CN101321730B - 作为组胺h3受体调节剂的环丙胺 - Google Patents
作为组胺h3受体调节剂的环丙胺 Download PDFInfo
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- CN101321730B CN101321730B CN2006800422596A CN200680042259A CN101321730B CN 101321730 B CN101321730 B CN 101321730B CN 2006800422596 A CN2006800422596 A CN 2006800422596A CN 200680042259 A CN200680042259 A CN 200680042259A CN 101321730 B CN101321730 B CN 101321730B
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- piperazine
- ylmethyl
- cyclopropyl
- phenyl
- ketone
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- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940020965 zoloft Drugs 0.000 description 1
- 229940036139 zyrtec Drugs 0.000 description 1
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Abstract
某些环丙胺是组胺H3调节剂,它们可用于治疗组胺H3受体介导的疾病。
Description
发明领域
本发明涉及环丙胺系列、它们的合成方法和用它们治疗涉及组胺H3受体的疾病和病症的方法。因这些活性,本发明化合物具有治疗多种与CNS有关的病症的治疗效用,这些病症包括但不限于嗜眠症、睡眠障碍、肥胖症、神经变性病症、认知障碍和过动症。
发明背景
组胺{2-(咪唑-4-基)乙胺}是生物活性分子。组胺通过多个不同的G蛋白偶联受体发挥生理作用。起初,组胺H3受体称为在中枢神经系统(CNS)中控制合成和释放组胺的突触前自身受体(Arrang,J.-M.et al.,Nature 1983,302,832-837)。新的证据表明作为异型受体的H3受体还位于5-羟色胺能、去甲肾上腺素能、多巴胺能、胆碱能和GABA能(含γ-氨基丁酸)神经元的突触前。近来,还在周围组织例如血管平滑肌中鉴定到这些H3受体。因此,组胺H3激动剂、拮抗剂和反向激动剂有许多潜在治疗用途(参见:″The Histamine H3 Receptor-A Target for NewDrugs″(组胺H3受体-新药物的靶),Leurs,R.and Timmerman,H.,(Eds.),Elsevier,1998;Morisset,S.et al.,Nature 2000,408,860-864)。
根据用已知组胺H3拮抗剂所做的动物药理学和其它实验,提出组胺H3拮抗剂和反向激动剂(例如噻普酰胺)的几种适应症。这些包括痴呆、早老性痴呆(Panula,P.et al.,Soc.Neurosci.Abstr.1995,21,1977)、癫痫(Yokoyama,H.et al.,Eur.J.Pharmacol.1993,234,129-133)、与猝倒有关或无关的嗜眠症、猝倒、睡眠/清醒体内平衡性障碍、自发性嗜眠、日间过度思睡(EDS)、昼夜节律紊乱、睡眠/疲劳障碍、疲劳症、与睡眠呼吸暂停有关的倦睡、由于近绝经期的荷尔蒙变化所致睡眠损害、时差症、与帕金森病有关的疲劳症、与多发性硬化(MS)有关的疲劳症、与抑郁有关的疲劳症、化疗引起的疲劳症、饮食性疾病(Machidori,H.et al.,Brain Res.1992,590,180-186)、运动病、眩晕、注意力缺陷过动症(ADHD)、学习和记忆(Barnes,J.C.et al.,Soc.Neurosci.Abstr.1993,19,1813)和精神分裂症(Schlicker,E.and Marr,I.,Naunyn-Schmiedeberg′s Arch.Pharmacol.1996,353,290-294)(再参见:Stark,H et al.,Drugs Future 1996,21(5),507-520;和Leurs,R.et al.,Prog.Drug Res.1995,45,107-165和其中引用的文献)。据报道,单独的组胺H3拮抗剂或与组胺H1拮抗剂联合可有效治疗上气道变态反应(U.S专利号5,217,986;5,352,707和5,869,479)。Tozer和Kalindjian(Exp.Opin.Ther.Patents 2000,10,1045)发表了关于该课题的最新综述。对于其它综述,参见:Celanire,S.Drug Discovery Today 2005,10(23/24),1613-1627;Hancock,A.A.Biochem.Pharmacol.2006,71,1103-1113。
通过测定与人组胺H3受体结合的受体,证明本发明化合物对人H3受体有效力(参见Lovenberg,T.W.et al.,Mol.Pharmacol.1999,55,1101-1107)。用人受体的筛选实验对鉴定治疗人疾病的新疗法尤其重要。例如用大鼠突触体(Garbarg,M.et al.,J.Pharmacol.Exp.Ther.1992,263(1),304-310)、大鼠皮层膜(West,R.E.et al.,Mol.Pharmacol.1990,38,610-613)和豚鼠脑(Korte,A.et al.,Biochem.Biophys.Res.Commun.1990,168(3),979-986)进行常规结合测定。过去,仅在少数研究中用过人组织或人受体,但这些说明啮齿类动物受体和灵长类动物受体之间存在显著差异(West,R.E.et al.Eur.J.Pharmacol.1999,377,233-239;Ireland,D.et al.Eur.J.Pharmacol.2001,433,141-150)。
为达到需要的药理作用,化合物必须对生物靶产生效力和具有合适的药代动力学特性。首先,化合物必须能到达其作用部位,无论作用部位在CNS还是在外周,如果作用部位在CNS,化合物还需要适当透过血脑屏障。通过各种生物膜的吸收取决于药物的物理性质(在生理pH下的离子化程度、分配系数、分子大小等)。一旦产生需要药理作用,药物必须以合适的速度从生物体中消除。当消除过程太慢时,可能发生药物蓄积,潜在造成有害副作用。
治疗H3介导的各种疾病可能需要具有独特和不同药代动力学特性的化合物。尤其是,给予半衰期短的化合物可对药物接触和作用期提供较强控制效果,可有利于治疗或预防特定疾病或病症。具有这种最佳曲线的化合物可用于实现这些结果的定制制剂、给药方案和/或递药策略。例如,具有较弱药代动力学特性的化合物可产生较短的药效作用,它们可优选治疗某些疾病。相反,可优选半衰期长的化合物治疗其中需要该药物持续占据靶,药物浓度不改变或仅极少改变的病症。
U.S.专利申请公布号US-2004-0110746-A1(2004年6月10日)公开了各种哌嗪基苯甲酰胺,其通过引用结合到本文中。
本发明的特征和优点对本领域普通技术人员而言是显而易见的。根据包括概述、详述、背景、实施例和权利要求在内的本发明公开,本领域普通技术人员将可进行改进并适合各种条件和用法。本文中所述出版物通过引用全文结合到本文中。
本文中所述是具有调节组胺受体,尤其H3受体活性能力的N-环丙基胺系列化合物。
发明概述
本发明的特征在于选自以下的化合物及其对映体、水合物、溶剂化物和药学上可接受的盐:
1)(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
2)(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
3)(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
4)(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮。
在特定实施方案中,化合物是(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮柠檬酸盐二盐酸盐或(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮柠檬酸盐。在再一些实施方案中,化合物是(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮柠檬酸盐、(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮柠檬酸盐或(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮柠檬酸盐。
本发明提供治疗或预防由组胺H3受体活性介导的疾病和病症的方法。本发明的特征还在于含此类化合物的药用组合物;和用此类组合物治疗或预防由组胺H3受体活性介导的疾病的方法。本发明还考虑治疗或预防疾病或病症的方法,其中组胺涉及用本发明化合物和以下任何药物一起给药的联合疗法:组胺H1拮抗剂、组胺H2拮抗剂、神经递质再摄取阻滞剂、选择性5-羟色胺再摄取抑制剂(SSRI)、5-羟色胺-去甲肾上腺素再摄取抑制剂、去甲肾上腺素能再摄取抑制剂;非选择性5-羟色胺-、多巴胺-或去甲肾上腺素-再摄取抑制剂;莫达非尼和托吡酯。
在生理pH环境中,给出的化合物的pKa影响离子化程度。因为非离子化形式亲脂性更强,它们可更容易地透过包括血脑屏障的膜。尽管本发明环丙胺化合物(实施例1)的理论pKa值与由异丙基类似物(比较实施例1)得到的相似,但实测pKa大不相同。尽管已经提示环丙胺的碱性是脂肪胺的约1/10(Zaragoza,et al.J.Med.Chem.2004,47,2833-2838),但并未有直接实验证据的报道(Love,et al.J.Am.Chem.Soc.1968,90(10),2455-2462)。因此,用环丙基代替脂族丙基可在生理pH环境中产生较高分数的非质子化胺,因此适于改善膜的透过性(Zaragoza,et al.J.Med.Chem.2005,48,306-311)。这些数据表明环丙胺的渗透性和分布体积(Vd)可倾向于比相似结构的脂肪胺的高。
本发明提供实验证据,证明相对于其异丙胺和环丁胺类似物,实施例1环丙胺的碱性显著下降。但是,本发明环丙胺实际显示的药代动力学特性与文献中预测的结果有明显差异。例如,与比较实施例1B和2B相比,实施例1B显示的半衰期(T1/2)较短和分布体积(Vd)较低。类似地,与比较实施例3B和4B相比,实施例2B显示的T1/2较短和Vd较低;与比较实施例5B相比,实施例3B显示的T1/2较短和Vd较低,和与比较实施例6B相比,实施例4B显示的T1/2较短和Vd较低。
根据以下详述和实施例及权利要求,本发明的其它特征和优点将变得显而易见。
发明详述
通过参考包括以下术语汇编和最后的实施例的以下描述,可更全面理解本发明。为简明扼要起见,本说明书中引用的出版物中的公开内容通过引用结合到本文中。
本文中使用的术语“包括”、“含有”和“包含”在本文中按它们的开放、非限制性含义使用。
本发明化合物及其药学上可接受的盐的异构形式包括在本发明中,本文中提及此类异构形式之一是指此类异构形式中的至少一种。本领域普通技术人员会意识到本发明化合物可以例如单一异构体形式存在,而其它化合物可以异构体混合物的形式存在。例如,本发明包括本文中所述化合物的旋光异构体,它们包括对映体及其混合物。另外,本文中涉及的某些化合物可存在溶剂化或水化和非溶剂化形式。可以理解,本发明包括本发明化合物的所有此类溶剂化和非溶剂化形式。
可通过某些分析技术检测的经修饰的本发明化合物也在本发明范围内。可用放射性元素例如125I、18F、11C、64Cu、3H、14C等标记本发明化合物,用于成像或放射治疗患者。此类化合物的实例是同位素标记的化合物,例如可在检测和/或成像技术例如正电子发射断层显像术(PET)和单光子发射计算机化断层显像(SPECT)中作为探针使用的18F同位素标记的化合物。优选,可用18F或11C标记的本发明化合物作为正电子发射断层显像术(PET)分子探针,用于研究组胺介导的病症。或者,用14C标记的本发明化合物可用于代谢研究。此类化合物的另一个实例是同位素标记的化合物,例如可用于反应动力学研究的氘和/或氚标记的化合物。可用常规化学方法使本文中所述化合物与适当官能化放射性试剂反应,提供放射性标记的化合物。
可按照本领域技术人员技能范围内的和/或以下流程和实施例所述的方法,制备上述化合物。为得到本文中各种化合物,可使用原料,该原料携带适当时保护或未保护的最终需要的取代基通过反应流程。这可通过常规保护基团例如在″Protective Groups in OrganicChemistry″,ed.J.F.W.McOmie,Plenum Press,1973;和T.W.Greene &P.G.M Wuts,″Protective Groups in Organic Synthesis″,第3版,JohnWiley & Sons,1999中所述那些完成。可在便利的后续阶段,用本领域中已知方法将保护基团除去。或者,可能需要在最终需要取代基的位置使用合适基团,该合适基团可被携带通过反应流程且在适当时可被需要的取代基置换。此类化合物、前体或前药也在本发明范围中。反应可在熔点和溶剂的回流温度之间,优选在0℃和溶剂的回流温度之间进行。
可按照以下流程A-C制备上述化合物。本领域技术人员会意识到某些化合物相对于其它化合物按照某一流程制备更有利。另外,U.S.专利申请号10/690,115中所述合成顺序通过引用结合到本文中,该顺序可用于制备本发明化合物。本领域技术人员会意识到式(I)化合物是本发明化合物,其中R1R2N-为吗啉基、4-氟哌啶基、硫代吗啉基或2-羟基甲基-吗啉-4-基。
流程A
按照流程A,可通过将酸活化为酰氯或酰氟,然后与胺反应,或在肽偶合条件例如1,1′-羰基二咪唑(CDI)或1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)/1-羟基苯并三唑(HOBt)下直接反应,使其中PG为环丙基或合适的保护基团例如苄基或叔丁基氨基甲酰基(Boc)的式(X)胺与式(XI)苯甲酸偶合。优选,在4-(二甲基氨基)吡啶(DMAP)存在下,在溶剂例如CH2Cl2中,与EDC/HOBt进行反应。然后可在还原胺化条件下,使式(XII)苯甲醛与合适的胺R1NR2H(其中R1NR2H为吗啉、4-氟哌啶、硫代吗啉或吗啉-2-基-甲醇)反应,得到苄胺(XIII)。合适的还原剂包括溶于溶剂例如甲醇或二氯乙烷的NaCNBH3或NaB(OAc)3H。优选的条件包括NaB(OAc)3H的甲醇溶液。然后可在标准脱保护条件下,将保护基″PG″除去,得到式(XIV)胺。其中PG为Boc,可用HCl的1,4-二噁烷溶液或三氟乙酸(TFA)的CH2Cl2溶液实现脱保护。在类似于J.Med.Chem.2004,47(11),2733-2738和Tetrahedron Lett.1995,36(41),7399-7402中所述那些条件下,通过与[(1-甲氧基环丙基)氧基]三甲基硅烷或[(1-乙氧基环丙基)氧基]-三甲基硅烷(R为甲基或乙基)反应,将胺(XV)转化为相应的式(I)环丙胺。
流程B
或者,可按流程B和C制备本发明化合物。最后,如J.Med.Chem.2004,47(11),2733-2738和Tetrahedron Lett.1995,36(41),7399-7402中所述,可使保护的其中PG定义同前的杂环(X)与[(1-甲氧基环丙基)氧基]-三甲基硅烷或[(1-乙氧基环丙基)氧基]三甲基硅烷反应。优选,PG为Boc基团。然后可在标准脱保护条件下,将″PG″基团除去,得到式(XVI)环丙胺。其中PG为Boc,优选的条件包括HCl在溶剂例如1,4-二噁烷中的混合物。
流程C
可使式(XI)酸与胺(XVI)偶合(通过流程A中所述活化或直接偶合),形成酰胺(XVII)。按流程A中所述,用合适的胺进行还原胺化,得到式(I)化合物。
可用本领域技术人员已知的方法,将本发明化合物转化为其相应的盐。例如,可在溶剂例如甲醇(MeOH)或乙醇(EtOH)中,将游离碱形式的本发明化合物用TFA、HCl或柠檬酸处理,得到相应的盐形式。
可得到按上述流程制备的化合物的单一对映体或非对映体,或外消旋混合物,或对映体或非对映体的混合物。当得到此类混合物时,可用常规方法例如层析或结晶将异构体分离。当得到对映体的外消旋(1∶1)和非外消旋(非1∶1)混合物时,可用本领域技术人员已知的常规分离方法分离到单一对映体。尤其有效的分离方法可包括手性色谱、重结晶、拆分、形成非对映体盐或分离后衍生为非对映体加合物。
本发明在其范围内包括本发明化合物的前药。一般而言,此类前药是化合物的官能团衍生物,它们在体内容易转化为需要的化合物。因此,在本发明治疗方法中,术语“给予”包括用本发明化合物或给予患者后在体内转化为本发明化合物的化合物治疗各种所述病症。在例如″Design of Prodrugs″,ed.H.Bundgaard,Elsevier,1985中有关于选择和制备合适的前药衍生物的常规方法论述。除盐外,本发明还提供所述化合物的酯、酰胺和其它保护或衍生化形式。
为了治疗用途,本发明化合物的盐是药学上可接受的那些盐。但是,非药学上可接受的酸和碱的盐也可在例如制备或纯化药学上可接受的化合物中找到用途。无论药学上可否接受,所有盐均包括在本发明范围内。
本发明化合物的药学上可接受的盐是指对药物化学技术人员而言是显而易见的本发明化合物的那些盐形式,即无毒的和有利影响所述本发明化合物的药代动力学性质例如足够的适口性、吸收、分布、代谢和排泄的那些盐形式。性质上更实用的在选择中也重要的其它因素是原料成本、得到的批量药物的结晶难易度、收率、稳定性、吸湿性和流动性。
可用于制备药学上可接受的盐的酸的实例包括以下酸:乙酸、2,2-二氯乙酸、酰化氨基酸、己二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、硼酸、(+)-樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、环己烷氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基-乙磺酸、甲酸、富马酸、粘酸、2,5-二羟苯甲酸、葡庚糖酸、D-葡糖酸、D-葡糖醛酸、L-谷氨酸、α-氧代-谷氨酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、月桂酸、马来酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、扑姆酸、高氯酸、磷酸、L-焦谷氨酸、糖酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸、十一碳烯酸和戊酸。
可通过用适当的有机和无机碱处理,将含酸性质子的本发明化合物转化为其治疗活性无毒金属或胺加成盐形式。适当的碱式盐形式包括例如铵盐;碱和碱土金属盐(例如锂、钠、钾、镁、钙盐,它们可通过用例如氢氧化镁、氢氧化钙、氢氧化钾、氢氧化锌或氢氧化钠处理制备);和用有机碱制备的胺盐(例如伯、仲和叔脂肪胺和芳胺的盐例如L-精氨酸、benethamine、苯乍生、胆碱、二甲基乙醇胺、二乙醇胺、二乙胺、二甲胺、二丙胺、二异丙胺、2-(二乙氨基)-乙醇、乙醇胺、乙胺、乙二胺、异丙胺、N-甲基-葡糖胺、哈胺青霉素G(hydrabamine)、1H-咪唑、L-赖氨酸、吗啉、4-(2-羟基乙基)-吗啉、甲胺、哌啶、哌嗪、丙胺、吡咯烷、1-(2-羟基乙基)-吡咯烷、吡啶、喹核碱、喹啉、异喹啉、仲胺、三乙醇胺、三甲胺、三乙胺、N-甲基-D-葡糖胺、2-氨基-2-(羟基甲基)-1,3-丙二醇和氨丁三醇的盐)。参见例如S.M.Berge,et al.,″Pharmaceutical Salts″(药用盐),J.Pharm.Sci,1977,66:1-19和Handbook of Pharmaceutical Salts,Properties,Selection,and Use;Stahl,P.H.,Wermuth,C.G.,Eds.;Wiley-VCH and VHCA:Zurich,2002,该文献通过引用结合到本文中。
本发明化合物是组胺H3受体调节剂,因此这些化合物可用于治疗由组胺H3受体活性介导的疾病。因此,本发明化合物可用于治疗患有或诊断为患有组胺H3受体活性介导的疾病的患者的方法,该方法包括给予需要这种治疗的患者有效量的本发明化合物或其药学上可接受的盐。尤其是,这些化合物可用于治疗或预防有需要的患者中神经障碍或神经精神病性障碍的方法,这些神经障碍或神经精神病性障碍包括睡眠/清醒和唤醒/警醒症(例如失眠和时差症)、注意力缺陷过动症(ADHD)、学习和记忆障碍、认知功能障碍、偏头痛、神经性炎症、痴呆、轻度认知损害(痴呆前期)、早老性痴呆、癫痫、与猝倒有关或无关的嗜眠症、猝倒、睡眠/清醒体内平衡性障碍、自发性嗜眠、日间过度思睡(EDS)、昼夜节律紊乱、睡眠/疲劳障碍、疲劳症、与睡眠呼吸暂停有关的倦睡、由于近绝经期的荷尔蒙变化所致睡眠损害、与帕金森病有关的疲劳症、与MS有关的疲劳症、与抑郁有关的疲劳症、化疗引起的疲劳症、饮食性疾病、肥胖症、运动病、眩晕、精神分裂症、物质滥用、双相性精神障碍、躁狂症和抑郁症;以及其中涉及组胺H3受体的其它病症例如上气道变态反应、哮喘、瘁病、鼻充血和过敏性鼻炎。例如,本发明的特征在于防止、抑制以下疾病发展或治疗以下疾病的方法:上气道变态反应、哮喘、痒病、鼻充血和过敏性鼻炎。日间过度思睡(EDS)发生可能与睡眠呼吸暂停、轮班工作、纤维肌痛、MS等有关或无关。
本发明化合物可用于治疗或预防选自以下的疾病的方法:认知障碍、睡眠障碍、精神病性障碍和其它病症。
认知障碍包括例如痴呆、早老性痴呆(Panula,P.et al.,Soc.Neurosci.Abstr.1995,21,1977)、认知功能障碍、轻度认知损害(痴呆前期)、注意力缺陷过动症(ADHD)、注意力缺陷障碍以及学习和记忆障碍(Barnes,J.C.et al.,Soc.Neurosci.Abstr.1993,19,1813)。学习和记忆障碍包括例如学习能力损害、记忆损害、与年龄相关的认知能力下降和记忆缺失。H3拮抗剂已在多个记忆试验中证实改善记忆,这些试验包括小鼠高架加(elevated plus)迷宫试验(Miyazaki,S.et al.Life Sci1995,57(23),2137-2144)、位置识别任务双实验(Orsetti,M.et al.Behav.Brain Res.2001,124(2),235-242)、小鼠被动躲避试验(Miyazaki,S.et al.Meth.Find.Exp.Clin.Pharmacol.1995,17(10),653-658)和大鼠径向迷宫试验(Chen,Z.Acta Pharmacol.Sin.2000,21(10),905-910)。H3拮抗剂还在作为学习能力损害的注意力缺陷障碍动物模型的原发性高血压大鼠中证实,改善记忆(Fox,G.B.et al.Behav.Brain Res.2002,131(1-2),151-161)。
睡眠障碍包括例如失眠、睡眠紊乱、嗜眠症(与猝倒有关或无关)、猝倒、睡眠/清醒体内平衡性障碍、自发性嗜眠、日间过度思睡(EDS)、昼夜节律紊乱、疲劳症、嗜眠、REM-行为障碍和时差症。疲劳症和/或睡眠损害可由各种原因造成或与这些原因有关,这些原因是例如睡眠呼吸暂停、近绝经期的荷尔蒙变化、帕金森病、多发性硬化(MS)、抑郁症、化疗或轮班工作制引起的疾病。
精神病性障碍包括例如精神分裂症(Schlicker,E.and Marr,I.,Naunyn-Schmiedeberg′s Arch.Pharmacol.1996,353,290-294)、双相性精神障碍、躁狂症、抑郁症(Lamberti,C.et al.Br.J.Pharmacol.1998,123(7),1331-1336;Perez-Garcia,C.et al.Psychopharmacology 1999,142(2),215-220)(再参见:Stark,H.et al.,Drugs Future 1996,21(5),507-520;和Leurs,R.et al.,Prog.Drug Res.1995,45,107-165和其中引用的参考文献)、强迫性障碍和创伤后紧张性障碍。
其它病症包括例如运动病、眩晕(包括眩晕和良性体位性眩晕)、耳鸣(tinitus)、癫痫(Yokoyama,H.et al.,Eur.J.Pharmacol.1993,234,129-133)、偏头痛、神经性炎症、饮食性疾病(Machidori,H.et al.,BrainRes.1992,590,180-186)、肥胖症、物质滥用障碍、运动障碍(例如多动腿综合征)和与眼有关的病症(例如黄斑变性和色素性视网膜炎)。
所述治疗和预防方法包括给予患有此类疾病的哺乳动物有效量的至少一种本发明化合物的步骤。
本发明还考虑用治疗过敏性鼻炎、鼻充血和过敏性充血的联合疗法治疗或预防组胺介导的疾病或病症的方法,该方法包括:a)给予有效量的至少一种本发明化合物,和b)给予有效量的一种或多种组胺H1或H2拮抗剂。合适的组胺H1拮抗剂包括:氯雷他定(loratidine)(CLARITINTM)、地氯雷他定(desloratidine)(CLARINEXTM)、非索非那定(ALLEGRATM)和西替利嗪(ZYRTECTM)。
本发明还考虑用治疗抑郁症、心境障碍或精神分裂症的联合疗法治疗或预防组胺介导的疾病或病症的方法,该方法包括:a)给予有效量的至少一种本发明化合物,和b)给予有效量的一种或多种神经递质再摄取阻滞剂。合适的神经递质再摄取阻滞剂包括:选择性5-羟色胺再摄取抑制剂(SSRI)、5-羟色胺-去甲肾上腺素再摄取抑制剂、去甲肾上腺素能再摄取抑制剂或非选择性5-羟色胺-、多巴胺-或去甲肾上腺素再摄取抑制剂。神经递质再摄取阻滞剂的特定实例包括氟西汀(PROZACTM)、舍曲林(ZOLOFTTM)、帕罗西汀(PAXILTM)和阿米替林。
本发明还考虑用治疗嗜眠症、日间过度思睡(EDS)、早老性痴呆、抑郁症、注意力缺陷障碍、与MS有关的疲劳症、麻醉后软弱无力、认知损害、精神分裂症、与脑麻痹有关的痉挛状态、与年龄相关的记忆力下降、自发性嗜眠或时差症的联合疗法治疗或预防组胺介导的疾病或病症的方法,该方法包括:a)给予有效量的至少一种本发明化合物,和b)给予有效量的莫达非尼。
在另一个实施方案中,本发明考虑用联合疗法治疗或预防组胺介导的疾病或病症的方法,该方法包括:a)给予有效量的至少一种本发明化合物,和b)给予有效量的托吡酯(Topamax)。尤其是,此类方法可用于治疗肥胖症。优选,联合方法使用约20-300mg/剂量的托吡酯剂量。
可通过药用组合物给予本发明化合物,治疗患有由H3受体介导的病症的患者(人和其它哺乳动物)。因此,本发明的特征在于含至少一种本发明化合物和药学上可接受的载体的药用组合物。本发明组合物还可包含至少一种其它治疗药物例如H1拮抗剂、SSRI、托吡酯或莫达非尼(例如用于联合疗法的复方制剂或分别配制的活性药物的联合药物)。
本发明的特征还在于使用或制备或配制此类药用组合物的方法。可用制剂领域技术人员已知的常规药物赋形剂和混合技术制备药用组合物。预计可通过口服、肠胃外、直肠、局部或眼途径或通过吸入给予本发明化合物。也可设计缓慢释放活性成分的制剂。制剂可以是片剂、胶囊剂、小药囊、小瓶、散剂、颗粒剂、锭剂、重新组成用粉末、液体制剂或栓剂形式。优选,可通过静脉内输注或局部给药,但更优选通过口服给予化合物。
对于经口给药,可按片剂或胶囊剂或溶液剂、乳剂或混悬剂形式提供本发明化合物。口服用片剂可包含与药学上可接受的赋形剂混合的活性成分,这些赋形剂是例如惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、矫味剂、着色剂和防腐剂。合适的惰性填充剂包括碳酸钠和碳酸钙;磷酸钠和磷酸钙;乳糖、淀粉、糖、葡萄糖、甲基纤维素、硬脂酸镁、甘露醇、山梨醇等;典型的液体口服赋形剂包括乙醇、甘油、水等。淀粉、聚乙烯吡咯烷酮、淀粉羟乙酸钠、微晶纤维素和藻酸是合适的崩解剂。粘合剂可包括淀粉和明胶。如存在,润滑剂通常是硬脂酸镁、硬脂酸或滑石粉。如果需要,可将片剂用物质例如甘油单硬脂酸酯或甘油二硬脂酸酯包衣,以延缓在胃肠道中吸收,或可用肠溶包衣剂包衣。口服用胶囊剂包括其中活性成分与固体、半固体或液体稀释剂混合的硬明胶胶囊,和其中活性成分与水、油例如花生油或橄榄油、液体石蜡;短链脂肪酸的单和二甘油酯的混合物;聚乙二醇400或丙二醇混合的软明胶胶囊。
经口给药的液体可以是混悬剂、溶液剂、乳剂或糖浆,或可以作为临用前用水或其它合适的溶媒重新组成溶液的干燥产品提供。此类液体组合物可含药学上可接受的赋形剂例如悬浮剂(例如山梨醇、甲基纤维素、藻酸钠、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶等);非水溶媒,它们包括油(例如杏仁油或分馏椰子油)、丙二醇、乙醇或水;防腐剂(例如尼泊金甲酯或丙酯或山梨酸);湿润剂例如卵磷脂;且如果需要,还含有矫味剂或着色剂。
也可通过非口服途径给予本发明化合物。可将组合物配制成用于直肠给药的栓剂。为了包括静脉内、肌内、腹膜内或皮下途径的肠胃外使用,通常通过缓冲至适当pH和等渗性的无菌水溶液或混悬液或肠胃外可接受的油提供本发明化合物。合适的水性溶媒包括林格氏液和等渗氯化钠。通过单位剂量形式例如安瓿或一次性注射装置;多次剂量形式例如可从中吸取适当剂量的瓶,或通过可用于制备注射制剂的固体形式或预浓缩物提供此类形式。另一种给予本发明化合物的模式可使用贴剂制剂,实现透皮递药。也可通过鼻吸入或口服途径,用含本发明化合物和合适的载体的喷雾制剂给予本发明化合物。
在本领域中已知确定用于治疗和预防目的的本发明药用组合物或药物联合的有效剂量的方法,不管是否配制在同一组合物中。任何具体患者所需的具体剂量水平取决于多种因素,它们包括所治疗的病症的严重程度、给药途径、代谢速度和患者的重量。对于治疗目的,“有效剂量”或“有效量”是指研究人员、兽医、医师或其它临床技术人员正在寻找的引起组织系统、动物或人生物或医学反应的单独或联合的各活性化合物或药物的量,生物或医学反应包括缓解所治疗疾病或病症的症状。对于预防目的(即预防或抑制病症发作或发展),术语“有效剂量”或“有效量”是指研究人员、兽医、医师或其它临床技术人员正在寻找的抑制患者病症发作或发展的单独或联合的各活性化合物或药物的量,该量延缓至少部分通过调节组胺H3受体介导的病症。联合治疗的方法包括一起给予含所有活性药物的单个制剂;基本上同时给予一种以上制剂;和给予分别配制的两种或多种活性药物。
预计日剂量(无论按单次剂量或分次剂量给药)范围为0.01-1000mg/日,更通常1-500mg/日,最通常10-200mg/日。按剂量/单位体重表示,期望典型的剂量为0.0001mg/kg-15mg/kg,尤其0.01mg/kg-7mg/kg,最尤其0.15mg/kg-2.5mg/kg。
优选,口服剂量范围为每日约0.05-200mg/kg,按1-4个分剂量给予。可在每日约0.05-约50mg/kg范围内,经口给予某些本发明化合物,每日可按0.05-约20mg/kg给予其它化合物,而每日可按0.1-约10mg/kg给予还其他的化合物。输注剂量范围可为约1-1000μg/kg/min抑制剂,持续几分钟-几天的时间,该抑制剂与药物载体混合在一起。对于局部给药,可按照约0.1%-约10%药物/溶媒浓度,将本发明化合物与药物载体混合。
实施例
为举例说明本发明,包括以下实施例。这些实施例不限制本发明。它们仅表示推荐实施本发明的方法。本领域技术人员可找到实施本发明的其它方法,这些方法对他们而言显而易见。但这些方法应视为在本发明范围内。
化学实施例和数据:
用指定的正或负模式进行电喷雾离子化(ESI),在Agilent系列1100 MSD上得到质谱。在Bruker型号DPX400(400MHz)、DPX500(500MHz)或DPX600(600MHz)分光计上得到核磁共振(NMR)图谱。以下1H NMR数据形式是:化学位移按距离四甲基硅烷参照物的低场ppm表示(多重性,偶合常数J,按Hz计,积分)。
在Hewlett Packard HPLC上进行反相高效液相色谱(HPLC)测定,色谱条件:Zorbax Eclipse XDB-C8,5μm,4.6×150mm柱,1-99%乙腈/水/0.05%TFA梯度洗脱8min。
用ChemDraw Ultra 6.0.2(CambridgeSoft Corp.,Cambridge,MA)生成化学名。
实施例1;(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮
步骤A:4-(4-甲酰基-苯甲酰基)-哌嗪-1-甲酸叔丁酯
将4-羧基苯甲醛(3.10g)的CH2Cl2悬浮液依次用哌嗪-1-甲酸叔丁酯(3.6g)、EDC(3.86g)、HOBt(2.68g)和DMAP(~0.020g)处理。18h后,将混合物依次用1N NaOH和1N HCl萃取。将有机层干燥(Na2SO4),浓缩,得到标题化合物(5.11g,78%)。MS(ESI):C17H22N2O4理论质量,318.16;m/z实测值219.3[(M-100)+H]+。
1H NMR(CDCl3):10.04(s,1H),7.93(d,J=8.2,2H),7.54(d,J=8.1,2H),3.82-3.67(m,2H),3.58-3.30(m,6H),1.46(s,9H).
步骤B:4-(4-吗啉-4-基甲基-苯甲酰基)-哌嗪-1-甲酸叔丁酯
将4-(4-甲酰基-苯甲酰基)-哌嗪-1-甲酸叔丁酯(2.06g)的甲醇(100ml)溶液用吗啉(4ml)和NaB(OAc)3H(6.98g,在1h内分批加入)处理。3h后,将混合物用饱和NaHCO3水溶液稀释,用CH2Cl2萃取。将有机层干燥(Na2SO4),浓缩。残渣经柱层析(SiO2)纯化,得到标题化合物(1.22g,48%)。MS(ESI):C21H31N3O4的理论质量,389.23;m/z实测值,390.4[M+H]+。
1H NMR(CDCl3):7.39-7.33(m,4H),3.75-3.66(m,6H),3.50(s,2H),3.51-3.33(m,6H),2.45-2.41(m,4H),1.46(s,9H).
步骤C:(4-吗啉-4-基甲基-苯基)-哌嗪-1-基-甲酮
将4-(4-吗啉-4-基甲基-苯甲酰基)-哌嗪-1-甲酸叔丁酯(1.163g)的CH2Cl2(10mL)溶液用TFA(~4mL)处理。30min后,再加入TFA(5mL),将混合物再搅拌2h。将混合物用饱和NaHCO3水溶液稀释,用CH2Cl2萃取。将有机层干燥(Na2SO4),浓缩。残渣经柱层析(SiO2)纯化,得到标题化合物(0.255g,30%)。MS(ESI):C16H23N3O2的理论质量,289.18;m/z实测值,290.4[M+H]+。
1H NMR(CDCl3):7.41-7.35(m,4H),3.95-3.70(m,6H),3.52(s,2H),3.09-2.80(m,6H),2.49-2.42(m,4H).
步骤D
将(4-吗啉-4-基甲基-苯基)-哌嗪-1-基-甲酮(0.128g)的甲醇(7.5mL)溶液用(1-乙氧基-环丙氧基)-三甲基-硅烷(1.5mL)、乙酸(0.2mL)和NaBH3CN(~400mg)处理。将混合物在60℃下加热18h,然后冷却至室温,浓缩。将残渣用1N NaOH稀释,用CH2Cl2萃取。将有机层干燥(Na2SO4),浓缩。残渣经柱层析(SiO2)纯化,得到标题化合物(0.0548g,38%)。MS(ESI):C19H27N3O2的理论质量,329.21;m/z实测值,330.4[M+H]+。
1H NMR(CDCl3):7.36(s,4H),3.79-3.68(m,6H),3.50(s,2H),3.44-3.32(m,2H),2.74-2.61(m,2H),2.60·2.50(s,2H),2.45-2.40(m,4H),1.66-1.62(m,1H),0.49-0.44(m,2H),0.44-0.39(m,2H).
实施例1的备选制备
步骤A:4-环丙基哌嗪-1-甲酸叔丁酯
将哌嗪-1-甲酸叔丁酯(75.0g)、四氢呋喃(THF)(500ml)、甲醇(500mL)、[(1-乙氧基环丙基)氧基]三甲基硅烷(161ml)、NaBH3CN(38.0g)和乙酸(37ml)的混合物在60℃下加热5h。将混合物冷却至室温,用水(30ml)处理,搅拌5min。然后将混合物用1N NaOH(130mL)处理,再搅拌15min。将混合物浓缩,将剩余水溶液用CH2Cl2(500mL)萃取。将有机层用1N NaOH(500mL)洗涤。将合并的水层用CH2Cl2(150mL)萃取。将合并的有机层用盐水(400mL)洗涤,干燥(Na2SO4),浓缩,得到标题化合物,为白色固体(92g,100%)。MS(ESI):C12H22N2O2的理论质量,226.17;m/z实测值,227.2[M+H+]。
1H NMR(400MHz,CDCl3):3.39(t,J=5.0Hz,4H),2.55(t,J=4.9Hz,4H),1.60(ddd,J=10.3,6.5,3.8Hz,1H),1.46(s,9H),0.49-0.38(m,4H).
步骤B:1-环丙基哌嗪二盐酸盐
将4-环丙基哌嗪-1-甲酸叔丁酯(92g)的1,4-二噁烷(200mL)溶液用HCl(4M的1,4-二噁烷溶液,500mL)处理10min,同时保持温度在40℃以下。加入结束后,将混合物在45℃下加热9h,然后冷却至室温。将稠悬浮液用己烷(400ml)稀释,冷却至10℃。将得到的固体过滤,收集,用己烷洗涤,干燥,得到标题化合物,为白色固体(78g,96%)。MS(ESI):C7H14N2的理论质量,126.12;m/z实测值,127.0[M+H+]。
1H NMR(400MHz,D2O):3.65(brt,J=4.7Hz,4H),3.47(brt,J=5.5Hz,4H),2.85(br五重峰,J=5.8Hz,1H),0.94(brs,2H),0.92(brs,2H).
步骤C:4-(4-环丙基-哌嗪-1-羰基)-苯甲醛
将4-甲酰基-苯甲酸(54.4g)、甲苯(500ml)、N,N-二甲基甲酰胺(DMF)(3.6ml)和亚硫酰氯(30.4mL)混合物在60℃下加热2h,然后冷却至5℃。在另一个烧瓶中,将NaOH(50.7g)、水(550mL)和甲苯(150mL)的5℃混合物用1-环丙基-哌嗪二盐酸盐(70.0g)分次处理,同时保持温度在10℃以下。加入结束后,将混合物冷却至5℃,按保持温度不超过10℃的速度,用按以上制备的粗酰氯溶液处理。加入结束后,让混合物升温至室温,搅拌过夜。将两相混合物用1N NaOH(300mL)碱化至pH~10。将各液层分离,将水层用甲苯(100mL×2)萃取。将合并的有机层用盐水(200mL)洗涤,干燥(Na2SO4),浓缩,得到标题化合物,为浅黄色粘稠油状物(56.0g,62%)。HPLC:RT=5.19min。MS(ESI):C15H18N2O2的理论质量,258.14;m/z实测值,258.9[M+H+]。
1H NMR(400MHz,CDCl3):10.1(s,1H),7.94(假d,J=8.2Hz,2H),7.56(假d,J=8.1Hz,2H),3.77(brs,2H),3.33(brs,2H),2.71(brs,2H),2.55(brs,2H),1.66(ddd,J=10.2,6.6,3.7Hz,1H),0.52-0.46(m,2H),0.45-0.40(brs,2H).
步骤D:(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基′)-甲酮
在5min内,向4-(4-环丙基-哌嗪-1-羰基)-苯甲醛(56.0g)的1,2-二氯乙烷(550mL)溶液中滴加吗啉(37.8ml)。将混合物冷却至10℃,在1h内,用NaB(OAc)3H(64.3g)分次处理。再经2h后,将混合物升温至室温,用水浴将温度保持在20℃以下。18h后,加入水(60ml),同时通过加入少量冰将温度保持在20℃以下。20min后,将混合物用1N NaOH(450ml)碱化至pH~10,将混合物搅拌10min。将各液层分离,将有机层用1N NaOH(150ml)洗涤。将合并的水层用CH2Cl2(200ml)萃取。将合并的有机层用盐水(200mL)洗涤,干燥(Na2SO4),浓缩,得到标题化合物,为浅黄色粘稠油状物(68.0g,95%)。HPLC:RT=4.39min。MS(ESI):C19H27N3O2理论质量,329.21;m/z实测值,330.2[M+H+]。
1H NMR(400MHz,CDCl3):7.35(brs,4H),3,73(brs,2H),3.69(t,J=4.6Hz,4H),3.50(s,2H),3.37(brs,2H),2.67(brs,2H),2.53(brs,2H),2.43(t,J=4.2Hz,4H),1.63(ddd,J=10.3,6.7,3.7Hz,1H),0.49-0.43(m,2H),0.42-0.39(brs,2H).13C NMR(101MHz,CDCl3):170.6,140.0,135.1,129.5,127.5,67.4,63.4,54.0,38.7,6.3.
实施例1A:(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮二盐酸盐
将(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮(68.0g)的乙醇(400mL)溶液加热至60℃,在40min内,滴加浓HCl(37.8mL)处理。加入~20mL HCl后,开始形成沉淀。加入结束后,经过3h,将稠悬浮液缓慢冷却至20℃。将固体过滤,收集,用乙醇洗涤,在真空烘箱中,在50℃下干燥过夜,得到标题化合物,为白色固体(56.2g,68%)。HPLC:RT=4.30min。MS(ESI):C19H27N3O2的理论质量,329.21;m/z实测值,330.0[M+H+]。
1H NMR(400MHz,D2O):7.64(假d,J=8.3Hz,2H),7.58(假d,J=8.3Hz,2H),4.44(brs,2H),4.20-3.10(m,16H),2.88(ddd,J=11.2,6.6,4.8Hz,1H),1.03-0.98(m,4H),13C NMR(101MHz,D2O):172.1,135.3,132.2,130.9,128.0,64.0,60.5,52.6,52.4,51.7,44.8,39.7,39.5,3.9.
实施例1B;(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮柠檬酸盐
将(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮(0.476g,1.45mmol)和柠檬酸(0.281g,1.46mmol)的混合物用甲醇(~10ml)稀释。将混合物加热至均相,然后浓缩。将得到的油状物用乙酸乙酯研磨,将形成的固体物质在真空下干燥,得到柠檬酸盐(0.760g)。
用类似于前述实施例中所述那些方法,通过适当改变取代基,制备实施例2-4化合物。
实施例2:(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮
MS(ESI):C20H28FN3O的理论质量,345.22;m/z实测值,346.4[M+H+]。
1HNMR(400MHz,CDCl3):7.39-7.33(m,4H),4.78-4.58(m,1H),3.82-3.66(m,2H),3.51(s,2H),3.46-3.33(m,2H),2.77-2.49(m,6H),2.43-2.32(m,2H),1.97-1.82(m,4H),1.68-1.63(m,1H),0.52-0.38(m,4H).
实施例2B;(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮柠檬酸盐
实施例3;(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮
MS(ESI):C19H27N3OS的理论质量,345.19;m/z实测值,346[M+H+]。
1HNMR(400MHz,CDCl3):7.37-7.32(m,4H),3.86-3.60(bm,2H),3.53(s,2H),3.53-3.25(bm,2H),2.75-2.61(bm,10H),2.61-2.45(bm,2H),1.66-1.60(m,1H),0.51-0.44(m,2H),0.44-0.38(m,6H).
实施例3B:(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮柠檬酸盐
实施例4:(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮
MS(ESI):C20H29N3O3的理论质量,359.22;m/z实测值,360[M+H+]。
1HNMR(400MHz,CDCl3):7.39-7.34(m,4H),3.93-3.87(m,1H),3.85-3.25(m,10H),2.75-2.45(bm,6H),2.25-2.15(m,1H),2.05-1.93(m,2H),1.67-1.60(m,1H),0.52-0.45(m,2H),0.45-0.40(m,2H).
实施例4B:(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮柠檬酸盐
比较实施例1:(4-异丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮
由U.S.专利申请号10/690,115(2003年10月21日)提供标题化合物的制备方法和分析数据。按实施例1A和1B中所述制备相应的盐形式。
比较实施例1A:(4-异丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮二盐酸盐
比较实施例1B:(4-异丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮柠檬酸盐
比较实施例2:(4-环丁基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮
按实施例1中所述方法制备标题化合物。MS(ESI):C20H29N3O2的理论质量,343.23;m/z实测值,344.4[M+H+]。
1H NMR(400MHz,CDCl3):7.39-7.32(m,4H),3.87-3.65(m,6H),3.66-3.36(m,4H),2.80-2.69(m,1H),2.50-2.18(m,8H),2.08-1.99(m,2H),1.93-1.81(m,2H),1.79-1.61(m,2H).
按实施例1A和1B中所述制备相应的盐形式。
比较实施例2A:(4-环丁基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮二盐酸盐
比较实施例2B:(4-环丁基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮柠檬酸盐
用类似于前述实施例中所述那些方法,通过适当改变取代基,制备比较实施例3-6化合物及其相应的盐形式。
比较实施例3:[4-(4-氟-哌啶-1-基甲基)-苯基]-(4-异丙基-哌嗪-1-基)-甲酮
MS(ESI):C20H30FN3O的理论质量,347.24;m/z实测值,348.4[M+H+]。
1HNMR(400MHz,CDCl3):7.36-7.33(m,4H),4.75-4.59(m,1H),3.84-3.71(m,2H),3.50(s,2H),3.49-3.38(m,2H),2.71(七重峰,J=6.6Hz,1H),2.64-2.31(m,8H),1.94-1.82(m,4H),1.04(d,J=6.3Hz,6H).
比较实施例3B:[4-(4-氟-哌啶-1-基甲基)-苯基]-(4-异丙基-哌嗪-1-基)-甲酮柠檬酸盐
比较实施例4:(4-环丁基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮
MS(ESI):C21H30FN3O的理论质量,359.24;m/z实测值,360.4[M+H+]。
1HNMR(400MHz,CDCl3):7.38-7.34(m 4H),4.77-4.60(m,1H),3.88-3.72(m,2H),3.52(s,2H),3.51-3.37(m,2H),2.80-2.71(m,1H),2.63-2.54(m,2H),2.46-2.20(m,6H),2.09-2.01(m,2H),1.97-1.64(m,8H).
比较实施例4B:(4-环丁基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮柠檬酸盐
比较实施例5:(4-环丁基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮
MS(ESI):C20H29N3OS的理论质量,359.20;m/z实测值,360[M+H+]。
1HNMR(400MHz,CDCl3):7.37-7.32(m,4H),3.88-3.65(bm,2H),3.52(s,2H),3.52-3.35(bm,2H),2.80-2.63(bm,9H), 2.45-2.28(bm,4H),2.10-1.98(m,2H),1.95-1.79(m,2H),1.78-1.65(m,2H).
比较实施例5B:(4-环丁基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮柠檬酸盐
比较实施例6:[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-(4-异丙基-哌嗪-1-基)-甲酮
MS(ESI):C20H31N3O3的理论质量,361.24;m/z实测值,362[M+H+]。
1HNMR(400MHz,CDCl3):7.38-7.34(m,4H),3.93-3.87(m,1H),3.87-3.35(m,10H),2.73(七重峰,J=6.6Hz,1H),2.70-2.62(m,2H),2.62-2.36(bm,4H),2.24-2.15(m,1H),2.05-1.92(bm,2H),1.05(d,J=6.5Hz,6H).
比较实施例6B:[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-(4-异丙基-哌嗪-1-基)-甲酮柠檬酸盐
物理化学数据
测得的实施例1中环丙胺的pKa值明显比理论预测值(用CompuDrug,Inc.的Pallas软件包)低,也明显比比较实施例1(异丙胺)的实测值低。由pION,Inc.(Woburn,Mass.)测定pKa、log P和log D实测值。
表1:物理化学数据
实施例 | pKa(理论值) | pKa(实测值) | log P | log D |
实施例1 | 8.5,6.2 | 6.5,5.3 | 0.89 | 0.86 |
比较实施例1 | 8.5,6.2 | 7.6,6.2 | 0.55 | 0.13 |
比较实施例2 | 7.8,6.2 | 7.4,6.5 | 2.09 | 1.77 |
生物学实施例和数据
A.用人组胺受体转染细胞
使细胞生长至约70%-80%融合,用胰蛋白酶将其从板中除下,使其在临床离心机中沉淀。然后将沉淀再悬浮于400μL完全培养基中,转移到电极间距0.4cm的电穿孔试管(Bio-Rad#165-2088)中。将1μg超螺旋H3受体cDNA加入细胞,轻轻混合。将电穿孔的电压设为0.25kV,电容设为960μF。电穿孔后,将细胞用10ml完全培养基稀释,按以下比例放入4只10cm表面皿中:1∶20、1∶10、1∶5和1∶2。让细胞复原24h,然后加入600μg G-418。使经选择后存活的集落生长,进行试验。使用SK-N-MC细胞,因为它们给出有效偶联,可抑制腺苷酸环化酶。在进一步研究中,使用抑制响应组胺的腺苷酸环化酶最强的集落。
B.[3H]-N-甲基组胺结合
将由表达组胺H3受体的SK-N-MC细胞得到的细胞沉淀在50mMTrisHCl/0.5mM EDTA中匀化。在800g下离心,收集上清液,将该上清液再在30,000g下离心30min。将沉淀再在50mM Tris/5mMEDTA(pH 7.4)匀化。将膜与0.8nM[3H]-N-甲基组胺+/-试验化合物在25℃下温育60min,经GF/C玻璃纤维滤器(用0.3%聚氮丙啶预处理)快速过滤,然后用缓冲液洗涤4次,收获。将收获的过滤物加入5ml闪烁混合物,然后在液体闪烁计数器上记录信号。用10μM组胺定义非特异性结合。按照公式Ki=(IC50)/(1+([L]/(KD)),根据KD=0.8nM,配体浓度([L])=0.8nM,计算pKi值。将在该测定中测得的化合物的数据以所得结果平均值列于表2。在U.S.专利申请号10/690,115(2003年10月21日)中提供比较实施例1的结合数据。
表2.对人H3受体的结合活性
实施例 | Ki(nM) | pKi |
实施例1 | 5.4 | 8.3 |
实施例1B | 6.5 | 8.2 |
实施例2 | 2.0 | 8.7 |
实施例2B | 2.0 | 8.7 |
实施例3 | 2.5 | 8.6 |
实施例4 | 6.0 | 8.2 |
实施例4B | 23 | 7.6 |
比较实施例2 | 1.0 | 9.0 |
比较实施例2A | 1.7 | 8.8 |
比较实施例2B | 2.0 | 8.7 |
比较实施例3 | 2.0 | 8.7 |
比较实施例3B | 1.0 | 9.0 |
比较实施例4 | 0.7 | 9.2 |
比较实施例5 | 1.0 | 9.0 |
比较实施例6 | 6.0 | 8.2 |
比较实施例6B | 5.0 | 8.3 |
C.环AMP蓄积
制备表达报道基因构件和人H3受体的SK-N-MC细胞的亚系。按Barbier,A.J.et al.(Br.J.Pharmacol.1994,143(5),649-661)中所述得到pA2值。将该测定中测得的化合物数据以所得结果平均值列于表3。
表3.功能活性
实施例 | pA2 |
实施例1 | 8.4 |
实施例2B | 9.0 |
比较实施例1 | 9.0 |
比较实施例1A | 8.9 |
比较实施例2 | 9.5 |
比较实施例3B | 9.6 |
比较实施例4 | 10.0 |
比较实施例6 | 8.2 |
D.药代动力学和生物分析
使用6只雄性Sprague Dawley大鼠/组(约300g体重;3只动物/时间点)。将它们分组饲养,给它们提供食物和随意饮水,并维持12-h光照和黑暗周期。从供应商接受后,让动物适应环境至少7天,然后开始研究。
对于经口给药,用0.5%羟丙基甲基纤维素将试验化合物配制为1mg/mL,按10mg/kg剂量释药。使用试验化合物的柠檬酸盐形式(按实施例1B中所述制备)。通过16号胃内灌饲,动物接受10mg/kg(10mL/kg)一次性大剂量各化合物。对于静脉内给药,用5%葡萄糖水溶液将试验化合物配制为1mg/mL,通过24号TerumoSurflo导管,在侧尾静脉中按一次性大剂量静脉内剂量给予1mg/kg(1ml/kg)剂量。所有给药溶液均在临注射前制备。
从侧尾静脉采集血样(250μl),收集至肝素化的Natelson血液收集试管中,倒入1.5ml微量离心管。按14,000rpm,将血样在微量离心机中离心5min。在冰箱中,将血浆保存在-20℃下以备LC-MS/MS分析用。
用WinNonlin 3.3或4.0.1版分析数据。用非房室模型(#200用于血管外给药,#201用于i.v.给药)测定表4和5中所示药代动力学参数(NA=不适用或未测定)。
表4.在大鼠中的药代动力学特性
实施例 | 模式 | Tmax(h) | Cmax(ng/mL) | AUCINF(h-ng/mL) | T1/2(h) | Cl(mL/min/kg) | Vd(L/kg) |
实施例1B | 口服 | 0.5 | 2787 | 8716 | 3.11 | 20.2 | 5.45 |
i.v. | NA | 935 | 777 | 0.92 | 21.6 | 1.72 | |
比较实施例1B | 口服 | 1.5 | 1050 | 9743 | 4.71 | 17.1 | 6.98 |
i.v. | NA | 4113 | 1560 | 3.2 | 12.8 | 3.55 | |
比较实施例2B | 口服 | 1.33 | 683 | 4104 | 2.89 | 43.2 | 10.33 |
i.v. | NA | 285 | 464 | 1.86 | 34.8 | 6.41 |
表5.在大鼠中的药代动力学特性
实施例 | 模式 | Tmax(h) | Cmax(μmol/mL) | AUCINF(h-μmol/mL) | T1/2(h) | Cl(mL/min/kg) | Vd(L/kg) |
实施例2B | 口服 | 1.67 | 0.42 | 1.91 | 2.72 | 431 | 112 |
i.v. | NA | 3.78 | 1.37 | 1.11 | 41.4 | 3.94 | |
比较实施例3B | 口服 | 1.33 | 0.16 | 1.95 | 8.22 | 270 | 180 |
i.v. | NA | 1.49 | 1.16 | 7.60 | 44.2 | 29.2 | |
比较实施例4B | 口服 | 0.67 | 0.48 | 1.28 | 3.44 | 1135 | 397 |
i.v. | NA | 0.46 | 0.41 | 2.08 | 113 | 20.3 | |
实施例3B | 口服 | 0.25 | 0.19 | 0.18 | 0.41 | NA | NA |
i.v. | NA | 0.86 | 0.18 | 0.27 | 282 | 6.48 | |
比较实施例5B | 口服 | 0.38 | 0.07 | 0.12 | 0.95 | NA | NA |
i.v. | NA | 2.68 | 0.42 | 1.33 | 154 | 17.8 | |
实施例4B | 口服 | 0.83 | 8.73 | 33.2 | 3.58 | NA | NA |
i.v. | NA | 2.92 | 3.07 | 1.47 | 15.2 | 1.91 | |
比较实施例6B | 口服 | 0.50 | 2.96 | 19.99 | 4.35 | NA | NA |
i.v. | NA | 1.41 | 1.34 | 2.36 | 34.9 | 7.04 |
Claims (37)
1.一种化合物,所述化合物选自:
(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮,
及其药学上可接受的盐。
2.一种化合物,所述化合物是(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮或其药学上可接受的盐。
3.一种化合物,所述化合物是(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮或其药学上可接受的盐。
4.一种化合物,所述化合物是(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮或其药学上可接受的盐。
5.一种化合物,所述化合物是(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮或其药学上可接受的盐。
6.一种化合物,所述化合物选自:(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮和(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮二盐酸盐。
7.一种化合物,所述化合物是(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮。
8.一种化合物,所述化合物是(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮二盐酸盐。
9.一种化合物,所述化合物是(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮柠檬酸盐。
10.一种化合物,所述化合物是
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮柠檬酸盐,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮柠檬酸盐,或
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮柠檬酸盐。
11.一种药用组合物,所述组合物包含药学上可接受的载体和有效量的至少一种化合物,所述化合物选自:
(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮,
及其药学上可接受的盐。
12.有效量的至少一种化合物在制备用于治疗或预防哺乳动物中中枢神经系统病症的药物中的用途,所述中枢神经系统病症选自:包括睡眠/清醒和唤醒/警醒症的神经障碍、注意力缺陷过动症、认知功能障碍、偏头痛、神经性炎症、痴呆、癫痫、猝倒、昼夜节律紊乱、睡眠/疲劳障碍、饮食性疾病、肥胖症、运动病、眩晕、精神分裂症、物质滥用、双相性精神障碍、躁狂症和抑郁症,所述化合物选自:
(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮,
及其药学上可接受的盐。
13.权利要求12的用途,其中所述认知功能障碍是学习和记忆障碍或轻度认知损害。
14.权利要求12的用途,其中所述痴呆是早老性痴呆。
15.权利要求12的用途,其中所述睡眠/疲劳障碍是疲劳症或与猝倒有关或无关的嗜眠症。
16.权利要求12的用途,其中所述睡眠/疲劳障碍是睡眠/清醒体内平衡性障碍、自发性嗜眠、日间过度思睡、与睡眠呼吸暂停有关的倦睡、由于近绝经期的荷尔蒙变化所致睡眠损害、与帕金森病有关的疲劳症、与多发性硬化有关的疲劳症、与抑郁有关的疲劳症或化疗引起的疲劳症。
17.有效量的至少一种化合物在制备一种治疗或预防哺乳动物中上气道变态反应、哮喘、痒病、鼻充血或过敏性鼻炎的药物中的用途,所述化合物选自:
(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮,
及其药学上可接受的盐。
18.有效量的至少一种化合物和有效量的一种或多种组胺H1或H2拮抗剂在制备一种治疗或预防过敏性鼻炎、鼻充血和过敏性充血的药物中的用途,所述化合物选自:
(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮及其药学上可接受的盐。
19.有效量的至少一种化合物和有效量的一种或多种神经递质再摄取阻滞剂在制备一种治疗或预防抑郁症、心境障碍或精神分裂症的药物中的用途,所述化合物选自:
(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮,及其药学上可接受的盐。
20.有效量的至少一种化合物和有效量的莫达非尼在制备一种治疗或预防嗜眠症、早老性痴呆、抑郁症、注意力缺陷障碍、与多发性硬化有关的疲劳症、麻醉后软弱无力、认知损害、精神分裂症、与脑麻痹有关的痉挛状态、或时差症的药物中的用途,所述化合物选自:
(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮及其药学上可接受的盐。
21.权利要求20的用途,其中所述嗜眠症是日间过度思睡或自发性嗜眠,所述认知损害是与年龄有关的记忆力下降。
22.作为正电子发射断层显像术分子探针的18F-标记或11C-标记的化合物在制备一种研究组胺介导的病症的药物中的用途,所述化合物选自:
(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮。
23.权利要求11的药用组合物,所述组合物还包含托吡酯。
24.有效量的化合物在制备一种治疗患有或诊断患有由组胺H3受体活性介导的疾病的药物中的用途,所述化合物选自:
(4-环丙基-哌嗪-1-基)-(4-吗啉-4-基甲基-苯基)-甲酮,
(4-环丙基-哌嗪-1-基)-[4-(4-氟-哌啶-1-基甲基)-苯基]-甲酮,
(4-环丙基-哌嗪-1-基)-(4-硫代吗啉-4-基甲基-苯基)-甲酮,和
(4-环丙基-哌嗪-1-基)-[4-(2-羟基甲基-吗啉-4-基甲基)-苯基]-甲酮,
及其药学上可接受的盐。
25.权利要求24的用途,其中所述疾病选自:认知障碍、睡眠障碍和精神病性障碍。
26.权利要求24的用途,其中所述疾病选自:痴呆、认知功能障碍、注意力缺陷过动症和注意力缺陷障碍。
27.权利要求24的用途,其中所述疾病选自早老性痴呆、学习和记忆障碍、轻度认知损害和痴呆前期。
28.权利要求24的用途,其中所述疾病选自:学习能力损害、记忆损害和记忆缺失。
29.权利要求24的用途,其中所述疾病选自:睡眠紊乱、猝倒、昼夜节律紊乱、疲劳症和时差症。
30.权利要求24的用途,其中所述疾病选自失眠、与猝倒有关或无关的嗜眠症、睡眠/清醒体内平衡性障碍和嗜眠。
31.权利要求24的用途,其中所述疾病选自日间过度思睡和自发性嗜眠。
32.权利要求24的用途,其中所述疾病选自:睡眠呼吸暂停、近绝经期的荷尔蒙变化、帕金森病、多发性硬化、抑郁症和化疗引起的疾病。
33.权利要求24的用途,其中所述疾病选自:精神分裂症、双相性精神障碍、躁狂症、抑郁症、强迫性障碍和创伤后紧张性障碍。
34.权利要求24的用途,其中所述疾病选自:运动病、眩晕、癫痫、偏头痛、神经性炎症、饮食性疾病、肥胖症和物质滥用障碍。
35.权利要求24的用途,其中所述疾病选自:抑郁症、睡眠紊乱、疲劳症、认知损害、注意力缺陷障碍和饮食性疾病。
36.权利要求24的用途,其中所述疾病选自嗜眠症、记忆损害、记忆缺失和学习能力损害。
37.权利要求24的用途,其中所述疾病选自:与年龄有关的认知下降、REM-行为障碍、良性体位性眩晕、耳鸣、运动障碍、多动腿综合征、黄斑变性和色素性视网膜炎。
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