CN109415347A - 酰胺取代的吡啶基三唑衍生物及其用途 - Google Patents
酰胺取代的吡啶基三唑衍生物及其用途 Download PDFInfo
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- CN109415347A CN109415347A CN201780041607.6A CN201780041607A CN109415347A CN 109415347 A CN109415347 A CN 109415347A CN 201780041607 A CN201780041607 A CN 201780041607A CN 109415347 A CN109415347 A CN 109415347A
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Abstract
本发明涉及:新型5‑(甲酰胺)‑1‑吡啶基‑1,2,4‑三唑衍生物,制备这样的化合物的方法,含有这样的化合物的药物组合物,以及这样的化合物或组合物用于治疗和/或预防疾病、特别是用于治疗和/或预防肾脏和心血管疾病的用途。
Description
本发明涉及:新型5-(甲酰胺)-1-吡啶基-1,2,4-三唑衍生物,制备这样的化合物的方法,含有这样的化合物的药物组合物,以及这样的化合物或组合物用于治疗和/或预防疾病、特别是用于治疗和/或预防肾脏和心血管疾病的用途。
加压素是一种神经激素,其基本上调节水稳态和血管张力。其在第三脑室(下丘脑)的壁中的视上核和室旁核中的专门内分泌神经元中产生,并且沿神经突从那里转运至脑垂体(神经垂体)的后叶。在那里,响应于不同的生理和病理生理刺激,激素被释放至血流中。受干扰的神经激素调节基本上自身表现为交感神经张力的升高和肾素-血管紧张素-醛固酮系统(RAAS)的不适当活化。尽管一方面β-受体阻滞剂和另一方面ACE抑制剂或血管紧张素受体阻滞剂对这些组分的抑制现在是心血管疾病的药物治疗的固有部分,但加压素分泌的不适当升高目前仍然不是充分可治疗的。
加压素主要经由与三种受体结合发挥其作用,所述受体被分类为V1a、V1b和V2受体且其属于G蛋白偶联受体的家族。
V2受体位于肾中的远端小管上皮和集合管的上皮中。它们的活化使这些上皮细胞可透过水。这种现象是由于在上皮细胞的腔膜中掺入水通道蛋白(特殊水通道)。因此,加压素对V2受体的作用的药理学抑制导致增加的尿排泄。因此,具有V2拮抗活性的药物似乎特别适合于治疗与身体超负荷水相关的所有疾病状况。
V1b受体(也称为V3受体)主要在中枢神经系统中可检测。与促肾上腺皮质激素释放激素(CRH)一起,加压素经由V1b受体调节促肾上腺皮质激素(ACTH)的基础和应激诱导的分泌。
V1a受体主要位于血管平滑肌细胞(VSMC)上,但也位于心肌细胞、成纤维细胞和专门的肾细胞如肾小球系膜细胞或控制肾素释放的致密斑细胞上[Wasilewski MA, MyersVD, Recchia FA, Feldman AM, Tilley DG, Cell Signal., 28(3), 224-233, (2016)]。加压素对VSMC V1a受体的活化引起细胞内钙释放和相应的血管收缩。因此,VSMC V1a受体的刺激引起增加的血管阻力和增加的心脏后负荷。V1a-介导的血管收缩不利地影响心输出量。后负荷的增加和心肌细胞上V1a受体的直接刺激可导致心脏肥大和包括纤维化的重塑。具有V1a受体的心脏特异性过表达的小鼠发生心脏肥大,其导致扩张和左心室功能障碍,提示V1a受体在心力衰竭的发展中的重要作用[Li X, Chan TO, Myers V, Chowdhury I,Zhang XQ, Song J, Zhang J, Andrel J, Funakoshi H, Robbins J, Koch WJ, HyslopT, Cheung JY, Feldman AM, Circulation.; 124, 572-581 (2011)]。
V1a受体也在肾皮质和髓质血管系统中表达,其在那里介导肾血管的血管收缩并影响整体肾血流。因此,V1a受体的活化可以减少肾髓质血流,诱导进一步的病理过程,如组织缺氧、对管转运过程的减少的氧气和相应的能量供应、以及系膜和致密斑细胞的直接损伤。已经证实,系膜V1a受体活化介导TGFβ信号传导并引起胶原蛋白IV的产生增加。尽管这种信号传导有助于肾中的细胞外基质积累和重塑,但类似的信号传导通路据信发生在心脏细胞中,特别是在心肌梗塞后,这强调了V1a受体在响应病理生理学升高的加压素水平的肥大和纤维化过程的发展中的核心作用[Wasilewski MA, Myers VD, Recchia FA, FeldmanAM, Tilley DG. Arginine vasopressin receptor signaling and functional outcomes in heart failure.Cell Signal., 28(3), 224-233 (2016)]。
由于V1a受体主要在VSMC上表达并因此参与血管功能,可以设想与血管疾病如包括跛行和严重肢体缺血的外周动脉疾病(PAD)以及冠状动脉微血管功能障碍(CMD)的关联。
除此之外,V1a受体也在人血小板上和肝脏中表达。血小板V1a受体的含义没有被完全理解,尽管加压素经由离体高浓度的V1a受体诱导人血小板的聚集。因此,V1a受体拮抗剂对加压素诱导的血小板聚集的抑制是一种有用的药理学离体测定,其利用内源性表达V1a受体的人组织[Thibonnier M, Roberts JM, J Clin Invest.; 76:1857-1864,(1985)]。
加压素经由肝脏V1a受体的活化刺激糖异生和糖原分解。动物研究已经显示,加压素损害葡萄糖耐量,其可被V1a受体拮抗剂抑制,由此提供加压素受体V1a与糖尿病的关联。[Taveau C, Chollet C, Waeckel L, Desposito D, Bichet DG, Arthus MF, Magnan C,Philippe E, Paradis V, Foufelle F, Hainault I, Enhorning S, Velho G, RousselR, Bankir L, Melander O, Bouby N. Vasopressin and hydration play a major rolein the development of glucose intolerance and hepatic steatosis in obeserats. Diabetologia, 58(5), 1081-1090, (2015)]。加压素在动物模型中显示有助于白蛋白尿和糖尿病诱发的肾病的发展,这与人中的流行病学发现一致。
最近发现,加压素似乎也在先兆子痫的发展中发挥因果作用。在小鼠妊娠期间慢性输注加压素足以诱导与人先兆子痫相关的所有主要母体和胎儿表型,包括妊娠特异性高血压[Santillan MK, Santillan DA, Scroggins SM, Min JY, Sandgren JA, PearsonNA, Leslie KK, Hunter SK, Zamba GK, Gibson-Corley KN, Grobe JL. Vasopressinin preeclampsia: a novel very early human pregnancy biomarker and clinicallyrelevant mouse model. Hypertension. 64(4), 852-859, (2014)]。
在月经期间,在患有痛经的女性(一种特征在于周期性痉挛性骨盆疼痛的妇科疾病)中,加压素水平可升高,这似乎增加子宫肌层平滑肌收缩。最近发现,选择性加压素V1a受体拮抗剂(瑞考伐普坦(relcovaptan)/SR-49059)可以减少由加压素引发的子宫内收缩。
由于这些原因,抑制加压素对V1a受体的作用的药剂似乎适合于治疗几种心血管疾病。具体而言,选择性地抑制加压素对V1a受体的作用的药剂为治疗否则正常血容量的患者提供了特别理想的概况(profile),所述患者即没有通过例如高剂量的袢利尿剂或V2拮抗剂减轻充血的资格、且该情况下经由V2抑制的诱导的促排水作用(aquaresis)可能是不希望的那些。
在WO 2005/063754-A1和WO 2005/105779-A1中已经描述了某些4-苯基-1,2,4-三唑-3-基衍生物充当加压素V1a受体拮抗剂,其可用于治疗妇科疾病,尤其是月经紊乱,诸如痛经。
在WO 2011/104322-A1中,特定组的双芳基键合的1,2,4-三唑-3-酮、包括其5-苯基-1,2,4-三唑-3-基和1-苯基-1,2,3-三唑-4-基衍生物已被公开为加压素V2和/或V1a受体的拮抗剂,其可用于治疗和/或预防心血管疾病。然而,所述化合物没有显示对V1a受体足够的选择性,并且主要显示对加压素V1a和V2受体两者的组合活性。然而,如上所概述,对于V1a受体的高亲和力以及选择性是治疗不期望减轻充血的疾病状况的理想先决条件,并且可导致否则正常血容量个体中失调的体液稳态,包括降低的血浆渗透压。
在WO 2016/071212-A1中,已经公开了某些5-(羟基烷基)-1-苯基-1,2,4-三唑衍生物,其充当加压素V1a和V2受体二者的有效拮抗剂,并且另外显示口服应用后体内显著增强的促排水效力。所述化合物被描述为可用于治疗和/或预防心血管和肾脏疾病。然而,如上所概述,对于V1a受体的高亲和力以及选择性是治疗不期望减轻充血的疾病状况的理想先决条件,并且可导致否则正常血容量个体中失调的体液稳态,包括降低的血浆渗透压。
对V1a受体具有高选择性的活性概况具有引起不需要的脱靶相关副作用的低可能性,并且还会有助于减少实现和维持期望治疗效果所需的物质量,因此在治疗可能已经处于高风险的患者(诸如,例如在急性或慢性心脏和肾疾病中)期间限制不可接受的副作用和/或不需要的药物-药物相互作用的可能性。
因此,在鉴定和提供充当加压素V1a受体的有效拮抗剂的新化合物中,可看到待根据本发明解决的技术问题。本发明的另一个目的是鉴定和提供对于加压素V1a受体具有高亲和力和选择性的新化合物。该化合物旨在避免经由V2抑制诱导促排水作用。所述化合物还旨在与根据现有技术已知的化合物相比具有相似或改进的治疗概况,例如关于其体内特性、例如其药代动力学和药效动力学特征和/或其代谢概况和/或它们的剂量-活性关系。
令人惊讶地,现已发现某些5-(甲酰胺)-1-吡啶基-1,2,4-三唑衍生物代表了V1a受体的非常有效和选择性的拮抗剂。该特定概况使得本发明的化合物可用于治疗和/或预防与V1a受体活化有关的疾病。本发明的化合物尤其可用于治疗和/或预防未患有流体超负荷且因此不应减轻充血的对象中的肾脏和心血管疾病。
本发明的化合物具有有价值的药理学特性,且可用于预防和/或治疗人和其它哺乳动物中的各种疾病和疾病诱导的状态。
在一个方面,本发明涉及通式(I)的5-(甲酰胺)-1-吡啶基-1,2,4-三唑衍生物
其中
R1代表下式的基团
其中
#1代表与氮原子的连接点,
Ar代表下式的基团
其中
#2代表与氮原子的连接点,
R2A代表选自以下的基团:氯原子、溴原子、三氟甲基、三氟甲氧基、乙氧基羰基和-C(=O)NH2,
R2B代表选自以下的基团:氯原子、三氟甲基和乙氧基羰基。
根据本发明的化合物还可以其盐、溶剂化物和/或盐的溶剂化物的形式存在。
在本说明书中使用时,术语“包含”包括“由……组成”。
如果本文本内将任何项目称为“如本文所述”,则意味着,其可在本文本中的任何地方提及。
如本文本中提及的术语具有下述含义:
术语“C1-C4-烷基”意味着具有1、2、3或4个碳原子的直链或支链的饱和一价烃基,例如甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基、叔丁基或者其异构体。特别地,所述基团具有1、2、3或4个碳原子(“C1-C4-烷基”),例如,甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基或叔丁基,更特别是1、2或3个碳原子(“C1-C3-烷基”),例如,甲基、乙基、正丙基或异丙基,甚至更特别是甲基。
通式(I)的化合物可能作为同位素变体存在。本发明因此包括通式(I)的化合物的一种或多种同位素变体,特别是含氘的通式(I)的化合物。
化合物或试剂的术语“同位素变体”被定义为表现出构成这样的化合物的同位素中的一种或多种的非天然比率的化合物。
术语“通式(I)的化合物的同位素变体”被定义为表现出构成这样的化合物的同位素中的一种或多种的非天然比率的通式(I)的化合物。
表述“非天然比率”意味着高于其天然丰度的这样的同位素的比率。应用于该上下文中的同位素的天然丰度被描述于“Isotopic Compositions of the Elements 1997”,Pure Appl.Chem.,70(1),217-235,1998。
这样的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的稳定和放射性同位素,分别诸如2H(氘)、3H(氚)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I和131I。
关于治疗和/或预防本文中所指的病症,通式(I)的化合物的一种或多种同位素变体优选含有氘(“含氘的通式(I)的化合物”)。其中并入了一种或多种诸如3H或14C的放射性同位素的通式(I)的化合物的同位素变体例如可用于药物和/或底物组织分布研究。这些同位素因其并入的容易性和可检测性而特别优选。可以将正电子发射同位素诸如18F或11C并入通式(I)的化合物中。通式(I)的化合物的这些同位素变体可用于体内成像应用。含氘和含13C的通式(I)的化合物可以用于在临床前或临床研究的背景下的质谱分析。
通常可以通过本领域技术人员已知的方法,诸如在本文中的方案和/或实施例中描述的那些,通过将试剂替换为所述试剂的同位素变体,优选替换为含氘的试剂,制备通式(I)的化合物的同位素变体。取决于期望的氘化位点,在一些情况中,可以将来自D2O的氘直接并入化合物中,或并入对于合成这样的化合物有用的试剂中。氘气也是对于将氘并入分子中有用的试剂。烯属键和炔属键的催化氘化是用于并入氘的直接途径。氘气存在下的金属催化剂(即Pd、Pt和Rh)可以用于在含烃的官能团中将氢直接更换为氘。多种氘化试剂和合成构件可从公司商购获得,所述公司诸如例如C/D/N Isotopes,Quebec,Canada;Cambridge Isotope Laboratories Inc.,Andover,MA,USA;和CombiPhos Catalysts,Inc.,Princeton,NJ,USA。
术语“含氘的通式(I)的化合物”被定义为通式(I)的化合物,其中一个或多个氢原子被一个或多个氘原子替代,并且其中通式(I)的化合物的各氘化位置处的氘的丰度高于为约0.015%的氘的天然丰度。特别地,在含氘的通式(I)的化合物中,通式(I)的化合物的各氘化位置处的氘的丰度高于10%、20%、30%、40%、50%、60%、70%或80%,优选在一个或多个所述位置处高于90%、95%、96%或97%,甚至更优选在一个或多个所述位置处高于98%或99%。要理解的是,在各氘化位置处的氘的丰度独立于其它的一个或多个氘化位置处的氘的丰度。
将一个或多个氘原子选择性地并入通式(I)的化合物可改变分子的物理化学特性(诸如例如,酸性[C. L. Perrin等人,J.Am. Chem.Soc.,2007,129,4490]、碱性[C. L.Perrin等人,J.Am. Chem.Soc.,2005,127,9641]、亲脂性[B. Testa等人,Int.J. Pharm.,1984,19(3),271])和/或代谢概况,并且可导致母体化合物与代谢物的比率或所形成的代谢物的量中的改变。这样的改变可导致某些治疗优点,并且因此在一些情况中可为优选的。已报道了其中改变了代谢物比率的减少的代谢率和代谢转换(A. E. Mutlib等人,Toxicol.Appl.Pharmacol.,2000,169,102)。关于含氘的通式(I)的化合物的药效动力学、耐受性和效能,在暴露于母体药物和代谢物中的这些改变可以具有重要的结果。在一些情况中,氘取代减少或消除不期望或毒性的代谢物的形成,并且提高期望的代谢物的形成(例如,奈韦拉平:A.M. Sharma等人,Chem.Res.Toxicol.,2013,26,410;依法韦仑:A.E.Mutlib等人,Toxicol.Appl.Pharmacol.,2000,169,102)。在其它情况中,氘化的主要效果是减少全身清除率。作为结果,提高了化合物的生物半衰期。潜在的临床益处将包括以减少的峰水平和增加的谷水平来维持相似全身暴露的能力。取决于特定化合物的药代动力学/药效动力学关系,这可导致更低的副作用和提高的效能。ML-337(C. J. Wenthur等人,J.Med.Chem.,2013,56,5208)和奥当卡替(K. Kassahun等人,WO2012/112363)是该氘效应的实例。还报告了另外其它的情况,其中降低的代谢率导致药物暴露中的增加而不改变全身清除率(例如,罗非考昔:F.Schneider等人,Arzneim.Forsch./ Drug.Res.,2006,56,295;特拉匹韦:F.Maltais等人,J.Med.Chem.,2009,52,7993)。显示出该效应的氘化药物可具有减少的给药要求(例如,更低的剂量数或更低的剂量以实现期望效果)和/或可产生更低的代谢物负载。
通式(I)的化合物可具有对于代谢的多个潜在的攻击位点。为了优化对物理化学特性和代谢概况的上述效果,可以选择具有某一形式的一个或多个氘-氢交换的含氘的通式(I)的化合物。特别地,一种或多种通式(I)的含氘的化合物的一个或多个氘原子连接于碳原子和/或位于通式(I)的化合物的那些位置,所述位置是对于代谢酶、诸如例如细胞色素P450的攻击位点。
在本文中使用词语化合物、盐、多晶型物、水合物、溶剂化物等的复数形式的情况下,其也被认为意味着单一的化合物、盐、多晶型物、异构体、水合物、溶剂化物等。
“稳定的化合物”或“稳定的结构”意味着充分稳健以经受(survive)从反应混合物分离至有用的纯度程度和配制为有效治疗剂的化合物。
取决于各种期望取代基的位置和性质,本发明的化合物任选含有一个不对称中心。一个不对称碳原子可能以(R)或(S)构型存在,其可以导致外消旋混合物。在某些情况中,由于围绕指定化合物的给定键、例如邻接两个取代芳族环的中心键的受限旋转,也可能存在不对称性。优选的化合物是产生更期望的生物活性的那些。本发明化合物的分离的、纯的或部分纯化的异构体和立体异构体或者外消旋混合物也包括在本发明的范围内。这样的材料的纯化和分离可以通过本领域已知的标准技术完成。
光学异构体可以通过根据常规方法来拆分外消旋混合物而获得,例如通过使用光学活性的酸或碱形成非对映异构盐、或者形成共价非对映异构体。适合的酸的实例是酒石酸、二乙酰基酒石酸、二甲苯酰酒石酸和樟脑磺酸。通过本领域已知的方法,例如通过色谱或分步结晶,可以基于它们物理和/或化学差异,将非对映异构体的混合物分离为其个别的非对映异构体。然后将光学活性的碱或酸从分离的非对映异构盐释放。用于分离光学异构体的不同工艺涉及在有或没有常规衍生化的情况下使用手性色谱(例如使用手性相的HPLC柱),其进行最佳选择以使得对映异构体的分离最大化。使用手性相的适合的HPLC柱是可商业获得的,诸如例如由Daicel制造的那些,例如Chiracel OD和Chiracel OJ和许多其它的柱,其均可常规选择。具有或不具有衍生化的酶分离也是有用的。本发明的光学活性的化合物可以同样地利用光学活性的起始材料通过手性合成获得。为了彼此区分不同类型的异构体,参照IUPAC Rules Section E (Pure Appl Chem 45,11-30,1976)。
本发明包括作为单一立体异构体、或者作为任何比率的所述立体异构体(例如(R)-或(S)-异构体)的任何混合物的本发明化合物的所有可能的立体异构体。例如,本发明的化合物的单一立体异构体(例如单一对映异构体或单一非对映异构体)的分离通过任何适合的现有技术方法、诸如色谱、尤其是例如手性色谱而实现。
进一步地,本发明的化合物可能作为互变异构体存在。本发明包括作为单一互变异构体、或者作为任何比率的所述互变异构体的任何混合物的本发明化合物的所有可能的互变异构体。
进一步地,本发明的化合物可以作为N-氧化物存在,其被定义为本发明的化合物的至少一个氮被氧化。本发明包括所有这样的可能的N-氧化物。
本发明还涵盖本发明的化合物的有用形式,诸如代谢物、水合物、溶剂化物、盐(特别是药学上可接受的盐)和/或共沉淀物。
本发明的化合物可以作为水合物或作为溶剂化物存在,其中,本发明的化合物含有极性溶剂,特别是例如水、甲醇或乙醇作为化合物晶格的结构要素。极性溶剂、特别是水的量可能以化学计量或非化学计量的比率存在。在化学计量的溶剂化物的情况中,例如水合物、半-(hemi-(semi-))、单-、倍半-、二、三-、四-、五-等溶剂化物或水合物分别是可能的。本发明包括所有这样的水合物或溶剂化物。在本发明的上下文中,水合物是优选的溶剂化物。
具体而言,根据本发明的式(I-B)的3,3,3-三氟-2-氧代丙基衍生物(酮形式)也可以3,3,3-三氟-2,2-二羟基丙基形式(I-B)'(水合物形式)(参见下面的方案1)存在;这两种形式明确地被本发明涵盖。
进一步地,本发明的化合物可能以游离形式、例如作为游离碱或作为游离酸或者作为两性离子存在,或者以盐的形式存在。所述盐可为任何盐,或是有机或是无机加成盐,特别是在制药业中惯常使用、或例如用于分离或纯化本发明的化合物的任何药学上可接受的有机或无机加成盐。
术语“药学上可接受的盐”是指本发明的化合物的无机或有机酸加成盐。例如参见S. M. Berge等人,“Pharmaceutical Salt,”J. Pharm.Sci.1977,66,1-19。
本发明的化合物的适合的药学上可接受的盐可为,例如在链中或在环中带有氮原子的、例如充分碱性的本发明的化合物的酸加成盐,诸如,与无机酸或“矿物酸”,诸如例如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸(sulfamic)、重硫酸(bisulfuric)、磷酸或硝酸的酸加成盐;或者与有机酸,诸如例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、帕莫酸、果胶酸、3-苯基丙酸、新戊酸、2-羟基乙磺酸、衣康酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、丁二酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸或硫氰酸的酸加成盐。
进一步地,充分酸性的本发明的化合物的另一适合的药学上可接受的盐是碱金属盐,例如钠或钾盐;碱土金属盐,例如钙、镁或锶盐;或者铝或锌盐;或者铵盐,其衍生自氨或具有1至20个碳原子的有机伯、仲或叔胺,诸如乙胺、二乙胺、三乙胺、乙基二异丙基胺、单乙醇胺、二乙醇胺、三乙醇胺、二环己基胺、二甲基氨基乙醇、二乙基氨基乙醇、三(羟基甲基)氨基甲烷、普鲁卡因、二苄基胺、N-甲基吗啉、精氨酸、赖氨酸、1,2-乙二胺、N-甲基哌啶、N-甲基-葡糖胺、N,N-二甲基-葡糖胺、N-乙基-葡糖胺、1,6-己二胺、氨基葡萄糖、肌氨酸、丝氨醇、2-氨基-1,3-丙二醇、3-氨基-1,2-丙二醇、4-氨基-1,2,3-丁三醇;或者与具有1至20个碳原子的季铵离子诸如四甲基铵、四乙基铵、四(正丙基)铵、四(正丁基)铵、N-苄基-N,N,N-三甲基铵、胆碱或苄烷铵的盐。
本领域技术人员将进一步认识到,要求保护的化合物的酸加成盐可能经由许多已知方法中的任一种、通过使化合物与适合的无机或有机酸反应而制备。可选地,本发明的酸性化合物的碱金属和碱土金属盐经由多种已知方法、通过使本发明的化合物与适合的碱反应而制备。
本发明包括作为单一盐、或者作为任何比率的所述盐的任何混合物的本发明的化合物的所有可能的盐。
在本文本中,特别是在实验部分中,为了合成本发明的中间体和实施例,当化合物被提及为与对应的碱或酸的盐形式时,由各制备和/或纯化工艺得到的所述盐形式的准确化学计量组成在大多数情况中是未知的。
除非另有说明,与盐相关的化学名或结构式的后缀诸如例如“盐酸盐”、“三氟乙酸盐”、“钠盐”,或“x HCl”、“x CF3COOH”、“x Na+”意味着盐形式,所述盐形式的化学计量没有指定。
这类似地应用于下述情况:其中已通过所描述的制备和/或纯化工艺获得了作为溶剂化物(诸如水合物)的合成中间体或实施例化合物或其盐,其具有(如果定义)未知的化学计量组成。
而且,本发明包括作为单一多晶型物、或作为任何比率的多于一种多晶型物的混合物的本发明的化合物的所有可能的结晶形式或多晶型物。
在一个不同实施方式中,本发明涉及上述式(I)的化合物,其中
R1代表下式的基团
其中
#1代表与氮原子的连接点,
Ar代表下式的基团
其中
#2代表与氮原子的连接点,
R2A代表选自以下的基团:氯原子、溴原子、三氟甲基、三氟甲氧基、乙氧基羰基和-C(=O)NH2,
或其药学上可接受的盐、水合物和/或溶剂化物。
在一个优选实施方式中,本发明涉及上述根据式(I)的化合物,其中
R1代表下式的基团
其中
#1代表与氮原子的连接点,
Ar代表下式的基团
其中
#2代表与氮原子的连接点,
R2A代表选自以下的基团:氯原子、三氟甲基和三氟甲氧基,
或其药学上可接受的盐、水合物和/或溶剂化物。
根据一个进一步优选实施方式,本发明涵盖上述通式(I)的化合物,其中
R1代表下式的(2S)-3,3,3-三氟-2-羟基丙基
其中
#1代表与氮原子的连接点,
或其药学上可接受的盐、水合物和/或溶剂化物。
R1代表下式的(2R)-3,3,3-三氟-2-羟基丙基
其中
#1代表与氮原子的连接点,
或其药学上可接受的盐、水合物和/或溶剂化物。
在第一方面的一个特别的进一步实施方式中,本发明涵盖在标题“本发明的第一方面的进一步的实施方式”下的上文提及的实施方式中的两个或更多个的组合。
本发明涵盖上述通式(I)的化合物在本发明的任何实施方式或方面内的任何亚组合。
本发明涵盖通式(II)、(III)、(IV)、(V)、(VI)和(VIII)、(VIII)的中间体化合物在本发明的任何实施方式或方面内的任何亚组合。本发明涵盖本文下文实施例部分中公开的通式(I)的化合物。
根据第二个方面,本发明涵盖制备如上所定义的通式(I)的化合物的方法,所述方法包括以下步骤
[A] 使式(II)的中间体化合物:
其中R1如对于如上文所定义的通式(I)的化合物所定义,且
R3代表(C1-C4)-烷基,特别是甲基,
在第一步中在碱存在的情况下与通式(III)的化合物反应:
其中
R4代表(C1-C4)-烷基,特别是甲基,
以产生中间体化合物,然后使其在碱和任选地铜盐存在的情况下在第二步中与通式(IV)的肼化合物或其各自的盐反应
其中Ar如对于如上文所定义的通式(I)的化合物所定义,
由此产生通式(V)的化合物:
其中R1和Ar如对于如上文所定义的通式(I)的化合物所定义,且
R4代表(C1-C4)-烷基,特别是甲基,
随后是后续步骤
[B] 使步骤[A]中获得的式(V)的化合物与氨反应,由此产生通式(I)的化合物:
其中R1和Ar如对于如上文所定义的通式(I)的化合物所定义,
任选地随后为步骤
[C] 使用已知的氧化方法将通式(I-A)的醇:
其中Ar如对于如上文所定义的通式(I)的化合物所定义,
转化为通式(I-B)的酮:
其中Ar如对于如上文所定义的通式(I)的化合物所定义,
在适当的情况下,每个[A]、[B]和[C]任选地随后为:(i)将因此获得的式(I)的化合物分离为它们各自的对映异构体,和/或(ii)通过用相应的溶剂和/或酸或碱处理,将式(I)的化合物转化为它们各自的水合物、溶剂化物、盐和/或盐的水合物或溶剂化物。
本发明涵盖制备通式(I)的本发明的化合物的方法,所述方法包括如本文实验部分中所述的步骤。
以下描述的方案和程序举例说明本发明的通式(I)的化合物的合成途径且不意欲是限制性的。本领域技术人员清楚的是,如方案2、3、4、5、6和7中所例举的转换顺序可以各种方式进行修改。因此,这些方案中例举的转换顺序不意欲是限制性的。此外,可在所例举的转换之前和/或之后实现取代基R1、R2、R3、R4和Ar中的任一的相互转化。这些修饰可以是诸如保护基的引入、保护基的裂解、官能团的还原或氧化、卤化、金属化、取代或本领域技术人员已知的其它反应。这些转换包括引入允许取代基的进一步相互转化的官能度的那些。适当的保护基及其引入和裂解是本领域技术人员公知的(参见例如T.W. Greene和P.G.M.Wuts,Protective Groups in Organic Synthesis, 第3版, Wiley 1999)。后续段落中描述了具体实例。
多组分环化(II)→(V)通过下列进行:首先使式(II)的酰亚胺酯(imidate)与式(III)的酰基氯在碱存在的情况下反应以形成中间体,所述中间体在随后的步骤中与式(IV)的芳基肼化合物反应。通常,形成的中间体不是分离的,并且在一锅(one-pot)中进行经两个步骤的反应。式(I)的芳基肼化合物也可以其盐(诸如盐酸盐或甲苯磺酸盐)的形式使用。在碱性反应条件下,肼盐将再转化成游离碱形式。然后可以在这方面调节添加的碱的量。可有益的是在第二步中加入铜或锌盐,诸如通常地硫酸铜(II)、氯化铜(II)、硫酸锌(II)和氯化锌(II),且优选使用硫酸铜(II)和硫酸锌(II)。
两个步骤的合适的碱通常是叔胺碱,诸如N,N-二异丙基乙胺(DIPEA)、三乙胺、三异丙胺、N-甲基咪唑、N-甲基吗啉、吡啶和4-(N,N-二甲基氨基)吡啶。优选地,使用N,N-二异丙基乙胺(DIPEA)作为碱。反应在惰性有机溶剂诸如二氯甲烷、1,2-二氯乙烷、甲基叔丁基醚、四氢呋喃、1,4-二氧杂环己烷、1,2-二甲氧基乙烷、甲苯、吡啶、乙酸乙酯、乙腈或N,N-二甲基甲酰胺或在这些溶剂的混合物中进行。优选地,使用四氢呋喃或二氧杂环己烷或其混合物作为溶剂。第一步通常在-10℃至+120℃范围内的温度、优选在0℃进行。第二步通常在+20℃至+120℃范围内的温度、优选在室温进行。伴随的微波照射可在该反应中以及在+60℃至+150℃范围内的温度、优选在+120℃具有有益效果。
氨解反应(V)→(I)通常在氨的溶液中进行。用于该步骤的合适的氨溶液是饱和氨溶液,特别是氨于甲醇、乙醇、异丙醇、四氢呋喃、二氧杂环己烷或水或其混合物中的溶液。优选地,使用甲醇氨溶液。该反应优选在任何其它反应溶剂不存在的情况下直接在氨溶液中进行。该步骤通常在+20℃至+120℃范围内的温度、优选在室温进行。伴随的微波照射可在该反应中以及在+60℃至+150℃范围内的温度、优选在+120℃具有有益效果。
氧化反应(I-A)→(I-B)使用根据文献已知的常规氧化方法进行[例如,JOC,1983, 48, 4155 (戴斯-马丁(Dess Martin)氧化);Tet Lett, 1994, 35, 3485 (IBX氧化);JOC, 1970, 35, 3589 (酸性重铬酸盐氧化);Tet Lett, 1979, 399 (PDC氧化);Tetrahedron, 1978, 34, 1651 (Swern氧化)]。因此,通式(I-A)的化合物中的醇基优选使用戴斯-马丁氧化剂(Dess-Martin periodinane,DMP)氧化。在典型的程序中,反应在二氯甲烷中在0℃的温度进行,并且随后温热至室温。
如上定义的通式(II)的化合物可以通过包括以下步骤的方法制备
[a]使式(VI)的中间体化合物:
其中R1如对于如上文所定义的通式(I)的化合物所定义,
与通式(VII)的腈化合物反应,
其中X代表离去基团,诸如氯、溴、碘、甲磺酸酯或甲苯磺酸酯,特别是氯或溴,
由此产生通式(VIII)的化合物
其中R1如对于如上文所定义的通式(I)的化合物所定义,
随后是后续步骤
[b]使步骤[a]中获得的式(VIII)的化合物与碱性醇化物、优选甲醇钠反应,由此产生通式(II)的化合物,
其中R1如对于如上文定义的通式(I)的化合物所定义,且
R3代表(C1-C4)-烷基,特别是甲基。
N-烷基化反应(VI)+(VII)→(VIII)(步骤[a])通常在碱存在的情况下进行。典型和示例性的碱包括乙腈、甲基异丁基酮、二氧杂环己烷、二甲基甲酰胺、二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜和环丁砜中的碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、叔丁醇钠或叔丁醇钾,优选甲基异丁基酮或乙腈中的碳酸钾。反应可任选地以有利的方式进行,且加入烷基化催化剂,诸如例如溴化锂、碘化钠、碘化锂、四正丁基溴化铵、四正丁基碘化铵或苄基三乙基氯化铵。反应通常在+40℃至+120℃的温度范围、优选在+60℃至+80℃进行。反应可以在大气压、高压或减压(例如0.5-5巴)进行;通常,反应在大气压进行。在较长的时间跨度内缓慢进行烷基化剂(VII)的添加可能是有利的。
可以通过本领域技术人员已知的标准反应方案实现向通式(II)的酰亚胺酯的转化(步骤[b]:(VIII)→(II))。该反应通常在碱性反应条件下通过与碱性醇化物反应进行。可使用的典型碱是甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇和叔丁醇中的甲醇钠、乙醇钠、丙醇钠、异丙醇钠、叔丁醇钠或叔丁醇钾。优选甲醇中的甲醇钠。反应通常在+20℃至+80℃的温度范围、优选在+20℃至+40℃进行。
可选地,通式(VIII)的腈化合物也可任选地如以下合成方案2中所示制备:
TFAA=三氟乙酸酐。
酰胺偶联(IX)→(X)可以在缩合剂或活化剂的帮助下在碱存在的情况下直接进行、或通过酰氯或羧酸咪唑(carboxylic acid imidazolide)经两步进行。用于方法步骤(IX)→(X)中的酰胺形成的典型缩合和活化剂包括例如:碳二亚胺,诸如N,N'-二乙基-、N,N'-二丙基-、N,N'-二异丙基-N,N'-二环己基碳二亚胺(DCC)或N-(3-二甲基氨基异丙基)-N'-乙基碳二亚胺盐酸盐(EDC),光气衍生物诸如N,N'-羰基二咪唑(CDI),1,2-噁唑鎓化合物诸如2-乙基-5-苯基-1,2-噁唑鎓-3-硫酸酯或2-叔丁基-5-甲基-异噁唑鎓高氯酸酯,酰基氨基化合物诸如2-乙氧基-1-乙氧基羰基-1,2-二氢喹啉,或氯甲酸异丁酯、丙烷膦酸酐、氰基膦酸二乙酯、双(2-氧代-3-噁唑烷基)磷酰氯、苯并三唑-1-基氧基三(二甲基氨基)鏻鎓六氟磷酸酯、苯并三唑-1-基氧基三(吡咯烷基)鏻鎓六氟磷酸酯(PyBOP)、O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸酯(TBTU)、O-(苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸酯(HBTU)、2-(2-氧代-1-(2H)-吡啶基)-1,1,3,3-四甲基脲鎓四氟硼酸酯(TPTU)、O-(7-氮杂-苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸酯(HATU)或O-(1H-6-氯-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸酯(TCTU),其任选与其它添加剂诸如1-羟基苯并三唑(HOBt)或N-羟基琥珀酰亚胺(HOSu)组合。酰氯通常在惰性溶剂如二氯甲烷或N,N-二甲基甲酰胺中用亚硫酰氯或草酰氯制备。还可能使用所提及溶剂的混合物。
典型和示例性的碱包括乙腈、甲基异丁基酮、二氧杂环己烷、二甲基甲酰胺、二甲基乙酰胺、N-甲基吡咯烷酮、二甲基亚砜和环丁砜中的碳酸钠、碳酸钾、碳酸铯、N,N-二异丙基乙胺、三乙胺、叔丁醇钠或叔丁醇钾,优选甲基异丁基酮或乙腈中的碳酸钾。反应可任选地以有利的方式进行,且加入烷基化催化剂,诸如例如溴化锂、碘化钠、碘化锂、四正丁基溴化铵、四正丁基碘化铵或苄基三乙基氯化铵。向腈(X)→(XI)的转化可以在脱水剂的帮助下进行。典型的脱水剂包括,例如三氟乙酸酐、五氧化二磷(P4O10)、磷酰氯(POCl3)、五氯化磷(PCl5)、CCl4-PPh3(Appel试剂)、六甲基磷酰胺(HMPA);N-(三乙基铵磺酰基)氨基甲酸甲酯(Burgess试剂)、(氯亚甲基)二甲基氯化铵(Vilsmeier试剂)、草酰氯/DMSO和亚硫酰氯(SOCl2)。
两个步骤(IX)→(X)和(X)→(XI)的典型和示例性溶剂包括例如:醚诸如二乙醚、二氧杂环己烷、四氢呋喃、二醇二甲醚或二乙二醇二甲醚,烃诸如苯、甲苯、二甲苯、己烷、环己烷或矿物油、馏分,卤代烃诸如二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、三氯乙烯或氯苯,或其它溶剂诸如丙酮、乙酸乙酯、乙腈、吡啶、二甲基亚砜、N,N-二甲基甲酰胺、N,N'-二甲基丙烯脲(DMPU)或N-甲基吡咯烷酮(NMP)。还可能使用所提及溶剂的混合物。
在典型和优选的程序中,羧酸(IX)首先在吡啶存在的情况下与新戊酰氯反应以形成中间体,所述中间体在随后的步骤中与氨反应。通常,形成的中间体不是分离的,并且在一锅中进行经两个步骤的反应。适合作为第一步的碱优选为吡啶、4-(N,N-二甲基氨基)吡啶或N,N-二异丙基乙胺(DIPEA)。然后羧酰胺(X)向腈(VIII)的转化通常通过与三氟乙酸酐反应来进行。两种反应均在惰性有机溶剂、优选四氢呋喃中进行。
式(VI)和(IX)的化合物可以通过国际专利申请WO 2010/105770和WO 2011/104322中描述的程序合成(还参见下面的合成方案3和4)。
式(III)、(IV)和(VII)的化合物可以商业获得、从文献中获知、或者可以通过改变文献中描述的标准方法从容易获得的起始材料制备。用于制备起始材料的详细程序和参考文献也可以在实验部分中关于制备起始材料和中间体的部分中找到。
可以通过以下合成方案的方式说明本发明化合物的制备:
[参考国际专利申请WO 2011/104322-A1]。
[参考国际专利申请WO 2011/104322-A1]。
TFAA:三氟乙酸酐。
本发明的通式(I)的化合物可以通过本领域技术人员已知的任何方法转化为如本文中描述的任何盐,优选药学上可接受的盐。类似地,本发明的通式(I)的化合物的任何盐可以通过本领域技术人员已知的任何方法转化为游离化合物。
本发明的化合物具有有价值的药理学特性,并且可用于在人和其它哺乳动物中预防和/或治疗各种疾病和疾病诱导的状况。本发明的通式(I)的化合物显示出有价值的药理学作用谱和药代动力学概况,这两者都无法预测。已出乎意料地发现,本发明的化合物有效地抑制加压素V1a受体,并且因此可能的是,将所述化合物用于在人和动物中治疗和/或预防疾病,优选肾脏和心血管疾病。
在本发明的上下文中,术语“治疗(treatment)”或“治疗(treating)”包括抑制、延迟、缓解、减轻、阻止、减少疾病、病症、状况或状态、其发展和/或进程和/或其症状,或引起疾病、病症、状况或状态、其发展和/或进程和/或其症状的消退。术语“预防(prevention)”或“预防(preventing)”包括减小具有、感染或经历疾病、病症、状况或状态、其发展和/或进程和/或其症状的风险。术语预防包括防治。病症、疾病、状况或状态的治疗或预防可为部分的或完全的。
贯穿本文件,为简便起见,相比于复数语言优先使用单数语言,但是如果不另外说明,通常意欲包括复数语言。例如,表述“治疗患者中的疾病的方法,其包括向患者施用有效量的式(I)的化合物”意欲包括同时治疗超过一种疾病以及施用超过一种式(I)的化合物。
本发明的化合物是加压素V1a受体的非常有效且特别选择性的拮抗剂。因此,预期本发明的化合物作为用于治疗和/或预防疾病、特别是用于治疗和/或预防肾脏和心血管疾病的治疗剂是非常有价值的。
如本文所用,术语“加压素V1a受体拮抗剂”是指通过抑制(部分地或完全地)或阻断加压素V1a受体而起作用、由此阻止由加压素活化受体的化合物。
在一个实施方式中,本文所述的化合物对V1a受体有活性。在另一个实施方式中,根据B-1中的研究,本文所述的化合物表现出V1a受体的抑制,且IC50<100 nM。在另一个实施方式中,根据B-1中的研究,本文所述的化合物表现出V1a受体的抑制,且IC50<20 nM。在另一个实施方式中,根据B-1中的研究,本文所述的化合物表现出V1a受体的抑制,且IC50<10 nM。在另一个实施方式中,根据B-1中的研究,本文所述的化合物表现出V1a受体的抑制,且IC50<5 nM。在另一个实施方式中,根据B-1中的研究,本文所述的化合物表现出V1a受体的抑制,且IC50<2 nM。
在一个进一步实施方式中,本文所述的化合物对V1a受体有选择性活性,并且对其它加压素受体诸如V1b和/或V2亚型活性较低、活性基本上较低和/或无活性。在另一个实施方式中,与V2受体相比,本文所述的化合物对V1a受体的选择性为至少10倍,如根据B-1中的研究所测定。在另一个实施方式中,与V2受体相比,本文所述的化合物对V1a受体的选择性为至少15倍,如根据B-1中的研究所测定。在另一个实施方式中,与V2受体相比,本文所述的化合物对V1a受体的选择性为至少20倍,如根据B-1中的研究所测定。在另一个实施方式中,与V2受体相比,本文所述的化合物对V1a受体的选择性为至少30倍,如根据B-1中的研究所测定。
根据本发明的化合物适用于治疗和/或预防肾脏疾病,特别是急性和慢性肾疾病、糖尿病肾疾病、以及急性和慢性肾衰竭。一般术语“肾脏疾病”或“肾疾病”描述了其中肾未能从血液过滤和去除废物的一类状况。存在两种主要形式的肾疾病:急性肾疾病(急性肾损伤,AKI)和慢性肾疾病(CKD)。根据本发明的化合物可进一步用于治疗和/或预防由多次损伤诸如缺血-再灌注损伤、放射性造影剂(radiocontrast)施用、心肺分流术、休克和败血症引起的急性肾损伤的后遗症。在本发明的意义上,术语肾衰竭或肾功能不全包括肾功能不全的急性和慢性表现,以及潜在或相关的肾疾病,诸如肾灌注不足、透析中低血压、阻塞性尿路病、肾小球病、IgA肾病、肾小球肾炎、急性肾小球肾炎、肾小球硬化、肾小管间质疾病、肾病诸如原发性和先天性肾疾病、肾炎、Alport综合征、肾炎症、免疫性肾疾病诸如肾移植排斥、免疫复合物诱导的肾疾病、由有毒物质诱导的肾病、造影介质诱导的肾病;微小变化肾小球肾炎(类脂);膜性肾小球肾炎;局灶性节段性肾小球硬化(FSGS);溶血性尿毒综合征(HUS)、淀粉样变性、Goodpasture综合征、Wegener肉芽肿病、Schönlein-Henoch紫癜、糖尿病和非糖尿病肾病、肾盂肾炎、肾囊肿、肾硬化、高血压性肾硬化和肾病综合征,其可以例如通过异常减少的肌酸酐和/或水排泄、异常增加的尿素、氮、钾和/或肌酸酐的血液浓度、改变的肾脏酶(诸如例如谷氨酰合成酶)的活性、改变的尿渗透压或尿体积、增加的微量白蛋白尿、大量白蛋白尿、肾小球和小动脉的病变、肾小管扩张、高磷酸盐血症和/或需要透析来诊断表征。本发明还包括根据本发明的化合物用于治疗和/或预防肾功能不全的后遗症的用途,所述后遗症例如肺水肿、心力衰竭、尿毒症、贫血、电解质紊乱(例如高钾血症、低钠血症)和骨骼和碳水化合物代谢中的紊乱。根据本发明的化合物还适用于治疗和/或预防多囊肾病(PCKD)和不足ADH分泌综合征(SIADH)。
在该背景下可以用本发明的化合物治疗和/或预防的心血管疾病包括但不限于以下:急性和慢性心力衰竭(包括恶化性慢性心力衰竭(或心力衰竭的住院治疗)和包括充血性心力衰竭)、动脉高血压、顽固性高血压、动脉性肺动脉高压、冠心病、稳定型和不稳定型心绞痛、房性和室性心律失常、心房和心室节律紊乱和传导障碍例如I-III级房室传导阻滞(AVB I-III)、室上性快速性心律失常、心房颤动、心房扑动、心室颤动、心室扑动、室性快速性心律失常、扭转型室性心动过速、心房和心室期外收缩、AV结期外收缩(AV-junctionextrasystoles)、病窦综合征、晕厥、AV-节点折返性心动过速和午-帕-怀三氏综合征、急性冠状动脉综合征(ACS)、自身免疫性心脏疾病(心包炎、心内膜炎、心瓣膜炎、主动脉炎、心肌病)、休克诸如心源性休克、感染性休克和过敏性休克、动脉瘤、Boxer心肌病(室性早搏)、此外血栓栓塞性疾病和缺血诸如外周灌注障碍、再灌注损伤、动脉和静脉血栓形成、心肌机能不全、内皮功能障碍、微血管和大血管损伤(血管炎),和用于预防再狭窄(诸如在溶栓治疗、经皮腔内血管成形术(PTA)、经皮腔内冠状动脉成形术(PTCA)、心脏移植和旁路手术后)、动脉硬化、脂质代谢紊乱、低脂蛋白血症、血脂异常、高甘油三酯血症、高脂血症和合并高脂血症、高胆固醇血症、无β脂蛋白血症、谷固醇血症、黄瘤病、丹吉尔病、脂肪过多、肥胖症、代谢综合征、短暂和缺血性发作、中风、炎症性心血管病、外周和心脏血管疾病、外周循环障碍、冠状动脉和外周动脉痉挛,以及水肿诸如例如肺水肿、脑水肿、肾脏水肿和心力衰竭相关的水肿。
在本发明的意义上,术语心力衰竭也包括更具体的或相关的疾病形式,诸如右心衰竭、左心衰竭、整体机能不全、缺血性心肌病、扩张型心肌病、先天性心脏缺陷、心脏瓣膜缺陷、伴随心脏瓣膜缺陷的心力衰竭、二尖瓣狭窄、二尖瓣闭锁不全、主动脉瓣狭窄、主动脉瓣闭锁不全、三尖瓣狭窄、三尖瓣闭锁不全、肺动脉瓣狭窄、肺动脉瓣闭锁不全、复合心脏瓣膜缺陷、心肌炎症(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病心力衰竭、酒精中毒性心肌病、心脏贮存疾病、射血分数正常性心力衰竭(HFpEF或舒张性心力衰竭)和射血分数减少性心力衰竭(HFrEF或收缩性心力衰竭)。
本发明的化合物对于治疗和/或预防心肾综合征(CRS)及其各种亚型可能是特别有用的。该术语包括心脏和肾脏的某些病症,由此一个器官中的急性或慢性功能障碍可诱发另一个器官的急性或慢性功能障碍。
而且,根据本发明的化合物可用于治疗和/或预防:外周动脉疾病(PAD),包括跛行并包括严重的肢体缺血,冠状动脉微血管功能障碍(CMD),包括CMD 1-4型,原发性和继发性雷诺现象,微循环紊乱,外周和自主神经病,糖尿病微血管病,糖尿病视网膜病,糖尿病性肢体溃疡,坏疽,CREST综合征,红斑病症,风湿性疾病;和用于促进伤口愈合。
而且,本发明的化合物适用于治疗泌尿系统疾病以及雄性和雌性泌尿生殖系统的疾病,诸如例如,良性前列腺综合征(BPS)、良性前列腺增生(BPH)、良性前列腺扩大(BPE)、膀胱出口梗阻(BOO)、下泌尿道综合征(LUTS)、神经源性的膀胱过度活动症(OAB)、间质性膀胱炎(IC)、尿失禁(UI)诸如例如混合性、急迫性、压力性和溢流性尿失禁(MUI、UUI、SUI、OUI)、骨盆疼痛、勃起功能障碍、痛经和子宫内膜异位。
根据本发明的化合物也可用于治疗和/或预防炎性疾病、哮喘疾病、慢性阻塞性肺疾病(COPD)、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、α-1抗胰蛋白酶缺乏症(AATD)、肺纤维化、肺气肿(例如吸烟诱发的肺气肿)和囊性纤维化(CF)。此外,本发明的化合物可用于治疗和/或预防动脉性肺动脉高压(PAH)和其它形式的肺动脉高压(PH),包括与左心室疾病、HIV感染、镰状细胞贫血、血栓栓塞(CTEPH)、结节病、慢性阻塞性肺疾病(COPD)或肺纤维化相关的肺动脉高压。
另外,根据本发明的化合物可用于治疗和/或预防肝硬化、腹水、糖尿病和糖尿病并发症诸如例如神经病和肾病。
进一步地,本发明的化合物适用于治疗和/或预防:中枢神经障碍诸如焦虑状态、抑郁症,青光眼,癌症诸如特别是肺肿瘤,以及昼夜节律错位诸如时差和轮班工作。
而且,根据本发明的化合物可用于治疗和/或预防:疼痛病症、肾上腺疾病诸如例如嗜铬细胞瘤和肾上腺卒中、肠疾病诸如例如克罗恩病和腹泻、月经失调诸如例如痛经、子宫内膜异位、早产和子宫收缩抑制。
由于它们的活性和选择性概况,据信本发明的化合物特别适用于治疗和/或预防:急性和慢性肾疾病、包括糖尿病肾病,急性和慢性心力衰竭,先兆子痫,外周动脉疾病(PAD),冠状动脉微血管功能障碍(CMD),雷诺综合征和痛经。
上述疾病已经在人中充分地表征,但是在其它哺乳动物中也存在类似的(comparable)病因,并且在所述动物中可使用本发明的化合物和方法治疗。
因此,本发明还涉及根据本发明的化合物用于治疗和/或预防疾病、尤其是上述疾病的用途。
本发明还涉及根据本发明的化合物用于制备药物组合物的用途,所述药物组合物用于治疗和/或预防疾病、尤其是上述疾病。
本发明还涉及根据本发明的化合物在用于治疗和/或预防疾病、尤其是上述疾病的方法中的用途。
本发明还涉及通过使用有效量的至少一种根据本发明的化合物治疗和/或预防疾病、尤其是上述疾病的方法。
根据另一个方面,本发明涵盖药物组合、特别是药物,其包含至少一种本发明的通式(I)的化合物和至少一种或多种另外的活性成分,其特别用于治疗和/或预防疾病、特别是前述疾病。
特别地,本发明涵盖药物组合,其包含:
●一种或多种第一活性成分,特别是如上所定义的通式(I)的化合物;和
●一种或多种另外的活性成分,特别是用于治疗和/或预防疾病、尤其是前述疾病。
本发明中的术语“组合”如本领域技术人员已知那样使用,所述组合可能为固定组合、非固定组合,或套装药剂盒(kit-of-parts)。
本发明中的“固定组合”如本领域技术人员已知那样使用,并且被定义为组合,其中,例如,第一活性成分、诸如一种或多种本发明的通式(I)的化合物和另外的活性成分以一个单位剂量或者一个单一实体共同存在。“固定组合”的一个实例是药物组合物,其中第一活性成分和另外的活性成分以用于同时施用的混合物存在,例如以制剂存在。“固定组合”的另一个实例是药物组合,其中第一活性成分和另外的活性成分以一个单位而不以混合物存在。
本发明的非固定组合或“套装药剂盒”如本领域技术人员已知那样使用,并且被定义为组合,其中第一活性成分和另外的活性成分以多于一个单位存在。非固定组合或套装药剂盒的一个实例是组合,其中第一活性成分和另外的活性成分分开存在。非固定组合或套装药剂盒的组分可能分开、接续、同时、同步或按时间顺序交错地施用。
本发明的化合物可以作为单独药学试剂施用,或者与一种或多种其它的药学活性成分组合施用,其中该组合不导致不可接受的副作用。本发明还涵盖这样的药物组合。例如,本发明的化合物可以与用于治疗和/或预防疾病、特别是前述疾病的已知药剂组合。
具体而言,本发明的化合物可与以下药剂以固定或单独组合使用:
●抗血栓形成剂,例如且优选地来自血小板聚集抑制剂、抗凝血剂和促纤维蛋白溶解物质;
●降血压剂,例如且优选地来自钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、NEP抑制剂、血管肽酶抑制剂、内皮缩血管肽拮抗剂、肾素抑制剂、α-阻滞剂、β-阻滞剂、盐皮质激素受体拮抗剂和利尿剂;
●抗糖尿病药(降血糖药或抗高血糖药),诸如例如和优选胰岛素和衍生物、磺酰脲、双胍、噻唑烷二酮、阿卡波糖、DPP4抑制剂、GLP-1类似物或SGLT抑制剂(gliflozins);
●有机硝酸酯和NO供体,例如硝普钠、硝酸甘油、单硝酸异山梨酯、二硝酸异山梨酯(isosorbide dinitrate)、吗多明或SIN-1和吸入的NO;
●抑制环鸟苷一磷酸(cGMP)的降解的化合物,例如磷酸二酯酶(PDE)1、2、5和/或9的抑制剂,特别是PDE-5抑制剂诸如西地那非、伐地那非、他达拉非、乌地那非、达生他非、阿伐那非、米罗那非、洛地那非、CTP-499或PF-00489791;
●利钠肽,诸如例如心房利钠肽(ANP,阿那立肽)、B-型利钠肽或脑利钠肽(BNP,奈西立肽)、C-型利钠肽(CNP)或尿扩张素;
●钙敏化剂,诸如例如且优选左西孟旦;
●不依赖于NO和血红素的可溶性鸟苷酸环化酶(sGC)的活化剂,例如且优选在WO 01/19355、WO 01/19776、WO 01/19778、WO 01/19780、WO 02/070462和WO 02/070510中描述的化合物;
●不依赖于NO的、但依赖于血红素的鸟苷酸环化酶(sGC)的刺激物,优选且优选在WO00/06568、WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO 2012/004258、WO 2012/028647和WO 2012/059549中描述的化合物;
●刺激cGMP合成的药剂,例如且优选sGC调节剂,例如并且优选利奥西呱、cinaciguat、维利西呱或BAY 1101042;
●人中性粒细胞弹性蛋白酶(HNE)的抑制剂,诸如例如西维来司他或DX-890(reltran);
●抑制信号转导级联的化合物,特别是酪氨酸和/或丝氨酸/苏氨酸激酶抑制剂,诸如例如尼达尼布、达沙替尼、尼洛替尼、波舒替尼、瑞戈非尼、索拉非尼、舒尼替尼、西地尼布、阿昔替尼、替拉替尼、伊马替尼、布立尼布、帕唑帕尼、伐拉尼布、吉非替尼、厄洛替尼、拉帕替尼、卡纽替尼、来妥替尼、培利替尼、司马尼布或坦度替尼;
●影响心脏的能量代谢的化合物,诸如例如且优选乙莫克舍、二氯乙酸盐、雷诺嗪或曲美他嗪,或者完全或部分腺苷A1受体激动剂如GS-9667(先前称为CVT-3619)、卡帕诺生和neladenoson bialanate(BAY 1067197);
●影响心率的化合物,诸如例如且优选伊伐布雷定;
●心脏肌球蛋白活化剂,诸如例如且优选omecamtiv mecarbil(CK-1827452);
●抗炎药物,诸如非甾体抗炎药(NSAID),包括乙酰水杨酸(阿司匹林)、布洛芬和萘普生,糖皮质激素,诸如例如且优选泼尼松、泼尼松龙、甲基泼尼松龙、曲安西龙、地塞米松、倍氯米松、倍他米松、氟尼缩松、布地奈德或氟替卡松,5-氨基水杨酸衍生物,白三烯拮抗剂,TNF-α抑制剂,和趋化因子受体拮抗剂诸如CCR1、2和/或5抑制剂;
●改变脂肪代谢的药剂,例如且优选地来自甲状腺受体激动剂,胆固醇合成抑制剂,诸如例如且优选HMG-CoA-还原酶或角鲨烯合成抑制剂、ACAT抑制剂、CETP抑制剂、MTP抑制剂、PPAR-α、PPAR-γ和/或PPAR-δ激动剂,胆固醇吸收抑制剂、脂肪酶抑制剂、聚合的胆汁酸吸附剂、胆汁酸重吸收抑制剂和脂蛋白(a)拮抗剂。
抗血栓形成剂优选地理解为来自血小板聚集抑制剂、抗凝血剂和促纤维蛋白溶解物质的化合物。
在本发明的一个优选实施方式中,根据本发明的化合物与血小板聚集抑制剂联合施用,所述血小板聚集抑制剂例如且优选是阿司匹林、氯吡格雷、噻氯匹定或双嘧达莫。
在本发明的一个优选实施方式中,根据本发明的化合物与凝血酶抑制剂联合施用,所述凝血酶抑制剂例如且优选是希美加群、达比加群、美拉加群、比伐芦定或依诺肝素。
在本发明的一个优选实施方式中,根据本发明的化合物与GPIIb/IIIa拮抗剂联合施用,所述GPIIb/IIIa拮抗剂例如且优选是替罗非班或阿昔单抗。
在本发明的一个优选实施方式中,根据本发明的化合物与因子Xa抑制剂联合施用,所述因子Xa抑制剂例如且优选是利伐沙班、阿哌沙班、奥米沙班、非德沙班、雷扎沙班、磺达肝素、依达肝素、DU-176b、PMD-3112、YM-150、KFA-1982、EMD-503982、MCM-17、MLN-1021、DX 9065a、DPC 906、JTV 803、SSR-126512或SSR-128428。
在本发明的一个优选实施方式中,根据本发明的化合物与肝素或低分子量(LMW)肝素衍生物联合施用。
在本发明的一个优选实施方式中,根据本发明的化合物与维生素K拮抗剂联合施用,所述维生素K拮抗剂例如且优选是香豆素。
降血压剂优选地理解为来自钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、NEP抑制剂、血管肽酶抑制剂、内皮缩血管肽拮抗剂、肾素抑制剂、α-阻滞剂、β-阻滞剂、盐皮质激素受体拮抗剂和利尿剂的化合物。
在本发明的一个优选实施方式中,根据本发明的化合物与钙拮抗剂联合施用,所述钙拮抗剂例如且优选是硝苯地平、氨氯地平、维拉帕米或地尔硫卓。
在本发明的一个优选实施方式中,根据本发明的化合物与α-1-受体阻滞剂联合施用,所述α-1-受体阻滞剂例如且优选是哌唑嗪或坦洛新。
在本发明的一个优选实施方式中,根据本发明的化合物与β-阻滞剂联合施用,所述β-阻滞剂例如且优选是普萘洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、阿普洛尔、氧烯洛尔、喷布洛尔、布拉洛尔、美替洛尔、纳多洛尔、甲吲洛尔、卡拉洛尔、索他洛尔、美托洛尔、倍他洛尔、塞利洛尔、比索洛尔、卡替洛尔、艾司洛尔、拉贝洛尔、卡维地洛、阿达洛尔、兰地洛尔、奈必洛尔、依泮洛尔或布新洛尔。
在本发明的一个优选实施方式中,根据本发明的化合物与血管紧张素AII受体拮抗剂联合施用,所述血管紧张素AII受体拮抗剂例如且优选是氯沙坦、坎地沙坦、缬沙坦、替米沙坦、厄贝沙坦、奥美沙坦、依普罗沙坦、恩布沙坦或阿齐沙坦。
在本发明的一个优选实施方式中,根据本发明的化合物与血管肽酶抑制剂或中性内肽酶(NEP)抑制剂联合施用,所述血管肽酶抑制剂或中性内肽酶(NEP)抑制剂例如且优选是沙库比曲、奥马曲拉或AVE-7688。
在本发明的一个优选实施方式中,根据本发明的化合物与双重血管紧张素AII受体拮抗剂/NEP抑制剂(ARNI)联合施用,所述双重血管紧张素AII受体拮抗剂/NEP抑制剂(ARNI)例如且优选是LCZ696。
在本发明的一个优选实施方式中,根据本发明的化合物与ACE抑制剂联合施用,所述ACE抑制剂例如且优选是依那普利、卡托普利、赖诺普利、雷米普利、地拉普利、福辛普利、喹那普利、培哚普利、贝那普利或川多普利。
在本发明的一个优选实施方式中,根据本发明的化合物与内皮缩血管肽拮抗剂联合施用,所述内皮缩血管肽拮抗剂例如且优选是波生坦、达卢生坦、安立生坦、替唑生坦、西他生坦、阿伏生坦、马西替坦或阿曲生坦。
在本发明的一个优选实施方式中,根据本发明的化合物与肾素抑制剂联合施用,所述肾素抑制剂例如且优选是阿利吉仑、SPP-600或SPP-800。
在本发明的一个优选实施方式中,根据本发明的化合物与盐皮质激素受体拮抗剂联合施用,所述盐皮质激素受体拮抗剂例如且优选是finerenone、螺内酯、坎利酮、坎利酸钾、依普利酮、esaxerenone(CS-3150)或apararenone(MT-3995)。
在本发明的一个优选实施方式中,根据本发明的化合物与利尿剂联合施用,所述利尿剂诸如例如且优选是呋塞米、布美他尼、吡咯他尼、托拉塞米、苄氟噻嗪、氯噻嗪、氢氯噻嗪、希帕胺、吲达帕胺、氢氟噻嗪、甲氯噻嗪、泊利噻嗪、三氯噻嗪、氯噻酮、美托拉宗、喹乙宗、乙酰唑胺、二氯苯磺胺、醋甲唑胺、甘油、异山梨醇、甘露醇、阿米洛利或氨苯蝶啶。
改变脂肪代谢的药剂优选地理解为来自下述的化合物:CETP抑制剂,甲状腺受体激动剂,胆固醇合成抑制剂诸如HMG-CoA-还原酶或角鲨烯合成抑制剂、ACAT抑制剂、MTP抑制剂、PPAR-α、PPAR-γ和/或PPAR-δ激动剂,胆固醇吸收抑制剂、聚合的胆汁酸吸附剂、胆汁酸重吸收抑制剂、脂肪酶抑制剂和脂蛋白(a)拮抗剂。
在本发明的一个优选实施方式中,根据本发明的化合物与CETP抑制剂联合施用,所述CETP抑制剂例如且优选是达塞曲匹、安塞曲匹、BAY 60-5521或CETP-疫苗(Avant)。
在本发明的一个优选实施方式中,根据本发明的化合物与甲状腺受体激动剂联合施用,所述甲状腺受体激动剂例如且优选是D-甲状腺素、3,5,3'-三碘甲状腺原氨酸(T3)、CGS 23425或阿昔替罗(CGS 26214)。
在本发明的一个优选实施方式中,根据本发明的化合物与HMG-CoA-还原酶抑制剂联合施用,所述HMG-CoA-还原酶抑制剂来自他汀类,例如且优选洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗舒伐他汀或匹伐他汀。
在本发明的一个优选实施方式中,根据本发明的化合物与角鲨烯合成抑制剂联合施用,所述角鲨烯合成抑制剂例如且优选是BMS-188494或TAK-475。
在本发明的一个优选实施方式中,根据本发明的化合物与ACAT抑制剂联合施用,所述ACAT抑制剂例如且优选是阿伐麦布、甲亚油酰胺、帕替麦布、依鲁麦布或SMP-797。
在本发明的一个优选实施方式中,根据本发明的化合物与MTP抑制剂联合施用,所述MTP抑制剂例如且优选是英普他派、R-103757、BMS-201038或JTT-130。
在本发明的一个优选实施方式中,根据本发明的化合物与PPAR-γ激动剂联合施用,所述PPAR-γ激动剂例如且优选是吡格列酮或罗格列酮。
在本发明的一个优选实施方式中,根据本发明的化合物与PPAR-δ激动剂联合施用,所述PPAR-δ激动剂例如且优选是GW 501516或BAY 68-5042。
在本发明的一个优选实施方式中,根据本发明的化合物与胆固醇吸收抑制剂联合施用,所述胆固醇吸收抑制剂例如且优选是依折麦布、替奎安或帕马苷。
在本发明的一个优选实施方式中,根据本发明的化合物与脂肪酶抑制剂联合施用,所述脂肪酶抑制剂例如且优选是奥利司他。
在本发明的一个优选实施方式中,根据本发明的化合物与聚合的胆汁酸吸附剂联合施用,所述聚合的胆汁酸吸附剂例如且优选是考来烯胺、考来替泊、colesolvam、CholestaGel或考来替兰。
在本发明的一个优选实施方式中,根据本发明的化合物与胆汁酸重吸收抑制剂联合施用,所述胆汁酸重吸收抑制剂例如且优选是ASBT(=IBAT)抑制剂诸如AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635。
在本发明的一个优选实施方式中,根据本发明的化合物与脂蛋白(a)拮抗剂联合施用,所述脂蛋白(a)拮抗剂例如且优选是吉卡宾钙(CI-1027)或烟酸。
在本发明的一个优选实施方式中,根据本发明的化合物与TGFβ拮抗剂联合施用,所述TGFβ拮抗剂例如且优选是吡非尼酮或fresolimumab。
在本发明的一个优选实施方式中,根据本发明的化合物与HIF-PH抑制剂联合施用,所述HIF-PH抑制剂例如且优选是molidustat或roxadustat。
在本发明的一个优选实施方式中,根据本发明的化合物与CCR2拮抗剂联合施用,所述CCR2拮抗剂例如且优选是CCX-140。
在本发明的一个优选实施方式中,根据本发明的化合物与TNFα拮抗剂联合施用,所述TNFα拮抗剂例如且优选是阿达木单抗。
在本发明的一个优选实施方式中,根据本发明的化合物与半乳凝素-3抑制剂联合施用,所述半乳凝素-3抑制剂例如且优选是GCS-100。
在本发明的一个优选实施方式中,根据本发明的化合物与BMP-7激动剂联合施用,所述BMP-7激动剂例如且优选是THR-184。
在本发明的一个优选实施方式中,根据本发明的化合物与NOX1/4抑制剂联合施用,所述NOX1/4抑制剂例如且优选是GKT-137831。
在本发明的一个优选实施方式中,根据本发明的化合物与影响维生素D代谢的药物联合施用,所述影响维生素D代谢的药物例如且优选是胆钙化醇或帕立骨化醇。
在本发明的一个优选实施方式中,根据本发明的化合物与细胞生长抑制剂联合施用,所述细胞生长抑制剂例如且优选是环磷酰胺。
在本发明的一个优选实施方式中,根据本发明的化合物与免疫抑制剂联合施用,所述免疫抑制剂例如且优选是环孢菌素。
在本发明的一个优选实施方式中,根据本发明的化合物与磷酸盐结合剂联合施用,所述磷酸盐结合剂例如且优选是司维拉姆或碳酸镧。
在本发明的一个优选实施方式中,根据本发明的化合物与用于治疗甲状旁腺功能亢进的拟钙剂联合施用。
在本发明的一个优选实施方式中,根据本发明的化合物与用于缺铁疗法的药剂联合施用,所述用于缺铁疗法的药剂例如且优选是铁产品。
在本发明的一个优选实施方式中,根据本发明的化合物与用于治疗高尿酸血症的药剂联合施用,所述用于治疗高尿酸血症的药剂例如且优选是别嘌呤醇或拉布立酶。
在本发明的一个优选实施方式中,根据本发明的化合物与用于治疗贫血的糖蛋白激素联合施用,所述用于治疗贫血的糖蛋白激素例如且优选是促红细胞生成素。
在本发明的一个优选实施方式中,根据本发明的化合物与用于免疫疗法的生物制剂联合施用,所述用于免疫疗法的生物制剂例如且优选是阿巴西普、利妥昔单抗、依库丽单抗或贝利木单抗。
在本发明的一个优选实施方式中,根据本发明的化合物与Jak抑制剂联合施用,所述Jak抑制剂例如且优选是鲁索替尼、托法替尼、巴瑞替尼、CYT387、GSK2586184、来他替尼、帕瑞替尼(pacritinib)(SB1518)或TG101348。
在本发明的一个优选实施方式中,根据本发明的化合物与用于治疗微血栓的前列环素类似物联合施用。
在本发明的一个优选实施方式中,根据本发明的化合物与碱疗法联合施用,所述碱疗法例如且优选是碳酸氢钠。
在本发明的一个优选实施方式中,根据本发明的化合物与mTOR抑制剂联合施用,所述mTOR抑制剂例如且优选是依维莫司或雷帕霉素。
在本发明的一个优选实施方式中,根据本发明的化合物与NHE3抑制剂联合施用,所述NHE3抑制剂例如且优选是AZD1722。
在本发明的一个优选实施方式中,根据本发明的化合物与eNOS调节剂联合施用,所述eNOS调节剂例如且优选是沙丙蝶呤。
在本发明的一个优选实施方式中,根据本发明的化合物与CTGF抑制剂联合施用,所述CTGF抑制剂例如且优选是FG-3019。
在本发明的一个优选实施方式中,根据本发明的化合物与抗糖尿病药(降血糖药或抗高血糖药)联合施用,所述抗糖尿病药诸如例如且优选是:胰岛素和衍生物,磺酰脲诸如甲苯磺丁脲、氨磺丁脲、乙酰己酰胺、氯磺丙脲、格列吡嗪、格列齐特、格列本脲(glibenclamide)、格列本脲(glyburide)、格列波脲、格列喹酮、格列派特、格列吡脲、格列美脲、JB253和JB558,美各里替尼诸如瑞格列奈和那格列奈,双胍诸如二甲双胍和丁二胍,噻唑烷二酮诸如罗格列酮和吡格列酮,α-葡萄糖苷酶抑制剂诸如米格列醇、阿卡波糖和伏格列波糖,DPP4抑制剂诸如维达列汀、西他列汀、沙格列汀、利格列汀、阿格列汀、septagliptin和替格列汀(teneligliptin),GLP-1类似物诸如艾塞那肽(也是毒蜥外泌肽-4、利拉鲁肽、利西拉肽和他司鲁泰,或SGLT抑制剂(gliflozins)诸如卡格列净、达格列净和依帕列净。
在一个特别优选的实施方式中,本发明的化合物与一种或多种额外治疗剂联合施用,所述额外治疗剂选自利尿剂、血管紧张素AII拮抗剂、ACE抑制剂、β-受体阻滞剂、盐皮质激素受体拮抗剂、抗糖尿病药、有机硝酸酯和NO供体、可溶性鸟苷酸环化酶(sGC)的活化剂和刺激物和正性肌力药剂。
在一个进一步特别优选的实施方式中,根据本发明的化合物与一种或多种额外治疗剂联合施用,所述额外治疗剂选自利尿剂、血管紧张素AII拮抗剂、ACE抑制剂、β-受体阻滞剂、盐皮质激素受体拮抗剂、抗糖尿病药、有机硝酸盐和NO供体、可溶性鸟苷酸环化酶(sGC)的活化剂和刺激剂、抗炎剂、免疫抑制剂、磷酸盐结合剂和/或调节维生素D代谢的化合物。因此,在一个进一步实施方式中,本发明涉及药物组合物,其包含根据本发明的化合物的至少一种、和一种或多种另外的治疗剂,所述药物组合物用于治疗和/或预防疾病、尤其是前述疾病。
而且,本发明的化合物可原样(as such)或者在组合物中使用、在研究和诊断中使用、或者用作分析参考标准品等,这是本领域公知的。
当本发明的化合物作为药物施于人和其它哺乳动物时,它们可以本身或者作为药物组合物给予,所述药物组合物含有例如与一种或多种药学上可接受的赋形剂组合的0.1%至99.5%(更优选地,0.5%至90%)的活性成分。
因此,在另一个方面,本发明涉及药物组合物,其包含根据本发明的化合物的至少一种,常规地连同一种或多种惰性的、无毒的、药学上可接受的赋形剂,并涉及该药物组合物用于治疗和/或预防疾病、尤其是前述疾病的用途。
根据本发明的化合物可能具有全身和/或局部活性。为该目的,它们可以适合的方式施用,诸如例如经由口服、肠胃外、肺、鼻、舌下、舌、颊、直肠、阴道、皮肤、经皮、结膜、耳途径或作为植入物或支架。
对于这些施用途径,根据本发明的化合物可能以适当的施用形式施用。
对于口服施用,可能的是,将根据本发明的化合物配制为迅速和/或以修改方式递送本发明化合物的本领域已知的剂型,诸如例如片剂(未包衣或包衣片剂,例如具有延迟溶解或不溶解的肠溶包衣或控释包衣)、口服崩解片剂、膜/薄片、膜/冻干物、胶囊(例如硬或软明胶胶囊)、糖衣片剂、颗粒剂、小丸剂、粉剂、乳剂、悬浮液、气雾剂或溶液。可能的是,将根据本发明的化合物以结晶和/或非晶和/或溶解形式并入所述剂型中。
肠胃外施用可以在避免吸收步骤(例如静脉内、动脉内、心内、脊柱内或腰内)或包括吸收(例如肌肉内、皮下、皮内、经皮或腹膜内)的情况下实现。适合于肠胃外施用的施用形式尤其是溶液、悬浮液、乳剂、冻干物或灭菌粉末的形式的注射和输注用制剂。
适合于其它施用途径的实例是用于吸入的药物形式[尤其是粉末吸入器、喷雾器]、滴鼻剂、鼻溶液、鼻喷雾;用于舌、舌下或颊施用的片剂/膜/薄片/胶囊;栓剂;滴眼剂、眼膏、洗眼器、眼插入物、滴耳剂、耳喷雾、耳粉剂、洗耳剂、耳塞;阴道胶囊、水悬浮液(洗剂、振荡混合物(mixturae agitandae))、亲脂悬浮液、乳剂、软膏、乳膏、经皮治疗系统(诸如例如贴剂)、乳、糊剂、泡沫剂、撒布剂、植入物或支架。
根据本发明的化合物可以被并入所述施用形式中。这可以本身已知的方式通过与药学上适合的赋形剂混合而实现。药学上适合的赋形剂尤其包括:
●填料和载体(例如纤维素、微晶纤维素(诸如例如Avicel®)、乳糖、甘露醇、淀粉、磷酸钙(诸如例如Di-Cafos®));
●软膏基质(例如凡士林、石蜡、甘油三酯、蜡、羊毛蜡、羊毛蜡醇、羊毛脂、亲水性软膏、聚乙二醇);
●用于栓剂的基质(例如聚乙二醇、可可脂、固体脂肪);
●溶剂(例如水、乙醇、异丙醇、甘油、丙二醇、中链甘油三酯脂肪油、液体聚乙二醇、石蜡);
●表面活性剂、乳化剂、分散剂或润湿剂(例如十二烷基硫酸钠)、卵磷脂、磷脂、脂肪醇(诸如例如Lanette®)、脱水山梨糖醇脂肪酸酯(诸如例如Span®)、聚氧乙烯脱水山梨糖醇脂肪酸酯(诸如例如Tween®)、聚氧乙烯脂肪酸甘油酯(诸如例如Cremophor®)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(诸如例如Pluronic®);
●缓冲剂、酸和碱(例如磷酸盐、碳酸盐、柠檬酸、乙酸、盐酸、氢氧化钠溶液、碳酸铵、氨丁三醇、三乙醇胺);
●等渗剂(例如葡萄糖、氯化钠);
●吸附剂(例如高分散二氧化硅);
●增粘剂、凝胶形成剂、增稠剂和/或粘合剂(例如聚乙烯吡咯烷酮、甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、淀粉、卡波姆、聚丙烯酸(诸如例如Carbopol®);藻酸盐、明胶);
●崩解剂(例如改性淀粉、羧甲基纤维素钠、淀粉乙醇酸钠(诸如例如Explotab®)、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠(诸如例如AcDiSol®));
●流动调节剂、润滑剂、助流剂和脱模剂(例如硬脂酸镁、硬脂酸、滑石、高分散二氧化硅(诸如例如Aerosil®));
●包衣材料(例如糖、虫漆)和快速溶解或以修改方式溶解的膜或扩散膜的成膜剂(例如聚乙烯吡咯烷酮(诸如例如Kollidon®)、聚乙烯醇、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、醋酸纤维素、邻苯二甲酸乙酸纤维素、聚丙烯酸酯、聚甲基丙烯酸酯(诸如例如Eudragit®));
●胶囊材料(例如明胶、羟丙基甲基纤维素);
●合成聚合物(例如聚丙交酯、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(诸如例如Eudragit®)、聚乙烯吡咯烷酮(诸如例如Kollidon®)、聚乙烯醇、聚乙酸乙烯酯、聚环氧乙烷、聚乙二醇以及它们的共聚物和嵌段共聚物);
●增塑剂(例如聚乙二醇、丙二醇、甘油、三醋精、三乙酰基柠檬酸酯、邻苯二甲酸二丁酯);
●渗透促进剂;
●稳定剂(例如抗氧化剂,诸如例如抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸钠、丁基羟基苯甲醚、丁基羟基甲苯、没食子酸丙酯);
●防腐剂(例如尼泊金、山梨酸、硫柳汞、苯扎氯铵、乙酸氯已定、苯甲酸钠);
●着色剂(例如无机颜料,诸如例如氧化铁、二氧化钛);
●矫味剂、甜味剂、味道和/或气味掩蔽剂。
本发明另外涉及药物组合物,其包含至少一种根据本发明的化合物,常规地连同一种或多种药学上适合的赋形剂,以及涉及所述药物组合物根据本发明的用途。
基于已知用于评价对于治疗心血管和肾脏病症有用的化合物的标准实验室技术,通过标准毒性测试和通过用于确定哺乳动物中上述鉴定状况的治疗的标准药理学测定,并且通过将这些结果与用于治疗这些状况的已知的活性成分或药物的结果进行对比,能够容易地确定治疗各期望适应症的本发明的化合物的有效剂量。在治疗这些状况之一中待施用的活性成分的量可以根据这样的考虑宽泛地改变,如采用的特定化合物和剂量单位、施用模式、治疗时间段、被治疗患者的年龄和性别、以及被治疗状况的性质和程度。
待施用的活性成分的总量将通常从每天约0.001 mg/kg至约200 mg/kg体重、并且优选从每天约0.01 mg/kg至约20 mg/kg体重变化。临床有用的给药时间表将从每天1至3次给药至每四周1次给药变化。此外,其中在特定的时间段内没有向患者给药的“停药期(drugholidays)”可能有益于药理学效果和耐受性之间的总体平衡。单位剂型可能含有约0.5 mg至约1500 mg的活性成分,并且可以每天一次或多次或者少于每天一次施用。通过注射(包括静脉内、肌肉内、皮下和肠胃外注射)和使用输注技术施用的平均每日剂量将优选为0.01至200 mg/kg总体重。说明性地,本发明的化合物可以约0.001 mg/kg至约10 mg/kg、优选约0.01 mg/kg至约1 mg/kg体重的剂量肠胃外施用。在口服施用中,示例性剂量范围为约0.01至100 mg/kg,优选约0.01至20 mg/kg,且更优选约0.1至10 mg/kg体重。上述值中间的范围也旨在是本发明的一部分。
当然,对于每个患者的具体的初始和持续剂量方案将根据参诊医生确定的状况的性质和严重程度、所采用的具体化合物的活性、患者的年龄和总体状况、施用时间、施用途径、药物排泄率、药物组合等而改变。本发明的化合物或者其药学上可接受的盐或酯或组合物的期望治疗模式和剂量数可以由本领域技术人员使用常规的治疗测试而确定。
下述示例性实施方式举例说明本发明。本发明不限于实施例。
除非另外说明,否则下述测试和实施例中的百分比是按重量计的,份是按重量计的。对于液体/液体溶液报道的溶剂比、稀释比和浓度各自基于体积。
实验部分
NMR峰形式在它们出现在光谱中时陈述,未考虑可能的更高阶效应。使用来自ACD/Labs的ACD/Name软件生成化学名称。在一些情况下,使用通常接受的市售试剂名称代替ACD/Name生成的名称。
下表1列出本段和实施例部分中使用的缩写,只要它们未在文本正文中解释。其它缩写本身具有对于技术人员通常的含义。
表1:缩写
下表列出本文使用的缩写。
缩写 含义
br 宽(1H-NMR信号)
CI 化学电离
d 双峰(1H-NMR信号)
dd 双重双峰(1H-NMR信号)
DMSO 二甲基亚砜
ESI 电喷雾(ES)电离
h 小时
HPLC 高效液相色谱
LC-MS 液相色谱质谱
m 多重峰(1H-NMR信号)
min 分钟
MS 质谱
NMR 核磁共振光谱:化学位移(δ)以ppm给出。除非另有说明,否则通过将DMSO信号设定为2.50 ppm来校正化学位移。
Rt 以分钟计的保留时间(如用HPLC或UPLC所测量)
s 单峰(1H-NMR信号)
SQD 单四极杆探测器
t 三重峰(1H-NMR信号)
THF 四氢呋喃
UPLC 超高效液相色谱。
本申请中描述的发明的各种方面通过下述实施例说明,所述实施例不意味着以任何方式限制本发明。
本文中描述的实施例测试实验用于说明本发明,并且本发明不限制于给出的实施例。
实验部分-总述部分
所有在实验部分没有描述合成的试剂是商业可获得的,或者是已知的化合物,或者可通过已知方法由本领域技术人员从已知化合物形成。
根据本发明的方法产生的化合物和中间体可要求纯化。有机化合物的纯化是本领域技术人员公知的,并且可存在纯化相同化合物的几种方式。在一些情况中,可不必纯化。在一些情况中,化合物可通过结晶纯化。在一些情况中,可使用适当的溶剂将杂质搅拌出来。在一些情况中,可通过色谱、特别是快速柱色谱,使用例如预填充的硅胶小柱(例如Biotage SNAP小柱KP-Sil®或KP-NH®)与Biotage自动纯化系统(SP4®或Isolera One®)和洗脱剂(诸如梯度的己烷/乙酸乙酯或二氯甲烷/甲醇)组合来纯化化合物。在一些情况中,可通过制备型HPLC,使用例如装配有二极管阵列检测器和/或在线电喷雾离子化质谱仪的Waters自动纯化器与适合的预填充反相柱和洗脱剂组合来纯化化合物,所述洗脱剂诸如梯度的水和乙腈,其可包含添加剂诸如三氟乙酸、甲酸或氨水。
在一些情况中,如上所述的纯化方法可以盐的形式提供具备充分碱性或酸性官能度的本发明的那些化合物,诸如,在充分碱性的本发明的化合物的情况中,例如为三氟乙酸盐或甲酸盐,或者在充分酸性的本发明的化合物的情况中,例如为铵盐。该类型的盐可以分别通过本领域技术人员已知的各种方法转变为其游离碱或游离酸形式,或者在后续的生物测定中作为盐使用。要理解的是,如在本文中分离并描述的本发明的化合物的具体形式(例如盐、游离碱等)不一定是其中所述化合物可以应用于生物测定以便定量具体生物活性的唯一形式。
UPLC-MS标准程序
方法1 (LC/MS):
仪器:Agilent MS Quad 6150;HPLC:Agilent 1290;柱:Waters Acquity UPLC HSS T31.8μ 50 x 2.1 mm;洗脱剂A:1 l水+0.25 ml 99%甲酸,洗脱剂B:1 l乙腈+0.25 ml 99%甲酸;梯度:0.0 min 90% A → 0.3 min 90% A → 1.7 min 5% A → 3.0 min 5% A,烘箱:50℃;流速:1,20 ml/min;UV-检测:205–305 nm。
方法2 (LC/MS):
仪器:Waters ACQUITY SQD UPLC系统;柱:Waters Acquity UPLC HSS T3 1.8μ 50 x1 mm;洗脱剂A:1 l水+0.25 ml 99%甲酸,洗脱剂B:1 l乙腈+0.25 ml 99%甲酸;梯度:0.0min 90% A → 1.2 min 5% A → 2.0 min 5% A,烘箱:50℃;流速:0.40 ml/min;UV-检测:208–400 nm。
方法3 (LC/MS):
仪器MS:Thermo Scientific FT-MS;Gerätetyp UHPLC+:Thermo ScientificUltiMate 3000;柱:Waters,HSST3,2.1 x 75 mm,C18 1.8 µm;洗脱剂A:1 l水+0.01%甲酸;洗脱剂B:1l乙腈+0.01%甲酸;梯度:0.0 min 10% B → 2.5 min 95% B → 3.5 min 95%B;烘箱:50℃;流速:0.90 ml/min;UV-检测:210 nm/ Optimum Integration Path 210-300nm。
方法4(LC/MS):
仪器:Waters ACQUITY SQD UPLC系统;柱:Waters Acquity UPLC HSS T3 1.8μ 50 x1 mm;洗脱剂A:1 l水+0.25 ml 99%甲酸,洗脱剂B:1 l乙腈+0.25 ml 99%甲酸;梯度:0.0min 95% A → 6.0 min 5% A → 7.5 min 5% A,烘箱:50℃;流速:0.35 ml/min;UV-检测:210–400 nm。
方法5(制备型HPLC):
柱:Chromatorex或Reprosil C18 10μm;125 x 30 mm,流速:75 ml/min,运行时间:20min,在210 nm处检测,洗脱剂A:水+0.1%甲酸,洗脱剂B:乙腈+0.1%甲酸;梯度:3 min 10%B;17.5 min:95% B;19.5 min 100% B,20 min 10% B。
实验部分-起始材料和中间体
实施例1A
5-(4-氯苯基)-4-[(2R)-3,3,3-三氟-2-羟基丙基]-2,4-二氢-3H-1,2,4-三唑-3-酮
将5-(4-氯苯基)-4-(3,3,3-三氟-2,2-二羟基丙基)-2,4-二氢-3H-1,2,4-三唑-3-酮(合成描述为WO 2010/105770-A1的实施例4A)(10.0 g, 30.9 mmol)、N-[(1R,2R)-2-氨基-1,2-二苯基乙基]-4-甲基苯磺酰胺(56.6 mg, 154 µmol)和1-甲基-4-(丙-2-基)苯-二氯钌(47.3 mg, 77.2 µmol)于乙酸乙酯中的溶液用三乙胺(8.6 ml, 62 mmol)处理,随后加入甲酸(5.8 ml, 150 mmol)。将所得混合物回流加热3小时,且然后冷却至室温。将反应混合物用盐酸(70ml, 1N)稀释。将有机相用盐酸(1N)洗涤两次。将水相用乙酸乙酯萃取两次。将合并的有机相蒸发。将残余物重新溶于甲醇(22.5 ml)中,并将所得悬浮液加热至60℃,直至固体完全溶解。加入盐酸(22.5 ml, 1N),并将所得悬浮液在78℃加热10分钟,并冷却至室温。将固体过滤出,并在真空下干燥。将固体重新溶于盐酸(30 ml,1N)中,在35℃加热。将所得悬浮液用甲醇(30 ml)处理,在35℃加热4小时,并在35℃过滤出。将滤液溶液蒸发,得到4.9 g (ee = 99.6%, 51%理论值)的5-(4-氯苯基)-4-[(2R)-3,3,3-三氟-2-羟基丙基]-2,4-二氢-3H-1,2,4-三唑-3-酮。
实施例2A
{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙腈
在2 L反应容器中,将100 g (273 mmol)的{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酸(合成描述为WO 2010/105770-A1的实施例8A)、43.3 g (547 mmol)吡啶和33 mg (0.3 mmol)的4-二甲基氨基吡啶溶于300 mlTHF中。将所得溶液在5℃用52.8 g(438 mmol)的2,2-二甲基丙酰氯经15分钟处理,并将所得混合物在室温搅拌2.5小时。冷却至0℃后,经1小时加入183 ml的28%氨水溶液,同时将溶液温度维持于10℃至20℃,且然后将所得混合物在5℃搅拌1小时的额外时间段。然后加入500 ml甲基叔丁醚和300 ml 20%柠檬酸水溶液,同时维持内部温度于10℃至20℃。将各相(phases)分离,并将有机相用300 ml的20%柠檬酸水溶液洗涤,随后用300 ml饱和碳酸氢钠水溶液洗涤,且最后用300 ml的10%氯化钠水溶液洗涤。将有机相在60℃在减压下蒸发,直至获得油状残余物。然后加入300 ml THF,并将溶液再次蒸发,直至获得油状溶液。此操作重复第二次。将油状残余物重新溶于360 ml THF中,并经20分钟在10℃至20℃的温度用172g (820 mmol)三氟乙酸酐处理。然后将所得溶液在室温搅拌1小时。在10℃至20℃的温度加入720 ml 4-甲基-2-戊酮和650 ml 7.5%氢氧化钠水溶液。最后使用7.5%氢氧化钠水溶液将pH值调整至pH=9.5。相分离后,将有机相用450 ml 10%氯化钠水溶液洗涤两次。将有机相在80℃的温度在减压下蒸发,同时加入1200 ml正庚烷。将所形成的悬浮液冷却至20℃并形成固体,将其过滤出,并用200 ml正庚烷洗涤,且然后在减压(50℃,30毫巴)下干燥,得到88g(理论值的93%)的作为固体的{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙腈。
实施例3A
{3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙腈
将40 g (130 mmol) 5-(4-氯苯基)-4-[(2R)-3,3,3-三氟-2-羟基丙基]-2,4-二氢-3H-1,2,4-三唑-3-酮(实施例1A)于400 ml甲基异丁酮中的溶液用17.9 g(143 mmol)溴乙腈和53.9 g(390 mmol)碳酸钾处理,并在60℃搅拌4小时。冷却至20℃后,加入200 ml水,并将混合物搅拌10分钟。相分离后,将有机相用200 ml水洗涤。将有机相在80℃在减压下蒸发,同时加入300 ml正庚烷。将所形成的悬浮液冷却至20℃,并形成固体,将其过滤出,并用50 ml正庚烷洗涤,且然后在减压(50℃,30毫巴)下干燥,得到25.2 g(理论值的56%)的{3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙腈。
实施例4A
2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯
在4 L反应容器中,将200 g(576.9 mmol)的{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙腈(实施例2A)于1600 ml甲醇中的溶液用5.2 g(28 mmol)甲醇钠(30%/甲醇)处理,并将所得混合物在50℃搅拌2.5小时。然后将溶液在50℃在减压下蒸发,直至获得油状溶液。加入2000 ml甲基叔丁醚,并将溶液浓缩,直至达到800 ml的体积。然后加入3000 ml正庚烷并形成悬浮液。在20℃冷却后,将固体过滤,并用500 ml正庚烷洗涤,且然后在减压(50℃,30毫巴)下干燥,得到175 g(理论值的80%)的作为固体的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯。
实施例5A
2-{3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯
将8.58 g(24.7 mmol)的{3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙腈(实施例3A)于甲醇(43 ml)中的溶液用229 µl(1.24mmol)的甲醇钠溶液(30%/甲醇)处理。将所得混合物在室温搅拌过夜,且然后蒸发,得到9.31 g(理论值的99%)的标题化合物。
实施例6A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-5-甲酸甲酯
将150 mg的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例4A)(26.4 mmol)于3 ml THF中的溶液冷却至0℃,且然后用58.2 mg(0.48 mmol)氯氧代乙酸甲酯和275 μL(1.58 mmol)N,N-二异丙基乙胺处理。将所得混合物温热至室温,并搅拌1小时,并再次冷却至0℃。然后加入62.6 mg(0.436 mmol)3-氯-2-肼基吡啶,并将反应混合物温热至室温,且然后搅拌1小时,随后在120℃在密封的小瓶中在微波照射下1小时。粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到25.3 mg(理论值的11%)的标题化合物。
实施例7A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酸甲酯
将1.0 g的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例4A)(2.64 mmol)于20 ml 1,4-二氧杂环己烷中的溶液冷却至10℃,且然后用388 mg(3.17 mmol)氯氧代乙酸甲酯和0.55 mL(3.18mmol)N,N-二异丙基乙胺处理。然后将所得混合物搅拌30分钟。将1.10 g(3.17 mmol)2-肼基-3-(三氟甲基)吡啶(4-甲苯磺酸盐1:1)、0.65 mL(3.72 mmol)N,N-二异丙基乙胺和506mg(3.19 mmol)无水硫酸铜(II)于10 ml的1,4-二氧杂环己烷中的预搅拌溶液加入反应混合物中,且然后将所得混合物在室温搅拌过夜。然后加入水,并将水相用乙酸乙酯萃取,合并的有机相用氯化钠水溶液洗涤,经硫酸镁干燥,并在真空中蒸发,得到777 mg(理论值的50%)的作为固体的标题化合物。
实施例8A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲氧基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酸甲酯
将150 mg的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例4A)(0.40 mmol)于3 ml THF中的溶液冷却至0℃,并用58 mg(0.48 mmol)氯氧代乙酸甲酯和275 μL(1.58 mmol)N,N-二异丙基乙胺处理。将所得混合物温热至室温,且然后搅拌1小时,且其后再次冷却至0℃。然后加入159 mg(0.44 mmol)2-肼基-3-(三氟甲氧基)吡啶(4-甲苯磺酸盐1:1),且然后将反应混合物温热至室温,并搅拌1小时,随后在120℃在密封的小瓶中在微波照射下1小时。粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到51.5 mg(理论值的21%)的作为固体的标题化合物。
实施例9A
1-(3-溴吡啶-2-基)-3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-5-甲酸甲酯
将1.0 g的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例4A)(2.64 mmol)于20 ml 1,4-二氧杂环己烷中的溶液冷却至10℃,且然后用388 mg(3.17 mmol)氯氧代乙酸甲酯和0.55 mL(3.18mmol)N,N-二异丙基乙胺处理。将所得混合物搅拌30分钟。然后将595 mg(3.17 mmol)3-溴-2-肼基吡啶和506 mg(3.19 mmol)无水硫酸铜(II)于10 ml的1,4-二氧杂环己烷中的预搅拌溶液加入反应混合物中,并将所得混合物在室温搅拌过夜。然后加入水,并将水相用乙酸乙酯萃取,合并的有机相用氯化钠水溶液洗涤,经硫酸镁干燥,并在真空中蒸发。粗产物通过柱色谱(硅胶,环己烷/EtOAc 12%→100%)纯化,得到696 mg(理论值的44%)的标题化合物。
实施例10A
2-[3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-5-(甲氧基羰基)-1H-1,2,4-三唑-1-基]烟酸乙酯
将2.35 g的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例4A)(26.19 mmol)于47 ml 1,4-二氧杂环己烷中的溶液冷却至10℃,且然后用910 mg(7.41 mmol)氯氧代乙酸甲酯和1.20 mL(7.41mmol)N,N-二异丙基乙胺处理。然后将所得混合物搅拌30分钟。然后将1.87 g(7.41 mmol)2-肼基烟酸乙酯和1.45 mg(9.10 mmol)无水硫酸铜(II)于23 mL 1,4-二氧杂环己烷中的预搅拌溶液加入反应混合物中,并将所得混合物在室温搅拌96小时。在真空中除去溶剂,且粗产物通过柱色谱(硅胶,二氯甲烷/甲醇,92/8)纯化,得到833 mg(理论值的23%)的作为固体的标题化合物。
实施例11A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-(4-氯吡啶-3-基)-1H-1,2,4-三唑-5-甲酸甲酯
将1.0 g的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例4A)(2.64 mmol)于18 ml THF中的溶液冷却至0℃,并用388 mg(3.17 mmol)氯氧代乙酸甲酯和1.06 mL(6.07 mmol)N,N-二异丙基乙胺处理。将所得混合物温热至室温,且然后搅拌1小时,并再次冷却至0℃。加入523 mg(2.90mmol)4-氯-3-肼基吡啶(盐酸盐1:1),并将反应混合物温热至室温,且然后搅拌1小时,随后在120℃在密封的小瓶中在微波照射下1小时。粗产物通过柱色谱(硅胶,环己烷/EtOAc,梯度)纯化,得到1.03 g(理论值的66%)的作为固体的标题化合物。
实施例12A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[4-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-5-甲酸甲酯
将150 mg的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例4A)(0.40 mmol)于3 ml THF中的溶液冷却至0℃,并用53 mg(0.44 mmol)氯氧代乙酸甲酯和75 μL(0.44 mmol)N,N-二异丙基乙胺处理。将所得混合物在0℃搅拌30分钟。加入77 mg(0.44 mmol)3-肼基-4-(三氟甲基)吡啶,且然后将反应混合物温热至室温,并搅拌1小时,随后在100℃在密封的小瓶中在微波照射下1小时。粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到104 mg(理论值的41%)的作为固体的标题化合物。
实施例13A
3-[3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-5-(甲氧基羰基)-1H-1,2,4-三唑-1-基]异烟酸乙酯
将500 mg的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例4A)(1.32 mmol)于10 ml THF中的溶液冷却至0℃,并用178 mg(1.45 mmol)氯氧代乙酸甲酯和252 μL(1.45 mmol)N,N-二异丙基乙胺处理。将所得混合物在0℃搅拌30分钟。然后加入309 mg(1.45 mmol)3-肼基异烟酸乙酯,并将反应混合物温热至室温,且然后搅拌16小时,随后加热至回流16小时。粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到416 mg(理论值的26%)的标题化合物。
实施例14A
3-({3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-5-甲酸甲酯
将546 mg的2-{3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例5A)(1.44 mmol)于10 ml THF中的溶液冷却至0℃,并用194 mg(1.59 mmol)氯氧代乙酸甲酯和277 μL(1.59 mmol)N,N-二异丙基乙胺处理。将所得混合物在0℃搅拌30分钟。然后加入227 mg(1.59 mmol)3-氯-2-肼基吡啶,并将反应混合物温热至室温,且然后搅拌1小时,随后在120℃在密封的小瓶中在微波照射下1小时,且在室温再36小时。然后将反应混合物用甲醇/水处理,并通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到121 mg(理论值的14%)的作为固体的标题化合物。
实施例15A
3-({3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酸甲酯
将340 mg的2-{3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例5A)(898 μmol)于8 ml 1,4-二氧杂环己烷中的溶液冷却至10℃,并用132 mg(1.08 mmol)氯氧代乙酸甲酯和305 μL(2.33 mmol)N,N-二异丙基乙胺处理。将所得混合物搅拌30分钟。然后将376 mg(1.08 mmol)2-肼基-3-(三氟甲基)吡啶(4-甲苯磺酸盐1:1)和172 mg(1.08 mmol)无水硫酸铜(II)于4 mL 1,4-二氧杂环己烷中的预搅拌溶液加入反应混合物中,并将所得混合物在室温搅拌16小时。在真空中除去溶剂,并将粗产物溶于EtOAc,并用10%EDTA于水中的溶液洗涤(重复四次),随后用水和饱和氯化钠水溶液洗涤。经硫酸镁干燥后,除去挥发物,且获得的粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到167 mg(理论值的31%)的作为固体的标题化合物。
实施例16A
3-({3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-(4-氯吡啶-3-基)-1H-1,2,4-三唑-5-甲酸甲酯
将330 mg的2-{3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例5A)(871 μmol)于6.6 ml THF中的溶液冷却至0℃,并用117 mg(958 μmol)氯氧代乙酸甲酯和166 μL(958 μmol)N,N-二异丙基乙胺处理。然后将所得混合物在0℃搅拌30分钟。加入166 μL(958 μmol)N,N-二异丙基乙胺和172 mg(958 μmol)4-氯-3-肼基吡啶(盐酸盐1:1),并将所得反应混合物温热至室温,且然后搅拌16小时,随后在100℃在密封的小瓶中在微波照射下再1小时。粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到126 mg(理论值的26%)的作为固体的标题化合物。
实施例17A
3-({3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[4-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-5-甲酸甲酯
将350 mg的2-{3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酰亚胺甲酯(实施例5A)(0.924 mmol)于7.0 ml THF中的溶液冷却至0℃,并用124 mg(1.02 mmol)氯氧代乙酸甲酯和177 μL(1.102 mmol)N,N-二异丙基乙胺处理。将所得混合物在0℃搅拌30分钟。加入180 mg(1.02 mmol)3-肼基-4-(三氟甲基)吡啶,并将反应混合物温热至室温,并搅拌16小时,随后在100℃在密封的小瓶中在微波照射下1小时。粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到125 mg(理论值的23%)的作为固体的标题化合物。
实验部分–实施例
实施例1
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-5-甲酰胺
将5.1 g 3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-5-甲酸甲酯(实施例6A,9.134 mmol)溶于42.5 mL的氨溶液(7N/甲醇, 297 mmol)中。将所得混合物在室温搅拌2小时。然后将溶液倒在冰上,并将混合物搅拌10分钟。将沉淀物滤出并用水洗涤,其得到3.5 g粗产物。将水相用乙酸乙酯萃取。将有机相经硫酸镁干燥、过滤并在真空中除去溶剂。粗产物通过快速色谱(硅胶,二氯甲烷/甲醇,97/3)纯化,得到4.00 g(理论值的81%)的作为固体的标题化合物。
实施例2
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酰胺
将1.80 g 3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酸甲酯(实施例7A, 3.04 mmol)溶于10.0 mL的氨溶液(7N/甲醇, 70.0 mmol)中。将所得混合物在室温搅拌1小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到1.49 g(理论值的85%)的作为固体的标题化合物。
实施例3
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲氧基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酰胺
将51.0 mg 3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲氧基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酸甲酯(实施例8A, 84 μmol)溶于5.0 mL的氨溶液(7N/甲醇, 35.0 mmol)中。将所得混合物在室温搅拌1小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到44.2 mg(理论值的89%)的作为固体的标题化合物。
实施例4
1-(3-溴吡啶-2-基)-3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-5-甲酰胺
将100 mg 1-(3-溴吡啶-2-基)-3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-5-甲酸甲酯(实施例9A, 0.166 mmol)溶于10.0 mL的氨溶液(7N/甲醇, 70.0 mmol)中。将所得混合物在室温搅拌1小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到83.1 mg(理论值的85%)的作为固体的标题化合物。
实施例5
2-[5-氨基甲酰基-3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-1-基]烟酸乙酯
将50.0 mg实施例10A(84 μmol)溶于1.25 mL的氨溶液(7N/甲醇, 0.175 mmol)中。将所得混合物在室温搅拌1小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到27.8 mg(理论值的57%)的作为固体的标题化合物。
实施例6
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-(4-氯吡啶-3-基)-1H-1,2,4-三唑-5-甲酰胺
将100 mg实施例11A (0.179 mmol)溶于1.0 mL的氨溶液(7N/甲醇, 7.09 mmol)中。将所得混合物在室温搅拌16小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到76.7 mg(理论值的79%)的作为固体的标题化合物。
实施例7
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[4-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-5-甲酰胺
将78.5 mg实施例12A (0.133mmol)溶于8.0 mL的氨溶液(7N/甲醇, 1.14 mmol)中。将所得混合物在室温搅拌1小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到49.7 mg(理论值的77%)的作为固体的标题化合物。
实施例8
3-[5-氨基甲酰基-3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-1-基]异烟酸乙酯
将100 mg实施例13A(151 μmol)溶于1.0 mL NH3/EtOH (2.00 mmol, 2 N)中。将所得混合物在室温搅拌16小时,并加入另外1.0 mL的氨溶液(7N/甲醇,2.00 mmol)并在室温继续搅拌16小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到46.0 mg(理论值的49%)的作为固体的标题化合物。
实施例9
2-[5-氨基甲酰基-3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-1-基]烟酰胺
将80 mg实施例10A (134 μmol)溶于10 mL的氨溶液(7N/甲醇, 70.0 mmol)中。将所得混合物在70℃搅拌10分钟,在真空中除去溶剂,并将残余物溶于10 mL的氨溶液(7N/甲醇,70.0 mmol)中,其在120℃在微波中搅拌3小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到22.0 mg(理论值的28%)的作为固体的标题化合物。
实施例10
3-({3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-5-甲酰胺
将110 mg实施例14A (0.197 mmol)溶于1.0 mL的氨溶液(7N/甲醇, 7.09 mmol)中。将所得混合物在室温搅拌1小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到92.0 mg(理论值的86%)的作为固体的标题化合物。
实施例11
3-({3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酰胺
将160 mg实施例15A (270 μmol)溶于5.0 mL的氨溶液(7N/甲醇, 2.00 mmol)中。将所得混合物在室温搅拌1.5小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到162.1 mg(定量)的作为固体的标题化合物。
实施例12
3-({3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-(4-氯吡啶-3-基)-1H-1,2,4-三唑-5-甲酰胺
将118 mg实施例16A (211 μmol)溶于5.0 mL的氨溶液(7N/甲醇, 35.0 mmol)中。将所得混合物在室温搅拌1小时。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到111 mg(理论值的97%)的作为固体的标题化合物。
实施例13
3-({3-(4-氯苯基)-5-氧代-4-[(2R)-3,3,3-三氟-2-羟基丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}甲基)-1-[4-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-5-甲酰胺
将118 mg实施例17A (199 μmol)溶于5.0 mL的氨溶液(7N/甲醇, 2.00 mmol)中。将所得混合物在室温搅拌20分钟。在真空中除去溶剂,且粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到99.5 mg(理论值的87%)的作为固体的标题化合物。
实施例14
3-{[3-(4-氯苯基)-5-氧代-4-(3,3,3-三氟-2-氧代丙基)-4,5-二氢-1H-1,2,4-三唑-1-基]甲基}-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-5-甲酰胺(酮形式)或3-{[3-(4-氯苯基)-5-氧代-4-(3,3,3-三氟-2,2-二羟基丙基)-4,5-二氢-1H-1,2,4-三唑-1-基]甲基}-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-5-甲酰胺(水合物形式)
将250 mg的实施例1 (460 μmol)于5.0 ml二氯甲烷中的溶液冷却至0℃并加入780 mg(1.84 mmol)戴斯-马丁氧化剂和9.0 μL(506 mmol)水。将所得混合物在室温搅拌1小时。向反应混合物中加入5 mL饱和硫代硫酸钠水溶液和5 mL饱和碳酸氢钠水溶液,并将所得混合物搅拌10分钟。分离各相,并将水层用乙酸乙酯(10 mL,重复三次)萃取,将合并的有机相经硫酸镁干燥并蒸发。粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到230 mg(理论值的87%)的作为固体的标题化合物。
实施例15
1-(3-溴吡啶-2-基)-3-{[3-(4-氯苯基)-5-氧代-4-(3,3,3-三氟-2-氧代丙基)-4,5-二氢-1H-1,2,4-三唑-1-基]甲基}-1H-1,2,4-三唑-5-甲酰胺(酮形式)或1-(3-溴吡啶-2-基)-3-{[3-(4-氯苯基)-5-氧代-4-(3,3,3-三氟-2,2-二羟基丙基)-4,5-二氢-1H-1,2,4-三唑-1-基]甲基}-1H-1,2,4-三唑-5-甲酰胺(水合物形式)
将68.0 mg的实施例4 (116 μmol)于1.3 ml二氯甲烷中的溶液冷却至0℃并加入196mg (463 mmol)戴斯-马丁氧化剂和2.3 μL (127 mmol)水。将所得混合物温热至室温,且然后搅拌1小时。向反应混合物中加入1.3 mL饱和硫代硫酸钠水溶液和1.3 mL饱和碳酸氢钠水溶液,并将混合物搅拌10分钟。分离各相,并将水层用乙酸乙酯(3x10 mL)萃取,然后将合并的有机相经硫酸镁干燥并蒸发。粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到30.1 mg(理论值的42%)的作为固体的标题化合物。
实施例16
3-{[3-(4-氯苯基)-5-氧代-4-(3,3,3-三氟-2-氧代丙基)-4,5-二氢-1H-1,2,4-三唑-1-基]甲基}-1-(4-氯吡啶-3-基)-1H-1,2,4-三唑-5-甲酰胺(酮形式)或3-{[3-(4-氯苯基)-5-氧代-4-(3,3,3-三氟-2,2-二羟基丙基)-4,5-二氢-1H-1,2,4-三唑-1-基]甲基}-1-(4-氯吡啶-3-基)-1H-1,2,4-三唑-5-甲酰胺(水合物形式)
将120 mg的实施例6 (221 μmol)和4.3 μL (243 mmol)水于2.4 ml二氯甲烷中的溶液冷却至0℃,且然后加入140.5 mg (331 mmol)戴斯-马丁氧化剂。将所得混合物温热至室温,且然后搅拌2小时。向悬浮液中加入5 mL THF,并在4℃延长搅拌72小时,随后在室温再3小时。向反应混合物中加入2 mL饱和硫代硫酸钠水溶液和2 mL饱和碳酸氢钠水溶液,且然后将混合物搅拌10分钟。分离各相,并将水层用二氯甲烷(10 mL,重复四次)萃取,合并的有机相用水和饱和氯化钠水溶液洗涤,经硫酸镁干燥并蒸发。粗产物通过快速色谱(硅胶,环己烷/乙酸乙酯1:1→乙酸乙酯)纯化。含有产物的级分的蒸发得到8.0 mg(理论值的7%)的作为固体的标题化合物。
实施例17
3-{[3-(4-氯苯基)-5-氧代-4-(3,3,3-三氟-2-氧代丙基)-4,5-二氢-1H-1,2,4-三唑-1-基]甲基}-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酰胺(酮形式)或3-{[3-(4-氯苯基)-5-氧代-4-(3,3,3-三氟-2,2-二羟基丙基)-4,5-二氢-1H-1,2,4-三唑-1-基]甲基}-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲酰胺(水合物形式)
将100 mg的实施例2 (173 μmol)于1.9 ml二氯甲烷中的溶液冷却至0℃且然后加入294 mg (693 mmol)戴斯-马丁氧化剂和3.5 μL (191 mmol)水。将所得混合物温热至室温,且然后搅拌1小时。向反应混合物中加入2 mL饱和硫代硫酸钠水溶液和2 mL饱和碳酸氢钠水溶液,且然后将所得混合物搅拌10分钟。将水层用二氯甲烷(10 mL,重复四次)萃取,合并的有机相用水和饱和氯化钠水溶液洗涤,经硫酸镁干燥并蒸发。粗产物通过制备型HPLC(方法5)纯化。含有产物的级分的冷冻干燥得到18.4 mg(理论值的19%)的作为固体的标题化合物。
实验部分-生物学测定
缩写和首字母缩略词:
Acc. No. 登记编号
AVP 精氨酸加压素
Bmax 最大配体结合能力
BSA 牛血清白蛋白
cAMP 环腺苷一磷酸
Cat. No. 目录号
cDNA 互补脱氧核糖核酸
CHO 中国仓鼠卵巢
CRE cAMP反应元件
Ct 循环阈值
DMEM/F12 Dulbecco氏改良的Eagle氏培养基/ Ham氏F12培养基(1:1)
DNA 脱氧核糖核酸
DMSO 二甲基亚砜
DTT 二硫苏糖醇
EC50 半最大有效浓度
EDTA 乙二胺四乙酸
FAM 羧基荧光素琥珀酰亚胺酯
f.c. 最终浓度
FCS 胎牛血清
HEPES 4-(2-羟乙基)哌嗪-1-乙磺酸
IC50 半最大抑制浓度
Kd 解离常数
Ki 抑制剂的解离常数
mRNA 信使核糖核酸
PBS 磷酸盐缓冲盐水
PEG 聚乙二醇
p.o. 口服,经口
RNA 核糖核酸
RTPCR 实时聚合酶链式反应
SPA 闪烁邻近测定(scintillation proximity assay)
TAMRA 羧基四甲基罗丹明
TRIS;Tris 2-氨基-2-羟甲基丙烷-1,3-二醇。
实施例在选定的生物测定中测试一次或多次。在测试多于一次时,数据被报告为平均值或中位数值,其中,
●平均值也称为算数平均值,表示所获得的值之和除以测试次数,并且
●中位数值表示以升序或降序排列时值的组的中间数。如果数据集中的值的数量是奇数,则中位数是中间值。如果数据集中的值的数量是偶数,则中位数是两个中间值的算数平均值。
实施例合成一次或多次。在合成多于一次时,来自生物测定的数据表示利用由一个或多个合成批次的测试获得的数据集计算的平均值或中位数值。
可通过本领域公知的体外、离体和体内测定来完成本发明化合物的活性的证明。例如,为了证明本发明化合物的活性,可使用以下测定。
B-1.用于测定加压素受体活性的细胞体外测定
使用重组细胞系进行来自人、大鼠和狗的V1a和V2加压素受体的激动剂和拮抗剂的鉴定以及本发明化合物的活性的定量。这些细胞系最初来源于仓鼠的卵巢上皮细胞(中国仓鼠卵巢,CHO K1,ATCC:美国典型培养物保藏中心,Manassas,VA 20108,USA)。测试细胞系组成型表达人、大鼠或狗V1a或V2受体。在Gαq-偶联的V1a受体的情况下,细胞也用钙敏感的发光蛋白水母发光蛋白(人和大鼠V1a)或螅蛋白(狗V1a)的修饰形式稳定转染,其在用辅因子腔肠素重构后当游离钙浓度增加时发光[Rizzuto R, Simpson AW, Brini M, Pozzan T,Nature 358, 325-327 (1992);Illarionov BA, Bondar VS, Illarionova VA, VysotskiES, Gene 153 (2), 273-274 (1995)]。所得加压素受体细胞通过钙离子的细胞内释放对重组表达的V1a受体的刺激反应,这可以通过所得发光蛋白发光来定量。将Gs-偶联的V2受体稳定转染到在CRE-响应启动子的控制下表达萤火虫荧光素酶的基因的细胞系中。V2受体的活化通过cAMP增加诱导CRE响应启动子的活化,从而诱导萤火虫荧光素酶的表达。由V1a细胞系的发光蛋白发出的光以及由V2细胞系的萤火虫荧光素酶发出的光对应于各自的加压素受体的活化或抑制。使用合适的发光计检测细胞系的生物发光[Milligan G, MarshallF, Rees S, Trends in Pharmacological Sciences 17, 235-237 (1996)]。
测试程序:
加压素V1a受体细胞系:
在测定前一天,将细胞在384-孔微量滴定板中在培养基(DMEM/F12, 2% FCS, 2 mM谷氨酰胺, 10 mM HEPES, 5 µg/ml腔肠素)中铺开并保持在细胞培养箱(96%湿度,5% v/vCO2,37℃)中。在测定当天,将各种浓度的测试化合物在微量滴定板的孔中放置10分钟,然后加入EC50浓度的激动剂[Arg8]-加压素。在发光计中立即测量所得光信号。
加压素V2受体细胞系:
在测定前一天,将细胞在384-孔微量滴定板中在培养基(DMEM/F12, 2% FCS, 2 mM谷氨酰胺, 10 mM HEPES)中铺开并保持在细胞培养箱(96%湿度,5% v/v CO2,37℃)中。在测定当天,将各种浓度的测试化合物和EC50浓度的激动剂[Arg8]-加压素一起加入孔中,并将板在细胞培养箱中温育3小时。在加入细胞裂解试剂Triton™和底物荧光素后,在发光计中测量萤火虫荧光素酶的发光。
下表1A列出从用人V1a或V2受体转染的细胞系获得的本发明化合物(包括外消旋混合物以及分离的对映异构体)的个别IC50值:
表1A
表1A中列出的IC50数据证明,本发明化合物充当选择性和有效的加压素V1a受体拮抗剂。
为了比较的目的,还在上述细胞V1a和V2测定中测试被认为是最接近的现有技术的代表的选择的苯基-三唑衍生物(参考国际专利申请WO 2011/104322-A1和其中描述的实例化合物)。从用人V1a或V2受体转染的细胞系获得的这些化合物的IC50值列于下表1B中:
表1B
为了比较的目的,还在上述细胞V1a和V2测定中测试被认为是最接近的现有技术的代表的进一步选择的苯基-三唑衍生物(参考国际专利申请WO 2016/071212-A1和其中描述的实例化合物)。从用人V1a或V2受体转染的细胞系获得的这些化合物的IC50值列于下表1C中:
表1C
B-2.放射性结合测定
在放射性结合测定中,使用表达各自的人加压素V1a和V2受体的重组人胚肾细胞系293(HEK293)或CHO-K1细胞系的膜级分,可以测定IC50和Ki值。
使用标准技术,在50 mM Tris-HCl缓冲液、pH 7.4、5 mM MgCl2、0.1% BSA中使用HEK293细胞中表达的人重组加压素V1a受体。将制备的膜的等分试样与一式两份的各种浓度的测试化合物和0.03nM[125I]苯基乙酰基-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2在25℃温育120分钟。在1 μM[Arg8]加压素存在的情况下估计非特异性结合。将受体过滤并洗涤,然后对过滤器计数以测定特异性结合的[125I]苯基乙酰基-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2。
使用标准技术,用编码人加压素V2受体的质粒稳定转染的CHO-K1细胞用于在50mM Tris-HCl缓冲液、pH 7.4、10 mM MgCl2、0.1% BSA中制备膜。将制备的膜的等分试样与一式两份的各种浓度的测试化合物和4 nM[3H](Arg8)-加压素在25℃温育120分钟。在1 mM(Arg8)-加压素存在的情况下估计非特异性结合。将膜过滤并洗涤3次,并将过滤器计数以测定特异性结合的[3H](Arg8)-加压素。
通过使用MathIQTM(ID Business Solutions Ltd., UK)的非线性最小二乘回归分析测定IC50值。使用Cheng和Prusoff的方程(Cheng, Y., Prusoff, W.H., Biochem.Pharmacol. 22:3099-3108, 1973)计算抑制常数Ki。
B-3.用于检测加压素V1a受体拮抗剂对促纤维化基因的调节的作用的细胞体外测定
描述为从大鼠心脏组织分离的心肌细胞类型的细胞系H9C2(美国典型培养物保藏中心ATCC No.CRL-1446)以高拷贝数内源性表达加压素V1a受体AVPRIA,而不能检测到AVPR2表达。同样地,从大鼠肾组织分离的细胞系NRK49F(ATCC No. CRL1570)显示高AVPR1A mRNA表达和减少的AVPR2表达的相似表达模式。对于检测受体拮抗剂对基因表达的AVPRIA受体依赖性调节的抑制的细胞测定,程序如下:
将H9C2细胞或NRK49F细胞接种于6-孔微量滴定板中,用于以50 000个细胞/孔的细胞密度在2.0 ml Opti-MEM培养基(Invitrogen Corp., Carlsbad, CA, USA, 目录号11058-021)中细胞培养,并保持在细胞培养箱(96%湿度, 8% v/v CO2, 37℃)中。24小时后,向三孔(一式三份)的集合中加入媒介物溶液(阴性对照)和加压素溶液([Arg8]-加压素乙酸盐,Sigma,目录号V9879)、或测试化合物(溶于具有20% v/v乙醇的媒介物:水)和加压素溶液。在细胞培养中,最终的加压素浓度为1 nM。将测试化合物溶液以小体积加入细胞培养物中,使得不超过细胞测定中0.03%乙醇的终浓度。在5小时的温育时间后,在抽吸下抽出培养物上清液,将贴壁细胞在350 µl RLT缓冲液(Qiagen, 目录号79216)中裂解,并使用RNeasy试剂盒(Qiagen,目录号74104)从裂解物中分离RNA。其随后进行DNA酶消化(Invitrogen,目录号18068-015)、cDNA合成(Promaga, ImProm-II逆转录系统,目录号A3800)和逆转录聚合酶链式反应(RTPCR)(pPCR MasterMix RT-QP2X-03-075, Eurogentec, Seraing, Belgium)。所有程序都根据测试试剂的制造商的工作方案进行。使用Primer3Plus程序用6-FAMTAMRA-标记的探针,基于mRNA基因序列(NCBI GenBank Entrez核苷酸数据库)选择用于RTPCR的引物组。使用Applied Biosystems ABI Prism 7700序列检测器,以384-孔微量滴定板形式,根据仪器操作说明书进行用于测定各种测定批次的细胞中的相对mRNA表达的RTPCR。参考核糖体蛋白L-32基因(GenBank登录号NM_013226)的表达水平和Ct=35的阈值Ct值,相对基因表达由Δ-ΔCt值代表[Applied Biosystems, User Bulletin No. 2 ABIPrism 7700 SDS, 1997年12月11日(更新于10/2001)]。
B-4.加压素诱导的人血小板聚集的抑制
人血小板内源性表达V1a受体。发现相对高的加压素浓度(约50-100nM)离体刺激血小板聚集。因此,从人血液富集的血小板可充当表达V1a的组织,用于用相应高浓度的加压素拮抗剂的药理学研究。
通过从无药物至少1周的不吸烟的健康志愿者(n=4-8)静脉穿刺来将人血收集于10 mM柠檬酸三钠溶液中。富含血小板的血浆(PRP)通过将血液样品在4℃以140 g离心20分钟来获得。将所得沉淀物进一步离心(15.000 rpm,2分钟)以产生血小板较少的血浆(PPP)。使用聚集计(APACT 4)以浊度法测量血小板聚集。反应之后,监测178μL PRP等分试样在37℃连续搅拌下针对PPP对照的光透射的变化。在加入20μL Arg-加压素(最终浓度100nM)之前5分钟,将各种浓度的加压素拮抗剂(2μL)加入PRP中。通过测量聚集波从与对照响应相比的形状变化的底部起的高度来确定化合物的抑制作用。通过迭代非线性回归程序计算剂量-反应抑制曲线的IC50值。
B-5.对分离的大鼠血管环的收缩的影响
分离的主动脉
可以在来自内源性表达V1a受体的雄性Wistar大鼠的分离的主动脉环上研究测试化合物。使用二氧化碳使雄性Wistar大鼠安乐死。取出主动脉并置于冰冷的以下组成(以mmol/l计)的Krebs-Henseleit缓冲液中:NaCl 112、KCl 5.9、CaCl2 2.0、MgCl2 1.2、NaH2PO4 1.2、NaHCO3 25、葡萄糖11.5。将主动脉切成3 mm环并转移至含有用95% O2、5% CO2在37℃平衡的Krebs-Henseleit溶液的20 ml器官浴中。为了记录等长张力,将环安装在两个钩子之间。将静息张力调整至3 g。在平衡期后,通过将制剂暴露于K+(50 mM)Krebs-Henseleit溶液来开始每次实验。使用1 nmol/l Arg-加压素使主动脉环预收缩。在建立稳定收缩后,构建测试化合物的累积剂量响应曲线。由Arg-加压素诱导的稳定收缩定义为100%张力。松弛表示为张力百分比。
分离的肾动脉(A. renalis)
使用二氧化碳使雄性Wistar大鼠(200-250 g)安乐死。取出肾动脉并置于冰冷的以下组成(以mmol/l计)的Krebs-Henseleit缓冲液中:NaCl 112、KCl 5.9、CaCl2 2.0、MgCl21.2、NaH2PO4 1.2、NaHCO3 25、葡萄糖11.5。为了测量等长张力,使用两根固定至安装钳口的钨丝将长度为2 mm的环段安装在小血管腔肌动描记器(Danish Myo Technology A/S,Denmark)中。一个安装钳口连接至千分尺,允许控制血管周长。另一个安装钳口连接至力传感器,用于测量张力发展。将整个制剂保持在具有37℃的生理盐溶液的室中,用氧气鼓泡。在30分钟平衡期后,将血管拉伸至其最佳管腔直径,用于主动张力发展,其基于内周长-壁张力比确定。如果血管暴露于等效于100 mmHg的跨壁压产生的那种的被动张力,则内周长设定为血管将具有的90%。
然后,将血管用Krebs-Henseleit缓冲液洗涤三次并使其平衡30分钟。然后通过双重暴露于高K+溶液(50mmol/l KCl)来测试收缩性。用Krebs-Henseleit缓冲液洗涤后,然后使用1nmol/l Arg-加压素使血管预收缩。在建立稳定收缩后,构建测试化合物的累积剂量响应曲线。由Arg-加压素诱导的稳定收缩定义为100%张力。松弛表示为张力百分比。
B-6.用于检测心血管作用的体内测定:麻醉大鼠中的血压测量(加压素'攻击'模型)
在氯胺酮/甲苯噻嗪/戊巴比妥注射麻醉下使用雄性Sprague-Dawley大鼠(250-350g体重)。将预填充有含肝素(500IU/ml)等渗氯化钠溶液的聚乙烯管(PE-50,Intramedic®)引入颈静脉和股静脉,且然后系住。在注射器的帮助下,经由一个静脉入口注射Arg-加压素(SIGMA);经由第二静脉入口施用测试物质。为了测定收缩血压,将压力导管(Millar SPR-320 2F)系在颈动脉中。将动脉导管连接至压力传感器,所述压力传感器将其信号馈送至配备有合适记录软件的记录计算机。在典型的实验中,实验动物用等渗氯化钠溶液中的限定量的Arg-加压素(30 ng/kg)以10-15分钟的间隔施用3-4次连续推注。当血压再次达到初始水平时,在合适的溶剂中,将测试物质作为推注施用,随后连续输注。此后,以限定的间隔(10-15分钟),再次施用与开始时相同量的Arg-加压素。基于血压值,确定测试物质抵消Arg-加压素的高血压作用的程度。对照动物仅接受溶剂而不是测试物质。
静脉内施用后,与溶剂对照相比,本发明化合物带来由Arg-加压素引起的血压升高的抑制。
B-7. 用于检测保护性肾脏作用的体内测定:啮齿动物中的急性缺血/再灌注损伤模型
从Taconic Biosciences获得6-8周龄的实验室培育的雄性C57B1/6J小鼠,从CharlesRiver获得雄性6-8周龄Sprague Dawley®大鼠。将大鼠和小鼠两者维持在标准实验室条件下,12小时光-暗循环,且随意获得正常食物和饮用水。对于缺血再灌注损伤模型,在每个对照和实验组中使用总共10-12只大鼠或小鼠。
用连续吸入的异氟烷麻醉动物。在对侧肾中缺血性手术前7天通过右侧腹切口进行右肾切除术。对于肾脏缺血,进行左侧腹切口。通过切开左肾蒂来暴露肾血管。非创伤性血管钳用于在缺血45分钟(大鼠)或25分钟(小鼠)期间停止血流(动脉和静脉)。通过移除钳来建立再灌注。用5.0聚丙烯缝合线封闭腹壁(肌肉层和皮肤)。应用Temgesic®(丁丙诺啡,0.025 mg/kg皮下)作为镇痛药。
在缺血后24小时处死前,将每只动物的尿液收集在代谢笼中过夜。处死时,在终末麻醉下获得血液样品。离心血液样品后,分离血清。经由临床生物化学分析仪(Pentra 400)测量血清肌酸酐和血清尿素两者。对于血清和尿肾损伤生物标志物(中性粒细胞明胶酶相关脂质运载蛋白[NGAL]、肾损伤分子-1[KIM-1]和骨桥蛋白)的评价,根据制造商的方案进行EL1SA。测量尿肌酸酐和白蛋白以确定白蛋白/肌酸酐比率。
从肾中分离总RNA。在处死时将左肾在液氮中快速冷冻。然后将肾匀浆化并获得RNA。总RNA被转录为cDNA。使用TaqMan实时PCR,在整个肾组织中分析肾脏NGAL、骨桥蛋白、KIM-1、Nephrin和Podocin mRNA表达。
通过单因素ANOVA用针对多重比较的Dunnett氏校正来分析组间差异。统计学显著性被定义为p <0.05。所有统计分析都使用GraphPad Prism 6完成。
B-8.用于检测心血管效应的体内测定:在麻醉的狗中的血液动力学研究
用戊巴比妥(30 mg/kg静脉内, Narcoren®, Merial, Germany)麻醉具有10kg至15 kg重量的雄性比格犬(Beagle, Marshall BioResources, USA),用于外科手术干预和血液动力学以及功能检查目的。泮库溴铵(Pancuronium Inresa, Inresa, Germany,2-4 mg/动物,静脉内)另外充当肌肉松弛药。对狗进行插管,并用氧气/环境空气混合物(30/70%)约2,5-4 L/min通气。使用来自GE Healthcare (Avance,Germany)的呼吸机进行通气,并使用二氧化碳分析仪(-Datex Ohmeda)进行监测。通过连续输注戊巴比妥(50µg/kg/min)维持麻醉;使用芬太尼作为止痛剂(10µg/kg/h)。
在准备性干预中,给狗安装心脏起搏器。在实验开始时,将来自Biotronik的心脏起搏器(Logos®,Germany)植入皮下皮囊中,并经由起搏器电极(Siello S60®,Biotronik, Germany)与心脏接触,所述起搏器电极利用透照法穿过颈外静脉延伸进入右心室中。
此后,去除入口,使狗自然地从麻醉中清醒。另外7天后,激活上述起搏器,并以220次搏动/分钟的频率刺激心脏。
在开始起搏器刺激之后28天,使用下述仪器实施实际药物测试实验:
●引入膀胱导管,用于舒缓膀胱和用于测量尿流量;
●将心电图(ECG)导联连接至四肢,用于ECG测量;
●将装满氯化钠溶液的鞘导引器(sheath introducer)引入股动脉中;将该管连接至压力传感器(Braun Melsungen, Melsungen , Germany),用于测量全身血压;
●经安装在颈动脉中的端口,引入Millar Tip导管(350 PC型, Millar Instruments,Houston, USA),用于测量心脏血液动力学;
●经由颈静脉将Swan-Ganz导管(CCOmbo 7.5F, Edwards, Irvine, USA)引入肺动脉中,用于测量心输出量、氧饱和度、肺动脉压和中心静脉压;
●将静脉导管放入头静脉中,用于输注戊巴比妥、用于液体更换和用于血液取样(确定物质的血浆水平或其它临床血液值);
●将静脉导管放入隐静脉中,用于输注芬太尼和用于施用物质;
●以增加的剂量输注加压素(Sigma),最高达4 mU/kg/min的剂量;然后用该剂量对药学物质进行测试。
如果必要的话,放大初级信号(ACQ 7700,Data Sciences Inc., Minneapolis,USA或Edwards-Vigilance-Monitor, Edwards, Irvine, USA),且随后将其输入Ponemah系统(Data Sciences Inc., Minneapolis, USA)用于评价。贯穿实验期间连续地记录信号,并通过所述软件进一步进行数字处理,并且经30秒计算平均值。
B-9.静脉内和口服施用后药代动力学参数的测定
在雄性C57b16-小鼠、雄性Wistar大鼠、雌性比格犬和雌性食蟹猴中测定根据本发明的化合物的药代动力学参数。在小鼠和大鼠的情况下通过物种特异性血浆/DMSO制剂、并且在狗和猴的情况下通过水/PEG400/乙醇制剂进行静脉内施用。在所有物种中,基于水/PEG400/乙醇制剂,经由管饲法进行溶解的物质的口服施用。通过在物质施用前将硅氧烷导管插入右侧颈外静脉内来简化从大鼠取血。在实验前至少一天用异氟烷麻醉和施用镇痛药(阿托品/Rimadyl(3/1)0.1 ml皮下)来实施手术。在时间窗口内采血(通常至少10个时间点),所述时间窗口包括物质施用后至少24小时至最多72小时的终末时间点。当采血时,将其通入肝素化管中。然后通过离心获得血浆,并任选地储存在-20℃,直至进一步处理。
将内标(其也可为化学上不相关的物质)加入根据本发明的化合物的样品、校准样品和限定剂(qualifiers)中,并且然后通过过量的乙腈进行蛋白质沉淀。加入与LC条件匹配的缓冲溶液,且随后涡旋,然后以1000 g离心。使用C18或联苯反相柱和可变流动相混合物通过LC-MS/MS分析上清液。经由来自特定选择的离子监测实验的提取离子色谱图的峰高或面积来定量物质。
确定的血浆浓度/时间图用于使用经验证的药代动力学计算程序计算药代动力学参数,诸如AUC(曲线下面积)、Cmax(最大浓度)、t1/2(终末半衰期)、F(生物利用度)、MRT(平均停留时间)和CL(清除率)。
由于物质定量在血浆中进行,有必要确定物质的血液/血浆分布,以便能够相应地调整药代动力学参数。为了该目的,将限定量的物质在所讨论物种的肝素化全血中在摇滚混合物(rocking roller mixture)中温育20分钟。在以1000 g离心后,测量(通过LC-MS/MS;参见上文)并通过计算全血浓度相比于血浆浓度的比率(C血液/C血浆值)确定血浆浓度。
B-10.代谢研究
为了确定根据本发明的化合物的代谢概况,将它们与重组人细胞色素P450(CYP)酶、来自各种动物物种(例如大鼠、狗、猴)以及也为人来源的肝微粒体或原代新鲜肝细胞温育,以便获得并比较关于基本上完全肝脏I期和II期代谢以及关于参与代谢的酶的信息。
将根据本发明的化合物以约0.1-10μM的浓度温育。为此,制备具有在乙腈中0.01-1 mM浓度的根据本发明的化合物的储备溶液,然后用1:100稀释度移液至温育混合物中。将肝微粒体和重组酶在37℃在50 mM磷酸钾缓冲液pH7.4中温育,所述缓冲液含有和不含有由1 mM NADP+、10 mM葡萄糖-6-磷酸和1单位葡萄糖6-磷酸脱氢酶组成的烟酰胺腺嘌呤二核苷酸磷酸(NADPH)-生成系统。同样在37℃,将原代肝细胞在Williams E培养基中悬浮温育。在0-4小时的温育时间后,用乙腈(终浓度约30%)终止温育混合物,并以约15 000 x g离心出蛋白。将因此终止的样品直接分析或储存在-20℃直至分析。
通过高效液相色谱用紫外和质谱检测(HPLC-UV-MS/MS)进行分析。为此,用合适的C18反相柱以及乙腈和10mM甲酸铵水溶液或0.05%甲酸的可变流动相混合物,将温育样品的上清液进行色谱。UV色谱图结合质谱数据用于代谢物的鉴定、结构解析和定量估计,以及用于温育混合物中根据本发明的化合物的定量代谢评价。
B-11.Caco-2渗透性测定
可以借助于Caco-2细胞系(用于胃肠屏障处的渗透性预测的确立体外模型)确定测试物质的渗透性(Artursson, P.和Karlsson, J. (1991). Correlation between oraldrug absorption in humans and apparent drug permeability coefficients inhuman intestinal epithelial (Caco-2) cells. Biochem. Biophys.175 (3), 880-885)。将CaCo-2细胞(ACC No. 169, DSMZ, Deutsche Sammlung von Mikroorganismenund Zellkulturen, Braunschweig, Germany)接种于具有插入物的24孔板中并培养14至16天。对于渗透性研究,将测试物质溶解在DMSO中并用转运缓冲液(Hanks缓冲盐溶液,Gibco/Invitrogen,具有19.9 mM葡萄糖和9.8 mM HEPES)稀释至最终测试浓度。为了确定测试物质从顶端侧至基底侧的渗透性(PappA-B),将包含测试物质的溶液置于Caco-2细胞单层的顶端侧,并且将转运缓冲液置于基底侧。为了确定测试物质从基底侧至顶端侧的渗透性(PappB-A),将包含测试物质的溶液置于Caco-2细胞单层的基底侧,并且将转运缓冲液置于顶端侧。在实验开始时,从各自的供体隔室取样以计算之后的质量平衡。在37℃温育2小时后,从两个隔室中取样。通过LC-MS/MS分析样品,并计算表观渗透系数(Papp)。对于每个细胞单层,确定荧光黄的渗透性以确保细胞层完整性。在每个测试运行中,阿替洛尔(低渗透性的标志物)和柳氮磺胺吡啶(活性排泄的标志物)的渗透性也被确定为质量对照。
C)药物组合物的工作实施例
根据本发明的物质可以如下转化为药物制剂:
片剂:
组成:
100 mg实施例1的化合物、50 mg乳糖(一水合物)、50 mg玉米淀粉、10 mg聚乙烯吡咯烷酮(PVP 25)(来自BASF,Germany)和2 mg硬脂酸镁。
片剂重量212 mg,直径8 mm,曲率半径12 mm。
生产:
将实施例1的化合物、乳糖和淀粉的混合物用PVP于水中的5%强度溶液(m/m)造粒。干燥后,将颗粒与硬脂酸镁混合5分钟。将该混合物在常规压片机中压制(对于片剂形式,参见上文)。
口服悬浮液:
组成:
1000 mg实施例1的化合物、1000 mg乙醇(96%)、400 mg Rhodigel(黄原胶)(来自FMC,USA)和99 g水。
10 ml口服悬浮液相当于单剂量的100 mg的本发明化合物。
生产:
将Rhodigel悬浮于乙醇中,并将实施例1的化合物加入悬浮液中。在搅拌的同时加入水。将混合物搅拌约6小时,直至Rhodigel的溶胀完全。
无菌静脉内溶液:
将根据本发明的化合物以低于饱和溶解度的浓度溶解于生理学上可接受的溶剂(例如等渗氯化钠溶液、5%葡萄糖溶液和/或30% PEG 400溶液)中。将溶液通过过滤灭菌并填充入无菌和无热原的注射容器中。
尽管已经参考具体实施方式公开了本发明,但是显而易见的是,在不脱离本发明的真实精神和范围的情况下,本领域的其它技术人员可设计本发明的其它实施方式和变型。权利要求旨在被解释为包括所有这样的实施方式和等同变型。
Claims (11)
1.通式(I)的化合物
其中
R1代表下式的基团:
其中
#1代表与氮原子的连接点,
Ar代表下式的基团:
其中
#2代表与氮原子的连接点,
R2A代表选自以下的基团:氯原子、溴原子、三氟甲基、三氟甲氧基、乙氧基羰基和-C(=O)NH2,
R2B代表选自以下的基团:氯原子、三氟甲基和乙氧基羰基,
或其药学上可接受的盐、水合物和/或溶剂化物。
2.根据权利要求1所述的通式(I)的化合物,其中
R1代表下式的基团:
其中
#1代表与氮原子的连接点,
Ar代表下式的基团:
其中
#2代表与氮原子的连接点,
R2A代表选自以下的基团:氯原子、溴原子、三氟甲基、三氟甲氧基、乙氧基羰基和-C(=O)NH2,
或其药学上可接受的盐、水合物和/或溶剂化物。
3.根据权利要求1或2所述的通式(I)的化合物,其中
R1代表下式的基团:
其中
#1代表与氮原子的连接点,
Ar代表下式的基团:
其中
#2代表与氮原子的连接点,
R2A代表选自以下的基团:氯原子、三氟甲基和三氟甲氧基,
或其药学上可接受的盐、水合物和/或溶剂化物。
4.制备根据权利要求1至3中任一项的通式(I)的化合物的方法,所述方法包括以下步骤:
[A] 使式(II)的中间体化合物:
其中,R1如对于根据权利要求1至3中任一项的通式(I)的化合物所定义,
R3代表(C1-C4)-烷基,特别是甲基,
在第一步中在碱和任选地铜盐存在的情况下,与通式(III)的化合物反应:
其中
R4代表(C1-C4)-烷基,特别是甲基,
以产生中间体化合物,然后在碱存在的情况下在第二步中,使所述中间体化合物与通式(IV)的肼化合物或其各自的盐反应
其中Ar如对于根据权利要求1至3中任一项的通式(I)的化合物所定义,
由此产生通式(V)的化合物:
其中R1和Ar如对于根据权利要求1至3中任一项的通式(I)的化合物所定义,且
R4代表(C1-C4)-烷基,特别是甲基,
随后为后续步骤:
[B] 使步骤[A]中获得的式(V)的化合物与氨反应,由此产生通式(I)的化合物:
其中R1和Ar如对于根据权利要求1至3中任一项的通式(I)的化合物所定义,
任选地随后为步骤:
[C] 使用已知的氧化方法,将通式(I-A)的醇:
其中Ar如对于根据权利要求1至3中任一项的通式(I)的化合物所定义,
转化为通式(I-B)的酮:
其中Ar如对于根据权利要求1至3中任一项的通式(I)的化合物所定义,
在适当的情况下,每一[A]、[B]和[C]任选地随后为:(i)将因此获得的式(I)的化合物分离为它们各自的对映异构体,和/或(ii)通过用相应的溶剂和/或酸或碱处理,将式(I)的化合物转化为它们各自的水合物、溶剂化物、盐和/或盐的水合物或溶剂化物。
5.如权利要求1至3中任一项中所定义的所用化合物,其用于治疗和/或预防疾病。
6.如权利要求1至3中任一项中所定义的化合物,其用于治疗和/或预防下列的方法:急性和慢性肾疾病,包括糖尿病肾病;急性和慢性心力衰竭;先兆子痫;外周动脉疾病(PAD);冠状动脉微血管功能障碍(CMD);雷诺综合征和痛经。
7.如权利要求1至3中任一项中所定义的化合物在制备用于治疗和/或预防下列的药物组合物中的用途:急性和慢性肾疾病,包括糖尿病肾病;急性和慢性心力衰竭;先兆子痫;外周动脉疾病(PAD);冠状动脉微血管功能障碍(CMD);雷诺综合征和痛经。
8.药物组合物,其包含:如权利要求1至3中任一项中所定义的化合物,和一种或多种药学上可接受的赋形剂。
9.权利要求8的药物组合物,其包含:一种或多种第一活性成分,特别是根据权利要求1至4中任一项所述的通式(I)的化合物;和一种或多种另外的活性成分,特别是一种或多种选自以下的额外的治疗剂:利尿剂、血管紧张素AII拮抗剂、ACE抑制剂、β-受体阻滞剂、盐皮质激素受体拮抗剂、抗糖尿病药、有机硝酸盐和NO供体、可溶性鸟苷酸环化酶(sGC)的活化剂和刺激剂、抗炎剂、免疫抑制剂、磷酸盐结合剂和/或调节维生素D代谢的化合物。
10.如权利要求8或9中所定义的药物组合物,其用于治疗和/或预防:急性和慢性肾疾病,包括糖尿病肾病;急性和慢性心力衰竭;先兆子痫;外周动脉疾病(PAD);冠状动脉微血管功能障碍(CMD);雷诺综合征和痛经。
11.用于治疗和/或预防人或其它哺乳动物中的下列的方法:急性和慢性肾疾病,包括糖尿病肾病;急性和慢性心力衰竭;先兆子痫;外周动脉疾病(PAD);冠状动脉微血管功能障碍(CMD);雷诺综合征和痛经;所述方法包括向有需要的人或其它哺乳动物施用治疗有效量的一种或多种如权利要求1至3中任一项中所定义的化合物、或如权利要求8至10中任一项中所定义的药物组合物。
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JP6911052B2 (ja) * | 2016-05-03 | 2021-07-28 | バイエル ファーマ アクチエンゲゼルシャフト | オキソアルキル置換フェニルトリアゾール誘導体およびその使用 |
UY37222A (es) * | 2016-05-03 | 2017-11-30 | Bayer Pharma AG | PROCEDIMIENTO PARA LA PREPARACIÓN DE DERIVADOS DE 1-FENILO-1,2,4-TRIAZOL SUSTITUIDOS POR 5-HIdroxIalQUILO |
US9988367B2 (en) * | 2016-05-03 | 2018-06-05 | Bayer Pharma Aktiengesellschaft | Amide-substituted pyridinyltriazole derivatives and uses thereof |
EP3458443B1 (en) | 2016-05-03 | 2020-08-19 | Bayer Pharma Aktiengesellschaft | Aromatic sulfonamide derivatives |
US10893352B2 (en) * | 2016-08-24 | 2021-01-12 | Matthew Hawkes | Programmable interactive stereo headphones with tap functionality and network connectivity |
WO2018163204A1 (en) * | 2017-03-08 | 2018-09-13 | Yogee's Bioinnovations Private Limited | Cathepsin-d and angiogenesis inhibitors and compositions thereof for treating breast cancer |
CA3072427C (en) | 2017-08-08 | 2023-12-05 | Fresenius Medical Care Holdings, Inc. | Systems and methods for treating and estimating progression of chronic kidney disease |
US11149023B2 (en) | 2017-10-24 | 2021-10-19 | Bayer Pharma Aktiengesellschaft | Substituted triazole derivatives and uses thereof |
EP3700899A1 (en) | 2017-10-24 | 2020-09-02 | Bayer Pharma Aktiengesellschaft | Substituted triazole derivatives and uses thereof |
US11331314B2 (en) | 2017-10-24 | 2022-05-17 | Bayer Pharma Aktiengesellschaft | Amine substituted triazole derivatives and uses thereof |
CA3084411A1 (en) | 2017-10-24 | 2019-05-02 | Bayer Pharma Aktiengesellschaft | Substituted triazole derivatives and uses thereof |
US11298367B2 (en) | 2017-10-24 | 2022-04-12 | Bayer Aktiengesellschaft | Prodrugs of substituted triazole derivatives and uses thereof |
WO2019081291A1 (en) | 2017-10-24 | 2019-05-02 | Bayer Aktiengesellschaft | PRODRUGS OF SUBSTITUTED TRIAZOLE DERIVATIVES AND USES THEREOF |
US11173151B2 (en) | 2017-10-24 | 2021-11-16 | Bayer Aktiengesellschaft | Substituted triazole derivatives and uses thereof |
TW201938171A (zh) | 2017-12-15 | 2019-10-01 | 匈牙利商羅特格登公司 | 作為血管升壓素V1a受體拮抗劑之三環化合物 |
HU231206B1 (hu) | 2017-12-15 | 2021-10-28 | Richter Gedeon Nyrt. | Triazolobenzazepinek |
US11020351B2 (en) * | 2018-03-26 | 2021-06-01 | Hetero Labs Limited | Stable bilayer tablet compositions |
WO2019199273A1 (en) * | 2018-04-10 | 2019-10-17 | Hewlett-Packard Development Company, L.P. | Preheat dyed build materials with preheating sources |
WO2021259852A1 (en) | 2020-06-25 | 2021-12-30 | Bayer Aktiengesellschaft | Process for preparing 5-(alkoxycarbonyl)-and 5-(carboxamide)-1-aryl-1,2,4-triazole derivatives |
WO2022112213A1 (en) | 2020-11-30 | 2022-06-02 | Bayer Aktiengesellschaft | Crystalline forms of 3-[[3-(4-chlorophenyl)-5-oxo-4-((2s)-3,3,3-trifluoro- 2-hydroxypropyl)-4,5-dihydro-1h-1,2,4-triazol-1-yl]methyl]-1-[3- (trifluoromethyl)pyridin-2-yl]-1h-1,2,4-triazole-5-carboxamide |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100854872B1 (ko) * | 2003-12-22 | 2008-08-28 | 화이자 인코포레이티드 | 바소프레신 길항제로서의 트리아졸 유도체 |
CN103119028A (zh) * | 2010-10-01 | 2013-05-22 | 大正制药株式会社 | 1,2,4-三唑酮衍生物 |
Family Cites Families (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3042466A1 (de) | 1980-11-11 | 1982-06-16 | A. Nattermann & Cie GmbH, 5000 Köln | N-substituierte (omega) -(2-oxo-4-imidazolin-l-yl)-alkansaeure-derivate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate |
US5468448A (en) | 1989-12-28 | 1995-11-21 | Ciba-Geigy Corporation | Peroxide disinfection method and devices therefor |
DE4107857A1 (de) | 1991-03-12 | 1992-09-17 | Thomae Gmbh Dr K | Cyclische harnstoffderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
WO1992020662A1 (en) | 1991-05-10 | 1992-11-26 | Merck & Co., Inc. | Acidic aralkyl triazole derivatives active as angiotensin ii antagonists |
WO1993017681A1 (en) | 1992-03-02 | 1993-09-16 | Abbott Laboratories | Angiotensin ii receptor antagonists |
SK94393A3 (en) | 1992-09-11 | 1994-08-10 | Thomae Gmbh Dr K | Cyclic derivatives of urea, process for their production and their pharmaceutical agents with the content of those |
GB9301192D0 (en) | 1993-06-09 | 1993-06-09 | Trott Francis W | Flower shaped mechanised table |
US6844005B2 (en) | 2002-02-25 | 2005-01-18 | Trutek Corp | Electrostatically charged nasal application product with increased strength |
FR2708608B1 (fr) | 1993-07-30 | 1995-10-27 | Sanofi Sa | Dérivés de N-sulfonylbenzimidazolone, leur préparation, les compositions pharmaceutiques en contenant. |
US5897858A (en) | 1994-02-03 | 1999-04-27 | Schering-Plough Healthcare Products, Inc. | Nasal spray compositions exhibiting increased retention in the nasal cavity |
US20010020100A1 (en) | 1994-06-14 | 2001-09-06 | G.D. Searle & Co. | N-substituted-1, 2, 4-triazolone compounds for treatment of cardiovascular disorders |
AU741769B2 (en) | 1997-12-17 | 2001-12-06 | Merck Sharp & Dohme Corp. | Integrin receptor antagonists |
DE19816882A1 (de) | 1998-04-17 | 1999-10-21 | Boehringer Ingelheim Pharma | Triazolone mit neuroprotektiver Wirkung |
JP2002521373A (ja) | 1998-07-24 | 2002-07-16 | バイエル アクチェンゲゼルシャフト | 置換されたベンゾイルシクロヘキサンジオン類 |
DE19834047A1 (de) | 1998-07-29 | 2000-02-03 | Bayer Ag | Substituierte Pyrazolderivate |
DE19834044A1 (de) | 1998-07-29 | 2000-02-03 | Bayer Ag | Neue substituierte Pyrazolderivate |
DE19914140A1 (de) | 1999-03-27 | 2000-09-28 | Bayer Ag | Substituierte Benzoylpyrazole |
SK13532001A3 (sk) | 1999-04-01 | 2003-02-04 | Pfizer Products Inc. | Aminopiridíny ako inhibítory sorbitoldehydrogenázy |
DE19920791A1 (de) | 1999-05-06 | 2000-11-09 | Bayer Ag | Substituierte Benzoylisoxazole |
DE19921424A1 (de) | 1999-05-08 | 2000-11-09 | Bayer Ag | Substituierte Benzoylketone |
DE19929348A1 (de) | 1999-06-26 | 2000-12-28 | Bayer Ag | Verfahren zur Herstellung von 2-Heterocyclylmethyl-benzoesäurederivaten |
US6531142B1 (en) | 1999-08-18 | 2003-03-11 | The Procter & Gamble Company | Stable, electrostatically sprayable topical compositions |
DE19943635A1 (de) | 1999-09-13 | 2001-03-15 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
DE19943636A1 (de) | 1999-09-13 | 2001-03-15 | Bayer Ag | Neuartige Dicarbonsäurederivate mit pharmazeutischen Eigenschaften |
DE19943634A1 (de) | 1999-09-13 | 2001-04-12 | Bayer Ag | Neuartige Dicarbonsäurederivate mit pharmazeutischen Eigenschaften |
DE19943639A1 (de) | 1999-09-13 | 2001-03-15 | Bayer Ag | Dicarbonsäurederivate mit neuartigen pharmazeutischen Eigenschaften |
AR027575A1 (es) | 2000-03-06 | 2003-04-02 | Bayer Ag | Benzoilciclohexenonas substituidas |
US7080644B2 (en) | 2000-06-28 | 2006-07-25 | Microdose Technologies, Inc. | Packaging and delivery of pharmaceuticals and drugs |
AR031176A1 (es) | 2000-11-22 | 2003-09-10 | Bayer Ag | Nuevos derivados de pirazolpiridina sustituidos con piridina |
WO2002066447A1 (en) | 2001-02-21 | 2002-08-29 | Ono Pharmaceutical Co., Ltd. | 4h-1,2,4-triazole-3(2h)-thione deratives as sphingomyelinase inhibitors |
DE10110749A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituierte Aminodicarbonsäurederivate |
DE10110750A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
US20040071757A1 (en) | 2001-11-20 | 2004-04-15 | David Rolf | Inhalation antiviral patch |
DE10220570A1 (de) | 2002-05-08 | 2003-11-20 | Bayer Ag | Carbamat-substituierte Pyrazolopyridine |
JP4673295B2 (ja) | 2003-03-14 | 2011-04-20 | メルク・シャープ・エンド・ドーム・コーポレイション | 単環式アニリドスピロヒダントインcgrp受容体拮抗物質 |
EP1689252A2 (en) | 2003-06-27 | 2006-08-16 | Berglin Corporation of Washington | Machine for precision low stress coring and slicing of apples and other soft-cored or pitted fruits |
WO2005086836A2 (en) | 2004-03-08 | 2005-09-22 | Wyeth | Ion channel modulators |
CN1933832A (zh) | 2004-03-08 | 2007-03-21 | 惠氏公司 | 离子通道调节剂 |
WO2005105779A1 (en) | 2004-04-28 | 2005-11-10 | Pfizer Limited | 3-heterocyclyl-4-phenyl-triazole derivatives as inhibitors of the vasopressin v1a receptor |
US7642275B2 (en) | 2004-12-16 | 2010-01-05 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
WO2006117657A1 (en) | 2005-05-03 | 2006-11-09 | Ranbaxy Laboratories Limited | Triazolone derivatives as anti-inflammatory agents |
DE102006024024A1 (de) | 2006-05-23 | 2007-11-29 | Bayer Healthcare Aktiengesellschaft | Substituierte Arylimidazolone und -triazolone sowie ihre Verwendung |
DE102008060967A1 (de) | 2008-12-06 | 2010-06-10 | Bayer Schering Pharma Aktiengesellschaft | Substituierte Phenylsulfonyltriazolone und ihre Verwendung |
DE102010001064A1 (de) | 2009-03-18 | 2010-09-23 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 2-Acetamido-5-Aryl-1,2,4-triazolone und deren Verwendung |
DE102009013642A1 (de) | 2009-03-18 | 2010-09-23 | Bayer Schering Pharma Aktiengesellschaft | Substituierte Phenylalaninderivate und deren Verwendung |
DE102009028929A1 (de) | 2009-08-27 | 2011-07-07 | Bayer Schering Pharma Aktiengesellschaft, 13353 | Heterocyclisch-substituierte 2-Acetamido-5-Aryl-1,2,4-triazolone und deren Verwendung |
PE20130683A1 (es) * | 2010-02-27 | 2013-06-20 | Bayer Ip Gmbh | Ariltriazolonas ligadas a bisarilo y su uso |
DE102010021637A1 (de) | 2010-05-26 | 2011-12-01 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung |
MX2013000198A (es) | 2010-07-09 | 2013-01-28 | Bayer Ip Gmbh | Pirimidinadas y triazinas condensadas y su uso. |
DE102010040187A1 (de) | 2010-09-02 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Substituierte N-Phenethyl-triazolonacetamide und ihre Verwendung |
DE102010040233A1 (de) | 2010-09-03 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Bicyclische Aza-Heterocyclen und ihre Verwendung |
DE102010043379A1 (de) | 2010-11-04 | 2012-05-10 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 6-Fluor-1H-Pyrazolo[4,3-b]pyridine und ihre Verwendung |
EP2675440B1 (en) | 2011-02-14 | 2020-03-25 | Merck Sharp & Dohme Corp. | Cathepsin cysteine protease inhibitors |
US9604976B2 (en) | 2012-03-22 | 2017-03-28 | Spero Gyrase, Inc. | Antibacterial compounds |
SG11201703199UA (en) | 2014-11-03 | 2017-05-30 | Bayer Pharma AG | Hydroxyalkyl-substituted phenyltriazole derivatives and uses thereof |
UY37222A (es) * | 2016-05-03 | 2017-11-30 | Bayer Pharma AG | PROCEDIMIENTO PARA LA PREPARACIÓN DE DERIVADOS DE 1-FENILO-1,2,4-TRIAZOL SUSTITUIDOS POR 5-HIdroxIalQUILO |
US9988367B2 (en) * | 2016-05-03 | 2018-06-05 | Bayer Pharma Aktiengesellschaft | Amide-substituted pyridinyltriazole derivatives and uses thereof |
JP6911052B2 (ja) * | 2016-05-03 | 2021-07-28 | バイエル ファーマ アクチエンゲゼルシャフト | オキソアルキル置換フェニルトリアゾール誘導体およびその使用 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100854872B1 (ko) * | 2003-12-22 | 2008-08-28 | 화이자 인코포레이티드 | 바소프레신 길항제로서의 트리아졸 유도체 |
CN103119028A (zh) * | 2010-10-01 | 2013-05-22 | 大正制药株式会社 | 1,2,4-三唑酮衍生物 |
Non-Patent Citations (1)
Title |
---|
DAVID M. BEAL等: "《Preparation of triazolobenzodiazepine derivatives as Vasopressin V1a antagonists》", 《TETRAHEDRON LETTERS》 * |
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