CN108430991A - Cgrp受体拮抗剂 - Google Patents
Cgrp受体拮抗剂 Download PDFInfo
- Publication number
- CN108430991A CN108430991A CN201680063940.2A CN201680063940A CN108430991A CN 108430991 A CN108430991 A CN 108430991A CN 201680063940 A CN201680063940 A CN 201680063940A CN 108430991 A CN108430991 A CN 108430991A
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- migraine
- compound
- methyl
- piperidines
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Veterinary Medicine (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
本公开涉及式(I)的杂环降钙素基因相关肽(CGRP)拮抗剂,其可用于治疗或预防脑血管或血管障碍例如偏头痛。
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1519194.3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是H或F,并且Ar1是含有至少两个氮原子的任选取代的5元杂环。
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式(I)的结构:
或其盐,其中R1是H或F,并且Ar1是含有至少两个氮原子的任选取代的5元杂环。
在特定实施方式中,Ar1是包括至少两个碳原子的任选取代的5元杂环,其中所述任选的取代基选自(C1-C6)烷基、CO2R2,其中R2是H或(C1-C3)烷基。
在特定实施方式中,R1是H。
在更特定实施方式中,Ar1是任选被(C1-C6)烷基取代的包括2或3个氮原子的5元杂环。
在特定实施方式中,Ar1选自:
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,ISBN 0-967-06710-3。
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
C1-C6烷基
烷基意味着脂族烃基。所述烷基可以是直链或支链的。“支链的”意味着在所述基团中存在至少一个碳分支点,例如异丙基或叔丁基。C1-C3烷基包括甲基、乙基、正丙基、异丙基。所述烷基可以是任选取代的。
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吲唑基、咪唑基、1,2,4-三唑基、喹啉-2(1H)-酮、哌啶基等。在所述杂芳基是5元的情况下,所述杂芳基包括咪唑基、1,2,4-三唑基等。
任选取代的
当应用于任何基团时,“任选取代的”意味着如果需要,所述基团可以被一个或多个取代基取代,所述取代基可以是相同或不同的。
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通过包括方案1中的那些的途径来制备。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
流程1
流程2
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或CDI,在溶剂例如DMF和/或DCM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中在碱例如DIPEA或三乙胺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MeOH或DCE中,任选地在添加剂例如乙酸或氯化锌存在下,使用胺、醛或酮以及还原剂例如三乙酰氧基硼氢化钠或氰基硼氢化钠的还原胺化;或在适合的溶剂例如DMF中使用烷基卤和强碱例如氢化钠的烷基化)来制备。在例如上述的标准转化后或在一系列这种转化期间,可能必需除去标准的保护基团,并且可以使用可以在参考教科书例如《保护基团》(ProtectingGroups)第三版,P.J.Kocieński,Georg Thieme Verlag(2005)中找到的条件来进行。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。使用标准转化例如上面详细描述的那些,例如利用如上面详述的那些的条件的酯的皂化,可以将本发明的实施例转化成其他实施例。
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℃。1H NMR谱是在Bruker、Varian或JEOL仪器上,在400MHz或500MHz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。在由于互变异构形式的存在而存在中间体或实施例的复杂NMR谱的情况下,为观察到的主要形式提供数据。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,2.1 x 20mm或Phenomenex Gemini-NX C-18,3微米,2.0 x 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,2.0 x 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。
方法C.仪器:Waters Acquity H Class,光电二极管阵列,SQ检测器;柱:BEH C18,1.7微米,2.1 x 50mm;梯度[时间(min)/溶剂在A中的B(%)]:0.00/5,0.40/5,0.8/35,1.20/55,2.50/100,3.30/100,4.00/5;溶剂:溶剂A=H2O中的5mM乙酸铵和0.1%甲酸;溶剂B=MeCN中的0.1%甲酸;进样体积2μL;UV检测200至400nM;质量检测100至1200AMU(+ve电喷雾);柱在环境温度下;流速0.5mL/min。
方法D.仪器:Waters Acquity H Class,光电二极管阵列,SQ检测器;柱:X-BridgeC18,5微米,150 x 4.6mm;梯度[时间(min)/溶剂在F中的E(%)]:0.01/10,5.00/90,7.00/100,11.00/100,11.01/10,12.00/10;溶剂:溶剂E=H2O中的0.1%氨;溶剂F=MeCN中的0.1%氨;进样体积10μL;UV检测200至400nM;质量检测60至1000AMU(+ve电喷雾);柱在环境温度下;流速1.0mL/min。
方法E.仪器:Acquity UPLC,偶联有SQD质谱仪;柱:Acquity UPLC BEH C18,1.7微米,2.1 x 50mm;梯度[时间(min)/溶剂在A中的B(%)]:0.00/5,1.50/5,8.75/80,9.50/90,9.80/90,12.00/5;溶剂:溶剂A=10mM NH4HCO3水溶液(用氨水调整到pH 10);溶剂B=MeCN;进样体积2μL;UV检测210至350nM;柱温40℃;流速0.9mL/min。
缩写
CDI=1,1′-羰基二咪唑
DCE=1,2-二氯乙烷
DCM=二氯甲烷
DIPEA=N,N-二异丙基乙胺
DMAC=N,N-二甲基乙酰胺
DMF=二甲基甲酰胺
DSC=N,N’-二琥珀酰亚胺基碳酸酯
DMSO=二甲基亚砜
ES=电喷雾
EtOAc=乙酸乙酯
h=小时
HATU=3-氧六氟磷酸1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶
L=升
LC=液相色谱
LCMS=液相色谱质谱
MeCN=乙腈
min=分钟
MS=质谱
NMR=核磁共振
rcf=相对离心力
rpm=每分钟转数
rt=室温
s=秒
THF=四氢呋喃
TLC=薄层层析
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4即(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)丙酸的制备为例
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3,6.05g,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1,6.99g,30.6mmol)、DIPEA(4.93mL,28.2mmol)和DCM(20mL),并将混合物在N2下加热至40℃,保持12h。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。通过快速层析进行纯化,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。
中间体5,(2R)-2-({[4-(7-氟-2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)-3-(7-甲基-1H-吲唑-5-基)丙酸
步骤1)向(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯(中间体3,700mg,3.0mmol)和DSC(845mg,3.3mmol)在DMF(20mL)中的溶液添加Et3N(1.25mL,9.0mmol),并将混合物在rt搅拌30min。然后分次添加7-氟-3-(哌啶-4-基)喹啉-2(1H)-酮盐酸盐(中间体2,933mg,3.3mmol),并将反应混合物在rt搅拌过夜,然后真空浓缩。将残留物在H2O与DCM之间分配,并添加少量MeOH以帮助溶解,并将水性相用H2O洗涤。在真空浓缩后,将残留物通过快速层析进行纯化,使用EtOAc的MeOH溶液(20:1)洗脱,得到作为黄色固体的(2R)-2-({[4-(7-氟-2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯(462mg,0.91mmol)。
LCMS(方法A):m/z 506.3(ES+),在3.35min处。
1H NMR:(400MHz,DMSO-d6)δ:ppm 1.22-1.37(m,2H),1.73(t,J=10.2,2H),2.47(s,3H),2.64-2.80(m,2H),2.82-2.94(m,1H),2.95-3.11(m,2H),3.59(s,3H),4.08(d,J=12.5,2H),4.21-4.33(m,1H),6.85(d,J=7.8,1H),6.97-7.10(m,3H),7.41(s,1H),7.59(s,1H),7.70(dd,J=8.2,6.2,1H),7.87-8.10(m,1H),11.85(s,1H),13.04(s,1H)。
步骤2)将(2R)-2-({[4-(7-氟-2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯(462mg,0.91mmol)溶解在THF(6mL)和MeOH(1.2mL)中,逐滴添加LiOH的水溶液(1M,1.82mL,1.82mmol)。在rt搅拌4h后,将反应混合物在氮气流下浓缩,将残留物溶解在最小体积的H2O中,并用1M HCl酸化。通过过滤分离得到的沉淀物,用冷H2O和Et2O洗涤,得到作为浅黄色固体的所述标题化合物(406mg,0.83mmol)。
数据在表1中。
胺中间体的制备
中间体8,4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶盐酸盐
步骤1)向4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶(中间体6,1.66g,10.0mmol)在DCE(60mL)中的悬液添加4-氧代哌啶-1-甲酸叔丁酯(中间体7,2.09g,10.5mmol)。将混合物在rt搅拌30min,然后添加三乙酰氧基硼氢化钠(2.97g,14.0mmol)。在rt搅拌过夜后,添加4-氧代哌啶-1-甲酸叔丁酯(中间体7,210mg,1.05mmol),并将混合物在rt搅拌8h,然后添加4-氧代哌啶-1-甲酸叔丁酯(中间体7,600mg,3.01mmol)和三乙酰氧基硼氢化钠(900mg,4.25mmol),并在rt搅拌4d。添加H2O(100mL),将所述混合物搅拌2min,然后进行相分离,并将水性层(调整到pH 4.7)用DCM(2 x 30mL)洗涤。向水性相添加DCM(30mL),并通过添加1MNaOH将所述水性相调整到pH 7,然后用DCM(7 x 30mL)萃取,在每次萃取之前将水性相的pH调整到7。将所述水性相进一步用DCM(5 x 30mL)萃取,在每次萃取之前将pH调整到7.5。将合并的有机相干燥(Na2SO4)、过滤并真空浓缩,得到4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-甲酸叔丁酯(2.27g,6.50mmol),其不需纯化即可用于后续步骤中。
LCMS(方法E):m/z 350.4(ES+),在3.91min处。
1H NMR:(500MHz,CD3OD)δ:ppm 1.43-1.48(m,1H),1.46(s,9H),1.87-2.02(m,6H),2.39-2.46(m,2H),2.51-2.58(m,1H),2.76(br s,2H),2.81-2.92(m,1H),3.10(dt,J=12.4,3.6,2H),3.71(s,3H),4.14(dt,J=13.4,2.4,2H),4.59(br s,1H),8.35(s,1H)。
步骤2)向4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-甲酸叔丁酯(2.27g,6.50mmol)在DCM(120mL)中的溶液添加1,4-二烷中的4N HCl(16.0mL,64.0mmol),并将混合物在rt搅拌2h。真空浓缩,得到作为盐酸盐的所述标题化合物(2.23g),其不需进一步纯化即可使用。
数据在表1中。
中间体8即4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶的可选合成
步骤1)向4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶(中间体6,16.0g,96.3mmol)在DCE(580mL)中的溶液添加4-氧代哌啶-1-甲酸苯甲酯(中间体22,23.6g,101.1mmol)和三乙酰氧基硼氢化钠(28.6g,134.8mmol)。在rt搅拌过夜后,添加乙酸(5mL),并在rt继续搅拌2h后,添加4-氧代哌啶-1-甲酸苯甲酯(中间体22,2.35g,10.1mmol)和三乙酰氧基硼氢化钠(2.86g,13.5mmol)。在rt搅拌2h后,添加4-氧代哌啶-1-甲酸苯甲酯(中间体22,7.05g,30.3mmol)和三乙酰氧基硼氢化钠(8.58g,40.4mmol),将混合物在rt搅拌2h,然后添加4-氧代哌啶-1-甲酸苯甲酯(中间体22,7.05g,30.3mmol)和三乙酰氧基硼氢化钠(8.58g,40.4mmol)。在rt搅拌过夜后,添加H2O(1L),进行相分离,并将水性相用DCM(3 x 300mL)萃取。用6N NaOH水溶液将水性相的pH调整到7.5,并用DCM(5 x 300mL)萃取。将合并的有机相干燥(Na2SO4)、过滤并真空浓缩,得到4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-甲酸苯甲酯(23.2g,60.6mmol)。
LCMS(方法A):m/z 384.3(ES+),在3.29min处。
1H NMR:(400MHz,CD3OD)δ:ppm 1.40-1.52(m,2H),1.86-2.05(m,6H),2.39-2.51(m,2H),2.53-2.66(m,1H),2.75-2.98(m,3H),3.04-3.18(m,2H),3.71(s,3H),4.22(d,J=13.4,2H),5.11(s,2H),7.29-7.39(m,5H),8.35(s,1H)
步骤2)将10%碳载钯(4.76g)和4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-甲酸苯甲酯(17.2g,44.8mmol)在EtOH(200mL)中的混合物在H2(1.5bar)气氛和rt下搅拌90min。将混合物通过硅藻土过滤,真空浓缩,重新溶解在DCM(200mL)中并真空浓缩。将所述重新溶解和浓缩过程重复5次,并在进一步真空干燥后,得到作为白色固体的所述标题化合物(10.0g,40.1mmol)。
1H NMR:(400MHz,DMSO-d6)δ:ppm 1.40-1.51(m,2H),1.63-1.77(m,4H),1.80-1.87(m,3H),2.21-2.32(m,2H),2.35-2.45(m,1H),2.52-2.63(m,2H),2.66-2.80(m,1H),2.87-2.99(m,2H),3.09(d,J=12.5,2H),3.59(br s,3H),8.31(s,1H)。
中间体10,4-(1H-咪唑-2-基)-1,4'-联哌啶盐酸盐
步骤1)将4-(1H-咪唑-2-基)哌啶盐酸盐(中间体9,2.30g,12.3mmol)、Et3N(4.96mL,35.6mmol)、4-氧代哌啶-1-甲酸叔丁酯(中间体7,2.44g,12.2mmol)和ZnCl2(84.6mg,0.61mmol)在MeOH(100mL)中的溶液在60℃搅拌5h。在冷却到rt后,分次添加氰基硼氢化钠(3.09g,49.2mmol),并将混合物在rt搅拌16h。在MeOH/DCM(1:9,300mL)与H2O(250mL)之间分配后,将水性相用MeOH/DCM(1:9,300mL)萃取,将合并的有机相干燥(Na2SO4)并真空浓缩,得到4-(1H-咪唑-2-基)-1,4'-联哌啶-1'-甲酸叔丁酯(5.0g,无色油状物),其不需纯化即可用于后续步骤中。
TLC:Rf 0.5(MeOH/DCM 1:9)。
LCMS(方法D):m/z 335.2(ES+),在4.95min处。
步骤2)向4-(1H-咪唑-2-基)-1,4'-联哌啶-1'-甲酸叔丁酯(5.0g)在DCM(100mL)中的溶液添加Et3N(4.16mL,29.8mmol)。在搅拌15min后,在0℃下分次添加二碳酸二叔丁酯(4.85g,22.2mmol),并将反应混合物在rt搅拌16h。在MeOH/DCM(1:9,300mL)与H2O(250mL)之间分配后,将水性相用MeOH/DCM(1:9,300mL)萃取,将合并的有机相干燥(Na2SO4)并真空浓缩。通过梯度快速层析进行纯化,用DCM中的0-3%MeOH洗脱,得到作为无色油状物的4-[1-(叔丁氧基羰基)-1H-咪唑-2-基]-1,4'-联哌啶-1'-甲酸叔丁酯(1.40g,3.22mmol)。
1H NMR:(400MHz,DMSO-d6)δ:ppm 1.22-1.32(m,3H),1.39(s,9H),1.57(s,9H),1.69-1.72(m,4H),1.85-1.91(m,2H),2.20(br s,2H),2.67(br d,3H),2.99(br s,2H),3.96(dd,J=10.0,2H),6.85(d,J=1.6,1H),7.42(d,J=1.2,1H)。
步骤3)在0℃下向4-[1-(叔丁氧基羰基)-1H-咪唑-2-基]-1,4'-联哌啶-1'-甲酸叔丁酯(1.40g,3.22mmol)在1,4-二烷(20mL)中的溶液逐滴添加1,4-二烷中的4M HCl(15mL,60mmol),随后将混合物在rt搅拌4h。在真空浓缩后,用Et2O研磨,得到作为灰白色固体的所述标题化合物(1.0g)。
数据在表1中。
中间体12,4-(4-甲基-1H-咪唑-5-基)-1,4'-联哌啶盐酸盐
步骤1)将4-(4-甲基-1H-咪唑-5-基)哌啶盐酸盐(中间体11,2.0g,9.9mmol)和三乙胺(1.7mL,11.9mmol)在DMF(40mL)中的混合物在rt搅拌。5min后,添加4-氧代哌啶-1-甲酸叔丁酯(中间体7,2.4g,11.9mmol)和乙酸(0.68mL,11.9mmol)。在rt搅拌30min后,添加三乙酰氧基硼氢化钠(2.52g,11.9mmol)。在rt搅拌过夜后,将反应混合物真空浓缩,并将残留物在DCM(100mL)与饱和NaHCO3水溶液(100mL)之间分配。将水性相用DCM(100mL)萃取,并将合并的有机相用盐水洗涤,并通过穿过疏水性玻璃料来进一步干燥。在真空中除去溶剂,并将结晶的产物油状物静置3d。在用二乙醚/异己烷研磨后,通过过滤收集固体并真空干燥,得到4-(4-甲基-1H-咪唑-5-基)-1,4'-联哌啶-1'-甲酸叔丁酯(1.64g,4.7mmol)。
LCMS(方法B):m/z 349.2(ES+),在1.24min处。
1H NMR:(400MHz,CDCl3)δ:ppm 1.39-1.51(m,11H),1.68-1.91(m,6H),2.20(s,3H),2.24-2.37(m,2H),2.40-2.53(m,1H),2.55-2.77(m,3H),2.97-3.07(m,2H),4.15(brs,2H),7.45(s,1H)(未观察到1个可交换的质子)。
步骤2)向4-(4-甲基-1H-咪唑-5-基)-1,4'-联哌啶-1'-甲酸叔丁酯(1.6g,4.6mmol)在DCM(20mL)中的溶液添加1,4-二烷中的4N HCl(10.0mL,40.0mmol),并将混合物在rt搅拌。2h后,将反应混合物真空浓缩,取出残留物并从DCM(x2)重新蒸发,得到所述标题化合物(3.22g,含有残留的溶剂),其不需进一步纯化即可用于实施例2的合成中。
数据在表1中。
将中间体12的样品(100mg)溶解在DCM(5mL)和最少量MeOH中,添加固体NaCO3(200mg)并将混合物搅拌2h。将反应混合物过滤,并将滤液在N2流下浓缩,然后真空浓缩,得到作为游离碱的所述标题化合物(31mg,0.12mmol)。
LCMS(方法A):m/z 249.3(ES+),在2.24min处。
1H NMR:(400MHz,CD3OD)δ:ppm 1.47(qd,J=12.3,4.1,2H),1.72-1.83(m,4H),1.86-1.93(m,2H),2.16(s,3H),2.30-2.39(m,2H),2.46(tt,J=11.6,3.5,1H),2.53-2.67(m,3H),3.02-3.14(m,4H),7.40(s,1H)(未观察到2个可交换的质子)。
中间体14,4-(1-丙基-1H-咪唑-2-基)哌啶盐酸盐
步骤1)在0℃下向4-(1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(中间体13,2.50g,9.95mmol)在DMF(50mL)中的溶液添加氢化钠(60%,在矿物油中,478mg,12.0mmol)。在0℃搅拌20min后,添加1-碘代丙烷(1.16mL,11.9mmol),将反应在rt搅拌2h,然后在EtOAc(200mL)与H2O(150mL)之间分配。将水性相用EtOAc(200mL)萃取,将合并的有机相干燥(Na2SO4),过滤并真空浓缩。通过梯度快速层析进行纯化,用DCM中的0-10%MeOH洗脱,得到作为黄色油状物的4-(1-丙基-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(2.90g,9.89mmol)。
LCMS(方法C):m/z 294.5(ES+),在1.77min处。
1H NMR:(400MHz,DMSO-d6)δ:ppm 0.81-0.92(m,3H),1.41(s,9H),1.51–1.70(m,6H),2.89-2.97(m,3H),3.81–3.88(m,2H),3.97–4.00(d,J=13.6,2H),6.78(s,1H),7.04(s,1H)。
步骤2)使用中间体10的方法的步骤3,从4-(1-丙基-1H-咪唑-2-基)哌啶-1-甲酸叔丁酯(2.90g,9.89mmol)和1,4-二烷中的4M HCl(15mL,60.0mmol)制备所述标题化合物(2.60g)。
数据在表1中。
中间体15,4-(1-丙基-1H-咪唑-2-基)-1,4'-联哌啶盐酸盐
使用中间体10的方法的步骤1和3,从4-(1-丙基-1H-咪唑-2-基)哌啶盐酸盐(中间体14,1.00g)和4-氧代哌啶-1-甲酸叔丁酯(中间体7,868mg,4.36mmol)制备所述标题化合物(0.70g,1.81mmol)。
数据在表1中。
中间体17,5-(1,4'-联哌啶-4-基)-4H-1,2,4-三唑-3-甲酸乙酯盐酸盐
使用中间体12的方法,从5-(哌啶-4-基)-4H-1,2,4-三唑-3-甲酸乙酯(中间体16,448mg,2.00mmol)、4-氧代哌啶-1-甲酸叔丁酯(中间体7,478mg,2.40mmol)、三乙酰氧基硼氢化钠(610mg,2.88mmol)和乙酸(137μL,2.39mmol)在两个步骤后制备得到所述标题化合物。
数据在表1中。
中间体19,4-(4H-1,2,4-三唑-3-基)-1,4'-联哌啶盐酸盐
步骤1)将4-(1H-1,2,4-三唑-5-基)哌啶盐酸盐(中间体18,377mg,2.00mmol)、4-氧代哌啶-1-甲酸叔丁酯(中间体7,478mg,2.40mmol)、乙酸(137μL,2.39mmol)和Et3N(279μL,2.00mmol)的混合物在rt搅拌30min,然后添加三乙酰氧基硼氢化钠(610mg,2.88mmol)并在rt搅拌3d.。添加另外的4-氧代哌啶-1-甲酸叔丁酯(中间体7,300mg,1.51mmol)和乙酸(100μL,1.75mmol),并将反应混合物在rt搅拌30min,然后添加三乙酰氧基硼氢化钠(400mg,1.89mmol)并在rt搅拌过夜。在真空浓缩后,通过梯度快速层析进行纯化,用DCM中的0-10%MeOH洗脱,然后用DCM中的10%(7N NH3,在MeOH中)洗脱,得到作为白色固体的4-(4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-甲酸叔丁酯(350mg,1.04mmol)。
LCMS(方法B):m/z 336.2(ES+),在0.94min处。
1H NMR:(400MHz,CD3OD)δ:ppm,1.45(s,9H),1.86-1.95(m,4H),2.10-2.13(m,2H),2.56-2.61(m,2H),2.69-2.81(m,3H),2.88-2.94(m,1H),3.03-3.19(m,4H),4.15-4.18(m,2H),8.16(s,1H)(未观察到1个可交换的质子)。
步骤2)使用中间体12的方法,在MeOH(10mL)中,从4-(4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-甲酸叔丁酯(350mg,1.04mmol)和1,4-二烷中的4M HCl(10mL,40.0mmol)制备所述标题化合物(320mg)。
数据在表1中。
中间体21,4-(5-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶盐酸盐
步骤1)将4-(3-甲基-1H-1,2,4-三唑-5-基)哌啶二盐酸盐(中间体20,478mg,2.00mmol)、4-氧代哌啶-1-甲酸叔丁酯(中间体7,478mg,2.40mmol)、乙酸(137μL,2.39mmol)和Et3N(558μL,4.00mmol)的混合物在rt搅拌30min,然后添加三乙酰氧基硼氢化钠(610mg,2.88mmol)并在rt搅拌过夜。在真空浓缩后,通过梯度快速层析进行纯化,用DCM中的0-10%(7N NH3在MeOH中)洗脱,得到作为无色固体的4-(5-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-甲酸叔丁酯(310mg,0.89mmol)。
LCMS(方法B):m/z 350.2(ES+),在1.01min处。
1H NMR:(400MHz,CD3OD)δ:ppm 1.45(s,9H),1.48-1.55(m,2H),1.91-1.99(m,7H),2.11-2.15(m,2H),2.68-2.90(m,6H),3.24-3.27(m,2H),4.16-4.20(m,2H)(未观察到1个可交换的质子)。
步骤2)使用中间体12的方法,在MeOH(5mL)中,从4-(5-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-甲酸叔丁酯(310mg,0.89mmol)和1,4-二烷中的4M HCl(5mL,20.0mmol)制备所述标题化合物(240mg,0.93mmol)。
数据在表1中。
表1.中间体
实施例的合成
通过酰胺偶联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-[4-(4-甲基-1H-咪唑-5-基)-1,4'-联哌啶-1'-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
将4-(4-甲基-1H-咪唑-5-基)-1,4'-联哌啶盐酸盐(中间体12,污染有溶剂残留物,假定为21.0mmol)、(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4,9.93g,21.0mmol)、HATU(8.00g,20.9mmol)和DIPEA(14.6mL,83.8mmol)在DMF(150mL)中的混合物在室温搅拌过夜,然后真空浓缩。通过梯度快速层析进行纯化,用DCM中的0-100%溶剂B洗脱(其中溶剂B是MeOH中的7N NH3/DCM,1:9),得到作为白色固体的所述标题化合物(7.50g,10.7mmol)。
数据在表2中。
实施例5,4-(7-氟-2-氧代-1,2-二氢喹啉-3-基)-N-{(2R)-3-(7-甲基-1H-吲唑-5-基)-1-[4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-基]-1-氧代丙-2-基}哌啶-1-甲酰胺
使用实施例4的方法,从(2R)-2-({[4-(7-氟-2-氧代-1,2-二氢喹啉-3-基)哌啶-1-基]羰基}氨基)-3-(7-甲基-1H-吲唑-5-基)丙酸(中间体5,74mg,0.15mmol)、4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶盐酸盐(中间体8,97mg)、HATU(69mg,0.18)和DMF(1.5mL)中的Et3N(0.21mL,1.51mmol)制备所述标题化合物(45mg,0.06mmol)。所述标题化合物通过梯度快速柱层析进行纯化,用DCM中的0-100%溶剂B洗脱(其中溶剂B是MeOH中的7N NH3/DCM,1:9),然后通过制备型反相HPLC进行纯化(Phenomenex Gemini-NX 5μm C18柱,100 x 30mm,以30mL/min的流速在12.5min内用10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处监测来收集级分)。
数据在表2中。
流程2:
实施例9,5-{1'-[(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]-1,4'-联哌啶-4-基}-4H-1,2,4-三唑-3-甲酸
向5-{1'-[(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]-1,4'-联哌啶-4-基}-4H-1,2,4-三唑-3-甲酸乙酯(实施例6,110mg,0.14mmol)在MeOH(10mL)和H2O(2mL)中的溶液添加单水氢氧化锂(9mg,0.21mmol),并将反应混合物在rt搅拌过夜。添加另外的单水氢氧化锂(10mg,0.24mmol),并在rt搅拌1d后,将混合物在真空中部分浓缩以除去MeOH。向残留物添加1N HCl水溶液,然后将其真空浓缩,并通过制备型反相HPLC进行纯化(Phenomenex Gemini-NX 5μm C18柱,100x 30mm,以30mL/min的流速在12.5min内用5至35%MeCN/溶剂B洗脱[其中溶剂B是H2O中的0.2%的(28%NH3/H2O)],并通过在205nm处监测来收集级分),得到作为无色固体的所述标题化合物(10mg,0.01mmol)。
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.
生物学和生物物理学方法
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-110L Pneumatic(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50mM HepespH 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),在室温下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)。本发明的某些化合物的pKi值(其中pKi=-log10Ki)在下文中列表。
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Sprague 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5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Sprague 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 (16)
1.一种式(I)的化合物:
或其盐,其中R1是H或F,并且Ar1是含有至少两个氮原子的任选取代的5元杂环。
2.权利要求1的化合物,其中Ar1是包括至少两个氮原子的任选取代的5元杂环,其中所述任选的取代基选自(C1-C6)烷基、CO2R2,其中R2是H或(C1-C3)烷基。
3.前述权利要求任一项的化合物,其中R1是H。
4.前述权利要求任一项的化合物,其中Ar1是任选被(C1-C6)烷基取代的包括2或3个氮原子的5元杂环。
5.前述权利要求任一项的化合物,其中Ar1是
6.前述权利要求任一项的化合物,其中Ar1是
7.权利要求1至5任一项的化合物,其中Ar1是
8.前述权利要求任一项的化合物,其中所述化合物选自:
N-[(2R)-1-[4-(1H-咪唑-2-基)-1,4'-联哌啶-1'-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-[4-(4-甲基-1H-咪唑-5-基)-1,4'-联哌啶-1'-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)-3-(7-甲基-1H-吲唑-5-基)-1-氧代-1-[4-(1-丙基-1H-咪唑-2-基)-1,4'-联哌啶-1'-基]丙-2-基}-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺;
N-{(2R)-3-(7-甲基-1H-吲唑-5-基)-1-[4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-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;
4-(7-氟-2-氧代-1,2-二氢喹啉-3-基)-N-{(2R)-3-(7-甲基-1H-吲唑-5-基)-1-[4-(4-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-基]-1-氧代丙-2-基}哌啶-1-甲酰胺;
5-{1'-[(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]-1,4'-联哌啶-4-基}-4H-1,2,4-三唑-3-甲酸乙酯;
N-{(2R)-3-(7-甲基-1H-吲唑-5-基)-1-氧代-1-[4-(4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-基]丙-2-基}-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺;
N-{(2R)-3-(7-甲基-1H-吲唑-5-基)-1-[4-(5-甲基-4H-1,2,4-三唑-3-基)-1,4'-联哌啶-1'-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;和
5-{1'-[(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]-1,4'-联哌啶-4-基}-4H-1,2,4-三唑-3-甲酸。
9.权利要求1的化合物,其中所述化合物是:
10.权利要求1至9任一项的化合物的用途,其通过非口服给药途径使用。
11.权利要求10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。
12.权利要求1至9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、或红斑痤疮、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。
13.一种使用权利要求1至9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、或红斑痤疮、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。
14.权利要求13的方法,其中所述化合物通过非口服途径给药。
15.权利要求14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。
16.一种合成权利要求1至9任一项的化合物的方法。
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2015
- 2015-10-30 GB GBGB1519194.3A patent/GB201519194D0/en not_active Ceased
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2016
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- 2016-10-28 WO PCT/IB2016/056519 patent/WO2017072723A1/en active Application Filing
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- 2016-10-28 SG SG11201803382XA patent/SG11201803382XA/en unknown
- 2016-10-28 JP JP2018541593A patent/JP6874014B2/ja active Active
- 2016-10-28 BR BR112018008416A patent/BR112018008416A2/pt not_active Application Discontinuation
- 2016-10-28 US US15/336,893 patent/US9688660B2/en active Active
- 2016-10-28 AR ARP160103294A patent/AR106487A1/es unknown
- 2016-10-28 AU AU2016344689A patent/AU2016344689A1/en not_active Abandoned
- 2016-10-28 CA CA3002625A patent/CA3002625A1/en not_active Abandoned
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2017
- 2017-05-05 US US15/588,051 patent/US9925178B2/en active Active
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2018
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GB201519194D0 (en) | 2015-12-16 |
JP6874014B2 (ja) | 2021-05-19 |
BR112018008416A2 (pt) | 2018-10-23 |
CN108430991B (zh) | 2021-01-05 |
IL258894A (en) | 2018-06-28 |
SG11201803382XA (en) | 2018-05-30 |
US10166226B2 (en) | 2019-01-01 |
TW201722936A (zh) | 2017-07-01 |
JP2018532790A (ja) | 2018-11-08 |
US20170121311A1 (en) | 2017-05-04 |
AU2016344689A1 (en) | 2018-05-17 |
EP3368526A1 (en) | 2018-09-05 |
US9925178B2 (en) | 2018-03-27 |
EP3368526B1 (en) | 2019-12-25 |
CA3002625A1 (en) | 2017-05-04 |
US20170239236A1 (en) | 2017-08-24 |
US9688660B2 (en) | 2017-06-27 |
US20180153876A1 (en) | 2018-06-07 |
AR106487A1 (es) | 2018-01-17 |
WO2017072723A1 (en) | 2017-05-04 |
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