CN111225921A - 被取代的三唑衍生物的前药及其用途 - Google Patents
被取代的三唑衍生物的前药及其用途 Download PDFInfo
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- CN111225921A CN111225921A CN201880068846.5A CN201880068846A CN111225921A CN 111225921 A CN111225921 A CN 111225921A CN 201880068846 A CN201880068846 A CN 201880068846A CN 111225921 A CN111225921 A CN 111225921A
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- triazol
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Abstract
本发明涉及3‑({3‑(4‑氯苯基)‑5‑氧代‑4‑[(2S)‑3,3,3‑三氟‑2‑羟丙基]‑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、3‑({3‑(4‑氯苯基)‑5‑氧代‑4‑[(2S)‑3,3,3‑三氟‑2‑羟丙基]‑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‑甲酰胺和3‑({3‑(4‑氯苯基)‑5‑氧代‑4‑[(2S)‑3,3,3‑三氟‑2‑羟丙基]‑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‑甲酰胺的前药,涉及制备这样的化合物的方法,涉及含有这样的化合物的药物组合物,和涉及这样的化合物或组合物用于治疗和/或预防疾病、具体地用于治疗和/或预防肾脏和心血管疾病的用途。
Description
本发明涉及3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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、3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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-甲酰胺和3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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-甲酰胺的前药,涉及制备这样的化合物的方法,涉及含有这样的化合物的药物组合物,和涉及这样的化合物或组合物用于治疗和/或预防疾病、具体地用于治疗和/或预防肾脏和心血管疾病的用途。
前药是活性成分的衍生物,其在释放出实际的活性成分之前在一个或多个阶段进行体内酶促的和/或化学的生物转化。通常使用前药残基以改善基础活性成分的特性的概况(profile)[P. Ettmayer等人, J. Med. Chem. 47, 2393 (2004)]。为了获得效果的最佳特性,在这方面有必要设计前药残基以及期望的释放机理以使其与各个活性成分、适应症、作用部位和施用途径非常准确地相符。大量药物作为前药施用,其与基础活性成分相比表现出改善的生物利用度,这例如通过改善理化特性(特别是溶解度)、主动或被动吸收特性或组织特异性分布来实现。从前药的广泛文献中可以提及的一个例子是:H. Bundgaard(编), Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities, Elsevier Science Publishers B.V., 1985。
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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(实施例4A)、3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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(实施例6A)和3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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(实施例8A)是V1a受体的强效和选择性拮抗剂,如在WO 2017/191102-A1 (实施例1和2)和WO 2017/191107-A1 (实施例1)中公开的。
加压素是一种主要调节水体内稳态和血管紧张度的神经激素。它由第三脑室(下丘脑)的壁中的视上核(Nucleus supraopticus)和室旁核(N. paraventricularis)中的专门内分泌神经元产生,并从那里沿神经突转运到垂体的后叶(神经垂体)。在那里,该激素响应于不同的生理学和病理生理学刺激而释放到血流中。神经激素调节紊乱主要表现为交感神经张力升高和肾素-血管紧张素-醛固酮系统(RAAS)的不适当活化。尽管一方面通过β-受体阻滞剂、另一方面通过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理学治疗的一个固有部分,但是加压素分泌的不适当升高目前仍然不是可适当治疗的。
加压素主要通过与三种受体结合而发挥它的作用,所述三种受体被分类为V1a、V1b和V2受体且属于G蛋白偶联受体家族。
V2受体位于肾中的远端管状上皮和集合小管的上皮中。它们的活化使得这些上皮可透过水。该现象是由于在上皮细胞的腔膜中的嵌入了水通道蛋白(特殊的水通道)。结果,加压素对V2受体的作用的药理学抑制会导致增加的尿排泄。因此,具有V2拮抗活性的药物似乎特别适合用于治疗与身体的水过载有关的所有疾病状态。
V1b受体(也称作V3受体)主要在中枢神经系统中是可检测的。与促肾上腺皮质素释放激素(CRH)一起,加压素经由V1b受体调节促肾上腺皮质激素(ACTH)的基础的和应激诱导的分泌。
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受体的激活引起细胞内钙释放和相应的血管收缩。因此,VSMC V1a受体的刺激引起血管阻力增加和心脏后负荷增加。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重塑,包括纤维化。具有心脏特异性的V1a受体过表达的小鼠会出现心脏肥大,从而导致扩张和左心室功能障碍,这提示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脉管系统中表达,在那里它介导肾血管的血管收缩并影响总肾血流量。因此,V1a受体的激活可以减少肾髓质血流量,从而引起进一步的病理过程如组织缺氧、氧减少和相应的肾小管运输过程的能量供给以及肾小球系膜的和致密斑细胞的直接损伤。已经证实,肾小球系膜的V1a受体激活会介导TGFβ信号传递并引起胶原IV的产生增加。虽然此信号传递促成肾脏中细胞外基质的积累和重塑,但是据信在心脏细胞中会发生类似的信号传递途径,尤其是在心肌梗塞后,这强调了V1a受体在响应于病理生理学升高的加压素水平的肥大性和纤维化过程发展中的中心作用[Wasilewski MA, Myers VD,Recchia FA, Feldman AM, 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,可以想到与血管疾病,如周围动脉疾病(PAD),包括跛行和临界性肢体缺血以及冠状动脉微血管功能障碍(CMD)的联系。
除此之外,V1a受体还在人血小板上和肝脏中表达。尽管加压素在高浓度离体下通过V1a受体诱导人血小板的聚集,但血小板V1a受体的含义尚未完全理解。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,其利用了内源性地表达V1a受体的人组织[Thibonnier M, Roberts JM, J Clin Invest.; 76:1857-1864,(1985)]。
加压素通过肝V1a受体的激活而刺激糖原异生和糖原分解。动物研究已经证实,加压素会损害葡萄糖耐量,而这可以被V1a受体拮抗剂抑制,从而提供了加压素受体V1a与糖尿病的联系。[Taveau C, Chollet C, Waeckel L, Desposito D, Bichet DG, ArthusMF, Magnan C, Philippe E, Paradis V, Foufelle F, Hainault I, Enhorning S,Velho G, Roussel R, Bankir L, Melander O, Bouby N. Vasopressin and hydrationplay a major role in the development of glucose intolerance and hepaticsteatosis in obese rats. Diabetologia, 58(5), 1081-1090, (2015)]。加压素被证明有助于动物模型中蛋白尿的发展和糖尿病诱导的肾病,这与人类的流行病学发现相一致。
最近发现,加压素似乎也在先兆子痫的发展中起着原因作用。在小鼠妊娠期间长期输注加压素足以诱导所有与人先兆子痫相关的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)]。
加压素水平可以在月经期间具有痛经(一种妇科病症,以周期性痛性痉挛性骨盆痛为特征)的女性中升高,这似乎会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(瑞考伐坦/SR-49059)可以减少由加压素引起的子宫内收缩。
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用于治疗几种心血管疾病。具体地,选择性地抑制加压素对V1a受体的作用的药剂为否则血量正常的患者(即不适合通过例如例如高剂量的袢利尿剂或V2拮抗剂来减轻充血的那些患者,且其中通过V2抑制引起的水肿可能是不希望的)的治疗提供了特别理想的特性。
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-基衍生物作为加压素V1a受体拮抗剂起作用,其可用于治疗妇科病症,尤其是月经不调诸如痛经。
在WO 2011/104322-A1中,特定的一组双芳基键合的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,已经被公开为加压素V2和/或V1a受体的拮抗剂,可用于治疗和/或预防心血管疾病。但是,所述的化合物没有表现出对V1a受体的足够选择性,并且大多表现出对加压素V1a和V2受体的联合活性。但是,如上所述,对V1a受体的高亲和力以及选择性是治疗不希望减轻充血,并且可能导致体液稳态失调,包括在否则血量正常的个体中下降的血浆重量摩尔渗透压浓度的疾病状况的理想先决条件。
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,其作为加压素V1a和V2受体的有效拮抗剂起作用,并且另外在口服施用后表现出显著增强的体内促排水效能。所述化合物被描述为可用于治疗和/或预防心血管疾病和肾疾病。但是,如上所述,对V1a受体的高亲和力以及选择性是治疗不希望减轻充血,并且可能导致体液稳态失调,包括在否则血量正常的个体中下降的血浆重量摩尔渗透压浓度的疾病状况的理想先决条件。
在WO 2017/191107-A1和WO 2017/191102-A1中已经描述了某些5-(甲酰胺)-1-苯基-1,2,4-三唑衍生物,以及在WO 2017/191114-A1中已经描述了特定的5-(羟基烷基)-1-杂芳基-1,2,4-三唑衍生物,它们代表V1a受体的强效和选择性拮抗剂,并且特别适用于在没有遭受流体超负荷且因此不应当减轻充血的对象中治疗和/或预防肾脏和心血管疾病。
在WO 2017/191105-A1、WO 2017/191112-A1、WO 2017/191115-A1和WO 2018/073144-A1中,其它的新颖的5-(甲酰胺)-取代的、5-(氟代烷基)-取代的和3-(羟基烷基)-取代的1,2,4-三唑衍生物已经被公开为加压素V2和/或V1a受体的拮抗剂。
对V1a受体具有高选择性的活性谱具有引起不希望的脱靶相关副作用的低可能性,并且还有助于减少实现和维持期望的治疗效果所需的物质的量,因此限制在可能已经处于高风险的患者(例如,在急性或慢性心脏病和肾脏疾病中)的治疗期间产生不可接受的副作用和/或不希望的药物-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时,可以看到根据本发明要解决的一个技术问题。本发明的另一个目的是鉴定并提供相对于加压素V1a受体具有高亲和力和选择性的新化合物。所述化合物意图避免通过V2抑制诱导利水作用(aquaresis)。与现有技术中已知的化合物相比,所述化合物还旨在具有相似或改善的治疗特性,例如就其体内特性,例如它们的药代动力学和药效动力学特性和/或它们的代谢特性和/或它们的剂量-活性关系而言。
但是,实施例4A、实施例6A和实施例8A的化合物(它们是V1a受体的强效和选择性拮抗剂)具有有限的在水和生理介质中的溶解度,例如使实施例4A、实施例6A和实施例8A的化合物难以静脉内施用。此外,应提高所述化合物在口服施用以后所述化合物的生物利用度。因此,本发明的另一个目的是鉴定实施例4A、实施例6A和实施例8A的化合物的衍生物或前药,它们在所述介质中具有提高的溶解度并且同时允许实施例4A、实施例6A和实施例8A的化合物在施用后在患者体内的受控释放,和/或在口服施用后具有良好的生物利用度。
令人惊奇地,现在已经发现,实施例4A、实施例6A和实施例8A的化合物的某些前药具有该特定特征,并且使得本发明的化合物可用于治疗和/或预防与V1a受体激活相关的疾病。本发明的化合物特别用于在没有遭受流体超负荷且因此不应当减轻充血的对象中治疗和/或预防肾脏和心血管疾病。
本发明提供了通式(I)的化合物及其药学上可接受的盐、其溶剂合物和其盐的溶剂合物
其中
R1代表下式
其中
#代表与1,2,4-三唑基-环的连接点。
在本文中提及的术语具有下述含义:
当用于本说明书中时,术语“包含”包括“由……组成”。
在代表R1的基团的式中,用#标记的线的端点不代表碳原子或CH2基团,而是与R1所连接的原子的键的一部分。
通式(I)的化合物可能作为同位素变体存在。因此,本发明包括通式(I)的化合物的一种或多种同位素变体,尤其是含氘的通式(I)的化合物。
化合物或试剂的术语“同位素变体”定义为表现出构成这样的化合物的一种或多种同位素的非天然比例的化合物。
术语“通式(I)的化合物的同位素变体”定义为表现出构成这样的化合物的一种或多种同位素的非天然比例的通式(I)的化合物。
表述“非天然比例”是指高于其天然丰度的这样的同位素的比例。在“IsotopicCompositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998中描述了要在此背景下应用的同位素的天然丰度。
这样的同位素的例子包括氢、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。
关于本文所述病症的治疗和/或预防,通式(I)的化合物的同位素变体优选地含有氘(“含氘的通式(I)的化合物”)。其中掺入一种或多种放射性同位素(诸如3H或14C)的通式(I)的化合物的同位素变体是有用的,例如在药物和/或基质组织分布研究中。这些同位素由于它们的易于掺入和可检测性而是特别优选的。可以将发射正电子的同位素诸如18F或11C掺入通式(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。在临床前或临床研究的背景下,含氘的和含13C的通式(I)的化合物可用于质谱分析中(H. J.Leis等人, Curr. Org. Chem., 1998, 2, 131)。
通常通过本领域技术人员已知的方法,诸如在本文的方案和/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,优选含氘的试剂,可以制备通式(I)的化合物的同位素变体。取决于期望的氘代位点,在某些情况下,可以将来自D2O的氘直接掺入化合物中或掺入可用于合成此类化合物的试剂中(Esaki等人, Tetrahedron, 2006, 62,10954; Esaki等人, Chem. Eur. J., 2007, 13, 4052)。氘气也是用于将氘掺入分子的有用试剂。烯键(H. J. Leis等人, Curr. Org. Chem., 1998, 2, 131; J. R. Morandi等人, J. Org. Chem., 1969, 34 (6), 1889)和炔键(N. H. Khan, J. Am. Chem. Soc.,1952, 74 (12), 3018; S. Chandrasekhar等人, Tetrahedron Letters, 2011, 52,3865)的催化氘化是掺入氘的直接途径。在有氘气存在下金属催化剂(即Pd、Pt和Rh)可以用来将氘直接交换含烃官能团中的氢(J. G. Atkinson等人, 美国专利3966781)。多种氘化试剂和合成的结构单元可商购得自公司,例如C/D/N Isotopes, Quebec, Canada;Cambridge Isotope Laboratories Inc., Andover, MA, USA;和CombiPhos Catalysts,Inc., Princeton, NJ, USA。关于氘-氢交换的现有技术的其它信息,在例如以下文献中给出:Hanzlik等人, J. Org. Chem. 55, 3992-3997, 1990; R. P. Hanzlik等人,Biochem. Biophys. Res. Commun. 160, 844, 1989; P. J. Reider等人, J. Org.Chem. 52, 3326-3334, 1987; M. Jarman等人, Carcinogenesis 16(4), 683-688,1995; J. Atzrodt等人, Angew. Chem., Int. Ed. 2007, 46, 7744; K. Matoishi等人,Chem. Commun. 2000, 1519−1520; K. Kassahun等人, WO2012/112363。
术语“含氘的通式(I)的化合物”定义为这样的通式(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,并且其中在通式(I)化合物的每个氘代位置处的氘的丰度高于氘的天然丰度,后者为约0.015%。具体地,在含氘的通式(I)的化合物中,在通式(I)的化合物的每个氘代位置处的氘的丰度比在所述位置处高10%、20%、30%、40%、50%、60%、70%或80%,优选地高90%、95%、96%或97%,甚至更优选地高98%或99%。应当理解,在每个氘代位置处的氘的丰度独立于在其它氘代位置的氘的丰度。
一个或多个氘原子向通式(I)的化合物中的选择性掺入可能改变分子的物理化学性质(例如酸度[C. L. Perrin, 等人, J. Am. Chem. Soc., 2007, 129, 4490; A.Streitwieser等人, J. Am. Chem. Soc., 1963, 85, 2759;]、碱度[C. L. Perrin等人,J. Am. Chem. Soc., 2005, 127, 9641; C. L. Perrin, 等人, J. Am. Chem. Soc.,2003, 125, 15008; C. L. Perrin in Advances in Physical Organic Chemistry, 44,144]、亲脂性[B. Testa等人, Int. J. Pharm., 1984, 19(3), 271])和/或代谢特性,并可能导致母体化合物与代谢物的比例或所形成的代谢物的量的变化。这样的变化可能导致某些治疗优点,并因此在某些情况下可能是优选的。已经报道,在代谢物比例发生变化的情况下,代谢率和代谢转换率降低(A. E. Mutlib等人, Toxicol. Appl. Pharmacol.,2000, 169, 102; D. J. Kushner等人, Can. J. Physiol. Pharmacol., 1999, 77,79)。向母体药物和代谢物的暴露的这些变化可能会对含氘的通式(I)的化合物的药效动力学、耐受性和效力具有重要影响。在某些情况下,氘置换会减少或消除不希望的或有毒的代谢产物的形成,并增强期望的代谢产物的形成(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)。在其它情况下,氘代的主要作用是降低全身清除率。结果,化合物的生物半衰期增加。潜在的临床益处将包括维持相似的全身暴露、降低峰值水平和增加谷值水平的能力。根据特定化合物的药代动力学/药效动力学关系,这可能导致降低的副作用和增强的效力。ML-337 (C. J. Wenthur等人, J. Med. Chem., 2013, 56, 5208)和奥达卡替(K. Kassahun等人, WO2012/112363)是该氘效应的例子。已经报道了其它案例,其中降低的代谢率导致药物暴露的增加,而没有改变全身清除率(例如罗非昔布: F.Schneider等人, Arzneim. Forsch. / Drug. Res., 2006, 56, 295;替拉瑞韦: F.Maltais等人, J. Med. Chem., 2009, 52, 7993)。表现出该效应的氘代药物可能具有降低的剂量要求(例如更低地剂量次数或更低的剂量以达到期望的作用)和/或可能产生更低的代谢产物负载。
通式(I)的化合物对于代谢而言可能具有多个潜在的攻击位点。为了优化上述对理化性质和代谢特性的影响,可以选择具有某种模式的一个或多个氘-氢交换的含氘的通式(I)的化合物。具体地,含氘的通式(I)的化合物的氘原子连接到碳原子和/或位于通式(I)的化合物的是代谢酶例如细胞色素P450的攻击位点的那些位置。
当在本文中使用复数形式的词语“化合物”、“盐”、“多晶型物”、“水合物”、“溶剂合物”等时,这还指单一的化合物、盐、多晶型物、异构体、水合物、溶剂合物等。
“稳定的化合物”或者“稳定的结构”是指这样的化合物:其足够稳固以承受从反应混合物中分离至有用的纯度和配制到有效的治疗剂中。
前药是活性成分的衍生物。术语“基础活性成分”、“基础相应药物”和“相应药物”在本发明中同义使用。
根据期望的各种取代基的位置和性质,本发明的化合物任选地含有一个不对称中心。一个不对称的碳原子可能以(R)或(S)构型存在,这可能产生外消旋混合物。在某些情况下,由于绕给定键,例如,与指定化合物的两个取代的芳环邻接的中心键的受限旋转,也可能存在不对称性。优选的化合物为产生更理想的生物学活性的那些。本发明的化合物的分离的、纯的或部分纯化的异构体和立体异构体或外消旋混合物也包括在本发明的范围内。所述物质的纯化和分离可通过本领域已知的标准技术完成。
光学异构体可通过根据常规方法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的盐或形成共价的非对映异构体而拆分。适当的酸的例子为酒石酸、二乙酰基酒石酸、二甲苯酰基酒石酸和樟脑磺酸。非对映异构体的混合物可基于各非对映异构体的物理和/或化学差异通过本领域已知的方法(例如,通过色谱法或分步结晶)分离为其单个的非对映异构体。光学活性的碱或酸随后从所分离的非对映异构的盐中释放。分离光学异构体的一种不同方法涉及利用手性色谱法(例如,使用手性相的HPLC柱),通过或不通过常规衍生化(最佳地被选择以使对映异构体的分离最大化)。合适的使用手性相的HPLC柱是商购可得的,诸如由Daicel制造的那些,例如,Chiracel OD和Chiracel OJ以及许多其它的柱,它们全部是常规可选择的。也可利用酶法分离,通过或不通过衍生化。本发明的光学活性的化合物也可通过使用光学活性原料的手性合成而获得。为了区分彼此不同类型的异构体,参考IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976)。
本发明包括本发明的化合物的所有可能的立体异构体,无论是单一的立体异构体的形式,或是任意比例的所述立体异构体(例如(R)-或(S)-异构体)的任意混合物的形式。本发明的化合物的单一的立体异构体(例如,单一的对映异构体或单一的非对映异构体)的分离通过任何合适的现有技术方法如色谱法,尤其是例如手性色谱法而实现。
在本发明的上下文中,术语“对映异构纯的”应当理解为是指,所讨论的化合物相对于手性中心的绝对构型以超过95%、优选地超过97%的对映体过量存在。在这里通过使用下式在手性相上评价对应的HPLC色谱图计算出对映体过量ee:
ee = [EA (面积%) - EB (面积%)] x 100%/[EA (面积%) + EB (面积%)]
(EA: 主要对映异构体,EB:次要对映异构体)。
本发明还涵盖了本发明化合物的有用形式,诸如代谢物、水合物、溶剂合物、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以水合物的形式或溶剂合物的形式存在,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元素。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例存在。对于化学计量的溶剂合物(例如水合物),可分别为半-(hemi-、(semi-))、单-、倍半-、二-、三-、四-、五-等溶剂合物或水合物。本发明包括所有这样的水合物或溶剂合物。水合物,特别是半水合物(半水化物),在本发明的上下文中是优选的溶剂合物。
此外,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,或作为两性离子)存在,或可能以盐的形式存在。所述盐可为任意盐,有机或无机加成盐,特别是药学中通常所使用的任何药学上可接受的有机或无机加成盐,或者其例如用于分离或纯化本发明的化合物。
术语“药学上可接受的盐”表示本发明的化合物的无机或有机加成盐。例如,参见S. M. Berge等人, “Pharmaceutical Salts,”J. Pharm. Sci. 1977, 66, 1-19。
具有足够酸性的本发明的化合物的合适的药学上可接受的盐是碱金属盐,例如钠盐、钾盐或锂盐,碱土金属盐,例如钙盐、镁盐或锶盐,或铝盐或锌盐,或从氨或从具有1-20个碳原子的有机伯、仲或叔胺(诸如乙胺、二乙胺、三乙胺、乙基二异丙胺、单乙醇胺、二乙醇胺、三乙醇胺、二环己胺、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-还原葡糖胺、N,N-二甲基-还原葡糖胺、N-乙基-还原葡糖胺、1,6-己烷二胺、葡糖胺、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)衍生出的铵盐,或与具有1-20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、胆碱或苯扎铵)形成的盐。优选的是钠盐、钾盐、锂盐、钙盐或镁盐,最优选的是钾盐。
通过经由多种已知方法使本发明的化合物与适当的碱反应来制备本发明的酸性化合物的碱金属和碱土金属盐。
本发明包括本发明的化合物的所有可能的盐,无论是单一的盐的形式,或是任意比例的所述盐的任意混合物的形式。
在本文中,特别是在实验部分中,关于本发明的中间体和实施例的合成,当提及化合物作为与对应的碱或酸形成的盐形式时,所述盐形式(如通过各种制备和/或纯化方法所得到的)的精确化学计量组成在大多数情况下是未知的。
除非另有说明,否则与盐有关的化学名称或结构式的后缀,诸如“钠盐”、“钾盐”或“x Na+”、“x K+”,均指盐形式,未指定所述盐形式的化学计量。
这类似地适用于这样的情况:其中通过所述的制备和/或纯化方法已经得到合成中间体或实施例化合物或其盐,它们作为溶剂合物,诸如水合物,具有(如果定义的话)未知的化学计量组成。
此外,本发明包括本发明的化合物的所有可能的结晶形式或多晶型物,作为单一多晶型物,或作为任何比例的超过一种多晶型物的混合物。
优选的是通式(I)的化合物,其中
R1代表下式的基团
其中
#代表与1,2,4-三唑基-环的连接点。
还优选的是具有下式的(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯
或其药学上可接受的盐、其溶剂合物和其盐的溶剂合物。
还优选的是具有下式的(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯
本发明涵盖在本文的实施例部分中公开的通式(I)的化合物。
本发明进一步提供了制备通式(I)的化合物或其药学上可接受的盐、其溶剂合物或其盐的溶剂合物的方法,其中
[A]使下式的化合物
其中
R1具有上面给出的关于通式(I)的化合物所定义的含义,
在第一步中与磷酰氯反应和在第二步中水解以得到通式(I)的化合物,
或者
[B]使下式的化合物
其中
R1具有上面给出的关于通式(I)的化合物所定义的含义,
在第一步中与二磷酸四苄酯反应和在第二步中在还原条件下除去苄基以得到通式(I)的化合物,
任选地随后,在适当的情况下,通过用相应的溶剂和/或碱处理,将通式(I)的化合物转化成它们的相应的其药学上可接受的盐、其溶剂合物或其盐的溶剂合物。
反应[A]中的第一步通常如下进行:在惰性溶剂中在有碱存在下,任选地在有添加剂存在下,优选地在从-10℃至+50℃的温度范围,更优选地在0℃至+30℃,使式(II)的化合物与磷酰氯反应。可以在大气压下、在升高的压强或降低的压强下(例如在0.5至5巴下)进行所述反应;一般而言,在大气压下进行所述反应。
惰性溶剂是,例如,卤代烃诸如二氯甲烷或三氯甲烷,醚诸如乙醚或甲基叔丁基醚,烃诸如苯或甲苯,或其它溶剂诸如二氧杂环己烷、二甲基甲酰胺或四氢呋喃。也可能使用溶剂的混合物。优选的是四氢呋喃。
合适的碱是,例如,有机碱诸如三烷基胺,例如三乙胺或二异丙基乙胺,或吡啶。优选的是三乙胺。
合适的添加剂是,例如,4-N,N-二甲基氨基吡啶。
反应[A]中的第二步通常如下进行:加入碱或水,优选地在从-10℃至+50℃的温度范围,更优选地在0℃至+30℃。可以在大气压下、在升高的压强或降低的压强下(例如在0.5至5巴下)进行所述反应;一般而言,在大气压下进行所述反应。
合适的碱是,例如,碱金属氢氧化物水溶液诸如氢氧化钠水溶液、氢氧化锂水溶液或氢氧化钾水溶液,或碱金属碳酸氢盐水溶液诸如碳酸氢钠水溶液或碳酸氢钾水溶液,或碱金属碳酸盐水溶液诸如碳酸钠水溶液或碳酸钾水溶液。优选的是碳酸氢钠水溶液。
反应[B]中的第一步通常如下进行:在惰性溶剂中在有碱存在下,优选地在从-10℃至+50℃的温度范围,更优选地在0℃至+30℃,使式(II)的化合物与二磷酸四苄酯反应。可以在大气压下、在升高的压强或降低的压强下(例如在0.5至5巴下)进行所述反应;一般而言,在大气压下进行所述反应。
惰性溶剂是,例如,卤代烃诸如二氯甲烷或三氯甲烷,醚诸如乙醚或甲基叔丁基醚,或其它溶剂诸如二氧杂环己烷、二甲基甲酰胺或四氢呋喃。也可能使用溶剂的混合物。优选的是四氢呋喃。
合适的碱是,例如,叔丁醇钾或叔丁醇钠、氢化钠、正丁基锂、二异丙基氨基锂、双(三甲基甲硅烷基)氨基钠或双(三甲基甲硅烷基)-氨基锂,优选的是双(三甲基甲硅烷基)氨基锂。
反应[B]中的第二步通常在惰性溶剂中用还原剂进行,优选地在从-10℃至+50℃的温度范围,更优选地在0℃至+30℃。可以在大气压下、在升高的压强或降低的压强下(例如在0.5至5巴下)进行所述反应;一般而言,在大气压下进行所述反应。
惰性溶剂是,例如,乙醇,或二氧杂环己烷和水或四氢呋喃和水的混合物。优选的是乙醇。
还原剂是,例如,炭载钯和氢、二氢氧化钯,二氯化锡、三氯化钛或甲酸铵。优选的是炭载钯和氢。
式(II)的化合物是商购可得的,从文献中已知的,或者可以通过采用文献中描述的标准方法从容易得到的起始原料制备。关于制备起始原料的详细的程序和文献参考也可以在实验部分的起始原料和中间体的制备部分中找到。
本发明涵盖了制备通式(I)的本发明化合物的方法,所述方法包括如本文实验部分所述的步骤。
下文所述的方案和程序举例说明了本发明的通式(I)的化合物的合成途径,并且不意图成为限制性的。
借助于下述合成方案可以举例说明本发明的化合物的制备:
方案1
通过本领域技术人员已知的任何方法,可以将本发明的通式(I)的化合物转化成本文所述的任何盐,优选药学上可接受的盐。类似地,通过本领域技术人员已知的任何方法,可以将本发明的通式(I)的化合物的任何盐转化成游离化合物。
本发明的化合物具有有价值的药理学性质,且可以用于预防和/或治疗人类和其它哺乳动物的多种疾病和疾病诱导的状态。本发明的通式(I)的化合物表现出有价值的药理作用谱和药代动力学特征。已经令人惊讶地发现,本发明的化合物有效地抑制加压素V1a受体,且因此可能将所述化合物用于治疗和/或预防人类和动物的疾病,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"treating")”包括抑制、延迟、缓解、减轻、阻止、减少疾病、病症、病况或状态、其发展和/或进程、和/或其症状,或造成疾病、病症、病况或状态、其发展和/或进程、和/或其症状的消退。术语“预防("prevention"或"preventing")”包括减小获得、感染或经历疾病、病症、病况或状态、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、病况或状态的治疗或预防可以是部分的或完全的。
贯穿该文件,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,通常意图包括复数语言。例如,表述“一种治疗患者的疾病的方法,所述方法包括向患者施用有效量的通式(I)的化合物”意在包括同时治疗超过一种疾病以及施用超过一种通式(I)的化合物。
本发明的化合物是高效的并且具体地是加压素V1a受体的选择性拮抗剂。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具有很高的价值。
本文中使用的术语“加压素V1a受体拮抗剂”表示通过抑制(部分地或完全地)或阻断加压素V1a受体从而防止加压素激活所述受体而起作用的化合物。
在一个实施方案中,本文所述化合物的基础相应药物对V1a受体具有活性。在另一个实施方案中,本文所述化合物的基础相应药物表现出V1a受体的抑制,根据在B-4中的研究,IC50 < 100 nM。在另一个实施方案中,本文所述化合物的基础相应药物表现出V1a受体的抑制,根据在B-4中的研究,IC50 < 20 nM。在另一个实施方案中,本文所述化合物的基础相应药物表现出V1a受体的抑制,根据在B-4中的研究,IC50 < 10 nM。在另一个实施方案中,本文所述化合物的基础相应药物表现出V1a受体的抑制,根据在B-4中的研究,IC50 < 5 nM。
在另一个实施方案中,本文所述化合物的基础相应药物对V1a受体具有选择性活性,并且对其它加压素受体诸如V1b和/或V2亚型具有较低活性、大幅降低的活性和/或无活性。在另一个实施方案中,本文所述化合物的基础相应药物对V1a受体的选择性是相对于V2受体的至少10倍,如根据在B-4中的研究所确定的。在另一个实施方案中,本文所述化合物的基础相应药物对V1a受体的选择性是相对于V2受体的至少15倍,如根据在B-4中的研究所确定的。在另一个实施方案中,本文所述化合物的基础相应药物对V1a受体的选择性是相对于V2受体的至少20倍,如根据在B-4中的研究所确定的。在另一个实施方案中,本文所述化合物的基础相应药物对V1a受体的选择性是相对于V2受体的至少30倍,如根据在B-4中的研究所确定的。
根据本发明的化合物适合用于治疗和/或预防肾脏疾病,特别是急性和慢性肾脏疾病、糖尿病性肾脏疾病以及急性和慢性肾衰竭。一般术语“肾病”或“肾脏疾病(“renaldisease”或“kidney disease”)”描述了其中肾脏不能过滤和除去血液中废物的一类病况。肾脏疾病有两种主要形式:急性肾脏疾病(急性肾损伤,AKI)和慢性肾脏疾病(CKD)。根据本发明的化合物可以进一步用于治疗和/或预防由多种损伤引起的急性肾损伤的后遗症,所述多种损伤是诸如缺血-再灌注损伤、放射造影剂施用、心肺旁路手术、休克和脓毒症。在本发明意义上,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,以及潜在的或相关的肾脏疾病诸如肾灌注不足、透析时低血压、梗阻性尿路病、肾小球病、IgA肾病、肾小球肾炎、急性肾小球肾炎、肾小球硬化症、小管间质性疾病、肾病诸如原发性和先天性肾脏疾病、肾炎、奥尔波特综合征、肾炎症、免疫性肾脏疾病诸如肾移植排斥、免疫复合物诱导的肾疾病、毒性物质诱发的肾病、造影剂诱导的肾病、轻微病变性肾小球肾炎(lipoid)、膜性肾小球肾炎、局灶性节段性肾小球硬化症(FSGS)、溶血性尿毒症综合征(HUS)、淀粉样变性、古德帕斯彻氏综合征、韦格纳氏肉芽肿病、舍-亨二氏紫癜、糖尿病和非糖尿病的肾病、肾盂肾炎、肾囊肿、肾硬化、高血压性肾硬化和肾病综合征,其可以在诊断上表征,例如,通过异常降低的肌酸酐和/或水排泄,异常增加的尿素、氮、钾和/或肌酸酐的血液浓度,改变的肾酶(例如谷氨酰基合成酶)的活性,改变的尿渗量或尿体积,增加的微白蛋白尿,巨白蛋白尿,肾小球和小动脉的病变,肾小管扩张,高磷酸酯酶血症和/或需要透析。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)以及骨和碳水化合物代谢紊乱的用途。根据本发明的化合物也适合用于治疗和/或预防多囊性肾病(PCKD)和ADH分泌不足综合征(SIADH)。
在该背景下可以使用本发明的化合物治疗和/或预防的心血管疾病包括、但不限于以下疾病: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)且包括充血性心力衰竭、动脉高血压、顽固性高血压、动脉性肺动脉高血压、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、室性快速型心律失常、尖端扭转型室性心动过速、心房和心室期外收缩、AV结期外收缩、病窦综合症、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、心瓣炎、主动脉炎、心肌病)、休克例如心源性休克、感染性休克和过敏性休克、动脉瘤、Boxer心肌病(心室早发性收缩)、以及血栓栓塞性疾病和局部缺血例如外周灌注障碍、再灌注损伤、动脉和静脉血栓、心肌机能不全、内皮功能障碍、微血管和大血管损伤(血管炎)和预防再狭窄(例如在溶栓治疗、经皮腔内血管成形术(PTA)、经皮腔内冠状动脉血管成形术(PTCA)、心脏移植和旁通手术后)、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、外周循环病症、冠状动脉和外周动脉痉挛,以及水肿例如肺水肿、脑水肿、肾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,例如右心衰竭、左心衰竭、总体功能不全、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或舒张期心力衰竭)和射血分数减少性心力衰竭(HFrEF或收缩期心力衰竭)。
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,其中一个器官的急性或慢性功能障碍可能诱发另一个器官的急性或慢性功能障碍。
此外,根据本发明的化合物可以用于治疗和/或预防周围动脉疾病(PAD),包括跛行且包括临界性肢体缺血以及冠状微血管功能障碍(CMD),包括CMD 1-4型、原发性和继发性雷诺现象、微循环紊乱、跛行、周围和自主神经病、糖尿病性微血管病、糖尿病性视网膜病变、糖尿病性四肢溃疡、坏疽、肢端硬皮综合征、红斑症、风湿性疾病,和用于促进伤口愈合。
此外,本发明的化合物适合用于治疗泌尿系疾病以及男性和女性泌尿生殖系统的疾病,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)例如混合性、急迫性、压力性和溢流性尿失禁(MUI、UUI、SUI、OUI)、骨盆痛、勃起功能障碍、痛经和子宫内膜异位症。
根据本发明的化合物也可以用于治疗和/或预防炎性疾病、哮喘疾病、慢性阻塞性肺病(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,本发明的化合物可以用于治疗和/或预防动脉性肺动脉高血压(PAH)和其它形式的肺动脉高血压(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血压。
另外,根据本发明的化合物可以用于治疗和/或预防肝硬化、腹水、糖尿病和糖尿病并发症,例如神经病和肾病。
此外,本发明的化合物适合用于治疗和/或预防中枢神经病症诸如焦虑状态、抑郁症、青光眼、癌症诸如特别是肺肿瘤和昼夜节律失调诸如时差综合症和轮班工作。
此外,根据本发明的化合物可以用于治疗和/或预防疼痛病况,肾上腺疾病例如嗜铬细胞瘤和肾上腺脑卒中,肠疾病例如克罗恩氏病和腹泻、月经失调例如痛经、子宫内膜异位症、早产和子宫收缩松解术。
由于它们的活性和选择性特性,据信本发明的化合物特别适合用于治疗和/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、周围动脉疾病(PAD)、冠状微血管功能障碍(CMD)、雷诺氏综合征和痛经。
上述疾病已经在人类中充分地表征,但是在其它哺乳动物中也存在可比较的病因学,并且在那些动物中可以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其它活性成分,特别是用于治疗和/或预防疾病,尤其是上述疾病的。
具体地,本发明涵盖药物组合,其包括:
● 一种或多种第一活性成分,特别是如前定义的通式(I)的化合物,和
● 一种或多种其它活性成分,特别是用于治疗和/或预防疾病,尤其是上述疾病的。
术语“组合”在本发明中如本领域技术人员已知地使用,所述组合可能是固定组合、非固定组合或部件套件。
“固定组合”在本发明中如本领域技术人员已知地使用,并且定义为这样的组合: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,与另一种活性成分一起存在于一个单位剂量中或一个单一实体中。“固定组合”的一个例子是这样的药物组合物:其中第一活性成分和另一种活性成分以混合物形式存在以同时施用,例如在制剂中。“固定组合”的另一个例子是这样的药物组合:其中第一活性成分和另一种活性成分存在于一个单元中而不是在混合物中。
非固定组合或“部件套件”在本发明中如本领域技术人员已知地使用,并且定义为这样的组合:其中第一活性成分和另一种活性成分存在于超过一个单元中。非固定组合或部件套件的一个例子是这样的组合:其中第一活性成分和其它活性成分单独存在。可能分开、依次、同时、并行或在时间上错开地施用非固定组合或部件套件的组分。
本发明的化合物可以作为唯一药学试剂或与一种或多种其它药学活性成分组合地施用,其中所述组合不会引起不可接受的不良作用。本发明还涵盖了此类药物组合。例如,本发明的化合物可以与已知的药剂组合用于治疗和/或预防疾病,尤其是上述疾病。
具体地,本发明的化合物可以与以下试剂固定地或单独地组合使用:
● 抗血栓形成剂,例如并优选地来自血小板聚集抑制剂、抗凝血剂和致纤溶物质;
● 降血压剂,例如并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;
● 抗糖尿病剂(降糖药或抗高血糖药),例如并优选胰岛素和衍生物、磺酰脲类、双胍类、噻唑烷二酮类、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、硝基甘油、单硝酸异山梨酯、硝酸异山梨酯、吗多明或SIN-1和吸入的NO;
● 抑制环磷酸鸟苷(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,尤其是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、罗地那非、CTP-499或PF-00489791;
● 正性肌力药剂,例如强心苷(地高辛)和β-肾上腺素能的和多巴胺能的激动剂诸如异丙肾上腺素、肾上腺素、去甲肾上腺素、多巴胺或多巴酚丁胺;
● 利钠肽,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,例如并优选左西孟旦;
● 不依赖于NO和血红素的可溶性鸟苷酸环化酶(sGC)活化剂,例如并优选在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、但是依赖于血红素的鸟苷酸环化酶(sGC)刺激物,例如并优选在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的合成的试剂,例如并优选sGC调节剂,例如并优选利奥西呱、西那西呱、vericiguat或BAY 1101042;
● 人嗜中性粒细胞弹性蛋白酶(HNE)的抑制剂,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,例如nintedanib、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,例如并优选乙莫克舍、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 (以前称作CVT-3619)、卡帕诺生和neladenoson bialanate (BAY 1067197);
● 影响心率的化合物,例如并优选伊伐布雷定;
● 心脏肌球蛋白活化剂,例如并优选omecamtiv mecarbil (CK-1827452);
● 抗炎药诸如非甾体类抗炎药(NSAIDs),包括乙酰基水杨酸(阿司匹林)、布洛芬和萘普生,糖皮质激素例如并优选泼尼松、泼尼松龙、甲泼尼龙、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,或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,例如并优选地来自甲状腺受体激动剂、胆固醇合成抑制剂(例如并优选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、抗凝血剂和致纤溶物质的化合物。
在本发明的一个优选实施方案中,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并优选地是阿司匹林、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案中,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并优选地是希美加群、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案中,根据本发明的化合物与GPIIb/IIIa拮抗剂联合施用,所述GPIIb/IIIa拮抗剂例如并优选地是替罗非班或阿昔单抗。
在本发明的一个优选实施方案中,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抑制剂例如并优选地是利伐沙班、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案中,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案中,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拮抗剂例如并优选地是香豆素。
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案中,根据本发明的化合物与钙拮抗剂联合施用,所述钙拮抗剂例如并优选地是硝苯地平、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案中,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-受体阻滞剂例如并优选地是哌唑嗪或坦洛新。
在本发明的一个优选实施方案中,根据本发明的化合物与β-阻滞剂联合施用,所述β-阻滞剂例如并优选地是普萘洛尔、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案中,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受体拮抗剂例如并优选地是氯沙坦、坎地沙坦、缬沙坦、替米沙坦、厄贝沙坦、奥美沙坦、依普罗沙坦、embursartan或阿齐沙坦。
在本发明的一个优选实施方案中,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)抑制剂例如并优选地是sacubitril、奥马曲拉或AVE-7688。
在本发明的一个优选实施方案中,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)例如并优选地是LCZ696。
在本发明的一个优选实施方案中,根据本发明的化合物与ACE抑制剂联合施用,所述ACE抑制剂例如并优选地是依那普利、卡托普利、赖诺普利、雷米普利、地拉普利、福辛普利、喹那普利(quinopril)、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案中,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并优选地是波生坦、达卢生坦、安立生坦、替唑生坦、西他生坦、阿伏生坦、马昔腾坦或阿曲生坦。
在本发明的一个优选实施方案中,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并优选地是阿利吉仑、SPP-600或SPP-800。
在本发明的一个优选实施方案中,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并优选地是finerenone、螺内酯、坎利酮、坎利酸钾、依普利酮、esaxerenone (CS-3150)或apararenone (MT-3995)、CS-3150或MT-3995。
在本发明的一个优选实施方案中,根据本发明的化合物与利尿剂联合施用,所述利尿剂例如并优选地是呋塞米、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案中,根据本发明的化合物与CETP抑制剂联合施用,所述CETP抑制剂例如并优选地是达塞曲匹、安塞曲匹、BAY 60-5521或CETP-疫苗(Avant)。
在本发明的一个优选实施方案中,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并优选地是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案中,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药物例如并优选洛伐他汀、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案中,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并优选地是BMS-188494或TAK-475。
在本发明的一个优选实施方案中,根据本发明的化合物与ACAT抑制剂联合施用,所述ACAT抑制剂例如并优选地是阿伐麦布、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案中,根据本发明的化合物与MTP抑制剂联合施用,所述MTP抑制剂例如并优选地是英普他派、R-103757、BMS-201038或JTT-130。
在本发明的一个优选实施方案中,根据本发明的化合物与PPAR-γ激动剂联合施用,所述PPAR-γ激动剂例如并优选地是吡格列酮或罗格列酮。
在本发明的一个优选实施方案中,根据本发明的化合物与PPAR-δ激动剂联合施用,所述PPAR-δ激动剂例如并优选地是GW 501516或BAY 68-5042。
在本发明的一个优选实施方案中,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并优选地是依折麦布、替奎安或帕马苷。
在本发明的一个优选实施方案中,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并优选地是奥利司他。
在本发明的一个优选实施方案中,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并优选地是考来烯胺、考来替泊、colesolvam、CholestaGel或考来替兰。
在本发明的一个优选实施方案中,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并优选地是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案中,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)拮抗剂例如并优选地是吉卡宾钙(CI-1027)或烟酸。
在本发明的一个优选实施方案中,根据本发明的化合物与TGFβ拮抗剂联合施用,所述TGFβ拮抗剂例如并优选地是吡非尼酮或夫苏木单抗。
在本发明的一个优选实施方案中,根据本发明的化合物与HIF-PH抑制剂联合施用,所述HIF-PH抑制剂例如并优选地是molidustat或roxadustat。
在本发明的一个优选实施方案中,根据本发明的化合物与CCR2拮抗剂联合施用,所述CCR2拮抗剂例如并优选地是CCX-140。
在本发明的一个优选实施方案中,根据本发明的化合物与TNFα拮抗剂联合施用,所述TNFα拮抗剂例如并优选地是阿达木单抗。
在本发明的一个优选实施方案中,根据本发明的化合物与半乳糖凝集素-3抑制剂联合施用,所述半乳糖凝集素-3抑制剂例如并优选地是GCS-100。
在本发明的一个优选实施方案中,根据本发明的化合物与BMP-7激动剂联合施用,所述BMP-7激动剂例如并优选地是THR-184。
在本发明的一个优选实施方案中,根据本发明的化合物与p53调节剂联合施用,所述p53调节剂例如并优选地是QPI-1002。
在本发明的一个优选实施方案中,根据本发明的化合物与NOX1/4抑制剂联合施用,所述NOX1/4抑制剂例如并优选地是GKT-137831。
在本发明的一个优选实施方案中,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代谢的药物例如并优选地是胆骨化醇或旁卡西醇。
在本发明的一个优选实施方案中,根据本发明的化合物与细胞抑制剂联合施用,所述细胞抑制剂例如并优选地是环磷酰胺。
在本发明的一个优选实施方案中,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并优选地是环孢素。
在本发明的一个优选实施方案中,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并优选地是司维拉姆或碳酸镧。
在本发明的一个优选实施方案中,根据本发明的化合物与用于治疗甲状旁腺功能亢进的钙模拟物联合施用。
在本发明的一个优选实施方案中,根据本发明的化合物与用于治疗铁缺乏的药剂联合施用,所述用于治疗铁缺乏的药剂例如并优选地是铁产品。
在本发明的一个优选实施方案中,根据本发明的化合物与用于治疗hyperurikaemia的药剂联合施用,所述用于治疗hyperurikaemia的药剂例如并优选地是别嘌呤醇或拉布立酶。
在本发明的一个优选实施方案中,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并优选地是促红细胞生成素。
在本发明的一个优选实施方案中,根据本发明的化合物与用于免疫治疗的生物制品联合施用,所述用于免疫治疗的生物制品例如并优选地是阿巴他塞、利妥昔单抗、依库珠单抗或贝利木单抗。
在本发明的一个优选实施方案中,根据本发明的化合物与Jak抑制剂联合施用,所述Jak抑制剂例如并优选地是鲁索替尼、托法替尼、巴瑞克替尼、CYT387、GSK2586184、来他替尼、pacritinib (SB1518)或TG101348。
在本发明的一个优选实施方案中,根据本发明的化合物与用于治疗小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案中,根据本发明的化合物与碱治疗剂联合施用,所述碱治疗剂例如并优选地是碳酸氢钠。
在本发明的一个优选实施方案中,根据本发明的化合物与mTOR抑制剂联合施用,所述mTOR抑制剂例如并优选地是依维莫司或雷帕霉素。
在本发明的一个优选实施方案中,根据本发明的化合物与NHE3抑制剂联合施用,所述NHE3抑制剂例如并优选地是AZD1722。
在本发明的一个优选实施方案中,根据本发明的化合物与eNOS调节剂联合施用,所述eNOS调节剂例如并优选地是沙丙蝶呤。
在本发明的一个优选实施方案中,根据本发明的化合物与CTGF抑制剂联合施用,所述CTGF抑制剂例如并优选地是FG-3019。
在本发明的一个优选实施方案中,根据本发明的化合物与抗糖尿病药(降糖药或抗高血糖药)联合施用,所述抗糖尿病药(降糖药或抗高血糖药)例如并优选地是胰岛素和衍生物、磺酰脲类诸如甲苯磺丁脲、氨磺丁脲、醋酸己脲、氯磺丙脲、格列吡嗪、格列齐特、格列本脲、格列本脲、格列波脲、格列喹酮、格列派特、格列吡脲、格列美脲、JB253和JB558、氯茴苯酸类诸如瑞格列奈和那格列奈、双胍类诸如二甲双胍和丁福明、噻唑烷二酮类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抑制剂诸如维格列汀、西格列汀、沙格列汀、利拉利汀、阿洛利汀、septagliptin和替格列汀、GLP-1类似物诸如艾塞那肽(也称作exendin-4、利拉糖肽、利司那肽和他泊鲁肽或SGLT抑制剂(gliflozins)诸如卡格列净、达格列净和empagliflozin。
在一个特别优选的实施方案中,本发明的化合物与一种或多种另外的治疗剂联合施用,所述另外的治疗剂选自利尿剂、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)的活化剂和刺激物以及正性肌力药剂。
在另一个特别优选的实施方案中,本发明的化合物与一种或多种另外的治疗剂联合施用,所述另外的治疗剂选自利尿剂、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、正性肌力药剂、抗炎药、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。
因而,在另一个实施方案中,本发明涉及包含至少一种根据本发明的化合物和一种或多种另外的治疗剂的药物组合物,所述药物组合物用于治疗和/或预防疾病、尤其是上述疾病。
此外,本发明的化合物可以原样使用、或者用于组合物、用于研究和诊断、或者用作分析参比标准品等,这是本领域众所周知的。
当本发明的化合物作为药物施用给人类和其它哺乳动物时,可以施用这些化合物本身,或者作为含有例如0.1%至99.5%(更优选地,0.5%至90%)的活性成分以及一种或多种药学上可接受的赋形剂的药物组合物施用。
因而,在另一个方面,本发明涉及药物组合物,其包含至少一种根据本发明的化合物,常规地与一种或多种惰性的、无毒的、药学上可接受的赋形剂一起,并涉及该药物组合物用于治疗和/或预防疾病、尤其是上述疾病的用途。
根据本发明的化合物可能具有全身和/或局部活性。为此目的,可以以合适的方式施用它们,例如,通过口服、胃肠外、肺、鼻、舌下、舌、含服、直肠、阴道、真皮、透皮、结膜、耳途径或作为植入物或支架。
对于这些施用途径,可能以合适的施用形式施用根据本发明的化合物。
对于口服施用,可能将根据本发明的化合物配制成本领域已知的剂型,其快速地和/或以改进的方式递送本发明的化合物,例如片剂(未包衣或包衣的片剂、例如具有肠溶或控释包衣(其延迟溶解或不溶))、口腔崩解片、薄膜/糯米纸囊剂、薄膜/冻干物、胶囊剂(例如硬或软明胶胶囊剂)、糖包衣片剂、颗粒、丸剂、粉剂、乳剂、混悬液、气雾剂或溶液。可能将结晶和/或无定形和/或溶解形式的根据本发明的化合物掺入所述剂型中。
可以以避免吸收步骤(例如静脉内、动脉内、贲门内、椎管内或腔内)或包括吸收(例如肌肉内、皮下、皮内、经皮或腹膜内)的方式实现胃肠外施用。适合用于胃肠外施用的施用形式尤其是用于以溶液、混悬液、乳剂、冻干物或无菌粉末形式注射和输注的制剂。
适用于其它施用途径的例子是用于吸入的药物形式[尤其是粉末吸入剂、雾化吸入剂]、滴鼻剂、鼻用溶液剂、鼻喷雾剂;用于舌、舌下或含服施用的片剂/薄膜/糯米纸囊剂/胶囊剂;栓剂;滴眼剂、眼膏剂、眼浴液、眼插入物、滴耳剂、耳喷雾剂、耳粉、洗耳液、耳塞(ear tampon);阴道胶囊剂、水性悬浮液(洗剂、摇动混合物(mixturae agitandae))、亲脂混悬液、乳剂、软膏剂、乳膏剂、透皮治疗系统(例如贴剂)、乳、糊剂、泡沫、扑粉剂、植入物或支架。
根据本发明的化合物可以掺入所述的施用形式中。这可以通过与药学上合适的赋形剂混合以本身已知的方式实现。药学上合适的赋形剂尤其包括:
● 填充剂和载体(例如纤维素、微晶纤维素(例如,Avicel®)、乳糖、甘露醇、淀粉、磷酸钙(例如,Di-Cafos®)),
● 软膏基质(例如石油胶、石蜡、甘油三酯、蜡类、羊毛蜡、羊毛蜡醇、羊毛脂、亲水软膏剂、聚乙二醇),
● 栓剂用基质(例如聚乙二醇、可可脂、硬脂肪),
● 溶剂(例如水、乙醇、异丙醇、甘油、丙二醇、中等链长甘油三酯脂肪油、液体聚乙二醇、石蜡),
● 表面活性剂、乳化剂、分散剂或湿润剂(例如十二烷基硫酸钠)、卵磷脂、磷脂、脂肪醇(例如Lanette®)、脱水山梨糖醇脂肪酸酯(例如Span®)、聚氧乙烯脱水山梨糖醇脂肪酸酯(例如,Tween®)、聚氧乙烯脂肪酸甘油酯(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(poloxamer)(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(例如高度分散的二氧化硅),
● 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、羧甲纤维素钠、淀粉、卡波姆、聚丙烯酸类(例如Carbopol®);海藻酸盐、明胶),
● 崩解剂(例如变性淀粉、羧甲基纤维素钠、淀粉羟乙酸钠(例如,Explotab®)、交联聚乙烯基吡咯烷酮、交联羧甲基纤维素钠(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、高度分散的二氧化硅(例如Aerosil®)),
● 包衣材料(例如糖、紫胶)和用于快速或以改进方式溶解的薄膜或扩散膜的成膜剂(例如聚乙烯吡咯烷酮(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、聚甲基丙烯酸酯例如Eudragit®)),
● 胶囊材料(例如明胶、羟丙基甲基纤维素),
● 合成的聚合物(例如聚丙交酯、聚乙醇酸交酯、聚丙烯酸酯、聚甲基丙烯酸酯(例如,Eudragit®)、聚乙烯吡咯烷酮(例如,Kollidon®)、聚乙烯醇、聚乙酸乙烯酯、聚氧化乙烯、聚乙二醇以及它们的共聚物和嵌段共聚物),
● 塑化剂(例如聚乙二醇、丙二醇、甘油、三醋汀、三乙酰基柠檬酸酯、邻苯二甲酸二丁酯),
● 穿透促进剂,
● 稳定剂(例如抗氧化剂,例如,抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸钠、丁基羟基茴香醚、丁基羟基甲苯、没食子酸丙酯),
● 防腐剂(例如对羟基苯甲酸酯、山梨酸、硫柳汞、苯扎氯铵、醋酸氯己定、苯甲酸钠),
● 着色剂(例如无机颜料例如氧化铁、二氧化钛),
● 芳香剂、甜味剂、味道掩蔽剂和/或气味掩蔽剂。
此外,本发明涉及一种药物组合物,其包含至少一种根据本发明的化合物,通常与一种或多种药学上合适的赋形剂一起,并涉及它们根据本发明的用途。
基于已知用来评价可用于治疗心血管和肾病症的化合物的标准实验室技术,通过标准毒性试验和通过用于确定哺乳动物中的上述鉴定的病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病况的已知活性成分或药物的结果进行对比,可以容易地确定用于治疗每种期望适应症的本发明化合物的有效剂量。在这些病症之一的治疗中要施用的活性成分的量可以根据诸如下述考虑因素广泛地变化:所采用的特定化合物和剂量单位、施用模式、疗程、所治疗的患者的年龄和性别,和所治疗的病况的性质和程度。
要施用的活性成分的总量通常为约0.001 mg/kg至约200 mg/kg体重/天,且优选约0.01 mg/kg至约20 mg/kg体重/天。临床上有用的定量施用方案是每日一至三次的定量施用至每四周一次的定量施用。另外,“休药期”(其中在某个时间段内不给患者施用药物)可能有利于药理学作用和耐受性之间的整体平衡。单位剂量可能含有约0.5 mg至约1500mg活性成分,并且可以每日一次或多次地施用,或者少于每日一次地施用。通过注射(包括静脉内、肌肉内、皮下和胃肠外注射)以及使用输注技术施用的平均每日剂量优选为0.01-200 mg/kg总体重。示例性地,可以以约0.001 mg/kg至约10 mg/kg、优选约0.01 mg/kg至约1 mg/kg体重的剂量胃肠外地施用本发明的化合物。在口服施用时,一个示例性的剂量范围是约0.01-100 mg/kg,优选约0.01-20 mg/kg,且更优选约0.1-10 mg/kg体重。介于上述值中间的范围也意图成为本发明的一部分。
当然,每位患者的具体开始和后续剂量方案会根据以下因素而变化:主治诊断医生确定的病况的性质和严重程度、使用的具体化合物的活性、患者的年龄和一般状况、施用时间、施用途径、药物的排泄速率、药物组合,等。本领域技术人员使用常规治疗试验可以确定期望的治疗模式和本发明的化合物或其药学上可接受的盐或酯或组合物的剂量数目。
下述示例性实施方案举例说明了本发明。本发明不限于实施例。
除非另外说明,否则下述试验和实施例中的百分比为重量百分比,份为重量份。为液体/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
实验部分–一般部分
NMR峰形式按照其在谱图中的出现进行说明,不考虑可能的更高阶效应。
使用ACD/Labs的ACD/Name软件生成化学名称。在某些情况下,使用商购可得的试剂的普遍接受的名称代替ACD/Name生成的名称。
下表1列出了在本段中和在实施例部分中使用的缩写(只要在正文中未对其进行解释)。其它缩写具有技术人员通常了解的它们的含义。
表1: 缩写
下表列出了本文中使用的缩写。
缩写 含义
abs 绝对
br 宽(1H-NMR信号)
conc. 浓缩的
CI 化学电离
d 双峰(1H-NMR信号)
d 天
DAD 二极管阵列检测器
DCM 二氯甲烷
dd 双双峰
戴斯-马丁过碘烷 1,1,1-三乙酰氧基-1,1-二氢-1,2-苯并碘杂氧杂环戊烷-3(1H)-酮
DMSO 二甲基亚砜
ESI 电喷射(ES)电离
h 小时
HATU 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐
HPLC 高效液相色谱法
LC-MS 液相色谱法质谱法
m 多重峰(1H-NMR信号)
min 分钟
MS 质谱法
MTBE 甲基-叔丁基醚
NMR 核磁共振光谱法: 按ppm给出化学位移(δ)。除非另有说明,否则通过将DMSO信号设定至2.50 ppm来校正化学位移。
of th. 理论值的
PDA 光电二极管阵列
Rt 按分钟计的保留时间(如用HPLC或UPLC测量的)
s 单峰(1H-NMR信号)
SFC 超临界流体色谱法
SQD 单个四极检测器
t 三重峰(1H-NMR信号)
td 三双峰(1H-NMR信号)
TFA 三氟乙酸
THF 四氢呋喃
UPLC 超高效液相色谱法。
通过以下实施例举例说明本申请描述的发明的各个方面,所述实施例并不意图以任何方式限制本发明。
本文所述的实施例试验实验用来举例说明本发明,并且本发明不限于所给出的实施例。
所有在实验部分中没有描述其合成的试剂是商购可得的,或是已知的化合物,或可以由本领域技术人员通过已知的方法从已知的化合物形成。
根据本发明的方法生产的化合物和中间体可能需要纯化。有机化合物的纯化是本领域技术人员众所周知的,并且可能存在数种纯化相同化合物的方法。在某些情况下,可能不需要纯化。在某些情况下,所述化合物可以通过结晶来纯化。在某些情况下,可以使用合适的溶剂进行搅拌来除去杂质。在某些情况下,可以如下纯化所述化合物:通过色谱法,特别是快速柱色谱法,使用例如预填充的硅胶筒,例如与Biotage自动纯化仪系统(SP4®或Isolera Four®)和洗脱液诸如己烷/乙酸乙酯或DCM/甲醇的梯度组合的Biotage SNAP筒KP-Sil®或KP-NH®。在某些情况下,通过制备型HPLC可以纯化所述化合物,其中使用例如与合适的预填充的反相柱和洗脱液诸如可能含有添加剂(诸如三氟乙酸、甲酸或氨水)的水和乙腈的梯度组合的Waters自动纯化仪,其配备二极管阵列检测器和/或在线电喷射电离质谱仪。
在某些情况下,如上文所述的纯化方法可以提供盐形式的具有足够碱性或酸性官能度的那些本发明的化合物,例如,在足够碱性的本发明化合物的情况下,例如三氟乙酸盐或甲酸盐,或者在足够酸性的本发明化合物的情况下,例如铵盐。这类盐可以通过本领域技术人员已知的各种方法分别转化成其游离碱或游离酸形式,或者作为盐用在随后的生物学测定中。应当理解,分离的和如本文中所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学测定以便定量具体生物学活性的唯一形式。
在下文描述的本发明的合成中间体和工作实施例的情况下,以对应的碱或酸的盐的形式指出的任何化合物通常是通过各自的制备和/或纯化方法得到的未知确切化学计量组成的盐。除非更详细地指出,否则向名称和结构式的添加,诸如“盐酸盐”、“三氟乙酸盐”、“钠盐”、“钾盐”、“二钾盐”、“磷酸氢盐”、“磷酸盐”或“x HCl”、“x CF3COOH”、“x Na+”、“x K+”、“x Ca2+”、“x Mg2+”因此在这样的盐的情况下不应当以化学计量的含义进行理解,而是仅仅具有关于其中存在的成盐组分的描述特征。
如果通过描述的制备和/或纯化方法以未知化学计量组成的溶剂合物(例如水合物)(如果它们属于确定的类型)的形式得到合成中间体或工作实施例或其盐,这相应地适用。
HPLC和LC-MS方法:
方法1 (LC-MS)
仪器:Waters ACQUITY SQD UPLC系统;柱: Waters Acquity UPLC HSS T3 1.8µ50 x1 mm;洗脱液A: 1 l水+ 0.25 ml 99%甲酸, 洗脱液B: 1 l乙腈+ 0.25 ml 99%甲酸;梯度:0.0 min 90%A→1.2 min 5%A→2.0 min 5%A;恒温箱:50℃;流速: 0.40 ml/min;紫外检测: 208-400 nm。
方法2 (LC-MS):
仪器MS: Thermo Scientific FT-MS;仪器类型UHPLC+: Thermo ScientificUltiMate 3000;柱: Waters, HSST3, 2.1 x 75 mm, C18 1.8µm;洗脱液A: 1 l水+ 0.01%甲酸;洗脱液B: 1 l乙腈+ 0.01%甲酸;梯度: 0.0 min 10%B→2.5 min 95%B→3.5 min95%B;恒温箱:50℃;流速: 0.90 ml/min;紫外检测: 210 nm/最适整合路径210-300 nm。
方法3 (LC-MS):
仪器:Agilent MS Quad 6150; HPLC: Agilent 1290;柱: Waters Acquity UPLC HSST3 1.8µ50 x 2.1 mm;洗脱液A: 1 l水+ 0.25 ml 99%甲酸, 洗脱液B: 1 l乙腈+ 0.25 ml99%甲酸;梯度: 0.0 min 90%A→0.3 min 90%A→1.7 min 5%A→3.0 min 5%A;恒温箱:50℃;流速:1.20 ml/min;紫外检测: 205 - 305 nm。
方法4 (制备型HPLC):
柱:Chromatorex或Reprosil C18 10µm, 125 x 30 mm;洗脱液A: 水+ 0.1%甲酸, 洗脱液B: 乙腈+ 0.1%甲酸;梯度: 3 min 10%B, 17.5 min 95%B, 19.5 min 100%B, 20 min10%B;流速:75 ml/min;运行时间: 20 min;在210 nm检测。
方法5 (LC-MS):
仪器:Waters Single Quad MS系统;仪器Waters UPLC Acquity;柱: Waters BEH C181.7µm 50 x 2.1 mm;洗脱液A: 1 l水+ 1.0 ml (氨水溶液, 25%)/l, 洗脱液B: 1 l乙腈;梯度: 0.0 min 92%A→0.1 min 92%A→1.8 min 5%A→3.5 min 5%A;恒温箱:50℃;流速:0.45 ml/min;紫外检测: 210 nm (208-400 nm)。
微波
使用的微波反应器是来自Biotage®的具有机器人60的Initiator+微波系统。
X-射线衍射学
具有PIXcel计数器(多通道)的透射衍射仪PANalytical X`Pert PRO:
辐射: 铜, Kα
基本单色仪: 聚焦X-射线镜子
波长(K1): 1.5406Å
波长(K2): 1.5444Å
发生器参数: 40 kV, 40 mA
测量范围: 2-38°
房间条件: 25℃,40 - 60%相对湿度。
热重法
TGA 7热重量分析仪;生产商:Perkin-Elmer;加热速率:10 Kmin-1;净化气体:氮气,20-30 ml/min;坩埚:开放铝坩埚;样品准备:无。
红外波谱
Bruker Tensor 37波谱仪;波谱分辨率2 cm-1;单次测量的数目64;波数范围4000-550cm-1;样品准备:无。
实验部分- 起始原料和中间体
实施例1A
{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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) {3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙酸(如在WO 2010/105770-A1的实施例8A中所述合成)、43.3 g (547 mmol)吡啶和33 mg (0.3 mmol) 4-二甲基氨基吡啶溶解在300ml THF中。将得到的溶液在5℃用52.8 g (438 mmol) 2,2-二甲基丙酰氯处理15分钟,并将得到的混合物在室温搅拌2.5小时。冷却至0℃以后,历时1 h加入183 ml 28%氨水溶液,同时将溶液温度保持在10℃和20℃之间,然后将得到的混合物在5℃搅拌1 h的额外时间段。然后加入500 ml甲基叔丁基醚和300 ml 20%柠檬酸水溶液,同时将内部温度保持在10℃和20℃之间。将各相分离,并将有机相用300 ml 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,最后用300 ml 10%氯化钠水溶液洗涤。将有机相在60℃在减压下蒸发直到得到油状残余物。然后加入300 ml THF,并再次蒸发溶液直到得到油状溶液。将该操作重复第二次。将油残余物重新放入360 ml THF中并在10℃和20℃之间的温度用172 g (820mmol)三氟乙酸酸酐处理20 min。然后将得到的溶液在室温搅拌1 h。在10℃和20℃之间的温度加入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-值调至pH = 9.5。相分离以后,将有机相用450 ml 10%氯化钠水溶液洗涤2次。将有机相在减压下在80℃的温度蒸发,同时加入1200 ml正庚烷。将形成的混悬液冷却至20℃并将形成的固体滤出,并用200 ml正庚烷洗涤,并然后在减压下(50℃, 30毫巴)干燥,得到88 g (理论值的93%)作为固体的{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙腈。
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.78 (d, 2H), 7.55 (d, 2H), 6.91(d, 1H), 5.17 (s, 2 H), 4.34-4.23 (m, 1 H), 3.98 (dd, 1H), 3.81 (dd, 1H)。
实施例2A
2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙亚氨酸甲酯
在4 l反应容器中,将在1600 ml甲醇中的200 g (576.9 mmol) {3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙腈(实施例1A)用5.2 g (28 mmol)甲醇钠(30%在甲醇中)处理,并将得到的混合物在50℃搅拌2.5小时。然后将溶液在50℃在减压下蒸发直到得到油状溶液。加入2000 ml甲基叔丁基醚并浓缩溶液直到达到800 ml的体积。然后加入3000 ml正庚烷,并形成混悬液。在20℃冷却以后,将固体过滤,并用500 ml正庚烷洗涤,并然后在减压下(50℃, 30毫巴)干燥,得到175 g (理论值的80%)作为固体的2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙亚氨酸甲酯。
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.01 (s, 1H), 7.78 (d, 2H), 7.62(d, 2H), 6.93 (br. s, 1H), 4.50 (s, 2 H), 4.35-4.23 (m, 1 H), 3.96 (dd, 1H),3.81 (dd, 1H), 3.67 (s, 3 H)。
实施例3A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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 2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙亚氨酸甲酯(实施例2A, 2.64 mmol)在20 ml 1,4-二氧杂环己烷中的溶液冷却至10℃,并然后用388 mg (3.17 mmol)草酰氯甲酯和0.55 ml (3.18 mmol) N,N-二异丙基乙胺处理。然后将得到的混合物搅拌30 min。将1.10 g (3.17 mmol) 2-肼基-3-(三氟甲基)吡啶4-甲基苯磺酸盐(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)在10 ml 1,4-二氧杂环己烷中的预搅拌溶液加入反应混合物,并然后将得到的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,将合并的有机相用氯化钠水溶液洗涤,经硫酸镁干燥和在真空中蒸发,得到777 mg (理论值的50%)作为固体的标题化合物。
LC-MS (方法1): Rt = 1.00 min; MS (ESIpos): m/z = 592.6 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.93 (d, 1H), 8.60 (dd, 1H), 7.98(dd, 1H), 7.75 (d, 2H), 7.67-7.57 (m, 2H), 6.91 (d, 1H), 5.22 (s, 2H), 4.37-4.22 (m, 1H), 4.10-3.97 (m, 1H), 3.85 (dd, 1H), 3.77 (s, 3H)。
实施例4A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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3A, 3.04 mmol)溶解在10.0 ml氨溶液(7N在甲醇中,70.0 mmol)中。将得到的混合物在室温搅拌1 h。在真空中除去溶剂,并将粗产物通过制备型HPLC (方法4)纯化。将含有产物的级分冷冻干燥,得到1.49 g (理论值的85%)作为固体的标题化合物。
LC-MS (方法3): Rt = 1.20 min; MS (ESIpos): m/z = 577 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.87 (d, 1H), 8.51 (d, 1H), 8.39 (s,1H), 7.99 (s, 1H), 7.90 (dd, 1H), 7.82-7.68 (m, 2H), 7.63 (d, 2H), 6.90 (s,1H), 5.22-5.07 (m, 2H), 4.29 (br s, 1H), 4.16-3.94 (m, 1H), 3.85 (dd, 1H)。
实施例5A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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-甲酸甲酯
在氩气下,将150 mg (0.40 mmol) 2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙亚氨酸甲酯(实施例2A)在3 ml无水THF中的溶液在0℃用75µl (0.44 mmol) N,N-二异丙基乙胺和40µl (0.44 mmol)草酰氯甲酯处理,然后将混合物在0℃搅拌30 min。然后加入93 mg (0.44 mmol) [2-(三氟甲基)苯基]肼,随后加入145µl (0.83 mmol) N,N-二异丙基乙胺。将得到的混合物在室温搅拌2 h,随后在120℃在微波中搅拌1 h,并然后蒸发。将得到的残余物通过制备型HPLC (方法4)纯化,得到75 mg (理论值的32%)的标题化合物。
LC-MS (方法2): Rt = 2.01 min; MS (ESIpos): m/z = 591.1 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.07-7.56 (m, 8H), 6.91 (d, 1H),5.17 (d, 2H), 4.37-4.21 (m, 1H), 4.09-3.80 (m, 2H), 3.74 (s, 3H)。
实施例6A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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
将55 mg (0.093 mmol) 3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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-甲酸甲酯(实施例5A)在氨溶液(7N在甲醇中,0.8 ml, 5.6 mmol)中的混合物在室温搅拌过夜,然后将混合物蒸发。将得到的残余物通过制备型HPLC (方法4)纯化,得到55 mg (定量)的标题化合物。
LC-MS (方法2): Rt = 1.77 min; MS (ESIpos): m/z = 576.1 [M+H]+
1H NMR (400 MHz, DMSO-d6): δ [ppm] = 8.23 (s, 1H), 8.00-7.55 (m, 9H),6.90 (d, 1H), 5.22-5.01 (m, 2H), 4.40-4.18 (m, 1H), 4.10-3.76 (m, 2H)。
实施例7A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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 2-{3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-4,5-二氢-1H-1,2,4-三唑-1-基}乙亚氨酸甲酯(实施例2A, 26.4 mmol)在3 ml THF中的溶液冷却至0℃,并然后用58.2 mg (0.48 mmol)草酰氯甲酯和275 μl (1.58 mmol) N,N-二异丙基乙胺处理。将得到的混合物温热至室温并搅拌1 h和再次冷却至0℃。然后加入62.6 mg (0.436mmol) 3-氯-2-肼基吡啶,并将反应混合物温热至室温,并然后搅拌1 h,随后在密封瓶中在微波辐射下在120℃搅拌1 h。将粗产物通过制备型HPLC (方法4)纯化。将含有产物的级分冷冻干燥,得到25.3 mg (理论值的11%)的标题化合物。
LC-MS (方法2): Rt = 1.82 min; MS (ESIpos): m/z = 558.1[M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.70-8.24 (m, 2H), 7.89-7.56 (m,5H), 6.92 (d, 1H), 5.22 (s, 2H), 4.46-4.20 (m, 1H), 3.79 (s, 5H)。
实施例8A
3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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7A,9.134 mmol)溶解在42.5 ml氨溶液(7N在甲醇中,297 mmol)中。将得到的混合物在室温搅拌2 h。然后将溶液倒在冰上,并将混合物搅拌10 min。将沉淀物滤出,并用水洗涤,得到3.5g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。将粗产物通过快速色谱法(硅胶, 二氯甲烷/甲醇, 97/3)纯化,得到4.00 g (理论值的81%)作为固体的标题化合物。
LC-MS (方法2): Rt = 1.62 min; MS (ESIpos): m/z = 543.1 [M+H]+
1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.55 (dd, 1H), 8.39 (s, 1H), 8.25(dd, 1H), 8.00 (s, 1H), 7.76 (d, 2H), 7.69 (dd, 1H), 7.62 (d, 2H), 6.90 (d,1H), 5.18 (d, 2H), 4.36-4.23 (m, 1H), 4.06-3.97 (m, 1H), 3.85 (dd, 1H)。
实验部分-实施例
实施例1
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯
在0℃,将3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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(实施例4A, 2.00 g, 3.47 mmol)在四氢呋喃(40 ml, 490 mmol)中的溶液用4-N,N-二甲基氨基吡啶(635 mg, 5.20 mmol)和三乙胺(720µl, 5.2 mmol)处理。然后逐滴加入磷酰氯(480µl,5.2 mmol)。将得到的混合物在0℃搅拌40 min,并然后在室温搅拌50 min。此后加入水(4.0ml)和饱和碳酸氢钠水溶液(24 ml),并将得到的混合物在室温搅拌过夜。然后在室温蒸发四氢呋喃。将得到的溶液用水稀释,并用乙酸乙酯萃取。将水相用盐酸溶液(1N)调至pH =1,用饱和氯化钠水溶液稀释,并用乙酸乙酯萃取。将合并的有机层用饱和氯化钠水溶液洗涤,经硫酸镁干燥和蒸发。将残余物通过制备型HPLC (方法4)纯化,得到1.32 g (理论值的58%)的标题化合物。
LC-MS (方法3): Rt = 0.94 min; MS (ESIpos): m/z = 657.0 [M+H]+
¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.86 (d, 1H), 8.58-8.29 (m, 2H),8.07-7.82 (m, 2H), 7.79-7.45 (m, 4H), 5.33-5.00 (m, 2H), 4.95 - 4.77 (br m,1H), 4.29-3.89 (m, 2H), 3.36 (br s, 2H,与HDO峰重叠)。
实施例1-1
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯半水合物
将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(4.46 g, 6.79 mmol)在446 ml甲苯中的混悬液在25℃搅拌7天。将固体滤出并蒸发滤液。将固体和从滤液得到的残余物混合在一起并悬浮于二氯甲烷/正庚烷的混合物(200ml, 55:45)中。将得到的混合物在40℃搅拌8天。将固体物质滤出并通过X-射线衍射学检查,且对应于作为结晶性物质(半水合物形式)的标题化合物。
表2: 在实施例1-1中作为结晶性物质得到的化合物的X-射线粉末衍射学
表3: 在实施例1-1中作为结晶性物质得到的化合物的红外波谱
用*标记的带是游离酸所特有的。
实施例2
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}-甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钾
将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例1, 104 mg, 158µmol)在水(3.0 ml)中的溶液用碳酸氢钾(31.6 mg, 316µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到124 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.67 min; MS (ESIpos): m/z = 657.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.87-8.80 (m, 1H), 8.52 (d, 1H), 7.95(dd, 1H), 7.72-7.57 (m, 4H), 5.45-5.36 (m, 1H), 5.35-5.26 (m, 1H), 4.99-4.55(m, 1H,与HDO峰重叠), 4.20-4.07 (m, 2H)。
实施例3
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}-甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钾
将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例1, 35.0 mg, 53.3µmol)在水(1.0 ml)中的溶液用碳酸氢钾(5.33 mg,53.3µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到39.5 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.67 min; MS (ESIpos): m/z = 657.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.87-8.80 (m, 1H), 8.54-8.48 (m, 1H),7.97-7.91 (m, 1H), 7.71-7.57 (m, 4H), 5.43-5.37 (m, 1H), 5.35-5.28 (m, 1H),4.90-4.64 (m, 1H,与HDO峰重叠), 4.23-4.10 (m, 2H)。
实施例4
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}-甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钠
将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例1, 35.0 mg, 53.3µmol)在水(1.0 ml)中的溶液用碳酸钠(5.65 mg, 53.3µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到41.2 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.68 min; MS (ESIpos): m/z = 657.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.86-8.82 (m, 1H), 8.54-8.49 (m, 1H),7.98-7.92 (m, 1H), 7.72-7.58 (m, 4H), 5.43-5.37 (m, 1H), 5.34-5.28 (m, 1H),4.88-4.65 (m, 1H,与HDO峰重叠), 4.20-4.06 (m, 2H)。
实施例5
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}-甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钠
将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例1, 35.0 mg, 53.3µmol)在水(1.0 ml)中的溶液用碳酸氢钠(4.48 mg,53.3µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到38.6 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.68 min; MS (ESIpos): m/z = 657 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.86-8.81 (m, 1H), 8.53-8.48 (m, 1H),7.97-7.92 (m, 1H), 7.71-7.58 (m, 4H), 5.42-5.36 (m, 1H), 5.34-5.27 (m, 1H),4.68 (s, 1H,与HDO峰重叠), 4.22-4.10 (m, 2H)。
实施例6
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}-甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢锂
将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例1, 35.0 mg, 53.3µmol)在水(1.0 ml)中的溶液用氢氧化锂水合物(1:1)(4.47 mg, 107µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到38.7 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.67 min; MS (ESIpos): m/z = 657.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.86-8.82 (m, 1H), 8.54-8.49 (m, 1H),7.98-7.91 (m, 1H), 7.72-7.58 (m, 4H), 5.43-5.37 (m, 1H), 5.34-5.28 (m, 1H),4.90-4.68 (m, 1H,与HDO峰重叠), 4.21-4.06 (m, 2H)。
实施例7
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}-甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢锂
将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例1, 35.0 mg, 53.3µmol)在水(1.0 ml)中的溶液用氢氧化锂水合物(1:1)(2.24 mg, 53.3µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到38.3 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.67 min; MS (ESIpos): m/z = 657.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.83 (d, 1H), 8.51 (d, 1H), 7.94 (dd,1H), 7.71-7.58 (m, 4H), 5.42-5.37 (m, 1H), 5.34-5.28 (m, 1H), 4.89-4.65 (m,1H,与HDO峰重叠), 4.22-4.10 (m, 2H)。
实施例8
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}-甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸钙
将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例1, 100 mg, 152µmol)在水(1 l)中的溶液用碳酸钙(15.2 mg, 152µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到93.9 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.69 min; MS (ESIpos): m/z = 657.1 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.86-8.82 (m, 1H), 8.54-8.49 (m, 1H),7.98-7.92 (m, 1H), 7.72-7.57 (m, 4H), 5.45-5.37 (m, 1H), 5.35-5.28 (m, 1H),4.91-4.66 (m, 1H,与HDO峰重叠), 4.21-4.09 (m, 2H)。
实施例9
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}-甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸镁
将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例1, 35.0 mg, 53.3µmol)在水(1.0 ml)中的溶液用碳酸镁(4.49 mg, 53.3µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到40.1 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.68 min; MS (ESIpos): m/z = 657.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.87-8.81 (m, 1H), 8.54-8.48 (m, 1H),7.98-7.91 (m, 1H), 7.73-7.58 (m, 4H), 5.43-5.37 (m, 1H), 5.35-5.27 (m, 1H),4.92-4.60 (m, 1H,与HDO峰重叠), 4.20-4.06 (m, 2H)。
实施例10
(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯
在0℃,将3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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(实施例6A,1000 mg, 1.74 mmol)在四氢呋喃(20 ml, 250 mmol)中的溶液用4-N,N-二甲基氨基吡啶(318 mg, 2.60 mmol)和三乙胺(360µl, 2.6 mmol)处理。逐滴加入磷酰氯(240µl, 2.6mmol)。将得到的混合物在0℃搅拌40 min,并然后在室温搅拌50 min。此后加入水(2.0 ml)和饱和碳酸氢钠水溶液(12 ml),并将得到的混合物在室温搅拌过夜。然后在室温蒸发四氢呋喃。将得到的溶液用水稀释,并用乙酸乙酯萃取。将水相用盐酸溶液(1N)调至pH = 1,用饱和氯化钠水溶液稀释,并用乙酸乙酯萃取。将合并的有机层用饱和氯化钠溶液洗涤,经硫酸镁干燥和蒸发。将残余物通过制备型HPLC (方法4)纯化,得到876 mg (理论值的77%)的标题化合物。
LC-MS (方法1): Rt = 0.74 min; MS (ESIpos): m/z = 656.0 [M+H]+
¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.30 (br s, 1H), 7.96-7.50 (m, 8H),5.25-4.96 (m, 2H), 4.97 - 4.74 (br m, 1H), 4.26-3.91 (m, 2H), 3.57 (br s, 2H,与HDO峰重叠)。
实施例11
(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钾
将(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例10, 35.0 mg, 53.4µmol)在水(1.0 ml)中的溶液用碳酸氢钾(10.7 mg, 107µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到40.4 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.73 min; MS (ESIpos): m/z = 656.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 7.97-7.93 (m, 1H), 7.87-7.79 (m, 2H),7.73-7.59 (m, 5H), 5.38-5.33 (m, 1H), 5.30-5.24 (m, 1H), 4.88-4.66 (m, 1H,与HDO峰重叠), 4.20-4.06 (m, 2H)。
实施例12
(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钾
将(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例10, 35.0 mg, 53.4µmol)在水(1.0 ml)中的溶液用碳酸氢钾(5.34 mg, 53.4µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到36.3 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.73 min; MS (ESIpos): m/z = 656.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 7.97-7.93 (m, 1H), 7.88-7.79 (m, 2H),7.71-7.58 (m, 5H), 5.39-5.24 (m, 2H), 4.90-4.67 (m, 1H,与HDO峰重叠), 4.19-4.09 (m, 2H)。
实施例13
(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钠
将(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例10, 35.0 mg, 53.4µmol)在水(1.0 ml)中的溶液用碳酸钠(5.66 mg, 53.4µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到37.9 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.74 min; MS (ESIpos): m/z = 656.1 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 7.97-7.93 (m, 1H), 7.89-7.78 (m, 2H),7.74-7.57 (m, 5H), 5.40-5.22 (m, 2H), 4.92-4.64 (m, 1H,与HDO峰重叠), 4.22-4.04 (m, 2H)。
实施例14
(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钠
将(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例10, 35.0 mg, 53.4µmol)在水(1.0 ml)中的溶液用碳酸氢钠(4.48 mg, 53.4µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到36.2 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.47 min; MS (ESIpos): m/z = 656.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 7.97-7.93 (m, 1H), 7.87-7.79 (m, 2H),7.72-7.59 (m, 5H), 5.39-5.24 (m, 2H), 4.90-4.65 (m, 1H,与HDO峰重叠), 4.20-4.09 (m, 2H)。
实施例15
(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸镁
将(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例10, 35.0 mg, 53.4µmol)在水(50 ml)中的溶液用碳酸镁(4.50 mg, 53.4µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到37.3 mg (定量)的标题化合物。
LC-MS (方法2): Rt = 1.34 min; MS (ESIpos): m/z = 656.1 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 7.97-7.93 (m, 1H), 7.88-7.79 (m, 2H),7.72-7.58 (m, 5H), 5.39-5.24 (m, 2H), 4.92-4.63 (m, 1H,与HDO峰重叠), 4.20-4.09 (m, 2H)。
实施例16
(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸钙
将(2S)-3-[1-({5-氨甲酰基-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例10, 35.0 mg, 53.4µmol)在水(15 ml)中的溶液用醋酸钙一水合物(9.40 mg,53.4µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到37.9 mg (定量)的标题化合物。
LC-MS (方法2): Rt = 1.33 min; MS (ESIpos): m/z = 656.1 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.00-7.91 (m, 1H), 7.89-7.77 (m, 2H),7.73-7.55 (m, 5H), 5.42-5.22 (m, 2H), 4.99-4.50 (m, 1H,与HDO峰重叠), 4.27-3.99 (m, 2H)。
实施例17
(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯-苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯
在0℃,将3-({3-(4-氯苯基)-5-氧代-4-[(2S)-3,3,3-三氟-2-羟丙基]-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(实施例8A, 200mg, 368µmol)在四氢呋喃(4.2 ml, 52 mmol)中的溶液用4-N,N-二甲基氨基吡啶(67.5mg, 552µmol)和三乙胺(77µl, 550µmol)处理。然后逐滴加入磷酰氯(52µl, 0.55 mmol)。将得到的混合物在0℃搅拌40 min,并然后在室温搅拌50 min。此后加入水(420µl)和饱和碳酸氢钠水溶液(2.5 ml),并将得到的混合物在室温搅拌过夜。然后在室温蒸发四氢呋喃。将得到的溶液用水稀释,并用乙酸乙酯萃取。将水相用盐酸溶液(1N)调至pH = 1,用饱和氯化钠水溶液稀释,并用乙酸乙酯萃取。将合并的有机层用饱和氯化钠溶液洗涤,经硫酸镁干燥和蒸发。将残余物通过制备型HPLC (方法4)纯化,得到126 mg (理论值的55%)的标题化合物。
LC-MS (方法2): Rt = 1.22 min; MS (ESIneg): m/z = 621.0 [M-H]-
¹H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.64-8.34 (m, 2H), 8.24 (dd, 1H),7.96 (s, 1H), 7.80-7.48 (m, 5H), 5.25-5.00 (m, 2H), 4.93 - 4.76 (br m, 1H),4.20-3.87 (m, 2H), 3.34 (br s, 2H,与HDO峰重叠)。
实施例18
(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钾
将(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例17, 35.0 mg, 56.2µmol)在水(2.0 ml)中的溶液用碳酸氢钾(11.2 mg, 112µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到40.2 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.64 min; MS (ESIpos): m/z = 623.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.54 (dd, 1H), 8.22 (dd, 1H), 7.76-7.58(m, 5H), 5.42 - 5.29 (m, 2H), 4.92-4.63 (m, 1H,与HDO峰重叠), 4.20-4.07 (m,2H)。
实施例19
(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钾
将(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例17, 35.0 mg, 56.2µmol)在水(2.0 ml)中的溶液用碳酸氢钾(5.62 mg, 56.2µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到37.1 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.65 min; MS (ESIpos): m/z = 623.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.55-8.51 (m, 1H), 8.23-8.18 (m, 1H),7.75-7.57 (m, 5H), 5.35 (q, 2H), 4.90-4.63 (m, 1H,与HDO峰重叠), 4.22-4.10 (m,2H)。
实施例20
(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钠
将(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例17, 35.0 mg, 56.2µmol)在水(2.0 ml)中的溶液用碳酸钠(5.95 mg, 56.2µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到38.9 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.65 min; MS (ESIpos): m/z = 623.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.56-8.53 (m, 1H), 8.25-8.20 (m, 1H),7.75-7.58 (m, 5H), 5.42-5.28 (m, 2H), 4.90-4.64 (m, 1H,与HDO峰重叠), 4.21-4.06 (m, 2H)。
实施例21
(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸氢钠
将(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例17, 35.0 mg, 56.2µmol)在水(2.0 ml)中的溶液用碳酸氢钠(4.72 mg, 56.2µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到36.4 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.64 min; MS (ESIpos): m/z = 623.1 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.56-8.51 (m, 1H), 8.24-8.18 (m, 1H),7.75-7.56 (m, 5H), 5.43-5.28 (m, 2H), 4.92-4.59 (m, 1H,与HDO峰重叠), 4.25-4.09 (m, 2H)。
实施例22
(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸镁
将(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例17, 35.0 mg, 56.2µmol)在水(53 ml)中的溶液用碳酸镁(4.74 mg, 56.2µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到37.8 mg (定量)的标题化合物。
LC-MS (方法2): Rt = 1.13 min; MS (ESIpos): m/z = 623.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.57-8.52 (m, 1H), 8.26-8.19 (m, 1H),7.77-7.58 (m, 5H), 5.43-5.28 (m, 2H), 4.95-4.58 (m, 1H,与HDO峰重叠), 4.07 (s,2H)。
实施例23
(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸钙
将(2S)-3-[1-{[5-氨甲酰基-1-(3-氯吡啶-2-基)-1H-1,2,4-三唑-3-基]甲基}-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例17, 35.0 mg, 56.2µmol)在水(2.0 ml)中的溶液用醋酸钙一水合物(1:1) (9.89 mg,56.2µmol)处理,然后在室温搅拌15 min并冷冻干燥,得到38.5 mg (定量)的标题化合物。
LC-MS (方法1): Rt = 0.65 min; MS (ESIpos): m/z = 623.0 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.56-8.52 (m, 1H), 8.25-8.19 (m, 1H),7.76-7.58 (m, 5H), 5.42-5.29 (m, 2H), 4.68 (s, 1H,与HDO峰重叠), 4.23-4.10 (m,2H)。
实施例24
(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二钾
在0℃,将(2S)-3-[1-({5-氨甲酰基-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-3-基}甲基)-3-(4-氯苯基)-5-氧代-1,5-二氢-4H-1,2,4-三唑-4-基]-1,1,1-三氟丙烷-2-基磷酸二氢酯(实施例1, 400 mg, 0.609 mmol)在乙腈(12 ml)中的溶液用碳酸氢钾溶液(1.2 ml, 1 M, 1.2 mmol)处理。将得到的混合物在0℃搅拌5 min,在室温搅拌5 min,并冷冻干燥。
将50 mg冷冻干燥的化合物溶解在2-丙醇(3 ml)中。将得到的溶液在搅拌下在室温缓慢地浓缩。3周以后,溶剂完全蒸发。将得到的固体通过X-射线衍射学检查,并对应于作为mesomorph物质的标题化合物。根据下式基于TGA分析(9.9%残余溶剂,按质量计)和离子色谱法(9.1%钾,按质量计)计算1.9±0.2的钾化学计量学:
化学计量学= [(%钾)/(1 -%残余溶剂-%钾)] x [(M游离酸)/(M钾)]。
LC-MS (方法5): Rt = 0.67 min; MS (ESIpos): m/z = 657.1 [M+H]+
¹H-NMR (500 MHz, D2O): δ [ppm] = 8.84 (d, 1H), 8.51 (d, 1H), 7.95 (dd,1H), 7.74-7.56 (m, 4H), 5.47-5.23 (m, 2H), 4.23-4.03 (m, 2H)。
表4:在实施例24中得到的化合物的X-射线粉末衍射学
表5: 在实施例24中得到的化合物的红外波谱
用*标记的带是钾盐所特有的。
实验部分- 生物学测定
缩写和首字母简略词:
Acc. No. 登录号
AP 碱性磷酸酶
AVP 精氨酸加压素
Bmax 最大配体结合能力
BSA 牛血清白蛋白
cAMP 环磷酸腺苷
Cat. No. 目录号
cDNA 互补的脱氧核糖核酸
CHO 中国仓鼠卵巢
CRE cAMP应答元件
Ct 周期阈值
DMEM/F12 Dulbecco氏改良的伊格尔培养基/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 半数最大有效浓度
EDTA 乙二胺-四乙酸
FAM 羧基荧光素琥珀酰亚胺基酯
f.c. 终浓度
FCS 胎牛血清
HEPES 4-(2-羟基乙基)哌嗪-1-乙磺酸
IC50 半数最大抑制浓度
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 闪烁迫近测定
TAMRA 羧基四甲基罗丹明
TRIS; Tris 2-氨基-2-羟基甲基丙烷-1,3-二醇
v/v 体积/体积;浓度,百分比溶液。
本发明化合物的活性的证实可以通过本领域中众所周知的体外、离体和体内测定完成。例如,为了证实本发明的化合物的活性,可以使用以下测定。
B-1. 用于确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类、大鼠和狗的V1a和V2加压素受体的激动剂和拮抗剂的鉴别以及本发明的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)。所述试验细胞系组成性地表达人、大鼠或狗V1a或V2受体。在Gαq偶联的V1a受体的情况下,还用钙敏感的发光蛋白水母发光蛋白(人和大鼠V1a)或obelin(狗V1a)的改进形式稳定地转染细胞,所述改进形式在用辅因子腔肠素重构后,在游离钙浓度增加时发射光[Rizzuto R,Simpson AW, Brini M, Pozzan T, Nature 358, 325-327 (1992); Illarionov BA,Bondar VS, Illarionova VA, Vysotski ES, Gene 153 (2), 273-274 (1995)]。所得到的加压素受体细胞对由钙离子的细胞内释放引起的重组地表达的V1a受体的刺激作出应答,这可以通过所得到的发光蛋白发光来定量。将Gs偶联的V2受体稳定地转染进细胞系中,所述细胞系表达在CRE负责的启动子的控制下的萤火虫荧光素酶的基因。V2受体的活化通过cAMP增加而诱导CRE-响应性启动子的活化,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。使用合适的光度计检测所述细胞系的生物发光[Milligan G, MarshallF, Rees S, Trends in Pharmacological Sciences 17, 235-237 (1996)]。
试验程序:
加压素V1a受体细胞系:
在测定前1天,将所述细胞铺板在384-孔微孔滴定板内的培养基(DMEM/F12, 2%FCS, 2mM谷氨酰胺, 10 mM HEPES, 5µg/ml腔肠素)中,并保持在细胞培养箱(96%湿度, 5%v/vCO2, 37℃)中。在测定当天,将不同浓度的试验化合物在微孔滴定板的孔中放置10分钟,然后加入在EC50浓度的激动剂[Arg8]-加压素。立即在光度计中测量得到的光信号。
加压素V2受体细胞系:
在测定前1天,将所述细胞铺板在384-孔微孔滴定板内的培养基(DMEM/F12, 2%FCS, 2mM谷氨酰胺, 10 mM HEPES)中,并保持在细胞培养箱(96%湿度, 5%v/v CO2, 37℃)中。在测定当天,将不同浓度的试验化合物与在EC50浓度的激动剂[Arg8]-加压素一起加入到孔中,并将所述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,在光度计中测量萤火虫荧光素酶的发光。
下面表1A列出了从使用人V1a或V2受体转染的细胞系得到的本发明的化合物(包括外消旋混合物以及分离的对映异构体)的各IC50值。这意味着这些IC50值是前药的值而不是基础相应药物的值,因为前药在测定条件下主要是稳定的。在下面提到的实验中显示了基础相应药物的数据。
表1A:
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受体的重组人胚胎肾细胞系293 (HEK293)或CHO-K1细胞系的膜部分,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中使用在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不同浓度的试验化合物和0.03nM [125I]苯基乙酰基-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2一起在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确定特异性结合的[125I]苯基乙酰基-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2。
使用标准技术,将用编码人加压素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不同浓度的试验化合物和4 nM [3H](Arg8)-加压素一起在25℃温育120分钟。在1mM (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,并将过滤器计数以确定特异性结合的[3H](Arg8)-加压素。
使用MathIQTM (ID Business Solutions Ltd., UK),通过非线性最小二乘法回归分析确定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。
为了验证前药向相应药物的转化,在有和没有碱性磷酸酶存在下温育前药。碱性磷酸酶对磷酸酯基团的切割会将前药转化成基础相应药物[Coleman J. E., Annu. Rev. Biophys. Biomol. Struct. 1992, 21, 441-483]。由于前药和基础相应药物表现出不同的IC50值,在碱性磷酸酶处理以后前药的值类似于相应药物的IC50。
B-3. 用于检测加压素V1a受体拮抗剂对促纤维化基因调节的作用的细胞体外测定
从大鼠心脏组织分离出的、被描述为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)以高拷贝数内源地表达加压素V1a受体AVPR1A,而AVPR2表达不可检测出。同样地,从大鼠肾组织分离的细胞系NRK49F (ATCC No. CRL1570)显示出高AVPR1A mRNA表达和减少AVPR2表达的类似表达谱。关于检测受体拮抗剂对基因表达的AVPR1A受体依赖性调节的抑制的细胞测定,程序如下:
以50 000个细胞/孔的细胞密度,将H9C2细胞或NRK49F细胞接种在用于细胞培养的6-孔微孔滴定板内的2.0 ml Opti-MEM培养基(Invitrogen Corp., Carlsbad, CA, USA, 目录号11058-021)中,并保持在细胞培养箱(96%湿度, 8%v/v CO2, 37ºC)中。24小时以后,给每组3个孔(一式三份)加入媒介物溶液(阴性对照)和加压素溶液([Arg8]-乙酸加压素,Sigma, 目录号V9879)、或试验化合物(溶解于媒介物: 含有20%v/v乙醇的水)和加压素溶液。在细胞培养中,最终的加压素浓度是1 nM。将试验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%的乙醇终浓度。在5小时的温育时间以后,在抽吸下抽出培养物上清液,在350µl RLT缓冲液(Qiagen, 目录号79216)中裂解粘附细胞,并使用RNeasy试剂盒(Qiagen, 目录号74104)从该裂解物中分离出RNA。这之后进行DNA酶消化(Invitrogen, 目录号18068-015)、cDNA合成(Promaga, ImProm-II反转录系统, 目录号A3800)和反转录聚合酶链式反应(RTPCR) (pPCR MasterMix RT-QP2X-03-075,Eurogentec, Seraing, 比利时)。根据试验试剂的生产商的工作方案,进行所有程序。使用Primer3Plus程序,使用6-FAM TAMRA-标记的探针,基于mRNA基因序列(NCBI GenBankEntrez核苷酸数据库)选择RTPCR的引物集合。使用Applied Biosystems ABI Prism 7700序列检测器,以384-孔微孔滴定板形式,根据仪器操作说明书,进行用于确定不同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 Acc. No. NM_013226)的表达水平和Ct = 35的阈Ct值,用δ-δCt值[Applied Biosystems,第2号用户公告,ABI Prism 7700 SDS, 1997年12月11日(2001年10月更新)]表示相对基因表达。
为了验证前药向相应药物的转化,在有和没有碱性磷酸酶存在下温育前药。碱性磷酸酶对磷酸酯基团的切割会将前药转化成基础相应药物[Coleman J. E., Annu. Rev. Biophys. Biomol. Struct. 1992, 21, 441-483]。由于前药和基础相应药物表现出不同的IC50值,在碱性磷酸酶处理以后前药的值类似于相应药物的IC50。
B-4. 用于验证前药向药物的转化的细胞体外测定
为了验证前药向相应药物的转化,在有和没有碱性磷酸酶存在下温育前药。碱性磷酸酶对磷酸酯基团的切割会将前药转化成基础相应药物[Coleman J. E., Annu. Rev. Biophys. Biomol. Struct. 1992, 21, 441-483]。由于前药和基础相应药物表现出不同的IC50值,在碱性磷酸酶处理以后前药的值类似于相应药物的IC50。使用重组细胞系进行本发明的化合物对人V1a受体的IC50值的确定。所述细胞系最初源自仓鼠卵巢上皮细胞(中国仓鼠卵巢, CHO K1, ATCC: 美国典型培养物保藏中心, Manassas, VA 20108, USA)。试验细胞系组成性地表达人V1a受体。细胞也用钙敏感的发光蛋白水母发光蛋白的修饰形式稳定转染,所述修饰形式在用辅因子腔肠素重构以后在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, Vysotski ES, Gene 153 (2), 273-274 (1995)]。得到的加压素受体细胞通过钙离子的细胞内释放对重组地表达的V1a受体的刺激做出反应,所述钙离子的释放可以通过得到的发光蛋白发光来量化。使用合适的光度计检测细胞系的生物发光[Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 17,235-237 (1996)]。
试验程序:
在测定前1天,将所述细胞接种在384-孔微孔滴定板内的培养基(DMEM/F12, 2%FCS, 2mM谷氨酰胺, 10 mM HEPES, 5µg/ml腔肠素)中,并保持在细胞培养箱(96%湿度, 5%v/vCO2, 37℃)中。在测定当天,将100µl在100µM浓度的试验化合物与500单位碱性磷酸酶一起在tyrode缓冲液(20 mM HEPES, 130 mM NaCl, 5 mM KCl, 5 mM NaHCO3, 2 mM MgCl2, pH7,4)中在37℃温育15分钟。温育以后,将化合物立即稀释并在37℃放置10分钟,然后接种V1a细胞。为了检测化合物的拮抗活性,加入EC50浓度的[Arg8]-加压素,并立即在光度计中测量得到的光信号。
在有和没有碱性磷酸酶(AP)存在下进行化合物样品(实施例4A和实施例1)的LC-MS。
方法6 (LC-MS):
仪器MS: Waters TOF仪器;仪器类型UPLC: Waters Acquity I-CLASS;柱: Waters,HSST3, 2.1 x 50 mm, C18 1.8µm;洗脱液A: 1 l水+ 0.01%甲酸;洗脱液B: 1 l乙腈+0.01%甲酸;梯度: 0.0 min 2%B→0.5 min 2%B→7.5 min 95%B→10.0 min 95%B;恒温箱:50℃;流速:1.00 ml/min;紫外检测: 210 nm。
实施例4A(有AP)
LC-MS (方法6): Rt = 3.83 min; MS (ESIpos): m/z = 577.1 [M+H]+。
实施例4A(没有AP)
LC-MS (方法6): Rt = 3.84 min; MS (ESIpos): m/z = 577.1 [M+H]+。
实施例1(有AP)
LC-MS (方法6): Rt = 3.83 min; MS (ESIpos): m/z = 577.1 [M+H]+。
实施例1(没有AP)
LC-MS (方法6): Rt = 3.19 min; MS (ESIpos): m/z = 657.1 [M+H]+。
表2A: 在有和没有碱性磷酸酶(AP)存在下药物和它们的相应前药的IC50值
实施例编号 | 药物 | 有AP的IC<sub>50 </sub>[µM] | 没有AP的IC<sub>50 </sub>[µM] |
1 | 前药 | 0.00145 | 0.01310 |
4A | 药物 | 0.00135 | 0.00125 |
10 | 前药 | 0.00130 | 0.01100 |
6A | 药物 | 0.00135 | 0.00135 |
17 | 前药 | 0.00103 | 0.00945 |
8A | 药物 | 0.00110 | 0.00170 |
B-5. 加压素诱导的人血小板聚集的抑制,用于验证前药向药物的转化
人血小板内源性表达V1a受体。发现相对高的精氨酸加压素(AVP)浓度(约50-100 nM)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的组织用于加压素拮抗剂的药理学研究。
为了验证前药向相应药物的转化,在有和没有碱性磷酸酶存在下温育前药。碱性磷酸酶对磷酸酯基团的切割会将前药转化成药物。由于前药和基础相应药物表现出不同的IC50值,在碱性磷酸酶处理以后前药的值类似于相应药物的IC50。
将100µl在100µM浓度的试验化合物与500单位碱性磷酸酶一起在改进的Tyrode缓冲液(134 mM NaCl, 12 mM NaH2PO4*H2O, 0.34 mM NaH2PO4*H2O, 2.9 mM KCl, 5 mMHEPES, 5 mM葡萄糖)中在37℃温育15分钟,并在进一步用于血小板聚集测定中之前在4℃保存。
通过从无药物至少1周的不吸烟的健康志愿者(n=4/组)静脉穿刺,将人血收集于含有1/10体积的0.106 M柠檬酸三钠的塑料管中。通过将血液样品在室温在140 g离心20分钟,获得富含血小板的血浆(PRP)。将所得沉淀物抛弃,并将PRP进一步离心(11.000 rpm, 1min)以产生血小板较少的血浆(PPP)。使用凝集计(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℃连续搅拌下相对于PPP对照的光透射的变化。在加入20µL AVP (终浓度100 nM)之前5分钟,将不同浓度的加压素拮抗剂(2µL)加入PRP中。通过测量聚集曲线相对于对照应答的最大幅度,确定化合物的抑制作用。通过迭代非线性回归程序基于浓度-应答抑制曲线计算IC50值。将所有值表达为平均值(表3A)。
表3A: 试验化合物对人血小板富集血浆中的聚集的影响。
实施例编号 | 药物 | 有AP的IC<sub>50 </sub>[µM] | 没有AP的IC<sub>50 </sub>[µM] |
1 | 前药 | 0.01274 | 0.14460 |
4A | 药物 | 0.01020 | 0.02115 |
B-6. 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试验化合物。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, NaH2PO41.2, 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℃平衡过的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,通过将制品暴露于K+ (50 mM) Krebs-Henseleit溶液来开始每次实验。然后使用1 nmol/l Arg-加压素使主动脉环预收缩。在建立稳定收缩后,构建试验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。将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2 mm长度的环段安装在小血管腔肌动描记器(Danish Myo Technology A/S,丹麦)中。一个安装钳口连接至千分尺,从而允许控制血管周长。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-壁张力比来确定)。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值的90%。
然后,将血管用Krebs-Henseleit缓冲液洗涤三次并使其平衡30分钟。然后通过双倍地露于高K+溶液(50 mmol/l KCl)来测试收缩性。用Krebs-Henseleit缓冲液洗涤后,然后使用1 nmol/l Arg-加压素使血管预收缩。在建立稳定收缩后,构建试验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。将松弛表示为张力百分比。
为了验证前药向相应药物的转化,在有和没有碱性磷酸酶存在下温育前药。碱性磷酸酶对磷酸酯基团的切割会将前药转化成基础相应药物[Coleman J. E., Annu. Rev. Biophys. Biomol. Struct. 1992, 21, 441-483]。由于前药和基础相应药物表现出不同的IC50值,在碱性磷酸酶处理以后前药的值类似于相应药物的IC50。
B-7. 用于检测心血管效应的体内测定:在麻醉的大鼠中的血压测量(加压素'挑战' 模型)
在氯胺酮/赛拉嗪/戊巴比妥注射麻醉下,使用雄性Sprague-Dawley大鼠(250-350 g体重)。将预装了含有肝素(500 IU/ml)的等渗氯化钠溶液的聚乙烯管(PE-50, Intramedic®)插入颈静脉和股静脉中,然后连接。经由一个静脉入口,借助于注射器,注射Arg-加压素(SIGMA);经由第二个静脉入口,施用试验物。为了确定收缩压,将压力导管(Millar SPR-320 2F)连接进颈动脉中。所述动脉导管连接至压力传感器,所述压力传感器将它的信号传递至配有合适记录软件的记录计算机。在一个典型实验中,以10-15 min的间隔,给实验动物施用3-4次连续推注,所述推注含有在等渗氯化钠溶液中的确定量的Arg-加压素(30 ng/kg)。当血压再次达到最初水平时,在合适的溶剂中,施用作为推注的试验物,随后进行连续输注。此后,在确定的间隔(10-15 min),再次施用与开始相同量的Arg-加压素。基于血压值,确定试验物抵消Arg-加压素的高血压效应的程度。对照动物仅接受溶剂来替代试验物。
在静脉内施用以后,与溶剂对照相比,本发明的化合物会抑制由Arg-加压素造成的血压增加。
B-8. 用于检测加压素V2受体介导的效应的体内测定:在保持在代谢笼中的有意 识的大鼠中的利尿研究
保持Wistar大鼠(400-500 g体重)自由接近食物(Altromin)和饮用水。在实验期间,在适合该重量级大鼠的代谢笼(Tecniplast Deutschland GmbH, D-82383 Hohenpeißenberg)中,单个地保持动物自由接近饮用水7小时。在实验开始时,通过静脉内施用,以1ml/kg体重的合适溶剂(2-羟基丙基-β-环糊精)的体积,将试验物施用给动物。对照动物仅接受溶剂。在同一天平行地进行对照和物质试验。对照组和物质给药组各自由6-8只动物组成。在实验过程中,将动物排泄的尿连续地收集在位于笼子底部的接收器中。为每只动物单独确定尿的体积。在实验开始以前,确定各只动物的体重。
在静脉内施用以后,与溶剂对照施用相比,加压素V2受体阻断化合物实现了增加的尿排泄,这主要基于增加的水排泄(利水作用)。
下面表4A显示了本发明的示例性化合物和比较化合物在3个不同剂量下所观察到的相对于溶剂对照(= 100%)的尿排泄的变化:
表4A:
实施例编号 | 剂量[mg/kg] | 尿体积[%相对于对照] | 剂量[mg/kg] | 尿体积[%相对于对照] | 剂量[mg/kg] | 尿体积[%相对于对照] |
WO2016/071212(实施例82) | 0.3 | 413 | 1.0 | 848 | 3.0 | 1416 |
4A | 0.3 | 95 | 1.0 | 154 | 3.0 | 134 |
1 | 0.3 | 127 | 1.0 | 117 | 3.0 | 108 |
表4A中所示的结果证实,本发明的化合物在体内在所示剂量下不具有任何显著的剂量依赖性V2阻断活性。这与WO2016/071212的实施例82相反,其在3mg/kg静脉内的剂量下与媒介物对照组相比导致尿体积的剂量依赖性增加(至多14倍)。
B-9. 用于检测保护性肾脏作用的体内测定:在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C57Bl/6J小鼠,从CharlesRiver获得6-8周龄的雄性Sprague Dawley®大鼠。将大鼠和小鼠都维持在标准实验室条件下,12小时光照-黑暗循环,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天通过右侧胁腹切口进行右肾切除术。对于肾脏缺血,做一左侧胁腹切口。通过剥离左肾蒂来暴露肾血管。使用非创伤性血管钳在缺血45 min (大鼠)或25 min (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。处死后,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。为了评估血清和尿肾损伤生物标志物(嗜中性粒细胞明胶酶-相关的脂质运载蛋白[NGAL]、肾损伤分子- 1 [KIM-1]和骨桥蛋白),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。
从肾分离总RNA。在处死时将左肾在液氮中快速冷冻。然后将肾组织匀浆化并获得RNA。将总RNA转录为cDNA。使用TaqMan实时PCR,在整个肾组织中分析肾NGAL、骨桥蛋白、KIM-1、Nephrin和Podocin mRNA表达。
通过单向方差分析用针对多重比较的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 7完成。
B-10. 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, 德国)麻醉具有10-15 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研究目的。泮库溴铵(Pancuronium Inresa, Inresa, 德国,2-4 mg/动物,静脉内)另外充当肌肉松弛药。对狗插管,并用约2,5-4 L/min的氧/环境空气混合物(30/70%)通气。使用来自GE Healthcare (Avance, 德国)的呼吸机通气,并使用二氧化碳分析仪(-Datex Ohmeda)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 (Logos®, 德国)的心脏起搏器植入皮下皮囊中,并经由起搏器电极(Siello S60®, Biotronik,德国)与心脏接触,所述起搏器电极利用照明穿过颈外静脉延伸进入右心室中。
此后,去除入口,使狗自发地从麻醉中清醒。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;
● 将心电描记术(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, 德国),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, MillarInstruments, 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。然后用该剂量对药理学物质进行测试。
如果必要的话,放大初级信号(ACQ 7700,Data Sciences International, USA或Edwards-Vigilance-Monitor, Edwards, Irvine, USA),且随后将其输入Ponemah系统(Data Sciences International, 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,并且计算30秒内的平均值。
B-11.对麻醉的大鼠中加压素介导的全身血液动力学、肾血流量和氧合的变化的急性影响
在雄性Sprague Dawley大鼠(Charles River, Deutschland; 350-450 g体重)上进行实验。在准备外科手术时,将大鼠用异氟烷麻醉,并置于加热的桌子上以将深部体温维持在37℃(使用插入的直肠温度计进行评估)。使用已校准的蒸发器应用异氟烷吸入麻醉,以诱导并维持分别为5体积%和2体积%异氟烷的麻醉。将PE50插管放置在右股动脉中以监测平均动脉压(MAP)。将另一根PE50导管插入股静脉用于静脉内输注。将左肾通过胁腹切口暴露,并与肾周附件分离。肾被膜保持完整。在外科手术以及随后的平衡和控制期间,大鼠以100µL/min的速率接受盐水(0.9%NaCl)的静脉内输注。使用连接并稳定在肾脏表面的激光多普勒血流探头(Oxford Optronix, UK)记录肾脏的肾血流量(RBF)测量值。将探头插入肾皮质至2 mm的深度,再将其插入肾髓质4 mm。通过组合式传感器探头(Oxford Optronix, UK)测量肾血流量、氧和温度。连续记录MAP、心率(HR)、RBF、温度和氧。外科手术和平衡后,确定基线测量值20分钟。然后将大鼠以50 ng/kg/min的速率在100µL/kg静脉内输注加压素20分钟。在第三阶段中,确定了以不同浓度作为推注施用的加压素和双重加压素受体拮抗剂(WO2016/071212的实施例82)或选择性V1a拮抗剂(实施例1)或媒介物的组合输注的效果。
表5A: 双重加压素受体拮抗剂WO2016/071212的实施例82对大鼠中加压素(AVP)
介导的全身和肾血液动力学的变化的影响.
表6A: 选择性加压素V1a受体拮抗剂实施例4A对大鼠中加压素(AVP)介导的全身
和肾血液动力学的变化的影响.
表7A: 加压素V1a受体拮抗剂实施例1对大鼠中加压素(AVP)介导的全身和肾血液
动力学的变化的影响.
B-12. pH稳定性
将0.15 mg试验化合物溶解在0.1 ml二甲基亚砜和0.4 ml乙腈中。为了完全溶解,将装有样品溶液的HPLC瓶摇动并用超声辐射处理。然后加入1.0ml相应的缓冲溶液并将样品涡旋。通过HPLC分析样品溶液以确定试验化合物在37℃在24小时时段内的特定时间的量。以百分比表示的峰面积用于定量。
缓冲液
pH 4.0: Fluka缓冲液,定货号33643 (11.76 g柠檬酸、2.57 g氯化钠和2.72 g氢氧化钠)。
pH 7.4: 将90 g氯化钠、13.61 g磷酸二氢钾和83.35 g 1 M氢氧化钠溶液用Millipore水补至1升,并然后1:10稀释。用磷酸调至pH = 7.4。
pH 10: Fluka缓冲液,定货号33649 (4.77 g硼砂、0.73 g氢氧化钠)。
在37℃在不同时间(0 h、1 h、2 h、4 h和24 h)通过HPLC分析样品溶液的15µl部分。以百分比表示的峰面积用于定量。
HPLC方法
洗脱液: A = 1 ml三氟乙酸/L在水中; B = 1 ml三氟乙酸/L在乙腈中
柱: Nucleodur 100 C18ec, 3µm, 50 x 2 mm
温度: 37℃
检测: 214 nm
注射: 15µl
梯度: 时间(min) A (%) B (%) 流速(ml/min)
0.0 98 2 0.75
1.0 98 2 0.75
15.0 5 95 0.75
17.5 5 95 0.75
17.7 98 2 1.50
18.2 98 2 1.50
18.5 98 2 1.00
19.0 98 2 0.75。
对于代表性实施例,在表8A中显示了在不同时间的峰面积(F)与在起点的峰面积之比:
表8A:
B-13. 溶解度
实验程序
对于每种物质,精确称量0.5 - 0.6 mg。在每种情况下,以得到c = 500 μg/ml的浓度的方式向样品中添加足够的介质。将该样品溶液在室温和1400 rpm摇动24小时。
DMSO校准溶液需要0.5 - 0.6 mg的另一个样品重量。给该样品填充DMSO至c =600 μg/ml的浓度。从该储备溶液制备了两种校准溶液。在2 ml HPLC瓶中,首先引入1000 μl DMSO,并吸取34.4 μl储备溶液(c = 20 μg/ml)。将71.4 μl该溶液(c = 20 μg/ml)放置在另一个含有500 μl DMSO (c = 2.5 μg/ml)的2 ml HPLC瓶中。
摇动试验溶液后,将230 μl上清液转移进离心管,并在42 000 rpm (223 000 g)离心30分钟。然后取180 μl上清液,并各自用DMSO (1:5样品1; 1:100样品2)稀释,并转移至HPLC瓶。通过HPLC分析两种校准溶液和稀释的样品溶液。在对应的峰面积上进行定量。
溶剂
蒸馏水;三氟乙酸(Merck; 1.08262.0100);乙腈(HPLC级);DMSO (Merck;8.02912.2500)。
介质
柠檬酸盐缓冲液pH4: Fluka缓冲液,定货号33643 (11.76 g柠檬酸, 2.57 g氯化钠和2.72 g氢氧化钠)。
缓冲液pH7: Fluka缓冲液,定货号33646 (3.52 g磷酸二氢钾、7.26 g磷酸氢钠)。
PBS缓冲液pH7.4:6.18 g氯化钠和3.96 g磷酸二氢钠在1 L蒸馏水中的溶液,用1M氢氧化钠水溶液调至pH 7.4。
Tris缓冲液pH8.5: 将0.6057 g TRIS溶解在95 ml水中,用盐酸水溶液调至pH8.5,补充水直到达到100 ml体积。
HPLC设备
具有可变波长紫外线检测(z.B. Diode-Array)的Agilent 1100或等同设备;超声浴;Vibromix von Janke & Kunkel;来自Eppendorf的恒温混合器。
HPLC-方法
洗脱液A: 1 ml三氟乙酸/L水;洗脱液B: 1 ml三氟乙酸/L乙腈
梯度: 时间(min) A (%) B (%) 流速(ml/min)
0.0 98 2 1.5
0.2 98 2 1.5
3.3 10 90 1.5
4.0 10 90 1.5
4.1 98 2 2.5
4.7 98 2 2.5
5.0 98 2 1.5
柱:Zorbax Extend-c18, 50 x 3.0 mm, 3.5µm;柱温度: 30℃;流速:1.5 ml/min;检测器: 214/254 nm;注射体积: 20µl。
代表性实施例的溶解度显示在表9A中。
表9A:
B-14. 在静脉内和口服施用以后药代动力学参数的确定
在雄性Wistar大鼠、雌性比格狗和雌性食蟹猴中确定根据本发明的化合物的药代动力学参数。借助于各个物种的合适制剂媒介物进行静脉内施用,例如,所述制剂媒介物对于大鼠而言是血浆/DMSO制剂或生理盐水(pH4或更高),或对于狗和猴而言是水/PEG400/乙醇制剂或生理盐水(pH4或更高)。在所有物种中,使用合适的制剂媒介物,诸如水/PEG400/乙醇制剂或生理盐水,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合适的导管插入右侧颈外静脉来简化从大鼠取血。该手术在实验前至少一天进行,采用异氟烷麻醉和施用镇痛药(阿托品/卡布洛芬(Rimadyl)(3/1)0.1 ml皮下)。在时间窗口内采血(通常至少6个时间点),所述时间窗口包括物质施用后至少7小时至最多72小时的终末时间点。当采血时,将其通入含有合适的抗凝剂(优选K-EDTA)的管中。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。
将内部标准品(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沉淀。可替换地,将内部标准品加入乙腈并然后将混合物以过量加入根据本发明的化合物的样品、校准样品和限定剂(qualifiers)中用于蛋白沉淀。加入与LC条件匹配的缓冲溶液,且随后涡旋,然后在2800g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。
使用经验证的药代动力学计算程序,将确定的血浆浓度/时间图用于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)。
由于在血浆中进行物质定量,有必要确定物质的血液/血浆分布,以便能够相应地调节药代动力学参数。为了该目的,将限定量的物质在所讨论物种的全血中在摇滚混合物(rocking roller mixture)中温育20分钟。在2800g离心后,测量血浆浓度(借助于LC-MS/MS,使用C18或联苯反相柱和可变流动相混合物),并通过计算全血浓度与血浆浓度的比率(C血液/C血浆值)来确定。
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成药物制剂:
片剂:
组合物:
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, 德国)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。干燥以后,将颗粒与硬脂酸镁一起混合5 min。将该混合物在常规压片机中压制(关于片剂形式,参见上文)。
口服混悬液:
组合物:
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口服混悬液对应于单剂量的100 mg本发明的化合物。
生产:
将Rhodigel悬浮于乙醇中,并将实施例1的化合物加入混悬液中。在搅拌下,加入水。将混合物搅拌约6小时,直至Rhodigel的溶胀结束。
无菌的静脉内溶液:
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且无热原的注射容器中。
尽管已经参考具体实施方案公开了本发明,但是显而易见,本领域技术人员可以设计本发明的其它实施方案和变化,而不脱离本发明的真实精神和范围。权利要求意图解释为包括所有这样的实施方案和等效变化。
Claims (12)
5. 用于制备根据权利要求1所述的通式(I)的化合物或其药学上可接受的盐、其溶剂合物或其盐的溶剂合物之一的方法,其特征在于
[A]使下式的化合物
其中
R1具有在权利要求1中给出的关于通式(I)的化合物所定义的含义,
在第一步中与磷酰氯反应和在第二步中水解以得到通式(I)的化合物,
或者
[B]使下式的化合物
其中
R1具有在权利要求1中给出的关于通式(I)的化合物所定义的含义,
在第一步中与二磷酸四苄酯反应和在第二步中在还原条件下除去苄基以得到通式(I)的化合物,
任选地随后,在适当的情况下,通过用相应的溶剂和/或碱处理,将通式(I)的化合物转化成它的相应的其药学上可接受的盐、其溶剂合物或其盐的溶剂合物。
6.用于在权利要求1-4中的任一项中所定义的用途的化合物,其用于治疗和/或预防疾病。
7.在权利要求1-4中的任一项中所定义的化合物,其用于治疗和/或预防急性和慢性肾疾病的方法中,所述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、周围动脉疾病(PAD)、冠状微血管功能障碍(CMD)、雷诺氏综合征、痛经、心肾综合征、血容量过多的和血容量正常的低钠血症、肝硬化、腹水、水肿和ADH分泌不足综合征(SIADH)。
8.在权利要求1-4中的任一项中所定义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、周围动脉疾病(PAD)、冠状微血管功能障碍(CMD)、雷诺氏综合征痛经、心肾综合征、血容量过多的和血容量正常的低钠血症、肝硬化、腹水、水肿和ADH分泌不足综合征(SIADH)。
9.药物组合物,其包含在权利要求1-4中的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。
10.权利要求9所述的药物组合物,其包含一种或多种第一活性成分,尤其是根据权利要求1-4中的任一项所述的通式(I)的化合物,和一种或多种其它活性成分,尤其是一种或多种选自以下的另外治疗剂: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、有机硝酸酯、NO供体、可溶性鸟苷酸环化酶的活化剂和刺激物、以及正性肌力药剂、抗炎药、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。
11.在权利要求9或10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、周围动脉疾病(PAD)、冠状微血管功能障碍(CMD)、雷诺氏综合征、痛经、心肾综合征、血容量过多的和血容量正常的低钠血症、肝硬化、腹水、水肿和ADH分泌不足综合征(SIADH)。
12.用于治疗和/或预防人或其它哺乳动物中的急性和慢性肾疾病的方法,所述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、周围动脉疾病(PAD)和冠状微血管功能障碍(CMD)、雷诺氏综合征痛经、心肾综合征、血容量过多的和血容量正常的低钠血症、肝硬化、腹水、水肿和ADH分泌不足综合征(SIADH),所述方法包括给有此需要的人或其它哺乳动物施用治疗有效量的在权利要求1-4中的任一项中所定义的一种或多种化合物、或在权利要求9-10中的任一项中所定义的药物组合物。
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AR076542A1 (es) * | 2009-05-22 | 2011-06-22 | Merck Sharp & Dohme | Antagonistas del receptor de orexina de isonicotinamida |
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