CN105579453B - 作为成像工具的咪唑并[1,2‑a]吡啶‑7‑胺类 - Google Patents
作为成像工具的咪唑并[1,2‑a]吡啶‑7‑胺类 Download PDFInfo
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- CN105579453B CN105579453B CN201480053175.7A CN201480053175A CN105579453B CN 105579453 B CN105579453 B CN 105579453B CN 201480053175 A CN201480053175 A CN 201480053175A CN 105579453 B CN105579453 B CN 105579453B
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- pyridine
- imidazo
- amine
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- 238000003384 imaging method Methods 0.000 title claims description 11
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 title description 3
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- 229910052722 tritium Inorganic materials 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 13
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- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 102000003802 alpha-Synuclein Human genes 0.000 claims abstract description 3
- 108090000185 alpha-Synuclein Proteins 0.000 claims abstract description 3
- IHFZRBQSSDQVOD-UHFFFAOYSA-N imidazo[1,2-a]pyridin-7-amine Chemical compound C1=C(N)C=CN2C=CN=C21 IHFZRBQSSDQVOD-UHFFFAOYSA-N 0.000 claims description 29
- 239000011737 fluorine Substances 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及通式(I)的化合物,其中R1是低级烷基或被卤素取代的低级烷基;R2、R3是氢或氚;或涉及药用酸加成盐。所述化合物可以用于结合和成像tau聚集体和相关的β‑折叠聚集体,尤其包括β‑淀粉状蛋白聚集体或α‑突触核蛋白聚集体。
Description
本发明涉及以下通式的化合物
其中
R1是低级烷基或被卤素取代的低级烷基;
R2、R3是氢或氚;
或涉及药用酸加成盐。
类似的化合物在例如WO2011/117264中被描述为用于治疗中枢神经系统疾病的磷酸二酯酶10A(PDE10A)的调节剂并且在WO2010/068453和WO2010/068452中被描述为脂肪酸酰胺水解酶的调节剂。2-芳基-3-(杂芳基)-咪唑并(1,2-a)嘧啶类在WO0134605中被描述为用于治疗通过减少炎性细胞因子而减轻的病症。
已经显示,本化合物可以用于结合和成像tau聚集体(tau aggregates)和相关的β(beta)折叠聚集体,尤其包括β-淀粉状蛋白聚集体或α(alpha)-突触核蛋白聚集体,特别是用于结合和成像在阿尔茨海默病患者中的tau聚集体。
阿尔茨海默病(AD)是进行性神经退行性疾病,其特征是认知下降,不可逆记忆丧失,定向障碍和语言丧失(Arch.Neurol.1985,42(11),1097-1105)。尸检AD脑切片显示大量的由β淀粉状蛋白(Aβ)肽组成的老年斑(SPs),和很多神经元纤维缠结(NFTs),所述神经元纤维缠结由高度磷酸化的tau蛋白的丝状物形成。
Tau属于微管相关蛋白家族并主要表达在神经元中,在那里它在微管蛋白单体组装为微管以构成作为轴突传输轨道的神经元微管网络中发挥重要作用(BrainRes.Rev.2000,33(1),95-130)。Tau从位于染色体17上的单个基因翻译并且表达由选择性剪切机制在发育上调节,在成人大脑中产生六种不同亚型,其可以由其结合结构域的数量区分。导致tau高度磷酸化,错误折叠和聚集的根本机制尚未很好理解,但tau聚集体的沉积物在细胞内水平以及在脑局部解剖水平上都接着模式化的时空路径(stereotypedspatiotemporal pathway)。
近来,导致帕金森病人额颞叶痴呆(FTD)的tau基因突变与染色体17相关的发现加强了归因于tau的在神经退行性疾病的发病机制中的显著作用并强调了在不同神经元群体中表达的tau亚型的不同组可能导致不同病理的事实(Biochim.Biophys.Acta 2005,1739(2)240-250)。特征为病理性tau积累的神经退行性疾病被称为‘tau蛋白病(tauopathies)’(Ann.Rev.Neurosci.2001,24,1121-1159)。除了AD和FTD以外,其它tau蛋白病包括进行性核上麻痹(progressive supranuclear palsy)(PSP),显性缠结痴呆(tangle-predominantdementia),皮克病(Pick’s disease),额颞叶退化(frontotemporal lobardegeneration)(FTLD),唐氏综合征(Down’s syndrome)等。
已经在新皮层区域的渐进性牵涉和增加的痴呆严重度之间建立了直接关联,揭示病理性的tau聚集体比如NFTs是神经变性过程的可靠标志物。AD中NFT牵涉的程度由Braak阶段定义(Acta Neuropathol.1991,82,239-259)。当NFT牵涉主要局限于脑的横嗅区域(transentorhinal region)时,定义为Braak阶段I和II,当牵涉边缘区域比如海马时,诊断为阶段III和IV,并且当发现大量的新皮层牵涉时,为阶段V和VI。
目前,tau聚集体的检测仅通过活检或尸检材料的组织学分析是可能的。tau病理的体内成像将提供对人脑中tau聚集体沉积物的新的深入理解并且允许非侵入性检查tau病理程度,定量tau沉积物随时间的改变,评估其与认知的关联和分析抗tau治疗的效力。用于在活体脑中检测tau聚集体的可能的配体必须跨过血脑屏障并且具有对tau聚集体的高亲和力和特异性。为此,成功的神经影像放射性示踪剂必须具有适当的亲油性(logD 1-3)和低分子量(<450),显示从血中的快速清除和低的非特异结合。
本申请的目的是找到成像工具,所述成像工具将通过鉴定脑中有过量tau聚集体的,可以可能发展为阿尔茨海默病的潜在患者而提高诊断。其也将可用于监测疾病的进展。当抗-tau聚集体药物变得可获得时,将脑中的tau缠结成像可以提供用于监测治疗的重要工具。
本发明的进一步目的是将tau聚集体沉积物成像的方法,所述方法包括
-向哺乳动物引入可检测量的组合物
-给予足够时间用于式I的化合物与tau-聚集体沉积物缔合,和
-检测与一种以上tau-聚集体沉积物缔合的化合物。
本发明的进一步目的是一种药物组合物,所述药物组合物含有式I的化合物和药用载体,所述药物组合物可以用于鉴定潜在患者。
不论所讨论的术语是否单独或组合出现,以下用于本说明书的一般术语的定义都适用。
如本文使用的,术语″低级烷基″表示饱和的,即脂肪烃基团,包括具有1-7个碳原子的直链或支链碳链。“烷基”的实例是甲基、乙基、正丙基和异丙基。
术语“卤素”表示氯、溴、氟或碘。
术语“被卤素取代的低级烷基”表示如以上所限定的烷基,其中至少一个氢原子被卤素原子替代。
3H表示氚原子。
术语“离去基团”表示卤素或磺酸根。磺酸根的实例有甲苯磺酸根、甲磺酸根、三氟甲磺酸根、硝基苯磺酸根(nosylate)或对溴苯磺酸根(brosylate)。
术语″药用盐″或“药用酸加成盐”包括无机和有机酸,比如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等的盐。
已经发现,式I的化合物可以用于结合和成像tau聚集体和相关的β-折叠聚集体,尤其包括β-淀粉状蛋白聚集体或α-突触核蛋白聚集体。
本发明的一个实施方案是式I的化合物,其中R1是低级烷基,例如以下化合物
2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺
[3H]-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺。
本发明的一个实施方案进一步是式I的化合物,其中R1是被卤素取代的低级烷基,例如以下化合物
2-(4-(氟甲氧基)苯基)咪唑并[1,2-a]吡啶-7-胺
2-[4-(3-氟丙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺
2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺
[3H]-2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺。
本发明的一个实施方案进一步是式I的化合物,其中R2和R3是氚,例如以下化合物
[3H]-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺
[3H]-2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺。
式I的化合物可以用于结合和成像tau聚集体,β-淀粉状蛋白聚集体,α-突触核蛋白聚集体或亨廷顿(huntingtin)聚集体。
式I的化合物的优选用途是用于结合和成像阿尔茨海默病患者中的tau聚集体。
此外,式I的化合物可以用于tau结合研究。
式I的化合物适用于哺乳动物脑中tau-聚集体的诊断成像。
本发明还用于哺乳动物脑中tau-聚集体沉积物的诊断成像。
本发明的式I的化合物,
及其药用盐可以通过下述方法制备,所述方法包括
a)式2的化合物(X=Cl、Br)用NH4OH的胺化
从而提供式I的化合物
其中R1是如以上所限定的,并且R2和R3是氢,并且,如果需要,将所得的化合物转化为药用酸加成盐,或
b)将式4的化合物
与式3的相应α-活化的酮(X是离去基团,例如Br)偶联
从而提供式I的化合物
其中R1是如以上所限定的,并且R2和R3是氢,并且,如果需要,将所得的化合物转化为药用酸加成盐,或
c)使式5的化合物与合适的烷基化剂R1-X(X是卤素或磺酸根)反应
从而提供式I的化合物
其中R1是如以上所限定的,并且R2和R3是氢,并且,如果需要,将所得的化合物转化为药用酸加成盐,以及
d)使式I的化合物与氚气在催化剂例如含铱、钌、铑或钯的络合物存在下,在合适的溶剂例如二氯甲烷、氯苯、DMF、DMSO或其混合物中,在环境或升高的温度反应
其中R2和R3是氢,
从而提供式I的化合物
其中R1是如以上所限定的和R2和R3是氚,并且,如果需要,将所得的化合物转化为药用酸加成盐。
以下方案1-3更详细地描述了用于制备式I的化合物的方法。起始物料是已知的化合物或可以根据本领域已知的方法制备。
本发明的式I的化合物的制备可以以顺序或会聚性路线进行。进行该反应和纯化产生的产物所需的技术对于本领域技术人员而言是已知的。以下过程描述中使用的取代基和标记具有本文给出的意义,除非有相反指示。
更详细地,可以通过下文给出的方法,通过实施例中给出的方法,或通过类似方法制造式I的化合物。用于各反应步骤的适当反应条件是本领域技术人员已知的。反应顺序不限于在方案1至3中显示的顺序,而是依赖于起始材料和其各自反应性,反应步骤的顺序可以随意改变。起始材料是可市购的或可以通过类似于下文给出的方法,通过说明书引用的参考文献中或实施例中描述的方法,或通过本领域已知的方法制备。
方案1
根据方案1,经由式2的化合物与合适的氨试剂例如氢氧化铵,在合适的催化剂例如氧化铜(I)存在下,在合适的溶剂例如N-甲基-2-吡咯烷酮中,在升高的或环境温度的胺化反应制备咪唑并吡啶的衍生物I,其中取代基R1是如以上所限定的并且R2和R3是氢。
方案2
根据方案2,将活化的酮3(其中取代基R1是如以上所限定的,R2和R3是氢并且X是卤素)与氨基-吡啶4在合适的溶剂例如丙酮或乙醇中,在升高的温度在油浴中或在微波反应器中反应从而提供化合物I的衍生物。
方案3
根据方案3,通过使用合适的烷基化剂R1-X例如烷基卤化物如1-氟乙基溴或甲苯磺酸烷基酯如甲苯磺酸氟甲酯,在合适的碱例如碳酸铯或氢化钠存在下,在合适的溶剂例如DMF中,在环境或升高的温度烷基化苯酚5,来合成另外的咪唑并吡啶的衍生物I,其中取代基R1是如以上所限定的。
化合物的分离和纯化
如果需要,可以通过任何合适的分离或纯化方法比如,例如,过滤,萃取,结晶,柱层析,薄层层析,厚层层析,制备型低或高压液相色谱或这些方法的组合,实现本文中描述的化合物和中间体的分离和纯化。合适的分离和离析方法的具体说明可以通过参考下文的制备和实施例发现。然而,当然也可以使用其它相当的分离或离析方法。
式I的化合物的盐
式I的化合物是碱性的并且可以转变为相应的酸加成盐。通过用至少化学计量量的适当的无机酸,比如盐酸、氢溴酸、硫酸、硝酸、磷酸等,或有机酸比如乙酸、丙酸、羟基乙酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸,对甲苯磺酸,水杨酸等处理完成转变。典型地,将游离碱溶解在惰性有机溶剂比如二乙醚,乙酸乙酯,氯仿,乙醇或甲醇等中,并将酸加在类似溶剂中。将温度维持在0℃和50℃之间。产生的盐自发沉淀或可以通过添加极性较小的溶剂沉淀。
可以通过用至少化学当量的合适的碱比如氢氧化钠或氢氧化钾、碳酸钾、碳酸氢钠、氨等处理,将式I的碱性化合物的酸加成盐转变为相应的游离碱。
根据下文给出的测试研究化合物。
TAU放射性配体体外置换测定
该体外结合测定评估化合物对天然的tau聚集体的亲和性。将化合物与沿用已久的tau特异性放射性配体[3H]T808共孵育并且通过体外放射自显影使用人阿尔茨海默病(AD)脑切片确定所述化合物的[3H]T808结合的置换效力(见图3)。
材料
AD人脑购自Banner Sun Health Research Institute(Sun City,AZ,USA)。AD的病理诊断根据标准NIA-Reagan Institute标准基于神经病理学数据进行。放射性配体[3H]T808内部合成([3H]-2-[4-(2-氟-乙基)-哌啶-1-基]-苯并[4,5]咪唑并[1,2-a]嘧啶,放射化学纯度99.0%)。使用冷的T808作为参比(2-[4-(2-氟-乙基)-哌啶-1-基]-苯并[4,5]咪唑并[1,2-a]嘧啶)。对于放射自显影,将FujiFilm Imaging Plates(BAS-IP TR 2025)暴露于切片并且利用FujiFilm IP读数计(BAS-5000)读数。
方法
利用低温恒温器(Leica CM3050)在-17℃室温度和-15℃物体温度,产生十μm厚的人AD脑切片。将切片转移到Histobond+显微镜载片(Marienfeld Laboratory Glasware)。在室温干燥3小时后,将切片储存于-20℃。将切片与放射性配体(10nM)和各自的冷化合物(以不同浓度)在50mM Tris缓冲液,pH 7.4中在室温孵育30min。在4℃在50mM Tris缓冲液,pH 7.4中洗涤3×10min并且在蒸馏H2O中在4℃进行3次快速浸泡后,将切片在4℃干燥3h。将切片放置在FujiFilm Cassette(BAS 2025)中,用成像板暴露五天并且之后以25μM/像素的分辨率进行扫描。
数据分析
放射自显影图的目的区域(ROI)中的信号强度(Dens-PSL/mm2)利用软件MCID分析(版本7.0,Imaging Research Inc.)量化。在不存在或存在化合物的情况下的[3H]T808结合的特异性结合(SB)通过减去白质中的非特异性结合信号计算,因此产生SB仅[3H]T808和SB化合物。不同化合物的%置换计算如下:
%置换=100-(SB化合物/SB仅[3H]T808)*100。
确认数据
在各个实验中,使用冷T808作为阳性内部对照。预期等摩尔量的热和冷T808的共孵育使特异性结合下降约50%。
参考文献
A.K.Szardenings等‘Imaging agents for detecting neurological disorders(用于检测神经病症的成像剂)’.美国专利申请号US20110182812
W. Zhang等,‘A highly selective and specific PET tracer for imaging oftau pathologies(用于成像tau病理学的高度选择性和特异性PET示踪剂)’.Journal ofAlzheimer’s Disease 31(2012)601-612。
表1
图1和2分别表示与获得自Braak V阶段的AD患者的人皮质脑切片孵育的[[3H]-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺(实施例5)和[3H]-2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺(实施例6)的放射自显影图。放射性配体浓度分别为2.6和2.5nM。两种放射性配体都显示白质中层状分布形式中的tau聚集体的点状染色和不同程度的非特异性结合。
式I的化合物及其药用盐可以以药物制剂的形式使用。所述药物制剂可以以注射液的形式施用。
式I的化合物及其药用盐可以与药用惰性、无机或有机载体一起加工以用于制备药物制剂。适用于制备溶液和糖浆的载体有,例如,水、多元醇、蔗糖、转化糖、葡萄糖等。辅剂,如醇、多元醇、甘油、植物油等,可以用于式I的化合物的水溶性盐的水性注射液,但通常不是必要的。适用于栓剂的载体有,例如,天然的或硬化油、蜡、脂肪、半液体或液体多元醇等。
此外,所述药物制剂可以含有防腐剂、增溶剂、稳定剂、湿润剂、乳化剂、增甜剂、着色剂、调味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。其也可以包含其他有治疗价值的物质。
剂量可以在很大的范围内变化,并且当然将适宜于各个特定情况中的个体需求。
实施例
使用的缩写:
h-小时
min-分钟
实施例1
2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺
将微波小瓶装入吡啶-2,4-二胺(400mg,3.67mmol),2-溴-1-(4-甲氧基苯基)乙酮(882mg,3.85mmol),碳酸氢钠(329mg,3.92mmol)和甲醇(3.5mL)。将反应混合物在回流搅拌4h。将反应混合物冷却至室温,用水和乙酸乙酯稀释,超声处理并在室温搅拌~15min。将悬浮液过滤,用水和乙酸乙酯清洗。将所得的浅黄色固体置于高真空下从而提供2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺氢溴酸盐。将其悬浮在~5mL饱和NaHCO3水溶液中,超声处理,过滤并用水清洗。将剩余物悬浮在~5mL 2M NaOH水溶液中,超声处理,过滤并用水清洗。将所得的剩余物置于高真空下从而提供标题化合物,为浅褐色固体(310mg,1.3mmol,35%产率)。MS m/z:240.1[M+H]+。
实施例2
2-(4-(氟甲氧基)苯基)咪唑并[1,2-a]吡啶-7-胺
a)7-溴-2-(4-(羟基苯基)咪唑并[1,2-a]吡啶
类似于实施例1,将代替吡啶-2,4-二胺的4-溴吡啶-2-胺和代替溴-1-(4-甲氧基苯基)乙酮的2-溴-1-(4-羟基苯基)乙酮转化为标题化合物(2.34g,80%),获得的标题化合物是灰色固体。MS m/z:289.3[M]+。
b)7-溴-2-(4-(氟甲氧基)苯基)咪唑并[1,2-a]吡啶
向4-(7-溴咪唑并[1,2-a]吡啶-2-基)苯酚(2.37g,6.56mmol)和4-甲基苯磺酸氟甲酯(1.34g,6.56mmol)在DMF(10.00mL)中的溶液加入碳酸铯(2.78g,8.52mmol)并加热至70℃达18h然后在100℃在微波中照射30分钟。将其倒入水中并用二氯甲烷萃取两次。将有机层合并,用硫酸钠干燥,过滤并浓缩。向所得的油状物加入甲苯(~200mL)并将溶剂蒸发以除去残留的DMF。加入一些NaOH水溶液1N并继续搅拌15分钟。将其过滤并在高真空中干燥,提供标题化合物(1.69g,纯度~60%),为浅褐色油状物,其在不进行进一步纯化的情况下被使用。MS m/z:321.3[M+H]+。
c)2-(4-(氟甲氧基)苯基)咪唑并[1,2-a]吡啶-7-胺
向7-溴-2-(4-(氟甲氧基)苯基)咪唑并[1,2-a]吡啶(112mg,349μmol)在N-甲基-2-吡咯烷酮(2mL)中的溶液加入氧化铜(I)(9.98mg,69.8μmol)和氢氧化铵(733mg,5.23mmol)。然后将小瓶封闭并将反应混合物在110℃搅拌3h。将其用二氯甲烷(15mL)稀释并用水(15mL)洗涤两次。将水层用二氯甲烷(15mL)萃取。将合并的有机层用硫酸镁干燥,过滤并浓缩。使用二氯甲烷∶二氯甲烷∶甲醇∶氨(90∶9∶1体积%)梯度85∶15至50∶50的急骤色谱法提供标题化合物(17mg,19%产率),为浅褐色固体。MS m/z:258.6[M+H]+。
实施例3
2-[4-(3-氟丙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺
a)4-(7-氨基咪唑并[1,2-a)吡啶-2-基)苯酚氢溴酸盐
在5mL微波小瓶中,将吡啶-2,4-二胺(500mg,4.58mmol)和2-溴-1-(4-羟基苯基)乙酮(1.03g,4.81mmol)与丙酮(8.0mL)合并从而产生灰白色悬浮液。将小瓶用氩气吹洗并密封。将反应混合物在65℃(油浴温度)搅拌过夜。将灰白色悬浮液过滤并用丙酮洗涤。将所得的灰白色固体在高真空下干燥过夜,从而提供标题化合物(363mg,18%产率),为灰白色固体。MS m/z:226.1[M+H]+。
b)2-[4-(3-氟丙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺
在5mL微波小瓶中,将4-(7-氨基咪唑并[1,2-a]吡啶-2-基)苯酚氢溴酸盐(150mg,343μmol)与DMF(2.5mL)合并从而产生无色溶液。加入碳酸铯(335mg,1.03mmol)。将反应混合物在室温搅拌1h(观察到气体逸出;反应混合物变成暗褐色悬浮液)。加入溶解在DMF(0.5mL)中的1-溴-3-氟丙烷(48.4mg,343μmol)。将小瓶用氩气吹洗并密封。将反应混合物在90℃(油浴温度)搅拌过夜。将反应混合物冷却至环境温度并用二氯甲烷和水萃取。将水层(pH~9)用二氯甲烷萃取。将有机层用水洗涤三次并用盐水洗涤一次。将有机层合并,用硫酸镁干燥,过滤并浓缩。将剩余物(褐色油状物)在高真空中干燥4h。将褐色固体与乙酸乙酯一起研磨,从而提供标题化合物(53mg,48%产率),为褐色固体。MS m/z:286.1[M+H]+。
实施例4
2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺
在氮气氛下在0℃向4-(7-氨基咪唑并[1,2-a]吡啶-2-基)苯酚氢溴酸盐(156mg,510μmol)在DMF(2mL)中的溶液加入氢化钠60%(81.5mg,2.04mmol)。在环境温度搅拌30min后,用1min的时间加入1-溴-2-氟乙烷(71.2mg,560μmol)。然后将反应混合物在环境温度搅拌2h。将其倒在水(15mL)上并用乙酸乙酯(15mL)萃取两次。将有机层用水(15mL)和盐水(10mL)洗涤。将合并的有机层用硫酸镁干燥,过滤并浓缩。使用二氯甲烷∶二氯甲烷∶甲醇∶氨(90∶9∶1体积%)梯度80∶20至40∶60的急骤色谱法提供标题化合物(80mg,58%产率),为灰白色固体。MS m/z:272.5[M+H]+。
实施例5
[3H]-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺
在2mL氚化烧瓶中,将2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺(2.0mg,8.4μmol)和Crabtree催化剂(10.1mg,15.5μmol)溶解在二氯甲烷(1.0mL)中。将烧瓶连接至氚支管(RC-TRITEC)并通过冷冻-抽吸-解冻除气。引入氚气,并将浅橙色溶液在氚气氛下在1050毫巴剧烈搅拌4小时。通过液氮将溶液冷却并将反应容器中过量的氚气重新吸收在用于废氚的铀阱(uranium-trap)中。将溶剂冻干除去并通过用乙醇和水的9∶1-混合物(3×1mL)和甲苯(2×1mL)冻干除去不稳定的氚。将剩余的褐色油状物溶解在二氯甲烷(25mL)中并转移到SCX-3阳离子交换柱上。将剩余的催化剂用二氯甲烷(15mL)洗脱并丢弃,将产物用在MeOH中的NH3(1N,25mL)洗脱,分开收集,并在减压下浓缩。将粗产物通过制备型HPLC(XBridgeC-18Prep,5μm,10×250mm)使用乙腈、水和pH 9缓冲液作为洗脱液进行纯化。获得833MBq(22.5mCi)的标题化合物,放射化学纯度为99%而比活为1.02TBq/mmol(27.6Ci/mmol)(由MS光谱测定法测定)。将所述化合物作为乙醇溶液储存。MS m/z:240.2[M+H]+(48%),242.2[M(T)+H]+(10%),244.2[M(T2)+H]+(40%),246.2[M(T3)+H]+(2%)。
实施例6
[3H]-2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺
在2ml氚化烧瓶中,将2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺(2.0mg,7.4μmol)和Crabtree催化剂(5.9mg,7.4μmol)溶解在DMF(1.0mL)中。将烧瓶连接至氚支管(RC-TRITEC)并通过冷冻-抽吸-解冻除气。引入氚气,并将浅橙色溶液在氚气氛下在550毫巴剧烈搅拌4小时。通过液氮将溶液冷却并将反应容器中过量的氚气重新吸收在用于废氚的铀阱中。将溶剂冻干除去并通过用乙醇和水的9∶1-混合物(3×1mL)和甲苯(2×1mL)冻干除去不稳定的氚。将剩余的褐色油状物溶解在二氯甲烷(10mL)中并转移到SCX-3阳离子交换柱上。将剩余的催化剂用MeOH(5mL)洗脱并丢弃,将产物用在MeOH中的NH3(3.5N,5mL)和MeOH(35mL)洗脱,分开收集,并在减压下浓缩。将粗产物通过制备型HPLC(XBridge C-18Prep,5μm,10×250mm)使用乙腈、水和pH 7缓冲液作为洗脱液进行纯化。获得833MBq(22.5mCi)的标题化合物,放射化学纯度为98%而比活为1.58TBq/mmol(42.6Ci/mmol)(由MS光谱测定法测定)。将所述化合物作为甲醇溶液储存。MS m/z:272.2[M+H]+(7%),274.2[M(T)+H]+(39%),276.2[M(T2)+H]+(54%)。
Claims (13)
1.一种式I的化合物
其中
R1是C1-7烷基或被卤素取代的C1-7烷基;
R2、R3是氢或氚;
或药用酸加成盐。
2.根据权利要求1所述的式I的化合物,其中R1是C1-7烷基并且R2和R3如权利要求1中所述。
3.根据权利要求1或2所述的式I的化合物,所述化合物是
2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺
[3H]-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺。
4.根据权利要求1所述的式I的化合物,其中R1是被卤素取代的C1-7烷基并且R2和R3如权利要求1中所述。
5.根据权利要求1或4所述的式I的化合物,所述化合物是
2-(4-(氟甲氧基)苯基)咪唑并[1,2-a]吡啶-7-胺
2-[4-(3-氟丙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺
2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺
[3H]-2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺。
6.根据权利要求1所述的式I的化合物,其中R2和R3是氚并且R1如权利要求1中所述。
7.根据权利要求1或6所述的式I的化合物,所述化合物是
[3H]-2-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-7-胺
[3H]-2-[4-(2-氟乙氧基)苯基]咪唑并[1,2-a]吡啶-7-胺。
8.一种用于制备如权利要求1至5中任一项所限定的式I的化合物的方法,所述方法包括
a)式2的化合物用NH4OH的胺化,式2中的X=Cl、Br,
从而提供式I的化合物
其中R1是如以上所限定的,并且R2和R3是氢,并且,如果需要,将所得的化合物转化为药用酸加成盐,或
b)使式4的化合物
与式3的相应α-活化的酮偶联,式3中的X是离去基团,
从而提供式I的化合物
其中R1是如以上所限定的,并且R2和R3是氢,并且,如果需要,将所得的化合物转化为药用酸加成盐,或
c)使式5的化合物与合适的烷基化剂R1-X反应,其中X是卤素或磺酸根,
从而提供式I的化合物
其中R1是如以上所限定的,并且R2和R3是氢,并且,如果需要,将所得的化合物转化为药用酸加成盐,以及
d)使式I的化合物与氚气在选自含铱、钌、铑或钯的络合物的催化剂存在下,在选自二氯甲烷、氯苯、DMF、DMSO或其混合物的合适溶剂中,在环境或升高的温度反应
其中R2和R3是氢,
从而提供式I的化合物
其中R1是如以上所限定的并且R2和R3是氚,并且,如果需要,将所得的化合物转化为药用酸加成盐。
9.根据权利要求1-7中任一项所述的式I的化合物用于制备药物的用途,所述药物用于结合和成像tau聚集体、β-淀粉状蛋白聚集体或α-突触核蛋白聚集体。
10.根据权利要求1-7中任一项所述的式I的化合物用于制备药物的用途,所述药物用于结合和成像阿尔茨海默病患者中的tau聚集体。
11.根据权利要求1-7中任一项所述的式I的化合物用于制备药物的用途,所述药物用于tau结合研究。
12.根据权利要求1-7中任一项所述的式I的化合物用于制备药物的用途,所述药物用于哺乳动物脑中tau-聚集体的诊断成像。
13.一种药物组合物,所述药物组合物包含根据权利要求1-7中任一项所述的式I的化合物和药用载体。
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