CN101003526A - 茋衍生物及其用于结合和成像淀粉样蛋白斑的用途 - Google Patents
茋衍生物及其用于结合和成像淀粉样蛋白斑的用途 Download PDFInfo
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- CN101003526A CN101003526A CNA2007100789205A CN200710078920A CN101003526A CN 101003526 A CN101003526 A CN 101003526A CN A2007100789205 A CNA2007100789205 A CN A2007100789205A CN 200710078920 A CN200710078920 A CN 200710078920A CN 101003526 A CN101003526 A CN 101003526A
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- Prior art keywords
- alkyl
- compound
- heterocycle
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- hydrogen
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Abstract
本发明涉及一种成像淀粉样蛋白沉积物的方法和标记的化合物,以及用于成像淀粉样蛋白沉积物的标记化合物的制备方法。本发明还涉及用于抑制淀粉样蛋白聚集形成淀粉样蛋白沉积物的化合物以及这种化合物的制备方法,并涉及向淀粉样蛋白沉积物输送治疗剂的方法。
Description
本申请是申请日为2002年8月27日的中国专利申请02816829.1的中国专利申请的分案申请,原申请的发明名称为“茋衍生物及其用于结合和成像淀粉样蛋白斑的用途”。
发明领域
本发明涉及新的生物活性化合物,使用发射性标记化合物的诊断成像的方法,以及发射性标记的化合物的制备方法。
背景技术
阿尔茨海默氏病(AD)是一种渐进的神经变性紊乱,特征是认知降低、不可逆的记忆损失、定向力障碍和语言减损。AD脑切片尸检证实有大量由淀粉样蛋白-β(Aβ)肽构成的老年斑(SP)和许多由高度磷酰化τ蛋白的细丝形成的神经原纤维团(NFTs)(最近评论和其它引证参见Ginsberg,S.D.等人,″Molecular Pathology of Alzheimer’sDisease and Related Disorders,″ in Cerebral Cortex:Neurodegenerative and Age-related Changes in Structure andFunction of Cerebral Cortex,Kluwer Academic/Plenum,NY(1999),第603-654页;Vogelsberg-Ragaglia,V.等人,″Cell Biology of Tauand Cytoskeletal Pathology in Alzheimer’s Disease,″Alzheimer’s Disease, Lippincot,Williams & Wilkins,Philadelphia,PA(1999),第359-372页)。家族AD(FAD)是在A前体蛋白质(APP)、过早衰老素(presenilin)1(PS1)和过早衰老素2(PS2)基因多处突变引起的(Ginsberg,S.D.等人,″MolecularPathology of Alzheimer’s Disease and Related Disorders,″inCerebral Cortex:Neurodegenerative and Age-related Changes inStructure and Function of Cerebral Cortex,KluwerAcademic/Plenum,NY(1999),第603-654页;Vogelsberg-Ragaglia,V.等人,″Cell Biology of Tau and Cytoskeletal Pathology inAlzheimer’s Disease,″Alzheimer’s Disease,Lippincot,Williams & Wilkins,Philadelphia,PA(1999),第359-372页)。
尽管基本的AD的精确机理还不完全了解,但是由此研究的所有致病FAD突变使得更多的产淀粉样蛋白的42-43氨基酸长形式的Aβ肽大大增加。因此,至少在FAD中,Aβ生产的调节障碍呈现足够诱导导致神经变性事件级联。事实上,该淀粉样蛋白级联假设暗示在脑内形成的细胞外纤维状Aβ聚集物可能是AD致病的关键事件(Selkoe,D.J.,″Biology of B-amyloid Precursor Protein and the Mechanismof Alzheimer’s Disease,″Alzheimer’s Disease, LippincotWilliams & 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))。
尝试抑制脑内纤维Aβ产生并诱导其聚集的各种方案目前正作为AD的潜在疗法加以评价(Skovronsky,D.M.和Lee,V.M.,TrendsPharmacol.Sci. 21:161-163(2000);Vassar,R.,等人,Science286:735-741(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.,Biochimica et Biophysica Acta 1502:76-84(2000);Kuner,P.,Bohrmann等人,J.Biol.Chem.275:1673-1678(2000))。因此对于开发特异性地结合纤维状Aβ聚集物的配体具有浓厚的兴趣。由于细胞外SPs是可接近的目标,因此这些新的配体能够用作体内诊断工具并作为活患者中AD产淀粉样蛋白研究中的探针显现Aβ的渐进沉积。
为此,已报道了几个开发纤维状Aβ聚集物-特异性配体的方案(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,Society forNeuroscience Abstract 23:1638(1997);Mathis,C.A.等人,Proc.XIIth Intl. Symp. Radiopharm. Chem.,Uppsala,Sweden:94-95(1997);Lorenzo,A.和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))。最吸引人的方案基于高度共轭的黄芬宁-G(CG)和刚果红(CR),并且后者已用于荧光染色死后AD脑切片内的SPs和NFTs(Ashburn,T.T.等人,Chem.Biol. 3:351-358(1996);Klunk,W.E.等人,J. Histochem. Cytochem.37:1273-1281(1989))。CR、CG以及CG的3’-溴-和3’-碘衍生物用于结合纤维状Aβ聚集物上的抑制常数(Ki)分别是2,800、370、300和250nM(Mathis,C.A.等人,Proc. XIIth Intl. Sump. Radiopharm. Chem.,Uppsa1a,Sweden:94-95(1997))。这些化合物已显示在体外选择性地结合Aβ(1-40)肽聚集物并在AD脑切片结合纤维状Aβ沉积物(Mathis,C.A.等人,Proc. XIIth Intl. Symp.Radiopharm. Chem.,Uppsala,Sweden:94-95(1997))。
淀粉样蛋白病症的特征是各种不溶性的纤维蛋白聚集在患者的组织内。淀粉样蛋白沉积物是通过聚集淀粉样蛋白、接着进一步将聚集物和/或淀粉样蛋白结合形成的。β-淀粉样蛋白(Aβ)肽的聚集物在脑内的形成和聚集是AD呈现并发展的关键因素。这些淀粉样蛋白的纤维聚集物,Aβ1-40和Aβ1-42,是得自在老年斑中发现的淀粉样蛋白前体蛋白和AD患者的脑血管淀粉样蛋白沉积物的主要代谢肽(Xia,W.等人,J.Proc. Natl. Acad. Sci.U.S.A. 97:9299-9304(2000))。AB斑形成的预防和逆转一直是作为这种疾病治疗的目标(Selkoe,D.,J.JAMA283:1615-1617(2000);Wolfe,M.S.等人,J.Med. Chem. 41:6-9(1998);Skovronsky,D.M.和Lee,V.M.,Trends Pharmacol. Sci.21:161-163(2000))。
除了淀粉样蛋白沉积物在阿尔茨海默氏病中的作用之外,淀粉样蛋白沉积物的存在已呈现在如下疾病中:地中海热病、Muckle-Wells综合征、自发性骨髓瘤,淀粉样蛋白多发性神经病、淀粉样蛋白心肌病、全身性老年淀粉样蛋白病、淀粉样蛋白多发性神经病、具有淀粉样变的遗传性脑出血、Down氏综合征、瘙痒病、Creutzfeldt-Jacob病、苦鲁病、Gerstamnn-Straussler-Scheinker综合征、甲状腺的骨髓癌、分离的心房性淀粉样蛋白、透析患者内β2-微球蛋白淀粉样蛋白、包涵体肌炎、肌肉萎缩病中的β2-淀粉样蛋白沉积物和胰岛II型糖尿病胰岛瘤。
因此,迫切寻找一种简单且非侵入性在患者中检测并定量淀粉样蛋白沉积物的方法。目前,淀粉样蛋白沉积物的检测包括活组织检查或尸检材料的组织学分析。这两种方法都有缺陷。例如,尸检仅能用于死后诊断。
成像剂可能基于两种同位素。99mTc(T1/2,6小时;140KeV)和123I(T1/2,13小时;159KeV)常用于单光子发射计算的X线断层摄影术(SPECT),而11C(T1/2,20分钟;511KeV)和18F(T1/2,110分钟;511KeV)常用于正电子发射X线断层摄影术(PET)。
由于淀粉样蛋白沉积物与正常组织具有许多相同的物理性能(例如,密度和水分含量),因此这些沉积物在体内难以直接成像。试图使用磁共振成像(MRI)和计算机辅助的X线断层摄影术(CAT)成像淀粉样蛋白沉积物已令人失望并且仅在某些有利条件下检测到淀粉样蛋白沉积物。此外,试图用抗体、血清淀粉样蛋白P蛋白或其它探针分子标记淀粉样蛋白沉积物已给外围组织提供了一定的选择性,但是提供组织内部的成像差。
检测活脑内的Aβ聚集物的潜在配体必需穿过整个血脑屏障。因此使用相对小分子(与刚果红相比)的配体可以提高脑摄取并增加亲脂性。高度共轭的硫黄素(thioflavin)(S和T)常用作染色AD脑中Aβ聚集物用的染料(Elhaddaoui,A.等人,Biospectroscopy 1:351-356(1995))。这些化合物基于苯并噻唑为主,具有相对小的分子大小。
一种在患者内成像并定量淀粉样蛋白沉积物的非侵入性的技术将是有用的。此外,提供抑制淀粉样蛋白聚集形成淀粉样蛋白沉积物的化合物和一种检测化合物抑制淀粉样蛋白聚集的能力的方法将是有用的。
发明概述
本发明提供了式I、II、III、IV或V的新化合物。
本发明还提供了诊断组合物,它包括一种发射性标记的式I、II、III、IV或V的化合物和一种药用可接受的载体或稀释剂。
本发明还提供了一种成像淀粉样蛋白沉积物的方法,该方法包括将可检测量的式I、II、III、IV或V的标记化合物或其药用可接受的盐、酯、酰胺或前药引入到患者体内。
本发明还提供了一种抑制淀粉样蛋白聚集的方法,该方法包括给予哺乳动物一种淀粉样蛋白抑制量的式I、II、III、IV或V的化合物或一种药用可接受的盐、酯、酰胺或前药。
本发明的另一方面涉及合成本文所述的式I、II、III、IV或V的淀粉样蛋白抑制和成像化合物的方法和中间体。
附图简述
图1、3、4和5描述了本发明的代表性化合物和这些化合物的结合数据。
图2描述了本发明的化合物的结合数据。
发明详述
本发明的第一个方面涉及式I的化合物:
或其药用可接受的盐,其中:
R5是氢或C1-4烷基;
在每一种情况下,R1、R2和R3独立地选自如下基团:氢、卤素、C1-4烷基、氰基、羧基(C1-5)烷基、三氟甲基、硝基、甲基氨基、二甲基氨基、卤(C1-4)烷基和甲酰基;
R4选自如下基团:
a.C1-4烷硫基,
b.卤(C1-4)烷氧基,
c.羧基(C1-5)烷基,
d.羟基,
e.C1-4烷氧基,
f.NR6R7,其中
R6和R7是氢、卤(C1-4)烷基或C1-4烷基,
g.苯基(C1-4)烷基,
h.C6-10芳基,
i.杂芳基,
j.杂环,
k.杂环(C1-4)烷基,和
l.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下的取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基;
和,
X’是125I、123I、131I、18F、18氟(C1-4)烷基、[18氟(C1-4)烷基]烷基氨基、[18氟(C1-4)烷基]氨基、76Br、77Br或Sn(烷基)3。
落入式I范围的有用的化合物包括其中R5是氢或C1-4烷基的化合物。R5的特别有用的取值是氢和甲基。R5的最有用的取值是氢。
有用的化合物是其中在每一种情况下,R1、R2和R3独立地选自如上所述的基团的式I的化合物。优选,R3是氢。在该优选实施方式中,特别优选R1和R2独立地选自如下基团:氢和C1-4烷基。更优选,R1和R2中至少一个是氢。最优选,R1和R2都是氢。
式I的有用的化合物还包括其中R4如上所述的那些化合物。R4在C6-10芳基的范围内的优选取值包括苯基、萘基或四氢萘基。R4在杂芳基的范围内的优选取值包括噻吩基、呋喃基、吡喃基、吡咯基、吡啶基、吲哚基和咪唑基。R4在杂环的范围内的优选取值包括哌啶基、吡咯烷基和吗啉基。在其中R4是C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基的一个优选实施方式的化合物中,最优选该环被如下的取代基之一取代:C1-4烷硫基、羧基(C1-5)烷基、羟基、甲氧基、二甲基氨基或甲基氨基。在另一实施方式中,R4更优选选自如下基团:C1-4烷硫基、卤(C1-4)烷氧基、羧基(C1-5)烷基、羟基、C1-4烷氧基和NR6R7,其中R6和R7独立地是氢、卤(C1-4)烷基或C1-4烷基。最优选,R4选自如下基团:甲硫基、羧甲基、羧乙基、羧丙基、羟基、甲氧基或NR6R7,其中R6和R7独立地是氢、氟(C1-4)烷基或甲基。
X’的有用取值包括125I、123I、131I、18F、18氟(C1-4)烷基、[18氟(C1-4)烷基]烷基氨基、[18氟(C1-4)烷基]氨基、76Br、77Br或Sn(烷基)3。X’的特别有用的取值是123I、18氟甲基、18氟乙基和18氟丙基。
本发明还涉及式II的化合物:
或其药用可接受的盐,
Z是O、S或NRa,其中
Ra是C1-4烷基;
在每一种情况下,R9、R10和R11独立地选自如下基团:氢、卤素、C1-4烷基、氰基、羧基(C1-5)烷基、三氟甲基、硝基、甲基氨基、二甲基氨基、卤(C1-4)烷基和甲酰基;
R12选自如下基团:
a.C1-4烷硫基,
b.卤(C1-4)烷氧基,
c.羧基(C1-5)烷基,
d.羟基,
e.C1-4烷氧基,
f.NR13R14,其中
R13和R14是氢、卤(C1-4)烷基或C1-4烷基,
g.苯基(C1-4)烷基,
h.C6-10芳基,
i.杂芳基,
j.杂环,
k.杂环(C1-4)烷基,和
l.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下的取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基;
和,
X’是123I、123I、131I、18F、18氟(C1-4)烷基、[18氟(C1-4)烷基]烷基氨基、[18氟(C1-4)烷基]氨基、76Br、77Br或Sn(烷基)3。
落入式II范围内的有用的化合物包括其中Z是O、S或NRa的化合物,其中Ra是C1-4烷基。特别有用的化合物是其中Z是O的化合物。
有用的化合物是其中在每一种情况下,R9、R10和R11独立地选自如上所述的基团的式I的化合物。优选,R11是氢。在该优选实施方式中,特别优选R9和R10独立地选自如下基团:氢和C1-4烷基。更优选,R9和R10中至少一个是氢。最优选,R9和R10都是氢。
式I的有用的化合物还包括其中R12如上所述的那些化合物。R12在C6-10芳基的范围内的优选取值包括苯基、萘基或四氢萘基。R12在杂芳基的范围内的优选取值包括噻吩基、呋喃基、吡喃基、吡咯基、吡啶基、吲哚基和咪唑基。R12在杂环的范围内的优选取值包括哌啶基、吡咯烷基和吗啉基。在其中R12是C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基的一个优选实施方式的化合物中,最优选该环被如下的取代基之一取代:C1-4烷硫基、羧基(C1-5)烷基、甲氧基、羟基、二甲基氨基或甲基氨基。在另一实施方式中,R12更优选选自如下基团:C1-4烷硫基、卤(C1-4)烷氧基、羧基(C1-5)烷基、羟基、C1-4烷氧基和NR13R14,其中R13和R14独立地是氢、卤(C1-4)烷基或C1-4烷基。最优选,R12选自如下基团:甲硫基、羧甲基、羧乙基、羧丙基、羟基、甲氧基或NR13R14,其中R13和R14独立地是氢、氟(C1-4)烷基或甲基。
X’的有用取值包括125I、123I、131I、18F、18氟(C1-4)烷基、[18氟(C1-4)烷基]烷基氨基、[18氟(C1-4)烷基]氨基、76Br、77Br或Sn(烷基)3。X’的特别有用的取值是123I、18氟甲基、18氟乙基和18氟丙基。
本发明的另一方面涉及式III的化合物:
或其药用可接受的盐,其中:
n等于0-4的数值,
R28是氢或C1-4烷基,
Z是O、S或一CR15=CR16-,其中
R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和R25在每一种情况下,独立地选自如下基团:氢、卤素、Sn(烷基)3、C1-4烷基、C1-4烷基硫烷基、C1-4烷基磺酰基、C1-4烷氧基、羟基、C6-10芳基、羧基烷基、羧基和NR26R27,其中
R26和R27独立地是氢、C1-4烷基、苯基(C1-4)烷基、卤(C1-4)烷基、卤芳基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基,其中
所述C6-10芳基、C6-10杂芳基、杂环或C3-6环烷基未被取代或者被如下取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基、
和,
RP是氢或一个保护硫的基团,例如甲氧基甲基、甲氧基乙氧基甲基、对-甲氧基苄基或苄基。
式III的四配位基金属配体部分能够与金属络合,例如99m-高锝酸根,如本文所述形成金属螯合物,例如下式:
此外,铼发射性同位素可以与该四配位基金属配体络合。
式III的有用的化合物是其中Z是O、S或-CR15=CR16-的那些化合物,其中R15和R16如上所述。优选,Z是-CR15=CR16-,其中R15和R16如上所述。更优选,R15和R16都是氢。
本发明的有用的化合物是其中R17至R25都如上面定义的那些化合物。R17至R25落入C6-10芳基的范围内的优选取值包括苯基、萘基或四氢萘基。R17至R25落入杂芳基的范围内的优选取值包括噻吩基、呋喃基、吡喃基、吡咯基、吡啶基、吲哚基和咪唑基。R17至R25落入杂环的范围内的优选取值包括哌啶基、吡咯烷基和吗啉基。在R17至R25是C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基的一个优选实施方式的化合物中,最优选该环被如下的取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基。在另一实施方式中,更优选的化合物包括其中R17至R25中一个或多个是氢的那些化合物。在该实施方式中,优选R17不是氢。更优选,R17选自如下基团:C1-4烷硫基、C1-4烷基磺酰基、羟基、C1-4烷氧基、NR26R27,其中R26和R27独立地是氢或C1-4烷基。最优选,R17是NR26R27,其中R26和R27都是甲基。
有用的化合物还包括其中n等于0-4的数值的式III的那些化合物。优选,n等于0-2的数值。更优选,n等于0。
本发明的又一方面涉及式IV的化合物:
或其药用可接受的盐,其中
n等于0-4的数值,
R29、R30、R31、R32、R33、R34和R35独立地选自如下基团:
a.氢,
b.C1-4烷硫基,
c.C1-4烷基磺酰基,
d.羟基,
e.C1-4烷氧基,
f.NR6R7,其中
R6和R7是氢或C1-4烷基,
g.苯基(C1-4)烷基,
h.C6-10芳基,
i.杂芳基,
j.杂环,
k.杂环(C1-4)烷基,和
l.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下的取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基;
条件是R29至R35中一个是一烷基氨基苯基或二烷基氨基苯基;和
RP是氢或一个硫保护基团,例如甲氧基甲基、甲氧基乙氧基甲基、对-甲氧基苄基或苄基。
式IV的有用的化合物是其中R29、R30、R31、R32、R33、R34和R35如上所述的那些化合物。R29至R35落入C6-10芳基的范围内的优选取值包括苯基、萘基或四氢萘基。R29至R35落入杂芳基的范围内的优选取值包括噻吩基、呋喃基、吡喃基、吡咯基、吡啶基、吲哚基和咪唑基。R29至R35落入杂环的范围内的优选取值包括哌啶基、吡咯烷基和吗啉基。在其中R29至R35是C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基中的优选实施方式的化合物中,最优选该环被如下的取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基。在另一实施方式中,特别有用的化合物是其中R29、R30、R31和R33都是氢的那些化合物。在该实施方式中,特别优选R32和34中一个如上所述,R32和R34中另一个是氢。更优选,R32和R34中一个是氨基苯基、一烷基氨基苯基或二烷基氨基苯基,R32和R34中另一个是氢。最优选,R32和R34中一个是二二甲基氨基苯基,R32和R34中另一个是氢。R35的有用取值还包括氢、甲氧基、C1-4烷硫基、C1-4烷基磺酰基、羟基和C1-4烷基。最优选,R35是氢或C1-4烷基。
式IV的有用的化合物还包括其中n等于0-4的数值的化合物。更优选,n等于0或1。最优选,n等于0。
还应理解的是,本发明考虑包括立体异构体以及光学异构体,例如旋光对映体的混合物以及单个旋光对映体和非对映异构体,它们起源于所述的本系列化合物中结构不对称的结果。
式I、II、III或IV的化合物也可以溶剂化,特另是水合。水合作用在制备这些化合物或者包括这些化合物的组合物的过程中发生,或者由于这些化合物的吸湿性,该水合作用可以随着时间进行。此外,本发明的化合物可以未溶剂化以及与药用可接受的溶剂如水、乙醇等溶剂化的形式存在。一般说来,为了本发明的目的,认为溶剂化形式与未溶剂化形式等价。
本发明的又一方面涉及式V的化合物:
或其药用可接受的盐或者含有发射性同位素络合物的式V化合物的衍生物,其中:
R是C1-4烷基或者如上面R29-R35定义的,和
RP如上面定义的。
当在任意组份或式I、II、III、IV或V中发生不只一次的任意改变时,每一中情形的定义不依赖于每一种其它情形的定义。同样,仅仅如果取代基和/或变量的组合获得稳定的化合物时,这种组合才允许。
本文所用的术语“烷基”本身或者作为另一基团的一部分是指多至8个碳的直链或支链自由基,优选6个碳,更优选4个碳,例如甲基、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”是指与氧原子相连的直链或支链烷基自由基,如上所述,除非链长限于此,它们包括,但不限于,甲氧基、乙氧基、正丙氧基、异丙氧基等。优选该烷氧基链长是1-6个碳原子,更优选链长是1-4个碳原子。
本文所用的术语“一烷基胺”本身或者作为另一基团的一部分是指取代有一个如上所述的烷基的氨基。
本文所用的术语“二烷基胺”本身或者作为另一基团的一部分是指取代有两个如上所述的烷基的氨基。
本文所用的术语“卤”本身或者作为另一基团的一部分是指氯、溴、氟或碘。
本文所用的术语“卤烷基”是指被一个或多个氯、溴、氟或碘取代的任意上面的烷基,优选取代有氟和氯,例如氯甲基、碘甲基、三氟甲基、2,2,2-三氟乙基和2-氯乙基。
本文所用的术语“烷硫基”本身或者作为另一基团的一部分是指硫醚结构:R-S,其中R是上面定义的C1-4烷基。
本文所用的术语“烷基磺酰基”本身或者作为另一基团的一部分是指砜结构:R-SO2,其中R是如上面定义的C1-4烷基。
本文所用的术语“芳基”本身或者作为另一基团的一部分是指在环部分含有6-12个碳的单环或双环芳族基团,优选在环部分含有6-10个碳,例如苯基、萘基或四氢萘基。
本文所用的术语“杂环”或“杂环环”,除了注明了的之外,代表一个稳定的5-至7-元单杂环环系,它们可以是饱和或不饱和的,并且由碳原子和1-3个选自N、O、和S的杂原子组成,并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氮以及一个氧或硫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、imidazinyl、咪唑烷基、吡啶基、吡嗪基、嘧啶基、唑基、唑烷基、异唑基、异唑烷基、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、吡嗪基和吗啉基。
本文所用的术语“杂原子是指氧原子(“O”)、硫原子(“S”)或氮原子(“N”)。应想到,当该杂原子是氮时,它可以形成NRaRb部分,其中Ra和Rb彼此独立地是氢或C1-4烷基、C2-4氨基烷基、C1-4卤烷基、卤苄基,或者R1和R2在一起形成5-至7-元杂环,它们在所述环中任选具有O、S或NRc,其中Rc是氢或C1-4烷基。
本文所用的术语“杂芳基”是指这样的基团:它们具有5-14个环原子;在一个环阵列中共享的6、10或14个π电子;并且含有碳原子和1、2或3个氧、氮或硫杂原子(其中杂芳基的实例是:噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、苯并唑基、色烯基、呫吨基、苯并氧硫杂环己二烯基(phenoxathiinyl)、2H-吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲嗪基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、酞菁基、萘啶基、喹唑啉基、噌啉基、蝶啶基、4aH-咔唑基、咔唑基、β-咔啉基、菲啶基、吖啶基、萘嵌二氮苯基(perimidinyl)、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异唑基、呋咱基和吩嗪基。
本文所用的术语“芳烷基”或“芳基烷基”本身或者作为另一基团的一部分是指具有一个芳基取代基的上面讨论的C1-6烷基,例如苄基、苯基乙基或2-萘基甲基。
本发明的另一方面涉及式I、II、III、IV或V的制备方法。
在式III、IV或V的实施方式中,基团RP都是氢或者可以是任意种类的可用于保护硫的基团,包括甲氧基甲基、甲氧基乙氧基甲基、对-甲氧基苄基或苄基。硫保护基团详细描述在Greene,T.W.和Wuts,P.G.M.,Protective Groups in Organic Synthesis,第2版,JohnWiley and Sons,Inc.,New York(1991)。保护基团RP可以通过有机化学领域公知的适当方法除去,例如三氟乙酸、氯化汞或液氨中的钠。在为包括乙酰氨基甲基和苯甲酰氨基甲基的路易斯酸不稳定基团的情况下,RP可以保持完整。在这种情况下用锝标记该配体将使该保护基团裂开,使得受到保护的二胺二硫醇相当于未受保护的形式。
Tc-99m络合物可以如下制得。将少量未发射性标记的化合物(1-2mg)溶解在100μL EtOH中并与200μL HCl(1N)和1mL葡庚糖酸锡溶液(含有8-32μg SnCl2和80-320μg葡庚糖酸钠,pH6.67)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。在100℃下将该反应加热30分钟,然后冷却至室温。在TLC(EtOH∶浓NH3 9∶1)上分析反应混合物以检测产物的形成和纯度。用磷酸盐缓冲液中和该混合物至pH5.0。
本发明还涉及一种锝-99m络合物的制备方法,根据本发明,在有还原剂和任选适当螯合剂的情况下将锝-99m以高锝酸盐的形式与适当的含Ch化合物反应。
该还原剂用于还原Tc-99m高锝酸盐(它是从钼-锝发生器在生理盐水溶液中洗脱的)。合适的还原剂例如有、连二亚硫酸盐、甲脒亚磺酸、二氨基乙二亚磺酸酯(diaminoethane disulphinate)或合适的金属还原剂如Sn(II)、Fe(II)、Cu(I)、Ti(III)或Sb(III)。已证实Sn(II)特别合适。
就上述形成络合物的反应而言,锝-99m以盐或者与相对弱的螯合剂结合的锝的形式与本发明的适宜化合物反应。在后一情况下所需的锝-99m络合物是通过配体交换形成的。发射性核素用的合适螯合剂的实例是二羧酸,例如草酸、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;例如焦磷酸盐的磷化合物;或烯醇盐。柠檬酸、酒石酸、抗坏血酸、葡庚糖酸或其衍生物是为此目的的特别合适的螯合剂,这是由于锝-99m与这些螯合剂中一个的螯合物特别容易经受所需的配体交换。
最常用的制备[TcVO]+3N2S2络合物的步骤是基于[99mTc]高锝酸盐(常用的起始原料)的氯化亚锡(II)还原。该标记步骤通常依赖Tc-99m(Sn)-葡庚糖酸盐与该N2S2配体之间的Tc-99m配体交换反应。氯化亚锡(II)的制备并保持其恒定的亚锡(II)形式对标记反应的成功是至关重要的。为了稳定对空气敏感的亚锡离子,在核医疗学中通常采用一种冻干试剂盒,其中在例如氮或氩的惰性气体中将二价锡离子以冻干粉末形式与过量的葡庚糖酸盐混合。制备冻干氯化亚锡/葡庚糖酸钠试剂盒保证了标记反应是可再现并且可预测的。这些N2S2配体通常对空气敏感(硫醇容易被空气氧化)并且存在一系列反应,导致这些配体分解。保存这些配体的最方便并且最可预测的方法是在氩或氮下生产含有100-500μg这些配体的冻干试剂盒。
本发明还涉及上面的式I、II、III、IV或V的制备方法。本发明的这些化合物可以通过反应路线1-9中所述的反应制备。
反应路线1-5描述了一种使用维蒂希试剂形成式I的茋衍生物的合成路径。
路线1
路线2
路线3
路线4
路线5
反应路线6描述了一种形成式II衍生物的合成路径。
路线6
反应路线7描述了一种形成式III衍生物的合成路径。
路线7
反应路线8描述了一种式IV衍生物的合成路径。
路线8
反应路线9描述了形成式IV衍生物的合成路径。
路线9
反应路线10和11描述了形成式I衍生物的合成路径。
路线10
路线11
反应路线12描述了一种形成式V中间体的合成路径。
路线12
反应路线13描述了一种形成式V衍生物的合成路径。
路线13
当将本发明的化合物用作成像剂时,它们必需用合适的发射性卤素同位素标记。尽管125I-同位素可用于实验室测定,但是它们通常不能用于实际的诊断目的,这是由于125I具有相对长的半衰期(60天)和低的γ-辐射(30-65Kev)。同位素123I具有13小时的半衰期和159KeV的γ能,因此预料用于诊断目的的配体的标记将用该同位素。可以使用的其它同位素包括131I(半衰期为2小时)。合适的溴同位素包括77Br和76Br。
本发明的发射性卤代化合物使得本身易于从能够以试剂盒提供给使用者的材料形成。用于形成成像剂的试剂盒可以含有例如含有式I、II、III、IV或V的中间体的生理上适宜的溶液的小瓶,其浓度和pH适用于最佳络合条件。使用者将向该小瓶中加入适量的该发射性同位素,例如Na123I,以及一种氧化剂,例如过氧化氢。然后可以将所得标记的配体经静脉内给药到患者,并通过测定γ射线或从其中的相片辐射使脑中的受体成像。
由于本发明的发射性药用组合物可以容易且简单地制得,因此其制备可以由使用者容易地进行。因此,本发明和涉及一种试剂盒,它包括:
(1)本发明的未发射性标记的化合物,该化合物任选为干态;还任选向其中加入一药用可接受的惰性载体和/或辅助物质;和
(2)一种还原剂和任选一种螯合剂;
其中组份(1)和(2)可以任选混合;并且进一步其中可以任选包括描述实施组份(1)和(2)与以高锝酸盐溶液形式存在的锝-99m反应的上述方法的使用说明。
用于上面试剂盒的合适的还原剂和螯合剂的实例如上所述。该高锝酸盐溶液可以由使用者从钼-锝发生器获得。这种发生器可以在进行发射性诊断步骤的许多机构获得。如上所述,组份(1)和(2)可以混合,条件是它们可以相容。这种单组份试剂盒,其中优选将混合的组份冻干,特别适合由使用者以简单的方式与该高锝酸盐溶液反应。
如果需要的话,该发射性诊断剂可以含有任意的添加剂如pH控制剂(例如,酸、碱、缓冲剂)、稳定剂(例如,抗坏血酸)或等渗剂(例如,氯化钠)。
本文所用的术语“药用可接受的盐”是指本发明化合物的这些羧酸盐或酸加成盐,它们在声音医学诊断的范围内适用于与患者的组织接触,没有不适当的毒性、辐射、变态反应等,与合理的益处/风险比相称,并且对所需用途有效,如果可能的话,还指本发明化合物的两性离子形式。术语“盐”是指本发明化合物的相对无毒、无机和有机酸加成盐。还包括由无毒有机酸如脂族一羧酸和二羧酸,例如乙酸、苯基取代的链烷酸、羟基链烷酸和链烷二酸、芳族酸、以及脂族和芳族磺酸获得的这些盐。这些盐可以在这些化合物最终分离和纯化期间就地制得,或者通过单独地将纯化化合物以其自由碱形式与合适的有机或无机酸反应并将由此形成的盐分离制得。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、乳糖酸盐和月桂基磺酸盐、丙酸盐、新戊酸盐、环己烷氨基磺酸盐、羟乙基磺酸盐等。它们可以包括基于碱金属和碱土金属的阳离子,例如钠、锂、钾、钙、镁等,以及无毒铵、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),将其引入本文作为参考。)
在本成像方法的第一步中,将式I、II、III、IV或V的标记化合物以可检测量引入到组织或患者体内。该化合物通常是药用组合物的一部分并且通过本领域技术人员公知的方法给予组织或患者。
例如,该化合物可以经口、直肠、非肠道(静脉内、通过肌内或皮下)、池内、阴道内、腹膜内、膀胱内、局部(粉剂、膏剂或液滴)或作为颊或鼻喷剂给药。
在本发明的优选实施方式中,以可检测量将该标记化合物引入到患者内,并在该化合物与淀粉样蛋白沉积物结合足够时间之后,在患者内非侵入性地检测该标记化合物。在本发明的另一实施方式中,将式I、II、III、IV或V的标记化合物引入到患者内,使该化合物与淀粉样蛋白沉积物结合足够时间,然后从患者内取出组织样品,并离开患者检测组织内的标记化合物。在本发明的第三个实施方式中,从患者内取出组织样品,将式I、II、III、IV或V的标记化合物加入到组织样品中。在该化合物与淀粉样蛋白沉积物结合足够时间之后,检测该化合物。
将该标记化合物给予患者可以通过常规或者局部给药途径进行。例如,可以将标记化合物给予患者,以便它释放至全身。或者,可以将标记化合物给予有兴趣的特定器官或组织。例如,为了诊断或跟踪患者的阿尔茨海默氏病的进展,希望定位并定量脑内淀粉样蛋白沉积物。
术语“组织”是指患者身体的一部分。组织的实例包括大脑、心脏、肝、血管和动脉。可检测量是必需通过所选检测方法检测到的标记化合物的量。为了提供检测而引入到患者中的标记化合物的量可以由本领域技术人员容易地测定。例如,可以将增加量的标记化合物给予患者,直到通过选择的检测方法测定到该化合物。将一标记引入到该化合物中以能够检测到该化合物。
术语“患者”是指人和其它动物。本领域技术人员也能够熟练地决定化合物与淀粉样蛋白沉积物结合的足够时间。所需的时间量可以通过将可检测量的式I、II、III、IV或V的标记化合物引入到患者内,然后在给药之后的不同时间检测该标记化合物来容易地测定。
术语“结合”是指在标记化合物和淀粉样蛋白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。
本领域技术人员熟悉检测标记化合物的各种方式。例如,磁共振成像(MRI)、正电子辐射X线断层摄影术(PET)或单光子辐射计算的X线断层摄影术(SPECT)可用于检测发射性标记的化合物。加入到该化合物内的该标记将取决于所需的检测方法。例如,如果选择PET作为检测方法,那么该化合物必需具有正离子发射原子,例如11C或18F。
该发射性诊断剂应具有足够的发射性和发射性浓度,这样可以保证可靠的诊断。例如,在发射性金属是锝-99m的情况下,给药时通常可以包括0.1-50mCi的约0.5-5.0ml的量。式I、II、III、IV或V的化合物的量例如可以足够与发射性金属形成稳定的螯合化合物。
由此形成的螯合化合物作为发射性诊断剂足够稳定,因此本身可以立即给药或者贮藏直到其使用。如果需要的话,该发射性诊断剂可以含有任意添加剂如pH控制剂(例如,酸、碱、缓冲剂)、稳定剂(例如,抗坏血酸)或等渗剂(例如,氯化钠)。
淀粉样蛋白沉积物的成像也可以定量地进行,以便可以测定淀粉样蛋白沉积物的量。
成像用的优选化合物包括发射性同位素如123I、125I、131I、18F、76Br或77Br。
本发明还涉及一种淀粉样蛋白沉积物的成像方法。脑的体内成像剂的一个关键条件是在静脉推注之后通过整个血-脑屏障的能力。
本发明的另一方面是一种抑制淀粉样蛋白斑聚集物的方法。本发明还提供了一种抑制淀粉样蛋白聚集形成淀粉样蛋白沉积物的方法,包括向患者给予淀粉样蛋白抑制量的上面式I、II、III、IV或V的化合物。
本领域技术人员能够通过简单地以增加量给予患者式I、II、III、IV或V的化合物、直到淀粉样蛋白沉积物的生长减少或停止而容易地测定淀粉样蛋白抑制量。该生长速度是使用如上所述的成像或者通过从患者内取出组织样品并观察其中的淀粉样蛋白沉积物来评价的。本发明的化合物可以每天约0.1-约1,000mg的剂量水平给予患者。对正常人而言,体重为约70kg的成年人,剂量为约0.01-约100mg/kg体重/天就足够了。然而,所用的具体剂量可以变化。例如,该剂量可以取决于许多因素,它们包括患者的要求、正在治疗的症状的严重程度、以及所用化合物的药理学活性。具体患者的最佳剂量的确定对本领域技术人员来说是公知的。
以下实施例描述了本发明的方法和组合物,但并不限于此。通常遇到并且对本领域技术人员显而易见的对这些条件和参数的其它适宜的修改和改变都在本发明的精神和范围内。
实施例1
2-碘苄基膦酸二乙酯(11)
在160℃下将2-碘苄基溴10(5g,16.84mmol)和亚磷酸三乙酯(3.3g,20mmol)的混合物搅拌。4小时之后,将该混合物冷却至室温.残余物经受闪式色谱(EtOAc∶Hex,l∶4),得到2.3g的11(39%)。1H NMR(200MHz,CDCl3):δ1.24(t,J=7.04Hz,6H),3.40(d,J=22.00Hz,2H),4.03(m,4H),6.91(m,1H),7.32(m,1H),7.44(m,1H),7.82(m,1H);13C NMR(50MHz,CDCl3):δ16.27(J=6.00Hz),38.31(J=137.50Hz),62.16(J=6.70Hz),101.16(J=9.45Hz),128.23(J=3.35Hz),128.45(J=3.55Hz),130.60(J=5.10Hz),135.36(J=8.80Hz),139.60(J=2.85Hz)。
实施例2
(E)-2’-碘-N,N-二甲基-4-茋胺(4)
在80℃、氮气环境下向NaH(2mmol,80%油悬液),膦酸3-碘苄酯2(500mg,1.42mmol)的6mL的THF混合物中滴加4-(二甲基胺)苯甲醛(210mg,1.41mmol)。室温下过夜之后,加入NH4Cl溶液(饱和,5mL)并且该混合物用CH2Cl2萃取(3×30mL)。将合并的有机萃取液在Na2SO4上干燥并蒸发,得到(E)-2’-碘-N,N-二甲基-4-茋胺11,将其通过闪式色谱纯化(EtOAc∶Hex,1∶9),得到3(330mg,67%)。1H NMR(200MHz,CDCl3):δ3.06(s,6H),6.82(m,2H),6.93-7.02(m,1H),7.01(d,J=15.98Hz,1H),7.25(d,J=15.99Hz,1H),7.40(m,1H),7.53-7.59(m,2H),7.69(dd,J=7.88Hz,J=1.54Hz,1H),7.95(dd,J=7.92Hz,J=1.20Hz,1H);13C NMR(50MHz,CDCl3):δ40.26,100.20,112.22,125.12,125.61,127.83,127.87,127.97,128.2,131.66,139.42,140.84,150.23;HRMS:m/z计算为C16H16IN:349.0328;实测:349.0342。
实施例3
3-碘苄基膦酸二乙酯(13)
在160℃下将3-碘苄基溴12(5g,16.84mmol)和亚磷酸三乙酯(3.3g,20mmol)的混合物搅拌。4小时之后,将该混合物冷却至室温。残余物经过闪式色谱(EtOAc∶Hex,1∶4),得到5.4g的13(91%)。1H NMR(200MHz,CDCl3):δ1.15(t,J=7.05Hz,6H),2.97(d,J=21.65Hz,2H),3.92(m,4H),6.93(t,J=7.76Hz,1H),7.17(m,1H),7.52(m,2H);13C NMR(50MHz,CDCl3):δ16.25(J=5.95Hz),33.15(J=137.60Hz),62.19(J=6.70Hz),94.13(J=3.50Hz),128.89(J=6.35Hz),130.07(J3.00Hz),133.95(J=9.10Hz),135.87(J=3.55Hz),138.51(J=6.65Hz)。
实施例4
(E)-3’-碘-N,N-二甲基-4-茋胺(5)
在80℃、氮气环境下向NaH(2mmol,80%油悬液)和3-碘苄基膦酸酯13(370mg,1.05mmol)的5mL THF的混合物中滴加4-(二甲基胺)苯甲醛(155mg,1.05mmol)。室温下过夜之后,加入NH4Cl溶液(饱和,5mL),混合物用CH2Cl2萃取(3×20mL)。合并的有机萃取液在Na2SO4上干燥并蒸发,得到(E)-3’-碘-N,N-二甲基-4-茋胺5,将其通过闪式色谱纯化(EtOAc∶Hex,1∶9),得到3(209mg,57%)。1HNMR(200MHz,CDCl3):δ2.99(s,6H),6.71(m,2H),6.77(d,J=16.41Hz,1H),7.02(d,J=16.22Hz,1H),7.04(t,J=7.8Hz,1H),7.36-7.52(m,4H),7.82(s,1H);13C NMR(50MHz,CDCl3):δ40.37,94.78,112.38,112.53,122.21,127.76,128.56,130.19,134.76,135.34,140.56,150.36;HRMS:m/z计算为C16H16IN:349.0328;实测:349.0302.
实施例5
4-碘苄基膦酸二乙酯(15)
在160℃下将4-碘苄基溴14(5.2g,17.51mmol)和亚磷酸三乙酯(3.3g,20mmol)的混合物搅拌。4小时之后,将该混合物冷却至室温。残余物经受闪式色谱(EtOAc∶Hex,1∶4),得到3.27g的15(53%)。1H NMR(200MHz,CDCl3):δ1.24(t,J=7.04Hz,6H),3.07(d,J=21.72Hz,2H),4.01(m,4H),7.04(m,2H),7.62(m,2H);13C NMR(50MHz,CDCl3):δ16.24(J=5.90Hz),33.21(J=137.55Hz),62.04(J=6.70Hz),92.15(J=4.80Hz),131.31(J=9.10Hz),131.57(J=6.55Hz),137.43(J=2.95Hz)。
实施例6
(E)-4’-碘-N,N-二甲基-4-茋胺(6)
在80℃、氮气环境下向NaH(2mmol,80%油悬液)和4-碘苄基膦酸酯15(420mg,1.19mmol)的5mL的THF混合物中滴加4-(二甲基胺)苯甲醛(180mg,1.20mmol)。室温下过夜之后,加入水(5mL)。将形成的固体过滤出并用醚洗涤,得到粗产物6,将其通过用CH2Cl2/己烷再结晶纯化,得到纯的6(156mg,38%)。1H NMR(200MHz,CDCl3):δ2.99(s,6H),6.71(d,J=8.60Hz,2H),6.81(d,J=16.65Hz,1H),7.04(d,J=16.12Hz,1H),7.21(d,J=8.15Hz,1H),7.38(d,J=8.59Hz,2H),7.63(d,J=8.28Hz,2H);13C NMR(50MHz,CDCl3):δ40.39,91.32,112.38,123.04,127.69,127.73,128.23,129.65,137.55,137.77,150.29;HRMS:m/z计算为C16H16IN:349.0328;实测:349.0288。
实施例7
(E)-4’-碘-4-O-甲氧基茋醇(8)
在80℃、氮气环境下向NaH(2mmol,80%油悬液)和3-碘苄基膦酸酯13(450mg,1.27mmol)的7mL的THF的混合物中滴加茴香醛(172mg,1.27mmol)。室温下3天之后,加入NH4Cl溶液(饱和,5mL),该混合物用CH2Cl2萃取(3×30mL)。合并的有机萃取液在Na2SO4上干燥,蒸发并通过闪式色谱纯化(EtOAc∶Hex,1∶9),得到(E)-1-碘-3-[2-(4-甲氧基苯基)乙烯基]苯8(400mg,90%)。1H NMR(200MHz,CDCl3):δ3.84(s,3H),6.84(d,J=16.29Hz,1H),6.90(m,2H),7.05(d,J=16.30Hz,1H),7.07(t,J=7.8Hz,1H),7.42-7.56(m,4H),7.85(s,1H);13C NMR(50MHz,CDCl3):δ55.32,94.76,114.20,124.85,125.48,127.88,129.58,129.62,130.25,135.00,135.91,139.97,159.62;HRMS:m/z计算为C15H13IO:336.0011;实测:336.0006。
实施例8
(E)-3’-碘-4-茋醇(9)
在-78℃、干冰-丙酮浴中向8(350mg,1.00mmol)的CH2Cl2(200mL)的溶液中滴加BBr3(10mL,1M的己烷中)。将该混合物加热至室温。加入水,同时在冰浴中在0℃下冷却该反应混合物。混合物用CH2Cl2萃取。将该有机相干燥并过滤。滤液通过闪式色谱纯化(EtOAc∶Hex,1∶9)得到9(296mg,92%)。1H NMR(200MHz,CDCl3):δ4.81(s,1H),6.83(d,J=16.17Hz,1H),6.84(m,2H),7.03(d,J=16.32Hz,1H),7.06(t,J=7.8Hz,1H),7.36-7.57(m,4H),7.84(s,1H);13C NMR(50MHz,CDCl3):δ94.75,115.67,124.96,125.49,128.09,129.48,129.87,130.25,135.01,135.96,139.90,155.53;HRMS:m/z计算为C14H11IO:321.9855;实测:321.9840。
实施例9
4-氟苄基膦酸二乙酯(17)
在170℃下将4-氟苄基溴16(1.89g,10mmol)和亚磷酸三乙酯(1.66g,10mmol)的混合物搅拌4小时。将该混合物冷却至室温。残余物经受闪式色谱(EtOAc∶Hex,1∶4)得到1.4g的17(57%)。1H NMR(200MHz,CDCl3):δ1.23(t,J=7.1Hz,6H),3.10(d,J=21.4Hz,2H),3.92(q,J=7.1Hz,4H),7.02(m,2H),7.25(m,2H)。
实施例10
(E)-4-氟-4’-二甲基氨基-茋(7):
在室温下向磷酸酯17(246mg,1mmol)和4-二甲基氨基苯甲醛(149mg,1mmol)的DMF(2mL)的混合物中分份以固体形式加入KOtBu(224mg,2mmol)。所得混合物在室温下搅拌过夜。加入水(10mL),通过抽滤收集固体并用水洗涤,干燥得到190mg产物(80%)。
1H NMR(200MHz,CDCl3):δ2.99(s,6H),6.71(d,J=8.9Hz,2H),6.85(d,J=16.3Hz,1H),7.01(t,J=8.7Hz,2H),7.40(d,J=9.0Hz,2H),7.43(m,2H);13C NMR(200MHz,CDCl3):δ41.00,113.01,115.78,116.21,123.76,126.18,127.83,127.99,128.05,129.19,134.91,150.72,164.81.
实施例11
(E)-3-三丁基甲锡烷基-4’-二甲基氨基-茋(18)
在90℃下将5(139mg,0.38 mmol)、双-(三丁基锡)(0.4mL)和Pd(Ph3P)4(30mg)的混合溶剂(20mL,二烷∶三乙胺,3∶1)的混合物搅拌过夜。除去溶剂并将残余物通过PTLC纯化(Hex∶EtOAc,2∶1)得到35mg产物(18%,非最佳产率)。1H NMR(200MHz,CDCl3):δ0.94(t,J=7.2Hz,9H),1.08-1.66(m,18H),3.01(s,6H),6.75(m,2H),6.94(d,J=16.3Hz,1H),7.08(d,J=16.3Hz,1H),7.25-7.57(m,6H);13C NMR(50MHz,CDCl3):δ9.56,13.67,27.37,29.10,40.45,112.45,124.84,125.44,125.98,127.51,128.01,128.51,134.36,134.89,137.41,142.09,150.06;HRMS:m/z计算为C28H44NSn(MH+):514.2496;分析:514.2512.
实施例12
发射性碘标记的配体的制备
使用与5的三丁基锡前体的碘化甲锡烷基化反应制备所需的125I-标记的化合物。将过氧化氢(50μL,3%w/v)加入到在密封小瓶中的50μL相应的三丁基锡前体18(1μg/μL EtOH)、50μL 1N HCl和[125I]NaI(1-5mCi)的混合物中。室温下将该反应进行10分钟并通过加入100μL饱和NaHSO3将其终止。反应混合物用乙酸乙酯萃取(3×1mL),之后用饱和碳酸氢钠溶液中和。将合并的萃取液蒸发至干。残余物溶解在100μL的EtOH中并使用反相柱通过HPLC纯化(Waters C-18ubondpad,3.9×300mm),使用等度溶剂80%乙腈-20%缓冲剂,3,3-二甲基戊二酸(5mM,pH7.0),流速为0.8mL/min。将含有产物的所需馏分收集,浓缩,再次用乙酸乙酯萃取。将未加入载体的产物蒸发至干并再次溶解在100%EtOH(lμCi/μL)中,该最终125I探针的特异性活性为2,200Ci/mmole,发射化学纯度大于95%,贮藏在-20℃下至多6周,然后用于体外结合研究。
实施例13
使用聚集的Aβ(1-40)肽的溶液的结合试验
固体形式的肽Aβ(1-40)购自Bachem(King of Prussia,PA)。通过将该肽(0.5mg/mL)轻轻溶解在含有10mM磷酸钠和1mM EDTA的缓冲液(pH7.4)中进行肽聚集。在37℃下将该溶液培养36-42小时,同时轻轻且恒定地摇动。在12×75mm硼硅酸盐玻璃管中按照所述步骤1进行结合研究。将聚集的原纤维(在最终测定混合物中为10-50nM)加入到含有50μl发射性配体(0.01-0.5nM的40%EtOH溶液)和10%EtOH、最终体积为1mL的混合物中用于饱和研究。EtOH的最终浓度是10%。在有2μM硫黄素T的存在下定义为非特异性结合。就抑制研究而言,1mL该反应混合物含有40μl抑制剂(10-5-10-10M的10%EtOH中)和0.05nM发射性示踪剂的40%EtOH。在室温下将该混合物培养3小时,在室温下使用Brandel M-24R细胞收获器通过Whatman GF/B过滤器经真空过滤将结合和游离的发射活性分离,接着用2×3mL的10%乙醇洗涤。含有结合的I-125配体的过滤器在γ计数器(Packard5000)(计数效率是70%)中计数。在这些测定条件下,特异性结合部分的百分比小于总发射活性的20%。将饱和和抑制试验的结果使用软件EBDA2进行非线性回归分析,由此计算Kd和Ki取值。取值(Ki,nM)是3个独立试验的平均取值±SEM,每个试验重复一次。式I的化合物的其它Ki取值提供在图1和图2中。
在体外结合试验中,使用预先形成的合成肽的Aβ聚集物和[125I]TZDM作为配体,这些新的茋显示与TZ部位极高的结合亲和力(2-40nM),而与SB部位的亲和力非常低(>1,000nM)。显而易见,含有给电子基团如二甲基氨基-、-OH或-OMe基团的茋类,显示出对Aβ聚集物优异的结合亲和力。苯并噻唑环对在Aβ聚集物的TZ结合部位的结合似乎不必要。该信息是非常重要的,这是由于它减少了与TZ部位结合所需的分子的大小(TZDM和1的分子量分另是380和349);其本身显著提高了设计新配体的灵活性。碘化茋类,例如2和5呈现结构简单性,这提示结合Aβ聚集物的最低要求可能有3个:1)被乙烯基分开的两个苯环。2)一个芳族环含有电负性基团,二甲基氨基-、-OH或-OMe基团。3)对于在第二个芳族环上的取代似乎有体积耐受性。为了进一步表征这些化合物,发射性碘化配体,[125I]2是在有Na[125I]I和过氧化氢的情况下转化相应的三丁基锡衍生物制备的,由此以高产率获得没有加入载体的产物(发射化学纯度>95%)。该直接结合试验显示采用[125I]2的死后的AD脑切片的新评价提示,正如所预期的,该新的配体标记Aβ斑。
实施例14
新探针在正常小鼠体内的生物分布
在醚麻醉下,将0.15mL含有标记剂(5-10μCi)的盐水溶液直接注入ICR小鼠(2-3月龄,平均体重20-30g)的尾静脉。在照射后的不同时间点通过切除心脏将小鼠杀死。取出感兴趣的器官并称重,用自动γ计数器(Packard 5000)计数其发射活性。通过将组织计数与适当稀释的注射物料的等分试液比较,计算每个器官的百分比剂量。在如下假定下计算血液和肌肉的总活性:它们分别是总体重的7%和40%。
静脉内注射之后[125I]2在正常小鼠中的体内生物分布研究显示了良好的脑渗透性。在注射之后的2、30、60和120分钟,脑摄取分别是0.84、1.08、0.91和0.54%剂量/器官(在所有时间点,血液水平相对低,为5.2-3.6%剂量/器官)。与Aβ1-40聚集物结合的发射性配体是可饱和的,Kd是0.2nM。
尽管现在详细描述了本发明,但是本领域技术人员应理解的是,在条件、配方和其它参数的宽泛且等价的范围内,在不影响本发明的范围或其任何实施方式的情况下,同样可以实施。本文引证的所有专利、专利申请和出版物全部通过引用全文加入本文。
Claims (30)
1、通式II的化合物:
或其药用可接受的盐,
Z是O、S或NRa,其中
Ra是C1-4烷基;
在每一种情况下,R9、R10和R11独立地选自氢、卤素、C1-4烷基、氰基、羧基(C1-5)烷基、三氟甲基、硝基、甲基氨基、二甲基氨基、卤(C1-4)烷基和甲酰基;
R12选自如下基团:
a.C1-4烷硫基,
b.卤(C1-4)烷氧基,
c.羧基(C1-5)烷基,
d.羟基,
e.C1-4烷氧基,
f.NR13R14,其中
R13和R14是氢、氟(C1-4)烷基或C1-4烷基,
g.苯基(C1-4)烷基,
h.C6-10芳基,
i.杂芳基,
j.杂环,
k.杂环(C1-4)烷基,和
l.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下的取代基之一取代:C1-4烷硫基、C1-4烷基硫酰基、甲氧基、羟基、二甲基氨基或甲基氨基;
和,
X′是125I、123I、131I、18F、18氟(C1-4)烷基、[18氟(C1-4)烷基]氨基、[18氟(C1-4)烷基]烷基氨基、76Br、77Br或Sn(烷基)3。
2、权利要求1的化合物,其中
R11是氢。
3、权利要求1的化合物,其中
R9和R10是氢或C1-4烷基。
4、权利要求1的化合物,其中
Z是0。
5、权利要求1的化合物,其中
R9是氢,
R12是C1-4烷硫基、卤(C1-4)烷氧基、羟基、C1-4烷氧基或NR13R14,其中
R13和R14是氢、氟(C1-4)烷基或C1-4烷基。
6、权利要求5的化合物,其中
R10是氢。
7、权利要求1的化合物,其中
R12是甲硫基、羟基、甲氧基或NR13R14,
其中R13和R14是氢、氟(C1-4)烷基或甲基。
8、权利要求7的化合物,其中X′是123I。
9、通式III的化合物:
或其药用可接受的盐,其中:
R28是氢或C1-4烷基,
n等于0-4的数值,
Z是O、S或-CR15=CR16-,其中
R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和R25独立地选自如下基团:
a.氢、
b.C1-4烷硫基、
c.羟基、
d.C1-4烷氧基、
e.NR26R27,其中
R26和R27是氢或C1-4烷基,
f.苯基(C1-4)烷基、
g.C6-10芳基、
h.杂芳基、
i.杂环、
j.杂环(C1-4)烷基,和
k.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下取代基之一取代:C1-4烷硫基、C1-4烷基、甲氧基、羟基、二甲基氨基或甲基氨基;
条件是R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和R25中一个或多个不是氢;
和,
RP是氢或硫保护基团,例如甲氧基甲基、甲氧基乙氧基甲基、对-甲氧基苄基或苄基。
10、权利要求9的化合物,其中Z是0。
11、权利要求9的化合物,其中Z是S。
12、权利要求9的化合物,其中Z是
CR15=CR16,其中在每一种情况下,R15和R16如上所述。
13、权利要求9的化合物,其中
R17是NR26R27,其中
R26和R27如上所述,和
R15、R16、R18、R19、R20、R21、R22、R23、R24、R25和R28是氢。
14、权利要求12的化合物,其中n等于0。
15、权利要求9的化合物,其中R26和R27独立地是氢或C1-4烷基。
16、权利要求15的化合物,其中R26和R27是甲基。
17、一种含有发射性同位素络合物并且具有下式的化合物:
其中:
R28是氢或C1-4烷基,
n等于0-4的数值,
Z是O、S或-CR15=CR16-,其中
R15、R16、R17、R18、R19、R20、R21、R22、R23、R24和R25独立地选自如下基团:
a.氢、
b.C1-4烷硫基、
c.羟基、
d.C1-4烷氧基、
e.NR26R27,其中
R26和R27是氢或C1-4烷基,
f.苯基(C1-4)烷基、
g.C6-10芳基、
h.杂芳基、
i.杂环、
j.杂环(C1-4)烷基,和
k.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下取代基之一取代:C1-4烷硫基、C1-4烷基、甲氧基、羟基、二甲基氨基或甲基氨基;
条件是
a)R15、R16、R17、R18、R19、R21、R22、R24和R25中一个或多个不是氢;和
b)R20和R23之一选自如下基团:
a.氢、
b.苯基(C1-4)烷基、
c.C6-10芳基、
d.杂芳基、
e.杂环、
f.杂环(C1-4)烷基、和
g.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基;
R20和R23中的另一个代表未取代的位置。
18、通式IV的化合物:
或其药用可接受的盐,其中
n等于0-4的数值,
R29、R30、R31、R32、R33、R34和R35独立地选自如下基团:
a.氢,
b.C1-4烷硫基,
c.C1-4烷基磺酰基,
d.羟基,
e.C1-4烷氧基,
f.NR6R7,其中
R6和R7是氢或C1-4烷基,
g.苯基(C1-4)烷基,
h.C6-10芳基,
i.杂芳基,
j.杂环,
k.杂环(C1-4)烷基,和
l.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下的取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基;
条件是R29至R35中的一个是一烷基氨基苯基或二烷基氨基苯基;和
RP是氢或硫保护基团,例如甲氧基甲基、甲氧基乙氧基甲基、对-甲氧基苄基或苄基。
19、权利要求18的化合物,其中
R34是一烷基氨基苯基或二烷基氨基苯基。
20、权利要求18的化合物,其中
R34是一甲基氨基苯基或二甲基氨基苯基,
R29、R30、R31、R32、R33和R35是氢,并且
N等于0。
21、权利要求18的化合物,其中
R32是一烷基氨基苯基或二烷基氨基苯基。
22、权利要求21的化合物,其中
R32是一甲基氨基苯基或二甲基氨基苯基,
R29、R30、R31、R33、R34和R35是氢,并且
N等于0。
23、一种含有发射性同位素络合物并且具有下式的化合物:
其中:
n等于0-4的数值,
R29、R30、R31、R32、R33、R34和R35独立地选自如下基团:
a.氢、
b.C1-4烷硫基、
c.C1-4烷基磺酰基、
d.羟基、
e.C1-4烷氧基、
f.NR6R7,其中
R6和R7是氢或C1-4烷基,
g.苯基(C1-4)烷基、
h.C6-10芳基、
i.杂芳基、
j.杂环、
k.杂环(C1-4)烷基,和
l.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基;
条件是
a)R33至R35中的一个是一烷基氨基苯基或二烷基氨基苯基;和
b)R29和R32之一选自如下基团:
a.氢、
b.苯基(C1-4)烷基、
c.C6-10芳基、
d.杂芳基、
e.杂环、
f.杂环(C1-4)烷基、和
g.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基;
R29和R32中的另一个代表未取代的位置。
24、权利要求8的化合物,其中X′是18氟甲基、18氟乙基或18氟丙基。
25、通式V的化合物:
或其药用可接受的盐,其中:
R选自如下基团:
a.C1-4烷硫基、
b.卤(C1-4)烷氧基、
c.羧基(C1-5)烷基、
d.羟基、
e.C1-4烷氧基、
f.NR36R37,其中
R36和R37是氢、氟(C1-4)烷基或C1-4烷基、
g.苯基(C1-4)烷基、
h.C6-10芳基、
i.杂芳基、
j.杂环、
k.杂环(C1-4)烷基、
l.C3-6环烷基,
其中所述苯基(C1-4)烷基、C6-10芳基、杂芳基、杂环、杂环(C1-4)烷基或C3-6环烷基被如下的取代基之一取代:C1-4烷硫基、C1-4烷基磺酰基、甲氧基、羟基、二甲基氨基或甲基氨基,和
m.烷基;和
RP是氢或硫保护基团。
26、权利要求25的化合物,其中所述保护基团选自:甲氧基甲基、甲氧基乙氧基甲基、对-甲氧基苄基或苄基。
27、药用组合物,包含权利要求1-26任一项的化合物。
28、用于成像淀粉样蛋白沉积物的诊断组合物,它包括权利要求1-24任一项的发射性标记化合物;和
药用可接受的赋形剂或稀释剂。
29、用于成像淀粉样蛋白沉积物的方法,该方法包括:
a.将可检测量的权利要求28的诊断组合物引入到哺乳动物体内;和
b.使所述标记化合物与淀粉样蛋白沉积物结合足够的时间;和
c.检测与一种或多种淀粉样蛋白沉积物结合的所述标记化合物。
30、抑制哺乳动物体内淀粉样蛋白斑聚集的方法,该方法包括给予有效抑制淀粉样蛋白斑聚集量的权利要求27的组合物。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105622431A (zh) * | 2011-01-28 | 2016-06-01 | 肯塔基大学研究基金会 | 茋类似物和治疗癌症的方法 |
CN103709050A (zh) * | 2012-09-28 | 2014-04-09 | 中山大学 | 白藜芦醇衍生物及其在制备抗阿尔茨海默病药物中的应用 |
Also Published As
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EP1432453A4 (en) | 2007-01-24 |
US7250525B2 (en) | 2007-07-31 |
HK1110313A1 (en) | 2008-07-11 |
EP1432453A1 (en) | 2004-06-30 |
CA2456411A1 (en) | 2003-03-06 |
AU2008203856B2 (en) | 2011-02-17 |
US20080108840A1 (en) | 2008-05-08 |
ES2435070T3 (es) | 2013-12-18 |
US20060002853A1 (en) | 2006-01-05 |
CN1549731A (zh) | 2004-11-24 |
US7297820B2 (en) | 2007-11-20 |
WO2003018070A1 (en) | 2003-03-06 |
AU2008203856B8 (en) | 2011-02-24 |
KR100947913B1 (ko) | 2010-03-17 |
EP1432453B1 (en) | 2013-08-14 |
CA2456411C (en) | 2011-02-15 |
AU2002323417B2 (en) | 2008-05-15 |
CN1299777C (zh) | 2007-02-14 |
JP2009197037A (ja) | 2009-09-03 |
TWI267381B (en) | 2006-12-01 |
AU2008203856A1 (en) | 2008-09-04 |
JP4436928B2 (ja) | 2010-03-24 |
US7759502B2 (en) | 2010-07-20 |
KR20040029093A (ko) | 2004-04-03 |
US20030149250A1 (en) | 2003-08-07 |
DK1432453T3 (da) | 2013-11-18 |
CN101003526B (zh) | 2012-02-22 |
JP2005504055A (ja) | 2005-02-10 |
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