CN108431005A - Cgrp受体拮抗剂 - Google Patents
Cgrp受体拮抗剂 Download PDFInfo
- Publication number
- CN108431005A CN108431005A CN201680063997.2A CN201680063997A CN108431005A CN 108431005 A CN108431005 A CN 108431005A CN 201680063997 A CN201680063997 A CN 201680063997A CN 108431005 A CN108431005 A CN 108431005A
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- Prior art keywords
- migraine
- compound
- yls
- methyl
- acid
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Landscapes
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Abstract
本公开涉及新的式(I)的化合物，其中R1、R2和R3如本文中所定义，以及它们在治疗、预防、改善、控制或减轻与CGRP受体功能相关的脑血管或血管障碍中的用途。
Description
与相关申请的交叉引用
本申请要求2015年10月30日提交的大不列颠专利申请号1519195.0的权益，所述申请整体通过参考并入本文。
技术领域
本申请涉及新的化合物以及它们作为CGRP受体拮抗剂的用途。本文中描述的化合物可能在脑血管或血管障碍例如偏头痛的治疗或预防中有用。本申请还涉及包含这些化合物的药物组合物、这些化合物和组合物的制造及其在这些脑血管或血管障碍的预防或治疗中的用途。
背景技术
偏头痛是一种高度使人丧失劳动能力的神经血管障碍，以中度至重度头痛发作为特征，并通常伴有恶心、呕吐、畏光和畏声。发作可以持续4至72h，并且平均发作频率为每月1或2次。约20-30％的偏头痛患者经历被称为先兆的短暂的局灶性神经系统症状，其通常是视觉上的并且可以先于或伴随着头痛。偏头痛在世界范围内影响约11％的成年人，并在生活质量和生产力损失两方面造成显著的社会经济负担。
尽管偏头痛的病理机制仍不清楚，但一种主导假说是基于三叉神经血管系统(TS)的激活。几种神经肽参与这种激活，其中降钙素基因相关肽(CGRP)发挥关键作用。CGRP通过外周和中枢神经系统(CNS)发挥各种不同的生物学效应。有功能的CGRP-受体(CGRP-R)复合物已被充分表征，并且新的治疗方法靶向CGRP本身及其受体。本发明涉及CGRP受体拮抗剂(CGRP-RA)的开发。
CGRP这种源自于编码降钙素的基因的37个氨基酸的神经肽，从位于11号染色体上的降钙素/CGRP基因的可选剪接形成。在人类中，CGRP具有两种同工型：α-和β-CGRP。β-同工型与α-同工型的差异在于位于第3、22和25位处的氨基酸。CGRP的化学结构包括第2和7位残基之间的二硫桥和酰胺化的C-末端。环状的半胱氨酸2-半胱氨酸7基序在受体激活中具有基础性作用。在人类三叉神经节(TRIG)中，CGRP免疫反应性神经元占所有神经元的高达50％。通过原位杂交技术已证实，所有神经细胞体的40％含有CGRP mRNA和CGRP。双重免疫染色已显示，在人类TRIG中，CGRP与一氧化氮合酶、底物P(SP)、垂体腺苷酸环化酶激活肽(PACAP)和可能在偏头痛的病理机制中发挥作用的痛敏肽共定位。
有功能的CGRP-R由三种蛋白质构成：i)降钙素受体样受体(被称为CRLR、CALCRL或CLR)，其是一种7次跨膜蛋白，并形成配体结合位点；ii)RAMP1，决定所述受体的特异性；以及iii)CGRP-R组分蛋白(RCP)，其将所述受体偶联到细胞内信号转导途径和腺苷酸环化酶。
据认为，CGRP的C-末端区域一开始结合到所述受体的大的N-末端细胞外结构域(ECD)，可能使CLR与RAMP1两者相互作用。这种初始结合事件极大提高了CGRP的N-末端区域在CLR的近膜部分附近的局部浓度，允许它们发生相对弱的相互作用并导致受体激活。由于诱变实验表明大多数小分子拮抗剂与CLR/RAMP1的ECD相互作用，因此假设它们结合到受体的这个区域并阻止CGRP初始结合到所述受体。这种肽结合和小分子受体拮抗作用模型的值得注意的例外是羟基吡啶类型的拮抗剂，其明显地与CLR中的跨膜结构域7(TM7)相互作用，而不与细胞外结构域相互作用(Bell IM,J.Med.Chem.,2014,57(19),7838-58)。
临床上测试的第一种CGRP-RA是olcegepant，其基于二肽骨架，具有高分子量，并且不可口服生物利用。然而，当静脉内给药时，olcegepant被证明是有效的抗偏头痛药剂，并且这种概念证明式研究极大提高了本领域中的兴趣。在olcegepant成功之后，大量口服起效的CGRP-RA被推向临床试验。Telcagepant和化合物BI 44370、MK-3207和BMS-927711都已被作为口服药剂用于偏头痛的急性治疗。来自于这些临床研究的结果合在一起，证实了CGRP-RA可以表现出与黄金标准曲坦类药物相似的抗偏头痛功效，但具有比使用曲坦时通常观察到的显著更低的不良事件发生率。值得注意的是，可用数据表明这些CGRP阻断剂不引起血管收缩，并提示它们可能具有优于曲坦类的心血管安全性。伴随某些CGRP-RA已报道的一种可能的顾虑是在某些患者中观察到肝转氨酶水平升高，这据报道造成MK-3207的停药。尽管在长期给药telcagepant后在少量对象中也发现肝酶的升高，但尚不清楚这些发现是在某种程度上基于机制的还是对这两种化合物特异的。在急性偏头痛疗法的临床试验中，CGRP-RA表现出有利的效果，但是它们的频繁给药伴有肝毒性(肝转氨酶升高)，这限制了它们的临床使用。因此，对开发不引起肝损伤的新的CGRP-RA，存在着需求。
发明内容
解决肝损伤风险的一种可能性是以小分子的非口服递送途径为目标，这将通过首过暴露对肝脏施加较低负担。本发明的化合物可用于皮下、静脉内和/或鼻内给药途径。旨在用于这些给药途径的CGRP-RA的分子特性与口服分子所需的特性不同：需要极高的亲和性和功能效力以及极高的溶解度。本文公开了新的化合物以及所述化合物作为CGRP受体拮抗剂的首次医疗用途。
本发明的化合物包括式(I)的化合物
或其盐，其中R1选自
R2是H或与R3形成螺环杂环；
R3与R2形成螺环杂环，或者如果R2是H，则R3是杂环。
具体实施方式
本发明涉及新的化合物。本发明还涉及新的化合物作为CGRP受体拮抗剂的用途。本发明还涉及化合物在制造用作CGRP受体拮抗剂的药物中的用途。本发明还涉及用于治疗脑血管或血管障碍的化合物、组合物和药物，所述脑血管或血管障碍例如偏头痛(包括多种亚型，例如无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、先兆偏头痛、家族性偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛)、偏头痛重积状态(status migrainosus)、丛集性头痛、透析性头痛、阵发性偏头痛、骨关节炎、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、连续性偏头痛、周期性呕吐综合征、过敏性鼻炎或红斑痤疮。本发明还涉及用于治疗涉及神经源性炎症的更广泛的疼痛状态和疾病的化合物、组合物和药物，所述疼痛状态和疾病包括牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、与炎性肠病-克罗恩病相关的疼痛、痛风、复杂性区域疼痛综合征、贝歇氏病( disease)、子宫内膜异位疼痛、背痛或咳嗽。
本文中示例的化合物是基于下述结构：
式(I)：
其中R1选自
R2是H或与R3形成螺环杂环；
R3与R2形成螺环杂环，或者如果R2是H，则R3是杂环。
在更特定实施方式中，R1取代基是
在特定实施方式中，R2取代基是H，并且R3选自：
在更特定实施方式中，R3是
在特定实施方式中，R2与R3形成螺环杂环，以形成：
本发明的其他实施方式包括治疗方法，所述方法包括将式(I)的化合物作为CGRP受体拮抗剂给药。使用式(I)的化合物的治疗可以是脑血管障碍的治疗，所述脑血管障碍例如偏头痛(包括多种亚型例如无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、先兆偏头痛、家族性偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛)、偏头痛重积状态、丛集性头痛、透析性头痛、阵发性偏头痛、骨关节炎、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、连续性偏头痛、周期性呕吐综合征、过敏性鼻炎或红斑痤疮。本发明还涉及用于治疗涉及神经源性炎症的更广泛的疼痛状态和疾病的化合物、组合物和药物，所述疼痛状态和疾病包括牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、与炎性肠病-克罗恩病相关的疼痛、痛风、复杂性区域疼痛综合征、贝歇氏病、子宫内膜异位疼痛、背痛或咳嗽。
本发明的某些新化合物显示出特别高的作为CGRP受体拮抗剂的活性。
示例性化合物包括：
这些化合物的NMR和LCMS性质以及生物学活性陈列在表2和3中。
在所描述的任何化合物具有手性中心的情况下，本发明扩展到这些化合物的所有光学异构体，不论是消旋体还是拆分的对映异构体形式。本文描述的发明涉及所公开的任何化合物的所有如此制备的晶体形式、溶剂化物和水合物。在本文中公开的任何化合物和中间体具有酸性或碱性中心例如羧酸或氨基基团的情况下，则所述化合物的所有盐形式都被包括在本文中。在制药用途的情形中，所述盐应该被看作是可药用盐。
可以提到的可药用盐包括酸加成盐和碱加成盐。这些盐可以通过常规手段形成，例如通过化合物的游离酸或游离碱形式与一个或多个当量的适合的酸或碱任选地在溶剂中或在所述盐不溶于其中的介质中反应，然后使用标准技术(例如在真空中，通过冷冻干燥或通过过滤)除去所述溶剂或所述介质。也可以例如使用适合的离子交换树脂，通过将盐形式的化合物的平衡离子与另一种平衡离子进行交换来制备盐。
可药用盐的实例包括源自于无机酸和有机酸的酸加成盐，以及源自于金属例如钠、镁或优选地钾和钙的盐。
酸加成盐的实例包括与下述酸形成的酸加成盐：乙酸，2,2-二氯乙酸，己二酸，海藻酸，芳基磺酸(例如苯磺酸、萘-2-磺酸、萘-1,5-二磺酸和对甲苯磺酸)，抗坏血酸(例如L-抗坏血酸)，L-天冬氨酸，苯甲酸，4-乙酰氨基苯甲酸，丁酸，(+)-樟脑酸，樟脑磺酸，(+)-(1S)-樟脑-10-磺酸，癸酸，己酸，辛酸，肉桂酸，柠檬酸，环拉酸，十二烷基硫酸，乙烷-1,2-二磺酸，乙磺酸，2-羟基乙磺酸，甲酸，延胡索酸，粘酸，龙胆酸，葡庚糖酸，葡萄糖酸(例如D-葡萄糖酸)，葡萄糖醛酸(例如D-葡萄糖醛酸)，谷氨酸(例如L-谷氨酸)，α-酮戊二酸，乙醇酸，马尿酸，氢溴酸，盐酸，氢碘酸，羟基乙磺酸，乳酸(例如(+)-L-乳酸和(±)-DL-乳酸)，乳糖醛酸，马来酸，苹果酸(例如(-)-L-苹果酸)，丙二酸，(±)-DL-扁桃酸，偏磷酸，甲磺酸，1-羟基-2-萘甲酸，烟酸，硝酸，油酸，乳清酸，草酸，棕榈酸，帕莫酸，磷酸，丙酸，L-焦谷氨酸，水杨酸，4-氨基-水杨酸，癸二酸，硬脂酸，琥珀酸，硫酸，鞣酸，酒石酸(例如(+)-L-酒石酸)，硫氰酸，十一碳烯酸和戊酸。
盐的特定实例是源自于无机酸例如盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸的盐，源自于有机酸例如酒石酸、乙酸、柠檬酸、苹果酸、乳酸、延胡索酸、苯甲酸、乙醇酸、葡萄糖醛酸、琥珀酸、芳基磺酸、帕莫酸的盐，以及源自于金属例如钠、镁或优选地钾和钙的盐。
还涵盖了所述化合物及其盐的任何溶剂化物。优选的溶剂化物是通过将无毒可药用溶剂(在下文中被称为溶剂化溶剂)的分子并入到本发明的化合物的固态结构(例如晶体结构)中而形成的溶剂化物。这些溶剂的实例包括水、醇(例如乙醇、异丙醇和丁醇)和二甲基亚砜。溶剂化物可以通过用含有所述溶剂化溶剂的溶剂或溶剂混合物对本发明的化合物进行重结晶来制备。在任何给定情况下是否已形成溶剂化物，可以通过使用公知和标准的技术例如热重量分析(TGE)、差示扫描量热术(DSC)和X-射线晶体学对所述化合物的晶体进行分析来确定。
所述溶剂化物可以是化学计量或非化学计量的溶剂化物。具体的溶剂化物可以是水合物，并且水合物的实例包括半水合物、单水合物和二水合物。
对于溶剂化物和用于制造和表征它们的方法的更详细讨论，参见Bryn等，《药物的固态化学》(Solid-State Chemistry of Drugs)，第二版，由SSCI,Inc of WestLafayette,IN,USA出版，1999,ISBN0-967-06710-3。
本文中所定义的化合物的“有药物功能的衍生物”包括酯衍生物和/或具有或提供与本发明的任何相关化合物相同的生物学功能和/或活性的衍生物。因此，出于本发明的目的，所述术语还包括本文中所定义的化合物的前体药物。
术语相关化合物的“前体药物”包括在口服或肠胃外给药后在体内被代谢，以可实验检测的量并在预定时间内(例如在6至24小时之间的给药间隔内(即每日1至4次))形成该化合物的任何化合物。
化合物的前体药物可以通过以下来制备：修饰所述化合物上存在的官能团，使得当这种前体药物被给药到哺乳动物对象时，所述修饰在体内被切开。所述修饰通常通过合成带有前体药物取代基的母体化合物来实现。前体药物包括其中化合物中的羟基、氨基、巯基、羧基或羰基被键合到可以在体内被切开以分别重新产生游离羟基、氨基、巯基、羧基或羰基的任何基团的化合物。
前体药物的实例包括但不限于羟基官能团的酯和氨基甲酸酯、羧基官能团的酯基团、N-酰基衍生物和N-曼尼希碱。关于前体药物的一般性信息可以在例如Bundegaard,H.，《前体药物设计》(Design of Prodrugs)，p.1-92,Elsevier,New York-Oxford(1985)中找到。
定义
杂环
杂环意味着其中至少一个环成员不是碳的可以是芳香族的环状基团。例如，至少一个环成员(例如1、2或3个环成员)可以选自氮、氧和硫。杂芳基的附连点可以是经由所述环系统的任何原子。示例性的杂芳基包括吡啶基、吲唑基、1,4-二氢-2H-吡啶并[2,3-d][1,3]嗪-2-酮、1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮、3,4-二氢喹唑啉-2(1H)-酮、喹啉-2(1H)-酮、哌啶基、吡咯烷基、2,8-二氮杂螺[4.5]癸烷等。
在本发明的情形中，术语“药物组合物”意味着包含活性药剂并另外包含一种或多种可药用载体的组合物。取决于给药模式和剂型的性质，所述组合物还可以含有选自例如稀释剂、佐剂、赋形剂、介质、防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、调味剂、增香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂的成分。所述组合物可以采取例如片剂、糖衣丸、粉剂、酏剂、糖浆、液体制剂包括悬液、喷雾剂、吸入剂、片剂、含片、乳液、溶液、扁囊剂、颗粒剂、胶囊和栓剂以及注射用液体制剂包括脂质体制剂的形式。
剂量可以随着患者的需要、待治疗病症的严重性、所使用的化合物而变。对特定情况适合的剂量的确定在本领域的技术范围之内。一般来说，以小于所述化合物的最佳剂量的更小的剂量开始治疗。随后以小的增量提高所述剂量，直至达到在所述情况下的最佳效果。为方便起见，如果需要，可以将每日总剂量分开并在一日内分次给药。
化合物的有效剂量的大小当然将随着待治疗病症的严重性性质并随着具体化合物及其给药途径而变。适合的剂量的选择在本领域普通技术人员的能力之内，没有过大负担。一般来说，每日剂量范围可以是每kg人类和非人类动物体重约10μg至约30mg，优选为每kg人类和非人类动物体重约50μg至约30mg，例如每kg人类和非人类动物体重约50μg至约10mg，例如每kg人类和非人类动物体重约100μg至约30mg，例如每kg人类和非人类动物体重约100μg至约10mg，最优选为每kg人类和非人类动物体重约100μg至约1mg。
本发明的化合物的制备
本发明的化合物可以例如通过包括方案1中所描绘的途径来制备。许多标准的转化例如下面的途径和可用于进行相同转化的其他途径中的转化的详细情况，可以在标准参考教科书例如《有机合成》(Organic Synthesis)，M.B.Smith,McGraw-Hill(1994)或《高等有机化学》(Advanced Organic Chemistry)第四版，J.March,John Wiley & Sons(1992)中找到。
方案1
氨基酸中间体例如氨基酸的甲基酯与胺中间体之间的脲形成，可以在使用偶联剂例如DSC，在溶剂例如DMF中存在碱例如三乙胺或DIPEA的条件下形成。随后形成的脲衍生物的甲基酯部分可以在适合的溶剂例如THF、MeOH、1,4-二烷、EtOAc或其混合物中，使用水性碱例如氢氧化锂来皂化。由此形成的酸中间体可以在标准条件下，例如在适合的溶剂例如DMF或DCM中在碱例如DIPEA存在下使用偶联剂例如HATU，而被转变成酰胺实施例。用于这种酰胺偶联的胺配偶体可以使用标准转化的适当组合(例如在溶剂例如DCM中，在乙酸存在下使用胺、醛或酮以及还原剂例如三乙酰氧基硼氢化钠的还原胺化；或在例如上面详细描述的条件下的酰胺形成；或亲核芳香族取代(SNAr)反应)来制备。在本发明的化合物的合成中，胺与卤代杂环之间的SNAr反应通常在80℃下，在适合的溶剂例如MeCN中，并在碱例如K2CO3存在下进行。在例如上述的标准转化后，或在一系列这种转化期间，标准保护基团的去除可能是必需的，并且可以使用可以在参考教科书例如《保护基团》(Protecting Groups)第三版，P.J.Kocieński,Georg Thieme Verlag(2005)中找到的条件进行。一种这样的转化是在酸性条件例如HCl下，在溶剂例如1,4-二烷、MeOH、EtOH、DCM或其组合中，从胺除去叔丁氧基羰基(通常被称为Boc基团)。可以认识到，本发明的具有另外的碱性中心的胺中间体的Boc去保护可以产生不同化学计量的盐酸盐。例如，具有一个另外的碱性中心的中间体的Boc去保护将导致形成新的胺中间体，其是例如单盐酸盐或二盐酸盐，它们通常不需中和所述盐酸盐以产生所述中间体的游离碱即可使用，因为可以认识到，在随后的酰胺形成中通常使用过量的碱例如DIPEA或三乙胺来中和所述盐酸盐。本发明的通过Boc去保护而形成并且不需中和成游离碱即可使用的胺中间体，在本文中被称为盐酸盐(x HCl)，并且本发明扩展到所述中间体的所有盐形式。另一种这样的保护基团去除是在溶剂例如EtOH或EtOH水溶液中，在气态H2存在下，使用还原条件例如碳载钯催化的羰基苯甲氧基保护的胺(通常被称为CBZ或Z基团)的去保护。用于除去CBZ保护基团的可选条件包括转移氢化，例如使用碳载钯催化剂，在甲酸铵存在下，在溶剂例如EtOH或EtOH水溶液中，在高温例如70℃下进行转移氢化。
通用流程
在不包括制备途径的情况下，相关中间体是可商购的。商品化试剂不需进一步纯化即可使用。室温(rt)是指大约20-27℃。除非另有规定，否则1H NMR谱是在Bruker、Varian或JEOL仪器上，在环境温度下，在400MHz或600MHz下记录的。化学位移值用百万分率(ppm)表示，即(δ)-值。下述缩写用于NMR信号的多重性：s＝单峰，br＝宽峰，d＝双重峰，t＝三重峰，q＝四重峰，quin＝五重峰，h＝七重峰，dd＝双重双重峰，dt＝双重三重峰，m＝多重峰。耦合常数作为J值列出，以Hz为单位度量。NMR和质谱结果是校正过的以将背景峰考虑在内。层析是指使用二氧化硅进行并在正压力(快速层析)条件下执行的柱层析。LCMS实验使用电喷雾条件，在下述条件下进行。LCMS数据以下述格式给出：离子质量，电喷雾模式(正或负)，保留时间(实验文本和表1)；离子质量，电喷雾模式(正或负)，保留时间，近似纯度(表2)。
方法A.仪器：Hewlett Packard 1100，带有G1315A DAD，Micromass ZQ；柱：WatersX-Bridge C-18，2.5微米，2.1x 20mm或Phenomenex Gemini-NX C-18，3微米，2.0x 30mm；梯度[时间(min)/溶剂在C中的D(％)]：0.00/2，0.10/2，8.40/95，10.00/95；溶剂：溶剂C＝2.5L H2O+2.5mL 28％氨水溶液；溶剂D＝2.5L MeCN+135mL H2O+2.5mL 28％氨水溶液；进样体积1μL；UV检测230至400nM；柱温45℃；流速1.5mL/min。
方法B.仪器：Agilent Technologies 1260Infinity LC，带有Chemstation软件，二极管阵列检测器，Agilent 6120B Single Quadrupole MS，带有API-ES源；柱：Phenomenex Gemini-NX C-18，3微米，2.0x 30mm；梯度[时间(min)/溶剂在C中的D(％)]：0.00/5，2.00/95，2.50/95，2.60/5，3.00/5；溶剂C和D如上面方法A中所述；进样体积0.5μL；UV检测190至400nM：柱温40℃；流速1.5mL/min。
缩写
前缀n-、s-、i-、t-和tert-具有它们通常的意义：正、仲、异和叔。
中间体的合成
羧酸中间体的制备
通过脲形成和随后的皂化来制备羧酸中间体的典型流程，以中间体6即(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-氧代-1',2'-二氢-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]嗪]-1-基)羰基]氨基}丙酸的制备为例
步骤1)向(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯二盐酸盐(中间体5，995mg，3.3mmol)和DSC(917mg，3.6mmol)在DMF(20mL)中的溶液添加Et3N(2.26mL，16.3mmol)，并将所述混合物在rt搅拌30min。然后分次添加螺[哌啶-4,4'-[4H]吡啶并[2,3-d][1,3]嗪]-2'(1'H)-酮(中间体4，785mg，3.6mmol)，并将反应混合物在rt搅拌18h，然后真空浓缩。将残留物在H2O与MeOH/DCM(1:9)之间分配，进行相分离，并将水性层用H2O洗涤。将来自于所述分离步骤的残留固体溶解在MeOH中，并将合并的有机层真空浓缩并通过快速层析进行纯化，使用EtOAc的MeOH溶液(20:1)洗脱，得到作为白色固体的(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-氧代-1',2'-二氢-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]嗪]-1-基)羰基]氨基}丙酸甲酯(1.06g，2.22mmol)。
LCMS(方法A)：m/z 479.3(ES+)，在2.61min处，100％。
1H NMR：(400MHz,DMSO-d6)δ：1.59-1.75(m,2H),1.78-1.90(m,2H),2.45(s,3H),2.90-3.08(m,4H),3.59(s,3H),3.86-3.96(m,2H),4.28-4.38(m,1H),6.94-7.06(m,3H),7.32(dd,J＝7.4,1.2,1H),7.39(s,1H),7.95(s,1H),8.18(dd,J＝5.1,1.6,1H),10.79(s,1H),13.04(s,1H)。
步骤2)将(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-氧代-1',2'-二氢-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]嗪]-1-基)羰基]氨基}丙酸甲酯(1.06g，2.22mmol)溶解在THF(15mL)和MeOH(3mL)中，并逐滴添加LiOH水溶液(1M，4.4mL，4.4mmol)。在rt搅拌3.5h后，逐滴添加另外的LiOH水溶液(1M，2.2mL，2.2mmol)，并将所述混合物在rt搅拌1h，然后在氮气流下浓缩。将残留物溶解在最小体积的H2O中并冷却到0℃。逐滴添加1M HCl水溶液以将pH调整到≤3，通过过滤分离得到的沉淀物，用冷H2O和Et2O洗涤，以得到作为浅黄色固体的标题化合物(877mg，1.89mmol)。
数据在表1中。
中间体7，(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-基]羰基}氨基)丙酸
使用中间体6的方法，从(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯(中间体5，1.00g，4.3mmol)和1-(哌啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(中间体1，1.02g，4.7mmol)在两个步骤后制备得到所述标题化合物(1.50g，3.2mmol)。
数据在表1中。
中间体9，(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-氧代-1,4-二氢喹唑啉-3(2H)-基)哌啶-1-基]羰基}氨基)丙酸
使用中间体6的方法，从(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯(中间体5，917mg，3.93mmol)和3-(哌啶-4-基)-3,4-二氢喹唑啉-2(1H)-酮(中间体3，1.00g，4.32mmol)在两个步骤后制备得到所述标题化合物(561mg，1.18mmol)。
数据在表1中。
中间体8，(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)丙酸
步骤1)在N2和约-20℃下向(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯(中间体5，6.05g，25.9mmol)在DMF(60mL)中的溶液添加CDI(8.40g，51.8mmol)，并将所述混合物搅拌15min，同时保持温度低于-10℃。添加H2O(2.34mL)在几mL DMF中的溶液并继续搅拌15min，同时保持温度低于-10℃。然后依次添加3-(哌啶-4-基)喹啉-2(1H)-酮(中间体2，6.99g，30.6mmol)、DIPEA(4.93mL，28.2mmol)和DCM(20mL)，并将混合物在N2下加热至40℃，保持12小时。在冷却到rt后，添加2M HCl(水溶液)(38.7mL)，并将混合物用DCM萃取两次。将合并的有机萃取物用H2O洗涤三次，干燥(Na2SO4)并真空浓缩。通过快速层析纯化，用MeOH/DCM(5:95)洗脱，得到作为浅褐色固体的(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)丙酸甲酯(10.4g，21.3mmol)。
1H NMR：(400MHz,CDCl3)δ：1.40-1.60(m,2H),1.95-1.97(m,2H),2.46(s,3H),2.90-3.00(m,2H),3.11-3.26(m,3H),3.76(s,3H),4.07-4.12(m,2H),4.86-4.91(m,1H),5.18(d,J＝7.6,1H),6.93(s,1H),7.17-7.21(m,1H),7.24(s,1H),7.32(s,1H),7.43-7.54(m,3H),7.95(s,1H),10.70(s,2H)。
步骤2)向(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)丙酸甲酯(9.79g，20.1mmol)在1,4-二烷(150mL)中的溶液添加LiOH·H2O(1.26g，30.0mmol)在H2O(150mL)中的溶液，并将所述混合物在rt搅拌2h。将反应混合物真空浓缩至接近干燥并重新溶解在H2O中，然后用2M HCl水溶液(约15mL)酸化，同时快速搅拌。通过过滤分离得到的浓厚白色沉淀物并用H2O洗涤，直到洗涤液接近中性pH。真空干燥，得到作为灰白色固体的标题化合物(8.11g，17.1mmol)。
数据在表1中。
胺中间体的制备
中间体12，4-(2,8-二氮杂螺[4.5]癸-8-基)哌啶-1-甲酸苯甲酯盐酸盐
步骤1)将2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯(中间体10，0.50g，2.08mmol)、4-氧代哌啶-1-甲酸苯甲酯(中间体11，583mg，2.50mmol)、乙酸(143μL，2.50mmol)和三乙酰氧基硼氢化钠(530mg，2.50mmol)在DCM(10mL)中的混合物在rt搅拌过夜。添加另外的4-氧代哌啶-1-甲酸苯甲酯(中间体11，600mg，2.57mmol)和乙酸(150μL，2.62mmol)，将混合物在rt搅拌1h，然后添加另外的三乙酰氧基硼氢化钠(550mg，2.59mmol)。将所述混合物在rt搅拌过夜，然后真空浓缩并通过梯度快速层析纯化，用DCM中的0-10％MeOH洗脱，得到8-{1-[(苯甲氧基)羰基]哌啶-4-基}-2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯(620mg，1.35mmol)。
LCMS(方法B)：m/z 458.2(ES+)，在1.70min处。
1H NMR：(400MHz,CDCl3)δ：ppm 1.45(s,9H),1.48-1.56(m,1H),1.64-1.74(m,4H),1.87-1.96(m,2H),2.51-1.85(m,10H),3.30-3.43(m,4H),4.19-4.32(m,2H),5.11(s,2H),7.30-7.40(m,5H)。
步骤2)向8-{1-[(苯甲氧基)羰基]哌啶-4-基}-2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯(310mg，0.68mmol)在MeOH(5mL)中的溶液添加HCl在1,4-二烷中的溶液(4M，5.0mL，20.0mmol)。将所述混合物在rt搅拌3d，然后真空浓缩，得到所述标题化合物(无色固体，290mg)。
数据在表1中。
中间体14，[(2R)-1-(2,8-二氮杂螺[4.5]癸-8-基)-1-氧代丙-2-基]甲基氨基甲酸苯甲酯盐酸盐
步骤1)将2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯(中间体10，865mg，3.60mmol)、N-[(苯甲氧基)羰基]-N-甲基-D-丙氨酸(中间体13，712mg，3.00mmol)、HATU(1.37g，3.60mmol)和DIPEA(2.68mL，15.0mmol)在DCM(25mL)中的混合物在rt搅拌过夜。添加饱和NaHCO3水溶液，进行相分离并将有机相真空浓缩。通过梯度快速层析进行纯化，用DCM中的2-10％MeOH洗脱，然后进行制备型HPLC(Phenomenex Gemini-NX 5μm C18柱，100x 30mm，以30mL/min的流速在12.5min内用50至80％MeCN/溶剂B洗脱[其中溶剂B是H2O中的0.2％的(28％NH3/H2O)]，通过在205nm处监测收集级分)，得到作为无色泡沫的8-{N-[(苯甲氧基)羰基]-N-甲基-D-丙氨酰基}-2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯(1.08g，2.19mmol)。
LCMS(方法A)：m/z 460.5(ES+)，在4.68min处。
1H NMR：(400MHz,DMSO-d6)δ：1.10-1.29(m,5H),1.30-1.47(m,1H),1.39(s,9H),1.52-1.77(m,2H),2.67-2.77(m,3H),2.87-3.12(m,3H),3.12-3.35(m,5H),3.46-3.76(m,1H),4.88-5.09(m,2H),5.12-5.22(m,1H),7.25-7.42(m,5H)。
步骤2)使用中间体12的方法，在MeOH(15mL)中，从步骤1材料(1.08g，2.19mmol)和1,4-二烷中的4M HCl(15mL，60.0mmol)制备所述标题化合物(白色泡沫，1.08g)。
数据在表1中。
中间体16，8-(吡啶-4-基)-2,8-二氮杂螺[4.5]癸烷盐酸盐
步骤1)将2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯(中间体10，1.00g，4.16mmol)、4-氟吡啶盐酸盐(中间体15，614mg，4.60mmol)和K2CO3(1.74g，12.6mmol)在MeCN(80mL)中的混合物在80℃加热过夜，然后冷却至rt并真空干燥。将残留物在EtOAc和H2O之间分配，将有机相用盐水洗涤，干燥(MgSO4)并真空浓缩。通过梯度快速层析进行纯化，用DCM中的0-100％溶剂B(其中溶剂B是1:9的MeOH/DCM中的7N NH3)洗脱，得到作为棕色粘稠油状物的8-(吡啶-4-基)-2,8-二氮杂螺[4.5]癸烷-2-甲酸叔丁酯(610mg，1.92mmol)。
LCMS(方法B)：m/z 318.2(ES+)，在1.36min处。
1H NMR：(400MHz,CD3OD)δ：1.46(s,9H),1.63-1.68(m,4H),1.81-1.85(m,2H),3.23(s 2H),3.36-3.54(m,6H),6.82-6.83(m,2H),8.07-8.09(m,2H)。
步骤2)使用中间体12的方法，从步骤1的材料(610mg，1.92mmol)和1,4-二烷中的4M HCl(10mL)制备所述标题化合物(棕色油状物，550mg)，并且所述标题化合物不需纯化即可用于实施例7的制备中。
数据在表1中。
表1.
实施例的合成
通过酰胺偶联以及适合情况下去保护来制备实施例的典型流程，以下述实施例的制备为例。
流程1：
实施例2，N-[(2R)-1-[8-(N-甲基-D-丙氨酰基)-2,8-二氮杂螺[4.5]癸-2-基]-3-(7-甲基-1H-吲唑-5-基)-1-氧代丙-2-基]-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺
步骤1)将(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)丙酸(中间体8，100mg，0.21mmol)、[(2R)-1-(2,8-二氮杂螺[4.5]癸-8-基)-1-氧代丙-2-基]甲基氨基甲酸苯甲酯盐酸盐(中间体14，99mg，0.25mmol)、HATU(96mg，0.25mL)和DIPEA(146μL，0.84mmol)在DMF(5mL)中的混合物在rt搅拌过夜，然后真空浓缩。通过梯度快速层析进行纯化，用DCM中的0-10％MeOH洗脱，得到作为浅黄色固体的甲基[(2R)-1-{2-[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)丙酰基]-2,8-二氮杂螺[4.5]癸-8-基}-1-氧代丙-2-基]氨基甲酸苯甲酯(160mg，0.20mmol)。
LCMS(方法B)：m/z 815.2(ES+)，在1.41min处，95％。
步骤2)向甲基[(2R)-1-{2-[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-({[4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)丙酰基]-2,8-二氮杂螺[4.5]癸-8-基}-1-氧代丙-2-基]氨基甲酸苯甲酯(160mg，0.20mmol)在EtOH(10mL)和H2O(2mL)中的混合物添加甲酸铵(126mg，2.0mmol)。添加碳载钯(10％，10mg)并将反应混合物在70℃加热过夜。在冷却至rt后，添加另外的甲酸铵(126mg，2.0mmol)和碳载钯(10％，10mg)，并将混合物在70℃加热1h，然后冷却至rt，通过硅藻土过滤，并将滤液真空浓缩。通过梯度快速层析进行纯化，使用DCM中的0-10％MeOH洗脱，然后进行制备型HPLC(Phenomenex Gemini-NX5μm C18柱，100x 30mm，以30mL/min流速在12.5min内用20至40％MeCN/溶剂B洗脱[其中溶剂B是H2O中的0.2％的(28％NH3/H2O)]，通过在205nm处监测收集级分)，得到作为无色固体的标题化合物(20mg，0.03mmol)。
数据在表2中。
流程2：
实施例5，N-[(2R)-1-[8-(N-甲基-D-丙氨酰基)-2,8-二氮杂螺[4.5]癸-2-基]-3-(7-甲基-1H-吲唑-5-基)-1-氧代丙-2-基]-2'-氧代-1',2'-二氢-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]嗪]-1-甲酰胺
步骤1)使用实施例2的方法的步骤1，从DMF(2mL)中的(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-氧代-1',2'-二氢-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]嗪]-1-基)羰基]氨基}丙酸(中间体6，70mg，0.15mmol)、[(2R)-1-(2,8-二氮杂螺[4.5]癸-8-基)-1-氧代丙-2-基]甲基氨基甲酸苯甲酯盐酸盐(中间体14，71mg，0.18mmol)、HATU(68mg，0.18mmol)和DIPEA(0.13mL，0.18mmol)制备甲基[(2R)-1-{2-[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-氧代-1',2'-二氢-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]嗪]-1-基)羰基]氨基}丙酰基]-2,8-二氮杂螺[4.5]癸-8-基}-1-氧代丙-2-基]氨基甲酸苯甲酯(26mg，0.03mg)。
LCMS(方法A)：m/z 806.7(ES+)，在3.64min处。
1H NMR：(400MHz,CD3OD)δ：ppm 0.17-1.06(m,2H),1.06-1.47(m,7H),1.47-1.75(m,1H),1.76-1.96(m,1H),2.03(d,J＝5.1,3H),2.19-2.43(m,1H),2.52(s,3H),2.69-2.96(m,5H),2.96-3.24(m,7H),3.40-3.55(m,1H),3.55-3.97(m,1H),4.07(d,J＝10.5,2H),4.52-4.74(m,1H),4.97-5.12(m,1H),5.13-5.33(m,1H),6.93-7.19(m,3H),7.20-7.65(m,9H),7.89-8.06(m,1H),8.20(d,J＝4.7,1H)。
步骤2)将甲基[(2R)-1-{2-[(2R)-3-(7-甲基-1H-吲唑-5-基)-2-{[(2'-氧代-1',2'-二氢-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]嗪]-1-基)羰基]氨基}丙酰基]-2,8-二氮杂螺[4.5]癸-8-基}-1-氧代丙-2-基]氨基甲酸苯甲酯(26mg，0.03mg)和碳载钯(10％，10mg)在EtOH(2.5mL)和H2O(0.5mL)中的混合物，在H2气氛下在rt搅拌过夜。在除去H2气氛后，将所述混合物通过硅藻土过滤并将滤液真空浓缩，得到标题化合物(22mg，0.03mmol)。
数据在表2中。
表2中详细描述了通过上述流程制备的其他实施例。
表2.
生物学方法
克隆、杆状病毒产生、Sf21细胞的大规模感染和膜制备。将人类降钙素受体样受体(CRLR)和人类RAMP1克隆在Invitrogen(ThermoFisher Scientific,UK)的pFastBac双重表达载体中。CRLR/RAMP1DNA的转座使用Invitrogen的Bac-to-Bac杆状病毒表达系统来进行。通过使用 II转染试剂(ThermoFisher Scientific,UK，目录号10362-100)用杆粒DNA转染SF9细胞来产生P0杆状病毒。在P0产生之后，随后产生P1病毒以备大规模感染和膜制备。将Sf21细胞生长在增补有10％热失活FBS和1％Pen/Strep的表达培养基ESF921(Expression Systems,USA，目录号96-001-01)中，并以2.5x106个细胞/mL的细胞密度和2的MOI进行感染。在设置为27℃的摇床中进行超过48h的表达。将细胞培养物在4℃下以2,500rcf离心10min。将细胞团块重悬浮在增补有Roche的无EDTA完全蛋白酶抑制剂混合物片剂(Roche Applied Sciences，目录号05056489001)、1mM PMSF和1mM EDTA的冷PBS中。然后将重悬浮的细胞浆液在4℃下以3,273rcf离心12min。舍弃上清液，并将细胞团块冷冻在-80℃。将来自于4L培养物的细胞团块重悬浮在含有50mM Hepes pH 7.5、150mM NaCl、8片Roche的无EDTA蛋白酶抑制剂混合物片剂和1mM PMSF的缓冲液中。将所述悬液留在rt搅拌1h，然后使用VDI 25(VWR,USA)匀浆器以9,500rpm匀浆90s。然后使用Microfluidizer处理机M-110LPneumatic(Microfluidics,USA)裂解细胞。在裂解后，将所述混合物以9,500rpm匀浆90s，然后以335rcf离心10min。然后将上清液进一步以42,000rpm超速离心90min。在超速离心后，将上清液舍弃，并将团块重悬浮在50mL(每个2L培养物各25mL)含有50mMHepespH 7.5、150mM NaCl、3片Roche的无EDTA蛋白酶抑制剂混合物片剂和1mM PMSF的缓冲液中。然后将所述悬液以9,500rpm匀浆90s。然后将得到的膜储存在-80℃。
放射性配体结合测定法。将在昆虫Sf21细胞膜匀浆液中表达的人类CGRP受体(由CRLR和RAMP1构成)重悬浮在结合缓冲液(10mM HEPES，pH 7.4，5mM MgCl2，0.2％BSA)中至最终测定浓度为每孔0.6μg蛋白。饱和等温线通过添加各种不同浓度的3H-telcagepant(Ho等，The Lancet,2008,372,2115)(总反应体积为250μL)，在rt下60min来确定。在温育结束时，将膜在过滤微孔板(unifilter)(连有与0.5％PEI预温育的GF/B滤膜并带有Tomtec细胞收集器的96孔白色微孔板)上过滤，并用蒸馏水洗涤5次。在10nM MK-3207盐酸盐(CASNo.957116-20-0)存在下测量非特异性结合(NSB)。在添加50μL闪烁液后，在微型β计数器上对滤膜上的放射活性进行计数(1min)。对于抑制实验来说，将膜与0.5nM 3H-telcagepant和10种浓度的抑制性化合物(0.001-10μM)温育。从抑制曲线推演IC50值，并使用Cheng-Prussoff方程计算亲和常数(Ki)值(Cheng等，Biochem.Pharmacol.1973,22,3099-3108)。表3中详述了本发明的某些化合物的pKi值(其中pKi＝-log10Ki)。
cAMP功能测定法。使用均相时间分辨荧光(HTRF)cAMP动态-2测定法(Cisbio,France)来确定受体激活后cAMP的产生。将内源表达人类CGRP受体的人类成神经细胞瘤细胞系SK-N-MC以12,500个细胞/孔的密度接种在实心壁96孔半区板(Costar，目录号3688，Corning Life Sciences,Germany)中。在37℃温育16h后，除去培养基，并将细胞在含有500μM IBMX(Tocris,Abingdon,UK，目录号2845)和浓度逐渐提高的测试拮抗剂的无血清培养基中，在37℃温育30min。在这之后，将该细胞用EC80浓度的人类CGRP(0.3nM)在37℃下进一步激惹30min，然后按照制造商的说明书确定cAMP的产生，然后在PheraStar荧光读板器(BMG LabTech,Germany)上读板。从抑制曲线推演IC50值。使用改良的Cheng-Prussoff方程将pIC50值(其中pIC50＝-log10IC50)转变成功能性pKb值，其中Kd＝激动剂EC50，L hot＝激动剂激惹浓度。表3中详述了本发明的某些化合物的pKb值。
表3.
药代动力学情况分析。在雄性大鼠中通过静脉内(iv)、皮下(sc)和鼻内(IN)递送途径，并在雄性食蟹猴中通过iv和sc递送途径，评估了实施例和参比化合物的药代动力学情况。表4和5中详述了本发明的实施例和参比化合物olcegepant的药代动力学数据。
方法：对于大鼠研究来说，使用表4中指定的剂量、给药体积和介质，通过下述途径之一：iv，sc或IN，向三只体重通常在180至300g范围内的雄性大鼠的组，提供单剂量的实施例或参比化合物。在IN给药之前，将大鼠用25-30mg/kg氯胺酮混合物(盐水中的氯胺酮、甲苯噻嗪盐酸盐和乙酰丙嗪马来酸盐)的肌肉内剂量进行麻醉，并且药剂通过插入到大鼠鼻腔内约5mm的聚乙烯PE-10管，在20-30s内导入。
对于食蟹猴研究来说，使用表5中指定的剂量、给药体积和介质，通过下述途径之一：iv或sc，向三只体重通常在3.0至4.5kg范围内的雄性猴的组，提供单剂量的实施例或参比化合物。在通过上述途径给药后，在几个时间点(通常为给药前、0.083、0.25、0.5、1、2、4、8和24h)通过连续尾静脉取血(大鼠)或者头部或隐静脉(猴)从动物获取血液样品，并进行离心以分离血浆，用于通过LC/MS/MS测定法进行分析。使用WinNonlin v6.2统计学软件(Pharsight Corporation,California,USA)，使用非区室模型产生药代动力学参数。
表4.
表5.
热力学溶解度情况分析。制备测试化合物的50mM DMSO储用溶液，并通过用DMSO稀释，从该溶液制备1mM的工作溶液。从220nm至1000nm扫描工作溶液的UV吸光度，以鉴定测试化合物的最大波长。然后将所述1mM工作溶液在DMSO中连续稀释至不同浓度，以确定线性度/校准曲线。为了确定测试化合物的热力学水溶解度，向一定体积的PBS缓冲液(pH 7.4)或磷酸钠缓冲液(pH 6.0)添加样品，如果所有测试化合物溶解的话，所述体积适合于产生1mg/mL的最终浓度。然后将得到的溶液在50rpm的RotoSpin摇床上在rt保持24h，然后使用0.45微米PVDF注射式滤器过滤所述溶液，以便除去所述化合物的不溶性级分。随后取150uL滤液，使用UV分光光度计进行定量，获取标准溶液和测试化合物在同一最大波长处的光密度。从所述测试化合物的光密度，使用线性度/校准曲线计算热力学溶解度，并以微摩尔浓度(μM)为单位表示。表6中详述了本发明的某些化合物的溶解度情况。
表6.
Claims (14)
1.一种式(I)的化合物
或其盐，其中R1是
R2是H或与R3形成螺环杂环；
R3与R2形成螺环杂环，或者如果R2是H，则R3是杂环。
2.权利要求1的化合物，其中R1是
3.前述权利要求任一项的化合物，其中R2是H并且R3是
4.权利要求3的化合物，其中R3是
5.权利要求1或2的化合物，其中R2与R3形成螺环杂环，以形成
6.前述权利要求任一项的化合物，其中所述化合物选自：
N-{(2R)-3-(7-甲基-1H-吲唑-5-基)-1-氧代-1-[8-(哌啶-4-基)-2,8-二氮杂螺[4.5]癸-2-基]丙-2-基}-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺；
N-[(2R)-1-[8-(N-甲基-D-丙氨酰基)-2,8-二氮杂螺[4.5]癸-2-基]-3-(7-甲基-1H-吲唑-5-基)-1-氧代丙-2-基]-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺；
N-[(2R)-1-[8-(N-甲基-D-丙氨酰基)-2,8-二氮杂螺[4.5]癸-2-基]-3-(7-甲基-1H-吲唑-5-基)-1-氧代丙-2-基]-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺；
N-{(2R)-3-(7-甲基-1H-吲唑-5-基)-1-氧代-1-[8-(哌啶-4-基)-2,8-二氮杂螺[4.5]癸-2-基]丙-2-基}-4-(2-氧代-1,4-二氢喹唑啉-3(2H)-基)哌啶-1-甲酰胺；
N-[(2R)-1-[8-(N-甲基-D-丙氨酰基)-2,8-二氮杂螺[4.5]癸-2-基]-3-(7-甲基-1H-吲唑-5-基)-1-氧代丙-2-基]-2'-氧代-1',2'-二氢-1H-螺[哌啶-4,4'-吡啶并[2,3-d][1,3]嗪]-1-甲酰胺；
N-[(2R)-1-[8-(N-甲基-D-丙氨酰基)-2,8-二氮杂螺[4.5]癸-2-基]-3-(7-甲基-1H-吲唑-5-基)-1-氧代丙-2-基]-4-(2-氧代-1,4-二氢喹唑啉-3(2H)-基)哌啶-1-甲酰胺；和
N-{(2R)-3-(7-甲基-1H-吲唑-5-基)-1-氧代-1-[8-(吡啶-4-基)-2,8-二氮杂螺[4.5]癸-2-基]丙-2-基}-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺。
7.前述权利要求任一项的化合物，其中所述化合物是
8.权利要求1至7任一项的化合物的用途，其通过非口服给药途径使用。
9.权利要求8的用途，其中所述非口服给药途径是鼻内途径、皮下途径或静脉内途径。
10.权利要求1至7任一项的化合物在治疗脑血管或血管障碍中的用途，所述脑血管或血管障碍包括无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、先兆偏头痛、家族性偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛、偏头痛重积状态、丛集性头痛、透析性头痛、阵发性偏头痛、骨关节炎、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、连续性偏头痛、周期性呕吐综合征、过敏性鼻炎、红斑痤疮、牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、与炎性肠病-克罗恩病相关的疼痛、痛风、复杂性区域疼痛综合征、贝歇氏病、子宫内膜异位疼痛、背痛或咳嗽。
11.一种使用权利要求1至7任一项的化合物治疗脑血管或血管障碍的方法，所述脑血管或血管障碍包括无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、先兆偏头痛、家族性偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛、偏头痛重积状态、丛集性头痛、透析性头痛、阵发性偏头痛、骨关节炎、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、连续性偏头痛、周期性呕吐综合征、过敏性鼻炎、红斑痤疮、牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、与炎性肠病-克罗恩病相关的疼痛、痛风、复杂性区域疼痛综合征、贝歇氏病、子宫内膜异位疼痛、背痛或咳嗽。
12.权利要求11的方法，其中所述化合物通过非口服途径给药。
13.权利要求12的方法，其中所述非口服给药途径是鼻内途径、皮下途径或静脉内途径。
14.一种合成权利要求1至7任一项的化合物的方法。
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| PCT/IB2016/056518 WO2017072722A1 (en) | 2015-10-30 | 2016-10-28 | Cgrp receptor antagonists |
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| SG (1) | SG11201803380RA (zh) |
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| WO2024046223A1 (zh) * | 2022-08-30 | 2024-03-07 | 熙源安健医药（上海）有限公司 | 吲唑甲酰胺类衍生物及其制备方法和用途 |
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| GB201519195D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP Receptor Antagonists |
| GB201519196D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP Receptor Antagonists |
| GB201908430D0 (en) | 2019-06-12 | 2019-07-24 | Heptares Therapeutics Ltd | Cgrp antagonist compounds |
| GB201908420D0 (en) | 2019-06-12 | 2019-07-24 | Heptares Therapeutics Ltd | Cgrp antagonist compounds |
| CN116806150A (zh) * | 2021-01-05 | 2023-09-26 | 载度思生命科学有限公司 | 新的自分泌运动因子抑制剂 |
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| WO2024046223A1 (zh) * | 2022-08-30 | 2024-03-07 | 熙源安健医药（上海）有限公司 | 吲唑甲酰胺类衍生物及其制备方法和用途 |
Also Published As
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| BR112018008419A2 (pt) | 2018-11-06 |
| US20180009808A1 (en) | 2018-01-11 |
| SG11201803380RA (en) | 2018-05-30 |
| AU2016344688A1 (en) | 2018-05-17 |
| US20170121331A1 (en) | 2017-05-04 |
| JP2018532789A (ja) | 2018-11-08 |
| WO2017072722A1 (en) | 2017-05-04 |
| TW201722952A (zh) | 2017-07-01 |
| EP3368536B1 (en) | 2019-03-06 |
| US9802935B2 (en) | 2017-10-31 |
| IL258893A (en) | 2018-06-28 |
| JP6874013B2 (ja) | 2021-05-19 |
| US10259812B2 (en) | 2019-04-16 |
| GB201519195D0 (en) | 2015-12-16 |
| AR106488A1 (es) | 2018-01-17 |
| EP3368536A1 (en) | 2018-09-05 |
| CA3002623A1 (en) | 2017-05-04 |
| CN108431005B (zh) | 2020-12-25 |
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