CN1849319A - 作为5-羟色胺-6配体的磺酰基二氢咪唑并吡啶酮化合物 - Google Patents
作为5-羟色胺-6配体的磺酰基二氢咪唑并吡啶酮化合物 Download PDFInfo
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- CN1849319A CN1849319A CNA2004800205472A CN200480020547A CN1849319A CN 1849319 A CN1849319 A CN 1849319A CN A2004800205472 A CNA2004800205472 A CN A2004800205472A CN 200480020547 A CN200480020547 A CN 200480020547A CN 1849319 A CN1849319 A CN 1849319A
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- Prior art keywords
- imidazo
- circumstances
- pyridin
- dihydro
- ones
- Prior art date
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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
本发明提供一种式(I)化合物及其在治疗一与5-HT6受体有关或受其影响的中枢神经系统病症方面的治疗作用。
Description
技术领域
本发明提供一种式(I)化合物及其在治疗一与5-HT6受体有关或受其影响的中枢神经系统病症方面的治疗作用。
背景技术
血清素(5-羟色胺)(5-HT)受体在人类和动物的许多生理和行为功能中发挥关键作用。这些功能通过多种分布于全身各处的5-HT受体调节。现已有大约15种不同人类5-HT受体亚型得到克隆,许多在人类中发挥定义明确的作用。最近鉴定的5-HT受体亚型之一是5-HT6受体,其首先于1993年自大鼠组织中克隆得到(Monsma,F.J.;Shen,Y.;Ward,R.P.;Hamblin,M.W.Molecular Pharmacology 1993,43,320-327)且随后自人类组织中克隆得到(Kohen,R.;Metcalf,M.A.;Khan,N.;Druck,T.;Huebner,K.;Sibley,D.R.Journal of Neurochemistry 1996,66,47-56)。所述受体是一正向偶联至腺苷酸环化酶的G蛋白偶联受体(GPCR)(Ruat,M.;Traiffort,E.;Arrang,J-M.;Tardivel-Lacombe,L;Diaz,L;Leurs,R.;Schwartz,J-C.Biochemical Biophysical ResearchCommunications 1993,793,268-276)。发现所述受体于大鼠和人类二者中几乎全部分布在中枢神经系统(CNS)区域内。使用mRNA的大鼠脑部5-HT6受体原位杂交研究显示其主要定位于5-HT投射区域,包括纹状体、阿肯伯氏核、嗅结节及海马结构(Ward,R.P.;Hamblin,M.W.;Lachowicz,J.E.;Hoffman,B.J.;Sibley,D.R.;Dorsa,D.M.Neuroscience 1995,64,1105-1111)。
依据来自可获得的科学研究的直接效果和适应症,发现5-HT6配体在人类中具有许多潜在治疗用途。这些研究包括受体定位、对具有已知活体内活性配体的亲和力和目前为止所实施的各种动物研究。
5-HT6受体功能调节剂的一潜在治疗用途是在人类疾病(诸如阿尔茨海默氏症(Alzheimer’s))中增强认知力和记忆力。于前脑(包括尾壳核、海马、阿肯伯氏核和皮质)重要结构中发现高水平受体表明所述受体在记忆及认知方面发挥作用,原因在于已知这些区域在记忆方面可发挥关键作用(Gerard,C.;Martres,M.-P.;Lefevre,K.;Miquel,M.C.;Verge,D.;Lanfumey,R.;Doucet,E.;Hamon,M.;EI Mestikawy,S.BrainResearch,1997,746,207-219)。已知5-HT6受体配体在增强胆碱能神经传导方面的能力也支持所述潜在认知作用(Bentley,J.C;Boursson,A.;Boess,F.G.;Kone,F.C;Marsden,C.A.;Petit,N.;Sleight,A.J.British Journal of Pharmacology,1999,126(7),1537-1542)。曾有研究发现一已知5-HT6选择性拮抗剂可显着增加额皮质中谷氨酸盐和天冬氨酸盐水平而同时不会引起去甲肾上腺素、多巴胺或5-HT水平升高。已知会参与记忆和认知的神经化学物质的这种选择性升高表明5-HT6配体可在认知方面发挥作用(Dawson,L.A.;Nguyen,H.Q.;Li,P.British Journal of Pharmacology,2000,130(1),23-26)。用一已知的择性动5-HT6拮抗剂进行的动物记忆和学习研究曾发现阳性征候(Rogers,D.C;Hatcher,P.D.;Hagan,J.J.,Society of Neuroscience,Abstracts 2000,26,680和Foley,A.G.等人,Neuropsychopharmacology,2004,29(1),93-100)。
一5-HT6配体的有关潜在治疗用途是治疗儿童和成年人二者的注意力缺乏症(ADD,也称作注意力缺乏过动症或ADHD)。因为5-HT6拮抗剂似乎会增强黑质纹状体多巴胺途径的活性且因为ADHD曾与尾状核异常有关(Ernst,M;Zametkin,A.J.;Matochik,J.H.;Jons,P.A.;Cohen,R.M.Journal of Neuroscience 1998,18(15),5901-5907),因此5-HT6拮抗剂会减轻注意力缺乏症。
检测各种具有已知治疗用途或与已知药物具有很强结构相似性的CNS配体的亲和性的早期研究表明,5-HT6配体可在治疗精神分裂症和抑郁症方面发挥作用。例如,氯氮平(clozapine)(一有效临床抗精神病药)对5-HT6受体亚型具有高亲和性。并且,若干临床抗抑郁药对所述受体同样具有高亲和性,并可作为此位点一拮抗剂(Branchek,T.A.;Blackburn,T.P.Annual Reviews in Pharmacology and Toxicology 2000,40,319-334)。
此外,最近大鼠活体内研究表明5-HT6调节剂可用于治疗运动病症,包括癫痫(Stean,T.;Routledge,C;Upton,N.British Journal of Pharmacology 1999,127 Proc.增刊131P和Routledge,C;Bromidge,S.M.;Moss,S.F.;Price,G.W.;Hirst,W.;Newman,H.;Riley,G.;Gager,T.;Stean,T.;Upton,N.;Clarke,S.E.;Brown,A.M.British Journalof Pharmacology 2000,130(7),1606-1612)。
总之,上述研究强烈表明,为5-HT6受体调节剂(即:配体)的化合物可用于治疗下列征候,包括:治疗记忆、认知力和学习缺乏相关疾病,诸如阿尔茨海默氏症(Alzheimer’s)和注意力缺乏症;治疗人格障碍,诸如精神分裂症;治疗行为病症,例如焦虑症、抑郁症和强迫症;治疗行动或运动病症,诸如帕金森氏症(Parkinson’sdisease)和癫痫;治疗神经变性相关疾病,诸如中风和头部外伤;或药物成瘾(包括尼古丁、酒精和其他滥用物质成瘾)的戒断症状。
因此,本发明一目标是提供可在与5-HT6受体有关或受其影响的多种中枢神经系统病症治疗中用作治疗剂的化合物。
本发明一目标是提供用于治疗与5-HT6受体有关或受其影响的中枢神经系统病症的治疗方法和医药组合物。
本发明一特征是:所提供化合物也可用于进一步研究和阐明5-HT6受体。
发明内容
本发明提供一式I化合物
其中
W是CR1或N;
X是CR7或N;
Y是CR8或N;
Z是CR9或N,但限制条件是W、X、Y或Z中至少一个且不超过两个是N;
R是一视情况经取代的C3-C7环烷基、芳基或杂芳基或一视情况经取代的8至13元二环或三环环系,所述环系在桥头含有一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;
R1、R7、R8和R9各自独立是H、卤素、CN、OCO2R10、CO2R11、CONR12R13、SOxR14、NR15R16、OR17、COR18或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、芳基或杂芳基,各自视情况经取代;
x是0或一选自1,2或3的整数;
R2和R3各自独立是H或一视情况经取代的C1-C6烷基;
n是一选自2、3、4或5的整数;
p是0或一选自1或2的整数;
R4和R5各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代,或R4和R5可连同二者连接至其上的原子一起形成一视情况经取代且视情况包含一选自O、NR19或SOx的额外杂原子的5至8元环;
R6、R19、R20和R21各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代;
R10、R11、R14、R17和R18各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代;
R12和R13各自独立是H或一视情况经取代的C1-C6烷基,或R12和R13可连同二者连接至其上的原子一起形成一视情况含有另一选自O、NR20或SOx的杂原子的5至7元环;
R15和R16各自独立是H或一视情况经取代的C1-C4烷基,或R15和R16可连同二者连接至其上的原子一起形成一视情况含有另一选自O、NR21或SOx的杂原子的5至7元环;且
其一立体异构体或其一医药上可接受的盐。
本发明也提供用于治疗中枢神经系统病症的方法和组合物。
具体实施方式
5-羟色胺-6(5-HT6)受体是最近通过分子克隆鉴定的受体之一。其可结合广泛用于精神病学的治疗化合物的能力以及其在脑部的有吸引力的分布已激发起人们对能够与所述受体相互作用或影响所述受体的新颖化合物的极大兴趣。所取得的显着成果使人们了解到5-HT6受体可能在精神病学、认知力功能障碍、运动功能和控制、记忆、情绪及诸如此类方面发挥作用。所以,确定需要对5-HT6受体展现结合亲和性的化合物以帮助研究5-HT6受体并可作为治疗中枢神经系统病症的潜在治疗剂,例如参见C.Reavill和D.C.Rogers,Current Opinion in Investigational Drugs,2001,2(1):104-109,Pharma Press Ltd。
惊人的是,目前已发现,式I的磺酰基二氢咪唑并吡啶酮化合物展现出5-HT6亲和性并伴随有显着的亚型选择性。有利的是,所述式I化合物是用于治疗与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的磺酰基二氢咪唑并吡啶酮化合物;或其一立体异构体或其一医药上可接受的盐
其中
W是CR1或N;
X是CR7或N;
Y是CR8或N;
Z是CR9或N,但限制条件是W、X、Y或Z中至少一个且不超过两个是N;
R是一视情况经取代的C1-C6烷基、C3-C7环烷基、芳基或杂芳基或一视情况经取代的8至13元二环或三环环系,所述环系在桥头含有一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;
R1、R7、R8和R9各自独立是H、卤素、CN、OCO2R10、CO2R11、CONR12R13、SOxR14、NR15R16、OR17、COR18或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、芳基或杂芳基,各自视情况经取代;
x是0或一选自1,2或3的整数;
R2和R3各自独立是H或一视情况经取代的C1-C6烷基;
n是一选自2、3、4或5的整数;
p是0或一选自1或2的整数;
R4和R5各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代,或R4和R5可连同二者连接至其上的原子一起形成一视情况经取代且视情况包含一选自O、NR19或SOx的额外杂原子的5至8元环;
R6、R19、R20和R21各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代;
R10、R11、R14、R17和R18各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代;
R12和R13各自独立是H或一视情况经取代的C1-C6烷基,或R12和R13可连同二者连接至其上的原子一起形成一视情况含有另一选自O、NR20或SOx的杂原子的5至7元环;
R15和R16各自独立是H或一视情况经取代的C1-C4烷基,或R15和R16可连同二者连接至其上的原子一起形成一视情况含有另一选自O、NR21或SOx的杂原子的5至7元环;且
如说明书和权利要求中所用术语卤素意指F、Cl、Br或I,且术语杂环烷基意指一含有1或2个杂原子并视情况含有一双键的5至7元环烷基环系,所述杂原子可相同或不同且选自N、O或S。涵盖于如本文所定义术语中的杂环烷基环系实例是下列各环,其中X′是NR′、O或S;且R′是H或一如本文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意指一含有1、2或3个杂原子的5至10元芳族环系,所述杂原子可相同或不同且选自N、O或S。所述杂芳基环系包括吡咯基、唑基、恶唑基、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、苯并异恶唑基或诸如此类。术语芳基意指一碳环芳族环系,诸如苯基、萘基、蒽基或诸如此类。如本文所用术语卤代烷基意指一具有1至2n+1个卤素原子的CnH2n+1基团,且如本文所用术语卤代烷氧基意指一具有1至2n+1个可相同或不相同的卤素原子的OCnH2n+1基团。
涵盖于本文所定义术语中于桥头具有一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8至13元二环或三环环系的实例是下列环系,其中W′是NR′、O或S;且R′是H或一一如本文下文所述的可选取代基:
在说明书和权利要求书中,当指明术语C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、杂环烷基、芳基或杂芳基视情况可经取代时,视情况存在的所述取代基可以是一或多个那些在研制医药化合物或改进所述化合物中通常采用的旨在影响其结构/活性、持续性、吸收、稳定性或其他有益性质的取代基。所述取代基的具体实例包括卤素原子、硝基、氰基、氰硫基、氰氧基、羟基、烷基、卤代烷基、烷氧基、卤代烷氧基、胺基、烷基胺基、二烷基胺基、甲酰基、烷氧基羰基、羧基、烷酰基、烷硫基、烷基亚磺酰基、烷基磺酰基、胺基甲酰基、烷基胺基羰基、苯基、苯氧基、苄基、苄氧基、杂芳基、吲哚基、杂环基或环烷基,较佳是卤素原子或低碳烷基或低碳烷氧基。通常,可出现0至3个取代基。当出现任一前述取代基或包含一烷基取代基时,其可以是直链或支链的且可包含多至12个,较佳多至6个,更佳多至4个碳原子。当术语杂环基用于本文时其涵盖杂环烷基和杂芳基二者。
医药上可接受的盐可以是由一式I化合物与一医药上可接受的酸形成的任一酸加成盐,所述酸诸如磷酸、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、甲磺酸,或诸如此类。
本发明化合物包括酯、胺基甲酸盐或其他习用前药形式,其通常是本发明化合物的功能衍生物,且其易于在活体内转化成本发明活性部分。相应地,本发明方法包括用一式I化合物或用一并未明确揭示但当施予时可在活体内转化成式I化合物的化合物治疗各种本文上文所述病症。所包括的还有本发明化合物的代谢产物,所述代谢产物被定义为在导入一生物系统时所产生的活性物质。
本发明化合物可以一或多种立体异构体形式存在。所述各种立体异构体包括对映异构体、非对映异构体、滞转异构体和几何异构体。所属技术领域的技术人员会了解,一立体异构体当相对于其他立体异构体得到富集或当与其他立体异构体分离开来时可更具活性或可展现有益作用。另外,所属技术领域的技术人员知晓如何分离、富集或选择性制备所述立体异构体。因此,本发明包括式I化合物、其立体异构体及其医药上可接受的盐。本发明化合物可以立体异构体混合物、单个立体异构体或以一光学活性或对映异构体纯形式存在。
当一式I化合物能够以不只一种互变异构体形式(例如以一烯醇或一酮形式)存在时,所有互变异构体均涵盖在本文中。
本发明较佳化合物是彼等式I化合物,其中R是一视情况经取代的芳基或杂芳基,或一视情况经取代的于桥头具有一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8至13元二环或三环环系。另一组本发明较佳化合物是彼等式I化合物,其中Q是-(CR2R3)n-NR4R5或
同样较佳者是彼等式I化合物,其中W是N;X是CR7;Y是CR8且Z是CR9。
在某些实施例中,Q是-CH2CH2NH2、-CH2CH2NMe2或吡咯烷-3-基。
在某些实施例中,R系选自3-氟苯基、2-氯咪唑并[2,1-b]吡啶-3-基、2,6-二氯咪唑并[2,1-b][1,3]噻唑-5-基、3-溴苯基、噻吩-2-基、苯基、3-氯苯基、5-氯噻吩-2-基、6-氯咪唑并[2,1-b][1,3]噻唑-5-基、2-萘基、3-甲氧基苯基、2-氟苯基、2-氯苯基、4-氯苯基、2,3-二氯苯基、5-溴噻吩-2-基、2,5-二氯噻吩-3-基和萘-1-基。
本发明较佳化合物之一是:
3-[2-(二甲基胺基)乙基]-1-[(3-氟苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-[(2-氯咪唑并[2,1-b]吡啶-3-基)磺酰基]-3-[2-(二甲基胺基)乙基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-[(2,6-二氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-3-[2-(二甲基胺基)乙基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-[(3-溴苯基)磺酰基]-3-[2-(二甲基胺基)乙基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-[2-(二甲基胺基)乙基]-1-(噻吩-2-基磺酰基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-(苯基磺酰基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;3-(2-胺基乙基)-1-[(3-氯苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(5-氯噻吩-2-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-(2-萘基磺酰基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(3-甲氧基苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(2-氟苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(3-氟苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(2-氯苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(4-氯苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(2,3-二氯苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(3-溴苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(5-溴噻吩-2-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(2,5-二氯噻吩-3-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-(2-胺基乙基)-3-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
3-(2-胺基乙基)-1-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
1-(2-胺基乙基)-3-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-(2-胺基乙基)-3-[(萘-1-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
3-(2-胺基乙基)-1-[(萘-1-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
1-(2-胺基乙基)-3-[(萘-1-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-[2-(二甲基胺基)乙基]-3-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
3-[2-(二甲基胺基)乙基]-1-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
1-[2-(二甲基胺基)乙基]-3-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-苯基磺酰基-1-(吡咯烷-3-基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
1-苯基磺酰基-3-(吡咯烷-3-基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
3-苯基磺酰基-1-(吡咯烷-3-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
其一立体异构体;和
其一医药上可接受的盐。
有利的是,本发明提供一用于制备一式I化合物的方法,所述方法包括使一式II化合物与一磺酰氯(ClSO2-R)在一碱存在下反应。所述方法示于流程图I中。
流程图I
适用于本发明方法的碱包括下列碱,诸如NaH、KOt-Bu、二异丙基乙基胺或任一能够从一氮原子上去除一质子的习用碱。
式II化合物可使用习用合成方法且(如果需要)使用标准分离或离析技术来制备。例如,式II化合物可易于通过下列方式制备:使一式III的邻位-卤代硝基-吡啶与适宜的式IV的胺反应以得到相应的式V硝基化合物;用一适宜还原剂(诸如SnCl2或肼和拉尼镍(Raney-Nickel))或催化氢化作用还原所述式V化合物以得到式VI的二胺;并用1,1′-羰基二咪唑(CDI)环化所述式VI化合物以得到期望的式II化合物。所述反应如流程图II中所示,其中Hal是Cl或F。
流程图II
当式IV化合物包含一具有一碱性氮原子的Q基团时,例如当Q是4-哌啶基时,则所述式IV化合物可在进行流程图I中所示反应之前得到保护且视情况在磺酰化后去保护。
适用于本文上文所示反应的保护基团包括:第三-丁基氧基羰基、苄基、乙酰基、苄氧基羰基或任何已知可在标准合成程序中保护一碱性氮原子的习用基团。
有利的是,本发明式I化合物可用于治疗与5-HT6受体有关或受其影响的CNS病症,所述病症包括情绪、人格、行为、精神病、认知力、神经变性,或诸如此类病症,例如阿尔茨海默氏症(Alzheimer’s disease)、帕金森氏症(Parkinson’s disease)、注意力缺乏症、焦虑症、癫痫、抑郁症、强迫症、睡眠障碍、神经变性病症(诸如头部外伤或中风)、进食病症(诸如厌食症或暴食症)、精神分裂症、记忆力丧失、与药物或尼古丁滥用戒断相关的病症,或诸如此类,或某些胃肠病症,诸如刺激性肠综合症。因此,本发明提供一用于在一有其需要的患者中治疗一与5-HT6受体有关或受其影响的中枢神经系统病症的方法,所述方法包括向所述患者提供一治疗有效量的如本文上文所述的式I化合物。所述化合物可通过口服或非经肠施予方式或以任一已知可向一有其需要的患者有效施予一治疗剂的习用方式来提供。
当本文所用术语[提供]与提供一本发明涵盖的化合物或物质有关时,其意指直接施予此一化合物或物质,或施予一可在体内形成一等量化合物或物质的前药、衍生物或类似物。
在治疗一具体CNS病症过程中所提供的治疗有效量可根据下列因素而有所变化:拟治疗的具体病症、患者体型大小、年龄和反应方式、病症严重程度、主治医师的判断,或诸如此类。一般而言,每日口服施予的有效量可以是约0.01至1,000mg/kg,较佳约0.5至500mg/kg,且非经肠施予的有效量可以是约0.1至100mg/kg,较佳约0.5至50mg/kg。
在实际应用中,本发明化合物可通过以固体或液体形式施予所述化合物或其一前体,或单独或与一或多种习用医药载剂或赋形剂结合施予来提供。因此,本发明提供一医药组合物,其包括一医药上可接受的载剂和一有效量的如本文上文所述的式I化合物。
适用于本发明组合物的固体载剂包括一或多种可起调味剂、润滑剂、增溶剂、悬浮剂、填充剂、滑动剂、压缩助剂、黏结剂、锭剂崩解剂或封装材料作用的物质。在粉剂中,载剂可以是存于与细碎式I化合物混合物中的细碎固体。在锭剂中,式I化合物可与一具有必要压缩性质的载剂以适宜比例混合,且可压缩成期望的形状和大小。所述粉剂和锭剂可包含多至99%重量比的式I化合物。适用于本发明组合物的固体载剂包括磷酸钙、硬脂酸镁、滑石粉、糖类、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧基甲基纤维素纳、聚乙烯吡咯烷酮、低熔点蜡和离子交换树脂。
可于本发明组合物中采用任一适用于制备溶液、悬浮液、乳液、糖浆和酏剂的医药上可接受的液体载剂。可将式I化合物溶解于或悬浮于一医药上可接受的液体载剂中,诸如水、有机溶剂或一医药上可接受的油或脂肪或其一混合物。所述液体组合物可包含其他适宜医药添加剂,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、黏度调节剂、稳定剂、渗透调节剂,或诸如此类。适用于口服和非经肠施予的液体载剂实例包括水(尤其是包含上述添加剂(例如纤维素衍生物)的水,较佳是羧基甲基纤维素钠溶液)、醇类(包括一元醇和多元醇,例如二醇类)或其衍生物、或油类(例如,精制椰子油和花生油)。对于非经肠施予,载剂也可以是一油酯,诸如油酸乙酯或肉豆蔻酸异丙酯。
为无菌溶液或悬浮液的本发明组合物适用于肌内、腹膜腔内或皮下注射。无菌溶液也可经静脉施予。适用于口服施予的本发明组合物可呈现液体或固体组合物形式。
为使理解更为清楚并更清楚地阐明本发明,本文下文对其具体实例加以阐述。下列实例仅为阐明而不应以任何方式将其理解成对本发明范围和基本原理的限制。
除非另有说明,否则所有份数均指体积份数。术语NMR意指核磁共振法。术语HPLC和TLC分别意指高效液相层析法和薄层层析法。术语THF、DMF和EtOAc分别意指四氢呋喃、二甲基甲酰胺和乙酸乙酯。
实例1
N,N-二甲基-N′-(3-硝基吡啶-2-基)乙-1,2-二胺的制备
用Me2NCH2CH2NH2(3.17g,20.0mmol)处理一溶于乙醇的2-氯-3-硝基吡啶(1.76g,20.0mmol)溶液,于环境温度下搅拌17h,加热至回流温度持续7h,然后冷却至室温并于真空中浓缩。用乙醇研磨所得固体剩余物并吸滤。将滤饼于空气中干燥以得到黄色固态标题化合物,3.20g(61%产率),mp为202至203℃,由NMR和质谱分析鉴定。
实例2
N-[2-(二甲基胺基)乙基]吡啶-2,3-二胺的制备
用10%碳载钯(0.50g)处理存于乙醇的N,N-二甲基-N′-2-(3-硝基吡啶-2-基)乙-1,2-二胺(2.96g,12.0mmol)不均匀混合物,并在一帕尔仪器(Parr apparatus)上接受55psi氢气处理持续22h。将所述反应物抽吸过滤过硅藻土。将滤液于真空下浓缩以得到一褐色油状物(约2.5g)。用10∶90浓NH4OH∶乙醇作为洗脱剂对一部分油状物(约1.5g)进行层析分离以得到一褐色油状的标题化合物,1.49g,由NMR鉴定。
实例3
3-(2-二甲基胺基乙基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮的制备
用羰基二咪唑(CDI)(2.01g,12.4g)在氮气下处理一溶于DMF的N-[2-(二甲基胺基)乙基]吡啶-2,3-二胺(1.49g,8.3mmol)溶液,于75至80℃下搅拌24h,然后冷却至室温并于真空中浓缩。通过用10∶90浓NH4OH∶乙醇洗脱对所得剩余物进行层析分离以得到一固体,将所述固体用乙醇∶乙酸乙酯研磨以得到棕褐色固态标题化合物,0.387g,mp是141至142℃,由NMR和质谱分析鉴定。
实例4
3-(2-二甲基胺基乙基)-1-[(3-氟苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮的制备
于室温用3-氟苯基-磺酰氯(26mg,0.12mmol)处理一溶于THF的3-(2-二甲基胺基乙基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(20mg,0.10mmol)溶液,接着用二异丙基乙基胺(25μL,0.20mmol)和DMAP(5mg)处理,于室温搅拌12h并于真空中浓缩。将所得剩余物溶解在DMSO、甲醇和水的混合物中并通过Gilson制备型HPLC纯化以得到标题化合物,[M+H]365,保留时间(RT)2.54分钟。
1HPLC条件:HP1100HPLC系统;Waters Xterra MS C18,2mm(i.d.)×50mm(长度),3.5μm柱,设置在50℃:流速1.0mL/min;溶剂A:0.02%存于水的甲酸;溶剂B:0.02%存于ACN的甲酸;梯度:时间0:10%B;2.5分钟90%B;3分钟90%B;样品浓度:~2.0mM;注射体积:5μL;检测:220nm,254nmDAD。
实例5至8
3-[2-(二甲基胺基)乙基-1-(芳基磺酰基)-1,3-二氢-2H-苯并咪唑-2-酮衍生物的制备
使用与本文上文实例4中所述程序基本相同的程序并采用适宜磺酰氯来制备表I中所示化合物并通过HPLC1和质谱分析鉴定。
1HPLC条件:HP1100HPLC系统;Waters Xterra MS C18,2mm(i.d.)×50mm(长度),3.5μm柱,设置在50℃;流速1.0mL/min;溶剂A:0.02%存于水的甲酸;溶剂B:0.02%存于ACN的甲酸;梯度:时间0:10%B;2.5分钟90%B;3分钟90%B;样品浓度:~2.0mM;注射体积:5μL;检测:220nm,254nmDAD。
表I
实例编号 | R | 观测离子 | HPLCRT(分钟) |
5678 | 2-氯咪唑并[2,1-b]吡啶-3-基2,6-二氯咪唑并[2,1-b][1,3]噻唑-5-基3-溴苯基2-噻吩基 | 423[M+H]461[M+]425[M+]353[M+H] | 2.672.822.742.46 |
实例10
N-1-(3-硝基吡啶-2-基)乙-1,2-二胺的制备
将一2-氟-3-硝基吡啶(8.0g.50mmol)和乙二胺(3.6g,60mmol)存于异丙醇中的混合物于100℃加热48h,然后冷却至0℃并过滤。用冰冷的异丙醇洗涤滤饼并于空气中干燥以得到棕褐色固态化合物,8.5g,由HPLC和质谱分析鉴定。
实例11
{[2-(3-硝基吡啶-2-基)胺基]乙基}胺基甲酸第三-丁基酯的制备
用K2CO3(3.5g,25mmol)和二-第三-丁氧基二羰基(3.3g,15.2mmol)处理—溶于1∶1丙酮/水的N-1-(3-硝基吡啶-2-基)乙-1,2-二胺(2.3g,12.7mmol)溶液,于室温搅拌4h并于真空中浓缩以去除丙酮。用EtOAc萃取水性剩余物。合併萃取物,经由MgSO4干燥并于真空中浓缩以得到固态产物,3.5g,由HPLC和质谱分析鉴定。
实例12
{[2-(3-胺基吡啶-2-基)胺基]乙基}胺基甲酸第三-丁基酯的制备
逐滴用肼(0.8mL,25mmol)处理一{[2-(3-硝基吡啶-2-基)胺基]乙基}胺基甲酸第三-丁基酯(2.0g,7.1mmol)和拉尼镍(Raney-Nickel)(0.5g)存于甲醇的混合物,于室温搅拌16h,然后用硅藻土和MgSO4处理并过滤。将滤饼用甲醇洗涤。合併滤液并于真空中浓缩以得到一褐色油状标题产物,1.8g,由HPLC和质谱分析鉴定。
实例13
[2-(2-氧代-2,3-二氢-2H-咪唑并[4,5-b]吡啶-2-基)乙基]胺基甲酸第三-丁基酯的制备
将一{[2-(3-胺基吡啶-2-基)胺基]乙基}胺基甲酸第三-丁基酯(5.04g,20mmol)和羰基二咪唑(3.4g,22mmol)存于DMF的混合物于110℃下加热16h,然后冷却至室温并用EtOAc萃取。合併萃取物,用水洗涤,经由MgSO4干燥并于真空中浓缩。所得剩余物通过快速层析法纯化(SiO2,以氯仿∶甲醇∶NH4OH,90∶9∶1作为洗脱剂)以得到澄清油状标题化合物,2.9g,由HPLC和质谱分析鉴定。
实例14
3-(2-胺基乙基)-1-[(5-氯噻吩-2-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮的制备
于室温用(5-氯噻吩-2-基)磺酰氯(26mg,0.12mmol)处理溶于THF的[2-(2-氧代-2,3-二氢-2H-咪唑并[4,5-b]吡啶-2-基)乙基]-胺基甲酸第三-丁基酯(27mg,0.1mmol)溶液,接着用二异丙基乙基胺(25μL,0.2mmol)和DMAP(5mg)处理,于室温搅拌12h并于真空中浓缩。将所得剩余物溶解于THF中,用存于二氧杂环己烷的4N HCl(1mL)处理,搅拌8h并于真空中浓缩。将此剩余物溶解于DMSO、甲醇和水的混合物中并通过Gilson制备型HPLC1纯化以得到标题化合物,6mg,[M+H]359,保留时间(RT)2.04分钟。
1HPLC条件:HP1100HPLC系统;Waters Xterra MS C18,2mm(i.d.)×50mm(长度),3.5μm柱,设置在50℃;流速1.0mL/min;溶剂A:0.02%存于水的甲酸;溶剂B:0.02%存于ACN的甲酸;梯度:时间0:10%B;2.5分钟90%B;3分钟90%B;样品浓度:~2.0mM;注射体积:5μL;检测:220nm,254nmDAD。
实例15至27
3-(2-胺基乙基)-1-(芳基磺酰基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮衍生的制备物
使用与本文上文实例14中所述程序基本相同的程序并采用适宜烷基磺酰氯来获得表II中所示化合物并通过HPLC1和质谱分析鉴定。
1HPLC条件:HP1100HPLC系统;Waters Xterra MS C18,2mm(i.d.)×50mm(长度),3.5μm柱,设置在50℃;流速1.0mL/min;溶剂A:0.02%存于水的甲酸;溶剂B:0.02%存于ACN的甲酸;梯度:时间0:10%B;2.5分钟90%B;3分钟90%B;样品浓度:~2.0mM;注射体积:5μL;检测:220nm,254nmDAD。
表II
实例编号 | R | 观测离子 | RT(分钟) |
15161718192021222324252627 | 苯基3-氯苯基6-氯咪唑并[2,1-b][1,3]噻唑-5-基2-萘基3-甲氧基苯基2-氟苯基3-氟苯基2-氯苯基4-氯苯基2,3-二氯苯基3-溴苯基5-溴噻吩-2-基2,5-二氯噻吩-3-基 | 319[M+H]353[M+H]399[M+H]369[M+H]349[M+H]337[M+H]337[M+H]353[M+H]353[M+H]387[M+H]397[M+H]403[M+H]393[M+H] | 1.822.061.932.211.961.881.911.972.062.182.12.082.26 |
实例28
对测试化合物5-HT6结合亲和性的比较评估
以下列方法评估测试化合物对血清素5-HT6受体的亲和性。收集表达克隆的人类5-HT6受体的Hela培养细胞并以低速(1,000×g)离心10.0分钟以去除培养基。将收集的细胞悬浮于一半体积的新鲜生理磷酸缓冲盐溶液中并再次以相同速率离心。重复此操作。然后将收集到的细胞于10体积50mM Tris.HCl(pH7.4)和0.5mM EDTA中匀浆。将匀浆液以40,000×g离心30.0分钟并收集沉淀。将所得沉淀重悬于10体积Tris.HCl缓冲液中并再次以相同速率离心。将最终得到的沉淀悬浮于小体积Tris.HCl缓冲液中并于10至25μl体积等份中测定组织蛋白含量。根据Lowry等人在
J.Biol. Chem.193:265(1951)中所述方法用牛血清白蛋白作为蛋白测定的标准物。调整悬浮细胞膜体积以得到一组织蛋白浓度为1.0mg/ml的悬浮液。将所制备的膜悬浮液(10倍浓缩)等分成1.0ml体积的小份,并在用于后续结合实验之前保存在-70℃下。
结合实验在96孔微量滴定板中实施,总体积为200μl。向每一孔中添加下列混合物:于含有10.0mM MgCl2和0.5mM EDTA的50mM Tris.HCl缓冲液(pH7.4)中制备的80.0μl培育缓冲液和20μl[3H]-LSD(S.A.,86.0Ci/mmol,购自Amersham LifeScience),3.0nM。[3H]LSD对人类血清素5-HT6受体的离解常数KD是2.9nM,如通过随[3H]LSD浓度增加的饱和结合所测定。本反应通过最终添加100.0μl组织悬浮液来起始。在10.0μM美赛西平存在下测量非特异性结合。测试化合物以20.0μl体积添加。
使所述反应于室温下在暗处持续120min,其间将已结合的配体-受体复合体于一配有一Packard Filtermate196 Harvester的96孔Unifilter上过滤去除。在向各浅孔中添加40.0μlMicroscint-20闪烁剂后,将附着于过滤片上的已结合复合体于空气中干燥并于一配有6个光电倍增管检测器的Packard TopCount中测量放射活性。将Unifilter板加热密封并于一PackardTopCount中计数,其中氚效率为31.0%。
将对5-HT6受体的特异性结合定义为:总结合放射活性减去10.0μM未标记美赛西平存在下的结合量。将不同浓度测试化合物存在下的结合表示为不存在测试化合物时特异性结合的百分比。将结果以log%结合对log测试化合物浓度作图。用一计算机辅助程序Prism进行数据点的非线性回归分析进而得到测试化合物的IC50和Ki值二者,其中置信界限为95%。绘制数据点的线性回归线,其中IC50值的测定和Ki值的测定根据下列公式进行:
Ki=IC50/(1+L/KD)
其中L是所用放射性配体的浓度且KD是所述配体对受体的离解常数,二者皆以nM表示。
使用本分析,测定下列Ki值并将其与彼等由已知可对5-HT6受体展现结合的代表性化合物得到的数值加以比较。所述数据示于下列表III中。
表III
测试化合物(实例编号) | 5-HT6结合KI(nM) |
4714151617181920222324252627 | 80231844164514775517912922 |
比较实例 | 5-HT6结合KI |
氯氮平洛沙平(Loxapine)溴隐亭(Bromocriptine)美赛西平(Methiothepin)米安舍林(Mianserin)奥兰扎平(Olanzepine) | 6.041.423.08.344.219.5 |
Claims (16)
1、一种式I化合物
其中
W是CR1或N;
X是CR7或N;
Y是CR8或N;
Z是CR9或N,但限制条件是W、X、Y或Z中至少一个且不超过两个是N;
R是一视情况经取代的C3-C7环烷基、芳基或杂芳基或一视情况经取代的8至13元二环或三环环系,所述环系在桥头含有一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;
R1、R7、R8和R9各自独立是H、卤素、CN、OCO2R10、CO2R11、CONR12R13、SOxR14、NR15R16、OR17、COR18或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、芳基或杂芳基,各自视情况经取代;
x是0或一选自1,2或3的整数;
R2和R3各自独立是H或一视情况经取代的C1-C6烷基;
n是一选自2、3、4或5的整数;
p是0或一选自1或2的整数;
R4和R5各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代,或R4和R5可连同二者连接至其上的原子一起形成一视情况经取代且视情况包含一选自O、NR19或SOx的额外杂原子的5至8元环;
R6、R19、R20和R21各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代;
R10、R11、R14、R17和R18各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代;
R12和R13各自独立是H或一视情况经取代的C1-C6烷基,或R12和R13可连同二者连接至其上的原子一起形成一视情况含有另一选自O、NR20或SOx的杂原子的5至7元环;
R15和R16各自独立是H或一视情况经取代的C1-C4烷基,或R15和R16可连同二者连接至其上的原子一起形成一视情况含有另一选自O、NR21或SOx的杂原子的5至7元环;且
其一立体异构体或其一医药上可接受的盐。
2、如权利要求1所述的化合物,其中R是一视情况经取代的芳基或杂芳基或一视情况经取代的8至13元二环或三环环系,所述环系在桥头含有一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。
3、如权利要求2所述的化合物,其中R是一视情况经取代的苯基、萘基、噻吩基或咪唑并[2,1-b][1,3]噻唑基。
4、如权利要求1至3中任一项所述的化合物,其中Q是-(CR2R3)n-NR4R5或
5、如权利要求1至4中任一项所述的化合物,其中R2和R3是H;n是一整数2;R6是H;且p是一整数1。
6、如权利要求1至5中任一项所述的化合物,其中W是N;X是CR7;Y是CR8且Z是CR9。
7、如权利要求1所述的化合物,其系选自由下列组成的群组:
3-[2-(二甲基胺基)乙基]-1-[(3-氟苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-[(2-氯咪唑并[2,1-b]吡啶-3-基)磺酰基]-3-[2-(二甲基胺基)乙基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-[(2,6-二氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-3-[2-(二甲基胺基)乙基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-[(3-溴苯基)磺酰基]-3-[2-(二甲基胺基)乙基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-[2-(二甲基胺基)乙基]-1-(噻吩-2-基磺酰基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-(苯基磺酰基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(3-氯苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(5-氯噻吩-2-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;3-(2-胺基乙基)-1-[(6-氯咪唑并[2,1-b][1,3]噻唑-5-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-(2-萘基磺酰基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(3-甲氧基苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(2-氟苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(3-氟苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(2-氯苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(4-氯苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(2,3-二氯苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;3-(2-胺基乙基)-1-[(3-溴苯基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(5-溴噻吩-2-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-(2-胺基乙基)-1-[(2,5-二氯噻吩-3-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-(2-胺基乙基)-3-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
3-(2-胺基乙基)-1-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
1-(2-胺基乙基)-3-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-(2-胺基乙基)-3-[(萘-1-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
3-(2-胺基乙基)-1-[(萘-1-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
1-(2-胺基乙基)-3-[(萘-1-基)磺酰基]-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
1-[2-(二甲基胺基)乙基]-3-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
3-[2-(二甲基胺基)乙基]-1-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
1-[2-(二甲基胺基)乙基]-3-苯基磺酰基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
3-苯基磺酰基-1-(吡咯烷-3-基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
1-苯基磺酰基-3-(吡咯烷-3-基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮;
3-苯基磺酰基-1-(吡咯烷-3-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮;
其一立体异构体;和
其一医药上可接受的盐。
8、一种用于在一有其需要的患者中治疗一与5-HT6受体有关或受其影响的中枢神经系统病症的方法,其包括向所述患者提供一治疗有效量的一如权利要求1至7中任一项所述的式I化合物。
9、如权利要求8所述的方法,其中所述病症是一焦虑症或一认知障碍。
10、如权利要求8所述的方法,其中所述病症是一神经变性病症。
11、如权利要求9所述的方法,其中所述病症系选自由下列组成的群组:注意力缺乏症、强迫症、药物、酒精或尼古丁成瘾的戒断症状、精神分裂症、抑郁症和阿尔茨海默氏症(Alzheimer’s disease)。
12、如权利要求8所述的方法,其中所述病症系选自由下列组成的群组:中风、头部外伤和神经疼。
13、一种医药组合物,其包括一医药上可接受的载剂和一有效量的一如权利要求1至7中任一项所述的式I化合物。
14、一种用于制备一式I化合物的方法,本发明提供一式I化合物
其中
Q是-(CR2R3)n-NR4R5,
W是CR1或N;
X是CR7或N;
Y是CR8或N;
Z是CR9或N,但限制条件是W、X、Y或Z中至少一个且不超过两个是N;
R是一视情况经取代的C3-C7环烷基、芳基或杂芳基或一视情况经取代的8至13元二环或三环环系,所述环系在桥头含有一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;
R1、R7、R8和R9各自独立是H、卤素、CN、OCO2R10、CO2R11、CONR12R13、SOxR14、NR15R16、OR17、COR18或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、芳基或杂芳基,各自视情况经取代;
x是0或一选自1,2或3的整数;
R2和R3各自独立是H或一视情况经取代的C1-C6烷基;
n是一选自2、3、4或5的整数;
p是0或一选自1或2的整数;
R4和R5各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代,或R4和R5可连同二者连接至其上的原子一起形成一视情况经取代且视情况包含一选自O、NR19或SOx的额外杂原子的5至8元环;
R6、R19、R20和R21各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代;
R10、R11、R14、R17和R18各自独立是H或一C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、杂环烷基、芳基或杂芳基,各自视情况经取代;
R12和R13各自独立是H或一视情况经取代的C1-C6烷基,或R12和R13可连同二者连接至其上的原子一起形成一视情况含有另一选自O、NR20或SOx的杂原子的5至7元环;
R15和R16各自独立是H或一视情况经取代的C1-C4烷基,或R15和R16可连同二者连接至其上的原子一起形成一视情况含有另一选自O、NR21或SOx的杂原子的5至7元环;且
该方法包括使一式II化合物与一磺酰氯,RSO2Cl在一碱存在下且视情况在一溶剂存在下反应
其中Q、W、X、Y和Z如本文上文所述;且RSO2Cl中的R也如本文上文所述。
15、一种如权利要求1至7中任一项所界定的可用作一药物的式I化合物。
16、一种如权利要求1至7中任一项所界定的式I化合物于制备一用于治疗一与5-HT6受体有关或受其影响的中枢神经系统病症的药物的用途。
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US8119676B2 (en) | 2006-08-26 | 2012-02-21 | Abbott GmbH & Co. HG | Substituted benzimidazolone derivatives, medicaments comprising them and their use |
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US9859455B2 (en) * | 2013-02-08 | 2018-01-02 | International Business Machines Corporation | Interdigitated back contact heterojunction photovoltaic device with a floating junction front surface field |
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