在清除率可按比例扩大为体内肝内在清除率,且用于通过使用肝脏模型(搅拌良好的模型)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/公克肝脏]×肝因子[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])
肝细胞数,人类:120×10e6个细胞/公克肝脏
肝因子,人类:25.7g/kg体重
血流量,人类:21ml/(min×kg)
表7:如在分析C中获得的本发明化合物的生物资料
表8:如在分析C中获得的现有技术化合物(WO2017/060488中的例子28及29)的生物资料.
表9:如在分析C中获得的现有技术化合物(L.Schenkel等人,J.Med.Chem.2016,59,2794-2809中的例子31)的生物数据.
渗透率的评估
将Caco-2细胞(1-2×105个细胞/1cm2区域)接种在过滤器插件(Costartranswell聚碳酸酯或PET过滤器,0.4μm孔径)上且培养(DMEM)持续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)施用至顶部或基侧的供体侧以用于分别测量A-B或B-A渗透率(重复过滤3次)。在实验开始及最后自供体收集样本且在各个时间间隔处亦自受体侧收集样本,时间持续2小时,以通过HPLC-MS/MS或闪烁计数来进行浓度测量。用新制受体溶液替换取样后的受体容积。
血浆蛋白质结合的评估
此平衡透析(ED)技术用于测定测试化合物与血浆蛋白质的近似体外分级结合。使用Dianorm Teflon透析单元(0.2ml)。各单元由供体室及受体室组成,由具有5kDa分子量截断的超薄半透膜分隔。在DMSO中以1mM制备用于各测试化合物的储备溶液且稀释至1.0μM的最终浓度。后续透析溶液在来自雄性及磁性供体的合并的人类或大鼠血浆(含NaEDTA)中制备。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腔室中。将200μL测试化合物透析溶液的等分试样分配至血浆腔室中。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内标物溶液混合。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内标物溶液及200μL ACN混合。在HPLC-MS/MS-系统上测量样本且借助于Analyst-Software加以评估。用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。
溶解度的评估
通过将适当体积的所选液体介质(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0.5-5.0mg范围内)的各孔中来在孔盘(格式视机器人而定)中制备饱和溶液。将各孔震荡或搅拌预定时间段(通常在2-24h范围内)且接着使用适当的过滤薄膜(通常为具有0.45μm孔径的PTFE-滤膜)过滤。通过丢弃前几滴滤液来避免滤膜吸收。通过UV光谱分析测定经溶解的原料药的量。另外,使用玻璃电极pH计来测量饱和水溶液的pH。
啮齿动物中的药物动力学特征的评估
测试化合物为经静脉内施用进食大鼠或经口施用禁食大鼠。在施加测试化合物后的若干时间点获取血液样本,进行抗凝处理且离心。
对血浆样本中作为分析物的所施用的化合物和/或代谢物的浓度进行定量。PK参数使用非室体方法加以计算。将AUC及Cmax标准化至1μmol/kg的剂量。
体外人类肝细胞代谢的评估
使用呈悬浮液形式的初级人类肝细胞来研究测试化合物的代谢路径。在自冷冻保存复原之后,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/500ml氢皮质酮的杜氏改良伊格尔培养基中培育。
在细胞培养培育箱(37℃,10% CO2)中预培育30min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(视伴随初级人类肝细胞所观测到的化合物的代谢转换率而定)、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,且视代谢转换率而定在0、0.5、1、2、4或6小时之后自培育移除样本。样本用乙腈淬灭且通过离心集结。将上清液转移至96深孔盘,在氮气下蒸发且再悬浮,之后通过液相色谱-高分辨率质谱分析进行生物分析,以用于鉴别推定的代谢物。
基于Fourier-Transform-MSn数据暂时指配结构。以人类肝细胞培育中母体的百分比报导代谢物,临界值≥4%。
治疗方法
本发明涉及通式1化合物,其适用于预防和/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、关节的炎性疾病及鼻咽部、眼部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、嗜酸性疾病、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、慢性疼痛及抑郁症以及膀胱病症)。
通式1化合物适用于预防和/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(诸如与胶原病相关的肺炎或间质性肺炎),例如红斑性狼疮、全身性硬皮病类风湿性关节炎、多发性肌炎及皮肌炎、特发性间质性肺炎(诸如特发性肺纤维化(IPF))、非特异性间质性肺炎、呼吸性细支气管炎相关的间质性肺病、脱屑性间质性肺炎、隐原性机化性肺炎、急性间质性肺炎及淋巴球性间质性肺炎、淋巴管肌瘤病、肺泡蛋白沉积症、兰格汉氏细胞组织细胞增生症(Langerhan's cell histiocytosis)、胸膜实质性纤维弹性组织增生症、已知病因的间质性肺病,诸如因职业性接触(诸如石棉沉着病、硅粉沉着病、矿工肺(煤粉)、农民肺(干草及霉菌)、养鸽人肺(Pidgeon fanciers lung)(鸟类)或其他职业性空气传播诱因(诸如金属粉尘或分枝杆菌)或因治疗(诸如辐射、甲胺喋呤、胺碘酮、呋喃妥因(nitrofurantoin)或化学治疗剂)而引起的间质性肺炎或肉芽肿性疾病,诸如肉芽肿性多发性血管炎、彻奇-斯全司综合征(Churg-Strauss syndrome)、类肉瘤病、过敏性肺炎或由不同病因(例如吸入有毒气体、蒸气、支气管炎或肺炎)引起的间质性肺炎或由心衰竭、X射线、辐射、化疗、伯克病(M.boeck)或类肉瘤病、肉芽肿病、囊肿性纤维化或黏稠性黏液病或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,诸如肝桥接纤维化、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、旧心肌梗塞、神经胶质疤、动脉硬度、关节纤维化、杜普宜特朗氏挛缩(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、佩罗尼氏病(Peyronie's disease)、肾源性全身性纤维化、腹膜后纤维化、黏连性囊炎。
(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、慢性鼻窦炎、急性鼻窦炎、哮喘、儿童哮喘、过敏性支气管炎、肺泡炎、高反应性气管、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、支气管炎或局部肺炎、嗜酸性蜂窝织炎(例如,韦尔斯综合征(Well's syndrome))、嗜酸性肺炎(例如吕佛勒氏综合征(Loeffler's syndrome)、慢性嗜酸性肺炎、嗜酸性筋膜炎(例如,舒尔曼氏综合征(Shulman's syndrome))、迟发型过敏、非过敏性哮喘;运动诱发性支气管收缩;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;全身性过敏反应或超敏反应、药物过敏(例如,对青霉素、头孢菌素)、因摄入经污染的色氨酸而引起的嗜伊红血球肌痛综合征、昆虫螯针过敏;自身免疫性疾病,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、全身性红斑性狼疮症、重症肌无力、免疫性血小板减少症(成人ITP/新生血儿小板减少症、小儿ITP)、免疫性溶血性贫血(自体免疫及药物引起)、伊凡氏综合征(Evanssyndrome)(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病)、乳糜泻、自身免疫性心肌病幼发型糖尿病;丝球体肾炎、自体免疫性甲状腺炎、白塞氏病(Behcet's disease);移植排斥(例如,在移植中),包括同种异体移植排斥反应或移植物抗宿主病;炎性肠病,诸如克罗恩氏病(Crohn'sdisease)及溃疡性结肠炎;脊椎关节病;牛皮癣(包括T细胞介导的牛皮癣)及炎性皮肤病(诸如皮炎、湿疹、异位性皮炎、过敏性接触性皮炎、风疹);脉管炎(例如坏死性、皮肤性及超敏性脉管炎);结节性红斑;嗜酸性肌炎、嗜酸性筋膜炎、皮肤或器官有白细胞浸润的癌症;眼科疾病,诸如年龄相关黄斑变性、糖尿病性视网膜病变及糖尿病黄斑水肿、角膜炎、嗜酸性角膜炎、角膜结膜炎、春季角膜结膜炎、瘢痕、前节瘢痕(anterior segment scarring)、睑炎、睑结膜炎、大疱性病症、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、环状肉芽肿瘤、格雷夫氏眼病(Graves'ophthalmopathy)、眼内黑素瘤、结膜黄斑、增生性玻璃体视网膜病变、翼状胬肉、巩膜炎、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、神经痛、感觉迟钝、触摸痛、偏头痛、牙痛及术后疼痛。
(6)抑郁、焦虑、糖尿病神经病变及膀胱病症,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局部缺血损伤。
因此,本发明涉及一种通式1化合物,其用作药剂。
此外,本发明涉及一种通式1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、关节的炎性疾病及鼻咽部、眼部及皮肤的炎性疾病、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、嗜酸性疾病、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、慢性疼痛及抑郁症以及膀胱病症)。
此外,本发明涉及一种通式1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的、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(诸如与胶原病相关的肺炎或间质性肺炎),例如红斑性狼疮、全身性硬皮病类风湿性关节炎、多发性肌炎及皮肌炎、特发性间质性肺炎(诸如特发性肺纤维化(IPF))、非特异性间质性肺炎、呼吸性细支气管炎相关的间质性肺病、脱屑性间质性肺炎、隐原性机化性肺炎、急性间质性肺炎及淋巴球性间质性肺炎、淋巴管肌瘤病、肺泡蛋白沉积症、兰格汉氏细胞组织细胞增生症、胸膜实质性纤维弹性组织增生症、已知病因的间质性肺病,诸如因职业性接触(诸如石棉沉着病、硅粉沉着病、矿工肺(煤粉)、农民肺(干草及霉菌)、养鸽人肺(鸟类)或其他职业性空气传播诱因,诸如金属粉尘或分枝杆菌)或因治疗(诸如辐射、甲胺喋呤、胺碘酮、呋喃妥因或化学治疗剂)而引起的间质性肺炎或肉芽肿性疾病,诸如肉芽肿性多发性血管炎、彻奇-斯全司综合征、类肉瘤病、过敏性肺炎或由不同病因(例如吸入有毒气体、蒸气、支气管炎或肺炎)引起的间质性肺炎,或由心衰竭、X射线、辐射、化疗、伯克病或类肉瘤病、肉芽肿病、囊肿性纤维化或黏稠性黏液病或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,诸如肝桥接纤维化、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、旧心肌梗塞、神经胶质疤、动脉硬度、关节纤维化、杜普宜特朗氏挛缩、瘢痕瘤、硬皮病/全身性硬化症、纵隔纤维化、骨髓纤维化、佩罗尼氏病、肾源性全身性纤维化、腹膜后纤维化、黏连性囊炎。
(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、慢性鼻窦炎、急性鼻窦炎、哮喘、儿童哮喘、过敏性支气管炎、肺泡炎、高反应性气管、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、支气管炎或局部肺炎、嗜酸性蜂窝织炎(例如,韦尔斯综合征)、嗜酸性肺炎(例如吕佛勒氏综合征、慢性嗜酸性肺炎)、嗜酸性筋膜炎(例如,舒尔曼氏综合征)、迟发型过敏、非过敏性哮喘;运动诱发性支气管收缩;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;全身性过敏反应或超敏反应、药物过敏(例如,对青霉素、头孢菌素)、因摄入经污染的色氨酸而引起的嗜伊红血球肌痛综合征、昆虫螯针过敏;自身免疫性疾病,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、全身性红斑性狼疮症、重症肌无力、免疫性血小板减少症(成人ITP/新生血儿小板减少症、小儿ITP)、免疫性溶血性贫血(自体免疫及药物引起)、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病)、乳糜泻、自身免疫性心肌病幼发型糖尿病;丝球体肾炎、自体免疫性甲状腺炎、白塞氏病;移植排斥(例如,在移植中),包括同种异体移植排斥反应或移植物抗宿主病;炎性肠病,诸如克罗恩氏病及溃疡性结肠炎;脊椎关节病;牛皮癣(包括T细胞介导的牛皮癣)及炎性皮肤病(诸如皮炎、湿疹、异位性皮炎、过敏性接触性皮炎、风疹);脉管炎(例如坏死性、皮肤性及超敏性脉管炎);结节性红斑;嗜酸性肌炎、嗜酸性筋膜炎、皮肤或器官有白细胞浸润的癌症;眼科疾病,诸如年龄相关黄斑变性、糖尿病性视网膜病变及糖尿病黄斑水肿、角膜炎、嗜酸性角膜炎、角膜结膜炎、春季角膜结膜炎、瘢痕、前节瘢痕、睑炎、睑结膜炎、大疱性病症、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、环状肉芽肿瘤、格雷夫氏眼病、眼内黑素瘤、结膜黄斑、增生性玻璃体视网膜病变、翼状胬肉、巩膜炎、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、神经痛、感觉迟钝、触摸痛、偏头痛、牙痛及术后疼痛。
(6)抑郁、焦虑、糖尿病神经病变及膀胱病症,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局部缺血损伤。
在另一方面中,本发明涉及一种通式1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,本发明涉及一种通式1化合物的用途,其用于制备用于治疗和/或预防上文所提及的疾病及病状的药剂。
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,额外治疗剂选自以下的组:适用于治疗上文所描述,尤其与纤维变性疾病、炎性及免疫调节病症、呼吸道或胃肠道疾病或不适、关节或鼻咽部、眼部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、嗜酸性疾病、慢性阻塞性肺病、异位性皮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;或适用于治疗眼科疾病、疼痛及抑郁的治疗剂。
适用于此类组合的额外治疗剂尤其包括例如增强一种或多种活性物质对所提及的适应症中的一者的治疗作用和/或使一种或多种活性物质的剂量减少的那些治疗剂。
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、抗咳嗽剂、抗炎剂、抗异位性皮炎剂、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。
抗纤维变性剂例如为尼达尼布(nintedanib)、吡非尼酮(pirfenidone)、磷酸双酯酶4型抑制剂(PDE4)(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)、重组正五聚素蛋白-2(PTX-2)(诸如PRM-151);c-Jun N端激酶(JNK)抑制剂,诸如CC-90001;半乳凝集素-3抑制剂,诸如TD-139;G-蛋白偶合受体84(GPR84)抑制剂,诸如GLPG-1205;G-蛋白偶合受体84/G-蛋白偶合受体40双重抑制剂,诸如PBI-4050;Rho相关卷曲螺旋蛋白激酶2(ROCK2),诸如KD-025;热休克蛋白47(HSP47)小干扰RNA/ND-L02-s0201,诸如BMS-986263;Wnt路径抑制剂,诸如SM-04646;LD4/PDE3/4抑制剂,诸如泰鲁司特(Tipelukast);组氨酰基tRNA合成酶(HARS)的重组免疫调节域,诸如ATYR-1923;前列腺素合成酶抑制剂,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2(LOXL2)抑制剂,诸如PAT-1251,PXS-5382/PXS-5338;磷脂肌醇3-激酶(PI3K)/哺乳动物雷帕霉素靶蛋白(mTOR)双重抑制剂,诸如HEC-68498;钙蛋白酶抑制剂,诸如BLD-2660;促分裂原活化蛋白激酶(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。
例如,止咳剂为嘌呤受体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次单位刺激剂,诸如ATA-101/布达克兰(bradanicline)、可待因(codeine)、加巴喷丁(gabapentin)、普瑞巴林(pregablin)或阿奇霉素(azithromycin)。例如,抗炎剂为皮质类固醇,诸如普赖苏秾(prednisolone)或地塞米松(dexamethasone);环氧化酶-2(COX2)抑制剂,诸如塞来昔布(celecoxib)、罗非考昔(rofecoxib)、帕瑞考昔(parecoxib)、伐地考昔(valdecoxib)、地拉考昔(deracoxib)、依托考昔(etoricoxib)或罗米昔布(lumiracoxib);前列腺素E2拮抗剂;白三烯(leukotriene)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)。
例如,抗异位性皮肤炎剂为环孢素(cyclosporin)、甲胺喋呤(methotrexate)、霉酚酸吗啉乙酯(mycophenolate mofetil)、硫唑嘌呤、磷酸二酯酶抑制剂(例如,阿普斯特(apremilast)、克立硼罗(crisaborole))、詹纳斯(Janus)相关激酶(JAK)抑制剂(例如托法替尼(tofacitinib))、抗IL-4/IL-13的中和抗体(例如度匹单抗(dupilamab))、IL-13(例如雷布瑞奇单抗(lebrikizumab)、曲罗芦单抗(tralokinumab))及IL-31(尼立珠单抗(nemolizumab))。
例如,镇痛剂为类鸦片型,诸如吗啡碱、羟吗啡(oxymorphine)、左旋丙醇(levopanol)、羟考酮、丙氧芬、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)、丁丙诺啡(buprenorphine)、布托啡诺(butorphanol)、纳布啡(nalbuphine)、戊唑新(pentazocine);或诸如乙酰烯胺的非类鸦片型。
例如,抗抑郁剂为三环抗抑郁剂,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抗抑郁剂(SSRI),诸如氟西汀(fluoxetine)、帕罗西汀(paroxetine)、舍曲林(sertraline)、西它普兰(citalopram)、依地普兰(escitalopram);去甲肾上腺素再吸收抑制剂抗抑郁剂(SNRI),诸如马普替林(maprotiline)、洛夫帕明(lofepramine)、米氮平(mirtazapine)、羟丙替林(oxaprotiline)、非唑拉明(fezolamine)、托莫西汀(tomoxetine)、米安色林(mianserin)、丁胺苯丙酮、羟基丁胺苯丙酮(hydroxybuproprion)、诺米芬辛(nomifensine)、维洛沙嗪(viloxazine);双重血清素-去甲肾上腺素再吸收抑制剂抗抑郁剂(SNRI),诸如度洛西汀(duloxetine)、文拉法辛(venlafaxine)、去甲文拉法辛(desvenlafaxine)、左旋体米那普仑(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;单胺氧化酶抑制剂抗抑郁剂(MAOI),诸如反苯环丙胺(tranylcypromine)、苯乙肼(phenelzine)或异卡波肼(isocarboxazid)。
例如,抗焦虑剂为苯并二氮杂卓,诸如阿普唑仑(alprazolam)、溴西泮(bromazepam)、氯二氮环氧化物(chlordiazepoxide)、氯硝西泮(clonazepam)、氯氮平酸盐、安定(diazepam)、氟西泮(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);或其为非苯并二氮杂卓催眠药,诸如右唑匹可隆(eszopiclone)、扎来普隆(zaleplon)、唑吡坦(zolpidem)或唑匹可隆(zopiclone);或其为胺甲酸酯,例如美普巴(meprobamate)、肌安宁(carisoprodol)、泰巴氨酯(tybamate)或洛巴甲酸酯(lorbamate);或其为抗组织胺,诸如羟嗪、氯芬尼拉明(chlorpheniramine)或苯海拉明(diphenhydramine)。
例如,镇定剂为巴比妥酸盐(barbiturate)镇静剂,诸如异戊巴比妥(amobarbital)、阿普比妥(aprobarbital)、布塔巴比妥(butabarbital)、布他比妥(butabital)、甲苯巴比妥(mephobarbital)、甲巴比妥(metharbital)、美索比妥(methohexital)、戊巴比妥(pentobarbital)、司可巴比妥(secobarbital)、他布比妥(talbutal)、塞米乐(theamylal)或硫喷妥(thiopental);或其为非巴比妥酸盐镇静剂,诸如格鲁米特(glutethimide)、美普巴、甲喹酮(methaqualone)或氯醛比林(dichloalphenazone)。
例如,骨骼肌松弛剂为氯苯胺丁酸(baclofen)、美普巴、肌安宁、环苯扎平(cyclobenzaprine)、美他沙酮(metaxalone)、美索巴莫(methocarbamol)、替扎尼定(tizanidine)、氯唑沙宗(chlorzoxazone)或奥菲那特林(orphenadrine)。
其他适合的组合搭配物为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;抗心律不整剂,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)、弗斯特罗定(fesoterodine)、索非那新(solifenacin)或曲司铵(trospium);或其为膀胱肌松弛剂,诸如米拉贝隆(mirabegron);或其为α阻断剂,诸如他苏洛辛(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正常建议最低剂量的1/5至正常建议剂量的1/1。
因此,在另一方面中,本发明涉及与一种或多种上下文中所描述的额外治疗剂组合的根据本发明的化合物的用途,其用于治疗可受TRPA1影响或介导的疾病或病状,尤其如上下文中所描述的疾病或病状。
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与治疗有效量的一种或多种额外治疗剂的组合。
在另一方面中,本发明涉及与一种或多种额外治疗剂组合的式(I)化合物或其药学上可接受的盐的用途,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经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与治疗有效量的一种或多种上下文中所描述的额外治疗剂的组合。
与其他治疗剂组合的根据本发明的化合物的使用可同时进行或以错开的时间进行。
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的调配物中(例如呈所谓的分装部分的试剂盒(kit-of-part))。
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描述的额外治疗剂,任选连同一种或多种惰性载剂和/或稀释剂。
在又一方面中,本发明涉及一种根据本发明的化合物的用途,其用于咳嗽测量装置中。
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见,所述实施例以举例方式说明本发明的原理。
制备
可使用本领域技术人员已知且描述于有机合成的文献中的合成方法来获得本发明的化合物及其中间体。优选地,以与下文更充分解释,尤其如实验部分中所描述的制备方法类似的方式来获得化合物。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未在本文中详细描述的反应方法的变型。
制备根据本发明的化合物的通用方法对于研究以下流程的本领域技术人员将变得显而易见。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。这些保护基可使用本领域技术人员熟悉的方法在反应序次内的适合阶段再次裂解。
根据本发明的化合物通过下文所描述的合成方法制备,其中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,但不限制其主题及这些实施例所主张的化合物的范畴。在未描述起始化合物的制备的情况下,其可商购或可以本文中所述的已知化合物或方法类似的方式制备。文献中所述的物质为根据所公布的合成方法制备。缩写如实施例部分中所定义。
流程1:
在流程1中,在碱(例如K2CO3)的存在下,用携载邻近羰基的离去基“LG”(例如Cl或Br)的适当乙酮衍生物使氯甲基四唑N-烷基化,得到两种区位异构体的混合物。可通过使用适当梯度的色谱移除非所需区位异构体(未图示)。可通过使用适当的催化系统,使用过渡金属配合物(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(诸如甲酸三乙胺复合物)组合以镜像选择性方式还原所得酮(A),得到醇(B)。
尿嘧啶衍生物(D)可由单取代脲及2-(乙氧基亚甲基)丙二酸1,3-二乙酯在高温下在纯条件下合成以直接产生(D),或产生(C),其可在高温下在诸如NaOEt的EtOH溶液的碱性条件下进一步反应,得到(D)。一级酰胺(E)可由酯(D)通过在密封容器中在处于高温下的诸如水或醇的溶剂中与氨一起搅拌来合成。
最终化合物(I)可通过使(E)与中间体(B)在诸如K2CO3的碱存在下烷基化来合成。替代地,中间体(D)与(B)在碱的存在下烷基化得到(F),其可用诸如LiOH的适合试剂水解得到酸(G)。酸(G)可随后在诸如HATU的酰胺偶合剂的存在下且在诸如DIPEA的碱的存在下与胺偶合,得到最终化合物(I)。
替代地,式(I)化合物可如以下流程2中所示制备。
流程2:
在流程2中,可通过在诸如DIPEA的碱存在下,用携载离去基“LG”(例如Cl或Br)的乙腈衍生物使(E)烷基化来制备中间体(H)。可通过用于形成四唑的典型反应条件(例如在TEA/TEA盐酸盐的DMF溶液的存在下使用NaN3)来实现四唑(J)的形成。在诸如DIPEA的碱的存在下,用携载邻近羰基的离去基“LG”(例如Cl或Br)的适当乙酮衍生物操作四唑(J)的烷基化,得到两种区位异构体的混合物。可通过使用适当梯度的色谱移除非所需区位异构体(未图示)。最后,可通过使用适当的催化系统,使用过渡金属配合物(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(诸如甲酸三乙胺复合物)组合以镜像选择性方式还原(K)的酮基,得到最终化合物(I)。替代地,可通过在诸如DIPEA的碱存在下,用携载邻近羟基的离去基“LG”(例如Cl或Br)的适当的芳族或杂芳族乙醇衍生物使中间体(J)烷基化,且随后分离出所需区位异构体来制备最终化合物(I)。
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的文献中的合成方法,例如使用描述于“Comprehensive Organic Transformations”,第2版,Richard C.Larock,John Wiley&Sons,2010及“March's Advanced OrganicChemistry”,第7版,Michael B.Smith,John Wiley&Sons,2013中的方法获得。优选地,以类似于下文更充分阐述的制备方法,尤其如实验部分中所述来获得化合物。在某些状况下,实施反应方案所采用的顺序可变化。亦可使用本领域技术人员已知但未在本文中详细描述的这些反应的变型。基于研究以下流程,用于制备根据本发明的化合物的一般方法对于本领域技术人员将变得显而易见。起始化合物为可商购的或可通过描述于文献或本文中的方法来制备,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对应官能基可使用常规保护基加以保护。这些保护基可在反应序次内的适合阶段使用本领域技术人员熟悉且例如“Protecting Groups”,第3版,Philip J.Kocienski,Thieme,2005及“ProtectiveGroups in Organic Synthesis”,第4版,Peter G.M.Wuts,Theodora W.Greene,JohnWiley&Sons,2006的文献中所描述的方法再次裂解。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(通用程序)
2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-氯苯基)乙-1-酮
在RT下,将1.63g(11.8mmol)K2CO3在搅拌下添加至1.00g(8.44mmol)5-(氯甲基)-2H-1,2,3,4-四唑及2.17g(9.28mmol)4-氯苯甲酰甲基溴的15mL DMA溶液中。将反应混合物在RT下搅拌30min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。经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,得到产物。
C10H8Cl2N4O (M=271.1g/mol)
ESI-MS: 271[M+H]+
Rt(HPLC): 1.01min(方法B)
使用类似于中间体I.1所描述的程序,使用适当起始物质制备以下化合物。如本领域技术人员所了解,这些类似实施例可涉及一般反应条件的变化形式。
*在18℃下将对甲氧基苯甲酰甲基溴(1.05eq.)缓慢添加至氯甲基四唑及K2CO3(1.4eq)于DMA中的搅拌溶液中;在RT下搅拌混合物1.5h;经由反相HPLC(ACN/H2O梯度,0.1% TFA)纯化。
中间体II
中间体II.1(通用程序)
(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)氯化([(1S,2S)-2-氨基-1,2-二苯基乙基](4-甲苯磺酰基)酰胺基)钌(II)(CAS 174813-81-1),接着逐滴添加0.72mL(1.73mmol)甲酸三乙胺复合物(5:2)。在RT下搅拌3h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。合并有机层,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): 0.96min(方法B)
使用类似于中间体II.1所描述的程序,使用适当起始物质制备以下化合物。如本领域技术人员所了解,这些类似实施例可涉及一般反应条件的变化形式。
中间体III
3-甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酰胺
将10.0g(50.46mmol)3-甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酸乙酯(CAS:154942-22-0,中间体XII.6)的33%氨水溶液(120mL)在100℃下在密封容器中搅拌10h。将反应混合物冷却至RT且在减压下浓缩。用ACN湿磨残余物,滤出且在50℃下干燥,得到中间体III。
C6H7N3O3 (M=169.1g/mol)
ESI-MS: 170[M+H]+
Rt(HPLC): 0.48min(方法B)
中间体IV
中间体IV.1(通用程序)
1-(5,6-二氟-1-苯并呋喃-2-基)乙-1-酮
在0℃下在氩气下用6.99g(50.6mmol)碳酸钾处理5.00g(31.6mmol)4,5-二氟-2-羟基苯甲醛的50mL丙酮溶液。在0℃下再搅拌10min之后,逐滴添加3.78mL(47.4mmol)氯丙酮且在70℃下搅拌反应混合物3h。将反应混合物冷却至RT且浓缩。粗产物用EtOAc/水萃取且在减压下浓缩有机相,得到中间体IV.1。
C10H6F2O2 (M=196.2g/mol)
1H NMR(300MHz,DMSO-d6)δppm:2.56(s,3H),7.89(m,1H),7.92(m,1H),8.01(m,1H)
使用类似于中间体IV.1所描述的程序,使用适当起始物质制备以下化合物。如本领域技术人员所了解,这些类似实施例可涉及一般反应条件的变化形式。
中间体V
5-溴-1-苯并呋喃-2-甲酸
在0℃下将1.23g(29.3mmol)LiOH*H2O添加至6.58g(24.4mmol)5-溴-1-苯并呋喃-2-甲酸乙酯(IV.4)于3mL EtOH、66ml THF及33mL水中的溶液中。反应混合物在RT下搅拌2h且随后在减压下浓缩。残余物用1M HCl酸化至pH5且滤出所得沉淀物且干燥,得到中间体V。
C9H5BrO3 (M=241.0g/mol)
1H NMR(300MHz,DMSO-d6)δppm:7.59-7.76(m,3H),8.02(d,J=2.0Hz,1H),13.5-14.2(br s,1H)。
中间体VI
5-溴-2-氟-1-苯并呋喃
将5.00g(20.7mmol)5-溴-1-苯并呋喃-2-甲酸(V)、14.70g(41.5mmol)Selectflour及4.82g(83.0mmol)氟化钾于185ml DCE及95ml水中的溶液在70℃下在密封管中搅拌20h。随后,用DCM/水萃取反应混合物。有机层用盐水洗涤,经Na2SO4干燥且在减压下浓缩。通过柱色谱(硅胶,DCM)纯化残余物。
C8H4BrFO (M=215.0g/mol)
1H NMR(300MHz,DMSO-d6)δppm:6.36(dd,J=6.4,0.9Hz,1H),7.47(dd,J=8.7,2.1Hz,1H),7.58(d,J=8.7Hz,1H),7.82(d,J=2.1Hz,1H)
中间体VII
1-(2-氟-1-苯并呋喃-5-基)乙-1-酮
在RT下,将168mg(1.2mmol)碳酸钾在搅拌下添加至218mg(1.0mmol)5-溴-2-氟-1-苯并呋喃(VI)于3mL DMF及0.3mL水中的溶液中。用氩气吹扫混合物,接着添加25mg(0.1mmol)1,3-双(二苯膦基)丙烷(dppp)、7mg乙酸钯(II)及183mg(2.5mmol)乙基乙烯醚。反应混合物在80℃下搅拌隔夜,接着冷却至RT且用1M HCl(20mL)水溶液处理。在RT下搅拌30min后,用EtOAc萃取混合物且在减压下浓缩合并的有机层。通过柱色谱(硅胶;EtOAc/己烷,梯度)纯化粗产物。
C10H7FO2 (M=178.2g/mol)
1H NMR(300MHz,DMSO-d6)δppm:2.63(s,3H),6.49(dd,J=6.4,0.8Hz,1H),7.70(dt,J=8.7,0.8Hz,1H),7.93(dd,J=8.7,1.9Hz,1H),8.25(dd,J=1.9,0.6Hz,1H)
中间体VIII
中间体VIII.1(通用程序)
2-溴-1-(2-氟-1-苯并呋喃-5-基)乙-1-酮
在RT下用0.34g(0.71mmol)三溴化四丁铵于0.08mL MeOH及0.8mL THF中的溶液逐滴处理126mg(0.71mmol)1-(2-氟-1-苯并呋喃-5-基)乙-1-酮(VII)的1.5mL THF溶液。在搅拌2h之后,在减压下浓缩反应混合物且用EtOAc/水萃取残余物。在减压下浓缩有机层且通过柱色谱(硅胶;己烷/EtOAc,梯度)纯化粗产物。
C10H6BrFO2 (M=257.1g/mol)
1H NMR(300MHz,DMSO-d6)δppm:4.99(s,2H),6.53(dd,J=6.4,0.9Hz,1H),7.75(d,J=8.7,1H),7.88-8.03(m,1H),8.31(dd,J=1.9,0.6Hz,1H)
使用类似于中间体VIII.1所描述的程序,使用适当起始物质制备以下化合物。如本领域技术人员所了解,这些类似实施例可涉及一般反应条件的变化形式。
*:反应在RT下用溴(13.6eq)在二噁烷/乙醚中进行2h且用硫代硫酸钠溶液淬灭。
中间体IX
1-({2-[(2R)-2-(4-氯苯基)-2-羟乙基]-2H-1,2,3,4-四唑-5-基}甲基)-3-甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酸乙酯
将303mg(1.11mmol)(1R)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-氯苯基)乙-1-醇(中间体II.1)及418mg(3.03mmol)K2CO3添加至200mg(1.01mmol)3-甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酸乙酯(CAS:154942-22-0,中间体XII.6)的8mL DMF溶液中且将混合物在50℃下搅拌5h,随后在RT下搅拌17h。通过反相HPLC(ACN/H2O梯度,0.1%TFA)纯化粗产物,得到所需产物。
C18H19ClN6O5 (M=434.8g/mol)
ESI-MS: 435[M+H]+
Rt(HPLC): 0.48min(方法A)
中间体X
1-({2-[(2R)-2-(4-氯苯基)-2-羟乙基]-2H-1,2,3,4-四唑-5-基}甲基)-3-甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酸
将44mg(1.8mmol)氢氧化锂添加至200mg(0.46mmol)中间体IX于1mL甲醇、1mL THF及100μl水中的溶液中。反应混合物在50℃下搅拌1h且随后冷却至RT且用水稀释。水层用DCM洗涤三次,用甲酸酸化,滤出所得沉淀物且将沉淀物在50℃下干燥,得到所需产物。
C16H15ClN6O5 (M=406.8g/mol)
ESI-MS: 407[M+H]+
Rt(HPLC): 0.46min(方法A)
中间体XI
中间体XI.1(通用程序)
2-{[(环丁基胺甲酰基)氨基]亚甲基}丙二酸1,3-二乙酯
将1.00g(8.76mmol)环丁基脲及3.79g(17.52mmol)2-(乙氧基亚甲基)丙二酸1,3-二乙酯在100℃下在纯条件下加热2.5h,且在130℃下加热5h。使反应混合物冷却至RT,用甲醇稀释且通过反相HPLC(ACN/H2O梯度,0.1% TFA)纯化,得到中间体XI.1。
C13H20N2O5 (M=284.3g/mol)
ESI-MS: 285[M+H]+
Rt(HPLC): 0.53min(方法A)
使用类似于中间体XI.1所描述的程序,使用适当起始物质制备以下化合物。如本领域技术人员所了解,这些类似实施例可涉及一般反应条件的变化形式。
中间体XII
中间体XII.1(通用程序)
1-环丁基-2-羟基-6-氧代-1,6-二氢嘧啶-5-甲酸乙酯
将957mg(14.1mmol)乙醇钠添加至2.00g(7.03mmol)中间体XI.1的30ml乙醇溶液且在80℃下搅拌混合物3h,随后用乙醇稀释且通过反相HPLC(ACN/H2O梯度,0.1% TFA)纯化。
C11H14N2O4 (M=238.2g/mol)
ESI-MS: 239[M+H]+
Rt(HPLC): 0.37min(方法A)
使用类似于中间体XII.1所描述的程序,使用适当起始物质制备以下化合物。如本领域技术人员所了解,这些类似实施例可涉及一般反应条件的变化形式。
中间体XII.6
3-甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酸乙酯
将500mg(6.75mmol)甲基脲及1.36g(6.75mmol)2-(甲氧基亚甲基)丙二酸1,3-二乙酯在纯条件下在120℃下搅拌2h,在RT下搅拌17h,在100℃下搅拌66h,在150℃下搅拌17h,且在120℃下搅拌17h。随后,用EtOAc稀释混合物且回流。将混合物缓慢冷却至RT且滤出沉淀中间体。
C8H10N2O4 (M=198.2g/mol)
ESI-MS: 199[M+H]+
Rt(HPLC): 0.24min(方法A)
中间体XIII
中间体XIII.1(通用程序)
1-环丁基-2-羟基-6-氧代-1,6-二氢嘧啶-5-甲酸胺
将630mg(0.03mmol)中间体XII.1的10ml氨水溶液(33%)在密封容器中在85℃下搅拌17h。在100℃下继续搅拌且添加氨水溶液直至起始物质完全耗尽为止。随后,在减压下浓缩反应混合物以得到中间体XIII.1。
C9H11N3O3 (M=209.2g/mol)
ESI-MS: 210[M+H]+
Rt(HPLC): 0.31min(方法A)
使用类似于中间体XIII.1所描述的程序,使用适当起始物质制备以下化合物。如本领域技术人员所了解,这些类似实施例可涉及一般反应条件的变化形式。
*处理:用HCl水溶液(1M)酸化,用DCM萃取,在减压下浓缩有机层,经由反相HPLC(ACN/H2O梯度,0.1% TFA)纯化。
**经由反相HPLC纯化
中间体XIV.1
(环丙基甲基)脲
将599mg(7.39mmol)氰酸钾添加至530mg(4.93mmol)1-环丙基甲胺盐酸盐的2ml水溶液中且将混合物在100℃下搅拌3h。使反应混合物在RT下静置14h,随后过滤出中间体XIV.1。
C5H10N2O (M=114.2g/mol)
ESI-MS: 115[M+H]+
Rt(HPLC): 0.15min(方法A)
中间体XIV.2
(2-甲氧乙基)脲
以小份将3.24g(39.94mmol)氰酸钾添加至2.0g(26.63mmol)2-甲氧基乙胺的8ml水溶液中且将混合物在100℃下搅拌3h,冷却至RT,用水/甲醇稀释且通过反相HPLC(ACN/H2O梯度,0.1% TFA)纯化。
C4H10N2O2 (M=114.2g/mol)
ESI-MS: 119[M+H]+
Rt(HPLC): 0.11min(方法A)
制备最终化合物
实施例1(通用程序)
1-({2-[(2R)-2-(4-氯苯基)-2-羟乙基]-2H-1,2,3,4-四唑-5-基}甲基)-3-甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酰胺
将178mg(0.65mmol)(1R)-2-[5-(氯甲基)-2H-1,2,3,4-四唑-2-基]-1-(4-氯苯基)乙-1-醇(中间体II.1)及245mg(1.77mmol)K2CO3添加至100mg(0.59mmol)3-甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酰胺(中间体III)的5mL DMF溶液中且将混合物在RT下搅拌隔夜。通过反相HPLC(ACN/H2O梯度,0.1%TFA)纯化混合物,得到所需产物。
C16H16ClN7O4 (M=405.8g/mol)
ESI-MS: 406[M+H]+
Rt(HPLC): 1.05min(方法B)
1H NMR(400MHz,DMSO-d6)δppm:3.21(s,3H),4.73-4.84(m,2H),5.13(m,1H),5.45(s,2H),5.92(d,J=2.4Hz,1H),7.35-7.42(m,4H),7.64(br d,J=3.4Hz,1H),8.20(br d,J=3.4Hz,1H),8.77(s,1H)
使用类似于实施例1所描述的程序,使用适当起始物质制备以下化合物。如本领域技术人员所了解,这些类似实施例可涉及一般反应条件的变化形式。
化合物的分析数据描述于上表中:
实施例22(通用程序)
1-({2-[(2R)-2-(4-氯苯基)-2-羟乙基]-2H-1,2,3,4-四唑-5-基}甲基)-N-(2-甲氧乙基)-3-甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲酰胺
在RT搅拌下,将25μl(0.15mmol)DIPEA及22mg(0.06mmol)HATU添加至20mg(0.05mmol)中间体X的1.0mL DMF溶液中。30分钟后,添加8μl(0.10mmol)2-甲氧基乙-1-胺且将混合物在RT下搅拌90min。随后通过反相HPLC(ACN/H2O梯度,0.1% TFA)纯化,得到所需产物。
C19H22ClN7O5 (M=463.9g/mol)
ESI-MS: 464[M+H]+
Rt(HPLC): 0.48min(方法A)
1H NMR(400MHz,DMSO-d6)δppm 3.22(s,3H),3.28(s,3H),3.41-3.51(m,4H),4.73-4.84(m,2H),5.13(m,1H),5.45(s,2H),5.5-6.4(br s,1H),7.38(m,4H),8.77(s,1H),8.94(m,1H)。
使用类似于实施例22所描述的程序,使用适当起始物质制备以下化合物。如本领域技术人员所了解,这些类似实施例可涉及一般反应条件的变化形式。
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:60℃
方法B
分析柱:Stable Bond(Agilent)C18_3.0×30mm_1.8μm;柱温:60℃
方法C
分析柱:XBridge(Waters)C18_3.0×30mm_2.5μm;柱温:60℃
方法D
分析柱:XBridge C18_3.0×30mm_2.5μm(Waters);柱温:60℃
方法E
分析柱:Sunfire(Waters);C18_3.0×30mm_2.5μm;柱温:60℃
方法F
分析柱:XBridge BEH(Waters)C18_2.1×30mm_2.5μm;柱温:60℃
方法G
分析柱:Zorbax StableBond C18(Agilent)1.8μm;2.1×30mm;柱温:60℃
方法H
分析柱:Sunfire(Waters)2.5μm;3.0×30mm;柱温:60℃
方法I
分析柱:Sunfire C18(Waters)2.5μm;3.0×30mm;柱温:60℃
方法J
分析柱:Acquity UPLC BEH;C8_2.1×150mm_1.7μm;柱温:55℃
Claims (15)
1.一种根据式(I)的化合物
其中
A选自由苯基、噻吩基、苯并噻吩基或苯并呋喃基组成的组,其未经取代或经由卤素、C1-4烷基、C1-4氟烷基、C3-4环烷基、C3-4环氟烷基、O-C1-4烷基、O-环丙基及NC-组成的组R3的一个、两个或三个的成员取代;
或
A选自由以下组成的组:
R1选自由C1-4烷基、C1-4氟烷基、C3-6环烷基、R4-(H2C)m-及R5-(H2C)n-组成的组;
其中
m为1或2;
n为2;
R4为C3-6环烷基;
R5为-O-C1-4烷基或-O-C1-4氟烷基;
R2选自由H、C1-4烷基、C3-6环烷基、C3-6环氟烷基、HO-C1-4烷基-、C1-4氟烷基、R6-(H2C)p-、R7-(H2C)q-、R6-(H(R8)C)p-及R7-(H(R9)C)q-组成的组;
其中
p为1或2;
q为2;
R6选自由HO-C1-2烷基-、C3-6环烷基、C-吗啉基、C-咪唑基及C-吡唑基组成的组;
其中该C-吡唑基、C-咪唑基及C-吗啉基未经取代或经C1-4烷基或C1-4氟烷基取代;
R7选自由C1-4烷基-O-、C1-4氟烷基-O-、C1-4烷基-S(O)2-、N-吗啉基、N-咪唑基及N-吡唑基组成的组;
其中该N-吡唑基、N-咪唑基、N-吗啉基未经取代或经C1-4烷基或C1-4氟烷基取代;
R8及R9为独立地选自H或C1-4烷基。
4.根据权利要求1至3中任一项的式(I)化合物,其中R1选自由C1-4烷基、C3-6环烷基、R4-(H2C)m-及R5-(H2C)n-组成的组;
其中
m为1;
n为2;
R4为C3-6环烷基;及
R5为-O-C1-4烷基。
5.根据权利要求1至3中任一项的式(I)化合物,其中R1选自由C1-4烷基、C3-4环烷基、R4-(H2C)m-及R5-(H2C)n-组成的组;
其中
m为1;
n为2;
R4为C3-4环烷基;及
R5为-O-C1-4烷基。
6.根据权利要求1至5中任一项的式(I)化合物,其中R2选自由H、C1-4烷基、C3-6环烷基、HO-C1-4烷基-、C1-4氟烷基、R6-(H2C)p-及R7-(H2C)q-组成的组;
其中
p为1;
q为2;
R6选自由C3-6环烷基、C-吗啉基、C-咪唑基及C-吡唑基组成的组;
其中该C-吡唑基、C-咪唑基及C-吗啉基未经取代或经C1-4烷基取代;
R7选自由-O-C1-4烷基、-O-C1-4氟烷基、C1-4烷基-S(O)2-、N-吗啉基、N-咪唑基及N-吡唑基组成的组;
其中该N-吡唑基、N-咪唑基、N-吗啉基未经取代或经C1-4烷基取代。
7.根据权利要求1至5中任一项的式(I)化合物,其中R2选自由H、C1-4烷基、C3-6环烷基、HO-C1-4烷基-、C1-2氟烷基、R6-(H2C)p-及R7-(H2C)q-组成的组;
其中
p为1;
q为2;
R6选自由C3-6环烷基、C-吗啉基、C-咪唑基及C-吡唑基组成的组;
其中该C-吡唑基、C-咪唑基及C-吗啉基为未经取代或经H3C取代;
R7选自由H3C-O、-O-氟甲基、H3C-S(O)2-、N-吗啉基、N-咪唑基及N-吡唑基组成的组;
其中该N-吡唑基、N-咪唑基、N-吗啉基未经取代或经H3C取代。
11.一种根据权利要求1至10中任一项的化合物的盐,尤其为药学上可接受的盐。
12.一种药物组合物,其包含至少一种根据权利要求1至10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。
13.根据权利要求1至10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。
14.一种根据权利要求1至10中任一项的化合物或其药学上可接受的盐的用途,其用于治疗或预防炎性气管疾病或纤维变性疾病或咳嗽。
15.一种根据权利要求1至10中任一项的化合物或其药学上可接受的盐的用途,其用于治疗或预防特发性肺病(idiopathic lung disease;IPF)或咳嗽。
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EP20182988 | 2020-06-29 | ||
EP20182988.4 | 2020-06-29 | ||
PCT/EP2021/067470 WO2022002782A1 (en) | 2020-06-29 | 2021-06-25 | Tetrazole derivatives as trpa1 inhibitors |
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EP (1) | EP4171563A1 (zh) |
JP (1) | JP2023531924A (zh) |
KR (1) | KR20230028547A (zh) |
CN (1) | CN115803029A (zh) |
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AU (1) | AU2021298800A1 (zh) |
BR (1) | BR112022021865A2 (zh) |
CA (1) | CA3181350A1 (zh) |
CL (1) | CL2022003329A1 (zh) |
CO (1) | CO2022016755A2 (zh) |
CR (1) | CR20220667A (zh) |
DO (1) | DOP2022000262A (zh) |
EC (1) | ECSP22088664A (zh) |
IL (1) | IL299175A (zh) |
MX (1) | MX2022016357A (zh) |
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AR128431A1 (es) * | 2022-02-03 | 2024-05-08 | De Shaw Res Llc | Compuestos de uracilo n3-sustituidos como inhibidores de trpa1 |
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US7361654B2 (en) | 2005-01-13 | 2008-04-22 | Bristol-Myers Squibb Co. | Substituted heteroaryl amide modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
WO2017060488A1 (en) | 2015-10-09 | 2017-04-13 | Almirall, S.A. | New trpa1 antagonists |
IL306065A (en) | 2021-04-14 | 2023-11-01 | Boehringer Ingelheim Int | Uracil history as TRPA1 inhibitors |
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2021
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CO2022016755A2 (es) | 2022-11-29 |
KR20230028547A (ko) | 2023-02-28 |
US11884652B2 (en) | 2024-01-30 |
CA3181350A1 (en) | 2022-01-06 |
IL299175A (en) | 2023-02-01 |
CL2022003329A1 (es) | 2023-03-31 |
EP4171563A1 (en) | 2023-05-03 |
AU2021298800A1 (en) | 2022-11-24 |
DOP2022000262A (es) | 2023-01-31 |
JP2023531924A (ja) | 2023-07-26 |
CR20220667A (es) | 2023-02-03 |
ECSP22088664A (es) | 2022-12-30 |
TW202216688A (zh) | 2022-05-01 |
BR112022021865A2 (pt) | 2023-01-24 |
MX2022016357A (es) | 2023-01-24 |
AR122779A1 (es) | 2022-10-05 |
US20220002270A1 (en) | 2022-01-06 |
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