CN1976928A - 作为5-羟基色胺-6配体的吲哚基烷基胺代谢物 - Google Patents
作为5-羟基色胺-6配体的吲哚基烷基胺代谢物 Download PDFInfo
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- CN1976928A CN1976928A CNA2005800206836A CN200580020683A CN1976928A CN 1976928 A CN1976928 A CN 1976928A CN A2005800206836 A CNA2005800206836 A CN A2005800206836A CN 200580020683 A CN200580020683 A CN 200580020683A CN 1976928 A CN1976928 A CN 1976928A
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- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 239000007885 tablet disintegrant Substances 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
本发明提供式I化合物及其用于治疗性治疗与5-HT6受体相关或受其影响的病症的用途。
Description
技术领域
本发明涉及作为5-羟基色胺-6配体的吲哚基烷基胺代谢物、含有其的医药组合物、使用其的治疗方法和使用其来测定(1-芳基磺酰基-1H-吲哚-3-基)乙胺衍生物的代谢的方法。
背景技术
诸如焦虑、抑郁、运动障碍等的各种中枢神经系统病症被认为涉及神经递质5-羟基色胺(5-HT)或血清素的紊乱。血清素局限于中枢及外周神经系统中,且已知其影响多种类型的病状,尤其包括精神病症、运动、摄食行为、性行为和神经内分泌调控。血清素的作用是由各种5-HT受体亚型调控的。已知的5-HT受体包括5-HT1家族(例如5-HT1A)、5-HT2家族(例如5-HT2A)、5-HT3、5-HT4、5-HT5、5-HT6和5-HT7亚型。
已经克隆人类5-羟基色胺-6(5-HT6)受体亚型,且已经报导其mRNA的广泛分布。已经在嗅结节、纹状体、伏隔核(nucleus accumbens)、齿状回和海马体的CA1、CA2及CA3区中观测到最高含量的5-HT6受体mRNA。而在小脑粒层、若干间脑核、扁桃体和皮层中发现较低含量的5-HT6受体mRNA。Northern印迹法已经揭示5-HT6受体mRNA似乎在大脑中广泛存在,而关于其在外周组织中存在的证据却很少。除5-HT6受体的mRNA局限于纹状体、嗅结节和伏隔核中之外,多种抗精神病药剂对5-HT6受体的高亲和力表明这些化合物的一些临床作用可能是经由所述受体介导。因此,认为5-HT6受体配体在治疗某些CNS病症(例如焦虑、抑郁、癫痫、强迫症、注意力不足症、偏头痛、认知记忆力增强(例如用于治疗阿兹海默氏病(Alzheimer′s disease))、睡眠障碍、摄食障碍(例如厌食症或贪食症)、神经退化病症(例如中风或头部外伤)、恐慌发作、戒除药物滥用(例如可卡因、酒精、尼古丁或苯二氮卓(benzodiazepine))、精神分裂症等等)或治疗某些肠胃障碍(例如肠易激综合症)方面具有潜在用途。
诸如专利申请公开案US2003-0171353A-1中所述衍生物的吲哚基烷基胺衍生物为有效且具选择性的5-HT6配体。至今为止,尚未确认、分离、纯化或合成所述吲哚基烷基胺衍生物的代谢物。
因此,本发明的一目的在于提供作为吲哚基烷基胺5-HT6配体的代谢物且适用作治疗与5-HT6受体相关或受其影响的各种中枢神经系统病症的治疗剂的化合物。
本发明的另一目的在于提供适用于治疗由5-HT6配体缓解的中枢神经系统病症的治疗方法和医药组合物。
本发明的另一目的在于提供测定吲哚基烷基胺衍生物的代谢的方法。
通过下文所述的实施方式,本发明的这些及其它目的和特征将变得更加显而易见。
发明内容
本发明提供式I化合物:
其中
Q为CO2R5或CH2NR6COR7;
R1为H或C1-C6烷基;
R2为各自视情况经取代的芳基或杂芳基,或在桥头具有N原子且视情况含有1、2或3个选自N、O或S的额外杂原子的视情况经取代的8至13元双环或三环系统;
R3和R4各自独立地为H、卤素、CN、OCO2R8、CO2R9、CONR10R11、CNR12NR13R14、SOmR15、NR16R17、OR18、COR19或C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、环杂烷基、芳基或杂芳基,其各自视情况经取代;
R5和R6各自独立地为H或C1-C6烷基;
R7为C1-C6烷基或
m为0或者整数1或2;
R8、R9、R15和R19各自独立地为H或各自视情况经取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、环杂烷基、芳基或杂芳基;
R10、R11和R18各自独立地为H或各自视情况经取代的C1-C6烷基、芳基或杂芳基;或者R10和R11可与其所连接的原子一起形成视情况含有选自O、N或S的另一杂原子的5至7元环;且
R12、R13、R14、R16和R17各自独立地为H或各自视情况经取代的C1-C4烷基、芳基或杂芳基;或者R13和R14或R16和R17可与其所连接的原子一起形成视情况含有选自O、N或S的另一杂原子的5至7元环;或
其立体异构体或其医药学上可接受的盐。
本发明还提供适用于治疗性治疗与5-HT6受体相关或受其影响的中枢神经系统病症的方法和组合物以及测定吲哚基烷基胺衍生物的代谢的方法。
附图说明
无
具体实施方式
结合5-羟基色胺-6(5-HT6)受体在大脑中的令人关注的分布,所述受体结合多种用于精神病学的治疗性化合物的能力已经刺激人们显著关注能够与所述受体相互作用或影响所述受体的新颖化合物。主要致力于了解5-HT6受体在精神病学、认知功能障碍、运动功能及控制、记忆力、情绪等等中的可能作用。为此,迫切需要寻求作为用于治疗中枢神经系统病症的潜在治疗剂的化合物,其证实对5-HT6受体具有结合亲和力,例如参看C.Reavill和D.C.Rogers,Current Opinion in Investigational Drugs,2001,2(1):104-109,Pharma Press Ltd。
对5-HT6受体具有有效且具选择性的结合亲和力的吲哚基烷基胺衍生物及其制备在专利申请公开案US2003-0171353A-1(其以引用的方式并入本文)中有所描述。至今为止,尚未确认、分离、纯化或合成所述吲哚基烷基胺衍生物的代谢物。
令人惊奇的是,现在已经发现式I化合物为吲哚基烷基胺5-HT6衍生物的代谢物。有利的是,所述式I化合物可用作治疗与5-HT6受体有关或受其影响的中枢神经系统(CNS)病症的有效治疗剂。因此,本发明提供式I化合物:
其中
Q为CO2R5或CH2NR6COR7;
R1为H或C1-C6烷基;
R2为各自视情况经取代的芳基或杂芳基,或在桥头具有N原子且视情况含有1、2或3个选自N、O或S的额外杂原子的视情况经取代的8至13元双环或三环系统;
R3和R4各自独立地为H、卤素、CN、OCO2R8、CO2R9、CONR10R11、CNR12NR13R14、SOmR15、NR16R17、OR18、COR19或C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、环杂烷基、芳基或杂芳基,其各自视情况经取代;
R5和R6各自独立地为H或C1-C6烷基;
R7为C1-C6烷基或
m为0或者整数1或2;
R8、R9、R15和R19各自独立地为H或各自视情况经取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、环杂烷基、芳基或杂芳基;
R10、R11和R18各自独立地为H或各自视情况经取代的C1-C6烷基、芳基或杂芳基;或者R10和R11可与其所连接的原子一起形成视情况含有选自O、N或S的另一杂原子的5至7元环;且
R12、R13、R14、R16和R17各自独立地为H或各自视情况经取代的C1-C4烷基、芳基或杂芳基;或者R13和R14或R16和R17可与其所连接的原子一起形成视情况含有选自O、N或S的另一杂原子的5至7元环;或
其立体异构体或其医药学上可接受的盐。
如说明书和权利要求中所用,术语卤素表示Br、Cl、I或F。术语环杂烷基表示含有1或2个选自N、O或S的可相同或不同的杂原子且视情况含有一个双键的5至7元环烷基环系统。本文所表示的术语中所包括的环杂烷基环系统的实例为以下各环,其中X为NR、O或S,且R为H或如下文所述的可选取代基:
类似地,如说明书和权利要求中所用,术语杂芳基表示含有1、2或3个选自N、O或S的可相同或不同的杂原子的5至10元芳环系统。所述杂芳基环系统包括吡咯基、唑基、噁唑基、噻唑基、咪唑基、呋喃基、噻吩基、喹啉基、异喹啉基、吲哚基、苯并噻吩基、苯并呋喃基、苯并异噁唑基等等。术语芳基表示(例如)具有6-14个碳原子的碳环芳环系统,诸如苯基、萘基、蒽基等等。如本文所用的术语卤代烷基表示具有1至2n+1个可相同或不同的卤素原子的CnH2n+1基团,且如本文所用的术语卤代烷氧基表示具有1至2n+1个可相同或不同的卤素原子的OCnH2n+1基团。
如本文所表示的术语中所包括的8至13元双环或三环系统(其在桥头具有N原子且视情况含有1、2或3个选自N、O或S的额外杂原子)的实例为以下环系统,其中W为NR、O或S,且R为H或如下文所述的可选取代基:
在说明书和权利要求中,当术语C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、环杂烷基、芳基、杂芳基或在桥头具有N原子的8至13元双环或三环系统被表示为视情况经取代时,视情况存在的取代基可为一个或一个以上(例如两个或三个),且与通常用于开发医药化合物或修饰所述化合物以影响其结构/活性、持续性、吸收、稳定性或其它有益性质的取代基相同或不同。所述取代基的特定实例包括卤素原子、硝基、氰基、硫氰氧基、氰氧基、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、烷基氨基、二烷基氨基、甲酰基、烷氧羰基、羧基、烷酰基、烷硫基、烷基亚磺酰基、烷基磺酰基、氨甲酰基、烷基酰胺基、苯基、苯氧基、苯甲基、苯甲氧基、杂芳基、环杂烷基或环烷基,优选为卤素原子或C1-C6烷基。通常可存在0-3个相同或不同的取代基。当任何前述取代基表示或含有烷基取代基(例如烷氧基、烷酰基)时,其可为直链或支链的且可含有至多12个、优选至多6个、更优选至多4个碳原子。
医药学上可接受的盐可为由式I化合物与医药学上可接受的酸(诸如磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、乙酸、乳酸、硝酸、磺酸、对甲苯磺酸、甲烷磺酸等等)形成的任何酸加成盐。
本发明化合物包括酰胺、酯、氨基甲酸酯或其它常规前药形式,其一般为本发明化合物的官能衍生物且易于在活体内转化成本发明的活性部分。相应地,本发明的方法涵盖用式I化合物或未特定揭示但在投与后随即于活体内转化成式I化合物的化合物治疗上文所述的各种病状。还包括本发明化合物的代谢物,其被定义为在将这些化合物引入生物系统中之后所产生的活性物质。
当式I化合物含有一个或一个以上手性中心或不对称碳时,所述式I化合物可以一种或一种以上的立体异构体形式存在。各种立体异构体包括对映异构体、非对映异构体、位阻异构体和几何异构体。所属领域技术人员将认识到,当一种立体异构体相对于其它立体异构体富集时或当与其它立体异构体分离时,其可能更具活性或者可呈现有益作用。此外,熟练技术人员了解如何分离、富集或选择性地制备所述立体异构体。因此,本发明包含式I化合物、其立体异构体及其医药学上可接受的盐。本发明化合物可以立体异构体的混合物、单独立体异构体或光学活性形式存在。
优选的本发明化合物为其中R1、R3和R4为H的式I化合物。其中R2为各自视情况经取代的咪唑基或咪唑并噻唑基的式I化合物也是优选的。另一组优选的式I化合物为其中Q是
CO2H,CH2NHCOCH3或
的化合物。
更优选的本发明化合物为其中R1、R3和R4为H且R2为各自视情况经取代的咪唑基或咪唑并噻唑基的式I化合物。另一组更优选的化合物为其中R1、R3和R4为H且R2为各自视情况经取代的咪唑基或咪唑并噻唑基且Q为CH2NHCOCH3或
的式I化合物。
优选的本发明化合物为:
N-(2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙基)乙酰胺;
1-O-{[(2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙基)氨基]羰基}-β-D-葡吡喃糖醛酸;
{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙酸;
N-[(1-{[4-氯-2-(甲硫基)-1H-咪唑-5-基]磺酰基}-1H-吲哚-3-基)甲基]乙酰胺;其立体异构体;或其医药学上可接受的盐。
可使用常规合成方法且在必要时使用标准分离和离析技术方便地制备本发明化合物。举例而言,可通过使式II的吲哚衍生物与强碱(例如正丁基锂、KOt-Bu或NaH)和芳基磺酰基卤化物ClSO2R2依次反应来制备其中Q为CO2R5的式I化合物(Ia)。所述反应显示于流程图I中。
流程图I
可通过在碱(诸如N(C2H5)3)存在下且视情况在催化量的4-二甲基氨基吡啶(DMAP)存在下使式III化合物与式IV的酸酐反应来制备其中Q为CH2NR6COR7且R7为C1-C6烷基的式I化合物(Ib)。所述反应显示于流程图II中。
流程图II
可通过以下步骤制备其中Q为O-葡吡喃糖醛酸的式I化合物(Ic):在催化量的DMAP存在下使式III化合物与二碳酸二叔丁酯[(Boc)2O]和CH3CN反应以当场形成式IV的异氰酸酯;及使所述异氰酸酯与式V的羟基葡糖醛酸酯反应以生成式VI的氨甲酰酯;并用碱(诸如LiOH)水解所述酯以生成所要的式Ic化合物。反应流程显示于流程图III中,其中Ac表示COCH3。
流程图III
式II化合物可由商业来源获得,或者可易于使用已知合成方法来制备,例如Baldi,B.G.等人,Journal of Labelled Compounds and Radiopharmaceuticals(1985),22(3),279-285或Samizu,K.和Ogasawara,K.,Synlett(1994),(7),499-500。
式III化合物及其制备在US 2003-0171353A-1、US 6,187,805和US 6,403,808中有所描述。
或者,可通过将吲哚基烷基胺衍生物(例如式III化合物)提供给哺乳动物测试受检者并从所述受检者的血浆中分离式I化合物来获得式I化合物。
有利的是,本发明的式I化合物适用于治疗与5-HT6受体相关或受其影响的中枢神经系统病症,诸如焦虑症、情绪障碍、精神病症、认知障碍或神经退化病症等等,例如阿兹海默氏病、注意力不足症、急性焦虑症、一般焦虑症、癫痫、抑郁、强迫症、偏头痛、睡眠障碍、神经退化病症(诸如头部外伤或中风)、摄食障碍(诸如厌食症或贪食症)、精神分裂症、记忆力丧失、与戒除药物或尼古丁滥用相关的病症等等或某些肠胃障碍(诸如肠易激综合症)。因此,本发明提供在有需要的患者体内治疗与5-HT6受体相关或受其影响的中枢神经系统(CNS)病症的方法,其包含向所述患者提供治疗有效量的如上文所述的式I化合物。可通过经口或非经肠投与或以已知可将治疗剂有效投与有需要的患者的任何常用方式提供所述化合物。
针对特定CNS病症治疗所提供的治疗有效量可根据所治疗的特定病状、患者的体形、年龄和反应模式、病症严重性、主治医师的判断等等而有所变化。一般而言,用于每日经口投与的有效量可为约0.01至1,000mg/kg、优选为约0.5至500mg/kg,且用于非经肠投与的有效量可为约0.1至100mg/kg、优选为约0.5至50mg/kg。
在实践中,通过投与固体或液体形式的化合物或前体(其为纯净的或与一种或一种以上常规医药载剂或赋形剂组合)来提供本发明化合物。因此,本发明提供包含医药学上可接受的载剂和有效量的如上文所述的式I化合物的医药组合物。
适用于本发明组合物中的固体载剂包括一种或一种以上还可用作调味剂、润滑剂、增溶剂、悬浮剂、填充剂、助流剂、压制助剂、粘合剂、片剂崩解剂或囊封材料的物质。在粉剂中,载剂可为与细碎的式I化合物相混合的细碎固体。在片剂中,可将式I化合物与具有必需压制性质的载剂以合适比例相混合并压制成所要形状及大小。所述粉剂和片剂可含有至多99重量%的式I化合物。适用于本发明组合物中的固体载剂包括磷酸钙、硬脂酸镁、滑石粉、糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、低熔点蜡和离子交换树脂。
任何适用于制备溶液、悬浮液、乳液、糖浆和酏剂的医药学上可接受的液体载剂都可用于本发明组合物中。可将式I化合物溶解或悬浮于医药学上可接受的液体载剂中,诸如溶解或悬浮于水、有机溶剂或医药学上可接受的油或脂肪或其混合物中。所述液体组合物可含有其它合适的医药添加剂,诸如增溶剂、乳化剂、缓冲剂、防腐剂、甜味剂、调味剂、悬浮剂、增稠剂、着色剂、粘度调节剂、稳定剂、渗透调节剂等等。适用于经口和非经肠投与的液体载剂的实例包括水(尤其含有上述添加剂,例如纤维素衍生物,优选为羧甲基纤维素钠溶液)、醇类(包括一元醇和多元醇,例如二醇)或其衍生物,或油类(例如经分馏的可可油和花生油)。为用于非经肠投与,载剂也可为油酯,例如油酸乙酯或肉豆蔻酸异丙酯。
作为无菌溶液或悬浮液的本发明组合物适用于肌内、腹膜内或皮下注射。也可静脉内投与无菌溶液。适用于经口投与的本发明组合物可为液体或固体组合物形式。
有利的是,式I化合物可用于确认或测定吲哚基烷基胺衍生物的吸收或代谢。因此,本发明提供测定(1-芳基磺酰基-1H-吲哚-3-基)乙胺衍生物的代谢的方法,其包含评估测试样品中式I化合物的存在。
为了更清晰地了解且为了更清晰地说明本发明,下文阐述其特定实例。以下实例仅具说明性,且不应理解为以任何方式对本发明的范畴和基本原则构成限制。
除非另外说明,否则所有份数都是重量份数。术语NMR和HPLC分别表示核磁共振和高效液相色谱。术语THF表示四氢呋喃。
实例1
制备N-(2-{1-[(6-氯-咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}-乙基)乙酰胺
在室温下,于氮下用催化性4-二甲基氨基吡啶(DMAP)(约5mg)处理2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙胺盐酸盐(417mg,1.00mmol)于二氯甲烷和三乙胺(0.40mL,3.0mmol)中的经搅拌混合物。用乙酸酐(0.30mL,3.2mmol)处理所述均匀混合物且反应变成均匀的。16h后,用饱和NaHCO3水溶液(8mL)处理反应0.3h,然后用二氯甲烷萃取。合并萃取物,经MgSO4干燥并真空浓缩成泡沫。用20∶80乙酸乙酯∶己烷处理泡沫并真空浓缩成固体。用醚湿磨所述固体并过滤。干燥滤饼以提供389mg(92%产率)白色固体状的标题产物,mp 150-152℃,以C H N元素分析和1H NMR对其进行表征。
实例2
制备{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基]磺酰基]-1H-吲哚-3-基}乙酸
在氮下将3-吲哚基乙酸(175mg,1.00mmol)于THF中的经搅拌溶液冷却至-78℃,并经10min的时期用己烷中的2.5M正丁基锂(0.84mL,2.10mmol)逐份处理。在-78℃下历时1h后,用THF中的(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰氯(257mg,1.00mmol)处理反应混合物,将其温至周围温度,搅拌24h并真空浓缩。用1M HCl水溶液(约2mL)和水(3mL)处理所得残余物并用二氯甲烷萃取。合并萃取物,干燥(MgSO4)并真空浓缩。用乙酸乙酯洗提,对所述残余物执行色谱法以提供32mg浅棕黄色固体状的标题化合物,mp 220-222℃(在>200℃时变黑),以质谱和NMR分析加以确认。
实例3
制备3,4,5-三乙酰氧基-6-(2-(1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙基氨甲酰氧基)四氢吡喃-2-羧酸甲酯
将(Boc)2O(1.8g,8.3mmol,1.2eq)于CH3CN中的溶液冷却至0℃(冰-水浴),用CH3CN中的DMAP(203mg,1.66mmol,0.2eq)逐滴处理,搅拌5min,用CH3CN中的2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙胺(2.6g,6.9mmol)逐滴处理,在0℃下搅拌30min(当场产生异氰酸酯),使用旋转蒸发器浓缩以去除CH3CN并用甲苯驱赶。将所得残余物溶解于甲苯中,用羟基葡糖醛酸酯(2.6g,7.7mmol,1.1eq)于甲苯中的溶液逐滴处理,随后用三乙胺(1.2mL)逐滴处理,在0℃下搅拌2h,将其温至室温,搅拌16h并浓缩至干。通过管柱色谱法(庚烷中的20-50%THF作为洗提剂)纯化所述残余物以提供2g(39%产率)标题产物的纯β异头物和2.5g(49%产率)α与β异头物的混合物(1∶1.6)。通过NMR分析来确认异头物。1H NMR(300MHz,CDCl3):β异头物4:8.01(d,1H,J=4.5Hz),7.95-7.91(m,1H),7.53-7.50(m,1H),7.45(s,1H),7.35-7.26(2H,m),7.17(d,1H,J=4.5Hz),5.74(d,1H,J=8.1Hz),5.36-5.09(m,3H),4.99(1H,m),4.19(d,1H,J=9.9Hz),3.75(s,3H),3.57-3.41(2H,m),2.92(2H,t,J=7.0Hz),2.04,2.03,2,02(3s,9H)。MS[M+H]+=741。α异头物(200mg,含有2%β异头物),1HNMR(300MHz,CDCl3):8.03(d,1H,J=4.2Hz),7.94-7.91(m,1H),7.56-7.53(m,1H),7.45(s,1H),7.35-7.26(2H,m),7.14(d,1H,J=4.8Hz),6.33(d,1H,J=3.6Hz),5.52-5.46(m,1H),5.26-5.10(3H,m),4.38(d,1H,J=10.2Hz),3.74(s,3H),3.57-3.46(2H,m),2.92(2H,t,J=7.0Hz),2.03(3s,9H)。
实例4
制备1-O-{[(2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙基)氨基]羰基}-β-D-葡吡喃糖醛酸
用CH3OH(38.8mL)和H2O(10mL)处理3,4,5-三乙酰氧基-6-(2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙基氨甲酰氧基)四氢吡喃-2-羧酸甲酯(1.0g,1.35mmol)于THF中的溶液,冷却至0℃(冰-水浴),用LiOH·H2O(340mg,8.1mmol,6eq)于H2O(5.5mL)中的溶液[0.1N LiOH/MeOH/THF/H2O]处理并在0℃下于N2气氛下搅拌2h。经由反相TLC(SiO2-C18 MeCN/H2O,3/7)监测去保护进程。用150mL H2O稀释反应混合物,通过加入10g安珀莱特-120(amberlite-120)(正)阳离子交换材料(H+形式)进行中和并过滤。将滤液减压浓缩成水性悬浮液。将所述悬浮液冷冻干燥并冻干以生成700mg(86%产率)标题产物。通过硅胶管柱色谱法(CHCl3/CH3OH/H2O(7∶3∶0.5)作为洗提剂)进一步纯化以提供310mg标题产物(98%纯度),以质谱和NMR分析加以确认。1H NMR(300MHz,DMSO-d6):8.31(d,1H,J=4.5Hz),7.94-7.91(m,1H),7.82(s,1H),7.69(d,1H,J=4.2Hz),7.64-7.57(m,2H),7.39-7.27(m,2H),5.31(d,1H,J=8.1Hz),3.69(d,1H,J=9.0Hz),3.37-3.13(m,5H),2.82(t,2H,J=7.0Hz);13C(75MHz,DMSO-d6):170.6,155.4,155.3,152.3,139.2,134.9,131.6,125.7,124.5,124.4,121.1,121.1,120.7,118.8,116.6,113.8,95.5,76.6,76.5,72.8,72.0,25.2;LC/MS(ESI)滞留时间=35.12,[M+H]+=600.7。
以上述相同方式获得α异头物(57mg),以HPLC和质谱分析加以确认。LC/MS(ESI)滞留时间=27.11min,[M+H]+=600.8。
实例5
比较性评估测试化合物的5-HT6结合亲和力
以如下方式评估测试化合物对血清素5-HT6受体的亲和力。采集表达人类克隆5-HT6受体的经培养Hela细胞并低速(1,000×g)离心10.0min以去除培养基。将所采集细胞悬浮于一半体积的新鲜生理磷酸盐缓冲食盐水溶液中并以相同速度再离心。重复所述操作。然后在10体积的50mM Tris.HCl(pH7.4)和0.5mM EDTA中均质化所收集细胞。在40,000×g下将匀浆离心30.0min并收集沉淀物。将所得离心块再悬浮于10体积的Tris.HCl缓冲液中并以相同速度再离心。将最终离心块悬浮于少量Tris.HCl缓冲液中,并以10-25μl体积的等分试样测定组织蛋白含量。在根据Lowry等人,
J.Biol.Chem.,193:265(1951)中所述的方法的蛋白测定中使用牛血清白蛋白作为标准物。调节所悬浮细胞膜的体积以得到1.0mg/ml悬浮液的组织蛋白浓度。将所制备的膜悬浮液(10倍浓度)等分成1.0ml体积,并存储在-70℃下直到用于随后结合实验中为止。
以96孔微量滴定板格式进行结合实验,总体积为200μl。向各孔中加入以下混合物:在含有10.0mM MgCl2和0.5mM EDTA的50mM Tris.HCl缓冲液(pH7.4)中所制得的80.0μl培育缓冲液,和20μl[3H]-LSD(S.A.,86.0Ci/mmol,购自Amersham Life Science)(3.0nM)。如用递增浓度的[3H]LSD进行的饱和结合所测定,[3H]LSD对人类血清素5-HT6受体的解离常数KD为2.9nM。通过最终加入100.0μl组织悬浮液来开始反应。在10.0μM甲基硫氨酸复合制剂(methiothepin)存在下测量非特异性结合。加入20.0μl体积的测试化合物。
使反应在室温下于黑暗中进行120min,此时将所结合的配体-受体复合物过滤到具备Packard Filtermate196 Harvester的96孔过滤型微孔板(unifilter)上。在将40.0μlMicroscin-20闪烁体加入各浅孔中之后,将过滤片上所采集的结合复合物风干并在配备有6个光电倍增管检测器的Packard TopCoun中测量放射性。热封过滤型微孔板并在PackardTopCoun中以31.0%的氚效率计数。
与5-HT6受体的特异性结合被定义为总结合放射性减去在10.0μM未标记甲基硫氨酸复合制剂存在下所结合的量。在各种浓度的测试化合物存在下的结合被表达为在没有测试化合物存在下特异性结合的百分比。以log结合%对测试化合物的log浓度对结果进行作图。用计算机辅助型程序Prism进行数据点的非线性回归分析,得到测试化合物的IC50和KI值,置信限度为95%。对数据点的线性回归线作图,自其确定IC50值并基于以下等式确定KI值:KI=IC50/(1+L/KD)
其中L为所用放射性配体的浓度且KD为受体的配体的解离常数,都以nM表示。
使用所述检定,确定以下Ki值并将其与通过已知的代表性化合物获得的值进行对比以证实与5-HT6受体的结合。数据显示于下表I中。
表I
测试化合物(实例编号) | 5-HT6结合Ki(nM) |
124 | 26248 |
5-HT6结合Ki | |
比较实例 | (nM) |
氯扎平(Clozapine) | 6.0 |
洛沙平(Loxapine) | 41.4 |
溴麦角隐亭(Bromocriptine) | 23.0 |
甲基硫氨酸复合制剂 | 8.3 |
米安舍林(Mianserin) | 44.2 |
奥氮平(Olanzepine) | 19.5 |
自上述结果可见,本发明化合物证实对5-HT6受体的显著亲和力。
Claims (13)
1.一种式I化合物:
其中
Q为CO2R5或CH2NR6COR7;
R1为H或C1-C6烷基;
R2为各自视情况经取代的芳基或杂芳基,或在桥头具有N原子且视情况含有1、2或3个选自N、O或S的额外杂原子的视情况经取代的8至13元双环或三环系统;
R3和R4各自独立地为H、卤素、CN、OCO2R8、CO2R9、CONR10R11、CNR12NR13R14、SOmR15、NR16R17、OR18、COR19或C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、环杂烷基、芳基或杂芳基,其各自视情况经取代;
R5和R6各自独立地为H或C1-C6烷基;
m为0或者整数1或2;
R8、R9、R15和R19各自独立地为H或各自视情况经取代的C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、环杂烷基、芳基或杂芳基;
R10、R11和R18各自独立地为H或各自视情况经取代的C1-C6烷基、芳基或杂芳基;或者R10和R11可与其所连接的原子一起形成视情况含有选自O、N或S的另一杂原子的5至7元环;且
R12、R13、R14、R16和R17各自独立地为H或各自视情况经取代的C1-C4烷基、芳基或杂芳基;或者R13和R14或R16和R17可与其所连接的原子一起形成视情况含有选自O、N或S的另一杂原子的5至7元环;或其立体异构体或其医药学上可接受的盐。
2.根据权利要求1所述的化合物,其中R1、R3和R4为H。
3.根据权利要求1或2所述的化合物,其中R2为各自视情况经取代的咪唑基或咪唑并噻唑基。
5.根据权利要求1所述的化合物,其选自由下列各物组成的群组:
N-(2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙基)乙酰胺;
1-O-{[(2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙基)氨基]羰基}-β-D-葡吡喃糖醛酸;
{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙酸;
N-[(1-{[4-氯-2-(甲硫基)-1H-咪唑-5-基]磺酰基}-1H-吲哚-3-基)甲基]乙酰胺;
其立体异构体;及
其医药学上可接受的盐。
6.根据权利要求5所述的化合物,其为N-(2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙基)乙酰胺。
7.根据权利要求5所述的化合物,其为1-O-{[(2-{1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1H-吲哚-3-基}乙基)氨基]羰基}-β-D-葡吡喃糖醛酸。
8.一种用于在有需要的患者体内治疗与5-HT6受体相关或受其影响的中枢神经系统病症的方法,其包含向所述患者提供治疗有效量的根据权利要求1至7中任一权利要求所述的式I化合物。
9.根据权利要求8所述的方法,其中所述病症选自由神经退化病症、焦虑症和认知障碍组成的群组。
10.根据权利要求9所述的方法,其中所述焦虑症或认知障碍选自由注意力不足症、强迫症和一般焦虑症组成的群组。
11.一种医药组合物,其包含医药学上可接受的载剂和有效量的根据权利要求1至7中任一权利要求所述的式I化合物。
12.一种测定(1-芳基磺酰基-1H-吲哚-3-基)乙胺衍生物的代谢的方法,其包含评估测试样品中根据权利要求1至7中任一权利要求所述的式I化合物的存在。
13.一种根据权利要求1至7中任一权利要求所述的化合物的用途,其用于制造用以治疗神经退化病症、焦虑症或认知障碍的药物。
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