CN114981257A - 取代的吡唑并哌啶羧酸 - Google Patents
取代的吡唑并哌啶羧酸 Download PDFInfo
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- CN114981257A CN114981257A CN202180008063.XA CN202180008063A CN114981257A CN 114981257 A CN114981257 A CN 114981257A CN 202180008063 A CN202180008063 A CN 202180008063A CN 114981257 A CN114981257 A CN 114981257A
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Abstract
本发明涉及取代吡唑并哌啶羧酸、其盐类及其制备方法,以及它们在制备用于治疗和/或预防疾病的药物的用途,特别是心血管疾病和心脏疾病,优选射血分数降低和保留的心力衰竭(HFrEF、HFmrEF和HFpEF)、高血压(HTN)、外周动脉疾病(PAD、PAOD)、心肾和肾脏疾病,优选慢性肾脏疾病和糖尿病肾脏疾病(CKD和DKD)、心肺和肺部疾病,优选肺动脉高压(PH)和其他疾病,优选神经退行性疾病和不同形式的痴呆、纤维化疾病、系统性硬化症(SSc)、镰状细胞病(SCD)、伤口愈合障碍如糖尿病足溃疡(DFU)。
Description
本发明涉及取代的吡唑并哌啶羧酸、其盐及其制备方法,以及它们在制备用于治疗和/或预防疾病的药物方面的用途,特别是心血管疾病和心脏疾病,优选射血分数降低和保留的心力衰竭(HFrEF,HFmrEF和HFpEF)、高血压(HTN)、外周动脉疾病(PAD,PAOD)、心肾和肾脏疾病,优选慢性肾脏疾病和糖尿病肾脏疾病(CKD和DKD)、心肺和肺部疾病,优选肺动脉高压(PH)和其他疾病,优选神经退行性疾病和不同形式的痴呆、纤维化疾病、系统性硬化症(SSc)、镰状细胞病(SCD)、伤口愈合障碍如糖尿病足溃疡(DFU)。
此外,当对具有输血指征的患者进行输血(例如,例如通过贮存等使游离血红蛋白浓度升高)时,上述相同的病理生理机制也是有效的。
此外,在未来,sGC激活剂与合成血红蛋白氧载体的结合可能会减轻迄今为止发现的由于NO的可用性降低引起的副作用[Weiskopf,Anaesthesia&Analgesia,110:3;659-661,2010],从而允许临床应用。
环磷酸鸟苷(cGMP)是哺乳动物细胞中最重要的细胞传递系统之一。它与内皮细胞释放的传递激素和机械信号的一氧化氮(NO)一起,形成NO/cGMP体系。鸟苷酸环化酶催化三磷酸鸟苷(GTP)生物合成cGMP。目前所公开的这一家族的代表,根据结构特征和配体类型可分为两类:可被钠尿肽刺激的颗粒状鸟苷酸环化酶和可被NO刺激的可溶性鸟苷酸环化酶。可溶性鸟苷酸环化酶由两个亚基组成且每个异源二聚体很可能含有一个血红素,该血红素是调控位点的一部分。后者对激活机制至关重要。NO能够与血红素的铁原子结合,从而显著提高酶的活性。相比之下,不含血红素的制剂不能被NO刺激。一氧化碳(CO)也能附着在血红素的中心铁原子上,但CO的刺激作用明显小于NO。
通过产生cGMP以及调节由此产生的磷酸二酯酶、离子通道和蛋白激酶,鸟苷酸环化酶在各种生理过程中,特别是在平滑肌细胞的松弛和增殖、血小板聚集和粘附、神经元信号传递以及上述过程受损引起的病症中发挥着至关重要的作用。在病理生理条件下,NO/cGMP系统可能受到抑制,这可能例如导致高血压、血小板活化、细胞增殖和纤维化增加、内皮功能障碍、动脉粥样硬化、心绞痛、心力衰竭、血栓形成、中风和心肌梗死。
一种可治疗此类疾病的不依赖于NO并旨在影响生物体中的cGMP信号通路的方法是很有前途的,因为其效率高且预期的副作用少。
化合物例如有机硝酸盐的作用基于NO,迄今为止已专门用于可溶性鸟苷酸环化酶的治疗性刺激。NO由生物转化产生,并通过附着在血红素的中心铁原子上激活可溶性鸟苷酸环化酶。除了副作用之外,耐受性的发展是这种治疗方法的重要缺点之一[O.V.Evgenovet al.,Nature Rev.Drug Disc.5(2006),755]。
近年来已发现可直接刺激可溶性鸟苷酸环化酶即不预先释放NO的物质。吲唑衍生物YC-1是所述的第一个不依赖NO但依赖血红素的sGC刺激剂[Evgenov et al.,ibid.]。基于YC-1,发现了比YC-1更强效且对磷酸二酯酶(PDE)没有相关抑制作用的其他物质。这导致了吡唑并吡啶衍生物BAY 41-2272、BAY 41-8543、BAY 63-2521和BAY 102-1189的发现。这些化合物与最近发表的结构不同的物质CMF-1571和A-350619一起,形成了新类别的sGC刺激剂[Evgenov et al.,ibid.]。该类物质的一个共同特征是不依赖NO和选择性地激活含血红素的sGC。此外,基于亚硝基-血红素复合物的稳定性,sGC刺激剂与NO结合对sGC的活化具有协同作用。sGC刺激剂在sGC上的确切结合位点仍存在争议。如果从可溶性鸟苷酸环化酶中除去血红素基团,该酶仍具有可检测的催化基础活性,即仍在形成cGMP。上述任何刺激物都不能刺激无血红素酶的剩余催化基础活性[Evgenov et al.,ibid.]。
此外,还发现了不依赖NO和血红素的sGC激活剂,其中BAY 58-2667是此类激活剂的原型。这些物质的共同特点是,与NO结合时,它们仅对酶的活化具有累加作用,并且氧化酶或无血红素酶的活化作用显著高于含血红素酶的活化作用[Evgenov et al.,ibid.;J.P.Stasch et al.,Br.J.Pharmacol.136(2002),773;J.P.Stasch et al.,J.Clin.Invest.116(2006),2552]。光谱研究表明,BAY 58-2667取代了由于铁-组氨酸键的减弱仅微弱地附着在sGC上的氧化血红素基团。研究还表明,特征性的sGC血红素结合基序Tyr-x-Ser-x-Arg对于血红素基团的带负电荷的丙酸的相互作用和BAY 58-2667的作用都是非常必要的。在此背景下,假设sGC上BAY 58-2667的结合位点与血红素的结合位点相同[J.P.Stasch et al.,J.Clin.Invest.116(2006),2552]。
sGC激活剂Runcaciguat(Hahn et al.,Drugs Future 43(2018),738,WO 2012/139888)正在由BAYER进行临床开发(https://www.clinicaltrials.gov/NCT04507061)。我们对健康和疾病中sGC的氧化还原平衡的理解是有限的。因此,sGC激活剂的治疗潜力尚不完全清楚。然而,由于氧化应激可以提供无血红素的sGC酶的sGC激活剂,因此sGC激活剂可能具有更广泛的治疗潜力,但这一潜力仍有待于未来进一步识别和证实。
本发明中描述的化合物现在同样能够激活无血红素的可溶性鸟苷酸环化酶。这也被以下事实证实:首先这些新型活化剂在含血红素的酶上与NO没有协同作用,其次它们的作用不能被可溶性鸟苷酸环化酶的血红素依赖性抑制剂1H-1,2,4-噁二唑并[4,3-a]喹喔啉-1-酮(ODQ)阻断,却能被这种抑制剂增强[参见O.V.Evgenov et al.,Nature Rev.DrugDisc.5(2006),755;J.P.Stasch et al.,J.Clin.Invest.116(2006),2552]。
在WO 2012/058132中,取代的吡唑并吡啶羧酸被公开为sGC活化剂。与本发明的化合物相比,这些化合物确实具有一个将吡唑羧酸与分子的其余部分连接起来的杂芳吡啶部分。此外,吡啶氮具有不同于本发明化合物的哌啶氮的位置。然而,在临床前药代动力学模型中,这些化合物仅显示出一般的药代动力学特性,例如静脉内(iv)给药后的中等清除率(CL)和中度半衰期和平均停留时间(MRT)。
因此,本发明的一个目的是提供新型sGC激活剂化合物,用于治疗和/或预防在人和动物中的疾病,特别是心血管和心脏疾病,优选射血分数降低和保留的心力衰竭(HFrEF、HFmrEF和HFpEF)、高血压(HTN)、外周动脉疾病(PAD、PAOD)、心肾和肾脏疾病,优选慢性肾脏疾病和糖尿病肾脏疾病(CKD和DKD)、心肺和肺部疾病,优选肺动脉高压(PH),以及其他疾病,优选神经退行性疾病和不同形式的痴呆、纤维化疾病、系统性硬化症(SSc)、镰状细胞病(SCD)、伤口愈合障碍如糖尿病足溃疡(DFU),这些化合物显示出良好的药代动力学行为,具有良好的药理活性特征以及有益的物理化学性质(例如溶解度)。
令人惊讶的是,现已发现某些取代吡唑并哌啶羧酸及其相应的盐是高效的sGC活化剂,这些活化剂具有良好的药代动力学行为,具有良好的药理活性特征以及有益的物理化学性质(例如溶解度)。
本发明提供公式(I)的化合物及其盐、其溶剂化物和其盐的溶剂化物
其中
R1代表氢或卤素,
R2代表氢或卤素,
R3代表氯或三氟甲基
R4代表氢或C1-C4-烷基
R5代表C1-C6-烷基
X1代表氮或碳
X2代表氮或碳。
“取代”一词是指特定的原子或基团上的一个或多个氢原子被从指定基团中选择的一个基团替代,前提是不超过现有情况下指定原子的正常价态。允许取代基和/或变量的组合。
本文中所使用的术语“一个或多个”,例如在本发明通式(I)化合物的取代基的定义中,意味着“1、2、3、4或5个,特别是1、2、3或4个,更具体而言是1、2或3个,甚至更具体指1或2”。
在本发明的上下文中,除非另有说明,否则取代基定义如下:
术语“卤素”或“卤代”如在组合,例如在卤代烷基中,是指氟、氯、溴或碘原子,特别是氟、氯或溴原子,甚至更具体而言是氟或氯。
术语“C1-C4烷基”、“C1-C5烷基”和“C1-C6烷基”是指含有1、2、3或4个碳原子、1、2、3、4或5个碳原子和1、2、3、4、5或6个碳原子的直链或支链的饱和单价烃基,如甲基、乙基、丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1-乙基丁基、2-乙基丁基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、2,3-二甲基丁基、1,2-二甲基丁基或1,3-二甲基丁基,或其同分异构体。具体而言,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,更具体而言有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。
术语“C1-C6-卤代烷基”、“C2-C6-卤代烷基”、“C1-C4-卤代烷基”、“C2-C4-卤代烷基”、“C1-C3-卤代烷基”和“C1-C2-卤代烷基”表示直链或支链的饱和单价烃基,其中“烷基”定义同上,并且其中一个或多个氢原子被卤素原子相同或不同地取代。特别地,所述卤素原子为氟原子。所述C1-C6卤代烷基为例如氟甲基、二氟甲基、三氟甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、五氟乙基、3,3,3-三氟丙-1-基、1,1,1-三氟丙-2-基、1,3-二氟丙-2-基、3-氟丙-1-基、1,1,1-三氟丁-2-基和3,3,3-三氟-1-甲基-丙-1-基。
术语“C1-C4-卤代烷氧基”和“C1-C3-卤代烷氧基”表示直链或支链的饱和单价C1-C4-烷氧基或C1-C3-烷氧基(其中烷氧基表示具有1~4或1~3个碳原子的直链或支链的饱和单价烷氧基,例如且优选甲氧基、乙氧基、正丙氧基、异丙氧基),其中一个或多个氢原子被卤素原子相同或不同地取代。特别地,所述的卤素原子是氟原子。例如,所述的C1-C3卤代烷氧基是氟甲氧基、二氟甲氧基、三氟甲氧基、2,2,2-三氟乙氧基或五氟乙氧基。
术语“C3-C6环烷基”是指含有3、4、5或6个碳原子的饱和、单价、单环烃环。例如,所述C3-C6-环烷基是环丙基、环丁基、环戊基或环己基。
只要式(I)所涵盖的和在下文中详细说明的化合物还不是盐、溶剂化物和盐的溶剂化物,则本发明所述的化合物是式(I)的化合物及其盐、其溶剂化物和其盐的溶剂化物,以及式(I)所涵盖的并且在下文中详述的作为实施例的化合物,及其盐,其溶剂化物和其盐的溶剂化物。
根据它们的结构,本发明的化合物可以不同的立体异构形式存在,即以构型异构体的形式存在,或者在适当的情况下以构象异构体(对映异构体和/或非对映异构体,包括旋转异构体和阻转异构体的情况)的形式存在。因此,本发明包含了对映异构体和非对映异构体及其各自的混合物。立体异构均一的成分可以以已知方式从对映异构体和/或非对映异构体的混合物中分离;为此优选使用色谱法,尤其是非手性或手性相上的HPLC色谱。
本发明包括本发明化合物所有可能的互变异构体,作为单一互变异构体,或作为任意比例的所述互变异构体的任何混合物。
在本发明中,术语“对映异构纯”应理解为,所讨论的化合物在手性中心的绝对构型方面以大于95%,优选大于97%的对映异构体过量值存在。在这种情况下,对映异构体过量值(ee值)是通过借助以下公式评估手性相上相应的HPLC色谱图来计算的:
ee=[EA(面积%)-EB(面积%)]x100%/[EA(面积%)+EB(面积%)]
(EA:较多的对映体,EB:较少的对映体)
本发明还涵盖了本发明化合物所有合适的同位素变体。本发明化合物的同位素变体在本文中被理解为本发明化合物中至少一个原子被同一原子序数但原子质量与自然界中通常或主要存在的原子质量不同的另一个原子替换的化合物。纳入本发明化合物的同位素实例有氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的同位素,如2H(氘)、3H(氚)、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。本发明化合物的特定同位素变体,特别是含有一个或多个放射性同位素的变体,可有益于比如研究化合物的作用机制或体内活性成分的分布;由于比较容易制备和检测,特别是用3H或14C同位素标记的化合物适用于此目的。此外,掺入同位素(例如氘),由于化合物的代谢稳定性增强,例如延长体内半衰期或减少所需的活性剂量,可带来特殊的治疗效果。因此,在某些情况下,本发明化合物的这种修饰也可以构成本发明的优选实施方案。本发明化合物的同位素变体可以通过本领域技术人员已知的方法制备,例如通过下文进一步描述的方法和实施例中描述的步骤,通过对相应的试剂和/或起始化合物进行相应的同位素修饰。
本发明中的优选盐是本发明化合物的生理上可接受的盐。但是,本发明还包含了本身不适合药物应用但可以用于诸如分离或纯化本发明化合物的盐类。
本发明化合物的生理上可接受的盐包括无机酸、羧酸和磺酸的酸加成盐,如盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、苹果酸、柠檬酸、富马酸、马来酸和苯甲酸的盐。
本发明化合物的生理上可接受的盐还包括常规碱的盐,例如并优选碱金属盐(例如钠盐和钾盐)、碱土金属盐(例如钙盐和镁盐)和铵盐,这些铵盐来源于氨或带有1至16个碳原子的有机胺,例如并优选乙胺、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、二环己胺、二甲氨基乙醇、普鲁卡因、二苄胺、N-甲基吗啉、精氨酸、赖氨酸、乙二胺、N-甲基哌啶和胆碱。
本发明包括本发明化合物的所有可能的盐,作为单一盐或任意比例的所述盐的任何混合物
本发明中所述的溶剂化物是指那些通过与溶剂分子配位而在固态或液态形成复合物的本发明化合物的形式。本发明的化合物可含有极性溶剂,特别是如水、甲醇或乙醇,例如作为化合物晶格的结构单元。水合物是与水相配位的溶剂化物的一种特定形式。极性溶剂的量,特别是水,有可能以化学计量或非化学计量比存在。在化学计量溶剂化物的情况下,如水合物、半-、(半-)、单-、倍半-、二-、三-、四-、五-等溶剂化物或水合物分别是可能存在的。本发明包括所有此类水合物或溶剂化物。
此外,本发明所述化合物可作为N-氧化物存在,其定义是本发明化合物中至少有一个氮以已知的方式被氧化。本发明包括所有此类可能的N-氧化物。
此外,本发明还包括本发明化合物的前体药物。术语“前体药物”包含这样的化合物,其本身而言可能具有生物活性或无生物活性,但其在体内的停留时间内转化为本发明所述的化合物(例如通过新陈代谢或水解作用)。
优选式(I)的化合物及其盐、其溶剂化物和其盐的溶剂化物,其中
R1代表氢、氟
R2代表氢、氟
R3代表氯或三氟甲基
R4代表氢或甲基
R5代表C1-C5-烷基
X1代表氮或碳
X2代表氮或碳。
还优选式(I)的化合物及其盐、其溶剂化物和其盐的溶剂化物,其中
R1代表氢、氟
R2代表氢、氟
R3代表氯或三氟甲基
R4代表氢或甲基
R5代表甲基、乙基、正丙基、异丙基、2,2,-二甲基-丙基、异丁基
X1代表氮或碳
X2代表氮或碳。
还优选式(I)的化合物及其盐、其溶剂化物和其盐的溶剂化物,其中
R1代表氢
R2代表氢
R3代表氯或三氟甲基
R4代表氢或甲基
R5代表甲基、乙基、正丙基、异丙基、2,2,-二甲基-丙基、异丁基
X1代表碳或氮
X2代表碳。
还优选式(I)的化合物及其盐、其溶剂化物和其盐的溶剂化物,其中
R1代表氢
R2代表氢
R3代表氯或三氟甲基
R4代表氢
R5代表甲基、乙基、正丙基、异丙基、2,2,-二甲基-丙基、异丁基
X1代表碳
X2代表碳。
还优选式(I)的化合物及其盐、其溶剂化物和其盐的溶剂化物,其中
R1代表氢
R2代表氢
R3代表氯
R4代表氢
R5代表异丁基
X1代表碳
X2代表碳。
还优选下式化合物及其盐、其溶剂化物或其盐的溶剂化物
还优选下式化合物对映体1及其盐、其溶剂化物或其盐的溶剂化物
还优选下式化合物对映体2及其盐、其溶剂化物或其盐的溶剂化物
还优选下式化合物及其盐、其溶剂化物或其盐的溶剂化物
还优选下式化合物及其盐、其溶剂化物或其盐的溶剂化物
特别优选下式化合物
特别优选下式化合物,对映体1
特别优选下式化合物,对映体2
特别优选下式化合物
特别优选下式化合物
特别优选下式化合物
本发明进一步提供了制备式(I)的化合物或其盐、其溶剂化物或其盐的溶剂化物的方法,其中
在第一步[B]中,在还原剂、合适的碱和合适的溶剂存在下,将式(IV)的化合物与式(III)的化合物反应生成式(II)的化合物
其中R1、R2、R3、R4和X1和X2定义同上,
R5a-CHO (III),
其中R5a代表C1-C3-烷基,优选异丙基
其中R1,R2,R3,R4,R5和X1和X2定义如上
并且
在第二步[A]中
将式(II)化合物在合适的溶剂中与碱反应生成式(I)的化合物
其中R1、R2、R3、R4、R5和X1和X2定义如上。
任选地在第三步[A]*中,将式(I)化合物在合适的溶剂中有合适的酸存在的条件下,转化为相应的式(Ia)的盐
其中R1、R2、R3、R4、R5和X1、X2定义同上。
或者
在第一步[D]中,在钯源、合适的配体和碱的存在下,将式(VIII)的化合物与式(VII)的化合物反应生成式(II)的化合物
其中R1、R2和R3定义如上,
其中R4、R5、以及X1和X2定义如上,
其中R9代表氢、甲基或两个R9通过相邻的氧原子形成4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷
其中R1、R2、R3、R4、R5和X1、X2定义如上
并且
在第二步[A]中,将式(II)化合物在合适的溶剂中与碱反应,生成式(I)的化合物
其中R1、R2、R3、R4、R5和X1和X2定义如上。
任选地在第三步[A]*中,将式(I)化合物在合适的溶剂中合适的酸存在下,转化为相应的式(Ia)的盐
反应[A]*(盐形成)
反应[A]*通常在惰性溶剂中在酸存在的条件下进行,优选在大气压下0℃至60℃的温度范围内进行。
用于盐形成的合适的酸通常是硫酸、氯化氢/盐酸、溴化氢/氢溴酸、磷酸、乙酸、三氟乙酸、甲苯磺酸、甲磺酸或三氟甲磺酸,或它们的混合物,任选地加入水。优选氯化氢、溴化氢、甲苯磺酸、甲磺酸或硫酸。
用于盐形成的合适的惰性溶剂包括醚类如乙醚、二噁烷、四氢呋喃、乙二醇二甲醚或二乙二醇二甲醚,或其他溶剂如丙酮、乙酸乙酯、乙醇、正丙醇、异丙醇、乙腈、二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N'-二甲基丙烯脲(DMPU)或N-甲基吡咯烷酮(NMP)。也可以使用上述溶剂的混合物。优选乙醚、二噁烷、四氢呋喃或这些溶剂的混合物。
反应[A](酯水解)
式II的化合物中酯基的水解通过常规方法进行,通过在惰性溶剂中用酸或碱处理酯,其中在后一种变形中,最初形成的盐经酸处理转化为游离羧酸。在叔丁基酯的情况下,酯水解优选用酸进行。
适合这些反应的惰性溶剂是水或常用于酯裂解的有机溶剂。这些优选包括醇类如甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇,醚类如乙醚、四氢呋喃、1,4-二噁烷或1,2-二甲氧基乙烷,或其他溶剂如二氯甲烷、丙酮、甲乙酮、N,N-二甲基甲酰胺或二甲亚砜。同样可以使用这些溶剂的混合物。在碱性酯水解的情况下,优选使用水与二噁烷、四氢呋喃、甲醇、乙醇和/或二甲基甲酰胺的混合物或四氢呋喃与甲醇或乙醇的混合物。在与三氟乙酸反应的情况下,优选使用二氯甲烷,在与氯化氢反应的情况下,优选使用四氢呋喃、乙醚、二噁烷或水。
合适的碱是常用的无机碱。其中特别包括碱金属或碱土金属氢氧化物,例如氢氧化锂、氢氧化钠、氢氧化钾或氢氧化钡,或碱金属或碱土金属碳酸盐,例如碳酸钠、碳酸钾或碳酸钙。优选氢氧化锂、氢氧化钠或氢氧化钾。
适用于酯水解的酸通常是硫酸、氯化氢/盐酸、溴化氢/氢溴酸、磷酸、乙酸、三氟乙酸、甲苯磺酸、甲磺酸或三氟甲磺酸,或它们的混合物,任选地加入水。在叔丁基酯的情况下优选氯化氢或三氟乙酸,在甲基酯的情况下优选盐酸。
酯水解通常在-20℃至+120℃的温度范围内进行,优选在0℃至+80℃进行。
式(II)的化合物为新型的,
其中R1、R2、R3、R4、R5和X1、X2的定义同上。
式(II)的化合物可以由相应的式(IV)的起始化合物通过
[B]在还原剂、合适的碱和合适的溶剂存在下,将式(IV)化合物与式(III)的化合物反应生成式(II)的化合物而合成
其中R1、R2、R3、R4和X1、X2定义同上,
R5a-CHO(III),
其中R5a代表C1-C3烷基,优选异丙基,
其中R1、R2、R3、R4、R5以及X1和X2定义如上。
反应[B](还原胺化)
步骤[B]的反应通常在还原剂存在下在惰性溶剂中进行,如果合适的话,在碱和/或任选地在脱水剂存在的情况下进行,优选在大气压下0℃至60℃的温度范围内进行。
适用于还原胺化的还原剂是通常用于此用途的碱金属硼氢化物,例如硼氢化钠、氰基硼氢化钠或三乙酰氧基硼氢化钠;优选使用三乙酰氧基硼氢化钠。
在这些反应中添加酸尤其例如乙酸,和/或脱水剂例如分子筛或原甲酸三甲酯或原甲酸三乙酯,可能是有利的。
碱例如是有机碱,例如三烷基胺如三乙胺、N-甲基吗啉、N-甲基哌啶、4-二甲基氨基吡啶或二异丙基乙胺或吡啶。尤其是N,N-二异丙基乙胺和三乙胺等碱,在这些反应中可能是有利的。
适合这些反应的溶剂尤其是醇类如甲醇、乙醇、正丙醇或异丙醇,醚类如二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷或1,2-二甲氧基乙烷,极性非质子溶剂如乙腈或N,N-二甲基甲酰胺(DMF)或这些溶剂的混合物;优选使用四氢呋喃。
反应一般在0℃到+60℃的温度范围内进行。
公式(Ⅲ)中的醛是市售的,已知的或可以由已知的原料通过已知的工艺合成。
式(IV)的化合物为新型的,
其中R1、R2、R3、R4和X1、X2定义同上。
式(IV)的化合物可以由相应的式(V)的化合物通过
[C]将式(V)化合物在合适的酸和合适的溶剂存在下反应而合成
其中R1、R2、R3、R4和X1和X2定义同上。
反应[C](脱保护)
反应[C]一般是在合适的酸存在下,在惰性溶剂中进行的,优选在大气压下0℃至60℃的温度范围内进行。
酸是例如有机或无机酸,如硫酸、氯化氢/盐酸、溴化氢/氢溴酸、磷酸、乙酸、三氟乙酸、甲苯磺酸、甲磺酸或三氟甲磺酸等,或它们的混合物,任选地加入水。优选氯化氢或三氟乙酸。
适合这些反应的溶剂尤其是醇类如甲醇、乙醇、正丙醇或异丙醇,醚类如二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷或1,2-二甲氧基乙烷,极性非质子溶剂如乙腈或N,N-二甲基甲酰胺(DMF)或此类溶剂的混合物;优先使用四氢呋喃。
反应通常在0℃至+60℃的温度范围内进行。
式(V)的化合物为新型的,
其中R1、R2、R3、R4和X1、X2定义同上。
式(V)化合物可以由相应的式(VIII)化合物通过
[G]使式(VIII)化合物在合适的钯催化剂、碱和合适的溶剂存在下与式(VI)的化合物反应而合成
其中R1、R2和R3定义同上,
其中R4、R9以及X1、X2定义同上。
反应[G](Suzuki偶联)
反应[G]一般是在适当的钯催化剂和适当的碱存在下在惰性溶剂中进行的,优选在大气压下在室温至溶剂回流的温度范围内进行。
用于反应步骤[G]的惰性溶剂例如是醇类如甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇,醚类如二乙醚、二噁烷、四氢呋喃、乙二醇二甲醚或二乙二醇二甲醚,烃类如苯、二甲苯、甲苯、己烷、环己烷或石油,或其他溶剂如二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、N,N'-二甲基丙烯脲(DMPU)、N-甲基吡咯烷酮(NMP)、吡啶、乙腈或水。也可以使用上述溶剂的混合物。优选的是二甲基甲酰胺/水和甲苯/乙醇的混合物。
适用于反应步骤的碱是常用的无机碱。其中特别包括碱金属或碱土金属氢氧化物,如氢氧化锂、氢氧化钠、氢氧化钾或氢氧化钡,碱金属碳酸氢盐如碳酸氢钠或碳酸氢钾,或碱金属或碱土金属碳酸盐如锂、钠、钾、钙或铯的碳酸盐,或碱金属磷酸氢盐如磷酸氢二钠或磷酸氢二钾。优选的碱是碳酸钠或碳酸钾。
适用于反应步骤[“Suzuki偶联”]的钯催化剂的实例有:钯炭、乙酸钯(Ⅱ)、四-(三苯基膦)-钯(0)、双-(三苯基膦)-氯化钯(Ⅱ)、双-(乙腈)-氯化钯(Ⅱ)和[1,1′-双(二苯基膦)二茂铁]二氯钯(Ⅱ)-二氯甲烷络合物[参见如Hassan J.et al.,Chem.Rev.102,1359-1469(2002)]。
反应步骤通常在+20℃至+150℃的温度范围内进行,优选在+50℃至+100℃进行。
式(VI)的化合物是新型的、市售的或可通过已知方法获得的。
式(VIII)的化合物为新型的,
其中R1、R2和R3定义同上。
式(VIII)化合物可通过
[H]使式(IX)的化合物在碱和惰性溶剂存在下与三氟甲磺酸酐反应来制备
其中
R1、R2和R3定义同上。
反应[H](三氟甲磺酸化(triflatization))
反应[H]一般是在惰性溶剂中碱存在下和三氟甲磺酸酐进行反应,优选在大气压下在室温至溶剂回流的温度范围内进行。
碱例如是有机碱如碱胺或吡啶,或无机碱如氢氧化钠、氢氧化锂或氢氧化钾,或碱金属碳酸盐如碳酸铯、碳酸钠或碳酸钾,或醇盐如叔丁醇钾、叔丁醇钠,或吡啶如吡啶或2,6-二甲基吡啶,或碱胺如三乙胺或N,N-二异丙基乙胺;优选三乙胺。
惰性溶剂例如是醚类如二乙醚、甲基叔丁基醚、1,2-二甲氧基乙烷、二噁烷或四氢呋喃,或其他溶剂如二氯甲烷、二甲基甲酰胺、二甲基乙酰胺、乙腈或吡啶,或溶剂的混合物;优选二氯甲烷。
式(IX)的化合物为新型的,
其中R1、R2和R3定义同上。
式(IX)的化合物可通过
[I]任选地在惰性溶剂中使式(X)的化合物与酸反应来制备
其中R1,R2和R3定义同上。
反应[I](酸性脱保护)
反应[I]通常在惰性溶剂中或在没有溶剂的情况下和酸进行反应,优选在大气压下在0℃至溶剂回流的温度范围内进行。
惰性溶剂例如是卤代烃如二氯甲烷、三氯甲烷、四氯化碳或1,2-二氯乙烷,醇类如甲醇或乙醇,醚类如二乙醚、甲基叔丁基醚、1,2-二甲氧基乙烷、二噁烷或四氢呋喃,或其他溶剂如二甲基甲酰胺、二甲氧基乙烷、N-甲基-吡咯烷酮、二甲基乙酰胺、乙腈、丙酮或吡啶,或溶剂的混合物;优选二氯甲烷或二噁烷。
适用于酸性脱保护的酸通常是硫酸、氯化氢/盐酸、溴化氢/氢溴酸、磷酸、乙酸、三氟乙酸、甲苯磺酸、甲磺酸或三氟甲磺酸,或它们的混合物,任选地加入水。优选氯化氢或三氟乙酸。
式(X)的化合物为新型的,
其中
R1、R2和R3定义同上。
式(X)的化合物可通过
[J]使式(XII)的化合物在钯源、合适的配体和碱存在下,与式(XI)的化合物反应制备
其中
R1和R2定义同上,
其中
R3定义同上。
反应[J](Buchwald Hartwig偶联)
反应[J]通常在钯源、合适的配体和碱的存在下在惰性溶剂中进行,优选在大气压下在室温至溶剂回流的温度范围内进行。
钯源和合适的配体为例如钯炭、乙酸钯(Ⅱ)、三(二亚苄基丙酮)钯(0)、四-(三苯基膦)-钯(0)、双-(三苯基膦)-氯化钯(Ⅱ)、双-(乙腈)-氯化钯(Ⅱ)、[1,1′-双(二苯基膦基)二茂铁]二氯钯(Ⅱ)及相应的二氯甲烷络合物,任选地与其他膦配体如2,2'-双(二苯基膦基)-1,1’-联萘(BINAP)、(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)[2-(2’-氨基-1,1’-联苯)]甲磺酸钯(Ⅱ)(XPhos-Pd-G3,CAS-No:1445085-55-1)、(2-联苯)二叔丁基膦、二环己基[2’,4’,6’-三(1-甲基乙基)联苯-2-基]膦(XPhos,CAS-No:CAS-No:564483-18-7)、双(2-苯基膦基苯基)醚(DPEphos)或4,5-双(二苯基膦基)-9,9-二甲基呫吨(Xantphos:CAS-No:161265-03-8)[参见例如Hassan J.et al.,Chem.Rev.2002,102,1359-1469]、2-(二环己基膦)-3,6-二甲氧基-2’,4’,6’-三异丙基-1,1’-联苯(BrettPhos,CAS-No:1070663-78-3)、2-二环己基膦-2’,6’-二甲氧基联苯(SPhos,CAS-No:657408-07-6)、2-二环己基膦-2′,6′-二异丙氧基联苯(RuPhos,CAS-No:787618-22-8)、2-(二叔丁基膦基)-3-甲氧基-6-甲基-2',4',6'-三异丙基-1,1'-联苯(RockPhos)和2-二叔丁基膦基-2',4',6'-三异丙基联苯(tert-ButylXPhos)结合使用。也可以使用相应的预催化剂如氯-[2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯][2-(2-氨基乙基))-苯基]钯(II)(BrettPhos预催化剂)[参见例如S.L.Buchwald et al.,Chem.Sci.2013,4,916],任选地与其他膦配体如2-(二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯(BrettPhos)结合使用。
优选2,2'-双(二苯基膦)-1,1'-联萘(BINAP)、三(二亚苄基丙酮)钯(0),或结合4,5-双(二苯基膦)-9,9-二甲基呫吨(Xantphos)或或二环己基[2',4',6'-三(1-甲基乙基)联苯-2-基]膦(XPhos)使用。
碱为例如适宜的无机或有机碱,如碱金属或碱土金属碳酸盐如锂、钠、钾、钙或铯的碳酸盐,或碳酸氢钠或碳酸氢钾,碱金属碳酸氢盐如碳酸氢钠或碳酸氢钾,碱金属或碱土金属氢氧化物,如氢氧化钠、氢氧化钡或氢氧化钾;碱金属或碱土金属磷酸盐,如磷酸钾;碱金属醇盐如叔丁酸钠或叔丁酸钾和甲醇钠,碱金属酚盐如酚钠、乙酸钾,酰胺如酰胺钠、锂-、钠-或钾-双(三甲基甲硅烷基)酰胺或二异丙酰胺锂或有机胺如1,5-二氮杂二环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)。优选碳酸铯、碳酸钠、碳酸钾或碳酸氢钠。
惰性溶剂是例如醚类如二噁烷、二乙醚、四氢呋喃、2-甲基四氢呋喃、二正丁基醚、环戊基甲基醚、乙二醇二甲醚或二乙二醇二甲醚,醇类如叔丁醇或戊醇,或二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜、N-甲基吡咯烷酮、甲苯或乙腈或所述溶剂的混合物;优选叔丁醇、1,4-二噁烷和甲苯。
式(XI)中的化合物是已知的,或者可以通过已知的方法由相应的、市售起始化合物合成。
式(XII)的化合物是新型的
其中
R1和R2定义同上。
式(XII)化合物可通过
[K]使式(XIII)的化合物与酸在惰性溶剂中反应来制备
其中
R1和R2定义同上。
反应[K](去叔丁氧羰基化(debocylation))
反应[K]通常在惰性溶剂中在合适的酸存在下进行,优选在大气压下0℃至60℃的温度范围内进行。
酸是如有机或无机酸,例如硫酸、氯化氢/盐酸、溴化氢/氢溴酸、磷酸、乙酸、三氟乙酸、甲苯磺酸、甲磺酸或三氟甲磺酸,或它们的混合物,任选地加入水。优选氯化氢或三氟乙酸。
惰性溶剂包括醇类如甲醇、乙醇或异丙醇,醚类如二乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃或1,4-二噁烷、二氯甲烷,极性非质子溶剂如乙腈或N,N-二甲基甲酰胺(DMF)或此类溶剂的混合物;优选使用1,4-二噁烷。
式(XIII)的化合物为新型的,
其中R1和R2如上所述定义。
式(XIII)的化合物可以通过
[L]使式(XV)的化合物与式(XIV)的化合物在溶剂中反应来制备
其中,R1和R2定义同上,
反应[L](吡唑形成)
反应[L]通常在室温至回流温度下,在溶剂中进行。
合适的溶剂包括醇类如甲醇、乙醇或异丙醇,醚类如乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃或1,4-二噁烷、二氯甲烷,极性非质子溶剂如乙腈或N,N-二甲基甲酰胺(DMF)或这些溶剂的混合物;优选使用乙醇。
式(XIV)的化合物为已知、市售或可由相应的起始化合物经已知方法合成。
式(XV)的化合物为新型的
其中,R1和R2定义同上。
式(XV)的化合物可以通过
[M]使式(XVI)的化合物与氢气在钯炭存在下在合适的溶剂中反应来制备
其中R1和R2定义同上。
反应[M](Z脱保护)
反应[M]通常在钯炭存在下在合适的溶剂中,在室温至回流温度下进行,优选在1bar下进行。
合适的溶剂有醇类例如甲醇、乙醇或异丙醇,醚类如二乙醚、二异丙醚、甲基叔丁基醚、四氢呋喃或1,4-二噁烷、二氯甲烷,极性溶剂如乙腈、N,N-二甲基甲酰胺(DMF)、NMP、乙酸或水或此类溶剂的混合物;优选乙醇/乙酸。
式(XVI)的化合物为新型的,
其中,R1和R2定义同上。
式(XVI)的化合物可通过
[N]使式(XVII)的化合物与式(XVIII)的化合物在还原剂和合适溶剂的存在下反应来制备。
其中R1和R2定义同上
反应[N](还原性肼化(hydrazination))
反应[N]通常在还原剂和合适溶剂的存在下,在大气压下在室温至溶剂回流的温度范围内进行。
合适的溶剂有醇类如甲醇、乙醇、正丙醇或异丙醇,醚类如二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷或1,2-二甲氧基乙烷,极性非质子溶剂如乙腈或N,N-二甲基甲酰胺(DMF)或这些溶剂的混合物;优选使用四氢呋喃/甲醇。
合适的还原剂是碱金属硼氢化物,例如硼氢化钠、氰基硼氢化钠或三乙酰氧基硼氢化钠;优选使用硼氢化钠。
式(XVIII)的化合物是已知且市售的或可以通过已知方法由相应的起始化合物合成。
式(XVII)化合物是已知且市售的或可以通过已知方法由相应的起始化合物合成。
或者,式(II)的化合物可以通过
[D]使式(VIII)的化合物与式(VII)的化合物在适当的钯催化剂、碱和适当的溶剂存在下反应获得
其中R1、R2和R3定义同上
其中R4、R5、R9和X1、X2定义同上。
反应[D](Suzuki偶联)
反应[D]通常在合适的钯催化剂和碱存在下在惰性溶剂中进行,优选在大气压下在室温至溶剂回流的温度范围内进行。
用于反应[D]的惰性溶剂例如有醇类如甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇,醚类如二乙醚、二噁烷、四氢呋喃、乙二醇二甲醚或二乙二醇二甲醚,烃类如苯、二甲苯、甲苯、己烷、环己烷或石油,或其他溶剂如二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、N,N'-二甲基丙烯基脲(DMPU)、N-甲基吡咯烷酮(NMP)、吡啶、乙腈或水。也可以使用上述溶剂的混合物。优选二甲基甲酰胺/水和甲苯/乙醇的混合物。
适用于反应步骤的碱是常用的无机碱。其中特别包括碱金属或碱土金属氢氧化物,例如氢氧化锂、氢氧化钠、氢氧化钾或氢氧化钡,碱金属碳酸氢盐如碳酸氢钠或碳酸氢钾,或碱金属或碱土金属碳酸盐如碳酸锂、碳酸钠、碳酸钾、碳酸钙或碳酸铯,或碱金属磷酸氢盐,如磷酸氢二钠或磷酸氢二钾。优选使用的碱是碳酸钠或碳酸钾。
用于反应步骤[“Suzuki-偶联”]的合适钯催化剂的实例包括钯炭、乙酸钯(II)、四-(三苯基膦)-钯(0)、双-(三苯基膦)-氯化钯(II)、双-(乙腈)-氯化钯(II)和[1,1'-双(二苯基膦基)二茂铁]二氯钯(II)-二氯甲烷络合物[参见例如Hassan J.et al.,Chem.Rev.102,1359-1469(2002)]。
反应步骤通常在+20℃至+150℃的温度范围内进行,优选在+50℃至+100℃进行。
式(VIII)的化合物为新型的,
其中R1、R2和R3定义同上
式(VIII)的化合物的合成如上所述。
式(VII)的化合物为新型的
其中R4、R5和R9以及X1、X2定义同上。
式(VII)的化合物通过
[E]使式(XIX)的化合物与式(III)的化合物在还原剂、合适碱和合适溶剂的存在下反应获得
其中R4、R5和R9以及X1、X2定义同上
R5a-CHO(III)
其中R5a定义同上。
反应[E](还原胺化)
反应[E]通常在还原剂存在下在惰性溶剂中进行,适当时可以在碱和/或脱水剂存在的条件下进行,优选在大气压下0℃至60℃的温度范围内进行。
适用于还原胺化的还原剂包括通常用于此用途的碱金属硼氢化物,例如硼氢化钠、氰基硼氢化钠或三乙酰氧基硼氢化钠;优选使用三乙酰氧基硼氢化钠。
在这些反应中添加酸尤其是乙酸,和/或脱水剂如分子筛、原甲酸三甲酯或原甲酸三乙酯可能是有利的。
碱是例如有机碱,如三烷基胺,如三乙胺、N-甲基吗啉、N-甲基哌啶、4-二甲基氨基吡啶或二异丙基乙胺或吡啶。尤其是N,N-二异丙基乙胺和三乙胺等碱,在这些反应中可能是有利的。
适合这些反应的溶剂有醇类如甲醇、乙醇、正丙醇或异丙醇,醚类如二异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二噁烷或1,2-二甲氧基乙烷,极性非质子溶剂如乙腈或N,N-二甲基甲酰胺(DMF)或此类溶剂的混合物;优选使用四氢呋喃。
反应通常在0℃至+60℃的温度范围内进行。
式(III)的醛是市售的或可以通过已知方法由已知的起始原料合成。
式(XIX)的起始物质是市售的、已知的或可通过已知方法获得的。
起始化合物和式(I)的化合物的制备可通过以下合成方案1至5来说明。
方案1
方案2
方案3
方案4
方案5
本发明的化合物具有宝贵的药理学性质,可用于人和动物中疾病的预防和治疗。
本发明的化合物是可溶性鸟苷酸环化酶的有效激活剂。本发明的化合物可引起血管舒张、抑制血小板聚集和降低血压以及增加冠脉和肾脏血流。这些作用是通过可溶性鸟苷酸环化酶的直接非血红素依赖性激活作用和细胞内cGMP的增加来介导的。
此外,本发明所述化合物具有有利的药代动力学特性,具体而言是在静脉注射或口服给药后它们的生物利用度和/或作用时间方面。
与现有技术(WO 2012/058132)公开的化合物相比,本发明的化合物显示出优越的药代动力学(PK)特性(参见实验部分,表3至6)。例如,与WO 2012/058132中作为实施例174公开的现有技术化合物相比,本发明的实施例2在大鼠和狗中均显示出较低的血浆清除率(CL血浆)(高达10倍)和由此产生的较高的暴露量(AUC标准)。实施例2也显示出了所有受试物种在口服(p.o.)给药后的长半衰期和平均停留时间(MRT)。由于所有受试物种口服给药后,实施例2显示出明显较低的血浆清除率和由此产生的具有良好生物利用度的极高暴露量(AUC标准,暴露量,归一化曲线下面积),我们看到与WO 2012/058132中公开的实施例174相比,药代动力学(PK)特性具有明显优势。
本发明的化合物具有不可预见的有用的药理活性谱和良好的药代动力学行为,特别是口服给药后的给定给药间隔内,这种化合物在血液中的充分的暴露量高于最低有效浓度。这一特征导致给定的给药间隔内峰谷比(最大浓度与最小浓度的商)的提高,其优点是可以以较少的频率和显著较低的剂量给药该化合物来达到效果。它们是激活可溶性鸟苷酸环化酶的化合物。
在本发明的语境中,术语“治疗(treatment)”或“处理(treating)”包括抑制、延缓、阻碍、缓解、减轻、限制、减弱、阻止、抵御或治愈疾病、病症、障碍、损伤或健康问题,或这些状态和/或这些状态的症状的发展、病程或进展。术语“疗法(therapy)”在这里被理解为与术语“治疗(treatment)”同义。
在本发明的语境中,“防治(prevention)”、“预防(prophylaxis)”和“防止(preclusion)”作为同义词使用,是指避免或降低来自感染、经受、罹患或具有疾病、病症、障碍、损伤或健康问题,或这些状态和/或这些状态的症状的发展或推进的风险。
对一种疾病、病症、障碍、损伤或健康问题的治疗或预防可能是部分或完全的。
此外,本发明所述的化合物具有更多的优异特性,特别是在肺内给药后其肺选择性作用(与全身性作用相比)、肺滞留时间和/或作用持续时间方面。
本发明所述的化合物特别适用于治疗和/或预防心血管和心脏疾病、心肾疾病、心肺疾病、神经退行性疾病、血栓栓塞疾病、纤维化疾病和伤口愈合障碍。
本发明所述的化合物特别适用于治疗和/或预防心血管和心脏疾病,优选射血分数降低和保留的心力衰竭(HFrEF、HFmrEF和HFpEF)、高血压(HTN)、外周动脉疾病(PAD、PAOD)、心肾疾病,优选慢性肾脏疾病和糖尿病肾脏疾病(CKD和DKD)、心肺疾病,优选肺动脉高压(PH)等疾病,优选神经退行性疾病和不同形式的痴呆、纤维化疾病,系统性硬化症(SSc)、镰状细胞病(SCD)、伤口愈合障碍如糖尿病足溃疡(DFU)。
因此,本发明所述的化合物可在治疗和/或预防以下疾病的药物中使用,例如心血管、心肺和心肾疾病,如高血压(高血压)、心力衰竭、冠心病、稳定型和不稳定型心绞痛、肺动脉高压(PAH)和继发性肺动脉高压(PH)、慢性血栓栓塞性肺动脉高压(CTEPH)、肾性高血压、肾血管性高血压和难治性高血压、外周和心血管疾病、心律失常、房性和室性心律失常和传导障碍,如I-III级房室传导阻滞、室上性心动过速、房颤、房扑、室颤、室扑、室性心动过速、扭转型室性心动过速、心房和心室期外收缩、房室交界性期外收缩、病态窦房结综合征、晕厥、房室结折返性心动过速、Wolff-Parkinson-White综合征、急性冠状动脉综合征(ACS)、自身免疫性心脏病(心包炎、心内膜炎、心瓣膜炎、主动脉炎、心肌病)、拳师犬心肌病、动脉瘤、休克如心源性休克、感染性休克和过敏性休克,此外用于治疗和/或预防以下疾病的药物中,例如血栓栓塞性疾病和局部缺血如心肌缺血、心肌梗塞、中风、心肌肥大、短暂性局部缺血发作、子痫前期、炎症性心血管疾病、冠状动脉和外周动脉痉挛、形成水肿例如肺水肿、脑水肿、肾水肿或心力衰竭引起的水肿、外周灌注受损、再灌注损伤、动静脉血栓形成、微量白蛋白尿、心力衰竭、内皮功能障碍、微血管和大血管损伤(血管炎),以及用于预防如溶栓治疗、经皮腔内血管成形术(PTA)、经皮腔内冠状动脉成形术(PTCA)、心脏移植和搭桥手术之后的再狭窄的药物中。
在本发明的语境中,术语“肺动脉高压”包括原发性和继发性两种亚型,如下文根据其各自病因的Dana Point分类所定义[参见D.Montana和G.Simonneau,在以下文章中:A.J.Peacock et al.(Eds.),Pulmonary Circulation.Diseases and their treatment,3rd edition,Hodder Arnold Publ.,2011,pp.197-206;M.M.Hoeper et al.,J.Am.Coll.Cardiol.2009,54(1),S85-S96]。其中具体包括第1组肺动脉高压(PAH),其中包括特发性和家族性形式(分别为IPAH和FPAH)。此外,肺动脉高压还包括新生儿的持续性肺动脉高压和与下列疾病相关的相关性肺动脉高压(APAH):胶原性疾病、先天性全身性肺分流病变、门静脉高压、HIV感染、某些药物和药剂的摄入(例如食欲抑制剂),具有显著静脉/毛细血管成分的疾病如肺静脉闭塞症和肺毛细血管瘤,或其他疾病如甲状腺疾病、糖原贮积病、戈谢病(Gaucher disease)、遗传性毛细血管扩张症(hereditaryteleangiectasia)、血红蛋白病、骨髓增殖性疾病和脾切除术。Dana Point分类的第2组包括左心疾病(例如心室、心房或瓣膜疾病)所致的肺动脉高压患者。第3组包括与肺部疾病(例如慢性阻塞性肺病(COPD)、间质性肺病(ILD)、肺纤维化(IPF))和/或低氧血症(例如睡眠呼吸暂停综合征、肺泡通气不足、慢性高原病、遗传性畸形)相关的肺动脉高压形式。第4组包括患有慢性血栓性疾病和/或栓塞性疾病的肺动脉高压患者,例如近端和远端肺动脉血栓栓塞阻塞(CTEPH)或非血栓性栓塞(如由于肿瘤疾病、寄生虫、异物等引起)的情况。第5组总结了不太常见的肺动脉高压形式,如存在于患有结节病、组织细胞增生症X或淋巴管瘤病的患者中的肺动脉高压形式。
在本发明语境下,术语“心力衰竭”包括急性心力衰竭和慢性心力衰竭,以及更具体或相关类型的疾病,如急性失代偿性心力衰竭、右心衰竭、左心衰竭、全心衰竭,还有舒张性心力衰竭和收缩性心力衰竭,射血分数降低的心力衰竭(HFrEF),射血分数保留的心力衰竭(HFpEF),射血分数中等的心力衰竭(HFmEF),缺血性心肌病,扩张型心肌病,肥厚型心肌病、特发性心肌病、先天性心脏病和心肌病、心脏瓣膜缺损、与心脏瓣膜缺损相关的心力衰竭、二尖瓣狭窄、二尖瓣关闭不全、主动脉瓣狭窄、主动脉瓣关闭不全、三尖瓣狭窄、三尖瓣关闭不全、肺动脉瓣狭窄、肺动脉瓣关闭不全、混合性心脏瓣膜缺损、心肌炎症(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病性心力衰竭、酒精性心肌病、心脏贮积症,以及舒张性心力衰竭和收缩性心力衰竭、射血分数降低的心力衰竭(HFrEF)、射血分数保留的心力衰竭(HFpEF)。
此外,本发明所述化合物还可用于治疗和/或预防动脉硬化、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、混合性高脂血症、高胆固醇血症、无β脂蛋白血症、谷甾醇血症、黄瘤病、丹吉尔病(Tangier disease)、肥胖症、肥胖以及代谢综合征。
此外,本发明所述化合物可用于治疗和/或预防原发性和继发性雷诺现象,如微循环障碍、跛行、听力障碍、耳鸣、外周和自主神经病变、糖尿病性微血管病变、糖尿病性视网膜病变、糖尿病性四肢溃疡、坏疽、CREST综合征、红斑狼疮、甲癣和风湿病。
此外,本发明所述化合物可用于治疗镰状细胞病(SCD)、镰状细胞性贫血以及其他与镰状细胞病相关的疾病症状(例如影响肺、脑、肾或心脏的终末器官损伤),还可用于治疗疟疾、地中海贫血、溶血性尿毒症综合征、阵发性夜间血红蛋白尿、药物性溶血性贫血或横纹肌病等血管闭塞事件或疼痛危象、贲门失弛缓症、溶血性血管病。此外,由于上述类似的病理生理机制在给具有输血指征的患者输血(例如通过储存等方式使游离血红蛋白浓度升高)时是有效的,因此该化合物可用于接受输血的患者。最后,在未来,sGC激活剂与合成的血红蛋白类氧载体结合可能会减轻迄今为止发现的由NO可用性降低引起的副作用[Weiskopf,Anesthesia&Analgesia,110:3;659-661,2010],从而允许进一步的临床应用。
本发明所述化合物还可用于预防器官或组织的缺血性损伤和/或再灌注相关损伤,还可以用作来源于人或动物的器官、器官部分、组织或组织部分灌注和保存溶液的添加剂,特别是用于外科干预或移植医学领域。
此外,本发明所述的化合物适用于治疗和/或预防肾病,尤其是肾功能不全和肾衰竭。在本发明中,肾功能不全和肾衰竭包括急性和慢性症状(慢性肾病;CKD),以及潜在或相关肾脏疾病,例如肾灌注不足、透析相关性低血压、梗阻性尿路病、肾小球病、肾小球肾炎、急性肾小球肾炎、肾小球硬化、肾小管间质疾病、肾病如原发性和先天性肾病、肾炎、免疫性肾病如肾移植排斥反应和免疫复合物诱导的肾病、毒性物质诱导的肾病、造影剂诱导的肾病、糖尿病和非糖尿病肾病、糖尿病肾病(DKD)、肾盂肾炎、肾囊肿和多囊肾病、肾硬化症、高血压肾硬化症和肾病综合征,其诊断特征是例如肌酐和/或水排泄异常减少,尿素、氮、钾和/或肌酐的血液浓度异常升高,肾酶(例如谷氨酰合成酶)活性改变,尿渗透压或尿量改变,微量白蛋白尿、巨量白蛋白尿增加,肾小球和小动脉损伤,肾小管扩张,高磷血症和/或需要透析。本发明还涵盖了本发明化合物在治疗和/或预防肾功能不全的后遗症方面的用途,例如高血压、肺水肿、心力衰竭、尿毒症、贫血、电解质紊乱(例如高钙血症、低钠血症)以及骨骼和碳水化合物代谢紊乱。
此外,本发明所述化合物适用于治疗和/或预防泌尿系统疾病,如良性前列腺综合征(BPS)、良性前列腺增生(BPH)、良性前列腺增大(BPE)、膀胱出口梗阻(BOO),下尿路综合征(LUTS)、前列腺炎、神经源性膀胱过度活动症(OAB)、尿失禁例如混合性、急迫性、压力性或溢出性尿失禁(MUI,UUI,SUI,OUI)、盆腔疼痛、间质性膀胱炎(IC)以及勃起功能障碍和女性性功能障碍。
本发明所述化合物还适用于治疗和/或预防哮喘病、慢性阻塞性肺病(COPD)、急性呼吸窘迫综合征(ARDS)和急性肺损伤(ALI)、α-1抗胰蛋白酶缺乏症(AATD))、肺纤维化、肺气肿(例如由香烟烟雾引起的肺气肿)和囊性纤维化(CF)。
本发明所述化合物也是用于控制以NO/cGMP系统紊乱为特征的中枢神经系统疾病的活性化合物。尤其适用于改善认知障碍后的知觉、注意力、学习或记忆力,所述认知障碍例如尤其伴随以下情况/疾病/综合征出现:如轻度认知障碍、年龄相关性学习和记忆障碍、年龄相关性记忆丧失、血管性痴呆、颅脑外伤、中风、中风后发生的痴呆(中风后痴呆)、创伤后颅脑损伤、一般注意力障碍、有学习和记忆问题的儿童的注意力障碍、阿尔茨海默病、路易体痴呆、额叶退行性痴呆包括皮克综合征、帕金森病、进行性核麻痹、皮质基底节变性痴呆、肌萎缩侧索硬化症(ALS)、亨廷顿病、脱髓鞘、多发性硬化、丘脑变性、Creutzfeld-Jacob痴呆、HIV痴呆、精神分裂症伴痴呆或Korsakoff精神病。它们还适用于治疗和/或预防中枢神经系统疾病,例如焦虑、紧张和抑郁、中枢神经系统相关性功能障碍和睡眠障碍,以及用于控制食物、兴奋剂和成瘾物质摄入的病理障碍。
此外,本发明所述化合物还适用于调节脑血流,因此是控制偏头痛的有效药剂。还适用于预防和控制例如中风、脑缺血和颅脑外伤等脑梗死(脑卒中)后遗症。本发明的化合物同样可用于控制疼痛状态。
此外,本发明所述化合物具有抗炎作用,因此可作为治疗和/或预防败血症(SIRS)、多器官衰竭(MODS、MOF)、肾脏炎症性病症、慢性肠道炎症(IBD,克罗恩病,UC)、胰腺炎、腹膜炎、类风湿疾病、炎症性皮肤病和炎症性眼病的消炎药物。
此外,本发明的化合物还适用于治疗和/或预防肺、心脏、肾、骨髓及特别是肝脏等内脏器官的纤维化病症,以及皮肤病学纤维化和眼部纤维化疾病。在本发明的语境中,术语“纤维化病症”尤其包括诸如肝纤维化、肝硬化、非酒精性脂肪性肝炎(NASH)、肺纤维化、心内膜心肌纤维化、肾病、肾小球肾炎、间质性肾纤维化、由糖尿病引起纤维化损害、骨髓纤维化和类似的纤维化疾病、硬皮病、系统性硬化症、硬斑病、瘢痕疙瘩、增生性瘢痕、痣、糖尿病视网膜病变、增殖性玻璃体视网膜病变和结缔组织疾病(例如结节病)等疾病。本发明所述化合物同样可用于促进伤口愈合,包括手指溃疡和糖尿病足溃疡的愈合,用于控制术后疤痕,例如由青光眼手术引起的疤痕,以及用于老化和角质化皮肤的美容。
根据其活性特征,本发明的化合物特别适用于治疗和/或预防心血管和心肺疾病,例如原发性和继发性肺动脉高压、心力衰竭、心绞痛和高血压,也用于治疗和/或预防血栓栓塞性疾病、局部缺血、血管疾病、微循环受损、肾功能不全、纤维化疾病和动脉硬化。
本发明还提供了本发明所述的化合物用于治疗和/或预防疾病,特别是上述疾病的用途。
本发明还提供了本发明所述化合物在制备用于治疗和/或预防疾病,特别是上述疾病的药物中的用途。
本发明还提供包含至少一种本发明化合物的药物,用于治疗和/或预防疾病,特别是上述疾病。
本发明还提供本发明化合物在治疗和/或预防疾病,特别是上述疾病的方法中的用途。
本发明还提供了使用有效量的至少一种本发明化合物用于治疗和/或预防疾病,特别是上述疾病的方法。
因此它们适合作为治疗和/或预防人类和动物疾病的药物使用。
本发明进一步提供了本发明化合物用于治疗和/或预防以下疾病的用途,特别是心血管疾病,优选血栓性疾病或血栓栓塞性疾病和/或血栓性并发症或血栓栓塞并发症,如急性冠状动脉综合征或心肌梗塞或缺血性中风或外周动脉闭塞性疾病,和/或糖尿病和/或泌尿生殖系统疾病,尤其是那些关联疾病。
就本发明的目的而言,“血栓性疾病或血栓栓塞性疾病”包括优选发生在动脉血管内并可用本发明所述化合物治疗的疾病,特别是导致外周动脉闭塞性疾病和发生在心脏冠状动脉内的疾病,如急性冠状动脉综合征(ACS)、ST段抬高型心肌梗死(STEMI)和非ST段抬高型心肌梗死(非STEMI)、稳定型心绞痛、不稳定型心绞痛、冠状动脉介入治疗(如血管成形术、支架植入或主动脉冠状动脉搭桥术)后的再闭塞和再狭窄,以及脑血管中的血栓性疾病或血栓栓塞性疾病,如短暂性脑缺血发作(TIA)、缺血性中风包括心源性中风如心房颤动引起的中风、非心源性中风如腔隙性中风、由大动脉或小动脉疾病引起的中风,或由于不确定因素引起的中风、隐源性中风、栓塞性中风、来源不明的栓塞性中风,或导致中风或TIA的血栓性和/或血栓栓塞性起源事件。
此外,本发明所述化合物特别适用于治疗和/或预防促炎成分起重要作用的疾病,包括血管炎,如川崎病、大动脉炎和血栓闭塞性脉管炎(伯格氏病)以及炎症性疾病如心肌炎。
此外,本发明所述化合物适用于治疗和/或预防泌尿生殖道疾病如膀胱过度活动症、间质性膀胱炎和膀胱疼痛综合征。
此外,本发明所述化合物适用于治疗和/或预防糖尿病,包括其终末器官表现如糖尿病视网膜病变和糖尿病肾病。
此外,本发明所述化合物特别适用于治疗和/或预防神经性疾病如神经病理性疼痛、神经退行性疾病和痴呆如血管性痴呆或阿尔茨海默病和帕金森病。
此外,本发明所述化合物特别适用于治疗和/或预防肺部疾病如慢性咳嗽、哮喘和慢性阻塞性肺疾病(COPD)。
本发明进一步提供本发明化合物治疗和/或预防疾病,尤其是上述疾病的用途。
本发明进一步提供本发明化合物在制备用于治疗和/或预防疾病,尤其是上述疾病的药物中的用途。
本发明进一步提供了使用治疗有效量的本发明化合物治疗和/或预防疾病,尤其是上述疾病的方法。
本发明进一步提供了用于治疗和/或预防疾病尤其是上述疾病的方法中的本发明化合物,该方法使用了治疗有效量的本发明化合物。
本发明特别提供了用于治疗和/或预防血栓性或血栓栓塞尤其是动脉粥样硬化血栓性病症的方法中的本发明化合物,该方法使用了治疗有效量的本发明化合物。
本发明还提供了包括本发明所述的化合物和一种或多种其他活性化合物的药物。
此外,本发明所述化合物还可用于预防离体凝血,例如用于保护待移植的器官免受由血块形成造成的器官损伤和保护器官受体免受来自移植器官的血栓栓塞,用于保存血液和血浆制品,用于清洁/预处理导管及其他医疗辅助设备和器械,用于涂覆在体内或离体使用的医疗辅助设备和器械的合成表面,或用于可包含XIa因子或血浆激肽释放酶的生物样品。
本发明还提供了一种防止体外血液凝固的方法,特别是在可包含XIa因子或血浆激肽释放酶或这两种酶的库血或生物样品中,该方法的特征是加入了抗凝血有效量的本发明化合物。
本发明的化合物可以全身和/或局部作用。为此,它们可采用合适的方式给药,例如通过口服、肠胃外、肺、鼻、舌下、舌、颊、直肠、真皮、透皮、结膜或耳道途径给药,或作为植入物或支架给药。
对于这些给药途径,本发明的化合物可以以合适的给药形式给药。
对于口服给药,可以将本发明化合物配制成本领域已知的可以快速和/或以改进的方式递送本发明化合物的剂型,例如片剂(无包衣或包衣片剂,例如具有延迟溶解或不溶解的肠溶或控释包衣)、口腔崩解片、膜剂/囊剂(wafer)、膜剂/冻干剂、胶囊(如硬明胶或软明胶胶囊)、糖衣片、颗粒、丸剂、粉末、乳剂、悬浮剂、气雾剂或溶液。可以将根据本发明的化合物以结晶和/或无定形和/或溶解形式掺入所述剂型中。
肠胃外给药可以避免吸收步骤(例如静脉内、动脉内、心内、脊柱内或腰椎内)或包括吸收步骤(例如肌内、皮下、皮内、经皮或腹膜内)而进行。适合肠胃外给药的给药形式尤其是以溶液、悬浮液、乳剂、冻干剂或无菌粉末等形式注射和输液用的制剂。
适合眼外(局部)给药的是根据现有技术操作的给药形式,其以快速和/或以改进或可控方式释放活性化合物,并含有结晶和/或无定形和/或溶解形式的活性化合物,例如滴眼剂、喷雾剂和洗剂(例如溶液、混悬剂、囊泡/胶体体系、乳剂、气雾剂)、用于滴眼剂、喷雾剂和洗剂的粉剂(例如研磨的活性化合物、混合物、冻干物、沉淀活性化合物)、半固体眼部制剂(例如水凝胶、原位水凝胶、乳膏和软膏)、眼引入物(固体和半固体制剂,例如生物粘合剂、膜剂/囊剂、片剂、隐形眼镜)。
眼内给药包括如玻璃体内、视网膜下、巩膜下、脉络膜内、结膜下、眼球后和结膜下给药。适合于眼内给药的给药形式是根据现有技术操作的给药形式,其能快速和/或以改良或可控方式释放活性化合物,并含有结晶和/或无定形和/或溶解形式的活性化合物,例如注射用制剂和注射用制剂浓缩物(例如溶液、混悬液、囊泡/胶体体系、乳液)、注射用制剂的粉剂(例如研磨的活性化合物、混合物、冻干物、沉淀的活性化合物)、注射用制剂凝胶(半固体制剂,例如水凝胶、原位水凝胶)和植入物(固体制剂,例如可生物降解和不可生物降解的植入物、植入泵)。
优选口服给药。
适用于其他给药途径的实例有用于吸入的药物形式[尤其是粉末吸入器、喷雾器]、滴鼻剂、鼻用溶液、鼻喷雾剂;用于舌、舌下或口腔给药的片剂/膜剂/囊剂/胶囊;栓剂;眼药水、眼药膏、洗眼液、眼用插入物、滴耳剂、耳喷雾剂、耳粉、洗耳液、耳插塞;阴道胶囊、水性混悬剂(洗剂、振荡混合剂)、亲脂性混悬剂、乳剂、软膏剂、霜剂、透皮治疗系统(例如贴剂)、乳液、糊剂、泡沫剂、撒粉剂、植入物或支架。
本发明的化合物可以掺入所述的给药形式中。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包括,尤其是,
·软膏基质(例如石油胶、石蜡、甘油三酯、蜡、羊毛蜡、羊毛蜡醇、羊毛脂、亲水软膏、聚乙二醇),
·栓剂基质(例如聚乙二醇、可可脂、硬脂),
·溶剂(例如水、乙醇、异丙醇、甘油、丙二醇、中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、分散剂或润湿剂(例如十二烷基硫酸钠)、卵磷脂、磷脂、脂肪醇(例如)、山梨醇酐脂肪酸酯(例如)、聚氧乙烯山梨醇酐脂肪酸酯(例如,)、聚氧乙烯脂肪酸甘油酯(例如,)、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(例如,),
·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、缓血酸胺、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(例如);藻酸盐,明胶),·崩解剂(例如改性淀粉、羧甲基纤维素钠、羟基乙酸淀粉钠(例如)、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠(例如)),
·包衣材料(例如糖、虫胶)和用于快速溶解或以改良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)、聚乙烯醇、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸纤维素、邻苯二甲酸乙酸纤维素、聚丙烯酸酯、聚甲基丙烯酸酯例如),
·胶囊材料(例如明胶,羟丙基甲基纤维素),
·增塑剂(例如聚乙二醇、丙二醇、甘油、三乙酸甘油酯、柠檬酸三乙酰酯、邻苯二甲酸二丁酯),
·渗透促进剂,
·稳定剂(例如抗氧化剂,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、乙酸氯己定、苯甲酸钠),
·着色剂(例如无机颜料,如氧化铁、二氧化钛),
·调味剂、甜味剂、风味和/或气味掩蔽剂。
本发明还涉及包括至少一种本发明化合物、通常与一种或多种药学上合适的赋形剂一起的药物组合物,还涉及它们根据本发明所述的用途。
本发明的一个实施方案是包含至少一种本发明所述的式(I)化合物、优选与至少一种惰性、无毒、药学上合适的辅料一起的药物组合物,以及这些药物组合物用于上述目的的用途。
根据另一方面,本发明涵盖药物组合物,特别是药物,其包含至少一种本发明通式(I)的化合物和至少一种或多种其他活性成分,特别是用于治疗和/或预防心血管疾病,优选血栓性疾病或血栓栓塞性疾病和糖尿病,以及泌尿生殖系统和眼科疾病。
本发明中的术语“组合”如本领域技术人员已知的使用,所述组合可以是固定组合、非固定组合或试剂盒组成分(kit-of-parts)。
本发明中的“固定组合”如本领域技术人员已知的使用并且被定义为其中第一活性成分如一种或多种本发明所述通式(I)化合物和其他活性成分一起存在于一个单位剂量或一个单一实体中的组合。“固定组合”的一个实例是药物组合物,其中第一活性成分和其他活性成分存在于混合物如调配物中以便同时给药。“固定组合”的另一个实例是药物组合,其中第一活性成分和其他活性成分存在于一个单位中而不是混合物形式。
本发明的非固定组合或“试剂盒组成分”如本领域技术人员已知的使用并且被定义为第一活性成分和其它活性成分存在于多于一个单位中的组合。非固定组合或试剂盒组成分的一个实例是第一活性成分和其它活性成分分别存在的组合。非固定组合或试剂盒组成分的组分可以单独、顺序、同时、同步或按时间顺序交错给药。
本发明的化合物可以单独使用,或者如果需要的话,可以与其他活性成分组合使用。本发明进一步提供包含至少一种本发明化合物和一种或多种其他活性成分的药物,特别是用于治疗和/或预防上述疾病的药物。合适的活性成分组合的优选实例包括:
·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、吗多明或SIN-1,以及吸入NO;
·抑制环磷酸鸟苷(cGMP)分解的化合物,例如磷酸二酯酶(PDE)1、2、5和/或9抑制剂,尤其是PDE 5抑制剂,例如西地那非、伐地那非、他达拉非、乌地那非、得桑他非(desantafil)、阿伐那非,米罗那非、洛地那非或PF-00489791;
·抑制环磷酸腺苷(cAMP)分解的化合物,例如磷酸二酯酶(PDE)3和4抑制剂,尤其是西洛他唑、米力农、罗氟司特、阿普斯特(apremilast)或克立硼罗(crisaborole);
·降血压的活性成分,例如并优选钙拮抗剂、血管紧张素AII拮抗剂、血管紧张肽转换酶(ACE)抑制剂、中性肽链内切酶(NEP)抑制剂、血管肽酶抑制剂、内皮素拮抗剂、肾素抑制剂、α-受体阻滞剂,β-受体阻滞剂、盐皮质激素受体拮抗剂、rho-激酶抑制剂和利尿剂;
·抗心律失常药,例如并优选钠通道阻滞剂、β-受体阻滞剂、钾通道阻滞剂、钙拮抗剂、If-通道阻滞剂、洋地黄、副交感神经阻滞剂(vagoliytics)、拟交感神经药和其他抗心律失常药如腺苷,腺苷受体激动剂以及维纳卡兰;
·正向强心剂,例如强心苷(Dogoxin)、β-肾上腺素能和多巴胺能激动剂,例如异丙基肾上腺素、肾上腺素、去甲肾上腺素、多巴胺或多巴酚丁胺;
·血管加压素-受体-拮抗剂,例如并且优选考尼伐坦、托伐普坦、利希普坦、莫扎伐普坦、沙特伐普坦(satavaptan)、pecavaptan、SR-121463、RWJ 676070或BAY 86-8050,以及WO2010/105770、WO2011/104322和WO 2016/071212中所描述的化合物;
·改变脂质代谢的活性成分,例如并优选甲状腺受体激动剂、胆固醇合成抑制剂,例如并优选HMG-CoA还原酶抑制剂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、聚合胆汁酸吸附剂、胆汁酸重吸收抑制剂和脂蛋白(a)拮抗剂。
·支气管扩张剂,例如并优选β-肾上腺素能受体激动剂,例如并且优选沙丁胺醇、异丙肾上腺素、奥西那林、特布他林、福莫特罗或沙美特罗,或抗胆碱能药,例如并优选异丙托溴铵;
·抗炎剂,例如并优选糖皮质激素,例如并优选泼尼松、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,以及非甾体抗炎药(NSAID),例如且优选乙酰水杨酸(阿司匹林)、布洛芬和萘普生、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,例如CCR1、2和/或5抑制剂;
·调节免疫系统的药物,例如免疫球蛋白;
·抑制信号转导级联的药物,例如并优选激酶抑制剂,例如并优选酪氨酸激酶和/或丝氨酸/苏氨酸激酶抑制剂;
·抑制细胞外基质降解和修饰的药物,例如并优选基质金属蛋白酶(MMP)抑制剂,例如并优选糜蛋白酶、基质溶素、胶原酶、明胶酶和聚集蛋白聚糖酶的抑制剂(优选MMP-1、MMP-3、MMP-8、MMP-9、MMP-10、MMP-11和MMP-13)以及金属弹性蛋白酶(MMP-12)和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;
·阻断血清素与其受体结合的药物,例如并优选5-HT2b受体拮抗剂;·有机硝酸酯和NO供体,例如并优选硝普钠、硝化甘油、单硝酸异山梨酯、二硝酸异山梨酯、吗多明或SIN-1,以及吸入的NO;
·可溶性鸟苷酸环化酶的NO非依赖性但血红素依赖性刺激剂,例如且优选WO 00/06568、WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO 2012/004258、WO2012/028647和WO 2012/059549中所述的化合物。
·可溶性鸟苷酸环化酶的NO非依赖性但血红素依赖性的活化剂,例如并且优选WO01/19355、WO 01/19776、WO 01/19778、WO 01/19780、WO 02/070462和WO 02/070510中所述的化合物;
·刺激环磷酸鸟苷合成的药物,例如可溶性鸟苷酸环化酶调节剂,例如并优选利奥西呱、西那西呱、维利西呱(vericiguat)或runcaciguat;
·前列环素类似物,例如并优先伊洛前列素、贝拉前列素、曲前列环素或依前列醇;
·抑制可溶性环氧化物水解酶(sEH)的药物,例如并优选N,N'-二环己基脲、12-(3-金刚烷-1-基脲基)-十二烷酸或1-金刚烷-1-基-3-{5-[2-(2-乙氧基乙氧基)乙氧基]戊基}-脲;
·与葡萄糖代谢相互作用的药物,例如并优选胰岛素、双胍、噻唑烷二酮、磺酰脲、阿卡波糖、DPP4抑制剂、GLP-1类似物或SGLT-2抑制剂,例如恩格列净、达格列净、卡格列净、索格列净;
·利钠肽,例如并优选心房利钠肽(ANP)、利钠肽B型(BNP,Nesiritid)利钠肽C型(CNP)或尿扩张素(urodilatin);
·心肌肌球蛋白的激活剂,例如并优选omecamtiv mecarbil(CK-1827452);
·钙增敏剂,例如并优选左西孟旦;
·影响心脏能量代谢的药物,例如并优选依托莫西、二氯乙酸酯、雷诺嗪或曲美他嗪、完全或部分腺苷A1受体激动剂,如GS-9667(以前称为CVT-3619)、卡帕地松(capadenoson)、neladenoson和neladenoson bialanate;
·影响心率的药物,例如并优选伊伐布雷定;
·环氧合酶抑制剂,例如溴芬酸和奈帕芬胺;
·激肽释放酶-激肽系统的抑制剂,例如沙替班特、和艾卡仑肽;
·鞘氨醇1-磷酸信号通路的抑制剂,例如,sonepcizumab;
·补体C5a受体抑制剂,例如依库珠单抗;
·纤溶酶原激活剂(溶栓剂/纤溶剂)和促进溶栓/纤溶的化合物,例如纤溶酶原激活物抑制剂的抑制剂(PAI抑制剂)或凝血酶激活纤溶抑制剂的抑制剂(TAFI抑制剂),例如组织纤溶酶原激活剂(t-PA,例如)、链激酶、瑞替普酶和尿激酶或导致纤溶酶形成增加的纤溶酶原调节物质;
·抗凝物质(抗凝剂),例如肝素(UFH)、低分子量肝素(LMW),如亭扎肝素、舍托肝素、帕肝素、那屈肝素、阿地肝素、依诺肝素、低分子肝素、达肝素、达那肝素、司莫肝素(AVE5026)、阿多米肝素(M118)和EP-42675/ORG42675;
·直接凝血酶抑制剂(DTI),例如普栓达(Pradaxa)(达比加群)、阿替加群(AZD-0837)、DP-4088、SSR-182289A、阿加曲班、比伐卢定和他诺吉群(BIBT-986和前药BIBT-1011)和水蛭素;
·直接Xa因子抑制剂,例如,利伐沙班、阿哌沙班、依多沙班(DU-176b)、贝曲沙班(PRT-54021)、R-1663、达瑞沙班(YM-150)、奥米沙班(FXV-673/RPR-130673)、来他沙班(TAK-442)、雷扎沙班(DPC-906)、DX-9065a、LY-517717、他诺吉群(BIBT-986,前药:BIBT-1011)、艾卓肝素和磺达肝癸钠;
·凝血因子XI和XIa的抑制剂,例如FXI ASO-LICA、非索美生(fesomersen)、BAY121-3790、MAA868、BMS986177、EP-7041和AB-022;
·抑制血小板聚集的物质(血小板聚集抑制剂、血酸细胞聚集抑制剂),例如乙酰水杨酸(例如阿司匹林)、P2Y12拮抗剂,例如噻氯匹定(抵克立得)、氯吡格雷(波立维)、普拉格雷、替格瑞洛、坎格瑞洛和依诺格雷,以及PAR-1拮抗剂,例如沃拉帕沙和PAR-4拮抗剂;
·血小板粘附抑制剂,例如GPVI和/或GPIb拮抗剂,例如Revacept或卡普塞珠单抗(caplacizumab);
·纤维蛋白原受体拮抗剂(糖蛋白-IIb/IIIa拮抗剂),例如阿昔单抗、依替巴肽、替罗非班、拉米非班、来达非班和弗雷非班(fradafiban);
·重组人活化蛋白C,例如除栓素(Xigris)或重组血栓调节蛋白。
抗血栓形成剂优选理解为来自血小板聚集抑制剂、抗凝剂或纤维蛋白溶酶物质的化合物。
在本发明的一个优选实施方案中,本发明化合物与血小板聚集抑制剂联合给药,例如并优选阿司匹林、氯吡格雷、普拉格雷、替格瑞洛、噻氯匹定或双嘧达莫。
在本发明的一个优选实施方案中,本发明化合物与凝血酶抑制剂联合给药,例如并优选希美加群、达比加群、美拉加群、比伐卢定或克赛。
在本发明的一个优选实施方案中,本发明化合物与GPIIb/IIIa拮抗剂联合给药,例如并优选替罗非班或阿昔单抗。
在本发明的一个优选实施方案中,本发明化合物与Xa因子抑制剂联合给药,例如并优选利伐沙班(BAY 59-7939)、DU-176b、阿哌沙班、贝曲沙班、奥米沙班、非德沙班、雷扎沙班、来他沙班、eribaxaban、磺达肝癸钠、艾卓肝素、PMD-3112、达瑞沙班(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,本发明化合物与因子XI或因子XIa抑制剂联合给药,例如且优选FXI ASO-LICA、非索美生、BAY 121-3790、MAA868、BMS986177、EP-7041或AB-022。
在本发明的一个优选实施方案中,本发明化合物与肝素或低分子量(LMW)肝素衍生物联合给药。
在本发明的一个优选实施方案中,本发明化合物与维生素K拮抗剂联合给药,例如并优选香豆素。
降血压剂优选理解为选自钙拮抗剂、血管紧张素AII拮抗剂、ACE抑制剂、内皮素拮抗剂、肾素抑制剂、α-受体阻滞剂、β-受体阻滞剂、盐皮质激素受体拮抗剂、rho-激酶抑制剂和利尿剂的化合物。
在本发明的一个优选实施方案中,本发明化合物与钙拮抗剂联合给药,例如并优选硝苯地平、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,本发明化合物与α-1-受体阻滞剂联合给药,例如并优选哌唑嗪。
在本发明的一个优选实施方案中,本发明化合物与β-受体阻滞剂联合给药,例如并优选普萘洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、阿普洛尔、心得平、喷布洛尔、氯甲苯心安、美替洛尔、纳多洛尔、甲吲哚心安、卡拉洛尔(carazalol)、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、依泮诺尔或布心洛尔。
在本发明的一个优选实施方案中,本发明化合物与血管紧张素AII拮抗剂联合给药,例如并优选氯沙坦、坎地沙坦、缬沙坦、替米沙坦或恩布沙坦,或与双重血管紧张素AII拮抗剂/脑啡肽酶抑制剂,例如并且优选LCZ696(缬沙坦/沙库巴曲)。
在本发明的一个优选实施方案中,本发明化合物与ACE抑制剂联合给药,例如并优选依那普利、卡托普利、赖诺普利、雷米普利、地拉普利、福辛普利、喹诺普利、培哚普利或群多普利(trandopril)。
在本发明的一个优选实施方案中,本发明化合物与内皮素拮抗剂联合给药,例如并且优选波生坦、达鲁生坦、安贝生坦或西他生坦。
在本发明的一个优选实施方案中,本发明化合物与肾素抑制剂联合给药,例如并优选阿利吉仑、SPP-600或SPP-800。
在本发明的一个优选实施方案中,本发明化合物与盐皮质激素受体拮抗剂联合给药,例如并优选螺内酯、AZD9977、非奈利酮或依普利酮。
在本发明的一个优选实施方案中,本发明化合物与下列物质联合给药:袢利尿剂,例如呋塞米、托拉塞米、布美他尼和吡咯他尼;保钾利尿剂,例如阿米洛利和氨苯蝶啶;醛固酮拮抗剂,例如螺内酯,坎利酸钾和依普利酮;噻嗪类利尿剂,例如氢氯噻嗪、氯噻酮、希帕胺和吲达帕胺。
脂质代谢调节剂优选理解为来自以下化合物:CETP抑制剂、甲状腺受体激动剂、胆固醇合成抑制剂如HMG-CoA还原酶抑制剂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,本发明化合物与CETP抑制剂联合给药,例如并优选达塞曲匹、安塞曲匹、托彻普(CP-529 414)、JJT-705或CETP疫苗(Avant)。
在本发明的一个优选实施方案中,本发明化合物与甲状腺受体激动剂联合给药,例如并优选D-甲状腺素、3,5,3'-三碘甲状腺原氨酸(T3)、CGS 23425或阿西替罗(CGS26214)。
在本发明的一个优选实施方案中,本发明化合物与他汀类HMG-CoA还原酶抑制剂联合给药,例如并且优选洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗苏伐他汀或匹伐他汀。
在本发明的一个优选实施方案中,本发明化合物与角鲨烯合成抑制剂联合给药,例如并优选BMS-188494或TAK-475。
在本发明的一个优选实施方案中,本发明化合物与ACAT抑制剂联合给药,例如且优选阿伐麦布、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,本发明的化合物与MTP抑制剂联合给药,例如并且优选为英普他派、BMS-201038、R-103757或JTT-130。
在本发明的一个优选实施方案中,本发明化合物与PPAR-γ激动剂联合给药,例如并优选吡格列酮或罗格列酮。
在本发明的一个优选实施方案中,本发明化合物与PPAR-δ激动剂联合给药,例如并且优选GW 501516或BAY 68-5042。
在本发明的一个优选实施方案中,本发明化合物与胆固醇吸收抑制剂联合给药,例如并且优选依折麦布、替奎安或帕马苷。
在本发明的一个优选实施方案中,本发明化合物与脂肪酶抑制剂联合给药,优选的实例是奥利司他。
在本发明的一个优选实施方案中,本发明化合物与聚合胆汁酸吸附剂联合给药,例如并且优选消胆胺、考来替泊、考来索文(colesolvam)、考来胶或考来替兰(colestimide)。
在本发明的一个优选实施方案中,本发明化合物与胆汁酸重吸收抑制剂联合给药,例如并优选ASBT(=IBAT)抑制剂,例如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,本发明化合物与脂蛋白(a)拮抗剂联合给药,例如并优选吉卡宾钙(CI-1027)或烟酸。
在本发明的一个优选实施方案中,本发明化合物与脂蛋白(a)拮抗剂联合给药,例如并优选吉卡宾钙(CI-1027)或烟酸。
在本发明的一个优选实施方案中,本发明化合物与sGC调节剂联合给药,例如并优选利奥西呱、西那西呱或维利西呱。
在本发明的一个优选实施方案中,本发明化合物与影响葡萄糖代谢的药剂联合给药,例如并优选胰岛素、磺酰脲、阿卡波糖、DPP4抑制剂、GLP-1类似物或SGLT-1抑制剂恩格列净、达格列净、卡格列净(kanagliflozin)、索格列净。
在本发明的一个优选实施方案中,本发明的化合物与TGFβ拮抗剂联合给药,例如并优选吡非尼酮或非苏木单抗(fresolimumab)。
在本发明的一个优选实施方案中,本发明的化合物与CCR2拮抗剂联合给药,例如并优选CCX-140。
在本发明的一个优选实施方案中,本发明的化合物与TNFα拮抗剂联合给药,例如并优选阿达木单抗。
在本发明的一个优选实施方案中,本发明的化合物与半乳糖凝集素-3抑制剂联合给药,例如并优选GCS-100。
在本发明的一个优选实施方案中,本发明的化合物与Nrf-2抑制剂联合给药,例如并优选巴多索隆。
在本发明的一个优选实施方案中,本发明化合物与BMP-7激动剂联合给药,例如并优选THR-184。
在本发明的一个优选实施方案中,本发明化合物与NOX1/4抑制剂联合给药,例如并优选GKT-137831。
在本发明的一个优选实施方案中,本发明化合物与影响维生素D代谢的药物联合给药,例如并优选骨化三醇、阿法骨化醇、度骨化醇、马沙骨化醇、帕立骨化醇、胆钙化醇或旁卡西醇((paracalcitol)。
在本发明的一个优选实施方案中,本发明的化合物与细胞生长抑制剂联合给药,例如并优选环磷酰胺。
在本发明的一个优选实施方案中,本发明化合物与免疫抑制剂联合给药,例如并优选环孢素。
在本发明的一个优选实施方案中,本发明的化合物与磷酸盐结合剂联合用药,例如并优选考来替兰、盐酸司维拉姆和碳酸司维拉姆、镧和碳酸镧。
在本发明的一个优选实施方案中,本发明的化合物与肾近端小管磷酸钠协同转运蛋白联合给药,例如并优选烟酸或烟酰胺。
在本发明的一个优选实施方案中,本发明的化合物与治疗甲状旁腺功能亢进的拟钙剂联合给药。
在本发明的一个优选实施方案中,本发明的化合物与治疗铁缺乏症的药物联合给药,例如并优选铁产品。
在本发明的一个优选实施方案中,本发明的化合物与治疗高尿酸血症的药物联合给药,例如并优选别嘌呤醇或拉布立酶。
在本发明的一个优选实施方案中,本发明的化合物与治疗贫血的糖蛋白激素联合给药,例如并优选促红细胞生成素、达普司他、莫利司他、罗沙司他、伐度司他(vadadustat)、德度司他。
在本发明的一个优选实施方案中,本发明的化合物与用于免疫治疗的生物制剂联合给药,例如并且优选阿巴西普、利妥昔单抗、依库珠单抗或贝利木单抗(belimumab)。
在本发明的一个优选实施方案中,本发明的化合物与治疗心力衰竭的血管加压素拮抗剂(伐普坦类(vaptanes))联合给药,例如并且优选托伐普坦、考尼伐坦、利希普坦、莫扎伐普坦、沙特伐普坦、pecavaptan或瑞考伐普坦(relcovaptan)。
在本发明的一个优选实施方案中,本发明的化合物与Jak抑制剂联合给药,例如并优选芦可替尼、托法替尼、巴瑞替尼、CYT387、GSK2586184、来他替尼、帕瑞替尼(SB1518)或TG101348。
在本发明的一个优选实施方案中,本发明的化合物与治疗微血栓的前列环素类似物联合给药。
在本发明的一个优选实施方案中,本发明的化合物与碱疗法联合给药,例如并优选碳酸氢钠。
在本发明的一个优选实施方案中,本发明的化合物与mTOR抑制剂联合给药,例如并优选依维莫司或雷帕霉素。
在本发明的一个优选实施方案中,本发明的化合物与NHE3抑制剂联合给药,例如并优选AZD1722或特纳帕诺。
在本发明的一个优选实施方案中,本发明的化合物与eNOS调节剂联合给药,例如并优选沙丙蝶呤。
在本发明的一个优选实施方案中,本发明的化合物与CTGF抑制剂联合给药,例如并优选FG-3019。
本发明还提供包含至少一种本发明化合物、通常与一种或多种惰性、无毒、药学上合适的助剂一起的药物,并且提供该药物用于上述目的的用途。
本发明的化合物可以全身和/或局部作用。为此,它们可以以合适的方式给药,例如通过口服、肠胃外、肺、鼻、舌下、舌、颊、直肠、真皮、透皮、结膜、耳部途径给药或作为植入物或支架给药。
本发明所述化合物可采用适合这些给药途径的给药形式给药。
适合口服给药的给药形式是根据现有技术起作用的给药形式,其快速和/或以改良的方式释放本发明的化合物,并且以结晶和/或非晶态和/或溶解形式包含本发明所述化合物,例如片剂(无包衣或包衣片剂,例如具有能控制本发明化合物释放的抗胃液或缓溶或不溶性包衣)、在口腔中快速崩解的片剂或膜剂/囊剂、膜剂/冻干剂或胶囊(例如硬明胶胶囊或软明胶胶囊)、糖衣片剂、颗粒剂、丸剂、粉末、乳剂、悬浮液、气雾剂或溶液。
肠胃外给药可以绕过吸收步骤(例如静脉内、动脉内、心内、脊柱内或腰椎内)或包括吸收步骤(例如肌肉内、皮下、皮内、经皮或腹膜内)。适合肠胃外给药的给药形式包括以溶液、悬浮液、乳剂、冻干剂或无菌粉末形式存在的注射和输液用制剂。
对于其他给药途径,合适的实例是可吸入药物形式(包括粉末吸入器、雾化器)、滴鼻剂、溶液或喷雾剂、片剂、用于舌、舌下或口腔给药的膜剂/囊剂或胶囊、栓剂、耳或眼用制剂、阴道胶囊、水性悬浮液(洗剂、振荡混合物)、亲脂性悬浮液、软膏、乳膏、透皮治疗系统(例如贴剂)、乳液、膏剂、泡沫剂、洒粉剂、植入物或支架。
优选口服或肠胃外给药,尤其是口服和静脉给药。
本发明的化合物可以转化为所述的给药形式。这可以用本身已知的方式,通过与惰性、无毒、适合药用的赋形剂混合来完成。这些赋形剂包括载体(例如微晶纤维素、乳糖、甘露醇)、溶剂(例如液态聚乙二醇)、乳化剂和分散剂或润湿剂(例如十二烷基硫酸钠、聚氧失水山梨醇油酸酯)、粘合剂(例如聚乙烯吡咯烷酮)、合成和天然聚合物(例如白蛋白)、稳定剂(例如抗氧化剂如抗坏血酸)、染料(例如无机颜料如氧化铁)和调味剂和/或矫味剂。
通常,已发现在肠胃外给药的情况下,给药量约为体重的0.001至1mg/kg,优选约体重的0.01至0.5mg/kg,对获得有效结果是有利的。在口服给药的情况下,剂量约为体重的0.01-100mg/kg,优选约为体重的0.01-20mg/kg,最优选为体重的0.1-10mg/kg。
然而,在适当的情况下可能有必要偏离规定的量,特别是根据体重、给药途径、个体对活性化合物的反应、制剂的性质和进行给药的时间或间隔而偏离。例如,在某些情况下,少于上述最小量可能就足够了,而在其他情况下,必须超过所提到的上限。在给药量比较大的情况下,建议将这些药分成一天中的几个单独的剂量。
待给药的活性成分总量范围通常为每天约0.001mg/kg至约200mg/kg体重,优选每天约0.01mg/kg至约50mg/kg体重,更优选每天约0.01mg/kg至约20mg/kg体重。临床上有用的给药时间表从每天给药一到三次到每四周给药一次。此外,“药物假期”,即患者在一段时间内不服药,可能有利于药理作用和耐受性之间的整体平衡。单位剂量可能含有约0.5mg至约1500mg的活性成分,每天可给药一次或多次或少于每天一次。注射给药,包括静脉、肌肉、皮下和肠胃外注射以及使用输液技术的平均日剂量优选为总体重的0.01至200mg/kg。平均每日直肠给药方案优选为总体重的0.01至200mg/kg。平均每日阴道给药方案优选为总体重的0.01至200mg/kg。平均每日局部给药方案优选为0.1至200mg,每天施用1至4次。透皮浓度优选为维持0.01至200mg/kg的日剂量所需的浓度。平均每日吸入给药方案优选为总体重的0.01至100mg/kg。
当然,每个患者的具体初始和持续给药方案将根据主治诊断医师确定的病症的性质和严重程度、所用特定化合物的活性、患者的年龄和一般状况、给药时间、给药途径、药物的排泄率、药物组合等情况而有所不同。本发明所述化合物或其药学上可接受的盐或酯或其组合物的所需治疗模式和剂量,可由本领域技术人员采用常规治疗试验确定。
然而,可能有必要偏离规定的量,即根据体重、给药途径、个体对活性物质的反应、制剂类型和进行给药的时间点或间隔而定。因此,在某些情况下,使用少于上述最小量可能就足够了,而在其他情况下,则必须超过规定的上限。当施用较大剂量时,建议将这些药物分成一天中的几个单独的剂量。
根据另一个实施方案,本发明所述式(I)的化合物每天口服给药一次或两次或三次。根据另一个实施方案,本发明所述式(I)的化合物每天口服给药一次或两次。根据另一个实施方案,本发明所述式(I)的化合物每天口服给药一次。对于口服给药,可以使用快速释放或改良释放剂型。
除非另有说明,以下测试和实施例中的百分比均为重量百分比;份数是重量份。液体/液体溶液的溶剂比、稀释比和浓度数据在每种情况下基于体积计。“w/v”是指“重量/体积”。例如,“10%w/v”是指:100ml溶液或悬浮液包含10g物质。
实验部分
表1:缩写
下表列出了本文中使用的缩写。
缩写 含义
BH3·THF 硼烷-四氢呋喃
BINAP 2,2'-双-二苯基膦基-1,1'-联萘
br 宽峰(1H-NMR信号)
CI 化学电离
d 二重峰(1H-NMR信号)
d 天
DAD 二极管阵列检测器
dd 双二重峰
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
ESI 电喷雾(ES)电离
EtOAc 乙酸乙酯
h 小时
HATU 1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑[4,5-b]吡啶3-氧化物六氟磷酸盐,CAS 148893-10-1
HPLC 高效液相色谱法
LC-MS 液相色谱-质谱联用法
m 多重峰(1H-NMR信号)
M 摩尔
min 分钟
MS 质谱分析法
MTBE 甲基叔丁基醚
NaBH4 硼氢化钠、四氢硼酸钠
NaHCO3 碳酸氢钠
Na2SO4 硫酸钠
NMR 核磁共振光谱:化学位移(δ)以ppm为单位给出。除非另有说明,否则通过将二甲基亚砜信号设置为2.50ppm来校正化学位移。
PDA 光电二极管阵列
Pd2dba3 三(二亚苄基丙酮)二钯(0),CAS 51364-51-3
Pd(PPh3)4 四(三苯基膦)钯(0),CAS 14221-01-3
quant. 定量
rac 外消旋
Rt,Rt 保留时间(用HPLC或UPLC测量)以分钟为单位
RuPhos Pd G3 (2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]甲磺酸钯(II),CAS 1445085-77-7
s 单峰(1H-NMR信号)
SFC 超临界流体色谱法
SQD 单四极杆检测器
t 三重峰(1H-NMR信号)
td 三二重峰(1H-NMR信号)
TFA 三氟乙酸
THF 四氢呋喃
UPLC 超高效液相色谱法
X-Phos 2-二环己基膦基-2',4',6'-三异丙基联苯,CAS 564483-18-7
本文未注明的其他缩写具有技术人员惯用的含义。
本申请中描述的本发明的各个方面通过以下实施例进行说明,这些实施例并不意味着以任何方式限制本发明。本文提及的所有出版物全文均以引用的方式纳入本说明书。
本文描述的实施例测试实验是为了说明本发明,并且本发明不限于给出的实施例。
实验部分-总则部分
合成方法未在实验部分描述的所有试剂,或者是市售的,或者是已知化合物,或者可以由本领域技术人员通过已知方法由已知化合物形成。
按照本发明所述的方法生成的化合物和中间体可能需要纯化。有机化合物的纯化为本领域技术人员所熟知,对同一化合物的纯化可能有几种方法。在某些情况下,可能不需要纯化。在某些情况下,化合物可以通过结晶提纯。在某些情况下,杂质可以使用合适的溶剂搅拌出来。在某些情况下,化合物可以通过色谱法,特别是快速柱色谱法,例如使用预先装好的硅胶柱,例如Biotage SNAP cartidges KP-或KP-结合Biotage自动纯化系统(或Isolera)和洗脱液(如己烷/乙酸乙酯或二氯甲烷/甲醇的梯度溶液)来纯化。在某些情况下,化合物可以通过制备型HPLC进行纯化,例如使用配备有二极管阵列检测器和/或在线电喷雾电离质谱仪的Waters自动纯化器,结合适当的预填充反相柱和洗脱液,如其中可含有三氟乙酸、甲酸或氨水等添加剂的水和乙腈的梯度溶液。
在某些情况下,上述纯化方法可以盐的形式提供那些具有足够的碱性或酸性官能度的本发明化合物,例如就足够碱性的本发明化合物而言,如三氟乙酸盐或甲酸盐,或者就足够酸性的本发明的化合物而言,如铵盐。这种类型的盐可以通过本领域技术人员已知的各种方法分别转化为其游离碱或游离酸形式,或者在随后的生物学测定中作为盐使用。应当理解,如本文所述分离的本发明化合物的具体形式(例如盐、游离碱等)不必是所述化合物可以应用于生物学测定以定量具体生物活性的唯一形式。
在下文描述的本发明的合成中间体和工作实施例中,任何以相应碱或酸的盐形式描述的化合物,通常是通过各自的制备和/或纯化方法得到的确切化学计量组成未知的盐。因此,除非有更详细的说明,否则名称和结构式的附加词,例如“盐酸盐”、“三氟乙酸盐”、“钠盐”或“x HCl”、“x CF3COOH”、“x Na+”,在此类盐的情况下不应以化学计量意义来理解,而应对其中存在的成盐组分仅具有描述性。
如果合成中间体或工作实施例或其盐是通过所述的制备和/或纯化方法以化学计量组成未知(如果它们是确定的类型)的溶剂合物例如水合物的形式获得的,则这相应适用。
NMR峰形是按照它们在光谱中出现的形式描述的,未考虑可能的高阶效应。
所选化合物的1H-NMR数据以1H-NMR峰表的形式列出。对于每个信号峰,给出以ppm为单位的δ值,然后在括号中报告信号强度。不同峰的δ值-信号强度对用逗号分隔开。因此,用通用形式描述一个峰值列表:δ1(强度1),δ2(强度2),...,δi(强度i),...,δn(强度n)。
在打印的核磁共振谱图中,尖锐信号的强度与信号的高度(以cm为单位)相关。当与其他信号相比时,该数据可以与信号强度的实际比率相关联。在宽信号的情况下,与频谱中显示的最强信号相比,显示了多于一个峰值或信号中心及其相对强度。1H-NMR峰表类似于经典的1H-NMR读数,因此通常包含经典NMR解释中列出的所有峰。此外,类似于经典的1H-NMR图谱,峰表可以显示溶剂信号、源自目标化合物(也是本发明的对象)立体异构体的信号和/或杂质峰。与目标化合物(例如,纯度>90%)的峰相比,立体异构体的峰和/或杂质的峰通常显示出较低的强度。这些立体异构体和/或杂质可能是特定制造方法的典型代表,因此它们的峰可能有助于根据“副产品指纹”识别我们制造方法的再现。通过已知方法(MestReC、ACD模拟或使用经验评估的期望值)计算目标化合物峰的专家,可以根据需要分离目标化合物的峰,任选地使用额外的强度滤波器。这样的操作类似于经典1H-NMR解释中的分峰处理(peak-picking)。以峰表形式报告核磁共振数据的详细描述,可在出版物《专利申请中的核磁共振峰表数据引用》中找到(参见Research Disclosure Database Number605005、2014、01Aug 2014或http://www.researchdisclosure.com/searching-disclosures)。在分峰处理过程中,正如Research Disclosure Database Number 605005中所述,参数“最小高度”可以在1%和4%之间调整。根据化学结构和/或被测量化合物的浓度,设定参数“最小高度”<1%可能是合理的。
在立体异构体混合物的NMR谱图中,带有“/”的数字表示立体异构体对各自的氢原子显示出单独的信号,即“…/…(2s,1H)”表示一个氢原子由2个单峰表示,每个单峰来自一种或多种不同的立体异构体。
以下中间体和实施例化合物的IUPAC名称是使用ACD/Name软件(批量版本14.00;Advanced Chemistry Development,Inc.)或在BIOVIA Draw软件(版本4.2SP1;DassaultSystèmes SE)中装备的命名工具生成的。
LC-MS分析方法
方法1
MS仪器类型:SHIMADZU LCMS-2020,色谱柱:Kinetex EVO C18 30*2.1mm,5um,流动相A:0.0375%TFA水溶液(v/v),B:0.01875%TFA乙腈溶液(v/v),梯度:0.0min 0%B→0.8min 95%B→1.2min 95%B→1.21min 5%B→1.55min 5%B,流速:1.5ml/min,烘箱温度:50℃;UV检测:220nm和254nm。
方法2
HPLC仪器型号:SHIMADZU LCMS-2020,色谱柱:Kinetex EVO C18 50*4.6mm,5um,流动相A:0.0375%TFA水溶液(v/v),B:0.01875%TFA乙腈溶液(v/v),梯度:0.0min 10%B→2.4min 80%B→3.7min 80%B→3.71min 10%B→4.0min 10%B,流速:1.5ml/min,烘箱温度:50℃;UV检测:220nm&215nm&254nm。
方法3(LC-MS)
仪器MS:Thermo Scientific FT-MS;仪器类型UHPLC+:Thermo ScientificUltiMate 3000;色谱柱:Waters,HSST3,2.1x75mm,C18 1.8μm;洗脱液A:1l水+0.01%甲酸;洗脱液B:1l乙腈+0.01%甲酸;梯度:0.0min 10%B→2.5min 95%B→3.5min 95%B;烘箱温度:50℃;流速:0.90ml/min;UV检测:210nm/最佳积分路径210-300nm。
方法4(LC-MS)
仪器:Waters ACQUITY SQD UPLC系统;色谱柱:Waters Acquity UPLC HSS T31.8μm 50x1mm;洗脱液A:1l水+0.25ml甲酸,洗脱液B:1l乙腈+0.25ml甲酸;梯度:0.0min90%A→1.2min 5%A→2.0min 5%A;烘箱温度:50℃;流速:0.40ml/min;UV检测:210nm。
方法5(LC-MS)
仪器:Waters ACQUITY SQD UPLC系统;色谱柱:Waters Acquity UPLC HSS T31.8μm 50x1mm;洗脱液A:1l水+0.25ml甲酸,洗脱液B:1l乙腈+0.25ml甲酸;梯度:0.0min95%A→6.0min 5%A→7.5min 5%A;烘箱温度:50℃;流速:0.35ml/min;UV检测:210nm。
方法6(LC-MS)
仪器:Agilent MS Quad 6150;HPLC:Agilent 1290;色谱柱:Waters AcquityUPLC HSS T3 1.8μm 50x2.1mm;洗脱液A:1l水+0.25ml甲酸,洗脱液B:1l乙腈+0.25ml甲酸;梯度:0.0min 90%A→0.3min 90%A→1.7min 5%A→3.0min 5%A;烘箱温度:50℃;流速:1,20ml/min;UV检测:205–305nm。
方法7(LC-MS)
仪器:Waters Single Quad MS系统;仪器Waters UPLC Acquity;色谱柱:WatersBEH C18 1.7μ50x2.1mm;洗脱液A:1l水+1.0mL(25%氨水)/L,洗脱液B:1l乙腈;梯度:0.0min 92%A→0.1min 92%A→1.8min 5%A→3.5min 5%A;烘箱温度:50℃;流速:0.45ml/min;UV检测:210nm。
方法8(LC-MS)
系统MS:Waters TOF仪器;系统UPLC:Waters Acquity I-CLASS;色谱柱:WatersAcquity UPLC HSS T3 1.8μm 50x1mm;洗脱液A:1l水+0.100ml 99%ige甲酸,洗脱液B:1l乙腈+0.100ml 99%ige甲酸;梯度:0.0min 90%A→1.2min 5%A→2.0min 5%A;烘箱温度:50℃;流量:0.40ml/min;UV检测:210nm。
方法9(LC-MS):
系统MS:Waters TOF仪器;系统UPLC:Waters Acquity I-CLASS;色谱柱:WatersAcquity UPLC HSS T3 1.8μm 50x1mm;洗脱液A:1l水+0.100ml 99%ige甲酸,洗脱液B:1l乙腈+0.100ml 99%ige甲酸;梯度:0.0min 95%A→6.0min 5%A→7.5min 5%A烘箱温度:50℃;流量:0.35ml/min;UV检测:210nm。
制备型HPLC法
仪器:Waters Prep LC/MS系统,色谱柱:Phenomenex Kinetex C18 5μm 100x30mm,UV检测200-400nm,室温,拟柱上进样(完全进样),洗脱液A:水,洗脱液B:乙腈,洗脱液C:2%甲酸水溶液,洗脱液D:乙腈/水(80vol.%/20vol.%);流速:80ml/min,梯度曲线:0至2分钟:洗脱液A 47ml/min,洗脱液B 23ml/min;2到10分钟:洗脱液A从47ml/min到23ml/min,洗脱液B从23ml/min到47ml/min;10到12分钟,洗脱液A 0ml/min,洗脱液B 70ml/min;洗脱液C和洗脱液D在整个运行时间内均保持5ml/min的恒定流速。
当本发明化合物由制备型HPLC通过上述其中洗脱液含有添加剂(如三氟乙酸、甲酸或氨)的方法纯化时,如果本发明的化合物含有足够的碱性或酸性官能度,则可以获得以盐的形式存在的本发明化合物,例如三氟乙酸盐、甲酸盐或铵盐。这种盐可以由本领域技术人员通过已知的各种方法转化为相应的游离碱或酸。
在下文描述的本发明的合成中间体和工作实施例中,任何以相应碱或酸的盐形式描述化合物,通常是由各自的制备和/或纯化方法获得的确切化学计量组成未知的盐。因此,除非有更详细的说明,名称和结构式的附加词,例如“盐酸盐”、“三氟乙酸盐”、“钠盐”或“xHCl”、“x CF3COOH”、“x Na+”,在这类盐的情况下不应以化学计量意义来理解,而应就其中存在的成盐组分仅具有描述性。
如果合成中间体或工作实施例或其盐通过所述的制备和/或纯化方法以化学计量组成未知(如果它们是确定的类型)的溶剂合物例如水合物的形式获得,则这相应适用。
对映异构体1是首先从柱中洗脱出来的对映异构体。
对映异构体2是第二个从柱中洗脱出来的对映异构体。
对于实施例3(对映异构体2),其绝对构型通过单晶X射线结构分析确定为R。因此,
所有注释为对映异构体2的化合物都应具有R的绝对构型。由于其取代模式,相应的立体化
学应该在所有合成条件下都存在。
非对映异构体混合物1定义了一种化合物,其起始物质定义为对映异构体1,并与包含至少一个手性中心的结构单元反应,且其构型未被定义。
非对映异构体混合物2定义了一种化合物,其起始物质定义为对映异构体2,并与包含至少一个手性中心的结构单元反应,且其构型未被定义。
非对映异构体1和非对映异构体2定义了由上述非对映异构体混合物1的手性分离产生的两种化合物。
非对映异构体3和非对映异构体4定义了由上述非对映异构体混合物2的手性分离产生的两种化合物。
立体异构体1定义了一种化合物,其起始物质定义为对映异构体1,并与包含至少一个手性中心的结构单元反应,且其构型被定义。
立体异构体2定义了一种化合物,其起始物质定义为对映异构体2,并与包含至少一个手性中心的结构单元反应,且其构型被定义。
起始化合物和中间体
中间体1A
实施例1A
3-{2-[(苄氧基)羰基]肼基}哌啶-1-羧酸叔丁酯(外消旋体)
在25℃向3-氧代哌啶-1-羧酸叔丁酯[CAS号989-36-7](300g,1.51mol)的四氢呋喃(1.50L)和甲醇(300mL)溶液中加入苄基肼甲酸酯[CAS号5331-43-1](250g,1.51mol),然后将混合物在25℃下搅拌1小时。然后在25℃将NaBH4(114g,3.01mol)分批加入混合物中并在25℃搅拌2小时。将反应混合物冷却至10℃,静置。滴加NH4Cl至pH~6。混合物用乙酸乙酯(EtOAc)(300mL×2)萃取并真空浓缩。将残余物溶解在甲基叔丁基醚(MTBE)(300mL)中并加入石油醚(300mL)。将混合物过滤,并用石油醚(100mL)洗涤沉淀物,得到呈白色固体状的标题化合物(400g,1.14mol,76.0%产率)。
LC-MS:(方法1)Rt=0.832min,MS(M-100+1=250.4)。
实施例2A
3-肼基哌啶-1-羧酸叔丁酯乙酸(外消旋体)
在H2(15Psi)存在下,向3-{2-[(苄氧基)羰基]肼基}哌啶-1-羧酸叔丁酯(参照实施例1A制备,1.20kg,3.43mol)的乙醇(11.0L)溶液中加入乙酸(415g,6.91mol,395mL)和Pd/C(120g,20%纯度)。将混合物在25℃搅拌12小时。过滤混合物,沉淀用乙醇(11.0L)洗涤,得到标题化合物的乙醇溶液(945g,乙酸盐),为黑色液体,滤液不经纯化直接用于下一步。
1H-NMR(400MHz,CDCl3)δ[ppm]:7.52(s,5H),3.59(d,J=6.0Hz,12H),3.30-3.24(m,2H),2.75-2.71(m,2H),1.38-1.34(m,1H),1.20-1.18(m,1H),1.10(s,9H)
LC-MS:(方法1)Rt=0.263min,MS(M-56+1=160.2)
实施例3A
2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯
将4,4-二氟-3-氧代丁酸乙酯[CAS号352-24-9](120g,722mmol)和(二乙氧基甲氧基)乙烷(240ml,1.4mol)的乙酸酐(200ml,2.2mol)溶液在140℃搅拌过夜并蒸发至干燥状态,得到155g(定量)的标题化合物,其不进一步纯化而用于下一步骤。
11H-NMR(600MHz,CDCl3)δ[ppm]:1.306(6.05),1.318(16.00),1.330(14.48),1.341(4.56),1.428(5.99),1.436(5.01),1.440(12.20),1.448(9.25),1.451(6.31),1.460(4.48),2.095(1.59),2.225(1.56),4.247(1.97),4.260(5.79),4.271(5.85),4.277(1.55),4.289(2.00),4.289(4.40),4.301(4.37),4.308(2.03),4.313(1.64),4.320(5.74),4.332(5.78),4.340(1.60),4.344(2.01),4.351(4.21),4.364(4.20),4.375(1.37)、6.262(1.79)、6.339(1.35)、6.352(3.56)、6.429(2.63)、6.442(1.72)、6.519(1.28)、7.867(5.48)、7.880(7.31)。
实施例4A
3-[5-(二氟甲基)-4-(乙氧基羰基)-1H-吡唑-1-基]哌啶-1-羧酸叔丁酯(外消旋体)
向3-肼基哌啶-1-羧酸叔丁酯乙酸(实施例2A,945g,3.43mol)的乙醇(20.0L)混合物中加入2-(乙氧基亚甲基)-4,4-二氟-3-氧代丁酸乙酯(参照实施例3A制备,840g,3.78mol)。将混合物在25℃搅拌12小时。浓缩反应混合物。将残余物倒入饱和NaHCO3水溶液(10.0L)中,并用乙酸乙酯(10.0L*2)萃取。合并的有机层用盐水(10.0L)洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过硅胶柱色谱用石油醚:乙酸乙酯(50:1-25:1-10:1,Rf=0.3)洗脱纯化,得到530g(41.4%产率)标题化合物。
1H-NMR(400MHz,CDCl3)δ[ppm]:7.84(s,1H),7.51(t,J=12.8Hz,1H),4.47-4.41(m,1H),4.30-4.10(m,4H),3.19-3.13(m,1H),2.69(s,1H),2.15-2.10(m,2H),1.83-1.78(m,1H),1.60-1.55(m,1H),1.40(s,9H),1.32-1.29(m,3H)
LC-MS(方法1)Rt=0.992min,MS(M-56+1=318.0)。
实施例5A
5-(二氟甲基)-1-(哌啶-3-基)-1H-吡唑-4-羧酸乙酯(外消旋体)
将3-[5-(二氟甲基)-4-(乙氧基羰基)-1H-吡唑-1-基]哌啶-1-羧酸叔丁酯(参照实施例4A制备,593g,1.59mol)添加加入到氯化氢的二噁烷(4M,2.50L)溶液中,将混合物在25℃搅拌12小时。蒸发混合物并将残余物溶解在1.00L水中并用500mL MTBE萃取。分离水相并用NaHCO3调节pH至8-9。水相用二氯甲烷(1.00L x 2)萃取,合并的有机相用盐水(1.00L)洗涤,经Na2SO4干燥并浓缩,得到350g(80.6%产率)标题化合物。
H-NMR(400MHz,CDCl3)δ[ppm]:7.87(s,1H),7.54(t,J=12.8Hz,1H),4.55-4.54(m,1H),4.34-4.28(m,2H),3.25-3.03(m,3H),2.71-2.65(m,1H),2.19-1.86(m,4H),1.63-1.60(m,1H),1.35(t,J=7.2Hz,3H)
LC-MS:(方法1)Rt=0.644min,MS(M+1)=274.6
类似于实施例5A,使用不同的保护基制备5-(二氟甲基)-1-(哌啶-3-基)-1H-吡唑-4-羧酸乙酯(外消旋体)。通过SFC分离两种对映体[样品制备:将20g溶解在500ml甲醇中;注射量:15ml;色谱柱:Daicel AZ SCF 20μm,400x50mm;洗脱液:二氧化碳/甲醇/氨水(1%)80:19:1至60:39:1;流速:400ml/min;温度:40℃;UV检测:220nm]。分离后得到先洗脱的对映异构体1(实施例6A)8.1g和后洗脱的对映异构体2(实施例7A)8.0g。
实施例6A
5-(二氟甲基)-1-(哌啶-3-基)-1H-吡唑-4-羧酸乙酯(对映异构体1)
分离条件参见实施例5A。
分析SFC:Rt=0.980min,e.e.=100%[色谱柱Chiralpak IC-3:50x4.6mm;洗脱液:CO2/[甲醇+0.2%二乙胺]:90:10流速:3.0ml/min;温度:25℃;UV检测:220nm]。
H-NMR(400MHz,DMSO-d6)δ[ppm]:8.00(s,1H),7.75-7.44(m,1H),4.50-4.36(m,1H),4.33-4.18(m,2H),3.10-2.95(m,1H),2.91-2.76(m,2H),2.48-2.33(m,2H),2.08-1.94(m,2H),1.81-1.66(m,1H),1.62-1.40(m,1H),1.37-1.21(m,3H)。
实施例7A
5-(二氟甲基)-1-(哌啶-3-基)-1H-吡唑-4-羧酸乙酯(对映异构体2)
分离条件参见实施例5A。
分析SFC:Rt=1.227min,e.e.=97%[色谱柱Chiralpak IC-3:50x4.6mm;洗脱液:CO2/[甲醇+0.2%二乙胺]:90:10流速:3.0ml/min;温度:25℃;UV检测:220nm]。
H-NMR(400MHz,DMSO-d6)δ[ppm]:8.01(s,1H),7.75-7.43(m,1H),4.50-4.37(m,1H),4.27(q,2H),3.09-2.97(m,1H),2.94-2.81(m,2H),2.47-2.34(m,2H),2.06-1.92(m,2H),1.79-1.66(m,1H),1.60-1.41(m,1H),1.29(t,3H)。
实施例8A
2-溴-4-氯-1-[(4-甲氧基苯基)甲氧基]苯
用碳酸钾(13.3g,96.4mmol)、碘化钾(12.0g,72.3mmol)和1-(氯甲基)-4-甲氧基苯(7.55g,48.2mmol)处理2-溴丙烷-4-氯酚[CAS号695-96-5](10.0g,48.2mmol)的丙酮(75ml)溶液。将所得混合物在70℃搅拌约19小时。将反应混合物用水稀释并用乙酸乙酯萃取两次。合并的有机层用硫酸钠干燥并蒸发。将残余物通过快速色谱(硅胶,环己烷/乙酸乙酯梯度)纯化,得到13.8g(86%产率)的标题化合物。
LC-MS(方法3):Rt=2.48min;MS(ESIneg):m/z=324[M-H]-
1H-NMR(600MHz,DMSO-d6)δ[ppm]:3.349(10.98),5.124(16.00),6.949(0.87),6.954(8.36),6.957(2.68),6.965(2.83),6.968(8.92),6.973(1.00),7.218(5.23),7.233(6.21),7.380(0.90),7.384(7.80),7.399(7.44),7.402(4.47),7.406(3.89),7.417(3.04),7.421(3.07),7.697(6.51),7.702(6.34)。
实施例9A
1-[1-{5-氯-2-[(4-甲氧基苯基)甲氧基]苯基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(对映异构体1)
在氩气下,用碳酸铯(29.8g,91.6mmol)、Pd2dba3(2.80g,3.05mmol)和rac-BINAP(3.80g,6.10mmol)处理2-溴-4-氯-1-[(4-甲氧基苯基)甲氧基]苯(参照实施例8A制备,10.0g,30.5mmol)和5-(二氟甲基)-1-[哌啶-3-基]-1H-吡唑-4-羧酸乙酯(参照实施例6A制备,对映异构体1,8.34g,30.5mmol)的1,4-二噁烷(100ml)溶液,并将所得混合物在100℃搅拌过夜。将反应混合物与500mg测试反应物合并,经硅藻土过滤,用乙酸乙酯冲洗并蒸发。将残余物重新溶解在水中并用乙酸乙酯萃取3次。合并的有机层用饱和氯化钠溶液洗涤,用硫酸钠干燥并蒸发。通过快速色谱(硅胶,环己烷/乙酸乙酯梯度)纯化残余物,得到10.1g(60%产率)的标题化合物。
LC-MS(方法4):Rt=1.44min;MS(ESIpos):m/z=520[M+H]+
实施例10A
1-[1-(5-氯-2-羟基苯基)哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(对映异构体1)
用三氟乙酸处理1-[1-{5-氯-2-[(4-甲氧基苯基)甲氧基]苯基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(实施例9A,对映异构体1,10.1g,19.4mmol)的二氯甲烷(200ml)溶液并在室温下搅拌过夜。蒸发反应混合物。将残余物重新溶于乙酸乙酯中并用水洗涤一次,用碳酸氢钠饱和溶液洗涤一次,最后用氯化钠饱和溶液洗涤一次。有机相用硫酸钠干燥并蒸发。残余物通过快速色谱(硅胶,环己烷/乙酸乙酯梯度)纯化,得到7.17g(83%纯度,77%产率)的标题化合物。
LC-MS(方法8):Rt=1.26min;MS(ESIpos):m/z=400[M+H]+
实施例11A
1-[1-{5-氯-2-[(三氟甲磺酰基)氧基]苯基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(对映异构体1)
在氩气下,用三乙胺(5.2ml,37mmol)处理1-[1-(5-氯-2-羟基苯基)哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(实施例10A,对映异构体1,7.17g,83%纯度,14.9mmol)的二氯甲烷(160ml)溶液,并冷却至0℃。滴加三氟甲磺酸酐并将所得混合物在0℃搅拌45分钟。反应混合物用二氯甲烷(150ml)稀释并用水洗涤3次。有机相用硫酸钠干燥并蒸发。通过快速色谱(硅胶,环己烷/乙酸乙酯梯度)纯化残余物,得到7.89g(定量)标题化合物。
LC-MS(方法4):Rt=1.47min;MS(ESIpos):m/z=532[M+H]+
实施例12A
1-[1-{5-氯-2-[(4-甲氧基苯基)甲氧基]苯基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(对映异构体2)
在氩气下,用Pd2(dba)3(14.6g,16.0mmol)、rac-BINAP(19.9g,31.9mmol)和新研磨的碳酸铯(156g,479mmol)处理5-(二氟甲基)-1-[哌啶-3-基]-1H-吡唑-4-羧酸乙酯(参照实施例7A制备,对映异构体2,43.6g,160mmol)和2-溴-4-氯-1-[(4-甲氧基苯基)甲氧基]苯(参照实施例8A制备,52.3克,160mmol)的1,4-二噁烷(680ml)溶液,并在100℃搅拌18小时。反应混合物用乙酸乙酯和10%氯化钠溶液稀释,经硅藻土过滤并用乙酸乙酯冲洗。滤液的水相用乙酸乙酯萃取。合并的有机层用10%氯化钠溶液洗涤,用硫酸钠干燥并蒸发。残余物经硅胶(二氯甲烷/石油醚4∶1)进行快速色谱纯化,得到42g(82%产率)标题化合物。
LC-MS(方法3):Rt=2.78min;MS(ESIpos):m/z=520[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.272(3.65),1.290(7.68),1.307(3.76),1.686(0.44),1.717(0.54),1.852(0.73),1.885(0.50),1.989(0.47),2.019(0.56),2.058(0.99),2.084(0.61),2.587(0.51),2.616(0.89),2.642(0.45),3.030(0.76),3.057(1.51),3.084(0.83),3.447(0.72),3.474(0.69),3.613(0.74),3.640(0.67),3.737(16.00),4.251(1.13),4.269(3.48),4.287(3.45),4.304(1.12),4.624(0.40),4.639(0.48),4.650(0.76),4.661(0.51),5.035(6.45),6.872(3.47),6.893(5.67),6.947(0.98),6.952(0.85),6.968(1.72),6.974(1.67),7.017(2.84),7.039(1.57),7.305(3.66),7.326(3.43),7.340(0.56),7.380(0.41),7.439(0.93),7.463(0.64),7.476(0.48),7.569(1.65),7.699(0.76),8.044(3.66)。
实施例13A
1-[1-(5-氯-2-羟基苯基)哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(对映异构体2)
用三氟乙酸(100ml,1.3mol)处理1-[1-{5-氯-2-[(4-甲氧基苯基)甲氧基]苯基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(参照实施例12A制备,对映异构体2,67.5g,130mmol)的二氯甲烷(1.0L)溶液,并在室温下搅拌过夜。将反应混合物用水(750ml)稀释并用10%碳酸钠溶液(450ml)仔细处理直至不再产生二氧化碳。有机相用硫酸钠干燥并蒸发,得到52g(90%产率)的标题化合物,其无需进一步纯化即用于下一步。
LC-MS(方法3):Rt=2.42min;MS(ESIpos):m/z=400[M+H]+
实施例14A
1-[1-{5-氯-2-[(三氟甲磺酰基)氧基]苯基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(对映异构体2)
将1-[1-(5-氯-2-羟基苯基)哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(实施例13A,对映异构体2,52.0g,117mmol)和三乙胺(49ml,350mmol)的二氯甲烷(330ml)溶液冷却至-50℃。滴加三氟甲磺酸(28ml,160mmol)并将所得混合物在-50℃搅拌1小时。然后将反应混合物用二氯甲烷(330ml)和水(370ml)稀释。水相用二氯甲烷(330ml)萃取。合并的有机层用(370ml)洗涤用硫酸钠干燥并蒸发。所得混合物通过快速色谱(硅胶,二氯甲烷/石油醚6:4)纯化,得到60g(96%产率)的标题化合物。
LC-MS(方法3):Rt=2.74min;MS(ESIpos):m/z=532[M+H]+
H-NMR(600MHz,DMSO-d6)δ[ppm]:-0.021(0.65),1.082(0.51),1.270(7.69),1.282(16.00),1.294(7.63),1.772(0.48),1.780(0.51),1.787(0.63),1.793(0.66),1.801(0.62),1.808(0.60),1.910(1.25),1.914(0.99),1.927(0.67),1.932(0.89),2.068(0.72),2.075(1.03),2.086(2.45),2.091(2.40),2.100(1.41),2.792(0.71),2.796(0.83),2.812(1.48),2.816(1.50),2.832(0.83),2.836(0.72),3.142(1.17),3.161(1.04),3.201(1.21),3.219(2.80),3.237(1.83),3.278(1.37),3.285(1.56),4.251(2.26),4.263(7.09),4.275(7.06),4.287(2.20),4.755(0.50),4.765(0.90),4.773(0.89),4.781(0.90),4.791(0.49),5.734(2.17),7.261(2.19),7.265(2.27),7.275(2.69),7.279(2.82),7.391(4.65),7.406(3.75),7.431(4.73),7.435(4.51),7.492(1.26),7.579(2.61),7.666(1.07),8.026(6.37)。
实施例15A
4-(4'-氯-2'-{3-[5-(二氟甲基)-4-(乙氧基羰基)-1H-吡唑-1-基]哌啶-1-基}[1,1'-联苯]-4-基)哌嗪-1-羧酸叔丁酯(对映异构体2)
在氩气下,用碳酸钠(160ml,2.0M,320mmol)和四(三苯基膦)钯(0)(6.19g,5.36mmol)水溶液处理1-[1-{5-氯-2-[(三氟甲磺酰基)氧基]苯基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-甲酸乙酯(实施例14A,对映异构体2,57.0g,107mmol)和4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]哌嗪-1-羧酸叔丁酯[CAS No.470478-90-1](49.9g,129mmol)在甲苯(600ml)和乙醇(600ml)中的溶液。将所得混合物在100℃搅拌4小时。将反应混合物冷却至室温,经硅藻土过滤,用乙酸乙酯洗涤并蒸发。通过快速色谱(硅胶,石油醚/乙酸乙酯9:1至8:2)纯化残余物,得到62g(89%产率)的标题化合物。
LC-MS(方法3):Rt=3.15min;MS(ESIpos):m/z=644[M+H]+
实施例16A
1-{1-[4-氯-4'-(哌嗪-1-基)[1,1'-联苯]-2-基]哌啶-3-基}-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯盐酸盐(对映异构体2)
用氯化氢的二噁烷(230ml,4.0M,930mmol)溶液处理4-(4'-氯-2'-{(3-[5-(二氟甲基)-4-(乙氧基羰基)-1H-吡唑-1-基]哌啶-1-基}[1,1'-联苯]-4-基)哌嗪-1-羧酸叔丁酯(实施例15A,对映异构体2,60.0g,93.1mmol)的二氯甲烷(250ml)溶液。将所得混合物在室温下搅拌3小时并蒸发。将残余物与乙醚(250ml x 2)一起蒸发两次,在二异丙醚中搅拌4天。过滤悬浮液,固体物用二异丙醚洗涤两次,得到57g(定量)标题化合物。
LC-MS(方法3):Rt=1.78min;MS(ESIpos):m/z=544[M+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.029(13.49),1.044(13.77),1.262(7.53),1.280(16.00),1.297(7.81),1.496(0.79),1.506(0.62),1.527(0.91),1.559(0.40),1.716(1.24),1.749(0.95),1.888(0.84),1.897(0.78),1.918(0.98),1.926(0.93),1.966(1.38),1.995(0.69),2.580(1.54),2.606(0.83),2.992(1.21),3.018(2.69),3.044(2.33),3.063(1.24),3.435(5.96),3.448(7.25),3.460(5.00),3.570(5.78),3.586(0.87),3.601(1.12),3.616(0.85),4.227(5.38),4.238(6.62),4.256(9.26),4.273(7.97),4.291(2.70),4.444(0.41),4.455(0.77),4.470(0.89),4.481(1.31),4.491(0.92),4.507(0.68),7.045(6.02),7.067(6.86),7.074(5.10),7.079(5.42),7.099(2.25),7.104(1.49),7.120(3.55),7.125(3.10),7.164(6.27),7.185(3.37),7.383(1.62),7.483(6.90),7.505(6.40),7.513(3.75),7.643(1.34),8.005(5.77),9.399(1.97)。
实施例17A
1-[1-{4-氯-4'-[4-(2-甲基丙基)哌嗪-1-基][1,1'-联苯]-2-基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(对映异构体2)
用N,N-二异丙基乙胺(59ml,340mmol)和2-甲基丙醛[CAS号78-84-2](38ml,420mmol)处理1-{1-[4-氯-4'-(哌嗪-1-基)[1,1'-联苯]-2-基]哌啶-3-基}-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯盐酸盐的四氢呋喃溶液,并在室温下搅拌1小时。然后加入三乙酰氧基硼氢化钠(71.5g,337mmol)并将所得混合物在室温下搅拌18小时。反应混合物用碳酸氢钠(10%)水溶液和乙酸乙酯稀释。水层用乙酸乙酯萃取两次。合并的有机层用氯化钠水溶液洗涤,用硫酸钠干燥并蒸发。通过快速色谱(硅胶,石油醚/乙酸乙酯8:2)纯化残余物,得到47g(93%产率)的标题化合物。
LC-MS(方法9):Rt=3.42min;MS(ESIpos):m/z=600[M+H]+
实施例18A
1-(2-甲基丙基)-4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]哌嗪
将1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]哌嗪(350mg,1.21mmol)溶解在7.4ml四氢呋喃中,加入N,N-二异丙基乙胺(320μl,1.8mmol)。然后加入2-甲基丙醛(440μl,4.9mmol)并将混合物搅拌10分钟。然后加入三乙酰氧基硼氢化钠(772mg,3.64mmol)并将混合物在55℃搅拌4小时。将反应混合物冷却至室温,加入饱和碳酸氢钠水溶液并将混合物用乙酸乙酯萃取3次。将合并的有机相用饱和氯化钠水溶液洗涤一次,用硫酸钠干燥,过滤并蒸发。得到342mg目标化合物(理论值的79%,纯度97%)。
LC-MS(方法3):Rt=1.23min;MS(ESIpos):m/z=345[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.058(0.55),0.927(4.09),0.938(4.13),1.316(16.00),2.121(0.98),2.133(0.89),2.492(0.99),2.508(0.99),2.559(2.25),2.599(2.62),3.241(1.07),3.249(1.38),3.257(0.98),6.935(1.05),6.949(1.07),7.552(1.15),7.566(1.07).
实验部分——实施例化合物
实施例1
1-[1-{4-氯-4'-[4-(2-甲基丙基)哌嗪-1-基][1,1'-联苯]-2-基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸盐酸盐(对映异构体1)
将1-[1-{5-氯-2-[(三氟甲磺酰基)氧基]苯基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(参照实施例11A制备,对映异构体1,80.0mg,147μmol)和1-(2-甲基丙基)-4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]哌嗪(实施例18A 62.8mg,97%纯度,177μmol)在氩气下置于甲苯/乙醇(820/820μl)中。加入2M碳酸钠溶液(220μl,2.0M,440μmol)和四(三苯基膦)钯(0)(8.52mg,7.37μmol),混合物在100℃搅拌过夜。反应混合物用乙酸乙酯稀释并加入1M盐酸。水相用乙酸乙酯萃取3次。有机相用硫酸钠干燥,过滤并蒸发。将粗混合物用四氢呋喃/乙醇(2.0/0.2ml)溶解,加入1M氢氧化锂溶液(1.5ml,1.5mmol)并将混合物在室温搅拌过夜。再次加入1M氢氧化锂溶液(740μl,740μmol)。约6小时后,将反应混合物在50℃蒸发。将残余物溶解在乙腈/水/0.25ml三氟乙酸中并通过制备型HPLC(RP18柱,加入0.1%三氟乙酸的乙腈/水梯度)纯化。粗产物通过厚层色谱(二氯甲烷/甲醇/甲酸:10/1/0.1)纯化。将硅胶混合物与二氯甲烷/1M盐酸的二噁烷溶液(10/1)在乙醇中一起搅拌,过滤并在30℃小心蒸发并冻干,得到34mg目标化合物(理论值的36%,纯度95%)。
LC-MS(方法6):Rt=1.23min;MS(ESIpos):m/z=572[M-HCl+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.004(15.87),1.015(16.00),1.500(0.51),1.521(0.57),1.728(0.73),1.750(0.61),1.897(0.57),1.917(0.62),1.975(0.79),2.122(0.42),2.133(0.84),2.144(1.02),2.156(0.79),2.571(0.47),2.587(0.91),2.610(0.52),3.004(0.84),3.022(2.01),3.026(2.20),3.038(3.72),3.048(2.50),3.065(0.75),3.154(2.66),3.161(2.75),3.169(2.36),3.177(1.88),3.224(0.84),3.237(0.70),3.589(1.41),3.602(1.80),3.825(1.02),3.841(0.78),3.866(1.05),3.882(0.75),4.223(2.57),4.445(0.68),4.463(0.97),4.481(0.57),7.045(0.55),7.055(3.63),7.070(3.72),7.084(2.72),7.087(3.09),7.110(1.47),7.113(1.11),7.123(2.19),7.127(2.02),7.163(3.67),7.177(2.19),7.215(0.46),7.428(0.83),7.495(4.24),7.510(4.02),7.515(2.07),7.602(0.82),7.959(4.79),9.484(0.54).
实施例2
1-[1-{4-氯-4'-[4-(2-甲基丙基)哌嗪-1-基][1,1'-联苯]-2-基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸(对映异构体2)
方法A
用氢氧化锂(850ml,1.0M,850mmol)水溶液处理1-[1-{4-氯-4'-[4-(2-甲基丙基)哌嗪-1-基][1,1'-联苯]-2-基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(制备类似于实施例17A,对映异构体2,50.8g,84.6mmol)在四氢呋喃/甲醇混合物9:1(1.0L)中的溶液,在室温下搅拌过夜。将反应混合物浓缩,用二氯甲烷(1.5L)稀释并用氯化氢水溶液2N调节至pH=2。将所得悬浮液在室温下搅拌45分钟。过滤固体,用水洗涤并真空干燥,得到43g(90%产率)的标题化合物。
LC-MS(方法7):Rt=1.27min;MS(ESIpos):m/z=572[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.002(15.68),1.013(16.00),1.080(0.57),1.092(1.18),1.103(0.63),1.498(0.74),1.519(0.83),1.719(1.03),1.741(0.88),1.902(0.78),1.908(0.74),1.922(0.88),1.928(0.83),1.943(0.45),1.978(1.13),1.994(0.74),2.102(0.71),2.112(0.85),2.123(0.70),2.571(1.40),2.591(0.77),2.882(1.10),3.018(1.27),3.035(3.01),3.053(2.14),3.239(2.40),3.254(2.32),3.368(1.13),3.379(1.40),3.391(1.33),3.403(0.92),3.493(0.76),4.463(0.65),4.482(1.12),4.500(0.62),7.033(4.22),7.048(4.45),7.074(3.47),7.077(4.04),7.100(1.85),7.103(1.52),7.113(2.53),7.117(2.34),7.162(4.18),7.175(2.71),7.439(1.03),7.481(4.88),7.495(4.57),7.526(2.04),7.613(0.91),7.952(5.28)。
方法B
将1-{1-[4-氯-4'-(4-异丁基哌嗪-1-基)[联苯]-2-基]哌啶-3-基}-5-(二氟甲基)-1H-吡唑-4-羧酸盐酸盐(制备参照实施例3,对映异构体2,31.2mg,51.3μmol)溶解在17ml二氯甲烷和1ml甲醇中。将该溶液与1.5ml饱和碳酸氢钠水溶液一起振荡一次。将各相分离。将5ml二氯甲烷和3ml甲醇加入到有机相中。然后将有机相用硫酸钠干燥,过滤,蒸发并通过制备型HPLC(RP18柱,乙腈/水梯度,中性,不加酸)纯化。合并产物馏分并冻干。得到22mg(理论值的74%)目标化合物。
LC-MS(方法3):Rt=1.73min;MS(ESIpos):m/z=572[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:0.887(15.60),0.898(16.00),1.493(0.64),1.514(0.70),1.695(0.89),1.718(0.74),1.799(0.48),1.811(0.88),1.822(1.12),1.833(0.92),1.844(0.48),1.890(0.68),1.910(0.74),1.977(0.93),1.995(0.62),2.118(3.91),2.130(3.66),2.516(5.14),3.017(1.09),3.035(2.76),3.053(1.94),3.181(5.03),3.185(5.02),3.267(1.53),4.473(0.55),4.491(0.96),4.509(0.54),6.963(3.96),6.977(4.06),7.048(3.13),7.051(3.31),7.081(1.60),7.084(1.26),7.095(2.21),7.098(1.89),7.152(3.52),7.165(2.42),7.434(4.45),7.448(4.50),7.533(1.51),7.621(0.67),7.930(4.14)。
实施例3
1-{1-[4-氯-4'-(4-异丁基哌嗪-1-基)[联苯]-2-基]哌啶-3-基}-5-(二氟甲基)-1H-吡唑-4-羧酸盐酸盐(对映异构体2)
方法A
用氯化氢的乙醚(84ml,1.0M,84mmol)溶液处理1-[1-{4-氯-4'-[4-(2-甲基丙基)哌嗪-1-基][1,1'-联苯]-2-基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸(参照实施例2制备,对映异构体2,43.5g,76.0mmol)的乙醚(870ml)悬浮液。将所得混合物在室温下搅拌过夜并蒸发,得到46.1g(定量)标题化合物。
LC-MS(方法3):Rt=1.72分钟;MS(ESIpos):m/z=572[M+H]+
1H-NMR(600MHz,DMSO-d6)δ[ppm]:1.026(15.64),1.037(16.00),1.497(0.56),1.519(0.61),1.722(0.78),1.743(0.65),1.903(0.59),1.910(0.53),1.924(0.66),1.930(0.61),1.978(0.82),1.994(0.50),2.142(0.45),2.154(0.91),2.165(1.11),2.176(0.89),2.187(0.45),2.557(0.64),2.577(1.02),2.594(0.55),2.992(1.81),3.002(2.77),3.012(1.87),3.018(1.15),3.036(2.40),3.054(1.60),3.133(1.12),3.148(1.19),3.168(0.53),3.237(0.88),3.250(0.76),3.338(0.81),3.360(1.42),3.379(0.88),3.580(1.61),3.791(0.89),3.819(1.25),3.844(0.81),4.463(0.89),4.474(0.97),4.481(1.26),4.488(0.99),4.499(0.88),7.051(3.56),7.065(3.77),7.077(2.72),7.080(3.14),7.103(1.42),7.106(1.13),7.116(2.00),7.120(1.84),7.165(3.40),7.178(2.22),7.443(0.84),7.489(4.04),7.504(3.79),7.531(1.66),7.618(0.72),7.954(4.33),10.519(0.49)。
方法B
在氩气下将1-[1-{5-氯-2-[(三氟甲磺酰基)氧基]苯基}哌啶-3-基]-5-(二氟甲基)-1H-吡唑-4-羧酸乙酯(参照实施例14A制备,对映异构体2,80.0mg,150μmol)和1-(2-甲基丙基)-4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]哌嗪(实施例18A,64.1mg,97%纯度,180μmol)溶解在甲苯/乙醇(0.83/0.83ml)中。加入四(三苯基膦)钯(0)(8.69mg,7.52μmol)和2M碳酸钠溶液(226μl,452μmol),并将混合物在100℃搅拌过夜。反应混合物用乙酸乙酯和水稀释。水相用1M盐酸酸化。将各相分离,水相用乙酸乙酯萃取两次。合并的有机相用硫酸钠干燥,过滤并蒸发。将粗产物溶解在四氢呋喃/乙醇(3.9/0.39ml)中,加入1M氢氧化锂水溶液(1.5ml,1.5mmol)并将混合物在室温下搅拌过夜。蒸发混合物,将残余物溶解在乙腈/三氟乙酸/水中并使用制备型HPLC(RP18柱,加入0.1%三氟乙酸的乙腈/水梯度)纯化。合并产物馏分并蒸发。将残余物与含0.1M盐酸的二噁烷混合,在30℃下小心蒸发(两次),然后冻干。得到53mg(理论值的55%,纯度95%)目标化合物。
LC-MS(方法4):Rt=0.91min;MS(ESIpos):m/z=572[M-HCl+H]+
1H-NMR(400MHz,DMSO-d6)δ[ppm]:1.004(15.46),1.020(16.00),1.491(0.44),1.522(0.50),1.722(0.68),1.753(0.55),1.890(0.47),1.920(0.55),1.967(0.84),2.129(0.76),2.146(0.96),2.163(0.76),2.582(0.91),2.613(0.48),2.999(0.86),3.010(1.71),3.025(3.88),3.041(2.30),3.131(0.88),3.161(1.25),3.177(2.08),3.213(1.75),3.242(1.16),3.467(1.06),3.496(0.84),3.503(0.60),3.519(0.54),3.525(0.50),3.549(0.75),3.555(0.84),3.572(1.57),3.582(1.48),3.589(1.38),3.601(2.78),3.608(1.89),3.633(0.44),3.640(0.41),3.811(0.94),3.847(1.32),3.878(0.71),4.329(0.49),4.439(0.46),4.466(0.73),4.477(0.52),4.839(0.49),7.047(3.30),7.070(3.64),7.082(2.61),7.087(3.29),7.104(1.46),7.109(0.86),7.124(2.34),7.129(2.03),7.160(3.99),7.181(1.96),7.388(0.88),7.490(4.02),7.512(3.81),7.519(2.20),7.650(0.72),7.959(3.78),9.708(0.41)。
[a]D 20=-73.05°,c=0.465g/100cm3,三氯甲烷。
实施例3对映异构体2具有如以下实施例4所示的R的绝对构型。
1-{3(R)-1-[4-氯-4'-(4-异丁基哌嗪-1-基)[联苯]-2-基]哌啶-3-基}-5-(二氟甲基)-1H-吡唑-4-羧酸盐酸盐
实施例4
1-{3(R)-1-[4-氯-4'-(4-异丁基哌嗪-1-基)[联苯]-2-基]哌啶-3-基}-5-(二氟甲基)-1H-吡唑-4-羧酸盐酸盐半水合物
在60℃下,将100mg 1-{1-[4-氯-4'-(4-异丁基哌嗪-1-基)[联苯]-2-基]哌啶-3-基}-5-(二氟甲基)-1H-吡唑-4-羧酸盐酸盐(对映异构体2)(实施例3)溶解在3.5ml 2-丙醇中,其中2-丙醇在60℃下以每次100μl分批加入,直到得到澄清溶液。然后用隔膜将容器封闭并放入从60℃到室温缓慢冷却的沙浴中经过整个周末,检测到少量固体。此后,在隔膜上安装套管,以使溶剂缓慢蒸发。4周后收集晶体并在显微镜下检测。
单晶X射线结构分析:
晶体结构测定使用配备Apex II-CCD面探检测器、带有CuKa辐射的IμS微源、作为单色器的反光镜和Cryostream低温装置()的Bruker衍射计(QS-no.:02506)进行。全球面数据收集,ω和扫描。程序使用:数据收集和还原Apex II v2014.11.0(BrukerAXS,2014)、吸收校正/缩放SADABS。使用SHELXTL Version 6.14(Bruker AXS,2003)中的直接方法实现晶体结构的求解,并使用XP程序进行可视化。随后从差分傅里叶合成中定位丢失的原子并将其添加到原子列表中。利用程序SHELXTL Version 6.14(Bruker AXS,2003)进行使用所有测量强度以最小二乘法对F2的精修。所有非氢原子均被精修,包括各向异性位移参数。
*
H.D.Flack,Acta Cryst.,1983,A39,876-881
H.D.Flack,G.Bernardinelli,J.Appl.Cryst.,2000,33,1143-1148
S.Parsons,H.D.Flack,T.Wagner,Acta Cryst.,2013,B69,249-259
表1.实施例4的晶体数据和结构精修
用于生成等效原子的对称变换:#1y-1,x+1,-z+1
表3.实施例4的扭转角[°]
用于生成等效原子的对称变换:#1y-1,x+1,-z+1
图1:带有标记方案的Ortep图(50%)(没有不规则),实施例4
图1:不对称单元中的独立分子(有不规则),实施例4
图2:C22的构型,实施例4
比较实施例174(WO2012/058132)
1-{1-[4-氯-4'-(4-环丙基甲基哌嗪-1-基)[联苯]-2-基]吡啶-3-基}-5-(三氟甲基)-1H-吡唑-4-羧酸
根据WO 2012/058132(实验部分,第58-84页)中公开的方法合成该化合物。
B.药理功效和药代动力学特征的评估
使用以下缩写:
ATP 三磷酸腺苷
Brij35 聚氧乙烯(23)月桂基醚
BSA 牛血清白蛋白
DTT 二硫苏糖醇
TEA 三乙醇胺
生物学研究
本文所述的实施例测试实验是为了说明本发明并且本发明不限于给出的实施例。
以下试验可用于说明本发明化合物的商业用途。
实施例在选定的生物试验中进行一次或多次测试。当测试不止一次时,记录的数据为平均值或中值,其中
·平均值,也称为算术平均值,表示获得的值的总和除以测试的次数,
·中值表示按升序或降序排列时一组值的中间数。如果数据集中值的个数为奇数,则中值为中间值。如果数据集中的值的个数为偶数,则中值为中间两个值的算术平均值。
实施例被合成一次或多次。当合成不止一次时,来自生物试验的数据代表利用从一个或多个合成批次的测试中获得的数据集计算的平均值。
本发明化合物的体外活性可以在以下试验中证明。
本发明化合物的药理作用可以在以下试验中证明:
B-1.对重组鸟苷酸环化酶报告细胞系的影响
使用重组鸟苷酸环化酶报告细胞系测定本发明化合物的细胞活性,如F.Wunderet al.,Anal.Biochem.339,104-112(2005)所述。
本发明化合物的代表性MEC值(MEC=最小有效浓度)和EC50值(半最大有效浓度)见下表(在某些情况下为多个单独测定的平均值):
表2.
实施例 | MEC[nM] | EC<sub>50</sub>[nM] |
1 | 2.3 | 9.2 |
2 | 1.0 | 8.6 |
3 | 0.6 | 2.7 |
B-2.体外血管舒张作用
兔子在深度麻醉下被杀死并放血。将主动脉从粘附组织中分离出来并分成宽度为1.5mm的多个环,37℃下,在预应力下将其分别放置在含供应卡波金气体的Krebs-Henseleit溶液的5ml器官浴中,该溶液中含有以下成分(每个成分均以mM为单位):氯化钠:119;氯化钾:4.8;二水氯化钙:1;七水硫酸镁:1.4;磷酸二氢钾:1.2;碳酸氢钠:25;葡萄糖:10。为了产生收缩,去氧肾上腺素以增加的浓度渐增地添加到器官浴中。经过几个控制循环后,待研究物质在之后的每一次循环中每次增加剂量加入,并将收缩幅度与前一次循环获得的收缩幅度进行比较。以此计算出控制值幅度降低50%(IC50值)所需的浓度。标准给药体积为5μl;浴液中的DMSO含量相当于0.1%。
B-3.麻醉大鼠的血压测量
用硫喷妥钠(thiopental)(100mg/kg i.p.)麻醉体重为300-350g的雄性Wistar大鼠。气管切开后,将导管插入股动脉以测量血压。待测物质以溶液形式给药,通过管饲法口服给药或通过股静脉注射给药(Stasch et al.Br.J.Pharmacol.2002;135:344-355)。
B-4.清醒的、自发性高血压大鼠的无线电遥测血压
DATA SCIENCES INTERNATIONAL DSI,USA市售的遥测系统用于测量以下描述的清醒大鼠的血压。
该系统由3个主要部件组成:
-数据采集计算机。
所述遥测系统可以连续记录有意识动物在其通常栖息地的血压、心率和身体运动。
动物材料
这些研究是在体重>200g的成年雌性自发性高血压大鼠(SHR Okamoto)上进行的。来自1963年,冈本京都医学院的SHR/NCrl,是血压显著升高的雄性Wistar Kyoto大鼠和血压略微升高的雌性大鼠的杂交体,并在F13被移交给美国国立卫生研究院。
发射器植入后,将实验动物单独饲养在3型Makrolon笼中。它们可以自由获得标准饲料和水。
实验室的昼夜节律通过早上6:00和晚上7:00的房间照明改变。
发射器植入
使用的HD S 10遥测发射器在首次实验使用前至少14天在无菌条件下手术植入实验动物体内。以这种方式安装器械的动物可以在伤口愈合和植入物稳定后重复使用。
为了植入,将禁食的动物用异氟醚(Rimadyl镇痛剂)麻醉,并在其腹部大面积剃毛和消毒。沿腹白线打开腹腔后,将系统的充液测量导管沿分叉上方的颅骨方向插入降主动脉,并用组织胶(VetBonD TM,3M)固定。将发射器壳体经腹腔固定在腹壁肌肉上,逐层闭合创面。
术后给予抗生素(Ursocyclin 10%pro inj.,Serumwerk,s.c.)以预防感染。
物质和溶液
除非另有说明,研究物质分别以管饲法口服给药给各组动物(n=6)。按照2ml/kg体重的给药体积,将测试物质溶解在合适的溶剂混合物中或悬浮在0.5%的Tylose中。
用溶剂处理的动物组作为对照。
测试方法
将遥测测量单元配置于24只动物中。每个实验都记录在一个实验编号(V年月日)下。
生活在系统中的每只带仪器的大鼠都被分配了单独的接收天线(RPC-1Receiver,DSI)。
植入式发射器可以通过内置的磁性开关从外部激活。在测试开始前,它们被切换到传输模式。发出的信号可以通过数据采集系统(Physio Tel HD,DSI)在线检测并进行相应处理。在每种情况下,数据都存储在为此创建并带有实验编号的文件中。
在标准程序中,在每种情况下,以下指标均被测量10秒:
收缩压(SBP)
舒张压(DBP)
平均动脉压(MAP)
心率(HR)
活性(TEMP)。
在计算机控制下每隔5分钟重复一次测量值的采集。以绝对值获得的源数据在图表中使用当前测量的气压(环境压力参考监测器;APR-1)进行校正,并作为单独数据存储。制造商公司(DSI)的技术资料中提供了更多技术细节。
除非另有说明,试验物质在实验当天上午9:00给药。给药后,在24小时内测量上述参数。
评估
实验结束后,使用分析软件(Ponemah V 6.x)对获取的个体数据进行整理。本文假设空白值为给药前2小时的时间,因此所选数据集包括从实验当天上午7:00到次日上午9:00的时间段。
通过测定平均值(30分钟平均值)在可预定义的时间段内对数据进行平滑处理,并以excel文件的形式传输到存储介质中。将这种方式预分类和压缩的测量值传输到Excel模板并制成表格。实验的每一天,所获得的数据都存储在一个带有实验编号的专用文件中。结果和测试方案以按数字排序的纸质形式存储在文件中。
文献:
Klaus Witte,Kai Hu,Johanna Swiatek,Claudia Müssig,Georg Ertl andLemmer:Experimental heart failure in rats:effects on cardiovascular circadianrhythms and on myocardialβ-adrenergic signaling.Cardiovasc Res 47(2):203-405,2000;Kozo Okamoto:Spontaneous hypertension in rats.Int Rev Exp Pathol 7:227-270,1969;Maarten van den Buuse:Circadian Rhythms of Blood Pressure,HeartRate,and Locomotor Activity in Spontaneously Hypertensive Rats as MeasuredWith Radio-Telemetry.Physiology&Behavior 55(4):783-787,1994.
B-5.静脉给药和口服给药后药代动力学参数的测定
本发明化合物的药代动力学参数在雄性Wistar大鼠和/或雌性比格犬和/或食蟹猴和/或雄性CD-1小鼠中测定。小鼠和大鼠通过物种特异性血浆/DMSO制剂进行静脉给药,犬和猴子通过水/PEG400/乙醇制剂进行静脉给药。在所有物种中,基于水/PEG400/乙醇制剂,通过强饲法实施所溶解物质的口服给药。
将内标物(也可以是化学上不相关的物质)加入本发明化合物的样品、校准样品和合格品(qualifier)中,然后用过量的乙腈沉淀蛋白质。加入与LC条件相匹配的缓冲溶液,随后进行涡旋,然后在1000g下离心。上清液采用C18反相柱和可变流动相混合物进行LC-MS/MS分析。通过特异性选择离子监测实验提取的离子色谱图中的峰高或峰面积对物质进行量化。
通过已验证的药代动力学计算程序,将测定的血浆浓度/时间图用于计算药代动力学参数,例如AUC、Cmax、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量化,因此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。为此,将限定量的物质在所述物种的K3 EDTA全血中置于摇摆辊式混合器中孵育20分钟。在1000g下离心后,测量血浆浓度(通过LC-MS/MS;见上文)并通过计算C血液/C血浆的比值来确定。
表3列出了本发明的代表性化合物在大鼠中静脉给药后的数据:
表3:
表4列出本发明的代表性化合物在大鼠中口服给药(p.o.)后的数据:
表4:
表5列出了本发明的代表性化合物在狗中静脉给药后的数据:
表5:
表6列出了本发明的代表性化合物在狗中口服给药(p.o.)后的数据:
表6:
与现有技术(WO 2012/058132)中公开的化合物相比,本发明的化合物显示出优异的药代动力学(PK)特性(参见表3至6)。例如,与在WO 2012/058132中作为实施例174公开的现有技术化合物相比,本发明的实施例2在大鼠以及在狗中均显示出较低的血浆清除率(CL血浆)(高达10倍)和由此产生的较高的暴露量。实施例2还显示了所有测试物种在口服后的较长的半衰期和平均停留时间(MRT)。由于所有受试物种口服后,实施例2显示出显著较低的血浆清除率以及由此产生的具有良好生物利用度的极高暴露量(AUC标准,暴露量,归一化曲线下面积),我们看到药代动力学(PK)特性与WO 2012/058132中公开的实施例174相比具有明显优势。
B-6.代谢研究
为了确定本发明化合物的代谢特征,将它们与重组人细胞色素P450(CYP)酶、肝微粒体或来自各种动物种类(例如大鼠、狗)以及人源的原代新鲜肝细胞一起孵育,以获得并比较以下信息:基本完整的肝脏I期和II期代谢,以及参与所述代谢的酶。
本发明的化合物以约0.1-10μM的浓度孵育。为此,制备浓度为0.01-1mM的本发明化合物的乙腈储备溶液,然后以1:100的稀释度移液至孵育混合物中。在37℃下,肝微粒体和重组酶在50mM磷酸钾缓冲液(pH 7.4)中孵育,所述缓冲液含有和不含有由1mM NADP+、10mM葡萄糖-6-磷酸和1单位葡萄糖-6-磷酸脱氢酶组成的NADPH生成系统。原代肝细胞在Williams E培养基中悬浮孵育,同样在37℃下进行。孵育0-4小时后,用乙腈(终浓度约30%)终止孵育混合物,并以约15 000x g离心分离出蛋白质。由此终止的样品直接用于分析,或在-20℃下储存直至分析。
采用高效液相色谱-紫外-质谱联用检测(HPLC-UV-MS/MS)进行分析。为此,用合适的C18反相柱和乙腈与10mM甲酸铵水溶液或0.05%甲酸的可变流动相混合物对孵育样品的上清液进行色谱分析。紫外谱图结合质谱数据可用于代谢物的鉴定、结构解析和定量估算,并可用于计算本发明化合物在孵育混合物中的定量代谢减少量。
B-7.Caco-2渗透性测试
借助Caco-2细胞系测定所测试物质的渗透性,Caco-2细胞系是已建立的用于胃肠道屏障渗透性预测的体外模型(Artursson,P.and Karlsson,J.(1991).Correlationbetween oral drug absorption in humans and apparent drug permeabilitycoefficients in human intestinal epithelial(Caco-2)cells.Biochem.Biophys.175(3),880-885)。将Caco-2细胞(ACC No.169,DSMZ,Deutsche Sammlung vonMikroorganismen und 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,将所测试物质溶解在DMSO中并用转运缓冲液(Hanks缓冲盐溶液,Gibco/Invitrogen,含19.9mM葡萄糖和9.8mM HEPES)稀释至最终测试浓度。为了测定所测试物质从顶端到基底外侧的渗透性(PappA-B),将包含所测试物质的溶液施用于Caco-2细胞单层的顶端侧,并将转运缓冲液施用于基底外侧。为了测定所测试物质从基底外侧至顶端的渗透性(PappB-A),将包含所测试物质的溶液施用于Caco-2细胞单层的基底外侧,并将转运缓冲液输施用于顶端侧。在实验开始时,从各自的供体隔室中取样以确保质量平衡。在37℃下孵育两小时后,从两个隔室中取出样品。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,测定荧光黄的渗透性以确保细胞层的完整性。在每个测试运行中,测定阿替洛尔(低渗透性标志物)和柳氮磺胺吡啶(主动外排标志物)的渗透性作为质量对照组。
B-8 pH 6.5缓冲液中物质的溶解度测定
将2-4mg待测化合物溶解在DMSO中,使其浓度达到50g/L(溶液A,515μg/l)。向10μl该溶液中加入960μl pH 6.5的PBS缓冲液;混合物置于96孔板中在室温下振摇24小时。将一等分试样以42000rpm离心30分钟。上清液分别用乙腈/水(8:2)1:10和1:1000稀释。此稀释样品通过LC-MSMS进行分析。
校准:10μl溶液A用823μl DMSO(终浓度:600μg/ml)稀释,再用乙腈/水(8:2)稀释100倍(溶液B)。
用乙腈/水(8:2)进一步稀释溶液B,得到目标浓度为1.2-12–60-600ng/ml的溶液,然后注入这四种溶液进行质谱测定,得到校准曲线。
质谱方法优化:
溶液B用于质谱方法优化。
PBS-Puffer:将6.18g氯化钠和3.96g磷酸二氢钠溶解在1L蒸馏水中,用1N氢氧化钠调节pH至6.5。
LC-MSMS优化:
以下配置用于优化
AB Sciex TRIPLE QUAD 4500、Agilent 1260Infinity(G1312B)、脱气机(G4225A)、柱温箱(G1316C或G1316A)、CTC Analytics PAL进样系统HTS-xt或HTC-xt。
洗脱液A:0.5ml甲酸(50%ig)/L水,洗脱液B:0.5ml甲酸(50%ig)/L乙腈
自动进样器:无自动进样提前设置
色谱柱:不锈钢毛细管
烘箱温度:22℃
流量:流量梯度
进样体积:2μl
Water Quattro Micro MS、Agilent 1100(G1312A)、脱气机(G1322A)、柱温箱(G1316A)、CTC Analytics PAL进样系统HTS、洗脱液同上
时间[min] 流量[μl/min] %B
0.00 250 70
1.50 250 70
自动进样器:有自动进样提前设置
色谱柱:不锈钢毛细管
烤箱温度:22℃
流速:流量梯度
进样体积:5μl
质谱方法:用于优化的流动注射分析(FIA)(“MS-OPTI”);
电离模式ABSciex-MS:ESI-pos/neg,Waters-MS:ESI-pos
HPLC方法进行MSMS定量:
洗脱液A、B同上
ABSciex-MS
自动进样器:无自动进样提前设置
色谱柱:Waters OASIS HLB,2.1x20mm,25μ
柱温:30℃
流速:2.5ml
进样体积:2μl
分流器(splitter)(MS之前)1:20
Waters-MS
自动进样器:有自动进样提前设置
色谱柱:Waters OASIS HLB,2.1x20mm,25μ
柱温:30℃流速:2.5ml
进样体积:5μl
分流器(MS之前)1:20
MS方法:多反应监测(MRM)
B-9固体溶解度的测定
对于每种溶剂,在Eppendorf塑料小瓶中装入0.5–1mg的待测化合物(精确重量)、2-3个玻璃珠(直径3mm)和1.0ml的相应溶剂。将小瓶封闭并在室温下振荡24小时(1400rpm;Thermomixer,Eppendorf)。此后,将230μl各溶液/悬浮液转移到一个或多个离心管(Beckman Coulter)中并以42000rpm离心30分钟(Beckman Coulter Optima L90)。提取出至少100μl上清液并进一步用DMSO以两种稀释强度1:5和1:50进行稀释(通过1:5稀释步骤随后添加DMSO中得到后者)。这种液体处理可以手动完成,也可以在移液机器人(Lissy,Zinsser Analytic)的帮助下完成。
为了进行HPLC定量,配制了待测化合物的DMSO校准溶液。从600μg/ml的初始浓度开始,配制了三种校准溶液:100μg/ml、20μg/ml和2.5μg/ml(手动或通过Lissy)。
校准溶液和上清液均通过HPLC/UV-检测器以合适的波长进行分析。使用线性校准曲线确定溶解度。
HPLC系统:
Hewlett Packard/Agilent HPLC系统,G1311A+G1316A+G1315B以及G1312A+G1316A+G1315A
进样器系统:CTC-Analytik HTC PAL
或使用Agilent HPLC系统(G7117C、G7116B、G7167B和G7120)
柱箱温度:30℃,检测:210和/或254nm,进样体积:20μl
洗脱液A:0.1%TFA水溶液,洗脱液B:0.1%TFA乙腈溶液
色谱柱:ZORBAX Extend-C18,3.0x50mm,3.5μm
梯度:
C.药物组合物的工作实施例
本发明的化合物可以转化为如下药物制剂:
片剂:
成分:
100mg本发明化合物、50mg乳糖(一水合物)、50mg玉米淀粉(天然)、10mg聚乙烯吡咯烷酮(PVP 25)(来自BASF,Ludwigshafen,Germany)和2mg硬脂酸镁。
片剂重212mg。直径8mm,曲率半径12mm。
生产:
本发明的化合物、乳糖和淀粉的混合物用5%的PVP水溶液(w/w)制粒。将颗粒干燥,然后与硬脂酸镁混合5分钟。使用传统的压片机将该混合物压片(片剂规格见上文)。用于压制的指导值是15kN的压力。
用于口服给药的悬浮液剂:
成分:
10ml口服悬浮液剂相当于100mg本发明化合物的单剂量。
生产:
Rhodigel悬浮在乙醇中;将本发明的化合物加入到悬浮液中。边搅拌边加入水。将混合物搅拌约6小时,直到Rhodigel完全溶胀。
用于口服给药的溶液剂:
成分:
500mg本发明化合物、2.5g聚山梨醇酯和97g聚乙二醇400。20g口服液相当于100mg本发明化合物的单剂量。
生产:
本发明的化合物在搅拌下悬浮在聚乙二醇和聚山梨醇酯的混合物中。持续搅拌直到本发明的化合物完全溶解。
静脉注射溶液:
本发明的化合物以低于饱和溶解度的浓度溶解在生理学上可接受的溶剂(例如等渗盐水、5%葡萄糖溶液和/或30%PEG 400溶液)中。溶液经过滤灭菌,用于填充无菌和无热原的注射容器。
Claims (14)
2.根据权利要求1所述的化合物,其特征在于
R1代表氢、氟,
R2代表氢、氟,
R3代表氯或三氟甲基,
R4代表氢或甲基,
R5代表异丁基,
X1代表碳,
X2代表碳,
或其盐、其溶剂化物或其盐的溶剂化物中的一种。
7.根据权利要求1至3中任一项所述的式(I)化合物或其盐、其溶剂合物或其盐的溶剂合物中的一种的制备方法,其特征在于:
在第一步[D]中,在钯源、合适的配体和碱存在的条件下,将式
(VIII)的化合物与式(VII)的化合物反应提供式(II)的化合物,
其中R1、R2和R3定义同上,
其中R4、R5、R9和X1和X2定义同上,
其中R1,R2,R3,R4,R5和X1和X2定义同上
并且
在第二步[A]中
将式(II)的化合物在合适的溶剂中与碱反应以提供式(I)的化合物,
其中R1,R2,R3,R4,R5和X1和X2定义同上,
任选地在第三步[A]*中,在合适的溶剂中有合适的酸存在的条件下,将式(I)化合物转化为相应的式(Ia)的盐,
8.根据权利要求1至6中任一项所述的化合物,其用于治疗和/或预防疾病。
9.根据权利要求1至6中任一项所述的化合物,其用于治疗和/或预防心力衰竭(HFrEF、HFmrEF和HFpEF)、高血压(HTN)、慢性肾脏疾病和糖尿病肾脏疾病(CKD、DKD)、肺动脉高压(PH)、系统性硬化症(SSc)、镰状细胞病(SCD)、神经退行性疾病和痴呆,以及糖尿病足溃疡(DFU)。
10.根据权利要求1至6中任一项所述的化合物在制备用于治疗和/或预防疾病的药物中的用途。
11.根据权利要求1至6中任一项所述的化合物在制备用于治疗和/或预防以下疾病的药物中的用途:心力衰竭(HFrEF、HFmrEF和HFpEF)、高血压(HTN)、慢性肾脏疾病和糖尿病肾脏疾病(CKD、DKD)、肺动脉高压(PH)、系统性硬化症(SSc)、镰状细胞病(SCD)、神经退行性疾病和痴呆,以及糖尿病足溃疡(DFU)。
12.一种药物,其包含权利要求1至6中任一项所述化合物与惰性、无毒、药学上合适的赋形剂的组合。
13.根据权利要求12所述的药物,其用于治疗和/或预防心力衰竭(HFrEF、HFmrEF和HFpEF)、高血压(HTN)、慢性肾脏疾病和糖尿病肾脏疾病(CKD、DKD)、肺动脉高压(PH)、系统性硬化症(SSc)、镰状细胞病(SCD)、神经退行性疾病和痴呆,以及糖尿病足溃疡(DFU)。
14.用于治疗和/或预防人类或动物中的以下疾病的方法,其通过施用治疗有效量的至少一种根据权利要求1至6中任一项所述化合物、根据权利要求12或13所述的药物或根据权利要求10或11获得的药物进行,所述疾病为心力衰竭(HFrEF、HFmrEF和HFpEF)、高血压(HTN)、慢性肾脏疾病和糖尿病肾脏疾病(CKD、DKD)、肺动脉高压(PH)、系统性硬化症(SSc)、镰状细胞病(SCD),以及糖尿病足溃疡(DFU)。
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EP20213016.7A EP4011873A1 (en) | 2020-12-10 | 2020-12-10 | Substituted pyrazolo piperidine carboxylic acids |
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PCT/EP2021/084980 WO2022122910A1 (en) | 2020-12-10 | 2021-12-09 | Substituted pyrazolo piperidine carboxylic acids |
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US20230265072A1 (en) | 2023-08-24 |
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AU2021393987A1 (en) | 2023-06-22 |
EP4259615A1 (en) | 2023-10-18 |
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