CN112823157A - 螺色满衍生物 - Google Patents
螺色满衍生物 Download PDFInfo
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- CN112823157A CN112823157A CN201980046665.7A CN201980046665A CN112823157A CN 112823157 A CN112823157 A CN 112823157A CN 201980046665 A CN201980046665 A CN 201980046665A CN 112823157 A CN112823157 A CN 112823157A
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Classifications
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
本发明涉及螺色满衍生物,或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物,以及含有它们的药物组合物及它们用作为哺乳动物受试者的α7烟碱乙酰胆碱受体活性的调节剂的用途
Description
【技术领域】
本发明涉及药理活性螺色满(spirochromane)化合物、或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物,以及关于含有它们的药物组合物及它们作为哺乳动物受试者的α7烟碱乙酰胆碱受体活性的调节剂的用途。
【发明背景】
乙酰胆碱(ACh)通过与胆碱能受体的结合而在哺乳动物中枢神经系统(CNS)中发挥其神经递质的功能。根据毒蕈个s2碱和烟碱的促效活性,哺乳动物CNS含有二种主要类型的ACh受体:分别为蕈毒(mAChR)和烟碱(nAChR)受体。烟碱乙酰胆碱受体为由五个亚单元组成的配体闸控离子通道(Purves et al.Neuroscience 4th ed.(2008)122-126)。烟碱受体的亚单元属于多基因家族且根据它们的胺基酸序列分成二组;一组含有α亚单元,另一组含有β亚单元。不同亚单元组合的五聚体组合体导致大量具有各种药理学性质的受体亚型。最广泛表达的亚型的组合体包括肌型((α1)2β1δε)、神经节型((α3)2(β4)3)和CNS型(α4)2(β2)3或(α7)5)nAChR亚型(Le Novère N et al.Journal of Molecular Evolution 40(1995)155-172)。α7亚单元已显示当单独表达时,形成功能性受体,并因此推测形成同源寡聚物(homooligomeric)五聚体。
nAChR离子通道的活化主要由配体结合在已知激动剂的结合位置来控制,但也受负向或正向异位调节剂(positive allosteric modulator)(NAM和PAM)的调节。nAChR的异位过渡状态模式至少涉及静止状态、活化状态和“脱敏”封闭通道状态、受体变得对激动剂不敏感的过程。不同的nAChR配体可稳定它们优先结合的受体的构形状态。例如,激动剂ACh和(-)-烟碱分别稳定活化和脱敏状态。烟碱受体的活性的改变与许多疾病有关。烟碱受体的减少已被假设可媒介疾病中所见的认知缺陷,诸如阿尔茨海默病和精神分裂症。来自烟草的烟碱的作用也是由烟碱受体媒介,并且因为烟碱的作用是稳定在脱敏状态下的受体,所以烟碱受体的活性增加可能会降低吸烟的欲望。
然而,以作用于与ACh相同的位置的烟碱受体激动剂治疗是有问题的,因为ACh不仅活化,而且也通过过程阻断受体活性,其包括脱敏和非竞争性阻断。此外,长时间的活化似乎会诱发持久的去活。因此,可预期ACh的激动剂在长期施用(chronic administration)后失去效用。
而α7nAChR的特征在于其相较于其他亚型的快速活化动力学及对Ca2+的高渗透性(Delbono et al.J.Pharmacol.Exp.Ther.280(1997)428-438),其在暴露于正构(orthosteric)位置上的激动剂后也展现快速脱敏(Castro et al.Neurosci.Lett.164(1993)137-140;Couturier et al.Neuron 5(1990)847-856)。尽管近年来已进行经开发各种α7-选择性激动剂和部分激动剂,但由于激动剂活化之后的此受体阻断(脱敏),它们临床疗效被证明是次优的。此问题可通过用PAM治疗,增强由内源激动剂媒介的α7nAChR活化而克服。在各种临床前模式中已证明α7nAChRs的正调节具有认知效益(Thomsen et al.CurrPharm Des 16(2010)323-343;Lendvai et al.Brain Res Bull 93(2013)86-96)。
本发明的化合物可用于治疗由α7nAChR的正向异位调节媒介或与其相关的疾病和病况,包括但不限于精神病症,例如精神分裂症(Deutsch SI et al.Schizophr Res 148(2013)138-144)、精神分裂症样障碍(Rowe AR et al.J Psychopharmacol 29(2015)197-211)、情感性分裂症(Martin LF et al.Am J Med Genet B Neuropsychiatr Genet 144B(2007)611-614)、妄想症(Carson R et al.Neuromolecular Med 10(2008)377-384)、短时精神障碍、一般医学病症诱发的精神病症、物质诱发的精神病症或未另外指明的精神病症)、认知损伤(包括例如治疗认知功能损伤,以及由于中风引起的认知损伤)、阿尔茨海默病(Lewis AS et al.Prog Neuropsychopharmacol Biol Psychiatry 75(2017)、亨廷顿病(Foucault-Fruchard L et al.Neural Regen Res 13(2018)737-741)、匹克症(Fehér Aet al.Dement Geriatr Cogn Disord 28(2009)56-62)、与HIV相关痴呆症(Capó-Vélez CMet al.Sci Rep 8(2018)1829)、额颞叶痴呆症(Minami SS et al.Biochem Pharmacol 97(2015)454-462)、路易氏体痴呆症(Perry EK et al.Neuroscience 64(1995)385-395)、血管型痴呆症(Putignano S et al.Clin Interv Aging 7(2012)113-118)、脑血管疾病(SiML和Lee TJF Circ Res 91(2002)62-69)或其他痴呆症状态、及与其他退化性疾病(肌肉萎缩性侧索硬化症)相关的痴呆症(Kawamata et al.Ther Adv Chronic Dis 2(2011)197-208)、等等)、其他可引起认知衰退的急性或亚急性病况诸如精神错乱(Sfera A etal.Front Med 2(2015)56)、外伤性脑损伤(Shin SS et al.Neural Regen Res 10(2015)1552-1554)、老年痴呆症(Whitehouse PJ et et al.Science 215(1982)1237-1239)、轻度认知损伤(Ikonomovic MD et al.Arch Neurol 66(2009)646-651)、唐氏综合征(DeutschSI et al.Clin
Neuropharmacol 26(2003)277-283)、抑郁和与其他疾病相关的认知缺陷)及运动障碍(Parameswaran N et al.Soc Neurosci Abstr(2007)(诸如帕金森氏病症(Quik M etal.Biochem Pharmacol 97(2015)399-407)、以及精神抑制剂诱发的帕金森病、或迟发性运动障碍(Terry AV和Gearhart DA Eur J Pharmacol 571(2007)29-32)、抑郁和情绪障碍,包括抑郁障碍和发作(Philip NS et al.Psychopharmacology 212(2010)1-12)、双相障碍(Leonard S和Freedman R.Biol Psychiatry 60(2006)115-122)、循环型情绪障碍(AncínI et al.J Affect Disord 133(2011)340-345)和未另外指明的双相障碍、其他情绪障碍(Shytle RD et al.Depression和Anxiety 16(2002)89-92)、物质诱发的情绪障碍和未另外指明的情绪障碍、焦虑症(Picciotto MR et al.Neuropharmacology 96(2015)235-243)、惊恐障碍和惊恐发作(Zvolensky MJ et al.Clin Psychol Rev 25(2005)761-789)、强迫症(Tizabi Y et al.Biol Psychiatry 51(2002)164-171)、创伤后应激障碍(Sun Ret al.Neuroscience 344(2017)243-254)、急性应激障碍(Mineur YS etal.Neuropsychopharmacology 41(2015)1579-1587)、广泛性焦虑症(Cocores JA PrimCare Companion J Clin Psychiatry 10(2008)253-254)、一般医学病症诱发的焦虑症、物质诱发的焦虑症、恐惧症和未另外指明的焦虑症)、与物质相关障碍例如物质使用或物质诱发的障碍,例如酒精-(de Fiebre NC和de Fiebre CM Alcohol 31(2003)149-153;DiaperAM et al.Br J Clin Pharmacol 77(2014)302-314)、烟碱-(Leslie FM et al.MolPharmacol 83(2013)753-758)、安非他命-(Pubill D et al.Pharmaceuticals 4(2011)822-847)、苯环利定-(Thomsen MS et al.Neuropharmacology 56(2009)1001-1009)、阿片样物质-(Zhang W,Int J Clin Exp Med 8(2015)1871-1879)、大麻-(Solinas M et al.JNeurosci 27(2007)5615-5620)、古柯碱-(Francis MM et al.Mol Pharmacol 60(2001)71-79)、咖啡因-、迷幻剂-、吸入剂-、镇静剂-、催眠剂-、抗焦虑药-、多物质-或其他物质-相关病症;睡眠障碍(McNamara JP et al.Psychol Health Med 19(2014)410-419)诸如嗜眠发作(Krahn et al J Clin Sleep Med 5(2009)390)、睡眠障碍、原发性嗜睡症、与呼吸相关的睡眠障碍、昼夜节律性睡眠障碍和未另外指明的睡眠障碍;异睡症、睡眠惊恐障碍、梦游症和未另外指明的异睡症(parasomnia);与另一种神精障碍相关的睡眠障碍(包括另一种精神障碍相关的失眠症和另一种精神障碍相关的嗜眠发作)、一般医学病症诱发的睡眠障碍和物质诱发的睡眠障碍;代谢和饮食障碍(Somm E Arch Immunol Ther Exp 62(2014)62:87-101),诸如神经性厌食症(Cuesto G et al.J Neurogenet 31(2017)266-287)、神经性贪食症、肥胖症(Lakhan SE和Kirchgessner A J Transl Med 9(2011)129-139)、强迫性饮食障碍、暴食症和未另外指明的饮食障碍;糖尿病(Marrero MB et al.J Pharmacol ExpTher 332(2010)173-180)、溃疡性结肠炎(Salaga et al.JPET 356(2016)157-169)、克隆病(Bencherif M et al.Cell Mol Life Sci 68(2011)931-949)、肠易激综合征(Keszthelyi D et al.Neurogastroenterol Motil 21(2009)1239-1249)、自闭症谱系障碍(Deutsch et al.Clin Neuropharmacol 33(2010)114-120),包括自闭症、阿斯伯格症、雷特氏症、儿童期崩解症和其他未另外指明的广泛性发展障碍;注意力缺陷过动症(WilensTE和Decker MW Biochem Pharmacol 74(2007)1212-1223)、破坏性行为障碍、对立违抗障碍和未另外指明的破坏性行为障碍;及抽动障碍诸如妥瑞症(Gotti C和Clementi F ProgNeurobiol 74(2004)363-396)、人格障碍(Kamens HM et al.Behav Genet 46(2016)693-704);性功能障碍诸如性欲障碍、性兴奋障碍、性高潮障碍、性疼痛障碍、未另外指明的性功能障碍)、性倒错、性别认同障碍、不孕症(Bray C et al.Biol Reprod 73(2005)807-814)、经前综合征(Gündisch D和Eibl C Expert Opin Ther Pat 21(2011)1867-1896)、和未另外指明的性功能障碍、呼吸系统的病症如咳嗽(Canning BJ Am J Respir Crit Care Med195(2017)A4498)、哮喘(Santana FPR et al.Eur Respir J 48(2016)PA5066)、慢性阻塞性肺脏疾病(Maouche K et al.Proc Natl Acad Sci USA 110(2013)4099-4104)、肺部炎症(Enioutina EY et al.PLoS One 10(2015)e0121128)、心血管系统的病症诸如心脏衰竭(Mai XK et al.J Immunol 200(2018)108.11)、心律不整(Mazloom R et al.PLoS One 8(2013)e82251)、和高血压(Chen JK et al.BMC Cardiovasc Disord 12(2012)38)。
本发明的化合物也可用于治疗炎症、炎性和神经性疼痛(Alsharari SD etal.Biochem Pharmacol 86(2013)1201-1207)、类风湿性关节炎(van Maanen MA etal.Arthritis&Rheumatism 60(2009)1272-1281)、骨关节炎(Lee SE Neurosci Lett 548(2013)291-295)、过敏(Yamamoto T et al.PLoS One 9(2014)e85888)、类肉瘤病(Nicotine Treatment for Pulmonary Sarcoidosis:A Clinical Trial Pilot StudyElliott Crouser MD,Principal Investigator,Ohio State UniversityClinicalTrials.gov Identifier:NCT02265874)、牛皮癣(Westman M et al.Scand JImmunol 70(2009)136-140)、失调症(Taslim N et al.Behav Brain Res 217(2011)282-292)、肌肉紧张不足(Zimmerman CN et al.Front Syst Neurosci 11(2017)43)、全身性红斑狼疮(Fairley AS和Mathis KW Physiol Rep 5(2017)e13213)、躁狂症(Janowsky DS etal.Lancet 2(1972)632-635)、不宁腿综合征(Buchfuhrer MJ Neurotherapeutics 9(2012)776-790)、进行性核上麻痹(Warren NM et al.Brain 128(2005)239-245)、癫痫(Bertrand D Epilepsy Curr 2(2002)191-193)、肌阵挛(Leppik IE Epilepsia 44(2003)2-6)、偏头痛(Liu Q et al.J Pain Res 11(2018)1129-1140)、健忘症(Bali Zs K etal.Front Cell Neurosci 11(2017)271)、慢性疲劳综合征(Shan ZY et al.J Magn ResonImaging 44(2016)1301-1311)、猝倒症(Ebben MR和Krieger AC J Clin Sleep Med 8(2012)195-196)、脑缺血(Han Z et al.J Neurochem 131(2014)498-508)、多发性硬化症(Di Bari M et al.Cent Nerv Syst Agents Med Chem 17(2017)109-115)、脑脊髓炎(HaoJ et al.Exp Neurol 227(2011):110-119)、时差(Shi M et al.eLife 3(2014)e01473)、大脑类淀粉血管病变(Clifford PM et al.Brain Res 1234(2008)158-171)、败血症(RenC et al.Int J Biol Sci 14(2018)748-759),且通常,可用于治疗与nAChR的正向异位调节相关的所有类型的疾病和病症。
此外,这些化合物也可与包括但不限于下列的其他治疗剂组合:乙酰胆碱酯酶抑制剂(诸如加兰他敏(galantamine)、利斯的明(rivastigmine)、多奈派齐(donepezil)、他克林(tacrine)、吩色兰(phenserine)、拉多替吉(ladostigil)和ABT-089);NMDA受体激动剂或拮抗剂(诸如美金刚胺(memantine)、奈拉美生(neramexane)、EVT101和AZD4282);抗类淀粉蛋白抗体,包括抗类淀粉蛋白人源化单株抗体(诸如巴匹珠单抗(bapineuzumab)、ACCOOl、CAD 106、AZD3102、H12A11V1);β-(诸如维罗斯他(verubecestat)、和AZD3293)或γ-分泌酶抑制剂(诸如LY450139和TAK 070)或调节剂;tau磷酸化抑制剂;ApoE4构形调节剂;p25/CDK5抑制剂;NK1/NK3受体拮抗剂;COX-2抑制剂(诸如塞来昔布(celecoxib)、罗非昔布(rofecoxib)、伐地昔布(valdecoxib)、406381和644784);LRRK2抑制剂;HMG-CoA还原酶抑制剂;NSAID(诸如伊布洛芬(ibuprofen));维生素E;甘氨酸运输抑制剂;甘氨酸位置拮抗剂(诸如拉科酰胺(lacosamide));LXRβ激动剂;雄性激素受体调节剂;Aβ寡聚物形成的阻断剂;NR2B拮抗剂、抗发炎化合物(诸如(R)-氟比洛芬(flurbiprofen)、硝基氟比洛芬(nitroflurbiprofen)、ND-1251、VP-025、HT-0712、和EHT-202);PPARγ激动剂(诸如匹格列酮(pioglitazone)和罗格列酮(rosiglitazone));CB-1受体拮抗剂或逆激动剂(诸如AVE1625);CB-2激动剂(诸如842166和SAB378);VR-1拮抗剂(诸如AMG517、705498、782443、PAC20030、VI 14380和A425619);缓激肽Bl受体拮抗剂(诸如SSR240612和NVPSAA164);钠通道阻断剂和拮抗剂(诸如VX409和SPI860);NOS抑制剂(诸如SD6010和274150);抗生素;生长激素促泌素(诸如伊布莫仑(ibutamoren)、伊布莫仑甲磺酸盐(ibutamoren mesylate)、和卡莫瑞林(capromorelin));钾通道开放剂;AMPA激动剂或AMPA调节剂(诸如CX-717、LY451395、LY404187和S-18986);GSK3抑制剂(诸如AZD1080、SAR502250和CEP16805);神经元烟碱激动剂;MARK配体;M1或M4 mAChR激动剂或PAM;mGluR2拮抗剂或NAM或PAM;mGluR5拮抗剂(诸如AZD9272);α-肾上腺素能激动剂;ADAM-10配体;镇定剂、催眠剂、抗焦虑剂、抗精神病药、环吡咯酮、咪唑并吡啶、吡唑并嘧啶、轻镇静剂、褪黑激素激动剂和拮抗剂、褪黑激素剂;食欲激素拮抗剂和激动剂;前动力蛋白(prokineticin)激动剂和拮抗剂;T型钙通道拮抗剂;三唑并吡啶苯并二氮平、巴比妥酸盐;5-HT1A拮抗剂(诸如列可左坦(lecozotan));5-HT2拮抗剂;5-HT4激动剂(诸如PRX-03140);5-HT6拮抗剂(诸如GSK 742467、SGS-518、FK-962、SL-65.0155、SRA-333和扎利罗登(xaliproden));组织胺H3受体拮抗剂和逆激动剂(诸如S38093、ABT-834、ABT 829、GSK 189254和CEP16795);PDE4抑制剂(诸如HT0712);PDE9抑制剂(诸如BI40936);PDE10抑制剂;HDAC抑制剂;KCNQ拮抗剂;GABAA逆激动剂;GABA信号增强剂;GABA激动剂、GABAA受体α5亚单元NAM或PAM、抗精神病药;MAO-B抑制剂;多巴胺转运抑制剂;降肾上腺素转运抑制剂;D2激动剂和部分激动剂;抗胆碱剂(诸如比哌立登(biperiden));COMT抑制剂(诸如恩他卡朋(entacapone));A2a腺苷受体拮抗剂;胆碱能激动剂;来自精神抑制剂的吩噻嗪、噻吨(thioxanthene)(诸如氯普噻吨(chlorprothixene)和替沃噻吨(thiothixene))、杂环二苯并氮平(诸如氯氮平(clozapine))、丁酰苯(诸如氟派醇(haloperidol))、二苯基丁基哌啶(诸如匹莫齐特(pimozide))和吲哚酮(诸如吗啉吲酮(molindolone))的类别的化合物;洛沙平(loxapine)、舒必利(sulpiride)和利培酮(risperidone);左旋多巴;钙通道阻断剂(诸如齐考诺肽(ziconotide)和NMED160);MMP抑制剂;血栓溶解剂;阿片样物质止痛剂(诸如可待因、芬太尼(fentanyl)、氢吗啡酮(hydromorphone)、左啡诺(levorphanol)、哌替啶(meperidine)、美沙酮(methadone)、吗啡、羟考酮(oxycodone)、氧化吗啡酮(oxymorphone)、喷他佐辛(pentazocine)、丙氧芬(propoxyphene);普拉克索(pramipexole);罗匹尼罗(ropinirole);嗜中性细胞抑制因子;SSRI或SSNRI;三环抗抑郁药;降肾上腺素调节剂;锂;丙戊酸;加巴喷丁(gabapentin);普瑞巴林(pregabaline);利扎曲坦(rizatriptan);佐米曲坦(zolmitriptan);那拉曲坦(naratriptan)、和舒马曲坦(sumatriptan)或影响增加效力、安全性、方便性、或减少本发明化合物的不良副作用或毒性的受体或酶的其他药物。
α7烟碱乙酰胆碱受体的已知正向异位调节剂包括2-苯胺-4-芳基噻唑衍生物(WO2007/031440 A2,JANSSEN PHARMACEUTICA NV)、酰胺衍生物(WO 2009/100294 A2,ABBOTLAB.)、三取代的1,2,4-三唑(WO 2009/115547 A1,JANSSEN PHARMACEUTICA NV)、吲哚衍生物(WO 2009/127678 A1,GLAXO GROUP LTD.)和WO 2009/127679 A1,GLAXO GROUP LTD.)、四唑取代的芳基酰胺衍生物(WO 2009/043780 A1,HOFFMANN LA ROCHE)、环丙基芳基酰胺衍生物(WO 2009/043784 A1,HOFFMANN LA ROCHE)、被三取代的吡唑(WO 2009/135944 A1,JANSSEN PHARMACEUTICA NV)、吡咯衍生物(WO 2014/141091 A1,LUPIN LTD)、环丙基苯衍生物(WO 2017/165256 A1,MERCK SHARP&DOHME CORP.)、和被取代的双环杂芳基衍生物(WO2018/085171 A1,MERCK SHARP&DOHME CORP.)。
本发明涉及一种呈现α7烟碱乙酰胆碱受体的正向异位调节的化合物的新类别。
【附图的简单说明】
本发明的一示例性实施方案以举例的方式图示于附图中,其中相同的参考编号表示相同或相似的元素且其中:
图1说明化合物实施例1的位置识别试验的结果。描述用在Y形迷宫的新奇[N]对熟悉[O]臂的探索时间)。Scop:莨菪碱(1mg/kg,ip.)。+p<0.05;++p<0.01;+++p<0.001。
图2说明化合物实施例6的位置识别试验的结果。描述用在Y形迷宫的新奇[N]对熟悉[O]臂的探索时间)。Scop:莨菪碱(1mg/kg,ip.)。+p<0.05;++p<0.01;+++p<0.001。
图3说明化合物实施例7的位置识别试验的结果。描述用在Y形迷宫的新奇[N]对熟悉[O]臂的探索时间)。Scop:莨菪碱(1mg/kg,ip.)。+p<0.05;++p<0.01;+++p<0.001。
图4说明化合物实施例26的位置识别试验的结果。描述用在Y形迷宫的新奇[N]对熟悉[O]臂的探索时间)。Scop:莨菪碱(1mg/kg,ip.)。+p<0.05;++p<0.01;+++p<0.001。
图5说明化合物实施例41的位置识别试验的结果。描述用在Y形迷宫的新奇[N]对熟悉[O]臂的探索时间)。Scop:莨菪碱(1mg/kg,ip.)。+p<0.05;++p<0.01;+++p<0.001。
图6说明化合物实施例43的位置识别试验的结果。描述用在Y形迷宫的新奇[N]对熟悉[O]臂的探索时间)。Scop:莨菪碱(1mg/kg,ip.)。+p<0.05;++p<0.01;+++p<0.001。
图7说明化合物实施例52的位置识别试验的结果。描述用在Y形迷宫的新奇[N]对熟悉[O]臂的探索时间)。Scop:莨菪碱(1mg/kg,ip.)。+p<0.05;++p<0.01;+++p<0.001。
图8说明化合物实施例61的位置识别试验的结果。描述用在Y形迷宫的新奇[N]对熟悉[O]臂的探索时间)。Scop:莨菪碱(1mg/kg,ip.)。+p<0.05;++p<0.01;+++p<0.001。
【发明内容】
本发明涉及式(I)化合物,
其中
A为五元或六元杂环;
B为六元碳环或杂环;
X为C或N;
Y为C或N;
Z为C或N;
W为O或S;
R1为H、C1-6烷基、卤素或卤代C1-6烷基;
R2为H或O;
R3为H、C1-6烷基、卤素、卤代C1-6烷基或C1-6烷氧基;
R4为H或C1-6烷基;
R5为H或C1-6烷基;
n和m独立地为1或2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在另一方面中,本发明涉及式(II)化合物,
其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-6烷基、或卤代C1-6烷基;
R1b为H、C1-6烷基、卤素、或卤代C1-6烷基;
当V为碳时,R1c为H、C1-6烷基、卤素、或卤代C1-6烷基,或当V为硫时,R1c不存在;
R2为H或O;
R3为H、C1-6烷基、卤素、卤代C1-6烷基、或C1-6烷氧基;
n和m独立地为1或2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在另一方面中,本发明提供一种如上述所定义的式(I)或式(II)化合物,用于治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病。
在另一方面中,本发明提供一种如上述所定义的式(I)或式(II)化合物的用途,其用于制备治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病的药物。
在另一方面中,本发明提供一种治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病的方法,其包括将有效量的至少一种如上述所定义的式(I)或式(II)化合物施用于需要该治疗或预防的哺乳动物。
在另一方面中,如上述所定义的式(I)或式(II)化合物可与用于治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病的其他化合物组合施用。
在另一方面中,本发明提供一种制造式(II)化合物的方法。
发明的详细说明
本发明涉及式(I)化合物,
其中:
A为五元或六元杂环;
B为六元碳环或杂环;
X为C或N;
Y为C或N;
Z为C或N;
W为O或S;
R1为H、C1-6烷基、卤素或卤代C1-6烷基;
R2为H或O;
R3为H、C1-6烷基、卤素、卤代C1-6烷基或C1-6烷氧基;
R4为H或C1-6烷基;
R5为H或C1-6烷基;
n和m独立地为1或2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
术语“五元杂环”,如本文所用,是指任选地被取代的具有五个原子且并入一个、二个、三个或四个杂原子(选自氮、氧或硫)的饱和、不饱和或芳族环系统。五元杂环(heterocyclic)部分的实例包括但不限于吡咯烷基、吡咯基、四氢呋喃基、二氢呋喃基、呋喃基、四氢噻吩基、噻吩基、咪唑烷基、咪唑基、吡唑烷基、吡唑基、噁唑烷基、异噁唑烷基、噁唑基、异噁唑基、四氢噻唑基、四氢异噻唑基、噻唑基、异噻唑基、二氧环戊烷基、二硫环戊烷基、三唑基、噁二唑基、噻二唑基、四唑基。
术语“六元杂环”,如本文所用,是指任选地被取代的具有六个原子且并入一个、二个、三个或四个杂原子(选自氮、氧或硫)的饱和、不饱和或芳族环系统。六元杂环的实例包括但不限于哌啶基、吡啶基、哒嗪基、嘧啶基、二氢吡喃基、四氢吡喃基、吡喃基、硫吡喃基、哌嗪基、高哌嗪基、吗啉基、硫吗啉基。
术语“六元碳环”如本文所用,是指任选地被取代的具有六个碳原子的饱和、不饱和或芳族环系统,包括环己基、环己烯基、环己二烯基、和苯基。
术语“卤代”或“卤素”,如本文所用,原样或作为另一基团的一部分,是指氟、氯、溴或碘。
术语“C1-6烷基”,如本文所用,原样或作为另一基团的一部分,是指具有一、二、三、四、五或六个碳原子的支链或直链饱和烃基,包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、和叔丁基。
术语“卤代C1-6烷基”,如本文所用,是指通过如上述所定义的“C1-6烷基”基团键结至母分子部分的至少一种如上述所定义的卤素。当存在几个卤素时,卤素可为相同或不同且卤素可连接至不同的碳原子,或者几个卤素可连接至相同的碳原子。卤代C1-6烷基基团包括但不限于二氟甲基、三氟甲基和2-氯乙基。
术语“C1-6烷氧基”,如本文所用是指通过氧原子键结至母分子部分的如上述所定义的“C1-6烷基”基团,包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基和叔丁氧基。
术语“药学上可接受的”描述可用于制备药物组合物的成分通常为安全无毒的且不是生物学上也不是其他方面不合适的,并包括它们兽医用途以及人类药物用途可以接受者。
术语“药学上可接受的盐”是指已知酸加成盐或碱加成盐,其保留式(I)或式(II)化合物的生物效力和性质且可与适当无毒有机或无机酸或有机或无机碱形成。酸加成盐的实例包括衍生自无机酸(诸如但不限于盐酸、氢溴酸、氢碘酸、硫酸、胺磺酸、磷酸、硝酸和过氯酸)以及衍生自各种有机酸(诸如但不限于乙酸、丙酸、苯甲酸、乙醇酸、苯基乙酸、水杨酸、丙二酸、马来酸、油酸、双羟萘酸、棕榈酸、苯磺酸、甲苯磺酸、甲烷磺酸、草酸、酒石酸、琥珀酸、柠檬酸、苹果酸、乳酸、谷氨酸、富马酸)等等的盐。碱加成盐的实例为衍生自铵-、钾-、钠-和季铵氢氧化物,诸如氢氧化四甲基铵。
术语“前体药”是指根据本发明的式(I)或式(II)化合物的衍生物,本身没有治疗效果但含有这些在活体内化学或代谢降解(生物转化)后成为担当治疗效果的“生物学活性代谢物”的基团。与本发明的式(I)或式(II)化合物相关的这些分解基团,特别是适用于前药的基团,为本领域已知的且也可应用于本发明的化合物(Rautio et al.,NatureReviews-Drug Discovery 2008,7:255-270)。
术语“水合物”表示水和溶质之间的非共价组合。
术语“溶剂合物”表示溶剂和溶质之间的非共价组合。溶剂包括但不限于乙醇、2-丙醇、乙腈和四氢呋喃。
“任选的”或“任选地”表示随后描述的事件或状况可能但不一定发生,且该说明包括事件或状况发生的情况以及事件或状况不发生的情况。
“任选地被取代”表示未被取代或被一个或多个如本文所述的取代基取代。在此,“一个或多个”表示从一个到最高可能的取代数,即,从取代一个氢到取代所有的氢。给定原子上的一个、二个或三个取代基是优选的。
疾病状态的“治疗(Treating或treatment)”包括:
a)预防疾病状态,即在可能暴露于或易患疾病状态,但尚未经历或显示疾病状态的症状的受试者中不会发生导致疾病状态的临床症状,
b)抑制疾病状态,即阻止疾病状态或其临床症状的发生,或
c)缓解疾病状态,即导致疾病状态或其临床症状的暂时或永久消退。
在一个实施方案中,本发明涉及式(I)化合物,其中
A为五元杂环,其中该环的成员选自由下列所组成的群组:碳、氮、氧和硫;
B为六元碳环或杂环,其中该环的成员选自由下列所组成的群组:碳、氮、氧和硫;
X为C;
Y为C;
Z为C或N;
W为O或S;
R1为H、C1-6烷基、卤素或卤代C1-6烷基;
R2为H或O;
R3为H、C1-6烷基、卤素、卤代C1-6烷基或C1-6烷氧基;
R4为H;
R5为H;
n和m独立地为1或2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,
其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-6烷基、或卤代C1-6烷基;
R1b为H、C1-6烷基、卤素、或卤代C1-6烷基;
当V为C时,R1c为H、C1-6烷基、卤素、或卤代C1-6烷基;或当V为S时,R1c不存在;
R2为H或O;
R3为H、C1-6烷基、卤素、卤代C1-6烷基、或C1-6烷氧基;
n和m独立地为1或2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
当V为C时,R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;或当V为S时,R1c不存在;
R2为H;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n和m独立地为1或2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
当V为C时,R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;或当V为S时,R1c不存在;
R2为H;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n和m为1;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
R1c为H、C1-4烷基、卤素、或卤代C1-4烷基当V为C时;或R1c不存在当V为S时;
R2为H;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n和m为2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
当V为C时,R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;或当V为S时,R1c不存在;
R2为H;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n为1;
m为2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
当V为C时,R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;或当V为S时,R1c不存在;
R2为O;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n和m独立地为1或2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
当V为C时,R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;或当V为S时,R1c不存在;
R2为O;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n和m为1;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
当V为C时,R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;或当V为S时,R1c不存在;
R2为O;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n和m为2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C或S;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
当V为C时,R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;或当V为S时,R1c不存在;
R2为O;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n为1;
m为2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C;
Z为C或N;
W为O;
R1a为H、C1-6烷基、或卤代C1-6烷基;
R1b为H、C1-6烷基、卤素、或卤代C1-6烷基;
R1c为H、C1-6烷基、卤素、或卤代C1-6烷基;
R2为H或O;
R3为H、C1-6烷基、卤素、或卤代C1-6烷基;
n和m独立地为1或2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C;
Z为C或N;
W为O;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;
R2为H或O;
R3为H、C1-4烷基、卤素、或卤代C1-4烷基;
n和m独立地为1或2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;
R2为O;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n和m为1;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
R1c为H、C1-4烷基、卤素、或卤代C1-4烷基;
R2为O;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n和m为2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及式(II)化合物,其中
V为C;
Z为C或N;
W为O或S;
R1a为H、C1-4烷基、或卤代C1-4烷基;
R1b为H、C1-4烷基、卤素、或卤代C1-4烷基;
R1c为H、C1-4烷基、卤素、或卤代C1-4烷基
R2为O;
R3为H、C1-4烷基、卤素、卤代C1-4烷基、或C1-4烷氧基;
n为1;
m为2;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在一个实施方案中,本发明涉及选自下列群组的式(I)或式(II)化合物:
6'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-4-氧代-3,4-二氢螺[1-苯并吡喃-2,4'-哌啶]-1'-甲酰胺;
6'-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-3,4-二氢螺[1-苯并吡喃-2,4'-哌啶]-1'-甲酰胺;
N-[(3-氯-1-甲基-1H-吲哚-5-基)甲基]-6'-氟-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6'-氯-N-[(1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]螺[吖丁啶-3,2'-色烯]-1-甲酰胺;
N-[(1-甲基-1H-吲哚-5-基)甲基]-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6'-氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6',8'-二氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氯-N-[(2-氯-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-6'-(三氟甲基)-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-氧代-7'-(三氟甲基)-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-7'-(三氟甲基)-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6',8'-二氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氟-4'-氧代-N-{[2-(三氟甲基)-1H-吲哚-5-基]甲基}-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-{[2-(二氟甲基)-1H-吲哚-5-基]甲基}-7'-氟-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
在另一方面中,本发明提供一种用于治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病的如上述所定义的式(I)或式(II)化合物。
在另一方面中,本发明提供一种如上述所定义的式(I)或式(II)化合物的用途,其用于制备治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病的药物。
在另一方面中,本发明提供一种治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病的方法,其包括将有效量的至少一种如上述所定义的式(I)或式(II)化合物施用于需要该治疗或预防的哺乳动物。
在一个实施方案中,与α7烟碱乙酰胆碱受体活性相关的疾病选自下列群组:精神病症(包括但不限于精神分裂症、精神分裂症样障碍、情感性分裂症、妄想症、短时精神障碍、一般医学病症诱发的精神病症、物质诱发的精神病症或未另外指明的精神病症);认知损伤(包括但不限于由于中风引起的认知损伤)、阿尔茨海默病、亨廷顿病、匹克症、与HIV相关痴呆症、额颞叶痴呆症、路易氏体痴呆症、血管型痴呆症、脑血管疾病或其他痴呆症状态及与其他退化性疾病(包括但不限于肌肉萎缩性侧索硬化症)相关的痴呆症、其他可引起认知衰退的急性或亚急性病况(包括但不限于精神错乱、外伤性脑损伤、老年痴呆症、轻度认知损伤、唐氏综合征、抑郁和与其他疾病相关的认知缺陷)、及运动障碍(包括但不限于帕金森氏病症、精神抑制剂诱发的帕金森病、或迟发性运动障碍)、抑郁和情绪障碍(包括但不限于抑郁障碍和发作、双相障碍、循环型情绪障碍和未另外指明的双相障碍、其他情绪障碍、物质诱发的情绪障碍和未另外指明的情绪障碍);焦虑症、惊恐障碍和惊恐发作、强迫症、创伤后应激障碍、急性应激障碍、广泛性焦虑症、一般医学病症诱发的焦虑症、物质诱发的焦虑症、恐惧症和未另外指明的焦虑症);与物质相关障碍,包括但不限于物质使用或物质诱发的障碍,包括但不限于酒精-、烟碱-、安非他命-、苯环利定-、阿片样物质-、大麻-、古柯碱-、咖啡因-、迷幻剂-、吸入剂-、镇静剂-、催眠剂-、抗焦虑药-、多物质-或其他物质-相关病症);睡眠障碍(包括但不限于嗜眠发作、睡眠障碍、原发性嗜睡症、与呼吸相关的睡眠障碍、昼夜节律性睡眠障碍和未另外指明的睡眠障碍;异睡症、睡眠惊恐障碍、梦游症和未另外指明的异睡症;与另一种精神障碍相关的睡眠障碍、一般医学病症诱发的睡眠障碍和物质诱发的睡眠障碍;代谢和饮食障碍(包括但不限于神经性厌食症、神经性贪食症、肥胖症、强迫性饮食障碍、暴食症和未另外指明的饮食障碍);糖尿病、溃疡性结肠炎、克隆病、肠易激综合征、自闭症谱系障碍(包括但不限于孤独性障碍、阿斯伯格症、雷特氏症、儿童期崩解症和其他未另外指明的广泛性发展障碍);注意力缺陷过动症、破坏性行为障碍、对立违抗障碍和未另外指明的破坏性行为障碍;及抽动障碍(包括但不限于妥瑞症);人格障碍;性功能障碍(诸如性欲障碍、性兴奋障碍、性高潮障碍、性疼痛障碍、未另外指明的性功能障碍)、性倒错、性别认同障碍、不孕症、经前综合征和未另外指明的性功能障碍;呼吸系统的病症(如咳嗽、哮喘、慢性阻塞性肺脏疾病、肺部炎症)、心血管系统的病症(诸如心脏衰竭、心律不整、高血压);炎症、炎性和神经性疼痛、类风湿性关节炎、骨关节炎、过敏症、结节病、牛皮癣、共济失调、肌张力障碍、全身性红斑狼疮、躁狂症、不宁腿综合征、进行性核上麻痹、癫痫、肌阵挛、偏头痛、健忘症、慢性疲劳综合征、猝倒症、脑缺血、多发性硬化症、脑脊髓炎、时差、脑淀粉样血管病和败血症。
在一个实施方案中,与α7烟碱乙酰胆碱受体活性相关的疾病选自下列群组:认知损伤、精神分裂症和自闭症。
本发明进一步关于组合治疗,其中本发明化合物或包含本发明化合物的药物组合物或调配物是与另一种治疗剂或治疗剂等一起施用,用于治疗前示一种或多种病况。这些治疗剂可选自:乙酰胆碱酯酶抑制剂、NMDA受体激动剂或拮抗剂、抗类淀粉蛋白抗体(包括抗类淀粉蛋白人源化单株抗体)、β-或γ-分泌酶抑制剂或调节剂、tau磷酸化抑制剂、ApoE4构形调节剂、p25/CDK5抑制剂、NK1/NK3受体拮抗剂、COX-2抑制剂、LRRK2抑制剂、HMG-CoA还原酶抑制剂、NSAID、维生素E、甘氨酸运输抑制剂、甘氨酸位置拮抗剂、LXRβ激动剂、雄性激素受体调节剂、Aβ寡聚物形成的阻断剂、NR2B拮抗剂、抗发炎化合物、PPARγ激动剂、CB-1受体拮抗剂或逆激动剂、CB-2激动剂、VR-1拮抗剂、缓激肽Bl受体拮抗剂、钠通道阻断剂和拮抗剂、NOS抑制剂、抗生素、生长激素促泌素、钾通道开放剂、AMPA激动剂或AMPA调节剂、GSK3抑制剂、神经元烟碱激动剂、MARK配体、M1或M4 mAChR激动剂或PAM、mGluR2拮抗剂或NAM或PAM、mGluR5拮抗剂、α-肾上腺素能激动剂、ADAM-10配体、镇定剂、催眠剂、抗焦虑剂、抗精神病药、环吡咯酮、咪唑并吡啶、吡唑并嘧啶、轻镇静剂、褪黑激素激动剂和拮抗剂、褪黑激素剂、食欲激素拮抗剂和激动剂、前动力蛋白(prokineticin)激动剂和拮抗剂、T型钙通道拮抗剂、三唑并吡啶苯并二氮平、巴比妥酸盐、5-HT1A拮抗剂、5-HT2拮抗剂、5-HT4激动剂、5-HT6拮抗剂、组织胺H3受体拮抗剂和逆激动剂、PDE4抑制剂、PDE9抑制剂、PDE10抑制剂、HDAC抑制剂、KCNQ拮抗剂、GABAA逆激动剂、GABA信号增强剂、GABA激动剂、GABAA受体α5亚单元NAM或PAM、抗精神病药、MAO-B抑制剂、多巴胺转运抑制剂、降肾上腺素转运抑制剂、D2激动剂和部分激动剂、抗胆碱剂、COMT抑制剂、A2a腺苷受体拮抗剂、胆碱能激动剂、精神抑制剂、洛沙平(loxapine)、舒必利(sulpiride)和利培酮(risperidone)、左旋多巴、钙通道阻断剂、MMP抑制剂、血栓溶解剂、阿片样物质止痛剂、普拉克索(pramipexole)、罗匹尼罗(ropinirole)、嗜中性细胞抑制因子、SSRI或SSNRI、三环抗抑郁药、降肾上腺素调节剂、锂、丙戊酸、加巴喷丁(gabapentin)、普瑞巴林(pregabaline)、利扎曲坦(rizatriptan)、佐米曲坦(zolmitriptan)、那拉曲坦(naratriptan)、和舒马曲坦(sumatriptan)。
在一个实施方案中,治疗剂选自下列群组:乙酰胆碱酯酶抑制剂、NMDA受体拮抗剂、β-分泌酶抑制剂、抗精神病药、GABAA受体α5亚单元NAM或PAM、组织胺H3受体拮抗剂、5-HT6受体拮抗剂、M1或M4mAChR激动剂或PAM、mGluR2拮抗剂或NAM或PAM、和左旋多巴。
在另一方面中,本发明提供根据下列路径制造式(II)化合物的方法:
根据本发明的化合物根据下述合成路径和流程合成。
在整个说明书中,通式是以罗马数字(I)、(II)、(III)、等等表示。
流程1
流程2
流程1
使式(III)的苯乙酮衍生物与式(IV)的含氮环脂族酮衍生物反应,该反应或以二个分开的步骤经由式(VII)或直接以一步骤进行以提供一种式(V)的螺色满酮化合物,
-其中R3的含义如上对于式(II)化合物所述,
-其中n和m的含义如上对于式(II)化合物所述,
-其中n和m的含义如上对于式(II)化合物所述,
-其中R3、n和m的含义如上对于式(II)所述,
接着使式(V)化合物与
a.)氯化氢反应以提供式(VI)的螺色满酮(spirochromanone)盐衍生物,
-其中R3、n和m的含义如上对于式(II)所述,或与
b.)复合氢化物(complex hydrides)反应以提供适当式(VIII)的螺色满醇(spirochromanol)衍生物,
-其中R3、n和m的含义如上对于式(II)所述,接着用三乙膦将式(VIII)化合物还原以提供式(IX)的3,4-二氢螺色烯/螺色烯(spirochromene)衍生物,
-其中R3、n和m的含义如上对于式(II)所述。
流程2
接着,使如此获得的式(IX)或式(VI)衍生物与式(X)的杂环胺衍生物反应,提供式(II)的脲/硫脲衍生物,
-其中R1a、R1b、R1c、V和Z的含义如上对于式(II)所述,
-其中R1a、R1b、R1c、R2、R3、V、Z、n、m、和W的含义如上对于式(II)所述。
经保护的式(V)的螺色满-4-酮的合成可通过不同的路径进行:
a)式(III)的苯乙酮衍生物与式(IV)的含氮环脂族酮衍生物的缩合优选在适当溶剂(例如甲醇)中进行,优选在吡咯烷存在下进行。反应优选在溶剂的沸点下进行。必要的反应时间为15-20小时。这些反应以薄层层析法追踪。通过蒸发溶剂淬灭反应混合物。通过用适当有机溶剂萃取,或在除去有机溶剂后,通过过滤,或通过柱层析分离式(V)的产物。
b)式(III)的苯乙酮衍生物与式(IV)的含氮环脂族酮衍生物的反应优选在适当溶剂例如四氢呋喃中,优选在强碱(例如,二异丙基胺化锂)存在下进行。反应在-20℃至室温范围的温度下进行。必要的反应时间为3-4小时。这些反应的进展以薄层层析法追踪。通过添加饱和氯化铵溶液淬灭反应混合物。通过用适当有机溶剂萃取,及在除去有机溶剂后,通过过滤分离式(VII)的产物。
式(VII)的衍生物的脱氢环化优选在适当溶剂中,在例如三氟乙酸酐和DBU(1,8-二氮杂双环[5.4.0]十一-7-烯)的存在下进行。
除非另有说明,否则一般技术人士可容易地选择溶剂、温度和其他反应条件。实施例部分提供特定的程序。反应可以已知方式进一步处理,例如,从残余物中消除溶剂并通过根据该项技术通常已知的方法(包括但不限于结晶、萃取、研磨和层析法)进一步纯化。
使用与先前技术的不同方法,可获得所需脱保护的式(VI)的螺色满-4-酮。优选在EtOAc与盐酸中于0℃至室温的范围下进行。必要的反应时间为2-3小时。该反应的进展是以薄层层析法追踪,并通过过滤分离产物。
式(V)的衍生物(螺酮的羰基)的还原优选适当溶剂(例如乙醇)中与NaBH4进行。该反应的进展是以TLC追踪。通过消除溶剂分离粗制螺唍-4-醇,接着将残余物分溶在DCM和水之间,并蒸发有机相以获得标题化合物,其在未来的步骤中不经纯化而使用。
式(VIII)的螺色满-4-醇衍生物的还原脱氧是通过众所周知称为“离子氢化”的还原方法完成:通过将羟基衍生物以Et3SiH/CF3COOH系统在90℃下处理6-18小时。该反应的进展是以薄层层析法追踪。蒸发反应混合物,将残余物用饱和NaHCO3溶液处理,并通过用适当有机溶剂萃取分离式(IX)的产物。
大多数的式(X)的伯胺衍生物为市售,或者可由本领域技术人员使用与先前技术所述的不同方法从市售的起始材料和试剂合成。在实施例部分中描述一些新的式(X)的胺衍生物的合成。
上述式(II)化合物可通过使用标准程序和试剂(例如,CDI(1,1'-羰基二咪唑)、氯甲酸酯、或1,1′-硫羰基二咪唑)在适当溶剂(例如,DCM)中在氩氛围下活化式(X)的伯胺化合物,接着添加反应物(式(VI)或式(IX))来制备。反应在0℃至室温范围的温度下进行。必要的反应时间为15-20小时。这些反应的进展以薄层层析法追踪。反应混合物的后处理可通过不同的方法进行,通常通过加水来淬灭。通过用适当有机溶剂萃取来分离产物,并通过结晶或柱层析法来纯化。
本揭示内容在其范围内包括化合物的所有可能同位素标记形式。
本发明的化合物可以口服、肠胃外(例如、肌内、腹膜内、静脉内、关节内、鞘内、腹膜内、直接心室内、脑室内、髓内注射、脑池内注射或输注、皮下注射或植入)、眼、鼻、阴道、直肠、舌下和局部的施用路径且可单独或与以包含适用于各施用路径的药学上可接受的赋形剂的适当剂量单元调配物一起施用。
或者,人们可以局部而非全身方式,例如经由将化合物直接注射至肾脏或心脏区域中,经常以改良释放调配物来施用化合物。此外,人们可以靶向药物递送系统,例如以组织特异性抗体涂布的脂质体来施用药物。脂质体被靶向组织选择性吸收。
本发明的药物组合物通常在单一剂量单元中含有0.01至500mg的活性成分。然而,一些组合物中的活性成分的量可能超过上述定义的上限或下限。
化合物可以每天1至4次,优选每天一次或二次的方案施用。
可调整此剂量含量和方案以提供最佳治疗反应。然而,应该理解,任何特定患者的特定剂量含量和剂量频率可改变,且取决于各种因素包括所用特定化合物的活性、代谢稳定性和该化合物的作用长度、年龄、体重、一般健康、性别、饮食、施用的模式和时间、排泄率、药物组合、特定病况的严重性和接受治疗的宿主。
作为本发明的另一方面,提供含有式(I)或式(II)化合物或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物的药物的药物制造。
本发明的药物组合物可调配成不同的药物剂型,包括但不限于固体口服剂型如片剂(例如,颊、舌下、发泡性、咀嚼性、口腔分散性、冷冻干燥)、胶囊、口含锭、锭剂、丸剂、口腔分散膜、颗粒、粉末;液体口服剂型,包括但不限于溶液、乳液、悬浮液、糖浆、酏剂、口服滴剂;肠胃外剂型,包括但不限于静脉注射、肌内注射、皮下注射;其他剂型,包括但不限于滴眼液、半固体眼制剂、滴鼻液或喷雾剂、透皮剂型、栓剂、直肠胶囊、直肠溶液、乳液和悬浮液、等等。
本发明的药物组合物可以任何已知方式制造,例如,通过混合、溶解、乳化、悬浮、包埋、冷冻干燥、挤出、层压、薄膜铸造、制粒、研磨、包封、糖衣锭制造或压片方法制造。
根据本发明使用的药物组合物因此可以任何已知方式使用一种或多种生理学上可接受的赋形剂调配。如适合且如该项技术理解可使用任何众所周知的技术和赋形剂。
用于制备剂型的适当赋形剂可选自下列类别,包括但不限于片剂和胶囊填充剂、片剂和胶囊黏合剂、释放改良剂、崩解剂、助滑剂、润滑剂、甜味剂、味道掩盖剂、调味剂、涂布剂、表面活性剂、抗氧化剂、缓冲剂、错合剂、乳化剂、冻干助剂、微包封剂、软膏基剂、渗透增强剂、助溶剂、溶剂、栓剂基剂、和悬浮剂。
在一个实施方案中,本发明涉及特定赋形剂的使用,其能够改良活性成分的溶解性、溶解、渗透性、吸收性及/或生体可用率,包括但不限于亲水聚合物、热熔挤出赋形剂、表面活性剂、缓冲剂、错合剂、乳化剂、冻干助剂、超崩解剂、微包封剂、渗透增强剂、助溶剂、共溶剂、和悬浮剂。
上述成分和制造的不同路径仅仅是代表性的。也可使用该项技术中众所周知的其他材料和加工技术等等。
【具体实施方式】
实施例
本发明进一步定义于下列实施例中。应了解,实施例仅以说明的方式给出。从上述讨论及实例,本领域技术人员可确定本发明的必要特征,且在不悖离其精神和范畴下,可进行各种改变和修饰以使其适应各种用途及条件。因此,本发明不受以下本文所阐述的说明性实施例限制,而是由其随附的权利要求书限定。
通常,式(I)和式(II)化合物可根据本领域技术人员的一般知识及/或使用接着的实施例及/或中间体部分中所述的方法制备。一般技艺人士可容易地选择溶剂、温度、压力和其他反应条件。起始材料为市售的及/或由本领域技术人员容易地制备。
现将以下列非限制性实施例说明本发明。
在下列实施例中,“室温”表示范围从20℃至25℃的温度。
具体实施例中所使用的缩写具有下列意义:
AcOH 乙酸
abs. 绝对
aq. 水性
atm 大气压
Boc2O 二碳酸二-叔丁酯
BH3.THF 硼烷四氢呋喃络合物溶液
CDI 1,1'-羰基二咪唑
DBU 1,8-二氮杂双环[5.4.0]十一-7-烯
DCE 1,2-二氯乙烷
DCM 二氯甲烷
DIPEA N,N-二异丙基乙胺
DMF N,N'-二甲基甲酰胺
DMSO 二甲亚砜
EtOAc 乙酸乙酯
Et3SiH 三乙基硅烷
ESI 电喷雾离子化
HEPES (4-(2-羟乙基)-1-哌嗪乙磺酸)
HPLC 高效液相色谱法
LC-MS 液相色谱法-质谱法
MeOH 甲醇
n-BuLi 正丁基锂溶液
NMP N-甲基-2-吡咯烷酮
PCC 氯铬酸吡啶鎓
sat. 饱和
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层层析法
中间体1
6'-氯-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-4'-酮盐酸盐
步骤1:6'-氯-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酸叔丁酯
将3.42g(20mmol)3-氧代吖丁啶-1-甲酸叔丁酯、3.41g(20mmol)的1-(5-氯-2-羟苯基)乙-1-酮和1.42g(1.67mL,20mmol)的吡咯烷在甲醇(20mL)中的溶液回流20小时。在真空中蒸发反应混合物,将棕色残余物溶解于二氯甲烷(120mL)中,并用1N HCl分溶,接着将有机层用水(2×50mL)和盐水(50mL)洗涤,用无水硫酸钠干燥,过滤及在真空中浓缩。在硅凝胶上用DCM:MeOH洗脱将粗制产物层析以产生3.02g(46%)的标题化合物。
步骤2:6'-氯-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-4'-酮盐酸盐
在0℃下在10分钟内将在EtOAc中的20%盐酸(30mL)加至3.0g(8.9mmol)的6'-氯-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酸叔丁酯(来自上一步骤)在EtOAc(30mL)中的溶液。添加后,使混合物加热至室温并在此温度下搅拌2小时。接着将反应混合物在真空中浓缩至约15mL,并用乙醚(20mL)稀释。将沉淀的浅棕色晶体滤出,用乙醚洗涤及干燥以产生2.0g(90%)的标题化合物。
根据关于中间体1所述的方法在吡咯烷存在下从适当的苯乙酮和含氮环脂族酮制备表1的化合物。
表1
中间体18
3',4'-二氢螺[吖丁啶-3,2'-吡喃并[3,2-b]吡啶]-4'-酮盐酸盐
步骤1:4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯
将1-(3-羟基吡啶-2-基)乙酮(160mg;1.17mmol)、N-叔丁氧羰基-3-吖丁啶酮(azetidinon)(205mg,1.2mmol)和吡咯烷(0.1mL,1.2mmol)在甲苯(4mL)中的溶液在回流下搅拌28小时。一旦反应完成(以TLC监测),在真空下浓缩混合物,并将所得将深棕色残余物分溶在EtOAc(30mL)和1N盐酸(10mL)之间。分离各层。将水层用EtOAc(2×20mL)萃取。将合并的有机萃取液依次用水(2×20mL)、饱和NaHCO3溶液(20mL)和盐水(20mL)洗涤。通过快速硅胶柱层析法使用在EtOAc中的30%正己烷作为洗脱液将溶剂蒸发后所得的残余物纯化,以产生100mg(29%)的标题化合物。
步骤2:3',4'-二氢螺[吖丁啶-3,2'-吡喃并[3,2-b]吡啶]-4'-酮盐酸盐
在10分钟内在0℃下将在EtOAc的20%盐酸(2mL)中加至113mg(0.389mmol)的4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-吡喃并[3,2-b]吡啶]-1-甲酸叔丁酯(来自上一步骤)在EtOAc(2mL)中的溶液。添加后,使混合物加热至室温,并在此温度下搅拌2小时。接着将反应混合物在真空中浓缩至约15mL,并用乙醚(3mL)稀释。将沉淀的浅棕色晶体滤出,用乙醚洗涤,及干燥以产生80mg(91%)的标题化合物。
中间体19
7'-氟-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-4'-酮盐酸盐
步骤1:3-[2-(4-氟-2-羟苯基)-2-氧代乙基]-3-羟基吖丁啶-1-甲酸叔丁酯
将二异丙胺(17.7mL,125mmol)在THF(50mL)中的溶液冷却至-15℃,在氮氛围下滴加在己烷中的2.5M n-BuLi(50mL),及将混合物在-15℃下搅拌30分钟。接着滴加8.96g(58.14mmol)的4'-氟-2'-羟基苯乙酮在THF(50mL)中的溶液,并将混合物在-15℃下搅拌1小时,及接着用3-氧代吖丁啶-1-甲酸叔丁酯(12.9g,75.6mmol)在THF(50mL)中的溶液逐滴处理20分钟,使加热至室温并在此温度下搅拌1小时。通过添加饱和NH4Cl溶液(100mL)将反应混合物淬灭。将反应混合物用乙酸乙酯(2×90mL)萃取,将合并的有机层用盐水(120mL)洗涤,用无水Na2SO4干燥,过滤及在真空中浓缩。将残余物与异丙醚(50mL)一起研磨,将沉淀的白色晶体滤出,用二异丙醚洗涤,及干燥以产生16.79g(89%)的标题化合物。
步骤2:7'-氟-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酸叔丁酯
在氮氛围下于-10℃将14.48g(9.58mL,68.12mmol)的三氟乙酸酐滴加至14.2g(43.6mmol)的3-[2-(4-氟-2-羟苯基)-2-氧代乙基]-3-羟基吖丁啶-1-甲酸叔丁酯在干燥吡啶(35mL)中的溶液。添加后,使混合物加热至室温并在此温度下搅拌1至2小时。接着将反应混合物用乙醇(80mL)稀释,及用49g(48mL)的1,8-二氮杂双环[5.4.0]十一-7-烯处理。在添加期间,将混合物的温度升至50℃并在此温度下保持1小时。在真空中浓缩混合物,并将残余物溶解在EtOAc(160mL)中,并用水(2×80mL)、1N HCl(80mL)、1M NaHCO3溶液(80mL)和盐水(40mL)洗涤。将有机层经无水Na2SO4干燥,过滤及在真空中浓缩。将残余物与乙醚和正己烷(1:1,40mL)的混合物一起研磨,将沉淀的白色晶体滤出,用乙醚洗涤及干燥以产生4.9g(36%)的标题化合物。
将蒸发的母液在硅凝胶上用CH2Cl2洗脱进行层析以产生另外2.05g(15%)的标题化合物。
步骤3:7'-氟-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-4'-酮盐酸盐
在0℃下经10分钟将在EtOAc中的20%HCl(60mL)加至6.05g(19.7mmol)的7'-氟-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酸叔丁酯(来自上一步骤)在EtOAc(60mL)中的溶液。添加后,使混合物加热至室温,并在此温度下搅拌2小时。接着将反应混合物的体积在真空中减至15-20mL,并用乙醚(30mL)稀释。将沉淀的白色晶体滤出,用乙醚洗涤,及干燥以产生4.53g(94%)的标题化合物。
中间体20
3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃
步骤1.4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酸叔丁酯
此中间体根据关于中间体1所述的方法从适当的2-羟基-苯乙酮和3-氧代吖丁啶-1-甲酸叔丁酯与吡咯烷制备。
步骤2.4'-羟基-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酸叔丁酯
至在冰水冷却下将NaBH4(52.3mg,1.38mmol)分批加400mg(1.38mmol)的4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酸叔丁酯在MeOH(5mL)中的溶液。添加后,使混合物加热至室温,并在此温度下搅拌4小时。接着在真空中浓缩反应混合物,及将残余物溶解在EtOAc(15mL)中,用水和盐水洗涤。将有机层经无水Na2SO4干燥,过滤及在真空中浓缩,以产生320mg(79%)的标题化合物。将所得粗制螺色满-4-醇使用于下一步骤而无需任何纯化。
步骤3.3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃
将Et3SiH(450mg,4mmol)加至4'-羟基-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酸叔丁酯(292mg,1mmol)在三氟乙酸(4mL)中的溶液,并将混合物在90℃下搅拌16小时。接着在真空中浓缩反应混合物,并将残余物溶解在水中,及通过添加1.5N NaOH溶液将pH调节至9。用CH2Cl2(3x)萃取混合物,将合并的萃取液用无水Na2SO4干燥,过滤并在真空中浓缩,以产生80mg(50%)的标题化合物。所得粗制3,4-二氢螺色烯衍生物在未经任何纯化下用于下一步骤。
通过中间体20所述的方法从适当螺色满-4-酮、螺色满-4-醇、3,4-二氢螺色烯反应顺序制备表2的化合物。
表2
将源自6'-氟-4'-羟基-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酸叔丁酯的还原脱氧反应的中间体24和25使用于下一步骤而不分离。
中间体26
(1H-吲哚-5-基)甲胺
该化合物是可商购自Sigma Aldrich(目录编号:655864)。
中间体27
(1-甲基-1H-吲哚-5-基)甲胺
该化合物是可商购自Maybridge(目录编号:CC41413DA)。
中间体28
(2-甲基-1H-吲哚-5-基)甲胺
该化合物是可商购自Enamine(目录编号:EN300-209649)。
中间体29
(2-氯-1H-吲哚-5-基)甲胺
步骤1:3,3-二溴-2-氧代-2,3-二氢-1H-吲哚-5-甲腈
在25℃下将溴(42.5g;13.5mL,275mmol)滴加(20min)至1H-吲哚-5-甲腈(7.10g;50mmol,Combi-Blocks)在叔丁醇(250mL)中的搅拌溶液,并搅拌1.5小时。完成后,将反应混合物在真空下浓缩。将此残余物用EtOAc(400mL)稀释,并添加水(75mL)。将有机层用水(2×100mL)、盐水(100mL)洗涤,用无水Na2SO4干燥,过滤及在减压下浓缩。将粗制残余物与异丙醚(100mL)一起搅拌30分钟。将沉淀的晶体滤出,用异丙醚洗涤,并干燥以产生12.89g(81%)的呈红棕色固体的标题化合物。
步骤2:2-氧代-2,3-二氢-1H-吲哚-5-甲腈
将锌粉(16.3g;250mmol)分批(各约2克)加至3,3-二溴-2-氧代-2,3-二氢-1H-吲哚-5-甲腈(12.89g;40.8mmol)在AcOH(270mL)中的悬浮液。不允许混合物的温度升高到35℃以上并在30℃下搅拌2小时。完成后,将反应混合物在真空下浓缩。将此残余物悬浮在EtOAc(300mL)中,滤出,再次将固体与EtOAc(150mL)一起搅拌,接着滤出。将合并的有机层在真空中浓缩。将残余物与1N HCl溶液(100mL)一起搅拌1小时,滤出,用水(2×5mL)洗涤,及干燥以产生3.86g(60%)的标题化合物。
步骤3:2-氯-1H-吲哚-5-甲腈
在0℃下将POCl3(11.5g,6.95mL;74.79mmol)加至2-氧代吲哚啉-5-甲腈(5.8g;36.9mmol)在DCE(23ml)中的搅拌悬浮液。将反应混合物在90℃下回流30分钟。冷却反应后,添加咪唑(2.75g,44.55mmol)并在90℃下进一步加热2小时。完成后,将反应混合物浓缩并将残余物溶解在EtOAc(110mL)中并用饱和NaHCO3溶液(30mL)、盐水(50mL)洗涤,用无水Na2SO4干燥,过滤及在真空中浓缩。通过柱层析法在硅凝胶上用THF:正己烷9:1洗脱将该产物纯化以产生4.58g(70%)的呈黄色固体的标题化合物。
步骤4:(2-氯-1H-吲哚-5-基)甲胺
在氮氛围下于0℃下将LiAlH4(在THF中的1M;45mL;45mol)加至2-氯-1H-吲哚-5-甲腈(4.48g;25.3mmol)在干燥THF(23mL)中的搅拌溶液。将反应混合物在65℃下回流2小时。TLC显示产物形成。将反应混合物在0℃下用EtOAc(20mL)淬灭并滴加饱和Na2SO4水溶液(15mL)。将反应混合物通过硅藻土垫过滤并用乙酸乙酯(100mL)彻底洗涤。将滤液用盐水(50mL)洗涤,用无水Na2SO4干燥,过滤及在真空中浓缩。将粗制产物从EtOAc(50mL)结晶纯化以产生3.9g(85%)的呈灰白色固体的标题化合物。
中间体30
(3-氯-1-甲基-1H-吲哚-5-基)甲胺
步骤1:N-[(1-甲基-1H-吲哚-5-基)甲基]胺甲酸叔丁酯
在氮氛围下于0℃将二碳酸二-叔丁酯(Boc2O)(1.74g;7.97mmol)在CH2Cl2(10mL)中的溶液加至(1-甲基-1H-吲哚-5-基)甲胺(640mg;3.995mmol)和DIPEA(1.03g;1.39mL,7.98mmol)在CH2Cl2(40mL)中的搅拌溶液。将反应混合物在室温下搅拌过夜。TLC显示产物形成。将反应混合物用CH2Cl2(20mL)稀释并用水(50mL)洗涤。将有机相用盐水(50mL)洗涤,用无水Na2SO4干燥,过滤及在真空中浓缩。通过急速层析法纯化粗制产物以产生786mg(76%)的呈白色固体的标题化合物。
步骤2:N-[(3-氯-1-甲基-1H-吲哚-5-基)甲基]胺甲酸叔丁酯
在氩氛围下于0℃将N-氯琥珀酰亚胺(82mg;0.61mmol)加至N-[(1-甲基-1H-吲哚-5-基)甲基]胺甲酸叔丁酯(160mg;0.615mmol)在CH2Cl2(4mL)中的搅拌溶液。将反应混合物在室温下搅拌3.5小时。TLC显示产物形成。将反应混合物用CH2Cl2(20mL)稀释,并用水洗涤(20mL)。将有机相用盐水(15mL)洗涤,用无水Na2SO4干燥,过滤及在真空中浓缩。通过急速层析法纯化粗制产物以产生145mg(80%)的呈油的标题化合物。
步骤3:(3-氯-1-甲基-1H-吲哚-5-基)甲胺
在氩氛围下于0-2℃将CF3COOH(300mg;0.2mL,3mmol)加至N-[(3-氯-1-甲基-1H-吲哚-5-基)甲基]胺甲酸叔丁酯(72mg,0.244mmol)在干燥CH2Cl2(3mL)中的溶液。将反应混合物在室温下搅拌3小时。反应完成后(以TLC监测),在真空中浓缩混合物。将残余物溶于CH2Cl2(20mL)中,通过添加1N NaOH溶液将pH调节至10(在冷却下),用CH2Cl2(3×15mL)萃取水相,将有机相用无水Na2SO4干燥,过滤及在真空中浓缩。通过急速层析法在硅石上,以在CH2Cl2中的10%MeOH洗脱,将粗制产物纯化,以产生49mg的呈黄色固体的标题化合物。
中间体31
(3-氟-1-甲基-1H-吲哚-5-基)甲胺
步骤1:1-甲基-1H-吲哚-5-甲腈
在氩氛围下于0℃将NaH(840mg,在油中的60%,21mmol)加至lH-吲哚-5-甲腈(2.09g,14.7mmol)在DMF(16mL)中的溶液并激烈搅拌。将溶液搅拌30分钟,接着添加碘甲烷(9.12g,4mL,63mmol)。将反应混合物在室温下搅拌4小时。将反应物用水(50mL)淬灭,并用EtOAc(3×120mL)萃取。将有机层合并,用水(2×50mL)洗涤,用无水Na2SO4干燥,过滤及在真空中浓缩,及从残余物中蒸发干燥甲苯以产生2.3g的呈灰白色固体的标题化合物,使用于下一步骤而无需任何纯化。
步骤2:1-甲基-2,3-二氧代-2,3-二氢-1H-吲哚-5-甲腈
将PCC(7.6g,35.2mmol)加至1-甲基-1H-吲哚-5-甲腈(1.38g,8.83mmol)在乙腈(40mL)中的溶液,并将混合物回流7小时。反应完成后(以TLC监测),在真空中浓缩反应混合物,并将残余物分溶在H2O和EtOAc的间。将不溶部分滤出,将有机层用盐水洗涤,用无水Na2SO4干燥,并将溶剂蒸发至干。通过急骤层析法在硅石上以CH2Cl2洗脱将粗制残余物纯化以产生760mg的呈橙色固体的标题化合物。
步骤3:3,3-二氟-1-甲基-2-氧代-2,3-二氢-1H-吲哚-5-甲腈
在氩氛围下将1-甲基-2,3-二氧代-2,3-二氢-1H-吲哚-5-甲腈(502mg,2.7mmol)加至双(2-甲氧基乙基)胺基三氟化硫的溶液(Deoxofluor,在甲苯中的50%,5mL,10mmol),接着添加25μL abs.EtOH,及将混合物在90℃下加热1小时。
以MeOH(1mL)将反应物淬灭并用CH2Cl2(100mL)稀释,接着将混合物倒入冷饱和Na2SO4溶液,并将产物用二氯甲烷萃取。将萃取物用盐水洗涤,用无水Na2SO4干燥,并将溶剂蒸发至干。通过急速层析法在硅石上以0-20%EtOAc/己烷的梯度洗脱将粗制残余物纯化以产生322mg的呈黄色固体的标题化合物。
步骤4:(3-氟-1-甲基-1H-吲哚-5-基)甲胺
在氩氛围下于0-2℃将BH3.THF(在THF中的1M)(7.5mL,7.5mmol)加至3,3-二氟-1-甲基-2-氧代-2,3-二氢-1H-吲哚-5-甲腈(510mg,2.45mmol)在干燥THF(10mL)中的溶液。将反应混合物在室温下搅拌3小时。反应完成后(以TLC监测),在冷却下添加MeOH(10mL),及在真空中浓缩混合物。将残余物溶解在EtOAc(50mL)中,用饱和NaHCO3水溶液(25mL),接着用盐水(25mL)洗涤,用无水Na2SO4干燥,过滤及在真空中浓缩。通过急速层析法在硅石上以在CH2Cl2中的10%MeOH洗脱将粗制产物纯化以产生70mg的呈浅黄色固体的标题化合物。
中间体32
{1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
化合物5-溴-1H-吡咯并[2,3-b]吡啶可商购自Combi Blocks(目录编号:IN-0206),且所需的氮杂吲哚衍生物以如上所示的一系列步骤制备。
步骤1:1H-吡咯并[2,3-b]吡啶-5-甲腈
如EP1782811 A1(EISAI R&D MAN CO LTD)中所述制备中间体。
步骤2:1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
如WO 2009/155017 A2(MERCK&CO INC)中所述制备中间体。
步骤3:{1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
如WO 2012/042915 A1(RAQUALIA PHARMA INC)中所述制备中间体。
中间体33
{3-氯-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
化合物5-溴-1H-吡咯并[2,3-b]吡啶可可商购自Combi Blocks(目录编号:IN-0206),且所需的3-氯氮杂吲哚衍生物以如上所示的一系列步骤制备。
步骤1:1H-吡咯并[2,3-b]吡啶-5-甲腈
如EP 1782811 A1(EISAI R&D MAN CO LTD)中所述制备中间体。
步骤2:1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
如WO 2009/155017 A2(MERCK&CO INC)中所述制备中间体。
步骤3:3-氯-1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
在氩氛围下于室温将N-氯琥珀酰亚胺(502mg,3.76mmol)加至1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈(600mg,3.69mmol)在DMF(14mL)中的溶液并激烈搅拌。将溶液在室温下搅拌过夜。反应完成后(以TLC监测),在真空中浓缩混合物(从残余物中蒸发干燥甲苯数次)。将残余物溶于乙醚-EtOAc的混合物(1:1,40mL)中,并用水(3×15mL)洗涤。将有机层经无水Na2SO4干燥,过滤及在真空中浓缩以产生670mg的标题化合物,使用于下一步骤而无需任何纯化。
步骤4:{3-氯-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
如WO 2012/042915 A1(RAQUALIA PHARMA INC)中所述制备中间体。
中间体34
{3-溴-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
步骤1-2:
通过与EP 1782811 A1(EISAI R&D MAN CO LTD)和WO 2009/155017 A2(MERCK&COINC)中所述相同的方法以中间体33所述步骤的一系列步骤制备中间体。
步骤3:3-溴-1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
在氩氛围下于室温将N-溴琥珀酰亚胺(446mg,2.51mmol)加至1-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈(358mg,2.28mmol)在CH2Cl2(6.5mL)中的溶液并激烈搅拌。将溶液在下搅拌室温过夜。反应完成后(以TLC监测),将混合物用CH2Cl2(25mL)稀释并用水(3×20mL)洗涤。将有机层经无水Na2SO4干燥,过滤及在真空中浓缩以产生670mg的标题化合物,使用于下一步骤而无需任何纯化。
步骤4:{3-溴-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
如WO 2012/042915 A1(RAQUALIA PHARMA INC)中所述制备中间体。
中间体35
{1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺
步骤1:6-胺基-5-碘吡啶-3-甲腈
将三氟乙酸(574mg,386uL,1.2mol当量)加至2-胺基-5-氰吡啶(500mg,4.2mmol)在DMF(5mL)中的溶液。在室温下添加N-碘琥珀酰亚胺(1.04g,4.62mmol,1.1mol当量)并将反应混合物在50℃下加热3小时。以TLC指示完全转化。将反应混合物冷却至室温后,通过将反应混合物加至水中使产物沉淀。用Na2S2O3和1N NaOH中和后,通过过滤收集呈棕色固体的标题化合物(660mg)。将其使用于下一步骤而无需任何纯化。
步骤2:6-胺基-5-(丙-1-炔-1-基)吡啶-3-甲腈
在0-5℃下经由隔膜将丙炔(propyn)溶液(在THF中的3-4%;13.2mL)加至6-胺基-5-(丙-1-炔-1-基)吡啶-3-甲腈(329mg,1.34mmol)、双'(三苯膦)二氯钯(0)(95mg,0.134mmol)、碘化铜(I)(128mg,0.671mmol)和三乙胺(976mg,1.34mL,9.64mmol)在abs.THF(18mL)中的脱气混合物。将混合物在0-5℃下搅拌30分钟,接着在室温下搅拌18小时。通过添加NH4Cl溶液将反应物淬灭。通过过滤除去固体并将滤饼用CH2Cl2洗涤。将合并的有机层用无水Na2SO4干燥,过滤及在真空中浓缩。通过急速层析法在硅石上以在环己烷中的40%EtOAc洗脱将粗制产物纯化以产生150mg的呈黄色固体的标题化合物(71%)。
步骤3:2-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
将叔丁醇钾(428mg,3.82mmol,2mol当量)加至6-胺基-5-(丙-1-炔-1-基)吡啶-3-甲腈(300mg,1.91mmol)在DMF(5mL)中的溶液。将反应混合物在90℃下加热5.5小时。以TLC指示完全转化。将反应混合物冷却至室温后,将混合物倒入水中并用CH2Cl2萃取。将合并的有机层用无水Na2SO4干燥,过滤及在真空中浓缩以产生279mg(93%)的呈黄色固体的标题化合物。将其使用于下一步骤而无需任何纯化。
步骤4:1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈
在0℃下将氢化钠(在矿物油中的60%)(92mg,2.31mmol,1.3mol当量)加至2-甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈(279mg,1.78mmol)在DMF(7.5mL)中的溶液。将反应混合物在此温度下搅拌30分钟,接着滴加在DMF(1.5mL)中的碘甲烷(380mg,167uL)。将混合物在下搅拌室温过夜。以TLC指示完全转化。将混合物倒入水中并用CH2Cl2(3×20mL)萃取。将合并的有机层用无水Na2SO4干燥,过滤及在真空中浓缩,以产生298mg(98%)的呈黄色固体的标题化合物。将其使用于下一步骤而无需任何纯化。
步骤5:1-(1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-基)甲胺
将雷氏镍(200mg)加至1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-甲腈(297mg,1.73mmol)在MeOH(100mL)和25%氨溶液在水(25mL)中的混合物中的溶液并将混合物在1atm的H2下于室温搅拌16小时。将反应混合物通过硅藻土垫过滤,并将滤液在减压下浓缩以产生226mg(74%)的呈黄色固体的标题化合物。
中间体36
[2-(三氟甲基)-1H-吲哚-5-基]甲胺
如WO 2009/127678 A1(GLAXO GROUP LTD)中所述制备中间体。
中间体37
[2-(二氟甲基)-1H-吲哚-5-基]甲胺
化合物5-溴-1H-吲哚-2-甲酸乙酯可商购自Aldrich(目录编号:724718)及所需的2-二氟烷基吲哚-胺以如下所示的一系列步骤制备。
步骤1:(5-溴-1H-吲哚-2-基)甲醇
在氩氛围下于0-2℃将LiAlH4溶液(在THF中的1M)(7.0mL,7.0mmol)加至5-溴-1H-吲哚-2-甲酸酯(2.08g,7.77mmol)在干燥THF(30mL)中的溶液,接着将反应混合物在室温下搅拌4小时。反应完成后(以TLC监测),在冷却下添加NH4Cl溶液(20mL),并用EtOAc(2×50mL)萃取混合物。将合并的有机层用盐水洗涤,用无水Na2SO4干燥,过滤及在真空中浓缩,以产生1.73g的呈浅棕色固体的粗制化合物。将其使用于下一步骤而无需任何纯化。
步骤2:5-溴-1H-吲哚-2-甲醛
将MnO2(1.92g,22.1mmol)加至(5-溴-1H-吲哚-2-基)甲醇(1.0g,4.42mmol)在干燥乙腈(20mL)中的溶液,并将反应混合物在室温下搅拌过夜。反应完成后(以TLC监测),将悬浮物滤出,并用EtOAc(5×15mL)洗涤。将合并的有机层用盐水洗涤,用无水Na2SO4干燥,过滤及在真空中浓缩。从丙酮中结晶粗制棕色固体以产生656mg(66%)的标题化合物。
步骤3:5-溴-2-甲酰基-1H-吲哚-1-甲酸叔丁酯
在氮氛围下于0℃将Boc2O(965mg;4.4mmol)加至5-溴-1H-吲哚-2-甲醛(518mg;2.2mmol)和4-(二甲基胺基)吡啶(27mg;0.22mmol)在乙腈(20mL)中的搅拌溶液。将反应混合物在室温下搅拌过夜。TLC显示产物形成。将反应混合物蒸发至干燥,并通过急速层析法纯化粗制产物以产生664mg(93%)的呈黄色固体的标题化合物。
步骤4:5-溴-2-(二氟甲基)-1H-吲哚-1-甲酸叔丁酯
将在THF(6.28g,14.2mmol)中Deoxo-(双(2-甲氧基乙基)(三氟硫基)胺)溶液50%加至5-溴-2-甲酰基-1H-吲哚-1-甲酸叔丁酯(657mg,2.027mmol)在干燥二氯甲烷(20mL)中的溶液,并将反应混合物在室温下搅拌过夜。反应完成后(以TLC监测),将混合物用CH2Cl2稀释,用饱和NaHCO3溶液和盐水洗涤。将有机相用无水Na2SO4干燥,过滤及在真空中浓缩。通过急速层析法纯化粗制产物以产生642mg(91%)的呈黄色油的标题化合物。
步骤5:2-(二氟甲基)-1H-吲哚-5-甲腈
在氩氛围下将氰化锌(326mg,2.77mmol)和四(三苯膦)钯(0)(214mg,0.184mmol)加至5-溴-2-(二氟甲基)-1H-吲哚-1-甲酸叔丁酯(639mg,1.848mmol)在NMP(15mL)中的溶液并将反应混合物在70℃下搅拌3小时,接着在90℃下经3小时。通过TLC追踪反应进程。将混合物倒入水(100mL)中,并用EtOAc(3×30mL)萃取。将合并的有机相用水(4×50mL)和盐水洗涤。将有机相用无水Na2SO4干燥,过滤及在真空中浓缩。通过急速层析法纯化粗制产物以产生241mg(68%)的呈白色固体的标题化合物。
步骤6:[2-(二氟甲基)-1H-吲哚-5-基]甲胺
将雷氏镍(100mg)加至2-(二氟甲基)-1H-吲哚-5-甲腈(211mg,1.08mmol)在MeOH(24mL)和在水(6mL)中的25%氨溶液的混合物中并将混合物在1atm的H2下于室温搅拌3小时。将反应混合物通过硅藻土垫过滤,接着用MeOH(3×10mL)洗涤,接着将滤液在减压下浓缩以产生218mg(约100%)的呈浅棕色固体的标题化合物。
中间体38
1-(1,3-苯并噻唑-6-基)甲胺
如WO 2011/079804 A1(HUTCHISON MEDIPHARMA LTD)或US 20100298314 A1(SCHERING CORP)中所述制备中间体。
中间体39
1-(1-甲基-1,2,3,4-四氢喹啉-6-基)甲胺
该化合物是可商购自Enamine(目录编号:EN300-57206)。
实施例1
6'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺
在氩氛围下于0℃将氯甲酸4-硝苯酯(1020mg,5.06mmol)加至800mg(5.0mmol)的2-(甲基-1H-吲哚-5-基)甲胺(中间体26)和1.295g(1.75mL,10mmol)的DIPEA在120mL的二氯甲烷(CH2Cl2)的混合物。在此条件下将浅黄色悬浮液搅拌1小时。活化期后,添加6'-氟-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-4'-酮盐酸盐(1.22g,5mmol,中间体6)和1.75mL DIPEA(7.75mmol)在30mL CH2Cl2中的混合物。添加后,使混合物加热至室温并在此温度下搅拌22小时。反应完成后(以TLC监测),将混合物用水(2×40mL),接着用盐水洗涤。将有机层经无水Na2SO4干燥,过滤及在真空中浓缩,以产生1.8g的粗制化合物。将残余物在硅凝胶上,用CH2Cl2和MeOH(10:1)的混合物洗脱进行层析以产生1.02g(50%)的标题化合物。LC-MS(ESI)m/z[M+H]+=394.1。
根据关于实施例1所述的程序合成下列表3中的实施例。
表3
a根据从实施例1所述的方法从中间体26和中间体3标题化合物实施例5的外消旋形式。使用手性制备型HPLC分离两种(A和B)对映异构体。它们的绝对构型尚未确定。
b,c,d,e合成分别见下文。
实施例66b
6'-氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-硫代甲酰胺(carbothioamide)
在氩氛围下于室温将1,1'-硫羰基-二咪唑(98mg,0.55mmol)加至80.1mg(0.5mmol)的2-(甲基-1H-吲哚-5-基)甲胺(中间体28)在2mL的DMF中的溶液。将棕黄色溶液在该条件下搅拌1小时。活化期后,添加6'-氯-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-4'-酮盐酸盐(130mg,0.5mmol,中间体1)和0.131mL的DIPEA(0.75mmol)在2mL DMF中的混合物,并将混合物在此温度下搅拌20小时。反应完成后(以TLC监测),将混合物倒入水(8mL)中并用EtOAc(2×15mL)萃取。将有机层经无水Na2SO4干燥,过滤及在真空中浓缩。将残余物在硅凝胶上,用CH2Cl2和MeOH(10:1)的混合物洗脱进行层析以产生100mg(47%)的标题化合物。LC-MS(ESI)m/z[M+H]+=426.2
实施例71c
7'-氟-N-[(1-甲基-1,2,3,4-四氢喹啉-6-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺
在氩氛围下于0℃将氯甲酸4-硝苯酯(111mg,0.55mmol)加至88mg(0.5mmol)的1-(1-甲基-1,2,3,4-四氢喹啉-6-基)甲胺(中间体39)和175μL(1.0mmol)的DIPEA在20mL的二氯甲烷(CH2Cl2)中的混合物。将淡黄色悬浮液在此条件下搅拌1.5小时。活化期后,添加7'-氟-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-4'-酮盐酸盐(122mg,0.5mmol,中间体19)和131μL DIPEA(0.75mmol)在5mL CH2Cl2中的混合物。添加后,使混合物加热至室温,并在此温度下搅拌24小时。反应完成后(以TLC监测),将混合物用水(2×20mL),接着用盐水洗涤。将有机层经无水Na2SO4干燥,过滤及在真空中浓缩以产生300mg的粗制化合物。将残余物在硅凝胶上,用CH2Cl2和MeOH(99:1)的混合物洗脱进行层析,以产生30mg(15%)的标题化合物。LC-MS(ESI)m/z[M+H]+=410.2
实施例72d
N-[(3-氯-2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺
在氩氛围下于室温将N-氯琥珀酰亚胺(36mg,0.266mmol)加至N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺(实施例31)(100mg,0.266mmol)在DCM(2mL)中的溶液,并激烈搅拌。将溶液在室温下搅拌过夜。反应完成后(以TLC监测),将混合物用DCM(20mL)稀释,并用水(3×15mL)洗涤。将有机层经无水硫酸钠干燥,过滤及在真空中浓缩。通过柱层析法将粗制产物纯化以产生35mg的标题化合物。LC-MS(ESI)m/z[M+H]+=410.1
实施例74e
N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-吡喃并[3,2-b]吡啶]-1-甲酰胺
在氩氛围下于0℃将氯甲酸4-硝苯酯(71mg,0.35mmol)加至56mg(0.35mmol)的(1-甲基-1H-吲哚-5-基)甲胺(中间体27)和122μL(0.7mmol)的N,N-二异丙基乙胺(DIPEA)在10mL的二氯甲烷(CH2Cl2)中的混合物。将浅黄色悬浮液在此条件下搅拌1小时。活化期后,添加3',4'-二氢螺[吖丁啶-3,2'-吡喃并[3,2-b]吡啶]-4'-酮盐酸盐(80mg,0.35mmol,中间体18)和92μL DIPEA(0.53mmol)在2mL CH2Cl2中的混合物。添加后,使混合物加热至室温,并在此温度下搅拌24小时。反应完成后(以TLC监测),将混合物用水(2×10mL),接着用盐水洗涤。将有机层经无水Na2SO4干燥,过滤及在真空中浓缩,以产生60mg的粗制化合物。将残余物在硅凝胶上用CH2Cl2和MeOH(99:1)的混合物洗脱进行层析:以产生7mg(5%)的标题化合物。LC-MS(ESI)m/z[M+H]+=377.2
药物组合物的制备
下列调配物实施例说明本发明的代表性药物组合物。然而,本发明不限于下列药物组合物。
A)固体口服剂型
I.,片剂
II.,口腔分散膜
B)液体口服剂型
III.,口服悬浮液
IV.,糖浆
C)肠胃外剂型
V.,静脉注射
D)其他剂型
VI.,栓剂
VII.,滴鼻液或鼻喷雾剂
生物活性
人类α7烟碱乙酰胆碱受体[Ca2+]i分析
细胞:Flp-In 293细胞稳定地表达人类α7nAchR和人类RIC-3(α7细胞,机构内部产生)。
材料:涂布PDL(Falcon)的96孔板、培养基、分析缓冲液、DMSO、FLIPR钙5试剂盒(Molecular Devices)、丙磺舒、激动剂和PAM试验化合物。
该方法(Ca2+荧光测定法)的简要说明
在以上详述的培养基中培养稳定地表达人类α7nAchR的α7细胞,每周分离二次。关于细胞溶质Ca2+离子浓度([Ca2+]i)的荧光测量,将细胞以60000细胞/孔的密度接种在96孔微量培养板中,并在组织培养培养器中在95%空气/5%CO2的氛围下于37℃保持过夜。平板接种培养基与培养基相同。用细胞洗涤器(BioTek Elx405UCVWS)吸出50μl生长培养基。接着使用8通道移液器手动添加2倍稀释于分析缓冲液中的50μl/孔钙5试剂盒。培养期(20分钟,37℃)之后,手动添加50μl/孔含媒剂(DMSO,4%添加)或参考α7PAM(4倍的最终浓度)的分析缓冲液及将细胞在37℃下培养另外10分钟。使用FlexStation II(MolecularDevices,Sunnyvale,CA),具有集成的8通道流体添加性能的板式读数器荧光计,监测基线和激动剂诱发的[Ca2+]i改变。荧光测量在37℃下进行。染料于485nm激发,以1.4s间隔于525nm取样发射。记录基线20秒,接着进行激动剂刺激。使用FlexStation II的移液器将50μl 4×浓缩激动剂溶液加至细胞中,并监测荧光另外40秒。所有处理的最终DMSO浓度为1%。为此,从所有试验化合物制备一系列DMSO储备溶液。将这些储备溶液储存在0℃下,并进一步稀释于分析缓冲液中,以在测量前立即获得所需的最终浓度。分别在饱和浓度的PAM(主要是PNU-120596,5μM)和激动剂(主要是PNU-282987,1μM)存在下进行激动剂和PAM浓度-反应研究。使用SoftMax Pro软件(Molecular Devices)将结果表示为ΔF/F值,其中F为激动剂应用之前的静止荧光,ΔF为于给定时间的荧光增加(ΔF=刺激后的最大荧光强度值-刺激前的平均荧光强度值)。在所有实验中,所有处理在多个孔中平行测量,并且平均ΔF/F值用于分析。
表4显示在[Ca2+]i分析中的PAM EC50值:
表4
实施例 | EC<sub>50</sub>(nM) |
1 | 120 |
3 | 120 |
5 | 210 |
5a | 430 |
5b | 400 |
6 | 190 |
7 | 230 |
10 | 100 |
21 | 280 |
25 | 230 |
26 | 390 |
37 | 130 |
38 | 220 |
39 | 730 |
41 | 60 |
43 | 360 |
50 | 150 |
52 | 130 |
53 | 850 |
58 | 470 |
59 | 500 |
65 | 750 |
69 | 120 |
71 | 2300 |
活体内药理学(位置识别试验)
动物:雄性NMRI小鼠(Toxicoop,Hungary)
物质:将莨菪碱溶解于盐水中并以1mg/kg剂量i.p.施用。试验化合物在习得试验(acquisition trial)(T1)之前30分钟施用及习得试验(acquisition trial)之后以0.1ml/10g的体积施用莨菪碱。
程序:在透明塑料玻璃Y形迷宫(每臂具有40cm的长度,11cm的内部宽度,30cm的高度)进行作业。在臂周围放置许多目视提示,并且在实验期间保持不变。试验由二个间隔30分钟的试验间隔的试验(T1和T2)组成。在每次试验开始时将小鼠置于迷宫的起始臂中。在T1中,关闭迷宫的对称臂中的一个(在T2中其为新奇的)且允许动物探索迷宫5分钟(习得期)。在T2中,小鼠可自由进入所有三个臂2分钟(检索期)(retrieval phase)。测量在T2期间用在新奇和熟悉臂探索的时间。通过MANOVA评估各组用在迷宫的熟悉对新奇臂的探索时间之间的差异,接着Duncan事后试验(post hoc test)。
表5显示小鼠位置识别分析中莨菪碱诱发的健忘症的逆转:
表5
+p<0.05;++p<0.01;+++p<0.001
用在迷宫的新奇对熟悉臂的探索时间之间观察到显着差异(+p<0.05;++p<0.01;+++p<0.001)。
Claims (24)
5.根据权利要求1或4中任一项的化合物,其选自下列群组:
6'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-4-氧代-3,4-二氢螺[1-苯并吡喃-2,4'-哌啶]-1'-甲酰胺;
6'-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6-氯-N-[(1-甲基-1H-吲哚-5-基)甲基]-3,4-二氢螺[1]-苯并吡喃-2,4'-哌啶]-1'-甲酰胺;
N-[(3-氯-1-甲基-1H-吲哚-5-基)甲基]-6'-氟-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6'-氯-N-[(1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6'-氟-N-[(1-甲基-1H-吲哚-5-基)甲基]螺[吖丁啶-3,2'-色烯]-1-甲酰胺;
N-[(1-甲基-1H-吲哚-5-基)甲基]-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6'-氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6',8'-二氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氯-N-[(2-氯-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氟-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-6'-(三氟甲基)-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-[(1-甲基-1H-吲哚-5-基)甲基]-4'-氧代-7'-(三氟甲基)-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-7'-(三氟甲基)-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
6',8'-二氯-N-[(2-甲基-1H-吲哚-5-基)甲基]-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
7'-氟-4'-氧代-N-{[2-(三氟甲基)-1H-吲哚-5-基]甲基}-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
N-{[2-(二氟甲基)-1H-吲哚-5-基]甲基}-7'-氟-4'-氧代-3',4'-二氢螺[吖丁啶-3,2'-[1]苯并吡喃]-1-甲酰胺;
或其药学上可接受的盐、生物学活性代谢物、前体药、外消旋物、对映异构体、非对映异构体、溶剂合物和水合物。
6.根据权利要求1至5中任一项的化合物,其用于治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病。
7.根据权利要求6的化合物,其中该疾病选自下列群组:精神病症(包括但不限于精神分裂症、精神分裂症样障碍、情感性分裂症、妄想症、短时精神障碍、一般医学病症诱发的精神病症、物质诱发的精神病症或未另外指明的精神病症)、认知损伤(包括但不限于由于中风引起的认知损伤)、阿尔茨海默病、亨廷顿病、匹克症、与HIV相关痴呆症、额颞叶痴呆症、路易氏体痴呆症、血管型痴呆症、脑血管疾病或其他痴呆症状态及与其他退化性疾病(包括但不限于肌肉萎缩性侧索硬化症)相关的痴呆症、其他可引起认知衰退的急性或亚急性病况(包括但不限于精神错乱、外伤性脑损伤、老年痴呆症、轻度认知损伤、唐氏综合征、抑郁和与其他疾病相关的认知缺陷)、及运动障碍(包括但不限于帕金森氏病症、精神抑制剂诱发的帕金森病、或迟发性运动障碍)、抑郁和情绪障碍(包括但不限于抑郁障碍和发作、双相障碍、循环型情绪障碍和未另外指明的双相障碍、其他情绪障碍、物质诱发的情绪障碍和未另外指明的情绪障碍、焦虑症、惊恐障碍和惊恐发作、强迫症、创伤后应激障碍、急性应激障碍、广泛性焦虑症、一般医学病症诱发的焦虑症、物质诱发的焦虑症、恐惧症和未另外指明的焦虑症)、与物质相关障碍,包括但不限于物质使用或物质诱发的障碍(包括但不限于酒精-、烟碱-、安非他命-、苯环利定-、阿片样物质-、大麻-、古柯碱-、咖啡因-、迷幻剂-、吸入剂-、镇静剂-、催眠剂-、抗焦虑药-、多物质-或其他物质-相关病症)、睡眠障碍(包括但不限于嗜眠发作、睡眠障碍、原发性嗜睡症、与呼吸相关的睡眠障碍、昼夜节律性睡眠障碍和未另外指明的睡眠障碍、异睡症、睡眠惊恐障碍、梦游症和未另外指明的异睡症、与另一种精神障碍相关的睡眠障碍、一般医学病症诱发的睡眠障碍和物质诱发的睡眠障碍)、代谢和饮食障碍(包括但不限于神经性厌食症、神经性贪食症、肥胖症、强迫性饮食障碍、暴食症和未另外指明的饮食障碍)、糖尿病、溃疡性结肠炎、克隆病、肠易激综合征、自闭症谱系障碍(包括但不限于孤独性障碍、阿斯伯格症、雷特氏症、儿童期崩解症和其他未另外指明的广泛性发展障碍)、注意力缺陷过动症、破坏性行为障碍、对立违抗障碍和未另外指明的破坏性行为障碍、及抽动障碍(包括但不限于妥瑞症)、人格障碍、性功能障碍(诸如性欲障碍、性兴奋障碍、性高潮障碍、性疼痛障碍、未另外指明的性功能障碍)、性倒错、性别认同障碍、不孕症、经前综合征和未另外指明的性功能障碍、呼吸系统的病症(如咳嗽、哮喘、慢性阻塞性肺脏疾病、肺部炎症)、心血管系统的病症(诸如心脏衰竭、心律不整、高血压)、炎症、炎性和神经性疼痛、类风湿性关节炎、骨关节炎、过敏症、结节病、牛皮癣、共济失调、肌张力障碍、全身性红斑狼疮、躁狂症、不宁腿综合征、进行性核上麻痹、癫痫、肌阵挛、偏头痛、健忘症、慢性疲劳综合征、猝倒症、脑缺血、多发性硬化症、脑脊髓炎、时差、脑淀粉样血管病和败血症。
8.根据权利要求7的化合物,其中该疾病选自下列群组:认知损伤、精神分裂症、和自闭症。
9.根据权利要求1至5中任一项的化合物的用途,其用于制备治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病的药物。
10.根据权利要求9的用途,其中该疾病选自下列群组:精神病症(包括但不限于精神分裂症、精神分裂症样障碍、情感性分裂症、妄想症、短时精神障碍、一般医学病症诱发的精神病症、物质诱发的精神病症或未另外指明的精神病症)、认知损伤(包括但不限于由于中风引起的认知损伤)、阿尔茨海默病、亨廷顿病、匹克症、与HIV相关痴呆症、额颞叶痴呆症、路易氏体痴呆症、血管型痴呆症、脑血管疾病或其他痴呆症状态及与其他退化性疾病(包括但不限于肌肉萎缩性侧索硬化症)相关的痴呆症、其他可引起认知衰退的急性或亚急性病况(包括但不限于精神错乱、外伤性脑损伤、老年痴呆症、轻度认知损伤、唐氏综合征、抑郁和与其他疾病相关的认知缺陷)、及运动障碍(包括但不限于帕金森氏病症、精神抑制剂诱发的帕金森病、或迟发性运动障碍)、抑郁和情绪障碍(包括但不限于抑郁障碍和发作、双相障碍、循环型情绪障碍和未另外指明的双相障碍、其他情绪障碍、物质诱发的情绪障碍和未另外指明的情绪障碍、焦虑症、惊恐障碍和惊恐发作、强迫症、创伤后应激障碍、急性应激障碍、广泛性焦虑症、一般医学病症诱发的焦虑症、物质诱发的焦虑症、恐惧症和未另外指明的焦虑症)、与物质相关障碍,包括但不限于物质使用或物质诱发的障碍(包括但不限于酒精-、烟碱-、安非他命-、苯环利定-、阿片样物质-、大麻-、古柯碱-、咖啡因-、迷幻剂-、吸入剂-、镇静剂-、催眠剂-、抗焦虑药-、多物质-或其他物质-相关病症)、睡眠障碍(包括但不限于嗜眠发作、睡眠障碍、原发性嗜睡症、与呼吸相关的睡眠障碍、昼夜节律性睡眠障碍和未另外指明的睡眠障碍、异睡症、睡眠惊恐障碍、梦游症和未另外指明的异睡症、与另一种精神障碍相关的睡眠障碍、一般医学病症诱发的睡眠障碍和物质诱发的睡眠障碍)、代谢和饮食障碍(包括但不限于神经性厌食症、神经性贪食症、肥胖症、强迫性饮食障碍、暴食症和未另外指明的饮食障碍)、糖尿病、溃疡性结肠炎、克隆病、肠易激综合征、自闭症谱系障碍(包括但不限于孤独性障碍、阿斯伯格症、雷特氏症、儿童期崩解症和其他未另外指明的广泛性发展障碍)、注意力缺陷过动症、破坏性行为障碍、对立违抗障碍和未另外指明的破坏性行为障碍、及抽动障碍(包括但不限于妥瑞症)、人格障碍、性功能障碍(诸如性欲障碍、性兴奋障碍、性高潮障碍、性疼痛障碍、未另外指明的性功能障碍)、性倒错、性别认同障碍、不孕症、经前综合征和未另外指明的性功能障碍、呼吸系统的病症(如咳嗽、哮喘、慢性阻塞性肺脏疾病、肺部炎症)、心血管系统的病症(诸如心脏衰竭、心律不整、高血压)、炎症、炎性和神经性疼痛、类风湿性关节炎、骨关节炎、过敏症、结节病、牛皮癣、共济失调、肌张力障碍、全身性红斑狼疮、躁狂症、不宁腿综合征、进行性核上麻痹、癫痫、肌阵挛、偏头痛、健忘症、慢性疲劳综合征、猝倒症、脑缺血、多发性硬化症、脑脊髓炎、时差、脑淀粉样血管病和败血症。
11.根据权利要求10的用途,其中疾病为认知损伤、精神分裂症、或自闭症。
12.一种治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病的方法,其包括将有效量的至少一种根据权利要求1至5中任一项的化合物施用于需要该治疗或预防的哺乳动物。
13.根据权利要求12的方法,其中该疾病选自下列群组:精神病症(包括但不限于精神分裂症、精神分裂症样障碍、情感性分裂症、妄想症、短时精神障碍、一般医学病症诱发的精神病症、物质诱发的精神病症或未另外指明的精神病症)、认知损伤(包括但不限于由于中风引起的认知损伤)、阿尔茨海默病、亨廷顿病、匹克症、与HIV相关痴呆症、额颞叶痴呆症、路易氏体痴呆症、血管型痴呆症、脑血管疾病或其他痴呆症状态及与其他退化性疾病(包括但不限于肌肉萎缩性侧索硬化症)相关的痴呆症、其他可引起认知衰退的急性或亚急性病况(包括但不限于精神错乱、外伤性脑损伤、老年痴呆症、轻度认知损伤、唐氏综合征、抑郁和与其他疾病相关的认知缺陷)、及运动障碍(包括但不限于帕金森氏病症、精神抑制剂诱发的帕金森病、或迟发性运动障碍)、抑郁和情绪障碍(包括但不限于抑郁障碍和发作、双相障碍、循环型情绪障碍和未另外指明的双相障碍、其他情绪障碍、物质诱发的情绪障碍和未另外指明的情绪障碍、焦虑症、惊恐障碍和惊恐发作、强迫症、创伤后应激障碍、急性应激障碍、广泛性焦虑症、一般医学病症诱发的焦虑症、物质诱发的焦虑症、恐惧症和未另外指明的焦虑症)、与物质相关障碍,包括但不限于物质使用或物质诱发的障碍(包括但不限于酒精-、烟碱-、安非他命-、苯环利定-、阿片样物质-、大麻-、古柯碱-、咖啡因-、迷幻剂-、吸入剂-、镇静剂-、催眠剂-、抗焦虑药-、多物质-或其他物质-相关病症)、睡眠障碍(包括但不限于嗜眠发作、睡眠障碍、原发性嗜睡症、与呼吸相关的睡眠障碍、昼夜节律性睡眠障碍和未另外指明的睡眠障碍、异睡症、睡眠惊恐障碍、梦游症和未另外指明的异睡症(parasomnia)、与另一种精神障碍相关的睡眠障碍、一般医学病症诱发的睡眠障碍和物质诱发的睡眠障碍)、代谢和饮食障碍(包括但不限于神经性厌食症、神经性贪食症、肥胖症、强迫性饮食障碍、暴食症和未另外指明的饮食障碍)、糖尿病、溃疡性结肠炎、克隆病、肠易激综合征、自闭症谱系障碍(包括但不限于孤独性障碍、阿斯伯格症、雷特氏症、儿童期崩解症和其他未另外指明的广泛性发展障碍)、注意力缺陷过动症、破坏性行为障碍、对立违抗障碍和未另外指明的破坏性行为障碍、及抽动障碍(包括但不限于妥瑞症)、人格障碍、性功能障碍(诸如性欲障碍、性兴奋障碍、性高潮障碍、性疼痛障碍、未另外指明的性功能障碍)、性倒错、性别认同障碍、不孕症、经前综合征和未另外指明的性功能障碍、呼吸系统的病症(如咳嗽、哮喘、慢性阻塞性肺脏疾病、肺部炎症)、心血管系统的病症(诸如心脏衰竭、心律不整、高血压)、炎症、炎性和神经性疼痛、类风湿性关节炎、骨关节炎、过敏症、结节病、牛皮癣、共济失调、肌张力障碍、全身性红斑狼疮、躁狂症、不宁腿综合征、进行性核上麻痹、癫痫、肌阵挛、偏头痛、健忘症、慢性疲劳综合征、猝倒症、脑缺血、多发性硬化症、脑脊髓炎、时差、脑淀粉样血管病和败血症。
14.根据权利要求13的方法,其中该疾病选自下列群组:认知损伤、精神分裂症、和自闭症。
15.一种药物组合物,其包含作为活性成分的根据权利要求1至5中任一项的化合物和至少一种药学上可接受的赋形剂。
16.根据权利要求15的药物组合物,其中该组合物另外包含至少一种其他活性成分。
17.根据权利要求16的药物组合物,其中该其他活性成分选自下列群组:乙酰胆碱酯酶抑制剂、NMDA受体拮抗剂、β-分泌酶抑制剂、抗精神病药、GABAA受体α5亚单元NAM或PAM、组织胺H3受体拮抗剂、5-HT6受体拮抗剂、M1或M4 mAChR激动剂或PAM、mGluR2拮抗剂或NAM或PAM、和左旋多巴。
18.根据权利要求1至5中任一项的化合物与至少一种其他活性成分的组合,其用于治疗或预防与α7烟碱乙酰胆碱受体活性相关的疾病。
19.根据权利要求18的组合,其中该其他活性成分选自下列群组:乙酰胆碱酯酶抑制剂、NMDA受体拮抗剂、β-分泌酶抑制剂、抗精神病药、GABAA受体α5亚单元NAM或PAM、组织胺H3受体拮抗剂、5-HT6受体拮抗剂、M1或M4 mAChR激动剂或PAM、mGluR2拮抗剂或NAM或PAM、和左旋多巴。
20.一种制备根据权利要求3的式(II)化合物的方法,其特征在于使式(III)化合物与式(IV)化合物反应,该反应或以二个分开的步骤经由式(VII)或直接以一步骤进行以提供式(V)化合物,
-其中R3的含义如上对于式(II)化合物所述,
-其中n和m的含义如上对于式(II)化合物所述,
-其中n和m的含义如上对于式(II)化合物所述,
-其中R3、n和m的含义如上对于式(II)所述,
接着使式(V)化合物与
a.)氯化氢反应以提供式(VI),
-其中R3、n和m的含义如上对于式(II)所述,或与
b.)复合氢化物反应以提供式(VIII),
-其中R3、n和m的含义如上对于式(II)所述,接着用三乙膦将式(VIII)化合物还原以提供式(IX),
-其中R3、n和m的含义如上对于式(II)所述,
接着使所得式(IX)或式(VI)衍生物与式(X)反应,而提供式(II),
-其中R1a、R1b、R1c、V和Z的含义如上对于式(II)所述,
-其中R1a、R1b、R1c、R2、R3、V、Z、n、m、和W的含义如上对于式(II)所述。
21.{1,2-二甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺的化合物。
22.{3-氯-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺的化合物。
23.{3-溴-1-甲基-1H-吡咯并[2,3-b]吡啶-5-基}甲胺的化合物。
24.3',4'-二氢螺[吖丁啶-3,2'-吡喃并[3,2-b]吡啶]-4'-酮盐酸盐的化合物。
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CU20200108A7 (es) | 2021-07-02 |
HUP1800248A2 (en) | 2020-01-28 |
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AU2019300514A1 (en) | 2021-02-11 |
PH12020552183A1 (en) | 2021-06-21 |
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TW202035399A (zh) | 2020-10-01 |
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PE20211809A1 (es) | 2021-09-14 |
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BR112020026996A2 (pt) | 2021-04-06 |
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