CN111902414A - 取代的氧代吡啶衍生物 - Google Patents
取代的氧代吡啶衍生物 Download PDFInfo
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- CN111902414A CN111902414A CN201980023665.5A CN201980023665A CN111902414A CN 111902414 A CN111902414 A CN 111902414A CN 201980023665 A CN201980023665 A CN 201980023665A CN 111902414 A CN111902414 A CN 111902414A
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Abstract
本发明涉及5‑({6‑氨基‑2‑[4‑(5‑氯‑2‑氰基苯基)‑5‑甲氧基‑2‑氧代吡啶‑1(2H)‑基]‑3‑甲基己酰基}氨基)吡唑并[1,5‑a]吡啶‑3‑甲酰胺、其制备方法、其用于治疗和/或预防疾病的用途和其用于制备用于治疗和/或预防疾病,特别是心血管病症,优选血栓性或血栓栓塞性病症和水肿以及眼科病症的药物的用途、及其用于抑制对体外程序和分析测定的进行具有干扰性的血浆激肽释放酶活性的用途。
Description
本发明涉及5-({6-氨基-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基己酰基}氨基)吡唑并[1,5-a]吡啶-3-甲酰胺、其制备方法、其用于治疗和/或预防疾病的用途和其用于制备用于治疗和/或预防疾病,特别是心血管病症,优选血栓性或血栓栓塞性病症和水肿以及眼科病症的药物的用途,及其用于抑制对体外程序(extracorporeal procedures)和分析测定的进行具有干扰性的血浆激肽释放酶活性的用途。
血液凝固是有助于迅速可靠地“密封”血管壁中的缺陷的生物体保护机制。由此,可以避免或保持最低失血。血管损伤后的止血主要通过凝血系统实现,其中触发血浆蛋白的酶促复杂反应级联。许多凝血因子参与这一过程,各因子在活化后将各自的下一无活性前体转化成其活性形式。在该级联结束时可溶纤维蛋白原转化成不可溶纤维蛋白,以致形成血块。
成为焦点的是,特别可在带负电荷的表面上激活凝血系统,带负电荷的表面不仅包括外来细胞(例如细菌)的表面结构,还包括人工表面,如人造血管、支架和体外循环。在该表面上,最初将因子XII(FXII)活化成因子XIIa,其随后将因子XI活化成因子XIa。此外,因子XIIa也将血浆激肽释放酶原(PPK)活化成血浆激肽释放酶(PK),这在增强回路(potentiation loop)中首先导致进一步的因子XII活化,总体上导致扩大凝血级联的开始。此外,PK是重要的释放舒缓激肽的蛋白酶,其因此尤其导致提高的内皮通透性。已经描述的另一些底物是肾素原和尿激酶原,它们的活化可能影响肾素-血管紧张素系统的调节过程和纤维蛋白溶解。PK的活化因此是凝结过程和炎性过程之间的重要联系。
凝血系统的不受控活化或活化过程的缺陷抑制可能导致在脉管(动脉、静脉、淋巴管)或心腔中形成局部血栓或栓塞。此外,全身高凝状态可能导致整个系统的血栓形成并在弥散性血管内凝血的情况下最终导致消耗性凝血病。在体外循环系统中,如在血液透析过程中以及在人造血管或人工心脏瓣膜和支架中也可能发生血栓栓塞性并发症。
血浆激肽释放酶(PK)与其它和提高的血管通透性或慢性炎性病相关的病症相关联,如在糖尿病视网膜病变、黄斑水肿和遗传性血管水肿或慢性炎性肠道病症中的情况那样。糖尿病视网膜病变主要由微血管缺失造成,其导致血管的基底膜增厚和血管化周细胞的损失,接着发生血管闭塞和视网膜缺血,这由于因此造成的视网膜缺氧而可能导致提高的血管通透性并随之形成黄斑水肿,和由于存在的所有过程而导致患者失明。在遗传性血管水肿(HAE)中,生理激肽释放酶抑制剂C1-酯酶抑制剂的形成减少导致不受控的血浆激肽释放酶活化,以造成炎症及暴发性水肿形成和剧痛。来自实验性动物模型的迹象表明,对血浆激肽释放酶的抑制抑制了提高的血管通透性,因此可防止形成黄斑水肿和/或糖尿病视网膜病变或可改善HAE的急性症状。口服血浆激肽释放酶抑制剂也可用于HAE的预防。
借助血浆激肽释放酶生成的激肽在慢性炎性肠道病症(CID)的进展中尤其具有致病作用。它们经由缓激肽受体活化的促炎作用诱发并增强疾病进展。对克罗恩氏病患者的研究显示肠上皮中的激肽释放酶浓度与肠炎症程度之间的相关性。在实验性动物研究中同样观察到激肽释放酶-激肽系统的活化。通过激肽释放酶抑制剂抑制缓激肽合成因此也可用于慢性炎性肠道病症的预防和/或治疗。
对许多病症而言,抗血栓和抗炎原理的组合对防止凝血和炎症相互增强也特别有吸引力。
WO 2006/030032尤其描述了作为mGluR2受体的别构调节剂的取代的吡啶酮,且WO2008/079787描述了取代的吡啶-2-酮和它们作为葡糖激酶活化剂的用途。WO2005/123680、WO 2014/154794、WO 2014/160592、WO 2015/011087、WO 2015/063093、WO 2015/120777、WO2016/046156、WO 2016/046157、WO 2016/046158、WO 2016/046159、WO 2016/046164、WO2016/046166、WO 2016/146606、WO 2017/005725、WO 2017/037051和WO 2018/041122描述了取代的吡啶-2-酮和它们作为因子XIa抑制剂和/或激肽释放酶抑制剂的用途。
因此本发明的一个目的是提供用于治疗人类和动物的心血管病症,特别是血栓性或血栓栓塞性病症和用在含血浆激肽释放酶原(PPK)或血浆激肽释放酶(PK)的生物样本中以防止由PK引起的生理和人造底物(artificial substrates)的周转(turnover)造成的干扰效应的新型化合物。
令人惊讶地,现在已经发现某种取代的氧代吡啶衍生物代表高效和选择性的血浆激肽释放酶抑制剂。
本发明提供了化合物5-({6-氨基-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基己酰基}氨基)吡唑并[1,5-a]吡啶-3-甲酰胺,其对应于式(I)的化合物
及其盐、其溶剂化物和其盐的溶剂化物。
本发明还提供了化合物5-({6-氨基-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基己酰基}氨基)吡唑并[1,5-a]吡啶-3-甲酰胺三氟乙酸盐,其对应于式(Ia)的化合物
优选的是化合物5-({(2S)-6-氨基-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基己酰基}氨基)吡唑并[1,5-a]吡啶-3-甲酰胺,其对应于式(Ib)的化合物
及其盐、其溶剂化物和其盐的溶剂化物。
此外,优选的是化合物5-({(2S)-6-氨基-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基己酰基}氨基)吡唑并[1,5-a]吡啶-3-甲酰胺三氟乙酸盐,其对应于式(Ic)的化合物
本发明的化合物可以根据它们的结构以不同的立体异构形式,即以构型异构体或如果适当以构象异构体(对映体和/或非对映体,包括阻转异构体的情况中的那些)的形式存在。本发明因此包括对映体和非对映体和它们各自的混合物。可以以已知方式从对映体和/或非对映体的此类混合物中分离出立体异构一致的成分;为此优选使用色谱法,尤其是在非手性或手性相上的HPLC色谱法。
如果根据本发明的化合物可以互变异构形式存在,则本发明包含所有互变异构形式。
在本发明上下文中,术语“对映体纯”应被理解为是指所涉化合物相对于手性中心的绝对构型以大于95%,优选大于97%的对映体过量存在。在此使用下列公式通过评估手性相上的相应HPLC色谱图来计算对映体过量ee:
ee = [EA (面积%) - EB (面积%)] x 100% / [EA (面积%) + EB (面积%)]
(EA: 主要对映体,EB: 次要对映体)。
本发明还包括本发明的化合物的所有合适的同位素变体。本发明的化合物的同位素变体在此被理解为是指其中本发明的化合物内的至少一个原子已被具有相同原子序数但原子质量不同于自然界中通常或主要存在的原子质量的另一原子替换的化合物。可并入本发明的化合物中的同位素的实例是氢、碳、氮、氧、磷、硫、氟、氯、溴和碘的同位素,如2H(氘)、3H(氚)、13C、14C、15N、17O、18O和36Cl。本发明的化合物的特定同位素变体,尤其是其中已并入一种或多种放射性同位素的那些,可能有益于例如检查作用机制或体内的活性成分分布;由于比较容易制备和检测,用3H或14C同位素标记的化合物尤其适用于此用途。此外,同位素,例如氘的并入可由于该化合物的更大代谢稳定性而带来特定治疗益处,例如体内半衰期的延长或所需活性剂量的降低;本发明的化合物的此类改性因此在一些情况下也构成本发明的优选实施方案。可通过本领域技术人员已知的方法,例如通过下文进一步描述的方法和实施例中描述的程序、通过使用各自的试剂和/或起始化合物的相应同位素变体制备本发明的化合物的同位素变体。
在本发明上下文中,优选的盐是根据本发明的化合物的生理可接受盐。但是,本发明也包括其本身不适合药物用途但可例如用于根据本发明的化合物的分离或提纯的盐。
根据本发明的化合物的生理可接受盐包括无机酸、羧酸和磺酸的酸加成盐,例如盐酸、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。
在本发明上下文中被称为溶剂化物的是通过与溶剂分子配位而形成固态或液态配合物的本发明的化合物的那些形式。水合物是溶剂化物的一种特定形式,其中与水发生配位。
本发明另外还包括本发明的化合物的前药。术语“前药”包括其本身可能在生物学上有活性或无活性但在体内停留期间转化成根据本发明的化合物(例如通过代谢或水解)的化合物。
在本发明上下文中,术语“治疗”包括抑制、延迟、阻止、缓解、减弱、限制、降低、遏止、击退或治愈疾病、病况、病症、损伤或健康问题,或此类状态和/或此类状态的症状的发展、过程或进展。术语“疗法”在此与术语“治疗”同义使用。
术语“防止”、“预防”和“阻止(preclusion)”在本发明上下文中同义使用并且是指避免感染、发生、遭受或患上疾病、病况、病症、损伤或健康问题或此类状态和/或此类状态的症状的发展或加重或降低其风险。
疾病、病况、病症、损伤或健康问题的治疗或预防可以是部分或完全的。
本发明还提供一种制备式(I)、(Ia)、(Ib)和(Ic)的化合物或其盐、其溶剂化物或其盐的溶剂化物的方法。这些化合物可如合成方案1中所示合成:
方案1:
根据本发明的化合物具有不可预见的有益药理活性谱。它们是影响丝氨酸蛋白酶血浆激肽释放酶(PK)的蛋白水解活性的化合物。根据本发明的化合物抑制在血液凝固的活化、血小板聚集和特别涉及血管通透性提高的炎性过程中起到重要作用的受PK催化的底物的酶法裂解。
它们因此适合用作用于治疗和/或预防人类和动物的疾病的药物。
本发明还提供根据本发明的化合物用于治疗和/或预防病症,特别是心血管病症,优选血栓性或血栓栓塞性病症和/或血栓性或血栓栓塞性并发症,和/或眼科病症,特别是糖尿病视网膜病变或黄斑水肿,和/或炎性病症,特别是与过量血浆激肽释放酶活性相关的那些,如遗传性血管水肿(HAE)或慢性炎性病症,特别是肠的慢性炎性病症,如克罗恩氏病的用途。
在内源性活化的情况下,因子XIIa将血浆激肽释放酶原(PPK)活化成血浆激肽释放酶(PK),这在增强回路(potentiation loop)中尤其导致进一步的因子XII活化,总体上导致扩大表面上的凝血级联的开始。根据本发明的化合物的PK抑制活性因此减轻经由表面活化的凝血,因此具有抗凝作用。
相应地,根据本发明的化合物适用于治疗和/或预防可能由凝块形成引起的病症或并发症。
对本发明目的而言,“血栓性或血栓栓塞性病症”包括在动脉和静脉血管系统中发生并可用根据本发明的化合物治疗的病症,特别是在心脏的冠状动脉中的病症,如急性冠脉综合征(ACS)、存在ST段抬高(STEMI)和无ST段抬高(非STEMI)的心肌梗死、稳定型心绞痛、不稳定型心绞痛、在冠状动脉介入术如血管成形术、支架植入或主动脉冠状动脉搭桥术后的再闭塞和再狭窄,以及在导致外周动脉闭塞性病症、肺栓塞、静脉血栓栓塞、静脉血栓形成的其它脉管中,特别是在下肢深静脉和肾静脉中的血栓性或血栓栓塞性病症,短暂性脑缺血发作以及血栓性中风和血栓栓塞性中风。
凝血系统的刺激可由各种原因或相关病症造成。尤其在外科手术、不可动(immobility)、卧床、感染、炎症或癌症或癌症治疗的情况下,可高度激活凝血系统,并可能发生血栓性并发症,特别是静脉血栓形成。根据本发明的化合物因此适用于在癌症患者的外科手术的情况下预防血栓形成。根据本发明的化合物因此也适用于预防具有活化的凝血系统的患者中、例如在所述刺激情形中的血栓形成。
本发明的化合物因此也适用于预防和治疗具有急性、间歇性或持续性心律失常,例如心房颤动的患者和经受心脏复律的患者,以及具有心瓣膜病症或具有人工心瓣膜的患者的心源性血栓栓塞,例如脑缺血、中风和系统性血栓栓塞和缺血。
此外,本发明的化合物适用于治疗和预防弥漫性血管内凝血(DIC),其尤其与败血症相关发生,但也由于外科手术、肿瘤病症、烧伤或其它损伤发生并可能通过微血栓形成导致严重器官损伤。
此外,在微血管病性溶血性贫血中和在体外循环,例如血液透析、ECMO(“体外膜氧合”)、LVAD(“左心室辅助装置”)和类似方法、AV瘘管、人造血管和人工心脏瓣膜的情况下通过血液与异物表面的接触发生血栓栓塞性并发症。
此外,根据本发明的化合物适用于治疗和/或预防涉及微凝块形成或脑血管中的纤维蛋白沉积物(其可能导致痴呆病症,如血管性痴呆或阿尔茨海默氏病)的病症。在此,凝块可能通过闭塞和通过结合其它疾病相关因子来造成该病症。
此外,根据本发明的化合物特别适用于治疗和/或预防其中除促凝血组分外,促炎组分也起到重要作用的病症。特别可通过根据本发明的化合物防止凝血和发炎的相互增强,由此决定性地降低血栓性并发症的可能性。在这种情况下,因子XIa抑制组分(通过抑制凝血酶生成)和PK抑制组分都可有助于抗凝血和抗炎作用(例如经由缓激肽)。因此,尤其可考虑在动脉粥样硬化性血管病症、运动系统的风湿病情况下的炎症、肺的炎性病症,如肺纤维化,肾的炎性病症,如肾小球肾炎,肠的炎性病症,如克罗恩氏病或溃疡性结肠炎,或糖尿病基础疾病情况下可能存在的病症,如糖尿病视网膜病变或肾病情况下的治疗和/或预防。
借助血浆激肽释放酶生成的激肽尤其在慢性炎性肠道病症(CID)的进展中具有致病作用。它们经由缓激肽受体活化的促炎作用诱发并增强疾病进展。对克罗恩氏病患者的研究显示肠上皮中的激肽释放酶浓度与肠炎症程度之间的相关性。在实验性动物研究中同样观察到激肽释放酶-激肽系统的活化。通过激肽释放酶抑制剂抑制缓激肽合成因此也可用于慢性炎性肠道病症的预防和/或治疗。
此外,根据本发明的化合物可用于抑制肿瘤生长和转移瘤的形成,以及用于预防和/或治疗肿瘤患者,特别是经过大型外科手术或化疗或放射疗法的患者的血栓栓塞性并发症,例如静脉血栓栓塞。
此外,根据本发明的化合物也适用于治疗和/或预防在传染病和/或全身炎性综合征(SIRS)、败血性器官功能障碍、败血性器官衰竭和多器官衰竭、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、败血性休克和/或败血性器官衰竭情况下的弥散性血管内凝血。
在感染过程中,可能发生凝血系统的泛发性活化(弥散性血管内凝血或消耗性凝血病,下文称为“DIC”),伴随着各种器官中的微血栓形成和继发性出血并发症。此外,可能发生内皮损伤,随之提高血管通透性和体液和蛋白质扩散到血管外腔(extravasal space)中。随着感染进展,可能发生器官衰竭(例如肾衰竭、肝衰竭、呼吸衰竭、中枢神经缺陷和心血管衰竭)或多器官衰竭。
在DIC的情况中,在受损内皮细胞的表面、异物或交联血管外组织的表面发生凝血系统的大规模活化。因此,在各种器官的小血管中发生凝固,伴随着缺氧和后续器官功能障碍。继发效应是凝血因子(例如因子X、凝血酶原和纤维蛋白原)和血小板消耗,这降低血液的凝固能力并可能导致大出血。
除抗凝血活性外,血浆激肽释放酶还是重要的释放舒缓激肽的蛋白酶,其因此尤其导致提高的内皮通透性。该化合物因此可用于治疗和/或预防涉及水肿形成的病症,如眼科病症,特别是糖尿病视网膜病变或黄斑水肿或遗传性血管水肿。
“眼科病症”在本发明上下文中特别包括如糖尿病视网膜病变、糖尿病性黄斑水肿(DME)、黄斑水肿、与视网膜静脉闭塞相关的黄斑水肿、年龄相关性黄斑变性(AMD)、脉络膜新生血管(CNV)、脉络膜新生血管膜(CNVM)、囊样黄斑水肿(CME)、视网膜前膜(ERM)和黄斑穿孔、近视相关脉络膜新生血管、血管样条纹、血管条纹、视网膜脱离、视网膜色素上皮细胞的萎缩性变化、视网膜色素上皮细胞的肥厚性变化、视网膜静脉闭塞、脉络膜视网膜静脉闭塞、视网膜色素变性、Stargardt’s病、早产儿视网膜病变、青光眼、炎性眼病,如葡萄膜炎、巩膜炎或眼内炎、白内障、折射异常,如近视、远视或散光和圆锥角膜、眼前病症,如作为例如角膜炎、角膜移植或角膜成形术的后遗症的角膜血管新生、作为缺氧(例如由于过度使用隐形眼镜)后遗症的角膜血管新生、翼状胬肉结膜、角膜下水肿和角膜内水肿之类的病症。
根据本发明的化合物也适用于在基因突变导致增强的酶活性或提高的酶原水平并通过酶活性或酶原浓度的相关试验/测量确定这些的患者中原发性预防血栓性或血栓栓塞性病症和/或炎性病症和/或具有提高的血管通透性的病症。
本发明还提供根据本发明的化合物用于治疗和/或预防病症,尤其是上述病症的用途。
本发明还提供根据本发明的化合物用于制备用于治疗和/或预防病症,尤其是上述病症的药物的用途。
本发明还提供使用治疗有效量的根据本发明的化合物治疗和/或预防病症,尤其是上述病症的方法。
本发明还提供在使用治疗有效量的根据本发明的化合物治疗和/或预防病症,尤其是上述病症的方法中使用的根据本发明的化合物。
本发明特别提供在使用治疗有效量的根据本发明的化合物治疗和/或预防血栓性或血栓栓塞性病症的方法中使用的根据本发明的化合物。
本发明还提供包含根据本发明的化合物和一种或多种其它活性化合物的药物。
此外,根据本发明的化合物也可用于离体防止凝固,例如用于保护待移植的器官免受由凝块形成造成的器官损伤和用于保护器官接受者免受来自移植器官的血栓栓塞,用于保存血液和血浆产品,用于清洁/预处理导管和其它医疗辅助设备和仪器,用于涂布体内或离体使用的医疗辅助设备和仪器的合成表面。
根据本发明的化合物还可用在含血浆激肽释放酶原(PPK)或血浆激肽释放酶(PK)的生物样本中以防止由PK引起的生理和人造底物的周转造成的干扰效应。
本发明还提供一种体外防止血液凝固的方法,特别是在可能包含血浆激肽释放酶的库存血液或生物样品中,所述方法的特征在于加入抗凝血有效量的根据本发明的化合物。
本发明还提供包含根据本发明的化合物和一种或多种其它活性化合物的药物,其特别用于治疗和/或预防上述病症。
“组合”对本发明目的而言不仅是指含有所有组分的剂型(所谓的固定组合)和含有彼此分开的组分的组合包装,还是指同时或相继给药的组分,只要它们用于预防和/或治疗相同疾病。同样有可能将两种或更多种活性成分互相组合,意味着它们因此各自在双组分或多组分组合中。
本发明的化合物可全身和/或局部作用。为此,它们可以以合适方式给药,例如通过口服、肠道外、肺、鼻、舌下、舌、口腔、直肠、皮肤、透皮、结膜或经耳途径或作为植入物或支架。
本发明的化合物可以以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发挥功能并以快速和/或调控方式递送本发明的化合物并含有结晶和/或非晶和/或溶解形式的本发明的化合物的给药形式,例如片剂(未包衣或包衣片剂,例如具有肠溶包衣或不可溶或延迟溶出的包衣,它们控制本发明的化合物的释放)、在口腔中快速崩解的片剂、或薄膜剂/圆片、薄膜剂/冻干产物、胶囊(例如硬或软明胶胶囊)、糖衣片剂、颗粒剂、丸剂、粉剂、乳剂、混悬剂、气雾剂或溶液剂。
肠道外给药的实现可避开再吸收步骤(例如通过静脉内、动脉内、心脏内、脊柱内或腰内途径)或包括再吸收(例如通过肌肉内、皮下、皮内、经皮或腹膜内途径)。适合肠道外给药的给药形式包括溶液剂、混悬剂、乳剂、冻干产物或无菌粉末形式的注射和输液制剂。
适合眼外(局部)给药的是根据现有技术运作、快速和/或以调控或受控方式释放活性化合物并含有结晶和/或非晶和/或溶解形式的活性化合物的给药形式,例如滴眼剂、喷雾剂和洗剂(例如溶液剂、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(例如磨碎的活性化合物、混合物、冻干产物、沉淀活性化合物)、半固体眼制剂(例如水凝胶、原位水凝胶、霜剂和软膏)、眼插入物(固体和半固体制剂,例如生物粘附剂、薄膜剂/圆片、片剂、隐形眼镜)。
眼内给药包括例如玻璃体内、视网膜下、巩膜下、脉络膜内、结膜下、眼球后和眼筋膜囊内(subtenon)给药。适合眼内给药的是根据现有技术运作、快速和/或以调控或受控方式释放活性化合物并含有结晶和/或非晶和/或溶解形式的活性化合物的给药形式,例如,注射制剂和注射制剂的浓缩剂(例如溶液剂、混悬剂、囊泡/胶体体系、乳剂)、用于注射制剂的粉剂(例如磨碎的活性化合物、混合物、冻干产物、沉淀活性化合物)、用于注射制剂的凝胶(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)。
优选的是口服给药,或在眼科病症的情况下,眼外和眼内给药。
适合其它给药途径的给药形式是例如吸入剂型(包括粉末吸入器、喷雾器)、滴鼻剂、溶液剂或喷雾剂;舌、舌下或口腔给药的片剂,薄膜剂/圆片或胶囊、栓剂、耳或眼制剂、阴道胶囊、水混悬剂(洗剂、振荡混合物)、亲脂混悬剂、软膏、霜剂、透皮治疗系统(例如贴剂)、乳剂、糊剂、泡沫剂、扑粉剂、植入物或支架。
本发明的化合物可转化成所提到的给药形式。这可以以本身已知的方式通过与惰性、无毒、可药用赋形剂混合实现。这些赋形剂包括载体(例如微晶纤维素、乳糖、甘露醇)、溶剂(例如液体聚乙二醇)、乳化剂和分散剂或润湿剂(例如十二烷基硫酸钠、聚氧山梨糖醇酐油酸酯(polyoxysorbitan oleate))、粘合剂(例如聚乙烯基吡咯烷酮)、合成和天然聚合物(例如白蛋白)、稳定剂(例如抗氧化剂,例如抗坏血酸)、着色剂(例如无机颜料,例如氧化铁)和味道和/或气味矫正剂。
本发明还提供包含至少一种本发明的化合物,优选以及一种或多种惰性无毒的可药用赋形剂的药物,及其用于上文提到的目的的用途。
在肠道外给药的情况下,通常发现有利的是,每24小时给药大约5至250毫克的量以实现有效结果。在口服给药的情况下,该量为每24小时大约5至500毫克。
尽管如此,可能必须酌情偏离规定的量,尤其取决于体重、给药途径、个体对活性成分的反应、制剂类型和给药时间或给药间隔。
除非另行指明,下列试验和实施例中的百分比为重量百分比;份数为重量份。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:100毫升溶液或悬浮液包含10克物质。
A) 实施例
缩写:
aq. 水性
Boc 叔丁氧基羰基
br 宽(在NMR中)
brsm 基于回收的原材料
d 天,双重峰(在NMR中)
dd 双重双峰(在NMR中)
ddd 双组双重双峰(在NMR中)
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
ESI 电喷雾电离(在MS中)
h 小时
HATU 六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓
HPLC 高压高效液相色谱法
HV 高真空
LC-MS 液相色谱法-质谱法联用
m 多重峰(在NMR中)
min 分钟
MS 质谱法
NMR 核磁共振波谱法
Rt 保留时间(在HPLC中)
s 单峰(在NMR中)
t 三重峰(在NMR中)
THF 四氢呋喃
TFA 三氟乙酸
T3P 2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷杂环己烷 2,4,6-三氧化物。
LC-MS方法:
方法1: 仪器MS: Thermo Scientific FT-MS;HPLC仪器: Thermo ScientificUltiMate 3000;柱: Waters Acquity UPLC HSS T3,100 Å,1.8 µm,2.1 mm x 75 mm;洗脱剂A: 1 l水 + 0.01%甲酸;洗脱剂B: 1 l乙腈 + 0.01%甲酸;梯度: 0.0 min 10% B →2.5 min 95% B → 3.5 min 95% B;柱温箱: 50℃;流速: 0.90 ml/min;UV检测: 210 nm/最佳积分路径210-300 nm。
方法2: 仪器: Waters ACQUITY SQD UPLC System;柱: Waters Acquity UPLCHSS T3,100 Å,1.8 µm;1 mm x 50 mm;洗脱剂A: 1 l水 + 0.25 ml 99%甲酸,洗脱剂B: 1l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;柱温箱: 50℃;流速: 0.40 ml/min;UV检测: 210 nm。
当根据本发明的化合物通过其中洗脱剂含有添加剂例如三氟乙酸、甲酸或氨的色谱法提纯时,如果根据本发明的化合物含有足够碱性或酸性的官能,根据本发明的化合物可以盐形式,例如作为三氟乙酸盐、甲酸盐或铵盐获得。这样的盐可通过本领域技术人员已知的各种方法转化成相应的游离碱或酸。
在下述本发明的合成中间体和操作实施例的情况下,以相应的碱或酸的盐形式指定的任何化合物通常是通过各自的制备和/或提纯方法获得的确切化学计量组成未知的盐。除非更详细规定,名称和结构式上的附加词,如“盐酸盐”、“三氟乙酸盐”、“钠盐”或“xHCl”、“x CF3COOH”、“x Na+”因此在此类盐的情况下不应在化学计量的意义上理解,而是仅对其中存在的成盐组分具有描述特性。
如果合成中间体或操作实施例或其盐通过所述制备和/或提纯方法以化学计量组成未知的溶剂化物,例如水合物的形式获得(如果它们具有指定类型),这相应地适用。
起始化合物
实施例1A
[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]乙酸(2E)-丁-2-烯-1-基酯
将4-氯-2-(5-甲氧基-2-氧代-1,2-二氢吡啶-4-基)苯甲腈 [CAS-RN 1630193-83-7;WO2015/063093, p. 73f., expl. 2.1C](11.3 g, 43.2 mmol)、溴乙酸(2E)-丁-2-烯-1-基酯 [CAS-RN 93455-19-7;S. M. Weinreb等人, J. Org. Chem. 1984, 49, 5058-5064](10.0 g, 51.8 mmol)和碳酸钾(8.95 g, 64.8 mmol)在DMF (90 ml)中的混合物加热到100℃持续45 min。随后,在真空中除去溶剂。加入水,混合物用乙酸乙酯萃取三次。合并的有机层用盐水洗涤并经硫酸钠干燥。蒸发溶剂,残留物通过柱色谱法提纯(硅胶;洗脱剂:环己烷 – 乙酸乙酯梯度)以产生10.8 g(92%纯度,62%收率)标题化合物。
LC-MS (方法2): Rt = 0.92 min;MS (ESIpos): m/z = 373 [M+H]+
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 8.01-7.97 (m, 1H), 7.75-7.71 (m,2H), 7.58 (s, 1H), 6.52 (s, 1H), 5.88-5.78 (m, 1H), 5.65-5.55 (m, 1H), 4.74(s, 2H), 4.59 (d, 2H), 3.62 (s, 3H), 1.70 (dd, 3H)。
实施例2A
2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基戊-4-烯酸(非对映体的外消旋混合物)
将[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]乙酸(2E)-丁-2-烯-1-基酯(10.8 g, 92%纯度,26.7 mmol)溶解在THF (150 ml)中并冷却到-78℃。加入双(三甲基甲硅烷基)氨基化锂(58 ml, 1.0 M在THF中, 58 mmol)。反应在-78℃下搅拌30 min。随后,加入氯(三甲基)甲硅烷(7.4 ml, 58 mmol)。将其升温到60℃并搅拌1 h。将水添加到反应混合物中,其用1N盐酸水溶液酸化。其用二氯甲烷萃取三次。合并的有机层用1N氢氧化钠水溶液萃取三次。合并的碱性层用4N盐酸水溶液酸化并用二氯甲烷萃取五次。合并的有机相经硫酸钠干燥并蒸发溶剂以作为非对映体的外消旋混合物(比率38:62)产生6.95 g(70%收率)标题化合物。
LC-MS (方法1): Rt = 1.59 min (次要异构体), 1.62 min (主要异构体);MS(ESIpos): m/z = 373 [M+H]+
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 13.16 (br s, 1H), 7.99 (d, 1H, 主要异构体)和7.98 (d, 1H, 次要异构体), 7.76-7.69 (m, 2H), 7.44 (s, 1H, 主要)和7.38 (s, 1H, 次要), 6.52 (s, 1H, 主要)和6.46 (s, 1H, 次要), 5.95 (ddd, 1H, 主要)和5.59 (ddd, 1H, 次要), 5.20 (d, 1H, 主要)和5.02 (d, 1H, 次要), 5.18-5.15(m, 1H), 5.11 (dd, 1H, 主要)和4.92 (dd, 1H, 次要), 3.65 (s, 3H, 主要)和3.62(s, 3H, 次要), 3.26-3.11 (m, 1H), 1.18 (d, 3H, 次要)和0.87 (d, 3H, 主要)。
实施例3A
2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基-N-(丙-2-烯-1-基)-戊-4-烯酰胺(非对映体的外消旋混合物)
将2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基戊-4-烯酸(非对映体的外消旋混合物)(4.00 g, 10.7 mmol)和丙-2-烯-1-胺(12 ml, 160 mmol)溶解在吡啶(40 ml)中并加热到60℃。逐滴加入T3P在乙酸乙酯中的溶液(19 ml, 50%纯度,32mmol)并将该混合物在60℃下进一步搅拌1 h。加入水,其用乙酸乙酯萃取三次。合并的有机层经硫酸钠干燥并在真空中除去溶剂。残留物通过柱色谱法提纯(硅胶;洗脱剂: 环己烷 –乙酸乙酯梯度)以作为非对映体的外消旋混合物产生2.56 g(58%收率)标题化合物。
LC-MS (方法1): Rt = 1.81 min;MS (ESIpos): m/z = 412 [M+H]+
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 8.84 (t, 1H, 次要异构体)和8.69 (t,1H, 主要异构体), 7.99 (d, 1H, 主要)和7.97 (d, 1H, 次要), 7.76-7.68 (m, 2H),7.64 (s, 1H, 主要)和7.62 (s, 1H, 次要), 6.52 (s, 1H, 主要)和6.46 (s, 1H, 次要), 5.89-5.43 (m, 3H), 5.22-4.89 (m, 4H), 3.85-3.60 (m, 2H), 3.65 (s, 3H, 主要)和3.64 (s, 3H, 次要), 3.13-2.95 (m, 1H), 1.08 (d, 3H, 次要)和0.83 (d, 3H,主要)。
实施例4A
烯丙基{2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基戊-4-烯酰基}氨基甲酸叔丁酯(非对映体的外消旋混合物)
将2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基-N-(丙-2-烯-1-基)戊-4-烯酰胺(非对映体的外消旋混合物)(2.50 g, 6.07 mmol)溶解在乙腈(120 ml)中。加入二碳酸二-叔丁酯(2.8 ml, 12 mmol)和4-二甲基氨基吡啶(297 mg, 2.43 mmol)并将该混合物加热到60℃持续1 h。混合物随后在真空中浓缩且残留物直接通过柱色谱法提纯(硅胶;洗脱剂: 环己烷 – 乙酸乙酯梯度)以作为非对映体的外消旋混合物产生3.07g(99%收率)标题化合物。
LC-MS (方法1): Rt = 2.41 min;MS (ESIpos): m/z = 512 [M+H]+
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 7.99 (d, 1H, 主要异构体)和7.97 (d,1H, 次要异构体), 7.75-7.63 (m, 2H), 7.42 (s, 1H, 主要)和7.39 (s, 1H, 次要),6.51 (s, 1H, 主要)和6.46 (s, 1H, 次要), 6.45 (br. d, 1H, 主要)和6.36 (br. d,1H, 次要), 5.96-5.58 (m, 2H), 5.22-4.92 (m, 4H), 4.24-4.07 (m, 2H), 3.66 (s,3H, 主要)和3.62 (s, 3H, 次要), 3.35-3.20 (m, 1H), 1.484 (s, 9H, 次要)和1.478(s, 9H, 主要), 1.16 (d, 3H, 次要)和0.89 (d, 3H, 主要)。
实施例5A
3-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-4-甲基-2-氧代-2,3,4,7-四氢-1H-氮杂䓬-1-甲酸叔丁酯(非对映体的外消旋混合物)
将烯丙基{2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基戊-4-烯酰基}氨基甲酸叔丁酯(非对映体的外消旋混合物)(3.00 g, 5.86 mmol)溶解在二氯甲烷(1.0 l)中并将溶液脱气(氩气气氛)。加入亚苄基[1,3-双(2,4,6-三甲基苯基)咪唑烷-2-亚基]二氯化钌-三环己基膦(1/1) [CAS-RN 246047-72-3](249 mg, 293 µmol)并将反应在45℃下搅拌1.5 h。随后,加入饱和碳酸氢钠水溶液。分离有机层且水层用二氯甲烷萃取两次。合并的有机层用盐水洗涤并经硫酸钠干燥。蒸发溶剂且残留物通过柱色谱法提纯(硅胶;洗脱剂: 环己烷 – 乙酸乙酯梯度)以作为非对映体的外消旋混合物产生2.75 g(97%收率)标题化合物。
LC-MS (方法1): Rt = 2.04 (主要异构体)和2.06 min (次要异构体);MS(ESIneg): m/z = 482 [M-H]-
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 8.01 (m, 1H, 次要异构体)和8.00 (d,1H, 主要异构体), 7.78-7.71 (m, 2H), 7.47 (s, 1H, 主要)和7.31 (s, 1H, 次要),6.60 (s, 1H, 次要)和6.56 (s, 1H, 主要), 6.34 (d, 1H, 主要)和6.18 (d, 1H, 次要), 6.03-5.94 (m, 1H), 5.90-5.83 (m, 1H, 次要)和5.83-5.77 (m, 1H, 主要),4.57 (dd, 1H, 次要)和4.47 (dd, 1H, 主要), 4.44-4.33 (m, 1H), 3.684 (s, 3H, 次要)和3.676 (s, 3H, 主要), 3.48-3.38 (m, 1H, 主要), 3.07-2.97 (m, 1H, 次要),1.46 (s, 9H, 主要)和1.45 (s, 9H, 次要), 1.18 (d, 3H, 次要)和0.91 (d, 3H, 主要)。
实施例6A
3-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-4-甲基-2-氧代氮杂环庚烷-1-甲酸叔丁酯(非对映体的外消旋混合物)
将3-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-4-甲基-2-氧代-2,3,4,7-四氢-1H-氮杂䓬-1-甲酸叔丁酯(非对映体的外消旋混合物)(2.70 g, 5.58 mmol)溶解在乙酸乙酯(250 ml)中并加入钯(10%在木炭上,594 mg)。反应在氢气(大气压)下搅拌4h。混合物经硅藻土过滤并在真空中除去溶剂。残留物通过柱色谱法提纯(硅胶;洗脱剂: 环己烷 – 乙酸乙酯梯度)以产生0.54 g原材料的主要异构体和1.78 g(66%收率, 82% brsm收率)作为非对映体的外消旋混合物的标题化合物。
LC-MS (方法1): Rt = 2.05 min;MS (ESIneg): m/z = 484 [M-H]-
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 8.00 (d, 1H)和7.99 (d, 1H), 7.77-7.71 (m, 2H), 7.42 (s, 1H, 次要异构体)和7.16 (s, 1H, 主要异构体), 6.56 (s,1H, 主要)和6.52 (s, 1H, 次要), 5.89 (s, 1H, 主要)和5.86-5.66 (m, 1H, 次要),4.23-4.13 (m, 1H), 3.68 (s, 3H, 主要)和3.66 (s, 3H, 次要), 3.65-3.55 (m, 1H),2.64-2.56 (m, 1H)和(2.15-2.03 (m, 1H), 1.97-1.55 (m, 4H), 1.46 (s, 9H), 1.14(d, 3H, 主要)和0.86 (d, 3H, 次要)。
实施例7A
6-[(叔丁氧基羰基)氨基]-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基己酸(非对映体的外消旋混合物)
将3-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-4-甲基-2-氧代氮杂环庚烷-1-甲酸叔丁酯(非对映体的外消旋混合物)(1.77 g, 3.64 mmol)溶解在THF (25ml)中并加入氢氧化锂水溶液(3.6 ml, 2.0 M, 7.2 mmol)。混合物在30℃下搅拌1 h,然后在真空中浓缩并将残留物溶解在水中。其用乙酸乙酯洗涤。水相用1N盐酸水溶液酸化并用乙酸乙酯萃取两次。合并的有机层用盐水洗涤并经硫酸钠干燥以作为非对映体的外消旋混合物产生1.78 g(97%收率)标题化合物。
LC-MS (方法1): Rt = 1.80 min (次要异构体)和1.84 min (主要异构体);MS(ESIpos): m/z = 504 [M+H]+
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 13.13 (br. s, 1H), 8.01-7.97 (m,1H), 7.76-7.71 (m, 2H), 7.38 (s, 1H), 6.80 (br. t, 1H, 主要异构体)和6.70 (br.t, 1H, 次要异构体), 6.51 (s, 1H), 5.10 (d, 1H, 次要)和5.05 (d, 1H, 主要),3.64 (s, 3H, 次要)和3.63 (s, 3H, 主要), 3.01-2.71和2.49-2.37 (m, 总共3H),1.64-1.40和1.31-1.13和1.02-0.93 (m, 总共4H), 1.38 (s, 9H, 主要)和1.34 (s, 9H,次要), 1.05 (d, 3H, 次要)和0.72 (d, 3H, 主要)。
实施例8A
{6-[(3-氨基甲酰基吡唑并[1,5-a]吡啶-5-基)氨基]-5-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-4-甲基-6-氧代己基}氨基甲酸叔丁酯(非对映体的外消旋混合物)
将6-[(叔丁氧基羰基)氨基]-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基己酸(非对映体的外消旋混合物)(1.08 g, 2.14 mmol)和5-氨基吡唑并[1,5-a]吡啶-3-甲酰胺三氟乙酸盐 [CAS-RN 1891071-11-6;WO2016/046158, p. 53,expl. 1.1C](746 mg, 2.57 mmol)溶解在DMF (4.0 ml)中。逐滴加入作为在DMF (2.0 ml)中的溶液的HATU(1.22 g, 3.21 mmol)和随后N,N-二异丙基乙基胺(370 µl, 2.1 mmol)。反应在室温下搅拌1.5 h。进一步加入5-氨基吡唑并[1,5-a]吡啶-3-甲酰胺三氟乙酸盐(187 mg, 643 µmol)和N,N-二异丙基乙基胺(370 µl, 2.1 mmol)。在搅拌整夜后,加入另外的HATU(407 mg, 1.07 mmol)和N,N-二异丙基乙基胺(370 µl, 2.1 mmol)并在1 h后,反应在真空中浓缩。残留物用水结晶,通过抽吸过滤收集并用水洗涤,并在真空中干燥。化合物通过柱色谱法提纯(硅胶;洗脱剂: 二氯甲烷/甲醇梯度)以作为非对映体的外消旋混合物产生1.20 g(84%收率)标题化合物。
LC-MS (方法1): Rt = 1.75 min;MS (ESIpos): m/z = 662 [M+H]+
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 11.14 (br. s, 1H, 主要异构体)和11.12(br. s, 1H, 次要异构体), 8.73-8.66 (m, 2H), 8.47 (s, 1H, 主要)和8.46 (s, 1H,次要), 8.00 (d, 1H, 主要)和7.99 (d, 1H, 次要), 7.77-7.71 (m, 2H), 7.63 (s,1H), 7.60 (br. s, 1H), 7.26 (dd, 1H), 6.98 (br. s, 1H), 6.76-6.70 (m, 1H),6.56 (s, 1H, 次要)和6.55 (s, 1H, 主要), 5.57 (d, 1H, 主要)和5.56 (d, 1H, 次要), 3.72 (s, 3H, 主要)和3.71 (s, 3H, 次要), 2.96-2.76 (m, 2H), 1.64-0.96 (m,5H), 1.34 (s, 9H, 主要)和1.28 (s, 9H, 次要), 1.05 (d, 3H, 主要)和0.78 (d, 3H,次要)。
可通过手性色谱法实现四种立体异构体的分离: 柱和固相: 250 mm x 20 mm,Chiralpak IE, 5 µm;洗脱剂: 乙醇;流速15.0 ml/min。产生三个峰(7.0-8.5 min, 11.1min, 13.9 min)。第一个峰需要进一步色谱分离: 柱和固相: 250 mm x 20 mm,Chiralpak IC, 5 µm;洗脱剂: 乙醇;流速15.0 ml/min。产生两个峰(6.29 min, 7.33min)。
分析型HPLC: 柱250 mm x 4.6 mm, Chiralcel OX-H, 5 µm;洗脱剂: 异己烷/乙醇1:1;流速1.0 ml/min;温度: 40℃。
立体异构体1: Rt = 10.90 min。
立体异构体2: Rt = 7.50 min。
立体异构体3: Rt = 8.85 min。
立体异构体4: Rt = 9.19 min。
立体异构体1和4以及立体异构体2和3是彼此的对映异构体。
立体异构体1和4:
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 11.14 (br. s, 1H), 8.70-8.67 (m,2H), 8.47 (s, 1H), 8.00 (d, 1H), 7.75-7.71 (m, 2H), 7.60 (br. s, 1H), 7.62(br. s, 1H), 7.25 (dd, 1H), 6.98 (br. s, 1H), 6.76-7.70 (m, 1H), 6.55 (s,1H), 5.57 (d, 1H), 3.71 (s, 3H), 2.93-2.74 (m, 2H), 1.52-1.29 (m, 3H), 1.34(s, 9H), 1.26-0.96 (m, 2H), 1.05 (d, 3H)。
立体异构体2和3:
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 11.12 (br. s, 1H), 8.71 (d, 1H),8.68 (d, 1H), 8.46 (s, 1H), 7.99 (d, 1H), 7.76 (d, 1H), 7.73 (dd, 1H), 7.62(s, 1H), 7.59 (br. s, 1H), 7.25 (dd, 1H), 6.99 (br. s, 1H), 6.75 (br. t, 1H),6.56 (s, 1H), 5.56 (d, 1H), 3.70 (s, 3H), 2.95-2.83 (m, 2H), 2.48-2.39 (m,1H), 1.66-1.53 (m, 1H), 1.51-1.29 (m, 3H), 1.28 (s, 9H), 0.77 (d, 3H)。
操作实施例
实施例1
5-({6-氨基-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基-己酰基}氨基)吡唑并[1,5-a]吡啶-3-甲酰胺三氟乙酸盐(非对映体的外消旋混合物)
将{6-[(3-氨基甲酰基吡唑并[1,5-a]吡啶-5-基)氨基]-5-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-4-甲基-6-氧代己基}氨基甲酸叔丁酯(非对映体的外消旋混合物)(1.20 g, 1.81 mmol)溶解在二氯甲烷中并用冰水冷却。加入三氟乙酸(2.8 ml,36 mmol)。将该混合物升温到室温并搅拌1 h。然后蒸发混合物。加入二氯甲烷并在真空中除去。将这一程序重复一次。残留物通过柱色谱法提纯(硅胶;洗脱剂: 二氯甲烷/甲醇梯度)以作为非对映体的外消旋混合物产生785 mg(64%收率)标题化合物。
LC-MS (方法2): Rt = 0.64 min (主要异构体) 0.68 (次要异构体);MS(ESIpos): m/z = 562 [M+H]+
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 11.17 (s, 1H, 主要异构体)和11.14 (s,1H, 次要异构体), 8.73-8.67 (m, 2H), 8.48 (s, 1H), 8.00 (d, 1H, 主要)和7.99(d, 1H, 次要), 7.76-7.72 (m, 2H), 7.69 (br. s, 4H), 7.65 (s, 1H, 主要)和7.61(s, 1H, 次要), 7.28-7.25 (m, 1H), 6.98 (br. s, 1H), 6.58 (s, 1H, 次要)和6.57(s, 1H, 主要), 5.61-5.55 (m, 1H), 3.72 (s, 3H, 主要)和3.70 (s, 3H, 次要),2.87-2.51 (m, 3H), 1.80-1.09 (m, 4H), 1.08 (d, 3H, 主要)和0.79 (d, 3H, 次要)。
实施例2
5-({(2S)-6-氨基-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基己酰基}氨基)吡唑并[1,5-a]吡啶-3-甲酰胺三氟乙酸盐(立体异构体3)
根据实施例1中提到的程序,将分离的实施例8A立体异构体3的氨基甲酸酯单独脱保护。
立体异构体3:
LC-MS (方法1): Rt = 1.05 min;MS (ESIpos): m/z = 562 [M+H]+
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 11.15 (s, 1H), 8.72 (d, 1H), 8.69(d, 1H), 8.48 (s, 1H), 8.00 (d, 1H), 7.76-7.72 (m, 2H), 7.60 (s, 1H), 7.63(br s, 4H), 7.27 (dd, 1H), 6.98 (br s, 1H), 6.58 (s, 1H), 5.56 (d, 1H), 3.70(s, 3H), 2.88-2.72 (m, 2H), (1H在DMSO下), 1.81-1.67 (m, 1H), 1.63-1.44 (m,2H), 1.39-1.28 (m, 1H), 0.79 (d, 3H)。
实施例3
5-({(2S)-6-氨基-2-[4-(5-氯-2-氰基苯基)-5-甲氧基-2-氧代吡啶-1(2H)-基]-3-甲基己酰基}氨基)吡唑并[1,5-a]吡啶-3-甲酰胺三氟乙酸盐(立体异构体4)
根据实施例1中提到的程序,将分离的实施例8A立体异构体4的氨基甲酸酯单独脱保护。
立体异构体4:
LC-MS (方法1): Rt = 0.99 min;MS (ESIpos): m/z = 562 [M+H]+
1H-NMR (400 MHz, DMSO-d 6): δ [ppm] = 11.17 (s, 1H), 8.72-8.67 (m, 2H),8.48 (s, 1H), 8.03-7.98 (m, 1H), 7.77-7.72 (m, 2H), 7.65 (s, 1H), 7.62 (br s,4H), 7.26 (dd, 1H), 6.98 (br s, 1H), 6.57 (s, 1H), 5.59 (d, 1H), 3.72 (s,3H), 2.83-2.62 (m, 2H), 2.58-2.51 (m, 1H), 1.70-1.44 (m, 2H), 1.08 (d, 3H),1.26-1.06 (m, 2H)。
B) 生理效力的评估
可在下列测定系统中证实根据本发明的化合物用于治疗血栓栓塞病症的适用性:
a) 试验描述(体外)
a.1) 血浆激肽释放酶活性的测定
为了测定根据本发明的物质的血浆激肽释放酶抑制,使用利用肽类(peptidic)血浆激肽释放酶底物的反应测定人血浆激肽释放酶的酶活性的生物化学试验系统。在此,血浆激肽释放酶从消化性(peptic)血浆激肽释放酶底物上裂解C末端氨基甲基香豆素(AMC),测量其荧光。在微量滴定板中进行测定。
将受试物质溶解在二甲亚砜中并在二甲亚砜中连续稀释(3000 µM至0.0078 µM;该试验中的所得最终浓度:50 µM至0.00013 µM)。在每种情况下将1 µl稀释物质溶液置于来自Greiner的白色微量滴定板(384孔)的孔中。然后相继加入20 µl测定缓冲液(50 mMTris/HCl pH 7.4;100 mM氯化钠溶液;5 mM的氯化钙溶液;0.1%的牛血清白蛋白)和20 µl来自Kordia的血浆激肽释放酶(0.6 nM在测定缓冲液中)。在孵育15分钟后,通过添加20 µl来自Bachem的溶解在测定缓冲液中的底物H-Pro-Phe-Arg-AMC(10 µM在测定缓冲液中)引发酶反应,混合物在室温(22℃)下孵育30分钟,然后测量荧光(激发:360 nm,发射:460nm)。将含有受试物质的试验批次的测得发射与无受试物质的对照批次(仅二甲亚砜,而非在二甲亚砜中的受试物质)的测得发射进行比较,并由浓度/活性关系计算IC50值。来自这一试验的活性数据列在下表A中(一些作为来自多个独立的单独测定的平均值):
a.2) FXIa抑制的测量
使用利用肽类(peptidic)因子XIa底物的反应测定人因子XIa的酶活性的生物化学试验系统测定根据本发明的物质的因子XIa抑制。在此,因子XIa从消化性(peptic)因子XIa底物上裂解C末端氨基甲基香豆素(AMC),测量其荧光。在微量滴定板中进行测定。
将受试物质溶解在二甲亚砜中并在二甲亚砜中连续稀释(3000 µM至0.0078 µM;该试验中的所得最终浓度:50 µM至0.00013 µM)。在每种情况下将1 µl稀释物质溶液置于来自Greiner的白色微量滴定板(384孔)的孔中。然后相继加入20 µl测定缓冲液(50 mM的Tris/HCl pH 7.4;100 mM的氯化钠;5 mM的氯化钙;0.1%的牛血清白蛋白)和20 µl来自Kordia的因子XIa(0.45 nM在测定缓冲液中)。在孵育15分钟后,通过添加20 µl来自Bachem的溶解在测定缓冲液中的因子XIa底物Boc-Glu(OBzl)-Ala-Arg-AMC(10 µM在测定缓冲液中)引发酶反应,混合物在室温(22℃)下孵育30分钟,然后测量荧光(激发:360 nm,发射:460 nm)。将含有受试物质的试验批次的测得发射与无受试物质的对照批次(仅二甲亚砜,而非在二甲亚砜中的受试物质)的测得发射进行比较,并由浓度/活性关系计算IC50值。来自这一试验的活性数据列在下表B中(一些作为来自多个独立的单独测定的平均值):
a.3) 选择性的测定
为了证实物质对FXIa抑制的选择性,检查受试物质对其它的人丝氨酸蛋白酶,如因子Xa、胰蛋白酶和纤溶酶的抑制。为了测定因子Xa(1.3 nmol/l,来自Kordia)、胰蛋白酶(83mU/ml,来自Sigma)和纤溶酶(0.1 µg/ml,来自Kordia)的酶活性,将这些酶溶解(50 mmol/l的Tris缓冲液[C,C,C-三(羟甲基)氨基甲烷]、100 mmol/l NaCl、0.1% BSA [牛血清白蛋白]、5 mmol/l氯化钙,pH 7.4)并用在二甲亚砜中的各种浓度的受试物质以及用无受试物质的二甲亚砜孵育15分钟。然后通过添加适当的底物(用于因子Xa和胰蛋白酶的5 µmol/l的来自Bachem 的Boc-Ile-Glu-Gly-Arg-AMC,用于纤溶酶的50 µmol/l的来自Bachem的MeOSuc-Ala-Phe-Lys-AMC)引发酶促反应。在22℃下30分钟的孵育时间后,测量荧光(激发:360 nm,发射:460 nm)。将含有受试物质的试验混合物的测得发射与无受试物质的对照混合物(仅二甲亚砜,而非在二甲亚砜中的受试物质)的测得发射进行比较,并由浓度/活性关系计算IC50值。
a.4) 抗凝活性的测定
在人血浆和大鼠血浆中体外测定受试物质的抗凝活性。为此,使用0.11 M(molar)柠檬酸钠溶液作为接受体(receiver),以1:9的柠檬酸钠/血液混合比取出血液。在取出血液后立即将其充分混合并在大约4000 g下离心15分钟。吸移出上清液。
使用商业试验试剂盒(来自Siemens的aPTT试剂)在不同浓度的受试物质或相应溶剂存在下测定活化部分凝血活酶时间(APTT)。受试化合物在37℃下用血浆和aPTT试剂孵育3分钟。然后通过添加25 mM氯化钙引发凝血,并测定发生凝血的时间。测定使APTT延长50%或翻倍的受试物质浓度。
a.5) 内皮完整性的测定
借助对“人脐静脉细胞”(HUVEC)的体外通透性检测表征根据本发明的化合物的活性。使用EOS装置(EC IS: Electric Cell-substrate Impedance Sensing;AppliedBiophysics Inc;Troy, NY),可以连续测量跨过铺在金电极上的内皮细胞单层的跨内皮电阻(TEER)的变化。在96孔传感器电极板(96W1 E, Ibidi GmbH, Martinsried, Germany)上播种HUVEC。通过用激肽原、激肽释放酶原和因子XII(各100 nM)刺激,诱发形成的融合细胞单层的过高通透性。在加入上述物质前加入根据本发明的化合物。化合物的常规浓度为1 x10-10至1 x 10-6 M。
a.6) 内皮细胞的体外通透性的测定
在另一过高通透性模型中,测定物质对调节大分子通透性的活性。在纤连蛋白涂布的Transwell过滤膜(24孔板,具有0.4 μΜ聚碳酸酯膜的6.5 mm插件;Costar #3413)上播种HUVEC。该过滤膜将上部与下部细胞培养空间隔开,融合内皮细胞层在上部细胞培养空间的底上。将250 g/ml的40 kDa FITC dextan(Invitrogen, D1844)添加到上室的培养基中。通过用激肽原、激肽释放酶原和因子XII(各100 nM)刺激,诱发该单层的过高通透性。每30分钟从下室中取出培养基样品并使用荧光计测定相对荧光作为随时间发生的大分子通透性变化的参数。在加入上述物质前加入根据本发明的化合物。化合物的常规浓度为1 x 10-10至1 x 10-6 M。
b) 抗血栓形成活性的测定(体内)
b.1) 与兔子的耳朵出血时间结合的动脉血栓形成模型(氯化铁(II)诱发的血栓形成)
在动脉血栓形成模型中测试FXIa抑制剂的抗血栓形成活性。在此通过对兔子颈动脉中的一个区域造成化学损伤而引发血栓形成。同时,测定耳朵出血时间。
通过甲苯噻嗪和氯胺酮(Rompun, Bayer, 5 mg/kg和Ketavet, Pharmacia &Upjohn GmbH, 40 mg/kg体重)的肌内给药,将接受正常饮食并具有2.2 – 2.5 kg体重的雄性兔子(Crl:KBL (NZW)BR, Charles River)麻醉。还通过相同制剂经右耳静脉的静脉给药(团注(bolus):连续输注)保持麻醉。
暴露出右颈动脉,然后通过在不干扰血流的情况下围绕颈动脉包裹在Parafilm®条(25 mm x 12 mm)上的一片滤纸(10 mm x 10 mm),造成血管损伤。该滤纸含有100 µl的13%浓度的氯化铁(II)(Sigma)水溶液。在5分钟后,移除滤纸并用0.9%浓度氯化钠水溶液冲洗血管两次。在损伤后30分钟,手术提取颈动脉的受损区,移除任何血栓材料并称重。
在每种情况下分别在损伤前5分钟和2小时,将受试物质经股静脉静脉给药于麻醉动物或经管饲口服给药于清醒动物。
在颈动脉损伤后2分钟测定耳朵出血时间。为此,将左耳剃毛并平行于耳朵的纵轴切开指定的3毫米长切口(刀片Art. Number 10-150-10, Martin, Tuttlingen,Germany)。在此小心不要破坏任何可见血管。使用精确称重的滤纸片以15秒为间隔吸收渗出的任何血液,不要直接接触伤口。作为从制作切口到在滤纸上不再察觉到血液的时间点的时间计算出血时间。在将滤纸片称重后计算渗血体积。
c) 对外渗/水肿形成和/或眼中的新生血管的作用的测定(体内)
c.1) 在激光诱导的脉络膜新生血管模型中的物质效力的试验
这一研究用于调查受试物质在激光诱导的脉络膜新生血管的大鼠模型中对减轻外渗/水肿形成和/或脉络膜新生血管的效力。
为此,选择没有表现出任何眼科病症迹象的Brown-Norway品种的色素沉着(pigmented)大鼠并随机分入治疗组。在0天,通过腹腔内注射(15 mg/kg甲苯噻嗪和80 mg/kg氯胺酮),将动物麻醉。在滴注1滴0.5%浓度的托吡卡胺溶液以扩张瞳孔后,使用532 nm氩激光凝固器(直径50-75 µm,强度150 mW,持续时间100 ms)在视神经周围6个指定位置引发脉络膜新生血管。受试物质和适当的媒介物(例如PBS,等渗盐水)通过口服或腹腔内途径全身给药,或通过作为滴眼剂反复给药或玻璃体内注射而局部给药于眼睛。在开始研究前测定所有动物的体重,然后在研究过程中每天测定。
在第21天,使用荧光眼底照相机(例如Kowe, HRA)进行血管造影。在麻醉下和在另一次瞳孔扩张后,皮下注射(s.c.)10%浓度荧光素钠染料。2-10分钟后,获取眼睛背景的照片。由2至3名盲测观察者评估通过荧光素渗漏呈现的外渗/水肿程度并分级为0(无外渗)至3(超出实际损伤的强着色)的严重程度。
在第23天处死动物,此后取出眼睛并在室温下在4%浓度的低聚甲醛溶液中固定1小时。在洗涤一次后,小心剥离视网膜并使用FITC同工凝集素B4抗体将巩膜-脉络膜复合体染色,然后平铺到显微镜载片上。使用荧光显微镜(Apotom, Zeiss)在488纳米激发波长下评估以此方式获得的制品。通过使用Axiovision 4.6软件的形态测定分析,计算脉络膜新生血管的面积或体积(分别以µm²和µm³计)。
c.2) 在氧诱导的视网膜病变模型中的物质效力的试验
已经表明,氧诱导的视网膜病变是用于研究病理性视网膜血管新生的有用动物模型。这一模型基于下述观察:视网膜中的生后早期发育过程中的高氧导致正常视网膜血管生长的停止或延迟。当在7天高氧期后使动物回到常氧室内空气时,这相当于相对缺氧,因为视网膜失去确保在常氧条件下充分供应神经组织所需的正常血管。以此方式造成的缺血情形导致异常新生血管,这与眼病如湿性AMD中的病理生理性新生血管具有一些相似性。此外,所造成的新生血管高度可复制、可量化并且是用于检查各种形式的视网膜病症的疾病机理和可能的疗法的重要参数。
此研究的目的是检查每天全身给药剂量的受试化合物在氧诱导的视网膜病变模型中对视网膜血管生长的效力。使C57Bl / 6小鼠的新生儿和它们的母亲在出生后7天(PD7)暴露于高氧(70%氧)5天。从PD12,使小鼠处于常氧条件(室内空气,21%氧)直至PD17。从第12天到第17天,每天用受试物质或相应的媒介物治疗小鼠。在第17天,所有小鼠用异氟烷麻醉,然后通过颈椎骨折处死。取出眼睛并固定在4%福尔马林中。在磷酸盐缓冲盐水中洗涤后,切除视网膜,制备其平铺制品,用同工凝集素B4抗体染色。使用Zeiss ApoTome进行新生血管的量化。
C) 药物组合物的操作实施例
根据本发明的物质可如下转化成药物制剂:
片剂:
组成:
100 mg实施例1的化合物、50 mg乳糖(一水合物)、50 mg玉米淀粉、10 mg聚乙烯基吡咯烷酮(PVP 25)(来自BASF, Germany)和2 mg硬脂酸镁。
片剂重量212 mg,直径8 mm,曲率半径12 mm。
制备:
实施例1的化合物、乳糖和淀粉的混合物用5%浓度的PVP水溶液(m/m)造粒。在干燥后,将颗粒与硬脂酸镁混合5分钟。在常规压片机中压制这种混合物(关于片剂样式,见上文)。
口服混悬剂:
组成:
1000 mg实施例1的化合物、1000 mg乙醇(96%)、400 mg Rhodigel(黄原胶)(来自FMC,USA)和99 g水。
10 ml口服混悬剂相当于单剂100 mg本发明的化合物。
制备:
将Rhodigel悬浮在乙醇中,将实施例1的化合物添加到该悬浮液中。在搅拌的同时加入水。将混合物搅拌大约6小时,直至Rhodigel的溶胀完全。
局部给药于眼睛的溶液剂或混悬剂(滴眼剂):
可以通过在无菌盐水中重构本发明的化合物的冻干产物来制备局部给药于眼睛的无菌药物制剂。适用于这种溶液剂或混悬剂的防腐剂是例如在0.001至1重量%的浓度范围内的苯扎氯铵、硫柳汞或硝酸苯汞。
局部给药于眼睛的溶液剂或混悬剂(滴眼剂):
可以通过在无菌盐水中重构本发明的化合物的冻干产物来制备局部给药于眼睛的无菌药物制剂。适用于这种溶液剂或混悬剂的防腐剂是例如在0.001至1重量%的浓度范围内的苯扎氯铵、硫柳汞或硝酸苯汞。
Claims (9)
4.根据权利要求1至3任一项的化合物,其用于治疗和/或预防疾病。
5.根据权利要求1至3任一项的化合物用于制备用于治疗和/或预防疾病的药物的用途。
6.根据权利要求1至3任一项的化合物用于制备用于治疗和/或预防血栓性或血栓栓塞性病症的药物的用途。
7.根据权利要求5的药物,其用于治疗和/或预防血栓性或血栓栓塞性病症。
8.根据权利要求1至3任一项的化合物,其用于使用治疗有效量的根据本发明的化合物治疗和/或预防血栓性或血栓栓塞性病症的方法。
9.根据权利要求1至3任一项的化合物,其用在含血浆激肽释放酶原(PPK)或血浆激肽释放酶(PK)的生物样本中以防止由PK引起的生理和人造底物的周转造成的干扰效应。
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AU2019251699A1 (en) | 2020-09-24 |
SG11202008352YA (en) | 2020-09-29 |
JP2021521132A (ja) | 2021-08-26 |
EP3774796A1 (en) | 2021-02-17 |
US20210147414A1 (en) | 2021-05-20 |
SA520420308B1 (ar) | 2022-09-29 |
MX2020010635A (es) | 2020-10-28 |
AU2019251699B2 (en) | 2024-02-29 |
IL277811B1 (en) | 2023-08-01 |
EP3774796B1 (en) | 2022-04-27 |
CN111902414B (zh) | 2023-08-04 |
US11884660B2 (en) | 2024-01-30 |
WO2019197244A1 (en) | 2019-10-17 |
DK3774796T3 (da) | 2022-07-18 |
BR112020018237A2 (pt) | 2020-12-29 |
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