CN100422180C - 淀粉样斑块聚集抑制剂和诊断成像剂 - Google Patents
淀粉样斑块聚集抑制剂和诊断成像剂 Download PDFInfo
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- CN100422180C CN100422180C CNB028086708A CN02808670A CN100422180C CN 100422180 C CN100422180 C CN 100422180C CN B028086708 A CNB028086708 A CN B028086708A CN 02808670 A CN02808670 A CN 02808670A CN 100422180 C CN100422180 C CN 100422180C
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- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
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Abstract
本发明涉及一种淀粉样沉积物的成像方法和标记化合物,和用于淀粉样沉积物成像的标记化合物的制备方法。本发明还涉及化合物,用于抑制淀粉样蛋白聚集形成淀粉样沉积物的化合物的制备方法,和将治疗剂递送至淀粉样沉积物的方法。
Description
关于联邦赞助的研究和开发的声明
在本发明的开发过程中完成的部分工作利用美国政府基金。根据衰老研究所授予的许可号NS-18509和PO1 AG-11542,美国政府对本发明拥有一定的权利。
发明背景
发明领域
本发明涉及新的生物活性化合物,使用放射标记化合物的诊断成像方法,和放射标记化合物的制备方法。
背景技术
阿耳茨海默氏病(AD)是一种渐进性神经变性疾病,其特征在于认知衰退、不可逆的记忆丧失、定向障碍和语言障碍。AD脑部切片尸检揭示由淀粉样-β(Aβ)肽和多种由高度磷酸化的tau蛋白的纤丝形成的神经原纤维缠结(NFTs)组成的大量的老年斑(SPs)(关于最近的评论和附加的引述参见Ginsberg,S.D.等人,″Molecular Pathology ofAlzheimer’s Disease and Related Disorders,″in CerebralCortex:Neurodegenerative and Age-related Changes inStructure and Function of Cerebral Cortex,KluwerAcademic/Plenum,NY(1999),pp.603-654;Vogelsberg-Ragaglia,V.等人,″Cell Biology of Tau and Cytoskeletal Pathology inAlzheimer’s Disease,″Alzheimer’s Disease,Lippincot,Williams & Wilkins,Philadelphia,PA(1999),pp.359-372)。家族AD(FAD)是由A前体蛋白(APP)、早老素(presenilin)1(PS 1)和早老素2(PS2)基因的多重突变导致的(Ginsberg,S.D.等人,″Molecular Pathology of Alzheimer’s Disease and RelatedDisorders,″in Cerebral Cortex:Neurodegenerative andAge-related Changes in Structure and Function of CerebralCortex,Kluwer Academic/Plenum,NY(1999),pp.603-654;Vogelsberg-Ragaglia,V.等人,″Cell Biology of Tau andCytoskeletal Pathology in Alzheimer’s Disease,″Alzheimer’sDisease,Lippincot,Williams & Wilkins,Philadelphia,PA(1999),pp.359-372)。
虽然未完全了解确切的AD基本机理,但是所有的研究的致病FAD突变因此大大增加更多淀粉样基因长度为42-43个氨基酸形式的Aβ肽的产生。因此至少在FAD中,Aβ产生的失调似乎足以引起级联事件,导致神经变性。实际上,淀粉样级联假说认为脑部细胞外纤维Aβ聚集物的形成可能是AD发病机理中的关键事件(Selkoe,D.J.,″Biologyof B-amyloid Precursor Protein and the Mechanism ofAlzheimer’s disease,”Alzheimer’s Disease,Lippincot Williams& Wilkins,Philadelphia,PA(1999),pp.293-310;Selkoe,D.J.,J.Am.Med.Assoc.283:1615-1617(2000);Naslund,J.等人,J.Am.Med.Assoc.283:1571-1577(2000);Golde,T.E.等人,Biochimica et Biophysica Acta 1502:172-187(2000))。
目前认为多种尝试抑制产生和减少纤维状Aβ在脑部的蓄积的方法是AD的可能疗法(Skovronsky,D.M.和Lee,V.M.,TrendsPharmacol.Sci.21:161-163(2000);Vassar,R.等人,Science 286:735-741(1999);Wolfe,M.S.等人,J.Med.Chem.41:6-9(1998);Moore,C.L.等人,J.Med.Chem.43:3434-3442(2000);Findeis,M.A.,Biochinaica et Biophysica Acta 1502:76-84(2000);Kuner,P.,Bohrmann等人,J.Biol.Chem.275:1673-1678(2000)。因此研制特异性地结合纤维状Aβ聚集物的配基是非常有用的。由于细胞外SPs是可接触的靶体,这些新的配基可以用作体内诊断工具和探针,以在活患者的AD淀粉样产生的研究中显现Aβ的渐进性沉积。
为此目的,已报道了许多用于研制纤维状Aβ聚集物特异性配基的有用方法(Ashburn,T.T.等人,Chem.Biol.3:351-358(1996);Han,G.等人,J.Am.Chem.Soc.118:4506-4507(1996);Klunk,W.E.等人,Biol.Psychiatry 35:627(1994);Klunk,W.E.等人,Neurobiol.Aging 16:541-548(1995);Klunk,W.E.等人,Societyfor Neuroscience Abstract 23:1638(1997);Mathis,C.A.等人,Proc.Xllth Intl.Symp.Radiopharm.Chem.,Uppsala,Sweden:94-95(1997);Lorenzo,A.and Yankner,B.A.,Proc.Natl.Acad.Sci.U.S.A.91:12243-12247(1994);Zhen,W.等人,J.Med.Chem.42:2805-2815(1999))。最吸引人的方法基于高度共轭的柯胺-G(CG)和刚果红(CR),而后者已用于死后AD脑部切片的SPs和NFTs的荧光染色(Ashburn,T.T.等人,Chem.Biol.3:351-358(1996);Klunk,W.E.等人,J.Histochem.Cytochem.37:1273-1281(1989))。关于与CR、CG的纤维状Aβ聚集物和CG的3’-溴代和3’-碘代衍生物结合的抑制常数(Ki)分别为2,800、370,300和250nM(Mathis,C.A.等人,Proc.XIIth Intl.Symp.Radiopharm.Chem.,Uppsala,Sweden:94-95(1997))。这些化合物已表现出在体外与Aβ(1-40)肽聚集物和AD脑部的纤维状Aβ沉积物选择性结合(Mathis,C.A.等人,Proc.XIIth Intl.Symp.Radiopharm.Chem.,Uppsala,Sweden:94-95(1997))。
淀粉样变是一种病症,其特征在于许多不溶的纤维蛋白聚集在患者的组织中。淀粉样蛋白的聚集形成淀粉样沉积物,然后进一步与聚集物和/或淀粉样蛋白结合。
除了淀粉样沉积物在阿耳茨海默氏病中的作用以外,已表明在诸如以下的疾病中存在淀粉样沉积物:地中海热、默-韦综合征、自发性骨髓瘤、淀粉样多发性神经病、淀粉样心肌病、系统性老年性淀粉样变、淀粉样多发性神经病、具有淀粉样变的遗传性脑出血、唐氏综合征、瘙痒病、克罗伊茨费尔特-雅各布症、库鲁病、格-施-沙综合征、甲状腺髓样癌、孤立的围鳃淀粉样、渗析患者的β2-微球蛋白淀粉样、包涵体肌炎、肌肉消瘦症中的β2-淀粉样沉积物和郎格罕氏II型糖尿病胰岛瘤的胰岛。
因此,渴望寻找一种对患者的淀粉样沉积物的进行检测和定量的简单、非侵袭性方法。目前,淀粉样沉积物的检测包括活组织检查和尸体解剖材料的组织学分析。两种方法都有缺点。例如,尸体解剖仅可用于死后诊断。
淀粉样沉积物的直接体内成像是困难的,因为这些沉积物具有许多与正常组织相同的物理性能(例如密度和含水量)。使用磁共振成像(MRI)和计算辅助X线断层照相术(CAT)的尝试是令人失望的,且它们仅在某些有利的条件下检测淀粉样沉积物。此外,用抗体标记淀粉样沉积物、血清淀粉样P蛋白或其它探针分子的努力已提供某些对外周组织的选择性,但其提供的组织内部成像不良。
用于检测活脑中Aβ聚集物的可能配基必须穿过完整的血-脑屏障。因此使用具有相对较小的分子大小(与刚果红相比)和较高亲油性的配基可以改善脑摄入。高度共轭的thioflavins(S和T)通常用作AD脑中Aβ聚集物染色的染料(Elhaddaoui,A.等人,Biospectroscopy 1:351-356(1995))。这些化合物基于苯并噻唑,其具有相对较小的分子大小。但是,硫代黄素(thioflavins)包含离子型季铵,永久地带电并不利于脑摄入。
因此,拥有一种用于对患者的淀粉样沉积物进行成像和定量的非侵袭性方法是有用的。另外,拥有抑制淀粉样蛋白聚集形成淀粉样沉积物的化合物和用于测定化合物抑制淀粉样蛋白聚集的方法将是有用的。
发明概述
本发明提供可以优先与淀粉样聚集物结合的式I、II、III或III’的化合物。
本发明还提供含有式I、II、III或III’的放射标记化合物和药学上可接受的载体或稀释剂的诊断组合物。
本发明还提供一种淀粉样沉积物的成像方法,该方法包括给患者引入一种检测量的式I、II、III或III’的标记化合物或其药学上可接受的盐、酯、酰胺或前药。
本发明还提供一种用于抑制淀粉样蛋白聚集的方法,该方法包括给哺乳动物施用淀粉样抑制量的式I、II、III或III’的化合物或其药学上可接受的盐、酯、酰胺或前药。
本发明另一方面涉及用于合成本文所述的式I、II、III或III’的淀粉样抑制和成像化合物的方法和中间产物
附图的简要说明
图1A和图1B描述本发明的代表性化合物以及这些化合物的结合数据。
发明详述
本发明的第一方面涉及下式I的化合物或其药学上可接受的盐,
其中:
Y为CH、NR5、O、S或CH=N,其中R5为氢或C1-4烷基;
m和n均为零,或者m和n均为1;
R3为CH3、Br、I、F、125I、131I、123I、18F、76Br、77Br或Sn(烷基)3;
R1和R2独立地为氢、C1-4烷基、C2-4氨基烷基、C1-4卤代烷基、卤代芳基烷基、-L-Ch,或者R1和R2与它们结合的氮-起形成在环上任选具有O、S或NR6的5至7元杂环,其中
R6为氢或C1-4烷基;和R4为C1-4烷基;和
L为共价键或连接基团,如-(CH2)n-或-(CH2)n-C(O),其中n为1-5;和
Ch为能与金属络合的四配位配基,如选自以下的配基:
其中R9为氢或硫保护基,如甲氧基甲基,甲氧基乙氧基甲基,p-甲氧基苄基或苄基,而其它可变基团为本文所述的优选基团。
在此实施方案中,如本文所述,具有Ch配基,如式VIII、IX、X和XI的化合物与99m-高锝酸盐(pertechnetate)络合形成金属螯合物,其中Ch选自:
此外,铼放射性同位素可以与Ch配基络合。
本发明范围内的一组优选的化合物包括式I的化合物,其中Y选自NR5、O或S。特别优选的式I的化合物包括其中的Y为NR5或S,最优选Y为S的化合物。
其中的Y为NR5的式I的化合物中优选的R5为氢和C1-4烷基,更优选R5为氢或甲基,最优选R5为氢。
式I的化合物中优选的m和n的值为0-1,更优选0。
适宜的R3为Br、I、F、125I、131I、123I、18F、76Br、或77Br。
特别有用的R3为125I、131I、123I、18F、76Br或77Br,更优选123I、131I、76Br或77Br,最优选123I。优选的实施方案还包括用于制备其中的R3为Sn(烷基)3的式I的化合物的中间产物。
优选的化合物为如下的所述式I的化合物,其中R1和R2独立地为氢、C1-4烷基、C1-4卤代烷基、卤代苯基(C1-4)烷基中的一个基团,或者与它们结合的氮一起形成在环上任选具有O或NR6的5-至7-元杂环,其中R6为氢或C1-4烷基。有用的R1和R2独立地包括氢、甲基、乙基、丙基、异丙基、丁基、叔丁基、异丁基、3-氟丙基、4-氟丁基或4-氟苄基,或者R1和R2与它们结合的氮一起形成在环上具有NR6的哌啶基环,其中R6为氢或甲基。
本发明还涉及式II的化合物或其药学上可接受的盐,
其中:
Y为O或NR4其中R4为氢或C1-4烷基;
R3为Br、I、F、125I、131I、123I、18F、76Br、77Br或Sn(烷基)3;
R1和R2独立地为氢、C1-4烷基、C2-4氨基烷基、C1-4卤代烷基、卤代芳基烷基,或者R1和R2与它们结合的氮一起形成在环上任选具有O,S或NR5的5至7元杂环,其中R5为氢或C1-4烷基。
一组优选的化合物包括式II的化合物,其中Y为NR4,其中R4为氢或甲基。更优选的化合物包括其中的Y为O的化合物。
有用的R3为Br、I、F、125I、131I、123I、18F、76Br或77Br。特别适宜的R3为125I,131I,123I,18F,76Br,或77Br,更优选123I、131I、76Br或77Br,最优选123I。优选的实施方案还包括用于制备其中R3为Sn(烷基)3的式II化合物的中间产物。
优选的化合物为如下所述的式II的化合物,其中R1和R2独立地为氢、C1-4烷基、C1-4卤代烷基、卤代苯基(C1-4)烷基之一,或者与它们结合的氮一起形成在环上任选具有O或NR6的5-至7-元杂环,其中R6为氢或C1-4烷基。有用的R1和R2独立地包括氢、甲基、乙基、丙基、丁基、叔丁基、异丁基、3-氟丙基、4-氟丁基或4-氟苄基,或者R1和R2与它们结合的氮一起形成在环上具有NR6的哌啶基环,其中R6为氢或甲基。
本发明还涉及式III的化合物或其药学上可接受的盐,
其中:
R3为Br、I、F、125I、131I、123I、18F、76Br、77Br或Sn(烷基)3;
R1和R2独立地为氢、C1-4烷基、C2-4氨基烷基、C1-4卤代烷基、卤代芳基烷基、-L-Ch,或者R1和R2与它们结合的氮一起形成在环上任选具有O,S或NR5的5至7元杂环,其中R5为氢或C1-4烷基。
有用的R3为Br、I、F、125I、131I、123I、18F、76Br或77Br。特别适宜的R3为125I、131I、123I、18F、76Br或77Br,更优选123I、131I、76Br或77Br,最优选123I或125I。优选的实施方案还包括用于制备式III的化合物的中间产物,其中R3为Sn(烷基)3。
优选的化合物为如下所述的式III的化合物,其中R1和R2独立地为氢、C1-4烷基、C1-4卤代烷基、卤代苯基(C1-4)烷基之一,或者与它们结合的氮一起形成在环上任选具有O或NR6的5-至7-元杂环,其中R6为氢或C1-4烷基。有用的R1和R2独立地包括氢、甲基、乙基、丙基、丁基、叔丁基、异丁基、3-氟丙基、4-氟丁基或4-氟苄基,或者R1和R2与它们结合的氮一起形成在环上具有NR6的哌啶基环,其中R6为氢或甲基。最优选R1和R2为甲基。
另一组优选的化合物为式I、II、或III的化合物,其中R1为-L-Ch,R2为氢或甲基,而R3为I或甲基。优选的Ch为式IV。优选的L为-(CH2)n-,其中n为1、2或3。
在一个单独的实施方案中,式III的化合物具有上述的R1和R2基团,而R3为-L-Ch,其中L和Ch如以上定义。
在另一个实施方案中,本发明涉及式III’的化合物或其药学上可接受的盐,
其中:
A、B和D为CH或N,附带条件是A、B和D中不超过两个为N;
R3为Br、I、F、125I、131I、123I、18F、76Br、77Br、卤代烷基、Sn(烷基)3或-L-Ch;
R1和R2独立地为氢、C1-4烷基、C2-4氨基烷基、C1-4卤代烷基、卤代芳基烷基、-L-Ch,或者R1和R2与它们结合的氮一起形成在环上任选具有O、S或NR5的5至7元杂环,其中R5为氢或C1-4烷基;
L为共价键或连接基团,如-(CH2)n-或-(CH2)n-C(O),其中n为0-5;和
Ch为能够与金属络合的四配位配基;
附带条件是R1、R2和R3中仅有一个可以为-L-Ch。
有用的R3为Br、I、F、125I、131I、123I、18F、76Br、77Br或18F/氟代(C1-5)烷基。特别适宜的R3为18F/氟甲基、18F/氟乙基、18F/氟丙基、18F/氟丁基或18F/氟戊基。优选的实施方案还包括用于制备式III’的化合物的中间产物,其中R3为Sn(烷基)3。
在一组优选的化合物中,A和B为CH,而D为N。在另一组优选的化合物中,A和D为CH,而B为N。在另一组优选的化合物中,B和D为CH,而A为N。
优选的化合物为如下所述的式III’的化合物,其中R1和R2独立地为氢,C1-4烷基、C1-4卤代烷基、卤代苯基(C1-4)烷基之一,或者与它们结合的氮一起形成在环上任选具有O或NR6的5-至7-元杂环,其中R6为氢或C1-4烷基。有用的R1和R2独立地包括氢、甲基、乙基、丙基、丁基、叔丁基、异丁基、3-氟丙基、4-氟丁基或4-氟苄基,或者R1和R2与它们结合的氮一起形成在环上具有NR6的哌啶基环,其中R6为氢或甲基。最优选R1和R2为甲基。
另一组优选的化合物为式I、II、III或III’的化合物,其中R1为-L-Ch,R2为氢或甲基,而R3为I或甲基。优选的Ch为式IV。优选的L为-(CH2)n-,其中n为1、2或3。
在一个单独的实施方案中,式III’的化合物具有以上定义的R1和R2基团,而R3为-L-Ch,其中L为共价键或连接基团,如-(CH2)n-或-(CH2)n-C(O)-,其中n为0-5,而Ch为能与以上定义的金属络合的四配位配基。最优选L为-(CH2)n-,其中n为0,Ch为式XI,而R1和R2独立地为氢或C1-4烷基。在此实施方案中,最优选R1和R2均为甲基。
也可以理解本发明考虑包括立体异构体和光学异构体,如对映异构体的混合物和单独的对映异构体和非对映异构体,它们是在所选择的本发明化合物种类中的结构不对称的结果。
式I、II、III或III’的化合物还可以被溶剂化,特别是水合。水合可以在化合物或含有此化合物的组合物的制备过程中发生,或者水合可以由于化合物的吸湿性而随着时间发生。此外,本发明的化合物可以非溶剂化或含有药学上可接受的溶剂如水、乙醇等的溶剂化形式存在。一般地,认为溶剂化形式等同于用于本发明的目的的非溶剂化形式。
当任何组分或式I、II、III或III’发生多于一次的任何变化时,其每种情况下的定义独立于其在每一个其它情况下的定义。取代和/或变化的组合物也是允许的,条件仅仅是这些组合物产生稳定化合物。
本发明的另一方面涉及式I、II、III或III’的化合物的制备方法。第一种方法的特征是通过以下方法形成其中的Y为S的式I的苯并噻唑:使2-氨基苯硫酚与:a)4-氨基苯甲醛在DMSO中在100℃-220℃的温度范围内反应,并收集该苯并噻唑;或者b)4-卤代苯甲酸衍生物在溶剂中在多磷酸存在下反应,并收集反应产物,然后使该反应产物与胺反应形成该苯并噻唑,并收集该苯并噻唑;并任选使其中的Y为S的式I的苯并噻唑与(烷基)3Sn在溶剂中和在氧化钯II存在下反应形成三烷基甲锡烷基苯并噻唑,并收集此反应产物;和任选使其中的Y为S的式I的三烷基甲锡烷基苯并噻唑与:a)碘在室温下及在溶剂中反应,并萃取产物;或者b)与NaI或Na[125I]I在过氧化氢存在下反应,并萃取产物。
第二种方法的特征是通过以下方法形成其中的Y为O的式I的苯并噁唑:使2-氨基-5-硝基苯酚与4-氨基苯甲酸反应形成硝基取代的苯并噁唑中间产物,并收集该中间产物;然后将该硝基催化氢化成氨基,并收集此反应物;使该产物与NaNO2在H+和卤化钾存在下反应产生式I的苯并噁唑,其中Y为O;并任选使其中的Y为O的式I的苯并噁唑与(烷基)3Sn在溶剂中在氧化钯II存在下反应形成三烷基甲锡烷基苯并噁唑,收集此反应产物;并任选使其中的Y为O的三烷基甲锡烷基苯并噁唑与:a)碘在溶剂中在室温下反应,并萃取产物;或者b)NaI或Na[125I]I在过氧化氢存在下反应,并萃取产物。
第三种方法的特征是通过以下方法形成其中的Y为N的式I的苯并咪唑:使4-溴-1,2-二氨基苯与:a)4-氨基苯甲醛反应形成其中的Y为N的式I的苯并咪唑,并收集产物,或者b)4-卤代苯甲醛反应形成中间产物苯并咪唑,并使该中间产物与一烷基胺、二烷基胺或杂环胺在氧化钯II存在下反应形成其中的Y为N的式I的苯并咪唑,并收集产物;和任选使其中的Y为N的式I的苯并咪唑与(烷基)3Sn在溶剂中在氧化钯II存在下反应形成三烷基甲锡烷基苯并咪唑,并收集此反应产物;并任选使其中的Y为N的式I的三烷基甲锡烷基苯并咪唑与:a)碘在溶剂中在室温下反应,并萃取产物;或者b)NaI或Na[125I]I在过氧化氢存在下反应,并萃取产物。
第四种方法的特征是形成其中的R1或R2为-L-Ch的式I的化合物。在其中的R1或R2为-L-Ch的实施方案中,基团R9均为氢,或者可以是任何可获得的硫保护基团种类,包括甲氧基甲基、甲氧基乙氧基甲基、对-甲氧基苄基或苄基。在以下文献中详述了硫保护基团:Greene,T.W.and Wuts,P.G.M.,Protective Groups in Organic Synthesis,2nd Edition,John Wiley和Sons,Inc.,New York(1991)。保护基R9可以通过有机合成技术中已知的适宜的方法除去,如使用三氟乙酸、氯化汞或在液体氨中的钠。在路易斯酸不稳定基团,包括乙酰氨基甲基和苯甲酰氨基甲基的情况下,R9可以保持完整。在此情况下用锝标记配基将裂解保护基,使保护的双胺二硫醇(diaminedithiol)等同于未受保护的形式。
Tc-99m络合物可以如下制备。将少量非放射标记化合物(1-2mg)溶于100μl EtOH,并与200μL HCl(1N)和1mL Sn-葡庚糖酸盐溶液(含有8-32μg SnCl2和80-320μg Na-葡庚糖酸盐,pH 6.67)和50μLEDTA溶液(0.1N)混合。然后加入[99mTc]高锝酸盐(100-200μL;范围为2-20mCi)盐水溶液。将反应物于100℃下加热30分钟,然后冷却至室温。用TLC(EtOH∶浓NH3 9∶1)分析反应产物,以对产物的形成及纯度进行检查。可以用磷酸盐缓冲液将混合物中和至pH 5.0。
本发明还涉及一种通过以下步骤制备本发明的锝-99m络合物的方法:使高锝酸盐形式的锝-99m在还原剂存在下、并任选有适宜的螯合剂存在下与适宜的含Ch化合物反应。
还原剂用于还原从生理盐水溶液中的钼-锝发生器洗脱的Tc-99m高锝酸盐。例如,适宜的还原剂为连二亚硫酸盐,甲脒亚磺酸,二氨基乙烷二亚磺酸盐(disulphinate)或适宜的金属还原剂如Sn(II)、Fe(II)、Cu(I)、Ti(III)或Sb(III)。已证明Sn(II)特别适宜。
关于上述络合物形成反应,将锝-99m与作为盐或与较弱螯合剂结合的锝形式的适宜的本发明的化合物反应。在后一种情况下,通过配基交换形成所需的锝-99m络合物。适宜的放射性核的螯合剂的实例为二羧酸,如草酸、丙二酸、琥珀酸、马来酸、邻苯二甲酸、苹果酸、乳酸、酒石酸、柠檬酸、抗坏血酸、水杨酸或这些酸的衍生物;磷化合物如焦磷酸酸盐;或烯醇化物。柠檬酸、酒石酸、抗坏血酸、葡庚糖酸或其衍生物是用于此目的的特别适宜的螯合剂,因为锝-99m与这些螯合剂中的一种的螯合物特别容易经历所需的配基交换。
用于制备[TcVO]+3N2S2络合物的最为常用的方法基于最常用的原料[99mTc]高锝酸盐的氯化亚锡(II)还原。标记方法一般取决于Tc-99m(Sn)-葡庚糖酸盐和N2S2配基之间的Tc-99m配基交换反应。制备氯化亚锡(II)并将其保存在一致的亚锡(II)形态对于标记反应的成功特别重要。
为了稳定对空气敏感的亚锡离子,在核医学的通常实务中使用冻干试剂盒,其中亚锡离子为在惰性气体如氮或氩下的与过量葡庚糖酸盐混合的冻干粉形式。冻干氯化亚锡制剂/葡庚糖酸钠试剂盒确保标记反应是可重复的和可预测的。N2S2配基通常是对空气敏感的(硫醇容易被空气氧化),随后的反应导致配基分解。用于保持配基的最方便和可预测的方法是在氩或氮气氛下生产含有100-500μg配基的冻干试剂盒。
第五种方法的特征是通过以下方法形成其中的Y为O的式II的异噁唑:使3-卤代-2-羟基苯甲醛与取代的苄胺如4-(卤代甲基)-苄胺反应形成苯氧基苄基醚中间产物,并收集中间产物,然后使该中间产物在溶剂中在NaOMe或NaOEt存在下反应形成其中的Y为O的式II的异噁唑,并收集产物,并任选在溶剂中在氧化钯II存在下使其中的Y为O的式I的异噁唑与(烷基)3Sn反应形成其中的Y为O的式I的三烷基甲锡烷基异噁唑,并收集此反应产物;任选使其中的Y为O的式I的三烷基甲锡烷基异噁唑与:a)与碘在溶剂中在室温下反应,并萃取产物;或者b)NaI或Na[125I]I在过氧化氢存在下反应,并萃取产物。
第六种方法的特征是通过以下方法形成其中的Y为NR4的式II的吲哚:使2-硝基-4-溴甲苯与N-异丙基-2,2’-亚氨基二乙醇反应形成N,N-二甲基-苯乙烯基-2-硝基-4-溴苯中间产物,然后使该中间产物与酰氯在三乙基胺存在下反应产生α,β-不饱和酮,通过在二噁烷/水中加热使其发生分子内成环,然后使其与连二亚硫酸钠反应形成其中的Y为NR4的式II的吲哚,并收集产物;任选使该吲哚与碘甲烷在氢化钠存在下反应产生式II的吲哚,其中Y为NR4,其中R4为甲基,并收集产物;任选使其中的Y为NR4的式II的吲哚与(烷基)3Sn在溶剂中在氧化钯II存在下反应形成其中的Y为NR4的式II的三烷基甲锡烷基吲哚,并收集此反应产物;任选使其中的Y为NR4的式II的三烷基甲锡烷基吲哚与:a)碘在溶剂中在室温下反应,并萃取产物;或者b)NaI或Na[125I]I在过氧化氢存在下反应,并萃取产物。
第七种方法的特征是通过以下方法形成式III的咪唑并[1,2a]吡啶:使2-氨基-5-溴-吡啶与:a)4’-卤代-1-卤代-二苯甲酮在溶剂中在碳酸氢钠存在下反应形成中间产物咪唑并[1,2a]吡啶,并收集反应产物;然后使该中间产物与一烷基胺、二烷基胺或杂环胺在氧化钯II存在下反应形成式III的咪唑并[1,2a]吡啶,或者b)4’-氨基-1-卤代-苯乙酮在溶剂中在碳酸氢钠存在下反应形成式III的咪唑并[1,2a]吡啶,并收集反应产物;任选使式III的咪唑并[1,2a]吡啶与(烷基)3Sn在溶剂中在氧化钯II存在下反应形成式III的三烷基甲锡烷基咪唑并[1,2a]吡啶,并收集此反应产物;任选使式III的三烷基甲锡烷基咪唑并[1,2a]吡啶与:a)碘在溶剂中在室温下反应,并萃取产物;或者b)NaI或Na[125I]I在过氧化氢存在下反应,并萃取产物。
在本文中作为本身或另一基团的部分使用的术语“烷基”指至多8个碳、优选6个碳、更优选4个碳的直链和支链基团,如甲基、乙基、丙基、异丙基、丁基、叔丁基和异丁基。
本文所用的术语“烷氧基”意指与一个氧原子结合的以上定义的直链或支链烷基,链长度受其限制,包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基等等。优选的烷氧基链长度为1-6个碳原子,更优选长度为1-4个碳原子。
在本文中作为本身或另一基团的部分使用的术语“一烷基胺”指被一个以上定义的烷基取代的氨基。
在本文中作为本身或另一基团的部分使用的术语“二烷基胺”指被两个以上定义的烷基取代的氨基。
在本文中作为本身或另一基团的部分使用的术语“卤”指氯、溴、氟或碘。
在本文中作为本身或另一基团的部分使用的术语“芳基”指在环部分含有6-12个碳、优选在环部分含有6-10个碳的单环或双环芳香基团,例如苯基、萘基或四氢萘基。
本文所用的术语“杂环(heterocycle)”或“杂环(heterocyclicring)”除了其中指明以外,代表可以是饱和或不饱和的稳定的5-至7-元单环系统,且它由碳原子和1-3个选自以下的杂原子组成:N、O和S,且其中该氮和硫杂原子可以任选被氧化。特别有用的是含有一个与一个氧或硫结合的氮或者两个氮杂原子的环。这些杂环基团的实例包括哌啶基、吡咯基、吡咯烷基、咪唑基、咪唑啉基、咪唑烷基、吡啶基、吡嗪基、嘧啶基、噁唑基、噁唑烷基、异噁唑基、异噁唑烷基、噻唑基、噻唑烷基、异噻唑基、高哌啶基、高哌嗪基、哒嗪基、吡唑基和吡唑烷基,最优选硫杂吗啉基、哌嗪基和吗啉基。
本文所用的术语“杂原子”意指氧原子(″O″)、硫原子(″S″)或氮原子(″N″)。可以认识到当杂原子为氮时,它可以形成NRaRb部分,其中Ra和Rb彼此独立地为氢或C1-4烷基、C2-4氨基烷基、C1-4卤代烷基、卤代苄基,或者R1和R2一起形成任选在环上具有O、S或NRc的5至7元杂环,其中Rc为氢或C1-4烷基。
本发明还涉及以上式I、II、III或III’的化合物的制备方法。本发明的化合物可以通过路线1-13所述的反应制备。
路线1和2描述形成式I的苯并噻唑的合成途径。将5-溴-2-氨基-苯硫醇(Mital,R.L.和Jain,S.K.,J.Chem.Soc.(C):2148(1969);Lin,A.-J.和Kasina,S.,J Heterocycl Chem.18:759(1981))和4-二甲基氨基苯甲醛或4-(4-甲基哌嗪-1-基)苯甲醛(Tanaka,A.等人,J.Med.Chem.41:2390(1998))在DMSO中加热产生苯并噻唑1和4。使用相同的Pd(O)-催化的Br进行三丁基锡交换反应,将这两种溴衍生物成功地转化为对应的三丁基锡衍生物2和5。它们成功地用于碘代去甲锡烷基反应以产生对应的碘化化合物3和6(产率为25-35%;反应未被最优化)。因此,三丁基锡衍生物用于两个有用的目的:i)它们用作将溴转化为碘衍生物的中间产物;ii)它们还用作制备放射性碘化“热”配基的原料。
路线1
路线2
路线3描述一种合成途径,其中制备N-一甲基化胺,然后将其用于平行合成二取代的氨基苯基苯并噻唑衍生物。
路线3
路线4至6描述形成本发明苯并噁唑的合成途径。
路线4
路线5
路线6
路线7、8、9描述用于制备本发明吲哚衍生物和苯并咪唑衍生物的合成途径。
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路线10描述用于形成本发明的苯并呋喃衍生物的合成途径。可选择地,可以通过分子Wittig途径制备苯并呋喃(Twyman等人,Tetrahedron Lett 40:9383(1999)),如在路线11中所述。
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路线12提供用于平行合成本发明的苯并呋喃的合成途径。
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路线13至17涉及本发明的咪唑并[1,2,a]吡啶衍生物。
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路线18和19描述用于形成本发明的苯并嘧啶的合成途径。
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路线20描述本发明的金属螯合络合物的合成,其中R9如上定义,并且Ar为选自包含以下的双环系统:苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并呋喃基、咪唑并[1,2a]吡啶基和苯并嘧啶基。
路线20
路线21至23涉及式III’的咪唑并[1,2a][1,3]二氮杂衍生物。
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当本发明的化合物用作成像试剂时,它们必须用适宜的放射性卤素同位素标记。虽然125I-同位素用于试验室试验,它们一般不用于实际诊断目的,因为它们具有较长的半衰期(60天)和低125Iγ-发射(30-65Kev)。同位素123I的半衰期为13小时,而γ能量为159KeV,因此预计用于诊断目的的配基标记将用此同位素。
其它可以使用的同位素包括131I(半衰期为2小时)。适宜的溴同位素包括77Br和76Br。
本发明的放射卤化化合物本身容易地由以试剂盒提供给使用者的物质形成。例如,用于形成成像试剂的试剂盒可以包括一个含有生理学上适宜具有一定浓度并处在适于最优化络合反应的pH下的式I、II或III的中间产物的溶液的小瓶。使用者可以往小瓶中加入适量的放射性同位素,例如Na123I和氧化剂如过氧化氢。然后可以将所得的标记配基静脉内施用于患者,并通过测定γ射线或其光电发射而将脑内受体成像。
由于本发明的放射性药物组合物可以容易而简单地制备,可以由使用者容易地完成制备。因此,本发明还涉及一种试剂盒,所述试剂盒包含:
(1)一种本发明的非放射标记化合物,该化合物任选处在干燥条件下;还任选具有加到其中的惰性、药学上可接受的载体和/或助剂;和
(2)一种还原剂和任选的螯合剂;其中成分(1)和(2)可任选组合;且其中可以任选包含指示通过成分(1)和(2)与高锝酸盐溶液形式的锝-99m反应而完成上述方法的使用者说明。
用于以上试剂盒的适宜的还原剂和螯合剂的实例已如上述。使用者可以由钼-锝发生器获得高锝酸盐溶液。这些发生器在许多进行放射诊断方法的机构中可以得到。如上述,成分(1)和(2)可以组合,条件它们是相容的。其中的组合成分优选冻干的单一成分试剂盒非常适于被使用者用于以简单的方式与高锝酸盐溶液反应。
如果需要的话,该放射性诊断试剂可以包含任何添加剂如pH控制剂(如酸、碱、缓冲剂)、稳定剂(如抗坏血酸)或离子化试剂(如氯化钠)。
本文所用的术语“药学上可接受的盐”指如下的本发明的化合物的羧酸盐或酸加成盐:它们在合理的药学评价的范围之内,适于与患者的组织接触使用而没有不适当的毒性、放射性、变态反应等,合理的优点/风险率相当,和有效地用于目标应用;如果可能的话,它们也可以指本发明化合物的两性离子形式。术语“盐”指具有较小毒性的本发明化合物的无机和有机酸加成盐。还包括由无毒有机酸如脂肪一和二羧酸,例如乙酸、苯基取代的链烷酸、羟基链烷酸和链烷二羧酸、芳香酸和脂肪与芳香磺酸衍生的盐。这些盐可以在化合物的最终的分离和纯化期间现场制备,或者通过单独使游离碱形式的纯化化合物与适宜的有机或无机酸反应并分离如此形成的盐而现场制备。其它代表性的盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘酸盐、甲磺酸盐、葡庚糖酸盐、乳酸生物酸盐和月桂基磺酸盐、丙酸盐、新戊酸盐、环己氨磺酸盐、羟乙磺酸盐等。这些盐可以包括基于碱或碱土金属的阳离子如钠、锂、钾、钙、镁等,和无毒铵、季铵和胺阳离子,包括但不限于铵、四甲基铵、四乙基铵、甲基胺、二甲基胺、三甲基胺、三乙基胺、乙基胺等(例如参见Berge S.M.等人,Pharmaceutical Salts,J.Pharm.Sci.66:1-19(1977),本文引用作为参考)。
在发明成像方法的第一步,将式I、II、III或III’的标记化合物以可检测量引入组织或患者。该化合物一般为药物组合物的部分,并通过本领域中已知的方法将它施用于组织或患者。
例如,该化合物可以进行口、直肠、肠胃外(静脉内、通过肌内或皮下)、脑池内、阴道内、腹膜内、膀胱内、局部(散剂、膏剂或滴剂)或者作为口或鼻喷雾剂给药。
在本发明的一个优选的实施方案中,将可检测量的标记化合物引入患者,在充足的时间之后该化合物与淀粉样沉积物发生结合,非侵袭性地检测患者内的标记化合物。在本发明的另一实施方案中,将式I、II、III或III’的标记化合物引入患者,并使该化合物在充足的时间内与淀粉样沉积物发生结合,然后移出患者的组织样品,并在患者体外检测组织中的标记化合物。在本发明的第三个实施方案中,从患者身上取出组织样品,并将式I、II、III或III’的标记化合物引入该组织样品。在使该化合物在充足的时间内与淀粉样沉积物发生结合之后,检测该化合物。
可以通过常规或局部给药途径给患者施用标记化合物。例如,可以给患者施用标记化合物,以将其递送到整个身体。
可选择地,可以将标记化合物施用于特定的感兴趣的器官或组织。例如,需要对脑部的淀粉样沉积物进行定位和定量,以诊断或跟踪患者阿耳茨海默氏病的发展。
术语“组织”意指患者身体的部分。组织的实例包括脑、心、肝、血管和动脉。可检测量为通过所选择的检测方法进行检测所需的标记化合物的数量。可以容易地由本领域技术人员决定引入患者体内以进行检测的标记化合物的数量。例如,可以给患者施用大量的标记化合物直至通过所选择的检测方法检测该化合物。将标记引入该化合物以检测化合物。
术语“患者”意指人和其它动物。本领域技术人员也熟悉测定使化合物与淀粉样沉积物发生结合的充足的时间数量。可以通过以下方法测定必需时间数量:将可检测量的式I-III’的标记化合物引入患者,然后在施用之后的不同时间检测该标记化合物。
术语“结合的”意指标记化合物和淀粉样沉积物之间的化学相互作用。结合的实例包括共价键、离子键、亲水-亲水相互作用、疏水-疏水相互作用和络合物等。
本领域技术人员熟悉各种用于检测标记化合物的方法。例如,磁共振成像(MRI),正电子发射断层扫描(PET)或单光子发射计算断层扫描技术(SPECT)可以用于检测放射标记化合物。引入化合物的标记将取决于目标检测方法。例如,如果选择PET作为检测方法,则该化合物必须具有正电子发射原子,如11C或18F。
放射性诊断试剂应该具有可以确保可靠诊断的充足的放射活性和放射活性浓度。例如,在放射性金属为锝-99m的情况下,在给药时在大约0.5-5.0ml中通常包含0.1-50mCi的量。式I-III’的化合物的数量可以是足以与放射性金属形成稳定的螯合化合物的数量。
如此形成的作为诊断试剂的螯合化合物有足够的稳定性,因而其本身可以立即给药或储存直至使用。如果需要的话,放射性诊断试剂可以包含任何添加剂如pH控制剂(如酸、碱、缓冲剂)、稳定剂(如抗坏血酸)或离子化试剂(如氯化钠)。
还可以定量地完成淀粉样沉积物的成像,因而可以检测淀粉样沉积物的量。
用于成像的优选的化合物包括放射性同位素如1231、125I、131I、18F、76Br或77Br。
本发明还涉及一种淀粉样沉积物的成像方法。脑的体内成像试剂的一个重要的先决条件是在一次性大剂量静脉注射之后跨过完整的血-脑屏障的能力。本发明的化合物具有一个含有多种取代的、稠合的5-和6-元芳环的核心环系统。本发明的多种化合物含有一个苯并噻唑核心并且是硫代黄素的衍生物。这些化合物不含季铵离子,因而它们的尺寸较小、呈中性和亲脂性(对于3和6a分配系数分别为70和312)。
为测试跨过完整血脑屏障的渗透性,将多种式I或III的化合物注入正常小鼠。在静脉注射后小鼠的最初脑摄入的3和6a分别为0.67和1.50%剂量/器官(见表1)。两种化合物的脑摄入的峰值在60分钟,其中最大脑摄入分别为1.57和1.89%剂量/器官。在所评价的全部时间点的血液水平较低。对于这一系列的配基,脑的特定摄入较高且在脑中保持长久。
本发明的另一方面是一种抑制淀粉样斑块聚集的方法。本发明还提供一种如下的抑制淀粉样蛋白聚集形成淀粉样沉积物的方法:给患者施用淀粉样抑制量的式I、II、III或III’的化合物。
本领域技术人员能够容易地通过以下方法测定淀粉样抑制量:简单地给患者施用增加量的式I、II、III或III’的化合物直至淀粉样沉积物的生长减少或停止。可以使用上述的成像或通过移取患者组织样品并观察其中的淀粉样沉积物而评价生长速率。可以给患者施用剂量水平范围为大约0.1至大约1,000mg/天的本发明的化合物。对于体重为大约70kg的正常成人,大约0.01至大约100mg/千克体重/天范围内的剂量足够。但是,特定的应用剂量可以改变。例如,剂量取决于大量的因素,包括患者的要求、治疗症状的严重程度和所用化合物的药理学活性。特定患者的最佳剂量的测定对本领域技术人员来说是已知的。
以下的实施例是例示性的,但不限定本发明的方法和组合物。本领域技术人员通常遇到的和显而易见的其它适宜的多种条件和参数的修改和修正在本发明的构思和范围之内。
实施例1
2-(4’-二甲基氨基苯基)-6-碘代苯并噻唑,(3)
2-(4’-二甲基氨基苯基)-6-溴苯并噻唑(1):(Stevens,M.F.G.等人,J.Med.Chem.37:1689-1695(1994);Stevens,M.F.G.等人,PCT Int.Appl.WO19940830:47(1995))
将在DMSO中的5-溴-2-氨基-苯硫醇(Mital,R.L.和Jain,S.K.,J.Chem.Soc.(C):2148(1969);Lin,A.-J.和Kasina,S.,J.Heterocycl Chem.18:759(1981))(306mg,1.5mmol)和4-二甲基氨基苯甲醛(224mg,1.5mmol)的混合物于180℃下加热15分钟。将混合物冷却后加入水(10mL)。抽滤收集固体,并用乙酸乙酯重结晶得到340mg产物(68%)。
1H NMR(200MHz,CDCl3):(3.06(s,6H),6.74(d,J=9.0Hz,2H),7.52(d,d,J=8.7,2.0Hz,1H),7.82(d,J=8.6Hz,1H),7.93(d,J=8.8Hz,2H),7.95(s,1H)。
HRMS:m/z计算值:C15H14BrN2S(MH+):333.0061;实验值:333.0072。
2-(4’-二甲基氨基苯基)-6-三丁基甲锡烷基苯并噻唑(2):向在1,4-二噁烷(2mL)、甲苯(2mL)和三乙基胺(2mL)中的2-(4’-二甲基氨基苯基)-6-溴苯并噻唑(16a)(60mg,0.18mmol)的溶液加入(Bu3Sn)2(0.2mL),然后加入Pd(Ph3P)4(20mg)。将混合物于90℃下搅拌过夜。除去溶剂并用PTLC(Hex∶EtOAc,6∶1)将残余物纯化得到33mg产物(产率33.6%)。
1H NMR(200MHz,CDCl3):δ0.90(t,J=7.1Hz,9H),1.10(t,J=8.0,Hz,6H),1.34(hex,J=7.3,Hz,6H),1.57(m,6H),3.05(s,6H),6.74(d,J=9.0Hz,2H),7.50(d,d,J=7.9,0.9Hz,1H),7.93(s,1H),7.95(d,J=8.5Hz,1H),7.97(d,J=9.0Hz,2H)。
HRMS:m/z计算值:C27H41N2SSn(MH+):545.2012;实验值:545.2035。
2-(4’-二甲基氨基苯基)-6-碘代苯并噻唑,(3):RT下向在CHCl3(10mL)中的2(45mg,0.08mmol)溶液中滴加碘溶液(1mL,1M,在CHCl3中)直至颜色保持不变。将所得的混合物于室温下搅拌10分钟。连续地加入NaHSO3溶液(2mL,5%,在水中)和KF(1mL,1M,在MeOH中)。将混合物搅拌5分钟并分离有机相。用CH2Cl2萃取含水相,并用Na2SO4干燥合并的有机相,过滤并浓缩得到粗产物,用PTLC(Hex∶EtOAc,6∶1)纯化得到9mg目标产物(产率29%)。
1H NMR(200MHz,CDCl3):δ3.06(s,6H),6.73(d,J=9.0Hz,2H),7.69(s,1H),7.70(s,1H),7.93(d,J=9.0Hz,2H),8.15(s,1H)。
HRMS:m/z计算值:C15H15N2IS(MH+):380.9922,实验值:380.9914。
分析(C15H14N3IS):C,H,N。
实施例2
2-[4’-(4″-甲基哌嗪-1-基)-苯基]-6-碘代苯并噻唑,(6)
2-[4’-(4″-甲基哌嗪-1-基)-苯基]-6-溴苯并噻唑(4):使用上述制备1的方法,由4-(4-甲基哌嗪-1-基)苯甲醛(Tanaka,A.等人,J.Med.Chem.41:2390(1998))(204mg,1mmol)和5-溴-2-氨基-苯硫醇(204mg,1mmol)得到57.2%产物4。
1H NMR(200MHz,CDCl3):δ2.38(s,3H),2.60(t,J=5.0Hz,4H),3.38(t,J=5.0Hz,4H),6.96(d,J=8.9Hz,2H),7.54(d,d,J=8.5,1.9Hz,1H),7.83(d,J=8.5Hz,1H),7.95(d,J=8.9Hz,2H),7.98(s,1H)。
HRMS:m/z计算值:C18H19BrN3S(MH+):388.0483;实验值:388.0474。
2-4’-(4″-甲基哌嗪-1-基)-苯基]-6-三丁基甲锡烷基苯并噻唑(5):使上述制备2的方法,由4得到23%产率的5。
1H NMR(200MHz,CDCl3):δ0.89(t,J=7.2Hz,9H),1.06(t,J=8.2Hz,6H),1.30(hex,J=7.3Hz,6H),1.57(pen,J=7.2Hz,6H),2.38(s,3H),2.60(m,4H),3.36(t,J=5.0Hz,4H),6.96(d,J=8.9Hz,2H),7.52(d,J=7.9Hz,1H),7.93(s,1H),7.95(d,J=7.9Hz,1H),7.98(d,J=8.9Hz,2H)。
HRMS:m/z计算值:C30H46N3SSn(MH+):600.2434;实验值:600.2449。
2-[4’-(4″-甲基哌嗪-1-基)-苯基]-6-碘代苯并噻唑,(6):采用与上述制备3的方法相同的方法,由5制备36%产率的6。
1H NMR(200MHz,CDCl3):δ2.42(s,3H),263(t,J=4.8Hz,4H),3.40(t,J=4.9Hz,4H),6.95(d,J=9.0Hz,2H),7.71(s,1H),7.72(s,1H),7.95(d,J=8.9Hz,2H),8.17(t,J=1.0Hz,IM.HRMS:m/z计算值:C18H19N3IS(MH+):436.0344;实验值:436.0364.分析(C18H18N3SI):C,H,N。
实施例3
6-三丁基甲锡烷基-2-(4’-二甲基氨基-)苯基-咪唑并[1,2a]吡啶(18)的制备
6-溴-2-(4’-二甲基氨基-)苯基-咪唑并[1,2-a]吡啶(17)
将在EtOH(25mL)中的2-溴-4’-二甲基氨基苯乙酮(968mg,4mmol)和2-氨基-5-溴-吡啶(692mg,4mmol)的混合物回流搅拌2小时。在将混合物冷却后加入NaHCO3(500mg)。将所得的混合物回流搅拌4.5小时。将混合物冷却,过滤得到655mg产物,17(52%)。
1H NMR(200MHz,CDCl3,δ):3.00(s,6H),6.78(d,J=8.7Hz,2H),7.17(d,d,J=9.5,1.7Hz,1H),7.49(d,J=9.5Hz,1H),7.69(s,1H),7.80(d,J=8.7Hz,2H),8.21(d,d,J=1.7,0.8Hz,1H).分析3a,(C15H14BrN3)
6-三丁基甲锡烷基-2-(4’-二甲基氨基-)苯基-咪唑并[1,2-a]吡啶(18)。
向在1,4-二噁烷(10mL)和三乙基胺(2mL)中的6-溴-2-(4’-二甲基氨基-)苯基-咪唑并[1,2-a]吡啶,17(80mg,0.26mmol)的溶液加入纯(Bu3Sn)2(0.2mL),然后加入Pd(Ph3P)4(20mg)。
将混合物于90℃下搅拌过夜。除去溶剂并用PTLC(Hex∶EtOAc=1∶1作为展开剂)纯化残余物得到23mg产物,18(17%)。
1H NMR(200MHz,CDCl3,δ):0.90(t,J=7.2Hz,9H),1.10(t,J=8.0Hz,6H),1.33(hex,J=7.1Hz,6H),1.54(pen,J=7.2Hz,6H),3.00(s,6H),6.78(d,J=8.9Hz,2H),7.11(d,J=8.8Hz,1H),7.57(d,J=8.8Hz,1H),7.71(s,1H),7.84(d,J=8.8Hz,2H),7.95(d,J=0.8Hz,1H).HRMS:m/z计算值:C27H42N3Sn(M++H):528.2400;实验值:528.2402。分析4,(C27H41N3Sn.2H2O)
6-碘-2-(4’-二甲基氨基-)苯基-咪唑并[1,2-a]吡啶,IMPY,(16)
将在EtOH(25mL)中的2-溴-4’-二甲基氨基苯乙酮,(484mg,2mmol)和2-氨基-5-碘-吡啶(440mg,2mmol)的混合物回流搅拌2小时。将混合物冷却后加入NaHCO3(250mg)。将所得的混合物回流搅拌4小时。将混合物冷却,过滤得到348mg产物,3b(48%)。
1H NMR(200MHz,CDCl3,δ):3.00(s,6H),6.77(d,J=8.8Hz,2H),7.27(d,d,J=9.4,1.5Hz,1H),7.38(d,J=9.5Hz,1H),7.66(s,1H),7.79(d,J=8.8Hz,2H),8.32(d,J=0.7Hz,1H).分析3b,(C15H14IN3)。
实施例4
放射性碘配基[125I]IMPY,[125I]18的制备
使用三丁基锡前体17的碘代甲锡烷基化反应制备化合物[125I]18。将过氧化氢(50μL,3%w/v)加到在密封小瓶中的对应的50μL三丁基锡前体(1μg/μL EtOH)、50μL 1N HCl和[125/123I]NaI(1-5mCi)的混合物中。反应在室温下继续进行10分钟,并通过加入100μl饱和NaHSO3终止反应。用乙酸乙酯(3×1mL)直接萃取反应混合物(苯乙烯基苯)或在用饱和碳酸氢钠溶液中和后萃取(硫代黄素)。将合并的萃取物蒸发至干。对于苯乙烯基苯,将残余物溶于100μL EtOH,并用HPLC纯化,使用反相柱(Waters ubondpad,3.9×300mm)和65%乙腈-35%三氟乙酸(0.1%)的恒溶剂洗脱,流速为0.8mL/分。用C4柱(Phenomenex Inc.,Torrance,CA)纯化硫代黄素,用80%乙腈-20%3,3-二甲基-戊二酸(5mM,pH 7.0)的恒溶剂洗脱,流速为0.8mL/分。收集含有产物的目标馏分,浓缩并用乙酸乙酯再萃取。将无载体加入的产物蒸发至干,并再溶于100%EtOH(1μCi/μL),最终的18具有的特定的活性为2,200Ci/mmole而放射化学纯度大于95%,将其于-20℃下储存至多6周以进行体外结合和自动射线照相术研究。
实施例5
分配系数测定
通过将[125I]示踪剂与3g在试管中的每一种1-辛醇和缓冲剂(0.1M磷酸盐,pH 7.4)混合测定分配系数。将试管于室温下旋转3分钟,然后离心5分钟。在池式计数器中对来自1-辛醇和缓冲剂层的两份称重样品(各0.5g)进行计数。通过计算1-辛醇与缓冲剂的cpm/g的比率而确定分配系数。将来自1-辛醇层的样品再分配直至获得一致的分配系数值。以三式一份进行测定并重复三次。
实施例6
使用在溶液中聚集的Aβ(1-40)或Aβ(1-42)肽的结合试验
从Bachem(King of Prussia,PA)购得固体形式的肽Aβ(1-40)和Aβ(1-42)。通过将肽(对于Aβ(1-40)为0.5mg/mL,而对于Aβ(1-42)为0.25mg/mL)缓慢溶于含有10mM的磷酸钠和1mM EDTA的缓冲液(pH7.4)中而完成肽的聚集。将溶于37℃下温育36-42小时,并缓慢而恒定地振荡。根据某些改型(Klunk,W.E.等人,Biol.Psychiatry 35:627(1994))所述的方法在12×75mm硼硅酸盐玻璃管中完成结合研究。将聚集的纤丝(10-50nM,在最终的分析混合物中)加到含有在最终体积为1ml的40%EtOH和10%EtOH中的50ml放射配基(0.01-0.5nM)的混合物以进行饱和研究。对于硫代黄素在2mM硫代黄素T存在限定非特异性结合。关于抑制研究,1mL反应混合物含有在40%EtOH中的40ml抑制剂(10-5-10-10M,在10%EtOH中)和0.05nM放射性示踪剂。将混合物于室温下温育3小时,通过Whatman GF/B过滤器进行真空过滤而分离结合和游离的放射活性,使用Brandel M-24R池式收集器,然后在室温下用10%乙醇进行2×3mL洗涤。在计数效率为70%的γ计数器(Packard 5000)中对含有结合的I-125配基的过滤器进行计数。使用软件EBDA52对饱和和抑制实验的结果进行非线性回归分析,由此计算Kd和Ki值。在图1A和图1B中提供本发明化合物的附加Ki值。
表1
25℃下化合物对与Aβ(1-40)和Aβ(1-42)的聚集物结合的配基的抑制常数(Ki,nM)
Aβ(1-40)聚集物 | Aβ(1-42)聚集物 | |
化合物 | vs[<sup>125</sup>I]3 | vs[<sup>125</sup>I]3 |
柯胺G | >1,000 | >2,000 |
硫代黄素T | 116±20 | 294±40 |
1 | 1.9±0.3 | 0.8±0.3 |
4 | 1.6±0.5 | 5.0±0.8 |
3 | 0.9±0.2 | 2.2±0.4 |
6 | 5.4±0.7 | 6.4±0.7 |
上述值为三个独立实验的平均SEM,每个实验重复两次。
实施例7
正常小鼠体内新探针的生物分布
在醚麻醉下将含有标记试剂(5-10mCi)的0.15mL盐水溶液直接注射到ICR小鼠(2-3月龄,平均重量20-30g)的尾静脉。通过在注射后不同时间点进行心脏切除而将小鼠处死。移出感兴趣器官并称重,并用自动γ计数器(Packard 5000)对放射活性进行计数。通过比较组织计数和适当稀释的注射物质的等分试样而计算每个器官的剂量百分数。假设血液和肌肉分别为总体重的7%和40%,计算它们的总活性。
表2
[125I]化合物3(PC=70)
[125I]化合物6(PC=312)
[125I]化合物8(PC=124)
[125I]化合物19(PC=100)
%剂量/器官,3只小鼠的平均值±SD;平均器官重量为:血液,2g;肌肉,12g;肝,g;脑0.4g,根据它们可以计算各器官或组织的%剂量/g值。
*(%剂量/器官,3或4只小鼠的平均值±SD)
现在已完整地描述了本发明,本领域技术人员可以理解可以在不影响本发明或它的任何实施方案的范围的情况下,在宽泛和等同的条件、制剂和其它参数范围内完成本发明。本文完整地引用本文所述的所有的参数、专利申请和公开的全部作为参考。
Claims (12)
2. 权利要求1的化合物,或其药学上可接受的盐,
其中
R3为Br、I、F、125I、131I、123I、18F、76Br、77Br或Sn(烷基)3;和
R1和R2独立地为氢、C1-4烷基、C2-4氨基烷基、C1-4卤代烷基、卤代芳基烷基,或者R1和R2与它们结合的氮一起形成任选在环上具有O、S或NR5的5至7元杂环,其中
R5为氢或C1-4烷基。
3. 权利要求2的化合物,其中R3为125I、131I、123I、18F、76Br或77Br。
4. 权利要求3的化合物,其中:
R1和R2独立地选自氢、C1-4烷基、C1-4卤代烷基或4-氟苄基。
5. 权利要求2的化合物,其中:
R3为123I或125I;和
R1和R2均为甲基。
6. 权利要求2的化合物,其中:
R3为Sn(烷基)3;和
R1和R2独立地为氢、C1-4烷基、C1-4卤代烷基或4-氟苄基。
7. 权利要求6的化合物,其中R1和R2独立地为C1-4烷基。
8. 权利要求7的化合物,其中R1和R2均为甲基。
9. 药物组合物,所述组合物包含权利要求1-5之任一项的化合物,和药学上可接受的赋形剂或稀释剂。
10. 用于淀粉样沉积物成像的诊断组合物,所述组合物包含权利要求3-5之任一项的放射性标记化合物,和药学上可接受的赋形剂或稀释剂。
11. 权利要求10的组合物用于制备成像与淀粉样蛋白有关的疾病的药物的用途。
12. 权利要求11的用途,所述的疾病为阿耳茨海默氏病。
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Families Citing this family (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7544511B2 (en) * | 1996-09-25 | 2009-06-09 | Neuralstem Biopharmaceuticals Ltd. | Stable neural stem cell line methods |
GB0018473D0 (en) * | 2000-07-27 | 2000-09-13 | Merck Sharp & Dohme | Therapeutic agents |
US7270800B2 (en) | 2000-08-24 | 2007-09-18 | University Of Pittsburgh | Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition |
ES2536449T3 (es) * | 2000-08-24 | 2015-05-25 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Derivados de tioflavina para uso en diagnosis de la enfermedad de Alzheimer |
CN100422180C (zh) | 2001-04-23 | 2008-10-01 | 宾夕法尼亚州大学理事会 | 淀粉样斑块聚集抑制剂和诊断成像剂 |
EP1474178A1 (en) * | 2002-02-13 | 2004-11-10 | Amersham plc | Benzothiazole derivatives for in vivo imaging of amyloid plaques |
US20040185429A1 (en) * | 2002-12-09 | 2004-09-23 | Judith Kelleher-Andersson | Method for discovering neurogenic agents |
US8293488B2 (en) | 2002-12-09 | 2012-10-23 | Neuralstem, Inc. | Method for screening neurogenic agents |
AU2004206956A1 (en) * | 2003-01-22 | 2004-08-05 | The General Hospital Corporation | Amyloid-binding, metal-chelating agents |
CA2438032C (en) * | 2003-03-14 | 2013-05-07 | University Of Pittsburgh | Benzothiazole derivative compounds, compositions and uses |
CN102532055B (zh) * | 2003-03-14 | 2016-05-11 | 匹兹堡大学联邦制高等教育 | 苯并噻唑衍生物化合物、组合物及用途 |
GB0307855D0 (en) * | 2003-04-04 | 2003-05-14 | Novartis Ag | Organic compounds |
EP1631561B1 (en) | 2003-05-07 | 2010-08-18 | General Electric Company | Compositions and methods for non-invasive imaging of soluble beta-amyloid |
US8236282B2 (en) | 2003-08-22 | 2012-08-07 | University of Pittsburgh—of the Commonwealth System of Higher Education | Benzothiazole derivative compounds, compositions and uses |
US20050049487A1 (en) * | 2003-08-26 | 2005-03-03 | Johnson Bruce Fletcher | Compounds and kits for preparing imaging agents and methods of imaging |
US8257680B1 (en) | 2004-02-24 | 2012-09-04 | The General Hospital Corporation | Catalytic radiofluorination |
US9017724B2 (en) | 2004-02-24 | 2015-04-28 | The General Hospital Corporation | Catalytic radiofluorination |
JP5311739B2 (ja) * | 2004-03-18 | 2013-10-09 | サントリーホールディングス株式会社 | 放射性ラベル基を有する3−[3−(ベンゾイルアミド)ベンジルオキシ]アスパラギン酸誘導体とその製造方法 |
BRPI0512893B8 (pt) * | 2004-07-02 | 2021-07-27 | Univ Pittsburgh | métodos de determinação da eficácia da terapia no tratamento da amiloidose e de identificação de paciente como prodrômico para doença associada com a deposição amilóide e respectivos compostos |
JP2008505116A (ja) * | 2004-07-02 | 2008-02-21 | ユニバーシティー オブ ピッツバーグ | アミロイド沈着を伴う疾患の前駆形態の診断方法 |
WO2006026184A2 (en) * | 2004-08-20 | 2006-03-09 | Washington University | Blood brain barrier permeation peptides |
EP2913393B8 (en) | 2004-11-17 | 2020-02-26 | Seneca Biopharma, Inc. | Transplantation of human neural cells for treatment of neurodegenerative conditions |
AU2006261917A1 (en) * | 2005-06-24 | 2007-01-04 | The Trustees Of The University Of Pennsylvania | Radiolabeled-pegylation of ligands for use as imaging agents |
US7666886B2 (en) * | 2005-07-15 | 2010-02-23 | The Regents Of The University Of California | Compounds and methods for the diagnosis and treatment of amyloid associated diseases |
EP1928237A4 (en) | 2005-09-02 | 2011-03-09 | Abbott Lab | NEW HETEROCYCLES BASED ON IMIDAZO |
US20080219922A1 (en) * | 2005-09-12 | 2008-09-11 | Goodman Mark M | Alzheimer's Disease Imaging Agents |
CA2627722A1 (en) † | 2005-10-31 | 2007-06-21 | Merck & Co., Inc. | Cetp inhibitors |
JP4738419B2 (ja) | 2005-11-30 | 2011-08-03 | 富士フイルムRiファーマ株式会社 | アミロイドの凝集及び/又は沈着に起因する疾患の診断薬及び治療薬 |
JPWO2007069565A1 (ja) * | 2005-12-12 | 2009-05-21 | 小野薬品工業株式会社 | 二環式複素環化合物 |
WO2007078335A2 (en) * | 2005-12-21 | 2007-07-12 | Decode Genetics, Ehf. | Biaryl nitrogen heterocycle inhibitors of lta4h for treating inflammation |
TW201018678A (en) | 2006-01-27 | 2010-05-16 | Astrazeneca Ab | Novel heteroaryl substituted benzothiazoles |
TW200803903A (en) * | 2006-04-28 | 2008-01-16 | Nihon Mediphysics Co Ltd | Novel compound having affinity to amyloid |
EP2023919A4 (en) * | 2006-05-08 | 2010-12-22 | Molecular Neuroimaging Llc | COMPOUNDS AND AMYLOID PROBES FOR THERAPY AND IMAGING USES |
NZ573363A (en) | 2006-05-19 | 2012-01-12 | Nihon Mediphysics Co Ltd | Compound having affinity for amyloid based on an imidazopyridine-phenyl skeleton |
TW200813035A (en) | 2006-06-19 | 2008-03-16 | Astrazeneca Ab | Novel heteroaryl substituted benzoxazoles |
US8277777B2 (en) | 2006-06-21 | 2012-10-02 | Nihon Medi-Physics Co., Ltd. | Compound having affinity for amyloid |
JPWO2008056481A1 (ja) * | 2006-11-09 | 2010-02-25 | 日本メジフィジックス株式会社 | 放射性画像診断剤 |
WO2008059714A1 (fr) * | 2006-11-17 | 2008-05-22 | Nihon Medi-Physics Co., Ltd. | Composés inédits présentant une affinité pour la substance amyloïde |
KR20090083414A (ko) | 2006-11-30 | 2009-08-03 | 니혼 메디피직스 가부시키가이샤 | 신규 아밀로이드 친화성 화합물 |
BRPI0806621A2 (pt) * | 2007-01-22 | 2011-09-13 | Astrazeneca Ab | composto, uso de um composto, composição farmacêutica, e, método in vivo para medir depósitos amilóides em um indivìduo |
EP2119458B9 (en) | 2007-02-13 | 2013-08-21 | Nihon Medi-Physics Co., Ltd. | Method for production of radiation diagnostic imaging agent |
EP1964840A1 (en) | 2007-02-28 | 2008-09-03 | sanofi-aventis | Imidazo[1,2-a]pyridines and their use as pharmaceuticals |
WO2008108729A1 (en) * | 2007-03-06 | 2008-09-12 | Astrazeneca Ab | Novel 2-heteroaryl substituted indoles 695 |
TW200901998A (en) | 2007-03-06 | 2009-01-16 | Astrazeneca Ab | Novel 2-heteroaryl substituted benzothiophenes and benzofuranes |
FR2913886B1 (fr) | 2007-03-22 | 2012-03-02 | Guerbet Sa | Utilisation de nanoparticules metalliques dans le diagnostique de la maladie d'alzheimer |
WO2008134618A2 (en) * | 2007-04-27 | 2008-11-06 | The General Hospital Corporation | Novel imaging tracers for early detection and treatment of amyloid plaques caused by alzheimer's disease and related disorders |
WO2009054496A1 (ja) | 2007-10-24 | 2009-04-30 | Nihon Medi-Physics Co., Ltd. | 新規アミロイド親和性化合物 |
AU2008314871A1 (en) | 2007-10-26 | 2009-04-30 | Nihon Medi-Physics Co., Ltd. | Novel compound having affinity for amyloid |
CA2704137A1 (en) * | 2007-10-30 | 2009-05-07 | Nihon Medi-Physics Co., Ltd. | Use of novel compound having affinity for amyloid, and process for production of the same |
JPWO2009057575A1 (ja) * | 2007-10-30 | 2011-03-10 | 日本メジフィジックス株式会社 | 新規アミロイド親和性化合物の使用及び製造方法 |
US20100267952A1 (en) * | 2007-10-30 | 2010-10-21 | Nihon Medi-Physics Co., Ltd. | Use of novel compound having affinity for amyloid, and process for production of the same |
JPWO2009057578A1 (ja) * | 2007-10-30 | 2011-03-10 | 日本メジフィジックス株式会社 | 新規アミロイド親和性化合物の使用及び製造方法 |
US20110046378A1 (en) | 2008-02-14 | 2011-02-24 | Siemens Medical Solutions Usa, Inc. | Novel Imaging Agents for Detecting Neurological Dysfunction |
US8932557B2 (en) | 2008-02-14 | 2015-01-13 | Eli Lilly And Company | Imaging agents for detecting neurological dysfunction |
US20100331676A1 (en) * | 2008-02-27 | 2010-12-30 | Avid Radiopharmaceuticals, Inc. | Gamma probe detection of amyloid plaque using radiolabeled a-beta binding compounds |
CN104974024B (zh) * | 2008-03-21 | 2017-11-14 | 综合医院公司 | 检测和治疗阿尔茨海默病和相关疾病的化合物和组合物 |
JP5603855B2 (ja) * | 2008-04-04 | 2014-10-08 | アビッド レディオファーマシューティカルズ、インク. | 神経変成疾患の放射性薬剤による画像化 |
US8409419B2 (en) | 2008-05-21 | 2013-04-02 | Paul R. Kruesi | Conversion of carbon to hydrocarbons |
WO2009146388A1 (en) | 2008-05-28 | 2009-12-03 | The Trustees Of Columbia University In The City Of New York | Voxel-based methods for assessing subjects using positron emission tomography |
KR20110017407A (ko) * | 2008-05-30 | 2011-02-21 | 포스터 휠러 에너지아 오와이 | 순산소 연소에 의해 전력을 생성하는 방법과 시스템 |
AU2009260526A1 (en) * | 2008-05-30 | 2009-12-23 | Merck Sharp & Dohme Corp. | Novel substituted indoles |
US8530483B2 (en) | 2008-05-30 | 2013-09-10 | Merck Sharp & Dohme Corp. | Substituted azabenzoxazoles |
US8420052B2 (en) | 2008-07-24 | 2013-04-16 | Siemens Medical Solutions Usa, Inc. | Imaging agents useful for identifying AD pathology |
EP2910945B1 (en) * | 2008-09-30 | 2018-07-18 | Case Western Reserve University | Molecular probes for imaging of myelin |
JP2012508889A (ja) * | 2008-11-13 | 2012-04-12 | アビッド レディオファーマシューティカルズ、インク. | 神経変性疾患の検出と診断のためのヒストグラムに基づいた分析方法 |
US9925282B2 (en) | 2009-01-29 | 2018-03-27 | The General Hospital Corporation | Cromolyn derivatives and related methods of imaging and treatment |
EP2218464A1 (en) * | 2009-02-11 | 2010-08-18 | Technische Universität München | Compounds for non-invasive measurement of aggregates of amyloid peptides |
FR2942227B1 (fr) | 2009-02-13 | 2011-04-15 | Guerbet Sa | Utilisation de tampons pour la complexation de radionucleides |
CA2756137C (en) * | 2009-03-23 | 2015-11-24 | Siemens Medical Solutions Usa, Inc. | Imaging agents for detecting neurological disorders |
US8691187B2 (en) | 2009-03-23 | 2014-04-08 | Eli Lilly And Company | Imaging agents for detecting neurological disorders |
CU23844B1 (es) | 2009-04-17 | 2012-10-15 | Ct De Neurociencias De Cuba | Procedimiento de obtención de nuevos derivados de naftaleno para el diagnóstico in vivo de la enfermedad de alzheimer |
US8476449B2 (en) | 2010-03-01 | 2013-07-02 | Nihon Medi-Physics Co., Ltd. | Radioactive iodine labeled organic compound or salt thereof |
US9540611B2 (en) | 2010-07-28 | 2017-01-10 | Neuralstem, Inc. | Methods for treating and/or reversing neurodegenerative diseases and/or disorders |
EP2627361B1 (en) | 2010-10-12 | 2017-09-20 | Mayo Foundation For Medical Education And Research | Imaging of meningiomas using phenylbenzothiazole, stilbene, or biphenylalkyne derivatives |
RU2013125326A (ru) * | 2010-11-16 | 2014-12-27 | ДжиИ ХЕЛТКЕР ЛИМИТЕД | Гетероциклические соединения в качестве зондов для визуализации tau-патологии |
FR2968999B1 (fr) | 2010-12-20 | 2013-01-04 | Guerbet Sa | Nanoemulsion de chelate pour irm |
WO2012161116A1 (ja) | 2011-05-20 | 2012-11-29 | 日本メジフィジックス株式会社 | 新規アミロイド親和性化合物 |
CN103596950B (zh) | 2011-06-24 | 2017-12-19 | 日本医事物理股份有限公司 | 对淀粉状蛋白具有亲和性的化合物 |
FR2980364B1 (fr) | 2011-09-26 | 2018-08-31 | Guerbet | Nanoemulsions et leur utilisation comme agents de contraste |
WO2013082508A1 (en) * | 2011-12-02 | 2013-06-06 | The Regents Of The University Of Michigan | Compositions and methods for the treatment and analysis of neurological disorders |
WO2014004664A2 (en) | 2012-06-27 | 2014-01-03 | Mayo Foundation For Medical Education And Research | Treatment of meningiomas using phenylbenzothiazole, stilbene, biphenylalkyne, or pyridine derivatives |
EP3563849A3 (en) | 2012-10-25 | 2020-02-12 | The General Hospital Corporation | Combination therapies for the treatment of alzheimer's disease and related disorders |
US10058530B2 (en) | 2012-10-25 | 2018-08-28 | The General Hospital Corporation | Combination therapies for the treatment of Alzheimer's disease and related disorders |
CN103073520B (zh) * | 2012-12-24 | 2014-10-08 | 湖南大学 | 一种合成2-苯基苯并噻唑及其衍生物的方法 |
FR3001154B1 (fr) | 2013-01-23 | 2015-06-26 | Guerbet Sa | Magneto-emulsion vectorisee |
JP2016514091A (ja) | 2013-02-08 | 2016-05-19 | ミスフォールディング ダイアグノスティクス, インコーポレイテッド | トランスサイレチン抗体およびその使用 |
PL2991983T3 (pl) | 2013-04-29 | 2017-07-31 | F.Hoffmann-La Roche Ag | Pochodne 2-fenylo lub 2-hetaryloimidazolo[1,2-a]pirydyny |
US10525005B2 (en) | 2013-05-23 | 2020-01-07 | The General Hospital Corporation | Cromolyn compositions and methods thereof |
EP3049411B1 (en) | 2013-09-26 | 2017-04-26 | F. Hoffmann-La Roche AG | Imidazo[1,2-a]pyridin-7-amines as imaging tools |
CA2928028A1 (en) | 2013-10-22 | 2015-04-30 | The General Hospital Corporation | Cromolyn derivatives and related methods of imaging and treatment |
WO2016064737A1 (en) | 2014-10-20 | 2016-04-28 | Neuralstem, Inc. | Stable neural stem cells comprising an exogenous polynucleotide coding for a growth factor and methods of use thereof |
EP3384960B1 (en) * | 2015-12-30 | 2019-06-05 | Neuboron Medtech Ltd. | NEUTRON CAPTURE THERAPY SYSTEM FOR ELIMINATING AMYLOID ß-PROTEIN |
CN108395446B (zh) * | 2015-12-30 | 2020-02-28 | 南京中硼联康医疗科技有限公司 | 和β淀粉样蛋白特异性结合的化合物的制备方法 |
CN116889562A (zh) | 2016-08-31 | 2023-10-17 | 通用医疗公司 | 与神经退行性疾病相关的神经炎症中的巨噬细胞/小胶质细胞 |
AU2017423862A1 (en) | 2017-07-20 | 2020-02-06 | Aztherapies, Inc. | Powdered formulations of cromolyn sodium and ibuprofen |
JP6831802B2 (ja) * | 2018-01-12 | 2021-02-17 | 上海富吉医療器械有限公司Shanghai Chartwell Medical Instrument Co., Ltd. | 放射性核種標識化合物及びこれを含有するイメージング剤 |
WO2020007822A1 (en) | 2018-07-02 | 2020-01-09 | Conservatoire National Des Arts Et Metiers (Cnam) | Bismuth metallic (0) nanoparticles, process of manufacturing and uses thereof |
AU2019299347A1 (en) | 2018-07-02 | 2021-01-21 | Aztherapies, Inc. | Powdered formulations of cromolyn sodium and alpha-lactose |
KR102240400B1 (ko) * | 2020-11-19 | 2021-04-15 | 한국원자력연구원 | 베타-아밀로이드 검출용 수용성 화합물 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5552415A (en) * | 1993-12-21 | 1996-09-03 | Eli Lilly And Company | Method of inhibiting Alzheimer's Disease |
WO1997041856A1 (en) * | 1996-05-08 | 1997-11-13 | Massachusetts Institute Of Technology | ORGANOMETALLIC LIGANDS FOR THE LOCALIZATION AND QUANTIFICATION OF AMYLOID IN VIVO AND $i(IN VITRO) |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9317949D0 (en) | 1993-08-28 | 1993-10-13 | Stevens Malcolm F G | Benzothiazole compounds |
US6168776B1 (en) | 1994-07-19 | 2001-01-02 | University Of Pittsburgh | Alkyl, alkenyl and alkynyl Chrysamine G derivatives for the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition |
US6417178B1 (en) | 1994-07-19 | 2002-07-09 | University Of Pittsburgh | Amyloid binding nitrogen-linked compounds for the antemortem diagnosis of alzheimer's disease, in vivo imaging and prevention of amyloid deposits |
AU4988997A (en) | 1996-10-23 | 1998-05-15 | Osteoscreen, Inc. | Compositions and methods for treating bone deficit conditions |
US5869500A (en) | 1996-12-13 | 1999-02-09 | Hoffmann-La Roche Inc. | Pyridone compounds useful in treating Alzheimer's disease |
US6037473A (en) | 1997-11-13 | 2000-03-14 | Haarmann & Reimer Gmbh | Use of substituted benzazoles as UV absorbers, new benzazoles and processes for their preparation |
CN100422180C (zh) * | 2001-04-23 | 2008-10-01 | 宾夕法尼亚州大学理事会 | 淀粉样斑块聚集抑制剂和诊断成像剂 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5552415A (en) * | 1993-12-21 | 1996-09-03 | Eli Lilly And Company | Method of inhibiting Alzheimer's Disease |
WO1997041856A1 (en) * | 1996-05-08 | 1997-11-13 | Massachusetts Institute Of Technology | ORGANOMETALLIC LIGANDS FOR THE LOCALIZATION AND QUANTIFICATION OF AMYLOID IN VIVO AND $i(IN VITRO) |
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EP1381604B1 (en) | 2006-12-27 |
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USRE44338E1 (en) | 2013-07-02 |
KR20040058111A (ko) | 2004-07-03 |
JP4317955B2 (ja) | 2009-08-19 |
US20060051293A1 (en) | 2006-03-09 |
US20030059369A1 (en) | 2003-03-27 |
ATE349446T1 (de) | 2007-01-15 |
US20040131545A1 (en) | 2004-07-08 |
EP1381604A2 (en) | 2004-01-21 |
WO2002085903A3 (en) | 2003-02-27 |
CN1620454A (zh) | 2005-05-25 |
DE60217090D1 (de) | 2007-02-08 |
US7425318B2 (en) | 2008-09-16 |
WO2002085903A2 (en) | 2002-10-31 |
US6946116B2 (en) | 2005-09-20 |
CA2444214A1 (en) | 2002-10-31 |
USRE44354E1 (en) | 2013-07-09 |
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